TW201136930A

TW201136930A - Bridged morpholino substituted purines

Info

Publication number: TW201136930A
Application number: TW099145077A
Authority: TW
Inventors: Stephanie Blanchard; Di-Zhong Chen; Harish Kumar Mysore Nagaraj; Meredith Williams
Original assignee: S Bio Pte Ltd
Priority date: 2009-12-21
Filing date: 2010-12-21
Publication date: 2011-11-01
Also published as: WO2011078795A1; AR079565A1

Abstract

The present invention relates to purine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to purine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative conditions or disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative conditions or disorders including tumours and cancers as well as other disorders or conditions related to or associated with PI3K and/or mTOR kinases.

Description

201136930 六、發明說明：【發明所屬之技術領域】本發明係關於可用作激酶抑制劑之嘌呤化合物。更特定言之，本發明係關於橋聯經2·(嗎啉_4_基）、6_(吡嗪_2_基）取代之嗓呤衍生物，其製備方法，含有此等化合物之醫藥組合物及此等化合物於治療某些醫學病狀（諸如激酶相關病症/病狀）中之用途。【先前技術】激酶抑制劑之探索已被證明為用於開發適用醫藥活性物質之卓有成效的領域。激酶，或者稱為磷酸轉移酶，係以稱為磷酸化之過程將磷酸酯基自高能量供體分子（例如 ATP)轉移至特異性標靶分子（通常稱為受質）之酶。最大組激酶之一為蛋白激酶，其作用於特異性蛋白質並改變其活性。由於此活性，此等激酶與許多細胞過程有關，諸如信號傳導及在代謝中引發細胞之生物化學反應。已暗示某些細胞信號傳導過程在許多醫學病狀及某些細胞信號傳導過程之有效抑制t至關重要，由此可能會中止此等病狀發展。因此，激酶代表對於藥物化學家具有吸引力之標靶，因為激酶抑制劑之提供可能使得某些信號傳導過程得到控制，從而使得某些醫學病狀得到控制。個與體内不當醫學病狀相關之家族的激酶為磷酸肌醇 3激6|(PI3)家族之激酶’其與諸如細胞遷移、細胞增殖、 &癌轉型 '細胞存活、信號轉導及蛋白質細胞内運輸之各種細胞事件有關。近年來，此家族之激酶已成為旨在開發 152948.doc 201136930 多種病症之療法的很多研究之焦點。碗酸肌醇3-激酶(PI3)家族係'组產生磷脂醯肌醇『第二信使』之酶。此^旨質隨後與各魅理學㈣有關Μα 信號傳導路徑經由其調節廣泛不同之生理學過程而對於細胞生長及存活之許多態樣至關重要，豸等生理學過程包括細胞週期進程、分化、轉錄、轉譯及細胞凋亡。ρΐ3κ路徑之組成性活化與各種癌症之發病與進程有關且現在快速積累中的大量證據結論性地證明！>13尺信號傳導常常在癌症中失調。認為ΡΙ3Κ信號傳導之失調以兩種不同方式發生。第一種為由ΡΙ3Κ或活化ΡΙ3Κ之上游受體的活化基因突變、擴增及過表現引起ΡΙ3Κ信號傳導增加。舉例而言，ρΙ3Κα催化次單元在卵巢癌及子宮頸癌中擴增並過表現。類似地，活化ΡΙ3Κ之上游受體路胺酸激酶通常突變、擴增及過表現，例如乳癌、卵巢癌及肺癌中之EGFR。另外’ ΡΙ3Κ下游之效應因子的活化亦可造成ρΐ3κ路徑之失調’例如Akt/PKB(蛋白激酶Β)尤其在乳癌、胰臟癌及卵巢癌中過表現及活化。又’ PI3K活化所涉及之Ras家族成員常常突變，例如在結腸直腸癌及胰臟癌中。第二種PI3K 失調機制涉及腫瘤抑制因子磷酸酶ΡΤΕΝ之損失，其在許多侵襲性腦腫瘤、子宮内膜癌及乳癌及黑色素瘤中發生。一種由ΡΙ3家族之激酶介導的特異性細胞信號傳導路徑為磷脂醯肌醇3-激酶（PI3K)/Akt路徑。此路徑決定性地與細胞存活之介導有關且為生長因子受體酪胺酸激酶（RTK) 下游之主要信號傳導組分《生長因子RTK接合la型PI3K， ]52948.doc 201136930 其為包含p85調節及pllO催化次單元之雜二聚體β小gtp 酶Ras亦可經由直接結合於p 110而募集及活化pi3K。在細胞膜處，PI3K催化脂質第二信使璘脂醯肌醇_3,4,5·三填酸酯（PIP3)之生產。隨後，PIP3經由結合於其血小板_白細胞 C激酶受質（pleckstrin)同源性（PH)域而募集其他下游分子 (尤其絲胺酸-蘇胺酸激酶Akt及PDK1)。在膜處，Akt經由 PDK1使其活化環中之蘇胺酸308磷酸化而部分活化。Akt 之C端絲胺酸473的額外碌酸化致使其完全活化。此第二構酸化由雷帕黴素（rapamycin)之哺乳動物標靶（mir〇R)進行。Akt又調節各種標乾蛋白質’其中一者為mTOR。因此’ mTOR在ΡΙ3Κ及Akt之下游信號傳導中起關鍵作用且由此作為各種病症之潛在治療性標靶而受到許多關注。細胞中PIP3之含量經嚴格調節且數種脂質填酸酶用於快速將其移除。備受關注的是磷酸酶PTEN，其使PIP3轉化回PIP2 且由此中斷PI3K信號傳導。PI3K-Akt信號傳導路徑調節許多正常細胞過程，包括細胞增殖、存活、生長及移動，其為對於腫瘤形成為關鍵之過程。 PI3K/Akt路徑在腫瘤生成中之作用亦已廣泛研究且大部分路徑組分之突變或表現改變已普遍與許多癌症有關。在人類卵巢癌之一些情況下發生pll〇之基因擴增，且在卵巢癌、乳癌及結腸癌中找到Akt擴增。另外，已在卵巢癌及結腸癌中鑑別出p85之活化突變。最重要的是，已鑑別出 PTEN為人類主要腫瘤抑制因子且pTEN基因之損失功能突變在偶發性膠質母細胞瘤、黑色素瘤、***癌及子宮内 152948.doc 201136930 膜癌中極其常見，且相當大百分數之***腫瘤、肺癌及淋巴瘤亦帶有PTEN突變。因此，經由各種機制，高百分數之人類癌症具有經活化之PI3K信號傳導。明顯地，已顯示 (mTOR)對於由PI3K及Akt誘導之致癌轉型很重要。除以上所呈現之令人信服的相關資料外，癌症中涉及失調之PI3K信號傳導的直接證據來自小鼠遺傳模型。舉例而言，具有組成性活化之PI3K的p85調節次單元之小鼠在與 p53基因剔除小鼠雜交後發展成惡性淋巴瘤。此外，Akt及 Ras之反轉錄病毒引入會使小鼠產生膠質母細胞瘤。綜上所述，所有此等資料均提供開發此路徑所靶向之新穎抗癌策略的有力驗證。 mTOR為289 kDa之絲胺酸/蘇胺酸激酶且為使有絲*** 刺激及營養狀況與細胞生長及***相關之PI3K樣激酶。 mTOR在如上文所論述之PI3K-Akt路徑中起關鍵酶之作用。在為瞭解雷帕黴素之作用機制所進行的研究期間發現 mTOR。進入細胞後，雷帕黴素結合於其細胞内標乾 FKBP12，且接著複合物結合於mTOR並具體來說抑制 mTOR。因此，mTOR亦稱為FKBP-RAP相關蛋白（FRAP)、 RAP FKBP12標靶（RAFT1)及RAP標靶（RAPT1)。負責器官排斥之細胞由於雷帕黴素抑制由mTOR協調之同化信號的能力而停止生長。因為細胞生長之抑制表示治療癌症之有效目標，所以設計抑制mTOR之新藥將潛在地具有治療性價值。在人類中，mTOR介導來自2個來源之通化信號，亦即進 152948.doc 201136930 入細胞之營養物及活化之生長因子受體。其存在於至少兩種不同複合物中：雷帕黴素敏感性複合物，稱為mTOR複合物l(mTORCl)，由其與輔助蛋白raptor(mTOR之調節相關蛋白）之相互作用定義。mTOR之正常活化導致蛋白質轉譯增加，因為mTORC 1磷酸化且活化轉譯調節因子真核起始因子4E-結合蛋白1及核糖體p70 S6激酶。因此，藉由抑制mTOR，雷帕黴素使得此等效應因子之磷酸化減少及蛋白質合成減少，從而有效地阻斷mTOR之原生長作用。第二複合物，mTOR複合物2(mTORC2)為雷帕黴素非敏感性的且由其與rictor(mTOR之雷帕黴素非敏感性配對物）之相互作用定義。mTORC2與藉由磷酸化S473來調節原存活激酶Akt/PKB有關。S473磷酸化以及PDK1使T308磷酸化為完全Akt活化所必需的。最新報導表明在一些細胞中長時間用雷帕黴素治療亦抑制mTORC2之組裝及功能以抑制 Akt且雷帕黴素之此性質有助於藥物之抗細胞凋亡作用。 mTOR亦為磷脂醯肌醇3-激酶（PI3K)/Akt路徑之主要下游效應因子之一且因此mTOR之抑制提供另一抑制（至少部分）PI3K/Akt路徑之機會。受mTOR影響且似乎在腎細胞癌中尤其重要之另一路徑涉及低氧誘導因子（HIF)。在損失透明細胞腎細胞癌中常見之逢希伯-林道（Von Hippel-Lindau，VHL)基因功能的情況下，積累氧敏感性轉錄因子HIF-1及HIF-2。此等因子之積累使得血管内皮生長因子（VEGF)、血小板衍生生長因子及轉型生長因子之刺激增加。此作用藉由活化mTOR來加 152948.doc 201136930 強，此刺激蛋白質穩定功能與蛋白質轉譯功能，且由此增加HIF-1活性。亦已確定結節性硬化症複雜基因產物TSC丨及TSC2共同起抑制mTOR介導之下游信號傳導的作用。在結節性硬化症中發生此等基因之突變且其功能之損失產生另一路徑，其導致mTOR之活性增加且誘導VEGF產生。TSC2亦調節 HIF。因此’評估TSC1ATSC2突變之影響的研究證明增加之VEGF及活化imT0R路徑與血管生成之關聯。雷帕黴素，亦稱為西羅莫司（sirolimus)，係由吸水鏈黴菌（Streptomyces hygroscopicus)產生之天然抗生素。其最初開發為針對白色念珠菌（Candida albicans)、新型隱球菌 (Cryptococcus ne0f0rmans)及於麯黴（Aspergillus 化爪⑼⑽）之抗真菌藥物。隨後，雷帕黴素開發為免疫抑制劑且彼等研究有助於瞭解此藥劑之作用機制。作為抗癌劑，雷帕黴素顯示在組織培養與異種移植模型中以濃度依賴性方式抑制數種鼠類及人類癌細胞株之生長。在美國國家癌症研究所（National Cancer Institute in the USA)所篩選之六十個腫瘤細胞株中，在低於2000 ng/ml之劑量下可見對藥物之一般敏感性，在白血病、卵巢癌、乳癌、中枢神經系統癌及小細胞肺癌細胞株中更明顯。另外，雷帕黴素抑制由ρΐ3κ 或Akt誘導之人類細胞的致癌轉型且已在活體内小鼠模型中顯示轉移性腫瘤生長抑制及抗血管生成作用。基於此等臨床刖結果’進行使用雷帕黴素作為抗癌藥之臨床試驗且開發具有更有利藥物性質之雷帕黴素類似物。 152948.doc 201136930 CCI-779(替羅莫司（Temsir〇limus))，雷帕黴素之一種更易溶於水之酯衍生物，係由Wyeth Ayerst之研究者鑑別為活體外抑制腫瘤細胞增殖之非細胞毒性劑。在動物中，在數種無毒性劑量下，CCI_779證明單獨抗腫瘤活性或在各種人類癌症模型中與細胞毒性劑組合之抗腫瘤活性，該等模型諸如神經膠質瘤、橫紋肌肉瘤、原始神經外胚層瘤（諸如神經管胚細胞瘤）、頭頸部癌、***癌、胰臟癌及乳癌細胞。用CCI-779處理小鼠可抑制P70S6K活性且減少贅生性增生。如同雷帕黴素，缺乏PTEN之人類腫瘤對CCI-779介導之生長抑制比表現pTEN之細胞更敏感。具體而 3，關於一組八個人類乳癌細胞株之活體外研究顯示所研究之八個癌細胞株中之六個由CCI-779抑制，其IC50在低毫微莫耳範圍内《然而’發現兩個細胞株具有抗性，其 IC5〇>l μΜ。敏感性細胞株呈***受體陽性或過表現 HER-2/Neu，或已損失腫瘤抑制基因產物ΡΤΕΝ。CCI-779 之主要毒性包括皮膚毒性及輕度骨髓抑制（主要為血小板增多症）。已在大量癌症適應症之許多臨床試驗中評估 CCI-779。近年來’ CCI-779已受FDA批准用於藉由靜脈内輸注（以TORISELtm銷售）治療晚期腎細胞癌（rCC)。已報導與Torisel相關之最常見不良反應為皮疹、乏力、黏膜炎、噁心、水腫及厭食症。此外，臨床試驗正在進行中。 RAD001 (依維莫司（Everolimus))，40-0-(2-經基乙基）-雷帕黴素，係可經口投與之雷帕黴素的另一類似物。已在活 Λ 體外不同人類癌細胞株中及在活體内異種移植模型中評估 152948.doc 201136930 其抗贅生性活性。已在此等模型中顯示p70S6K抑制及抗贅生性作用。類似地，RAD001在具有間歇給藥時程之同系大鼠胰臟癌模型中證明濃度依賴性抗腫瘤活性。RAD001 已亦顯示抗血管生成活性且抑制人類血管内皮細胞 (HUVEC)增殖。對於RAD001所報導之毒性包括高膽固醇血症、高三酸甘油i旨血症、輕度白jk球減少症及血小板減少症。RAD001以單一藥劑及與其他治療劑組合形式在大量臨床試驗中進行評估。如同CCI-779，其現已受FDA批准用於RCC。因此’許多研究證明mT〇R抑制劑可改善癌症患者存活率。然而’雷帕黴素及其類似物在早期臨床試驗中未顯示普遍抗腫瘤活性。在癌症類型中，反應速率自在具有膠質母細胞瘤及晚期腎細胞癌之患者中小於10%之低值至在具有套細胞淋巴瘤之患者中約40%之高值變化。PTEN及 PI3K/Akt/mTOR相關路徑之情況的知識可有助於選擇將對 mTOR抑制劑有反應之腫瘤類型。此外，因為許多腫瘤類型仍對用雷帕黴素衍生物之單一藥劑療法無反應，所以重要的是繼續尋找預示對mT〇R抑制劑之抗性或敏感性的因子。直接抑制mTOR激酶活性之分子將備受關注，理論為該等分子將抑制mTORCl與mTORC2兩者。該抑制劑可有利於治療具有高Akt磷酸化之腫瘤且可調降與Akt活化相關之生長、增殖及存活作用。若mTOR-rictor為Akt依賴性存活過程之關鍵活化劑，則該藥物可促進適合於Akt依賴性調節機制之腫瘤細胞凋亡。現在正相當努力開發mTOR激 152948.doc •10· 201136930 酶抑制劑且諸如OSI-Ol 7及AZD8055之更先進化合物已進入1期臨床試驗。因此，mTOR抑制劑可能進一步提供將預期在激酶相關病狀或病症之治療令具體適用之改良藥物性質的生物活性化合物。詳言之，mTOR抑制劑可潛在地用於治療各種癌症及相關過度增生性病症。此外，最新研究涉及在許多非腫瘤學疾病領域（包括炎症、心血管疾病及某些代謝以及神經病症）中之mTOR。【發明内容】本發明提供式（I)化合物：201136930 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to an anthraquinone compound which can be used as a kinase inhibitor. More specifically, the present invention relates to an anthracene derivative substituted with 2 ((morpholine-4-yl), 6-(pyrazine-2-yl), a preparation method thereof, and a pharmaceutical composition containing the same And the use of such compounds in the treatment of certain medical conditions, such as kinase-related disorders/conditions. [Prior Art] The exploration of kinase inhibitors has proven to be an effective field for the development of suitable pharmaceutical active substances. A kinase, or phosphotransferase, is an enzyme that transfers a phosphate group from a high energy donor molecule (e.g., ATP) to a specific target molecule (commonly referred to as a substrate) in a process known as phosphorylation. One of the largest group kinases is a protein kinase that acts on specific proteins and alters their activity. Because of this activity, these kinases are involved in many cellular processes, such as signal transduction and the biochemical reactions that trigger cells in metabolism. It has been suggested that certain cellular signaling processes are critical for effective inhibition of many medical conditions and certain cellular signaling processes, and thus may delay the progression of such conditions. Thus, kinases represent an attractive target for medicinal chemical furniture because the provision of kinase inhibitors may allow certain signaling processes to be controlled, thereby allowing certain medical conditions to be controlled. A family of kinases associated with inappropriate medical conditions in the body is the kinase of the phosphoinositide 3-excited 6|(PI3) family, which interacts with such things as cell migration, cell proliferation, & cancer transformation, cell survival, signal transduction, and protein. Various cellular events involved in intracellular transport. In recent years, this family of kinases has become the focus of much research aimed at developing therapies for the various diseases of 152948.doc 201136930. The enzyme in the group of acid inositol 3-kinase (PI3) family produces the phospholipid inositol "second messenger" enzyme. This trait is followed by various philosophical (four) Μα signaling pathways through which a wide variety of physiological processes are regulated, which are essential for many aspects of cell growth and survival, such as cell cycle progression, differentiation, Transcription, translation and apoptosis. The constitutive activation of the ρΐ3κ pathway is associated with the onset and progression of various cancers and is now largely evidenced by the rapid accumulation of evidence! > 13-foot signaling is often dysregulated in cancer. It is believed that the dysregulation of ΡΙ3Κ signaling occurs in two different ways. The first is the activation gene mutation, amplification and overexpression of the upstream receptor from ΡΙ3Κ or activated ΡΙ3Κ, resulting in increased ΡΙ3Κ signaling. For example, the ρΙ3Κα catalytic subunit is amplified and overexpressed in ovarian cancer and cervical cancer. Similarly, the upstream receptor for the activation of ΡΙ3Κ typically mutates, amplifies, and overexpresses EGFR, such as breast cancer, ovarian cancer, and lung cancer. In addition, activation of the effector downstream of the ΡΙ3Κ can also cause dysregulation of the ρΐ3κ pathway. For example, Akt/PKB (protein kinase Β) is particularly expressed and activated in breast cancer, pancreatic cancer, and ovarian cancer. Furthermore, members of the Ras family involved in PI3K activation are often mutated, for example, in colorectal cancer and pancreatic cancer. The second PI3K dysregulation mechanism involves the loss of the tumor suppressor phosphatase, which occurs in many invasive brain tumors, endometrial cancer, and breast cancer and melanoma. A specific cellular signaling pathway mediated by the ΡΙ3 family of kinases is the phospholipid 醯 inositol 3-kinase (PI3K)/Akt pathway. This pathway is decisively related to cell survival and is a major signaling component downstream of the growth factor receptor tyrosine kinase (RTK) "growth factor RTK binding to laPI3K," 52948.doc 201136930 which contains p85 regulation And the heterodimeric beta small gtp enzyme Ras of the pllO catalytic subunit can also recruit and activate pi3K via direct binding to p110. At the cell membrane, PI3K catalyzes the production of lipid second messenger 璘5,4,5·three-acid ester (PIP3). Subsequently, PIP3 recruits other downstream molecules (especially the serine-threonine kinases Akt and PDK1) via binding to its platelet-leukocyte C kinase pleckstrin homology (PH) domain. At the membrane, Akt is partially activated by phosphorylation of threonine 308 in its activation loop via PDK1. The additional acidification of the C-terminal serine 473 of Akt results in complete activation. This second structuring is carried out by the mammalian target of rapamycin (mir〇R). Akt regulates a variety of standard dry proteins, one of which is mTOR. Therefore, mTOR plays a key role in the downstream signaling of ΡΙ3Κ and Akt and has received much attention as a potential therapeutic target for various conditions. The amount of PIP3 in the cells is tightly regulated and several liposteric enzymes are used to quickly remove them. Of particular interest is the phosphatase PTEN, which converts PIP3 back to PIP2 and thereby disrupts PI3K signaling. The PI3K-Akt signaling pathway regulates many normal cellular processes, including cell proliferation, survival, growth, and movement, which are critical processes for tumor formation. The role of the PI3K/Akt pathway in tumorigenesis has also been extensively studied and mutations or alterations in most of the pathway components have been commonly associated with many cancers. In some cases of human ovarian cancer, gene amplification of pll〇 occurs, and Akt amplification is found in ovarian cancer, breast cancer, and colon cancer. In addition, activating mutations of p85 have been identified in ovarian cancer and colon cancer. Most importantly, PTEN has been identified as a major tumor suppressor of humans and loss of functional mutations in the pTEN gene is extremely common in occasional glioblastoma, melanoma, prostate cancer, and uterine 152948.doc 201136930 Membrane cancer, and is quite Large percentages of breast tumors, lung cancer, and lymphoma also carry PTEN mutations. Thus, a high percentage of human cancers have activated PI3K signaling via various mechanisms. Obviously, it has been shown that (mTOR) is important for the carcinogenic transformation induced by PI3K and Akt. In addition to the compelling and relevant information presented above, direct evidence of dysregulated PI3K signaling in cancer comes from the mouse genetic model. For example, mice with constitutively activated PI3K p85 regulatory subunits develop malignant lymphoma after hybridization with p53 knockout mice. In addition, the introduction of retroviruses of Akt and Ras causes mice to develop glioblastoma. In summary, all of this information provides a powerful validation of the novel anti-cancer strategy targeted by this pathway. mTOR is a 289 kDa serine/threonine kinase and is a PI3K-like kinase that is involved in mitotic stimulation and nutritional status associated with cell growth and division. mTOR acts as a key enzyme in the PI3K-Akt pathway as discussed above. mTOR was discovered during a study conducted to understand the mechanism of action of rapamycin. Upon entry into the cell, rapamycin binds to its intracellular standard FKBP12, and then the complex binds to mTOR and specifically inhibits mTOR. Therefore, mTOR is also known as FKBP-RAP related protein (FRAP), RAP FKBP12 target (RAFT1) and RAP target (RAPT1). The cells responsible for organ rejection stop growing due to the ability of rapamycin to inhibit the assimilation of signals coordinated by mTOR. Since inhibition of cell growth represents an effective target for the treatment of cancer, designing new drugs that inhibit mTOR will potentially be of therapeutic value. In humans, mTOR mediates the signaling signals from two sources, namely the nutrient and the activated growth factor receptors that enter the cell 152948.doc 201136930. It is present in at least two different complexes: a rapamycin-sensitive complex, called mTOR complex l (mTORCl), defined by its interaction with the accessory protein raptor (a regulatory protein associated with mTOR). Normal activation of mTOR results in increased protein translation as mTORC 1 phosphorylates and activates the translational regulatory factor eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycin reduces the phosphorylation of these effectors and reduces protein synthesis, thereby effectively blocking the growth of mTOR. The second complex, mTOR complex 2 (mTORC2), is rapamycin non-sensitive and is defined by its interaction with rictor (the rapamycin non-sensitive counterpart of mTOR). mTORC2 is involved in the regulation of the intact living kinase Akt/PKB by phosphorylation of S473. Phosphorylation of S473 and PDK1 phosphorylation of T308 are required for complete Akt activation. Recent reports indicate that treatment with rapamycin for a prolonged period of time also inhibits the assembly and function of mTORC2 to inhibit Akt and that this property of rapamycin contributes to the anti-apoptotic effect of the drug. mTOR is also one of the major downstream effectors of the phospholipid inositol 3-kinase (PI3K)/Akt pathway and thus inhibition of mTOR provides another chance to inhibit (at least in part) the PI3K/Akt pathway. Another pathway that is affected by mTOR and appears to be particularly important in renal cell carcinoma involves hypoxia inducible factor (HIF). The oxygen-sensitive transcription factors HIF-1 and HIF-2 are accumulated in the absence of the Von Hippel-Lindau (VHL) gene function in clear cell renal cell carcinoma. The accumulation of these factors increases the stimulation of vascular endothelial growth factor (VEGF), platelet-derived growth factor and transforming growth factor. This effect is enhanced by activating mTOR by adding 152948.doc 201136930, which stimulates protein stabilizing function and protein translation function, and thereby increases HIF-1 activity. The complex gene products TSC丨 and TSC2 of tuberous sclerosis have also been identified to act together to inhibit mTOR-mediated downstream signaling. Mutations in these genes occur in tuberous sclerosis and loss of function results in another pathway that results in increased activity of mTOR and induces VEGF production. TSC2 also regulates HIF. Thus, studies evaluating the effects of TSC1ATSC2 mutations demonstrated an association between increased VEGF and activated imT0 pathways and angiogenesis. Rapamycin, also known as sirolimus, is a natural antibiotic produced by Streptomyces hygroscopicus. It was originally developed as an antifungal against Candida albicans, Cryptococcus ne0f0rmans, and Aspergillus (9) (10). Subsequently, rapamycin was developed as an immunosuppressive agent and their research helped to understand the mechanism of action of this agent. As an anticancer agent, rapamycin has been shown to inhibit the growth of several murine and human cancer cell lines in a tissue-culture and xenograft model in a concentration-dependent manner. In the sixty tumor cell lines screened by the National Cancer Institute in the USA, the general sensitivity to drugs can be seen at doses below 2000 ng/ml in leukemia, ovarian cancer, breast cancer. It is more obvious in central nervous system cancer and small cell lung cancer cell lines. In addition, rapamycin inhibits the oncogenic transformation of human cells induced by ρΐ3κ or Akt and has shown metastatic tumor growth inhibition and anti-angiogenic effects in an in vivo mouse model. Based on these clinical findings, a clinical trial using rapamycin as an anticancer drug was conducted and a rapamycin analogue having more favorable drug properties was developed. 152948.doc 201136930 CCI-779 (Temsir〇limus), a more water-soluble ester derivative of rapamycin, identified by Wyeth Ayerst as an in vitro inhibitor of tumor cell proliferation. Non-cytotoxic agent. In animals, CCI_779 demonstrates anti-tumor activity alone or in combination with cytotoxic agents in various human cancer models, such as glioma, rhabdomyosarcoma, and primitive neuroectoderm, at several non-toxic doses. Tumors (such as neural tube blastoma), head and neck cancer, prostate cancer, pancreatic cancer, and breast cancer cells. Treatment of mice with CCI-779 inhibited P70S6K activity and reduced neoplastic hyperplasia. Like rapamycin, human tumors lacking PTEN are more sensitive to CCI-779-mediated growth inhibition than cells expressing pTEN. Specifically, 3, an in vitro study of a group of eight human breast cancer cell lines showed that six of the eight cancer cell lines studied were inhibited by CCI-779, and their IC50 was found in the low nanomolar range. Two cell lines are resistant with an IC5 〇 > l μΜ. The sensitive cell line is estrogen receptor positive or overexpressing HER-2/Neu, or has lost the tumor suppressor gene product ΡΤΕΝ. The main toxicity of CCI-779 includes dermal toxicity and mild myelosuppression (mainly thrombocytopenia). CCI-779 has been evaluated in many clinical trials for a large number of cancer indications. In recent years, 'CCI-779 has been approved by the FDA for the treatment of advanced renal cell carcinoma (rCC) by intravenous infusion (sold as TORISELtm). The most common adverse reactions reported with Torisel have been rash, fatigue, mucositis, nausea, edema, and anorexia. In addition, clinical trials are ongoing. RAD001 (Everolimus), 40-0-(2-transethylethyl)-rapamycin, is another analog of rapamycin that can be administered orally. It has been evaluated in different human cancer cell lines in vitro and in in vivo xenograft models. 152948.doc 201136930 Its anti-neoplastic activity. The p70S6K inhibition and anti-hypergenic effects have been shown in these models. Similarly, RAD001 demonstrated concentration-dependent anti-tumor activity in a homologous rat pancreatic cancer model with intermittent dosing schedule. RAD001 has also been shown to have anti-angiogenic activity and inhibit proliferation of human vascular endothelial cells (HUVEC). Toxicity reported for RAD001 includes hypercholesterolemia, hypertriglyceridemia, mild white jk reduction, and thrombocytopenia. RAD001 is evaluated in a number of clinical trials in a single agent and in combination with other therapeutic agents. Like CCI-779, it is now approved by the FDA for RCC. Therefore, many studies have demonstrated that mT〇R inhibitors can improve survival in cancer patients. However, rapamycin and its analogs did not show general anti-tumor activity in early clinical trials. In cancer types, the rate of response varies from a low value of less than 10% in patients with glioblastoma and advanced renal cell carcinoma to a high value of about 40% in patients with mantle cell lymphoma. Knowledge of the PTEN and PI3K/Akt/mTOR related pathways can help select the type of tumor that will respond to mTOR inhibitors. In addition, because many tumor types remain unresponsive to single agent therapy with rapamycin derivatives, it is important to continue to look for factors that predict resistance or sensitivity to mT〇R inhibitors. Molecules that directly inhibit mTOR kinase activity will be of interest, the theory being that these molecules will inhibit both mTORCl and mTORC2. The inhibitor may be useful in the treatment of tumors with high Akt phosphorylation and which may be associated with growth, proliferation and survival associated with Akt activation. If mTOR-rictor is a key activator of the Akt-dependent survival process, the drug promotes apoptosis of tumor cells suitable for Akt-dependent regulatory mechanisms. There is now considerable effort to develop mTOR 152948.doc •10·201136930 enzyme inhibitors and more advanced compounds such as OSI-Ol 7 and AZD8055 have entered Phase 1 clinical trials. Thus, an mTOR inhibitor may further provide a biologically active compound that will be expected to be specifically adapted for use in a therapeutic regimen of a kinase-associated condition or disorder. In particular, mTOR inhibitors can potentially be used to treat a variety of cancers and related hyperproliferative disorders. In addition, the latest research involves mTOR in many non-oncological diseases, including inflammation, cardiovascular disease, and certain metabolic and neurological disorders. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I):

式⑴ 其中： Η、自素及視情況經取代之 R1係選自由以下組成之群：Η C 1 -Cs烧基；、鮮：Η、鹵素、OH、N02、CN、 -C12烷基、視情況經取代之c2_c12 CyC〗2炔基、視情況經取代之c2- R係選自由以下組成之群，Η、^ ΝΗ2、視情況經取代之Ci_Ci2烧基、烯基、視情況經取代之快式 152948.doc 201136930 c〗2雜烷基、視情況經取代之C3_Ci2環烷基、視情況經取代之C3_C丨2環烯基、視情況經取代之C2_C12雜環烷基、視情況經取代之Cz-C,2雜環烯基、視情況經取代之C6_C18芳基、視情況經取代之C丨-c 18雜芳基、視情況經取代之c丨_ Cu烷氧基、視情況經取代之C2_Ci2烯氧基、視情況經取代之C2-C丨2炔氧基、視情況經取代之c2_c丨2雜烷氧基、視情況經取代之C^-C!2環烷氧基、視情況經取代之C3_C12環烯氧基、視情況經取代之C：2-Cl2雜環烷氧基、視情況經取代之Cz-Cu雜環烯氧基、視情況經取代之芳氧基、視情況經取代之C^-Cu雜芳氧基、視情況經取代之Ci_Ci2烷基胺基、SR8、S03H、S02NR8R9、S〇2r8、s〇nr8r9、 SOR8、COR8、COOH、COOR8、c〇NR8R9、NR8COR9、 NR8COOR9、nr«S〇2r9、NR8C〇nr8r9、nr8r9a 醯基，或R2為下式基團：Formula (1) wherein: Η, 自 and optionally substituted R1 are selected from the group consisting of Η C 1 -Cs alkyl; fresh: hydrazine, halogen, OH, N02, CN, -C12 alkyl, The substituted c2_c12 CyC 2 alkynyl group, optionally substituted c2-R is selected from the group consisting of Η, ^ ΝΗ 2, optionally substituted Ci_Ci2 alkyl, alkenyl, as the case may be replaced Formula 152948.doc 201136930 c] 2 heteroalkyl, optionally substituted C3_Ci2 cycloalkyl, optionally substituted C3_C丨2 cycloalkenyl, optionally substituted C2_C12 heterocycloalkyl, optionally substituted Cz-C, 2 heterocycloalkenyl, optionally substituted C6_C18 aryl, optionally substituted C丨-c 18 heteroaryl, optionally substituted c丨_Cu alkoxy, optionally substituted C2_Ci2 alkenyloxy, optionally substituted C2-C丨2 alkynyloxy, optionally substituted c2_c丨2 heteroalkoxy, optionally substituted C^-C! 2 cycloalkoxy, optionally Substituted C3_C12 cycloalkenyloxy, optionally substituted C: 2-Cl2 heterocycloalkoxy, optionally substituted Cz-Cu heterocycloalkenyloxy, optionally substituted Aryloxy, optionally substituted C^-Cu heteroaryloxy, optionally substituted Ci_Ci2 alkylamino, SR8, S03H, S02NR8R9, S〇2r8, s〇nr8r9, SOR8, COR8, COOH, COOR8 , c〇NR8R9, NR8COR9, NR8COOR9, nr«S〇2r9, NR8C〇nr8r9, nr8r9a fluorenyl, or R2 is a group of the formula:

各尺2!1係獨立地選自由以下組成之群：H、鹵素、〇H N〇2、CN、NH2、福取代之c2-c12烯基、視情況經取代2C1_C12烷基、視情況經、視情況經取代之G-Ci2炔基、視情況經取代之c^c】2雜烷基、視情況經取代之c3_c丨2環烷基、Each ruler 2!1 is independently selected from the group consisting of H, halogen, 〇HN〇2, CN, NH2, substituted c2-c12 alkenyl, optionally substituted 2C1_C12 alkyl, optionally, by visual a substituted G-Ci2 alkynyl group, optionally substituted c^c] 2 heteroalkyl, optionally substituted c3_c丨2 cycloalkyl,

152948.doc •12- 201136930 q-CH雜芳基、視情況經取代之Ci_Ci2烷氧基、視情況經取代之C2-Cu烯氧基、視情況經取代之CyCu炔氧基、視情況經取代之q-c,2雜烷氧基、視情況經取代之c3-Ci2環烷氧基、視情況經取代之C：3_Cl2環烯氧基、視情況經取代之Ci-C丨2雜環烷氧基、視情況經取代之C2_C12雜環烯氧基、視情況經取代之C0-Cl8芳氧基、視情況經取代之Cl· C1S雜芳氧基、視情況經取代之Ci_Ci2烷基胺基、SR8、 S03H、S02NH2、S02R8、SONH2、SOR8、COR8、 COOH、COOR8、CONR8r9、NR8C0R9、nr8c〇〇r9、 nr8so2r9、NR8c〇NR8R9、NR8R9及醯基； r為選自由1、2及3組成之群的整數；152948.doc •12- 201136930 q-CH Heteroaryl, optionally substituted Ci_Ci2 alkoxy, optionally substituted C2-Cu alkenyloxy, optionally substituted CyCu alkynyloxy, optionally substituted Qc, 2 heteroalkoxy, optionally substituted c3-Ci2 cycloalkoxy, optionally substituted C: 3_Cl2 cycloalkenyloxy, optionally substituted Ci-C丨2 heterocycloalkoxy , optionally substituted C2_C12 heterocycloalkenyloxy, optionally substituted C0-Cl8 aryloxy, optionally substituted Cl.C1S heteroaryloxy, optionally substituted Ci_Ci2 alkylamine, SR8 , S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8r9, NR8C0R9, nr8c〇〇r9, nr8so2r9, NR8c〇NR8R9, NR8R9 and sulfhydryl; r is selected from the group consisting of 1, 2 and 3. Integer

R3係選自由Η、F、Cl、Br、〇H、視情況經取代之Ci Q 烷基、OR8、OCOR8、Ch2〇H、NH2、NR8R9、NR8c〇R4 nr8so2r9組成之群； R6 係選自由 Η、OH、0R8、〇Pg〇、〇c〇r8、CH2〇H NH2、NR8R9、NR8PgN、N(PgN)2、nr8c〇r9、nr8c〇nr8r9 及nr8so2r9組成之群； R7 係選自由 Η、F、C1、Br、0H、〇r8、〇c〇r8、 ch2oh、nh2、NRV、nr8c〇r9及nr8s〇2R^成之群各R8及R9係獨立地選自由以下組成.之群·· H、視情況經取代之CVCu烧基、視情況經取代之C2_Ci2稀基、視情況經取代之c2-c12炔基、視情況經取代之c2_Ci2雜烧基、視情況經取代之C3_C12環烧基、視情況經取代之W衰烯基視凊況經取代之雜環烷基、視情況經取代之 152948.doc •13· 201136930 雜環烯基、視情況經取代之C6_Ci8芳基及視情況經取代之C!-Ci8雜芳基，或 R及R連同其所連接之原子一起形成視情況經取代之環狀部分； pgQ為氧之保護基；各PgN獨立地為氮之保護基；各尺2係獨立地選自由以下組成之群：C「C6烷基、齒基· G-C6烷基、羥基Cl_c6烷基、Ci_c6烷氧基Ci_C6烷基、氰基<^-(：6烷基、胺基Ci_C6烷基、Ci_C6烷基胺基^-^烷基、及二（C丨-C6烷基）胺基C丨-c6烷基； q為選自由0、1、2、3及4組成之群的整數； x為式（CR102)m2基團；各R係獨立地選自由以下組成之群：狀視情況經取代之c〗-c6燒基； m為選自由G、1、2、3及4組成之群的整數；或其醫藥學上可接受之鹽、N_氧化物或前藥。如同任-組具有特定效用之結構相關化合物，式⑴化合物之變數的某些實施例尤其適用於其最終用途。在各種實施例中’q為選自由〇、1、2、3及4組成之群的整數。在—些實施例中，q為4。在-些實施例中，幀3。 j二實施例中’ q為2。在—些實施例中，9為^。在一此實施例中，q為〇。二在q不為〇之甲基、三氟甲一些實施例中，各可選自由F、CM、Br 基及乙基組成之群。1^取代基可連接於7 員 152948.doc 201136930 環上之任何可用位置。在存在多個R/取代基之情況下，各 Rz取代基之位置獨立於其他取代基。在一些實施例中’ q 為1且Rz取代基位於環氮之α位。此提供式（la)化合物。 R6R3 is selected from the group consisting of ruthenium, F, Cl, Br, 〇H, optionally substituted Ci Q alkyl, OR8, OCOR8, Ch2〇H, NH2, NR8R9, NR8c〇R4 nr8so2r9; R6 is selected from Η , OH, 0R8, 〇Pg〇, 〇c〇r8, CH2〇H NH2, NR8R9, NR8PgN, N(PgN)2, nr8c〇r9, nr8c〇nr8r9 and nr8so2r9; R7 is selected from Η, F, Each of R8 and R9 is independently selected from the group consisting of C1, Br, 0H, 〇r8, 〇c〇r8, ch2oh, nh2, NRV, nr8c〇r9, and nr8s〇2R^. Substituted CVCu alkyl, optionally substituted C2_Ci2 dilute, optionally substituted c2-c12 alkynyl, optionally substituted c2_Ci2 heteroalkyl, optionally substituted C3_C12 cycloalkyl, optionally Substituted W-following alkenyl substituted heterocycloalkyl, optionally substituted 152948.doc • 13· 201136930 Heterocycloalkenyl, optionally substituted C6_Ci8 aryl and optionally substituted C !-Ci8 heteroaryl, or R and R together with the atom to which they are attached form an optionally substituted cyclic moiety; pgQ is a protecting group for oxygen; each PgN is independently nitrogen Base 2; each ruler 2 is independently selected from the group consisting of C "C6 alkyl, dentyl G-C6 alkyl, hydroxyCl_c6 alkyl, Ci_c6 alkoxy Ci_C6 alkyl, cyano" (: 6 alkyl, amino Ci_C6 alkyl, Ci_C6 alkylamino^-^alkyl, and di(C丨-C6 alkyl)amino C丨-c6 alkyl; q is selected from 0, 1, An integer of the group consisting of 2, 3, and 4; x is a group of formula (CR102) m2; each R is independently selected from the group consisting of: c-c6 alkyl; An integer of the group consisting of G, 1, 2, 3, and 4; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. As with any structurally related compound having a specific utility, the variable of the compound of formula (1) Certain embodiments are particularly suitable for their end use. In various embodiments 'q is an integer selected from the group consisting of 〇, 1, 2, 3, and 4. In some embodiments, q is 4. In - In some embodiments, frame 3. j is in the embodiment where 'q is 2. In some embodiments, 9 is ^. In this embodiment, q is 〇. In some embodiments of trifluoromethyl, each can be a group of free F, CM, Br groups and ethyl groups. The 1^ substituent may be attached to any available position on the ring of 7 member 152948.doc 201136930. In the presence of multiple R/substituents, each Rz substituent The position is independent of the other substituents. In some embodiments 'q is 1 and the Rz substituent is at the alpha position of the ring nitrogen. This provides a compound of formula (la). R6

或其醫藥學上可接受之鹽或前藥，其中R、R、r3、R6、r7、m X如上文所定義。在一些實施例中，（}為〇。此提供式（Ib)化合物： R6Or a pharmaceutically acceptable salt or prodrug thereof, wherein R, R, r3, R6, r7, m X are as defined above. In some embodiments, (} is 〇. This provides a compound of formula (Ib): R6

或其醫藥學上可接受其中 R丨、R2、R3、R6 之鹽或前藥，、R7及X如上文所定義 152948.doc -15· 201136930 在一些實施例中， R係選自由Η、OR8及視情況經取代之Ci-C6烷基組成之群在一些實施例中 ’ R3為OR8 ’其中R8為視情況經取代之Or a pharmaceutically acceptable salt or prodrug thereof wherein R丨, R2, R3, R6, R7 and X are as defined above 152948.doc -15· 201136930 In some embodiments, R is selected from Η, OR8 And optionally substituted Ci-C6 alkyl group in some embodiments 'R3 is OR8' wherein R8 is optionally substituted

CrC6烷基。此類型之R3基團的實例包括甲氧基、三氟甲氧基、乙氧基、異丙氧基、丙氧基及丁氧基。在一些實施例中，R3為甲氧基。在一些實施例中’ R3為視情況經取代之Ci_c6烷基。此類型之R3基團的實例包括甲基、三氟曱基、乙基、丙基、異丙基及丁基。在一些實施例中，R3為曱基。在一些實施例中，R3係選自由Η、曱氧基及甲基組成之群。在一些實施例中，R3為Η。在一些實施例中，R7係選自由Η、F、Cl、Br、〇11及 NH2組成之群。在一些實施例中，R7為Η。在一些實施例中，R3及R7皆為Η。在一些實施例中’ q=0，R3為Η且R7為Η。此提供式（Ic) 化合物：CrC6 alkyl. Examples of R3 groups of this type include methoxy, trifluoromethoxy, ethoxy, isopropoxy, propoxy and butoxy. In some embodiments, R3 is methoxy. In some embodiments 'R3 is an optionally substituted Ci_c6 alkyl group. Examples of R3 groups of this type include methyl, trifluoromethyl, ethyl, propyl, isopropyl and butyl. In some embodiments, R3 is a fluorenyl group. In some embodiments, R3 is selected from the group consisting of ruthenium, osmiumoxy, and methyl. In some embodiments, R3 is deuterium. In some embodiments, R7 is selected from the group consisting of ruthenium, F, Cl, Br, 〇11, and NH2. In some embodiments, R7 is deuterium. In some embodiments, both R3 and R7 are deuterium. In some embodiments 'q=0, R3 is Η and R7 is Η. This provides a compound of formula (Ic):

式 201136930 或其醫藥學上可接受之鹽或前藥，其中R1、R2、R6及X如上文所定義。在含有基團R8之化合物的一些實施例中，R8選自Η及C,-C6烷基。在一些實施例中，R8為甲基。在一些實施例中， R8 為 Η。在含有基團R9之化合物的一些實施例中，R9選自 C6烷基。在一些實施例中，R9為曱基。在一些實施例中， R9 為 Η。如先前所述，X為式（CR1G2)m之基團。在一些實施例中，m係選自由0、1及2組成之群。在一些實施例中，m為 0或1。在一些實施例中，m為0。在一些實施例中，m為 1 ° 在一些實施例中，q=0，R3為Η，R7為Η且m為〇。此提供式（II)化合物：Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R6 and X are as defined above. In some embodiments of the compound containing group R8, R8 is selected from the group consisting of hydrazine and C,-C6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R8 is Η. In some embodiments of the compound containing a group R9, R9 is selected from the group consisting of C6 alkyl. In some embodiments, R9 is a fluorenyl group. In some embodiments, R9 is Η. As previously stated, X is a group of formula (CR1G2)m. In some embodiments, m is selected from the group consisting of 0, 1, and 2. In some embodiments, m is 0 or 1. In some embodiments, m is zero. In some embodiments, m is 1 °. In some embodiments, q = 0, R3 is Η, R7 is Η and m is 〇. This provides a compound of formula (II):

(式 II) 或其醫藥學上可接受之鹽或前藥，其中R1、R2及R6如上文所定義。 152948.doc -17- 201136930 。此提供在一些實施例中，q=〇，R3為Η，R7為H且m為1 式（III)化合物：(Formula II) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2 and R6 are as defined above. 152948.doc -17- 201136930. This provides, in some embodiments, q = 〇, R3 is Η, R7 is H and m is 1 a compound of formula (III):

式（III) 或其醫藥學上可接受之鹽或前藥，其中R1、R2、尺6及汉1〇如上文所定義。在式（I)、（la)、（lb)、（Ic)及（ΙΠ)之化合物的一些實施例中，各R10為Η。在一些實施例中，各R】〇獨立地為視情況經取代之C〗-C6炫基。在一些實施例中，一個R10為H且另一個R1Q為Η或視情況經取代之Cl_C6烷基。在一些實施例中，一個R10為Η且另一個為CH3。在式（I)、（la)、（lb)、（Ic)及（in)之化合物的一些實施例中’一個R10為Η且X因此為下式基團：Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, 6 and 6 are as defined above. In some embodiments of the compounds of formula (I), (la), (lb), (Ic), and (ΙΠ), each R10 is deuterium. In some embodiments, each R] is independently a C-C6-based group that is optionally substituted. In some embodiments, one R10 is H and the other R1Q is deuterium or optionally substituted C1-C6 alkyl. In some embodiments, one R10 is Η and the other is CH3. In some embodiments of the compounds of formula (I), (la), (lb), (Ic), and (in), one R10 is deuterium and X is therefore a group of the formula:

在一些實施例中’ R3及R7為Η ’ m為1，q為〇且一個r1〇為Η。此提供式（IV)化合物： 152948.doc •18· 201136930 R6In some embodiments, 'R3 and R7 are Η' m is 1, q is 〇 and one r1 〇 is Η. This product provides the compound of formula (IV): 152948.doc •18· 201136930 R6

或其醫藥學上可接受之鹽或前藥，其中Rl、R2、R6及R10如上文所定義。在一些實施例中，Ri係選自由Η、氟基、氣基、溴基、曱基乙基、異丙基、丙基、2-乙基-丙基、3,3 -二甲基_ 丙基、丁基、異丁基、3,3-二甲基-丁基、2-乙基-丁基、戊基、2-曱基、戊基及己基組成之群。在一些實施例中， R1為 Η。在一些實施例中’ R6係選自由Η、ΝΗ2及NR8R9組成之群’其中R8及R9如上文所定義。在一些實施例中，R6為 NH2。在一些實施例中，R2係選自由以下組成之群：Η、氛基、視情況經取代之Ci-Cu烷基、視情況經取代之c2_c^ 稀基 '視情況經取代之C 2 - C 1 2雜烧基、視情況經取代之c 3 _ C〗2環烷基、視情況經取代之Q-C,2雜環烷基、視情況經取代之C6-C18芳基及視情況經取代之(^-(：18雜芳基。在一些實施例中，R2為視情況經取代之C6_C】8芳基。在 152948.doc -19· 201136930 R之一些實施例中，視情況經取代之Ce_Ci8芳基（及因此 R2)為下式基團：Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R6 and R10 are as defined above. In some embodiments, Ri is selected from the group consisting of hydrazine, fluoro, carbyl, bromo, decylethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl A group consisting of butyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-indenyl, pentyl and hexyl. In some embodiments, R1 is Η. In some embodiments the 'R6 is selected from the group consisting of ruthenium, osmium 2, and NR8R9 wherein R8 and R9 are as defined above. In some embodiments, R6 is NH2. In some embodiments, R 2 is selected from the group consisting of hydrazine, an aryl group, optionally substituted Ci-Cu alkyl, optionally substituted c 2 —c^, and optionally substituted C 2 -C 1 2 miscellaneous, optionally substituted c 3 _ C 2 cycloalkyl, optionally substituted QC, 2 heterocycloalkyl, optionally substituted C6-C18 aryl, and optionally substituted (^-(:18heteroaryl. In some embodiments, R2 is optionally substituted C6_C]8 aryl. In some embodiments of 152948.doc -19·201136930 R, Ce_Ci8 is optionally substituted The aryl group (and thus R2) is a group of the formula:

其中P為選自由(^^、^仪恤成之群的整數；各R係獨立地選自由以下組成之群：H、鹵素、OH、 N〇2、CN、NH2、視情況經取代iCi_Ci2烷基、視情況經取代之C2-cu烯基、視情況經取代之Q-Cu炔基、視情况經取代之c^-Ci2雜烷基、視情況經取代之C3_Ci2環烷基、視情況經取代之C2_Cl2雜環烷基、視情況經取代之雜環稀基、視情況經取代之C6_C丨8芳基、視情況經取代之 CrC,8雜芳基、視情況經取代之CI_C〗2烷氧基、視情況經取代之C^-C,2烯氧基、視情況經取代之QC〗2炔氧基、視情況經取代之C2_C】2雜烷氧基、視情況經取代之C3_C12環烷氧基、視情況經取代之2環烯氧基、視情況經取代之C^c丨2雜環烷氧基、視情況經取代之C2_Ci2雜環烯氧基、視情況經取代之c^c〗8芳氧基、視情況經取代之C1_ 雜芳氧基、視情況經取代之c〗_Ci2烷基胺基、SR8、 S〇3H、S02NH2、S02R8、SONH2、SOR8、COR8、 COOH、COOR8、c〇NR8R9、nr8cor9、nr8coor9、 NR8S02R9、NR8CONR8R9、NR8R9及醯基，或任何兩個相鄰R13可連同彼此及其所連接之碳原子一起 152948.doc -20- 201136930 形成環狀部分；其中R8及R9如上文所定義。苯基可未經取代或可視情況經一或多個適合之取代基取代。若苯基經取代，則可能存在i、2、3、4或5個取代基。在一些貫施例中，p為〇、丨或2。在一些實施例中P為 1。在一些實施例中，p為2。在一些實施例中，R1為Η ’ R3為H，尺6為1^2，R7為η， X為（CH2)m ’其中m為〇，且r2為下式基團：Wherein P is an integer selected from the group consisting of (^^, ^); each R is independently selected from the group consisting of H, halogen, OH, N〇2, CN, NH2, optionally substituted iCi_Ci2 Substituted, optionally substituted C2-cu alkenyl, optionally substituted Q-Cu alkynyl, optionally substituted c^-Ci2 heteroalkyl, optionally substituted C3_Ci2 cycloalkyl, optionally Substituted C2_Cl2 heterocycloalkyl, optionally substituted heterocyclic dilute, optionally substituted C6_C丨8 aryl, optionally substituted CrC, 8 heteroaryl, optionally substituted CI_C Oxyl, optionally substituted C^-C, 2 alkenyloxy, optionally substituted QC 2 alkynyloxy, optionally substituted C2_C] 2 heteroalkoxy, optionally substituted C3_C12 ring Alkoxy, optionally substituted 2-cycloalkenyloxy, optionally substituted C^c丨2 heterocycloalkoxy, optionally substituted C2_Ci2 heterocycloalkenyloxy, optionally substituted c^ c] 8 aryloxy, optionally substituted C1_heteroaryloxy, optionally substituted c _Ci2 alkylamine, SR8, S〇3H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH , COOR8, c〇NR8R9, nr8cor9, nr8coor9, NR8S02R9, NR8CONR8R9, NR8R9 and fluorenyl, or any two adjacent R13 may form a cyclic moiety together with each other and the carbon atom to which they are attached 152948.doc -20-201136930; Wherein R 8 and R 9 are as defined above. The phenyl group may be unsubstituted or optionally substituted with one or more suitable substituents. If the phenyl group is substituted, i, 2, 3, 4 or 5 substituents may be present. In some embodiments, p is 〇, 丨 or 2. In some embodiments P is 1. In some embodiments, p is 2. In some embodiments, R1 is Η ' R3 is H, 6 is 1^2, R7 is η, X is (CH2)m 'where m is 〇, and r2 is a group of the formula:

此提供式（V)化合物：This provides a compound of formula (V):

式（V) 或其醫藥學上可接受之鹽或前藥，其中R13及p如上文所定義。 152948.doc •21· 201136930 在一些實施例中，R1為Η，R3為H，r^NH2，R、H， X為（CR102)m，其中m為1，且R2為下式基團：Or a pharmaceutically acceptable salt or prodrug thereof, wherein R13 and p are as defined above. 152948.doc • 21· 201136930 In some embodiments, R1 is deuterium, R3 is H, r^NH2, R, H, X is (CR102)m, wherein m is 1, and R2 is a group of the formula:

此提供式（Va)化合物：This provides a compound of formula (Va):

或其醫藥學上可接受之鹽或前藥，其中R、R13及p如上文所定義。在含有只1 0 之化合物的一些實施例中，R10係選自由Η、 Ci-C6齒烧其 _ ^ 签、C1-C6羥基烷基及c〗-C6烷基組成之群。在一些貫施例中 D 1 0 干’R係選自由甲基、乙基、丙基、異丙基及丁基組成之救辞。在一些實施例中，係選自由Η、曱基及乙基組成之群。 ▲實施例中，R2係選自由氰基、視情況經取代之 C1 - C丨2燒基、支目达視情況經取代之C3-C12環烷基、視情況經取 152948.doc •22- 201136930 代之G-c,2雜環烷基及視情況經取代之C2_Ci2雜烷基組成之群。在一些實施例中，R2係選自由氰基、視情況經取代之 CrC!2烷基及視情況經取代之C2_Ci2雜烷基組成之群。在一些實施例中，R2係選自由甲基、乙基、異丙基、丙基、2-乙基-丙基、 3,3-—甲基-丙基、丁基、異丁基、3,3- 一甲基-丁基、2-乙基-丁基、戊基、2_曱基、戊基、己基、庚基及辛基組成之群。在一些實施例中’ R2為下式之視情況經取代之甲基：Or a pharmaceutically acceptable salt or prodrug thereof, wherein R, R13 and p are as defined above. In some embodiments containing only 10 compounds, R10 is selected from the group consisting of hydrazine, Ci-C6 acetonide, C1-C6 hydroxyalkyl, and c-C6 alkyl. In some embodiments, the D<10>dry'R is selected from the group consisting of methyl, ethyl, propyl, isopropyl and butyl. In some embodiments, it is selected from the group consisting of ruthenium, osmium, and ethyl. ▲ In the examples, R2 is selected from a C1-C丨2 alkyl group substituted by a cyano group, as the case may be, or a C3-C12 cycloalkyl group substituted by a C. striatum, as the case may be, 152948.doc • 22- 201136930 The group consisting of Gc, 2 heterocycloalkyl and optionally substituted C2_Ci2 heteroalkyl. In some embodiments, R2 is selected from the group consisting of cyano, optionally substituted CrC!2 alkyl, and optionally substituted C2_Ci2 heteroalkyl. In some embodiments, R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-methyl-propyl, butyl, isobutyl, 3 a group consisting of 3-methyl-butyl, 2-ethyl-butyl, pentyl, 2-hydrazino, pentyl, hexyl, heptyl and octyl. In some embodiments 'R2 is a methyl group substituted as appropriate in the following formula:

其中R 0、R21及R22各獨立地選自由Η、ci、Br、F、 OH、N02、CN、NH2、視情況經取代之Cl_Cl2烷基及視情況經取代之CrCu雜烷基組成之群。在一些實施例中，各R20、R2 1及R22係獨立地選自由以下組成之群：Η、Cl、Br、F、OH、N〇2、CN、NH2、甲基、乙基、丙基、異丙基、丁基、戊基、甲氧基曱基、2_ 甲氧基乙基、3 -曱氧基丙基、2-乙氧基乙基、3 -乙氧基丙基、胺基甲基、2-胺基乙基、3-胺基丙基、4-胺基丁基、 5-胺基戊基、曱基胺基甲基、2-甲基胺基乙基、3-曱基胺基丙基、4-曱基胺基丁基、5-甲基胺基戊基、乙基胺基曱基、2-乙基胺基乙基、3-乙基胺基丙基、4-乙基胺基丁基、5-乙基胺基戊基、二甲胺基甲基、2-二甲基胺基乙 152948.doc -23- 201136930 基、3-二甲基胺基丙基、4·二甲基胺基丁基、5_二甲基胺基戊基、二乙基胺基甲基、2_二乙基胺基乙基、3_二乙基胺基丙基、4-二乙基胺基丁基及5_二乙基胺基戊基。在一些實施例中，R2為視情況經取代之C3_Ci2環烷基。在一些實施例中，R2係選自由視情況經取代之環丙基、視情況經取代之環丁基、視情況經取代之環戊基及視情況經取代之環己基組成之群。在一些實施例中，R2為環丙基。在一些實施例中，視情況經取代之c3_Ci2環烷基係選自由以下組成之群：Wherein R 0, R21 and R22 are each independently selected from the group consisting of ruthenium, ci, Br, F, OH, N02, CN, NH2, optionally substituted Cl_Cl2 alkyl, and optionally substituted CrCu heteroalkyl. In some embodiments, each R20, R2, and R22 are independently selected from the group consisting of hydrazine, Cl, Br, F, OH, N 〇 2, CN, NH 2, methyl, ethyl, propyl, Isopropyl, butyl, pentyl, methoxyindenyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, amine , 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, decylaminomethyl, 2-methylaminoethyl, 3-mercapto Aminopropyl, 4-mercaptoaminobutyl, 5-methylaminopentyl, ethylaminoindenyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4- Ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl 152948.doc -23- 201136930, 3-dimethylaminopropyl, 4. Dimethylaminobutyl, 5-dimethylaminopentylpentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4- Diethylaminobutyl and 5-diethylaminopentyl. In some embodiments, R 2 is optionally substituted C 3 —Ci 2 cycloalkyl. In some embodiments, R2 is selected from the group consisting of optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl. In some embodiments, R2 is cyclopropyl. In some embodiments, the optionally substituted c3_Ci2 cycloalkyl is selected from the group consisting of:

其中R23係獨立地選自由以下組成之群：H、視情況經取代之q-c,2烷基、視情況經取代之C2_Ci2烯基、視情況經取代之q-c〗2炔基、視情況經取代之C2_Ci2雜烷基、視情況經取代之C3-C,2環烷基、視情況經取代之C3-C12環烯基、視情況經取代之(：2_Cl2雜環烷基、視情況經取代之c2_ C12雜環烯基、視情況經取代之MW基、視情況經取代之Ci-C〗8雜芳基 '視情況經取代之Ci_c〗2燒氧基、視情況經取代之q-c,2烯氧基、視情況經取代之C2_C〗2炔氧基' 視晴况經取代之C2-C1Q雜烷氧基、視情況經取代之C3_C12 環烧氧基、視情況經取代之wu氧基、視情況經取代之C心雜環垸氧基、視情I絲代之^12雜環稀氧基視情況經取代之Ce-C!8芳氧基、視情況經取代之c · 152948.doc •24· 201136930 cls雜芳氧基、視情況經取代之Ci_c〗2烷基胺基 so2nr24r25、SOR24、so2r24、sonr24r25、S〇R24、c〇r2 COOH、COOR24及 CONR24R25 ; 各R24及R25係獨立地選自由以下組成之群·· H、視情況經取代之^/^烷基、視情況經取代之C2_c〗2烯基、視情況經取代之c2-c,2快基、視情況經取代之C2_CiG雜炫基、視情況經取代之C3_Cl2環烧基、視情況經取代之Μ。環烯基、視情況經取代之C2_Ci2雜環烧基、視情況經取代之 C2-cls雜環烯基、視情況經取代之芳基及視情況經取代之CrC丨8雜芳基。Wherein R23 is independently selected from the group consisting of H, optionally substituted qc, 2 alkyl, optionally substituted C2_Ci2 alkenyl, optionally substituted qc 2 alkynyl, optionally substituted C2_Ci2 heteroalkyl, optionally substituted C3-C, 2 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted (: 2_Cl2 heterocycloalkyl, optionally substituted c2_) C12 heterocycloalkenyl, optionally substituted MW group, optionally substituted Ci-C 8 heteroaryl 'Ci_c substituted as appropriate 2 alkoxy, optionally substituted qc, 2 olefin Substituted C2_C 2 alkenyloxy as appropriate - C2-C1Q heteroalkoxy substituted, optionally substituted C3_C12 cycloalkoxy, optionally substituted wuoxy, optionally Substituted C-heterocyclic fluorenyloxy, as appropriate, I12, which is substituted by a Ce-C!8 aryloxy group, optionally substituted c · 152948.doc •24 · 201136930 cls heteroaryloxy, optionally substituted Ci_c 2 alkyl amine based so2nr24r25, SOR24, so2r24, sonr24r25, S〇R24, c〇r2 COOH, COOR24 and CONR24R25; Each of R24 and R25 is independently selected from the group consisting of H.subst. H, optionally substituted ^/^alkyl, optionally substituted C2_c 2 alkenyl, optionally substituted c2-c, 2 fast Substituted C2_CiG heterocyclyl, optionally substituted C3_Cl2 cycloalkyl, optionally substituted, cycloalkenyl, optionally substituted C2_Ci2 heterocyclic alkyl, optionally substituted C2 -cls heterocycloalkenyl, optionally substituted aryl and optionally substituted CrC 丨 8 heteroaryl.

在-些實施例中’視情況經取代之C3_C12環院由以下組成之群： H R23In some embodiments, the C3_C12 ring hospital, as appropriate, is replaced by the following group: H R23

其中R23如上文所定義。在—些實施例中 r2為下式基團：Wherein R23 is as defined above. In some embodiments r2 is a group of the formula:

152948.doc •25· 201136930 其中各Μ獨立地為N或CR2a ; 各R係獨立地選自由以下組成之群：H、鹵素、、 N02、CN、NH2、視情況經取代烷基、視情況經取代之c^-c,2烯基、視情況經取代之C2_Ci2炔基、視情況經取代之Cz-Cn雜烷基、視情況經取代之。/。環烷基、視情況經取代之G-c,2雜環烷基、視情況經取代之c2_Ci2 雜環烯基、視情況經取代之Q-Cu芳基、視情況經取代之 G-Cu雜芳基、視情況經取代之c】_c〗2烷氧基、視情況經取代之Cz-Cn烯氧基、視情況經取代之C2_Ci2炔氧基、視情況經取代之CyCu雜烷氧基、視情況經取代、視情況經取代之c^c丨2環烷氧基、視情況經取代之c3_c】2環烯氧基、視情況經取代之q-c〗2雜環烷氧基、視情況經取代之 C2_C〗2雜環烯氧基、視情況經取代之C6_Ci8芳氧基、視情況經取代之C】-C〗8雜芳氧基、視情況經取代之c〗_Ci2烷基胺基、SR8、S03H、S02NH2、S02R8、SONH2、SOR8、 COR8、COOH、COOR8、CONR8R9、NR8COR9、 NR8COOR9、NR8so2R9、NR8c〇NR8R9、nr8r9及醯基；其中R8及R9如上文所定義； r為選自由1、2及3組成之群的整數。在一些實施例中’ r為丄且尺2為下式基團：152948.doc •25· 201136930 wherein each Μ is independently N or CR 2a ; each R is independently selected from the group consisting of H, halogen, N02, CN, NH2, optionally substituted alkyl, optionally Substituted c^-c, 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted Cz-Cn heteroalkyl, optionally substituted. /. Cycloalkyl, optionally substituted Gc, 2 heterocycloalkyl, optionally substituted c2_Ci2 heterocycloalkenyl, optionally substituted Q-Cu aryl, optionally substituted G-Cu heteroaryl , as the case may be substituted c] _c〗 2 alkoxy, optionally substituted Cz-Cn alkenyloxy, optionally substituted C2_Ci2 alkynyloxy, optionally substituted CyCu heteroalkoxy, optionally Substituted, optionally substituted c^c丨2 cycloalkoxy, optionally substituted c3_c] 2 cycloalkenyloxy, optionally substituted qc 2 heterocycloalkoxy, optionally substituted C2_C〗 2 Heterocyclic alkenyloxy, optionally substituted C6_Ci8 aryloxy, optionally substituted C]-C〗 8 heteroaryloxy, optionally substituted c _Ci2 alkylamine, SR8, S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8so2R9, NR8c〇NR8R9, nr8r9 and fluorenyl; wherein R8 and R9 are as defined above; r is selected from 1, 2 and 3 integers of the group. In some embodiments 'r is 丄 and the rule 2 is a group of the formula:

其中各m如上文所述。 152948.doc •26· 201136930 在一些實施例中，1*為2且R2為下式基團：Wherein each m is as described above. 152948.doc •26· 201136930 In some embodiments, 1* is 2 and R2 is a group of the formula:

其中各Μ如上文所定義。在一些實施例中，各Μ為CR2、在一些實施例中，一個 Μ基團為Ν且另一個Μ基團為CR2a。在一些實施例中，R2為下式基團：Each of them is as defined above. In some embodiments, each oxime is CR2. In some embodiments, one oxime group is oxime and the other oxime group is CR2a. In some embodiments, R 2 is a group of the formula:

其中R2aW上文所定義； s為選自由0、1、2、3及4組成之群的整數； r為選自由1、2及3組成之群的整數。在一些實施例中，各Μ為CR2a，r為1且R2為下式基團：Wherein R2aW is as defined above; s is an integer selected from the group consisting of 0, 1, 2, 3 and 4; r is an integer selected from the group consisting of 1, 2 and 3. In some embodiments, each oxime is CR2a, r is 1 and R2 is a group of the formula:

其中R2aW上文所定義。在一些實施例中’各Μ為CR2a，r為2且R2為下式基團： 152948.doc •27· 201136930 R2aWhere R2aW is as defined above. In some embodiments, each Μ is CR2a, r is 2 and R2 is a group of the formula: 152948.doc •27·201136930 R2a

其中R2a如上文所定義。在一些實施例中，一個Μ為N且其他為CR2a «在一實施例中，R2為下式基團： R2aWherein R2a is as defined above. In some embodiments, one Μ is N and the other is CR2a « In one embodiment, R2 is a group of the formula: R2a

其中1123及r如上文所定義。在一些實施例中，r係選自由丨及2組成之群。在—此實施例中，r為1。在一些實施例中，鸿2。各R2a取代基可選自任何適合之視情況存在之取代基在一些實施例中，各係獨立地選自由H、f、 CH2CH3、OCH3、CN、0CF3、c〇2CH3、N〇2、叫 nhcoch3、nhso2ch3、NHCH2CH3及CI?3組成之群。Where 1123 and r are as defined above. In some embodiments, r is selected from the group consisting of ruthenium and 2. In this embodiment, r is 1. In some embodiments, Hung 2 is. Each R2a substituent may be selected from any suitable substituents as appropriate. In some embodiments, each line is independently selected from the group consisting of H, f, CH2CH3, OCH3, CN, 0CF3, c〇2CH3, N〇2, and nhcoch3. , nhso2ch3, NHCH2CH3 and CI?3 group.

在一些實施例中，R2為葙悴M而A 马視匱況經取代之CVC12雜環尤基0 / 在-些實施例中’R2係選自由以下組成之群：視情況經取代之心心·基、視情況經取代之対咬_2_基、視情況經取代之。比…-基、視情況經取代之二氧雜環戍炫_ 2-基、視情驗取狀：氧雜^m視情況經取代 152948.doc -28- 201136930 之四氫呋喃-2-基、視情況經取代之四氬呋喃_3_基、視情況經取代之哌啶-1-基、視情況經取代之哌啶_2_基、視情況經取代之哌啶-3-基、視情況經取代之哌啶_4_基、視情況經取代之嗎啉-1-基、視情況經取代之嗎啉-2-基、視情況經取代之嗎琳-3-基、視情況經取代之丨，4_二氧雜環戊烷-2-基、視情況經取代之硫代嗎啉_丨_基、視情況經取代之硫代嗎啉-2·基、視情況經取代之硫代嗎啉_3•基、視情況經取代之硫代嗎啉_4_基、視情況經取代之哌嗪_丨_基及視情況經取代之哌嗪_2-基。在一些實施例中，視情況經取代之C2_Ci2雜環烷基係選自由以下組成之群： ^n^N、r26 、其中R26係獨立地選自由以下组成之群：H、視情況經取代之q-C,2烷基、視情況經取代之C2_Ci2烯基、視情況經取代之C2-cu炔基、視情況經取代之雜烷基、視情況經取代之c^c,2環烷基、視情況經取代之C3_Ci2環烯基視清I㉔取代之雜環烧、視情況經取代之c2_ CI2雜輯基、㈣況經取代α6·(:18芳基、視情況經取代之CVC1S雜芳基、視情況經取代之Ci_c】2院氧基、視情況經取代ic2-c12稀氧基、視情況經取代之C2-Ci2块氧基、視清況經取代之C2_Cl〇雜炫氧基、視情況經取代之環炫氧基、視情況經取代之C3_Ci2環缔氧基、視情況經取2 152948.doc •29· 201136930 代之c^c,2雜環烷氧基、視情況經取代之C2_C〗2雜環烯氧基、視情況經取代之Q-C】8芳氧基、視情況經取代之 C!8雜芳氧基、視情況經取代之Ci_Ci2烷基胺基、 S02NR27R28 > SOR27 ' S02R27 . SONR27R28 , SOR27 COR27、COOH、COOR27及 CONR27R28 ; 各R27及R28係獨立地選自由以下組成之群：h、視情況經取代之（VCW基、視情況經取代之Μ”縣、視情況經取代之C2-C12炔基、視情況經取代之c2_c丨。雜烷基、視情況經取代之C3-C”環院基、視情況經取代之c3_c12環 , 視凊況經取代之C2-CI2雜環烷基、視情況經取代之 c2-Ci2雜料基、視情I絲代之基及視情況經取代之CrCu雜芳基。 j-些實施例中，視情·取代之C心雜環烧基係選自由以下組成之群：In some embodiments, R2 is 葙悴M and A is replaced by CVC12 heterocyclic uneyl 0 / in some embodiments 'R2 is selected from the group consisting of: Base, depending on the situation, the bite _2_ base is replaced, as appropriate. More than ...-based, depending on the situation, the dioxetane _ 2- base, depending on the situation: oxygen ^ m as appropriate to replace 152948.doc -28- 201136930 tetrahydrofuran-2-yl, depending Substituted tetrahydrofuran-3-yl, optionally substituted piperidin-1-yl, optionally substituted piperidinyl-2-yl, optionally substituted piperidin-3-yl, optionally Substituted piperidine-4-yl, optionally substituted morpholin-1-yl, optionally substituted morpholin-2-yl, optionally substituted morphin-3-yl, optionally substituted Thereafter, 4_dioxol-2-yl, optionally substituted thiomorpholine _ 丨 _ group, optionally substituted thiomorpholine-2 group, optionally substituted sulfur a morpholine _3• group, optionally substituted thiomorpholine _4_ group, optionally substituted piperazine _ 丨 _ group and optionally substituted piperazine 2 - group. In some embodiments, the optionally substituted C2_Ci2 heterocycloalkyl is selected from the group consisting of: nn^N, r26, wherein R26 is independently selected from the group consisting of: H, optionally substituted QC, 2 alkyl, optionally substituted C2_Ci2 alkenyl, optionally substituted C2-cu alkynyl, optionally substituted heteroalkyl, optionally substituted c^c, 2 cycloalkyl, visual a substituted C3_Ci2 cycloalkenyl group I24 substituted heterocyclic ring, optionally substituted c2_CI2 heterocyclic group, (d) a substituted α6·(:18 aryl group, optionally substituted CVC1S heteroaryl group, Substituted Ci_c] 2 hospitaloxy, optionally substituted ic2-c12 diloxy, optionally substituted C2-Ci2 loxy, C2_Cl nonyloxy substituted according to conditions, as appropriate Substituted cyclohexyloxy, optionally substituted C3_Ci2 epoxide, as appropriate 2 152948.doc •29· 201136930 substituted c^c, 2 heterocycloalkoxy, optionally substituted C2_C 〖2 heterocycloalkenyloxy, optionally substituted QC] 8 aryloxy, optionally substituted C! 8 heteroaryloxy, optionally substituted Ci_Ci2 Alkylamino, S02NR27R28 > SOR27 ' S02R27 . SONR27R28 , SOR27 COR27, COOH, COOR27 and CONR27R28 ; each R27 and R28 are independently selected from the group consisting of: h, optionally substituted (VCW based, optionally) Substituted Μ" County, optionally substituted C2-C12 alkynyl, optionally substituted c2_c丨. Heteroalkyl, optionally substituted C3-C" ring-based, optionally substituted c3_c12 ring , a C2-CI2 heterocycloalkyl group substituted, optionally substituted c2-Ci2 heterolyzed group, optionally a substituted I-based group, and optionally a substituted CrCu heteroaryl group. Wherein, the C-heterocyclic ring-burning group is optionally selected from the group consisting of:

,0 其中R26如上文所定義。之群實施例中，R26係選自由Η、COR27及COOR28組成在一些實施例中，R27私.西Α 1 Γ p. R k選自由Η、視情況經取代之C,- 11 2現基、葙格、、口 c P 、座取代之CpC丨8芳基及視情況經取代之 CVC丨8雜芳基組 Ά . 群。在一些實施例中，R27為C丨-C6烷基。在-些實施例中，R27為甲基。 152948.doc 201136930 在一些實施例中，R2為視情況經取代之C2-C12雜烷基。在一些實施例中，C^-Cn雜烷基係選自由羥基烷基、 C 1 - C 6院氧基C 1 - C 6烧基、胺基C1 - C 6烧基、C 1 - C 6燒基胺基 Ci-C6院基及二（Ci-C6烧基）胺基Ci-C6烧基組成之群。r2作為Cz-C!2雜烷基之可能含義的實例包括羥基甲基、經基乙基、羥基丙基、羥基丁基、羥基戊基、甲氧基甲基、2_曱氧基乙基、3 -甲氧基丙基、2-乙氧基乙基、3 -乙氧基丙基、胺基曱基、2 -胺基乙基、3 -胺基丙基、4 -胺基丁基、 5-胺基戊基、甲基胺基曱基、2-曱基胺基乙基、3_甲基胺基丙基、4-曱基胺基丁基、5-曱基胺基戊基、乙基胺基曱基、2-乙基胺基乙基、3-乙基胺基丙基、4-乙基胺基丁基、5-乙基胺基戊基、二曱胺基甲基、2_二甲基胺基乙基、3-二曱基胺基丙基、4-二曱基胺基丁基、5_二曱基胺基戊基、二乙基胺基曱基、2-二乙基胺基乙基、3_二乙基胺基丙基、4·二乙基胺基丁基及5-二乙基胺基戍基。在些實細•例中’ R係選自由以下組成之群：曱基、乙基、異丙基、丙基、2-乙基-丙基、3，3-二甲基-丙基、環丙基、環戊基、丁基、異丁基、3，3-二曱基_ 丁基、2-乙基·丁基、戊基、2-曱基、戊基、己基、庚基、辛基、氰基、甲氡基曱基及丁氧基曱基。許多（若非全部）上文所論述之變數可視情況經取代。若變數視情況經取代，則在一些實施例中，各視情況存在之取代基係獨立地選自由以下组成之群：自素、=〇、=s ' CN、-N〇2、-CF3、-犯3、烧基、稀基、炔基、齒烧基、 152948.doc •31 - 201136930 鹵烯基、齒炔基、雜烷基、環烷基、環烯基、雜環烷基、雜環烯基、芳基、雜芳基、環烷基烷基、雜環烷基烷基、雜芳基烷基、芳烷基、環烷基烯基、雜環烷基烯基、芳基烯基、雜芳基烯基、環烷基雜烷基、雜環烷基雜烷基、芳基雜烷基、雜芳基雜烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、烷氧基環烷基、烷氧基雜環烷基、烷氧基芳基、烷氧基雜芳基、烷氧羰基、烷基胺基羰基、烯氧基、快氧基、環烷氧基、環烯氧基、雜環烷氧基、雜環烯氧基、芳氧基、苯氧基、苯甲氧基、雜芳氧基、芳基烷氧基、胺基、烷基胺基、醯基胺基、胺基烷基、芳基胺基、磺酿基胺基、亞磺醯基胺基、磺酿基、烷基磺醯基、芳基續醯基、胺基績醯基、亞續醯基、烷基亞磺醯基、芳基亞磺醯基、胺基亞磺醯基胺基烷基、_C( =⑺〇H、_c( = 〇)Ra、 -C( = 〇)〇Ra、C( = 〇)NRaRb、c(=N〇H)Ra、c( = NRa)NRbRC、 NRaR 、NRaC( = 〇)Rb、NRaC(=0)〇Rb、, 0 where R26 is as defined above. In a group embodiment, R26 is selected from the group consisting of ruthenium, COR27, and COOR28. In some embodiments, R27 private. Α Α 1 Γ p. R k is selected from C, - 11 2葙格, cc P , substituted CpC丨8 aryl and optionally substituted CVC丨8 heteroaryl group Ά. Group. In some embodiments, R27 is a C丨-C6 alkyl group. In some embodiments, R27 is methyl. 152948.doc 201136930 In some embodiments, R2 is optionally substituted C2-C12 heteroalkyl. In some embodiments, the C^-Cn heteroalkyl group is selected from the group consisting of a hydroxyalkyl group, a C1-C6 alkoxy C1-C6 alkyl group, an amine C1-C6 alkyl group, and a C1-C6 group. A group consisting of an alkylamino-based Ci-C6 or a di-(Ci-C6 alkyl)-based Ci-C6 alkyl group. Examples of possible meanings of r2 as a Cz-C!2 heteroalkyl group include hydroxymethyl, transethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2-methoxyethyl , 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminoguanidino, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl , 5-Aminopentyl, methylaminoindenyl, 2-decylaminoethyl, 3-methylaminopropyl, 4-decylaminobutyl, 5-decylaminopentyl , ethylamino fluorenyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, diammonium methyl , 2-dimethylaminoethyl, 3-didecylaminopropyl, 4-didecylaminobutyl, 5-didecylaminopentyl, diethylaminoindenyl, 2 2-Diethylaminoethyl, 3-diethylaminopropyl, 4·diethylaminobutyl and 5-diethylaminoindenyl. In some embodiments, 'R is selected from the group consisting of sulfhydryl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, and ring. Propyl, cyclopentyl, butyl, isobutyl, 3,3-didecyl-butyl, 2-ethylbutyl, pentyl, 2-indenyl, pentyl, hexyl, heptyl, octyl A cyano group, a cyano group, a decyl fluorenyl group and a butoxy fluorenyl group. Many, if not all, of the variables discussed above may be superseded. If the variables are substituted as appropriate, in some embodiments, each of the substituents present as appropriate is independently selected from the group consisting of: self, 〇, =s ' CN, -N〇2, -CF3, - off 3, alkyl, dilute, alkynyl, dentate, 152948.doc • 31 - 201136930 haloalkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, aralkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylene , heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkane Alkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkoxy, naphthenic Oxyl, cycloalkenyloxy, heterocycloalkoxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkoxy, amine, alkylamine Base, mercaptoamine, aminoalkyl, arylamine, Sulfonic acid amine, sulfinylamino, sulfonyl, alkylsulfonyl, aryl sulfhydryl, amine fluorenyl, sulfhydryl, alkylsulfinyl, aryl Sulfonyl, aminosulfinylaminoalkyl, _C( =(7)〇H, _c(= 〇)Ra, -C( = 〇)〇Ra, C( = 〇)NRaRb, c(=N〇 H) Ra, c (= NRa) NRbRC, NRaR, NRaC (= 〇) Rb, NRaC (=0) 〇 Rb,

-ORa、 NRaC(=0)NRbRc、其中R、R、Rc及Rd各獨立地選自由以下組成之群: C2-C12稀基、块、C3-C12環稀基、Ci_c 連接之原子一-ORa, NRaC(=0)NRbRc, wherein R, R, Rc and Rd are each independently selected from the group consisting of: C2-C12 dilute, block, C3-C12 ring dilute group, Ci_c attached atomic one

，各視情況存在之取代基係獨立地選自 H、CVCu烧基、Ci_Ci2函烷基、基、q-c,·院基、c3_Ci2環烷基、雜環烧基、C 1 醯基，或Ra、在一些實施例中， 152948.doc •32· 201136930 由以下組成之群：F、CM、Br、=0、=S、-CN、-N〇2、烷基、烯基、雜烷基、函烷基、炔基、芳基、環烷基、雜環烷基、雜芳基、羥基、羥基烷基、烷氧基、烷基胺基、胺基烷基、醯基胺基、苯氧基、烷氧基烷基 '苯曱氧基、烷基磺醯基、芳基磺醯基、胺基磺醯基、-C(0)0Ra、 COOH、SH及醯基。在一些實施例中，各視情況存在之取代基係獨立地選自由以下組成之群：F、Br、C1、=0、=S、-CN、曱基、三氟甲基、乙基' 2,2，2 -二氟^乙基、異丙基、丙基、2-乙基· 丙基、3,3-二曱基-丙基、丁基、異丁基、3,3_二曱基-丁基、2-乙基-丁基、戊基、2_曱基-戊基、戊_4_烯基、己基、庚基、辛基、笨基、nh2、-no2、苯氧基、羥基、曱氧基、三氟曱氧基、乙氧基及亞曱基二氧基。或者，同一部分上之兩個視情況存在之取代基可連接在一起形成連接於視情況經取代之部分的稠合環狀取代基。因此，術語視情況經取代包括稠合環，諸如環烷基環、雜環烷基環、芳環或雜芳基環。除式I化合物外’所揭示之實施例亦關於該等化合物之醫藥學上可接受之鹽、醫藥學上可接受之N_氧化物、醫藥學上可接受之前藥及醫藥活性代謝物，及該等代謝物之醫藥學上可接受之鹽。本發明亦關於包括本發明之化合物及醫藥學上可接受之載劑、稀釋劑或賦形劑的醫藥組合物。在另態樣中，本發明提供一種抑制蛋白激酶、其片段 152948.doc •33· 201136930 或複合物或其功能等效物之方法，該方法包括使該蛋白激酶或其片段或複合物或其功能等效物及/或其輔因子接觸有效量之如本文所述的式（I)化合物。本文所揭示之化合物可直接且僅僅作用於激酶分子或其複合物或片段以抑制生物活性。然而，應瞭解該等化合物亦可至少部分作用於磷酸化過程所涉及之輔因子。已知激酶輔因子包括離子種類（例如鋅及鈣）、脂質（例如磷脂醯絲胺酸）及二醯基甘油。在一些實施例中，蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。在一些實施例中，絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為其mTOR蛋白激酶或片段、或其複合物或其功.能等效物❶在一些實施例中’絲胺酸/蘇胺酸蛋白激酶為mTORC 1或其片段或複合物或其功能等效物。在該方法之一實施例中，使一或多種蛋白激酶接觸化合物包括向含有一或多種蛋白激酶之哺乳動物投與化合物。在另一態樣中’本發明提供式（I)化合物抑制一或多種蛋白激酶之用途。在些貫施例中，蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。在一些實施例中，絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為其mT〇R蛋白激酶或片段、或其複合物或其功能等效物。在一些實施例中’絲胺酸/蘇胺酸蛋白激酶為mTORC 1或其片段戋複人物或其功能等效物。 152948.doc •34· 201136930 在另—態樣中，本發明提供一種治療或預防哺乳動物之病狀的方法’其中一或多種蛋白激酶或其片段或複合物或其功能等效物之抑制可預防、抑制或改善該病狀之病理或症狀，該方法包括投與治療有效量之式（I)化合物。在些貫施例中，蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。在一些實施例中，絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為其111丁〇11蛋白激酶或片奴、或其複合物或其功能等效物^在一些實施例中，絲胺酸/蘇胺酸蛋白激酶為mT〇RC1或其片段或複合物或其功能等效物。在些實施例中，該病狀係選自由以下組成之群：炎症、類風濕性關節炎、牛皮癬、動脈粥樣硬化、結腸炎、發炎性腸病、騰腺炎、多發性硬化症、自體免疫病症、狼瘡、過敏性腦脊髓炎、移植排斥反應、子宮内膜異位症、平滑肌瘤、多囊性印巢症候群、錯構瘤、結節性硬化症、阿茲海默氏病（Alzheimerls disease)、亨廷頓氏病 (HUntingtonis disease)、帕金森氏病的出㈣心心叫、胰島素依賴性糖尿病、肥胖、糖尿病性視網膜病、心臟肥大及自體顯性多囊性腎病。在些實細*例中，病狀為癌症。在一些實施例中，該癌症係選自由以下組成之群：血液癌症，諸如骨髓增生性病症（特發性骨髓纖維化、真性紅血球增多症、原發性血小板增多症、慢性月髓白血病）、骨髓細胞化生、慢性骨髓單核細胞性白血病、急性淋巴細胞白血病、急性紅血球母 152948.doc •35. 201136930 細胞白血病、霍奇金氏及非霍奇金氏病（Hodgkin’s and Non Hodgkin’s disease)、B細胞淋巴瘤、急性τ細胞白血病、骨髓發育不良徵候群、漿細胞病症、毛細胞白血病、卡波希氏肉瘤（kaposi's sarcoma)、淋巴瘤；婦科癌症，諸如乳癌、卵巢癌、子宮頸癌、***癌及外陰癌、子宮内膜增生；胃腸道癌’諸如結腸直腸癌、息肉、肝癌、胃癌、胰臟癌、膽囊癌；泌尿道癌，諸如***癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌，諸如黑色素瘤；腦腫瘤，諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經膠質瘤；頭頸部癌，諸如鼻咽癌、喉癌；呼吸道癌，諸如肺癌（1^8(：1^(：及3(：1^(：)、間皮瘤；眼病，諸如視網膜胚細胞瘤；肌肉骨骼疾病，諸如骨肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。在另-態樣中，本發明提供式⑴化合物於製備治療動物之病狀之藥劑中的用途，其中—或多種蛋白激酶或其片段或複合物或其功能等效物之抑制可預防、抑制或改善該病狀之病理或症狀。〆丙在另t樣中，本發明提供式（I)化合物或其醫藥學上可接受之鹽、N·氧化物或前藥於治療病狀中之用途，其中一或多種蛋白激酶或其片段或複合物或其功能等效物之抑制可預防、抑制或改善該病狀之病理或症狀。 _纟I明提供一種預防或治療個體之增< 性病狀的方法，马·古 ~ -方法包括投與治療有效量之式⑴化^ 152948.doc * 36 - 201136930 物。在另一態樣中，本發明提供式⑴化合物於製備治療個體之增生性病狀的藥劑中之用途。在一些實施例中，蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。在一些實施例中，絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為其mT〇R蛋白激酶或片段、或其複合物或其功能等效物。在一些實施例中，絲胺酸/蘇胺酸蛋白激酶為111丁〇11(：1或其片段或複合物或其功能等效物。在一些實施例中，該病狀係選自由以下組成之群：炎症、類風濕性關節炎、牛皮癖、動脈粥樣硬化、結腸炎、發炎性腸病、騰腺炎、多發性硬化症、自體免疫病症、狼瘡、過敏性腦脊髓炎、移植排斥反應、子宮内膜異位症、平滑肌瘤、多囊性印巢症候群、錯構瘤、結節性硬化症、阿兹海默氏病、亨廷頓氏病、帕金森氏病'姨島素依賴性糖尿病、肥胖、糖展病性視網膜病、心臟肥大及自體顯性多囊性腎病。在—貫把例中，病狀為癌症。在一些實施例中，該癌症係選自由以下組成之群：血液癌症，諸如f髓增生性病症(特發性骨髓纖維化、真性紅血球增多症、原發性到、板增多症、慢性骨髓白血病）、骨髓細胞化生、慢性骨髓皁核細胞性白血病'急性淋巴細胞白也病、急性紅血球母細胞白血病、霍奇金氏及非霍奇金氏病、B細胞淋巴瘤、急性τ細胞白血病、骨髓發育不良徵候群、楽細胞病症、 152948.doc -37· 201136930 毛細胞白血病、卡波希氏肉瘤、淋巴瘤；婦科癌症，諸如乳癌、卵巢癌、子宮頸癌、***癌及外陰癌、子宮内膜増生，胃腸道癌’諸如結腸直腸癌、息肉、肝癌、胃癌、騰臟癌、膽囊癌；泌尿道癌’諸如***癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌，諸如黑色素瘤；腦腫瘤’諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經膠質瘤；頭頸部癌，諸如鼻咽癌、喉癌；呼吸道癌，諸如肺癌（NSCLC及SCLC)、間皮瘤；眼病’諸如視網膜胚細胞瘤；肌肉骨骼疾病，諸如骨肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。本文中闡述本發明教示之此等及其他特徵。【實施方式】在本說明書中’使用許多熟練受定址者熟知之術語。然而’為清晰起見，將定義許多術語。如本文所使用，術語「未經取代」意謂不存在取代基或僅有的取代基為氫。如本說明書通篇所使用’術語「視情況經取代」表示基團可經或可未經一或多個非氫取代基進一步取代或稠合 (以形成稠合多環系統）。在某些實施例中，該等取代基為一或多個獨立地選自由以下組成之群的基團：鹵素、=〇、 =S、-CN、-N02、-CF3、-0CF3、烷基、烯基、炔基、卤烧基、i烯基、齒炔基、雜烷基、環烷基、環烯基、雜環炫基、雜環烯基、芳基、雜芳基、環烷基烷基、雜環烷基 152948.doc -38· 201136930 烷基、雜芳基烷基、芳烷基、環烷基烯基、雜環烷基烯基、芳基烯基、雜芳基烯基、環烷基雜烷基、雜環烷基雜烷基、芳基雜烷基、雜芳基雜烷基、羥基、羥基烷基、烷氧基、烷氧基烷基、烷氧基環烷基、烷氧基雜環烷基、烷氧基芳基、烷氧基雜芳基、烷氧羰基、烷基胺基羰基、烯氧基、块氧基、環院氧基、環烯氧基、雜環烧氧基、雜環烯氧基、芳氧基、苯氧基、苯甲氧基、雜芳氧基、芳基烷氧基、胺基、烷基胺基、醯基胺基、胺基烷基、芳基胺基、磺醯基胺基、亞磺醯基胺基、磺醯基、烷基磺醯基、芳基磺酿基、胺基磺醯基、亞磺醯基、烷基亞磺醯基、芳基亞確醢基、胺基亞續醯基胺基烧基、_C(=〇)〇H、_C(=〇)Ra ' -C(=0)0Ra . C(=〇)NRaRb > C(=NOH)Ra > C(=NRa)NRbRc > NR R、NRaC(=〇)Rb、NRaC(=0)0Rb、NRaC(=0)NRbRc、 NRaC(=NRb)NReRd、NRaS02Rb、_SRa、S02NRaRb、-〇R_a、〇C(=0)NRaRb、〇c(=〇)Ra及醯基，其中R、Rb、rc及Rd各獨立地選自由以下組成之群： Η、CVC12 炫基、Cl_Ci2 _ 烧基、C2_Ci2 稀基、C2_Ci2 快基、c2-Cl^院基、C3_Ci2環统基、C3_Ci2環烯基、C2_Ci2 雜環烷基、C2-Cl2雜環烯基、C6_Cis芳基、Ci_Ci8雜芳基及醯基，或Ra、Rb、RC&Rd之任何兩者或兩者以上連同其所連接之原子—起形成具有3至12個環原子之雜環系統。在一些實施例中，各視情況存在之取代基係獨立地選自由以下組成之群：_素、=0、=s、_CN、_N〇2、_Cf3、 •〇CF3、统基、缚基、快基、鹵烧基、㈣基、齒块基、 152948.doc •39· 201136930 雜院基、環烷基、環烯基、雜環烷基、雜環烯基、芳基、雜芳基、羥基、羥基烷基、烷氧基、烷氧基烷基、烷氧基芳基、烷氧基雜芳基、烯氧基、炔氧基、環烷氧基、環烯氧基、雜環烷氧基、雜環烯氧基、芳氧基、雜芳氧基、芳烧基、雜芳基烷基、芳基烷氧基、胺基、烷基胺基、醯基胺基、胺基烷基、芳基胺基、磺醯基、烷基磺醯基、芳基磺醯基、胺基磺醯基、胺基烷基、_COOH、-SH及醯基。尤其適合之視情況存在之取代基的實例包括F、C1、, the substituents present as the case may be independently selected from H, CVCu alkyl, Ci_Ci2, alkyl, qc, ..., c3_Ci2 cycloalkyl, heterocycloalkyl, C 1 decyl, or Ra, In some embodiments, 152948.doc •32· 201136930 is a group consisting of F, CM, Br, =0, =S, -CN, -N〇2, alkyl, alkenyl, heteroalkyl, Alkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, decylamino, phenoxy Alkoxyalkyl 'benzoxyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(0)0Ra, COOH, SH and mercapto. In some embodiments, each optionally present substituent is independently selected from the group consisting of F, Br, C1, = 0, =S, -CN, fluorenyl, trifluoromethyl, ethyl '2 , 2,2-difluoro^ethyl, isopropyl, propyl, 2-ethylpropyl, 3,3-dimercapto-propyl, butyl, isobutyl, 3,3_di -butyl, 2-ethyl-butyl, pentyl, 2-decyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, nh2, -no2, phenoxy , hydroxy, decyloxy, trifluoromethoxy, ethoxy and fluorenyldioxy. Alternatively, two optionally present substituents on the same moiety may be joined together to form a fused cyclic substituent attached to the optionally substituted moiety. Thus, the term optionally substituted includes fused rings such as cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings. The disclosed embodiments of the present invention are also directed to pharmaceutically acceptable salts of such compounds, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites, and A pharmaceutically acceptable salt of such metabolites. The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the invention provides a method of inhibiting a protein kinase, a fragment thereof 152948.doc • 33·201136930 or a complex or a functional equivalent thereof, the method comprising: the protein kinase or a fragment or complex thereof or The functional equivalent and/or its cofactor are contacted with an effective amount of a compound of formula (I) as described herein. The compounds disclosed herein act directly and exclusively on kinase molecules or complexes or fragments thereof to inhibit biological activity. However, it should be understood that these compounds may also act, at least in part, on the cofactors involved in the phosphorylation process. The kinase cofactors are known to include ionic species (e.g., zinc and calcium), lipids (e.g., phospholipid lysine), and dimercaptoglycerol. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or a fragment or complex thereof is its mTOR protein kinase or fragment, or a complex thereof, or a functional equivalent thereof, in some embodiments, a silk amine The acid/threonine protein kinase is mTORC 1 or a fragment or complex thereof or a functional equivalent thereof. In one embodiment of the method, contacting the one or more protein kinases with a compound comprises administering a compound to a mammal comprising one or more protein kinases. In another aspect, the invention provides the use of a compound of formula (I) for inhibiting one or more protein kinases. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or fragment or complex thereof is its mT〇R protein kinase or fragment, or a complex thereof or a functional equivalent thereof. In some embodiments the 'serine/threonine protein kinase is mTORC 1 or a fragment thereof, or a functional equivalent thereof. 152948.doc • 34· 201136930 In another aspect, the invention provides a method of treating or preventing a condition in a mammal, wherein inhibition of one or more protein kinases or fragments or complexes thereof or functional equivalents thereof Preventing, inhibiting or ameliorating the pathology or symptoms of the condition, the method comprising administering a therapeutically effective amount of a compound of formula (I). In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or fragment or complex thereof is a 111 〇11 protein kinase or a sheet slave, or a complex thereof or a functional equivalent thereof. In some embodiments, The serine/threonine protein kinase is mT〇RC1 or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, adrenitis, multiple sclerosis, self Immunity disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic sac syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease ( Alzheimerls disease), Huntington's disease, Parkinson's disease (4) heart, insulin-dependent diabetes, obesity, diabetic retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease. In some cases, the condition is cancer. In some embodiments, the cancer is selected from the group consisting of a hematological cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), Bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute red blood cell 152948.doc • 35. 201136930 Cell leukemia, Hodgkin's and Non Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, myelodysplastic syndrome, plasma cell disease, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, Vaginal cancer and vulvar cancer, endometrial hyperplasia; gastrointestinal cancer 'such as colorectal cancer, polyps, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer , penile cancer; skin cancer, such as melanoma; brain tumors, such as glioblastoma, neurogenic Tumor, astrocytoma, ependymoma, brain stem glioma, neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer Respiratory cancer, such as lung cancer (1^8(:1^(: and 3(:1^(:), mesothelioma; eye disease, such as retinoblastoma; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; Squamous cell carcinoma and fibroids. In another aspect, the invention provides the use of a compound of formula (1) for the manufacture of a medicament for treating a condition in an animal, wherein - or a plurality of protein kinases or fragments or complexes thereof, or functions thereof, etc. Inhibition of the agent prevents, inhibits or ameliorates the pathology or symptoms of the condition. In another example, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, an N-oxide or a former The use of a medicament for the treatment of a condition in which inhibition of one or more protein kinases or fragments or complexes thereof or a functional equivalent thereof prevents, inhibits or ameliorates the pathology or symptoms of the condition. Or a method of treating an individual's increase in sexual condition The method of administering the therapeutically effective amount of the formula (1) is 152948.doc * 36 - 201136930. In another aspect, the invention provides a compound of formula (1) for use in the preparation of a medicament for treating a proliferative condition in a subject Uses. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threon protein kinase or a fragment or complex thereof is its mT〇R protein kinase or fragment, or a complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase is 111 〇11 (: 1 or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory Enteropathy, adrenitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyomas, polycystic inoculation syndrome, hamartoma , tuberous sclerosis, Alzheimer Disease, Huntington's disease, Parkinson's disease 'aunt Insulin-dependent diabetes mellitus, obesity, sugar show retinopathy, cardiac hypertrophy and autosomal dominant polycystic kidney disease. In the case of the case, the condition is cancer. In some embodiments, the cancer is selected from the group consisting of a hematological cancer, such as a f-proliferative disorder (idiopathic myelofibrosis, polycythemia vera, primary to hyperplasia, chronic myeloid leukemia) ), bone marrow cell metaplasia, chronic bone marrow saponin leukemia 'acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's and non-Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, Myelodysplastic syndrome, sputum cell disease, 152948.doc -37· 201136930 hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, vaginal cancer and vulvar cancer, uterus Endometrial neoplasia, gastrointestinal cancer 'such as colorectal cancer, polyp, liver cancer, stomach cancer, sputum cancer, gallbladder cancer; urinary tract cancer 'such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer, penile cancer; skin cancer, Such as melanoma; brain tumors such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brain stem glioma, god Transectoblastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC and SCLC), mesothelioma; eye disease 'such as retina Germ cell tumor; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. These and other features of the present teachings are set forth herein. [Embodiment] In the present specification, a number of terms that are well known to those skilled in the art are used. However, for the sake of clarity, many terms will be defined. As used herein, the term "unsubstituted" means that no substituent is present or the only substituent is hydrogen. As used throughout the specification, the term "optionally substituted" means that the group may or may not be further substituted or fused (to form a fused polycyclic system) without one or more non-hydrogen substituents. In certain embodiments, the substituents are one or more groups independently selected from the group consisting of: halogen, = 〇, =S, -CN, -N02, -CF3, -0CF3, alkyl , alkenyl, alkynyl, haloalkyl, i alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocyclo, heterocycloalkenyl, aryl, heteroaryl, naphthenic Alkyl, heterocycloalkyl 152948.doc -38· 201136930 alkyl, heteroarylalkyl, aralkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylene , cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl,heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxy ring Alkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkoxy, cyclooxyl, cycloalkoxy , heterocyclic alkoxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkoxy, amine, alkylamino, decylamino , aminoalkyl, arylamine, sulfonylamino, sulfinyl , sulfonyl, alkylsulfonyl, arylsulfonic acid, aminosulfonyl, sulfinyl, alkylsulfinyl, aryl sulfhydryl, amino sulfhydryl Base group, _C(=〇)〇H, _C(=〇)Ra ' -C(=0)0Ra . C(=〇)NRaRb > C(=NOH)Ra > C(=NRa)NRbRc &gt ; NR R, NRaC (= 〇) Rb, NRaC (=0) 0Rb, NRaC (=0) NRbRc, NRaC (= NRb) NReRd, NRaS02Rb, _SRa, S02NRaRb, -〇R_a, 〇C(=0)NRaRb, 〇c(=〇)Ra and fluorenyl, wherein R, Rb, rc and Rd are each independently selected from the group consisting of: Η, CVC12 炫, Cl_Ci2 _ alkyl, C2_Ci2, C2_Ci2 fast, c2- Cl^, G3_Ci2, C3_Ci2 cycloalkenyl, C2_Ci2 heterocycloalkyl, C2-Cl2 heterocycloalkenyl, C6_Cis aryl, Ci_Ci8 heteroaryl and fluorenyl, or Ra, Rb, RC & Rd Any two or more of them together with the atoms to which they are attached form a heterocyclic ring system having from 3 to 12 ring atoms. In some embodiments, each of the optionally present substituents is independently selected from the group consisting of: _ prime, =0, = s, _CN, _N 〇 2, _Cf3, • 〇 CF3, cyclized, ligated, Fast group, halogenated group, (tetra) group, tooth block group, 152948.doc •39· 201136930 compound, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, Hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, heterocycloalkane Oxyl, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkoxy, amine, alkylamino, decylamino, aminoalkane Alkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, _COOH, -SH and fluorenyl. Examples of substituents that are particularly suitable, as the case may be, include F, C1.

Br、I、CH3、CH2CH3、OH、OCH3、CF3、OCF3、N〇2、 NH2及 CN。或者，同一部分上之兩個視情況存在之取代基可連接在一起形成連接於視情況經取代之部分的稠合環狀取代基。因此，術語視情況經取代包括稠合環，諸如環烷基環、雜環烷基環、芳環或雜芳基環。在以下許多取代基之定義中，陳述「該基團可為端基或橋基」。此意欲表示術語之用途意欲涵蓋基團為分子之兩個其他部分之間的鍵聯基團以及其為末端部分的情形。使用術語烷基舉例’一些公開案將對於橋基使用術語「伸烧基」’且因此在此等其他公開案中’術語「烷基」（端基）與「伸烧基」（橋基）之間存在區別。在本申請宰中，未提出該區別且大部分基團可為橋基或端基。「醯基」意謂R-C(=0)-基團，其中R基團可為如本文所疋義之炫基、環院基、雜環烧基、芳基或雜芳基。酿基之實例包括乙酿基及苯甲酿基。該基團可為端基或橋基。若 152948.doc -40- 201136930 該基團為端&，則纟經由幾基碳鍵結於分子之其餘部分。醯基胺基」意謂r_C(=〇)_nh_基團，其中尺基團可為如本文所定義之;^基、環燒基、雜環烧基、芳基或雜芳基玄基團可為端基或橋基。若該基團為端基，則其經由氮原子鍵結於分子之其餘部分。作為基團或基團之一部分，「烯基」表示含有至少一個碳-碳雙鍵且可為在正鏈中較佳具有2_12個碳原子 '更佳2_ H)個碳原子、最佳2·6個碳原子之直鏈或分支鏈的脂族烴基。該基團之正鏈中可含有複數個雙鍵且關於各鍵之位向獨立地為Ε或例示性稀基包括（但不限於）乙烯基、丙稀基丁烯基、戊烯基、己烯基、庚烯基、辛烯基及壬烯基。該基團可為端基或橋基。「烯基氧基」係指烯基基團，其中烯基如本文所定義。較佳烯基氧基為Cl_c6；)#基氧基。該基團可為端基或橋基。若該基團為端基，則其經由氧原子鍵結於分子之其餘部分。除非另外註釋，否則作為基團或基團之一部分，「烷基j係指直鏈或分支鏈脂族烴基，較佳為^七^烷基，更佳為Ci-Cio烧基’最佳為烧基 Ci-Ce院基取代基之實例包括甲基、基、正丁基、第二丁基、第三丁基、該基團可為端基或橋基。 °適合直鏈及分支鏈乙基、正丙基、2-丙己基及其類似基團。除非指定，否則「胺基。「單烷基胺基烷基胺基」包括單烷基胺基與二烷基」意謂院基-NH-基團’其中烷基如上 152948.doc •41- 201136930 文所定義。「二烷基胺基」意謂（烷基hN-基團，其中各垸基可相同或不同且各如本文關於烷基所定義。該烷基較佳為。!-^烧基。該基團可為端基或橋基》若該基團為端基’則其經由氮原子鍵結於分子之其餘部分。「院基胺基羰基」係指式（Alkyl)x(H)yNC(=0)-之基團，其中烷基如本文所定義，且χ+γ之和=2。該基團可為端基或橋基《若該基團為端基，則其經由羰基碳鍵結於分子之其餘部分。「烷氧基」係指烷基-〇_基團，其中烷基如本文所定義。S玄烧氧基較佳為c rC6院氧基。實例包括（但不限於）曱氧基及乙氧基。該基團可為端基或橋基。「院氧基烧基」係指烷氧基_烷基_基團，其中該等烷氧基及烷基部分如本文所定義，該基團可為端基或橋基。若該基團為端基，則其經由烷基鍵結於分子之其餘部分。「烷氧基芳基」係指烷氧基-芳基_基團，其中該等烷氧基及芳基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由芳基鍵結於分子之其餘部分。「烷氧羰基」係指烷基_〇_(：(=〇)_基團，其中烷基如本文所定義。該烷基較佳為匚,-^烷基。實例包括（但不限於）甲氧羰基及乙氧羰基。該基團可為端基或橋基。若該基團為端基，則其經由羰基碳鍵結於分子之其餘部分。「烷氧基環烷基」係指烷氧基-環烷基_基團，其中該等烷氧基及環烷基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由環烷基鍵結於分子之其餘 152948.doc •42- 201136930 部分。「烧氧基雜芳基」係㈣氧基.雜芳基基團，其中該等炫氧基及雜芳基部分如本文所定義。該基團可為端基或橋 . 纟。若該基®為端基，則其經由㈣基鍵結於分子之其餘部分。「烷氧基雜環烷基」係指烷氧基_雜環烷基-基團，其中該等烷氧基及雜環烷基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由雜環烷基鍵結於分子之其餘部分。「烷基亞磺醯基」意謂烷基·S_( = 〇)_基團，其中烷基如本文所定義。該烧基較佳為烷基◊例示性烷基亞磺 / 醯基包括（但不限於）甲基亞磺醯基及乙基亞磺醯基。該基團可為端基或橋基《若該基團為端基，則其經由硫原子鍵結於分子之其餘部分。「烧基磺醯基」係指烷基_S(=0)2·基團，其中烷基如上文所定義。該烷基較佳為匸广匕烷基《實例包括（但不限於）甲基磺醯基及乙基磺醯基。該基團可為端基或橋基。若該基團為端基，則其經由硫原子鍵結於分子之其餘部分。 ‘ 作為基團或基團之一部分，「炔基」意謂含有一個碳- ，碳參鍵且可為在正鏈中較佳具有2-12個碳原子、更佳2-10 個碳原子、更佳2-6個碳原子之直鏈或分支鏈的脂族烴基°例示性結構包括（但不限於）乙炔基及丙炔基。該基團可為端基或橋基。「炔基氧基」係指炔基-Ο-基團，其中炔基如本文所定 152948.doc -43· 201136930 義。較佳炔氧基為Cl_c6快基氧基。該基團可為端基或橋基。若該基團為端基，則其經由氧原子鍵結於分子之其餘部分。胺基烷基」意謂NH；j-烷基-基團，其中該烷基如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由烧基鍵結於分子之其餘部分。胺基硕醯基J意謂NH2_S(=0)2·基團。該基團可為端基或橋基。若該基團為端基，則其經由硫原子鍵結於分子之其餘部分。作為基團或基團之-部分，「芳基」表示⑴視情況經取代之單環或稠合多環芳族碳環（具有均為碳之環原子的環 '口構)母J衣較佳具有5至12個原子。芳基之實例包括苯基、萘基及其類似基團；（ii)視情況竿取代之部分飽和雙環芳族碳環部分，其中苯基及C5·7環烷基或^巧環烯基稠合在一起形成環狀結構，例如四氫萘基'茚基或二氫茚基。該基團可為端基或橋基。芳基通常為C6_Ci8芳基。「芳基烯基」意謂芳基-烯基-基團，其中該芳基及烯基如本文所定義。例示性芳基烯基包括苯基烯丙基。該基團可為端基或橋基。若該基團為端基，則其經由烯基鍵結於分子之其餘部分。芳基燒基」意謂芳基-院基_基團，其中該等芳基及烧基部分如本文所定義。較佳芳基烷基含有烷基部分。例示性芳烷基包括苯甲基、苯乙基、丨_萘甲基及2_萘甲基。該基團可為端基或橋基.若該基團為端基，則其經由 152948.doc 201136930 炫*基鍵結於分子之其餘部分。「芳基烷氧基」係指芳基_烷基_0_基團，其中該烷基及芳基如本文所定義。該基團可為端基或橋基。若該基團為竓基，則其經由氧原子鍵結於分子之其餘部分。除非指定，否則「芳基胺基」包括單芳基胺基及二芳基胺基。單芳基胺基意謂式芳基NH_之基團，其中芳基如本文所定義。二芳基胺基意謂式（芳基^Ν_之基團，其中各芳基可為相同或不同且各如本文對於芳基所定義。該基團可為端基或橋基。㈣基團為端m經由氛原子鍵結於分子之其餘部分。芳基雜烷基」意謂芳基_雜烷基_基團，其中該等芳基及雜烷基部分如本文所定義。該基團可為端基或橋基。若該基團為端基’則其㈣純基鍵結於分子之其餘部分。「芳氧基」係指芳基基團，其中該芳基如本文所定義。較佳芳氧基為Ce-C,8芳氧基、更佳為c6_CiQ芳氧基。該基團可為端基或橋基4該基團為絲，則其經由氧原子鍵結於分子之其餘部分。「芳基磺醯基」意謂芳基_S(=〇)2·基團，其中該芳基如本文所定義。該基團可為端基或橋基。若該㈣為端基，則其經由硫原子鍵結於分子之其餘部分。「鍵」為化合物或分子中各原子之間的鍵聯。該鍵可為單鍵、雙鍵或參鍵。「環烯基」意謂含有至少—個碳.碳雙鍵且每環較佳具有5-10個碳原子之非㈣單環或多環系統。例示性單環環 152948.doc •45- 201136930 烯基環包括環戊烯基、環己烯基或環庚烯基。環烯基可經一或多個取代基取代。環烯基通常為C3_Ci2烯基。該基團可為端基或橋基。除非另外指定，否則「環烷基」係指飽和單環或稠合或螺多環碳環，每環較佳含有3至9個碳，諸如環丙基、環丁基、環戊基、環己基及其類似基團》其包括諸如環丙基及環己基之單環系統，諸如十氫萘之雙環系統，及諸如金剛烷之夕％系統。環烷基通常為Cs-C!2烷基。該基團可為端基或橋基。環院基烧基」意謂環院基_烧基_基團，其中該等環炫基及烷基部分如本文所定義。例示性單環烷基烷基包括環丙基甲基、環戊基甲基、環己基甲基及環庚基曱基。該基團可為端基或橋基。若該基團為端基，則其經由烷基鍵結於分子之其餘部分。「環烷基烯基」意謂環烷基-烯基-基團，其中該等環烷基及烯基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由烯基鍵結於分子之其餘部分。「環烷基雜烷基」意謂環烷基_雜烷基_基團，其中該等環烷基及雜烷基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由雜烷基鍵結於分子之其餘部分。「環烷氧基」係指環烷基_〇_基團，其中環烷基如本文所定義。環烷氧基較佳為Cl_C6環烷氧基。實例包括（但不限於）環丙氧基及環丁氧基。該基團可為端基或橋基。若 152948.doc -46· 201136930 該基團為端基，則其經由氧原子鍵結於分子之其餘部分。 %烯氧基」係指環烯基基團，其中該環缚基如本文所定義q线氧基較佳為（:心環稀氧基。該基團可為端基或橋基。若該基團為端基’則其經由氧原子鍵結於^ 子之其餘部分。、77 「鹵烷基」係指如本文所定義之烷基，其中一或多個氫原子經選自由氟、a、溴及碘組成之群的鹵素原子置換。鹵烧基通常具有式CnH(2n+i m)Xm，其十各X係獨立地選自由F、C卜Br及I組成之群。在此類型之基團中’ n通常為工至10、更佳為1至6、最佳為u3em通常為丨至6、更佳為工至3。i烷基之實例包括氟甲基、二氟甲基及三氟甲基。「㈣基」係、指如本文敎義之烯基，《中—或多個氣原子經獨立地選自由F、α、〜及！組成之群的_素原子置換。「函快基」係指如本文所定義之炔基，纟中-或多個氫原子經獨立地選自由F、C1、B…組成之群㈣素原子置換。「i素」表示氯、氟、溴或碘。「雜烧基」係指鏈中較佳具有2至12個碳、更佳2至6布碳之直鏈或分支鏈院基，其中—❹個碳原子（及任何本關氫原子）各獨立地經選自卜…叹服之雜原子基㈣換，其中R，係選自由H、視情況經取代之Ci_Ci2烧基、福情況經取代之C3.C12環炫基、視情況經取代之芳遵及視情況經取代之Cl_Cl8雜芳基組成之群。例示性雜院遵 152948.doc •47· 201136930 包括烷基醚、二級及三級烷基胺、醯胺、烷基硫醚及其類似物。雜院基之實例亦包括羥基Cl-c6烷基、Ci-Cs烷氧基 cvc6烧基、胺基CrC6烷基、（^-(^烷基胺基c〗-c6烷基及二（C^-C：6烷基）胺基C”(：6烷基。該基團可為端基或橋基。「雜烷氧基J係指雜烷基-0_基團，其中雜烷基如本文所定義。雜烷氧基較佳為C2_C：6雜烷氧基。該基團可為端基或橋基。單獨或作為基團之一部分，「雜芳基」係指含有在芳環中具有一或多個雜原子作為環原子且其中其餘環原子為碳原子之芳環（較佳為5或6員芳環）的基團。適合之雜原子包括氮、氧及硫。雜芳基之實例包括噻吩、笨并噻吩、苯并吱喃、苯并咪唾、苯并噁唑、苯并噻唑、笨并異嗟唾、蔡幷[2,3-b]噻吩、呋喃、異吲哚嗪、二苯并哌喃、啡噁噻、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、噠嗪、丨，3 % = 氮烯、四唑、吲哚、異吲哚、1H-吲唑、笨并***、$ 呤、喹啉、異喹啉、酞嗪、喑啶、喹喏啉、啐啉、咔唑、啡啶、吖啶、啡嗪、噻唑、異噻唑、啡噻嗪、噁唑 '異噍唑、1，2,3-噁二唑、丨’2,4-噁二唑、1，2,3-***、三唑、1，2,4-噻二唑、噻二唑、呋咕、啡噁嗪、孓吡啶基、3-吡啶基或4-吡啶基、2_喹啉基、3-喹啉基、4_喹啉基、5-喹啉基或8-喹啉基、1-異喹啉基、3-異喹琳基、4 異啥琳基或5-異喹啉基、1·吲哚基、2-吲哚基或3_ι β朵基及2-噻吩基或3_噻吩基。雜芳基通常gCi_Cu雜芳基。該基團可為端基或橋基。 152948.doc •48· 201136930 雜芳基烷基」意謂雜芳基_烷基，其中該等雜芳基及烷基部分如本文所定義。較佳雜芳基烷基含有低碳烷基部刀。例不性雜芳基烷基包括吡啶基甲基。該基團可為端基或橋基。若該基團為端&，則其經由院基鍵結於分子之其餘部分。雜芳基烯基」意謂雜芳基.稀基基團，其中該等雜芳基及稀基部分如本文所定義。該基團可為端基或橋基。若 ”亥，團為端基’則其經㈣基鍵結於分子之其餘部分。雜芳基雜院基」意謂雜芳基-雜烧基-基團’其中該等雜=及雜烧基部分如本文所定義。該基團可為端基或橋基右》亥基團為端基，則其經由雜烧基鍵結於分子之部分。「雜芳氧基」係指雜芳基·0_基團，其中該雜芳基如本斤疋義雜芳氧基較佳為Ci_c】8雜芳氧基。該基團可為端基或橋基。若該基團為端基，則其經由氧原子鍵結於分子之其餘部分。「雜環」係指含有至少— 個選自由氮、硫及氧組成之群的雜原子作為環原子之飾^ 環、雙«多分不飽和或完全不飽和單環稀基及雜芳基。衣部分之實例包括雜環烧基、雜「雜環烯基」係扣‘ 士 ' θ 文所定義但含有至少一個雙鍵之雜％烷基。雜環烯基端基或橋基。為雜環烯基。該基團可為「雜環烷基」係指在社至J —個環中含有至少一個選自 152948.doc -49· 201136930 氮、硫、氧之雜原子、較佳〖至]個雜原子的飽和單環、雙環或多環。各環較佳為3至10員，更佳為4至7員。適合雜環烷基取代基之實例包括吡咯啶基、四氫呋喃基、四氫硫呋喃基、哌啶基、哌嗪基、四氫哌喃基、嗎啉基、13-二氮環庚烷、1，4-二氮環庚烷、i，4_氧氮環庚烷及丨，4_氧硫環庚烷。雜環烷基通常為C：2_C〗2雜環烷基。該基團可為端基或橋基。「雜環烷基烧基」係指雜環烷基-烷基_基團，其中該等雜環烷基及烷基部分如本文所定義。例示性雜環烷基烷基包括（2-四氫呋喃基）甲基、（2·四氫硫呋喃基）甲基。該基團可為端基或橋基。若該基團為端基，則其經由烷基鍵結於分子之其餘部分。「雜環烷基烯基」係指雜環烷基_烯基-基團，其中該等雜環烷基及烯基部分如本文所定義。該基團可為端基或橋基。若該基團為端基’則其經由烯基鍵結於分子之其餘部分。「雜環烷基雜烷基」意謂雜環烷基_雜烷基_基團，其中該等雜環烷基及雜烷基部分如本文所定義。該基團可為端基或橋基。若該基團為端基，則其經由雜烷基鍵結於分子之其餘部分。「雜環烷氧基」係指雜環烷基_〇_基團，其中該雜環烷基如本文所定義。雜環烷氧基較佳為Cl-C6雜環烷氧基。該基團可為端基或橋基。若該基圈為端基，則其經由氧原子鍵結於分子之其餘部分。 152948.doc •50· 201136930 雜％稀氧基」係指雜環烯基_G基團，其巾雜環稀基如本文所定義^雜環埽氧基較佳^_C6雜環稀氧基。該基團可為端基或橋基。若該基團為端基’則其經由氧原子鍵結於分子之其餘部分。羥基院基」係指如本文所定義之统基，其中一或多個氫原子經OH基團置換。經基烧基通常具有式叫_)剛。在此類型之基團+，n通常為佳為⑴、最‘ 為1至3。；^通常為1至6、更佳為丨至3。除非另外指定，否則作為基團，「低碳院基」意謂可為鏈中具有1至6個碳原子、更佳丨至4個碳原子之直鏈或分支鏈的脂族烴基，例如甲基、乙基、丙基(正丙基或異丙基) 或丁基（正丁基、異丁基或第三丁基）。該基團可為端基或橋基。亞續醯基」意謂R-S(=〇)-基團，其中r基團可為如本文所定義之OH、烷基、環烷基、雜環烷基；芳基或雜芳基。該基團可為端基或橋基。若該基團為端基，則其經由硫原子鍵結於分子之其餘部分。「亞磺酿基胺基」意謂R-S(=0)-NH-基團，其中R基團可為如本文所定義之OH、烷基、環烷基、雜環烷基；芳基或雜芳基。該基團可為端基或橋基。若該基團為端基，則其經由氮原子鍵結於分子之其餘部分。「磺酿基」意謂R-S(=0)2_基團，其中R基團可為如本文所定義之OH、烷基、環烷基、雜環烷基；芳基或雜芳基。該基團可為端基或橋基。若該基團為端基，則其經由 152948.doc • 51- 201136930 硫原子鍵結於分子之其餘部分。「磺醯基胺基」意謂R-S(=〇)2_NH-基團。該基團可為端基或橋基。若該基團為端基，則其經由氮原子鍵結於分子之其餘部分。應瞭解式（I)化合物豕族中包括包含非對映異構體、對映異構體、互變異構體及呈「Ej或ΓΖ」構型異構體或£與 ζ異構體之混合物的幾何異構體之異構形式。亦應瞭解諸如非對映異構體、對映異構體及幾何異構體之一些異構形式可由熟習此項技術者藉由物理及/或化學方法分離。所揭示之實施例的一些化合物可以單一立體異構體、外消旋體及/或對映異構體及/或非對映異構體之混合物形式存在。所有該等單一立體異構體、外消旋體及其混合物均欲在所述及所主張之標的物範疇内。另外，若適當，則式（I)意欲涵蓋該等化合物之溶劑化以及未溶劑化形S。因此，各4包括具有所指示結構之化合物’包括水合以及非水合形式。術語「醫藥學上可接受之鹽」係、指保留上文所鑑定之化合物的所需生物活性之鹽，且包括醫藥學上可接受之酸加成鹽及鹼加成鹽。式⑴化合物之適合醫藥學上可接受之酸加成鹽可由無機酸或由有機酸製備。該等無機酸之實例為鹽酸、硫酸及鱗酸。適當有機酸可選自有機酸之脂族、環脂族、芳族、雜環幾酸及績酸類，其實例為甲酸、乙酸、丙酸、丁二酸、乙醇酸、葡萄糖酸、乳酸、蘋果酸、酒石酸、檸檬酸、反丁烯二酸、順丁烯二酸、烷基磺酸、芳基 152948.doc -52· 201136930 磺酸。關於醫藥學上可接受之鹽的其他資訊可見於 Remington's Pharmaceutical Sciences,第 19版，Mack Publishing Co.，Easton, PA 1995中。在固體藥劑情況下，熟習此項技術者應理解本發明化合物、試劑及鹽可以不同結晶或多晶形式存在，其全部均意欲在本發明及指定各式之範疇内。「前藥」意謂在生物系統内，通常藉由代謝方法（例如藉由水解、還原或氧化）經歷轉化為式（I)化合物之化合物。舉例而言，含有經基之式（I)化合物的i旨前藥可藉由活體内水解而轉化為母分子。含有羥基之式（I)化合物的適合酯為例如乙酸酯、檸檬酸酯、乳酸酯、酒石酸酯、丙二酸酯、草酸酯、水楊酸酯、丙酸酯、丁二酸酯、反丁烯二酸酯、順丁烯二酸酯、亞甲基-雙-β-羥基萘酸酯、龍膽酸酯、羥乙磺酸酯、二-對曱苯醯基酒石酸酯、曱烷磺酸酯、乙烷磺酸酯、苯磺酸酯、對甲苯磺酸酯、環己基胺基磺酸酯及奎尼酸酯（quinate)。作為另一實例，含有羧基之式（I)化合物的酯前藥可藉由水解活體内轉化為母分子。 (酉旨前藥之實例為 F.J. Leinweber，Drug Metab. Res.，1 8:379, 1987所述之彼等前藥）。類似地，含有羥基之式（I)化合物的醯基前藥可藉由活體内水解而轉化為母分子。（用於此等及其他功能組之前藥的許多實例（包括胺）描述於 Prodrugs: Challenges and Rewards (Parts 1 and 2); V. Stella, R· Borchardt, M. Hageman，R· Oliyai, H· Maag及 J Tilley編；Springer，2007 中）。術語「氧之保護基」意謂可防止氧部分在受保護化合物 152948.doc •53· 201136930 之進一步衍生期間反應且需要時可容易移除的基團。在一實施例中，該保護基在生理狀態下可藉由天然代謝過程移除且實質上受保護化合物充當用於活性未受保護之物質的前藥。氧之保護基之實例包括醯基（諸如乙醯基）、醚（諸如甲氧基曱鱗（MOM)、Β-曱氧基乙氧基曱喊（ΜΕΜ)、對曱氧基苯甲醚（ΡΜΒ)、甲硫基甲醚、特戊醢基（piv)、四氫哌喃 (THP))及石夕院基謎（諸如三曱基石夕烧基（tms)、第三丁基二甲基石夕烧基（TBDMS)及三異丙基石夕院基（tips)。術語「氮之保護基」意謂可防止氮部分在受保護化合物之進一步衍生期間反應且需要時可容易移除的基團。在一實施例中’該保護基在生理狀態下可藉由天然代謝過程移除且實質上受保護化合物充當用於活性未受保護之物質的前藥。可使用之適合氮之保護基的實例包括甲醯基、三苯甲基、鄰苯二醯亞胺基乙醯基、三氣乙醯基、氣乙醯基、漠乙酿基、壤乙醯基；胺基甲酸酯型封端基團，諸如笨甲氧幾基（『CBz』）、4-苯基苯曱氧叛基、2-曱基苯曱氧幾基、4-曱氧基苯甲氧羰基、4·氟苯甲氧羰基、4-氣笨甲氧羰基、3-氣苯甲氧羰基、2-氣苯曱氧羰基、2,4-二氣笨甲氧羰基、4-溴苯甲氧羰基、3-溴苯甲氧羰基、4-硝基笨甲氧羰基、4-氰基苯甲氧羰基、第三丁氧羰基（『tBoc』）、 2-(4-聯苯基）-異丙氧羰基、1，1-二苯基乙-1-基氧幾基、 1，1-二苯基丙-1-基氧羰基、2-苯基丙-2-基氧羰基、2·(對甲苯甲醯基）-丙-2-基氧羰基、環戊氧羰基、1-甲基環戊氧罗炭基、環己氧羰基、1-甲基環己氧羰基、2-曱基環己氧羊炭 152948.doc • 54· 201136930 基、2-(4-甲笨甲醯基磺醯基）_乙氧羰基、2_(甲基磺醯基）乙乳幾基' 2-(三苯基膦）·乙氧羰基、苐基$氧羰基 (「FMOC」）、2_(三曱基矽烷基）乙氧羰基、烯丙氧羰基、 1_(三甲基矽烷基甲基）丙_卜乙氧羰基、5_苯并異噁唑曱氧碳基、4-乙酿氧基苯曱氧羰基、2,2,2•三氯乙氧羰基' 2_乙快基-2-丙氧羰基、環丙基甲氧羰基、4_(癸氧基）苯甲氧羰基、異冰片基氧羰基、1 ·哌啶基氧羰基及其類似基團；苯甲醯基曱基磺醯基、2-硝基苯基次磺醯基、二苯基膦氧化物及其類似物。所用之實際氮保護基並不關鍵，只要所衍生之氮基團在隨後反應條件下穩定且可按需要選擇性移除而不實質上破壞分子之其餘部分（包括任何其他氮保護基）即可。此等基團之其他實例見於以下文獻中：Greene, τ. W.及 Wuts，Ρ· G. Μ.，Protective Groups in Organic Synthesis,Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, N〇2, NH2 and CN. Alternatively, two optionally present substituents on the same moiety may be joined together to form a fused cyclic substituent attached to the optionally substituted moiety. Thus, the term optionally substituted includes fused rings such as cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings. In the definition of many substituents below, it is stated that "the group may be an end group or a bridging group". This intention is intended to mean that the term is intended to cover the case where the group is a linking group between two other moieties of the molecule and that it is an end portion. The use of the term alkyl is exemplified. 'Some publications will use the term "extension base" for a bridging group and thus, in these other publications, the terms 'alkyl' (end group) and "extension base" (bridge base) There is a difference between them. This distinction is not mentioned in the slaughter of the present application and most of the groups may be bridging or terminal groups. "Amidino" means an R-C(=0)- group in which the R group can be a succinyl group, a ring-based group, a heterocyclic alkyl group, an aryl group or a heteroaryl group as defined herein. Examples of brewing bases include ethyl and styrene. This group can be an end group or a bridging group. If the group is terminal & 152948.doc -40- 201136930, then 纟 is bonded to the rest of the molecule via a few base carbons. "Hydrazolylamino" means an r_C(=〇)_nh_ group, wherein the genomic group may be as defined herein; a thiol group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group It can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. As a group or a part of a group, "alkenyl" means having at least one carbon-carbon double bond and may preferably have 2 to 12 carbon atoms in the positive chain of 'better 2_H) carbon atoms, preferably 2·. A linear or branched aliphatic hydrocarbon group of 6 carbon atoms. The group may have a plurality of double bonds in the normal chain and the orientation of each bond is independently Ε or an exemplary dilute group including, but not limited to, vinyl, propylene butenyl, pentenyl, and Alkenyl, heptenyl, octenyl and decenyl. This group can be an end group or a bridging group. "Alkenyloxy" means an alkenyl group wherein alkenyl is as defined herein. Preferably, the alkenyloxy group is Cl_c6;)#-based oxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom. Unless otherwise noted, "alkyl" refers to a straight or branched aliphatic hydrocarbon group, preferably a cyanoalkyl group, more preferably a Ci-Cio alkyl group, as part of a group or a group. Examples of the alkyl-based Ci-Ce-based substituent include a methyl group, a group, a n-butyl group, a second butyl group, a third butyl group, and the group may be a terminal group or a bridging group. Base, n-propyl, 2-propylhexyl and the like. Unless otherwise specified, "amino" "monoalkylaminoalkylamino" includes monoalkylamino and dialkyl means -NH- group 'where alkyl is as defined above in 152948.doc • 41- 201136930. "Dialkylamino" means an alkyl hN- group in which each fluorenyl group may be the same or different and each is as defined herein with respect to an alkyl group. The alkyl group is preferably a .--alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. "Institutional amine carbonyl" means the formula (Alkyl) x (H) yNC (= a group of 0)-, wherein the alkyl group is as defined herein, and the sum of χ+γ = 2. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded via a carbonyl carbon. The remainder of the molecule. "Alkoxy" means an alkyl-hydrazone group wherein alkyl is as defined herein. S-saltoxy is preferably a c rC6 alkoxy. Examples include (but are not limited to) Alkoxy and ethoxy. The group may be a terminal group or a bridging group. "Alkoxy group" means an alkoxy-alkyl group, wherein the alkoxy group and the alkyl moiety are as herein As defined, the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an alkyl group. "Alkoxyaryl" means an alkoxy-aryl group. a group of alkoxy groups And an aryl moiety is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an aryl group. "Alkoxycarbonyl" means an alkyl group. a group of _〇_(:(=〇)_, wherein alkyl is as defined herein. The alkyl group is preferably oxime, -alkyl. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a carbonyl carbon. "Alkoxycycloalkyl" means an alkoxy-cycloalkyl group. a group wherein the alkoxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remaining 152948 of the molecule via a cycloalkyl group. .doc • 42- 201136930 part. "Alkoxyheteroaryl" is a (tetra)oxy.heteroaryl group wherein the decyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group. Or bridge. 纟. If the group is a terminal group, it is bonded to the rest of the molecule via a (iv) group. "Alkoxyheterocycloalkyl" means an alkoxy-heterocycloalkyl- group, Wherein the alkoxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heterocycloalkyl group. "Alkylsulfinyl" means an alkyl group S_(= 〇)- group wherein alkyl is as defined herein. Preferably, the alkyl group is an alkyl group exemplified alkyl sulfinic acid/fluorenyl group. (but not limited to) methylsulfinyl and ethylsulfinyl. The group may be a terminal or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a sulfur atom. "Alkylsulfonyl" means an alkyl group -S(=0)2. group wherein alkyl is as defined above. The alkyl group is preferably fluorene alkyl. Examples include (but are not limited to) Methylsulfonyl and ethylsulfonyl. This group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a sulfur atom. 'As a group or a part of a group, "alkynyl" means having one carbon-, carbon-bonded and preferably having from 2 to 12 carbon atoms, more preferably from 2 to 10 carbon atoms in the normal chain, More preferably, the linear or branched aliphatic hydrocarbon group of 2 to 6 carbon atoms. Exemplary structures include, but are not limited to, ethynyl and propynyl. This group can be an end group or a bridging group. "Alkynyloxy" means an alkynyl-fluorene group wherein the alkynyl group is as defined herein 152948.doc -43·201136930. Preferably, the alkynyloxy group is a Cl_c6 fast oxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. Aminoalkyl" means an NH;j-alkyl- group wherein the alkyl group is as defined herein. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a burn group. The amine-based sulfhydryl group J means an NH2_S(=0)2· group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a sulfur atom. As a group or a part of a group, "aryl" means (1) a monocyclic or fused polycyclic aromatic carbocyclic ring (optional ring structure having a ring atom of carbon) which is optionally substituted. It has 5 to 12 atoms. Examples of the aryl group include a phenyl group, a naphthyl group and the like; (ii) a partially saturated bicyclic aromatic carbocyclic moiety which is optionally substituted, wherein the phenyl group and the C5·7 cycloalkyl group or the cycloalkenyl group are thick. Together, they form a cyclic structure such as tetrahydronaphthyl 'fluorenyl or indanyl. This group can be an end group or a bridging group. The aryl group is usually a C6_Ci8 aryl group. "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenyl allyl groups. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkenyl group. "Arylalkyl" means an aryl-homo-based group wherein the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain an alkyl moiety. Exemplary aralkyl groups include benzyl, phenethyl, 丨-naphthylmethyl and 2-naphthylmethyl. The group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a 152948.doc 201136930. "Arylalkoxy" means an aryl-alkyl-0- group wherein the alkyl and aryl are as defined herein. This group can be an end group or a bridging group. If the group is a sulfhydryl group, it is bonded to the remainder of the molecule via an oxygen atom. Unless otherwise specified, "arylamino" includes monoarylamine and diarylamine. A monoarylamine group means a group of the formula aryl NH- wherein aryl is as defined herein. The diarylamine group means a group of the formula (aryl) wherein each aryl group may be the same or different and each is as defined herein for an aryl group. The group may be a terminal group or a bridging group. The group is bonded to the remainder of the molecule via an atomic atom. The arylheteroalkyl group means an aryl-heteroalkyl- group, wherein the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, then the (four) pure group is bonded to the rest of the molecule. "Aryloxy" means an aryl group, wherein the aryl group is as defined herein Preferably, the aryloxy group is Ce-C, 8 aryloxy group, more preferably c6_CiQ aryloxy group. The group may be a terminal group or a bridging group 4, wherein the group is a silk, and then it is bonded to the molecule via an oxygen atom. The remainder of the phrase "arylsulfonyl" means an aryl-S(=〇)2. group, wherein the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the (d) is The terminal group is bonded to the rest of the molecule via a sulfur atom. A "bond" is a bond between a compound or each atom in a molecule. The bond can be a single bond, a double bond, or a bond. "Cycloalkenyl" A non-tetracyclic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Exemplary monocyclic ring 152948.doc • 45- 201136930 Alkenyl ring including cyclopentane Alkenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituents. The cycloalkenyl group is typically a C3_Ci2 alkenyl group. The group may be a terminal group or a bridging group. Unless otherwise specified, Otherwise "cycloalkyl" means a saturated monocyclic or fused or spiro polycyclic carbocyclic ring, preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group includes a monocyclic system such as a cyclopropyl group and a cyclohexyl group, a bicyclic system such as decalin, and a system such as adamantane. The cycloalkyl group is usually a Cs-C! 2 alkyl group. It may be a terminal group or a bridging group. "A ring-based alkyl group" means a ring-based group and a alkyl group, wherein the cyclohexyl and alkyl moieties are as defined herein. Exemplary monocyclic alkylalkyl groups include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cycloheptyl fluorenyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is via The alkyl group is bonded to the rest of the molecule. "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group wherein the cycloalkyl and alkenyl moieties are as defined herein. a group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an alkenyl group. "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group, wherein The cycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heteroalkyl group. "A" refers to a cycloalkyl-hydrazine group wherein cycloalkyl is as defined herein. The cycloalkoxy group is preferably a Cl_C6 cycloalkoxy group. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. "N-alkenyloxy" means a cycloalkenyl group, wherein the cyclol group is preferably a q-oxy group as defined herein (: a cardinyloxy group. The group may be a terminal group or a bridging group. The group is a terminal group' which is bonded to the rest of the moiety via an oxygen atom. 77 "Haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms are selected from the group consisting of fluorine, a, The halogen atom of the group consisting of bromine and iodine is substituted. The halogen group usually has the formula CnH(2n+im)Xm, and each of the X groups is independently selected from the group consisting of F, Cb, and I. The group 'n is usually from 10 to 10, more preferably from 1 to 6, most preferably u3em is usually from 丨 to 6, more preferably from work to 3. Examples of the alkyl group include fluoromethyl, difluoromethyl and Fluoromethyl. "(4)", refers to an alkenyl group as defined herein, "middle- or multiple gas atoms are replaced by a group of atoms independently selected from the group consisting of F, α, ~, and !" "A" refers to an alkynyl group, as defined herein, wherein - or a plurality of hydrogen atoms are independently replaced by a group of (tetra) atoms consisting of F, C1, B, ... "i" means chlorine, fluorine, bromine or iodine "Hybrid" means a straight or branched chain of a chain preferably having from 2 to 12 carbons, more preferably from 2 to 6 carbons, wherein - one carbon atom (and any associated hydrogen atom) is independent The ground is selected from the hetero atomic group (4), which is selected from the group of sighs, where R is selected from the C.C12 ring group substituted by H, as the case may be substituted, and the C3.C12 ring leunt group substituted by the case. And a group of substituted Cl_Cl8 heteroaryl groups as appropriate. Exemplary miscellaneous s 152948.doc • 47· 201136930 includes alkyl ethers, secondary and tertiary alkylamines, decylamines, alkyl sulfides and the like Examples of the compound base include hydroxyCl-c6 alkyl, Ci-Cs alkoxy cvc6 alkyl, amine CrC6 alkyl, (^-(^alkylamino c-c6 alkyl and two ( C^-C: 6 alkyl)amino C" (: 6 alkyl. The group may be a terminal group or a bridging group. "Heteroalkoxy J means a heteroalkyl-0- group in which a heteroalkyl group The heteroalkoxy group is preferably a C2_C: 6 heteroalkoxy group. The group may be a terminal group or a bridging group. Separately or as part of a group, "heteroaryl" means containing Have one or more in the ring A group in which an atom is a ring atom and the remaining ring atoms are an aromatic ring of a carbon atom (preferably a 5- or 6-membered aromatic ring). Suitable hetero atoms include nitrogen, oxygen and sulfur. Examples of heteroaryl groups include thiophene and stupid. And thiophene, benzopyrene, benzopyrene, benzoxazole, benzothiazole, stupid and scorpion saliva, Cai 幷 [2,3-b] thiophene, furan, isooxazine, dibenzopyrazine Orphan, morphine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, hydrazine, 3%, nitrone, tetrazole, hydrazine, isoindole, 1H-carbazole, stupid triazole , 呤, quinoline, isoquinoline, pyridazine, acridine, quinoxaline, porphyrin, oxazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole Oxazole, 1,2,3-oxadiazole, 丨'2,4-oxadiazole, 1,2,3-triazole, triazole, 1,2,4-thiadiazole, thiadiazole, furazan , phenoxazine, indole pyridyl, 3-pyridyl or 4-pyridyl, 2-quinolinyl, 3-quinolyl, 4-quinolinyl, 5-quinolinyl or 8-quinolinyl, 1 -isoquinolyl, 3-isoquinolinyl, 4 isoindolyl or 5-isoquinolinyl, 1 fluorenyl, 2-indenyl or 3_ι β 2-thienyl group and a thienyl group or 3_. The heteroaryl group is usually a gCi_Cu heteroaryl group. This group can be an end group or a bridging group. 152948.doc •48·201136930 Heteroarylalkyl” means a heteroaryl-alkyl group wherein the heteroaryl and alkyl moieties are as defined herein. Preferably, the heteroarylalkyl group contains a lower alkyl moiety. Exemplary non-heteroarylalkyl groups include pyridylmethyl. This group can be an end group or a bridging group. If the group is terminal &, it is bonded to the remainder of the molecule via the nodal group. "Heteroarylalkenyl" means a heteroaryl.thenyl group wherein the heteroaryl and dilute moieties are as defined herein. This group can be an end group or a bridging group. If "Hai, the group is a terminal group", its (4) group is bonded to the rest of the molecule. "Heteroaryl" means "heteroaryl-heteroalkyl-group" where the impurity = and miscellaneous The base moiety is as defined herein. The group may be a terminal group or a bridge group. The group is a terminal group, and then it is bonded to a part of the molecule via a miscellaneous group. The "heteroaryloxy group" means a heteroaryl group - 0- group, and the heteroaryl group such as the quinone heteroaryloxy group is preferably a Ci_c]8 heteroaryloxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom. "Heterocyclic" means a heterocyclic ring containing at least one selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom, a double «polyunsaturated or fully unsaturated monocyclic and heteroaryl group. Examples of the clothes portion include a heterocycloalkyl group, a heterocycloalkylene group, and a hetero-alkyl group which is defined by the sth' θ θ but contains at least one double bond. Heterocyclenyl end group or bridging group. Is a heterocyclenyl group. The group may be "heterocycloalkyl" means at least one hetero atom selected from the group consisting of 152948.doc -49·201136930 nitrogen, sulfur, oxygen, preferably to a hetero atom. Saturated monocyclic, bicyclic or polycyclic. Each ring is preferably from 3 to 10 members, more preferably from 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 13-diazacycloheptane, 1 , 4-diazacycloheptane, i, 4-oxocycloheptane and anthracene, 4-oxothioheptane. The heterocycloalkyl group is usually C: 2_C 2 heterocycloalkyl. This group can be an end group or a bridging group. "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group wherein the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuranyl)methyl and (2. tetrahydrothiofuranyl)methyl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkyl group. "Heterocycloalkylalkenyl" means a heterocycloalkyl-alkenyl- group wherein the heterocycloalkyl and alkenyl moieties are as defined herein. This group can be an end group or a bridging group. If the group is a terminal group', it is bonded to the remainder of the molecule via an alkenyl group. "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group wherein the heterocycloalkyl and heteroalkyl moieties are as defined herein. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heteroalkyl group. "Heterocycloalkoxy" means a heterocycloalkyl-indenyl group, wherein the heterocycloalkyl is as defined herein. The heterocycloalkoxy group is preferably a Cl-C6 heterocycloalkoxy group. This group can be an end group or a bridging group. If the base ring is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. 152948.doc • 50·201136930 Hetero-l-oxyloxy” means a heterocycloalkenyl-G group, the heterocyclic ring of which is defined herein as a heterocyclic oxime group, preferably a ^_C6 heterocyclic oxy group. This group can be an end group or a bridging group. If the group is a terminal group', it is bonded to the rest of the molecule via an oxygen atom. "Hydroxyl" means a radical as defined herein, wherein one or more hydrogen atoms are replaced by an OH group. The base group usually has the formula _) just. In this type of group +, n is usually preferably (1) and most is '1 to 3. ;^ is usually from 1 to 6, more preferably from 丨 to 3. Unless otherwise specified, as a group, "low carbon yard" means an aliphatic hydrocarbon group which may be a straight or branched chain having from 1 to 6 carbon atoms, more preferably from 4 to 4 carbon atoms in the chain, such as Base, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tert-butyl). This group can be an end group or a bridging group. "Alkyl" means an R-S(=〇)- group, wherein the r group can be OH, alkyl, cycloalkyl, heterocycloalkyl, as defined herein; aryl or heteroaryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a sulfur atom. "Sulphonylamino" means an RS(=0)-NH- group, wherein the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl as defined herein; aryl or hetero Aryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. "Sulphonyl" means an R-S(=0)2- group wherein the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl, as defined herein; aryl or heteroaryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a 152948.doc • 51-201136930 sulfur atom. "Sulfonylamino" means an R-S(=〇)2_NH- group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. It is to be understood that the steroids of the formula (I) include diastereomers, enantiomers, tautomers and mixtures of the "Ej or ΓΖ" configuration or the oxime isomers. Heterogeneous forms of geometric isomers. It will also be appreciated that some isomeric forms such as diastereomers, enantiomers and geometric isomers may be separated by physical and/or chemical methods by those skilled in the art. Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or as mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter recited. Further, if appropriate, formula (I) is intended to cover the solvation of the compounds and the unsolvated form S. Thus, each 4 includes a compound' having the indicated structure' including both hydrated and non-hydrated forms. The term "pharmaceutically acceptable salts", refers to salts which retain the desired biological activity of the compounds identified above, and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acids for the compounds of formula (1) Addition salts can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid and scaly acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, heterocyclic and acid acids of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, apples. Acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, aryl 152948.doc -52·201136930 sulfonic acid. Additional information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of solid pharmaceuticals, it will be understood by those skilled in the art that the compounds, reagents and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formula. "Prodrug" means a compound that undergoes conversion to a compound of formula (I), usually by metabolic means (e.g., by hydrolysis, reduction or oxidation), within a biological system. For example, a prodrug containing a compound of formula (I) can be converted to a parent molecule by in vivo hydrolysis. Suitable esters of the compound of formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates , fumarate, maleate, methylene-bis-β-hydroxynaphthalate, gentisate, isethionate, di-p-quinone-based tartrate, hydrazine Alkane sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate, and quinate. As another example, an ester prodrug of a compound of formula (I) containing a carboxyl group can be converted to a parent molecule by hydrolysis in vivo. (Examples of prodrugs are F.J. Leinweber, Drug Metab. Res., 1 8:379, 1987, their prodrugs). Similarly, a sulfhydryl prodrug of a compound of formula (I) containing a hydroxy group can be converted to a parent molecule by in vivo hydrolysis. (Many examples of prodrugs used in these and other functional groups (including amines) are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007). The term "protecting group for oxygen" means a group which prevents the oxygen moiety from reacting during further derivatization of the protected compound 152948.doc •53·201136930 and which can be easily removed as needed. In one embodiment, the protecting group is removed under physiological conditions by a natural metabolic process and the substantially protected compound acts as a prodrug for the active unprotected material. Examples of the protecting group for oxygen include a mercapto group (such as an ethylidene group), an ether (such as methoxy fluorene scale (MOM), anthracene-methoxy ethoxy oxime (ΜΕΜ), p-methoxy anisole ( ΡΜΒ), methylthiomethyl ether, pentyl (piv), tetrahydropyran (THP)) and the stone burial mystery (such as triterpene (tms), t-butyl dimethyl Teddy base (TBDMS) and triisopropyl sylvestris. The term "nitrogen protecting group" means a group which prevents the nitrogen moiety from reacting during further derivatization of the protected compound and which can be easily removed when needed. In one embodiment, the protecting group is removed under physiological conditions by a natural metabolic process and the substantially protected compound acts as a prodrug for the unprotected substance. A suitable nitrogen protecting group can be used. Examples include mercapto, trityl, phthalimidoethylamino, triethylene sulfonyl, acetophenone, sulphate, sulphate; urethane type Blocking groups, such as stupid methoxy group ("CBz"), 4-phenylbenzoquinone oxo, 2-mercaptobenzoxanyl, 4-decyl benzoyl Carbonyl, 4·fluorobenzyloxycarbonyl, 4-acetomethoxycarbonyl, 3-oxobenzyloxycarbonyl, 2-p-benzophenoxycarbonyl, 2,4-dioxamethyloxycarbonyl, 4-bromobenzyl Oxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitro-p-methoxycarbonyl, 4-cyanobenzyloxycarbonyl, tert-butoxycarbonyl ("tBoc"), 2-(4-biphenyl)- Isopropyloxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylpropan-1-yloxycarbonyl, 2-phenylpropan-2-yloxycarbonyl, 2· (p-tolylmethyl)-propan-2-yloxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclopentoxycarbyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2-indenyl Cyclohexyloxyl charcoal 152948.doc • 54· 201136930 base, 2-(4-methyl carbaryl sulfonyl) ethoxycarbonyl, 2-(methylsulfonyl) ethoxylate ' 2- (three Phenylphosphine) · ethoxycarbonyl, fluorenyl oxycarbonyl ("FMOC"), 2 - (trimethyl decyl) ethoxycarbonyl, allyloxycarbonyl, 1 - (trimethyldecylmethyl) propyl Ethoxycarbonyl, 5-benzoxazole, oxacarbonyl, 4-ethyloxybenzoquinoneoxycarbonyl, 2,2,2•trichloroethoxycarbonyl '2-ethylidene-2-propoxycarbonyl Cyclopropyl Methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1 ·piperidinyloxycarbonyl and the like; benzhydrylsulfonyl, 2-nitrobenzene The sulfenyl group, the diphenylphosphine oxide and the like. The actual nitrogen protecting group used is not critical as long as the nitrogen group derived is stable under subsequent reaction conditions and can be selectively removed as needed Substantially destroy the rest of the molecule (including any other nitrogen protecting groups). Other examples of such groups are found in: Greene, τ. W. and Wuts, Ρ·G. Μ., Protective Groups in Organic Synthesis,

Second edition; Wiley-Interscience: 1991;第 7章；McOmie J. F. W.(編），Protective Groups in Organic Chemistry， Plenum Press，1973 ;及 Kocienski，P. J.，pr〇tecting Groups, 第二版，Theime Medical Pub·，2000。術語「治療有效量」或「有效量」為足以實現有益或所需臨床結果之量。有效量可以一或多次投藥來投與。有效量通常足以減輕、改善、穩定、逆轉、減緩或延遲疾病狀態之進展。術語「功能等效物」意欲包括本文所述之指定蛋白激酶種類的變異體。應瞭解激酶可具有同功異型物，使得當特定激酶之一級、二級、三級或四級結構不同於原型激酶 152948.doc •55· 201136930 刀子維持作為蛋白激酶之生物活性。同功異型物可自群體中之正常對偶基因變異產生且包括諸如胺基酸取 ' 、失添加、截斷或重複之突變。術語「功能等效物」亦包括在轉録t , 包括改變轉澤後變異體。其他功能等效物士㈣後修都（例如酿基化）之激酶。發明之特定化合物包括以下：Second edition; Wiley-Interscience: 1991; Chapter 7; McOmie JFW (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, PJ, pr〇tecting Groups, Second Edition, Theime Medical Pub, 2000 . The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount can be administered by one or more administrations. The effective amount is usually sufficient to alleviate, improve, stabilize, reverse, slow or delay the progression of the disease state. The term "functional equivalent" is intended to include variants of the specified protein kinase species described herein. It will be appreciated that kinases may have isoforms such that when a particular kinase has a grade, secondary, tertiary or quaternary structure different from the prototype kinase 152948.doc • 55· 201136930 Knife maintains biological activity as a protein kinase. Isoforms can be produced from normal dual gene variations in a population and include mutations such as amino acid extraction, loss of addition, truncation or repetition. The term "functional equivalent" is also included in the transcription of t, including alteration of post-transformation variants. Other functional equivalents (4) Post-repair (eg, brewing) kinases. Specific compounds of the invention include the following:

ΝΗ-ΝΗ-

152948.doc •56· 201136930152948.doc •56· 201136930

152948.doc -57- 201136930152948.doc -57- 201136930

152948.doc •58- 201136930152948.doc •58- 201136930

NH-NH-

或其醫藥學上可接受之鹽或前藥。該等化合物具有抑制某些蛋白激激酶活性之能力可為化合物直接且„。之活性的能力。抑讳抑制生物學活性之”…接且早獨作用於激酶分子 °果，，應瞭解該等化合物亦可3 八1作用於磷酸化過程所涉及之所討論激酶的輔因子。 /化0物可具有針對某些絲胺酸/蘇胺酸激酶（諸如mTOR 或其片段或複合物或功能等效物之活性。蛋白激酶之抑制可以許多此項技術令熟知之方式中之任 152948.doc • 59- 201136930 者進行。舉例而s ’若需要蛋白激酶之活體外抑制，則可將適當量之化合物添加至含有該激酶之溶液中。在需要在哺乳動物中抑制激酶活性之情況下，激酶之抑制通常包括向含有激酶之哺乳動物投與化合物〃因此，化合物可具有多種應用’其中可利用其抑制上述類型蛋白激酶之能力。舉例而言’化合物可用於抑制絲胺酸/棘胺酸蛋白激酶。化合物亦可用於治療或預防哺乳動物之病狀，其中蛋白激酶及/或其輔因子之抑制可預防、抑制或改善該病狀之病理或症狀。預期本發明之化合物將適用於治療各種與⑺了⑽激酶有關之病狀，包括選自由以下組成之群的病狀：炎症、類風濕性關節炎、牛皮癖、動脈粥樣硬化、結腸炎、發炎性腸病、騰腺炎、多發性硬化症、自體免疫病症、狼瘡、過敏性腦脊髓炎、移植排斥反應、子宮内膜異位症、平滑肌瘤、多囊性卵巢症候群、錯構瘤、結節性硬化症、阿茲海默氏病、亨廷頓氏病、帕金森氏病、冑島素依賴性糖尿病、肥胖、糖尿病性視網膜病、心臟肥大、自體顯性多性腎病》 ” 預期本發明之化合物將適用於治療各種癌症，包括（但不限於）骨癌、腦及CNS腫瘤、乳癌、結腸直腸癌、内分泌癌（包括腎上腺皮質癌）、胰臟癌、垂體癌、甲狀腺癌、副曱狀腺癌、胸腺癌、腸胃癌、肝癌、肝外膽管癌、腸胃類癌腫瘤、膽囊癌、生殖泌尿癌、婦科癌症、頭頸部癌、白血病、骨髓瘤、血液學病症、肺癌、淋巴瘤、眼癌、皮膚 152948.doc -60- 201136930 癌、軟組織肉瘤'成人軟組織肉瘤、卡波希氏肉瘤、泌尿糸統癌症。可由本發明之化合物治療的例示性癌症包括血液癌症， =如骨髓增生性病症（特發性骨髓纖維化、真性紅血球增多症、原發性血小板增多症、慢性骨髓白血病）、骨髓細胞化生、慢性骨髓單核細胞性白血病、急性淋巴細胞白血病、急性紅血球母細胞白金病、霍奇金氏及非霍奇金氏病、b細胞淋巴瘤、急性τ細胞白血病、骨趙發育不良徵候群、漿細胞病症、毛細胞白血病、卡波希氏肉瘤、淋巴瘤；婦科癌症，諸如乳癌、印巢癌、子宮頸癌、***癌及外陰癌、子宮内膜增生；胃腸道癌，諸如結腸直腸癌、息肉、肝癌、胃癌、騰臟癌、膽囊癌；泌尿道癌，諸如前列腺癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌，諸如黑色素瘤；腦腫瘤，諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經頭頸部 ;諸如鼻因癌、喉癌；呼吸道癌，諸如肺癌 SCLC)、fa’皮瘤；眼病’諸如視網膜胚細胞瘤；肌肉骨骼 ;；諸如月肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。 s物亦可用於製備治療動物病狀之藥劑，其中蛋白激 ,之抑制可預防、抑制或改善該病狀之病理或症狀。化合物亦可用於製備用於治療或預防激酶相關病症之藥劑。向人類投與式（1)化合物可藉由任何可接受之經腸投藥模 J52948.doc -61 - 201136930 式（例如口服或經直腸），或藉由非經腸投藥（諸如皮下、肌肉内、靜脈内及皮内途徑）進行。注射可為大丸劑或經由持續或間歇輸注。活性化合物通常包括於醫藥學上可接受之载劑或稀釋劑中且其量足以向患者傳遞治療有效劑量Γ 在各種實施例中，與正常細胞相比，抑制劑化合物可對例如癌腫瘤之快速增殖細胞具有選擇性毒性或毒性更大。在使用化合物時，其可呈使得化合物具有生物可利用性之任何形式或模式投與。熟習製備調配物技術者可視所選化合物之特定特徵、待治療病狀、待治療病狀之階段及其他相關情況，而容易選擇適當投藥形式及模式 ^者參考RemingtonsPh随似—㈤咖，㈣版， CkPubhshingCo. (1995)以獲得進一步資1。 :合物可單獨投與或呈與醫藥學上可接受之載劑、稀釋劑或賦形劑組合之醫藥組合物形式投與。雖然化合物本身 =效阳但其通常呈其醫藥學上可接受之鹽形式調配及投 :度因為此等形式通常更穩定、更容易結晶且具有更高溶然而’化合物通常呈視所需投藥模式而調配之醫藥組合物形式使用。因此在一些實施例中， ’、合物及醫藥學上可接受之載種包括式⑴化 #釋劑或賦形劑之醫藥組。物。该專組合物以此項技術中熟知之技術製備。在其他實施例中，本發明教示提供一種藥物包裝或套組’其包含一或多個埴^右__々令考太或多種醫藥組合物成分之容益。在該包裝或套組中可存在在具有早位劑量之藥劑的容 152948.doc •62· 201136930 器。該等套組可包括包含呈濃縮物形式之有效藥劑的組合物（包括凍乾組合物），可在使用之前經進一步稀釋，或其可呈使用濃度提供’其中小瓶可包括-或多個劑量。便利起見，在該等套組中，可由無菌小瓶提供單—劑量，以使得醫師可直接利用該等小瓶，其中小瓶將具有所需量及濃度之藥劑。諸如使用說明書或管理藥物或生物產品之製造、使用或銷售的政府機構所規定之形式的注意事項之各種書面材料可伴隨該（等）容器提供，該注意事項反映該機構批准用於人類投藥之製造、使用或銷售。化合物可與一或多種治療所提及病症/疾病之其他藥物組合使用或投與。組分可呈同-調配物或呈各別調配物形式投與。若呈各別調配物投與，則化合物可與其他藥物相繼或同時投與。除旎夠與-或多種其他藥物組合投與外，化合物亦可用於組合療法令。當如此進行時，化合物通常彼此組合投 :二此，一或多種化合物可同時(以組合製劑形式)或相 =·-、，以達成所需作用。當各化合物之料型態不同需要如此，以使得該兩種藥物之組合作用提供改非經腸注射之本發明的醫藥組合物包含醫荜學上可接受之無菌水性或非水性溶液、醫樂子上τ ^ ^ 刀政液、懸洋液或乳液，乂及…函籾末，以在臨使用之八拾你Λ. Λ j復原為無函可注射溶液或 ^ 載劑、稀釋劑、溶劑或媒劑之貫例包括水、乙醇、多元 (潘如甘油、丙二醇、聚乙 152948.doc -63- 201136930 二醇及其類似物)及其合適混合物、植物油(諸如撖欖油)及可注射之有機酯（諸如油酸乙酯）。適當流動性可例如藉由使用諸如卵磷脂之塗佈物質來維持，若為分散液時貝;藉由維持所需粒度來維持，及藉由使用界面活性劑來維持。曰此等組合物亦可含有諸如防腐劑、濕潤劑、乳化劑及分散劑之佐劑。可藉由包括各種抗細菌劑及抗真菌劑（例如對經基苯甲酸醋、氯丁醇、苯齡、山梨酸及其類似物)來預防微生物作用。亦可能需要包括等張劑，諸如糖類、氣化鈉及其類似物。可注射醫藥形式可藉由包括諸如單硬脂酸紹及明膠之延遲吸收劑來延長吸收。若需要，且為了更有效分佈’則可將化合物併入諸如聚合物基質、脂質體及微球體之緩慢釋放或靶向傳遞系統中。可注射調配物可例如藉由經由細菌保持過濾器過濾來滅菌或藉由在臨使用之前以可溶解或分散於無菌水或其他無菌可注射介質中之無菌固體組合物形式合併滅菌劑來滅菌。用於經口投藥之固體劑型包括膠囊、錠劑、藥丸、散劑及顆粒。在該等固體劑型中’活性化合物與至少一種惰性、醫藥學上可接受之賦形劑或載劑（諸如檸檬酸鈉或磷酸氫二鈣）及/或以下物質混合：…填充劑或增量劑，例如殿粉、乳糖、蔬糖、葡萄糖、甘露醇及石夕酸；b)黏合劑，例如羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯β比咯啶酮、蔗糖及***膠；C)保濕劑，例如甘油；d)崩解劑，例如 152948.doc -64 - 201136930 瓊月曰、碳酸鈣、馬鈐薯或木 . 粉、褐藻酸、某些矽酸鹽及妷酸鈉，e)溶液阻滯劑列如石蠟；f)吸收促進劑，例如四級錢化合物；g)済們 ’例如鯨蠟醇及單硬脂酸甘油酉曰，Η)吸附劑，例如高嶺土及门土，及1)潤滑劑，例如滑石粉、硬脂酸鈣' 硬脂酸 ^ 固體聚乙二醇、月桂基硫酸鈉及其混合物。在膠查、於杰丨隹膠囊叙劑及藥丸之情況下，劑型亦可包含緩衝劑。類似類型之固體组人榀介π m 、。々亦可用作軟填充及硬填充明膠膠囊中之填充劑，兮' 堂D3§ °等膠囊使用諸如乳糖（lactose/milk 叫〇之賦形劑以及高分子量聚乙二醇及其類似物。 0匕衣及外双（諸如腸溶衣及醫藥調配技術熟知之其他包衣)製備錠劑、糖衣藥丸、膠囊、藥丸及顆粒之固體劑型。其可視情況含有遮光劑且亦可為視情況以延遲方式僅僅或優選在腸道某―邱人越、、你师、呆4分釋放活性成分之組合物。可使用之包埋、组合物的實_包括聚合#質及蠟。適田時，活性化合物亦可與—或多種上述賦形劑呈微囊封形式❶ 用於絰口投藥之液體劑型包括醫藥學上可接受之乳液、溶液、懸浮液、糖衆及醜劑。除活性化合物外，液體劑型可含有此項技術中常用之惰性稀㈣，例如水或其他溶劑、助溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酉旨、乙酸乙酯、苯曱醇' 苯曱酸苯曱酯、丙二醇、丨，3-丁二醇、二曱基甲酿胺、油類（尤其棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油）、甘油、四氫糠醇、聚 152948.doc -65- 201136930 乙二醇及脫水山梨糖醇之脂肪酸酯及其混合物。除了惰性稀釋劑，口服組合物亦可包括助劑，諸如濕、間劑、乳化劑及懸浮劑、甜味劑、調味劑及加香劑。除活性化合物外’懸浮液亦可含有懸浮劑，例如乙氧其化異硬脂醯基醇、聚氧乙烯山梨糖醇及山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃蓍膠及其混合物0 用於直腸或***投藥之組合物較佳為栓劑，其可藉由將本發明之化合物與適合非刺激性賦形劑或載劑（諸如可可油、聚乙二醇或栓蠟）混合來製備，該等賦形劑或載劑在室溫下為固態，但在體溫下為液態，且因此在直腸或*** 腔中融化並釋放活性化合物。用於本發明之化合物局部投藥之劑型包括散劑、貼片、喷霧、軟膏及吸入劑。活性化合物在無菌條件下與醫藥學上可接受之載劑及任何所需防腐劑、緩衝液或可能需要之推進劑混合。化合物之投藥量較佳將治療及降低或減緩病狀。治療有效量可由主治診斷者使用習知技術及觀察在類似情況下獲得之結果容易地確定。在確定治療有效量中，應考慮許多因素包括（但不限於）動物物種、其大小、年齡及總體健康晴况所涉及之指定病狀、病狀嚴重程度、患者對治療之反應所投與之特定化合物、投藥模式、所投與之製劑生物可用性、所選給藥方案、使用其他藥劑及其他相關情況。 152948.doc •66- 201136930 較佳劑量將為每天每公斤體重約0.01 mg至300 mg之範圍。更佳劑篁將為每天每公斤體重〇.1 mg至100 mg、更佳每天每公斤體重0.2 mg至80 mg、更佳每天每公斤體重0.2 mg至50 mg之範圍。每天可以多次子劑量投與適合劑量。合成本發明之化合物各種實施例之藥劑可使用如下文所述之反應途徑及合成流程’使用此項技術中可獲得之技術，使用容易獲得之起始物質來製備。實施例之特定化合物的製備係在以下實例中詳細描述，但技術者將認識到所述化學反應可容易地適合於製備各種實施例之許多其他藥劑。舉例而言，非例示性化合物之合成可藉由熟習此項技術者顯而易見之改變而成功進行’例如藉由適當保護干擾基團、藉由變為此項技術中已知之其他適合試劑或藉由對反應條件進行常規修改。有機合成中之一系列適合保護基可見於T w GreeneisOr a pharmaceutically acceptable salt or prodrug thereof. The ability of such compounds to inhibit the activity of certain protein kinases can be a direct and singular activity of the compound. The inhibition of biological activity by sputum inhibition and the early action of kinase molecules should be understood. The compound may also act as a cofactor for the kinase in question involved in the phosphorylation process. /Chemicals may have activity against certain serine/threonine kinases, such as mTOR or fragments or complexes or functional equivalents thereof. The inhibition of protein kinases may be in the manner well known in the art. 152948.doc • 59-201136930. For example, if an in vitro inhibition of protein kinase is required, an appropriate amount of the compound can be added to the solution containing the kinase. Inhibition of kinase activity in mammals is required. Inhibition of kinases typically involves the administration of a compound to a mammal containing a kinase. Thus, a compound can have a variety of applications where it can be used to inhibit the ability of a protein kinase of the above type. For example, a compound can be used to inhibit serine/thorn Amino acid protein kinase. The compound can also be used to treat or prevent a condition in a mammal, wherein inhibition of the protein kinase and/or its cofactor can prevent, inhibit or ameliorate the pathology or symptoms of the condition. It is expected that the compound of the present invention will be applied. For treating various conditions associated with (7) (10) kinase, including a condition selected from the group consisting of inflammation, rheumatoid Tube inflammation, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, adrenitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis Symptoms, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, 胄-dependent diabetes, obesity, diabetic retinopathy , cardiac hypertrophy, autologous dominant polynephrosis"" The compounds of the invention are expected to be suitable for the treatment of various cancers including, but not limited to, bone cancer, brain and CNS tumors, breast cancer, colorectal cancer, endocrine cancer (including the adrenal gland) Cortical cancer), pancreatic cancer, pituitary cancer, thyroid cancer, accessory squamous adenocarcinoma, thymic carcinoma, intestinal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal cancer, gallbladder cancer, genitourinary cancer, gynecological cancer, head and neck Cancer, leukemia, myeloma, hematological disease, lung cancer, lymphoma, eye cancer, skin 152948.doc -60- 201136930 Cancer, soft tissue sarcoma 'adult soft tissue sarcoma, Kaposi's meat Tumor, urinary tract cancer. Exemplary cancers that can be treated by the compounds of the invention include hematological cancers, such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia) ), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell blastin, Hodgkin's and non-Hodgkin's disease, b-cell lymphoma, acute tau cell leukemia, bone Zhao dysplasia syndrome, plasma cell disease, hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, Indian cancer, cervical cancer, vaginal cancer and vulvar cancer, endometrial hyperplasia; gastrointestinal tract Cancer, such as colorectal cancer, polyp, liver cancer, stomach cancer, smear cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer, such as melanoma; brain tumor , such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brain stem glioma, nerve Germ cell tumor, meningioma, astrocytoma, oligodendrocyte head and neck; such as nasal cancer, laryngeal cancer; respiratory cancer, such as lung cancer SCLC), fa's skin tumor; eye disease 'such as retinoblastoma; musculoskeletal; Such as sarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. The s substance can also be used for the preparation of an agent for treating an animal condition, wherein protein inhibition inhibits, inhibits or ameliorates the pathology or symptoms of the condition. The compounds are also useful in the preparation of a medicament for the treatment or prevention of a kinase-related disorder. Administration of a compound of formula (1) to humans can be by any acceptable enteral dosage form (e.g., oral or rectal), or by parenteral administration (such as subcutaneous, intramuscular, Intravenous and intradermal routes). The injection can be a bolus or via continuous or intermittent infusion. The active compound will usually be included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound can be rapidly associated with, for example, a cancerous tumor as compared to normal cells. Proliferating cells are more selective or more toxic. When a compound is used, it can be administered in any form or mode that renders the compound bioavailable. Those skilled in the art of formulating preparations may select the appropriate dosage form and mode according to the specific characteristics of the selected compound, the condition to be treated, the stage of the condition to be treated, and other related conditions. For reference, refer to RemingtonsPh-like (5) coffee, (4) version , CkPubhshingCo. (1995) to obtain further funding1. The compound can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. Although the compound itself = yang, it is usually formulated and administered in the form of its pharmaceutically acceptable salt: because these forms are generally more stable, easier to crystallize and have a higher solubility, however, the compounds are usually in the desired mode of administration. It is used in the form of a formulated pharmaceutical composition. Thus, in some embodiments, the ', and the pharmaceutically acceptable carrier comprises a pharmaceutical group of formula (1) #释剂 or excipient. Things. This proprietary composition is prepared by techniques well known in the art. In other embodiments, the present teachings provide a pharmaceutical package or kit that includes one or more of the benefits of a pharmaceutical composition or ingredients. In the package or kit, there may be a volume of 152948.doc • 62·201136930 with a dose of the early dose. The kits can include compositions (including lyophilized compositions) comprising an effective pharmaceutical agent in the form of a concentrate, which can be further diluted prior to use, or can be provided in a concentration of use wherein the vial can include - or multiple doses . Conveniently, in such kits, a single dose can be provided from a sterile vial to allow the physician to directly utilize the vials, wherein the vials will have the desired amount and concentration of the medicament. Various written materials such as instructions for use or precautions in the form prescribed by government agencies that regulate the manufacture, use or sale of drugs or biological products may be provided with the container, which reflects the approval of the institution for human administration. Manufacture, use or sale. The compound can be used or administered in combination with one or more other drugs that treat the mentioned condition/disease. The components may be administered in the same formulation or in the form of separate formulations. If administered in separate formulations, the compound can be administered sequentially or simultaneously with other drugs. In addition to being administered in combination with - or a combination of other drugs, the compounds may also be used in combination therapy. When so carried out, the compounds are usually administered in combination with each other: Alternatively, one or more of the compounds may be simultaneously (in the form of a combined formulation) or phase = -, to achieve the desired effect. When the material form of each compound is different, such that the combination of the two drugs provides a pharmaceutical composition of the present invention which is modified by parenteral injection comprising a medically acceptable sterile aqueous or non-aqueous solution, medical music. On τ ^ ^ Knife Liquid, Suspension Liquid or Emulsion, 乂 and ... 籾 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Examples of vehicles include water, ethanol, poly (pan such as glycerol, propylene glycol, polyethyl 152948.doc-63-201136930 diols and the like) and suitable mixtures thereof, vegetable oils (such as eucalyptus oil) and injectables. Organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, in the case of a dispersion, by maintenance of the desired particle size, and by the use of a surfactant.曰 These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Microbial action can be prevented by including various antibacterial and antifungal agents (e.g., benzoic acid vinegar, chlorobutanol, benzoate, sorbic acid, and the like). It may also be desirable to include an isotonic agent such as a sugar, sodium vaporate, and the like. Injectable pharmaceutical forms can be extended by the inclusion of delayed absorbents such as monostearate and gelatin. If desired, and for more efficient distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by combining the sterilizing agents in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use. Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms the 'active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dibasic calcium phosphate) and/or the following: filler or increment Agents such as powder, lactose, vegetable sugar, glucose, mannitol, and aspartic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyethylene beta-pyrrolidone, sucrose, and gum arabic ; C) humectant, such as glycerin; d) disintegrant, for example, 152948.doc -64 - 201136930 Qiongyue, calcium carbonate, horse yam or wood. Powder, alginic acid, certain citrate and sodium citrate , e) solution blockers such as paraffin; f) absorption enhancers, such as quaternary compounds; g) ' 'such as cetyl alcohol and glyceryl monostearate, Η) adsorbents, such as kaolin and doors Soil, and 1) lubricants such as talc, calcium stearate 'stearic acid ^ solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of gelatine, Yujie 隹 capsules and pills, the dosage form may also contain a buffer. A similar type of solid group is referred to as π m . 々 can also be used as a filler in soft-filled and hard-filled gelatin capsules, such as lactose (lactose/milk sputum excipients and high molecular weight polyethylene glycols and the like). 0 匕及及 ( ( ( ( ( ( ( ( ( ( ( ( ( ( 固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体固体The delayed method is only or preferably in the intestines, a combination of Qiu Renyue, You Shi, and 4 minutes to release the active ingredient. The embedding can be used, and the composition of the composition includes the polymerization #质和蜡. The active compound may also be in microencapsulated form with or a plurality of the above-mentioned excipients. Liquid dosage forms for mouthwash administration include pharmaceutically acceptable emulsions, solutions, suspensions, sugars and ugly agents. The liquid dosage form may contain inert dilute (4) commonly used in the art, such as water or other solvents, co-solvents and emulsifiers, such as ethanol, isopropanol, ethylene carbonate, ethyl acetate, benzoquinone benzene benzoate Oxime ester, C Glycol, hydrazine, 3-butanediol, dimercaptoamine, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly 152948 .doc -65- 201136930 Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetters, lotions, emulsifiers and suspending agents, sweetness Agents, flavoring agents and flavoring agents. In addition to the active compounds, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose. , aluminum partial aluminum hydroxide, bentonite, agar and tragacanth and mixtures thereof. 0 The composition for rectal or vaginal administration is preferably a suppository, which can be prepared by combining the compound of the present invention with a non-irritating excipient or carrier. Prepared by mixing, such as cocoa butter, polyethylene glycol or wax, which is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and Release of the active compound. For use in the present invention Dosage forms for topical administration of the compounds include powders, patches, sprays, ointments and inhalants. The active compounds are mixed under sterile conditions withpharmaceutically acceptable carriers and any required preservatives, buffers or propellants which may be required. Preferably, the amount of the compound administered will treat and reduce or slow the condition. The therapeutically effective amount can be readily determined by the attending diagnostician using known techniques and observing the results obtained under similar circumstances. In determining the therapeutically effective amount, many should be considered. Factors include, but are not limited to, the species of the animal, its size, age, and the overall condition involved in the health of the condition, the severity of the condition, the specific compound to which the patient responds to the treatment, the mode of administration, and the mode of administration. Bioavailability of the formulation, selected dosing regimen, use of other agents, and other relevant conditions. 152948.doc •66- 201136930 The preferred dose will range from about 0.01 mg to 300 mg per kilogram of body weight per day. The preferred agent will be from 1 mg to 100 mg per kilogram of body weight per day, more preferably from 0.2 mg to 80 mg per kilogram of body weight per day, and more preferably from 0.2 mg to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day. Synthesis of Compounds of the Invention The agents of the various embodiments can be prepared using the reaction routes and synthetic procedures described below using techniques readily available in the art using readily available starting materials. The preparation of specific compounds of the examples is described in detail in the following examples, but the skilled artisan will recognize that the chemical reactions can be readily adapted to the preparation of many other agents of various embodiments. For example, the synthesis of a non-exemplified compound can be successfully carried out by modifications apparent to those skilled in the art, for example, by appropriate protection of the interfering group, by becoming other suitable reagents known in the art or by The reaction conditions were routinely modified. One of the organic synthesis suitable for protecting groups can be found in Tw Greeneis

Protective Groups，〇rganic Synthesis,第 3版，John Wiley & Sons，1991中。或者’本文所揭示或此項技術中已知之其他反應將視為適用於製備各種實施例之其他化合物。適用於合成化合物之試劑可根據此項技術中已知之技術獲得或製備。通用合成流程各種—取代之嘌呤可以簡單明瞭的三步驟程序，以2,6_ 二氯嗓呤作為起始物質來製備，該2,6-二氯㈣購自許多來源或可由嘌呤_2,6-二酮或黃嘌呤自身，使用例如磷醯氯 (Indian Journal 〇f Chemistry, ^B: Organic Chemistry 152948.doc •67- 201136930Protective Groups, 〇rganic Synthesis, 3rd edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of the various embodiments. Suitable reagents for the synthesis of the compounds can be obtained or prepared according to techniques known in the art. General Synthetic Process Various - Substituted 嘌呤 can be prepared in a straightforward three-step procedure using 2,6-dichloropurine as a starting material. The 2,6-dichloro(tetra) is purchased from many sources or can be obtained from 嘌呤_2,6 - Diketone or Astragalus itself, using, for example, phosphonium chloride (Indian Journal 〇f Chemistry, ^B: Organic Chemistry 152948.doc •67- 201136930

Including Medicinal Chemistry·, 23; 12; 1984; 1286-1288)^ 備。通用代表性程序展示於流程1中。流程1Including Medicinal Chemistry·, 23; 12; 1984; 1286-1288). A generic representative procedure is shown in Flow 1. Process 1

如圖所示，具有烷基鹵化物之2,6_二氣嘌呤的初反應主要在9位置產生烷基化2〇〇1， 20(4-7)，1067)。在典型程序中，醇可在膦及活化劑（諸如偶氮二甲酸二乙酯）存在下與2,6·二氣嘌呤反應。或者，烷基鹵化物可在適合之鹼（諸如碳酸鉀）存在下與起始嘌呤反應’以實現類似烷基化ά Me 山.cz.wa/ CTzewzjir;; 2004, 14(11)，2955)。隨後2與適合之芳基自朋酸或酯進行鈀催化之偶合，接著產生中間物 1995, 36, 1 1, 1945, Collect. Czech. Chem. Commun. 2002 67, 325)。8·氧雜-3-氮雜-雙環[3.2.1]辛烷之添加 Process Research & Development 2010， 14, 459)可接著在高溫下或使用微波輻射，在適合之溶劑（諸如DMA、 152948.doc -68 - 201136930 NMP、DMF或THF)中進行，產生所需三取代之嘌呤。流程2As shown, the initial reaction of 2,6-dioxane with an alkyl halide produces alkylation at the 9 position, 2〇〇1, 20(4-7), 1067). In a typical procedure, the alcohol can be reacted with 2,6·dione in the presence of a phosphine and an activator such as diethyl azodicarboxylate. Alternatively, the alkyl halide can be reacted with the starting oxime in the presence of a suitable base such as potassium carbonate to achieve a similar alkylation. Me Mountain.cz.wa/ CTzewzjir;; 2004, 14(11), 2955) . Subsequent palladium catalyzed coupling with a suitable aryl-p-acid or ester followed by the production of an intermediate 1995, 36, 1 1, 1945, Collect. Czech. Chem. Commun. 2002 67, 325). Addition of oxa-3-aza-bicyclo[3.2.1]octane Process Research & Development 2010, 14, 459) can then be carried out at elevated temperatures or using microwave radiation in suitable solvents (such as DMA, 152948) .doc -68 - 201136930 NMP, DMF or THF) is carried out to produce the desired trisubstituted enthalpy. Process 2

R1取代基可藉由使用8-經取代之二氣嘌呤作為起始物質 (流程1)改變或可在合成順序稍遲引入（流程2)。舉例而言’可在完成以上流程1中所說明之順序後，在8位置上進行化學反應。舉例而言，4之8位置可經溴化以產生5。溴化物可接著經例如有機金屬藥劑（諸如有機鋅）置換以如6中安裝R1。流程3描述三步驟程序中之三個變化，其中第一步驟中 152948.doc -69- 201136930 使用不同條件以在嘌呤骨架之9位置引入不同取代基。然而’原則上’熟練受定址者可修改流程1中所示之通用反應流程，其中嘌呤之9位置的氮部分可與反應物中含有適合離去基（諸如_化物）之部分反應’由此氮置換離去基，形成9位置之氮接著經該部分官能化之化合物。適合用於此類型反應中且可在該等反應中經氮置換之離去基為此項技術所已知且一般含有用於此等類型反應中之此類型離去基之部分的合成亦為此領域之熟練工人所熟知❶如流程3 中所示，得到本發明之化合物的三個最簡單途徑涉及二氯嗓吟與芳烧基_化物（諸如苯甲基函化物）或雜芳基烧基鹵化物（以在9位置引入經芳基或雜芳基取代之甲基”醇（以在9位置引入二取代之曱基）或芳基或雜芳基§明酸（以直接引入芳基或雜芳基）反應。 152948.doc •70· 201136930 流程3 jrSrN^ CI^N^N ΗThe R1 substituent can be changed by using 8-substituted dihalogen as a starting material (Scheme 1) or can be introduced later in the synthesis sequence (Scheme 2). For example, a chemical reaction can be performed at 8 positions after the sequence described in the above Scheme 1 is completed. For example, the 4-8 position can be brominated to produce 5. The bromide can then be replaced by, for example, an organometallic agent such as organozinc to mount R1 as in 6. Scheme 3 describes three variations in the three-step procedure in which the first step 152948.doc -69-201136930 uses different conditions to introduce different substituents at the 9 position of the anthracene skeleton. However, the 'principle' skilled attainment can modify the general reaction scheme shown in Scheme 1, in which the nitrogen portion of the 9-position of the ruthenium can react with a portion of the reactant containing a suitable leaving group (such as a _ compound). The nitrogen is displaced from the leaving group to form a nitrogen at the 9 position followed by a functionalized compound. Derivatives suitable for use in this type of reaction and which may be replaced by nitrogen in such reactions are those known in the art and which generally contain a portion of this type of leaving group for use in such types of reactions. As is well known to those skilled in the art, as shown in Scheme 3, the three simplest ways to obtain a compound of the invention involve dichloropurine with an aryl group (such as a benzyl group) or a heteroaryl group. a base halide (to introduce an aryl or heteroaryl substituted methyl" alcohol at the 9 position (to introduce a disubstituted fluorenyl group at the 9 position) or an aryl or heteroaryl § acid (to directly introduce an aryl group) Or heteroaryl) reaction. 152948.doc •70· 201136930 Process 3 jrSrN^ CI^N^N Η

在以下所述之實例中，除非另外指示，否則以下描述中所有溫度均以攝氏度為單位’且除非另外指示，否則所有份數及百分數均以重量計。各種起始物質及其域劑係蹲自諸如AldrichIn the examples described below, all temperatures in the following description are in degrees Celsius unless otherwise indicated and all parts and percentages are by weight unless otherwise indicated. Various starting materials and their domain agents are from, for example, Aldrich

Company或Lancaster Synthesis Ltd.之化學供應商，且除非另外指示，否則該等物質不經進一步純化即可使用。四氫吱口南（THF)及N，N-二f基甲醯胺（DMF)係以瓶構自The chemical supplier of Company or Lancaster Synthesis Ltd., and unless otherwise indicated, these materials can be used without further purification. Tetrahydrofuran (THF) and N,N-di-f-carboxamide (DMF) are constructed from a bottle

Aldrich且如接收到時使用。除非另外指示，否則所有溶劑均藉由使用此項技術中之標準方法來純化。以下所述之反應係在氮氣、备g ^ ^ 虱軋之正壓下或使用乾燥 152948.doc •71- 201136930 管，在周圍溫度下（除非另夕卜規定），在無水溶劑中進行，且反應燒瓶裝備有橡膠隔片以用於經由注射器引入受質及試劑。玻璃器具經烘箱乾燥及/或加熱乾燥。分析薄層層析係在玻璃底矽膠60 F 254板（E MerCk(0.25 mm))上進行且以適當溶劑比率（v/v)溶離。反應藉由TLC檢定且如藉由起始物質耗盡所判斷而終止。 TLC板藉由UV吸收或使用對大茴香醛喷霧試劑或磷鉬酸試劑（Aldrich Chemica卜20 wt%乙醇溶液）（其經熱活化）或藉由在碘室中染色來檢視。通常藉由用反應溶劑或萃取溶劑使反應體積加倍，接著使用25體積％萃取體積（除非另外指示）以所指示水性溶液洗滌來進行處理。經無水硫酸納乾燥產物溶液’隨後在旋轉蒸發器上減壓過濾並蒸發溶劑’且在真空中移除溶劑時注意。除非另外規定，否則急驟管柱層析[Still等人，J. Org. Chem.，43, 2923 (1978)]係使用E Merck級急驟矽膠（40-63 μιη)及約20:1至5〇:1之石夕膠：粗物質比率來進行。在所指示壓力下或在周圍壓力下進行氫解。在400 MHz下用Bruker儀記錄NMR光譜，且在1〇〇 MHz下記錄nC-NMR光譜。使用氯仿作為參考標準（7 27 ppm 及 77.00 ppm)或使用 CD3OD(3.4 及 4.8 ppm 及 49.3 ppm)，或適當時使用内部四曱基矽烷標準（〇.00 ppm)，以 CDC13溶液形式獲得NMR光譜（以ppm為單位報導）。視需要使用其他NMR溶劑。當報導峰值多樣性時，使用以下縮寫：s=單峰、雙重峰、t=三重峰、m=多重峰、br=寬、 152948.doc -72· 201136930 dd=雙二重峰、dt==三重峰之雙重峰。偶合常數（當給出時）以赫茲為單位報導。使用LC/MS以ESI或APCI獲得質譜。所有溶點均未校需要微波輻射之反應係在CEM Discover s-c/au反應器中進行。所有終產物之純度均大於90%(根據HPLC，在220 nm及 254 nm之波長下得到）。以下貫例意心說明所揭示之實施例且不應理解為對其限制。除以下所述之化合物外的其他化合物可使用以下所述之反應流程或其適當變化或修改來製備。通用程序二氣嘌呤烷基化Aldrich is used as received. All solvents were purified by standard methods in the art, unless otherwise indicated. The reaction described below is carried out under a positive pressure of nitrogen, g ^ ^ 虱 rolling or using a dry 152948.doc • 71- 201136930 tube, at ambient temperature (unless otherwise specified), in an anhydrous solvent, and The reaction flask was equipped with a rubber septum for introduction of the receptor and reagent via a syringe. The glassware is dried by oven and/or dried by heating. The analytical thin layer was carried out on a glass bottom silicone 60 F 254 plate (E MerCk (0.25 mm)) and dissolved at a suitable solvent ratio (v/v). The reaction is terminated by TLC and as judged by the depletion of the starting material. The TLC plate was examined by UV absorption or by using an anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemica 20 wt% ethanol solution) which was heat activated or by staining in an iodine chamber. The treatment volume is usually treated by doubling the reaction volume with a reaction solvent or an extraction solvent, followed by washing with the indicated aqueous solution using a 25% by volume extraction volume (unless otherwise indicated). The product solution was dried over anhydrous sodium sulfate, followed by filtration under reduced pressure on a rotary evaporator and evaporation of solvent and was taken care of. Unless otherwise specified, flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] uses E Merck grade sputum (40-63 μιη) and approximately 20:1 to 5 〇. :1 Shishi gum: The crude material ratio is carried out. Hydrogenolysis is carried out under the indicated pressure or at ambient pressure. NMR spectra were recorded on a Bruker instrument at 400 MHz and nC-NMR spectra were recorded at 1 〇〇 MHz. NMR spectra were obtained as CDC13 solutions using chloroform as a reference standard (7 27 ppm and 77.00 ppm) or using CD3OD (3.4 and 4.8 ppm and 49.3 ppm) or, if appropriate, internal tetradecyl decane standards (〇.00 ppm) (Reported in ppm). Use other NMR solvents as needed. When reporting peak diversity, the following abbreviations are used: s = singlet, doublet, t = triplet, m = multiplet, br = wide, 152948.doc -72 · 201136930 dd = doublet, dt == The double peak of the triplet. The coupling constant (when given) is reported in Hertz. Mass spectra were obtained using ESI or APCI using LC/MS. All melting points are unresolved The reaction requiring microwave irradiation is carried out in a CEM Discover s-c/au reactor. All final products were more than 90% pure (obtained at 220 nm and 254 nm according to HPLC). The following examples are intended to illustrate the disclosed embodiments and are not to be construed as limiting. Other compounds than the compounds described below can be prepared using the reaction schemes described below or their appropriate changes or modifications. General procedure

將2,6-二氣嘌呤（1當量）、醇（丨_3當量）及三苯基膦（丨·〗當量）溶解於適合之有機溶劑（例如THF)中至〇·ι_〇·2 Μ之激度。在室溫下經約30分鐘向此溶液中逐滴添加偶氮二羧酸二烷基酯（1-2當量）或等效偶合劑。在周圍至6〇t下攪拌反應混合物約12-24小時。藉由TLC及/或LC/MS監測轉化。接著用冰冷水使反應混合物驟冷。用諸如乙酸乙酯或二氯甲烷之有機溶劑萃取水層，得到粗產物。接著可在矽膠管柱 152948.doc -73- 201136930 上，使用適合之溶劑系統進行純化，得到iv-經取代嘌吟。鈴木偶合（Suzuki Coupling)2,6-dioxane (1 equivalent), alcohol (丨_3 equivalent), and triphenylphosphine (丨·〗) are dissolved in a suitable organic solvent (for example, THF) to 〇·ι_〇·2 The intensity of Μ. Dialkyl azodicarboxylate (1-2 equivalents) or an equivalent coupler was added dropwise to the solution at room temperature over about 30 minutes. The reaction mixture was stirred at around 6 Torr for about 12-24 hours. Transformation was monitored by TLC and/or LC/MS. The reaction mixture was then quenched with ice cold water. The aqueous layer is extracted with an organic solvent such as ethyl acetate or methylene chloride to give a crude material. Purification can then be carried out on a silicone column 152948.doc -73-201136930 using a suitable solvent system to give an iv-substituted oxime. Suzuki Coupling

Cl xV'〉Cl xV'〉

Cl人〆^ R, 將經取代之二氣嘌呤（1當量）、5_胺基吡嗪_2_蝴酸頻哪醇酯（1當量）及鈀（II)催化劑複合物（5·1〇 m〇1%)溶解於無過氧化物之有機溶劑（0·05·0·1 M)(諸如二噁烷、DME或 THF)中》在添加2 Μ碳酸鈉或碳酸鉀水溶液（4當量）後，使反應混合物脫氣且用氮氣淨化。接著在維持6〇_1〇〇t之油浴上攪拌此反應混合物1 _5小時。關於起始嘌呤之消失，藉由LC/MS監測轉化。使反應混合物冷卻至室溫並在減壓下移除溶劑。使殘餘物分配於乙酸乙酯與水之間，分離有機相且進-步用數份乙酸乙醋萃取水層。經硫酸鈉乾燥合 ::有機層且在真空下移除溶劑，產生5似_烷基. 不°令_6·基）“比嗪基胺。粗物f不經進—步純化即可進行下一階段。 8_氧雜-3·氮雜-雙環丨^"辛烷添加 152948.doc •74· 201136930Cl human 〆^ R, substituted digas (1 equivalent), 5-aminopyrazine-2-lemonic acid pinacol ester (1 equivalent) and palladium (II) catalyst complex (5·1〇 M〇1%) dissolved in a peroxide-free organic solvent (0·05·0·1 M) (such as dioxane, DME or THF) with the addition of 2 Μ sodium carbonate or potassium carbonate aqueous solution (4 equivalents) Thereafter, the reaction mixture was degassed and purged with nitrogen. The reaction mixture was then stirred for 1 to 5 hours on an oil bath maintained at 6 〇 1 Torr. Regarding the disappearance of the starting mash, the transformation was monitored by LC/MS. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous layer was extracted with several portions of ethyl acetate. Drying over sodium sulfate: organic layer and removing the solvent under vacuum, yielding 5 _alkyl groups. 不令 · ) ) “ 粗粗粗粗粗粗粗粗粗粗粗粗粗粗粗粗粗粗The next stage. 8_oxa-3·aza-bicyclic 丨^"octane addition 152948.doc •74· 201136930

在岔封小瓶中，使用微波輻射，在15〇18〇(>c下將含5_In the sealed vial, use microwave radiation at 5〇18〇(>c will contain 5_

3-氮雜-雙環[3.2.1]辛烷鹽酸鹽（5_1〇當量）及三乙胺（5_1()當量）之適合之極性微波活性溶劑（諸如Nmp、DMA或 DMF)(0.05-1 M)加熱20-40分鐘。關於產物形成，可藉由 LCMS監測轉化。藉由層析純化粗物質，得到所需三取代之°票吟。實例1，化合物6 合成2,6-二氣-9-(1-乙基·丙基）·9Η嘌呤Suitable polar microwave active solvents (such as Nmp, DMA or DMF) of 3-aza-bicyclo[3.2.1]octane hydrochloride (5_1 〇 equivalent) and triethylamine (5 +1 (eq) equivalent) (0.05-1 M) Heat for 20-40 minutes. Regarding product formation, the conversion can be monitored by LCMS. The crude material was purified by chromatography to give the desired tri-substituted. Example 1, Compound 6 Synthesis of 2,6-dioxa-9-(1-ethyl-propyl)·9Η嘌呤

將 2,6·二氯 °票呤（10.58 mm〇l，1 當量）、3_ 戊醇（15.87 mm〇l，1.5當量）及三苯基膦（15.87 mmol，1.5當量）溶解於 80 ml無水四氩呋喃中，在室溫下經3〇分鐘向其中逐滴添加偶氮二曱酸二異丙酯（1587 mm〇1 , 15當量）。在室溫下攪拌反應混合物24小時。藉由TLC或LC/MSg測轉化。將反應混合物傾倒於含有冰冷水之燒杯中。使用3份1〇〇 mi 152948.doc -75· 201136930 乙酸乙酯萃取水層，得到粗產物。在矽膠管柱（5_6〇%乙酸乙酯之石油醚溶液，梯度溶離）上純化此產物，產生所需化合物’產率為75%(2·4 g)。NMR CDC13 (ppm): 8.12 (s，1H); 4.46 (m，1H); 2.05 (m，4H); 0.96 (t，6H)。合成5-[2-氣-9-(1-乙基-丙基）·9η·嘌呤·6-基】-吡嗪-2-基胺2,6·Dichloro oxime (10.58 mm 〇l, 1 eq.), 3 pentanol (15.87 mm 〇l, 1.5 eq.) and triphenylphosphine (15.87 mmol, 1.5 eq.) were dissolved in 80 ml of anhydrous four. Diisopropyl azodicarboxylate (1587 mm 〇 1, 15 equivalents) was added dropwise thereto at room temperature over 3 minutes in argon. The reaction mixture was stirred at room temperature for 24 hours. Transformation was measured by TLC or LC/MSg. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was extracted with 3 portions of 1 〇〇 mi 152948.doc -75·201136930 ethyl acetate to give a crude product. This product was purified on a silica gel column (5-6 % ethyl acetate in petroleum ether, gradient elution) to yield the desired compound yield of 75% (2.4 g). NMR CDC13 (ppm): 8.12 (s, 1H); 4.46 (m, 1H); 2.05 (m, 4H); 0.96 (t, 6H). Synthesis of 5-[2-gas-9-(1-ethyl-propyl)·9η·嘌呤·6-yl]-pyrazin-2-ylamine

向2,6-二氯-9-(1-乙基-丙基）_9Η-嘌呤（1 mm〇1，i當量）、 5-胺基吡嗪-2-蝴酸頻哪醇酯（1 mm〇1，i當量）及^，-雙（二苯基膦基）二茂鐵氣化鈀（11)與二氣甲烷之複合物⑺i mmo卜10 mol%)於無過氧化物之二噁烷（2〇中的溶液中添加2 Μ碳酸納水溶液（4 mm。卜4#量）。使反應混合物接著在維持8〇t之油浴上攪拌此反應To 2,6-dichloro-9-(1-ethyl-propyl)_9Η-嘌呤 (1 mm〇1,i equivalent), 5-aminopyrazine-2-carboxate pinacol ester (1 mm 〇1,i equivalent) and ^,-bis(diphenylphosphino)ferrocene gasified palladium (11) complex with diqi methane (7) i mmo b 10 mol%) in peroxide-free dioxane (Add 2 Μ aqueous sodium carbonate solution (4 mm. Bu 4# amount) to the solution in 2 。. The reaction mixture was then stirred on an oil bath maintained at 8 Torr.

基胺。脫氣且用氮氣淨化》混合物3小時《關於化。使反鹿混会物；4Amine. Degas and purify the mixture with nitrogen for 3 hours. Make anti-deer mix; 4

152948.doc -76- 201136930152948.doc -76- 201136930

在密封小瓶中，使用微波輻射，在l65〇c下將含5_[2_氣_ 9-(1-乙基-丙基）-9H-嘌呤_6_基）比嗪_2_基胺（〇 163 mmol， 1當量）、8-氧雜-3-氮雜-雙環[3.2.1]辛烷鹽酸鹽（0.817 mmol ’ 5當量）及三乙胺（114 mm〇i，7當量）之3 mi NMP加熱25分鐘。使内含物冷卻至室溫且關於產物形成，藉由 LCMS監測轉化。25分鐘後，反應完成，有極少或無分解。藉由逆相HPLC純化粗物質，產生純度為98-99%之所需化合物（14%產率）。NMR DMSO-d6 (ppm): 9,17 (s， 1H), 9.00 (bs5 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.47-4.34 (m, 5H), 3.20-3.1 (m, 2H), 2.10-1.90 (m, 4H), 1.80 (m, 2H), 1.70 (m, 2H)，0.65 (t，6H)。m/z: 395.21 [MH+]。實例2，化合物10 合成4-(2,6-二氯-嘌呤-9_基）_哌啶甲酸第三丁酯In a sealed vial, using microwave irradiation, 5_[2_gas_9-(1-ethyl-propyl)-9H-indole-6-yl)pyrazine-2-amine is contained at 165 〇c ( 〇163 mmol, 1 equivalent), 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.817 mmol '5 equivalents) and triethylamine (114 mm〇i, 7 equivalents) 3 mi NMP was heated for 25 minutes. The contents were allowed to cool to room temperature and for product formation, the conversion was monitored by LCMS. After 25 minutes, the reaction was complete with little or no decomposition. The crude material was purified by reverse phase HPLC to give the desired compound (yield: 14%). NMR DMSO-d6 (ppm): 9,17 (s, 1H), 9.00 (bs5 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.47-4.34 (m, 5H), 3.20-3.1 ( m, 2H), 2.10-1.90 (m, 4H), 1.80 (m, 2H), 1.70 (m, 2H), 0.65 (t, 6H). m/z: 395.21 [MH+]. Example 2, Compound 10 Synthesis of tert-butyl 4-(2,6-dichloro-indol-9-yl)-piperidinecarboxylate

152948.doc 77- 201136930 將2，6-二氣嘌吟（2.0 mmol，1當量）、4-經基-娘咬-1-甲酸第三丁醋（1 ·3 mmol ’ 0_65當量）及三苯基膦（2.4 mmol， 1.2當量）溶解於16 ml無水四氫呋喃中，在室溫下經30分鐘向其中逐滴添加偶氮二甲酸二乙酯（2.2 mmol，1.1當量）。在60-70°C下攪拌反應混合物24小時。將反應混合物傾倒於含有冰冷水之燒杯中。使用3份25 ml乙酸乙酯萃取水層，得到粗產物。在矽膠管柱（20-50%乙酸乙酯之石油醚溶液，梯度溶離）上純化此產物，產生4-(2,6-二氣-嗓吟_9_ 基）-哌啶-1 -曱酸第三丁酯。合成4·【6-(5-胺基比嗓-2-基）-2-氣·嗓呤-9-基]-派贫-1-曱酸第三丁酯152948.doc 77- 201136930 2,6-dioxane (2.0 mmol, 1 equivalent), 4-carbyl-nitopic bite-1-carboxylic acid tert-butyl vinegar (1 ·3 mmol '0_65 equivalent) and triphenyl The phosphine (2.4 mmol, 1.2 eq.) was dissolved in 16 ml of anhydrous tetrahydrofuran, and diethyl azodicarboxylate (2.2 mmol, 1.1 eq.) was added dropwise at room temperature over 30 min. The reaction mixture was stirred at 60-70 ° C for 24 hours. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was extracted with 3 portions of 25 ml of ethyl acetate to give a crude material. This product was purified on a silica gel column (20-50% ethyl acetate in petroleum ether, gradient elution) to give 4-(2,6-di- s- -9 yl)-piperidine-1 - decanoic acid. Third butyl ester. Synthesis 4·[6-(5-Aminopyridin-2-yl)-2-azepine-9-yl]-Phenan-1-indole

向2,6-二氣冬⑴乙基.丙基）_9Η·嗓呤（〇83 _〇i，i當量）、5-胺基》比嗪·2·蝴酸頻哪醇醋（125 _〇丨，η當幻及 U’-雙（二苯基膦基）二茂鐵氯化_)與二氣甲燒之複合物 (8 mom ’ 0.07 mmol)於無過氧化物之二喔烧⑽甽中的溶液中添加2 M碳酸卸水溶液（2.49 _。卜3當量）。使反應混合物脫氣且用氛氣淨化。接著在維㈣t之油浴上搜掉 152948.doc •78- 201136930 此反應混合物3小時。關於起始嘌呤之消失，藉由lc/ms 監測轉化。使反應混合物冷卻至室溫並在減壓下移除溶劑。將殘餘物溶解於乙酸乙酯及水中。分離有機相且進一步用3份200 ml乙酸乙醋萃取水層。經硫酸鈉乾燥有機層且在真空下移除溶劑，產生4-[6·(5-胺基-吡嗪_2_基）·2氯嘌呤-9-基]-哌啶_丨_甲酸第三丁酯。藉由矽膠層析，使用乙酸乙酯之石油醚溶液來純化粗物質，得到所需產物合成4-[6-(5-胺基-吡嗪-2-基）_2_(8•氧雜_3氮雜雙環 [3.2.1】辛-3-基）-嗓呤-9-基】-痕咬-1·甲酸第三丁醋（1〇)To 2,6-dioxanthone (1)ethyl.propyl)_9Η·嗓呤(〇83 _〇i,i equivalent), 5-amino group,pyrazine·2·camate acid pinanol vinegar (125 〇丨, η当幻 and U'-bis(diphenylphosphino)ferrocene chlorination _) complex with two gas smoldering (8 mom ' 0.07 mmol) in a peroxide-free bismuth (10) 甽A 2 M aqueous solution of carbonic acid was added to the solution (2.49 _. Bu 3 equivalents). The reaction mixture was degassed and purged with an atmosphere. Then search for the 152948.doc •78- 201136930 oil bath on the oil bath for four hours. Regarding the disappearance of the initial enthalpy, the transformation was monitored by lc/ms. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and water. The organic phase was separated and the aqueous layer was further extracted with three portions of 200 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to yield 4-[6·(5-amino-pyrazine-2-yl)-2-chloroin-9-yl]-piperidine-indole-carboxylic acid Tributyl ester. The crude material was purified by silica gel chromatography using ethyl acetate petroleum ether to give the desired product 4-[6-(5-amino-pyrazin-2-yl)_2_(8•oxa~3 Azabicyclo[3.2.1]oct-3-yl)-purine-9-yl]-bite-1·carboxylic acid tert-butyl vinegar (1〇)

在150°C油浴上將含4-[6-(5-胺基-吡嗪_2_基）_2_氣__ 〇么 9-基]•哌啶-1-甲酸第三丁酯（〇.〇7 mm〇l，1當量）、8氧雜 3-氮雜-雙環[3.2.1]辛烷鹽酸鹽（〇.7〇 mm〇l，1〇當量）及=乙胺（0.35 mmol ’ 5當量）之2 ml DMA加熱12小時。使内含物冷卻至室溫且關於產物形成，藉由LCMS監測轉化。碎由逆相HPLC純化粗物質’產生所需產物（1.16 rngp iH NMr4-[6-(5-Amino-pyrazine-2-yl)_2_gas__〇9-yl]•piperidine-1-carboxylic acid tert-butyl ester was added to a 150 ° C oil bath ( 〇.〇7 mm〇l, 1 equivalent), 8-oxa-3-azino-bicyclo[3.2.1]octane hydrochloride (〇.7〇mm〇l, 1〇 equivalent) and =ethylamine (0.35 2 ml of DMA of mmol '5 equivalents) was heated for 12 hours. The contents were allowed to cool to room temperature and for product formation, the conversion was monitored by LCMS. Purification of the crude material by reverse phase HPLC produces the desired product (1.16 rngp iH NMr

MeOD (ppm): 9.30 (s，1H)，9.10 (s，1H)，8·15 (s，1H) 4 95 152948.doc -79- 201136930 (m，1H)，4.55-4.45 (m，4H)，4.30 (d，2H)，3.35-3.30 (m 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 (m 2H)，1.80-1.70 (m，2H)，1.52 (s，9H)。m/z: 508.27 [MH+]。實例3，化合物11 合成2,6-二氣-9-異丙基- 9H-嗓吟MeOD (ppm): 9.30 (s, 1H), 9.10 (s, 1H), 8·15 (s, 1H) 4 95 152948.doc -79- 201136930 (m, 1H), 4.55-4.45 (m, 4H) , 4.30 (d, 2H), 3.35-3.30 (m 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 (m 2H), 1.80-1.70 (m, 2H) , 1.52 (s, 9H). m/z: 508.27 [MH+]. Example 3, Compound 11 Synthesis of 2,6-dioxa-9-isopropyl-9H-indole

CICI

向溶解於40 mL DMSO中之2,6-二氣-9H-嘌呤（1.00 g， 5·29 mmol)溶液中添加2-碘丙烷（1.62 g，9 52 κπ〇3(ι.32 g，9·52 mmol)。在室溫下在氮氣氛圍中攪掉溶液1小時。用出0及乙酸乙酯稀釋反應混合物，分離有機層且用乙酸乙醋萃取水層兩次。藉由急驟管柱層析（矽膠，己烷/乙酸乙酯1:3)純化，得到呈白色固體狀之2,6_二氣-9-異丙基-9H-嗓吟（45%產率）。iH NMR CDCl3 (ppm): 8·17 (d，1H)，4·86-4.97 (七重峰，1h) 1 64 1 66 (山 6H)。 m/z: 231 [MH+] 合成5-(2-氣-9-異丙基-9H-嘌呤·6•基）_吡嗪·2_基胺Add 2-iodopropane (1.62 g, 9 52 κπ〇3 (ι.32 g, 9) to a solution of 2,6-diox-9H-indole (1.00 g, 5.29 mmol) dissolved in 40 mL of DMSO. • 52 mmol). The solution was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and ethyl acetate. The organic layer was separated and extracted twice with ethyl acetate. Purification by chromatography (EtOAc, EtOAc/EtOAc: EtOAc) Ppm): 8·17 (d, 1H), 4·86-4.97 (seven peaks, 1h) 1 64 1 66 (mountain 6H) m/z: 231 [MH+] Synthesis 5-(2-gas-9- Isopropyl-9H-嘌呤·6•yl)_pyrazine·2_ylamine

152948.doc -80- 201136930152948.doc -80- 201136930

向溶解於15 mL無水二噁烷中之2,6-二氣-9-異丙基·9Η-D票吟（0·50 g，2.16 mmol)溶液中添加5-胺基-賴酸頻哪醇酯 (〇·48 g，2.28 mmol)及1，1'-雙（二苯基膦基）二茂鐵氯化鈀 (II)與二氯甲烷之複合物（018 g，〇 22 mmol)。隨後將飽和 K2C03水溶液（〇_6〇 g，4.33 mmol)添加至溶液中。在9〇°C 下搜拌溶液4小時。冷卻後，蒸發溶劑且將反應混合物溶解於HsO及DCM中。分離有機層且用DCM萃取水相兩次。藉由急驟管柱層析（矽膠’ 2%曱醇之DCM溶液）純化，得到呈白色固體狀之5-(2-氯-9-異丙基-9H-嘌呤-6-基）-吡嗪-2-基胺（41。/❶產率）。NMR CDC13 (ppm): 9.48 (s，1H)，8.27 (d，1H), 8.21 (s，1H)，5.03 (s，2H)，4.94-5.03 (七重峰，1H)， 1.65-1.66 (d，6H)。m/z: 290 [MH+] 合成5-[9-異丙基-2-(8•氧雜-3-氮雜-雙環丨3.2.1】辛-3-基）-9H-嘌呤-6-基】比嗪·2-基胺（11)Add 5-amino-lysine to a solution of 2,6-dioxa-9-isopropyl·9Η-D 吟 (0.50 g, 2.16 mmol) dissolved in 15 mL of anhydrous dioxane. An alcohol ester (〇·48 g, 2.28 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride with dichloromethane (018 g, 〇22 mmol). A saturated aqueous solution of K2CO3 (〇_6〇 g, 4.33 mmol) was then added to the solution. The solution was mixed for 4 hours at 9 °C. After cooling, the solvent was evaporated and the reaction mixture was dissolved in HsO and DCM. The organic layer was separated and the aqueous phase was extracted twice with DCM. Purification by flash column chromatography (2% decyl alcohol in DCM) to give 5-(2-chloro-9-isopropyl-9H-purin-6-yl)-pyrazine as a white solid. 2-ylamine (41% / yield). NMR CDC13 (ppm): 9.48 (s, 1H), 8.27 (d, 1H), 8.21 (s, 1H), 5.03 (s, 2H), 4.94-5.03 (seven peak, 1H), 1.65-1.66 (d, 6H). m/z: 290 [MH+] Synthesis 5-[9-isopropyl-2-(8•oxa-3-aza-bicycloindole 3.2.1]oct-3-yl)-9H-indole-6- Bisylazine 2-ylamine (11)

向溶解於15 mL DMA中之5-(2-氯-9·異丙基-9Η-嘌呤·6_ 基）-0比嗪-2-基胺（0.46 g，1.60 mm〇i)溶液中添加8_氧雜·3_ 氮雜-雙環[3.2.1]辛烷（〇.81§，719111111〇1)及7 mL三乙胺。使用微波輻射加熱棕色溶液3〇分鐘❶將反應混合物溶解於 H2〇及乙酸乙酯中且分離有機層。用乙酸乙酯萃取水層兩 152948.doc 201136930 次。藉由急驟管柱層析（矽膠，2%甲醇之DCM溶液）純化，知到呈棕色固體狀之5-[9-異丙基-2-(8 -氧雜-3 -氮雜-雙環 [3.2.1]辛-3-基）-9^1-嘌呤-6-基]-吡嗪_2-基胺（51%產率）。11^ NMR CDC13 (ppm): 9·21 (d，1H)，8.25 (d，1H)，7.88 (s，1H)， 4.84 (s，2H)，4.74-4.82 (七重峰，111)，4.51(111，211)，3.26-3.30 (dd，4H)，1.87-1.97 (m，4H)，1.59-1.60 (d，6H)。m/z: 367.22 [MH+] 實例4，化合物19 合成5-[8-溴-9_異丙基-2(8-氧雜-3-氮雜-雙環[3·2·ι】辛_3_ 基）-9H-嘌呤-6·基】《比嗓-2-基胺（19)Add 8 to a solution of 5-(2-chloro-9.isopropyl-9Η-嘌呤·6-yl)-0-pyrazin-2-ylamine (0.46 g, 1.60 mm〇i) dissolved in 15 mL of DMA _oxa~3_aza-bicyclo[3.2.1]octane (〇.81§, 719111111〇1) and 7 mL of triethylamine. The brown solution was heated using microwave irradiation for 3 minutes. The reaction mixture was dissolved in H.sub.2 and ethyl acetate and organic layer was separated. The aqueous layer was extracted with ethyl acetate 152948.doc 201136930 times. Purification by flash column chromatography (silica gel, 2% methanol in DCM) afforded 5-[9-isopropyl-2-(8-oxa-3-aza-bicyclo[ 3.2.1] Oct-3-yl)-9^1-indol-6-yl]-pyrazine-2-ylamine (51% yield). 11^ NMR CDC13 (ppm): 9·21 (d, 1H), 8.25 (d, 1H), 7.88 (s, 1H), 4.84 (s, 2H), 4.74-4.82 (seven peak, 111), 4.51 ( 111, 211), 3.26-3.30 (dd, 4H), 1.87-1.97 (m, 4H), 1.59-1.60 (d, 6H). m/z: 367.22 [MH+] Example 4, Compound 19 Synthesis 5-[8-bromo-9-isopropyl-2(8-oxa-3-aza-bicyclo[3·2·ι]辛_3_ Base)-9H-嘌呤-6·yl] "比嗓-2-ylamine (19)

在5°C下向溶解於15 mL氣仿中之5-[9-異丙基_2-(8-氧雜_ 3-氮雜雙環[3.2.1]辛-3-基）-9H-嘌呤-6-基]-吡嗪_2_基胺 (11)(0.32 g’ 0.86 mmol)溶液中緩慢添加N-溴丁二酿亞胺 (0.18 g ’ 1.03 mmol)。在此溫度下攪拌棕色溶液2小時。隨後，將反應混合物溶解於DCM及H2〇中且分離有機層。用 DCM萃取水層兩次。藉由製備型HPLC純化，得到呈標色固體狀之5-[8-漠-9-異丙基- 2(8-氧雜-3-氮雜-雙環[3 2 1]辛 3-基）-9H-嘌呤-6-基]吡嗪-2-基胺（23%產率）。iH Nmr MeOD (ppm): 9.18 (s，1H)，9.01 (s，1H)，4.90 (m，1H)，4 36 152948.doc -82· 201136930 (m, 4H)，3.28 (m，1H)，3.13 (m，1Η)，1·88 (m，2H)，1.72 (m, 2H), 1.58 (d, 6H) ； m/z: 445/447 [MH+] 實例5，化合物20 合成5-[8-漠-9-(1-乙基-丙基）-2-(8-氧雜-3-氮雜-雙環 [3.2.1]辛-3-基）-9H-嗓吟-6-基]比嗪-2-基胺（20)5-[9-isopropyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9H- dissolved in 15 mL of gas at 5 °C N-bromobutanediamine (0.18 g '1.03 mmol) was slowly added to a solution of indole-6-yl]-pyrazine-2-amine (11) (0.32 g' 0.86 mmol). The brown solution was stirred at this temperature for 2 hours. Thereafter, the reaction mixture was dissolved in DCM and H 2 hydrazine and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC to give 5-[8----9-isopropyl- 2(8-oxa-3-aza-bicyclo[3 2 1]oct-3-yl) as a color solid. -9H-indol-6-yl]pyrazin-2-ylamine (23% yield). iH Nmr MeOD (ppm): 9.18 (s, 1H), 9.01 (s, 1H), 4.90 (m, 1H), 4 36 152948.doc -82· 201136930 (m, 4H), 3.28 (m, 1H), 3.13 (m,1Η),1·88 (m,2H), 1.72 (m, 2H), 1.58 (d, 6H); m/z: 445/447 [MH+] Example 5, Compound 20 Synthesis 5-[8 -95-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-indol-6-yl] Biazin-2-ylamine (20)

在5°C下向溶解於10 mL氣仿中之5-[9-(1-乙基-丙基）_2-(8-氧雜-3-氮雜-雙環[3.2.1]辛-3基）-9H-°票吟-6-基]-η比嗪·2_ 基胺（6)(40 mg ’ 0.1 mmol)溶液中緩慢添加Ν-溴丁二醯亞胺（20 mg ’ 〇·12 mmol)。在此溫度下攪拌棕色溶液2小時。隨後，將反應混合物溶解於DCM及Ηβ中且分離有機層。用DCM萃取水層兩次。製備型HPLC純化，得到呈標色固體狀之5-[8 -漠-9-(1-乙基-丙基）-2-(8-氧雜-3-氮雜-雙環 [3.2.1]辛-3-基）-9H-嗓吟-6-基]比嗓-2-基胺（18 mg，38% 產率）。4 NMR MeOD (ppm): 9.11 (s，1H)，9.03 (s，1H)，4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H) ； m/z: 473/475 [MH+] 實例6，化合物9 合成9-苯曱基-2,6-二氣-9H-嘌呤 152948.doc •83· 2011369305-[9-(1-ethyl-propyl)_2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3 dissolved in 10 mL of gas at 5 °C Base)-9H-°Pan-6-yl]-n-pyrazine·2_ylamine (6) (40 mg '0.1 mmol) solution was slowly added with bismuth-bromobutaneimide (20 mg '〇·12 Mm). The brown solution was stirred at this temperature for 2 hours. Subsequently, the reaction mixture was dissolved in DCM and Ηβ and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC to give 5-[8----9-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1] as a color solid. Oct-3-yl)-9H-indol-6-yl]pyridin-2-ylamine (18 mg, 38% yield). 4 NMR MeOD (ppm): 9.11 (s, 1H), 9.03 (s, 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H); m/z: 473/475 [MH+] Example 6, Compound 9 Synthesis of 9-benzoinyl-2,6-di--9H -嘌呤152948.doc •83· 201136930

在室溫下向經攪拌之2,6-二氣嘌呤（5·3〇 mm〇l，1當量）的10 m】無水DMSO溶液中添加無水碳酸鉀（6.34 mmol，1.2 當量）及苯甲基溴（6.34 mmol，1.2當量）。在此溫度下維持反應混合物20小時。可使用tlc或LC/MS監測反應。將反應混合物傾倒於含有冰冷水之燒杯中。使水層酸化至pH 5-6。使用3份75 ml乙酸乙酯萃取水層，得到粗產物。在矽膠官柱（1 0-70%乙酸乙酯之石油醚溶液，階段梯度）上純化此產物，產生所需化合物，產率為56%。合成5-(9-苯甲基-2-氣-9H-嘌呤-6-基）-®比嗪-2-基-胺Add anhydrous potassium carbonate (6.34 mmol, 1.2 eq.) and benzyl at room temperature to a stirred solution of 2,6-dioxane (5·3 〇mm〇l, 1 eq. Bromine (6.34 mmol, 1.2 eq.). The reaction mixture was maintained at this temperature for 20 hours. The reaction can be monitored using tlc or LC/MS. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was acidified to pH 5-6. The aqueous layer was extracted with 3 portions of 75 ml of ethyl acetate to give a crude material. The product was purified on a gum column (10-70% ethyl acetate petroleum ether, gradient) to yield the desired compound. Synthesis of 5-(9-benzyl-2-ox-9H-indol-6-yl)-®pyrazine-2-yl-amine

將 9-苯曱基-2,6-二氣嘌呤（〇159 mm〇1，i當量）、5_ 胺基吡嗪-2·關酸頻哪醇酯（0.159 mm〇1，i當量）及丨，广雙 (二苯基膦基）二茂鐵氣化鈀（11)與二氣曱烷之複合物（〇〇15 mmol，1〇 m〇l%)溶解於所添加的無過氧化物之二噁烷 ml)與2 Μ碳酸鈉水溶液（0.636 _〇1，4當量）的混合物中。使反應混合物脫氣且用氮氣淨化。接著在維持7〇_75工之 152948.doc •84- 201136930 油名上授掉反應混合物3小時。關於起始嗓吟之消失，料由LC/MS監測反應。使反應混合物冷卻至室溫並在減壓下移除溶劑。將殘餘物溶解於乙酸乙酯及水中。分離有機相且進一步用3份50 ml乙酸乙酯萃取水層。用鹽水溶液（1〇 ml)洗滌合併之乙酸乙酯層一次。經硫酸鈉乾燥有機層且在真空下移除溶劑，產生5_(9_苯甲基-2_氣_911-嘌呤-6-基）- °比°秦-2 -基-胺。此物質不經進一步純化即可進入下一階段。合成5-[9·苯曱基-2-(8-氧雜-3-氮雜-雙環[3.2.1】辛-3-基）-9H-嗓吟-6-基】·"比。秦-2-基-胺（9)9-Benzenyl-2,6-dioxane (〇159 mm〇1,i equivalent), 5-aminopyrazine-2·guanic acid pinacol ester (0.159 mm〇1,i equivalent) and hydrazine , a complex of bis(diphenylphosphino)ferrocene gasified palladium (11) and dioxane (〇〇15 mmol, 1〇m〇l%) dissolved in the added peroxide-free Dioxane ml) in a mixture with 2 Μ aqueous sodium carbonate solution (0.636 _ 〇 1, 4 eq.). The reaction mixture was degassed and purged with nitrogen. The reaction mixture was then allowed to stand for 3 hours while maintaining the oil name of 152948.doc •84-201136930. Regarding the disappearance of the starting enthalpy, the reaction was monitored by LC/MS. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and water. The organic phase was separated and the aqueous layer was further extracted with 3 portions of 50 ml of ethyl acetate. The combined ethyl acetate layer was washed once with a brine solution (1 mL). The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to yield <RTI ID=0.0>> This material was passed to the next stage without further purification. Synthesis of 5-[9-phenylindole-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-indol-6-yl]·" ratio. Qin-2-yl-amine (9)

在密封小瓶中’使用微波輻射，在165°C下將含5-(9-苯曱基-2-氯-9H-嘌呤·6-基）-吡嗪-2-基胺（0.1 mm〇1，1當量）、8-氧雜-3-氮雜-雙環[3.2.1]辛烷鹽酸鹽（0.5111111〇1，5 當量）及三乙胺（0.7 mmol ’ 7當量）之3 ml NMP加熱25分鐘。使内含物冷卻至室溫且關於產物形成，藉由Lcms監測轉化。2 5分鐘後’反應完成’未觀察到分解。藉由逆相 HPLC純化粗物質，產生純度為98%之5-[9-笨甲基·2-(8-氧雜-3-氮雜-雙環[3_2.1]辛-3-基）-9H-嘌呤-6-基]·。比嗪_2_基- 152948.doc -85 - 201136930In a sealed vial 'Using microwave radiation, containing 5-(9-benzoin-2-chloro-9H-indol-6-yl)-pyrazin-2-ylamine (0.1 mm〇1) at 165 °C , 1 equivalent), 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.5111111〇1,5 equivalents) and triethylamine (0.7 mmol '7 equivalents) of 3 ml NMP heating 25 minutes. The contents were allowed to cool to room temperature and for product formation, conversion was monitored by Lcms. After 2 minutes, 'reaction completed' no decomposition was observed. The crude material was purified by reverse phase HPLC to give 5-[9-m-methyl-2-(8-oxa-3-aza-bicyclo[3-2.1]oct-3-yl)-purity with a purity of 98%. 9H-嘌呤-6-based]·. Bisazine_2_yl - 152948.doc -85 - 201136930

1H)，8.30 (s，1H)，7.76 (s，1H)，7.46-7.30 (m，4ti)，7 37 (bs 2H)，5.39 (m，2H)，4.56 (m，2H), 4.34 (d，2H)，3·34 (d，2H) 2.11-1.85 (m，4H)，m/z: 415.20 [MH+]。實例7 ’化合物27 合成5-(2-氣-9-異丙基-8-甲基_9H-嘌呤-6-基）嘻_2·基胺1H), 8.30 (s, 1H), 7.76 (s, 1H), 7.46-7.30 (m, 4ti), 7 37 (bs 2H), 5.39 (m, 2H), 4.56 (m, 2H), 4.34 (d , 2H), 3·34 (d, 2H) 2.11-1.85 (m, 4H), m/z: 415.20 [MH+]. Example 7 'Compound 27 Synthesis of 5-(2-gas-9-isopropyl-8-methyl-9H-indol-6-yl)indole-2-ylamine

購得2,6-二氣_9_異丙基_8_甲基-9Η-嘌呤且使用與以上針對5-(2-氣異丙基_8_曱基_9Η嘌呤_6•基）·吡嗪基胺所述相同之程序轉化為5-(2-氣-9-異丙基-9Η-嘌呤_6_基）·吡嘻-2-基胺。粗產物不經純化即可用於下一步驟。〇成丨9-異丙基-8-甲基-2-(8-氧雜-3-氮雜-雙環[3 2工】辛基）_9H-嗓吟+基比嗪_2_基胺（η)2,6-diox_9_isopropyl_8-methyl-9Η-嘌呤 was purchased and used with the above for 5-(2-isopropyl _8-fluorenyl -9 Η嘌呤 _6• group) Pyrazinylamine The same procedure was used to convert to 5-(2-gas-9-isopropyl-9Η-嘌呤_6-yl)pyridin-2-ylamine. The crude product was used in the next step without purification. 〇成丨9-isopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3 2]octyl)_9H-indole+pyrazine-2_ylamine η)

使用與針對以上5_[9_異丙基_2_(8_氧雜氮雜-雙環 ]辛3-基）_9Η-嗓呤_6_基]比唤_2_基胺（11)所述相同 152948.doc -86 - 201136930 之程序’使5-(2-氣-9-異丙基-8-曱基-9H-嘌呤-6-基）_〇比。秦-2-基胺轉化為5_[9_異丙基_8_甲基_2_(8_氧雜氮雜·雙環 [3.2.1]辛·3-基）-9H-嘌呤-6-基]-吡嗪-2-基胺（27)。分離5_ [9-異丙基·8·甲基-2-(8-氧雜-3-氮雜-雙環[3.2.1]辛_3_基）· 9H_嗓吟-6-基]-π比唤_2_基胺’石夕膠層析後’經以市售2 6 二氣-9-異丙基-8-曱基-9H-嗓吟作為起始物質之兩個步驟產率為 22%。NMR d6-DMSO (ppm): 9.01 (s，1H). 8 〇9 (s，1H); 7.42 (bs，2H); 4.81 (q，1H); 4.45 (m，2H)，4.35 (m 2H)，3.18 (m，2H)，2.83 (s，3H)，1.83 (m，2H)，1.70 (m，2H) 1.63 (s, 6H), 1.60 (s, 6H) ； m/z: 381.18 [MH+] 按照上文所概述之程序或其變化形式合成表1中所概述之化合物。表1合成之化合物Use the same as described above for 5_[9_isopropyl-2-(8-oxaaza-bicyclo]oct-3-yl)_9Η-嗓呤_6_yl] than the 2-aminoamine (11) 152948.doc -86 - 201136930 The procedure 'to make 5-(2-gas-9-isopropyl-8-fluorenyl-9H-indol-6-yl)_〇 ratio. Conversion of Qin-2-ylamine to 5_[9-isopropyl_8-methyl_2_(8-oxaaza-bicyclo[3.2.1] osin-3-yl)-9H-嘌呤-6-yl ]-Pyrazine-2-ylamine (27). Isolation 5_ [9-isopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3.2.1]octyl-3-yl)·9H_嗓吟-6-yl]- π is a two-step yield of _2_ylamine-[Delta gel chromatography] after commercialization of 2 6 diox-9-isopropyl-8-mercapto-9H-indole as starting material It is 22%. NMR d6-DMSO (ppm): 9.01 (s, 1H). 8 〇9 (s, 1H); 7.42 (bs, 2H); 4.81 (q, 1H); 4.45 (m, 2H), 4.35 (m 2H) , 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H) 1.63 (s, 6H), 1.60 (s, 6H) ; m/z: 381.18 [MH+] The compounds outlined in Table 1 were synthesized according to the procedures outlined above or variations thereof. Table 1 synthesized compounds

*HNMR 一 |m/z — DMSO-d6 (ppm): 9.17 (s, 1H), 395 Γδ 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.50-4.30 (m, 5H), 3.20-3.10 (m, 2H), 2.30 (m, 1H), 1.80 (m, 2H), 1.70 (m, 2H), 1.60 (d, 3H)，1.00 (d，3H)，0.70 (d，3H)» _--- 152948.doc 87- 201136930 編號結構 ^NMR m/z 2 nh2 ό CDC13 (ppm): 9.14 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 4.62-4.65 (m, 2H), 4.41-4.55 (bs, 2H), 3.38 (d, 2H), 2.17-2.21 (m, 2H), 2.02-2.10 (m, 6H), 1.79-1.88 (m, 8H), 1.54 (q，2H)，0.99 (t, 3H)。 435.24 3 νη2 Λ k/N CDC13 (ppm): 9.14 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 4.58-4.60 (m, 2H), 4.30-4.46 (bs, 2H), 3.38 (d, 2H), 2.05-2.10 (m, 8H), 1.78-1.87(m，8H)。 449.24 4 FIFl^ Λ CDC13 (ppm): 9.15 (s, 1H), 8.56 (bs, 1H), 8.34 (s, 1H), 5.23 (m, 2H), 4.70 (m, 1H), 4.56 (m, 2H), 4.44 (m, 2H), 3.30 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H), 1.10-1.90 (m, 6H), 1.30 (m, 2H), 1.01 (t, 3H)。 421.21 5 nh2 Λ Wn DMSO-d6 (ppm): 9.19 (s, 1H), 9.00 (bs, lH),8.10(s, 1H), 7.30 (bs, 2H), 7.20 -7.10 (m, 4H), 4.92 (m, 1H), 4.44-4.32 (m, 4H), 3.5-2.90 (m, 6H), 2.30 (m, 2H), 1.90-1.70 (m, 4H) 〇 455.20 152948.doc -88 - 201136930 編號結構 'hnmr m/z 6 (mh2 Λ ^ΝΧ^ΙΧ) (Ο Ν ^ DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.47-4.34 (m, 5H), 3.20- 3.1 (m, 2H), 2.10-1.90 (m, 4H), 1.80 (m, 2H), 1.70 (m, 2H), 0.65 (t, 6H)。 395.21 7 νη2 [Ί\ xXNy MeOD (ppm): 9.18 (s, 1H), 8.96 (s, 1H), 8.06 (s, 1H), 4.95 (m, 1H), 4.42 (m, 4H), 3.18 (m, 2H), 2.28 (m, 2H), 2.12 (m, 2H), 1.88 (m，4H)，1.75 (m，4H)。 393.16 8 νη2 Λ Wn χχΝ> Ν V DMSO-d6 (ppm): 9.18 (s, 1H), 8.90(bs, 1H), 8.10 (s,lH), 7.29 (bs, 2H), 4.47-4.38 (m, 4H), 4.04 (s, 2H), 3.18-3.14 (m, 2H), 1.80 (m, 2H), 1.70 (m, 2H), 1.00 (d, 9H)。 395.21 9 νη2 ? il ^γΝ ^χΝ> CDC13 (ppm): 9.76 (d, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 7.76 (s, 1H), 7.46-7.30 (m, 4H), 7.37 (bs, 2H), 5.39 (m, 2H), 4.56 (m, 2H), 4.34 (d, 2H),3.34 (d, 2H), 2.11-1.85 (m，4H)。 415.20 152948.doc 89- 201136930 編號結構 !hnmr m/z 10 nh2 Λ Ν Λ MeOD (ppm): 9.30 (s, 1 Η), 9.10 (s, lH),8.15(s, 1H), 4.95 (m, 1H), 4.55-4.45 (m, 4H), 4.30 (d, 2H), 3.35-3.30 (m, 2H),3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 (m, 2H), 1.80-1.70 (m, 2H), 1.52 (s, 9H) 508.27 11 νη2 Λ XjC> θ' DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H),8.11 (s, 1H), 7.32 (bs, 2H), 4.88 (m, 1H), 4.48 (m, 2H)，4.37(d，2H),3.18(d，2H), 1.86 (m, 2H), 1.73 (m, 2H), 1.59 (d，6H) 〇 367.22 12 νη2 ψ χχ> , <0 Ν DMSO-d6 (ppm): 9.11 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 4.92-4.97 (m, 1H), 4.58 (d, 2H), 4.43 (bs, 2H), 3.37 (dd, 2H), 2.01-2.08 (m，3H)，1.87 (d，2H)，1.74-1.77 (m，1H), 1.68 (d，3H)，1.45 (q， 1H)，1.02 (d，3H)，0.97 (d，3H) 409.26 13 νη2 6 ΧΤΝ> DMSO-d6 (ppm): 9.04 (s, 1H), 8.98 (s, 1H), 8.46 (s, 1H), 6.02-6.18 (bs, 2H), 4.57 (d, 2H), 4.41-47 (m, 3H), 3.37 (dd, 2H), 2.33 (s, 1H), 2.02-2.07 (m, 4H), 1.87 (d, 2H), 1.16-1.20 (m, 2H), 1.10 (d, 3H), 0.94 (t, 3H), 0.88 (d, 3H) 423.26 152948.doc 90- 201136930 編號結構 lH NMR m/z 14 nh2 Λ χΧ% d DMS0-d6 (ppm): 9.20 (s, 1H), 8.75 (bs, 1H), 8.10 (s, 1H), 7.28 (bs, 2H), 5.25 (m, 1H), 4.48-4.36 (m, 4H), 4.15 (q, 2H), 4.08-4.00 (m, 2H), 3.92-3.87 (m, 2H), 3.17 (d, 2H), 1.86-1.84 (m, 2H), 1.77-1.71 (m，2H)。 395.21 15 νη2 Λ Wn χΧΝ} 0 Ν、 DMSO-d6 (ppm): 9.18 (s, 1H), 8.95 (bs, 1H), 8.10 (s, 1H), 7.31 (bs，2H), 4.48 (m，2H), 4.39 (d， 2H)，4.24 (dd，2H)，3.17 (d，2H)， 1.87-1.85 (m, 2H), 1.74-1.69 (m, 2H)，1.48 (t，3H)。 353.17 16 ΝΗ〇 Λ Wn ^ 6 MeOD (ppm): 9.21 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 4.68 (m, 1H), 4.38 (m, 4H), 4.05 (m, 1H), 3.1-3.3 (m, 4H),2.75 (m, 1H), 2.20 (m, 4H), 2.08 (s, 3H), 1.86 (m, 2H), 1.72 (m, 2H) 450.24 17 ΝΗ〇 Λ Wn (Ο Ν、 CDC13 (ppm): d 9.69 (s, 2H), 8.36-8.35 (m, 1H), 8.25 (d, 1H), 7.98 (s, 1H), 4.51 (brs, 2H), 4.27 (d, 2H), 4.18 (t, 2H), 3.29 (d, 2H), 1.96-2.09 (m, 2H), 1.68-1.92 (m, 9H), 1.29-1.18 (m, 4H), 1.03-0.98 (m, 2H) 435.27 152948.doc -91- 201136930 編號結構 *HNMR m/z 18 nh2 Λ (Ο ^ CDC13 (ppm): 9.02 (s, 1H), 8.99 (s, 1H), 8.42 (s, 1H), 6.06 (s, 2H), 4.69-4.72 (m, 1H), 4.53-4.54 (m, 2H), 4.37-4.38 (m, 2H), 3.33 (dd, 2H), 3.14 (sextet, 1H), 1.60-1.68 (m, 4H), 1.33 (t, 3H), 1.24-1.26 (m, 3H), 0.85-0.99 (m, 5H) 409.18 19 νη2 Λ XjCVer (Ο Ν \ MeOD (ppm): 9.18 (s, 1H), 9.01 (s, 1H), 4.90 (m, 1H), 4.36 (m, 4H), 3.28 (m, 1H), 3.13 (m, 1H), 1.88 (m, 2H), 1.72 (m, 2H), 1.58 (d, 6H) 447.41 20 νη2 Λ fVVer (0Ν Ν ^ MeOD (ppm): 9.11 (s, 1H), 9.03 (s, 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H) 474.38 21 νη2 Λ fVvci (Ο仏 MeOD (ppm): 9.30 (s, 1H), 9.08 (s, 1H), 4.58 (m, 1H), 4.47 (m, 4H), 3.32 (m, 1H), 3.25 (m, 1H), 2.12 (m, 4H), 1.98 (m, 2H), 1.79 (m, 2H), 0.89 (m, 6H) 429.11 152948.doc 92- 201136930 編號結構 !hnmr m/z 22 nh2 Λ CDC13 (ppm): 8.96 (s, 2Η), 8.45 (s, 1H), 6.35 (s, 2H), 4.54-4.55 (m, 2H), 4.26-4.42 (m, 3H), 3.33 (d, 2H), 2.31 (sextet, 1H), 2.0-2.11 (m, 4H), 1.81-1.83 (m, 2H), 1.06 (d, 3H), 0.80-0.85 (m, 6H) 409.17 23 νη2 Λ χΎΛ CDCI3 (ppm): 9.02 (s, 2H), 8.39 (s, 1H), 5.86 (s, 2H), 4.53-4.55 (m, 3H), 4.39 (d, 2H), 3.32 (dd, 2H), 2.49 (sextet, 1H), 1.96-2.03 (m, 4H), 1.83-1.85 (m, 2H), 1.69-1.79 (m, 2H), 1.64 (d, 3H), 1.52-1.56 (m, 2H), 1.32-1.37 (m, CH), 1.12-1.16 (m, 1H) 421.18 24 νη2 Λ Wn X ]ΓΝ"> (Ο ρ- CDCI3 (ppm): 9.00 (s, 1H), 8.94 (s, 1H), 8.41 (s, 1H), 6.05 (s, 2H), 4.53-4.58 (m，3H)，4.32-4.42 (m， 2H), 3.33 (dd, 2H), 1.99-2.05 (m5 4H), 1.90-1.98 (m, 2H), 1.82-1.84 (m, 2H), 1.19-1.29 (m, 2H), 0.92 (t, 3H), 0.87 (t, 3H) 409.17 25 ΝΗ2 Λ χίΛ CDCI3 (ppm): 9.04 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 6.72-6.96 (bs, 2H), 4.52-4.60 (m, 3H), 4.31-4.44 (m, 2H), 3.34 (dd, 2H), 1.95-2.12 (m, 6H), 1.81-1.83 (m, 2H), 1.21-1.41 (m, 4H), 1.09-1.19 (m, 1H), 0.84-0.91 (m, 6H) 423.20 152948.doc 93- 201136930 編號 Ή NMR m/z 26 nh2 ψ DMSO-d6(ppm): 9.11 (s, 1H), 9.0 (bs, 1H), 8.05 (s, 1H), 7.29 (bs, 2H), 4.61 (m, 1H), 4.44 (m, 2H), 4.35 (m, 2H), 3.15 (m, 2H), 2.11-2.06 (m, 4H), 1.81-1.57 (m,12H) 421.18 27 Λ (01¾ DMSO-d6(ppm): 9.01 (s, 1H), 8.09 (s, 1H), 7.42 (bs, 2H), 4.81 (q, 1H), 4.45 (m, 2H), 4.35 (m, 2H), 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H), 1.63 (s, 6H), 1.60 (s, 6H) 38U8 ' 28 Λ DMSO-d6(ppm): 9.13 (s, 1H), 9.0 (bs, 1H)} 8.05 (s, 1H), 7.29 (bs, 2H), 4.42 (m, 2H), 4.35 (m, 2H), 4.05 (m, 2H), 3.15 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H), 1.38 (m, 1H), 0.55-0.48 (m, 4H) 379J4 生物學測試 mTOR檢定實驗室產生全長mTOR激酶及標記His之4eBPl。[γ33Ρ]_ ATP購自Amersham(GE Healthcare)。除非另有規定，否則所有化學物質均來自Sigma-Aldrich。磷酸化檢定最初以20 pL之最終體積在384孔聚丙烯培養板（Greiner)中進行。通常在1〇〇 μΜ至0.006 μΜ之範圍内，以8個階段稀釋度測試化合物，一式兩份。首先將每孔1〇 μι -受質 >谷液（含 ι·5 pg/mL mTORl、40 pg/mL 4eBP 1 之 lx 檢定緩衝液：l〇 mM Hepes(pH 7.5)、50 mM NaCl 及 152948.doc •94- 201136930 10 mM MnCl2)添加至含有每孔1 μι測試化合物之純DMSO 溶液的樣品培養板中。藉由添加每孔10 μί之20 μΜ ATP溶液（最終檢定濃度為10 μΜ ATP及每孔0.4 gCi [γ33Ρ]-ΑΤΡ) 起始反應。在室溫下培育1小時後，用每孔40 μι 20 mM EDTA/1 mM ATP溶液終止反應。接著將每孔50 μί停止反應混合物轉移至預先添加有每孔 50 μί 1% 填酸之 384 孔 MultiScreenHTS-PH 過滤板 (Millipore)。經由真空過濾，用每孔120 μί 0.5°/。磷酸洗滌該板4次。最後，添加每孔10 pL OptiphaseTM SuperMix液體閃爍混合物（Perkin Elmer)。培育最少1小時後，在 Wallac MicroBeta TriLux閃爍計數器中，使用符合計數模式，經相互干擾校正進行計數。IC5Q定義為激酶酶活性之 5 0%抑制所需之化合物濃度。IC5〇資料展示於下表2中。表2-活體外mTOR抑制活性檢定IC5G資料化合物編號 IC50(mTOR)· 化合物編號 IC5〇(mTOR)* 1 -Η-+ 15 ++ 2 -ΗΗ- 16 ++ 3 17 + 4 ++ 18 -Η- 5 +++ 19 ++ 6 +-Η- 20 -Η- 7 +++ 21 -Η- 8 +++ 22 +-Η- 9 + 23 +++ 10 -Ι-+ 24 -Η- 11 -H-f 25 12 ++ 26 13 27 +++ 14 ++ 28 ++ <0.1 μΜ 0.1 μΜ-1 μΜ >1 μΜ*HNMR a|m/z — DMSO-d6 (ppm): 9.17 (s, 1H), 395 Γδ 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.50-4.30 (m , 5H), 3.20-3.10 (m, 2H), 2.30 (m, 1H), 1.80 (m, 2H), 1.70 (m, 2H), 1.60 (d, 3H), 1.00 (d, 3H), 0.70 ( d,3H)» _--- 152948.doc 87- 201136930 No. Structure ^NMR m/z 2 nh2 ό CDC13 (ppm): 9.14 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H) , 4.62-4.65 (m, 2H), 4.41-4.55 (bs, 2H), 3.38 (d, 2H), 2.17-2.21 (m, 2H), 2.02-2.10 (m, 6H), 1.79-1.88 (m, 8H), 1.54 (q, 2H), 0.99 (t, 3H). 435.24 3 νη2 Λ k/N CDC13 (ppm): 9.14 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 4.58-4.60 (m, 2H), 4.30-4.46 (bs, 2H) , 3.38 (d, 2H), 2.05-2.10 (m, 8H), 1.78-1.87 (m, 8H). 449.24 4 FIFl^ Λ CDC13 (ppm): 9.15 (s, 1H), 8.56 (bs, 1H), 8.34 (s, 1H), 5.23 (m, 2H), 4.70 (m, 1H), 4.56 (m, 2H) ), 4.44 (m, 2H), 3.30 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H), 1.10-1.90 (m, 6H), 1.30 (m, 2H), 1.01 (t, 3H). 421.21 5 nh2 Λ Wn DMSO-d6 (ppm): 9.19 (s, 1H), 9.00 (bs, lH), 8.10(s, 1H), 7.30 (bs, 2H), 7.20 -7.10 (m, 4H), 4.92 (m, 1H), 4.44-4.32 (m, 4H), 3.5-2.90 (m, 6H), 2.30 (m, 2H), 1.90-1.70 (m, 4H) 〇455.20 152948.doc -88 - 201136930 No. Structure 'hnmr m/z 6 (mh2 Λ ^ΝΧ^ΙΧ) (Ο Ν ^ DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, (H, 2H) 395.21 7 νη2 [Ί\ xXNy MeOD (ppm): 9.18 (s, 1H), 8.96 (s, 1H), 8.06 (s, 1H), 4.95 (m, 1H), 4.42 (m, 4H), 3.18 ( m, 2H), 2.28 (m, 2H), 2.12 (m, 2H), 1.88 (m, 4H), 1.75 (m, 4H). 393.16 8 νη2 Λ Wn χχΝ> Ν V DMSO-d6 (ppm): 9.18 (s, 1H), 8.90 (bs, 1H), 8.10 (s, lH), 7.29 (bs, 2H), 4.47-4.38 (m, 4H), 4.04 (s, 2H), 3.18-3.14 (m, 2H) ), 1.80 (m, 2H), 1.70 (m, 2H), 1.00 (d, 9H). 395.21 9 νη2 ? il ^γΝ ^χΝ> CDC13 (ppm): 9.76 (d, 1H), 8.38 (s, 1H) ), 8.30 (s, 1H), 7.76 (s, 1H), 7.46-7.30 (m, 4H), 7.37 (bs, 2H), 5.39 (m, 2 H), 4.56 (m, 2H), 4.34 (d, 2H), 3.34 (d, 2H), 2.11-1.85 (m, 4H). 415.20 152948.doc 89- 201136930 No. Structure! hnmr m/z 10 nh2 Λ Ν Λ MeOD (ppm): 9.30 (s, 1 Η), 9.10 (s, lH), 8.15 (s, 1H), 4.95 (m, 1H), 4.55-4.45 (m, 4H), 4.30 (d, 2H), 3.35-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 ( m, 2H), 1.80-1.70 (m, 2H), 1.52 (s, 9H) 508.27 11 νη2 Λ XjC> θ' DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.11 (s, 1H), 7.32 (bs, 2H), 4.88 (m, 1H), 4.48 (m, 2H), 4.37 (d, 2H), 3.18 (d, 2H), 1.86 (m, 2H), 1.73 ( m, 2H), 1.59 (d,6H) 〇367.22 12 νη2 ψ χχ> , <0 Ν DMSO-d6 (ppm): 9.11 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H) , 4.92-4.97 (m, 1H), 4.58 (d, 2H), 4.43 (bs, 2H), 3.37 (dd, 2H), 2.01-2.08 (m, 3H), 1.87 (d, 2H), 1.74-1.77 (m,1H), 1.68 (d,3H), 1.45 (q, 1H), 1.02 (d,3H), 0.97 (d,3H) 409.26 13 νη2 6 ΧΤΝ> DMSO-d6 (ppm): 9.04 (s, (H, 3H) (s, 1H), 2.02-2.07 (m, 4H), 1.87 (d, 2H), 1.16-1.20 (m, 2H), 1.10 (d, 3H), 4 结构 d d d 423 423 423 423 423 423 423 423 423 423 , 1H), 8.10 (s, 1H), 7.28 (bs, 2H), 5.25 (m, 1H), 4.48-4.36 (m, 4H), 4.15 (q, 2H), 4.08-4.00 (m, 2H), 3.92-3.87 (m, 2H), 3.17 (d, 2H), 1.86-1.84 (m, 2H), 1.77-1.71 (m, 2H). 395.21 15 νη2 Λ Wn χΧΝ} 0 Ν, DMSO-d6 (ppm): 9.18 (s, 1H), 8.95 (bs, 1H), 8.10 (s, 1H), 7.31 (bs, 2H), 4.48 (m, 2H) ), 4.39 (d, 2H), 4.24 (dd, 2H), 3.17 (d, 2H), 1.87-1.85 (m, 2H), 1.74-1.69 (m, 2H), 1.48 (t, 3H). 353.17 16 ΝΗ〇Λ Wn ^ 6 MeOD (ppm): 9.21 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 4.68 (m, 1H), 4.38 (m, 4H), 4.05 ( m, 1H), 3.1-3.3 (m, 4H), 2.75 (m, 1H), 2.20 (m, 4H), 2.08 (s, 3H), 1.86 (m, 2H), 1.72 (m, 2H) 450.24 17 ΝΗ〇Λ Wn (Ο Ν, CDC13 (ppm): d 9.69 (s, 2H), 8.36-8.35 (m, 1H), 8.25 (d, 1H), 7.98 (s, 1H), 4.51 (brs, 2H) , 4.27 (d, 2H), 4.18 (t, 2H), 3.29 (d, 2H), 1.96-2.09 (m, 2H), 1.68-1.92 (m, 9H), 1.29-1.18 (m, 4H), 1.03 -0.98 (m, 2H) 435.27 152948.doc -91- 201136930 No. Structure *HNMR m/z 18 nh2 Λ (Ο ^ CDC13 (ppm): 9.02 (s, 1H), 8.99 (s, 1H), 8.42 (s , 1H), 6.06 (s, 2H), 4.69-4.72 (m, 1H), 4.53-4.54 (m, 2H), 4.37-4.38 (m, 2H), 3.33 (dd, 2H), 3.14 (sextet, 1H ), 1.60-1.68 (m, 4H), 1.33 (t, 3H), 1.24-1.26 (m, 3H), 0.85-0.99 (m, 5H) 409.18 19 νη2 Λ XjCVer (Ο Ν \ MeOD (ppm): 9.18 (s, 1H), 9.01 (s, 1H), 4.90 (m, 1H), 4.36 (m, 4H), 3.28 (m, 1H), 3.13 (m, 1H), 1.88 (m, 2H), 1.72 ( m, 2H), 1.58 (d, 6H) 447.41 20 νη2 Λ fVVer (0Ν Ν ^ MeOD (ppm): 9.11 (s, 1H), 9.03 (s , 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H) 474.38 21 νη2 Λ fVvci (Ο仏MeOD (ppm): 9.30 (s, 1H), 9.08 (s, 1H), 4.58 (m, 1H), 4.47 (m, 4H), 3.32 (m, 1H), 3.25 (m, 1H), 2.12 (m, 4H), 1.98 (m, 2H), 1.79 (m, 2H), 0.89 (m, 6H) 429.11 152948.doc 92- 201136930 No. Structure!hnmr m/z 22 nh2 Λ CDC13 (ppm): 8.96 (s, 2Η), 8.45 (s, 1H), 6.35 (s, 2H), 4.54-4.55 (m, 2H), 4.26-4.42 (m, 3H), 3.33 (d, 2H ), 2.31 (sextet, 1H), 2.0-2.11 (m, 4H), 1.81-1.83 (m, 2H), 1.06 (d, 3H), 0.80-0.85 (m, 6H) 409.17 23 νη2 Λ χΎΛ CDCI3 (ppm ): 9.02 (s, 2H), 8.39 (s, 1H), 5.86 (s, 2H), 4.53-4.55 (m, 3H), 4.39 (d, 2H), 3.32 (dd, 2H), 2.49 (sextet, 1H), 1.96-2.03 (m, 4H), 1.83-1.85 (m, 2H), 1.69-1.79 (m, 2H), 1.64 (d, 3H), 1.52-1.56 (m, 2H), 1.32-1.37 ( m, CH), 1.12-1.16 (m, 1H) 421.18 24 νη2 Λ Wn X ]ΓΝ"> (Ο ρ- CDCI3 (ppm): 9.00 (s, 1H), 8.94 (s, 1H), 8.41 (s , 1H), 6.05 (s, 2H), 4.53-4.58 (m, 3H), 4.32-4.42 (m, 2H), 3.33 (dd, 2H) , 1.90-1.98 (m, 2H) 25 ΝΗ2 Λ χίΛ CDCI3 (ppm): 9.04 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 6.72-6.96 (bs, 2H), 4.52-4.60 (m, 3H), 4.31- 4.44 (m, 2H), 3.34 (dd, 2H), 1.95-2.12 (m, 6H), 1.81-1.83 (m, 2H), 1.21-1.41 (m, 4H), 1.09-1.19 (m, 1H), 0.84-0.91 (m, 6H) 423.20 152948.doc 93- 201136930 No. NMR m/z 26 nh2 ψ DMSO-d6 (ppm): 9.11 (s, 1H), 9.0 (bs, 1H), 8.05 (s, 1H ), 7.29 (bs, 2H), 4.61 (m, 1H), 4.44 (m, 2H), 4.35 (m, 2H), 3.15 (m, 2H), 2.11-2.06 (m, 4H), 1.81-1.57 ( m,12H) 421.18 27 Λ (013⁄4 DMSO-d6(ppm): 9.01 (s, 1H), 8.09 (s, 1H), 7.42 (bs, 2H), 4.81 (q, 1H), 4.45 (m, 2H) , 4.35 (m, 2H), 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H), 1.63 (s, 6H), 1.60 (s, 6H) 38U8 ' 28 Λ DMSO-d6 (ppm): 9.13 (s, 1H), 9.0 (bs, 1H)} 8.05 (s, 1H), 7.29 (bs, 2H), 4.42 (m, 2H), 4.35 (m, 2H) ), 4.05 (m, 2H), 3.15 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H), 1.38 (m, 1H), 0.55-0.48 (m, 4H) 379J4 Biology MTOR assay laboratory test 4eBPl generating full-length mTOR kinase and His tag of. [γ33Ρ]_ ATP was purchased from Amersham (GE Healthcare). All chemicals were from Sigma-Aldrich unless otherwise stated. Phosphorylation assays were initially performed in 384 well polypropylene plates (Greiner) in a final volume of 20 pL. Compounds were tested in 8-stage dilutions, usually in the range of 1 〇〇 μΜ to 0.006 μΜ, in duplicate. First, each well 1 μμι - 质质谷谷谷谷谷谷谷谷 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 .doc • 94- 201136930 10 mM MnCl2) was added to a sample culture plate containing 1 μl of test compound in pure DMSO solution per well. The reaction was initiated by adding 10 μί of 20 μΜ ATP solution per well (final assay concentration of 10 μΜ ATP and 0.4 gCi [γ33Ρ]-ΑΤΡ per well). After incubation at room temperature for 1 hour, the reaction was stopped with 40 μM of 20 mM EDTA/1 mM ATP solution per well. The 50 μί stop reaction mixture per well was then transferred to a 384-well MultiScreen HTS-PH filter plate (Millipore) pre-added with 50 μί of 1% acid per well. Filter through vacuum using 120 μί 0.5 °/ per well. The plate was washed 4 times with phosphoric acid. Finally, 10 pL of OptiphaseTM SuperMix liquid scintillation cocktail (Perkin Elmer) per well was added. After a minimum of 1 hour of incubation, the Wallac MicroBeta TriLux scintillation counter was counted using a coincidence counting mode with mutual interference correction. IC5Q is defined as the concentration of the compound required for 50% inhibition of kinase enzyme activity. The IC5〇 data is shown in Table 2 below. Table 2 - In vitro mTOR inhibitory activity assay IC5G data Compound number IC50 (mTOR) · Compound number IC5〇(mTOR)* 1 -Η-+ 15 ++ 2 -ΗΗ- 16 ++ 3 17 + 4 ++ 18 -Η - 5 +++ 19 ++ 6 +-Η- 20 -Η- 7 +++ 21 -Η- 8 +++ 22 +-Η- 9 + 23 +++ 10 -Ι-+ 24 -Η- 11 -Hf 25 12 ++ 26 13 27 +++ 14 ++ 28 ++ <0.1 μΜ 0.1 μΜ-1 μΜ >1 μΜ

152948.doc -95- 201136930 本發明中所述之特定實施例的細節不應理解為限制條件。在不脫離本發明之本質及範疇的情況下可作出各種等效物及修改，且應瞭解該等等效實施例為本發明之部分。 152948.doc -96-152948.doc -95- 201136930 The details of the specific embodiments described herein are not to be construed as limiting. Various equivalents and modifications can be made without departing from the spirit and scope of the invention, and it is understood that the equivalent embodiments are part of the invention. 152948.doc -96-

Claims

201136930 七、申請專利範圍： 1 · 一種式（I)化合物：201136930 VII. Patent application scope: 1 · A compound of formula (I):

R係選自由以下組成之群：H、_素及視情況經取代之c 1 -C6烧基； R係選自由以下組成之群：11、画素、〇Η、ν〇2、 CN、ΝΑ、視情況經取代之Ci_Ci2烷基、視情況經取代之h-c!2烯基、視情況經取代之C2_Ci2炔基、視情況經取代之Cs-Cu雜烷基、視情況經取代之C3_C12環烷基、視情況經取代之C^-C!2環烯基、視情況經取代之c2_Ci2雜環烷基、視情況經取代之C^-C!2雜環烯基、視情況經取代之 Q-Cu芳基、視情況經取代之Ci_c〗8雜芳基、視情況經取代之q-C丨2烷氧基、視情況經取代之C2_Ci2烯氧基、視情況經取代之C^-Cn炔氧基、視情況經取代之C2_C〗G雜烷氧基、視情況經取代之Cs-C〗2環烷氧基、視情況經取代之 C3-C!2環烯氧基、視情況經取代之C2_C]2雜環烷氧基、視情況經取代之C2_CU雜環烯氧基、視情況經取代之C6_Ci8 152948.doc 201136930 芳氧基、視情況經取代之Ci-Cu雜芳氧基、視情況經取代之c!-c丨2烷基胺基、SR8、so3h、S02NR8R9、S02R8、 SONR8R9、s〇r8、c〇r8、C00H、c〇〇r8 c〇nr8r9 NR8C〇r9、nr8c〇〇r9、nr8s〇2r9 nr8c〇nr8r9、 nr8r9及醯基，或R為下式基團：R is selected from the group consisting of H, _ and optionally substituted c 1 -C6 alkyl; R is selected from the group consisting of: 11, 画, 〇Η, ν 〇 2, CN, ΝΑ, Optionally substituted Ci_Ci2 alkyl, optionally substituted hc! 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted Cs-Cu heteroalkyl, optionally substituted C3_C12 cycloalkyl , optionally substituted C^-C!2 cycloalkenyl, optionally substituted c2_Ci2 heterocycloalkyl, optionally substituted C^-C!2 heterocycloalkenyl, optionally substituted Q- Cu aryl, optionally substituted Ci_c-8 heteroaryl, optionally substituted qC丨2 alkoxy, optionally substituted C2_Ci2 alkenyloxy, optionally substituted C^-Cn alkynyloxy , as the case may be substituted C2_C〗 G heteroalkoxy, optionally substituted Cs-C 2 ring alkoxy, optionally substituted C3-C! 2 cycloalkenyloxy, optionally substituted C2_C ] 2 heterocycloalkoxy, optionally substituted C 2 — CU heterocycloalkenyloxy, optionally substituted C 6 —Ci 8 152948.doc 201136930 aryloxy, optionally substituted Ci-Cu heteroaryloxy, optionally Substituted c!-c丨2 alkylamino group, SR8, so3h, S02NR8R9, S02R8, SONR8R9, s〇r8, c〇r8, C00H, c〇〇r8 c〇nr8r9 NR8C〇r9, nr8c〇〇r9 , nr8s〇2r9 nr8c〇nr8r9, nr8r9 and fluorenyl, or R is a group of the formula:

其中各Μ獨立地為N或CR2a，各尺23係獨立地選自由以下組成之群：Η、鹵素、〇H、 N〇2、CN、NH2、視情況經取代之烷基、視情況經取代之q-c〗2烯基、視情況經取代之C2_Ci2炔基、視情况經取代之C2_Cl2雜烷基、視情況經取代之環烷基視清况經取代之C2_C丨2雜環烧基、視情況經取代之 C2-C_環烯基、視情況經取代之C6_Ci8芳基、視情況經取代之c丨_c,8雜芳基、視情況經取代之C丨-C丨2烷氧基、視情況經取代之C2-C〗2烯氧基、視情況經取代之C2-Cl2炔氧基視凊況經取代之C2_C!2雜烷氧基、視情況經取代之 cvc12m院氧基、視情況經取代之C3_C4烯氧基、視情況’、歪取代之C^-C!2雜環烷氧基、視情況經取代之雜環烯氧基、視情況經取代之c6_Ci8芳氧基、視情況經取代雜芳氧基、視情況經取代之Ci_Ci2烷基胺基、 SR、S03H、S02NH2、S02R8、s〇NH2、SOR8、COR8、 COOH、COOR8、c〇NR8R9、nr8c〇r9、nr8c〇〇r9、 152948.doc 201136930 nr8so2r9、nr8conr8r9、nr8r9及醯基； r為選自由1、2及3組成之群的整數； R3係選自由Η、F、Cl、Br、OH、視情況經取代之Cl_ C6烷基、OR8、OCOR8、CH2OH、nh2、nr8r9、nr8cor9 及nr8so2r9組成之群； R 係選自由 Η、oh、OR8、〇Pg0、OCOR8、CI^OH、 NH2、NR8R9、NR8PgN、N(PgN)2、nr8c〇r9、NR8c〇NR8R9 及nr8so2r9組成之群； R 係選自由 Η、F、Cl、Br、OH、OR8、〇c〇R8、 CH2OH、NH2、NR8R9、NR8COR9及NR8S02R9組成之群；各R及R9係獨立地選自由以下組成之群：H、視情況經取代之Cl_C丨2烷基、視情況經取代之C^-Ci2烯基、視情況經取代之c^-Cu炔基、視情況經取代之C2_Cig雜烷基、視情況經取代之C3_cn環烷基、視情況經取代之C3_Ci2環稀基視情況經取代之C2_Cn雜環院基、視情況經取代之Q-c】2雜環烯基、視情況經取代之C6_Ci8芳基及視情況經取代之<^-(：18雜芳基，或 R及R連同其所連接之原子一起形成視情況經取代之環狀部分； Pg^為氧之保護基；各pgN獨立地為氮之保護基；各反2係獨立地選自由以下組成之群：Ci_c6烷基、齒基-q-C6烷基、羥基Ci_Ce烷基、Ci_C6烷氧基446烷基氰基Ci-C6烷基、胺基c「C6烷基、c】-C6烷基胺基匸广 152948.doc 201136930 c6炫基、及二（Cl_C6烷基）胺基Cl_C6烷基； q為選自由〇、1、2、3及4組成之群的整數； X為式基團；各Rl(>係獨立地選自由以下組成之群：Η及視情況經取代之Ci-C6烷基； m為選自由〇、1、2、3及4組成之群的整數；或其醫藥學上可接受之鹽、义氧化物或前藥。 2.如請求項1之化合物，其中q為〇。 3·如S月求項1或2之化合物，其中R3係選自由Η、OR8及視情況經取代之Cl-(：6烷基組成之群，其中r8如請求項1中所定義。 4·如請求項1或2之化合物，其中R3為H。 5. 如請求項1或2之化合物，其中R7*He 6. 如4求項之化合物，其中爪係選自由〇、上及之組成之群。 7. 如請求項1或2之化合物，其中„1為〇或1。 8. 如請求項1或2之化合物，其中⑺為^。 9·如凊求項1或2之化合物，其中m為1 » 1〇·如明求項9之化合物，其中一個Rl0為Η&χ為下式基團： 11 其中R10如請求項如請求項1之化合物Wherein each of the oximes is independently N or CR2a, and each of the spurs 23 is independently selected from the group consisting of hydrazine, halogen, hydrazine H, N 〇 2, CN, NH 2, optionally substituted alkyl, optionally substituted Qc 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted C2_Cl2 heteroalkyl, optionally substituted cycloalkyl, substituted C2_C丨2 heterocycloalkyl, optionally Substituted C2-C_cycloalkenyl, optionally substituted C6_Ci8 aryl, optionally substituted c丨_c, 8 heteroaryl, optionally substituted C丨-C丨2 alkoxy, Optionally substituted C2-C-2-alkenyloxy, optionally substituted C2-Cl2 alkynyloxy, substituted C2_C!2 heteroalkoxy, optionally substituted cvc12m alkoxy, visually Substituted C3_C4 alkenyloxy, optionally as defined, C^-C!2 heterocycloalkoxy, optionally substituted heterocycloalkenyloxy, optionally substituted c6_Ci8 aryloxy, optionally Substituted heteroaryloxy, optionally substituted Ci_Ci2 alkylamine, SR, S03H, S02NH2, S02R8, s〇NH2, SOR8, COR8, COOH, COOR8, c〇NR8R9, nr8c 〇r9, nr8c〇〇r9, 152948.doc 201136930 nr8so2r9, nr8conr8r9, nr8r9 and fluorenyl; r is an integer selected from the group consisting of 1, 2 and 3; R3 is selected from Η, F, Cl, Br, OH, a group consisting of Cl_C6 alkyl, OR8, OCOR8, CH2OH, nh2, nr8r9, nr8cor9 and nr8so2r9, as appropriate; R is selected from Η, oh, OR8, 〇Pg0, OCOR8, CI^OH, NH2, NR8R9, a group consisting of NR8PgN, N(PgN)2, nr8c〇r9, NR8c〇NR8R9 and nr8so2r9; R is selected from the group consisting of ruthenium, F, Cl, Br, OH, OR8, 〇c〇R8, CH2OH, NH2, NR8R9, NR8COR9 and a group consisting of NR8S02R9; each R and R9 are independently selected from the group consisting of H, optionally substituted C1-C丨2 alkyl, optionally substituted C^-Ci2 alkenyl, optionally substituted c ^-Cu alkynyl, optionally substituted C2_Cig heteroalkyl, optionally substituted C3_cn cycloalkyl, optionally substituted C3_Ci2 ring dilute, optionally substituted C2_Cn heterocyclic, optionally substituted Qc] 2 heterocycloalkenyl, optionally substituted C6_Ci8 aryl and optionally substituted <^-(:18 heteroaryl, or R and R together with the atom to which they are attached form an optionally substituted cyclic moiety; Pg^ is a protecting group for oxygen; each pgN is independently a protecting group for nitrogen; each inverse 2 is independently selected from the group consisting of :Ci_c6 alkyl, dentyl-q-C6 alkyl, hydroxy Ci_Ce alkyl, Ci_C6 alkoxy 446 alkylcyano-Ci-C6 alkyl, amine c "C6 alkyl, c]-C6 alkylamino匸广152948.doc 201136930 c6 leucoyl, and di(Cl_C6 alkyl)amino-based Cl_C6 alkyl; q is an integer selected from the group consisting of ruthenium, 1, 2, 3 and 4; X is a group; each Rl (> is independently selected from the group consisting of hydrazine and optionally substituted Ci-C6 alkyl; m is an integer selected from the group consisting of ruthenium, 1, 2, 3, and 4; or its medicinal Acceptable salts, antioxidants or prodrugs. 2. The compound of claim 1 wherein q is hydrazine. 3. A compound according to claim 1 or 2, wherein R3 is selected from the group consisting of ruthenium, OR8 and, optionally, a Cl-(:6 alkyl group, wherein r8 is as defined in claim 1. The compound of claim 1 or 2, wherein R3 is H. 5. The compound of claim 1 or 2, wherein R7*He 6. The compound of claim 4, wherein the claw is selected from the group consisting of ruthenium, ruthenium and ruthenium 7. The compound of claim 1 or 2, wherein „1 is 〇 or 1. 8. The compound of claim 1 or 2, wherein (7) is ^. 9. The compound of claim 1 or 2, wherein m is 1»1〇·, as the compound of claim 9, wherein one R10 is Η&χ is a group of the formula: 11 wherein R10 is as claimed in claim 1

1中所定義。 ’其中該化合物為下式化合物 152948.doc 201136930As defined in 1. ' wherein the compound is a compound of the formula 152948.doc 201136930

ΛΛ卜 R10ΛΛ卜 R10

12. 13. 14. 15. 16. 17. 18. 其中 R1、R2、R6 K R IOl 社 c ^ R K及R如凊求項丨中所定義。如請求項10之化合物，其中Rl〇係美、域自由H、C】-C6鹵烷土丨Ά羥基烷基及c丨-C6烷基組成之群。 :請求項1G之化合物，其中R,G係選自由Η、甲基、乙土、丙基、異丙基及丁基組成之群。 ^求項1〇之化合物，其中Rl°係選自Μ、曱基及乙基組成之群。如請求項卜2及U中任一項之化合物，其中。如請求項卜2及"中任一項之化合物，其中選自由肌及她'組成之群’其中rir9如請求項丄中所定義0 如請求項1、2及11中任一項之化合物，其中R6為NH2。如叫求項1、2及11中任一項之化合物，其中R2係選自由以下組成之群：Η、氰基、視情況經取代之Ci_c〗2烷基、視情況經取代之Cs-C!2烯基、視情況經取代之C2_Ci2雜烷基、視情況經取代之C3_C12環烷基、視情況經取代之c2-cu雜環烧基、視情況經取代之C6-C18芳基及視情況經取代之Ci-C!8雜芳基。 152948.doc 201136930 其中R2為下式基 19.如請求項丨 ' :及丨丨中任一項之化合物團：12. 13. 14. 15. 16. 17. 18. Where R1, R2, R6 K R IOl, c ^ R K and R are as defined in the request. The compound of claim 10, wherein the group consisting of R1 is a free radical, a C-C6 halocarbon hydroxyalkyl group, and a c丨-C6 alkyl group. The compound of claim 1G, wherein R, G is selected from the group consisting of hydrazine, methyl, ethyl, propyl, isopropyl and butyl. The compound of claim 1 wherein R1° is selected from the group consisting of ruthenium, osmium and ethyl. The compound of any one of the items 2 and U, wherein. A compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of muscle and her', wherein rir9 is as defined in claim 1 and the compound of any one of claims 1, 2 and 11 Wherein R6 is NH2. The compound of any one of claims 1, 2, and 11, wherein R2 is selected from the group consisting of hydrazine, cyano, optionally substituted Ci_c 2 alkyl, optionally substituted Cs-C Alkenyl, optionally substituted C2_Ci2 heteroalkyl, optionally substituted C3_C12 cycloalkyl, optionally substituted c2-cu heterocycloalkyl, optionally substituted C6-C18 aryl and Substituted Ci-C! 8 heteroaryl. 152948.doc 201136930 where R2 is the formula below. 19. If the claim 丨 ': and any of the compounds in the group:

其中各Μ獨立地為N或CR2a，各尺23係獨立地選自由以下組成之群：H、齒素、OH、 N〇2、CN、nh2、視情況經取代之Μ"燒基、視情況經取代之q-cu烯基、視情況經取代之C2_Ci2炔基、視情況經取代之C：2_C〗2雜烷基、視情況經取代之C3_c"環烷基、視情況經取代之c^c〗2雜環烷基、視情況經取代之 Q-C〗2雜環烯基、視情況經取代之Q_c〗8芳基、視情況經取代之q-c〗8雜芳基、視情況經取代之Ci_Ci2烷氧基、視 If況經取代之C2-Ci2烯氧基、視情況經取代之C2_Ci2炔氧基、視情況經取代之C：2_Cl2雜烷氧基、視情況經取代、視情況經取代之Cs-C!2環烷氧基、視情況經取代之c3_Ci2 環稀氧基、視情況經取代之C1_C12雜環烷氧基、視情況經取代之C^C〗2雜環烯氧基、視情況經取代之C6_Ci8芳氧基、視情況經取代之(^-(:以雜芳氧基、視情況經取代之 Ci-C丨2 烧基胺基、SR8、s〇3H、S02NH2、SO2R8、 SONH2、SOR8、COR8、COOH、COOR8、CONR8R9、 NR8COR9、NR8C00R9、NR8S02R9、nr8conr8r9、 NR8R9及醯基；其中r8及r9如請求項l中所定義； 152948.doc • 6 - 201136930 r為選自由i、2及3組成之群的整數。 20. 21. 如請求項19之化合物，其中]>為1或2。如請求項19之化合物，其中該化合物具有下式：Each of the ridges is independently N or CR2a, and each of the ridges 23 is independently selected from the group consisting of: H, dentate, OH, N〇2, CN, nh2, optionally substituted Μ"alkyl, depending on the situation Substituted q-cu alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted C: 2_C 2 heteroalkyl, optionally substituted C3_c" cycloalkyl, optionally substituted c^ c] 2 heterocycloalkyl, optionally substituted QC 2 heterocyclenyl, optionally substituted Q_c 8 aryl, optionally substituted qc 8 heteroaryl, optionally substituted Ci_Ci2 Alkoxy, substituted C2-Ci2 alkenyloxy, optionally substituted C2_Ci2 alkynyloxy, optionally substituted C: 2_Cl2 heteroalkoxy, optionally substituted, optionally substituted Cs-C! 2 cycloalkoxy, optionally substituted c3_Ci2 cycloaliphaticoxy, optionally substituted C1_C12 heterocycloalkoxy, optionally substituted C^C 2 heterocycloalkenyloxy, optionally Substituted C6_Ci8 aryloxy, optionally substituted (^-(: with heteroaryloxy, optionally substituted Ci-C丨2 alkylamino, SR8, s〇3H, S02NH2 , SO2R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8C00R9, NR8S02R9, nr8conr8r9, NR8R9 and fluorenyl; wherein r8 and r9 are as defined in claim 1; 152948.doc • 6 - 201136930 r is selected An integer of the group consisting of free i, 2, and 3. 20. 21. The compound of claim 19, wherein > is 1 or 2. The compound of claim 19, wherein the compound has the formula:

其中R2a&r如請求項19中所定義。 22. 23. 24. 如請求項19之化合物，其中各係獨立地選自由H、 F、〇CH3、CN、0Cf3、C〇2CH3、Ν〇2、ΝΗ2 nhcoCH3、NHS〇2CH3、NHCH2CH3、CH3及 cf[组成之群。如請求項18之化合物，其中r2係選自由氰基、視情況經取代之C^-C!2烷基、視情況經取代之C3_Ci2環烷基、視情況經取代之CrCu雜環烷基及視情況經取代之C2_Cu雜烷基組成之群。如請求項23之化合物，其中R2為下式之視情況經取代之烷基：Where R2a&r is as defined in claim 19. 22. 23. The compound of claim 19, wherein each of the lines is independently selected from the group consisting of H, F, 〇CH3, CN, 0Cf3, C〇2CH3, Ν〇2, ΝΗ2 nhcoCH3, NHS〇2CH3, NHCH2CH3, CH3 and Cf [composed of groups. The compound of claim 18, wherein r2 is selected from the group consisting of cyano, optionally substituted C^-C!2 alkyl, optionally substituted C3_Ci2 cycloalkyl, optionally substituted CrCu heterocycloalkyl, and A group of C2_Cu heteroalkyl groups which are optionally substituted. The compound of claim 23, wherein R2 is an alkyl group substituted as appropriate:

其中R20、R21及R22各獨立地選自由以下組成之群： Η、Cl、Br、F、OH、NO:、CN、NH2、視情況經取代之 q-Cu烷基、視情況經取代之C2_Ci2雜烷基、視情況經取代之Ca-C!2環烷基、視情況經取代之雜環烷基、視情況經取代之Ce-C〗8芳基及視情況經取代之Ci_Ci8雜芳 152948.doc 201136930 基’或R °、R21及R22之任何兩者或兩者以上連同其所連接之碳原子一起形成環狀部分。 25_如請求項24之化合物，其中各尺2〇、RZ1及r22係獨立地選自由以下組成之群：Η、Cl、Br、F、on、N02、CN、 NH2、甲基、乙基、丙基、異丙基、丁基、戊基、甲氧基曱基、2-曱氧基乙基、3·曱氧基丙基、2·乙氧基乙基、3-乙氧基丙基、胺基甲基、2_胺基乙基、3_胺基丙基、4-胺基丁基、5-胺基戊基、甲基胺基甲基、2甲基胺基乙基、3-甲基胺基丙基、4_甲基胺基丁基、5•甲基胺基戊基、乙基胺基甲基、2-乙基胺基乙基、3 -乙基胺基丙基、4-乙基胺基丁基、5·乙基胺基戊基、二甲胺基甲基、2-二甲基胺基乙基、3_二甲基胺基丙基、4二甲基胺基丁基、5-二甲基胺基戊基、二乙基胺基甲基、2_ 二乙基胺基乙基、3-二乙基胺基丙基、4-二乙基胺基丁基及5-二乙基胺基戊基。 26. 如請求項23之化合物，其中R2係選自由以下組成之群：曱基、乙基、異丙基、丙基、2-乙基-丙基、3，3-二甲基-丙基、環丙基、環戊基、丁基、異丁基、3,3-二甲基·丁基、2-乙基-丁基、戊基、2-曱基、戊基、戊-4-烯基、己基、庚基、辛基、氰基、曱氧基甲基及丁氧基曱基。 27. 如請求項1、2及11中任一項之化合物，其中該視情況存在之取代基係選自由以下組成之群：F、Br、C1、=0、 =S、-CN、甲基、三氟曱基、乙基、2,2,2-三氟乙基、異丙基、丙基、2-乙基-丙基、3，3-二曱基-丙基、丁基、異 152948.doc 201136930 丁基、3，3 -二甲基-丁基、2 -乙基-丁基、戍基、2 -甲基-戊基、戊-4-烯基、己基、庚基、辛基、苯基、NH2、-N02 、苯氧基、羥基、甲氧基、三氟甲氧基、乙氧基及亞曱基二氧基。 28.如請求項1之化合物，其選自由以下組成之群：Wherein R20, R21 and R22 are each independently selected from the group consisting of ruthenium, Cl, Br, F, OH, NO:, CN, NH2, optionally substituted q-Cu alkyl, optionally substituted C2_Ci2 Heteroalkyl, optionally substituted Ca-C!2 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ce-C 8 aryl and optionally substituted Ci_Ci8 heteroaryl 152948 .doc 201136930 The base 'or any two or more of R ° , R 21 and R 22 together with the carbon atom to which they are attached form a cyclic moiety. The compound of claim 24, wherein each of the ruthenium, RZ1 and r22 is independently selected from the group consisting of ruthenium, Cl, Br, F, on, N02, CN, NH2, methyl, ethyl, Propyl, isopropyl, butyl, pentyl, methoxyindenyl, 2-decyloxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl , aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3 -Methylaminopropyl, 4-methylaminobutyl, 5•methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl , 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethyl Aminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl And 5-diethylaminopentyl. 26. The compound of claim 23, wherein R2 is selected from the group consisting of thiol, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl , cyclopropyl, cyclopentyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-indenyl, pentyl, pent-4- Alkenyl, hexyl, heptyl, octyl, cyano, decyloxymethyl and butoxycarbonyl. 27. The compound of any one of claims 1, 2, and 11, wherein the optionally present substituent is selected from the group consisting of F, Br, C1, = 0, =S, -CN, methyl , trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimercapto-propyl, butyl, iso 152948.doc 201136930 Butyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, decyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl Base, phenyl, NH2, -N02, phenoxy, hydroxy, methoxy, trifluoromethoxy, ethoxy and fluorenyldioxy. 28. The compound of claim 1 which is selected from the group consisting of:

152948.doc -9- 201136930152948.doc -9- 201136930

152948.doc • 10· 201136930152948.doc • 10· 201136930

152948.doc • 11 - 201136930152948.doc • 11 - 201136930

或其醫藥學上可接受之鹽或前藥。 29. 30. 31. 一種醫藥組合物，其包含如請求項1至28中任一項之化合物及醫藥學上可接受之稀釋劑、賦形劑或載劑。一種活體外抑制蛋白激酶之方法，該方法包括使該蛋白激酶或其片段或複合物或其功能等效物及/或其輔因子接觸有效量之如請求項1至28中任一項之化合物。如明求項30之方法’其中該蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。 152948.doc -12· 201136930 32.如請求項31之方法，其中該絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為mTOR蛋白激酶或其片段、或其複合物或其功能等效物β . 33.如請求項31或32之方法，其中該絲胺酸/蘇胺酸蛋白激酶為mTORC 1或其片段或複合物或其功能等效物。 34. —種如請求項i至28中任一項之化合物的用途’其用於製造抑制一或多種蛋白激酶之藥劑。 35. 如請求項34之用途，其中該蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。 36. 如請求項35之用途，其中該絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為mTOR蛋白激酶或其片段、或其複合物或其功能等效物。 37. 如請求項35或36之用途，其中該絲胺酸/蘇胺酸蛋白激酶為mTORCl或其片段或複合物或其功能等效物。 38'種如凊求項1至28中任一項之化合物的用途，其用於製造治療或預防哺乳動物之病狀的藥劑，其中抑制一或多種蛋白激酶或其片段或複合物或其功能等效物可以預防、抑制或改善該病狀之病理或症狀。 3 9 ·如吻求項3 8之用途，其中該蛋白激酶為絲胺酸/蘇胺酸蛋 . 白激酶或其片段或複合物或其功能等效物。 4〇·如請求項39之用途，其中該絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為mTOR蛋白激酶或其片段、或其複合物或其功能等效物。 41.如請求項39或40之用途，其中該絲胺酸/蘇胺酸蛋白激酶 152948.doc •13· 201136930 為mTORCl或其片段或複合物或其功能等效物β 42. 如請求項38至40中任一項之用途，其中該病狀係選自由以下組成之群：炎症、類風濕性關節炎、牛皮癬、動脈粥樣硬化、結腸炎、發炎性腸病、胰腺炎、多發性硬化症、自體免疫病症、狼瘡、過敏性腦脊髓炎、移植排斥反應、子宮内膜異位症、平滑肌瘤、多囊性卵巢症候群、錯構瘤、結節性硬化症、阿茲海默氏病（Alzheimer,s disease)、予廷頓氏症（Huntington's disease)、帕金森氏病（Parkinson’s disease)、胰島素依賴性糖尿病、肥胖、糖尿病性視網膜病、心臟肥大及自體顯性多囊性腎病。 43. 如請求項38至40中任一項之用途，其中該病狀為癌症。 44. 如請求項43之用途，其中該癌症係選自由以下組成之群.血液癌症，諸如骨髓增生性病症（特發性骨髓纖維化 '真性紅血球增多症、原發性血小板增多症、慢性骨髓白血病）、骨髓細胞化生、慢性骨髓單核細胞性白血病、急性淋巴細胞白血病、急性紅血球母細胞白血病、霍奇金氏及非霍奇金氏病、B細胞淋巴瘤、急性丁細胞白病月髓發月不良徵候群、漿細胞病症、毛細胞白血病卡波希氏肉瘤、淋巴瘤；婦科癌症，諸如乳癌、印巢癌、子呂頸癌、***癌及外陰癌、子宮内膜增生；胃腸道癌，諸如結腸直腸癌、息肉、肝癌、胃癌、胰臟癌、膽囊癌；泌尿道癌，諸如***癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌’諸如黑色素瘤；腦腫瘤’諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞 152948.doc 201136930 瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經膠質瘤；頭頸部癌，諸如鼻咽癌、喉癌；呼吸道癌，諸如肺癌（NSCLC&SCLC)、 • 間皮瘤；眼病，諸如視網骐胚細胞瘤；肌肉骨骼疾病，諸如骨肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。 45. —種如請求項1至28中任—項之化合物或其醫藥學上可接受之鹽、N-氧化物或前藥的用途，其用於製造治療病狀之藥劑，其中抑制一或多種蛋白激酶或其複合物或其功能等效物可以預防、抑制或改善該病狀之病理或症狀。 46. 如咕求項45之用途，其中該蛋白激酶為絲胺酸/蘇胺酸蛋白激酶或其片段或複合物或其功能等效物。 47. 如請求項46之用途，其中該絲胺酸/蘇胺酸蛋白激酶或其片段或複合物為mTOR蛋白激酶或其片段、或其複合物或其功能等效物。 48. 如請求項46或47之用途，其中該絲胺酸/蘇胺酸蛋白激酶為mTORCl或其片段或複合物或其功能等效物。 49. 如請求項45至47十任一項之用途，其中該病狀係選自由 . 以下組成之群：炎症、類風濕性關節炎、牛皮癬、動脈 * 粥樣硬化、結腸炎、發炎性腸病、胰腺炎、多發性硬化症、自體免疫病症、狼瘡、過敏性腦脊髓炎、移植排斥反應、子宮内膜異位症、平滑肌瘤、多囊性卵巢症候群、錯構瘤、結節性硬化症、阿茲海默氏病、亨廷頓氏症、帕金森氏病、胰島素依賴性糖尿病、肥胖、糖尿病 152948.doc •15- 201136930 性視網膜病、心臟肥大及自體顯性多囊性腎病。 50.如請求項45至47中任一項之用途，其中該病狀為癌症。 51·如請求項50之用途，其中該癌症係選自由以下組成之群.血液癌症，諸如骨髓增生性病症（特發性骨髓纖維化、真性紅血球增多症、原發性血小板增多症、慢性骨髓白血病）、骨髓細胞化生、慢性骨髓單核細胞性白血病、急性淋巴細胞白血病、急性紅血球母細胞白血病、霍奇金氏及非霍奇金氏病（H〇dgkin，s and Non Hodgkin's disease)、B細胞淋巴瘤、急性τ細胞白血病、骨髓發育不良徵候群、漿細胞病症、毛細胞白血病、卡波希氏肉瘤（kaposi’s sarcoma)、淋巴瘤；婦科癌症，諸如乳癌、卵巢癌、子宮頸癌、***癌及外陰癌、子宮内膜增生；胃腸道癌’諸如結腸直腸癌、息肉、肝癌、胃癌、膜臟癌、膽囊癌；泌尿道癌’諸如***癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌，諸如黑色素瘤；腦腫瘤’諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經膠質瘤；頭頸部癌，諸如鼻咽癌、喉癌；呼吸道癌，諸如肺癌（NSCLC及SCLC)、間皮瘤；眼病，諸如視網膜胚細胞瘤；肌肉骨骼疾病，諸如骨肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。 52. —種如請求項1至28中任一項之化合物的用途，其用於製造預防或治療個體之增生性病狀的藥劑。 53. 如請求項52之用途’其中該病狀為癌症。 152948.doc -16- 201136930 54.如請求項53之用途，其令該癌症係選自由以下組成之群.血液癌症’諸如骨髓增生性病症（特發性骨髓纖維化、真性紅血球增多症、原發性血小板增多症、慢性骨髓白血病）、f趙細胞化±、慢性骨髓單核細胞性白血 =、急性淋巴細胞白血病、急性紅血球母細胞白血病、隹奇金氏及非霍奇金氏病、B細胞淋巴瘤、急性T細胞白血病、骨髓發育不良徵候群、聚細胞病症、毛細胞白血病、卡波希氏肉瘤、淋巴瘤；婦科癌症，諸如乳癌、卵巢癌 '子宮頸癌、***癌及外陰癌、子宮内膜增生；胃腸道癌，諸如結腸直腸癌、息肉、肝癌、胃癌、胰臟癌、膽囊癌；泌尿道癌，諸如***癌、腎癌；泌尿膀胱癌、尿道癌、陰莖癌；皮膚癌，諸如黑色素瘤；腦腫瘤，諸如神經膠母細胞瘤、神經母細胞瘤、星形細胞瘤、室管膜瘤、腦幹神經膠質瘤、神經管胚細胞瘤、腦膜瘤、星形細胞瘤、少突神經膠質瘤；頭頸部癌，諸如鼻咽癌 '喉癌；呼吸道癌，諸如肺癌（NSCLC及sclc)、間皮瘤，眼病，諸如視網膜胚細胞瘤；肌肉骨骼疾病，諸如骨肉瘤、肌肉骨骼腫瘤；鱗狀細胞癌及纖維瘤。 55.如凊求項【、2、11及28中任一項之化合物或其醫藥學上可接党之鹽、N-氧化物或前藥，其治療增生性病狀。 152948.doc •17· 201136930 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明：五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Or a pharmaceutically acceptable salt or prodrug thereof. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable diluent, excipient or carrier. A method of inhibiting a protein kinase in vitro, the method comprising contacting the protein kinase or a fragment or complex thereof or a functional equivalent thereof and/or a cofactor thereof with an effective amount of a compound according to any one of claims 1 to 28 . The method of claim 30 wherein the protein kinase is serine/threonine kinase or a fragment or complex thereof or a functional equivalent thereof. The method of claim 31, wherein the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof The method of claim 31 or 32, wherein the serine/threonine protein kinase is mTORC 1 or a fragment or complex thereof or a functional equivalent thereof. 34. Use of a compound according to any one of claims 1 to 28 which is for the manufacture of a medicament for inhibiting one or more protein kinases. 35. The use of claim 34, wherein the protein kinase is serine/threonuclease or a fragment or complex thereof or a functional equivalent thereof. 36. The use of claim 35, wherein the serine/threonine protein kinase or fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof. 37. The use of claim 35 or 36, wherein the serine/threonine protein kinase is mTORCl or a fragment or complex thereof or a functional equivalent thereof. The use of a compound according to any one of claims 1 to 28 for the manufacture of a medicament for treating or preventing a condition in a mammal, wherein the inhibition of one or more protein kinases or fragments or complexes thereof or functions thereof Equivalents may prevent, inhibit or ameliorate the pathology or symptoms of the condition. The use of the protein kinase is a serine/threonine egg white kinase or a fragment or complex thereof or a functional equivalent thereof. The use of claim 39, wherein the serine/threonine protein kinase or a fragment or complex thereof is mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. 41. The use of claim 39 or 40, wherein the serine/threonine protein kinase 152948.doc •13·201136930 is mTORCl or a fragment or complex thereof or a functional equivalent thereof β 42. The use according to any one of the preceding claims, wherein the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis Symptoms, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's Disease (Alzheimer, s disease), Huntington's disease, Parkinson's disease, insulin-dependent diabetes, obesity, diabetic retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease . The use of any one of claims 38 to 40, wherein the condition is cancer. 44. The use of claim 43, wherein the cancer is selected from the group consisting of a blood cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, true polycythemia, essential thrombocythemia, chronic bone marrow) Leukemia), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's and non-Hodgkin's disease, B-cell lymphoma, acute D-cell white matter month Symptoms of medullary dysplasia, plasma cell disease, hairy cell leukemia Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, Indian cancer, child lung cancer, vaginal cancer and vulvar cancer, endometrial hyperplasia; Cancer, such as colorectal cancer, polyp, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer 'such as melanoma; brain Tumors such as glioblastoma, neuroblastoma, astrocytes 152948.doc 201136930 tumor, ependymoma, brain stem glioma Neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC & SCLC), mesothelioma; eye disease, Such as retinal blastoma; musculoskeletal disorders, such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 45. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, N-oxide or prodrug thereof, for the manufacture of a medicament for treating a condition, wherein inhibition A variety of protein kinases or complexes thereof or functional equivalents thereof can prevent, inhibit or ameliorate the pathology or symptoms of the condition. 46. The use of claim 45, wherein the protein kinase is serine/threonine kinase or a fragment or complex thereof or a functional equivalent thereof. 47. The use of claim 46, wherein the serine/threonine protein kinase or fragment or complex thereof is mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof. 48. The use of claim 46 or 47, wherein the serine/threonine protein kinase is mTORCl or a fragment or complex thereof or a functional equivalent thereof. 49. The use of any one of claims 45 to 47, wherein the condition is selected from the group consisting of: inflammation, rheumatoid arthritis, psoriasis, arterial* atherosclerosis, colitis, inflammatory bowel Disease, pancreatitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovary syndrome, hamartoma, nodular Sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes, obesity, diabetes 152948.doc •15-201136930 Retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease. The use of any one of claims 45 to 47, wherein the condition is cancer. 51. The use of claim 50, wherein the cancer is selected from the group consisting of a blood cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic bone marrow) Leukemia), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's disease, and Non-Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, myelodysplastic syndrome, plasma cell disease, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, Vaginal cancer and vulvar cancer, endometrial hyperplasia; Gastrointestinal cancer such as colorectal cancer, polyps, liver cancer, stomach cancer, visceral cancer, gallbladder cancer; urinary tract cancer such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer , penile cancer; skin cancer, such as melanoma; brain tumors such as glioblastoma, neuroblastoma, star Tumor, ependymoma, brain stem glioma, neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as Lung cancer (NSCLC and SCLC), mesothelioma; eye diseases such as retinoblastoma; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 52. Use of a compound according to any one of claims 1 to 28 for the manufacture of a medicament for preventing or treating a proliferative condition in an individual. 53. The use of claim 52 wherein the condition is cancer. 152948.doc -16- 201136930 54. The use of claim 53, wherein the cancer is selected from the group consisting of: a blood cancer such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, original Thrombotic thrombocytosis, chronic myeloid leukemia), f cytochemistry ±, chronic myelomonocytic leukemia =, acute lymphoblastic leukemia, acute red blood cell line leukemia, 隹奇金氏和非霍奇金病, B Cellular lymphoma, acute T cell leukemia, myelodysplastic syndrome, polycytosis, hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer 'cervical cancer, vaginal cancer and vulvar cancer , endometrial hyperplasia; gastrointestinal cancer, such as colorectal cancer, polyps, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin Cancer, such as melanoma; brain tumors, such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brainstem glial Tumor, blastocystoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC and sclc), mesothelioma, eye disease , such as retinoblastoma; musculoskeletal disorders, such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 55. A compound according to any one of clauses 2, 11 and 28, or a pharmaceutically acceptable salt, N-oxide or prodrug thereof, for the treatment of a proliferative condition. 152948.doc •17· 201136930 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature:

152948.doc152948.doc