TW201130813A

TW201130813A - Therapeutic uses

Info

Publication number: TW201130813A
Application number: TW099143134A
Authority: TW
Inventors: John King-Underwood; Kazuhiro Ito; Peter Strong; Garth Rapeport; Catherine Charron; Peter John Murray; Jonathan Gareth Williams; Stuart Thomas Onions; Robert Fenton
Original assignee: Respivert Ltd
Priority date: 2009-12-11
Filing date: 2010-12-10
Publication date: 2011-09-16
Also published as: WO2011070368A1; GB0921731D0; UY33097A

Abstract

Compounds of formula (I): wherein R1, R2, R3, Ar, L, X and Q are as defined herein are useful for the treatment or prophylaxis of viral infections, especially influenza virus infections.

Description

201130813 六、發明說明：【發明所屬之技術領域】本揭示係有關式⑴化合物以單一治療或同時地或相繼地併用其他抗病毒劑用於治療及/或預防病毒感染 (例如治療及/或預防流感病之感染）的用途。本揭示也延伸至包含該等活性成分之組合調配物。【先前技術·】發明背景季節性流感為一種亞急性疾病，其在明確界定之人口亞群，特別是很年輕的人、老年人及該等患有慢性病 (諸如鬱血性心臟衰竭)者造成顯著死亡率。此外病毒感染在更廣泛的人口中產生顯著發病率(Nichol，K. L.等人 ’ N. Engl. J. Med., 1995, 333 : 889-893)。最近人類歷史也証明：有時候發生流感病毒之更毒株，其在“健康的年輕人”之中是實質死亡率及發病率原因。疫苗接種為用以控制季節性流感對有危險的族群及更廣泛的人π之衝擊的原則干預。多數有危險的患者 (諸如该等患有糖尿病、鬱i性心臟衰竭、腎衰竭性阻塞性職疾病者)適合於以疫苗接觀防性二然而’其不適合於其他免疫抑制族群，諸如接受化療之癌症患者。“，㈣大流行域所造成 = 要：此方案輔之以用直接針對病毒的繁殖之治療脅二 ;限，染個T中的臨床疾病。此為世界各地公共衛; 當局對最近全軸爆發之豬流感所採㈣方式ζ生適用於臨床使用之原則藥品對準^ 201130813 苷酶酵素且包括產品扎那米韋(zanamivir)(Relenza)及奥塞米韋(oseltamivir)(Tamiflu)。這些藥的效力被一些包括需要在預防性方案中或感染發作之後很快地投予之因素限制（Gubareva, L.V.等人，Lancet 2000，355 : 827-835.)。在更廣泛的人口中由確定（12-24小時)感染之治療產生的利益(症狀減輕及期間）已顯示為適中的，雖然神經胺糖酸苷酶抑制劑高劑量係用作加護病房上之治療方案的部份。和其他病毒一樣，流感菌株已經出現表現突變酵素，其使得病毒抵抗這些治療（參見例如，Aoki，F.Y.; Boivin，G.;及 Roberts, N. Antivir. Ther.，2007，12(4 Part B) ： 603-616) ° 這些因素使得鑑別能抑制流感病毒的繁殖且提供減輕或避免疾病的臨床結果之利益之新穎、安全及/或更有效的藥物被高度期待。病毒進入宿主細胞係與許多細胞内信號路徑之活化(相信其在病毒-媒介之發炎過程（由Ludwig，S.評論於 Signal Transduction，2007，7(1) : 81-88.)及病毒繁殖和後來的釋放中扮演突出角色）有關。一種該機制，其試管内媒介流感病毒繁殖，為PI3激酶/Akt路徑。此路徑被病毒之NS1蛋白質的活化已被描述(shin，Y-K. 等人，J. Gen. Virol. ’ 2007，88 : 13-18.)且已報導其抑制作用減少所產生的子代病毒之滴定度（Ehrhardt, C. 等人 ’ Cell Microbiol” 2006, 8(8) : 1336-1348)。此外，201130813 VI. Description of the invention: [Technical field to which the invention pertains] The present disclosure relates to the treatment of and/or prevention of viral infection (eg, treatment and/or prevention) of a compound of formula (1) in a single treatment or simultaneously or sequentially in combination with other antiviral agents. Use of influenza infections). The present disclosure also extends to combination formulations comprising such active ingredients. [Prior Art] Background of the Invention Seasonal influenza is a subacute disease that causes significant subgroups of well-defined populations, particularly young people, the elderly, and those with chronic diseases such as septic heart failure. mortality rate. In addition, viral infections produce significant morbidity in the wider population (Nichol, K. L. et al. 'N. Engl. J. Med., 1995, 333: 889-893). Recent human history has also shown that sometimes more virulent strains of influenza virus occur, which are the cause of substantial mortality and morbidity among “healthy young people”. Vaccination is a principle intervention to control the impact of seasonal influenza on at-risk groups and the wider population. Most patients at risk (such as those with diabetes, depression, renal failure, obstructive occupational disease) are suitable for vaccination. However, they are not suitable for other immunosuppressive groups, such as receiving chemotherapy. Cancer patients. ", (4) caused by the pandemic domain = to: This program is supplemented by the treatment of the virus directly against the virus 2; limit, dye a clinical disease in T. This is the public health around the world; the authorities on the recent full-axis outbreak The swine flu method (4) method is suitable for clinical use. The drug is aligned with the 201130813 glucosidase enzyme and includes the products zanamivir (Relenza) and oseltamivir (Tamiflu). The efficacy is limited by factors including those that need to be administered in a prophylactic regime or soon after the onset of infection (Gubareva, LV et al, Lancet 2000, 355: 827-835.) identified by the wider population ( 12-24 hours) The benefits of treatment (symptoms and periods) of infection have been shown to be moderate, although high doses of neuraminidase inhibitors are used as part of the treatment regimen in the intensive care unit. Similarly, influenza strains have been shown to exhibit mutant enzymes that make the virus resistant to these therapies (see, for example, Aoki, FY; Boivin, G.; and Roberts, N. Antivir. Ther., 2007, 12(4 Part B): 603- 616) ° These Factors that make it possible to identify novel, safe, and/or more effective drugs that inhibit the spread of influenza virus and provide the benefit of reducing or avoiding the clinical consequences of the disease are highly anticipated. Virus entry into host cell lines and activation of many intracellular signaling pathways (I believe It is involved in the viral-mediated inflammatory process (promoted by Ludwig, S. Review Signal Transduction, 2007, 7(1): 81-88.) and viral reproduction and subsequent release. One such mechanism The in-vitro vector influenza virus multiplies as the PI3 kinase/Akt pathway. This pathway has been described by the activation of the NS1 protein of the virus (shin, YK. et al., J. Gen. Virol. ' 2007, 88 : 13-18.) The titer of progeny virus produced by the reduction of its inhibitory activity has been reported (Ehrhardt, C. et al. 'Cell Microbiol' 2006, 8(8): 1336-1348). In addition,

已經報導MEK抑制劑，U0126，抑制病毒繁殖而沒有病毒的抗藥性變體的檢測（Ludwig，S.等人，FEBS 4 201130813MEK inhibitors, U0126, have been reported to inhibit the propagation of virus-free drug-resistant variants (Ludwig, S. et al., FEBS 4 201130813)

Lett.，2004，561(1-3) : 37-43)。除了研究流感病毒在細胞中的繁殖之外，可能使用活體内模式(諸如小鼠及鼬模式）將治療對病毒量之效果示性。藉由開發試管内及活體内系統之組合，可能比較意欲抑制流感病毒繁殖之新穎化合物的效果，與確定的臨床藥劑（諸如扎那米韋（zanamivir)(Relenza)及奥塞米韋(〇seltamivir)(Tamifhi)，呈單一治療方案及與這些及/ 或其藥試劑組合之性質。值得注意的是組合治療在減緩傳染病上會是一種十分有效的方法。此以HIV感染的藥物治療之發展充份地說明，其開始為單一治療但是已經穩定地發展到使用針對兩種不同的病毒蛋白之藥物的三重治療被黃金標準之情形。其實，最近出版品已報導：==Lett., 2004, 561(1-3): 37-43). In addition to studying the proliferation of influenza viruses in cells, it is possible to use an in vivo model (such as mouse and sputum mode) to treat the effect on the amount of virus. By developing a combination of in vitro and in vivo systems, it may be possible to compare the effects of novel compounds intended to inhibit influenza virus reproduction, with established clinical agents (such as zanamivir (Relenza) and oseltamivir (〇seltamivir). (Tamifhi), a single treatment regimen and the combination of these and / or its pharmaceutical agents. It is worth noting that combination therapy can be a very effective method to slow down infectious diseases. The development of drug treatment with HIV infection Sufficiently stated that it began as a single treatment but has been steadily developed to the gold standard using triple therapy for two different viral proteins. In fact, recent publications have reported: ==

糖酸苷酶抑制劑組合使用相容的新藥（特別是在房的環境中）是有利的。經胺護病【發明内容】發明之簡要說明我們已經發現某些式(I)之化合物It is advantageous to use a combination of glycosidase inhibitors in a compatible new drug, especially in the environment of a house. Amine Care [Invention] Brief Description of the Invention We have found certain compounds of formula (I)

201130813 -5-基)脲基]萘-1-基氧基}甲基)吼啶-2-基]-2-曱氧基乙醯胺（化合物實例1)在MDCK細胞中和活體内老鼠模式之抑制流感誘導之蛋白質表現（血球凝集素 (haemaglutinnin)或核蛋白質）和CPE之能力。此顯示化合物提供抵抗流感HlNl(PR8)(Newton，S. E.等人， Virology，1983，128(2) : 495-501 ; Reading，P.C.等人， J. Virol. 1997，71(11) : 8204-8212)及其他菌株之顯著地有效的試管内活性。因此本發明提供一種式(I)之化合物：201130813 -5-yl)ureido]naphthalen-1-yloxy}methyl)acridin-2-yl]-2-decyloxyacetamide (Compound Example 1) in MDCK cells and in vivo mouse model Its ability to inhibit influenza-induced protein expression (haemaglutinnin or nuclear protein) and CPE. This shows that the compound provides resistance against influenza HlNl (PR8) (Newton, SE et al, Virology, 1983, 128(2): 495-501; Reading, PC et al, J. Virol. 1997, 71(11): 8204-8212 Significantly effective in vitro activity of other strains. The invention therefore provides a compound of formula (I):

其中R1為視需要經羥基基團取代之Cl.6烷基； R2為Η或視需要經羥基基團取代之Cl_6烷基； R3為H'Cw烷基或Cq.3烷基（^6環烷基；Wherein R1 is a C.6 alkyl group optionally substituted by a hydroxyl group; R2 is a hydrazine or a C1-6 alkyl group substituted by a hydroxy group as required; and R3 is an H'Cw alkyl group or a Cq.3 alkyl group (^6 ring) alkyl;

Ar為萘基或笨基環，其任一可視需要經一或多個獨立地選自c〗_6院基、Cl 6烷氧基、胺基、Ci 4單或c2.8> 烷胺基之基團（例如1至3個，諸如1、2或3個基團）取代； L為飽和或不飽和支鏈或非支鏈Ci8伸烷基鏈，其中一或多個碳(例如1至3個’諸如1、2或3個碳）視需要經置換及該鏈視需要經一或多個鹵素原子(例如1至 6 201130813 6個）取代； X為包含至少一個氮原子及視要包括1或2個選自Ο、 S及N的另外雜原子之5或6員雜芳基； Q係選自： a) 飽和或不飽和支鏈或非支鏈C^o烷基鏈，其中至少一個碳(例如1、2或3個碳，適當地1或2個，特別是 1個碳)係經選自0、N、S(0)p之雜原子置換，其中該鏈視需要地經一或多個獨立地選自側氧基、li素、芳基、雜芳基、雜環基或C3_8環烷基之基團（例如1、2或3個基團）取代，各芳基、雜芳基、雜環基或C3_8環烷基具有0至3個取代基選自鹵素、羥基、Cu烷基、烷氧基、Cw鹵炫*基、胺基、Ci-4早或C2-8二院胺基、Ci_4早或C2-8二 -酿基胺基、S(0)qCi-6烧基、C〇-6烧基C(0)Ci—6烧基或 C〇_6烷基QCOCw雜烷基，其先決條件為直接地連接至-nr3c(o)-中之羰基的原子不為氧或硫原子；及 b) C〇_8烷基-雜環，該雜環基包含至少一個選自0、N及 S之雜原子(例如1、2或3個，適當地1或2個，特別是1個雜原子），及其視需要經一、二或三個獨立地選自鹵素、經基、Cu烧基、C】-6烧氧基、C!_6鹵烧基、胺基、Cm單及C2_8二-烷胺基、Cm單或C2_8二-醯基胺 201130813 暴、scov^烷基、Cq 6烷基c(0)Ci 6烧基、Cq 6烷基 C(0)NC〇_6烧基CQ 6烷基或cQ 6烷基c(〇)CG_6雜烷基之基團取代；及 P為0、1或2 ; q為〇、1或2 ;或或其醫藥上可接受的鹽或溶劑合物，包括其所有立體異構物、互變異構物及同位素衍生物，其先決條件為式⑴ 之化合物不為N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基 -lH-t坐-5-基）脲基）萘+基氧基）π比啶_2_基)_2_曱氧基乙醯胺或其醫藥上可接受的鹽或溶劑合物，於治療或預防病毒感染(例如流感病毒感染）之用途。因此提供式(I)化合物用於下列之用途：包括減少症狀的嚴重性及/或期間之治療；或防止或限制被流感病毒(例如其A、Β及c菌株)感染的嚴重性之預防。發明之詳細說明烷基如使用在本文中係指直鏈或支鏈烷基，諸如而沒有限制曱基、乙基、正丙基、異丙基、丁基、正丁基及第三-丁基。在一具體實例中烷基係指直鏈烷基。烷氧基如使用在本文中係指直鏈或支鏈烷氧基，例如曱氧基、乙氧基、丙氧基、丁氧基。烷氧基如使用在 8 201130813 本文中也延伸至其中氧原子位於烷基鏈内之具體實例，例如-Cw烷基〇Ci3烷基，諸如_CH2CH2〇CH3或 -CH2〇CH3。因此在—具體實例中’該烷氧基係經由碳連接至分子的剩餘部分。在一具體實例中，該烷氧基係經由氧連接至分子的剩餘部分’例如-C〇烷基0C!-6烷基。在一具體實例中，該揭示有關直鏈烷氧基。雜烷基如使用在本文中意指支鏈或直鏈烷基，其中一或多個諸如丨、2或3個碳)係經選自N、0或s(0) 亡雜原子取代’其中q表示〇、14 2。雜原子可置換q 一級、二級或三級碳，即，例如，置換CH3之SH、OH 或應2，或置換-(:如之NH或〇或s〇2或置換ch_ 或支鏈碳基之N，如技術上適當的話。鹵烷基如使用在本文中係指具有1至6個齒素原子 (例如1至5個鹵素)之烧基，諸如全_烧基，特別是全氟烷基，更特別是-CF2CF3或CF3。Ar is a naphthyl or a stupid ring, any of which may optionally be selected from one or more independently selected from the group consisting of c 6-6, C 6 alkoxy, amine, Ci 4 or c 2.8 > alkylamine a group (for example 1 to 3, such as 1, 2 or 3 groups) substituted; L is a saturated or unsaturated branched or unbranched Ci8 alkyl chain, of which one or more carbons (for example 1 to 3) 'such as 1, 2 or 3 carbons' are replaced as needed and the chain is optionally substituted by one or more halogen atoms (for example, 1 to 6 201130813 6); X is at least one nitrogen atom and includes 1 Or 2 or 6 membered heteroaryl groups of another hetero atom selected from the group consisting of hydrazine, S and N; the Q group is selected from the group consisting of: a) a saturated or unsaturated branched or unbranched C^o alkyl chain, at least one of which Carbon (for example 1, 2 or 3 carbons, suitably 1 or 2, in particular 1 carbon) is replaced by a hetero atom selected from 0, N, S(0)p, wherein the chain is optionally Or a plurality of groups (for example, 1, 2 or 3 groups) independently selected from the group consisting of a pendant oxy group, a licin, an aryl group, a heteroaryl group, a heterocyclic group or a C3-8 cycloalkyl group, each aryl group, hetero An aryl group, a heterocyclic group or a C3_8 cycloalkyl group having 0 to 3 substituents selected From halogen, hydroxy, Cu alkyl, alkoxy, Cw halo*, amine, Ci-4 early or C2-8 amphoteric amine, Ci_4 early or C2-8 di-bristyl amine, S ( 0) qCi-6 alkyl, C〇-6 alkyl C(0)C-6 alkyl or C〇_6 alkyl QCOCw heteroalkyl, the prerequisite being directly linked to -nr3c(o)- The atom of the carbonyl group is not an oxygen or sulfur atom; and b) a C〇_8 alkyl-heterocyclic ring containing at least one hetero atom selected from 0, N and S (for example 1, 2 or 3, Suitably 1 or 2, in particular 1 heteroatom), and optionally, one, two or three, independently selected from the group consisting of halogen, thiol, Cu, C -6 alkoxy, C! _6 Halogenated group, amine group, Cm mono and C2_8 di-alkylamino group, Cm mono or C2_8 di-decylamine 201130813 violent, scov^alkyl, Cq 6 alkyl c(0)Ci 6 alkyl, Cq 6 alkane a group of C(0)NC〇_6 alkyl CQ 6 alkyl or cQ 6 alkyl c(〇)CG_6 heteroalkyl; and P is 0, 1 or 2; q is 〇, 1 or 2; Or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers, tautomers and isotopic derivatives thereof, with the proviso that the compound of formula (1) is not N-(4-(4-( 3-(3-Terti-butyl-1-p-tolyl-lH-t-s--5-yl)ureido)naphthalene+yloxy)π-pyridyl-2-yl)_2-methoxy-4- Use of guanamine or a pharmaceutically acceptable salt or solvate thereof for treating or preventing a viral infection, such as an influenza virus infection. Thus, the use of a compound of formula (I) is provided for the following purposes: including reducing the severity and/or duration of treatment of the symptoms; or preventing or limiting the prevention of the severity of infection by influenza viruses (e.g., strains A, sputum and c). DETAILED DESCRIPTION OF THE INVENTION Alkyl as used herein, refers to a straight or branched alkyl group, such as without limitation sulfhydryl, ethyl, n-propyl, isopropyl, butyl, n-butyl, and tert-butyl. base. In one embodiment, an alkyl group refers to a linear alkyl group. Alkoxy, as used herein, refers to a straight or branched alkoxy group, such as a decyloxy group, an ethoxy group, a propoxy group, a butoxy group. The alkoxy group is also extended herein to the specific example in which the oxygen atom is located in the alkyl chain, such as -Cw alkyl 〇Ci3 alkyl, such as _CH2CH2〇CH3 or -CH2〇CH3, as used in 8 201130813. Thus in a particular embodiment the alkoxy group is attached to the remainder of the molecule via a carbon. In one embodiment, the alkoxy group is attached to the remainder of the molecule via an oxygen, such as a -C〇alkyl 0C!-6 alkyl group. In one embodiment, the disclosure relates to linear alkoxy groups. A heteroalkyl group, as used herein, means a branched or straight chain alkyl group, wherein one or more, such as deuterium, 2 or 3 carbons, are substituted by a heteroatom selected from N, 0 or s(0). Express 〇, 14 2. A hetero atom may replace q a primary, secondary or tertiary carbon, ie, for example, SH, OH or 2, or a substitution - (: such as NH or 〇 or s〇2 or a substituted ch_ or a branched carbon group N, as technically appropriate. Haloalkyl as used herein refers to a burnt radical having from 1 to 6 crypto atoms (eg 1 to 5 halogens), such as a full-alkyl group, especially a perfluoroalkane. Base, more particularly -CF2CF3 or CF3.

Cl-4單或（：2·8二-醯基胺基分別地意指烧基及(-NC^OXV;烷基)CXCOCw烷基）。Cl-4 mono or (: 2·8-di-decylamino group means alkyl and (-NC^OXV; alkyl) CXCOCw alkyl, respectively).

Ci_4單或CM二-烷胺基分別地意指·NHCi 4烷基及 -n(c].4 烷基)(Cl_4 烷基）。芳基如使用在本文中係指例如具有從丨至3個環之 Cq'單或多環基團，其中至少一個環為包括苯基、萘基、基、1，2,3,4·四氫萘基等等之芳族，諸如苯基及蔡基。 '、方i為6至10貝芳族單環或雙環系統，苴中^ 少-個環為包含-或多個(例如卜2、3或4個)獨立办選自〇、N及S之雜原子的芳族核。雜芳基的例子包括 201130813 一°又：坐塞唑、異噻唑、咪唑、D比唑、異°咢唑、吡 3疋及^ ΓΓ、终苯并°塞吩、笨并吱喃，或卜2、及1、2、4三嗤。如使用在本文中係指包含-或多_如至員飽“二)獨立地選自〇、N& S之雜原子的5 員I和或部分不飽和非芳 ::可具有側氡基取代基。C二== 包含，個(例如卜2、3或4 = 和非芳族碳環，其中各雜原 ^和或心不飽二個碳可具有側氧基取代基然:不 =:rr、子之任何價數視情== 環上的，代基視情況而定可在碳上咯淋吻各< =°雜钱C5·6雜環的例子包括°比吡唑啶、呼^ 喃、四氫麵、K和米唾琳、 S Μ '側、二氧戊_—、、派喃、二氫°底°南、派咬、娘口井、嗎啉、一圬烷、硫嗎啉及氧硫仙。氣括氟基、氣基、漠基或硬基，特別是氟基、氯基或溴基，尤其是氟基或氣基。側氧基如使用在本文㈣指c=〇及通常表示為 C(O)。早夕H燒基如使用在本文中意指包含3至8個碳原知和或部分不飽和非芳族環。 C 燒基包#C2'C3、C4、C5、C6、C7、WC9 以及C〗和Cl〇。 201130813 C〇_8炫基包括ρ 及 C〇和 C8。 2 C3 C4、Cs、C6，或 C7 以關料域或非找中至少一個碳(例如、〗-1〇烷基鏈，其特別是1個)係經選自^或3個石反’適當地1或2個，中該鏈視需要地經—“N、S(〇)P之雜原子置換，其素、芳基、雜芳基或^ ^立地選自側氧基、_ 者應清楚雜料可^ 代’㈣該項技術 -CH2+CH"戈支絲臭—級、二級或三級碳，即CH3、 2 $ 鏈碳基團，如技術上適當。在本揭不的一Θ J2A ^ 中^甲基、乙基例中，提供式⑴之化合物，其特別是第三-丁基。土異丙基、丁基或第三丁基’ 在-具體實例中，Ri為_c(CH3)2CH2〇h。在一具體實例中，R2兔田I 基、正m R為甲基、乙基、正丙基、異丙正丁基或第二·丁基，_是甲基。在一具體實例中，R2為_CH2〇H。在^體實例中’r2係在2、3或4位置(也就是位、間位或對位位置），特別是對位(4)位置。在一具體實例中，Ar為萘基。在-具體實例中，Ar不經視需要取代基取代。在—具體實例中，Ar經1《2個基團取代。在一具體實例中，Ar為視需要經i或2個獨立地甲=C】·3烷基或c!·3烷氧基的取代基取代之苯基，例如笨基、二曱苯基、大茴香醯基、二_曱氧基苯或曱氧二甲基苯。苯基環可(例如）經由碳1連接至脲之氮及、、、由％1 4連接至基團L·。該類情形中，視需要一或二 11 201130813 個選自Cu烧基或C〗_3烧氧基之取代基可位於芳族環中任何非占用位置，例如於位置2或於位置3或於位置 2及3或於位置2及6或於位置3及5。包含其他可能的位向異構物之具體實例也形成本揭示之一觀點。在一具體實例中，L為直鏈連結子，例如： -(匸112)11-，其中11為1、2、3、4、5、6、7或8;戋 -(CH2)nO(CH2)m-，其中 η 及 m 獨立地為〇、卜 2、3、4、 5、6或7’其先決條件為n+m為零或從1至7之整數，例如，其中η為0及m為1或2，或者，例如，其中η 為1或2及m為0。在一具體實例中 ’ L 為-〇CH2-、-〇Ch2CH2_、_Ch2〇_ 或-CH2CH20-。例如，L 可表示-〇CH2-。在一具體實例中’ L為支鏈連結子Ra〇(CH2)m，其中m為零或整數1、2、3、4或5和Ra為c2_7支鏈烷基，其先決條件為加到m的Ra中之碳數為2至7之整數，尤其是，其中m為零，諸如·〇Η(^Η；〇0-、 -C(CH3)20-、-CH2CH(CH3)0-、-CH(CH3)CH20-、 -c(ch3)2ch2o_或-ch2c(ch3)2o，特別是-CH(CH3)0_。在一具體實例中，L為支鏈連結子(CH2)n〇Rb，其中η為零或整數1、2、3、4或5和Rb為c2-7支鏈烧基，其先決條件為加到η的Rb中之碳數為從2到7 之整數，例如η為零，諸如-OCH(CH3)-、-〇C(CH3)2-、 OCH2CH(CH3)_、_〇ch(ch3)ch2-、_0C(CH3)2CH2_ 或 -OCH2C(CH3)2 及特別是-〇CH(CH3)-或-〇C(CH3)2CH2_。在一具體實例中，L為支鏈連結子Ra〇Rb，其中Ra 和Rb係獨立地選自CM支鏈伸烷基，其先決條件為Ra 12 201130813 和Rb中之碳的總數為從4至7之整數。在一具體實例中，L為飽和非支鏈CrC8伸烷基鏈或飽和支鏈或非支鏈C2_8伸烷基鏈。在一具體實例中，至少一個L中之碳被-0-置換。在一具體實例中，L為-0-。伸烷基如使用在本文中係指支鏈或非支鏈碳基團，諸如亞曱基(-CH2-)或其鏈。在本說明書上下文中，其中烷基為連結子則後者與術語伸烷基可交換使用。在一具體實例中，鏈L包括1、2或3個鹵素原子取代基，獨立地選自之氟基、氯基及溴基，例如伸烷基碳可合併一或二個氣原子或一或二個氟原子及端基碳原子，（例如伸烷基鏈之支鏈的端基碳原子）、可鍵結至一、二或三個氟原子或一、二或三個氯原子以提供基團諸如三氟曱基或三氯甲基基團。在一具體實例中，該鏈L不包括鹵素原子或原子等。在一具體實例中，R3為H。在一具體實例中，R3為曱基、乙基、正丙基或異丙基。在一具體實例中，R3為環丙基。在一具體實例中，X係選自吡咯、啐唑、噻唑、異 σ 塞。坐、P米0坐、π比唾、異$ σ坐、σ号二唾、。荅σ井、嘴π定、η比口井、或1,2,3及1，2,4三嗤，諸如°比唾、異$唾、σ号二唾、。比σ定、。荅σ井、Ρ密咬、Π比σ井，或1，2,3及1,2,4三唾，特別是，σ密咬、11米唾或°比°定，且尤其是°比唆或°密咬，更特別是°比啶。 13 201130813 在一具體實例中，Q之炫基鏈中卜2、3或4個碳原子經獨立地，自〇、N、S(0)p之雜原子置換。在一具體實例中’置換Q之絲鏈片段的碳之雜原子係選自N及〇。在-具體實例中，Q為飽和或不飽和支鏈或非支鏈 Cu烧基鍵或CK6燒基鏈，其中至少—個碳係經選自 Ο N S(0)p之雜原子置換。或者在此具體實例中，烧基鏈可為c2.8燒基或c36烧基，諸如C4烧基或C5 院基。在一具體實例中，烷基鏈中之氮原子直接鍵結至片段-NR3C(0)之羰基且此外可(例如）為端基胺基基團。在一具體實例中，Q表示Cl 6烷基NH2或ΝΑ。在一具體貫例中，Q表示_NHCV6烷基，諸如_NHCH3 或-nhch2ch3 或-NHCH(CH3)2。在一具體貫例中，該片段Q為飽和或不飽和支鏈或非支鏈C^o烧基鍵，其中至少一個碳(例如1、2、3 或4個碳，特別是1或2個碳)係經選自〇、N、s(〇)p 之雜原子置換，例如以該類提供穩定N_醯基基團， NR C(0)Q之方式’其中該鏈視需要經一或多個選自側氧基、鹵素、芳基、雜芳基、雜環基，或k環烧基之基團取代，各#基；料基或雜環基或Cw環烧基具有的0至3個獨立地選自上列式C0化合物之相_代基的取代基。The Ci_4 mono or CM di-alkylamino group means ·NHCi 4 alkyl and -n(c].4 alkyl) (Cl_4 alkyl), respectively. An aryl group as used herein, for example, refers to a Cq' mono- or polycyclic group having from 丨 to 3 rings, wherein at least one ring includes phenyl, naphthyl, yl, 1, 2, 3, 4·4 Aromatic groups such as hydroxynaphthyl and the like, such as phenyl and zeoli. ', square i is 6 to 10 shell aromatic single-ring or double-ring system, 苴中^ 少-rings contain - or more (for example, 2, 3 or 4) independently selected from 〇, N and S An aromatic core of a hetero atom. Examples of heteroaryl groups include 201130813 one °: sitoxazole, isothiazole, imidazole, D-biazole, iso-carbazole, pyridinium and pyrene, terminal benzophenanthrene, stupid and sputum, or 2, and 1, 2, 4 three. As used herein, a 5-membered I and or a partially unsaturated non-aromatic comprising: - or more, such as to a "two" heteroatom independently selected from hydrazine, N& S: may have a pendant thiol group C. C === Contains, (for example, Bu 2, 3 or 4 = and non-aromatic carbocycles, wherein each of the dimers and or the unsatisfied two carbons may have pendant oxygen substituents: no =: Rr, any price of the child depends on the situation == on the ring, depending on the situation, can be kissed on the carbon. Each example of the <=° miscellaneous C5·6 heterocycle includes °pyrazole, call ^ 喃, tetrahydrogen surface, K and rice salivin, S Μ 'side, dioxol _,, 派, dihydro ° bottom ° South, pie bite, Niangkou well, morpholine, monodecane, sulfur Morpholine and oxysulfan. The gas includes a fluorine group, a gas group, a molybdenum group or a hard group, especially a fluorine group, a chlorine group or a bromine group, especially a fluorine group or a gas group. The pendant oxygen group is used herein (4) to refer to c. = 〇 and is usually expressed as C(O). The use of H-base as used herein means that it contains 3 to 8 carbon atoms and or partially unsaturated non-aromatic rings. C 烧基包#C2'C3, C4 , C5, C6, C7, WC9 and C and Cl〇. 201130813 C〇_8 Hyun base includes ρ C〇 and C8. 2 C3 C4, Cs, C6, or C7 is selected from the range or non-finished at least one carbon (for example, 1-1 alkyl chain, especially one) selected from ^ or 3 a stone anti-appropriately 1 or 2, wherein the chain is optionally replaced by a hetero atom such as "N, S (〇) P, its aryl, aryl, heteroaryl or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the case of J2A ^ in the methyl group, the ethyl group, the compound of the formula (1), which is especially a tert-butyl group, a isopropyl group, a butyl group or a tert-butyl group. Wherein Ri is _c(CH3)2CH2〇h. In one embodiment, R2 rabbit field I base, positive m R is methyl, ethyl, n-propyl, isopropyl-n-butyl or second butyl , _ is a methyl group. In a specific example, R2 is _CH2〇H. In the example of ^, the 'r2 is at the 2, 3 or 4 position (that is, the bit, meta or para position), especially Position (4). In a specific example, Ar is a naphthyl group. In a specific example Ar is optionally substituted with a substituent. In a specific example, Ar is substituted with 1 "2 groups. In a specific example, Ar is optionally i or 2 independently A = C] · 3 alkyl groups. Or a phenyl group substituted with a substituent of a c. 3 alkoxy group, such as a strepto, a diphenyl phenyl group, an anisole group, a quinone oxy benzene or a fluorenyl dimethyl benzene. ) is attached to the urea nitrogen via carbon 1 and is connected to the group L· from % 14. In this case, one or two 11 201130813 are selected from the group consisting of Cu or C _ 3 alkoxy groups. The substituents can be located at any unoccupied position in the aromatic ring, such as at position 2 or at position 3 or at positions 2 and 3 or at positions 2 and 6 or at positions 3 and 5. Specific examples containing other possible ortho-isomers also form an aspect of the present disclosure. In a specific example, L is a linear linker, for example: -(匸112)11-, where 11 is 1, 2, 3, 4, 5, 6, 7, or 8; 戋-(CH2)nO (CH2 M-, where η and m are independently 〇, 卜2, 3, 4, 5, 6 or 7' with the precondition that n+m is zero or an integer from 1 to 7, for example, where η is 0 and m is 1 or 2, or, for example, where η is 1 or 2 and m is 0. In a specific example, 'L is -〇CH2-, -〇Ch2CH2_, _Ch2〇_ or -CH2CH20-. For example, L can represent -〇CH2-. In a specific example 'L is a branched linker Ra〇(CH2)m, wherein m is zero or an integer 1, 2, 3, 4 or 5 and Ra is a c2-7 branched alkyl group, the prerequisite being added to m The carbon number in Ra is an integer from 2 to 7, in particular, where m is zero, such as ·〇Η(^Η;〇0-, -C(CH3)20-, -CH2CH(CH3)0-,- CH(CH3)CH20-, -c(ch3)2ch2o_ or -ch2c(ch3)2o, especially -CH(CH3)0_. In one embodiment, L is a branched linker (CH2)n〇Rb, Wherein η is zero or the integers 1, 2, 3, 4 or 5 and Rb is a c2-7 branched alkyl group, with the proviso that the number of carbon atoms added to Rb of η is an integer from 2 to 7, for example η is Zero, such as -OCH(CH3)-, -〇C(CH3)2-, OCH2CH(CH3)_, _〇ch(ch3)ch2-,_0C(CH3)2CH2_ or -OCH2C(CH3)2 and especially - 〇CH(CH3)- or -〇C(CH3)2CH2_. In one embodiment, L is a branched linker Ra〇Rb, wherein Ra and Rb are independently selected from CM branched alkyl, preconditions thereof The total number of carbons in Ra 12 201130813 and Rb is an integer from 4 to 7. In one embodiment, L is a saturated unbranched CrC8 alkyl chain or a saturated branched or unbranched C2-8 alkyl chain. In a In a specific example, at least one of the carbons in L is replaced by -0. In one embodiment, L is -0-. The alkylene group, as used herein, refers to a branched or unbranched carbon group, such as a sub Mercapto (-CH2-) or a chain thereof. In the context of the present specification, wherein alkyl is a linker, the latter is used interchangeably with the term alkyl. In one embodiment, chain L comprises 1, 2 or 3 halogens. An atomic substituent independently selected from the group consisting of a fluoro group, a chloro group, and a bromo group. For example, an alkylene group may have one or two gas atoms or one or two fluorine atoms and a terminal carbon atom (eg, an alkyl chain). The branched end group carbon atom) may be bonded to one, two or three fluorine atoms or one, two or three chlorine atoms to provide a group such as a trifluoromethyl group or a trichloromethyl group. In a specific example, the chain L does not include a halogen atom or an atom, etc. In a specific example, R3 is H. In one embodiment, R3 is a decyl group, an ethyl group, a n-propyl group or an isopropyl group. In one embodiment, R3 is cyclopropyl. In one embodiment, X is selected from the group consisting of pyrrole, oxazole, thiazole, iso-sigma. Sit, P-m sitting, π Saliva, different $ σ sitting, σ number two saliva, 荅σ well, mouth π fixed, η than well, or 1, 2, 3 and 1, 2, 4 three, such as ° than saliva, different $ sal, σ号二唾,. σ定, 荅σ井, Ρ密 bite, Π ratio σ well, or 1,2,3 and 1,2,4 three saliva, especially, σ close bite, 11 m saliva or ° is determined by °, and especially ° is more than 唆 or ° bite, more particularly ° pyridine. 13 201130813 In one embodiment, 2, 3 or 4 carbon atoms in the Q chain of Q are independently substituted with heteroatoms of hydrazine, N, S(0)p. In one embodiment, the hetero atom of the carbon of the silk chain fragment of the replacement Q is selected from the group consisting of N and hydrazine. In a specific example, Q is a saturated or unsaturated branched or unbranched Cu alkyl bond or a CK6 alkyl chain wherein at least one carbon is replaced by a hetero atom selected from Ο N S(0)p. Or in this particular example, the alkyl chain can be a c2.8 alkyl or a c36 alkyl group, such as a C4 alkyl or a C5 building. In one embodiment, the nitrogen atom in the alkyl chain is directly bonded to the carbonyl group of the fragment -NR3C(0) and may, for example, be an end group amine group. In one embodiment, Q represents Cl 6 alkyl NH 2 or hydrazine. In a specific example, Q represents _NHCV6 alkyl, such as _NHCH3 or -nhch2ch3 or -NHCH(CH3)2. In a specific example, the fragment Q is a saturated or unsaturated branched or unbranched C^o group bond, wherein at least one carbon (eg 1, 2, 3 or 4 carbons, especially 1 or 2) Carbon) is replaced by a hetero atom selected from the group consisting of 〇, N, s(〇)p, for example, in such a manner as to provide a stable N_indenyl group, NR C(0)Q, wherein the chain is required to undergo one or a plurality of groups selected from the group consisting of a pendant oxy group, a halogen, an aryl group, a heteroaryl group, a heterocyclic group, or a k-cycloalkyl group, each of which has a base or a heterocyclic group or a Cw cycloalkyl group having 0 to Three substituents independently selected from the phase of the compound of the above formula C0.

在一具體實例中，該片段Q為飽和或不飽和支鏈或非支鏈Ci-10烷基鏈’其中至少一個碳(例如卜2、3 或4個碳，特別是個碳)係經選自〇、N 201130813 之，原子置換’例如以該類提供穩定Ν·醯基基團， mu式’其中該鏈視需要經—或多個選自側土」、、芳基、雜芳基或雜環基之基團取代，各芳基雜芳基或雜j衣基具有〇至3個獨立地選自上列式⑴ 化合物之相關取代基的取代基，例如鹵素、Q.6燒基、In one embodiment, the fragment Q is a saturated or unsaturated branched or unbranched Ci-10 alkyl chain wherein at least one carbon (eg, 2, 3 or 4 carbons, particularly carbon) is selected from 2011, N 201130813, atomic substitution 'for example, to provide a stable Ν 醯 group, mu type 'where the chain is selected as needed — or multiple selected from the side soils, aryl, heteroaryl or hetero Substituted by a group of a ring group, each arylheteroaryl or hetero group has a substituent selected from 3 to 3 independently selected from the substituents of the above formula (1), such as halogen, Q.6 alkyl,

Cl-6烧氧基/ Cl.6岐基、胺基、L單或C2.8二烧胺基及Cm單或CM二-醯基胺基。 —在具體錢例中，該後一鏈視需要經一或多個選自側氧基、鹵素、芳基、雜芳基或雜環基之基團取代，各芳基、雜芳基或雜環基具有〇至3個選自齒素、Cm烷基、Cw烷氧基、Cl 6函烷基、胺基，及Cw單或^ 8 二-烧胺基的取代基。在一具體實例中，Q為Cl 4烷基_V_R4，諸如^ 3 烷基-V-R4，其中·· V為選自NRV、〇或s(〇)p之雜原子；Cl-6 alkoxy/Cl.6 fluorenyl, amine, L or C2.8 dialkylamine and Cm mono or CM di-decylamino. - in a specific example, the latter chain is optionally substituted with one or more groups selected from pendant oxy, halogen, aryl, heteroaryl or heterocyclic groups, each aryl, heteroaryl or hetero The cyclic group has hydrazine to 3 substituents selected from the group consisting of dentate, Cm alkyl, Cw alkoxy, Cl 6 alkyl, amine, and Cw mono or VIII di-anisamine. In one embodiment, Q is Cl 4 alkyl_V_R4, such as ^ 3 alkyl-V-R4, wherein V is a hetero atom selected from NRV, hydrazine or s(〇)p;

Rv表示Η或Cw烷基； R4為Η或-C】·3烧基，及p如上述所定義，其先決條件為包括置換雜原子之總烷基鏈長不大於1〇個碳原子及所得基團Q為穩定基團，例如_CH2SCH3、 -ch2so2ch3、-ch2nhch3、-ch2n(ch3)2 -c(ch3)2nhch3、-ch(ch3)n(ch3)2、 -(CH2)3CHNHCH3、-(CH2)3N(CH3)2、-ch2〇h、 -CH2OCH3、-CH(CH3)OCH3 或-(CH2)20CH3。在一具體實例中，Q為Cw烷基_v_(Cl3烷基 -Z-R5)k，諸如 Cw 烷基-V-(C2-3 烷基-Z-R5)k，其中：Rv represents deuterium or Cw alkyl; R4 is deuterium or -C 3 ·3 alkyl, and p is as defined above, the prerequisites of including a replacement hetero atom having a total alkyl chain length of not more than 1 carbon atom and resulting The group Q is a stable group such as _CH2SCH3, -ch2so2ch3, -ch2nhch3, -ch2n(ch3)2-c(ch3)2nhch3, -ch(ch3)n(ch3)2, -(CH2)3CHNHCH3, -( CH2) 3N(CH3)2, -ch2〇h, -CH2OCH3, -CH(CH3)OCH3 or -(CH2)20CH3. In one embodiment, Q is Cw alkyl _v_(Cl3 alkyl-Z-R5)k, such as Cw alkyl-V-(C2-3 alkyl-Z-R5)k, wherein:

V為選自N、NH、Ο或S(0)p之雜原子，諸如N或NH 15 201130813 (在該其中k = 2之情形中，V為N，或在該其中k =1 之情形中，將選自NH、0或s(〇)p，特別是NH); Z係獨立地選自NH、Ο或s(〇); R5為Η或-Cm烷基； k為整數1或2(諸如1);及 p如上述所定義，其先決條件為包括置換雜原子之總烷基鏈長不大於1〇個碳原子及所得基團Q為穩定基團。適當地q為Ci 3 烷基-V-Cw烷基-OCH3例如Cl-3烷基-V-C2.3烷基 _OCH3，諸如 Ci-3 烷基 _v_(CH2)2〇CH3，特別是 -ch2o(ch2)2och3 及 ch2s(ch2)2och3 ，或 -CH2NH(CH2)2OCH3、CK3 烷基·v_(Cl 3 烷基_0CH3)k，其中k表示2，例如C!-3烷基_v_(c2 3烷基-OCHA，諸如 -CH2N[(CH2)2OCH3]2。在一具體實例中，(3為Cw烷基-v-Ci-2烷基-z-Cq 烧基-Y-R6’ 或 Ci_3 烧基-V-C2-3 烧基-Z-C2-3 烧基-Y-R6，其中V、Z及Y係獨立地選自NH、Ο或s(0)p之雜原子， R6為Η或曱基，及 ρ如上述所定義，其先決條件為包括置換雜原子之總烷基鏈長不大於10 個碳原子及所得基團Q為穩定基團。適當地Q為 -ch2v(ch2)2o(ch2)2och3，諸如 -ch2o(ch2)2o(ch2)2och3、 -ch2nh(ch2)2o(ch2)2och3 或 -ch2s(ch2)2o(ch2)2och3。 201130813 在一具體實例中，Q表示-NR7R8及-NR3C(〇)q形成脲’其中R7和R8獨立地表示氫或Cu9飽和或不飽和支鏈或非支鏈烧基鏈，其中一或多個碳，（諸如1、2或3 ，）視需要經選自〇、N或S (0)p之雜原子置換。該鏈視需要經一或多個獨立地選自側氧基、_素、芳基、雜芳基、雜環基或C：3·8環烷基之基團取代，各芳基、雜芳基或雜環基基團具有〇至3個獨立地選自上列式⑴化合物之相關取代基的取代基，例如鹵素、c16烧基、cN6烧氧基、C】_6鹵烧基、胺基、C!·4單或c2_8二-烷胺基及 Ci-4單或C2_8二-酸基胺基，其先決條件為包括置換雜原子之總烧基鏈長不大於10個礙原子及所得基團Q為穩定基團。在一具體實例中’ Q表示-NR7R8及-nr3c(o)q形成脲，其中R7和R8獨立地表示氫或CK9飽和或不飽和支鏈或非支鏈烷基鏈，其中一或多個碳(諸如1、2或3 個）視需要經選自〇、N或S(0)p之雜原子置換。該鏈視需要經一或多個獨立地選自側氧基、_素、芳基、雜芳基或雜環基之基團取代，各芳基、雜芳基或雜環基基團具有0至3個獨立地選自上列式⑴化合物之相關取代基的取代基，例如鹵素、Ci_6烧基、Ci—6烧氧基、c16鹵烷基、胺基、C〗-4單或C2·8二-烷胺基及Cw單或c2 8 二•醯基胺基，其先決條件為包括置換雜原子之總燒基鏈長不大於ίο個碳原子及所得基團Q為穩定基團。在此脲具體實例中，於一子具體實例中R7表示氣。脲類的例子包栝該等其中r7和r8皆為氫及Q為 -NH2，或，其中Q為-NHCH3或-N(CH3)2以提供(例如) 17 201130813 片段 -nr3c(o)nh2 或-nr3c(o)nhch3 或 -NR3C(0)N(CH3)2。烷基鏈中包含雜原子之脲類的例子包括該等其中 Q 為-NH(CH2)2OCH3 或-N[(CH2)2OCH3]]2 者。在一具體實例中’ Q表示-NHC2_6烷基OCu烷基，諸如 -NHCH2CH2OCH3。包含側氧基取代基之脲類的例子包括該等其中Q 為-NHCH2C(0)NH-C2_3烷基-Xi-Cw烷基，其中X1為選自N、Ο或S(0)p之雜原子及p如上述所定義。後者的例子包括該等其中Q為-nhch2c(o)nhch2ch2och3 者。因此在一具體實例中，Q表示-NHCm烷基 C(0)NHC2 烷基〇ch3 ，諸如 -nhch2c(o)nhch2ch2och3。在一具體實例中，Q表示-NHCw烷基C(0)RQ，其中RQ係選自OH或-NR’R”，其中R’為氫或Cu烷基和R”為氫或（^_3烷基，例如-NHCH2C(0)0H、 -NHCH2C(0)NH2 或-NHCH2C(0)NHCH3(諸如 -NHCH2C(0)0H 或-NHCH2C(0)NHCH3。在一具體實例中，該基團Q表示-NHC^烷基 (:(0)0(:,-3 烷基，諸如-NHCH2C(0)0CH2CH3。在另一脲子具體實例中，Q表示-N-MCw烷基 -V-(Ci-3 烷基-Z-R1Q)k 例如小-尺9(：2.3 烷基-V-(C2.3 烷基 -Z-R1Q)k，其中： V 表示 N、NH、Ο、s(0)p ; Z 表示 NH、Ο、S(0)p ; k為整數1或2 ; 201130813 p為整數0、1或2 R9表示Η或Cw烷基烷基-Z_Ri〇)k，諸如C2 3 烷基-V-(C2_3 烷基-Z-R1G)k ;及 R1G為H或Cw烷基，諸如Cl 3烷基；其先決條件為包括置換雜原子之總烧基鏈長不大於個碳原子及所得基圑Q為穩定基團。在一具體實例中，Q為飽和或不飽和支鏈或非支鏈 Ci-i〇烧基鏈，其中至少一個碳係經選自〇、n及s(〇)p 之雜原子置換，其中該鏈係經具有0至3個取代基(例如1、2或3，諸如1或2個取代基)獨立地選自上列式 (I)化合物之相關取代基(例如選自鹵素、Cl 6烷基、Cl 6 烷氧基、C〗·6鹵烷基、胺基及單或c2_8二·烷胺基及 Cm單或C2_8二-醯基胺基)之芳基基團取代，諸如飽和或不飽和支鏈或非支鏈CMQ燒基鏈，其中至少一個碳係經選自Ο、N及S(0)p之雜原子置換，其中該鏈係經具有0至3個取代基(例如1、2或3個，諸如1或2個取代基)獨立地選自鹵素、Cw烷基、Cy烷氧基、C】_6 鹵烷基、胺基及Cm單或C2_8二-烷胺基之芳基基團取代。在一具體實例中，該芳基為苯基，例如經取代之苯基或未經取代之苯基。在一具體實例中，Q表示-NHC〇_6烷基苯基，諸如 -NH苯基或NH苯曱基。片段-NR3C(0)Q(其中Q包含經取代之苯甲基）的例子包括： -nr3c(o)ch2nhch2c6h4(och3) ，諸如 -nhc(o)ch2nhch2c6h4(och3)，例如，其中該曱氧基 201130813 取代基在鄰位、間位或對位位置，諸如對位位置。在一具體實例中’ Q為飽和或不飽和支鏈或非支鍵 C^o烷基鏈，其中至少一個碳係經選自〇、N及s(〇) 之雜原子置換，其中該鏈係經具有〇至3個取代基(例如1、2或3個，諸如丨或2個取代基)獨立地選自上列式(I)化合物之相關取代基(例如鹵素、Ci 6烷基、Ci 6烷氧基、Cw烷胺基、cM單或Cw二-烧胺基及CM單或 CM二-醯基胺基)之雜芳基基團取代，諸如飽和或不飽和支鍵或非支鍵C^o烧基鏈，其中至少一個碳係經選自Ο、N及S(0)p之雜原子置換，其中該鏈係經具有〇至3個取代基(例如1、2或3個，諸如1或2個取代基）選自鹵素、Cm烷基、C〗-6烷氧基、Cw烷胺基、^ 單或CM二-烷胺基的雜芳基基團取代。在一具體實例1 中’該雜芳基係選自：。塞吩、吟β圭、ϋ塞唾、異0塞. 〆、王· 、口米唑、吡唑、異呤唑、異噻唑、呤二唑、丨，^或i 一唑、吡啶、嗒畊、嘧啶、吡啼且特別是吡啶及哺咬其是吼啶。尤在一具體實例中’ Q表示-NHCw烷基雜芳基，例如-NH(CH2)3咪基或-NHCH2異十坐’其中該異$ π坐視需要經取代，諸如-NHCH2異啐唑(CH3)。在一具體實例中，Q表示-NHCm烷基c(〇)NHCl3 烧基雜芳基，例如含氮雜芳基或含氮及氧雜芳基，更特別是-NHCH2C(0)NHCH2CH2吡啶基，特別是，其中吼 0定基係經由碳連接，例如°比。定_4-基或 -NHCH2C(0)NHCH2CH2CH2咪唑基，特別是，其中味唾基係經由氮連接。 20 201130813 在-具體實例中，Q為飽和或不飽和支鏈或非支鍵 cM0烷基鏈，其中至少一個碳係經選自〇、N & s(〇) 之雜原子置換’其中該鏈係經具有Q至3個取代基(例如1、2或3個，諸如1或2個取代基)獨立地選自上列式(I)化合物之相關取代基(例如鹵素、Cw烷基、Cm烷氧基2 Cw齒烷基、胺基、Cl_4單或c2 8二-烷胺基及 C〗-4單或Cw二-醯基胺基）的雜環基基團取代，諸如飽和或不飽和支鏈或非支鏈cM()烷基鏈，其中至少一個石炭係經選自0、N及s(0)p之雜原子置換，其中該鏈經具有0至3個的取代基(例如1、2或3個，諸如1或2 個取代基)選自齒素、Cl.6烧基、Cl.6燒氧基、Ci 6函烧基月女基、Ci_4單或C2_8二-烧胺基的雜環基取代。在一具體實例中，該雜環基係選自包含一或多個 (例如1、2或3個，特別是1或2個）獨立地選自〇、N 及S之雜原子的5或6員飽和或部分不飽和環系統，例如吡咯啶、四氫呋喃、四氫噻吩、哌咬、哌_、嗎琳、 1，4-二噚烷、吡咯啶及側氧咪唑啶諸如吡咯啶、四氫呋喃、四氫σ塞吩、π辰咬、旅σ井、嗎琳及1‘二#烧，特別是旅咬、Π底II井及嗎琳。雜環基團可經由碳或氮(特別是經由氮原子)連接至 Q之烷基鏈或至-NR3C(0)_之羰基。在一具體實例中，Q為-C〇_3烷基雜環(例如_c〇 i烷基雜環）’該雜環基團包含至少一個選自〇、N及S之雜原子(例如1、2或3個’特別是1或2個雜原子），及視需要經一個或二個或三個獨立地選自上列式⑴化合物之相關取代基(例如鹵素、Ci·6烷基、Cl6烷氧基、Cw 21 201130813 鹵烷基、胺基、Cw -..一 C2_8二-烷胺基及ci 4單一-醯基胺基)的基團取代。 4 在-具體實例中，Q為_C〇烷基雜環，例喃基或鱗錢或料基或㈣基或側氧基咪唆^ 團，諸如2-側氧基咪唑咬基團。土在:具體實例中其中Q^C遺基雜環，該經由碳連接，4例如C_連接之四氫㈣或&連= 哌啶或C-連接之嗎啉或c_連接之哌畊。呀< 在一具體實例中’其中Q為—c〇烷基雜環包含一或多個N原子之雜環基團經由N連接。此具體供其中脲氮之-係嵌人雜環内的脲。此具體實例包括但不限制於N·連接之嗎琳或N•連接之㈣或n_ 連接之哌畊’該N-連接之哌畊基團視需要地具有另外的 C-或N-取代基’諸如N-曱基或N-cp^cj^ocj^基團。在一具體實例中，Q為雜環基經由氮連接，諸如哌啶基，特別是4-羥基哌啶基或哌畊基，諸如4_曱基哌啩基 (pierazinyl)。在一具體實例中，Q表示雜環基，例如含氮雜環基，特別是經由N連接，諸如視需要經甲基(尤其是4_ 甲基)取代之嗎啉基或哌畊基、或哌啶基。在一具體實例中’Q為視需要地具有取代基(例如 Q-6烷基取代基，諸如甲基或c】_6烷氧基取代基，諸如 -CH2CH2〇CH3)之-C丨烧基雜環，例如四氫n底喃基甲基或 C-或N-連接之哌畊基甲基。其他例子包括c-或N_連接之°比17各咬基曱基’或C-或N-連接之側氧基。米唾啦基甲基(諸如2-側氧基咪唑啶基甲基），該雜環視需要地具有 22 201130813 取代基(諸如N-甲基或N-S02CH3)。在一具體實例中，Q表示-NH雜環基(其中該雜環基具有0至3個選自上列式(I)化合物之取代基的相關名單之取代基，例如鹵素、經基、Cu烧基、Cu烧氧基、 Ci.6鹵燒基、胺基、Ci_4單或C2-8二-烧胺基、烧基、Cm單或C2_8二-醯基胺基、C〇-6烧基烧基或C〇_6烧基CXCOCk雜烧基）’諸如其中該環係經由石炭連接，例如2-略咬基或3-旅咬基或4-旅咬基，特別是1-乙醯基派σ定-4-基、1-曱基派°定-4-基、1-(甲石黃醯基) 哌啶-4-基或1-(2-(2-曱氧基乙氧基）乙醯基)哌啶·4_基。在一具體實例中，Q表示-NHCk烧基雜環基例如含氮雜環基，特別是經由氮連接者，諸如嗎啉、-NH(CH2)3嗎啉或-NH(CH2)4嗎啉。在一具體實例中，Q表示-NHC〗·6烷基c(〇)雜環基 (其中該雜環基具有0至3個選自上列式(I)化合物之取代基的相關名單之取代基，例如鹵素、經基、C】_6烧基、 Cl-6烧氧基、Ci-6鹵烧基、胺基、Ci_4單或C2-8二-烧胺基、Cw單或C2-8二-醯基胺基、C〇-6烷基¢:(0)(:,-6烷基或CG_6烧基CXCOC!-6雜院基）’例如含氮雜環基，特別是經由氮連接者，諸如-NHCHzCCO)小吡咯咬基 (pyrrolindinyl)、-NHCH2C(0)-1-哌啶基、-NHCH2C(0)-4- 嗎琳基或-NHCH2C(0)派π井基諸如-NHCH2C(0)-4-曱基 _1-°底畊基。在一具體實例中，Q表示-NHCw烷基CCC^NHCy 燒基雜環基例如含氮雜環基或含氮及/或氧雜環基團，諸如-NHCH2C(0)NHCH2CH2嗎啉基，特別是，其中嗎 23 201130813 琳基係經由氮連接。在-具體實例中，Q表示_N(Cl-3垸基)C】6燒基雜環基，例如含氮雜環基，特別是經由氮連接，諸= -N(CH3)CH2CH2 嗎啉、_N(CH3)(CH2)3 嗎啉 ° -N(CH3)(CH2)4 嗎啉。 4 在具體貫例中，Q為-Ci·3烧基·G-CM院基雜環，其中G為選自NH、〇或8(0\之雜原子，該雜環基包含至少一個雜原子(例如i、2或3個，特別是i或2個雜原子）選自0、N及S，及視需要經一個或二個或三個獨立地選自上列式(1)化合物之相關取代基的基團（例如函素、Cw烷基、Cl_6烷氧基、Ci 6齒烷基、胺基、 Q·4單及CM二-烷胺基及Cl_4單或C2-8:_醯基胺基諸如一個或二個或三個基團鹵素、烷基、Ci6烷氧基、 Ci·6齒烷基、胺基' cM單及C2·8二-烷胺基)取代。適當 Q為-CH2G(CH2)2雜環例如_CH2G(CH2)2四氫哌喃基；或-CH2G(CH2)2嗎啉基，其中該雜環基係經由氮或碳連接，或CH2G(CH2)2哌畊基，其中該雜環基係經由氮或碳連接且視需要地具有另外的（:_或1^取代基(例如CI 6 烷基取代基，諸如曱基或C!_6烷氧基取代基，諸如 •CH2CH2〇CH3);或-CH2G(CH2)2^咯啶基，其 t 該雜環基係經由氮或碳連接’例如經由氮連接；或_CH2G(ch2)2 側氧基味唾琳基(諸如2-側氧基味唾σ定基），例如經由N 連接且視需要地具有另外的C-或Ν-取代基(諸如Ν-曱基或N-S02CH3)，及其中G為0或ΝΗ。在一具體實例中，G為Ο。在一具體實例中，G為NH。 24 201130813 在一具體實例中’ Q為飽和或不飽和燒基鏈，其中至少一個碳(例如1、2或3個碳)係經選自0、N、 S(0)p之雜原子置換，其中該鏈係經C3·8碳環基團取代及該烧基鏈視需要經一或多個（例如1或2個）選自側氧基及i素之基團取代。在一具體實例中，該C3_8碳環基團具有一或多個基團（例如1、2或3個基團.)獨立地選自鹵素、羥基、Ci-6烧基、C!-6烧氧基、Ck自燒基、胺基、Cm單或C2-8二-烧胺基、Ci_4單或C2-8二-酿基胺基、烧基、C〇-6烧基C(0)Ci.6烧基或Cq_6烧基 CXCOCk雜烷基。在一具體實例中，Q表示環丙基、-ΝΗ環戊基或-ΝΗ環己基在一具體實例中，該芳基、雜芳基或雜環基具有至 ’個"ΎΟ、。·6烧基取代基及視需要地呈有一一個獨立地選自上述式⑴化合物所定義之取S基二二I 另外相關取代基。平在一具體實例中，該c5 6雜俨百；以八、η 6雜衣具有至少一個 -Mo'c〗·6烷基取代基及視需要地具夕個選自上述用於式(I)化合物所定義個獨立地代基。的另外取六肢貝1夕1J τ 少一個經基取代基及視需要地具雜環基具有自上述式⑴化合物所定義之取 I〜個獨立地取代基。土的相關名單之另在-具體實例中，該c5-6雜環具代基及視需要地具有—或二_立—個經基: 硪自上述式(I), 25 201130813 合物所定義之取代基的相關名單之另外取代基。在一具體實例中，該芳基、雜芳基或雜環基具有至少一個Ci-4單及/或C2-8二-醯基胺基取代基及視需要地具有一或二個獨立地選自上述式（I)化合物所定義之相關名單的另外取代基。在一具體實例中，該Cs_6雜環具有至少一個Ci 4 單及/或C2-8二-醯基胺基取代基及視需要地具有一或二個獨立地選自上述式(I)化合物所定義的相關名單之另外取代基。在一具體實例中，該芳基、雜芳基或雜環基具有至少一個C〇_6烷基CXCOCk雜烷基取代基及視需要地具有一或二個獨立地選自上述式(I)化合物所定義的相關名單之另外取代基。在一具體實例中，該C5·6雜環具有至少一個c 烷基CXCOC!·6雜烷基取代基及視需要地具有一或二= 獨立地選自上述式（I)化合物所定義的相關名單之另外取代基。在一具體實例中，該芳基、雜芳基或雜環基具有至少一個C〇_6烧基¢:(0)(^-6烷基取代基及視需要地具有一或二個獨立地選自上述式(I)化合物所定義的相^名單之另外取代基。在一具體實例中，該Cw雜環具有至少一個c 烷基（:(0)(^-6烷基取代基及視需要地具有〜或二個立地選自上述式⑴化合物所定義之相關取代基的另外取代基。在一具體實例中’ Q表示四氫呋喃基、嗎啉基、娘 26 201130813 j(諸如具有-個經基取代基之旅咬基卜底啡基(諸如〃個甲基取代基之°辰σ井基）或。比π各咬基，該°比11各唆土八们一-曱胺基取代基。環可經由雜原子（諸如氮) 連，-或A可級由碳連接。取代基可(例如)在相對於私經其連接至分子剩餘部分之原子的對位。在一具體實例中，該需要之取代基。 Q之烷基鏈片段可具有任何視在一具體實例中，該烷基鏈為飽和。在一具體實例中，該烷基鏈為非支鏈。在一具體實例中，該Q之烷基鏈片段具有1、2或 3個，例如1或2個，特別是丨個視要之取代基。熟習該項技術者應清楚雜原子可置換一級、二級或二級碳（即CH3、-CHy或-CH-)基團，如技術上適當話。在一具體實例中，p為〇或2。在一具體實例中，p為1。在一具體實例中，本揭示的化合物包括該等其中片段Q為下列之化合物： -ch2oh ； -CHzOCu 烷基，特別是_CH2OCH3 ; -CH2CH2OCH3 ; -CH20(CH2)20CH3 ; -CH(CH3)OCH3 ; -ch2nhch3 或-ch2n(ch3)2 -ch2nhch2ch2och3 或-ch2nhc(o)ch2och3 ; -CH2SCH3、-CH2S(0)2CH3 或 -ch2nhc(o)ch2s(o)2ch3 ;或 * 27 201130813 -ch2nhc(o)ch2。在一具體實例中，本揭示的化合物包括該等其中式 (I)中的片段-NR3C(0)Q係以下列表示之化合物： -NR3C(0)CH20H ’ 且特別是-NHC(〇)CH2OH ; -NR^C^COCHzOCk 烷基’特別是_NR3C(0)CH20CH3，尤其是-nhc(o)ch2och3 ; -nr3c(o)ch2o(ch2)2och3，且特別是 -NHC(0)CH20(CH2)20CH3 ; -nr3c(o)ch(ch3)och3，且特別是 -nhc(o)ch(ch3)och3 ; -NR3C(0)CH(CH3)NHCi_3 烷基，且特別是 -NHC(0)CH(CH3)NHCH3 ; -NR3C(0)CH(CH3)N(Ci-3 烷基)2，且特別是 -nhc(o)ch(ch3)n(ch3)2 ; -nr3c(o)c(ch3)2nhch3，且特別是 -nhc(o)c(ch3)2nhch3 ; -NWC^OXCHAOCk 烷基，諸如 -NR3C(0)(CH2)2〇CH3 ’ 特別是->JHC(0)(CH2)2〇CH3 ; -NWc^OXCH^NHCm烷基，且特別是 -nhc(o)(ch2)3nhch3 ; NRSQOXCHaNO^w烷基)2，且特別是 -nhc(o)(ch2)3n(ch3)2 ; -NWcCCOCi^NHCM烷基，且特別是 -NHC(0)CH2NHCH3 ; _nr3c(o)ch2nh(ch2)2och3，且特別是 -nhc(o)ch2nh(ch2)2och3 ; 28 201130813 -NR3C(0)CH2SCH3，特別是-NHC(0)CH2SCH3 ; -nr3c(o)ch2s(ch2)2och3，特別是 -nhc(o)ch2s(ch2)2och3 ; -NR3C(0)CH2S(CH2)20(CH2)20CH3，且特別是 -NHC(0)CH2S(CH2)20(CH2)20CH3 -NR3C(0)CH2S0CH3，且特別是-NHC(0)CH2S0CH3 -nr3c(o)ch2s(o)2ch3，且特別是 -NHC(0)CH2S(0)2CH3 ； -nr3c(o)ch2n[(ch2)2och3]2，且特別是 -NHC(0)CH2N[(CH2)20CH3]2 ； -NR3C(0)NH2，且特別是-NHC(0)NH2 ; NRAcONHCw 烷基，（諸如 nrScXCONHCu 烷基，且特別是-nhc(o)nhch3 -NR C(0)N(C]_4烧基)Ci_5烧基，且特別是 -nhc(o)n(ch3)2 ;或 -nr3c(o)nhch2conh(ch2)2och3，特別是 -nhc(o)nhch2conh(ch2)2och3。在一具體貫例中本揭示的化合物包括其中片段 -NR C(0)C〇_8烧基雜壤基係以下列表示之式⑴化合物： -NHC(O)·(四氫哌喃基），諸如_NHC(〇)-(四氫-2H-哌喃 -4-基）： -NHC(〇H嗎啉基）諸如_NHC(0)-(4-嗎啉基）或 -NHC(0)-(3-嗎啉基）； -NHC(O)-(吡咯啶基），諸如_NHC(0)-(吡π各咬小基）； _NHC(〇H哌口井基），諸如·ΝΗ(：(〇Η^π井_1_基）； -NHC(〇H曱基派〇井基），諸如_NHC(0)-(4-曱基哌畊-1· 29 201130813 基）； -NHC(0)-[(甲氧基乙基）哌畊基]，諸如·NHC(〇)_[4_(2_ 曱氧基乙基)哌畊-1-基]; -NHC(0)-(侧氧基咪唑啶基）諸如_NHC(〇)_(2^^氧基咪。坐。定基），特別是_NHC(〇)-(2•側氧基咪唑啶小基）； -nhc(o)ch2-(四氫哌喃基），諸如_nhc(0)Ch2_(四氫 -2H-派喃-4-基）； -nhc(o)ch2-(嗎啉基）’諸如_NHC(〇)CH2-(4_嗎啉基）； -NHC(0)CH2十比咯啶基）’諸如_nhc(〇)CH2_(d比咯啶+ 基）； -nhc(o)ch2-(派。井基），諸如_NHC(〇)CH2 (派基）； -NHC(0)CH2-(曱基哌η井基），諸如_NHC(〇)CH2_(4_甲基派σ井-1-基）， -NHC(0)CH2_[(甲氧基烷基）哌畊基]，諸如 -NHC(0)CH2_[4-(2_曱氧基乙基)旅σ井小基]; -NHC(0)CH2SCH2CH2-(嗎琳基），諸如 _NHC(0)CH2SCH2CH2-(4-嗎啉基）或 -NHC(0)CH2SCH2CH2-(3-嗎啉基）；及 -NHC(0)CH2S〇2CH2CH2·(嗎琳基），諸如 -NHC(0)CH2S〇2CH2CH2-(4-嗎琳基）戍 -NHC(0)CH2S〇2CH2CH2-(3*^^n·!^基）。在片段Q之一具體實例中，飽和或不飽和支鏈或非支鏈CM0烷基鏈（其中至少一個碳係經選自_〇、_N、 s(0)p或雜原子置換）為選自：_CH2OCH2-、 -CH2NHCH2-、-CH2NH-及-CH2〇CH2CH2-之連結子。這些片段可視需要終止於芳基基團、雜芳基基團、雜環基 201130813 Q所定義之芳基、基團或C3_8環烧基’諸如如上述片段雜芳基、雜環基。在-具體實例t，該揭示係有關式(IA)之化合物ba·V is a hetero atom selected from N, NH, hydrazine or S(0)p, such as N or NH 15 201130813 (in the case where k = 2, V is N, or in the case where k =1 , will be selected from NH, 0 or s(〇)p, especially NH); Z is independently selected from NH, Ο or s(〇); R5 is Η or -Cm alkyl; k is an integer 1 or 2 ( Such as 1); and p are as defined above, with the proviso that the total alkyl chain length of the substituted hetero atom is not more than 1 碳 carbon atoms and the resulting group Q is a stabilizing group. Suitably q is Ci 3 alkyl-V-Cw alkyl-OCH3 such as Cl-3alkyl-V-C2.3alkyl_OCH3, such as Ci-3 alkyl_v_(CH2)2〇CH3, especially -ch2o(ch2)2och3 and ch2s(ch2)2och3, or -CH2NH(CH2)2OCH3, CK3 alkyl·v_(Cl 3 alkyl_0CH3)k, wherein k represents 2, for example C!-3 alkyl_v_ (c2 3 alkyl-OCHA, such as -CH2N[(CH2)2OCH3]2. In one embodiment, (3 is Cw alkyl-v-Ci-2 alkyl-z-Cq alkyl-Y-R6' Or Ci_3 alkyl-V-C2-3 alkyl-Z-C2-3 alkyl-Y-R6, wherein V, Z and Y are independently selected from heteroatoms of NH, hydrazine or s(0)p, R6 Is a hydrazine or a fluorenyl group, and ρ is as defined above, and the prerequisite is that the total alkyl chain length of the substitution hetero atom is not more than 10 carbon atoms and the resulting group Q is a stable group. Suitably Q is -ch2v ( Ch2) 2o(ch2)2och3, such as -ch2o(ch2)2o(ch2)2och3, -ch2nh(ch2)2o(ch2)2och3 or -ch2s(ch2)2o(ch2)2och3. 201130813 In a specific example, Q Represents that -NR7R8 and -NR3C(〇)q form urea' wherein R7 and R8 independently represent hydrogen or a Cu9 saturated or unsaturated branched or unbranched alkyl group, one or more carbons, such as 1, 2 or 3)) as needed Substituted by a hetero atom selected from hydrazine, N or S(0)p. The chain is optionally selected from one or more independently selected from pendant oxy, _, aryl, heteroaryl, heterocyclyl or C: Substituted by a group of 3·8 cycloalkyl, each aryl, heteroaryl or heterocyclyl group having from 〇 to 3 substituents independently selected from the substituents of the above formula (1), such as halogen, c16 An alkyl group, a cN6 alkoxy group, a C6-6 halogen group, an amine group, a C?.4 mono or c2_8 di-alkylamino group, and a Ci-4 mono or C2_8 di-acid amine group, the prerequisites including replacement The total alkyl chain length of the hetero atom is not more than 10 hindering atoms and the resulting group Q is a stabilizing group. In a specific example, 'Q means that -NR7R8 and -nr3c(o)q form urea, wherein R7 and R8 independently Represents hydrogen or CK9 saturated or unsaturated branched or unbranched alkyl chain in which one or more carbons (such as 1, 2 or 3) are optionally selected from heteroatoms selected from hydrazine, N or S(0)p Substituted. The chain is optionally substituted with one or more groups independently selected from pendant oxy, _, aryl, heteroaryl or heterocyclic groups, each aryl, heteroaryl or heterocyclyl group. Having 0 to 3 independently selected from the above list Substituents for the relevant substituents of the compound, such as halogen, Ci-6 alkyl, Ci-6 alkoxy, c16 haloalkyl, amine, C--4 mono or C2·8 di-alkylamino and Cw mono or c2 8 bis-decylamino group, which is preconditiond to include a replacement hetero atom having a total alkyl group length of not more than ίο carbon atoms and a resulting group Q being a stabilizing group. In this specific example of urea, R7 represents gas in a specific example. Examples of ureas include those in which both r7 and r8 are hydrogen and Q is -NH2, or wherein Q is -NHCH3 or -N(CH3)2 to provide, for example, 17 201130813 fragment -nr3c(o)nh2 or -nr3c(o)nhch3 or -NR3C(0)N(CH3)2. Examples of the urea having a hetero atom in the alkyl chain include those wherein Q is -NH(CH2)2OCH3 or -N[(CH2)2OCH3]]2. In a specific example, 'Q' represents -NHC2_6 alkyl OCualkyl, such as -NHCH2CH2OCH3. Examples of the urea containing a pendant oxy substituent include those wherein Q is -NHCH2C(0)NH-C2_3 alkyl-Xi-Cw alkyl, wherein X1 is selected from N, oxime or S(0)p Atoms and p are as defined above. Examples of the latter include those in which Q is -nhch2c(o)nhch2ch2och3. Thus, in one embodiment, Q represents -NHCmalkyl C(0)NHC2 alkyl 〇ch3, such as -nhch2c(o)nhch2ch2och3. In a specific example, Q represents -NHCw alkyl C(0)RQ, wherein RQ is selected from OH or -NR'R", wherein R' is hydrogen or Cu alkyl and R" is hydrogen or (^-3 alkane) a group such as -NHCH2C(0)0H, -NHCH2C(0)NH2 or -NHCH2C(0)NHCH3 (such as -NHCH2C(0)0H or -NHCH2C(0)NHCH3. In a specific example, the group Q represents -NHC^alkyl (:(0)0(:,-3 alkyl, such as -NHCH2C(0)0CH2CH3. In another urea specific example, Q represents -N-MCw alkyl-V-(Ci- 3 Alkyl-Z-R1Q)k For example, small-foot 9 (:2.3 alkyl-V-(C2.3 alkyl-Z-R1Q)k, wherein: V represents N, NH, Ο, s(0)p Z represents NH, Ο, S(0)p; k is an integer 1 or 2; 201130813 p is an integer 0, 1 or 2 R9 represents Η or Cw alkylalkyl-Z_Ri〇) k, such as C2 3 alkyl- V-(C2_3 alkyl-Z-R1G)k; and R1G is H or Cw alkyl, such as Cl 3 alkyl; the prerequisite is that the total alkyl chain length including the substitution hetero atom is not more than one carbon atom and the resulting group圑Q is a stabilizing group. In one embodiment, Q is a saturated or unsaturated branched or unbranched Ci-i fluorenyl chain, wherein at least one carbon is selected from the group consisting of ruthenium, n, and s(〇)p Heteroatom substitution, wherein the chain By a substituent having 0 to 3 substituents (for example 1, 2 or 3, such as 1 or 2 substituents) independently selected from the above listed compounds of formula (I) (for example selected from halogen, Cl 6 alkyl) An aryl group substitution of a C 6 alkoxy group, a C 6 · a haloalkyl group, an amine group and a mono or c 2 —8 dialkylamino group and a Cm mono or C 2 —8 di-fluorenylamino group, such as a saturated or unsaturated a branched or unbranched CMQ alkyl group in which at least one carbon is replaced by a hetero atom selected from the group consisting of hydrazine, N and S(0)p, wherein the chain has 0 to 3 substituents (eg 1, 2) Or 3, such as 1 or 2 substituents, independently selected from the group consisting of halogen, Cw alkyl, Cy alkoxy, C]-6 haloalkyl, amine and Cm mono or C2-8 dialkylamine aryl In one embodiment, the aryl group is a phenyl group, such as a substituted phenyl group or an unsubstituted phenyl group. In one embodiment, Q represents -NHC〇_6 alkylphenyl group, such as - NH phenyl or NH benzoquinone. Examples of the fragment -NR3C(0)Q (wherein Q contains a substituted benzyl group) include: -nr3c(o)ch2nhch2c6h4(och3) , such as -nhc(o)ch2nhch2c6h4(och3 ), for example, where the methoxy group 201130813 is taken The base is in the ortho, meta or para position, such as the alignment position. In one embodiment, 'Q is a saturated or unsaturated branched or unbranched C^o alkyl chain, wherein at least one carbon is replaced by a hetero atom selected from the group consisting of ruthenium, N and s(〇), wherein the chain is Substituent substituents having a hydrazine to 3 substituents (for example 1, 2 or 3, such as deuterium or 2 substituents) independently selected from the compounds of the above formula (I) (for example halogen, Ci 6 alkyl, Ci) Substituted by a heteroaryl group of a 6 alkoxy group, a Cw alkylamino group, a cM mono or Cw di-anisamine group, and a CM mono or CM di-decylamino group, such as a saturated or unsaturated branch or a non-branched bond a C^o alkyl group in which at least one carbon is replaced by a hetero atom selected from the group consisting of hydrazine, N and S(0)p, wherein the chain has from 〇 to 3 substituents (for example 1, 2 or 3, A heteroaryl group such as one or two substituents selected from the group consisting of halogen, Cm alkyl, C -6 alkoxy, Cw alkylamino, mono or CM di-alkylamino. In a specific example 1, the heteroaryl group is selected from the group consisting of:塞, 吟β圭, ϋ塞, 00. 〆, 王·, 米, azole, pyrazole, isoxazole, isothiazole, oxadiazole, hydrazine, ^ or i-azole, pyridine, arable , pyrimidine, pyridinium and especially pyridine and bite it is acridine. In a particular embodiment, 'Q denotes an -NHCw alkylheteroaryl group, such as -NH(CH2)3 methoxy or -NHCH2, which is substituted by a substituent such as -NHCH2 isoxazole ( CH3). In one embodiment, Q represents -NHCmalkyl c(〇)NHCl3 alkyl-heteroaryl, such as a nitrogen-containing heteroaryl or a nitrogen-containing and oxaheteroaryl group, more particularly -NHCH2C(0)NHCH2CH2 pyridyl, In particular, wherein the 吼0 base is linked via carbon, for example, a ratio. A 4-alkyl group or a -NHCH2C(0)NHCH2CH2CH2 imidazolyl group, in particular, wherein the taste-salt system is linked via nitrogen. 20 201130813 In a specific example, Q is a saturated or unsaturated branched or unbranched cM0 alkyl chain, wherein at least one carbon is replaced by a hetero atom selected from hydrazine, N & s(〇) By a substituent having from 10 to 3 substituents (for example 1, 2 or 3, such as 1 or 2 substituents) independently selected from the compounds of the above formula (I) (for example halogen, Cw alkyl, Cm) a heterocyclic group substitution of an alkoxy 2 Cw-tooth alkyl group, an amine group, a Cl 4 mono or c 2 8 di-alkylamino group, and a C 4 -4 mono or Cw di-decylamino group, such as a saturated or unsaturated a branched or unbranched cM() alkyl chain wherein at least one carbonaceous is replaced by a hetero atom selected from the group consisting of 0, N and s(0)p, wherein the chain has 0 to 3 substituents (eg 1 , 2 or 3, such as 1 or 2 substituents) selected from the group consisting of dentate, Cl.6 alkyl, Cl.6 alkoxy, Ci 6 functional base, Ci_4 mono or C2_8 di-amine Heterocyclic group substitution. In one embodiment, the heterocyclic group is selected from 5 or 6 comprising one or more (eg 1, 2 or 3, in particular 1 or 2) heteroatoms independently selected from the group consisting of hydrazine, N and S. Saturated or partially unsaturated ring systems, such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperonyl, phenanthrene, 1,4-dioxane, pyrrolidine and oxoxazoles such as pyrrolidine, tetrahydrofuran, tetra Hydrogen σ thiophene, π chen bite, brigade σ well, 琳琳 and 1 '二# burning, especially the brigade, the bottom of the well II and the lin. The heterocyclic group can be attached to the alkyl chain of Q or to the carbonyl group of -NR3C(0)_ via carbon or nitrogen, in particular via a nitrogen atom. In one embodiment, Q is a -C〇_3 alkyl heterocycle (eg, _c〇i alkylheterocycle)' the heterocyclic group contains at least one hetero atom selected from the group consisting of ruthenium, N, and S (eg, 1 , 2 or 3 'particularly 1 or 2 heteroatoms, and optionally one or two or three related substituents independently selected from the compounds of formula (1) above (eg halogen, Ci.6 alkyl, Substitution of a Cl6 alkoxy group, a Cw 21 201130813 haloalkyl group, an amine group, a Cw-..-C2_8 di-alkylamino group and a ci 4 mono-fluorenylamino group. 4 In a specific example, Q is a _C〇 alkyl heterocycle, such as a thiol or a gramin or a thiol or a quaternary or pendant oxy oxime group, such as a 2-sided oxyimidazole occluding group. In the specific example, wherein Q^C is a heterocyclic ring, which is via a carbon linkage, 4 such as C_linked tetrahydro (tetra) or < ligated = piperidine or C-linked morpholine or c-linked ploughing . < In a specific example, a heterocyclic group wherein Q is a -c〇alkylheterocyclic ring containing one or more N atoms is bonded via N. This is specifically for the urea in which the urea nitrogen is embedded in the heterocyclic ring. This specific example includes, but is not limited to, N. linkages or N. linkages (iv) or n-linkages. The N-linked piperage group optionally has additional C- or N-substituents. Such as N-fluorenyl or N-cp^cj^ocj^ groups. In one embodiment, Q is a heterocyclic group attached via a nitrogen such as piperidinyl, especially 4-hydroxypiperidinyl or piperylene, such as tetraazepyl. In a particular embodiment, Q represents a heterocyclic group, for example a nitrogen-containing heterocyclic group, in particular via N-bonding, such as morpholinyl or piperidinyl substituted by methyl (especially 4-methyl), or Pyridyl. In one embodiment, 'Q is optionally substituted with a substituent (eg, a Q-6 alkyl substituent such as methyl or c)-6 alkoxy substituent, such as -CH2CH2〇CH3). Rings such as tetrahydron-decylmethyl or C- or N-linked piperacinylmethyl. Other examples include c- or N-linkage ratios of 17 octyl groups or C- or N-linked pendant oxy groups. Rice succinylmethyl (such as 2-sided oxyimidazolidinylmethyl) which optionally has a 22 201130813 substituent (such as N-methyl or N-S02CH3). In a specific example, Q represents a -NH heterocyclyl group (wherein the heterocyclic group has 0 to 3 substituents selected from the related list of substituents of the above formula (I), such as halogen, thiol, Cu Alkyl group, Cu alkoxy group, Ci.6 halogen group, amine group, Ci_4 mono or C2-8 di-anistenyl group, alkyl group, Cm mono or C2_8 di-decylamino group, C〇-6 alkyl group An alkyl group or a C〇_6 alkyl group CXCOCk miscellaneous group) such as wherein the ring system is linked via a charcoal, such as a 2-bite group or a 3-branched bite group or a 4-bringe bite group, particularly a 1-ethyl fluorenyl group. Σσ定-4-yl, 1-indolylpyr-4-yl, 1-(methylglycosyl)piperidin-4-yl or 1-(2-(2-decyloxyethoxy)B Mercapto) piperidine · 4 - group. In one embodiment, Q represents a -NHCkalkylheterocyclyl such as a nitrogen-containing heterocyclic group, particularly via a nitrogen linker such as morpholine, -NH(CH2)3 morpholine or -NH(CH2)4 morpholine. . In one embodiment, Q represents a -NHC-6 alkyl c(anthracene) heterocyclic group (wherein the heterocyclic group has 0 to 3 substituents selected from the list of substituents of the above formula (I)) Base, for example, halogen, thiol, C -6 alkyl, Cl-6 alkoxy, Ci-6 haloalkyl, amine, Ci_4 mono or C2-8 di-anisamine, Cw or C2-8 - mercaptoamino group, C〇-6 alkyl hydrazine: (0) (:, -6 alkyl or CG_6 alkyl CXCOC!-6 complex) ', for example, a nitrogen-containing heterocyclic group, particularly via a nitrogen linker , such as -NHCHzCCO) pyrrolindinyl, -NHCH2C(0)-1-piperidinyl, -NHCH2C(0)-4- morphinyl or -NHCH2C(0) pi well group such as -NHCH2C ( 0) 4-mercapto-1-° bottom cultivating base. In one embodiment, Q represents -NHCw alkyl CCC^NHCy alkylidene heterocyclyl such as a nitrogen-containing heterocyclic group or a nitrogen-containing and/or oxygen heterocyclic group such as -NHCH2C(0)NHCH2CH2 morpholinyl, in particular Yes, where? 23 201130813 The Lynn system is connected via nitrogen. In a specific example, Q represents _N(Cl-3 fluorenyl)C]6 alkylidylheterocyclyl, for example a nitrogen-containing heterocyclic group, in particular via a nitrogen linkage, =-N(CH3)CH2CH2 morpholine, _N(CH3)(CH2)3 morpholine ° -N(CH3)(CH2)4 morpholine. 4 In a specific example, Q is a -Ci.3 alkyl group-G-CM-based heterocyclic ring, wherein G is a hetero atom selected from NH, hydrazine or 8 (0), the heterocyclic group containing at least one hetero atom (for example i, 2 or 3, in particular i or 2 heteroatoms) selected from 0, N and S, and optionally one or two or three independently selected from the compounds of formula (1) above Substituent group (eg, element, Cw alkyl, Cl_6 alkoxy, Ci 6 dentate, amine, Q.4 mono and CM di-alkylamine, and Cl_4 mono or C2-8: fluorenyl) The amine group is substituted with one or two or three groups of halogen, alkyl, Ci6 alkoxy, Ci. 6-dentylalkyl, amine 'cM mono and C2·8 di-alkylamino. CH2G(CH2)2 heterocyclic ring such as _CH2G(CH2)2 tetrahydropyranyl; or -CH2G(CH2)2 morpholinyl, wherein the heterocyclic group is linked via nitrogen or carbon, or CH2G(CH2)2 piperidine A cultivating group wherein the heterocyclic group is attached via nitrogen or carbon and optionally has an additional (:- or 1^ substituent (eg, a CI 6 alkyl substituent such as a fluorenyl or C!-6 alkoxy substituent) , such as • CH 2 CH 2 〇 CH 3 ); or —CH 2 G(CH 2 ) 2 bromopyridyl, which t the heterocyclic group is linked via nitrogen or carbon For example, via a nitrogen linkage; or a _CH2G(ch2)2 pendant oxy-saltyl group (such as a 2-sided oxy-saltidine group), for example via N linkage and optionally an additional C- or oxime-substituent (such as Ν-fluorenyl or N-S02CH3), and wherein G is 0 or ΝΗ. In a specific example, G is Ο. In one embodiment, G is NH. 24 201130813 In a specific example, 'Q is a saturated or unsaturated alkyl group, wherein at least one carbon (eg, 1, 2 or 3 carbons) is replaced by a hetero atom selected from 0, N, S(0)p, wherein the chain is via a C3·8 carbon ring The group substitution and the alkyl group are optionally substituted by one or more (for example, 1 or 2) groups selected from the group consisting of a pendant oxy group and an auxin. In one embodiment, the C3_8 carbocyclic group has one or A plurality of groups (eg 1, 2 or 3 groups.) are independently selected from the group consisting of halogen, hydroxy, Ci-6 alkyl, C!-6 alkoxy, Ck self-alkyl, amine, Cm or C2. -8--Acrylamine, Ci_4 or C2-8 bis-stylamino, alkyl, C〇-6 alkyl C(0)Ci.6 alkyl or Cq-6 alkyl CXCOCk heteroalkyl. In a specific example, Q represents cyclopropyl, -fluorenylcyclopentyl or -fluorenylcyclohexyl in a specific In the above, the aryl, heteroaryl or heterocyclic group has a substituent which is defined by the compound of the above formula (1), and optionally has a substituent which is independently selected from the compound of the above formula (1). Further related substituents. In a specific example, the c5 6 is heterogeneous; the octagonal -6 hexene has at least one -Mo'c -6 alkyl substituent and optionally It is selected from the above-mentioned independent substituents defined for the compound of formula (I). Further, the hexapods of the hexagrams of the hexagrams have a radical substituent and optionally a heterocyclic group having the substituents defined by the compound of the above formula (1) from 1 to 1 independently. Further examples of the soil-specific list, the c5-6 heterocyclic has a substituent and optionally has a - or a diagonal group: 硪 is defined by the above formula (I), 25 201130813 Additional substituents for the relevant list of substituents. In one embodiment, the aryl, heteroaryl or heterocyclic group has at least one Ci-4 mono- and/or C2-8 di-indenylamino substituent and optionally one or two independently selected Additional substituents from the related list defined by the above compounds of formula (I). In one embodiment, the Cs_6 heterocycle has at least one Ci 4 mono and/or C 2-8 bis-indenylamino substituent and optionally one or two independently selected from the compounds of formula (I) above. Additional substituents for the relevant list of definitions. In one embodiment, the aryl, heteroaryl or heterocyclic group has at least one C〇-6 alkyl CXCOCk heteroalkyl substituent and optionally one or two independently selected from the above formula (I) Additional substituents for the relevant list defined by the compound. In a specific embodiment, the C.6 heterocycle has at least one calkyl CXCOC!6 heteroalkyl substituent and optionally has one or two = independently selected from the definitions defined by the above compounds of formula (I) Additional substituents on the list. In one embodiment, the aryl, heteroaryl or heterocyclic group has at least one C 〇 6 alkyl group: (0) (^-6 alkyl substituents and optionally one or two independently An additional substituent selected from the list of compounds defined by the above formula (I). In one embodiment, the Cw heterocycle has at least one c alkyl group: (0) (^-6 alkyl substituent and Desirably having ~ or two additional substituents selected from the substituents defined by the above formula (1). In a specific example, 'Q represents tetrahydrofuranyl, morpholinyl, mai 26 201130813 j (such as having a a substituent of a base substituent, such as a base of a methyl group, or a ratio of π to a base of π, which is a ratio of 11 to 10 The ring may be attached via a heteroatom such as nitrogen, or - or A may be attached by a carbon. The substituent may, for example, be in the para position of the atom attached to the remainder of the molecule relative to the private phase. In a specific example, The desired substituent. The alkyl chain fragment of Q can have any particular embodiment in which the alkyl chain is saturated. In an embodiment, the alkyl chain is unbranched. In one embodiment, the alkyl chain fragment of Q has 1, 2 or 3, such as 1 or 2, particularly one of the desired substituents. It will be apparent to those skilled in the art that a heteroatom can replace a primary, secondary or secondary carbon (i.e., CH3, -CHy or -CH-) group, as technically appropriate. In one embodiment, p is deuterium or 2. In a specific example, p is 1. In a particular embodiment, the compounds of the present disclosure include such compounds wherein fragment Q is: -ch2oh; -CHzOCu alkyl, especially _CH2OCH3; -CH2CH2OCH3; -CH20( CH2)20CH3; -CH(CH3)OCH3; -ch2nhch3 or -ch2n(ch3)2-ch2nhch2ch2och3 or -ch2nhc(o)ch2och3; -CH2SCH3, -CH2S(0)2CH3 or -ch2nhc(o)ch2s(o)2ch3 Or * 27 201130813 -ch2nhc(o)ch2. In a specific example, the compounds of the present disclosure include those in which the fragment -NR3C(0)Q in the formula (I) is represented by the following: -NR3C(0 )CH20H ' and especially -NHC(〇)CH2OH; -NR^C^COCHzOCk alkyl', especially _NR3C(0)CH20CH3, especially -nhc(o)ch2och3; -nr3c(o)ch2o(ch2)2och3 And especially - NHC(0)CH20(CH2)20CH3; -nr3c(o)ch(ch3)och3, and especially -nhc(o)ch(ch3)och3; -NR3C(0)CH(CH3)NHCi_3 alkyl, and special Is -NHC(0)CH(CH3)NHCH3; -NR3C(0)CH(CH3)N(Ci-3 alkyl)2, and especially -nhc(o)ch(ch3)n(ch3)2; Nr3c(o)c(ch3)2nhch3, and especially -nhc(o)c(ch3)2nhch3; -NWC^OXCHAOCk alkyl, such as -NR3C(0)(CH2)2〇CH3 'particularly->JHC (0)(CH2)2〇CH3; -NWc^OXCH^NHCmalkyl, and especially -nhc(o)(ch2)3nhch3; NRSQOXCHaNO^walkyl)2, and especially -nhc(o)(ch2 3n(ch3)2; -NWcCCOCi^NHCM alkyl, and especially -NHC(0)CH2NHCH3; _nr3c(o)ch2nh(ch2)2och3, and especially -nhc(o)ch2nh(ch2)2och3; 28 201130813 -NR3C(0)CH2SCH3, especially -NHC(0)CH2SCH3; -nr3c(o)ch2s(ch2)2och3, especially -nhc(o)ch2s(ch2)2och3; -NR3C(0)CH2S(CH2)20 (CH2)20CH3, and especially -NHC(0)CH2S(CH2)20(CH2)20CH3-NR3C(0)CH2S0CH3, and especially -NHC(0)CH2S0CH3 -nr3c(o)ch2s(o)2ch3, and In particular -NHC(0)CH2S(0)2CH3; -nr3c(o)ch2n[(ch2)2och3]2, and especially -NHC(0)CH2N[(CH2)20CH3]2; -NR3C(0)NH2 And especially -NHC(0)NH2 NRAcONHCw alkyl, (such as nrScXCONHCu alkyl, and especially -nhc(o)nhch3 -NR C(0)N(C]_4 alkyl) Ci_5 alkyl, and especially -nhc(o)n(ch3) 2 ; or -nr3c(o)nhch2conh(ch2)2och3, especially -nhc(o)nhch2conh(ch2)2och3. In a specific example, the compounds of the present disclosure include a compound of the formula (1) wherein the fragment -NR C(0)C〇8 alkyl group is represented by the following: -NHC(O)·(tetrahydropyranyl) , such as _NHC(〇)-(tetrahydro-2H-pyran-4-yl): -NHC(〇H morpholinyl) such as _NHC(0)-(4-morpholinyl) or -NHC(0 - (3-morpholinyl); -NHC(O)-(pyrrolidinyl), such as _NHC(0)-(pyridylpyridyl); _NHC (〇H piperazine), such as ΝΗ(:(〇Η^π井_1_基); -NHC(〇H曱基派〇井基), such as _NHC(0)-(4-曱基培耕-1· 29 201130813 基); -NHC(0)-[(methoxyethyl)pipedyl], such as ·NHC(〇)_[4_(2_methoxyethyl)piped-1-yl]; -NHC(0)- (Sideoxyimidazolidinyl) such as _NHC(〇)_(2^^oxymi. sit. base), especially _NHC(〇)-(2• sideoxyimidazolidinyl); -nhc (o) ch2-(tetrahydropyranyl), such as _nhc(0)Ch2_(tetrahydro-2H-pyran-4-yl); -nhc(o)ch2-(morpholinyl)' such as _NHC (〇)CH2-(4_morpholinyl); -NHC(0)CH2-decapyridinyl)' such as _nhc(〇)CH2_(d-pyrrolidine+yl); -nhc(o)ch2-( Pie. Well base), Such as _NHC (〇) CH2 (Peiji); -NHC(0)CH2-(曱基培η井井), such as _NHC(〇)CH2_(4_methyl派σ井-1-yl), - NHC(0)CH2_[(methoxyalkyl)pipedyl], such as -NHC(0)CH2_[4-(2_decyloxyethyl) brigade σ wells]; -NHC(0)CH2SCH2CH2 - (Merlinyl), such as _NHC(0)CH2SCH2CH2-(4-morpholinyl) or -NHC(0)CH2SCH2CH2-(3-morpholinyl); and -NHC(0)CH2S〇2CH2CH2·(? (Linki), such as -NHC(0)CH2S〇2CH2CH2-(4-morphinyl)戍-NHC(0)CH2S〇2CH2CH2-(3*^^n·!^ base). In one embodiment of fragment Q, a saturated or unsaturated branched or unbranched CM0 alkyl chain (wherein at least one carbon system is replaced by a group selected from _〇, _N, s(0)p or a hetero atom) is selected from The linker of :_CH2OCH2-, -CH2NHCH2-, -CH2NH-, and -CH2〇CH2CH2-. These fragments may be terminated as desired in the aryl group, the heteroaryl group, the aryl group defined by the heterocyclic group 201130813 Q, or the C3-8 cycloalkyl group such as the above-mentioned fragment heteroaryl, heterocyclic group. In the specific example t, the disclosure relates to the compound ba of the formula (IA)

N 一 Ar_LN an Ar_L

Or R3Or R3

Ο II C—Q (ΙΑ) 其中R、R、&mQ係如上述所定義。在式（ΙΑ)化合物之—具體實 -nr3c(o)q係在2或3位置。取代土在另-具體實例中，該揭示係有關式(IB)之化合物: R1Ο II C—Q (ΙΑ) where R, R, & mQ are as defined above. In the formula (ΙΑ), the specific -nr3c(o)q is at the 2 or 3 position. Substituted soil In another embodiment, the disclosure relates to a compound of formula (IB): R1

其中fR2、Arm Q係如上述所定義。在又另一具體實例中，該揭示係有關式(1C)之化合物：Wherein fR2 and Arm Q are as defined above. In yet another embodiment, the disclosure relates to a compound of formula (1C):

(|〇 R3 (CH2>x-S(〇}p-(CH2)y-CH3 其中R、R2、Ar、[和R3係如上述所定義及p為〇、1 31 201130813 或2,特別是〇或2，石 4及5)及y為零或先決條件為X和y之紹例如x為1及y為1。 '，及X為從1至6之整數（包括2、3、或從1至5之整數（包括2、3及4)，其 y之總和為從1至8之整數諸如1至6, 在一具體實例中，該揭示係有關式⑽之化合物：(|〇R3 (CH2>xS(〇}p-(CH2)y-CH3 where R, R2, Ar, [and R3 are as defined above and p is 〇, 1 31 201130813 or 2, especially 〇 or 2 , stones 4 and 5) and y are zero or the prerequisites are X and y, for example x is 1 and y is 1. ', and X is an integer from 1 to 6 (including 2, 3, or from 1 to 5) An integer (including 2, 3, and 4), the sum of which is an integer from 1 to 8, such as 1 to 6, and in one embodiment, the disclosure relates to a compound of formula (10):

其中R、R、Ar、L和R3係如上述所定義， X為從1至6之整數（包括2、3、4及5)及丫為零或從ι 至5之整數（包括2、3及4)，其先決條件為χ和y之總和為從1至6之整數，例如X為1及y為〇。在式（ID)化合物之一具體實例中，以 -NR3C(0)(CH2)x0(CH2)yCH3 表示之片段為： -NR3C(0)CH20CH3，尤其是-NHC(0)CH20CH3。在一具體實例中，該揭示係有關式(IE)之化合物：Wherein R, R, Ar, L and R3 are as defined above, X is an integer from 1 to 6 (including 2, 3, 4 and 5) and 丫 is zero or an integer from ι to 5 (including 2, 3) And 4), the prerequisite is that the sum of χ and y is an integer from 1 to 6, for example, X is 1 and y is 〇. In one embodiment of the compound of formula (ID), the fragment represented by -NR3C(0)(CH2)x0(CH2)yCH3 is: -NR3C(0)CH20CH3, especially -NHC(0)CH20CH3. In one embodiment, the disclosure is related to a compound of formula (IE):

其申R1、R2、Ar、L、R3、汉7和R8係如上述所定義。在一具體實例中，該揭示係有關式(IF)之化合物： 32 201130813Its R1, R2, Ar, L, R3, Han 7 and R8 are as defined above. In one embodiment, the disclosure is related to a compound of formula (IF): 32 201130813

其中1^、112、八1·、]^和R3係如上述所定義及X2表示〇、 ch2、ΝΗ、nch3 或 NCH2CH2OCH3。在一方面’提供一種式(IG)之化合物：Wherein 1^, 112, 八1·, ^^ and R3 are as defined above and X2 represents 〇, ch2, ΝΗ, nch3 or NCH2CH2OCH3. In one aspect, a compound of formula (IG) is provided:

其中R1為視需要經羥基基團取代之C16烷基； R2為Η或視需要經羥基基團取代之ci 6烷基； R為Η、CK6烷基或C() 3烷基q 6環烷基；Wherein R1 is a C16 alkyl group optionally substituted by a hydroxy group; R2 is hydrazine or a ci 6 alkyl group optionally substituted by a hydroxy group; R is hydrazine, CK6 alkyl or C() 3 alkyl q 6 naphthenic base;

Ar為萘基或笨基環，其任一可視需要經一或多個獨立地選自CN6烷基、Cl6烷氧基、胺基、單或二· 烷胺基之基團取代； X為包含至少一個氮原子且視需要包括丨或2個選自〇、S及N之另外雜原子的5或6員雜芳基·， Q係選自： a)飽和或不飽和支鏈或非支鏈CM0烧基鏈，其中至少個石反(例如1、2或3個碳’適當地i或2個，特別是 1 個）係經選自〇、N、 S(〇)p之雜原子置換，其中該鏈視 33 201130813 需要地經一或多個（例如1、2或3)獨立地選自側氧基、函素、芳基、雜芳基、雜環基或C3_8環烷基之基團取代’ 各芳基、雜芳基或雜環基具有0至3個選自鹵素、羥基、 C】-6燒基、Cy烷氧基、Cl_6鹵烷基、胺基、Cm單或 C2-8二-烷胺基、Cl 4單或c2_8二-醯基胺基、SCCOqCw 炫•基、CQ.6烷基C(0)Ci 6烷基或C()_6烷基¢:(0)(^-6雜烧基之取代基，其先決條件為直接地連接至_Nr3C(〇)-中之羰基的原子不為氧或硫原子；及 b)C〇_8烷基c5_6雜環或包含至少一個選自〇、n及S之雜原子(例如1、2或3個，適當地1或2個，特別是1 個雜原子）’及視需要經一、二或三個獨立地選自函素、各基、Ci _6烧基、Ci .6炫·氧基、Cl-6鹵烧基、胺基、Ci.4 單及C2-8二-烷胺基、d-4單或C2-8二-醯基胺基、 SCCOqCM烷基、c〇_6烷基C(0)C〗-6烷基或c〇.6烷基雜烷基之基團取代的該雜環基；及 P為〇、1或2 ; 或其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。在一具體實例中，該揭示係有關式(IH)之化合物： 34 201130813 又 Ν Ν Ν一Ar—ϋ I Η Η ii^^TN-C-Q R3 (ΙΗ)Ar is a naphthyl or a stupid ring, any of which may optionally be substituted with one or more groups independently selected from the group consisting of CN6 alkyl, Cl6 alkoxy, amine, mono or dialkylamine; X is included At least one nitrogen atom and optionally 5 or 6 membered heteroaryl groups selected from hydrazine or 2 additional heteroatoms selected from the group consisting of hydrazine, S and N, Q is selected from the group consisting of: a) saturated or unsaturated branched or unbranched a CM0 alkyl group in which at least one stone counter (for example 1, 2 or 3 carbons 'suitably i or 2, in particular 1) is replaced by a hetero atom selected from 〇, N, S(〇)p, Wherein the chain of view 33 201130813 is desirably selected from one or more (eg 1, 2 or 3) groups independently selected from pendant oxy, haromeric, aryl, heteroaryl, heterocyclyl or C3_8 cycloalkyl groups. Substituting 'each aryl, heteroaryl or heterocyclic group having 0 to 3 selected from halogen, hydroxy, C]-6 alkyl, Cy alkoxy, Cl-6 halogen alkyl, amine, Cm or C2-8 Di-alkylamino, Cl 4 mono or c2_8 bis-indenylamino, SCCOqCw Hyun, CQ.6 alkyl C(0)Ci 6 alkyl or C()_6 alkyl hydrazine: (0) (^ a substituent of a -6 miscellaneous group, the prerequisite being the original of the carbonyl group directly attached to _Nr3C(〇)- Is not an oxygen or sulfur atom; and b) a C〇8 alkyl c5_6 heterocycle or a hetero atom comprising at least one selected from the group consisting of 〇, n and S (eg 1, 2 or 3, suitably 1 or 2, particularly Is a hetero atom) and optionally, one, two or three are selected from the group consisting of a single element, a group, a Ci-6 alkyl group, a Ci.6 oxime oxy group, a Cl-6 halogen group, an amine group, Ci.4 mono and C2-8 di-alkylamino, d-4 mono or C2-8 di-decylamino, SCCOqCM alkyl, c〇_6 alkyl C(0)C -6 alkyl or a heterocyclic group substituted with a group of a 6 alkylalkyl group; and P is hydrazine, 1 or 2; or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers thereof And isotope derivatives. In a specific example, the disclosure relates to a compound of formula (IH): 34 201130813 Ν Ν Ν Ar Ar-ϋ I Η Η ii^^TN-C-Q R3 (ΙΗ)

其中R、R2、Ar、R3及Q係如上述所定義。在另-具體實例中，該揭示係有關式(IJ)之化合物NV\X > N N-Ar-〇Wherein R, R2, Ar, R3 and Q are as defined above. In another embodiment, the disclosure relates to a compound of formula (IJ) NV\X > N N-Ar-〇

R3 Q (U) 其中1^、112、^、1^及（3係如上述所定義. 合物：在另其他具體實例中，該揭示係有關式㈤之化R3 Q (U) where 1^, 112, ^, 1^ and (3 are as defined above. Compound: In still other specific examples, the disclosure is related to formula (5)

其中V'R2、A:和W係如上述所定義及 Z表示餘和或不飽和支鏈或非支鏈^烧基鏈，其中至 ίΤ:例如^或3個碳’適當地1或2個’特別 ^個)係經選自〇、N、s(〇)p之雜原子置換，或 C5_6雜環’該雜環基包含至少—個選自及S之雜原子(例如卜2或3個，適當 35 90111^ 乃|J是1個雜原子）’及視需要經一個或二個或三個獨立地選自上述式(I)化合物之所列相關取代基的基團（例如鹵素、Cu烧基、Ci-6炫氧基、Ci.6 _烧基、胺基、Cw 單及C2-8二-烷胺基)取代。在式（IK)之一具體實例中，Z為-〇CH3或 OCH2CH2OCH3。在式(IK)之一具體實例中’ zg-S02CH3。在式(IK)之一具體實例中，z，其中ra 和Rb係獨立地選自氫、Cl-6烧基及c3_6烷氧基，以使例如 Z 表示-NH2、-NHCH3、_N(CH3)2 或 -NHCH2CH2OCH3。在式(IK)之一具體實例中，z g-S(0)qCH3，其中n 為〇、1或2，諸如0或2。在式(ΙΚ)之一具體實例中’ ζ表示-c5_6雜環，該雜環基包含至少一個選自〇、N及s之雜原子(例如1、2 或3個，適當地1或2個’特別是1個雜原子），及視需要經一、二或三個獨立地選自上述式⑴化合物之所列相關取代基的基團（例如鹵素、Ci_6烧基、C〗·6烧氧基、 Cl-δ鹵烧基、胺基、Q-4單及C2·8二-烧胺基)取代，例如：嗎琳基(特別是經由氮連接）或四氫哌喃基、或。底畊基（特別是經由氮連接），視需要在第二個氮上經 -CH3 或-CH2CH2OCH3 取代。在一具體實例中，該揭示係有關式(IL)之化合物： 36 201130813Wherein V'R2, A: and W are as defined above and Z represents a residual or unsaturated branched or unbranched chain, wherein to ί: for example ^ or 3 carbons' suitably 1 or 2 'Special^ is replaced by a hetero atom selected from 〇, N, s(〇)p, or a C5_6 heterocyclic ring containing at least one hetero atom selected from the group consisting of S (for example, 2 or 3) , suitably 35 90111^ is |J is a heteroatom) and optionally one or two or three groups independently selected from the listed substituents of the above formula (I) (eg, halogen, Cu) Substituted for alkyl, Ci-6 methoxy, Ci.6-alkyl, amine, Cw and C2-8 di-alkylamino. In one embodiment of formula (IK), Z is -〇CH3 or OCH2CH2OCH3. In one specific example of formula (IK) 'zg-S02CH3. In one embodiment of formula (IK), z, wherein ra and Rb are independently selected from the group consisting of hydrogen, Cl-6 alkyl, and c3-6 alkoxy, such that, for example, Z represents -NH2, -NHCH3, _N(CH3) 2 or -NHCH2CH2OCH3. In one specific example of formula (IK), z g-S(0)qCH3, where n is 〇, 1 or 2, such as 0 or 2. In one embodiment of the formula (ΙΚ), 'ζ denotes a -c5_6 heterocyclic ring containing at least one hetero atom selected from hydrazine, N and s (for example 1, 2 or 3, suitably 1 or 2) 'In particular, 1 hetero atom, and optionally, one, two or three groups independently selected from the listed substituents of the above formula (1) (for example, halogen, Ci-6 alkyl, C.6) Substituents such as a Cl-δ haloalkyl group, an amine group, a Q-4 mono group, and a C2·8 di-anisole group, for example, a morphyl group (particularly via a nitrogen linkage) or a tetrahydropyranyl group, or. The bottom cultivating base (especially via nitrogen connection) is optionally substituted with -CH3 or -CH2CH2OCH3 on the second nitrogen. In a specific example, the disclosure relates to a compound of formula (IL): 36 201130813

其中R1、R2、Ar和R3係如上述所定義及 R7’和R8’獨立地表示氫、Ci_6烷基，或 1-6 -烷胺基） R7’和R8’與它們所連接之氮一起表示視需要包含選〇、N及S之另外雜原子的5或6員雜環，其中該雜戸視需要經一個或二個或三個獨立地選自上述'式^匕^ 物之所列相關取代基的基團（例如鹵素、Cm烷美、烧乳基、Ci-6鹵烧基、胺基、Cj_4單及c 取代β 在式(IL)化合物之一具體實例中，基團_nr7，r8， -nh2、-nhch3 或 nhch2ch3。乂 R8表示嗎琳在式(IL)化合物之一具體實例中，^ w，基或α辰η井基。合物在一替代性具體實射，該揭示係有__之化Wherein R1, R2, Ar and R3 are as defined above and R7' and R8' independently represent hydrogen, Ci-6 alkyl, or 1-6-alkylamino) R7' and R8' are taken together with the nitrogen to which they are attached Optionally, a 5- or 6-membered heterocyclic ring containing an additional hetero atom of hydrazine, N and S, wherein the enthalpy is required to be selected from one or two or three independently selected from the above-mentioned formulas a substituent group (e.g., halogen, Cm alkene, calcined base, Ci-6 haloalkyl, amine group, Cj_4 mono and c substituted β in a specific example of a compound of formula (IL), group _nr7, R8, -nh2, -nhch3 or nhch2ch3. 乂R8 represents morphine in a specific example of a compound of the formula (IL), ^ w, 基 or 辰 η 井井. There is __

其中Ri_、R2、Α]:和R3係如上述所定義及細表示C5_6雜環’該雜環基包含至少一個選自…N 37 汉S之雜原子(例如1、2或3個，適當地1或2個，特別是1個雜肩子），及視需要經一個或二個或三個獨立地選自上述式⑴化合物之所列相關取代基的基團（例如鹵素、C】6院某、Cl-6炫氧基、C1·6函烧基、胺基、Cl-4 單及c2-8:_烷胺基)取代。在式(IM)化合物之一具體實例中，Het為嗎啉基或四氧Π底喝基。在一具體實例中，該化合物不為：N-(4-(4-(3-(3-第二-丁基-1_對-曱苯基-出-吼嗤-〗-基)脈基）萘-1-基氧基） «比啶-2-基)_2_曱氧基乙醯胺。在一具體實例中，該化合物為： N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基）曱基）吡啶-2-基)-2-曱氧基乙醯胺或其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。在一具體實例中，該化合物為：甲基4-((4-(3-(3-第三-丁基_1_對-曱苯基-1H-吡唑-5-基) 腺基)萘-1-基氧基）甲基)°比啶-2·基脲； n_(4-((4-(3-(3-第三-丁基小對_曱苯基_1H吼唑_5_基)脲基）萘-1-基氧基）曱基）η比啶_2_基）四氫-2H-哌喃-4-曱醯胺； (S)-N-(4-((4-(3-(3·第三-丁基-ΐ_對-甲苯基-1Η-吡唑-5- 基）脲基）萘-1·基氧基）曱基y比啶·2_基)_2_曱氧基丙醯胺； (R)-N-(4-((4-(3-(3-第三-丁基-ΐ_對-甲苯基-1Η-。比唑-5-基）腺基）萘-1-基氧基）曱基）吼啶_2_基)·2·曱氧基丙醯 38 201130813 胺； N-(4-((4-(3-(3-第三-丁基-1-對·曱苯基-1Η-°比唑-5-基）脲基）奈-1-基氧基）甲基)π比β定-2-基)-2-(甲硫基）乙酿胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）秦-1 -基氧基）甲基)π比σ定-2 -基)-2 -嗎嚇基乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1 -基乳基）甲基）吼咬-2-基）-2-(0比σ各β定-1 -基）乙酿胺； Ν-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑-5-基)脲基）萘-1-基氧基）曱基)°比啶-2-基)-2-(4-甲基哌畊-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基）蔡基氧基）曱基）。比咬_2_基）-2-(4-(2-曱氧基乙基) 哌畊-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）曱基)0比°定-2-基)-2-(2-曱氧基乙胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）曱基户比11定-2-基)-2-(二曱胺基）乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）曱基)°比。定-2-基)-2-(曱胺基）乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基）曱基比啶-2-基）-2-((4-曱氧基苯曱基)（曱基)胺基）乙醯胺； 1-(4-((3-曱基腺基α比咬-4-基）曱氧基）秦-1-基)-3-(3-第二 -丁基-1-對-曱苯基-1H-吡唑-5-基)脲； 39 201130813 以_(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-3-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基）曱基)°比啶-3-基)-2-(2-曱氧基乙氧基）乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η 比唑-5-基）脲基)萘-1-基氧基）乙基)°比啶-2-基)-2-曱氧基乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-甲苯基-1Η-η 比唑-5-基) 脲基）萘-1-基氧基）乙基)°比啶-2-基)-2-(2-曱氧基乙氧基) 乙醯胺； 4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）蔡-1-基氧基）乙基)-1-曱基-3-(0比咬-2-基)腺， 4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-°比唑-5-基）脲基)萘-1-基氧基）乙基)-3-(吼啶-2-基)脲； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-° 比唑-5-基) 脲基)萘-1-基氧基）乙基)。比啶-3-基)-2-(2-曱氧基乙氧基) 乙醯胺； N_(4-((4-(3-(3 -第二-丁基· 1 -對-曱苯基-1H-0比0坐-5-基)腺基)萘-1-基氧基）曱基)嘧啶-2-基)-2-曱氧基乙醯胺； N-(l-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基) 脲基）萘-1-基氧基）乙基)-1Η-咪唑-4-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(曱磺醯基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5_基)脲基）秦-1-基氧基）曱基)°比咬-2-基)-2-經基乙酿胺， 201130813 N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H_吡唑_5_基)脲基）萘-1-基氧基）甲基）吼啶-2-基)-2-甲基-2-(甲胺基）丙醯胺； (S)-N-(4-((4-(3-(3-第三-丁基巧-對·甲苯基_1Η·Π比唑·％基)脲基）萘-1-基氧基）曱基）吡啶_2_基)_2-(甲胺基）丙醯胺； (R) -N-(4-((4-(3-(3 -第三-丁基4_對_ 甲苯基·1H_吡唑_5· 基)脲基)萘-1-基氧基）甲基)吡啶_2_基)嗎啉_3_曱醯胺；Wherein Ri_, R2, Α]: and R3 are as defined above and are finely represented by a C5_6 heterocyclic ring. The heterocyclic group contains at least one hetero atom selected from the group consisting of N 37 Han S (for example 1, 2 or 3, suitably 1 or 2, especially 1 hetero-shoulder), and optionally 1 or 2 or 3 groups independently selected from the listed substituents of the above formula (1) (for example, halogen, C) 6 Substituted with a certain Cl-6 methoxy group, a C6·6 functional group, an amine group, a Cl-4 group and a c2-8:-alkylamino group. In a specific example of the compound of the formula (IM), Het is a morpholinyl group or a tetraoxindole group. In one embodiment, the compound is not: N-(4-(4-(3-(3-second-butyl-1_p-fluorenyl-p-indole-)-yl) )naphthalen-1-yloxy) «bipyridin-2-yl)_2_decyloxyacetamide. In one embodiment, the compound is: N-(4-((4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl))) Naphthyl-1-yloxy)indenyl)pyridin-2-yl)-2-decyloxyacetamide or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers thereof and Isotope derivative. In one embodiment, the compound is: methyl 4-((4-(3-(3-t-butyl-1-)-p-phenyl)-1H-pyrazol-5-yl) gland) Naphthalen-1-yloxy)methyl) ° pyridine-2·urea; n_(4-((4-(3-(3-tert-butyl)-p-phenylene) 5-()-ureido)naphthalen-1-yloxy)indenyl)n-pyridin-2-yl)tetrahydro-2H-piperazin-4-indole; (S)-N-(4-( (4-(3-(3·Terve-butyl-indole-p-tolyl-1Η-pyrazol-5-yl)ureido)naphthalen-1·yloxy)fluorenyl y-pyridyl·2_ ())-N-(4-((4-(3-(3-)-tert-butyl-indole-p-tolyl-1Η-. -based) glysyl)naphthalen-1-yloxy)indolyl)acridine_2_yl)·2·decyloxypropane 38 201130813 amine; N-(4-((4-(3-(3) -Third-butyl-1-p-anthracene-phenyl-1Η-°bazin-5-yl)ureido)n-1-yloxy)methyl)π ratio β-but-2-yl)-2 -(methylthio)ethanoamine; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido Qin-1 -yloxy)methyl)π ratio σ定-2 -yl)-2 - 吓基乙乙, N-(4-((4-(3-(3-)- -1--1-p-phenyl-1H-pyrazol-5-yl)ureido)-n-yl lactyl)吼-(4-(3-(3-T-butyl)-1) -p-p-phenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(4-methylpiped-1 -yl)acetamide; N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)))) Base 曱 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)-n-yloxy)indolyl) 0 to °-2-yl) -2-(2-decyloxyethylamino)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-pyrazole -5-yl)ureido)naphthalenyloxy)indoleyl 11-but-2-yl)-2-(diguanylamino)ethinamine, N-(4-((4-) 3-(3-tert-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)n-1-yloxy)indolyl). -2-(nonylamino)ethinamide, N-(4-((4-(3-(3-)-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl) Ureido)naphthalen-1-yloxy)indolyl-2-yl)-2-((4-decyloxyphenyl)(indenyl)amino)acetamide; -(4-((3-Mercapto-glycosyl-α- -4-yl) decyloxy)-heptan-1-yl)-3-(3-second-butyl-1-p-phenyl)- 1H-pyrazol-5-yl)urea; 39 201130813 as _(4-((4-(3-(3-tert-butyl-1-p-phenylene-1H-pyrazol-5-yl)) Ureido)naphthalen-1-yloxy)indolyl)pyridin-3-yl)-2-decyloxyacetamide; N-(4-((4-(3-(3-) -butyl-1-p-phenylene-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-3-yl)-2-(2-oxime Oxyethoxy)acetamide; N-(4-(2-(4-(3-(3-tri-butyl-1-p-phenyl)-lH-η-biazole-5-yl) Ureido)naphthalen-1-yloxy)ethyl)pyridin-2-yl)-2-decyloxyacetamide; N-(4-(2-(4-(3-(3-) Third-butyl-1-p-tolyl-1Η-η-biazole-5-yl)ureido)naphthalen-1-yloxy)ethyl)°pyridin-2-yl)-2-(2 - methoxy ethoxy) acetamidine; 4-(2-(4-(3-(3-tert-butyl-1-p- phenyl)-1H-pyrazol-5-yl)urea Base) lan-1-yloxy)ethyl)-1-mercapto-3-(0-bito-2-yl) gland, 4-(2-(4-(3-(3-third-butyl) 1-yl-p-nonylphenyl-1Η-°bazin-5-yl)ureido)naphthalen-1-yloxy)ethyl)-3-(acridin-2-yl)urea; N-( 4-(2-(4-(3-(3-Third-D) 1-p - phenylene -1Η- ° than Yue-5-yl) ureido) naphthalene-1-yl) ethyl). Bispin-3-yl)-2-(2-decyloxyethoxy) acetamidine; N_(4-((4-(3-(3-)-di-butyl- 1 -p- phenylene) A group of -1H-0 is 0-(a)glycosyl)naphthalen-1-yloxy)indolyl)pyrimidin-2-yl)-2-oxoethoxyacetamide; N-(l-(2) -(4-(3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-1Η- Imidazolyl-4-yl)-2-decyloxyacetamide; N-(4-((4-(3-(3-tert-butyl-l-butyl-p-phenyl)-l-pyrazole- 5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(indolyl)acetamide; N-(4-((4-(3) -(3-Terti-butyl-1-p-indolephenyl-1H-.Bizozol-5-yl)ureido)heptan-1-yloxy)indolyl)° than bit-2-yl) -2-Bisylamine, 201130813 N-(4-((4-(3-(3-T-butyl-1-p-tolyl-1H-pyrazole-5-yl)))) Naphthalen-1-yloxy)methyl)acridin-2-yl)-2-methyl-2-(methylamino)propanamine; (S)-N-(4-((4-(3) -(3-Terti-butyl-p-tolyl-1Η-indoleazole·% base)ureido)naphthalen-1-yloxy)indenyl)pyridine_2-yl)_2-(methylamine Propylamine; (R)-N-(4-((4-(3-(3)-tert-butyl 4_p-tolyl-1H-pyrazole-5)ureido) L-yloxy) methyl) pyridin _2_ yl) morpholine _3_ Yue Amides;

(S) -N-(4-((4-(3-(3-第三-丁基_丨_對-曱苯基_1H -0比〇坐-5_ 基)脲基)萘-1-基氧基）甲基)吡啶基)嗎啉_3_曱醯胺； N-(:-((4-〇(3_第三-丁基_丨·對_甲苯基_1H吡唑_5基)脲基)萘-1-基氧基）甲基)η比啶_2_基)_4_〒基哌畊小曱醯胺； Ν_(4-((4-(3-(3-第三丁基_1_對_曱苯基_1Η_〇比吐_5基）脲基)萘-1-基氧基）曱基)吨咬_2_基)嗎琳冬曱醯胺； Ν_(4-((4-(3-(3-第三-丁基_1_對_曱苯基_1Η_η比唑_5_基)脲基)萘-1-基氧基）甲基)吼咬_2_基)_3_甲氧基丙醯胺； 2-(3-(4-«4-(3-(3-第三-丁基+對_曱苯基_m吼嗤_5基）腺基）m氧基）曱基比咬_2_基)腺基甲氧基乙基）乙酿胺； Ν-(4-((4·(3-(3-第二丁基]_對_曱苯基-出-❸坐各基)脲基)萘小基氧基）曱基)n比咬_2_基)_4仁曱胺基)丁醯胺； Ν-(4-((4-(3·(3-第二丁基小對_甲苯基_1Η·π比嗤_5_基)脲基)萘-1-基氧基）曱基)吼咬_2_基)_3_(甲續醯基)丙酿胺； Ν-(4:((4-(3-(3-第三-丁基曱笨基_m_n比唾基)服基)萘小基氧基）甲基比咬_2_基)·3·(甲續隨奸>側氧咪唑啶-1-曱醯胺； ^-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基）°比啶-2-基)-2-(曱亞磺醯基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-lH-n比唑-5-基)脲基）萘-1-基氧基）甲基)D比啶-2-基)-2-(2-甲氧基乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基)脲基）萘-1-基氧基）曱基）°比啶-2-基)-2-(2-(2-曱氧基乙氧基) 乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-»比唑-5-基）脲基）蔡-1-基氧基）甲基)π比β定-2-基)-2-(2-嗎琳基乙硫基）乙醯胺； N-(4-((4_(3-(3-第三-丁基-1-對-曱苯基_1Η-°比唑-5-基)脲基）萘-1-基氧基）曱基)°比啶-2-基)-2-(2-嗎啉基乙磺醯基）乙醯胺； 2-(雙(2-曱氧基乙基）胺基)-N-(4-((4-(3-(3-第三-丁基-1 -對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基）曱基)。比啶-2-基）乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η 比唑-5-基）脲基)萘-1-基氧基）乙基)°比啶-3-基)-2-甲氧基乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-ΙΗ-η 比唑-5-基）脈基）奈_1_基）乙氧基)π比°定-2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基)奈_1_基氧基）乙基)°比°定_2-基)-2-曱氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基)秦_1_基氧基)-2-曱基 42 201130813 丙基)0比°定-2-基)-2-曱氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基）奈基氧基）丙基)ntba定-2-基)-2-甲氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-。比唑-5-基）腺基）秦-1_基氧基）丙-2-基)。比咬-2-基)-2 -曱氧基乙酿胺； N-(4-(l-(4-(3-(3-第三-丁基-1-對-甲苯基-1-吡唑-5-基)脲基）奈-1-基氧基)-2-曱基丙-2-基）°比°定-2-基)-2-曱氣基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-(4-(羥基曱基）苯基匕。全-5-基)腺基）奈-1-基乳基）曱基定-2-基)-2-曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）秦-1-基氧基）π比°定-2-基)-2-(曱續酿基）乙酿胺或其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。在一具體實例中，根據本揭示之化合物為：曱基4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-»比唑-5-基）脈基)奈-1_基氧基）曱基)π比咬-2-基腺， Ν-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑-5-基)脲基）萘-1-基氧基）曱基）°比啶-2-基）四氫-2Η-哌喃-4-曱醯胺； (S)-N-(4-((4-(3-(3-第三-丁基-1 -對-曱苯基-1Η-。比唑-5- 基）腺基）奈-1-基乳基）曱基）°比咬-2-基）-2-曱氧基丙酿胺； (r)_N-(4-((4-(3-(3-第三-丁基-1 -對-曱苯基-1H-°比唑-5- 基）腺基）奈-1-基氧i基）曱基）°比a定-2-基)-2-曱氧基丙酿 43 201130813 胺； N-(4-((4-(3-(3-第三-丁基-1-對·甲苯基-1Η-η比唑-5-基）脲基)萘-1-基氧基）曱基)。比啶-2-基)-2-(曱磺醯基）乙醯胺 N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-«比唑-5-基）脲基）蔡-1-基氧基）甲基)°比°定-2-基)-2-經基乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基）吼啶-2-基)-2-曱基-2-(曱胺基）丙醯胺； (S)-N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基）脈基）奈基氧基）曱基）0比°定_2_基)-2-(曱胺基）丙酿胺； (R) -N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基)脲基)萘-1-基氧基）曱基)°比啶-2-基)嗎啉-3-曱醯胺； (S) -N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基)脲基)萘-1-基氧基）甲基)。比啶-2-基)嗎啉-3-曱醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基）曱基)π比啶-2-基)-4-曱基哌畊-1-曱醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-«比唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-2-基)嗎啉-4-曱醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基)脲基)奈-1-基氧基）曱基)°比咬-2-基)-3 -曱氧基丙酿胺， 2-(3-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基) 脲基）萘-1-基氧基）曱基）°比啶-2-基）脲基)-N-(2-曱氧基乙基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)奈-1-基氧基）曱基)**比。定-2-基)-4·(二曱胺基）丁酿胺， 201130813 N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基)°比啶-2-基)-3-(曱磺醯基）丙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-吼唑-5-基)脲基）奈-1-基乳基）曱基）°比〇定-2-基)-3-(曱石黃酿基)-2-側氧咪唑啶-1-曱醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）曱基)°比。定-2-基)-2-(曱硫基）乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）曱基）α比σ定-2-基)-2-(曱亞石黃酿基）乙酿胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基)σ比啶-2-基)-2-嗎啉基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1 -基氧基）曱基）π比咬-2-基）-2-(0比洛〇定-1 -基）乙酸胺； Ν-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑-5-基)脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(4-曱基哌啡-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-。比唑-5-基)脲基）奈-1-基氧基）曱基）°比唆-2-基）-2-(4-(2-曱氧基乙基) 哌畊-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-。比唑-5-基)脲基）奈-1-基氧基）曱基)°比β定-2-基)-2-(2-曱乳基乙胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基乳基）曱基)ΰ比咬-2-基)-2-(二曱胺基）乙酿胺， 45 201130813 ιΝ_(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(曱胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基）°比啶-2-基）-2-((4-甲氧基苯曱基)（曱基)胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(2-曱氧基乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基)。比啶-2-基)-2-(2-(2-曱氧基乙氧基) 乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）蔡-1-基氧基）曱基)β比变-2-基)-2-(2-嗎嚇·基乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-ΙΗ-η比唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(2-嗎啉基乙磺醯基）乙醯胺； 2-(雙(2-甲氧基乙基）胺基)-N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-"比唑-5-基）脲基）萘-1-基氧基）曱基）。比啶 -2-基）乙醯胺； 1-(4-((3-曱基脲基吼啶-4-基）曱氧基）萘-1-基)-3-(3-第三 -丁基-1-對-曱苯基-1H-吡唑-5-基)脲； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基）甲基)°比啶-3-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基)脲基)萘-1-基氧基）曱基)°比啶-3-基)-2-(2-曱氧基乙氧基）乙 46 201130813 醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱笨基-1Η-η 比唑-5-基）腺基）奈-1-基乳基）乙基）°比咬-2-基)-2-甲氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）腺基）奈-1_基氧基）乙基)πΛσ定-2-基)-2-(2-曱氧基乙氧基）乙醯胺； 4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）乙基)-1-甲基-3-(atbn定-2-基)腺， 4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基）脲基）秦-1-基氧基）乙基)-3-(atbn定-2-基)腺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基）脈基）奈-1-基氧基）乙基）。比咬-3-基)-2-甲氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-» 比唑-5-基）腺基）奈基氧基）乙基）。比°定-3-基)-2-(2-曱氧基乙氧基) 乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基）蔡-1_基）乙乳基)π比σ定-2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1H_ 吡唑-5-基）腺基）奈-1-基氧基）乙基）°比咬-2-基)-2-甲氧基乙隨胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-α 比唑-5-基) 腺基）奈_1_基氧基)_2_甲基丙基)°比咬-2-基)-2-曱氧基乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基) 脈基)奈_1_基乳基）丙基)π比咬-2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基) 腺基)奈_1_基氧基）丙-2-基)ntba_^-2-基)-2 -曱氧基乙酿胺， 47 201130813 N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1-°比唑-5-基)脲基）萘-1-基氧基)-2-曱基丙-2-基）°比啶-2-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-(4-(羥基曱基）苯基）-1Η-。比 π坐-5-基)脈基)蔡-1-基氧基）曱基)°比咬-2-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-ΙΗ-η比唑-5-基)脲基)萘-1-基氧基）曱基)嘧啶-2-基)-2-曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基)°比啶-2-基)-2-(曱磺醯基）乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基）脲基）蔡-1-基氧基)°比°定-2-基)-2-曱氧基乙酿胺， N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基）脲基)蔡-1-基氧基)°比°定-2-基)-2-(2-曱氧基乙氧基）乙酿胺， N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-°比唑_5_基）脲基）萘-1-基氧基)°比啶-2-基）四氫-2H-哌喃-4-甲醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1Η-»比唑-5-基）脲基）萘-1-基氧基)°比啶-2-基)-2-(曱硫基）乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-«比唑-5-基）脲基)秦-1-基氧基)°比。定-2-基)-3-曱乳基丙酿胺， N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）秦-1-基氧基)°比°定-2-基)-2-經基乙酿胺， N-(4-(4-(3-(3-異丙基-1-對-曱苯基-1H-。比唑-5-基）脲基) 秦-1-基氧基基)-2-曱氧基乙酿胺， N-(4-(4-(3-(3-乙基-1-對-曱苯基-ΙΗ-η比唑-5-基）脲基）萘 -1-基氧基)°比啶-2-基)-2-曱氧基乙醯胺； 48 201130813 N-(4-(4-(3-(3-(l-經基-2-曱基丙-2-基)-1-對-甲苯基_ih_ 吼唑-5-基）脲基）萘-1-基氧基）吼啶-2-基)-2-甲氧基乙醯胺； ]^-(4-(4-(3-(3-第三-丁基-1-(2,3,5,6-四氛-4-(三氣甲基）苯基)-1Η_β比哇-5-基)腺基）萘-1-基氧基）吼σ定_2_基)_2_曱氧基乙醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-。比唾-5-基）脲基)萘-1-基氧基)π比咬-2·基)-2-嗎琳基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-Π比哇-5-基)脲基)萘-1-基氧基)0比〇定-2-基)-(二曱胺基）乙酿胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-。比。坐-5-基）脲基)萘-1-基氧基)π比咬-2-基)-2-(2-曱氧基乙胺基）乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-»比唾-5-基）腺基)萘-1-基氧基)°比咬-2-基)-2-脈基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1·對-曱苯基-iH-n比β坐_5_基）脲基）萘-1-基氧基)D比咬-2-基)-2-(2-曱氧基乙酿胺基）乙醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-曱苯基比嗤_5_基）脈基）4-1-基氧基）°比°定-2-基胺基）-2-側氧乙基）四氫 -2H-哌喃-4-甲醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-甲苯基比η坐-5-基）脲基）萘-1-基氧基）σ比咬-2-基胺基)-2-側氧乙基）異於驗醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1HH5-基）脲基）萘-1-基氧基）吼°定-2·基)-2-(2-(曱續醯基）乙醯胺基）乙酿胺； 49 201130813 N-(2-(4-(4-(3-(3-第三-丁基-1-對-甲本基-1Η-η 比唾_5•基) 脲基）萘-1-基氧基)吡啶-2_基胺基)-2-側氧乙基)_3_嗎琳基丙醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-甲苯基比(1坐_5-基) 脲基）萘-1-基氧基定-2-基胺基)-2_側氧乙基）嗎琳曱醯胺； Ν-(2-(4-(4-(3-(3-第三丁基對-甲苯基吡唑_5基) 脲基）萘-1-基氧基）吼啶-2-基胺基)-2-側氧乙基)_2,6_二氟-3-(2-(2-甲氧基乙氧基）乙氧基）苯甲醯胺； Ν-(4-(4·(3-(3-第三-丁基對-曱苯基基）脲基）笨氧基)0比咬-2-基)-2-曱氧基乙醯胺； Ν-(4-(4·(3-(3-第三-丁基·丨-對—甲苯基·m_吡唑_5基）脲基)_2_甲基苯氧基;)吼咬_2_基)士甲氧基乙醯胺； N_(4_(4-(3-(3-第三-丁基]_對_甲苯基•。比嗤j基德基)_3-甲基苯氧基)η比咬_2-基)_2_甲氧基乙酿胺； Ν-(4-(4-(3-(3-第三-丁基+對_甲苯基_1Η吼哇_5_基）腺基)-2-甲氧基苯氧基)β比咬·2_基)_2_曱氧基乙酿胺； Ν-(4-(4-(Η3_第三-丁基]务甲苯基·m_吼嗤·5_絲基>2,3_二甲基苯氧基)°比咬-2-基)_2·甲氧基乙醯胺； Ν (4 (4-(3·(3-第丁基].對_甲苯基·1Hm5·基)月基)_3_甲氧基苯氧基)対_2•基)2_甲氧基乙酿胺；基机4-(4-(3-(3 -第三-丁基-1 -對-甲苯基-m·^ -5-基)脲基)萘+基氧基)如定·2基脈； =(3-第三·丁基」♦甲苯基孤…基)縣奈基氧基)°比咬-2-基脲； Ν丙2基''Ν_4_(4·(3_(3·第三-Τ基_1·對·甲苯基·1Η4 50 201130813 〇坐-5-基)脈基)秦-1-基氧基)π比咬-2-基腺， 1-(3-(第三-丁基）-1-(對-曱苯基）-1Η-吼唑-5-基)-3-(4-((2-(3-苯基脈基)ntb^-4-基）氧基）奈-1-基)腺； 1-(4-((2-(3-苯曱基腺基）π比σ定-4-基）氧基）秦-1_ 基)-3-(3-(第三丁基)-1-(對·甲苯基)-1Η-吼唑-5-基)脲； 1-(4-((2-(3-壞丙基腺基）°比°定-4-基）氧基）奈-1_ 基)-3-(3-(第三-丁基)-1-(對-曱苯基)-1Η-°比唑-5-基)脲； 1-(3-(第三-丁基）-1-(對-曱苯基）-1Η-。比唑-5-基)-3-(4-((2-(3-(2-曱乳基乙基)腺基)°比咬-4-基）氧基)奈_1_基)腺， 1-(3-(第三-丁基）-1-(對-曱苯基）-1Η-吡唑-5-基)-3-(4-((2-(3 -壤戍基)腺基)π比咬-4-基）氧基）奈-1-基)腺， 1- (3-(第三-丁基）-1-(對-曱苯基）-1Η- «比唑-5-基)-3-(4-((2-(3-曱基)脲基)吼啶-4-基)氧基）萘-1-基)脲； 2- (3-(4-((4-(3-(3-(第三-丁基)-1-(對-曱苯基)-1Η-«比唑-5-基)脲基）萘-1-基）氧基)°比啶-2-基)脲基）乙酸乙酯； 4-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基) 脈基）奈_1_基氧基)D比σ定-2-基)腺基)娘σ定， Ν-乙醯基4-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-〇比0坐-5-基)脈基）奈-1 -基乳基)ntb σ定-2-基)腺基)旅0定， 2-(2-曱乳基乙氧基)-1-(4-(3-(4-(4-(3-(3-苐二-丁基-1-對_ 曱苯基-1H-吼唑-5-基）脲基）萘-1-基氧基）吼啶-2-基）脲基)哌啶-1-基）乙酮； N-曱磺醯基-4-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基 -1H-吼唑-5-基）脲基）萘-1-基氧基）吼啶-2-基）脲基）哌 51 201130813 哫； N-(4-(4-(3-(3-第三-丁基小對·甲苯基_1Η_η比嗤·5基）脲基)奈-1-基氧基)《比咬_2·基)嗎琳_4_曱醯胺； Ν-(4-((4-(3-(3-(第三-丁基)小(對_曱苯基)1Η_Π比唑_5_基）脲基)奈-1-基）氧基)吡啶_2_基)-4_曱基哌畊曱醯胺； 3-(4-((4-(3-(3-(第三-丁基)小(對_曱苯基)_1Η_β比唑_5_基）脲基)萘-1-基)氧基)吼咬士基)'“二曱基脲； Ν-(4-((4-(3-(3-(第三-丁基)小(對_曱苯基)_1Η_0比唑_5_基) 脲基)萘-1-基)氧基)吡啶-2-基)哌啶_丨_曱醯胺； Ν-曱基-Ν-(2-(嗎啉-4-基）乙基)-Ν，_4_(4_(3·(3_第三_丁基 -1-對-甲苯基-1Η-吡唑-5-基)脲基）萘_丨_基氧基）吡啶-2-基脈； N-(4-(嗎淋-4-基）丁基)_n'-4-(4-(3_(3-第三-丁基-1-對-曱苯基-lH-η比唾-5-基)脲基）萘_丨_基氧基y比啶_2_基脲； N-(2_(嗎琳_4_基）乙基)_ν'·4_(4·(3_(3·第三-丁基-1-對-甲苯基-1Η-吼唑_5_基)脲基)萘+基氧基)吼啶_2-基脲； Ν-(3-甲基異呤唑-5-基）曱基_ν，-4-(4-(3-(3-第三-丁基-1-對-曱笨基·1Η，η坐_5-基)脲基）萘小基氧基）吼啶_2_基腺； N-(l-曱基）哌啶-4-基-Ν，-4-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基)脲基)萘_丨_基氧基户比啶_2_基脲； N-(4_(4-(3_(3-第三·丁基小對·曱苯基-1H_吡唑_5-基）脲基)萘-1-基氧基)°比啶-2-基)-4-羥基哌啶-1-甲醯胺； N-(3-(咪唑-1-基）丙基)_N，_4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基)脲基)萘小基氧基)吼啶_2_基脲； N-(2-(3-(4_(4-(3-(3-第三-丁基小對-曱苯基-lH-n比唑-5- 52 201130813 基)腺基）奈-1_基氧基)β比σ定-2-基)腺基）乙酿基)Dtb洛σ定； (r)_N_(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吼唑 _5_基) 腺基）奈-1-基氧基)0比σ定-2-基)-3-(二曱胺基)π比p各α定-1-曱醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑-5-基）脲基）奈-1 -基氧基)°比σ定-2-基）0比σ各0定-1 -曱酿胺， 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-°比唑-5-基）脈基）奈_1_基氧基)°比咬-2-基)腺基)-Ν-曱基乙酿胺， 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η 比唑-5-基）腺基）备_ 1_基氧基）。比°定-2-基）腺基)-N-(2-嗎°林基乙基）乙醯胺； 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基）腺基)奈_ 1_基氧基)β比咬-2-基)脈基）乙酿基嗎嚇， 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η 比唑-5-基）腺基）奈_1_基氧基）°比咬-2-基）腺基）-N-(2-(Dtbπ定-4-基）乙基）乙醯胺； Ν-(3-(1Η-味唑-1-基）丙基）-2-(3-(4-(4-(3-(3-第三-丁基 -1-對-曱苯基-1Η-°比唑-5-基）脲基）萘-1-基氧基）吼啶-2-基)脲基）乙醯胺； 1-(2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5- 基)腺基）奈_1_基氧基)ntbσ·^-2-基)腺基）乙酿基)-4-曱基0底畊； Ν-(3-(1Η-咪唑-1-基）丙基）-2-(3-(4-(4-(3-(3-第三-丁基 -1-對-曱苯基-1H-°比0圭-5-基）腺基）奈-1 -基氧基）°比咬-2_ 基)脲基）乙醯胺； N-(6-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲 53 201130813 暴）蔡-1-基氧基)痛。定-4-基)-2-曱氧基乙酿胺， N-(6-(4-(3-(3-第三-丁基-1-對·曱苯基-1H-吡唑-5-基）脲基）苯氧基)嘧啶-4-基)-2-曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基)嘧啶-2-基)-2-曱氧基乙醯胺； 3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基）脲基)萘-1-基氧基)嘧啶-2-基)脲； 1-曱基-3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑 -5-基)脈基)秦-1-基氧基)11密咬-2-基)腺， 1，1-二曱基-3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基)嘧啶-2-基)脲； 1-環丙基-3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑 -5-基)腺基)秦-1-基氧基基)腺， (4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基)脲基) 萘-1-基氧基)嘧啶-2-基)嗎啉-4-曱醯胺； 3-(6-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基）脲基）萘-1-基氧基)嘧啶-4-基)脲；2-(3-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-。比唑-5-基）脲基）萘-1-基氧基）°比啶 -2-基)脲基）乙酸，或其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。化合物(I)之鹽類的例子包括所有醫藥上可接受的鹽，諸如（沒有限制）礦酸類之酸加成鹽類，諸如HC1及 HBr鹽類及有機酸的加成鹽類，諸如曱磺酸鹽。此處之揭示延伸至式(I)化合物之溶劑合物。溶劑合物的例子包括水合物。 54 201130813 本揭示的化合物包括該等其中一或多個所界定之原子為天然或非天然同位素。在一具體實例中，該同位素為穩定同位素。因此本揭示的化合物包括（例如）包含氘之化合物等等。本文中所述之化合物可包括一或多個掌性中心，且揭示延伸至包括從其產生之消旋物，二鏡像異構(例如每個實質上無其他鏡像異構)及所有立體異構物。在一具體實例中一個鏡像異構形式以實質上純的形式存在，其實質上沒有對應的鏡像異構形式。揭示也延伸至本文中所定義之化合物的所有多晶型。揭示也延伸至本文中所定義之化合物的所有多晶型。式(I)之化合物可藉由一種方法製備，該方法包含使式(II)之化合物：(S)-N-(4-((4-(3-(3-Terve-butyl-丨-p-p-phenyl-1H-0 is more than -5--5-yl)))))氧基oxy)methyl)pyridyl)morpholine_3_decylamine; N-(:-((4-〇(3_T-butyl-丨·p-tolyl-1H pyrazole_5) Ureyl)naphthalen-1-yloxy)methyl)nylpyridinyl-2-yl)-4-indolylpiperamide; Ν_(4-((4-(3-(3-) Butyl _1_p-曱 Η Η Η 〇〇〇〇 _ 5 5 5 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 4-((4-(3-(3-Terve-butyl_1_p-ylphenyl)-pyridyl]-5-yl)-ureido)-naphthalen-1-yloxy)methyl) _2_yl)_3_methoxypropionamide; 2-(3-(4-«4-(3-(3-t-butyl)-p-phenylene_m吼嗤_5) Glycosyl)moxy)indolyl nitrate-2-yl)glycosylmethoxyethyl)ethinamide; Ν-(4-((4·(3-(3-butyl))-pair)曱曱 - 出出 ) ) ) ) ) ) ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -(3·(3-t-butyl-p-p-tolyl-1Η·π-嗤_5_yl)ureido)naphthalen-1-yloxy)indenyl)dentate_2_yl)_3_( A 丙 ) ) 丙 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Base _m_n than sialyl) keto) naphthalenyloxy) methyl group bite _2 _ _) · 3 · (a continued with traits > side oxyimidazolidin-1-amine; ^- (4 -((4-(3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indenyl)° ratio Pyridin-2-yl)-2-(indenylsulfonyl)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-lH -n-biazole-5-yl)ureido)naphthalen-1-yloxy)methyl)D-pyridin-2-yl)-2-(2-methoxyethylthio)acetamide; N- (4-((4-(3-(3-tert-butyl-1-p-indolephenyl-1Η-η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)fluorenyl ° 啶啶-2-yl)-2-(2-(2-decyloxyethoxy)ethylthio)acetamide; N-(4-((4-(3-(3-) -butyl-1-p-oxime-phenyl-1Η-»bazin-5-yl)ureido)cain-1-yloxy)methyl)π ratio β-but-2-yl)-2-(2 -Merminylethylthio)acetamide; N-(4-((4_(3-(3-Terti-butyl-1-p-phenyl)-pyridyl-pyridyl-5-yl) Ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(2-morpholinylethanesulfonyl) acetamidine; 2-(bis(2-decyloxy) Ethyl)amino)-N-(4-((4-(3-(3-)-tert-butyl-1-p-indolephenyl-1H-pyrazole-5-) Urinyl) Naphthalen-1-yloxy)indenyl). Bis-2-yl)acetamidamine; N-(4-(2-(4-(3-(3-tert-butyl-1-p-phenyl)-lH-η-biazole-5- Ureyl)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-methoxyacetamide; N-(4-(2-(4-(3-(3) -T-butyl-1-p-phenylene-p-phenyl-p-n-b-azol-5-yl) fluorenyl)N-l-yl)ethoxy)π-pyrene-2-yl)-2-曱oxyethylamine, N-(4-(l-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl) gland) Nai-1_yloxy)ethyl)°°°_2-yl)-2-decyloxyethylamine, N-(4-(2-(4-(3-(3-)- Butyl-1-p-phenylene-1H-pyrazol-5-yl) glandyl)-methyl-1-yloxy)-2-indenyl 42 201130813 propyl)0 °°-2-yl) -2-decyloxyacetamide, N-(4-(2-(4-(3-(3-tert-butyl-1-p-p-phenyl)-1H-pyrazol-5-yl) Glycosyl)naphthyloxy)propyl)ntba-but-2-yl)-2-methoxyethenylamine, N-(4-(l-(4-(3-(3-tri-butyl) -1-p-tolyl-1H-.biazole-5-yl) glandyl)-l-yloxy)propan-2-yl). butyl-2-yl)-2-methoxyl Stearic amine; N-(4-(l-(4-(3-(3-tert-butyl-1-p-tolyl-1-pyrazol-5-yl))))) Oxy)-2-mercaptopropan-2- )) °-2-yl)-2-hydrazinylacetamide; N-(4-((4-(3-(3-)-tert-butyl-1-(4-(hydroxy) Phenyl hydrazide. all-5-yl) glycosyl)-n-l-propyl) decyl-denyl-2-yl)-2-decyloxyacetamide; N-(4-(4-( 3-(3-Terti-butyl-1-p-phenylene-1H-pyrazol-5-yl)ureido)heptyl-1-yloxy)π ratio °-2-yl)-2 - (continuously brewed) an enamine or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof. In one embodiment, the compounds according to the present disclosure are: Mercapto 4-((4-(3-(3-Terti-butyl-1-p-phenyl)-1Η-»bazol-5-yl))-yl-1-yloxy)indole )) π-bit-2-ylenosine, Ν-(4-((4-(3-(3-tert-butyl-1-p-phenyl)-pyridin-5-yl)) (na)-naphthalen-1-yloxy)indenyl)-pyridin-2-yl)tetrahydro-2-indole-pyran-4-anthracene; (S)-N-(4-((4-(3) -(3-Terti-butyl-1-p-p-phenyl-1Η-.bazol-5-yl)glycosyl)naphthalenyl)indolyl)° than bit-2-yl) -2-decyloxypropanol; (r)_N-(4-((4-(3-(3-)-tert-butyl-l-p-phenyl)-1H-°bazole-5- Gland) -1-yloxyi-yl)indolyl)°-but-2-yl)-2-decyloxypropene 43 201130813 Amine; N-(4-((4-(3-(3-)- Butyl-1-p-tolyl-1Η-η-biazole-5-yl)ureido)naphthalen-1-yloxy)indenyl). Bis-2-yl)-2-(indolyl)acetamide N-(4-((4-(3-(3-tert-butyl-butyl-p-phenyl)-1H-) «Bizozol-5-yl)ureido)cain-1-yloxy)methyl)°°-but-2-yl)-2-ylaminoamine, N-(4-((4-) 3-(3-Terti-butyl-1-p-phenylphenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)- 2-mercapto-2-(nonylamino)propanamide; (S)-N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H -.Bistazol-5-yl) fluorenyl)Nylideyloxy) fluorenyl) 0 to ° _2 yl)-2-(decylamino) propylamine; (R) -N-(4- ((4-(3-(3-Terti-butyl-1-p-indolephenyl-1H-.biazole-5-yl)ureido))naphthalen-1-yloxy)indenyl)° ratio (2-)-N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-p-yl- ηBizozol-5-yl)ureido)naphthalen-1-yloxy)methyl).pyridin-2-yl)morpholine-3-indolylamine; N-(4-((4-(3) -(3-Terti-butyl-1-p-phenylphenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)πpyridin-2-yl)- 4-mercaptopiperidine-1-amine; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-«bazole-5- Urinyl)naphthalen-1-yloxy)indolyl) Bis-2-yl)morpholine-4-decylamine; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-. 5-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-(4-) 3-(3-Terti-butyl-1-p-phenylene-1H-indazol-5-yl) ureido)naphthalen-1-yloxy)indolyl) °pyridin-2-yl) Ureido)-N-(2-decyloxyethyl)acetamidine; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H- Pyrazol-5-yl)ureido)-n-yloxy)indolyl)** ratio. Benz-2-yl)-4·(diamidoamine) butylamine, 201130813 N-(4- ((4-(3-(3-Terve-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)]naphthalen-1-yloxy)indolyl) °-pyridyl- 2-yl)-3-(indolyl)propanamine; N-(4-((4-(3-(3-tert-butyl-1-buty-tolyl-1H-carbazole)- 5-yl)ureido)naphthalenyl)indolyl)-pyridin-2-yl)-3-(indigo yellow)-2-oxoimidazolidine-1-decylamine N-(4-((4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)-n-yloxy)曱 base) ° ratio. Ding-2-yl)-2-(indolyl)ethinylamine, N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-pyridyl Azul-5-yl)ureido)n-yloxy)indolyl)α ratio sigma-2-yl)-2-(indenyl sulphate) ethylamine; N-(4-( (4-(3-(3-Terve-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl) σ-pyridine- 2-yl)-2-morpholinylacetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-pyrazole-5- )-(4-((4-)-) (3-(3-Terti-butyl-1-p-indolephenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl -2-(4-mercaptopiperidin-1-yl)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-tolyl-1H-) .Bistazol-5-yl)ureido)na-1-yloxy)indolyl) ° 唆-2-yl)-2-(4-(2-decyloxyethyl) piperene-1- Ethylamine; N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-.biazole-5-yl)))) -yloxy)indolyl)[rho]but-2-yl)-2-(2-indolylethylamino)acetamide; N-(4-((4-(3-(3-) Tri-butyl- 1-p-p-phenyl-1H-pyrazol-5-yl)ureido)naphthalenyl)indolyl)pyrene-2-yl)-2-(diguanylamino) Amine, 45 201130813 ιΝ_(4-((4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl))))曱) 曱)) 比 pyridine-2-yl)-2-(nonylamino)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-pair- Phenylphenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-((4-methoxyphenylhydrazino) ( Indenyl)amino)acetamide; N-(4-((4-(3-(3-tert-butyl-1-p-phenyl)-1H-.pyrazole-5-yl)urea) Naphthyl-1-yloxy)indolyl)pyridin-2-yl)-2-(2-decyloxyethylthio)acetamide; N-(4-((4-(3-) (3-tert-Butyl-1-p-p-phenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl).pyridin-2-yl)-2 -(2-(2-decyloxyethoxy)ethylthio)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenylene) -1H-pyrazol-5-yl)ureido)t-l-yloxy)indolyl)β-substituted-2-yl)-2-(2-infrared ethylthio)acetamide; N-(4-((4-(3-(3-Terti-butyl-1-p-indole-phenyl)-pyridyl-5-yl))) Naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(2-morpholinylethanesulfonyl)acetamide; 2-(bis(2-methoxyethyl) Amino)-N-(4-((4-(3-(3-tert-butyl)-1-p-phenyl)-1H-"bazin-5-yl)ureido)naphthalene-1 -yloxy)indenyl). Bis-2-yl)acetamide; 1-(4-((3-mercaptoureido)-4-yl) decyloxy)naphthalen-1-yl)-3-(3-third- Butyl-1-p-phenylene-1H-pyrazol-5-yl)urea; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenylene) -1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)-pyridin-3-yl)-2-decyloxyacetamide; N-(4-((4) -(3-(3-Terti-butyl-1-p-indolephenyl-1H-.bazol-5-yl)ureido)naphthalen-1-yloxy)indolyl) ° pyridine-3 -yl)-2-(2-decyloxyethoxy)ethyl 46 201130813 decylamine; N-(4-(2-(4-(3-(3-)-tert-butyl-1-p-oxime) Stupid-1Η-ηBizozol-5-yl) glandyl)N--1-yllacyl)ethyl)°Bite-2-yl)-2-methoxyethylamine, N-(4- (2-(4-(3-(3-Terve-butyl-1-p-tolyl-1H-pyrazol-5-yl) glycosyl)-n-yloxy)ethyl)πΛσ 2-yl)-2-(2-decyloxyethoxy)acetamide; 4-(2-(4-(3-(3-tri-butyl-1-p-phenyl)- 1H-pyrazol-5-yl)ureido)na-1-yloxy)ethyl)-1-methyl-3-(atbn-but-2-yl) gland, 4-(2-(4-( 3-(3-Terti-butyl-1-p-indolephenyl-1H-.Bistazol-5-yl)ureido)-hhenyl-1-yloxy)ethyl)-3-(atbn- 2-base ) gland, N-(4-(2-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-indazol-5-yl))) Benzyl)ethyl).Bis-3-yl)-2-methoxyethenylamine, N-(4-(2-(4-(3-(3-)-tert-butyl-1-) p-Phenylphenyl-1Η-»Bizozol-5-yl) glandyl)nyloxy)ethyl). °-3-yl)-2-(2-decyloxyethoxy) Indoleamine; N-(4-(2-(4-(3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl) gland)-1_ Ethyl) π-butyryl-2-yl)-2-decyloxyethylamine, N-(4-(l-(4-(3-(3-)-tert-butyl-1-) p-N-Phenyl-1H_pyrazol-5-yl) glycosyl)-n-yloxy)ethyl)°-Bis-2-yl)-2-methoxyethyl with amine, N-(4 -(2-(4-(3-(3-Terti-butyl-1-p-phenyl)-lH-α-biazole-5-yl) glandyl)N-l-yloxy)_2_ Methyl propyl) ° bite-2-yl)-2-decyloxyacetamide; N-(4-(2-(4-(3-(3-T-butyl-1-yl-)-曱Phenyl-lH-η-Bistazol-5-yl) fluorenyl)N-l-yl-based propyl)propyl)pyrylene-2-yl)-2-methoxy ethoxylated amine, N-(4 -(l-(4-(3-(3-Terve-butyl-1-p-phenyl)-1H-indazol-5-yl) glycosyl)-l-yloxy)propane-2 -base)ntba_^-2-yl)-2 -曱Ethylamine, 47 201130813 N-(4-(l-(4-(3-(3-T-butyl-1-p-phenyl)-1-pyrazole-5-yl))) Naphthyl-1-yloxy)-2-mercaptopropan-2-yl)-pyridin-2-yl)-2-decyloxyacetamide; N-(4-((4-(3-) (3-Terti-butyl-1-(4-(hydroxyindenyl)phenyl)-1Η-.比 -5 - -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 -1- -1- -1- -1- -1- N N N N N N N N N N N N 3-(3-Terve-butyl-1-p-indolephenyl-indole-n-biazole-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyrimidin-2-yl)- 2-methoxyacetamide; N-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido) naphthalene -1-yloxy)°pyridin-2-yl)-2-(indolyl)acetamide; N-(4-(4-(3-(3-T-butyl)-1-) p-N-Phenyl-1H-indazol-5-yl)ureido)Chan-1-yloxy) ° 定-2-yl)-2-methoxy ethoxylated amine, N-(4- (4-(3-(3-Terti-butyl-1-p-indolephenyl-lH-η-biazole-5-yl)ureido)Cate-1-yloxy)°°°-2 -yl)-2-(2-decyloxyethoxy)ethinamine, N-(4-(4-(3-(3-tri-butyl-butyl-p-phenyl)-phenyl)- °比β_5_yl)ureido)naphthalen-1-yloxy)°pyridin-2-yl)tetrahydro-2H-pyran-4-carbamide; N-(4-(4-( 3-(3-Terve-butyl-1-p-tolyl-1Η-»bisazol-5-yl)ureido)naphthalen-1-yloxy)°pyridin-2-yl)-2- (曱thio)acetamide; N-(4-(4-(3-(3-tert-butyl-1-p-indolephenyl-1H-«bazin-5-yl)ureido) Qin-1-yloxy)° Benzene-2-yl)-3-indene-based propylamine, N-(4-(4-(3-(3-tert-butyl-butyl-1-p-phenyl)-1H-pyrazole 5-(4-(4-(3-(3-(3-isopropyl)) N-(4-(4-pyrimidinyl-1H-.bazin-5-yl)ureido)-hhenyl-1-yloxy)-2-methoxy ethoxylated amine, N-(4-(4- (3-(3-ethyl-1-p-indolephenyl-indole-n-biazole-5-yl)ureido)naphthalen-1-yloxy)°pyridin-2-yl)-2-indole Oxyacetamide; 48 201130813 N-(4-(4-(3-(3-(l-)-yl-2-indolyl-2-yl)-1-p-tolyl_ih_carbazole- 5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)-2-methoxyacetamide; ]^-(4-(4-(3-(3-third-) Butyl-1-(2,3,5,6-tetrafluoro-4-(trimethylmethyl)phenyl)-1Η_βbiw-5-yl)glycosyl)naphthalen-1-yloxy)吼σ _2 _ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -yl)ureido)naphthalen-1-yloxy)π ratio bit-2-yl)-2-morphinylacetamide; N-(4-(4-(3-(3-third-butyl) Benz-1-y-p-phenyl-1Η-indole wow-5-yl)ureido)naphthalen-1-yloxy)0-pyridin-2-yl)-(diguanylamino)ethin ; Ν-(4-(4-( 3-(3-Terti-butyl-1-p-phenylene-1Η-. ratio. Sodium-5-yl)ureido)naphthalen-1-yloxy)π-biti-2-yl)-2-(2-decyloxyethylamino)acetamide; N-(4-(4- (3-(3-Terti-butyl-1-p-phenylphenyl-1Η-» than sal-5-yl) glycosyl)naphthalen-1-yloxy) ° bite-2-yl)- 2-cyanoacetamide; N-(4-(4-(3-(3-tri-butyl-l-p-phenyl)-iH-n ratio β-sodium)-ureido) Naphthalen-1-yloxy)D is more than 2-yl)-2-(2-decyloxyethylamino)acetamide; N-(2-(4-(4-(3-(3) -T-butyl-1-p-p-phenylene 嗤5-yl) fluorenyl) 4-n-oxyl) ° 定-2-ylamino)-2-oxoethyl Tetrahydro-2H-pentan-4-carboxamide; N-(2-(4-(4-(3-(3-tri-butyl-1-p-tolyl)-n--5- Urinyl)naphthalen-1-yloxy)σ 咬-2-ylamino)-2-oxoethyl) is different from decylamine; N-(4-(4-(3-(3) -T-butyl-1-p-phenyl-phenyl-1HH5-yl)ureido-naphthalen-1-yloxy) 吼定 -2 -yl)-2-(2-(曱) Ethylamine) Ethylamine; 49 201130813 N-(2-(4-(4-(3-(3-Terve-butyl-1-p-methyl-l-yl-l-n) than sal. Ureyl)naphthalen-1-yloxy)pyridine-2-ylamino)-2-oxoethyl)_3_morphinylpropionamide; N -(2-(4-(4-(3-(3-)-tert-butyl-1-p-tolyl ratio (1 sit-5-yl) ureido)naphthalen-1-yloxyl-2 -ylamino)-2_sideoxyethyl)morphinamide; Ν-(2-(4-(4-(3-(3-tert-butyl-p-tolylpyrazole-5)) Ureido)naphthalen-1-yloxy)acridin-2-ylamino)-2-oxoethyl)_2,6-difluoro-3-(2-(2-methoxyethoxy) Ethoxy)benzamide; Ν-(4-(4·(3-(3-t-butyl-p-p-phenyl))))) -2-decyloxyacetamide; Ν-(4-(4·(3-(3-Terti-butyl·丨-p-tolyl·m_pyrazole-5))))) Methylphenoxy;) bite _2_yl) methoxy acetamide; N_(4_(4-(3-(3-tri-butyl)-p-tolyl).基-(4-(4-(3-(3-)-butyl+ pair) _tolyl-1-Η吼w_5_yl)glycosyl)-2-methoxyphenoxy)β than bite·2_yl)_2_methoxy ethoxylated amine; Ν-(4-(4- (Η3_Third-butyl]tolyl·m_吼嗤·5_silyl>2,3-dimethylphenoxy)°biti-2-yl)_2·methoxyethyl hydrazine Amine; Ν (4 (4-(3·(3-tert-butyl). p-tolyl·1Hm5 ·Base) kiln)_3_methoxyphenoxy) 対_2•yl)2_methoxyethylamine; base 4-(4-(3-(3-tri-butyl-1) - p-tolyl-m·^ -5-yl)ureido)naphthalene + yloxy) as defined by 2 base veins; = (3-tert-butyl) ♦ tolyl-based base) Oxy)) 咬2-ylurea; Νpropyl 2 '''Ν_4_(4·(3_(3·Third-mercapto-1·p-tolyl·1Η4 50 201130813 〇 -5-5-yl)脉-)-l-yl-yloxy) π than -2- base gland, 1-(3-(tri-butyl)-1-(p-nonylphenyl)-1 Η-carbazole-5- 3-(4-((2-(3-phenyl) ntb^-4-yl)oxy)-n-yl) gland; 1-(4-((2-(3-) Phenylhydrazino) π ratio sigma-4-yl)oxy)methyl-1_yl)-3-(3-(t-butyl)-1-(p-tolyl)-1 Η-carbazole- 5-yl)urea; 1-(4-((2-(3-d-propylpropyl)))-)-4-yl)oxy)na-1_yl)-3-(3-(third -butyl)-1-(p-indolephenyl)-1Η-°bazol-5-yl)urea; 1-(3-(tri-butyl)-1-(p-nonylphenyl)- 1Η-. Bizozol-5-yl)-3-(4-((2-(3-(2-()-)-)-yl) gland) , 1-(3-(Third-butyl)-1-(p-nonylphenyl)-1Η-pyrazol-5-yl)-3-(4-((2-(3-)-) Gland) π than -4-yl)oxy)na-1-yl)gland, 1-(3-(tri-butyl)-1-(p-phenyl)-1Η- «bazole -5-yl)-3-(4-((2-(3-indolyl)ureido)acridin-4-yl)oxy)naphthalen-1-yl)urea; 2- (3-(4- ((4-(3-(3-(Tern-butyl)-1-(p-indolephenyl)-1Η-«bazin-5-yl)ureido)naphthalen-1-yl)oxy) Ethylpyridin-2-yl)ureido)ethyl acetate; 4-(3-(4-(4-(3-(3-)-tert-butyl-1-p-phenylene-1Η-η ratio) Oxazol-5-yl) fluorenyl)N-l-yloxy)D is more than sigma-2-yl) gland), Ν-acetyl group 4-(3-(4-(4-( 3-(3-Terti-butyl-1-p-indole-1-pyrene-1〇-〇 is 0--5-yl) fluorenyl)N--1-meryl)ntb sigma-2-yl) gland基)旅0定, 2-(2-曱-milylethoxy)-1-(4-(3-(4-(4-(3-(3-苐2-butyl-1-pair) 曱Phenyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido)piperidin-1-yl)ethanone; N-nonylsulfonyl- 4-(3-(4-(4-(3-(3-T-butyl-butyl-1-p-phenyl)-1H) -carbazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido)pipeline 51 201130813 哫; N-(4-(4-(3-(3-third) -butyl butyl p-tolyl-1 Η η 嗤 5 5 5 5 5 5 5 5 5 5 5 5 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (4-(3-(3-(tert-butyl) small (p-phenylene) 1 Η Π Π 唑 _ _ _ _ _ ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -4_ mercapto-peptidylamine; 3-(4-((4-(3-(3-(t-butyl)))(p-(phenyl)phenyl)) (naphthalen-1-yl)oxy) 吼基 )) ''dimercaptourea; Ν-(4-((4-(3-(3-(t-butyl))) Phenyl)_1Η_0biazole _5_yl) ureido)naphthalen-1-yl)oxy)pyridin-2-yl)piperidine _ 丨曱醯 ; ;; Ν-曱-Ν-(2-(?啉-4-yl)ethyl)-oxime, _4_(4_(3·(3_T-butyl-1-p-tolyl-1Η-pyrazol-5-yl)ureido)]naphthalene_丨_氧基oxy)pyridin-2-yl group; N-(4-(hept-4-yl)butyl)_n'-4-(4-(3_(3-tri-butyl-1-pair-)曱Phenyl-lH-η than spani-5-yl)ureido)naphthalene-丨-yloxy y-pyridyl-2-ylurea; N-(2_(?琳_4_yl)ethyl)_ν' ·4_(4·(3_(3·T-Butyl-1-p-tolyl-1Η-carbazole_5_ Urea)naphthalene+yloxy)anthracen-2-ylurea; Ν-(3-methylisoxazol-5-yl)indolyl_ν,-4-(4-(3-(3- Tertiary-butyl-1-p-anthracene·1Η,ηη_5-yl)ureido)naphthalenyloxy)acridine_2_yl gland; N-(l-fluorenyl)piperidine 4-yl-indole, 4-(4-(3-(3-tri-butyl-1-p-phenyl)-lH-η-pyrazol-5-yl)ureido)naphthalene_丨_ Alkoxybipyridyl-2-carbazide; N-(4_(4-(3_(3-Tertobutyl-p-indolylphenyl-1H-pyrazole-5-yl)ureido)naphthalene- 1-yloxy)-pyridin-2-yl)-4-hydroxypiperidine-1-carboxamide; N-(3-(imidazol-1-yl)propyl)_N,_4-(4-( 3-(3-Terve-butyl-1-p-indolephenyl-1H-indazol-5-yl)ureido)naphthalenyloxy)pyridin-2-ylurea; N-(2- (3-(4_(4-(3-(3-Terti-butyl-p-p-phenyl-lH-n-biazole-5- 52 201130813)) genosyl)-n-yloxy)β (r)_N_(4-(4-(3-(3-tert-butyl-1-p-phenyl)-) 1Η-carbazole _5_yl) glandyl)naphthalenyloxy)0 sigma-2-yl)-3-(diamidoamine)π ratio p each α-decylamine Ν-(4-(4-(3-(3-Terve-butyl-1-p-phenyl)-p-pyrazol-5-yl)ureido)-n-yloxy Base) ° ratio σ -2- base) 0 ratio σ each 0 to 1 - 曱, amine, 2-(3-(4-(4-(3-(3-)-tert-butyl-1-pair -曱Phenyl-1Η-°Bizozol-5-yl) fluorenyl)N-l-yloxy)°biti-2-yl)glycosyl)-indole-mercaptoamine, 2-(3 -(4-(4-(3-(3-Terti-butyl-1-p-phenyl)-lH-η-biazole-5-yl) gland) _ 1_yloxy).比-2-yl) gland)-N-(2-?-linylethyl) acetamidine; 2-(3-(4-(4-(3-(3-tri-butyl) -1-p-p-phenyl-1H-carbazol-5-yl) glandyl)N- 1_yloxy)β is more than -2-yl) fluorenyl) -(4-(4-(3-(3-Terti-butyl-1-p-phenyl)-lH-η-biazole-5-yl) glandyl)N-l-yloxy)° ratio咬-yl) gland)-N-(2-(Dtbπ-1,4-yl)ethyl)acetamide; Ν-(3-(1Η-isoxazol-1-yl)propyl)-2 -(3-(4-(4-(3-(3-Terti-butyl-1-p-indolephenyl-1Η-°bazin-5-yl)))-naphthalen-1-yloxy Acridine-2-yl)ureido)acetamide; 1-(2-(3-(4-(4-(3-(3-)-tert-butyl-1-p-phenyl)-1H -pyrazol-5-yl)glycosyl)N-l-yloxy)ntbσ·^-2-yl)glycosyl)diphenyl)-4-mercapto 0 bottom plough; Ν-(3-(1Η -imidazol-1-yl)propyl)-2-(3-(4-(4-(3-(3-)-tert-butyl-1-p-phenyl)-1H-° -based) genosyl)na-1 -yloxy) ° bite -2 -yl)ureido)acetamide; N-(6-(4-(3-(3-tri-butyl-1-) p-Tolyl-1H-pyrazol-5-yl)urea 53 201130813 violent) Tara-1-yloxy) Pain. D-4-yl)-2-methoxy ethoxylated amine, N-(6- (4 -(3-(3-Terve-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)phenoxy)pyrimidin-4-yl)-2-methoxy-4- Indoleamine; N-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy Pyrimidine-2-yl)-2-decyloxyacetamidine; 3-(4-(4-(3-(3-tri-butyl-1-p-phenyl-phenyl)-lH-η-pyrazole -5-yl)ureido)naphthalen-1-yloxypyrimidin-2-yl)urea; 1-mercapto-3-(4-(4-(3-(3-tert-butyl)-1 -p-Phenyl-1H-pyrazol-5-yl)-yl)heptyl-1-yloxy)11-deni-2-yl)gland, 1,1-dimercapto-3-(4- (4-(3-(3-Terve-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyrimidin-2-yl)urea ; 1-cyclopropyl-3-(4-(4-(3-(3-tert-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)) glandyl) -yloxy)gland, (4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-indazol-5-yl)ureido) naphthalene-1- Benzyl)pyrimidin-2-yl)morpholine-4-guanamine; 3-(6-(4-(3-(3-tri-butyl-1-butan-phenyl)-1H-. Bisazo-5-yl)ureido)naphthalen-1-yloxypyrimidin-4-yl)urea; 2-(3-(4-(4-(3-(3-tri-butyl-1) -p-tolyl-1H-.benzazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)ureido)acetic acid, or a pharmaceutically acceptable salt thereof, including All stereoisomers, tautomers and isotopic derivatives thereof. Examples of the salt of the compound (I) include all pharmaceutically acceptable salts such as (without limitation) acid addition salts of mineral acids, such as addition salts of HCl and HBr salts and organic acids, such as sulfonium. Acid salt. The disclosure herein extends to solvates of the compounds of formula (I). Examples of the solvate include hydrates. 54 201130813 The compounds of the present disclosure include those in which one or more of the defined atoms are natural or non-natural isotopes. In one embodiment, the isotope is a stable isotope. Thus, the compounds of the present disclosure include, for example, compounds containing hydrazine and the like. The compounds described herein may include one or more palmitic centers and are disclosed to extend to include racemates produced therefrom, two mirror image isomers (eg, each substantially free of other mirror image isomers), and all stereoisomers Things. In one embodiment, an image isomerized form exists in substantially pure form, substantially without a corresponding mirror image isoform. All polymorphs that also extend to the compounds defined herein are disclosed. All polymorphs that also extend to the compounds defined herein are disclosed. The compound of formula (I) can be prepared by a process comprising the compound of formula (II):

其中Q不為-NHR* (其中R*為Q片段之剩餘部分)與式(Ilia)之化合物反應：Where Q is not -NHR* (where R* is the remainder of the Q fragment) reacts with a compound of formula (Ilia):

Λ 其中LG!為脫離基例如鹵素，諸如氯基。當NR3C(0)Q為NR3C(0)NHR*時，式(I)之化合物 55 製 201130813 藉由使式（II)之化合物與式（Illb)之化合物反應而得： Q=C=〇 (lllb) 反應係在鹼(例如DIPEA)存在下適當地進行。反應係在非質子溶劑或溶劑混合物(例如DCM及DMF)中適當地進行。式(Π)之化合物可藉由使反應式(IV)之化合物： R1Λ wherein LG! is a leaving group such as a halogen such as a chlorine group. When NR3C(0)Q is NR3C(0)NHR*, compound 55 of formula (I), 201130813, is obtained by reacting a compound of formula (II) with a compound of formula (llb): Q=C=〇( The lllb) reaction is suitably carried out in the presence of a base such as DIPEA. The reaction is suitably carried out in an aprotic solvent or solvent mixture such as DCM and DMF. A compound of the formula (Π) can be obtained by reacting a compound of the formula (IV): R1

(IV) 其中R1和R2係如上述式⑴化合物所定義，與式(VI) 之化合物反應：〇 lg2人 lg3 (VI) 其中LG2及LG3各自獨立地表示脫離基(例如lg2及LG3 二者表示咪唑基），接著與式(V)之化合物反應：(IV) wherein R1 and R2 are as defined in the compound of formula (1) above, and are reacted with a compound of formula (VI): 〇lg2 human lg3 (VI) wherein LG2 and LG3 each independently represent a leaving group (eg, both lg2 and LG3) Imidazolyl), followed by reaction with a compound of formula (V):

.Ar X H2N xnhr3 (V) 其中Ar、L、X和R3係如上述式⑴化合物所定義而製備。反應係在非質子溶劑(例如二氯曱烷）中，使用化學敏感性基團的適當保護基及鹼(例如DIPEA)適當地進 56 201130813 行。明確地說式(ιι)之化合物可藉由使式(lVa)之化合物：.Ar X H2N xnhr3 (V) wherein Ar, L, X and R3 are prepared as defined by the compound of the above formula (1). The reaction is carried out in an aprotic solvent (e.g., dichloromethane) using a suitable protecting group for a chemically sensitive group and a base (e.g., DIPEA) as appropriate. Specifically, the compound of the formula (ι) can be obtained by making the compound of the formula (lVa):

(IVa) 其中R1和R2係如上述式(1)化合物所定義，與式(乂)之化合物反應而製備。反應可在位阻鹼諸如DIPEA存在下、於適當惰性溶劑諸如二氯甲烷中實施。 DIPEA、於適當惰性溶劑溶劑（諸如二氣曱烷）中。式(I)之化合物(其+ R2為經燒基)可(例如）藉由使 (肼基苯基)烷酸與烷醯基乙腈（諸如r1c(〇)CH2Cn反應而製備。偶合可在醇溶劑（諸如乙醇）及礦酸(諸如HCl) 存在下接㈣在溶劑(諸如THF)巾之錄德處理而產生。包含羥烷基之取代基R2可藉由使用在適當溶劑(例如THF)中之硼烷的還原作用顯露以提供式(IV)之化合物（其中R為羥基化烷基）。羥基然後可通過在此段中別處所述之其他所述路控進行而被保護，例如呈石夕醚及 (iV)，以產生一種其中R2為經保護羥烷基之式(1)化合物。羥基可藉由矽基基團之裂解，例如用四丁基氟化銨顯露。其中R1為經基化烷基種類之式⑴化合物可藉由使用類似於直接地描述於上的條件使經保護苯甲氧基烷 57 201130813 _基乙腈、芳肼反應而製備。式(IVa)之化合物可藉由使式(IV)之化合物與光氣或光氣相等物(諸如雙光氣或三光氣)在鹼(諸如DIPEA) 存在下反應而製備。熟習該項技術者應了解式(IVa)之化合物通常為反應中間物，且可分離及直接使用於隨後轉變或為瞬時中間物’其係就地產生且被使用而沒有分離。更明確說式（II)之化合物可藉由使式（Ivb)之化合物：(IVa) wherein R1 and R2 are as defined in the above formula (1), and are prepared by reacting with a compound of the formula (乂). The reaction can be carried out in the presence of a hindered base such as DIPEA in a suitable inert solvent such as dichloromethane. DIPEA, in a suitable inert solvent solvent such as dioxane. The compound of formula (I) (which + R2 is a burnt group) can be prepared, for example, by reacting (nonylphenyl)alkanoic acid with an alkylmercaptoacetonitrile such as r1c(〇)CH2Cn. Coupling can be in the alcohol The solvent (such as ethanol) and the mineral acid (such as HCl) are present in the presence of (iv) in a solvent (such as THF) towel. The substituent R2 comprising a hydroxyalkyl group can be used in a suitable solvent (such as THF). The reduction of the borane is revealed to provide a compound of formula (IV) wherein R is a hydroxylated alkyl group. The hydroxyl group can then be protected by other means of control as described elsewhere in this paragraph, for example as a stone Ether ether and (iV) to produce a compound of formula (1) wherein R2 is a protected hydroxyalkyl group. The hydroxy group can be cleaved by a thiol group, for example, with tetrabutylammonium fluoride. The compound of the formula (1) of the alkylated alkyl group can be prepared by reacting the protected benzyloxyalkane 57 201130813 acetonitrile, aryl hydrazine using conditions similar to those directly described above. The compound of the formula (IVa) can be borrowed. By making a compound of formula (IV) with phosgene or photo-vapor, etc. (such as diphosgene or triphosgene) in a base such as D IPEA) is prepared in the presence of a reaction. Those skilled in the art will appreciate that the compound of formula (IVa) is typically a reaction intermediate and can be isolated and used directly in subsequent transformations or as a transient intermediate which is produced in situ and used Without separation, it is more clear that the compound of formula (II) can be obtained by making a compound of formula (Ivb):

(ivb) 其中LG2如上述所定義，與式(VI)之化合物反應而製備。反應可在位阻鹼(諸如DIPEA)存在下、於適當惰性溶劑(諸如二氣曱烷)實施中。 (IVb)之化合物可藉由使式(IV)之化合物與式（Vi) 之化合物在鹼(諸如DIPEA)存在下反應而製備。熟習該項技術者應了解式(IVb)之化合物可為中間物，包括瞬時中間物，其不被分離。備：式(V)之化合物可藉由式(VII)化合物之還原作用製 58 201130813 〇2N’Ar、L/X、NHR3 (VII) 其中Ar、L、X和R3係如上述式(I)化合物所定義，例如藉由在觸媒（諸如受載於碳上之鉑）存在下之氫化作用。反應係在極性質子溶劑或溶劑之混合物（例如曱醇及乙酸）中適當地進行。或者，其中L為Ο之式(V)化合物可藉由將式(Vila) 之化合物去保護而製備·· P1P2N/Ar、〇/X、NR3.P3 其中P1、P2及P3為保護基和R3為保護基，例如乙酸基 (諸如-C(0)CH2〇CH3或R3如上述式(I)化合物所定義。其中 L 表示-(CH2)nO(CH2)m 或(CH2)nORb 之式(νΠ) 化合物，如上述所定義，其中η為零及連結子L包含至少一個-CHr，可藉由式(Villa)或(Vlllb)之化合物： HO"(~Rb十 X—NHR3’ (Vlllb) Η〇-(〇Η2)-Χ—NHR3' (Villa)(ivb) wherein LG2 is prepared as described above and reacted with a compound of formula (VI). The reaction can be carried out in the presence of a hindered base such as DIPEA in a suitable inert solvent such as dioxane. The compound of (IVb) can be produced by reacting a compound of the formula (IV) with a compound of the formula (Vi) in the presence of a base such as DIPEA. Those skilled in the art will appreciate that the compounds of formula (IVb) can be intermediates, including transient intermediates, which are not isolated. Preparation: The compound of the formula (V) can be produced by the reduction of the compound of the formula (VII). 58 201130813 〇 2N'Ar, L/X, NHR3 (VII) wherein Ar, L, X and R3 are as in the above formula (I) The compound is defined, for example, by hydrogenation in the presence of a catalyst such as platinum supported on carbon. The reaction is suitably carried out in a polar protic solvent or a mixture of solvents such as decyl alcohol and acetic acid. Alternatively, a compound of the formula (V) wherein L is hydrazine can be prepared by deprotecting a compound of the formula (Vila): P1P2N/Ar, 〇/X, NR3.P3 wherein P1, P2 and P3 are protecting groups and R3 Is a protecting group such as an acetate group (such as -C(0)CH2〇CH3 or R3 as defined by the above formula (I). wherein L represents a formula of -(CH2)nO(CH2)m or (CH2)nORb (νΠ a compound, as defined above, wherein n is zero and the linker L comprises at least one -CHr, which may be a compound of the formula (Villa) or (Vlllb): HO" (~Rb X X-NHR3' (Vlllb) Η 〇-(〇Η2)-Χ-NHR3' (Villa)

或其類似物’且其中m、X和Rb係如上述式⑴化人物所定義和R3’為保護基或R3如上述式⑴化合物所定二式(IX)或(X)化合物之反應製備： N 59 201130813Or an analog thereof' and wherein m, X and Rb are as defined by the above formula (1) and R3' is a protecting group or R3 is reacted with a compound of formula (IX) or (X) as defined by the above formula (1): N 59 201130813

(IX)(IX)

(X) 其中化合物(IX)及(X)可具有之視需要取代基。如上述式（I)化合物所定義反應可在Mit_bu條件下(諸如在三麵及偶氮二甲酸一異丙酯存在下）實施。反應係在極性非質子溶劑(例如四氫呋喃’特別是無水四氫呋喃）中適當地進行。在一替代性方法中，某些式(V)之化合物（其中Ar、 L及X係如上述式(I)化合物所定義）可藉由使反應式(χι) 之化合物： h，aWG4 (XI) 或其經保護衍生物，諸如胺甲酸酯（其中Ar、L* x係如上述所疋義及LG4表示脫離基諸如氣基，特別是，其中L表不0)與酿胺化试劑，例如與胺曱酸g旨(χι!):(X) wherein the compounds (IX) and (X) may have an optional substituent. The reaction as defined for the compound of the above formula (I) can be carried out under Mit_bu conditions such as in the presence of trihedral and monoisopropyl azodicarboxylate. The reaction is suitably carried out in a polar aprotic solvent such as tetrahydrofuran, especially anhydrous tetrahydrofuran. In an alternative method, certain compounds of formula (V) wherein Ar, L and X are as defined for the compound of formula (I) above may be obtained by reacting a compound of the formula (χι): h, aWG4 (XI Or a protected derivative thereof, such as a carbamate (wherein Ar, L* x is as defined above and LG4 represents a leaving group such as a gas group, in particular, wherein L is not 0) and a brewing aminating agent For example, with aminic acid g (χι!):

(XII) P3 其中P和R係如上述所定義’在無水惰性溶劑(諸如 THF及適當鈀觸媒存在下，例如在氮氛圍下之反應，接著原來及新引人之經保護胺類二者之去保護，例如使用二氯曱烷及TFA而製備。在一具體實例中，該化合物式(XII)為： 201130813 义人 H2N^〇*Bu or R3HN \〇*Bu (Xlla) (XHb) 式(XI)之化合物（其中L係經由O連接至X，例如，其中L表示-(CH2)n〇(CH2)m或RaO(CH2)m，如上述所定義’其中m為零）可藉由使式(XIII)之化合物：(XII) P3 wherein P and R are as defined above, in an anhydrous inert solvent such as THF and a suitable palladium catalyst, for example under a nitrogen atmosphere, followed by both the original and the newly introduced protected amines. Deprotection, for example, using dichloromethane and TFA. In a specific example, the compound of formula (XII) is: 201130813 H2N^〇*Bu or R3HN \〇*Bu (Xlla) (XHb) a compound of (XI) wherein L is attached to X via O, for example, wherein L represents -(CH2)n〇(CH2)m or RaO(CH2)m, as defined above, wherein m is zero A compound of formula (XIII):

H2iTAr、L/〇H (XIII) 或其經保護衍生物（例如，其巾麟離胺雜護成胺甲酸，）’其中_Ar如上述所定義及L*及OH-起表示L (特別是L*表讀燒基細)與式(χιν)之化合物反應而製 ,χ、 LG； LG4 (xiv) :- 所疋義及％表示脫離基諸如氣基及吨表不脫離基諸如氣武反應可在—諸如氳化純劑諸如DMF中實施。开貝卞/合式(ΧΠΙ)之化合物可從式(XV)化合物製備： Η，ΑΓ7 ^中°亥游離胺適當地被保護(例如）成胺曱酸醋，及Ar 、+、及，其中L表示-(CH2)n〇(CH2)m，如上 34所定義，其中n失。、馬2及m為零，措由與一種試劑（諸 201130813 划9侧)之硼氫化作用，接著使用過氧化氫在驗(諸如氫氧化鋼)存在下之氧化作用。式(XV)之化合物可以二步驟轉變從式(χνι)之化合物經由式(駡)之化合物製備，其巾Ar如上述所定義及游離胺係適當地被保護(例如)成胺甲酸醋： H〆、H2N/A、ch〇 iXVl) (XVII) 〇式(XVI)化合物用驗(諸如在惰性溶劑(諸如丁册）中之正1基鋰)處理’接著添加DMF提供式(χνπ)之化合物。藉由烯化作用步驟式（XVII)之化合物可轉變成式 (XV)之化合物，諸如藉由與就地產生之Wittig試劑（諸如從曱基二笨基溴化鱗在鹼諸如第三_丁醇鉀存在下產生之ylid)的反應。通常反應將在惰性溶劑（例如thf) 及在惰性氛圍下（諸如氮)在低溫度(諸如_78C)C)下實施。式⑴之化合物（其中Q係以CH2V，連接至 -NR3C(0)，其中V’為選自N、0，或S之雜原子）可藉由包含下列之方法製備：根據式(Ha)化合物：H2iTAr, L/〇H (XIII) or a protected derivative thereof (for example, a chelating amine to an amine carboxylic acid), wherein _Ar is as defined above and L* and OH- represent L (especially L*表读烧基细) is prepared by reacting with a compound of the formula (χιν), χ, LG; LG4 (xiv): - meaning and % means that the detachment group such as gas base and ton is not separated from the base such as gas reaction It can be implemented in, for example, a phlegm-purifying agent such as DMF. A compound of the formula (XV) can be prepared from a compound of the formula (XV): Η, ΑΓ7 ^ 中 ° free amine is suitably protected (for example) into an amine vinegar, and Ar, +, and, wherein L Represents -(CH2)n〇(CH2)m, as defined above 34, where n is lost. Horses 2 and m are zero, catalyzed by the hydroboration of a reagent (the 201130813 side 9) followed by the oxidation in the presence of hydrogen peroxide (such as steel hydroxide). The compound of the formula (XV) can be prepared in a two-step conversion from a compound of the formula (??) via a compound of the formula (?) wherein the towel Ar is as defined above and the free amine is suitably protected (for example) as a urethane: H 〆, H2N/A, ch〇iXVl) (XVII) A compound of formula (XVI) is treated with a test such as n-l-l-lithium in an inert solvent such as Ding. 'Substituting DMF to provide a compound of formula (χνπ) . The compound of formula (XVII) can be converted to a compound of formula (XV) by an alkylation step, such as by in situ formation of a Wittig reagent (such as a brominated scale from a fluorenyl diphenyl group in a base such as a third The reaction of ylid) produced in the presence of potassium alkoxide. Typically the reaction will be carried out in an inert solvent such as thf and under an inert atmosphere such as nitrogen at a low temperature such as _78C. A compound of formula (1) wherein Q is a CH2V, attached to -NR3C(0), wherein V' is a heteroatom selected from N, 0, or S, can be prepared by a process comprising: a compound according to formula (Ha) :

其中R1、R2、Ar、L、X、NR3係如上述式(I)化合物所定義及LG6表示脫離基，例如鹵素（諸如氣基）與式 (XVIII)化合物之親核置換反應： 62 201130813 Η——V—q (XVIII) 其中Η表示氫，V’表示選自Ν、ΝΗ、0或S之雜原子及q表示Q之剩餘部分(也就是_CH2V'-q = Q)。反應可在位阻鹼(例如DIPEA)存在下在惰性溶劑 (例如二氯甲烧）中實施。式(Ila)之化合物可藉由使式(II)之化合物與式(χνΐ) 之化合物反應製備：Wherein R1, R2, Ar, L, X, NR3 are as defined by the above formula (I) and LG6 represents a leaving group, for example a nucleophilic displacement reaction of a halogen (such as a gas group) with a compound of formula (XVIII): 62 201130813 Η - V - q (XVIII) wherein Η represents hydrogen, V' represents a hetero atom selected from ruthenium, osmium, 0 or S and q represents the remainder of Q (ie _CH2V'-q = Q). The reaction can be carried out in the presence of a hindered base such as DIPEA in an inert solvent such as methylene chloride. A compound of the formula (Ila) can be prepared by reacting a compound of the formula (II) with a compound of the formula (χνΐ):

lg6 其中LG6如上述(Ila)之化合物所定義式，及LG7為脫離基，例如鹵素，諸如氯基。反應可(例如）在位阻鹼(例如DIPEA)存在下於惰性溶劑（例如二氣甲烷）中實施。其中Q為NH-(CH2)d_C(0)NHR8之式(I)化合物可藉由包含：（lib) R1Lg6 wherein LG6 is as defined by the compound of the above (Ila), and LG7 is a leaving group such as a halogen such as a chloro group. The reaction can be carried out, for example, in the presence of a hindered base such as DIPEA in an inert solvent such as di-methane. The compound of formula (I) wherein Q is NH-(CH2)d_C(0)NHR8 can be included by: (lib) R1

其中Ri、R2、Ar、L·、X和R3 9係如上述式⑴化合物所定義及d為整數1至5 (諸如1至4)，和胺R8NH2之間使用偶合試劑（諸如EDC)的醯胺偶合之方法製備。式(lib)之化合物可藉由化合物(II)與式(Illb)之異氰酸酯（其中Q為N-(CH2)p-C〇2Et)之反應，接著所得乙酉旨 63 201130813 THF甲之氫氧化鋰水溶液的水解八Wherein Ri, R2, Ar, L., X and R3 9 are as defined by the compound of the above formula (1) and d is an integer from 1 to 5 (such as 1 to 4), and a coupling reagent (such as EDC) is used between the amine R8NH2. Prepared by amine coupling. The compound of the formula (lib) can be reacted with the isocyanate of the formula (II) and the isocyanate of the formula (Illb) (wherein Q is N-(CH2)pC〇2Et), followed by the obtained lithium hydroxide aqueous solution of 63 201130813 THF. Hydrolysis eight

產物使用（例如）在THF 成0 (例如二氣曱烷）中實施。其中Q為NR7R8之式（I)化合物可藉由包含胺 RR’NH與式(lie)化合物之間的反應之方法製備：The product is used, for example, in THF to 0 (e.g., dioxane). The compound of the formula (I) wherein Q is NR7R8 can be produced by a reaction comprising a reaction between an amine RR'NH and a compound of the formula (lie):

其中R1、R2、Ar、X和R3係如上述式⑴化合物所定義及LG2為脫離基(諸如2-異丙烯氧基。式（lie)之化合物可藉由化合物（π)與式（VI)化合物 (諸如異丙烯基曱酸酯）在位阻驗(例如DIPEA)存在下之反應合成。反應可在位阻鹼(例如DIPEA)存在下、於惰性溶劑 (例如二氣曱烷）中實施。提供取得各種本發明具體實例之廣泛合成利用性的中間物種類的製備及通用路徑概述如下（流程1至 16)。製備以表示中間物a之胺基吡啶結構單元之合成方法概述如下（流程1)，其中rUr2、r3及L係如上述式 (I)化合物所定義。流程1 64 201130813Wherein R1, R2, Ar, X and R3 are as defined by the compound of the above formula (1) and LG2 is a leaving group (such as 2-isopropenyloxy. The compound of the formula (lie) can be obtained by the compound (π) and the formula (VI) The compound (such as isopropenyl phthalate) is synthesized by reaction in the presence of a steric hindrance (e.g., DIPEA). The reaction can be carried out in the presence of a hindered base (e.g., DIPEA) in an inert solvent (e.g., dioxane). The preparation and general route of the intermediate species providing broad synthetic availability for various specific examples of the invention are summarized below (Schemes 1 to 16). The synthetic method for preparing the aminopyridine structural unit representing the intermediate a is summarized as follows (Scheme 1) Wherein rUr2, r3 and L are as defined by the compound of formula (I) above. Scheme 1 64 201130813

中間物cIntermediate c

從商業地可得之化合物製備以中卩卩札u 表示之活化胺基吡唑類（其中Rl及R/ 及中間物C 合物所定義）係說明如下(餘2)。$如上述式(I)化流程2The preparation of the aminopyrazoles (wherein R1 and R/ and the intermediate C compounds) represented by the intermediates are prepared from commercially available compounds as described below (the remainder 2). $ as in the above formula (I) Process 2

至以中間物d及中問你其中表示〇(CH細製備之化合物(其中L在流程3 ^係如下所示（流程3): 65To the middle of the intermediate d and ask you which represents 〇 (CH finely prepared compound (where L is in the process 3 ^ is as follows (flow 3): 65

OHOH

201130813 可被利用來製備以中間物d表示之種類（為此L在其中表示Ο及特定二胺中間物el)的化合物之方法概述如下（流程4)。流程4201130813 A method which can be utilized to prepare a compound represented by the intermediate d (for which L represents a hydrazine and a specific diamine intermediate el) is summarized as follows (Scheme 4). Process 4

以中間物f表示之化合物（其中R]、R2及L係如上述式(I)化合物所定義，Ar為萘基及X為吡啶基)之備概 66 201130813 述如下（流程5)。流程5The compound represented by the intermediate f (wherein R), R2 and L are as defined by the compound of the above formula (I), and Ar is a naphthyl group and X is a pyridyl group is described in the following paragraph (Process 5). Process 5

一種製備以表示中間物g之化合物（其中匕和尺3係如上述式(I)化合物所定義’Ar為萘基、X為吡咬基及q 為NRRC])的通用方法概述如下（流程6)。流程6A general method for preparing a compound represented by the intermediate g (wherein, 匕 and 尺3 are as defined by the compound of the above formula (I), 'Ar is a naphthyl group, X is a pyridyl group, and q is NRRC) is as follows (Scheme 6) ). Process 6

中間物g 以中間物h及中間物j表示之化合物（其中L、Ri、 R2及R3係如上述式(I)化合物所定義，Ar為蔡基及χ 為吡啶基）的製備概述如下（流程7)。流程7 67 201130813 中間物aIntermediate g The preparation of the compound represented by the intermediate h and the intermediate j (wherein L, Ri, R2 and R3 are as defined by the compound of the above formula (I), and Ar is a thiol group and the fluorene is a pyridyl group) is summarized as follows (process 7). Process 7 67 201130813 Intermediate a

1. LG1. LG

P 2.胺去保護 R3P 2. Amine deprotection R3

從上文所述之中間物（揭示的例子，其中L、R1、 R2、R3及Q係如上述式⑴化合物所定義，Ar為萘基及 X為吡啶基)可根據下述轉變（流程8a-f)製備。下述所揭示之特定路徑（流程8b及8c)提供式（I)化合物（其中NHR 或NRR'表示Q及其中Q與NHC(O)—起形成脲)之例子。流程8aFrom the above-mentioned intermediates (the disclosed examples, wherein L, R1, R2, R3 and Q are as defined by the compound of the above formula (1), Ar is a naphthyl group and X is a pyridyl group) can be converted according to the following (Scheme 8a) -f) Preparation. The specific routes (Schemes 8b and 8c) disclosed below provide examples of compounds of formula (I) wherein NHR or NRR' represents Q and Q and NHC(O) together form urea. Process 8a

XrXr

R3 I NHR3 I NH

醯胺偶合Indoleamine coupling

中間物b 脲偶合Intermediate b urea coupling

或中間物c 流程8b 68 201130813Or intermediate c process 8b 68 201130813

—中間物a 中間物g 中間物f ~ 流程8c- intermediate a intermediate g intermediate f ~ flow 8c

RR.NCOCIRR.NCOCI

RRNH 中間物b或中間物RRNH intermediate b or intermediate

相似的方法可用以製備其中Ar為苯基及X如上述式(I)化合物所定義之式(I)化合物。製備式（I)化合物之一般方法係提供於下（流程9)，其中Ar為萘基和X為吼啶基及片段NR3C(0)Q為甘胺酸胺衍生物。流程9A similar method can be used to prepare a compound of formula (I) wherein Ar is phenyl and X is as defined above for the compound of formula (I). A general procedure for the preparation of compounds of formula (I) is provided below (Scheme 9) wherein Ar is naphthyl and X is an acridinyl group and the fragment NR3C(0)Q is a glycine amine derivative. Process 9

相似的方法可用以製備其中Ar為苯基及X如上述式(I)化合物所定義之式(I)化合物。 69 201130813 3製備其中Ar為萘基及x為吡啶基及片段 NRC(0)Q為N-g盘基甘胺醯胺衍生物之式⑴化合物的合成方法係提供如下（流程10)，其+ LG為脫離基和 RC(0)NHCH2 為 Q。流程10A similar method can be used to prepare a compound of formula (I) wherein Ar is phenyl and X is as defined above for the compound of formula (I). 69 201130813 3 A synthetic method for preparing a compound of the formula (1) wherein Ar is a naphthyl group and x is a pyridyl group and the fragment NRC(0)Q is a Ng disc-glycine amine derivative is provided as follows (Scheme 10), wherein + LG is The leaving group and RC(0)NHCH2 are Q. Process 10

R2 N-酿基甘胺醯胺類似物中間物j 相似的方法可用以製備其中Ar為苯基及X如上述式(I)化合物所定義之式⑴化合物。適合於―產生製備其中該片段XNHR3表示2·胺基嘴嘧啶基之式⑴化合物的例子所需要之額外中間物的合成路徑係揭示如下。 σ U Al：為萘基和L為〇及片段X-NHR3為2- 胺基嘧定基的丨段H2N_Af_L_x_NHR3之方法概述如下 (流程11)。流程11 201130813R2 N-glycineamine amine analog Intermediate j A similar method can be used to prepare a compound of formula (1) wherein Ar is phenyl and X is as defined above for the compound of formula (I). A synthetic route suitable for the production of an additional intermediate required for the preparation of an example of the compound of the formula (1) wherein the fragment XNHR3 represents a 2-aminopyrimidinyl group is disclosed below. The method of σ U Al: a naphthyl group H2N_Af_L_x_NHR3 in which a naphthyl group and L are oxime and a fragment X-NHR3 is a 2-aminopyrimidinyl group is summarized as follows (Scheme 11). Process 11 201130813

製備其中Ar為萘基和L為0及片段Χ-NHR3為4-胺基嘧啶基的片段02N-Ar-L-X-NHR3之步驟係揭示如下（流程12)。流程12The procedure for preparing the fragment 02N-Ar-L-X-NHR3 wherein Ar is a naphthyl group and L is 0 and the fragment Χ-NHR3 is a 4-aminopyrimidinyl group is disclosed as follows (Scheme 12). Process 12

製備其中Ar為苯基和L為0及片段Χ-NHR3為4-胺基嘧啶基的片段02N-Ar-L-X-NHR3之步驟係揭示於下（流程13)。流程13The procedure for preparing the fragment 02N-Ar-L-X-NHR3 wherein Ar is phenyl and L is 0 and the fragment Χ-NHR3 is 4-aminopyrimidinyl is disclosed below (Scheme 13). Process 13

71 201130813 該等 ^N-Ar-L-X-NHR3 及〇2N-Ar-L-X-NHR3 種類 (其中該片段X-NHR3為胺基嘧啶基及其中L為非〇之連結子）的起始原料可藉由與上示方法類似的方法製備0 製備以中間物k表示之化合物（其中l和R3係如上述式(I)化合物所定義，Ar為萘基及片段XNR3為2_ 胺基嘧啶基[Y’=CH ; X，=N]或4-胺基嘧啶基[γ，=Ν ; X’=CH]及NR3C(〇)Q —起表示醯胺）的通用方法係概述如下（流程14)。流程14 R371 201130813 The starting materials of the ^N-Ar-LX-NHR3 and 〇2N-Ar-LX-NHR3 species (wherein the fragment X-NHR3 is an aminopyrimidinyl group and L is a non-quinone linker) Prepared by a method similar to the one shown above to prepare a compound represented by the intermediate k (wherein 1 and R3 are as defined in the above formula (I), Ar is a naphthyl group and the fragment XNR3 is a 2-aminopyrimidyl group [Y' The general method for the conversion of X,=N] or 4-aminopyrimidinyl [γ,=Ν; X'=CH] and NR3C(〇)Q, which represents decylamine, is summarized below (Scheme 14). Flow 14 R3

II

NHNH

o2nO2n

R3R3

以中間物m表示之類似結構(其中l和r3係如上 ^⑴化合物所定義’ Ar為萘基及片為基射基[Y，=CH;X，，流程15 72 201130813A similar structure represented by the intermediate m (wherein l and r3 are as defined above by the compound of (1)' Ar is a naphthyl group and a sheet is a base [Y,=CH; X,, Flow 15 72 201130813

以中間物η表示之化合物（其中R1、R2係如上述式 (I)化合物所定義，Ar為萘基和L為Ο及片段XNR3為 2-胺基嘧啶基和R3為H)可藉由說明於下之方法（流程 16)製備。流程16A compound represented by the intermediate η (wherein R1 and R2 are as defined by the compound of the above formula (I), Ar is a naphthyl group and L is an anthracene, and the fragment XNR3 is a 2-aminopyrimidinyl group and R3 is H) can be illustrated by Prepared by the method below (Scheme 16). Process 16

以中間物P表示之化合物（其中R1和R2係如上述式(I)化合物所定義，Ar為萘基和L為OCH2及片段 XNR3為2-胺基嘴咬基和R3為H)可如下述揭示（流程 17)製備。流程17 73 201130813The compound represented by the intermediate P (wherein R1 and R2 are as defined in the above formula (I), Ar is a naphthyl group and L is OCH2, and the fragment XNR3 is a 2-amine group bite group and R3 is H) may be as follows Revealed (Scheme 17) for preparation. Process 17 73 201130813

中間物p 從上文所述中間物，所揭示的例子（其中L、R1、 R2、R3及Q係如上述式(I)化合物所定義，^為萘基及其中s亥片段XNHR表不2-胺基鳴σ定基或4-胺基β密π定基) 可根據下述轉變（流程18a-d)製備。揭示於下之特定路徑（流程18c及18d)提供其中NHR或NRR'表示Q及其中Q與NHC(O) —起形成脲之式(I)化合物的例子。流程18aIntermediate p from the above described intermediates, examples disclosed (wherein L, R1, R2, R3 and Q are as defined by the above formula (I), ^ is naphthyl and its s-fragment XNHR is not 2 -Amino-Styrosine or 4-Amino-B-M-[subunit] can be prepared according to the following transformation (Scheme 18a-d). The specific pathways disclosed below (Schemes 18c and 18d) provide examples of compounds of formula (I) wherein NHR or NRR' represents Q and Q and NHC(O) together form urea. Flow 18a

201130813 流程18b201130813 Process 18b

流程18cFlow 18c

流程18d 中間物η 中間物mScheme 18d intermediate η intermediate m

RR'NH Base R3 = H, Χ·=Ν, Y'= CH 相似的方法可用以製備式(I)之化合物，苴中L、以2和R3係如上述式⑴化合物所定義，片段XN㈣ 75 2011；30811示2_胺基嘧啶基或4_胺基嘧啶基及其中NHR或 NRR'表示Q及其中Q與NHC(O) —起形成脲及其中Ar表示苯基。流程中所說明之式(Ilia)、（Illb)、（IV)、（IVa)、（IVb)、 (VI)、（Villa)、（Vlllb)、（IX)、（X)、（χπ)、（xna)、（XHb)、 (XIII)、（XIV)、（XV)、（XVI)、（XVI)及(XIX)之化合物及某些其他化合物為商業上可得者，或為已知的，或為新穎的且可藉由習知方法容易地製備。參見例如R e g a η， J.等人，J. Med. Chem.，2003，46，4676-4686、WO 00/043384、WO 2007/087448 及 WO 2007/089512。在一或多個上述反應期間可能需要保護基以保護化學敏基團，以確定方法是有效率的。因此若須要或如必要的話，中間物化合物可藉由使用習知保護基來保護。保護基及其除去方法係描述於“Protective Groups in Organic Synthesis”，Theodora W. Greene 及 Peter G.M. Wuts，由 John Wiley & Sons Inc 出版；4th Rev Ed” 2006, ISBN-10 : 0471697540。在一具體實例中，該病毒感染為流感，包括亞型流感A病毒、流感B病毒、禽流感病毒株H5m、A/HlNl 及/或流感大流行。本揭示也延伸至一種治療或預防病毒感染之方法’例如該感染由包括流感A病毒（其引起流感大流行’諸如在2009年春天由新流感A(H1N1)株引起之流感）；流感B及流感C病毒之流感病毒引起的感染，包含投予治療有效量之式⑴化合物。本揭示也延伸至一種治療或預防病毒感染（例如由 76 201130813 流感A病毒（包括亞犁H1N1/09 ’其在2009年春天引起流感大流行）、禽流感病毒株H5N1、H1N1、H1/N2、 H3/N2、H2/N3、流感B及流感C病毒引起之感染）之方法，包含投予治療有效量之式⑴化合物。本揭示也提供式(I)化合物供製造治療或預防病毒感染例如流感（包括亞型流感A病毒、流感B病毒、禽流感病毒株H5N1、A/H1N1、H3N2及/或流感大流行）的藥劑之用途。式⑴化合物如使用在本文中係意指本文中所揭示之化合物，包括式（IA)至（IF)之化合物及明確地命名之化合物，除非文中另有指明。在一具體實例中’式（I)之化合物係以單一治療提供。在一具體實例中’式(I)之化合物係以組合治療提供。化合物可以醫藥調配物物或組成物提供。，且j用邗預防或用於治療流感感染。鼻腔投予可能對預防特別地有幫助。鼻腔投予之調配物可為用於鼻滴劑或計量喷劑之形式的固體或水性或油性製劑，其中該治療劑為式(I)化合物單獨或式⑴之化合物與抗病毒劑(例如神經胺糖酸¥酶抑制劑(諸如但不限制於札那米韋（zanamivir))之組合。為了治療流感感$，局部投予至肺為治療有效的選項。因此在-具體實例中提供一種醫藥組成物，其包含式(I)之化合物，或本文中或多種局部可接受之稀釋劑或載劑。“要、、且口 77 201130813 ^ 在一替代性具體實例中，提供一種用於鼻滴劑或計量喷劑之形式的醫藥組成物，其包含式⑴化合物與抗病毒劑之組合(例如神經胺糖酸苷酶抑制劑，諸如但不限制於扎那米韋(zanamivir))。局部投予至肺可藉由使用氣溶膠調配物達成。氣溶膠調配物通常包含懸浮或溶解在適當氣溶膠推進劑，諸如氯氟碳(CFC)或氫氣碳(HFC)中之活性成分。適當CFC推進劑包括三氯單氟曱烷(推進劑n)、二氯四氟曱烷（推進劑114)及二氣二氟曱烷（推進劑 12)。適當HFC推進劑包括四氟乙烷(HFC_134a)及七氟丙烧(册(：-227)。推進劑通常包含40%至99.5%例如40〇/〇至90%重量之總吸入組成物。調配物可包含賦形劑，包括共溶劑(例如乙醇)及界面活性劑(例如卵填脂、去水山梨醇三油酸酸酯等等氣溶膠調配物係包裝在罐中並利用計量閥（例如如由Bespak、Valois或3M供應）遞送適當劑量。局部投予至肺也可藉由使用非加壓調配物（諸如水溶液或懸浮液）達成。此可利用喷霧器投予。局部投予至肺也可藉由使用乾粉調配物達成。乾粉調配物將包含一或多種磨碎的本揭示之化合物，通常具有1-10微米之質量平均直徑(MMAD)。調配物通常將包含局部可接受的稀釋劑(諸如乳糖，通常具有大粒徑例如100微米或更大之質量平均直徑(MMAD)。實例乾粉遞送系統包括 SPINHALER、DISKHALER、TURBOHALER、 DISKUS 及 CLICKHALER。在一具體實例中本發明化合物係以填充在裝置(諸 78 201130813 如DISKUS)内之超細乾粉調配物（例如包含適當等級之乳糖)提供。然而’在某些情況中’式⑴化合物之口服投予可能更適當。因此，提供一種用於口服投予之醫藥組成物，其包含式(I)化合物，或本文中所討論之組合，視需要組合一或多種口服可接受之稀釋劑或載劑。口服組成物可於任何習知形式，例如錠劑、膠囊、懸浮液、糖漿及酏劑。在一具體實例中，提供一種如本文中所定義之化合物，例如式⑴之化合物，其與抗病毒藥劑（例如神經醯胺酶(neuroamidase)抑制劑）組合調配。在一具體實例中，該調配物為共調配物，例如鼻調配物或局部諸如吸入調配物。在本說明書上下文中抗病毒劑包括神經胺糖酸苷酶抑制劑’諸如奥塞米韋（oseltamivir)、扎那米韋 (zanamivir)、帕拉米韋(peramivir)、金剛烷胺、金剛乙胺、利巴韋林(ribavirin);干擾素、阿昔洛韋（acyclovir) 及/或齊多夫定(zidovudine)。特定組合包括式⑴化合物與奥塞米韋、式(I)化合物與扎那米韋、式(I)化合物與帕拉米韋、式(I)化合物與安曼達地(amandadine)、式(I)化合物與金剛乙胺、式(I)化合物與利巴韋林、式(I)化合物與阿昔洛韋、式(I)化合物與齊多夫定、式(I)化合物、金剛烷胺與利巴韋林、式(I)化合物、奥塞米韋與金剛烷胺、式(I)化合物、奥塞米韋與利巴韋林、式(I)化合物、阿昔洛韋與齊多夫定或式(I)化合物、奥塞米韋、利巴韋林與金剛烷胺。 79 201130813 因此神經胺糖酸苷酶抑制劑可(例如）為奥塞米韋、扎那米韋、帕拉米韋。或者，或此外調配物可包含抑制劑’例如金剛烷胺或金剛乙胺。有利地，組合產品之使用允許一或多種活性劑以低於治療效果所需之劑量提供，採用單一活性成分作為單一治療。在一具體實例中，該神經胺糖酸苷酶抑制劑，例如扎那米韋、奥塞米韋、蘭那米韋(laninamivir)、帕拉米韋；利巴法林干擾素係以低於臨床實務中所使習用之劑量提供，例如對於抗病毒劑，諸如扎那馬韋 (zanamavir)，該劑量範圍可為每次治療〇.〇3至1〇毫克或較佳為每次治療0.3至3毫克。在一具體實例中，該抗病毒劑係提供下列劑量： 0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.1 卜 0.12、 0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20、0.21、 0.22、0.23、024、0.25、0.26、0,27、0.28、0.29、0.30、 0.3卜 0.32、0.33、0_34、0.35、0.36、0.37、0.38、0.39、 0.40、0.4卜 0.42、0.43、0.44、0.45、0.46、0.47、0.48、 0.49、0.50、0.5卜 0.52、0.53、0.54、0·55、0.56、0.57、 0.58、0.59、0.60、0.6卜 0.62、0.63、0.64、0.65、0.66、 0.67、0.68、0.69、0.70、0.7；1、0.72、0.73、0.74、0.75、 0.76、0.77、0.78、0.79、0.80、0.8卜 0.82、0.83、0.84、 0.85、0.86、0.87、0.88、0.89、0.90、0.9卜 0.92、0.93、 0.94、0.95、0.96、0.97、0.98、0.99、1.00、1.01、1.02、 1.03、1.04、1.05、1.06、1.07、1.08、1.09、1.10、1.11、 1.12、1.13、1.14、1.15、1.16、1.17、1.18、1.19、1.20、 201130813 1.21、1.22、1.23、1.24、1.25、1.26、1.27、1.28、1·29、 1.30、 1.31、1.32、1.33、1.34、1.35、1.36、1.37、1.38、 1.39、 1.40、1.4卜 1.42、1.43、1.44、1.45、1.46、1.47、 1.48、 1.49、1.50、1.5卜 1.52、1.53、1.54、1·55、1.56、 1.57、1.58、1.59、1.60、1.61、1_62、1.63、1.64、1.65、 1.66、 1.67、1.68、1.69、1.70、1.7卜 1.72、1.73、1.74、 1.75、 1.76、1.77、1.78、1·79、1.80、1.81、1_82、1.83、 1.84、 1.85、1.86、1.87、1.88、1.89、1.90、1.91、1.92、 1 93、1.94、1.95、1.96、1.97、1.98、2.00. 2.01、2·02、 2.03、2.04、2·05、2.06、2.07、2.08、2.09、2.10、2.11、 2.12、2.13、2.14、2.15、2.16、2.17、2.18、2.19、2.20、 2.2卜 2.22、2.23、2.24、2·25、2.26、2.27、2.28、2.29、 2.30、 2.3卜 2.32、2.33、2.34、2.35、2.36、2.37、2.38、 2.39、 2.40、2.4卜 2.42、2.43、2.44、2.45、2.46、2.47、 2.48、 2.49、2.50、2.5卜 2.52、2.53、2·54、2.55、2.56、 2·57、2.58、2.59、2.60、2.6卜 2.62、2.63、2.64、22.65、 2.66、 2.67、2.68、2.69、2.70、2.7卜 2.72、2.73、2.74、 2.75、 2.76、2.77、2.78、2.79、2.80、2.8卜 2.82、2.83、 2.84、 2.85、2.86、2.87、2.88、2.89、2.90、2.9卜 2.92、 2.93、2.94、2.95、2.96、2.97、2.98、2.99 或 3.00 毫克。式⑴之化合物可以每劑量〇〇1至5〇〇毫克範圍（例如〇.05至250毫克，諸如0.1至1〇〇毫克)投予。在一具體實例中’式⑴之化合物或包含式(I)化合物之組合每天投予一次或兩次。根據本揭示之組成物至少具有一種相加的治療效果，但可已有增效治療效果。 81 201130813 在一具體實例中，該等抗病毒活性劑（例如該等上文所描述者)係共投予。共投予如使用在本文中，其中該等活性劑以分開的調配物提供且大約同時予（在大約相同時間）或相繼地地投。相繼地投意欲指為其中當投予第二種或第三種活性時，一活性仍然存在於患者中。後來的活性劑可例如在第一種活性劑投予15、30、45 分鐘或 1、1.5、2、2.5、3、3.5、4、4.5、5、5.5、6、 6.5、7、7.5、8、8.5、9、9.5、10、11 或 12 小時之後投予。本揭示也延伸至一種本文中所述之組成物於治療或預防(例如治療或預防病毒感染（諸如，流感，特別是本文中所述之亞型）之用途。本揭示也延伸至一種治療或預防需要其之患者的方法’其包含投予治療有效量的本文中所述之組成物。在另一方面提供本文中所述之組成物供製造治療或預防病毒感染（例如流感，特別是本文中所定義之亞型）用藥劑之用途。在一方面提供治療或預防人類及其次族群(例如患有下列之患者)之用途：慢性疾病或病（諸如糖尿病、鬱血性心臟衰竭、腎衰竭、慢性阻塞性肺臟疾病、氣喘、及/或免疫抑制’諸如接受化學治療之患者、孕婦、HIV 及AIDS患者、及/或由流感感h引起的併發症，例如肺或全身性併發症。在一異體實例中，提供治療或預防嬰兒(從1天至1 82 201130813 歲）及兒童（例如5歲以下的小孩）之用途。在一具體實例中，提供治療或預防動物（例如農場動物（包括馬及豬）、鳥（包括家禽，諸如鳥、鵝、鴨子、天鵝等等）、家畜（包括貓及狗）)之用途。動物的治療在限制病毒傳染至人且因此減少流感的風險上是有利的。RR'NH Base R3 = H, Χ·=Ν, Y'= CH A similar method can be used to prepare the compound of formula (I), wherein L, 2 and R3 are as defined by the above formula (1), fragment XN (tetra) 75 2011;30811 shows 2_aminopyrimidinyl or 4-aminopyrimidinyl and wherein NHR or NRR' represents Q and Q and NHC(O) together form urea and wherein Ar represents phenyl. The formulas described in the scheme (Ilia), (Illb), (IV), (IVa), (IVb), (VI), (Villa), (Vlllb), (IX), (X), (χπ), Compounds of (xna), (XHb), (XIII), (XIV), (XV), (XVI), (XVI) and (XIX) and certain other compounds are commercially available or known Or is novel and can be readily prepared by conventional methods. See, for example, R e g a η, J. et al., J. Med. Chem., 2003, 46, 4676-4686, WO 00/043384, WO 2007/087448, and WO 2007/089512. A protecting group may be required during one or more of the above reactions to protect the chemosensitive group to determine that the method is efficient. Thus, if desired or if necessary, the intermediate compound can be protected by the use of conventional protecting groups. Protecting groups and methods for their removal are described in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter GM Wuts, published by John Wiley & Sons Inc; 4th Rev Ed" 2006, ISBN-10: 0471697540. In the example, the virus is infected with influenza, including subtype influenza A virus, influenza B virus, avian influenza virus strain H5m, A/H1N1 and/or influenza pandemic. The disclosure also extends to a method of treating or preventing a viral infection' For example, the infection consists of an influenza A virus (which causes an influenza pandemic such as influenza caused by a new influenza A (H1N1) strain in the spring of 2009); an influenza virus caused by influenza B and influenza C virus, including administration therapy. An effective amount of a compound of formula (1). The disclosure also extends to a treatment or prevention of a viral infection (eg, by 76 201130813 influenza A virus (including Yali H1N1/09 'which caused an influenza pandemic in the spring of 2009), avian influenza virus strain H5N1 A method of infecting an infection caused by H1N1, H1/N2, H3/N2, H2/N3, influenza B, and influenza C virus, comprising administering a therapeutically effective amount of a compound of formula (1). Also provided are compounds of formula (I) for the manufacture of a medicament for the treatment or prevention of a viral infection such as influenza (including influenza A virus, influenza B virus, avian influenza virus strain H5N1, A/H1N1, H3N2 and/or influenza pandemic) The use of a compound of formula (1), as used herein, means a compound disclosed herein, including a compound of formula (IA) to (IF), and a compound specifically designated, unless the context dictates otherwise. The compound of formula (I) is provided as a monotherapy. In one embodiment, the compound of formula (I) is provided in combination therapy. The compound can be provided as a pharmaceutical formulation or composition. Treatment of influenza infections. Nasal administration may be particularly helpful for prevention. Nasal administration may be in the form of a solid or aqueous or oily preparation for nasal drops or metered sprays, wherein the therapeutic agent is of formula (I a compound alone or in combination with an antiviral agent (such as a ceramide acidase inhibitor such as, but not limited to, zanamivir). Administration to the lung is a therapeutically effective option. Thus, in a specific embodiment, a pharmaceutical composition comprising a compound of formula (I), or a partially acceptable diluent or carrier herein or herein, is provided. And mouth 77 201130813 ^ In an alternative embodiment, there is provided a pharmaceutical composition in the form of a nasal drop or metered spray comprising a combination of a compound of formula (1) and an antiviral agent (eg, a neuraminidase) Inhibitors such as, but not limited to, zanamivir. Topical administration to the lungs can be achieved by using an aerosol formulation. Aerosol formulations typically comprise an active ingredient suspended or dissolved in a suitable aerosol propellant, such as chlorofluorocarbon (CFC) or hydrogen carbon (HFC). Suitable CFC propellants include trichloromonofluorodecane (propellant n), dichlorotetrafluorodecane (propellant 114), and difluorodifluorodecane (propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC_134a) and heptafluoropropene (booklet (:-227). Propellants typically contain 40% to 99.5%, for example 40 〇/〇 to 90% by weight of the total inhalation composition. The composition may comprise excipients, including cosolvents (eg, ethanol) and surfactants (eg, egg fat, sorbitan trioleate, etc., aerosol formulations are packaged in canisters and utilize metering valves (eg, The appropriate dose is delivered as supplied by Bespak, Valois or 3M. Topical administration to the lungs can also be achieved by using a non-pressurized formulation such as an aqueous solution or suspension. This can be administered using a nebulizer. Topical administration to The lungs can also be achieved by using a dry powder formulation. The dry powder formulation will comprise one or more of the ground compounds of the present disclosure, typically having a mass average diameter (MMAD) of from 1 to 10 microns. The formulation will generally comprise a locally acceptable Diluents, such as lactose, typically have a mass average diameter (MMAD) of large particle size, such as 100 microns or greater. Example dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS, and CLICKHALER. In one embodiment, the invention The compound is provided as an ultrafine dry powder formulation (e.g., containing an appropriate level of lactose) filled in a device (78, 2011, 308, 036, such as DISKUS). However, 'in some cases' oral administration of a compound of formula (1) may be more appropriate. Accordingly, there is provided a pharmaceutical composition for oral administration comprising a compound of formula (I), or a combination as discussed herein, optionally combining one or more orally acceptable diluents or carriers. In any conventional form, such as troches, capsules, suspensions, syrups and elixirs. In one embodiment, a compound as defined herein, eg, a compound of formula (1), which is associated with an antiviral agent (eg, a nerve) is provided. A neuroamidase inhibitor is formulated in combination. In one embodiment, the formulation is a co-formulation, such as a nasal formulation or a topical such as an inhalation formulation. In the context of this specification, an antiviral agent includes a ceramide Glycosidase inhibitors such as oseltamivir, zanamivir, peramivir, amantadine, rimantadine, ribavi Ribavirin; interferon, acyclovir and/or zidovudine. Specific combinations include a compound of formula (1) with oseltamivir, a compound of formula (I) and zanamivir, (I) a compound with peramivir, a compound of formula (I) and amandadine, a compound of formula (I) with rimantadine, a compound of formula (I) and ribavirin, a compound of formula (I) Acyclovir, a compound of formula (I) with zidovudine, a compound of formula (I), amantadine and ribavirin, a compound of formula (I), oseltamivir and amantadine, formula (I) Compound, oseltamivir and ribavirin, a compound of formula (I), acyclovir with zidovudine or a compound of formula (I), oseltamivir, ribavirin and amantadine. 79 201130813 Thus a neuraminidase inhibitor can be, for example, oseltamivir, zanamivir, and peramivir. Alternatively, or in addition, the formulation may comprise an inhibitor such as amantadine or rimantadine. Advantageously, the use of the combination product allows one or more active agents to be provided at a dose lower than the therapeutic effect, with a single active ingredient being used as a single treatment. In one embodiment, the neuraminidase inhibitors, such as zanamivir, oseltamivir, laninamivir, peramivir, and ribafatin interferon are lower than The dosages conventionally employed in clinical practice are provided, for example, for antiviral agents, such as zanamavir, which may range from 3 to 1 mg per treatment or preferably 0.3 to treatment per treatment. 3 mg. In one embodiment, the antiviral agent provides the following dosages: 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.1, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21 , 0.22, 0.23, 024, 0.25, 0.26, 0, 27, 0.28, 0.29, 0.30, 0.3, 0.32, 0.33, 0_34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.4, 0.42, 0.43, 0.44, 0.45 , 0.46, 0.47, 0.48, 0.49, 0.50, 0.5, 0.52, 0.53, 0.54, 0·55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.6, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69 , 0.70, 0.7; 1, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.8, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.9, 0.92, 0.93 , 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.10, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18 , 1.19, 1.20, 201130813 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.3 3. 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.4, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.5, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1_62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.7, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1_82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1 93, 1.94, 1.95, 1.96, 1.97, 1.98, 2.00. 2.01, 2·02, 2.03, 2.04, 2 ·05, 2.06, 2.07, 2.08, 2.09, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.20, 2.2, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28 2.29, 2.30, 2.3, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.40, 2.4, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.5, 2.52, 2.53 , 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.60, 2.6, 2.62, 2.63, 2.64, 22.65, 2.66, 2.67, 2.68, 2.69, 2.70, 2.7, 2.72 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.80, 2.8, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.90, 2.9, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99 or 3.00 mg. The compound of the formula (1) can be administered in a range of from 1 to 5 mg per dose (e.g., 〇.05 to 250 mg, such as 0.1 to 1 mg). In one embodiment, the compound of formula (1) or a combination comprising a compound of formula (I) is administered once or twice daily. The compositions according to the present disclosure have at least one additive therapeutic effect, but may have a synergistic therapeutic effect. 81 201130813 In one embodiment, the antiviral active agents (e.g., as described above) are co-administered. Co-administration as used herein, wherein the active agents are provided in separate formulations and administered at about the same time (at about the same time) or sequentially. Successively, it is intended to mean that when a second or third activity is administered, an activity is still present in the patient. Subsequent active agents can be administered, for example, at 15, 30, 45 minutes or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8 in the first active agent. After 8.5, 9, 9.5, 10, 11 or 12 hours. The disclosure also extends to the use of a composition described herein for the treatment or prevention (eg, treatment or prevention of a viral infection, such as influenza, particularly a subtype as described herein). The disclosure also extends to a treatment or A method of preventing a patient in need thereof comprising administering a therapeutically effective amount of a composition described herein. In another aspect, the compositions described herein are provided for the manufacture of a therapeutic or prophylactic viral infection (eg, influenza, particularly herein) The use of a medicament as defined in the subtypes. In one aspect, the use of a medicament for treating or preventing a human or a subgroup thereof (for example, a patient having the following): a chronic disease or disease (such as diabetes, septic heart failure, renal failure, Chronic obstructive pulmonary disease, asthma, and/or immunosuppression, such as patients receiving chemotherapy, pregnant women, HIV and AIDS patients, and/or complications caused by influenza flu, such as pulmonary or systemic complications. In the case of a variant, the use of a treatment or prevention infant (from 1 day to 1 82 201130813 years) and a child (for example a child under 5 years old) is provided. In the case of the body, the use of an animal for treatment or prevention, such as farm animals (including horses and pigs), birds (including poultry such as birds, geese, ducks, swans, etc.), livestock (including cats and dogs), is provided. Treatment is advantageous in limiting the risk of viral infection to humans and thus reducing influenza.

【實施方式】實驗部分縮寫 AcOH aq Ac ATP BALF 9-BBN Boc br BSA CatCart® CCID5〇 CDI COPD d DCM DIAD 冰醋酸水溶液乙醯基腺核苦二填酸支氣管肺泡灌洗液 9-硼雜雙環[3.3.1]壬烷第三-丁氧羰基寛牛血清白蛋白催化筒細胞培養感染劑量5 0 % U-羰基-二咪唑慢性阻塞性肺臟疾病二重線二氯曱烷二異丙基偶氮二曱酸酯 83 201130813 τ 二異丁基氫化鋁 DIPEA DMEM N，N-二異丙基乙胺達爾伯克改良伊格爾培養基 (Dulbecco's modified Eagle's medium) d-U937 分化U937細胞 DMF N，N-二曱基曱醯胺 DMSO 二曱亞硪 EDAC.HC1 1-乙基-3-(3-二曱胺基丙基）碳二醯亞胺 (ES+) 電喷灑游離，正電荷模式 Et 乙基 EtOAc 乙酸乙酯 FCS 胎牛也清 HOBt 1-羥基苯并*** hr 小時 HRP 山葵過氧酵素 HRV 人鼻病毒 i.n· 鼻内 i.p. 腹膜内 JNK c-Jun N-N端激酶 KHMDS 六曱基二矽氮鉀 (M+H)+ 質子化分子 MAPK 有絲***原蛋白活化蛋白質激酶 MDCK Madin-Darby狗腎細胞 Me 曱基 84 201130813 MeOH 曱醇 MHz 兆赫 min 分鐘 MOI 多重感染 MTT 溴化3-(4,5-二曱基唑-2-基)-2,5-二苯基四氮唆 m/z : 質荷比 NMP 1-曱基吡咯啶-2-酮（N-甲基-2-吡咯 π定酮） NMR 核磁共掁（光譜） OD 光學密度 OXONE⑧ 過氧單硫酸鉀 PBS 石粦酸鹽缓衝之食鹽水 Pd2(dba)3 三（二亞苄基丙酮）二鈀(0) PPh3 三苯膦 PyBOP® (苯并***-1-基氧基）°比咯啶基鱗六氟磷酸鹽 q 四重線 RSV ：呼吸道合胞病毒 R-EC5〇：相對EC50 RT 室溫 RP HPLC 逆相rfj效液相層析 s 單重線 sex 固體支撐之陽離子交換(樹脂） SDS t 十二基硫酸鈉二重線 85 201130813 Tn TFA THF TMB TNFa TPCK WB XantPhos 5 0%組織培養感染劑量三氣乙酸四氫吱喃 3,3'，5,5'-四甲基聯苯胺腔瘤壞死因子α L-1-曱苯磺醯胺基-2-苯乙基氣曱基酮洗滌緩衝液 4,5-雙(二苯膦基)_9,9_二甲基二苯并派喃化合物實例給予於實例中之中間物的標籤與在說明的其他部份中所給予之中間物的標籤無關。一般步驟所有起始原料及溶劑係商業來源獲得或根據引用文獻製備。有機溶液通常係經硫酸鎂乾燥。氫化作用係藉Thales Η-立方體流動反應器在所述條件下實施。SCX 係購自Supelco並在使用之前用1M鹽酸處理。除非另有指示，要純化之反應混合物先用MeOH稀釋及用數滴 AcOH使成酸性。將此溶液直接裝入scx並用Me〇H 洗滌。然後所要材料藉由用在Me〇H中之1%NH3洗滌溶析。官柱層析法係在預先裝填矽石（23〇4〇〇目，4〇_63 μΜ)简上使用指示的量實施。製備型逆相高效液相層析 :Agilent Scalar 管柱 86 201130813 C18，5微米（21.2x50毫米），流速28毫升.分鐘-1，用包含0.1%v/v曱酸之H2〇-MeCN梯度溶析10分鐘，使用在215及254奈米之UV檢測。梯度資訊：〇.〇-〇.5分鐘：95%H20-5%MeCN ; 0.5 _7.0分鐘；直線上升方式從 95%H20-5%MeCN 至 5%H20-95%MeCN ; 7.0-7.9 分鐘：固定於5%H20-95%MeCN ; 7.9-8.0分鐘：回到 95%H20-5%MeCN ; 8.0-10.0 分鐘：固定於 95〇/〇H20-5%MeCN。分析方法逆相高效液相層析係藉由下述二種方法之一實施：方法 1 : Agilent Scalar 管柱 C18，5 微米（4.6 X 50 毫米）或 Waters XBridge C18，5 微米（4.6 X 50 毫米），流速 2.5 毫升分鐘_1，用包含〇.1%ν/ν曱酸（方法1酸性）或丽3(方法1鹼性)之H20-MeCN梯度溶析經7分鐘，使用在215及254奈米之UV檢測。梯度資訊：〇.〇-〇.1分鐘，95%H20-5%MeCN ; 0.1-5.0分鐘，直線上升方式從 95%H20-5%MeCN 至 50/〇H20-95%MeCN; 5.0-5.5 分鐘，固定於5%H20-95%MeCN ; 5.5-5.6分鐘，固定於 5%H20-95%MeCN，流速增加至3.5毫升分鐘5.6-6.6 分鐘，固定於5%H20-95%MeCN，流速3.5毫升分鐘-1 ; 6.6-6.75 分鐘，回到 95%H20-5%MeCN，流速 3.5 毫升分鐘-1 ; 6.75-6_9 分鐘，固定於 95%H2〇-5%MeCN，流速 3.5 毫升分鐘1 ; 6.9-7.0分鐘，固定於 95%H20-5%MeCN，流速回到2.5毫升分鐘-1。方法 2 : Agilent Extend C18 管柱，1.8 微米（4.6 X 30 毫米）在40°C下；流速2.5-4.5毫升.分鐘-1，用包含 87 201130813 u.l°/〇v/v曱酸之H20-MeCN梯度溶析4分鐘，使用在254 奈米之UV檢測。梯度資訊：0-3.00分鐘，直線上升方式從 95%H2〇-5%MeCN 至 5%H20-95%MeCN; 3.00-3.01 分鐘’固定於5%H20-95%MeCN，流速增加至4.5毫升分鐘-1 ; 3.01-3.50 分鐘，固定於 5%H2O-950/〇MeCN ; 3.50-3.60 分鐘’回到 95%H2〇-5%MeCN，流速回到 3.50 毫升分鐘 1 ;3.6〇-3.90 分鐘，固定於 950/〇H20-5%MeCN; 3·9〇-4·〇〇分鐘，固定於95%H2〇_5%MeCN，流速回到 2.5毫升分鐘-1。 f NMR 光谱係在 Bruker Avance III 400 MHz 光譜儀上 =施，使用殘餘未氘化溶劑作為内參考標準物。美1物Α: ι·(4_((2_胺基吡啶_4_基）曱氧基）萘小土）- ·(3_第三-丁基-1·對-曱苯基-1Η-吡唾_5_基）脲。[Embodiment] Experimental part abbreviation AcOH aq Ac ATP BALF 9-BBN Boc br BSA CatCart® CCID5〇CDI COPD d DCM DIAD glacial acetic acid aqueous solution acetaminophen nucleus sulphate bronchial alveolar lavage fluid 9-boron bicyclo[ 3.3.1] decane third-butoxycarbonyl yak serum albumin catalytic tube cell culture infection dose 50% U-carbonyl-diimidazole chronic obstructive pulmonary disease double-line dichlorodecane diisopropyl azo Dicaptanate 83 201130813 τ Diisobutylaluminum hydride DIPEA DMEM N, N-Diisopropylethylamine Dulbecco's modified Eagle's medium d-U937 Differentiating U937 cells DMF N,N- Dimercaptosamine DMSO Dioxinium EDAC.HC1 1-Ethyl-3-(3-diamidinopropyl)carbodiimide (ES+) Electrospray free, positive charge mode Et Ethyl EtOAc Ethyl acetate FCS fetal bovine clear HOBt 1-hydroxybenzotriazole hr hour HRP wasabi peroxidase HRV human rhinovirus in · intranasal ip intraperitoneal JNK c-Jun NN-terminal kinase KHMDS hexamethylene diamine potassium (M+H)+ protonated molecule MAPK mitogen activity Protein kinase MDCK Madin-Darby dog kidney cell Me thiol 84 201130813 MeOH sterol MHz megaher min min MOI multiple infection MTT bromination 3-(4,5-diamidazol-2-yl)-2,5-diphenyl Tetrakisperidine m/z : mass-to-charge ratio NMP 1-decylpyrrolidin-2-one (N-methyl-2-pyrrole π-decanone) NMR nuclear magnetic resonance (spectrum) OD optical density OXONE8 peroxymonosulfuric acid Potassium PBS, sulphate buffered saline Pd2 (dba) 3 tris(dibenzylideneacetone) dipalladium (0) PPh3 triphenylphosphine PyBOP® (benzotriazol-1-yloxy) ° ratio Iridyl squamous hexafluorophosphate q quartet RSV: respiratory syncytial virus R-EC5〇: relative EC50 RT room temperature RP HPLC reverse phase rfj liquid chromatography s single line sex solid support cation exchange (resin) SDS t Sodium dodecyl sulfate double line 85 201130813 Tn TFA THF TMB TNFa TPCK WB XantPhos 5 0% tissue culture Infected dose Tris, tetrahydrofurfuryl acetate, 3,3',5,5'-tetramethylbenzidine Tumor necrosis factor α L-1-曱 benzenesulfonylamino-2-phenylethyl sulfhydryl ketone washing buffer 4,5-bis(diphenylphosphino)_9,9-dimethyldibenzophenan Chemical Examples of the tag label was given examples of the intermediate portion at the other parts of the description given regardless of intermediates. General Procedures All starting materials and solvents are obtained from commercial sources or prepared according to the cited literature. The organic solution is usually dried over magnesium sulfate. Hydrogenation was carried out under the conditions described above using a Thales(R)-cube flow reactor. SCX was purchased from Supelco and treated with 1 M hydrochloric acid prior to use. The reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH unless otherwise indicated. This solution was directly loaded into scx and washed with Me〇H. The desired material was then eluted by washing with 1% NH3 in Me〇H. The column chromatography method was carried out using pre-filled vermiculite (23〇4〇〇目, 4〇_63 μΜ) using the indicated amount. Preparative reverse phase high performance liquid chromatography: Agilent Scalar column 86 201130813 C18, 5 micron (21.2 x 50 mm), flow rate 28 ml. min.-1, gradient elution with H2 〇-MeCN containing 0.1% v/v citric acid For 10 minutes, UV detection at 215 and 254 nm was used. Gradient information: 〇.〇-〇.5 min: 95% H20-5% MeCN; 0.5 _7.0 min; straight rise from 95% H20-5% MeCN to 5% H20-95% MeCN; 7.0-7.9 min : fixed at 5% H20-95% MeCN; 7.9-8.0 minutes: returned to 95% H20-5% MeCN; 8.0-10.0 minutes: fixed at 95 〇 / 〇 H20 - 5% MeCN. Analytical methods Reverse phase high performance liquid chromatography is performed by one of two methods: Method 1: Agilent Scalar column C18, 5 micron (4.6 X 50 mm) or Waters XBridge C18, 5 micron (4.6 X 50 mm) ), flow rate 2.5 ml min _1, eluted with H20-MeCN gradient containing 〇.1% ν/ν 曱 acid (method 1 acid) or 丽 3 (method 1 basic) for 7 minutes, used at 215 and 254 Nano UV detection. Gradient information: 〇.〇-〇. 1 minute, 95% H20-5% MeCN; 0.1-5.0 minutes, straight rise from 95% H20-5%MeCN to 50/〇H20-95%MeCN; 5.0-5.5 minutes , fixed at 5% H20-95% MeCN; 5.5-5.6 minutes, fixed at 5% H20-95% MeCN, flow rate increased to 3.5 ml minutes 5.6-6.6 minutes, fixed at 5% H20-95% MeCN, flow rate 3.5 ml Minute-1; 6.6-6.75 minutes, return to 95% H20-5% MeCN, flow rate 3.5 ml min-1; 6.75-6_9 min, fixed at 95% H2〇-5%MeCN, flow rate 3.5 ml min 1 ; 6.9- At 7.0 minutes, fixed at 95% H20-5% MeCN, the flow rate returned to 2.5 ml min-1. Method 2: Agilent Extend C18 column, 1.8 micron (4.6 x 30 mm) at 40 ° C; flow rate 2.5-4.5 ml. min-1, with H20-MeCN containing 87 201130813 ul°/〇v/v citric acid The solution was analyzed by gradient for 4 minutes using UV detection at 254 nm. Gradient information: 0-3.00 minutes, straight rise from 95% H2 〇-5% MeCN to 5% H20-95% MeCN; 3.00-3.01 minutes 'fixed to 5% H20-95% MeCN, flow rate increased to 4.5 ml minutes -1 ; 3.01-3.50 min, fixed at 5% H2O-950/〇MeCN; 3.50-3.60 min 'back to 95% H2〇-5% MeCN, flow rate back to 3.50 ml min 1 ; 3.6〇-3.90 min, fixed At 950/〇H20-5%MeCN; 3·9〇-4·〇〇 minutes, fixed at 95% H2〇_5%MeCN, the flow rate returned to 2.5 ml min-1. The f NMR spectrum was applied on a Bruker Avance III 400 MHz spectrometer using residual undeuterated solvent as an internal reference standard. 11 substance: ι·(4_((2_Aminopyridin-4-yl)methoxy)naphthalene small earth)-·(3_T-butyl-1·p-indolephenyl-1Η- Pyridinium-5-yl)urea.

中間物A 將DIAD(8.07毫升，41.0毫莫耳)在_15〇(：下逐滴 4确基萘小醇⑽5.17克，27·3毫莫耳）、PPh3(10.75 88 201130813 克’ 41.0毫莫耳)及2-胺基吡啶_4-甲醇⑴(5.09克，41.0 毫莫耳)在THF(50毫升）中的溶液。將混合物在RT下攪拌過夜及在真空中除去揮發物。將粗製產物從Intermediate A will DIAD (8.07 ml, 41.0 mmol) at _15 〇 (: drop 4 quinone naphthalene small alcohol (10) 5.17 g, 27. 3 mmol), PPh3 (10.75 88 201130813 g ' 41.0 Milliol) and 2-aminopyridine- 4-methanol (1) (5.09 g, 41.0 mmol) in THF (50 mL). The mixture was stirred at RT overnight and the volatiles were removed in vacuo. The crude product from

EtOAc(150毫升）磨碎及藉由過濾收集並用Et〇Ac(100 毫升)洗滌。從MeOH(100毫升）第二次研磨產生呈黃色固體之2-胺基-4-((4-硝基萘基氧基）曱基）D比咬 (3)(4.54 克，56%) : m/z 296 (M+H)+ (ES+)。將(3)(4.50 克，15.24 毫莫耳)在]y[eOH (200 毫升）及AcOH (200毫升）的混合物中之溶液通過Thales H-立方體(2.0 毫升.分鐘·】，4〇°C，55 毫米 i〇〇/〇Pt/CCat-Cart，全氫模式）及在真空中除去揮發物。使粗製產物進行 SCX捕捉和釋放，用1〇/〇NH3之在MeOHe中溶液溶析並在真空中除去溶劑以產生呈紫色固體之2_胺基-4-((4-胺基萘-1_基氧基）曱基)吼啶（4)(3.82克，94%) : m/z 266 (M+H)+ (ES+)。經40分鐘在氮氣下將3-第三-丁基-i_對-曱苯基 -1H-吡唑-5-胺(5)(WO 200/0043384)(5.91 克，25.8 毫莫耳)在DCM中的溶液(15毫升)逐滴加至CDI (4.18克， 25.8毫莫耳)在DCM(15毫升）中的溶液。將所得溶液在 RT下攪拌1小時’然後在氮氣下逐滴加至2_胺基_4_((4_ 胺基萘-1-基氧基）曱基)。比啶(4)(3.80克，12.9毫莫耳)的溶液。將混合物攪拌過夜並在真空中除去揮發物。藉由管柱層析法純化粗製產物（120克）；用在DCM中之〇至6%MeOH溶析以產生呈灰白色固體之標題化合物，中間物 A (4.27 克，63%) : m/z 521 (M+H)+ (ES+)。實例1 : Ν-(4·((4·(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑 89 201130813 基)脲基)萘-1-基氧基）甲基)吼〇定_2_基)_2_甲氧基乙酿胺：The mixture was triturated with EtOAc (EtOAc)EtOAc. A second milling from MeOH (100 mL) gave 2-amino-4-((4-nitronaphthyloxy)fluorenyl)D as a yellow solid to a bit (3) (4.54 g, 56%): m/z 296 (M+H)+ (ES+). A solution of (3) (4.50 g, 15.24 mmol) in a mixture of y[eOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cucumber (2.0 ml. min.), 4 〇 ° C , 55 mm i〇〇/〇Pt/CCat-Cart, full hydrogen mode) and remove volatiles in vacuo. The crude product was subjected to SCX capture and liberation, eluted with 1 〇 / 〇 NH3 in MeOHe and solvent was removed in vacuo to yield 2-amino-4-(4-aminonaphthalene-1) as a purple solid. _ yloxy) fluorenyl) acridine (4) (3.82 g, 94%): m/z 266 (M+H) + (ES+). 3-Terti-butyl-i-p-p-phenyl-1H-pyrazole-5-amine (5) (WO 200/0043384) (5.91 g, 25.8 mmol) under nitrogen over 40 min The solution in DCM (15 mL) was added dropwise to a solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL). The resulting solution was stirred at RT for 1 hour' and then added dropwise to 2-amino-4-((4-aminonaphthalen-1-yloxy)indenyl) under nitrogen. A solution of pyridine (4) (3.80 g, 12.9 mmol). The mixture was stirred overnight and the volatiles were removed in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc: 521 (M+H)+ (ES+). Example 1: Ν-(4·((4·(3-(3-Terti-butyl-1-p-indolephenyl-1H-.bazole 89 201130813))ureido)naphthalen-1-yloxy Base) methyl) _2_2_yl)_2_methoxy ethoxylated amine:

將曱氧基乙醯氯(92微升，i.oi毫莫耳)加至中間物 A(526毫克’ 0.96毫莫耳)及〇ΙΡΕΑ(184微升，ι.〇6毫莫耳)在DCM/DMF(10 : 1，11毫升）中的混合物。在RT 下攪拌卜〗、時之後，隨後添加另DIPEA(184微升，丨〇6 毫莫耳)及曱氧基乙醯氣(92微升，1.01毫莫耳)並繼續攪拌1小時。添加10/〇ΝΗ3在MeOH中的溶液(4〇毫升) 之後，將混合物攪拌15分鐘並在真空中蒸發。藉由管柱層析法純化粗製產物(40克）；用在DCM中之〇至 6Q/〇Me〇H溶析以提供呈白色固體之標題化合物，實例 1(286 毫克，49%) :m/z 593 (M+H)+(ES+) ^HNMR (400 MHz, DMSO-d6) δ ： 1.27 (9 H, s), 2.39 (3 H, s), 3.32 (3 Η, s), 4.08 (2H, s), 5.39 (2H, s)5 6.36 (1H, s), 7.03 (1H, d), 7.28 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, 7.93 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.79 (1H，s)，10.02 (1H，s)。實例2 :甲基4_((4-(3_(3_第三-丁基小對·甲苯基_旧_吡 °坐-5-基)脲基)萘基氧基）甲基)吼啶_2_基脲： 201130813Add methoxyethyl chloroform (92 μl, i. oi millimolar) to Intermediate A (526 mg '0.96 mmol) and 〇ΙΡΕΑ (184 μL, ι.〇6 mmol) at Mixture in DCM/DMF (10: 1, 11 mL). After stirring at RT, additional DIPEA (184 μl, 丨〇6 mmol) and methoxy acetamidine (92 μL, 1.01 mmol) were added and stirring was continued for 1 hour. After addition of a 10/3 solution in MeOH (4 mL), the mixture was stirred 15 min and evaporated in vacuo. The crude product was purified by column chromatography eluting elut elut elut elut elut elut elut eluting /z 593 (M+H)+(ES+) ^HNMR (400 MHz, DMSO-d6) δ : 1.27 (9 H, s), 2.39 (3 H, s), 3.32 (3 Η, s), 4.08 ( 2H, s), 5.39 (2H, s)5 6.36 (1H, s), 7.03 (1H, d), 7.28 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, 7.93 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.02 (1H, s). Example 2: Methyl 4_((4- (3_(3_Third-butyl small p-tolyl_old_pyridyl-5-yl))ureido)naphthyloxy)methyl)acridine_2_ylurea: 201130813

MeNCOMeNCO

中間物AIntermediate A

NHMe 將異氰酸甲酯（14微升，0.24毫莫耳)加至中間物 A(70毫克，0.13毫莫耳)在無水吼啶(1.5毫升）中的溶液及使混合物在RT下攪拌72小時。在真空中除去吡啶及將殘餘物與DCM(3.0毫升）一起研磨。過濾提供呈白色粉末之標題化合物，實例2(36毫克，45 %) : m/z 578 (M+H)+ (ES+)° !Η NMR (400 MHz, DMSO-d6) δ： 1.27 (9H, s), 2.39 (3H, s), 2.74 (3H, d), 5.30 (2H, s), 6.36 (1H, s), 6.99 (1H, d), 7.05 (d, 1H), 7.35, (2H, d), 7.44 (2H, d), 7.54-7.64 (4H, m), 7.93 (1H, d), 8.19 (1H, d), 8.23 (1H, brs)，8.35 (1H，d), 8.58 (1H，s), 8.79 (1H，s)，9.36 (1H, s)。實例3 : N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑 -5-基)腺基）奈-1-基氧基）曱基）α比π定-2-基）四氮-2H-aj^0南 -4-曱醯胺NHMe A solution of methyl isocyanate (14 μL, 0.24 mmol) was added to a solution of Intermediate A (70 mg, 0.13 mmol) in anhydrous aq. (1.5 mL) and the mixture was stirred at RT 72 hour. The pyridine was removed in vacuo and the residue was crystallised eluted with DCM Filtration afforded the title compound as a white powder, mp. (2, 36 mg, 45%): m/z 578 (M+H) + (ES+) ° Η NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.74 (3H, d), 5.30 (2H, s), 6.36 (1H, s), 6.99 (1H, d), 7.05 (d, 1H), 7.35, (2H, d), 7.44 (2H, d), 7.54-7.64 (4H, m), 7.93 (1H, d), 8.19 (1H, d), 8.23 (1H, brs), 8.35 (1H, d), 8.58 (1H , s), 8.79 (1H, s), 9.36 (1H, s). Example 3: N-(4-((4-(3-(3-Terve-butyl-1-p-phenyl)-1H-pyrazol-5-yl)))-N-yloxy Base) sulfhydryl) alpha ratio π-but-2-yl) tetranitro-2H-aj^0-nan-4-decylamine

中間物AIntermediate A

(C〇CI)2, DIVIF, DIPEA(C〇CI) 2, DIVIF, DIPEA

將純DMF(2滴）加至四氫哌喃-2H-4-曱酸及草醯氣 91 201130813 (21微升，0.25毫莫耳)在DCM(1〇毫升）中的攪拌溶液且將所得溶液在RT下攪拌丨小時。在真空中蒸發溶液以產生無色油，將其溶解於DCM(1.0毫升）中並逐滴加至中間物A(50毫克，〇.1〇毫莫耳)及DIpEA(84微升，〇·5〇毫莫耳)在DCM(1.0毫升）中的攪拌混合物。繼續攪拌18小時。將反應混合物在Me〇H中之1〇/〇NH3(2〇毫升）中授拌30分鐘，在真空中蒸發，預吸附在矽石上，及藉由管柱層析法純化（12克，在DCM中之 0-5%Me〇H ’梯度溶析）以產生呈淺棕色固體之標題化合物，實例 3(18 毫克，28%) : m/z 633 (M+H)+ (ES+)。 NMR (400 MHz, DMSO-d6) δ： 1.26 (9H, s), 1.57-1.72 (4H, m)，2.38 (3H, s), 2.75 (1H, m), 3.28-3.33 (2H, m), 3.88 (2H，m)，5.35 (2H, s), 6.34 (1H, s), 6.99 (1H, d), 7.24 (1H, dd), 7.35 (2H, m), 7.43 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.27-8.33 (3H, m), 8.58 (1H, s), 8.78 (1H, s)，10.50 (1H, s)。實例 4: (S)-N-(4-((4-(3-(3-第三-丁基-1_對-甲苯基-1H-吼唑-5-基)脲基）萘-1-基氧基）甲基)咐•啶基)-2-曱氧基丙酿胺：Add pure DMF (2 drops) to a stirred solution of tetrahydropyran-2H-4-decanoic acid and oxalate 91 201130813 (21 μl, 0.25 mmol) in DCM (1 mL) and The solution was stirred at RT for a few hours. The solution was evaporated in vacuo to give a colorless oil which was dissolved in DCM (1. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Stir the mixture in DCM (1.0 mL). Continue stirring for 18 hours. The reaction mixture was stirred in 1 〇 / 〇 NH3 (2 mL) in Me〇H for 30 min, evaporated in vacuo, pre-adsorbed on vermicite, and purified by column chromatography (12 g, in The title compound was obtained as a light brown solid, m.p. </ s (M+H) + (ES+). NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 1.57-1.72 (4H, m), 2.38 (3H, s), 2.75 (1H, m), 3.28-3.33 (2H, m), 3.88 (2H, m), 5.35 (2H, s), 6.34 (1H, s), 6.99 (1H, d), 7.24 (1H, dd), 7.35 (2H, m), 7.43 (2H, m), 7.55 -7.64 (3H, m), 7.92 (1H, m), 8.27-8.33 (3H, m), 8.58 (1H, s), 8.78 (1H, s), 10.50 (1H, s). Example 4: (S)-N-(4-((4-(3-(3-Terti-butyl-1)-p-tolyl-1H-indazol-5-yl)ureido)naphthalene-1 -yloxy)methyl)indolyl)-2-decyloxypropanol:

將1-氣-N，N-二曱基乙烯胺(50微升，0.48毫莫耳) 加至(S)-2-曱氧基丙酸(50毫克，0.48毫莫耳)在DCM(1.0 92 201130813 毫升）中的攪拌溶液且將所得黃色溶液在RT下攪拌i小時。將溶液逐滴加至中間物A(5〇毫克，0 10毫莫耳) 及DIPEA(167微升’ 0.96毫莫耳)在DCM(1.0毫升）中的攪拌混合物。繼續攪拌過夜。將反應混合物在Me〇H 中之1%NH3(20毫升）中攪拌，在真空中蒸發，預吸附矽石上及藉由管柱層析法純化（12克，在異己烷中之 10-50%EtOAc ’梯度溶析）以產生呈無色固體之標題化合物，實例 4(18 毫克，3〇%) : m/z 6〇7 (M+H)+ (Es+)。 NMR (400 MHz, DMSO-d6) δ : 1.27 (9H, d)，1.31 (3H， s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.37 (1H，s)，7.00 (1H，d)，7.29 (1H，dd)，7.35 (2H，m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 (3H，m)，8.58 (1H, s)，8.79 (1H，s)，10.06 (1H，s)。貫例5 :⑻-Ν-(4-((4-(3·(3-第三-丁基_1_對-曱苯基_1H_ °比唑-5-基)脲基）萘_ι_基氧基）甲基)β比啶·2_基)_2_曱氧基丙酿胺：Add 1-S-N,N-dimercaptoetheneamine (50 μL, 0.48 mmol) to (S)-2-methoxypropionic acid (50 mg, 0.48 mmol) in DCM (1.0 The solution was stirred in 92 2011 308 13 ml) and the resulting yellow solution was stirred at RT for 1 hour. The solution was added dropwise to a stirred mixture of intermediate A (5 mg, 0 10 mmol) and DIPEA (167 </ RTI> </ RTI> <RTIgt; Continue stirring overnight. The reaction mixture was stirred in 1% NH3 (20 mL) EtOAc (EtOAc)EtOAc. EtOAc <RTI ID=0.0>>>>>>>> NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, d), 1.31 (3H, s), 2.38 (3H, s), 3.30 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.37 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H , m), 8.30-8.37 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.06 (1H, s). Example 5: (8)-Ν-(4-((4-(3·(3-Tern-Butyl-1)-p-phenyl)-H-[rho]-pyridin-5-yl)ureido)naphthalene_ _ yloxy)methyl)β-pyridyl-2-yl)_2_decyloxypropanol:

將1-氯-Ν，Ν-二甲基乙稀胺(38微升，〇 36毫莫耳) 加至W-2-甲氧基丙酸(37亳克，〇 %毫莫耳)在dcm(i 〇毫升）中的_溶液並將所得溶液在RT下麟小時。將溶液逐滴加至中間物A(75毫克，〇14毫莫耳）及 DIPEA(75微升，(M3毫莫耳)在DCM(2 〇毫升）中在〇〇c 93 201130813 下的攪拌混合物。繼續攪拌另48小時。將混合物倒進在MeOH中之1%NH3(20毫升)並攪拌經1小時，並在真空中蒸發以產生黃色殘餘物。管柱層析法(12克，在異己烷中之20-50%EtOAc)產生呈淺粉紅色固體之標題化合物，實例 5(39 毫克，43%): m/z 607 (M+H)+ (ES+)。 NMR (400 MHz, DMSO-d6) δ : 1.27 (9H，d)，1.30 (3H s)，2.39 (3H，s)，3.31 (3H，s)，4.02 (1H，q)，5.39 (2H，s)， 6.35 (1H，s), 7.02 (1H，d)，7.29 (1H，dd)，7.35 (2H，m)， 7.45 (2H，m), 7.56-7.64 (3H, m)，7.93 (1H，m)，8.30-8.37 (3H，m), 8.58 (1H，s), 8.79 (1H，s)，10.09 (1H，s)。貫例6 : N-(4-((4-(3-(3-第三-丁基-1-對—甲苯基比嗤基)脲基）萘-1-基氧基）曱基)〇比啶-2-基)-2-(甲續醯基) 乙酿胺：Add 1-chloro-indole, hydrazine-dimethylethylene amine (38 μl, 〇36 mmol) to W-2-methoxypropionic acid (37 gram, 〇% mmol) in dcm _ solution in (i 〇 ml) and the resulting solution was hr at RT. The solution was added dropwise to a stirred mixture of Intermediate A (75 mg, 〇 14 mmol) and DIPEA (75 μL, (M3 mmol) in DCM (2 mL) 〇〇c 93 201130813 Stirring was continued for another 48 hours. The mixture was poured into 1% NH3 (20 mL) in MeOH and stirred for 1 hour and evaporated in vacuo to give a yellow residue. The title compound was obtained as a light pink solid, m.p. (m.sup. D6) δ : 1.27 (9H, d), 1.30 (3H s), 2.39 (3H, s), 3.31 (3H, s), 4.02 (1H, q), 5.39 (2H, s), 6.35 (1H, s ), 7.02 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.45 (2H, m), 7.56-7.64 (3H, m), 7.93 (1H, m), 8.30-8.37 ( 3H,m), 8.58 (1H, s), 8.79 (1H, s), 10.09 (1H, s). Example 6: N-(4-((4-(3-(3-T-butyl) -1-p-tolylpyrimidyl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(methyl hydrazino)

將DMF(1滴）加至甲烧磺醯基乙酸(4〇毫克，〇 29 毫莫耳)及草醯氣(29微升，0.34毫莫耳)在DCM(l.〇毫升）甲的授拌懸浮液令並將反應混合物在RT下撥拌1小時。將溶液逐滴加至中間物A(50毫克，〇 1〇毫莫耳）及 DIPEA(167 微升，1.0 毫莫耳)在 DCM/DMF(10 :1 v/v， l.i毫升）中的攪拌混合物並繼續攪拌18小時。將反應混合物與在MeOH中之1%NH3(2.0毫升）一起攪拌並在 94 201130813 真空中蒸發。利用sex將殘餘物進行捕捉和釋放以提供呈淡黃色固體之標題化合物，實例6(11毫克，18%): m/z 641 (M+H)+ (ES+) 〇1H NMR (400M Hz, DMSO-d6) δ ： 1.27 (9H, s), 2.39 (3H, s), 3.17 (3H, s), 4.44 (2H, s), 5.40 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.33 (1H, dd), 7.36 (2H, m)，7.44 (2H，m)，7.56-7.64 (3H，重疊 m)，7.93 8.30-8.33 (2H,重疊 m)，8.39 (1H, dd), 8.59 (1H, br s)， 8.79 (1H，br s)，10.98 (lH，brs)。 ’ 實例7 : N-(4-((4-(3_(3-第三丁基對-曱苯基_1H_e比嗤 -5-基）脲基）萘-1-基氧基）曱基）D比。定_2_基）_2_羥基乙酿胺：Add DMF (1 drop) to a sulfonyl thioglycolic acid (4 〇 mg, 〇 29 mM) and grass 醯 (29 μl, 0.34 mM) in DCM (l. The suspension was mixed and the reaction mixture was stirred at RT for 1 hour. The solution was added dropwise to Intermediate A (50 mg, 1 Torr) and DIPEA (167 μL, 1.0 mmol) in DCM/DMF (10:1 v/v, li mL). The mixture was stirred for a further 18 hours. The reaction mixture was stirred with 1% aq. EtOAc (EtOAc)EtOAc. The residue was taken up and purified to give the title compound as a pale yellow solid, Example 6 (11 mg, 18%): m/z 641 (M+H)+ (ES+) 〇1H NMR (400M Hz, DMSO -d6) δ : 1.27 (9H, s), 2.39 (3H, s), 3.17 (3H, s), 4.44 (2H, s), 5.40 (2H, s), 6.35 (1H, s), 7.02 (1H , d), 7.33 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlap m), 7.93 8.30-8.33 (2H, overlap m), 8.39 (1H, Dd), 8.59 (1H, br s), 8.79 (1H, br s), 10.98 (lH, brs). Example 7: N-(4-((4-(3_(3-tert-butyl-p-phenyl)H_e-pyridin-5-yl)ureido)naphthalen-1-yloxy)indolyl) D ratio: fixed _2_ base)_2_hydroxyethylamine:

將乙醯氧基乙酸氣（39微升，0.36毫莫耳）在 DCM(0.25毫升）中的溶液加至中間物a(75毫克，0.14 毫莫耳)及DIPEA(125微升，0.72毫莫耳)在DCM中/ DMF(l〇 : 1 v/v，1.1〇毫升）的溶液。將反應混合物在 RT下攪拌2小時且然後添加在MeOH中之1%NH3(3.0 毫升)並繼續攪拌18小時。將反應混合物在真空中蒸發及藉由急驟管柱層析法純化殘餘物(Si〇2，π克，在異己烷中之30-100o/〇EtOAc’梯度溶析）以提供呈淡橙色固體之標題化合物，實例7(24毫克，28%):m/z 579 (M+H)+ 95 201130813 (ES+) 〇 NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2.39 (3H, s), 4.06 (2H, d), 5.39 (2H, s), 5.77 (1H, t), 6.35 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.36 (2H, m), 7.44 (2H，m)，7.56-7.64 (3H，重疊 m), 7.93 (1H，m)，8.32 (1H, m) 8.34 (1H, d), 8.36 (1H, br s), 8.60 (1H, br s), 8.81 (1H, br s)，9.75 (1H，br s)。貫例8 . N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基比〇坐基)脲基）萘_1_基氧基）曱基)B比啶_2_基)_2-曱基·2_(甲胺基）丙醯胺：A solution of acetoxyacetic acid gas (39 μl, 0.36 mmol) in DCM (0.25 mL) was added to intermediate a (75 mg, 0.14 mmol) and DIPEA (125 μL, 0.72 mmol) Ear) A solution in DCM / DMF (l〇: 1 v/v, 1.1 〇 ml). The reaction mixture was stirred at RT for 2 h then EtOAc (EtOAc &lt The reaction mixture was evaporated in EtOAc (EtOAc m.) The title compound, Example 7 (24 mg, 28%): m/z 579 (M+H) + 95 201130813 (ES+) NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H , s), 4.06 (2H, d), 5.39 (2H, s), 5.77 (1H, t), 6.35 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H, overlap m), 7.93 (1H, m), 8.32 (1H, m) 8.34 (1H, d), 8.36 (1H, br s), 8.60 ( 1H, br s), 8.81 (1H, br s), 9.75 (1H, br s). Example 8. N-(4-((4-(3-(3-Terve-butyl-1-p-tolyl)-yl)-ureido)naphthalen-1-yloxy)indolyl) B:pyridin-2-yl)_2-mercapto-2-(methylamino)propanamide:

將1-氣-Ν，Ν，2-三曱基丙烯·n(95微升，〇 72 毫莫耳)加至2-(第三-丁氧羰基（甲基)胺基)_2•曱基丙酸 (125毫克’〇.58毫莫耳)在DCM(2 〇毫升）中的擾摔懸浮液並將見合物在RT下攪拌2小時。然後將反應混合物加至:間物A(75毫克’〇 14毫莫耳)及⑽(⑼微升， 0.58毫莫耳)在DCM(1 〇毫升忡的溶液並攪拌小時。 96 201130813 =，在Me〇H中的溶液(7M，！毫升)且將混合物在真 =洛發。藉由管柱層析法將殘餘物純化二次(si〇2， ^，在異己烧令之0-100%Et〇Ac，梯度溶析）以提供呈灰白色固體之^4-((4-(3-(3-第三-丁基]_對_甲祕基）脲基）萘小基氧基）甲基）__2_基二基）-2-曱基_1_侧氧基丙_2_基（曱基）胺甲酸第三-丁酯 ⑹(3〇毫克 ’ 28〇/〇) : m/z 62〇 ((M-Boc)+H)+ (ES+)。將胺曱酸酯（6)(25毫克，〇.〇4亳莫耳）在DCM/ TFA(1 : i v/v，2.0毫升）中的溶液在RT下攪拌3〇分鐘。將反應混合物在真空中蒸發及將所得殘餘物進行s c χ 捕捉和釋放以提供呈淺椋色固體之標題化合物，實例 8(20 毫克，89%) : m/z 620 (M+H疒（ES+)。1h°nmr (働 MHz, DMSO-d6) δ： 1.25 (6Η, s), 1.27 (9HS s), 2.2〇 (3H, s), 2.39 (3H，s)，5.38 (2H，s)，6.35 (1H，s)，7.00 (1H，d)，乂27’ (1H，dd)，7.36 (2H，m)，7.44 (2H，m)，7.58,7 62’(3H，重疊 m)，7.93 (lH，m)，8.29-8.34 (3H，重疊 m)，8 59 |1H， br s)，8.79 (1H，br s)。 ’ ’ 實例9 : (S)-N-(4-((4-(3-(3•第三-丁基七對·甲苯基旧-π比0坐-5-基）脲基）萘-1-基氧基）曱基）》比。定_2·基)_2_(甲胺基）丙醯胺： 97 201130813Add 1-qi-indole, hydrazine, 2-trimercaptopropene·n (95 μL, 〇72 mmol) to 2-(T-butoxycarbonyl(methyl)amino)_2• fluorenyl Dispersion suspension of propionic acid (125 mg '〇.58 mmol) in DCM (2 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was then added to: Interstitial A (75 mg '〇 14 mmol) and (10) ((9) μL, 0.58 mmol) in DCM (1 mL 忡 solution and stirred for a few hours. 96 201130813 =, in The solution in Me〇H (7M, ! ml) and the mixture was in true = Luofa. The residue was purified twice by column chromatography (si〇2, ^, 0-100% in iso-burning order) Et〇Ac, gradient elution) to provide 4-((4-(3-(3-tert-butyl)-p-methyl)-ureido)-naphthalenyloxy)) as an off-white solid Base) __2_yldiyl)-2-mercapto_1_1-oxypropan-2-yl (indenyl) carbamic acid tert-butyl ester (6) (3 〇 mg ' 28 〇 / 〇) : m / z 62〇((M-Boc)+H)+ (ES+). A solution of the amine decanoate (6) (25 mg, 〇. 〇 4 亳 Mo) in DCM / TFA (1: i v / v, 2.0 mL) was stirred at RT for 3 min. The reaction mixture was evaporated in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; 1h°nmr (働MHz, DMSO-d6) δ: 1.25 (6Η, s), 1.27 (9HS s), 2.2〇(3H, s), 2.39 (3H, s), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 乂 27' (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58, 7 62' (3H, overlap m), 7.93 (lH,m), 8.29-8.34 (3H, overlap m), 8 59 |1H, br s), 8.79 (1H, br s). ' ' Example 9 : (S)-N-(4-((4-(3-(3•T-butyl-7-p-tolyl-o-π-0--5-yl)))-naphthalene-naphthalene- 1-yloxy)indolyl)". _2.yl)_2_(methylamino)propanamide: 97 201130813

將中間物A(75毫克，0.14毫莫耳）一次性加至 N-Boc-曱基-L·丙胺酸（117毫克，0.58毫莫耳）、 PyBOP®(30〇毫克，〇·58 毫莫耳)及 DIPEA(101 微升， 0.58毫莫耳)在DMF(2.0毫升）中的攪拌懸浮液。將反應混合物加熱至55。0並攪拌18小時並冷卻至RT及分溶在水(10毫升)和EtOAc(10毫升)之間。將有機層分離並在真空中蒸發且藉由急驟管枉層析法純化殘餘物 (SKV 12克’在異己烷中之〇_1〇〇%EtOAc，梯度溶析）。將所得不純產物以SCX捕捉和釋放純化以提供呈棕色固體之1-(4-((4-(3-(3-第三，丁基對-曱笨基-1H_吡唑 -5-基)脲基)萘_ι_基氧基）曱基)π比啶_2·基胺基)小側氧基丙基（甲基)胺甲酸(s)-第三·丁酯（7)(25毫克，23%): m/z 706 (M+H)+ (ES+)。將胺曱酸酯（7)(25亳克，0.04毫莫耳）在 DCM/TFA(1 : 1 v/v ’ 2.0亳升）中的溶液在rT下攪拌 98 201130813 分鐘。將反應混合物在真空中蒸發及將所得殘餘物進行 SCX捕捉和釋放且然後藉由急驟管柱層析法纟屯化 (Si02 ’ 4 克，在 MeOH 中之〇-l〇〇%EtOAc，梯度溶析) 以提供呈淡白色固體之標題化合物（實例9)(13毫克， 57%) : m/z 606 (M+H)+ (ES+)。巾 NMR (400 MHz DMSO-d6) δ： 1.20 (3Η, d), 1.27 (9H, s), 2.26 (3H, s), 2.39 (3H，s)，3.20 (1H, q), 5.38 (2H，s), 6.35 (1H, s)，7.01 (1H， d)，7.28 (1H, dd), 7.36 (2H，m)，7.44 (2H，m)，7.55-7.63’ (3H，重疊 m)，7.93 (iH，m)，8.31 (lH，m)，8.34 (lH，dd) 8.36 (1H，br s)，8.60 (1H，s)，8.80 (1H，s)。 ’ λ 例 10 . (R)-N-(4-((4-(3-(3-第三-丁基-1-對·甲苯基_旧_ °比嗤-5-基)脲基）萘-1-基氧基）曱基)π比。定_2·基)嗎琳甲醯胺：Intermediate A (75 mg, 0.14 mmol) was added in one portion to N-Boc-mercapto-L-alanine (117 mg, 0.58 mmol), PyBOP® (30 mg, 〇·58 mmol) Ear) and a stirred suspension of DIPEA (101 μl, 0.58 mmol) in DMF (2.0 mL). The reaction mixture was heated to EtOAc (3 mL). The organic layer was separated and evaporated in vacuo tolulululululululululululululululu The resulting impure product was purified by SCX capture and release to provide 1-(4-(3-(3-(3-)-butyl-p-phenyl]-1H-pyrazol-5-yl as a brown solid. Urea))naphthalene_ι_yloxy)fluorenyl)π-pyridyl-2.ylamino)sodiumoxypropyl(methyl)aminecarboxylic acid(s)-t-butyl ester (7) 25 mg, 23%): m/z 706 (M+H)+ (ES+). A solution of the amine phthalate (7) (25 gram, 0.04 mmol) in DCM/TFA (1 : 1 v/v </ </ RTI> 2.0 liters) was stirred at rT for 98, 2011, 318, 13 minutes. The reaction mixture was evaporated in vacuo and the residue obtained was taken and taken and taken and then evaporated and then then purified by flash column chromatography (Si02 ' 4 g, EtOAc - EtOAc The title compound (Example 9) (13 mg, 57%): m/z 606 (M+H)+ (ES+). NMR (400 MHz DMSO-d6) δ: 1.20 (3Η, d), 1.27 (9H, s), 2.26 (3H, s), 2.39 (3H, s), 3.20 (1H, q), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63' (3H, overlap m), 7.93 (iH,m), 8.31 (lH,m), 8.34 (lH,dd) 8.36 (1H, br s), 8.60 (1H, s), 8.80 (1H, s). ' λ Example 10. (R)-N-(4-((4-(3-(3-Terve-butyl-1-p-tolyl_old_°~-5-yl)ureido) Naphthalen-1-yloxy)indenyl)π ratio.

將中間物A(75毫克，0.14毫莫耳）一次性加至(R)_ 嗎啉-3,4-二甲酸_4_第三-丁酯（133毫克，0.58毫莫耳）、 99 201130813Intermediate A (75 mg, 0.14 mmol) was added in one portion to (R)-morpholine-3,4-dicarboxylic acid _4_tri-butyl ester (133 mg, 0.58 mmol), 99 201130813

PyBOP® (300 毫克，0.58 毫莫耳)及 DIPEA(101 微升， 0.58毫莫耳)在DMF(2.0毫升）中的攪拌懸浮液。將反應混合物加熱至55〇C並攪拌18小時。將反應混合物冷卻至RT且分溶在水（1〇毫升)和Et〇Ac(10毫升)之間。將有機萃取物在真空中蒸發並藉由急驟管柱層析法純化殘餘物（Si〇2 ’ 12克’在異己炫中之〇_i〇〇〇/〇Et〇Ac，梯度溶析）以提供不純產物，其進一步藉由scx捕捉和釋放純化以產生呈棕色固體之3-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基)脲基）萘]-基氧基）甲基）α比啶 -2-基胺曱醯基)嗎啉-4-曱酸(R)-第三丁 |旨⑻(28毫克， 25%) : m/z 734 (M+H)+ (ES+)。將胺甲酸酯（8)(28毫克，0.04毫莫耳）在 DCM/TFA(1 : 1 v/v ’ 2.0毫升）中的溶液在rt下攪拌30 分鐘。將反應混合物在真空中蒸發並利用SCX將所得殘餘物進行捕捉和釋放且從二乙_(1〇毫升）磨碎以提供呈灰白色固體之標題化合物，實例1〇(13毫克， 53%) : m/z 634 (M+H)+ (ES+)。NMR (400 MHz， DMSO-d6) δ ： 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, 重疊 m)，3.56-3.64 (4H,重疊 m)，3.82 (1H, m), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.36 (2H, m)，7.44 (2H，m)，7.58-7.62 (3H,重疊 m)，7.92 (1H，m)， 8.28-8.35 (3H，重疊 m)，8.58 (lH，brs)，8.79 (lH，brs)， 10.09 (lH，brs)[部分指定]。實例 11 : (S)-N-(4-((4-(3-(3-第三-丁基_1-對-曱苯基-1H-ϋ比唑-5-基)脲基)萘-1-基氧基）甲基)°比啶-2-基)嗎啉-3-曱酿胺： 100 201130813A stirred suspension of PyBOP® (300 mg, 0.58 mmol) and DIPEA (101 μl, 0.58 mmol) in DMF (2.0 mL). The reaction mixture was heated to 55 ° C and stirred for 18 hours. The reaction mixture was cooled to RT and partitioned between water (1 mL) and Et. The organic extract was evaporated in vacuo and the residue was purified by flash column chromatography (Si 〇 2 ' 12 g ' 〇〇〇〇〇〇〇〇 , , , , , , , An impure product is provided which is further purified by scx capture and release to give 3-(4-(3-(3-(3-)-tert-butyl-1-p-phenyl)-lH- as a brown solid. ηBizozol-5-yl)ureido)naphthalenyl]-yloxy)methyl)α-pyridin-2-ylamine fluorenyl)morpholine-4-decanoic acid (R)-third butyl | (28 mg, 25%): m/z 734 (M+H)+ (ES+). A solution of the carbamate (8) (28 mg, 0.04 mmol) in DCM/TFA (1: 1 v/v. The reaction mixture was evaporated in vacuo and EtOAc EtOAc (EtOAc) m/z 634 (M+H)+ (ES+). NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s), 2.73-2.92 (3H, overlap m), 3.56-3.64 (4H, overlap m), 3.82 (1H, m ), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.62 (3H, Overlap m), 7.92 (1H, m), 8.28-8.35 (3H, overlap m), 8.58 (lH, brs), 8.79 (lH, brs), 10.09 (lH, brs) [partial designation]. Example 11: (S)-N-(4-((4-(3-(3-Terti-butyl-1-)-p-phenyl)-1H-indolyl-5-yl)urea) -1-yloxy)methyl)°pyridin-2-yl)morpholine-3-indoleamine: 100 201130813

中間物AIntermediate A

PyBOP®, DIPEAPyBOP®, DIPEA

(9)(9)

BocBoc

TFA, DCM 將中間物耶錢’ 〇·ΐ4毫莫耳）—次性加至⑻· 嗎H4·二甲酸_4·第三·丁 _(133毫克，0.58毫莫耳）、 PyB〇P(D (300 毫克，0.58 亳莫耳)及 mpEA(i〇i 微升，〇_58毫莫耳)在DMF(2.〇毫升）中的獅懸浮液。在經預熱之油浴中將反應混合物加熱至w且攪拌18小時。將反應混合物冷卻至RT並分溶在水（1〇毫升）及 EtOAc(10毫升)之間。將有機層分離，在真空中蒸發及藉由管柱層析法純化殘餘物（12克，在異己烷^之 0-100%EtOAc ’梯度溶析）。將產物部分在真空中濃縮及將殘餘物從DCM(5.0毫升)及異己烷(5 〇毫升)磨碎以提供呈白色固體之3-(4-((4-(3-(3-第三-丁基_丨_對_曱苯基-1H-吼唑-5-基）脲基）萘_丨_基氧基）曱基）吡啶_2_基胺曱醯基)嗎啉·‘甲酸(S)-第三-丁酯(9)(50毫克，43%): m/z 734 (M+H)+ (ES+)。將胺甲酸酯（9)(30毫克，0.04毫莫耳）在DCM/ 101 201130813 ifA(l : 1 v/v ’ 2.0毫升）中的溶液在RT下攪拌i小時且然後在真空中蒸發。利用SCX將所得殘餘物進行捕捉和釋放且從DCM(5.0毫升)及異己烷(5·〇毫升)磨碎以提供呈棕色固體之標題化合物，實例11(15毫克，63%): m/z 634 (M+H)+ (ES+) ° !H NMR (400 MHz, DMSO-d6) δ : 1.26 (9H，s)，2.39 (3H，s)，2.73-2.92 (3H，重疊 m)， 3.56-3.64 (4H，重疊 m)，3.82 (1H，m)，5.38 (2H，s)，6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.42 (2H，m)，7,55-7.62 (3H，重疊 m)，7.91(1H m)，8 3〇(1H， dd), 8.32 (1H, br s), 8.35 (1H, dd), 8.56 (1H, br s), 8.77 (1H，br s) 10.16 (1H，br s)。實例12 : N-(4-((4-(3-(3-第三-丁基-卜對―曱苯基_1H4b 嗤_5-基）脲基）萘-1-基氧基）曱基）吡啶_2_基)_4_曱基哌畊-1-曱醯胺：TFA, DCM will add intermediates to the money '〇·ΐ 4 millimoles' - sub-sexuality to (8) · H4 · dicarboxylic acid _4 · third · butyl _ (133 mg, 0.58 millimoles), PyB 〇 P ( D (300 mg, 0.58 Torr) and mpEA (i〇i microliter, 〇_58 mmol) lion suspension in DMF (2. mM). React in preheated oil bath The mixture was heated to w and stirred for 18 h. The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc (EtOAc) eluting Triturated to provide 3-(4-((4-(3-(3-tert-butyl-)-p-p-phenylphenyl-1H-indazol-5-yl)))丨基基曱曱 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) +H)+ (ES+). The carbamate (9) (30 mg, 0.04 mmol) in DCM/101 201130813 ifA (l: 1 v/v ' 2.0 ml) The solution was stirred at rt for 1 h and then evaporated in vacuo. EtOAc EtOAc m. , Example 11 (15 mg, 63%): m/z 634 (M+H) + (ES+) ° !H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.39 (3H, s ), 2.73-2.92 (3H, overlap m), 3.56-3.64 (4H, overlap m), 3.82 (1H, m), 5.38 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H, dd), 7.35 (2H, m), 7.42 (2H, m), 7, 55-7.62 (3H, overlap m), 7.91 (1H m), 8 3 〇 (1H, dd), 8.32 ( 1H, br s), 8.35 (1H, dd), 8.56 (1H, br s), 8.77 (1H, br s) 10.16 (1H, br s). Example 12: N-(4-((4-(3 -(3-Terti-butyl-p-p-phenylphenyl-1H4b 嗤_5-yl)ureido)naphthalen-1-yloxy)indenyl)pyridine_2_yl)_4_mercaptopiped -1-nonylamine:

將4-曱基哌畊-1-曱醯氣鹽酸鹽(38毫克，〇 19毫莫耳)在°比啶（1.50毫升）中的懸浮液加至中間物A(5〇毫克，0.10毫莫耳）在吡啶（1.〇毫升）中的溶液。添加 DIPEA(50微升’ 0.29毫莫耳)且將混合物在RT下攪拌 3天。在真空中蒸發反應混合物並將殘餘物分溶在 DCM(10毫升)及水(10毫升)之間。將有機層分離並在真 102 201130813 空中蒸發及藉由急驟管柱層析法純化殘餘物（Si〇，4 克，在MeOH中之0-10〇/〇DCM，梯度溶析）以提供2呈棕色固體之標題化合物，實例12(17毫克，27〇/(〇: m/'z64"j (M+H)+ (ES+) 〇 ]Η NMR (400 MHz, DMSO-d6) δ ： 1 27 (9Η，s)，2.18 (3Η，s), 2.29 (4Η，t)，2.39 (3Η，s)，3 46 (4Η t)，5.32 (2H，s)，6.35 (1H，s)，6.99 (1H，d)，7.13 (1H, dd/ 7.36 (2H，m)，7.44 (2H，m)，7.55-7.63 (3H，重疊 m)， 7.92 (1H, m), 7.99 (1H, s), 8.25 (1H, d), 8.29 (1H, m), 8.60 (1H，br s)，8.80 (1H, br s)，9.22 (1H，br s)。 ’ ’ 貫例13 . N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基_出_。比唾-5-基)脲基）萘-1-基氧基）曱基;比„定_2_基)嗎琳_4_曱醯A suspension of 4-mercaptopiperidine-1-indole hydrochloride (38 mg, 〇19 mmol) in pyridine (1.50 mL) was added to Intermediate A (5 mg, 0.10 m) Mohr) A solution in pyridine (1. mM). DIPEA (50 μL '0.29 mmol) was added and the mixture was stirred at RT for 3 days. The reaction mixture was evaporated in vacuo. The organic layer was separated and evaporated in vacuo in EtOAc EtOAc (EtOAc) EtOAc (EtOAc EtOAc) The title compound as a brown solid, Example 12 (17 mg, 27 〇 / (〇: m/'z64 "j (M+H)+ (ES+) 〇] NMR (400 MHz, DMSO-d6) δ : 1 27 ( 9Η, s), 2.18 (3Η, s), 2.29 (4Η, t), 2.39 (3Η, s), 3 46 (4Η t), 5.32 (2H, s), 6.35 (1H, s), 6.99 (1H , d), 7.13 (1H, dd/ 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlap m), 7.92 (1H, m), 7.99 (1H, s), 8.25 ( 1H, d), 8.29 (1H, m), 8.60 (1H, br s), 8.80 (1H, br s), 9.22 (1H, br s). ' ' Example 13. N-(4-((4 -(3-(3-Terti-butyl-1-p-oximephenyl-exo-.pyran-5-yl)ureido)naphthalen-1-yloxy)indolyl; ratio „定_2 _基)么琳_4_曱醯

將嗎琳-4-甲酿氣(28微升，0.24毫莫耳)力口至中間物 A(70毫克，〇·13毫莫耳)在吡啶(15〇毫升）中的溶液及將溶液在RT下攪拌18小時。將另一部分嗎琳-曱醯氯(28微升’ 0.24毫莫耳)加至反應混合物中並繼續攪拌 24小時。混合物與在Me〇H中之1%nH3(3.0毫升)一起攪拌且然後在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ’ 12克’在DCM中之0-5%MeOH，梯度溶析）並從異丙醇(5.0毫升)再結晶以提供呈白色固體之標 103 201130813 題化合物，實例13(17毫克，20%) : m/z 634 (M+H)+ (ES+) 〇 NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2·39 (3H, s), 3.45 (4H, t), 3.59 (4H, t), 5.33 (2H, s), 6.35 (!Η, s), 6.99 (1H, d), 7.14 (1H, dd), 7.36 (2H, m), 7.44 (2H，m)，7.55-7.63 (3H，重疊 m)，7.92 (lH，m)，8.01 (1H, br s), 8.26 (1H, d), 8.29 (1H, m), 8.58 (1H, br s), 8.79 (1H, br s)，9·27 (1H，br s)。實例14 : Ν·(4-((4-(3-(3-第三-丁基小對_曱苯基_1H吡唑-5-基)脲基）萘_丨_基氧基）曱基)吡啶_2_基)_3_曱氧基丙酿胺：A solution of the intermediate A (70 μL, 0.24 mmol) into the intermediate A (70 mg, 〇 13 mmol) in pyridine (15 mL) and the solution Stir for 18 hours at RT. Another portion of morphine-hydrazine (28 μL '0.24 mmol) was added to the reaction mixture and stirring was continued for 24 hours. The mixture was stirred with 1% nH3 (3.0 mL) in EtOAc and evaporated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut Standard 103 201130813 Compound, Example 13 (17 mg, 20%): m/z 634 (M+H)+ (ES+) NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2· 39 (3H, s), 3.45 (4H, t), 3.59 (4H, t), 5.33 (2H, s), 6.35 (!Η, s), 6.99 (1H, d), 7.14 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlap m), 7.92 (lH, m), 8.01 (1H, br s), 8.26 (1H, d), 8.29 (1H, m), 8.58 (1H, br s), 8.79 (1H, br s), 9·27 (1H, br s). Example 14: Ν·(4-((4-(3-(3-Terve-butyl-p-p-phenyl)-H-pyrazol-5-yl)))]]] Pyridyl-2-yl)_3_decyloxypropanol:

將草醯氣（11.0微升，0.115毫莫耳)且然後DMF〇滴）加至3-甲氧基丙酸(9.0微升，0.096毫莫耳)在DCM(l 毫升）中的懸浮液及將混合物在〇qC下攪拌1〇分鐘且麸後使加熱至RT。）小時之後在真空中除去溶劑及將殘餘物溶解在DCM(1毫升）中且加至中間物A(5〇毫克，、 0.096毫莫耳）及DIPEA(33.5微升，〇 192㈣耳uAdding a solution of 3-methoxypropionic acid (9.0 μl, 0.096 mmol) in DCM (1 mL) with a solution of oxalate (11.0 μl, 0.115 mmol) and then DMF) The mixture was stirred at 〇qC for 1 Torr and the bran was allowed to warm to RT. After a few hours, the solvent was removed in vacuo and the residue was taken in DCM (1 mL) and applied to Intermediate A (5 mM, 0.096 mM) and DIPEA (33.5 dl, 192 192 (4)

rm3隹Meuu宁的溶痛然Rm3隹Meuu Ning's soothing pain

Meuu宁的溶液#腌人此..Meuu Ning's solution # pickle this..

104 201130813 (Si02，4克，在異己烷中之0至100%EtOAc，梯度溶析）以提供呈淡黃色固體之標題化合物，實例14，（15 毫克，26%)。m/z 607 (M+H)+ (ES+)。NMR (400 MHz， DMSO-d6) δ ： 1.27 (9H, s), 2.39 (3H, s), 2.65 (2H, t), 3.23 (3H, s), 3.61 (2H, t), 5.37 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.25 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.63 (3H，重疊 m), 7.83-7.85 (lH，d)，7.93(lH，d)，8.29-8.34 (3H,重疊 m)，8.62 (lH，brs), 8.82 (lH，brs), 10.54 (1H， br s)。實例 15 : 2-(3-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-π比0坐-5-基）腺基）奈-1-基氧基）曱基）α比〇定-2-基）腺基)-Ν-(2-曱氧基乙基）乙酸胺.104 201130813 (Si02, 4 g, EtOAc (EtOAc) elute m/z 607 (M+H)+ (ES+). NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.65 (2H, t), 3.23 (3H, s), 3.61 (2H, t), 5.37 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.25 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.63 (3H, overlap m), 7.83- 7.85 (lH,d), 7.93 (lH,d), 8.29-8.34 (3H, overlap m), 8.62 (lH,brs), 8.82 (lH,brs), 10.54 (1H, br s). Example 15: 2-(3-(4-(4-(3-(3-(3-tert-butyl-1-p-tolyl-1H-π))) 1-yloxy)indenyl)α is a quinone-2-yl)glycosyl)-indole-(2-decyloxyethyl)acetic acid amine.

實例15 將異氰酸基乙酸乙酯（129微升，1.152毫莫耳)加至中間物Α(200毫克，0.384毫莫耳)在吼啶(3毫升）中的溶液且將反應在RT下攪拌16小時。將混合物在真空中 105 201130813 ^ 热發且然後與曱苯共蒸發及殘餘物與曱醇一起研磨以提供呈固體之2-(3-(4-((4-(3_(3-第三-丁基-1-對-甲苯基 -1Hn5-基)脲基)萘-1-基氧基）甲基)°比啶_2_基)脲基) 乙酸乙酯（i〇)(191 毫克，76%) : m/z 650 (M+H)+，（ES+)。將氫氧化鋰（1〇·〇毫克，0.418毫莫耳）加至酯 (1〇)(200 亳克，0.308 毫莫耳)在 THF/H20 (4 : 1 v/v，5 毫升）的現合物中的懸浮液並將混合物在RT下授拌1小時。藉由添加1M鹽酸將反應混合物酸化成pH3，並在真二中凑發至其原體積的一半。藉由過濾、收集所得沈物並用水洗滌及在真空中乾燥以提供 2-(3-(4-((4-(3-(3-)-丁基-1-對-曱苯基 _1Η_Π 比唑 _5_ 基）脲基）萘-1-基氧基）曱基）》比啶基)脲基）乙酸（u)(185毫克，97%) : m/z 622 (M+H)+，（ES+)。將2·曱氧基乙胺(25.0微升，〇 290毫莫耳）、HOBt (19.56 毫克 ’ 0.145 毫莫耳）、DIpEA(5〇 5 微升，〇 29〇毫莫耳）’及EDC. HC1 (27.8毫克，0.145毫莫耳)加至酸(11)(60毫克’ 0.097毫莫耳)在DCM(1.5毫升）中的懸浮液並將混合物在RT下攪拌丨小時。反應混合物變成非常黏並用DMF(1毫升)稀釋及攪拌16小時。將反應混合物用DCM稀釋及用水洗滌。將有機相乾燥(MgS〇4) 並在真空中蒸發/谷劑。殘餘物與Me〇H 一起研磨以提供呈灰白色固體之標題化合物’實例15(22毫克，34%): m/z 679 (M+H) ’（ES )。4 NMR (4〇〇 MHz，DMS〇 d^ δ ： 1.27 (9Η, s), 2.39 (3H, s), 3.24 (3H, s), 3.25 (2H, m), 3.34 (2H, m)，3.82 (2H，d)，s.m pH，s)，6 35 (m，s)，7 〇〇 (1H，d)，7.07 (1H，d)，7.36 (2H，m)，7 44 (2H,蛛 106 201130813 7·58·7.65(4Η，重疊 m), 7.93 (lH，m)，8.03 (m，t) 8 21 (1H, d), 8.34 (1H, m), 8.51 (1H, very br s), 8.58 (Ih] br s), 8.79 (lH，brs)，9.46 (lH,brs) ’ 實例16 : N_(4_((4_(3_(3_第三-丁基小對_甲苯基·ιη_。比坐5-基）脲基）萘_ι_基氧基）曱基）π比咬_2_基)_4_(二甲胺基）丁醯胺：Example 15 Ethyl isocyanate (129 μL, 1.152 mmol) was added to a solution of EtOAc (200 mg, 0.384 mmol) in EtOAc (3 mL). Stir for 16 hours. The mixture was heated in a vacuum 105 201130813 ^ and then co-evaporated with toluene and the residue was triturated with decyl alcohol to provide 2-(3-(4-(4-(3-(3-)- Butyl-1-p-tolyl-1Hn5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)ureido)ethyl acetate (i 〇) (191 mg, 76%) : m/z 650 (M+H)+, (ES+). Add lithium hydroxide (1 〇·〇 mg, 0.418 mmol) to the ester (1 〇) (200 ,g, 0.308 mmol) in THF/H20 (4: 1 v/v, 5 mL) The suspension in the mixture was stirred and the mixture was stirred at RT for 1 hour. The reaction mixture was acidified to pH 3 by the addition of 1 M hydrochloric acid and was taken to half of its original volume in the true two. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 2-(3-(4-(3-(3-)-butyl-1-p-phenylphenyl)比 _ 5 _ 萘萘萘萘萘萘萘萘萘萘萘萘萘 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 185 , (ES+). 2 曱 oxyethylamine (25.0 μl, 〇 290 mM), HOBt (19.56 mg '0.145 mM), DIpEA (5 〇 5 μl, 〇 29 〇 millimoles) and EDC. HC1 (27.8 mg, 0.145 mmol) was added to a suspension of acid (11) (60 mg <RTI ID=0.0>> The reaction mixture became very viscous and was diluted with DMF (1 mL) and stirred for 16 h. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried (MgS 4) and evaporated in vacuo. The residue was triturated with EtOAc (EtOAc m.). 4 NMR (4〇〇MHz, DMS〇d^ δ : 1.27 (9Η, s), 2.39 (3H, s), 3.24 (3H, s), 3.25 (2H, m), 3.34 (2H, m), 3.82 (2H,d),sm pH,s),6 35 (m,s),7 〇〇(1H,d),7.07 (1H,d),7.36 (2H,m),7 44 (2H, spider 106 201130813 7·58·7.65 (4Η, overlap m), 7.93 (lH,m), 8.03 (m,t) 8 21 (1H, d), 8.34 (1H, m), 8.51 (1H, very br s), 8.58 (Ih) br s), 8.79 (lH, brs), 9.46 (lH, brs) ' Example 16: N_(4_((4_(3_(3_T-butyl)-p-tolyl·ιη_. Sodium 5-yl)ureido)naphthalene_ι_yloxy)fluorenyl)π ratio bition_2_yl)_4_(dimethylamino)butanamine:

實例16 將亞硫醯氣(42.0微升’ 0.576毫莫耳)和DMF(—滴）加至在0oC下的4-(二甲胺基)丁酸.HC1(97毫克，0.576 耄莫耳)在DCM(2毫升）中的攪拌懸浮液並使混合物加熱至RT。16小時之後將反應混合物在真空中蒸發並將殘餘物溶解在DCM/THF(1 : 1 v/v，2毫升）中及加至中間物A(60毫克，0.115毫莫耳)在包含DIPEA〇〇1微升， 0.576亳莫耳)之THF(1毫升）中的溶液.在55〇c下攪拌 /¾合物且4小時之後將混^合物冷卻至RT，用水（丨〇毫升)稀釋並用EtOAc(10毫升）萃取。將有機層分離並用氨的溶液(在MeOH中之7M，2毫升)處理5分鐘及在真空中蒸發混合物。藉由急驟管柱層析法純化殘餘物 (Sl〇2，12 克，（在 MeOH 中之 1〇〇/〇nh3) - EtOAc 梯度溶析）以提供呈淺棕色固體之標題化合物，實例16(25 毫克，34%): m/z 634 (M+H)+ (ES+); 4 NMR (400 MHz, 107 201130813 j^MSO-d6) δ ： 1.27 (9 H, s), 1.74 (2Η, m), 2.21 (6H, s), 2.35 (2H, m), 2.39 (3 H, s), 2.40 (2H, m), 5.36 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.24 (1H, d), 7.36 (2H, m), 7.44 (2H，m)，7.54-7.63 (3H，重疊 m)，7.93 (1H，m)， 8.30-8.37 (3H，重疊 m)，8.59 (1H，s)，8.79 (1H，s)，10.54 (1H，br s)。實例17 : N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡 β坐-5-基）腺基）奈-1-基氧基）曱基）α比α定-2-基)-3-(曱績酿基）丙酿胺：Example 16 Thionylene gas (42.0 μl '0.576 mmol) and DMF (-drop) were added to 4-(dimethylamino)butyric acid.HC1 (97 mg, 0.576 mmol) at 0 °C. The suspension was stirred in DCM (2 mL) and the mixture was warmed to RT. The reaction mixture was evaporated in vacuo <RTI ID=0.0></RTI></RTI> <RTI ID=0.0></RTI></RTI> <RTIgt; 〇1 μl, 0.576 mmol of THF in THF (1 mL). Stir the mixture at 55 ° C and after 4 hours, cool the mixture to RT and dilute with water (ml) It was extracted with EtOAc (10 mL). The organic layer was separated and treated with aq. EtOAc (EtOAc EtOAc. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut 25 mg, 34%): m/z 634 (M+H)+ (ES+); 4 NMR (400 MHz, 107 201130813 j^MSO-d6) δ : 1.27 (9 H, s), 1.74 (2Η, m ), 2.21 (6H, s), 2.35 (2H, m), 2.39 (3 H, s), 2.40 (2H, m), 5.36 (2H, s), 6.35 (1H, s), 7.01 (1H, d ), 7.24 (1H, d), 7.36 (2H, m), 7.44 (2H, m), 7.54-7.63 (3H, overlap m), 7.93 (1H, m), 8.30-8.37 (3H, overlap m), 8.59 (1H, s), 8.79 (1H, s), 10.54 (1H, br s). Example 17: N-(4-((4-(3-(3-Terti-butyl-1-p-phenyl)-1H-pyridin-5-yl)-glycosyl)-n-yl Oxy) sulfhydryl) alpha ratio α-but-2-yl)-3-(anthracene) propylamine:

將草醯氣(85.0微升，0.97毫莫耳），接著DMF(2 滴）加至3-曱烷硫丙酸（117毫克，0.97毫莫耳）在 DCM(1.0毫升）中的懸浮液並將混合物在RT下攪拌1 小時。藉由在真空中蒸發除去溶劑並將殘餘物再溶解於 DCM(2.5毫升）中且然後逐滴加至中間物A(145毫克， 0.28毫莫耳）及DIPEA(218微升，1.25毫莫耳）在 108 201130813 DCM(2.0毫升）中的溶液。2小時之後添加氨在Me〇H 中的溶液(7M ’ 3.0毫升)且繼續攪拌1小時。在真空中蒸發揮發物且藉由急驟管柱層析法純化殘餘物（si〇2， 12克’在DCM中之0-5%MeOH，梯度溶析）以提供 N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基比唾_5_基)脲基）奈-1 _基氧基）f基）吼咬-2-基）-3-(甲硫基）丙酷胺 (12)(110 毫克，61%) : m/z 623 (M+H)+ (ES+)。將Oxone(93毫克，0.151毫莫耳)在水（1 〇毫升）中的丨谷液加至硫化物（12)(47毫克，0.075毫莫耳）在 DMF(0.5毫升）中的擾拌溶液。1〇分鐘之後，沈殿物已形成及添加MeOH(2毫升)且繼續攪拌1小時。將混合物用另一部分的MeOH(2.0毫升）稀釋及添加冰 AcOH(0.5毫升）。將懸浮液進行SCX捕捉和釋放且然後藉由急驟管柱層析法純化(Si〇2，12克在DCM中之， 2-8%MeOH，梯度溶析）以提供標題化合物，實例17， (20 毫克，38%) : m/z 655 (M+H)+ (ES+)。NMR (400 MHz, DMSO-d6) δ： 1.27 (9H, s), 2.39 (3H, s), 2.90 (2H, t), 3.01 (3H, s), 3.43 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.65 (3H,重疊 m), 7.93 (1H, m), 8.29-8.33 (2H, 重疊 m)，8.34 (1H，d)，8.58 (1H，br s), 8.79 (1H, br s)， 10.72 (1H, br s)。實例18 : N-(4_((4-(3-(3-第三-丁基-卜對·甲苯基^沁吡唑基)脲基）萘-1-基氧基）甲基）。比啶_2_基)_3_(曱磺醯基)-2-側氧咪唑啶-1-曱醯胺： 109 201130813Grass helium (85.0 μl, 0.97 mmol) followed by DMF (2 drops) to a suspension of 3-decanethiopropionic acid (117 mg, 0.97 mmol) in DCM (1.0 mL) The mixture was stirred at RT for 1 hour. The solvent was removed by evaporation in vacuo and the residue was redissolved in DCM (2.5 <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; ) A solution in 108 201130813 DCM (2.0 ml). A solution of ammonia in Me〇H (7M '3.0 mL) was added after 2 h and stirring was continued for 1 hour. The volatiles were evaporated in vacuo and the residue was purified (jjjjjjjjjj -(3-(3-Terti-butyl-1-p-anthranylphenyl)-sulfanyl-5-yl)ureido)na-1 _yloxy)f-based)-bito-2-yl)-3 -(Methylthio)propanolamine (12) (110 mg, 61%): m/z 623 (M+H) + (ES+). A solution of Oxone (93 mg, 0.151 mmol) in water (1 mL) was added to the solution of sulfide (12) (47 mg, 0.075 mmol) in DMF (0.5 mL). . After 1 minute, the precipitate was formed and MeOH (2 mL) was added and stirring was continued for one hour. The mixture was diluted with a further portion of MeOH (EtOAc) (EtOAc) The suspension was subjected to SCX capture and liberation and then purified by flash column chromatography (Si2, 12 g in DCM, 2-8% MeOH, gradient elution) to afford the title compound, Example 17 ( 20 mg, 38%): m/z 655 (M+H)+ (ES+). NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.90 (2H, t), 3.01 (3H, s), 3.43 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.00 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.65 (3H, overlap m), 7.93 ( 1H, m), 8.29-8.33 (2H, overlap m), 8.34 (1H, d), 8.58 (1H, br s), 8.79 (1H, br s), 10.72 (1H, br s). Example 18: N-(4-((4-(3-(3-T-butyl-p-p-tolyl)pyridyl)ureido)-naphthalen-1-yloxy)methyl). Pyridin-2-yl)_3_(oxasulfonyl)-2-oxoxicillinium-1-amine: 109 201130813

中間物A 將在η比啶(1.5毫升）中之3_氣羰基曱烷磺醯基_2_ 咪唑啶酮（131毫克，〇_576毫莫耳)加至中間物Α(1〇〇毫克’0.192毫莫耳)在β比咬（1.5毫升）中的溶液並在RT下攪拌反應混合物。3天之後將反應混合物在真空中蒸發及殘餘物與NH3(l〇/〇v/v在MeOH中）一起攪拌。在真空中蒸發溶劑並藉由急驟管柱層析法純化殘餘物(Si〇2，4 克，100%DCM然後在DCM中之2%MeOH，等度溶析）以提供不純產物，其從曱醇再結晶以產生呈白色結晶固體之標題化合物，實例18(12毫克，9%):m/z7ll (M+H)+ (ES+) 〇 !Η NMR (400 MHz, DMSO-d6) δ ： 1.27 (9Η, s), 2.39 (3Η, s), 3.39 (3H, s), 3.87 (4H, s), 5.40 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, m), 7.93 (1H, m), 8.21 (1H, br s), 8.31 (1H, m), 8.35 (1H, d), 8.58 (1H, br s), 8.79 (1H, br s), 10.40 (lH，brs)〇中間物B :N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）曱基户比啶-2-基)-2-氣乙醯胺。 110 201130813Intermediate A will be added to the intermediate Α (1 〇〇 mg) in η-pyridine (1.5 ml) of 3-methoxycarbonyl decanesulfonyl-2-imidazolidinone (131 mg, 〇_576 mmol). 0.192 mmol) solution in beta ratio bite (1.5 ml) and the reaction mixture was stirred at RT. After 3 days the reaction mixture was evaporated in vacuo and the residue was stirred with <RTI ID=0.0>> The solvent was evaporated in vacuo and the residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut The alcohol was recrystallized to give the title compound as a white crystalline solid. Example 18 (12 mg, 9%): m/z 7ll (M+H) + (ES+) 〇!Η NMR (400 MHz, DMSO-d6) δ: 1.27 (9Η, s), 2.39 (3Η, s), 3.39 (3H, s), 3.87 (4H, s), 5.40 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.31 ( 1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, m), 7.93 (1H, m), 8.21 (1H, br s), 8.31 (1H, m), 8.35 (1H, d), 8.58 (1H, br s), 8.79 (1H, br s), 10.40 (lH, brs) 〇 intermediate B: N-(4-((4-(3-(3-) Tri-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indoleylpyridin-2-yl)-2-ethaneacetamide. 110 201130813

中間物A α』αIntermediate A α』α

DIPEA 〇,DIPEA,

將氯乙醯氯（0.61毫升，7.68毫莫耳）加至〇1卩£八(1.37毫升，7.68毫莫耳)及中間物八(2.00克，3.84 毫莫耳)在DCM(40毫升)及DMF(8.0毫升）中的溶液。將反應混合物在RT下攪拌1小時及添加另一部分氣乙醯氣(100微升，1.25毫莫耳）。在RT下1小時之後，將反應混合物分溶在DCM(40毫升)及NaHC03飽和水溶液(40毫升)之間。將有機相在真空中濃縮並藉由管柱層析法純化(80克，在DCM中之0-10%MeOH，梯度溶析）。將產物部分在真空中濃縮且將殘餘物與二***(20 毫升)及異己烷(20毫升）一起研磨。藉由過濾收固體集以提供呈淡紫色固體之標題化合物，中間物B(1.07克， 42%) : m/z 597, 599 (M+H)+ (ES+)。實例19 : Ν-(4-((4-(3·(3-第三-丁基小對-曱苯基_1H_〇tb °坐-5-基)脲基）萘-1-基氧基）曱基)《»比咬_2-基)-2-(曱硫基) 乙醯胺；Add chloroacetic acid chloride (0.61 ml, 7.68 mmol) to 〇1卩8 (1.37 ml, 7.68 mmol) and Intermediate 8 (2.00 g, 3.84 mmol) in DCM (40 mL) and Solution in DMF (8.0 ml). The reaction mixture was stirred at RT for 1 hour and another portion of hexanes (100 liters, 1.25 mM) was added. After 1 hour at RT, the reaction mixture was partitioned between DCM (40 mL) and NaHCO? The organic phase was concentrated in vacuo and purified by column chromatography eluting eluting The product was concentrated in vacuo and the residue was crystalljjjjjjjj The title compound was obtained as a yellow solid, Intermediate B (1.07 g, 42%): m/z 597, 599 (M+H) + (ES+). Example 19: Ν-(4-((4-(3)(3-Terve-butyl-p-p-phenyl)H-〇tb°--5-yl)ureido)naphthalen-1-yloxy Base) 《))»比 bit_2-yl)-2-(indolyl) acetamamine;

將中間物B (100毫克，〇.17毫莫耳)逐部分地加至曱硫醇鈉(35毫克’0.50毫莫耳)在Me〇H(5 〇毫升）中的 111 201130813 授摔溶液並將所得混合物在RT下撥摔1小時。將混合物在真空中蒸發且分溶在鹽水(20毫升)及DCm(3〇毫升) 之間。將有機層在真空中濃縮，將殘餘物預吸附在石夕石上並藉由管柱層析法純化(Si〇2 ’ 12克，在異己烧中之 10-100°/〇EtOAc，梯度溶析）。在真空中蒸發產物部分以產生呈淡黃色固體之標題化合物實例19(28毫克， 26%) ： m/z 610 (M+H)+ (ES+) 〇 ]Η NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.26 (1H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H, s), 8.78 (1H, s)，10.60 (1H，s)。實例20 : Ν-(4·((4-(3-(3_第三-丁基小對-甲苯基-1H_吡唑-5-基）脲基）萘-1-基氧基）曱基）η比咬_2-基)-2_(甲亞續醯基）乙醯胺：Intermediate B (100 mg, 〇.17 mmol) was added portionwise to a solution of sodium thiomerate (35 mg '0.50 mmol) in Me〇H (5 〇 ml) 111 201130813 The resulting mixture was dropped for 1 hour at RT. The mixture was evaporated in vacuo and partitioned between brine (20 mL) and DCM (3 mL). The organic layer was concentrated in vacuo, and the residue was pre-adsorbed on the stone and purified by column chromatography (Si 〇 2 ' 12 g, 10-100 ° / 〇 EtOAc in iso-hexane, gradient elution ). The product fractions were evaporated in vacuo to give title compound 19 (28 mg, 26%): m/z 610 (M+H) + (ES+) 〇] NMR (400 MHz, DMSO-d6) δ : 1.27 (9H, s), 2.16 (3H, s), 2.39 (3H, s), 3.53 (2H, s), 5.37 (2H, s), 6.35 (1H, s), 7.01 (1H, d) , 7.26 (1H, dd), 7.35 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, m), 7.92 (1H, m), 8.30-8.35 (3H, m), 8.58 (1H , s), 8.78 (1H, s), 10.60 (1H, s). Example 20: Ν-(4·((4-(3-(3_T-butyl-butyl-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indole Base) η than bite 2 - base) - 2_ (methyl sulfhydryl) acetamidine:

將ΟΧΟΝΕ® (10毫克，〇.〇3毫莫耳)加至化合物實例 19 (20 毫克 ’ 〇.〇3 毫莫耳)在 DMF /Η20 (1 : 1 ν/ν， 1.0毫升）的混合物中之溶液並將反應在RT下攪拌3 天。添加第二部分之〇χ〇ΝΕ®(ΐ〇毫克，〇.〇3毫莫耳），將混合物攪拌另24小時且然後分溶在鹽水(20毫升)及 DCM(20毫升)之間。將有機萃取物用鹽水(2〇毫升）洗 112 201130813 滌’乾燥(MgSCU)並在真空中蒸發並藉由急驟管柱層析法純化殘餘物（Si〇2，4克，在異己燒中胃之 30-100%EtOAc’梯度溶析）及進行SCX捕捉和釋放以提供呈淺棕色固體之標題化合物，實例20(11毫克， 52%) : m/z 625 (M+H)+ (ES+)。]H NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2.39 (3H, s), 2.69 〇H, s), 3.88 (2H，d), 4.04 (2H，d) 5.39 (2H, s), 6.35 (1H，s)，7.02 (1H d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64ΟΧΟΝΕ® (10 mg, 〇.〇3 mmol) was added to compound Example 19 (20 mg '〇.〇3 mmol) in a mixture of DMF / Η20 (1 : 1 ν / ν, 1.0 mL) The solution was stirred and the reaction was stirred at RT for 3 days. A second portion of hydrazine® (ΐ〇 mg, 〇. 〇 3 mmol) was added and the mixture was stirred for another 24 hours and then partitioned between brine (20 mL) and DCM (20 mL). The organic extract was washed with brine (2 mL) 112 201130813 Polyester 'Dry (MgSCU) and evaporated in vacuo and the residue was purified by flash column chromatography (Si 〇 2, 4 g, in the stomach The title compound was obtained as a light brown solid, Example 20 (11 mg, 52%): m/z 625 (M+H)+ (ES+) . ]H NMR (400 MHz, DMSO-d6) δ : 1.27 (9H, s), 2.39 (3H, s), 2.69 〇H, s), 3.88 (2H,d), 4.04 (2H,d) 5.39 (2H , s), 6.35 (1H, s), 7.02 (1H d), 7.31 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.58-7.64

(3H,重疊 m)，7.93 (1H，m)，8.30-8.33 (2H，重疊 m) 8.37 (1H, d), 8.59 (1H, br s)，8·79 (1H，br s)，10.85 (1H br s)。實例21 : N-(4-((4-(3-(3-第三-丁基_1_對_甲苯基」士吡唑_5-基)脲基）萘-1-基氧基）曱基比啶_2_基)-2-嗎琳基乙醯胺：(3H, overlap m), 7.93 (1H, m), 8.30-8.33 (2H, overlap m) 8.37 (1H, d), 8.59 (1H, br s), 8.79 (1H, br s), 10.85 ( 1H br s). Example 21: N-(4-((4-(3-(3-Tern-butyl-1-)-p-tolyl)pyrazol-5-yl)ureido)naphthalen-1-yloxy) Indolylpyridinium-2-yl)-2-morphinylacetamide:

將嗎啉（11.0微升，0.13亳莫耳)加至中間物b(5〇毫克，0.08毫莫耳)在DCM(l.〇毫升）、DMF(〇j毫升) 及DIPEA(21.9微升’ 〇·ΐ3毫莫耳）的混合物中的攪拌溶液並將反應混合物在RT下攪拌3小時且然後在4〇〇c 下經12小時。添加另一部分之嗎啉（u 〇微升，〇13毫莫耳)且將反應混合物在40〇C下攪拌5小時。藉由管柱 113 201130813 層析法純化粗製反應混合物（12克，在DCM中之 0-10%MeOH，梯度溶析）。將產物部分在真空中濃縮並將殘餘物與MeOH(5.0毫升）一起研磨。藉由過濾收集固體以提供呈淡黃色固體之標題化合物實例21(11毫克， 20%) : m/z 648 (M+H)+ (ES+)。NMR (400 MHz, DMSO-d6) δ ： 1.27 (9 H, s), 2.39 (3 Η, s), 2.54 (4 Η, 3·20 (2 Η，s)，3.63 (4 Η，m)，5.39 (2Η，s)，6.35 (1Η，s)， 7.01 (1H，d)，7.28 (1H，d)，7.35 (2H，d)，7.43 (2H，d)， 7.63 - 7.56 (3H，m)，7.92 (1H，d)，8.37 8·29 (3H，m)， 8.58 (1H，S)，8.79 (1H，s)，l〇_〇l (iH，s)。實例22 : N-(4-((4-(3-〇第三-丁基對-曱苯基-1H_吡唑-5-基）脲基）萘_丨_基氧基）曱基）吡啶_2·基>2·(吡咯啶 -1-基）乙醯胺： JBu ΙχχAdd morpholine (11.0 μl, 0.13 mmol) to intermediate b (5 mg, 0.08 mmol) in DCM (1 mL), DMF (JM) and DIPEA (21.9 L) Stirring solution in a mixture of 毫·ΐ3 mmol) and the reaction mixture was stirred at RT for 3 hours and then at 4 ° C for 12 hours. Another portion of morpholine (u 〇 microliter, 〇 13 mmol) was added and the reaction mixture was stirred at 40 ° C for 5 hours. The crude reaction mixture (12 g, 0-10% MeOH in DCM, gradient elution) was purified by column. The product portion was concentrated in vacuo and EtOAc EtOAc m. The solid was collected by filtration to give the title compound Compound 21 (11 mg, 20%): m/z 648 (M+H) + (ES+). NMR (400 MHz, DMSO-d6) δ : 1.27 (9 H, s), 2.39 (3 Η, s), 2.54 (4 Η, 3·20 (2 Η, s), 3.63 (4 Η, m), 5.39 (2Η, s), 6.35 (1Η, s), 7.01 (1H, d), 7.28 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.63 - 7.56 (3H, m) , 7.92 (1H, d), 8.37 8·29 (3H, m), 8.58 (1H, S), 8.79 (1H, s), l〇_〇l (iH, s). Example 22: N-(4 -((4-(3-〇T-butyl-p-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalene-yl-yloxy)indenyl)pyridine_2-yl group> 2·(pyrrolidin-1-yl)acetamide: JBu Ιχχ

中間物ΒIntermediate

CnhCnh

dipea ...w 實例22 將吡咯啶(7.0微升，〇.〇8毫莫耳)加至中間物Dipea ...w Example 22 Adding pyrrolidine (7.0 μL, 〇.〇8 mmol) to the intermediate

B 毫克’ 0.08毫莫耳)在DCM(1 〇毫升）、dmf(〇]毫 =，IPEA(22微升’ 〇.13毫莫耳）巾的紐。將反應渴 RT下撥拌3小時且然後在歡下經12小時。 trir^(7.G微升，_毫莫耳)且將反肩 2在40C下授拌5小時。藉由管柱層析法純化相，應展,物（12克’在職中之G1G%M禮，梯肩析)以提供呈淡撥色㈣之標題化合物，實例22(17 114 201130813 克，32%) : m/z 632 (M+H)+ (ES+)。NMR (400 MHz， DMSO-d6) δ ： 1.27 (9 H, s), 1.76 (4 H, m), 2.39 (3 H, s), 2.62 (4 H，m)，5.39 (2H, s)，6.35 (1H, s), 7.01 (1H，d)， 7.28 (1H, d), 7.34 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.92 (1H, d), 8.36-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.93 (1H，s)。實例23 : N-(4-((4-(3-(3-第三-丁基-1-對·曱苯基-1Η·吡唑-5-基）脲基）萘-1-基氧基）曱基）吡啶-2-基)-2-(4-曱基哌畊-1-基）乙醯胺：B mg '0.08 mmol> in DCM (1 〇 ml), dmf (〇) 毫 =, IPEA (22 μl '〇.13 mmol) towel, and mix for 3 hours under RT Then, under the funeral for 12 hours, trir^(7.G microliter, _mole) and the backing shoulder 2 was mixed for 5 hours at 40 C. The phase was purified by column chromatography, and the product was 12g 'on-the-job G1G%M ceremony, stepped shoulders) to provide the title compound in light shade (4), example 22 (17 114 201130813 grams, 32%): m/z 632 (M+H)+ (ES+ NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 1.76 (4 H, m), 2.39 (3 H, s), 2.62 (4 H, m), 5.39 (2H, s ), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, d), 7.34 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.92 (1H, d), 8.36-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.93 (1H, s). Example 23: N-(4-((4-(3-(3) -Third-butyl-1-p-p-phenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(4- Mercapto-1-yl)acetamide:

將N-甲基哌畊(9.3微升，〇.〇8毫莫耳)加至中間物 B(50 毫克，0.08 毫莫耳)在 DCM(1.0 毫升）、DMF(〇.l 毫升)及DIPEA(22微升，0.13毫莫耳）的混合物中之溶液。將反應混合物在RT下攪拌3小時且然後在4〇°c 下12小時。添加另一部分N-曱基哌畊(9.0微升，〇.〇8 毫莫耳)且將反應混合物在40。(：下攪拌5小時。藉由管柱層析法純化粗製反應混合物（12克，在DCM中之 0-10%MeOH，梯度溶析）。將產物部分在真空中濃縮並將殘餘物與二***、DCM及異己烷的混合物(2: 1 : 2， 5.0毫升）一起研磨以產生呈淡橙色固體之標題化合物’實例 23(26 毫克，47%) : m/z 661 (M+H)+ (ES+)。4 115 201130813 丄、MR (400 MHz，DMSO-d6) δ: 1.27 (9 H，s)，2.39 (3 H s) 2.69-2.60 (3 H，br m)，2.88-2.73 (3 H，br m)，3.17-2.95 (4 H，br m)，5.39 (2H，s)，6.34 (1H，s)，7.00 (1H，d)，7.29 (1H d)，7.35 (2H，d)，7.45 (2H，d)，7.66-7.56 (3H，m)，7.98 (ih d), 8.37-8.28 (3H，m)，8.73 (1H，s)，8.91 (1H, s)，i〇.12 (1H，s)。實例24 : Ν-(4-((4-(3·(3-第三丁基巧對-甲笨基-出“比 c坐·5_基）腺基）萘-1-基氧基）甲基）η比。定_2_基)_2_(4_(2_曱氧基乙基)哌畊-1-基）乙醯胺：Add N-methyl piperene (9.3 μL, 〇. 〇 8 mmol) to Intermediate B (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (〇.1 mL) and DIPEA A solution in a mixture of (22 microliters, 0.13 millimoles). The reaction mixture was stirred at RT for 3 hours and then at 4 °C for 12 hours. Another portion of N-decylpiperidine (9.0 μL, 〇. 8 mM) was added and the reaction mixture was at 40. (The mixture was stirred for 5 hours. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). The product fraction was concentrated in vacuo and residue A mixture of diethyl ether, DCM and isohexane (2: 1 : 2, 5.0 mL) eluted to give the title compound <RTI ID=0.0>#</RTI> <RTIgt; (ES+). 4 115 201130813 丄, MR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H s) 2.69-2.60 (3 H, br m), 2.88-2.73 (3 H, br m), 3.17-2.95 (4 H, br m), 5.39 (2H, s), 6.34 (1H, s), 7.00 (1H, d), 7.29 (1H d), 7.35 (2H, d) , 7.45 (2H, d), 7.66-7.56 (3H, m), 7.98 (ih d), 8.37-8.28 (3H, m), 8.73 (1H, s), 8.91 (1H, s), i〇.12 (1H, s). Example 24: Ν-(4-((4-(3·(3-tert-butyl butyl-p-phenyl)-) 1-yloxy)methyl)η ratio. _2_yl)_2_(4_(2_曱oxyethyl)piped-1-yl)acetamide:

將Ν-曱氧基乙基派》井(12.5微升，〇.〇8毫莫耳)力口至中間物Β(50毫克，0.08毫莫耳)在dCM(1.〇毫升）、 DMF(0.1毫升)及DIPEA(22微升，0.13毫莫耳）的混合物中之溶液。將反應混合物在RT下攪拌3小時且然後在40°C下經12小時。添加另一部分N_曱氧基乙基哌畊（12.5微升’ 0.08毫莫耳)且將反應混合物在4〇〇c下攪拌5小時。藉由管柱層析法純化粗製反應混合物 (Si02 ’ 12 克’在 DCM 中之〇_i〇〇/〇MeOH，梯度溶析）以提供呈淡橙色固體之標題化合物，實例24(45毫克， 73%) ： m/z 705 (M+H)+ (ES+)〇 !H NMR (400 MHz, DMSO) δ : 1.27 (9 H，s)，2.39 (3 H，s)，2.46-2.48 (3 H，m，被 DMSO 掩蓋)，2.57-2.50 (4 H，m)，3.17 (2 H，s)，3.23 (3 H， 116 201130813 s), 3.42 (2 H, t), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d) 7.29 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65 - 7.55 m), 7.93 (1H, d), 8.36 - 8.30 (3H, m), 8.58 (1H, s) 8 7Q (1H,s),9.92(1H,s)〇實例 25 : N-(4-((4-(3-(3-第三-丁基_1_對_ 曱苯基_1H_^ 0坐-5-基）脲基）萘-1-基氧基）甲基甲氧基乙胺基）乙酿胺：The Ν-曱 oxyethyl group well (12.5 μL, 〇. 〇 8 mmol) was applied to the intermediate Β (50 mg, 0.08 mmol) in dCM (1. 〇 ml), DMF ( A solution of 0.1 ml) and a mixture of DIPEA (22 μl, 0.13 mmol). The reaction mixture was stirred at RT for 3 hours and then at 40 °C for 12 hours. Another portion of N_methoxyethylpiperidine (12.5 [mu]L <RTI ID=00&0>> The crude reaction mixture was purified by column chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc 73%) : m/z 705 (M+H)+ (ES+)〇!H NMR (400 MHz, DMSO) δ : 1.27 (9 H, s), 2.39 (3 H, s), 2.46-2.48 (3 H, m, masked by DMSO), 2.57-2.50 (4 H, m), 3.17 (2 H, s), 3.23 (3 H, 116 201130813 s), 3.42 (2 H, t), 5.39 (2H, s ), 6.35 (1H, s), 7.01 (1H, d) 7.29 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.65 - 7.55 m), 7.93 (1H, d), 8.36 - 8.30 (3H, m), 8.58 (1H, s) 8 7Q (1H, s), 9.92 (1H, s) 〇 Example 25: N-(4-((4-(3-(3-)- Butyl_1_p-_phenylphenyl_1H_^ 0--5-yl)ureido)naphthalen-1-yloxy)methylmethoxyethylamine)

將2-曱氧基乙胺(7.0微升，0.08毫莫耳)力σ至中間物Β(50宅克’ 0.08毫莫耳)在DCM(1.0毫升）、DMF(〇 1 毫升）及DIPEA(17微升’ 0.10毫莫耳）的混合物中之溶液。將反應混合物加熱至40。(：並攪拌12小時。藉由管柱層析法純化粗製反應混合物（Si〇2, 12克，在DCM令之0-10%MeOH，梯度溶析）。將產物部分在真空中濃縮並將殘餘物與二***、DCM及異己烷的混合物(2 : 1 : 2, 5.0毫升）一起研磨以提供呈灰白色固體之標題化合物，實例 25(6 毫克，11%) ·· m/z 637 (M+H)+ (ES+)。 NMR (400 MHz，DMSO-d6) δ: 1.27 (9 H，s)，2.39 (3 H，s)， 2.71 (2 H，t)，3.24 (3 H，s), 3.33 (2 H，m (被 DHO 掩蓋))， 3.40 (2 H, t), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.36 (2H, d), 7.43 (2H, d), 7.64 - 7.57 (3H, m), 7.92 (1H, m), 8.36 - 8.30 (3H, m), 8.59 (1H, s), 8.79 (1H, 117 201130813 基）乙醯胺：實例26 : N-(4-((4-(3-(3-第三-丁基·丨·對-甲苯基 D坐_5_基）脲基）萘-1-基氧基）曱基）°比咬-2-基)-2-(二曱胺2-曱-oxyethylamine (7.0 μL, 0.08 mmol) force σ to intermediate Β (50 克 ' 0.08 mmol) in DCM (1.0 mL), DMF (〇 1 mL) and DIPEA ( A solution of 17 microliters of '0.10 millimolar' of the mixture. The reaction mixture was heated to 40. (: and stirred for 12 hours. The crude reaction mixture was purified by column chromatography (Si.sub.2, 12 g, 0-10% MeOH in DCM, gradient elution). The residue was triturated with a mixture of EtOAc (EtOAc m.) +H)+ (ES+) NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 H, s), 2.71 (2 H, t), 3.24 (3 H, s) , 3.33 (2 H,m (masked by DHO)), 3.40 (2 H, t), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.36 (2H, d), 7.43 (2H, d), 7.64 - 7.57 (3H, m), 7.92 (1H, m), 8.36 - 8.30 (3H, m), 8.59 (1H, s), 8.79 (1H, 117 201130813 base) acetamide: Example 26: N-(4-((4-(3-(3-tert-butyl)-p-tolyl-D-yl)-ureido)-naphthalene- 1-yloxy)indenyl)°biti-2-yl)-2-(diamine

將二曱胺(在THF中之2.0M溶液)(41微升，〇〇8 毫莫耳)加至中間物B (50毫克，〇.〇8毫莫耳)在dcmq 〇毫升）、DMF(0.1毫升)及DipEA(17微升，〇丨毫莫耳) 中的溶液。將反應混合物加熱至4〇。(：並擾拌12小時。藉由管柱層析法純化粗製反應混合物（12克矽石，在 DCM中之O-ioo/oMeOH，梯度溶析）。將產物部分在真空中濃縮並將殘餘物與二乙鱗、DCM及異己烧的混合物(2 . 1 : 2，5.0毫升）一起研磨以提供呈橙色固體之標題化合物，實例26(18毫克’ 35%) : m/z 607 (M+H)+ (ES )。NMR (400 MHz，DMSO-d6) δ : 1.27 (9 H，s)， 2.31 (6 H, s), 2.39 (3 H, s), 3.14 (2 H, s), 5.39 (2H, s), 6·35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1H, m), 8.38-8.28 (3H, m)，8·59 (1H，s)，8.79 (1H, s), 9.93 (1H，s)。實例27 : N-(4-((4-(3-(3-第三-丁基對-甲苯基“Η·。比唾-5-基)脲基）萘-i_基氧基）曱基)β比咬_2_基)_2_(曱胺基) 乙酿胺： 118 201130813Diamine (2.0 M solution in THF) (41 μL, 〇〇 8 mmol) was added to Intermediate B (50 mg, 〇. 〇 8 mmol) in dcmq 〇 ml, DMF ( 0.1 ml) and a solution of DipEA (17 μl, 〇丨 millimol). The reaction mixture was heated to 4 Torr. (: and stir-fry for 12 hours. The crude reaction mixture was purified by column chromatography (12 g of vermiculite, O-ioo/oMeOH in DCM, gradient elution). Part product was concentrated in vacuo and residue The mixture was triturated with a mixture of diethyl ether, DCM and hexanes (2. 1 : 2, 5.0 mL) to give the title compound as an orange solid, Example 26 (18 mg ' 35%): m/z 607 (M+ H)+ (ES). NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.31 (6 H, s), 2.39 (3 H, s), 3.14 (2 H, s), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.29 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.65-7.55 (3H, m), 7.94 (1H, m), 8.38-8.28 (3H, m), 8.59 (1H, s), 8.79 (1H, s), 9.93 (1H, s). Example 27: N-(4- ((4-(3-(3-Terve-butyl-p-tolyl" Η·. than sial-5-yl) ureido) naphthalene-i-yloxy) fluorenyl) β ratio bite_2_ Base)_2_(Amidino) Ethylamine: 118 201130813

中間物BIntermediate B

MeNH2MeNH2

DIPEADIPEA

實例27 將曱胺(在THF中之2.0M溶液)(41微升，〇〇8毫莫耳)加至中間物B(50宅克’ 0·08毫莫耳)在dcm(1.0 毫升）、DMF(0.2宅升)及DIPEA(17微升，〇1〇毫莫耳) 的混合物中之溶液。將反應混合物加熱至4〇°c並攪拌 12小時。藉由管柱層析法純化粗製反應混合物（12克，在DCM中之〇-l〇〇/〇MeOH，梯度溶析）。產物部分被雜質污染及藉由管柱層析法再純化粗製材料（Si〇2，12 克’在DCM中之〇-l〇%MeOH，梯度溶析）以產生呈淡棕色固體之標題化合物，實例27(6毫克，12%): m/z 593 (M+H)+ (ES+)。NMR (400 MHz，DMSO-d6) δ : 1·27 (9 H, s), 2.32 (3 Η, s), 2.39 (3 Η, s), 3.28 (2 Η, s), 5.39 (2Η, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1H, m), 8.37 - 8.30 (3H，m), 8.59 (1H，s)，8.80 (1H，s)。實例28 : Ν-(4_((4-(3-(3·第三-丁基-1-對-甲苯基-1H-吡唾-5-基)脲基）萘小基氧基）甲基）π比啶-2-基)-2-((4·曱氧中間物Β 基苯曱基)（甲基)胺基）乙醯胺：Example 27 decylamine (2.0 M solution in THF) (41 μL, 〇〇 8 mmol) was added to Intermediate B (50 Km '0·08 mmol) in dcm (1.0 mL), A solution of a mixture of DMF (0.2 house liter) and DIPEA (17 microliters, 〇 1 〇 millimolar). The reaction mixture was heated to 4 ° C and stirred for 12 hours. The crude reaction mixture was purified by column chromatography (12 g, EtOAc EtOAc EtOAc) The product was partially contaminated with impurities and the crude material was repurified by column chromatography (Si </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 27 (6 mg, 12%): m/z 593 (M+H) + (ES+). NMR (400 MHz, DMSO-d6) δ: 1·27 (9 H, s), 2.32 (3 Η, s), 2.39 (3 Η, s), 3.28 (2 Η, s), 5.39 (2 Η, s ), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, d), 7.35 (2H, d), 7.44 (2H, d), 7.63-7.55 (3H, m), 7.93 (1H, m), 8.37 - 8.30 (3H,m), 8.59 (1H,s), 8.80 (1H,s). Example 28: Ν-(4_((4-(3-(3)-tert-butyl-1-p-tolyl-1H-pyran-5-yl)ureido)naphthalenyloxy)methyl Π-pyridin-2-yl)-2-((4. oxime intermediate mercaptophenyl) (methyl)amino) acetamidine:

DIPEADIPEA

實例28Example 28

OMe 119 201130813 將N-(4-曱氧基苯曱基)_N_曱胺（15 5微升，〇〇9毫莫耳)加至中間物B (50毫克，0.08毫莫耳)在DCMQ 〇毫升）、DMF(0.2毫升)及DIPEA(17.5微升，0.10毫莫耳）的混合物中之溶液且將反應混合物在$下攪拌12 小時。藉由管柱層析法純化粗製反應混合物（Si〇2，12 克’在DCM中之〇-l〇%MeOH，梯度溶析）。將產物部分在真空中濃縮並將殘餘物與二乙峻、DCM及異己烧的混合物(2 : 1 : 2，5.0毫升）一起研磨以提供呈白色固體之標題化合物，實例28(7毫克，ll%):m/z713(M+H；)+ (ES+)。iH NMR (400 MHz，DMSO-d6) δ : 1.27 (9 H，s)， 2.25 (3 Η, s), 2.39 (3 Η, s), 3.22 (2 Η, s), 3.59 (2 Η, s), 3.72 (3 Η, s), 5.38 (2Η, s), 6.35 (1H, s), 6.90 (2H, m), 7.01 (1H, m), 7.27 (3H, m), 7.35 (2H, m), 7.43 (2H, m), 7.64-7.55 (3H, m), 7.94 (1H, m), 8.37-8.28 (3H, m), 8.58 (1H, s)，8.79 (1H，s), 9.97 (1H, s)。實例29 : N-(4-((4-(3-(3-第三-丁基小對_曱苯基·1Η_〇Λ °坐-5-基）脲基）萘-1-基氧基）甲基）〇比咬_2_基)_2_(2_曱氧基乙硫基）乙醯胺：OMe 119 201130813 Add N-(4-decyloxyphenyl)-N-decylamine (15 5 μL, 〇〇 9 mmol) to Intermediate B (50 mg, 0.08 mmol) in DCMQ 〇 A solution of a mixture of ML), DMF (0.2 mL) and DIPEA (17.5 μL, 0.10 mmol) and the reaction mixture was stirred for 12 hours. The crude reaction mixture was purified by column chromatography (Si.sub.2, 12 g. <RTIgt; The product was concentrated in vacuo and EtOAc EtOAc m. %): m/z 713 (M+H;) + (ES+). iH NMR (400 MHz, DMSO-d6) δ : 1.27 (9 H, s), 2.25 (3 Η, s), 2.39 (3 Η, s), 3.22 (2 Η, s), 3.59 (2 Η, s) ), 3.72 (3 Η, s), 5.38 (2Η, s), 6.35 (1H, s), 6.90 (2H, m), 7.01 (1H, m), 7.27 (3H, m), 7.35 (2H, m ), 7.43 (2H, m), 7.64-7.55 (3H, m), 7.94 (1H, m), 8.37-8.28 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.97 ( 1H, s). Example 29: N-(4-((4-(3-(3-Terti-butyl-p-p-phenyl)-1Η_〇Λ °-5-yl)ureido)naphthalen-1-yloxy Base) methyl) hydrazine bite_2_yl)_2_(2_decyloxyethylthio)acetamide:

將2-曱氧基乙烷-1-硫醇(8_〇微升，（χιό毫莫耳)加 120 201130813 至中間物B (50毫克，0·08毫莫耳)在DCM(i.〇亳升）、 DMF(0.1毫升)及DIPEA(17微升，0·1〇毫莫耳）的混合物中之溶液。將反應混合物加熱至40 °C並撥摔18小時’其後添加另一部分之2-曱氧基乙烧硫醇(8.〇微升，0.10毫莫耳)及DIPEA(17微升，0.10毫莫耳)並在 40°C下繼續攪拌2天。將反應混合物在真空中蒸發並藉由急驟管柱層析法純化殘餘物(Si02，12克，在DCM 中之0-10%MeOH，梯度溶析）以提供不純產物，其與二 ***(3.0毫升）一起研磨及進一步藉由SCX捕捉和釋放純化以產生標題化合物，實例29，（25毫克，44%): m/z 653 (M+H)+ (ES+)。4 NMR (400 MHz，DMSO-d6) δ ： 1.27 (9Η, s), 2.39 (3Η, s), 2.80 (2H, t), 3.22 (3H, s), 3.41 (2H, s), 3.51 (2H, t), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56_7·64 (3H,重疊 m)，7.93 (1H，m), 8.29-8.33 (2H, 重疊 m)，8.35 (1H, m)，8.58 (1H, br s)，8.79 (1H，br s)， 10.61 (lH，br s)。實例30 : Ν·(4-((4-(3-(3-第三-丁基-1-對·曱苯基-1Η-»比唑-5-基）脲基）萘小基氧基）曱基）。比啶-2_基)_2_(2-(2-甲氧基乙氧基）乙硫基）乙醯胺：2-Methoxyethane-1-thiol (8_〇 microliter, (χιό millimol) plus 120 201130813 to intermediate B (50 mg, 0·08 mmol) in DCM (i.〇 a solution of a mixture of DMF, DMF (0.1 ml) and DIPEA (17 μl, 0.1 μm). Heat the reaction mixture to 40 ° C and drop for 18 hours. Then add another part. 2-methoxy ethoxylated mercaptan (8. 〇 microliter, 0.10 mmol) and DIPEA (17 μL, 0.10 mmol) and stirring was continued for 2 days at 40 ° C. The reaction mixture was placed in vacuo. Evaporation and purification by flash column chromatography (EtOAc EtOAc (EtOAc) Purification by SCX capture and liberation to give the title compound, mp., (29, (44%, 44%): m/z 653 (M+H) + (ES+). 4 NMR (400 MHz, DMSO-d6) δ: 1.27 (9Η, s), 2.39 (3Η, s), 2.80 (2H, t), 3.22 (3H, s), 3.41 (2H, s), 3.51 (2H, t), 5.38 (2H, s), 6.35 ( 1H, s), 7.01 (1H, d), 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56_7·64 (3H, overlap m), 7.93 (1H, m ), 8.29-8.33 (2H, overlap m), 8.35 (1H, m), 8.58 (1H, br s), 8.79 (1H, br s), 10.61 (lH, br s). Example 30: Ν·(4 -((4-(3-(3-Terti-butyl-1-p-p-phenyl-1Η-»bisazol-5-yl)ureido)naphthalenyloxy)indenyl). -2_yl)_2_(2-(2-methoxyethoxy)ethylthio)acetamide:

121 201130813 將2-(2-曱氧基乙氧基）乙烷硫醇(14微升，〇.10毫莫耳)加至中間物B(50毫克，0.08毫莫耳)在DCM(1.0 毫升）、DMF(0.1毫升)及DIPEA(17微升，0.10毫莫耳）的混合物中之溶液。將反應混合物加熱至40 °C並擾摔 18小時，其後添加另一部分之2-(2-曱氧基乙氧基）乙烧硫醇（14微升’ 〇.1〇毫莫耳)及DIPEA〇7微升，〇 1〇毫莫耳)並在40〇C下繼續攪拌2天。將反應混合物在真空中蒸發及藉由急驟管柱層析法純化殘餘物（Si〇2，12 克’在DCM中之，梯度溶析)以提供不純產物’其與二***(3.0毫升）一起研磨及進一步藉由scx 捕捉和釋放純化以產生標題化合物，實例3〇，（19毫克， 32〇/〇) ： m/z 697 (M+H)+ (ES+) 〇 ^ NMR (400 MhJ DMSO-d6) δ ： 1.27 (9Η, s), 2.39 (3Η, s), 2.79 (2Η, t), 3.21 (3H，s)，3.39-3.42 (4H，ί 疊 m)，3.49 (lH，d)，3.50(lH, dd), 3.59 (2H, t), 5.38 (2H, s), 6.35 (iH, s)j 7.〇1 (m d) 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H 重疊 m)，7.93 (1H，m), 8.29-8.32 (2H，重疊叫 835 (1H, dd), 8.58 (1H, br s), 8.79 (1H, br s), l〇.6l (lH, br s)。實例31 : N-(4-((4-(3_(3_第三-丁基小對_甲苯基κ 峻-5-基)脲基）萘-i_基氧基）曱基)。比。定基)_2·(2·嗎啉基乙硫基）乙醯胺： 122 201130813121 201130813 Add 2-(2-decyloxyethoxy)ethanethiol (14 μL, 〇.10 mmol) to Intermediate B (50 mg, 0.08 mmol) in DCM (1.0 mL) A solution of a mixture of DMF (0.1 mL) and DIPEA (17 μL, 0.10 mmol). The reaction mixture was heated to 40 ° C and spoiled for 18 hours, after which another portion of 2-(2-decyloxyethoxy) ethene thiol (14 μl '〇.1 〇 millimolar) was added and DIPEA 〇 7 μl, 〇 1 〇 millimolar) and continue stirring at 40 ° C for 2 days. The reaction mixture was evaporated in vacuo and EtOAc EtOAc (EtOAc) Grinding and further purification by scx capture and release to give the title compound, Example 3 〇, (19 mg, 32 〇/〇) : m/z 697 (M+H)+ (ES+) 〇^ NMR (400 MhJ DMSO- D6) δ : 1.27 (9Η, s), 2.39 (3Η, s), 2.79 (2Η, t), 3.21 (3H, s), 3.39-3.42 (4H, ί m), 3.49 (lH, d), 3.50(lH, dd), 3.59 (2H, t), 5.38 (2H, s), 6.35 (iH, s)j 7.〇1 (md) 7.27 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.56-7.64 (3H overlap m), 7.93 (1H, m), 8.29-8.32 (2H, overlap 835 (1H, dd), 8.58 (1H, br s), 8.79 (1H, br s), l〇.6l (lH, br s). Example 31: N-(4-((4-(3_(3_T-butyl-butyl-p-tolyl)-ytyl-5-yl)) Naphthyl-i-yloxy)indenyl). Ratio. Base)_2·(2·morpholinylethylthio)acetamide: 122 201130813

中間物BIntermediate B

DIPEADIPEA

實例31Example 31

Ο 將2-嗎啉-4-基-乙烷-1-硫醇（12微升，0.10毫莫耳) 加至中間物B(50毫克，0.08毫莫耳)在DCM(l.〇毫升）、 DMF(〇.l毫升）及DIPEA(17微升，〇 1()毫莫耳）的混合物中之溶液。將反應混合物加熱至40°C經18小時，其後添加另一部分之2-嗎啉-4-基-乙烷-1-硫醇（12微升， 0.10亳莫耳)&DIPEA(17微升，0.10毫莫耳)並在4〇〇c 下繼續攪拌2天。將反應混合物在真空中蒸發並藉由急驟管柱層析法純化（Si〇2，12克，在DCM中之 0-10 X>MeOH ’梯度溶析）以提供不純產物，其與二乙峻 (3.0毫升）、DCM(3.0毫升)及異己烷(5.0毫升）的混合物一起研磨且進一步藉由SCX捕捉和釋放純化以提供標題化合物’實例 31 ’（14 毫克，21%) : m/z 708 (M+H)+ (ES+)。咕 NMR (400 MHz，DMS〇-d6) δ : 1.27 (9H，s), 2.39 (3H，s)，2.43 (4H，very br s)，2.59 (2H，very br s), 2.78 (2H, br t), 3.42 (2H, s), 3.55 (4H, br s), 5.38 (2H, s), 6.35 (1H, s), 7.01 (m, d), 7.27 (lH, dd), 7.36 (2H, m), 7.44 (2H，m), 7.55-7.64 (3H,重疊 m)，7.95 (1H，m), 8.29-8.32 (2H，重疊 m)，8.35 (ih, dd), 8.63 (1H，s)， 8_83 (1H，s)，10.63 (lH，s)。實例32 : N_(4-((4-(3-(3-第三-丁基小對·甲苯基-1H-吼 123 201130813 。坐-5-基）脲基）萘-1-基氧基）曱基）》比咬_2_基）_2-(2-嗎琳基乙磺醯基）乙醯胺：2- Add 2-morpholin-4-yl-ethane-1-thiol (12 μl, 0.10 mmol) to Intermediate B (50 mg, 0.08 mmol) in DCM (1 mL) A solution of a mixture of DMF (〇.l mL) and DIPEA (17 μl, 〇1 () millimolar). The reaction mixture was heated to 40 ° C for 18 hours, after which another portion of 2-morpholin-4-yl-ethane-1-thiol (12 μL, 0.10 mmol) & DIPEA (17 micron) was added l, 0.10 mmol) and continue stirring for 2 days at 4 °c. The reaction mixture was evaporated in vacuo and purified by flash column chromatography eluting eluting eluting eluting eluting A mixture of (3.0 mL), DCM (3.0 mL), EtOAc (EtOAc) (M+H)+ (ES+).咕NMR (400 MHz, DMS〇-d6) δ : 1.27 (9H, s), 2.39 (3H, s), 2.43 (4H, very br s), 2.59 (2H, very br s), 2.78 (2H, br t), 3.42 (2H, s), 3.55 (4H, br s), 5.38 (2H, s), 6.35 (1H, s), 7.01 (m, d), 7.27 (lH, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.64 (3H, overlap m), 7.95 (1H, m), 8.29-8.32 (2H, overlap m), 8.35 (ih, dd), 8.63 (1H, s) , 8_83 (1H, s), 10.63 (lH, s). Example 32: N_(4-((4-(3-(3-Terve-butyl-p-tolyl-1H-indole 123 201130813. Sodium-5-yl))ureido)naphthalen-1-yloxy ) 曱 base)" than bite_2_ base)_2-(2-morphinylethanesulfonyl) acetamidine:

將OXONE®(39毫克，0.13毫莫耳)在水(〇.4毫升）中的溶液加至化合物，實例31，（30毫克，〇.〇4毫莫耳）在DMF(2.0毫升）中的溶液並將混合物在RT下授拌α 小時。將反應混合物用冰AcOH(1.0毫升)及鹽水(4.0毫升)稀釋且用DCM(4.0毫升)萃取。在真空中蒸發有機相且將殘餘物進行SCX捕捉和釋放及然後藉由急驟管柱層析法純化(Si02’ 12克，在DCM中的0-10〇/〇(在MeOH 中之1%NH3)，梯度溶析）。如此獲得之不純產物與 DCM(0.5毫升)及異己烷(3.0毫升）一起研磨以提供呈白色固體之標題化合物，實例32(7毫克，21%) : m/z 740 (M+H)+ (ES+)〇 ]H NMR (400 MHz, DMSO-d6) δ： 1.27 (9H, s), 2.39 (3H, s), 2.43 (4H, br m), 2.77 (2H, t), 3.51 (2H, t), 3.56 (4H, br t), 4.53 (2H, s), 5.40 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.32 (1H} m), 7.35 (2H, m), 7.44 (2H, m), 7.54-7.63 (3H，重疊 m)，7.93 (1H，m)，8.30-8.32 (2H, 重疊 m)，8.38 (1H，d)，8.64 (1H，br s)，8.84 (1H，br s)， 10.98 (1H，br s)。實例33 : 2·(雙(2-甲氧基乙基)胺基)-N-(4-((4-(3-(3-第三 124 201130813 -丁基-1-對·曱苯基-1H-«比唾-5-基)脲基）萘·i•基氧基）甲基)吡啶-2-基）乙醯胺：A solution of OXONE® (39 mg, 0.13 mmol) in water (〇. 4 mL) was added to the compound, Example 31, (30 mg, 〇. 〇 4 mM) in DMF (2.0 mL) The solution was mixed and allowed to mix for 5 hours at RT. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. The organic phase was evaporated in vacuo and the residue was taken <[Lambda]&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& ), gradient elution). The impure product thus obtained was triturated with DCM (0.5 mL) EtOAc (EtOAc) ES+)〇]H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.43 (4H, br m), 2.77 (2H, t), 3.51 (2H, t ), 3.56 (4H, br t), 4.53 (2H, s), 5.40 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.32 (1H} m), 7.35 (2H, m ), 7.44 (2H, m), 7.54-7.63 (3H, overlap m), 7.93 (1H, m), 8.30-8.32 (2H, overlap m), 8.38 (1H, d), 8.64 (1H, br s) , 8.84 (1H, br s), 10.98 (1H, br s). Example 33: 2·(bis(2-methoxyethyl)amino)-N-(4-((4-(3-(3-third 124 201130813)-butyl-1-p-phenyl) -1H-«pyr-5-yl)ureido)naphthalene·i•yloxy)methyl)pyridin-2-yl)acetamide:

將雙(2-曱氧基乙基)胺（15微升，0.10毫莫耳)加至中間物B(50毫克，0.08毫莫耳)在DCM(l.〇毫升）、 DMF(〇.l毫升）及DlPEA(i7微升，〇 1〇毫莫耳）中的混合物的溶液。將反應混合物在40°C下攪拌18小時且然後添加另一部分的雙(2_甲氧基乙基）胺（15微升，〇 = 毫莫耳)及DIPEA(17微升，0.10毫莫耳)並在4〇〇c下繼續攪拌4天。在真空中蒸發反應混合物並藉由急驟管柱層析法將殘餘物純化三次(Si〇2，2x 12克，在DCM中之 0-20%MeOH 及 Si〇2，4 克’在 DCM 中的〇_ι〇(^[在 MeOH中之1%NH3]，梯度溶析）以提供標題化合物，實例 33，（13 毫克，22%): m/z 694 (M+H)+ (ES+)。 (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2.39 (3H, s) 2.79-2.81 (4H, t)，3.21 (6H，s)，3.34 (2H，s)，3.42 (4H，t)’ 5.38 (2H，s)，6.35 (1H，s)，7.01 (1H, d)，7.27 (1H，邮， 7.36 (2H, m)，7.44 (2H，m)，7.56-7.63 (3H，重叠 m)’ 7.93 (1H, m)，8.30-8.35 (2H，重疊 m)，8.38 (1H, br s)’ 8.58 (1H，br s)，8.79 (1H，br s)，10.14 (1H，br s)。 ’ 中間物C: 1-(4-((3-胺基吨啶-4-基）曱氧基)萘+基 125 弟三-丁基-1-對-甲苯基_1H_吡唑-5·基)脲。Add bis(2-decyloxyethyl)amine (15 μL, 0.10 mmol) to Intermediate B (50 mg, 0.08 mmol) in DCM (1 mL), DMF (〇.l) ML) and a solution of the mixture in DlPEA (i7 μl, 〇 1 〇 millimolar). The reaction mixture was stirred at 40 ° C for 18 hours and then another portion of bis(2-methoxyethyl)amine (15 μL, 〇 = mmol) and DIPEA (17 μL, 0.10 mmol) was added. ) and continue stirring for 4 days at 4 °c. The reaction mixture was evaporated in vacuo and the residue was purified EtOAc EtOAc EtOAc EtOAc 〇〇〇〇 ^ ^ ^ 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 (400 MHz, DMSO-d6) δ : 1.27 (9H, s), 2.39 (3H, s) 2.79-2.81 (4H, t), 3.21 (6H, s), 3.34 (2H, s), 3.42 (4H, t)' 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.27 (1H, post, 7.36 (2H, m), 7.44 (2H, m), 7.56-7.63 (3H, Overlap m)' 7.93 (1H, m), 8.30-8.35 (2H, overlap m), 8.38 (1H, br s)' 8.58 (1H, br s), 8.79 (1H, br s), 10.14 (1H, br s). Intermediate C: 1-(4-((3-aminotoxin-4-yl)methoxy)naphthalene+yl 125-tris-tert-butyl-1-p-tolyl-1H-pyridyl Azul-5-yl)urea.

201130813 ^ 將氫化鈉（1.55克，38.7毫莫耳，60重量t%)加至(3_ 胺基-吡啶基)-曱醇（13)(4.00克，32.2亳莫耳)在無水 THF(160毫升）中於〇〇c下的溶液。攪拌2〇分鐘之後，添加1-氟-4-硝基萘（14)(6.16克，32.2毫莫耳），移除冰浴且留下反應混合物加熱至RT並攪拌12小時。將反應混合物分溶在EtOAc (200毫升)及NaHC03飽和水溶液（150毫升)之間。將殘留黃色固體以過濾收集及隨後用水(50毫升）、MeOH(50毫升)及二***（100毫升）洗務且以LC-MS及1H NMR確認為所要產物。濾液回到分液漏斗；收集有機相並用鹽水(100毫升)洗滌，乾燥並在真空中濃縮以提供橙色殘餘物。橙色殘餘物與 MeOH(200毫升）一起磨提供橙色固體，將其用二乙趟 126 201130813 (200毫升）洗滌。橙色固體之LC-MS及1HNMR分析和觀察早先不溶解固體所獲得者相同。將二個產物合併以提供4-((4-硝基萘-1-基氧基）曱基）π比啶-3-胺（15)(7.80 克，77%) : m/z 296 (M+H)+ (ES+)。將二碳酸二-第三-丁酯（2.33克，10.7毫莫耳）在 THF(15毫升）中的溶液加至（15)(3.〇〇克，10.2毫莫耳）及DMAP(0.25克，2.03毫莫耳)在THF(30毫升）中的懸浮液。2-3分鐘之後獲得溶液。將反應混合物在RT下攪拌12小時因此添加另外的二碳酸二_第三_丁酯（2.33 克，10.7毫莫耳)且將反應混合物在RT下攪拌12小時。將反應分溶在EtOAc(100毫升)及NaHC03飽和水溶液 (50毫升）之間。將有機層收集，乾燥並在真空中濃縮以提供撥色油。藉由管柱層析法純化該油（在異己烷中之 0-50%EtOAc ’梯度溶析）以提供呈橙色油之4-((4-硝基萘-1-基氧基）甲基）吡啶_3_基亞胺基二碳酸二_第三_丁醋（16) ’其後來在靜置時結晶(2 33克，43%) : m/z 496 (M+H)+ (ES+)。將（16)(2.30克，4.64毫莫耳)在]^011(100毫升)及 Ac〇H (20毫升）中的溶液通過Thales H-立方體（1.0毫升. 分鐘 1 ’ 25°C，55 毫米 l〇%pt/c Cat-Cart，全氫模式）並在真空中除去揮發物以提供呈棕色油之4_((4胺萘小基氧基）曱基）η比咬_3_基亞胺基二碳酸二_第三·丁酯（17) (2.12 克，82°/〇) : m/z 466 (M+H)+ (ES+)。將(5)(1.55克，6.77毫莫耳)在DCM(4.0毫升）中的201130813 ^ Add sodium hydride (1.55 g, 38.7 mmol, 60 wt%) to (3-amino-pyridyl)-nonanol (13) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) ) a solution in 〇〇c. After stirring for 2 minutes, 1-fluoro-4-nitronaphthalene (14) (6.16 g, 32.2 mmol) was added, the ice bath was removed and the reaction mixture was allowed to warm to RT and stirred for 12 hours. The reaction mixture was partitioned between EtOAc (EtOAc) (EtOAc) The residual yellow solid was collected by EtOAc (EtOAc) elute The filtrate was returned to a sep. funnel; the organic phase was collected and washed with brine (100 mL). The orange residue was triturated with EtOAc (EtOAc)EtOAc. The LC-MS and 1H NMR analyses of the orange solid were identical to those obtained for the earlier insoluble solids. The two products were combined to give 4-((4-nitronaphthalen-1-yloxy)indenyl) π-pyridin-3-amine (15) (7.80 g, 77%): m/z 296 (M) +H)+ (ES+). A solution of di-tert-butyl dicarbonate (2.33 g, 10.7 mmol) in THF (15 mL) was added to (15) (3 g, 10.2 mmol) and DMAP (0.25 g) , 2.03 mmol of a suspension in THF (30 mL). The solution was obtained after 2-3 minutes. The reaction mixture was stirred at RT for 12 h then additional di-tert-butyl ester (2.33 g, 10.7 mmol) was added and the mixture was stirred at RT for 12 h. The reaction was partitioned between EtOAc (EtOAc)EtOAc. The organic layer was collected, dried and concentrated in vacuo to give a coloured oil. The oil was purified by column chromatography (0-50% EtOAc in hexanes) eluted to afford 4-((4-naphthalaphthalen-1-yloxy)methyl as an orange oil. Pyridine _3_iminoimidodicarbonate _ third _ vinegar (16) 'which later crystallizes upon standing (2 33 g, 43%): m/z 496 (M+H)+ (ES+ ). A solution of (16) (2.30 g, 4.64 mmol) in ^^ 011 (100 mL) and Ac 〇 H (20 mL) was passed through Thales H-cucumber (1.0 ml. min 1 ' 25 ° C, 55 mm L〇%pt/c Cat-Cart, full hydrogen mode) and remove volatiles in vacuo to provide 4_((4-aminonaphthalenyloxy)) fluorenyl) η as a brown oil. Di-tert-butyl phthalate (17) (2.12 g, 82°/〇): m/z 466 (M+H)+ (ES+). (5) (1.55 g, 6.77 mmol) in DCM (4.0 mL)

溶液經25分鐘逐滴加至cdi (1.1〇克，6.77毫莫耳)在 DCM(4.0毫升）中於RT的懸浮液，將反應混合物在RT 127 201130813 下攪拌80分鐘並將4-((4-胺基萘_丨_基氧基）甲基)吡啶 -3-基亞胺基二碳酸二-第三·丁酯（17)(2.10克，4.51毫莫耳)在DCM(l〇毫升）中的溶液一次性加至反應混合物並攪拌12小時。將反應混合物分溶在NaHC03飽和水溶液(20毫升)及DCM(20毫升)之間。將有機層收集、乾燥並在真空中濃縮以提供紫色殘餘物。藉由管柱層析法純化粗製材料(80克，在異己烷中之〇_i〇〇〇/〇Et〇Ac，梯度溶析）以提供呈紫色固體之4-((4-(3-(3-第三-丁基-1-對·甲苯基-1Η-πΛπ坐-5-基）脲基）萘_ι·基氧基）甲基）吼咬 -3-基亞胺基二碳酸二-第三-丁酯（18)(1.77克，53%): m/z 721 (M+H)+ (ES+)。將TFA(2.0毫升）加至亞胺基二碳酸酯（i8)(i.7〇克，2.36毫莫耳)在DCM(10毫升）中的溶液。在rt下 1小時之後添加另外TFA(2.0毫升）並反應混合物在rt 下攪拌12小時。在真空中除去溶劑及將產物藉由scx 捕捉和釋放純化，接著與DCM(20毫升）一起研磨以提供呈淺黃色固體之標題化合物，中間物C(〇.96克， 77%) : m/z 521 (M+H)+ (ES+)。NMR (400 MHz， DMSO-d6) δ ： 1.27 (9 H, s), 2.39 (3 Η, s), 5.16 (2 Η, s), 5.38 (2 Η，s)，6.35 (1Η，s)，7·05 (1Η, d)，7.32 (1Η，d)，7.35 (2H, d), 7.43 (2H, m), 7.64-7.51 (2H, m), 7.63 (1H, d), 7.82 (1H, d), 7.91 (1H, m), 8.03 (1H, s), 8.29 (1H, m), 8.57 (1H，s)，8.78 (1H, s)。實例34: 1-(4-((3•曱基脲基。比咬_4_基）曱氧基）萘小基)-3-(3-第三-丁基_1_對-甲笨基·吡唑_5_基)脲： 128 201130813The solution was added dropwise to a suspension of cdi (1.1 g, 6.77 mmol) in DCM (4.0 mL) in RT over 25 min and the reaction mixture was stirred at RT 127 201130813 for 80 min and 4-((4) -Aminonaphthalene-丨-yloxy)methyl)pyridin-3-ylimidodicarbonate di-t-butyl ester (17) (2.10 g, 4.51 mmol) in DCM (1 mL) The solution in the solution was added to the reaction mixture in one portion and stirred for 12 hours. The reaction mixture was partitioned between EtOAc (EtOAc m. The organic layer was collected, dried and concentrated in vacuo to afford a purple residue. The crude material was purified by column chromatography (80 g, EtOAc EtOAc EtOAc EtOAc EtOAc (3-Terti-butyl-1-p-tolyl-1Η-πΛπ-spin-5-yl)ureido)naphthalene_ι·yloxy)methyl)indan-3-ylimidodicarbonate Di-tertiary-butyl ester (18) (1.77 g, 53%): m/z 721 (M+H) + (ES+). A solution of the iminodicarbonate (i8) (i.7 g, 2.36 mmol) in DCM (10 mL). Additional TFA (2.0 mL) was added 1 h after rt and the mixture was stirred at rt for 12 h. The solvent was removed in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; z 521 (M+H)+ (ES+). NMR (400 MHz, DMSO-d6) δ : 1.27 (9 H, s), 2.39 (3 Η, s), 5.16 (2 Η, s), 5.38 (2 Η, s), 6.35 (1 Η, s), 7·05 (1Η, d), 7.32 (1Η, d), 7.35 (2H, d), 7.43 (2H, m), 7.64-7.51 (2H, m), 7.63 (1H, d), 7.82 (1H, d), 7.91 (1H, m), 8.03 (1H, s), 8.29 (1H, m), 8.57 (1H, s), 8.78 (1H, s). Example 34: 1-(4-((3•曱-ureido) than 咬4_yl) methoxy)naphthalene)-3-(3-tert-butyl_1_p--stupid Base pyrazole _5_yl) urea: 128 201130813

中間物c MeNCOIntermediate c MeNCO

C(50 反應混合物在RT下攪拌2小時及添加另一部分之異氰酸曱醋(8.5微升，0.14毫莫耳)且在RT下揽摔繼續72 小時。在真空中除去溶劑且藉由管柱層析法純化粗製產物（Si〇2’4克’在DCM中之10-25%MeOH，梯度溶析）。將粗製產物部分合併並與DCM(2〇毫升）一起研磨。過濾出固體以提供標題化合物(實例34)(8毫克，14%): m/z 578 (M+H)+ (ES+)。巾 NMR (400 MHz，DMSO-d6) δ ： 1.27 (9 H, s), 2.39 (3 Η, s), 2.68 (3 Η, d), 5.27 (2Η, s), 6.35 (1H, s), 6.53 (1H, m), 6.98 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.65 - 7.52 (4H, m), 7.92 (1H, d), 8.16 (1H, s)，8·28 (2H，m)，8·61 (1H, s)，8·82 (1H，s)，8.88 (1H，s)。實例35 : N，(4-((4-(3-(3-第三-丁基_1-對-曱苯基-1H-口比唑-5-基)脲基）萘基氧基）曱基户比啶·3_*)_2ν曱氧基乙醯胺：C (50 reaction mixture was stirred at RT for 2 hours and another portion of isocyanic acid vinegar (8.5 μL, 0.14 mmol) was added and the mixture was dropped at RT for 72 hours. The solvent was removed in vacuo and passed through a tube. The crude product was purified by column chromatography eluting with EtOAc (EtOAc: EtOAc:EtOAc. The title compound was obtained (Example 34) (8 mg, 14%): m/z 578 (M+H) + (ES+). NMR (400 MHz, DMSO-d6) δ: 1.27 (9 H, s), 2.39 (3 Η, s), 2.68 (3 Η, d), 5.27 (2Η, s), 6.35 (1H, s), 6.53 (1H, m), 6.98 (1H, d), 7.35 (2H, d), 7.45 (2H, d), 7.65 - 7.52 (4H, m), 7.92 (1H, d), 8.16 (1H, s), 8·28 (2H, m), 8.61 (1H, s), 8· 82 (1H, s), 8.88 (1H, s). Example 35: N,(4-((4-(3-(3-)-tert-butyl-l-p-phenyl)-1H-port ratio Oxazol-5-yl)ureido)naphthyloxy)indoleylpyridinium·3_*)_2ν曱oxyacetamide:

將曱氧基乙醯氣（1〇微升，011毫莫耳)加至中間物 129 201130813 ι(50毫克，0.10毫莫耳)及DIPEA(33 5微升，〇 19毫莫耳)在無水DCM(l.〇毫升)及無水DMF(〇1毫升）中的溶液並將反應混合物在RT下攪拌12小時。添加另外甲氧基乙醯氯（10微升，0.11毫莫耳）且將反應混合物在 RT下攪拌5小時。添加另一部分甲氧基乙醯氣(8微升， 0.09毫莫耳）且2小時之後添加氨的溶液(在馗6〇11中之1%’ 10毫升）且將反應混合物在RT下攪拌2〇分鐘。在真空中除去溶劑以提供紫色油狀固體。將此溶解在 MeOH(2.0毫升）中及添加3滴AcOH。使溶液進行scx 捕捉和釋放’用在MeOH中之1%NH3溶析產物。在真空中除去溶劑及將殘餘物與二***（1〇毫升）一起研磨以提供呈淡紫色固體之標題化合物，實例35(24毫克， 41%) m/Z 593 (M+H)+(ES+)。咕 NMR (400 MHz， DMSO-d6) δ : 1.27 (9 H，s)，2,39 (3 H，s)，3.31 (3 H，S (被 DHO 峰掩蓋))，4.06 (2Η，s)，5.34 (2Η，s)，6.35 (1Η，s), 6.96 (1Η, d), 7.35 (2H, d), 7.43 (2H, d), 7.64-7.54 (4H, m), 7.93 (1H, d), 8.29 (1H, dd), 8.45 (1H, d), 8.58 (1H, s), 8.70 (1H, s), 8.79 (1H，S)，9.76 (1H，S)。 ’ ’ 實例36 : Ν-(4-((4·(3-(3_第三-丁基小對-曱苯基-m_吡哇-5-基）脲基）萘-1-基氧基）曱基）吡啶_3_基)_2_(2_曱氧基乙氧基）乙醯胺：Add methoxyethyl oxime (1 〇 microliter, 011 mmol) to intermediate 129 201130813 ι (50 mg, 0.10 mmol) and DIPEA (33 5 μl, 〇19 mmol) in anhydrous A solution of DCM (1 mL) and dry DMF (1 mL) Additional methoxyethyl hydrazine chloride (10 μL, 0.11 mmol) was added and the reaction mixture was stirred at RT for 5 h. Add another portion of methoxyacetamidine (8 μL, 0.09 mmol) and add ammonia solution (1% '10 mL in 馗6〇11) after 2 hours and stir the reaction mixture at RT 2 Minutes. The solvent was removed in vacuo to afford a purple oily solid. This was dissolved in MeOH (2.0 mL) and 3 drops of AcOH were added. The solution was subjected to scx capture and release '1% NH3 eluted product in MeOH. The solvent was removed in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> ).咕NMR (400 MHz, DMSO-d6) δ : 1.27 (9 H, s), 2, 39 (3 H, s), 3.31 (3 H, S (masked by DHO peak)), 4.06 (2Η, s) , 5.34 (2Η, s), 6.35 (1Η, s), 6.96 (1Η, d), 7.35 (2H, d), 7.43 (2H, d), 7.64-7.54 (4H, m), 7.93 (1H, d ), 8.29 (1H, dd), 8.45 (1H, d), 8.58 (1H, s), 8.70 (1H, s), 8.79 (1H, S), 9.76 (1H, S). Example 36: Ν-(4-((4·(3-(3_T-butylbutyl-p-phenyl)-m-pyran-5-yl)ureido)naphthalen-1-yloxy Base) hydrazino) pyridine _3_yl)_2_(2_decyloxyethoxy)acetamide:

實例36 130 201130813 將2-(2-甲氧基乙氧基）乙醯氯(15微升〇11毫莫耳) 加炱中間物C(50毫克，0·10毫莫耳)及DIpEA(33 5微升，0·19氅莫耳)在無水DCM(1.0毫升)及無水DMF(0.2 毫升）的混合物中之溶液並將反應混合物在RT下攪拌 12小時。添加第二部分之2-(2-甲氧基乙氧基）乙醯氣（15 微升，0.11毫莫耳)且將反應混合物在RT下攪拌6小時。添加甲醇(2.0毫升)及AcOH(5滴）並使反應混合物進·^丁 SCX捕捉和釋放’用在MeOH中之1%NH3溶析。在真空中除去溶劑及藉由管柱層析法純化粗製材料 (Si02，4克’在Et〇Ac中之〇1〇%Me〇H，梯度溶析）以提供呈白色固體之標題化合物，實例36(27毫克， 43/〇) · m/z 637 (M+H)+ (ES+)。b NMR (400 MHz, DMS〇-d6) δ ： 1.27 (9 H, s), 2.39 (3 Η, s), 3.18 (3 Η, s), 3.36 (2 Η，m)，3.61 (2 Η, m)，4.14 (2Η，s)，5·33 (2Η，s)， 6-35 (1H, S), 6.97 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67 -7.55 (4H, m), 7.92 (1H, d), 8.27 (1H, d), 8.46 (1H, d), 8 58 (1H，s)，8.74 (1H，s)，8.80 (1H，s)，9.65 (1H, s)。中間物D: 1-(4-(2-(2-胺基吼啶_4_基）乙氧基）.4-基)-3-(3-第三•丁基·^對―甲苯基_1H_吡唑_5_基)脲。 131 201130813 C02Et ΌΗExample 36 130 201130813 2-(2-Methoxyethoxy)ethyl hydrazine chloride (15 μl 〇 11 mmol) plus intermediate C (50 mg, 0·10 mmol) and DIpEA (33 A solution of 5 microliters, 0. 19 moles in a mixture of anhydrous DCM (1.0 mL) and dry DMF (0.2 mL) A second portion of 2-(2-methoxyethoxy)acetamidine (15 μL, 0.11 mmol) was added and the mixture was stirred at RT for 6 h. Methanol (2.0 mL) and AcOH (5 drops) were added and the reaction mixture was taken to <RTI ID=0.0>> The solvent was removed in vacuo and the crude material was purified by column chromatography (EtOAc, EtOAc (EtOAc: EtOAc) 36 (27 mg, 43/〇) · m/z 637 (M+H)+ (ES+). b NMR (400 MHz, DMS〇-d6) δ : 1.27 (9 H, s), 2.39 (3 Η, s), 3.18 (3 Η, s), 3.36 (2 Η, m), 3.61 (2 Η, m), 4.14 (2Η, s), 5·33 (2Η, s), 6-35 (1H, S), 6.97 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.67 -7.55 (4H, m), 7.92 (1H, d), 8.27 (1H, d), 8.46 (1H, d), 8 58 (1H, s), 8.74 (1H, s), 8.80 (1H, s) , 9.65 (1H, s). Intermediate D: 1-(4-(2-(2-Aminoacridinyl-4-yl)ethoxy). 4-yl)-3-(3-t-butyl-butyl-p-tolyl _1H_pyrazole-5-yl)urea. 131 201130813 C02Et ΌΗ

R = H;中間物D 經1小時將DIBAL(在THF中之1M溶液，71.3毫升，71.3毫莫耳)加至2-(2-(第三-丁氧羰胺基)比啶_4· 基）乙酸乙酯（19)(WO 2007/089512)(10.0 克，35.7 毫莫耳)在氮氣下在THF (100毫升）中於-78°C的攪拌溶液β 將反應混合物在-78至-60°C下攪拌40分鐘且然後經 1小時加熱至-15°C。將溶液再冷卻至_780C且用另 DIBAL(在THF中之1M溶液，35毫升，35.7毫莫耳) 處理。使混合物加熱至-40°C並攪拌1小時。慎重地加水(10毫升）以使反應停止’接著添加MgS〇4(20克)及藉由過濾移出固體。在真空中將濾液蒸發至乾並使殘餘物進行管柱層析法（Si〇2，330克，在己烷中之65 %Et〇Ae) 以產生黃色固體之4-(2-經乙基比。定_2_基胺曱酸第三· 丁西曰（20)(6.00 克，64%)呈：m/z 239 (M+H)+ (ES+)。將II化鈉（2.52克，63.0毫莫耳，60重量％)在〇〇c 下加至4-(2-羥乙基）吡啶_2_基胺曱酸第三·丁酯 (2〇)(6.00克’ M.2毫莫耳)在THF(7〇毫升）中的溶液。將鮮黃色懸浮液在0°C下攪拌20分鐘及以單一部分添 132 201130813 加1-1-44肖基萘(14)(4.81克，25.2毫莫耳）。在RT下攪拌2小時之後，加水(100毫升)接著加EtOAc(100毫升）。藉由過濾收集在層之間所形成之固體並將有機相用NaHC03飽和水溶液(1〇〇毫升）、鹽水（1〇〇毫升)洗滌及乾燥。除去揮發物以產橙色固體。將固體合併並與 MeOH(50毫升）一起研磨以產生呈黃色固體之4-(2-(4-罐基萘-1-基氧基）乙基）°比咬-2-基胺曱酸第三-丁酯 (21)(11.0 克，98%) : m/z 410 (M+H)+ (ES+)。將4-(2-(4-石肖基萘-1-基氧基）乙基)〇比〇定_2_基胺曱酸第三-丁酯（21)(5.20克’ 12.7毫莫耳)及鐵網(4.30克，76 毫莫耳）的混合物懸浮於AcOH及EtOH(l :2，120毫升) 中且加熱至60°C並快速地攪拌直到反應以LC-MS判斷為完全。將混合物冷卻至RT，心地倒進NaHC03飽和水溶液（1000毫升）中且用EtOAc萃取(500毫升X 2)。將合併之有機層用NaHC03飽和水溶液（1〇〇〇毫升）、水 (1000毫升）、鹽水（1〇〇〇毫升)洗滌及乾燥。將溶液過濾並在真空中蒸發以產生呈黃色油之4-(2-(4-胺基萘-1-基氧基）乙基）°比啶-2-基胺曱酸第三-丁酯（22)(5.00克， 95%) : m/z 380 (M+H)+ (ES+)。經1.5小時將吡唑胺(5)(4.17克，18.18毫莫耳)在 DCM(40毫升）中的溶液加至cdi (3.00克，18.18毫莫耳)在DCM(15毫升）中的攪拌懸浮液。在RT下2小時之後添加萘胺(22)(3.00克，7.91毫莫耳)在DCM(15毫升）中的溶液。攪拌過夜之後，將溶液用Me〇H (10毫升) 稀釋及預吸附在矽凝膠(3〇克）上且進行管柱層析法 (Si〇2 ’ 330克’在異己烷中之3〇%至1〇〇%Et〇Ac且然 133 201130813 设在EtOAc中之0%至6%MeOH)以產生呈米黃色固體之第三-丁基-4-(2-(4-(3-(3-第三-丁基·1·對-甲苯基_1Η· °比。坐_5_基）脈基）萘_ι_基氧基）乙基）η比咬_2-基胺曱酸酉旨 (23) (4.20 克，80%) : m/z 635 (M+H)+ (ES+)。將TFA(10毫升)力σ至胺曱酸酯(23)(1.35克，2.20毫莫耳)在DCM(10毫升）中的懸浮液。在RJ下撥拌2小時之後，蒸發揮發物並將殘餘物溶解在EtOAc(50毫升) 中且用NaHC〇3飽和水溶液(50毫升）萃取。將有機層分離並用鹽水(50毫升）洗滌’且然後乾燥及蒸發以產生呈淡粉紅色固體之標題化合物，中間物D(l.20克， 100%) : m/z 535 (M+H)+ (ES+)。貫例37 . N-(4-(2-(4-(3-(3-第三-丁基-1-對曱苯基_出_ 〇比哇-5_基)脈基）奈-1·基氧基）乙基)0比咬_2_基)-2-曱氧基乙醯胺：R = H; Intermediate D DIBAL (1 M solution in THF, 71.3 mL, 71.3 mmol) was added to 2-(2-(T-butoxycarbonylamino)pyridinium_4· over 1 hour. Ethyl acetate (19) (WO 2007/089512) (10.0 g, 35.7 mmol) in a stirred solution of -78 ° C in THF (100 mL) under nitrogen. Stir at 60 ° C for 40 minutes and then heat to -15 ° C over 1 hour. The solution was re-cooled to _780C and treated with additional DIB (1M solution in THF, 35 mL, 35.7 m.). The mixture was heated to -40 ° C and stirred for 1 hour. Water (10 ml) was carefully added to stop the reaction. Then MgS 4 (20 g) was added and the solid was removed by filtration. The filtrate was evaporated to dryness in vacuo andqqqqqqqqqqqqqqq The ratio of _2_ sulphonic acid third · Dingxi (20) (6.00 g, 64%) is: m / z 239 (M + H) + (ES +). II sodium (2.52 g, 63.0 millimoles, 60% by weight) is added to 4-(2-hydroxyethyl)pyridine-2-aminoamine decanoic acid tert-butyl ester (2 〇) under 〇〇c (6.00 g 'M. 2 mil a solution of the molar in THF (7 mL). The fresh yellow suspension was stirred at 0 °C for 20 minutes and added to a single portion of 132 201130813 plus 1-1-44 succinyl (14) (4.81 g, After stirring for 2 hours at RT, water (100 mL) was added followed by EtOAc (100 mL). The solid formed between layers was collected by filtration and the organic phase was saturated with NaHC03 (1 〇 Washed and dried with brine (1 mL). EtOAc (EtOAc m.) (naphthalen-1-yloxy)ethyl) ° bite-2-ylamine citrate tri-butyl ester (21) (11.0 g, 98%): m/z 410 (M+H)+ (ES+). 4-(2-(4-Synylnaphthalen-1-yloxy)ethyl) 〇 A mixture of tert-butyl amide (21) (5.20 g '12.7 mmol) and iron mesh (4.30 g, 76 mmol) was suspended in AcOH and EtOH (1:2, 120 mL) and The mixture was heated to 60 ° C and stirred rapidly until the reaction was judged to be complete with LC-MS. The mixture was cooled to RT, poured into a saturated aqueous NaHCO3 (1000 mL) and extracted with EtOAc (500 mL). The organic layer was washed with aq. aq. NaH.sub.3 (1 mL), EtOAc (EtOAc) -(4-Aminonaphthalen-1-yloxy)ethyl)-pyridin-2-ylamine decanoic acid tert-butyl ester (22) (5.00 g, 95%): m/z 380 (M+ H) + (ES+). A solution of pyrazolamine (5) (4.17 g, 18.18 mmol) in DCM (40 mL) was added to EtOAc (3. Stirred suspension in 15 ml). Add naphthylamine (22) (3.00 g, 7.91 mmol) in DCM after 2 hours at RT (15 m The solution in liter. After stirring overnight, the solution was diluted with Me〇H (10 ml) and pre-adsorbed on a ruthenium gel (3 gram) and subjected to column chromatography (Si〇2 '330 g' at 3〇% to 1〇〇%Et〇Ac in isohexane and 133 201130813 in 0% to 6% MeOH in EtOAc to give a tris-butyl-4-(2-( 4-(3-(3-Terti-butyl·1·p-tolyl-1Η·° ratio. Sit _5_yl) ketone) naphthalene_ι_yloxy)ethyl) η than bite 2-aminoamine citrate (23) (4.20 g, 80%): m/z 635 (M+ H)+ (ES+). A suspension of TFA (10 mL) from EtOAc (EtOAc) (EtOAc) After 2 hrs of EtOAc (3 mL), EtOAc. The organic layer was separated and washed with brine (50 mL) then dried and evaporated to give the title compound as a pale pink solid, Intermediate D (1.20 g, 100%): m/z 535 (M+H) + (ES+). Example 37. N-(4-(2-(4-(3-(3-Terti-butyl-1-p-phenylene)- 〇〇哇哇-5_yl))) · ethoxy)ethyl)0 than bite_2_yl)-2-decyloxyacetamide:

將DIPEA(23微升，〇.131毫莫耳)及甲氧基乙酿氯 (7微升，0.072毫莫耳)加至中間物D(35毫克，〇〇65毫莫耳)在DCM(0.5毫升）中的懸浮液且在RT下攪拌混合物，直到以LC-MS判斷為完全。將反應混合物用 NaHC〇3飽和水溶液（1.5毫升)稀釋及通過相分離離該等層。收集有機物，在減壓下蒸發並使殘餘物^刀 sex捕捉和釋放。藉由製備型RPHPLC進—步純化= 134 201130813 得殘餘物以產生呈白色固體之標題化合物’實例37(5 毫克，13%): m/z 607 (M+H)+ (ES+)。】H NMR (40〇 MHz， DMSO-d6) δ ： 1.26 (9 H, s), 2.37 (3 H, s), 3.20 (2 H, t), 3.37 (3 H, s), 4.06 (2 H, s), 4.38 (2 H, t), 6.33 (1 H, s), 6.95 (1 H, d), 7.19 (1 H, dd), 7.33 (2 H, m), 7.42-7.47 (3 H, m), 7.54 (1 H, m), 7.59 (1 H, d), 7.87 (1 H, d), 8.12 (1 H，d)，8.18 (1 H，br s)，8.23 (1 H，d)，8.67 (1 H，s)，8.84 (1 H，s)，9.89 (1 H，s)。實例38 : N-(4-(2-(4-(3-(3-第三-丁基小對-曱苯基-1H-°比唑-5-基）脲基）萘-1-基氧基）乙基广比啶-2-基)-2-(2-甲氧基乙氧基）乙醯胺：DIPEA (23 μl, 131.131 mmol) and methoxyethyl chloride (7 μL, 0.072 mmol) were added to Intermediate D (35 mg, 〇〇 65 mmol) in DCM ( The suspension in 0.5 ml) and the mixture was stirred at RT until it was judged to be complete by LC-MS. The reaction mixture was diluted with a saturated aqueous solution of NaHC.sub.3 (l.sub.1 mL) and the layers were separated by phase. The organics were collected, evaporated under reduced pressure and the residue was taken and taken. The residue was purified by preparative EtOAc EtOAc EtOAc (EtOAc) H NMR (40 〇 MHz, DMSO-d6) δ : 1.26 (9 H, s), 2.37 (3 H, s), 3.20 (2 H, t), 3.37 (3 H, s), 4.06 (2 H , s), 4.38 (2 H, t), 6.33 (1 H, s), 6.95 (1 H, d), 7.19 (1 H, dd), 7.33 (2 H, m), 7.42-7.47 (3 H , m), 7.54 (1 H, m), 7.59 (1 H, d), 7.87 (1 H, d), 8.12 (1 H, d), 8.18 (1 H, br s), 8.23 (1 H, d), 8.67 (1 H, s), 8.84 (1 H, s), 9.89 (1 H, s). Example 38: N-(4-(2-(4-(3-(3-Terve-butyl-p-p-phenyl)-1H-~bazin-5-yl)ureido)naphthalen-1-yl Oxy)ethylpolypyridin-2-yl)-2-(2-methoxyethoxy)acetamide:

將DIPEA(23微升’ 0.Π1毫莫耳)及2_(2_曱氧基）乙氧基乙醯氯(11毫克，0.072毫莫耳)加至中間物D(35 毫克’ 0.〇65毫莫耳)在DCM(0.5亳升）中的懸雜並在混合物用飽和水NaHCQ3^(1.5 14、"^。將反應分離筒分離料層。收集有機物，在稀f及通過相餘物進行sex敵和麟。藉由製備U蒸發及使殘步純化所得殘餘物以產生呈灰白“ PHPLC進一物，實例38(13毫克，31%) : m/z6 ^體之標題化合DIPEA (23 μl '0.Π1 mmol) and 2_(2_曱oxy)ethoxyethoxyethyl chloride (11 mg, 0.072 mmol) were added to Intermediate D (35 mg '0.〇) 65 mmoles of suspension in DCM (0.5 liters) and in the mixture with saturated water NaHCQ3^ (1.5 14, "^. Separation of the reaction separation column to collect the organic matter, in the thin and pass the phase The product was subjected to a mixture of sulphur and sulphate. The residue obtained by evaporation of the U and the residue was purified to give a pale white "PHPLC", Example 38 (13 mg, 31%): m/z.

NMR _ MHz，DMs〇_d6) δ: ! 26 +H)+ (ES+)。lH s)，2.38 (3 H，s)， 135 201130813 .,.21 (2 H, t), 3.28 (3 Η, s), 3.49-3.51 (2 Η, m), 3.66-3.68 (2 Η, m), 4.13 (2 Η, s), 4.38 (2 Η, t), 6.34 (1 Η, s), 6.95 (1 Η, d), 7.19 (1 Η, dd), 7.34 (2 Η, m), 7.41-7.48 (3 Η, m), 7.51-7.56 (1 Η, m), 7.59 (1 Η, d), 7.87 (1 Η, d), 8.11-8.14 (1 Η, dd), 8.20 (1 Η, br s), 8.23-8.25 (1 H, dd), 8.55 (1 Η, s), 8.75 (1 H，s)，9·83 (1 H, s)。實例39 : 4-(2-(4-(3-(3-第三-丁基小對-曱苯基-1H-吡唑 -5-基)腺基）秦-1-基氧基）乙基)-1-甲基-3-(β比咬-2-基)脈：NMR _ MHz, DMs 〇 _d6) δ: ! 26 +H)+ (ES+). lH s), 2.38 (3 H, s), 135 201130813 .,.21 (2 H, t), 3.28 (3 Η, s), 3.49-3.51 (2 Η, m), 3.66-3.68 (2 Η, m), 4.13 (2 Η, s), 4.38 (2 Η, t), 6.34 (1 Η, s), 6.95 (1 Η, d), 7.19 (1 Η, dd), 7.34 (2 Η, m) , 7.41-7.48 (3 Η, m), 7.51-7.56 (1 Η, m), 7.59 (1 Η, d), 7.87 (1 Η, d), 8.11-8.14 (1 Η, dd), 8.20 (1 Η, br s), 8.23-8.25 (1 H, dd), 8.55 (1 Η, s), 8.75 (1 H, s), 9·83 (1 H, s). Example 39: 4-(2-(4-(3-(3-Terve-butyl-p-p-phenyl)-1H-pyrazol-5-yl)glycosyl)-l-yl-yloxy) ))-1-methyl-3-(β than bit-2-yl) pulse:

將異氰酸甲酯（5.3毫克，0.094毫莫耳)加至中間物 D(50毫克，0.094毫莫耳)在吡啶(1.0毫升）中的溶液並將混合物在RT下攪拌72小時。在減壓下蒸發溶劑並將所得殘餘物從MeOH (5.0毫升)磨碎以產生呈灰白色固體之標題化合物，實例39(7毫克，13%):m/z 592 (M+H)+ (ES+)。】H NMR (400 MHz，DMSO-d6) δ : 1.26 (9 H，s)， 2.38 (3 H，s)，3.13 (2 H, t)，3.31 (3 H，s，被 Η20 掩蓋)， 4.32 (2 Η, t), 6.34 (1 Η, s), 6.93 (1 Η, d), 7.34 (2 Η, m), 7.40-7.48 (6 Η, m), 7.53-7.57 (1 Η, m), 7.61 (1 Η, d), 7.81-7.83 (2 Η, d), 7.86-7.89 (1 Η, d), 8.02-8.04 (1 Η, dd), 8·55 (1 Η，s)，8.75 (1 Η，s)。貫例 40 . 4-(2-(4-(3-(3-第二-丁基-1-對-曱苯基 -5-基)脲基)萘-1-基氧基）乙基)-3十比啶-2-基)脲： 136 201130813Methyl isocyanate (5.3 mg, 0.094 mmol) was added to a solution of Intermediate D (50 mg, 0.094 m. The solvent was evaporated under reduced pressure and EtOAc EtOAcjjjjjjjjjj ). H NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.38 (3 H, s), 3.13 (2 H, t), 3.31 (3 H, s, masked by Η20), 4.32 (2 Η, t), 6.34 (1 Η, s), 6.93 (1 Η, d), 7.34 (2 Η, m), 7.40-7.48 (6 Η, m), 7.53-7.57 (1 Η, m) , 7.61 (1 Η, d), 7.81-7.83 (2 Η, d), 7.86-7.89 (1 Η, d), 8.02-8.04 (1 Η, dd), 8·55 (1 Η, s), 8.75 (1 Η, s). Example 40. 4-(2-(4-(3-(3-Second-butyl-1-p-phenyl)-5-yl)ureido)naphthalen-1-yloxy)ethyl) -3 decapyridin-2-yl)urea: 136 201130813

中間物DIntermediate D

Cl3c 、NCO °比啶Cl3c, NCO ° than pyridine

NHj 將一氣乙基異氰酸S旨（12微升，0.103毫莫耳)加至:間物D(5〇毫克，〇.，毫莫耳)在吡咬（1 〇毫升）中口的溶液並將混合物在RT下龄直M LC_MS判斷為完全。在真空中蒸發溶劑及將所得殘餘物進行scx捕捉和釋放且從DCM(10毫升)磨碎以產生呈灰白色固體之標題化合物’實例40(25宅克’ 44%) : m/z 578 (ES+)。iH NMR (400 MHz, DMSO-d6) δ : j 26 (9 h，s), 2.38 (3 H，s)，3.12 (2 H，t)，4.35 (2 tj，〇，6.34 (1 H，s)， 6.94-6.99 (2 H，m)，7.19 (1 H，dd)，7.33.7 35 (2 h，m)， 7.4卜7.50 (5 H，m)，7.52-7.56 (1 H，m)，7 6〇〇 H，d)，7 87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H，s)。中間物E: 1-(4-(2-(3-胺基°比咬-4-基）乙氧基）萘基)-3-(3-第三-丁基-1-對-曱苯基-lH-nth唾j基)腺。 137 201130813NHj adds one gas ethyl isocyanate S (12 μL, 0.103 mmol) to a solution of the intermediate D (5 mg, 〇., millimolar) in a bite (1 ml) The mixture was judged to be complete at RT at RT M LC_MS. The solvent was evaporated in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; ). iH NMR (400 MHz, DMSO-d6) δ : j 26 (9 h, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 tj, 〇, 6.34 (1 H, s ), 6.94-6.99 (2 H,m), 7.19 (1 H,dd),7.33.7 35 (2 h,m), 7.4 b 7.50 (5 H,m),7.52-7.56 (1 H,m) ,7 6〇〇H,d),7 87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s). Intermediate E: 1-(4-(2-(3-amino) ethoxy-4-yl) ethoxy)naphthyl)-3-(3-tert-butyl-1-p-indene benzene Basyl-lH-nth salivary g) gland. 137 201130813

雙光氣 (5)- NaHCOjDouble phosgene (5)- NaHCOj

中間物EIntermediate E

2·(3-硝基。比啶·4_基）乙醇（24)(w〇誦/⑽⑽謂克，U.S9毫莫耳)在_即5〇毫升) 中的溶液通過Thales H-立方體(2 〇毫升分鐘-】，3〇〇c， 30巴，Pd/C Cat-Cart ’ 55毫米，控制模式）。藉由LC_MS 之分析顯示仍存在㈣㈣起始原料並將歸通過H_ 立方體二次以上(2.G毫升.分鐘·】，全氫模式，RT，及2 〇毫升.分鐘】’全氫模式，4〇。〇。揮發物之蒸發產生呈紫色油之2-(3-胺基η比咬_4·基）乙醇(25)(1 3〇克，8 m/z 139 (M+H)+ (ES.)。將DIAD(590微升，3.75毫莫耳)在七。c下逐滴加至4-石肖基萘小醇(2)(0.95克，5 〇〇毫莫耳）、㈣⑼ 克，7.5〇毫莫耳)及2_(3·胺基^比。定_4_基）乙醇吻⑽ 克’ 7·50毫莫耳)在THF(2〇毫升）中的溶液。將混合物在RT下授拌】小時並在真空中除去揮發物。將殘餘^ 吸附树石(2〇克)上及藉由管柱層析法純化⑸％ , 克，在異己烧中之5(M(K)%Et0Ae，梯度溶析且缺 138 2011308132·(3-nitro.pyridinyl-4-yl)ethanol (24) (w〇诵/(10)(10) gram, U.S9 millimolar) solution in _ ie 5 〇 ml) through Thales H-cube (2 〇 ml min -), 3 〇〇 c, 30 bar, Pd / C Cat-Cart ' 55 mm, control mode). Analysis by LC_MS shows that (iv) (iv) starting material is still present and will pass through H_ cube twice or more (2.G ml.min·), perhydrogen mode, RT, and 2 〇ml.min] 'all hydrogen mode, 4 〇.〇. Evaporation of volatiles produces 2-(3-amino η than _4·yl)ethanol (25) in purple oil (13 g, 8 m/z 139 (M+H)+ ( ES.). Add DIAD (590 μl, 3.75 mmol) to the 4-stone Schottylnaphthalene (2) (0.95 g, 5 〇〇 mmol), (iv) (9) g, 7.5 at 7.c. 〇莫 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) The mixture was stirred at RT for an hour and the volatiles were removed in vacuo. Residual ^ adsorbed stone (2 gram) and purified by column chromatography (5)%, gram, 5 (M(K)%Et0Ae in iso-hexane, gradient elution and lack 138 201130813

EtOAc中之5%MeOH，等度溶析）以產生4-(2-(4-硝基萘 -1-基氧基）乙基)吼啶_3_胺（26)(1.36 克 ’ 88 %):m/z31〇 (M+H)+ (ES+)。將4-(2-(4-硝基萘-1-基氧基）乙基）η比啶_3_胺 (26) (700毫克，2.263毫莫耳)在MeOH (50毫升）、 EtOAc(25毫升)和DCM(25毫升）的混合物中之溶液通過Thales H·立方體（1〇 %Pt/c ’ 30毫米’ 1.〇毫升分鐘 _1 ’ 40°C，全氫模式）。在真空中除去溶劑以產生呈棕色固體之4-(2-(4-胺基萘-1-基氧基）乙基）吡啶_3_胺 (27) (612 毫克，92%)。m/z 280 (M+H)+ (ES+)。將NaHC〇3之飽和水溶液(6〇毫升)加至3-第三-丁基-1-對-曱苯基-1H-吡唑-5-胺(5)(1·〇〇克，4.36毫莫耳) 在DCM(90毫升）中的溶液。將混合物用力地搜拌，冷卻至0 °C及一次性添加雙光氣(2.1毫升，17.4毫莫耳）。在RT下檀拌1小時之後，分離該等層並將有機物乾燥及蒸發以產生棕色油。該油與異己烷(5.0毫升）—起研磨及過濾固體。在真空中濃縮濾液以產生呈淡棕色油之弟二-丁基-5-異氣酸基-1-對-曱苯基π比σ坐 (28) (1.00 克 ’ 3.92 毫莫耳，90 %)。m/z 288 (in5% MeOH in EtOAc, isocratically isolated to give 4-(2-(4-nitronaphthalen-1-yloxy)ethyl) acridine-3-amine (26) (1.36 g < 88 % ): m/z31〇(M+H)+ (ES+). 4-(2-(4-Niphthylnaphthalen-1-yloxy)ethyl)n-pyridyl-3-amine (26) (700 mg, 2.263 mmol) in MeOH (50 mL)EtOAc The solution in a mixture of 25 ml) and DCM (25 ml) was passed through a Thales H. cube (1 〇 % Pt / c ' 30 mm ' 1. 〇 ml min _1 '40 ° C, full hydrogen mode). The solvent was removed in vacuo to give 4-(2-(4-aminonaphthalen-1-yloxy)ethyl)pyridine-3-amine (27) (612 mg, 92%). m/z 280 (M+H)+ (ES+). Add a saturated aqueous solution of NaHC〇3 (6 mL) to 3-tri-butyl-1-p-phenyl-1H-pyrazole-5-amine (5) (1·〇〇克, 4.36 m Mohr) A solution in DCM (90 ml). The mixture was vigorously mixed, cooled to 0 ° C and diphosgene (2.1 ml, 17.4 mmol) added in one portion. After 1 hour of sanding at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with isohexane (5.0 mL) and the solid was filtered. The filtrate was concentrated in vacuo to give the di-bromo-5-iso-sulphonic acid-l-p-indole phenyl pyrazine (28) (1.00 g ' 3.92 mmol, 90 %) ). m/z 288 (in

MeOH)(M+H+MeOH)+ (ES+)。將3-第三-丁基-5-異氰酸基-1-對-甲苯基_m•吡唑 (28)(530毫克’ 2.076毫莫耳)在THF(2.〇毫升）中的溶液加至4_(2_(4-胺基萘-1-基氧基）乙基比咬_3·胺（27)(580 毫克，2.076毫莫耳)和DIPEA(1085微升，6.23毫莫耳）在THF (10毫升)和MeCN(1.0毫升）中的溶液並將反應合物在RT下授掉過仪。將混合物倒進鹽水(2 5毫升） 139 201130813 丁且用EtOAc(2 x 25毫升）萃取，乾燥，過據及在真空下除去溶劑。將產物預吸附在hyfl〇(10克)上，及藉由逆相管柱層析法純化(4〇克，Cl8 [來自Silicycle]，乙腈 /水，0至100%)且在真空中濃縮產物部分以產生呈灰白色固體之標題化合物，中間物E(410毫克，36%)。m/z 535 (M+H)+ (ES+)。貫例 41 . N-(4-(2-(4-(3-(3-第三-丁基-1-對_ 甲苯基 °比°坐·5-基)脲基)萘基氧基）乙基)°比°定-3-基)_2-曱氧基乙醯胺：MeOH) (M+H+MeOH) + (ES+). a solution of 3-tert-butyl-5-isocyanato-1-p-tolyl-m•pyrazole (28) (530 mg ' 2.076 mmol) in THF (2 mL) Add to 4_(2-(4-aminonaphthalen-1-yloxy)ethyl) to bite _3.amine (27) (580 mg, 2.076 mmol) and DIPEA (1085 μl, 6.23 mmol) A solution of THF (10 mL) and MeCN (1.0 mL) was applied and the mixture was applied at RT. The mixture was poured into brine (25 ml) 139 201130813 and extracted with EtOAc (2 x 25 mL) The product was pre-adsorbed on hyfl(R) (10 g) and purified by reverse phase column chromatography (4 g, Cl8 [from Silicycle], acetonitrile/water. The product fraction was concentrated in vacuo to give the title compound mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj N-(4-(2-(4-(3-(3-Terti-butyl-1-p-tolyl)) ureido)naphthyloxy)ethyl) °°°-3-yl)_2-decyloxyacetamide:

將曱氧基乙醯氯(25.7微升，0.281毫莫耳)在〇〇c 下加至中間物E (50毫克，0.094毫莫耳)及DMAp (5 71 毫克，0.047毫莫耳)在DCM(3.0毫升）中的溶液且將反應混合物在RT下攪拌1.5小時。在真空中除去溶劑及將殘餘物進行SCX捕捉和釋放。藉由急驟管柱層析法純化不純產物（Si〇2,4.0克，在DCM中之uoo/oMeOH, 梯度溶析）以產生呈淡粉紅色固體之標題化合物，實例 41(45 毫克，77%): m/z 607 (M+H)+ 。4 NMR (4〇〇 MHz, DMSO-d6) δ： 1.27 (9H, s), 2.39 (3H, s), 3.18 (2H, t), 3.40 (3H，s)，4.08 (2H，s)，4.39 (2H，t)，6.35 (1H，s)，6.96’ (1H，d)，7.35 (2H，m)，7.43 (2H，m)，7.50 (2H，m)，’ 7.58 (1H，m)，7.61 (1H，d)，7.88 (1H，d)，8.09 (1H，dd)，8.37 140 201130813 (1H, d), 8.52 (1H, s), 8.56 (1H. brs), 8.76 (1H, br s), 9.66 (1H，br s.)。貫例42 : N-(4-(2-(4-(3-(3-第三-丁基-丨_對_甲苯基_1H_ 〇比〇坐-5-基）脲基）萘基氧基）乙基）《比α定-3_基)-2-(2-曱氧基乙氧基）乙醯胺：Add methoxyethyl hydrazine chloride (25.7 μl, 0.281 mmol) to intermediate E (50 mg, 0.094 mmol) and DMAp (5 71 mg, 0.047 mmol) in DCM under 〇〇c The solution in (3.0 mL) and the reaction mixture was stirred at RT for 1.5 h. The solvent is removed in vacuo and the residue is subjected to SCX capture and release. The impure product (Si 2 , 4.0 g, uoo/o MeOH in DCM, gradient elution) was purified by flash column chromatography to give the title compound as a pale pink solid, Example 41 (45 mg, 77% ): m/z 607 (M+H)+ . 4 NMR (4〇〇MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.18 (2H, t), 3.40 (3H, s), 4.08 (2H, s), 4.39 (2H, t), 6.35 (1H, s), 6.96' (1H, d), 7.35 (2H, m), 7.43 (2H, m), 7.50 (2H, m), ' 7.58 (1H, m), 7.61 (1H,d),7.88 (1H,d),8.09 (1H,dd),8.37 140 201130813 (1H, d), 8.52 (1H, s), 8.56 (1H. brs), 8.76 (1H, br s ), 9.66 (1H, br s.). Example 42: N-(4-(2-(4-(3-(3-Terve-butyl-indole-p-tolyl-1H_ 〇) -5-5-yl) ureido)naphthyloxy Ethyl) ethyl) "specific ratio -3 -yl)-2-(2-decyloxyethoxy)acetamide:

將2-(2-曱氧基乙氧基）乙酿氣(3〇微升，〇 281毫莫耳)在0°C下加至中間物e (50毫克，0.094毫莫耳)及 DMAP(5.71毫克，0.047毫莫耳)在DCM(3 〇毫升）中的溶液且將反應混合物在RT下攪拌15小時。在真空中除去溶劑並將殘餘物進行Scx捕捉和釋放。藉由管柱層析法純化殘餘物（Si〇2，4.0克，在DCM中之 0-8°/〇MeOH，梯度溶析)及在真空中濃縮產物部分以產生王淡紫色固體之標題化合物，實例42(35毫克，56°/。）： m/z 651 (M+H)+ (HS+) 〇 lR NMR (400 MHz, DMSO-d6) δ ： 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H. br s)，8.60 (1H, s)，8.76 (1H，br s)，9.55 (1H, br s.)。中間物F: 1-(4-(2-(2-胺基比啶4-基氧基）乙基）萘-1-基)-3-(3-第三-丁基_1_對_曱苯基_1H_吡唑基)脲。 141 n-BuLi CHO Ph3CH3P+ Br*2-(2-decyloxyethoxy)ethane (3 〇 microliter, 〇281 mmol) was added at 0 ° C to intermediate e (50 mg, 0.094 mmol) and DMAP ( A solution of 5.71 mg, 0.047 mmol, in DCM (3 mL). The solvent was removed in vacuo and the residue was subjected to Scx capture and release. The residue was purified by column chromatography (EtOAc EtOAc (EtOAc) eluting elut elut elut elut elut , Example 42 (35 mg, 56°/.): m/z 651 (M+H)+ (HS+) 〇lR NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d ), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d) , 8.56 (1H. br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s.). Intermediate F: 1-(4-(2-(2-aminopyridin-4-yloxy)ethyl)naphthalen-1-yl)-3-(3-tri-butyl_1_p-曱Phenyl-1H_pyrazolyl)urea. 141 n-BuLi CHO Ph3CH3P+ Br*

201130813 將n-BuLi(在己烷中之1.6M，20.4毫升，32.6毫莫耳)加至4-溴萘-1-基胺曱酸第三-丁酯（29)(3.00克，9.31 毫莫耳)在THF(100毫升）中於-78。(：在氮氣下之溶液並將反應混合物在-78°C下攪拌1小時。添加純DMF(4.50 毫升’ 58.1毫莫耳)且將反應混合物在_78。(：下搜拌i小時’然後加熱至RT並攪拌另1小時。加水(5毫升)且將混合物分溶在乙酸乙酯（100毫升)及水（1〇〇毫升)之間。將有機相用鹽水洗滌，乾燥(MgSOd並在真空中蒸發。將殘餘物與異己烷一起研磨以提供呈米黃色固體之心甲醯基萘-1-基胺甲酸第三·丁酯（30)(2.20克，87%广m/z 272 (M+H)+ (ES)+。將第三-丁醇鉀（1.20克，10.69毫莫耳)加至甲基三苯基溴化鱗(3·82克’ 10.69毫莫耳)在THF(20毫升）中於0。〇在氮氣下的懸浮液並將反應混合物在〇〇c下授掉 142 201130813 15分鐘，然後加熱至RT且攪拌另45分鐘。將懸浮液冷卻至〇°C及逐滴添加(30)(1.16克，4.28毫莫^：)在 THF(10毫升）中的溶液。將反應混合物加熱至並攪拌1小時。添加ΝΗβ1飽和水溶液(30亳升)且用乙酸^ 酯萃取混合物。將乙酸乙酯萃取物用鹽水洗滌，乾燥 (MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si〇2 ’在異己烷中之0-10%乙酸乙酯，梯度溶析）以提供呈白色固體之4_乙烯基萘·基胺甲酸第三_丁酯 (31)(0.831 克 ’ 72%) : m/z 268 (M-Η)· (ES.)。將9-BBN(0.5M在THF中’9.9毫升，4.95毫莫耳）於〇°C在氮氣下逐滴加至(31)(〇 83克，3 〇8毫莫耳)在 THF(10毫升）中的溶液。將混合物力〇熱至並授拌μ 小時。添加水（1毫升）、Na0H水溶液(3Μ，1〇〇毫升， 30毫莫耳)及過氧化氫(35%在水中，8 〇毫升）。將反應混合物加熱至50〇C並攪拌2小時且然後用乙酸乙酯^ 取。將乙酸乙酯萃取物用水和鹽水洗滌，乾燥亚在真空中蒸發。藉由急驟管柱層析法純化殘餘物 (Si〇2 ’在異己烷中之10-60%乙酸乙酯，梯度溶析）以提供4-(2-羥乙基）萘-1-基胺曱酸第三_丁酯（32)(763毫克，86%) ; m/z 288 (M+H)+，（ES+) 將氫化鈉(0.267克，60%在礦油中之分散液，6 68 毫莫耳)於0°C在氮氣下加至(32)(0.64克，2.23毫莫耳）在dmf(io毫升）中的除氣溶液將溶液加熱至RT並攪拌30分鐘且然後冷卻至〇。〇將2_氣_4_氟_吡啶(〇 381 克，2.90毫莫耳)在DMF(5.〇毫升）中的溶液加至此混合物並將反應混合物加熱至RT並攪拌16小時。添加水並 143 201130813 , /73乙酸乙酯萃取混合物。將乙酸乙酯萃取物用鹽水洗滌 (3x) ’乾燥(MgS04)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2，在異己烧中之0-40%乙酸乙酯，梯度溶析）以提供4-(2-(2-氯。比啶-4-基氧基）乙基）萘-1-基胺甲酸第三-丁酯（33)(670毫克，75%) ; m/z 399 (M+H)+，（ES+) 將Pd2dba3(34毫克，0.038毫莫耳)加至(33)(600毫克’ 1.50毫莫耳）、胺曱酸第三-丁酯（176毫克，丨5〇毫莫耳）、Cs2C03(733 毫克，2.26 毫莫耳)及 xathphos(43 毫克，0.075毫莫耳)在THF(10毫升）中的除氣懸浮液並將反應混合物在氮氣下於回流加熱16小時。加水並用乙酸乙酯萃取反應混合物。將有機萃取物用鹽水洗滌，乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物 (Si〇2 ’在乙酸乙酯中之0-50%己烷，梯度溶析）以提供所要Boc保護之產物及起始原料的混合物，將其溶解在 DCM(2毫升)及TFA(2毫升）的混合物中及在rt下擾拌 1小時。在真空中蒸發溶劑並將殘餘物溶解在DCM中及用飽和NaHC〇3水溶液及鹽水洗務，然後乾燥 (MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ’在DCM中之5%Me〇H，等度溶析）以提供 4-(2-(4-胺基萘-1-基）乙氧基）n比υ定_2-胺（34)(45毫克， 11%) ; m/z 280 (M+H)+，（ES+)。將(5)(172毫克，0.752毫莫耳)在DCM(2.0毫升）中的溶液加至CDI(122毫克’ 0.752毫莫耳)在DCM(2毫升）中的懸浮液並將反應混合物在RT下搜摔16小時。將一部分（1.0毫升)之此反應混合物加至的（34)(42毫 144 201130813 克，〇.15〇毫莫耳)在DCM(2 〇毫升）中攪拌懸浮液。添加THF(0.5毫升)且將反應混合物祕1小時。添加第二部分（1.0毫升)之CDI反應混合物並將混合物在RT 下攪拌另20小時。添加曱醇並繼續攪拌30分鐘。蒸發溶劑及藉由急驟管柱層析法純化殘餘物(Si〇2，在DCM 中之0 5 AMeOH，梯度溶析）。將所得不純產物溶解在乙酸乙酯中，用水和鹽水洗滌，乾燥(MgS〇4)並在真空中蒸發以提供標題化合物，中間物F，（42毫克，52〇/〇); m/z 535 (M+H)+，（ES+)。實例 43 : N-(4-(2-(4-(3-(3-第三-丁基-i_對甲苯基·1H_ 吡唑-5-基)脲基）萘基）乙氧基)吡啶_2_基)_2_曱氧基乙201130813 Add n-BuLi (1.6M in hexane, 20.4 ml, 32.6 mmol) to 4-bromo-naphthalen-1-ylamine decanoic acid tert-butyl ester (29) (3.00 g, 9.31 mmol) The ear was in -78 in THF (100 mL). (: solution under nitrogen and the reaction mixture was stirred at -78 ° C for 1 hour. Add pure DMF (4.50 mL '58.1 mmol) and the reaction mixture was at -78. Heat to RT and stir for another hour. Add water (5 mL) and dissolve the mixture between ethyl acetate (100 mL) and water (1 mL). Evaporation in vacuo. The residue was triturated with hexanes to afford EtOAc (30) (2.20 g, 87% wide m/z 272 M+H)+ (ES)+. Potassium tert-butoxide (1.20 g, 10.69 mmol) was added to methyltriphenyl bromide scale (3·82 g ' 10.69 mmol) in THF ( 20 ml) in 0. 悬浮 suspension under nitrogen and the reaction mixture was given 142 201130813 for 15 minutes, then heated to RT and stirred for another 45 minutes. The suspension was cooled to 〇 ° C and A solution of (30) (1.16 g, 4.28 mmol) in THF (10 mL) was added dropwise. The mixture was stirred and stirred for 1 hour. A saturated aqueous solution of ΝΗβ1 (30 liters) was added and used The mixture was extracted with an acid. The ethyl acetate extract was washed with brine, dried (MgSO.sub.4) and evaporated in vacuo. The residue was purified by flash column chromatography. -10% ethyl acetate, gradient elution) to afford 4-vinylnaphthalene carbamic acid tert-butyl ester (31) (0.831 g '72%) as a white solid: m/z 268 (M-Η ) (ES.). 9-BBN (0.5 M in THF '9.9 ml, 4.95 mmol) was added dropwise to ( ° C under nitrogen (31) (〇 83 g, 3 〇 8 mmol) A solution of the mixture in THF (10 mL). The mixture was stirred and stirred for one hour. Water (1 mL), aqueous Na0H (3 Μ, 1 liter, 30 mM) and hydrogen peroxide (35% in water, 8 mL). The reaction mixture was heated to 50 ° C and stirred for 2 hr and then taken with ethyl acetate. The ethyl acetate extracts were washed with water and brine and evaporated and evaporated. The residue was purified by flash column chromatography (10-60% ethyl acetate in hexanes elute elute elute elute elute Citrate third-butyl ester (32) (763克,86%) ; m/z 288 (M+H)+, (ES+) sodium hydride (0.267 g, 60% dispersion in mineral oil, 6 68 mmol) at 0 ° C under nitrogen Add to (32) (0.64 g, 2.23 mmol) degassing solution in dmf (io ml). The solution was heated to RT and stirred for 30 minutes and then cooled to hydrazine. A solution of 2_gas_4_fluoro-pyridine (〇 381 g, 2.90 mmol) in DMF (5 mL) was added to this mixture and the mixture was warmed to RT and stirred for 16 hours. Water was added and 143 201130813, /73 ethyl acetate extraction mixture. The ethyl acetate extract was washed with brine (3x) dry (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) elute Benzyl)ethyl)naphthalen-1-ylaminecarboxylic acid, tert-butyl ester (33) (670 mg, 75%); m/z 399 (M+H)+, (ES+) Pd2dba3 (34 mg, 0.038 millimolar) to (33) (600 mg ' 1.50 mmol), amine-butyrate tri-butyl ester (176 mg, 丨 5 〇 millimolar), Cs2C03 (733 mg, 2.26 mmol) And a degassed suspension of xathphos (43 mg, 0.075 mmol) in THF (10 mL). Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated in vacuo. The residue was purified by flash column chromatography (0-50% hexanes eluted elute eluted elute elute elute The mixture was stirred for 1 hour in a mixture of DCM (2 mL) and TFA (2 mL). The solvent was evaporated in vacuo <RTI ID=0.0></RTI> and the residue was purified eluting eluting The residue was purified by flash column chromatography (Si 〇 2 ' 5% Me 〇H in DCM, isocratic) to afford 4-(2-(4-aminonaphthalen-1-yl) Oxy)n υ _2 2 -amine (34) (45 mg, 11%); m/z 280 (M+H)+, (ES+). A solution of (5) (172 mg, 0.752 mmol) in DCM (2OmL) was added to a suspension of CDI (122 mg < Search for 16 hours. A portion (1.0 mL) of this reaction mixture was added to (34) (42 s s s s s s s s s s s s. THF (0.5 mL) was added and the reaction mixture was taken for 1 hour. A second portion (1.0 mL) of the CDI reaction mixture was added and the mixture was stirred at RT for another 20 hours. Add sterol and continue stirring for 30 minutes. The solvent was evaporated and the residue was purified by flash chromatography eluting elut elut The resulting impure product was taken up in ethyl acetate, washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHH (M+H)+, (ES+). Example 43: N-(4-(2-(4-(3-(3-Terve-butyl-i-p-tolyl-1H-pyrazol-5-yl)ureido)naphthyl)ethoxy) Pyridine_2_yl)_2_曱oxy B

將甲氧基乙醯氯(32毫克，0.299毫莫耳)加至中間物 F(40 毫克，0.075 毫莫耳)及 DII>EA(0.059 毫升，0.337 宅莫耳)在DCM(1.5毫升）中的溶液並將反應混合物在 RT下授拌16小時。添加氨的溶液(在甲醇中之1%)且繼續攪拌30分鐘。在真空中蒸發溶劑及藉由sCX捕捉和釋放純化殘餘物。藉由急驟管柱層析法純化粗製產物 (Si〇2 ’在DCM中之〇-5%MeOH，梯度溶析）以提供標題化合物，實例 43 ’（1〇毫克，20%) : m/z 607 (M+H)+ (ES+) ； ]H NMR (400 MHz, DMSO-d6) δ ： 1.28 (9H, s), 145 201130813 .39 (3H, s), 3.35 (3H, s), 3.51 (2H, t), 4.03 (2H, s), 4.35 (2H, t), 6.39 (1H, s), 6.72 (1H, dd), 7.35 (2H, d), 7.42-7.47 (3H，重疊 m), 7.55-7.63 (2H，重疊 m)，7.67 (1H，d)，7.82 (1H，d)，8.03 (1H，m)，8.10 (1H，d)，8.19 (1H， d)，8.72 (1H，br s)，9.01 (1H, br s)，9.87 (1H, br s)。中間物G . 1 _(4-(l -(2-胺基〇比咬-4-基）乙氧基）奈-1_ 基)-3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲。Add methoxyethyl hydrazine chloride (32 mg, 0.299 mmol) to intermediate F (40 mg, 0.075 mmol) and DII > EA (0.059 mL, 0.337 house Mo) in DCM (1.5 mL) The solution was stirred and the reaction mixture was stirred at RT for 16 hours. A solution of ammonia (1% in methanol) was added and stirring was continued for 30 minutes. The solvent was evaporated in vacuo and the residue was purified by sCX. The crude product was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut elut elut 607 (M+H)+ (ES+) ; ]H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 145 201130813 .39 (3H, s), 3.35 (3H, s), 3.51 ( 2H, t), 4.03 (2H, s), 4.35 (2H, t), 6.39 (1H, s), 6.72 (1H, dd), 7.35 (2H, d), 7.42-7.47 (3H, overlap m), 7.55-7.63 (2H, overlap m), 7.67 (1H, d), 7.82 (1H, d), 8.03 (1H, m), 8.10 (1H, d), 8.19 (1H, d), 8.72 (1H, br s), 9.01 (1H, br s), 9.87 (1H, br s). Intermediate G. 1 _(4-(l-(2-Aminopyridin-4-yl-4-yl)ethoxy)na-1_yl)-3-(3-tri-butyl-1-pair- Phenylphenyl-1H-pyrazol-5-yl)urea.

經10分鐘將曱基鋰(在二***之1.6 Μ，16.4毫升， 26.3毫莫耳）加至曱基-2-胺基吡啶-4-曱酸酯（35)(1.00 克，6.57毫莫耳)在THF(100毫升）中於-78°C在氮氣下的攪拌溶液。在-78°C下另30分鐘之後，將黏反應混合物加熱至〇°C。另3小時之後，藉由在0°C下謹慎添加異丙醇（8.0毫升)停止反應。將混合物加熱至RT，添 146 201130813 加鹽水(200毫升)及EtOAc(150毫升），並分離該等層。用EtOAc萃取水層（3 xl00毫升），並將合併之有機萃取物乾燥且在真空下除去溶劑。藉由管柱層析法純化粗製殘餘物(Si〇2，80克，在EtOAc中之〇_8%MeOH，梯度;谷析）以產生呈育色粉末之1_(2_胺基吼咬_4_基）乙酉同 (36) (176 毫克 ’ 20%) : m/z 137 (M+H)+ (ES+)。將硼氫化鈉(46.7毫克，1.234毫莫耳)加至(36)(168 毫克，1.234毫莫耳)在MeOH(l〇毫升）中於〇〇c在氮氣下的混合物。將反應混合物在RT下攪拌2小時，及在減壓下除去揮發物。將殘餘物溶解在Et〇Ac (25毫升）中，並用NaHC〇3飽和水溶液(3〇毫升）萃取。用Et〇Ac 回萃取水層（2 X 20耄升），及將合併之有機萃取物用鹽水(30鼋升）洗滌，乾燥且在真空下除去溶劑以產生呈黃色油之1-(2-胺基吡啶_4-基）乙醇(37)(77毫克，45%): m/z 139(M+H)+(ES+)。將氫化鈉(32毫克，0.793毫莫耳’ 6〇重量％)加至 (37) (73毫克，0.528亳莫耳)在DMF(15毫升）中於〇〇c 在氮氣下的攪拌溶液。將所得混合物在〇。€下攪拌4〇 ^鐘，並逐滴添加1-氟+磺基萘〇4)(1〇1毫克，〇似毫莫耳)在DMF(1.5毫升）中的溶液。將所得暗紅色混合物在0°C下授拌5分鐘及在RT下經4〇分鐘且藉由添加 1.〇毫升NH/l溶液停止反應。加水（2〇毫升）及Thiol lithium (1.6 二 in diethyl ether, 16.4 ml, 26.3 mmol) was added to the decyl-2-aminopyridine-4-furoate (35) (1.00 g, 6.57 mmol) over 10 min. The solution was stirred in THF (100 mL) at -78 ° C under nitrogen. After another 30 minutes at -78 °C, the viscous reaction mixture was heated to 〇 °C. After another 3 hours, the reaction was stopped by cautiously adding isopropanol (8.0 ml) at 0 °C. The mixture was heated to RT, 146 EtOAc EtOAc (EtOAc) (EtOAc) The aqueous layer was extracted with EtOAc (3×10 mL)EtOAc. The crude residue was purified by column chromatography (Si.sub.2, 80 g, EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 4_base) acetamidine (36) (176 mg '20%): m/z 137 (M+H)+ (ES+). Sodium borohydride (46.7 mg, 1.234 mmol) was added to a mixture of (36) (168 mg, 1.234 mmol) in MeOH (1 mL) EtOAc. The reaction mixture was stirred at RT for 2 h and then evaporated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc) The aqueous layer was extracted with Et EtOAc (2×20 liters), and the combined organic extracts were washed with brine (30 liters), dried and evaporated in vacuo to give 1-(2- Aminopyridine _4-yl)ethanol (37) (77 mg, 45%): m/z 139 (M+H) + (ES+). Sodium hydride (32 mg, 0.793 mmol) was added to a stirred solution of (37) (73 mg, 0.528 mmol) in DMF (15 mL) EtOAc. The resulting mixture was placed in a crucible. The mixture was stirred for 4 Torr, and a solution of 1-fluoro-sulfonaphthoquinone 4) (1 〇 1 mg, m.m.) in DMF (1.5 mL) was added dropwise. The resulting dark red mixture was stirred at 0 °C for 5 minutes and at RT for 4 minutes and stopped by the addition of 1. liters of NH/1 solution. Add water (2 ml) and

Et〇Ac(2〇毫升）’及分離該等層。EtOAc萃取水層（3 X Η毫升）。將合併之有機萃取物用鹽水洗縣，乾燥且在真空下除去溶劑。袓製產物藉由管柱層析法純化 (Si〇2 ’ 12克，在異己燒中之〇 8〇%Et〇Ac，梯度溶析） 147 …產生呈橙色膠之4-(1-(4-硝基萘-1-基氧基）乙基)吼啶 -2-胺(38)(94.6 毫克 ’ 57%) : m/z 310 (M+H)+ (ES+)。將(38)(91毫克，0.294毫莫耳)在MeOH(15毫升) 及AcOH(3.0毫升）中的溶液通過Thales H-立方體（1.0 毫升.分鐘J，30°C ’ 55 毫米，l〇%Pt/C Cat-Cart，全氫模式）。在減壓下除去揮發物，留下紫色固體，然後將其進行SCX捕捉和釋放以產生呈紫色油之4-(1-(4-胺基萘-1-基氧基）乙基)η比啶-2-胺(39)(81毫克，99%) : m/z 280 (M+H)+ (ES+)。將NaHC〇3飽和水溶液(（ο毫升）加至（5)(57毫克’ 0.250毫莫耳)在DCM(6.0毫升）中的溶液。將混合物用力地攪拌並冷卻至〇。(：及一次性添加氣甲酸三氯曱酯（0.091毫升，0.750毫莫耳）。將所得混合物在〇〇c 下攪拌1.5小時。將二相混合物分離及將有機萃取物乾燥且在減壓下除去溶劑以提供油，其在高真空下於乾燥35分鐘。將所得油溶解在THF(5.0毫升）中，且然後加至4-(1-(4-胺基萘-1-基氧基）乙基)β比咬_2_胺(39)(81 毫克，0.290毫莫耳）中。添加DIPEA(179微升，1.029 毫莫耳）’並將反應混合物在RT下授拌16小時。將水 (15毫升)及EtOAc(10毫升)加至反應混合物並分離該等層。用EtOAc(15毫升）萃取水層。將合併之有機萃取物用鹽水(20毫升)洗滌，乾燥及在減壓下除去溶劑。將所得殘餘物溶解在MeOH(5.〇毫升)及AcOH(2.0毫升）中炎進行SCX捕捉和釋放。藉由管柱層析法純化粗製混合物(Si〇2 ’ 12克，在DCM中之0-i0〇/〇MeOH，梯度溶析）以產生呈米黃色粉末之標題化合物，中間物G , (63毫 148 201130813 克 ’ 38%) : m/z 535 (M+H)+ (ES+)。實例44 : N-(4_(1_(4_(3_(3_第三·丁基小對_曱苯基_ih_ t坐_5_基)腺基）萘-基氧基）乙基)％啶冬基峰乙酿胺： 1Et〇Ac (2 〇 ml)' and separate the layers. The aqueous layer was extracted with EtOAc (3× EtOAc). The combined organic extracts were washed with brine, dried and evaporated in vacuo. The tanning product was purified by column chromatography (Si〇2 '12 g, 〇8〇% Et 〇Ac in iso-hexane, gradient elution) 147 ... yielded 4-(1-(4) in orange gum -N-Naphthalen-1-yloxy)ethyl)acridin-2-amine (38) (94.6 mg <RTI ID=0.0> A solution of (38) (91 mg, 0.294 mmol) in MeOH (15 mL) and AcOH (3.0 mL) was passed <RTI ID=0.0> Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure to leave a purple solid which was then subjected to SCX capture and elution to give 4-(1-(4-aminonaphthalen-1-yloxy)ethyl) Pyridin-2-amine (39) (81 mg, 99%): m/z 280 (M+H) + (ES+). A saturated aqueous solution of NaHC 3 (( ο mL) was added to a solution of (5) (57 mg <RTI ID=0.0>> Add chloroformic acid trichloromethane ester (0.091 ml, 0.750 mmol). The resulting mixture was stirred under 〇〇c for 1.5 hours. The biphasic mixture was separated and the organic extract was dried and solvent was evaporated under reduced pressure to provide oil It was dried under high vacuum for 35 minutes. The obtained oil was dissolved in THF (5.0 mL) and then added to 4-(1-(4-aminonaphthalen-1-yloxy)ethyl) Bite _2_amine (39) (81 mg, 0.290 mmol). Add DIPEA (179 μL, 1.029 mmol) and mix the reaction mixture at RT for 16 hours. Water (15 mL) The mixture was extracted with EtOAc (EtOAc m. The resulting residue was dissolved in MeOH (5. <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was prepared (Si 〇 2 ' 12 g, 0-i0 〇 / 〇 MeOH in DCM, gradient eluted) to give the title compound as a beige powder, Intermediate G, (63 148 201130813 grams ' 38%) : m/z 535 (M+H)+ (ES+). Example 44: N-(4_(1_(4_(3_(3_3············· Glycosyl)naphthyl-yloxy)ethyl)%pyridinyl Ethylamine: 1

將甲氧基乙醯氣（17.5微升，〇·192毫莫耳)逐滴加至中間物G(41毫克’ 〇·〇77毫莫耳)及DIpEA(4〇]微 =’ 0.230毫莫耳)在DCM(3毫升）中於在氮氣下的溶液。15分鐘之後將反應混合物加熱至RT並攪拌15 小時。添加NH3的溶液(在MeOH中之ι〇/〇，1>5毫升）且繼續攪拌另2小時。將反應混合物在真空中蒸發及使殘餘物進行SCX捕捉和釋放。合併包含所要材料之部分’在真空中蒸發及藉由急驟管柱層析法純化 (Si02 ’ 12克’ 3-6%在DCM中之MeOH，梯度溶析；然後Si〇2 ’ π克，在***中之〇_4〇〇/〇Et〇Ac，梯度溶析）以產生呈米黃色固體之標題化合物，實例44(24毫克，51%) : m/z 607 (M+h)+ (ES+) ; b NMR (400 MHz， DMSO d6) δ ： 1.26 (9H, s), 1.67 (3H, d), 2.38 (3H, s), 4.03 (2H, s), 5.75 (1H, q), 6.32 (1H, s), 6.81 (1H, d), 7.22 (1H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.48 (1H, s), 7.59 (2H, m), 7.88 (1H, m), 8.24 (1H, br s), 8.27 (1H, d), 8.36 (1H, 149 201130813 m)，8·59 (1H，br s)，8.76 (1H，br s)，9.99 (1H，br s)。中間物H: 胺基吡啶_4_基)_2_曱基丙-2-基氧基）萘-1-基)-3-(3-第三-丁基-1-對-曱苯基坐-5-基) 脲。Methoxyacetone (17.5 μl, 192·192 mmol) was added dropwise to the intermediate G (41 mg '〇·〇 77 mmol) and DIpEA (4〇) micro = '0.230 mmol Ear) in DCM (3 mL) in a solution under nitrogen. After 15 minutes the reaction mixture was heated to RT and stirred for 15 h. A solution of NH3 (m 〇 / 〇 in MeOH, 1 > 5 mL) was added and stirring was continued for another 2 hours. The reaction mixture was evaporated in vacuo and the residue was subjected to SCX capture and elution. Combine the fractions containing the desired material 'evaporated in vacuo and purified by flash column chromatography (SiO 2 ' 12 g ' 3-6% MeOH in DCM, gradient elution; then Si 〇 2 ' π g, at The title compound was obtained as a beige solid in EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: b NMR (400 MHz, DMSO d6) δ : 1.26 (9H, s), 1.67 (3H, d), 2.38 (3H, s), 4.03 (2H, s), 5.75 (1H, q), 6.32 ( 1H, s), 6.81 (1H, d), 7.22 (1H, dd), 7.35 (2H, m), 7.42 (2H, m), 7.48 (1H, s), 7.59 (2H, m), 7.88 (1H , m), 8.24 (1H, br s), 8.27 (1H, d), 8.36 (1H, 149 201130813 m), 8·59 (1H, br s), 8.76 (1H, br s), 9.99 (1H, Br s). Intermediate H: Aminopyridine _4_yl)_2-mercaptopropen-2-yloxy)naphthalen-1-yl)-3-(3-tri-butyl-1-p-phenyl) -5-base) Urea.

經⑺分鐘將曱基裡(在二乙趟中之1.6 Μ，33毫升’ 53毫莫耳)加至曱基-2-胺基吡啶-4-曱酸酯（35)(2.00 克’ 13毫莫耳)在THF(200毫升）中於-78°C在氮氣下的攪拌溶液，30分鐘之後將黏反應混合物加熱至〇°C經 3.5小時且在〇。(：下藉由謹慎添加異丙醇（15毫升)停止反應。將混合物加熱至RT，及添加鹽水(400毫升）及 EtOAc(300毫升）。將水層分離且用EtOAc萃取(3 x200 毫升）並將合併之有機萃取物乾燥(MgS04)並在真空中蒸發。藉由急驟管柱層析法純化粗製殘餘物(Si〇2，12〇克’在EtOAc中之〇-1 〇%MeOH ’梯度溶析）以提供呈黃色非晶形固體之2-(2-胺基°比〇定-4-基）丙_2-醇(4〇)(127 克，63%):巾 NMR (400 MHz，CD3〇D) δ : 1.47 (6H，s)， 6.68-6.71 (2Η，重疊 m)，7.80-7.81 (1H，dd)。 ’ ’ 150 201130813 將氫化鈉（60%重量，〇·6ΐ克，15.0毫莫耳）加至 (40)(1.55克，1〇.〇毫莫耳)在dmf(30毫升）中於〇。(：在氮氣下的攪拌溶液，及將所得混合物在〇。匚下揽拌5分鐘’逐滴添加1-氟_4_硝基萘（丨叹丨％克，1〇毫莫耳）在DMF(3 0毫升）中的溶液且將所得暗紅色混合物在〇〇c 下攪拌另5分鐘且然後在RT下經2小時。將反應混合物藉由添加NKUCl飽和水溶液（1〇毫升)停止反應。加水（150宅升)及EtOAc(150毫升）’及分離該等層。用 EtOAc(3 X 1〇〇毫升）萃取水層及將合併之有機萃取物用鹽水洗滌，乾燥(MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化粗製殘餘物（Si〇2，8〇克，在異己炫中之 0-60%EtOAc，梯度溶析）以提供呈紅色油之4_(2 (4硝基萘-1-基氧基）丙_2·基)η比啶_2_胺(41)(282毫克，8%): m/z 324 (M+H)+ (ES+)。將(41)(282毫克，0.87毫莫耳)在Me〇H(45毫升）中的溶液通過Thales H-立方體(1.〇亳升分鐘-1，3〇〇c， 55毫米10%Pt/C Cat-Cart，全氫模式）。將反應混合物在真空中蒸發以提供呈棕色泡沫之‘(2_(4•胺基萘基氧基）丙-2-基)吼咬-2-胺(42)(253 毫克，89%) : m/z 294 (M+H)+ (ES+)。將NaHC〇3飽和水溶液(27亳升）加至⑺(447毫克，I.75毫莫耳)在DCM(4〇毫升）中的溶液。將混合物用力_拌並冷卻至0X及然後—魏加至氯甲酸三氣曱醋(0.63毫升’ 5.25毫莫耳。將所得混合物在〇〇c 下授拌1·5小時。將二相混合物分離及將有機層乾燥 (Mgso4)並在真空中蒸發。將油狀殘餘物溶解在THF〇5 151 201130813 毫升）中並加至(42)(253毫克，0.86毫莫耳)在THF(2.0 宅升）中的溶液。添加純DIPEA(451微升，2.59毫莫耳) 且將反應混合物在RT下攪拌2小時。添加水(3〇毫升）及EtOAc(20毫升)並分離該等層。用Et〇Ac萃取水層 (3 X 15毫升)及用鹽水(4〇毫升）洗滌合併之有機層，乾燥(MgS〇4)，並在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si02 ’ 40克，在DCM中之〇-i〇%MeOH，梯度溶析）以提供呈紫色非晶形固體之標題化合物，中間物 Η，（249 毫克，51%) : m/z 549 (M+H)+ (ES+)。實例 45 : Ν-(4-(2-(4-(3_(3·第三-丁基]_對_ 曱苯基·1H_ 0比0坐-5-基）脲基）蔡-1-基氧基）_2_曱基丙基）0比咬_2_ 基)-2-甲氧基乙醢胺：Add hydrazino (1.6 二 in diethyl hydrazine, 33 ml '53 mmol) to decyl-2-aminopyridine-4-furoate (35) (2.00 g '13 mM) (7) minutes The mixture was stirred in THF (200 mL) at -78 ° C under nitrogen. After 30 min, the viscous reaction mixture was heated to 〇 ° C over 3.5 hrs. The reaction was quenched with EtOAc (15 mL). The combined organic extracts were dried (MgSO4) and evaporated in vacuo. Solute to give 2-(2-aminopyroxy-4-yl)propan-2-ol (4 g) (127 g, 63%) as a yellow amorphous solid: NMR (400 MHz, CD3〇D) δ : 1.47 (6H, s), 6.68-6.71 (2Η, overlap m), 7.80-7.81 (1H, dd). ' ' 150 201130813 Sodium hydride (60% by weight, 〇·6 gram, 15.0) Add to (40) (1.55 g, 1 〇. 〇 millimolar) in dmf (30 ml) in 〇. (: stirring solution under nitrogen, and the resulting mixture in 〇. Mix for 5 minutes' dropwise addition of 1-fluoro-4_nitronaphthalene (丨丨克 gram, 1 〇 millimol) solution in DMF (30 ml) and the resulting dark red mixture under 〇〇c Stir for another 5 minutes and then at RT for 2 hours The reaction mixture was quenched with EtOAc (3×1 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. 60% EtOAc (gradient elution) to afford 4-(2(4-nitronaphthalen-1-yloxy)propan-2-yl)n-pyridin-2-amine (41) as a red oil (. %): m/z 324 (M+H)+ (ES+). A solution of (41) (282 mg, 0.87 mmol) in Me〇H (45 mL) was passed through Thales H-cube (1. Soaring minutes -1,3 〇〇c, 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo to provide a brown foam of '(2_(4•aminonaphthyl) Oxy)propan-2-yl)bite-2-amine (42) (253 mg, 89%): m/z 294 (M+H) + (ES+). NaHC〇3 saturated aqueous solution (27 liters) Add to (7) (447 mg, 1.75 mmol) in DCM (4 mL). Mix the mixture with force_mix and cool But to 0X and then - Wei Jia to trichloro chloroacetic acid vinegar (0.63 ml ' 5.25 mmol). The resulting mixture was mixed under 〇〇c for 1.5 hours. The biphasic mixture was separated and the organic layer was dried (MgSO4) and evaporated in vacuo. The oily residue was taken up in THF (5 s s s s s s s s s s s s s s) and added to a solution of (42) (253 mg, 0.86 mmol) in THF (2.0 liter). Pure DIPEA (451 μL, 2.59 mmol) was added and the reaction mixture was stirred at RT for 2 h. Water (3 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3.times.15 mL) and the combined organic layer was washed with brine (4 mL) and dried (MgS s 4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut , 51%) : m/z 549 (M+H)+ (ES+). Example 45: Ν-(4-(2-(4-(3_(3·T-butyl)_p-ylphenyl) 1H_ 0 to 0--5-yl) Urea))-1-yl Oxy)_2_mercaptopropyl)0 than bite_2_yl)-2-methoxyacetamide:

將曱氧基乙酿氯(28微升，〇.3〇毫莫耳)在氮氣下逐滴加至中間物H(66毫克’ 0.12毫莫耳)在DCM(3 〇毫升)及DIPEA(63微升’ 0.36毫莫耳）中於〇〇C下的溶液。將反應混合物在0〇C下攪拌15分鐘且然後在RT下經 2.5小時。添加NH3的溶液(在MeOH中之1%，ι·5毫升)且將混合物搜拌30分鐘及然後在真空中蒸發。將殘餘物進行SCX捕捉和釋放，然後藉由管柱層析法純化三次(Si02 ’ 12克，在DCM中之〇-7%MeOH，梯度溶析；C18 ’ 12克，在水中之0-100%MeCN，梯度溶析及 152 201130813The methoxy bromide chloride (28 μL, 〇.3 〇 millimolar) was added dropwise to the intermediate H (66 mg '0.12 mmol) in DCM (3 mL) and DIPEA (63) under nitrogen. A solution of 微C under a microliter of '0.36 millimolars. The reaction mixture was stirred at 0 ° C for 15 minutes and then at RT for 2.5 hours. A solution of NH3 (1% in MeOH, <RTI ID=0.0>> The residue was subjected to SCX capture and release, and then purified three times by column chromatography (SiO 2 ' 12 g, 〇-7% MeOH in DCM, gradient elution; C18 ' 12 g, 0-100 in water %MeCN, gradient elution and 152 201130813

Si〇2，12克，在Et2〇之0-65%EtOAc，梯度溶析）以提供呈白色固體之標題化合物，實例45(18毫克，24%): m/z 621 (M+H)+ (ES+)。4 NMR (400 MHz，DMSO-d6) δ ： 1.28 (9Η, s), 1.39 (6Η, s), 2.39 (3H, s), 3.22 (3H, s), 3.80 (1H, d), 4.16 (1H, d), 5.27 (1H, s), 6.41 (1H, s), 7.26 (1H, dd), 7.37 (2H, m), 7.46 (2H, m), 7.56 (1H, d), 7.60 (2H，重疊 m)，7.76 (lH，brs), 7.95 (lH,m)，8.01 (lH，d)， 8.09 (1H, m), 8.22 (1H, d), 8.94 (1H, br s), 9.28 (1H, br s)。中間物J . 1-(4-(1-(2-胺基σ比σ定-4-基）丙-2-基氧基）奈-1_ 基)-3-(3-第三-丁基-1-對-曱苯基-1Η-°比唑-5-基)脲。</RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (ES+). 4 NMR (400 MHz, DMSO-d6) δ: 1.28 (9Η, s), 1.39 (6Η, s), 2.39 (3H, s), 3.22 (3H, s), 3.80 (1H, d), 4.16 (1H , d), 5.27 (1H, s), 6.41 (1H, s), 7.26 (1H, dd), 7.37 (2H, m), 7.46 (2H, m), 7.56 (1H, d), 7.60 (2H, Overlap m), 7.76 (lH, brs), 7.95 (lH, m), 8.01 (lH, d), 8.09 (1H, m), 8.22 (1H, d), 8.94 (1H, br s), 9.28 (1H , br s). Intermediate J. 1-(4-(1-(2-Amino σ σ -4--4-yl)propan-2-yloxy)-n-yl)-3-(3-tri-butyl -1-p-indole-1-yl-pyridyl-5-yl)urea.

經3小時將LDA(2.0M在THF中，809毫升，1.62 153 201130813 莫耳）的溶液逐滴加至2-氣甲吼α定(43)(59.1毫升，674 毫莫耳)在THF(500毫升）中於-78°C的授拌溶液。將反應混合物擾拌另15分鐘且然後以單一部分添加碳酸二乙酯（106毫升，876毫莫耳）。1〇分鐘之後使反應混合物加熱至0°C’在此溫度下攪拌20分鐘且然後添加 NH4C1之飽和水溶液(800毫升）。用乙鱗萃取混合物並將有機相用水洗滌’乾燥(MgS04)，並在真空中蒸發以產生黑色油，（〜200克），其以急驟管柱層析法分三批次純化（Si〇2，330克，在異己烷中之5_2〇%Et〇Ac，梯度溶析）以產生2-(2-氣吡啶-4-基）乙酸乙酯（44)(72克， 51%) ： m/z 200 (M+H)+ (ES+) 將(44)(15.0克，75.0毫莫耳）、第三_丁基胺甲酸酯 (26.4 克 ’ 225 毫莫耳）、Pd2(dba)3 (1.719 克，1.88 毫莫耳）、碳酸鉋(36.7克，113毫莫耳)及Xantph〇s® (2.17 克’ 3.76毫莫耳)在THF(l〇〇毫升）中的混合物用氮吹洗且然後在65°C下攪拌8小時。將混合物冷卻至RT並用水稀釋及用***萃取。將***萃取物合併及用水和鹽水洗滌且然後乾燥(MgSCM，並在真空中蒸發》藉由急驟管柱層析法純化殘餘物(Si〇2，33〇克，在異己烷中之 5-20°/()EtOAc，梯度溶析）’然後進行SCx捕捉和釋放以提供2-(2-(第三-丁氧羰胺基）吡啶_4_基）乙酸乙酯 (45)(12.0 克 ’ 51%) : m/z 281 (M+H)+ (ES+)。經12分鐘將曱基鋰(在二***中之j 6 μ，17.4毫升’ 27.9毫莫耳）的溶液逐滴加至(45)(1.56克，5.58毫莫耳)在THF (140毫升）中於jpc在氮氣下的攪拌溶液。3小時之後添加異丙醇(5 〇毫升)且將反應混合物分 154 201130813 溶在水及EtOAc之間。用EtOAc萃取水層二次且將合併之有機萃取物用鹽水洗滌，然後乾燥(MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2，8〇克’在異己烧中之0-80%EtOAc，梯度溶析）以提供呈白色固體之4-(2-側氧基丙基)D比咬-2-基胺甲酸第三-丁酯 (46)(300 毫克，21%) : m/z 251.0 (M+H)+ (ES+)。將硼氳化鈉(45.3毫克’ 1.20毫莫耳)加至(46)(3〇〇毫克，1.20毫莫耳)在甲醇（12毫升）中於〇〇c在氮氣下的攪拌溶液。10分鐘之後將反應混合物加熱至RT並繼續授拌75分知。在真空中蒸發混合物及將殘餘物溶解在EtOAc中及用NaHC0；j水溶液洗滌。用EtOAc萃取二次水層及將合併之有機萃取物用鹽水洗滌，然後乾燥 (MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2，12克’在異己烷中之i〇_8〇%Et〇Ac，梯度溶析）以提供呈白色粉末之4-(2-羥丙基）吡啶_2·基胺甲酸第二-丁酯（47)(262 毫克 ’ 85%) ; m/z 253.0 (M+H)+ (ES+)。將氫化鈉（119毫克，2.97毫莫耳)加至(47)(25〇毫克，0.991毫莫耳)在DMF(6 〇毫升）中於〇0(：在氮氣下的攪拌溶液且45分鐘之後，經2分鐘逐滴添加丨·氟·4_ 硝基奈（14)(189毫克，0.991毫莫耳)在DMF(6.0毫升）中的✓谷液。將所得深棕色反應混合物在〇。匚下授拌5分鈿，且然後加熱至RT。7〇分鐘之後，添加NH4C1之飽和水溶液（3.0毫升）且將混合物分溶在水及Et〇Ac之間。用EtOAc萃取水層二次並將合併之有機萃取物用鹽水洗務’乾燥(MgS〇4)並在真空中蒸發。藉由急驟管 155 杜層析法純化殘餘物（Si〇2，40克；在異己烧中之 0-70%EtOAc，梯度〉谷析）以提供呈撥色泡珠之4_(2_(4 石肖基萘-1 -基氧基）丙基）°比°定-2-基胺曱酸第三_ 丁酉旨 (48)(293 毫克 ’ 65%) : m/z 424.0 (M+H)+ (ES+)。將(48)(271毫克，0.614毫莫耳)在Me〇H(3〇毫升) 中的溶液通過Thales H-立方體（1.0毫升分鐘-1 , 3〇〇c , 55毫米，10%Pt/C Cat-Cart，全氫模式)並在真空中除去揮發物以提供呈紫色泡沫之4-(2-(4-胺基萘基氧基) 丙基)°比°定-2-基胺曱酸第三-丁 g旨（49)(241毫克，1〇〇%): m/z 394.0 (M+H)+ (ES+)。經5分鐘將(5)(212毫克’ 0.923毫莫耳)在DCM(1 毫升）中的溶液加至CDI(150毫克，0.923毫莫耳）在 DCM(1毫升）中於RT在氮氣下的攪拌溶液。丨5小時之後添加(49)(242毫克’ 0.615毫莫耳)在DCM(2毫升）中的溶液且在RT下繼續攪拌16小時。以與第一次相似的方式藉由與在DCM(1毫升）中之CDI(100毫克，0.615 毫莫耳)反應處理第二部分之在〇CM(l毫升）中的3-第三-丁基-1·對-甲苯基·1Η-吡唑-5-胺（141毫克，〇·615亳莫耳）’及然後將所得加合物加至反應混合物。另2 $ 小時之後將混合物分溶在水及DCM之間。用DCM萃取水層及將合併之有機萃取物用鹽水洗滌且然後乾燥 (MgSCU)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ’40克，在異己烷中之〇_i〇〇%Et〇Ac，梯度溶析）以提供呈紫色泡沫之4-(2-(4-(3-(3-第三-丁基-l_對 -曱苯基-1H-吡唑_5_基)脲基）萘小基氧基）丙基)π比啶_2_ 基胺曱酸第三-丁酯（50)(163毫克，40%) : m/z 649 156 201130813 (M+H)+ (ES+)。將TFA(2.0毫升)加至胺曱酸第三_丁酯（5〇)(i58毫克，0.244宅莫耳)在DCM(4.0毫升）中於〇〇c在氮氣下的攪拌溶液。5分鐘之後，將反應混合物加熱至並攪拌另2小時。將混合物在真空中蒸發且使殘餘物進行 sex捕捉和釋放以提供標題化合物，中間物了，邛毫克，>100%) : m/z 549 (M+H)+ (ES+)。實例 46 : N-(4-(2-(4-(3-(3-第三-丁基-1_對_ 甲苯基 _1H_ °比°坐-5-基)脲基）萘小基氧基）丙基)11比咬_2_基)_2_曱氧美乙醯胺： &A solution of LDA (2.0 M in THF, 809 mL, 1.62 153 201130813 Mo) was added dropwise to 2-carbazepine (43) (59.1 mL, 674 mmol) in THF (500). Mixing solution at -78 ° C in ml). The reaction mixture was spoiled for another 15 minutes and then diethyl carbonate (106 mL, 876 mmol) was added in a single portion. After 1 minute, the reaction mixture was heated to 0 ° C. and stirred at this temperature for 20 minutes and then a saturated aqueous solution of NH 4 C1 (800 mL) was added. The mixture was extracted with an acetite and the organic phase was washed with water <""&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& , 330 g, 5 2 〇% Et 〇Ac in isohexane, gradient eluted to give ethyl 2-(2-pyridin-4-yl)acetate (44) (72 g, 51%): m/ z 200 (M+H)+ (ES+) will be (44) (15.0 g, 75.0 mmol), third butylbutyl carbamate (26.4 g '225 mM), Pd2(dba)3 ( a mixture of 1.719 g, 1.88 mmol, carbonic acid planer (36.7 g, 113 mmol) and Xantph〇s® (2.17 g ' 3.76 mmol) in THF (10 mL) was purged with nitrogen and It was then stirred at 65 ° C for 8 hours. The mixture was cooled to RT and diluted with water and extracted with diethyl ether. The ether extracts were combined and washed with water and brine and then dried (MgSO.sub. °/() EtOAc, gradient elution)' then subjected to SCx capture and elution to afford ethyl 2-(2-(tris-butoxycarbonylamino)pyridine-4-yl)acetate (45) (12.0 g. 51%) : m/z 281 (M+H) + (ES+). A solution of decyllithium (j 6 μ in diethyl ether, 17.4 ml '27.9 mmol) was added dropwise over 12 minutes ( 45) (1.56 g, 5.58 mmol) in THF (140 mL) in a stirred solution of jpc under nitrogen. After 3 hours, add isopropanol (5 mL) and the reaction mixture is divided into 154 201130813 dissolved in water and The mixture was extracted with EtOAc (EtOAc) EtOAc (EtOAc m. , 8 grams of '0-80% EtOAc in iso-firing, gradient elution) to provide 4-(2-oxopropyl)D as a white solid. Ester (46) (300 mg, 21% : m/z 251.0 (M+H)+ (ES+). Add sodium borohydride (45.3 mg ' 1.20 mmol) to (46) (3 mg, 1.20 mmol) in methanol (12) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was extracted with EtOAc (EtOAc).克 'i〇_8〇%Et〇Ac in isohexane, gradient elution) to provide a white powder of 4-(2-hydroxypropyl)pyridine-2-yl carbamic acid second-butyl ester (47 (262 mg ' 85%); m/z 253.0 (M+H) + (ES+). Add sodium hydride (119 mg, 2.97 mmol) to (47) (25 mg, 0.991 mmol) In DMF (6 mM), 〇0 (: stirring solution under nitrogen and 45 minutes later, 丨·Fluoro- 4 nitronaphthalene (14) (189 mg, 0.991 mmol) was added dropwise over 2 minutes. ✓ Valley solution in DMF (6.0 ml). The resulting dark brown reaction mixture was stirred for 5 minutes under hydrazine, and then heated to RT. After 7 min, a saturated aqueous solution of NH.sub.4Cl.sub.3 (.sup.3 mL) was then applied and the mixture was partitioned between water and Et. . The aqueous layer was extracted twice with EtOAc and EtOAc (EtOAc) The residue was purified by flash chromatography 155 (yield: EtOAc, EtOAc, EtOAc (EtOAc) Naphthalene-1 -yloxy)propyl) ° 定-2-ylamine decanoic acid _ _ 酉酉 (48) (293 mg ' 65%): m / z 424.0 (M + H) + (ES + ). A solution of (48) (271 mg, 0.614 mmol) in Me〇H (3 mL) was passed through a Thales H-cube (1.0 mL min-1, 3〇〇c, 55 mm, 10% Pt/C Cat-Cart, in full hydrogen mode) and remove volatiles in vacuo to provide 4-(2-(4-aminonaphthyloxy)propyl)-pyral-2-ylamine decanoic acid as a purple foam The third-butan (49) (241 mg, 1%): m/z 394.0 (M+H)+ (ES+). A solution of (5) (212 mg '0.923 mmol) in DCM (1 mL) was added to CDI (150 mg, 0.923 mmol) in DCM (1 mL) Stir the solution. After 5 hours, a solution of (49) (242 mg ' 0.615 mmol) in DCM (2 mL). The second part of the 3-third-but in 〇CM (1 ml) was treated in a similar manner to the first time by reaction with CDI (100 mg, 0.615 mmol) in DCM (1 mL). Base-1·p-tolyl·1Η-pyrazole-5-amine (141 mg, 〇·615 亳mol)' and then the resulting adduct was added to the reaction mixture. After another 2 hours, the mixture was dissolved between water and DCM. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine and then dried (MgSCU) and evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2 '40 g, 异〇〇 E E E E , , , , , , , , , , , , , , , , , , , , , , 4-(3-(3-Terti-butyl-l-p-p-phenyl)-1H-pyrazole-5-yl)ureido)naphthalenyloxy)propyl)π-pyridyl-2-ylamine Tri-butyl phthalate (50) (163 mg, 40%): m/z 649 156 201130813 (M+H)+ (ES+). TFA (2.0 ml) was added to a stirred solution of the third-butyl ester of ammonic acid (5 Torr) (i.sup.58 g, 0.244 m.) in DCM (4.0 mL) EtOAc. After 5 minutes, the reaction mixture was heated to and stirred for another 2 hours. The mixture was evaporated in vacuo and <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 46: N-(4-(2-(4-(3-(3-Terve-butyl-1_p-tolyl-1H_ ° ratio)-5-) Urea-based) naphthalene small oxygen Base)propyl)11 than bite_2_yl)_2_oximemethamine: &

將甲氧基乙醯氯（17微升，0.18毫莫耳)逐滴加至中間物J(40毫克，0.073毫莫耳)及DIPEA(38微升，〇 22 毫莫耳)在DCM(3毫升）中於〇。〇在氮氣下的攪拌溶液。20分鐘之後將反應混合物加熱至RT。另4小時之後，添加NH3的溶液(在MeOH中之1%，3毫升)且繼續授拌1小時。在真空中蒸發反應混合物及使殘餘物進行SCX捕捉和釋放且然後藉由急驟管柱層析法純化 (Si〇2 ’ 12克，在DCM中之〇_5%MeOH，梯度溶析）以產生標題化合物，實例46，（5.6毫克，12%) : m/z 621 (M+H)+ (ES+) 〇 JH NMR (400 MHz, CDC13) δ ： 1.31 (9H, s), 1.45 (3H, d), 2.22 (3H, s), 3.06 (1H, dd), 3.20 (1H, dd), 157 201130813 3.47 (3H, s), 3.95 (2H, s), 4.86 (1H, m), 6.42 (1H, s), 6.50 (1H, br s), 6.56 (1H, br s), 6.71 (1H, d), 6.89 (2H, br d), 6.97 (2H, br d), 7.00 (1H, dd) 7.31 (1H, d), 7.49 (2H, m), 7.81 (1H, br m), 8.17 (1H, d), 8.19 (1H, br s), 8.26 (1H, m), 8.83 (1H, br s)。中間物K . 1 -(4-(2-(2-胺基。比。定-4-基）丙氧基）奈-1 -基)-3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲Methoxyethyl chloride (17 μL, 0.18 mmol) was added dropwise to Intermediate J (40 mg, 0.073 mmol) and DIPEA (38 μL, 〇22 mmol) in DCM (3) In milliliters). Stir the solution under nitrogen. The reaction mixture was heated to RT after 20 minutes. After another 4 hours, a solution of NH3 (1% in MeOH, 3 mL) was then weighed and continued for 1 hour. The reaction mixture was evaporated in vacuo and the residue was taken to EtOAc (EtOAc) eluting eluting eluting Title Compound, Example 46, (5.6 mg, 12%): m/z 621 (M+H) + (ES+) 〇JH NMR (400 MHz, CDC13) δ: 1.31 (9H, s), 1.45 (3H, d ), 2.22 (3H, s), 3.06 (1H, dd), 3.20 (1H, dd), 157 201130813 3.47 (3H, s), 3.95 (2H, s), 4.86 (1H, m), 6.42 (1H, s), 6.50 (1H, br s), 6.56 (1H, br s), 6.71 (1H, d), 6.89 (2H, br d), 6.97 (2H, br d), 7.00 (1H, dd) 7.31 ( 1H, d), 7.49 (2H, m), 7.81 (1H, br m), 8.17 (1H, d), 8.19 (1H, br s), 8.26 (1H, m), 8.83 (1H, br s). Intermediate K. 1-(4-(2-(2-Amino). 1,4--4-yl)propoxy)na-1-yl)-3-(3-tri-butyl-1- p-Phenylphenyl-1H-pyrazol-5-yl)urea

將KHMDS的溶液(在曱苯中之0.5M，26.3毫升， 13.2毫莫耳）加至2-(2-氯吡啶-4-基）乙酸乙酯（44)(2.5 克，12.52毫莫耳)在THF(25毫升）中於-78°C在氮氣下的攪拌溶液。將混合物加熱至RT經10分鐘，然後再冷卻至-78 °C及以單一部分添加碘曱烷(0.820毫升，13.15 毫莫耳)及使混合物加熱至RT。添加NH4C1飽和水溶液且用***稀釋混合物。將有機層用水和鹽水洗滌且然後 158 201130813 乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物 (Si〇2，100克，在異己烷中之5-10%EtOAc，梯度溶析) 以提供2-(2-氣吡啶-4-基）丙酸乙酯（51)(1.57克，56%): m/z 214 (M+H)+ (ES+)。將（51)(1.55克’ 7.25毫莫耳）、第三-丁基胺甲酸酷 (2.55 克，21.76 毫莫耳）、Pd2dba3(0.166 克，0.181 毫莫耳）、碳酸飽(3.55克，10.88毫莫耳)及\3吻11〇5(〇.21〇克，0.363毫莫耳)在THF(10毫升）中的混合物用氮吹洗並在65°C下加熱48小時。然後將混合物冷卻至rt，用水稀釋且用***萃取。將***層用水和鹽水洗滌且然後乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ’ 100克，在異己烷中之5_1〇%Et〇Ac，梯度溶析）以提供2-(2-(第三-丁氧|炭胺基）π比咬_4-基）丙酸乙酉旨 (52)(1.35 克，61%) : m/z 295 (M+H)+ (ES+) 經10分鐘將DIBAL的溶液(在DCM中之1Μ，13.8 毫升’ 13.8毫莫耳)逐滴加至酯(52)(ι.35克，4.59毫莫耳)在THF(25毫升）中於_78。(：在氮氣下的攪拌溶液。將反應混合物加熱至RT且然後再冷卻至_78 〇c及添加第二部分之DIBAL(在DCM中之1M，4.5毫升，4.5毫莫耳）。使反應混合物加熱至RT，然後冷卻至MC且添加水(5毫升)及然後添加MgS〇4。將混合物用DCM稀釋及過渡除去固體。用EtOAc、MeOH及DCM洗滌濾餅且將合併之濾液及洗滌在真空中蒸發。藉由急驟管枉層析法純化殘餘物（Si02，40克，在異己烷中之 25-50%Et〇Ac’梯度溶析）以提供4_(ι_羥丙_2_基)吡啶-2- 基胺曱酸第三·丁酯（53)(0.62 克，50%): m/z 253 (M+H)+ 159 201130813 (es+)。將氫化鈉(60%在礦油中之分散液，〇 246克，6.14 毫莫耳）以單一部分加至醇(53)(0.62克，2.46毫莫耳)在 D M F (4.0 4升）巾力溶液及將混合物在氣流下用超音波處理且然後纟RTT授拌30分鐘。將所得黃色懸浮液冷部至0。〇及經10分鐘添加J氟·4_硝基萘㈣(47〇毫克，2.46毫莫耳)在DMF(2 〇毫升）中的溶液。將反應混合物加熱至RT及添加冰醋酸(1〇毫升）。將混合物倒進 NaHC〇3飽和水溶液且用Et〇Ac萃取。將有機層用 NaaCO3飽和水溶液洗滌，用水洗滌三次及用鹽水洗滌一次，然後乾燥(MgS〇4)並在真空中蒸發以產生黃色固 f °將固體懸浮在Me〇H(2〇毫升）中並用超音波處理及藉由過濾收集不溶殘餘物且用MeOH(l0毫升)及然後乙鍵洗條以提供呈灰白色固體之4-(1-(4-硝基萘-1-基氧基) 丙-2-基)吡啶_2_基胺甲酸第三-丁酯（54)(〇 73克，67%): m/z 424 (M+H)+ (ES+)。A solution of KHMDS (0.5 M in toluene, 26.3 mL, 13.2 mmol) was added to ethyl 2-(2-chloropyridin-4-yl) (44) (2.5 g, 12.52 mmol) The solution was stirred in THF (25 mL) at -78 ° C under nitrogen. The mixture was heated to RT for 10 minutes, then cooled to -78 °C and succinimide (0.820 mL, 13.15 mmol) was added in a single portion and the mixture was warmed to RT. A saturated aqueous solution of NH4Cl was added and the mixture was diluted with diethyl ether. The organic layer was washed with water and brine and then dried 158. The residue was purified by flash column chromatography (EtOAc mjjjjjjjjjjjjj Ethyl ester (51) (1.57 g, 56%): m/z 214 (M+H) + (ES+). (51) (1.55 g ' 7.25 mmol), tributyl-butylcarbamate (2.55 g, 21.76 mmol), Pd2dba3 (0.166 g, 0.181 mmol), carbonate (3.55 g, 10.88) The mixture was stirred with nitrogen and heated at 65 ° C for 48 hours. The mixture was then cooled to rt, diluted with water and extracted with diethyl ether. The ether layer was washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (Si 〇 2 '100 g, 5 1 〇% Et 〇Ac in isohexane, gradient elution) to provide 2-(2-(T-butoxy)|carbon Amino) π ratio _4-base) propionate acetazone (52) (1.35 g, 61%): m/z 295 (M+H)+ (ES+) DIBAL solution in 10 minutes (in DCM) 1 Μ, 13.8 mL ' 13.8 mmoles) was added dropwise to the ester (52) (m.35 g, 4.59 mmol) in THF (25 mL). (: Stirring solution under nitrogen. The reaction mixture was heated to RT and then cooled to _78 〇c and a second portion of DIBAL (1M in DCM, 4.5 mL, 4.5 mmol). Heat to RT, then cooled to MC and added water (5 mL) and then added EtOAc. EtOAc EtOAc EtOAc EtOAc. Evaporation. Purify the residue by flash chromatography (SiO2, 40 g, gradient elution from 25-50% Et EtOAc in isohexane) to afford 4-(m-hydroxypropyl-2-yl) Pyridin-2-ylamine decanoic acid tert-butyl ester (53) (0.62 g, 50%): m/z 253 (M+H)+ 159 201130813 (es+) sodium hydride (60% in mineral oil) The dispersion, 〇246 g, 6.14 mmol) was added in a single portion to the alcohol (53) (0.62 g, 2.46 mmol) in DMF (4.0 4 L) towel solution and the mixture was subjected to ultrasonic waves under air flow. Treatment and then 纟RTT for 30 minutes. The resulting yellow suspension was cooled to 0. J and added JF 4 nitronaphthalene (4) (47 〇 mg, 2.46 mmol) in DMF over 2 minutes (2 〇) The reaction mixture was heated to RT and glacial acetic acid (1 mL) was added. The mixture was poured into a saturated aqueous solution of NaHC 3 and extracted with Et EtOAc. The organic layer was washed with aq. And washing once with brine, then drying (MgS〇4) and evaporating in vacuo to give a yellow solid. The solid was suspended in Me〇H (2 mL) and treated by ultrasonication and collected by filtration and insoluble residue. The strip was washed with MeOH (10 mL) and then ethyl acetate to afford 4-(1-(4-nitronaphthalen-1-yloxy)propan-2-yl)pyridine-2-aminocarbamic acid Tri-butyl ester (54) (〇 73 g, 67%): m/z 424 (M+H) + (ES+).

將硝基芳烴(54)(0.61克，1.441毫莫耳)在MeOH (2〇.〇亳升）、AcOH (5·0毫升)及EtOAc(l〇.〇毫升）的混合物中之>谷液通過Thales H-立方體（1.0毫升.分鐘-1， 45°C，55亳米，1〇%pt/C(：at_Cart，全氫模式）。在真空中蒸發溶劑及將殘餘物分溶在NaHC03飽和水溶液及a nitroaromatic hydrocarbon (54) (0.61 g, 1.441 mM) in a mixture of MeOH (2 〇. liter), AcOH (5.0 mL) and EtOAc (1 〇. The solution was passed through a Thales H-cube (1.0 ml.min-1, 45 ° C, 55 亳m, 1 〇% pt/C (:at_Cart, full hydrogen mode). The solvent was evaporated in vacuo and the residue was dissolved in NaHC03. Saturated aqueous solution and

EtOAc之間。將有機層用水和鹽水洗滌且然後乾燥並在真空中凑發以提供4-(1-(4-胺基萘-1-基氧基）丙_2_基)0比啶_2_基胺甲酸第三-丁酯（55)(610毫克，97〇/〇” m/z 394 (M+H)+ (ES+)。經1.5小時將(5)(612毫克，2.67毫莫耳)在DCM(2.0 160 201130813 毫升）中的溶液逐滴加至CDI(433毫克，2.67毫莫耳)在 DCM(2.0毫升）中在氮氣下的懸浮液且將混合物在RT 下攪拌1小時。以單一部分加添胺(55)(700毫克，1.78 毫莫耳)在DCM(4.0毫升）中的溶液並將反應混合物授拌16小時’在這期間，沈澱物形成。將混合物溶解在 DCM(10毫升）中並藉由急驟管柱層析法純化(Si〇2，8〇克’在異己烷中之0-20%EtOAc，梯度溶析）以提供 4-(1-(4-(3-(3-第三-丁基小對曱苯基-1H_吡唑_5_基）脲基）萘-1-基氧基）丙-2-基）吡啶-2-基胺曱酸第三-丁酯 (56)(590 毫克，50%) : m/z 649 (M+H)+ (ES+) 將TFA(5.0毫升）加至胺曱酸第三-丁酯（56)(0 57 克’ 0.88毫莫耳)在DCM(10.0毫升）中的懸浮液及將所传深綠色溶液在RT下擾拌1小時。將混合物在真空中蒸發及將殘餘物溶解在MeOH(10.0毫升）中並進行scx 捕捉和釋放以提供呈紅色油之標題化合物，中間物 K(488 毫克，98%) : m/z 549 (M+H)+ (ES+)。實例 47 : Ν·(4-(1-(4-(3-(3-第三-丁基-1-對-曱笨基·1H_ 0比唾-5-基）腺基）蔡_ι_基氧基）丙基）η比咬_2_基)·2_曱氧基乙醯胺：Between EtOAc. The organic layer was washed with water and brine and then dried and taken in vacuo to give 4-(1-(4-aminonaphthalen-1-yloxy)propan-2-yl)-pyridin-2-ylamine Formic acid tert-butyl ester (55) (610 mg, 97 〇/〇" m/z 394 (M+H) + (ES+). (5) (612 mg, 2.67 mmol) in DCM over 1.5 hrs The solution (2.0 160 201130813 ml) was added dropwise to a suspension of CDI (433 mg, 2.67 mmol) in DCM (2.0 mL) under nitrogen and the mixture was stirred at RT for one hour. Add a solution of the amine (55) (700 mg, 1.78 mmol) in DCM (4.0 mL) and stir the reaction mixture for 16 hrs during which time a precipitate formed. The mixture was dissolved in DCM (10 mL) Purified by flash column chromatography (Si 〇 2, 8 g of '0-20% EtOAc in isohexane, gradient elution) to afford 4-(1-(4-(3-(3-) Third-butyl-p-p-phenyl-1H-pyrazole-5-yl)ureido)naphthalen-1-yloxy)propan-2-yl)pyridin-2-ylamine decanoic acid tert-butyl ester (56) (590 mg, 50%): m/z 649 (M+H)+ (ES+) TFA (5.0 ml) was added to the amine-butyric acid s-butyl ester (56) (0 57 g ' 0.88 m The suspension in DCM (10.0 mL) and the dark green solution was stirred at RT for 1 hour. The mixture was evaporated in vacuo and the residue was dissolved in MeOH (10.0 mL) and scx. And released to provide the title compound in red oil, intermediate K (488 mg, 98%): m/z 549 (M+H) + (ES+). Example 47: Ν·(4-(1-(4- (3-(3-Terti-butyl-1-p-anthracene·1H_0 is more than spani-5-yl) gland) C._ι_yloxy)propyl) η than bite_2_yl )·2_methoxyacetamide:

將曱氧基乙醯氯(9.7微升，0.106毫莫耳），接著 DIPEA(18.4微升，〇·ι〇6毫莫耳)加至中間物Κ(58毫克， 161 201130813 u.106毫莫耳)在DCM(2.〇毫升）中的攪拌溶液且將混合物在RT下攪拌1小時。添加Nh3的溶液(在Me〇H中之1%，3.0毫升)及將混合物攪拌30分鐘且然後在真空中蒸發。將殘餘物進行SCX捕捉和釋放及將產物與 MeCN(5.0毫升）一起研磨並用MeCN(5.〇毫升)及然後乙醚(5.0毫升）洗滌以提供呈白色固體之標題化合物（實例 47)(32 毫克，48%) : m/z 621 (M+H)+ (ES+); 4 NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 1.42 (3H, d), 2.39 (3H, s), 3.38 (3H, s), 3.40 (1H, m), 4.07 (2H, s), 4.21-4.30 (2H, 重疊 m)，6·35 (1H，s)，6.95 (1H，d), 7.22 (1H，dd), 7.35 (2H，d), 7.40-7.47 (3H，重疊 m), 7.54 (lH，m)，7.60 (1H， d), 7.86 (1H, d), 8.07 (1H, d), 8.20 (1H, br s), 8.25 (1H, d), 8.55 (1H，br s)，8.75 (1H, d)，9.94 (1H，br s)。中間物L: 1-(4-(2-(2-胺基n比啶-4-基)-2-曱基丙氧基）萘 -1-基)-3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲。Add methoxyethyl hydrazine chloride (9.7 μl, 0.106 mmol) followed by DIPEA (18.4 μl, 〇·ι〇6 mmol) to the intermediate Κ (58 mg, 161 201130813 u.106 mmol) The ear was stirred in DCM (2 mL) and the mixture was stirred at RT for 1 hour. A solution of Nh3 (1% in Me〇H, 3.0 mL) was added and the mixture was stirred for 30 min and then evaporated in vacuo. The residue was subjected to SCX capture and elution and the product was crystallised from EtOAc (EtOAc) (EtOAc) , 48%) : m/z 621 (M+H)+ (ES+); 4 NMR (400 MHz, DMSO-d6) δ : 1.27 (9H, s), 1.42 (3H, d), 2.39 (3H, s ), 3.38 (3H, s), 3.40 (1H, m), 4.07 (2H, s), 4.21-4.30 (2H, overlap m), 6.35 (1H, s), 6.95 (1H, d), 7.22 (1H, dd), 7.35 (2H, d), 7.40-7.47 (3H, overlap m), 7.54 (lH, m), 7.60 (1H, d), 7.86 (1H, d), 8.07 (1H, d) , 8.20 (1H, br s), 8.25 (1H, d), 8.55 (1H, br s), 8.75 (1H, d), 9.94 (1H, br s). Intermediate L: 1-(4-(2-(2-Amino-n-pyridin-4-yl)-2-mercaptopropoxy)naphthalen-1-yl)-3-(3-Third-butyl Alkyl-1-p-phenylene-1H-pyrazol-5-yl)urea.

162 201130813 將KHMDS的溶液(36.5亳升，在曱苯中之〇.5M， 18.25毫莫耳）以單一部分加至2_(2·氯吡啶_4_基）乙酸乙162 201130813 Add a solution of KHMDS (36.5 liters, 曱.5M, 18.25 mmol in benzene) to a single part to 2_(2·chloropyridin-4-yl)acetate

酉曰(44)(3.47克，17.4毫莫耳)在THF(4〇毫升）中於-780C 在氣氣下的攪拌溶液。將混合物加熱至RT經1〇分鐘且然後再冷卻至-78 °C，並用碘甲烷（丨14毫升，18·3毫莫耳）處理。將混合物加熱至RT，期間沈澱物掉下。將混合物冷卻至-78 °C並添加另一部分之KHMDS溶液 (36.5毫升，在曱笨中之〇 5M，18 25毫莫耳）。將混合物加熱至rT經1〇分鐘且然後將懸浮液再冷卻至 -78°C，並添加第二部分的碘曱烷（1;1毫升，183毫莫耳）。將混合物加熱至RT及添加氫化鈉（0 730克，18 25 ，莫耳)並將混合物在此溫度下攪拌丨小時且然後添加第三部分之碘甲烷（丨」毫升，183毫莫耳）t>1小時之後，添加NH4C1之飽和水溶液且將混合物用***萃取。將合併之有機層用水和鹽水洗滌且然後乾燥並在真空中蒸七。藉由急驟管柱層析法純化殘餘物(Si〇2，1 〇〇克，在異己烷中之5-10%EtOAc，梯度溶析）以提供2_(2·氣吡啶-4-基)-2-甲基丙酸乙酯（57)(2.8ι克，67%) : m/z 〇Vl+H)+ (ES+)。將(57)(2.80克，12.3毫莫耳）、第三-丁基胺甲酸酯 (4.32 克 ’ 36.9 毫莫耳）、Pd2(dba)3 (281 毫克，0 307 毫莫耳）、Xantph〇S(355毫克’0.615毫莫耳)及碳酸铯(6 〇1 克，18.5毫莫耳)在THF(10.0毫升）中的混合物用氮吹洗且然後在65°C下攪拌72小時。將混合物冷卻至RT並 163 201130813 用水稀釋及用***萃取。將有機層用水和鹽水洗滌且然後乾燥，並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ’ 120克，在異己烷中之5-8%EtOAc，梯度溶析）以產生2-(2-(第三-丁氧羰胺基)吡啶-4-基）乙酸乙基酯（58)(1.47 克，37%) : m/z 309 (M+H)+ (ES+)。經10分鐘將DIBAL(18.5毫升，在DCM中之1M, 18.5毫莫耳）的溶液逐滴加至酯（58)(1.43克，4.64毫莫耳)在THF(25毫升）中於-78°C在氮氣下的攪拌溶液。將反應混合物加熱至RT，然後冷卻至〇。〇及加水(5.0毫升）’接著加MgS〇4。將混合物用DCM稀釋及過濾且將濾餅用EtOAc、MeOH及DCM連續地洗滌。合併渡液及洗液，並在真空中蒸發及藉由急驟管柱層析法純化殘餘物(Si〇2 ’ 40克，在異己烷中之25-50o/〇EtOAc，梯度/谷析）以產生4-(1-經基-2-曱基丙-2-基)η比咬-2-基胺曱酸第三-丁酯（59)(1.13 克，86%): m/z 267 (M+H)+ (ES+)。將氫化鈉(350毫克，8.75毫莫耳）以單一部分加至醇(59)(1.11克’4.17毫莫耳)在〇]\^(10.〇毫升）中於0。(：在氮氣下的授摔溶液。將混合物加熱至RT經30分鐘且然後用超音波處理，用氮冲洗並再冷卻至〇〇C。經5分鐘添加1-氟-4-硝基萘（14)(797毫克，4.17毫莫耳)在 DMF(4.0毫升）中的溶液且使反應混合物加熱至RT及 30分鐘之後添加冰醋酸（1.0毫升）。將反應混合物倒進飽和NaHC〇3水溶液中並用EtOAc萃取二次。合併之有機萃取物用水洗滌三次及用鹽水洗滌且然後乾燥 (MgS〇4) ’並在真空中蒸發。將殘餘物從EtOAc磨碎及用***(20毫升）洗滌以提供呈黃色固體之4_(2_甲基 164 201130813 -1-(4-瑞基萘-1-基氧基）丙-2-基户比《定-2-基胺曱酸第三_ 丁酯（60)(1.23 克，64%):111/2 438 (]^+11)+(£8+)。將硝基芳烴(60)(1.15克，2.63毫莫耳)在MeOH(40 亳升）、AcOH(10毫升)及DCM(20亳升）的混合物中之溶液通過Thales H-立方體（1.〇毫升.分鐘-1，45°C，55 毫米10%Pt/C Cat-Cart，全氫模式）。在真空中蒸發溶劑並將殘餘物進行SCX捕捉和釋放以提供4_(1_(4_胺基萘-1-基氧基)-2-曱基丙-2-基）吼咬-2-基胺曱酸第三_ T^(61)(1.15*，84%):m/z408(M+H)+(ES+)。經1.5小時將(5)(760毫克，3.31毫莫耳)在DCM(2.0 毫升）中的溶液逐滴加至CDI (537毫克，3.31毫莫耳）在DCM(2.0毫升）中在氮氣下的懸浮液且將溶液在RT 下攪拌1小時。以單一部分添加萘胺(61)(100克，221 毫莫耳)在DCM(4.0毫升）中的溶液且將溶液攪拌16小時，在這期間，沈澱物形成。將反應混合物溶解在 DCM(10毫升）中並藉由急驟管柱層析法純化(Si〇2, 80 克，在異己烷中之2〇_8〇%Et〇Ac，梯度溶析）以提供 4-(1-(4-(3-(3-第三·丁基-卜對-曱苯基_1H—吡唑_5•基)脲基）奈-1-基氧基)_2·甲基丙_2_基）吡啶_2_基胺曱酸第三_ 丁酯(62)(780 毫克，52%) : m/z 663 (M+H)+ (ES+) 將TFA(8.〇毫升)加至(62)(78〇毫克，丨18毫莫耳）在DCM(1G毫升）+㈣浮狀所得深綠色溶液在灯下攪拌2 j %。在真空中蒸發混合物及將殘餘物溶解在 Me〇H(10毫升）+並進行scx捕捉和釋放以提供標題化合物’中間物 L，_ 毫克，1〇〇%) : m/z 563 (M+H)+ 165 201130813 員例48 : N-(4-(l-(4-(3-(3-第三-丁基_ι_對-曱苯基-i_吡唑-5-基）脲基）萘-i_基氧基）_2_甲基丙_2_基）吡啶_2_ 基)-2-甲氧基乙醯胺：A stirred solution of hydrazine (44) (3.47 g, 17.4 mmol) in THF (4 mL) at -780 C under air. The mixture was heated to RT for 1 min and then cooled to -78 °C and treated with EtOAc (EtOAc <RTI ID=0.0>> The mixture was heated to RT during which time the precipitate fell. The mixture was cooled to -78 °C and another portion of KHMDS solution (36.5 mL, 〇 5M, 18 25 mmol) was added. The mixture was heated to rT over 1 min and then the suspension was re-cooled to -78 <RTI ID=0.0>>> The mixture was heated to RT and sodium hydride (0 730 g, 18 25 m.) was added and the mixture was stirred at this temperature for one hour and then a third portion of iodomethane ( </ RTI> </ RTI> After 1 hour, a saturated aqueous solution of NH4Cl was added and the mixture was extracted with diethyl ether. The combined organic layers were washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc EtOAc (EtOAc) Ethyl 2-methylpropionate (57) (2.8 MPa, 67%): m/z 〇Vl+H)+ (ES+). (57) (2.80 g, 12.3 mmol), tri-butylcarbamate (4.32 g '36.9 mmol), Pd2 (dba) 3 (281 mg, 0 307 mmol), Xantph A mixture of 〇S (355 mg '0.615 mmol) and cesium carbonate (6 〇 1 g, 18.5 mmol) in THF (10.0 mL) was washed with nitrogen and then stirred at 65 ° C for 72 hours. The mixture was cooled to RT and 163 201130813 was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (EtOAc mjjjjjjjjjjjjjjjj Ethyl pyridin-4-yl)acetate (58) (1.47 g, 37%): m/z 309 (M+H) + (ES+). A solution of DIBAL (18.5 ml, 1 M in DCM, 18.5 mmol) was added dropwise to the ester (58) (1.43 g, 4.64 mmol) in THF (25 mL) at -78. C Stirring solution under nitrogen. The reaction mixture was heated to RT and then cooled to hydrazine. Add water (5.0 ml) and then add MgS〇4. The mixture was diluted with EtOAc and filtered and EtOAc EtOAc &EtOAc The combined liquids and washings were combined and evaporated in vacuo and the residue was purified by flash column chromatography eluting eluting eluting Yield 4-(1-Phenyl-2-mercaptopropan-2-yl)n-b-but-2-ylamine decanoic acid tert-butyl ester (59) (1.13 g, 86%): m/z 267 ( M+H)+ (ES+). Sodium hydride (350 mg, 8.75 mmol) was added in a single portion to the alcohol (59) (1.11 g <'>> (: Drop solution under nitrogen. The mixture was heated to RT for 30 minutes and then treated with ultrasound, rinsed with nitrogen and re-cooled to 〇〇C. 1-Fluoro-4-nitronaphthalene was added over 5 minutes ( 14) (797 mg, 4.17 mmol) in DMF (4.0 mL) and EtOAc (EtOAc) The mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. 4_(2_methyl 164 201130813 -1-(4-reylnaphthalen-1-yloxy)propan-2-yl-pyrene as a yellow solid than the third-butyl butyl-2-amine amide 60) (1.23 g, 64%): 111/2 438 (]^+11) + (£8+). Nitroaromatic (60) (1.15 g, 2.63 mmol) in MeOH (40 liters) , a solution of a mixture of AcOH (10 ml) and DCM (20 liters) passed through a Thales H-cube (1. 〇ml. min-1, 45 ° C, 55 mm 10% Pt/C Cat-Cart, perhydrogen) Mode). Evaporate in vacuum And subjecting the residue to SCX capture and release to provide 4_(1_(4-amino-4-naphthalenyl)-2-mercaptopropan-2-yl)-indan-2-ylamine decanoic acid _ T^(61)(1.15*,84%): m/z 408 (M+H) + (ES+). (5) (760 mg, 3.31 mmol) in DCM (2.0 mL) The solution was added dropwise to a suspension of CDI (537 mg, 3.31 mmol) in DCM (2.0 mL) under nitrogen and the solution was stirred at RT for 1 hour. Add naphthylamine (61) in a single portion (100) </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Purification by purification (Si 〇 2, 80 g, 2 〇 8 〇 % Et 〇 Ac in isohexane, gradient elution) to provide 4-(1-(4-(3-(3-)-butyl) -Bu-p-phenyl-1H-pyrazole-5(5)-ureido)-n-yloxy)_2-methylpropan-2-yl)pyridine-2-aminoamine decanoic acid _ Ester (62) (780 mg, 52%): m/z 663 (M+H) + (ES+) TFA (8 ml) was added to (62) (78 mg, 丨18 mmol) DCM (1G ml) + (four) floating dark green solution The mixture was stirred at EtOAc (2 mL). m/z 563 (M+H)+ 165 201130813 例 Example 48: N-(4-(1-(4-(3-(3-T-butyl)-p-p-phenyl)-i-pyridyl Zyrid-5-yl)ureido)naphthalene-i-yloxy)_2-methylpropan-2-yl)pyridine_2-yl)-2-methoxyacetamide:

將曱氧基乙醯氯(8.5微升，0.092毫莫耳）、接著 DIPEA(16.微升，0.092毫莫耳)加至中間物L(52毫克， 0.092毫莫耳)在DCM(2.0毫升）中的溶液且將混合物在 RT下攪拌1小時。添加NH3的溶液(在Me〇H中之i〇/〇, 3.0毫升）且將混合物攪拌30分鐘及然後在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si〇2，12克，在異己烷中之0-100%EtOAc，梯度溶析）以提供標題化合物，實例 48，（32 毫克，53%) : m/z 幻5 (M+H)+ (ES+)°; !H NMR (400 MHz, DMSO-d6) δ 1.27 (9H, s), 1.50 (6H, s)，2·39 (3H，s)，3.37 (3H，s)，4.06 (2H，s)，4.19 (2H，s) 6.35 (1H, s), 6.95 (1H, d), 7.30 (lH, dd), 7.34 (2H, m)! 7.43 (2H, m)，7.45 (1H，m), 7.53 (1H, m)，7.61 (1H，句， 7.87 (1H, d), 8.02 (1H, dd), 8.25 (1H, d), 8.34 (1H, br s) 8.54 (1H，br s), 8·75 (1H，br s)，9.90 (1H，br s)。中間物M : N-(4-((4-胺基萘-1-基氧基）甲基）。比基)-2-曱氧基乙酿胺。 166 201130813Add methoxyethyl hydrazine chloride (8.5 μl, 0.092 mmol) followed by DIPEA (16. μL, 0.092 mmol) to intermediate L (52 mg, 0.092 mmol) in DCM (2.0 mL) The solution in ) and the mixture was stirred at RT for 1 hour. A solution of NH3 (i〇/〇 in Me〇H, 3.0 ml) was added and the mixture was stirred for 30 minutes and then evaporated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut elut elut m/z 幻5 (M+H)+ (ES+)°; !H NMR (400 MHz, DMSO-d6) δ 1.27 (9H, s), 1.50 (6H, s), 2·39 (3H, s) , 3.37 (3H, s), 4.06 (2H, s), 4.19 (2H, s) 6.35 (1H, s), 6.95 (1H, d), 7.30 (lH, dd), 7.34 (2H, m)! 7.43 (2H, m), 7.45 (1H, m), 7.53 (1H, m), 7.61 (1H, sentence, 7.87 (1H, d), 8.02 (1H, dd), 8.25 (1H, d), 8.34 (1H , br s) 8.54 (1H, br s), 8·75 (1H, br s), 9.90 (1H, br s) Intermediate M: N-(4-((4-aminonaphthalen-1-yl) Oxy)methyl).pyridyl)-2-methoxy ethoxylated amine. 166 201130813

經10分鐘將曱氧基乙酸氯(24.2毫升，264毫莫耳）逐滴加至胺(3)(60.0克’203毫莫耳)在DCM(300毫升）、 THF(450毫升)及rnpEApyi毫升，3〇5毫莫耳）的混合物中於-5°C在氮氣下的攪拌懸浮液。1〇分鐘之後使反應混合物加熱至RT，在這期間，黑色溶液形成。3〇分鐘之後添加在MeOH中之NH3的溶液(7M，30毫升)且繼續擾拌1小時，在這期間，沈澱物形成。在真空中蒸發懸浮液及將殘餘物與水(5〇〇毫升）一起研磨。將沈澱物藉由過濾收集，及用水(3〇〇毫升)和二***(5〇〇毫升) 洗滌且然後在真空中於60〇C乾燥以提供呈黃色固體之 2_曱氧基·Ν-(4-((4·硝基萘-1-基氧基）甲基)B比啶_2_基）乙醯胺（63) (68 克，88%) : m/z 368 (M+H)+ (ES+)。Chloroacetate chloride (24.2 mL, 264 mmol) was added dropwise to the amine (3) (60.0 g < 203 mmol) in DCM (300 mL), THF (450 mL) and rnpEApyi , a mixture of 3 〇 5 mmoles in a stirred suspension at -5 ° C under nitrogen. After 1 minute, the reaction mixture was heated to RT, during which a black solution formed. A solution of NH3 in MeOH (7M, 30 mL) was added after 3 min and stirring was continued for 1 hour, during which time a precipitate formed. The suspension was evaporated in vacuo and the residue was triturated with water (5 mL). The precipitate was collected by filtration, washed with water (3 mL) and diethyl ether (5 mL) and then dried in vacuo to afford (4-((4.nitronaphthalen-1-yloxy)methyl)B)pyridin-2-yl)acetamide (63) (68 g, 88%): m/z 368 (M+H ) + (ES+).

將硝基芳烴(63)(30.0克，82.0毫莫耳)及鐵粉(22.8 克，408氅莫耳)在AcOH(300毫升）中的懸浮液在50oC 下加熱1.5小時，且然後冷卻至rt。將固體碳酸鈉逐部分地加至反應混合物直到不再觀察到起泡。用乙酸乙酯 (2 X 700毫升）萃取混合物並將合併之有機萃取物用碳酸鈉飽和水溶液及用鹽水洗滌且然後乾燥(MgS04)。在真空中蒸發提供呈棕色固體之標題化合物，中間物 M(25.0 克，77%) : m/z 338 (M+H)+ (ES+)。中間物N: 3-第三-丁基-1-(4-((第三-丁基二甲矽氧基) 167A suspension of nitroaromatic (63) (30.0 g, 82.0 mmol) and iron powder (22.8 g, 408 mmol) in AcOH (300 mL) was heated at 50 °C for 1.5 h and then cooled to rt . Solid sodium carbonate was added portionwise to the reaction mixture until no foaming was observed. The mixture was extracted with EtOAc (2 X EtOAc) (EtOAc)EtOAc. Evaporation in vacuo afforded the title compound mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Intermediate N: 3-tert-butyl-1-(4-((tert-butyldimethyl methoxy) 167

笨基)-1Η-吡唑-5-胺 ΧΒ CN 201130813 τ基）Stupid)-1Η-pyrazole-5-amine ΧΒ CN 201130813 τ base)

TBDMS^CL lBuTBDMS^CL lBu

Cl η2ν、 ΝΗ.Ηι NH2 味嗤 ΨCl η2ν, ΝΗ.Ηι NH2 miso Ψ

"OTBDMS 中間物N co2h (64) 將三甲基乙醯基乙腈(0.730克，5.83毫莫耳)加至 4-肼基笨甲酸(64)(1.00克’ 5.30毫莫耳)在包含濃鹽酸 (〇.5毫升)之EtOH(2〇毫升）中的懸浮液並將混合物加熱至回流經5小時❶將反應混合物在RT下攪拌64小時且在真空中蒸發溶劑。將殘餘物懸浮在THF中及添加 LiOH的水溶液(1河，30毫升，30毫莫耳）且將混合物在 RT下搜拌2小時。藉由蒸發在真空中除去THF且將所得水溶液用AcOH稀釋及進行SCX捕捉和釋放。將包含所要化合物之部分合併並在真空中蒸發。將殘餘物溶解在DCM中及乾燥(MgS〇4)且在真空中蒸發。在真= 中與乙腈共蒸發提供呈橙色固體之4·(5_胺基_3_第三= 基-1Η-吡唑-1-基）苯曱酸(65)(1.5〇克，>1〇〇 %回收）： m/z 260 (M+H)+ (ES+) ; 258 (M-Η). (ES.)。將硼烷的溶液(在THF中之2Μ，7.4毫升，34.8毫莫耳)加至本甲酸(65)(1.50克，5.7毫莫耳)在THF中於〇°c下的攪拌溶液。將反應混合物加熱至]11並攪拌16 小時。添加另一部分之BH3溶液(在THF中之2M，8 〇毫升’毫莫耳)且繼續攪拌另3小時。將反應混合物冷卻至0°C並添加1M鹽酸以停止反應。中和溶液並萃 168 201130813 取於EtOAc中。將萃取物用Na2C〇3水溶液和鹽水洗滌且然後乾燥並在真空中蒸發以提供(4·(5_胺基_3_第三_ 丁基-1Η-。比唑-1-基)苯基）甲醇(66)(〇 64克，45 %)。將TBDMS-C1(590毫克，3.91毫莫耳)加至苯曱基醇(66)(640毫克，2.61毫莫耳)及咪唑（266毫克，3 91 毫莫耳)在DMF(5.0毫升）中於RT下的攪拌溶液。3小時之後將反應混合物用水稀釋且用玢2〇萃取。將有機層用鹽水洗滌，乾爍(MgS〇4)且然後在真空中蒸發以提供標題化合物，中間物N，（875毫克，89%) : m/z 360 (M+H)+ (ES+)。實例49 : N-(4-((4-(3-(3-第三-丁基_W4_(經基甲基）苯基）-lH“比吐_5·基）脲基）萘小基氧基）曱基）β比啶-2_ 基)-2-曱氧基乙醯胺："OTBDMS Intermediate N co2h (64) Trimethylglycidylacetonitrile (0.730 g, 5.83 mmol) was added to 4-mercaptobenzoic acid (64) (1.00 g ' 5.30 mmol) in concentrated A suspension of hydrochloric acid (5 mL) in EtOAc (2 mL) was evaporated and evaporated and evaporated. The residue was suspended in THF and aq. EtOAc (EtOAc &lt The THF was removed by vacuum in vacuo and the aqueous solution was diluted with AcOH and subjected to SCX capture and elution. The fractions containing the desired compound were combined and evaporated in vacuo. The residue was dissolved in DCM and dried (MgSO4) and evaporated in vacuo. Co-evaporation with acetonitrile in true = afforded 4·(5_amine_3_3=yl-1Η-pyrazol-1-yl)benzoic acid (65) (1.5 g, > 1%% recovery): m/z 260 (M+H)+ (ES+); 258 (M-Η). (ES.). A solution of borane (2 Torr in THF, 7.4 mL, 34.8 mmol) was added to a stirred solution of the present toluic acid (65) (1.50 g, 5.7 mmol) in THF at EtOAc. The reaction mixture was heated to 11 and stirred for 16 hours. Another portion of BH3 solution (2M in THF, 8 mL) <EMI ID> The reaction mixture was cooled to 0 ° C and 1M hydrochloric acid was added to stop the reaction. Neutralization solution and extraction 168 201130813 taken in EtOAc. The extract was washed with aqueous Na.sub.2 C.sub.3 and brine and then dried and evaporated in vacuo to afford <""""5"5' Methanol (66) (〇 64 g, 45%). Add TBDMS-C1 (590 mg, 3.91 mmol) to phenylhydrinol (66) (640 mg, 2.61 mmol) and imidazole (266 mg, 3 91 mmol) in DMF (5.0 mL) Stir the solution at RT. After 3 hours the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with EtOAc (EtOAc) (EtOAc m. . Example 49: N-(4-((4-(3-(3-)-tert-butyl-W4_(yl)methyl)phenyl)-lH"pyridyl-5)yl) naphthalene small group Oxy)indenyl)β-pyridin-2-yl)-2-decyloxyacetamide:

經1小時將吡唑胺中間物N(100毫克，〇 278毫莫耳）逐部分地加至CDI(45.1亳克，〇 278毫莫耳）在 DCM(0.5 f；升）中的授拌懸浮液並將混合物在rt下擾摔16小時。經2小時逐滴添加中間物M(47毫克，〇 139 毫莫耳)在DCM(0.5毫升）中的溶液加且另2小時之後將混合物在真空巾蒸發及藉由急料㈣析法純化殘餘物（si〇2 ’ 12克，在異己燒中之30_7〇%Et〇Ac，梯度溶析）以產生N-(4-((4-(3_(3-第三·丁基]_(4_((第三-丁基二 169 201130813 ^ Γ矽氧基）曱基）苯基)-1Η-吼唑-5-基)脲基)萘小基氧基）曱基)。比啶-2-基)-2-甲氧基乙醯胺(67)(42毫克，20%): m/z 723 (M+H)+ (ES+)。將TBAF的溶液(在THF中之1M，58微升，58 微莫耳)加至矽醚(67)(42毫克，58微莫耳)在THF中於 -5°C在氮氣下的溶液。將混合物加熱至rT並添加第二部分之TBAF(在THF中之1M，58微升，58微莫耳）。 1小時之後將混合物用EtOAc稀釋及用氣化銨飽和水溶液洗滌。用EtOAc萃取水層並將合併之有機層用水和鹽水洗鲦且然後乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si02，12克，在DCM中之 2-6%MeOH，梯度溶析）以提供標題化合物，實例49， (23 毫克，63%) : m/z 609 (M+H)+ (ES+) ; 4 NMR (400 MHz, DMSO-dg) δ： 1.28 (9 H, s), 3.37 (3Η, s) 4.08 (2H, s), 4.59 (2H, d), 5.32 (1H, t), 5.39 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H，重疊 m)，7.93 (1H，m), 8.30-8.37 (3H，重疊 m)，8.63 (1H，s)，8.81 (1H，s)，10.02 (1H，br s)。中間物P: 1-(4-((2-胺基嘧啶-4-基）甲氧基)萘-1_基)-3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲。 170 201130813The pyrazolamide intermediate N (100 mg, 〇278 mmol) was added portionwise to CDI (45.1 g, 278 278 m) in DCM (0.5 f; liter). The solution was shaken down for 16 hours at rt. A solution of the intermediate M (47 mg, 〇 139 mmol) in DCM (0.5 mL) was added dropwise over 2 hrs and the mixture was evaporated in vacuo and the residue was purified by flash (4). (si〇2 '12 g, 30_7〇%Et〇Ac in iso-burn, gradient elution) to produce N-(4-(3_(3-third·butyl)_(4_ ((Third-butyl 169 201130813 ^ decyloxy) fluorenyl) phenyl)-1 fluorene-5-yl) ureido) naphthalenyloxy) fluorenyl). 2-methoxyacetamide (67) (42 mg, 20%): m/z 723 (M+H) + (ES+). A solution of TBAF (1 M in THF, 58 microliters, 58 micromoles) was added to a solution of oxime ether (67) (42 mg, 58 micromol) in THF at -5 °C under nitrogen. The mixture was heated to rT and a second portion of TBAF (1M in THF, 58 microliters, 58 micromoles) was added. After 1 hour the mixture was diluted with EtOAc and washed with a saturated aqueous solution of ammonium sulfate. The aqueous layer was extracted with EtOAc and EtOAc evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut 609 (M+H)+ (ES+) ; 4 NMR (400 MHz, DMSO-dg) δ: 1.28 (9 H, s), 3.37 (3 Η, s) 4.08 (2H, s), 4.59 (2H, d) , 5.32 (1H, t), 5.39 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H, overlap m), 7.93 (1H, m), 8.30-8.37 (3H, overlap m), 8.63 (1H, s), 8.81 (1H, s), 10.02 (1H, br s). Intermediate P: 1-(4-((2-aminopyrimidin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tri-butyl-1-p-phenylene) -1H-pyrazol-5-yl)urea. 170 201130813

將鹽酸(2M，207毫升，414毫莫耳)加至4_(二甲氧基甲基)鳴啶-2-胺(68)(WO 2007/096764)(14.0 克，83 毫莫耳)並將混合物在48°C下加熱16小時。將混合物冷卻至RT並用固體NafO3中和，其在pH 7下產生& 澱物。將懸浮液用Et〇Ac(300毫升)稀釋及藉由過濾移b 出固體。將有機層分離及用在THF中之1 %MeOH萃取水層（4 x 300毫升）。將有機物合併，乾燥且然後在真空中蒸發。將殘餘物（約4.0克）懸浮於Me〇H(100毫升）、 THF (1〇〇毫升）及水（1〇〇毫升）的混合中物並用 NaBH4(1.57克，41.4毫莫耳)處理。攪拌1小時之後添加NaOH(lM，20毫升）的溶液且使混合物在rt下靜置 48小時。將溶劑蒸發以產生黃色固體，將其分溶在水(5〇毫升)及EtOAc(100毫升)之間。藉由過濾移出在界面形成之固體及將水層用THF(3 x 300毫升）萃取，然後乾燥及蒸發以產生黃色固體。將材料懸浮在THF(l〇〇毫升) 和MeOH(50毫升）中及吸收在矽凝膠(20克)上並進行管柱層析法(80克’在DCM中之i5%MeOH等度溶析）以 171 201130813 ^ ^ y生生呈灰白色固體之(2-胺基嘧啶-4-基）甲醇(69)(720毫克，7%) : m/z 126 (M+H)+ (ES+)。經5分鐘將DIAD(996微升’4.70毫莫耳)逐滴加至 (69)(700毫克，3.92毫莫耳）、4_硝基萘酚（2)(741毫克， 3.92毫莫耳)及PPh3(1 23克’ 4 7〇毫莫耳)在THF(2〇毫升）中於-5〇。(：在氮氣下的攪拌混合物。使混合物加熱至 RT並攪拌經1小時，在這期間，黃色沈澱物形成。將懸浮液授拌過夜並在真空中蒸發揮發物。將殘餘物從 MeOH(50毫升)磨碎及藉由過濾收集淡黃色固體並用二 ***(50毫升）洗滌以產生4-((4-硝基萘基氧基）甲基) °密咬胺(70)(1.10 克，93 %) : m/z 297 (M+H)+ (ES+)。將硝基芳烴(70)(1.10克’3.71毫莫耳)在1)(：：]^(5〇毫升)及AcOH(40毫升）的混合物中之溶液通過Thales Η-立方體（1.0毫升分鐘-1，55毫米，i〇%pt/C，4〇〇c，全氫模式）。所得溶液之LC-MS分析顯示主要包含起始原料及約20%產物之混合物。藉由在真空中蒸發除去 DCM且使用相同條件在rt下將溶液再進行還原。在真空中蒸發揮發物以產生呈紫色固體之4-((4-胺基萘-卜基氧基）甲基）喷咬-2-胺(71)(約70%，藉由LC-MS)(0.90 克，64 %產率）：m/z 267 (M+H)+ (ES+)。經1小時將(5)(980毫克’ 4.26毫莫耳)在dcM(4.0 毫升）中的溶液逐滴加至CDI (690毫克，4.26毫莫耳）在〇CM(3.0毫升）中的懸浮液並將混合物在RT下授摔2 小時。然後將此溶液逐滴加至萘胺(71)(9〇〇毫克，2 37 笔莫耳)在DCM(10毫升）中的溶液，以使在各個之後添力毫升部分’將反應授掉1小時。用Me〇H(20毫 172 201130813 升)停止反應，及添加秒石（20克)並在真空中蒸發揎發Hydrochloric acid (2M, 207 ml, 414 mmol) was added to 4-(dimethoxymethyl)-hydanidine-2-amine (68) (WO 2007/096764) (14.0 g, 83 mmol) and The mixture was heated at 48 ° C for 16 hours. The mixture was cooled to RT and neutralized with solid NafO3 which gave & The suspension was diluted with EtOAc (300 mL) and filtered to give a solid. The organic layer was separated and extracted with 1% MeOH in THF (4 x 300 mL). The organics were combined, dried and then evaporated in vacuo. The residue (ca. 4.0 g) was suspended in a mixture of MeH (100 mL), THF (1 mL) and water (1 mL) and treated with NaBH4 (1.57 g, 41.4 mmol). After stirring for 1 hour, a solution of NaOH (1 M, 20 mL) was added and the mixture was allowed to stand at rt for 48 hours. The solvent was evaporated to give a yellow solid which was partitioned between water (5 <RTIgt; The solid formed at the interface was removed by filtration and the aqueous layer was extracted with THF (3 x 300 mL) then dried and evaporated to give a yellow solid. The material was suspended in THF (10 ml) and MeOH (50 ml) and taken up in a hydrazine gel (20 g) and subjected to column chromatography (80 g of i5% MeOH in DCM) (2-Aminopyrimidin-4-yl)methanol (69) (720 mg, 7%): m/z 126 (M+H) + (ES+). DIAD (996 μl '4.70 mmol) was added dropwise to (69) (700 mg, 3.92 mmol) and 4_nitronaphthol (2) (741 mg, 3.92 mmol) over 5 minutes. And PPh3 (1 23 g '47 7 mmol) in THF (2 mL) at -5 Torr. (The mixture was stirred under nitrogen. The mixture was heated to RT and stirred over 1 h during which time a yellow precipitate formed. The suspension was stirred overnight and evaporated in vacuo. The mixture was triturated with EtOAc (EtOAc) (EtOAc) %) : m/z 297 (M+H)+ (ES+). Nitroarrene (70) (1.10 g '3.71 mmol) in 1) (::)^ (5 mL) and AcOH (40) The solution in the mixture of ML) was passed through Thales(R)-cube (1.0 ml min-1,55 mm, i〇%pt/C, 4〇〇c, full hydrogen mode). LC-MS analysis of the resulting solution showed mainly A mixture of the starting material and about 20% of the product was removed by evaporation of the DCM in vacuo and the residue was re-reduced at rt using the same conditions. The volatiles were evaporated in vacuo to give 4-((4-amine) as a purple solid. Naphthalene-buyloxy)methyl) ace-2-amine (71) (about 70% by LC-MS) (0.90 g, 64% yield): m/z 267 (M+H) + (ES+). After 5 hours (5) (980 mg' 4.2 A solution of 6 mmoles in dcM (4.0 mL) was added dropwise to a suspension of CDI (690 mg, 4.26 mmol) in 〇CM (3.0 mL) and the mixture was dropped for 2 hours at RT. This solution was then added dropwise to a solution of naphthylamine (71) (9 mg, 2, 37 moles) in DCM (10 mL), so that after each portion of the force portion was added 'rejected 1 Hours. Stop the reaction with Me〇H (20 157 201130813 liters), add the second stone (20 g) and evaporate in a vacuum

唑-5-基)脲基)萘-1-基氧基）甲基)哺啶_2•基)_2_甲氧基乙醯胺：Oxazol-5-yl)ureido)naphthalen-1-yloxy)methyl)glycine-2-yl)_2-methoxyacetamide:

將中間物P(52毫克’ 〇.1〇毫莫耳)在DCM(1 〇毫升）及DMF(100微升）中的懸浮液用曱氧基乙醯氯(27微升，0.30毫莫耳)接著DIPEA(52微升，〇.3〇毫莫耳)處理並將混合物在RT下擾拌過夜。在真空中蒸發揮發物且將殘餘物懸浮在MeOH(2.0毫升)及AcOH(2.0毫升）的混合物中。使懸浮液在標準條件下進行SCX捕捉和釋放。如只有獲得低回收率之材料，將SCX筒用 MeOH(50毫升）萃取並將溶劑蒸發，以產生灰白色固體。此將從MeOH(1.0毫升)及二***(5.0毫升）磨碎以產生呈白色固體之標題化合物，實例50(12毫克，19 %)： m/z 594 (M+H)+ (ES+)° ]H NMR (400 MHz, DMSO-d6) δ ： 1.27 (9H, s), 2.40 (3H, s), 3.34 (3H, s), 4.24 (2H, s), 173 201130813 ^.34 (2H, s), 6.35 (1H, s), 7.02 (1H, d), 7.35 (2H, d), 7.44 (3H, m), 7.60 (3H, m), 7.95 (1H, m), 8.36 (1H, m), 8.59 (1H，br s)，8.68 (1H，d)，8.80 (1H，br s)，10.44 (1H，br s)。中間物Q : 1-(4_(2_胺基°比啶-4-基氧基)萘-1-基)-3-(3-第三-丁基-1-對-曱苯基嗤-5-基)脈。A suspension of intermediate P (52 mg '〇.1 〇 millimolar) in DCM (1 mL) and DMF (100 μL) with ethyl oxyethyl chloride (27 μL, 0.30 mmol) Then DIPEA (52 μL, 〇.3 〇 millimoles) was processed and the mixture was scrambled overnight at RT. The volatiles were evaporated in vacuo <RTI ID=0.0> The suspension was subjected to SCX capture and release under standard conditions. If only a low recovery material is obtained, the SCX cartridge is extracted with MeOH (50 mL) and the solvent is evaporated to give an off-white solid. This was triturated from MeOH (1.0 mL) and EtOAc (EtOAc) (EtOAc) H NMR (400 MHz, DMSO-d6) δ : 1.27 (9H, s), 2.40 (3H, s), 3.34 (3H, s), 4.24 (2H, s), 173 201130813 ^.34 (2H, s ), 6.35 (1H, s), 7.02 (1H, d), 7.35 (2H, d), 7.44 (3H, m), 7.60 (3H, m), 7.95 (1H, m), 8.36 (1H, m) , 8.59 (1H, br s), 8.68 (1H, d), 8.80 (1H, br s), 10.44 (1H, br s). Intermediate Q: 1-(4_(2_Aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-indolephenylhydrazine- 5-base) pulse.

Boc2〇, DMAP H; (72) 一 Boc; (73)Boc2〇, DMAP H; (72) a Boc; (73)

將第三-丁醇鉀（1.290克，11.50毫莫耳)加至2_氯·4_ 氟吡啶（1.26克，9·58毫莫耳)及4-胺基-1_萘酚鹽酸鹽 (750毫克’ 3.83毫莫耳)在ΝΜΡ(40毫升）中於-20°C的攪拌溶液。使反應混合物加熱至RT及2.5小時之後將反應混合物用水（100毫升)稀釋且用EtOAc萃取（100毫升，然後2x80毫升）。將合併之有機萃取物用鹽水（15〇毫升)洗滌，乾燥並在真空中蒸發。將粗製產物進行scx 捕捉和釋放及在真空中除去溶劑以產生呈棕色固體之 4-(2-氯《比啶-4-基氧基)萘_ι_胺(72)(i 02 克，92%) : m/z 271 (M+H)+ (ES+)。將DMAP(0.034克，0.282毫莫耳)及二碳酸二-第三 -丁醋(0.904克，4.14毫莫耳)加至(72)0 02克，3 76毫 174 201130813 莫耳)在THF(30毫升）中於0°C的攪拌溶液並將反應混合物在0°C下攪拌30分鐘，且然後在rT下經L5小時。將混合物冷卻至o°c ’及添加另一部分之二碳酸二 -第三-丁酯（0.904克，4.14毫莫耳)且在〇〇c下繼續攪拌 15分鐘及然後在rt下經16小時。將反應混合物用水 (40毫升)稀釋且用EtOAc(2 X 40毫升）萃取。將合併之有機萃取物用鹽水(75毫升）洗滌，乾燥並在真空中蒸發。粗藉由急驟管柱層析法純化製材料(Si〇2 ; 80克，在異己烷中之0-40%EtOAc，梯度溶析）以產生呈紫色固體之4-(2-氣吡啶-4-基氧基）萘-1-N，N-二-第三-丁基胺曱酸酯（73)(892 毫克，48%) : m/z 471 (M+H)+ (ES+)。將氣D比啶(73)(892毫克，1.89毫莫耳）、胺曱酸第三 -丁酯（666毫克，5.68毫莫耳）、碳酸鉋(926毫克，2.84 毫莫耳）、Pd2(dba)3(43毫克，0.047毫莫耳）及 XantPhos(55毫克，0.095毫莫耳）的混合物懸浮在 THF(l〇毫升）中。將反應混合物用氮吹洗，且然後在回流下加熱15小時。將混合物冷卻至RT。用水(35毫升) 稀釋且用EtOAc萃取(35毫升，25毫升）。將合併之有機萃取物用鹽水(50毫升)洗滌，乾燥並在真空中蒸發。藉由急驟管柱層析法純化粗製材料(Si02 ; 80克，在異己烷中之0-30%EtOAc，梯度溶析）以產生呈白色固體之 4-(4·(Ν,Ν-二-第三-丁基胺曱醯基）萘小基氧基户比啶-2-基胺曱酸第三-丁酯（74)(289毫克，28%) : m/z 552 (M+H)+ (ES+)。將TFA(4.0毫升)加至胺曱酸雙第三-丁酯（74)(289 毫克，0.524毫莫耳)在DCM(8.0毫升）中於〇°C的攪拌 175 201130813 j。將所得混合物麟並使加熱至RTcj 5小時之後， ^具空中除去揮發物並將殘餘物溶解在Me〇H(5毫升) j進行SCX顺和釋放。在真Μ除去㈣以提供 ^色，撥色油之4_⑷胺基萘+基氧基）〇比咬_2_胺 )⑴6 毫克，85%) : m/z 252 (M+H)+ (ES+)。將NaHC〇3之飽和水溶液（14毫升)加至（5)(206毫 0.900毫莫耳)在DCM(2〇毫升）中的溶液。將混合 ^用力地，冷卻至㈣及以-次添性加三氯甲基氣騃酯（0.326毫升’ 2.70毫莫耳卜將反應混合物在〇〇c I用力地攪拌另80分鐘。分離該等層及將有機層乾燥在真空中蒸發並將所得橙色油在高真空下乾燥另 30分鐘。然後將所得粗製異氰酸酯溶解在THF(6 〇毫升）中並保持於〇QC在氮氣下。將一部分的上述製得之異氰酸酯溶液(2.0毫升，0.30毫莫耳)加至(75)(116毫克，0.462毫莫耳)及DIPEA(241微升，丨385毫莫耳) 在THF(3.0毫升）中於〇〇C下的攪拌溶液，及所得混合物用力地攪拌且使加熱至RT。將二另外部分之異氰酸酯溶液加至反應混合物，1.5小時之後第一次（1〇毫升’0.15毫莫耳)及3.5小時之後第二次(〇.5〇毫升，0.075 耄莫耳）。另20小時之後加水(30毫升）且將混合物用Potassium tert-butoxide (1.290 g, 11.50 mmol) was added to 2-chloro-4-pyridinium (1.26 g, 9.58 mmol) and 4-amino-1 -naphthol hydrochloride ( A stirred solution of 750 mg ' 3.83 mmoles in hydrazine (40 ml) at -20 ° C. The reaction mixture was heated to rt EtOAc (EtOAc) (EtOAc) The combined organic extracts were washed with brine (15 mL) dried and evaporated The crude product was scx captured and released and the solvent was removed in vacuo to give 4-(2-chloro <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; %) : m/z 271 (M+H)+ (ES+). Add DMAP (0.034 g, 0.282 mmol) and di-third-butane diacetate (0.904 g, 4.14 mmol) to (72) 0 02 g, 3 76 174 201130813 mol) in THF ( The stirred solution at 0 ° C in 30 ml) and the reaction mixture was stirred at 0 ° C for 30 minutes and then L5 at rT for 5 hours. The mixture was cooled to o ° c ' and another portion of di-tert-butyl dicarbonate (0.904 g, 4.14 mmol) was added and stirring was continued for 15 minutes at 〇〇c and then at rt for 16 hours. The reaction mixture was diluted with EtOAc (EtOAc) The combined organic extracts were washed with brine (75 mL) dried and evaporated in vacuo. The material was purified by flash column chromatography (Si EtOAc; EtOAc (EtOAc:EtOAc) -Alkyl)naphthalene-1-N,N-di-t-butylamine decanoate (73) (892 mg, 48%): m/z 471 (M+H) + (ES+). Gas D is pyridine (73) (892 mg, 1.89 mmol), amine-butyrate tri-butyl ester (666 mg, 5.68 mmol), carbonic acid planer (926 mg, 2.84 mmol), Pd2 ( A mixture of dba) 3 (43 mg, 0.047 mmol) and XantPhos (55 mg, 0.095 mmol) was suspended in THF (1 mL). The reaction mixture was flushed with nitrogen and then heated under reflux for 15 hours. The mixture was cooled to RT. Diluted with water (35 mL) and EtOAc (EtOAc m. The combined organic extracts were washed with brine (50 mL) dried and evaporated in vacuo. The crude material was purified by flash column chromatography (SiO2; EtOAc (EtOAc: EtOAc) Third-butylaminoindenyl)naphthalenyloxybutyryl-2-ylamine decanoic acid tert-butyl ester (74) (289 mg, 28%): m/z 552 (M+H) + (ES+). Add TFA (4.0 mL) to a mixture of bis-tert-butyl phthalate (74) (289 mg, 0.524 mmol) in DCM (8.0 mL) After the mixture was obtained and heated to RTcj for 5 hours, the volatiles were removed in the air and the residue was dissolved in Me〇H (5 ml) to carry out the SCX cis- liberation. In the true enthalpy (4) to provide the color, dial Color oil 4_(4)Aminonaphthalene+yloxy)pyrene than bite_2_amine)(1)6 mg, 85%): m/z 252 (M+H)+ (ES+). A solution of (5) (206 mmol 0.900 mmol) in DCM (2 mL) was applied. The mixture was vigorously cooled, cooled to (iv) and added with trimethylmethyl sulphate (0.326 ml ' 2.70 mmol) and the reaction mixture was vigorously stirred at 〇〇c I for another 80 minutes. Separation of these The layers were dried and evaporated in vacuo and the obtained orange oil was dried under high vacuum for another 30 min. The obtained crude isocyanate was then dissolved in THF (6 mL) and kept in 〇QC under nitrogen. The isocyanate solution prepared above (2.0 ml, 0.30 mmol) was added to (75) (116 mg, 0.462 mmol) and DIPEA (241 μL, 丨385 mmol) in THF (3.0 mL) Stir the solution under 〇〇C, and the resulting mixture was vigorously stirred and heated to RT. Two additional portions of the isocyanate solution were added to the reaction mixture, the first time after 1.5 hours (1 〇 ml '0.15 mmol) and 3.5 The second time after the hour (〇.5〇 ml, 0.075 耄mol). After another 20 hours, add water (30 ml) and use the mixture

Et〇Ac(2 X 30毫升）萃取。將合併之有機萃取物用鹽水洗滌(50毫升），然後乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2 ; 12克，在異己烷中之 25-100%[在EtOAc中之5〇/〇MeOH]’梯度溶析）以提供呈棕色油之標題化合物，中間物Q，（127毫克，49%): m/z 507 (M+H)+ (ES+)。 176 201130813 -曱苯基-1H-吡唑實例51 : N-(4-(4-(3-(3-第三-丁基小對 -5-基）脲基）奈小基氧基）π比咬_2_基)_2_(甲基）乙醯Extracted with Et〇Ac (2 X 30 mL). The combined organic extracts were washed with brine (50 mL) then dried and evaporated. The residue was purified by flash column chromatography (EtOAc: EtOAc (EtOAc: EtOAc) The title compound, intermediate Q, (127 mg, 49%): m/z 507 (M+H) + (ES+). 176 201130813 - Phenylphenyl-1H-pyrazole Example 51: N-(4-(4-(3-(3-Terti-butyl-p--5-yl))))-n-yloxy) π Than bite_2_base)_2_(methyl)acetamidine

將1-氣-Ν，Ν，2-_^曱基丙烯胺(48微升，〇毫莫耳）力:至甲橫醯基乙酸(40毫克’ 〇·29毫莫耳)在DCM(2 〇毫升）中在氮氣下的懸浮液，並將混合物在RT下攪拌2 小時。將所得混合物加至_間物Q(37毫克，〇〇7毫莫耳)及DIPEA(51微升，〇·29毫莫耳)在DCM(2 〇毫升）中的溶液並在RT下繼續攪拌3小時。將反應混合物用在MeOH中之1%ΝΗ3(3.〇毫升)處理45分鐘且然後在真空中蒸發。將殘餘物進行SCX捕捉和釋放且然後藉由急驟管柱層析法純化(Si〇2，12克，在異己烷中之 0-70%[在EtOAc中之5%MeOH]，梯度溶析）以提供呈白色粉末之標題化合物，實例51(13毫克，28%): m/z 627 (M+H)+ (ES+)〇 ιη NMR (400 MHz, DMSO-d6) δ ： 1.29 (9Η, s), 2.39 (3Η, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1H, s), 6.71 (1H，dd)，7.33-7.38 (3H，重疊 m)，7.47 (2H，m), 7.56 (1H, m), 7.65 (1H, m), 7.69 (1H, m), 7.85 (1H, d), 7.96 (1H，d)，8.11 (1H，d)，8.22 (1H, d)，8.91 (1H, br s)， 9.23 (1H, brs)，10.96 (1H，br s)。實例52 : 4-(4-(3-(3-第三·丁基-1-對-曱苯基-1H·-比唑-5- 177 201130813 腺基)奈-1-基氧基)π比σ定_2-基腺： 1.1-Sodium-indole, hydrazine, 2-ylpropenyl acrylamide (48 μL, 〇 millimolar) Force: to yamyl thioglycolic acid (40 mg '〇·29 mmol) in DCM (2 A suspension under nitrogen was added in liters of hexane and the mixture was stirred at RT for 2 hours. The resulting mixture was added to a solution of _substrate Q (37 mg, 〇〇 7 mmol) and DIPEA (51 μL, 〇·29 mmol) in DCM (2 mL) and stirring was continued at RT. 3 hours. The reaction mixture was treated with 1% EtOAc (3 mL) in MeOH for 45 min and then evaporated in vacuo. The residue was subjected to SCX capture and elution and then purified by flash column chromatography (Si2, 12 g, 0-70% in isohexane [5% MeOH in EtOAc] The title compound was obtained as a white powder, m.p. (m.p.) (M.sup.) (M+H) + (ES+) 〇ιη NMR (400 MHz, DMSO-d6) δ: 1.29 (9 Η, s ), 2.39 (3Η, s), 3.10 (3H, s), 4.36 (2H, s), 6.40 (1H, s), 6.71 (1H, dd), 7.33-7.38 (3H, overlap m), 7.47 (2H , m), 7.56 (1H, m), 7.65 (1H, m), 7.69 (1H, m), 7.85 (1H, d), 7.96 (1H, d), 8.11 (1H, d), 8.22 (1H, d), 8.91 (1H, br s), 9.23 (1H, brs), 10.96 (1H, br s). Example 52: 4-(4-(3-(3-Third-butyl-1-p-indolephenyl-1H--b-azole-5-177 201130813 gland)N--1-yloxy)π Ratio σ-_2-base gland: 1.

中間物QIntermediate Q

CI3C 又 2. NH3CI3C again 2. NH3

NCONCO

實例52Example 52

nh2 將異氰酸三氯乙醯酯（15微升，0.12毫莫耳)加至中間物Q(50毫克，0.099宅莫耳)在無水吼咬。$毫升）中於0°C在氮氣下之溶液及30分鐘之後在下將反應混合物加熱至RT。24小時之後添加另一部分之異氰酸二氣乙醯酯（29微升，0.25毫莫耳)且42小時之後藉由添加在MeOH中之1%ΝΗ3(2.0毫升)停止反應。另30 分鐘之後將所得混合物在真空中蒸發並藉由急驟管柱層析法純化殘餘物（Si〇2’ 12克’在異己烷中之[在EtOAc 中之5%MeOH]，0-75% ’梯度溶析）以提供呈白色固體之標題化合物’實例52(7毫克，13%) : 1^2.21分鐘（方法 2) ; m/z 550 (M+H)+ (ES+) ; 'H NMR (400 MHz， DMSO-d6) δ ： 1.28 (9H, s), 2.40 (3H, s), 6.41 (1H, s), 6.52 (1H, dd), 6.95 (1H, d), 7.31 (1H, d), 7.37 (2H, d), 7.45-7.47 (2H, m), 7.54-7.61 (1H, m), 7.62-7.67 (1H, m), 7.83 (1H, dd), 7.95 (1H, d), 8.06 (1H, d), 8.09 (1H, d), 8.81 (1H, s)，9.03 (1H，s)，9.15 (1H, s)。實例53: 1-(3-(第三-丁基)_l-(對·曱苯基)-iH-吡唑_5_ 基)-3-(4·((2-(3-曱基)脲基)σ比σ定-4-基）氧基）萘-1-基)腺： 178 201130813Nh2 Trichloroethionate (15 μL, 0.12 mmol) was added to Intermediate Q (50 mg, 0.099 house moles) in an anhydrous bite. The reaction mixture was heated to RT at 0 ° C under nitrogen and after 30 minutes. After another 24 hours, another portion of isocyanate (29 μL, 0.25 mmol) was added and after 42 hours the reaction was quenched by the addition of 1% ΝΗ3 (2.0 mL) in MeOH. After a further 30 minutes, the mixture was evaporated in vacuo and purified EtOAc EtOAcjjjjjjj 'gradient elution to give the title compound <RTI ID=0.0>#</RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; (400 MHz, DMSO-d6) δ : 1.28 (9H, s), 2.40 (3H, s), 6.41 (1H, s), 6.52 (1H, dd), 6.95 (1H, d), 7.31 (1H, d ), 7.37 (2H, d), 7.45-7.47 (2H, m), 7.54-7.61 (1H, m), 7.62-7.67 (1H, m), 7.83 (1H, dd), 7.95 (1H, d), 8.06 (1H, d), 8.09 (1H, d), 8.81 (1H, s), 9.03 (1H, s), 9.15 (1H, s). Example 53: 1-(3-(Third-Butyl)-l-(p-Phenylphenyl)-iH-pyrazole-5-yl)-3-(4.((2-(3-indolyl))urea Base) σ ratio sigma-4-yl)oxy)naphthalen-1-yl) gland: 178 201130813

MeNCOMeNCO

中間物QIntermediate Q

實例53 將異氰酸曱醋(50微升，〇·8〇6毫莫耳)加至中間物 Q(50毫克，0.099毫莫耳)在n比咬(1 〇毫升）中的溶液及將混合物在RT下維持24小時。添加額外部分的異氛酸曱醋（150微升’ 0.26毫莫耳)和吨咬(〇 5毫升)及將反應混合物在RT下維持96小時且然後分溶在DCM(3〇毫升）及NaHC〇3飽和水溶液（1〇毫升)之間。將水層分離且用DCM( 10笔升）萃取並將合併之有機萃取物乾燥 (MgS〇4)並在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si02 ’ 12克，在DCM中之MeOH，0-10%，梯度溶析）以提供呈白色固體之標題化合物，實例53(12毫克 ’ 21%) : Rt 5.24 分鐘（方法 1 驗性）；m/z 564 (M+H)+ (ES+) ; iH NMR (400 MHz，DMSO-d6) δ : 1.28 (9H，s)， 2.39 (3H, s), 2.65 (3H, d), 6.40 (1H, s), 6.54 (1H, dd), 6.87 (1H, d), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, m), 7.58 (1H，m)，7.64 (1H，m)，7.81 (1H, d)，7.88 (1H，br s)， 7.95 (1H, d), 8.05 (1H, d), 8.08 (1H, d), 8.76 (1H, s), 9.09 (1H，s)，9.11(1H，s)。實例54: 3-(4-((4-(3-(3-(第三-丁基)小(對-曱苯基)·ιη_ π比唆-5-基）腺基）蔡-1-基）氧基）β比β定-2-基）-1，1-二曱基脲： 179 201130813Example 53 Adding isocyanate vinegar (50 μl, 〇·8 〇 6 mmol) to a solution of Intermediate Q (50 mg, 0.099 mmol) in n ratio (1 〇 ml) and The mixture was maintained at RT for 24 hours. Add an additional portion of the sulphuric acid vinegar (150 μl '0.26 mmol) and ton of bite (〇5 ml) and maintain the reaction mixture at RT for 96 hours and then dissolve in DCM (3 mL) and NaHC 〇 3 between saturated aqueous solution (1 〇 ml). The aqueous layer was separated and extracted with DCM (10 liters) and the combined organic extracts were dried (MgS 〇 4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut : Rt 5.24 min (method 1); m/z 564 (M+H)+ (ES+); iH NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 2.39 (3H, s) , 2.65 (3H, d), 6.40 (1H, s), 6.54 (1H, dd), 6.87 (1H, d), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, m), 7.58 (1H, m), 7.64 (1H, m), 7.81 (1H, d), 7.88 (1H, br s), 7.95 (1H, d), 8.05 (1H, d), 8.08 (1H, d), 8.76 (1H, s), 9.09 (1H, s), 9.11 (1H, s). Example 54: 3-(4-((4-(3-(3-(tert-butyl)) small (p-quinophenyl)·ιη_ π than 唆-5-yl) gland)) ))oxy)β ratio β-but-2-yl)-1,1-dimercaptourea: 179 201130813

中間物Q 將二曱基胺曱醯氣（18微升，0.20毫莫耳)加至中間物Q(50毫克，0.099毫莫耳）及DIPEA(34微升，0.20 毫莫耳)在無水吡啶（1.5毫升）中的溶液且將反應混合物在RT下維持64小時。藉由添加在MeOH中之 1%NH3(2.0毫升)停止反應及30分鐘之後將所得混合物在真空中蒸發。藉由急驟管柱層析法純化殘餘物 (Si02，12克，在DCM中之MeOH，0-5%，梯度溶析；然後Si02，4克，在異己烷中之[在EtOAc中之 5%MeOH]，50-90%，梯度溶析）以提供呈灰白色固體之標題化合物，實例54(5毫克，8%) : 1^5.15分鐘（方法 1 鹼性）；m/z 578 (M+H)+ (ES+);NMR (400 MHz， DMSO-d6) δ ： 1.28 (9Η, s), 2.40 (3Η, s), 2.86 (6H, s), 6.41 (1H, s), 6.67 (1H, br s), 7.32 (2H, d), 7.37 (2H, d), 7.47 (2H, d), 7.58 (1H, t), 7.65 (1H, t), 7.84 (1H, d), 7.97 (1H, d), 8.09-8.13 (2H, m), 8.82 (1H, s), 9.00 (1H, br s), 9.15 (1H, s)。實例55 : N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑 -5-基)腺基）秦-1-基氧基)α比1^-2-基)嗎琳-4-曱酿胺. 180Intermediate Q Adds decylamine helium (18 μL, 0.20 mmol) to Intermediate Q (50 mg, 0.099 mmol) and DIPEA (34 μL, 0.20 mmol) in anhydrous pyridine The solution in (1.5 ml) and the reaction mixture was maintained at RT for 64 hours. The reaction was stopped by the addition of 1% NH3 (2.0 mL) in MeOH and 30 min. The residue was purified by flash column chromatography (EtOAc EtOAc EtOAc EtOAc MeOH], 50-90%, eluted with EtOAc (EtOAc: EtOAc) ) + (ES+); NMR (400 MHz, DMSO-d6) δ : 1.28 (9Η, s), 2.40 (3Η, s), 2.86 (6H, s), 6.41 (1H, s), 6.67 (1H, br s), 7.32 (2H, d), 7.37 (2H, d), 7.47 (2H, d), 7.58 (1H, t), 7.65 (1H, t), 7.84 (1H, d), 7.97 (1H, d ), 8.09-8.13 (2H, m), 8.82 (1H, s), 9.00 (1H, br s), 9.15 (1H, s). Example 55: N-(4-(4-(3-(3-Terve-butyl-1-p-phenyl)-1H-pyrazol-5-yl)glycosyl)-l-yl-yloxy ) α ratio 1^-2-yl) 琳琳-4-曱胺 amine. 180

201130813 將嗎啉-4-曱醯氯（14微升，〇 12毫莫耳)逐滴加至中間物Q(5〇宅克’ 0.099毫莫耳)及DIPEA(52微升，〇 3〇毫莫耳)在無水吡啶（1·5毫升）中於〇cC在氮氣下的溶液。將反應混合物在〇。(：下維持於15分鐘，經4小時加熱至40°C且然後在RT下留置20小時。將反應混合物再加熱至40oC經3小時且然後藉由添加在Me〇H中之1%ΝΗ3(2.〇毫升)停止反應。45分鐘之後將所得混合物在真空中蒸發及藉由急驟管柱層析法純化殘餘物 (Sl〇2’ 12克’在異己烷中之[在EtOAc中之5%MeOH]， 0-80%’梯度溶析）以提供呈淺棕色粉之標題化合物，實例 55(16 亳克，25%) _· R1 2.18 分鐘（方法 2) ; m/z 620 (M+H) (ES+); NMR (400 MHz, DMSO-d6) δ ： 1.28 (9H, s), 2.40 (3H, S), 3.36 (4H, t), 3.53 (4H, t), 6.41 (1H, s), 6.61 (1H, dd), 7.31 (1H, d), 7.34-7.41 (3H, m), 7.46 (2H, d), 7.55-7.59 (1H, m), 7.63-7.68 (1H, m), 7.84 (1H, dd), 7.96 (1H, d), 8.08 (1H, d), 8.11 (1H, d), 8.80 (1H, s), 9.13 (1H，s)，9.25 (1H，s)。實例 56 : N-(4-((4-(3-(3-(第三-丁基)-1-(對-曱苯基)-1Η- °比唾-5_基)脲基)萘-1-基)氧基户比啶-2-基)-4-甲基哌畊-1-曱醯胺： 181 201130813201130813 Add morpholine-4-indole chloride (14 μl, 〇12 mmol) to the intermediate Q (5 〇克 '0.099 mmol) and DIPEA (52 μl, 〇 3 〇〇 Mohr) A solution of 〇cC under nitrogen in anhydrous pyridine (1.5 mL). The reaction mixture was placed in a crucible. (: maintained at 15 minutes, heated to 40 ° C over 4 hours and then left at RT for 20 hours. The reaction mixture was heated again to 40 ° C for 3 hours and then added by 1% ΝΗ 3 in Me〇H ( 2. 〇ml) Stop the reaction. After 45 minutes, the mixture was evaporated in vacuo and the residue was purified by flash column chromatography ( EtOAc EtOAc EtOAc MeOH], 0-80% gradient elution to give the title compound as a light brown powder, Example 55 (16 gram, 25%) _· R1 2.18 min (method 2); m/z 620 (M+H (ES+); NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 2.40 (3H, S), 3.36 (4H, t), 3.53 (4H, t), 6.41 (1H, s) , 6.61 (1H, dd), 7.31 (1H, d), 7.34-7.41 (3H, m), 7.46 (2H, d), 7.55-7.59 (1H, m), 7.63-7.68 (1H, m), 7.84 (1H, dd), 7.96 (1H, d), 8.08 (1H, d), 8.11 (1H, d), 8.80 (1H, s), 9.13 (1H, s), 9.25 (1H, s). : N-(4-((4-(3-(3-(tert-butyl)-1-(p-phenyl)phenyl)-1Η-° than sal-5-yl)ureido)naphthalene-1 -yl)oxybenzidine-2-yl)-4-methylpiped-1-amine: 181 201130813

中間物QIntermediate Q

Me 實例56 將4-甲基哌畊-i_曱醯氯鹽酸鹽（138毫克，〇 69i毫莫耳）加至中間物Q(7〇毫克，0.138毫莫耳）和 DIPEA(120微升，0.691毫莫耳)在無水吡啶（1.5毫升）中的溶液並將混合物在RT下維持64小時。藉由添加在 MeOH中之1°/{)ΝΗ3(2·0毫升)停止反應及30分鐘之後將所得混合物在真空中蒸發並將殘餘物溶解在EtOAc 中。將有機溶液用水和鹽水洗滌及乾燥(MgS04)且在真空中蒸發。藉由急驟管柱層析法純化殘餘物（Si〇2，在 DCM中之[在MeOH中之7%NH3]，0-5%，梯度溶析）以k供呈淺棕色固體之標題化合物，實例56(28毫克， 31%) : R/ 5.15 分鐘（方法 1 鹼性）；m/z 633 (M+H)+ (ES+);】H NMR (400 MHz, DMSO-d6) δ : 1.28 (9H，s)， 2.15 (3H，s)，2·23 (4H，t), 2.40 (3H，s)，3.37 (4H，t)，6.41 (1H, s), 6.58 (1H, dd), 6.95 (1H, d), 7.31 (1H, d), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.84 (1H, d), 7.95 (1H, d), 8.07-8.11 (2H, m), 8.79 (1H, s), 9.12 (1H, s)，9.19 (1H, s)。實例 57 : Ν·(3·(味《坐-1-基）丙基)_n，-4-(4-(3-(3_第三-丁基 -卜對-曱苯基-1H-吡唑-；5-基)脲基）萘-1-基氧基）吼啶_2_ 基脲： 182 201130813Me Example 56 4-Methylpiperidine-i-indole chloride hydrochloride (138 mg, 〇69i mmol) was added to Intermediate Q (7 mg, 0.138 mmol) and DIPEA (120 μl) , 0.691 mmol) in a solution of anhydrous pyridine (1.5 mL) and the mixture was maintained at RT for 64 hours. The reaction was quenched by the addition of 1 <RTI ID=0.0>> The organic solution was washed with water and brine and dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut Example 56 (28 mg, 31%): R / 5.15 min (Method 1 basic); m/z 633 (M+H) + (ES+); H NMR (400 MHz, DMSO-d6) δ: 1.28 ( 9H, s), 2.15 (3H, s), 2·23 (4H, t), 2.40 (3H, s), 3.37 (4H, t), 6.41 (1H, s), 6.58 (1H, dd), 6.95 (1H, d), 7.31 (1H, d), 7.38 (2H, d), 7.46 (2H, d), 7.57 (1H, t), 7.65 (1H, t), 7.84 (1H, d), 7.95 ( 1H, d), 8.07-8.11 (2H, m), 8.79 (1H, s), 9.12 (1H, s), 9.19 (1H, s). Example 57: Ν·(3·(味的坐-1-基)propyl)_n,-4-(4-(3-(3_T-butyl-butyl-p-phenyl)-1H-pyridyl Oxazole-;5-yl)ureido)naphthalen-1-yloxy)acridine_2_ylurea: 182 201130813

將氯甲酸丙-1_烯-2-基酯（280微升，2.6毫莫耳)在 THF(l〇毫升）中的溶液逐滴加至中間物Q(i丨克，22 毫莫耳)及N-甲基嗎啉(290微升，2.6毫莫耳)在THF(2〇毫升）中於-78〇C下的溶液且在加入完成時，將混合物加熱至RT。16小時之後添加另外部分之N-曱基嗎琳(29〇微升’ 2.6毫莫耳）’將反應混合物冷卻至_78。匚並添加丙-1-烯-2-基氯曱酸酯（280微升，2.6毫莫耳)在THF(5 毫升）中的溶液。將反應混合物維持在RT下經另2小時且然後藉由添加在MeOH(7 M，4.0毫升)之nh3中停止反應。1小時之後將所得混合物用Et〇Ac(30毫升)稀釋並用水(3〇毫升)及鹽水(3〇毫升)洗滌且然後乾燥並在真空中蒸發。殘餘物與乙酸乙酯(20毫升）一起研磨及藉由急驟管柱層析法純化（si〇2 ’在DCM中之EtOAc， 20-50%，梯度溶析）以提供呈灰白色固體之第三-丁基-1-對-曱苯基-lH-η比唑_5_基)脲基）萘_丨_基氧基)。比啶-2-基胺曱酸丙-1-烯-2-基酯（76)(0.60克，84%純 183 201130813 度，藉由 HPLC，40%) Rt 2.78 分鐘（方法 2) ; m/z 591 (M+H)+ (ES+) ; 589 (M-Η). (ES·)。將3-(1Η-味唾-1-基）丙+胺(1〇 6毫克，85微莫耳) 加至(76)(50毫克，85微莫耳)及N_甲基嗎啉（1〇微升， 9微莫耳)在THF(5.0毫升）中的溶液並將反應混合物加熱至55°C經16小時。將所得混合物在真空中蒸發及藉由急驟管柱層析法純化殘餘物(Si〇2，4克，在DCM中之MeOH，2-5%，梯度溶析，然後si02，12克，在 DCM中之4%[在MeOH申之l〇/〇NH3]，等度溶析）以提供呈紫色固體之標題化合物，實例57(9毫克，16%): W 5.37 分鐘（方法 1 鹼性）；m/z 658 (M+H)+ (ES+) : NMR (400 MHz, DMSO-d6) δ ： 1.28 (9H, s), 1.85 (2H, m), 2.39 (3H, s), 3.06 (2H, m), 3.95 (2H, m), 6.40 (1H, s), 6.56 (1H, dd), 6.86 (1H, t), 6.89 (1H, d), 7.16 (1H, t), 7.31 (1H, d), 7.37 (2H, d), 7.46 (2H, d), 7.57 (1H, m), 7.60 (1H, t), 7.64 (1H, m), 7.81 (1H, d), 7.95 (1H, d), 8.06-8.10(3H,重疊 m)，8.77(lH，s)，9.07(lH，s)，9.i2 (1H，s)。實例58 : N-(4-(4-(3-(3-第三-丁基_1-對-曱苯基-1H-«比唾 -5-基)脲基）萘-1-基氧基>比啶-2-基)-2-(2-曱氧基乙醯胺基）乙醯胺： 184 201130813A solution of propylene-1-en-2-yl chloroformate (280 μl, 2.6 mmol) in THF (10 mL) was added dropwise to intermediate Q (i gram, 22 mM) And a solution of N-methylmorpholine (290 microliters, 2.6 millimoles) in THF (2 mL) at -78 ° C and at the completion of the addition, the mixture was heated to RT. Additional portion of N-mercaptoline (29 〇 microliters '2.6 mmol) was added after 16 hours to cool the reaction mixture to _78. A solution of prop-1-en-2-yl chlorodecanoate (280 μL, 2.6 mmol) in THF (5 mL) was added. The reaction mixture was maintained at RT for an additional 2 hours and then quenched by the addition of nh3 in MeOH (7 M, 4.0 mL). After 1 hour the mixture was diluted with EtOAc (30 mL) and washed with water (3 mL) and brine (3 mL) and then evaporated and evaporated in vacuo. The residue was triturated with EtOAc (EtOAc (EtOAc)EtOAc. -Butyl-1-p-nonylphenyl-lH-η-biazole-5-yl)ureido)naphthalene-丨-yloxy). Bipyridin-2-ylamine citrate prop-1-en-2-yl ester (76) (0.60 g, 84% pure 183 201130813 degrees by HPLC, 40%) Rt 2.78 min (Method 2); m/ z 591 (M+H)+ (ES+) ; 589 (M-Η). (ES·). 3-(1Η-Saliva-1-yl)propanylamine (1〇6 mg, 85 μmol) was added to (76) (50 mg, 85 μmol) and N-methylmorpholine (1) 〇升, 9 μmol of a solution in THF (5.0 mL) and the reaction mixture was heated to 55 ° C for 16 h. The resulting mixture was evaporated in vacuo <RTI ID=0.0></RTI> </RTI>jjjjjjjjjjjjjjjjjjjjjjjjj 4% [in MeOH (1 〇〇 3 3 3 , , , , , , , , , , , , ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; m/z 658 (M+H)+ (ES+): NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 1.85 (2H, m), 2.39 (3H, s), 3.06 (2H, m), 3.95 (2H, m), 6.40 (1H, s), 6.56 (1H, dd), 6.86 (1H, t), 6.89 (1H, d), 7.16 (1H, t), 7.31 (1H, d ), 7.37 (2H, d), 7.46 (2H, d), 7.57 (1H, m), 7.60 (1H, t), 7.64 (1H, m), 7.81 (1H, d), 7.95 (1H, d) , 8.06-8.10 (3H, overlap m), 8.77 (lH, s), 9.07 (lH, s), 9.i2 (1H, s). Example 58: N-(4-(4-(3-(3-Terve-butyl_1-p-indolyl-1H-«)-pyran-5-yl)ureido)naphthalen-1-yloxy Base>pyridin-2-yl)-2-(2-decyloxyethylamino)acetamide: 184 201130813

將山中間物（5_毫克，ο.%】毫莫耳)加至2_(第三_ 丁氧羰胺基）乙酸[B〇c_Gly_〇H](415毫克，2 37毫莫耳）、=yB〇P(1.23 克 ’ 2.37 毫莫耳)及 DIPEA(413 微升， 2·37毫莫耳)在無水DMF(12毫升）中於ye在氮氣下之混合物並將混合物加熱至50°C經16小時。將所得混合物冷卻至RT且分溶在Et〇Ac(6〇毫升)及NaHC〇3飽和水溶液(80毫升)之間。將水層用Et〇Ac(6〇毫升）萃取及將合併之有機萃取物用鹽水(80毫升）洗滌，乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si02， 40克’在異己烷中之EtOAc，0-65%，梯度溶析）以提供呈紫色固體之2-(4-(4-(3-(3-第三-丁基-1-對-曱苯基 _1HH5·基）脲基）萘-1-基氧基）°比啶-2-基胺基)-2-側氧乙基胺曱酸第三-丁酯（77)(197毫克，92%純度， 46%) ; Rt 2.65 分鐘（方法 2) ; m/z 664 (M+H)+ (ES+)。將TFA(2.〇毫升)加至胺曱酸酯（77)(187毫克，92% 純度’ 0.259毫莫耳)在無水DCm(6.0毫升）中於0°C在氮氣下的攪拌溶液及將反應混合物維持在〇cC下經20 185 201130813 /刀、，且然後加熱至RT經3小時。將所得混合物在中蒸發及藉由SCX捕捉和釋放純化殘餘物以提供呈二色固體之2-胺基,4-(4-(3-(3-第三·丁基小對-甲 -iH-t坐-5-基）腺基）蔡·i•基氧朴比咬 ς ㈣(削毫克，87%);Rtl 82分鐘（方法2);)m胺 (M+H)+ (ES+)。將2-甲氧基乙酿氣(17〇微升，186微莫耳)加至 (78)(35毫克’ 62微莫耳)及mpEA(43 3微升，2 耳)在f水而(2.5 «粉於㈣在氮氣下的溶液及將反應混合物維持在G°C下經15分鐘且然後加熱至RT。 1.75小時之後藉由添加贿3在Me〇H中之ι%溶液⑽ 毫升)將反應停止及將所得混合物保持在RT下經i小時且然後在真空巾蒸發。將殘餘物進行scx捕捉和釋放且將如此獲狀粗製產物藉由急料柱層析法純化 (Si02 ’ 12克，在異己院中之[在Et〇Ac中之5%Me〇H]， 25-100% ’梯度溶析）以提供呈淺棕色固體之標題化合物，實例58(14毫克，34°/。）； Rt 2 28分鐘（方法2); m/z 636 (M+H)+ (ES+) ; /h NMR (400 MHz，DMSO-d6) δ · 1.28 (9H, s), 2.40 (3H, s), 3.30 (3H, s), 3.82 (2H, s), 3.90 (2H, d), 6.41 (1H, s), 6.72 (1H, dd), 7.33 (1H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (2H, m), 7.64 (1H, m), 7.83 (1H, dd), 7.92 (1H, t), 7.95 (1H> d)j g.09 (1H, d), 8.20 (1H, d), 8.82 (1H, br s), 9.14 (1H, br s), 10.59 (1H, br s)。實例59 : 4-(2-(4-(3-(3-第三-丁基心务甲苯基·m_a比唑 _5_基)脲基)萘-1-基氧基）乙基)_3十比啶_2基)脲： 186 201130813Add the mountain intermediate (5 mg, ο.%) millimolar to 2_(t-butoxycarbonylamino)acetic acid [B〇c_Gly_〇H] (415 mg, 2 37 mmol), =yB〇P (1.23 g ' 2.37 mmol) and DIPEA (413 μl, 2.37 mmol) in anhydrous DMF (12 mL) in ye under nitrogen and the mixture was heated to 50 ° C After 16 hours. The mixture was cooled to RT and partitioned between Et EtOAc (6 mL) and NaCI EtOAc (EtOAc) The aqueous layer was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut (3-Terti-butyl-1-p-indolephenyl_1HH5.yl)ureido)naphthalen-1-yloxy)-pyridin-2-ylamino)-2-oxoethylamine Tri-butyl phthalate (77) (197 mg, 92% purity, 46%); Rt 2.65 min (method 2); m/z 664 (M+H)+ (ES+). Add TFA (2. 〇 ml) to the amine phthalate (77) (187 mg, 92% purity '0.259 mmol) in anhydrous DCm (6.0 mL) at 0 ° C under nitrogen and stir The reaction mixture was maintained at 20 185 201130813 / knives at 〇cC and then heated to RT for 3 hours. The resulting mixture was evaporated in vacuo and the residue was purified by SCX to afford to afford 2-amino, 4-(4-(3-(3)-butyl-butyl---- -t sit -5-based) glandular) Cai·i•基氧朴比比ς(4) (milligram, 87%); Rtl 82 minutes (method 2);)mamine (M+H)+ (ES+) . Add 2-methoxyethane (17 μL, 186 μmol) to (78) (35 mg '62 micromoles) and mpEA (43 3 μl, 2 ears) in water ( 2.5 «Powder in (iv) a solution under nitrogen and maintain the reaction mixture at G ° C for 15 minutes and then heat to RT. After 1.75 hours by adding bribe 3 in Me〇H in 1% solution (10 ml) The reaction was stopped and the resulting mixture was kept at RT for 1 hour and then evaporated in a vacuum. The residue was scx-captured and released and the crude product thus obtained was purified by flash column chromatography (SiO 2 ' 12 g, in aliquots [5% Me〇H in Et〇Ac], 25 -100% 'gradient elution</RTI> to provide the title compound as a light brown solid, Example 58 (14 <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; ES+) ; /h NMR (400 MHz, DMSO-d6) δ · 1.28 (9H, s), 2.40 (3H, s), 3.30 (3H, s), 3.82 (2H, s), 3.90 (2H, d) , 6.41 (1H, s), 6.72 (1H, dd), 7.33 (1H, d), 7.38 (2H, d), 7.47 (2H, m), 7.57 (2H, m), 7.64 (1H, m), 7.83 (1H, dd), 7.92 (1H, t), 7.95 (1H> d)j g.09 (1H, d), 8.20 (1H, d), 8.82 (1H, br s), 9.14 (1H, br s), 10.59 (1H, br s). Example 59: 4-(2-(4-(3-(3-Terve-butyl)tolyl·m_abiazole-5-yl)ureido)naphthalen-1-yloxy)ethyl)_3 Decidin-2-yl urea: 186 201130813

中間物FIntermediate F

PyridinePyridine

Ο CljC^^NCOΟ CljC^^NCO

將二氣乙酸基異鼠酸g旨（12微升，0.103毫莫耳)力至中間物F(50毫克，0.094毫莫耳)在η比啶（1 〇毫升）中° 的溶液及將混合物在RT下攪拌直到藉由LC_MS判斷為完全，在真空中蒸發溶劑及將所得殘餘物進行scx 捕捉和釋放且從DCM(10毫升）磨碎以產生呈灰白色固體之標題化合物，實例59(25毫克，44%) : m/z 578 (M+H)+ (ES+)。NMR (400 MHz，DMSO-d6) δ : 1.26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 Η, s)，6.94-6.99 (2 H，m)，7.19 (1 H，dd)，7.33-7.35 (2 H，m)， 7.41-7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H，d)，8.09-8.13 (2 H，m)，8.54 (1 H, s), 8.75 (1 H，s)， 9.08 (1 H，s)。 ’ 實例60 : (^_Ν_(4_(4·(3_(3_第三_丁基小對一甲苯基_1H_ °比唑_5_基）脲基）萘-1-基氧基）吡啶-2-基)-3-(二曱胺基) 0比洛咬-1-甲酿胺： 187A solution of di-acetic acid iso-nanoate g (12 μL, 0.103 mmol) to intermediate F (50 mg, 0.094 mmol) in n-pyridine (1 mL) and mixture Stir at RT until it was judged to be complete by LC_MS, eluent solvent was evaporated in vacuo and the residue was taken and taken and taken and taken from DCM (10 mL) to give the title compound , 44%) : m/z 578 (M+H)+ (ES+). NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.38 (3 H, s), 3.12 (2 H, t), 4.35 (2 H, t), 6.34 (1 Η, s) , 6.94-6.99 (2 H,m), 7.19 (1 H,dd),7.33-7.35 (2 H,m), 7.41-7.50 (5 H, m), 7.52-7.56 (1 H, m), 7.60 (1 H, d), 7.87 (1 H, d), 8.09-8.13 (2 H, m), 8.54 (1 H, s), 8.75 (1 H, s), 9.08 (1 H, s). Example 60: (^_Ν_(4_(4·(3_(3_Third-butyl-p-p-tolyl-1H_ °biazole-5-yl)ureido)naphthalen-1-yloxy)pyridine- 2-yl)-3-(didecylamino) 0 piroxime-1-cartoamine: 187

I 201130813I 201130813

經30分鐘將DBU(1〇2毫升，678毫莫耳)逐滴加至，基比°定醇(53.9克，489毫莫耳)在MeCN(5〇0毫的檀拌_液巾。賴得溶I轉在RT下經30分 1且然後用L氟確基萘(14)(72.0克，377毫莫耳)在 ^猜(400毫升）中的溶液逐滴處理經％分鐘。將反應混 5物在尺丁下搜拌過夜且然後加熱至50°C經2小時。移除加熱且將攪拌混合物用水(600毫升)慎重地稀釋，之後使其冷卻至RT經2小時且然後進一步冷卻至〇 C。如此產生之黃色沈澱物藉由過濾收集並用水及乙腈的混合物（1 : 1，2 X 100毫升）且然後用水(5〇〇毫升) 連續地=滌以產生4_(4_硝基萘_丨_基氧基）吡啶_2_胺 (77)，呈只色固體(76.0 克，70〇/〇): m/z 283 (M+H)+ (ES+) 〇將氣曱酸笨酯（98微升，0.78毫莫耳)加至(77)(200 亳克，0.71毫莫耳)及玢办(0.2〇毫升，i 42毫莫耳)在無水THF中的溶液及將反應混合物維持在RT下經J 小時。將一部分的(R)_N，N•二曱基吡咯啶_3•胺(27〇微升，2.13耄莫耳）加至此混合物且在rt下Μ小時之後 188 201130813 添加第二部分之（r)_N，N-二甲基吡咯啶-3-胺（100微升，0.79毫莫耳)及將混合物維持在下RT經另1小時。將所得混合物分溶在NH4C1水溶液（1〇毫升）及DCM(10 毫升)之間且分離水層並用DCM(3 X 1〇毫升）萃取。將合併之有機萃取物乾燥並在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si02 ’ 40克，在DCM中之[在DCM 中之5%MeOH]，0-100%，梯度溶析及然後，在DCM 中之 10%[在 MeOH 中之 2%NH3(在]yieOH 中之 7M)]，等度溶析及最後，在DCM中之3〇%MeOH，等度溶析）以提供呈黃色/棕色固體之(R)-3-(二甲胺基)_N_(4-(4-硝基萘-1-基氧基)°比啶-2-基户比咯啶小甲醯胺，（78)，（25〇毫克，81%) ; R1 1.54 分鐘（方法 2) ; m/z 422 (M+H)+ (ES+)。藉由通過Thales Η-立方體（i.o毫升分鐘-ι，25〇c， 70 耄米 l〇%Pt/CCat-Cart，全氫模式）使(78)(25〇毫克，〇.593毫莫耳)在包含AcOH(4滴)之MeOH(40毫升）中的 /谷液進行氫化且然後在真空中蒸發。將粗製產物分溶在 DCM(20毫升)及NaHC〇3水溶液（1〇毫升）之間及將有機層分離並用鹽水（10毫升）洗滌，乾燥且在真空中蒸發以提供呈綠色非晶形固體之(R)七-(4_(4-胺基萃·ι_基氧基）咐細二甲胺基克，78°/〇’90%純），R 1.13 分鐘（方法 2);m/z 392 (M+H)+ (ES+)，其直接使用於下一步驟中。經20分鐘將(5)(85毫克，〇 37〇毫莫耳)逐部分地加至CDI(100毫克，0.370 ¾莫耳)在無水dcm(i〇毫升) 中的溶液，及將所得溶液維持於RT下經2 5小時。將 189 201130813 一部分之此溶液(0·70毫升)加至(79)(100毫克，0.255毫莫耳)在DCM(1.0毫升）中的溶液並將混合物維持於rt 下經18小時。藉由添加MeOH(3.0毫升)將反應停止並將混合物在真空中蒸發。藉由急驟管柱層析法純化殘餘物(Si〇2，4 克，[在 DCM 中之 5%NH3(在 MeOH 中之 7M)] 在DCM中，0-100% ’梯度溶析）以提供呈棕色玻璃之標題化合物，實例60(52毫克，30%) ; R； 4.92分鐘（方法 1 鹼性）；m/z 647 (M+H)+ (ES+);丨H NMR (400 MHz， DMSO-d6) δ ： 1.28 (9H, s), 1.61 (1H, m), 1.98 (1H, m), 2.12 (6H, s), 2.39 (3H, s), 2.58 (1H, m), 3.03 (1H, m), 3.25 (1H, m), 3.49 (1H, m), 3.58 (1H, m), 6.41 (1H, s), 6.60 (1H, dd), 7.30 (1H, d), 7.37 (2H, d), 7.44-7.47 (3H, 重疊 m)，7.56 (1H，m)，7.64 (1H，m), 7.83 (1H，d)，7.95 (1H，d)，8.08 (1H，d)，，8.10 (ih，d)，8.70 (1H，s)，8.79 (1H，s)，9.12 (1H，s)。生物試驗使用三個不同的實驗計劃在MDCK細胞中，比較化合物實例1抵抗流感病毒菌株(H1N1 (PR8)、H1N1 (A/WSN/33)、H3N2 (A/Wuhan/359/95)及流感 B)之抗病毒活性與作為正對照組的神經胺糖酸苷酶抑制劑扎那米韋(zanamivir)之抗病毒活性，以及比較BIRB之抗病毒活性：分析方法1:測量試驗化合物抑制病毒誘導之血球凝集素(haemaglutinnin)的表現之活性的ELISA分析。 190 201130813 分析方法2:測量試驗化合物抑制病毒誘導之核蛋白質的表現之活性的ELISA分析。分析方法3 :使用檢測用MTT評估之試驗化合物抑制病毒誘發之細胞病變效應(CPE)的活性之測量。分析方法4 :使用檢測用亞曱藍評估之試驗化合物抑制病毒誘發之細胞病變效應(CPE)的活性之測量。然後於初生人類上皮細胞證實抵抗流感之抗病毒活性。此外，評估化合物抵抗下列之效果：（i) RSV或 HRV-16感染之後的病毒量，（ii)RSV-或HRV-16誘發之 IL-8釋放及(iii)HRV-16誘發之ICAM表現。實驗方法流感：細胞為基礎的ELISA分析（方法1及2) 作為評估細胞有關流感複製之方法，使用適當的 ELISA分析測定企球凝集素(haemaglutinnin)(方法1)或細胞核蛋白質（方法2)表現。在包含1.5微克/毫升TPCK 處理之胰蛋白的無FCS之DMEM中以0.1之MOI將 Madin-Darby狗腎(MDCK)細胞用流感病毒(H1N1，菌株 A/PR/8/34’HPA’Salisbury，UK)感染及為了吸附在 370C 下培養1小時。然後將細胞用PBS洗蘇，添加新鮮培養基且將細胞培養2天（43-50小時）。用在PBS溶液中之4%曱醛固定細胞。需要時，將細胞用化合物預培養 2小時，且然後沖盡非感染病毒之後再次添加。將細胞用洗滌緩衝液（包括0.5%BSA及 0.05%Tween-20之PBS)洗滌並用封閉液（在包括 191 201130813 u.05%Tween-20之PBS中的5%牛奶）培養1小時。然後將細胞用洗滌緩衝液洗滌及在37°C下用抗流感A病毒企球凝集素抗體（小鼠單株)(Abcam)或流感a病毒核蛋白質抗體(兔子單株；Abeam)培養1小時。洗務之後，將細胞用HRP-結合之二級抗體(Dako)培養且使用TjyfB 受質（由R&D Systems, Inc.供應之受質試劑）以比色法確定(OD : 450奈米’使用655奈米之參考波長)所產生的信號。此反應以添加50微升的2N H2S04停止。然後將細胞用PBS洗滌及施用2.5%結晶紫溶液經30分鐘。用PBS洗滌之後，將1%SDS加至各孔且在讀取於 595奈米的吸光度之前將該盤輕搖1小時。測得之〇〇450-655讀數校正細胞數，以結晶紫染色測定，藉由 ODd655除以OD595讀數。計算各孔百分比抑制及從由化合物之連續稀釋液所產生之濃度反應曲線測定 IC50 值。流感CPE分析（方法3) 在包含1.5微克/毫升TPCK處理之胰蛋白的無FCS 之培養基中以0.1之MOI將MDCK細胞用流感 (H1N1A/PR/8/34、H1N1 (A/WSN/33)、H3N2 (A/Wuhan/359/95)或流感 B、ΗΡΑ，Salisbury，UK)感DBU (1 〇 2 ml, 678 mmol) was added dropwise over 30 minutes, and the base was fixed in alcohol (53.9 g, 489 mmol) in MeCN (5 〇 0 毫檀 _ _ I was subjected to a drop of 30 minutes 1 at RT and then treated dropwise with a solution of L-fluorodecylnaphthalene (14) (72.0 g, 377 mmol) in ^ guess (400 ml) over % min. The mixture was sifted overnight under the ruler and then heated to 50 ° C for 2 hours. The heat was removed and the stirred mixture was carefully diluted with water (600 mL), then allowed to cool to RT for 2 hours and then further cooled to 〇 C. The yellow precipitate thus produced is collected by filtration and mixed with water and acetonitrile (1:1, 2 x 100 ml) and then continuously with water (5 ml) to give 4-(4-nitronaphthalene). _丨_yloxy)pyridine-2-amine (77), as a color solid only (76.0 g, 70 〇 / 〇): m / z 283 (M + H) + (ES +) 〇曱曱酯酯(98 μl, 0.78 mmol) added to (77) (200 g, 0.71 mmol) and solution (0.2 mL, i 42 mmol) in anhydrous THF and maintain the reaction mixture J hours at RT. Part of the (R)_N, N• dip Pyrrolidine _3•amine (27 〇 microliters, 2.13 耄mol) was added to the mixture and Μ rt after rt 188 201130813 Add the second part of (r)-N,N-dimethylpyrrolidin-3-amine (100 μL, 0.79 mmol) and the mixture was maintained at RT for another hour. The resulting mixture was partitioned between aqueous NH4C1 (1 mL) and DCM (10 mL) and the aqueous layer was separated and DCM (3) Extraction of X 1 mL). The combined organic extracts were dried <RTI ID=0.0></RTI> and evaporated in vacuo. , 0-100%, gradient elution and then, 10% in DCM [2% NH3 in MeOH (7M in] yieOH)], isocratic and finally, 3% in DCM MeOH, isocratic elution) to provide (R)-3-(dimethylamino)-N-(4-(4-nitronaphthalen-1-yloxy)-pyridin-2- as a yellow/brown solid Base berberine small formamide, (78), (25 〇 mg, 81%); R1 1.54 min (method 2); m/z 422 (M+H)+ (ES+). by Thales Η - cube (io ml min - ι, 25 〇 c, 70 〇 l〇% Pt / CCat-Cart, Hydrogen mode) of (78) (25〇 mg, 〇.593 mmol) in MeOH containing AcOH (4 drops) of (40 mL) / trough was hydrogenated and then evaporated in vacuo. The crude product was partitioned between EtOAc EtOAc (EtOAc m. (R) s-(4-(4-Amino-based ι-yloxy) hydrazine dimethylamine ketone, 78°/〇 '90% pure), R 1.13 minutes (method 2); m/z 392 (M+H)+ (ES+), which is used directly in the next step. (5) (85 mg, 〇37 〇 millimolar) was added portionwise to a solution of CDI (100 mg, 0.370 3⁄4 mol) in anhydrous dcm (i 〇 ml) over 20 minutes, and the resulting solution was maintained After 2 5 hours at RT. A solution of this solution (0. 70 mL) of 189 201130813 was added to a solution of (79) (100 mg, 0.25 mM) in DCM (1.0 mL) and the mixture was maintained at rt for 18 hours. The reaction was quenched by the addition of MeOH (3.0 mL) and the mixture evaporated in vacuo. The residue was purified by flash column chromatography (Si2, 4 g, 5% NH3 in DCM (7M in MeOH) in DCM, 0-100% gradient elution) The title compound was obtained as a brown glass, Example 60 (52 mg, 30%); R; 4.92 min (method 1 basic); m/z 647 (M+H)+ (ES+); 丨H NMR (400 MHz, DMSO -d6) δ : 1.28 (9H, s), 1.61 (1H, m), 1.98 (1H, m), 2.12 (6H, s), 2.39 (3H, s), 2.58 (1H, m), 3.03 (1H , m), 3.25 (1H, m), 3.49 (1H, m), 3.58 (1H, m), 6.41 (1H, s), 6.60 (1H, dd), 7.30 (1H, d), 7.37 (2H, d), 7.44-7.47 (3H, overlap m), 7.56 (1H, m), 7.64 (1H, m), 7.83 (1H, d), 7.95 (1H, d), 8.08 (1H, d), 8.10 (ih,d), 8.70 (1H, s), 8.79 (1H, s), 9.12 (1H, s). The biological assay used three different experimental programs in MDCK cells to compare compound case 1 against influenza virus strains (H1N1 (PR8), H1N1 (A/WSN/33), H3N2 (A/Wuhan/359/95), and influenza B. Antiviral activity of the anti-viral activity of the neuraminidase inhibitor zanamivir as a positive control group, and comparison of the antiviral activity of BIRB: Analytical method 1: Measurement of test compound inhibits virus induction ELISA analysis of the activity of the performance of hemagglutinin. 190 201130813 Analytical Method 2: ELISA analysis measuring the activity of test compounds to inhibit the performance of virus-induced nuclear proteins. Analytical Method 3: Measurement of the activity of a test compound evaluated by MTT for inhibition of virus-induced cytopathic effect (CPE). Analytical Method 4: Measurement of the activity of a test compound evaluated by using indigo blue to inhibit virus-induced cytopathic effect (CPE). The anti-viral activity against influenza is then confirmed in newborn human epithelial cells. In addition, compounds were evaluated for their effects against (i) the amount of virus following RSV or HRV-16 infection, (ii) RSV- or HRV-16 induced IL-8 release, and (iii) HRV-16 induced ICAM performance. Experimental Methods Influenza: Cell-Based ELISA Assays (Methods 1 and 2) As a method for assessing cell-associated influenza replication, assays for haemaglutinnin (Method 1) or nuclear protein (Method 2) were performed using appropriate ELISA assays. . In a FCS-free DMEM containing 1.5 μg/ml TPCK-treated trypsin, Madin-Darby dog kidney (MDCK) cells were treated with influenza virus (H1N1, strain A/PR/8/34 'HPA'Salisbury, at an MOI of 0.1, UK) infection and incubation for 1 hour at 370C for adsorption. The cells were then washed with PBS, fresh medium was added and the cells were incubated for 2 days (43-50 hours). The cells were fixed with 4% furfural in PBS solution. When necessary, the cells were preincubated with the compound for 2 hours and then added again after flushing out the non-infected virus. The cells were washed with wash buffer (PBS containing 0.5% BSA and 0.05% Tween-20) and incubated with blocking solution (5% milk in PBS including 191 201130813 u.05% Tween-20) for 1 hour. The cells were then washed with washing buffer and incubated with anti-influenza A virus elicitin antibody (mouse monoclonal) (Abeam) or influenza a virus nuclear protein antibody (rabbit single plant; Abeam) for 1 hour at 37 °C. . After washing, the cells were cultured with HRP-conjugated secondary antibody (Dako) and determined by colorimetry using a TjyfB substrate (substance reagent supplied by R&D Systems, Inc.) (OD: 450 nm' A signal generated using a reference wavelength of 655 nm). This reaction was stopped by the addition of 50 microliters of 2N H2S04. The cells were then washed with PBS and a 2.5% crystal violet solution was applied for 30 minutes. After washing with PBS, 1% SDS was added to each well and the disk was gently shaken for 1 hour before reading the absorbance at 595 nm. The measured 细胞450-655 readings were corrected for cell count as determined by crystal violet staining by dividing the ODd655 by the OD595 reading. The percent inhibition of each well was calculated and the IC50 value was determined from the concentration response curve generated from serial dilutions of the compound. Influenza CPE analysis (Method 3) MDCK cells were used for influenza (H1N1A/PR/8/34, H1N1 (A/WSN/33) in an FCS-free medium containing 1.5 μg/ml TPCK-treated trypsin at an MOI of 0.1. , H3N2 (A/Wuhan/359/95) or flu B, ΗΡΑ, Salisbury, UK)

染及為了吸附在37°C下培養1小時。然後將細胞用PBS 洗滌’添加新鮮培養基且將細胞培養2天(44_56小時）。需要時’將細胞用化合物預培養2小時，且然後其在沖盡病毒之後再次添加。然後將細胞用l〇%FCS DMEM 洗滌，並在包含0.25毫克/毫升MTT之10%FCSDMEM 192 201130813 中培養2小時。然後移除培養基，將2〇〇微升的dms〇加至各孔且在讀取於550奈米的吸光度之前將該盤輕搖1小時。由治療產生之CPE的抑㈣以i微克/毫升之扎那米韋(Zanamivir)所達成的百分比表示，於試驗化合物之各濃度與媒液對照組比較。從所得化合物實例1之濃度反應曲線(表1)測定相對於1微克/毫升之扎那米韋的效果之50/ί»有效濃度值(R-EC5Q)。對於其他實例之示性(表 3)，與媒液比較而計算各孔之百分比抑制。從由化合物之連續稀釋液所產生的濃度反應曲線計算IC5〇值。流感CPE分析（方法4) 在包含1.5微克/毫升TPCK處理之胰蛋白的無FCS 之培養基中以0.1之MOI將MDCK細胞用流感 (H1N1A/PR/8/34 ’ ΗΡΑ，Salisbury，UK)感染。為了吸附在37°C下培養1小時之後，將細胞用無fcS之培養基洗滌’且在包含1.5微克/毫升TPCK處理之胰蛋白的 DMEM培養基中培養2天（41:56小時）。需要時，將細胞用試驗化合物預培養2小時，且其在沖盡病毒之後再次添加。接著將細胞用10%FCS DMEM洗滌，並在40 微升之亞甲藍溶液(2%甲醛、10%曱醇、0.175 %亞甲藍在水中）中培養2小時。然後將細胞用PBS洗滌三次，及用200微升的PBS在RT下培養1小時。用PBS洗滌一次之後，將1%SDS溶液（100微升)加至各孔及且在讀取於660奈米的吸光度之前將該盤將該盤輕搖1小時。 193 201130813 如下所示計算用試驗化合物治療所產生之CPE的百分比抑制： CPE之抑制％ = 100 X 1-[(在試驗化合物之各濃度的吸光度值減非感染對照組的吸光度值)除以（感染對照組的吸光度值減非感染對照組的吸光度值)]。50%抑制濃度值(ICsq值)係從各化合物的連續稀釋液之作圖結果所產生的濃度反應曲線計算。使用3D培養之支氣管上皮細胞的流感滴定度分析使用空氣·液體界面培養之初生支氣管上皮細胞係從Mattek公司（Boston，USA)蹲得。將包含於所選濃度之試驗化合物或媒液(DMSO，0.5%之最後濃度）的新鮮加熱之培養基(30微升)轉移到頂室。培養2小時之後，將20微升之H1N1病毒(產生在1〇6的估計細胞數/孔之約2的M0I)加至頂孔並將細胞感染1小時。然後藉由抽吸移除頂培養基且用熱PBS洗滌該等孔二次。該盤在37°C下培養72小時。然後將I>BS(50微升)加至頂室並將製劑留置10分鐘。從頂室收集上澄液及以CPE分析在MDCK細胞中估計病毒滴定度如下。收集一部分 (20微升)之上澄液並製備於包含1.5微克/毫升TPCK處理之胰蛋白的無FCS之培養基中的10-倍連續稀釋液。所有滴定係藉由用連續稀釋之上澄液製劑（1/10 -1/100000)感染匯合MDCK細胞單層（96孔盤)實施。感染3天之後藉由目視檢查評估所產生之細胞病變效應。計算各治療之感染50%MDCK的細胞所需要的病毒量並以log[TCID5〇] (U/20微升)報告。 194 201130813 RSV :初生支氣管上皮細胞泰此蛋白質ELISA)中之試管内RSA病毒量在包含 15mM氧务雜+ τ 軋化鎂之LHC8培養基： RPMI-1640 (50 : 50)中以〇〇〇1 夕以八了 m U.UUi 之 MOI 用 RSV (Strain A2，ΗΡΑ ’ Saiisbury，UK)感染在％孔盤令生長之 NHBEC細胞。為了吸附在37。〇下培養丨小時之後，將細胞用PBS祕’添加新鮮的培養基城後將細胞培養另4天。將細胞用試驗化合物或DMSO預培養2小時’且其在沖盡病毒之後再次添加。最初用在PBS溶液中之4%甲醒將細胞固定2〇分在里，用WB(洗滌緩衝液，包括〇 5%BSA及 0.05%Tween-20之PBS)洗滌並用封閉液(在pBS中之5% 煉乳）培養1小時。然後將細胞用WB洗滌並用抗 -RSV(2F7) F-融合蛋白質抗體（小鼠單株；批次 798760 ，目錄號ab43812，Abeam)在RT下培養1小時。洗滌之後’添加TMB受質（受質試劑包，批次269472，目錄號 DY999 ’ R&D Systems，Inc.)之前，將細胞用 HRP-結合之二級抗體(批次00053170,目錄號p〇447，Dako)培養。此反應以添加2N H2S04 (50微升)停止及所產生的信號以使用微量滴盤讀出器（Varioskan® Flash，Dyeing and incubation for 1 hour at 37 ° C for adsorption. The cells were then washed with PBS' fresh medium was added and the cells were incubated for 2 days (44-56 hours). The cells were preincubated with the compound for 2 hours as needed, and then added again after the virus was washed out. The cells were then washed with 1% FCS DMEM and incubated for 2 hours in 10% FCSDMEM 192 201130813 containing 0.25 mg/ml MTT. The medium was then removed and 2 microliters of dms was added to each well and the plate was shaken for 1 hour before reading the absorbance at 550 nm. The CPE produced by the treatment was expressed as a percentage of iam/vir of Zanamivir, and each concentration of the test compound was compared with the vehicle control group. The 50/ί» effective concentration value (R-EC5Q) relative to the effect of 1 μg/ml of zanamivir was determined from the concentration reaction curve of the obtained compound Example 1 (Table 1). For the other examples (Table 3), the percent inhibition of each well was calculated as compared to the vehicle. The IC5 enthalpy was calculated from the concentration response curve generated from serial dilutions of the compound. Influenza CPE Assay (Method 4) MDCK cells were infected with influenza (H1N1A/PR/8/34 'ΗΡΑ, Salisbury, UK) at an FCS-containing medium containing 1.5 μg/ml of TPCK-treated tryptone at an MOI of 0.1. After incubating for 1 hour at 37 ° C for adsorption, the cells were washed with a medium without fcS and cultured for 2 days (41: 56 hours) in DMEM medium containing 1.5 μg/ml of TPCK-treated trypsin. When necessary, the cells were preincubated with the test compound for 2 hours, and they were added again after the virus was washed out. The cells were then washed with 10% FCS DMEM and incubated for 2 hours in 40 microliters of methylene blue solution (2% formaldehyde, 10% sterol, 0.175% methylene blue in water). The cells were then washed three times with PBS and incubated with 200 microliters of PBS for 1 hour at RT. After washing once with PBS, a 1% SDS solution (100 μl) was added to each well and the disk was shaken for 1 hour before reading the absorbance at 660 nm. 193 201130813 Calculate the percentage inhibition of CPE produced by treatment with test compound as follows: % inhibition of CPE = 100 X 1-[(absorbance value at each concentration of test compound minus absorbance value of non-infected control group) divided by ( The absorbance value of the infected control group was reduced by the absorbance value of the non-infected control group)]. The 50% inhibition concentration value (ICsq value) was calculated from the concentration response curve produced by the results of the mapping of serial dilutions of each compound. Influenza titer analysis using 3D cultured bronchial epithelial cells The nascent bronchial epithelial cell line cultured using an air/liquid interface was obtained from Mattek (Boston, USA). Freshly heated medium (30 microliters) containing the test compound or vehicle (DMSO, 0.5% final concentration) at the selected concentration was transferred to the top chamber. After 2 hours of culture, 20 μl of H1N1 virus (generating the estimated number of cells at 1〇6/about 2 mM of MOI) was added to the top well and the cells were infected for 1 hour. The top medium was then removed by aspiration and the wells were washed twice with hot PBS. The plate was incubated at 37 ° C for 72 hours. I>BS (50 microliters) was then added to the top chamber and the formulation was left for 10 minutes. The supernatant was collected from the top chamber and analyzed by CPE to estimate the virus titer in MDCK cells as follows. A portion (20 μl) of the supernatant was collected and prepared in 10-fold serial dilutions in FCS-free medium containing 1.5 μg/ml TPCK-treated trypsin. All titrations were performed by infecting confluent MDCK cell monolayers (96-well plates) with serial dilutions of the supernatant preparation (1/10 - 1/100000). The cytopathic effect produced was assessed by visual inspection after 3 days of infection. The amount of virus required for each treatment of cells infected with 50% MDCK was calculated and reported as log [TCID5〇] (U/20 μL). 194 201130813 RSV: Primary bronchial epithelial cells in this protein ELISA) The amount of RSA virus in the test tube is in the LHC8 medium containing 15 mM oxygen mixed + τ rolled magnesium: RPMI-1640 (50: 50) The NHBEC cells grown in % wells were infected with RSV (Strain A2, ΗΡΑ 'Saiisbury, UK) with an MOI of m U.UUi. In order to adsorb at 37. After squatting for an hour, the cells were cultured for another 4 days by adding fresh medium to the cells with PBS. The cells were pre-incubated with test compound or DMSO for 2 hours' and they were added again after flushing out the virus. The cells were initially fixed in 2% with 4% Awake in PBS solution, washed with WB (wash buffer, including 5% 5% BSA and 0.05% Tween-20 in PBS) and blocked (in pBS) 5% condensed milk) was incubated for 1 hour. The cells were then washed with WB and incubated with anti-RSV (2F7) F-fusion protein antibody (mouse individual; lot 798760, catalog number ab43812, Abeam) for 1 hour at RT. After washing, 'Add TMB receptor (substance reagent kit, lot 269472, catalog number DY999 'R&D Systems, Inc.), use HRP-conjugated secondary antibody (lot 0053170, catalog number p〇) 447, Dako) culture. This reaction was stopped with 2N H2S04 (50 μl) and the resulting signal was used to use a micro drip reader (Varioskan® Flash,

ThermoFisher Scientific)之比色法(〇D : 450 奈米，使用 655奈米之參考波長）測定。然後洗滌細胞及施用2.5% 結晶紫溶液（批次8656，目錄號PL7000，Pro-LabThermoFisher Scientific) colorimetric method (〇D: 450 nm, using a reference wavelength of 655 nm). The cells are then washed and 2.5% crystal violet solution is applied (batch 8506, catalog number PL7000, Pro-Lab

Diagnostics)經30分鐘。用WB洗滌之後，將1〇〇微升之1%SDS加至各孔，且在讀取於595奈米的吸光度之 195 201130813 丽將該盤輕搖1小時。胞數，以結晶紫染色·畴之OD450-655讀數校正細讀數。計算各孔百分比=由0D450·655除以〇吻所產生之濃度反應曲線===合物之連續稀釋液使用3D培養分析之支氣官上皮細胞的 RSV滴定度及il_8 7空氣·液體界㈣養之初生支氣管上皮細胞俾 P &娜瑞士日内瓦)購得。將包含於所選濃产之試驗化合物或媒液_S〇，〇.5%之最後濃度）的新^ 加熱之培養基⑽微升)轉移到頂室及包含於所選濃度之試驗化合物或舰(DMSQ，Q挪之最後濃度）的新鮮加熱之培養基(700微升)轉移到底室。培養2小時之後，將上孔中的培養基小心地移除。次日，將包含於所選濃度之試驗化合物或媒液(DMSO，0.5%之最後濃度）的新鮮加熱之培養基(200微升)再次轉移到頂室，及培養2 小時之後移除培養基。在第三天，細胞以相同的方式處理2小時且移除培養基。將端孔中之細胞用rSvDiagnostics) after 30 minutes. After washing with WB, 1 〇〇 microliter of 1% SDS was added to each well, and the disk was gently shaken for 1 hour at 195 201130813, which was read at 595 nm. The number of cells was corrected for fine readings by crystal violet staining and OD450-655 readings of the domains. Calculate the percentage of each hole = the concentration response curve generated by dividing 0D450·655 by the kiss. ============================================================================================== The nascent bronchial epithelial cells were purchased from P & Na Geneva, Switzerland. Transfer the new heated medium (10 μL) contained in the selected concentrated test compound or vehicle _S〇, 最后.5% of the final concentration) to the top chamber and the test compound or ship contained in the selected concentration ( The freshly heated medium (700 μl) of DMSQ, the final concentration of Q was transferred to the bottom chamber. After 2 hours of incubation, the medium in the upper well was carefully removed. The next day, the freshly heated medium (200 μl) containing the test compound or vehicle (DMSO, 0.5% final concentration) at the selected concentration was again transferred to the top chamber, and the medium was removed after 2 hours of culture. On the third day, the cells were treated in the same manner for 2 hours and the medium was removed. Use the cells in the end hole with rSv

Memphis 37病毒（Meridian ;約0.1之MOI之估計細胞數；106/孔)感染並培養1小時。然後藉由抽吸移除頂培養基且用加熱之PBS洗滌該等孔二次，且在37°C下培養該盤。在感染之後1小時及1、2、3、4、5、6、7、 8、9及10天，將加熱之PBS(300微升，37°C)加至頂室並將製劑留置10分鐘。從頂室收集上澄液及儲存在 -20°C用於IL-8細胞激素分析’及其他部分（150微升) 與培養基（包含15 %蔗糖）混合且然後儲存(-2 0。C)用於 196 201130813 病毒滴定濃度分析。 IL-8濃度係使用Duoset ELISA發展套組(R&D Systems ’ Minneapolis，MN)測定。病毒滴定度係在收集上澄液(20微升)及以5%_FCSDMEM製備1〇_倍連續稀釋液之後以CPE分析在Hep2細胞中評估。所有滴定係藉由用連續稀釋之上澄液製劑（10·1至1〇_5)感染匯合Hep2細胞單層（96孔盤)實施。感染3天之後藉由目視檢查評估所產生之CPE。計算各治療之感染5〇%HeP 細胞所需要的病毒量並以l〇g[TCID5〇] (U/20微升)報告。人類鼻病毒：使用MRC-5細胞之CPE分析將MRC-5細胞（人類肺纖維母細胞，ATcc，Memphis 37 virus (Meridian; estimated cell number of MOI of about 0.1; 106/well) was infected and cultured for 1 hour. The top medium was then removed by aspiration and the wells were washed twice with heated PBS and the plate was incubated at 37 °C. Heated PBS (300 μl, 37 ° C) was added to the top chamber 1 hour after the infection and 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 days and the preparation was left for 10 minutes. . Collect the supernatant from the top chamber and store at -20 °C for IL-8 cytokine analysis' and other parts (150 μl) mixed with medium (containing 15% sucrose) and then stored (-2 0 C) For 196 201130813 virus titration concentration analysis. IL-8 concentrations were determined using the Duoset ELISA Development Kit (R&D Systems ' Minneapolis, MN). The virus titer was evaluated in Hep2 cells by CPE analysis after collecting the supernatant (20 μl) and preparing 1 〇 _ serial dilution in 5% _FCSDMEM. All titrations were carried out by infecting a confluent Hep2 cell monolayer (96-well plate) with serial dilutions of the supernatant preparation (10·1 to 1〇_5). The CPE produced was evaluated by visual inspection after 3 days of infection. The amount of virus required to infect 5 % of HeP cells in each treatment was calculated and reported as l〇g [TCID5〇] (U/20 μL). Human rhinovirus: CPE analysis using MRC-5 cells MRC-5 cells (human lung fibroblasts, ATcc,

Manassas ’ VA)用在包含 5%FCS 及 1.5 毫米 MgCl2 之 DMEM中的HRV16 (於1之MOI)感染。為了吸附在 33°C下培養1小時之後，抽吸上澄液，添加新鮮的培養基且將細胞培養另4天。將細胞用試驗化合物或 DMSO預培養2小時’其在沖盡病毒之後再次添加。抽吸上澄液及用亞曱藍溶液(2〇/〇甲醛、ι〇〇/0曱醇及〇 175 〇/〇亞甲藍）將細胞在RT下培養2小時。洗滌之後，將 1%SDS加至各孔’且在讀取於660奈米的吸光度之前將該等盤溫和搖動1_2小時。計算各孔之百分比抑制。由藉由從各化合物之連續稀釋液獲得之結果的作圖所產生之濃度反應曲線計算IC5〇值。人類鼻病毒：使用BEASE2B細胞之IL-8釋放及ICAM1 表現 197 201130813 人類鼻病毒之備料（HRV16，獲自ATCC，Manassas' VA) was infected with HRV16 (MOI at 1) in DMEM containing 5% FCS and 1.5 mm MgCl2. After the incubation for 1 hour at 33 ° C for adsorption, the supernatant was aspirated, fresh medium was added and the cells were cultured for another 4 days. The cells were pre-incubated with test compound or DMSO for 2 hours' which was added again after flushing out the virus. The supernatant was aspirated and the cells were incubated with an indigo solution (2 〇/〇 aldehyde, 〇〇〇〇 /0 曱〇 and 175 175 〇 / 〇 methylene blue) for 2 hours at RT. After washing, 1% SDS was added to each well' and the disks were gently shaken for 1 to 2 hours before reading the absorbance at 660 nm. Calculate the percent inhibition of each well. The IC5 〇 value was calculated from the concentration response curve generated by plotting the results obtained from serial dilutions of each compound. Human rhinovirus: IL-8 release and ICAM1 expression using BEASE2B cells 197 201130813 Preparation of human rhinovirus (HRV16, obtained from ATCC,

Manassas，VA)係用HRV感染Hela細胞直到80%之細胞有細胞病變而產生。將BEAS2B細胞用病毒感染於5 之MOI且為了吸附在33°C下培養2小時並溫和搖動。 HRV感染之前2小時及感染之後2小時當剩餘細胞外 HRV被洗掉時添加試驗化合物。然後將細胞用PBS洗滌，添加新鮮的培養基且將細胞培養另72小時。收集上澄液用於使用Duoset ELISA發展套組（R&D Systems，Minneapolis，MN)的 IL-8 濃度之分析。在細胞表面之IC AM -1表現的含量係以細胞為基礎的ELISA測定。適當培養之後，將細胞用在PBS中之 4%甲醛固定。藉由添加0.1%疊氮化鈉及1%過氧化氫淬滅内源性過氧化物酶之後，將該等孔用緩衝液（在 PBS中之0.05%Tween : PBS-Tween)洗條。用封閉液(在 PBS-Tween中之5°/〇牛奶經1小時)培養之後，將細胞用在 5%BSA PBS-Tween (1 : 500)中之抗人類 ICAM-1 抗體培養過夜。然後將該等孔用PBS-Tween洗滌並用二級抗體(HRP-結合之抗兔子IgG，DakoLtd.)培養。以添加受體檢測之ICAM-1信號及光密度係使用光譜儀於 450奈米的波長及於655奈米的參考波長讀取。然後將該等孔用PBS-Tween洗滌及各孔中的總細胞數係藉由結晶紫染色及以1% SDS溶液溶析之後讀取於595 奈米的吸光度測定。藉由除以在各孔中〇D595讀數，測得之OD45G-655讀數校正細胞數。 LPS誘發之TNF α釋放：效力 198 201130813 藉由°卜嚇醇肉立宼酸乙酸g旨（ph〇rbol myristate acetate)(PMA; 100奈克/毫升)培養48至72小時將U937 細胞（人單核細胞系株）分化成巨噬細胞型細胞。需要時’將細胞用最後濃度之化合物預培養2小時。然後用0.1微克/毫升的LPS (來自大腸桿菌：〇iii:b4，Sigma) 將細胞刺激4小時’並收集上澄液用於以三明治型 ELISA(Duo-set ’ R&D 系統）測定 TNFa 濃度。TNFa 產生之百分比抑制係藉由與比較媒液對照組計算為於試驗化合物之各濃度的10微克/毫升BIRB 796之相對值，及相對於10微克/毫升BIRB 796之50%有效遭度值(R-ECsq :相對-ECso)係從所產生之濃度-反應曲線測定。在d-U937細胞中之MTT分析將分化型U937細胞用化合物預培養4小時、在 5%FCS或10%FCS培養24小時及72小時。用200微升新培養基替換上澄液並將1〇微升的MTT儲備液(5 毫克/毫升)加至各孔。培養1小時之後，移除培養基，將200微升的DMSO加至各孔且在讀取於550奈米的吸光度之前將等該盤輕搖1小時。計算各孔相對於媒液 (0.5%DMSO)-治療之細胞存活率的損失百分比。結果相對於媒液之藥物治療，細胞存活率之明顯增加係表列為負百分比值。在MDCK細胞中之MTT分析將MDCK細胞用化合物在包含1,5微克/毫升 199 WCK處理之胰蛋白的無FCS培養基中培養54小時。然後將細胞用10%FCS DMEM洗滌，及在包含0.25毫克/毫升MTT之1〇〇/〇FCSDMEM中培養2小時。然後移除培養基，將200微升的DMSO加至各孔。且在讀取於550奈米的吸光度之前將等該盤輕搖1小時。活體内試驗··在老鼠肺中之流感病毒量首先將小鼠（η = 6每組)在香煙煙霧中暴露14天 (母天3次）。在第15天用流感(Η3Ν1 Memphis 71)將動物鼻内劑量。在第14、15、16、17及18天用2微克的化合物實例1或媒液將動物氣管内劑量每天一次。在第18天將動物犧牲及取得肺以使用噬菌斑檢定估計病毒滴定度。將連續稀釋液加至接近匯合之細胞單層。感染一小之後將單層用設定的溶化洋菜糖覆蓋且用流感培養細胞，然後將細胞固定在曱醛中且接著用染料染色。計算菌斑及以菌斑形成單位(pfu)測定滴定度。活體内試驗：在小鼠肺中由流感感染產生之死亡率雌性BALB/c小鼠（17-19克)係從查爾斯河實驗室 (Charles River Laboratories) (Wilmington，MA)獲得且在使用之前隔離48小時。以i.p.注射克他明（ketamine)/嗟拉嗪(xylazine)(50/5毫克/公斤）麻醉小鼠且然後用流感病毒’ A/NWS/33(H1N1 ; 90微升）的懸浮液鼻内感染 (i.n.)。傳染病接種為約135 CCID%/小鼠。在病毒攻擊之前24小時開始（天-1至天+4)，將化合物實例1的水懸浮液(1.0毫克/毫升，等於5.5毫克/公斤/天)及安慰 200 201130813 劑投予i.M5〇微升卜天二次經6天。在第〇天，病毒感染之前2小時給予劑量以使不干擾初始感染方法。將奥塞米韋（osdtamivir)-天D服投予二次經相同的時間周期。將十隻藥物治療之“小鼠及1()隻安慰劑治療之對照組㈣並每天觀察一❹彳0天死亡發生。包括* 10隻未錢之未治療Μ㈣的正常對照組用於體重比較。存活動物數之成對比㈣以雙尾費雪精準檢定分析。存活曲綠分析係使用 Gehan-Breslow-Wilcoxon 檢定實施。結果下述數據(表1)証明：化合物實例1以在2_5〇 nM範圍内之ICw值一貫地抑制CPE，當細胞用流感病毒接種之前2小時用試驗化合物治療時。病毒菌株對札那馬韋(zanamavir)之敏感性顯示較大可變性，且流感B對神經胺糖酸苷酶抑制劑特別不敏感。數據進一步証明： BIRB 796顯示對抗病毒誘發之血球凝集素 (haemaglutinnin)表現的適中活性但是對抵抗病毒誘發之核蛋白質表現或CPE並沒有一貫地可檢測活性。因為化合物實例1顯示在MDCK細胞中與扎那米韋相同或較佳的效力，所以證實在初生人類支氣管上皮細胞之效力（表2)。表1 ··扎那米韋、BIRB 796及化合物實例1對流感誘發之jk球凝集素（haemaglutinnin)及核蛋白質表現及對 CPE的效果 201 201130813 試驗化合物(nM)之R-EC5〇及[CC5Qal值病毒株分析扎那米韋 BIRB 796 實例1 Him，PR8 lb 16 118 5 Him，PR8 2C 43 >2000 11 H1N1，PR8 3d 45 1368 30 Him， A/WSN/33 3 87 NTe 50 H3N2， A/Wuhan/359 3 5 >2000 19 /95 流感B 3 . 395 >2000 2 無 MTTf [>29000] [9335] [1422] a) 50%細胞毒濃度；b)藉由ELISA之血球凝集素 (haemaglutinnin)的表現；c)藉由ELISA之核蛋白質的表現；d)病毒誘發之細胞病變效應(CPE) ; e)不測試； f)在MDCK細胞中進行之分析表2 :扎那米韋及化合物實例1對3D培養之初生支氣管上皮細胞中的流感病毒量之效果。治療濃度 (微克/毫升） Log TCID50 / 20微升 (平均土 SEM) 統計分析 ρ值a 沒有感染 - H1N1 對照組 11.0 ±0.61 化合物實 1 8.2 士0.60 p<0.001 例1 _ 0.1 一 9.2 ±0.62 p<0.05 202 201130813 扎那米韋 0.01 0.001 1 0.10.010.001 10.0 ±0.00 10.6 ±0.20Manassas, VA) infects HeLa cells with HRV until 80% of the cells have cytopathic effects. BEAS2B cells were infected with virus at an MOI of 5 and cultured for 2 hours at 33 ° C for gentle adsorption and gently shaken. Test compounds were added 2 hours before HRV infection and 2 hours after infection when the remaining extracellular HRV was washed away. The cells were then washed with PBS, fresh medium was added and the cells were incubated for an additional 72 hours. The supernatant was collected for analysis of the IL-8 concentration using the Duoset ELISA Development Kit (R&D Systems, Minneapolis, MN). The amount of IC AM-1 expression on the cell surface is determined by a cell-based ELISA. After appropriate incubation, the cells were fixed with 4% formaldehyde in PBS. After quenching the endogenous peroxidase by the addition of 0.1% sodium azide and 1% hydrogen peroxide, the wells were washed with buffer (0.05% Tween in PBS: PBS-Tween). After culturing with blocking solution (5 °/〇 milk in PBS-Tween for 1 hour), the cells were cultured overnight with anti-human ICAM-1 antibody in 5% BSA PBS-Tween (1:500). The wells were then washed with PBS-Tween and cultured with a secondary antibody (HRP-conjugated anti-rabbit IgG, Dako Ltd.). The ICAM-1 signal and optical density detected by the addition of the receptor were read using a spectrometer at a wavelength of 450 nm and a reference wavelength of 655 nm. The wells were then washed with PBS-Tween and the total number of cells in each well was determined by staining with crystal violet and elution in a 1% SDS solution and reading at 595 nm. The number of cells was corrected by dividing the OD45G-655 reading by 除D595 reading in each well. LPS-induced TNF alpha release: potency 198 201130813 U937 cells (personal single) cultured for 48 to 72 hours by ph〇rbol myristate acetate (PMA; 100 ng/ml) The nuclear cell line strain differentiates into macrophage type cells. The cells were pre-incubated with the final concentration of the compound for 2 hours as needed. The cells were then stimulated with 0.1 μg/ml LPS (from E. coli: 〇iii: b4, Sigma) for 4 hours' and the supernatant was collected for determination of TNFa concentration by sandwich ELISA (Duo-set 'R&D system) . The percent inhibition of TNFa production was calculated as the relative value of 10 μg/ml BIRB 796 for each concentration of the test compound and 50% effective for 10 μg/ml BIRB 796 by comparison with the vehicle control group ( R-ECsq: relative-ECso) is determined from the concentration-response curve produced. MTT assay in d-U937 cells Differentiated U937 cells were preincubated with compounds for 4 hours, incubated at 5% FCS or 10% FCS for 24 hours and 72 hours. Replace the supernatant with 200 μl of new medium and add 1 μL of MTT stock (5 mg/ml) to each well. After 1 hour of incubation, the medium was removed, 200 microliters of DMSO was added to each well and the plate was shaken for 1 hour before reading the absorbance at 550 nm. The percent loss of cell survival for each well relative to vehicle (0.5% DMSO)-treated cells was calculated. As a result, a significant increase in cell viability was shown as a negative percentage value compared to vehicle-based drug therapy. MTT assay in MDCK cells MDCK cells were cultured with compounds in FCS-free medium containing 1,5 μg/ml of 199 WCK-treated trypsin for 54 hours. The cells were then washed with 10% FCS DMEM and incubated for 2 hours in 1 〇〇/〇FCSDMEM containing 0.25 mg/ml MTT. The medium was then removed and 200 microliters of DMSO was added to each well. The plate was then shaken for 1 hour before reading the absorbance at 550 nm. In vivo test · Amount of influenza virus in the lungs of mice First, mice (η = 6 per group) were exposed to cigarette smoke for 14 days (3 times for mother's day). The intranasal dose of the animal was administered with flu (Η3Ν1 Memphis 71) on day 15. Intratracheal doses of animals were administered once daily on days 14, 15, 16, 17 and 18 with 2 micrograms of Compound Example 1 or vehicle. Animals were sacrificed and lungs were harvested on day 18 to estimate viral titers using plaque assays. Serial dilutions were added to the confluent cell monolayer. After a small infection, the monolayer was covered with the set dissolved canola sugar and the cells were cultured with influenza, and then the cells were fixed in furfural and then dyed with a dye. The plaque was counted and the titer was determined in plaque forming units (pfu). In vivo test: Mortality from influenza infection in mouse lungs Female BALB/c mice (17-19 g) were obtained from Charles River Laboratories (Wilmington, MA) and isolated prior to use. 48 hours. Mice were anesthetized with ip injection of ketamine/xylazine (50/5 mg/kg) and then intranasally with a suspension of influenza virus 'A/NWS/33 (H1N1; 90 μl) Infection (in). The infectious disease was inoculated to approximately 135 CCID%/mouse. Starting from 24 hours before the virus challenge (day-1 to day +4), the aqueous suspension of Compound Example 1 (1.0 mg/ml, equal to 5.5 mg/kg/day) and the comfort of 200 201130813 were administered to i.M5〇. Microliters of Butian twice a day for 6 days. On day 13, the dose was administered 2 hours prior to viral infection so as not to interfere with the initial infection method. Osemide (osdtamivir)-day D was administered twice for the same period of time. Ten drug-treated "mouse and 1 () placebo-treated control group (four) were observed daily for one day of death. The normal control group including *10 untreated untreated sputum (four) was used for weight comparison. The comparison of the number of surviving animals (4) was analyzed by two-tailed Fisher's precision test. The survival curve analysis was carried out using the Gehan-Breslow-Wilcoxon test. Results The following data (Table 1) proved that the compound example 1 was in the range of 2_5〇nM. The ICw value within the strain consistently inhibits CPE, when the cells are treated with the test compound 2 hours prior to inoculation with the influenza virus. The sensitivity of the viral strain to zanamavir shows greater variability, and influenza B versus ceramide The glucosidase inhibitors are particularly insensitive. The data further demonstrate that BIRB 796 shows moderate activity against viral-induced haemaglutinnin but has no consistent detectable activity against viral-induced nuclear protein expression or CPE. Compound Example 1 shows the same or better potency as zanamivir in MDCK cells, thus confirming the efficacy in nascent human bronchial epithelial cells (Table 2) Table 1 · · Zanamivir, BIRB 796 and Compound Example 1 for influenza-induced jk glutinin and nuclear protein performance and effect on CPE 201 201130813 Test compound (nM) R-EC5〇 [CC5Qal value strain analysis zanamivir BIRB 796 Example 1 Him, PR8 lb 16 118 5 Him, PR8 2C 43 > 2000 11 H1N1, PR8 3d 45 1368 30 Him, A/WSN/33 3 87 NTe 50 H3N2, A/Wuhan/359 3 5 >2000 19 /95 Influenza B 3 . 395 > 2000 2 No MTTf [>29000] [9332] a) 50% cytotoxic concentration; b) blood cells by ELISA Performance of haemaglutinnin; c) expression of nuclear proteins by ELISA; d) virus-induced cytopathic effect (CPE); e) no test; f) analysis in MDCK cells Table 2: Zana Effect of Miver and Compound Example 1 on the amount of influenza virus in primary bronchial epithelial cells cultured in 3D. Treatment concentration (μg/ml) Log TCID50 / 20 μl (average soil SEM) Statistical analysis ρ value a No infection - H1N1 control Group 11.0 ± 0.61 Compound 1 8.2 ± 0.60 p < 0.001 Case 1 _ 0.1 A 9.2 ±0.62 p<0.05 202 201130813 zanamivir 0.01 0.001 1 0.10.010.001 10.0 ±0.00 10.6 ±0.20

NS NS 5.3 ±0.33_ 7.8 土0.40 8,7 土〇·互二 9.9 ±0.24~~NS NS 5.3 ±0.33_ 7.8 Soil 0.40 8,7 Soils and mutual two 9.9 ±0.24~~

P50.0Q1 P50.001 _£<0.0! NS a)與H1N1對照組比較之p值（單程Ann〇va，杜納多重比較檢定(Dunnett’s multiple comparison test)) 為了證實試管内研究之相關性，在小鼠中活體内評估化合物實例1抑制流感病毒量之能力。對抗流感 H3N1’Memphis 71株之所得結果顯示於下（表3)並証明相較於媒液對照組，治療導致約80%之病毒量減少。數據提示以一次/天劑量方案用式(I)化合物治療可有效治療流感^ 表3 .用化合物貫例1治療對小鼠肺中病毒量的效果治療肺病毒量 — DfU/ 克肺組織（X 106)P50.0Q1 P50.001 _£<0.0! NS a) p-value compared to the H1N1 control group (one-way Ann〇va, Dunnett's multiple comparison test) To confirm the relevance of in vitro studies, The ability of Compound Example 1 to inhibit the amount of influenza virus was evaluated in vivo in mice. The results obtained against the influenza H3N1'Memphis 71 strain are shown below (Table 3) and it is demonstrated that the treatment resulted in a reduction in virus amount of about 80% compared to the vehicle control group. The data suggest that treatment with a compound of formula (I) in a one-day/dose regimen is effective in treating influenza. Table 3. Effect of treatment with compound Example 1 on the amount of virus in the lungs of mice. Treatment of lung virus volume - DfU / gram lung tissue (X 106)

媒液 46.6 ± 16.6 在這些系統中也已經評估其他式(I)化合物的例子之活性且發現共有試管内對流感病毒繁殖的抑制之能 f。從這些研究獲得之結果歸納如下（表4)。治療的保護效果與MTT分析中之MDCK細胞内的毒性之任何證據無關。化合物抑制流感誘發之CPE之效力與其抑制 203 201130813 d-U937細胞釋放LPS誘發之TNFa的能力之間沒有明顯的關係。表4 :試驗化合物對LPS誘發之TNFa釋放、對流感誘發之CPE及其細胞耐受性的效果。試驗化合物 LPS誘發之流感誘發之 TNFa釋放 CPEb MTT分析實例編號 R-EC5〇 (nM) IC5〇 (nM) d-U937 細胞' MDCK 細胞e 1 0.88 6 -ve -ve 2 39 11 -ve -ve 16 2.9 166 +ve -ve 17 5.3 64 -ve -ve 20 2.8 486* —+ve -ve 40 41 97 -ve -ve 49 1.6 32 +ve -ve a)在d-U937細胞實施之分析；b)參見方法3 ; c) <30%= -ve ;〉30%= +ve ; d)筛選於1〇微克/毫升經μ 小時；e)篩選於0.2微克/毫升；*線性回歸。此外，發現：包含化合物實例丨及神經抑制劑札那米韋(Zanamivir)之組合治療，涵 ^人物之0.32 - 40奈克/毫升的濃度範圍，產生活性的^上增加。抗病毒活性的增加程度為兩種藥用之特徵(參見表4及圖1}。化合物實 _冋= -起之組合治療的有利效果特別值得注意，因上物可經由吸人路徑奸，所以產生將二種化合物 204 201130813 一起而提供單一組合產品的機會。化合物實例1及神經醯胺酶抑制劑之間的協同作用’試管内觀察，已藉由評估小鼠感染流感病毒之後的死亡率進一步活體内研究 (圖 2)。神經胺糖酸苷酶抑制劑當使用於治療流感時在達成臨床利益之效用係與相對於感染之劑量開始的時機有關鍵性關聯。此顯示為當藥物治療以預防性給予時達成更大的臨床利益，如在確定感染之後的期間發生效力的迅速減少，與延遲治療的開始。表5 :化合物實例丨及扎那馬韋之組合的預防治療感病毒誘發之血球凝集素表現的效果。机 [扎那米韋] (奈克 /毫升） 40 1.6 【I军駟龚伞Vehicle liquid 46.6 ± 16.6 The activity of other examples of the compound of formula (I) has also been evaluated in these systems and the ability to inhibit the proliferation of influenza virus in a test tube has been found f. The results obtained from these studies are summarized below (Table 4). The protective effect of the treatment was not related to any evidence of toxicity in MDCK cells in the MTT assay. Compounds inhibit the efficacy of influenza-induced CPE and its inhibition 203 201130813 There is no significant relationship between the ability of d-U937 cells to release LPS-induced TNFa. Table 4: Effect of test compounds on LPS-induced TNFa release, on influenza induced CPE and its cellular tolerance. Test compound LPS-induced influenza-induced TNFa release CPEb MTT assay Example number R-EC5〇(nM) IC5〇(nM) d-U937 cells 'MDCK cells e 1 0.88 6 -ve -ve 2 39 11 -ve -ve 16 2.9 166 +ve -ve 17 5.3 64 -ve -ve 20 2.8 486* —+ve -ve 40 41 97 -ve -ve 49 1.6 32 +ve -ve a) Analysis performed on d-U937 cells; b) See also Method 3; c) <30% = -ve; >30% = +ve; d) Screened at 1 μg/ml for μ hours; e) Screened at 0.2 μg/ml; * Linear regression. In addition, it was found that a combination treatment comprising a compound example and a neuroinhibitor Zanamivir, which has a concentration range of 0.32 - 40 Ng/ml, increases the activity. The degree of increase in antiviral activity is characteristic of two medicinal properties (see Table 4 and Figure 1). The beneficial effects of the combination therapy of the compound _冋 = are particularly noteworthy, because the upper substance can be smothered through the inhalation path, so The opportunity to provide a single combination of the two compounds 204 201130813 is produced. Synergistic effect between compound example 1 and a neuroguanamine inhibitor 'in vitro, has been further evaluated by assessing the mortality of mice after infection with influenza virus In vivo studies (Figure 2). The effects of a neuroglycosidase inhibitor when it comes to treating the flu in achieving a clinical benefit are critically related to the timing of the dose relative to the infection. This is shown as A greater clinical benefit is achieved in prophylactic administration, such as a rapid decrease in efficacy during the period following the determination of infection, and the onset of delayed treatment. Table 5: Combination of Compound Examples and Combinations of Zanamavir for the Prevention of Sense of Virus Induction The effect of hemagglutinin performance. Machine [Zanamiwei] (Nike / ml) 40 1.6 [I Army Gong Gong Umbrella

8 0.32 08 0.32 0

100 77 74 88 76 72 91 89 84 87 80 60 85 47 54 管試治療利益之時間依賴性可由文變病毒接 205 201130813 w及藥物的投予時間之相對時間模擬。神經胺糖酸苷酶 2制劑，效力之顯著時間依賴性損失顯示為相對於用病毒感染，治療被逐步延遲。對比於以下揭示之結果，（圖 3)，其係使方法3獲得，指示當暴露於病毒24時後治療開始時，用式(I)之化合物治療持續証明顯著利益。除此之外，結果顯示式(I)化合物與神經胺糖酸苷酶抑制劑之組合顯示顯著優於單獨用任一藥物治療之效果。臨床利益的時間依賴性對治療劑量之開始可在小鼠中藉由改變病毒接種及藥物投予的開始之間的相對時間模擬。此處所揭示之結果証明延遲用神經胺糖酸苷酶抑制劑治療導致防止病毒感染之副作用的損失。對照於用包含式(I)化合物與神經胺糖酸苷酶抑制劑之組合治療，導致保護效果的維持。下面提出的數據(表6)顯示式(I)化合物的選擇例子試管内對抗包括RSV及HRV-16之病毒片之輪廓。表6 :試管内式(I)化合物的你丨早對枕癍卷只之活性。在細胞分析中之ICa值a(nM)及所指示之病毒 RSV HRV 流感(PR8) 實例編號 F-ELIS CPEC IL-8d ICAM- CPEe CPEe 1 41 341.2 1.0 >1689 6 7.3 2 nt >346 nt nt 11 92 40 102.8 nt nt nt 97 74.0 20 nt >320 nt nt 486 >320 52 nt 2.9 0.019 nt 1.3 7.9 206 201130813 55 nt 9.5 0.069 nt 1.7 4.6 54 nt 9.4 0.04 0.098 1.0 2.4 53 71.7%f 24.0 0.12 0.029 0.79 nt 58 nt 16.0 nt nt 0.72 nt a)數據以1-4個複製觀察的平均顯示；b)使用NBEC 細胞且如下實施之實驗；c) MRC5細胞；d) BEAS2B 細胞；e)MDCK細胞；〇於0.04微克/毫升之濃度達成的％抑制；nt，不測試發現化合物實例1抑制從用RSV感染之初生3D 鼻上皮細胞釋放IL-8(圖4)並抑制在相同細胞中的病毒量（圖5)。在說明書及下列申請專利範圍整篇中，除非上下文另有要求，字‘包含’，及變化(諸如‘包含(comprises)’及 4包含(comprising)’，應了解暗示包含所述整數、步驟、整數組、步驟組在内但不排除包含任何的其他整數、步驟、整數組、步驟組在内。本發明說明書整篇中提及之所有專利及專利申請案以其全文引用之方式併入本文中。本發明包含較佳與更佳群組及適當與更適當的群組及以上引述的具體實例之組合。 207 201130813 【圖式簡單說明】圖1顯示用化合物實例1和札那馬韋(zanamavir)組合預防性治療對流感誘發之血球凝集素(haemaglutinnin) 表現的效果，使用方法1評估。圖2顯示由用化合物實例1及奥塞米韋(oseltamivir) 之單獨和組合治療產生的存活曲線，根據在老鼠中流感 A/NWS/33(H1N1)病毒感染之後的死亡率。圖3顯示於用流感病毒接種2或24小時之後由用扎那馬韋（圖3a)或化合物實例1(圖3b)治療產生的對 CPE之效果，如以MTT分析評估。圖4顯示用化合物實例1治療所產生之在初生3D 培養之鼻上皮細胞中RSV Memphis 37誘發之IL-8釋放。圖5顯示用化合物實例1治療所產生之在初生3D 培養之鼻上皮細胞中RSV Memphis ；37病毒量。【主要元件符號說明】無 208100 77 74 88 76 72 91 89 84 87 80 60 85 47 54 The time dependence of the therapeutic benefit can be modeled by the relative time of the administration of the virus and the time of administration of the drug. The neuraminidase 2 formulation, a significant time-dependent loss in potency, was shown to be progressively delayed relative to infection with the virus. In contrast to the results disclosed below, (Fig. 3), which resulted in Method 3, indicating that treatment with a compound of formula (I) continued to demonstrate significant benefit when treatment was initiated upon exposure to virus 24. In addition, the results show that the combination of the compound of the formula (I) and the neuraminidase inhibitor shows a significantly better effect than the treatment with either drug alone. The time dependence of clinical benefit on the start of the therapeutic dose can be simulated in mice by changing the relative time between viral vaccination and the onset of drug administration. The results disclosed herein demonstrate that delaying treatment with a neuraminidase inhibitor results in a loss of side effects from viral infection. The control is treated with a combination comprising a compound of formula (I) and a neuraminidase inhibitor, resulting in maintenance of the protective effect. The data presented below (Table 6) shows examples of selection of compounds of formula (I) in vitro against the contours of viral tablets including RSV and HRV-16. Table 6: The activity of the compound of formula (I) in the test tube to your pillow. ICa value a (nM) in the cell analysis and the indicated virus RSV HRV influenza (PR8) Example number F-ELIS CPEC IL-8d ICAM- CPEe CPEe 1 41 341.2 1.0 >1689 6 7.3 2 nt >346 nt Nt 11 92 40 102.8 nt nt nt 97 74.0 20 nt >320 nt nt 486 >320 52 nt 2.9 0.019 nt 1.3 7.9 206 201130813 55 nt 9.5 0.069 nt 1.7 4.6 54 nt 9.4 0.04 0.098 1.0 2.4 53 71.7% f 24.0 0.12 0.029 0.79 nt 58 nt 16.0 nt nt 0.72 nt a) Data are shown as an average of 1-4 replicate observations; b) experiments performed using NBEC cells as follows; c) MRC5 cells; d) BEAS2B cells; e) MDCK cells; % inhibition achieved at a concentration of 0.04 μg/ml; nt, no test found that Example 1 inhibits the release of IL-8 from naive 3D nasal epithelial cells infected with RSV (Fig. 4) and inhibits the amount of virus in the same cells ( Figure 5). Throughout the specification and the following claims, the word 'comprising' and variations (such as 'comprises' and 4 'comprising'', unless the context requires otherwise, should be understood to include the integers, steps, The entire array, the group of steps, but not including any other integers, steps, integer groups, step groups, etc. All patents and patent applications mentioned in the entire specification of the present specification are hereby incorporated by reference in its entirety. The present invention comprises a combination of preferred and better groups and appropriate and more suitable groups and the specific examples cited above. 207 201130813 [Simplified Schematic] Figure 1 shows the use of Compound Example 1 and Zanamavir ( The effect of zanamavir combined prophylactic treatment on influenza-induced hemagglutinin expression was assessed using Method 1. Figure 2 shows the survival curves produced by treatment with Compound Example 1 and oseltamivir alone and in combination. According to the mortality rate of influenza A/NWS/33 (H1N1) virus infection in mice. Figure 3 shows the use of the influenza virus after 2 or 24 hours of inoculation. The effect of treatment with Marve (Fig. 3a) or Compound Example 1 (Fig. 3b) on CPE was assessed by MTT assay. Figure 4 shows RSV Memphis in nasal epithelial cells produced in primiparous 3D cultures treated with Compound Example 1. 37 Induced IL-8 release Figure 5 shows the amount of RSV Memphis; 37 virus produced in primary 3D cultured nasal epithelial cells treated with Compound Example 1. [Key Symbol Description] No 208

Claims

201130813 七、甲請專利範圍： L 一種用於治療或預防病毒感染之式⑴化合物：201130813 VII. A patent scope: L A compound of formula (1) used to treat or prevent viral infections:

其2中R1為視需要經羥基基團取代之Ci 6烷基； R3 或視需要經羥基基團取代之Ci_6烷基； R為Η、CN6烷基或Cq_3烷基c3 6環烷基； Ar為萘基或苯基環，其任—可視需要經—或多個基團 (例如1至3個’諸如卜2或3個基團）獨立地選自cN6 燒基、C!·6烷氧基、胺基、Ci·4單或c28二-烷胺基取代； —為飽和或不姊支鏈或非支鏈c18躲基鏈，其中 =或多個碳(例如！至3個，諸如卜2或3個碳)視需要心〇_置換及該鍵視需要經一或多個鹵素原子(例如1至 6個)取代； Χ為包含至少—個氮原子且視需要包括1或2個選自 0、S及Ν之另外雜原子之5或6員雜芳基； Q係選自： —個碳(例如1、2或3個碳 1個碳)係經選自〇、N、視需要地經一或客偷罝HI .丨 a)飽和或㈣和域或較鏈‘院基鏈，其中至少Wherein R1 is a Ci 6 alkyl group optionally substituted by a hydroxyl group; R3 or a Ci_6 alkyl group optionally substituted by a hydroxyl group; R is an anthracene, a CN6 alkyl group or a Cq_3 alkyl c3 6 cycloalkyl group; Is a naphthyl or phenyl ring, which may optionally be selected from - or a plurality of groups (for example, 1 to 3 'such as 2 or 3 groups) independently selected from cN6 alkyl, C! 6 alkoxy a group, an amine group, a Ci. 4 mono or a c28 di-alkylamino group; a saturated or unbranched branched or unbranched c18 group, wherein = or more carbons (eg, up to 3, such as 2 or 3 carbons) If necessary, the substitution and substitution of the bond by one or more halogen atoms (for example, 1 to 6); Χ containing at least one nitrogen atom and optionally including 1 or 2 5 or 6 membered heteroaryl groups from 0, S and 杂 other heteroatoms; Q series selected from: - a carbon (eg 1, 2 or 3 carbons and 1 carbon) selected from 〇, N, as needed The ground is one or the guest steals HI.丨a) saturated or (four) and the domain or the chain of the 'hospital base chain, at least

自〇 N、S(0)p之雜原子置換，其中該鏈或多個基團（例如1、2或3個基團）獨立地鹵素、芳某、躲芏盆、攸@ a > 、芳基、雜芳基、雜環基或c3_8環烷選自側氧基、齒素、芳基、基取代， 209 201130813 β #芳基、雜芳基、雜環基或C3_8環烷基具有0至3個選自函素私基、〇)!·6统基、Ci _6烧氧基、Ci-6鹵烧基、胺基、Cl·4單或C2-8二-烷胺基、Q-4單或C2_8二-醯基胺基、S(〇)qCV6烧基、Cq 6烷基C(〇)Ci 6烧基或C()-6烷基 0(〇)^·6雜烷基之取代基，其先決條件為直接地連接至-NR3C(0)-中之羰基的原子不為氧或硫原子；及 b) c〇_8院基·雜環，該雜環基包含至少一個雜原子(例如 1、2或3個，適當地1或2個，特別是丨個雜原子）選自〇、N及S，及其視需要經一、二或三個獨立地選自鹵素、羥基、Ci-6烷基、Cm烷氧基、Cw齒烷基、胺基、C!·4單及C2·8二-烷胺基、Ci 4單或c2 8:_醯基胺基、 SiCOqCw烷基、cQ6烷基c(〇)Ci6烷基、cG6烷基 C(0)NC〇_6烷基C〇_6烷基或q 6烷基C(0)C() 6雜烷基之基團取代；及 p為0、1或2 ; q為0、1或2 ;或或其醫藥上可接受的鹽或溶劑合物，包括其所有的立體異構物、互變異構物及同位素衍生物，其先決條件為式 (I)之化合物不為N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基 -lH-°比唑-5-基）脲基)萘·丨_基氧基)吡啶_2_基)_2_甲氧基乙醯Jk或其醤藥上可接受的鹽或溶劑合物。 2. 根據申請專利範圍第1項之用於治療或預防病毒感染之化合物’其中Ar為萘基。 3. 根據申請專利範圍第1或2項之用於治療或預防病毒感染之化合物，其中L為-〇ch2-或-0-。 210 201130813 4. 根據申請專利範圍第1至3項中任一項之用於治療或預防病毒感染之化合物，其中χ為吡啶基。、 5. 根據申請專利範圍第1至4項中任一項之用於治療或預防病毒感染之化合物，其中q為： a. C!-4烷基_V_R4，諸如Ci3烷基_Vr4 ，其中： V為選自1^乂、〇或8(〇)1)之雜原子； RV表示Η或Cm烷基； R為Η或-Cy烷基’及p如申請專利範圍第i項中所定義，其先決條件為包括置換雜原子之總烷基鏈長不大於10 個碳原子，及所得基團q為穩定基團； b. ci-3 烧基-V-(Ci-3 烧基-Z-R5)k 諸如 Cu 烧基_v_(c 烷基-Z-R5)k，其中： - V為選自N、NH、Ο或S(0)p之雜原子，（諸如N或NH (V為N，在其中k = 2之情況中，或將選自NH、〇或 s(〇)P，在其中k =1之情況中，特別是NH); Z為獨立地選自之NH、〇或s(〇)p ; R5為Η或-Cw烷基； k為整數1或2 (諸如1);及 P如申請專利範圍第1項中所定義，其先決條件為包括置換雜原子之總烷基鏈長不大於ι〇個碳原子及所得基團Q為穩定基團；或、 c· CN3 烷基-V-CK2 烷基-Z-Cy 烷基-Y-R6，或 Cw烧基-V-C2_3烷基-Z-C2_3烧基-Y-R6，其中 v、z及γ獨立地為選自NH、〇或s(〇)p之雜原子， R6為Η或甲基，及 ' 211 10 201130813^ 申§月專利範圍第1項中所定蠢其先決條件為包括置換雜原子 H 個碳原子及所得基團Q為穩〜〈〜烷基鏈長不大於 6.根據申請專利範園第广團治療或預防病毒感染之化人芏4項中任一項之用於 _nr3c(o)q形成脲，其中，8其中Q為-NR7R8及飽和或不飽和支鏈或非支"R獨立地表示氫或CU9 諸如卜2或3個視需要經=鍵’其中-或多個碳，子置換及’其中該鏈視需、— 自。、N或_p之雜原基、齒素、芳基、雜芳A私或多個獨立地選自側氧取代，各芳基、雜芳基基或&環烧基之基團專利範圍第1項中所定義之有0至3個如申請 7. 根據申清專利範圍第1 治療或預防病毒感染之化^1至4項中任—項之用於環，該雜環基基團包含至小，其中Q為-c〇-3烷基雜子，及視需要經-個或二個劣個選自0’及s之雜原請專利範圍第i項中所定義^個基團獨立地選自如申 8. 根據申請專利範圍第相關取代基取代。毒感染之化合物，其中Q ^項之用於治療或預防病團係經由碳連接。基雜環，其中雜環基 9. 根據申請專利範圍窜毒感染之化合物，其中項之用於治療或預防病 ^ ^ 芍、C〇烷基雜環，其中雜環基團包含-或夕個N原子且緩由 1 0.根據申請專利範圍筻，治療或預防病毒感染之化合物，項之用於 -CH2OH ；、 Q ‘、. 212 201130813 -CH^OCu 烷基’特別是-CH2OCH3 ; -CH2CH2OCH3 ; -CH20(CH2)20CH3 ； -CH(CH3)OCH3 ; -ch2nhch3 或-ch2n(ch3)2 -ch2nhch2ch2och3 或-ch2nhc(o)ch2och3 ; -CH2SCH3, -ch2s(o)2ch3 或 -ch2nhc(o)ch2s(o)2ch3 ;或 -CH2NHC(0)CH2。 11.在根據申請專利範圍第1至4項中任一項之用於治療或預防病毒感染之化合物中，其中式(I)中之片段 -NR3C(0)Q係以下列表示： -NR3C(0)CH20H，特別是-NHC(〇)CH2OH ; -NR^CXCOCHsOCu 烷基，特別是-NR3C(0)CH20CH3，尤其是-nhc(o)ch2och3 ; -nr3c(o)ch2o(ch2)2och3，特別是 -nhc(o)ch2o(ch2)2och3 ; -nr3c(o)ch(ch3)och3，特別是 -NHC(0)CH(CH3)0CH3 ; -nVcxc^ckkchonhCu 烷基，特另,J是 -nhc(o)ch(ch3)nhch3 ; -NreCCCOCHCCHONCC^ 烷基)2,特別是 -nhc(o)ch(ch3)n(ch3)2 ; -nr3c(o)c(ch3)2nhch3，特別是 -nhc(o)c(ch3)2nhch3 ; -Ni^CCOXCH^OCw烷基，諸如 213 201130813 NR3C(0)(CH2)2〇CH3，特別；^_NHC(〇)(CH2)2〇CH3 ; nWCCOXCHANHCh烷基，特別是 -NHC(0)(CH2)3NHCH3 ； NfC^OXCH^NCCw 烷基)2，特別是 -NHC(0)(CH2)3N(CH3)2 ; -Nf^CCC^Ci^NHCw 烧基，特別是_NHC(〇)CH2NHCH3; -nr3c(o)ch2nh(ch2)2och3，特別是 -nhc(o)ch2nh(ch2)2och3 ; -NR3C(0)CH2SCH3 ’ 特別是-NHC(〇)CH2SCH3 ; -nr3c(o)ch2s(ch2)2och3，特別是 -NHC(0)CH2S(CH2)20CH3 ; -NR3C(0)CH2S(CH2)2〇(CH2)2〇CH3，特別是 -NHC(0)CH2S(CH2)20(CH2)20CH3 -NR3C(0)CH2S0CH3 ’ 特別是-NHC(0)CH2S0CH3 -NR3C(0)CH2S(0)2CH3，特別是-NHC(0)CH2S(0)2CH3 ; -nr3c(o)ch2n[(ch2)2och3]2，特別是 -NHC(0)CH2N[(CH2)20CH3]2 ； -NR3C(0)NH2 ’ 特別是-NHC(0)NH2 ; -NWCCCONHCm 烷基，諸如 NR3C(0)NHCi_7 烷基，特別是-nhc(o)nhch3 -NR^CXC^IS^Cm烧基)Cu院基，特別是 -nhc(o)n(ch3)2 ;或 -nr3c(o)nhch2conh(ch2)2och3，特別是 -NHC(0)NHCH2C0NH(CH2)20CH3 ; -NHC(0)-(四氫派喃基），諸如-NHC(〇)-(四氫_2H-略喃 -4-基）： 214 201130813 -NHC(0)-(嗎啉基），諸如_NHC(〇)_(4_嗎啉基）或 -NHC(0)-(3-嗎啉基）； -NHC(0)-(吡咯啶基），諸如_NHc(〇)-(吡咯啶-1-基）； -NHC(0)-(哌啡基），諸如_NHC(0)-(哌畊-1-基）； -NHC(0)-(甲基哌畊基），諸如_Nhc(〇)-(4-曱基哌畊-1-基）； -NHC(0)-[(曱氧基乙基）哌畊基]，諸如_Nhc(0)-[4-(2-曱氧基乙基)旅。井-1-基]; -NHC(0)-(侧氧基咪唑啶基），諸如_NHc(〇)-(2-側氧基咪唑啶基），特別是-NHC(0)-(2-侧氧基咪唑啶-1-基）； -NHC(0)CH2_(四氫哌喃基），諸如_Nhc(o)ch2-(四氫 -2H-派喃-4-基）； -NHC(0)CH2-(嗎琳基），諸如-NHC(0)CH2-(4-嗎啉基）； -NHC(0)CH2·(吡咯啶基），諸如-NHC(0)CH2-(吡咯啶-1- 基）； -NHC(0)CH2-(哌畊基），諸如_NHC(0)CH2-(哌畊-1-基）； -NHC(0)CH2-(曱基旅σ井基），諸如-NHC(0)CH2-(4-曱基〇辰啡_ 1_基）， -NHC(0)CH2_[(曱氧基乙基）哌畊基]，諸如 -NHC(0)CH2-[4-(2-曱氧基乙基)派η井小基]； -nhc(o)ch2sch2ch2-(嗎啉基），諸如 -NHC(0)CH2SCH2CH2-(4-嗎啉基），或 -NHC(0)CH2SCH2CH2-(3-嗎啉基）；及 -NHC(0)CH2S02CH2CH2-(嗎啉基），諸如 -NHC(0)CH2S02CH2CH2-(4-嗎啉基），或 -NHC(0)CH2S02CH2CH2-(3_嗎啉基）。 215 201130813 12.種用於治療或預防病毒感染之化合物，其係選自：甲基4-((4-(3-(3-第三-丁基小對_曱苯基吡唑_5_基）脲基)萘-1-基氧基）甲基)n比啶_2_基脲； Ν-(4-((4-(3-(3-第三·丁基小對·曱苯基]Η_吡唑_5_基）脲基）备-1-基氧基）甲基）η比咬_2_基）四氮_211_0底0南_4•甲酿胺； (S)-N-(4-((4-(3-(3-第三·丁基 _丨_對_ 曱苯基·1Η -«>比哇基）脲基）萘-1-基氧基）甲基）吡啶_2_基）_2•曱氧基丙醯胺； (R)-N-(4-((4-(3-(3-第三-丁基小對_甲苯基_1Η_吡唑_5_ 基）脲基）萘-1-基氧基）曱基）吡啶_2_基)_2_甲氧基丙醯胺； Ν-(4-((4-(3-(3-第三-丁基小對_曱苯基·m_吡唑_5_基)脲基)萘-1-基氧基）曱基)》比啶_2-基)_2-(曱硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基小對·曱苯基_1H吡唑_5基)脲基)萘-1-基氧基）曱基)》比咬_2-基)-2-嗎琳基乙醯胺； N-(4-((4-(3-(3-第三-丁基_丨_對-甲苯基_m_吡唑_5_基）脲基）萘-1-基氧基）曱基）吡啶-2-基)-2-(吼咯啶-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-i_對-曱笨基-瓜吡唑：基)脲基)萘-1-基氧基）曱基)B比啶-2-基)-2-(4-曱基哌畊-1-基）乙醯胺； N-(4-((4-(3-(3-第三·丁基-1·對-甲苯基_1H_吡唑·5_基)脲基）萘-1-基氧基）曱基）°比啶-2-基)-2-(4-(2-曱氧基乙基) 哌畊-1-基）乙醯胺； 216 201130813 N-(4-((4-〇(3-第三·丁基4•對_曱苯基_1H_吡唑_5_基)脲基）萘-1-基氧基）〒基户比啶-2-基)-2-(2-甲氧基乙胺基）乙醯胺； Ν-(4·((4-(3-(3-第三-丁基·；^對_曱苯基_111_吡唑_5_基)脲基)萘-1-基氧基）甲基)吡啶-2-基)-2-(二f胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基q•對_曱苯基_1H_吡唑_5基)脲基)萘-1-基氧基）曱基)吼啶-2-基)-2-(曱胺基）乙醯胺； N-(4-((4-(3-(3-第三丁基_ι_對·曱苯基_1H•吡唑_5-基)脲基）萘-1-基氧基）甲基）¾啶_2_基）-2-((4-甲氧基苯甲基)（甲基)胺基）乙酿胺； 1-(4-((3-甲基脲基η比啶-4-基）曱氧基）萘_1_基)_3_(3_第三 -丁基-1-對-曱苯基唾-5-基)脲； Ν-(4·((4_(3-(3-第三-丁基_丨-對甲苯基-1H_吡唑_5_基）脲基)萘-1-基氧基）甲基)吼啶冬基)_2_曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基·ι_對-曱苯基·1H_吡唑_5_基)脲基)萘-1-基氧基）曱基)。比啶-3-基)-2-(2-甲氧基乙氧基）乙醯胺； Ν-(4_(2-(4·(3-(3•第三·丁基-1-對-曱苯基比。坐-5-基）脲基）萘-1-基氧基）乙基)吼。定-2-基)-2-甲氧基乙醯胺； N-(4-(2-(4-(3-(3•第三-丁基小對甲苯基_出_0比唑_5·基）脲基）萘-1-基氧基）乙基)吼啶-2-基)-2-(2-甲氧基乙氧基）乙酿胺， 4-(2-(4-(3-(3-第三-丁基_1_對-曱苯基-1H·-比唑-5-基）脲基)萘-1-基氧基）乙基)-1-曱基-3十比啶_2_基)脲； 4-(2-(4-(3-(3-第三-丁基_1_對-曱苯基-1H-吡唑-5-基）脲基)蔡_1·基氧基）乙基)-3-(°比咬-2-基)腺； 217 iN_(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η 比唑-5-基) 脲基）萘-1-基氧基）乙基)°比啶-3-基)-2-(2-曱氧基乙氧基) 乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-lH-η比唑-5-基）脲基）奈-1-基氧基）曱基)13密σ定-2-基)-2-曱氧基乙酿胺， N-(l-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基) 脲基）萘-1-基氧基）乙基)-1Η-咪唑-4-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-lH-η比唑-5-基）脲基）奈-1-基氧基）曱基)°比。定-2-基)-2-(曱續酿基）乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）曱基)°比β定-2-基)-2-經基乙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基）脲基）奈-1-基氧基）曱基）0比α定-2-基)-2-曱基-2-(曱胺基）丙醯胺； (S)-N-(4-((4-(3-(3-第三丁基-1 -對-曱苯基-1H-η比唑-5-基）脲基）萘-1-基氧基）曱基）。比啶-2-基)-2-(甲胺基）丙醯胺； (R) -N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1Η-»比唑-5-基)脈基）奈-1-基氧基）曱基)α比β定-2-基)嗎琳-3-甲酿胺， (S) -N-(4-((4-(3-(3-第三-丁基-1-對·曱笨基-1Η-吡唑-5-基)腺基)奈-1-基氧基）甲基)°比°定_2_基)嗎琳-3-曱酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）曱基)°比咬-2-基)-4-曱基〇辰0井-1-曱酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基)脲基）奈-1-基氧基）曱基)°比α定-2-基)嗎嚇·_4-曱酿胺， 218 201130813 N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）曱基)°比咬-2-基)-3 -曱氧基丙酷胺； 2-(3-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-。比唑-5-基）脲基）萘-1-基氧基）曱基）°比啶-2-基)脲基)-N-(2-曱氧基乙基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基乳基）曱基)π比°定-2-基)-4-(二曱胺基）丁蕴胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈_1_基氧基）曱基)σ比σ定-2-基)-3-(曱石黃酸基）丙酿胺， N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）曱基）°比咬-2-基)-3-(曱項酿基)-2-側氧咪唑咬-1-曱醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基）曱基）°比°定-2-基)-2-(曱亞績酿基）乙臨胺； N-(4-((4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基）奈_1_基氧基）曱基)°比σ定-2-基)-2-(2-曱氧基乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基)腺基）萘-1-基氧基）甲基)°比啶-2-基)-2-(2-(2-曱氧基乙氧基) 乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）萘-1-基氧基）曱基)°比啶-2-基)-2-(2-嗎啉基乙硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基）脲基）秦-1-基氧基）曱基)°比咬-2-基)-2-(2-嗎琳基乙石黃酿基） 219 201130813 酿胺， 2-(雙(2-曱氧基乙基）胺基)-N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-lH-η比唑-5-基）脲基）萘-1-基氧基）曱基）。比啶 -2-基）乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基) 脈基）奈-1-基氧基）乙基)°比咬-3-基)-2-曱氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-«比唑-5-基) 脈基）奈-1-基）乙氧基)ntba定-2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-» 比唑-5-基) 脈基）秦_1_基氧基）乙基)π比°定基)-2-曱氧基乙酿胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基) 腺基）秦基氧基)-2-曱基丙基)π比α定-2-基)-2-曱氧基乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基) 腺基）奈_1_基氧基）丙基)°比°定_2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基) 腺基）奈基氧基）丙-2-基比唆-2-基)-2 -曱氧基乙酿胺； N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-I-。比唑-5-基)脲基）奈-1-基氧基)-2-曱基丙-2-基彡吼咬-2-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-(4-(羥基曱基）苯基）-1Η-吼唑-5-基)脲基）萘-1-基氧基）曱基)吼啶-2-基)-2-曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）秦_1_基氧基)B比咬-2-基)-2-(曱續S篮基）乙酿胺或其醫藥上可接受的鹽，包括其所有的立體異構物、互 220 201130813 變異構物及同位素衍生物。在一具體實例中’根據該揭示之化合物為：曱基4-((4-(3-(3-第三-丁基-丨-對―曱苯基_1H_吡唑_5_基) 脲基)萘-1-基氧基）甲基)η比π定·2·基腺； Ν-(4-((4-(3-(3-第三-丁基小對_曱苯基心〆比唑_5_基)脲基）奈-1-基氧基）甲基）π比咬-2-基）四氫-2Η-旅喃-4-曱醯胺； (S)-N-(4-((4-(3-(3-第三-丁基_丨·對 _ 曱苯基]Η_α比唑 _5_ 基）脲基）萘-1-基氧基）曱基ρ比啶_2_基)_2_曱氧基丙醯胺； (r)_N-(4-((4-(3-(3-第三-丁基_丨_對_甲苯基_丨Η_σ比唑_5_ 基）脲基）萘-1-基氡基）甲基）η比啶_2_基)_2_曱氧基丙醯胺； Ν-(4-((4-(3-(3-第三，丁基_ι·對-曱苯基。比唾_5_基)腺基)奈-1-基氧基）曱基)吼啶_2_基)_2_(甲磺醯基）乙醯胺 Ν-(4-((4-(3-(3·第三-丁基-曱苯基]Η_π比嗤_5_基)腺基）萘-1-基氧基）曱基)吼啶-2-基)-2-羥基乙醯胺； Ν-(4·((4-(3-(3-第三-丁基___曱苯基吡唑_5基）脲基）萘-1-基氧基）曱基）吼啶-2-基)-2-甲基_2-(曱胺基）丙醯胺； (S)-N-(4-((4-(3_(3-第三-丁基小對_曱笨基_m吼唑_5_ 基)脲基)萘-1_基A基）甲基)D比咬_2_基)_2_(甲胺基）丙酿胺； ⑻-N-(4-((4-(3-(3-第三·丁基對-甲苯基·m•吼唑净基)腺基)奈-1-基氧基)曱基)吼唆-2·基)嗎琳_3_甲醯胺； (S)-N-(4-((4-(3-(3-t_丁基]_對_ 甲笨基.η 比唑 _5_ 221 脲基)萘-1-基氧基）甲基)吡啶-2-基)嗎啉-3-曱醯胺； Ν·(4-((4-(3-(3-第三-丁基_ι_對-甲苯基_1H_吡唑_5-基)脲基)萘-1-基氧基）甲基)。比啶_2·基)-4-甲基哌畊-1-甲醢胺； Ν-(4-((4·(3-(3-第三-丁基-1_對_曱苯基_1H_C比唑_5_基)脲基)萘-1-基氧基）曱基)η比啶_2·基)嗎啉_4_曱醯胺； Ν-(4-((4-(3-(3-第三-丁基_丨_對_曱苯基_1Η_吡唑_5_基)脲基)萘-1-基氧基）曱基)。比啶-2-基)-3-甲氧基丙醯胺； 2-(3-(4-((4-(3-(3-第三-丁基]_對_甲苯基-出』比0坐-5·基) 腺基）萘-1-基氧基）甲基）吡啶_2_基）脲基)_N_(2_曱氧基乙基）乙醯胺； N-(4-((4-(3-(3-第三-丁基-丨_對_甲苯基_1Η_β比唑_5•基)脲基)萘小基氧基）曱基)吼咬·2_基)_4_(二甲胺基)丁醯胺； N-(4-((4-(3-(3-第三-丁基4_對_甲苯基_1H_吡唑_5_基)脲基)萘-1-基氧基）曱基)吡啶-2_基)-3-(曱磺醯基）丙醯胺； N-(4-((4-(3-(3-第三-丁基_丨_對_曱苯基_1H_吡唑_5_基)脲基）萘-1-基氧基）曱基；Kb啶_2_基)-3-(曱磺醯基)-2-側氧咪嗤咬-1-曱醯胺； N-(4-((4-(3-(3-第三-丁基對·曱苯基_1]9[_吡唑_5_基)脲基)萘-1-基氧基）曱基)吡啶-2-基)-2-(曱硫基）乙醯胺； N-(4-((4-(3-(3-第三-丁基一-對·曱苯基“仏吡唑^基)脲基）萘-1-基氧基）甲基）吼啶基)-2-(曱亞磺醯基）乙醯胺； N-(4-((4-(3-(3-第三-丁基4_對_曱苯基_1H_吡唑_5•基)脲基)萘-1-基氧基）曱基)吡啶-2-基)-2-嗎啉基乙醯胺； N-(4-((4-(3-(3-第三-丁基·卜對-曱苯基·1H_吡唑_5•基)脲基）萘-1-基氧基）甲基；Kt咬-2-基)-2十比咯啶-1-基）乙醯 222 201130813 胺； Ν-(4-((4_(3·(3·第二·丁基]养曱苯基_1H“比峻_5_基)脲基)萘-1-基氧基）曱基)吼咬_2_基)_2普甲基旅〇井小基）乙醯胺； Ν-(4·((4-(3-(3-第二-丁基]•對_甲苯基_1H “比唾_5_基)脈基）萘-1·基氧基）甲基)dh2D_2_(4_(2甲氧基乙基）哌畊-1-基）乙醯胺； N-(4-((4-(3-(3-第三-丁基七對_甲笨基.吼嗤_5_基)腺基)萘-1-基氧基）曱基)吼咬-2_基)_2_(2_曱氧基乙胺基）乙醯胺； N-(4-((4-(3-(3-第三-丁基七對-甲笨基_m•吡唑_5_基）脲基)萘-1-基氧基)曱基Μ咬_2_基)_2_(二曱胺基）乙酿胺； Ν-(4-((4-(3-(3·第三-丁基小對.甲苯基•対_5•基)腺基)萘-1-基氧基)曱基)吼咬_2舟2•(曱胺基）乙酿胺； Ν-(4-((4_(3_(3_第三-丁基小對_甲苯基_1Ηκ5·基)脈基）萘-1-基氧基）曱基）吼啶_2_基）_2_((4·曱氧基笨曱基)（曱基)胺基）乙醯胺； Ν-(4-((4-(3-(3-第三-丁基小對_甲苯基_m_n比嗤_5基)腺基)萘小基氧基）曱基Κ咬_2_基)_2_(2·甲氧基乙硫基）乙醢胺； Ν-(4-((4·(3-(3-第三-丁基對-甲笨基“比嗤_5_基)腺基)萘-1-基氧基）曱基)吼咬_2舟Mm基乙氧基) 乙硫基）乙醯胺； Ν-(4·((4_(3-(3-第三-丁基]♦甲笨基_心比唾_5基)腺基)萘-1-基氧基）曱基)吼咬_2-基)-2-(2-嗎#基乙硫基）乙醯胺； 223 201130813 iN-(4-((4-(3-(3-第三-丁基-1-對·曱苯基-1H-吼唑-5-基）脲基)萘-1-基氧基）曱基)°比啶-2-基)-2-(2-嗎啉基乙磺醯基) 乙酿胺； 2-(雙(2_曱氧基乙基)胺基)-N-(4-((4-(3-(3-第三-丁基-1-對-曱本基-1H-°比嗤-5 -基）腺基）蔡-1-基氧基）甲基）比咬 -2-基）乙酿胺； 1-(4-((3-曱基脲基〇比啶-4-基）曱氧基）萘-1_基)-3-(3-第三丁基-1-對-甲苯基-1H-吡唑-5-基)脲； Ν-(4-((4-(3-(3·第三丁基-1-對·曱苯基-lH-η比唑-5-基)脲基)蔡·1_基氧基）曱基)°比啶-3-基)-2-甲氧基乙醯胺； Ν·(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基)萘-1-基氧基）曱基)°比啶-3-基)-2-(2-曱氧基乙氧基）乙醯胺； Ν-(4-(2-(4-(3·(3·第三丁基-1-對-曱苯基-1Η-»比唑-5-基) 腺基）奈-1-基氧基）乙基)D比咬-2-基)-2-曱氧基乙酿胺； N-(4-(2-(4-(3-(3-第三-丁基小對-曱苯基-1Η-»比唑-5-基) 脲基）萘-1-基氧基）乙基)》比啶-2-基)-2-(2-曱氧基乙氧基) 乙醯胺； 4-(2-(4-(3-(3-第三丁基-1-對-曱苯基·1Η-η比唑-5-基）脲基)秦-1-基氧基）乙基)-1-甲基-3-(°比。定-2-基)腺； 4-(2-(4-(3-(3-第三丁基小對-曱苯基-1Η-吡唑-5-基）脲基)萘-1-基氧基）乙基)-3十比啶-2-基)脲； N-(4-(2-(4-(3-(3-第三-丁基-1-對·甲笨基-1Η-»比唑-5-基) 腺基)萘-1-基氧基）乙基)°比咬-3-基)-2-曱氧基乙醯胺； Ν-(4-(2·(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基) 脲基)萘-1-基氧基）乙基比啶-3-基)-2-(2-曱氧基乙氧基) 224 201130813 乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-"比唑-5-基) 腺基）奈-1-基）乙氧基)π比°定-2-基)-2-曱氧基乙酿胺； N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基）奈-I-基氧基）乙基)α比咬-2-基)-2-曱氧基乙酸胺， N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-ΙΗ-η 比唑-5-基) 腺基）奈基乳基)-2-曱基丙基）。比咬-2-基)-2-曱乳基乙醯胺； N-(4-(2-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）腺基）奈基乳基）丙基)σ比咬-2-基)-2-曱氧基乙酿胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-° 比唑-5-基）脈基）秦_ 1-基氧基）丙-2-基)17比α定-2-基)-2-曱氧基乙酸胺， N-(4-(l-(4-(3-(3-第三-丁基-1-對-曱苯基-1-吼唑-5-基)脲基）奈-1 -基氧基)-2-曱基丙-2-基）°比。定-2-基)-2 -曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-(4-(羥基甲基）苯基）-1Η-。比。坐-5-基)腺基)奈-1-基氧基）曱基)°比σ定-2-基)-2-曱氧基乙醯胺； N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基)脲基）奈-1-基氧基）甲基)°密σ定-2-基)-2-甲氧基乙酿胺， N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基)萘-1-基氧基)°比啶-2-基)-2-(曱磺醯基）乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基)°比σ定-2-基)-2-曱氧基乙酿胺， N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基)奈-1-基氧基)11比'7定-2-基)-2-(2-曱氧基乙氧基）乙酸胺； 225 201130813 ιν-(4-(4-(3-(3-第三-丁基_1_對_曱苯基_ιη-π比唑-5-基）脲基）萘-1-基氧基)0比0定冬基）四氫_；2H-口底喃_4_曱醯胺； N-(4-(4-(3-(3-第三-丁基_1_對_曱苯基_1H吡唑_5_基）脲基)萘-1-基氧基)《比啶_2_基)_2·(曱硫基）乙醯胺； Ν-(4-(4-(3-(3-第三-丁基_1_對_曱苯基·1Η_Π比唑_5•基）脲基)条-1-基氧基)°比°定-2-基)-3-甲氧基丙酿胺； Ν-(4·(4-(3-(3-第三-丁基·ι·對甲苯基_阳-«比唑-5-基）脲基)蔡-1-基氧基)°比啶-2-基)-2-經基乙醯胺； N-(4-(4-(3-(3-異丙基-1-對-曱苯基_iH-n比哇-5-基）脲基) 萘小基氧基)°比°定基)_2_甲氧基乙醯胺； Ν-(4·(4-(3-(3-乙基-1-對-甲苯基-1H-吡唑-5-基）脲基）萘 -1-基氧基）吡啶-2-基)-2-甲氧基乙醯胺； Ν-(4-(4-(3_(3·(1-經基-2-曱基丙冬基)-1-對-曱苯基_ih_ °比哇-5_基)脲基）萘-1-基氧基)吼啶_2_基)_2_曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-i_(2,3,5,6-四氘-4-(三氘曱基）苯基HH-吡唑-5-基)脲基）萘-丨·基氧基)51比啶·24)·2^ 氧基乙醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-曱苯基·1Η-吡唑_5_基）脲基)萘-1-基氧基)。比啶基)_2_嗎啉基乙醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-甲苯基_1Η_吡唑_5_基）脲基)萘-1-基氧基)吡啶-2-基)_(二曱胺基）乙醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-甲苯基_1Η_吡唑_5_基）脲基)萘-1-基氧基)。比啶-2-基)_2-(2-曱氧基乙胺基）乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對_曱苯基_1H_吡唑_5_基）脲基)蔡小基氧基)。比务2-基)_2_脲基乙醯胺； 226 201130813 N-(4-(4-(3-(3-苐二-丁基-1-對-曱苯基-111-0比〇坐-5-基)脈基）萘-1-基氧基）π比啶-2-基)-2-(2-甲氧基乙醯胺基）乙醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-。比唑-5-基) 脲基）萘-1-基氧基）°比啶-2-基胺基）-2-側氧乙基）四氫 -2H-哌喃-4-曱醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基) 脲基）萘-1-基氧基）吡啶-2-基胺基)-2-側氧乙基）異菸鹼醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）。比啶-2-基)-2-(2-(甲磺醯基）乙醯胺基) 乙醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基) 脈基）奈-1_基氧基）°比咬-2-基胺基)-2-側氧乙基)-3-嗎琳基丙醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1Η-» 比唑-5-基) 脈基）奈_1_基乳基）**比σ定-2-基胺基)-2-側氧乙基）嗎琳-4_ 曱醯胺； N-(2-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η 比唑-5-基) 腺基）条_1_基乳基）π比咬-2-基胺基)-2-側氧乙基)-2,6-二氟-3-(2-(2-曱氧基乙氧基）乙氧基)苯甲醯胺； N-(4-(4-(3-(3-第三-丁基-1-對·曱苯基-1H-吡唑-5-基）脲基）苯氧基)αι^σ定-2-基)-2-甲氧基乙酸胺， N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲基)-2-曱基苯氧基)°比π定-2-基)-2-曱氧基乙酿胺； N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吡唑-5-基）脲 227 201130813 恶)-3-曱基苯氧基)吼啶_2_基)-2·•甲氧基乙醯胺； Ν-(4-(4-(3-(3 -第三-丁基-1-對-曱笨基]坐-5-基）腺基)-2-曱氧基苯氧基)η比咬-2-基)-2-曱氧基乙醯胺； N-(4-(4-(3-(3-第三-丁基-1-對-甲苯基比唾-5-基）脲基)-2,3-二曱基苯氧基)吼咬_2-基)-2-曱氧基乙醢胺； >Κ4-(4-(3-(3-第三-丁基小對-曱苯基·m_D比唑_5_基）腺基)-3-曱氧基苯氧基)n比啶_2_基)_2_曱氧基乙醯胺； N-乙基-Ν’·4-(4-(3 -(3 -第三-丁基-1 -對·曱苯基]H_吡唑 -5-基)脲基）萘-1-基氧基)吼啶_2_基脲； 4-(4_(3-(3-第三-丁基-1-對-曱苯基·1H_吡唑_5_基）腺基) 萘-1_基氧基)《比啶-2-基脲； N-丙-2-基-N’-4-(4-(3_(3-第三-丁基_1_對-甲苯基-1H_吡 °坐-5-基)脲基)奈小基氧基)D比咬_2_基脲； 1-(3-(第三-丁基）+(對_甲苯基）_1H吡唑-5_ 基)-3-(4-((2-(3-苯基脲基)。比啶·4_基)氧基）萘_丨_基)脲； 1-(4-((2-(3-苯甲基脲基）吼Β定冰基）氧基）萘· 基）3_(3_(第二-丁基)-1-(對-甲苯基)-lH~n比η坐_5_基)脲； 1-(4-((2-(3-環丙基脲基）„比啶_4_基）氧基）蔡_】基)-3-(3-(第三-丁基甲苯基)_1H，唑_5_基姆； H3-(第三-丁基）+(對-甲苯基）_1H_吡唑-5 基)_3_(4·((2_(3_(2-甲氧基乙基)脲基)。比啶冰基）氧基）凑小基)服； 1-(3-(第三-丁基）]•(對_ f苯基）·ιη_呢唑-5_ 基>3-(4-((2-(3-環戊基)脲基）°比咬+基）氧基）萘基) -(3-(第三·丁基）」_(對_ f苯基）_ιη•吼唑乃 228 201130813 基)-3-(4-((2-(3-曱基)脲基)《比啶-4-基)氧基)萘-1-基)脲； 2-(3-(4-((4-(3-(3-(第三-丁基)-1-(對-曱苯基)-1Η-。比唑 _5_ 基)腺基）奈-1-基）氧基)π比咬-2-基)腺基）乙酸乙g旨； 4-(3-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吼唑-5-基）脲基)萘-1-基氧基)吼啶-2-基)脲基)哌啶； N-乙醯基4-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H_ 。比唑-5-基)脲基)萘-1-基氧基)吡啶-2-基)脲基)哌啶； 2- (2-曱氧基乙氧基)-1-(4-(3-(4-(4-(3-(3-第三-丁基_1_對一曱苯基-1H-D比σ坐-5-基）腺基）萘-1-基氧基）η比咬_2-基）脲基)哌啶-1-基）乙酮； N-曱石黃醯基-4-(3-(4-(4-(3-(3-第三-丁基小對_曱苯基 -1Η-»比β坐_5_基）脲基）萘_ι_基氧基）D比咬_2_基）脲基）派啶； N-(4_(4_(3_(3_第三丁基小對_曱苯基_1H_吡唑基）腺基)萘-1-基氧基)°比咬-2-基)嗎琳-4-曱酿胺； Ν-(4-((4-(3-(3·(第三-丁基)-1-(對-甲苯基比唑基) 服基)萘-1-基)氧基)11比咬-2-基)_4_甲基〇底〇井小甲醢胺. 3- (4-((4-(3-(3_(第三-丁基)小(對-曱苯基)_1H_吡唑5基）脲基)萘-1-基)氧基)吼啶-2-基)-1,1-二曱基脲； Ν-(4-((4·(3-(3-(第三-丁基)小(對-甲苯基)_1H-吡唑_5基) 脲基）萘-1-基）氧基)°比啶_2_基)哌啶-1-曱醯胺； N-曱基-N-(2-(嗎啉-4-基）乙基)-N，-4-(4-(3-(3-第三 _丁基 -1-對-曱苯基-lH-t坐_5·基)脲基)萘小基氧基)吼咬基脲； N-(4-(嗎啉-4-基）丁基)·Ν，·4-(4-(3-(3-第三-丁基]_對_甲本基-1Η-σΛσ坐_5_基)脲基)萘-1-基氧基比咬_2·基腺. 229 201130813 jn-(2-(嗎琳-4-基）乙基)_n'-4-(4-(3-(3-第三-丁基-1 -對-甲苯基-lH-t坐-5-基)脲基)蔡基氧基基脲； N-(3-曱基異喝唑-5-基）曱基_Nl4-(4-(3-(3-第三-丁基_1_ 對-甲苯基-1H-他哇-5-基）脲基）萘-丨基氧基”比啶_2_基脲； N-(l-曱基）哌啶-4-基-Ν'- 4-(4-(3-(3-第三-丁基-1-對-甲苯基-1Η-η比唑-5-基)脲基)萘小基氧基)n比啶_2_基脲； N-(4-(4-(3-(3-第三-丁基_1_對_甲苯基比唑-5-基）脲基)萘-1-基氧基)°比啶-2-基)-4羥基哌啶-1-曱醯胺； Ν_(3-(0米0坐-1-基）丙基)-N’-4-(4-(3-(3-第三-丁基小對_曱苯基-1H-D比嗤_5-基)脲基)萘_1_基氧基)吼。定_2·基脲； N-(2-(3-(4_(4-(3-(3-第三丁基小對·曱苯基-1H-。比哇_5_ 基)腺基)蔡-1-基氧基定-2-基)腺基）乙酿基)n比洛咬； (R)-N-(4-(4-(3_(3·第三·丁基-1_對-曱苯基-1H_吡唑_5_基) 腺基）萘-1-基氧基)°比°定-2_基)-3-(二曱胺基)η比略Π定小曱醯胺； Ν-(4-(4-(3-(3-第三-丁基-1-對-甲苯基_1H-D比哇-5-基）脲基)萘-1-基氧基)"比"定-2-基)°比略t»定-1-曱醢胺； 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基坐-5-基）腺基)萘-1-基氧基)°比β定-2-基)腺基)-Ν-甲基乙醯胺； 2-(3-(4-(4-(3-(3-第三-丁基-1·對-曱苯基-lH-n比。坐_5•基）腺基）萘-1-基氧基）D比咬-2-基）脲基)-N-(2-嗎淋基乙基）乙醯胺； 2-(3-(4-(4-(3-(3-第三·丁基-1-對-曱苯基-1^>比唑_5_ 基）脲基)萘-1-基氧基)吼啶-2-基)脲基）乙醯基嗎啉； 2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基） 230 201130813 脈基）奈-1_基氧基）°比α定-2-基）腺基)-N-(2-(ntbσ定-4-基）乙基）乙醯胺； Ν-(3-(1Η-咪唑-1-基）丙基）-2-(3-(4-(4-(3-(3-第三-丁基 -1-對-甲苯基-1H-吡唑-5-基）脲基）萘-1-基氧基）吼啶-2-基)脲基）乙醯胺； 1-(2-(3-(4-(4-(3-(3-第三-丁基-1-對-甲苯基-1H-吼唑-5- 基)腺基）奈_1_基氧基)D比咬-2-基)脈基）乙酿基)-4-甲基派畊； Ν-(3-(1Η-咪唑-1-基）丙基）-2-(3-(4-(4-(3-(3-第三-丁基 -1-對-曱苯基-1H-吡唑-5-基）脲基）萘-1-基氧基户比啶-2-基)脲基）乙醯胺； N-(6-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基）脲基)备-1-基氧基基)-2-曱氧基乙酸胺； N-(6-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）苯氧基)°密°定-4-基)-2-曱氧基乙酷胺， N-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基）脲基)备-1-基氧基)。密。定-2-基)-2-曱氧基乙酿胺； 3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡唑-5-基）脲基）奈-1-基氧基)σ密咬-2-基)腺， 1-曱基-3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑 -5-基)脈基)秦-1-基氧基)°密0定-2-基)脈， 1,1-二曱基-3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吡 π坐-5-基)腺基）奈-1-基氧基)α·σ定-2-基)腺， 1 _壤丙基- 3-(4-(4-(3-(3 -第二-丁基-1 -對-甲苯基-1 。坐 -5-基)腺基）奈-1-基氧基)α密咬-2-基)腺， (4-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-η比唑-5-基)脲基) 231 •>pr-l-基氧基定-2-基)嗎琳-4-甲酿胺， 3-(6-(4-(3-(3-第三-丁基-1-對-曱苯基-1Η-吡唑-5-基）脲基)萘-1-基氧基)嘧啶-4-基)脲；2-(3-(4-(4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基)脲基）萘-1-基氧基）吼啶 -2-基)腺基）乙酸。及其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。 13. —種用於治療或預防病毒感染之化合物，其中該化合物為N-(4-((4-(3-(3-第三-丁基-1-對-曱苯基-1H-吼唑-5-基)脲基）萘-1-基氧基）曱基)°比啶-2-基)-2-曱氧基乙醯胺或其醫藥上可接受的鹽，包括其所有的立體異構物、互變異構物及同位素衍生物。 14. 一種治療或預防病毒感染之方法，該方法包含將有效量的如申請專利範圍第1至13項中任一項所定義之化合物投予至需要該治療之患者。 15. 根據申請專利範圍第14項之方法，另包含將有效量的抗病毒劑投予至患者。 16. —種如申請專利範圍第1至13項中任一項所定義之化合物於製備供治療或預防病毒感染用藥劑之用途。 17. 根據申請專利範圍第16項之用途，其中該藥劑另包含一種抗病毒劑。 18. 根據申請專利範圍第1至17項中任一項之化合物、方法或用途，其中該病毒感染係由流感病毒引起。 19. 根據申請專利範圍第18項之化合物、方法或用途，其中該病毒感染係由流感A病毒引起。 232 201130813 20. 根據申請專利範圍第18項或19之化合物、方法或用途’其中該病毒感染係在患有下列之患者中：慢性疾病或病（諸如糖尿病、鬱血性心臟衰竭、腎衰竭、慢性阻塞性肺臟疾病、氣喘、及/或免疫抑制，諸如接受化學治療之患者、孕婦、HIV及 AIDS患者、及/或由流感感染引起的併發症，例如肺或全身性併發症。 21. —種醫藥組成物，其包含如申請專利範圍第1 至13項中任一項所定義之化合物和抗病毒劑（例如神經胺糖酸苷酶抑制劑)之組合。 22. —種產品’其包含呈同時、分開或相繼使用於治療或預防病毒感染的組合製劑之如申請專利範圍第！至13項中任一項所定義之化合物及抗病毒劑。 23. 根據申請專利範圍第21項之醫藥组成物或根據申請專利範圍第22項之產品，其中該抗病毒劑為奥塞米早（oseltamivir)、扎那米韋（zanamivir)、帕拉米韋 (peramivir)、金剛烷胺、金剛乙胺、利巴韋林(ribavirin); 干擾素、阿昔洛韋（aCyCl〇vir)及/或齊多夫定 (zidovudine) 〇 24. 根據申請專利範圍第2i至23項中任一項之醫藥組成物或產品，用於鼻腔投予、局部投予至肺或口服投予。 25·根據申請專利範圍第24項之醫藥組成物或產品，其係於鼻滴劑或計量噴霧、氣溶膠調配物、非加壓調配物諸如水溶液或懸浮液或乾粉調配物之形式。 233A hetero atom substitution of 〇N, S(0)p, wherein the chain or groups (eg 1, 2 or 3 groups) are independently halogen, aryl, sputum, 攸@ a > Aryl, heteroaryl, heterocyclyl or c3-8 cycloalkane selected from the group consisting of pendant oxy, dentate, aryl, radical, 209 201130813 β #aryl, heteroaryl, heterocyclyl or C3_8 cycloalkyl having 0 Up to 3 from the elemental base, 〇)··6 base, Ci -6 alkoxy, Ci-6 halogen, amine, Cl·4 or C 2-8 di-alkylamine, Q- 4mono or C2_8 bis-indenylamino, S(〇)qCV6 alkyl, Cq 6 alkyl C(〇)Ci 6 alkyl or C()-6 alkyl 0(〇)^·6 heteroalkyl a substituent which is presumed to be an atom directly bonded to a carbonyl group in -NR3C(0)- which is not an oxygen or a sulfur atom; and b) a c〇_8 yard group·heterocyclic ring containing at least one impurity Atoms (for example 1, 2 or 3, suitably 1 or 2, in particular one hetero atom) are selected from the group consisting of hydrazine, N and S, and optionally, one, two or three, independently selected from halogen, hydroxy. , Ci-6 alkyl, Cm alkoxy, Cw-tooth alkyl, amine, C!·4 mono and C2·8 di-alkylamino, Ci 4 mono or c 2 8: mercaptoamine Base, SiCOqCw alkyl, cQ6 alkyl c(〇)Ci6 alkyl, cG6 alkyl C(0)NC〇_6 alkyl C〇_6 alkyl or q 6 alkyl C(0)C() 6 a group substituted with an alkyl group; and p is 0, 1 or 2; q is 0, 1 or 2; or a pharmaceutically acceptable salt or solvate thereof, including all stereoisomers, tautomers thereof And isotopic derivatives, the prerequisite of which is that the compound of formula (I) is not N-(4-(3-(3-tert-butyl-l-p-tolyl-lH-° azole) -5-yl)ureido)naphthylquinone-yloxy)pyridine_2-yl)_2-methoxyacetamidine Jk or a pharmaceutically acceptable salt or solvate thereof. 2. A compound for treating or preventing a viral infection according to the first aspect of the patent application, wherein Ar is a naphthyl group. 3. A compound for treating or preventing a viral infection according to claim 1 or 2, wherein L is -〇ch2- or -0-. 210 201130813 4. A compound for treating or preventing a viral infection according to any one of claims 1 to 3 wherein the hydrazine is a pyridyl group. , 5. A compound for treating or preventing a viral infection according to any one of claims 1 to 4, wherein q is: a. C!-4alkyl_V_R4, such as Ci3 alkyl_Vr4, wherein: V is a hetero atom selected from 1 乂, 〇 or 8 (〇) 1); RV represents Η or Cm alkyl; R is Η or -Cy alkyl' and p are as defined in the scope of claim ii, the prerequisites of including a replacement hetero atom having a total alkyl chain length of no more than 10 carbon atoms, and the resulting group q being a stabilizing group; . Ci-3 alkyl-V-(Ci-3 alkyl-Z-R5)k such as Cu alkyl _v_(c alkyl-Z-R5)k, wherein: - V is selected from N, NH, hydrazine or a hetero atom of S(0)p, such as N or NH (V is N, in the case where k = 2, or will be selected from NH, 〇 or s(〇)P, in the case where k =1 , especially NH); Z is independently selected from NH, 〇 or s(〇)p; R5 is Η or -Cw alkyl; k is an integer 1 or 2 (such as 1); and P is as claimed in the patent scope As defined in Item 1, the prerequisite is that the total alkyl chain length of the substituted hetero atom is not more than ι〇 carbon atoms and the resulting group Q is a stabilizing group; or, c· CN3 alkyl-V-CK2 alkyl -Z-Cy alkyl-Y-R6, or Cw alkyl-V-C2_3 alkyl-Z-C2_3 alkyl-Y-R6, wherein v, z and γ are independently selected from NH, hydrazine or s (〇) a hetero atom of p, R6 is hydrazine or methyl, and '211 10 201130813^ § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § <~Alkyl chain length is not more than 6. According to any one of the four patents for the treatment or prevention of viral infections of the patent application, the method for the formation of urea, wherein 8 is Q-NR7R8 and saturated or unsaturated branches. Or non-supported " R independently represents hydrogen or CU9 such as 2 or 3 as needed = key 'where - or more carbon, sub-permutation and 'where the chain is as needed. , N or _p heterooriginal, dentate, aryl, heteroaryl A or a plurality of groups independently selected from pendant oxygen, each aryl, heteroaryl or & cycloalkyl group There are 0 to 3 as defined in item 1, as in application 7. According to the scope of the patent application, the first treatment or the prevention of viral infection, wherein the heterocyclic group is contained in a small ring, wherein Q is a -c〇-3 alkyl group And, if necessary, one or two inferior ones selected from 0' and s. The groups defined in item i of the patent range are independently selected from, for example, Shen 8. Replaced by the relevant substituents in the scope of the patent application. A toxically-infected compound wherein the Q^ term is used to treat or prevent a disease group via a carbon linkage. a heterocyclic group in which a heterocyclic group is 9. A compound which is scorpion-infected according to the scope of the patent application, wherein the compound is used for the treatment or prevention of a disease, a C 〇 alkyl heterocycle, wherein the heterocyclic group contains - or an N atom and is delayed by 1 0. According to the scope of the patent application, the compound for treating or preventing viral infection is used for -CH2OH; Q ‘,. 212 201130813 -CH^OCu alkyl 'specifically -CH2OCH3; -CH2CH2OCH3; -CH20(CH2)20CH3; -CH(CH3)OCH3; -ch2nhch3 or -ch2n(ch3)2-ch2nhch2ch2och3 or -ch2nhc(o)ch2och3; -CH2SCH3, -ch2s(o)2ch3 or -ch2nhc(o)ch2s(o)2ch3; or -CH2NHC(0)CH2. 11. In the compound for treating or preventing a viral infection according to any one of claims 1 to 4, wherein the fragment -NR3C(0)Q in the formula (I) is represented by the following: -NR3C(0) CH20H, especially -NHC(〇)CH2OH; -NR^CXCOCHsOCu alkyl, especially -NR3C(0)CH20CH3, especially -nhc(o)ch2och3; -nr3c(o)ch2o(ch2)2och3, especially - Nhc(o)ch2o(ch2)2och3; -nr3c(o)ch(ch3)och3, especially -NHC(0)CH(CH3)0CH3; -nVcxc^ckkchonhCu alkyl, in particular, J is -nhc(o )ch(ch3)nhch3 ; -NreCCCOCHCCHONCC^ alkyl)2, especially -nhc(o)ch(ch3)n(ch3)2; -nr3c(o)c(ch3)2nhch3, especially -nhc(o) c(ch3)2nhch3; -Ni^CCOXCH^OCw alkyl, such as 213 201130813 NR3C(0)(CH2)2〇CH3, special; ^_NHC(〇)(CH2)2〇CH3; nWCCOXCHANHCh alkyl, especially - NHC(0)(CH2)3NHCH3; NfC^OXCH^NCCw alkyl)2, especially -NHC(0)(CH2)3N(CH3)2; -Nf^CCC^Ci^NHCw alkyl, especially _NHC (〇)CH2NHCH3; -nr3c(o)ch2nh(ch2)2och3, especially -nhc(o)ch2nh(ch2)2och3; -NR3C(0)CH2SCH3 'Specially -NHC(〇)CH2SCH3 ; -nr3c(o) Ch2s(ch2)2och3, especially - NHC(0)CH2S(CH2)20CH3; -NR3C(0)CH2S(CH2)2〇(CH2)2〇CH3, especially -NHC(0)CH2S(CH2)20(CH2)20CH3-NR3C(0)CH2S0CH3 'Specially -NHC(0)CH2S0CH3 -NR3C(0)CH2S(0)2CH3, especially -NHC(0)CH2S(0)2CH3; -nr3c(o)ch2n[(ch2)2och3]2, especially - NHC(0)CH2N[(CH2)20CH3]2; -NR3C(0)NH2' especially -NHC(0)NH2; -NWCCCONHCm alkyl, such as NR3C(0)NHCi_7 alkyl, especially -nhc(o) Nhch3 -NR^CXC^IS^Cm alkyl) Cu-based, especially -nhc(o)n(ch3)2; or -nr3c(o)nhch2conh(ch2)2och3, especially -NHC(0)NHCH2C0NH( CH2)20CH3; -NHC(0)-(tetrahydropyranyl), such as -NHC(〇)-(tetrahydro-2H-monopyran-4-yl): 214 201130813 -NHC(0)-(morpholine) Base), such as _NHC(〇)_(4_morpholinyl) or -NHC(0)-(3-morpholinyl); -NHC(0)-(pyrrolidinyl), such as _NHc(〇) -(pyrrolidin-1-yl); -NHC(0)-(piperidinyl), such as _NHC(0)-(piped-1-yl); -NHC(0)-(methylpipedyl) ), such as _Nhc(〇)-(4-mercapto-peptidin-1-yl); -NHC(0)-[(decyloxyethyl)pipedyl], such as _Nhc(0)-[4 -(2-decyloxyethyl) brigade. Well-1-yl]; -NHC(0)-(sideoxyimidazolidinyl), such as _NHc(〇)-(2-sided oxyimidazolidinyl), especially -NHC(0)-(2 - sideoxyimidazolidin-1-yl); -NHC(0)CH2_(tetrahydropyranyl), such as _Nhc(o)ch2-(tetrahydro-2H-pyran-4-yl); -NHC (0) CH2-(Merlinyl), such as -NHC(0)CH2-(4-morpholinyl); -NHC(0)CH2.(pyrrolidinyl), such as -NHC(0)CH2-(pyrrole) - pyridine-1-yl); -NHC(0)CH2-(piperage), such as _NHC(0)CH2-(piped-1-yl); -NHC(0)CH2-(曱基旅σ井Base), such as -NHC(0)CH2-(4-mercaptopurine _ 1_yl), -NHC(0)CH2_[(decyloxyethyl)pipedyl], such as -NHC(0) CH2-[4-(2-decyloxyethyl)pine η well small base]; -nhc(o)ch2sch2ch2-(morpholinyl), such as -NHC(0)CH2SCH2CH2-(4-morpholinyl), Or -NHC(0)CH2SCH2CH2-(3-morpholinyl); and -NHC(0)CH2S02CH2CH2-(morpholinyl), such as -NHC(0)CH2S02CH2CH2-(4-morpholinyl), or -NHC ( 0) CH2S02CH2CH2-(3_morpholinyl). 215 201130813 12. A compound for treating or preventing a viral infection, which is selected from the group consisting of: methyl 4-((4-(3-(3-t-butyl)-p-nonylphenylpyrazole-5-yl))) Naphthyl-1-yloxy)methyl)npyridinyl-2-ylurea; Ν-(4-((4-(3-(3-t-butyl)-p-phenyl)] Pyrazole _5_ yl) ureido) -1-yloxy)methyl) η ratio bit _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4-((4-(3-(3-Tern. butyl 丨对对对曱 · · · « « « « « « « « ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) _2_yl)_2•nonoxypropionamide; (R)-N-(4-((4-(3-(3-T-butyl)-p-tolyl-1Η-pyrazole_5_ Ureyl)naphthalen-1-yloxy)indenyl)pyridine_2-yl)_2-methoxypropionamide; Ν-(4-((4-(3-(3-)- Small 对曱曱 · · m m m m m 萘萘萘萘萘 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; N-(4-((4-(3-(3-Terve-butyl-p-p-phenyl)-l-pyrazole-5-yl)-ureido)-naphthalen-1-yloxy)indolyl) 2-(2-(4-(3-(3-T-butyl)-p-tolyl-yl-pyrazole-5) Urea group Naphthalen-1-yloxy)indolylpyridin-2-yl)-2-(indolyl-1-yl)acetamide; N-(4-((4-(3-(3-) -butyl-i-p-anthracenyl-guapazole:yl)ureido)naphthalen-1-yloxy)indenyl)B-pyridin-2-yl)-2-(4-mercaptopiped -1-yl) acetamidine; N-(4-((4-(3-(3-t-butyl)-1·p-tolyl-1H-pyrazole-5-yl))) -1-yloxy)indolyl)pyridin-2-yl)-2-(4-(2-decyloxyethyl)piped-1-yl)acetamide; 216 201130813 N-(4 -((4-〇(3-Third-butyl 4•p-phenylphenyl-1H-pyrazole-5-yl)ureido)naphthalen-1-yloxy)indoleylpyridin-2- )-(2-methoxyethylamino)acetamide; Ν-(4·((4-(3-(3-T-butyl); ^~_phenyl)_111_ Pyrazole-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-(di-f-amino)acetamide; N-(4-((4-) 3-(3-Terti-butyl q•p-phenylphenyl_1H_pyrazole-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2- (nonylamino)acetamide; N-(4-((4-(3-(3-tert-butyl)-p-p-phenyl)-pyridylphenyl) -1-yloxy)methyl)3⁄4-pyridin-2-yl)-2-((4-methoxybenzyl) Methyl)amino)ethinamide; 1-(4-((3-methylureido)pyridin-4-yl)nonyloxy)naphthalene-1-yl)_3_(3_tri-butyl 1-(p-phenyl-phenyl-5-yl)urea; Ν-(4·((4_(3-(3-T-butyl-丨-p-tolyl-1H-pyrazole-5-yl) Ureido)naphthalen-1-yloxy)methyl)acridinylyl)_2_decyloxyacetamide; N-(4-((4-(3-(3-T-butyl) Io_p-p-phenyl·1H_pyrazole-5-yl)ureido)naphthalen-1-yloxy)indenyl). Bispin-3-yl)-2-(2-methoxyethoxy)acetamidine; Ν-(4_(2-(4·(3-(3•T3·butyl-1-pair-)曱Phenyl ratio. Sodium-5-yl) Urea-based)-naphthalen-1-yloxy)ethyl) hydrazinium-2-yl)-2-methoxyacetamide; N-(4-(2) -(4-(3-(3•Third-butyl-p-p-tolyl_e-oxo-butyryl-5)-ureido)naphthalen-1-yloxy)ethyl)acridin-2-yl -2-(2-methoxyethoxy) ethanoamine, 4-(2-(4-(3-(3-tri-butyl-1-)-p-phenyl)-1H·- ratio Zin-5-yl)ureido)naphthalen-1-yloxy)ethyl)-1-indolyl-3-decapyridin-2-yl)urea; 4-(2-(4-(3-(3) -Third-butyl_1_p-p-phenyl-1H-pyrazol-5-yl)ureido)cainyloxy)ethyl)-3-(° ratio bit-2-yl) Gland; 217 iN_(4-(2-(4-(3-(3-Terti-butyl-1-p-phenyl)-1Η-η-biazole-5-yl))))) Benzyl)ethyl)-pyridin-3-yl)-2-(2-decyloxyethoxy)acetamide; N-(4-((4-(3-(3-)- Butyl-1-p-tolyl-lH-η-pyridyl-5-yl)ureido)n-1-yloxy)indolyl)13-denyl-2-yl)-2-methoxy-4- Amine, N-(l-(2-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-.bazol-5-yl)))) -yloxy)ethyl)-1Η-imidazol-4-yl)-2-decyloxyacetamide; N-(4-(3-(3-(3-T-butyl)-1-) p-Tolyl-lH-η-pyridyl-5-yl)ureido)-n-yloxy)indolyl). Ratio-2-yl)-2-(anthracene) , N-(4-((4-(3-(3-Terve-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)-n-yloxy)曱 base) ° ratio β-2-yl)-2-ylaminoacetamide, N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)- 1Η-ηBizozol-5-yl)ureido)na-1-yloxy)indolyl) 0-pyridyl-2-yl)-2-mercapto-2-(nonylamino)propanamide; (S)-N-(4-((4-(3-(3-tert-butyl-1-)-p-phenyl)-1H-η-pyrazol-5-yl)ureido)naphthalen-1-yl Oxy)indolyl).pyridin-2-yl)-2-(methylamino)propanamine; (R)-N-(4-((4-(3-(3-)-tert-butyl) -1-p-p-phenyl-1Η-»bisazol-5-yl) fluorenyl)-n-yloxy)indolyl)α ratio β-but-2-yl)-lin-3--3-branched amine , (S) -N-(4-((4-(3-(3-Terti-butyl-1-p-(indolyl-1)-pyrazol-5-yl)))氧基 oxy)methyl) ° ratio _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Phenylphenyl-1H-pyrazole-5- Ureyl)N-yl-1-yloxy)indenyl)°Bite-2-yl)-4-indenyl 〇辰0 Well-1-曱, amine, N-(4-((4-( 3-(3-Terti-butyl-1-p-phenylene-1H-. Bizozol-5-yl)ureido)na-1-yloxy)indolyl)° ratio α--2-yl) 吓 _ _ 4- 曱胺, 218 201130813 N-(4-((4- (3-(3-Terti-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)n-1-yloxy)indolyl)°biti-2-yl -3 - methoxy propyl carbamide; 2-(3-(4-(4-(3-(3-)-tert-butyl-1-p-tolyl-1H-. azole-5- Ureyl)naphthalen-1-yloxy)indolyl)pyridin-2-yl)ureido)-N-(2-decyloxyethyl)acetamide; N-(4-(( 4-(3-(3-Terve-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)N--1-yllacyl) fluorenyl) π ratio - 2-yl)-4-(diguanylamino)butanamine, N-(4-((4-(3-(3-tert-butyl-1-butyl-p-phenyl)-1H-pyrazole) -5-yl)ureido)N-l-yloxy)indolyl)σ ratio σ-but-2-yl)-3-(phosphinic acid) propylamine, N-(4-((4) -(3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)-n-yloxy)indolyl)°Bite-2- Base)-3-(anthracene)-2-oxo-imidazole bite-1-decylamine; N-(4-((4-(3-(3-)-tert-butyl-1-pair-曱Phenyl-1H-pyrazol-5-yl)ureido)-n-yloxy)indenyl)°°°-2-yl)-2-(曱亚Ethylamine; N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)))) 1_yloxy)fluorenyl)° ratio σ-2-phenyl)-2-(2-decyloxyethylthio)acetamide; N-(4-((4-(3-(3- Third-butyl-1-p-indole-phenyl-lH-η-biazole-5-yl)glycosyl)naphthalen-1-yloxy)methyl)-pyridin-2-yl)-2-( 2-(2-decyloxyethoxy)ethylthio)acetamide; N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl)-1H -pyrazol-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(2-morpholinylethylthio)acetamide; N-( 4-((4-(3-(3-Terti-butyl-1-p-phenyl)-lH-η-pyrazol-5-yl)ureido)-hhenyl-1-yloxy)indolyl) °Bitter-2-yl)-2-(2-morphinyl ethoxylate) 219 201130813 Amine, 2-(bis(2-decyloxy)amino)-N-(4- ((4-(3-(3-Terti-butyl-1-p-indolephenyl-lH-η-biazole-5-yl)ureido)naphthalen-1-yloxy)indenyl). Pyridin-2-yl)acetamide; N-(4-(2-(4-(3-(3-tert-butyl-1-yl-p-phenyl)-1H-. Butyr-5-yl) fluorenyl)-n-yloxy)ethyl) ° butyl-3-yl)-2-methoxy ethoxylated amine, N-(4-(2-(4- (3-(3-Terti-butyl-1-p-phenylene-1H-«bazin-5-yl) fluorenyl)na-1-yl)ethoxy)ntba-but-2-yl) -2-methoxy ethoxylated amine, N-(4-(l-(4-(3-(3-tert-butyl-1-p-anthranylphenyl-1Η-»)-pyrazole-5-yl ) 基) _1 _ _ 基 ) ) ) ) ) ) ) ) ) ) ) ) 曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱曱Butyl-1-p-phenylene-1H-pyrazol-5-yl) glandyl)-methyloxy)-2-mercaptopropyl)π ratio α-but-2-yl)-2-oxo Ethylamine; N-(4-(2-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl))) _ 基 ) ) ) _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 _2 , , , , , , , , , , , , , , , , -1-p-tolyl-1H-pyrazol-5-yl) glycosyl)nyloxy)propan-2-ylpyrimidin-2-yl)-2-methoxyoxyethylamine; N-( 4-(l-(4-(3-(3-Terti-butyl-1-p-indolephenyl-I-.bazol-5-yl)ureido)-n-yloxy)- 2-mercaptopropan-2-ylindole-2-yl)-2-decyloxyacetamide; N-(4-((4-(3-(3-)-tert-butyl-1-) (4-(hydroxyindenyl)phenyl)-1 Η-carbazol-5-yl)ureido)naphthalen-1-yloxy)indenyl)acridin-2-yl)-2-oxoethoxyacetamide; N-(4-(4-(3) -(3-Terti-butyl-1-p-phenylphenyl-1H-pyrazol-5-yl)ureido)heptyl-1-yloxy)B than bit-2-yl)-2-( Continuing S-basic) ethinylamine or a pharmaceutically acceptable salt thereof, including all stereoisomers thereof, mutated 2011 20111313 isomers and isotopic derivatives. In one embodiment, the compound according to the disclosure is : Mercapto 4-((4-(3-(3-Terti-butyl-indole-p-p-phenyl)H-pyrazole-5-yl) Ureido)naphthalen-1-yloxy) A )) η · · · 2 2 2 2 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Na-n-yloxy)methyl)π-biti-2-yl)tetrahydro-2-indole-bran-4-amine; (S)-N-(4-((4-(3-( 3-Terti-butyl 丨对对曱 Η Η Η α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α α Indoleamine; (r)_N-(4-((4-(3-(3-tert-butyl)-p-p-tolyl-[indolyl]-pyridyl]-5-yl)-ureido-naphthalen-1-yl Mercapto)methyl)ηpyridin-2-yl)_2_nonoxypropionamide; (4-((4-(3-(3-), butyl-ι-p-phenyl).唾 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (3. tert-butyl-fluorenylphenyl) Η_π than 嗤_5_yl) glandyl)naphthalen-1-yloxy)indenyl)acridin-2-yl)-2-hydroxyacetamide; Ν-(4·((4-(3-(3-Terve-butyl___phenyl)-pyridyl-5-yl)))-naphthalen-1-yloxy)indolyl) acridine-2 -yl)-2-methyl-2-(nonylamino)propanamide; (S)-N-(4-((4-(3_(3-)-butyl-butyl-p-yl] M-carbazole _5_ yl) ureido)naphthalenyl-1 yl A)methyl)D than bite_2_yl)_2_(methylamino) propylamine; (8)-N-(4-((4- (3-(3-Ter-butyl-p-tolyl·m•carbazole) grytyl)N--1-yloxy)indolyl)吼唆-2·yl))______ Indoleamine; (S)-N-(4-((4-(3-(3-t-butyl))-p-methyl). η azole _5_ 221 ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)morpholine-3-decylamine; Ν·(4-((4-(3-(3-) Third-butyl_ι_p-tolyl-1H-pyrazole-5-yl)ureido)naphthalen-1-yloxy)methyl).pyridin-2-yl)-4-methylper Cultivated 1-carbamamine; Ν-(4-((4·(3-(3-Terve-butyl-1_p-ylphenyl)H_C-pyrazole-5-yl)))-naphthalene- 1-yloxy)indenyl)n-pyridin-2-yl)morpholine_4_decylamine; Ν-(4-((4-(3-(3-)-tert-yl-丨-pair _曱Phenyl-1Η_pyrazole-5-yl)ureido)naphthalen-1-yloxy)indolyl).pyridin-2-yl)-3-methoxypropanamide; 2-(3 -(4-((4-(3-(3-tert-butyl)-p-tolyl--) is more than 0-(yl)-glycosyl)-naphthalen-1-yloxy)methyl) Pyridine-2-yl)ureido)_N_(2-methoxyethyl)acetamide; N-(4-((4-(3-(3-)-tert-butyl-p-tolyl) Η β β β β β _ _ _ _ _ _ _ _ 吼吼吼吼吼吼吼吼吼吼吼吼吼 N N N N N N N N ; ; N N N ; ; ; ; ; ; ; ; ; ; -(3-Terti-butyl 4_p-tolyl-1H-pyrazole-5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridine-2-yl)-3-(anthracene Sulfhydryl)propanamide; N-(4-((4-(3-(3-)-tert-yl)-p-phenylene Base_1H_pyrazole-5-yl)ureido)naphthalen-1-yloxy)indenyl; Kbpyridine_2-yl)-3-(indolyl)-2-oxoxime-bite- 1-nonanamine; N-(4-((4-(3-(3-tert-butyl-p-phenyl)]][[pyrazol-5-yl)ureido]naphthalene-1 -yloxy)indenyl)pyridin-2-yl)-2-(indolyl)acetamide; N-(4-((4-(3-(3-)-tert-butyl-- Phenylphenyl "oxapyrazolyl] ureido)naphthalen-1-yloxy)methyl)acridinyl)-2-(indolylsulfenyl)acetamide; N-(4-((4) -(3-(3-Terti-butyl 4_p-phenylphenyl-1H-pyrazole-5)-ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)- 2-morpholinylacetamide; N-(4-((4-(3-(3-t-butyl)-p-p-phenyl)1H-pyrazole-5)ureido) -1-yloxy)methyl; Ktbit-2-yl)-2-decapyridin-1-yl)ethyl 222 201130813 amine; Ν-(4-((4_(3·(3·2) · butyl] 曱 phenyl _1H "比 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Indoleamine; Ν-(4·((4-(3-(3-second-butyl)•p-tolyl-1H” is more than sino-5)yl)naphthalenyl-1·yloxy) Methyl)dh2D_2_(4_(2methoxyethyl) Piperidin-1-yl)acetamidamine; N-(4-((4-(3-(3-tert-butyl)-p-phenyl]. 吼嗤_5_yl)glycosyl)naphthalen-1-yloxy)indenyl) 吼-2_yl)_2_(2_decyloxyethylamino)acetamide; N-(4-(( 4-(3-(3-Terve-butyl-7-p-phenyl)-m-pyrazole-5-yl)ureido-naphthalen-1-yloxy)indenyl bromide_2_yl)_2_ (diammonium) ethylamine; Ν-(4-((4-(3-(3)-tert-butyl small pair. Tolyl) 対 5 5 5 5 ) 萘舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟舟 ( ( 3_Third-butyl small p-tolyl-1Ηκ5·yl) ketone)naphthalen-1-yloxy)fluorenyl)acridine_2_yl)_2_((4·曱oxy alum) (indenyl)amino)acetamide; Ν-(4-((4-(3-(3-tert-butyl)-p-tolyl_m_n 嗤_5yl) glycosyl) naphthalene氧基)(曱((4·(3-(3-T-butyl-p-)-) Stupid base "specific 嗤5_yl) gland) naphthalen-1-yloxy) fluorenyl) bite _2 boat Mm-based ethoxy) ethylthio) acetamidine; Ν-(4·(( 4_(3-(3-Terti-butyl) ♦ phenyl group _ heart than sal _ 5 group) glandyl) naphthalen-1-yloxy) fluorenyl) 吼 2 - yl) -2- ( 2-?#ethylethylthio)acetamide; 223 201130813 iN-(4-((4-(3-(3-tert-butyl-1-yl)-phenyl-1H-indazole-5) -yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-(2-morpholinylethanesulfonyl)ethene; 2-(double(2_曱oxyethyl)amino)-N-(4-((4-(3-(3-Terti-butyl-1-p-oxime)-1H-° 嗤-5-yl) gland Cai) Ethyl)methyl) butyl-2-yl)ethinylamine; 1-(4-((3-mercaptoureido)pyridin-4-yl)nonyloxy)naphthalenyl-1-yl)-3- (3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea; Ν-(4-((4-(3-(3·T-butyl-1-)·曱Phenyl-lH-η-biazole-5-yl)ureido)Cai·1_yloxy)indolyl)pyridin-3-yl)-2-methoxyacetamide; Ν·(4 -((4-(3-(3-Terve-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)indenyl)° ratio Pyridin-3-yl)-2-(2-decyloxyethoxy)acetamidine; Ν-(4-(2-(4-(3·(3·3⁄4-butyl-1-pair-oxime) Phenyl-1Η-»Bizozol-5-yl) glandyl)naphthalen-1-yloxy)ethyl)D-biti-2-yl)-2-methoxyacetate; N-(4- (2-(4-(3-(3-Terve-butyl-p-p-phenyl)-1Η-»bisazol-5-yl) ureido)naphthalen-1-yloxy)ethyl) Pyridin-2-yl)-2-(2-decyloxyethoxy) acetamidine; 4-(2-(4-(3-(3-tert-butyl-1-p-phenylene) 1Η-ηBizozol-5-yl)ureido)qin-1-yloxy)ethyl)-1-methyl-3-(° ratio 1,4-yl) gland; 4-(2-( 4-(3-(3-tert-butyl-p-p-indolylphenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-3 -2-yl)urea; N-(4-(2-(4-(3-(3-tert-butyl-1-p-methylidyl-1Η-»bisazol-5-yl))) Naphthyl-1-yloxy)ethyl)° 咬-3-yl)-2-decyloxyacetamide; Ν-(4-(2·(4-(3-(3-)- Butyl-1-p-p-phenyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethylpyridin-3-yl)-2-(2-decyloxy B Oxy) 224 201130813 acetamamine; N-(4-(2-(4-(3-(3-tert-butyl-butyl-p-phenyl)-1H-"Glycosyl)naphthalenyl)ethoxy)π-pyridyl-2-yl)-2-nonyloxyethylamine; N-(4-(l-(4-(3-(3-) Tertiary-butyl-1-p-phenylene-1H-pyrazol-5-yl) glandyl)N-I-yloxy)ethyl)α-biti-2-yl)-2-oxo Acetylamine, N-(4-(2-(4-(3-(3-tert-butyl-l-p-phenyl)-indolyl-5-yl) glycosyl) Milky)-2-mercaptopropyl). N-(4-(4-(3-(3-T-butyl)-1-p-phenyl)-1H- Pyrazol-5-yl) glycosyl)Nylideyl)propyl)pyranidyl-2-yl)-2-methoxyacetamidine, N-(4-(l-(4-(3-) (3-Terti-butyl-1-p-phenylene-1Η-°Bizozol-5-yl) fluorenyl)-methyl-1-yloxy)propan-2-yl)17 than α--2 -yl)-2-decyloxyacetic acid amine, N-(4-(l-(4-(3-(3-tert-butyl)-1-p-phenylene-1-oxazole-5- ))ureido)N-l-yloxy)-2-mercaptopropan-2-yl) ° ratio of di-2-yl)-2-methoxyacetamide; N-(4-(( 4-(3-(3-Terti-butyl-1-(4-(hydroxymethyl)phenyl)-1Η-. ratio. Sodium-5-yl) glandyl)-n-yloxy) N-(4-((4-(3-(3-)-tert-butyl-1-p-phenyl) phenyl) -1H-pyrazol-5-yl)ureido)-n-yloxy)methyl) succinyl-2-yl)-2-methoxyethenylamine, N-(4-(4 -(3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)-pyridin-2-yl)- 2-(4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl)urea; Naphthalene-1-yloxy °°σσ-2-yl)-2-decyloxyethylamine, N-(4-(4-(3-(3-Terti-butyl-1-p-tolyl-1H-py) Azul-5-yl)ureido)naphthalenyloxy)11 than '7-but-2-yl)-2-(2-decyloxyethoxy)acetic acid amine; 225 201130813 ιν-(4- (4-(3-(3-Terve-butyl_1_p-phenylphenyl)-ytylpyridin-5-yl)ureido)naphthalen-1-yloxy)0 to 0 Tetrahydro-; 2H-oral sulphonium _4_ decylamine; N-(4-(4-(3-(3-tri-butyl-1-)-p-phenylphenyl-H-pyrazole-5 _ )) ureido)naphthalen-1-yloxy) "pyridin-2-yl]_2 ((thiol) acetamide; Ν-(4-(4-(3-(3-third-) Butyl-1-p-p-phenylene-1Η-indoleazole _5•yl)ureido)-l-yloxy) ° dec-2-yl)-3-methoxypropanol; -(4·(4-(3-(3-Terti-butyl·ι·p-tolyl_yang-«bazin-5-yl)ureido)cain-1-yloxy)°-pyridyl- 2-yl)-2-ylacetamide; N-(4-(4-(3-(3-isopropyl-1-p-indolephenyl)-iH-nbiw-5-yl)urea Base) naphthalene small oxy) ° base) _2 methoxy acetamide; Ν-(4·(4-(3-(3-ethyl-1-p-tolyl-1H-pyrazole) -5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide; Ν-(4-(4-(3_(3·(1-)-yl-2-mercaptopropyl-l-yl-p-phenyl)-ih_° than wow-5-yl)ureido)-naphthalene- 1-yloxy)acridine_2-yl)_2-decyloxyacetamide; N-(4-(4-(3-(3-tri-butyl-i-(2,3,5, 6-tetramethyl-4-(trimethyl)phenylHH-pyrazol-5-yl)ureido)naphthalenyl-fluorenyloxy)51-pyridyl·24)·2^oxyacetamide; Ν-(4-(4-(3-(3-Terve-butyl-1-p-indolephenyl)1Η-pyrazole-5-yl)ureido)naphthalen-1-yloxy).比-(4-(4-(3-tert-butyl-1-p-tolyl-1Η-pyrazole-5-yl)urea Naphthyl-1-yloxy)pyridin-2-yl)-(diguanylamino)acetamide; Ν-(4-(4-(3-(3-T-butyl-1-) -tolyl-1-indole-pyrazole-5-yl)ureido)naphthalen-1-yloxy).pyridin-2-yl)_2-(2-decyloxyethylamino)acetamide; N- (4-(4-(3-(3-Terve-butyl-1-p-phenyl)phenyl]H-pyrazole-5-yl)ureido)Cate small oxy). _Urea acetamide; 226 201130813 N-(4-(4-(3-(3-苐2-butyl-1-p-phenyl)-111-0 〇-5-yl)) Naphthyl-1-yloxy)π-pyridin-2-yl)-2-(2-methoxyacetamido)acetamide; N-(2-(4-(4-(3-( 3-tert-butyl-1-p-p-phenyl-1H-.bazol-5-yl)ureido)naphthalen-1-yloxy)°pyridin-2-ylamino)-2- Side oxyethyl)tetrahydro-2H-pentan-4-indoleamine; N-(2-(4-(4-(3-(3-tri-butyl-1-p-phenylene)- 1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-ylamino)-2-oxoethyl)isonicotinamine amide; N-(4-(4- (3-(3-Terti-butyl-1-p-indolephenyl-1H-pyrazol-5-yl)ureido)naphthalene-1- Oxy))pyridin-2-yl)-2-(2-(methylsulfonyl)acetamido) acetamidine; N-(2-(4-(4-(3-(3-) Tri-butyl-1-p-tolyl-1H-pyrazol-5-yl) fluorenyl)-l-yloxy) ° butyl-2-ylamino)-2-oxoethyl) -3-Merynyl propylamine; N-(2-(4-(4-(3-(3-Terti-butyl-1-p-tolyl-1Η-»-bazin-5-yl))脉 ) 奈 _ _ _ ) ** 奈奈奈基基基基 -2- -2- -2- -2- -2- -2- -4 -4 N N ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; (3-(3-Terti-butyl-1-p-indolephenyl-1Η-η-biazole-5-yl) gland) strip_1_yl lactyl)π-biti-2-ylamino -2- side oxyethyl)-2,6-difluoro-3-(2-(2-decyloxyethoxy)ethoxy)benzamide; N-(4-(4-( 3-(3-Terve-butyl-1-p-phenylene-1H-pyrazol-5-yl)ureido)phenoxy)αι^σ-but-2-yl)-2-methoxy Amine acetate, N-(4-(4-(3-(3-Terve-butyl-1-p-tolyl-1H-pyrazol-5-yl))))-yloxyphenoxy )° ratio π-but-2-yl)-2-methoxy ethoxyethylamine; N-(4-(4-(3-(3-tri-butyl-1-buty-tolyl-1H-pyridyl)) Oxazol-5-yl)urea 227 201130813 oxa)-3-mercaptophenoxy)acridine_2_yl)-2·•methoxyacetamide; Ν -(4-(4-(3-(3 -tris-butyl-1-p-phenyl)]-5-yl)glycosyl)-2-nonyloxyphenoxy) η than bite- 2-yl)-2-decyloxyacetamide; N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-pyran-5-yl))) -2,3-dimercaptophenoxy) _22-yl)-2-decyloxyacetamide; > Κ4-(4-(3-(3-tert-butyl)-pair-曱Phenyl·m_Dbiazole _5_yl)glycosyl)-3-decyloxyphenoxy)npyridin-2-yl)_2-decyloxyacetamide; N-ethyl-Ν'· 4-(4-(3 -(3 -tris-butyl-1-p-indolylphenyl)H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)acridine_2_ 4-urea; 4-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazole-5-yl) gland) naphthalen-1-yloxy) -2-ylurea; N-propan-2-yl-N'-4-(4-(3_(3-tri-butyl-l-_1-p-tolyl-1H-pyridyl-5-yl) Urea-based)N-butyloxy)D is more specific than 2-aminourea; 1-(3-(Third-butyl)+(p-tolyl)_1H-pyrazole-5-yl)-3-(4- ((2-(3-phenylureido)). Bisyl-4-yl)oxy)naphthalene-yl)urea; 1-(4-((2-(3-benzylidene))) (3_(second-butyl)-1-(p-tolyl)-lH~n ratio η _5_yl)urea; 1-(4-((2-(3-cyclopropylureido))) „Bistidine_4_yl)oxy)Chao_]yl)-3-(3-(Third-butyltolyl)_1H, oxazol-5-kim; H3-(T-butyl)+ (p-tolyl)_1H_pyrazol-5yl)_3_(4·((2_(3_(2-methoxyethyl)ureido).) (pyridyl) oxy)) 1-(3-(Third-butyl)]•(p-_p-phenyl)·ιη_ oxazol-5_yl>3-(4-((2-(3-cyclopentyl)))) ° ratio biting + yl) oxy) naphthyl) - (3-(Third butyl)" _ (p-_p phenyl)_ιη• carbazole is 228 201130813 ))-3-(4-((2 -(3-indolyl)ureido) "pyridin-4-yl)oxy)naphthalen-1-yl)urea; 2-(3-(4-(4-(3-(3-(3) -butyl)-1-(p-indolephenyl)-1Η-.Bistazole_5_yl)glycosyl)naphthalenyloxy)pyrene-2-yl)glycine) 4-(3-(4-(4-(3-(3-Terve-butyl-1-p-tolyl-1H-indazol-5-yl))))]-naphthalen-1-yloxy Acridine-2-yl)ureido)piperidine; N-ethinyl 4-(3-(4- (4-(3-(3-Terti-butyl-1-p-indolephenyl-1H_.bazin-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)urea Piperidine; 2-(2-decyloxyethoxy)-1-(4-(3-(4-(4-(3-(3-)-tert-butyl-1-yl-p-phenylene) -1-1H-D ratio σ sit-5-yl) glandyl)naphthalen-1-yloxy) η than _2-yl)ureido)piperidin-1-yl)ethanone; N-valve ruthenium -4-(3-(4-(4-(3-(3-Terve-butyl)-p-phenylene-1Η-» ratio β _5_yl) ureido)naphthalene_ι_yloxy Base) D is a bit of 2-amino-2-phenylpyrazine; N-(4_(4_(3_(3_t-butyl-p-p-phenyl)-H-pyrazolyl))-naphthalene-1 -yloxy) ° bite-2-yl) morphine-4-anthracene; Ν-(4-((4-(3)(T-butyl)-1-)- Tolylzozolyl) (naphthalene-1-yl)oxy) 11 than bit-2-yl) _4_methyl 〇 bottom 〇 well small carbamide. 3-(4-((4-(3-(3-(3-tert-butyl))(p-(phenyl)phenyl)-l-pyrazole-5-yl)-ureido)-naphthalen-1-yl)oxy)acridine -2-yl)-1,1-dimercaptourea; Ν-(4-((4·(3-(3-(t-butyl)) small (p-tolyl)-1H-pyrazole _5 Ureyl)naphthalen-1-yl)oxy)pyridin-2-yl)piperidine-1-indenylamine; N-mercapto-N-(2-(morpholin-4-yl)ethyl -N,-4-(4-(3-(3-Tertiary-tert-butyl-p-phenyl)-lH-t-s-yl)-ureido)-naphthalenyloxy)indole Digestive urea; N-(4-(morpholin-4-yl)butyl)·Ν,·4-(4-(3-(3-tri-butyl)_p-methylbenyl-1Η- σΛσ sits _5_base) ureido)naphthalen-1-yloxy than bite _2. 229 201130813 jn-(2-(morphin-4-yl)ethyl)_n'-4-(4-(3-(3-tri-butyl-1-)-p-tolyl-lH-t-sitting- 5-yl)ureido)cainyloxyurea; N-(3-mercaptoisoxazol-5-yl)indolyl_Nl4-(4-(3-(3-tri-butyl-1-) p-Tolyl-1H-tawa-5-yl)ureido)naphthyl-fluorenyloxy"pyridinyl-2-carbazide; N-(l-fluorenyl)piperidin-4-yl-indole-- 4-(4-(3-(3-Terti-butyl-1-p-tolyl-1Η-η-biazole-5-yl)ureido)naphthalenyloxy)n-pyridyl-2-yl Urea; N-(4-(4-(3-(3-tert-butyl-1-)-p-tolyloxazol-5-yl)ureido)naphthalen-1-yloxy)-pyridyl- 2-yl)-4-hydroxypiperidin-1-indenylamine; Ν_(3-(0 mM-1-yl)propyl)-N'-4-(4-(3-(3-third) -butyl quinone-p-phenylene-1H-D is more than 嗤5-yl) ureido)naphthalen-1-yloxy) hydrazine. 1-2 carbamide; N-(2-(3-(4_) (4-(3-(3-tert-butyl-p-p-phenyl)-1H-.~ww_5_yl) gland)-lan-1-yloxy-2-yl) gland) (r)-N-(4-(4-(3_(3·3·butyl-1_p-phenyl)-1H-pyrazole-5-yl) gland) Naphthalen-1-yloxy)° ratio -2 -yl)-3-(diguanylamino)η ratio slightly succinimide; Ν-(4-(4-(3-(3- Tri-butyl-1-p-tolyl-1H-D than wow-5-yl)ureido)naphthalen-1-yloxy)"ratio"dine-2-yl)° ratio slightly -1-decylamine; 2-(3-(4-(4-(3-(3-tert-butyl-1-yl-p-phenyl)-5-yl) glycosyl)-naphthalene-1-氧基oxy)°ββ-2-yl)glycosyl)-oxime-methylacetamide; 2-(3-(4-(4-(3-(3-tri-butyl-1) p-Phenylphenyl-lH-n ratio. Sodium _5•yl) glandyl)naphthalen-1-yloxy)D than butyl-2-yl)ureido)-N-(2- morphineethyl Ethylamine; 2-(3-(4-(4-(3-(3-t-butyl)-1-p-phenyl)-1^>biazole-5-yl) ureido)naphthalene -1-yloxy)acridin-2-yl)ureido)ethinylmorpholine; 2-(3-(4-(4-(3-(3-tri-butyl-1-yl-)-曱Phenyl-1H-pyrazole-5-yl) 230 201130813 基 ))-1-1-yloxy) ° ratio α -2-yl) gland)-N-(2-(ntb σ -4- Ethyl)ethylamine; Ν-(3-(1Η-imidazol-1-yl)propyl)-2-(3-(4-(4-(3-(3-tri-butyl-)- 1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl)ureido)acetamide; 1-(2-(3-( 4-(4-(3-(3-Terti-butyl-1-p-tolyl-1H-indazol-5-yl)glycosyl)N-l-yloxy)D Bite-2-yl) sulfhydryl)-4-branched hydrazine; Ν-(3-(1Η-imidazol-1-yl)propyl)-2-(3-(4-(4- (3-(3-Terti-butyl-1-p-phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxybenzil-2-yl)ureido) Acetamine; N-(6-(4-(3-(3-tert-butyl-1-p-indolephenyl-1Η-η-biazole-5-yl)ureido)--1-yl Oxyl)-2-nonoxyacetic acid amine; N-(6-(4-(3-(3-tert-butyl-1-p-phenyl)-1H-pyrazol-5-yl) Urea-based) phenoxy) butyl-4-yl)-2-methoxy acetamide, N-(4-(4-(3-(3-T-butyl-1-)-曱Phenyl-1Η-η-biazole-5-yl)ureido)--1-yloxy). dense. 3-(4-(4-(3-tert-butyl-1-p-phenylene-1H-pyrazole-5) -yl)ureido)na-1-yloxy) sigma-2-yl) gland, 1-mercapto-3-(4-(4-(3-(3-tri-butyl-1) -p-Phenyl-1 -pyrazol-5-yl)-yl)hhenyl-1-yloxy)-densin-2-yl)-, 1,1-didecyl-3-(4 -(4-(3-(3-Terti-butyl-1-p-phenyl)-1H-pyridin-5-yl)glycosyl)-n-yloxy)α·σ- 2-base) gland, 1 _ soil propyl - 3-(4-(4-(3-(3 - 2 - butyl-1 - p-tolyl-1. sit-5-yl) gland) Nat-1-yloxy)α-deni-2-yl) gland, (4-(4-(3-(3-Terve-butyl-1-p-phenyl)-p-n-b-azole- 5-yl)ureido) 231 •>pr-l-yloxydin-2-yl)morphine-4-cartoamine, 3-(6-(4-(3-(3-third-) Butyl-1-p-indolephenyl-1Η-pyrazol-5-yl)ureido)naphthalen-1-yloxypyrimidin-4-yl)urea; 2-(3-(4-(4- (3-(3-Terti-butyl-1-p-indolephenyl-1H-indazol-5-yl)ureido)naphthalen-1-yloxy)acridin-2-yl) gland) Acetic acid and its pharmaceutically acceptable salts, including all stereoisomers, tautomers and isotopic derivatives thereof. a compound for treating or preventing a viral infection, wherein the compound is N-(4-(3-(3-(3-tert-butyl)-1-p-phenyl)-1H-carbazole- 5-yl)ureido)naphthalen-1-yloxy)indolyl)pyridin-2-yl)-2-nonyloxyacetamide or a pharmaceutically acceptable salt thereof, including all stereoisomeric Structures, tautomers and isotopic derivatives. 14. A method of treating or preventing a viral infection, which comprises administering an effective amount of a compound as defined in any one of claims 1 to 13 to a patient in need of such treatment. 15. According to the method of claim 14, the method further comprises administering an effective amount of the antiviral agent to the patient. 16. - The use of a compound as defined in any one of claims 1 to 13 for the preparation of a medicament for the treatment or prevention of viral infection. 17. The use according to item 16 of the patent application, wherein the medicament further comprises an antiviral agent. 18. The compound, method or use according to any one of claims 1 to 17, wherein the viral infection is caused by an influenza virus. 19. A compound, method or use according to claim 18, wherein the viral infection is caused by an influenza A virus. 232 201130813 20. A compound, method or use according to claim 18 or 19 wherein the viral infection is in a patient suffering from: a chronic disease or disease (such as diabetes, septic heart failure, renal failure, chronic obstructive pulmonary disease) , asthma, and/or immunosuppression, such as patients receiving chemotherapy, pregnant women, HIV and AIDS patients, and/or complications caused by influenza infection, such as pulmonary or systemic complications. A pharmaceutical composition comprising a combination of a compound as defined in any one of claims 1 to 13 and an antiviral agent (e.g., a neuroglycosylase inhibitor). twenty two. - A product comprising a combination of simultaneous, separate or sequential use in the treatment or prevention of a viral infection, as claimed in the patent application! a compound as defined in any one of 13 and an antiviral agent. twenty three. A pharmaceutical composition according to claim 21 or a product according to claim 22, wherein the antiviral agent is oseltamivir, zanamivir, peramivir ), amantadine, rimantadine, ribavirin; interferon, acyclovir (aCyCl〇vir) and / or zidovudine 〇 24. A pharmaceutical composition or product according to any one of claims 2 to 23 for nasal administration, topical administration to the lung or oral administration. 25. A pharmaceutical composition or product according to claim 24, in the form of a nasal drop or metered spray, an aerosol formulation, a non-pressurized formulation such as an aqueous solution or suspension or a dry powder formulation. 233