TW201217379A

TW201217379A - Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators

Info

Publication number: TW201217379A
Application number: TW100124648A
Authority: TW
Inventors: Nidhi Arora; Shaoqing Chen; Johannes Cornelius Hermann; Andreas Kuglstatter; Sharada Shenvi Labadie; Clara Jeou Jen Lin; Matthew C Lucas; Amy Geraldine Moore; Eva Papp; Francisco Xavier Talamas; Jutta Wanner; Yansheng Zhai
Original assignee: Hoffmann La Roche
Priority date: 2010-07-13
Filing date: 2011-07-12
Publication date: 2012-05-01

Abstract

Compounds of the formula I or II: wherein X, m, Ar, R1 and R2 are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.

Description

201217379 六、發明說明：【發明所屬之技術領域】本發明係關於適用於治療與介白素-1受體相關之激酶 (Interleukin-l Receptor Associated Kinase ; IRAK)有關的自體免疫及發炎疾病之化合物，且更特定言之調節IRAK-1 及/或IRAK-4功能之化合物。201217379 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to autoimmune and inflammatory diseases suitable for the treatment of interleukin-l Receptor Associated Kinase (IRAK)-related kinases (IRAK). Compounds, and more specifically compounds that modulate IRAK-1 and/or IRAK-4 function.

【先前技術J 含有TIR結構域之細胞表面受體（諸如Toll樣受體以及IL-1 φ 及IL-18受體）在先天免疫中起關键作用且已涉及於自體免疫之發病機制中。TLR例如辨識病原性或内源配位體且提供樹突狀細胞成熟必需之信號及T細胞之抗原呈現（13)。類似地，介導來自此等受體之信號傳導之蛋白質亦已顯示在自體免疫病症之發病機制中起重要作用。舉例而言，缺乏MyD88(與TIR結構域直接相互作用之接附蛋白）之小鼠更容易受到細菌、真菌及寄生物感染影響。此外，缺乏 MyD88之小鼠對實驗性自體免疫腦脊髓炎（EAE)及鏈球菌 # 細胞壁誘導之關節炎有抗性（7、11、18)。 r 介白素-1受體相關激酶（IRAK)家族包含4個家族成員， IRAK-1、IRAK-2、IRAK-3/M 及 IRAK-4。此等蛋白質特徵在於介導與MyD8 8家族接附蛋白之相互作用的典型N端死亡結構域及位於中心之激酶結構域。IRAK-1及IRAK-4具有激酶活性，而IRAK-2及IRAK-3/M具有催化不活化性。在活化上游同源受體時，認為IRAK-4磷酸化IRAK-1，導致IRAK-1之活化及自體磷酸化以及下游受質之隨後磷酸 157102.doc 201217379 化。IRAK-1之過度磷酸化引導其自受體複合物之解離及其最終泛素化作用及蛋白酶體降解。下游受質（諸如pelHn〇_2) 之鱗酸化最終導致MAPK(諸如p38)及c-Jun N端激酶（JNK) 及NF-kB之活化，隨後產生促炎性細胞激素、趨化因子及破壞性酶（8、10、22)。 IRAK-1及IRAK-4於先天免疫及自體免疫疾病之發病機制中的作用正在顯露。在IRAK-4中具有去穩定化或剔除式突變（null mutation)之患者表明TLR信號傳導缺陷及促炎性細胞激素（諸如IL-1及TNF)(2、3、5、17)以及抗病毒細胞激素（諸如IFNa及IFNP)(27)之產生。此等患者顯示對革蘭氏陽性細菌（gram-positive bacterial)感染之易感性增加，但其一般對革蘭氏陰性細菌（gram_negative bacteria〇、病毒及真菌感染有抗性。類似地，缺乏之小鼠在TLR 介導及IL-1介導之細胞激素產生中具有缺陷且對感染之易感性增加。缺乏IRAK· 1之小鼠顯示對脂多醣（Lps)、IL_ j、 IL-18之反應性失去以及異常TM產生（9)。此等小鼠對實驗性自體免疫腦脊髓炎具有抗性，展現幾乎無CNS發炎。因此，調知IRAK-1及/或irAK_4之功能的化合物代表開發用於治療與IRAK介導之信號轉導有關的發炎性、細胞增殖及免疫相關病狀及疾病之治療劑的有吸引力之方法，諸如類風濕性關節炎、發炎性腸病、多發性硬化症、糖尿病、肥胖症、過敏性疾病、牛皮癖、哮喘、移植排斥反應、癌症及敗血症。 SYK路胺酸_之活化在肥大細胞活化後的信號傳導路 157102.doc 201217379 徑中為重要的（J. A. Taylor 等人，Molec. and Cell Biol.， 1995，15, 4149) » Fc ε RI(高親和力IgE受體）介導之介體自肥大細胞的釋放考慮SYK激酶活化及活性。SYK激酶之抑制劑因此可阻斷過敏性及促炎性介體及細胞激素之釋放，且潛在適用於治療發炎及過敏性病症，諸如哮喘、慢性阻塞性肺病（COPD)、成人呼吸窘迫症候群（ARDS)、潰瘍性結腸炎、克羅恩氏病（Crohn's disease)、支氣管炎、結膜炎、牛皮癖、硬皮病、蓴麻疹、皮炎及過敏性鼻炎。 • 【發明内容】本發明提供式I或式II之化合物：[Prior Art J cell surface receptors containing TIR domains (such as Toll-like receptors and IL-1 φ and IL-18 receptors) play a key role in innate immunity and have been implicated in the pathogenesis of autoimmunity . The TLR, for example, recognizes pathogenic or endogenous ligands and provides signals necessary for dendritic cell maturation and T cell antigen presentation (13). Similarly, proteins that mediate signaling from such receptors have also been shown to play an important role in the pathogenesis of autoimmune disorders. For example, mice lacking MyD88 (an attachment protein that interacts directly with the TIR domain) are more susceptible to bacterial, fungal, and parasitic infections. In addition, mice lacking MyD88 are resistant to experimental autoimmune encephalomyelitis (EAE) and streptococcal #cell wall-induced arthritis (7, 11, 18). The r-interleukin-1 receptor-associated kinase (IRAK) family contains four family members, IRAK-1, IRAK-2, IRAK-3/M, and IRAK-4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with the MyD8 8 family of attached proteins and a centrally located kinase domain. IRAK-1 and IRAK-4 have kinase activity, while IRAK-2 and IRAK-3/M have catalytic inactivation. Upon activation of upstream homologous receptors, IRAK-4 is thought to phosphorylate IRAK-1, resulting in activation and autophosphorylation of IRAK-1 and subsequent phosphorylation of downstream receptors. Hyperphosphorylation of IRAK-1 directs its dissociation from the receptor complex and its final ubiquitination and proteasomal degradation. Squamization of downstream receptors (such as pelHn〇_2) ultimately leads to activation of MAPK (such as p38) and c-Jun N-terminal kinase (JNK) and NF-kB, followed by pro-inflammatory cytokines, chemokines and disruption Sexase (8, 10, 22). The role of IRAK-1 and IRAK-4 in the pathogenesis of innate immunity and autoimmune diseases is emerging. Patients with destabilizing or null mutations in IRAK-4 indicate defects in TLR signaling and pro-inflammatory cytokines (such as IL-1 and TNF) (2, 3, 5, 17) and antiviral Production of cytokines such as IFNa and IFNP (27). These patients show an increased susceptibility to Gram-positive bacterial infection, but are generally resistant to Gram-negative bacteria (gram_negative bacteria, viral and fungal infections. Similarly, lack of smallness Mice are defective in TLR-mediated and IL-1 mediated cytokine production and are susceptible to infection. Mice lacking IRAK-1 show reactivity to lipopolysaccharide (Lps), IL_j, IL-18 Loss and abnormal TM production (9). These mice are resistant to experimental autoimmune encephalomyelitis, showing almost no CNS inflammation. Therefore, compounds that modulate the function of IRAK-1 and/or irAK_4 represent development. An attractive method for the treatment of inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis , diabetes, obesity, allergic diseases, psoriasis, asthma, transplant rejection, cancer and sepsis. SYK-Lialine _ activation in the signal transduction pathway after mast cell activation 157102.doc 201217379 Is important in the path (JA Taylor et al., Molec. and Cell Biol., 1995, 15, 4149) » Fc ε RI (high affinity IgE receptor) mediated release of mediators from mast cells Considering SYK kinase activation and Inhibitors of SYK kinase can therefore block the release of allergic and pro-inflammatory mediators and cytokines, and are potentially useful for the treatment of inflammatory and allergic conditions such as asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress Syndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis, conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis, and allergic rhinitis. [Invention] The present invention provides Compound of formula I or formula II:

或其醫藥學上可接受之鹽其中： X為N或CH ; m為1或2 ;Or a pharmaceutically acceptable salt thereof: wherein X is N or CH; m is 1 or 2;

Ar為：視情況經取代之芳基；或視情況經取代之雜芳基； R1為：氫； 157102.doc 201217379Ar is: an optionally substituted aryl group; or a heteroaryl group optionally substituted; R1 is: hydrogen; 157102.doc 201217379

Cw烷基；Cw alkyl;

Ci-6院氧基；羥基；經基-C 1 - 6炫基’Ci-6 alkoxy; hydroxy; trans-C 1 -6 leukolide

Cw烷基-胺基；胺基-Cl.6烧基’ 胺基-Cw烷基-胺基；經基-Cl.6烧基胺基； C3.6環烷基胺基；胺基-c3.6環烷基胺基；Cw alkyl-amino; amine-Cl.6 alkyl 'amino-Cw alkyl-amino; trans-Cl.6 alkylamino; C3.6 cycloalkylamino; amine-c3 .6 cycloalkylamine group;

胺基-C 3-6 雜環烷基胺基；胺基羰基；鹵基；經基-C!.6院基；或羥基-Cw烷氧基；及 R2為：氫；或 C 1.6烧基。本發明亦提供包含該等化合物之醫藥組合物、該等化合物之使用方法及該等化合物之製備方法。定義除非另外說明，否則本申請案（包括本說明書及申請專利範圍）中所用之以下術語具有下文給出之定義。應床意’如本說明書及隨附申請專利範圍中所用’除#上下 157102.doc 201217379 另外明確說明指示物》否則單數形式 —」及「該」包括複數個「貌基」意謂具有1至12個声 .^ 個炭原子之単價直鏈或分支鏈飽和烴部分，該烴部分僅由磁由炭及虱原子組成。「低碳烷土」係才日具有1至6個碳原子之，j*·其反另卞之烷基，亦即c丨-c6烷基。烷基之實例包括(但不限於)甲基、乙基、丙基、異丙基、異丁基、第二丁基、第三丁基、戊基、正己基、辛基、十二烷基及其類似基團。Amino-C 3-6 heterocycloalkylamino; aminocarbonyl; halo; trans-C..6 fen; or hydroxy-Cw alkoxy; and R 2 : hydrogen; or C 1.6 alkyl . The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds, and methods of making such compounds. DEFINITIONS Unless otherwise stated, the following terms used in this application (including this specification and the scope of the patent application) have the definitions given below. The meaning of the bed should be as used in the specification and the scope of the attached patent application. 'Except #上上157102.doc 201217379 and clearly state the indicator. Otherwise, the singular form -" and "the" includes a plurality of "forms" meaning that it has 1 to 12 sounds. The tantalum or branched-chain saturated hydrocarbon portion of the carbon atom, which is composed only of magnetic carbon and germanium atoms. "Low-carbonized alkane" has a carbon number of 1 to 6 carbon atoms, and is a c-c6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, t-butyl, t-butyl, pentyl, n-hexyl, octyl, dodecyl And similar groups.

烯基」意謂具有2至6個碳原子之直鏈單價烴基或具有 3至6個碳原子之分支鏈單價烴基，其含有至少一個雙鍵，例如乙烯基、丙烯基及其類似基團。炔基」意謂具有2至6個碳原子之直鏈單價烴基或具有 3至6個碳原子之分支鏈單價烴基，其含有至少一個參鍵，例如乙炔基、丙炔基及其類似基團。「伸烧基J意謂具有1至6個碳原子之直鏈飽和二價烴基或具有3至6個碳原子之分支鏈飽和二價烴基，例如亞曱基、伸乙基、2,2-二曱基伸乙基、伸丙基' 2·甲基伸丙基、伸丁基、伸戊基及其類似基團。烧氧基」與「烧基氧基」可互換使用’意謂式-〇R之部分，其中R為如本文所定義之烷基部分。烷氧基部分之實例包括（但不限於）曱氧基、乙氧基、異丙氧基及其類似基團。「烷氧基烷基」意謂式Ra-0-Rb-之部分，其中Ra為如本文所定義之烷基且Rb為如本文所定義之伸烷基。例示性烷 157102.doc 201217379 氧基烷基包括例如2-曱氧基乙基、3_甲氧基丙基、丨·甲基_ 2-甲氧基乙基、1-(2-甲氧基乙基）_3_甲氧基丙基及丨气^甲氧基乙基）-3 -甲氧基丙基。「烧氧基烧氧基」意謂式-〇_R_R·之基團，其中r為如本文所疋義之伸院基且R’為如本文所定義之烧氧基。「烧基羰基」意謂式-C(0)-R之部分，其中R為如本文所定義之烷基。「烷氧羰基」意謂式-C(0)-R之基團，其中R為如本文所定義之烷氧基。「烷基羰基烷基」意謂式-R-C(〇)-R之基團，其中R為如本文所定義之伸烷基且R’為如本文所定義之烷基。「烧氧幾基烧基」意謂式-R-C(〇)-R之基團，其中R為如本文所定義之伸烧基且R’為如本文所定義之烷氧基。「烷氧羰基烷氧基」意謂式-〇-R_C(〇)-R’之基團，其中 R為如本文所定義之伸烷基且R，為如本文所定義之烷氧基。「烧基徵基胺基」意謂式-NRR’-C(0)-R·'之基團，其中R 為氫或如本文所定義之烷基，R·為如本文所定義之伸院基且RM為如本文所定義之烷基。「羥基羰基烷氧基」意謂式-0-R-C(0)-OH之基團，其中 R為如本文所定義之伸烷基。「烧基胺基叛基烧氧基」意謂式_〇_r_C(0)-NHR'之基團’其中R為如本文所定義之伸烷基且R|為如本文所定義之烷基。 157102.doc 201217379 一烷基胺基％基烷氧基」意謂式_〇_rc(〇)_nr，r，，之基團’其中R為如本文所定義之伸燒基且r，及r，，為如本文所定義之烷基。「烷基胺基烷氧基」意謂式_〇_R_NHRI之基團，其中R 為如本文所定義之伸烷基且Rl為如本文所定義之烷基。「二烷基胺基烷氧基」意謂式_〇_R_NR,R，，之基團，其中 R為如本文所定義之伸烷基且化及尺"為如本文所定義之烷基。「烷基磺醯基」意謂式_s〇2_R之部分，其中尺為如本文所定義之烷基》「烷基磺醯基烷基」意謂式_R，_S〇2_RM之部分，其中R，為如本文所定義之伸烷基且R"為如本文所定義之烷基。「烷基磺醯基烷氧基」意謂式_〇_R_s〇2_R，之基團，其中R為如本文所定義之伸烷基且R，為如本文所定義之烷基。「胺基」意謂式-NRR·之部分，其中汉及R,各自獨立地為氫或如本文所定義之烷基。「胺基」因此包括「烷基胺基」（其中R及R’中之一者為烷基且另_者為氫）及「二烷基胺基」（其中R及R'皆為烷基）。「經基烧基胺基」意謂式-NRR’之部分，其中r及R，為氫或如本文所定義之烷基且R，為如本文所定義之羥基烷基。「胺基幾基」意謂式-C(0)-R之基團，其中r為如本文所定義之胺基。「院氧基胺基」意謂式-NR-OR'之部分，其中r為氫或 157102.doc 201217379 如本文所定義之烷基且R'為如本文所定義之烷基。「烧基硫基」意謂式-SR之部分，其中R為如本文所定義之烷基。「胺基烷基」意謂基團-R-R'，其中R'為如本文所定義之胺基且R為如本文所定義之伸烷基。「胺基烷基」包括胺基甲基、胺基乙基、1-胺基丙基、 2-胺基丙基及其類似基團。「胺基烷基」之胺基部分可經烧基取代一次或兩次以分別提供「烷基胺基烷基」及「二烧基胺基烷基」。「烷基胺基烷基」包括甲基胺基甲基、曱基胺基乙基、甲基胺基丙基、乙基胺基乙基及其類似基團。「二烧基胺基烷基」包括二曱基胺基曱基、二曱基胺基乙基、二曱基胺基丙基、N_曱基_N_乙基胺基乙基及其類似基團。「胺基垸氧基」意謂基團_OR_R，，其中尺，為如本文所定義之胺基且R為如本文所定義之伸烷基。「院基磺醯胺基」意謂式-NR，S02-R之部分，其中R為烷基且R'為氫或烧基。「胺基幾基氧基烷基」或「胺甲醯基烷基」意謂式-R-0-C(〇)-NR’R’'之基團，其中r為如本文所定義之伸烷基且R’、R"各自獨立為氫或如本文所定義之烷基。块基院氧基」意謂式_〇_R_R，之基團，其中R為如本文所疋義之伸烷基且R，為如本文所定義之炔基。芳基」意謂由單環、雙環或三環芳族環組成之單價環，t族部分。芳基可如本文所定義視情況經取代。芳基部分之實例包括（但不限於）苯基、萘基、菲基、第基、茚 157102.doc 201217379 基、并環戊二烯基（pentalenyl)、奠基、氧基二苯基、聯苯基、亞甲基二苯基、胺基二苯基、二苯基硫基、二苯基績醯基、二苯基亞異丙基、苯并二噁烷基、笨并呋喃基、苯并一氧雜環戌烯基（benzodioxylyl)、苯并哌喃基、笨并噁嗪基、苯并噁嗪酮基、苯并哌啶基、苯并哌嗪基、苯并处洛咬基、苯并嗎淋基、亞曱基二氧基苯基、伸乙基二氧基苯基及其類似基團，包括其部分氫化之衍生物，其各自視情況經取代。芳基烷基」與「芳烷基」可互換使用，意謂基團-RaRb ’其中為如本文所定義之伸烷基且^為如本文所疋義之芳基；例如苯基烷基，諸如苯甲基、苯基乙基、 3-(3-氣苯基）-2-甲基戊基，且類似基團為芳基烷基之實例0 「芳基磺醯基」意謂式-SC^-r之基團，其中尺為如本文所定義之芳基。「芳基氧基」意謂式-0-R之基團，其中R為如本文所定義之芳基。「芳烷基氧基J意謂式-0_R_R||之基團，其令尺為如本文所定義之伸烷基且R，為如本文所定義之芳基。「羧基」或「羥基羰基」可互換使用，意謂式_c(〇)_〇H 之基團。「氰基烷基」意謂式-R，-R”之部分，其中R，為如本文所定義之伸烷基且R"為氰基或腈。「環烷基」意謂由單環或雙環組成之單價飽和碳環部 157102.doc -11- 201217379 分。較佳環烷基未經取代或經烷基取代。除非另外明確說明，否則環烷基可視情況經一或多個取代基取代，其中各取代基獨立為羥基、烷基、烷氧基、齒基、齒烷基、胺基、單烷基胺基或二烷基胺基。環烷基部分之實例包括 (但不限於）環丙基、環丁基、環戊基、環己基、環庚基及其類似基團’包括其部分不飽和（環烯基）衍生物。「環烷基烷基」意謂式-R’_R，，之部分，其中R，為如本文所定義之伸烧基且R"為如本文所定義之環烧基。環烧基娱》氧基」意謂式-〇_R_R’之基團，其中r為如本文所定義之伸烷基且R'為如本文所定義之環烷基。「雜烷基J意謂如本文所定義之烷基，其中1、2或3個氫原子已置換為獨立選自由以下組成之群的取代基：-ORa、-NRbRc及-S(0)nRd(其中!!為0至2之整數），應瞭解雜烷基之連接點係經由碳原子，其中Ra為氫、醯基、院基、環烧基或環烧基烧基，^及Re彼此獨立為氫、醢基、烧基、環烧基或環烧基烧基；且當η為〇時，Rd為氫、燒基、環烧基或環院基烧基，且當η為1或2時，1^為烧基、環烷基、環烷基烷基、胺基、醯基胺基、單烷基胺基或二烷基胺基。代表性實例包括（但不限於）2-羥基乙基、3_經基丙基、2-經基-1-經基甲基乙基、2,3-二經基丙基、1-經基曱基乙基、3-經基丁基、2,3-二經基丁基、2·經基-1-甲基丙基、2-胺基乙基、3-胺基丙基、2-甲基磺醯基乙基、胺基續醯基甲基、胺基磺醯基乙基、胺基罐醯基丙基、甲基胺基續酿基甲基、甲基胺基績醯基乙基、甲基胺基續酿 157102.doc -12- 201217379 基丙基及其類似基團。「雜芳基」意謂具有至少_個芳族環的5至12個環原子之單環或雙環基團，該芳族環含有i、2或3個選自Ν、〇或 S之環雜原子，其餘環原子為C，應瞭解雜芳基之連接點將在方族環上。雜芳基環可如本文所定義視情況經取代。雜芳基部分之實例包括（但不限於）視情況經取代之咪唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、噁二唑基、噻二唑基、吡嗪基、噻吩基（thienyl)、苯并噻吩基噻吩基籲（―)、呋喃基、哌喃基、吡啶基、吡咯基吡唑基、嘧啶基、喧啉基、異喹啉基、苯并呋喃基、苯并噻吩基、苯并噻喃基、苯并咪唑基、苯并噁唑基、苯并噁二唑基、苯并噻唑基、苯并噻二唑基、苯并哌喃基、吲哚基、異吲哚基、三唑基、三嗪基、喹喏啉基、嘌呤基、喹唑啉基、喹嗪基、喑啶基、喋啶基、咔唑基、氮呼基、二氮呼基、吖啶基及其類似基團，包括其部分氫化之衍生物，其各自視情況經取代。 ® 「雜芳基烷基」或「雜芳烷基」意謂式_R_R，之基團，其中R為如本文所定義之伸烷基且R，為如本文所定義之雜芳基。「雜芳基磺醯基」意謂式_S〇2_r之基團，其中R為如本文所定義之雜芳基。「雜芳基氧基」意謂式-Ο-R之基團，其中r為如本文所定義之雜芳基。「雜芳烷基氧基」意謂式-〇-R_R，，之基團，其中R為如本 157102.doc -13· 201217379 文所定義之伸烷基且R’為如本文所定義之雜芳基。了互換使用之術語「鹵基」、「齒素」及「齒」係指取代基氟、氣、溴或碘》「鹵烷基」意謂一或多個氫已置換為相同或不同鹵素的如本文所定義之烷基》例示性鹵烷基包括_CH2C1、_CH2CF3 、-CHzCCl3、全氟烷基（例如_cf3)及其類似基團β _烧氧基」意谓式-OR之部分，其中r為如本文所定義之_烷基部分。例示性齒烷氧基為二氟〒氧基。「雜環胺基」意謂至少一個環原子為N、NH或N-烷基且其餘環原子形成伸烷基的飽和環。「雜環基」意謂由1至3個環組成之併有1個、2個或3個或4個雜原子（選自氮、氧或硫）的單價飽和部分》雜環基環可如本文所定義視情況經取代。雜環基部分之實例包括 (但不限於）視情況經取代之哌啶基、哌嗪基、高哌嗪基、氮呼基、°比洛咬基、》比β坐咬基、咪唾琳基、β米唾咬基、〇比咬基、噠嗪基、嘧啶基、噁唑啶基、異噁唑啶基、嗎啉基、噻唑啶基、異噻唑啶基、嗝啶基、喹啉基、異喹啉基、苯并咪唑基、噻二唑啶基、苯并噻唑啶基、苯并唑啶基、二氫°夫喊基、四氫咬喃基、二氫D底喊基、四氫^辰喃基、噻嗎啉基、噻嗎啉基亞砜、噻嗎啉基砜、二氫喹啉基、二氫異喹啉基、四氫喹啉基、四氫異喹啉基及其類似基團β 「雜環烷基」意謂式-R-R'之部分，其中r為如本文所定義之伸烷基且R，為如本文所定義之雜環基。 157102.doc • 14· 201217379 雜環基氧基」意謂式-OR之部分’其中R為如本文所定義之雜環基。「雜環基烷氧基」意謂式-OR-R，之部分，其中R為如本文所定義之伸烷基且R，為如本文所定義之雜環基。「羥基烷氧基」意謂式-OR之部分，其中r為如本文所定義之羥基烷基。「羥基烯基j意謂式-R-OH之部分，其中R為如本文所定義之烯基。「羥基烷基胺基」意謂式-NR-R，之部分，其中r為氫或如本文所定義之烷基且R|為如本文所定義之羥基烷基。「羥基烷基胺基羰基」意謂式-C(0)NR-R，之部分，其中 R為氫或如本文所定義之烷基且R，為如本文所定義之羥基烷基。「羥基烷基胺基烷基」意謂式-R-NR’-R"之部分，其中R 為如本文所定義之伸烷基，R'為氫或如本文所定義之烷基’且R"為如本文所定義之經基院基。「經基幾基院基」或「叛基烧基」意謂式_r_(C〇)_〇h之基團，其中R為如本文所定義之伸烷基。「經基幾基炫•氧基」意謂式-〇-R-C(〇)-〇H之基團，其中 R為如本文所定義之伸烷基。「羥基烷基氡羰基烷基」或「羥基烷氧羰基烷基」意謂 S_r-c(o)-o-r-oh之基團，其中各R為伸烷基且可相同或不同·。「經基烧基」意謂經一或多個，諸如1、2或3個羥基取 157102.doc -15· 201217379 代之如本文所定義之烧基部分，其限制條件為同一碳原子不帶有一個以上羥基。代表性實例包括（但不限於）羥基罗基、2-羥基乙基、2-羥基丙基、3_羥基丙基、】_(羥基甲基）-2-甲基丙基、2-羥基丁基、3-羥基丁基、4-羥基丁基、 2,3-二羥基丙基、2-羥基-1-羥基曱基乙基、23·二羥基丁基、3,4-二羥基丁基及2-(羥基甲基）_3_羥基丙基。「羥基環烷基」意謂環烷基中之丨、2或3個氫原子已置換為羥基取代基的如本文所定義之環烷基部分。代表性實例包括（但不限於）2-羥基環己基、3_羥基環己基或4_羥基環己基，及其類似基團。「烧氧基羥基烧基」與「羥基院氧基烧基」可互換使用，意謂經羥基取代至少一次且經烷氧基取代至少一次的如本文所定義之烷基。「烷氧基羥基烷基」及「羥基烷氧基烷基」因此涵蓋例如2-羥基-3-甲氧基-丙-1-基及其類似基團。「苯基胺基羰基」意謂式_C(〇)-NR-R，之基團，其中R為氫或如本文所定義之烷基且R，為如本文所定義之苯基。「腺」或「脲基」意謂式_NR，-C(0)-NRMR，'’之基團，其中R，' R，，及R，，·各自獨立為氫或烷基。「胺基甲酸酯」意謂式_0_C(0)_NR'R"之基團，其中R’ 及R"各自獨立為氫或烷基。「羧基」意謂式_〇-C(〇)_〇h之基團。「續酿胺基」意謂式·S〇2_nr，R'·之基團，其中R·、R，’及 R'"各自獨立為氫或烷基。 157102.doc 201217379 當與「芳基」、「苯基」、「雜芳基」、「環烷基」或「雜環基」結合使用時，「視情況經取代」意謂芳基、苯基、雜芳基、環烷基或雜環基視情況獨立經1至4個，較佳1或2個選自以下之取代基取代：烷基、環烷基、環烷基烷基、雜烷基、羥基烷基、齒基、硝基、氰基、羥基、烷氧基、胺基、醯基胺基、單烧基胺基、二烧基胺基、函烧基、鹵烧氧基、雜烷基、-COR、-S02R(其中R為氫、烷基、苯基或苯基院基）、-(CR'R")n-COOR(其中η為0至5之整數，R’及 R"獨立為氫或烷基’且R為氫、烷基、環烷基、環烷基烷基、苯基或苯基烷基），或_(CR|R，，)n-CONRaRb(其中η為0至 5之整數，R'及RM獨立為氫或烷基，且Ra及Rb彼此獨立為氫、烷基、環烷基、環烷基烷基、苯基或苯基烷基）。「芳基」、「苯基」、「雜芳基」、「環烷基」或「雜環基」之某些較佳可選取代基包括烷基、鹵基、鹵烷基、烷氧基、氰基、胺基及烧基項醯基》更佳取代基為甲基、氣、氣、三氟甲基、曱氧基、胺基及甲烷磺醯基。「離去基」意謂具有通常與其合成有機化學有關之含義的基團’亦即在取代反應條件下可置換之原子或基團。離去基之實例包括（但不限於）函素、烷烴磺醯氧基或伸芳基續醯氧基’諸如甲烷磺醢氧基、乙烷磺醢氧基、硫基曱基、苯磺醯氧基、甲苯磺醯氧基及噻吩基氧基、二自基膦酿氧基、視情況經取代之苯甲氧基、異丙氧基、酿氧基及其類似基團。「調節劑」意謂與目標相互作用之分子。相互作用包括 157102.doc •17- 201217379 (但不限於)如本文所定義之促效劑、拮抗劑及其類似物。視清況可選」或「視情況」意謂可能出現但並非必需出現隨後所述之事件或情形，且該描述包括該事件或情形出現之狀況及該事件或情形不出現之狀況。「疾病」及「疾病病況」意謂任何疾病、病狀、症狀、病症或適應症。「惰性有機溶劑」或「惰性溶劑」意謂溶劑在與其結合描述之反應條件下呈惰性，包括例如苯、甲苯、乙腈、四氫咬痛、Ν，Ν-二甲基f酿胺、氣仿、二氣甲燒、二氯乙烷、乙醚、乙酸乙酯、丙酮、甲基乙基酮、甲醇 '乙醇、丙醇、異丙醇、第三丁醇、二噁烷、吡啶及其類似物。除非相反說明，否則本發明反應中所用之溶劑為惰性溶劑。「醫藥學上可接受」意謂適於製備一般安全、無毒且不為生物學上或其他方面不合需要之醫藥組合物的物質且包括獸醫用途以及人類醫藥用途上可接受者。化合物之「醫藥學上可接受之鹽」意謂如本文所定義之醫藥學上可接受且具有母體化合物之所要藥理學活性的鹽。該等鹽包括：與無機酸’諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似酸；或與有機酸，諸如乙酸、苯磺酸、苯甲酸、樟腦續酸、檸檬酸、乙烧續酸、反丁烯二酸、葡糖庚酸、葡萄糖酸、麩胺酸、乙醇酸、羥基萘酸、2-羥基乙烷磺酸、乳酸、順丁烯二酸、蘋果酸、丙二酸、扁桃酸、曱烷磺酸、黏康酸' 2-萘磺酸、丙酸、水揚酸、丁二酸、酒石酸、對 157102.doc -18 - 201217379 甲笨命酸、二甲基乙酸及其類似酸形成之酸加成鹽；或田母體化合物中存在之酸性質子經金屬離子（例如，鹼金屬離子、鹼土離子或鋁離子）置換或與有機或無機鹼配位形成之鹽。可接受之有機鹼包括二乙醇胺、乙醇胺、N- 甲基葡糖胺、二乙醇胺、緩血酸胺及其類似物。可接受之無機鹼包括氫氧化鋁 '氫氧化鈣、氫氧化鉀、碳酸鈉及氫氧化納。較佳的醫藥學上可接受之鹽為自乙酸、鹽酸、硫酸、甲鲁院項酸、順丁烯二酸、磷酸、酒石酸、檸檬酸、鈉、鉀、鈣、鋅及鎂形成之鹽。應瞭解，對醫藥學上可接受之鹽的所有提及均包括同一酸加成鹽的如本文所定義之溶劑加成形式（溶劑合物）或晶體形式（多晶型物）。「保護基」意謂在合成化學中通常與其有關之含義中，選擇性阻斷多官能基化合物中之一個反應位點使得化學反 ^ 應可在另一未經保護之反應位點選擇性進行的基團。本發明之某些方法依賴於阻斷反應物中存在之反應性氮及/或氧原子之保護基。舉例而言，術語「胺基保護基」及「氮保護基」在本文甲可互換使用且係指意欲在合成程序期間保護氮原子免於發生非所要反應之彼等有機基團。例示性氮保護基包括（但不限於）三氟乙醢基、乙醯胺基、苯甲基 (Bn)、苯甲氧羰基（CBZ)、對甲氧基苯甲氧羰基、對硝基苯甲氧幾基、第三丁氧羰基（B〇c)及其類似基團。熟習此項技術者將知曉如何針對容易移除且針對承受隨後反應之 157102.doc -19· 201217379 能力選擇基團。溶劑合物」意謂含有化學計量或非化學計量之量的溶劑之溶劑加成形式。—些化合物具有將固定莫耳比之溶劑刀子捕捉於結晶固體狀態中，因此形成溶劑合物之趨勢。若劑為水，則形成之溶劑合物為水合物，當溶劑為醇時，形成之溶劑合物為醇化物。水合物係藉由使一或多個水刀子與物質中之-者組合形成（其中水保持其Η2〇之分子狀態），該組合能夠形成一或多種水合物。"Alkenyl" means a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain monovalent hydrocarbon group having 3 to 6 carbon atoms, which contains at least one double bond, such as a vinyl group, a propenyl group and the like. "Alkynyl" means a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain monovalent hydrocarbon group having 3 to 6 carbon atoms, which contains at least one reference bond such as an ethynyl group, a propynyl group and the like. . "Stretching base J means a linear saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched divalent hydrocarbon group having 3 to 6 carbon atoms, such as an anthracene group, an extended ethyl group, 2,2- Diterpene-based ethyl, propyl- 2,methyl-propyl, butyl, pentyl and the like. Alkoxy" and "alkyloxy" are used interchangeably to mean - Part of 〇R, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, decyloxy, ethoxy, isopropoxy and the like. "Alkoxyalkyl" means a moiety of the formula Ra-0-Rb- wherein Ra is alkyl as defined herein and Rb is alkyl as defined herein. Exemplary alkane 157102.doc 201217379 The oxyalkyl group includes, for example, 2-methoxyethyl, 3-methoxypropyl, hydrazinomethyl-2-methoxyethyl, 1-(2-methoxy Ethyl)_3_methoxypropyl and anthracene^methoxyethyl)-3-methoxypropyl. "Alkoxylated alkoxy" means a radical of the formula -〇_R_R. wherein r is a radical as defined herein and R' is an alkoxy group as defined herein. "Carborylcarbonyl" means a moiety of the formula -C(0)-R wherein R is alkyl as defined herein. "Alkoxycarbonyl" means a radical of the formula -C(0)-R wherein R is alkoxy as defined herein. "Alkylcarbonylalkyl" means a radical of the formula -R-C(〇)-R wherein R is alkylene as defined herein and R' is alkyl as defined herein. "Oxygenated aryl group" means a group of the formula -R-C(〇)-R wherein R is a stretching group as defined herein and R' is an alkoxy group as defined herein. "Alkoxycarbonylalkoxy" means a radical of the formula -R-C(〇)-R' wherein R is alkyl and R, as defined herein, is an alkoxy group, as defined herein. "Alkylamino" means a radical of the formula -NRR'-C(0)-R. ', wherein R is hydrogen or alkyl as defined herein, and R is a extender as defined herein. And RM is an alkyl group as defined herein. "Hydroxycarbonylalkoxy" means a radical of the formula-0-R-C(O)-OH wherein R is alkylene as defined herein. "Acetylamino-based alkoxy" means a group of the formula _〇_r_C(0)-NHR' wherein R is an alkylene group as defined herein and R| is an alkyl group as defined herein . 157102.doc 201217379 monoalkylamino-alkylalkoxy" means a radical of the formula _〇_rc(〇)_nr,r,, wherein R is a stretching group as defined herein and r, and r , is an alkyl group as defined herein. "Alkylaminoalkoxy" means a group of the formula _〇_R_NHRI wherein R is alkyl as defined herein and R1 is alkyl as defined herein. "Dialkylaminoalkoxy" means a radical of the formula _〇_R_NR, R, wherein R is alkyl as defined herein and is defined as alkyl as defined herein. . "Alkylsulfonyl" means a moiety of the formula _s〇2_R, wherein the ampule is an alkyl group as defined herein, "alkylsulfonylalkyl" means a moiety of the formula _R, _S〇2_RM, wherein R, is an alkylene group as defined herein and R" is an alkyl group as defined herein. "Alkylsulfonylalkoxy" means a radical of the formula _〇_R_s〇2_R, wherein R is alkylene as defined herein and R is alkyl as defined herein. "Amine" means a moiety of the formula -NRR. wherein Han and R are each independently hydrogen or an alkyl group as defined herein. "Amine" thus includes "alkylamino" (wherein one of R and R' is alkyl and the other is hydrogen) and "dialkylamino" (wherein R and R' are both alkyl ). "Carboalkylamino" means a moiety of the formula -NRR' wherein r and R are hydrogen or alkyl as defined herein and R is hydroxyalkyl as defined herein. "Amino" means a group of the formula -C(0)-R wherein r is an amine group as defined herein. "Homoyloxyamino" means a moiety of the formula -NR-OR' wherein r is hydrogen or 157102.doc 201217379 alkyl as defined herein and R' is alkyl as defined herein. "Acidylthio" means a moiety of the formula -SR wherein R is alkyl as defined herein. "Aminoalkyl" means a radical -R-R' wherein R' is an amine group as defined herein and R is alkylene as defined herein. The "aminoalkyl group" includes an aminomethyl group, an aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group, and the like. The amine moiety of the "aminoalkyl group" may be substituted one or two times with an alkyl group to provide "alkylaminoalkyl" and "dialkylaminoalkyl", respectively. The "alkylaminoalkyl group" includes methylaminomethyl, decylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. "Dialkylaminoalkyl" includes dinonylaminoindenyl, dinonylaminoethyl, dinonylaminopropyl, N-fluorenyl-N-ethylaminoethyl and the like Group. "Amino methoxy" means a group _OR_R, wherein amp, an amine group as defined herein and R is an alkylene group as defined herein. "Hospital sulfonamide" means a moiety of the formula -NR, S02-R wherein R is alkyl and R' is hydrogen or alkyl. "Aminoalkyloxyalkyl" or "aminomethylalkylalkyl" means a radical of the formula -R-0-C(〇)-NR'R'' wherein r is as defined herein. Alkyl and R', R" are each independently hydrogen or alkyl as defined herein. "Bulk oxy" means a group of the formula _〇_R_R, wherein R is alkylene as defined herein and R is alkynyl as defined herein. "Aryl" means a monovalent ring, a t-membered moiety consisting of a monocyclic, bicyclic or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, decyl, 茚157102.doc 201217379, pentalenyl, base, oxydiphenyl, biphenyl , methylene diphenyl, amino diphenyl, diphenylthio, diphenyl fluorenyl, diphenyl isopropylidene, benzodioxyl, benzofuranyl, benzo Benzodioxylyl, benzopipetanyl, benzoxazinyl, benzoxazinone, benzopiperidinyl, benzopiperazinyl, benzoxyl, benzene And thiolinyl, fluorenyldioxyphenyl, ethylenedioxyphenyl and the like, including partially hydrogenated derivatives thereof, each of which is optionally substituted. "Arylalkyl" is used interchangeably with "aralkyl" to mean a radical -RaRb' wherein alkyl is alkyl as defined herein and is aryl as defined herein; for example phenylalkyl, such as Example of benzyl, phenylethyl, 3-(3-phenylphenyl)-2-methylpentyl, and the like group is an arylalkyl group. "Arylsulfonyl" means a formula -SC a group of ^-r, wherein the ruler is an aryl group as defined herein. "Aryloxy" means a radical of the formula -0-R wherein R is aryl as defined herein. "Aralkyloxy group J means a group of the formula -0_R_R||, which has an alkylene group as defined herein and R, which is an aryl group as defined herein. "Carboxyl" or "hydroxycarbonyl" Interchangeable use means a group of the formula _c(〇)_〇H. "Cyanoalkyl" means a moiety of the formula -R, -R" wherein R is alkyl as defined herein and R" is cyano or nitrile. "Cycloalkyl" means monocyclic or The monovalent saturated carbon ring portion composed of double rings 157102.doc -11- 201217379 points. Preferably, the cycloalkyl group is unsubstituted or substituted with an alkyl group. Unless otherwise specifically stated, a cycloalkyl group may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, dentate, dentate, amine, monoalkylamine Or a dialkylamino group. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including their partially unsaturated (cycloalkenyl) derivatives. "Cycloalkylalkyl" means a moiety of the formula -R'_R, wherein R is a stretching group as defined herein and R" is a cycloalkyl group as defined herein. "Alkyl" means a group of the formula -〇_R_R' wherein r is alkyl as defined herein and R' is cycloalkyl as defined herein. "Heteroalkyl J means an alkyl group as defined herein, wherein 1, 2 or 3 hydrogen atoms have been replaced by substituents independently selected from the group consisting of -ORa, -NRbRc and -S(0)nRd (where !! is an integer from 0 to 2), it should be understood that the point of attachment of the heteroalkyl group is via a carbon atom, wherein Ra is hydrogen, fluorenyl, pendant, cycloalkyl or cycloalkyl, ^ and Re each other Independently hydrogen, fluorenyl, alkyl, cycloalkyl or cycloalkyl; and when η is hydrazine, Rd is hydrogen, alkyl, cycloalkyl or ring-based, and when η is 1 or At 2 o'clock, 1 is a decyl group, a cycloalkyl group, a cycloalkylalkyl group, an amine group, a decylamino group, a monoalkylamino group or a dialkylamino group. Representative examples include, but are not limited to, 2- Hydroxyethyl, 3-cysopropyl, 2-yl-1-methylmethylethyl, 2,3-dipropylpropyl, 1-ylhydrazinoethyl, 3-carbylbutyl , 2,3-di-transbutyl, 2,yl-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, amine Mercaptomethyl, aminosulfonylethyl, amine-based canlylpropyl, methylamino-based chloromethyl, methylamine-based decylethyl, Methylamino group continuation 157102.doc -12- 201217379 propyl group and the like. "Heteroaryl" means a monocyclic or bicyclic group having 5 to 12 ring atoms of at least _ aromatic ring. The aromatic ring contains i, 2 or 3 ring heteroatoms selected from the group consisting of ruthenium, osmium or S, and the remaining ring atoms are C. It should be understood that the point of attachment of the heteroaryl group will be on the family ring. A heteroaryl ring can be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, Thienyl, benzothienylthiophene (-), furyl, piperidyl, pyridyl, pyrrolylpyrazolyl, pyrimidinyl, porphyrin, isoquinolyl, benzofuranyl, Benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, fluorenyl , isodecyl, triazolyl, triazinyl, quinoxalinyl, fluorenyl, quinazolinyl, quinazinyl, acridinyl, acridinyl, oxazolyl, aziridine, diazepam The base, acridinyl group and the like, including partially hydrogenated derivatives thereof, are each optionally substituted. ® "heteroarylalkyl" or "heteroaralkyl" means a radical of the formula _R_R, wherein R is alkylene as defined herein and R is heteroaryl as defined herein. "Heteroarylsulfonyl" means a group of the formula _S〇2_r wherein R is a heteroaryl group as defined herein. "Heteroaryloxy" means a radical of the formula -Ο-R wherein r is heteroaryl as defined herein. "Heteroaralkyloxy" means a radical of the formula -〇-R_R, wherein R is alkyl as defined in 157102.doc -13 201217379 and R' is as defined herein. Aryl. The terms "halo", "dentate" and "dentate" are used interchangeably to refer to a radical, fluoro, iodine or iodine. "Haloalkyl" means that one or more hydrogens have been replaced by the same or different halogens. An alkyl group, as defined herein, includes _CH2C1, _CH2CF3, -CHzCCl3, perfluoroalkyl (eg, _cf3), and the like, β-alkoxy, meaning part of the formula -OR, Wherein r is an _alkyl moiety as defined herein. An exemplary dentate alkoxy group is a difluorodecyloxy group. "Heterocyclic amine group" means a saturated ring in which at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group. "Heterocyclyl" means a monovalent saturated moiety consisting of 1 to 3 rings and having 1, 2 or 3 or 4 heteroatoms (selected from nitrogen, oxygen or sulfur). The definitions herein are superseded as appropriate. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azirretyl, phlodolyl, "beta", and sodium saliva Base, β-salt base, indole, oxazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, acridinyl, quinoline Alkyl, isoquinolyl, benzimidazolyl, thiadiazolidinyl, benzothiazolidinyl, benzoxazinyl, dihydro oxime, tetrahydronethane, dihydro D Tetrahydro-n-butyl group, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dihydroquinolyl, dihydroisoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolinyl And a similar group β "heterocycloalkyl" means a moiety of the formula -R-R' wherein r is alkyl as defined herein and R is heterocyclyl as defined herein. 157102.doc • 14· 201217379 Heterocyclyloxy” means a moiety of the formula -OR wherein R is a heterocyclyl group as defined herein. "Heterocyclylalkoxy" means a moiety of the formula -OR-R, wherein R is alkyl as defined herein and R is heterocyclyl as defined herein. "Hydroxyalkoxy" means a moiety of the formula -OR wherein r is hydroxyalkyl as defined herein. "Hydroxyalkenyl j means a moiety of the formula -R-OH wherein R is alkenyl as defined herein. "Hydroxyalkylamino" means a moiety of the formula -NR-R, wherein r is hydrogen or Alkyl as defined herein and R| is hydroxyalkyl as defined herein. "Hydroxyalkylaminocarbonyl" means a moiety of the formula -C(O)NR-R, wherein R is hydrogen or alkyl as defined herein and R is hydroxyalkyl as defined herein. "Hydroxyalkylaminoalkyl" means a moiety of the formula -R-NR'-R" wherein R is alkyl as defined herein, R' is hydrogen or alkyl as defined herein and R"; is a base based as defined herein. "基基基基基基" or "叛基基基" means a group of the formula _r_(C〇)_〇h, wherein R is an alkylene group as defined herein. "Homo-based oxime-oxy" means a radical of the formula -R-C(〇)-〇H, wherein R is alkylene as defined herein. "Hydroxyalkyl hydrazinocarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of S_r-c(o)-o-r-oh wherein each R is an alkylene group and may be the same or different. By "base group" is meant a group of one or more, such as 1, 2 or 3 hydroxyl groups, 157102.doc -15. 201217379, as defined herein, with the limitation that the same carbon atom is not There is more than one hydroxyl group. Representative examples include, but are not limited to, hydroxycyclyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, _(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl , 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxydecylethyl, 23·dihydroxybutyl, 3,4-dihydroxybutyl And 2-(hydroxymethyl)_3_hydroxypropyl. "Hydroxycycloalkyl" means a cycloalkyl moiety as defined herein wherein hydrazine, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl or 4-hydroxycyclohexyl, and the like. "Alkoxylated hydroxyalkyl" is used interchangeably with "hydroxyloxyalkyl", meaning an alkyl group, as defined herein, substituted at least once with a hydroxy group and at least once with an alkoxy group. "Alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" thus encompass, for example, 2-hydroxy-3-methoxy-prop-1-yl and the like. "Phenylaminocarbonyl" means a radical of the formula _C(〇)-NR-R, wherein R is hydrogen or alkyl as defined herein and R is phenyl as defined herein. "Gland" or "ureido" means a group of the formula _NR, -C(0)-NRMR, '', wherein R, 'R, and R,, are each independently hydrogen or an alkyl group. "Aminoformate" means a group of the formula _0_C(0)_NR'R", wherein R' and R" are each independently hydrogen or alkyl. "Carboxy" means a group of the formula _〇-C(〇)_〇h. "Continuous amine group" means a group of the formula: S〇2_nr, R'. wherein R·, R, ' and R'" are each independently hydrogen or alkyl. 157102.doc 201217379 When used in combination with "aryl", "phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl", "optionally substituted" means aryl, phenyl a heteroaryl, cycloalkyl or heterocyclic group optionally substituted by 1 to 4, preferably 1 or 2 substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl Base, hydroxyalkyl, dentyl, nitro, cyano, hydroxy, alkoxy, amine, decylamino, monoalkylamino, dialkylamino, functional alkyl, halooxy, Heteroalkyl, -COR, -S02R (wherein R is hydrogen, alkyl, phenyl or phenyl), -(CR'R")n-COOR (where η is an integer from 0 to 5, R' and R" independently hydrogen or alkyl ' and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or _(CR|R,,)n-CONRaRb (where η is an integer of 0 to 5, R' and RM are independently hydrogen or alkyl, and Ra and Rb are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Some preferred substituents of "aryl", "phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl, alkoxy More preferred substituents for the cyano group, the amine group and the alkyl group are methyl, gas, gas, trifluoromethyl, decyloxy, amine and methanesulfonyl. "Leaving group" means a group having the meaning commonly associated with its synthetic organic chemistry, i.e., an atom or group that is replaceable under the conditions of the substitution reaction. Examples of leaving groups include, but are not limited to, a functional element, an alkane sulfonyloxy group or an aryl aryloxy group such as methanesulfonyloxy, ethanesulfonyloxy, thiosulfonyl, phenylsulfonate An oxy group, a tosyloxy group and a thienyloxy group, a bis-phosphinyloxy group, an optionally substituted benzyloxy group, an isopropoxy group, a ethoxylated group and the like. "Regulator" means a molecule that interacts with a target. Interactions include 157102.doc • 17-201217379 (but not limited to) agonists, antagonists, and analogs thereof as defined herein. "Optional" or "as appropriate" means that an event or circumstance may occur, but is not required to occur, and that the description includes the condition in which the event or circumstance occurs and the condition in which the event or circumstance does not occur. "Disease" and "disease condition" means any disease, condition, symptom, condition or indication. "Inert organic solvent" or "inert solvent" means that the solvent is inert under the reaction conditions described in connection therewith, and includes, for example, benzene, toluene, acetonitrile, tetrahydrobite, hydrazine, hydrazine-dimethyl-f-amine, gas imitation. , methane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol 'ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like . Unless otherwise stated, the solvent used in the reaction of the present invention is an inert solvent. "Pharmaceutically acceptable" means a material suitable for the preparation of a pharmaceutical composition which is generally safe, non-toxic and which is not biologically or otherwise undesirable and which is acceptable for veterinary use as well as for human medical use. "Pharmaceutically acceptable salt" of a compound means a salt which is pharmaceutically acceptable as defined herein and which has the desired pharmacological activity of the parent compound. Such salts include: with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphoric acid, citric acid, ethidium Continued acid, fumaric acid, glucomannanic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid , mandelic acid, decane sulfonic acid, muconic acid '2-naphthalene sulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, 157102.doc -18 - 201217379 A benzoic acid, dimethyl acetic acid and An acid addition salt similar to an acid; or a salt formed by a metal ion (for example, an alkali metal ion, an alkaline earth ion or an aluminum ion) or a complex with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, diethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide 'calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Preferred pharmaceutically acceptable salts are those formed from acetic acid, hydrochloric acid, sulfuric acid, gallic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium. It will be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt. "Protecting group" means selectively blocking one of the polyfunctional compounds in a meaning that is normally associated with it in synthetic chemistry such that the chemical reaction can be selectively carried out at another unprotected reaction site. Group. Certain methods of the invention rely on blocking the protecting groups of reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms "amino protecting group" and "nitrogen protecting group" are used interchangeably herein and refer to those organic groups that are intended to protect the nitrogen atom from undesired reactions during the synthetic procedure. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetamido, etidinyl, benzyl (Bn), benzyloxycarbonyl (CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzene A methoxy group, a third butoxycarbonyl group (B〇c) and the like. Those skilled in the art will know how to select groups for easy removal and for 157102.doc -19· 201217379 capacity to withstand subsequent reactions. By solvate is meant a solvent addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some of these compounds have a tendency to capture a molar molar ratio solvent knife in a crystalline solid state, thus forming a solvate. If the agent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. The hydrate is formed by combining one or more water knives with a substance in which the water maintains its molecular state, which combination is capable of forming one or more hydrates.

「個體」意謂哺乳動物及非哺乳動物"•乳動物意謂，乳綱之任何成員’包括(但不限於)人類；非人類靈長類鸯物’諸如黑㈣及其他猿類及狼類；農畜，諸如牛馬、羊山羊及豬’豕畜’諸如家兔、犬及貓；實驗動物， ::截齒動物，諸如大鼠、小鼠及天竺鼠；及其類似哺勒哺乳動物之實例包括（但不限於）鳥類及其類㈣動物。術語「個體」不指示特定年齡或性別。“Individual” means mammalian and non-mammalian • Milky animal means that any member of the milk family includes (but is not limited to) humans; non-human primate animals such as black (four) and other apes and wolves Farm animals, such as cattle and horses, goats and pigs, such as rabbits, dogs and cats; experimental animals, :: truncated animals, such as rats, mice and guinea pigs; and similar mammals Examples include, but are not limited to, birds and their class (iv) animals. The term "individual" does not indicate a particular age or gender.

發炎疾病」思謂伴隨發炎、過敏及/或增生過程之疾病病況或適應症且可包括：、 (0肺病：任何起源之慢 —如匣生阻塞性肺病，尤其支氣管喘及慢性阻塞性肺病 rARDS、. * u QPD)，成人呼Μ迫症候 (ARDS)，支氣管擴張.女#上， ’ ·種起源之支氣管炎；所有开;{ 之限制性肺病，尤I所有形尤其毒性肺水腫之肺水腫 ,..^ Λ 何起源的所有形式之間質性肺病，如放射性肺炎；以及尚 1用 . 肉狀瘤病及甲狀腺腫，尤其倍克氏 (Boeck disease)。、兄氏 157102.doc -20- 201217379 (ii) 風濕性疾病或自體免疫疾病或關節疾病：所有形式之風濕性疾病，尤其類風濕性關節炎、急性風濕熱及風濕性多肌痛；反應性關節炎；風濕性軟組織疾病；其他起源之發炎性軟組織疾病；退化性關節疾病（關節病）中之關節炎症狀；創傷性關節炎；任何起源之膠原蛋白病 (collagenose) ’例如全身性紅斑性狼瘡症、硬皮病、多發性肌炎、皮肌炎、休格連症候群（Sj0gren Syndr〇ine)、斯蒂爾病（Still disease)及費爾蒂症候群（Felty syndrome); (iii) 過敏性疾病：所有形式之過敏反應，例如血管神經性水腫、花粉熱、昆蟲咬傷、對藥物、血液衍生物、對比劑等之過敏反應、過敏性休克（全身性過敏反應）、蓴麻疹、血管神經性水踵及接觸性皮炎； (iv) jk管炎疾病：結節性全動脈炎、結節性多動脈炎、顯肌動脈炎、華格納氏肉芽腫病（Wegner granulomatosis)、巨細胞關節炎及結節性紅斑； (v) 皮膚科疾病：異位性皮炎，尤其在兒童中；牛皮癖；毛髮紅糠疹；由多種有害物引發之紅斑性疾病，例如射線、化學品、劣質品等；水泡性皮膚病；苔蘚樣複合疾病；搔癢症（例如過敏性起源）；脂溢性皮炎；紅斑痤瘡；尋常天疱瘡；滲出性多形紅斑；龜頭炎；外陰炎；毛髮減少’諸如斑形脫髮中所出現；及皮膚T細胞淋巴瘤； (vi) 腎病：腎病症候群；及所有類型之腎炎，例如絲球體腎炎； (vii) 肝病：急性肝細胞崩解；各種起源之急性肝炎，例 157102.doc -21 · 201217379 如病毒、毒素、藥物誘發；及慢性侵襲性及/或慢性間歇性肝炎； (viiO胃腸疾病：發炎性腸病，例如局部性腸炎(克羅恩氏病（Crohn disease))、潰瘍性結腸炎；胃炎；消化性食道炎（回流性食道炎（reflUX〇es〇Phagitis));及其他起源之胃腸炎，例如非熱帶性口瘡；直腸疾病：肛門濕療；肛裂；痺瘡；及特發性直腸炎； (X) 眼病：過敏性角膜炎、葡萄膜炎或虹膜炎；結膜炎；眼瞼炎；視神經炎；脈絡膜炎；及交感性眼炎； (XI) 耳、鼻及喉（ENT)區域之疾病：過敏性鼻炎或花粉熱；外耳炎’例如由接觸性濕疹、感染等引起；及中耳炎； (xii)神經疾病：腦水腫，尤其腫瘤相關之腦水腫；多發性硬化症；急性腦脊髓炎；腦膜炎；急性脊髓損傷；中風；及各種形式之發作，例如點頭狀抽搐； (X111)血液疾病：後天溶血性貧血；及特發性血小板減少症； (xiv) 腫瘤疾病：急性淋巴性白血病；惡性淋巴瘤；淋巴肉芽腫；淋巴肉瘤；廣泛轉移，尤其在乳癌、支氣管癌及前列腺癌中； (xv) 内分泌疾病：内分泌眼病變；内分泌眼寫症；曱狀腺危症（thyrotoxic crisis);奎汶氏甲狀腺炎（Thyr〇iditis deInflammatory disease is a disease condition or indication associated with inflammation, allergy, and/or hyperplasia and may include: (0 lung disease: any slowness of origin - such as axillary obstructive pulmonary disease, especially bronchial asthma and chronic obstructive pulmonary disease rARDS , * u QPD), adult snoring syndrome (ARDS), bronchiectasis. female #上, ' · bronchitis of origin; all open; { restrictive lung disease, especially all forms of lungs with toxic pulmonary edema Edema, ..^ Λ All forms of origin between qualitative pulmonary disease, such as radiation pneumonitis; and still used. Sarcoidosis and goiter, especially Boeck disease. , brother 157102.doc -20- 201217379 (ii) rheumatic diseases or autoimmune diseases or joint diseases: all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever and rheumatic polymyalgia; Arthritis; rheumatic soft tissue disease; inflammatory soft tissue disease of other origin; arthritic symptoms in degenerative joint disease (arthrosis); traumatic arthritis; collagenage of any origin 'eg systemic erythema Lupus, scleroderma, polymyositis, dermatomyositis, Sj0gren Syndr〇ine, Still disease, and Felty syndrome; (iii) Allergies Sexual diseases: all forms of allergic reactions, such as angioedema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, anaphylactic shock (systemic allergic reactions), urticaria, vascular nerves Sexual leeches and contact dermatitis; (iv) jk tuberculosis disease: nodular arteritis, nodular polyarteritis, myosinulitis, Wagner's granuloma (Wegner granulomatosis), giant cell arthritis and nodular erythema; (v) Dermatological diseases: atopic dermatitis, especially in children; psoriasis; red pityriasis; erythematous diseases caused by various harmful substances, such as Radiation, chemicals, inferior products, etc.; vesicular skin disease; mossy compound disease; pruritus (eg allergic origin); seborrheic dermatitis; rosacea; pemphigus vulgaris; exudative polymorphous erythema; balanitis; vulva Inflammation; hair loss such as occurs in plaque alopecia; and cutaneous T-cell lymphoma; (vi) nephropathy: renal syndrome; and all types of nephritis, such as spheroid nephritis; (vii) liver disease: acute hepatocyte disintegration; Acute hepatitis of various origins, 157102.doc -21 · 201217379 such as virus, toxin, drug induced; and chronic invasive and / or chronic intermittent hepatitis; (viiO gastrointestinal disease: inflammatory bowel disease, such as local enteritis (g Crohn's disease, ulcerative colitis; gastritis; digestive esophagitis (reflUX〇es〇Phagitis); and other origins Enteritis, such as non-tropical mouth sores; rectal disease: anal wet therapy; anal fissure; hemorrhoids; and idiopathic proctitis; (X) eye disease: allergic keratitis, uveitis or iritis; conjunctivitis; orbital inflammation; Optic neuritis; choroiditis; and sympathetic ophthalmia; (XI) diseases in the ear, nose and throat (ENT) area: allergic rhinitis or hay fever; otitis externa' caused by contact eczema, infection, etc.; (xii) Neurological diseases: cerebral edema, especially tumor-related cerebral edema; multiple sclerosis; acute encephalomyelitis; meningitis; acute spinal cord injury; stroke; and various forms of seizures, such as nodular convulsions; (X111) Blood diseases: acquired hemolytic anemia; and idiopathic thrombocytopenia; (xiv) neoplastic disease: acute lymphocytic leukemia; malignant lymphoma; lymphogranuloma; lymphosarcoma; extensive metastasis, especially in breast, bronchial and prostate cancers (xv) endocrine disease: endocrine eye lesions; endocrine ocular writes; thyrotoxic crisis; quarantine thyroiditis (Thyr〇iditis de

Quervain)，橋本曱狀腺炎（Hashimoto thyroiditis);巴塞多 157102.doc ·22· 201217379 病（Morbus Basedow);肉芽腫性曱狀腺炎；淋巴瘤性曱狀腺鹰（struma lymphomatosa)；及格雷夫斯病（Grave disease)； (xvi) 器官及組織移植及移植物抗宿主疾病； (xvii) 嚴重狀態之休克，例如敗血性休克、過敏性休克及全身性發炎反應症候群（SIRS); (xviii) 取代療法：先天原發性腎上腺機能不全，例如賢上腺性生殖腺症候群；後天原發性腎上腺機能不全，例如艾迪森氏病（Addison disease)、自體免疫腎上腺炎、感染後、腫瘤、轉移等；先天繼發性腎上腺機能不全，例如先天垂體低能症；及後天繼發性腎上腺機能不全，例如感染後、腫瘤、轉移等； (xix) 發炎性起源之疼痛，例如腰痛；及 (XX)各種其他疾病病況或病狀，包括I型糖尿病（騰島素依賴性糖尿病）、骨關節炎、格林_巴利徵候群（GuiUain_ Barre syndrome)、經皮經管腔冠狀動脈血管成形術後再狹窄、阿k海默氏病（Alzheimer disease)、急性及慢性疼痛、動脈粥樣硬化、再灌注損傷、骨骼再吸收疾病、充血性心臟衰竭、心肌梗塞、熱損傷、外傷後繼發之多器官損傷、急性化膿性腦膜炎、壞死性小腸結腸炎及與血液透析、白細胞去除術及粒細胞輸注有關之症候群。「關節炎」意謂損傷身體關節之疾病或病狀及與該關節指傷相關之疼痛。關郎炎包括類風濕性關節炎、骨關節炎、牛皮癬性關節炎、敗血性關節炎及痛風性關節炎。 157102.doc •23· 201217379 疼痛」包括（但不限於）發炎性疼痛；外科疼痛；内臟痛；牙痛；經前疼痛；中樞疼痛；灼傷所致疼痛；偏頭痛或叢集性頭痛；神經損傷；神經炎；神經痛；中毒；缺血性損傷；間質性膀胱炎；癌痛；病毒、寄生物或細菌感染；創傷後損傷·，或與大腸急躁症相關之疼痛。「治療有效量」意謂投與至個體以治療疾病病況時足以實現該疾病病況之治療的化合物之量β「治療有效量」將視化合物、待治療之疾病病況、所治療疾病的嚴重程度、個體之年齡及相對健康狀況、投藥途徑及形式、主治醫生或獸醫從業者之判斷及其他因素而變化。當提及變數時，術語「上文所定義之彼等」及「本文所定義之彼等」以引用方式併入變數之廣泛定義以及可能存在之較佳、更佳及最佳定義。治療」疾病病況尤其包括抑制疾病病況，亦即阻止疾病病況或其臨床症狀發展，及/或減輕疾病病況，亦即使疾病病況或其臨床症狀暫時或永久衰退。當提及化學反應時，術語「處理」、「接觸」及「反應」意謂在適當條件下添加或混合兩種或兩種以上試劑以產生指定及/或所要產物。應瞭解，產生所指示及/或所要產物之反應可不必直接由最初所添加的兩種試劑之組合產生，亦即，可存在在混合物中產生的一或多種中間物，其最終導致形成所指示及/或所要產物。上文給出定義之化學基團的較佳基團為在實例中特定例示之彼等基團。 157102.doc -24· 201217379 命名法及結構一般而言，本申請案中所用之命名法係基於aut〇n〇mTM 4.0版’即用於產生IUPAC系，统命名之BeiUtein Insti_電腦化系統。本文所示之化學結構使用1813@第22版制定。除非另外指示’ ^則在本文結構Μ現於碳、&、硫或氮原子上的任何開放價數表明存在氫原子。若含氮雜芳基環顯示在氮原子上具有開放價數且在雜芳基環上顯示諸如Quervain), Hashimoto thyroiditis; Barcelo 157102.doc ·22· 201217379 Disease (Morbus Basedow); granulomatous squamous cellulitis; lymphoma morphological eagle (struma lymphomatosa); (Grave disease); (xvi) organ and tissue transplantation and graft versus host disease; (xvii) severe shock, such as septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS); (xviii Substitute therapy: congenital primary adrenal insufficiency, such as adrenal gonads syndrome; acquired primary adrenal insufficiency, such as Addison disease, autoimmune adrenalitis, post-infection, tumor, Metastasis, etc.; congenital secondary adrenal insufficiency, such as congenital pituitary hypoxia; and acquired secondary adrenal insufficiency, such as post-infection, tumor, metastasis, etc.; (xix) pain of inflammatory origin, such as low back pain; and (XX a variety of other disease conditions or conditions, including type 1 diabetes (Tengdao-dependent diabetes), osteoarthritis, Green-Bali syndrome (GuiUain_ Barre syndrome), restenosis after percutaneous transluminal coronary angioplasty, Alzheimer's disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone resorption, congestive Heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, acute suppurative meningitis, necrotizing enterocolitis, and syndromes associated with hemodialysis, leukapheresis, and granulocyte infusion. "Arthritis" means a disease or condition that damages the joints of the body and the pain associated with the finger joints. Guan Langyan includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis and gouty arthritis. 157102.doc •23· 201217379 Pain includes, but is not limited to, inflammatory pain; surgical pain; visceral pain; toothache; premenstrual pain; central pain; pain caused by burns; migraine or cluster headache; Neuritis; neuralgia; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury, or pain associated with large bowel irritation. "Therapeutically effective amount" means the amount of a compound "a therapeutically effective amount" which is sufficient to effect treatment of a disease condition in an individual to treat a disease condition, depending on the compound, the condition of the disease to be treated, the severity of the disease being treated, The age and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and other factors vary. When the terms are referred to, the terms "the ones defined above" and "the ones as defined herein" are incorporated by reference to the broad definition of the variables and the preferred, better and best definitions that may exist. Treatment of a disease condition includes, inter alia, inhibiting the condition of the disease, i.e., preventing the development of the condition or its clinical symptoms, and/or alleviating the condition of the disease, even if the condition of the disease or its clinical symptoms temporarily or permanently decline. When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" mean adding or mixing two or more reagents under appropriate conditions to produce a specified and/or desired product. It will be appreciated that the reaction to produce the indicated and/or desired product may not necessarily result directly from the combination of the two agents initially added, i.e., one or more intermediates may be present in the mixture which ultimately result in the formation of the indication. And / or the desired product. Preferred groups of the chemical groups defined above are those specifically exemplified in the examples. 157102.doc -24· 201217379 Nomenclature and Structure In general, the nomenclature used in this application is based on the aut〇n〇mTM version 4.0, the BeiUtein Insti_ computerized system used to generate the IUPAC system. The chemical structure shown in this article was developed using the 1813@22nd edition. Any open valence present on the carbon, & sulfur or nitrogen atom in the structure herein unless otherwise indicated '^ indicates the presence of a hydrogen atom. If the nitrogen-containing heteroaryl ring is shown to have an open valence on the nitrogen atom and exhibits on the heteroaryl ring, such as

Ra、Rb或Re之變數，則該等變數可與開放價數之氮結合或接合。若結構中存在對掌性中心，但未針對該對掌性中心展示特定立體化學結構，則該結構涵蓋與對掌性中心相關之兩種對映異構體。若本文所示結構可以多種互變異構形式存在’職結構涵蓋所有料互變㈣體。本文結構中所提出之原子欲涵蓋該等原子的所有天然存在之同位素。因此’舉例而t，本文提出之氫原子欲包純及氣，且碳原子欲包括C13及C14同位素。The variables of Ra, Rb or Re may be combined or bonded to the nitrogen of the open valence. If there is a palm center in the structure, but no specific stereochemistry is exhibited for the pair of palm centers, then the structure covers the two enantiomers associated with the palm center. If the structure shown in this paper can exist in multiple tautomeric forms, the job structure covers all material interconversions (IV). The atoms proposed in the structure of this document are intended to cover all naturally occurring isotopes of such atoms. Therefore, by way of example, the hydrogen atom proposed herein is intended to be pure and gas, and the carbon atom is intended to include C13 and C14 isotopes.

本文所涉及之所有專利及公開㈣以全文引用的入本文中。 W 本發明化合物本發明提供式I或式II之化合物：All patents and publications (4) referred to herein are hereby incorporated by reference in their entirety. W Compounds of the Invention The invention provides a compound of formula I or formula II:

157102.doc •25- 201217379 或其醫藥學上可接受之鹽，其中： X為N或CH ; m為1或2 ;157102.doc •25- 201217379 or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; m is 1 or 2;

Ar為：視情況經取代之芳基；或視情況經取代之雜芳基； R1為：氫； C ι_6烧基； C 1.6烧氧基；羥基；經基-Ci _6烧基； C 1 烧基-胺基；胺基-Ci_6烧基；胺基-Ci-6烧基-胺基；經基-Ci _6烧基胺基； c3_6環烷基胺基；胺基- C3.6環院基胺基；胺基-C3_6雜環烧基胺基；胺基羰基；齒基，經基-Ci.6烧基；或羥基-cN6烷氧基；及 157102.doc •26· 201217379 R2為：風，或Ar is: an optionally substituted aryl group; or a heteroaryl group optionally substituted; R1 is: hydrogen; C ι_6 alkyl; C 1.6 alkoxy; hydroxy; thio-Ci -6 burning; C 1 burning Amino-Ci_6 alkyl; alkyl-Ci-6 alkyl-amino; alkyl-Ci-6 alkylamino; c3-6 cycloalkylamino; amine-C3.6 ring Amino; Amino-C3_6 heterocycloalkylamino; Aminocarbonyl; dentate, thio-Ci.6 alkyl; or hydroxy-cN6 alkoxy; and 157102.doc •26· 201217379 R2: Wind ,or

Cl-6貌基。在某些實施例令，本發明化合物具有式卜在某些實施例中’本發明化合物具有式„。在式Π之某些實施例中，X為n。在式11之某些實施例中，X為CH。在式I或式II之某些實施例t，R2為氫。在式I或式II之某些實施例中，瓜為1。在式I或式II之某些實施例中，111為2。在式I或式II之某些實施例中，Ar為視情況經取代之芳基。在式Ϊ或式II之某些實施例中，Ar為視情況經取代之笨基或視情況經取代之萘基。在式I或式II之某些實施例中，Ar為經取代之苯基。在式I或式II之某些實施例中，Ar為經取代之萘基。在式I或式II之某些實施例中，Ar為經獨立地選自以下之基團取代一次、兩次或三次的苯基：鹵基；Cw烷基；鹵基-(^1.6烧基；匚1-6稀基；〇1-6炫>氧基；画基_匸1_6炫1氧基；經基-Cw烷基；羥基-Cw烷基胺基；Ck烷基-胺基；羥基；胺基；胺基-Cw烷基；胺基羰基；羥基-Cw烧氧基；羥基-Cu烯基；Ci-6烷氧基-Cw烷氧基；C!-6烧基續醯基； Ck烷基硫基；哌啶基’其中哌啶基部分視情況經經基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；笨 157102.doc • 27· 201217379 基胺基羰基；羥基-Cw烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cm 烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Ci.6烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Ci-6烧基、經基-Ci_6烧基或胺基幾基取 _ 代；吡咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cl _6烧基、經基-Cl.6烧基或胺基幾基取代：略°秦基，其中哌嗪基部分視情況經CN6烷基取代；噁唑-Cw烷氧基，其中其噁唑部分視情況經Cw烷基取代；嗎啉基；羥基-Cw烷基胺基羰基；03.6環烷基；氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基_(^-6烷基、羥基-Cw烷基或胺基羰基取代；苯甲基，其中其苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基參或胺基羰基取代；C!.6烷氧羰基-Cm烷氧基；及Cw烷基羰基胺基。在式I或式II之某些實施例中，Ar為經獨立地選自以下之基團取代一次或兩次的苯基：鹵基；CN6烷基；鹵基-C〗-6 院基；Ci·6稀基；C〗·6院氧基；鹵基-C〗_6烧氧基；經基-Ci·6 烧基，經基-Ci-6烧基胺基，Ci-6炫基-胺基；經基；胺基；胺基-Cw烧基；胺基幾基；經基-Cl-6院氧基；經基_Ci-6稀 157102.doc •28· 201217379 基；0^1_6烧氧基-(^1-6炫》氧基；（^1.6烧基續醯基；（^1.6烧基硫基；哌啶基，其中哌咬基部分視情況經經基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基胺基羰基；羥基-Cw烷基胺基；環己基氧基’其中其環己基部分視情況經經基、胺基、胺基-C 1.6烧基或經基-C〗.6院基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Ck烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基’其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-CN6烷基或胺基羰基取代；吡咯啶基氧基’其中吡咯啶基部分視情況經羥基、胺基、胺基-C!·6烷基、羥基-Cw烷基或胺基羰基取代；哌嗪基，其中哌嗪基部分視情況經CN6烷基取代；噁唑-Cw烷氧基，其中其噁唑部分視情況經Ck烷基取代；嗎啉基；羥基-Cw 烧基胺基幾基；C3·6環烷基；氮雜環庚烷基，其中氮雜環庚烧基部分視情況經羥基、胺基、胺基_c16烷基、羥基-C〗.6烷基或胺基羰基取代；苯曱基，其中其苯基部分視情況經胺基、羥基、胺基_C16烷基、羥基烷基或胺基羰基取代·’ Cw烷氧羰基-(：16烷氧基；及烷基羰基胺基。在式1或式11之某些實施例中，Ar為經卤基取代一次且經選自以下之基團取代一次的苯基：鹵基；c"烷基；鹵 157102.doc •29· 201217379 基-Ci-6烷基；CN6烯基；Cw烷氧基；鹵基-Cw烷氧基；羥基-Cw烷基；羥基-Ci-6烷基胺基；Cw烷基-胺基；羥基；胺基；胺基-CN6烷基；胺基羰基；羥基-CN6烷氧基；羥基-Cw烯基；Cw烷氧基-CN6烷氧基；Cm烷基磺醯基； Ci-6烷基硫基；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基胺基羰基；羥基-Cw烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Ci-6烷基或羥基-CN6 烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Ck烷基或羥基-Cm烷基取代；哌啶基氧基’其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Ck烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基氧基’其中吡咯啶基部分視情況經羥基、胺基、胺基-CN6烷基、羥基-(:“烷基或胺基羰基取代；哌嗪基’其中哌嗪基部分視情況經CN6烷基取代；噁唑-Cw烷氧基’其中其噁唑部分視情況經Ck烷基取代；嗎啉基；羥基-Cw烷基胺基羰基；c3.6環烷基；氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ci-6烷基或胺基羰基取代；苯甲基，其中其苯基部分視情況經胺基、羥基、胺基-Ck烷基、羥基-(^.6烷基或胺基羰基取代；C〗-6烷氧羰基-CN6烷氧基；及(：!.6烷基羰 157102.doc •30· 201217379 基胺基。在式I或式II之某些實施例中，八^為選自以卞之經取代之芳基：2-(4_胺基甲基Hi-基）-5-氣-苯基；2-(4-胺基甲基-旅咬-1-基）-4-苯基胺甲醯基_苯基；5_氯_2_[4_(1_羥基_ 乙基）-哌啶-1-基]_苯基；5_氯_2_(4_羥基甲基-哌啶苯基；5-氯_2-(4_羥基·•環己基氧基）-苯基；5_氯-2-哌啶-1-基-苯基；2-(4-胺基甲基_哌啶_丨_基）_5_氯苯基；2_[4_(1_ 胺基-乙基）-娘。定-1-基]_5_氯_笨基；2_(4_胺甲醢基_旅啶基）-5-氯-苯基；5_氯·2_[3-(1-經基-乙基）“比哈。定-1-基]-苯基；4·-胺基甲基_4_氯-聯苯_2_基；5_氣_2_甲氧基_苯基； 3-胺基-2-(4-胺基甲基-哌啶苯基；弘胺基_2_哌啶基-苯基；5-羥基曱基_2_哌啶·丨_基_苯基；4_氯_4，_羥基甲基-聯苯-2-基；5-氯-2_異丙氧基·苯基；5_氯_2_(3_羥基曱基-環戊基氧基）-苯基；5-氣-2-吼咯啶-1_基_苯基；5-氯-2-(3-羥基-環戊基氧基）_苯基；5_氯_2_(3_羥基-丙氧基）_苯基，5-氯-2-(4-羥基··丁氧基）_苯基；2_甲氧基_4_苯基胺甲醯基-苯基；5-氯-2-(3-羥基-哌啶_1_基）_苯基；5_氣_2_(哌啶-4-基氧基）-苯基’· 4_氯-4，-羥基-聯苯_2_基；5_氯_2_(3_羥基比咯啶-1-基）-苯基；5·氯·2·(3,4_二羥基_ 丁氧基)_苯基； 5-氣-2-(4-甲基-Β底噪_1_基）_苯基；5-氯_2-("惡u坐_5_基甲氧基）_ 本基，5-氯-2-嗎琳-4-基-苯基；4-氯-聯苯_2_基；2-(3-胺基甲基-吡咯啶-1-基）-5-氯-苯基；5-氯-2-(3-羥基-環己基氧基）_ 苯基；4-(3-羥基-丙基胺甲醯基）-2-甲氧基-苯基；5_氯·2_(3_ 羥基甲基-吼咯啶-1-基）-苯基；5-氯_2_二氟甲氧基-苯基； I57102.doc -31 - 201217379 5-氣-2-二甲基胺基-苯基；2-(3-胺基-吡咯啶_1_基）-5-氣-苯基，5 -氯-2-甲基硫基-苯基；5 -氯-2-環己基-苯基；3-(2 -經基乙基胺基）-2 -旅咬-1-基-苯基；5 -氯-2-(4-甲基惡β坐_5_ 基曱氧基）-苯基；聯苯-2-基；5-氣-2-(3-羥基-1，1-二曱基_ 丙氧基）-苯基；2-(4-胺基-環己基氧基）-5-氣-苯基；2-氮雜環庚烷-1-基-5-氣-苯基；4-(2-羥基-乙基胺甲醯基）-2-甲氧基-苯基；4-羥基-環己基氧基）-苯基；5-氣-2-(2-甲氧基-乙氧基）_本基，4 -氣-31-經基-聯苯-2-基，5 ->臭-2 -甲氧基-苯基；5-氣-2-[(2-羥基-乙基）-曱基-胺基]-苯基；5-氣-2-(4-經基-苯氧基）-苯基；4-胺甲醯基-2-曱氧基-苯基；5-氯-2-異丁氧基-本基，5 -氯- 2-(2，3-二經基-丙氧基）-苯基；5 -氣-2_ (3-曱氧基-丙氧基）-苯基；5-氣-2-(3-羥基甲基-哌啶_丨_基）_ 苯基；5-氣-2-(3-羥基-苯曱氧基；5-氣-2,4-二曱氧基-苯基，2-甲氧基-5-乙烯基-苯基；3-(3-經基-丙基胺基）_2_〇辰 0定-1·'基-本基，5-氯-2-(4-經基-丁基）-苯基；2-[3-(1-胺基_ 乙基）-η比咯啶-1-基]-5-氯-苯基；5-氯-2-[(3-羥基-丙基甲基-月女基]-本基，5 -亂-2-(4-甲基胺基曱基-〇底咬_1_基）_笨基’ 5-(3 -沒基-丙稀基）-2-曱氧基-苯基；5 -氣-2-乙基-苯基；4-曱烷磺醯基-2-曱氧基-苯基；5-氯-2-(3-羥基-苯氧基）-苯基；2,4-二曱氧基-苯基；5-氟-2-曱氧基-苯基；5_ 氣-2 -本氧基-苯基；5-(3-經基-丙基）-2-曱氧1基_苯基；5_ 氣-2-(2-羥基曱基-哌啶-i_基）_苯基；5-氯-2-(4-二甲基胺基甲基-0底咬-1-基）-苯基；3 -曱氧基聯苯-4-基；5 -乙基-2-曱氧基-苯基；5 -曱氧基-2-甲基-聯苯-4-基；2-甲氧基-3,5-二 157102.doc •32· 201217379 曱基-苯基；4-二曱基胺曱醯基_2_甲氧基-苯基；5_乙醯基胺基-2-甲氧基-苯基；5-氣_2-曱氧基_4_苯基胺曱醯基-苯基；及4-羥基曱基-2-甲氧基_苯基；3(3_羥基_環戊基氧基）-萘-2-基；3-(3-羥基-丙氧基）_萘_2_基；7_羥基甲基_3_ 甲氧基-萘-2-基；3-(4-羥基_環己基氧基）_萘_2_基；及3_甲氧基-秦-2-基。在式I或式II之某些貫施例中，Ar為選自以下之經取代之苯基：2-(4-胺基甲基-哌啶_丨_基）_5_氣_苯基；2 (4_胺基甲 • 基_哌啶_1_基）-4-苯基胺甲醯基-苯基；5-氣-2-[4-(l-羥基_ 乙基）-哌啶-1_基]-苯基；5_氯_2_(4_羥基曱基_哌啶―卜基分笨基；5-氯-2-(4-羥基-環己基氧基）_苯基；5_氯_2_哌啶4 — 基_苯基；2-(4-胺基甲基-哌啶_丨_基）_5•氣-苯基；胺基-乙基）-哌啶-1-基]-5-氯-苯基；2-(4-胺曱醯基-哌啶-1-基）-5-氣-苯基；5-氯-2-[3-(l-羥基-乙基）-»比咯啶_ι_基]-苯基；41-胺基曱基_4_氯-聯苯_2_基；5_氣_2_甲氧基_苯基； 3-胺基-2-(4-胺基甲基-哌啶_；!_基）_苯基；3_胺基_2_哌啶基-苯基’· 5-羥基甲基_2_哌啶_1_基_苯基；4_氣_41_羥基甲基-聯苯-2-基；5-氯-2-異丙氧基-苯基；5-氯-2-(3-羥基曱基-環戊基氧基）-苯基；5-氯-2-π比咯啶-1-基-苯基；5-氯-2-(3-羥基-環戊基氧基）_苯基；5_氯_2_(3_羥基_丙氧基）苯基； 5-氣-2-(4-羥基-丁氧基）_苯基；2_甲氧基_4_苯基胺曱醯基_ 苯基；5-氯-2-(3-羥基-哌啶-1-基）-苯基；5_氯_2_(哌啶_4_基氧基）-苯基；4-氯-4，-羥基·聯苯-2-基；5-氣-2-(3-羥基-吨咯啶-1-基）-苯基；5-氯-2-(3,4-二羥基-丁氧基）-苯基；5_氣_2_(4_ 157I02.doc -33· 201217379 甲基-η底嗓-1-基）-苯基；5-氣-2-(噁唑-5-基曱氧基）_苯基； 5-氣-2-嗎琳-4-基-苯基；4-氣-聯苯-2-基；2-(3-胺基甲基_ °比咯啶-1-基）-5-氣-苯基；5-氣-2-(3-羥基-環己基氧基）_苯基；4-(3-羥基-丙基胺甲醯基）-2-曱氧基-苯基；5-氯-2-(3-羥基曱基比咯啶-1-基）-苯基；5-氯-2-二氟甲氧基-苯基； 5-氣-2-二曱基胺基-苯基；2-(3-胺基-吡嘻咬-1-基）-5-氯-苯基；5-氣-2-甲基硫基-苯基；5-氣-2-環己基-苯基；3-(2-經基-乙基胺基）-2-哌啶-1-基-苯基；5-氯-2-(4-曱基-噁唑-5-基甲氧基）-苯基；聯苯-2-基；5-氣-2-(3-羥基-1，1-二甲基_ 丙氧基）-苯基；2-(4-胺基-環己基氧基）-5-氯-苯基；2-氮雜環庚烷-1-基-5-氯-苯基；4-(2-羥基-乙基胺曱醯基）_2-甲氧基-苯基；4-羥基-環己基氧基）-苯基；5-氯-2-(2-曱氧基-乙氧基）-本基，4 -氣-3'-經基-聯苯-2 -基；5 -漠-2-曱氧基-笨基；5-氯-2-[(2-羥基-乙基）-甲基-胺基]•苯基；5-氯-2-(4-羥基-苯氧基）-苯基；4-胺曱醯基-2-甲氧基-苯基；5-氣-2-異丁氧基-苯基；5-氯-2-(2,3-二經基-丙氧基）-苯基；5-氣-2-(3-甲氧基-丙氧基）-苯基；5-氣-2-(3-羥基曱基-哌啶-1-基）_ 苯基；5-氯-2-(3-經基-苯甲氧基；5-氯-2,4-二曱氧基-苯基；2-曱氧基-5-乙稀基-苯基；3-(3-羥基-丙基胺基）-2-哌咬-1-基-苯基；5-氣-2-(4-羥基-丁基）-苯基；2-[3-(1-胺基-乙基）-°比洛咬-1-基]-5-氣-苯基；5-氣-2-[(3-經基-丙基）-曱基-胺基]-苯基；5-氯-2-(4-甲基胺基甲基-哌啶-丨_基）-苯基；5-(3-經基-丙烯基）-2-甲氧基-苯基；5_氯_2_乙基-苯基；4-甲烷磺醯基-2-甲氧基·苯基；5_氯_2_(3_羥基-苯氧 I57102.doc •34- 201217379 基)-苯基；2’4-二甲氧基·笨基；5·氟·2_甲氧基_苯基；5· 氯-2-苯氧基-苯基；5-(3-羥基_丙基）_2_甲氧基_苯基；5_ 氯-2-(2-經基曱基-錢]_基）_苯基；及5-氣么(4_二甲基胺基甲基-旅0定-1-基）-苯基Cl-6 appearance. In certain embodiments, the compounds of the invention have the formula. In certain embodiments, the compounds of the invention have the formula „. In certain embodiments of the formula, X is n. In certain embodiments of Formula 11. X is CH. In certain embodiments of Formula I or Formula II, R2 is hydrogen. In certain embodiments of Formula I or Formula II, the melon is 1. Some embodiments of Formula I or Formula II Wherein 111 is 2. In certain embodiments of Formula I or Formula II, Ar is an optionally substituted aryl group. In certain embodiments of Formula Ϊ or Formula II, Ar is a stupid substitution Substituted or optionally substituted naphthyl. In certain embodiments of Formula I or Formula II, Ar is substituted phenyl. In certain embodiments of Formula I or Formula II, Ar is substituted naphthalene In certain embodiments of Formula I or Formula II, Ar is phenyl substituted once, twice or three times with a group independently selected from the group consisting of: halo; Cw alkyl; halo-(^1.6 Anthracene; 匚1-6 稀; 〇1-6炫>oxy; benzyl 匸1_6 11 oxy; thio-Cw alkyl; hydroxy-Cw alkylamino; Ck alkyl-amine Base; hydroxyl; amine; amine-Cw alkyl; amine carbonyl; -Cw alkoxy; hydroxy-Cu alkenyl; Ci-6 alkoxy-Cw alkoxy; C!-6 alkyl thiol; Ck alkylthio; piperidinyl' wherein piperidinyl Substituted by a trans-group, an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; stupid 157102.doc • 27· 201217379 arylaminocarbonyl group; hydroxy-Cw alkylamino group; cyclohexyl group An oxy group wherein the cyclohexyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group or a hydroxy-Cm alkyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally a hydroxyl group, an amine group, Amino-Cw alkyl or hydroxy-Ci.6 alkyl substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally via a hydroxy, amine, amino-Cw alkyl, hydroxy-Cw alkyl or amine Substituted by a carbonyl group; a phenyl group, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; and a pyrrolidinyl group in which a pyrrolidinyl moiety is optionally subjected to a hydroxyl group. , an amine group, an amine group -Ci-6 alkyl group, a group based on a -Ci_6 alkyl group or an amino group; a pyrrolidinyloxy group, wherein the pyrrolidinyl group is optionally a hydroxyl group, an amine group, an amine group - Cl -6 alkyl, substituted by a radical -Cl.6 alkyl or an amino group: a slightly thiol group, wherein the piperazinyl moiety is optionally substituted by a CN6 alkyl group; an oxazole-Cw alkoxy group, wherein the oxazole Partially substituted by Cw alkyl; morpholinyl; hydroxy-Cw alkylaminocarbonyl; 03.6 cycloalkyl; azepanyl, wherein the azepanyl moiety is optionally via a hydroxyl group, an amine group, Amino-(^-6 alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted; benzyl, wherein the phenyl moiety thereof is optionally amino, hydroxy, amino-Cw alkyl, hydroxy-Cw alkyl Substituted with an aminocarbonyl group; C!.6 alkoxycarbonyl-Cm alkoxy; and Cw alkylcarbonylamino. In certain embodiments of Formula I or Formula II, Ar is phenyl substituted once or twice with a group independently selected from the group consisting of: halo; CN6 alkyl; halo-C-6-6; Ci·6 dilute; C 〖·6 oxime; halo-C _6 alkoxy; base-Ci·6 alkyl, via-Ci-6 alkylamino, Ci-6 leuko- Amino group; alkyl group; amine group; amine group-Cw alkyl group; amino group; base group -Cl-6 alkoxy group; base group -Ci-6 salt 157102.doc •28· 201217379 base; 0^1_6 Alkoxy-(^1-6 H) oxy; (^1.6 alkyl thiol); (^1.6 alkylthio; piperidinyl, wherein the piperidine moiety is optionally via a base, an amine group, an amine Substituted by a base group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a phenylaminocarbonyl group; a hydroxy-Cw alkylamino group; a cyclohexyloxy group wherein a cyclohexyl moiety thereof is optionally subjected to a trans group, an amine group, Amino-C 1.6 alkyl or via -C.6 substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group or a hydroxy-Ck alkane Substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group, a hydroxy-Cw alkane Or an aminocarbonyl group; a phenyl group, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; and a pyrrolidinyl group wherein the pyrrolidinyl moiety is optionally Substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-CN6 alkyl group or an aminocarbonyl group; a pyrrolidinyloxy group wherein a pyrrolidinyl moiety is optionally a hydroxyl group, an amine group or an amine group-C!·6 Alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted; piperazinyl, wherein piperazinyl moiety is optionally substituted by CN6 alkyl; oxazole-Cw alkoxy, wherein the oxazole moiety is optionally Ck alkyl a hydroxyl-Cw alkylamino group; Alkyl, hydroxy-C.6 alkyl or aminocarbonyl substituted; phenylhydrazine, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amine group -C16 alkyl group, a hydroxyalkyl group or an amine carbonyl group. 'Cw alkoxycarbonyl-(:16 alkoxy; and alkylcarbonylamino. In certain embodiments of Formula 1 or Formula 11, Ar is substituted once with a halo group and A phenyl group substituted one time from the group consisting of: a halogen group; a c" alkyl group; a halogen 157102.doc • 29·201217379 a base-Ci-6 alkyl group; a CN6 alkenyl group; a Cw alkoxy group; a halo-Cw alkane Oxyl; hydroxy-Cw alkyl; hydroxy-Ci-6 alkylamino; Cw alkyl-amine; hydroxy; amine; amine-CN6 alkyl; aminocarbonyl; hydroxy-CN6 alkoxy; -Cw alkenyl; Cw alkoxy-CN6 alkoxy; Cm alkylsulfonyl; Ci-6 alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted; phenylaminocarbonyl; hydroxy-Cw alkylamino; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - Ci-6 alkyl or hydroxy-CN6 alkyl substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally substituted by hydroxyl, amine, amino-Ck alkyl or hydroxy-Cm alkyl; piperidinyl The oxy group wherein the piperidinyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; and a phenyl group, wherein the phenyl moiety is optionally an amino group, a hydroxyl group, Amino-Cw alkyl, a hydroxy-Cw alkyl or an aminocarbonyl group; a pyrrolidinyl group in which a pyrrolidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Ck alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; pyrrolidinyloxy group Wherein the pyrrolidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group -CN6 alkyl group, a hydroxy group (: "alkyl or aminocarbonyl group; piperazinyl' wherein the piperazinyl moiety is optionally CN6 alkyl Substituted; oxazole-Cw alkoxy' wherein the oxazole moiety is optionally substituted by Ck alkyl; morpholinyl; hydroxy-Cw alkylaminocarbonyl; c3.6 cycloalkyl; azepanyl, Wherein the azacycloheptyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Ci-6 alkyl group or an aminocarbonyl group; a benzyl group in which a phenyl moiety is optionally an amine group , hydroxy, amino-Ck alkyl, hydroxy-(^.6 alkyl or aminocarbonyl substituted; C -6 alkoxycarbonyl-CN6 alkoxy; and (:!. 6 alkyl carbonyl 157102.doc • 30· 201217379 Amino group. In certain embodiments of Formula I or Formula II, 八 is selected from aryl substituted with hydrazine: 2-(4-aminomethylHi-yl)-5-a-phenyl; 2- (4-Aminomethyl-Bistylene-1-yl)-4-phenylaminecarbamyl-phenyl; 5-Chloro-2_[4_(1-hydroxy-ethyl)-piperidin-1-yl ]_phenyl; 5-chloro-2-(4-hydroxymethyl-piperidinylphenyl; 5-chloro-2-(4-hydroxy·•cyclohexyloxy)-phenyl; 5-chloro-2-piperidin Pyridin-1-yl-phenyl; 2-(4-aminomethyl-piperidine-hydrazinyl)-5-chlorophenyl; 2-[4-(1-amino-ethyl)-nietum. Base]_5_chloro_styl; 2_(4_amine-carbamoyl-bristidyl)-5-chloro-phenyl; 5-chloro-2_[3-(1-trans-ethyl-ethyl)"Bi Ding-1-yl]-phenyl; 4·-aminomethyl_4_chloro-biphenyl-2-yl; 5-nitrox-2-methoxy-3-phenyl; 3-amino-2- (4-Aminomethyl-piperidinylphenyl; hydroxyamino-2-piperidinyl-phenyl; 5-hydroxyindenyl-2-piperidinyl-yl-phenyl; 4-chloro- 4, _hydroxymethyl-biphenyl-2-yl; 5-chloro-2-isopropoxy phenyl; 5-chloro-2-(3-hydroxyindolyl-cyclopentyloxy)-phenyl; 5- Gas-2-pyrrolidin-1_yl-phenyl; 5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl; 5-chloro-2-(3-hydroxy-propoxy) _ Phenyl, 5-chloro-2-(4-hydroxy-butoxy)-phenyl; 2-methoxy-4-phenylenemethionyl-phenyl; 5-chloro-2-(3- Hydroxy-piperidinyl-1-yl)-phenyl; 5-nitrox-2-(piperidin-4-yloxy)-phenyl'·4_chloro-4,-hydroxy-biphenyl-2-yl; _Chloro-2-(3-hydroxypyrrolidin-1-yl)-phenyl; 5·chloro·2·(3,4-dihydroxy-butoxy)-phenyl; 5-gas-2-(4) -methyl-purine noise _1_yl) phenyl; 5-chloro- 2-(" 恶u sitting_5_ylmethoxy)_, 5-chloro-2-lin-4 -yl-phenyl; 4-chloro-biphenyl-2-yl; 2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl; 5-chloro-2-(3 -hydroxy-cyclohexyloxy)-phenyl; 4-(3-hydroxy-propylaminemethanyl)-2-methoxy-phenyl; 5-chloro-2-(3-hydroxymethyl-indenylpyridine -1-yl)-phenyl; 5-chloro-2-difluoromethoxy-phenyl; I57102.doc -31 - 201217379 5-gas-2-dimethylamino-phenyl; 2-(3 -amino-pyrrolidin-1-yl)-5-a-phenyl, 5-chloro-2-methylsulfanyl-phenyl; 5-chloro-2-cyclohexyl-phenyl; 3-(2- Benzylamino))-2-Bent-1-yl-phenyl; 5-chloro-2-(4-methyloxo-sodium-5-yloxy)-phenyl;biphenyl-2- Base; 5-gas-2-(3 -hydroxy-1,1-dimercapto-propoxy)-phenyl; 2-(4-amino-cyclohexyloxy)-5-a-phenyl; 2-azepane-1 5--5-phenyl-phenyl; 4-(2-hydroxy-ethylamine-methylmethyl)-2-methoxy-phenyl; 4-hydroxy-cyclohexyloxy)-phenyl; 5-gas- 2-(2-methoxy-ethoxy)-benyl, 4-carbo-31-carbyl-biphenyl-2-yl, 5->odor-2-methoxy-phenyl; 5- Gas-2-[(2-hydroxy-ethyl)-indolyl-amino]-phenyl; 5-aero-2-(4-carbyl-phenoxy)-phenyl; 4-aminocarbinyl -2-decyloxy-phenyl; 5-chloro-2-isobutoxy-benyl, 5-chloro-2-(2,3-di-propyl-propoxy)-phenyl; 5- gas -2_(3-decyloxy-propoxy)-phenyl; 5-gas-2-(3-hydroxymethyl-piperidine-indenyl)-phenyl; 5-gas-2-(3- Hydroxy-phenyl hydroxy; 5- gas-2,4-dimethoxy-phenyl, 2-methoxy-5-vinyl-phenyl; 3-(3-trans-propylamino) _2_〇辰0定-1·'yl-benyl, 5-chloro-2-(4-carbyl-butyl)-phenyl; 2-[3-(1-amino-ethyl)-η Bilobidine-1-yl]-5-chloro-phenyl; 5-chloro-2-[(3-hydroxy-propylmethyl-indolyl)-benyl, 5-disorder-2-(4- Methylamino thiol-intestinal bite _1_ base) _笨基' 5-(3-unyl-propyl)-2-decyloxy-phenyl; 5-oxo-2-ethyl-phenyl; 4-nonanesulfonyl-2-oxo 5-phenyl-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl; 5-fluoro-2-indolyl-phenyl; 5_ Gas-2 - oxy-phenyl; 5-(3-carbyl-propyl)-2-indoleoxy-1-yl-phenyl; 5-nitro-2-(2-hydroxyindenyl-piperidine-i_ Base) phenyl; 5-chloro-2-(4-dimethylaminomethyl-0 guanidin-1-yl)-phenyl; 3-methoxyoxybiphenyl-4-yl; 5-B 2-yloxy-phenyl; 5-methoxy-2-methyl-biphenyl-4-yl; 2-methoxy-3,5-di 157102.doc •32· 201217379 thiol- Phenyl; 4-didecylamine indenyl-2-methoxy-phenyl; 5-ethylaminomethyl-2-methoxy-phenyl; 5-aero-2-oxooxy-4 _Phenylaminoindenyl-phenyl; and 4-hydroxyindenyl-2-methoxy-phenyl; 3(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl; 3-(3 -hydroxy-propoxy)-naphthalene-2-yl; 7-hydroxymethyl_3_methoxy-naphthalen-2-yl; 3-(4-hydroxy-cyclohexyloxy)-naphthalene-2-yl; And 3-methoxy-Qin-2-yl. In certain embodiments of Formula I or Formula II, Ar is a substituted phenyl group selected from the group consisting of 2-(4-aminomethyl-piperidine-indenyl)-5-gas-phenyl; 2 (4-aminomethyl)-piperidine-1-yl)-4-phenylamine-methylhydrazine-phenyl; 5-gas-2-[4-(l-hydroxy-ethyl)-piperidine -1_yl]-phenyl; 5-chloro-2-(4-hydroxyindenyl-piperidine-diyl-based; 5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl; 5-Chloro-2-piperidinyl-4-yl-phenyl; 2-(4-aminomethyl-piperidine-hydrazinyl)-5-gas-phenyl; amino-ethyl)-piperidine-1 -yl]-5-chloro-phenyl; 2-(4-aminoindolyl-piperidin-1-yl)-5-a-phenyl; 5-chloro-2-[3-(l-hydroxy- Ethyl)-»Byrrolidine_ι_yl]-phenyl; 41-aminoindenyl_4_chloro-biphenyl-2-yl; 5-nitrox-2-methoxy-phenyl; 3- Amino-2-(4-aminomethyl-piperidine _;!-yl)-phenyl; 3-amino-2-piperidinyl-phenyl'· 5-hydroxymethyl-2-piperidine _1_yl-phenyl; 4_gas_41-hydroxymethyl-biphenyl-2-yl; 5-chloro-2-isopropoxy-phenyl; 5-chloro-2-(3-hydroxyindole -cyclopentyloxy)-phenyl; 5-chloro-2-πpyrrolidin-1-yl-phenyl; 5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl ;5_氯_2_ (3-hydroxy-propoxy)phenyl; 5-aero-2-(4-hydroxy-butoxy)-phenyl; 2-methoxy-4-phenylene fluorenyl phenyl; 5 -Chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl; 5-chloro-2-(piperidinyl-4-yloxy)-phenyl; 4-chloro-4,-hydroxyl-linked Benzene-2-yl; 5-aero-2-(3-hydroxy-tonolidin-1-yl)-phenyl; 5-chloro-2-(3,4-dihydroxy-butoxy)-phenyl ;5_气_2_(4_ 157I02.doc -33· 201217379 methyl-η 嗓嗓-1-yl)-phenyl; 5-gas-2-(oxazol-5-yl decyloxy)-phenyl ; 5- gas-2-morphin-4-yl-phenyl; 4- gas-biphenyl-2-yl; 2-(3-aminomethyl-°-pyrrolidin-1-yl)-5- Gas-phenyl; 5-gas-2-(3-hydroxy-cyclohexyloxy)-phenyl; 4-(3-hydroxy-propylaminemethanyl)-2-decyloxy-phenyl; -Chloro-2-(3-hydroxyindolylpyrrolidin-1-yl)-phenyl; 5-chloro-2-difluoromethoxy-phenyl; 5-oxo-2-didecylamino- Phenyl; 2-(3-amino-pyridin-1-yl)-5-chloro-phenyl; 5-ox-2-methylsulfanyl-phenyl; 5-ox-2-cyclohexyl- Phenyl; 3-(2-trans-ethylamino)-2-piperidin-1-yl-phenyl; 5-chloro-2-(4-mercapto-oxazol-5-ylmethoxy )-phenyl; biphenyl-2-yl; 5-gas-2- (3-hydroxy-1,1-dimethyl-propoxy)-phenyl; 2-(4-amino-cyclohexyloxy)-5-chloro-phenyl; 2-azepane- 1-yl-5-chloro-phenyl; 4-(2-hydroxy-ethylaminoindenyl)_2-methoxy-phenyl; 4-hydroxy-cyclohexyloxy)-phenyl; 5-chloro -2-(2-decyloxy-ethoxy)-benyl, 4-carbo-3'-carbyl-biphenyl-2-yl; 5-oxa-2-oxo-phenyl; 5- Chloro-2-[(2-hydroxy-ethyl)-methyl-amino]•phenyl; 5-chloro-2-(4-hydroxy-phenoxy)-phenyl; 4-aminoindenyl- 2-methoxy-phenyl; 5-oxo-2-isobutoxy-phenyl; 5-chloro-2-(2,3-di-propyl-propoxy)-phenyl; 5-gas- 2-(3-methoxy-propoxy)-phenyl; 5-gas-2-(3-hydroxyindolyl-piperidin-1-yl)-phenyl; 5-chloro-2-(3- Benzyl-benzyloxy; 5-chloro-2,4-dimethoxy-phenyl; 2-decyloxy-5-ethenyl-phenyl; 3-(3-hydroxy-propylamino 2-piperidin-1-yl-phenyl; 5-gas-2-(4-hydroxy-butyl)-phenyl; 2-[3-(1-amino-ethyl)-°Bilo Benzo-1-yl]-5-gas-phenyl; 5-gas-2-[(3-carbyl-propyl)-indolyl-amino]-phenyl; 5-chloro-2-(4- Methylaminomethyl-piperidine-hydrazinyl)-phenyl; 5-(3-基-propenyl)-2-methoxy-phenyl; 5-chloro-2-ethyl-phenyl; 4-methanesulfonyl-2-methoxyphenyl; 5-chloro-2-( 3_hydroxy-phenoxy 157102.doc •34- 201217379 yl)-phenyl; 2'4-dimethoxy-phenyl; 5·fluoro·2_methoxy-phenyl; 5· chloro-2- Phenoxy-phenyl; 5-(3-hydroxy-propyl)_2-methoxy-phenyl; 5-chloro-2-(2-pyridinyl-m-]-yl)-phenyl; - qi (4_dimethylaminomethyl-Brigade 0-1,4-yl)-phenyl

Ar為選自以下之經取代萘 3-(3-羥基-丙氧基 3-(4-羥基-環己 Ar為2-(4-胺基甲基-派咬_ Ar為2-(4·胺基甲基-哌啶- Ar為5-氣-2-[4-(l-羥基-乙 Ar為5 -氣- 2-(4-經基甲基_ Ar為5 -氯- 2-(4 -經基-環己 Ar為5 -氯-2-派咬-1 -基-苯在式I或式II之某些實施例中基：3-(3 -經基-環戊基氧基）_萘_2_基；萘-2-基；7-羥基曱基-3_甲氧基_萘_2_基；基氧基）-萘-2-基；及3-甲氧基·萘_2_基。Ar is a substituted naphthalene selected from the group consisting of 3-(3-hydroxy-propoxy 3-(4-hydroxy-cyclohexene Ar is 2-(4-aminomethyl-pyro- _ Ar is 2-(4·) Aminomethyl-piperidine-Ar is 5-gas-2-[4-(l-hydroxy-ethyl Ar is 5-a-2-(4-ylmethyl-Ar is 5-chloro-2-( 4-Hydroxy-cyclohexene Ar is 5-chloro-2-pyrene-1 -yl-benzene. In certain embodiments of formula I or formula II: 3-(3-hydroxy-cyclopentyloxy) ) naphthalene-2-yl; naphthyl-2-yl; 7-hydroxyindolyl-3-methoxy-naphthalene-2-yl; oxy)-naphthalen-2-yl; and 3-methoxy Naphthalene-2-yl.

在式I或式II之某些實施例中 1-基）-5-氣-苯基。在式I或式II之某些實施例中 1-基）-4-苯基胺曱醯基-苯基。在式I或式II之某些實施例中基）-哌啶-1-基]-苯基。在式I或式II之某些實施例中 0底咬-1-基）-苯基。在式I或式II之某些實施例中基氧基）-笨基。在式I或式II之某些實施例中基。在式I或式II之某些實施例中，Ar為2-(4-胺基甲基-D底咬_ 1-基）-5-氣-苯基。在式I或式II之某些實施例中，八!*為2-[4-(卜胺基-乙基）-哌啶-1-基]_5·氣-苯基。 157102.doc -35- 201217379 在式I或式II之某些實施例中’ Ar為2-(4-胺甲酿基- η辰咬-1 -基）-5-氣-苯基。在式I或式II之某些實施例中’ Ar為5-氣·2-[3-(1-經基-乙基）-°比咯啶-1-基]-笨基。在式I或式II之某些實施例中’ Ar為4-胺基曱基-4-氣-聯苯-2-基。在式I或式II之某些實施例中’ Ar為5 -氣-2-曱氧基-笨基。在式I或式II之某些實施例中，Ar為3-胺基-2-(4-胺基乙基-娘咬-1-基）-苯基。在式I或式II之某些實施例中，Ar為3-胺基-2-哌啶-1-基· 苯基。在式I或式II之某些實施例中，Ar為5-羥基曱基-2-哌咬_ 1-基-苯基。在式I或式II之某些實施例中，Ar為3-(3-羥基-環戊基氧基）_秦'-2-基。在式I或式II之某些實施例中，Ar為4-氣-4'-羥基甲基-聯苯-2·基。在式I或式II之某些實施例中，Ar為5-氣-2·異丙氧基-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(3-羥基甲基-環戊基氧基）-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-吡咯啶-l-基-苯基。 157102.doc • 36· 201217379 在式I或式II之某些實施例中’ Al為3-(3-羥基-丙氧基）-秦-2-基。在式I或式II之某些實施例中，Ar為7-羥基甲基-3-甲氧基-蔡-2-基* 在式I或式II之某些實施例中，Ar為5-氣-2-(3-羥基-環戊基氧基）-苯基。在式I或式II之某些實施例中，Ar為5-氯-2-(3-羥基-丙氧基）-苯基。 # 在式I或式II之某些實施例中，Ar為3-(4-羥基-環己基氧基）"奈-2-基。在式I或式II之某些實施例中，Ar為5-氣-2-(4-羥基-丁氧基）-苯基。在式I或式II之某些實施例中，^為2_甲氧基_4_苯基胺甲醯基-苯基。在式I或式II之某些實施例中，^為5_氯_2_(3_羥基_哌啶-1 -基）-苯基。鲁纟式1或式11之某些實施例中，Ar為5-氯-2-(娘。定-4-基氧基）-苯基。在式I或式II之某些實施例中，Μ4_氯冬經基_聯苯_2_ 基。在式1或式Π之某些實施例中，Ar為5_氣-2-(3-經基各。定-1-基）-苯基。在式I或式II之某些實施例中，^為5•氯-2_(3,4_二經基_ 丁氧基苯基。 157102.doc •37- 201217379 在式1或式Π之某些實施例中，Ar為5-氯-2-(4-甲基-哌嗪-1-基）-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(°惡嗤-5-基曱氧基）-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-嗎啦-4-基-苯基。在式I或式II之某些實施例中，Ar為4-氣-聯苯_2_基。在式I或式II之某些實施例中，ArS 2-(3-胺基曱基-吡咯 0定-1-基）-5 -氯-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(3-羥基-環己基氧基）-苯基。在式I或式II之某些實施例中，Ar為3-甲氧基-萘-2-基。在式I或式Π之某些實施例中，Ar為4-(3-羥基-丙基胺曱 Θ盛基）-2 -曱氧基_苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(3-羥基甲基-°比咯啶-1-基）-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-二氟曱氧基-苯基。在式Ϊ或式11之某些實施例中，A r為5 -氣-2 -二甲基胺基_ 苯基。在式I或式II之某些實施例中，Ar為2-(3-胺基-吡咯啶-1-基）_5-氣-苯基。在式I或式II之某些實施例中，Ar為5-氯-2-甲基硫基-苯基。 157102.doc -38" 201217379 在式I或式II之某些實施例中，Ar為5·氣-2-環己基-苯基。在式I或式II之某些實施例中，Ar為3-(2-羥基-乙基胺基）-2-旅咬-1-基-苯基。在式I或式II之某些實施例中，Ar為5-氯·2-(4-甲基-噁唑-5-基甲氧基）-苯基。在式I或式II之某些實施例中，Ar為聯苯-2-基。在式I或式II之某些實施例中，Ar為5-氯-2-(3-羥基-1，1-# 二甲基-丙氧基）-笨基。在式I或式II之某些實施例中，Ar為2-(4·胺基-環己基氧基）-5-氣-苯基。在式I或式II之某些實施例中，Ar為2-氮雜環庚烷-l-基-5 -氣-苯基。在式I或式II之某些實施例中，Ar為4-(2-羥基-乙基胺甲醯基）-2-甲氧基_苯基。在式I或式II之某些實施例中，Ar為4-羥基-環己基氧基）- 鲁苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(2-甲氧基-乙氧基）-苯基。在式I或式II之某些實施例中，Ar為4-氯-3·-羥基-聯苯-2- 基。在式I或式II之某些實施例中，Ar為5-溴-2-曱氧基-苯基。在式I或式II之某些實施例中，Ar為5 -氯-2-[(2-經基-乙 157102.doc •39· 201217379 基）-甲基-胺基]-苯基》在式I或式II之某些實施例中，Ar為5-氯-2-(4-羥基-笨氧基）-苯基。在式I或式II之某些實施例中，Ar為4-胺曱醯基-2-甲氧基-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-異丁氧基-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(2,3-二羥基-丙氧基）-苯基。在式I或式II之某些實施例中，Ar為5-氣-2-(3-曱氧基-丙氧基）-苯基。在式I或式Π之某些實施例中，Ar為5-氣-2-(3-羥基甲基-哌啶-1_基）-笨基。在式I或式II之某些實施例中，Ar為5-氣-2-(3-羥基-苯甲氧基。在式Ϊ或式II之某些實施例中，Ar為5-氣-2,4-二甲氧基-苯基》在式I或式II之某些實施例中，Ar為2-甲氧基-5-乙烯基-苯基。在式I或式II之某些實施例中，八!*為3-(3-羥基-丙基胺基）-2-略咬-1_基_苯基。在式Ϊ或式II之某些實施例中，Ar為5-氣-2-(4-羥基-丁基）·苯基。在式1或式Π之某些實施例中，Ar為2-[3-(1-胺基-乙基）- 157102.doc 201217379 "比咯啶-1-基]-5-氣-苯基。在式I或式π之某些實施例中，^為5_氯_2_[(3經基丙基）-曱基-胺基]_苯基。在式I或式II之某些實施例中，Ar為5_氣_2_⑷甲基胺基曱基-哌啶-1-基）·苯基。在式I或式II之某些實施例中，^為5_(3經基丙稀基）_2_ 甲氧基-苯基。In certain embodiments of Formula I or Formula II, 1-yl)-5-a-phenyl. In certain embodiments of Formula I or Formula II, 1-yl)-4-phenylaminoindenyl-phenyl. In certain embodiments of Formula I or Formula II, the base is -piperidin-1-yl]-phenyl. In certain embodiments of Formula I or Formula II, the base is -1-yl)-phenyl. In certain embodiments of Formula I or Formula II, the oxy)-phenyl group. In certain embodiments of Formula I or Formula II. In certain embodiments of Formula I or Formula II, Ar is 2-(4-aminomethyl-D-bottom-1-yl)-5-a-phenyl. In certain embodiments of Formula I or Formula II, VIII!* is 2-[4-(imino-ethyl)-piperidin-1-yl]-5. gas-phenyl. 157102.doc -35- 201217379 In certain embodiments of formula I or formula II, 'Ar is 2-(4-aminoglycanyl-n-n-n-l-yl)-5-a-phenyl. In certain embodiments of formula I or formula II, 'Ar is 5-gas·2-[3-(1-trans-ethyl-ethyl)-pyrrolidin-1-yl]-styl. In certain embodiments of formula I or formula II, 'Ar is 4-aminomercapto-4-pyrene-2-yl-2-yl. In certain embodiments of Formula I or Formula II, 'Ar is 5-a-2-nonyloxy-phenyl. In certain embodiments of Formula I or Formula II, Ar is 3-amino-2-(4-aminoethyl-indiyl-1-yl)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 3-amino-2-piperidin-1-yl-phenyl. In certain embodiments of formula I or formula II, Ar is 5-hydroxyindenyl-2-piperidin-1-yl-phenyl. In certain embodiments of formula I or formula II, Ar is 3-(3-hydroxy-cyclopentyloxy)-methyl'-2-yl. In certain embodiments of formula I or formula II, Ar is 4-a-4'-hydroxymethyl-biphenyl-2.yl. In certain embodiments of Formula I or Formula II, Ar is 5-aza-2.isopropoxy-phenyl. In certain embodiments of formula I or formula II, Ar is 5-gas-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl. In certain embodiments of formula I or formula II, Ar is 5-a-2-pyrrolidinyl-l-yl-phenyl. 157102.doc • 36· 201217379 In certain embodiments of Formula I or Formula II, 'Al is 3-(3-hydroxy-propoxy)-hhenyl-2-yl. In certain embodiments of Formula I or Formula II, Ar is 7-hydroxymethyl-3-methoxy-cain-2-yl*. In certain embodiments of Formula I or Formula II, Ar is 5- Gas-2-(3-hydroxy-cyclopentyloxy)-phenyl. In certain embodiments of formula I or formula II, Ar is 5-chloro-2-(3-hydroxy-propoxy)-phenyl. # In certain embodiments of Formula I or Formula II, Ar is 3-(4-hydroxy-cyclohexyloxy)"na-2-yl. In certain embodiments of formula I or formula II, Ar is 5-gas-2-(4-hydroxy-butoxy)-phenyl. In certain embodiments of formula I or formula II, is 2-methoxy-4-phenylaminecarbenyl-phenyl. In certain embodiments of formula I or formula II, is 5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl. In certain embodiments of Formula 1 or Formula 11, Ar is 5-chloro-2-(indenyl-4-yloxy)-phenyl. In certain embodiments of formula I or formula II, Μ4_chlorobutyro-biphenyl-2-yl. In certain embodiments of Formula 1 or Formula ,, Ar is 5-gas-2-(3-transyldin-1-yl)-phenyl. In certain embodiments of Formula I or Formula II, ^ is 5•chloro-2_(3,4-di-di-butoxyphenyl. 157102.doc •37-201217379 in Formula 1 or Formula In some embodiments, Ar is 5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-gas-2. - (°ox-5-yloxy)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-a-2-nonyl-4-yl-phenyl. In certain embodiments of Formula I or Formula II, Ar is 4-a-biphenyl-2-yl. In certain embodiments of Formula I or Formula II, ArS 2-(3-aminoindenyl-pyrrole0 Din-1-yl)-5-chloro-phenyl. In certain embodiments of formula I or formula II, Ar is 5-a-2-(3-hydroxy-cyclohexyloxy)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 3-methoxy-naphthalen-2-yl. In certain embodiments of Formula I or Formula, Ar is 4-(3-hydroxy-propyl Amidoxime-2-yloxy-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-gas-2-(3-hydroxymethyl-pyrrolidine-1 -yl)-phenyl. In certain embodiments of formula I or formula II, Ar is 5-a-2-difluoromethoxy-phenyl. In formula or formula 11 In some embodiments, Ar is 5- gas-2-dimethylamino-phenyl. In certain embodiments of Formula I or Formula II, Ar is 2-(3-amino-pyrrolidine-1 -基)_5-Gas-Phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-chloro-2-methylsulfanyl-phenyl. 157102.doc -38" 201217379 In Formula I or In certain embodiments of Formula II, Ar is 5·gas-2-cyclohexyl-phenyl. In certain embodiments of Formula I or Formula II, Ar is 3-(2-hydroxy-ethylamino) -2-Bent-1-yl-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-chloro-2-(4-methyl-oxazol-5-ylmethoxy) -Phenyl. In certain embodiments of Formula I or Formula II, Ar is a biphenyl-2-yl group. In certain embodiments of Formula I or Formula II, Ar is 5-chloro-2-(3- Hydroxy-1,1-# dimethyl-propoxy)-styl. In certain embodiments of Formula I or Formula II, Ar is 2-(4.amino-cyclohexyloxy)-5- Gas-Phenyl. In certain embodiments of Formula I or Formula II, Ar is 2-azepane-l-yl-5-a-phenyl. Certain embodiments of Formula I or Formula II Wherein Ar is 4-(2-hydroxy-ethylaminecarbamimidoyl)-2-methoxy-phenyl. Some of Formula I or Formula II Embodiment, Ar is 4-hydroxy - cyclohexyloxy) - phenyl Lu. In certain embodiments of formula I or formula II, Ar is 5-gas-2-(2-methoxy-ethoxy)-phenyl. In certain embodiments of formula I or formula II, Ar is 4-chloro-3.-hydroxy-biphenyl-2-yl. In certain embodiments of formula I or formula II, Ar is 5-bromo-2-indolyl-phenyl. In certain embodiments of formula I or formula II, Ar is 5-chloro-2-[(2-carbo-ethyl 157102.doc •39·201217379)-methyl-amino]-phenyl" In certain embodiments of formula I or formula II, Ar is 5-chloro-2-(4-hydroxy-indolyl)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 4-aminoindenyl-2-methoxy-phenyl. In certain embodiments of formula I or formula II, Ar is 5-a-2-isobutoxy-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-gas-2-(2,3-dihydroxy-propoxy)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-gas-2-(3-decyloxy-propoxy)-phenyl. In certain embodiments of formula I or formula, Ar is 5-gas-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-gas-2-(3-hydroxy-benzyloxy. In certain embodiments of Formula Ϊ or Formula II, Ar is 5-gas- 2,4-Dimethoxy-phenyl" In certain embodiments of Formula I or Formula II, Ar is 2-methoxy-5-vinyl-phenyl. Certain of Formula I or Formula II In the examples, VIII!* is 3-(3-hydroxy-propylamino)-2-slightly 1-1-yl-phenyl. In certain embodiments of Formula Ϊ or Formula II, Ar is 5- Gas-2-(4-hydroxy-butyl)-phenyl. In certain embodiments of formula 1 or formula, Ar is 2-[3-(1-amino-ethyl)-157102.doc 201217379 "Byrrolidin-1-yl]-5-gas-phenyl. In certain embodiments of Formula I or Formula π, ^ is 5-chloro-2-[[3-propylpropyl)-fluorenyl- Amino]-Phenyl. In certain embodiments of Formula I or Formula II, Ar is 5-nitrox-2-(4)methylaminoindolyl-piperidin-1-yl)-phenyl. In certain embodiments of formula I or formula II, ^ is 5-(3-propylpropenyl)_2-methoxy-phenyl.

在式1或式Π之某些實施例中，Ar為5-氯-2-乙基-苯基。在弋或式II之某些實施例中，^為4_甲烷磺醯基曱氧基-苯基。在式I或式II之某些實施例中，Ar為5_氣·2(3經基·苯氧基）-苯基。在式I或式II之某些貫施例中，Ar為2,4_二甲氧基_苯基。在式1或式Π之某些實施例中，Ar為5备2-曱氧基-苯基。在式I或式II之某些實施例中，^為5_氣_2_苯氧基·苯基。在式I或式II之某些實施例中，A05_(3經基丙基>2甲氧基-笨基。在式I或式II之某些實施例中，Ar為5_氣_2兴2·羥基甲基_ 哌啶-1-基）-笨基。在式1或式11之某些實施例中，Ar為5-氣-2-(4-二曱基胺基甲基·娘啶-1-基）_笨基。在式1或式Π之某些實施例中，Ar為3-曱氧基-聯苯-4- 157102.doc -41· 201217379 基。在式I或式II之某些實施例中，Ar為5-乙基-2-曱氧基-苯在式I或式II之某些實施例中，Ar為5-甲氧基-2·甲基-聯本-4-基。在式I或式II之某些實施例中，Ar為2-曱氧基-3,5-二甲基-苯基。在式Ϊ或式Π之某些實施例中，Ar為4-二甲基胺曱醯基_ 2-甲氧基-苯基。在式Ϊ或式II之某些實施例中，Ar為5-乙醯基胺基-2-甲氧基-苯基。在式I或式II之某些實施例中，八!*為5-氣-2-甲氧基_4_笨基胺甲醯基-苯基。在式I或式II之某些實施例中，^為4_羥基甲基_2-甲氧基-苯基。在式I或式II之某些實施例中，^為視情況經取代之雜芳基。在式I或式II之某些實施例中，Ar為選自以下之雜芳基： °比咬基；苯并[1，3]二氧雜環戊烯基；喹啉基；2_側氧基-2,3-二氫-叫丨哚基；吲哚基；苯并咪唑基；或吲唑基；各自視情況經獨立地選自以下之基團取代一次或兩次：鹵基；c〗-6烧基；鹵基·Cl.6烷基；Cl-6烯基；Cl_6烷氧基；鹵基-Cw烧氧基；羥基_Cl 6烷基；羥基-(：16烷基胺基；Cl6 烧基-胺基；經基；胺基；胺基_Ci6烷基；胺基羰基；羥 157102.doc -42- 201217379 基-C 1.6烧氧基；經基-Ci-6稀基，Ci-6烧氧基_ C 1 ·6烧氧基’ Ci-6烷基磺醯基；Cw烷基硫基；哌啶基，其中哌啶基部分視情況經經基、胺基、胺基-Cl.6院基、經基_Ci-6烧基或胺基羰基取代；苯基胺基羰基；羥基-Cw烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Ci-6 烷基或羥基烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Ci.6烷基或羥基-Ci.6烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-cN6烷基或胺基羰基取代；吡咯啶基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ci.6烷基或胺基幾基取代；°比嘻咬基氧基，其中β比嘻咬基部分視情況經羥基、胺基、胺基-C,-6烷基、羥基-CN6烷基或胺基羰基取代；哌嗪基’其中哌嗪基部分視情況經c1-6烷基取代；噁唾-Ci.6烷氧基’其中其噁唑部分視情況經Cl_6烷基取代；嗎啉基；羥基-Ci·6烷基胺基羰基；c3.6環烷基；氮雜環庚烷基’其中氮雜環庚烷基部分視情況經羥基、胺基、胺基-C!·6烷基、羥基-Cw烷基或胺基羰基取代；苯甲基，其中其苯基部分視情況經胺基、羥基、胺基院基、羥基-Cw烷基或胺基羰基取代；Cw烷氧羰基{“烷氧基；及Cw烷基羰基胺基。在式I或式II之某些實施例中，Ar為選自以下之雜芳美. 喹啉基；2-側氧基-2,3-二氫·吲哚基；吲哚基；苯并咪唑 157102.doc -43- 201217379 基；或吲唑基；各自視情況經獨立地選自以下之基團取代一次或兩次：鹵基；C!-6烧基；鹵基·〇1-6院基；稀基；In certain embodiments of formula 1 or formula, Ar is 5-chloro-2-ethyl-phenyl. In certain embodiments of the formula or formula II, ^ is methanesulfonyloxy-phenyl. In certain embodiments of formula I or formula II, Ar is 5-gas-2 (3-carbophenoxy)-phenyl. In certain embodiments of Formula I or Formula II, Ar is 2,4-dimethoxy-phenyl. In certain embodiments of Formula 1 or Formula, Ar is 5 quinone 2-decyloxy-phenyl. In certain embodiments of formula I or formula II, ^ is a gas stream of 5_gas_2_phenoxy-phenyl. In certain embodiments of Formula I or Formula II, A05_(3-propylpropyl>2 methoxy-styl. In certain embodiments of Formula I or Formula II, Ar is 5_gas_2 Xing 2 · hydroxymethyl _ piperidin-1-yl) - stupid. In certain embodiments of Formula 1 or Formula 11, Ar is 5-gas-2-(4-didecylaminomethyl-n-din-1-yl)-phenyl. In certain embodiments of Formula 1 or Formula, Ar is 3-indolyl-biphenyl-4-157102.doc-41.201217379. In certain embodiments of Formula I or Formula II, Ar is 5-ethyl-2-indolyl-benzene. In certain embodiments of Formula I or Formula II, Ar is 5-methoxy-2. Methyl-biben-4-yl. In certain embodiments of formula I or formula II, Ar is 2-decyloxy-3,5-dimethyl-phenyl. In certain embodiments of the formula or formula, Ar is 4-dimethylaminoindenyl-2-methoxy-phenyl. In certain embodiments of Formula Ϊ or Formula II, Ar is 5-ethenylamino-2-methoxy-phenyl. In certain embodiments of formula I or formula II, VIII!* is 5-gas-2-methoxy-4-phenylaminomercapto-phenyl. In certain embodiments of formula I or formula II, is 4-hydroxymethyl-2-methoxy-phenyl. In certain embodiments of formula I or formula II, ^ is optionally substituted heteroaryl. In certain embodiments of Formula I or Formula II, Ar is a heteroaryl group selected from the group consisting of: a butyl group; a benzo[1,3]dioxolyl group; a quinolinyl group; Oxy-2,3-dihydro-decyl; fluorenyl; benzimidazolyl; or oxazolyl; each optionally substituted once or twice with a group independently selected from the group consisting of: halo; c -6-alkyl; halo·Cl.6 alkyl; Cl-6 alkenyl; Cl_6 alkoxy; halo-Cw alkoxy; hydroxy-C 6 alkyl; hydroxy-(: 16 alkylamine a group; an alkyl group; an amine group; an amine group; a aryl group; an amino group; ,Ci-6 alkoxy _ C 1 ·6 alkoxy 'Ci-6 alkylsulfonyl; Cw alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally via a base, an amine, an amine Substituted with a base group, a benzyl group or an aminocarbonyl group; a phenylaminocarbonyl group; a hydroxy-Cw alkylamino group; a cyclohexyloxy group in which a cyclohexyl moiety is optionally subjected to a hydroxyl group. , an amine group, an amino-Ci-6 alkyl group or a hydroxyalkyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally hydroxy , amino, amino-Ci. 6 alkyl or hydroxy-Ci. 6 alkyl substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group, a hydroxyl group -Cw alkyl or aminocarbonyl substituted; phenyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Cw alkyl group, a hydroxy-cN6 alkyl group or an amine carbonyl group; a pyrrolidinyl group in which pyrrolidine The base moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Ci.6 alkyl group or an amino group; the ratio of the β group to the base group, wherein , amine, amino-C, -6 alkyl, hydroxy-CN6 alkyl or aminocarbonyl substituted; piperazinyl' wherein the piperazinyl moiety is optionally substituted by c1-6 alkyl; caesium-Ci.6 Alkoxy' wherein the oxazole moiety is optionally substituted by a C1-6 alkyl group; morpholinyl; hydroxy-Ci.6 alkylaminocarbonyl; c3.6 cycloalkyl; azepanyl' The heptyl moiety is optionally substituted by a hydroxyl group, an amine group, an amine group -C!·6 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a benzyl group in which a phenyl moiety is optionally an amine group or a hydroxyl group. Amine base , hydroxy-Cw alkyl or aminocarbonyl substituted; Cw alkoxycarbonyl {"alkoxy; and Cw alkylcarbonylamino. In certain embodiments of Formula I or Formula II, Ar is selected from the group consisting of芳美. quinolyl; 2-sided oxy-2,3-dihydroindolyl; fluorenyl; benzimidazole 157102.doc -43- 201217379; or carbazolyl; each independently Substituting one or two groups selected from the group consisting of: halo; C!-6 alkyl; halo·〇1-6; base;

Cw烷氧基；鹵基-CN6烷氧基；羥基-Cw烷基；羥基-Cw 烷基胺基；Ck烷基-胺基；羥基；胺基；胺基-Cw烷基；胺基幾基；經基_^11.6烧氧基；經基_^11.6稀基，匚1_6炫氧基-Cw烷氧基；Cw烷基磺醯基；Cw烷基硫基；哌啶基’ 其中哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基胺基羰基；羥基-Cw烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、 _ 胺基、胺基-Cm烷基或羥基-Cw烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-C^烷基或羥基-C^烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cu烷基或胺基羰基取代；吡咯啶基氧基，其中吡咯鲁啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-CN6 烷基或胺基羰基取代；哌嗪基，其中哌嗪基部分視情況經 Q.6烷基取代；噁唑-Cw烷氧基，其中其噁唑部分視情況經匸“烷基取代；嗎啉基；羥基-Cw烷基胺基羰基；c3.6環烷基；氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基-Ci.6烷基、羥基-Ck烷基或胺基羰基取代；苯甲基，其中其苯基部分視情況經胺基、羥基、胺 157102.doc -44- 201217379 基-Cw烷基、羥基-C!.6烷基或胺基羰基取代；Cw烷氧羰基-Cw烷氧基；及匚“烷基羰基胺基。在式I或式II之某些實施例中，Ar為選自以下之雜芳基：啥琳基；2-側氧基-2,3-二氫- n朵基；叫丨D朵基；苯并味嗤基；或吲唑基；各自視情況經獨立地選自以下之基團取代一次或兩次：Ci-6烧基；Ci_6烧氧基；經基-Ci_6烧氧基；經基-C^烷基胺基；胺基-Cw烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基- Ci-6烧基、經基_Ci-6烧基或胺基幾基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；及吼咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cl-6烧基或胺基幾基取代。在式I或式II之某些實施例中，Ar為選自以下之雜芳基：喹啉基；2-側氧基-2,3-二氫-吲哚基；吲哚基；苯并咪唑基；或吲唑基；各自經獨立地選自以下之基團取代一次或兩次：Cw烷基；Cw烷氧基；羥基-Cw烷氧基；羥基-Ck 烷基胺基；胺基-C^烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-(^-6烷基或羥基-Ck烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-C!.6烷基、羥基-Cw烷基或胺基羰基取代；哌啶基氧 157102.doc -45- 201217379 基’其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Ci.6烧基取代；及》比洛咬基氧基，其中β比洛咬基部分視情況經羥基、胺基、胺基-Ci.6烷基、羥基-C!.6烷基或胺基羰基取代》在式I或式II之某些實施例中，Ar為視情況經獨立地選自以下之基團取代一次或兩次之喹啉基：Ci-6烷基；Cw烷氧基；羥基-CV6烷氧基；羥基-Cw烷基胺基；胺基-(^.6烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ck 烷基或胺基羰基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烧基或經基-Cl-6烧基取代；及°比嘻咬基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-C〗-6烷基、羥基-Cw烷基或胺基羰基取代。在式I或式II之某些實施例中，Ar為視情況經獨立地選自以下之基團取代一次或兩次之2-側氧基-2,3·二氫-吲哚基.Cl·6烧基，Cl.6烧氧基；經基-Ci-6烧氧基；經基-Cl.6院基胺基；胺基-Cw烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基 '胺基-Ci.6烷基或羥基-Cw烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺 •46- 157102.doc 201217379 基-Ci_6烧基、經基-Ci-6烧基或胺基幾·基取代；D底咬基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-C^烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cu烷基取代；及吼咯啶基氧基，其中吼咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代。在式I或式II之某些實施例中，Ar為視情況經獨立地選自以下之基團取代一次或兩次之吲哚基：Cu烷基；Cu烷氧基，經基-(^1.6烧氧基；經基-(111_6炫>基胺基；胺基-〇1_6院氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基- Ci_6烧基或經基- Ci_6烧基取代；派咬基，其中派啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw 烷基或胺基羰基取代；哌啶基氧基，其中其哌啶基部分視情況經經基、胺基、胺基-Cl·6院基、經基-Cl.6烧基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Ci_6烧基或經基-Ci_6烧基取代；及吼略咬基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代》在式I或式II之某些實施例中，Ar為視情況經獨立地選自以下之基團取代一次或兩次之吲唑基·· Cu烷基；Cw烷氧基；羥基-Ck烷氧基；羥基-Cw烷基胺基；胺基-Cw烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基- Ci.6烧基或經基- Ci-6烧基取代；D底咬基，其中u底 157102.doc -47· 201217379 啶基部分視情況經羥基、胺基、胺基-Ck烷基、羥基-Cw 烧基或胺基羰基取代；°辰咬基氧基，其中其派咬基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-C!·6院基或經基-Ci-6烧基取代；及η比洛咬基氧基’其中吡咯啶基部分視情況經羥基、胺基、胺基-C!-6烧基、羥基-Ci-6烧基或胺基羰基取代。在式I或式II之某些實施例中，Ar為視情況經獨立地選自以下之基團取代一次或兩次之苯并咪唑基：CN6烷基；（：丨-6 φ 烷氧基；羥基-Cw烷氧基；羥基-Cw烷基胺基；胺基-Cw 烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；及吡 _ 咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Ck烷基、羥基-CN6烷基或胺基羰基取代。在式I或式II之某些實施例中，Ar為經獨立地選自以下之基團取代一次或兩次之喹啉-6-基：CN6烷基；Cw烷氧基；經基-Cw烧氧基；經基_cN6烧基胺基；胺基-Ci.6烧氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Cw烧基或經基_C!.6烧基取代；娘咬基，其中娘 157102.doc -48- 201217379 啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw 烧基或胺基羰基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-CN6烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基 '胺基-Cw烷基或羥基-CN6烷基取代；及吡咯啶基氧基，其中°比咯啶基部分視情況經羥基、胺基、胺基-Cl-6烧基、經基-Cl _6烧基或胺基幾基取代。在式I或式II之某些實施例中，Ar為經獨立地選自以下之基團在7位取代且視情況在2位取代之喹啉-6-基：CU6烷基》(^1.6烧氧基，經基-(111.6烧氧基；經基-^1-6烧基胺基，胺基-Cw烷氧基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Ci.6烷基或羥基-Cw烷基取代；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Ci-6烷基、羥基-Cw烷基或胺基羰基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；及吡咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代。在式I或式II之某些實施例中，Ar為選自以下之雜芳基： 7-(4-胺基甲基-哌啶-1-基）-喹啉-6-基；2-(2-羥基-乙基胺基）-7-曱氧基-喧琳-6-基；7-(4-經基-環己基氧基）-喹琳-6-基；7-甲氧基-喹啉-6-基；7-哌啶-1-基-喹啉-6-基；7-(3- 157102.doc -49- 201217379 羥基-環戊基氧基）-喹啉-6_基；7-(3-羥基_ι_甲基-丁氧基）_ 喧1#-6-基；7-(3-經基-丁氧基）-〇|；嚇__6-基；7-(旅咬-4-基氧基）-喹啉-6-基；7-(3-羥基-1，1-二甲基-丙氧基）_喹啉_6_ 基；7-(3-胺基-丙氧基）-喹琳-6-基；7-(3-羥基-環戊基氧基）-喹淋-6-基；7-(派咬-4-基氧基）-啥咐_6-基；7-(3-羥基-丙氧基）-喧琳-6-基；7-("比略咬-3-基氧基）_喧琳_6_基；7-(4-羥基甲基-哌啶-1-基）-喹啉-6-基；7-(4-胺基甲基-哌啶_ 1- 基）-喹*#-6-基；喹啉-6-基；5-(4-羥基曱基-哌啶-1-基）- 2- 側氧基-2,3-二氩-1H-吲哚-6-基；5-(4-羥基甲基-苯基）-2-曱基-1H-吲哚-6-基；2-側氧基-5-哌啶-1-基-2,3-二氫-1H-吲哚-6-基；6-甲氧基-1H-吲唑-5-基；5-甲氧基-2-甲基-1H-吲哚-6-基；5-曱氧基-1H-吲哚-6-基；或ι_(3-羥基-丙基）· 1H-苯并咪唑-2-基。在式I或式Π之某些實施例中，Ar為選自以下之雜芳基： 7-(4-胺基甲基-哌啶-1·基）_喹啉_6_基；2_(2_羥基_乙基胺基）-7·曱氧基-喹啉-6-基；7-(4_羥基-環己基氧基）-喹啉·6-基；7-曱氧基-喹啉-6-基；7-哌啶_1-基_喹啉-6-基；7-(3-羥基-環戊基氧基）-喹啉-6-基；7-(3-羥基-1-甲基-丁氧基）_ 喹啉-6-基；7-(3-羥基·丁氧基）_喹啉_6_基；7_(哌啶_4·基氧基喹啉_6·基；7-(3-羥基-二甲基_丙氧基喹啉基；7-(3-胺基-丙氧基喹啉_6_基；7_(3羥基_環戊基氧基）-喹啉-6-基；7-(哌啶-4-基氧基）-喹啉-6-基；7-(3-羥基_ 丙氧基）-喹啉-6-基；7-(吡咯啶_3_基氧基）-喹啉-6-基；ΤΟ-羥基甲基-哌啶-1-基）·喹啉_6_基； 7_(4_胺基甲基_哌啶- 157102.doc •50· 201217379 1- 基）-喹啉-6-基；5-(4-羥基曱基-哌啶-1-基）-2-側氧基_2,3_ 二氫-1H-吲哚_6_基；5-(4-羥基曱基-苯基）-2-甲基-1H-吲哚-6-基；2-側氧基_5•哌啶_丨_基·2,3-二氫-1H-嗍嘴_6_基； 6- 曱氧基-1Η-吲唑·5_基；5-甲氧基-2-甲基-1Η-11弓丨哚_6_基； 5-曱氧基-1Η_吲哚·6_基；或1-(3-羥基-丙基）-lH-笨并咪唑- 2- 基。在式Ϊ或式II之某些實施例中，Ar為選自以下之喹琳基·· 7- (4-胺基曱基-哌啶基）_喹啉_6_基；2_(2_羥基-乙基胺基）-7-曱氧基··喹啉_6_基；7-(4-羥基-環己基氧基）-喹啉-6_ 基；7-曱氧基-喹啉_6_基；7_哌啶―卜基-喹啉-6-基；7-(3-羥基-環戊基氧基）-喹啉-6-基；7-(3-羥基-1-甲基-丁氧基）_ 喹啉-6-基；7-(3-羥基-丁氧基）-喹啉-6-基；7-(哌啶-4-基氧基）-喹啉-6-基；7-(3-羥基-1,1-二甲基-丙氧基）_喹啉-6-基；7-(3-胺基-丙氧基）-喹琳-6-基；7-(3-經基·環戊基氧基）-喹啉-6-基；7-(哌啶-4-基氧基）-喹啉-6·基；7-(3-羥基-丙氧基）-喧琳-6 -基；7-(ntt洛咬-3-基氧基）-啥淋-6 -基’ 7 -(4-羥基曱基-哌啶-1-基）·喹啉-6-基；7-(4-胺基甲基-哌啶_ 1 -基）-啥淋-6 -基，及啥琳-6 -基。在式I或式II之某些實施例中，Ar為選自以下之喹啉基： 7-(4 -胺基甲基-略咬-1 -基）·啥琳-6 -基；2-(2 -經基-乙基胺基）-7-甲氧基-喹啉-6-基；7-(4-羥基-環己基氧基）-喹啉-6-基；7-曱氧基-喧琳-6-基；7-π底咬-1-基-啥琳-6-基；7-(3-羥基-環戊基氧基）-喹啉-6-基；7_(3_羥基_1_甲基-丁氧基）-喹啉-6-基；7-(3-羥基-丁氧基）-喹啉-6-基；7-(哌啶基氧 157102.doc •51 · 201217379 基）-喹啉-6-基，· 7-(3-羥基_u_二甲基丙氧基）喹啉_6_ 基，7-(3-胺基-丙氧基）-喹啉_6基；7(3羥基環戊基氧基）-喹啉-6-基；7-(哌啶-4-基氧基）_喹啉_6_基；7_(3_羥基_ 丙氧基）-喹啉-6-基；7-(吡咯啶_3基氧基）_喹啉_6基；7_ (4-羥基甲基·哌啶-1-基）-喹啉_6基；及7(4胺基甲基_哌咬-1 -基）-哇琳-6 -基。在式I或式II之某些實施例中，…為：氩；Ci 6烷基；Ci 6 烷氧基；羥基；羥基-C!·6烷基；Ci 6烷基_胺基；胺基_Ci 6 烷基，胺基-Cw烷基-胺基；羥基_Ci 6烷基胺基；c36環烷基胺基，胺基羰基；鹵基；羥基_C16烷基；或羥基_C16烷氧基。在式I或式II之某些實施例中，各R1獨立地為：氫；Ci 6 烷基；Cw烷氧基；羥基；羥基_Ci6烷基；烷基胺基；胺基-C,.6烷基；胺基-cK6烷基-胺基；羥基_Ci6烷基胺基’ 〇3.6環烧基胺基；鹵基；或胺基幾基。在式I或式II之某些實施例中，R1為氫。在式I或式II之某些實施例中，R1為C16院基。在式I或式II之某些實施例中，R1為C16烧氧基。在式I或式II之某些實施例中，R1為經基。在式I或式II之某些實施例中，R1為羥基_Ci 6烷基。在式I或式II之某些實施例中，R1為C16烷基_胺基。在式I或式II之某些實施例中，R1為胺基{^烷基。在式I或式II之某些實施例中，R1為胺基_Ci6烷基胺基。 157102.doc •52- 201217379 在式I或式II之某些實施例中，R1為羥基-Cw烷基胺基。在式I或式II之某些實施例中，R1為C3-6環烷基胺基。在式I或式II之某些實施例中，R1為胺基羰基。在式I或式II之某些實施例中，R1為鹵基。在式I或式II之某些實施例中，R1為羥基-Cw烷基。在式I或式II之某些實施例中，R1為羥基-Cw烷氧基。在式I或式II之某些實施例中，R1為：氫；羥基；2-胺基-乙基）-甲基-胺基；2-胺基-乙基胺基；甲基；甲氧基； 2-羥基-乙基）-甲基·胺基；羥基曱基；2-羥基-1-曱基-乙基胺基；2-環丙基胺基；2_羥基-乙基胺基；2,3-二羥基-丙基胺基’ 3 -胺基-丙基胺基；胺基||炭基；2 -經基-乙基）-異丙基-胺基；溴；異丁基胺基；異丙基-甲基-胺基；3-羥基-丙基胺基；1-羥基曱基-丙基胺基；2-羥基-乙基；2-乙醯基胺基-乙基胺基；3-羥基·丙基；或異丙基-胺基。在式I或式II之某些實施例中，R1為羥基。在式I或式II之某些實施例中，R1為2-胺基-乙基）-甲基-胺基。在式I或式II之某些實施例中，R1為2-胺基-乙基胺基。在式I或式II之某些實施例中，R1為甲基。在式I或式II之某些實施例中，R1為曱氧基。在式I或式II之某些實施例中，R1為2-羥基-乙基）-甲基_ 胺基。在式I或式II之某些實施例中，R1為羥基曱基。在式I或式II之某些實施例中，R1為2-羥基-1-甲基-乙基 157102.doc -53- 201217379 胺基。在式I或式II之某些實施例中，R1為2-環丙基胺基。在式I或式II之某些實施例中，R1為2-羥基-乙基胺基。在式Ϊ或式II之某些實施例中’ R1為2,3-二羥基-丙基胺基。在式I或式II之某些實施例中’ W為3-胺基-丙基胺基。在式I或式II之某些實施例中’ R1為胺基羰基。在式I或式II之某些實施例中’ R1為2-羥基-乙基）-異丙基-胺基。在式I或式II之某些實施例中’ R1為溴。在式I或式II之某些實施例中’ R1為異丁基胺基。在式I或式II之某些實施例中，R1為異丙基-曱基-胺基。在式I或式II之某些實施例中，R1為3-羥基-丙基胺基。在式Ϊ或式II之某些實施例中’R1為1-羥基曱基-丙基胺在式I或式II之某些實施例中，R1為2-羥基-乙基。在式I或式II之某些實施例中’R1為2-乙醯基胺基-乙基胺基。在式I或式II之某些實施例中，R1為3-羥基-丙基》在式I或式II之某些實施例中，R1為異丙基-胺基。在某些實施例中，式I及式II之化合物可分別具有式la或式 Ila : 157102.doc • 54· 201217379Cw alkoxy; halo-CN6 alkoxy; hydroxy-Cw alkyl; hydroxy-Cw alkylamino; Ck alkyl-amino; hydroxy; amine; amine-Cw alkyl; ; base group _^11.6 alkoxy; base _^11.6, 匚1_6 methoxy-Cw alkoxy; Cw alkyl sulfonyl; Cw alkylthio; piperidinyl' wherein piperidinyl Partially substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl; phenylaminocarbonyl; hydroxy-Cw alkylamino; cyclohexyloxy, wherein cyclohexyl Partially substituted by hydroxy, _amino, amino-Cm alkyl or hydroxy-Cw alkyl; cyclopentyloxy, wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine group, an amine group-C alkane Substituted or hydroxy-C^alkyl; piperidinyloxy, wherein the piperidinyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl; phenyl Wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a pyrrolidinyl group in which a pyrrolidinyl moiety is optionally subjected to a hydroxyl group, an amine group or an amine group. -Cw alkyl, Substituted with a Cu- or alkyl-carbonyl group; a pyrrolidinyloxy group, wherein the pyrrolidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-CN6 alkyl group or an amine carbonyl group; a pyrazinyl group, wherein the piperazinyl moiety is optionally substituted with a Q.6 alkyl group; the oxazole-Cw alkoxy group, wherein the oxazole moiety thereof is optionally substituted by an alkyl group; a morpholino group; a hydroxy-Cw alkylamine Alkylcarbonyl; c3.6 cycloalkyl; azepanyl, wherein the azepanyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Ci. 6 alkyl group, a hydroxy-Ck alkyl group or an amine group. Carbonyl substituted; benzyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amine 157102.doc-44-201217379-Cw alkyl group, a hydroxy-C!.6 alkyl group or an amine carbonyl group; Cw alkane Oxycarbonyl-Cw alkoxy; and hydrazine "alkylcarbonylamino. In certain embodiments of Formula I or Formula II, Ar is a heteroaryl group selected from the group consisting of: fluorene; 2-sided oxy-2,3-dihydro-n-mole; a benzoxanthyl group; or a carbazolyl group; each of which is optionally substituted once or twice with a group independently selected from the group consisting of: Ci-6 alkyl; Ci-6 alkoxy; alkyl-Ci-6 alkoxy; -C^alkylamino;amino-Cw alkoxy; cyclohexyloxy, wherein the cyclohexyl moiety is optionally substituted by hydroxyl, amine, amino-Cw alkyl or hydroxy-Cw alkyl; piperidine a group wherein the piperidinyl moiety is optionally substituted with a hydroxy group, an amine group, an amino group-Ci-6 alkyl group, a thiol-Ci-6 alkyl group or an amino group; a piperidinyloxy group in which a piperidinyl group Partially substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl; cyclopentyloxy, wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine group, an amine group - Cw alkyl or hydroxy-Cw alkyl substituted; and oxaridinyloxy, wherein the pyrrolidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group, a hydroxy group - a C 6 alkyl group or an amine group Substituted. In certain embodiments of Formula I or Formula II, Ar is a heteroaryl group selected from the group consisting of: quinolinyl; 2-sided oxy-2,3-dihydro-indenyl; fluorenyl; benzo Imidazolyl; or carbazolyl; each substituted once or twice with a group independently selected from the group consisting of Cw alkyl; Cw alkoxy; hydroxy-Cw alkoxy; hydroxy-Ck alkylamino; -C^ alkoxy; cyclohexyloxy, wherein the cyclohexyl moiety is optionally substituted by hydroxy, amine, amino-(^-6 alkyl or hydroxy-Ck alkyl; piperidinyl, wherein piperidinyl Partially substituted by hydroxyl, amine, amino-C!.6 alkyl, hydroxy-Cw alkyl or aminocarbonyl; piperidinyloxy 157102.doc -45- 201217379 base 'wherein its piperidinyl moiety In the case of a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw alkane Substituted or substituted with hydroxy-Ci.6 alkyl; and "Bilobityloxy", wherein β is more than hydroxy, amine, amine-Ci.6 alkyl, hydroxy-C!. Alkyl or aminocarbonyl substitutions in Formula I or Formula II And R&lt Alkylamino;amino-(^.6 alkoxy; cyclohexyloxy, wherein the cyclohexyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cw alkyl; piperidine a group wherein the piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Ck alkyl group or an aminocarbonyl group; a piperidinyloxy group in which a piperidinyl moiety is optionally subjected to a hydroxyl group, Substituted with an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw alkyl group or a hydroxyl group. -Cl-6 alkyl group substitution; and ° ratio of the base oxygen group, wherein the pyrrolidinyl moiety is optionally substituted by a hydroxyl group, an amine group, an amine group -C -6 alkyl group, a hydroxy-Cw alkyl group or an amine carbonyl group In certain embodiments of Formula I or Formula II, Ar is 2-positionoxy-2,3·dihydro-indenyl, which is optionally substituted one or two times, optionally independently selected from the group below. Cl·6 alkyl, Cl.6 Oxyl; alkyl-Ci-6 alkoxy; alkyl-Cl.6-based amine; amine-Cw alkoxy; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group' Amino-Ci.6 alkyl or hydroxy-Cw alkyl substituted; piperidinyl, wherein the piperidinyl moiety is optionally hydroxy, amine, amine, 46-157102.doc 201217379-Ci_6 alkyl, via- a Ci-6 alkyl or an amino group substituted; a D-bottomyloxy group, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amino group-Cw alkyl group, a hydroxy-C alkyl group or an amine group. Substituted by a carbonyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group or a hydroxy-Cu alkyl group; and a fluorenyloxy group in which a fluorenyl group Partially substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl. In certain embodiments of Formula I or Formula II, Ar is optionally substituted with one or two substituents independently selected from the group consisting of: Cualkyl; Cu alkoxy, via--^ 1.6 alkoxy; thiol-(111_6 炫>arylamino; amine-〇1_6 oxime; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Ci-6 group Or substituted by a base - Ci_6 alkyl; a thiol group, wherein the pyridyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a piperidinyloxy group, Wherein the piperidinyl moiety is optionally substituted with a thiol, an amine group, an amine group - a hexyl group, a thiol group or an amine carbonyl group; a cyclopentyloxy group in which a cyclopentyl moiety is Optionally substituted with a hydroxyl group, an amine group, an amine group-Ci_6 alkyl group or a base group -Ci_6 alkyl group; and a slightly occluded base group, wherein the pyrrolidinyl group is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw alkyl group. , hydroxy-Cw alkyl or aminocarbonyl substituted. In certain embodiments of Formula I or Formula II, Ar is optionally substituted once or twice with a group selected from the group consisting of oxazolyl·Cu alkyl Cw alkoxy; hydroxy-Ck alkoxy; hydroxy-Cw alkylamino; amine-Cw alkoxy; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - Substituted by Ci.6 or by a base - Ci-6 alkyl; D bottom base, wherein u is 157102.doc -47· 201217379 The pyridine group is optionally via a hydroxyl group, an amine group, an amine group - a Ck alkyl group, a hydroxyl group. -Cw alkyl or aminocarbonyl substituted; thiol methoxy, wherein the thiol moiety is optionally substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl; a pentyloxy group, wherein the cyclopentyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group -C 6 ·6 or a base group -Ci-6 alkyl group; and a η 比洛基基基' The pyridine group moiety is optionally substituted with a hydroxyl group, an amine group, an amine group -C!-6 alkyl group, a hydroxy-Ci-6 alkyl group or an amine carbonyl group. In certain embodiments of Formula I or Formula II, Ar is a view. a benzimidazolyl group substituted one or two times independently by a group selected from: CN6 alkyl; (: 丨-6 φ alkoxy; hydroxy-Cw alkoxy; hydroxy-Cw alkylamino; Amino-Cw alkoxy; cyclohexyl a group wherein the cyclohexyl moiety is optionally substituted with a hydroxy group, an amine group, an amino-Cw alkyl group or a hydroxy-Cw alkyl group; a piperidinyl group in which a piperidinyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw Alkyla, hydroxy-Cw alkyl or aminocarbonyl substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally via a hydroxy, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl group Substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cw alkyl; and pyrrolidinyloxy, wherein pyrrolidinyl moiety Substituted by a hydroxyl group, an amine group, an amino-Ck alkyl group, a hydroxy-CN6 alkyl group or an aminocarbonyl group. In certain embodiments of formula I or formula II, Ar is quinoline-6-yl substituted with one or two groups independently selected from: CN6 alkyl; Cw alkoxy; via-Cw An alkoxy group; an alkyl group based on a base group; an amine group-Ci.6 alkoxy group; a cyclohexyloxy group in which a cyclohexyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw alkyl group or a mercapto group. _C!.6 alkyl group substitution; mother bite base, which is 157102.doc -48- 201217379 The pyridine group is optionally substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or amine carbonyl a piperidinyloxy group in which a piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-CN6 alkyl group or an aminocarbonyl group; a cyclopentyloxy group in which a cyclopentyl group is substituted Partially substituted with a hydroxyl group, an amino group 'amino-Cw alkyl group or a hydroxy-CN6 alkyl group; and a pyrrolidinyloxy group, wherein the ratio of the pyridyl group to the hydroxy group, the amine group, the amine group-Cl- 6 alkyl group, substituted with a base-Cl -6 alkyl group or an amino group. In certain embodiments of Formula I or Formula II, Ar is a quinoline-6-yl group substituted at the 7 position and optionally substituted at the 2 position: CU6 alkyl (^1.6) An alkoxy group, via a base - (111.6 alkoxy; a base -^1-6 alkylamino group, an amine-Cw alkoxy group; a cyclohexyloxy group, wherein the cyclohexyl moiety is optionally a hydroxyl group, an amine group , amino-Ci.6 alkyl or hydroxy-Cw alkyl substituted; piperidinyl, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group -Cw alkyl group, a hydroxy-Cw alkyl group or an amine carbonyl group Substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally substituted by hydroxy, amine, amino-Ci-6 alkyl, hydroxy-Cw alkyl or aminocarbonyl; cyclopentyloxy, wherein The cyclopentyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Cw alkyl group or a hydroxy-Cw alkyl group; and a pyrrolidinyloxy group in which a pyrrolidinyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw Alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted. In certain embodiments of Formula I or Formula II, Ar is a heteroaryl group selected from 7-(4-aminomethyl-piperidine- 1-yl)-quinolin-6-yl; 2-(2-hydroxy-B Amino)-7-methoxy-indolyl-6-yl; 7-(4-yl-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl 7-piperidin-1-yl-quinolin-6-yl; 7-(3- 157102.doc -49- 201217379 hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(3- Hydroxy_ι_methyl-butoxy)_喧1#-6-yl; 7-(3-carbo-butoxy)-indole|; scare __6-yl; 7-(Brigade bite-4-氧基oxy)-quinolin-6-yl; 7-(3-hydroxy-1,1-dimethyl-propoxy)-quinoline-6-yl; 7-(3-amino-propoxy) -Quinolin-6-yl; 7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(pyrylene-4-yloxy)-oxime-6-yl; -(3-hydroxy-propoxy)-indolyl-6-yl; 7-("bicinch-3-yloxy)-喧琳_6_yl; 7-(4-hydroxymethyl- Piperidin-1-yl)-quinolin-6-yl; 7-(4-aminomethyl-piperidine-1-yl)-quino*#-6-yl; quinoline-6-yl; 5- (4-hydroxyindolyl-piperidin-1-yl)-2-one-oxy-2,3-diar-argon-1H-indol-6-yl; 5-(4-hydroxymethyl-phenyl)- 2-mercapto-1H-indol-6-yl; 2-sided oxy-5-piperidin-1-yl-2,3-dihydro-1H-indol-6-yl; 6-methoxy -1H-carbazol-5-yl; 5-methoxy-2-methyl-1H-indol-6-yl; 5- Oxy-1H-indol-6-yl; or i-(3-hydroxy-propyl). 1H-benzimidazol-2-yl. In certain embodiments of Formula I or Formula, Ar is selected from The following heteroaryl: 7-(4-aminomethyl-piperidin-1yl)-quinoline-6-yl; 2-(2-hydroxy-ethylamino)-7-decyloxy-quin啉-6-yl; 7-(4-hydroxy-cyclohexyloxy)-quinoline·6-yl; 7-decyloxy-quinolin-6-yl; 7-piperidin-1-yl-quinoline -6-yl; 7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl; 7-(3-Hydroxy-butoxy)-quinoline-6-yl; 7-(piperidin-4-yloxyquinolin-6-yl; 7-(3-hydroxy-dimethyl-propoxy) Quinolyl; 7-(3-amino-propoxyquinoline-6-yl; 7-(3hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(piperidin-4-yl Oxy)-quinoline-6-yl; 7-(3-hydroxy-propoxy)-quinolin-6-yl; 7-(pyrrolidin-3-yloxy)-quinolin-6-yl; ΤΟ-Hydroxymethyl-piperidin-1-yl)·quinoline-6-yl; 7-(4-aminomethyl-piperidine-157102.doc •50·201217379 1-yl)-quinoline-6- 5-(4-hydroxyindolyl-piperidin-1-yl)-2-oxooxy-2,3-dihydro-1H-indole-6-yl; 5- (4-hydroxyindolyl-phenyl)-2-methyl-1H-indol-6-yl; 2-sided oxy-5<piperidinyl-indoleyl-2,3-dihydro-1H-indole Mouth_6_yl; 6-decyloxy-1Η-carbazole·5-yl; 5-methoxy-2-methyl-1Η-11丨哚丨哚_6_yl; 5-decyloxy-1Η _吲哚·6_ group; or 1-(3-hydroxy-propyl)-lH-benzimidazole-2-yl. In certain embodiments of Formula Ϊ or Formula II, Ar is quinolinyl 7-(4-aminoindolyl-piperidinyl)-quinoline-6-yl selected from the group consisting of: 2_(2_ Hydroxy-ethylamino)-7-decyloxy·quinoline-6-yl; 7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-decyloxy-quinoline _ 6-yl; 7-piperidin-buki-quinolin-6-yl; 7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(3-hydroxy-1-methyl -butoxy)-quinoline-6-yl; 7-(3-hydroxy-butoxy)-quinolin-6-yl; 7-(piperidin-4-yloxy)-quinoline-6 -yl; 7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl; 7-(3-amino-propoxy)-quinolin-6-yl; 7-(3-trans)cyclopentyloxy)-quinolin-6-yl; 7-(piperidin-4-yloxy)-quinolin-6-yl; 7-(3-hydroxy-propyl Oxy)-indolyl-6-yl; 7-(ntt-L--3-yloxy)-indolyl-6-yl- 7-(4-hydroxyindolyl-piperidin-1-yl)quin Phenyl-6-yl; 7-(4-aminomethyl-piperidine-1-yl)-indole-6-yl, and fluorene-6-yl. In certain embodiments of Formula I or Formula II, Ar is a quinolinyl group selected from the group consisting of: 7-(4-aminomethyl-slightly-doped 1-yl)-啥琳-6-yl; (2-propionyl-ethylamino)-7-methoxy-quinolin-6-yl; 7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-decyloxy -喧琳-6-yl; 7-π-Bottom-1-yl-啥-lin-6-yl; 7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl; 7_(3_ Hydroxy-1-methyl-butoxy)-quinolin-6-yl; 7-(3-hydroxy-butoxy)-quinolin-6-yl; 7-(piperidinyloxy 157102.doc •51 · 201217379 base)-quinoline-6-yl, · 7-(3-hydroxy-u-dimethylpropoxy)quinoline-6-yl, 7-(3-amino-propoxy)-quinoline _6 base; 7 (3hydroxycyclopentyloxy)-quinolin-6-yl; 7-(piperidin-4-yloxy)-quinoline-6-yl; 7-(3-hydroxy-propoxy ))-quinolin-6-yl; 7-(pyrrolidin-3-yloxy)-quinoline-6-yl; 7-(4-hydroxymethyl-piperidin-1-yl)-quinoline-6-yl; And 7 (4 aminomethyl-piperidin-1 -yl)-wowolin-6-yl. In certain embodiments of Formula I or Formula II, are: argon; Ci 6 alkyl; Ci 6 alkoxy; hydroxy; hydroxy-C!·6 alkyl; Ci 6 alkyl-amino; _Ci 6 alkyl, amino-Cw alkyl-amino; hydroxy-Ci 6 alkylamino; c36 cycloalkylamino, aminocarbonyl; halo; hydroxy-C16 alkyl; or hydroxy-C16 alkane Oxygen. In certain embodiments of Formula I or Formula II, each R1 is independently: hydrogen; Ci6 alkyl; Cw alkoxy; hydroxy; hydroxy-Ci6 alkyl; alkylamino; amine-C,. 6 alkyl; amino-cK6 alkyl-amino; hydroxy-Ci6 alkylamino' 〇3.6 cycloalkylamino; halo; or amino group. In certain embodiments of formula I or formula II, R1 is hydrogen. In certain embodiments of Formula I or Formula II, R1 is a C16 yard base. In certain embodiments of formula I or formula II, R1 is C16 alkoxy. In certain embodiments of Formula I or Formula II, R1 is a trans-group. In certain embodiments of formula I or formula II, R1 is hydroxy-Ci 6 alkyl. In certain embodiments of Formula I or Formula II, R1 is C16 alkyl-amino. In certain embodiments of Formula I or Formula II, R1 is an amino group. In certain embodiments of formula I or formula II, R1 is an amino-Ci6 alkylamino group. 157102.doc • 52- 201217379 In certain embodiments of formula I or formula II, R1 is hydroxy-Cw alkylamino. In certain embodiments of formula I or formula II, R1 is C3-6 cycloalkylamino. In certain embodiments of formula I or formula II, R1 is an aminocarbonyl group. In certain embodiments of formula I or formula II, R1 is halo. In certain embodiments of formula I or formula II, R1 is hydroxy-Cw alkyl. In certain embodiments of formula I or formula II, R1 is hydroxy-Cw alkoxy. In certain embodiments of formula I or formula II, R1 is: hydrogen; hydroxy; 2-amino-ethyl)-methyl-amino; 2-amino-ethylamine; methyl; methoxy 2-hydroxy-ethyl)-methyl-amino group; hydroxy fluorenyl; 2-hydroxy-1-indolyl-ethylamino group; 2-cyclopropylamino group; 2-hydroxy-ethylamino group ; 2,3-dihydroxy-propylamino] 3 -amino-propylamino; amine group || carbon-based; 2-hydroxy-ethyl)-isopropyl-amino group; bromine; Amino group; isopropyl-methyl-amino group; 3-hydroxy-propylamino group; 1-hydroxyindenyl-propylamino group; 2-hydroxy-ethyl group; 2-ethylidylamino group-B Amino group; 3-hydroxy-propyl group; or isopropyl-amino group. In certain embodiments of formula I or formula II, R1 is hydroxy. In certain embodiments of formula I or formula II, R1 is 2-amino-ethyl)-methyl-amino. In certain embodiments of formula I or formula II, R1 is 2-amino-ethylamino. In certain embodiments of formula I or formula II, R1 is methyl. In certain embodiments of formula I or formula II, R1 is a decyloxy group. In certain embodiments of formula I or formula II, R1 is 2-hydroxy-ethyl)-methyl-amino. In certain embodiments of formula I or formula II, R1 is hydroxyindenyl. In certain embodiments of formula I or formula II, R1 is 2-hydroxy-1-methyl-ethyl 157102.doc-53-201217379 amine. In certain embodiments of formula I or formula II, R1 is 2-cyclopropylamino. In certain embodiments of formula I or formula II, R1 is 2-hydroxy-ethylamino. In certain embodiments of Formula Ϊ or Formula II, 'R1 is 2,3-dihydroxy-propylamino. In certain embodiments of Formula I or Formula II, 'W is 3-amino-propylamino. In certain embodiments of Formula I or Formula II, ' R1 is an aminocarbonyl group. In certain embodiments of Formula I or Formula II, 'R1 is 2-hydroxy-ethyl)-isopropyl-amino. In certain embodiments of Formula I or Formula II, 'R1 is bromine. In certain embodiments of Formula I or Formula II, ' R1 is isobutylamino. In certain embodiments of formula I or formula II, R1 is isopropyl-indenyl-amino. In certain embodiments of formula I or formula II, R1 is 3-hydroxy-propylamino. In certain embodiments of Formula Ϊ or Formula II, 'R1 is 1-hydroxyindolyl-propylamine. In certain embodiments of Formula I or Formula II, R1 is 2-hydroxy-ethyl. In certain embodiments of Formula I or Formula II, 'R1 is 2-ethinylamino-ethylamine. In certain embodiments of Formula I or Formula II, R1 is 3-hydroxy-propyl. In certain embodiments of Formula I or Formula II, R1 is isopropyl-amino. In certain embodiments, the compounds of Formula I and Formula II can have Formula la or Formula Ila, respectively: 157102.doc • 54· 201217379

其中： R3及R4各獨立地為：鹵基；C!-6烧基，函基_Ci-6烧基； Ci-6稀基；C〗_6烧氧基；鹵基-Ci-6炫·氧基；經基-Ci-6烧基；羥基-Cm烷基胺基；Cw烷基·胺基；羥基；胺基；胺基-Cw烷基；胺基羰基；羥基-Cw烷氧基；羥基-Cm烯基；CK6烷氧基-Cw烷氧基；Ci-6烷基磺醯基；Cw烷基硫基；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-Ck烷基、羥基-Cw烷基或胺基羰基取代；苯基胺基羰基；羥基-cU6烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基-Ci-6烷基或羥基-Cw烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Ci.6烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ci_6烧基或胺基幾基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基羰基取代；吡咯啶基，其中咣咯啶基部分視情況經羥基、胺基、胺基-C!.6烷基、羥基-Ck烷基或胺基羰基取代；吡咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺 157102.doc •55· 201217379 基-Cl ·6炫基、經基-C 1-6院基或胺基幾基取代；略秦基，其中哌嗪基部分視情況經C〗.6烷基取代；噁唑-Cw烷氧基，其中其噁唑部分視情況經CN6烷基取代；嗎啉基；羥基-CN6 烷基胺基羰基；（：3_6環烷基；氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基-CN6烷基、羥基-C!·6烷基或胺基羰基取代；苯甲基，其中其苯基部分視情況經胺基、羥基、胺基-Ci.6烷基、羥基-Cw烷基或胺基羰基取代；Cw烷氧羰基-Cw烷氧基；或匸“烷基羰基胺基；及 Φ R1如本文所定義。在式la或式Ila之某些實施例中，R4為鹵基。在式la或式Ila之某些實施例中，R4為氣。在式la或式Ila之某些實施例中，R3為鹵基。在式la或式Ila之某些實施例中，R3為Cl_6烷基。在式la或式Ila之某些實施例中’ R3為鹵基_c]6烷基。在式la或式Ila之某些實施例中，R3為Cl6烯基。在式la或式IIa之某些實施例中，R3為Ci 6烷氧基。籲在式la或式Ila之某些實施例中，R3為鹵基/^烷氧基。在式la或式Ila之某些實施例中’ R3為羥基_Ci6烷基。在式la或式Ila之某些實施例中’ R3為羥基_Ci6烷基胺基。在式la或式lla之某些實施例中，R3為Ci 6烷基_胺基。在式la或式Ila之某些實施例中，R3為羥基；胺基。在式la或式Ila之某些實施例中，R3為胺基_Ci6烷基。 157102.doc •56· 201217379 在式la或式Ila之某些實施例中，r3為胺基羰基β 在式la或式Ila之某些實施例中，R3為羥基—(^^烷氧基。在式la或式Ila之某些實施例中，r3為羥基_Ci 6烯基。在式la或式Ila之某些實施例中，R3為Cl_6烷氧基_Cl6烷氧基。在式la或式Ila之某些實施例中，R3為Cl_6烷基磺醯基。在式la或式Ila之某些實施例中，R3為Cl_6烷基硫基。在式la或式Ila之某些實施例中，R3為哌啶基，其中哌啶 ® 基部分視情況經羥基、胺基、胺基-Ci-6烷基、羥基-Cw烷基或胺基羰基取代。在式la或式Ila之某些實施例中，R3為苯基胺基羰基。在式la或式Ila之某些實施例中，r3為經基& 6烧基胺基。在式la或式Ila之某些實施例中，R3為環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基_Ci_6烷基或羥基_Ci_6烧基取代》鲁在式1a或式IIa之某些實施例中，R3為環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基_Ci 6烷基或羥基-Ci _6烧基取代。在式la或式Ila之某些實施例中，R3為派咬基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基_Ci6烷基、羥基_^1·6烧基或胺基叛基取代。在式la或式Ila之某些實施例中，R3為苯基，其中苯基部分視情況經胺基、羥基、胺基_Ci_6烷基、羥基—CM烷基或 157102.doc •57· 201217379 胺基羰基取代。在式la或式Ila之某些實施例中，R3為0比洛咬基，其中η比哈咬基部分視情況經經基、胺基、胺基-Ci·6烧基、經基-Ci _6烧基或胺基幾基取代。在式la或式Ila之某些實施例中，尺3為〇比咯啶基氧基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ci-6烧基或胺基叛基取代。在式la或Ila之某些實施例中，R3為哌嗪基，其中哌嗪基部分視情況經Cw烷基取代。在式la或Ila之某些實施例中，R3為噁唑_cN6烷氧基，其中其噁唑部分視情況經CN6烷基取代。在式la或式Ila之某些實施例中，R3為嗎啉基。在式la或式Ila之某些實施例中，R3為羥基—(^^烷基胺基幾基* 在式la或式Ila之某些實施例中，R3為(^3_6環烷基。在式la或式Ila之某些實施例中，R3為氮雜環庚院基，其中氮雜環庚燒基部分視情況經羥基、胺基、胺基_c^ —烧基、羥基-Cw烷基或胺基羰基取代。在式la或式Ila之某些實施例中，R3為苯甲基，其中其苯基部分視情況經胺基、羥基、胺基_Cl·6烷基、羥基'Μ烷基或胺基幾基取代。在式la或式IIa之某些實施例中，R3為Ci 6烷氧羰基/〗— 烷氧基。在式la或式Ila之某些實施例中，r3為Cm烷基羰基胺 157102.doc -58- 201217379 基。在某些實施例中’式I及式Η之化合物可分別具有式lb或式 lib :Wherein: R3 and R4 are each independently: halo; C!-6 alkyl, functional group -Ci-6 alkyl; Ci-6 dilute; C _6 alkoxy; halo-Ci-6 dazzle Oxy; thio-Ci-6 alkyl; hydroxy-Cm alkylamino; Cw alkylamino; hydroxy; amine; amino-Cw alkyl; aminocarbonyl; hydroxy-Cw alkoxy; hydroxy-Cm alkenyl; CK6 alkoxy-Cw alkoxy; Ci-6 alkylsulfonyl; Cw alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group -Ck alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted; phenylaminocarbonyl; hydroxy-cU6 alkylamino; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group -Ci-6 alkyl or hydroxy-Cw alkyl substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Ci.6 alkyl; Piperidinyloxy, wherein the piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Ci-6 group or an amino group; a phenyl group, wherein the phenyl moiety is optionally an amine Base, hydroxyl, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl Substituted; pyrrolidinyl, wherein the oxaridinyl moiety is optionally substituted by hydroxy, amine, amino-C!.6 alkyl, hydroxy-Ck alkyl or aminocarbonyl; pyrrolidinyloxy, pyrrolidine The phenyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine 157102.doc • 55· 201217379 yl-Cl hexyl group, a benzyl-C 1-6 or an amino group; a slightly dimethyl group, wherein the piperazinyl group Partially substituted by C.6 alkyl; oxazole-Cw alkoxy, wherein the oxazole moiety is optionally substituted by CN6 alkyl; morpholinyl; hydroxy-CN6 alkylaminocarbonyl; (: 3-6 ring Alkyl; azepanyl, wherein the azacycloheptyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group -CN6 alkyl group, a hydroxy-C!.6 alkyl group or an amine carbonyl group; Wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Ci.6 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a Cw alkoxycarbonyl-Cw alkoxy group; or a fluorene "alkylcarbonyl group" Amine; and Φ R1 are as defined herein. In certain embodiments of Formula la or Formula 11a, R4 is halo. In certain embodiments of Formula la or Formula Ila, R4 is qi. Ila In certain embodiments, R3 is halo. In certain embodiments of Formula la or Formula Ila, R3 is Cl-6 alkyl. In certain embodiments of Formula la or Formula Ila, 'R3 is halo-c In certain embodiments of formula la or formula Ila, R3 is a Cl6 alkenyl group. In certain embodiments of formula la or formula IIa, R3 is Ci6 alkoxy. In certain embodiments of Ila, R3 is halo/alkyloxy. In certain embodiments of Formula la or Formula Ila, 'R3 is hydroxy-Ci6 alkyl. In certain embodiments of Formula la or Formula 11a, ' R3 is hydroxy-Ci6 alkylamino. In certain embodiments of formula la or formula 11a, R3 is Ci6 alkyl-amino. In certain embodiments of Formula la or Formula 11a, R3 is hydroxy; an amine group. In certain embodiments of Formula la or Formula 11a, R3 is amino-Ci6 alkyl. 157102.doc •56·201217379 In certain embodiments of formula la or formula Ila, r3 is an aminocarbonyl group β. In certain embodiments of formula la or formula Ila, R3 is hydroxy-(^^ alkoxy. In certain embodiments of Formula la or Formula 11a, r3 is hydroxy-Ci 6 alkenyl. In certain embodiments of Formula la or Formula 11a, R3 is Cl-6 alkoxy-Cl6 alkoxy. Or in certain embodiments of Formula Ila, R3 is Cl-6 alkylsulfonyl. In certain embodiments of Formula la or Formula Ila, R3 is Cl-6 alkylthio. Some embodiments of Formula la or Formula Ila In the above, R3 is piperidinyl, wherein the piperidinyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino-Ci-6 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group. In certain embodiments, R.sup.3 is phenylaminocarbonyl. In certain embodiments of Formula la or Formula Ila, r3 is viayl & 6 alkylamino. Some embodiments of Formula la or Formula Ila Wherein R 3 is a cyclohexyloxy group, wherein the cyclohexyl moiety is optionally substituted with a hydroxy group, an amine group, an amine group -Ci_6 alkyl group or a hydroxy group -Ci_6 alkyl group, in some embodiments of formula 1a or formula IIa, R3 is a cyclopentyloxy group, wherein The cyclopentyl moiety is optionally substituted with a hydroxy, amine, amine-Ci 6 alkyl or hydroxy-Ci -6 alkyl group. In certain embodiments of formula la or formula Ila, R3 is a aryloxy group, Wherein the piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group -Ci6 alkyl group, a hydroxy group, or an amine group. In certain embodiments of formula la or formula Ila, R3 Is a phenyl group, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amine group -Ci_6 alkyl group, a hydroxy group-CM alkyl group or a 157102.doc •57·201217379 aminocarbonyl group. Some of the formula la or the formula Ila In the examples, R3 is a 0 butyl group, wherein the η is more than a carbyl group, optionally substituted by a benzyl group, an amine group, an amine group, a Ci.6 alkyl group, a group-Ci -6 alkyl group or an amine group. In certain embodiments of Formula la or Formula 11a, Rule 3 is an indolopyridinyloxy group, wherein the pyrrolidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group-Cw alkyl group, or a hydroxyl group-Ci-6. In some embodiments of formula la or Ila, R3 is piperazinyl, wherein the piperazinyl moiety is optionally substituted by Cw alkyl. Some embodiments of formula la or Ila In the middle, R3 is evil An azole-cN6 alkoxy group wherein the oxazole moiety is optionally substituted with a CN6 alkyl group. In certain embodiments of formula la or formula Ila, R3 is morpholino. Certain embodiments of formula la or formula Ila Wherein R3 is hydroxy-(^^alkylamino)* In certain embodiments of formula la or formula Ila, R3 is (^3_6 cycloalkyl. In certain embodiments of formula la or formula Ila And R3 is azacyclononyl, wherein the azacycloheptyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group, a hydroxy group, a hydroxy-Cw alkyl group or an aminocarbonyl group. In certain embodiments of Formula la or Formula 11a, R3 is benzyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amine group _Cl.6 alkyl group, a hydroxy 'alkyl group or an amine group. Substituted. In certain embodiments of formula la or formula IIa, R3 is Ci6alkoxycarbonyl/y-alkoxy. In certain embodiments of Formula la or Formula 11a, r3 is Cm alkylcarbonylamine 157102.doc-58-201217379. In certain embodiments, the compounds of Formula I and Formulae can have Formula lb or Formula lib, respectively:

其中： R5與R6各自獨立地為：氫；鹵基；Cw烷基；鹵基-Cb6 烧基，Ci_6稀基，Ci_6烧氧基；鹵基-Ci_6貌氧基；經基-Ci_6 烷基；羥基-Cw烷基胺基；Ci-6烷基-胺基；羥基；胺基；胺基-CN6烷基；胺基羰基；羥基-Cu烷氧基；羥基-Cu烯基；CN6烷氧基-Cw烷氧基；Cw烷基磺醯基；Cw烷基硫基；哌啶基，其中哌啶基部分視情況經羥基、胺基、胺基-C1:6烷基、羥基-Cl_6烷基或胺基羰基取代；苯基胺基羰基；羥基-Cw烷基胺基；環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基_CN6烷基或羥基_Cl_6烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基_Cl6烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥 157102.doc •59· 201217379 基-C ! .6烷基或胺基羰基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基_Cl 6烷基或胺基羰基取代；°比咯啶基’其中吡咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Ck烷基或胺基羰基取代；吡咯啶基氧基’其中。比咯啶基部分視情況經羥基、胺基、胺基-C〗·6烷基、羥基-Cw烷基或胺基羰基取代；哌嗪基，其中哌嗪基部分視情況經(^_6烷基取代；噁唑-c16烷氧基，其中其噁唑部分視情況經Cl·6烷基取代；嗎啉基；羥基_C16 烷基胺基羰基；C3-6環烷基；氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基_c16烷基、羥基-Cw烷基或胺基羰基取代；苯曱基，其中其苯基部分視情況經胺基、羥基、胺基-Cw烷基、羥基-Cw烷基或胺基幾基取代；C!.6烷氧羰基-Cw烷氧基；或Ci.6烷基羰基胺基；及 R1如本文所定義。在式lb或式lib之某些實施例中，R5與R6各自獨立地為：齒基；Cw烷基；鹵基-Cw烷基；Ck烯基；Cw烷氧基；鹵基-Cu烷氧基；羥基-Cu烷基；羥基-Cl6烷基胺基；Cl_6 烧基-胺基；羥基；胺基；胺基-Cm烷基；胺基羰基；羥基-C,·6烧氧基；羥基_Cl6烯基；Cl，6烷氧基_Cl_6烷氧基； Cw烧基磺醯基；Cl 6烷基硫基；哌啶基，其中哌啶基部分視情況經經基、胺基、胺基_Cl_6烷基、羥基_Ci 6烷基或胺基幾基取代；苯基胺基羰基；羥基_Cl.6烷基胺基；環己基氧基’其中其環己基部分視情況經羥基、胺基、胺基-C ! .6 157102.doc 201217379 烷基或羥基-c^烷基取代；環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基-Cw烷基或羥基-Cw烷基取代；哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烧基、經基-Cw烧基或胺基幾基取代；苯基，其中苯基部分視情況經胺基、羥基、胺基_c16烷基、輕基-C 1 ·6烧基或胺基裁基取代；β比洛唆基，其中。比洛D定基部分視情況經羥基、胺基、胺基-Cw烷基、羥基_Cl 6烷基或胺基羰基取代；°比σ各咬基氧基，其中吼嘻。定基部分視情況經輕基、胺基、胺基-Cw烧基、經基-Cw烧基或胺基幾基取代；哌嗪基，其中哌嗪基部分視情況經C1_6烷基取代；11 惡唾-C!—6烷氧基，其中其噁唑部分視情況經c16烷基取代，嗎琳基，輕基-Ci_6烧基胺基幾基；c3.6環烧基；氮雜環庚烧基’其中氮雜環庚烧基部分視情況經經基、胺基、胺基-Cw烷基、羥基-C!.6烷基或胺基羰基取代；苯甲基’其中其本基部分視情況經胺基、經基、胺基_ C丨6烧基、輕基-C!—6烧基或胺基幾基取代；c1-6烷氧羰基_(^16烷氧基，或Ci-6烧基幾基胺基。在式lb或式lib之某些實施例中，R5為氫。在式lb或式lib之某些實施例中，R5為!|基。在式lb或式lib之某些實施例中，R5為c! 6烧其。在式ib或式iib之某些實施例中，r5為鹵基_Ci 6烷基。在式lb或式lib之某些實施例中，R5為6稀某。在式lb或式lib之某些實施例中，R5為Ci 6烧氧基。在式ib或式iib之某些實施例中，尺5為_基<16烷氧基。 157102.doc •61 - 201217379 在式lb或式lib之某些實施例中，R5為羥基_Ci 6烷基β 在式lb或式lib之某些實施例中，R5為羥基_Ci 6烷基胺基。在式lb或式lib之某些實施例中，R5為Cl_6烷基-胺基。在式lb或式lib之某些實施例中，r5為羥基；胺基。在式lb或式lib之某些實施例中，R5為胺基_Ci 6烷基。在式lb或式lib之某些實施例中，r5為胺基羰基。在式lb或式lib之某些實施例中，r5為羥基—(^^烷氧基。在式lb或式lib之某些實施例中，r5為經基_Ci 6烯基。在式lb或式lib之某些實施例中，尺5為Ci6烷氧基{“烷氧基。在式lb或式lib之某些實施例中，R5為Ci 6烷基磺醯基。在式lb或式lib之某些實施例中，R5為Cl_6烷基硫基。在式lb或式lib之某些實施例中，R5為哌啶基，其中哌咬基部分視情況經羥基、胺基、胺基-Cw烷基、羥基_Ci 6烧基或胺基羰基取代。在式lb或式lib之某些實施例中，R5為笨基胺基幾基。在式lb或式lib之某些實施例中，R5為羥基_Ci6烷基胺基。在式lb或式lib之某些實施例中，R5為環己基氧基，其中其環己基部分視情況經羥基、胺基、胺基_Ci 6烧基或經基-Cw烷基取代。在式lb或式lib之某些實施例中，R5為環戊基氧基’其中其環戊基部分視情況經羥基、胺基、胺基<16烷基或經 157102.doc •62· 201217379 基-Cw烷基取代。在式lb或式lib之某些貫施例中，r5為〇底咬基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-CU6烷基、羥基-Cu烷基或胺基羰基取代。在式lb或式lib之某些實施例中，r5為苯基，其中苯基部分視情況經胺基、羥基、胺基-Cl-6烷基、羥基-Cw烷基或胺基羰基取代。在式lb或式lib之某些實施例中，R5為《·比洛唆基，其中0比 _ 咯啶基部分視情況經羥基、胺基、胺基-Cw烷基、經基-Cl _6烧基或胺基幾基取代。在式lb或式lib之某些實施例中，R5為η比略唆基氧基，其中D比咯啶基部分視情況經羥基、胺基、胺基_c16烷基、羥基-Cl ·6烧基或胺基幾基取代β 在式lb或lib之某些實施例中，R5為哌嗪基，其中哌唤基部分視情況經(^_6烷基取代。在式1b*IIb之某些實施例中，R5為噁唑-Cw烷氧基，其中其噁唑部分視情況經CN6烷基取代。在式lb或式lib之某些實施例中，R5為嗎啉基。在式lb或式lib之某些實施例中，R5為羥基_Ci6烷基胺基数基。在式lb或式lib之某些實施例中，R5為c3 6環烷基。在式lb或式lib之某些實施例中，R5為氮雜環庚烷基，其中氮雜環庚烷基部分視情況經羥基、胺基、胺基_Ci 6烧基、經基-Cw烷基或胺基羰基取代。 157102.doc •63- 201217379 在式lb或式lib之某些實施例中，苯曱基，其中其苯基部分視情龍«、㈣、胺基_C16縣、祕々6烧基或胺基羰基取代。 R5為Cw烷氧羰基-Cw ’ R5為Cw烷基羰基胺在式lb或式lib之某些實施例中烷氧基。在式lb或式lib之某些實施例中基。在式lb或式lib之某些實施例中.，r6為氮在式lb或式lib之某些實施例中，R6為齒其。在式lb或式lib之某些實施例中，R6為a 6烧美。在式lb或式lib之某些實施例中，基·〜烧基。在式lb或式lib之某些實施例中，R6為Ci 6稀基。在式ib或式IIb之某些實施例中，1^為（：1-6烷氧基。在式lb或式lib之某些實施例中，R6為鹵基_Ci 6烷氧基。在式ib或式iib之某些實施例中，R6為羥基_Ci 6烷基。在式lb或式lib之某些實施例中，R6為羥基_Ci6烷基胺基。在式ib或式iib之某些實施例中’ r6為Cl_6烷基-胺基。在式lb或式lib之某些實施例中’ R6為羥基；胺基。在式ib或式iib之某些實施例中，r6為胺基_Ci 6烷基。在式lb或式lib之某些實施例中，R6為胺基幾基。在式Ib或式lib之某些實施例中，R6為羥基^“烷氧基。在式Ib或式lib之某些實施例中，R6為羥基_Cl 6烯基。在式Ib或式lib之某些實施例中’ R6為Cl_6烷氧基-Cw烷 157102.doc -64· 201217379 氧基。在式lb或式lib之某些實施例中，R6為cl6烷基磺醯基。在式lb或式lib之某些實施例中’ R6為cl 6烷基硫基。在式lb或式lib之某些實施例中，R6為娘B定基，其中n底咬基部分視情況經經基、胺基、胺基-CN6烷基、羥基_(^-6烷基或胺基羰基取代。在式lb或式lib之某些實施例中，R6為苯基胺基羰基。在式lb或式lib之某些實施例中，；R6為羥基_Ci 6烷基胺基。在式lb或式lib之某些實施例中，R6為環己基氧基，其中其環己基部分視情況經經基、胺基、胺基{“烧基或經基-Ci-6烧基取代。在式lb或式lib之某些實施例中，R6為環戊基氧基，其中其環戊基部分視情況經羥基、胺基、胺基_(^_6烷基或經基-Ci.6烧基取代。在式lb或式lib之某些實施例中，R6為哌啶基氧基，其中其哌啶基部分視情況經羥基、胺基、胺基-Cw烷基、羥基-Cl-6烧基或胺基幾·基取代。在式lb或式lib之某些實施例中，R6為苯基，其中苯基部分視情況經胺基、羥基、胺基-Ck烷基、羥基-Cw烷基或胺基羰基取代。在式lb或式lib之某些實施例中，R6為〇比咯啶基，其中吡咯啶基部分視情況經羥基、胺基、胺基-Cm烷基、羥基-Ci-6烧基或胺基幾基取代。 157102.doc -65- 201217379 在式lb或式lib之某些實施例中，尺6為B比咯啶基氧基，其中。比咯啶基部分視情況經羥基、胺基、胺基_Ci 6烷基、羥基- Ci_6烧基或胺基幾基取代。在式lb或lib之某些實施例中，R6為哌嗪基，其中哌嗪基部分視情況經CN6烷基取代。在式lb或lib之某些實施例中’ R6為噁唑_Ci 6烷氧基，其中其噁唑部分視情況經Cw烷基取代。在式lb或式lib之某些實施例中，R6為嗎啉基。在式lb或式lib之某些實施例中，R6為羥基_Ci 6烷基胺基幾基。在式lb或式lib之某些實施例中，R6為c3 6環烧基。在式lb或式lib之某些實施例中，R6為氮雜環庚烧基，其中氮雜環庚烧基部分視情況經經基、胺基、胺基i 6烧基、羥基-Cu烷基或胺基羰基取代。在式lb或式lib之某些實施例中，R6為苯甲基，其中其苯基部分視情況經胺基、羥基、胺基_Cl_6烷基、羥基Cm烷基或胺基幾基取代。在式lb或式nb之某些實施例中，116為（：16烷氧羰基<16 烷氧基。在式Ib或式nb之某些實施例中’ R、Ci.道基幾基胺基。其中^、“、㈣中之任一者為院基或含有烷基部分’該烷基較佳為低碳烷基，亦即广其，且在許多實施例中，為（^-山烷基。 157102.doc • 66· 201217379 本發明提供式Γ或式ΙΓ之化合物：Wherein: R5 and R6 are each independently: hydrogen; halo; Cw alkyl; halo-Cb6 alkyl, Ci_6 dilute, Ci-6 alkoxy; halo-Ci_6 morphoxy; trans-Ci_6 alkyl; hydroxy-Cw alkylamino group; Ci-6 alkyl-amino group; hydroxyl group; amine group; amino group-CN6 alkyl group; aminocarbonyl group; hydroxy-Cu alkoxy group; hydroxy-Cu alkenyl group; CN6 alkoxy group -Cw alkoxy; Cw alkylsulfonyl; Cw alkylthio; piperidinyl, wherein piperidinyl moiety is optionally via hydroxy, amine, amine-C1:6 alkyl, hydroxy-Cl-6 alkyl Or an aminocarbonyl group; a phenylaminocarbonyl group; a hydroxy-Cw alkylamino group; a cyclohexyloxy group in which a cyclohexyl moiety is optionally a hydroxyl group, an amine group, an amine group - a CN6 alkyl group or a hydroxyl group - a C 6 alkyl group. Substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cl6 alkyl; piperidinyloxy, wherein the piperidinyl moiety is optionally Substituted by a hydroxyl group, an amine group, an amino group-Cw alkyl group, a hydroxy group 157102.doc •59·201217379 group-C. .6 alkyl or aminocarbonyl group; a phenyl group, wherein the phenyl moiety is optionally an amine group, a hydroxyl group, Amino-Cw alkane a hydroxy-C 6 alkyl or an aminocarbonyl group; wherein the pyrrolidinyl group is optionally substituted with a hydroxy group, an amine group, an amino group, a Cw alkyl group, a hydroxy-Ck alkyl group or an aminocarbonyl group; Pyrrolidinyloxy' therein. The pyrrolidinyl moiety is optionally substituted with a hydroxy group, an amine group, an amine group -C -6 alkyl group, a hydroxy-Cw alkyl group or an amine carbonyl group; a piperazinyl group, wherein the piperazinyl moiety is optionally treated as a ^^6 alkane Substituent; oxazole-c16 alkoxy, wherein the oxazole moiety is optionally substituted by Cl.6 alkyl; morpholinyl; hydroxy-C16 alkylaminocarbonyl; C3-6 cycloalkyl; azepan An alkyl group, wherein the azacycloheptyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group - c16 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a phenyl fluorenyl group in which a phenyl moiety is optionally an amine Substituent, hydroxy, amino-Cw alkyl, hydroxy-Cw alkyl or amino group; C!.6 alkoxycarbonyl-Cw alkoxy; or Ci.6 alkylcarbonylamino; and R1 as herein In certain embodiments of Formula lb or Formula lib, R5 and R6 are each independently: dentate; Cw alkyl; halo-Cw alkyl; Ck alkenyl; Cw alkoxy; Cu alkoxy; hydroxy-Cu alkyl; hydroxy-Cl6 alkylamino; Cl-6 alkyl-amino; hydroxy; amine; amino-Cm alkyl; amine carbonyl; hydroxy-C, ·6 oxygenated Base; hydroxy-Cl6 alkenyl; Cl, 6 alkoxy _Cl_6 alkane An oxy group; a C 6 alkylsulfonyl group; a C 6 alkylthio group; a piperidinyl group, wherein the piperidinyl moiety is optionally a trans group, an amine group, an amine group - a C 6 alkyl group, a hydroxyl group - a C 6 alkyl group or an amine. Substituted by a phenylamino group; phenylaminocarbonyl; hydroxy-Cl.6 alkylamino; cyclohexyloxy' wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - C ! . 6 157102.doc 201217379 Alkenyl or hydroxy-c^alkyl substituted; cyclopentyloxy wherein the cyclopentyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cw alkyl; piperidinyloxy Wherein the piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amine group-Cw alkyl group, a group-Cw alkyl group or an amine group; a phenyl group, wherein the phenyl moiety is optionally an amine group, a hydroxyl group, Amino-c16 alkyl, light-C 1-6 alkyl or amine-based substituent; β piroxime, wherein the piroxicam D-part moiety is optionally via a hydroxyl group, an amine group, an amine group-Cw alkyl group , hydroxy-Cl 6 alkyl or aminocarbonyl substituted; ° ratio σ each methoxy group, wherein 吼嘻. The base moiety is optionally light, amino, amine-Cw alkyl, base-Cw alkyl Amino group a piperazinyl group, wherein the piperazinyl moiety is optionally substituted by a C1_6 alkyl group; 11 isocyanine-C!-6 alkoxy group, wherein the oxazole moiety is optionally substituted by a c16 alkyl group, a linalyl group, a light group -Ci_6 alkylamino group; c3.6 cycloalkyl; azacycloheptyl' wherein the azepanyl moiety is optionally via a trans group, an amine group, an amine group - a Cw alkyl group, a hydroxy group -C !.6 alkyl or aminocarbonyl substituted; benzyl 'wherein its base moiety is optionally amino group, trans group, amine group _ C丨6 alkyl group, light group -C!-6 alkyl group or amine group Substituent substitution; c1-6 alkoxycarbonyl _(^16 alkoxy, or Ci-6 alkylamino group. In certain embodiments of Formula lb or Formula lib, R5 is hydrogen. In some embodiments of Equation lb or Equation lib, R5 is a !| base. In certain embodiments of Formula lb or Formula lib, R5 is c! 6 burned. In certain embodiments of formula ib or formula IIb, r5 is halo-Ci 6 alkyl. In some embodiments of Equation lb or Equation lib, R5 is 6 faint. In certain embodiments of Formula lb or Formula lib, R5 is Ci 6 alkoxy. In certain embodiments of Formula ib or Formula IIb, Rule 5 is a _ group <16 alkoxy group. 157102.doc • 61 - 201217379 In certain embodiments of Formula lb or Formula lib, R5 is hydroxy-Ci 6 alkyl β. In certain embodiments of Formula lb or Formula lib, R 5 is hydroxy-Ci 6 alkyl Amine. In certain embodiments of Formula lb or Formula lib, R5 is a Cl-6 alkyl-amino group. In certain embodiments of Formula lb or Formula lib, r5 is hydroxy; amine. In certain embodiments of Formula lb or Formula lib, R5 is amino-Ci 6 alkyl. In certain embodiments of Formula lb or Formula lib, r5 is an aminocarbonyl group. In certain embodiments of Formula lb or Formula lib, r5 is hydroxy-(^^alkoxy. In certain embodiments of Formula lb or Formula lib, r5 is a thiol-Ci 6 alkenyl group. Or in certain embodiments of the formula lib, the rule 5 is Ci6 alkoxy {"alkoxy. In certain embodiments of Formula lb or Formula lib, R5 is Ci6 alkylsulfonyl. In Formula lb or In certain embodiments of the formula lib, R5 is a Cl-6 alkylthio group. In certain embodiments of Formula lb or Formula lib, R5 is piperidinyl, wherein the piperidyl moiety is optionally via a hydroxyl group, an amine group, or an amine. Substituted by a -Cw alkyl group, a hydroxy-Ci 6 alkyl group or an amine carbonyl group. In certain embodiments of Formula lb or Formula lib, R5 is a strepylamino group. Some embodiments of Formula lb or Formula lib In one embodiment, R5 is hydroxy-Ci6 alkylamino. In certain embodiments of Formula lb or Formula lib, R5 is cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group _Ci 6 is substituted or substituted with a base-Cw alkyl. In certain embodiments of formula lb or formula lib, R5 is cyclopentyloxy' wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine group, an amine group <;16 alkyl or by 157102.doc •62· 201217379 Substituted by a base-Cw alkyl group. In some embodiments of formula lb or formula lib, r5 is a guanidine group, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a CU6 alkyl group. , hydroxy-Cu alkyl or aminocarbonyl substituted. In certain embodiments of Formula lb or Formula lib, r5 is phenyl, wherein the phenyl moiety is optionally an amine group, a hydroxyl group, an amine group-Cl-6 alkyl group. , hydroxy-Cw alkyl or aminocarbonyl substituted. In certain embodiments of Formula lb or Formula lib, R5 is ".Biloxime, wherein the 0-to-pyridyl moiety is optionally via a hydroxyl group, an amine group, Amino-Cw alkyl, substituted with a yl-C6 alkyl or an amino group. In certain embodiments of Formula lb or Formula lib, R5 is η than fluorenyloxy, wherein D is a pyridyl group. Partially substituted by hydroxyl, amine, amino-c16 alkyl, hydroxy-Cl.6 alkyl or amino group. In certain embodiments of formula lb or lib, R5 is piperazinyl, wherein The moieties are optionally substituted by (^-6 alkyl). In certain embodiments of Formula 1b*IIb, R5 is oxazol-Cw alkoxy, wherein the oxazole moiety is optionally substituted with a CN6 alkyl group. Some implementations of lb or lib In certain embodiments, R5 is morpholino. In certain embodiments of Formula lb or Formula lib, R5 is hydroxy-Ci6 alkylamino group. In certain embodiments of Formula lb or Formula lib, R5 is c3 6 In certain embodiments of Formula lb or Formula lib, R5 is azacycloheptyl, wherein the azepanyl moiety is optionally via a hydroxyl group, an amine group, an amine group -Ci 6 alkyl group, Substituted by a base-Cw alkyl or an aminocarbonyl group. 157102.doc • 63- 201217379 In certain embodiments of formula lb or formula lib, a phenylhydrazine group wherein the phenyl moiety is as defined by the dragon «, (4), an amine group _C16 county, secret 6 alkyl or aminocarbonyl substitution. R5 is Cw alkoxycarbonyl-Cw'R5 is Cw alkylcarbonylamine. In certain embodiments of formula lb or formula lib alkoxy. In some embodiments of Equation lb or Equation lib. In certain embodiments of Formula lb or Formula lib, r6 is nitrogen. In certain embodiments of Formula lb or Formula lib, R6 is a tooth thereof. In certain embodiments of Formula lb or Formula lib, R6 is a 6 burnt. In certain embodiments of Formula lb or Formula lib, the base is burned. In certain embodiments of Formula lb or Formula lib, R6 is a Ci 6 dilute group. In certain embodiments of Formula ib or Formula IIb, 1 is (1-6 1-6 alkoxy. In certain embodiments of Formula lb or Formula lib, R6 is halo-Ci 6 alkoxy. In certain embodiments of Formula ib or Formula IIb, R6 is hydroxy-Ci 6 alkyl. In certain embodiments of Formula lb or Formula lib, R6 is hydroxy-Ci6 alkylamino. Formula ib or Formula iib In certain embodiments, 'r6 is a Cl-6 alkyl-amino group. In certain embodiments of Formula lb or Formula lib, 'R6 is hydroxy; amine. In certain embodiments of Formula ib or Formula iib, r6 Amino-Ci 6 alkyl. In certain embodiments of Formula lb or Formula lib, R6 is an amino group. In certain embodiments of Formula Ib or Formula lib, R6 is hydroxy""alkoxy In certain embodiments of Formula Ib or Formula lib, R6 is hydroxy-C 6 alkenyl. In certain embodiments of Formula Ib or Formula lib, 'R6 is Cl-6 alkoxy-Cw alkane 157102.doc-64 · 201217379 oxy. In certain embodiments of Formula lb or Formula lib, R6 is a cl6 alkylsulfonyl group. In certain embodiments of Formula lb or Formula lib, 'R6 is a cl 6 alkylthio group. In certain embodiments of Formula lb or Formula lib, R6 is a mother B-based group, wherein the n-bottom base portion The case is substituted with a benzyl group, an amine group, an amine group -CN6 alkyl group, a hydroxy group (hydroxy-6) or an amine carbonyl group. In certain embodiments of formula lb or formula lib, R6 is phenylaminocarbonyl. In certain embodiments of Formula lb or Formula lib, R6 is hydroxy-Ci 6 alkylamino. In certain embodiments of Formula lb or Formula lib, R6 is cyclohexyloxy, wherein the cyclohexyl moiety Optionally substituted by a benzyl group, an amine group, an amine group {"alkyl or a thiol-Ci-6 alkyl group. In certain embodiments of formula lb or formula lib, R6 is cyclopentyloxy, wherein the ring thereof The pentyl moiety is optionally substituted with a hydroxy, amine, amine-(^-6 alkyl or via-Ci.6 alkyl group. In certain embodiments of Formula lb or Formula lib, R6 is piperidinyloxy. Wherein the piperidinyl moiety is optionally substituted with a hydroxy, amine, amino-Cw alkyl, hydroxy-Cl-6 alkyl or amine group. In certain embodiments of Formula lb or Formula lib, R6 is phenyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Ck alkyl group, a hydroxy-Cw alkyl group or an amine carbonyl group. In certain embodiments of Formula lb or Formula lib, R6 is Pyridoxidine Substituted by a hydroxyl group, an amine group, an amino-Cm alkyl group, a hydroxy-Ci-6 alkyl group or an amino group. 157102.doc -65- 201217379 In certain embodiments of Formula lb or Formula lib, 6 is a B-pyridyloxy group, wherein the specific ratio of the pyridyl group is optionally substituted by a hydroxyl group, an amine group, an amino group -Ci 6 alkyl group, a hydroxy-Cio-6 group or an amino group. In certain embodiments of Formula lb or lib, R6 is piperazinyl, wherein the piperazinyl moiety is optionally substituted with a CN6 alkyl group. In certain embodiments of Formula lb or lib, ' R6 is oxazol-Ci 6 alkoxy, wherein the oxazole moiety is optionally substituted with a Cw alkyl group. In certain embodiments of Formula lb or Formula lib, R6 is morpholinyl. In certain embodiments of Formula lb or Formula lib, R6 is hydroxy-Ci 6 alkylamino group. In certain embodiments of Formula lb or Formula lib, R6 is c3 6 cycloalkyl. In certain embodiments of Formula lb or Formula lib, R6 is azacycloheptyl, wherein the azepanyl moiety is optionally subjected to a trans-group, an amine group, an amine group i6 alkyl group, a hydroxy-caline group. Substituted by an amino or carbonyl group. In certain embodiments of Formula lb or Formula lib, R6 is benzyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amine group -Cl_6 alkyl group, a hydroxy Cm alkyl group or an amino group. In certain embodiments of Formula lb or Formula nb, 116 is (:16 alkoxycarbonyl <16 alkoxy. In certain embodiments of Formula Ib or Formula nb, 'R, Ci. Dobutylamine Wherein any of ^, ", (4) is a hospital base or contains an alkyl moiety - the alkyl group is preferably a lower alkyl group, that is, widely, and in many embodiments, is (^-mountain) Alkyl. 157102.doc • 66· 201217379 The present invention provides a compound of the formula or formula:

或其醫藥學上可接受之鹽，其中： φ X為Ν或CH ; m為1或2 ;Or a pharmaceutically acceptable salt thereof, wherein: φ X is Ν or CH; m is 1 or 2;

Ar為：視情況經取代之芳基；或視情況經取代之雜芳基； R1為：氫；Ar is: an optionally substituted aryl group; or a heteroaryl group optionally substituted; R1 is: hydrogen;

Ci.6烧基； • Cu烧氧基；羥基；經基-Ci_6烧基；Ci.6 alkyl; • Cu alkoxy; hydroxyl; base-Ci_6 alkyl;

Ci.6烧基-胺基；胺基-C 1 _6烧基；胺基-Ci.6烧基-胺基；羥基-Cm烷基胺基； C3-6環烧基胺基； 157102.doc -67- 201217379 胺基幾基；鹵基；經基-Ci.6烧基；或羥基_(：!_6烷氧基；及 R2為：氫；或 C 1 烧基。本發明亦提供治療由IRAK受體介導或另外與IRAK受體Ci.6 alkyl-amino; amine-C 1 -6 alkyl; amino-Ci.6 alkyl-amino; hydroxy-Cm alkylamino; C3-6 cycloalkylamino; 157102.doc -67- 201217379 Aminomethyl; halo; thio-Ci.6 alkyl; or hydroxy-(:!-6 alkoxy; and R2: hydrogen; or C1 alkyl. The invention also provides IRAK receptor mediated or otherwise associated with IRAK receptor

相關之疾病或病狀之方法’該方法包含向有需要之個體投與有效量之本發明化合物。本發明亦提供治療由SYK受體介導或另外與SYK受體相關之疾病或病狀之方法，該方法包含向有需要之個體投與有效量之本發明化合物。疾病可為發炎疾病，諸如關節炎，且更特定言之類風濕性關節炎、骨關節[牛皮癖、過敏性皮炎、哮喘、慢性Methods of Related Diseases or Conditions The method comprises administering to a subject in need thereof an effective amount of a compound of the invention. The invention also provides a method of treating a disease or condition mediated by or otherwise associated with a SYK receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention. The disease can be an inflammatory disease such as arthritis, and more specifically rheumatoid arthritis, bone and joint [psoriasis, allergic dermatitis, asthma, chronic

阻塞性肺病、氣管過度反應、敗血性休克、絲球體腎炎、大腸急躁症及克羅恩氏病。疾病可為疼痛病狀’諸如發炎性)疼痛；外科疼痛；内臟痛；牙痛 '經前疼痛；中樞疼痛；灼傷所致疼痛；偏頭痛或叢集性頭痛；神經損傷；神經炎：神經痛；中毒；缺血性損傷；間質性膀胱炎；癌痛；病毒、寄生物或細菌感染’’創傷後損傷；或與大腸急躁症相關之疼痛。疾病可為呼吸道病症，諸如慢性阻塞性肺病（C0PD)、哮喘或支氣管痙攣、或胃腸(GI)障礙，諸如大腸急躁症 157102.doc •68- 201217379 (IBS)、發炎性腸病（IBD)、膽絞痛及其他膽病症、腎絞痛、腹瀉型IBS、與以膨脹有關之疼痛。本申清案提供用於治療發炎或自體免疫病狀之上文所述化合物。本申請案提供用於治療上文所述之任一種病狀之上文所述化合物。根據本發明方法之代表性化合物以及所選化合物關於 IRAKI、IRAK4及SYK之1(：5〇值（微莫耳）顯示於參考下文之實驗實例的表1中。表1 # 結構化學名稱 IRAK4 IRAKI SYK 實例 1 h2n/V^v1 6-經基-e比唾并 [1，5-α]嘧咬-3-甲酸[2-(4-胺基曱基-0底咬-1-基)-5-氣-苯基]-酿胺 0.001 0.055 14 2 Η2Ν^γ^| ^νυυνι 'n=7 0比唑并[1，5-α] 嘧啶-3·甲酸[7-(4-胺基甲基-哌咬-1-基)-喧琳-6-基]-醯胺 0.002 15 3 N=/ 0 OH 。比"坐并[1,5-α] 嘧啶-3-甲酸[2-(2·經基-乙基胺基）-7-甲氧基-啥嚇·_6-基]-醯胺 0.003 1 157102.doc •69· 201217379 4 N=/ O 0比。坐并[l，5-a] 嘧啶-3-甲酸[2-(4-胺基甲基-哌咬-1 -基)-4-苯基胺甲醯基-苯基]•醢胺 0.004 0.45 15 5 w 〇^NH CH3 °比〇全并[1,5-a] 嘧啶-3-曱酸 {5-氯-2-[4-(l-經基-乙基)-。底咬-1-基]-苯基}-醯胺 0.005 0.97 5 6 nnh A°o,h 噻吩并[3,2-d] 嘧啶-7-曱酸[7-(4-羥基-環己基氧基)-喹啉-6-基]-醯胺 0.007 0.07 5 7 V〇L .ch3 γ^ν n 3 〇从 L NH rV〇, NHz cr CH3 2-似-胺基乙基）-曱基-胺基]-噻吩并[3,2-d]嘴咬-7-曱酸 (7-甲氧基-喹啉-6-基)-醯胺 0.008 0.9825 0.41 12 8 〇 0比0圭并[l，5-a] 嘧啶-3-甲酸(Τη底咬 -1- 基 - 啥淋-6-基)-醯胺 0.008 1 9 HsC" T^T 1 H0Y^n hna>^ 6-經基比°坐并 [1，5-〇〇嘧啶-3-甲酸（7-甲氧基-喹啉-6-基)-醯胺 0.009 0.20 14 157102.doc -70- 201217379 10 n，hC〇〇\h 咖。噻吩并[3,2-d] 嘧啶-7-曱酸[2-(2-經基-乙基胺基）-7-曱氧基·啥嚇*-6-基]-醯胺 0.010 0.20 1 11 h2n^-nh h3c^°V^V% N^N 2-(2-胺基-乙基胺基)-噻吩并 [3,2-d]嘧啶-7-甲酸（7-甲氧基-嗜嚇>-6-基)_ 醯胺 0.010 0.712 0.017 12 12 噻吩并[3,2-d] 嘧啶-7-甲酸[7-(4-羥基-環己基氧基)-喧嚇 -6-基]-醯胺 0.011 0.168 5 13 rS；x» v^〇噻吩并[3,2-d] 嘧啶-7-曱酸(7-娘咬-1-基-喧琳-6-基)-酿胺 0.012 1 14 Η2Ν-γ^ 二:CO 吩。噻吩并[3,2-d] 嘧啶-7-甲酸[7-(4-胺基曱基-0辰咬-1-基)-啥嚇 -6-基]-酿胺鹽酸鹽 0.012 0.85 15 15 0p5 NH 噻吩并[3,2-d] 嘧啶-7-曱酸[7-(3-羥基-環戊基氧基)-喹啉-6-基]-醯胺鹽酸鹽 0.015 0.246 5 157102.doc •71 · 201217379Obstructive pulmonary disease, tracheal overreaction, septic shock, spheroid nephritis, colonic urgency, and Crohn's disease. The disease may be a pain condition such as inflammatory pain; surgical pain; visceral pain; toothache 'premenstrual pain; central pain; pain caused by burns; migraine or cluster headache; nerve damage; neuritis: neuralgia; Poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection ''post-traumatic injury; or pain associated with large bowel irritation. The disease can be a respiratory condition such as chronic obstructive pulmonary disease (COPD), asthma or bronchospasm, or gastrointestinal (GI) disorders such as colonic urgency 157102.doc •68-201217379 (IBS), inflammatory bowel disease (IBD), Biliary colic and other biliary disorders, renal colic, diarrhea-type IBS, and pain associated with swelling. This application provides the above-described compounds for the treatment of inflammatory or autoimmune conditions. The present application provides the above compounds for use in the treatment of any of the conditions described above. Representative compounds of the process according to the invention and selected compounds with respect to IRAKI, IRAK4 and SYK 1 (:5 〇 value (micromolar) are shown in Table 1 of the experimental examples below. Table 1 # Structural Chemistry Name IRAK4 IRAKI SYK Example 1 h2n/V^v1 6-trans-base-e ratio saliva[1,5-α]pyrimidine-3-carboxylic acid [2-(4-aminopurinyl-0-beta-1-yl)- 5-Gas-phenyl]-bristamine 0.001 0.055 14 2 Η2Ν^γ^| ^νυυνι 'n=7 0-pyrazolo[1,5-α]pyrimidine-3·carboxylic acid [7-(4-Amino A) --piperidin-1-yl)-喧琳-6-yl]-decylamine 0.002 15 3 N=/ 0 OH. Ratio "sit and [1,5-α]pyrimidine-3-carboxylic acid [2-( 2·Phenyl-ethylamino)-7-methoxy-infrared·_6-yl]-decylamine 0.003 1 157102.doc •69· 201217379 4 N=/ O 0 ratio. Sit and [l,5 -a] pyrimidine-3-carboxylic acid [2-(4-aminomethyl-piperidin-1 -yl)-4-phenylamine-mercapto-phenyl]-decylamine 0.004 0.45 15 5 w 〇^NH CH3 ° is more than [1,5-a] pyrimidine-3-decanoic acid {5-chloro-2-[4-(l-trans-yl-ethyl)-. bottom bit-1-yl]-phenyl }-decylamine 0.005 0.97 5 6 nnh A°o,h thieno[3,2-d]pyrimidin-7-decanoic acid [7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl ]-decylamine 0.007 0.07 5 7 V〇L .ch3 γ^ν n 3 〇 from L NH rV〇, NHz cr CH3 2-like-aminoethyl)-fluorenyl-amino]-thieno[3, 2-d] mouth bite-7-decanoic acid (7-methoxy-quinolin-6-yl)-decylamine 0.0088 0.9825 0.41 12 8 〇0 to 0 gram [[,5-a] pyrimidine-3- Formic acid (Τη底 bit-1-yl- 啥--6-yl)-decylamine 0.008 IX 1 9 HsC" T^T 1 H0Y^n hna>^ 6-by base ratio °[1,5-〇〇 Pyrimidine-3-carboxylic acid (7-methoxy-quinolin-6-yl)-decylamine 0.009 0.20 14 157102.doc -70- 201217379 10 n,hC〇〇\h Coffee. Thio[3,2-d]pyrimidin-7-decanoic acid [2-(2-trans-ethylamino)-7-methoxyl-infrared*-6-yl]-nonylamine 0.010 0.20 1 11 h2n^-nh h3c^°V^V% N^N 2-(2-Amino-ethylamino)-thieno[3,2-d]pyrimidin-7-carboxylic acid (7-methoxy- Intimidation >-6-yl)_decalamine 0.010 0.712 0.017 12 12 thieno[3,2-d]pyrimidin-7-carboxylic acid [7-(4-hydroxy-cyclohexyloxy)-indole-6- ]]-decylamine 0.011 0.168 5 13 rS;x» v^〇thieno[3,2-d]pyrimidin-7-decanoic acid (7-negant-1-yl-喧琳-6-yl)- Amine 0.012 1 14 Η2Ν-γ^ Two: CO pheno. Thio[3,2-d]pyrimidine-7-carboxylic acid [7-(4-aminoindolyl-0-chenyl-1-yl)-indole-6-yl]-nitramine hydrochloride 0.012 0.85 15 15 0p5 NH thieno[3,2-d]pyrimidin-7-decanoic acid [7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl]-indoleamine hydrochloride 0.015 0.246 5 157102 .doc •71 · 201217379

6-經基-°比嗤并 [1，5-α]嘧啶-3-曱酸[5-氯-2-(4-經基甲基-β底啶-1-基)-苯基]-醯胺 0.018 0.836 14 噻吩并[3,2-d] 嘧啶-7-曱酸(7-甲氧基-喹啉-6-基)-醯胺 6-經基-°比°坐并 [1,5-α]嘧啶-3-曱酸[5-氣-2-(4-羥基-環己基氧基)-苯基]-醯胺噻吩并[3,2-d] 嘧啶-7-甲酸[7-(4-羥基-環己基氧基)-啥啦-6-基]-醯胺 6-經基-°比°坐并 [1，5-α]嘧啶-3-曱酸(5-氣-2-哌咬-1-基-苯基)- 醯胺 0.018 0.622 0.023 0.163 0.024 0.024 0.123 0.644 20 157102.doc 72- 201217379 21 〇P〇N NH ^-N H3c 噻吩并[3,2-d] 嘴咬-7-甲酸[7-(3-羥基-1-甲基-丁氧基)-喹啉-6-基]•醯胺 0.024 0.76 0.449 5 22 "XU^1 N=/ 6-甲基比嗤并 [1，5-α],咬-3-曱酸[5-氣-2-(4-羥基甲基-哌啶-1-基)-苯基]-醯胺 0.028 1 23 p 0==nnh OH 0比0坐并[1，5-α] 嘧啶-3-曱酸[7-(4-羥基-環己基氧基)-喹啉-6-基]-酿胺 0.029 0.103 5 24 ch3 h〇x^n^ch3 ό 2-[(2-羥基-乙基）_甲基-胺基]-噻吩并[3,2-d]嘧啶-7-甲酸 (7-曱氧基-喹嚇-6-基)-酿胺 0.029 0.3 12 25 CV_ 。比唑并[1，5-α] 嘧啶-3-甲酸[2-(4-胺基甲基-哌咬-1-基)-5-氯-苯基]-醯胺 0.031 0.92 11 26 :Λ°^ 2-異丙基胺基-噻吩并[3,2-d] 嘧啶-7-曱酸(7-曱氧基-喹琳-6-基)-醯胺 0.031 0.463 0.725 12 -73- 157102.doc 201217379 27 2-異丙基胺基-噻吩并[3,2-d] 嘧啶-7-曱酸(7-甲氧基-喹啉-6-基)-醯胺 0.031 12 28 0 NH f==l HO cP"°^CH3 噻吩并[3,2-d] 嘧啶-7-曱酸[7-(3-羥基-丁氧基)-啥琳-6-基]- 醯胺 0.033 1 29 η^Χ\λ〇 c, N=/ 6-甲氧基比0坐并[1，5-α]嘧啶-3-曱酸[5-氣-2-(4-經基曱基-派咬_1_基)-苯基]_ 醯胺 0.033 1 30 ch3 ^功 s 6-經基甲基-β塞吩并[3,2-β]。比啶-3-曱酸(7-甲氧基-啥琳-6-基)-醯胺 0.035 0.746 13 31 CM \j T rv^ 。比唑并[1,5-α] 嘧啶-3-曱酸[2-(4-胺基甲基-哌咬-1-基)-5-氣· 苯基]-醯胺 0.037 11 32 〇乂 NH 々A 0比0坐并[1,5-α] 嘴咬-3-曱酸[7-(哌啶-4-基氧基)-啥嚇·_6-基]-醯胺鹽酸鹽 0.040 15 157102.doc -74- 201217379 33 HaC" 1 n HN sV^〇 «比唑并[1，5-α] 嘧啶-3-曱酸(7-曱氧基-喹咐-6-基)-酿胺 0.043 1 34 OH y^N Νγ^ν^>=〇、H』〇 "比唑并[1，5-α] 嘧啶-3-甲酸[5-(4-羥基甲基-哌咬-1-基）·2-側氧基-2,3-二氫· 1Η-吲哚-6-基]-醯胺 0.049 0.478 1 35 0 NH 噻吩并[3,2-d] 嘧啶-7-曱酸[7-(3-經基·1，1-二曱基·丙氧基)-啥琳-6-基]-酿胺鹽酸鹽 0.049 0.364 1 36 N=/ ° 。比唑并[1，5-α] 嘧啶-3-曱酸[5-(4-經基甲基-苯基)-2-曱基-1H-吲哚-6-基]-醢胺 0.052 1 37 邮、八 ch3 U丫、 HXU c， N=/ 6-經基-°比°坐并 [1，5-α]嘧咬-3-甲酸[5-氣-2-(4-二曱基胺基甲基-π底咬-1-基)-苯基]-醯胺 0.053 0.307 21 38 。/NH r^\」CH3 口比0坐并[1，5-α] 嘴咬-3-曱酸 {2-[4·(1-胺基-乙基)-娘咬-1 -基]·5·氯-苯基}-醯胺 0.053 15 157102.doc -75- 2012173796-Phase-by-p-[1,5-α]pyrimidine-3-decanoic acid [5-chloro-2-(4-transmethyl-β-endridin-1-yl)-phenyl]- Indoleamine 0.018 0.836 14 thieno[3,2-d]pyrimidin-7-decanoic acid (7-methoxy-quinolin-6-yl)-decylamine 6-permeo-° ratio °[1, 5-α]pyrimidine-3-decanoic acid [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine thieno[3,2-d]pyrimidine-7-carboxylic acid [7 -(4-hydroxy-cyclohexyloxy)-indol-6-yl]-nonylamine 6-transpyranyl-[1,5-α]pyrimidin-3-indoleic acid (5-gas- 2-piperidin-1-yl-phenyl)-guanamine 0.018 0.622 0.023 0.163 0.024 0.024 0.123 0.644 20 157102.doc 72- 201217379 21 〇P〇N NH ^-N H3c thieno[3,2-d] mouth Bite-7-formic acid [7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl]•decylamine 0.024 0.76 0.449 5 22 "XU^1 N=/ 6-methyl嗤嗤 [1,5-α], -3- 曱曱 [5-Gas-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-decylamine 0.028 1 23 p 0 ==nnh OH 0 is 0 to sit and [1,5-α] pyrimidine-3-decanoic acid [7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl]-nitramine 0.029 0.103 5 24 Ch3 h〇x^n^ch3 ό 2-[(2-hydroxy-ethyl)-methyl-amino]-thieno[3,2-d]pyrimidin-7-carboxylic acid (7-decyloxy-quino-6-yl)-nitramine 0.029 0.3 12 25 CV_. Bisazo[1,5-α]pyrimidine-3-carboxylic acid [2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-decylamine 0.031 0.92 11 26 :Λ °^ 2-Isopropylamino-thieno[3,2-d]pyrimidin-7-decanoic acid (7-decyloxy-quinolin-6-yl)-decylamine 0.031 0.463 0.725 12 -73- 157102 .doc 201217379 27 2-Isopropylamino-thieno[3,2-d]pyrimidin-7-decanoic acid (7-methoxy-quinolin-6-yl)-decylamine 0.031 12 28 0 NH f ==l HO cP"°^CH3 Thio[3,2-d]pyrimidin-7-decanoic acid [7-(3-hydroxy-butoxy)-indolyl-6-yl]-nonylamine 0.033 1 29 η^Χ\λ〇c, N=/ 6-methoxyl ratio 0 and [1,5-α]pyrimidine-3-decanoic acid [5-gas-2-(4-carbyl-based) _1_yl)-phenyl]-decylamine 0.033 1 30 ch3 ^ work s 6-carbylmethyl-β-senteno[3,2-β]. Bipyridine-3-decanoic acid (7-methoxy-indolyl-6-yl)-decylamine 0.035 0.746 13 31 CM \j T rv^. Bisazo[1,5-α]pyrimidin-3-indole[2-(4-aminomethyl-piperidin-1-yl)-5-a-phenyl]-decylamine 0.037 11 32 〇乂NH 々A 0 is 0 to sit and [1,5-α] mouth bite -3-decanoic acid [7-(piperidin-4-yloxy)-infrared _6-yl]-nonylamine hydrochloride 0.040 15 157102.doc -74- 201217379 33 HaC" 1 n HN sV^〇«Bizozolo[1,5-α]pyrimidin-3-indole (7-decyloxy-quino-6-yl)- Amine 0.043 1 34 OH y^N Νγ^ν^>=〇,H』〇"Bizozolo[1,5-α]pyrimidine-3-carboxylic acid [5-(4-hydroxymethyl-piperider- 1-yl)·2-sidedoxy-2,3-dihydro·1Η-吲哚-6-yl]-nonylamine 0.049 0.478 1 35 0 NH thieno[3,2-d]pyrimidin-7-oxime Acid [7-(3-carbazhen-1,1-dimercaptopropoxy)-indolyl-6-yl]-bristamine hydrochloride 0.049 0.364 1 36 N=/ °. Bisazo[1,5-α]pyrimidin-3-indole[5-(4-carbylmethyl-phenyl)-2-indolyl-1H-indol-6-yl]-decylamine 0.052 1 37 mail, eight ch3 U丫, HXU c, N=/ 6-base-° ratio ° sit and [1,5-α] pyridine-3-carboxylic acid [5-gas-2-(4-didecyl) Aminomethyl-π-bottom-1-yl)-phenyl]-nonylamine 0.053 0.307 21 38 . /NH r^\"CH3 mouth is sitting at 0 and [1,5-α] mouth biting -3- citric acid {2-[4·(1-amino-ethyl)-ninuine-1 -yl]· 5·Chloro-phenyl}-decylamine 0.053 15 157102.doc -75- 201217379

0比唑并[1，5-α] 嘴咬-3-甲酸[2-(4-胺曱醯基-哌咬-1-基)-5-氣-苯基]-醯胺噻吩并[3,2-β] 吡啶-3-曱酸[2-(4-胺基曱基-哌咬小基)-5-氣-苯基]-醯胺 0比0坐并[1，5-α] 嘧啶-3-曱酸[5-氣-2·(4-羥基曱基-π底咬-1 -基)-苯基]-醯胺 2-環丙基胺基-噻吩并[3,2-d] 嘧啶-7-曱酸(7-曱氧基-喹啉-6-基)-醯胺 2-(2-羥基小曱基-乙基胺基)-噻吩并[3,2-d] 嘧啶-7-曱酸(7-甲氧基_啥琳_6_ 基)-醯胺 0.063 0.492 12 0.069 0.070 0.072 0.074 0.575 0.5 0.81 11 12 157102.doc 76- 201217379 44 pi 0 XCW0H CH3 °比σ坐并[l，5-a] 嘧啶·3-甲酸{5-氯-2·[3-(1-經基-乙基)-α比洛咬-1·基]-苯基}-醯胺 0.076 0.897 1 45 ηο^^νη 2-(2-羥基-乙基胺基)-噻吩并 [3,2-d]嘧啶-7-曱酸（7-曱氧基-啥琳基)_ 醯胺 0.076 0.216 12 46 p °^NH r^V^NH 〇比唑并[1,5-a] 嘧啶-3-曱酸 (4·-胺基甲基-4-氯-聯苯-2- 基)-醯胺 0.081 15 47 IXXfc：i» v>^〇 2-(2,3-二羥基-丙基胺基)-噻吩并[3,2-d]嘧啶-7-曱酸(7-曱氧基-喹 -6-基)-醯胺 0.082 0.608 12 48 Oy, Cur^0 N=/ 0比0坐并[1,5-a] 嘧啶-3-甲酸(2-側氧基-5-11 底咬-1-基-2,3-二氮-1沁吲哚-6-基)-醯胺 0.098 1 49 〇P NH OH a^S-Cr1 噻吩并[3,2-d] 嘧啶-7-曱酸[5-氯-2-(4-羥基甲基-旅咬-1-基)-苯基]-醯胺 0.100 0.70 1 157102.doc -77- 201217379 50 專;cco 2-(3-胺基-丙基胺基)-噻吩并 [3,2-d]嘧啶-7-曱酸（7-曱氧基-啥咐-6-基)-醯胺 0.101 12 51 噻吩并[3,2-d] 嘧啶-7-甲酸[7-(3-胺基-丙氧基)-啥嚇*-6-基]-醯胺 0.103 0.529 0.376 15 52 0 N—N^V^NH2 αΑχχΗ °比0坐并[1，5-α] 咬-3,6-二曱酸6-醯胺3-{[5-氣-2-(4- 經基-環己基氧基)-苯基]-醯胺} 0.107 5 53 h2n^^ H^〇YS ηνΛΧ Vr^〇 ci 2-(2-胺基-乙基胺基)-噻吩并 [3,2-d]嘧啶-7-曱酸(5-氣-2-甲氧基-苯基)-酿胺} 0.107 0.813 0.35 12 54 NH 噻吩并[3,2-d] 喊咬-7-甲酸[7-(3-羥基-環戊基氧基)-喹啉-6-基]-醯胺鹽酸鹽 0.122 0.5 50-pyrazolo[1,5-α] mouth bite-3-carboxylic acid [2-(4-aminoindolyl-piperidin-1-yl)-5-a-phenyl]-guanamine thieno[3 ,2-β]pyridine-3-decanoic acid [2-(4-aminoindolyl-piperidinyl)-5-a-phenyl]-guanamine 0 to 0 sits [1,5-α] Pyrimidine-3-decanoic acid [5-gas-2·(4-hydroxyindolyl-π-bottom-1 -yl)-phenyl]-nonylamine 2-cyclopropylamino-thieno[3,2- d] pyrimidine-7-decanoic acid (7-decyloxy-quinolin-6-yl)-nonylamine 2-(2-hydroxyindolyl-ethylamino)-thieno[3,2-d] Pyrimidine-7-decanoic acid (7-methoxy_啥琳_6_yl)-decylamine 0.063 0.492 12 0.069 0.070 0.072 0.074 0.575 0.5 0.81 11 12 157102.doc 76- 201217379 44 pi 0 XCW0H CH3 ° [l,5-a]pyrimidine·3-carboxylic acid {5-chloro-2·[3-(1-trans-ethyl-ethyl)-α piroxicam-1·yl]-phenyl}-decylamine 0.076 0.897 1 45 ηο^^νη 2-(2-hydroxy-ethylamino)-thieno[3,2-d]pyrimidin-7-decanoic acid (7-decyloxy-fluorenyl)_ decylamine 0.076 0.216 12 46 p °^NH r^V^NH 〇唑并 [1,5-a] pyrimidine-3-decanoic acid (4·-aminomethyl-4-chloro-biphenyl-2-yl)-醯Amine 0.081 15 47 IXXfc:i» v>^〇2-(2,3-dihydroxy-propylamino)-thieno[3,2-d] Pyridin-7-decanoic acid (7-decyloxy-quino-6-yl)-nonylamine 0.082 0.608 12 48 Oy, Cur^0 N=/ 0 ratio 0 sitting and [1,5-a] pyrimidine-3- Formic acid (2-o-oxy-5-11 benzo-1-yl-2,3-diaza-1沁吲哚-6-yl)-decylamine 0.098 1 49 〇P NH OH a^S-Cr1 thiophene And [3,2-d] pyrimidine-7-decanoic acid [5-chloro-2-(4-hydroxymethyl-bunken-1-yl)-phenyl]-decylamine 0.100 0.70 1 157102.doc -77 - 201217379 50 special; cco 2-(3-Amino-propylamino)-thieno[3,2-d]pyrimidin-7-decanoic acid (7-decyloxy-indol-6-yl)- Indoleamine 0.101 12 51 thieno[3,2-d]pyrimidine-7-carboxylic acid [7-(3-amino-propoxy)-indole *-6-yl]-nonylamine 0.103 0.529 0.376 15 52 0 N-N^V^NH2 αΑχχΗ ° sits at 0 and [1,5-α] bites-3,6-didecanoic acid 6-decylamine 3-{[5-gas-2-(4-perylene-ring) Hexyloxy)-phenyl]-nonylamine} 0.107 5 53 h2n^^ H^〇YS ηνΛΧ Vr^〇ci 2-(2-Amino-ethylamino)-thieno[3,2-d] Pyrimidine-7-decanoic acid (5-vapor-2-methoxy-phenyl)-bristamine} 0.107 0.813 0.35 12 54 NH thieno[3,2-d] shout bite-7-formic acid [7-(3 -hydroxy-cyclopentyloxy)-quinolin-6-yl]-nonylamine hydrochloride 0.122 0.5 5

157102.doc -78 ·157102.doc -78 ·

201217379 55 NH 0比嗅并[l，5-a] 嘧啶-3-曱酸[3-(4-羥基-環己基氧基)-萘-2-基]-醯胺 0.124 0.817 0.628 1 56 fO NH 噻吩并[3,2-d] 嘧啶-7-甲酸[7-(哌啶-4-基氧基)-唾琳_6_基]-醯胺鹽酸鹽 0.125 15 57 CH3 ho^^n ch3 °y^y>n V^〇 2-[(2-經基乙基)-異丙基-胺基]_噻吩并[3,2-d]嘧啶-7-甲酸 (7-甲氧基-喹琳-6-基)-酿胺 0.127 12 58 /^N HN 人JO 吩。噻吩并[3,2-d] 嘧啶-7-甲酸[7-(3-羥基-丙氧基)-喧嚇*-6-基]-醯胺 0.131 5 59 N—— NH2 0 人 NH 0(σ ^^nh2 0比0坐并[1,5-a] 嘧啶-3-甲酸[3-胺基-2-(4-胺基曱基-0辰唆-1-基)-苯基]-醯胺 0.133 15 79- 157102.doc 201217379 60 H〇^ 匕Vi r^N 0比0坐并[1,5-a] 嘧啶-3-曱酸[5-氣-2-(4-羥基-略咬_ 1_基)_苯基]-酿胺 0.136 1 61 Br N-N/=^C (X/ 0入NH 6-溴-°比°坐并 [l，5-a]嘧啶-3-曱酸[5-氣-2-(4-羥基-環己基氧基)-苯基]-醢胺 0.137 5 62 ¢0 0乂NH 力。XX 噻吩并[3,2-d] 响咬-7-曱酸[5-氣-2-(4- 經基-環己基氧基)-苯基]-醯胺 0.149 0.126 1 63 Ο Γ2 N=/ 〇 °比σ坐并[1,5-a] 嘴咬-3-曱酸(3_ 胺基-2_σ底咬-1-基-苯基)-醯胺 0.156 1 64 N^N p V^NCrJ- 噻吩并[3,2-d] 嘧啶-7-曱酸[2-(4-胺基曱基-哌咬-1-基)-5-氯-苯基]_醯胺 0.167 0.80 11201217379 55 NH 0 ratio olficiency [l,5-a] pyrimidine-3-decanoic acid [3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-decylamine 0.124 0.817 0.628 1 56 fO NH Thio[3,2-d]pyrimidine-7-carboxylic acid [7-(piperidin-4-yloxy)-salin-6-yl]-indolyl hydrochloride 0.125 15 57 CH3 ho^^n ch3 °y^y>n V^〇2-[(2-transethylethyl)-isopropyl-amino]-thieno[3,2-d]pyrimidin-7-carboxylic acid (7-methoxy- Quinolin-6-yl)-bristamine 0.127 12 58 /^N HN Human JO. Thieno[3,2-d]pyrimidine-7-carboxylic acid [7-(3-hydroxy-propoxy)-indole *-6-yl]-nonylamine 0.131 5 59 N - NH2 0 human NH 0 ( σ ^^nh2 0 is sitting at 0 and [1,5-a] pyrimidine-3-carboxylic acid [3-amino-2-(4-aminoindenyl-2-chen唆-1-yl)-phenyl]- Guanamine 0.133 15 79- 157102.doc 201217379 60 H〇^ 匕Vi r^N 0 is sitting at 0 and [1,5-a] pyrimidine-3-decanoic acid [5-gas-2-(4-hydroxy-slightly Bite _ 1_ base) _ phenyl]-bristamine 0.136 1 61 Br NN / = ^ C (X / 0 into NH 6 - bromine - ° ° sit and [l,5-a] pyrimidine-3-decanoic acid [5-Gas-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine 0.137 5 62 ¢0 0乂NH force. XX thieno[3,2-d] 咬-7-曱Acid [5-Gas-2-(4-carbyl-cyclohexyloxy)-phenyl]-decylamine 0.149 0.126 1 63 Ο Γ2 N=/ 〇° ratio σ sits and [1,5-a] mouth bite -3-decanoic acid (3_amino-2_σ bottom-1-yl-phenyl)-decylamine 0.156 1 64 N^N p V^NCrJ-thieno[3,2-d]pyrimidin-7-decanoic acid [2-(4-Aminoguanidino-piperidin-1-yl)-5-chloro-phenyl]-decylamine 0.167 0.80 11

157102.doc -80 -157102.doc -80 -

201217379 65 〇^0 NH C^〇U-〇H 吼唑并[1,5-a] 嘧啶-3-曱酸[3-(3-羥基-環戊基氧基)-蔡-2-基]-醯胺 0.177 1 66 Q (ajx5^〇h N=/ °比唑并[l，5-a] 嘧啶-3-曱酸(5-羥基曱基-2-哌咬** 1 -基-苯基)_ 醯胺 0.199 1 67 0 N— W 0人H 力XX °比唑并[l，5-a] 嘧啶-3,6-二甲酸6-醯胺3-{[5-氯-2-(4- 經基-環己基氧基)-苯基]-醯胺} 0.203 6 68 N—— 〇iS：^NH °比唑并[1,5-a] 嘧啶-3-曱酸(4-氣-4’-經基曱基-聯苯-2-基)-醯胺 0.218 1 69 H3C，〇V^ H Ok 0比0坐并[1,5-a] 嘧啶-3-曱酸(6-曱氧基-1H-吲唑-5-基)-醯胺 0.231 1 157102.doc -81 · 201217379 70 h2n^\ 0比0圭并[1,5-a] 嘧啶-3-曱酸[2-(4-胺基-哌啶-1-基)-5-氣-苯基]-醯胺 0.251 15 71 H2N^^γ^) ?H3 Ύ^ιΙ 6-曱氧基-0比0坐并[1，5-〇1]嘴 °定-3-曱酸[2-(4-胺基曱基-派咬-1-基)-5-氣-苯基]-醯胺 0.254 11 72 ch3 _ °χγν^3 C\X〇 K N=^ »比唑并[l，5-a] 嘧啶-3-曱酸(5-曱氧基-2-曱基-111-0弓|〇朵-6-基)-醯胺 0.255 1 73 Η3〇γ^ΝΗ h3c-°Y^% CHs n^n hn 人，^ 2-異丁基胺基-噻吩并[3,2-d] 嘧啶-7-甲酸(7-甲氧基-啥·#-6-基)-醯胺 0.271 12 74 NH j^Y〇丫c' ci-\J 6h3 噻吩并P，2-d] 嘧啶-7-曱酸(5-氯-2-異丙氧基-苯基)_醯胺 0.290 1 75 ho^X jPT、 HN 乂 v^〇 2-(2-經基-乙基胺基)-噻吩并 [3,2-d]嘧啶-7-甲酸喹啉-6-基醯胺 0.300 12 157102.doc -82- 201217379201217379 65 〇^0 NH C^〇U-〇H carbazo[1,5-a]pyrimidin-3-indole [3-(3-hydroxy-cyclopentyloxy)-cai-2-yl] - guanamine 0.177 1 66 Q (ajx5^〇h N=/ ° oxazolo[l,5-a]pyrimidin-3-indole (5-hydroxyindol-2-piperiding** 1 -yl-benzene Base)_ guanamine 0.199 1 67 0 N- W 0 human H force XX ° ratio oxazolo[l,5-a] pyrimidine-3,6-dicarboxylic acid 6-decylamine 3-{[5-chloro-2- (4-carbyl-cyclohexyloxy)-phenyl]-nonylamine} 0.203 6 68 N—— 〇iS: ^NH ° ratio oxazolo[1,5-a]pyrimidin-3-indoleic acid (4- Gas-4'-pyridinyl-biphenyl-2-yl)-nonylamine 0.218 1 69 H3C, 〇V^H Ok 0 is 0 and 0[1,5-a]pyrimidin-3-indole (6 -decyloxy-1H-indazol-5-yl)-decylamine 0.231 1 157102.doc -81 · 201217379 70 h2n^\ 0 to 0 gram [1,5-a] pyrimidine-3-decanoic acid [2 -(4-Amino-piperidin-1-yl)-5-a-phenyl]-decylamine 0.251 15 71 H2N^^γ^) ?H3 Ύ^ιΙ 6-曱oxy-0 is 0 [1,5-〇1] Mouth 定-3-decanoic acid [2-(4-Amino fluorenyl-pyrylene-1-yl)-5-gas-phenyl]-decylamine 0.254 11 72 ch3 _ °χγν^3 C\X〇KN=^ »Bizozolo[l,5-a]pyrimidin-3-indole (5-decyloxy-2-mercapto-111-0 bow|〇朵-6- Amine 0.255 1 73 Η3〇γ^ΝΗ h3c-°Y^% CHs n^n hn human,^ 2-isobutylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (7-methoxy -啥·#-6-yl)-decylamine 0.271 12 74 NH j^Y〇丫c' ci-\J 6h3 Thiophene P,2-d] Pyrimidine-7-decanoic acid (5-chloro-2-iso Propoxy-phenyl)-decylamine 0.290 1 75 ho^X jPT, HN 乂v^〇2-(2-trans-ethylamino)-thieno[3,2-d]pyrimidin-7- Formic acid quinoline-6-ylguanamine 0.300 12 157102.doc -82- 201217379

76 尹7、 NH OH 6-曱氧基-°比0坐并[l，5-a]嘧啶-3-曱酸[5-氣-2-(4-羥基-環己基氧基)-苯基]-醯胺 0.301 5 77 dp η o H〇-y 吼唑并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(3-羥基曱基-環戊基氧基)-苯基]-醯胺 0.306 1 78 ftp 0 H 0 °比唑并[l，5-a] 嘧啶-3-曱酸(5-氯-2- °比洛咬-1 -基-苯基)-醯胺 0.312 1 79 NH °比唑并[l，5-a] 嘧啶-3-曱酸(5-氣-2-哌啶-1-基-苯基)-醯胺 0.314 1 80 '比唆并[l，5-a] 嘧啶-3-甲酸[3-(3-經基-丙氧基)-蔡-2-基]- 醯胺 0.327 1 157102.doc 83- 201217379 81 0 乂 ΜΗ 々η OH 噻吩并[3,2-d] 嘧啶-7-曱酸[5-氣-2-(4- 經基-環己基氧基)-苯基]-醢胺 0.338 0.60 1 82 "比唑并[1，5-α] 嘧啶-3-曱酸(7-經基曱基-3-甲氧基-秦-2-基)-醯胺 0.358 1 83 广7 〇 /0Η aXr° 0比0坐并[1,5-α] 嘴咬-3-甲酸[5-氣-2-(3- 羥基-環戊基氧基)-苯基]-醢胺 0.361 0.656 1 84 O^NH H 0比0坐并[1，5-α] 嘧啶-3-曱酸[5-氣-2-(3- 經基-丙氧基)-苯基]· 醯胺 0.430 5 85 H31 ch3 2-(異丙基-甲基-胺基)-售吩并[3,2-d]嘧啶-7-甲酸(7-曱氧基-啥琳-6-基)-醯胺 0.432 12 86 u K. /CH3 H3C-°V^ N ΗνΑΛ Vr^o Cl 2-[(2-胺基-乙基）-曱基-胺基]-售吩并[3,2-d]嘧啶-7-曱酸 (5-氯-2-甲氧基-苯基)-醯胺 0.436 12 157102.doc -84· 201217379 87 P °^NH «比唑并[1,5-a] 嘧啶-3-曱酸[5-氣-2-(4-經基-丁氧基)-苯基]-醯胺 0.437 1 88 ¢0 〇入NH 噻吩并[3,2-d] 嘧啶-7-曱酸[7-(吡咯啶-3-基氧基)-喧嚇'-6-基]-醯胺鹽酸鹽 0.455 15 89 0/ o N=/ 0 °比0坐并[l，5-a] 嘧啶-3-曱酸P-曱氧基-4-苯基胺曱醯基-苯基)-醯胺 0.455 1 90 Ϊ0 O^NH 方UQH °比°坐并[1,5-a] 嘧啶-3-曱酸[5-氣-2-(4- 經基-環己基氧基)-苯基]-醯胺 0.459 0.806 1 91 NH 0比嗅并[1,5-a] 嘧啶-3-曱酸[5-氣-2-(3-經基-0底咬-1 -基)-苯基]-酿胺 0.474 1 85- 157102.doc 201217379 92 N—— w 0人H 力。Oh 0比0坐并[1,5-a] 嘧啶-3-甲酸[5-氣-2-(略咬-4-基氧基)-苯基]-醯胺鹽酸鹽 0.476 15 93 NH ^H 噻吩并[3,2-d] 嘧啶-7-甲酸[5-氣-2-(派咬-4-基氧基)-苯基]-醯胺三氟-乙酸 0.476 0.93 11 94 N—— 〇人NH广^0H 0比0圭并[l，5-a] 嘧啶-3-甲酸(4-氣-4^經基-聯苯-2-基)-醯胺 0.477 5 95 <XJ 0 丄 f r\ A 0比嗅并[l，5-a] 嘧啶-3-甲酸[5-氣-2-(3- 經基-。比洛咬-l-基)-苯基]-醯胺 0.493 1 96 HO 、 °比唾并[l，5-a] 嘧啶-3-甲酸[5-氯-2-(3,4-二羥基-丁氧基)-苯基]-醯胺 0.506 1876 Yin 7, NH OH 6-methoxy-° sits at 0 and [l,5-a]pyrimidin-3-indole [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl ]-decylamine 0.301 5 77 dp η o H〇-y oxazolo[l,5-a]pyrimidine-3-decanoic acid [5-gas-2-(3-hydroxyindolyl-cyclopentyloxy) -phenyl]-decylamine 0.306 1 78 ftp 0 H 0 ° than oxazolo[l,5-a]pyrimidin-3-indoleic acid (5-chloro-2-° piroxime-1 -yl-phenyl) - indoleamine 0.312 1 79 NH ° than oxazolo[l,5-a]pyrimidin-3-decanoic acid (5-a-2-piperidin-1-yl-phenyl)-decylamine 0.314 1 80 ' And [l,5-a]pyrimidine-3-carboxylic acid [3-(3-carbo-propoxy)-cai-2-yl]-decylamine 0.327 1 157102.doc 83- 201217379 81 0 乂ΜΗ 々η OH thieno[3,2-d]pyrimidin-7-decanoic acid [5-gas-2-(4-carbyl-cyclohexyloxy)-phenyl]-decylamine 0.338 0.60 1 82 " [1,5-α] pyrimidine-3-decanoic acid (7-ylhydrazino-3-methoxy-qin-2-yl)-decylamine 0.358 1 83 broad 7 〇/0Η aXr° 0 to 0 sitting And [1,5-α] mouth bite-3-carboxylic acid [5-gas-2-(3-hydroxy-cyclopentyloxy)-phenyl]-decylamine 0.361 0.656 1 84 O^NH H 0 ratio Sit and [1,5-α]pyrimidine-3-decanoic acid [5-gas-2-(3-carbyl-propoxy)-phenyl] Indoleamine 0.430 5 85 H31 ch3 2-(isopropyl-methyl-amino)-extained benzo[3,2-d]pyrimidine-7-carboxylic acid (7-decyloxy-inden-6-yl) - guanamine 0.432 12 86 u K. /CH3 H3C-°V^ N ΗνΑΛ Vr^o Cl 2-[(2-Amino-ethyl)-fluorenyl-amino]----[3,2- d]pyrimidine-7-decanoic acid (5-chloro-2-methoxy-phenyl)-decylamine 0.436 12 157102.doc -84· 201217379 87 P °^NH «Bizozolo[1,5-a] Pyrimidine-3-decanoic acid [5-gas-2-(4-carbyl-butoxy)-phenyl]-decylamine 0.437 1 88 ¢0 indole NH thieno[3,2-d]pyrimidine-7 -Citrate [7-(pyrrolidin-3-yloxy)-indole '-6-yl]-decylamine hydrochloride 0.455 15 89 0/ o N=/ 0 ° ratio 0 sitting and [l, 5 -a] pyrimidine-3-decanoic acid P-methoxy-4-phenylamine decyl-phenyl)-decylamine 0.455 1 90 Ϊ0 O^NH square UQH ° ratio °[1,5-a Pyrimidine-3-decanoic acid [5-gas-2-(4-carbyl-cyclohexyloxy)-phenyl]-decylamine 0.459 0.806 1 91 NH 0 than oleno[1,5-a] pyrimidine- 3-decanoic acid [5-gas-2-(3-carbyl-0-bottom-1 -yl)-phenyl]-bristamine 0.474 1 85- 157102.doc 201217379 92 N——w 0 human H force. Oh 0 is sitting at 0 and [1,5-a] pyrimidine-3-carboxylic acid [5-gas-2-(slightly -4-yloxy)-phenyl]-decylamine hydrochloride 0.476 15 93 NH ^ H thieno[3,2-d]pyrimidine-7-carboxylic acid [5-gas-2-(pyrylene-4-yloxy)-phenyl]-nonylamine trifluoro-acetic acid 0.476 0.93 11 94 N—— 〇人NH广^0H 0 to 0 并[l,5-a] pyrimidine-3-carboxylic acid (4-gas-4^-trans-biphenyl-2-yl)-decylamine 0.477 5 95 <XJ 0丄fr\ A 0 is more than olfactory [l,5-a] pyrimidine-3-carboxylic acid [5-gas-2-(3-carbyl-.Bilo-l-yl)-phenyl]-decylamine 0.493 1 96 HO , ° than saliva [l,5-a] pyrimidine-3-carboxylic acid [5-chloro-2-(3,4-dihydroxy-butoxy)-phenyl]-decylamine 0.506 18

157102.doc 86- 201217379 97 ^NH °比0全并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(4-曱基-略唤-1-基)-苯基]-酿胺 0.512 1 98 cuH >比唑并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(噁唑-5-基曱氧基)-苯基]-酿胺 0.516 16 99 1 0比0坐并[1,5-a] 嘧啶-3-甲酸(5-氯-2-嗎淋-4-基-苯基)-醯胺 0.523 1 100 NH 0比0坐并[l，5-a] 嘧啶-3-曱酸(4-氣-聯苯-2-基)-醯胺 0.534 1 101 ,L·6 0比0坐并[l，5-a] 嘧啶-3-曱酸[2-(3-胺基甲基比嘻咬-1-基)-5-氣-苯基]-醯胺 0.564 11 102 噻吩并[3,2-d] 嘧啶-7-甲酸(5-甲氧基-1H-吲哚-6-基)-醯胺 0.596 1 157102.doc -87 - 201217379 103 HO 7nh Cl 。比唑并[l，5-ct] 嘧啶-3-曱酸[5-氣-2-(3- 羥基-環己基氧基)-苯基]-醯胺 0.605 1 104 h3c"°YY^] ^ HN人〆^ 0比0坐并[1，5-α] 嘧啶-3-曱酸(3_ 曱氧基-萘-2-基)-醯胺 0.613 1 105 h3c^°n^y^〇 ^〇h (,^Λ〇 0比0坐并[1，5-α] 嘧啶-3-曱酸[4-(3-羥基-丙基胺曱醯基)-2-甲氧基-苯基]-醯胺 0.640 5 106 jX? 〇=( y-oH cAd 0比0坐并[1，5-α] 嘧啶-3-曱酸[5-氣-2-(3-羥基曱基-B比哈咬-1-基)-苯基]-醯胺 0.650 1 107 fyf 广7 hn人〆Si S^o 0比0坐并[1，5-α] 嘧啶-3-甲酸(5-氣-2-二氟甲氧基-苯基)-醯胺 0.717 1 108 CH« Η，ΝΧ\ CU, Cl N=/ 0比°坐并[1,5-α] 嘧啶-3-曱酸(5-氣-2-二甲基胺基-笨基)-醯胺 0.739 1157102.doc 86- 201217379 97 ^NH ° ratio 0 and [l,5-a] pyrimidine-3-decanoic acid [5-gas-2-(4-indolyl-r-but-1-yl)-phenyl --Tainamine 0.512 1 98 cuH > Bisazo[l,5-a]pyrimidin-3-indole [5-Gas-2-(oxazol-5-ylindoleoxy)-phenyl]- Amine 0.516 16 99 1 0 is sitting at 0 and [1,5-a] pyrimidine-3-carboxylic acid (5-chloro-2-n-butyl-4-yl-phenyl)-decylamine 0.523 1 100 NH 0 is 0 And [l,5-a] pyrimidine-3-decanoic acid (4-a-biphenyl-2-yl)-decylamine 0.534 1 101 , L·60 0 than 0 sitting and [l,5-a] pyrimidine- 3-decanoic acid [2-(3-aminomethyl to decyl-1-yl)-5-a-phenyl]-nonylamine 0.564 11 102 thieno[3,2-d]pyrimidin-7-carboxylic acid (5-Methoxy-1H-indol-6-yl)-nonylamine 0.596 1 157102.doc -87 - 201217379 103 HO 7nh Cl . Bisazo[l,5-ct]pyrimidin-3-indole [5-gas-2-(3-hydroxy-cyclohexyloxy)-phenyl]-decylamine 0.605 1 104 h3c"°YY^] ^ HN human 〆 ^ 0 to 0 sitting and [1,5-α] pyrimidine-3-decanoic acid (3_ methoxy-naphthalen-2-yl)-decylamine 0.613 1 105 h3c^°n^y^〇^〇 h (,^Λ〇0 is 0 to sit and [1,5-α] pyrimidine-3-decanoic acid [4-(3-hydroxy-propylaminoindolyl)-2-methoxy-phenyl]- Indoleamine 0.640 5 106 jX? 〇=( y-oH cAd 0 is sitting at 0 and [1,5-α] pyrimidine-3-decanoic acid [5-gas-2-(3-hydroxyindolyl-B is bitten) -1-yl)-phenyl]-nonylamine 0.650 1 107 fyf broad 7 hn human 〆Si S^o 0 to 0 sitting and [1,5-α] pyrimidine-3-carboxylic acid (5-gas-2-two Fluoromethoxy-phenyl)-decylamine 0.717 1 108 CH« Η,ΝΧ\ CU, Cl N=/ 0 ratio °[1,5-α]pyrimidine-3-decanoic acid (5-gas-2 -dimethylamino-phenyl)-decylamine 0.739 1

157102.doc -88 - 201217379 109 HN 人^Cl N=^ °比唑并[l，5-a] 嘧啶-3-甲酸[2-(3-胺基·a比洛咬-1-基)-5-氣-苯基]-醯胺 0.766 19 110 CU〇 K °比唑并[l，5-a] 嘧啶-3-曱酸(5-曱氧基-1H-吲嗓-6-基)-酿胺 0.787 1 111 H，sY^i CV c, 'n=/ 0 "比唑并[l，5-a] 嘧啶-3-甲酸(5-氣-2-甲基硫基-苯基)-醯胺 0.798 1 112 N—— 0人 H |^V 。比唑并[l，5-a] 嘧啶-3-甲酸(5-氣-2-環己基-苯基)_酿胺 0.799 1 113 ch3 HN^I °Ύ^1ί^0 0H N 八^ 噻吩并[3,2-d] 嘧啶-7-甲酸[4-(3-羥基-丙基胺甲醯基)-2-甲氧基-苯基]-酿胺 0.833 5 114 Γ^) HN \^0H 0 °比°坐并[l，5-a] 嘧啶-3-曱酸[3-(2-羥基-乙基胺基）·2-σ底咬-1-基-苯基]-酿胺 1.029 1 157102.doc 89- 201217379 115 VC。噻吩并[3,2-d] 嘧啶-7-曱酸[5-氯-2-(4-曱基-噁唑-5-基曱氧基)-苯基]-醯胺 1.050 1 116 CXq °比°主并[1，5-α] 嘧啶-3-曱酸聯苯-2-基醯胺 1.224 1 117 ho\^\ZH3 ΓΧ n^n hn^^ci V>^〇噻吩并[3,2-d] 嘧啶-7-曱酸 [5-氯-2-(3-羥基-1,1-二曱基· 丙氧基）-苯基]-醯胺 1.459 1 118 ¢0 0 乂 NH 〇A〇U nh2 噻吩并[3,2-d] 喊咬-7-曱酸[2-(4-胺基-環己基氧基)-5-氣-苯基]-醯胺 1.471 15 119 (Χλ〇 c, N=^ 0比嗤并[1,5-α] 嘧啶-3-甲酸(2-氮雜環庚烷-1-基-5-氣-苯基)-醯胺 1.503 1 120 ΗΟχν〇噻吩并[3,2-d] 鳴咬-7-甲酸[5-氣-2-(3- 經基-環戊基氧基)-苯基]-醯胺 1.521 5 157102.doc •90- 201217379157102.doc -88 - 201217379 109 HN Human^Cl N=^ °Bizozolo[l,5-a]pyrimidine-3-carboxylic acid [2-(3-Amino-a-Bile-1-yl)- 5-Gas-phenyl]-nonylamine 0.766 19 110 CU〇K ° oxazolo[l,5-a]pyrimidin-3-indole (5-decyloxy-1H-indol-6-yl)- Amine amine 0.787 1 111 H, sY^i CV c, 'n=/ 0 "Bizozolo[l,5-a]pyrimidine-3-carboxylic acid (5-Gas-2-methylthio-phenyl) - guanamine 0.798 1 112 N - 0 people H | ^ V. Bisazo[l,5-a]pyrimidine-3-carboxylic acid (5-vapor-2-cyclohexyl-phenyl)-bristamine 0.799 1 113 ch3 HN^I °Ύ^1ί^0 0H N VIII thiophene [3,2-d] Pyrimidine-7-carboxylic acid [4-(3-hydroxy-propylaminemethanyl)-2-methoxy-phenyl]-bristamine 0.833 5 114 Γ^) HN \^0H 0 ° ratio ° sitting and [l,5-a] pyrimidine-3-decanoic acid [3-(2-hydroxy-ethylamino)·2-σ bottom bit-1-yl-phenyl]-bristamine 1.029 1 157102.doc 89- 201217379 115 VC. Thio[3,2-d]pyrimidin-7-decanoic acid [5-chloro-2-(4-indolyl-oxazol-5-ylindoleoxy)-phenyl]-decylamine 1.050 1 116 CXq ° °[1,5-α]pyrimidine-3-phthalic acid biphenyl-2-yl decylamine 1.224 1 117 ho\^\ZH3 ΓΧ n^n hn^^ci V>^〇 thieno[3, 2-d] pyrimidine-7-decanoic acid [5-chloro-2-(3-hydroxy-1,1-didecyl-propoxy)-phenyl]-decylamine 1.459 1 118 ¢0 0 乂NH 〇 A〇U nh2 thieno[3,2-d] shouting -7-decanoic acid [2-(4-amino-cyclohexyloxy)-5-a-phenyl]-nonylamine 1.471 15 119 (Χλ 〇c, N=^ 0 is more than 嗤[1,5-α]pyrimidine-3-carboxylic acid (2-azepane-1-yl-5-a-phenyl)-decylamine 1.503 1 120 ΗΟχν〇 Thio[3,2-d] gnat-7-formic acid [5-gas-2-(3-carbyl-cyclopentyloxy)-phenyl]-decylamine 1.521 5 157102.doc •90- 201217379

121 ¢0 °^ΝΗ /°Ί\ ch3 °比唑并[1，5-α] 嘧啶-3-甲酸[5-氣-2-(4-曱基-噁唑-5-基曱氧基)-苯基]-酿胺 1.553 1 122 /CH3 y—OH Ν-Λ 0 ( s—f 〇噻吩并[3,2-d] 嘧啶-7-曱酸[4-(2-羥基-乙基胺甲醯基)-2-甲氧基-苯基]-醯胺 1.619 5 123 ch3 她，。比唑并[1,5-α] 嘧啶-3-曱酸(5-氣-2-曱氧基-苯基)-醯胺 1.633 1 124 喊。H3 N=/ 0 ci °比 °坐并[1,5-α] 嘧啶-3-甲酸[5-氣-2-(2-甲氧基-乙氧基)-苯基]-酿胺 1.710 1 125 N—N^i • W 0人NH广 cl^r^〇H °比唑并[1，5-α] 嘧啶-3-曱酸(4-氣-31-經基-聯苯-2-基>•醯胺 2.047 5 126 η〇/^-νη h3c-°Y^j n^n hn^^^ci 咖。 2-(3-經基-丙基胺基)-每吩并[3,2-d]嘧啶-7-曱酸(5-氯-2-曱氧基-苯基)-醯胺 2.062 12 127 h3c/〇V^| ςνι认吼唑并[1，5-α] 嘧啶-3-甲酸(5->臭-2-曱氧基-苯基)-酿胺 2.144 1 157102.doc -91- 201217379 128 V>^〇噻吩并[3,2-d] 嘧啶-7-曱酸(5-氣-2-曱氧基-苯基)-醯胺 2.200 1 129 ch3 ho^^n 丫1 HN/kAc| »比唑并[1，5-α] 嘧啶-3-甲酸{5-氣-2-[(2-羥基-乙基)-曱基-胺基]-苯基}-醯胺 2.203 1 130 ^NH OH 0比0坐并[1,5-α] 嘧啶-3-甲酸[5-氣-2-(4- 羥基-苯氧基)-苯基]-醯胺 2.221 1 131 r0H 〇h3 hn)、/CH3 vy^〇 c, 2-(1-經基曱基-丙基胺基)-11 塞吩并[3,2-d]嘧啶-7-曱酸（5-氣-2-曱氧基-苯基)-醯胺 2.226 12 132 —x H^〇 ΐ 1 h/nJ^ V^o C， 2-(2-經基-乙基胺基)-噻吩并[3,2-d]嘧啶-7-曱酸(5-氣-2-曱氧基-苯基)-醯胺 2.237 12 133 N——N^t^OH 0人NH cA〇^〇H 6-經基曱基_0比 °坐并[1，5-α]嘴啶-3-曱酸[5-氣-2-(4- 羥基-環己基氧基)-苯基]-醯胺 2.253 6 157102.doc -92- 201217379 134 胁：〇 0比0坐并[l，5-a] 嘧啶-3-曱酸 (4-胺甲醯基-2-曱氧基-苯基)-醯胺 2.256 3 135 N— w 0 人 NH CH3 CA°入 '比唑并[l，5-a] 嘧啶-3-甲酸(5- 氣-2-異丁氧基-苯基)-醯胺 2.280 1 136 ^S〇H 噻吩并[3,2-d] 嘧啶-7-曱酸[1-(3-經基-丙基)· 1H-苯并咪唑-2-基]-酿胺 2.310 1 137 h〇vj?h v-o H 0 。比唑并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(2,3-二羥基-丙氧基)-苯基]-酿胺 2.311 18 138 N—— W 0人NH °比0坐并[1,5-a] 嘧啶-3-甲酸[5-氯-2-(3-曱氧基-丙氧基)_苯基]-醢胺 2.419 1 139 o 噻吩并[3,2-d] 嘧啶-7-甲酸[5-氣-2-(3- 經基-丙氧基)-苯基]-醯胺 2.452 5 140 H0-O 0比0坐并[1,5-a] 嘧啶-3-曱酸[5-氣-2-(3-羥基甲基-〇底咬-1-基)-苯基]-醯胺 2.465 1 157102.doc -93- 201217379 141 ciA〇Xi〇h 。比唑并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(3-經基-苯曱氧基)-苯基]-醯胺 2.626 7 142 H3C Y] CH3 HN人丨 -比唑并[l，5-a] 嘧啶-3-曱酸(5-氣-2,4-二甲氧基-苯基)-醯胺 2.738 1 143 广^ HN人 '比唑并[1,5-a] 嘧啶-3-甲酸(2-曱氧基-5-乙烯基-苯基)-醯胺 2.748 1 144 〇；0 cuo N=/ 吼唑并[1,5-a] 嘧啶-3-曱酸[3-(3-羥基-丙基胺基）-2-11 底咬-1-基-苯基]-酿胺 2.849 1 145 N—— 〇人H clir^0H 。比唑并[l，5-a] 嘧啶-3-甲酸 [5-氣-2-(4-羥基-丁基）-苯基]-醯胺 2.949 1 146 HO N=/ 0 °比0坐并[l，5-a] 嘧啶-3-曱酸[4-(2-羥基-乙基胺甲酿基)-2-甲氧基-苯基]-醯胺 2.961 5121 ¢0 °^ΝΗ /°Ί\ ch3 ° oxazolo[1,5-α]pyrimidine-3-carboxylic acid [5-gas-2-(4-mercapto-oxazol-5-yloxy) -phenyl]-bristamine 1.553 1 122 /CH3 y-OH Ν-Λ 0 ( s-f 〇 thieno[3,2-d] pyrimidine-7-decanoic acid [4-(2-hydroxy-ethylamine) Methyl)-2-methoxy-phenyl]-nonylamine 1.619 5 123 ch3 her, biszolo[1,5-α]pyrimidine-3-furic acid (5-Ga-2-indoleoxy) -phenyl)-decylamine 1.633 1 124 shout. H3 N=/ 0 ci ° ratio °[1,5-α]pyrimidine-3-carboxylic acid [5-gas-2-(2-methoxy-B Oxy)-phenyl]-bristamine 1.710 1 125 N-N^i • W 0 human NH wide cl^r^〇H ° than oxazolo[1,5-α]pyrimidine-3-furic acid (4- Gas-31-trans-based-biphenyl-2-yl>•decylamine 2.047 5 126 η〇/^-νη h3c-°Y^jn^n hn^^^ci 咖. 2-(3-经基- Propylamino)- per benzo[3,2-d]pyrimidin-7-decanoic acid (5-chloro-2-indolyloxy-phenyl)-decylamine 2.062 12 127 h3c/〇V^| ςνι Oxazolo[1,5-α]pyrimidine-3-carboxylic acid (5->odor-2-oxyloxy-phenyl)-bristamine 2.144 1 157102.doc -91- 201217379 128 V> [3,2-d] pyrimidine-7-decanoic acid (5-gas-2-decyloxy-phenyl)-guanamine 2.200 1 129 ch3 ho^^n 丫1 HN/kAc| »Bizozolo[1,5-α]pyrimidine-3-carboxylic acid {5-gas-2-[(2-hydroxy-ethyl)-indenyl-amino group ]-Phenyl}-nonylamine 2.203 1 130 ^NH OH 0 is 0-position and [1,5-α]pyrimidine-3-carboxylic acid [5-gas-2-(4-hydroxy-phenoxy)-phenyl ]-decylamine 2.221 1 131 r0H 〇h3 hn), /CH3 vy^〇c, 2-(1-pyridyl-propylamino)-11 pheno[3,2-d]pyrimidine-7 -capric acid (5-Gas-2-decyloxy-phenyl)-decylamine 2.226 12 132 —x H^〇ΐ 1 h/nJ^ V^o C, 2-(2-trans-ethylamine ))-thieno[3,2-d]pyrimidin-7-decanoic acid (5-Gas-2-decyloxy-phenyl)-decylamine 2.237 12 133 N——N^t^OH 0 human NH cA 〇^〇H 6- via 曱 _0 _0 _0 并 and [1,5-α] 啶曱-3-decanoic acid [5-Gas-2-(4-hydroxy-cyclohexyloxy)-phenyl ]-nonylamine 2.253 6 157102.doc -92- 201217379 134 Threat: 〇0 to 0 sitting and [l,5-a] pyrimidine-3-decanoic acid (4-aminomethylcarbonyl-2-methoxy-benzene ))-nonylamine 2.256 3 135 N—w 0 human NH CH3 CA° into 'biszolo[l,5-a]pyrimidine-3-carboxylic acid (5-Gas-2-isobutoxy-phenyl)- Indole 2.280 1 136 ^S〇H Thio[3,2-d]pyrimidin-7-decanoic acid [1-(3-carbyl-propyl)· 1H- And imidazol-2-yl] - amine stuffed h〇vj 2.310 1137 h v-o H 0?. Bisazo[l,5-a]pyrimidine-3-decanoic acid [5-gas-2-(2,3-dihydroxy-propoxy)-phenyl]-bristamine 2.311 18 138 N - W 0 Human NH ° is 0 and [1,5-a] pyrimidine-3-carboxylic acid [5-chloro-2-(3-decyloxy-propoxy)-phenyl]-nonylamine 2.419 1 139 o thieno [3,2-d] pyrimidine-7-carboxylic acid [5-gas-2-(3-carbyl-propoxy)-phenyl]-nonylamine 2.452 5 140 H0-O 0 sits at 0 and [1, 5-a] pyrimidine-3-decanoic acid [5-gas-2-(3-hydroxymethyl-indenyl-1-yl)-phenyl]-nonylamine 2.465 1 157102.doc -93- 201217379 141 ciA 〇Xi〇h. Bisazo[l,5-a]pyrimidin-3-decanoic acid [5-gas-2-(3-carbyl-benzofluorenyloxy)-phenyl]-decylamine 2.626 7 142 H3C Y] CH3 HN丨-Bizozolo[l,5-a]pyrimidine-3-decanoic acid (5-Gas-2,4-dimethoxy-phenyl)-decylamine 2.738 1 143 广^HN human 'Bizozolo[ 1,5-a] pyrimidine-3-carboxylic acid (2-decyloxy-5-vinyl-phenyl)-decylamine 2.748 1 144 〇; 0 cuo N=/ carbazo[1,5-a] pyrimidine -3-decanoic acid [3-(3-hydroxy-propylamino)-2-11 benzo-1-yl-phenyl]-bristamine 2.849 1 145 N - 〇H Clir^0H. Bisazo[l,5-a]pyrimidine-3-carboxylic acid [5-gas-2-(4-hydroxy-butyl)-phenyl]-decylamine 2.949 1 146 HO N=/ 0 ° sits at 0 [l,5-a] pyrimidine-3-decanoic acid [4-(2-hydroxy-ethylamine-mercapto)-2-methoxy-phenyl]-decylamine 2.961 5

157102.doc -94. 201217379157102.doc -94. 201217379

6-(2-經基-乙基)-°比唑并[1，5-〇0喊咬-3-曱酸 [5-氣-2-(4-羥基-環己基氧基)-苯基]-醯胺 °比唑并[1，5-α] 嘧啶-3-曱酸{2-[3-(1-胺基-乙基)_ ° 比^-1 -基]-5-氯-苯基}-醯胺鹽酸鹽 °比唑并[1,5-α] 嘧啶-3-甲酸{5-氣-2-[(3-經基-丙基)-甲基-胺基]-苯基}-酿胺噻吩并[3,2-β] 吡啶-3-曱酸(5-氯-2-曱氧基-苯基)-醯胺噻吩并[3,2-d] 嘧啶-7-甲酸[5-氯-2-(4-曱基胺基曱基-派咬-1-基)-苯基]-醯胺 »比唑并[1，5-α] 嘧啶-3-曱酸[5-(3-經基-丙稀基)-2-甲氧基-苯基]-醯胺 3.045 3.083 3.395 3.461 3.545 3.698 15 10 157102.doc -95- 201217379 153 N— w 0人NH j^T°、CH3 h3c>^ °比嗤并[l，5-a] 嘧啶-3-甲酸(2-曱氡基-5-曱基-苯基)-醯胺 3.769 1 154 〇 H3h>X N=/ 0 Cl 0比0坐并[l，5-a] 嘧啶-3-甲酸(5-氣-2-乙基-笨基)-酿胺 3.796 1 155 H3C^〇V^3y〇 N=/ 0比嗅并[l，5-a] 嘧啶-3-甲酸(4-曱烷磺酿基-2-曱氧基-苯基)-醯胺 4.011 1 156 NH 0比嗤并[l，5-a] 嘧啶-3-甲酸[5-氣-2-(3- 經基-苯氧基)-苯基]-醯胺 4.047 1 157 N^N HN-^^CI 咖。 2-[(2-經基-乙基）_曱基-胺基]-嗟吩并[3,2-d]嘧啶-7-曱酸 (5-氣-2-甲氧基-苯基)-醯胺 4.133 12 158 〇Η3η>χ，η3 N=/ 0 0比0坐并[1,5-a] 嘧啶-3-甲酸 (2,4-二曱氧基-苯基)-醯胺 4.169 1 159 〇Hr_K l^N M O F 0比0坐并P，5-a] 嘧啶-3-曱酸(5-氟-2-甲氧基-苯基)-醯胺 4.302 1 -96- 157102.doc 201217379 160 N— O^NH 0 {4-氣-2-[(° 比0坐并[1，5-α]啦咬-3-羰基)-胺基]-苯氧基}-乙酸曱酯 4.305 2 161 NH °比0坐并[1,5-α] 嘧啶-3-曱酸(5-氣-2-苯氧基-苯基)-醯胺 4.647 1 162 HO^^^NH H3C-0y^ 5-(2-經基-乙基胺基)-嗟吩并[3,2-β]〇比啶-3-甲酸(5-氯-2-曱氧基-苯基)-醯胺 4.655 12 163 0比0坐并[1，5-α] 嘧啶-3-曱酸[5-氯-2-(2,3-二羥基-丙氧基)-苯基]-醢胺 4.664 18 164 rv^〇H 0比吐并[1,5-α] 嘧啶-3-甲酸[5-氯-2-(2-羥基甲基-娘咬-1-基)-苯基]-醯胺 4.848 1 165 N=/ 0 0比σ坐并[1，5·α] 嘧啶-3-甲酸(3-曱氧基-聯苯-4-基)-酿胺 5.205 1 157102.doc 97- 201217379 166 0比嗤并[1，5-α] 痛咬-3-甲酸(5-乙基-2-甲氧基-苯基)-醯胺 5.885 1 167 Ν=/ 0 CH3 «比唑并[1,5-α] 嘴咬_3-曱酸 (5_甲氧基-2-曱基-聯苯-4-基)-醯胺 5.941 1 168 ?Η3 °yS °比0坐并[1，5-α] 喊咬-3-曱酸 (2-甲氧基-3,5-二甲基-笨基)-醯胺 6.516 1 169 ν^ν州人> V^o 噻吩并[3,2-d] 嘧啶-7-曱酸P-甲氧基-苯基)-醯胺 6.559 1 170 Ν-Ν/：=：=：\ (XrT0^ 0人ΝΗ 方XX 5-曱基-吡唑并 [1，5-α]嘴咬-3-曱酸[5-氣-2-(4-羥基-環己基氧基)-苯基]-醯胺 6.561 9 171 〇ΤΚ Ν-(/ΝΛ7 Ν==/ 0 0比。坐并[1,5-α] 嘧啶-3-曱酸(2-甲氧基-苯基)-醯胺 7.337 1 157102.doc 98- 201217379 172 CH3 H3CYCH3 «比唑并[l，5-a] 嘧啶-3-曱酸(4-二曱基胺甲醢基-2-曱氧基-苯基)-酿胺 7.651 1 173 H3C"°Y^i O^CHj N=/ 0比0坐并[l，5-a] 嘧啶_3-曱酸(5-乙醯基胺基-2-曱氧基-笨基)-醯胺 7.697 1 174 C^\C， »比唑并[1,5-a] 嘧啶-3-曱酸(5-氯-2-曱氧基-4-苯基胺甲醯基-苯基)-醯胺 7.915 1 175 Η3〇γΝ^ΝΗ H3C^〇Y% 0 N '"'N V^〇 2-(2-乙醯基胺基-乙基胺基)-噻吩并[3,2-d] 嘴咬-7-甲酸-(5-氯-2-曱氧基-苯基)-醯胺 8.087 12 176 ςζί^0Η N=/ η比唑并[1,5-a] 嘧啶-3-甲酸[5-(3-經基-丙基)-2-甲氧基-苯基]-醯胺 8.361 1 177 N=/ 0 "比唑并[l，5-a] 嘧啶-3-曱酸 (4-羥基甲基-2-曱氧基-苯基)-醯胺 8.673 5 157102.doc 99- 201217379 178 〇/ NH cAXxqh 6-(3-經基-丙基)-°比唑并[1,5-a]°S咬-3-曱酸 [5-氣-2-(4-羥基-環己基氧基)-苯基]-醯胺 9.417 1 179 f^N °C?〇H N=/ 0 ci 0比唑并[l，5-a] 嘧啶-3-曱酸[5-氣-2-(2- 經基-乙氧基)-苯基]-醯胺 5 5 180 H^Nri C\i〇 c, N=/ '比唑并[l，5-a] 嘧啶-3-甲酸[5-氣-2-(4-曱基胺基曱基-略咬-1_ 基)-苯基]-醯胺 8 181 ^NY^fN^| °比°全并[l，5-a] 嘧啶-3-甲酸[7-(4-羥基甲基-哌咬-1-基)-啥嚇-6-基]-酿胺 1 182 h2n^t^ 噻吩并[3,2-β] 吡啶-3-甲酸[7-(4-胺基甲基-哌啶-1-基)-喹琳-6-基]-醯胺 11 183 Η2Ν-γ^ ΐΝΥΎΊ H〇Y^n 6-經基-°比°坐并 [1，5-α]嘧啶-3-甲酸[7-(4-胺基甲基-娘咬_1_ 基)-啥嚇'-6-基]-醯胺鹽酸鹽 14 157102.doc •100- 201217379 1846-(2-trans-ethyl-ethyl)-pyrazole[1,5-〇0 shouting -3-decanoic acid [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl ]-guanamine ° thiazolo[1,5-α]pyrimidine-3-decanoic acid {2-[3-(1-amino-ethyl)_ ° ratio ^-1 -yl]-5-chloro- Phenyl}-guanamine hydrochloride salt oxazolo[1,5-α]pyrimidine-3-carboxylic acid {5-gas-2-[(3-carbyl-propyl)-methyl-amino]- Phenyl}-chiral amine thieno[3,2-β]pyridine-3-decanoic acid (5-chloro-2-indolyl-phenyl)-decylamine thieno[3,2-d]pyrimidine-7 -formic acid [5-chloro-2-(4-decylaminoindolyl-pyridyl-1-yl)-phenyl]-nonylamine»biazo[1,5-α]pyrimidin-3-indole [5-(3-Pyloryl-propyl)-2-methoxy-phenyl]-nonylamine 3.045 3.083 3.395 3.461 3.545 3.698 15 10 157102.doc -95- 201217379 153 N— w 0 people NH j^ T°, CH3 h3c>^° 嗤[l,5-a]pyrimidine-3-carboxylic acid (2-mercapto-5-fluorenyl-phenyl)-decylamine 3.769 1 154 〇H3h>XN=/ 0 Cl 0 is sitting at 0 and [l,5-a] pyrimidine-3-carboxylic acid (5-gas-2-ethyl-phenyl)-nitramine 3.796 1 155 H3C^〇V^3y〇N=/ 0 ratio Olfactory [l,5-a]pyrimidine-3-carboxylic acid (4-nonanesulfonyl-2-yloxy-phenyl)-decylamine 4.011 1 156 NH 0 is more than 嗤[l,5- a] Pyrimidine-3-carboxylic acid [5-gas-2-(3-carbyl-phenoxy)-phenyl]-nonylamine 4.047 1 157 N^N HN-^^CI Coffee. 2-[(2-P-ethyl-ethyl)-indolyl-amino]-indeno[3,2-d]pyrimidin-7-decanoic acid (5-Ga-2-methoxy-phenyl) - guanamine 4.133 12 158 〇Η 3η > χ, η3 N = / 0 0 is 0 and 0 [1,5-a] pyrimidine-3-carboxylic acid (2,4-dimethoxy-phenyl)-decylamine 4.169 1 159 〇Hr_K l^NMOF 0 is sitting with 0 and P,5-a] pyrimidine-3-decanoic acid (5-fluoro-2-methoxy-phenyl)-decylamine 4.302 1 -96- 157102.doc 201217379 160 N—O^NH 0 {4-Gas-2-[(° ratio 0 sits and [1,5-α] ticks-3-carbonyl)-amino]-phenoxy}-acetic acid oxime ester 4.305 2 161 NH ° is more than 0 and [1,5-α]pyrimidin-3-decanoic acid (5-Gas-2-phenoxy-phenyl)-decylamine 4.647 1 162 HO^^^NH H3C-0y^ 5 -(2-trans-ethylamino)-mermano[3,2-β]indolepyridin-3-carboxylic acid (5-chloro-2-indolyloxy-phenyl)-decylamine 4.655 12 163 0 to 0 sitting and [1,5-α]pyrimidin-3-decanoic acid [5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl]-decylamine 4.564 18 164 rv^〇 H 0 is more than spit [1,5-α]pyrimidine-3-carboxylic acid [5-chloro-2-(2-hydroxymethyl-nitopic -1-yl)-phenyl]-decylamine 4.848 1 165 N= / 0 0 is more than σ and [1,5·α]pyrimidine-3-carboxylic acid (3-decyloxy-biphenyl-4-yl)-bristamine 5.205 1 15 7102.doc 97- 201217379 166 0 than 嗤[1,5-α] biting-3-carboxylic acid (5-ethyl-2-methoxy-phenyl)-decylamine 5.858 1 167 Ν=/ 0 CH3 «Bizozolo[1,5-α] Mouth bit _3-capric acid (5-methoxy-2-indolyl-biphenyl-4-yl)-decylamine 5.941 1 168 ?Η3 °yS ° ratio 0 Sit and [1,5-α] shout bite -3-decanoic acid (2-methoxy-3,5-dimethyl-phenyl)-decylamine 6.516 1 169 ν^ν州人> V^o Thio[3,2-d]pyrimidin-7-decanoic acid P-methoxy-phenyl)-decylamine 6.559 1 170 Ν-Ν/:=:=:\ (XrT0^ 0人ΝΗ Fang XX 5- Mercapto-pyrazolo[1,5-α] mouth bite-3-decanoic acid [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine 6.561 9 171 〇ΤΚ Ν -(/ΝΛ7 Ν==/ 0 0 ratio. Sit and [1,5-α]pyrimidine-3-decanoic acid (2-methoxy-phenyl)-decylamine 7.373 1 157102.doc 98- 201217379 172 CH3 H3CYCH3 «Bizozolo[l,5-a] Pyrimidine-3-decanoic acid (4-didecylaminecarboxynon-2-yloxy-phenyl)-nitramine 7.651 1 173 H3C"°Y^i O^CHj N=/ 0 ratio 0 sitting and [ l,5-a] pyrimidine _3-decanoic acid (5-ethylhydrinylamino-2-decyloxy-phenyl)-decylamine 7.769 1 174 C^\C, »Bizozolo[1,5- a] pyrimidine-3-decanoic acid (5-chloro-2-indolyl-4-phenylamine-mercapto-phenyl)-decylamine 7.915 1 175 Η3〇γΝ^ΝΗ H3C^〇Y% 0 N ' "'NV^〇2-(2-Ethylamino-ethylamino)-thieno[3,2-d] mouth bite-7-formic acid-(5-chloro-2-nonyloxy- Phenyl)-decylamine 8.087 12 176 ςζί^0Η N=/ η-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(3-carbyl-propyl)-2-methoxy- Phenyl]-decylamine 8.361 1 177 N=/ 0 "Bizozolo[l,5-a]pyrimidin-3-indole (4-hydroxymethyl-2-decyloxy-phenyl)-decylamine 8.673 5 157102.doc 99- 201217379 178 NH/ NH cAXxqh 6-(3-trans-propyl-propyl)-°bizozolo[1,5-a]°S 2-3-3-decanoic acid [5-gas-2 -(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine 9.417 1 179 f^N C?〇HN=/ 0 ci 0-pyrazolo[l,5-a]pyrimidin-3-indole [5-gas-2-(2-trans-ethoxy-phenyl)-phenyl]-decylamine 5 5 180 H^Nri C\i〇c, N=/ 'Bizozolo[l,5-a]pyrimidine-3-carboxylic acid [5-gas-2-(4-decylamino fluorenyl-slightly bite- 1_yl)-phenyl]-nonylamine 8 181 ^NY^fN^| ° ratio of total [1,5-a] pyrimidine-3-carboxylic acid [7-(4-hydroxymethyl-piperidine-1- Base)-infested-6-yl]-bristamine 1 182 h2n^t^ thieno[3,2-β]pyridine-3-carboxylic acid [7-(4-aminomethyl-piperidin-1-yl) )-Quinolin-6-yl]-nonylamine 11 183 Η2Ν-γ^ ΐΝΥΎΊ H〇Y^n 6-trans-base-° ratio of [1,5-α]pyrimidine-3-carboxylic acid [7-( 4-aminomethyl-ninja bite_1_ base)-infested '-6-yl]-guanamine hydrochloride 14 157102.doc •100- 201217379 184

2-((lR，2S)-2-胺基-環己基胺基)-噻吩并[3,2-闺嘧啶-7-曱酸喹啉-8-基醯胺 22 1852-((lR,2S)-2-amino-cyclohexylamino)-thieno[3,2-pyrimidin-7-decanoic acid quinolin-8-ylguanamine 22 185

2-((lR，2S)-2-胺基-環己基胺基)-噻吩并[3,2-司嘧啶-7-曱酸苯并[1,3]二氧雜環戊烯-5-基醯胺 23 1862-((lR,2S)-2-amino-cyclohexylamino)-thieno[3,2-silazin-7-decanoic acid benzo[1,3]dioxol-5- Glutamine 23 186

2-((lR,2S)-2-胺基-環己基胺基)-噻吩并[3,2-司嘧啶-7-甲酸 (3,4-二曱氧基-苯基)-醯胺 24 1872-((lR,2S)-2-Amino-cyclohexylamino)-thieno[3,2-pyrimidin-7-carboxylic acid (3,4-dimethoxy-phenyl)-decylamine 24 187

2-((lS，2R)-2-胺基-環己基胺基)-噻吩并[3,2-4°¾咬-7-甲酸 (1-曱基-1//-苯并咪β坐-4-基)-醯胺 25 157102.doc -101 - 201217379 188 1。u H'N f 2-((lS，2R)-2-胺基-環己基胺基)-噻吩并[3,2-ύ〇嘧啶-7-甲酸 (2,4-二曱氧基-苯基)-醢胺 26 189 tfVv 〇 h2n<^ W/。 2-((1 S,2R)-2-胺基-環己基胺基）-噻吩并 [3,2-4 嘧啶-7-曱酸(5,6-二曱氧基-n比咬-2-基)-醯胺 27 190 H 七 0^Ν^γ。、 2-((lS,2R)-2-胺基-環己基胺基)-噻吩并[3,2-ί/J嘧啶-7-曱酸 (3,4,5-三甲氧基-苯基)-醯胺 28 191 .¾ 〇 ^ 2-((lS，2R)-2-胺基-環己基胺基)-噻吩并[3,2-4嘧啶-7-曱酸嗜咐·_6-基醯胺 29 192 4^^n^h2 0人H 夕。、 2-((3R,4R)-3-胺基-四氮-旅嗔-4-基胺基)-噻吩并[3,2叫嘧啶-7-曱酸(7-甲氧基-唾啦-6-基)-醯胺 157102.doc -102· 2012173792-((lS,2R)-2-amino-cyclohexylamino)-thieno[3,2-4°3⁄4 bite-7-carboxylic acid (1-mercapto-1//-benzopyrimidine beta -4-yl)-nonylamine 25 157102.doc -101 - 201217379 188 1. u H'N f 2-((lS,2R)-2-Amino-cyclohexylamino)-thieno[3,2-pyrimidin-7-carboxylic acid (2,4-dimethoxy-benzene) Base) - guanamine 26 189 tfVv 〇 h2n < ^ W /. 2-((1 S,2R)-2-amino-cyclohexylamino)-thieno[3,2-4-pyrimidin-7-decanoic acid (5,6-dimethoxy-n ratio bite-2 -yl)-guanamine 27 190 H 七0^Ν^γ. , 2-((lS,2R)-2-Amino-cyclohexylamino)-thieno[3,2-ί/J-pyrimidine-7-decanoic acid (3,4,5-trimethoxy-phenyl )-decylamine 28 191 .3⁄4 〇^ 2-((lS,2R)-2-amino-cyclohexylamino)-thieno[3,2-4-pyrimidine-7-decanoic acid eosin·6-yl Indoleamine 29 192 4^^n^h2 0 people H eve. , 2-((3R,4R)-3-Amino-tetrazo-l--4-ylamino)-thieno[3,2 is pyrimidin-7-decanoic acid (7-methoxy-saliva) -6-yl)-nonylamine 157102.doc -102· 201217379

本發明化合物可藉由下文所展示且描述之說明性合成反應流程中所描繪的各種方法製備β 用於製備此等化合物之初始物質及試劑一般可獲自商業供應商’諸如Aldrich Chemical Co.，或由熟習此項技術者遵循諸如以下參考文獻中所述之程序加以製備：諸如 Fieser and Fieser's Reagents for Organic Synthesis ； Wiley & Sons: New York, 1991，第 1-15卷；CTiewWr；； 0/The compounds of the present invention can be prepared by various methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents for the preparation of such compounds are generally available from commercial suppliers such as Aldrich Chemical Co., Or prepared by those skilled in the art following procedures such as those described in the following references: such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Vol. 1-15; CTiewWr;;

Carbon Compounds, Elsevier Science Publishers, 1989 > 第 1-5 卷及增刊；及Wiley & Sons: New York，1991，第1-40卷。以下合成反應流程僅說明可用以合成本發明化合物之一些方法，且可對此等合成反應流程做出各種修改且熟習此項技術者參考本申請案中所含之揭示内容將想到該等各種修改。若需要，則可使用習知技術（包括（但不限於）過濾、蒸餾、結晶、層析及其類似技術）分離及純化合成反應流程之初始物質及中間物。可使用習知方式（包括物理常數及 157102.doc • 103- 201217379 光譜資料）來表徵該等物質。除非相反說明，否則本文所述之反應較佳在惰性氛圍下’在大氣壓下，在約_78它至約15〇艺，更佳約〇β(：至約 125 C之反應溫度範圍内及最佳且宜在約室溫（或環境溫度）(例如約20°C)下進行。以下流程A說明一種可用於製備之特定化合物的合成程序，其中R為低碳烧基且在每次出現時可相同或不同，且Ar及R1及R2如本文所定義。Carbon Compounds, Elsevier Science Publishers, 1989 > Volumes 1-5 and Supplements; and Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes merely illustrate some of the methods that can be used to synthesize the compounds of the present invention, and various modifications can be made to these synthetic reaction schemes. Those skilled in the art will recognize the various modifications with reference to the disclosure contained in the present application. . If desired, the starting materials and intermediates of the synthetic reaction scheme can be separated and purified using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These materials can be characterized using conventional means, including physical constants and spectral data from 157102.doc • 103-201217379. Unless stated to the contrary, the reactions described herein are preferably in an inert atmosphere at atmospheric pressure, from about _78 to about 15 Å, more preferably about 〇β (: to a reaction temperature range of about 125 C and most Preferably, it is carried out at about room temperature (or ambient temperature) (e.g., about 20 ° C.) Scheme A below illustrates a synthetic procedure for a particular compound that can be used in the preparation, wherein R is a low carbon burn group and at each occurrence The same or different, and Ar and R1 and R2 are as defined herein.

流程A 在流程A之步驟A中，進行環化反應，其中胺基吡唑酯达與胺基烯醛（aminoenal)化合物匕在鹼存在下反應，獲得吡 °坐并嘧啶酯化合物2。可在極性非質子性溶劑條件下，在氫化鈉存在下進行反應。在步驟B中，吡唑并嘧啶酯^水解產生相應吡唑并嘧啶羧酸在步驟C中，藉由使化合物立與务基胺t反應進打酿胺偶合反應’獲得η比唾并痛咬醯胺化合物£’其為根據本發明之式I化合物。步驟C中之醢胺偶合可藉由以亞硫醯氣處理化合物4形成酸氯化物中間物 157102.doc -104· 201217379 進行，或可使用碳化二亞胺或其他醯胺偶合試劑實玉下文之流程B說明用於製備本發明化合物 -^7 一程序其中R為低碳烧基且Ar及R1及R2如本文所定義。In the step A of the step A, a cyclization reaction is carried out in which an aminopyrazole ester is reacted with an aminoenal compound hydrazine in the presence of a base to obtain a pyridylpyrimidinium ester compound 2. The reaction can be carried out in the presence of sodium hydride under polar aprotic solvents. In step B, the pyrazolopyrimidine ester is hydrolyzed to give the corresponding pyrazolopyrimidine carboxylic acid. In step C, the reaction is carried out by reacting the compound with the amine t to the amine coupling reaction. The guanamine compound is a compound of formula I according to the invention. The indole coupling in step C can be carried out by treating compound 4 with sulfite to form acid chloride intermediate 157102.doc -104· 201217379, or carbodiimide or other indole coupling reagent can be used. Scheme B illustrates a procedure for the preparation of a compound of the invention - wherein R is a lower carbon group and Ar and R1 and R2 are as defined herein.

流程B 在流程B之步驟A中，進行環化反應，其中以曱醯胺處理噻吩酯民，獲得侧氧基-噻吩并嘧啶化合物匕。在步驟8中以氧氯化磷或類似氯化試劑處理化合物h，獲得氣_嗟吩并喊咬化合物L。在步驟C中，氯-噻吩并嘧啶化合物藉由在催化劑存在下氫化進行還原性脫氣作用，形成噻吩并嘧啶化合物i。在步驟d中進行第一氧化，其中噻吩并嘧啶化合物i之甲基經氧化成醛，因此獲得噻吩并嘧啶羧醛化合物在步驟E中，對噻吩并嘧啶羧醛化合物匕進行第二氧化反應’獲得售吩并鳴π定缓酸化合物步驟E之氧化可在 157102.doc 201217379 亞氯酸納存在下利用例如胺基續酸。在步_中，化合物 m在醢胺偶合反騎以芳基心處理，獲得售吩并㈣酿胺化合物n’丨為根據本發明之式π化合物。此步驟中可使用如上文所述用於流程Α之各種醯胺偶合試劑。流程Α及流程Β之程序的許多變化為可能的且其本身將為熟習此項技術者所知1備本發明化合物之衫細節描述於下文之實例部分中。效用本發明化合物適用於治療寬泛範圍之發炎疾病及病狀，諸如關節炎，包括（但不限於）類風濕性關節炎、脊椎關節病、痛風性關節炎、骨關節炎、全身性紅斑性狼瘡症及幼年性關節炎、骨關節炎、痛風性關節炎及其他關節炎病狀。本發明化合物將適用於治療肺病症或肺部炎症，包括成人呼吸箸迫症候群、肺結節病、哮喘、料病、支氣管癌攣及慢性肺發炎疾病，包括慢性阻塞性肺病（c〇pD)。本發明化合物可進-步適用於治療發炎性腸病、多發性硬化症、糖尿病、肥胖症、過敏性疾病、牛皮癬、哮喘、移植排斥反應、癌症及敗血症。投藥及醫藥组合物本發明包括醫藥組合物，其包含至少—種本發明化合物或其個別異構體、異構體之外消旋或非外消旋混合物或醫藥學上可接受之鹽或溶劑合物，以及至少一種醫藥學上可接受之載劑，及視情況選用的其他治療及/或預防成分。一般而言，本發明化合物將以治療有效量藉由投與提供 157102.doc •106_ 201217379 類似效用之藥劑的任何可接受模式投藥。適合劑量範圍視多種因素而定且通常為每天^500 mg，較佳每天ιι〇〇 mg’且最佳每天i-30 mg，該等因素諸如待治療疾病之嚴重程度、個體之年齡及相對健康狀況、所用化合物之效能、投藥途徑及形式、投藥所針對之適應症及所涉及醫生之偏好及經驗。一般熟習治療該等疾病之技術者無需過多實驗且根據個人知識及本申請案之揭示内容即能夠確定本發明化合物用於指定疾病之治療有效量。本發明化合物可以醫藥調配物形式投與，包括適於經口 (包括經頰及舌下）、經直腸、經鼻、局部、經肺、經陰道或非經腸（包括肌肉内、動脈内、鞘内、皮下及靜脈内）投與或以適於藉由吸入或吹入投與之形式投藥的醫藥調配物。較佳投藥方式一般為使用可根據病痛程度調整之適宜每曰劑量方案經口投與。一或多種本發明化合物以及一或多種習知佐劑、載劑或稀釋劑可置於醫藥組合物及單位劑量之形式中。醫藥组合物及單位劑型可包含習知比例之習知成分，其中有或無其他活性化合物或成分，且單位劑型可含有與待採用之預期每日劑量範圍相符合的任何適合有效量之活性成分。醫藥組合物可以以下形式使用：固體，諸如錠劑或填充膠囊；半固體’散劑；持續釋放調配物；或液體，諸如經口服用之溶液、懸浮液、乳液、酏劑或填充膠囊；或用於直腸或陰道投與之㈣彳形式；或供非經腸使用之無g可注射溶液形式。每鍵劑含有約1 mg活性成分，或更廣泛而言約〇〇1 157102.doc 201217379 mg至約100 mg活性成分之調配物因此為合適的代表性單位劑型。本發明化合物可以多種經口投與劑型調配。醫藥組合物及劑型可包含-或多種本發明化合物或其醫藥學上可接受之鹽作為活性組分。醫藥學上可接受之載劑可為固體或：體。固體形式製劑包括散劑、鍵劑、藥丸、膠囊、扁膠劑、栓劑及可分散性顆粒。固體載劑可為一或多種亦可充當稀釋劑、調味劑、增溶劑、潤滑劑、懸浮劑、黏合劑、防腐劑m解劑或囊封材料之物f。在散劑中:载劑一般為細粉狀固體，其與細粉狀活性組分形成混合物。在錠劑中，活性組分-般與具有必要結合能力之載劑以合適比例忍合且壓製成所要形狀及尺寸。散劑及錠劑較佳含有約1%至約70%活性化合物。合適的載劑包括（但不限於）碳酸鎂、硬脂酸鎂、滑石粉、糖、乳糖、果膠、糊精、殿叙、明膠、黃蓍膠、甲基纖維素、缓甲基纖維素納、低溶點壤、可可脂及其類似載劑。術語「製劑」意欲包括以囊封材料作為載劑之活性化合物的調配物，提供其中活性組分（具有或不具有載劑）係由與其締合之載劑所圍繞的膠囊。類似地，亦包括扁膠劑及口含劑。錠劑、散劑、膠囊、藥丸、扁膠劑及口含劑可為適於經口投與之固體形式。適於經口投與之其他形式包括液體形式製劑，包括乳液、糖漿、酏劑、水溶液、水性懸浮液；或固體形式製劑，其意欲在即將使用前轉化成液體形式製劑。乳液可於 157102.doc •108· 201217379 例如丙二醇水溶液之溶液中製備且可含有例如㈣脂、脫水山梨糖醇單油酸酯或阿拉伯膠之乳化劑。水溶液可藉由將活性組分溶解於水令且添加適合著色劑'調味劑、穩定劑及增稠劑來製備。水性懸浮液可藉由將細粉狀活性組分分散於含有黏性材料之水中來製備，該黏性材料諸如天然或合成膠、樹脂、甲基纖維素、幾甲基纖維素納及其他熟知懸浮劑。固體形式製劑包括溶液、懸浮液及乳液，且除活性組分外亦可含有著色劑、調味劑、穩定劑、緩衝劑、人造及天然甜味劑、分散劑、增稠劑、增溶劑及其類似物。本發明化合物可經調配用於非經腸投與（例如藉由注射，例如快速注射或連續輸注）且可以含有附加防腐劑之安瓿、預填充注射器、小體積輸注或多劑量容器中之單位劑型呈現。組合物可採用諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式，例如於水性聚乙二醇中之溶液。油性或非水性載劑、稀釋劑、溶劑或媒劑之實例包括丙二醇、聚乙二醇、植物油（例如撖欖油）及可注射有機酯（例如油酸乙酯）’且可含有諸如防腐劑、濕潤劑、乳化劑或懸浮劑、穩定劑及/或分散劑之調配劑。或者，活性成分可為藉由無菌分離無菌固體或藉由自溶液凍乾獲得之粉末形式，其供在使用前以合適媒劑（例如無菌無熱原質水）復原。本發明化合物可經調配用於以軟膏、乳膏或洗劑形式或以經皮貼片形式向表皮局部投與。軟膏及乳膏可例如用水 157102.doc •109- 201217379 性或油性基質調配，其中添加合適增稠劑及/或膠凝劑。洗劑可用水性或油性基質調配且一般將亦含有一或多種乳化劑、穩定劑、分散劑、懸浮劑、增稠劑或著色劑。適於口腔局部投與之調配物包括口含劑，其包含於通常為蔗糖及阿拉伯膠或黃蓍膠之調味基質中之活性劑；片劑，其包含於諸如明膠及甘油或蔗糖及阿拉伯膠之惰性基質中之活性成分·’及漱口劑，其包含於合適液體載劑中之活性成分β 本發明化合物可經調配用於以栓劑形式投與。首先使諸如脂肪酸甘油醋之混合物或可可脂之低熔點蠟熔融且例如藉由攪拌均質地分散活性組分。接著將熔融均質混合物傾入適宜尺寸之模具中，使其冷卻且固化。本發明化合物可經調配用於陰道投與。除活性成分之外亦含有諸如此項技術中已知之載劑的子宮托、棉塞、乳膏、凝膠、糊劑、發泡體或喷霧為適當的。本發明化合物可經調配用於經鼻投與。溶液或懸浮液係藉由習知方式（例如用滴管、吸管或喷霧器）直接施用於鼻腔。調配物可以單劑量或多劑量形式提供。在後者滴管或吸管之狀況中，此可藉由投與患者適當預定體積之溶液或懸浮液來實現。在喷霧器狀況中，此可例如藉助於計量霧化喷射泵來實現。本發明化合物可經調配用於氣霧劑投與，尤其向呼吸道投與且包括鼻内投與。化合物一般將具有例如約5 μιη或5 μιη以下之小粒徑。該粒徑可藉由此項技術中已知之方式 157102.doc -110- 201217379 獲得，例如藉由微米尺寸化。活性成分於具有合適推進劑加墨包裝中提供’該推進劑為諸如氣氟碳化物（咖)(例如二氯二敗甲燒、三氣氟甲炫或二氣四貌乙烧）或二氧化碳或其他合適氣體。氣霧劑亦宜含有諸如印碟脂之界面活性劑。藥物劑量可由計量間控制。或者，活性成分可以乾粉形式提供’例如化合物於合適粉末基質中之粉末現合物，該粉末基質諸如乳糖、殿粉、搬粉衍生物（諸如經丙基甲基纖維素）及聚乙埽料咬（PVP)。粉末載劑將在鼻腔中形成凝膠。粉末組合物可以單位劑型呈現於例如明膠或發泡包裝之例如膠囊或藥筒令，粉末可藉助於吸入器自該等膠囊或藥筒投與。需要時，靠物可經製備成具有適於活性成分之持續或控制釋放投與的腸溶衣β舉例而言，本發明化合物可於經皮或皮下藥物傳遞裝置中調配。當必需化合物之持續釋放且當患者對治療方案之順應性極其重要時，此等傳遞系統為有利的。，經皮傳遞系、统中之&合物通常附著於皮膚黏著固體支撐物上。相關化合物亦可與例如Az〇ne(1_+二烷基氮雜環庚-2-酮）之滲透增強劑組合。持續釋放傳遞系統藉由手術或注射皮下插入至皮下層。皮下植入物將化合物囊封於脂質可溶膜（例如聚矽氧橡膠）或生物可降解聚合物（例如聚乳酸）十。醫藥製劑較佳呈單位劑型。在該形式中，製劑細分成含有適量活性組分之單位劑量。單位劑型可為包裝製劑，該包裝含有離散量之製劑，諸如封包錠劑、膠囊及於小瓶或 157102.doc •111· 201217379 安瓿中之散劑。單位劑型亦可為膠囊、錠劑、扁膠劑或口含劑本身，或其可為適當數目之包裝形式之此等單位劑型中的任一種。其他合適醫藥載劑及其調配物描述於77ϊβ 1995, E. W. Martin編， Mack Publishing Company，第 19版，Easton, Pennsylvania 中。下文描述含有本發明化合物之代表性醫藥調配物。【實施方式】實例提供以下製備及實例以使得熟習此項技術者能夠更清楚地理解本發明及實施本發明。其不應理解為限制本發明之範疇，而是僅具有說明性及代表性。除非另外說明，否則包括熔點（亦即MP)之所有溫度皆以攝氏度（°C)為單位。應瞭解產生所指示及/或所要產物之反應可不必直接由最初所添加之兩種試劑之組合產生，亦即，可存在在混合物中產生之一或多種中間物，其最終導致形成所指示及/或所要產物。在製備及實例中可使用以下縮寫。縮寫清單Scheme B In step A of Scheme B, a cyclization reaction is carried out in which a thiophene ester is treated with decylamine to obtain a pendant oxy-thienopyrimidine compound oxime. Compound b is treated with phosphorus oxychloride or a similar chlorinating reagent in step 8, to obtain a gas porphin and to bite compound L. In the step C, the chloro-thienopyrimidine compound is subjected to reductive degassing by hydrogenation in the presence of a catalyst to form a thienopyrimidine compound i. The first oxidation is carried out in step d, wherein the methyl group of the thienopyrimidine compound i is oxidized to an aldehyde, thereby obtaining a thienopyrimidinecarboxaldehyde compound, in step E, a second oxidation reaction of the thienopyrimidine carboxaldehyde compound oxime Oxidation of the step E of obtaining the phenoxy compound can be carried out using, for example, an amino acid in the presence of 157102.doc 201217379 sodium chlorite. In the step _, the compound m is treated with an aryl core in a guanamine coupling anti-riding, and the phenanthroline compound n' oxime is obtained as a compound of the formula π according to the present invention. Various guanamine coupling reagents for use in the process described above can be used in this step. Many variations of the procedures and procedures of the procedures are possible and will be known per se to those skilled in the art. The details of the preparation of the compounds of the present invention are described in the Examples section below. Utility The compounds of the invention are useful in the treatment of a wide range of inflammatory diseases and conditions, such as arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus Symptoms and juvenile arthritis, osteoarthritis, gouty arthritis and other conditions of arthritis. The compounds of the invention will be useful in the treatment of pulmonary conditions or pulmonary inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, disease, bronchial cancer and chronic pulmonary inflammatory diseases, including chronic obstructive pulmonary disease (c〇pD). The compounds of the present invention are further useful for the treatment of inflammatory bowel disease, multiple sclerosis, diabetes, obesity, allergic diseases, psoriasis, asthma, transplant rejection, cancer and sepsis. Administration and Pharmaceutical Compositions The present invention includes pharmaceutical compositions comprising at least one compound of the present invention or an individual isomer, isomer thereof, racemic or non-racemic mixture or pharmaceutically acceptable salt or solvent. And at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients. In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration of a medicament that provides a similar utility to 157102.doc • 106_ 201217379. The appropriate dosage range will depend on a number of factors and will usually be ^500 mg per day, preferably ιι〇〇mg' per day and optimally i-30 mg per day, such factors as the severity of the condition to be treated, the age and relative health of the individual. The condition, the efficacy of the compound used, the route and form of administration, the indications for which the drug is administered, and the preferences and experience of the doctor involved. Those skilled in the art of treating such diseases will be able to determine the therapeutically effective amount of the compounds of the present invention for a given condition without undue experimentation and based on the knowledge of the individual and the disclosure of the present application. The compounds of the invention may be administered in the form of a pharmaceutical formulation, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, Intrathecal, subcutaneous, and intravenous) are administered or formulated as a pharmaceutical formulation suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral administration according to the appropriate dosage regimen. One or more of the compounds of the invention and one or more conventional adjuvants, carriers or diluents can be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may contain conventional ingredients in the ordinary proportions, with or without other active compounds or ingredients, and the unit dosage form may contain any suitable effective amount of active ingredient in accordance with the intended daily dosage range to be employed. . The pharmaceutical composition may be used in the form of a solid such as a lozenge or a filled capsule; a semi-solid 'powder; a sustained release formulation; or a liquid, such as a solution, suspension, lotion, elixirs or capsules for oral use; or It is administered in the form of a rectal or vaginal (iv) sputum; or a g-injectable solution for parenteral use. The formulation containing about 1 mg of active ingredient per button, or more broadly, about 171 157102.doc 201217379 mg to about 100 mg of the active ingredient is therefore a suitable representative unit dosage form. The compounds of the invention may be formulated in a variety of oral dosage forms. The pharmaceutical compositions and dosage forms may comprise, as an active ingredient, one or more compounds of the invention or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable carrier can be a solid or a body. Solid form preparations include powders, binders, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more of a diluent, a flavoring agent, a solubilizing agent, a lubricant, a suspending agent, a binder, a preservative m decomposing agent or an encapsulating material. In powders: The carrier is typically a finely divided solid which forms a mixture with the finely divided active component. In the tablet, the active ingredient is normally combined with the carrier having the necessary binding ability in a suitable ratio and compressed into a desired shape and size. The powders and lozenges preferably contain from about 1% to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, dinosaur, gelatin, tragacanth, methylcellulose, slow methylcellulose. Nano, low solubility point, cocoa butter and similar carriers. The term "formulation" is intended to include a formulation of the active compound with the encapsulating material as a carrier, providing a capsule in which the active ingredient (with or without a carrier) is surrounded by a carrier associated therewith. Similarly, flat gels and buccal agents are also included. Tablets, powders, capsules, pills, cachets and buccals may be in a solid form suitable for oral administration. Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted into liquid form preparations immediately before use. The emulsion may be prepared in a solution of 157102.doc • 108· 201217379, such as an aqueous solution of propylene glycol, and may contain an emulsifier such as (iv) lipid, sorbitan monooleate or gum arabic. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable coloring agents, flavoring, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water containing a viscous material such as natural or synthetic gums, resins, methylcellulose, methylcellulose, and others. Suspending agent. Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents and analog. The compounds of the invention may be formulated for parenteral administration (for example by injection, such as bolus injection or continuous infusion) and may contain additional preservatives in ampoules, prefilled syringes, small volume infusions or unit dosage forms in multi-dose containers. Presented. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example, in aqueous polyethylene glycol. Examples of oily or non-aqueous vehicles, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg, eucalyptus oil), and injectable organic esters (eg, ethyl oleate) and may contain, for example, preservatives. , a humectant, an emulsifier or a suspending agent, a stabilizer and/or a dispersing agent. Alternatively, the active ingredient may be in the form of a powder obtained by sterile separation of sterile solids or by lyophilization from solution, which may be reconstituted with a suitable vehicle (for example, sterile pyrogen-free water) before use. The compounds of the invention may be formulated for topical administration to the epidermis in the form of an ointment, cream or lotion or in the form of a transdermal patch. Ointments and creams can be formulated, for example, with water or 157102.doc • 109- 201217379, or a suitable thickening agent and/or gelling agent. The lotion may be formulated with an aqueous or oily base and will generally contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents, thickening agents or coloring agents. Formulations suitable for topical administration to the oral cavity include buccal agents, which are included in the active ingredient in a flavoring base which is usually sucrose and gum arabic or tragacanth; tablets, which are included in, for example, gelatin and glycerin or sucrose and gum arabic Active ingredient in an inert matrix, and a mouthwash, which comprises the active ingredient in a suitable liquid carrier. The compound of the invention may be formulated for administration as a suppository. First, a mixture such as a mixture of fatty acid glycerin or a low melting wax of cocoa butter is melted and the active component is homogeneously dispersed, for example, by stirring. The molten homogeneous mixture is then poured into a mold of suitable size which is allowed to cool and solidify. The compounds of the invention may be formulated for vaginal administration. It is suitable to contain, in addition to the active ingredient, a pessary, tampons, cream, gel, paste, foam or spray, such as a carrier known in the art. The compounds of the invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means (e.g., using a dropper, pipette or spray). Formulations may be provided in single or multiple doses. In the case of the latter dropper or straw, this can be accomplished by administering a suitable predetermined volume of solution or suspension to the patient. In the case of a nebulizer, this can be achieved, for example, by means of a metered mist spray pump. The compounds of the invention may be formulated for aerosol administration, especially to the respiratory tract and include intranasal administration. The compound will generally have a small particle size of, for example, about 5 μηη or less. The particle size can be obtained by means known in the art 157102.doc - 110 - 201217379, for example by micron size. The active ingredient is provided in a suitable propellant ink refill package such that the propellant is, for example, a gas fluorocarbon (caffeine) (eg, dichlorohexamethoxazole, tris, or trigas) or carbon dioxide or Other suitable gases. The aerosol should also contain an interfacial activator such as a printing disc. The dose of the drug can be controlled by the metering. Alternatively, the active ingredient may be provided in the form of a dry powder such as a powder of the compound in a suitable powder base such as lactose, a powder, a powdered derivative (such as propylmethylcellulose) and a polyethylene Bite (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, e.g., in a gelatin or blister pack, such as a capsule or cartridge, from which the powder may be administered by means of an inhaler. If desired, the substrate can be prepared to have an enteric coating beta suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the invention can be formulated in a transdermal or subcutaneous drug delivery device. Such delivery systems are advantageous when sustained release of the essential compound is critical and the patient's compliance with the treatment regimen is extremely important. The transdermal delivery system, the <RTI ID=0.0> Related compounds can also be combined with permeation enhancers such as Az〇ne (1_+dialkylazepane-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. The subcutaneous implant encapsulates the compound in a lipid soluble membrane (e.g., polyoxyxene rubber) or a biodegradable polymer (e.g., polylactic acid). The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a package preparation containing discrete quantities of preparation such as a packaged lozenge, capsules, and powder in a vial or 157102.doc •111· 201217379 ampoules. The unit dosage form can also be a capsule, lozenge, troche or the granule itself, or it can be any one of these unit dosage forms in a suitable number of packages. Other suitable pharmaceutical carriers and their formulations are described in 77 ϊ β 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the invention are described below. [Examples] The following preparations and examples are provided to enable those skilled in the art to understand the invention and practice the invention. It is not intended to limit the scope of the invention, but is merely illustrative and representative. Unless otherwise stated, all temperatures including the melting point (i.e., MP) are in degrees Celsius (°C). It will be appreciated that the reaction to produce the indicated and/or desired product may not necessarily result from the combination of the two agents initially added, i.e., one or more intermediates may be present in the mixture which ultimately result in the formation of the indicated / or the desired product. The following abbreviations can be used in the preparation and examples. Abbreviated list

AcOH 乙酸 AIBN 2,2'-偶氮雙（2-甲基丙腈）AcOH acetic acid AIBN 2,2'-azobis(2-methylpropionitrile)

Atm. 大氣壓 (boc)2o 二碳酸二第三丁酯 DCM 二氣曱烷 157102.doc -112- 201217379Atm. Atmospheric pressure (boc) 2o di-tert-butyl dicarbonate DCM dioxane 157102.doc -112- 201217379

DIAD DIPEA DMAP DME DMF DMSO Et20 EtOH EtO.Ac HBTUDIAD DIPEA DMAP DME DMF DMSO Et20 EtOH EtO.Ac HBTU

HOBT HPLC i-PrOH MeOH MW NBS NMP PSI RT TBDMS TFA THF TLC 偶氮二甲酸二異丙醋二異丙基乙胺 4-二甲基胺基《比啶 1，2-二曱氧基乙烷 N，N-二曱基曱醯胺二曱亞砜乙乙醇乙酸乙酯六氟磷酸0-苯并三唑-1-基-N，N，N’，N’-四曱錄 1-羥基苯并三唑高壓液相層析法異丙醇甲醇微波 N-溴代丁二醢亞胺 1-甲基-2-吡咯啶酮磅/平方吋室溫第三丁基二曱基矽烷基三氟乙酸四氫呋喃薄層層析法 157102.doc -113 - 201217379 製備1 :合成6-甲醢基-吡唑并丨jjj】嘧啶_3_甲酸根據流程1中所示之方法合成6_甲醯基_吡唑并。，^…嘧咬-3 -甲酸。HOBT HPLC i-PrOH MeOH MW NBS NMP PSI RT TBDMS TFA THF TLC azodicarboxylic acid diisopropyl acetonate diisopropylethylamine 4-dimethylamino "pyridyl 1,2-dimethoxyethane N , N-dimercaptoamine disulfoxide, ethyl alcohol ethyl acetate, hexafluorophosphate, 0-benzotriazol-1-yl-N, N, N', N'-tetrazole, 1-hydroxybenzo Triazole High Pressure Liquid Chromatography Isopropanol Methanol Microwave N-Bromobutadienimide 1-Methyl-2-pyrrolidone Pounds per square 吋 Room Temperature Tributyl Dimercaptoalkyl Trifluoroacetic Acid Tetrahydrofuran thin layer chromatography 157102.doc -113 - 201217379 Preparation 1: Synthesis of 6-mercapto-pyrazolozolidine jjj]pyrimidine_3_carboxylic acid 6-methylmercapto-pyridyl according to the method shown in Scheme 1 Azole. , ^... pyrimidine bite-3 - formic acid.

流程1 在至溫下擾拌3-胺基〇比唾_4_甲酸（1〇〇 mg，0.787 mmol) 及2- —曱基胺基亞甲基-丙二越（办《^/765^ 1989 (11)，856- 860)(100 mg ’ 〇,787 mmol)於鹽酸水溶液（6 μ，2 mL)中之混合物30分鐘；所得混合物在9〇°c下加熱2小時，接著在室溫下攪拌64小時。藉由過濾收集所形成之固體，以水、甲醇及乙醚洗滌兩次’在真空烘箱中乾燥，未經進一步純化即獲得75 mg(50%產率）呈淺棕色固體形式之6_曱醯基_ °比唑并[1,5-α]嘧啶-3-甲酸。製備2.合成2-[4-(第三丁基-二甲基-矽烷基氧基）_環己基氧基】-5-氣-苯胺根據流程2中所示之方法合成2-[4-(第三丁基-二甲基_石夕烷基氧基）-環己基氧基]-5-氣·苯胺。Procedure 1 Dissipate 3-aminopyrene at a temperature to salivary _4_carboxylic acid (1 〇〇 mg, 0.787 mmol) and 2- fluorenylaminomethylene-propanoid ("^/765^ 1989 (11), 856-860) (100 mg '〇, 787 mmol) in a mixture of aqueous hydrochloric acid (6 μ, 2 mL) for 30 min; the mixture was heated at 9 ° C for 2 h, then at room temperature Stir under 64 hours. The solid formed was collected by filtration, washed twice with water, methanol and diethyl ether. <"&&&&&&&&&&&&&&&&&& _ °Bizozolo[1,5-α]pyrimidine-3-carboxylic acid. Preparation 2. Synthesis of 2-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-5-gas-aniline 2-(4-) was synthesized according to the method shown in Scheme 2. (Third butyl-dimethyl-oxacyloxy)-cyclohexyloxy]-5-a gas aniline.

流程2 157102.doc 114· 201217379 步驟A:合成4-(第三丁基-二甲基_矽烷基氧基）_環己醇在0C下，向1,4-環己二醇（i〇 g，86 mmol)及咪η坐（1 5 g ’ 22·0 mmol)於無水四氫呋喃（5 mL)中之溶液中逐滴添加第二丁基二甲基矽烷基氣（1.5 g，9.9 mmol)於無水jv，#·二甲基甲醯胺（5 mL)中之溶液。添加完成後，添加鹽水，且以乙酸乙酯萃取所得混合物3次。以水及鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。在矽膠柱塞（己烷/EtOAc，80/20)上純化粗殘餘物，獲得j 3 鲁 g(66%產率）呈無色油狀之4-(第三丁基-二甲基-矽烷基氧基）-環己醇》步称B.合成第二丁基_【4-(4-氣-2-硝基-苯氧基）_環己基氧基】·二甲基-矽烷在 0 C 下，向 4-氣-2-硝基苯酚（0.75 g，4.32 mmol)、4- (第二丁基-二曱基·石夕烧基氧基）_環己醇U 2 g，5 21 及二笨膦（2.27 g，8.65 mmol)於無水四氫吱味〇〇 mL)中之溶液中逐滴添加偶氮二曱酸二異丙酯（1.65 g，&16 mm〇l) 籲於無水四氫呋喃（5 mL)中之溶液》所得混合物在〇〇c下攪拌1小時，且在室溫下攪拌隔夜。反應混合物接著在室溫下音波處理20分鐘，且在40°C下音波處理3〇分鐘，接著在室溫下攪拌24小時。減壓蒸發溶劑’且使殘餘物分配於乙酸乙酯與碳酸氫鈉水溶液（5%)之間，分離有機層，且以乙酸乙酯萃取水層3次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥’過濾且減壓蒸發。在石夕膠柱塞（己烧/ EtOAc，99/1至90/10)上純化黃色油性殘餘物，獲得黃色油 157102.doc -115· 201217379 狀物。將此物質溶解於乙酸乙酷與己院之混合物〇⑴中，且所得溶液以氫氧化鈉水溶液（3 M)洗滌兩次且以鹽水洗滌一次，經無水硫酸納乾燥，過濾且減壓蒸發，獲得ι 28 g(所。產率）呈淺黃色油狀之第三丁基如⑷氣·2石肖基苯氧基）-環己基氧基]_二甲基_石夕统。步驟C :合成2_[4_(第三丁基·二甲基-矽烷基氧基)環己基氧基]-5-氣·苯胺向第三丁基-[4-(4-氯-2-硝基-苯氧基）·環己基氧基]_二甲基-矽烷（1.28 g，3.32 mm〇i)於乙醇與乙酸乙酯之混合物 (1/1，40 mL)中之溶液中添加氯化亞錫（3 2 g，16% mmol)，且在室溫下攪拌所得混合物24小時。添加冰及碳酸氫鈉水溶液（5%，15〇 mL)，且過濾所形成之固體，以乙酸乙酯洗滌且丟棄》分離濾液層且以乙酸乙酯萃取水層3 次。經合併之有機萃取物以鹽水洗滌，經無水硫酸鈉乾燥，經由CELITE μ塾過濾且減塵蒸發。藉由急驟層析法 (EtOAc/己烷，5/95至80/20)純化黃色油性殘餘物，獲得〇5 g(42%產率）呈黃色油狀之2-[4-(第三丁基-二甲基·矽烷基氧基）-環己基氧基]-5-氣-苯胺及803 mg( 16%產率）4-(2-胺基· 4-氯-苯氧基）-環己醇。利用適當起始物質及上述程序，製備以下化合物：廢-2-[4-(第三丁基-二甲基-矽烷基氧基環己基氧基卜 5 -氣-苯胺；及-2-[4-(第三丁基-二甲基-矽烷基氧基）_環己基氧基]_ 5 -氣-苯胺； 157102.doc 116- 201217379 2- [3-(第三丁基-二甲基-石夕炫基氧基）-環戊基氧基]_5_ 氯-苯胺； 3- (6-胺基·喹啉-7-基氧基）-3-曱基-丁-1-醇（步驟B及步驟C); 3_(2-胺基-4-氯-苯氧基）-3-甲基-丁-1-醇（步驟B及步驟 C); 5-氯-2-環己基氧基-苯胺（步驟B及步驟C); 5-氣-2-異丙氧基-苯胺（步驟B及步驟C); φ 5-氣-2-((S)-2,2-二甲基-[1，3]二氧戊環-4-基甲氧基）-苯胺（步驟B及步驟C); 5-氣-2-((R)-2,2-二甲基-[1，3]二氧戊環-4-基甲氧基）-苯胺（步驟B及步驟C); [3-(2-胺基-4-氣-苯氧基）-環戊基]·甲醇（步驟B及步驟 C); 3-(2-胺基-4-氯-苯氧基）-環己醇（步驟B及步驟C); 1-(2-胺基-4-氣-苯基）-°比咯啶-3-醇（步驟B及步驟C); • - 2-[3-(第三丁基-二曱基-矽烷基氧基）_丙氧基]_5·氣-苯胺； -2-[2-(第三丁基-二甲基-矽烷基氧基）_乙氧基]-5·氣-苯胺； [4-(2-胺基-4-氣-苯氧基）-環己基]-胺基曱酸第三丁酯 (步驟B及步驟C); 5-氯_2-[2-(2,2-二甲基-[1，3]二氧戊環-4·基）-乙氧基]· 苯胺（步驟B及步驟C);及 157102.doc -117- 201217379 4-(2-胺基-笨氧基）-環己醇（步驟b及步驟c)。製備3:合成4-胺基-3-甲氧基-苯甲酸甲酯根據流程3中所示之方法，合成4_胺基_3_曱氧基-苯曱酸甲酯。Scheme 2 157102.doc 114· 201217379 Step A: Synthesis of 4-(t-butyl-dimethyl-decyloxy)-cyclohexanol at 0 C to 1,4-cyclohexanediol (i〇g , </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; A solution of anhydrous jv, #. dimethylformamide (5 mL). After the addition was completed, brine was added, and the resulting mixture was extracted with ethyl acetate three times. The combined organic extracts were washed with EtOAcq. The crude residue was purified on EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) Oxy)-cyclohexanol. Step B. Synthesis of the second butyl group [4-(4-Ga-2-nitro-phenoxy)-cyclohexyloxy] dimethyl-decane at 0 C Next, to 4-gas-2-nitrophenol (0.75 g, 4.32 mmol), 4-(t-butyl-diindenyl oxalyloxy)-cyclohexanol U 2 g, 5 21 and Diisopropylphosphonium diisopropylate (1.65 g, & 16 mm〇l) was added dropwise to a solution of diphenylphosphine (2.27 g, 8.65 mmol) in anhydrous tetrahydromethane (mL). The resulting mixture in tetrahydrofuran (5 mL) was stirred at EtOAc for 1 hour and stirred at room temperature overnight. The reaction mixture was then sonicated for 20 minutes at room temperature and sonicated at 40 °C for 3 minutes, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (5%). The combined organic extracts were washed with brine, dried over anhydrous sodium The yellow oily residue was purified on EtOAc (EtOAc/EtOAc:EtOAc:EtOAc This material was dissolved in a mixture of acetonitrile and hexanes (1), and the solution was washed twice with aqueous sodium hydroxide (3 M) and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The butyl 28 g (yield) was obtained as a pale yellow oil in the form of a tributyl group, for example, (4) gas, <RTI ID=0.0>>> Step C: Synthesis of 2_[4_(t-butyl-dimethyl-decyloxy)cyclohexyloxy]-5-gas·aniline to the third butyl-[4-(4-chloro-2-nitrate) Chloro-phenoxy)cyclohexyloxy]-dimethyl-nonane (1.28 g, 3.32 mm 〇i) is added to a solution of a mixture of ethanol and ethyl acetate (1/1, 40 mL). Stannous (3 2 g, 16% mmol), and the resulting mixture was stirred at room temperature for 24 hours. An ice and a sodium hydrogencarbonate aqueous solution (5%, 15 mL) were added, and the solid formed was filtered, washed with ethyl acetate and evaporated to separate the filtrate layer and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate Purification of the yellow oily residue by flash chromatography (EtOAc / hexanes: 5/95 to 80/20) -Methyl-decyloxy)-cyclohexyloxy]-5-a-aniline and 803 mg (16% yield) of 4-(2-amino-4-chloro-phenoxy)-cyclo Hexanol. The following compounds were prepared using the appropriate starting materials and the above procedure: Waste-2-[4-(t-butyl-dimethyl-decyloxycyclohexyloxybu 5- gas-aniline; and -2-[ 4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-5-a-aniline; 157102.doc 116- 201217379 2- [3-(t-butyl-dimethyl - Shi Xi Xuan oxy)-cyclopentyloxy]_5_ chloro-aniline; 3-(6-amino quinolin-7-yloxy)-3-indolyl-butan-1-ol (step B and Step C); 3-(2-Amino-4-chloro-phenoxy)-3-methyl-butan-1-ol (Step B and Step C); 5-Chloro-2-cyclohexyloxy - aniline (Step B and Step C); 5-Gas-2-isopropoxy-aniline (Step B and Step C); φ 5-Gas-2-((S)-2,2-dimethyl- [1,3]dioxolan-4-ylmethoxy)-phenylamine (Step B and Step C); 5-Gas-2-((R)-2,2-dimethyl-[1,3 Dioxol-4-ylmethoxy)-aniline (Step B and Step C); [3-(2-Amino-4- methoxy-phenoxy)-cyclopentyl]·Methanol (Step B And Step C); 3-(2-Amino-4-chloro-phenoxy)-cyclohexanol (Step B and Step C); 1-(2-Amino-4-Gayl-phenyl)-° Bilpyridin-3-ol (steps B and C); • 2-[3-(t-butyl-didecyl-decyloxy)-propoxy]_5·gas-aniline; -2-[2-(t-butyl-dimethyl-decane)氧基oxy)-ethoxy]-5-gas-aniline; [4-(2-amino-4- oxo-phenoxy)-cyclohexyl]-amino decanoic acid tert-butyl ester (step B and Step C); 5-Chloro-2-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-aniline (Steps B and C) And 157102.doc -117- 201217379 4-(2-Amino-indolyl)-cyclohexanol (Steps b and c). Preparation 3: Synthesis of 4-amino-3-methoxy-benzoic acid The methyl ester was synthesized according to the procedure shown in Scheme 3 to give methyl 4-amino-3-methoxy-benzoate.

COOMe COOMe 流程3 步琢A:合成3-甲氧基-4-確基_苯甲酸曱酯向3 -曱氧基-4-硝基苯甲酸（1〇 g，5.07 mmol)於無水甲醇（15 mL)中之懸浮液中添加三氟化硼合二乙醚（2 mL， 16.3 mmol) ’且在回流下加熱所得混合物24小時。減壓蒸發溶劑且使殘餘物分配於水與二氣甲烷之間；以二氣甲烷萃取水層3次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。經矽膠柱塞（Et〇Ac/己烷，40/60至50/50) 純化殘餘物’獲得1.09 g呈淺黃色固體形式之3_甲氧基_4_ 硝基-苯甲酸曱酯》步驟B:合成4-胺基-3-甲氧基-苯甲酸甲酯向3-甲氧基-4-硝基-苯甲酸甲酯（1_08 g，5.u mm〇1)於甲醇（40 mL)與二氯甲烷（數滴）之混合物中之溶液中添加把/ 碳（10°/。，催化量）。在氮氣氛圍（氣球壓力）下攪拌所得混合物隔夜。在CELITEtm墊上濾出催化劑且蒸發溶劑，獲得 157102.doc • 118· 201217379 0.929 g呈黃色固體瑕形式之4-胺基-3-甲氧基·苯甲酸甲酯。利用上述程序；5、A也上 ^ 次適當起始物質，還原3-甲氧基-4-硝基· i^基·笨曱酿胺’獲得4-胺基·3·甲氧基善苯基-笨曱酿胺。製備4 ·合成4-(第三丁基二甲基矽烷基氧基甲基甲氧基-苯胺根據流程4中所示之方法，合成4 (第三丁基_二甲基、石夕烷基氧基甲基）-2-甲氧基_苯胺。COOMe COOMe Scheme 3 Step A: Synthesis of 3-methoxy-4-decyl benzoic acid oxime ester to 3-methoxy-4-nitrobenzoic acid (1 〇g, 5.07 mmol) in anhydrous methanol (15 To the suspension in mL) was added boron trifluoride diethyl ether (2 mL, 16.3 mmol) and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water and dichloromethane. The combined organic extracts were dried with anhydrous sodium sulfate. Purification of the residue by a ruthenium plunger (Et 〇Ac / hexanes, 40/60 to 50/50) to obtain 1.09 g of 3-methoxy_4_nitro-benzoic acid ester as a pale yellow solid. Step B : Synthesis of 4-amino-3-methoxy-benzoic acid methyl ester to methyl 3-methoxy-4-nitro-benzoate (1_08 g, 5.u mm〇1) in methanol (40 mL) Add / carbon (10 ° /., catalytic amount) to the solution in a mixture with dichloromethane (several drops). The resulting mixture was stirred overnight under a nitrogen atmosphere (balloon pressure). The catalyst was filtered off on a pad of CELITEtm and solvent was evaporated to afford 157102.doc: 118·201217379 0.929 g as a yellow solid, 4-amino-3-methoxy-benzoic acid methyl ester. Using the above procedure; 5, A also appropriate appropriate starting material, reduction of 3-methoxy-4-nitro·i^yl· abbreviated amine' to obtain 4-amino-3·methoxy benzene Base - awkwardly brewed amine. Preparation 4 · Synthesis of 4-(t-butyldimethylsilyloxymethylmethoxy-aniline) According to the procedure shown in Scheme 4, synthesis 4 (t-butyl-dimethyl, oxalate Oxymethyl)-2-methoxy-phenylamine.

流程4Process 4

步驟A:合成第三丁基_(3_甲氧基_4硝基苯甲氧基）二甲基-矽烷向2曱氧基-4-硝基苯甲醇（i_〇 g, 5.46 mmol)及味唾（〇.9 g，13.2 mmol)於無水二氣曱烷（15 mL)中之溶液中添加第二丁基二甲基矽烷基氣（〇·9 g’ 5.97 mmol)，且在室溫下授拌所得混合物隔夜。接著使反應混合物分配於水與二氣甲烷之間，分離有機層，且以二氯甲烷萃取水層3次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。在石夕膠柱塞（己烷/EtOAc，80/20)上純化粗殘餘物，獲得丨58 g(97%產率）呈淺黃色固體形式之第三丁基（3•甲氧基心硝 157102.doc -119- 201217379 基-本曱氧基）-二甲基_碎烧。步驟B. p成4-(第三丁基_二甲基_矽烷基氧基甲基甲氧基-苯胺 -藉由如裝備3步驟B中所述之氫化，還原第三丁基_(3·甲氧基-4-硝基-苯甲氧基）_二甲基_錢獲得4(第三丁基_ 二甲基-矽烷基氧基甲基）_2_曱氧基_笨胺。製備5:合成3-甲氧基-聯苯_4_基胺根據流程5中所示之方法，合成3_甲氧基_聯苯冬基胺。Step A: Synthesis of tert-butyl-(3-methoxy-4-nitrobenzyloxy)dimethyl-decane to 2-methoxy-4-nitrobenzyl alcohol (i_〇g, 5.46 mmol) Add a second butyl dimethyl hydrazine gas (〇·9 g' 5.97 mmol) to a solution of sulphur (〇.9 g, 13.2 mmol) in anhydrous dioxane (15 mL), and in the room The mixture was mixed overnight and warmed overnight. The reaction mixture was then partitioned between water and dioxane, the organic layer was separated, and the aqueous layer was extracted three times with dichloromethane. The combined organic extracts were dried with anhydrous sodium The crude residue was purified on EtOAc (EtOAc/EtOAcEtOAcEtOAcEtOAc 157102.doc -119- 201217379 --N-methoxy)-dimethyl-crushed. Step B. p to 4-(t-butyl-dimethyl-decyloxymethylmethoxy-aniline - reduction of the third butyl group by hydrogenation as described in Apparatus 3, Step B • Methoxy-4-nitro-benzyloxy)-dimethyl-methanol affords 4 (t-butyl-dimethyl-decyloxymethyl)_2-decyloxy-p-amine. 5: Synthesis of 3-methoxy-biphenyl-4-ylamine According to the procedure shown in Scheme 5, 3-methoxy-biphenylmethyleneamine was synthesized.

流程5 步驟A:合成3-甲氧基-4-硝基-聯苯在0°C下’向5-氣-2-硝基苯甲_(〇·5 g，2.66 mmol)、苯基自朋酸（0·42 g，3.44 mmol)、雙（二苯亞甲基丙酮）鈀（47 mg，0.082 mmol)、氯化1，3-雙（2,6-二異丙基苯基）0米唑鑌 (35 mg，0.082 mmol)及溴化四丁基銨（86 mg，0.267 mmol) 於無水甲苯（20 mL)中之混合物中添加曱醇鉀（〇 56 g，7.98 mmol)於無水甲醇（5 mL)中之溶液。反應混合物在6〇°c下攪拌24小時，接著分配於乙酸乙酯與水之間《分離有機層且以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。在 157102.doc •120· 201217379 碎膠柱塞（EtOAc/己烷，20/80)上純化粗殘餘物，獲得0.7 g 呈黃色油狀之3-甲氧基-4-硝基-聯苯。步称B:合成3-甲氧基·聯苯-4-基胺藉由如製備3步驟B中所述之氫化，還原3_曱氧基_4-硝基-聯苯’獲得3-曱氧基-聯苯-4-基胺。利用適當起始物質及上述程序合成4_氣·聯苯_2_基胺，如製備9步驟D中所述在氯化亞錫存在下進行還原步驟。製備6 ·合成6-胺甲酿基_吼吐并[ι，5-α】鳴咬_3-甲酸根據流程6中所示之方法合成6-胺甲醯基-吡唑并[15^] 嘧啶-3-甲酸。Scheme 5 Step A: Synthesis of 3-methoxy-4-nitro-biphenyl at 0 ° C 'to 5-gas-2-nitrobenzamide (〇·5 g, 2.66 mmol), phenyl self Phenic acid (0·42 g, 3.44 mmol), bis(dibenzylideneacetone)palladium (47 mg, 0.082 mmol), 1,3-bis(2,6-diisopropylphenyl) chloride Potassium steroxide (〇56 g, 7.98 mmol) in anhydrous methanol was added to a mixture of carbazol (35 mg, 0.082 mmol) and tetrabutylammonium bromide (86 mg, 0.267 mmol) in anhydrous toluene (20 mL) Solution in (5 mL). The reaction mixture was stirred at 6 ° C for 24 hr then EtOAc (EtOAc)EtOAc. The crude residue was purified on EtOAc EtOAc EtOAc EtOAc (EtOAc) Step B: Synthesis of 3-methoxy-biphenyl-4-ylamine by reduction of 3-methoxyl_4-nitro-biphenyl as obtained by the hydrogenation as described in Preparation 3, Step B Oxy-biphenyl-4-ylamine. The 4_gas·biphenyl-2-amine is synthesized using a suitable starting material and the above procedure, and the reduction step is carried out in the presence of stannous chloride as described in Preparation 9, Step D. Preparation 6 · Synthesis of 6-amine methyl ketone _ 吼并 and [ι, 5-α] 咬 bit _3-carboxylic acid according to the method shown in Scheme 6 to synthesize 6-amine carbazino-pyrazole [15^] Pyrimidine-3-carboxylic acid.

流程6 步驟A:合成6·氰基_吡唑并[15α】嘧啶_3甲酸乙酯 • 在〇C下’向3 -胺基比。坐_4_曱酸乙醋（〇9 g，5.8 mmol)及3-二曱基胺基_2_甲醯基-丙烯腈（〇 72 g，5 8 mmol)於無水四氫呋喃（3〇 mL)中之混合物中添加氫化鈉 (礦物油中60〇/〇分散液，0.52 g，13.0 mm〇l)，且攪拌反應混合物隔夜，同時升溫至室溫。添加冰-水，且使所得混合物分配於水與乙酸乙酯之間；分離有機層且以乙酸乙酯萃取水層3次。合併之有機萃取物以鹽水洗滌，經無水硫酸鈉乾燥，過濾且蒸發。在矽膠柱塞（Et〇Ac/己烷）上純化 157102.doc •121- 201217379 兴色粗殘餘物兩次，獲得〇·4 g(32%產率）6-氰基-吡唑并 [1，5-α]嘧啶_3_曱酸乙酯。步驟Β:合成6-胺甲醢基吡唑并【lsm】嘧啶_3_甲酸向6-氰基比唑并嘧啶3-曱酸乙酯（〇35 mg，1.62 mmol)於乙醇（5 mL)中之懸浮液中添加氫氧化鈉水溶液 (10 /。，5 mL)，且反應混合物在6〇它下加熱5小時。添加冰水’且藉由添加鹽酸水溶液（3 M)酸化所得混合物直至 pH< 1藉由過濾收集析出之固體，以水、曱醇及乙醚洗滌兩人減壓乾燥，獲得0.25 g(75%產率）6-胺甲醯基-吡唑并Π，5-α]嘴咬_3_曱酸。製備7 :合成2_甲氧基_苯_1，3_二胺根據流程7中所示之方法，合成2-甲氧基-苯_U-二胺。Scheme 6 Step A: Synthesis of 6·cyano-pyrazolo[15α]pyrimidine-3-carboxylate ethyl ester • Under 〇C to 3-aminol ratio. _4_ 曱乙乙〇〇〇〇 g 〇〇〇〇〇 g g g g g g g _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Sodium hydride (60 〇/〇 dispersion in mineral oil, 0.52 g, 13.0 mm 〇l) was added to the mixture, and the reaction mixture was stirred overnight while warming to room temperature. Ice-water was added, and the resulting mixture was partitioned between water and ethyl acetate; organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate. Purification on a silica gel plunger (Et〇Ac/hexane) 157102.doc •121-201217379 The crude residue was colored twice to obtain 〇·4 g (32% yield) of 6-cyano-pyrazole[1] , 5-α]pyrimidine _3_ decanoic acid ethyl ester. Step Β: Synthesis of 6-amine-methylpyridylpyrazole and [lsm]pyrimidine_3_carboxylic acid to 6-cyanopyrazolopyrimidine 3-decanoic acid ethyl ester (〇35 mg, 1.62 mmol) in ethanol (5 mL) An aqueous sodium hydroxide solution (10 /., 5 mL) was added to the suspension, and the mixture was heated under 6 Torr for 5 hours. Add ice water' and acidify the resulting mixture by adding aqueous hydrochloric acid (3 M) until pH <1. The precipitated solid was collected by filtration, and washed with water, methanol and diethyl ether under reduced pressure to obtain 0.25 g (75% yield) Rate) 6-Aminomethylmercapto-pyrazoloindole, 5-α] mouth biting _3_decanoic acid. Preparation 7: Synthesis of 2-methoxy-benzene-1,3-diamine According to the procedure shown in Scheme 7, 2-methoxy-benzene-U-diamine was synthesized.

流程7Process 7

OMe nh2 步驟A:合成2_甲氧基_1>3_二確基苯向3 2-氣-2,3-二石肖基苯（3 26 g)於無水甲醇（3〇叫中之 L浮液中添加甲醇鈉於甲醇中之溶液（25% ’ 2 Μ mL)，且 =室/皿下授拌所得混合物隔夜。藉由過濾收集所形成之淺 κ色固體’未經進一步純化即獲得^μ自I甲氧基-二頌基-苯。步琢B:合成2_甲氧基苯_13二胺 157102.doc 201217379 在氫氣氛圍（1大氣壓）下攪拌2-甲氧基_ι，3_二硝基-苯 (1.49 g)及把/碳（1〇。/0’ 15〇 mg)於乙醇（75 mL)中之混合物隔夜。在CELITEtm墊上濾出催化劑，且以乙醇洗滌濾餅。減壓蒸發濾液’未經進一步純化即獲得丨.1 g呈淺黃色固體形式之2-甲氧基-笨·二胺。製備8 :合成3-(3-胺基-2-哌啶_1_基-苯基胺基丙_1_醇根據流程8中所示之方法，合成3_(3_胺基·2_哌啶_丨_基_ 苯基胺基）-丙-1-醇。OMe nh2 Step A: Synthesis of 2_methoxy_1>3_di- benzene to 3 2-gas-2,3-distone succinylbenzene (3 26 g) in anhydrous methanol (3 〇中中 L float A solution of sodium methoxide in methanol (25% '2 Μ mL) was added, and the resulting mixture was stirred overnight at room/dish. The resulting pale-kappa solid was collected by filtration and was obtained without further purification. From Imethoxy-didecyl-benzene. Step B: Synthesis of 2-methoxybenzene_13 diamine 157102.doc 201217379 Stirring 2-methoxyl under hydrogen atmosphere (1 atm), 3_ Dinitro-benzene (1.49 g) and a mixture of / carbon (1 〇. / 0' 15 〇 mg) in ethanol (75 mL) overnight. The catalyst was filtered off on a CELITEtm pad and the filter cake was washed with ethanol. The pressure-evaporated filtrate was obtained without further purification to obtain 0.1 g of 2-methoxy-stupolediamine as a pale yellow solid. Preparation 8: Synthesis of 3-(3-amino-2-piperidine_1_ The phenyl-phenylaminopropan-1-ol was synthesized according to the procedure shown in Scheme 8 to give 3-(3-amino-2-piperidin-yl-phenylamino)-propan-1-ol.

流程8Process 8

步驟A :合成1-(2,6-二硝基-苯基哌啶向2-氣-2,3-二硝基苯（2.〇 g ’ 9.87 mmol)於無水二氯甲烷 (80 mL)中之溶液中添加哌啶u 96 mL，19.75 mmol)，且授拌反應混合物2小時。減壓蒸發溶劑，且以水洗務燈色固體殘餘物’在乾燥後且未經進一步純化即獲得2.31 ^呈淺橙色固體形式之1-(2,6-二硝基··苯基哌啶。步驟B:合成2-哌啶-1·基-苯_ι，3_二胺在氫氣氛圍（1大氣壓）下，在室溫下，攪拌卜(2,6-二硝基-笨基）-哌啶（2.31 g)及鈀/碳（10〇/〇，23〇 mg)於乙醇（8〇 mL)中之混合物40小時。在ceutetm墊上濾出催化劑。減壓蒸發滤液且藉由急驟層析法（己烷/Et〇Ac，80/2〇)純化殘 157102.doc -123- 201217379 餘物，未經進一步純化即獲得1.29 g呈橙色固體形式之2-哌啶-1-基-苯-1，3-二胺。利用上述程序及適當起始物質，製備以下化合物： -[1-(2,6-二胺基-苯基）-哌啶-4-基甲基]-胺基曱酸第三丁酯；及 _ 5-氣-2-娘咬-1-基-苯胺。步驟C :合成3-(3-胺基-2-哌啶-1-基_苯基胺基卜丙-丨·醇向 2-n底咬-1-基-苯-1，3-二胺（300 mg，1_57 mmol)於 7v，;y_ 二曱基曱醯胺（4 mL)中之溶液中添加氫化鈉（礦物油中之 60%懸浮液’ 63 mg，1.57 mmol)，隨後添加3-溴-1-丙醇 (0· 14 mL，1.57 mmol)，且反應混合物在60°C下搜拌隔夜。所得混合物接著以乙酸乙酯（150 mL)萃取，且有機層以水（80 mL)洗滌兩次且以鹽水（80 mL)洗滌一次，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己燒 /EtOAc，60/40)純化粗殘餘物，獲得22 mg 3-(3-胺基·2·哌啶-1-基-苯基胺基）·丙-卜醇。利用上述程序及適當起始物質製備2-(3-胺基-2-哌咬基-苯基胺基）-乙醇。製備9 :合成4-胺基-2-氣-5-甲氧基-iV-苯基-苯甲醯胺根據流程9中所示之方法合成4-胺基-2-氯-5-甲氧基笨基-苯甲醜胺。 157102.doc •124· 201217379Step A: Synthesis of 1-(2,6-dinitro-phenylpiperidine to 2- gas-2,3-dinitrobenzene (2. 〇g ' 9.87 mmol) in anhydrous dichloromethane (80 mL) Piperidine u 96 mL, 19.75 mmol) was added to the solution and the reaction mixture was stirred for 2 hours. Evaporation of the solvent <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Step B: Synthesis of 2-piperidin-1·yl-benzene-ι, 3-diamine under a hydrogen atmosphere (1 atm), stirring at room temperature (2,6-dinitro-phenyl) Mixture of piperidine (2.31 g) and palladium on carbon (10 〇 / 〇, 23 〇 mg) in ethanol (8 〇 mL) for 40 hours. The catalyst was filtered off on a ceutetm pad. The filtrate was evaporated under reduced pressure and flash chromatography Purification of residue 157102.doc -123 - 201217379 by EtOAc (EtOAc / EtOAc / EtOAc) 1,3-Diamine The following compounds were prepared using the procedure described above and the appropriate starting materials: -[1-(2,6-diamino-phenyl)-piperidin-4-ylmethyl]-amine oxime Acidic butyl butyl ester; and _ 5-gas-2-nitopic -1-yl-aniline. Step C: Synthesis of 3-(3-amino-2-piperidin-1-yl-phenylamine propyl propyl -丨· alcohol to 2-n-bottom-1-yl-benzene-1,3-diamine (300 mg, 1-57 mmol) in 7v,; y-didecylguanamine (4 mL Sodium hydride (60% suspension in mineral oil '63 mg, 1.57 mmol) was added to the solution, followed by 3-bromo-1-propanol (0.4 mL, 1.57 mmol), and the reaction mixture was at 60 The mixture was stirred overnight at EtOAc (EtOAc) (EtOAc)EtOAc. Evaporation under reduced pressure. The crude residue was purifiedjjjjjjjjjjjjjjjjjjjjj • Propyl alcohol. Preparation of 2-(3-amino-2-piperidinyl-phenylamino)-ethanol using the above procedure and the appropriate starting material. Preparation 9: Synthesis of 4-amino-2- gas- 5-Methoxy-iV-phenyl-benzamide The 4-amino-2-chloro-5-methoxyphenyl-benzamide was synthesized according to the procedure shown in Scheme 9. 157102.doc • 124· 201217379

流程9 步驟A:合成1-氣-4-甲氧基-2-甲基-5-硝基-苯鲁向4-氣-5-曱基-2-确基-苯酌^(1.0 g，5.33 mmol)及二異丙基乙基胺（1.04 mL ’ 6.13 mmol)於無水曱醇與無水乙腈之混合物（1/1 ’ 50 mL)中的混合物中添加（三甲基矽烷基）重氮甲烧溶液（己院中2.0 Μ ’ 13.3 mL，26.6 mmol)，且授摔反應混合物1小時。接著添加冰醋酸（5滴），且減壓蒸發所得混合物。使殘餘物分配於乙醚（100 mL)與水（50 mL)之間；分離有機層’經無水硫酸鈉乾燥，過濾且減壓蒸發， • 未經進一步純化即獲得1.07 g呈淺橙色固體形式之1_氣_4_ 甲氧基-2-甲基-5-硝基_苯。利用上述程序及適當起始物質製備2-曱氧基-1,5-二曱基-3-琐基·苯。步琢B.合成2-氣_5_甲氧基_4頌基苯甲酸將1氣甲氧基甲基-5-確基-苯（1.05 g，5.21 mmol) 於祉咬與水之混合物（1/2, 15叫中之懸浮液加熱至 97°C ’接著添加高猛酸舒(4 53 §，28 64隱〇1)。反應混合物在C下加熱4小時；添加第二部分之吡啶/水混合物 157102.doc •125· 201217379 (1/1，10 mL) ’隨後添加高錳酸鉀（1 g);所得混合物加熱至10(TC隔夜。熱反應混合物經由CELITETM墊過濾，以熱水洗滌濾餅且藉由添加鹽酸水溶液（6 M)酸化濾液直至pH 1。以乙酸乙酯萃取所得混合物；有機層經無水硫酸鈉乾燥’過濾且減壓蒸發《淺黃色固體殘餘物（9〇3 mg)以小部分之一氣甲烧洗滌兩次，未經進一步純化即獲得呈灰白色固體形式之2-氣-5-曱氧基-4-硝基-苯甲酸。步驟C:合成2-氣-5-甲氧基-4-硝基_iV-苯基-苯甲酿胺向2-氣-5-曱氧基-4_硝基-苯曱酸（2〇〇 mg，ο.% mm〇i)於乙腈（10 mL)中之溶液中添加HBTU(327 mg，0.86 mmol)，隨後添加苯胺（0.08 mL，0.86 mmol)及二異丙基乙基胺 (0.56 mL，3.20 mmol)，且在室溫下攪拌所得混合物。反應混合物接著在60°C下攪拌24小時且減壓濃縮。使殘餘物分配於乙酸乙酯（50 mL)與水（50 mL)之間；分離有機層且以水（50 mL)及鹽水（50 mL)洗務’經無水硫酸納乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/Et〇Ac，75/25)純化粗殘餘物，獲得182 mg呈淺黃色固體形式之2_氣_5_甲氧基-4-石肖基-iV·苯基-苯甲酿胺。步驟D :合成4-胺基-2-氣-5-甲氧基-ΛΓ-苯基-苯甲醯胺向2 -氣-5-甲氧基-4-硝基-苯基-苯甲酿胺（18〇 mg， 0·59 mmol)於乙酸乙酯與乙醇之混合物（1/1，8 mL)中之溶液中添加氯化亞錫（334 mg，1.76 mmol)，且在室溫下搜摔反應在合物隔仪。使所得混合物分配於乙酸乙醋（5〇 mL) 與碳酸鉀水溶液（5% ’ 30 mL)中；分離有機層，以鹽水（3〇 157I02.doc •126· 201217379 mL)洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/Et〇AC，70/30)純化粗殘餘物，獲得82 mg 呈灰白色固體形式之4_胺基_2_氯_5_曱氧基•苯基_苯甲醯胺。製備1〇 :合成4-胺基_3_甲氧基_N，N_二甲基_苯甲醯胺根據流程10中所示之方法，合成4_胺基_3_甲氧基·处#_ 二甲基-苯甲醯胺。Scheme 9 Step A: Synthesis of 1-gas-4-methoxy-2-methyl-5-nitro-benzo- to 4-ox-5-mercapto-2- surey-benzene (1.0 g, 5.33 mmol) and diisopropylethylamine (1.04 mL ' 6.13 mmol) in a mixture of anhydrous decyl alcohol and anhydrous acetonitrile (1/1 '50 mL), (trimethyl decyl) diazo The solution was burned (2.0 Μ ' 13.3 mL, 26.6 mmol) in the hospital and the reaction mixture was allowed to stand for 1 hour. Then glacial acetic acid (5 drops) was added, and the resulting mixture was evaporated under reduced pressure. The residue was partitioned between EtOAc (EtOAc (EtOAc)EtOAc. 1_Gas_4_Methoxy-2-methyl-5-nitro-benzene. 2-Methoxy-1,5-diamidino-3-zino-benzene was prepared by the above procedure and the appropriate starting material. Step B. Synthesis of 2-gas _5_methoxy-4-mercaptobenzoic acid 1 gas methoxymethyl-5-de-yl-benzene (1.05 g, 5.21 mmol) in a mixture of bite and water ( The suspension in 1/2, 15 is heated to 97 ° C. Then add high acid (4 53 §, 28 64 concealed 1). The reaction mixture is heated at C for 4 hours; the second part of pyridine is added / Water mixture 157102.doc •125· 201217379 (1/1,10 mL) 'Subsequent addition of potassium permanganate (1 g); the resulting mixture was heated to 10 (TC overnight. The hot reaction mixture was filtered through a pad of CELITETM and washed with hot water The filter cake was acidified and the mixture was acidified (aq) to pH 1 and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. It was washed twice with a small portion of a gas-burning, and 2-fur-5-methoxy-4-nitro-benzoic acid was obtained as an off-white solid without further purification. Step C: Synthesis 2-A-5 -methoxy-4-nitro-iV-phenyl-benzamide to 2-ox-5-nonyloxy-4_nitro-benzoic acid (2〇〇mg, ο.% mm〇i ) in a solution in acetonitrile (10 mL) HBTU (327 mg, 0.86 mmol) was added followed by aniline (0.08 mL, 0.86 mmol) and diisopropylethylamine (0.56 mL, 3.20 mmol), and the mixture was stirred at room temperature. Stir at ° C for 24 hours and concentrate under reduced pressure. EtOAc EtOAc (EtOAc) Drying over anhydrous sodium sulfate, filtered and evaporated <RTI ID=0.0> _Methoxy-4-stone base-iV·phenyl-benzamide A. Step D: Synthesis of 4-amino-2-ox-5-methoxy-oxime-phenyl-benzamide to 2 - Gas-5-methoxy-4-nitro-phenyl-benzamide (18 mg, 0·59 mmol) in a mixture of ethyl acetate and ethanol (1/1, 8 mL) Stannous chloride (334 mg, 1.76 mmol) was added and the reaction was applied to the mixture at room temperature. The resulting mixture was partitioned between ethyl acetate (5 mL) and aqueous potassium carbonate (5% '30 mL). ); separate organic layer with brine (3〇 157I02.doc • 126·201217379 mL), washed with anhydrous sodium sulfate, filtered and evaporated under reduced vacuum. The crude residue was purified by flash chromatography (hexane/EtOAc/EtOAc, 70/30) 4-amino-2_chloro-5-methoxy-phenyl-benzamide in the form of an off-white solid. Preparation 1 : Synthesis of 4-amino-3-methoxy-N,N-dimethyl-benzamide The synthesis of 4-amino-3_methoxy at the procedure shown in Scheme 10 #_ Dimethyl-benzamide.

流程10 步称A :合成3-甲氧基_iv，iV-二甲基-4-破基-苯甲醯胺向3-曱氧基-4-硝基苯甲酸（3〇〇 mg，1.52 mmol)於無水 i，2·二曱氧基乙烷（15 mL)中之溶液中添加二曱基磷醯胺基一氯化物（1.8 mL ’ 15.22 mmol) ’且在回流下加熱所得混合物約110小時。接著冷卻反應混合物，且傾入冰_水 (50 mL)中；所得混合物以乙醚（5〇 mL)萃取，分離有機層且以二氣曱烷（50 mL)萃取水層，減壓濃縮合併之有機萃取物；使殘餘物溶解於二氣曱烷中且以水（3〇 mL)洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法 (DCM/MeOH，98/2)純化棕褐色液體殘餘物，獲得i 85 mg 呈黃色油狀之3-曱氧基项，尽二曱基-4·硝基-苯曱醯胺。 157102.doc •127· 201217379 步称B:合成4-胺基-3-甲氧基-iV，iV-二甲基-苯甲醢胺在氫氣氛圍（氣球壓力）下，在室溫下，攪拌3 -曱氧基二甲基-4-硝基-苯甲醯胺（185 mg)與鈀/碳（10%，20 mg)於乙醇（6 mL)中之混合物隔夜。在CELITETM墊上過逯反應混合物，且減壓濃縮濾液。藉由急驟層析法 (DCM/MeOH, 98/2)純化粗殘餘物，獲得6〇 mg 4_胺基甲氧基-#，#·二曱基-苯曱醯胺。利用上述程序還原2-曱氧基“,5-二甲基硝基-苯，獲得2-甲氧基-3,5-二曱基-苯胺。製備11 :合成6-氣·嗟吩并[2,3-Α】咬-3-甲酸根據流程11中所示之方法合成6-氣-嗟吩并[2,3_&] η比咬_ 3 -甲酸。Scheme 10 Step A: Synthesis of 3-methoxy-iv, iV-dimethyl-4-keto-benzamide to 3-methoxy-4-nitrobenzoic acid (3 〇〇 mg, 1.52) Addition of dimercaptophosphonium monochloride (1.8 mL ' 15.22 mmol)' to a solution of anhydrous i,2·dimethoxyethane (15 mL) and heating the mixture to about 110. hour. The reaction mixture was cooled with EtOAc EtOAc (EtOAc) The organic extract was taken up in EtOAc (3 mL). Purification of the tan liquid residue by flash chromatography (DCM / MeOH, 98/2) afforded <RTI ID=0.0> Guanamine. 157102.doc •127· 201217379 Step B: Synthesis of 4-amino-3-methoxy-iV, iV-dimethyl-benzamide under hydrogen atmosphere (balloon pressure), stirring at room temperature A mixture of 3-methoxymethoxy-4-nitro-benzamide (185 mg) and palladium on carbon (10%, 20 mg) in ethanol (6 mL) overnight. The reaction mixture was passed through a CELITETM pad and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography (DCM / MeOH, 98/2) to afford 6 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Reduction of 2-nonyloxy ",5-dimethylnitro-benzene by the above procedure gave 2-methoxy-3,5-dimercapto-aniline. Preparation 11: Synthesis of 6-gas·嗟并 [ 2,3-Α] Bite-3-carboxylic acid was synthesized according to the method shown in Scheme 11 [6,3-&] η than _ 3 -carboxylic acid.

步驟A :合成3_甲基-4丑-噻吩并[3,2-b]吡啶_5,7_二酮向3-胺基-4-曱基噻吩-2-甲酸曱酯（4 g，23 mm〇i)及三乙胺（4.2 mL，30 mmol)於二氯甲烷（50 mL)中之溶液中添乙基丙二酿氣（4.29 g，28 mmol)，且攪拌所得混合物^分 157102.doc •128- 201217379 鐘。反應混合物以二氣甲烷稀釋，以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。向油性殘餘物中添加新鮮製備的乙醇鈉之乙醇溶液（0.5 g，於25 mL Et〇Hf)，且反應混合物在回流下加熱隔夜。減壓蒸發溶劑且向殘餘物中添加水（50 mL)，隨後添加氫氧化鈉〇 5 g)。所得混合物在回流下加熱隔夜，接著冷卻，且藉由添加鹽酸水溶液（6 M)酸化。藉由過濾收集所形成之固體，以水洗滌且減壓乾燥，獲得2.0 g 3-曱基-4丑·噻吩并[3,2-Z>]吡啶_5,7_二酮。步称B:合成5,7-二氣-3-甲基-噻吩并【3,2-办】吡啶在微波反應器中將3·甲基-4丑·噻吩并[3,2_6]吡啶_5,7_二酮（0.8 g)與氧氣化磷（2.5 mL)之混合物加熱至18〇。〇持續15 分鐘。將冷卻之反應混合物傾入冰_水與乙酸乙酯之混合物中，分離有機層，以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM)純化粗殘餘物，獲得5,7_二氣-3 -曱基-噻吩并[3,2-6]°比咬。步驟C:合成5-氣-3-甲基-噻吩并[3,2-6】吡啶在氫氣氛圍（55 PSI)下，在帕爾設備（Parr apparatus)中震盪5,7-二氯_3_甲基-噻吩并[3,2-6]吡啶（1_2 g)、氫氧化鈀/ 碳（20%，600 mg)及乙酸鈉（1.〇 g)於乙酸乙酯（5〇 mL)中之混合物62小時。在CELITEtm墊上過濾所得混合物，以二氣曱烷洗滌濾餅，且減壓蒸發濾液。藉由急驟層析法（丙酮/己烷）純化粗殘餘物，獲得〇.4 g 5_氣_3_甲基_噻吩并 [3,2-6]°比咬及0.2 g 3 -曱基塞吩并[3,2-6]π比咬。步驟D:合成5-氣·噻吩并[3,2-ft]吡啶-3-甲醛 157102.doc •129- 201217379 在100°C下，在微波反應器中加熱5_氯-3-甲基-噻吩并 [3,2-ό] °比咬（0.5 g ’ 2·7 mmol)、#-溴代丁二醯亞胺（〇·48 g，2_7 mmol)及過氧化苯甲醢（50 mg)於四氯化碳（3 mL)中之混合物持續15分鐘。傾析上清液且減壓蒸發，將殘餘物懸浮於甲苯（3 mL)申且添加"比啶-N-氧化物（〇.5 g)，隨後添加碳酸氫鈉（0.4 g)及二異丙基乙基胺（3滴）=反應混合物在微波反應器中在150°C下加熱5分鐘，接著以乙酸乙酯稀釋’以水及鹽水洗滌’經無水硫酸納乾燥，過濾且減壓蒸發。藉由急驟層析法（EtOAc/己烷，20/80)純化粗殘餘物，獲得150 mg 5-氣-噻吩并[3，24]吡啶-3-曱醛。步驟E :合成6-氣-噻吩并[2,3-6]吡啶-3-甲酸向5-氣-嗟吩并[3,2_H吡啶-3_甲醛（15〇 mg，〇 76瓜则。於四氫呋喃、第三丁醇與水之混合物（1/1/1 , 6 mL)中之溶液中添加胺基磺酸（150 mg)。接著添加亞氯酸鈉（丨〇〇 mg) 及麟酸二氫鉀（300 mg)於水（2 mL)中之溶液，且攪拌所得 /尾合物30分鐘。接著減壓濃縮反應混合物以移除揮發物，藉由過濾收集所形成之固體，以水及乙酸乙酯洗滌，在真空烘箱中乾燥’未經進一步純化即獲得7〇 mg 6_氯-噻吩并 [2,3-6]吡啶_3_曱酸。製備12 :合成噻吩并丨3 2-内嘧啶_7甲酸根據流程12中所示之方法合成噻吩并[3 2 ί/]嘧啶_7_甲酸0 157102.doc 201217379Step A: Synthesis of 3-methyl-4 ugly-thieno[3,2-b]pyridine-5,7-dione to 3-amino-4-mercaptothiophene-2-carboxylic acid decyl ester (4 g, Add ethyl propylene dimer (4.29 g, 28 mmol) to a solution of 23 mm 〇i) and triethylamine (4.2 mL, 30 mmol) in dichloromethane (50 mL). .doc •128- 201217379 clock. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. A freshly prepared ethanolic solution of sodium ethoxide (0.5 g in 25 mL of EtHH) was added to the oily residue, and the reaction mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure and water (50 mL) was added to the residue, followed by sodium hydroxide (5 g). The resulting mixture was heated under reflux overnight, then cooled and acidified with aqueous hydrochloric acid (6 M). The solid formed was collected by filtration, washed with water and dried under reduced pressure to give <RTI ID=0.0>>>>> Step B: Synthesis of 5,7-dioxa-3-methyl-thieno[3,2-handy]pyridine in the microwave reactor 3·methyl-4 ugly thieno[3,2_6]pyridine_ A mixture of 5,7-diketone (0.8 g) and phosphorus oxychloride (2.5 mL) was heated to 18 Torr. 〇 lasts 15 minutes. The cooled reaction mixture was poured into a mixture of ice-water and ethyl acetate. The crude residue was purified by flash chromatography (DCM) to afford 5,7-dis- 3 -mercapto-thieno[3,2-6]. Step C: Synthesis of 5-gas-3-methyl-thieno[3,2-6]pyridine under a hydrogen atmosphere (55 PSI), shaking 5,7-dichloro-3 in a Parr apparatus _Methyl-thieno[3,2-6]pyridine (1_2 g), palladium hydroxide/carbon (20%, 600 mg) and sodium acetate (1. g) in ethyl acetate (5 mL) The mixture was 62 hours. The resulting mixture was filtered on a pad of CELITEtm, and the filter cake was washed with dioxane and evaporated. Purification of the crude residue by flash chromatography (acetone / hexanes) afforded s. 4 g of 5 _ _ _ _ _ _ thiophene [3, 2-6] ° bit and 0.2 g of 3 - fluorenyl The phenotype [3, 2-6] π is bitten. Step D: Synthesis of 5-gas·thieno[3,2-ft]pyridine-3-carbaldehyde 157102.doc •129- 201217379 Heating 5-chloro-3-methyl- in a microwave reactor at 100 ° C Thio[3,2-ό] ° ratio bite (0.5 g '2.7 mmol), #-bromosuccinimide (〇·48 g, 2_7 mmol) and benzamidine peroxide (50 mg) The mixture in carbon tetrachloride (3 mL) was continued for 15 minutes. The supernatant was decanted and evaporated under reduced pressure. The residue was suspended in toluene (3 mL) and "bipyridine-N-oxide (〇.5 g), followed by sodium bicarbonate (0.4 g) and Isopropylethylamine (3 drops) = reaction mixture was heated in a microwave reactor at 150 ° C for 5 minutes, then diluted with ethyl acetate 'washed with water and brine' dried over anhydrous sodium sulfate, filtered and decompressed evaporation. The crude residue was purified by flash chromatography (EtOAc / EtOAc EtOAc) Step E: Synthesis of 6-gas-thieno[2,3-6]pyridine-3-carboxylic acid to 5-gas-hydrazino[3,2-H-pyridine-3-formaldehyde (15 mg, 〇76 melon. Aminosulfonic acid (150 mg) was added to a solution of tetrahydrofuran, a mixture of tert-butanol and water (1/1/1, 6 mL), followed by sodium chlorite (丨〇〇mg) and linonic acid A solution of potassium hydrogen (300 mg) in water (2 mL), and the resulting mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure to remove volatiles, and the solid formed was collected by filtration. Ethyl acetate was washed and dried in a vacuum oven to give <RTI ID=0.0>>&&&&&&&&&&&&&&&&&& Synthesis of thieno[3 2 ί/]pyrimidine_7_carboxylic acid according to the method shown in Scheme 12 for the endosulfan-7carboxylic acid 0 157102.doc 201217379

步辟^合成7-甲基㈣吩并[3,2__… 將3-胺基-4-甲基-嗔吩_2_甲酴甲沾 Τ酸甲酯（3.0 g)與甲醯胺（50 mL)之混合物加熱i15(rc隔夜。Synthesis of 7-methyl(tetra)-pheno[3,2__... 3-amino-4-methyl-porphin-2-methylcarboxamide methyl ester (3.0 g) with formamide (50 A mixture of mL) was heated i15 (rc overnight).

按考冷部反應混合物且以水稀釋。藉由過濾收集所形成驭之固體，以水洗滌且減壓乾燥’未經進一步純化即獲得2 1 7田役付人1 g 7-甲基_3仏噻吩并[3U] 喊咬-4 -嗣。步麻B :合成4-氣-7-甲基·嗟吩并[3 2 ^鳴唆在l〇〇°C下加熱7-甲基_3丑-噻吩并n 9 %开[3,2-闳嘧啶-4-酮（2.1 g)於氧氣化填（10 mL)中之懸浮_涪牲接 W液持續1小時。接著冷卻反應混合物’且傾入冰-水與乙酸乙酯之混合物卜分離有機層’以鹽水洗務’經無水硫酸鈉乾燥，㈣且減壓蒸發。藉由急驟層析法（DCM)純化粗殘氯-7-〒基-嘆吩并[3,2-3]喷η定。餘物，獲得2.0 g 4- 步称C :合成7-甲基-嘆吩并pu】嘴咬在氫氣氛圍(50 PSI)下’在帕爾設備中震盪4_氣·7_甲基_ 嗔吩并以—邮…氫氧㈣/祁㈣^及乙酸納 (2 g)於乙酸乙S旨與異丙醇之混合物（5/1，3()机）中的混合物隔夜。在CELITEtm墊上過濾所得混合物，以二氯甲烷洗滌濾餅’且減壓蒸發濾液。藉由急驟層析法（丙酮/ 157102.d〇c -131 · 201217379 DCM，3/97)純化粗殘餘物，獲得1 g 7_曱基_隹吩并[3 2 喊咬。步称D:合成嘆吩并[3,2-3]嘧咬_7_甲醛在回流下加熱7-曱基-噻吩并[3,2_^]嘧啶（1 2 g)及沁溴代丁二醯亞胺（2.9 g)於四氯化碳（5〇 mL)中之混合物i小時。接著冷卻反應混合物，濾出所形成之固體且減壓濃縮濾液。使殘餘物懸浮於水（10 mL)f，且在回流下加熱懸/浮液1小時。藉由添加碳酸氫鈉飽和水溶液鹼化所得混人物’且以二氣甲烷(100 mL)萃取兩次。經合併之有機層二鹽水洗滌，經無水硫酸鈉乾燥，過滤且減壓蒸發。M 餘物以乙酸乙醋及己烷濕磨’接著藉由過渡收殘 0.8 g嘆吩并[3,2-〇?]喷咬_7-甲酿。得步称E .合成嗔吩并[3,2-</】喷咬_7_甲酸使用製備11步驟E中所述之程序氧化。塞吩 2 7-甲醛，獲得相應羧酸。，-幻嘧啶- 製備13 :合成2-氣-噻吩并丨3,2_引嘧啶_7•甲酸根據流程13中所示之方法合成2 7-甲酸。 -氣-噻吩并[3,2The cold reaction mixture was tested and diluted with water. The solid formed ruthenium was collected by filtration, washed with water and dried under reduced pressure. </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; . Step B: Synthesis of 4-gas-7-methyl· porphin [3 2 ^ 唆加热 heating 7-methyl _3 ugly - thiophene n 9 % open at 3 ° C [3,2- Suspension of pyrimidin-4-one (2.1 g) in oxygenated fill (10 mL) was carried out for 1 hour. Then, the reaction mixture was cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude residual chloro-7-mercapto-snap-[3,2-3] was sprayed by flash chromatography (DCM). Remaining, obtained 2.0 g 4-step C: Synthetic 7-methyl-exclamation pu] mouth bite in hydrogen atmosphere (50 PSI) 'shock in Parr equipment 4_gas·7_methyl_ 嗔The mixture was incubated overnight with a mixture of hydrogen peroxide (tetra)/niobium (tetra) and sodium acetate (2 g) in a mixture of ethyl acetate and a mixture of isopropanol (5/1, 3 ()). The resulting mixture was filtered on a pad of CELITEtm, and the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography (acetone / 157102.d?c -131 · 201217379 DCM, 3/97) to give 1 g of 7-mercapto- 隹并 [3 2 Step D: Synthetic exclamation and [3,2-3] pyrimidine _7_formaldehyde heated under reflux of 7-mercapto-thieno[3,2_^]pyrimidine (1 2 g) and hydrazine bromide A mixture of quinone imine (2.9 g) in carbon tetrachloride (5 〇 mL) for 1 hour. The reaction mixture was then cooled, the solid formed was filtered off and the filtrate was concentrated under reduced pressure. The residue was suspended in water (10 mL), and the suspension was suspended under reflux for one hour. The resulting mixture was basified by the addition of a saturated aqueous solution of sodium bicarbonate and extracted twice with di-methane (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The residue of M was wet-milled with ethyl acetate and hexane, followed by a 0.8 g sigh and a [3,2-?? Step E. Synthetic porphin [3,2-</] blasting _7_carboxylic acid was oxidized using the procedure described in Preparation 11, Step E. The phenanthrene 2-7-formaldehyde gives the corresponding carboxylic acid. , - phantom pyrimidine - Preparation 13: Synthesis of 2-gas-thienoindole 3,2-pyrimidine-7-carboxylic acid The synthesis of 2 7-carboxylic acid according to the procedure shown in Scheme 13. - gas-thieno[3,2

157102.doc •132· 201217379 步驟A :合成7-甲基-1孖·噻吩并卩^-^嘧啶^心二酮向3-胺基-4-甲基噻吩_2-甲酸甲酯（1.3 g)於乙腈（i〇 mL) 中之溶液中添加異氰酸三氣乙酿酯（2·〇 g)，且攪拌所得混合物15分鐘。藉由過濾收集析出之固體，且懸浮於甲醇（5 mL)中’接著添加氨於甲醇中之溶液（7 M，$ mL)，且所得混合物在7(TC下加熱15分鐘。冷卻反應混合物，藉由過濾收集所形成之固體，減壓乾燥，獲得〇·8 g 7-曱基_liy_售吩并[3,2-c?]嘴咬-2,4-二酮。步驟B :合成2,4-二氣—7-甲基-噻吩并[3,2-rf】嘧啶將7-曱基- li/-噻吩并[3,2-c?]嘧咬-2,4-二酮（2 8 g)與氧氯化磷（5 mL)之混合物分成2份，且兩份皆在微波反應器中在180 C下加熱15分鐘。冷卻合併之反應混合物，且分配於冰-水與乙酸乙酯之間。分離有機層，以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。以己烷濕磨粗殘餘物，且藉由過濾收集固體，獲得25 g 2,4_二氣_7_曱基-噻吩并[3,2-刃嘧啶。步驟C:合成2-氣-7-甲基-噻吩并[3,2-rf】嘧咬在氫氣氛圍（50 PSI)下，在帕爾設備中震盪2,4_二氣·7_ 甲基·噻吩并[3,2·β嘧啶（2.5 g)、氫氧化鈀/碳（20% , 0_5 g) 及乙酸鈉（2.0 g)於乙酸乙酯（40 mL)與異丙醇（5 mL)之混合物中的混合物隔夜。上過濾反應混合物，且減壓蒸發濾液。藉由急驟層析法（DCM)純化粗殘餘物，獲得g 2-氯-7-甲基-噻吩并[3,2d]嘧啶。步驟D:合成2-氣-噻吩并【3,2-rf]嘧啶_7_甲醛 157102.doc -133- 201217379 在回流下加熱2 -氣-7-甲基-隹吩并[3,2-ΰ?]嘴咬（1.8 g)、_/V~ /臭代丁二醢亞胺（1 _8 g)、2,2’-偶氮雙（2-甲基丙腈）（〇. 1 g)於四氯化碳（50 mL)中之混合物1小時。冷卻所得混合物，濾出固體且減壓蒸發濾液。使殘餘物溶解於乙腈（2〇 mL)中且添加二異丙基乙基胺（2.〇 mL)，隨後添加吡啶氧化物 (3 g)，且在1 〇〇 c下加熱所得混合物3 〇分鐘。冷卻反應混合物，以乙酸乙酯稀釋，以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/Et〇Ac)純化粗殘餘物，獲得0.25 g 2-氣-噻吩并[3,2_闺嘧啶_7_甲醛及1 g 2-氯-7-甲基-噻吩并[3,2-d]嘧啶起始物質。步驟E :合成2-氣-噻吩并[3,2-rf]嘧啶_7_甲酸三丁醇/四向2-氣-噻吩并[3,2d]嘧啶_7_曱醛（〇6 g)於第氫吱喃/水之混合物（細，45 mL)中的溶液中添加胺基續酸（1.0 g)’隨後添加亞氣酸_.9 g)及⑽二氫鉀（3 0 於水（1〇 mL)中之溶液，且攪拌所得混合物2小時。接著以乙酸乙醋稀釋反應混合物；分離有機層且以鹽水洗務，唾無水硫酸鈉乾燥’過渡且減壓蒸發。卩乙酸乙醋濕磨殘餘物且藉由過滤收集固體’獲狀5 g 2务售吩并[3知]嚷製備14:合成5-甲基-吡唑并口，“】嘧啶_3甲酸根據流程I4中所示之方法人士。吓丁夂万去合成5·曱基吡唑并[15_ 啶-3-曱酸。 J炎 157102.doc -134- 201217379157102.doc •132· 201217379 Step A: Synthesis of 7-methyl-1孖·thiophene 卩^-^pyrimidine^xindione to methyl 3-amino-4-methylthiophene-2-carboxylate (1.3 g To the solution in acetonitrile (i 〇 mL) was added triethylerethane isocyanate (2·〇g), and the resulting mixture was stirred for 15 minutes. The precipitated solid was collected by filtration and suspended in methanol (5 mL), then a solution of ammonia in methanol (7 M, <RTI ID=0.0> The solid formed was collected by filtration, and dried under reduced pressure to give y······························· 2,4-diqi-7-methyl-thieno[3,2-rf]pyrimidine 7-mercapto-li/-thieno[3,2-c?]pyrimidine-2,4-dione A mixture of (2 8 g) and phosphorus oxychloride (5 mL) was divided into 2 portions, and both were heated in a microwave reactor at 180 C for 15 minutes. The combined reaction mixture was cooled and distributed in ice-water and The organic layer was separated, washed with EtOAc EtOAc m. _Two gas _7_ fluorenyl-thieno[3,2-purine. Step C: Synthesis of 2-gas-7-methyl-thieno[3,2-rf] pyrimidine in hydrogen atmosphere (50 PSI) Under the turbulence of 2,4_digas·7_methyl·thieno[3,2·β-pyrimidine (2.5) g), a mixture of palladium hydroxide/carbon (20%, 0_5 g) and sodium acetate (2.0 g) in a mixture of ethyl acetate (40 mL) and isopropyl alcohol (5 mL). The filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM) to afford g2-chloro-7-methyl-thiophene[3,2d]pyrimidine. Step D: Synthesis of 2-oxo-thiophene [3,2-rf]pyrimidine_7_formaldehyde 157102.doc -133- 201217379 Heating 2- gas-7-methyl- porphin [3,2-ΰ?] mouth bite (1.8 g) under reflux, _/V~ / odorant diimine (1 _8 g), 2,2'-azobis(2-methylpropionitrile) (〇. 1 g) in carbon tetrachloride (50 mL) The mixture was cooled for 1 hour. The mixture was cooled, the solid was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The mixture was heated (3 g), and the mixture was evaporated, m. Purification of crude residue by flash chromatography (hexane/Et〇Ac) 0.25 g of 2-gas-thieno[3,2-pyrimidinium-7-formaldehyde and 1 g of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine starting material are obtained. Step E: Synthesis of 2-oxo-thieno[3,2-rf]pyrimidin-7-carboxylic acid tributanol/tetragonal 2-gas-thieno[3,2d]pyrimidin-7-furfural (〇6 g) in hydrogen Add the amine-based acid (1.0 g) to the solution in the mixture of sulphur/water (fine, 45 mL) followed by the addition of nitrous acid _.9 g) and (10) potassium dihydrogenate (3 0 in water (1 〇 mL) The solution was stirred and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was wet-milled with ethyl acetate in acetonitrile and the solid was collected by filtration. 5 g 2 sold benzene [3] 嚷 Preparation 14: Synthesis of 5-methyl-pyrazole, "] pyrimidine _3 formic acid according to the procedure The method shown in I4. Severe Ding Wan to synthesize 5 · mercaptopyrazole [15_ pyridine-3-decanoic acid. J Yan 157102.doc -134- 201217379

0 OMe0 OMe

COOH 流程14COOH Process 14

在回流下加熱3-胺基-4-吡唑甲酸乙酯（l.o g，6.4 mmol) 及乙酿基乙路二甲縮酿（1.7 g，13 mmol)於曱苯（5 mL)中之混合物隔夜。冷卻所得混合物且藉由急驟層析法（己烷/乙酸乙酯）純化，獲得0.7 g酯。接著將酯溶解於甲醇與之混合物（1/1，10 mL)及氫氧化納（〇.7 g)中，且在回流下加熱隔夜。冷卻反應混合物，以鹽酸水溶液（6 中和至pH 7 ’且以乙酸乙酯萃取。分離有機層，以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得 5·甲基-0比0坐并[1，5-α]嘯咬-3 -曱酸。製備I5 ··合成7_甲基-哺唾并[1，5_β】嘴咬_3•甲酸根據流程15中所示之方法合成7_曱基·吡唑并⑴：吶嘧咬-3 -甲酸。A mixture of ethyl 3-amino-4-pyrazolecarboxylate (lo g, 6.4 mmol) and ethyl acetonitrile (1.7 g, 13 mmol) in toluene (5 mL) was heated under reflux. Overnight. The resulting mixture was cooled and purified by flash chromatography (hexane/ethyl acetate) to afford 0.7 g. The ester was then dissolved in a mixture of methanol (1/1, 10 mL) and sodium hydroxide (〇.7 g) and heated under reflux overnight. The reaction mixture was cooled with EtOAc EtOAc EtOAc EtOAc. Methyl-0 is sitting at 0 and [1,5-α] squirting -3 - citric acid. Preparation of I5 ··Synthesis 7_methyl-feeding and [1,5_β] mouth biting _3• formic acid according to the process 15 The method shown therein synthesizes 7-mercapto-pyrazole and (1): guanidine--3-carboxylic acid.

流程15 在60C下加熱3·胺基_4_吡唑曱酸乙酯（25〇 mg)、乙醯基乙醛二曱縮醛（200 μί)與濃鹽酸（〇 5 mL)之混合物。分鐘。冷部所得混合物，且藉由過濾收集析出之固體，以乙 157102.doc -135 - 201217379 酸乙酯洗滌且在真空烘箱中乾燥’獲得2〇〇 mg 7_甲基_吡唑并[1，5-α]嘧啶-3-甲酸。製備16 :合成（Ε)-3-(4-甲氧基-3-硝基-苯基）_丙烯酸甲酯根據流程16所示之方法合成（ε)_3_(4_甲氧基_3_硝基_笨基）-丙烯酸甲酯。Scheme 15 A mixture of 3·amino-4-pyrazole decanoate (25 〇 mg), acetonitrile acetaldehyde diacetal (200 μί) and concentrated hydrochloric acid (〇 5 mL) was heated at 60 °C. Minutes. The mixture obtained in the cold portion, and the precipitated solid was collected by filtration, washed with ethyl 157102.doc - 135 - 201217379 acid ethyl ester and dried in a vacuum oven to obtain 2 〇〇mg 7_methyl-pyrazole [1, 5-α]pyrimidine-3-carboxylic acid. Preparation 16: Synthesis of (Ε)-3-(4-methoxy-3-nitro-phenyl)-methacrylic acid methyl ester according to the method shown in Scheme 16 (ε)_3_(4_methoxy_3_ Nitro-stupyl)-methyl acrylate.

OMe (丁步驟今 CHOOMe (Ding Steps Today CHO

COOMe 流程16COOMe Process 16

nh2Nh2

SCSC

步驟A :合成（E)-3-(4-曱氧基-3-硝基-苯基）_丙烯酸甲酯在回流下加熱4-甲氧基-3-硝基苯甲醛（15 g，8.2 mmol) 及（二本基亞膦）乙酸甲醋（4.4 g，13 mmol)於四氫0夫0南（30 mL)中之混合物隔夜。冷卻反應混合物且減壓蒸發；藉由急驟層析法（丙酮/己烷，20/80)純化粗殘餘物，獲得0.5 g (Ε)-3-(4·甲氧基-3-硝基-苯基）-丙烯酸甲酯。步驟Β :合成（Ε)-3-(3-胺基-4-甲氧基-苯基）-丙烯酸甲酯向（Ε)-3-(4-甲氧基-3-硝基-苯基）-丙烯酸甲酯（〇.5 g)於二氯甲烷（5 mL)中之溶液中添加鋅粉（2 g)，隨後添加乙酸（1 mL) ’且在室溫下攪拌所得混合物30分鐘。濾出固體且以二氯曱烷洗滌。減壓蒸發濾液且藉由急驟層析法（DCM/丙酮，95/5)純化殘餘物，獲得（Ε)_3·(3-胺基-4-曱氧基-苯基）-丙婦酸甲S旨。 157102.doc ηήStep A: Synthesis of methyl (E)-3-(4-decyloxy-3-nitro-phenyl)-acrylate by heating 4-methoxy-3-nitrobenzaldehyde (15 g, 8.2) under reflux A mixture of mmol) and (di-bromophosphine)acetic acid methyl vinegar (4.4 g, 13 mmol) in tetrahydro-carbamine (30 mL) overnight. The reaction mixture was cooled and evaporated <RTI ID=0.0>; Phenyl)-methyl acrylate. Step Β: Synthesis of (Ε)-3-(3-amino-4-methoxy-phenyl)-methyl acrylate to (Ε)-3-(4-methoxy-3-nitro-phenyl - A solution of methyl acrylate (0.5 g) in dichloromethane (5 mL) was added with zinc powder (2 g) followed by acetic acid (1 mL) and the mixture was stirred at room temperature for 30 min. The solid was filtered off and washed with dichloromethane. The filtrate was evaporated under reduced pressure and the residue was purified (jjjjjjjjjj S purpose. 157102.doc ηή

S 201217379 步驟C :合成（E)-3-(3-胺基-4-甲氧基_苯基）_丙_2_烯-1-醇在0°C下，向（Ε)-3-(3-胺基-4-曱氧基-苯基）_丙烯酸曱酯 (400 mg)於四氫呋喃（10 mL)中之溶液中添加氫化鋰鋁溶液 (於THF中，1 Μ，4 mL) ’且攪拌所得混合物！ 5分鐘。接著藉由添加氯化銨飽和水溶液淬滅反應混合物，過濾、所得混合物且以乙酸乙酯洗滌濾餅。分離濾液，且經無水硫酸鈉乾燥有機層’過濾且減壓蒸發，未經進一步純化即獲得 90 mg (Ε)·3-(3-胺基-4-甲氧基-苯基）丙-2-稀-1-醇。步驟D:合成3-(3-胺基-4-甲氧基-苯基）_丙醇在氫氣氛圍（氣球壓力）下，攪拌（E)_3_(3_胺基_4_甲氧基_ 苯基）-丙-2-烯-1-醇（250 mg)及氫氧化鈀/碳（2〇%，5〇 mg) 於乙酸乙酯（10 mL)中之混合物隔夜。所得混合物經由 CELITEtm墊過濾，以二氣曱烷洗滌濾餅，且減壓蒸發濾液，未經進一步純化即獲得1〇〇 mg 3_(3_胺基_4_甲氧基-苯基）-丙-1 -醇β 製備I7:合成5·乙基-2-甲氧基-苯胺根據流程17中所示之方法，合成5_乙基_2甲氧基苯胺。S 201217379 Step C: Synthesis of (E)-3-(3-Amino-4-methoxy-phenyl)-propan-2-en-1-ol at 0 ° C to (Ε)-3- (3-Amino-4-indolyl-phenyl)- decyl acrylate (400 mg) was added to a solution of lithium aluminum hydride (in THF, 1 Μ, 4 mL) in tetrahydrofuran (10 mL). And stir the resulting mixture! 5 minutes. The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride, filtered, and the mixture was washed with ethyl acetate. The filtrate was separated and dried <RTI ID=0.0> - Dil-1-ol. Step D: Synthesis of 3-(3-Amino-4-methoxy-phenyl)-propanol under a hydrogen atmosphere (balloon pressure), stirring (E)_3_(3_Amino_4_methoxy_ A mixture of phenyl)-prop-2-en-1-ol (250 mg) and palladium hydroxide/carbon (2%, 5 mg) in ethyl acetate (10 mL) overnight. The resulting mixture was filtered through a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc). -1 -Alcohol β Preparation I7: Synthesis of 5-ethyl-2-methoxy-aniline 5-ethyl-2-methoxyaniline was synthesized according to the procedure shown in Scheme 17.

CHOCHO

步驟Α:合成1_甲氧基_2_硝基·4乙烯基·苯 157102.doc -137- 201217379 向4-甲氧基-3-硝基苯甲醛（〇·6 g)於四氫呋喃（l〇 mL)中之溶液中添加氫化鈉（礦物油中之50%懸浮液，0.5 g)，隨後添加溴化曱基三苯基鱗（1 ·8 g)，且在回流下加熱所得混合物1小時。冷卻反應混合物，以水稀釋，以鹽水萃取，經無水硫酸鈉乾燥，過濾且減壓蒸發《藉由急驟層析法 (己烷/EtOAc，90/10)純化粗殘餘物，獲得150 mg 1-甲氧基-2-琐基-4-乙稀基-苯。步驟B:合成5-乙基-2-甲氧基·苯胺在氫氣氛圍（氣球壓力）下，在室溫下攪拌1-曱氧基_2_硝基-4-乙烯基-苯（150 mg)及纪/碳（10%，25 mg)於乙酸乙醋 (10 mL)中之混合物隔夜。經由CELITEtm，過濾反應混合物’且蒸發濾液’未經進一步純化即獲得5-乙基-2-甲氧基-苯胺。製備18:合成2-甲氧基_5_乙烯基-苯胺根據流程18中所示之方法，合成2_曱氧基胃5_乙烯基苯胺。Step Α: Synthesis of 1-methoxy-2-nitro-4-vinylbenzene 157102.doc -137- 201217379 to 4-methoxy-3-nitrobenzaldehyde (〇·6 g) in tetrahydrofuran (l Sodium hydride (50% suspension in mineral oil, 0.5 g) was added to the solution in 〇mL), followed by the addition of decyltriphenylsulfonium bromide (1·8 g), and the resulting mixture was heated under reflux for 1 hour. . The reaction mixture was cooled with EtOAc EtOAc EtOAc m. Methoxy-2-schyl-4-ethenyl-benzene. Step B: Synthesis of 5-ethyl-2-methoxyaniline Under stirring in a hydrogen atmosphere (balloon pressure), 1-oximeoxy-2-nitro-4-vinyl-benzene (150 mg) A mixture of genomic/carbon (10%, 25 mg) in ethyl acetate (10 mL) overnight. The reaction mixture was filtered through <RTI ID=0.0>CELITEtm</RTI> and evaporated <RTI ID=0.0> Preparation 18: Synthesis of 2-methoxy-5-vinyl-aniline According to the procedure shown in Scheme 18, 2-methoxyoxy-5-vinylaniline was synthesized.

nh2 流程18 向1-甲氧基-2-硝基_4_乙稀基_苯（1〇〇 mg)於二氣曱院（2 mL)中之溶液中添加鋅粉（大量過量），隨後添加乙酸（〇 5 mL)，且在室溫下攪拌所得混合物3〇分鐘。過濾固體，以 157102.doc 201217379 二氯曱烧洗條且丢棄。減壓蒸發遽液，且藉由急驟層析法 (己烷/EtOAc，90/10)純化殘餘物，獲得50 mg 2-甲氧基-5-乙烯基-苯胺。製備19 :合成[1-(2-胺基-4-氣-苯基）-哌啶-4-基】-甲醇根據流程19中所示之方法，合成[ι_(2-胺基-4-氯-苯基）-娘咬-4-基]-甲醇。Nh2 Scheme 18 Add zinc powder (a large excess) to a solution of 1-methoxy-2-nitro-4-methyl-benzene (1 mg) in dioxane (2 mL), followed by Acetic acid (〇 5 mL) was added, and the resulting mixture was stirred at room temperature for 3 〇. The solid was filtered and washed with 157102.doc 201217379 dichlorohydrazine and discarded. The mash was evaporated under reduced pressure and the residue was purifiedjjjjjjjjjjj Preparation 19: Synthesis of [1-(2-Amino-4-oxo-phenyl)-piperidin-4-yl]-methanol [Method 1] Chloro-phenyl)-nitopic bit-4-yl]-methanol.

流程19 步驟A :合成[1-(4-氣-2-硝基-苯基）-哌啶-4-基]-甲醇在80°C下加熱2,5-二氣硝基苯（〇.7 g)、4-哌啶甲醇（0.6 g) 及碳酸鉀（1 g)於W-二曱基曱醯胺（1〇 mL)中之混合物1小時。冷卻反應混合物，以水稀釋且以乙酸乙酯萃取。以水及鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM/丙酮，90/10)純化粗殘餘物’獲得0.8 g [1-(4-氣-2-硝基-苯基）-哌啶-4-基]•甲醇0 步驟B :合成[1-(2-胺基-4-氣-苯基）-哌啶-4-基]-甲醇根據製備16步驟B中所述之程序還原[1-(4-氯-2-硝基-苯基）-派咬-4-基]-甲醇（200 mg)，獲得90 mg [1-(2-胺基-4- 157102.doc •139· 201217379 氣-苯基）-哌啶-4-基]-曱醇。利用上述程序及適當起始物質製備以下化合物： -[1-(2-胺基-4-氣··苯基）_哌啶-4-基曱基]-胺基甲酸第三丁酯； -1-(2-胺基-4-氯-苯基）-哌啶-4-甲酸醯胺； -Π-(2-胺基-4-氣-苯基）-哌啶-3-基]-甲醇； -2-氮雜環庚烷-1-基-5-氣-苯胺； -(3-胺基-4-派咬-1-基-苯基）-曱醇； -5-氣-2-吡咯啶-1-基-苯胺； -Π-(2-胺基-4-氣-苯基）-"比咯啶-3-基]-曱醇； -5-氯-2-(4-曱基底嗪-1-基）-苯胺； -4-(2-胺基-4-氣-苯氧基）-哌啶-1-曱酸第三丁酯； -2-[4-(第三丁基-二甲基·矽烷基氧基曱基）_哌啶_l-基]-5-氣-苯胺； • 5-氯-2-派咬-1-基·苯胺； -2-[(2-胺基-4-氣·苯基）-甲基-胺基]_乙醇； • 1-(2-胺基-4-氣-苯基）_略咬_4_醇； -1-(2-胺基-4-氣-苯基）-哌啶_3_醇； -[1-(2-胺基-4-氣-苯基）_哌啶_2_基]-曱醇； -3-[(2-胺基-4-氣-苯基甲基-胺基]_丙_^醇；及 -1-[1-(2-胺基_4_氣_苯基）比咯啶_3_基]·乙醇。製備20 :合成3-(2-胺基-4-氣·苯氧基）-環戊烷甲酸乙酯根據流程20中所示之方法合成3-(2-胺基-4-氣·苯氧基）-環戊烷甲酸乙酯。 157102.doc 201217379 COOEtScheme 19 Step A: Synthesis of [1-(4-Ga-2-nitro-phenyl)-piperidin-4-yl]-methanol at 80 ° C to heat 2,5-dinitrobenzene (〇. 7 g), a mixture of 4-piperidinemethanol (0.6 g) and potassium carbonate (1 g) in W-didecylamine (1 mL) for 1 hour. The reaction mixture was cooled, diluted with water and ethyl acetate. The combined organic extracts were washed with EtOAcq. Purification of the crude residue by flash chromatography (DCM/EtOAc, 90/10) afforded <RTI ID=0.0> Step B: Synthesis of [1-(2-Amino-4-oxo-phenyl)-piperidin-4-yl]-methanol was reduced according to the procedure described in Preparation 16 Step B [1-(4-chloro-2) -nitro-phenyl)-pyrylene-4-yl]-methanol (200 mg), obtained 90 mg [1-(2-amino-4- 157102.doc •139· 201217379 gas-phenyl)-peri Pyridin-4-yl]-nonanol. The following compounds were prepared by the above procedure and the appropriate starting materials: -[1-(2-Amino-4- s.phenyl)-piperidin-4-ylindenyl]-carbamic acid tert-butyl ester; 1-(2-Amino-4-chloro-phenyl)-piperidine-4-carboxylic acid decylamine; - fluorene-(2-amino-4-pyro-phenyl)-piperidin-3-yl]- Methanol; -2-azepane-1-yl-5-a-aniline; -(3-amino-4-pyran-1-yl-phenyl)-nonanol; -5-gas-2 -pyrrolidin-1-yl-aniline; -Π-(2-amino-4-carbo-phenyl)-"pyrrolidin-3-yl]-nonanol; -5-chloro-2-(4 - hydrazine azine-1-yl)-aniline; -4-(2-amino-4- oxo-phenoxy)-piperidine-1-decanoic acid tert-butyl ester; -2-[4-( Tributyl-dimethyl-decyloxyindenyl)-piperidine-1-yl]-5-gas-aniline; • 5-chloro-2-pyrene-1-yl-aniline; -2-[ (2-Amino-4-oxo-phenyl)-methyl-amino]-ethanol; • 1-(2-Amino-4-gas-phenyl)_slightly bite_4-alcohol; -1- (2-Amino-4-oxo-phenyl)-piperidine-3-ol; -[1-(2-Amino-4-pyranyl)-piperidin-2-yl]-nonanol; -3-[(2-Amino-4-methoxy-phenylmethyl-amino]-propanol; and 1-[1-(2-amino-4-yl-phenyl)pyrene Acridine_3_yl]·ethanol. Preparation 20: 3-(2-Amino-4-oxophenoxy)-cyclopentanecarboxylic acid ethyl ester was synthesized according to the method shown in Scheme 20 to give 3-(2-amino-4- phenoxy) Ethyl pentanecarboxylate. 157102.doc 201217379 COOEt

流程20 步驟A:合成3-(4-氣-2-硝基·苯氧基）-環戊烷甲睃乙酯在室溫下攪拌1，4_二氯-2-硝基-苯（190 mg，1.1 mmol)、 ^ 3-經基-環戊烧曱酸乙酯（180 mg，1.14 mmol)、三苯膦（448 mg)及DIAD(345 mg)於二氣曱烷（10 mL)中之混合物隔夜。接著減壓蒸發反應混合物，且藉由急驟層析法純化粗殘餘物，獲得280 mg 3-(4-氯-2-硝基-苯氧基）-環戊烷甲酸乙酯。步驟B :合成3-(2-胺基_4_氣-苯氧基）_環戊烷甲睃乙酯向3-(4-氣-2-硝基-苯氧基）-環戊烷甲酸乙酯（28〇 mg)於二氯曱烷（20 mL)中之溶液中添加鋅粉（2 g)，隨後添加冰醋 • 酸（1 mL)，且在室溫下攪拌所得混合物20分鐘》過濾固體，以二氯甲烧洗滌且丢棄。減M蒸發滤液且藉由急驟層析法（己烷/丙酮，80/20)純化殘餘物，獲得2〇〇 mg 3(2_胺基-4-氣-苯氧基）·環戊烷甲酸乙g旨。利用上述程序及適當起始物質製備丨_甲氧基-萘基胺。製備21 :合成吡咯并卩山刀丨^^三嗪^甲酸根據流程21中所示之方法合成対并三嗓- 157102.doc *141- 201217379 7-曱酸。Scheme 20 Step A: Synthesis of 3-(4-Ga-2-nitrophenoxy)-cyclopentanecarboxamide Ethyl acetate 1,4- chloro-2-nitro-benzene (190) Mg, 1.1 mmol), ^ 3-yl-cyclopentanyl decanoate (180 mg, 1.14 mmol), triphenylphosphine (448 mg) and DIAD (345 mg) in dioxane (10 mL) The mixture is overnight. The reaction mixture was evaporated under reduced pressure. Step B: Synthesis of 3-(2-amino-4-yl-phenoxy)-cyclopentanecarbazide to 3-(4-Gas-2-nitro-phenoxy)-cyclopentanecarboxylic acid Add ethyl zinc (2 g) to a solution of ethyl acetate (28 mg) in dichloromethane (20 mL), then add glacial acetic acid (1 mL) and stir the mixture for 20 min at room temperature. The solid was filtered, washed with dichloromethane and discarded. The filtrate was evaporated, and the residue was purified by flash chromatography (hexane/hexane, 80/20) to afford 2 </ RTI> B. The oxime-methoxy-naphthylamine was prepared using the procedure described above and the appropriate starting materials. Preparation 21: Synthesis of pyrrole oxime oxime ^^ triazine ^carboxylic acid According to the method shown in Scheme 21, hydrazine tris - 157102.doc *141- 201217379 7-decanoic acid was synthesized.

流程21Process 21

SC 步驟A :合成1好-吡咯-2,5-二甲酸2-乙酯5-甲酯向5-曱醯基-1//-吡咯-2-甲酸乙酯（1 g ’ 6 mmol)於第三丁醇/四氫呋喃/水之混合物（1 /1 /1，60 mL)中之溶液中添加胺基磺酸（1.0 g，9 mmol)，且攪拌所得混合物10分鐘。接著添加亞氣酸納（0.76 g，8.4 mmol)及填酸二氫鉀（1.6 g，12 mmol)於水（5 mL)中之溶液，且攪拌反應混合物30分鐘。接著以乙酸乙酯萃取所得混合物，且以水及鹽水洗滌有機萃取物’經無水硫酸鈉乾燥，過濾且減壓蒸發。使殘餘物 /谷解於一氯甲烧（20 mL)中’且添加三甲基石夕烧基重氮曱烧（trimetisilidiazomethane)溶液（於己烧中，2 M，5 mL); 攪拌所得混合物直至氣體逸出停止.添加冰醋酸（數滴）且減壓蒸發所得混合物。藉由急驟層析法（己烷/Et〇Ac， 85/15)純化殘餘物，獲得〇.7 g !扒吡咯_2,5-二曱酸2_乙酯 5 -曱S旨。步帮B :合成1-胺基-i仏咐洛_2,5·二甲酸2乙輯5甲酯向1丑-吡咯-2,5·二甲酸2_乙酯5_甲酯（1〇〇 mg)於从沁二甲 157102.doc -142- 201217379 基甲醯胺（2 mL)中之溶液中添加氫化鈉（礦物油中6〇〇/〇懸浮液’ 90 mg)，且攪拌所得混合物5分鐘。接著添加2,4,6_三曱基-苯磺醯基羥基胺（如1973，1239中所述自〇.5 g均三甲苯草胺酸酯（mesitilene oxamate)製備），且攪拌混合物 5分鐘。接著藉由添加水淬滅反應混合物，且以乙酸乙醋萃取所得混合物。以水及鹽水洗務經合併之有機層，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷 /EtOAc，90/10)純化粗殘餘物，獲得100 mg卜胺基咯-2,5-二甲酸2_乙酯5-甲酯。步称C :合成4-侧氧基-3,4-二氫-咕洛并[2，1_刀[1，2,4】三嗓· 7-甲酸乙酯在140C下授拌1-胺基- l/f-n比洛_2,5·二甲酸2-乙醋5 -甲酉旨 (140 mg)與曱醯胺（1 mL)之混合物隔夜。接著冷卻反應混合物且以水稀釋，藉由過濾收集析出之固體且真空乾燥，獲得60 mg 4-側氧基-3,4-二氫-吡咯并[2,丨jpjj]三嗪_7_ 甲酸乙酯。步驟D :合成4-氣-吡咯并三嗪_7•甲酸乙酯在微波反應器中在160°C下加熱4-側氧基_3,4·二氫-吡咯并[2，1-/][1，2,4]三嗪-7-曱酸乙酯（3〇〇 mg)與氧氯化磷（1 mL)之混合物15分鐘。冷卻所得混合物，且傾入冰-水與乙酸乙酯之混合物中。分離有機層，以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/ EtOAc，90/10)純化殘餘物，獲得12〇 mg含有4氣吡咯并 [2’1-/1[1，2,4]三嗪-7-甲腈之4-氯_1)比咯并[2，1_刀[1,2,4]三嗪_ 157102.doc •143- 201217379 7-甲酸乙酯。步驟Ε :合成吡咯并[2，1_/]【1，2,4】三嗪-7-甲酸乙酯在室溫下，在氫氣氛圍（氣球壓力）下攪拌4_氣_。比咯并 [2，1-/][1，2,4]三嗪_7_曱酸乙酯（12〇 mg)、氫氧化鈀/碳 (20/ό 4〇 mg)及乙酸納（6〇〇 mg)於乙酸乙醋與異丙醇之混合物（5/1，12 mL)中的混合物隔夜。在上過濾所得混合物，且減壓蒸發濾液。藉由急驟層析法純化粗殘餘物’獲得45 mg吡咯并[2，1-/][1，2,4]三嗪-7-曱酸乙酯。步驟F:合成吡咯并[^刀丨^^三嗪^-甲酸在70°C下加熱η比咯并三嗪_7_甲酸乙酯（4〇 mg)及氫氧化鈉水溶液（6 M，1 mL)於四氫呋喃與曱醇之混合物（1/1，1 mL)中的混合物1小時。接著冷卻反應混合物’藉由添加鹽酸水溶液（6 酸化，且減壓蒸發。使殘餘物溶解於二氣甲烷與水之混合物（1〇/1，55 mL)中，分離有機層，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得i 5 mg吡咯并[2，1-/][1，2,4]三嗪-7-甲酸。製備22 :合成6_胺基_5_哌啶4基-二氫吲哚_2酮根據流程22中所示之方法，合成6_胺基_5_哌啶_丨基- —風-°引σ朵酮。SC Step A: Synthesis of 1 -pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester to 5-mercapto-1//-pyrrole-2-carboxylic acid ethyl ester (1 g '6 mmol) A solution of the third butanol/tetrahydrofuran/water mixture (1 /1 /1, 60 mL) was added with an aminesulfonic acid (1.0 g, 9 mmol), and the mixture was stirred for 10 min. A solution of sodium sulfite (0.76 g, 8.4 mmol) and potassium dihydrogen (1.6 g, 12 mmol) in water (5 mL) was then added and the mixture was stirred for 30 min. The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue/gluten was dissolved in monochloromethane (20 mL) and trimethyl sulfonium trimetisilidiazomethane solution (2 M, 5 mL) was added; the mixture was stirred until gas The evolution ceased. Glacial acetic acid (several drops) was added and the resulting mixture was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc / EtOAc / EtOAc). Step B: Synthesis of 1-Amino-i仏咐luo-2,5·dicarboxylic acid 2B series 5 methyl ester to 1 ugly-pyrrole-2,5-dicarboxylic acid 2_ethyl ester 5-methyl ester (1〇〇mg) Add sodium hydride (6 〇〇 / 〇 suspension '90 mg in mineral oil) to a solution of dimethyl 157102.doc -142- 201217379 carbamide (2 mL) and stir the mixture 5 minutes. Next, 2,4,6-tridecyl-benzenesulfonylhydroxylamine (prepared from 5.5 g mesilene oxamate as described in 1973, 1239) was added, and the mixture was stirred for 5 minutes. . The reaction mixture was then quenched by the addition of water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. The crude residue was purified by flash chromatography (hexane /EtOAcEtOAcEtOAc) Step C: Synthesis of 4-sided oxy-3,4-dihydro-indolo[2,1_knife [1,2,4]triterpene-7-carboxylic acid ethyl ester at 140C A mixture of bis-l/fn piroxim-2,5·dicarboxylic acid 2-ethylacetate 5-methylhydrazine (140 mg) and decylamine (1 mL) was taken overnight. The reaction mixture was then cooled and diluted with water, and the precipitated solid was collected by filtration and dried in vacuo to give <RTI ID=0.0>>&&&&&&&&&&&&&&& ester. Step D: Synthesis of 4-oxo-pyrrolotriazine_7•ethyl formate in a microwave reactor at 160 ° C to heat 4-sided oxy-3,4·dihydro-pyrrolo[2,1-/ [1,2,4] A mixture of triazine-7-decanoate (3 mg) and phosphorus oxychloride (1 mL) for 15 minutes. The resulting mixture was cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (hexane / EtOAc, EtOAc) to afford 12 </ </ 4-chloro-1) is more than [2,1_knife [1,2,4]triazine_157102.doc •143- 201217379 7-carboxylic acid ethyl ester. Step Ε: Synthesis of pyrrole [2,1_/][1,2,4]triazine-7-carboxylic acid ethyl ester 4_gas_ was stirred under a hydrogen atmosphere (balloon pressure) at room temperature. Bis-[2,1-/][1,2,4]triazine_7_decanoate (12〇mg), palladium hydroxide/carbon (20/ό 4〇mg) and sodium acetate (6 〇〇mg) A mixture of a mixture of ethyl acetate and isopropanol (5/1, 12 mL) overnight. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure. Purification of the crude residue by flash chromatography gave 45 mg of pyrrolo[2,1-/][1,2,4]triazin-7-decanoate. Step F: Synthesis of pyrrole [^ knife 丨 ^ ^ triazine ^ - formic acid at 70 ° C heating η than s-tris-triazine _7-carboxylic acid ethyl ester (4 〇 mg) and aqueous sodium hydroxide solution (6 M, 1 mL) A mixture of tetrahydrofuran and decyl alcohol mixture (1/1, 1 mL) for 1 hour. Then, the reaction mixture was cooled, and the organic layer was separated, and dried over anhydrous sodium sulfate, and the residue was dissolved in a mixture of dimethane and water (1 〇 /1, 55 mL). Dry, filter and evaporate under reduced pressure to give <5><"&&&&&&&&&&&&&&&&&&&&&&&&&& -Dihydroindole-2-one synthesizes 6-amino-5-piperidine-indolyl-wind-in-sigma ketone according to the procedure shown in Scheme 22.

157102.doc157102.doc

S -144· 201217379 步驟A :合成2-(5-氣-2,4-二硝基-苯基）-丙二酸第三丁酯乙酯向丙二酸第三丁酯乙酯（300 mg)於1-曱基-2-吡咯啶酮（3 mL)中之混合物中添加氫化納（礦物油中60%懸浮液，1.60 mmol)，且隨後添加1，5-二氯_2,4•二硝基苯（0.45 g)。授拌反應混合物15分鐘，接著藉由添加稀鹽酸水溶液淬滅。接著以乙酸乙酯萃取所得混合物；以鹽水洗滌合併之有機萃取物’經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（EtOAc/己烷，5/95至15/85)純化殘餘物，獲得0.4 g 2-# (5_氣-2,4-二硝基-苯基）-丙二酸第乓丁酯乙酯。步驟B:合成（5-氣-2,4-二硝基-苯基）-乙酸乙酯在密封試管中’在7〇°C下加熱2-(5-氣-2,4-二硝基-苯基）-丙二酸第三丁酯乙酯（〇4 g)於二氣甲烷（3 mL)與三氟乙酸（0.5 mL)之混合物中之溶液3〇分鐘。接著減壓蒸發反應混合物’且藉由急驟層析法（Et〇ac/己烷，10/90)純化殘餘物，獲得150 mg(5-氯-2,4-二硝基-苯基）·乙酸乙酯。步驟C :合成6-胺基-5-旅啶-1-基-i，3-二氫-吲哚-2-酮向（5-氯-2,4-二硝基-苯基）_乙酸乙酯（15〇 mg)於二氯曱烧 (5 mL)中之溶液中添加派咬（12〇 mg)，且在室溫下擾拌所得混合物10分鐘。添加冰醋酸（〇 3 mL)及辞粉（1匙），且在室溫下攪拌反應混合物2〇分鐘。所得混合物經由 CELITEtm墊過濾，以二氣甲烷洗滌濾餅，且減壓蒸發濾液。殘餘物接著以乙酸乙酯稀釋，以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得（2,4_二胺基_5•哌啶基-苯基）-乙酸乙酯。將此物質溶解於曱苯（2 5 mL)中，且 157102.doc •145· 201217379 在微波反應器中在150°C下加熱10分鐘。接著冷卻反應混合物，減壓蒸發且藉由急驟層析法（DCM/MeOH ’ 95/5)純化殘餘物’獲得30 mg 6-胺基-5-哌啶-1-基-丨，％二氛引哚_ 2-酮。MS=232 [Μ+Η]+。根據上述程序且利用適當起始物質製備6_胺基_(4_經基曱基·0底咬-1-基）·1，3-二氫引|>朵_2-酮。製備23 .合成[4-(6-胺基-2-甲基-1丑_β弓丨鳴_5_基）_苯基卜甲醇根據流程23中所示之方法，合成[4·(6-胺基_2_曱基_1//_ 吲哚-5-基）-苯基]-曱醇。S -144· 201217379 Step A: Synthesis of tert-butyl 2-(5-gas-2,4-dinitro-phenyl)-malonate to tert-butyl malonate (300 mg) Adding sodium hydride (60% suspension in mineral oil, 1.60 mmol) to a mixture of 1-mercapto-2-pyrrolidone (3 mL), followed by the addition of 1,5-dichloro-2,4• Dinitrobenzene (0.45 g). The reaction mixture was stirred for 15 minutes and then quenched by the addition of dilute aqueous hydrochloric acid. The resulting mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography (EtOAc/hexanes: 5/95 to 15/85) to afford 0.4 g of 2-# (5- s. Pentabutyl ester ethyl ester. Step B: Synthesis of (5-gas-2,4-dinitro-phenyl)-ethyl acetate in a sealed tube 'heated 2-(5-gas-2,4-dinitro) at 7 °C A solution of -phenyl)-tert-butyl malonate (〇4 g) in a mixture of di-methane (3 mL) and trifluoroacetic acid (0.5 mL) for 3 min. The reaction mixture was then evaporated under reduced pressure and the residue was purified by flash chromatography (EtOAc, hexane, 10/90) to give 150 mg (5-chloro-2,4-dinitro-phenyl). Ethyl acetate. Step C: Synthesis of 6-amino-5-brazidin-1-yl-i,3-dihydro-indol-2-one to (5-chloro-2,4-dinitro-phenyl)-acetic acid Ethyl acetate (15 mg) was added to a solution of dichlorohydrazine (5 mL) to give a bite (12 mg) and the mixture was stirred at room temperature for 10 minutes. Glacial acetic acid (〇 3 mL) and powder (1 teaspoon) were added, and the reaction mixture was stirred at room temperature for 2 minutes. The resulting mixture was filtered through a pad of CELITEtm, and the filter cake was washed with di-methane, and the filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc EtOAc (EtOAc m.) This material was dissolved in toluene (25 mL) and heated in a microwave reactor at 150 °C for 10 minutes. The reaction mixture was then cooled, evaporated <RTI ID=0.0></RTI> EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjj哚哚 2-ketone. MS=232 [Μ+Η]+. 6-Amino-(4-yl)-1,3-dihydro-injection|>-to-one-one was prepared according to the above procedure and using a suitable starting material. Preparation 23. Synthesis of [4-(6-Amino-2-methyl-1 ugly-ββ丨丨_5_yl)-phenyl bromide according to the method shown in Scheme 23, synthesis [4·(6) -Amino-2_indolyl-1//_吲哚-5-yl)-phenyl]-nonanol.

步驟A :合成（5’-曱基-2，，4’-二硝基-聯苯_4_基甲醇在微波反應器中在170°C下加熱5-氣-2,4-二硝基曱苯（1.0 g)、4-(經基曱基）苯基自明酸（0.84 g)、氣化雙（三苯膦）把 (11)(150 mg)及碳酸鉀（2.0 8)於1，4_二噁烷與水之混合物 (10/1 ’ 11 mL)中的混合物1 〇分鐘。接著冷卻反應混合物且以乙酸乙酯稀釋。有機層以水及鹽水洗滌，經無水硫酸鈉 157102.doc •146· 201217379 乾燥，過濾且減壓蒸發。藉由急驟層析法（丙酮/DCM， 3/97)純化粗殘餘物’獲得0.6 g (5,·曱基_2，，4·_二硝基_聯苯-4-基）-曱醇。步驟Β :合成1-(4’-羥基甲基_4,6_二硝基_聯苯_3•基）丙_2·酮在100°C下加熱（5·-甲基_21,4，_二硝基_聯苯_4_基）甲醇 (0.6 g)於从二甲基乙醯胺二曱縮醛（5 mL)中之溶液2小時。接著冷卻反應混合物，以乙酸乙酯稀釋，以稀鹽酸水溶液、水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（丙酮/DCM，3/97)純化粗殘餘物，獲得1-(4^羥基曱基-4,6-二硝基-聯苯基）_丙_2_酮。步驟C :合成[4_(6·胺基-2-甲基-1好·•吲哚_5_基）_苯基卜甲醇在氫氣氣圍（50 PSI)下’在帕爾設備中震蘆ι_(4，_經基曱基-4,6-二硝基-聯苯-3-基）-丙-2-酮（20〇111§)及纪/碳（1〇〇/0， 80 mg)於乙酸乙g旨中之混合物隔夜。接著在celitEtm塾上過濾反應混合物’減壓蒸發濾液，且藉由急驟層析法純化粗殘餘物，獲得[4-(2-甲基-6-硝基-1丑_吲哚_5·基）_苯基]_ 曱醇及[4-(6-經基胺基-2-曱基-i/f_吲哚_5_基）_苯基]_甲醇。合併兩種產物且溶解於二氣甲烷（5 mL)*。添加鋅粉 (大量過量）及冰醋酸（1 mL)且所得混合物在70°c下加熱3〇分鐘。接著在CELITEtm墊上過濾反應混合物，以乙酸乙酯洗滌濾餅。以鹽水洗滌濾液，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（MeOH/DCM，5/95)純化粗殘餘物’獲得55 mg [4-(6-胺基-2-曱基-1//-吲哚-5-基）-笨基]-曱醇。MS=253 [M+H]+。 157102.doc •147· 201217379 製備24.合成咳吩并丨3,2_办】吼咬_3,6二甲酸6乙酯根據流程24中所示之方法合成噻吩并[3,2功]吡啶-3，6-二甲酸6-乙酯。Step A: Synthesis of 5'-mercapto-2,4'-dinitro-biphenyl-4-yl-methanol in a microwave reactor at 170 ° C to heat 5-gas-2,4-dinitro Toluene (1.0 g), 4-(transmethyl phenyl) phenyl self-acid (0.84 g), gasified bis(triphenylphosphine), (11) (150 mg) and potassium carbonate (2.0 8) at 1, 4_ Mixture of a mixture of dioxane and water (10/1 '11 mL) for 1 min. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine • 146· 201217379 Drying, filtration and evaporation under reduced pressure. Purification of crude residue by flash chromatography (acetone/DCM, 3/97) afforded 0.6 g (5,· decyl 2,, 4·_ dinitrate Base _biphenyl-4-yl)-nonanol. Step Β: Synthesis of 1-(4'-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)propan-2-one at 100° Heating (5·-methyl-21,4,-dinitro-biphenyl-4-yl)methanol (0.6 g) in a solution from dimethylacetamide diacetal (5 mL) After 2 hours, the reaction mixture was cooled, diluted with ethyl acetate, washed with aq. The crude residue was purified by flash chromatography (EtOAc/EtOAc /EtOAc) 2_ketone. Step C: Synthesis of [4_(6·Amino-2-methyl-1···吲哚_5_yl)-phenyl bromide under hydrogen gas (50 PSI) in Par Equipment in the earthquake 芦 ι_ (4, _ 曱曱 -4 4,6-dinitro-biphenyl-3-yl)-propan-2-one (20 〇 111 §) and Ji / carbon (1 〇〇 / 0, 80 mg) mixture of ethyl acetate in EtOAc over EtOAc (EtOAc) EtOAc. -6-nitro-1 ugly _吲哚_5·yl)_phenyl]_ sterol and [4-(6-alkylamino-2-mercapto-i/f_吲哚_5_ group) _Phenyl]-methanol. The two products were combined and dissolved in di-methane (5 mL)*. Zinc powder (large excess) and glacial acetic acid (1 mL) were added and the mixture was heated at 70 ° C for 3 min. The reaction mixture was then filtered on a pad of CELITEtm eluting with ethyl acetate. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of Crude Residue by Method (MeOH/DCM, 5/95) afforded 55 mg [4-(6-amino-2-mercapto-1//-indol-5-yl)-phenyl]-decanol MS=253 [M+H]+. 157102.doc •147· 201217379 Preparation 24. Synthesis of cough and 丨3,2_ do] bite _3,6 dicarboxylic acid 6 ethyl ester according to the process shown in Method Synthesis of thieno[3,2 work]pyridine-3,6-dicarboxylic acid 6-ethyl ester.

流程24 步驟A:合成3-甲基·噻吩并丨3,2功】吡啶_6_甲酸乙酯在微波反應器中’在150°C下加熱3_甲基_7_侧氧基·4,7_ 二氫-售吩并[3,2-6]吡啶-6-曱酸乙酯（WO 2003/059878 Α2)(1·〇 g)與氧氣化鱗（3 mL)之混合物15分鐘。接著冷卻反應混合物，且傾入冰-水與乙酸乙酯之混合物中β攪拌所得混合物10分鐘；分離有機層，以水（5〇 mL)及鹽水洗滌兩次，經無水硫酸鈉乾燥，過濾且減壓蒸發。向溶解於乙酸乙S旨與異丙醇之混合物（1〇n，55 mL)的固體殘餘物中添加三水合乙酸鈉（2.〇 g)及氫氧化鈀/碳（20%，0.3 g)，且所得混合物在氫氣氛圍（50 PSI)下在帕爾設備中震盪隔夜。接著在CELITEtm墊上過濾反應混合物，減壓蒸發濾液且藉由急驟層析法（Et0Ac/己烷，10/90)純化粗殘餘物，獲得 0-7883-甲基_噻吩并[32_^吡啶_6_甲酸乙酯。步驟B :合成3-甲醯基·噻吩并[3,2-0】吡啶-6-甲酸乙酯 157102.doc 201217379 向含3-甲基-售吩并[3,2-6]。比啶-6-曱酸乙酯（12 g)之四氣化碳（50 mL)中之溶液中添加ΑΓ-溴代丁二醯亞胺（2 4 g)，隨後添加AIBN(50 mg)，且在回流下加熱所得混合物4小時。冷卻反應混合物，藉由過遽移除固體，且以四氣化碳充分洗滌。減壓蒸發濾液’使殘餘物溶解於二曱亞硬（2〇 mL) 中’且在80°C下加熱所得混合物1小時。冷卻反應混合物’以水稀釋’藉由添加碳酸氫鈉飽和水溶液驗化且以乙酸乙酯萃取。以鹽水洗滌經合併之有機層，經無水硫酸鈉 ® 乾燥’過濾且減壓蒸發。藉由急驟層析法（丙酿I /DCM， 5/95)純化殘餘物，獲得0.8 g 3-甲醯基_噻吩并[3,2_6]吡啶_ 6-曱酸乙酯。步驟C:合成噻吩并[3,2-6]吡啶-3,6-二甲酸6_乙醋將3-曱醯基-噻吩并[3,2-6]吡啶-6-曱酸乙酯（0.8 g，3.4 mmol)及胺基磺酸（0.66 g，6.8 mmol)於第三丁醇/四氫呋喃/ 水之混合物（1/1/1 ’ 60 mL)中的混合物攪拌2〇分鐘。添加亞氯酸鈉（0.55 g，6 mmol)及磷酸二氫鉀（1 36 g，1〇籲 mmo1)於水（5 mL)中之溶液且攪拌所得黃色溶液20分鐘。以水及乙酸乙酯稀釋反應混合物，藉由過濾收集所形成之固體’以水洗滌且在真空烘箱中在60*>c下乾燥。以乙酸乙酯萃取濾液，有機層以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得與先前所收集之固體合併的〇 5 g噻吩并[3,2-6]°比咬-3,6-二甲酸6-乙g旨。製備25 :合成5-氣-2-乙基-苯胺根據流程25中所示之方法合成5_氣_2-乙基_苯胺。 157102.doc -149- 201217379Scheme 24 Step A: Synthesis of 3-methyl-thienoindole 3, 2 work] pyridine _6-formic acid ethyl ester in a microwave reactor 'heating at 3 ° C_methyl_7_sideoxy 4 , 7_ Dihydro-sodium [3,2-6]pyridine-6-decanoate (WO 2003/059878 Α 2) (1·〇g) and a mixture of oxygenated scales (3 mL) for 15 minutes. The reaction mixture was then cooled and poured into a mixture of ice-water and ethyl acetate. The mixture was stirred for 10 minutes. The organic layer was separated, washed twice with water (5 mL) and brine. Evaporate under reduced pressure. Add sodium acetate trihydrate (2. g) and palladium hydroxide / carbon (20%, 0.3 g) to a solid residue of a mixture of ethyl acetate and isopropyl alcohol (1 〇, 55 mL). And the resulting mixture was shaken overnight in a Parr apparatus under a hydrogen atmosphere (50 PSI). The reaction mixture was then filtered on a pad of EtOAc (EtOAc) (EtOAc). _ ethyl formate. Step B: Synthesis of 3-methylindenyl-thieno[3,2-0]pyridine-6-carboxylic acid ethyl ester 157102.doc 201217379 To a 3-methyl-containing benzo[3,2-6]. ΑΓ-bromobutaneimine (24 g) was added to a solution of pyridinium-6-caprate (12 g) in four vaporized carbon (50 mL), followed by AIBN (50 mg). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was cooled, the solid was removed by hydrazine and washed thoroughly with four carbonized carbon. The filtrate was evaporated under reduced pressure, and the residue was dissolved in hexanes (2 mL) and the mixture was heated at 80 ° C for 1 hour. The cooled reaction mixture was diluted with water and purified by the addition of a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate The residue was purified by flash chromatography (EtOAc / EtOAc /EtOAc) Step C: Synthesis of thieno[3,2-6]pyridine-3,6-dicarboxylic acid 6-acetic acid ethyl 3-mercapto-thieno[3,2-6]pyridine-6-decanoate ( A mixture of 0.8 g, 3.4 mmol) and aminosulfonic acid (0.66 g, 6.8 mmol) in a mixture of tert-butanol/tetrahydrofuran/water (1/1/1 '60 mL) was stirred for 2 min. A solution of sodium chlorite (0.55 g, 6 mmol) and potassium dihydrogen phosphate (1 36 g, 1 mmmmo) in water (5 mL) was added and the resulting yellow solution was stirred for 20 min. The reaction mixture was diluted with water and ethyl acetate, and the solid formed was collected by filtration, washed with water and dried in a vacuum oven at 60*>c. The filtrate was extracted with EtOAc. EtOAc (EtOAc)EtOAc. 3,6-dicarboxylic acid 6-B g. Preparation 25: Synthesis of 5-gas-2-ethyl-aniline 5-Hydroxy-2-ethylaniline was synthesized according to the procedure shown in Scheme 25. 157102.doc -149- 201217379

NHAcNHAc

ch3Ch3

nh2Nh2

步驟DStep D

流程25Process 25

步驟A:合成7V-(4-乙基-苯基）-乙醯胺向4-乙基苯胺（5.0 g，41.32 mmol)與°比唆（20 mL)之混合物中添加乙酸酐（4.3 mL，45.45 mmol)，且在室溫下擾拌所得混合物隔夜。使反應混合物分配於二氣甲烷與鹽酸水溶液之間。分離有機層，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得6.857 g呈棕色固體形式之iV-(4-乙基-苯基）-乙醯胺。步驟B :合成;V-(4-乙基-3-硝基-苯基）-乙醯胺向濃硫酸（8 mL)中逐份添加#-(4-乙基-苯基）-乙醯胺（2.0 g，12.27 mmol)，且將混合物冷卻至-15°C，接著逐滴添加發煙硝酸（0.505 mL，12.27 mmol)。將反應混合物在-20°C 至-10°C的溫度範圍中攪拌75分鐘。接著將反應混合物傾入冰中，藉由添加碳·酸鈉中和，且以乙醚萃取兩次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/EtOAc，100/0至70/30)純化粗殘餘物，獲得2.231 g(88%產率）#-(4-乙基-3-硝基-苯基）-乙醯胺。 157102.doc -150- 201217379 步驟C:合成4-乙基-3-硝基-苯胺在回流下加熱#-(4-乙基-3-硝基-苯基）-乙醯胺（1.0 g)與濃鹽酸（5 mL)之混合物4小時。接著冷卻反應混合物，藉由添加氫氧化鈉鹼化且以乙醚萃取兩次。經無水硫酸鈉乾燥經合併之有機萃取物，過濾且減壓蒸發，未經進一步純化即獲得0.601 g 4-乙基-3-硝基-苯胺》MS = 167 [M+H]+。步驟D :合成4-氯-1-乙基-2-硝基-苯（第32042-86頁）向4-乙基-3-硝基-苯胺（80%，0.25 g，1.20 mmol)於濃鹽酸（2 mL)與水（4 mL)之混合物中的懸浮液中逐滴添加亞硝酸鈉（0.11 g，1.32 mmol)於水（1 mL)中之溶液。在〇°C下授拌反應混合物5分鐘，接著添加腺（15 mg，0.24 mmol)。搜拌所得混合物10分鐘，接著在8(TC下傾入氯化亞銅（〇.18 g ’ 1.8 mmol)於濃鹽酸（1.5 mL)與水（0.6 mL)之混合物中的懸浮液中。在80。(：下攪拌反應混合物2小時，接著以乙酸乙6旨萃取。有機萃取物以氫氧化鈉水溶液（丨μ)及水洗條’經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得200 mg(90%產率）呈油狀之4-氣-1-乙基_2_硝基-苯。利用上述程序及適當起始物質製備4-氣4-(4-曱氧基_丁基）-2-硝基-苯。步驟E:合成5_氣_2_乙基-苯胺向4-氣-1_乙基-2_硝基-苯（0.57 g，3.08 mm〇1)K乙酸乙 S旨與乙醇中之混合物(1/1 ’ 3〇 mL)中之溶液中添加氯化亞錫（1.7 g，9·24 mmol)，且在室溫下攪拌所得混合物隔夜。接著將反應混合物傾入水中，且藉由添加碳酸鉀鹼化直至 157102.doc -151- 201217379 PH>10。以二氣甲烷萃取所得混合物；有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法純化粗殘餘物，獲得0.503 g呈棕色油狀之5_氣_2_乙基_苯胺。製備26 :合成（7-胺基-6-甲氧基-萘_2_基）_甲醇根據流程26中所示之方法，合成（7_胺基_6甲氧基_萘_2_ 基）-曱醇。Step A: Synthesis of 7V-(4-ethyl-phenyl)-acetamide To a mixture of 4-ethylaniline (5.0 g, 41.32 mmol) and 唆 (20 mL), acetic anhydride (4.3 mL, 45.45 mmol) and the resulting mixture was scrambled overnight at room temperature. The reaction mixture was partitioned between di-methane and aqueous hydrochloric acid. The organic layer was separated, dried over anhydrous NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Step B: Synthesis; V-(4-ethyl-3-nitro-phenyl)-acetamide Adding #-(4-ethyl-phenyl)-acetamidine to concentrated sulfuric acid (8 mL) Amine (2.0 g, 12.27 mmol), and the mixture was cooled to -15 <0>C then EtOAc (0.55 mL, 12. The reaction mixture was stirred at a temperature ranging from -20 ° C to -10 ° C for 75 minutes. The reaction mixture was then poured into ice, neutralized by addition of sodium carbonate and extracted twice with diethyl ether. The combined organic extracts were dried with anhydrous sodium The crude residue was purified by flash chromatography (hexane /EtOAcEtOAc /EtOAc /EtOAc - Acetamide. 157102.doc -150- 201217379 Step C: Synthesis of 4-ethyl-3-nitro-aniline heated under reflux #-(4-ethyl-3-nitro-phenyl)-acetamide (1.0 g) Mixture with concentrated hydrochloric acid (5 mL) for 4 hours. The reaction mixture was then cooled, basified by addition of sodium hydroxide and extracted twice with diethyl ether. The combined organic extracts were dried with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step D: Synthesis of 4-chloro-1-ethyl-2-nitro-benzene (pages 32042-86) to 4-ethyl-3-nitro-phenylamine (80%, 0.25 g, 1.20 mmol) in concentrated A solution of sodium nitrite (0.11 g, 1.32 mmol) in water (1 mL) was added dropwise to a suspension of a mixture of hydrochloric acid (2 mL) and water (4 mL). The reaction mixture was stirred at 〇 ° C for 5 min, followed by the addition of gland (15 mg, 0.24 mmol). The resulting mixture was mixed for 10 minutes, then poured into a suspension of cuprous chloride (〇.18 g '1.8 mmol) in a mixture of concentrated hydrochloric acid (1.5 mL) and water (0.6 mL). 80. (: The reaction mixture was stirred for 2 hours, followed by extraction with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate with aqueous sodium hydroxide (MgSO) and water. (90% yield) 4-Oth-1-ethyl-2-nitro-benzene as an oil. Preparation of 4-gas 4-(4-decyloxy-butyl) using the above procedure and appropriate starting material -2-Nitro-benzene. Step E: Synthesis of 5-gas-2-ethyl-aniline to 4-gas-1-ethyl-2-nitro-benzene (0.57 g, 3.08 mm 〇1) K acetic acid Stannous chloride (1.7 g, 9·24 mmol) was added to a solution in a mixture (1/1 '3 mL) in ethanol, and the resulting mixture was stirred overnight at room temperature. Into the water, and alkalized by the addition of potassium carbonate until 157102.doc -151 - 201217379 PH > 10. The resulting mixture was extracted with di-methane; the organic extract was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by chromatography to give 0.53 g (yield::::::::::::: Methanol (7-Amino-6-methoxy-naphthalene-2-yl)-nonanol was synthesized according to the procedure shown in Scheme 26.

流程26Process 26

步驟A :合成7-溴-3-曱氧基_萘_2_甲酸甲酯在回流下加熱7-溴-3-羥基.萘_2_甲酸c/zew 1990，33(1)，171)(5.3 g ’ 19.85 mm〇l)、碳酸鉀（13.7 g， 99.25 mmol)及硫酸二甲酯（3 8 ，45 66 mmol)於丙酮（50 mL)中之混合物3.5小時。接著過濾反應混合物；以水（5 mL)處理濾液’且攪拌所得混合物1〇分鐘。減壓濃縮反應混合物，使殘餘物溶解於二氣甲烷中，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得5.946 g 7_ 溴-3 -曱氧基-萘-2-甲酸曱酷。Step A: Synthesis of methyl 7-bromo-3-indolyl_naphthalene-2-carboxylate under reflux. 7-Bromo-3-hydroxy.naphthalene-2-carboxylic acid c/zew 1990, 33(1), 171) (5.3 g ' 19.85 mm 〇l), a mixture of potassium carbonate (13.7 g, 99.25 mmol) and dimethyl sulfate (38, 45 66 mmol) in acetone (50 mL) for 3.5 hours. The reaction mixture was then filtered; the filtrate was treated with water (5 mL) and the mixture was stirred for 1 min. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ It’s cool.

步驟BStep B

合成7-溴_3-甲氧基·萘-2-甲酸Synthesis of 7-bromo-3-methoxynaphthalene-2-carboxylic acid

157102.doc -152- 201217379 向7·溴小甲氧基冬2_曱酸曱醋（5.9 g，20函〇1)於乙醇 (100 mL)中之溶液中添加氫氧化鈉〇 6 g，4〇 mm〇i)於水 (30 mL)中之溶液，且所得混合物在回流下加熱2小時。接著冷卻反應混合物且減壓濃縮。藉由添加鹽酸水溶液酸化殘餘物直至約pH 3。以二氣甲烷萃取所得混合物兩次，且合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得5.329 g呈奶白色固體形式之7_溴_3·曱氧基·萘_2_甲酸。步驟C :合成7-溴-3-甲氧基-萘_2-基胺在回流下加熱7-溴-3-甲氧基-萘_2_甲酸Q 〇 g，3 56 mmol)與亞硫醯氯（5 mL)之混.合物2小時。減壓蒸發反應混合物，且使殘餘物溶解於丙酮（30 mL)*。向此溶液中逐滴添加疊氮化鈉（0.23 g)於水（0.5 mL)中之溶液，且在室溫下攪拌所得混合物15分鐘。添加水（100 mL),且以苯（5〇 mL)萃取所得混合物兩次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且加熱至回流丨小時。接著添加氫氧化鉀水溶液（50%，1〇〇 mL)，且在回流下加熱所得混合物i小時。冷卻反應混合物，分離有機層且以二氯甲烷萃取水層兩次°合併之有機萃取物經無水硫酸納乾燥，過滤且減壓蒸發。藉由急驟層析法（己烧/EtOAc)純化粗殘餘物，獲得 0.678 g呈奶白色固體形式之7_溴_3·甲氧基_萘_2_基胺。步驟D :合成τν-(7_溴_3_甲氧基_萘_2_基）·乙醯胺在室溫下攪拌7-溴-3-曱氧基-萘-2-基胺（2.2 g，8.76 mmol)、乙酸酐（1.4 g，13.14 mmol)與。比《定（20 mL)之混合 157102.doc •153· 201217379 物3小時。添加水（300 mL)，且藉由過濾收集固體沈澱物，且以水充分洗滌。使固體殘餘物溶解於二氯甲烧中，經無水琉酸納乾燥’過渡且減塵蒸發，獲得2.569 g呈淺粉紅色固體形式之#-(7-溴-3-甲氧基-萘·2_基）_乙醯胺。步驟Ε:合成iV-(7-氰基-3-甲氧基-萘_2-基）_乙酿胺向#-(7-溴-3 -曱氧基-萘-2-基）-乙醯胺〇 2 g , 4 〇 mm〇1) 於水與况#-二曱基曱醯胺的先前經脫氣之混合物（3/1，4〇 mL)中的溶液中添加氰化辞（〇·28 g，2.4 mmol)，隨後添加參（二苯亞甲基丙酮）二把（0)(0.18 g，〇·22 mmol)及1，Γ-雙 (二苯膦基）二茂鐵（0.27 g，0.48 mmol)，且在i20°C下加熱所得混合物隔夜。將反應混合物傾入水中且以乙酸乙醋萃取。有機萃取物以水洗滌3次’經無水硫酸納乾燥，過渡且減壓蒸發。藉由急驟層析法（己院/EtOAc)純化粗殘餘物’獲得0.621 g呈奶白色固體形式之#-(7•氰基_3_曱氧基_ 萘-2-基）-乙醯胺。MS = 241 [M+H]+。步驟F:合成7-胺基-6-甲氧基-萘-2-甲酸向(7-氰基-3-甲氧基-秦-2 -基）-乙醯胺（〇.2 g，0.83 mmol)於乙二醇（2 mL)中之懸浮液中添加氫氧化鈉（〇_17 g，4.17 mmol)，且在回流（195°C )下加熱所得混合物隔夜。接著冷卻反應混合物，添加水且將pH值調整至4。藉由過濾收集沈澱物且乾燥，獲得0.156 g呈棕色固體形式之 7-胺基-6-甲氧基-萘-2-曱酸。MS=218 [M+H]+。步驟G:合成（7-胺基·6·甲氧基_萘_2·基）-甲醇在〇C下，向7 -胺基-6-甲氧基-蔡-2·甲酸（0.1 g，0.46 157102.doc •154- 201217379 mmol)於無水四氫呋喃（2 mL)中之懸浮液中添加甲硼烷四氫呋喃複合物（1 mL，0.92 mmol)，且在室溫下攪拌所得混合物隔夜。藉由添加甲醇淬滅反應混合物，接著在室溫下攪拌2小時。減壓濃縮所得混合物，分配於二氣曱烷與碳酸氫納飽和水溶液之間。分離有機層’經無水硫酸納乾燥，過濾且減壓蒸發，未經進一步純化即獲得（7_胺基-心甲氧基-萘-2-基）-甲醇。MS=204 [M+H]+。製備27:合成ι_(4·甲氧基_ 丁基）_4_硝基苯根據流程27中所示之方法，合成卜⑷甲氧基_ 丁基）_4石肖基-苯。157102.doc -152- 201217379 Add 7 g of sodium hydroxide 〇6 g to a solution of 7·bromo small methoxy winter 2_capric acid vinegar (5.9 g, 20 〇 1) in ethanol (100 mL) 〇mm〇i) a solution in water (30 mL) and the mixture was heated under reflux for 2 h. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was acidified by the addition of aqueous hydrochloric acid until about pH 3. The resulting mixture was extracted twice with methylene chloride, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 5.29 g of br. _ Formic acid. Step C: Synthesis of 7-bromo-3-methoxy-naphthalene-2-ylamine under reflux. 7-Bromo-3-methoxy-naphthalene_2-carboxylic acid Q 〇g, 3 56 mmol) and sulphur A mixture of hydrazine (5 mL) was added for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in acetone (30 mL). A solution of sodium azide (0.23 g) in water (0.5 mL) was added dropwise to this solution, and the mixture was stirred at room temperature for 15 minutes. Water (100 mL) was added, and the resulting mixture was extracted twice with benzene (5 mL). The combined organic extracts were dried over anhydrous sodium s Then, a potassium hydroxide aqueous solution (50%, 1 mL) was added, and the resulting mixture was heated under reflux for 1 hour. The reaction mixture was cooled, the organic layer was evaporated, mjjjjd The crude residue was purified by flash chromatography eluting EtOAc (EtOAc) Step D: Synthesis of τν-(7_bromo-3-ylmethoxy-naphthalene-2-yl)·acetamide The 7-bromo-3-indolyl-naphthalen-2-ylamine (2.2) was stirred at room temperature. g, 8.76 mmol), acetic anhydride (1.4 g, 13.14 mmol) and. A mixture of 定 (20 mL) 157102.doc • 153· 201217379 for 3 hours. Water (300 mL) was added, and the solid precipitate was collected by filtration and washed thoroughly with water. The solid residue was dissolved in methylene chloride, dried over anhydrous sodium phthalate, and the mixture was evaporated and evaporated to afford 2.69 g of #-bromo-3-methoxy-naphthalene as a light pink solid. 2_base) _ acetamidine. Step Ε: Synthesis of iV-(7-cyano-3-methoxy-naphthalene-2-yl)-ethylamine to #-(7-bromo-3-indolyl-naphthalen-2-yl)-B Amidoxime 2 g , 4 〇mm〇1) Add cyanide in a solution of water and a previously degassed mixture of #-didecylguanamine (3/1, 4〇mL) (〇 · 28 g, 2.4 mmol), followed by the addition of two (0) (0.18 g, 〇·22 mmol) and 1, bis-bis(diphenylphosphino)ferrocene (0.27) g, 0.48 mmol), and the resulting mixture was heated at i20 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed 3 times with water, dried over anhydrous sodium sulfate, and then evaporated and evaporated. Purification of the crude residue by flash chromatography (H.sub.EtOAc/EtOAc) afforded <RTI ID=0.0>&&&&&&&&&&&&&&& . MS = 241 [M+H]+. Step F: Synthesis of 7-amino-6-methoxy-naphthalene-2-carboxylic acid to (7-cyano-3-methoxy-qin-2-yl)-acetamide (〇.2 g, 0.83) Sodium hydroxide (〇_17 g, 4.17 mmol) was added to a suspension of EtOAc (2 mL) and the mixture was warmed to reflux (195 ° C) overnight. The reaction mixture was then cooled, water was added and the pH was adjusted to 4. The precipitate was collected by filtration and dried to give <RTIgt;</RTI> MS = 218 [M+H]+. Step G: Synthesis of (7-amino-6-methoxy-naphthalene-2-yl)-methanol to 7C to 7-amino-6-methoxy-cai-2·carboxylic acid (0.1 g, 0.46 157102.doc • 154-201217379 mmol) A suspension of borane tetrahydrofuran (1 mL, 0.92 mmol) was added to a suspension in anhydrous tetrahydrofuran (2 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of methanol and then stirred at room temperature for 2 hr. The resulting mixture was concentrated under reduced pressure and partitioned between dioxane and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated evaporated. MS=204 [M+H]+. Preparation 27: Synthesis of ι_(4·methoxy-butyl)_4-nitrobenzene According to the procedure shown in Scheme 27, (4) methoxy-butyl)-4 succinyl-benzene was synthesized.

OMe 向氫化鈉（礦物油中峨分散液，Q 49 g，i2 3g 於無水四氫。夫喃中之懸浮液中逐滴添加4_(4·硝基苯基）小丁醇（2 g，H).26随叫，且在室溫下搜拌所得混合物⑽ 鐘。添加蛾甲院（2 mL)，且授拌所得混合物62小時。減塵蒸發反應混合物；使殘餘物分配於：氯甲统與水之間“分OMe Add 4_(4.nitrophenyl)butanol (2 g, H) dropwise to a suspension of sodium hydride (mineral oil in hydrazine dispersion, Q 49 g, i2 3 g in anhydrous tetrahydrofuran). .26 was called, and the resulting mixture was mixed for 10 minutes at room temperature. Moths (2 mL) was added and the resulting mixture was mixed for 62 hours. The reaction mixture was evaporated to lightness; the residue was partitioned: Chloroform Between the water and the water

離有機層’經無水硫酸納乾燥，過攄且減壓蒸發。藉由I 驟層析法（Ε·㈣，叫純化殘餘物，獲得i.996 g呈;; 狀之1-(4-甲氧基_丁基）_4_硝基苯。製備28:合成4-(4_氯_2_硝基_苯基）丁·^醇根據流程33中所示之方法合成4·⑷氣·2_硝基.苯基）_ 丁· 157102.doc •155· 201217379The organic layer was dried over anhydrous sodium sulfate, dried and evaporated. By I-Chromatography (Ε·(4), the residue is purified to give i.996 g: 1-(4-methoxy-butyl)_4_nitrobenzene. Preparation 28: Synthesis 4 -(4_Chloro-2-nitro-phenyl)butanol was synthesized according to the method shown in Scheme 33. 4·(4)Ga·2_Nitro.phenyl)_丁·157102.doc •155· 201217379

流程28 向4_氣-1-(4-曱氧基-丁基）-2-石肖基-苯（0.2 g ’ 0.995 mmol)於二氣甲烧（10 mL)中之經冷卻混合物中添力口三漠化硼（1.24 g，4.925 mmol)，且在室溫下攪拌所得混合物隔夜。以乙酸乙酯萃取反應混合物，且有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得80 mg呈油狀之4-(4 -氣- 2-·δ肖基-苯基）-丁-1-醇。製備29 :合成7-甲氧基-喹啉-6-基胺根據流程29中所示之方法，合成7-甲氧基-喹啉-6-基胺。Scheme 28 Addition of a cooled mixture to 4-methyl-1-(4-decyloxy-butyl)-2-stone-based-benzene (0.2 g '0.995 mmol) in two gas (10 mL) Boron was partially deserted (1.24 g, 4.925 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m. Phenyl)-butan-1-ol. Preparation 29: Synthesis of 7-methoxy-quinolin-6-ylamine 7-Methoxy-quinolin-6-ylamine was synthesized according to the procedure shown in Scheme 29.

步驟Α:合成乙酸3-乙酿基胺基-苯酯在0°C下，向3-胺基苯酚（25 g，225.0 mmol)及4-二甲基胺基吡啶（催化量）於吡啶（100 mL)中之混合物中緩慢添加 157102.doc -156- 201217379 乙酸酐（53 mL ’ 572.0 mmol)，且在室溫下攪拌反應混合物 62小時。添加水（1 L)，且以乙酸乙酯萃取所得混合物。有機萃取物以鹽酸水溶液、碳酸氮納飽和水溶液及水洗條，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得21.79 g呈固體形式之乙酸3 -乙酿基胺基_苯醋。第二批（2.978 g)此物質在靜置後自水層析出，且藉由過滤收集。步驟B:合成乙酸5-乙醯基胺基-2-硝基-苯醋在-15°C下，向發煙硝酸（1〇9 mL)中逐份添加乙酸3_乙醯基胺基-苯酯（21.7 g，112.4 mmol)，保持溫度低於_丨〇。〇。反應混合物在-10 °C下擾拌3小時，接著傾入冰中。接著以乙酸乙酯萃取所得混合物3次，且以鹽水洗滌合併之有機萃取物’經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（EtOAc/己烷，1/1)純化粗殘餘物，獲得2〇 6〇8 g(77%產率）呈奶白色固體形式之乙酸5•乙醯基胺基_2硝基-苯酯。步驟C:合成iV-(3-羥基-4-硝基-苯基）-乙醯胺在室溫下攪拌乙酸5-乙醯基胺基·2_硝基-苯酯（20.5 g， 85.77 mmol)及碳酸鉀（26 g，188.4 mmol)於甲醇（200 mL) 中之混合物3小時。減壓濃縮反應混合物，添加水（25〇 mL)且藉由添加濃鹽酸酸化所得混合物。將析出之固體濕磨’藉由過濾收集，以水洗滌且真空乾燥，獲得#·(3_羥基-4-硝基-苯基）_乙酿胺。步驟D ·*合成iV-(3-甲氧基-4-硝基-苯基）_乙醯胺 157102.doc -157- 201217379 向^(3-羥基-4_硝基-苯基）_乙醯胺（2 g，1〇15 mm〇i)於無水况沁二甲基甲醯胺（5 mL)中之溶液中添加碳酸鉀（2.6 g，18.88 mmol)，隨後添加碘甲烷（〇 71社，^ 16 mmol)，且在室溫下攪拌反應混合物】小時。接著添加第二部分之碘曱烷（〇·15 mL)，且攪拌所得混合物丨小時。添加乙酸乙酯（100 mL)及鹽水（1〇0 mL)，分離有機層，以水洗滌兩次，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得甲氧基-4-硝基-笨基）·乙醯胺。步驟E:合成3-甲氧基_4_硝基-苯胺回/机7V-(3-甲氧基_4-石肖基-苯基）-乙醢胺（16.6 g，78.67 mmol)與鹽酸水溶液（1 5 M，2〇〇 mL)之混合物直至獲得澄清溶液。藉由添加碳酸鉀水溶液鹼化反應混合物，接著以二氣甲烷（200 mL)萃取4次；合併之有機萃取物經無水硫酸納乾燥’過攄且減壓蒸發，獲得1356 g(定量產率）呈黃色固體形式之3_曱氧基硝基-苯胺。MS=109 [M+H]+ » 步驟Γ:合成7-甲氧基-6_硝基-喹啉在100°C下，向3-甲氧基-4-硝基-苯胺（13.4 g，80.0 mmol)、五氧化二砷（11 〇 g，" ο mmol)與丙三醇（33 mL ’ 216.0 mmol)之混合物中逐滴添加濃硫酸7 mL， 88.〇 mmo1)。反應混合物接著在15(TC至160°C之溫度範圍中加熱2小時，接著冷卻。添加水（2〇〇 mL)，且以乙酸乙醋萃取所得混合物四次。合併之有機萃取物經無水硫酸鈉乾燥’過滤且減壓蒸發。藉由急驟層析.法（Et〇Ac)純化粗殘餘物’獲得9.00 g(61%產率）呈橙色固體形式之7-曱氧 157102.doc -158· 201217379Step Α: Synthesis of 3-ethylenylamino-phenyl acetate to 3-aminophenol (25 g, 225.0 mmol) and 4-dimethylaminopyridine (catalytic amount) in pyridine at 0 ° C 157102.doc -156 - 201217379 acetic anhydride (53 mL '572.0 mmol) was slowly added to the mixture in 100 mL), and the mixture was stirred at room temperature for 62 hr. Water (1 L) was added, and the resulting mixture was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate (MgSO4), filtered and evaporated. vinegar. The second batch (2.978 g) of this material was chromatographed from water after standing and collected by filtration. Step B: Synthesis of 5-ethinylamino-2-nitro-benzene vine acetate Acetic acid 3-ethylaminomethyl group was added to fuming nitric acid (1〇9 mL) at -15 °C. Phenyl ester (21.7 g, 112.4 mmol), keeping the temperature below 丨〇. Hey. The reaction mixture was scrambled at -10 °C for 3 hours and then poured into ice. The mixture was extracted with EtOAc (3 mL). The crude residue was purified by flash chromatography (EtOAc / hexanes / 1 / 1) to afford EtOAc EtOAc EtOAc Nitro-phenyl ester. Step C: Synthesis of iV-(3-hydroxy-4-nitro-phenyl)-acetamide Stabilized 5-ethoxymethylamino-2-nitro-phenyl acetate (20.5 g, 85.77 mmol) at room temperature And a mixture of potassium carbonate (26 g, 188.4 mmol) in methanol (200 mL) for 3 h. The reaction mixture was concentrated under reduced pressure, water (25 mL) was added and the mixture was acidified by adding concentrated hydrochloric acid. The precipitated solid wet-grinding was collected by filtration, washed with water and dried in vacuo to give #·(3-hydroxy-4-nitro-phenyl)-ethylamine. Step D ·* Synthesis of iV-(3-methoxy-4-nitro-phenyl)-acetamide 157102.doc -157- 201217379 to ^(3-hydroxy-4_nitro-phenyl)_B Potassiumamine (2.6 g, 18.88 mmol) was added to a solution of guanamine (2 g, 1 〇 15 mm 〇i) in anhydrous dimethylformamide (5 mL), followed by iodomethane (〇71) , ^ 16 mmol), and the reaction mixture was stirred at room temperature for an hour. Next, a second portion of iodonane (〇·15 mL) was added, and the resulting mixture was stirred for a few hours. Ethyl acetate (100 mL) and brine (1 mL) were evaporated, evaporated, evaporated, evaporated. Base) · acetamidine. Step E: Synthesis of 3-methoxy-4-yl-aniline back/machine 7V-(3-methoxy-4-4-stone-phenyl-phenyl)-acetamide (16.6 g, 78.67 mmol) and aqueous hydrochloric acid ( A mixture of 1 5 M, 2 mL) was obtained until a clear solution was obtained. The reaction mixture was basified by the addition of aqueous potassium carbonate solution, and then extracted four times with di-methane (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate. ) 3-methoxyl-nitroaniline in the form of a yellow solid. MS=109 [M+H]+ » Step Γ: Synthesis of 7-methoxy-6-nitro-quinoline at 100 ° C to 3-methoxy-4-nitro-aniline (13.4 g, 80.0 mmol), arsenic pentoxide (11 〇g, " ο mmol) and glycerol (33 mL '216.0 mmol) were added dropwise 7 mL of concentrated sulfuric acid, 88. 〇mmo1). The reaction mixture was then heated at 15 (TC to 160 ° C for 2 hours, followed by cooling. Water (2 mL) was added and the mixture was extracted four times with ethyl acetate. Drying with sodium <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 201217379

基-6-硝基-唾琳D 步驟G:合成7-甲氡基-喹啉-6-基胺在回流下加熱7 -甲氧基-6-硝’基-啥琳（5 g，24.0 mmol)、鐵粉（9.8 g，172 mmol)與氯化銨（9.1 g，172 mmol)於乙醇與水之混合物（3/1 ’ 160 mL)中的混合物隔夜《所得混合物經由CELITEtm墊過濾’減壓蒸發濾液且使殘餘物分配於水與乙酸乙酯之間。分離有機層，經無水硫酸鈉乾燥，過遽且減壓蒸發。藉由急驟層析法（Et〇Ac)純化殘餘物，獲得3.551 g呈灰色固體形式之7_甲氧基_喹啉_6基胺。製備30 :合成iV2_[2-(第三丁基_二甲基_矽烷基氧基）_乙基]_ 7-甲氧基·喹琳-2,6-二胺根據流程30中所示之方法合成#2_[2_(第三丁基-二甲基· 石夕烧基氧基）-乙基]-7-甲氧基_啥琳_2,6_二胺。-6-6-Nitro-Salina D Step G: Synthesis of 7-methylindolyl-quinolin-6-ylamine heated under reflux of 7-methoxy-6-nitro-yl-indole (5 g, 24.0 Mixture of mmol), iron powder (9.8 g, 172 mmol) and ammonium chloride (9.1 g, 172 mmol) in a mixture of ethanol and water (3/1 '160 mL) overnight "Filtered mixture is filtered through CELITEtm pad" minus The filtrate was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc EtOAc) eluting Preparation 30: Synthesis of iV2_[2-(t-butyl-dimethyl-decyloxy)-ethyl]-7-methoxyquinolin-2,6-diamine according to Scheme 30 Method Synthesis #2_[2_(T-butyl-dimethyl-stone)-ethyl]-7-methoxy_啥琳_2,6-diamine.

流程30 步驟A :合成（E)-3-乙氧基甲氧基_4硝基_苯基）·丙 157102.doc •159· 201217379 稀酿胺向 3,3-二乙氧基-丙酸（五《"· 乂（>g. C/zem. 2001，2041) (〇·20 g，1.10 mmol)中添加亞硫醯氯（1 mL)，且在80°C下加熱所得混合物1小時。接著減壓蒸發反應混合物，且使殘餘物溶解於二氣甲烷（2 mL)中。在〇。(：下，向3_甲氧基_ 4-硝基-苯胺（0.13 g，0.77 mmol)及吡咬（0.12 g，1.54 mmol)於二氣甲烧（5 mL)中之混合物中添力σ所得溶液。在至/凰下搜拌反應混合物隔夜’接著藉由添加鹽酸水溶液（6 Μ)中和ΡΗ值。以乙酸乙酯萃取所得混合物兩次，且合併之有機萃取物以水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得225 mg呈橙色固體形式之（E)_3_乙氧基项_(3_甲氧基-4-硝基-苯基）_丙烯醯胺。步驟B:合成7-甲氧基-6-硝基-1孖-喹啉·2_鲖在冷卻下向（Ε)-3-乙氧基-ΛΓ-(3-甲氧基-4-硝基-苯基）_丙烯酿胺（225 mg)中添加濃硫酸（1 mL)，且在室溫下授拌所得混合物1.5小時。接著將反應混合物傾入冰-水中且攪拌i 小時。藉由過濾收集析出之固體且真空乾燥，獲得142 mg 呈棕色固體形式之7-曱氧基-6-硝基喹啉_2_綱。 MS;221 [M+H]+。步驟C:合成2-氯-7-甲氧基硝基-喹啉在110C下加熱7-甲氧基-6-石肖基_1丑_啥琳_2•酮（〇 I] g)與氧氣化磷（1 mL)之混合物2小時。接著冷卻所得混合物且傾入冰中。藉由過濾收集所形成之固體且真空乾燥，獲得〇·Π9 g呈棕色固體形式之2-氣-7-甲氧基-6·硝基_喹啉。 157102.doc •160· 201217379 步驟D ·合成2-(7-f氧基·6-硝基·喹啉_2_基胺基）_乙醇在90C下加熱2-氯-7-曱氧基-6-石肖基-喧咐（〇.1 g, 0.42 mmol)與2-胺基乙醇（38 μΐ^，0.63 mmol)於無水l，4-二噁烧 (5 mL)中之混合物隔夜。添加第二部分之2胺基乙醇（38 μΐ^，0.63 mmol)且在90t下加熱所得混合物隔夜。接著減壓濃縮反應混合物，殘餘物以水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得7〇 mg呈固體形式之2-(7-甲氧基-6-硝基-喧琳_2_基胺基）_乙醇。 MS=264 [M+H]+ 〇步驟E :合成2-(6-胺基-7-甲氡基-喹啉_2_基胺基）_乙醇在回流下加熱2-(7-甲氧基-6-硝基-喹啉-2-基胺基）-乙醇 (0.5 g ’ 1.90 mmol)、鐵粉（〇.32 g，5 7〇 mm〇1)及氯化銨 (0·32 g，5.70 mmol)於乙醇與水之混合物（3/1.，16 mL)* 的混合物2小時。接著經由CELITEtm墊過濾反應混合物，減壓蒸發濾液，且以二氣甲烷與曱醇之混合物（9/1 , 5〇 mL)濕磨殘餘物1〇次。減壓濃縮殘餘物，獲得〇 425 g呈棕色固體形式之2-(6-胺基-7-甲氧基-喹啉_2·基胺基）-乙醇。步驟F :合成λγ2_[2-(第三丁基-二甲基_矽烷基氧基）·乙基】_ 7-甲氧基-喹琳_2,6-二胺在室溫下攪拌2-(6-胺基-7-甲氧基-喹啉-2-基胺基）-乙醇 (〇·4 g，1.72 mmol)、第三丁基二甲基氣矽烷（0.8 g，515 及咪唑（0.4 g，5.15 mmol)於二氣曱烷（20 mL)中之混合物62小時。以水洗滌所得混合物且分離有機層，經無水硫酸納乾燥，過濾且減壓蒸發。藉由急驟層析法（Et〇Ac/ 157102.doc 201217379 己烷’ 3/7)純化粗殘餘物，獲得2〇6 mg呈棕色油狀之#2-[2-(第二丁基-二甲基_矽烷基氧基）乙基]_7·曱氧基喹啉_ 2,6-二胺。MS=348 [M+H]+。製備31 .合成（2，·胺基_4’-氣-聯苯_4_基）_甲醇根據流程31中所示之方法，合成（2，_胺基_4,_氣_聯苯_4_ 基）-甲醇。Scheme 30 Step A: Synthesis of (E)-3-ethoxymethoxy_4nitro-phenyl)·propane 157102.doc •159· 201217379 Thin amine to 3,3-diethoxy-propionic acid (Five ""· 乂(>g. C/zem. 2001, 2041) (〇·20 g, 1.10 mmol) was added with sulphur chloride (1 mL), and the mixture was heated at 80 ° C. The reaction mixture was evaporated under reduced pressure and the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs And a mixture of pyridine (0.12 g, 1.54 mmol) in a mixture of two gas (5 mL), adding the solution of σ. Mix the reaction mixture under ～凤凰 overnight, then add aqueous hydrochloric acid (6 Μ) The enthalpy was neutralized. The mixture was extracted twice with ethyl acetate. EtOAc (EtOAc m. _ethoxy item _(3_methoxy-4-nitro-phenyl)-propenylamine. Step B: Synthesis of 7-methoxy-6-nitro-1 quinone-quinoline·2_鲖(冷却)-3-ethoxy-oxime-(3-methoxy- under cooling) Concentrated sulfuric acid (1 mL) was added to 4-nitro-phenyl)-acrylamide (225 mg), and the resulting mixture was stirred at room temperature for 1.5 hours. Then the reaction mixture was poured into ice-water and stirred for 1 hour. The precipitated solid was collected by filtration and dried in vacuo to give </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Synthesis of 2-chloro-7-methoxynitro-quinoline at 110C to heat 7-methoxy-6-stone succinyl-1 ugly 啥 _2 _2 ketone (〇I] g) with oxygenated phosphorus (1 Mixture of mL) for 2 hours. The resulting mixture was then cooled and poured into ice. The solid formed was collected by filtration and dried in vacuo to give y········ ·Nitro-quinoline. 157102.doc •160· 201217379 Step D ·Synthesis of 2-(7-foxy·6-nitroquinoline-2-ylamino)-ethanol by heating 2-chloro at 90C -7-decyloxy-6-succinyl-hydrazine (〇.1 g, 0.42 mmol) and 2-aminoethanol (38 μΐ^, 0.63 mmol) in anhydrous l,4-dioxacin (5 mL) The mixture was overnight. A second portion of 2 aminoethanol (38 μΐ, 0.63 mmol) was added and at 90t The resulting mixture was heated overnight. The mixture was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjJ Base-6-nitro-喧琳_2_ylamino)_ethanol. MS=264 [M+H]+ 〇Step E: Synthesis of 2-(6-amino-7-methylindolyl-quinolin-2-ylamino)_ethanol 2-(7-methoxy) heated under reflux 5--6-nitro-quinolin-2-ylamino)-ethanol (0.5 g ' 1.90 mmol), iron powder (〇.32 g, 5 7〇mm〇1) and ammonium chloride (0·32 g) , 5.70 mmol) of a mixture of ethanol and water (3/1., 16 mL)* for 2 hours. The reaction mixture was then filtered through a pad of EtOAc (EtOAc) elute. The residue was concentrated under reduced pressure to give EtOAc (EtOAc: EtOAc Compound: Step F: Synthesis of λγ2_[2-(t-butyl-dimethyl-decyloxy)ethyl]-7-methoxy-quinolin-2,6-diamine Stir at room temperature 2- (6-Amino-7-methoxy-quinolin-2-ylamino)-ethanol (〇·4 g, 1.72 mmol), tert-butyldimethyl decane (0.8 g, 515 and imidazole) A mixture of 0.4 g, 5.15 mmol) in dioxane (20 mL) EtOAc (EtOAc) Et〇Ac/ 157102.doc 201217379 hexane '3/7) Purify the crude residue to give 2 - 6 mg as a brown oil. #2-[2-(2-butyl-dimethyl-decyloxy) Ethyl]_7·decyloxyquinoline 2,6-diamine. MS=348 [M+H]+. Preparation 31. Synthesis (2,·Amino-4'-gas-biphenyl_4_ Base (Methanol) According to the procedure shown in Scheme 31, (2, -amino-4, _ gas-biphenyl-4-yl)-methanol was synthesized.

流程31 步驟A :合成（4，-氣-2’-硝基-聯苯_4_基）-甲醇使氮氣鼓泡通過1-溴-4-氯-2-硝基-苯（1.25 g，5.3 mm〇l)、氣化雙（二苯膦）纪（11)(90 mg，0.13 mmol)及碟酸三鉀（4.2 g ’ 19·7 mmol)於無水ι，2-二甲氧基乙烷（30 mL)中之混合物15分鐘添加4-(羥基甲基）苯基g朋酸（0.8 g，5.3 mmol)於無水l，2-二甲氧基乙烷（1.5 mL)中之溶液且在80t：下加熱所得混合物隔夜。接著將反應混合物傾入水中，且以乙酸乙酯萃取兩次。合併之有機萃取物經無水硫酸鈉乾燥，過渡且減壓蒸發。藉由急驟層析法（己烧/EtOAc， 70/30)純化粗殘餘物，獲得0.367 g呈固體形式之（4，-氯-2·-硝基-聯苯-4-基）-甲醇。步驟B:合成（2·-胺基-4*-氣-聯苯-4-基）-甲醇利用製備9步驟D中所述之程序還原（4'-氣-2^硝基-聯苯-4-基）-f醇。 157102.doc -162· 201217379 利用上述程序及適當起始物質製備以下化合物： -(2'-胺基-4·-氯-聯苯-3-基）-曱醇；及 -(2·-胺基-4’-氣-聯苯-4-基曱基）-胺基甲酸第三丁酯。製備32 :合成6-(3-羥基-丙基）·吡唑并[i，5-fl]嘧啶-3-甲酸根據流程32中所示之方法合成6-(3-羥基-丙基）_吡唑并 [1，5-α]嘧啶-3-曱酸》Scheme 31 Step A: Synthesis of (4,-Gas-2'-nitro-biphenyl-4-yl)-methanol. Nitrogen was bubbled through 1-bromo-4-chloro-2-nitro-benzene (1.25 g, 5.3 mm〇l), gasified bis(diphenylphosphine) (11) (90 mg, 0.13 mmol) and tripaconate (4.2 g '19·7 mmol) in water, ι, 2-dimethoxy A mixture of alkane (30 mL) was added a solution of 4-(hydroxymethyl)phenyl g-ponic acid (0.8 g, 5.3 mmol) in anhydrous l. The resulting mixture was heated at 80 t: overnight. The reaction mixture was then poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium The crude residue was purified by flash chromatography (EtOAc /EtOAcEtOAcEtOAc Step B: Synthesis of (2·-Amino-4*-gas-biphenyl-4-yl)-methanol was carried out by the procedure described in Preparation 9 Step D (4'-Ga-2^nitro-biphenyl- 4-yl)-f alcohol. 157102.doc -162· 201217379 The following compounds were prepared using the above procedure and the appropriate starting materials: -(2'-Amino-4.-chloro-biphenyl-3-yl)-nonanol; and -(2.-amine Tert-butyl 4'-gas-biphenyl-4-ylindenyl)-carbamic acid. Preparation 32: Synthesis of 6-(3-hydroxy-propyl)-pyrazolo[i,5-fl]pyrimidine-3-carboxylic acid 6-(3-hydroxy-propyl)_ according to the procedure shown in Scheme 32 Pyrazolo[1,5-α]pyrimidine-3-decanoic acid

流程32 步驟A :合成6-(3-羥基-丙基）·吡唑并[15^]嘧啶_3_甲酸乙酯在〇°C下，向5-胺基- 比唑_4_曱酸乙酯（1.4 g，§ 9 mmol)及 5,6-二氫-4ii-哌喃·3_ 甲醛（0.5 g，4.5 mmol)於無水二甲基甲醯胺（10 mL)中之溶液中添加氫化鈉（礦物油中之60%懸浮液，350 mg，8.78 mmol)，且在(TC下攪拌所 ® 得混合物30分鐘。在室溫下攪拌反應混合物隔夜，接著在 5〇°C下加熱2小時。使所得混合物分配於水與乙酸乙酯之間且分離有機層，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法純化粗殘餘物，獲得〇 24 g呈白色固體形式之6-(3-羥基-丙基）_吡唑并[15_β]嘧啶·3_曱酸乙酯。 MS=250 [M+H]+ 〇步驟Β :合成6-(3-羥基-丙基卜吡唑并丨嘧啶_3甲酸在室溫下攪拌6-(3-羥基·丙基）_β比唑并[丨，5_α]嘧啶甲 157102.doc •163- 201217379 酸乙酯（5 mg)與氫氧化鈉水溶液（5滴）之混合物“小時。接著藉由添加鹽酸水溶液（3 M)酸化反應混合物。藉由過滹收集沈澱物，獲得6-(3-羥基-丙基）_吡唑并[15α]嘧啶^ 甲酸。MS=222 [M+H]+。製備33 :合成6-苯甲氧基-吡唑并嘧啶_3曱酸根據流程33中所示之方法合成6_苯甲氧基吡唑并[15^ 嘧啶-3-曱酸。 ’ Ο 0Scheme 32 Step A: Synthesis of ethyl 6-(3-hydroxy-propyl)-pyrazolo[15^]pyrimidine-3-carboxylate at 〇 ° C to 5-amino-butyrazole _4_ decanoic acid Hydrogenation of ethyl ester (1.4 g, § 9 mmol) and 5,6-dihydro-4ii-pyran·3_formaldehyde (0.5 g, 4.5 mmol) in anhydrous dimethylformamide (10 mL) Sodium (60% suspension in mineral oil, 350 mg, 8.78 mmol), and the mixture was stirred for 30 minutes at (TC). The reaction mixture was stirred at room temperature overnight, followed by heating at 5 ° C for 2 hours. The resulting mixture was partitioned between EtOAc EtOAc (EtOAc m. 6-(3-Hydroxy-propyl)-pyrazolo[15_β]pyrimidine·3_capric acid ethyl ester. MS=250 [M+H]+ 〇Step Β: Synthesis 6-(3-hydroxy-propyl b Pyrazolopyrimidine_3 formic acid is stirred at room temperature with 6-(3-hydroxypropyl)-β-pyrolo[丨,5_α]pyrimidin 157102.doc •163- 201217379 Ethyl acetate (5 mg) and hydrogen a mixture of sodium hydroxide solution (5 drops) "hour. Then borrow The reaction mixture was acidified by the addition of aqueous hydrochloric acid (3 M). The precipitate was collected by hydrazine to give 6-(3-hydroxy-propyl)-pyrazolo[15α]pyrimidine^carboxylic acid. MS=222 [M+H]+ Preparation 33: Synthesis of 6-benzyloxy-pyrazolopyrimidine-3-decanoic acid 6-Benzyloxypyrazolo[15^pyrimidin-3-indoleic acid was synthesized according to the procedure shown in Scheme 33. ' Ο 0

OH OHOH OH

HOOC H2N 流程33 向乙二酿氯（0.6 mL，6.87 mmol)於無水二氣甲烧（15 mL)中之冷卻至-78 °C的溶液中逐滴添加無水二曱亞硬（L2 mL，16.5 mmol)於二氣曱烷（2 mL)中之溶液’且在_78°c 下擾拌所得混合物10分鐘。接著在_78°C下逐滴添加2-苯甲氧基-1，3-丙二醇（0.5 g’ 2.75 mmol)於二氯甲烷（2 mL)中之溶液’且攪拌反應混合物15分鐘。接著在_78。(：下逐滴添加三乙胺（4.6 mL，33 mmol)，且攪拌所得混合物1小時。移除冷浴槽且添加鹽酸水溶液（6 μ，6 mL，36 mmol)，隨後添加5-胺基-1//-吡唑-4-甲酸（0.35 g，2.75 mmol)，且在 7〇°C下加熱反應混合物1小時。藉由過濾收集所形成之固體’以水洗滌且真空乾燥》接著以二氯甲烷洗滌固體殘餘 157102.doc -164 - 201217379 物（0.53 g)，獲得65 mg(9%產率）6_笨甲氧基-吼唑并[^5^] 嘧啶-3-甲酸。MS=270 [M+H]+。製備34:合成5-氣-2-(3-甲氧基-丙氧基）_苯胺根據流程34中所示之方法合成5_氣_2_(3_甲氧基丙氧基）-苯胺。HOOC H2N Process 33 To a solution of acetyl chloride (0.6 mL, 6.87 mmol) in anhydrous two-gas (15 mL) cooled to -78 °C, anhydrous diterpene (L2 mL, 16.5) Methyl) solution in dioxane (2 mL) and the mixture was stirred at -78 °C for 10 min. Next, a solution of 2-benzyloxy-1,3-propanediol (0.5 g' 2.75 mmol) in dichloromethane (2 mL) was added dropwise at -78 °C and the reaction mixture was stirred for 15 min. Then at _78. (:Triethylamine (4.6 mL, 33 mmol) was added dropwise, and the resulting mixture was stirred for 1 hour. The cold bath was removed and aqueous hydrochloric acid (6 μ, 6 mL, 36 mmol) was added, followed by 5-amino group- 1//-pyrazole-4-carboxylic acid (0.35 g, 2.75 mmol), and the reaction mixture was heated at 7 ° C for 1 hour. The solid formed was collected by filtration, washed with water and dried in vacuo. Methyl chloride washed solid residue 157102.doc -164 - 201217379 (0.53 g) to obtain 65 mg (9% yield) of 6-bromomethoxy-carbazolo[^5^]pyrimidine-3-carboxylic acid. 270 [M+H]+. Preparation 34: Synthesis of 5- gas-2-(3-methoxy-propoxy)-phenylamine. Propyloxy)-aniline.

CICI

OHOH

步驟A:合成4-氯-1-(3-甲氧基_丙氧基）_2_硝基_苯在室溫下，向4-氯-2-硝基苯酚（0.5 g，2 88 mm〇1)於無水愚烙二曱基甲醯胺（15 mL)中之溶液中添加氫化鈉（礦物油中60%懸浮液，0.15 g，3·75 mm〇1)，且攪拌所得混合物Step A: Synthesis of 4-chloro-1-(3-methoxy-propoxy)_2_nitro-benzene at room temperature to 4-chloro-2-nitrophenol (0.5 g, 2 88 mm 〇 1) Add sodium hydride (60% suspension in mineral oil, 0.15 g, 3.75 mm 〇1) to a solution of anhydrous decylcarbamide (15 mL) and stir the mixture

5分鐘。接著添加1-溴-3-甲氧基·丙烷（〇 485 g，3 17 mmol) ’且在8(TC下加熱反應混合物62小時。使所得混合物分配於氫氧化鈉水溶液（3 M)與乙酸乙酯之間，分離有機層，以氫氧化鈉水溶液（3 M)洗滌兩次且以鹽水洗滌一次，經無水硫酸鈉乾燥，法（己烷/EtOAc，90/10至過濾且減壓蒸發。藉由急驟層析 50/50)純化粗殘餘物，獲得〇 455 g(64%產率）呈黃色固體形式之4_氯·j 2-硝基-苯。 (3_曱氧基-丙氧基）- 157102.doc •165- 201217379 步驟B:合成5_氣叫甲氧基-丙氧基)-苯胺向4'氯-M3-甲氧基_丙氧基）_2_確基苯（〇 448 g，ι )於乙醇與乙酸乙g旨之混合物（ι/ι，社）中的溶液氣化亞錫（1.04 g，5 49 mm〇1)，且在室溫下授掉所得混合物隔夜。再添加氯化亞錫(0.76 g，4 mmol)，且擾〜冤s物1天。使所得混合物分配於碳酸氫鈉水溶液 ()與乙酸乙s曰之間，分離水溶液且以乙酸乙酯萃取兩人〇併之有機萃取物以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己院，80/20至 60/40)純化黃色油性殘餘物，獲得〇 29 ❶產率）呈黃色油狀之5-氣-2·(3-甲氧基·丙氧基）_苯胺。利用上述程序及適當起始物質製備以下化合物： -5_氣-2-(2-甲氧基·乙氧基）_苯胺；及 -5-氣-2-異丁氧基-苯胺。製備35 :合成4-(2-胺基-4-氣-苯氧基）-哌啶-1-甲酸第三丁酯根據流程35中所示之方法合成4_(2_胺基_4_氯_苯氧基）_ 派咬-1-甲酸第三丁醋。5 minutes. Then 1-bromo-3-methoxypropane (〇485 g, 3 17 mmol) was added and the reaction mixture was heated at 8 (TC) for 62 hours. The resulting mixture was partitioned between aqueous sodium hydroxide (3 M) and acetic acid. The organic layer was separated with EtOAc EtOAc EtOAc. The crude residue was purified by flash chromatography (50/50) to afford EtOAc (EtOAc: EtOAc: Base)- 157102.doc •165- 201217379 Step B: Synthesis of 5_gas called methoxy-propoxy)-aniline to 4'-chloro-M3-methoxy-propoxy)_2-decylbenzene (〇) 448 g, ι ) A solution of stannous chloride (1.04 g, 5 49 mm 〇 1) was vaporized from a solution of ethanol and a mixture of ethyl acetate (m/m), and the mixture was allowed to stand overnight at room temperature. Further stannous chloride (0.76 g, 4 mmol) was added and the ~~ss was sifted for 1 day. The mixture was partitioned between aqueous sodium hydrogencarbonate (aq.) and EtOAc (EtOAc). . The yellow oily residue was purified by flash chromatography (H.sub.s., 80/20 to 60/40) to give the product as a yellow oil. Oxy) aniline. The following compounds were prepared using the procedure described above and the appropriate starting materials: -5- gas-2-(2-methoxyethyloxy)-phenylamine; and -5-gas-2-isobutoxy-aniline. Preparation 35: Synthesis of tert-butyl 4-(2-amino-4-oxo-phenoxy)-piperidine-1-carboxylate 4-(2-amino-4-yl chloride) was synthesized according to the procedure shown in Scheme 35 _ phenoxy) _ bite 1-carboxylic acid third vinegar.

流程35 步驟A :合成4-(4-氣-2-硝基-苯氧基）-哌啶-1-甲酸第三丁酯在 0°C 下，向4-氯-2-确基苯驗（2.0 g，11.52 mmol)、1- 157102.doc • 166 - 201217379 BOC-4-羥基哌啶（3·48 g，17.3 mmol)及三苯膦（4 6 g，17 5 mmol)於無水四氫呋喃（25 mL)中之溶液中添加偶氮二甲酸二異丙酯（3.4 mL，17.55 mmol)於無水四氫呋喃（5 mL)中之溶液’且在0°C下攪拌所得混合物1小時。接著在室溫下攪拌反應混合物24小時；使殘餘物分配於水與乙酸乙醋之間。分離有機層，且以乙酸乙酯萃取水層兩次；合併之有機萃取物以鹽水洗滌’經無水硫酸鈉乾燥，過據且減壓蒸發。藉由急驟層析法（己烷/EtOAc，90/10至70/30)純化粗 • 殘餘物，獲得油性殘餘物，其以己烷洗滌，獲得6.5 g灰白色固體材料β藉由急驟層析法純化此固體殘餘物，獲得 3.61 g(88%產率）呈白色固體形式之4_(4_氣-2·硝基苯氧基）-0底咬-1-曱酸第三丁酯。步爾B .合成4-(2-胺基-4-氣-苯氧基）_旅咬甲酸第三丁 _ 遵照製備37步驟E中所述之程序還原4_(4_氯·2_硝基·苯氧基）-°底啶-1 -曱酸第三丁酯，獲得76%產率之呈淺黃色油狀之4-(2-胺基-4·氯-苯氧基）_哌啶_丨_甲酸第三丁酯。 ® - 4-(6-胺基-喧琳-7-基氧基）_丁_2_醇； -4-(2-胺基-4-氯-苯氧基）_苯齡；及 -3-(2-胺基-4-氣-苯氧基）_苯齡。製備36 :合成3’-(第三丁基·二甲基-矽烷基氧基）_4氣聯苯-2-基胺利用上述程序及適當起始物質製備以下化合物：根據流程36中所示之方法，合成3, ·（第三丁基_二甲基-矽烷基氧基）-4-氯-聯苯-2-基胺。 157102.doc •167· 201217379Scheme 35 Step A: Synthesis of tert-butyl 4-(4-carbo-2-nitro-phenoxy)-piperidine-1-carboxylate at 0 ° C to 4-chloro-2-decene benzene (2.0 g, 11.52 mmol), 1-157102.doc • 166 - 201217379 BOC-4-hydroxypiperidine (3·48 g, 17.3 mmol) and triphenylphosphine (46 g, 17 5 mmol) in anhydrous tetrahydrofuran ( A solution of diisopropyl azodicarboxylate (3.4 mL, 17.55 mmol) in anhydrous tetrahydrofuran (5 mL) was added to the solution in 25 mL) and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was then stirred at room temperature for 24 hours; the residue was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The crude residue was purified by flash chromatography (hexane / EtOAc (EtOAc /EtOAc) elute The solid residue was purified to give 3. <RTI ID=0.0>#</RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Step B. Synthesis of 4-(2-Amino-4- oxo-phenoxy)_Bed formic acid tert-butyl _ Reducing 4_(4_chloro·2_nitrol according to the procedure described in Preparation 37, Step E Benzyl)-pyridin-1 - butyl decanoate, 4-(2-amino-4-chloro-phenoxy)-piperidine in 76% yield as a light yellow oil _丨_T-butyl formate. ® - 4-(6-Amino-indolyl-7-yloxy)-but-2-ol; -4-(2-amino-4-chloro-phenoxy)-benzene; and -3 -(2-Amino-4-vapor-phenoxy)-benzene age. Preparation 36: Synthesis of 3'-(t-butyl-dimethyl-decyloxy)- 4 phen-2-ylamine The following compounds were prepared using the procedure described above and the appropriate starting materials: Method, Synthesis 3, (Third butyl-dimethyl-decyloxy)-4-chloro-biphenyl-2-ylamine. 157102.doc •167· 201217379

流程36 步稱A :合成第三丁基_(4，_氣2，·硝基聯苯_3_基氧基二甲基-矽烷在室溫下，向4，-氯_2·-硝基-聯苯·3_醇（1.05 g，4.21 mmol)及咪唾（〇·58 ’ 8.52 mmol)於無水iV，#-二曱基甲醯胺 (30 mL)中之溶液中添加第三丁基二甲基氣矽烷（〇82 g， 5.44 mmol) ’且在室溫下攪拌所得混合物4天。反應混合物接著分配於水與乙酸乙酯之間，分離有機層，且以乙酸乙醋萃取水層兩次。以水及鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。在矽膠柱塞（己烷 /EtOAc，90/10)上純化粗殘餘物，獲得丨43 g(94%產率）呈黃色油狀之第三丁基-(4，-氯-2'-硝基·聯苯-3-基氧基）_二甲基-珍院。步驟B:合成3，-(第三丁基-二甲基_矽烷基氧基）_4_氣_聯苯-2-基胺根據製備37步驟E中所述之程序還原第三丁基_(4，_氣_2,_ 硝基-聯苯-3-基氧基）-二甲基-碎院，獲得88 %產率之呈無色油狀之3，-(第三丁基-二甲基-矽烷基氧基）_4_氣_聯苯·2_ 基胺。根據上文所述之程序且利用適當起始物質製備4,·(第三丁基-二甲基-矽烷基氧基）-4-氯-聯苯·2_基胺。 157102.doc •168- 201217379 製備37 :合成[ι_(2_胺基_5_苯基胺甲斑基-苯基）_痕咬-4_基甲基】-胺基甲暖第三丁酿根據流程37中所示之方法合成[1-(2-胺基_5_苯基胺曱醯基-苯基）-哌啶-4_基甲基]-胺基甲酸第三丁酯。Scheme 36 Step A: Synthesis of tert-butyl _ (4, _ gas 2, · nitrobiphenyl _3_ yloxy dimethyl-decane at room temperature, to 4,-chloro 2 ·-nitrate Add a third butyl group to a solution of bis-biphenyl-3-ol (1.05 g, 4.21 mmol) and sodium salivation (〇·58 ' 8.52 mmol) in anhydrous iV, #-dimercaptocaramine (30 mL) Dimethyl gas decane (〇 82 g, 5.44 mmol) ' and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was then partitioned between water and ethyl acetate, and the organic layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. 43 g (94% yield) of tert-butyl-(4,-chloro-2'-nitro-biphenyl-3-yloxy)-dimethyl-reservative as a yellow oil. Step B: Synthesis of 3,-(t-butyl-dimethyl-decyloxy)_4_gas-biphenyl-2-ylamine The third butyl group was reduced according to the procedure described in Preparation 37, Step E (4, _ Gas 2, _ nitro-biphenyl-3-yloxy)-dimethyl-broken, obtained 88% yield Color oily 3,-(t-butyl-dimethyl-decyloxy)_4_gas_biphenyl·2_ylamine. Preparation according to the procedure described above and using the appropriate starting materials 4, (Third butyl-dimethyl-decyloxy)-4-chloro-biphenyl-2-ylamine. 157102.doc •168- 201217379 Preparation 37: Synthesis [ι_(2_Amino_5_Benzene) Alkylmethyl-phenyl-phenyl)-dentate-4-ylmethyl]-Aminomethyl-terminated third-butan is synthesized according to the method shown in Scheme 37 [1-(2-amino-5-phenyl) Acetyla-phenyl)-piperidine-4-ylmethyl]-carbamic acid tert-butyl ester.

步驟D NHBOC 流程37Step D NHBOC Process 37

S 步驟A:合成氯-4_甲基4硝基苯在〇C下’向3_氣甲苯（3 mL，25 4 mm〇i)及濃硫酸（6 mL)於冰醋酸（20 mL)中之溶液中緩慢添加濃硝酸（16 mL) ’且授拌所得混合物24小時，使溫度升至室溫。接著將反應混合物傾入冰·水中，且分配於水與乙醚之間。分離水相Μ乙料取兩:欠；合狀㈣萃取物財及鹽水洗滌’經無水硫酸納乾燥，過滤且㈣蒸發。切膠柱塞上純化黃色油性殘餘物且進行兩次急驟層析法得 g(14%產率）呈黃色油 ^ 22 狀之2_氣-4-甲基-1-硝基-苯及3 39 g(39%產率）4-氯_2_甲基小確基-苯。 .39 步驟B:合成3-氣_4_硝基_苯甲酸在9〇tT加熱含2_氯基]-硝基-苯U.2 g，6.99 157102.doc 201217379 mm〇1)的水與吡啶之愿合物（2/1，30 mL)，接著以丨.5小時之時間間隔分4份添加高猛酸鉀（52 g，32 9随川。在 9〇°C下加熱反應混合物8小時’接著再添加高猛酸卸（2 g)，且在90°C 7*授拌所得混合物隔冑。再添加冑猛酸卸（2 g)，且在90 C下攪拌所得混合物i小時，經由celiteTM墊濾出固體。向濾液中添加水（5〇 mL);酸化所得混合物直至pH<2，且以乙酸乙酯萃取3次。合併之有機萃取物以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得i. 19 g(84%產率）呈淺黃色固體形式之％氯-4-硝基-苯甲酸β 步驟C:合成3-氣-4-硝基·λγ·苯基-苯甲醢胺向3-氯-4-硝基-苯甲酸（〇 2 g ’ 〇 992 mm〇1)、苯胺（〇」 mL’ 1.1 mmol)及HBTU(0.42 g，la mm〇1)於乙腈（2〇机）中之混合物中添加二異丙基乙基胺（〇 65 ，3 7 mm〇1)，且在80°C下攪拌反應混合物8小時，接著在室溫下攪拌62 小時。所得混合物接著分配於水與乙酸乙酯之間，分離有機層，且以乙酸乙酯萃取水層兩次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。在矽膠柱塞（己烧/EtOAc ’ 80/20)上純化粗殘餘物，獲得135 mg(49%產率）呈黃色固體形式之3_氣·4_硝基#•苯基-笨曱醯胺。步驟D :合成【1-(2-硝基_5_苯基胺甲醯基-苯基卜哌啶_4-基甲基】-胺基甲酸第三丁酯向3-氯-4-硝基-沁苯基-苯甲醯胺（0.13 g，0.47 mm〇l)於 157102.doc -170- 201217379 兄#-二甲基曱醯胺（10 mL)中之溶液中添加哌啶_4_基甲基_ 胺基曱酸第二丁酉曰（0.12 g，0.56 mm〇i)及碳酸鉀（〇」g， 0.72 mmol)，且在50°C下加熱所得混合物隔夜。接著在 80°C下加熱反應混合物8小時；接著再添加哌啶_4_基曱基胃胺基甲酸第三丁酯（0.33 mmol)及碳酸鉀（0.14 g，i mmol)，且在85°C下加熱所得混合物隔夜。使反應混合物分配於水與乙酸乙酯之間’分離有機層，且以乙酸乙§旨萃取水層兩次。以水及鹽水洗條經合併之有機萃取物，經無水硫酸納乾燥’過遽且減壓蒸發。在碎膠柱塞（己烧/S Step A: Synthesis of chloro-4-methyl 4-nitrobenzene under 〇C to 3_gas toluene (3 mL, 25 4 mm〇i) and concentrated sulfuric acid (6 mL) in glacial acetic acid (20 mL) Concentrated nitric acid (16 mL) was slowly added to the solution and the resulting mixture was stirred for 24 hours to allow the temperature to rise to room temperature. The reaction mixture was then poured into ice water and partitioned between water and diethyl ether. Separation of the aqueous phase Μ 料取取取 : ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 四四四四四四四四四四The yellow oily residue was purified on a gel-cut plunger and subjected to two flash chromatography to give g (14% yield) as a yellow oil. 39 g (39% yield) of 4-chloro-2-methylsuccinyl-benzene. .39 Step B: Synthesis of 3-gas _4_nitro-benzoic acid at 9 〇tT to heat water containing 2_chloro]-nitro-benzene U.2 g, 6.99 157102.doc 201217379 mm〇1) Pyridine conjugate (2/1, 30 mL), followed by the addition of potassium perchlorate in 4 portions at intervals of 5 hours (52 g, 32 9 with Chuan. Heating the reaction mixture at 9 ° C) The hour was followed by the addition of high acid removal (2 g), and the resulting mixture was partitioned at 7 °C at 90 ° C. The hydrazine acid was removed (2 g) and the resulting mixture was stirred at 90 C for 1 hour. The solid was filtered off through a pad of celiteTM. Water (5 mL) was added to the filtrate; the mixture was acidified to pH <2> and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine Drying, filtration and evaporation under reduced pressure EtOAc (m.) -Nitro-λγ·phenyl-benzamide to 3-chloro-4-nitro-benzoic acid (〇2 g ' 〇992 mm〇1), aniline (〇) mL' 1.1 mmol) and HBTU (0.42) g,la mm〇1) in acetonitrile (2〇 machine) Diisopropylethylamine (〇65, 3 7 mm〇1) was added to the mixture, and the reaction mixture was stirred at 80 ° C for 8 hours, followed by stirring at room temperature for 62 hours. The resulting mixture was then partitioned between water and The organic layer was separated between EtOAc and EtOAc (EtOAc)EtOAc. The crude residue was purified on EtOAc EtOAc (EtOAc/EtOAc). 1-(2-Nitro-5-phenylamine-methane-phenylpiperidine-4-ylmethyl)-aminocarboxylic acid tert-butyl ester to 3-chloro-4-nitro-indolephenyl - piperidine (0.13 g, 0.47 mm 〇l) in a solution of 157102.doc -170-201217379 brother #-dimethyl decylamine (10 mL) with piperidine-4-ylmethylamine Base bismuth citrate (0.12 g, 0.56 mm 〇i) and potassium carbonate (〇, g, 0.72 mmol), and the resulting mixture was heated overnight at 50 ° C. The reaction mixture was then heated at 80 ° C for 8 hours. Then add piperidine_4_ Tert-butyl carbamic acid tert-butyl ester (0.33 mmol) and potassium carbonate (0.14 g, i mmol), and the resulting mixture was heated overnight at 85 ° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was extracted twice with acetic acid. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. In the broken rubber plunger (burned /

EtOAc ’ 20/80至40/60)上純化粗殘餘物，獲得〇 η g(6i% 產率）呈橙色固體形式之[1-(2-硝基-5-苯基胺曱醯基-苯基哌啶-4-基甲基]-胺基甲酸第三丁酯。步驟E :合成[1-(2-胺基-5-苯基胺甲醢基_苯基）_旅咬_4_基甲基】-胺基甲酸第三丁酯向[1-(2-硝基-5-笨基胺甲醯基-苯基）_派咬_4_基曱基]_胺基甲酸第三丁酯（0.13 g，0.286 mmol)於乙醇（8 mL)、乙酸乙酯（3 mL)與水（3 mL)之混合物中的溶液中添加氣化銨The crude residue was purified on EtOAc EtOAc <RTI ID=0.0>> Step 3: Synthesis of [1-(2-amino-5-phenylaminecarbamyl-phenyl)_Brigade bite_4_ Methyl]-tert-butyl carboxylic acid tert-butyl ester to [1-(2-nitro-5-phenylaminocarbazinyl-phenyl)- _4_yl fluorenyl]-aminocarboxylic acid Add carbamide to a solution of butyl ester (0.13 g, 0.286 mmol) in a mixture of ethanol (8 mL), ethyl acetate (3 mL) and water (3 mL)

(0.12 g，7.6 mmol)及鐵粉（0.12 g，7.5 mmol)，且在 80°C 下加熱所得混合物4小時。經由CELITEtm$過濾反應混合物，以乙酸乙酯洗務濾餅。濾液以碳酸氫鈉水溶液（5%)及鹽水洗滌’經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得 0.12 g(定量產率）呈淺黃色泡沫形式之[ι_(2-胺基_5_苯基胺甲醯基-苯基）-哌啶-4-基甲基]-胺基甲酸第三丁酯。製備38 :合成7-丨4-(第三丁基_二甲基-矽烷基氧基）_環己基 157102.doc -171 · 201217379 氧基】-喹琳-6-基根據流程38中所不之方法合成7_叫第三了u基燒基氧基）_環己基氧基]___6基胺。(0.12 g, 7.6 mmol) and iron powder (0.12 g, 7.5 mmol), and the mixture was heated at 80 ° C for 4 hours. The reaction mixture was filtered through EtOAc (EtOAc) elutingEtOAc. The filtrate was washed with aqueous sodium bicarbonate (5%) and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 0.12 g (yield yield) as a pale yellow foam. _Phenylamine-mercapto-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester. Preparation 38: Synthesis of 7-anthracene 4-(t-butyl-dimethyl-decyloxy)-cyclohexyl 157102.doc -171 · 201217379 oxy]-quinolin-6-yl according to Scheme 38 The method of synthesizing 7_ is called the third sulfoyloxy)cyclohexyloxy]___6-amine.

流程38 步驟A:合成6_硝基_喹啉·7醇在150C下加熱7-曱氧基_6•硝基喹琳（1 5 g，7 35瓜㈣) 與比定鹽酸鹽（2.6 g，22.58 mmol)之混合物約5小時。將殘餘物溶解於氫氧化鈉水溶液（3 M)中且以乙酸乙醋萃取兩人σ併之有機萃取物以氫氧化鈉水溶液（3 M)洗滌兩次，接著丢棄。藉由添加濃鹽酸中和合併之水層（pH乃，且以乙酸乙酯萃取4次。合併之有機萃取物經無水硫酸鈉乾燥’過滤減壓蒸發。在碎膠柱塞上純化黃色固體殘餘物，獲得1.29 g(69%產率）呈黃色固體形式之6_硝基喹啉_ 7-醇。步播B:合成7_【4_(第三丁基_二甲基，燒基氧基）環己基氧基]-6-確基·啥淋根據製備2步驟B中所述之程序合成7_[4•(第三丁基·二甲 157102.doc •172- 201217379 基-矽烷基氧基）-環己基氧基]-6-硝基-喹啉。步驟C :合成7-[4·(第三丁基-二甲基-矽烷基氧基）_環己基氣基】-啥琳-6-基胺如製備37步驟E中所述還原7-[4-(第三丁基-二甲基-矽烷基氧基）-環己基氧基]-6-硝基-喧琳，獲得31%產率之7-[4-(第三丁基-二甲基-矽烷基氧基）-環己基氧基]-喹啉_6_基胺。利用上述程序及適當起始物質製備以下化合物： -7-[3-(第三丁基-二甲基-矽烷基氧基）_環戊基氧基]_喹啉_ 6-基胺； -7-[3-(第三丁基-二甲基-矽烷基氧基）·ι_甲基-丁氧基喹淋-6-基胺； -7-[3-(第三丁基-二甲基-矽烷基氧基）·丙氧基]-喹啉·6_基胺； -[3-(6-胺基-喹啉-7-基氧基）-丙基]-胺基甲酸第三丁酯； -3-(6-胺基-喹啉-7-基氧基）-吡咯啶-1-甲酸第三丁酯； -及-7-[4-(第三丁基-二苯基-矽烷基氧基）-環己基氧基]-啥啉-6-基胺、（4-(及-第三丁基-二苯基-矽烷基氧基）-環己醇及廢-第三丁基-二苯基-矽烷基氧基）-環己醇如製備2 步驟A中所述製備，且藉由急驟層析法（EtOAc/己烷， 1/1)分離）；及 -廣'-7-[4-(第三丁基-二苯基-碎烧基氧基）-環己基氧基]•嗅嚇· -6-基胺。製備39 :合成4-胺基-N-[2-(第三丁基-二甲基-矽烷基氣 157102.doc •173· 201217379 基）-己基]-3-甲氧基-苯甲醢胺根據流程39中所示之方法合成4_胺基·#_[2·(第三丁基_二甲基-矽烷基氧基）-乙基]-3-甲氧基-苯甲醯胺。Scheme 38 Step A: Synthesis of 6-nitro-quinoline-7 alcohol at room temperature by heating 7-decyloxy_6•nitroquine (1 5 g, 7 35 melon (4)) with quaternary hydrochloride (2.6) A mixture of g, 22.58 mmol) was for about 5 hours. The residue was dissolved in aqueous sodium hydroxide (3 M) and the mixture was extracted with ethyl acetate. The organic extracts were washed twice with aqueous sodium hydroxide (3 M) and then discarded. The combined aqueous layer was neutralized by adding concentrated hydrochloric acid (pH was extracted 4 times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate) filtered and evaporated under reduced pressure. Obtained 1.29 g (69% yield) of 6-nitroquinoline-7-ol as a yellow solid. Step B: Synthesis 7_[4_(t-butyl-dimethyl, yloxy) Cyclohexyloxy]-6-deacetyl-phosphonium was synthesized according to the procedure described in Preparation 2, Step B. 7_[4•(Tertiary dimethyl dimethyl 157102.doc • 172-201217379 yl-decyloxy) -cyclohexyloxy]-6-nitro-quinoline. Step C: Synthesis of 7-[4·(t-butyl-dimethyl-decyloxy)-cyclohexyl group]-啥琳-6 - alkylamine reduced 7-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-6-nitro-indole as described in Preparation 37, Step E, affording 31% Yield of 7-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-quinoline-6-amine. The following compounds were prepared using the procedure described above and the appropriate starting materials: -7-[3-(t-butyl-dimethyl-decyloxy)-cyclopentyloxy]-quinoline -6- Amine; -7-[3-(t-butyl-dimethyl-decyloxy)·ι_methyl-butoxyquinolin-6-ylamine; -7-[3-(third -3-dimethyl-decyloxy)-propoxy]-quinoline-6-ylamine; -[3-(6-amino-quinolin-7-yloxy)-propyl]-amine Tert-butyl carboxylic acid; -3-(6-amino-quinolin-7-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester; - and -7-[4-(t-butyl -diphenyl-decyloxy)-cyclohexyloxy]-porphyrin-6-ylamine, (4-(and-t-butyl-diphenyl-decyloxy)-cyclohexanol and Waste-tert-butyl-diphenyl-decyloxy)-cyclohexanol was prepared as described in Preparation 2, Step A, and isolated by flash chromatography (EtOAc/hexanes, 1/1); And - broad '-7-[4-(t-butyl-diphenyl-pyroxy)-cyclohexyloxy] • sniffing -6-ylamine. Preparation 39: Synthesis of 4-amino-N-[2-(t-butyl-dimethyl-decanealkyl 157102.doc •173· 201217379)-hexyl]-3-methoxy-benzamide 4-Amino group ##[[(tributyl-dimethyl-decyloxy)-ethyl]-3-methoxy-benzamide was synthesized according to the method shown in Scheme 39.

流程39 步驟A :合成羥基-乙基）_3_甲氧基_4_硝基-苯甲醯胺在回流下加熱3-曱氧基·4·硝基-苯曱酸（1.5 g，761 mmol)於亞硫醯氣（2〇 mL)及二曱基甲醯胺（2滴）中之懸浮液2小時。接著減壓蒸發溶劑，獲得淺黃色固體。將一份此殘餘物（3,8 mmol)溶解於丙酮（先前經無水硫酸鈉乾燥）（20 mL)中且在冰浴中冷卻。接著在下添加乙二胺 (〇·46 mL，7.62 mmol)於水（1〇 mL)中之溶液，且在室溫下攪拌所得混合物30分鐘。使反應混合物分配於水與乙酸乙酯之間；分離水相且以乙酸乙酯萃取兩次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。在矽膠柱塞（EtOAc/Me〇H，100/0至98/2)上純化粗殘餘物，獲得(M2 g(46%，2步驟產率）羥基_乙基）_3甲氧基-4-硝基、苯曱醯胺。步驟B :合成tv_[2_(第三丁基_二甲基_矽烷基氧基）乙基】_ 3_甲氧基-4-硝基-苯甲醯胺如製備36步驟A中所述，利用適當起始物質合成…[2_ 157102.doc 201217379 (第三丁基-二甲基-矽烷基氡基乙基]-3-甲氧基-4-硝基-苯甲酿胺’且獲得定量產率之淺黃色固體。步驟C ··合成4-胺基-ΛΓ-[2-(第三丁基-二甲基-珍烷基氧基）-乙基]-3-甲氧基-笨甲醯胺如製備37步驟Ε中所述，利用適當起始物質還原iV~ [ 2 -(第三丁基-二曱基-矽烷基氧基）-乙基]-3-甲氧基-4·硝基-苯曱酿胺’獲得91%產率呈無色油狀之4_胺基_#_[2-(第三丁基-二曱基-矽烷基氧基）_乙基卜3_甲氧基_苯曱醯胺。利用上述程序及適當起始物質製備4_胺基第三丁基-一甲基-矽烷基氧基）_丙基卜3_甲氧基_苯甲醯胺。製備40 :合成2-[3·(第三丁基_二甲基矽烷基氧基）丙氧基】-5-氣-苯胺根據流程40中所示之方法合成2[3(第三丁基二甲基石夕烧基氧基）-丙氧基]-5-氣-苯胺。Scheme 39 Step A: Synthesis of hydroxy-ethyl)_3_methoxy_4_nitro-benzamide The 3-methoxy-4·nitro-benzoic acid (1.5 g, 761 mmol) was heated under reflux. A suspension of sulfite (2 〇 mL) and dimethylformamide (2 drops) for 2 hours. The solvent was then evaporated under reduced pressure to give a pale yellow solid. A portion of this residue (3,8 mmol) was dissolved in EtOAc (EtOAc) Next, a solution of ethylenediamine (〇·46 mL, 7.62 mmol) in water (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate; the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate The crude residue was purified on a EtOAc (EtOAc / EtOAc /EtOAc) Nitro, benzoguanamine. Step B: Synthesis of tv_[2_(t-butyl-dimethyl-decyloxy)ethyl]_3_methoxy-4-nitro-benzimidamide as described in Preparation 36, Step A, Synthesis using appropriate starting materials... [2_ 157102.doc 201217379 (Third butyl-dimethyl-nonylalkyl decylethyl]-3-methoxy-4-nitro-benzamide" and obtained A light yellow solid in mass yield. Step C · Synthesis of 4-amino-indole-[2-(t-butyl-dimethyl-andyloxy)-ethyl]-3-methoxy- Benzomethanamine is reduced as described in Preparation 37, using the appropriate starting material to reduce iV~[2-(t-butyl-didecyl-decyloxy)-ethyl]-3-methoxy- 4·Nitro-benzoquinone amine's yield of 91% yield in the form of colorless oil 4_amine _#_[2-(t-butyl-didecyl-decyloxy)_ethyl b 3 _Methoxy-benzoguanamine. Preparation of 4-aminotributyl-monomethyl-decyloxy)-propyl b-methoxy-benzonitrile by the above procedure and appropriate starting materials amine. Preparation 40: Synthesis of 2-[3·(t-butyl-dimethyl-decyloxy)propoxy]-5-a-aniline was synthesized according to the procedure shown in Scheme 40 2 [3 (t-butyl) Dimethyl sulphate oxy)-propoxy]-5-gas-aniline.

CICI

步驟CStep C

X^\^〇TBDMS 流程40 sc 步騍A :兮成3-(4- 下刊签内_1_醇根據製備2步驟B中所述之，合之黃 ;之程序，利用適當起如成3-(4-氯-2-硝基·苯氧基）_ ° 内K醇，且獲得48〇/〇 157102.doc •175· 201217379 色油狀物。步爾Β:合成第三丁基-[3-(4-氣·2·確基_笨氧基）丙氧基二甲基-矽烷如製備36步驟a中所述，利用適當起始物質，合成第三丁基[3 (4-氣-2-硝基-苯氧基）_丙氧基]二甲基石夕烧，且獲得82°/。產率之黃色油狀物。步驟C:合成3-(2-胺基-4-氣-苯氧基）·丙醇向第二丁基-[3-(4-氣-2-硝基-笨氧基）_丙氧基]_二甲基_ 矽烷（0.37 g，1·〇7 mmol)於乙醇（1〇 mL)與水（3 mL)之混合物中的溶液中添加氯化銨（0.3 g，5.37 mm〇1)及鐵粉（〇3 g，5.6 mmol)，且在80〇C下加熱所得混合物隔夜。經由 CELITE塾過濾固體，以乙酸乙酯洗蘇滤餅。以水及鹽水洗滌濾液，經無水硫酸鈉乾燥，過濾且減壓蒸發。在矽膠柱塞上純化粗殘餘物，獲得〇 188 g(87〇/。產率）呈黃色由狀之3-(2-胺基-4-氣-苯氧基）_丙醇。步驟D :合成2-【3-(第三丁基-二甲基-矽烷基氧基）_丙氧基】-5-氣-苯胺如製備36步驟A中所述，利用適當起始物質，合成 (第二丁基-一甲基-石夕院基氧基）_丙氧基]_5_氣_苯胺。製備41 :合成[1-(6-胺基-喹啉_7_基）-哌啶-4-基甲基卜胺基甲酸第三丁酯根據流程41中所示之方法合成胺基-喹啉_7_基）哌咬-4-基甲基]-胺基甲酸第三丁酯。 157102.doc •176· 201217379X^\^〇TBDMS Process 40 sc Step A: 3-成3-(4-下刊内内_1_Alcohol according to the preparation described in Step 2 of Preparation 2, the combination of yellow; the procedure, using appropriate 3-(4-Chloro-2-nitrophenoxy)_ ° K-cohol, and obtained 48 〇 / 〇 157102.doc • 175 · 201217379 color oil. Step Β: synthesis of tert-butyl - [3-(4-Gas·2·Acidyl)-propoxy-propoxy-dimethyl-decane as described in Preparation 36, step a, using a suitable starting material to synthesize a tert-butyl [3 (4- Gas-2-nitro-phenoxy)-propoxy] dimethyl sulphur was obtained, and a yellow oil was obtained in a yield of 82°. Step C: Synthesis of 3-(2-amino-4) - gas-phenoxy)·propanol to the second butyl-[3-(4-gas-2-nitro-p-oxy)-propoxy]-dimethyl-decane (0.37 g, 1· 〇7 mmol) ammonium chloride (0.3 g, 5.37 mm 〇1) and iron powder (〇3 g, 5.6 mmol) in a solution of a mixture of ethanol (1 mL) and water (3 mL), and The mixture was heated overnight at 80 ° C. The solid was filtered through EtOAc (EtOAc) eluted eluted with ethyl acetate. The crude residue was purified on a silica gel plunger to give 188 g (yield: 87 y yield) of 3-(2-amino-4- benzene-phenoxy)-propanol as a yellow. D: Synthesis of 2-[3-(t-butyl-dimethyl-decyloxy)-propoxy]-5-a-aniline as described in Preparation 36, Step A, using the appropriate starting materials. (Second butyl-monomethyl-stone-oxyl)-propoxy]_5_gas-aniline. Preparation 41: Synthesis of [1-(6-amino-quinoline-7-yl)-peri Synthesis of amino-quinoline-7-yl)piperidin-4-ylmethyl]-carbamic acid tert-butyl according to the method shown in Scheme 41 ester. 157102.doc •176· 201217379

流程41Process 41

步驟A:合成#-(3·氣-4·硝基·苯基）_乙醯胺在-50°CT ’經5G分鐘之時段，向#_(3_氣_苯基）_乙酿胺 (45 g)中緩慢添加發煙硝酸（150 mL).使反應混合物升溫至-20°C，接著傾入冰-水中。藉由過濾收集所形成之固體，以水洗滌，且減壓乾燥。殘餘物以二氣甲烷洗滌且減壓乾燥，獲得14 g呈淺粉色固體形式之#_(3_氯·4_硝基-笨基）-乙醯胺。步驟B:合成3-氯-4-硝基-苯胺在回流下加熱TV-(3-氯-4-硝基-苯基）_乙醯胺（18 55 g， 86_4 mmol)與鹽酸水溶液（6 Μ，120 mL)之混合物2小時。冷卻所得混合物且傾入水（800 mL)中；藉由過濾收集析出之黃色固體，以水洗滌且減壓乾燥，獲得5 g 3-氣-4-石肖基_ 苯胺。藉由添加碳酸鉀鹼化水層直至pH 8，接著以二氣甲烷萃取。經無水硫酸鈉乾燥有機層，過濾且減壓蒸發，獲得7.2 g 3 -氣-4-ί肖基-苯胺。 157102.doc -177- 201217379 步縣C:合成7-氣-6-硝基-喹啉在 loot 下，向3-氣-4-硝基-苯胺（10·6 g，61 4 mm〇1)、五氧化二砷（8_79 g，38.2 mmol)與丙三醇（26 mL，172」 mmol)之混合物中逐滴添加濃硫酸（1〇 5机，6 mmol)。在150°C下加熱反應混合物2小時，接著在8〇<>c下冷卻。添加水（300 mL)，且以乙酸乙酯所得混合物萃取3 次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得8.7 g棕色固體殘餘物。藉由急驟層析法（DCM)純化一份（2.7 g)此粗物質，獲得974 mg呈淺黃色固體形式之 7-氣-6-琐基-喧啦及1.108 g 5-氯-6-硝基-哇淋。步锁D :合成[1-(6-硝基-啥琳-7-基）-娘咬-4·基甲基]-胺基甲酸第三丁酯向 7-氯-6-硝基-喹啉（974 mg ’4.67 mmol)於二曱基曱醯胺（25 mL)中之溶液中添加碳酸鉀〇 93 g，14.01 mmol)及哌啶-4-基甲基-胺基曱酸第三丁酯〇〇〇 g，4.67 mmol) ’且在100°C下加熱所得混合物隔夜❶冷卻反應混合物且分配於水（500 mL)與乙酸乙酯（3〇〇 mL)之間。分離有機層，以水（500 mL)洗滌兩次，經無水硫酸納乾燥，過渡且減壓蒸發。藉由急驟層析法純化粗殘餘物兩次，獲得 415 mg呈橙色固體形式之[1-(6-硝基-喹啉-7-基）-哌啶-4-基曱基]-胺基甲酸第三丁酯。步驟E :合成[1-(6-胺基_喹啉-7-基）_哌啶-4-基甲基】-胺基甲酸第三丁酯如製備37步驟E中所述還原[1-(6-硝基-喹啉-7-基底啶- 157102.doc •178· 201217379 4-基甲基]•胺基曱酸第二丁 ’獲得93%產率呈淺黃色固體形式之[W6-胺基-喧琳-7-基）_娘^4_基甲基]_胺基甲酸第三丁酯。利用上述程序及適當起始物質製備以下化合物： -7 -派咬-1 -基-啥嚇^ - 6 -基胺； _ [1-(2-胺基-4-氯-笨基）-〇比洛咬3其甘疋h基曱基]·胺基曱酸第三丁酯（步驟D及步驟E); -[1-(2-胺基-4-氯-苯基）-娘咬_4其Step A: Synthesis #-(3·Gas-4·nitro-phenyl)_acetamide at -50 ° CT '5G minutes to #_(3_气_phenyl)_乙胺胺Fumigation nitric acid (150 mL) was slowly added (45 g). The reaction mixture was allowed to warm to -20 ° C then poured into ice-water. The solid formed was collected by filtration, washed with water, and dried under reduced pressure. The residue was washed with di-methane and dried under reduced pressure to give <RTI ID=0.0>> Step B: Synthesis of 3-chloro-4-nitro-aniline under reflux of TV-(3-chloro-4-nitro-phenyl)-acetamide (18 55 g, 86_4 mmol) and aqueous hydrochloric acid (6) A mixture of hydrazine, 120 mL) for 2 hours. The resulting mixture was cooled and poured into water (800 mL); and the precipitated solid solid was collected by filtration, washed with water and dried under reduced pressure to give 5 g of 3- s. The aqueous layer was basified by the addition of potassium carbonate until pH 8 and then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated evaporated evaporated. 157102.doc -177- 201217379 Step County C: Synthesis of 7-gas-6-nitro-quinoline to 3-methoxy-4-nitro-aniline (10·6 g, 61 4 mm〇1) under loot Concentrated sulfuric acid (1 〇 5 machine, 6 mmol) was added dropwise to a mixture of arsenic pentoxide (8-79 g, 38.2 mmol) and glycerol (26 mL, 172" mmol). The reaction mixture was heated at 150 ° C for 2 hours, followed by cooling at 8 ° <>>c. Water (300 mL) was added, and the mixture obtained with ethyl acetate was extracted three times. The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated. One part (2.7 g) of this crude material was purified by flash chromatography (DCM) to afford 974 mg of s. Base - wow. Step lock D: Synthesis of [1-(6-nitro-啥琳-7-yl)-Nandidyl-4-ylmethyl]-carbamic acid tert-butyl ester to 7-chloro-6-nitro-quin To a solution of porphyrin (974 mg '4.67 mmol) in dimethyl decylamine (25 mL), added potassium carbonate 〇93 g, 14.01 mmol) and piperidin-4-ylmethyl-amino decanoic acid tributyl Ester 〇〇〇g, 4.67 mmol) 'When the mixture was heated at 100 ° C overnight, the reaction mixture was cooled and partitioned between water (500 mL) and ethyl acetate (3 mL). The organic layer was separated, washed twice with water (500 mL), dried over anhydrous sodium sulfate, and evaporated and evaporated. The crude residue was purified twice by flash chromatography to yield </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; [1-(6-nitro-quinolin-7-yl)-piperidin-4-ylindenyl]-amine Tert-butyl formate. Step E: Synthesis of [1-(6-Amino-quinoline-7-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as described in Preparation 37, Step E. (6-nitro-quinoline-7- basal pyridine - 157102.doc •178· 201217379 4-ylmethyl]•amino phthalic acid dibutyl” obtained 93% yield in the form of a pale yellow solid [W6- Amino-喧琳-7-yl)_Niang^4_ylmethyl]-butylic acid tert-butyl ester. The following compounds were prepared using the procedures described above and the appropriate starting materials: -7 - ketone-1 -yl- 啥 ^ ^ - 6 - ylamine; _ [1-(2-amino-4-chloro-phenyl)-oxime Bilo bites 3 its glycosyl h-mercapto] aminobutyric acid tert-butyl ester (step D and step E); -[1-(2-amino-4-chloro-phenyl)-negant bite_ 4 its

基甲基]-胺基甲酸第三丁酯（步驟D及步驟E);及一 _ [1-(6-胺基-喹啉-7-基）_派咬哫馭基]-曱醇（步驟D及步驟 L·)。製備仏合成3·(2_胺基_4_氣·苯氧基卜丙小醇根據流程42中所示之方法合成3 丙-l-醇。 ·(2-胺基氣-苯氧基）·Tert-butyl 3-methyl]-carbamic acid (Step D and Step E); and 1-[1-(6-Amino-quinolin-7-yl)-pyrene-yl]-sterol Step D and step L·). Preparation of hydrazine synthesis 3. (2-amino-4 _ phenoxypropanol) 3 propyl-1-ol was synthesized according to the method shown in Scheme 42. (2-Amino-phenoxy) ·

流程42 步縣A ··合成;^3·(第三丁基_ 基J-5-氣-苯胺 _梦境基氧基）·丙氧合成2-Π- 如製備2步驟b尹所述利用適當起始物質 I57I02.doc •179- 201217379 =基：甲…基氧基)，氧基]·5-氣·苯胺，且獲付71/。產率之淺黃色油狀物。步称Β:合成3·(2_胺基_4_氣_苯氧基）丙^醇如製備34步驟Β中所述還原2-[3_(第：r 丁 | 並备甘、丞-二曱基-矽烷基氧基）-丙氧基]_5•氣_苯胺，獲得42 3,0 0.« , 度年呈黃色油狀之胺基-4-氣-苯氧基）-丙-1-醇。製備43 :合成S•氣-2_(2_三異丙基矽烷基基)-苯胺％唑5-基甲氧根據流程43中所示之方法合成5_氯_2你三異丙基石夕烧基-噁唑-5-基曱氧基苯胺。Scheme 42 Step County A ··Synthesis; ^3·(Tertiary butyl group J-5-gas-aniline_dream base oxy group)·Propoxy synthesis 2-Π- As described in Preparation 2 Step b Yin Starting material I57I02.doc • 179-201217379 = group: methyl...yloxy), oxy]·5-gas·aniline, and was given 71/. Yield of light yellow oil. Step: 合成: Synthesis 3 · (2_Amino _4_ gas _ phenoxy) propyl alcohol as described in the preparation of step 34 2- 2-[3_(第:r丁| and 甘, 丞-二Mercapto-decyloxy)-propoxy]_5•gas-aniline, obtained 42 3,0 0.« , a yellow oil-like amino-4-pyrene-phenoxy)-propan-1 -alcohol. Preparation 43: Synthesis of S•gas-2_(2_triisopropyldecylalkyl)-aniline-% oxazole 5-carbomethoxy. According to the method shown in Scheme 43, 5-chloro-2 is synthesized. Base-oxazole-5-ylnonyloxyaniline.

流程43Process 43

0HC0HC

SC 步驟A :合成5-(4-氣-2-硝基-苯氧基甲基）_2_三異丙基矽烷基-噁唑向2-三異丙基矽烷基-噁唑-5-曱醛（0.7 g，2.7 mmol)於甲醇與四氫呋喃之混合物（1/1，20 mL)中的溶液中添加硼氫化鈉（200 mg ’ 5.5 mmol)，且在室溫下攪拌所得混合物2〇分鐘。反應混合物接著以乙酸乙目旨稀釋，以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得（2-三異丙基矽烷基-噁唑-5-基）-曱醇。如製備20 步驟A中所述，以4-氯-2-硝基-苯酚處理此物質，獲得0.7 g 157102.doc -180 - 201217379 5-(4-氯-2-硝基-苯氧基甲基）_2_三異丙基矽烷基-噁唑。步驟B.合成5_氣_2_(2_三異丙基矽烷基噁唑_5基甲氧基）·苯胺如製備20步驟B中所述’利用辞粉還原5_(4_氣-2-硝基-苯氧基甲基）-2-三異丙基矽烷基-噁唑，獲得1〇〇 mg 5•氯_ 2-(2-二異丙基矽烷基_噁唑_5_基甲氧基广苯胺。製備44 :合成3_【4-(第三丁基_二甲基矽烷基氧基）環己基氧基】-蔡-2-基胺根據流程44中所示之方法合成3·[4_(第三丁基_二甲基矽烷基氧基）-環己基氧基卜萘基胺。SC Step A: Synthesis of 5-(4-Ga-2-nitro-phenoxymethyl)_2_triisopropyldecyl-oxazole to 2-triisopropyldecyl-oxazole-5-oxime To a solution of a mixture of methanol and tetrahydrofuran (1,1,20 mL), sodium borohydride (200 mg <RTI ID=0.0> The reaction mixture was then diluted with EtOAc EtOAc (EtOAc)EtOAc. )-sterol. This material was treated with 4-chloro-2-nitro-phenol as described in Preparation 20 Step A to give 0.7 g 157102.doc - 180 - 201217379 5-(4-chloro-2-nitro-phenoxymethyl) Base)_2_triisopropyldecyl-oxazole. Step B. Synthesis of 5_gas_2_(2_triisopropyldecyloxaxazole-5-methoxy) aniline as described in Preparation 20, Step B, using the pollen reduction 5_(4_gas-2- Nitro-phenoxymethyl)-2-triisopropyldecyl-oxazole, obtaining 1〇〇mg 5•chloro-2-(2-diisopropyldecyl-oxazole_5_yl group Oxy-aniline aniline. Preparation 44: Synthesis of 3-[4-(t-butyl-dimethyl decyloxy)cyclohexyloxy]-cain-2-ylamine was synthesized according to the method shown in Scheme 44. [4_(Third butyl-dimethyl decyloxy)-cyclohexyloxynaphthylamine.

OTBDMSOTBDMS

SC 流程44SC Process 44

步称Α:合成（3-羥基-萘-2-基）-胺基甲酸第三丁酯向3-胺基-2-萘酌·（0.5 g，3.14 mmol)於四氫吱喃（15 mL) 中之溶液中添加二碳酸二第三丁酯（1.37 g，6.28 mmol)，且在室溫下攪拌所得混合物62小時。反應混合物接著分配於水與乙酸乙酯之間；分離水層且以乙酸乙酯萃取兩次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過慮且減壓蒸發。在梦膠柱塞（己烧/EtOAc，80/20)上純化粗殘餘物’獲得棕色固體，其經己烷洗滌兩次，獲得〇 69 157102.doc -181- 201217379 g(85%產率）呈灰色固體形式之（3羥基-萘_2_基卜胺基甲酸第三丁酯。步驟B :合成丨3-(4-羥基-環己基氧基）_萘_2_基卜胺基甲酸第三丁酯根據製備2步驟B中所述之程序，合成[3 _(4_羥基_環己基氧基）-萘-2-基]-胺基甲酸第三丁酯（無色油狀物產率）。步驟C :合成4-(3-胺基-萘_2_基氧基）_環己醇在室溫下攪拌[3-(4-羥基-環己基氧基）_萘_2_基]_胺基甲酸第三丁酯（0.15 g，〇·58 mmol)及三氟乙酸（〇.2 mL)於二氣甲烧（5 mL)中之混合物16小時。藉由添加氫氧化鈉水溶液驗化反應混合物’且以二氯甲院萃取兩次。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/EtOAc ’ 75/25)純化粗殘餘物，獲得38 mg 4_(3· 胺基-萘-2-基氧基）-環己醇及66 mg三氟-乙酸4-(3·胺基_蔡_ 2-基氧基）-環己酯。以氫氧化鈉（11 mg)於乙醇（2 mL)及水中之溶液處理三氟乙酸酯，且在室溫下攪拌所得混合物隔夜。濃縮反應混合物’且使殘餘物分配於水與二氣甲燒之間，經無水硫酸納乾燥有機層’過濾且減壓蒸發，獲得另外40 mg 4-(3-胺基-蔡-2-基氧基）-環己醇。利用上述程序及適當起始物質製備以下化合物： 3-(3-胺基-萘-2-基氧基）·丙-1-醇；及 3-(3-胺基-萘-2-基氧基）-環戊醇。製備45 :合成[3-(2-胺基-4-氣_苯氧基）_環戊基】甲醇 157102.doc •182· 201217379 根據流程45中所示之方法合成[3-(2-胺基-4-氯本氡基）· 環戊基]-甲醇》Step by step: synthesis of (3-hydroxy-naphthalen-2-yl)-carbamic acid tert-butyl ester to 3-amino-2-naphthyl (0.5 g, 3.14 mmol) in tetrahydrofuran (15 mL) Di-tert-butyl dicarbonate (1.37 g, 6.28 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 62 hours. The reaction mixture was partitioned between water and ethyl acetate; aqueous layer was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate. The crude residue was purified <RTI ID=0.0></RTI> to </RTI> <RTI ID=0.0></RTI> (3 hydroxy-naphthalene-2-ylaminocarbamic acid tert-butyl ester in the form of a gray solid. Step B: Synthesis of 丨3-(4-hydroxy-cyclohexyloxy)-naphthalene-2-ylaminocarbamic acid Synthesis of tert-butyl [3 _(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-carbamic acid according to the procedure described in Preparation 2, Step B (colorless oil yield) Step C: Synthesis of 4-(3-amino-naphthalene-2-yloxy)-cyclohexanol [3-(4-hydroxy-cyclohexyloxy)-naphthalene-2-yl at room temperature a mixture of tert-butyl carbazate (0.15 g, 〇·58 mmol) and trifluoroacetic acid (〇. 2 mL) in hexanes (5 mL) for 16 hr. The reaction mixture was tested and extracted twice with chloroform. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated evaporated evaporated. The residue obtained 38 mg of 4_(3·amino-naphthalen-2-yloxy -cyclohexanol and 66 mg of trifluoro-acetic acid 4-(3.Amino-Cai-2-yloxy)-cyclohexyl ester. A solution of sodium hydroxide (11 mg) in ethanol (2 mL) and water The trifluoroacetate was treated, and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was partitioned between water and hexanes. An additional 40 mg of 4-(3-amino-cain-2-yloxy)-cyclohexanol was obtained. The following compound was prepared using the procedure described above and the appropriate starting material: 3-(3-amino-naphthalen-2-yl) Oxy)·propan-1-ol; and 3-(3-amino-naphthalen-2-yloxy)-cyclopentanol. Preparation 45: Synthesis of [3-(2-Amino-4-gas-benzene) Oxy)-cyclopentyl]methanol 157102.doc •182· 201217379 Synthesis of [3-(2-amino-4-chlorobenzyl)·cyclopentyl]-methanol according to the method shown in Scheme 45

流程45Process 45

向3-(2-胺基-4-氣·苯氧基環戊烷曱酸乙酯（0.2 g)於四氫吱喃（5 mL)中之經冷卻（0〇c)溶液中添加氫化鋰鋁溶液（1 Μ，3 mL)，且攪拌所得混合物3〇分鐘。接著藉由添加氯化錢飽和水溶液淬滅反應混合物且過據。以乙酸乙醋洗蘇濾餅’且濾液經無水硫酸鈉乾燥’過濾且減壓蒸發，未經 I::化即獲付180叫Μ2-胺基I氯·笨氧基)_環戍製備46·•合成6_甲氧基_ljyr_吲唑_5基胺Addition of lithium hydride to a cooled (0 〇c) solution of ethyl 3-(2-amino-4- phenoxycyclopentane decanoate (0.2 g) in tetrahydrofuran (5 mL) Aluminium solution (1 Μ, 3 mL), and the resulting mixture was stirred for 3 hrs. The reaction mixture was then quenched by the addition of a saturated aqueous solution of chlorinated hexanes, and the mixture was washed with ethyl acetate and the filtrate was dried over anhydrous sodium sulfate. Dry 'filtered and evaporated under reduced pressure, without I:: is paid 180 called 2-amino-1 chloro-p-oxy) _ ring oxime preparation 46 · synthesis 6_methoxy _ljyr_carbazole _5 Amine

胺。 -吲唑-5-基根據流程46中所示之方法，合成心甲氧基j好amine. -carbazole-5-yl, according to the method shown in Scheme 46, synthesizing cardiac methoxyl is good

流程46 157102.doc •183· 201217379 步合成甲氧基_2·甲基苯基）·乙酿胺向5_曱氧基-2-甲基·苯胺（5〇 g，36 44丽叫於。比咬⑼ mL)中之溶液中添加乙酸肝（56 g，从66 ·〇ι)，且在室溫下授拌所得混合物隔夜。添加水且藉由添加鹽酸水溶液 (3 M)將pH值調整至5。以二氯甲垸萃取所得混合物；分離有機層且以碳酸氫鈉飽和水溶液及鹽水洗滌，經無水硫酸鈉乾燥，過濃且減壓蒸發，未經進—步純化即獲得5·93 g 呈白色固體形式之iV-(5-甲氧基_2_曱基-苯基)_乙醯胺。步稱B :合成iV-(5·甲氧基_2_甲基·4_確基苯基）乙醢胺在5°C至10°C之範圍内的溫度下，向沁（5甲氧基_2_甲基_ 苯基）-乙酿胺（3.0 g，16·76 mm〇i)及濃硫酸（1〇 mL)於冰醋酸（20 mL)中之混合物中逐滴添加硝酸（7〇%，2 5 , 25.14 mmol)，且攪拌所得混合物3小時。將反應混合物傾入冰水中，且藉由過濾收集所形成之固體。使殘餘物溶解於一氣曱烷中，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得2.135 g呈灰白色固體形式之#_(5_曱氧基·2·甲基_4硝基_ 苯基）-乙醯胺。步称C:合成6-甲氧基-5-確基·;弓丨唾在40C下，向#-(5-甲氧基_2-甲基-4-硝基-苯基）-乙醯胺 (0.5 g，2·23 mmol)、碳酸鉀（0·26 g，2 68 mm〇1)、冰醋酸 (0.15 mL，2.68 mmol)及乙酸酐（0.42 mL，4 46 mm〇1)於氣仿（20 mL)中之混合物中添加異戊腈（〇 6 mL，4.46 mmol) ’且在60°C下加熱所得混合物隔夜。接著藉由添加碳酸氫鈉飽和水溶液鹼化反應混合物，且以二氣曱院萃取 157102.doc -184· 201217379 兩次。合併之有機萃取物經無水硫酸鈉乾燥，過遽且減壓蒸發。向殘餘物中添加鹽酸水溶液（3 Μ，10 mL)與曱醇 (10 mL)之混合物，且在80°C下加熱所得混合物2小時。冷卻反應混合物’藉由添加碳酸氫鈉飽和水溶液驗化，且以二氣甲院萃取。有機萃取物經無水硫酸納乾燥，過遽且減壓蒸發。藉由急驟層析法（EtOAc/己烷，0/1 〇〇至70/30)純化粗殘餘物’獲得169 mg呈燈色固體形式之6-甲氧基-5-石肖基-1 n引σ坐。Scheme 46 157102.doc • 183·201217379 Step synthesis of methoxy-2-methylphenyl)·Ethylamine to 5-methoxy-2-methylaniline (5〇g, 36 44 丽. Acetic acid liver (56 g, from 66 · 〇ι) was added to the solution in the bite (9) mL), and the resulting mixture was mixed overnight at room temperature. Water was added and the pH was adjusted to 5 by the addition of aqueous hydrochloric acid (3 M). The mixture was extracted with chloroformic acid. The organic layer was separated and washed with sat. iV-(5-methoxy-2-indolyl-phenyl)-acetamide in solid form. Step B: Synthesis of iV-(5·methoxy-2-methyl-4-yl-2-phenyl)acetamide at a temperature ranging from 5 ° C to 10 ° C to 沁 (5 methoxy) Addition of nitric acid (7-methyl-phenyl)-ethonamide (3.0 g, 16.76 mm〇i) and concentrated sulfuric acid (1 mL) in a mixture of glacial acetic acid (20 mL) 〇%, 2 5 , 25.14 mmol), and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into ice water, and the solid formed was collected by filtration. The residue was dissolved in EtOAc (EtOAc m.) )-acetamide. Step C: Synthesis of 6-methoxy-5-definite group; bowing saliva at 40C, to #-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamidine Amine (0.5 g, 2.23 mmol), potassium carbonate (0.26 g, 2 68 mm 〇1), glacial acetic acid (0.15 mL, 2.68 mmol) and acetic anhydride (0.42 mL, 4 46 mm 〇1) Isovaleronitrile (〇6 mL, 4.46 mmol) was added to the mixture in the mixture (20 mL) and the mixture was heated overnight at 60 °C. The reaction mixture was then basified by the addition of a saturated aqueous solution of sodium bicarbonate, and 157102.doc - 184. The combined organic extracts were dried over anhydrous sodium A mixture of aqueous hydrochloric acid (3 Torr, 10 mL) and decyl alcohol (10 mL) was added to the residue, and the mixture was heated at 80 ° C for 2 hr. The reaction mixture was cooled and verified by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and extracted with a gas chamber. The organic extract was dried over anhydrous sodium sulfate, dried over reduced pressure and evaporated. Purification of the crude residue by flash chromatography (EtOAc / hexanes / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc) sit.

步驟D :合成6-甲氧基-1好-吲唑-5-基胺在〇°C下，向6-甲氧基-5-硝基-If吲唑（0.16 g，0.83 mmol)、鹽酸水溶液（6 μ，5 mL)與濃鹽酸（2 mL)之混合物中添加氯化亞錫（0J1 g，1.66 mmol)’且所得混合物升溫至至溫。在室溫下擾拌反應混合物4小時，接著藉由添加碳酸氫鈉飽和水溶液淬滅。以二氣甲烷萃取所得混合物；有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。以二氣甲烧濕磨粗殘餘物，獲得6_甲氧基_l/f-吲唑_5_基胺與3_氣_ 曱氧基-1//-吲唑-5-基胺之2/1混合物。製備47 :合成6-[2-(第三丁基-二甲基-矽烷基氧基乙基】_ 哺唾并[l，5-fl】嘧啶-3-甲酸根據流程47中所示之方法合成6-[2-(第三丁基-二甲基-矽烷基氧基）-乙基]-吡唑并Ujm]嘧啶_3_曱酸。Step D: Synthesis of 6-methoxy-1-deoxazol-5-ylamine to 6-methoxy-5-nitro-Ifcarbazole (0.16 g, 0.83 mmol), HCl Stannous chloride (0 J1 g, 1.66 mmol) was added to a mixture of aqueous (6 μ, 5 mL) and concentrated hydrochloric acid (2 mL) and the mixture was warmed to warm. The reaction mixture was stirred at room temperature for 4 hours and then quenched by aqueous saturated sodium hydrogen carbonate. The resulting mixture was extracted with EtOAc (EtOAc). The crude residue was triturated with a second gas to obtain 6-methoxyl/f-carbazole-5-ylamine and 3_gas_methoxy-1//-carbazole-5-ylamine. 2/1 mixture. Preparation 47: Synthesis of 6-[2-(t-butyl-dimethyl-decyloxyethyl)- hydrazino[l,5-fl]pyrimidine-3-carboxylic acid according to the method shown in Scheme 47 Synthesis of 6-[2-(t-butyl-dimethyl-decyloxy)-ethyl]-pyrazolo-Ujm]pyrimidine_3_decanoic acid.

流程47 157102.doc 201217379 步琢A .合成6-(2-幾基-乙基）-¾嗅并丨嘴咬甲酸向3- 一乙氧基甲基_2-乙氧基-四氫呋喃（根據w〇 2005/095317 製備）（350 mg，1.61 mmol)於二氣甲烷（2 mL) 中之經冷卻（0°C )溶液中添加鹽酸水溶液（6 M，2 mL)，隨後添加5-胺基-1//-吡唑_4_甲酸（25〇 mg，i 97 mm〇1)，且所得混合物在70°C下逐漸加熱1小時。在加熱下蒸發有機溶劑，且藉由過濾、水層收集所形成之固體，獲得5〇 5胺基-1//-吡唑-4-甲酸殘餘物。濾液以乙醚重複濕磨，傾析且凍乾，獲得6-(2-羥基-乙基）_吡唑并uja]嘧啶_3•甲酸。步驟B :合成6-[2-(第三丁基-二甲基_矽烷基氧基）乙基卜哺唑并[1，5-α】嘧啶-3-甲酸根據製備2步驟Α中所述之程序保護6_(2·羥基·乙基）·吡唑并[1，5_α]嘧啶-3-曱酸。製備48 :合成6-甲基-吡唑并口，5…】嘧啶_3甲酸根據流程48中所示之方法合成6_甲基_吡唑并[^-…嘧咬_ - 3 _甲酸。Scheme 47 157102.doc 201217379 Step A. Synthesis of 6-(2-monoethyl-ethyl)-3⁄4 olfactory and grinning formic acid to 3-monoethoxymethyl_2-ethoxy-tetrahydrofuran (according to w 〇2005/095317 Preparation (350 mg, 1.61 mmol) in a cooled (0 ° C) solution in di-methane (2 mL), aqueous hydrochloric acid (6 M, 2 mL), then 5-amino- 1//-pyrazole_4_carboxylic acid (25 mg, i 97 mm 〇1), and the resulting mixture was gradually heated at 70 ° C for 1 hour. The organic solvent was evaporated under heating, and the solid formed was collected by filtration and aqueous layer to obtain a residue of 5? The filtrate was repeatedly wet-ground with diethyl ether, decanted and lyophilized to obtain 6-(2-hydroxy-ethyl)-pyrazolo-uja]pyrimidine_3•carboxylic acid. Step B: Synthesis of 6-[2-(t-butyl-dimethyl-decyloxy)ethyltraconazole [1,5-α]pyrimidine-3-carboxylic acid according to Preparation 2 The procedure protects 6_(2.hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-decanoic acid. Preparation 48: Synthesis of 6-methyl-pyrazole hydrazine, 5...]pyrimidine _3 carboxylic acid 6-Methyl-pyrazole[^-...pyrimidine_-3 carboxylic acid was synthesized according to the procedure shown in Scheme 48.

流程48 在狁封試管中在95°C下加熱5-胺基-lif-ii比唑·4_甲酸（271 mg，2.1 mmol)& 113 3_四乙氧基_2甲基丙烷（根據以 126(7)，2004, 2194中所述之程序製備）（〇 5 g ，2.1 mmol)於 157102.doc 201217379 鹽酸水溶棒M，丨.3 mL)巾之時，固體物質完全溶解，接著‘、、液。虽溫度達到82。匚續授拌5分鐘。將所得混合物A溶液析出固體沈殿物，繼隹圊艚，以^、士呔 7部至室溫’且藉由過濾收集固體，以水沖洗且在真二玖相中乾燥，獲得305.1 g(產率）6-曱基,并[心]㈣_3_甲酸。製備49 :合成6-甲氧基·吡唑异开赞咬_3_甲酸根據流程49中所示之方法合朴甲酸。成甲氧基_。比唾并Π，5-咖Scheme 48 heating 5-amino-lif-ii azole-4-acid (271 mg, 2.1 mmol) & 113 3_tetraethoxy-2-methylpropane at 95 ° C in a sealed tube (according to Prepared by the procedure described in 126(7), 2004, 2194) (〇5 g, 2.1 mmol) in 157102.doc 201217379 hydrochloric acid water-soluble stick M, 丨.3 mL) towel, the solid matter is completely dissolved, then ' ,,liquid. Although the temperature reached 82.续 Continue to mix for 5 minutes. The resulting mixture A solution was precipitated into a solid sediment, followed by hydrazine, and the mixture was collected by filtration, and the solid was collected by filtration, washed with water and dried in a true diterpene phase to obtain 305.1 g. Rate) 6-mercapto, and [heart] (four) _3_ formic acid. Preparation 49: Synthesis of 6-methoxy-pyrazole iso-opening _3_carboxylic acid The formic acid was purified according to the procedure shown in Scheme 49. Form methoxy _. More than swearing, 5-ca

向乙二醯氣（6.9 mL)於二氯甲烷（65 mL)中之在_78(>c下冷卻的溶液中逐滴添加二甲亞砜〇3 mL)於二氣甲烷（Μ mL)中之溶液，且攪拌所得混合物1〇分鐘。接著逐滴添加 2-0-甲基-丙三醇（3.3 g’ 31.5 mm〇1)於二氣甲烷（16社）中之溶液，且攪拌反應混合物15分鐘。逐滴添加三乙胺（52 mL) ’且授拌所得混合物1小時。反應混合物升溫至室溫，且添加鹽酸水溶液（6 Μ ’ 35 mL) ’隨後添加5_胺基^汉^比唑-4-甲酸（4 g ’ 31.5 mmol)，且所得混合物經2〇分鐘加熱至95°C ’溫度保持為95°C持續20分鐘。所得混合物冷卻至室溫’且在室溫下儲存24小時，且在4°C下儲存62小時。藉由過濾收集所形成之固體，且在真空烘箱中乾燥，獲得 1.087 g(18%產率）6-曱氧基-0比0坐并[1，5-<2]啦咬_3_甲酸。 157102.doc -187- 201217379 製備50:合成6·溴-吡唑并【15-^】嘧啶_3甲酸根據流程50中所示之方法合成6_溴_吡唑并"μ嘧啶· 3-曱酸。To ethylene dioxane (6.9 mL) in dichloromethane (65 mL), add dimethyl sulfoxide (3 mL dropwise) to _78 (>c cooled solution) in di-methane (Μ mL) The solution was stirred and the resulting mixture was stirred for 1 min. Then, a solution of 2-0-methyl-glycerol (3.3 g' 31.5 mm 〇1) in dioxane (16) was added dropwise, and the reaction mixture was stirred for 15 minutes. Triethylamine (52 mL) was added dropwise and the resulting mixture was stirred for 1 hour. The reaction mixture was warmed to room temperature, and aqueous hydrochloric acid (6 Μ '35 mL) was then added, and then 5-amino-amine-biazole-4-carboxylic acid (4 g '31.5 mmol) was added, and the mixture was heated over 2 Torr. The temperature was maintained at 95 ° C for 20 minutes at 95 ° C. The resulting mixture was cooled to room temperature' and stored at room temperature for 24 hours and stored at 4 °C for 62 hours. The formed solid was collected by filtration and dried in a vacuum oven to obtain 1.087 g (18% yield) of 6-decyloxy-0 to 0 and [1,5-<2] bite_3_ Formic acid. 157102.doc -187- 201217379 Preparation 50: Synthesis of 6-bromo-pyrazolo[15-^]pyrimidine-3-carboxylic acid according to the procedure shown in Scheme 50 for the synthesis of 6-bromo-pyrazole "μpyrimidine· 3- Tannic acid.

BrBr

NH2 + OHC^^CHO 流程50 在95C下加熱5·胺基]m心甲酸（1 g，7 8 及 2_/臭丙一醛（1·2 g，7·8 mmo1)於鹽酸水溶液（6 Μ , 20 mL) 中之懸浮液15分鐘1所得混合物冷卻至室溫，且藉由過慮收集所形成之固Μ，以水沖洗且在真空烘箱中乾燥，獲得6_溴-吡唑并Π，5-ω]嘧啶-3-甲酸。製備51 :合成1_吡咯啶_3_基_乙醇三氟乙酸鹽根據流程51中所示之方法，合成i吡咯啶_3基三氟乙酸鹽。一NH2 + OHC^^CHO Scheme 50 Heating 5·Amino]m cardioic acid (1 g, 7 8 and 2_/ odoraceous aldehyde (1·2 g, 7·8 mmo1) in aqueous hydrochloric acid (6 Μ at 95 ° C) , 20 mL) of the suspension for 15 minutes 1 The resulting mixture was cooled to room temperature, and the formed solid was collected by over-treatment, rinsed with water and dried in a vacuum oven to obtain 6-bromo-pyrazole, 5 -ω]pyrimidine-3-carboxylic acid. Preparation 51: Synthesis of 1-pyrrolidinyl-3-yl-ethanol trifluoroacetate The pyrrolidine-3-yl trifluoroacetate was synthesized according to the procedure shown in Scheme 51.

流程51 在氮就氛圍下，在〇°c下，向3_甲酿基“比略咬· ^甲酸第三丁醋（2 g，1G.G随。1}於四氫β夫喃（15 mL)中之溶液中添加碘化甲基鎂溶液（於Et2〇中，3.0 Μ，1〇，3〇 mm〇1) ’且在室溫下授拌所得混合物1小時。接著添加第二 157102.doc 201217379 部为之四氫呋喃（55 mL)。藉由添加氣化銨飽和水溶液淬滅反應混合物，直至固體溶解。減壓蒸發揮發物，且殘餘物以二氣甲烷萃取兩次。合併之有機萃取物以碳酸氫鈉飽和水浴液洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，獲得2.149 3-(1-羥基-乙基）_吡咯啶_丨_甲酸第三丁酯。向一部分此物質（875 mg，4_1 mm〇l)中添加三氟乙酸溶液（於dcM 中，5%，10 mL)，且在室溫下攪拌所得混合物3〇分鐘。接著減壓蒸發反應混合物，獲得1_吡咯啶_3_基-乙醇三氟乙酸鹽，其未經進一步純化即使用。製備52 :合成{1-[1-(2·胺基-4-氣_苯基）·吡咯啶-3-基卜乙基}-胺基甲酸第三丁酯根據流程52中所示之方法合成胺基_4_氣-苯基）-0比嘻咬-3-基]-乙基}-胺基曱酸第三丁醋。In a nitrogen atmosphere, under the 〇 °c, to the 3_ 甲 BASE "Bitter bite ^ ^ formic acid third vinegar (2 g, 1G. G with .1} in tetrahydro beta fumon (15 Add methyl magnesium iodide solution (in Et2, 3.0 Μ, 1 〇, 3 〇 mm 〇 1) to the solution in mL) and mix the resulting mixture for 1 hour at room temperature. Then add the second 157102. Doc 201217379 is tetrahydrofuran (55 mL). The reaction mixture is quenched by the addition of a saturated aqueous solution of ammonium sulfate until the solid is dissolved. The volatiles are evaporated under reduced pressure and the residue is extracted twice with methane. Washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give <RTI ID=0.0>> Trifluoroacetic acid solution (5%, 10 mL in dcM) was added to 875 mg, 4_1 mm 〇l), and the resulting mixture was stirred at room temperature for 3 Torr. The reaction mixture was evaporated under reduced pressure to give 1-pyrrolidine. _3_yl-ethanol trifluoroacetate, which was used without further purification. Preparation 52: Synthesis of {1-[1-(2.Amino-4- gas) _Phenyl)pyrrolidin-3-ylethyl}-carbamic acid tert-butyl ester was synthesized according to the method shown in Scheme 52. The amine group _4_gas-phenyl)-0 is more than benzyl-3-yl] -Ethyl}-amino phthalic acid tert-butyl vinegar.

步驟A :合成甲烷磺酸1-[1-(4-氣-2-硝基-苯基）·吡咯啶-3-基】-乙醋在氮氣氛圍下，在室溫下，攪拌卜Π-(2·胺基-4-氣-苯基）-吡咯啶-3-基]-乙醇（320.7 mg，1.2 mmol)、三乙胺（0.5 mL)及對甲笨磺醯氯（272 mg)於二氯甲烷（15 mL)中之混合 157102.doc -189- 201217379 物62小時。接著添加4-二曱基胺基吡啶（催化量），且在回流下加熱反應混合物3小時。減壓蒸發所得混合物；使殘餘物溶解於》比啶中，且再添加對甲苯磺醯氣（272 mg)。在至>胤下授摔反應混合物隔夜’接著減壓蒸發。殘餘物以水稀釋’且以乙酸乙酯萃取3次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥’過濾且減壓蒸發。向此物質於二氯曱烧（15 mL)中之溶液中添加三乙胺（0.5 mL)，隨後添加甲烷磺醯氯（0.26 mL) ’且在氮氣氛圍下，在室溫下授拌所得混合物2小時。以水洗滌反應混合物兩次，且以二氣曱院萃取水層3次。以鹽水洗蘇經合併之有機萃取物，經無水硫酸鈉乾燥’過濾且減壓蒸發。藉由急驟層析法 (己烷/EtOAc ’ 90/10至50/50)純化粗殘餘物，獲得285.9 mg 曱烧確酸1-[1-(4-氣-2-硝基-苯基）-n比洛咬-3-基]-乙醋及 55.2 mg曱苯-4_續酸1-[1-(4-氯-2-硝基·苯基）_π比洛咬_3_基]_ 乙酯。步驟Β ··合成3-(1-疊氮基-乙基氣-2_硝基_苯基）_咕略咬曱院績酸1-[1-(4-氯-2-硝基-苯基）_”比洛咬_3_基]-乙酯 (285.9 mg)、甲苯-4-磺酸1-[1-(4-氣-2-硝基-笨基）_吡咯啶· 3-基]-乙酯（55.2 mg)及叠氮化鈉（185 mg)於愚二曱基曱酿胺（約5 mL)中之混合物在80 C下加熱隔夜。冷卻反應混〇物’以水稀釋且以乙酸乙醋萃取3次。以鹽水洗務經合併之有機萃取物，經無水硫酸納乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷/EtOAc ’ 90/10)純化粗殘餘物，獲得 157102.doc •190- 201217379 214 mg(76%產率）3·(1_疊氮基-乙基）硝基笨基）_ 0比洛咬。步称C :合成1^(4·氣_2_硝基_苯基）咯啶_3基】乙胺在5〇°C下加熱3-U-疊氮基-乙基）-1-(4-氯-2-硝基-苯基）- 0 比 σ各咬（214 mg，〇.7 mm〇l)、三苯膦（5〇〇 mg)及水（0,171 mL)於四氫呋喃（2〇 mL)中之混合物隔夜。減壓蒸發所得混合物；殘餘物以乙酸乙酯稀釋，以水洗滌兩次且以鹽水洗務一次’經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM/MeOH)純化粗殘餘物，獲得127 mg(65%產率）卜Π-(4-氯-2-硝基-苯基）比咯啶_3_基卜乙胺。步称D :合成{141(4-氣-2-硝基-苯基）-«*咯啶-3-基]-乙基}-胺基甲酸第三丁酯向在0°C下冷卻的ΐ-[ι_(4-氯-2-硝基-苯基）-〇比咯啶-3-基]-乙胺（127 mg，0.47 mmol)於二氯曱烷（約5 mL)中的混合物中添加二碳酸二第三丁酯（113 mg)，且在〇。〇下攪拌所得混合物3 0分鐘《接著使反應混合物升溫至室溫且攪拌2.5小時。所得混合物以碳酸氩鈉飽和水溶液及鹽水洗滌，經無水硫酸納乾燥，過濾且減壓蒸發。藉由急驟層析法（己烷 /EtOAc，90/10至50/50)純化粗殘餘物，獲得146 mg(84〇/〇產率）{1 - 氣-2-确基-苯基比洛咬_3_基]•乙基胺基曱酸第三丁酯》步驟E :合成{ΐ-【ι_(2·胺基-4-氣-苯基）_哺咯啶_3_基】-乙基}-胺基甲酸第三丁酯根據製備20步驟B中所述之程序還原{i_[i _(4·氣_2_硝基- 157102.doc •191 - 201217379 苯基）-°比洛啶-3-基]·•乙基}·胺基曱酸第三丁酯’獲得定量產率之{1-[1-(2-胺基-4-氣-苯基比咯啶_3_基]-乙基}-胺基曱酸第三丁酯。實例1 ··合成吡唑并丨l，S_e】嘧啶_3_甲酸【5-氣_2_(4_羥基_環己基氧基）-苯基]_酿胺根據流程53中所示之方法合成吡唑并[1，5-α]嘧啶-3-曱酸 [5-氯-2-(4-羥基·環己基氧基）苯基]醯胺。Step A: Synthesis of 1-[1-(4-Ga-2-nitro-phenyl)-pyrrolidin-3-yl]-ethane sulfonic acid methanesulfonate Under a nitrogen atmosphere, stir the dip at room temperature - (2.Amino-4-oxo-phenyl)-pyrrolidin-3-yl]-ethanol (320.7 mg, 1.2 mmol), triethylamine (0.5 mL) and p-chlorosulfonyl chloride (272 mg) Mix 157102.doc -189 - 201217379 in dichloromethane (15 mL) for 62 hours. Next, 4-didecylaminopyridine (catalytic amount) was added, and the reaction mixture was heated under reflux for 3 hours. The resulting mixture was evaporated under reduced pressure; the residue was dissolved in <EMI ID> The reaction mixture was dropped overnight to > and then evaporated under reduced pressure. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine dried over anhydrous sodium Add triethylamine (0.5 mL) to a solution of this material in dichloromethane (15 mL), then add methanesulfonium chloride (0.26 mL) and mix the mixture at room temperature under nitrogen. 2 hours. The reaction mixture was washed twice with water, and the aqueous layer was extracted three times with dioxane. The combined organic extracts were washed with brine, dried over anhydrous sodium The crude residue was purified by flash chromatography (hexane /EtOAc EtOAc EtOAc EtOAc EtOAc -n pirate-3-yl]-ethyl vinegar and 55.2 mg fluorene benzene-4_supply 1-[1-(4-chloro-2-nitrophenyl)_π 洛洛____ base] _ Ethyl ester. Step Β ···················································· Base)_"Bilo bite_3_yl]-ethyl ester (285.9 mg), toluene-4-sulfonic acid 1-[1-(4-gas-2-nitro-phenyl)pyrrolidine· 3- A mixture of ethyl]-ethyl ester (55.2 mg) and sodium azide (185 mg) in stilbene-based amine (about 5 mL) was heated overnight at 80 C. The reaction mixture was cooled and diluted with water. The mixture was extracted with EtOAc (3 mL). EtOAc (EtOAc) Residue, obtained 157102.doc • 190-201217379 214 mg (76% yield) 3 · (1_azido-ethyl) nitro stupyl) _ 0 than the bite. Step C: Synthesis 1 ^ ( 4·Gas_2_Nitro-phenyl)rhodium-3-yl]ethylamine heated 3-U-azido-ethyl)-1-(4-chloro-2-nitro) at 5 °C -Phenyl)- 0 is a mixture of sigma (214 mg, 〇.7 mm 〇l), triphenylphosphine (5 〇〇 mg) and water (0,171 mL) in tetrahydrofuran (2 〇 mL) overnight. Evaporating the resulting mixture; the residue is B Diluted with ethyl acetate, washed twice with water and dried with brine s s s s s s s s s s s s s s s s s s s s s s s s s % yield) di-(4-chloro-2-nitro-phenyl)pyrrolidin-3-ylbiethylamine. Step D: Synthesis {141(4-Gas-2-nitro-phenyl) )-«*-r-hexyl-3-yl]-ethyl}-carbamic acid tert-butyl ester to ΐ-[ι-(4-chloro-2-nitro-phenyl)-fluorene cooled at 0 ° C Dibromodicarbonate dihydrate (113 mg) was added to a mixture of bromopyridin-3-yl]-ethylamine (127 mg, 0.47 mmol) in dichloromethane (about 5 mL). The mixture was stirred for 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 2.5 hr. The mixture was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by EtOAc (EtOAc/EtOAc (EtOAc/EtOAc) ·•Ethylamino decanoic acid tert-butyl ester Step E: Synthesis {ΐ-[ι_(2·Amino-4-gas-benzene) Base _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ .doc •191 - 201217379 Phenyl)-°Birozin-3-yl]·•ethyl}·aminobutyric acid tert-butyl ester' to obtain quantitative yield of {1-[1-(2-amine Base 4-gas-phenylpyrrolidinyl-3-yl]-ethyl}-aminobutyric acid tert-butyl ester. Example 1··Synthesis of pyrazoloindole, S_e]pyrimidine_3_carboxylic acid [5-gas_2_(4-hydroxy-cyclohexyloxy)-phenyl]-bristamine was synthesized according to the method shown in Scheme 53 Pyrazolo[1,5-α]pyrimidine-3-decanoic acid [5-chloro-2-(4-hydroxycyclohexyloxy)phenyl]decylamine.

流程53 在室溫下’向4-(2-胺基-4-氣-苯氧基）-環己醇（127 mg， 0.525 mmol)、吡唑并[ι，5_α]嘧啶 _3_ 曱酸（85 mg，〇 521 mmol)及 HBTU(0.21 g，0.55 mmol)於無水乙腈（15 mL)t 之懸洋液中添加二異丙基乙基胺（0.35 mL，2.01 mmol)，且在80°C下加熱所得溶液隔夜《使所得混合物分配於乙酸乙酯與碳酸氫納水溶液（5%)之間。接著以乙酸乙酯萃取水層3次’且以鹽水洗滌合併之有機萃取物，經無水硫酸鈉乾燥’過濾且減壓蒸發。在矽膠柱塞上且藉由急驟層析法 (DCM/MeOH/NH4〇H)純化標色油性殘餘物，獲得淺黃色固體’其以二氣甲烷及甲醇洗滌’獲得75 mg(38〇/〇產率）呈白 157102.doc -192- 201217379 色粉末形式之《比唾并[15_α]嘴啶甲酸[5氯_2_(4羥基環己基氧基）-苯基]-醢胺。Ms=387 [μ+η]+。以類似方式，利用適當起始物質，製備以下化合物： 3_甲氧基_4·[(°比。坐并Π，5-α]嘧啶-3-羰基）-胺基]-苯甲酸甲酯；吡唑并[1，5-α]嘧啶-3-甲酸[4_(第三丁基_二甲基-矽烷基氧基甲基）-2-曱氧基·苯基]_醯胺； 6-甲醯基-吡唑并[15_α]嘧啶_3曱酸（2-[4-(第三丁基_ 一甲基-矽烷基氧基）_環己基氧基卜5_氯_苯基卜醯胺； °比唑并[1，5-α]嘧啶·3_甲酸（3_曱氧基_聯苯_4_基）_醯胺 (淺黃色固體）；MS=345 [Μ+Η]+ ; 吡唑并[1，5-α]嘧啶_3,6_二曱酸6醯胺第三丁基-一甲基-石夕燒基氧基）-環己基氧基]-5-氣-苯基}-醯胺）； 3-甲氧基-4-硝基苯基_苯甲醯胺；吡唑并[1，5-α]嘧啶-3-甲酸（2-甲氧基-4-苯基胺曱醯基-苯基）-酿胺（淺黃色結晶固體）；MS=388 [Μ+Η]+ ; 吡唑并[1’5_α]嘧啶-3-甲酸（3-胺基-2-甲氧基-苯基）-醯胺（淺黃色粉末）；MS=284 [M+H]+ ; °比°坐并[1，5_α]喷啶-3-曱酸[3-(3-羥基-丙基胺基）-2-哌咬_1_基-苯基]-醯胺（淺黃色粉末）；MS=395 [M+H]+ ; °比0圭并[1，5_α]嚷啶-3-曱酸[3-(2-羥基-乙基胺基）-2-哌咬1_基-苯基]-醯胺（淺黃色粉末）；MS=381 [M+H]+ ; °«^并[1’51]’。^3_甲酸（5_氣_2_甲氧基_4_苯基胺甲 157102.doc 201217379 酿基-苯基）-醯胺（白色粉末）；MS=422 [M+H]+ ; 吡唑并[1，5-α]嘧啶-3_甲酸（4_二甲基胺曱醯基_2_甲氧基-苯基）-醯胺（白色粉末）；MS=340 [M+H]+ ; 。比唾并[1，5-α]嘧啶_3-甲酸（2_甲氧基_3 5_二甲基苯基）-酿胺（淺黃色粉末）；MS=297 [M+H]+ ; 5-甲基-»比唑并[ι，5·α]嘧啶_3_曱酸{2_[4_(第三丁基_二曱基-矽烷基氧基）-環己基氧基]_5_氣_苯基卜醯胺； 7_甲基比嗤并[1，5-α]嘧啶_3-甲酸{2_[4-(第三丁基-二曱基-石夕烧基氧基）-環己基氧基]_5_氯_苯基卜醯胺； | 吡唑并[1，5-α]嘧啶·3-甲酸[5_(3-羥基-丙基）-2-甲氧基_ 苯基]-醯胺（淺棕色結晶固體）；MS=327 [M+H]+ ; MP=189.7-190.2°C ；。比0坐并[1，5·α]嘧啶·3-甲酸（2_曱氧基_5_乙烯基-苯基）· 醯胺（淺黃色固體）；MS=295 [M+H]+ ; 0比嗤并[1，5-α]嘧啶-3-曱酸（5-乙基-2-甲氧基-苯基）-醯胺（粉紅色粉末）；MS=297 [M+H]+ ; 吼吐并[1,5-α]嘧啶·3-甲酸[5-氣-2-(4-羥基曱基-哌啶· 鲁 1- 基）-苯基]-醯胺（灰白色固體）；MS=386 [M+H]+ ; (l-{4-氯-2-[(n比唑并[l，5-fl]嘧啶-3-羰基）-胺基]-苯基}-哌啶-4-基曱基）-胺基甲酸第三丁酯； °比咯并[2,1-/][1，2,4]三嗪-7-甲酸[5-氣-2-(4羥基-環己基氧基）-苯基]-醯胺（灰白色固體）；MS=386 [M+H]+ ; 2- 氣-噻吩并[3，2-d]嘧啶-7-甲酸（7-甲氧基-喹啉-6-基）-醯胺； -194· 157102.docScheme 53 'To 4-(2-Amino-4- gas-phenoxy)-cyclohexanol (127 mg, 0.525 mmol), pyrazolo[ι,5_α]pyrimidine_3_decanoic acid (at room temperature) 85 mg, 〇 521 mmol) and HBTU (0.21 g, 0.55 mmol) were added diisopropylethylamine (0.35 mL, 2.01 mmol) in anhydrous acetonitrile (15 mL) EtOAc. The resulting solution was heated under overnight. The resulting mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate (5%). The aqueous layer was extracted with EtOAc (3 mL). The oily residue was purified by flash chromatography (DCM/MeOH/NH.sub.H) to give a pale-yellow solid, which was washed with di-methane and methanol to afford 75 mg (38 〇/〇). Yield) is white 157102.doc -192- 201217379 in the form of a color powder of "pino-[15_α]-pyridinic acid [5-chloro-2-(4-hydroxycyclohexyloxy)-phenyl]-guanamine. Ms = 387 [μ + η] +. In a similar manner, using the appropriate starting materials, the following compounds were prepared: 3_methoxy_4·[(° ratio. sit-and-oxime, 5-α]pyrimidin-3-carbonyl)-amino]-benzoic acid methyl ester ; pyrazolo[1,5-α]pyrimidine-3-carboxylic acid [4_(t-butyl-dimethyl-decyloxymethyl)-2-indolyloxyphenyl]-decylamine; -Methylmercapto-pyrazolo[15_α]pyrimidine-3-tridecanoic acid (2-[4-(t-butyl-1-methyl-decyloxy)-cyclohexyloxybu 5_chloro-phenyl)醯amine; ° oxazolo[1,5-α]pyrimidine·3_carboxylic acid (3-methoxy-biphenyl-4-yl)-decylamine (light yellow solid); MS=345 [Μ+Η] + ; pyrazolo[1,5-α]pyrimidine_3,6-diphthalic acid 6-decylamine tert-butyl-monomethyl-stone-oxyl-cyclohexyloxy]-5-gas -phenyl}-decylamine; 3-methoxy-4-nitrophenyl-benzamide; pyrazolo[1,5-α]pyrimidine-3-carboxylic acid (2-methoxy-4) -phenylaminoindenyl-phenyl)-chiral amine (light yellow crystalline solid); MS = 388 [Μ + Η] + ; pyrazolo[1'5_α]pyrimidine-3-carboxylic acid (3-amino- 2-methoxy-phenyl)-decylamine (light yellow powder); MS=284 [M+H]+ ; ° ratio °[1,5_α]pyridin-3-decanoic acid [3-(3 -hydroxy-propylamino)-2-piperidin-1_yl-phenyl]-decylamine (light yellow powder); MS=395 [M+H]+ ; ° ratio 0 gram [1,5_α] Acridine-3-decanoic acid [3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl]-guanamine (light yellow powder); MS = 381 [M+H]+ ; °«^ and [1'51]'. ^3_carboxylic acid (5_gas_2_methoxy_4_phenylamine A 157102.doc 201217379 Stucco-phenyl)-guanamine (white powder); MS=422 [M+H]+ ; Zoxa[1,5-α]pyrimidine-3-carboxylic acid (4-dimethylaminoindenyl-2-methoxy-phenyl)-decylamine (white powder); MS=340 [M+H] + ; Specific saliva [1,5-α]pyrimidine_3-carboxylic acid (2-methoxy-3-35-dimethylphenyl)-bristamine (light yellow powder); MS = 297 [M+H]+; 5-methyl-»benzazolo[ι,5·α]pyrimidine_3_decanoic acid {2_[4_(t-butyl-didecyl-decyloxy)-cyclohexyloxy]_5_gas _Phenyl oxime; 7-methyl hydrazino[1,5-α]pyrimidine _3-carboxylic acid {2_[4-(t-butyl-diindenyl-stone) Hexyloxy]_5_chloro-phenyl-p-oxime; | pyrazolo[1,5-α]pyrimidine·3-carboxylic acid [5-(3-hydroxy-propyl)-2-methoxy-phenyl] - decylamine (light brown crystalline solid); MS = 327 [M+H]+; MP = 189.7-190.2 ° C; Sit more than 0 and [1,5·α]pyrimidine·3-carboxylic acid (2-methoxyl_5-vinyl-phenyl)·guanamine (light yellow solid); MS=295 [M+H]+; 0 is more than [1,5-α]pyrimidine-3-decanoic acid (5-ethyl-2-methoxy-phenyl)-decylamine (pink powder); MS = 297 [M+H]+ ; 吼并 and [1,5-α]pyrimidine·3-carboxylic acid [5-Gas-2-(4-hydroxyindolyl-piperidine·Lu 1-yl)-phenyl]-decylamine (off-white solid); MS=386 [M+H]+ ; (l-{4-chloro-2-[(n-pyrazolo[l,5-fl]pyrimidin-3-carbonyl)-amino]-phenyl}-piperidine -4-ylmercapto)-tert-butyl carboxylic acid tert-butyl ester; ° ratio of p-[2,1-/][1,2,4]triazine-7-carboxylic acid [5-gas-2-(4-hydroxyl) -cyclohexyloxy)-phenyl]-decylamine (off-white solid); MS = 386 [M+H]+; 2- gas-thieno[3,2-d]pyrimidine-7-carboxylic acid (7-A Oxy-quinolin-6-yl)-guanamine; -194· 157102.doc

S 201217379 吡唑并[1，5-α]嘧啶_3_甲酸（2-侧氧基-5-哌啶-卜基_2,3-二氫-1丑-吲哚-6-基）-醯胺（黑色固體）；MS=377 [M+H]+ ； "比唾并[1，5-α]嘧啶-3-甲酸（5-甲氧基-2-甲基q/z-i 〇朵_ 6-基）-醯胺（黃色固體）；MS=322 [M+H]+ ; 3- (7-曱氧基-啥琳_6-基胺甲酿基）-。塞吩并[3,2-办]<|比咬-6-曱酸乙酯；嗔吩并[3,2-rf]嘧咬_7_甲酸[2-(2-羥基-乙基胺基）_7_甲氧基-喧咐 -6-基]-醯胺鹽酸鹽（鹽酸鹽係利用含hci之S 201217379 Pyrazolo[1,5-α]pyrimidine_3_carboxylic acid (2-o-oxy-5-piperidin-buyl-2,3-dihydro-1 ugly-indol-6-yl)- Indoleamine (black solid); MS = 377 [M+H]+ ; " than salivation [1,5-α]pyrimidine-3-carboxylic acid (5-methoxy-2-methyl q/zi 〇 _ 6-yl)-decylamine (yellow solid); MS = 322 [M+H]+; 3- (7-decyloxy- phthalene-6-ylamineyl). Sepheno[3,2-do]<|Bit-6-capric acid ethyl ester; porphin [3,2-rf] pyrimidine _7_carboxylic acid [2-(2-hydroxy-ethylamine) )7_methoxy-indol-6-yl]-nonylamine hydrochloride (hydrochloride salt containing hci

Et20 產生）（黃色粉末）；]VIS=396 [Μ+Η]+; ΜΡ=265·1-269.9°C ； 4- {4-氯-2-[(吡唑并[υ-α]嘧啶-3-羰基）-胺基]-苯氧基}-哌啶-1-甲酸第三丁酯；。比。坐并[1，5-α]嘧啶_3_曱酸[3ι_(第三丁基-二曱基_矽烷基氧基）-4-氣-聯苯_2_基]-酿胺； (1-{5-苯基胺甲醯基_2_[(吡唑并嘧啶·3_羰基胺基]-苯基卜哌啶_4_基甲基）-胺基甲酸第三丁酯；。比唾并[1，5-α]嘧啶_3_甲酸{7_[4_(第三丁基_二甲基_矽烧基氧基）-環己基氧基卜喹啉_6_基卜醯胺； (1-{2-胺基-6·[(。比唑并[15_α]嘧啶_3_羰基）_胺基]-苯基}-派咬-4-基甲基）_胺基甲酸第三丁酯；吡唑并[1，5-α]嘧啶·3·曱酸[5_氯_2_(4_羥基_丁氧基）_苯基]-醯胺（白色粉末）；MS=361 [Μ+Η]+ ; »比。坐并[1，5-α]嘧啶_3_甲酸（3_胺基_2•哌啶―卜基·苯基）· 157102.doc -195- 201217379 醯胺（灰白色粉末）；MS=337 [M+H]+ ; °比唑并[1，5-α]嘧啶-3-甲酸（4-氯-聯苯-2-基）-醯胺（淺黃色粉末）；MS=349 [M+H]+ ; °坐并[1，5-α]嘧啶-3-甲酸（7-哌啶-1-基-喹啉-6-基）-酿胺鹽酸鹽（橙色粉末）（向游離鹼於二氣甲烷與甲醇的 1/1混合物中之溶液中添加3當量含HC1之Et20來製備鹽酸鹽）；MS=373 [M+H]+ ; MP=285-287°C ; °比唾并[1，5-α]嘧啶-3-甲酸（2-甲氧基-苯基）-醯胺（淺黃色粉末）；MS=268 [Μ]+ ; φ 0比唑并[1，5-α]嘧啶-3-曱酸（2,4-二曱氧基-苯基）-醯胺 (淺黃色粉末）；MS=298 [M]+ ; °比唑并[1，5-α]嘧啶·3-甲酸（2-曱氧基-4-甲基-苯基）-醢胺（淺黃色粉末）；MS=283 [M+H]+ ; °比唑并[1，5-α]嘧啶·3_曱酸（5-氣-2-氟-苯基）-醯胺（淺黃色粉末）；MS=291 [M+H]+ ; 0比。坐并[1，5-α]嘧啶·3_甲酸（2-曱氧基-5-曱基-苯基）_醯胺（淺黃色固體）；MS=283 [M+H]+ ; # °比唾并[1，5-α]嘧啶_3-曱酸（5-氟-2-曱氧基-苯基）-酿胺 (淺黃色粉末）；MS=287 [M+H]+ ; 。比唑并[1，5-α]嘧啶_3_甲酸[5-氣-2-(3-曱氧基-丙氧基）-苯基]-醯胺（灰白色粉末）；MS=361 [M+H]+ ; 。比唾并[1，5-α]嘧啶_3·甲酸（5-甲氧基-2_甲基-聯苯-4-基）-醯胺（淺黃色粉末）；MS=359 [M+H]+ ; 。比唾并[1，5-α]嘧啶_3_曱酸（2,5-二甲氧基-苯基）-醯胺 157102.doc -196- 201217379 (淺黃色結晶固體）；MS=299 [M+H]+ ; 。比唑并[1，5-α]嘧啶_3_甲酸（7-曱氧基-喹啉-6-基）-醯胺 (灰白色粉末）；MS=320 [M+H]+ ; MP=256-257.3°C ; 0比唑并[1，5-α]吡啶-3-甲酸（5-氯-2-哌啶-1-基-苯基）-醯胺（白色結晶固體）；MS=355 [M+H]+ ; MP=186.4-188.5°C ； °比唑并[1，5-α]吡啶_3·曱酸（7-甲氧基-喹啉-6-基）-醯胺鹽酸鹽（黃色粉末）（向游離鹼於二氯曱烷與甲醇的 • 混合物中之溶液中添加3當量含HC1之Et20來製備鹽酸鹽）；MS=319 [M+H]+ ; 廣-噻吩并[3,2-d]嘧啶-7-甲酸[5-氣-2-(4-羥基-環己基氧基）-苯基]-醯胺（淺黃色粉末）；MS=4〇4 [M+H]+ ; 及-噻吩并[3,2-闳嘧啶-7-甲酸[5-氣_2-(4-羥基-環己基氧基）-苯基]-醯胺（黃色粉末）；MS=4〇4 [M+H]+ ; 11比唾并[1，5-α]嘧啶-3-曱酸{4-[2·(第三丁基·二甲基·石夕炫基氧基）-乙基胺甲醯基]-2-甲氧基-苯基卜醯胺； ® 噻吩并[3,2d]嘧啶-7-甲酸{4-[2-(第三丁基-二甲基·矽烷基氧基）_乙基胺曱醯基]-2-甲氧基-苯基卜醯胺；噻吩并[3,2-ύΠ嘧啶-7-甲酸{4-[3-(第三丁基-二曱基_矽烧基氧基）-丙基胺甲醯基]-2-甲氧基_苯基卜醯胺；吡唑并[1，5-α]嘧啶-3-曱酸{4-[3·(第三丁基-二甲基·矽烧基氧基）-丙基胺曱醯基]-2-甲氧基_苯基卜醯胺； (1-{4-氯·2-[(»比唑并[1，5〜]嘧啶·3·羰基）_胺基]_苯基卜哌啶-4-基）_胺基甲酸第三丁酯； 157102.doc •197· 201217379 吡唑并[1，5-α]嘧啶_3_甲酸[2(4·胺甲醯基哌啶d基）· 5_氣-苯基]•醯胺（灰白色粉末）；MS=3 99 [M+H]+ ; {4’-氯-2’-[("比》坐并[15_α]嘧啶_3•羰基）胺基]聯苯_4_ 基甲基}-胺基甲酸第三丁醋；吡唑并[1，5-α]嘧啶_3·曱酸[3_(3_羥基_環戍基氧基）_萘_ 2-基]-酿胺（灰白色固體）；ms=389 [Μ+Η]+ ; 比。坐并[1，5-α]嘧啶_3_曱酸（1_曱氧基·萘_2-基）-醯胺（灰白色固體）；MS=319 [M+H]+ ; 。比唾并[1，5-α]嘧啶-3-甲酸[5-(4-羥基甲基-哌啶-1-基）-2-侧氧基-2,3-二氫-1//-吲哚-6-基]-醯胺（黑色固體）； MS=407 [M+H]+ ； "比。坐并[1，5-α]嘧啶-3-甲酸（5-溴-2-曱氧基-苯基）-醢胺 (淺棕色粉末）；MS=347 [M+H]+ ; °比唑并[1，5·α]嘧啶-3-甲酸聯苯-2-基醢胺（淺黃色粉末）；MS=315 [Μ+Η]+ ; °比°坐并[1，5-α]嘴咬-3 -甲酸（5 -氣_2 -嗎琳-4-基-苯基）-酿胺（白色粉末）；MS=358 [M+H]+ ; °比"坐并[1，5-α]喊0定-3-甲酸（5_氯-2-甲基硫基-苯基）-酿胺（淺黃色針狀物）；MS=3 19 [M+H]+ ; (1-{6-[(。比β坐并[ι，5-α]喊咬-3-幾基）-胺基]-嗤嚇*-7-基}-哌啶-4-基曱基）_胺基甲酸第三丁酯； °塞吩并[3,2-c/]嘴咬-7-甲酸（7-°底咬基-唾嚇·_6-基）-酿胺（淺黃色粉末）；MS=390 [Μ+Η]+ ; ΜΡ=234·0_ 236.0°C ； 201217379 噻吩并[3,2-of]嘧啶_7_甲酸[7_(3_羥基二甲基丙氧基）-喹啉-6-基]•醯胺鹽酸鹽（鹽酸鹽係利用含hci之 Et20產生）（淺黃色粉末）；MS=400 [m+H]+ ; MP>300°C ；噻吩并[3,2d]嘧啶_7_甲酸[7_(3_羥基-丁氧基）_喹啉_6_ 基]-醯胺（淺黃色粉末）；MS=395 [Μ+Η]+ ; ΜΡ=256·0-257.0°C ；售吩并[3,2-d]嘧啶-7_甲酸[5_氣_2_(3_羥基-1}1二甲基-丙氧基）-苯基]•醯胺（黃色蠟狀固體）；MS=392 [M+H]+ ； MP=52.0-54.0〇C ；噻吩并[3,24]嘧啶_7_甲酸（5_氣_2_環己基氧基-苯基）_ 酿胺（白色粉末）；MS=388 [Μ+Η]+ ; ΜΡ = 153·4-155.7°C ；噻吩并[3,2-d]嘧啶甲酸（5_氣_2異丙氧基苯基）醯胺（白色粉末）；MS=348 [M+H]+ ; mp=149.6- 150.6°C ；吡唑并[1，5-α]嘧啶_3•甲酸[2_(2·羥基乙基胺基）7甲氧基-喧琳-6-基]_醢胺（淺棕色粉末）；mS=379 [M+H]+； MP=26l.3-264.8〇C ；比坐并[1，5-α]嚷唆·3_曱酸[5_氣-2_(3羥基曱基-吡咯咬1基）_苯基酿胺（黃色粉末）；MS=372 [M+H]+ ; MP—174.4-175.9°Q · 比坐并[1，5_α]’咬、3_曱酸[7-(4-羥基甲基-哌啶-1-基）_ 喧琳6基]-酿胺（淺黃色粉末）；MS=403 [M+H]+ ; 157102.doc 201217379 MP=247.7-249.0°C ； °比唾并[1，5-α]嘧啶-3-甲酸[3-(3_羥基-丙氧基）_萘_2- 基]-醯胺（淺棕色粉末）；MS=363 [Μ+Η]+ ; ΜΡ=227·7-230.2°C ；。比唾并嘧啶-3-甲酸[3_(4_羥基-環己基氧基>萘一 2-基]-醢胺（淺棕色粉末）；ms=403 [M+H]+ ; 吼唾并[1，5-α]嘧啶-3-甲酸[5-氣-2-(3-羥基-環戊基氧基）-苯基]-醯胺（淺棕色粉末）；MS=373 [M+H]+ ; MP=256.9-258.4°C ； · °比唾并[1，5-α]嘧啶-3-甲酸[5-氯-2-(3-羥基甲基-環戊基氧基）-苯基]-醯胺（灰白色固體）；MS=3 87 [M+H]+ ; "比唑并[1，5-α]嘧啶-3-甲酸[5-氣-2·(3-羥基-環己基氧基）-苯基]-醯胺（灰白色固體）；MS = 3 87 [Μ+Η]+ ; 噻吩并[3,2-闳嘧啶-7·曱酸（5-氯-2-曱氧基-苯基）-醯胺 (橙色結晶固體）；MS=320 [M+H]+ ; MP=213.1-214.0°C ；吡唑并[1，5-α]嘧啶-3-甲酸[5-氯-2-(3-羥基甲基-哌啶《 φ 1-基）-苯基]-醯胺（深棕色固體）；MS=386 [Μ+Η]+ ; "比唑并[1，5-α]嘧啶-3-甲酸（2-氮雜環庚烷-1-基-5-氣-苯基）-醯胺（粉紅色固體）；MS=370 [Μ+Η]+ ; 吡唑并[1，5-α]嘧啶-3-甲酸（5-羥基甲基-2-哌啶-1-基-苯基）-醯胺（淺黃色固體）；MS=352 [Μ+Η]+ ; ΜΡ=196·6-197.9°C ；噻吩并[3,2-i/]嘧啶甲酸[5-氯_2-(4-羥基甲基-哌啶- 157102.doc .200-Et20 produced) (yellow powder);] VIS=396 [Μ+Η]+; ΜΡ=265·1-269.9 °C; 4-{4-chloro-2-[(pyrazolo[υ-α]pyrimidine- 3-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester; ratio. And [1,5-α]pyrimidine_3_decanoic acid [3ι_(t-butyl-diindenyl-nonylalkyloxy)-4-a-biphenyl-2-yl]-bristamine; (1 -{5-Phenylaminocarbazyl-2-[[pyrazolopyrimidin-3-ylcarbonylamino]-phenylpiperidine-4-ylmethyl)-carbamic acid tert-butyl ester; And [1,5-α]pyrimidine_3_carboxylic acid {7_[4_(t-butyl-dimethyl-anthracenyloxy)-cyclohexyloxybuquinoline-6-glycidylamine; 1-{2-Amino-6·[(.pyrazolo[15_α]pyrimidine_3_carbonyl)-amino]-phenyl}-pyrylene-4-ylmethyl)-carbamic acid tert-butyl Ester; pyrazolo[1,5-α]pyrimidine·3·decanoic acid [5-chloro-2-(4-hydroxy-butoxy)-phenyl]-decylamine (white powder); MS=361 [Μ +Η]+ ; » ratio. Sit and [1,5-α]pyrimidine_3_carboxylic acid (3_amino-2-piperidinyl-phenyl) 157102.doc -195- 201217379 indoleamine Off-white powder); MS = 337 [M+H]+ ; ° oxazolo[1,5-α]pyrimidine-3-carboxylic acid (4-chloro-biphenyl-2-yl)-decylamine (light yellow powder) ;MS=349 [M+H]+ ; °[1,5-α]pyrimidine-3-carboxylic acid (7-piperidin-1-yl-quinolin-6-yl)-nitramine hydrochloride ( Orange powder) (to free base in two gas Add 3 equivalents of Et20 containing HC1 to the solution in a 1/1 mixture of alkane and methanol to prepare the hydrochloride salt; MS=373 [M+H]+; MP=285-287°C; ° ratio saliva[1 ,5-α]pyrimidine-3-carboxylic acid (2-methoxy-phenyl)-decylamine (light yellow powder); MS=268 [Μ]+ ; φ 0 ratio of oxazo[1,5-α]pyrimidine -3-decanoic acid (2,4-dimethoxy-phenyl)-decylamine (light yellow powder); MS=298 [M]+ ; ° ratio oxazolo[1,5-α]pyrimidine·3- Formic acid (2-decyloxy-4-methyl-phenyl)-decylamine (light yellow powder); MS = 283 [M+H]+ ; ° oxazolo[1,5-α]pyrimidine·3_ Citrate (5-Gas-2-fluoro-phenyl)-decylamine (light yellow powder); MS=291 [M+H]+; 0 ratio. Sit and [1,5-α]pyrimidine·3_carboxylic acid (2-decyloxy-5-mercapto-phenyl)-decylamine (light yellow solid); MS = 283 [M+H] + ; # ° ratio saliva[1,5-α]pyrimidine_3- Citrate (5-fluoro-2-decyloxy-phenyl)-bristamine (light yellow powder); MS = 287 [M+H]+; biszolo[1,5-α]pyrimidine_3_ Formic acid [5-Gas-2-(3-decyloxy-propoxy)-phenyl]-decylamine (off-white powder); MS = 361 [M+H]+; than saliva [1,5- α]pyrimidine_3·formic acid (5-methoxy-2-methyl-biphenyl- 4-yl)-guanamine (light yellow powder); MS = 359 [M+H]+; Specific saliva [1,5-α]pyrimidine_3_decanoic acid (2,5-dimethoxy-phenyl)-decylamine 157102.doc -196- 201217379 (light yellow crystalline solid); MS=299 [ M+H]+ ; Bisazo[1,5-α]pyrimidine_3_carboxylic acid (7-decyloxy-quinolin-6-yl)-decylamine (off-white powder); MS=320 [M+H]+; MP=256 -257.3 ° C; 0-pyrazolo[1,5-α]pyridine-3-carboxylic acid (5-chloro-2-piperidin-1-yl-phenyl)-decylamine (white crystalline solid); MS = 355 [M+H]+ ; MP=186.4-188.5°C; °Bizozolo[1,5-α]pyridine_3·decanoic acid (7-methoxy-quinolin-6-yl)-nonylamine salt Acid salt (yellow powder) (3 eq of Et20 containing HC1 was added to a solution of the free base in a mixture of dichloromethane and methanol to prepare the hydrochloride salt); MS = 319 [M+H]+; Thieno[3,2-d]pyrimidine-7-carboxylic acid [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (light yellow powder); MS = 4 〇 4 [ M+H]+ ; and -thieno[3,2-pyrimidin-7-carboxylic acid [5-gas-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (yellow powder); MS=4〇4 [M+H]+ ; 11 than salino[1,5-α]pyrimidin-3-indole {4-[2·(t-butyl-dimethyl-stone) ))-ethylamine-methyl hydrazino]-2-methoxy-phenyl hydrazide; ® thieno[3,2d]pyrimidine-7-carboxylic acid {4-[2-(t-butyl-dimethyl) Base 矽alkyloxy)-ethyl Amidino]-2-methoxy-phenyl-p-oxime; thieno[3,2-pyrimidin-7-carboxylic acid {4-[3-(t-butyl-diindenyl) Oxy)-propylamine-methyl hydrazino]-2-methoxy phenyl phenyl hydrazide; pyrazolo[1,5-α]pyrimidin-3-indole acid {4-[3·(third butyl Benzyl-dimethyl sulfonyloxy)-propylamine hydrazino]-2-methoxy phenyl phenyl hydrazide; (1-{4-chloro- 2-[(»- 1,5~]pyrimidine·3·carbonyl)-amino]-phenylpiperidin-4-yl)-aminobutyl acid tert-butyl ester; 157102.doc •197· 201217379 pyrazolo[1,5- α]pyrimidine_3_carboxylic acid [2(4.amine-carbamoylpiperidinedyl)·5_gas-phenyl]•decalamine (off-white powder); MS=3 99 [M+H]+ ; {4 '-Chloro-2'-[(" ratio" sits and [15_α]pyrimidine_3•carbonyl)amino]biphenyl_4_ylmethyl}-carbamic acid tert-butyl vinegar; pyrazolo[1, 5-α]pyrimidine_3·decanoic acid [3_(3-hydroxy-cyclodecyloxy)-naphthalene-2-yl]-bristamine (gray-white solid); ms=389 [Μ+Η]+; ratio. And [1,5-α]pyrimidine _3_decanoic acid (1_decyloxynaphthalene-2-yl)-decylamine (gray white solid); MS = 319 [M+H]+; More than salino[1,5-α]pyrimidine-3-carboxylic acid [5-(4-hydroxymethyl-piperidin-1-yl)-2-yloxy-2,3-dihydro-1//-吲哚-6-yl]-nonylamine (black solid); MS = 407 [M+H]+ ; " ratio. Sodium [1,5-α]pyrimidine-3-carboxylic acid (5-bromo-2-indolyl-phenyl)-decylamine (light brown powder); MS=347 [M+H]+ ; And [1,5·α]pyrimidine-3-carboxylic acid biphenyl-2-yl decylamine (light yellow powder); MS=315 [Μ+Η]+ ; ° ratio ° sitting and [1,5-α] mouth Bite-3 - formic acid (5-gas-2 -morphin-4-yl-phenyl)-bristamine (white powder); MS=358 [M+H]+ ; ° ratio "sitting and [1,5 -α] shouted 0 -3-carboxylic acid (5-chloro-2-methylthio-phenyl)-bristamine (light yellow needle); MS = 3 19 [M+H] + ; (1 {6-[(. is more than β and [ι,5-α] shouts -3-amino)-amino]-infested *-7-yl}-piperidin-4-ylindenyl)-amine Tert-butyl carboxylic acid; ° phenathion [3,2-c/] mouth bite-7-formic acid (7-° bottom bite-salt _6-yl)-nitramine (light yellow powder); MS =390 [Μ+Η]+ ; ΜΡ=234·0_ 236.0°C ; 201217379 thieno[3,2-of]pyrimidine_7_carboxylic acid [7-(3-hydroxydimethylpropoxy)-quinoline- 6-yl]• decylamine hydrochloride (hydrochloride produced by Et20 containing hci) (light yellow powder); MS=400 [m+H]+; MP>300°C; thieno[3,2d Pyrimidine_7_carboxylic acid [7_(3-hydroxy-butoxy)_quinoline_6_yl] - guanamine (light yellow powder); MS = 395 [Μ + Η] + ; ΜΡ = 256 · 0-257.0 ° C; sold pheno[3,2-d]pyrimidine-7-carboxylic acid [5_ gas_2_ (3_Hydroxy-1}1 dimethyl-propoxy)-phenyl]-decylamine (yellow waxy solid); MS=392 [M+H]+; MP=52.0-54.0〇C; thiophene [3,24]pyrimidine_7_carboxylic acid (5_gas_2_cyclohexyloxy-phenyl)_bristamine (white powder); MS=388 [Μ+Η]+ ; ΜΡ = 153·4-155.7 °C; thieno[3,2-d]pyrimidinecarboxylic acid (5-gas-2isopropoxyphenyl)decylamine (white powder); MS=348 [M+H]+; mp=149.6- 150.6° C ; pyrazolo[1,5-α]pyrimidine_3•carboxylic acid [2_(2·hydroxyethylamino) 7-methoxy-indolyl-6-yl]-decylamine (light brown powder); mS =379 [M+H]+; MP=26l.3-264.8〇C; than sitting and [1,5-α]嚷唆·3_decanoic acid [5_gas-2_(3hydroxydecyl-pyrrole bite 1 base) phenyl phenylamine (yellow powder); MS=372 [M+H]+ ; MP-174.4-175.9°Q · than sitting and [1,5_α]' bite, 3_capric acid [7-( 4-hydroxymethyl-piperidin-1-yl)-indolyl 6-yl]-bristamine (light yellow powder); MS = 403 [M+H]+; 157102.doc 201217379 MP=247.7-249.0 °C; ° than saliva [1,5- Pyrimidine-3-carboxylic acid [3-(3-hydroxy-propoxy)-naphthalene-2-yl]-decylamine (light brown powder); MS=363 [Μ+Η]+ ; ΜΡ=227·7- 230.2 ° C; Ratio of salidopyrimidine-3-carboxylic acid [3_(4-hydroxy-cyclohexyloxy>naphthalene-2-yl]-decylamine (light brown powder); ms=403 [M+H]+ ; 1,5-α]pyrimidine-3-carboxylic acid [5-Gas-2-(3-hydroxy-cyclopentyloxy)-phenyl]-decylamine (light brown powder); MS = 373 [M+H] + ; MP = 256.9 -258.4 ° C ; · ° than salino [1,5-α]pyrimidine-3-carboxylic acid [5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl ]-guanamine (gray-white solid); MS = 3 87 [M+H]+ ; "Bizozolo[1,5-α]pyrimidine-3-carboxylic acid [5-gas-2·(3-hydroxy-ring) Hexyloxy)-phenyl]-nonylamine (gray-white solid); MS = 3 87 [Μ+Η]+; thieno[3,2-pyrimidin-7-decanoic acid (5-chloro-2-indoleoxy) -Phenyl)-guanamine (orange crystalline solid); MS = 320 [M+H] + ; MP = 213.1 - 214.0 ° C; pyrazolo[1,5-[alpha]pyrimidine-3-carboxylic acid [5- Chloro-2-(3-hydroxymethyl-piperidine " φ 1-yl)-phenyl]-decylamine (dark brown solid); MS = 386 [Μ + Η] + ; "Bizozolo[1, 5-α]pyrimidine-3-carboxylic acid (2-azepane-1-yl-5-a-phenyl)-guanamine (pink solid); MS=370 [Μ+Η]+ ; pyrazole And [1,5-α]pyrimidine-3-carboxylic acid (5-hydroxymethyl-2- Piperidin-1-yl-phenyl)-guanamine (light yellow solid); MS = 352 [Μ+Η]+; ΜΡ=196·6-197.9 ° C; thieno[3,2-i/]pyrimidine Formic acid [5-chloro-2-(4-hydroxymethyl-piperidine-157102.doc.200-

S 201217379 1_基）·笨基]-醯胺（灰白色固體）；MS=4〇3 [M+H]+ ; 嘆吩并[3,24]嘧啶_7_曱酸（2_曱氧基-苯基）-醯胺（橙色固體）；MS=286 [M+H]+ ; 嘆吩并[3,2-6]吡啶甲酸（5-氣-2-甲氧基-苯基）-醯胺 (淺黃色粉末）；MS=319 [M+H]+ ; 0比唾并[1，5-α]嘧啶_3_曱酸（5_氯吡咯啶-1-基-苯基）-醢胺（結晶灰白色固體）；MS=342 [M+H]+ ; 。比。坐并[1，5-α]嘧啶_3-甲酸[5-(4_羥基甲基-苯基）-2-曱基-1丑-吲哚-6-基]-醯胺（橙色半固體）；MS=398 [M+H]+ ；。比唾并[1，5-α]嘧啶-3-曱酸（5-曱氧基-1丑-吲哚-6-基）-醯胺（淺綠色粉末）；MS=3 08 [M+H]+ ; 噻吩并[3,2-c?]嘧啶_7_甲酸（5-甲氧基-1β-吲哚-6-基）-醯胺（淺綠色粉末）；MS=325 [M+H]+ ; °比。坐并[1，5-α]嘧啶_3_甲酸[5-氣-2-(4-曱基-哌嗪-1-基）-苯基]-醯胺（灰白色固體）；MS = 371 [M+H]+ ; 。比唑并[1，5-α]嘧啶_3-甲酸[5-氣-2·(4-甲基·噁唑-5-基曱氧基）-苯基]-醯胺（灰白色固體）；MS=384 [Μ+Η]+ ; ΜΡ=240.9-242.5°C ；噻吩并[3,2-c/]嘧啶_7_曱酸[5-氣-2-(4-曱基-噁唑-5-基甲氧基）-本基]-酿胺（淺栋色結晶固體）；MS=401 [M+H]+ ； MP=233.3-234.3°C ；吡唑并[1，5-α]嘧啶_3_曱酸[5-氯-2-(3-羥基-吡咯啶基）-苯基]-醯胺（灰白色固體）；MS=358 [M+H]+ ; 157102.doc -201· 201217379 (1-{6-[(噻吩并[3,2乃]吡啶-3-羰基）-胺基]-喹啉-7-基}-0底咬-4-基曱基）_胺基甲酸第三丁酯； °比唾并[1，5·β]嘧啶-3-甲酸{5-氣-2-[3-(2,2,2-三氟-乙醢基胺基）-。比咯啶_1_基]-苯基卜醯胺； 0比。坐并[1，5-α]嘧啶-3-曱酸（5-氣-2-甲氧基-苯基）-醯胺 (結晶灰白色固體）；MS=303 [Μ+Η]+ ; 0比唑并[1，5-α]嘧啶-3-甲酸{2-[3-(第三丁基-二甲基-矽燒基氧基）-丙氧基]-5-氣-苯基}-醯胺； °比唾并[1，5-α]嘧啶_3_甲酸{2-[2-(第三丁基-二曱基-矽鲁烧基氧基）-乙氧基]-5-氣·苯基}-醢胺； η比唾并[1，5-α]嘧啶-3·曱酸[5_氣_2_(2_曱氧基·乙氧基）· 苯基]-醯胺（灰白色固體）；MS=347 [Μ+Η]+ ; °比°坐并[1，5-α]嘧啶·3—甲酸（5-氣-2-乙基-苯基）-醯胺（灰白色粉末）；MS=301 [M+H]+ ; D比嗤并[1，5-α]嘧啶·3·甲酸（5_氣_2_異丁氧基-苯基）-醯胺（灰白色粉末）；MS=345 [M+H]+ ; °比°坐并Π，5-α]嘧啶-3-曱酸[5-氯-2-(4-羥基丁基）-苯鲁基]-酿胺（白色粉末）；MS=345 [M+H]+ ; °比《坐并[1，5-α]嘧啶_3-甲酸氣-2-環己基·苯基）-醯胺 (白色粉末）；MS=355 [M+H]+ ; "比唾并[1，5-α]嘧啶_3_甲酸（4_氣·4，_羥基甲基聯苯_2_ 基）-醯胺（灰白色粉末）；MS=379 [M+H]+ ; 。比唾并[1，5-α]嘧啶·3_曱酸（7_羥基曱基_3_甲氧基_萘_2-基）-醯胺（灰白色粉末）；MS=349 [Μ+Η]+ ; 157102.doc -202·S 201217379 1_基)·笨基]-decylamine (gray-white solid); MS=4〇3 [M+H]+ ; s-[3,24]pyrimidine_7-decanoic acid (2_decyloxy) -Phenyl)-guanamine (orange solid); MS = 286 [M+H]+; sinter[3,2-6]picolinic acid (5-vapor-2-methoxy-phenyl)-indole Amine (light yellow powder); MS = 319 [M+H] + ; 0 ratio saliva [1,5-α]pyrimidine _3_decanoic acid (5-chloropyrrolidin-1-yl-phenyl)-oxime Amine (crystalline grayish white solid); MS = 342 [M+H]+; ratio. Sodium [1,5-α]pyrimidine_3-carboxylic acid [5-(4-hydroxymethyl-phenyl)-2-indolyl-1 ugly-indol-6-yl]-decylamine (orange semi-solid ); MS=398 [M+H]+ ; Specific saliva [1,5-α]pyrimidine-3-decanoic acid (5-decyloxy-1 ugly-indol-6-yl)-decylamine (light green powder); MS=3 08 [M+H ]+ ; thieno[3,2-c?]pyrimidine_7-carboxylic acid (5-methoxy-1β-indol-6-yl)-decylamine (light green powder); MS=325 [M+H ]+ ; ° ratio. And [1,5-α]pyrimidine_3_carboxylic acid [5-Gas-2-(4-indolyl-piperazin-1-yl)-phenyl]-decylamine (off-white solid); MS = 371 [ M+H]+ ; Bisazo[1,5-α]pyrimidine_3-carboxylic acid [5-gas-2·(4-methyloxazol-5-ylindoleoxy)-phenyl]-decylamine (off-white solid); MS=384 [Μ+Η]+ ; ΜΡ=240.9-242.5°C; thieno[3,2-c/]pyrimidine_7_decanoic acid [5-gas-2-(4-mercapto-oxazole- 5-ylmethoxy)-benzyl]-bristamine (light-colored crystalline solid); MS=401 [M+H]+; MP=233.3-234.3°C; pyrazolo[1,5-α] Pyrimidine _3_decanoic acid [5-chloro-2-(3-hydroxy-pyrrolidinyl)-phenyl]-decylamine (off-white solid); MS=358 [M+H]+; 157102.doc -201· 201217379 (1-{6-[(thieno[3,2]pyridin-3-carbonyl)-amino]-quinolin-7-yl}-0-bottom-4-ylindenyl)-aminocarboxylic acid Third butyl ester; ° than salino [1,5·β]pyrimidine-3-carboxylic acid {5-gas-2-[3-(2,2,2-trifluoro-ethylideneamino)-. Bilobidine_1_yl]-phenylbudecamide; 0 ratio. Sit and [1,5-α]pyrimidine-3-decanoic acid (5-Gas-2-methoxy-phenyl)-decylamine (crystalline grayish white solid); MS=303 [Μ+Η]+; Oxazo[1,5-α]pyrimidine-3-carboxylic acid {2-[3-(t-butyl-dimethyl-sulfenyloxy)-propoxy]-5-a-phenyl}- Indoleamine; ° than saliva [1,5-α]pyrimidine_3_carboxylic acid {2-[2-(t-butyl-didecyl-fluorenyloxy)-ethoxy]-5- Gas·phenyl}-decylamine; η than salino[1,5-α]pyrimidine-3·decanoic acid [5_gas_2_(2_decyloxyethoxy) phenyl]-decylamine (gray white solid); MS = 347 [Μ + Η] + ; ° ° ° ° [1,5-α]pyrimidine·3-formic acid (5-Gas-2-ethyl-phenyl)-decylamine (gray white Powder);MS=301 [M+H]+ ; D is more than 嗤[1,5-α]pyrimidine·3·carboxylic acid (5_gas_2_isobutoxy-phenyl)-decylamine (off-white powder) );MS=345 [M+H]+ ; °°°°Π,Π5-α]pyrimidine-3-decanoic acid [5-chloro-2-(4-hydroxybutyl)-phenyl]] Amine (white powder); MS = 345 [M+H] + ; ° ratio "Sit and [1,5-α]pyrimidine_3-carboxylic acid gas-2-cyclohexyl-phenyl)-decylamine (white powder) ;MS=355 [M+H]+ ; " than saliva[1,5-α]pyrimidine_3_carboxylic acid (4 _ gas · 4, _ hydroxymethylbiphenyl 2 - yl) - decylamine (off-white powder); MS = 379 [M + H] + ; Specific saliva [1,5-α]pyrimidine·3_decanoic acid (7-hydroxyindenyl_3_methoxy-naphthalene-2-yl)-decylamine (off-white powder); MS=349 [Μ+Η ]+ ; 157102.doc -202·

201217379 吡唑并[1，5-α]嘧啶_3•甲酸（4_甲烷磺醯基_2_甲氧基_苯基）-酿胺（灰白色粉末）；（根據 J. Med. Chem. 37, 2002，461中所報導之程序製備4·甲烷磺酿基_2_甲氧基-苯胺）；MS=347 [Μ+Η]+ ; 0比。圭并[1，5-α]嘧啶曱酸（6_曱氧基]开-吲唑_5_基）_ 醯胺（黃色粉末）；MS=309 [Μ+Η]+ ; 噻吩并[3,2-d]嘧啶曱酸（7_甲氧基_喹啉_6_基）_醯胺 (灰白色粉末）；MS=337 [M+H]+ ； MP=249.0- % 252.2t：; 廢-噻吩并[3,2-c/]嘧啶_7_甲酸{7_[4_(第三丁基-二苯基· 矽烷基氧基）-環己基氧基]_喹啉_6_基卜醯胺； 3-{6-[(噻吩并[32_£^嘧啶_7_羰基）_胺基]_喹啉_7_基氧基卜吡咯啶-1-甲酸第三丁酯； (3胃{6-[(噻吩并[3,24]嘧啶_7_羰基）_胺基]_喹啉-7_基氧基}-丙基）-胺基曱酸第三丁酯；噻吩并[3,2-βΠ嘧啶-7-曱酸{7-[3-(第三丁基-二曱基-矽鲁 ⑥基氧基)·丙氧基l·喧淋-6-基}-酿胺； 4_{6-[(噻吩并[3,2 j]嘧啶_7_羰基）_胺基]_喹啉_7•基氧基}-哌啶·1_甲酸第三丁酯； (1-{6-[(噻吩并[3,2 j]嘧啶_7_羰基）-胺基]-喹啉-7-基卜哌啶-4-基甲基）_胺基曱酸第三丁酯； (1-{6-[(吧唑并嘧啶_3羰基）胺基]_喹啉_7_基}_ 〇底咬_4·基甲基）-胺基曱酸第三丁酯；噻吩并[3,2_4嘧啶-7-甲酸{7-[4-(第三丁基-二曱基-矽 157I02.doc 201217379 烧基氧基）-環己基氧基]-of琳-6-基}-醯胺； (4-{4-氯-2-[(噻吩并[3,2-ί/]嘧啶-7-羰基）-胺基]-笨氧基}_環己基）-胺基曱酸第三丁酯； 4-{6-[(°比唑并[1，5-〇]嘧啶-3-羰基）_胺基]-喹啉-7-基氧基}-π底啶-1-曱酸第三丁酯； 6-(3-羥基-丙基）-吡唑并[ι，5-α]嘧啶_3_曱酸[5_氣-2_(4_ 羥基-環己基氧基）-苯基]-醯胺（灰白色粉末）；MS=445 [M+H]+ ； MP=236.7-237.7°C ； 6-[2-(第三丁基-二甲基-矽烷基氧基兴乙基吡唑并參 [1，5-α]嘲咬-3-甲酸{2-[4-(第三丁基·二曱基-矽烷基氧基）-環己基氧基]-5-氯-苯基}-醯胺；。比唑并[1，5-α]嘧啶·3-甲酸（2-{4-[1-(第三丁基-二曱基-矽烧基氧基）-乙基]_哌啶_1_基}_5·氣·苯基）_醯胺（根據 WO 20〇5/080394中所述之程序製備1·哌啶-4-基-乙醇）； [1-(1-{4-氯-2-[〇比唑并[1,5-司嘧啶-3-羰基）-胺基]-笨基}-哌啶-4-基）_乙基]-胺基甲酸第三丁酯（根據w〇 2005/080394中所述之程序製備哌啶_4_基-乙基胺）；。比唑并[1，5-α]嘧啶·3 -甲酸（5-乙醯基胺基-2-曱氧基·笨基）-醯胺（淺棕色粉末）；MS=326 [Μ+Η]+ ; ΜΡ=232.3· 233.8°C ； °比唑并[1，5·α]嘧啶_3-曱酸（3_甲氧基-萘_2-基）-醯胺（淺黃色粉末）；MS=319 [M+H]+ ; MP=202.3-205.0t：; 157102.doc -204- 201217379 °比唑并[1，5-α]嘧啶·3-甲酸（5·氯-2,4-二甲氧基-苯基）- 酿胺（淺棕色粉末）；MS=333 [M+H]+ ; MP=243.0-247.0°C ； °比°坐并[1’5-α]嘧啶-3-曱酸（5-氯-2-苯氧基-苯基）-醯胺 (白色粉末）；MS=365 [M+H]+ ; MP = 184.5-186.(TC ; °比唾并[1，5-α]嘧啶-3-曱酸（5-氣-2-哌啶-1-基-苯基）-醯 @ (淺黃色粉末）；MS=356 [Μ+Η]+ ; ΜΡ=171.2-172.5°C ；〇比0坐并[1，5·α]嘧啶-3-甲酸{5-氯-2-[(2-羥基-乙基）-甲基-胺基]•笨基卜醯胺（灰白色粉末）；MS = 346 [M+H]+ ； MP = i5〇 2-i51.7°C ；吡唑并[1，5-α]嘧啶-3-甲酸（5-氯-2-二甲基胺基-苯基）- 酿胺（灰白色粉末）；MS=316 [Μ+Η]+ ; ΜΡ=179·8-180.6°C ； °比°坐并[i，5-a]嘧啶-3-曱酸[5-氣-2-(4-羥基-哌啶-1-基）-苯基]醯胺（灰白色粉末）；MS=372 [M+H]+ ; MP=130.7-132.〇°C ； "比0坐并[1，5-α]嘧啶_3_甲酸[5_氣_2_(3_羥基-哌啶基）_ 苯基]-酿胺（灰白色粉末）；MS=372 [M+H]+ ; MP=185.7-186.9°C ； °比唾并[1，5-α]嘧啶_3_曱酸[5-氣_2-(2-羥基甲基-哌啶-1-基）-苯基卜醯胺（灰白色粉末）；MS=3 86 [M+H]+ ; MP=232.0-235.〇°C ； °比唑并[1，5-α]嘧啶-3-曱酸[5-氯-2-(4_羥基-苯氧基）-苯 157102.doc -205- 201217379 基]-酿胺（白色粉末）；MS=381 [M+H]+ ; MP=284.7-285.4°C ； °比唑并[1，5·α]嘧啶-3-曱酸[5-氯-2-(3-羥基-苯氧基）-苯基]-酿胺（灰白色粉末）；MS=381 [Μ+Η]+ ; ΜΡ=245·3-247.0°C ； (l-{4-氣-2-[(D比唑并[ny嘧啶_3_羰基）_胺基]_苯基}_ 哌啶-4-基曱基）_胺基甲酸第三丁酯； D比唑并[1，5-“]嘧啶_3-甲酸{5_氯_2_[(3_羥基-丙基曱基-胺基]-苯基卜醯胺（白色粉末）；MS=36〇 [M+H]+ ; 6-甲基-吡唑并[15^]嘧啶_3_甲酸[5_氣-2-(4-羥基曱基-哌啶-1-基）-苯基]-醯胺（灰白色粉末）；MS=400 [M+H]+ ; 6-甲氧基-吡唑并[i，5·^嘧啶_3_甲酸（2-[4-(第三丁基-二甲基-矽烷基氧基）_環己基氧基]_5-氯-苯基}-醯胺； 6-溴-吡唑并[ΐ，5-α]嘧啶_3_甲酸{2-[4-(第三丁基-二甲基·矽烷基氧基）-環己基氧基]_5_氯-苯基}-醯胺；咪唑并[1，2-α]吡啶-8-甲酸{2_[4_(第三丁基-二甲基-矽烷基氧基）-環己基氧基]-5_氯_苯暴}-醯胺； 6-曱氧基-吡唑并[1，5_α]嘴咬_3-甲酸（5-氯-2-哌啶-1-基-苯基）-酿胺； [1，2,4]二 11 坐并[4,3-<^]。比咬_8_ 甲酸{2-[4-(第三丁基-二甲基-矽烷基氧基）-環己基氧基氯-苯基}-醯胺； 6-甲氧基比唑并[1，5-α]嘧啶_3_甲酸[5-氣-2-(4-羥基甲基底咬-1-基）-苯基]、酿胺（白色固體）；MS=416 157102.doc 201217379 [M+H]+ ； MP=257.5-258.3°C ； (l-{4-氣-2-[(6-甲氧基比唑并[1,5-^]嘧啶_3-羰基）-胺基]-苯基}-哌啶-4-基甲基）-胺基曱酸第三丁酯； (1-{4-氣-2-[(6-曱氧基-吡唑并[ι，5-α]嘧啶-3-羰基）-胺基]-苯基}-哌啶-4-基甲基）-胺基甲酸第三丁酯； °比唑并[1，5-α]嘧啶-3-甲酸{5-氣-2-[3-(1_羥基-乙基）-0比咯啶-1-基]-苯基}-醯胺（淺黃色固體）；MS=386 [M+H]+ ； MP=175.5-175.9°C ； • °比唑并Π，5-α]嘧啶-3-曱酸（5-氯-2-二氟曱氧基-苯基）- 醯胺（白色固體）；MS = 339 [M+H]+ ； MP=228.0-230.5°C ； [1-(1-{4-氣-2-[(。比唑并[1,5-〇]嘧啶-3-羰基）-胺基]-苯基}-。比咯啶-3-基）-乙基]-胺基曱酸第三丁酯；噻吩并[3,2-c?]嘧啶-7_甲酸[1-(3-羥基-丙基）-1好-苯并咪嗅-2-基]-醯胺（黃色泡沫）(根據w〇 03/030902 A1中所述之程序製備3-(2-胺基-苯并咪唑-1-基）_丙-丨-醇）；籲 MS=354 [M+H]+ ;及噻吩并[3,2d]嘧啶-7-曱酸{7-[4-(第三丁基-二甲基-矽烧基氧基）-環己基氧基]•喹淋_6-基}_醯胺。實例2 :合成{4·氣_2-[(吡唑并[1，5·α]嘧啶-3-羰基）-胺基卜苯氧基}-乙酸甲酯根據流程54中所示之方法合成μ-氣_2-[(吡唑并密啶-3-羰基）·胺基]-苯氧基卜乙酸曱酯。 157102.doc •207· 201217379201217379 Pyrazolo[1,5-α]pyrimidine_3•carboxylic acid (4_methanesulfonyl-2-methoxy-phenyl)-chiral amine (off-white powder); (according to J. Med. Chem. 37 , 2002, 461, the procedure for the preparation of 4 methanesulfonyl 2 -methoxy-aniline; MS = 347 [Μ + Η] + ; 0 ratio.圭[1,5-α]pyrimidine decanoic acid (6-decyloxy)open-carbazole _5_yl)_ decylamine (yellow powder); MS=309 [Μ+Η]+ ; thieno[3] , 2-d]pyrimidine decanoic acid (7-methoxy-quinoline-6-yl)-decylamine (off-white powder); MS=337 [M+H]+; MP=249.0-% 252.2t:; -thieno[3,2-c/]pyrimidine_7_carboxylic acid {7_[4_(t-butyl-diphenyl-decyloxy)-cyclohexyloxy]-quinoline_6_yldipyridinium Amine; 3-{6-[(thieno[32_£^pyrimidin-7-carbonyl)-amino]-quinoline-7-yloxypyrrolidine-1-carboxylic acid tert-butyl ester; (3 stomach { 6-[(thieno[3,24]pyrimidin-7-carbonyl)-amino]-quinoline-7-yloxy}-propyl)-amino decanoic acid tert-butyl ester; thieno[3, 2-βpyrimidin-7-decanoic acid {7-[3-(t-butyl-diindenyl-indolyl-6-yloxy)-propoxyl-phosphonium-6-yl}-bristamine; 4_ {6-[(thieno[3,2 j]pyrimidin-7-carbonyl)-amino]-quinoline-7-yloxy}-piperidine·1-carboxylic acid tert-butyl ester; (1-{6 -[(thieno[3,2 j]pyrimidin-7-carbonyl)-amino]-quinolin-7-ylpipiperidin-4-ylmethyl)-aminobutyric acid tert-butyl ester; (1 -{6-[(barzopyrimidine_3carbonyl)amino]]quinoline_7_yl}_ 〇 bottom bite _4· Methyl)-amino decanoic acid tert-butyl ester; thieno[3,2_4 pyrimidine-7-carboxylic acid {7-[4-(t-butyl-diindenyl-hydrazine 157I02.doc 201217379 alkyloxy) -cyclohexyloxy]-of-lin-6-yl}-decylamine; (4-{4-chloro-2-[(thieno[3,2-ί/]pyrimidin-7-carbonyl)-amino] - stupidoxy}_cyclohexyl)-aminobutyric acid tert-butyl ester; 4-{6-[(°-pyrazolo[1,5-fluorene]pyrimidin-3-carbonyl)-amino]-quinoline -7-yloxy}-π- stilbene-1-decanoic acid tert-butyl ester; 6-(3-hydroxy-propyl)-pyrazolo[ι,5-α]pyrimidine_3_decanoic acid [5 _ gas-2_(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (off-white powder); MS = 445 [M+H]+; MP = 236.7-237.7 ° C; 6-[2-( Tributyl-dimethyl-decyloxyethylethylpyrazole ginseng [1,5-α] singly 3-carboxylic acid {2-[4-(t-butyl-didecyl-decyl) Oxy)-cyclohexyloxy]-5-chloro-phenyl}-decylamine; biszolo[1,5-α]pyrimidine·3-carboxylic acid (2-{4-[1-(third) --Dimercapto-fluorenyloxy)-ethyl]-piperidinyl-1-yl}_5·gas·phenyl)-decylamine (prepared according to the procedure described in WO 20〇5/080394) Piperidin-4-yl-ethanol); [1-(1-{4-chloro-2-[deuterium ratio Zirta[1,5-synapin-3-carbonyl)-amino]-phenyl}-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester (according to w〇2005/080394 The procedure described for the preparation of piperidine-4-yl-ethylamine); Bisazo[1,5-α]pyrimidine·3-formic acid (5-ethylaminomethyl-2-indolyl)-decylamine (light brown powder); MS=326 [Μ+Η] + ; ΜΡ = 232.3 · 233.8 ° C ; ° carbazolo[1,5·α]pyrimidine _3-decanoic acid (3-methoxy-naphthalene-2-yl)-decylamine (light yellow powder); MS =319 [M+H]+ ; MP=202.3-205.0t:; 157102.doc -204- 201217379 °Bizozolo[1,5-α]pyrimidine·3-carboxylic acid (5·chloro-2,4-di Methoxy-phenyl)-bristamine (light brown powder); MS=333 [M+H]+ ; MP=243.0-247.0°C; °°°[['5-α]pyrimidine-3- Citrate (5-chloro-2-phenoxy-phenyl)-guanamine (white powder); MS = 365 [M+H] + ; MP = 184.5-186. (TC; ° than saliva [1, 5-α]pyrimidine-3-decanoic acid (5-Gas-2-piperidin-1-yl-phenyl)-oxime@ (light yellow powder); MS=356 [Μ+Η]+ ; ΜΡ=171.2- 172.5 ° C; 〇 is 0 sitting and [1,5·α]pyrimidine-3-carboxylic acid {5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]] stupid oxime (off-white powder); MS = 346 [M+H]+; MP = i5〇2-i51.7 °C; pyrazolo[1,5-α]pyrimidine-3-carboxylic acid (5-chloro-2-di Methylamino-phenyl)-bristamine (off-white powder) ;MS=316 [Μ+Η]+ ; ΜΡ=179·8-180.6°C ; °°°[i,5-a]pyrimidin-3-indole [5-gas-2-(4-hydroxyl) -piperidin-1-yl)-phenyl]decylamine (off-white powder); MS=372 [M+H]+; MP=130.7-132.〇°C; "Sit with 0[1,5- α]pyrimidine_3_carboxylic acid [5_gas_2_(3-hydroxy-piperidinyl)_phenyl]-bristamine (off-white powder); MS=372 [M+H]+ ; MP=185.7-186.9° C ; ° ratio saliva [1,5-α]pyrimidine _3_decanoic acid [5-gas 2 - (2-hydroxymethyl-piperidin-1-yl)-phenyl hydrazide (off-white powder) ;MS=3 86 [M+H]+ ; MP=232.0-235.〇°C ; ° ratio oxazolo[1,5-α]pyrimidine-3-decanoic acid [5-chloro-2-(4-hydroxyl) -phenoxy)-benzene 157102.doc -205- 201217379 base]-bristamine (white powder); MS=381 [M+H]+ ; MP=284.7-285.4 °C; ° ratio azole [1,5 ·α]pyrimidine-3-decanoic acid [5-chloro-2-(3-hydroxy-phenoxy)-phenyl]-bristamine (off-white powder); MS=381 [Μ+Η]+ ; ΜΡ=245 · 3-247.0 ° C; (l-{4-gas-2-[(D-pyrazolo[ny-pyrimidine-3-ylcarbonyl)-amino]-phenyl}-piperidin-4-ylindenyl)_ D-butyl carbamic acid; D-pyrazolo[1,5-"]pyrimidine_3-carboxylic acid {5_chloro-2_[(3_hydroxy-propylhydrazine) -Amino]-phenyl-p-guanamine (white powder); MS = 36 〇 [M + H] + ; 6-methyl-pyrazolo[15^]pyrimidine _3_carboxylic acid [5_gas-2 -(4-hydroxyindolyl-piperidin-1-yl)-phenyl]-decylamine (off-white powder); MS=400 [M+H]+; 6-methoxy-pyrazolo[i,5 ·^pyrimidine_3_carboxylic acid (2-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]_5-chloro-phenyl}-decylamine; 6-bromo-pyridyl Zoxa[ΐ,5-α]pyrimidine_3_carboxylic acid {2-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]_5-chloro-phenyl}-oxime Amine; imidazo[1,2-α]pyridine-8-carboxylic acid {2_[4_(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-5-chloro-benzophene}- Indoleamine; 6-decyloxy-pyrazolo[1,5_α] mouth bite_3-formic acid (5-chloro-2-piperidin-1-yl-phenyl)-bristamine; [1,2,4 ] 2 11 sit and [4,3-<^]. Specific bite_8_ formic acid {2-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxychloro-phenyl}-decylamine; 6-methoxybiszolo[1 ,5-α]pyrimidine_3_carboxylic acid [5-gas-2-(4-hydroxymethyl-deptin-1-yl)-phenyl], catalyzed amine (white solid); MS=416 157102.doc 201217379 [ M+H]+ ; MP=257.5-258.3°C; (l-{4-Ga-2-[(6-methoxybisazolo[1,5-^]pyrimidin-3-yl))-amino group ]-phenyl}-piperidin-4-ylmethyl)-amino decanoic acid tert-butyl ester; (1-{4-gas-2-[(6-decyloxy-pyrazolo[ι,5] -α]pyrimidine-3-carbonyl)-amino]-phenyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester; ° ratio oxazolo[1,5-α]pyrimidine-3 -formic acid {5-gas-2-[3-(1-hydroxy-ethyl)-0-pyridin-1-yl]-phenyl}-decylamine (light yellow solid); MS = 386 [M+H ]+ ; MP=175.5-175.9°C ; • ° azole oxime, 5-α]pyrimidine-3-decanoic acid (5-chloro-2-difluorodecyloxy-phenyl)-decylamine (white solid) MS= 339 [M+H]+ ; MP=228.0-230.5°C; [1-(1-{4-Ga-2-[(.)-azolo[1,5-indole]pyrimidine-3- Carbonyl)-amino]-phenyl}-.pyridin-3-yl)-ethyl]-amino decanoic acid tert-butyl ester; thieno[ 3,2-c?]pyrimidine-7-carboxylic acid [1-(3-hydroxy-propyl)-1-benzoimymid-2-yl]-decylamine (yellow foam) (according to w〇03/030902 3-(2-Amino-benzimidazol-1-yl)-propan-indole-ol was prepared by the procedure described in A1; MS=354 [M+H]+; and thieno[3,2d] Pyrimidine-7-decanoic acid {7-[4-(t-butyl-dimethyl-fluorenyloxy)-cyclohexyloxy]quinaline-6-yl}-decylamine. Example 2: Synthesis of {4·Gas_2-[(pyrazolo[1,5·α]pyrimidin-3-carbonyl)-aminophenylphenoxy}-acetic acid methyl ester was synthesized according to the method shown in Scheme 54 --Gas_2-[(pyrazolo-pyridine-3-carbonyl)-amino]-phenoxy-p-acetate. 157102.doc •207· 201217379

步驟A:合成吡唑并[i，5-fl]嘧啶_3_甲酸（5_氣_2_羥基苯基）-醯胺將吡唑并[1，5-α]嘧啶-3-曱酸（〇.5 g，3.06 mmol)懸浮於亞硫酿氣（25 mL)中’且所得混合物在85°c下加熱i 5小時。接著在高真空下蒸發揮發物，且將殘餘物懸浮於吡啶 (25 mL)中。添加 2-胺基-4-氣苯紛（0.46 g，3.2 mmol)，且在回流下加熱所得混合物隔夜。接著在高真空下蒸發揮發物’向殘餘物中添加水及二氣甲烷，且減壓蒸發混合物。以二氣曱烷與甲醇之混合物（96/4)洗滌固體殘餘物，獲得 0.588 g(67°/〇產率）與吡唑并嘧啶_3_曱酸4_氣_2 [(吡 0坐并[1，5-(3],咬-3-幾基）-胺基]-苯醋混合的„比唾并[ι，5_α] 嘧啶-3-甲酸（5-氯-2-羥基-苯基）-醯胺》步称Β :合成{4-氣-2-[("比唑并[1，5-α】嘧啶-3-羰基）-胺基】-苯氧基}-乙酸甲酯向0比"坐并[1，5-α]嘧啶_3_甲酸（5-氯-2-羥基-苯基）_醯胺 (200 mg ’ 0.693 mmol)於無水恳沁二曱基甲醯胺（15 mL)中之溶液中添加碳酸鉀（1 _0 g，7.2 mmol)，隨後添加溴乙酸曱酯（0.2 mL ’ 2·11 mrn〇l) ’且在60°C下加熱所得混合物6 小時。將反應混合物冷卻至室溫，且分配於水與乙酸乙醋 157102.doc -208- 201217379 之間；分離有機層且以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM/Me〇H/ NH4〇H及己烷/EtOAc)純化粗殘餘物兩次，獲得8〇 mg棕色固體。以乙腈、乙醚及乙酸乙酯洗滌此物質，獲得28 呈淺粉紅色粉末形式之氯·2_[(吡唑并π，5•闫嘧啶·3_羰基）-胺基]-苯氧基}-乙酸甲酯。MS=361 [Μ+Η]+。利用上述程序及適當起始物質製備吡唑并嘧啶-3_ 甲酸[2-(3-羥基-笨甲氧基）_苯基]_醯胺。Step A: Synthesis of pyrazolo[i,5-fl]pyrimidine_3_carboxylic acid (5-gas-2-hydroxyphenyl)-decylamine pyrazolo[1,5-α]pyrimidine-3-decanoic acid (〇5 g, 3.06 mmol) was suspended in sulphuric acid (25 mL) and the mixture obtained was heated at 85 ° C for 5 hours. The volatiles were then evaporated under high vacuum and the residue was suspended in pyridine (25 mL). 2-Amino-4-gasbenzene (0.46 g, 3.2 mmol) was added, and the obtained mixture was heated under reflux overnight. The volatiles were then evaporated under high vacuum. Water and di-methane were added to the residue, and the mixture was evaporated under reduced pressure. The solid residue was washed with a mixture of dioxane and methanol (96/4) to obtain 0.588 g (67 ° / 〇 yield) and pyrazolopyrimidine _3_ decanoic acid 4 _ _2 [( And [1,5-(3], -3-amino)-amino]-benzene vinegar mixed „比唾和[ι,5_α]pyrimidine-3-carboxylic acid (5-chloro-2-hydroxy-benzene ))-decylamine step Β: synthesis {4-gas-2-[("biazolo[1,5-α]pyrimidin-3-carbonyl)-amino]-phenoxy}-acetate Ester to 0 ratio " sit and [1,5-α]pyrimidine_3_carboxylic acid (5-chloro-2-hydroxy-phenyl)-decylamine (200 mg '0.693 mmol) in anhydrous hydrazine Potassium carbonate (1 _0 g, 7.2 mmol) was added to the solution of decylamine (15 mL), followed by the addition of bromoacetate (0.2 mL '2·11 mrn〇l)' and the resulting mixture was heated at 60 °C. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc EtOAc EtOAc EtOAc EtOAc. The crude residue was purified twice by flash chromatography eluting elut elut elut elut elut This material was washed with acetonitrile, diethyl ether and ethyl acetate to give <RTI ID=0.0>>&&&&&&&&&&&& Methyl ester. MS = 361 [Μ + Η] +. Pyrazolopyrimidine-3_carboxylic acid [2-(3-hydroxy-mutemethoxy)-phenyl]-indoleamine was prepared using the procedure described above and the appropriate starting material.

實例3 :合成吡唑并U，5_fl】嘧啶_3_甲酸（4_胺曱醯基_2_曱氧基-苯基）-醯胺根據流程55中所示之方法合成吡唑并[15α]嘧啶_3曱酸 (4·胺甲酿基-2·甲氧基-苯基）·醯胺。Example 3: Synthesis of pyrazolo-U,5-fl]pyrimidine_3_carboxylic acid (4-aminoindolyl-2-yloxy-phenyl)-guanamine The synthesis of pyrazolo[15α according to the procedure shown in Scheme 55 Pyrimidine _3 decanoic acid (4. Aminomethyl-2 - methoxy-phenyl) decylamine.

流程55 在室溫下攪拌3-甲氧基-4-[(吼唑并[ny嘧啶_3_羰基）_ 胺基]-苯曱酸甲酯（5 mg)與氫氧化銨水溶液（濃，丨mL)之混合物及3-甲氧基_M(D比唑并π，5_β]喊咬_3幾基）胺基]_ 苯甲酸曱醋（5 mg)與氨溶液（於Me〇H中，2 μ, i mL)之混合物2天。接著合併兩混合物且添加二曱亞砜（i mL)，隨後添加乙腈（1 mL)。接著添加氨溶液（於Me〇Ht , 2 M，j I57102.doc -209- 201217379 mL)及氫氣化敍水溶液(漢，2叫，且將所得混合至5(TC持續24小時。添加第二份3_甲氧基_4介比唾并u #咬-3-幾基）-胺基]•苯甲酸曱醋（35㈣，隨後添加二甲亞砜（5 mL)、乙腈（5 mL) '氨溶液（於Me〇H中，2 μ，$ mL)及氫氧化敍水溶液（濃，5紅），且將所得混合物加執至价持續3天。ϋ由過濾收集所形成之白色沈澱物，以、水、甲醇及乙縫洗滌’在乾燥後獲得15 mg(35%產率）呈淺黃色固體形式之吡唑并"，5_α]嘧啶_3•曱酸(4_胺，醯基』· 甲氧基-本基）-酿胺。MS=312 [Μ+Η]+。實例4:合成咣唑并甲酸（2甲氧基_4·甲氧基甲基-苯基）-醯胺根據流程56中所示之方法合成坐并π，5_㈣咬_3_甲酸 (2-曱氧基-4-曱氧基曱基_苯基）_醯胺。Scheme 55 Stabilize 3-methoxy-4-[(carbazo[ny-pyrimidin-3-ylcarbonyl]-amino]-benzoic acid methyl ester (5 mg) with aqueous ammonium hydroxide (concentrated, a mixture of 丨mL) and 3-methoxy-M (D is more than oxazolidine π,5_β) singly _3 amino group] amino] benzoic acid vinegar (5 mg) and ammonia solution (in Me〇H , 2 μ, i mL) mixture for 2 days. The two mixtures were then combined and disulfoxide (i mL) was added followed by acetonitrile (1 mL). Then add ammonia solution (in Me〇Ht, 2 M, j I57102.doc -209- 201217379 mL) and hydrogenated aqueous solution (Han, 2, and mix the mixture to 5 (TC for 24 hours. Add second) 3_methoxy_4 ratio salivary u #bit-3-yl)-amino]• benzoic acid vinegar (35 (iv), followed by dimethyl sulfoxide (5 mL), acetonitrile (5 mL) 'Ammonia Solution (2 μ, $ mL in Me〇H) and aqueous solution (concentrated, 5 red), and the resulting mixture was added for 3 days. The white precipitate formed by filtration was collected. , water, methanol and sew-washing 'after drying, 15 mg (35% yield) of pyrazole in the form of a pale yellow solid ",5_α]pyrimidine _3•decanoic acid (4-amine, fluorenyl) Methoxy-benphate)-bristamine.MS=312 [Μ+Η]+. Example 4: Synthesis of carbazole and formic acid (2methoxy-4-methylmethoxy-phenyl)-decylamine The method shown in Scheme 56 synthesizes a sitting and π,5_(tetra) bite_3_carboxylic acid (2-methoxy-4-indolyl phenyl)-decylamine.

流程56 向吡唑并[1，5-α]嘧啶·3_甲酸[4_(第三丁基_二甲基_矽烷基氧基甲基）·2-曱氧基-笨基]-醯胺（160 mg，0.388 mmol) 於一氣曱烷（20 mL)中之溶液中添加鹽酸溶液（於Et2〇中，1 M ’ 2 mL) ’且在室溫下攪拌所得混合物10分鐘。添加第一部分之鹽酸溶液（於Et2〇中，1 Μ，2 mL)且攪拌反應混 157102.doc -210- 201217379 合物1小時。減壓蒸發所得混合物，且h 、且从已烷、乙酸乙Scheme 56 to pyrazolo[1,5-α]pyrimidine·3_carboxylic acid [4_(t-butyl-dimethyl-decyloxymethyl)-2-methoxy-phenyl]-decylamine (160 mg, 0.388 mmol) A solution of hydrochloric acid (1 M '2 mL) was added to a solution of hexanes (20 mL) and the mixture was stirred at room temperature for 10 min. The first part of the hydrochloric acid solution (in Et 2 ,, 1 Μ, 2 mL) was added and the reaction mixture was stirred for 157102.doc -210 - 201217379 for 1 hour. Evaporating the resulting mixture under reduced pressure, and h, and from hexane, ethyl acetate

酯、乙醚及二氯曱烷洗滌黃色固體殘餘物。接箸將固體與濾液組合，且分配於二氣曱烷與碳酸氫鈉水溶液（5%)之間。分離有機層，且以二氣甲烷萃取水層3次。以鹽水洗滌經合併之有機萃取物’經無水硫酸鈉乾燥，過渡且減壓蒸發。藉由急驟層析法（DCM/Me〇H/NH4〇H)純化黃色固體殘餘物，獲得8〇 mg°比唑并[1，5-α]嘧啶-3-曱酸（2-曱氧基_4-曱氧基甲基-苯基）_醯胺及40 mg吡唑并[丨，％…嘧啶_3•甲酸 (4-經基甲基-2-甲氧基-笨基）-酿胺》藉由製備裂 TLC(DCM/MeOH/NH4OH)再純化吡唑并[1，5_α]喊哮·3_甲酸 (2-甲氧基-4-曱氡基曱基-苯基）-醯胺化合物，且以乙醚及己烷洗滌，在真空烘箱中乾燥後獲得64 mg白色固體。 MS=313 [M+H]+。實例5 :合成吡唑并[1,5-fl】嘧啶-3-甲酸（4-羥基曱基-2-甲氧基-苯基酿胺根據流程57中所示之方法合成吡唑并[1,5-α]嘧啶-3-甲酸 (4-羥基甲基-2-甲氧基-苯基）-醯胺。The yellow solid residue was washed with ester, diethyl ether and dichloromethane. The solid was combined with the filtrate and partitioned between dioxane and aqueous sodium bicarbonate (5%). The organic layer was separated and the aqueous layer was extracted three times with dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The yellow solid residue was purified by flash chromatography (DCM /Me /H /H.sup.H) to afford 8 </ RTI> </ RTI> oxazolo[1,5-[alpha]pyrimidin-3-indoleic acid (2-methoxyl) _4-methoxymethyl-phenyl)-decylamine and 40 mg pyrazolo[丨,%...pyrimidine_3•carboxylic acid (4-carbylmethyl-2-methoxy-stupyl)- Repurification of pyrazolo[1,5_α] shouting 3_carboxylic acid (2-methoxy-4-indolyl-phenyl)-oxime by preparative splitting TLC (DCM/MeOH/NH4OH) The amine compound was washed with diethyl ether and hexanes and dried in vacuo to give a white solid. MS = 313 [M+H]+. Example 5: Synthesis of pyrazolo[1,5-fl]pyrimidine-3-carboxylic acid (4-hydroxyindol-2-methoxy-phenyl-bronamide) Pyrazolo[1] was synthesized according to the procedure shown in Scheme 57. , 5-α]pyrimidine-3-carboxylic acid (4-hydroxymethyl-2-methoxy-phenyl)-guanamine.

流程57 157102.doc -211- 201217379 向。比。坐并[1，5-’咬-3_甲酸[4_(第三丁基二甲基石夕烷基氧基甲基）·2·甲氧基·苯基]·酿胺⑽邮，Q 364 於二氯甲烷(20mL)中之溶液中添加鹽酸溶液(於扮2〇中，i Μ’ 3 mL)’且在室溫下搜拌所得混合物2小時。接著添加冰及水’且藉由添加氫氧化鈉水溶液(5%)中和混合物之pH 值。以二^料取所得混合物3次。以鹽水洗滌經合併之有機萃取物，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法及製備型TLC純化粗殘餘物，獲得黃色固體’其以水、曱醇、二氯甲烧、己烧及乙醚洗滌，在乾燥後獲得呈淺黃色固體形式之吡唑并嘧啶_3_曱酸（4_ 經基甲基甲氧基-苯基）-醯胺。MS=2" [M+H]+。利用上述程序及適當起始物質製備以下化合物： °比唾并[1，5-α]嘧啶_3,6_二甲酸6_醯胺3_{[5_氯_2_(4_羥基·環己基氧基）-苯基]-醯胺}(黃色粉末）；MS = 430 [M+H]+ ； 0比嗤并[1，5-α]嘧啶_3_曱酸（4-氯-3，-羥基-聯苯-2-基）-酿胺（灰白色粉末）；MS=365 [M+H]+ ; °比》坐并[1，5-α]嘧啶_3_甲酸[7_(4·羥基-環己基氧基）_喹淋-6-基]-醯胺（白色粉末）；mS=404 [Μ+Η]+ ; ΜΡ=273.8-275.1°Q ; 吡唑并[1，5-α]嘧啶_3_甲酸（4_氯_4，_羥基-聯苯-2-基）-醯胺（淺黃色粉末）；Ms=365 [M+H]+ ; 比0坐并Π，5-α]嘴咬_3,6-二曱酸6-醢胺3-{[5 -氯-2-(4-廢-羥基-環己基氧基苯基醢胺}(黃色粉末）； 157102.doc 201217379 MS=430 [M+H]+ ；噻吩并[3,2-d]嘧啶-7-甲酸[7-((1R，3R)_3·羥基-環戊基氧基）-喹啉-6-基]-醯胺鹽酸鹽（淺黃色粉末）；MS = 407 [M+H]+ ； °塞吩并[3,2-6?]喊咬-7-甲酸[7_((lR，3S)-3·經基-環戊基氧基）-喹啉-6-基]-醯胺鹽酸鹽（淺黃色粉末）；MS=407 [M+H]+ ; 噻吩并[3,2-〇Π嘧啶-7-曱酸[7-(3-羥基-1-甲基-丁氧基）-Φ 喹啉-6-基]-醯胺雙鹽酸鹽（灰白色粉末）；MS=409 [M+H]+ ；噻吩并[3,2-岣嘧啶-7-甲酸[5-氯-2-(3-羥基-環戊基氧基）-苯基]-醯胺鹽酸鹽（黃色粉末）；MS=39〇 [M+H]+ ; MP=220.0-221.5°C ；嗟吩并[3,2-ύ?]嘧啶-7-曱酸[5-氣-2-(3-羥基-丙氧基）-苯基]-醯胺鹽酸鹽（黃色粉末）；MS=364 [M+H]+ ; MP=215.5-218.0°C ； • °比°坐并Π，5_α]嘧啶-3-曱酸[4-(2-羥基-乙基胺甲醯基）- 2-甲氧基-苯基]-醯胺（棕色粉末）；MS=356 [M+H]+ ; MP=267.5-268.5°C ；噻吩并[3,2d]嘧啶甲酸[4_(2_羥基-乙基胺甲酿基）_ 2-甲氧基-苯基]-醯胺鹽酸鹽（黃色粉末）；MS=373 [M+H]+ ； MP=223-226°C ；噻吩并[3,2-d]嘧啶曱酸[4_(3_羥基_丙基胺曱醯基）_ 2-甲氧基-苯基]•醯胺（白色粉末）；MS=387 [m+h]+ ; 157102.doc •213· 201217379 MP=229.3-229.8°C ； °比°坐并[1，5-<a]嘴咬-3 -甲酸[4-(3-經基·丙基胺曱酿基）-2-曱氧基-苯基]-醯胺（白色粉末）；MS=370 [M+H]+ ; MP=230.8-232.3°C ； 0比0坐并[1，5-<2]嘴咬-3 -甲酸[5-氯_2_(3-經基-丙氧基）-苯基]-醢胺（白色粉末）；MS=347 [M+H]+ ; '•比唑并[1，5-α]嘧啶-3-曱酸[5-氣-2-(2-羥基-乙氧基）-苯基]-醯胺（白色粉末）；MS=333 [M+H]+ ; 噻吩并[3，2-ί/]嘧啶-7-曱酸[7-(4-羥基-環己基氧基）-喹鲁啉-6-基]-醯胺（灰白色粉末）；MS=421 [M+H]+ ; 噻吩并[3，2-rf]嘧啶-7-甲酸[7-(3-羥基-丙氧基）-喹啉-6-基]-醯胺鹽酸鹽（黃色結晶固體）；MS=381 [M+H]+ ; MP=269.9-271.〇°C ；廣-噻吩并[3,24]嘧啶-7-甲酸[7_(4·羥基-環己基氧基嗤嚇 -6-基]-醯胺鹽酸鹽（白色粉末）；ms=421 [M+H]+ ； MP=281.1-283.6°C ； 6-(2-羥基-乙基）-吡唑并[ι，5_α]嘧啶甲酸[5_氯_2_(4_ φ 經基-環己基氧基）-苯基]-醯胺（淺黃色粉末）；Μ§=431 [M+H]+ ; 吡唑并[1，5-ω]嘧啶-3-曱酸{5-氯-2-[4-(l-羥基-乙基）_ 0底咬-1-基]-本基}-醯胺（灰白色粉末）；Ms=4〇〇 [M+H]+ ； MP=180.6-181.8°C ； 6-甲氧基-吡唑并[1，5-α]嘧啶-3-甲酸[5_氣_2_(4_羥基_ 環己基氧基）-本基]-酿胺（灰白色固體）；=417 157102.doc - 214 -Flow 57 157102.doc -211- 201217379 to. ratio. Sit and [1,5-'bite-3_carboxylic acid [4_(t-butyldimethyl oxalyloxymethyl)·2·methoxy phenyl]·enamine (10) post, Q 364 A solution of hydrochloric acid (in 2 , '3 mL) was added to a solution in dichloromethane (20 mL) and the mixture was stirred at room temperature for 2 hr. Then ice and water were added and the pH of the mixture was neutralized by the addition of aqueous sodium hydroxide (5%). The resulting mixture was taken 3 times with two feeds. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate Purification of the crude residue by flash chromatography and preparative TLC to afford a yellow solid, which was washed with water, decyl alcohol, methylene chloride, hexane and diethyl ether. Pyrimidine _3_decanoic acid (4-methylmethylmethoxy-phenyl)-decylamine. MS=2" [M+H]+. The following compounds were prepared using the above procedure and the appropriate starting materials: ° ratio of salino[1,5-α]pyrimidine_3,6-dicarboxylic acid 6-decylamine 3_{[5_chloro_2_(4_hydroxy·cyclohexyl) Oxy)-phenyl]-nonylamine} (yellow powder); MS = 430 [M+H]+; 0 嗤[[,5-α]pyrimidine_3_decanoic acid (4-chloro-3, -hydroxy-biphenyl-2-yl)-bristamine (off-white powder); MS = 365 [M+H] + ; ° ratio "s, and [1,5-α]pyrimidine _3_carboxylic acid [7_(4· Hydroxy-cyclohexyloxy)-quinoline-6-yl]-nonylamine (white powder); mS=404 [Μ+Η]+ ; ΜΡ=273.8-275.1°Q; pyrazolo[1,5-α Pyrimidine _3_carboxylic acid (4_chloro-4, hydroxy-biphenyl-2-yl)-decylamine (light yellow powder); Ms=365 [M+H]+; sit and Π5, 5- α] mouth bite _3,6-dicapric acid 6-decylamine 3-{[5-chloro-2-(4-waste-hydroxy-cyclohexyloxyphenyl decylamine) (yellow powder); 157102.doc 201217379 MS=430 [M+H]+ ; thieno[3,2-d]pyrimidine-7-carboxylic acid [7-((1R,3R)_3·hydroxy-cyclopentyloxy)-quinoline-6- ]]-decylamine hydrochloride (light yellow powder); MS = 407 [M+H]+ ; °Septo[3,2-6?] shouted -7-formic acid [7_((lR,3S) -3·trans-cyclopentyloxy)-quinoline-6- ]-decylamine hydrochloride (light yellow powder); MS = 407 [M+H]+; thieno[3,2-pyrimidin-7-decanoic acid [7-(3-hydroxy-1-methyl) -butoxy)-Φ quinolin-6-yl]-guanamine dihydrochloride (off-white powder); MS = 409 [M+H]+; thieno[3,2-pyrimidin-7-carboxylic acid [ 5-Chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl]-indoleamine hydrochloride (yellow powder); MS = 39 〇 [M+H] + ; MP = 220.0 - 221.5 ° C ; 嗟-[3,2-ύ?]pyrimidine-7-decanoic acid [5-Gas-2-(3-hydroxy-propoxy)-phenyl]-decylamine hydrochloride (yellow powder); MS =364 [M+H]+ ; MP=215.5-218.0°C; • °°°°Π,5_α]pyrimidine-3-decanoic acid [4-(2-hydroxy-ethylaminemethanyl)-2 -methoxy-phenyl]-nonylamine (brown powder); MS = 356 [M+H] + ; MP = 267.5-268.5 ° C; thieno[3,2d]pyrimidinecarboxylic acid [4_(2_hydroxy- Ethylamine-based 2-phenyloxy-phenyl]-guanamine hydrochloride (yellow powder); MS=373 [M+H]+; MP=223-226°C; thieno[3 , 2-d]pyrimidine decanoic acid [4_(3-hydroxy-propylaminoindenyl)-2-methoxy-phenyl]-decylamine (white powder); MS=387 [m+h]+; 157102.doc •213· 201217379 MP=229.3-229.8° C ; ° ratio ° and [1,5-<a] mouth bite-3 -formic acid [4-(3-trans-propyl propyl amide)-2-decyloxy-phenyl]-oxime Amine (white powder); MS = 370 [M+H] + ; MP = 230.8-232.3 ° C; 0 to 0 sitting and [1,5-<2] mouth bite-3 - formic acid [5-chloro_2_ (3-carbyl-propoxy)-phenyl]-nonylamine (white powder); MS = 347 [M+H] + ; '•Bizozolo[1,5-α]pyrimidin-3-indole [5-Gas-2-(2-hydroxy-ethoxy)-phenyl]-decylamine (white powder); MS = 333 [M+H]+; thieno[3,2- </RTI> 7-decanoic acid [7-(4-hydroxy-cyclohexyloxy)-quinololin-6-yl]-decylamine (off-white powder); MS=421 [M+H]+; thieno[3,2 -rf]pyrimidine-7-carboxylic acid [7-(3-hydroxy-propoxy)-quinolin-6-yl]-indolyl hydrochloride (yellow crystalline solid); MS = 381 [M+H]+; MP=269.9-271.〇°C; ubi-thieno[3,24]pyrimidine-7-carboxylic acid [7_(4.hydroxy-cyclohexyloxyindole-6-yl)-decylamine hydrochloride (white Powder);ms=421 [M+H]+ ; MP=281.1-283.6°C; 6-(2-hydroxy-ethyl)-pyrazolo[ι,5_α]pyrimidinecarboxylic acid [5_chloro_2_(4_ φ via-cyclohexyloxy)-phenyl]-decylamine (light yellow powder); Μ§=431 [M+H]+ ; pyrazolo[1,5-ω]pyrimidine-3-decanoic acid {5-chloro-2-[4-(l-hydroxy-ethyl)_ 0 bottom-1-yl] -benzyl}-guanamine (off-white powder); Ms=4〇〇[M+H]+ ; MP=180.6-181.8°C; 6-methoxy-pyrazolo[1,5-α]pyrimidine- 3-carboxylic acid [5_gas_2_(4-hydroxy-cyclohexyloxy)-benyl]-bristamine (off-white solid); =417 157102.doc - 214 -

S 201217379 [M+H]+ ； MP=258.9-260.7°C « 6-溴-°比°坐并[1，5-a]嘴咬_3 -甲酸[5 -氣-2-(4-經基-環己基氧基）·苯基]-醢胺（灰白色固體）；MS=465 [M+H]+ ; MP=289.4-290.8°C ； [1，2,4]三唑并[4,3-α]吡啶_8-甲酸[5-氯-2-(4-羥基-環己基氧基）-笨基]-醯胺（黃色固體）；MS=3 87 [M+H]+ ; MP=216.3-217.3°C ； 6-羥基-吡唑并[1，5·β]嘧啶_3-甲酸[5-氣-2-(4-羥基-環 # 己基氧基）-苯基]-醯胺（黃色固體）；MS=403 [M+H]+ ;及噻吩并[3，2-ί/]嘧啶-7-甲酸[7-(4-羥基-環己基氧基）-喹啉-6-基]-醯胺鹽酸鹽（灰白色粉末）；mS=421 [M+H]+。實例6:合成6·羥基甲基-味唑并【1，5-<|】嘧啶_3-甲酸丨5-氣-2-(4-羥基-環己基氧基卜苯基卜醯胺根據流程58中所示之方法合成6·羥基甲基_吡唑并嘧啶-3-甲酸[5-氯-2-(4-羥基-環己基氧基）_笨基]_醯胺。S 201217379 [M+H]+ ; MP=258.9-260.7°C « 6-Bromo-° ratio ° sit and [1,5-a] mouth bite _3 - formic acid [5 - gas-2-(4-jing) Benzyl-cyclohexyloxy)-phenyl]-decylamine (gray-white solid); MS = 465 [M+H]+; MP = 289.4-290.8 ° C; [1,2,4]triazolo[4, 3-α]pyridine-8-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (yellow solid); MS = 3 87 [M+H]+ ; =216.3-217.3 ° C ; 6-hydroxy-pyrazolo[1,5·β]pyrimidine_3-carboxylic acid [5-gas-2-(4-hydroxy-cyclo#hexyloxy)-phenyl]-oxime Amine (yellow solid); MS = 403 [M+H]+; and thieno[3,2-ί/]pyrimidine-7-carboxylic acid [7-(4-hydroxy-cyclohexyloxy)-quinoline-6 -yl]-decylamine hydrochloride (off-white powder); mS = 421 [M+H]+. Example 6: Synthesis of 6-hydroxymethyl-isoxazole [1,5-<|]pyrimidine_3-formate oxime 5-gas-2-(4-hydroxy-cyclohexyloxybuphenyl bromide according to The method shown in Scheme 58 synthesizes 6-hydroxymethyl-pyrazolopyrimidine-3-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine.

步爾A.合成經基甲基-吼峻并【l，5-a]变咬-3-甲暖{2-[4- (第二丁基-二甲基_矽烷基氧基）環己基氧基】_5氣苯基卜酿胺 157102.doc •215- 201217379 向6-甲醯基_吡唑并[ι，5-α]嘧啶_3_甲酸{2_[4_(第三丁基_ 曱基-石夕院基氧基）-環己基氧基]_5-氣-苯基卜醯胺（2〇 mg，0.038 mmol)於四氫呋喃（1.5 mL)與水（〇〗mL)之混合物中之溶液中添加硼氫化鈉（30mg，〇〇79mm〇1)，且在室溫下攪拌所得混合物25小時。減壓蒸發溶劑，獲得呈油性殘餘物形式之6·羥基甲基-„比唑并π，5嘧啶·3•甲酸{2_ [4-(第三丁基-二甲基_矽烷基氧基）環己基氧基]巧氣苯基}-酿胺。Step A. Synthesis of methylidene-methyl and [l,5-a] biting-3-methyl warm {2-[4-(t-butyl-dimethyl-decyloxy)cyclohexyl Oxy] _5 gas phenyl bromoamine 157102.doc • 215- 201217379 to 6-mercapto _pyrazolo[ι,5-α]pyrimidine _3_carboxylic acid {2_[4_(Third butyl 曱曱a solution of a mixture of tetrahydrofuran (1.5 mL) and water (〇 mL) in a mixture of thioxyloxy)-cyclohexyloxy]-5-a-phenyl-p- oxime (2 〇 mg, 0.038 mmol) Sodium borohydride (30 mg, 〇〇79 mm 〇1) was added thereto, and the resulting mixture was stirred at room temperature for 25 hr. Evaporation of the solvent under reduced pressure afforded 6-hydroxymethyl- <RTI ID=0.0>&&&&&&&&&&&&&&&&& Cyclohexyloxy] Qiaoqi phenyl}-bristamine.

步驟Β:合成6-羥基甲基-吡唑并丨j，5_fl】嘧啶·3甲酸[5氣 2-(4-羥基-環己基氧基）_苯基】醢胺如實例5中所述將6·羥基甲基_吡唑并嘧啶_3_甲酸 {2-[4-(第三丁基-二甲基-石夕烷基氧基）-環己基氧基]-5-氯-苯基}•酿胺脫除保護基’獲得呈黃色粉末形式之6-經基甲基-y坐并[1，5-α]嘯咬_3_甲酸[5_氯_2_(4·經基·環己基氧基）-本基]-醢胺。MS=417 [Μ+Η]+。實例7 :合成吡唑并I1，5-。】嘧啶-3·甲酸[s-氣-2-(3-羥基-甲氧基）-苯基】-酿胺Step Β: Synthesis of 6-hydroxymethyl-pyrazolo 丨j,5_fl]pyrimidine·3 carboxylic acid [5 gas 2-(4-hydroxy-cyclohexyloxy) phenyl] decylamine as described in Example 5 6-hydroxymethyl-pyrazolopyrimidine_3_carboxylic acid {2-[4-(t-butyl-dimethyl-oxacyloxy)-cyclohexyloxy]-5-chloro-phenyl }•••··················································································· Cyclohexyloxy)-benzyl]-guanamine. MS=417 [Μ+Η]+. Example 7: Synthesis of pyrazolo I1,5-. Pyrimidine-3·formic acid [s-gas-2-(3-hydroxy-methoxy)-phenyl]-bristamine

根據流程59中所示之方法合成°比唾并[1，5-α]嘴咬_3_甲 [5-氯-2-(3經基-笨甲氧基苯基卜酿胺。According to the method shown in Scheme 59, the ratio of salivation to [1,5-α] mouth bite_3_methyl [5-chloro-2-(3-amino-p-methoxyphenyl) was synthesized.

157102.doc •216· 201217379 向。比峰并[ι，5-α]嘴咬_3·甲酸[Μ—M基·苯甲氧基）苯基]-醯胺（70 mg’ 0.14 mmol)於乙醇與水之混合物⑼，6 mL)中之懸浮液中添加氫氧化鋼水溶液（2 %，q μ心， 0.28 mmol)，且在室溫下攪拌所得混合物丨小時。在6〇t下加熱反應混合物15小時’接著減壓蒸發。藉由添加鹽酸水溶液（1 M)酸化殘餘物（pH 5)，且以二氣甲燒（5〇叫萃取。分離有機層，經無水硫酸納乾燥，過渡且減壓蒸發。藉由製備型TLC(DCM/Me0H，96/4)純化粗殘餘物，獲得呈白色固體形式之地唾并[1，5·α]嘯咬_3_甲酸[5·氣經基-本甲氧基）-苯基]-酿胺。MS=395。實例8 :合成噻吩并卩，2_内嘧啶_7_甲酸[5氣_2(4甲基胺基甲基-哌啶-1_基）·苯基]-醯胺根據流程60中所示之方法合成噻吩并[3,2_4嘧啶_7_曱酸 [5-氣-2-(4-曱基胺基曱基-哌啶―卜基）—苯基]_醯胺。157102.doc •216· 201217379 Towards.倍,和[ι,5-α] mouth bite_3·formic acid [Μ-M-yl]benzyloxy)phenyl]-decylamine (70 mg' 0.14 mmol) in a mixture of ethanol and water (9), 6 mL Aqueous steel hydroxide solution (2%, q μ heart, 0.28 mmol) was added to the suspension, and the resulting mixture was stirred at room temperature for a few hours. The reaction mixture was heated at 6 Torr for 15 hours' then evaporated under reduced pressure. The residue was acidified (pH 5) by addition of aqueous hydrochloric acid (1 M), and was then evaporated with methylene chloride (5 〇萃取 extraction. The organic layer was separated, dried over anhydrous sodium sulfate, and then evaporated and evaporated under reduced pressure. The crude residue was purified (DCM/Me. Base]-bristamine. MS=395. Example 8: Synthesis of thienofluorene, 2_endo-pyrimidine-7-carboxylic acid [5 gas 2 (4 methylaminomethyl-piperidine-1 -yl)-phenyl]-guanamine according to Scheme 60 The method synthesizes thieno[3,2_4 pyrimidine-7-decanoic acid [5-gas-2-(4-decylaminoindolyl-piperidinyl)-phenyl]-decylamine.

流程60 向噻吩并[3,2-rf]嘧啶-7-曱酸[2_(4·胺基甲基-哌啶^―基）— 5-氯-本基]•酿胺（7〇 mg’ 〇·ΐ7 mmol)於水（1 mL)中之懸浮液中添加曱酸（22 ，0,59 mmol)，隨後添加曱酸·（360/〇水 157102.doc -217- 201217379 溶液’ 0.4 mL)，且在室溫下㈣所得混合物隔夜。藉由添加氫氧化鈉水溶液（2 M)驗化反應混合物直至ρΗ Μ，接著以二氯甲烧萃取。分離有機層，經無水硫酸納乾燥，過渡且減壓$發。藉由製備型TLC(DCM/Me〇H+NH4〇H， 93/7 + 0.5)純化粗殘餘物若干次，獲得25 mg呈淺黃色固體形式之噻吩并[3,2-闳嘧啶_7_甲酸[5_氯_2_(4甲基胺基曱基_ 哌啶-1-基）-苯基]-醯胺；Ms=416 [M+H]+ ; MPWO O- BS.SC ，及3 mg 呈白色粉末形式之噻吩并 [32 闳嘧啶 _7_ 曱酉文[5_氣-2-(4_二曱基胺基甲基-哌啶-1-基）-苯基]-醯胺； MS=430 [M+H]+ 〇利用上述程序及適當起始物質製備以下化合物： 0比唑并[1，5-α]嘴咬-3 -曱酸[5-氯-2-(4-二曱基胺基甲基- 0底咬-1-基）-苯基]-醯胺（白色粉末）；MS=413 [M+H]+ ;及吡唑并[1，5-α]嘧啶-3-曱酸[5-氣-2-(4-曱基胺基甲基-哌 °定-1-基）-苯基]-酿胺（淺黃色粉末）；MS=399 [M+H]+ ； MP=139.0-146.5°C ° 實例9 :合成7-甲基-吡唑并【1，5-λτ】嘧啶-3-甲酸【5-氣-2-(4-羥基-環己基氧基）-苯基卜醯胺根據流程61中所示之方法合成7-甲基-吡唑并[1，5-α]喷啶-3-甲酸[5_氣-2-(4-羥基-環己基氧基）-苯基]-醯胺。 157102.doc -218- 201217379Scheme 60 to thieno[3,2-rf]pyrimidin-7-decanoic acid [2_(4.aminomethyl-piperidinyl)-5-chloro-benzyl]-enamine (7〇mg' 〇·ΐ 7 mmol) citric acid (22,0,59 mmol) was added to the suspension in water (1 mL), followed by the addition of citric acid (360/〇水157102.doc -217-201217379 solution '0.4 mL) And the mixture obtained at room temperature (iv) was overnight. The reaction mixture was acidified by adding an aqueous solution of sodium hydroxide (2 M) until ρΗ Μ, followed by extraction with methylene chloride. The organic layer was separated, dried over anhydrous sodium sulfate, and then evaporated and evaporated. The crude residue was purified several times by preparative TLC (DCM/Me.sup.+H.sup.sup.sup.sup.ssssssssssssssssssssssssssssssssssssssssss Formic acid [5-chloro-2-(4-methylaminoindolyl-piperidin-1-yl)-phenyl]-guanamine; Ms=416 [M+H]+; MPWO O-BS.SC, and 3 Mg is a white powder in the form of thieno[32 pyrimidine _7_ 曱酉 [5_ gas-2-(4-didecylaminomethyl-piperidin-1-yl)-phenyl]-guanamine; MS=430 [M+H]+ 制备 The following compounds were prepared using the procedure described above and the appropriate starting materials: 0 azole [1,5-α] mouth bite-3 - decanoic acid [5-chloro-2-(4- Dimethylaminomethyl-O-l-yl-1-yl)-phenyl]-decylamine (white powder); MS=413 [M+H]+; and pyrazolo[1,5-α]pyrimidine -3-decanoic acid [5-gas-2-(4-decylaminomethyl-piperidine-1-yl)-phenyl]-bristamine (light yellow powder); MS=399 [M+H ]+ ; MP=139.0-146.5°C ° Example 9: Synthesis of 7-methyl-pyrazolo[1,5-λτ]pyrimidine-3-carboxylic acid [5-gas-2-(4-hydroxy-cyclohexyloxy) Synthesis of 7-methyl-pyrazolo[1,5-α]pyridin-3-carboxylic acid [5-gas-2-(4-hydroxy-) according to the method shown in Scheme 61 ring Yloxy) - phenyl] - Amides. 157102.doc -218- 201217379

流程61 向7-甲基-吡唑并[1，5-α]嘧啶_3·甲酸{2·[4_(第三丁基-二 φ 曱基-矽烷基氧基）·環己基氧基]-5-氣-苯基}_醯胺（約〇,22 mmol)於甲醇（3 mL)中之溶液中添加鹽酸（濃，5滴），且在 8 0 C下加熱所得混合物3 0分鐘。冷卻所得混合物，藉由添加氫氧化鈉水溶液（4 Μ，數滴）鹼化且減壓蒸發。藉由急驟層析法純化粗殘餘物’獲得28 mg 7-曱基-吡唑并[1，5-α] 嘧啶-3-甲酸[5-氣-2-(4-羥基-環己基氧基苯基卜醯胺（灰白色固體）。MS=401 [M+H]+。利用上述程序及適當起始物質製備5-曱基-吡唑并[ΐ 5_α] φ 嘧啶-3-甲酸[5-氯-2-(4-羥基-環己基氧基）_苯基]_醯胺（白色固體）；MS=401 [M+H]+ ; MP=179-182°C。實例10 :合成吡唑并[1，5-α】嘧啶-3-甲酸[5-((E)-3-經基_丙烯基）-2-甲氧基-苯基】-醯胺根據流程62中所示之方法合成0比°坐并[1，5-α],咬·]甲酸 [5-((Ε)-3-羥基-丙烯基）-2-甲氧基-苯基]-醯胺。 157102.doc -219- 201217379Scheme 61 to 7-methyl-pyrazolo[1,5-α]pyrimidine_3·carboxylic acid {2·[4_(t-butyl-di-φ-decyl-decyloxy)·cyclohexyloxy] Hydrochloric acid (concentrated, 5 drops) was added to a solution of -5-methane-phenyl}-decanamine (c. The resulting mixture was cooled, basified by adding aqueous sodium hydroxide (4 Μ, a few drops) and evaporated under reduced pressure. Purification of the crude residue by flash chromatography to give 28 mg of 7-mercapto-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid [5-gas-2-(4-hydroxy-cyclohexyloxy) Phenyl guanidinamine (off-white solid). MS = 401 [M+H] +. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (white solid); MS = 401 [M+H] + ; MP = 179-182 ° C. Example 10: Synthesis of pyrazole And [1,5-α]pyrimidine-3-carboxylic acid [5-((E)-3-yl-propenyl)-2-methoxy-phenyl]-nonylamine according to the method shown in Scheme 62 Synthesis 0 to ° sit and [1,5-α], bite ·] formic acid [5-((Ε)-3-hydroxy-propenyl)-2-methoxy-phenyl]-decylamine. 157102.doc -219- 201217379

流程62 將二異丙基乙基胺（0.25 mL)、（E)_3_(3_胺基_4甲氧基_ 苯基)-丙-2-烯-1-醇(90 mg)、吡唑并嘧啶_3甲酸⑹ mg)、HOBT(85 mg)及HBTU(0.2〇 g)於無水乙腈（5叫中之混合物加熱至80°C隔夜。減壓蒸發所得混合物且使殘餘物分配於乙酸乙S旨與水之間。分離有機層，以鹽水洗條，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法 (MeOH/EtOAc，3/97)純化粗殘餘物，獲得油狀物。以乙酸乙酯濕磨此殘餘物，靜置丨小時後獲得2〇 mg呈淺棕色固體形式之（E)-3-(3-胺基_4_甲氧基-苯基）_丙_2烯醇其藉由過濾收集。MS=325 [M+H]+。實例11 :合成吼唾并15·«】痛咬_3·甲酸【2_(4·胺基甲基派啶-1-基）-5-氣-苯基】-醢胺根據流程63中所示之方法合成吡唑并[15_〇]嘧啶·3•甲酸 [2 (4胺基曱基-派咬_ι_基）_5_氯_苯基]_酿胺。 I57102.doc -220- 201217379Scheme 62 Diisopropylethylamine (0.25 mL), (E)_3_(3_Amino-4 methoxyphenyl)-prop-2-en-1-ol (90 mg), pyrazole And pyrimidine _3 formic acid (6) mg), HOBT (85 mg) and HBTU (0.2 〇g) were heated to 80 ° C overnight in an anhydrous acetonitrile mixture. The mixture was evaporated under reduced pressure and the residue was partitioned from ethyl acetate. The organic layer was separated with EtOAc (EtOAc m. m. The residue was wet-milled with ethyl acetate. After standing for 2 hours, 2 mg of (E)-3-(3-amino-4-yloxy-phenyl) was obtained as a light brown solid. The propylene-2-enol was collected by filtration. MS = 325 [M+H] +. Example 11: Synthesis of sputum and 15·«] bite _3·carboxylic acid [2_(4·Aminomethylpyridinidine- 1-Base)-5-Gas-Phenyl]-decylamine Synthesis of pyrazolo[15_〇]pyrimidine·3•carboxylic acid according to the method shown in Scheme 63 [2 (4 Aminothiol-Phit__) _基)_5_chloro_phenyl]_bristamine. I57102.doc -220- 201217379

流程63 向（l-{4-氣·2-[(«比唑并[ΐ,5-α]嘧啶-3-羰基）-胺基]_苯基卜哌啶-4-基甲基）·胺基曱酸第三丁酯（80 mg)於二氣曱烷（2Scheme 63 to (l-{4-gas·2-[(«βZolo[ΐ,5-α]pyrimidin-3-carbonyl)-amino]-phenylpiperidin-4-ylmethyl)· Tert-butyl amide (80 mg) in dioxane (2

mL)中之溶液中添加三氟乙酸（1 mL) ’且在室溫下授拌反應混合物2小時。減壓蒸發所得混合物，且將殘餘物溶解於一氯甲烧中’添加碳酸醋樹脂（2.8 mmol/g，200 mg)且授拌混合物隔夜。濾出固體且減壓蒸發濾液，藉由急驟層析法（DCM/MeOH/NH4〇H)純化殘餘物，獲得4〇 mg泡沐。以乙酸乙酯與己烷之混合物（1/1)濕磨此物質，藉由過濾收集固體，溶解於二氣甲烷與甲醇之混合物中，且減壓蒸發混合物，獲得20 mg呈淺黃色泡沫形式之吡唑并[1，5-司嘧咬-3-甲酸[2-(4_胺基甲基-派咬+基）_5_氣_苯基]_酿胺。 MS=385 [M+H]+ 〇利用上述程序及適當起始物質製備以下化合物： _吡唑并[1，5-α]嘧啶_3_甲酸[2_(3·胺基曱基-吡咯啶_ 1-基），5_氣-苯基]_酿胺（淺黃色蝶狀固體乂藉由以氣氧化鈉水溶液（2 Μ)處理來中和三氟乙酸鹽）：ms=37i [M+H]+ ；嗟吩弁嘯咬-甲酸[2-(4-胺基甲基-哌啶-1-基）_ 157102.doc -221· 201217379 5_氣-苯基]-醯胺（橙色泡沫）；MS=4〇3 [M+H]+ ; 嗟吩并[3,2-δ]吡啶_3_甲酸[2-(4-胺基曱基-哌啶-1-基）_ 5·氣-苯基]-醯胺（粉紅色泡沫）；MS=4〇l [M+H]+ ; °塞吩并[3,2-rf]嘧啶_7_甲酸[5-氯-2-(哌啶-4-基氧基）-笨基]-醯胺三氟乙酸鹽（灰白色固體）；MS=389 [Μ+Η]+ ； ΜΡ>3〇〇°ς ; 嗟吩并[3,2-ό]吡啶_3_甲酸[7-(4-胺基曱基-哌啶-1-基）_ 啥琳-6-基]-醯胺（灰白色固體）；mS=418 [Μ+Η]+ ; °比。坐并[1，5-α]嘧啶甲酸[2-(4-胺基曱基-哌啶-1_基）_ · 5- 氣-苯基]•醯胺三氟乙酸鹽（白色固體）；ms=3 85 [M+H]+ ; MP=ll〇.〇_ii2.rc ;及 6- 甲氧基-吡唑并嘧啶-3-甲酸[2·(4_胺基甲基_哌咬-1-基）-5-氣·苯基]-醯胺（淺黃色固體）；MS=415 [M+H]+ ； MP=2l〇.0-214.4°C ° 實例12 :合成2-異丙基胺基-噻吩并[3,2-rf】嘧啶-7-甲酸（7-甲氧基-啥琳-6-基）-醯胺根據流程64所示之方法合成2-異丙基胺基_噻吩并[3，2-d] · 嘧啶-7-甲酸（7-甲氧基_喹啉_6_基）_醯胺。在l〇〇°C下加熱2-氣-噻吩并[3,2-闳嘧啶-7-甲酸（7-甲氧基-唾琳-6-基）-醯胺（2〇〇 mg)及異丙胺（200 pL)於1，4-二噁烧（5 mL)中之混合物2〇小時。接著冷卻反應混合物，且藉由過濾收集析出之固體，以水及乙酸乙酯洗滌。以水及鹽水洗蘇濾液’經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（丙鲖/DCM)純化粗殘餘物，在真空下在60。(：下 157102.doc -222- 201217379 乾燥後獲得與先前獲得之固體合併的137 mg 2-異丙基胺基-噻吩并[3，2-c/]嘧啶-7-甲酸（7-曱氧基-喹啉-6-基）·酿胺》 MS=394 [M+H]+ ; MP=221.4-222.7°C。利用上述程序及適當起始物質製備以下化合物： • 5-(2-羥基-乙基胺基）-噻吩并[3，2-6]吡啶-3-甲酸（5-氯-2-甲氧基-苯基）-醯胺（橙色半固體）；MS=378 [M+H]+ ； 2-(2-羥基-乙基胺基）-噻吩并[3,2d]嘧啶-7-曱酸（5-氣-# 2-甲氧基-苯基）-醯胺（黃色粉末）；MS=379 [M+H]+ ; 2-(3-羥基-丙基胺基）-噻吩并[3,24]嘧啶-7-曱酸（5-氣-2-曱氧基-苯基）-醯胺（淺黃色粉末）；MS=393 [M+H]+ ; MP=178.0-181.0°C ； 2-(2-羥基-乙基胺基）-噻吩并[3,2-c/]嘧啶-7-甲酸喹啉-6-基醯胺（淺黃色固體）；MS=366 [M+H]+ ; MP> 300°C ； 2-[(2-羥基-乙基）-曱基-胺基]-噻吩并[3,2-<]嘧啶-7-曱 ® 酸（5·氯-2-曱氧基-苯基）-醯胺（黃色固體）；MS=393 [M+H]+ ; MP=185.0-188.0〇C ; 2-(2_羥基-乙基胺基）-噻吩并[3,2-d]嘧啶-7-曱酸（7-甲氧基-喹啉-6-基）-醯胺（淺黃色固體）；MS=396 [M+H]+ ； MP=227.0-229.0°C ； 2-((S)-l-羥基曱基-丙基胺基）-噻吩并[3,2-c/]嘧啶-7-甲酸（5-氯-2-甲氧基-苯基）-醯胺（淺黃色固體）；MS=407 [M+H]+ ; MP=195.5-197.0〇C ; 157102.doc •223· 201217379 2-[(2-經基-乙基）-甲基-胺基]-嚷吩并[3,2-c?]嘴咬-7-甲酸（7 -甲氧基-啥嚇>-6-基）-醯胺（淺黃色粉末）；MS = 410 [M+H]+ ； MP=205.0-207.0°C ； 2-環丙基胺基-嗟吩并[3,2-〇嘧啶-7-曱酸（7-甲氧基-啥琳-6-基）-醯胺（黃色固體）；MS = 392 [M+H]+ ; MP= 256.6-260.1°C ； 2-[(2-經基-乙基）-異丙基-胺基]-嗔吩并[3,2_d]嘴咬_7_ 曱酸（7-曱氧基-唾琳-6-基）-醯胺（淺黃色固體）； MS=438 [Μ+Η]+ ; · 2-(2,3-二經基-丙基胺基）-嗟吩并[3，2-c/]喊咬-7-甲酸 (7-甲氧基-喹淋-6-基）-醯胺（紫色固體）；mS=426 [M+H]+ ; 2-異丙基胺基-嗟吩并[3，2-ύ?]嘧咬-7-甲酸（7-甲氧基-喹琳-6-基）-醯胺（黃色固體）；MS=394 [Μ+Η]+ ; 2-(異丙基-甲基-胺基）-噻吩并[3，2-d]喊咬-7-甲酸（7-甲氧基-喹琳-6-基）-醯胺（灰白色固體）；mS = 408 [Μ+Η]+ ； φ 2-異丁基胺基-°塞吩并[3,2-ί/]响咬_7_甲酸（7-甲氧基-啥琳-6-基）-醯胺（黃色固體）；ms=4〇8 [μ+Η]+ ; ΜΡ=194.4-198.9°C ； -2_異丙基胺基-噻吩并[3,2_内嘧啶_7_曱酸[5_氯_2-(4-羥基-環己基氧基）_苯基]_醯胺（灰白色固體）； MS=460 [M]+ ； MP=112.9-113.9°C ； 2-((R)-2-羥基-1-甲基-乙基胺基）噻吩并[3，u]嘧啶- 157102.doc . 224 - 201217379 7-甲酸（7-曱氧基-喧琳-6-基）-醢胺（淺黃色固體）； MS=410 [M+H]+ ； 2-(2-胺基-乙基胺基）-噻吩并[3，2d]嘧啶-7-甲酸（5_氯-2-甲氧基-苯基）_醯胺（白色固體）；MS=378 [M+H]+ ; -2-(2 -乙酿基胺基乙基胺基）-°塞吩并[3，2-c?]嘴d定-7-曱酸（5-氣-2-甲氧基-苯基）-醯胺（淺黃色固體）； MS=420 [M+H]+ ； MP=238.0-240.9°C ； -2-[ (2-胺基-乙基）-曱基-胺基]塞吩并[3,2-喷咬- 7-鲁甲酸（5-氣-2-曱氧基-苯基）-醢胺（灰白色固體）； MS=392 [M+H]+ ； MP=144.0-147.6°C ； -2-[(2-胺基-乙基）-曱基_胺基]-嗔吩并[3,2_£/]„密咬_7-甲酸（7-曱氧基·喹啉-6_基）-醯胺（淺棕色固體）； MS=409 [M+H]+ ； MP=195.0-197.0°C ； -2-(3-胺基-丙基胺基）-<»塞吩并[3,2-<i]鳴咬·7_甲酸（7-甲氧基-喹啉-6-基）-醯胺（灰白色固體）；ms=4〇9 [M+H]+ ;及 ® - 2-(2-胺基-乙基胺基）·噻吩并[3,2-ί/]嘧咬_7_曱酸（7_ 甲氧基嚇·_6-基）·酿胺（橙色固體）；MS=395 [M+H]+。實例13 :合成6-羥基甲基-噻吩并【32_6】吡啶_3甲酸（7甲氧基-啥嘛-6-基）·醜胺根據流程65所示之方法合成6_經基曱基_售吩并[3,2_6]πΛ 咬-3-甲酸（7-甲氧基·啥啉_6_基）·醯胺。 157102.doc -225- 201217379Trifluoroacetic acid (1 mL) was added to the solution in mL) and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was evaporated under reduced pressure and the residue was dissolved in <RTI ID=0.0>>> The solid was filtered off and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjj This material was wet-milled with a mixture of ethyl acetate and hexane (1/1), and the solid was collected by filtration, dissolved in a mixture of methane and methanol, and the mixture was evaporated under reduced pressure to give 20 mg as pale yellow foam. Pyrazolo[1,5-sodium sulfa-3-carboxylic acid [2-(4-aminomethyl-pyro-indenyl)_5_gas_phenyl]-bristamine. MS=385 [M+H]+ 〇 The following compound was prepared using the procedure described above and the appropriate starting material: _pyrazolo[1,5-α]pyrimidine_3_carboxylic acid [2_(3·aminomercapto-pyrrolidine) _ 1-yl), 5_gas-phenyl]-bristamine (light yellow butterfly solid 乂 neutralized with trifluoroacetate by treatment with aqueous sodium sulphate (2 ))): ms=37i [M+ H]+ ; 嗟弁 - - - - formic acid [2-(4-aminomethyl-piperidin-1-yl)_ 157102.doc -221· 201217379 5_ gas-phenyl]-decylamine (orange foam MS=4〇3 [M+H]+ ; 嗟-[3,2-δ]pyridine_3_carboxylic acid [2-(4-aminoindolyl-piperidin-1-yl)_ 5· Gas-phenyl]-guanamine (pink foam); MS = 4 〇 l [M+H]+ ; ° pheno[3,2-rf]pyrimidine _7-carboxylic acid [5-chloro-2-( Piperidin-4-yloxy)-phenyl]-decylamine trifluoroacetate (off-white solid); MS = 389 [Μ + Η] + ; ΜΡ > 3 〇〇 ° ς ; 嗟并 [3, 2 -ό]pyridine_3_carboxylic acid [7-(4-aminoindolyl-piperidin-1-yl)-indolyl-6-yl]-nonylamine (off-white solid); mS=418 [Μ+Η] + ; ° ratio. And [1,5-α]pyrimidinecarboxylic acid [2-(4-aminoindolyl-piperidin-1-yl)- 5-pyro-phenyl]-decylamine trifluoroacetate (white solid); Ms=3 85 [M+H]+ ; MP=ll〇.〇_ii2.rc ; and 6-methoxy-pyrazolopyrimidine-3-carboxylic acid [2·(4-aminomethyl) -1-yl)-5-gas·phenyl]-guanamine (light yellow solid); MS=415 [M+H]+; MP=2l〇.0-214.4°C ° Example 12: Synthesis 2-Different Synthesis of 2-isopropylamine according to the procedure shown in Scheme 64, propylamino-thieno[3,2-rf]pyrimidine-7-carboxylic acid (7-methoxy-indolyl-6-yl)-nonylamine Base - thieno[3,2-d] pyrimidine-7-carboxylic acid (7-methoxy-quinoline-6-yl)-decylamine. Heating 2-gas-thieno[3,2-pyrimidin-7-carboxylic acid (7-methoxy-salin-6-yl)-decylamine (2〇〇mg) and different at 10 °C A mixture of propylamine (200 pL) in 1,4-dioxin (5 mL) was taken for 2 hrs. The reaction mixture was then cooled, and the precipitated solid was collected by filtration and washed with water and ethyl acetate. The threonate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography (EtOAc / DCM) (:下157102.doc -222- 201217379 After drying, 137 mg of 2-isopropylamino-thieno[3,2-c/]pyrimidine-7-carboxylic acid (7-oxime) was obtained in combination with the previously obtained solid. Benzyl-quinoline-6-yl)-bristamine MS=394 [M+H]+; MP=221.4-222.7 ° C. The following compounds were prepared using the procedure described above and the appropriate starting materials: • 5-(2-hydroxyl -ethylamino)-thieno[3,2-6]pyridine-3-carboxylic acid (5-chloro-2-methoxy-phenyl)-decylamine (orange semi-solid); MS = 378 [M+ H]+ ; 2-(2-hydroxy-ethylamino)-thieno[3,2d]pyrimidin-7-decanoic acid (5-gas-# 2-methoxy-phenyl)-decylamine (yellow Powder); MS = 379 [M+H]+; 2-(3-hydroxy-propylamino)-thieno[3,24]pyrimidin-7-decanoic acid (5-ox-2-oxooxy- Phenyl)-guanamine (light yellow powder); MS = 393 [M+H] + ; MP = 178.0-181.0 ° C; 2-(2-hydroxy-ethylamino)-thieno[3,2- c/]pyrimidine-7-carboxylic acid quinoline-6-ylguanamine (light yellow solid); MS = 366 [M+H] + ; MP > 300 ° C; 2-[(2-hydroxy-ethyl)- Mercapto-amino]-thieno[3,2-<]pyrimidin-7-indole® acid (5·chloro-2-decyloxy-phenyl)-decylamine (yellow solid); MS=393 [ M+H]+ ; MP=185.0-188.0〇C; 2-(2-hydroxy-ethylamino)-thieno[3,2-d]pyrimidin-7-decanoic acid (7-methoxy-quinoline Phenyl-6-yl)-decylamine (light yellow solid); MS = 396 [M+H]+; MP = 227.0-229.0 ° C; 2-((S)-l-hydroxyindolyl-propylamino - thieno[3,2-c/]pyrimidine-7-carboxylic acid (5-chloro-2-methoxy-phenyl)-decylamine (light yellow solid); MS = 407 [M+H]+; MP=195.5-197.0〇C; 157102.doc •223· 201217379 2-[(2-P-ethyl-ethyl)-methyl-amino]-indole [3,2-c?] mouth bite-7 - formic acid (7-methoxy-anthracene <-6-yl)-guanamine (light yellow powder); MS = 410 [M+H] + ; MP = 205.0 - 207.0 ° C; 2-cyclopropyl Amino-mermano[3,2-pyrimidin-7-decanoic acid (7-methoxy-indolyl-6-yl)-decylamine (yellow solid); MS = 392 [M+H]+; MP = 256.6-260.1 ° C; 2-[(2-trans-ethyl)-isopropyl-amino]-oxime [3,2_d] mouth bite _7_ decanoic acid (7-decyloxy- Salicyl-6-yl)-guanamine (light yellow solid); MS=438 [Μ+Η]+; · 2-(2,3-di-propyl-propylamino)-oxime [3, 2-c/] shout bite-7-formic acid (7-methoxy-quinolin-6-yl)-guanamine (purple solid); mS =426 [M+H]+ ; 2-isopropylamino-deutero[3,2-ύ?]pyrimidine-7-carboxylic acid (7-methoxy-quinolin-6-yl)-oxime Amine (yellow solid); MS = 394 [Μ+Η]+; 2-(isopropyl-methyl-amino)-thieno[3,2-d] shouting-7-carboxylic acid (7-methoxy) --Quinolin-6-yl)-nonylamine (gray-white solid); mS = 408 [Μ+Η]+ ; φ 2-isobutylamino-° pheno[3,2-ί/] _7_carboxylic acid (7-methoxy-phthalene-6-yl)-guanamine (yellow solid); ms=4〇8 [μ+Η]+ ; ΜΡ=194.4-198.9°C ; -2_ Propylamino-thieno[3,2-endyrazine-7-decanoic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-decylamine (gray-white solid); MS= 460 [M]+ ; MP=112.9-113.9 ° C; 2-((R)-2-hydroxy-1-methyl-ethylamino)thieno[3,u]pyrimidine-157102.doc. 224 - 201217379 7-carboxylic acid (7-decyloxy-indolyl-6-yl)-decylamine (light yellow solid); MS=410 [M+H]+; 2-(2-amino-ethylamino) -thieno[3,2d]pyrimidine-7-carboxylic acid (5-chloro-2-methoxy-phenyl)-decylamine (white solid); MS = 378 [M+H]+; -2- (2 -Ethylaminoethylamino)-°seno[3,2-c?] mouth d-7- Citrate (5-Gas-2-methoxy-phenyl)-guanamine (light yellow solid); MS = 420 [M+H]+; MP = 238.0-240.9 ° C; -2-[ (2- Amino-ethyl)-fluorenyl-amino]cereno[3,2-powder- 7-rubecarboxylic acid (5-Gas-2-decyloxy-phenyl)-decylamine (off-white solid); MS=392 [M+H]+; MP=144.0-147.6°C; -2-[(2-amino-ethyl)-fluorenyl-amino]- oxime [3,2_£/] Bite_7-formic acid (7-decyloxyquinolin-6-yl)-decylamine (light brown solid); MS=409 [M+H]+; MP=195.0-197.0 °C; (3-Amino-propylamino)-<»cembran [3,2-<i] bite·7-formic acid (7-methoxy-quinolin-6-yl)-decylamine (off-white solid); ms=4〇9 [M+H]+ ; and ® -2-(2-amino-ethylamino)·thieno[3,2-ί/]pyrimidine_7_曱Acid (7-methoxy ketone -6-yl)-bristamine (orange solid); MS = 395 [M+H]+. Example 13: Synthesis of 6-hydroxymethyl-thieno[32_6]pyridine-3-carboxylic acid (7-methoxy-oxime-6-yl)· ugly amine was synthesized according to the method shown in Scheme 65. The benzo[3,2_6]πΛ bite-3-carboxylic acid (7-methoxy porphyrin-6-yl)·guanamine was sold. 157102.doc -225- 201217379

向3-(7-曱氧基-喹啉-6-基胺甲醯基）-噻吩并[3,2_6]吡啶_ 6-甲酸乙酯（30 mg)於四氫呋喃（2 mL)中之懸浮液中添加氫化鋰鋁溶液（於甲苯中，3.5 Μ，〇.1 mL)，且攪拌所得橙色溶液10分鐘。接著藉由添加氣化銨飽和水溶液淬滅反應混合物。經由CELITEtm墊過濾所得混合物，且以乙酸乙醋洗條濾餅。分離渡液，且有機$經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM/MeOH，97/3)純化粗殘餘物，獲得8 mg呈灰自色固體形式之6經基甲基·嘆吩并[3,2_外比咬_3-曱酸（7_甲氧L-6-基）-酿胺。MS=365 [M+H]+。 IT例a suspension of ethyl 3-(7-decyloxy-quinolin-6-ylaminocarbamoyl)-thieno[3,2-6]pyridine-6-carboxylate (30 mg) in tetrahydrofuran (2 mL) A lithium aluminum hydride solution (in toluene, 3.5 Torr, 〇. 1 mL) was added, and the resulting orange solution was stirred for 10 min. The reaction mixture was then quenched by the addition of a saturated aqueous solution of ammonium sulfate. The resulting mixture was filtered through a pad of Celitetm and washed with ethyl acetate. The liquid was separated and dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography (DCM / MeOH, 97/3) to afford 8 mg of s. Capric acid (7-methoxy L-6-yl)-bristamine. MS=365 [M+H]+. IT example

丞· ％唑开iHa】嘧啶· 基】_酿胺鹽酸鹽丞·% azole open iHa]pyrimidine·yl]_bristamine hydrochloride

根據流程66中所示之方法人 ^ , m 〇成6_羥基-吡唑并[1,5-, 咬-3-甲酸[7-(4-胺基甲甚说# , 鹽。胺基甲基娘啶-1、基)-啥啉-6-基]_醢胺〗 157102.doc -226· 201217379According to the method shown in Scheme 66, m ^ is converted to 6-hydroxy-pyrazole [1,5-, biting-3-carboxylic acid [7-(4-aminocarbazide #, salt. Amino A) Alkylidine-1, yl)-porphyrin-6-yl]-decylamine 157102.doc -226· 201217379

流程66Process 66

SC 步称A :合成（1·{6_【(6_苯甲氧基“比唾并【^㈣咬冬揉基）-胺基】-喧琳-7-基}-旅咬_4_基甲基）胺基甲酸第三丁醋在至酿下，向6-苯甲氧基，吡唑并^，％“]嘧啶_3_甲酸 (0.25 g，〇·94 mmol)中添加亞硫醯氯（〇 27 ^，3 7SC Step A: Synthesis (1·{6_[(6_Benzyloxy" is more than saliva [^(4) biting winter base)-Amine]-喧琳-7-基}-Brigade bite_4_ base Add methyl sulfite to the third butyl ketone of methyl carbamic acid to 6-benzyloxy, pyrazolo, % "] pyrimidine _3 - formic acid (0.25 g, 〇 · 94 mmol) Chlorine (〇27 ^, 3 7

mm〇1)’且搜拌所得混合物直至獲得澄清溶液。減壓濃縮反應混合物，向殘餘物中添加二氣甲烷（1〇 mL)，隨後在 0C下添加[1-(6-胺基-喹啉_7·基）_哌啶_4_基甲基]-胺基曱酸第三丁酯（0.33 g，0.94 mmol)及二異丙基乙基胺（0.16 mL，0.94 mmol)於二氣曱烷（2 mL)中之溶液，且在室溫下攪拌所得混合物隔夜。在60°C下加熱反應混合物6小時，接著使其分配於水與二氣曱烷之間。分離有機層，經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（EtOAc/ 己烷，1/1)純化殘餘物，獲得0.420 g呈固體形式之（l-{6-[(6-苯曱氧基-地唑并[1，5-α]嘧啶-3-羰基）-胺基]-喹啉-7- 157102.doc •227· 201217379 基}-哌啶-4-基曱基）-胺基甲酸第三丁酯。步称B :合成（1-{6-[(6-幾基-nt峻并[ι，5-α]嘴咬-3-擬基）-胺基]-喹啉-7-基卜哌啶-4-基甲基）·胺基甲酸第三丁酯在氩氣氛圍（氣球壓力）下攪拌（1-{6-[(6-苯曱氧基比唑并[1，5-α],啶-3-羰基）-胺基]-喹琳-7-基}-派咬-4-基曱基）胺基曱酸第三丁酯（〇·4 g)及把/碳（ι〇〇/0，50 mg)於乙醇（20 mL)中之混合物2天。經由CELITEtm墊過濾所得混合物，且減壓蒸發濾液。藉由急驟層析法純化粗殘餘物，獲得 0.220 g呈黃色固體形式之（ι_{6-[(6-經基-°比°坐并[1，5-β]°^ 鲁啶-3-羰基）-胺基]-喹啉-7-基}-哌啶_4-基甲基）-胺基甲酸第三丁酯。利用上述程序及適當起始物質製備以下化合物： -6_羥基-吡唑并[1，5-α]嘧啶-3-甲酸（7-曱氧基-喹啉-6-基）-醢胺（淺黃色粉末）；MS=336 [Μ+Η]+ ; ΜΡ=265-268°C ;及 -6-羥基-°比唑并[1，5-α]嘧啶-3-曱酸[5-氣-2-(4-羥基甲基-娘啶-1-基）-苯基]-醯胺（灰白色粉末）；MS=402 φ [M+H]+。步驟C:合成6-羥基-吡唑并【i，5-fl]嘧啶-3-甲酸【7-(4-胺基甲基-哌啶-1-基）-喹啉-6-基】-醯胺鹽酸鹽向（1-{6-[(6-羥基-吡唑并[ι，5-α]嘧啶-3-羰基）-胺基]-喹啉-7-基}-哌啶-4-基甲基）·胺基甲酸第三丁酯（〇·22 g)於二氣曱烷與曱醇之混合物（1/1，1 〇 mL)中之溶液中添加鹽酸溶液（於Et20中，1 Μ ’ 5 mL)，且在室溫下攪拌所得混合 157102.doc •228·Mm 〇 1)' and the resulting mixture was mixed until a clear solution was obtained. The reaction mixture was concentrated under reduced pressure and dichloromethane (1 mL) was added to the residue, followed by the addition of [1-(6-amino-quinoline-7-yl)-piperidine-4-ylmethyl at 0C. a solution of tert-butyl citrate (0.33 g, 0.94 mmol) and diisopropylethylamine (0.16 mL, 0.94 mmol) in dioxane (2 mL) at room temperature The resulting mixture was stirred overnight. The reaction mixture was heated at 60 ° C for 6 hours and then partitioned between water and dioxane. The organic layer was separated, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (EtOAc / EtOAc /EtOAc) eluting α]pyrimidine-3-carbonyl)-amino]-quinoline-7-157102.doc •227·201217379 base}-piperidin-4-ylindenyl)-aminocarboxylic acid tert-butyl ester. Step B: Synthesis (1-{6-[(6-Mercapto-nt succinyl][ι,5-α]-mouth -3-methyl)-amino]-quinoline-7-ylpiperidine -4-ylmethyl)-tert-butyl methacrylate is stirred under argon atmosphere (balloon pressure) (1-{6-[(6-benzoquinoneoxypyrazolo[1,5-α], Acridine-3-carbonyl)-amino]-quinolin-7-yl}-pyrene-4-ylindenyl) tert-butyl amide (〇·4 g) and /carbon (ι〇〇) /0,50 mg) mixture in ethanol (20 mL) for 2 days. The resulting mixture was filtered through a pad of Celitet, and evaporated. The crude residue was purified by flash chromatography to give 0.220 g (yield: </RTI> <RTIgt; Carbonyl)-amino]-quinolin-7-yl}-piperidine-4-ylmethyl)-carbamic acid tert-butyl ester. The following compounds were prepared using the above procedure and the appropriate starting materials: -6-hydroxy-pyrazolo[1,5-α]pyrimidine-3-carboxylic acid (7-decyloxy-quinolin-6-yl)-decylamine ( Light yellow powder); MS = 336 [Μ + Η] + ; ΜΡ = 265-268 ° C; and -6-hydroxy--pyrazolo[1,5-α]pyrimidine-3-decanoic acid [5-gas -2-(4-Hydroxymethyl-n-dinyl-1-yl)-phenyl]-decylamine (off-white powder); MS = 402 φ [M+H]+. Step C: Synthesis of 6-hydroxy-pyrazolo[i,5-fl]pyrimidine-3-carboxylic acid [7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]- Indoleamine hydrochloride to (1-{6-[(6-hydroxy-pyrazolo[ι,5-α]pyrimidin-3-carbonyl)-amino]-quinolin-7-yl}-piperidine- 4-butylmethyl)-tert-butyl carboxylic acid tert-butyl ester (〇·22 g) is added to a solution of a mixture of dioxane and decyl alcohol (1/1,1 〇mL) in hydrochloric acid (in Et20) , 1 Μ ' 5 mL), and the resulting mixture is stirred at room temperature 157102.doc •228·

S 201217379 物隔夜。藉由過濾收集所形成之固體，以乙醇洗滌且減壓乾燥，獲得224 mg呈淺黃色粉末形式之6-羥基-吡唑并 [1，5-α]喊咬-3-甲酸[7-(4-胺基甲基-派咬-i_基）_啥淋_6_基]_ 醯胺鹽酸鹽。MS=418 [M+H]+ ; MP>30(TC。利用上述程序及適當起始物質製備6-羥基-吡唑并[丨^〜] 嘧啶-3-曱酸[2-(4-胺基曱基-哌啶·丨-基兴^氣―苯基]_醯胺雙鹽酸鹽（白色粉末）；如實例1中所述進行步驟A。MS=401 [M+H]+ ; MP=285.0-288.(TC。實例15 :合成吡唑并[1，5-α]嘧啶_3_甲酸[5_氣_2_(哌啶_4基氧基）-苯基]-醯胺鹽酸鹽根據流程67中所示之方法合成η比唾并[1，5_α]痛咬甲酸 [5-氯-2-(痕咬-4-基氧基）-笨基]-醯胺鹽酸鹽。S 201217379 Things are overnight. The solid formed was collected by filtration, washed with ethanol and dried under reduced pressure to give 224 mg of 6-hydroxy-pyrazolo[1,5-[alpha] 4-Aminomethyl-pyro-i_yl)_啥淋_6_基]_ decylamine hydrochloride. MS=418 [M+H]+; MP>30 (TC. 6-hydroxy-pyrazolo[丨^~]pyrimidine-3-decanoic acid [2-(4-amine) using the above procedure and appropriate starting materials Hydrazinyl-piperidine-hydrazinyl-pyridyl-p-phenyl]-guanamine dihydrochloride (white powder); Step A was carried out as described in Example 1. MS = 401 [M+H] + ; MP = 285.0-288. (TC. Example 15: Synthesis of pyrazolo[1,5-α]pyrimidine_3_carboxylic acid [5_gas_2_(piperidin-4-yloxy)-phenyl]-nonylamine salt The acid salt is synthesized according to the method shown in Scheme 67. η than salivation [1,5_α] pain biting formic acid [5-chloro-2-(dentate-4-yloxy)-phenyl]-decylamine hydrochloride .

流程67Process 67

.—、，.—…〜1印那盥酸浴孜（於E20中，1 Μ，10 mL)，且在室溫下攪拌所得混合物6〇小時。藉由過濾收集所形成之固體，且以二滌三次，再以二氯曱烷洗滌一且以二氣甲烧洗務一次，以甲醇洗洗膝一次且以己烷洗滌一次，接著 157102.doc -229· 201217379 在真空烘箱中在60°C下乾燥，獲得125 mg(72%產率）呈灰白色固體形式之吡唑并[1，5_α]嘧啶_3•曱酸[5_氣_2_(哌啶_4_ 基氧基）-苯基]-醯胺鹽酸鹽。MS = 372 [Μ+Η]+。利用上述程序及適當起始物質製備以下化合物：吡唑并[1，5-α]嘧啶_3_甲酸[2-(4-胺基曱基-哌啶_ι_基）_ 4-苯基胺甲醯基-苯基;μ醯胺雙鹽酸鹽（淺黃色粉末）； MS=470 [M+H]+ ； °比嗅并[1，5心]嘧啶_3-曱酸[3_胺基_2_(4_胺基曱基-哌咬-1-基）-苯基]-醯胺三鹽酸鹽（灰白色粉末）；MS=366 [M+H]+ ；吡唑并[1，5-α]嘧啶-3-曱酸[2-(4-胺基·哌啶-1-基）-5-氣-苯基]-醯胺（灰白色粉末）；MS=371 [M+H]+ ; MP= 213.5-232.4°C ； °比。坐并[1，5-α]嘧啶_3-曱酸（4，·胺基甲基·4_氣-聯苯_2_ 基）-酿胺鹽酸鹽（白色粉末）；MS=378 [Μ+Η]+ ; ΜΡ= 286.1-288.7°C ；。比。坐并[1，5-α]嘧啶·3_甲酸[7·(4_胺基曱基_哌啶-丨-基）· 啥琳-6-基]-醯胺雙鹽酸鹽（淺黃色粉末）；mS=402 [M+H]+ ； MP=197.0-198.0°C ；售吩并[3,2-d]嘧啶·7_曱酸[7_(4_胺基曱基-哌啶―丨—基兴唾啉·6·基]-醯胺鹽酸鹽（黃色粉末；MS=419 [M+H]+ ； MP=255.9-260.0°C ； °塞吩并[3,2-幻嘧啶_7_曱酸[7-(哌啶-4-基氧基）-喹啉-6-基]-醯胺鹽酸鹽（白色粉末）；MS=406 [M+H]+ ; 157102.doc 201217379 MP>300°C ；噻吩并[3,2-d]喊咬-7-甲酸[7-(3_胺基-丙氧基）_喧淋冬基l·醯胺鹽酸鹽（白色粉末）；MS=38〇 [M+H]+; MP=234.0-237.0°C ；噻吩并[3,2-t/]嘧啶_7_甲酸[7-(吡咯啶_3_基氧基）-喹啉_ 6-基]-酿胺鹽酸鹽（白色粉末），MS=392 [M+H]， MP>300°C ；噻吩并[3,2-<|嘧啶-7-甲酸[2-(4_胺基·環己基氧基）-5-Φ 氯-苯基]-醯胺鹽酸鹽（灰白色粉末）；MS=4〇3 [M+H]+ ； MP=284.9-288.1°C ; 吡唑并[1，5-α]嘧啶·3·曱酸[7-(哌啶_4_基氧基）-喹啉-6-基]-酿胺（灰白色粉末）；MS=389 [M+H]+ ; MP> 3 00°C ； °比唑并[1,5-^]嘧啶_3_曱酸{2-[4-(1-胺基-乙基）-哌啶-1-基]-5-氣-苯基卜醯胺（白色粉末）；MS=399 [M+H]+ ; MP=178.8-179.7°C ;及 • °比°坐并[1，5·α]嘧啶-3-甲酸{2-[3-(l-胺基-乙基吡咯咬-1-基]-5-氣-苯基}_醯胺（橙色固體）；mS=385 [M+H]+ ; MP=228.0-229.0°C。實例16 :合成吡唑并μβπ】嘧啶_3_甲酸[5_氣·2_(噁唑_5•基甲氧基）-苯基]-醜胺根據流程68中所示之方法合成吡唑并嘧啶_3_甲酸 [5-氯-2-(噁唑-5-基曱氧基）_苯基]-醯胺。 157102.doc -231- 201217379.—, ,.—...~1 Inna citrate bath (1 Μ, 10 mL in E20), and the resulting mixture was stirred at room temperature for 6 hr. The formed solid was collected by filtration and washed twice with two times, then washed with dichloromethane and once with two gas, washed once with methanol and once with hexane, then 157102.doc -229· 201217379 Drying at 60 ° C in a vacuum oven gave 125 mg (72% yield) of pyrazolo[1,5_α]pyrimidine_3•decanoic acid [5_gas_2_ (in the form of an off-white solid) Piperidine_4_yloxy)-phenyl]-nonylamine hydrochloride. MS = 372 [Μ+Η]+. The following compounds were prepared using the above procedure and the appropriate starting materials: pyrazolo[1,5-α]pyrimidine_3_carboxylic acid [2-(4-aminoindolyl-piperidinyl)- 4-phenyl Aminomethyl hydrazino-phenyl; μ decylamine dihydrochloride (light yellow powder); MS = 470 [M+H] + ; ° ratio ol[1,5 core]pyrimidine _3-decanoic acid [3_ Amino 2-(4-aminoguanidino-piperidin-1-yl)-phenyl]-indoleamine trihydrochloride (off-white powder); MS=366 [M+H]+; pyrazolo[1] ,5-α]pyrimidine-3-decanoic acid [2-(4-amino)piperidin-1-yl)-5-a-phenyl]-decylamine (off-white powder); MS=371 [M+H ]+ ; MP = 213.5-232.4 ° C ; ° ratio. Sodium [1,5-α]pyrimidine-3-pyruic acid (4,·Aminomethyl·4_gas-biphenyl-2-yl)-chiral amine hydrochloride (white powder); MS=378 [Μ +Η]+ ; ΜΡ = 286.1-288.7 °C; ratio. Sodium [1,5-α]pyrimidine·3_carboxylic acid [7·(4-aminoguanylidene-piperidinyl-fluorenyl)·啥琳-6-yl]-guanamine dihydrochloride (light yellow Powder);mS=402 [M+H]+ ; MP=197.0-198.0°C; pheno[3,2-d]pyrimidine·7-decanoic acid [7_(4-aminoguanidino-piperidine)丨-Kiesing serotonin·6·yl]-decylamine hydrochloride (yellow powder; MS=419 [M+H]+; MP=255.9-260.0°C; °Septo[3,2-dioxin _7_Citrate [7-(piperidin-4-yloxy)-quinolin-6-yl]-nonylamine hydrochloride (white powder); MS=406 [M+H]+; 157102.doc 201217379 MP>300°C; thieno[3,2-d] shouting -7-formic acid [7-(3-amino-propoxy)-indole-glycolyl l-decylamine hydrochloride (white powder MS=38〇[M+H]+; MP=234.0-237.0°C; thieno[3,2-t/]pyrimidine_7_carboxylic acid [7-(pyrrolidin-3-yloxy)- Quinoline-6-yl]-chiralamine hydrochloride (white powder), MS = 392 [M+H], MP > 300 ° C; thieno[3,2-<|pyrimidine-7-carboxylic acid [2 -(4_Amino-cyclohexyloxy)-5-Φ chloro-phenyl]-indoleamine hydrochloride (off-white powder); MS = 4 〇 3 [M+H] + ; MP = 284.9-288.1 ° C ; pyrazolo[1,5-α]pyrimidine·3·decanoic acid [7-(piperidine _4_) Oxy)-quinolin-6-yl]-bristamine (off-white powder); MS = 389 [M+H] + ; MP > 3 00 ° C ; ° oxazolo[1,5-^]pyrimidine _3 _Citrate {2-[4-(1-Amino-ethyl)-piperidin-1-yl]-5-a-phenyl-p-guanamine (white powder); MS=399 [M+H]+ ; MP=178.8-179.7°C; and • °°°[1,5·α]pyrimidine-3-carboxylic acid {2-[3-(l-amino-ethylpyrrolidone-1-yl)- 5-Gas-phenyl}-decylamine (orange solid); mS=385 [M+H]+; MP=228.0-229.0 ° C. Example 16: Synthesis of pyrazole and μβπ]pyrimidine_3_carboxylic acid [5_ Synthesis of pyrazolopyrimidine _3_carboxylic acid [5-chloro-2-(oxazole-5) according to the method shown in Scheme 68, gas·2_(oxazole-5-ylmethoxy)-phenyl]- ugly amine -yloxy)phenyl]-decylamine. 157102.doc -231- 201217379

如實例1中所述，在hbtu存在下，使5氣_2_(2 _ 基石夕燒基4。[5_基¥氧基）_苯胺與対并曱酸偶合。藉由於甲醇中與氫氧化納水溶液—起加熱= 時使產物脫除保護基。冷卻反應混合物；藉由過濾收集=# 形成之固體且以水洗滌。藉由急驟層析法純化粗殘餘物，獲得18 mg呈灰白色固體形式之吡唑并嘧啶_3_曱酸 [5-氣-2-(。惡唾_5·基甲氧基）_苯基]_醯胺。ms=37〇 [M+H]+。實例17:合成噻吩并【3,2_rf]嘧啶_7甲睃醯胺根據流程69中所示之方法合成噻吩并[3，2_4]嘧啶_7_曱酸醯胺。As described in Example 1, 5 gas 2_(2 _ ketone alkyl group 4. [5-yl ke oxy) aniline was coupled with anthraindole in the presence of hbtu. The product is removed by removal of the product from the aqueous sodium hydroxide solution in methanol. The reaction mixture was cooled; the solid formed by filtration = # was collected and washed with water. The crude residue was purified by flash chromatography to give <RTI ID=0.0>>&&&&&&&&&&&&&& ]_醯amine. Ms=37〇 [M+H]+. Example 17: Synthesis of thieno[3,2_rf]pyrimidine-7 carboxamide A thieno[3,2~4]pyrimidin-7-nonanoate amide was synthesized according to the procedure shown in Scheme 69.

流程69 步规A :合成嗟吩并[3,2-rf]嘧啶-7-甲酸甲酯向嗟吩并[3，2-〇?]喷咬·7甲酸（5〇 mg)於二氯甲炫與曱醇 157102.docScheme 69 Step A: Synthesis of benzophenone [3,2-rf]pyrimidine-7-carboxylic acid methyl ester to sputum [3,2-〇?] squeezing ·7 carboxylic acid (5 〇mg) in dichloroa Hyun and sterol 157102.doc

•232- B 201217379 之混合物（95/5，！ mL)中之懸浮液中添加三甲基石夕烧基重氮f則於己燒中’2 M’ i mL)’且在室溫下搜拌所得混合物1小時》接著減磨蒸發反應混合物，且藉由急驟層析法（DCM/MeOH，97/3)純化粗殘餘物，獲得4〇 mg噻吩并 [3,2-刃嘧啶-7-甲酸甲@旨。步驟B:合成噻吩并[3,2_rf】嘧啶_7甲酸醢胺向嗟吩并[3，2今密咬_7_甲酸甲醋（4〇叫)於1，心工噁院（2 mL)中之溶液中添加氫氧化銨（濃，2 mL)，且在密封試管籲巾在100 C下加熱所得混合物隔夜。接著冷卻反應混合物且以乙I乙g曰萃取。合併之有機萃取物經無水硫酸鈉乾燥，過濾且減壓蒸發。藉由急驟層析法（DCM/MeOH， 95/5)純化粗殘餘物，獲得12 mg呈淺棕色固體形式之噻吩并[3,2-rf]嘧啶-7-曱酸醯胺。MS=18〇 [M+H]+。實例18 ·合成nt也并丨嘧啶_3甲酸[5氯_2(⑻_23_ 二羥基-丙氧基）-苯基]-醯胺根據流程70中所示之方法合成d比唾并tl，5㈣咬_3_甲酸 [5氣-2-((R)-2,3-二羥基_丙氧基）苯基]醯胺。• Add chloroform of the 232-B 201217379 mixture (95/5, ! mL) to the suspension of '2 M' i mL) in the suspension and mix at room temperature The mixture was evaporated to dryness and the crude residue was purified by flash chromatography (DCM/MeOH, 97/3) to afford 4 </ RTI> @Purpose. Step B: Synthesis of thieno[3,2_rf]pyrimidine_7-formic acid decylamine to sputum [3,2 密密 bite_7_carboxylic acid methyl vinegar (4 〇) in 1, heart labor hospital (2 mL) Ammonium hydroxide (concentrated, 2 mL) was added to the solution, and the resulting mixture was heated overnight at 100 C in a sealed tube. The reaction mixture was then cooled and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium The crude residue was purified by flash chromatography (DCM / MeOH, 95/5) to afford 12 mg of thiopheno[3,2-rf]pyrimidine-7-decanoate as a light brown solid. MS=18〇 [M+H]+. Example 18 - Synthesis of nt also pyrimidine _3 formic acid [5 chloro-2((8)_23_dihydroxy-propoxy)-phenyl]-decylamine was synthesized according to the method shown in Scheme 70, d is more than sal, and tl, 5 (four) bites _3_carboxylic acid [5 gas-2-((R)-2,3-dihydroxy-propoxy)phenyl]decylamine.

流程70 在70 C下加熱吡唑并[Ι 5 α]嘧啶_3甲酸[5氯_2_((s)_2 2_ 曱基-[1，3]二氧戊環_4_基甲氧基）苯基]醯胺（4() mg)及 157102.doc •233- 201217379 鹽酸水溶液（2M，5mL)於四氫吱喃（5mL)中之混合物i5 分鐘。冷料得混合物且藉由喊收集所形成之固體，以氮氧化納稀溶液及水洗滌，在真空烘箱中乾燥，獲得30 ^呈白色固體形式之°比°坐并[Ha]咳咬-3-甲酸[5_氣·2_ ((R)_2’3-二經基·丙氧基）_苯基]_醢胺。MS=362 [Μ]+。利用上述程序及適當起始物質製備以下化合物：Scheme 70 Heating pyrazolo[Ι 5 α]pyrimidine_3carboxylic acid [5-chloro-2-((s)_2 2_indolyl-[1,3]dioxolan-4-yloxy) at 70 C Phenyl]decylamine (4 () mg) and 157102.doc • 233 - 201217379 A mixture of aqueous hydrochloric acid (2M, 5 mL) in tetrahydrofuran (5 mL) for 5 min. The mixture was cooled and the solid formed was collected by shouting, washed with a nitrogen-nitrating solution and water, and dried in a vacuum oven to obtain a solution of 30^ as a white solid, and [Ha] cough-3 - Formic acid [5_gas·2_((R)_2'3-di-propyl-propoxy)-phenyl]-decylamine. MS=362 [Μ]+. The following compounds were prepared using the procedures described above and the appropriate starting materials:

吡唑并:1’5-α]嘧啶_3_曱酸卜氣_2((卟23二羥基丙氧基）-苯基]-醯胺（灰白色固體）；Ms=362 [μ]+ ;及吡唑并[1，5-α]喷咬_3_甲酸[5·氣_2 (3 4二經基丁氧基）_本基醯胺（白色粉末）；MS=377 [Μ+Η]+ ; MP=223.0-224.5°C 〇咬-3-甲酸[2-(3-胺基-吡咯實例19 :合成吡唑并[1,5·«】嘧啶-1-基）-5-氣-笨基卜醯胺根據流程71中所示之方法合成。比唾并Π，5·α]対_3_曱酸 [2-(3-胺基-㈣咬小基）_5_氣苯基]-酿胺。Pyrazolo: 1 '5-α]pyrimidine _3_ decanoic acid b 2 ((卟23 dihydroxypropoxy)-phenyl]-decylamine (off-white solid); Ms=362 [μ]+; And pyrazolo[1,5-α] squeezing _3_carboxylic acid [5·gas_2 (3 4 di-butyryloxy)-benylguanamine (white powder); MS=377 [Μ+Η ]+ ; MP=223.0-224.5°C Bite 3-carboxylic acid [2-(3-Amino-pyrrole Example 19: Synthesis of pyrazolo[1,5·«]pyrimidin-1-yl)-5-gas - Stupid oxime is synthesized according to the method shown in Scheme 71. It is more than salivary, 5·α]対_3_decanoic acid [2-(3-amino-(tetra)-bito) _5_gas phenyl ]--Amine.

流程71 -it ου u r 开嘧啶 _3_ 甲酸{5_ 氣 _2_[3_ (2,2,2-三氟-乙醜基脸基胺基）_吡咯啶-1-基]-笨基}-醯胺（50 157102.doc -234· 201217379 mg)、甲醇（2mL)與氫氧化鈉水溶液（4M，i mL)之混合物 1小時。冷卻所得混合物，以乙酸乙酯稀釋，以水及鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓蒸發，未經進一步純化即獲得30 mg吡唑并嘧啶_3_甲酸[2 (3胺基吡咯啶小基）-5-氣·笨基]_醯胺（淺黃色泡沫）。ms=356 [M]+。實例20 :合成6-經基-啦峡并⑴^]吨咬_3甲睃氣_2派咬-1-基-苯基）·酿胺根據流程72中所示之方法合成6_經基_対并⑴5_α]嚷啶-3·甲酸（5-氣-2-哌啶-1·基-苯基）_醯胺。Scheme 71 -it ου ur pyrimidine _3_ formic acid {5_ gas_2_[3_(2,2,2-trifluoro-ethylidylamino)-pyrrolidin-1-yl]-stupyl}-醯A mixture of the amine (50 157102.doc - 234 · 201217379 mg), methanol (2 mL) and aqueous sodium hydroxide (4M, i mL) for 1 hour. The mixture was cooled, diluted with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Pyrrolidine small group)-5-gas·stupyl]-decylamine (light yellow foam). Ms=356 [M]+. Example 20: Synthesis of 6-meridyl-la gorge and (1)^] ton of bite _3 formazan _2 ketone-1-yl-phenyl) styroamine was synthesized according to the method shown in Scheme 72. _対(1)5_α]Acridine-3·carboxylic acid (5-Gas-2-piperidin-1·yl-phenyl)-decylamine.

在密封試管中，在160〇C下加熱6_甲氧基_。比。坐并fi，〜] 嘧咬-3-甲酸（5-氯-2-娘咬+基_苯基）醯胺（ι〇〇㈣及甲硫醇納（45 mg)於二甲基甲酿胺（約2社）中之混合物料小時》減壓蒸發所得混合物，且使殘餘物溶解於氯仿與甲醇之混合物中，吸收於矽膠上且藉由急驟層析法 (DCM/Me0H/Ac0H)純化，獲得25 4吨(26%產率）呈黃色固體形式之6-經基·η比。坐并口，〜]鳴咬^甲酸（5氣_2_娘咬- 157102.doc -235· 201217379 1-基-苯基）-醯胺。MS=372 [M+H]+ ; MP>300°C。利用上述程序及適當起始物質合成6-羥基比唑并[1，5-α] 嘧啶-3-甲酸{2-[4-(第三丁基-二甲基-矽烷基氧基）-環己基氧基]-5-氣-苯基}-醯胺。實例21 :合成6-羥基·吡唑并[1，5-α]嘧啶-3-甲酸【5-氣-2-(4-二甲基胺基甲基-哌啶-1_基）-苯基】-醯胺根據流程73中所示之方法合成6-羥基-吡唑并[1,5-α]嘧啶-3-曱酸[5-氣-2-(4-二甲基胺基曱基-哌啶-1-基）-苯基]-醯胺0The 6-methoxy group was heated at 160 ° C in a sealed tube. ratio. Sit and fi, ~] pyrimidine-3-carboxylic acid (5-chloro-2-nitopic bite + phenyl-phenyl) decylamine (methane (tetra) and methyl mercaptan (45 mg) in dimethyl amide The mixture was evaporated under reduced pressure. The residue was evaporated to dryness crystals eluted eluted Obtained 25 4 tons (26% yield) in the form of a yellow solid in the form of a 6-base η ratio. Sit and mouth, ~] squeaking ^ formic acid (5 gas _2 _ mother bite - 157102.doc -235· 201217379 1- Benzyl-phenyl)-guanamine. MS = 372 [M+H] + ; MP > 300 ° C. Synthesis of 6-hydroxypyrazolo[1,5-α]pyrimidine-3 using the above procedure and appropriate starting materials -formic acid {2-[4-(t-butyl-dimethyl-decyloxy)-cyclohexyloxy]-5-a-phenyl}-decylamine. Example 21: Synthesis of 6-hydroxy·pyridyl Zoledolo[1,5-α]pyrimidine-3-carboxylic acid [5-gas-2-(4-dimethylaminomethyl-piperidine-1-yl)-phenyl]-guanamine according to Scheme 73 Synthesis of 6-hydroxy-pyrazolo[1,5-α]pyrimidin-3-indole[5-gas-2-(4-dimethylaminodecyl-piperidin-1-yl) by the method shown -phenyl]-guanamine 0

流程73 在密封試管中’在微波反應器中在220。(：下加熱1-{4_氣-2-[(6-甲氧基比唑并[ΐ，5-α]嘧啶-3-羰基）-胺基]-苯基卜哌 0定-4-基曱基）-胺基甲酸第三丁醋（120 mg，0.23 mmol)及甲硫醇鈉（164 mg)於二甲基曱醯胺（約3 mL)中之混合物 20分鐘》減壓蒸發所得混合物，且使殘餘物溶解於二氯曱烷與曱醇之混合物中，吸收於矽膠上且藉由急驟層析法 (DCM/MeOH)純化’獲得32.0 mg呈棕色固體形式之6-羥基-吡唑并[1，5·α]嘧啶_3_曱酸[5_氣_2-(4-二甲基胺基甲基· 哌啶-1-基）-苯基]-醯胺。MS=429 [M+H]+。 157102.doc •236· 201217379 2-氣-噻吩并[3,2-d】嘧啶-7-甲酸Flow 73 is in a sealed tube 'in a microwave reactor at 220. (: heating 1-{4_gas-2-[(6-methoxybisazolo[ΐ,5-α]pyrimidin-3-carbonyl)-amino]-phenyl-piperidine 0--4- a mixture of thioglycolic acid terpene carboxylic acid (120 mg, 0.23 mmol) and sodium thiomethoxide (164 mg) in dimethyl decylamine (about 3 mL) for 20 minutes. The mixture was dissolved in a mixture of dichloromethane and decyl alcohol, taken up on silica gel and purified by flash chromatography (DCM/MeOH) to afford 32.0 mg of 6-hydroxy-pyridyl as a brown solid. Zizo[1,5·α]pyrimidine_3_decanoic acid [5_gas_2-(4-dimethylaminomethylpiperidin-1-yl)-phenyl]-guanamine. MS=429 [M+H]+. 157102.doc •236· 201217379 2-Gas-thieno[3,2-d]pyrimidine-7-carboxylic acid

OH 步称a 經由加料漏斗向15.0 g(87.6 mmol)3-胺基-4-曱基嗟吩_2· 曱酸曱酯於437 mL乙酸與45 mL水之溶液中添加含216 g(263 mmol)氰酸鉀之71 mL水《在室溫下攪拌混合物隔夜。移除75%溶劑。觀測到沈澱且過濾《添加45〇 6% 氫氧化鈉水溶液❶在13〇。(：下回流混合物4小時，接著冷卻且以60 ml 12N鹽酸酸化至pH 6。觀測到沈殿，過減，以水洗滌且在高真空中乾燥隔夜’獲得10.55 g呈白色固體形式之7-曱基噻吩并[3,2-d]嘧啶-2,4(1H，3H)-二酿|。步驟b 使 10.0 g(54.9 mmol)7-甲基噻吩并[3,2-d]嘧啶 _2,4 (1H，3H)-二酮與140 mL氧氯化磷之混合物回流隔夜，接著減壓濃縮。將殘餘物緩慢添加至冰水中，且以乙酸乙醋萃取3次。有機層以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以己烷-乙酸乙酯（梯度ι〇〇:〇_ 80:20)溶離）純化殘餘物，獲得9_5 g呈黃色固體形式之2,4_ 二氣-7-甲基-噻吩并[3,2-d]嘧啶。步驟c 向 4.8 g(21.9 mm〇l)2,4-二氯-7·曱基-噻吩并[32_d]嘧啶於80 mL乙酸乙酯及10 mL異丙醇中之溶液中添加3 % 157102.doc -237- 201217379 g(48.2 mmol)乙酸鈉及0.97 g(6.91 mmol)氫氧化把。混合物在45 psi氫氣下置於帕爾震盪器上隔夜。反應物經由石夕藻土餅過濾，以二氯甲烷洗滌且減壓移除。藉由矽膠層析法（以己烷-乙酸乙酯（梯度100:0-75:25)溶離）純化殘餘物，獲得4.28 g呈白色固體形式之2-氣-7-曱基-噻吩并[3,2-d], 咬。步驟d 向 2.00 g(l〇.8 mmol)2-氯-7-甲基-2-氣·噻吩并[3,2-d]嘧啶於72 mL無水四氯化碳中之溶液中分別添加199 g(U 2 mmol)N·溴代丁二醯亞胺及〇·142 g(〇 867 mm〇1)2 2，偶氮雙（2-甲基丙腈”將混合物加熱至回流持續8小時，冷卻，過濾且減壓濃縮，獲得4.23 g呈黃色油狀之7_溴曱基·2_氯_ °塞吩并[3,2-d]嘧啶’其用於下一步驟。步驟eOH step a Add 216 g (263 mmol) to a solution of 15.0 g (87.6 mmol) of 3-amino-4-mercaptophene-2· decanoate in 437 mL of acetic acid and 45 mL of water via an addition funnel. ) 71 mL of potassium cyanate "Stir the mixture overnight at room temperature. Remove 75% solvent. A precipitate was observed and filtered. Add 45 〇 6% aqueous sodium hydroxide solution at 13 Torr. (: The mixture was refluxed for 4 hours, then cooled and acidified to pH 6 with 60 ml of 12N hydrochloric acid. Observed, reduced, washed with water and dried overnight in high vacuum to obtain 10.55 g of 7-曱 as a white solid. Thiophene[3,2-d]pyrimidine-2,4(1H,3H)-di-branched |. Step b 10.0 g (54.9 mmol) of 7-methylthieno[3,2-d]pyrimidine_2 , a mixture of 4 (1H,3H)-dione and 140 mL of phosphorus oxychloride was refluxed overnight, then concentrated under reduced pressure. The residue was slowly added to ice water and extracted with ethyl acetate three times. The residue was dried over anhydrous sodium sulfate (MgSO4) 2,4_diqi-7-methyl-thieno[3,2-d]pyrimidine in solid form. Step c to 4.8 g (21.9 mm 〇l) 2,4-dichloro-7-mercapto-thiophene [32_d] Pyrimidine in a solution of 80 mL of ethyl acetate and 10 mL of isopropanol was added 3 % 157102.doc -237 - 201217379 g (48.2 mmol) sodium acetate and 0.97 g (6.91 mmol) of hydr. 45 psi hydrogen placed in a Parr oscillator Over the night. The reaction was filtered through a pad of Celite, washed with dichloromethane and evaporated under reduced pressure. eluted by EtOAc (EtOAc (EtOAc: EtOAc) The residue was purified to give 4. <RTI ID=0.0>#</RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -Methyl-2-gas·thieno[3,2-d]pyrimidine was added to a solution of 72 mL of anhydrous carbon tetrachloride, respectively, to add 199 g (U 2 mmol) of N·bromobutaneimine and hydrazine. · 142 g (〇 867 mm 〇 1) 2 2, azobis(2-methylpropanenitrile) The mixture was heated to reflux for 8 hours, cooled, filtered and concentrated under reduced pressure to give 4. _Bromoguanidino 2_chloro_ °seno[3,2-d]pyrimidine' is used in the next step.

g呈黃色固體形式之2·氣甲醛。 :4〇)溶離）純化殘餘物， U噻吩并[3,2_d]嘧啶_7_ 步驟f 157102.doc -238- 201217379 向0_640 g(3.22 mmol)2-氣-噻吩并[32-d]鳴咬_7_甲搭於 20 mL四氫呋喃、10 mL第三丁醇及1〇瓜^水中之懸浮液中添加1.25 g(12.9 mmol)胺基磺酸。經由加料漏斗緩慢添加〇·729 g(8·06 mm〇l)亞氯酸鈉及 3.33 g(24.5 mmol)磷酸二氫卸於24 mL水中之溶液。在室溫下攪拌反應混合物隔夜。添加水及乙酸乙酯，分離。以乙酸乙酯洗滌水層。有機層以鹽水洗務’經無水硫酸鈉乾燥，過濾且減壓濃縮。將固體殘餘物在高真空中乾燥隔夜，獲得0 66〇 g呈黃色固體形式之2_氣-噻吩并[3,2_d]嘧啶-7-甲酸。MH+/Z=215。實例22 : 2-(順-2-胺基_環己基胺基）-噻吩并[3,2-d】嘧啶-7-甲酸喹啉-8-基醯胺g is a gas solid in the form of a yellow solid. :4〇)Solution) Purification residue, U-thieno[3,2_d]pyrimidine_7_ Step f 157102.doc -238- 201217379 To 0-640 g (3.22 mmol) 2-gas-thieno[32-d] bite _7_ 1.25 g (12.9 mmol) of aminosulfonic acid was added to a suspension of 20 mL of tetrahydrofuran, 10 mL of tert-butanol and 1 〇 of water. A solution of 亚·729 g (8·06 mm〇l) sodium chlorite and 3.33 g (24.5 mmol) of dihydrogen phosphate in 24 mL of water was slowly added via an addition funnel. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added and separated. The aqueous layer was washed with ethyl acetate. The organic layer was dried with EtOAc EtOAc EtOAc. The solid residue was dried under high vacuum overnight to afford <RTI ID=0.0>> MH+/Z=215. Example 22: 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinoline-8-ylguanamine

步驟a 向〇_〇50 g(〇.235 mmol)2-氯-噻吩并[3,2-d]嘧啶曱酸、 0.034 g(0.235 mm〇l)8·胺基喹咻及 0.12 ml(0.7 mmol)二異丙基乙基胺及2 mL·二甲基曱醯胺之溶液中添加〇.12 g(〇.28 mmol)六氟磷酸〇_(苯并三唑_卜基）-队>1，1<[,，：^’-雙（四亞甲基）錁》在室溫下搜拌混合物3小時。添加破酸納水/谷液，以CH2C12萃取，有機層以碳酸鈉、鹽水洗滌’經無水 157102.doc -239· 201217379Step a To 〇〇 50 g (〇.235 mmol) 2-chloro-thieno[3,2-d]pyrimidine decanoic acid, 0.034 g (0.235 mm 〇l) 8 ·aminoquinoxaquinone and 0.12 ml (0.7 Add 〇.12 g (〇.28 mmol) 六 hexafluorophosphate 〇((benzotriazole-b)-team> gt) of diisopropylethylamine and 2 mL·dimethylamine ;1,1<[,,:^'-bis(tetramethylene)anthracene) The mixture was searched for 3 hours at room temperature. Add sodium sulphate/salt solution, extract with CH2C12, and wash the organic layer with sodium carbonate and brine ‘ anhydrous 157102.doc -239· 201217379

NaaSO4乾燥’過濾且濃縮，獲得呈微黃色固體形式之2_ 氣-β塞吩并[3,2-d]嘧啶_7_曱酸喹啉基醯胺與2_(苯并三。坐-1-基氧基）-噻吩并[3,2_d]嘧啶_7_甲酸喹啉_8_基醯胺的 80 mg混合物’其未經進一步純化即用於下一步驟。步驟b 在60C下授拌80 mg 2_氯-噻吩并[3,2-d]嘴咬-7-曱酸啥淋-8-基酿胺與2·(苯并三唑_丨_基氧基噻吩并[3,2_d]嘧啶_ 7-曱酸喹啉-8-基醯胺之混合物及〇17 g(14i mmol)順-1，2-二胺基環己烧（來自步驟a)於二嗯烧（3 mL)中之懸浮液隔夜。冷卻反應物’且以CH2C12稀釋，以Na2C03水溶液、鹽水洗滌’經無水Na2S04乾燥，濃縮且藉由急驟層析法（矽膠，40 g，含0。/。至 30% MeOH(0.7 N)之 CH2C12)純化，獲得 40 mg呈淺黃色固體形式之2-(順-2-胺基-環己基胺基）_噻吩并[3,2-(1]嘴°定-7-甲酸啥淋-8-基酿胺。MH+/Z=419。實例23 : 2-(順-2-胺基-環己基胺基）_嗟吩并[3,2-d]鳴咬-7-甲酸苯并[1，3]二氧雜環戊烯-5-基醯胺NaaSO4 was dried 'filtered and concentrated to give 2_ gas-β-phene[3,2-d]pyrimidine-7-decanoic acid quinolylguanamine in the form of a yellowish solid with 2_(benzotriene. An 80 mg mixture of methoxy)-thieno[3,2-d]pyrimidin-7-carboxylic acid quinoline _8- decylamine was used in the next step without further purification. Step b: Mix 80 mg of 2_chloro-thieno[3,2-d] mouth bite-7-decanoate -8-ylamine and 2·(benzotriazole_丨_yloxy) at 60C a mixture of thieno[3,2_d]pyrimidin-7-nonanoic acid quinoline-8-ylguanamine and 〇17 g (14i mmol) of cis-1,2-diaminocyclohexane (from step a) The suspension in the sulphur (3 mL) was cooled overnight. The reaction was cooled and diluted with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Purify to 30% MeOH (0.7 N) in CH2C12 to afford 40 mg of 2-(cis-2-amino-cyclohexylamino)-thiophene[3,2-(1) ] ° 定 -7-carboxylic acid -8-8-ylamine. MH+ / Z = 419. Example 23: 2-(cis-2-amino-cyclohexylamino)- 嗟并 [3,2- d] 咬-7-carboxylic acid benzo[1,3]dioxol-5-yl decylamine

步称a 向 0.050 g(0.235 mmol)2-氣-噻吩并[3 2_d]嘧啶_7_甲酸、 157102.doc •240· 201217379 0.032 g(〇_235 mmol)3,4-(亞甲基二氧基）苯胺及〇12 ml(〇7 mmol)二異丙基乙基胺及2 mL二甲基甲醯胺之溶液中添加 0.12 g(0.28 mmol)六氟磷酸〇·(苯并三唑· 雙（四亞曱基）錁。在室溫下攪拌混合物3小時。添加碳酸鈉水溶液，以CHAh萃取，有機層以碳酸鈉、鹽水洗滌，經無水Na2S〇4乾燥，過濾且濃縮，獲得呈微黃色固體形式之 2-氣-噻吩并[3,2-d]嘧啶-7-甲酸苯并[丨,3]二氧雜環戊烯_5_ 基醯胺與2-(苯并三唑_ι_基氧基噻吩并[3,2_d]嘧啶_7_甲酸苯并[1，3]二氧雜環戊烯-5 —基醯胺之8〇 mg混合物，其未經進一步純化即用於下一步驟中。步驟b 將80 mg 2-氯-噻吩并[3,2-d]嘧啶·7·甲酸苯并[ι，3]二氧雜環戊烯-5-基醯胺與2-(苯并三唑_丨_基氧基噻吩并[3,2_d] 嘧啶-7-曱酸苯并[1，3]二氧雜環戊烯_5_基醯胺之混合物（來自步驟a)及0_17 g(1.41mm〇l)順·ι，2-二胺基環己烷於二噁烷 (3 mL)中之懸浮液在60它下攪拌隔夜。冷卻反應物，且以 CHzCl2稀釋，以NazCO3水溶液、鹽水洗滌，經無水Na2S〇4 乾餘辰縮且藉由急驟層析法（碎膠，4〇 g，含〇%至3〇% MeOH(0.7 N)之CHzCl2)純化，獲得4〇 mg£淺黃色固體形式之2-(順-2-胺基·環己基胺基噻吩并[3,2_d]嘧啶_7_甲酸苯并[1，3]二氧雜環戊稀_5_基酿胺β mh+/Z=412。實例24 : 2-(順-2-胺基-環己基胺基噻吩并[3,2_d丨嘧啶_7_ 曱酸（3,4-一甲氧基-苯基）_酿胺 157102.doc •241· 201217379 ^~~~^."1 nh2 "nh {Λ 步驟a 向 0.050 g(0.235 mm〇1)2_氯“塞吩并[3 2_d]^_7 甲酸、 0.032 g(0.235 mm^，^ 甲氧基苯胺及〇 12 mI(〇 7 咖叫二異丙基乙基胺及2 ml二甲基甲醯胺之溶液中添加〇i2 g(0.28 mmol)六氟磷酸〇_(笨并三唑_丨_基）·Ν，Ν，Ν,，Ν|雙（四亞曱基）錁。在室溫下攪拌混合物3小時。添加碳酸鈉水溶液，以CHaCh萃取，有機層以碳酸鈉、鹽水洗滌，經無水 NaJO4乾燥，過濾且濃縮，獲得呈微黃色固體形式之氯-噻吩并[3,2-d]嘧啶-7-甲酸（3,4-二甲氧基-笨基）_醯胺與 2-(苯并三唑-1-基氧基）_噻吩并[3,2_d]嘧啶_7甲酸（3,4•二曱氧基-苯基）-醯胺之85 mg混合物，其未經進一步純化即用於下一步驟中β 步驟b 將85 mg 2-氣-噻吩并[3,2-d]嘧咬-7-甲酸（3,4·二曱氧基_ 苯基）-醯胺與2-(苯并三唑-1 -基氧基）_噻吩并[3,2_d]嘧啶甲酸（3,4-二甲氧基-苯基）-醯胺之混合物（來自步驟a)及0.17 g(1.41mmol)順.12-:胺基環己烷於二噁烷（3 mL)中之懸浮液在60°c下攪拌隔夜。冷卻反應物，且以CH2C12稀釋，以 NaAO3水溶液、鹽水洗滌’經無水Na2S04乾燥，濃縮且藉 157102.doc -242· 201217379 由急驟層析法（矽膠，40 g，含0%至3〇% Me〇H(〇 7 N)之 CHzCh)純化，獲得50 mg呈淺黃色固體形式之2 (順_2胺基-環己基胺基）-售吩并[3,2-d]喷咬_7_甲酸（3 4二曱氧基_ 苯基）-醯胺。MH+/Z=428。實例25 : 2-(順-2-胺基-環己基胺基）_噻吩并[32d]嘧啶_7_ 甲酸（1_甲基-1H-苯并咪唑-4-基）_酿胺。Step a to 0.050 g (0.235 mmol) 2-oxo-thieno[3 2_d]pyrimidine_7-carboxylic acid, 157102.doc •240· 201217379 0.032 g (〇_235 mmol) 3,4-(methylene II) Add 0.12 g (0.28 mmol) of hexafluorophosphonate·(benzotriazole) to a solution of oxy)aniline and hydrazine 12 ml (〇7 mmol) diisopropylethylamine and 2 mL dimethylformamide The mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium carbonate was added and the mixture was extracted with CH.sub.2, and the organic layer was washed with sodium carbonate and brine, dried over anhydrous Na? 2-Gas-thieno[3,2-d]pyrimidin-7-carboxylic acid benzo[丨,3]dioxol-5-ylguanamine and 2-(benzotriazole-y) as a yellow solid a mixture of 8 〇g of benzyloxythieno[3,2_d]pyrimidin-7-carboxylic acid benzo[1,3]dioxol-5-ylguanamine, which was used in the next In a step. Step b 80 mg of 2-chloro-thieno[3,2-d]pyrimidin-7-benzoic acid benzo[ι,3]dioxol-5-yl decylamine with 2-( Mixture of benzotriazole-丨-yloxythieno[3,2_d]pyrimidine-7-decanoic acid benzo[1,3]dioxol-5-ylguanamine (from step a) and 0_17 g (1.41 mm 〇l) of a suspension of cis,2-diaminocyclohexane in dioxane (3 mL) was stirred overnight at 60. The reaction was cooled. And diluted with CHzCl2, washed with NazCO3 aqueous solution, brine, dried over anhydrous Na2S 〇4, and by flash chromatography (4 g, 4 〇g, 〇% to 3 〇% MeOH (0.7 N) CHzCl2 Purification to obtain 4-(cis-2-amino)cyclohexylaminothiophene[3,2-d]pyrimidin-7-carboxylic acid benzo[1,3]dioxole in 4 mg mg as a pale yellow solid Pentene _5_ylamine II mh+/Z=412. Example 24: 2-(cis-2-amino-cyclohexylaminothiophene[3,2-d-pyrimidine-7-decanoic acid (3,4-a) Methoxy-phenyl)- aryl amine 157102.doc •241· 201217379 ^~~~^."1 nh2 "nh {Λ Step a to 0.050 g (0.235 mm〇1) 2_Chloro [3 2_d]^_7 Formic acid, 0.032 g (0.235 mm ^, ^ methoxyaniline and 〇 12 mI (〇7 咖二 diisopropylethylamine and 2 ml dimethylformamide) I2 g (0.28 mmol) bismuth hexafluorophosphate _ (stupid triazole _ 丨 _ group) · Ν, Ν, Ν, Ν | bis (tetradecyl) fluorene. The mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium carbonate was added, and the mixture was extracted with EtOAc (EtOAc). (3,4-dimethoxy-styl)-decylamine with 2-(benzotriazol-1-yloxy)-thieno[3,2_d]pyrimidine_7-formic acid (3,4•dioxin 85 mg mixture of oxy-phenyl)-guanamine which was used in the next step without further purification. Step b: 85 mg of 2-oxo-thieno[3,2-d]pyrimidine-7- Formic acid (3,4·dimethoxy-phenyl)-guanamine and 2-(benzotriazol-1-yloxy)-thieno[3,2_d]pyrimidinecarboxylic acid (3,4-dimethoxy) a mixture of phenyl-phenyl)-guanamine (from step a) and 0.17 g (1.41 mmol) of a suspension of cis.12-:aminocyclohexane in dioxane (3 mL) was stirred at 60 °. Overnight. The reaction was cooled and diluted with CH2C12, washed with aqueous Na.sub.3.sub.3, brine. Purification of CHzCh) of 〇H(〇7 N) to obtain 50 mg of 2 (cis-2-amino-cyclohexylamino)-p-[3,2-d] _7_ as a pale yellow solid Formic acid (3 4 dimethoxy-phenyl)-decylamine. MH+/Z=428. Example 25: 2-(cis-2-amino-cyclohexylamino)-thieno[32d]pyrimidine-7-carboxylic acid (1-methyl-1H-benzimidazol-4-yl)-bristamine.

步称a 向 0.050 g(0.233 mmol)2-氣-噻吩并[3,2-d]嘴咬-7-甲酸、 0.0686 g(0.466 mmol)l-曱基-1H-苯并[d]咪唑-4-胺、0.122 mL(0.699 mmol)N，N-二異丙基乙基胺及1.55 mL二曱基曱酿胺之溶液中添加0.111 g(〇.256 mmol)六氟磷酸0-(苯并三嗤-1-基）-N，N，N’，N’-雙（四亞甲基）錁。將混合物在室溫下攪拌隔夜。添加水及二氣曱烷。以二氣曱烷洗滌水層3次。合併之有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥’過濾且減壓濃縮。藉由矽膠層析法（以己烷-乙酸乙酯（梯度50:50-〇:1〇〇)溶離）純化，獲得0.042 g呈黃色固體形式之2-氯-噻吩并[3,2-d]嘧啶-7-曱酸（1-甲基-1H-苯并咪唑-4-基）-酿胺。步驟b 157102.doc -243- 201217379 向 0.041 g(〇.ii9 mmol)2-氣·噻吩并[3,2-d]嘧啶-7-甲酸 (1 -甲基-1 Η-苯并咪唑-4-基）-酿胺於1.19 mL二噁烷中之溶液中添加0.082 g(0.716 mmol)順-環己烷_ι，2-二胺。在 100C下加熱混合物隔夜。添加水及二氣甲烷，分離。以二氣甲烷洗滌水層兩次。有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以二氣甲烷-Ο.7 N氨之甲醇溶液（梯度100:0-90:10)溶離）純化，獲得0.019 g呈淺黃色固體形式之2_(順_2•胺基環己基胺基）-噻吩并[3,2_d]嘧啶_7_甲酸（1_甲基^札苯并咪唑_4_ 基）-醯胺。MH+/Z=422。實例26 : 2-(順-2-胺基-環己基胺基）_噻吩并[3,2_d】嘧啶_7_ 甲酸（2,4-二甲氧基·苯基）_醯胺。 ^ ^)·"'ΝΗ2 ΝΗStep a to 0.050 g (0.233 mmol) 2-gas-thieno[3,2-d] mouth bite-7-carboxylic acid, 0.0686 g (0.466 mmol) l-mercapto-1H-benzo[d]imidazole- Add 0.111 g (〇.256 mmol) of hexafluorophosphate 0-(benzophenone) to a solution of 4-amine, 0.122 mL (0.699 mmol) of N,N-diisopropylethylamine and 1.55 mL of dimercaptoamine. Triterpene-1-yl)-N,N,N',N'-bis(tetramethylene)fluorene. The mixture was stirred overnight at room temperature. Add water and dioxane. The aqueous layer was washed 3 times with dioxane. The combined organic layers were washed with aq. Purification by silica gel chromatography (solvent in hexane-ethyl acetate (gradient 50: 50 - 〇: 1 〇〇)) afforded 0.042 g of 2-chloro-thiophene[3,2-d as a yellow solid. Pyrimidine-7-decanoic acid (1-methyl-1H-benzimidazol-4-yl)-bristamine. Step b 157102.doc -243- 201217379 to 0.041 g (〇.ii9 mmol) 2-oxo-thieno[3,2-d]pyrimidine-7-carboxylic acid (1-methyl-1 oxime-benzimidazole-4 -Base) - A solution of the amine in 1.19 mL of dioxane was added 0.082 g (0.716 mmol) of cis-cyclohexane-l,2-diamine. The mixture was heated overnight at 100 °C. Add water and di-methane to separate. The aqueous layer was washed twice with di-methane. The organic layer was washed with EtOAcq. Purified by silica gel chromatography (dissolved in a solution of di-methane-Ο.7 N ammonia in methanol (gradient 100:0-90:10)) to give <RTI ID=0.0> Cyclohexylamino)-thieno[3,2-d]pyrimidin-7-carboxylic acid (1-methyl-2-benzoimidazole-4-yl)-guanamine. MH+/Z=422. Example 26: 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidin-7-carboxylic acid (2,4-dimethoxyphenyl)-decylamine. ^ ^)·"'ΝΗ2 ΝΗ

步驟a 向 0.050 g(0.233 mmol)2-氣-噻吩并[3,2-d]嘧啶_7 甲酸、 0.0714 g(〇.466 甲基-1H-苯并[d]咪唑胺、〇 122 mL(0.699 mm〇l)N，N-二異丙基乙基胺及U5机二甲基曱醯胺之溶液中添加0.111 g(0.256 mm〇1)A氟磷酸〇(苯二三唾小基）-N，N，N，，N，-雙（四亞甲基）錁。在室溫下攪拌混合: 隔夜。添加水及二氯曱烷。以二氯曱烷洗滌水層3欠。人 157102.doc •244· 201217379 併之有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以己烷-乙酸乙酯 (梯度100.0-60:40)溶離）純化，獲得0 050 g呈黃色固體形式之2·氣-噻吩并[3,2_d]嘧啶_7_甲酸（2,4_二甲氧基-苯基醯胺。步驟b 向 0.047 g(〇.134 mmol)2-氯-噻吩并[3,2-d]嘧啶-7-曱酸 (2,4-二甲氧基-苯基）-醯胺於1.34 mL二噁烷中之溶液中添加 0.0967 mL(0.806 mmol)順-環己烷-1，2-二胺。在 i〇〇°c 下加熱混合物隔夜《添加二氯甲烷且以碳酸氩鈉水溶液洗滌。以二氯曱烧洗滌水層兩次。有機層以鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以二氯甲烷-0·7 N氨之甲醇溶液（梯度ι〇〇:0-90:10)溶離）純化，獲得0_052 g呈黃色固體形式之2-(順-2-胺基-環己基胺基）-噻吩并[3,2-d]嘧啶-7·甲酸（2,4-二曱氧基苯基）-醯胺。 MH+/Z=428 ° 實例27 : 2-(順-2-胺基-環己基胺基）_噻吩并【3,2_d】嘧啶·7_ 甲酸（5,6-二甲氧基-吡啶-2-基）-醯胺。Step a to 0.050 g (0.233 mmol) of 2-oxo-thieno[3,2-d]pyrimidin-7carboxylic acid, 0.0714 g (〇.466 methyl-1H-benzo[d]imidazolium, 〇122 mL ( Add 0.111 g (0.256 mm 〇1) A fluorophosphate (benzotrisinyl) to a solution of 0.699 mm 〇l) N,N-diisopropylethylamine and U5 dimethyl decylamine - N,N,N,,N,-bis(tetramethylene)anthracene. Stir and mix at room temperature: overnight. Add water and dichloromethane. Wash water layer 3 with dichloromethane. Human 157102. Doc • 244·201217379 and the organic layer was washed with aqueous sodium sulfate and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by dissolving) to obtain 0 050 g of 2·gas-thieno[3,2_d]pyrimidine-7-carboxylic acid (2,4-dimethoxy-phenylguanamine) as a yellow solid. Step b to 0.047 g (〇.134 mmol) 2-Chloro-thieno[3,2-d]pyrimidin-7-decanoic acid (2,4-dimethoxy-phenyl)-guanamine in 1.34 mL of dioxane Add 0.0967 mL (0.806 mmol) of cis-cyclohexane-1,2-diamine. Heat the mixture overnight at i〇〇°c The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced vacuum. Purification of methane-0·7 N ammonia in methanol (gradient ι 〇〇: 0-90:10) eluted to give 0-052 g of 2-(cis-2-amino-cyclohexylamino) as a yellow solid. Thio[3,2-d]pyrimidin-7-carboxylic acid (2,4-dimethoxyoxyphenyl)-decylamine. MH+/Z=428 ° Example 27: 2-(cis-2-amino-ring Hexylamino)-thieno[3,2-d]pyrimidin-7-carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-decylamine.

〈〉…"nh2 NH〈〉..."nh2 NH

步驟a 157102.doc •245· 201217379 向 0.050 g(〇.233 mmol)2-氯-噻吩并[3,2-d]嘧啶 _7_ 甲酸、 0.0718 g(0.466 mmol)5,6·二甲氧基吡啶 _2 胺、〇 m mL(0.699 mmol)N，N-二異丙基乙基胺及i 55如二甲基甲醯胺之溶液中添加0.111 g(〇.256 mmol)六氟磷酸〇_(苯并二唑-1 -基）-N，N，N，，N，-雙（四亞曱基）錁。在室溫下攪拌混合: 隔夜。添加水及二氣曱烷。以二氯甲烷洗滌水層3次。合併之有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。在高真空中乾燥殘餘物，獲得呈累、色固體形式之2-氣·噻吩并[3,2-d]嘧啶-7-甲酸（5,6_二甲氧基-ϋ比咬-2 -基）-酿胺。步驟b 向 0.0817 g(0.233 mmol)2_ 氣-噻吩并[32d]嘧啶-7 甲酸 (5,6-二曱氧基-吡啶-2-基）_醯胺於2.33 mL二噁烷中之溶液中添加0.168 mL(1.4 mmol)順-環己烷+2·二胺。在1〇〇艺下加，熱混合物隔夜》添加水及二氯甲烷，分離。以二氣甲烷洗滌水層兩次。有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以二氯曱烷-0.7 N氨之甲醇溶液（梯度1〇〇:〇9〇:1〇)溶離）純化’獲得0.048 g呈淺黃色固體形式之2 (順_2胺基環己基胺基）-噻吩并[3,2-d]嘧啶_7_甲酸（5,6_二甲氧基-吡啶_2_基）_ 醯胺 ° MH+/Z=429 〇實例28 : 2-(順-2·胺基·環己基胺基）噻吩并[32d】嘧啶_7_ 甲酸（3,4,5-二甲氧基-笨基）_酿胺。 157102.doc -246- 201217379Step a 157102.doc •245· 201217379 to 0.050 g (〇.233 mmol) 2-chloro-thieno[3,2-d]pyrimidine_7_carboxylic acid, 0.0718 g (0.466 mmol) 5,6·dimethoxy Add 0.111 g (〇.256 mmol) of hexafluorophosphate to a solution of pyridine-2-amine, 〇m mL (0.699 mmol) N,N-diisopropylethylamine and i 55 such as dimethylformamide. (Benzadiazol-1-yl)-N,N,N,,N,-bis(tetradecyl)fluorene. Stir at room temperature: overnight. Add water and dioxane. The aqueous layer was washed 3 times with dichloromethane. The combined organic layer was washed with EtOAcq. The residue was dried under high vacuum to give 2- gas-thieno[3,2-d]pyrimidine-7-carboxylic acid as a sm. Base) - Amine. Step b to a solution of 0.0817 g (0.233 mmol) of 2_gas-thieno[32d]pyrimidin-7carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-decylamine in 2.33 mL of dioxane 0.168 mL (1.4 mmol) of cis-cyclohexane + 2 diamine was added. Add in 1 〇〇艺, hot mixture overnight, add water and dichloromethane, and separate. The aqueous layer was washed twice with dioxane. The organic layer was washed with EtOAcq. Purified by gelatin chromatography (dissolved in methylene chloride-0.7 N ammonia in methanol (gradient 1 〇〇: 〇9 〇: 1 〇)) to obtain 0.048 g of 2 as a pale yellow solid (cis _2 Aminocyclohexylamino)-thieno[3,2-d]pyrimidine_7-carboxylic acid (5,6-dimethoxy-pyridin-2-yl)-decylamine ° MH+/Z=429 〇Example 28 : 2-(cis-2.amino-cyclohexylamino)thieno[32d]pyrimidine_7_carboxylic acid (3,4,5-dimethoxy-phenyl)-bristamine. 157102.doc -246- 201217379

^-"NH2 NH^-"NH2 NH

步驟a 向 0.050 g(0.23 3 mmol)2-氣-噻吩并[3,2-d]嘧啶_7_甲酸、 0.0854 g(0.466 mmol)3,4,5-三甲氧基苯胺、0.122 mL(() 699 • mmol)N，N-二異丙基乙基胺及i.55 mL二甲基甲醯胺之溶液中添加0.111 g(0.256 mmol)六氟磷酸〇-(笨并三唑-i基）_ Ν，Ν，Ν’，Ν·-雙（四亞甲基）錁。在室溫下攪拌混合物2小時。添加水及二氣甲烷。以二氣曱烷洗滌水層3次。合併之有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸納乾燥，過渡且減壓濃縮。在高真空中乾燥殘餘物，獲得呈黃色固體形式之2-氣-噻吩并[3,2-d]嘧啶-7-曱酸（3,4,5-三曱氧基·苯基）-S蓝胺。 # 步驟b 向 0.0885 g(0.233 mmol)2-氣-噻吩并[32_d]嘧啶 _7_ 甲酸 (3，4,5-三曱氧基-苯基）-醮胺於2.33 mL二《«惡烧中之溶液中添加 0.168 mL(1.4 mmol)順-環己烷 _1，2_ 二胺》在1〇〇1 下加熱混合物隔夜。添加水及二氣甲烷，分離。以二氣甲烧洗蘇水層兩次。有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥’過濾且減壓濃縮。藉由梦膠層析法（以二氯甲烷-0.7 Ν氨之曱醇溶液（梯度100:0-90:10)溶離）純化， 157102.doc •247· 201217379 獲得0.064 g呈淺黃色固體形式之2-(順_2_胺基-環己基胺基）·噻吩并[3,2-d]嘧啶-7-甲酸（3,4,5-三甲氧基-苯基）-醮胺。MH+/Z=458 0 實例29 : 2-(順-2-胺基-環己基胺基）·噻吩并【3,2-d】嘧啶-7-甲酸喹啉-6-基醯胺。Step a to 0.050 g (0.23 3 mmol) of 2-oxo-thieno[3,2-d]pyrimidine_7-carboxylic acid, 0.0854 g (0.466 mmol) of 3,4,5-trimethoxyaniline, 0.122 mL (( 699 • mmol) N,N-diisopropylethylamine and i.55 mL of dimethylformamide were added with 0.111 g (0.256 mmol) bismuth hexafluorophosphate-(stupid triazole-i group) ) _ Ν, Ν, Ν ', Ν · - bis (tetramethylene) 锞. The mixture was stirred at room temperature for 2 hours. Add water and digas methane. The aqueous layer was washed 3 times with dioxane. The combined organic layers were washed with aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was dried under high vacuum to give 2- gas-thieno[3,2-d]pyrimidin-7-decanoic acid (3,4,5-trimethoxyoxyphenyl)-S as a yellow solid. Blue amine. #步b to 0.0885 g (0.233 mmol) 2-gas-thieno[32_d]pyrimidine_7_carboxylic acid (3,4,5-trimethoxy-phenyl)-guanamine in 2.33 mL two "« To the solution was added 0.168 mL (1.4 mmol) of cis-cyclohexane-1,2-diamine. The mixture was heated at 1 Torr overnight. Add water and di-methane to separate. The aqueous layer was washed twice with two gas. The organic layer was washed with aq. Purified by Membrane Chromatography (dissolved in dichloromethane-0.7 hydrazine in methanol (gradient 100:0-90:10)), 157102.doc •247· 201217379 Obtained 0.064 g as a light yellow solid 2-(cis_2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4,5-trimethoxy-phenyl)-decylamine. MH+/Z=458 0 Example 29: 2-(cis-2-amino-cyclohexylamino)·thieno[3,2-d]pyrimidine-7-carboxylic acid quinoline-6-ylguanamine.

步驟a 向 0.050 g(0.233 mmol)2-氯-噻吩并[3,2-d]嘧啶-7-曱酸、 0.0672 g(0.466 mmol)喹啉-6-胺、0.122 mL(0.699 mmol) N，N-二異丙基乙基胺及1.55 mL二甲基甲醯胺之溶液中添加0.111 g(0.256 mmol)六氟磷酸〇_(苯并三唑小基）_ N，N，N'，N'-雙（四亞曱基）錁。在室溫下攪拌混合物2小時。添加水及二氯甲烷。以二氯甲烷洗滌水層3次。合併之有機層以碳酸納水溶液、鹽水洗務’經無水硫酸鈉乾燥，過 ;慮且減壓濃縮。在高真空中乾燥殘餘物，獲得呈黃綠色固體形式之2-氣-噻吩并[3,2-d]嘧啶-7-甲酸喹啉基醯胺。步驟b 向 0.0794 g(0.233 mmol)2-氣-噻吩并[3,2_d]嘧啶 _7 甲酸喹啉-6-基醯胺於2.33 mL二噁烷中之溶液φ ; t 伙〒添加0.168 157I02.doc •248· 201217379 mL(l .4 mmol)順-環己炫《 -1，2-二胺。在100°C下加熱混合物2 小時。添加水及二氣曱烷，分離。以二氯曱烷洗滌水層兩次。有機層以碳酸鈉水溶液、鹽水洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由矽膠層析法（以二氯曱烷-〇·7 N 氨之曱醇溶液（梯度100:0-90:10)溶離）純化，獲得0.054 g呈淺黃色固體形式之2-(順-2-胺基-環己基胺基）-噻吩并[3,2-d]嘧啶-7-曱酸喹啉-6-基醯胺。MH+/Z=419。實例30 :調配物 # 如下表中所示調配藉由各種途徑傳遞之醫藥製劑。如表中所用之「活性成分」或「活性化合物」意謂一或多種式 I化合物。用於經口投與之組合物成分 % w/w 活性成分 20.0% 乳糖 79.5% 硬脂酸鎂 0.5%Step a to 0.050 g (0.233 mmol) of 2-chloro-thieno[3,2-d]pyrimidin-7-decanoic acid, 0.0672 g (0.466 mmol) of quinoline-6-amine, 0.122 mL (0.699 mmol) N, 0.111 g (0.256 mmol) of hexafluorophosphate 〇((benzotriazole small)_N,N,N',N was added to a solution of N-diisopropylethylamine and 1.55 mL of dimethylformamide. '-Double (four subunits). The mixture was stirred at room temperature for 2 hours. Add water and dichloromethane. The aqueous layer was washed 3 times with dichloromethane. The combined organic layers were washed with aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was dried under high vacuum to give 2-yt-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolinylamine as a yellow-green solid. Step b To a solution of 0.0794 g (0.233 mmol) of 2-oxo-thieno[3,2-d]pyrimidin-7-carboxylic acid quinoline-6-ylguanamine in 2.33 mL of dioxane; t 〒〒 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 Doc •248· 201217379 mL (1.44 mmol) cis-cyclohexanthene -1,2-diamine. The mixture was heated at 100 ° C for 2 hours. Add water and dioxane and separate. The aqueous layer was washed twice with dichloromethane. The organic layer was washed with EtOAcq. Purified by silica gel chromatography (dissolved in a solution of dichloromethane, 〇·7N ammonia in methanol (gradient 100:0-90:10)) to give 0.054 g of 2-(cis- 2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidin-7-decanoic acid quinoline-6-ylguanamine. MH+/Z=419. Example 30: Formulation # A pharmaceutical preparation delivered by various routes was formulated as shown in the following table. As used herein, "active ingredient" or "active compound" means one or more compounds of formula I. Composition for oral administration Ingredient % w/w Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

混合各成分且分配至各含有約100 mg之膠囊中；一膠囊將大約為每日總劑量。用於經口投與之組合物成分 % w/w 活性成分 20.0% 硬脂酸鎂 0.5% 交聯羧甲基纖維素鈉 2.0% 乳糖 76.5% PVP(聚乙烯吡咯啶） 1.0% 157102.doc -249- 201217379 合併各成分且使用諸如甲醇之溶劑粒化。接著乾燥調配物且以適當壓錠機成形為錠劑（含有約20 mg活性化合物）。用於經口投與之組合物成分量活性化合物 1-0 g 反丁烯二酸 0.5 g 氯化鈉 2.0 g 對羥基苯曱酸曱酯 0.15 g 對羥基苯甲酸丙酯 0.05 g 晶粒砂糖 25.5 g 山梨糖醇(70%溶液） 12.85 g Veegum K(Vanderbilt Co.) 1.0 g 調味劑 0.035 ml 著色劑 0.5 mg 蒸餾水補足至100 ml 混合各成分形成用於經口投與之懸浮液。非經腸調配物成分 % w/w 活性成分 0.25 g 氯化鈉適量以達到等張注射用水 100 ml 將活性成分溶解於一部分注射用水中。接著在攪拌下添加足夠量之氯化鈉以使溶液等張。以剩餘注射用水補足溶液重量，經由0.2 μιη膜過濾器過濾且在無菌條件下包裝。 157102.doc •250- 201217379 栓劑調配物成分 % w/w 活性成分 1.0% 聚乙二醇1000 74.5% 聚乙二醇4000 24.5% 將各成分溶融在一起且在蒸氣浴上混合，且傾入含有 2.5 g總重量之模具中。局部調配物成分公克活性化合物 0.2-2 Span 60 2 Tween 60 2 礦物油 5 石蠟脂 10 對羥基苯曱酸曱酯 0.15 對羥基苯曱酸丙酯 0.05 BHA(丁基化羥基甲氧苯） 0.01 水補足至100The ingredients are mixed and dispensed into capsules each containing about 100 mg; one capsule will be approximately the total daily dose. Composition for oral administration % w/w Active ingredient 20.0% Magnesium stearate 0.5% Croscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0% 157102.doc - 249- 201217379 Combine the ingredients and granulate using a solvent such as methanol. The formulation is then dried and shaped into a tablet (containing about 20 mg of active compound) by a suitable tablet press. Composition for oral administration Amount of active compound 1-0 g Fumaric acid 0.5 g Sodium chloride 2.0 g P-Hydroxybenzoate 0.15 g Propyl hydroxybenzoate 0.05 g Crystal sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring agent 0.035 ml Coloring agent 0.5 mg Distilled water to 100 ml The ingredients are mixed to form a suspension for oral administration. Parenteral Ingredients Ingredients % w/w Active Ingredient 0.25 g Sodium Chloride Appropriate amount to achieve isotonic water for injection 100 ml The active ingredient is dissolved in a portion of water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution is isotonic. The solution weight was made up with the remaining water for injection, filtered through a 0.2 μm membrane filter and packaged under sterile conditions. 157102.doc •250- 201217379 Suppository Formulation % w/w Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5% The ingredients are mixed together and mixed on a steam bath, and poured into the containing 2.5 g total weight in the mold. Topical formulation ingredients Gram active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil 5 Paraffin fat 10 p-Hydroxybenzoate 0.15 p-hydroxybenzoate 0.05 BHA (butylated hydroxymethoxybenzene) 0.01 water Make up to 100

將所有成分（水除外）組合且在攪拌下加熱至約60°C。接著在約60°C下添加足夠量之水，同時劇烈攪拌以使成分乳化，且隨後添加水補足約100 g。鼻喷霧調配物將含有約0.025-0.5%活性化合物之若干水性懸浮液製成鼻喷霧調配物。調配物視情況含有非活性成分，諸如微晶纖維素、羧甲基纖維素鈉、右旋糖及其類似物。可添加鹽 157102.doc -251 - 201217379 酸以調節？11值。鼻喷霧調配物可經由通常每次致動傳遞約 50-100 μΐ調配物之鼻喷霧計量泵傳遞。典型的給藥時程為每4-12小時2-4次喷霧。實例31:活體外IRAK-1及IRAK-4檢定將經純化重組IRAK-4蛋白與250 μΜ合成肽 (KKARFSRFAGSSPSQSSMVAR)—起在 30 μΐ激酶緩衝液（包括 20 mM MOPS pH 7.2、25 mM β磷酸甘油酯、5 mM EGTA、1 mM正釩酸鈉、1 mM DTT、50 μΜ ATP、20 mM MgCl2、10 μ(：ί γ-33Ρ、0.1% BSA)中培育指定時間。經純化重組IRAK-1蛋白激酶檢定使用50 μΜ ATP。將反應混合物之25 μΐ等分試樣轉移至p81磷酸纖維素方格 (phosphocellulose square)(Upstate Biotechnology, Lake Placid，NY)上。檢定方格以0.75%磷酸洗滌三次且以丙酮洗滌一次。藉由液體閃爍計數測定結合放射能來量測酶活性。實例32 :活體外SYK激酶檢定脾臟酪胺酸激酶（SYK)為在B細胞信號轉導中起重要作用的酪胺酸激酶。藉由以[γ-33Ρ] ATP磷酸化肽受質（生物素-EPEGDYEEVLE)量測 SYK活性。在 20 μΜ具有 0.05 pCi [γ-33Ρ]ΑΤΡ之ΑΤΡ(40 μΐ檢定使用2 μ(：ί)及10 μΜ肽受質下在最終體積40 μΐ下於含有50 mM Hepes(pH 7.2)、1 mM二硫蘇糖醇、10 mM MgCl2、100 μΜ Na3V〇4、0.1% BSA及 10% DMSO之緩衝液中進行酶反應。使用人類全長SYK在有或無10種化合物濃度存在下進行酶檢定。將SYK與化合All ingredients (except water) were combined and heated to about 60 °C with stirring. A sufficient amount of water was then added at about 60 ° C while vigorously stirring to cause the ingredients to be emulsified, and then water was added to make up about 100 g. Nasal Spray Formulations A number of aqueous suspensions containing from about 0.025 to 0.5% active compound are formulated into nasal spray formulations. The formulation optionally contains inactive ingredients such as microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and the like. Salt can be added 157102.doc -251 - 201217379 Acid to adjust? 11 values. The nasal spray formulation can be delivered via a nasal spray metering pump that typically delivers about 50-100 μM of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours. Example 31: In vitro IRAK-1 and IRAK-4 assays Purified recombinant IRAK-4 protein with 250 μM synthetic peptide (KKARFSRFAGSSPSQSSMVAR) in 30 μL of kinase buffer (including 20 mM MOPS pH 7.2, 25 mM β-glycerol phosphate) Ester, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 50 μΜ ATP, 20 mM MgCl2, 10 μ (:ί γ-33Ρ, 0.1% BSA) were incubated for the indicated time. Purified recombinant IRAK-1 protein The kinase assay used 50 μΜ ATP. A 25 μΐ aliquot of the reaction mixture was transferred to a p81 phosphocellulose square (Upstate Biotechnology, Lake Placid, NY). The assay grid was washed three times with 0.75% phosphoric acid and Wash once with acetone. Enzyme activity was measured by binding to radioactivity by liquid scintillation counting. Example 32: In vitro SYK kinase assay Spleen tyrosine kinase (SYK) is a tyramine that plays an important role in B cell signaling. Acid kinase. SYK activity was measured by phosphorylation of peptide [γ-33Ρ] ATP (biotin-EPEGDYEEVLE) with 0.05 pCi [γ-33Ρ]ΑΤΡ at 20 μΜ (2 μ(40 μΐ assay) : ί) and 10 μΜ peptide under the quality of the final body Enzyme reaction was carried out in a buffer containing 50 mM Hepes (pH 7.2), 1 mM dithiothreitol, 10 mM MgCl2, 100 μΜ Na3V〇4, 0.1% BSA and 10% DMSO at 40 μL. Using human full-length SYK Enzyme assay in the presence or absence of 10 compound concentrations. Combine SYK with

157102.doc -252- S 201217379 物預培育ίο分鐘。接著，藉由添加ATP及肽受質開始酶促反應。在室溫下培育反應混合物3〇分鐘。在培育結束時，藉由將25 μΐ反應混合物轉移至1〇〇 μι含有1〇〇 m]VI EDTA之 1〇0/。抗生蛋白鏈菌素漿液中來終止反應。將反應產物捕捉於親和力樹脂上且在過濾板（Millip〇re，MABVNOB50)上以2 M NaC卜2 Μ含NaCl之1%磷酸及水依序洗滌以移除游離放射性核苷酸。接著，在微定量盤閃爍計數器上定量肽受質中併入33p之量。藉由ICm值量測化合物對SYK之抑制效能’其中ICm值由根據3參數模型擬合之10倍濃度抑制曲線產生：抑制最大值/(1+(IC50/[抑制劑])斜牟）。在用於參數估算之Microsoft Excel上分析資料。儘管本發明已參考其特定實施例加以描述，但熟習此項技術者應瞭解，可作出各種改變且等效物可經取代而不悖離本發明的真實精神及範鳴。此外，可作出許多修改以使特定狀況、材料、所關注組合物、方法、一或多個方法步驟適應本發明之目標精神及範疇。所有該等修改意欲在隨附申請專利範圍之範_内。 157102.doc •253-157102.doc -252- S 201217379 Pre-incubation ίο min. Next, the enzymatic reaction is initiated by the addition of ATP and peptide acceptor. The reaction mixture was incubated for 3 minutes at room temperature. At the end of the incubation, the 25 μΐ reaction mixture was transferred to 1〇〇0/ containing 1〇〇 m]VI EDTA. The reaction was stopped in a streptavidin slurry. The reaction product was captured on an affinity resin and washed sequentially on a filter plate (Millip〇re, MABVNOB50) with 2 M NaC 2 2 NaCl-containing 1% phosphoric acid and water to remove free radionucleotides. Next, the amount of 33p incorporated into the peptide substrate was quantified on a micro-quantitative disk scintillation counter. The inhibitory potency of the compound against SYK was measured by ICm value, where the ICm value was generated from a 10-fold concentration inhibition curve fitted according to the 3-parameter model: inhibition maximum/(1+(IC50/[inhibitor]) slant). Analyze the data on Microsoft Excel for parameter estimation. While the invention has been described with respect to the specific embodiments thereof, it will be understood that In addition, many modifications may be made to adapt a particular situation, material, composition of interest, method, method, or method. All such modifications are intended to be within the scope of the appended claims. 157102.doc •253-

Claims

201217379 VII. Patent application scope: 1. A compound of formula I or formula II,

Or a pharmaceutically acceptable salt thereof,

Wherein: X is N or CH; m is 1 or 2; Ar is. optionally substituted aryl; or optionally substituted heteroaryl; R1 is: hydrogen; C 1-6 alkyl; Cw alkoxy a hydroxy group; a thiol group; a C 1_6 alkyl group; an amine group - a C 1 -6 alkyl group; an amine group - a Ci_6 alkyl group - an amine group; a base group - a Ci_6 alkyl group; 157102.doc 201217379 C3-6 cycloalkylamino; Amino-C3-6 cycloalkylamino; Amino-(: 3-6 heterocycloalkylamino; Aminocarbonyl; Halo; Hydroxy-Cw alkyl; And a compound of claim 1, wherein R1 is: hydrogen; C a 6 alkyl; a broad oxy group; a hydroxy group; hydroxy-C..6 alkyl; Cw alkyl-amino; amino-J衮 alkyl; amino-Cw alkyl-amino; hydroxy-Cw alkylamino; C3-6 ^ m alkylamine An aminocarbonyl group; a halogen group; a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group, a hydroxy group Or a compound of 2, wherein m is 1. 5. A compound of claim 1 or 2 wherein Ar is substituted benzene 6. A compound according to claim 1 or 2, wherein Ar is a phenyl group which is independently selected from the group consisting of a hydrazine group, one or two or three times: a halogen group, a Ci6 hexyl group, a halo-Cm alkane C -6 alkenyl; Cw alkoxy; halo-C,-6 decyloxy; hydroxy-Cw alkyl; hydroxy-C, -6 alkylamino; Cw alkyl-amine; Amino group; amino-Cw alkyl group; aminocarbonyl group; hydroxy-Ci.6 decyloxy; thiol-(^1-6-based; 匚1.6 alkoxy-匚1-6 alkoxy group, 〇1_6炫1 157102.doc S 201217379 sulfonyl sulfhydryl; Cw alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally via hydroxy, amine, amine-Cw alkyl, hydroxy-Ci-6 Alkyl or aminocarbonyl substituted; phenylaminocarbonyl; hydroxy-Cw alkylamino; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Ci-6 alkyl group or a hydroxyl group. -Ci.6 alkyl substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cw alkyl; piperidinyloxy, wherein The piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Ci. 6 alkyl group, a hydroxy-Cw alkyl group. Or an aminocarbonyl group; a phenyl group, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino group -CN6 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a pyrrolidinyl group, wherein the pyrrolidinyl moiety Optionally substituted with a hydroxyl group, an amine group, an amino-Ck alkyl group, a hydroxy-Ck alkyl group or an aminocarbonyl group; a pyrrolidinyloxy group in which a pyrrolidinyl moiety is optionally subjected to a hydroxyl group, an amine group, an amine group-Cw alkane a hydroxy-C, .6 alkyl or aminocarbonyl group; a piperazinyl group, wherein the piperazinyl moiety is optionally substituted with a Ci-6 alkyl group; an oxazole-Ci.6 alkoxy group, wherein the oxazole thereof Partially substituted with Ci.6 alkyl; morpholino; hydroxy-Cm alkylaminocarbonyl; C3.6 cycloalkyl; azepanyl, wherein the azepanyl moiety is optionally a hydroxy group, an amine group, an amino group-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a benzyl group, wherein the phenyl moiety thereof is optionally an amino group, a hydroxyl group, an amine group-Cw alkyl group, or a hydroxyl group-Cm Alkyl or aminocarbonyl substituted; Cw alkoxycarbonyl-Cw alkoxy, and Cl.6 alkylamino. 7. The compound of claim 1 or 2, wherein Ar is a phenyl group substituted once with a halo group and substituted once with a group selected from the group consisting of: a dentate group; a Cu alkyl group; a halogen 157102.doc 201217379 base-Ci-6 Alkyl; Ci-6 alkyl; Ci-6 alkoxy, functional-Cl.6 alkoxy' hydroxy-Ci.6 alkyl; hydroxy-CU6 alkylamino; C..6 alkyl-amine Alkyl; hydroxy; amine; amine-Cw alkyl; aminocarbonyl; hydroxy-C!.6 alkoxy; hydroxy-Cm-alkenyl; Ck alkoxy 6 alkoxy; C!·6 alkyl sulfonate Sulfhydryl; Ci-6 alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally substituted by a benzyl group, an amine group, an amine group _Ci_6 danyl group, a thiol group or a carbonyl group ; phenylaminocarbonyl; hydroxy-Cl-6 alkylamino; cyclohexyloxy, wherein the cyclohexyl moiety is optionally substituted by hydroxy, amine, amino-Cw alkyl or hydroxy-Cw alkyl; a pentyloxy group in which a cyclopentyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino group-Ci-6 alkyl group or a hydroxy-Cw alkyl group; a piperidinyloxy group in which a piperidinyl moiety is optionally used By hydroxyl, amine, amino-Ci-6 alkyl, hydroxy-CN6 alkyl or amine carbonyl Substituent; phenyl, wherein the phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Cm alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a pyrrolidinyl group, wherein the pyrrolidinyl moiety is optionally a hydroxy, amine, amino-Cw alkyl, hydroxy-C alkyl or aminocarbonyl group; pyrrolidinyloxy, wherein the pyrrolidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group, a Cw alkyl group , hydroxy-Cw alkyl or aminocarbonyl substituted; piperazinyl, wherein the piperazinyl moiety is optionally substituted by Cw alkyl; oxazole-Cw alkoxy, wherein the oxazole moiety is optionally Ci. 6 alkane Substituent; morpholino; hydroxy-Cw alkylaminocarbonyl; C3.6 cycloalkyl; azepanyl, wherein the azepanyl moiety is optionally via a hydroxyl group, an amine group, an amine group - Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted; benzyl, wherein the phenyl moiety is optionally amino, hydroxy, amine-C -6 alkyl, 157102.doc -4-

201217379 Light-based - Ci_6 alkyl or amine gas group substitution, c] _6 oxooxyloxy, and C 1.6 alkyl phenylamine β 8 · Compound of claim 1 or 2, wherein Ar is selected The substituted aryl group from the group consisting of 2-(4-aminomethyl-piperidin-1-yl)-5-a-phenyl-phenyl; 2-(4-aminomethyl-piperidin-1-yl) 4-phenylaminoindenyl-phenyl; 5-nitrox-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl; 5-chloro-2-(4-hydroxyl Mercapto-piperidinyl-phenyl; 5- gas-2-(4-hydroxy-cyclohexyloxy)-phenyl; 5-chloro-2-piperidin-1-yl-phenyl; 2-(4 -aminomethyl-piperidine-1-yl)_5-chloro-phenyl; 2-[4-(1-amino-ethyl)-piperidin-1-yl]_5_qi·phenyl; 2_( 4-aminobutyryl-piperidin-1·yl)-5-chloro-phenyl; chloro-2-[3-(l-hydroxy-ethyl)-n-pyridyl-1-yl]-phenyl; 4'-Aminomethyl-4-chloro-biphenyl-2-yl; 5-Chloro-2-methoxy-phenyl, 3-amino-2-(4-aminoindenyl--bite-丨-yl)-phenyl; 3-amino-2-piperidine-l-yl-phenyl; 5-hydroxymethyl-2-piperidinyl-phenyl-phenyl; 4-chloro-41-hydroxymethyl -biphenyl-2-yl; 5_gas_2_isopropoxy-phenyl; 5_chloro-2-(3-hydroxymethyl-cyclopentyl) Oxy) phenyl; hongqi ^ — ^ specific pyridyl-phenyl; 5-chloro-2-(3-hydroxy·.cyclopentyloxy)-phenyl; 5-nitrox_2_(3_hydroxyl -propoxy)-phenyl; 5-chloro-2-(4-hydroxy-butoxy)-phenyl; 2-methoxy-4-phenylamine-methyl phenyl-phenyl; 5- _ 2-(3-hydroxy-piperidinyl)-phenyl, 5-chloro-2-(indolyl-4-yloxy)-phenyl; 4_gas_4,_trans-based-biphenyl- 2-yl; 5-gas-2-(3-hydroxy-pyrrolidinyl)-phenyl; 5-nitrox-2-(3,4-dihydroxy-butoxy)-phenyl; 5-gas _2_(4_Methylpiperazine·indolyl)·phenyl; 5-chloro-2-(oxazole-5-ylmethoxy)phenyl; 5-chloro-2-morpholine_4_yl -phenyl; 4-chloro-biphenyl-2-yl; 2-(3-aminomethyl-indolylpyridin-1-yl)_ 5-chloro-phenyl; 5-gas-2-(3 -trans-cyclohexyloxyphenyl; 4-(3_hydroxy I57102.doc 201217379-propylaminomethyl)-2-methoxy-phenyl; 5-gas-2-(3-hydroxyl) Base _ °pyrrolidin-1-yl)-phenyl; 5- gas-2-difluoromethoxy-phenyl; 5-gas_2·dimethylamino-phenyl; 2-(3- Amino-»byrrolidin-1-yl)-5-a-phenyl; 5-chloro-2-indolylthio-phenyl; 5-chloro-2-cyclohexyl-phenyl; 3-(2 -hydroxy-ethylamino)-2-piperidin-1-yl-phenyl; 5-aero-2-(4-methyl-oxazol-5-ylmethoxy)-benyl, biphenyl- 2-based; 5- gas-2-(3-carbyl-1,1-dimethyl-propoxy)-phenyl; 2-(4-amino-cyclohexyloxy)-5-a- Phenyl; 2-azepane-1-yl-5-chloro-phenyl; 4-(2-hydroxy-ethylamine decyl)_2-methoxy-phenyl; 4-hydroxy-cyclohexyl Oxy)-phenyl; 5-gas-2-(2-methoxy-ethoxy)-phenyl; 4-chloro-3,-hydroxy-biphenyl-2-yl; 5-bromo-2- F-oxy-phenyl; 5-chloro-2-[(2-hydroxy-ethyl)-indolyl-amino]-phenyl; 5-nitro-2-(4-hydroxy-phenoxy)-phenyl 4-aminomercapto-2-methoxy-phenyl; 5-chloro-2-isobutoxy-phenyl; 5- gas-2-(2,3-dihydroxy-propoxy)- Stupid base; 5-gas-2-(3-decyloxy-propoxy)-phenyl; 5- gas-2-(3-hydroxyindolyl-piperidin-1-yl)-phenyl; 5- Gas-2-(3-hydroxy-benzoinoxy; 5-aero-2,4-dimethoxy-phenyl; 2-decyloxy-5-vinyl-phenyl; 3-(3-hydroxyl -propylamino)_2_piperidin-1-yl-phenyl; 5-chloro-2-(4-hydroxy-butyl)-benyl, 2-[3-(1-amino-ethyl) - ° Bilo. 5-yl]-5-chloro-phenyl; 5-gas-2-[(3-hydroxy-propyl)-indolyl-amino]-phenyl; 5-gas-2-(4-methyl Aminoguanidino-piperidin-1-yl)-phenyl; 5-(3-hydroxy-propenyl)-2-methoxy-benyl, 5-chloro-2-ethyl-phenyl, 4 - 曱石石夤基-2-methoxy-stupyl; 5-gas-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl; 5- Fluor-2-nonyloxy-phenyl; 5- gas-2-phenoxy-phenyl; 5-(3-hydroxy-propyl)-2-nonyloxy-phenyl; 5-gas-2- (2-hydroxyindolyl-piperidine-1-157102.doc 201217379)-benton; 5-chloro-2-(4-dimethylaminopurine substrate 0 丨丨基 yl) phenyl; -decyloxy-biphenyl-4-yl; 5-ethyl-2-methoxy-phenyl; 5-methoxyoxy-2-nonyl-biphenyl-4-yl; 2-decyloxy- 3,5-dimercapto-phenyl; 4-dimethylaminoindenyl-2-methoxy-phenyl; 5-ethoxycarbonylamino-2-methoxy-phenyl, 5-chloro -2-methoxy-4-phenylamine-mercapto-phenyl; and 4-hydrazino-2-methoxy-phenyl; 3-(3-trans-cyclopentyloxy) _Naphthalene-2-yl; 3-(3-hydroxy-propoxy)-naphthalen-2-yl; 7-hydroxyindenyl-3-methoxy-naphthalen-2-yl; 3-(4-hydroxy- Ring Oxy) _ _2_ naphthyl group; and 3_ methoxynaphthalene _2_ group. 9. The compound of claim 1 or 2, wherein Ar is a substituted phenyl group selected from the group consisting of 2-(4-aminoindenyl-piperidin-1-yl)-5-chloro-phenyl; (4-Aminomethyl-piperidin-1-yl)-4-phenylamine fluorenyl-phenyl; 5-chloro-2_|; 4-(1-hydroxy-ethyl)-piperidine-1 ·-]phenyl; 5-chloro-2-(4-hydroxyindolyl-piperidin-1-yl)-phenyl; 5-chloro-2-(4-trans-cyclohexyloxy)-benzene 5-[4--2-dentyl-1-yl-phenyl; 2-(4-aminoindolyl-piperidinyl)-5-chloro-phenyl; 2-[4-(1-amino- Ethyl)-piperidinyl-1-yl]_5-chloro-phenyl; 2-(4-aminomethylindenyl-bottomidine)_5_gas-bensyl, 5-air- 2- [3-(l- Mercapto-ethyl)-. Ratio 11 σ _ 1-yl]-phenyl; 4 ·-aminomethyl-4-chloro-biphenyl-2-yl; 5-chloro-2-methoxy-phenyl; 3-amino -2-(4-Aminoguanidino-piperidin-1-yl)-phenyl; 3-amino-2-piperidin-1-yl-phenyl; 5-hydroxyindenyl-2-piperidine- 1-yl-phenyl; 4-a gas-4'-hydroxymethyl-biphenyl; 5- gas-2-isopropoxy-phenyl; 5- gas-2-(3-hydroxymethyl-ring Pentyloxy)-phenyl; 5-chloropyrrolidinyl-i-yl-phenyl; 5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl; 5-chloro-2- (3-hydroxy-propoxy)-phenyl; 5-aero-2-(4-hydroxy-butoxy)-phenyl; 2-methoxy-4-phenylamine-methyl-phenyl-phenyl; 5-Chloro-2-(3-hydroxy-piperidin-1-yl)-157102.doc 201217379 Phenyl; 5-Gas-2-(piperidin-4-yloxy)-phenyl; 4-Chloro- 4'-hydroxy-biphenyl-2-yl; 5-nitro-2-(3-trans- η-π ratio π each) phenyl; 5- gas-2-(3,4-dihydroxy-butyl Oxy)-phenyl; 5-gas-2-(4-methyl-piperazin-1-yl)-phenyl; 5-chloro-2-(oxazol-5-ylmethoxy)-phenyl 5-chloro-2-morpholin-4-yl-phenyl; 4-a-biphenyl-2-yl; 2-(3-aminomethylpyrrolidin-1-yl)-5-chloro- Phenyl; 5-gas-2-(3-hydroxy-cyclohexyloxy)- 4-(3-hydroxy-propylaminoindenyl)-2-decyloxy-phenyl; 5-gas-2-(3-hydroxyindolyl-«pyrrolidin-1-yl)-benzene 5-chloro-2-difluoromethoxy-phenyl; 5- gas-2-didecylamino-phenyl; 2-(3-amino-pyrrolidin-1-yl)-5- Gas-phenyl; 5-gas-2-mercaptothio-phenyl; 5-chloro-2-cyclohexyl-phenyl; 3-(2-hydroxy-ethylamino)-2-piperidine-1- Base-phenyl; 5_gas_2-(4-methyl-oxazol-5-ylmethoxy)-phenyl; biphenyl-2-yl; 5-gas-2-(3-hydroxy-1 ,1-dimethyl-propoxy)·stupyl; 2-(4-amino-cyclohexyloxy)-5-a-phenyl-phenyl; 2-azepane-1-yl-5- Chloro-phenyl; 4-(2-hydroxy-ethylaminoindenyl)-2-decyloxy-phenyl; 4-hydroxy-cyclohexyloxy)-phenyl; 5-nitrox-2-(2 -decyloxy-ethoxy)-phenyl; 4-gas-3,-hydroxy-biphenyl-2-yl; 5-bromo-2-indolyl-phenyl; 5-chloro-2-[( 2-hydroxy-ethyl)-indolyl-amino]-phenyl; 5-nitro-2-(4-hydroxy-phenoxy)-phenyl; 4-aminomethylcarbonyl-2-methoxyphenyl 5-oxo-2-isobutoxy-phenyl; 5-chloro-2-(2,3·dihydroxy-propoxy)-phenyl; 5-gas-2-(3-decyloxy-propenyl) Oxyphenyl; 5- -2-(3-hydroxymethyl-bottom-1-yl)-phenyl; 5-chloro-2-(3-hydroxy-benzoinoxy; 5-nitro-2,4-dimethoxy-phenyl; 2-decyloxy-5-vinyl-phenyl; 3-(3-hydroxy-propylamino)-2-piperidine-i-yl-phenyl; 5_gas_2_(4_hydroxy-but Phenyl; 2-[3-(1-amino-ethyl)-α-pyrrolidine-丨-yl]_5_gas-phenyl; 5-chloro-2[(3_157102.doc 201217379)- Methyl-amino]-benzene & 5_ gas is methylaminomethyl-dozen-1-yl)-phenyl; 5-(3-carbyl-propyl)_2-methoxy _phenyl; 5 gas-2-ethyl-phenyl; 4-decanesulfonyl-2-methoxy-phenyl; 5-nitro-2(3-hydroxyphenoxy)-phenyl; 2,4-dimethoxy-phenyl; 5-fluoro-2-methoxy-phenyl; 5-chloro-2-phenoxy-phenyl; 5-(3-hydroxy-propyl)_2_曱Oxy-phenyl; 5-gas-2-(2-transmethyl-cyano)-phenyl; and 5-gas-2-(4-dimethylaminomethyl-nirine bite_1_ Base)_ Stupid base.

10. The compound of claim 1 or 2, wherein Ar is optionally substituted heteroaryl. 11_ The compound of claim 1 or 2 wherein Ar is a heteroaryl group selected from the group consisting of: "pyridinyl;benzo[1,3]dioxolyl;quinolyl; 2_side Oxy-2,3·dihydro-indole; 4 丨朵; benzopyranyl; or oxime; each optionally substituted one or two times independently of the group selected below: Halo; c!_6 alkyl; halo-Ci-6 alkyl; CV6 alkenyl; Cw alkoxy, ifiyl-C 1 · 6 alkoxy, via -C 1.6 alkyl; 1 - 6 hexylamino group; Cb6 alkyl-amino group; hydroxy group; amine group; amino group - Cw alkyl group; aminocarbonyl group; hydroxy-Ck alkoxy group; hydroxy-Cw alkenyl group; Ci-6 alkoxy group alkyl-CN6 alkoxy; Cm alkylsulfonyl; Cw alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group, a hydroxyl group - Ci. Alkyl or aminocarbonyl substituted; phenylaminocarbonyl; hydroxy-Ci-6 alkylamino; cyclohexyloxy, wherein the cyclohexyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a CN6 alkyl group or a hydroxyl group. -Cw alkyl substituted; cyclopentyloxy, wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine 'amine group' Cw alkyl or hydroxy-Cw alkyl substituted; piperidinyloxy' wherein 157102.doc 201217379 slightly biti-based moiety is optionally hydroxy, amino, amine-Ci 6 alkyl, hydroxy-C!.6 Substituted with an aminocarbonyl group; a phenyl group, wherein the stupid moiety is optionally substituted with an amine group, a hydroxyl group, an amino-Ck alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; and a pyrrolidinyl group wherein the pyrrolidinyl group Partially substituted by hydroxyl group, amine group, amino-Cw alkyl group, hydroxy-Ci-6 alkyl group or aminocarbonyl group; ° ratio of each bite base, wherein the a hydroxy, amine, amino-Ck alkyl, hydroxy-Ci-6 alkyl or aminocarbonyl group; piperazinyl, wherein the piperazinyl moiety is optionally substituted by Cw alkyl; oxazole-Ck alkoxy 'wherein the oxazole moiety is optionally substituted by Cm alkyl; morpholinyl; hydroxy-Cw alkylaminocarbonyl; c3-6 cycloalkyl; azepanyl, wherein the azepanyl moiety is optionally Substituted by a hydroxyl group, an amine group, an amino-Ci-6 alkyl group, a hydroxy-Cm alkyl group or an aminocarbonyl group; a benzyl group in which a phenyl moiety thereof is optionally an amine group or a hydroxyl group -Cw alkyl group, hydroxy alkyl or -Cw substituted aminocarbonyl; Cw of -C 1 · 6 alkoxy group burning gas; and C 1 _ 6-ylamino burning several groups. 12. The compound of claim 1 or 2, wherein Ar is quinolyl which is optionally substituted once or twice with a group independently selected from the group consisting of CU6 alkyl; Cu alkoxy; hydroxy 6 alkoxy; a hydroxy-Cm alkylamino group; an amine-Cw alkoxy group; a cyclohexyloxy group in which a cyclohexyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group or a hydroxy-Cw alkyl group; a group wherein the piperidinyl moiety is optionally substituted with a hydroxy group, an amine group, an amine group, a thio-alkyl group or an amino group; and a piperidinyl group wherein the piperidinyl moiety is optionally Substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl; cyclopentyloxy, wherein ring 157102.doc -10· 201217379 pentyl moiety optionally via hydroxyl, amine , amino-Cw alkyl or hydroxy-C!-6 alkyl substituted; and pyrrolidinyloxy, wherein the pyrrolidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group-Ch6 alkyl group, a hydroxy-Cw alkyl group Or an aminocarbonyl group. 13. The compound of claim 1 or 2, wherein Ar is a quinoline-6-yl group substituted at the 7 position and optionally substituted at the 2 position: Cw alkyl, C 1 -6焼•oxy group, alkoxy groups via a base — C 1 -6 , a cis-C 1 -6 hexylamino group; an amine group—Cw alkoxy group; a cyclohexyloxy group in which a cyclohexyl moiety is optionally subjected to a hydroxyl group. Substituted with an amine group, an amino-Ci-6 alkyl group or a hydroxy-Cw alkyl group; a piperidinyl group, wherein the pyridyl group is optionally a hydroxy group, an amine group, an amine group-Ci_6 alkyl group, a carbyl group or Substituted with an amino group; wherein the piperidinyl moiety is optionally substituted with a hydroxyl group, an amine group, an amino-Cw alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a cyclopentyloxy group, Wherein the cyclopentyl moiety is optionally substituted by a hydroxyl group, an amine group, an amine group -CN6 alkyl group or a hydroxy-Cu alkyl group; and a pyrrolidinyloxy group, wherein the f is more than a pyridyl group, optionally via a hydroxyl group, an amine group, Amino-CN6 alkyl, hydroxy-Cw alkyl or aminocarbonyl substituted. 14_ The compound of claim 1 or 2 wherein Ar is a heteroaryl group selected from the group consisting of: 7-(4-aminoindolyl-piperidin-1-yl)-quinolin-6-yl; 2-( 2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl; 7-(4-hydroxy-cyclohexyloxy)-quinoline-6-yl; 7-methoxy-oxime 6-6-yl; 7-pin-1-yl-喧-lin-6-yl; 7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl; 7-(3-hydroxyl 1-nonyl-butoxy)-lipid-6-yl, 7-(3-carbyl-butoxy)-wolyl-6-yl; 7-(pyro- 4-yloxy) -啥琳-6-yl,7-(3-carbyl-l,l-dimethyl-propoxy)quine·157102.doc -11- 201217379 phenyl-6-yl; 7-(3-amine -propoxy)-quinolin-6-yl; 7-(3-hydroxy-cyclopentyloxy)-indolyl-6-yl; 7-(Nionbita-4-yloxy)-喧琳-6-yl; 7 _(3. hydroxy-propoxy)-quinolin-6-yl; 7-(pyrrolidin-3-yloxy)-quinolin-6-yl; 7-(4-hydroxyl Methyl-piperidin-1-yl)-quinolin-6-yl; 7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl; quinoline-6-yl; 5-(4-hydroxymethyl-lati-1-yl)-2-yloxy-2,3-dihydro-1H-indol-6-yl; 5-(4-hydroxymethyl-benyl) )-2-methyl- 1H-0 bow 丨 0 -6 - group; 2 - side oxy-5-0 bottom bite - 1_ yl-2,3 - nitro-1 Η-β 丨〇丨〇 -6-based; 6-methoxy Base-1H-0 丨° sit-5-yl; 5_methoxy-2-methyl-1Η-吲哚-6-yl; 5-methoxy-1Η-吲哚-6-yl; or hydroxy -propyl)-1Η-benzimidazol-2-yl. 15. The compound of claim i or 2, wherein each of the ranges is independently: hydrogen; Cl 6 alkyl; CU 6 alkoxy; hydroxy; hydroxy - Cw alkyl; Cw alkyl-amino; amine-Cw alkyl; amino-CN6 alkyl-amino; hydroxy-Cw alkylamino; C3-6 cycloalkylamino; halo; or aminocarbonyl . 16. The compound of claim 1 or 2, wherein each Ri is independently: hydrogen; hydroxy; 2-amino-ethyl)-methyl-amino; 2-amino-ethylamino; methyl; Methoxy; 2-hydroxy-ethyl)-fluorenyl-amino; hydroxyindenyl; 2-hydroxyindenyl-ethylamino; 2-cyclopropylamino; 2-hydroxy-ethylamino; 2,3-dihydroxy-propylamino; 3-amino-propylamino; amino group; 2-hydroxy-ethyl)-isopropyl-amino; bromo; isobutylamino; Isopropyl-methyl-amino; 3-hydroxy-propylamino; 1-hydroxymethyl-propylamino; 2-hydroxy-ethyl; 2-ethenylamino-ethylamine; 3-hydroxy-propyl; or isopropyl-amino. 17. The compound of claim 1, wherein the compound has the formula Ia*IIa: 157102.doc 201217379

Wherein: R3 and R4 are each independently: halo; Cu alkyl; halo-Cw alkyl; Cw alkenyl; Cu alkoxy; halo-Cu alkoxy; hydroxy-CN6 alkyl; hydroxy-C !.6 alkylamino group; Cw alkyl-amine group; hydroxyl group; amine group, amine group -C 1.6 alkyl group; amino group; base group -C 1 alkoxy group, via group - (^1_6 thin. (1!1.6 alkoxy-〇^1-6 alkoxy; 匚1.6 alkyl base; <^-6 alkylthio; piperidinyl, wherein the piperidinyl moiety is optionally a hydroxy group, an amine group, an amino group-Cp6 alkyl group, a hydroxy-Cw alkyl group or an aminocarbonyl group; a phenylaminocarbonyl group; a hydroxy-Cw alkylamino group; a cyclohexyloxy group, wherein the cyclohexyl moiety is optionally a hydroxy, amine, amino-Ck alkyl or hydroxy-Cw alkyl group; cyclopentyloxy, wherein the cyclopentyl moiety is optionally via a hydroxyl group, an amine group, an amine group -Cw alkyl group or a oxindole-CN6 group. Alkyl substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally substituted with a hydroxy, amine, amino-Cw alkyl, hydroxy-Cw alkyl or aminocarbonyl group; phenyl, wherein the phenyl moiety Amino, hydroxy, amino-Cw alkyl, hydroxy-Cw alkyl, as appropriate Aminocarbonyl substituted; pyrrolidinyl, wherein the pyrrolidinyl moiety is optionally substituted by hydroxyl, amine, amino-Cw alkyl, hydroxy-Ci-6 alkyl or amino group; Wherein the 11 ratio 157102.doc •13· 201217379 The pyridine group is optionally substituted by a hydroxyl group, an amine group, an amino group-Cw alkyl group, a thio-Ci.6 alkyl group or an amine carbonyl group; The thiol moiety is optionally substituted by C!·6 alkyl; oxazole-CN6 alkoxy, wherein the oxazole moiety is optionally substituted by (^-6 alkyl; morpholinyl; hydroxy-Cm alkylamino a C3_6 cycloalkyl group; azacycloheptyl, wherein the azepanyl moiety is optionally via a hydroxyl group, an amine group, an amine group _c16 alkyl group, a hydroxy-C!.6 alkyl group or an amine group. a carbonyl group; a benzyl group in which a phenyl moiety is optionally substituted with an amine group, a hydroxyl group, an amino group -C16 alkyl group, a hydroxy-Ci 6 alkyl group or an aminocarbonyl group; and a C,-6 alkoxycarbonyl group _Cl6 alkoxy group And a compound of claim 17, wherein R4 is a halo group. 1 Compound, wherein the compound has the formula lb or lib:

Lb ; wherein: r5 and R6 are each independently: hydroalkyl; C]-6 alkenyl; CVdi, halo, (1; 1_6 alkyl; halo-(^1.6^yl, functional-Ci-6 Oxyl; 157102.doc -14- 201217379 yl-C,.6 alkyl; hydroxy-Ci.6 alkylamino; Cu6 alkyl-amine; hydroxy; amine; amine-CN6 alkyl; amine Alkylcarbonyl; hydroxy-Ci-6 alkoxy; hydroxy-CN6 alkenyl; CN6 alkoxy-Cw alkoxy; CN6 alkylsulfonyl; Cw alkylthio; piperidinyl, wherein the piperidinyl Partially substituted with hydroxy, amine, amino-Ci.6 alkyl, hydroxy-Cw alkyl or aminocarbonyl; phenylaminocarbonyl; hydroxy-CN6 alkylamino; cyclohexyloxy, wherein The cyclohexyl moiety is optionally substituted by a hydroxyl group, an amine group, an amino group-C alkyl group or a hydroxy-Cw alkyl group; a cyclopentyloxy group in which a cyclopentyl moiety is optionally a hydroxyl group, an amine group or an amine group-Cw Alkyl or hydroxy-(^.6 alkyl substituted; piperidinyloxy, wherein the piperidinyl moiety is optionally via a hydroxyl group, an amine group, an amine group - a Cw alkyl group, a hydroxy group - a 6 alkyl group or an amine Substituted by a carbonyl group; a phenyl group, wherein the phenyl moiety is optionally an amine group a hydroxyl group, an amino-Ci-6 leukoyl group, a substituted group based on a —Ci-6 alkyl group or an amino group; a β-pyridyl group, wherein the pyrrolidinyl moiety is optionally a hydroxyl group, an amine group or an amine group-C. |_6 炫, substituted by a phenyl group or an amino group; 吼11 each β-based oxy group, wherein the ratio of a little bite base is via a base group, an amine group, an amine group-Ci_6, a base group, and a base group. C|_6 alkyl or amino group substitution; ° azine group, wherein the part of the Qin group is replaced by the C 1 - yard base; 恶. sit-C! -6 oxy, which is evil The azole moiety is optionally substituted by a Cm alkyl group; a phenanthrenyl group; a hydroxy-C!-6 alkylaminocarbonyl group; a C3·6 cycloalkyl group; an azepanyl group, wherein the azacycloheptyl group is partially regarded In the case of a hydroxyl group, an amine group, an amine group-Cl-6 alkyl group, a light group-Cl-6 alkyl group or an amine group, a benzyl group, wherein the phenyl moiety thereof is optionally an amine group, a hydroxyl group or an amine group. _cN6, hydroxy-Cw alkyl or aminocarbonyl substituted; Cw alkoxycarbonyl-Ck alkoxy 157102.doc 201217379; or hydrazine, 6 alkylcarbonylamino; and R1 as claimed in 1, 2 As stated in any of 15 or 16. 20. 21. 22. 23. 24. 25. 26. 27. 28. The compound of claim 1 which is selected from the group consisting of compounds 1 to 93 in Table 1. A composition comprising: (a) a pharmaceutically acceptable carrier; and (b) A compound according to any one of claims 1 to 2, wherein the use of a compound according to any one of claims 1 to 2 is for the manufacture of a medicament for the treatment of arthritis. Use of a compound according to any one of 20 for the manufacture of a medicament for the treatment of a respiratory condition selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma and bronchospasm. Use of a compound according to any one of claims 1 to 2 for the manufacture of a medicament for the treatment of a disease or condition mediated by the IRAK receptor or otherwise associated with the IRak receptor. Use of a compound according to any one of claims 1 to 2 for the treatment of a medicament for the treatment of a disease or condition mediated by the syk receptor or otherwise associated with the SYK receptor. The compound of any one of items 1, 2 and 17 to 20 for use in the treatment of an inflammatory or autoimmune condition. A compound according to any one of claims 1, 2, and 17 to 20, which is used for the treatment of any of the conditions as described in claim 23. The use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of an inflammatory or autoimmune disorder. 157102.doc S 16 201217379 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula:

157102.doc