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TW200417546A - New compounds - Google Patents

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Publication number
TW200417546A
TW200417546A TW092133696A TW92133696A TW200417546A TW 200417546 A TW200417546 A TW 200417546A TW 092133696 A TW092133696 A TW 092133696A TW 92133696 A TW92133696 A TW 92133696A TW 200417546 A TW200417546 A TW 200417546A
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Taiwan
Prior art keywords
bipyridin
aniline
urea
anilino
alkyl
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TW092133696A
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Chinese (zh)
Inventor
Niklas Plobeck
Britt-Marie Swahn
Elisabet Kallin
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Astrazeneca Ab
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Publication of TW200417546A publication Critical patent/TW200417546A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention relates to new compounds of formula I, wherein: R1 is aryl or heteroaryl, each of which is optionally substituted with one or more of R3, OR3,OCOR3,COOR3,COR3,CONR3R4,NHCOR3,NR3R4,NHSO2R3,SO2R3,SO2NR3R4,SR3,CN,halogeno or NO2; R2 is R5,R6,COR5,COR6,CONHR5,CONHR6, CON(R6)2,COOR5,COOR6,SO2R5 or SO2R6; a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

200417546 玖、發明說明： 【發明所屬之技術領域】 本發明係關於新穎说淀衍生物，其可用於治療各種病症。 本發明係關於製造此等化合物之方法。本發明亦提供包含 本發明化合物之醫藥組合物，及在各種病症之治療上利用 此等組合物之方法。 【先前技術】 蛋白質激酶為胞内發出訊息途徑之重要成份，且激酶係涉 及多種細胞功能之調節。MAP激酶發出訊息途徑係藉由許 多細胞表面受體之銜接而被活化。JNK途徑為此等途徑之一 ，其係藉由應力或預發炎細胞活素而被專一性地活化。活 化劑包括LPS、細胞活素腫瘤壞死因子（TNF-α)與間白血球活 素-1 (IL-1)、滲透衝擊、化學應力及UV輕射（Cohen，P. Trends in Cell Biol· 7 : 353-361 1997)。JNK途徑之標的包括多種轉錄因子，譬 如但不排外地為 c-jun 與 ATF-2 (Whitmarsh，A·與 Davis，R. J. Mol· Med· 74 : 589-607 1998)。 三種不同基因·· INK1、JNK2及JNK3 ;使酵素之JNK族群編 碼。此等基因之替代疊接形式可獲致10種不同異構重組物 :四種關於JNK1，四種關於JNK2，及兩種關於JNK3 (Gupta，S. 等人，EMBO J. 15 : 2760-2770 1996)。JNK1 與 JNK2 係遍佈地表現 於人類組織中，然而JNK3係選擇性地表現於腦、心及睪丸 中（Dong，C·等人，Science 270 : 1-4 1998)。 JNK 1、2及3已在老鼠中，單一及合併地被此等激酶之顯 性負形式之基因缺失及/或轉基因表現兩者，選擇性地剔除 89385 200417546 (Dong，C.等人，Science 282 : 2092-2095, 1998 ; Yang，D·等人，Immunity 9 :575-585 1998 ; Dong，C.等人，Nature405 : 91-942000 ; Yang，D·等 人，Nature 389 : 865-870 1997)。具有JNK3基因標的分裂之老鼠 係正常地發育，並被保護而免於刺激毒素所引致之神經元 細胞凋零。此項發現指出JNK3之專一抑制劑可有效治療特 徵為細胞死亡之神經病症，譬如阿耳滋海默氏疾病與中風 。在無論是JNK1或2中分裂之老鼠亦正常地發育。得自任一 類型老鼠之末梢T細胞可經活化以製造IL2，但在兩種情況 中，於Thl細胞發展上有一項缺陷。在JNK1 -/-老鼠之情況中 ，此係由於無法製造7干擾素（Thl細胞分化所必須之關键細 胞活素）。對照上而言，JNK2 -/-老鼠會製造干擾素r，但未 能對此細胞活素有回應。在T細胞生物學（正常IL2生產，但 阻斷Thl細胞分化）中之類似缺陷，係在MKK7基因中分裂之 T細胞中見及，確定JNK途徑在T細胞分化中之角色（Dong，C. 等人，Nature 405 : 91-94 2000)。 JNK亦在細胞凋零中扮演一項主要角色（Davis，RJ. Cell. 103 : 239-252, 2000)。JNK為對於UV所引致經過細胞色素C所媒介途 徑之細胞洞零所必須（Toumier，C·等人，Science 288 : 870-874 2000) 。絕血及與再灌注結合之絕血以及限制血液流動本身，已 被証實係伴隨著JNK之活化作用。細胞死亡可以被轉染至細 胞中之JNK顯性負形式預防，証實JNK在特徵為應力所引致 之細胞凋零之症狀上之可能利用性。 JNK途徑之活化作用已在許多人類腫瘤與經轉變細胞系中 被發現（Davis，RJ· Cell· 103 ·· 239-252, 2000)。事實上，JNK 之主要 89385 200417546 標的之一，c-jun，最初係經確認為致癌基因，顯示此途徑參 與未經調節細胞生長之可能性。JNK亦會調節p53之磷醯化 作用，且因此調制細胞循環進展（Chen T·等人，Mol· Carcinogenesis 15 : 215-226, 1996)。因此，JNK之抑制在一些人類癌症中是有 益的。 以目前知識為基礎，JNK發出信號，尤其是JNK3，係牽連 神經變性疾病之領域，譬如阿耳滋海默氏疾病、巴金生氏 病、ALS、亨丁頓氏疾病、外傷性腦部傷害以及絕血性與出 血性中風。因此，對可用於治療各種與JNK活化作用有關聯 症狀之JNK專一抑制劑，有高而未達到之醫療需求。 【發明内容】 已發現式I化合物，其係為經取代之吡啶化合物，為特別 有效且於是適合各種症狀之治療。 於一方面，本發明係關於通式I化合物200417546 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to novel said lake derivatives, which can be used to treat various diseases. The present invention relates to a method for making such compounds. The present invention also provides a pharmaceutical composition comprising a compound of the present invention, and a method for using these compositions for the treatment of various disorders. [Prior art] Protein kinases are important components of the intracellular signaling pathway, and kinases are involved in the regulation of a variety of cellular functions. The MAP kinase signaling pathway is activated by the engagement of many cell surface receptors. The JNK pathway is one of these pathways, which is specifically activated by stress or pre-inflammatory cytokines. Activators include LPS, cytokine tumor necrosis factor (TNF-α) and interleukin-1 (IL-1), osmotic impact, chemical stress, and UV light (Cohen, P. Trends in Cell Biol · 7: 353-361 1997). The target of the JNK pathway includes a variety of transcription factors such as, but not exclusively, c-jun and ATF-2 (Whitmarsh, A. and Davis, R. J. Mol. Med. 74: 589-607 1998). Three different genes: INK1, JNK2, and JNK3; encoding the JNK population of enzymes. Alternative splicing forms of these genes can result in 10 different heterologous recombinants: four for JNK1, four for JNK2, and two for JNK3 (Gupta, S. et al., EMBO J. 15: 2760-2770 1996 ). The JNK1 and JNK2 lines are widely expressed in human tissues, while the JNK3 lines are selectively expressed in the brain, heart, and testes (Dong, C. et al., Science 270: 1-4 1998). JNK 1, 2, and 3 have been selectively eliminated in mice, both individually and in combination, by a dominant negative form of these kinases and both gene deletions and / or transgenic expression, 89385 200417546 (Dong, C. et al., Science 282: 2092-2095, 1998; Yang, D. et al., Immunity 9: 575-585 1998; Dong, C. et al., Nature 405: 91-942000; Yang, D. et al., Nature 389: 865-870 1997 ). Divided mice bearing the JNK3 gene target develop normally and are protected from neuronal cell decay caused by toxin stimulation. This finding indicates that a specific inhibitor of JNK3 is effective in treating neurological disorders characterized by cell death, such as Alzheimer's disease and stroke. Mice that split in either JNK1 or 2 also developed normally. Peripheral T cells obtained from either type of mouse can be activated to make IL2, but in both cases there is a defect in the development of ThI cells. In the case of JNK1-/-mice, this is due to the inability to produce 7 interferon (a key cytokine necessary for ThI cell differentiation). In contrast, JNK2-/-mice produced interferon r but failed to respond to this cytokine. Similar defects in T cell biology (normal IL2 production, but blocking Th1 cell differentiation) are seen in T cells that divide in the MKK7 gene and determine the role of the JNK pathway in T cell differentiation (Dong, C. Et al., Nature 405: 91-94 2000). JNK also plays a major role in cell decay (Davis, RJ. Cell. 103: 239-252, 2000). JNK is necessary for zero cell holes induced by UV through the cytochrome C-mediated pathway (Toumier, C. et al., Science 288: 870-874 2000). Hemostasis and hemorrhage combined with reperfusion and restriction of blood flow itself have been shown to be accompanied by the activation of JNK. Cell death can be prevented by the dominant negative form of JNK transfected into cells, confirming the possible availability of JNK in the symptoms of cell dysfunction characterized by stress. The activation of the JNK pathway has been found in many human tumors and transformed cell lines (Davis, RJ · Cell · 103 ·· 239-252, 2000). In fact, one of JNK's main 89385 200417546 targets, c-jun, was originally identified as an oncogene, suggesting the possibility of this pathway participating in unregulated cell growth. JNK also regulates the phosphorylation of p53, and thus regulates cell cycle progression (Chen T. et al., Mol. Carcinogenesis 15: 215-226, 1996). Therefore, inhibition of JNK is beneficial in some human cancers. Based on current knowledge, JNK sends signals, especially JNK3, that are involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, traumatic brain injury, Hemostasis and hemorrhagic stroke. Therefore, there is a high unmet medical need for JNK-specific inhibitors that can be used to treat a variety of symptoms associated with JNK activation. [Summary of the Invention] The compound of formula I, which is a substituted pyridine compound, has been found to be particularly effective and thus suitable for the treatment of various symptoms. In one aspect, the invention relates to compounds of formula I

其中： R1為芳基或雜芳基，其每一個係視情況被一或多個R3、or3 、OCOR3、COOR3、COR3、CONR3R4、NHCOR3、NR3R4、NHS02R3 、S〇2R3、S02NR3R4、SR3、CN、鹵基及N02取代； R2 為 R5、R6、COR5、COR6、CONHR5、CONHR6、CON(R6)2、COOR5 89385 200417546 、C〇〇r6、8〇2^5或 s〇2R6 ; R3與R4各獨立為氫、Cb6烷基、c2-6晞基、c2_6炔基、〇3_8環 烷基、（C3_8環烷基烷基、雜環、雜環Cl_6烷基、（^乂氟 垸基、Ci_6三氟烷氧基； R5為芳基或雜芳基，其每一個係視情況被一或多個R7、〇R7 、OCOR7、COOR7、COR7、CONR7R8、CONHOR7、NHCOR7、NR7R8 、NHS02R7、S02R7、S02NR7R8、SR7、R7SR8、CN、鹵基、 氧及N02取代； R6為氳、CV6烷基、〇3_8環烷基、（(^3_8環烷基）Cu烷基、雜 環、雜環Ci_6烷基、雜芳*Cl-6烷基、芳基Cl_6烷基、Ci 6烷 氧基或C^6晞基，其中任何Cl 6烷基、（^3 8環烷基、（(：3 8環 垸基）Ch烷基、雜環、雜環Ci6烷基、雜芳*Ci6烷基、芳 基。-6貌基、Ci-6烷氧基及c2_6烯基，係視情況被一或多個 A取代； R7與R8各獨立為氫、Cl_6烷基、C3_8環烷基、（C3 8環烷基）Ci 6 燒基、C^6烯基、芳基、雜芳基、雜芳基心^烷基、雜環、 雜環q—6烷基、芳基、〇1-6氟烷基及Cl-6氯基烷基，其中任 何垸基、c3-8環烷基、（c3_8環烷基）Ci_6烷基、C2_6烯基 、雜芳基、雜芳基Cl_6烷基、雜環及雜環Ci-6燒基，係視情 況被一或多個B取代； R9與R1G各獨立為氫、Ci_6烷基、〇3_8環烷基、（C3_8環烷基）Ci6 燒基、C2_6烯基、雜環、雜環烷基、雜芳基、雜芳基(^_6 虎基、芳基或芳基Cl_6烷基，其中任何烷基、0：3-8環烷 基、扣3 -8環燒基_ 6燒基、c2 - 6烯基、雜環、雜環C! _ 6垸基 89385 -10- 200417546 、雜芳基、雜芳基Cl.6縣、芳基或芳基Ci 6垸基，係視情 況被一或多個B取代； A 為 R、OR9、〇C〇R9、c〇〇R9、c〇r9、c〇嫌9r1。、⑺丽〇R9 、NHCOR9、NR9Rl〇、服93〇2汉10、s〇2R9、s〇2nr9r1〇、张9、 R9SR10、CN或鹵基； B為Ch燒基、Cl_6燒氧基、Ci_6燒胺基、二燒基）胺基 或鹵基； 作為其自由態驗或鹽。 下又所列7F者為在本專利說明書與申請專利範圍中用以說 明本發明之各種術語之定義。 為避免疑惑，應明瞭的是，在本專利說明書中，於一種基 團又雨文足我或”定義於前文”限定之情況下，該基團係 涵盍第一次出現且最寬廣之定義，以及對該基團之每一個 及所有較佳定義。 為避免疑惑，應明瞭的是，在本專利說明書中，”c卜6，f係 意謂石炭基，具有1，2,3,4,5或6個碳原子。 在本專利說明書中，除非另有述及，否則，，烷基”一詞係包 括直鏈與分枝鏈乾基兩者。燒基可為甲基、乙基、正· 丙基、異-丙基、正_ 丁基、異-丁基、第二-丁基、第三-丁 基、正-戊基、異-戊基、第三-戊基、新-戊基及己基。 在本專利說明書中，除非另有述及，否則’，C3_8環烷基，，一 巧’係包括非芳族完全飽和環狀脂族烴基，含有3至8個原 子。該環fe基之實例，包括但不限於環丙基、環丁基、環 戊基及環己基。 89385 -11· 200417546 、本又中使用&lt; I烷氧基”一詞，除非另有述及，否則係包 括”…基圈，丨中，，境基”係如前文定義。C16垸氧基可 為甲氧基、乙氧基、正-丙氧基、異·丙氧基、正-丁氧基、 異-丁氧基、第二_ 丁氧基、第三_ 丁氧基、正_戊氧基、異· 戊氧基、第三戊氧基、新-戊氧基、己氧基。cl-6三氟坡氧 基表示被三個氟原子取代之q_6垸氧基。 4係有利地扣具有2至5個碳原子，較佳為3至4個碳原子之 鏈。c2.6缔基可為乙婦基、丙晞基、2_甲基丙㈣、丁缔基 及2- 丁錦·基。 在本專利說明書中，除非另有述及，否則&quot;婦基”一詞係包 括直鏈與分枝鏈缔基兩者，但對個別烯基之指稱，譬如2_丁 少布基’係僅專指直鏈變型。除非另有述及，否則”稀基”一 在本專利說明書中，除非另有述及，否則，，炔基”一詞係包 括直鏈與分枝鏈炔基兩者，但對個別炔基之指稱，譬如孓丁 炔基，係僅專指直鏈變型。除非另有述及，否則，，炔基，，一 闷係有利地指具有2至5個碳原子，較佳為3至4個碳原子之 鏈。 在本專利說明書中，除非另有述及，否則”雜環，，一詞係包 括3-至10-員非芳族部份或完全飽和烴基兩者，其含有一或 兩個環，及至少一個雜原子。該雜環之實例，包括但不限 於四氫吡咯基、四氫吡咯酮基、六氫吡啶基、六氫吡畊基 、嗎啉基、嘮唑基、2-呤唑啶酮基、四氫哌喃基或四氫呋 喃基。 在本專利說明書中，除非另有述及，否則”芳基，，一詞可為 89385 -12- 200417546 C6 cM万狹烴’且包括但不限於苯、茬、茚、蒽、菲。 、在。本^專利祝明書中，除非另有述及，否則&quot;雜芳基，，一詞可 =單衣狀_万秩或雙環狀稠合環雜芳族基團。該雜芳基之 貝例’包括但不限於吡啶基、吡咯基、呋喃基”塞吩基、 咪唆基、口号口坐其 田w ^ 丞、井，唑基、噻唑基、嘧二唑基、吡唑基 田I Μ ^基' 4’基_4,5,6,7,氫小苯并味喃基、♦来基、 表并米吱基、2_酮基苯并ρ号嗤基、塔咬基、喃淀 基、吡畊基、四唑基或三唑基。 f本專利說明書中’除非另有述及，否則鹵基一詞可為氟 、氯、溴或碘。 ^在本專利說明書中，除非另有述及，否則&quot;Ch氟烷基”一 5 口為被或夕個氟原子取代之烷基。該氟烷基之實例， 匕括仁不限於單氟基甲i、三氟甲基、二氟甲基及三氟乙 基0 在本專利說明書中，除非另有述及，否則，，Ch氯基烷基，， 一同可為被一或多個氯原子取代之烷基。該氯基烷基之實 例’包括但不限於單氯甲基、三氯甲基、二氯甲基及三氯 乙基。 於本發明之一方面，係提供式I化合物，其中R1為芳基或 雜万基，視情況被一或多個R3、〇R3、nr3r4、商基或N〇2取 代； R 為 R、R6、C〇R5、c〇r6、c〇nhr5、c〇丽r6、c〇〇r6 或 s〇2R6 ; R:與R4各獨立為氫、烷基或c卜6氟烷基； R為方基或雜芳基，其每一個係視情況被/或多個R7、〇R7 89385 -13- 200417546 、COOR7、COR7、CONHOR7、NR7R8、S02R7、S02NR7R8、SR7 、鹵基、氧及no2取代； R6為氮、Ci - 6燒基、（C3 - 8元基）Ci_ 6虎基、雜環、雜環q 6 燒基，其中任何Ci -6健基、（A - s環燒基_6燒基或雜環係視 情況被一或多個A取代； R7與R8各獨立為氫、烷基、C3_8環烷基、芳基、雜環， 其中任何(^_6烷基係視情況被一或多個B取代； R9與R1 Q各獨立為氮或Ci _6纟元基’其中任何Ci _6燒基係視情況 被一或多個B取代； A為 COOR9、COR9、CONR9R10、NHCOR9、NR9R1()、SR9、R9SR10 或CN ; B為鹵基或二（Cu烷基）胺基。 於本發明之另一方面，其係提供式I化合物，其中Rl為芳 基，視情況被一或多個R3、OR3及NR3R4取代。 在此方面之一項具體實施例中，其係提供式j化合物，其 中R為方基’而該芳基為苯基。 於本發明之又另一方面，其係提供式I化合物，其中R3係 選自C1-6氟烷基、甲基及齒基。 於本發明之又另一方面，其係提供式I化合物，其中R2係 選自 R5、COR5 及 CONHR5。 在此方面之一項具體實施例中，其係提供式1化合物，其 中R為芳基’視情況被一或多個r7、〇r7、coopj、COR7、 C〇NH〇R7、nr7r8、s〇2R7、s〇2Nr7r8、sr7、自基、氧及n〇2 取代。 89385 14- 200417546 在此方面之另一項具體實施例中，其係提供式I化合物， 其中R7與R8各獨立為氫、G _6燒基、c3 _ 8環燒基、芳基、雜 環’其中Ci —6烷基係視情況被一或多個B取代，該B為画基。 於本發明之又另一方面，其係提供式j化合物，其中R2係 選自 R6、COR6、CONHR6 及 S02R6。 在此方面之一項具體實施例中，其係提供式I化合物，其 中R6係選自氫、Ci_6烷基、（Ch環烷基）Ch烷基、雜環、雜 烷基，其中任何烷基、（Cw環烷基）Ci_6烷基及雜 環係視情況被一或多個A取代。 在此方面之另一項具體實施例中，其係提供式I化合物， 其中該 A 係選自 COOR9、COR9、CONR9R1〇、NHC〇R9、¥〇 、SR9、R9SRl〇及CN;且R^Rl0各獨立為氫或CH燒基。 本發明係關於如前文定義之式][化合物以及其鹽之用途。 供使料醫藥配方中之鹽係為藥學上可接受之Μ，但其他 I可用表產生式I化合物。此種鹽可能 酸與驗加成鹽。式工化合物之適當藥學上可接受鹽 夠鹼性〈式I化合物之酸加成鹽，例如與無機或有機酸譬如 -酸《酸加成鹽，或例如足夠酸性之式1化合物之鹽，例如 鹼金屬或鹼土金屬鹽，或與有機鹼之鹽。 、、本I明之另一項具體實施例中，其係提供呈藥學 上可接受鹽形式之式I化合物。 7!=式1化合物可具有對掌中心及/或幾何異構中心(Ε-鱼 二構物），且應明瞭的是，本發明係涵蓋所有此種光學、、 非對映異構物及幾何異構物。 89385 -15- 200417546 本發明之某些化合物可以互變異構物存在。應明瞭的是， 本發明係涵蓋所有此種互變異構物。 特定式I化合物為·· N，Nf-雙[4-(三氟甲基）苯基]_4,4’·聯吡啶-2,2，_二胺； N，N’-雙（4-氟苯基）-4,4’-聯吡啶-2,2’-二胺； N，Nf-雙（3,4-二氣苯基）_4,4’_聯 p比淀-2,2f-二胺； N，N’-雙[3-(三氟甲基）苯基]-4,4f-聯吡啶_2,2，-二胺； N，N’-雙[3-(三氟甲氧基）苯基]-4,4f-聯吡啶_2,2，-二胺； N，N’-雙（2-氟苯基）-4,4’-聯吡啶-2,2f-二胺； N，N’-雙（2-甲基苯基）-4,4f-聯吡啶-23-二胺； N，N’-雙（2-胺基苯基）-4,4’-聯吡啶-2,2’-二胺； N，Nf-雙（2-甲氧苯基）-4,4’-聯吡啶-2,2’-二胺； N，Nf-雙（2-乙氧苯基）_4,4’-聯吡啶-2,2’-二胺； N-(2’-苯胺基-4,4’-聯叶1：淀-2-基）-反式-4-甲氧基環己燒叛酿胺； N-(2’-夺胺基W，#-聯外t*淀-2-基）-順式-4-甲氧基環己燒致酿胺； N-{2f-[(4-氟苯基）胺基]-4,4f-聯外1：淀-2_基}-反式甲氧基_環己燒 羧醯胺； N_{2’-[(4-氟苯基）胺基]-4,4’-聯叶1：症-2-基卜順式冰甲氧基_環己燒 羧醯胺； N-(6-甲基吡啶-2-基）·Ν，_苯基-4,4，-聯吡啶-2,二胺； Ν-苯基-Ν4比啶-2-基-4,4’-聯吡啶-2，Τ-二胺； N_{4-[(4-甲基六氫^: _ -1-基）續驗基]笨基卜N，_苯基_4,4，-聯被淀-2,2’_二胺； N-苯基-N’-p比淀-3-基-4,4’-聯外匕淀-2,2 , 89385 -16 - 200417546 N-苯基-N1-喊啶-2-基-4,4’-聯吡啶-2,2，-二胺； N-苯基-NU密啶_5-基-4,4’-聯吡啶_2,2，-二胺； (2E) 1 {4 [(2冬胺基_4,4 -聯峨淀-2-基）胺基]苯基}-3-(二甲胺基）丙 -2-稀-1-酉同； 4-[(2f-苯胺基-4,4f-聯吡啶-2-基）胺基]善(2-四氫吡咯小基乙基）苯 續酸胺； 4-[(2’-苯胺基-4,4f-聯吡啶-2-基）胺基]-N-(2-嗎福啉-4-基乙基）苯績 醯胺； N-{4-[(4-乙基六氫吡啡小基）績醯基]苯基卜Ν’_苯基_4,4L聯吡啶_ 2,2’·二胺； N-苯基-N1-吡啶-4-基-4,4f-聯吡啶-2,2，-二胺； N-(2’_苯胺基-4,聯吡啶-2-基）四氫呋喃-3-羧醯胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基）各六氫吡啶小基丙醯胺； N-(2’-苯胺基_4,4’_聯吡啶-2-基）四氫呋喃-3-羧醯胺； N-(2’_苯胺基-4,4’-聯吡啶-2-基）菸鹼醯胺； Ν-(2^苯胺基_4,4’_聯吡啶-2-基）-4-(二甲胺基）苯甲醯胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）-2,6-二甲氧基菸鹼醯胺； N-(2’_苯胺基-4,4’-聯吡啶-2-基）-1Ηβ丨哚-2-羧醯胺； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）吡啶-2-羧醯胺； N-(2f-苯胺基_4,4^聯υ比淀-2-基）-3-咬喃醒胺， N-(2，-苯胺基_4,4，_聯吡啶-2_基）-1，2,3-嘧二唑冰羧醯胺； N-(2’-苯胺基·4,4’-聯吡啶-2-基）異哼唑-5-竣醯胺； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-5-甲基異崎唑各羧醯胺； N-(2f-苯胺基_4,4，_聯吡啶-2-基）吡畊-2-羧醯胺； 89385 -17- 200417546 N-(2L苯胺基-4,4’-聯叶1：淀-2-基）-1-甲基-1H-咪嗤-4-瘦驢胺； N-(2 -冬胺基-4,4f-聯ρ比淀-2-基）-2-咬喃醒胺， Ν_(2^苯胺基-4，-聯吡啶-2-基）_4_甲氧基苯甲醯胺； Ν-(2’-苯胺基-4,4f-聯吡啶-2-基）-5-溴基-2-呋喃醯胺； N-(2f-苯胺基_4,4f-聯吡啶-2-基）-2-(甲硫基）菸鹼醯胺； 4-{[(2'-苯胺基-4，-聯吡啶-2-基）胺基]羰基}苯甲酸甲酯； 3-(乙醯胺基）-N-(2’-苯胺基-4,4，-聯吡啶-2-基）苯甲醯胺； N-(2f-苯胺基-4,咎聯吡啶-2-基）冰酮基-4,5,6,7-四氫小苯并呋喃-3-羧醯胺； N-(2f-苯胺基-4,4’-聯吡啶冬基&gt;5-[(吡啶-2-基硫基）甲基]-2-呋喃醯 胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）菸鹼醯胺1-氧化物； N-(2 -本胺基-4,4f-聯峨淀-2-基）-3-經基ρ比淀-2-竣酿胺， N-(2 -本胺基-4,4f-聯峨淀-2-基）-6-溪基ρ比淀-2-複S盛胺； N-(2 -冬胺基_4,4’_聯ρ比淀-2-基）異於驗驢胺1-氧化物； N-(2 -麥胺基-4,4’-聯峨淀-2-基）-2-¾基於驗酸胺； N-(2 -冬胺基_4,4^聯峨淀_2-基）-6-幾基p比淀-2_致醒胺； N-(2 -冬胺基_4,4’_聯ρ比淀-2-基）_3-苯甲驢基p比淀-2-叛酿胺； N-(2 -本胺基-4,4^聯峨淀-2-基）-6-甲基p比淀-2-叛醒胺； N-(2 -本胺基-4,4f-聯ρ比淀-2-基）-3,5-二甲基異吟哇-4-叛酿胺， N-(2 -冬胺基_4,4^聯p比淀-2-基）-2-甲氧基於驗酸胺； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-4-甲基-l，2,3-嘧二唑-5-羧醯胺； N-(2 -冬胺基-4,4’-聯p比淀-2-基）-2-氯基異|f驗酸胺； N-(2 -冬胺基-4,4’-聯峨淀-2-基）-5-甲基異p号嗤-4·叛S备胺； 89385 -18- 200417546 N-(2f-苯胺基-4,4’-聯吡啶-2-基）各甲基異哼唑-4-羧醯胺； N-(2’-苯胺基_4,4’-聯吡啶-2-基）小甲基-1H-吡咯-2-羧醯胺 N-(2 -冬胺基_4,4’-聯ρ比淀-2-基）-2-氯基於驗酸胺； N-P-苯胺基-4,4’-聯吡啶-2-基）-5-氯基-1H-啕哚-2-羧醯胺 N-(2’-苯胺基_4,4’-聯吡啶-2-基&gt;4-氯基-1H_吡唑-3-羧醯胺 N-(2 -冬胺基_4,4’-聯ρ比淀-2-基）-5-甲基-lH-p比峻-3-竣醒胺 (2E)-N-(2 -冬胺基-4,4f-聯ρ比淀-2-基）-3-(3-咬喃基）丙稀醒胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基&gt;3-(2-酮基-1，3-苯并哼唑-3(2H)-基）丙 醯胺； N’-(2’-苯胺基-4,4f-聯吡啶-2-基）-N，N-二甲基琥ί白醯胺； Ν-(2 -冬胺基_4,4’-聯ρ比淀-2-基）-2-[(4-氯苯基）績酸基]乙驗胺； Ν-(2 -冬胺基_4,4’-聯ρ比淀-2-基）-5-銅基膽胺酸胺； N-(2 -冬胺基_4,4’·聯ρ比淀-2-基）-3-甲氧基丙酸胺； N_(2L苯胺基_4,4’-聯吡啶-2-基）冰甲氧基環己烷羧醯胺； Ν-(2^苯胺基_4,4’-聯吡啶-2-基）-3•甲氧基丙醯胺； Ν-(2^苯胺基-4,4f-聯峨淀-2-基）四氫吃喃-3-叛醯胺； N-(2’-苯胺基4,4’-聯吡啶-2-基）斗(二甲胺基）丁醯胺； N-(2’_苯胺基_4,4’-聯吡啶-2-基）菸鹼醯胺； Ν-(Τ-苯胺基_4,4’-聯吡啶-2-基）-4-(二甲胺基）苯甲醯胺； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-2,6-二甲氧基菸鹼醯胺； N-(2’-苯胺基-4,4f-聯吡啶-2-基哚-2-羧醯胺； N-(2f-苯胺基_4,4f-聯吡啶-2-基）-5-甲基吡畊-2-羧醯胺； N-(2’-苯胺基_4,4〔聯吡啶-2-基）吡啶-2-羧醯胺； N-(2’-苯胺基-4,4f-聯吡啶-2-基）各呋喃醯胺； 89385 -19- 200417546 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-Ν’-苯基脲； Ν-(2’-苯胺基-4,4f-聯吡啶-2-基）-Nf-苯基脲； N-(2’-苯胺基-4,4f-聯吡啶·2-基）-N41_(4-溴苯基）乙基]脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N%塞吩-3-基脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-Nf-(2_甲基苯基）脲； 苯胺基_4,4’_聯吡啶-2-基）-N’-(4-甲基苯基）脲； N-(2f-苯胺基_4,4^聯吡啶_2_基）-N’-(3-氟苯基)脲； N-(2f-苯胺基_4,4’_聯吡啶-2-基）-N’-(2-氟苯基)脲；Among them: R1 is aryl or heteroaryl, each of which is optionally one or more of R3, or3, OCOR3, COOR3, COR3, CONR3R4, NHCOR3, NR3R4, NHS02R3, S〇2R3, S02NR3R4, SR3, CN, Halo and N02 substitutions; R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, CON (R6) 2, COOR5 89385 200417546, Co〇r6, 802 ^ 5 or so2R6; R3 and R4 are each independent Is hydrogen, Cb6 alkyl, c2-6 fluorenyl, c2-6 alkynyl, 〇3_8 cycloalkyl, (C3_8 cycloalkylalkyl, heterocycle, heterocycle Cl_6 alkyl, (^ fluorfluorfluorenyl, Ci-6 trifluoro Alkoxy; R5 is aryl or heteroaryl, each of which is optionally one or more of R7, 〇R7, OCOR7, COOR7, COR7, CONR7R8, CONHOR7, NHCOR7, NR7R8, NHS02R7, S02R7, S02NR7R8, SR7 , R7SR8, CN, halo, oxygen, and N02 substitution; R6 is fluorene, CV6 alkyl, 0_8 cycloalkyl, ((^ 3_8 cycloalkyl) Cu alkyl, heterocycle, heterocyclic Ci_6 alkyl, heteroaryl * Cl-6 alkyl, aryl Cl-6 alkyl, Ci 6 alkoxy, or C ^ 6, where any Cl 6 alkyl, (^ 3 8 cycloalkyl, ((: 3 8 cyclofluorenyl) Ch Alkyl, heterocyclic, heterocyclic Ci6 alkyl, heteroaryl * Ci6 And aryl. -6 aryl, Ci-6 alkoxy and c2_6 alkenyl are optionally substituted by one or more A; R7 and R8 are each independently hydrogen, Cl_6 alkyl, C3_8 cycloalkyl, ( C3 8 cycloalkyl) Ci 6 alkyl, C 6 alkenyl, aryl, heteroaryl, heteroaryl, alkyl, heterocyclic, heterocyclic q-6 alkyl, aryl, 〇1-6 Fluoroalkyl and Cl-6 chloroalkyl, of which any fluorenyl, c3-8 cycloalkyl, (c3_8 cycloalkyl) Ci_6 alkyl, C2_6 alkenyl, heteroaryl, heteroaryl Cl_6 alkyl, hetero Ring and heterocyclic Ci-6 alkyl, which are optionally substituted by one or more B; R9 and R1G are each independently hydrogen, Ci_6 alkyl, 〇3_8 cycloalkyl, (C3_8 cycloalkyl) Ci6 alkyl, C2_6 Alkenyl, heterocyclic, heterocycloalkyl, heteroaryl, heteroaryl (^ _6 tiger, aryl, or aryl Cl_6 alkyl, where any alkyl, 0: 3-8 cycloalkyl, 3- 8-ring alkyl group_ 6 alkyl group, c 2-6 alkenyl group, heterocyclic ring, heterocyclic ring C! _ 6 fluorenyl group 89385 -10- 200417546, heteroaryl group, heteroaryl group Cl. 6, aryl or aryl Ci 6 fluorenyl, which is substituted by one or more B, as appropriate; A is R, OR9, 〇CR9, 〇〇R9, ＣＯＲ9, Ｃ〇 9r1, ⑺ 丽 〇R9 , NHCOR9, NR9R10, service 9302, 10, s2R9, s2nr9r10, Zhang 9, R9SR10, CN, or halo; B is chloro, Cl_6, oxy, Ci_6, amine Group) amino or halo; as its free state or salt. The 7F listed below are definitions of various terms used to describe the present invention in the scope of this patent specification and patent applications. For the avoidance of doubt, it should be clear that, in this patent specification, a group is the first and broadest definition in the context of the definition of a group or "defined above". , And each and all better definitions of the group. For the avoidance of doubt, it should be understood that in the present specification, "c6, f" means a charcoal-based group having 1, 2, 3, 4, 5, or 6 carbon atoms. In this patent specification, unless It is mentioned otherwise, otherwise, the term "alkyl" includes both straight chain and branched chain stem groups. The alkyl group may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, second-butyl, third-butyl, n-pentyl, iso-pentyl Base, tertiary-pentyl, neo-pentyl and hexyl. In this patent specification, unless otherwise mentioned, the ', C3_8 cycloalkyl, and coincidence' system includes a non-aromatic fully saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of the cyclofe group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 89385-11 · 200417546, the term &quot; I alkoxy &quot; is used in this text, and unless otherwise mentioned, it includes &quot; base ring, 丨, and 基, &quot; as defined above. C16 垸 oxy May be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, second_butoxy, third_butoxy, n_ Pentyloxy, iso-pentyloxy, tertiary pentyloxy, neo-pentyloxy, hexyloxy. Cl-6 trifluoropoxyl represents q_6fluorenyloxy substituted with three fluorine atoms. 4 is advantageous The floor clasp has a chain of 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. The c2.6 alkenyl group may be ethynyl, propionyl, 2-methylpropionyl, butyl and 2- In this patent specification, unless otherwise mentioned, the term &quot; women &quot; includes both straight chain and branched chain alkenyl, but the designation of individual alkenyl groups, such as 2_ 丁Shaobuji 'refers only to the straight-chain variant. Unless stated otherwise, "diluted" is used in this patent specification. Unless otherwise mentioned, the term "alkynyl" includes both straight and branched alkynyl, but for individual alkynyl References, such as fluorene butynyl, refer exclusively to straight-chain variants. Unless otherwise mentioned, alkynyl, a sullen, advantageously refers to having 2 to 5 carbon atoms, preferably 3 to 4 A chain of one carbon atom. In this patent specification, unless otherwise mentioned, the term "heterocyclic," includes both 3- to 10-membered non-aromatic partially or fully saturated hydrocarbon groups, which contain one or Two rings, and at least one heteroatom. Examples of the heterocyclic ring include, but are not limited to, tetrahydropyrrolyl, tetrahydropyrrolidinyl, hexahydropyridyl, hexahydropyridyl, morpholinyl, oxazolyl, 2-pyrazolidone, tetrahydro Piperanyl or tetrahydrofuranyl. In this patent specification, unless otherwise mentioned, the term "aryl" may be 89385-12-200417546 C6 cM narrow hydrocarbons' and includes, but is not limited to, benzene, stubble, indene, anthracene, phenanthrene. In this patent, unless otherwise mentioned, the term &quot; heteroaryl, &quot; may be = single-coating_10,000 rank or bicyclic fused ring heteroaromatic group. Examples of such heteroaryl groups 'Including, but not limited to, pyridyl, pyrrolyl, furyl', sedenyl, imidino, slogan, etc. ^ 丞, well, azolyl, thiazolyl, pyrimidazolyl, pyrazolyl 1 M ^ '4' group_4,5,6,7, Hydroxybenzobenzoyl group, lysyl group, epimethyl group, 2-ketobenzo group fluorenyl group, tower group, ranyl group , Pyryl, tetrazolyl, or triazolyl. f In this patent specification, unless otherwise mentioned, the term halo may be fluorine, chlorine, bromine or iodine. ^ In this patent specification, unless otherwise mentioned, &quot; Chfluoroalkyl group &quot; -5 is an alkyl group substituted with or a fluorine atom. Examples of the fluoroalkyl group are not limited to monofluoro In this patent specification, unless mentioned otherwise, Chchloroalkyl, together, may be one or more chloro groups. Atom-substituted alkyl groups. Examples of such chloroalkyl groups include, but are not limited to, monochloromethyl, trichloromethyl, dichloromethyl, and trichloroethyl. In one aspect of the invention, compounds of formula I are provided , Where R1 is aryl or heterowanyl, and optionally substituted by one or more R3, OR3, nr3r4, commercial group or No2; R is R, R6, COR5, cor6, coonhr5 , C0r6, c0r6 or so2R6; R: each independently of R4 is hydrogen, alkyl or c6fluoroalkyl; R is a square or heteroaryl group, each of which is / Or multiple R7, OR7 89385 -13- 200417546, COOR7, COR7, CONHOR7, NR7R8, S02R7, S02NR7R8, SR7, halo, oxygen and no2 substitution; R6 is nitrogen, Ci-6 alkyl, (C3-8 Yuanji) Ci_ 6 Tiger Heterocyclic ring, heterocyclic ring Q 6 alkyl, wherein any Ci -6 alkyl group, (A-s ring alkyl-6 ring or hetero ring is optionally substituted by one or more A; R7 and R8 are each independently hydrogen , Alkyl, C3_8 cycloalkyl, aryl, heterocyclic ring, wherein any (^ _6 alkyl is optionally substituted by one or more B; R9 and R1 Q are each independently nitrogen or Ci_6 fluorenyl group 'any of Ci_6 alkyl is optionally substituted by one or more B; A is COOR9, COR9, CONR9R10, NHCOR9, NR9R1 (), SR9, R9SR10, or CN; B is halo or di (Cualkyl) amino. In another aspect of the present invention, it provides a compound of formula I, wherein R1 is an aryl group, optionally substituted by one or more R3, OR3, and NR3R4. In a specific embodiment of this aspect, it provides formula j A compound wherein R is a square group and the aryl group is a phenyl group. In yet another aspect of the present invention, it provides a compound of formula I, wherein R3 is selected from the group consisting of C1-6 fluoroalkyl, methyl and dentyl. In yet another aspect of the present invention, it provides a compound of formula I, wherein R2 is selected from R5, COR5, and CONHR5. In a specific embodiment of this aspect, it provides formula 1. Compounds, where R is aryl 'optionally by one or more of r7, 〇r7, coopj, COR7, CON〇R7, nr7r8, so2R7, so2Nr7r8, sr7, free radical, oxygen and no.2 89385 14- 200417546 In another specific embodiment of this aspect, it provides a compound of formula I, wherein R7 and R8 are each independently hydrogen, G_6alkyl, c3_8cycloalkyl, aryl, hetero Ring 'where Ci-6 alkyl is optionally substituted by one or more B, which B is a base. In yet another aspect of the present invention, it provides a compound of formula j, wherein R2 is selected from the group consisting of R6, COR6, CONHR6, and S02R6. In a specific embodiment of this aspect, it provides a compound of formula I, wherein R6 is selected from hydrogen, Ci-6 alkyl, (Ch cycloalkyl) Ch alkyl, heterocyclic, heteroalkyl, wherein any alkyl (Cw cycloalkyl) Ci-6 alkyl and heterocyclic ring are optionally substituted by one or more A. In another specific embodiment of this aspect, it provides a compound of formula I, wherein the A is selected from the group consisting of COOR9, COR9, CONR9R10, NHCOR9, ¥ 〇, SR9, R9SR10, and CN; and R ^ R10 Each is independently hydrogen or CH. The present invention relates to the use of the compound as defined above] [compounds and salts thereof. The salt in the pharmaceutical formulation of the feedstock is pharmaceutically acceptable M, but other I can be used to produce a compound of formula I. Such salts may be acid and addition salts. Suitable pharmaceutically acceptable salts of the compound of formula are sufficiently basic <acid addition salts of compounds of formula I, for example with inorganic or organic acids such as -acids, acid addition salts, or for example salts of compounds of formula 1 that are sufficiently acidic, for example Alkali or alkaline earth metal salts, or salts with organic bases. In another embodiment of the present invention, the compound of formula I is provided in the form of a pharmaceutically acceptable salt. 7! = The compound of formula 1 may have a palm center and / or a geometric isomer (E-fish distructure), and it should be understood that the present invention encompasses all such optical, diastereomeric and Geometric isomers. 89385 -15- 200417546 Certain compounds of the invention may exist as tautomers. It should be understood that the invention encompasses all such tautomers. Specific compounds of formula I are: N, Nf-bis [4- (trifluoromethyl) phenyl] -4,4'-bipyridine-2,2, _diamine; N, N'-bis (4-fluoro Phenyl) -4,4'-bipyridine-2,2'-diamine; N, Nf-bis (3,4-dioxophenyl) _4,4'_bi-p ratio-2,2f-di Amine; N, N'-bis [3- (trifluoromethyl) phenyl] -4,4f-bipyridine_2,2, -diamine; N, N'-bis [3- (trifluoromethoxy) Phenyl) phenyl] -4,4f-bipyridine_2,2, -diamine; N, N'-bis (2-fluorophenyl) -4,4'-bipyridine-2,2f-diamine; N, N'-bis (2-methylphenyl) -4,4f-bipyridine-23-diamine; N, N'-bis (2-aminophenyl) -4,4'-bipyridine- 2,2'-diamine; N, Nf-bis (2-methoxyphenyl) -4,4'-bipyridine-2,2'-diamine; N, Nf-bis (2-ethoxyphenyl) ) _4,4'-bipyridine-2,2'-diamine; N- (2'-anilino-4,4'-bifoliate 1: lake-2-yl) -trans-4-methoxy Cyclohexyl benzamine; N- (2'-Amino group W, #-Lexyl t * Yide-2-yl) -cis-4-methoxycyclohexyl alcohol; N- {2f -[(4-fluorophenyl) amino] -4,4f-exo-1: Yodo-2_yl} -transmethoxy_cyclohexylcarboxamidine; N_ {2 '-[(4- Fluorophenyl) amino] -4,4 ' -Lianye 1: Zheng-2-jib cis-ice-methoxy-cyclohexylcarboxamide; N- (6-methylpyridin-2-yl) · N, _phenyl-4,4,- Bipyridine-2, diamine; N-phenyl-N4 than pyridin-2-yl-4,4'-bipyridine-2, T-diamine; N_ {4-[(4-methylhexahydro ^: _-1-yl) Continuing group] Benzylb N, _phenyl_4,4, -di-pyridine-2,2'_diamine; N-phenyl-N'-p than Dian-3- N-phenyl-4,4'-exopyridine-2,2, 89385 -16-200417546 N-phenyl-N1-methylpyridin-2-yl-4,4'-bipyridine-2,2, -diamine ; N-phenyl-NU amidin_5-yl-4,4'-bipyridine_2,2, -diamine; (2E) 1 {4 [(2 winter amino_4,4 -diamine -2-yl) amino] phenyl} -3- (dimethylamino) propan-2-di-1-isopropyl; 4-[(2f-aniline-4,4f-bipyridin-2-yl ) Amine group] (2-tetrahydropyrrole small ethyl) benzoic acid amine; 4-[(2'-aniline-4,4f-bipyridin-2-yl) amino] -N- (2 -Morpholine-4-ylethyl) benzidine; N- {4-[(4-ethylhexahydropyridine small group) benzyl] phenyl group N′_phenyl_4,4L Bipyridine_ 2,2 '· diamine; N-phenyl-N1-pyridin-4-yl-4,4f-bipyridine-2,2, -diamine; N- (2'_aniline-4, Bipyridin-2-yl) tetrahydrofuran-3-carboxamidine Amine; N- (2f-anilino-4,4'-bipyridin-2-yl) each hexahydropyridine small propylamidine; N- (2'-anilino_4,4'_bipyridine-2 -Yl) tetrahydrofuran-3-carboxamidine; N- (2'_aniline-4,4'-bipyridin-2-yl) nicotinamide; N- (2 ^ anilino_4,4'_ Bipyridin-2-yl) -4- (dimethylamino) benzidine; N- (2'-aniline-4,4'-bipyridin-2-yl) -2,6-dimethoxy N- (2'-anilino-4,4'-bipyridin-2-yl) -1'β-indol-2-carboxamide; N- (2'-anilino-4,4 '-Bipyridin-2-yl) pyridine-2-carboxamidamine; N- (2f-aniline-4,4 ^ biphenyl-2-yl) -3-carboxanamine, N- (2 ， -Anilino_4,4, _bipyridin-2-yl) -1,2,3-pyrimidiazole cyperamide; N- (2'-anilino · 4,4'-bipyridine-2 -Yl) isohumidazole-5-endamidine; N- (2'-anilino-4,4'_bipyridin-2-yl) -5-methylisoazazol, each carboxyamidine; N- ( 2f-anilino_4,4, _bipyridin-2-yl) pyroxy-2-carboxamide; 89385 -17- 200417546 N- (2L anilino-4,4'-binye 1: Yodo-2 -Yl) -1-methyl-1H-imidyl-4-letanylamine; N- (2-dongamido-4,4f-bi-p-pyridine-2-yl) -2-tetrahydropyridine Amine, N_ (2 ^ anilino-4, -bipyridin-2-yl) _4_methoxybenzylamine; N- (2'-anilino-4,4f-bipyridin-2-yl)- 5-bromo-2-furanamine; N- (2f-anilino-4,4f-bipyridin-2-yl) -2- (methylthio) nicotinamide; 4-{[(2 ' -Anilino-4, -bipyridin-2-yl) amino] carbonyl} methyl benzoate; 3- (acetamido) -N- (2'-anilino-4,4, -bipyridine- 2-yl) benzamidine; N- (2f-aniline-4, bipyridin-2-yl) cetonyl-4,5,6,7-tetrahydro- small benzofuran-3-carboxamidine Amine; N- (2f-anilino-4,4'-bipyridyl) &gt; 5-[(pyridin-2-ylthio) methyl] -2-furanamine; N- (2'-aniline -4,4'-bipyridin-2-yl) nicotinamide amine 1-oxide; N- (2-benzylamino-4,4f-bienedian-2-yl) -3-mer Biyodo-2-Junamine, N- (2-benzyl-4,4f-dianedian-2-yl) -6-xiji p-pyridin-2-complex S amine; N- (2 -Deramido_4,4'-bi-p-pyridin-2-yl) is different from donkey amine 1-oxide; N- (2-Metamine-4,4'-bienedian-2-yl ) -2-¾ Based on acid test amines; N- (2-Deramido_4,4 ^ Lianedian_2-yl) -6-Chloryl p-pyridine-2_Awake amines; N- (2 -Aspartyl_4,4 ' _Bi-p-pyridine-2-yl) _3-benzyl-pyridyl-2-pyridylamine; N- (2-benzylamine-4,4 ^ biyanide-2-yl) -6- N- (2-benzylamino-4,4f-bi-p-bidian-2-yl) -3,5-dimethylisoindowa-4 Amine, N- (2 -Arylamido_4,4 ^ bi-p-pyridine-2-yl) -2-methoxyamine amine; N- (2'-anilino_4,4'_bipyridine -2-yl) -4-methyl-1,2,3-pyrimidazol-5-carboxamide; N- (2-dongamido-4,4'-bi-p-pyridine-2-yl) -2-Chloroisoiso | f-amine amine; N- (2 -Deramido-4,4'-biyanide-2-yl) -5-methylisop-number 嗤 -4 · Betamine ; 89385 -18- 200417546 N- (2f-anilino-4,4'-bipyridin-2-yl) each methylisohumidazole-4-carboxamidine; N- (2'-anilino-4, 4'-bipyridin-2-yl) small methyl-1H-pyrrole-2-carboxamidamine N- (2-dongamido_4,4'-bi-p-pyridin-2-yl) -2-chloro Based on acid test amine; NP-anilino-4,4'-bipyridin-2-yl) -5-chloro-1H-pyridin-2-carboxamide N- (2'-anilino_4,4 '-Bipyridin-2-yl &gt; 4-chloro-1H_pyrazole-3-carboxamido N- (2-dongamido_4,4'-bi-p-pyridin-2-yl) -5 -Methyl-lH-p than Jun-3- Junamine (2E) -N- (2-Erylamino-4,4f-linked Biyodo-2-yl) -3- (3-octanoyl) propanamine; N- (2f-aniline-4,4'-bipyridin-2-yl) &gt; 3- (2-keto -1,3-benzohumidazole-3 (2H) -yl) propanilamide; N '-(2'-aniline-4,4f-bipyridin-2-yl) -N, N-dimethyl Stilbene stilbene amine; Ν- (2-dongamido_4,4'-bi-p-pyridine-2-yl) -2-[(4-chlorophenyl) acetic acid] ethylamine; Ν- (2 -Deramido_4,4'-bi-p-pyridin-2-yl) -5-copperyl choline amine; N- (2- Dongamido_4,4'-bi-pyridine- 2-yl) -3-methoxypropanoic acid amine; N_ (2L aniline_4,4'-bipyridin-2-yl) glacial methoxycyclohexanecarboxamide; Ν- (2 ^ aniline _4,4'-bipyridin-2-yl) -3 methoxypropanamide; Ν- (2 ^ aniline-4,4f-bienedian-2-yl) tetrahydroanan-3- Betamine; N- (2'-aniline 4,4'-bipyridin-2-yl) pyridine (dimethylamino) butanamide; N- (2'_aniline_4,4'-linked Pyridin-2-yl) nicotinamide; N- (T-anilino_4,4'-bipyridin-2-yl) -4- (dimethylamino) benzidine; N- (2 ' -Anilino-4,4'-bipyridin-2-yl) -2,6-dimethoxynicotinamide; N- (2'-anilino-4,4f-bipyridin-2-ylindole -2-carboxamide ; N- (2f-aniline_4,4f-bipyridin-2-yl) -5-methylpyridin-2-carboxamide; N- (2'-aniline_4,4 [bipyridine- 2-yl) pyridine-2-carboxamidine; N- (2'-anilino-4,4f-bipyridin-2-yl) furanamine; 89385 -19- 200417546 N- (2'-aniline -4,4'-bipyridin-2-yl) -N'-phenylurea; N- (2'-aniline-4,4f-bipyridin-2-yl) -Nf-phenylurea; N- (2'-anilino-4,4f-bipyridine · 2-yl) -N41_ (4-bromophenyl) ethyl] urea; N- (2'-anilino_4,4'_bipyridine-2 -Yl) -N% thiophen-3-ylurea; N- (2f-aniline-4,4'-bipyridin-2-yl) -Nf- (2-methylphenyl) urea; aniline_ 4,4'_bipyridin-2-yl) -N '-(4-methylphenyl) urea; N- (2f-aniline_4,4 ^ bipyridin_2_yl) -N'-( 3-fluorophenyl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -N '-(2-fluorophenyl) urea;

N-(2f-苯胺基-4,4’-聯吡啶_2_基）-NH4·氟苯基)脲； N-(2 -冬胺基-4,4’-聯π比淀-2-基）-ϊνΓ-[4-(氯基甲基）苯基]服； Ν-Θ-苯胺基-4,4f-聯吡啶-2-基）-ΝΗ3-氰基苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(4-氰基苯基）脲； NW-苯胺基_4,4〔聯吡啶-2-基）_NH2-氰基苯基）脲；N- (2f-aniline-4,4'-bipyridin_2_yl) -NH4 · fluorophenyl) urea; ) -ΪνΓ- [4- (chloromethyl) phenyl]; Ν-Θ-aniline-4,4f-bipyridin-2-yl) -NΗ3-cyanophenyl) urea; N- ( 2f-aniline-4,4'-bipyridin-2-yl) -N '-(4-cyanophenyl) urea; NW-aniline_4,4 [bipyridin-2-yl) _NH2-cyanide Phenyl) urea;

N-(2f-苯胺基-4,聯吡啶-2-基）-N’-(2,3-二甲基苯基）脲； N-(2’-苯胺基-4，-聯吡啶-2-基）-N’-(2,5-二曱基苯基）脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(4-乙基苯基）脲； N-(2’-苯胺基-4,4^聯p比淀-2-基）-N’-(3-乙基苯基）赚； N-(2’-苯胺基-4,4’-聯吡啶-2_基）-Ν’-(4·甲氧苯基)脲； Ν-(2’-苯胺基4,4’-聯吡啶冬基）-Nf-(3-甲氧苯基)脲； N-(2L苯胺基-4,聯吡啶-2-基&gt;N’-(2-甲氧苯基）脲； Ν-(2^苯胺基-4,4f-聯p比淀-2-基）界(5-說基-2-甲基苯基)脲； N-(2’·苯胺基-4,4’-聯吡啶-2-基)-N’-(2-氟基芊基)脲； Ν-(2^苯胺基-4,4’-聯吡啶-2-基）-N’-(2-氟基-5-甲基苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）养(3-氟基苄基)脲； 89385 -20- 200417546 Ν-(2^苯胺基-4,4，-聯吡啶-2-基）-N’-(2-氯苯基)脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-NH3-氯苯基)脲； Ν-(2^苯胺基-4,心聯吡啶-2-基）-N，-(2-氯苄基)脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-N，-(2,5-二氟苯基)脲； Ν·(Τ-苯胺基-4,4f-聯吡啶-2-基）界(2,4-二氟苯基)脲； N-(2L苯胺基·4,4’_聯吡啶-2-基）-N，-(3,4-二氯芊基)脲； N-(4-乙醯基苯基）-ν'-(2，-苯胺基-4,4，-聯吡啶-2-基）脲； N-(3-乙醯基苯基）·ν，-(2’-苯胺基-4,4’-聯吡啶-2-基）脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-ΝΗ4·異丙基苯基）脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N，-(2_異丙基苯基)脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N，-(2_乙基-6-甲基苯基)脲； Ν-(2^苯胺基-4,4·-聯吡啶-2-基）-Ν’-三甲苯基脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）·Ν，-(2-丙基苯基)脲； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）|[4-(二甲胺基）苯基]脲； N-(2f-苯胺基_4,4’_聯吡啶-2-基）-N’-l，3-苯并二氧伍圜烯基脲； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-Ν，-(4-甲氧基-2-甲基苯基)脲； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-Ν，-(2-甲氧基_5_甲基苯基观； Ν-(2’-苯胺基_4,4胃-聯吡啶-2-基）-ΝΗ4-乙氧苯基）脲； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-Ν’-(4-甲氧基苄基)脲； Ν-(2’-苯胺基-4,4f-聯峨淀-2-基）-Ν’-(4-硝基苯基)脲； Ν-(2 -丰胺基-4,4f-聯ρ比淀-2-基）-Ν’-(3-硝基苯基)月尿； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基&gt;Ν，-〇(甲硫基）苯基]脲； Ν-(2 -笨胺基-4,4’-聯ρ比淀-2-基）-Ν’-[4-(甲硫基）苯基]脲； Ν-(2^苯胺基-4,4f-聯外1：淀-2-基）-Ν’-(2-甲宇基)脲； 89385 -21 - 200417546 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-N，-(5-氯基-2-甲基苯基)脲； N_(2L苯胺基_4,4，-聯吡啶1基）-N，-(2-氣基·5_甲基苯基)脲； N-(2f-苯胺基_4,4’-聯吡啶-2-基）-ΝΗ2-氯苄基)脲； N-(2f-苯胺基_4,4’-聯吡啶-2-基）-Nf-(3-氯基-4-氟苯基)脲； N-(2f-苯胺基_4,4，-聯吡啶-2-基）-Nf-(2,3,4-三氟苯基）脲； N-(2’-苯胺基_4,4，-聯吡啶-2-基）-N，_(4-丁基苯基)脲； N-(2f-苯胺基_4，_聯吡啶—2-基）_N，-(2-異丙基-6-甲基苯基)脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-NH2-第三-丁基苯基）脲； 4-({[(2f-苯胺基_4,4’-聯吡啶-2-基）胺基]羧基}胺基）苯甲酸甲酯； N-(2f-苯胺基_4,4’-聯吡啶-2-基）-N，-(3,4-二甲氧基苯基）脲； N-(2f-苯胺基_4,4’-聯吡啶—2-基）-N，-(3,5-二甲氧基苯基）脲； N-(2’-苯胺基_4,4’-聯吡啶-2-基）-N’-(3-氯基-4-甲氧苯基)脲； N-(2’-苯胺基_4,4’-聯吡啶-2-基&gt;N44-(二氟甲氧基）苯基]脲； N-(2’-苯胺基_4,4，-聯吡啶-2-基）-N，-[2-(三氟甲基）苯基]脲； N-(2f-苯胺基_4,4’-聯吡啶-2-基）-N，-[3-(三氟甲基）苯基]脲； N-(2’-苯胺基_4,4’-聯吡啶-2-基）-N’-[4-(三氟甲基）苯基]脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2,5-二氯苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶_2_基）-Nf-(3,5-二氯苯基)脲； N-(2’-苯胺基-4,4’-聯吡啶-2_基）-N’-(3,4-二氯苯基)脲； N-(2’-苯胺基·4,4’_聯吡啶-2-基）-N’-(2,3-二氯苯基)脲； N-(2’-苯胺基-4,4’-聯吡啶冬基）-NH2,4-二氯苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶-2_基）-NH4-溴基-3-甲基苯基)脲； N-(2’-苯胺基-4,仁聯吡啶-2-基）-N^(2,6-二氣吡啶-4-基）脲； N-(2’-苯胺基-4,4’-聯吡啶-2-基）-N’-(4-丁基-2-曱基苯基）脲； 89385 -22- 200417546 N-(2 -丰胺基-4,4’-聯ρ比淀-2-基）-N’-[5-甲基·2-(三氟甲基）-3-吱喃基] 脲； 3- ({[(2 -冬胺基-4,4f-聯p比淀-2-基）胺基]談基}胺基）苯甲酸乙酉旨； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-NH4-丁氧基苯基）脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N’-(2,6-二異丙基苯基）脲； N-(2’-苯胺基_4,4’_聯吡啶-2_基）-N’_(4-甲芊基)脲； Ν-(2^苯胺基_4,4’_聯外I：淀-2-基）-Nf-(5-氯基-2,4-二甲氧基苯基)脲； N-(2f-苯胺基-4，f聯吡啶-2-基&gt;N’_{4-[(三氟甲基）硫基]苯基}脲； N-(2 -本胺基-4,4f-聯π比淀-2-基）-N’-[3,5-雙（三氟甲基）苯基]服； 1-乙Si：基-N-(2’-苯胺基-4/-聯ρ比淀-2-基）六氫p比淀-4-羧酸胺； N-(2’-苯胺基-4,4f-聯^:途-2-基&gt;5-g同基脯胺酸胺； N3 -乙醯基-N1 -(2f-苯胺基-4,4，-聯吡啶-2-基）-少胺基丙醯胺； N-(2’-苯胺基-七#-聯^:淀-2-基）六氫p比淀-4-複酿胺； 3_胺基-N-(2f-苯胺基-4,4’-聯p比症-2-基）丁酸胺； N-(2'-苯胺基-4,4’-聯p比淀-2-基）-L-脯胺酿胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）乙醯胺； 2’-苯胺基-4,4’-聯叶1：淀-2-基胺基甲酸甲酯； N-(2f-苯胺基-4,4^聯外1：淀-2-基）甲燒續醯胺； N-(2’_苯胺基-4,4f-聯峨淀-2-基）環己燒叛酸胺； 1-乙醯基-N-(2f-苯胺基-4,4f-聯吡啶冬基）六氫吡啶-2-羧醯胺； 1·乙醯基-N-(2f-苯胺基-4,4f-聯吡啶-2-基）六氫吡啶-3-叛醯胺； 4- [(2^苯胺基-4,4f-聯p比啶-2-基）胺基]-4-酮基丁酸乙酯； N-(2f-苯胺基-4，^-聯峨啶-2-基）四氫吱喃-2-叛醯胺； (S)-3 N2-乙醯基-Nl_(2f-苯胺基_4,4’-聯吡啶-2-基）甲硫胺醯胺； 89385 -23- 200417546 N-(2’-私胺基-4,4’-聯p比淀-2-基）四氫-2H-p瓜喃-4-羧酿胺； 3- [(2^冬胺基-4,4f·聯外1：淀-2-基）胺基]-3-酮基丙酸乙酯； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-3-(甲硫基）丙醯胺； (± )N-(2f-苯胺基-4,4f-聯吡啶-2-基）-2-四氫吡咯-2-基乙醯胺； (3S)-3-胺基-Ν·(2’-苯胺基-4,4’-聯峨淀-2-基）_4_氰基丁酸胺；N- (2f-aniline-4, bipyridin-2-yl) -N '-(2,3-dimethylphenyl) urea; N- (2'-aniline-4, -bipyridine-2 -Yl) -N '-(2,5-diamidinophenyl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -N'-(4-ethylbenzene ) Urea; N- (2'-anilino-4,4 ^ biphenyl-2-yl) -N '-(3-ethylphenyl); N- (2'-anilino-4 , 4'-bipyridin-2-yl) -N '-(4 · methoxyphenyl) urea; Ν- (2'-aniline 4,4'-bipyridolyl) -Nf- (3-methyl Oxyphenyl) urea; N- (2L aniline-4, bipyridin-2-yl) &gt; N '-(2-methoxyphenyl) urea; Ν- (2 ^ aniline-4,4f-bi-p Biyodo-2-yl) bound (5-syl-2-methylphenyl) urea; N- (2 '· aniline-4,4'-bipyridin-2-yl) -N'-(2 -Fluorofluorenyl) urea; N- (2 ^ anilino-4,4'-bipyridin-2-yl) -N '-(2-fluoro-5-methylphenyl) urea; N- ( 2f-anilino-4,4'-bipyridin-2-yl) (3-fluorobenzyl) urea; 89385 -20- 200417546 N- (2 ^ anilino-4,4, -bipyridine-2 -Yl) -N '-(2-chlorophenyl) urea; N- (2'-aniline_4,4'_bipyridin-2-yl) -NH3-chlorophenyl) urea; Ν- (2 ^ Anilino-4, cardiac bipyridin-2-yl) -N,-(2-chloro ) Urea; N- (2f-aniline-4,4f-bipyridin-2-yl) -N,-(2,5-difluorophenyl) urea; Ν · (Τ-aniline-4,4f -Bipyridin-2-yl) bound (2,4-difluorophenyl) urea; N- (2L aniline · 4,4'_bipyridin-2-yl) -N,-(3,4-di Chlorofluorenyl) urea; N- (4-ethylfluorenylphenyl) -ν '-(2, -aniline-4,4, -bipyridin-2-yl) urea; N- (3-ethylfluorenyl Phenyl) · ν,-(2'-aniline-4,4'-bipyridin-2-yl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -ΝΗ4 · Isopropylphenyl) urea; N- (2'-anilino-4,4'_bipyridin-2-yl) -N,-(2-isopropylphenyl) urea; N- (2 ' -Anilino-4,4'-bipyridin-2-yl) -N,-(2-ethyl-6-methylphenyl) urea; N- (2 ^ anilino-4,4 · -bipyridine -2-yl) -N'-trimethylphenylurea; N- (2f-aniline-4,4'-bipyridin-2-yl) · N,-(2-propylphenyl) urea; Ν- (2'-aniline-4,4'-bipyridin-2-yl) | [4- (dimethylamino) phenyl] urea; N- (2f-aniline_4,4'_bipyridine- 2-yl) -N'-l, 3-benzodioxolenyl urea; N- (2'-anilino-4,4'_bipyridin-2-yl) -N,-(4- Methoxy-2-methylphenyl) urea; N- (2 '-Anilino_4,4'_bipyridin-2-yl) -N,-(2-methoxy-5_methylphenyl group; N- (2'-anilino_4,4 stomach- Bipyridin-2-yl) -NΗ4-ethoxyphenyl) urea; Ν- (2'-aniline_4,4'_bipyridin-2-yl) -N '-(4-methoxybenzyl ) Urea; Ν- (2'-anilino-4,4f-bienedian-2-yl) -N '-(4-nitrophenyl) urea; Ν- (2-fungamino-4,4f -Bi-p-pyridin-2-yl) -N '-(3-nitrophenyl) lunate urine; Ν- (2'-aniline-4,4'-bipyridin-2-yl> N,- 〇 (methylthio) phenyl] urea; Ν- (2-benzylamino-4,4'-bi-pyridine-2-yl) -N '-[4- (methylthio) phenyl] urea ; N- (2 ^ anilino-4,4f-exo 1: Dian-2-yl) -N '-(2-methylyl) urea; 89385 -21-200417546 N- (2'-anilino- 4,4'-bipyridin-2-yl) -N,-(5-chloro-2-methylphenyl) urea; N_ (2L anilino-4,4, -bipyridyl 1yl) -N, -(2-Gas · 5-methylphenyl) urea; N- (2f-anilino-4,4'-bipyridin-2-yl) -NΗ2-chlorobenzyl) urea; N- (2f- Aniline_4,4'-bipyridin-2-yl) -Nf- (3-chloro-4-fluorophenyl) urea; N- (2f-aniline_4,4, -bipyridine-2- ) -Nf- (2,3,4-trifluorophenyl) urea N- (2'-aniline_4,4, -bipyridin-2-yl) -N, _ (4-butylphenyl) urea; N- (2f-aniline_4, _bipyridine-2 -Yl) _N,-(2-isopropyl-6-methylphenyl) urea; N- (2f-aniline-4,4f-bipyridin-2-yl) -NH2-third-butylbenzene Methyl) urea; 4-({[(2f-aniline_4,4'-bipyridin-2-yl) amino] carboxy} amino) benzoic acid methyl ester; N- (2f-aniline_4, 4'-bipyridin-2-yl) -N,-(3,4-dimethoxyphenyl) urea; N- (2f-aniline_4,4'-bipyridin-2-yl) -N ,-(3,5-dimethoxyphenyl) urea; N- (2'-aniline-4,4'-bipyridin-2-yl) -N '-(3-chloro-4-methyl Oxyphenyl) urea; N- (2'-aniline_4,4'-bipyridin-2-yl &gt; N44- (difluoromethoxy) phenyl] urea; N- (2'-aniline -4,4, -bipyridin-2-yl) -N,-[2- (trifluoromethyl) phenyl] urea; N- (2f-aniline-4,4'-bipyridin-2-yl ) -N,-[3- (trifluoromethyl) phenyl] urea; N- (2'-aniline_4,4'-bipyridin-2-yl) -N '-[4- (trifluoro Methyl) phenyl] urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -N '-(2,5-dichlorophenyl) urea; N- (2f-aniline -4,4'-bipyridin-2-yl) -Nf- (3,5-dichlorophenyl) urea; N- (2'-aniline-4,4'-bipyridin-2-yl) -N '-(3,4-dichlorophenyl) urea; N -(2'-aniline · 4,4'_bipyridin-2-yl) -N '-(2,3-dichlorophenyl) urea; N- (2'-aniline-4,4'- Bipyridyl) -NH2,4-dichlorophenyl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -NH4-bromo-3-methylphenyl) Urea; N- (2'-aniline-4, rendipyridin-2-yl) -N ^ (2,6-dipyridin-4-yl) urea; N- (2'-aniline-4, 4'-bipyridin-2-yl) -N '-(4-butyl-2-fluorenylphenyl) urea; 89385 -22- 200417546 N- (2-pentamino-4,4'-bi Biyodo-2-yl) -N '-[5-methyl · 2- (trifluoromethyl) -3-creanyl] urea; 3-({[((2-dongamido-4,4f- Bi-p-pyridin-2-yl) amino] anyl} amino) benzoic acid ethyl ester; N- (2f-aniline-4,4f-bipyridin-2-yl) -NH4-butoxyphenyl ) Urea; N- (2'-aniline_4,4'_bipyridin-2-yl) -N '-(2,6-diisopropylphenyl) urea; N- (2'-aniline _4,4'_bipyridin-2_yl) -N '_ (4-methylfluorenyl) urea; Ν- (2 ^ aniline_4,4'_exo I: Yodo-2-yl)- Nf- (5-chloro-2,4-dimethoxyphenyl) urea; N- ( 2f-aniline-4, f-bipyridin-2-yl &gt; N '_ {4-[(trifluoromethyl) thio] phenyl} urea; N- (2-benzamino-4,4f- Bi-π ratio 2-yl) -N '-[3,5-bis (trifluoromethyl) phenyl]; 1-ethylSi: yl-N- (2'-aniline-4 / -bi ρ Biyodo-2-yl) hexahydrop Biyodo-4-carboxylic acid amine; N- (2'-aniline-4,4f-bi ^: Tu-2-yl &gt; 5-g isopropylproline Acid amines; N3 -ethynyl-N1-(2f-anilino-4,4, -bipyridin-2-yl) -oligoaminopropionamine; N- (2'-aniline-seven # -linked ^: Yodo-2-yl) hexahydro p-pyridine-4-rejuvenated amine; 3-amino-N- (2f-aniline-4,4'-bi-p-pyridin-2-yl) butyric acid amine ; N- (2'-aniline-4,4'-bi-p-pyridin-2-yl) -L-proline amine; N- (2'-aniline-4,4'-bipyridine-2 -Yl) acetamidinium; 2'-aniline-4,4'-bifoliate 1: methyl ylide-2-ylaminocarboxylate; N- (2f-aniline-4,4 ^ exo 1: dianline -2-yl) methanesulfonylamine; N- (2'_aniline-4,4f-bienedian-2-yl) cyclohexylamine; 1-ethynyl-N- (2f- Anilino-4,4f-bipyridylolyl) hexahydropyridine-2-carboxamidine; 1 · Ethyl-N- (2f-aniline-4,4f-bipyridin-2-yl) hexahydropyridine -3-betamine; 4- [ (2 ^ anilino-4,4f-bi-p-pyridin-2-yl) amino] -4-ketobutyric acid ethyl ester; N- (2f-anilino-4, ^-bieridine-2- Group) Tetrahydrosuccin-2-amine; (S) -3 N2-Ethyl-N- (2f-anilino-4,4'-bipyridin-2-yl) methanamine; 89385 -23- 200417546 N- (2'-private amino-4,4'-bi-p-pyridine-2-yl) tetrahydro-2H-p citran-4-carboxamide; 3-[(2 ^ 冬Amino-4,4f · Lex1: Yodo-2-yl) amino] -3-ketopropionic acid ethyl ester; N- (2f-aniline-4,4f-bipyridin-2-yl)- 3- (methylthio) propanilamide; (±) N- (2f-anilino-4,4f-bipyridin-2-yl) -2-tetrahydropyrrole-2-ylacetamidamine; (3S) -3-amino-N · (2'-aniline-4,4'-bienedian-2-yl) _4-cyanobutanoic acid amine;

Nl-(2’-笨胺基-4,4’-聯峨淀-2-基）環丙燒-ΐ，ΐ-二致酸胺； (3S)-1-乙醯基-Ν-(2，-苯胺基-4,4，-聯吡啶-2-基）六氫吡啶-3-羧醯胺； Ν_(2’_苯胺基-4,4’-聯峨淀-2-基）四氫吱喃各叛酸胺（+)與（-); Ν-{2f-[(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}四氫呋喃-3-羧醯胺； Ν-{2’-[(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}四氫-2Η-♦喃-4-羧醯胺； 4- ({2f-[(4-氟苯基）胺基]_4，心聯吡啶-2-基}胺基）-4-酮基丁酸乙酯； 4-({2f-[(4-氟苯基）胺基]_4,4’_聯吡啶-2-基}胺基）-4-酮基丁酸； N-{2’-[(4-氟苯基）胺基]-4，-聯吡啶-2-基}-3_(甲硫基）丙醯胺； (± )-1-乙驗基-N-{2’-[(4-氟苯基）胺基]-4,4’-聯p比淀-2-基}六氫ρ比淀-3-瘦S盈胺； (3R)-1-乙醯基-N-{2，-[(4-氟苯基）胺基]-4,4，-聯吡啶-2-基}六氫吡啶_ 3-羧醯胺； (3S)-1-乙酉监基-N-{2’-[(4-氣苯基）胺基]-4,4’-聯π比淀-2-基}六氯p比淀-3-羧醯胺； 1- 乙醯基-N-{2’-[(4-氟苯基）胺基]-4,4f-聯吡啶-2-基}四氫吡咯各羧 醯胺； 3-(胺基磺醯基）-N-{2’-[(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}苯甲醯 胺； 2- {[(2’-苯胺基-4,4f-聯吡啶-2-基）胺基]甲基}環丙烷叛酸乙酯； 89385 -24- 200417546 2_{[(2f-笨胺基_4,4f-聯吡啶-2-基）胺基]甲基}環丙烷羧酸； N_苯基七X四氫-2H-哌喃斗基甲基）-4,4，-聯吡啶_2,2，_二胺； N-苯基以气四氫呋喃各基甲基）-4,4’-聯吡啶-2,2，-二胺； 作為自由態鹼或鹽。 本發明係關於新穎吡啶衍生物，其係為〇jun N-末端激酶 (JNK)之抑制劑。胃係與媒介多種病症有關聯。本發明係關 於製造此等抑制劑之方法。本發明亦提供醫藥組合物，其 包含本發明之抑制劑，及在各種病症之治療上利用此等組 合物之方法。 醫藥組合物 根據本發明之一方面，係提供一種醫藥組合物，其包含式 I化合物，作為自由態鹼或藥學上可接受之鹽、溶劑合物或 其鹽之溶劑合物，用於預防及/或治療與(^皿队末端激酶 (JNK)有關聯之症狀。 此组合物可呈適於口服投藥之形式，例如作成片劑，供非 經腸注射，作成無菌溶液或懸浮液。一般士 刀又阳3，上述組合 物可以習用方式，使用醫藥載劑或稀釋劑製備。在哺乳動 物包括人類之治療中，式I化合物之適當日服劑量，在崾口 投藥下’ A大約謂毫克/公斤體$，而在非經腸：藥 下’為約0.001至250毫克/公斤體重。活性成份之典型日服 劑量係在廣範圍内改變，且係依各種因去 M I而疋，譬如有關 聯之適應徵、投藥途徑，病患之年齡、麯舌 ^ 肢重及性別，並可 由醫師決定。 式I化合物或藥學上可接受之鹽 落劑合物或其鹽之溶劑 -25- 89385 200417546 合物，可獨自# 可接疼之稀s ^ ，合*彳合物（活性成份）係伴隨著藥學上 =5?:劑或載劑。依投藥模式而定，醫藥組合“ 已；0,05 土 99% w (重哥石八々、 份，所有重量百分比^1、例如_至50%w之活性成 比均以全邵組合物為基準。 稀釋劑或載劑包括水、聚乙 赛、供 每尺冷履蛟酞鎂、硬脂酸 t :“、糖(譬如乳糖）、果膠、糊精、澱粉、 膠、微晶性纖維辛、甲芙输 封 〒基、減維素、羧甲基纖維素鈉或 豆脂。 可 本發明之組合物可呈片劑或可注射形式。片劑可另外包人 朋解劑，及/或可經塗覆（例如以腸溶性塗層或使用塗層： 譬如羥丙甲基纖維素塗覆）。 曰戶, 本發明進一步提供一種製備本發明醫藥組合物之方法，其 包括使前文定義之式；!化合物或藥學上可接受之鹽、溶劑ς 物或其鹽之溶劑合物’與藥學上可接受之稀釋劑或载劑i 合。 本發明醫藥組合物之實例為可注射溶液，其含有如前文定 義之本發明化合物或藥學上可接受之鹽、溶劑合物或其鹽 之溶劑合物，及無菌水，且若必要，則有無論是氫氧:: 或鹽酸’以使最後組合物之pH值來到約pH 5，及選用之界 面活性劑，以幫助溶解。 __、&quot;上匕 /七卜〆PJ、 L j ypt L j 、 ^&gt;4 | 溶 毫克/毫升 化合物X 5.0% w/v 純水 1----- 至 100% 89385 -26- 200417546 醫藥用途 弋化口物具有作為藥劑之活 古弋P 狩疋5心，式I化合物為 有效Μ抑制劑，且較佳化合物為選s^ 物為選擇性JNK3抑制劑。本發 叫供式!化合物作為藥劑使用。特定言 供式I化合物，供佶兩认箱r 4、 月係 , 吏用万；預防或治療與胤活化作用有關聯 之症狀。 ，本發明係、提供_種治療或預防與狐活化作用有關聯症狀 工万’/、其包括對有需要之哺乳動物(特別是人類，包括病 患）投予治療上有效量之式J化合物。 於進:步方面，本發明係提供式I化合物在藥劑製造上之 用途」該藥劑係祕治療與職活化作用有關聯之症狀。 、、可藉由本*明根據式^化合物，或含其之醫藥組合物治 療4症狀’係包括任何與狐活化作用有關聯之症狀。與腹 活化作用有關聯之症狀，包括但不限於·· 中樞或末梢神經變性録，包括阿耳滋海默氏疾病、認知 病症、巴金生氏病、亨丁頓氏疾病、肌萎縮性側索硬化、 备、3 ”顳月癡呆症巴金生氏型、Gaum之巴金生癡呆症複徵 、HIV癡呆症、腎上腺基底變性、拳擊手癡呆症、氏徵 候跃、驷炎後巴金生氏徵候簇、進行性核上麻痺、朽汰氏病 Niemann-Pick氏病、癲癇、末梢神經病、脊髓損傷、頭部損 傷； 〃 自身免疫疾病，包括多發性硬化、炎性腸疾病、克隆氏病 、風濕性關節炎、氣喘、敗血性休克、移植排斥； 心與血f疾病，包括中風、動脈硬化、心肌梗塞、心肌再 89385 -27- 200417546 灌注損傷； 癌症，包括乳房、結腸直腸、胰、前列腺癌。 此外’本發明之JNK抑制劑能夠抑制可引致之預發炎蛋白 質之表現。因此，可藉由本發明化合物治療之其他症狀， 包括水腫、痛覺缺失、發熱及疼痛，譬如神經與肌肉疼痛 、頭痛、癌症疼痛、牙痛及關節炎疼痛。 就本專利說明書而論，”治療”一詞亦包括，，預防，，，除非 有相反之特走‘示。〉台療的’與’’治療上’’兩術語應據此 釋。 症狀Θ除非另有述及，否則係意謂任何與胤活性有 關聯之病症與疾病。 非醫療用途 式I化合物或其鹽，除τ盆 ^ , 除了其在治繚醫藥上之用途以外，亦 理學工且使用、V驗系統&lt;發展與標準化中，作為藥 之作估職抑制劑相關活性在實驗室動物中 &lt; rp用，譬如貓、、 τ 搜尋新穎治療劑之_部份。、猴子、大白鼠及老鼠，作為 製備方法 本發明化合物可藉 製備，如藉由下文一私 關於類似化合物之方法 說明者。起始物皙化人:式。私序及藉由後文製備實例所 口物係為市購可得，除非另有述及。 89385 -28- 200417546 合成圖式方法1 :Nl- (2'-benzylamino-4,4'-biyanide-2-yl) cyclopropane-fluorene, fluorene, diacid amine; (3S) -1-ethylfluorenyl-N- (2 , -Anilino-4,4, -bipyridin-2-yl) hexahydropyridine-3-carboxamidine; Ν_ (2'_aniline-4,4'-bienedian-2-yl) tetrahydro (+) And (-); N- {2f-[(4-fluorophenyl) amino] -4,4'-bipyridin-2-yl} tetrahydrofuran-3-carboxamide ; Ν- {2 '-[(4-fluorophenyl) amino] -4,4'-bipyridin-2-yl} tetrahydro-2Η- ♦ ran-4-carboxamide; 4-({2f -[(4-fluorophenyl) amino] -4, cardiac bipyridin-2-yl} amino) -4-ketobutyric acid ethyl ester; 4-({2f-[(4-fluorophenyl) amine [4,4'-bipyridin-2-yl} amino) -4-ketobutanoic acid; N- {2 '-[(4-fluorophenyl) amino] -4, -bipyridine-2 -Yl} -3_ (methylthio) propanilamide; (±) -1-ethoxyl-N- {2 '-[(4-fluorophenyl) amino] -4,4'-bi-p ratio Yodo-2-yl} hexahydroρ than yodo-3-succinic amine; (3R) -1-ethylamido-N- {2,-[(4-fluorophenyl) amino] -4,4 , -Bipyridin-2-yl} hexahydropyridine_3-carboxamidine; (3S) -1-ethylpyridinyl-N- {2 '-[(4-aminophenyl) amino] -4,4 '-Biπ Biyodo-2-yl} hexachloro p Biyodo-3-carboxamide; 1-Ethyl-N -{2 '-[(4-fluorophenyl) amino] -4,4f-bipyridin-2-yl} tetrahydropyrrole, each carboxamidine; 3- (aminosulfonyl) -N- {2 '-[(4-fluorophenyl) amino] -4,4'-bipyridin-2-yl} benzimidamine; 2- {[(2'-aniline-4,4f-bipyridine-2 -Yl) amino] methyl} cyclopropane ethyl methanoate; 89385 -24- 200417546 2 _ {[((2f-benzylamino_4,4f-bipyridin-2-yl) amino] methyl] cyclopropane Carboxylic acid; N-phenylhepta-tetrahydro-2H-piperanylmethyl) -4,4, -bipyridine_2,2, _diamine; N-phenyl-methyl tetrahydrofuran methyl group) -4,4'-bipyridine-2,2, -diamine; as a free base or salt. The present invention relates to novel pyridine derivatives, which are inhibitors of Ojun N-terminal kinase (JNK). The stomach system is associated with a variety of mediator disorders. The present invention relates to a method for manufacturing such inhibitors. The present invention also provides a pharmaceutical composition comprising the inhibitor of the present invention, and a method for using these compositions for the treatment of various disorders. Pharmaceutical composition According to one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I as a free state base or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof for use in prevention and And / or treatment of symptoms associated with JNK. This composition can be in a form suitable for oral administration, such as tablets, parenteral injections, and sterile solutions or suspensions. General Daoyouyang 3, the above composition can be prepared in a conventional manner using a pharmaceutical carrier or diluent. In the treatment of mammals, including humans, an appropriate daily dose of a compound of formula I is administered in the mouth. Kg body weight, while in the parenteral: sub-medicine 'is about 0.001 to 250 mg / kg body weight. The typical daily dosage of active ingredients varies within a wide range, and depends on various factors for MI, for example, if relevant The indications, route of administration, patient's age, tongue flexion, limb weight, and sex can be determined by the physician. The compound of Formula I or a pharmaceutically acceptable salting compound or a solvent of its salt-25- 89385 200417546物 ， 可 独 # The rare s ^ that can be painful, together with the compound (active ingredient) is accompanied by pharmacological = 5 ?: agent or carrier. Depending on the mode of administration, the pharmaceutical combination "has; 0,05 Soil 99% w (heavy brother Shibajiu, parts, all weight percentages ^ 1, for example _ to 50% w activity ratio is based on the whole Shao composition. Diluents or carriers include water, polyethylene, For cold feet, magnesium phthalate, stearic acid t: "", sugar (such as lactose), pectin, dextrin, starch, gum, microcrystalline fiber, carbofuran, oxydextrin, carboxyl Sodium methylcellulose or soy fat. The composition of the present invention may be in the form of a tablet or injectable. The tablet may additionally contain an antidote, and / or may be coated (for example with an enteric coating or used Coating: such as hydroxypropyl methylcellulose coating). The present invention further provides a method for preparing the pharmaceutical composition of the present invention, which comprises the formula defined above; a compound or a pharmaceutically acceptable salt, a solvent A solvate of a compound or salt thereof is combined with a pharmaceutically acceptable diluent or carrier i. Examples of the pharmaceutical composition of the present invention An injectable solution containing a compound of the invention as defined hereinbefore or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, and sterile water, and if necessary, whether it is hydroxide :: or hydrochloric acid 'In order to bring the pH of the final composition to about pH 5, and the selected surfactants to help dissolve. __, &quot; Shang Diao / Qi Bu〆 PJ, L j ypt L j, ^ &gt; 4 | Mg / ml compound X 5.0% w / v pure water 1 ----- to 100% 89385 -26- 200417546 medicinal product Mouthpiece has a live guava P as a medicament 5 heart, the compound of formula I is effective M inhibitor, and the preferred compound is a selective JNK3 inhibitor. This is called a compound of formula! For use as a medicament. Specific words for compounds of formula I for the two recognition box r 4, month system, official use million; prevention or treatment of symptoms associated with thallium activation. The present invention provides a method for treating or preventing symptoms associated with fox activation, which includes administering a therapeutically effective amount of a compound of formula J to mammals (especially humans, including patients) in need. . In a further aspect, the present invention provides the use of a compound of formula I in the manufacture of a medicament. "The medicament is a symptom associated with myocardial activation. The 4 symptoms can be treated by the compound according to formula ^ or a pharmaceutical composition containing the same according to the present invention, including any symptoms related to the activation of foxes. Symptoms associated with abdominal activation, including, but not limited to, records of central or peripheral neurodegeneration, including Alzheimer's disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis , Preparation, 3 "Temporal Moon Dementia Parkinson's type, Gaum's Parkinson's dementia recurrence, HIV dementia, adrenal basal degeneration, boxer dementia, leukemia syndrome, post-inflammation Parkinson's syndrome cluster, proceed Sexual paralysis, Niemann-Pick's disease, epilepsy, peripheral neuropathy, spinal cord injury, head injury; 〃 Autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis , Asthma, septic shock, transplant rejection; heart and blood diseases, including stroke, arteriosclerosis, myocardial infarction, myocardial re-injury 89385 -27- 200417546 perfusion injury; cancer, including breast, colorectal, pancreatic, prostate cancer. The JNK inhibitor of the present invention can inhibit the expression of the pre-inflammatory protein that can be caused. Therefore, other symptoms that can be treated by the compound of the present invention include edema, Analgesia, fever, and pain, such as nerve and muscle pain, headache, cancer pain, tooth pain, and arthritis pain. For the purposes of this patent specification, the term "treatment" also includes, prevents, unless specifically contraindicated. "Indications." The terms "therapeutic" and "therapeutic" should be interpreted accordingly. Symptoms Θ, unless stated otherwise, means any condition or disease that is associated with tritium activity. Non-medical use Formula I Compounds or their salts, in addition to τ ^^, in addition to its use in treating medicine, are also used in scientific research and use, V test system &lt; development and standardization, as drug inhibitors related activities in the laboratory <Rp in animals, such as cats, and τ search for novel therapeutic agents., Monkeys, rats and mice, as preparation methods The compounds of the present invention can be prepared by, for example, the following method of similar compounds Illustrator. Starter to make people: formula. Private sequence and the materials described in the following preparation examples are commercially available unless otherwise mentioned. 89385 -28- 200417546 Synthesis Scheme Method 1:

r、nh2 &quot;Pd-觸媒r, nh2 &quot; Pd-catalyst

α, 其中R1係如上述。 在方法1中，係使2,2’-二氣-(4,4&gt;聯吡啶與胺及過渡金屬觸 媒，譬如鈀觸媒，在醚或烴溶劑中反應，而得N，N，, _芳美 Γ ' 聯吡啶-2,2’-二胺。反應係於高溫譬如12(TC下進行，歷經長時 間，譬如15小時，或在微波爐中，於16(rc下，歷經較短時 間’譬如1小時。反應係藉層析監測直到完成為止。 合成圖式方法2 :α, where R1 is as described above. In method 1, 2,2'-digas- (4,4 &gt; bipyridine is reacted with an amine and a transition metal catalyst, such as a palladium catalyst, in an ether or a hydrocarbon solvent to obtain N, N ,,, _ Fangmei Γ 'bipyridine-2,2'-diamine. The reaction is carried out at high temperature, such as 12 ° C, over a long time, such as 15 hours, or in a microwave oven at 16 (rc, a shorter time. For example, 1 hour. The reaction is monitored by chromatography until completion. Synthesis Scheme Method 2:

其中R1與R5均如上述。 在方法2中，係使4.4l聯吡啶_2,2，_二胺與芳基卣化物及過渡 金屬觸媒’譬如銅或鈀觸媒，於鹼譬如第三-丁醇趣（免）或 鱗酸_ (銅）存在下，在醚或烴溶劑中反應，獲得N_芳基乂4，_ 聯吡哫-2,2’&quot;二胺（中間物）。反應係於室溫或高溫譬如8〇至1〇〇 89385 -29- 200417546 ^下進仃’歷經長時間’譬如i5小時，或在微波爐中，於⑽ 、、歷、、二軚銓時間，譬如1小時。反應係藉層析監測直到 完成為止。藉層析純化後]吏中間物接受第二種芳基化反 應’以獲得不對稱聯二芳基m咐淀_2,2L二胺。 合成圖式方法3 :Wherein R1 and R5 are as described above. In method 2, 4.4 l of bipyridine_2,2, _diamine is used with an aryl halide and a transition metal catalyst such as a copper or palladium catalyst, and a base such as a third-butanol (free) or In the presence of phosphonic acid (copper), it is reacted in an ether or a hydrocarbon solvent to obtain N_arylfluorene 4,2bipyridine-2,2 '&quot; diamine (intermediate). The reaction is carried out at room temperature or high temperature, such as 80 to 10089385 -29- 200417546, and 'over a long time', such as i5 hours, or in a microwave oven, for a period of time, such as, 1 hour. The reaction was monitored by chromatography until completion. After purification by chromatography] the intermediate was subjected to a second arylation reaction 'to obtain an asymmetric biaryl m2 + 2,2L diamine. Synthetic Schema Method 3:

醯胺偶合試劑 或 R5C0C1 或者 r6 COC1 N 'NH2 中間物 Η醯 Amine coupling reagent or R5C0C1 or r6 COC1 N 'NH2 intermediate Η

ΗΗ

其中R1、R5及R6均如上述Where R1, R5, and R6 are as described above

在方法3中，係使中間物與叛酸，於肤偶合戟劑譬如瓶 與HOBt ’及驗譬如二異丙基乙胺存在下，在惰性溶劑譬如 麗中二應。反應綱5tT進行⑴天之日㈣，而得M 胺。或者，使中間物與幾酸氯化物，在 甲燒中’於驗存在下，或在溶劑譬如_中，上=; 反應1小時至12小時，獲得幾酿胺。以類似方式，胺基甲酸 酯類與績_類可製自氯基碳酸0旨或氯化㉞類。反應係 89385 -30- 200417546 藉層析監測。 合成圖式方法4 :In the method 3, the intermediate and the acid are used in the presence of a skin-coupled halberd agent such as a bottle and HOBt 'and a test such as diisopropylethylamine in an inert solvent such as Lizhong. The reaction program 5tT is carried out on the next day to obtain M amine. Alternatively, the intermediate is reacted with chitosan chloride in the presence of methylbenzene 'in the presence of a test, or in a solvent such as _, and the reaction is carried out for 1 hour to 12 hours to obtain chitosan. In a similar manner, urethanes and esters can be made from chlorocarbonic acid or phosphonium chloride. The reaction system 89385 -30- 200417546 was monitored by chromatography. Synthetic schema method 4:

S 其中R1、R5及R6均如上述。 在方法4中，係使中間物與羧酸，按方法3反應，接著以 還原劑譬如氫化鋰鋁，或另一種氫化物試劑，在溶劑譬如thf 中還原成胺。反應較佳係於高溫譬如65°C下進行約12小時之 時間。或者，使中間物與羧醛，於還原劑譬如爛氣化物試 劑存在下反應。反應係於譬如25°C之溫度下，m ^ 遲行約12小時 合成圖式方法5 :S wherein R1, R5 and R6 are as described above. In the method 4, the intermediate is reacted with the carboxylic acid according to the method 3, and then reduced with a reducing agent such as lithium aluminum hydride or another hydride reagent to a amine in a solvent such as thf. The reaction is preferably carried out at a high temperature such as 65 ° C for about 12 hours. Alternatively, the intermediate is reacted with carboxaldehyde in the presence of a reducing agent such as an offgas reagent. The reaction is, for example, at a temperature of 25 ° C, and m ^ is delayed for about 12 hours. Synthesis Scheme 5:

R、lR, l

R 1/R 1 /

N ”Pd-觸媒1 89385N ”Pd-catalyst 1 89385

Cl 中間物 -31 - r5nco 或者 r6ncoCl intermediate -31-r5nco or r6nco

200417546 在方法5中，係使中間物與異氰酸酯，在溶劑譬如二氧陸 圜中反應。反應較佳#在25°C之溫度下，進行約16小時之時 間。 於另一方面，本發明係提供一種製備式I化合物之方法， 其包括使式II化合物反應：200417546 In method 5, the intermediate is reacted with an isocyanate in a solvent such as dioxolane. The reaction is preferably performed at a temperature of 25 ° C for a period of about 16 hours. In another aspect, the invention provides a method for preparing a compound of formula I, comprising reacting a compound of formula II:

RR

(II) c 其中R1為芳基或雜芳基，其每一個係視情況被一或多個下 列 R3、OR3、OCOR3、COOR3、C0R3、c〇nr3r4、nhc〇r3、nr3r4 、NHS02R3、S02R3、S02NR3R4、SR3、CN、鹵基或N02取代； R與R各獨互為氫、_基、q 6烷基，視情況被Nr3 r4取代 之Cuk基，（：3_8裱烷基、C&gt;6埽基，視情況被nrI4取代之 c3_6缔基’（c3_8i衣烷基）Ci 6烷基、雜環、雜環u完基、Ch 氣燒基，或者，NR3R4可形成具有3至7個原子之環，該環係 視情況包含一或多個其他雜原子，視情況被一或多個A取 代； A為Ci _6燒基或卣基； 作為自由態驗或鹽。 由=合:存:按方法2或3中所述製備，化合物- 且被請求作為本發 式II化5物係為新穎、有用之中間物 89385 -32- 200417546 明之另一方面。 根據式π化合物係舉例如下，但不限於： N-冬基-4,4f-聯ρ比呢-2,2f-二胺， N-(4-氟苯基）-4,4f-聯吡啶-2,2’-二胺； 作為自由態驗或鹽。 【實施方式】 實施例 現在，本發明將以下述實例更詳細地加以說明，其並非欲 被解釋為限制本發明。 所有化學品與試劑均以自供應商接收時之情況使用。iH 與13C核磁共振（NMR)光譜係被記錄在BRUKERDPX400(400 MHz)光譜儀上，使用下列溶劑與參考物。 CDC13 : 1H NMR TMS (0.0 ppm)與 13 C，CDC13 之中心吸收♦ (77.0) 〇 CD3 OD : 1H NMR 3.31 ppm (中心吸收辛）與 13 C 49.0 ppm (中心 吸收♦)。 DMSO-d6 : 1 H NMR 2.50 ppm (中心吸收峰）與 13 C 39.51 ppm (中 心吸收學）。 質譜（TSP)係被記錄在Finigan MAT SSQ 7000光譜儀上。 質譜（EI)係被記錄在Finigan MAT SSQ 710光譜儀上。 LC-MS 係被記錄在裝有 Mass Lynx 3.5 軟體之 Waters Alliance 2790 + ZMD光譜儀上。 急驟式管柱層析係於矽膠60 (230-400網目）上進行。 實例1 N，N，-雙[4-(三氟甲基）苯基]_4,4’_聯吡啶-2,2，·二胺 89385 -33- 200417546 (i) 2-氣基-3-蛾基p比淀 腺 mu(II) c wherein R1 is aryl or heteroaryl, each of which is optionally one or more of the following R3, OR3, OCOR3, COOR3, COR3, cOnr3r4, nhc〇r3, nr3r4, NHS02R3, S02R3, S02NR3R4, SR3, CN, halo or N02 substitution; R and R are each independently hydrogen, _ group, q 6 alkyl, optionally Cuk group substituted by Nr3 r4, (: 3_8 alkyl, C &gt; 6 埽C3_6 alkenyl '(c3_8i caprylyl) Ci 6 alkyl, heterocyclic ring, heterocyclic cyclyl, Ch alkynyl, optionally substituted by nrI4, or NR3R4 can form a ring with 3 to 7 atoms The ring system optionally contains one or more other heteroatoms and is optionally substituted by one or more A; A is Ci_6 alkyl or fluorenyl; as a free state test or salt. Prepared as described in 2 or 3, the compound-and is claimed as a novel and useful intermediate of the formula II H5 system 89385 -32- 200417546 Another aspect of the invention. The compounds according to formula π are exemplified below, but not limited to : N-Deryl-4,4f-bi-rhodan-2,2f-diamine, N- (4-fluorophenyl) -4,4f-bipyridine-2,2'-diamine; as a free state Test or salt. Examples The present invention will now be illustrated in more detail by the following examples, which are not intended to be construed as limiting the invention. All chemicals and reagents are used as received from the supplier. IH and 13C Nuclear Magnetic Resonance (NMR) The spectra were recorded on a BRUKERDPX400 (400 MHz) spectrometer using the following solvents and references: CDC13: 1H NMR TMS (0.0 ppm) and 13 C, CDC13 central absorption ♦ (77.0) 〇CD3 OD: 1H NMR 3.31 ppm ( Central absorption octave) and 13 C 49.0 ppm (central absorption ♦). DMSO-d6: 1 H NMR 2.50 ppm (central absorption peak) and 13 C 39.51 ppm (central absorption science). Mass spectrometry (TSP) was recorded on Finigan MAT SSQ 7000 spectrometer. Mass spectrum (EI) was recorded on a Finigan MAT SSQ 710 spectrometer. LC-MS was recorded on a Waters Alliance 2790 + ZMD spectrometer with Mass Lynx 3.5 software. Flash column chromatography was performed on Silicone 60 (230-400 mesh). Example 1 N, N, -bis [4- (trifluoromethyl) phenyl] _4,4'_bipyridine-2,2, · diamine 89385 -33- 200417546 (i) 2-amino-3-mothyl p ratio gland mu

愛升四氫呋喃中之己烷中正-丁 内。於-78 C下2小時後，將混少 升，14克，0·1莫耳）與2-氯 1 1莫耳）於-78°C下，連續添加至150 正-丁基鋰1.6 Μ (62.5毫升，〇·1莫耳） 將混合物以碘（25.5克，〇·1莫耳）在 TOF(5〇^升）中之溶液處理，並攪拌3〇分鐘，然後於水（ι〇〇 毛升）與乙醚（3 X 50耄升）之間作分液處理。將合併之有機層 、匕#此代;^酸鈉水溶液（2 χ 5〇毫升）洗滌，以硫酸鎂脫水 乾煤，過漉，及在真空下濃縮，而得粗製固體，使其藉急 騾式層析（庚燒/醋酸乙酯90/10)純化。產率：72% (17·3克）， 黃色固體。1㈣敵⑽％): 58.38(dd，J = 46/17HzlH)816(邮 J 8.0/1.6 Hz, 1H)? 6.96 (dd? J = 8.0/4.6 Hz? 1H).13 C NMR (CDC13 )： δ 154.5, 148.9, 148.8, 123.2, 94.9. MS (El) m/z 240 (M+l). (ii) 2-鼠基-4-破基p比淀 將2-氯基各琪基吡啶（12克，50毫莫耳）在2〇毫升Tffi7中之溶 液，慢慢添加至冷（-7VC)鋰二異丙基胺溶液（藉由將己烷中 ;正-丁基鋰1·6 Μ 01.25毫升，50毫莫耳）添加至二異丙基胺（7 笔升，50耄莫耳）在THF (100毫升）中之溶液内而製成）。3小 時後，將水（20耄升）添加至混合物中，將其以醚（2 X 1〇〇毫升） 萃取。使有機層以硫酸鎂脫水乾燥，過濾，及在真空（2〇t：) 下濃縮，而得褐色固體，使其在矽膠（醋酸乙酯/庚烷8/2)上 藉過濾純化。產率：95^(14克），淡黃色針狀物jHNMR(CDCl3) ·· (5 8.07 (d? J = 5.3 Hz? 1H)? 7.76 (d? J = U Hz5 1H)? 7.59 (dd? J = 5.0/1.1 Hz? 89385 -34- 200417546 1H)· 13CNMR(CDC13) : 5 151.7, 149.6, 133.0, 131.5, 106·6· MS (El) m/z 240 (M+l). (iii) 2,2f-二氯-(4,4’)_聯吡啶 將己燒中之正-丁基鐘1·6Μ (6.25毫升，1〇·〇毫莫耳）慢慢添 加至2-氯基-4-破基叶I：淀（4_79克，20·0毫莫耳）在200毫升THF中 之冷（-78 C )落液内。於-78 C下20分鐘後，逐滴添加氯化三甲 基錫（2.0克，10.0毫莫耳）在10毫升THF中之溶液。30分鐘後 ，移除冰浴，並使混合物達到室溫。1小時後，添加水（1〇毫 升），並以醚（2 X 50毫升）萃取溶液。使有機層以硫酸鎂脫水 乾燥’過遽’及在真更下濃縮’而得橘色油。將此粗產物 以甲苯（50毫升）稀釋，並以氮沖洗1〇分鐘。然後添加肆（三 苯膦）免（578毫克，0_5毫莫耳），並將混合物於h〇°c下加熱3 天。於室溫下過濾混合物，並將沉澱物以水（2 X 20毫升）、 庚烷（3 X 30毫升）洗滌，及在真空下乾燥，而得白色固體。 產率：53% (1.20 克）。1H NMR (CDC13): 5 8.55 (d，J = 5·1 Ηζ，2Η)，7.57 (d， J = 1·3 Ηζ，2Η)，7.45 (dd，J = 5.1/1.3 Ηζ，2Η)·13 C NMR (CDC13) : (5152.81， 150.71，147.35, 122.14, 120.21. MS (TSP) m/z 225, 227 (M+l). (iv) N，N’-雙[4-(三氟甲基）苯基]-4,4’-聯吡啶_2,2，·二胺 使2,2-一鼠-(4,4)-聯外1：淀（50毫克’〇.22毫莫耳）、醋酸飽（5.6 毫克，0.022毫莫耳）、雙[三-(第三-丁基）膦]飽（12 5毫克，〇.〇22 ΐ莫耳）、第三-丁醇鈉（60毫克，〇·61毫莫耳）及4-三敦曱基 冬月；（0.3當升’ 2.4毫莫耳）在Schlenk管件中，以氮沖洗分鐘 。然後添加1毫升無水二氧陸圜，密封管件，並將混合物於 -35- 89385 200417546 120 C下攪拌15小時。接著，使混合物冷卻至2〇。〇，過遽，並 以醋酸乙酯（5x10毫升）與水（3x5毫升）洗滌固體。分離有機 液層，以硯酸鎂脫水乾燥，及過濾。將矽膠添加至濾液中 ，於真空下蒸發落劑，並使粗產物藉急騾式層析（醋酸乙酯 /庚、丨元8/2)純化，而得標題化合物12毫克（19% )，為黃色固 體。1 H NMR (DMSO-d6) H72 (s，2H)，8.36 (d，j = 5 2 取 2H)，7 93 (d， J = 8·4 Hz，4H)，7·62 (d，卜 8·5 Hz，4H)，7·18 (s，2H)，7.16 (d，J = 5_1 Hz，2H)· 19 F NMR (DMSO-d6) : 5 _60.09 (s，6F). MS (TSP) m/z 475 (M+l). 實例2 NW-雙（4-氟苯基)-4,4f-聯峨淀-2,2，-二胺 使2,2’-二氯_(4,4’)-聯吡啶（5〇毫克，0·22毫莫耳）、醋酸鈀（5 6 毫克，0.022毫莫耳）、雙[三_(第三_丁基）膦]免（12·5毫克，〇 〇22 毫莫耳）、第三· 丁醇鈉（60毫克，0.61毫莫耳）及4_氟苯胺（〇 3 耄升，3.1耄莫耳），在Schlenk管件中，以氮沖洗1〇分鐘。然 後’添加1毫升無水二氧陸圜，密封管件，並將混合物於12〇 °C下攪拌15小時。接著使混合物冷卻至2〇r，過濾，並以醋 酸乙醋（5 X 10毫升）與水（3 x 5毫升）洗滌固體。使所形成之粉 末於真空下乾燥’而產生48毫克（59% )標題化合物，為黃色 固體。1H NMR (DMSO-d6) : δ 9.46 (s，2H)，8.23 (d，J = 5.3 Hz，2H)，7.73 (m，4H)，7.09 (m，6H)，6·99 (dd，J = 1.0/5.3 Hz，2H). 19 F NMR (DMSO-d6): 5-123.27 (m，2F). 實例3 N，Nf-雙（3,4-二氟苯基聯吡啶 _2,2，_二胺 89385 -36- 200417546 使2,2’-二氯_(4,4’)-聯吡啶（50毫克，〇·22毫莫耳）、醋酸鈀（5·6 毫克’ 0.022毫莫耳）、雙[三-(第三-丁基）膦]免（12.5毫克，0·022 毫莫耳）、第三-丁醇鈉（60毫克，〇 61毫莫耳）及3,4_二氟苯胺 (〇·5毫升，4.0毫莫耳），在Schlenk管件中，以氮沖洗1〇分鐘。 然後添加1毫升無水二氧陸圜，密封管件，並將混合物於120 °C下揽拌15小時。接著，使混合物冷卻至2(rc，過濾，並以 甲苯（5 X 10毫升）、水x 5毫升）及二氯甲烷χ 2毫升）洗滌 固體。使所形成之粉末於真空下乾燥，而產生35毫克（66% ) 標題化合物，為稍微褐色固體。iHNMR(DMsad6): 5 9 71 (s，2Η)， 8.29 (d，J = 5·3 Ηζ，2Η)，8.07 (ddd，J = 7·8/6·4/1 ·9 Ηζ，2Η)，7.38-7.28 (m，4Η)， 7.12 (s，2H)，7.06 (d，J = 5.4 Hz，2H)· 19FNMR(DMSO_d6) : 5 -138.17 (m，2F)，-149.26 (m，2F). MS (TSP)m/z411 (M+l). 實例4 雙[3-(三氟甲基）苯基】-4,4，-聯吡啶-2,2，-二胺 使2,2'-二氯-(4，件聯吡啶（50毫克，0.22毫莫耳）、醋酸鈀（5·6 毫克，0.022毫莫耳）、雙[三-(第三-丁基）膦]免（12·5毫克，〇 〇22 耄莫耳）、第三-丁醇鋼（60毫克，0.61毫莫耳）及3-三氟甲基 苯胺（0.5毫升，4.0毫莫耳），在Schlenk管件中，以氮沖洗1〇分 鐘。然後添加1毫升無水二氧陸圜，密封管件，並將混合物 於120°C下擾拌15小時。接著，使混合物冷卻至，過滤， 並以甲苯（5 xlO毫升）、水（3x5毫升）及二氯甲烷（5χ2毫升） 洗滌固體。使所形成之粉末於真空下乾燥，而產生8〇毫克（76 % )標題化合物。1H NMR (DMSO-d6): 5 9.86 (s，2Η)，8.34 (d，J = 5.3 Ηζ， 89385 -37- 200417546 2H)，8.28 (s，2H)，7·94 (d，J = 8.3 Hz，2H)，7.51 (t，J = 8.0 Hz，2H)，7·21 (d，J = 8.0 Hz? 2H)? 7.19 (s5 2H)5 7.10 (dd, J = 5.4/1.5 Hz5 2H). 19F NMR (DMSO-d6) :5-61.57(s，6F). MS (TSP) m/z 475 (M+l). 實例5 N，N，_雙[3-(三氟甲氧基）苯基卜4,4’·聯吡啶-2,2’-二胺 使2,2f-二氣-(4,4&gt;聯吡啶（22·5毫克，〇·1〇毫莫耳）、醋酸鈀（3·〇 毫克，0.013毫莫耳）、雙[三_(第三-丁基）膦μ巴（7.05毫克，0.013 毫莫耳）、第三-丁醇鈉（36毫克，0.375毫莫耳）及3-三氟甲氧 基苯胺（〇·5毫升，3·1毫莫耳），在Schlenk管件中，以氮沖洗10 分鐘。然後，添加1毫升無水二氧陸圜，密封管件，並將混 合物於120°C下攪拌15小時。接著使混合物冷卻至2〇°c，過濾 ，並以甲苯（5 X 10毫升）、水（3 X 5毫升）及二氯甲烷（5 X 2毫升） 洗滌固體。使所形成之粉末於真空下乾燥，產生35毫克（70 % )標題化合物。1H NMR (DMSO-d6): 6 9.75 (s，2H)，8.34 (d，J = 5·3 Hz， 2H)，8·01 (s，2H)，7.60 (d，J = 7.9 Hz，2H)，7·38 (t，J 二 8.3 Hz, 2H)，7.17 (s，2H), 7·11 (d，J = 5·3 Hz，2H)，6.86 (d，J 二 8.0 Hz，2H). 19 F NMR (DMSO-d6) ·· δ -56.80 (s? 6F). MS (TSP) m/z 507 (M+l). 實例6 N，N’-雙（2-氟苯基)-4,4’-聯吡啶-2,2，-二胺 使2,2’-二氯-(4,4’)_聯吡啶（22.5毫克，0.10毫莫耳）、醋酸鈀（3.0 毫克，〇_〇13毫莫耳）、雙[三-(第三丁基）膦]飽（7 〇5毫克，〇 〇13 毫莫耳）、第三-丁醇鈉（36毫克，0.375毫莫耳）及2-氟基苯胺 89385 -38- 200417546 (〇·5笔升’ 5.2毫莫耳），在Schlenk管件中，以氮沖洗i〇分鐘。 然後添加1毫升無水二氧陸圜，密封管件，並將混合物於12〇 C下攪拌15小時。接著，使混合物冷卻至2〇°c，過濾，並以 水（3x5毫升）與醋酸乙酯（5χ2毫升）洗滌固體。使有機層以 硫酸鎂脫水乾燥，過濾，及在真空下濃縮，而得褐色固體 ’使其藉急驟式層析（庚燒/醋酸乙酯7/3)純化，而產生㊇毫 克（50%)標題化合物。iHNMR(CDC13): 58.32(d，J = 5.1Hz，2H)， 8·〇5 (t，J = 8·1 Hz, 2H)，7·17-7·12 (m，4H)，7.04-6.96 (m，6H)，6.73 (bs，2H). 19 F NMR (CDC13) : δ -130.25 (m? 2F). 13 C NMR (CDC13) ： 5 155.93, 153.54 (d? J = 243.7 Hz)? 148.99, 148.01, 128.60 (d? J = 10.5 Hz)? 124.47 (d? J = 3.6 Hz)，122.84 (d，J = 7.4 Hz)，121.10, 115.40 (d，J= 19.5 Hz)，113.66, 106.96. MS (TSP) m/z 375 (M+l). 實例7 N，N’-雙（2-甲基苯基)-4,4，_聯吡啶-2,2，_二胺 使2,2’-二氯_(4,4&gt;聯吡啶（22.5毫克，〇·1〇毫莫耳）、醋酸鈀（3 〇 *克’ 0.013毫莫耳）、雙[三_(第三_丁基购衫巴⑽5毫克，〇 〇13 *莫耳）、第三-丁醇鈉（36毫克，0.375毫莫耳）及2-甲基苯胺 (0.5 *升，4.0耄莫耳），在§chlenk管件中，以氮沖洗1〇分鐘。 然後，添加1 *升無水二氧陸圜，密封管件，並將混合物於 120°C下攪拌15小時。接著使混合物冷卻至2(rc，過滤，並以 水（3x5毫升）與醋酸乙酯（5χ2毫升）洗滌固體。使有機層以 硫酸鎂脫水乾燥，過濾，及在真空下濃縮，而得褐色固體 ，使其藉急驟式層析（庚烷/醋酸乙酯1Α)純化，產生標題化 合物。1H NMR (DMSO-d6) ·· 5 8.31 (s，2Η)，8.14 (d，J = 5·3Ηζ，2Η)，7.60 89385 -39- 200417546 (d，J = 8.0 Hz，2H)，7.20 (d，J = 7.4 Hz，2H)，7.15 (t，J = 7.4 Hz，2H)，6.99 (t，J = 7·6 Hz，2H)，6.95 (s，2H)，6.91 (d，J = 5.3 Hz，2H)，1.98 (s，6H). MS (TSP)m/z367 (M+l). 實例8 N，Nf-雙（2-胺基苯基)-4,4’-聯吡啶-2,2f•二胺 使2,2’-二氯-(4，件聯吡啶（50毫克，〇_22毫莫耳）、醋酸鈀（5.6 毫克，0.022毫莫耳）、雙[三-(第三-丁基）膦]飽（12.5毫克，0.022 毫莫耳）、第三-丁醇鈉（60毫克，0.61毫莫耳）及2-胺基苯胺（144 Φ克，1_33毫莫耳），在Schlenk管件中，以氮沖洗10分鐘。然 後添加1毫升無水二氧陸圜，密封管件，並將混合物於12〇°c 下攪拌15小時。接著，使混合物冷卻至20°C，過濾，並以醋 酸乙酯（5 X 10毫升）、甲醇（3 X 5毫升）及水（5 x2毫升）洗滌固 體。使有機層以硫酸鍰脫水乾燥，過濾，及在真空下濃縮 ’而得褐色固體，使其藉急驟式層析（庚烷/醋酸乙酯1/1)純 化，而產生27毫克（33%)標題化合物。iHNMRCMeOD-c^)·· 5 8·05 (d，J = 5.4 Hz，2H)，7.13 (dd，J = 7.7/1.2 Hz，2H)，7.04 (td，J = 8.1/1.5 Hz， 2H)5 6.88 (d? J = 1.2 Hz? 2H)? 6.87 (dd5 J = 3.2/1.5 Hz? 2H)? 6.72 (td5 J - 7.7/1.5 Hz，2H)，6.69 (s，2H)· 13 C NMR (MeOD-d4) : δ 160.05, 149.75, 149.44， 144.75, 128.04, 127.93, 127.27, 119.78, 118.02, 112.81，107·20· MS (TSP) mJz 369 (M+l). 實例9 N，N’-雙（2-甲氧苯基)-4,4’-聯吡啶-2,2，-二胺 使2,2’-二氯-(4,4’)_聯吡啶（50毫克，0.22毫莫耳）、醋酸鈀（5.6 毫克，0.022毫莫耳）、雙[三_(第三-丁基）膦]免（12.5毫克，〇_〇22 89385 -40- 200417546 笔莫耳）、第二-丁醇鈉（6〇毫克，〇·6ΐ毫莫耳）及2_甲氧基苯 月女（0.5笔升，4.4耄莫耳），在Schlenk管件中，以氮沖洗1〇分鐘 。然後，添加1毫升無水二氧陸圜，密封管件，並將混合物 於120°C下攪拌15小時。接著使混合物冷卻至2(rc，過濾，並 以醋酸乙酯（5 X 10毫升）、甲醇（3 χ 5毫升）及水（5 χ 2毫升）洗 滕固fa。使有機層以硫酸鎂脫水乾燥，過遽，及在真空下 濃縮，而得褐色固體，使其藉急騾式層析（庚烷/醋酸乙酯8/2) 純化，而產生40毫克（46%)標題化 5 8·29_8·25 (m，4H)，8.22 (d，J = 5·7 Hz，2H)，7.35 (m，2H)，7.02-7·。1 (m，4H)，響 6.96-6.88 (m，4H)，3.85 (s，6H). MS (TSP) m/z 399 (M+l). 實例10 N，N’-雙（2_乙氧苯基)-4,4’_聯峨淀_2,2，_二胺 使2,2’-二氯_(4,4’)·聯吡啶（5〇毫克，〇·22毫莫耳）、醋酸鈀（5·6 晕克’ 0.022毫莫耳）、雙[三兴第三_丁基）騰]飽（12·5毫克，〇 〇22 耄莫耳）、第三-丁醇鈉（60毫克，〇·6ΐ毫莫耳）及2-乙氧基苯 g 胺（0.5笑升，3_3耄莫耳），在Schlenk管件中，以氮沖洗1〇分鐘 。然後添加1耄升無水二氧陸圜，密封管件，並將混合物於 120 C下攪拌15小時。接著’使混合物冷卻至2〇它，過濾，並 以醋酸乙酯（5\10毫升）、甲醇（3乂5毫升）及水（5\2毫升）洗 滌固體。使有機層以硫酸鎂脫水乾燥，過濾、，及在真空下 濃縮，而得褐色固體，使其藉急驟式層析（庚烷/醋酸乙酯8/2) 純化，而產生35毫克（37%)標題化合物。iHNMR(DMSO-d6): 5 8.22 (d，J = 4.9 Hz，2H)，8·21 (m，2H)，8.12 (s，2H)，7.32 (s，2H)，7.03 (dd， 89385 -41 - 200417546 J = 5.4/1.2 Hz，2H)，7.00 (dd，J = 7.9/1.9 Hz，2H)，6.94-6.87 (m，4H)，4.10 (q5 J = 7·0 Hz，4H)，1.36 (t，J 7.0 Hz，6H). MS (TSP) m/z 427 (M+l). 實例11 Ν·苯基-4,4’_聯吡啶_2,2f-二胺 於氮氣下，使4,4’-聯吡啶-2,2f-二胺（描述於J. Org_ Chem· 1997第 62卷，第2774-2781頁中）(744毫克，4.0毫莫耳）、碘苯（0.448毫 升，4.0毫莫耳）、參（二苯亞甲基丙酮）二鈀⑼-氣仿加成物（2〇8 毫克，〇·2毫莫耳）、1，1’_雙（二苯基膦基）二環戊二烯鐵(220毫 克，〇·4毫莫耳）及第三-丁醇鈉（538毫克，5.6毫莫耳），在100 毫升圓底燒瓶中沖洗20分鐘。然後添加20毫升無水DMF， 並將混合物於100°C下攪拌15小時。使混合物冷卻至室溫， 於矽藻土墊上過濾，將矽膠添加至濾液中，及在真空下蒸 發溶劑。使粗產物藉急騾式層析（醋酸乙酯/甲醇/三乙胺 94/3/3)純化，而產生277毫克（26% )標題化合物。iHNMR (DMSO-d6): δ 9.16 (s，1H)，8.22 (d，J = 5.3 Hz，1H)，8·01 (d，J = 5.3 Hz，1H)， 7.68 (d，J = 7·9 Hz，2H)，7.26 (t，J = 8·1 Hz，2H)，7·03 (s，1H)，6·94 (dd，J = 5.1/ 0·9 Hz，1H)，6·89 (t，J = 7.3 Hz，1H)，6.73 (dd，J = 5.1/1.1 Hz，1H)，6.68 (s，1H)， 6.10 (s，2H)· 13CNMR(DMSO-d6): 5 160.94, 157.00, 149.23, 148.60, 147.29, 146.65, 141.94, 129.04, 120.99, 118.54, 112.22, 109.86, 108.00, 105.23. MS (TSP) m/z 263 (M+l). 實例12 N-(4-氟苯基）-4,4’-聯吡啶-2,2，-二胺 使4,4’-聯吡啶-2,二胺（187毫克，1.0毫莫耳）、4-氟基碘苯(222 89385 -42- 200417546 毫克，1·〇毫莫耳）、銅碘化物（10毫克，〇 〇5毫莫耳）、磷酸 钾（425需克，2.0耄莫耳）、乙二醇（in微升，2 〇毫莫耳）、2_ 丙醇（1_〇毫升）及無水二甲基甲醯胺（1.〇毫升），在有螺帽之試 官中，以氮沖洗10分鐘。密封管件，並在16〇t下之微波爐 中放置1小時。添加水（5毫升），並以醋酸乙酯（4 X 5毫升）萃 取混合物。使有機層以硫酸鎂脫水乾燥，過濾，及在真空 下濃縮，而得褐色固體，使其藉急驟式層析（醋酸乙酯/甲 醇/三乙胺94/3/3)純化，而產生98毫克（35% )標題化合物。 1H NMR (DMSO-d6) ： δ 9.17 (s5 1H)5 8.20 (d5 J = 5.3 Hz? 1H)5 8.00 (d? J = 5·3 Hz，1H)，7·70_7·68 (m，1H)，7.11 (t，J = 8.8 Hz，2H)，7.08 (s，1H)，6.95 (dd，Hexanes in tetrahydrofuran in n-butane. After 2 hours at -78 C, add 1 litre of mixed, 14 g, 0.1 mol) and 2-chloro 1 1 mol) at -78 ° C, continuously add 150 n-butyllithium 1.6 Μ (62.5 ml, 0.1 mole) The mixture was treated with a solution of iodine (25.5 g, 0.1 mole) in TOF (50 liters) and stirred for 30 minutes, then in water (ι〇〇. Gross liters) and ether (3 X 50 耄 liters) were separated. Wash the combined organic layers and the sodium hydroxide solution (2 x 50 ml), dehydrate the dried coal with magnesium sulfate, dry it, and concentrate under vacuum to obtain a crude solid. Purification by column chromatography (heptane / ethyl acetate 90/10). Yield: 72% (17.3 g), yellow solid. 1% of enemies): 58.38 (dd, J = 46 / 17HzlH) 816 (post J 8.0 / 1.6 Hz, 1H)? 6.96 (dd? J = 8.0 / 4.6 Hz? 1H). 13 C NMR (CDC13): δ 154.5, 148.9, 148.8, 123.2, 94.9. MS (El) m / z 240 (M + 1). G, 50 mmol) in 20 ml of Tffi7, slowly added to cold (-7VC) lithium diisopropylamine solution (by adding hexane; n-butyllithium 1.6 M 01.25 (ML, 50 mmol) was added to a solution of diisopropylamine (7 pens, 50 μmol) in THF (100 mL)). After 3 hours, water (20 liters) was added to the mixture and it was extracted with ether (2 X 100 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum (20 t :) to give a brown solid, which was purified by filtration on silica gel (ethyl acetate / heptane 8/2). Yield: 95 ^ (14 g), light yellow needles jHNMR (CDCl3) ·· (5 8.07 (d? J = 5.3 Hz? 1H)? 7.76 (d? J = U Hz5 1H)? 7.59 (dd? J = 5.0 / 1.1 Hz? 89385 -34- 200417546 1H) 13CNMR (CDC13): 5 151.7, 149.6, 133.0, 131.5, 106 · MS (El) m / z 240 (M + l). (Iii) 2,2f-Dichloro- (4,4 ')-bipyridine Slowly add n-butyl bell 1. 6M (6.25 ml, 10.0 mmol) to 2-chloro- 4-broken leaf I: cold (-78 C) falling in 200 ml of THF (4-79 g, 20.0 mmol) into the liquid. After 20 minutes at -78 C, trichloride was added dropwise. A solution of methyltin (2.0 g, 10.0 mmol) in 10 ml of THF. After 30 minutes, the ice bath was removed and the mixture was allowed to reach room temperature. After 1 hour, water (10 ml) was added and The solution was extracted with ether (2 X 50 ml). The organic layer was dehydrated and dried over magnesium sulfate and 'concentrated' to give an orange oil. This crude product was diluted with toluene (50 ml) and nitrogen Rinse for 10 minutes. Then add triphenylphosphine (578 mg, 0-5 mmol) and heat the mixture at 0 ° C for 3 minutes. The mixture was filtered at room temperature, and the precipitate was washed with water (2 X 20 mL), heptane (3 X 30 mL), and dried under vacuum to give a white solid. Yield: 53% (1.20 g ). 1H NMR (CDC13): 5 8.55 (d, J = 5 · 1 Ηζ, 2Η), 7.57 (d, J = 1.3 · Ηζ, 2Η), 7.45 (dd, J = 5.1 / 1.3 Ηζ, 2Η) 13 C NMR (CDC13): (5152.81, 150.71, 147.35, 122.14, 120.21. MS (TSP) m / z 225, 227 (M + 1). (Iv) N, N'-bis [4- (trifluoro (Methyl) phenyl] -4,4'-bipyridine_2,2, · diamine makes 2,2-monorat- (4,4) -exo 1: lake (50 mg '0.22 mmol) Ear), acetic acid (5.6 mg, 0.022 mmol), bis [tri- (tertiary-butyl) phosphine] (12 5 mg, 0.022 mole), tert-butoxide ( 60 mg, 0.61 mmol) and 4-trimethylpyrene; (0.3 dL '2.4 mmol) in a Schlenk tube, flush with nitrogen for one minute. Then add 1 ml of anhydrous dioxin, The tube was sealed and the mixture was stirred at -35- 89385 200417546 120 C for 15 hours. Then, the mixture was cooled to 20. Then, the solid was washed with ethyl acetate (5 x 10 ml) and water (3 x 5 ml). The organic liquid layer was separated, dried over magnesium acetate, and filtered. Silicone was added to the filtrate, and the solvent was evaporated under vacuum, and the crude product was purified by flash chromatography (ethyl acetate / heptane, 8/2) to obtain 12 mg (19%) of the title compound. As a yellow solid. 1 H NMR (DMSO-d6) H72 (s, 2H), 8.36 (d, j = 5 2 2H), 7 93 (d, J = 8.4 Hz, 4H), 7.62 (d, Bu 8 5 Hz, 4H), 7.18 (s, 2H), 7.16 (d, J = 5_1 Hz, 2H) 19 F NMR (DMSO-d6): 5 _60.09 (s, 6F). MS (TSP ) m / z 475 (M + l). Example 2 NW-Bis (4-fluorophenyl) -4,4f-Lianedian-2,2, -diamine makes 2,2'-dichloro_ (4 , 4 ')-bipyridine (50 mg, 0.22 mmol), palladium acetate (56 mg, 0.022 mmol), bis [tri- (tertiary-butyl) phosphine] free (12 · 5 mg, 0.0022 mmol), sodium tert-butoxide (60 mg, 0.61 mmol), and 4-fluoroaniline (0.3 μl, 3.1 μmol) in a Schlenk fitting with nitrogen Rinse for 10 minutes. Then, 1 ml of anhydrous dioxin was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. The mixture was then cooled to 200 r, filtered, and the solid was washed with ethyl acetate (5 x 10 mL) and water (3 x 5 mL). The resulting powder was dried under vacuum 'to give 48 mg (59%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.46 (s, 2H), 8.23 (d, J = 5.3 Hz, 2H), 7.73 (m, 4H), 7.09 (m, 6H), 6.99 (dd, J = 1.0 / 5.3 Hz, 2H). 19 F NMR (DMSO-d6): 5-123.27 (m, 2F). Example 3 N, Nf-bis (3,4-difluorophenylbipyridine_2,2, _ Diamine 89385 -36- 200417546 makes 2,2'-dichloro_ (4,4 ')-bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 mg' 0.022 mmol) , Bis [tri- (tertiary-butyl) phosphine] imine (12.5 mg, 0.022 mmol), tertiary-butoxide (60 mg, 061 mmol) and 3,4_difluoro Aniline (0.5 ml, 4.0 mmol) was flushed with nitrogen in a Schlenk tube for 10 minutes. Then 1 ml of anhydrous dioxin was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. Then, the mixture was cooled to 2 (rc, filtered, and the solid was washed with toluene (5 x 10 ml), water x 5 ml) and dichloromethane x 2 ml. The resulting powder was dried under vacuum to yield 35 mg (66%) of the title compound as a slightly brown solid. iHNMR (DMsad6): 5 9 71 (s, 2Η), 8.29 (d, J = 5 · 3 Ηζ, 2Η), 8.07 (ddd, J = 7 · 8/6 · 4/1 · 9 Ηζ, 2Η), 7.38-7.28 (m, 4Η), 7.12 (s, 2H), 7.06 (d, J = 5.4 Hz, 2H) · 19FNMR (DMSO_d6): 5 -138.17 (m, 2F), -149.26 (m, 2F). MS (TSP) m / z411 (M + 1). Example 4 Bis [3- (trifluoromethyl) phenyl] -4,4, -bipyridine-2,2, -diamine gives 2,2'- Dichloro- (4, bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 mg, 0.022 mmol), bis [tri- (third-butyl) phosphine] free (12 · 5 mg, 002 mol), tertiary-butanol steel (60 mg, 0.61 mmol) and 3-trifluoromethylaniline (0.5 ml, 4.0 mmol), in a Schlenk tube, to Nitrogen was flushed for 10 minutes. Then 1 ml of anhydrous dioxin was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. Then, the mixture was cooled to, filtered, and washed with toluene (5 x 10 ml), The solid was washed with water (3x5 ml) and dichloromethane (5x2 ml). The resulting powder was dried under vacuum to yield 80 mg (76%) of the title compound. 1H N MR (DMSO-d6): 5 9.86 (s, 2Η), 8.34 (d, J = 5.3 Ηζ, 89385 -37- 200417546 2H), 8.28 (s, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz? 2H)? 7.19 (s5 2H) 5 7.10 (dd, J = 5.4 / 1.5 Hz5 2H). 19F NMR (DMSO-d6): 5-61.57 (s, 6F). MS (TSP) m / z 475 (M + 1). Example 5 N, N, _bis [3- (trifluoromethoxy) phenyl) phenyl 4,4 '· bipyridine-2,2'-diamine made 2,2f-digas- (4,4> bipyridine (22.5 mg, 0.1 mmol), palladium acetate (3 · 〇mg, 0.013 millimoles), bis [tri- (third-butyl) phosphine μbar (7.05 milligrams, 0.013 millimoles), sodium tertiary-butoxide (36 mg, 0.375 millimoles), and 3 -Trifluoromethoxyaniline (0.5 ml, 3.1 mmol) in a Schlenk fitting, flushed with nitrogen for 10 minutes. Then, add 1 ml of anhydrous dioxolane, seal the fitting, and place the mixture in Stir at 120 ° C for 15 hours. The mixture was then cooled to 20 ° C, filtered, and the solid was washed with toluene (5 X 10 mL), water (3 X 5 mL), and dichloromethane (5 X 2 mL). The resulting powder was dried under vacuum to yield 35 mg (70%) of the title compound. 1H NMR (DMSO-d6): 6 9.75 (s, 2H), 8.34 (d, J = 5.3 Hz, 2H), 8.01 (s, 2H), 7.60 (d, J = 7.9 Hz, 2H) , 7.38 (t, J 8.3 Hz, 2H), 7.17 (s, 2H), 7.11 (d, J = 5.3 Hz, 2H), 6.86 (d, J 8.0 Hz, 2H). 19 F NMR (DMSO-d6) ·· δ -56.80 (s? 6F). MS (TSP) m / z 507 (M + 1). Example 6 N, N'-bis (2-fluorophenyl) -4 , 4'-bipyridine-2,2, -diamine makes 2,2'-dichloro- (4,4 ')-bipyridine (22.5 mg, 0.10 mmol), palladium acetate (3.0 mg, 〇_ (0013 mmol), bis [tri- (third-butyl) phosphine] saturation (705 mg, 0.013 mmol), sodium third-butoxide (36 mg, 0.375 mmol), and 2-Fluoroaniline 89385 -38- 200417546 (0.5 pen liters' 5.2 mmol), in a Schlenk fitting, flush with nitrogen for 10 minutes. Then 1 ml of anhydrous dioxan was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. The mixture was then cooled to 20 ° C, filtered, and the solid was washed with water (3 x 5 ml) and ethyl acetate (5 x 2 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a brown solid, which was purified by flash chromatography (heptane / ethyl acetate 7/3) to yield ㊇mg (50%) Title compound. iHNMR (CDC13): 58.32 (d, J = 5.1 Hz, 2H), 8.05 (t, J = 8.1 Hz, 2H), 7.17-7 · 12 (m, 4H), 7.04-6.96 (m, 6H), 6.73 (bs, 2H). 19 F NMR (CDC13): δ -130.25 (m? 2F). 13 C NMR (CDC13): 5 155.93, 153.54 (d? J = 243.7 Hz)? 148.99 , 148.01, 128.60 (d? J = 10.5 Hz)? 124.47 (d? J = 3.6 Hz), 122.84 (d, J = 7.4 Hz), 121.10, 115.40 (d, J = 19.5 Hz), 113.66, 106.96. MS (TSP) m / z 375 (M + 1). Example 7 N, N'-bis (2-methylphenyl) -4,4, _bipyridine-2,2, _diamine is 2,2 ' -Dichloro_ (4,4 &gt; bipyridine (22.5 mg, 0.10 mmol), palladium acetate (30 * g '0.013 mmol), bis [tri_ (third_butyl shopping shirt) Babb 5 mg, 001 * Moore), sodium tert-butoxide (36 mg, 0.375 mmol) and 2-methylaniline (0.5 * L, 4.0 mg), in §chlenk tubing, Rinse with nitrogen for 10 minutes. Then, add 1 * liter of anhydrous dioxin, seal the tube, and stir the mixture at 120 ° C for 15 hours. Then cool the mixture to 2 (rc, filter, and wash with water (3x5 Ml) with ethyl acetate (5x2 ml) The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a brown solid, which was purified by flash chromatography (heptane / ethyl acetate 1A) to give the title compound. 1H NMR ( DMSO-d6) ·· 5 8.31 (s, 2Η), 8.14 (d, J = 5 · 3Ηζ, 2Η), 7.60 89385 -39- 200417546 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 7.4 Hz, 2H), 7.15 (t, J = 7.4 Hz, 2H), 6.99 (t, J = 7.6 Hz, 2H), 6.95 (s, 2H), 6.91 (d, J = 5.3 Hz, 2H) , 1.98 (s, 6H). MS (TSP) m / z367 (M + 1). Example 8 N, Nf-bis (2-aminophenyl) -4,4'-bipyridine-2,2f • di Amine made 2,2'-dichloro- (4, bipyridine (50 mg, 0-22 mmol), palladium acetate (5.6 mg, 0.022 mmol), bis [tri- (third-butyl) ) Phosphine] saturated (12.5 mg, 0.022 mmol), sodium tert-butoxide (60 mg, 0.61 mmol) and 2-aminoaniline (144 Φ g, 1-33 mmol) in Schlenk fittings Rinse with nitrogen for 10 minutes. Then, 1 ml of anhydrous dioxin was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. Then, the mixture was cooled to 20 ° C, filtered, and the solid was washed with ethyl acetate (5 X 10 ml), methanol (3 X 5 ml) and water (5 x 2 ml). The organic layer was dried over hydration sulfate, filtered, and concentrated under vacuum to give a brown solid, which was purified by flash chromatography (heptane / ethyl acetate 1/1) to yield 27 mg (33%) Title compound. iHNMRCMeOD-c ^) · 5 8 · 05 (d, J = 5.4 Hz, 2H), 7.13 (dd, J = 7.7 / 1.2 Hz, 2H), 7.04 (td, J = 8.1 / 1.5 Hz, 2H) 5 6.88 (d? J = 1.2 Hz? 2H)? 6.87 (dd5 J = 3.2 / 1.5 Hz? 2H)? 6.72 (td5 J-7.7 / 1.5 Hz, 2H), 6.69 (s, 2H), 13 C NMR (MeOD -d4): δ 160.05, 149.75, 149.44, 144.75, 128.04, 127.93, 127.27, 119.78, 118.02, 112.81, 107 · 20 · MS (TSP) mJz 369 (M + l). Example 9 N, N'-Double ( 2-methoxyphenyl) -4,4'-bipyridine-2,2, -diamine makes 2,2'-dichloro- (4,4 ') _ bipyridine (50 mg, 0.22 mmol) , Palladium acetate (5.6 mg, 0.022 mmol), bis [tri- (tertiary-butyl) phosphine] free (12.5 mg, 〇_〇22 89385 -40- 200417546 pen mole), second-butanol Sodium (60 mg, 0.6 μmol) and 2-methoxybenzone (0.5 liter, 4.4 μmol) were flushed in a Schlenk tube with nitrogen for 10 minutes. Then, 1 ml of anhydrous dioxan was added, the tube was sealed, and the mixture was stirred at 120 ° C for 15 hours. The mixture was then cooled to 2 (rc, filtered and washed with ethyl acetate (5 x 10 ml), methanol (3 x 5 ml) and water (5 x 2 ml). The organic layer was dehydrated with magnesium sulfate Dry, filter, and concentrate under vacuum to give a brown solid, which was purified by flash chromatography (heptane / ethyl acetate 8/2) to yield 40 mg (46%) of the title compound 5 8 · 29_8 · 25 (m, 4H), 8.22 (d, J = 5.7 Hz, 2H), 7.35 (m, 2H), 7.02-7 ·. 1 (m, 4H), 6.96-6.88 (m, 4H) ), 3.85 (s, 6H). MS (TSP) m / z 399 (M + l). Example 10 N, N'-Bis (2_ethoxyphenyl) -4,4'_lianedian_2 , 2, _diamine makes 2,2'-dichloro_ (4,4 ') · bipyridine (50 mg, 0.22 mmol), palladium acetate (5.6 halo g' 0.022 mmol) ), Bis [Sanxing tertiary butyl] Teng] full (12.5 mg, 002 mol), sodium tert-butoxide (60 mg, 0.6 mol) and 2-ethyl Oxybenzamine (0.5 liters, 3-3 mol) in a Schlenk fitting, flush with nitrogen for 10 minutes. Then 1 liter of anhydrous dioxin was added, the tube was sealed, and the mixture was stirred at 120 C for 15 hours. The mixture was then cooled to 20 ° C, filtered, and the solid was washed with ethyl acetate (5 \ 10 ml), methanol (3.5 ml) and water (5 \ 2 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a brown solid, which was purified by flash chromatography (heptane / ethyl acetate 8/2) to yield 35 mg (37% ) The title compound. iHNMR (DMSO-d6): 5 8.22 (d, J = 4.9 Hz, 2H), 8.21 (m, 2H), 8.12 (s, 2H), 7.32 (s, 2H), 7.03 (dd, 89385 -41 -200417546 J = 5.4 / 1.2 Hz, 2H), 7.00 (dd, J = 7.9 / 1.9 Hz, 2H), 6.94-6.87 (m, 4H), 4.10 (q5 J = 7.0 Hz, 4H), 1.36 ( t, J 7.0 Hz, 6H). MS (TSP) m / z 427 (M + l). Example 11 N · phenyl-4,4'_bipyridine_2,2f-diamine under nitrogen to make 4 , 4'-bipyridine-2,2f-diamine (described in J. Org_Chem. 1997 Vol. 62, pages 2774-2781) (744 mg, 4.0 mmol), iodobenzene (0.448 ml, 4.0 Millimolar), ginseng (diphenylmethyleneacetone) dipalladium europium-aeroform adduct (208 mg, 0.2 millimolar), 1,1'_bis (diphenylphosphino) Iron dicyclopentadiene (220 mg, 0.4 mmol) and sodium tert-butoxide (538 mg, 5.6 mmol) were rinsed in a 100 ml round bottom flask for 20 minutes. Then 20 ml of anhydrous DMF was added, and the mixture was stirred at 100 ° C for 15 hours. The mixture was allowed to cool to room temperature, filtered on a pad of diatomaceous earth, silica gel was added to the filtrate, and the solvent was evaporated under vacuum. The crude product was purified by flash chromatography (ethyl acetate / methanol / triethylamine 94/3/3) to give 277 mg (26%) of the title compound. iHNMR (DMSO-d6): δ 9.16 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.26 (t, J = 8.1 Hz, 2H), 7.03 (s, 1H), 6.94 (dd, J = 5.1 / 0.9 Hz, 1H), 6.89 ( t, J = 7.3 Hz, 1H), 6.73 (dd, J = 5.1 / 1.1 Hz, 1H), 6.68 (s, 1H), 6.10 (s, 2H) · 13CNMR (DMSO-d6): 5 160.94, 157.00, 149.23, 148.60, 147.29, 146.65, 141.94, 129.04, 120.99, 118.54, 112.22, 109.86, 108.00, 105.23. MS (TSP) m / z 263 (M + l). Example 12 N- (4-fluorophenyl)- 4,4'-bipyridine-2,2, -diamine is 4,4'-bipyridine-2, diamine (187 mg, 1.0 mmol), 4-fluoroiodobenzene (222 89385 -42- 200417546 mg, 1.0 mmole), copper iodide (10 mg, 0.05 mmole), potassium phosphate (425 g, 2.0 μmol), ethylene glycol (in microliters, 2.0 mmol) Mol), 2-propanol (1.0 ml) and anhydrous dimethylformamide (1.0 ml). In a nut-testing officer, flush with nitrogen for 10 minutes. The tube was sealed and placed in a microwave oven at 160 t for 1 hour. Water (5 ml) was added and the mixture was extracted with ethyl acetate (4 X 5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give a brown solid, which was purified by flash chromatography (ethyl acetate / methanol / triethylamine 94/3/3) to give 98 Mg (35%) of the title compound. 1H NMR (DMSO-d6): δ 9.17 (s5 1H) 5 8.20 (d5 J = 5.3 Hz? 1H) 5 8.00 (d? J = 5 · 3 Hz, 1H), 7.70_7 · 68 (m, 1H) , 7.11 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.95 (dd,

J = 5·3/1·4 Hz，1H)，6·74 (dd，J = 5.2/1.5 Hz，1H)，6.08 (s，2H). 1 9F NMR (DMSO-d6)： 5-123.25 (m5 IF). MS (TSP) m/z281 (M+l). 實例13 N-(2’-苯胺基_4,4’·聯吡啶-2-基)_反式_4-甲氧基環己烷羧醯胺 於氮氣及20°C下，將乙基二異丙基胺（129毫克，1〇毫莫耳） 慢慢添加至四氟硼酸n，n，n，，n’-四甲基_鄰-(苯并三唑小基）錁 (241毫克’ 〇·75毫莫耳）、羥基苯并三唑⑼丨毫克，〇·75毫莫 耳）及4-甲氧基環己燒幾酸（78毫克，〇·5毫莫耳）在3毫升乙腈 中之溶液内。5分鐘後，於氮氣下，將此溶液添加至队苯基_ 4,4f-聯吡啶j，二胺（131毫克，0.5毫莫耳）在2毫升二甲基甲 酉m胺中之4液内。攪拌4天後，以飽和碳酸氫納水溶液（j毫 升）使反應淬滅。以二氯甲烷萃取水層。使有機層以硫酸鎂 脫水乾燥’於減壓下移除溶劑，而得粗產物，使其藉逆相 89385 -43- 200417546 層析純化，而產生6毫克標題化合物。1HNMR(CDC13): 5 8.51 (s，1H)，8.32 (s，1H)，8·31 (d，J = 4.9 Hz，1H)，8.28 (d，J = 5.0 Hz，1H)，7.42. 7.34 (m，4H)，7.23 (dd，J = 1.6/5.1 Hz，1H)，7.10 (m，2H)，7·01 (dd，J = 1_5/5·2 Hz? 1HX 6.89 (s? 1H)5 3.38 (s? 3H)? 3.19 (m? 1H)? 2.29 (m? 1H)5 2.20-1.89 (m5 3H)，1.75 (m，1H)，1.64 (m，2H)，1.30 (m，2H). MS (TSP) m/z 403 (M+l). 實例14 N-(2’-苯胺基-4,4^聯吡啶-2-基）-順式斗甲氧基環己烷羧醯胺 於氮氣及20°C下，將乙基二異丙基胺（129毫克，1.0毫莫耳） 慢慢添加至四氟硼酸N，N，N’，Nf-四甲基-鄰-(苯并三唑-1-基）錁 (241毫克，〇·75毫莫耳）、羥基苯并三唑（101毫克，〇.75毫莫 耳）及4-甲氧基環己烷羧酸（78毫克，0.5毫莫耳）在3毫升乙腈 中之溶液内。於氮氣下，5分鐘後，將此溶液添加至N-苯基-4,4’-聯吡啶-2,2f-二胺（131毫克，0·5毫莫耳）在2毫升二甲基甲 醯胺中之溶液内。攪拌4天後，以飽和碳酸氫鈉水溶液（5毫 升）使反應淬滅。以二氯甲烷萃取水層。使有機層以硫酸鎂 脫水乾燥，於減壓下移除溶劑，而得粗產物，使其藉逆相 層析純化，而產生8毫克標題化合物。1HNMR(CDC13): δ 8.53 (s，lH)，8.31(d，J = 5.1Hz，lH)，8.28(d，J = 5.2Hz，lH)，8.19(s，lH)，7.42- 7.34 (m，4H)，7.21 (dd，J = 1.5/5.2 Hz，1H)，7.10 (m，2H)，7·01 (dd，J = 1.3/5.2 Hz? 1H)5 6.84 (s? 1H)? 3.49 (m? 1H)? 3.33 (s? 3H)? 2.37 (1H)5 2.05-1.89 (m? 4H)5 1.80-1.76 (m，2H)，1.55-1.47 (m，2H). MS (TSP) m/z 403 (M+l). 實例15 -44- 89385 200417546 N-{2 -[(4-氟苯基）肢基】_4,4f_聯u比淀_2-基}_反式_4_甲氧基-環己燒 羧醯胺 於氮氣及20 C下，將氯化草驢（171毫克，1.35毫莫耳）慢慢 添加至4-甲氧基-環己烷羧酸（7〇毫克，〇·45毫莫耳）在2毫升二 氯甲中之溶液内。攪拌30分鐘後，於真空下濃縮混合物 ’而得無色油’將其在1.0毫升二氣甲燒中稀釋。然後，將 此溶液添加至N-(2-氟苯基_4,4，-聯吡啶-2,2，-二胺（127毫克，0.45 毫莫耳）在5毫升吡啶中之溶液内。攪拌5分鐘後，添加5毫 升飽和碳酸氫鈉水溶液，並以二氯甲烷萃取水層。使有機 層以硫酸4美脫水乾燥，過遽，及在減壓下濃縮，而得粗產 物’使其藉逆相層析純化，而產生1〇毫克標題化合物。 1H NMR (CDC13): (5 8.49 (s，1H)，8.32 (d，J = 5.3 Hz，1H)，8.27 (d，J = 5.2 Hz， 1H)，8.17 (s，1H)，7·4(Κ7·36 (m，2H)，7.21 (dd，J = 1.5/5.2 Hz，1H)，7.08 (m，2H)， 7.00 (dd，J = 1·4/5·3 Hz，1H)，6.94 (s，1H)，6.66 (s，1H)，3.39 (s，3H)，3.20 (m， 1H)，2.30-2.06 (m，5H)，1.64 (m，2H)，1.30 (m, 2H). 19 F NMR (CDC13) : 5 -119.48 (m5 IF). MS (ES) m/z 421 (M+l). 實例16 N_{2f_[(4-氟苯基）胺基】-4,4’_聯吡啶-2-基}_順式_4-甲氧基_環己烷 羧醯胺 於氮氣及20°C下，將氯化草醯（171毫克，1·35毫莫耳）慢慢 添加至4-甲氧基-環己烷羧酸（70毫克，0.45毫莫耳）在2毫升二 氯甲烷中之溶液内。攪拌30分鐘後，使混合物於真空下濃 縮’而得無色油，將其在1.0毫升二氯甲烷中稀釋。然後， 89385 -45- 200417546J = 5 · 3/1 · 4 Hz, 1H), 6.74 (dd, J = 5.2 / 1.5 Hz, 1H), 6.08 (s, 2H). 1 9F NMR (DMSO-d6): 5-123.25 ( m5 IF). MS (TSP) m / z281 (M + 1). Example 13 N- (2'-aniline_4,4 '· bipyridin-2-yl) _trans_4-methoxy ring Hexylcarboxamide under nitrogen and 20 ° C, ethyldiisopropylamine (129 mg, 10 mmol) was slowly added to tetrafluoroborate n, n, n ,, n'-tetramethyl -O- (benzotriazole small group) fluorene (241 mg '0.75 mg), hydroxybenzotriazole ⑼ mg, 0.75 mol) and 4-methoxycyclohexane A solution of chilic acid (78 mg, 0.5 mmol) in 3 ml of acetonitrile. After 5 minutes, this solution was added to 4 liquids of phenylphenyl-4,4f-bipyridine j, diamine (131 mg, 0.5 mmol) in 2 ml of dimethylformamide under nitrogen. Inside. After stirring for 4 days, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (jmL). The aqueous layer was extracted with dichloromethane. The organic layer was dehydrated and dried with magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by reverse phase chromatography using 89385 -43- 200417546 to give 6 mg of the title compound. 1HNMR (CDC13): 5 8.51 (s, 1H), 8.32 (s, 1H), 8.31 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 5.0 Hz, 1H), 7.42. 7.34 ( m, 4H), 7.23 (dd, J = 1.6 / 5.1 Hz, 1H), 7.10 (m, 2H), 7.01 (dd, J = 1_5 / 5 · 2 Hz? 1HX 6.89 (s? 1H) 5 3.38 (s? 3H)? 3.19 (m? 1H)? 2.29 (m? 1H) 5 2.20-1.89 (m5 3H), 1.75 (m, 1H), 1.64 (m, 2H), 1.30 (m, 2H). MS (TSP) m / z 403 (M + 1). Example 14 N- (2'-Anilino-4,4 ^ bipyridin-2-yl) -cis-methoxymethoxycyclohexanecarboxamide under nitrogen Ethyl diisopropylamine (129 mg, 1.0 mmol) was slowly added to N, N, N ', Nf-tetramethyl-o- (benzotriazole) at 20 ° C. 1-yl) pyrene (241 mg, 0.75 mmol), hydroxybenzotriazole (101 mg, 0.75 mmol) and 4-methoxycyclohexanecarboxylic acid (78 mg, 0.5 MM) in a solution of 3 ml of acetonitrile. After 5 minutes under nitrogen, this solution was added to N-phenyl-4,4'-bipyridine-2,2f-diamine (131 mg, 0 · 5 mmol) in a solution of 2 ml of dimethylformamide. After stirring for 4 days, a saturated sodium bicarbonate aqueous solution was used. 5 ml) to quench the reaction. The aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by reverse phase chromatography to produce 8 Mg of the title compound. 1HNMR (CDC13): δ 8.53 (s, 1H), 8.31 (d, J = 5.1Hz, 1H), 8.28 (d, J = 5.2Hz, 1H), 8.19 (s, 1H), 7.42- 7.34 (m, 4H), 7.21 (dd, J = 1.5 / 5.2 Hz, 1H), 7.10 (m, 2H), 7.01 (dd, J = 1.3 / 5.2 Hz? 1H) 5 6.84 (s? 1H) 3.49 (m? 1H)? 3.33 (s? 3H)? 2.37 (1H) 5 2.05-1.89 (m? 4H) 5 1.80-1.76 (m, 2H), 1.55-1.47 (m, 2H). MS (TSP ) m / z 403 (M + l). Example 15 -44- 89385 200417546 N- {2-[(4-fluorophenyl) limb group] _4,4f_ 联 u 比 岭 _2-based} _trans _4_Methoxy-cyclohexylcarboxamide under nitrogen and 20 C, slowly add grass chloride (171 mg, 1.35 mmol) to 4-methoxy-cyclohexanecarboxylic acid ( 70 mg, 0.45 mmol) in 2 ml of dichloromethane. After stirring for 30 minutes, the mixture was concentrated under vacuum to obtain a colorless oil, which was diluted in 1.0 ml of digas. Then, this solution was added to a solution of N- (2-fluorophenyl_4,4, -bipyridine-2,2, -diamine (127 mg, 0.45 mmol) in 5 ml of pyridine. Stir After 5 minutes, 5 ml of a saturated sodium bicarbonate aqueous solution was added, and the aqueous layer was extracted with dichloromethane. The organic layer was dehydrated and dried over sulphuric acid, filtered, and concentrated under reduced pressure to obtain the crude product, Purification by reverse phase chromatography yielded 10 mg of the title compound. 1H NMR (CDC13): (5 8.49 (s, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.4 (K7 · 36 (m, 2H), 7.21 (dd, J = 1.5 / 5.2 Hz, 1H), 7.08 (m, 2H), 7.00 (dd, J = 1 · 4/5 · 3 Hz, 1H), 6.94 (s, 1H), 6.66 (s, 1H), 3.39 (s, 3H), 3.20 (m, 1H), 2.30-2.06 (m, 5H), 1.64 (m, 2H), 1.30 (m, 2H). 19 F NMR (CDC13): 5 -119.48 (m5 IF). MS (ES) m / z 421 (M + l). Example 16 N_ {2f _ [(4 -Fluorophenyl) amino] -4,4'_bipyridin-2-yl} _cis_4-methoxy_cyclohexanecarboxamide under nitrogen and 20 ° C (171 mg, 1.35 mmol) slowly added to 4-methoxy- A solution of hexanecarboxylic acid (70 mg, 0.45 mmol) in 2 ml of dichloromethane. After stirring for 30 minutes, the mixture was concentrated under vacuum to give a colorless oil, which was taken up in 1.0 ml of dichloromethane. Diluted. Then, 89385 -45- 200417546

將此溶液添加至N-(2-氟苯基-4,4，-聯吡啶-2,2’-二胺（127毫克，0.45 毫莫耳）在5毫升吡啶中之溶液内。攪拌5分鐘後，添加5毫 升飽和碳酸氫鈉水溶液，並以二氯甲烷萃取水層。使有機 層以硫酸鎂脫水乾燥，過濾，及在減壓下濃縮，而得粗產 物，使其藉逆相層析純化，而產生17毫克標題化合物。iHNMR (CDC13) : δ 8.52 (d，J = 0.8 Hz，1H)，8_31 (d，J = 5·2 Hz，1H)，8.27 (s，1H)， 8·26 (d，J = 5·5 Hz，1H)，7.40-7.37 (m，2H)，7.19 (dd，J = 1.6/5.2 Hz，1H)，7.08 (m，2H)，6.98 (dd，J = 1.5/5.3 Hz，1H)，6.95 (s，1H)，6.85 (s，1H)，3_48 (m，1H)， 3.33(s，3H)，2.38(m，lH)，2.05-1.93 (m，4H)，1.77(m，2H)，L51(m，2H)· 19FNMR(CDC13) ： δ -119.91 (m? IF). MS (ES) m/z 421 (M+l). 實例17 Ν·(6_甲基p比淀-2_基）_Nf_苯基-4,4’·聯叶b淀_2,2’_二胺 於(N-苯基-4/-聯吡啶-2,2’-二胺(53毫克，〇·20毫莫耳）、參（二 苯亞甲基丙酮）二鈀（0)(9.2毫克，0.01毫莫耳）、1·1’_雙（二苯基 膦基）二環戊二燁鐵（11毫克，〇·〇2毫莫耳）及第三-丁醇鈉（14.4 毫克，0.15毫莫耳）在2毫升無水二氧陸圜中之混合物内，在 氮氣下，添加2-溴基-6-甲基吡啶（34.5毫克，0.20毫莫耳）。將 混合物於氬氣及100°C下攪拌14小時，過濾，在減壓下蒸發 ，並於矽膠上，在異辛烷：醋酸乙酯1 ·· 1中層析。將適當 溶離份合併，並濃縮至乾涸，而產生4〇毫克（56% )標題化合 物，為淡色漿液。1 H NMR (CDC13) 5 8.27 (d，J = 5.4 Hz，2H)，7.98 (s，1H， NH)，7.87 (s，1H)，7·47 (t，J = 7.7 Hz，1H)，7.34 (s，2H)，7.33 (d，J = 1.5 Hz，2H)， 7.31 (s，1H，NH)，7.28 (d，8.2 Hz，1H)，7.10 (s，1H)，7.06 (m，1H)，6.95 (ddd， 89385 -46- 200417546 J=1.6/5.3/9.65,2H)，6.7〇(d，7.5HZ5lHU.4〇(s，3H)· ΗΡΙ^Μδ〇^ΕΧ_α管柱，含有〇.1%三氟醋酸之0-職 甲醇之8·6分鐘梯度液。 UV-二極體陣列偵測器、CLND及 具有 m/z 354 (M+l). C22H19N5, MSD-ESI偵測）顯示單一化合物 MW = 353.4. 實例18 N-苯基-N’_峨啶-2-基-4,4，-聯吡啶_2,2,·二胺 於⑼-苯基_4,4’-聯❹处二帅7 ί克，0.10毫莫耳）、參（二 苯亞曱基丙酮）二鈀⑼(9.2亳克，0.01毫莫耳）、1,1，-雙（二苯基 膦基）二環戊二烯鐵（11毫克，002毫莫耳）及第三_丁醇鈉（144 *克’ 0.15當莫耳）在2毫升無水二氧陸圜中之混合物内，在 氮氣下，添加2-溴基吡啶（15·8毫克，〇1〇毫莫耳）。將混合物 於氬氣及95°C下攪拌14小時，過濾，在減壓下蒸發，並於C8-矽膠上，使用自動化預備HPLC系統（Waters 2767/2525)，以0.05M 醋酸銨水溶液中之35% -100%乙腈梯度液層析。將適當溶離 份合併，並濃縮至乾涸，而產生2毫克（6% )標題化合物。 HPLC-MS (Waters Exterra C8-管柱，含有 0.1% 三氟醋酸之 0-100% 甲醇之8.6分鐘梯度液。UV-二極體陣列偵測器、CLND及 MSD-ESI 偵測）顯示單一化合物，具有 m/z 340 (M+l). C21H17N5, MW = 339.4 實例19 N_{4_[(4-甲基六氳吡畊小基）磺醯基】苯基}-N’-苯基-4,4’_聯吡啶- 2,2匕二胺 於(N-苯基-4,4f-聯吡啶-2,2f-二胺（27毫克，0.10毫莫耳）、參（二 89385 -47- 200417546 苯亞甲基丙酮）二鈀（0)(9.2毫克，0.01毫莫耳）、1，1’-雙（二苯基 膦基）二環戊二烯鐵（11毫克，0.02毫莫耳）及第三-丁醇鈉（14.4 毫克，0.15毫莫耳）在2毫升無水二氧陸圜中之混合物内，在 氮氣下，添加1-[(4-溴苯基）磺醯基；H-甲基六氫吡畊（32毫克， 〇.1〇毫莫耳）。將混合物於氬氣及95t下攪拌16小時，過濾， 在減壓下蒸發，並於C8-矽膠（Waters XTerraMSC8，19x300毫米 ，7微米）上，使用自動化預備HPLC系統（Gilson自動化預備 HPLC、二極體陣列偵測），以0.1 Μ醋酸銨水溶液中之20% -60 %乙腈梯度液，在20毫升/分鐘下，層析13分鐘。將適當溶 離份合併，並濃縮至乾涸，而產生26.6毫克（53% )標題化合 物。使物質溶於甲醇中，並添加1Μ鹽酸（0.5毫升）。使溶液 蒸發至乾涸，溶於水中，並凍乾。1HNMR(D20) 6 7.86-6.80 (15Η)，This solution was added to a solution of N- (2-fluorophenyl-4,4, -bipyridine-2,2'-diamine (127 mg, 0.45 mmol) in 5 ml of pyridine. Stir for 5 minutes Then, 5 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was subjected to reverse phase chromatography Purification yielded 17 mg of the title compound. IHNMR (CDC13): δ 8.52 (d, J = 0.8 Hz, 1H), 8_31 (d, J = 5 · 2 Hz, 1H), 8.27 (s, 1H), 8 · 26 (d, J = 5.5 Hz, 1H), 7.40-7.37 (m, 2H), 7.19 (dd, J = 1.6 / 5.2 Hz, 1H), 7.08 (m, 2H), 6.98 (dd, J = 1.5 / 5.3 Hz, 1H), 6.95 (s, 1H), 6.85 (s, 1H), 3_48 (m, 1H), 3.33 (s, 3H), 2.38 (m, lH), 2.05-1.93 (m, 4H ), 1.77 (m, 2H), L51 (m, 2H) · 19FNMR (CDC13): δ -119.91 (m? IF). MS (ES) m / z 421 (M + l). Example 17 Ν · (6 _Methyl p ratio lake-2_yl) _Nf_phenyl-4,4 '· Biye b lake_2,2'_diamine in (N-phenyl-4 / -bipyridine-2,2' -Diamine (53 mg, 0.20 mol), ginseng (diphenylmethyleneacetone) dipalladium 0) (9.2 mg, 0.01 mmol), 1.1'-bis (diphenylphosphino) dicyclopentafluorene iron (11 mg, 0.002 mmol) and sodium tert-butoxide (14.4 mg, 0.15 mmol) In a mixture of 2 ml of anhydrous dioxane, under nitrogen, 2-bromo-6-methylpyridine (34.5 mg, 0.20 mmol) was added. Stir for 14 hours at 100 ° C under argon, filter, evaporate under reduced pressure, and chromatograph on silica gel in isooctane: ethyl acetate 1.1. The appropriate fractions are combined and concentrated to dryness. , And produced 40 mg (56%) of the title compound as a light-colored slurry. 1 H NMR (CDC13) 5 8.27 (d, J = 5.4 Hz, 2H), 7.98 (s, 1H, NH), 7.87 (s, 1H ), 7.47 (t, J = 7.7 Hz, 1H), 7.34 (s, 2H), 7.33 (d, J = 1.5 Hz, 2H), 7.31 (s, 1H, NH), 7.28 (d, 8.2 Hz , 1H), 7.10 (s, 1H), 7.06 (m, 1H), 6.95 (ddd, 89385 -46- 200417546 J = 1.6 / 5.3 / 9.65, 2H), 6.70 (d, 7.5HZ51HU. 4〇 (s , 3H) · HPI ^ Μδ〇 ^ Εχ_α column containing a gradient solution of 0.1% trifluoroacetic acid in 0-methanol for 8.6 minutes. UV-diode array detector, CLND and m / z 354 (M + l). C22H19N5, MSD-ESI detection) shows a single compound MW = 353.4. Example 18 N-phenyl-N'_eridine -2-yl-4,4, -bipyridine_2,2, · diamine in hydrazone-phenyl_4,4'-bifluorene at 7 gram, 0.10 millimolar), ginseng (diphenyl Amidylene acetone) dipalladium hydrazone (9.2 g, 0.01 mmol), 1,1, -bis (diphenylphosphino) dicyclopentadiene iron (11 mg, 002 mmol) and third _ Sodium butoxide (144 * g '0.15 mol) in a mixture of 2 ml of anhydrous dioxolane, under nitrogen, 2-bromopyridine (15.8 mg, 0.10 mol) . The mixture was stirred under argon and 95 ° C for 14 hours, filtered, evaporated under reduced pressure, and 35% in 0.05M ammonium acetate aqueous solution on a C8-silicone using an automated preparative HPLC system (Waters 2767/2525). % -100% acetonitrile gradient chromatography. The appropriate fractions were combined and concentrated to dryness to yield 2 mg (6%) of the title compound. HPLC-MS (Waters Exterra C8-column, 0.1% trifluoroacetic acid, 0-100% methanol, 8.6 minute gradient. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound , With m / z 340 (M + l). C21H17N5, MW = 339.4 Example 19 N_ {4 _ [(4-methylhexamethylpyridyl) sulfonyl} phenyl} -N'-phenyl-4 , 4'_Bipyridine-2,2 diamine in (N-phenyl-4,4f-bipyridine-2,2f-diamine (27 mg, 0.10 mmol), Ginseng (Di 89385 -47- 200417546 benzylideneacetone) dipalladium (0) (9.2 mg, 0.01 mmol), 1,1'-bis (diphenylphosphino) dicyclopentadiene iron (11 mg, 0.02 mmol) And a mixture of sodium tert-butoxide (14.4 mg, 0.15 mmol) in 2 ml of anhydrous dioxolane, under nitrogen, add 1-[(4-bromophenyl) sulfonyl; H- Methylhexahydropyridine (32 mg, 0.10 mmol). The mixture was stirred under argon at 95 t for 16 hours, filtered, evaporated under reduced pressure, and dried on C8-silicone (Waters XTerraMSC8, 19x300 mm). , 7 μm) using an automated preparative HPLC system (Gilson Automated Preparative HPLC) Diode array detection), using a 20% -60% acetonitrile gradient solution in 0.1 M ammonium acetate aqueous solution at 20 ml / min for 13 minutes. Combine the appropriate fractions and concentrate to dryness to produce 26.6 mg (53%) of the title compound. The material was dissolved in methanol and 1M hydrochloric acid (0.5 ml) was added. The solution was evaporated to dryness, dissolved in water, and lyophilized. 1HNMR (D20) 6 7.86-6.80 (15%) ,

3·65 (d，J = 12.0 Ηζ，2Η)，3.38 (d，2Η)，3·02 (m，2Η)，2.69 (s，3Η)，2.59 (m，2Η). HPLC-MS (Waters ExterraC8-管柱，含有 0_1% 三氟醋酸之 0-100% 甲醇之8.6分鐘梯度液。UV-二極體陣列偵測器、CLND及 MSD-ESI 偵測）顯示單一化合物，具有 m/z 501 (M+l). C27H28N602S， MW-500.6. 實例20-27 化合物20-27係根據實例19中提出之程序，使用適當溴基芳 基或溴基雜芳基衍生物及按實例11中所述製成之N-苯基-4,4’-聯p比淀-2,2’-二胺製成。 89385 -48- 200417546 實例 名稱 MW 實測值m/z 產量 20 Ν-苯基-Ν’-ρ比咬各基-4,4，-聯 吡啶-2,2f-二胺 339.4 340 9.3毫克 21 N-苯基-N%密啶基_4,4，-聯 吡啶-2,2f-二胺 340.4 - 341 14.0毫克 22 N-苯基-N%密啶-5-基 _4,4，-聯 340.4 吡啶-2,2L二胺 | 341 6.1毫克 23 (2Ε)-1-{4-[(2’_苯胺基 _4,4，_聯吡 啶-2-基）胺基]苯基}_3_(二甲 胺基）丙-2-稀小酉同 435.5 436 10.8毫克 24 4-[(2’-苯胺基_4,4’-聯峨淀_2- 基）胺基]-N-(2-四氫p比洛小 基乙基）苯磧g盔胺 514.7 515 31.1毫克 25 4_[(2^苯胺基-4,4’-聯咐淀-2_ 基）胺基]-N-(2-嗎福p林-4-基 乙基）苯橫驗胺 530.7 531 15.3毫克 26 N-{4-[(4-乙基六氫响畊小基） 磺醯基]苯基卜Ν’-苯基-4,4’· 聯吡啶-2,2’-二胺 514.7 515 17.8毫克 27 Ν-苯基-Ν’-ρ比啶*4-基-4,4，-聯 吡啶-2,2’-二胺 339.4 340 4.0毫克 實例28 N-(2 -苯胺基_4,4f_聯p比淀-2-基）四氮咬喃-3·羧醯胺 使四氫呋喃-3-羧酸（1L6毫克，0.1毫莫耳）在氮氣下溶於二 氣甲烷（0.5毫升）中。添加二甲基甲醯胺（5〇微升）。使氯化草 醯(43微升，〇.5毫莫耳）溶於二氯甲烷φ·5毫升）中，並逐嘀艿 加至羧酸中。攪拌10分鐘後，使溶液蒸發至乾涸，溶=二 氣甲烷(1毫升)中’並再-次蒸發至乾涸。添加吡啶㈣; ’接著是無水四氫味喃（0.5 *升）中之Ν_苯基叫聯^处 89385 -49- 200417546 二胺（26毫克，0.1毫莫耳）。將混合物於室溫下攪拌16小時 。HPLC-MS (Waters ExterraC8-管柱，含有 0.1% 三氟醋酸之（H00 %甲醇之8.6分鐘梯度液。UV-二極體陣列偵測器、CLND及 MSD-ESI 偵測）顯示單一化合物，具有 m/z 361 (M+l). C21H20N4O2, MW = 360.4·1H NMR (CD3 OD): (510.51 (s，1H)，8_86 (s，1H)，8.40 (s，1H)， 8.31 (d，J = 5·2 Hz，1H)，7.95 (d，J = 6·5 Hz，1Η)，7·45_7·00 (m，8H)，4.01-3.90 (m，3H)，3.77 (m，1H)，3.15 (m，1H)，2.20 (m，2H). 實例29 N-(2f-苯胺基-4,4f-聯p比淀-2-基)-3-六氫p比淀-1-基丙酿胺 將3-六氫外ti咬·1-基丙酸（15.7毫克，〇·1毫莫耳）稱重置於5毫 升玻璃管中。添加二氯甲燒（1毫升） ，接著是二甲基甲醯胺：二氯甲烷（1 : 1〇，5〇微升）。添 加以二氯甲烷（60微升）稀釋之氯化草醯（43微升，〇·5毫莫耳） 。將混合物於室溫及氬氣下攪拌2小時，或直到起泡已停止 為止，而獲得均勻溶液。然後，將250微升此溶液（相當於〇 〇2 毫莫耳羧酸）轉移至96-井格式箱中之i毫升聚苯乙晞管内， 並於熱氮氣流下蒸發至乾涸（3分鐘，35t)。使殘留漿液溶 於二氯甲烷（100微升）中，並添加吡啶（3〇〇微升）中之n_苯基_ 4,4，-聯吡啶-2,2，-二胺（5.2毫克，0.02毫莫耳）。將井加蓋，並^ 室溫及氮氣下’在軌道振盪器上攪拌16小時。使溶液於熱 氮氣流下蒸發至乾滴（5分鐘’耽）。使粗製物f溶於甲醇 中，過濾，並在C8-矽膠上，使用自動化預備HpLc系統 2767/2525)，以_M醋酸銨水溶液中之35% _轉乙腈梯度液 層析。將適當溶離份合併，並濃縮至乾涸，而產生Μ毫2(49 89385 -50- 200417546 % )標題化合物。HPLC-MS (Waters Exterra C8-管柱，含有 〇 1 % 二 氟酷之0-100%甲醇之8.6分鐘梯度液。UV-二極體陣列侦測 器、CLND及MSD-ESI偵測）顯示單一化合物，具有4〇2 (M+1). C24H27N50, MW = 401.5. 化合物30-73係根據實例29中提出之程序，使用適當羧酸及 按實例11中所述製成N-苯基-4,4’-聯吡啶_2,2，-二胺製成。 實例30-73 實例 名稱 MW 實測值 m/z 產量 (毫克） 30 N-(2’-苯胺基-4,4’-聯吡啶-2- 基）四氫呋喃-3-羧醯胺 360.4 361 3.1 31 N-(2’-苯胺基-4,4’-聯p比淀-2- 基）菸鹼醯胺 367.4 368 3.5 32 N-(2’-本胺基-4,4’-聯p比淀-2-基）-4-(二甲胺基）苯甲醯胺 409.5 410 0.8 33 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-2,6-二甲氧基菸鹼醯胺 427.5 428 0.1 34 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-1Η-啕哚-2-羧醯胺 405.5 406 0.1 35 Ν-(2^苯胺基-4,4’-聯吡啶-2-基）吡啶-2-羧醯胺 367.4 368 2.7 36 N_(2’_苯胺基-4,4’-聯吡啶-2-基）-3-咬喃驗胺 356.4 357 0.1 37 N-(2f-苯胺基-4,4’-聯吡啶-2-基)-1，2,3_嘧二唑-4-羧醯胺 374.4 375 0.5 38 N-(2’-苯胺基-4,4’-聯吡啶-2- 基）異噚唑冬羧醯胺 357.4 358 2.6 39 N-(2’-苯胺基-4,4f-聯吡啶-2- 基&gt;5-甲基異崎唑-3-羧醯胺 371.4 372 5.3 89385 -51- 200417546 40 N-(2’-苯胺基-4,4’-聯吡啶-2- 基）外1：啡-2-羧醯胺 368.4 369 2.7 41 N-(2’-苯胺基-4,4’-聯吡啶-2-基）小甲基-1H-咪唑-4-羧醯胺 370.4 371 4.9 42 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-2-呋喃醯胺 356.4 357 0.5 43 Ν-β-苯胺基-4,4’-聯吡啶-2-基）-4-甲氧基苯甲醯胺 396.4 397 2.4 44 Ν-(2^苯胺基-4,4f-聯^比淀-2_ 基）-5-&gt;臭基-2-咬喃驢胺 435.3 435 4.2 45 N_(2’_苯胺基-4,4〔聯吡啶-2-基）-2-(甲硫基）於驗驗胺 413.5 414 1.3 46 ^{[^’-苯胺基-七^^-聯^比淀-二- 基）胺基懷基}苯甲酸甲酯 424.5 425 0.8 47 3-(乙醯胺基）-N-(2’-苯胺基-4,4’-聯ρ比淀-2-基）苯甲SS胺 423.5 424 0.3 48 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-4-酮基-4,5,6,7-四氫-1-苯 并呋喃-3-羧醯胺 424.5 425 3.6 49 N-(T-苯胺基-4,4’-聯吡啶-2-基）-5-[(p比淀-2-基硫基）甲基 ]-2-呋喃醯胺 479.6 480 0.8 50 N-(2’-苯胺基-4,4f-聯吡啶-2- 基）菸鹼醯胺1-氧化物 383.4 384 0.5 51 N-(2〔苯胺基-4,4’-聯吡啶-2- 基）-3-羥基吡啶-2-羧醯胺 383.4 384 0.3 52 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-6-溴基4淀-2-叛醯胺 446.3 446 6.2 53 N-(2f-苯胺基-4,4’-聯吡啶-2- 基）異菸鹼醯胺1-氧化物 383.4 384 2.3 54 N-(2f-苯胺基-4,4f-聯ρ比淀-2- 基）-2-經基於驗醒胺 383.4 384 0.4 89385 -52- 200417546 55 N-(2’-豕胺基-4,4’-聯p比淀-2_ 基）-6-起基p比淀-2-叛i盈胺 383.4 384 2.6 56 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-3-苯甲縫基p比淀-2-瘦酸胺 471.5 472 1.8 57 N-(2f-苯胺基-4,4f-聯ρ比淀-2-基）-6-甲基外b淀-2-瘦酸胺 381.4 382 0.8 58 Ν-(2^本胺基-4,4f-聯ρ比淀-2_ 基）-3,5-二甲基異噚唑-4-羧 醯胺 385.4 386 0.5 59 N-(2L苯胺基-4,4’-聯吡啶-2- 基）-2- T氧基於驗S篮胺 397.4 398 0.6 60 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-4-甲基-1，2,3-嘧二唑-5- 羧醯胺 388.5 389 5.6 61 N-(2’-苯胺基-4,4’-聯p比淀-2_ 基）-2-氯基異菸鹼醯胺 401.9 402 5.7 62 N-(2f-苯胺基-4,4f-聯ρ比淀-2- 基）-5•甲基異噚唑-4-羧醯胺 371.4 372 1.3 63 N-(2’-表胺基-4,4’-聯p比淀-2_ 基）-3-甲基異噚唑-4-羧醯胺 371.4 372 4.3 64 N-(2’-本胺基-4,4’-聯p比淀-2_ 基）小甲基-1H-吡咯-2-羧醯胺 369.4 370 2.1 65 N-(2f-苯胺基-4,4’-聯ρ比淀-2_ 基）-2-鼠基於驗廳胺 401.9 402 4.1 66 N-(2f-苯胺基-4,4’-聯p比淀-2-基）-5-氣基-1H-W哚-2-羧醯胺 439.9 440 0.4 67 Ν-(2^苯胺基-4,4’-聯ρ比咬-2_ 基）冬氯基-1Η-吡唑-3-羧醯胺 390.8 391 0.9 68 Ν-(2^苯胺基-4,4’-聯ρ比咬-2_ 基）-5-甲基-1Η-吡唑-3-羧醯胺 370.4 371 0.6 69 (2E)-N-(2’_苯胺基-4,4’-聯吡啶 -2-基）_3-(3-呋喃基）丙烯醯胺 382.4 383 0.7 89385 -53- 200417546 70 -----—__ N-(T-苯胺基聯吡啶-2-基）-3-(2-酮基-1，3-苯并哼唑-3(2H)-基）丙酸胺 451.5 452 0.7 71 —--—一-— N’-(2f-苯胺基-4,4’-聯T?比淀-2-基）-N，N-二甲基琥珀醯胺 389.5 390 0.3 72 *-------- N-(2f-苯胺基-4,4f-聯吡啶-2-基）-2-[(4-氯苯基）續酸基]乙 醯胺 479.0 479 1.1 73 -— N-(2f-苯胺基-4,4’-聯吡啶-2-基）-5-酮基脯胺醯胺 373.4 374 1.3 N_(2L苯胺基_4,4’_聯吡啶_2_基)-3-甲氧基丙醯胺 一般程序：3.65 (d, J = 12.0 Ηζ, 2Η), 3.38 (d, 2Η), 3.02 (m, 2Η), 2.69 (s, 3Η), 2.59 (m, 2Η). HPLC-MS (Waters ExterraC8 -Column, containing 0_1% trifluoroacetic acid, 0-100% methanol, 8.6 minute gradient. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m / z 501 ( M + l). C27H28N602S, MW-500.6. Examples 20-27 Compounds 20-27 were prepared according to the procedure set out in Example 19 using the appropriate bromoaryl or bromoheteroaryl derivative and prepared as described in Example 11. It is made of N-phenyl-4,4'-bi-p-pyridine-2,2'-diamine. 89385 -48- 200417546 Example name MW Measured value m / z Yield 20 N-phenyl-N'-ρ ratio of each base-4,4, -bipyridine-2,2f-diamine 339.4 340 9.3 mg 21 N- Phenyl-N% melidin-4,4, -bipyridyl-2,2f-diamine 340.4-341 14.0 mg 22 N-phenyl-N% melidin-5-yl_4,4, -bi 340.4 Pyridine-2,2L diamine | 341 6.1 mg 23 (2E) -1- {4-[(2'_aniline_4,4, _bipyridin-2-yl) amino] phenyl} _3_ (di Methylamino) propan-2-isopyrazine with 435.5 436 10.8 mg 24 4-[(2'-aniline_4,4'-biyanido_2-yl) amino] -N- (2-tetra Hydrogen p-bileoylethyl) phenylhydrazine g helmet amine 514.7 515 31.1 mg 25 4 _ [(2 ^ anilino-4,4'-coated yodo-2_yl) amino] -N- (2-morpho p-Lin-4-ylethyl) benzamine 530.7 531 15.3 mg 26 N- {4-[(4-ethylhexahydrocyclopentyl) sulfofluorenyl] phenylbenzene N′-phenyl-4 , 4 '· bipyridine-2,2'-diamine 514.7 515 17.8 mg 27 N-phenyl-N'-p-pyridine * 4-yl-4,4, -bipyridine-2,2'-diamine 339.4 340 4.0 mg Example 28 N- (2-Anilino-4,4f-bi-pyridine-2-yl) tetraazepine-3 · carboxamidine makes tetrahydrofuran-3-carboxylic acid (1L6 G, 0.1 mmol) was dissolved under nitrogen gas of methane (0.5 mL). Add dimethylformamide (50 μl). Chlorhexidine chloride (43 µl, 0.5 mmol) was dissolved in dichloromethane (φ · 5 ml) and added to the carboxylic acid one by one. After stirring for 10 minutes, the solution was evaporated to dryness, dissolved in methane (1 ml) and evaporated again to dryness. Add pyridine hydrazone; 'followed by the N-phenyl group in anhydrous tetrahydrofuran (0.5 * liters), which is called biphenyl 89385 -49- 200417546 diamine (26 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 hours. HPLC-MS (Waters ExterraC8-column, 0.1% trifluoroacetic acid (H00% methanol 8.6 minute gradient. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound with m / z 361 (M + l). C21H20N4O2, MW = 360.4 · 1H NMR (CD3 OD): (510.51 (s, 1H), 8_86 (s, 1H), 8.40 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.95 (d, J = 6.5 Hz, 1Η), 7.45_7 · 00 (m, 8H), 4.01-3.90 (m, 3H), 3.77 (m, 1H), 3.15 (m, 1H), 2.20 (m, 2H). Example 29 N- (2f-anilino-4,4f-bi-p-pyridine-2-yl) -3-hexahydrop-pyridine-1-ylpropane Styramine was re-set 3-hexahydroouterine- 1-ylpropionic acid (15.7 mg, 0.1 mmol) into a 5 ml glass tube. Dichloromethane (1 ml) was added, followed by two Methylformamide: dichloromethane (1: 1, 50 microliters). Chloramphetamine chloride (43 microliters, 0.5 millimoles) diluted with dichloromethane (60 microliters) was added. The mixture was stirred at room temperature under argon for 2 hours, or until the foaming had stopped, to obtain a homogeneous solution. Then, 250 microliters of this solution (equivalent to 0.02 millimolar carboxylic acid Transfer to a 1 ml polyphenylene terephthalate tube in a 96-well format box and evaporate to dryness (3 minutes, 35t) under a stream of hot nitrogen. Dissolve the residual slurry in dichloromethane (100 μl) and add pyridine (300 μl) of n-phenyl-4,4, -bipyridine-2,2, -diamine (5.2 mg, 0.02 mmol). The well was capped, and room temperature and nitrogen Stir on the orbital shaker for 16 hours. Evaporate the solution to dry drops under a stream of hot nitrogen (5 minutes). Dissolve the crude f in methanol, filter, and use H8 to prepare HpLc on a C8-silicone gel. System 2767/2525), 35% _acetonitrile gradient chromatography in _M ammonium acetate aqueous solution. The appropriate fractions were combined and concentrated to dryness to give MH 2 (49 89385 -50- 200417546%). Compound. HPLC-MS (Waters Exterra C8-column, 8.6 minute gradient containing 0% difluorocoll 0-100% methanol. UV-diode array detector, CLND and MSD-ESI detection) Shows a single compound with 40.2 (M + 1). C24H27N50, MW = 401.5. Compounds 30-73 follow the procedure set forth in Example 29, using the appropriate carboxylic acid Prepared as described in Example 11 N- diphenyl-4,4'-bipyridine _2,2, - diamines made. Examples 30-73 Example name MW Measured value m / z Yield (mg) 30 N- (2'-anilino-4,4'-bipyridin-2-yl) tetrahydrofuran-3-carboxamide 360.4 361 3.1 31 N -(2'-anilino-4,4'-bi-p-pyridin-2-yl) nicotinamide 367.4 368 3.5 32 N- (2'-benzyl-4,4'-bi-p-pyridine- 2-yl) -4- (dimethylamino) benzamidine 409.5 410 0.8 33 N- (2f-aniline-4,4f-bipyridin-2-yl) -2,6-dimethoxy smoke Base amine 427.5 428 0.1 34 N- (2'-aniline-4,4'-bipyridin-2-yl) -1 fluorenyl-2-carboxamide 405.5 406 0.1 35 N- (2 ^ aniline -4,4'-bipyridin-2-yl) pyridine-2-carboxamide 367.4 368 2.7 36 N_ (2'_aniline-4,4'-bipyridin-2-yl) -3-bran Amine 356.4 357 0.1 37 N- (2f-aniline-4,4'-bipyridin-2-yl) -1,2,3-pyrimidazole-4-carboxamidine 374.4 375 0.5 38 N- (2 ' -Anilino-4,4'-bipyridin-2-yl) isoxazolone carboxamide 357.4 358 2.6 39 N- (2'-anilino-4,4f-bipyridin-2-yl) &gt; 5- Methylisozazol-3-carboxamidine 371.4 372 5.3 89385 -51- 200417546 40 N- (2'-aniline-4,4'-bipyridin-2-yl) outer 1: morphin-2-carboxamidine Amine 3 68.4 369 2.7 41 N- (2'-aniline-4,4'-bipyridin-2-yl) small methyl-1H-imidazole-4-carboxamidine 370.4 371 4.9 42 N- (2f-aniline- 4,4'-bipyridin-2-yl) -2-furanamidamine 356.4 357 0.5 43 N-β-anilino-4,4'-bipyridin-2-yl) -4-methoxybenzidine Amine 396.4 397 2.4 44 N- (2 ^ anilino-4,4f-bipyridine-2_yl) -5- &gt; Stanyl-2-benzylamine 435.3 435 4.2 45 N_ (2'_aniline -4,4 [bipyridin-2-yl) -2- (methylthio) in test amine 413.5 414 1.3 46 ^ {[^ '-anilino-hepta ^ -bi ^ pyridine-di-yl) Amine group: methyl benzoate 424.5 425 0.8 47 3- (acetamido) -N- (2'-aniline-4,4'-bi-pyridine-2-yl) benzyl samine 423.5 424 0.3 48 N- (2'-aniline-4,4'-bipyridin-2-yl) -4-one-4,5,6,7-tetrahydro-1-benzofuran-3-carboxy Amine 424.5 425 3.6 49 N- (T-anilino-4,4'-bipyridin-2-yl) -5-[(p-Hydro-2-ylthio) methyl] -2-furanamidine 479.6 480 0.8 50 N- (2'-aniline-4,4f-bipyridin-2-yl) nicotinamide amine 1-oxide 383.4 384 0.5 51 N- (2 [aniline-4,4'-diamine Pyridine-2-yl) -3-hydroxypyridine-2 -Carboxamide 383.4 384 0.3 52 N- (2'-aniline-4,4'-bipyridin-2-yl) -6-bromo-4Hydro-2-amine 446.3 446 6.2 53 N- (2f -Anilino-4,4'-bipyridin-2-yl) isonicotinamine 1-oxide 383.4 384 2.3 54 N- (2f-anilino-4,4f-bi-p-pyridin-2-yl) -2-Based on awake amine 383.4 384 0.4 89385 -52- 200417546 55 N- (2'-fluorenylamino-4,4'-bi-p-pyridine-2_yl) -6-base p-pyridine-2 -Resinamine 383.4 384 2.6 56 N- (2'-aniline-4,4'-bipyridin-2-yl) -3-benzylidene p-pyridine-2-lepinate 471.5 472 1.8 57 N- (2f-anilino-4,4f-bi-p-pyridin-2-yl) -6-methylexo-b-pyridine-2-leptiamine 381.4 382 0.8 58 N- (2 ^ benzamino-4, 4f-bi-p-pyridin-2_yl) -3,5-dimethylisoxazole-4-carboxamidine 385.4 386 0.5 59 N- (2L aniline-4,4'-bipyridin-2-yl) -2- T-oxyl S-amine 397.4 398 0.6 60 N- (2'-aniline-4,4'-bipyridin-2-yl) -4-methyl-1,2,3-pyrimidazole -5- Carboxamidamine 388.5 389 5.6 61 N- (2'-anilino-4,4'-bi-pyridine-2_yl) -2-chloroisonicotinamine amine 401.9 402 5.7 62 N- (2f -Anilino-4,4f-bi-rhodido-2-yl) -5 • Methylisoxazole-4-carboxyamidamine 371.4 372 1.3 63 N- (2'-epiamino-4,4'-bi-p-pyridine-2-yl) -3-methylisoxazole-4-carboxy Hydrazine 371.4 372 4.3 64 N- (2'-benzyl-4,4'-bi-p-pyridine-2_yl) small methyl-1H-pyrrole-2-carboxamide 369.4 370 2.1 65 N- (2f -Anilino-4,4'-bi-p-pyridine-2_yl) -2-murine based on laboratory amine 401.9 402 4.1 66 N- (2f-aniline-4,4'-bi-p-pyridine-2-yl ) -5-Amino-1H-W indole-2-carboxamidine 439.9 440 0.4 67 N- (2 ^ anilino-4,4'-bi-p-ratio-2_yl) orthochloro-1H-pyrazole -3-carboxamidine 390.8 391 0.9 68 Ν- (2 ^ aniline-4,4'-bi-ratio-2-yl) -5-methyl-1pyrazol-pyrazole-3-carboxamide 370.4 371 0.6 69 (2E) -N- (2'_aniline-4,4'-bipyridin-2-yl) _3- (3-furyl) acrylamide 382.4 383 0.7 89385 -53- 200417546 70 ---- ---__ N- (T-anilinobipyridin-2-yl) -3- (2-keto-1,3-benzohumazol-3 (2H) -yl) propionate amine 451.5 452 0.7 71 — --- mono --- N '-(2f-aniline-4,4'-bi-T? Pyridine-2-yl) -N, N-dimethylsuccinimide 389.5 390 0.3 72 * ---- ---- N- (2f-aniline-4,4f-bipyridin-2-yl) -2-[(4-chloro Phenyl) contanoic acid] ethylammonium amine 479.0 479 1.1 73 --- N- (2f-aniline-4,4'-bipyridin-2-yl) -5-ketoproline amine 373.4 374 1.3 N_ ( 2L aniline_4,4'_bipyridin_2_yl) -3-methoxypropanamide General procedure:

於3-甲氧基丙酸（11毫克，〇.1毫莫耳）、N_苯基_4,4，_聯吡啶-2,2L —胺（26毫克，0.1毫莫耳）、輕基苯并三唑（14毫克，〇 1毫莫 耳）、聚苯乙烯結合之二異丙基胺(N，N-(二異丙基）胺基甲基聚 笨乙晞，32毫克，0.12毫莫耳）及聚苯乙烯結合之碳化二亞 胺(N-環己基碳化二亞胺-NL丙氧基甲基聚苯乙烯，I%毫克， 0.3毫莫耳）中之混合物内，添加2毫升二曱基甲醯胺i。將混 合物於120 C及氬氣下攪拌48小時。過濾並蒸發，獲得褐色 永液，使其▲於一曱亞楓（2〇〇微升）中，並使其在eg—石夕膠上 使用自動化預備HPLC系統（waters 2767/2525)，以〇.〇5M醋酸 餘水溶液中之25%销乙腈梯度液接受層析。將適當溶離份 合併’並於真空下濃縮至乾涸’而產生53毫克標題化合物 。管柱’含有⑽三氟醋酸之議 %甲醇之8·6分鐘梯度液。UV_二極體陣列偵測器、clnd及 89385 -54- 200417546 MSD-ESI偵測）顯示單一化合物，具有滅349 (M+1). C2〇H2〇N4〇2, MW-348.4. 實例75-85 化合物75-85係根據實例74中提出之程序，使用適當羧酸及 j安U丨AL?戶7!^製成之N-苯基1，4，-聯4啶-2,2，-二胺製成。 實例 ---------1 一 ” 名稱 MW 义厶，厶-—文方 實測值m/z 5L成0 產量 9.2 毫 F 75 N-(2’-苯胺基-4,4’-聯吨淀-2-基）-4-甲氧基環己烷幾醯胺 402.5 403 76 N-(2f-苯胺基-4,4f-聯吨淀-2-基）-3-甲氧基丙酿胺 348.4 349 5.3毫克 77 N-(2’-苯胺基-4,4’-聯吡啶-2- 基）四氫咬喃-3-叛S盛胺 360.4 361 17.4毫克 78 N-(2’-苯胺基-4,4f-聯p比淀-2«· 基）-4-(二甲胺基）丁醯胺 375.5 376 9.6毫克 79 N_(2f-苯胺基-4,4’-聯吡啶-2- 基）於驗驢胺 367.4 368 9.2毫克 80 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-4-(二甲胺基）苯甲醯胺 409.5 410 3.8毫克 81 Ν-(2’·苯胺基-4,4’-聯吡啶-2-基）-2,6-二甲氧基菸鹼醯胺 427.5 428 3.3毫克 82 Ν-(2’_苯胺基-4,4’-聯吡啶-2- 基丨嗓-2-複酿胺 405.5 406 3.1毫克 83 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-5-甲基吡畊-2-羧醯胺 382.4 383 3.9毫克 84 N-(2f-苯胺基-4,4’-聯p比淀-2- 基）外1：啶-2-羧醯胺 367.4 368 9.2毫克 85 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-3-吱喃醯胺 356.4 357 5.5毫克 實例86 89385 -55 - 200417546 N-(2’_苯胺基-4,4’-聯吡啶_2_基)_N’_苯基脲 程序乂 ： 於N-苯基-4,4’-聯吡啶-2,2’-二胺（131毫克，0.5毫莫耳）在二氧 陸圜（5毫升）中之溶液内，在氮氣下，添加已溶於二氧陸圜（1 毫升）中之異氰酸苯酯（60毫克，0.5毫莫耳）。將混合物於室 溫下攪拌16小時。濾出已沉澱之物質，並藉NMR與HPLC-MS 確認為標題化合物（104毫克，55% )，96%純度（uv-偵測）。 1H NMR (DMS〇-D6) 5 8.40 (d，J = 5.6 Hz，1H), 5 8.30 (d，J = 5.6 Hz，1H)， 7.99 (d，J = 5.1 Hz，1H)，7.73 (d，J = 8·1 Hz，2H)，7.54 (d，J = 8·1 Hz，2H)，7.30 (m，5H)，7.15 (s，1H，NH)，7.04 (m，2H)，6.92 (t，7·1 Hz，1H). 13 C NMR (DMSO-D6) 5 156.7, 152.1，148.5, 147.5, 145.9, 141.5, 139.0, 138.9, 128.9， 128.7, 122.6, 120.7, 118.8, 118.7, 118.1，115.3, 111.8, 108.8, 107.9· 15NNMR (DMSO-D6) 5 -275.0, -260.4, -269.5, -113.3, 108_1·氮原子之化學位移 與位置係使用15NHSQC與15NHMBC，併用1H-1HCOSY測得 。15N化學位移係相對於0.0 ppm下之外部硝基甲烷給予。15N 實驗係於Brnker DRX600 NMR光譜儀上進行，在600 MHz下操作 ，對氮-15提供質子60 MHz，並裝有5毫米TXI探針與Z-梯度 。實驗係於攝氏22度下進行。 HPLC-MS (Waters Exterra C8-管柱，含有 0.1% 三氟醋酸之 0-100 % 甲醇之8.6分鐘梯度液。UV-二極體陣列偵測器、CLND及 MSD-ESI 偵測）顯示單一化合物，具有 m/z 382 (M+1)· C24H27N50, MW = 381.4. 程序5 : 於異氰酸苯酯（72微升，0.5 Μ，在二氧陸圜，0.036毫莫耳） 89385 -56- 200417546 在2毫升深井96-井板中之溶液内，在氮氣下，添加二氧陸圜 (200微升）中&lt; N-苯基_4,4，-聯吡啶_2,2，_二胺（7.9毫克，〇 〇3毫莫 耳）。將板於軌道振盪器上，在室溫下攪拌16小時。濾出已 沉澱之物質’ I溶於二甲亞颯中。產物之分析妓量係使 用裝有uv-二極體陣列偵測器' CLND (氮偵測器）及msd_esi 偵測器之 Agilem HP 1100 HPLC-MS 系統（Waters ExtermC8_ 管柱，含 有0_1%三氟醋酸之〇_1〇〇%甲醇之86分鐘梯度液）進行。 化合物87-166係根據程序B中提出之程序，使用適當異氯 酸酯衍生物及按實例U中所述製成之N_苯基_4，聯吡 二胺製備。 實例87-166 登錄號 87 名稱 N-(2f-苯胺基_4,4’_聯吡啶-2-基）-Ν’-苯基脲 MW 381.4 實測值 382 產量 (毫克） 3.6 88 Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-N’-[l-(4-溴苯基）乙基]脲 488.4 488 0.1 89 Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-Ν’-噻吩_3-基脲 387.5 388 2.8 90 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-Nf-(2_甲基苯基)脲 395.5 396 1.9 91 N-(2’-苯胺基_4,4’_聯吡啶-2^ 基）-N’-(4-甲基苯基)脲 395.5 396 1.8 92 N-(2’-笨胺基_4,4’_聯吡啶_2_ 基）-Nf-(3-氟苯基)脲 399.4 400 2.9 93 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-NH2-氟苯基)脲 399.4 400 0.4 89385 -57- 200417546 94 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-NH4-氟苯基)脲 399.4 400 0.1 95 N-(2’-冬胺基_4,4’_聯p比淀-2_ 基）·Ν’_[4-(氯基甲基)苯基]脲 429.9 430 2.2 96 Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-Ν’-(3-氰基苯基)脲 406.4 407 1.7 97 Ν-(2^冬胺基-4,4f-聯ρ比淀-2_ 基）-N’-(4-氰基苯基)月尿 406.4 407 0.3 98 N-(2’-苯胺基-4,4f-聯ρ比淀-2· 基）-N’-(2-氰基苯基)脲 406.4 407 0.1 99 N-(2’-苯胺基-4,4f-聯π比淀-2· 基）-N’-(2,3-二甲基苯基)月尿 409.5 410 0.8 100 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2,5-二甲基苯基)脲 409.5 410 0.3 101 Ν-(2’-苯胺基-4,4’-聯ρ比淀-2·* 基）-Ν’-(4-乙基苯基)脲 409.5 410 0.7 102 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-Nf-(3-乙基苯基）月尿 409.5 410 1.6 103 N-(2’-苯胺基-4,4f-聯p比淀-2_ 基）-N’-(4-甲氧苯基)脲 411.5 412 2.6 104 N-(2’-苯胺基-4,4’-聯ρ比淀-2-基）-N’-(3-甲氧苯基)脲 411.5 412 0.2 105 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2-甲氧苯基)脲 411.5 412 0.2 106 N-(2’-苯胺基-4,4’-聯ρ比淀-2_ 基）-NH5-氟基-2-甲基苯基)月尿 413.5 414 0.4 107 N-(2’-苯胺基-4,4f-聯ρ比症-2-基）-ΤνΓ-(2-氟基卞基）月尿 413.5 414 2.7 108 N-(2’-苯胺基-4,4’-聯p比呢-2_ 基）-N’-(2-氣基-5-甲基苯基） 脲 413.5 414 0.3 200417546 109 N-(2’-苯胺基-4,4f-聯吡啶-2-基）-N’-(3-氟基基）月尿 413.5 414 1.5 110 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2-氯苯基)脲 415.9 416 0.3 111 N-(2’-苯胺基-4,4’-聯吡啶-2- 基氯苯基)脲 415.9 416 0.2 112 N-(2f-苯胺基-4,4’-聯ρ比淀-2_ 基）-N’-(2-氯卞基）月尿 429.9 430 2.3 113 N-(2f-苯胺基-4,4’-聯峨淀-2_ 基）-Nl(2,5-二氟苯基)脲 417.4 418 0.2 114 N-(2’-苯胺基-4,4’-聯p比淀-2· 基）-N’_(2,4-二氟苯基）脲 417.4 418 0.1 115 N-(2f-苯胺基-4,4’-聯p比淀-2_ 基）-Ν’-(3,4-二氯苄基)脲 464.4 464 1.6 116 Ν-(4-乙醯基苯基）-NH2f-苯胺 基-4,4f-聯吡啶-2-基）脲 423.5 424 0.2 117 N-(3-乙醯基苯基）-Nf-(2’-苯胺 基-4,4’-聯吡啶-2-基）脲 423.5 424 3.2 118 N-(2’-本胺基-4,4’-聯p比淀-2_ 基）-N’-(4-異丙基苯基)脲 423.5 424 0.4 119 N-(2’-苯胺基-4,4’-聯ρ比淀-2_ 基）-N’-(2-異丙基苯基)月尿 423.5 424 0.9 120 Ν-(2’-苯胺基-4,4’-聯p比淀-2_ 基）-Ν’-(2-乙基-6-甲基苯基） 脲 423.5 424 0.2 121 N-(2f-苯胺基-4,4^聯ρ比呢-2_ 基）-N’-2,4,6-三甲苯基脲 423.5 424 0.1 122 N-(2f-苯胺基-4,4’-聯p比淀-2-基）-N’-(2-丙基苯基)脲 423.5 424 1.0 123 N-(2f-苯胺基峨淀-2-基）-N’_[4-(二甲胺基）苯基]脲 424.5 425 0.1 89385 -59- 200417546 124 N-(2’-苯胺基-4,4’-聯吡啶-2-基）-N’-l，3-苯并二氧伍圜烯-5-基脲 425.4 426 0.2 125 N-(2’-苯胺基-4,4〔聯吡啶-2-基）-N’-(4-甲氧基-2-甲基苯 基)脲 425.5 426 0.4 126 N-(2’-苯胺基-4,4f-聯吡啶-2-基）-N’-(2-甲氧基-5-甲基苯 基)脲 425.5 426 0.1 127 N-(2^本胺基聯1?比咬-2-基）-Ν’-(4-乙氧苯基）月尿 425.5 426 0.9 128 Ν-(2^苯胺基-4,4’-聯ρ比淀-2_ 基）_Nf-(4-甲氧基卞基)月尿 425.5 426 1.6 129 Ν-(2^木胺基-4,4f-聯ρ比淀-2-基）-NH4-硝基苯基)脲 426.4 427 0.5 130 N-(2f-苯胺基-4,4f-聯ρ比淀-2- 基）硝基苯基)月尿 426.4 427 0.6 131 N-(2f-苯胺基-4,4’-聯p比淀-2_ 基）-N’-[3-(甲硫基）苯基]脲 427.5 428 3.3 132 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-N’-[4-(甲硫基）苯基]脲 427.5 428 0.4 133 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2-甲苄基)脲 409.5 410 2.7 134 N-(2f-冬胺基-4,4^聯ρ比淀-2_ 基）-N’-(5-氯基-2-甲基苯基） 脲 429.9 430 0.3 135 N-(2L苯胺基-4,4f-聯ρ比淀-2_ 基）-Nf-(2-氯基-5-甲基苯基） 脲 429.9 430 0.4 136 N-(2f-苯胺基-4,4’-聯ρ比淀-2_ 基）-N’-(2-氯苄基)脲 429.9 430 2.1 89385 -60- 200417546 137 N-(2’-苯胺基-4,4’-聯吡啶-2-基)-N’-(3-氯基-4-氟苯基)月尿 433.9 434 0.2 138 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2,3,4-三氟苯基)脲 435.4 436 0.1 139 N-(2’-苯胺基-4,4’-聯ρ比淀-2_ 基）-N’-(4-丁基私基）月尿 437.5 438 0.1 140 N-(2’-苯胺基-4,4f-聯ρ比淀-2_ 基）-N’-(2-異丙基-6-甲基苯 基)脲 437.5 438 0.1 141 N-(2’-苯胺基-4,4f-聯π比淀-2-基）-N’-(2-第二-丁基苯基）月尿 437.5 438 0.4 142 々-({[^’-苯胺基-七^^-聯^比淀·^-基）胺基滕基}胺基）苯甲酸 甲酯 439.5 440 0.1 143 N-(2f-苯胺基-4,4’-聯吡啶-2-基）-1^’-(3,4-二甲氧基苯基）月尿 441.5 442 3.6 144 N-(2f-豕胺基-4,4’-聯ρ比p定-2_ 基）-N’-(3,5-二甲氧基苯基)脲 441.5 442 0.8 145 N-(2f-苯胺基-4,4f-聯ρ比淀-2_ 基）-1ΝΓ-(3-氯基-4-甲氧苯基） 脲 445.9 446 0.8 146 Ν-(2’-苯胺基-4,4f-聯吡啶-2-基）-N’-[4-(二氟甲氧基）苯基] 脲 447.4 448 0.6 147 N-(2f-本胺基-4,4f-聯p比淀-2_ 基）-N’-[2-(三氟甲基）苯基]脲 449.4 450 0.2 148 N-(2f-苯胺基-4,4f•聯ρ比淀-2-基）-N’-[3-(三氟甲基）苯基]脲 449.4 450 0.1 149 N-(2’-苯胺基-4,4f-聯吡啶-2-基）-Nf-[4-(三氟甲基）苯基]脲 449.4 450 0.1 150 N-(2’-苯胺基-4,4f-聯ρ比淀-2_ 基）-NH2,5-二氯苯基)脲 450.3 450 0.1 89385 -61 - 200417546 151 Ν-(Τ-苯胺基-4,仁聯吡啶-2-基）-Nf-(3,5-二氯苯基)脲 450.3 450 0.0 152 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-N’-(3,4-二氯苯基)脲 450.3 450 0.3 153 N-(2’-本胺基-4,4f-聯p比淀-2_ 基）-N’-(2,3-二氯苯基)脲 450.3 450 0.2 154 N-(2f-豕胺基-4,4f-聯ρ比淀-2-基）-N’-(2,4-二氯苯基)脲 450.3 450 1.2 155 N-(2f-苯胺基-4,4f-聯p比淀-2_ 基）-N’-(4-溪基-3-甲基苯基） 脲 474.4 474 0.1 156 N-(2f-苯胺基-4,4f-聯p比淀-2-基）-Nf-(2,6-二氯p比淀-4-基）月尿 451.3 451 0.1 157 N-(2’-苯胺基-4,4^聯ρ比淀-2_ 基）_Nf-(4-丁基-2-甲基苯基） 脲 451.6 452 0.0 158 N-(2’-苯胺基-4,4f·聯吡啶-2-基）-N45-甲基-2-(三氟甲基）-3-呋喃基]脲 453.4 454 0.2 159 3-({[(2\苯胺基-4,4’-聯1：7比淀-2-基）胺基]羰基}胺基）苯甲酸 乙酯 453.5 454 0.2 160 N-(2f-苯胺基-4,4’-聯ρ比淀-2-基）-Nf-(4-丁氧基苯基）月尿 453.5 454 0.2 161 N-(2’-苯胺基-4,4’-聯p比淀-2_ 基）-Nf-[4-(三氟甲氧基）苯基] 脲 465.4 466 0.1 162 N-(2’-苯胺基-4,4f-聯ρ比淀-2-基）-N’-(2,6-二異丙基苯基)脲 465.6 466 0.1 163 N-(2f-苯胺基-4,4’*聯ρ比淀-2_ 基:)-Ν’-(4-甲苄基)脲 409.5 410 0.5 89385 -62- 200417546 164 N-(2’-苯胺基_4,4’_聯吡啶_2_ 基）_N’-(5-氯基-2,4-二甲氧基 苯基)脲 475.9 476 1.6 165 N-(2^苯胺基-4,4’-聯吡啶-2-基）-1^{4-[(三氟甲基）硫基] 苯基}脲 481.5 482 0.1 166 N-(2’-苯胺基-4,4f-聯吡啶-2-基）-Nf-[3,5-雙（三氟甲基）苯 基]脲 517.4 518 0.1 實例167 1-乙酿基-N-(2’-苯胺基-4,4’_聯p比淀-2-基）六氮p比淀-4-叛酿胺 如實例14之程序。與1-乙醯六氫吡啶-4-羧酸反應5天。於 矽膠（在CH2C12中之〇至10% MeOH)上純化，獲得5毫克（5% ) 標題化合物。將產物以1當量之三氟醋酸處理，並凍乾，而 得TFA鹽。 MS (ES) m/z416(M+l). 實例168 N-(2’-苯胺基-4,4’_聯吡啶-2_基)-5·酮基脯胺醯胺 如實例14之程序。與D，L-焦麩胺酸反應5天，獲得12毫克（13 % )標題化合物。將產物以1當量TFA處理，並〉東乾，而得三 氟醋酸鹽。1 H NMR (CD3 OD): δ 8.54-8.48 (m，2H)，7.98 (d，J = 6.5 Hz， 1Η)，7.56-7.35 (m，7H)，7.30 (dd，J = 6·5,2 Hz，1H)，4.44 (m，1H)，2.65-2.15 (m， 4H)，1.30 (m，1H). MS (ES) m/z 374 (M+l). 實例169 89385 -63- 200417546 N3 -乙酿基-N1 -(2，-苯胺基-4,4，-聯吡啶-2-基）-f胺基丙醯胺 如貫例14之程序。與N-乙醯基-/?-丙胺酸反應5天，獲得30 晕克（31% )標題化合物。將產物以1當量之TFA處理，並凍乾 ’而得三氟醋酸鹽。4 NMR (CD3 OD) : 8.50-8.46 (m，2H)，7.96 (d，J = 6.5 Hz，1H)，7.59-7.39 (m，7H)，7.33 (dd，J = 6·5，1·5 Hz，1H)，3.53 (m， 2H)，2.68 (m，2H)，1.92 (s，3H). 實例170 N-(2’-苯胺基-4,4’-聯峨淀_2_基）六氫η比淀_4-叛醯胺 如實例14之程序。與i-(第三-丁氧羰基）六氫吡啶冰羧酸反 應8天。逆相層析，接著以TFA/CH2Cl2丨：1移除b〇c。第二次 逆相層析，獲得16毫克（17% )標題化合物，為自由態鹼。 1H NMR (CD3 OD): 5 8.42 (s，1H)，8.37 (d，J = 5 Hz，1H)，8.19 (d，J = 5·5 Hz， 1H)，7.54 (m，2H)，7.37 (dd，J = 5.5, 1.5 Hz，1H)，7.29 (m，2H)，7.10 (s，1H)， 7.03 (dd，J = 5.5, 1.5 Hz，1H)，6.97 (m，1H)，3·11 (m，2H)，2.64 (m，3H)，1.87 (m， 2H)，1.73(m，2H). 實例171 3-胺基_N_(2，_苯胺基-4,4，-聯吡啶-2_基）丁醯胺 如實例14之程序。與（+/-)-3-[(第三-丁氧羰基）胺基]丁酸反應 5天，接著如同關於26757之N-boc移除，獲得10毫克（11% )標 題化合物。將產物以1當量之HC1 (水溶液）處理，並凍乾， 而得 HC1 鹽。1 H NMR (CD3 OD) : δ 8_43 (s，1H)，8·36 (d，J = 5 Hz，1H)， 8·19 (d，J = 5 Hz，1H)，7·53 (m，2H)，7.36 (dd, J = 5,2 Hz，1H)，7.28 (m，2H)， 7·09 (s，1H)，7.02 (dd，J = 5.5, 1.5 Hz，1H)，6.97 (m，1H)，3.40 (m，1H)，3.34 (s， 3H)，2.60-2.43 (m，2H)，1.18 (d，J = 6.5 Hz，3H). 89385 -64- 200417546 MS (ES) m/z 348 (M+l). 實例172 N-(2’-苯胺基-4,4’-聯峨淀-2-基）_L_脯胺醯胺 如實例14之程序。與1-(第三-丁氧羰基）_L-脯胺酸反應8天， 接著如同關於26757之N-boc移除，獲得7毫克（9% )標題化合 物。將產物以1當量之HC1 (水溶液）處理，並凍乾，而得HC1 鹽。1HNMR(CD3OD): 58_48(s，lH)，8.37(d，J = 5Hz，lH)，8.20(d，J = 5.5 Hz，1Η)，7·53 (m，2H)，7·40 (dd，J = 5, 1.5 Hz，1H)，7_29 (m，2Η)5 7·10 (s， 1H)，7·03 (dd，J = 5, 1.5 Hz，1H)，6.97 (m，1H)，3.86 (m，1H)，3.03 (m，2H)， 2.23 (m，1H)，1.93 (m，1H)，1.79 (m，2H). MS (ES) m/z 360 (M+l). 實例173 N-(2 -苯胺基-4,4f•聯p比淀-2-基）乙酿胺 使N_苯基-4,4’-聯吡啶-2,2’-二胺（50毫克，〇·ΐ9毫莫耳）溶於吡 淀（2毫升）中，並在〇°C下添加氯化乙醯（14微升，〇·2〇毫莫耳） ，且於25°C下攪拌1小時，接著在真空中濃縮。藉逆相層析 純化’獲得16晕克（27% )標題化合物，為自由態驗。1 η NMR (CD3 OD) ： 5 8.50 (m5 1H)? 8.16 (s? 1H)? 8.01 (d? J = 5 Hz? 1H)? 7.68 (m? 1H)? 7.59 (m，2H)，7.52-7.44 (m，4H)，7.36 (m，1H)，3.22 (s，3H)· MS (ES) m/z 305 (M+l). 實例174 2’-苯胺基-4,4f-聯吡啶-2-基胺基甲酸曱酯 如貫例173之程序。於〇°C下添加氯甲酸甲酯（16微升，〇·2〇 耄莫耳），接著在12小時後，添加第二份（5毫升），並於25Qc 89385 -65 - 200417546 下持、〶擾拌2天。藉矽膠層析（在Et〇Ac中之〇至1〇% Μ〇〇Η)純 化，獲得5耄克（8% )標題化合物。將產物以丨當量之HCi (水 落液）處理，並凍乾，而得 HC1 鹽。1 H NMR (CD3 0D): 3 8.45 (m，1H)， 8.13 (s? 1H)? 7.97 (d? J = 6.5 Hz? 1H)5 7.58 (m3 2H)5 7.51 (m? 1H)5 7.48-7.43 (m9 4H)，7.35 (m5 1H)，3.84 (s，3H)· MS (ES) m/z 322 (M+l). 實例175 N-(2f-苯胺基-4,4’-聯吡啶-2-基）甲烷磺醯胺 如實例173之程序。於〇°C下添加氯化甲烷磺醯（16微升，0.20 毫莫耳），並在25°C下持續攪拌3天。藉矽膠層析（在EtOAc中 之0至5% MeOH)純化，接著逆相層析，獲得2毫克（3% )標題 化合物。將產物以1當量之HC1(水溶液）處理，並凍乾，而 得 HC1 鹽。1 H NMR (CD3 OD) : 5 8·46 (m，1H)，7.96 (d，J = 6.5 Hz，1H)， 7.56 (m，2H)，7.47-7.28 (m，7H)，3·29 (s，3H)· MS (ES) m/z 341 (M+l). 實例176 N-(2’-苯胺基_4,4’_聯峨淀-2_基）環己燒叛酿胺 如實例173之程序。於0°C下添加環己羰基氯化物（28微升， 〇·20毫莫耳）並在25°C下持續攪拌12小時。藉逆相層析純化， 獲得4毫克（5% )標題化合物。將產物以1當量之HC1 (水溶液） 處理，並凍乾，而得 HC1 鹽。1 H NMR (CD3 OD): 5 8.46 (m，2H)，8.00 (d， J = 6.5 Hz，1H)，7.55-7.40 (m，5H)，7.35 (m，2H)，7·27 (m，1H)，2·50 (m5 1H)， 1.97-1.22 (m5 10H). MS (ES) m/z 373 (M+l). 89385 -66- 200417546 實例177 1-乙醯基-N-(2’-苯胺基-4,4’-聯吡啶-2-基）六氫吡啶-2-羧醯胺 如貫例14之程序。與1-(第二-丁氧援基）ττ氮咐i淀-2-叛酸（描 述於 Costa，Brian R. de ; Dominguez，Celia ; He，Xiao-shu ; Williams，Wanda ；Radesca, Lilian； Bowen, Wayne； J.Med.Chem. ； 35； 23； 1992； 4334-4343 中）反應7天，接著一般處理，並以TFA/CH2C12 1 : 1處理30分 鐘。以逆相層析純化，獲得5毫克（13微莫耳）N-boc去除保護 之產物，使其與三乙胺（2.1微升，15微莫耳）一起溶於CH2C12(2 毫升）中，並以醋酸酐（1·4微升，14微莫耳）處理。於25°C下 攪掉12小時’並在真至中蒸發溶劑後，以逆相層析純化， 獲得2毫克（1%，3個步驟）標題化合物。將產物以1當量之 HC1(水溶液）處理，並凍乾，而得HC1鹽。1HNMR(CD3OD): 5 8.40 (m，2H)，8.20 (m，1H)，7·54 (m，2H)，7.40 (m，1H)，7.29 (m，2H)，7·11 (m，lH)，7_04(m，lH)，6.97(m，lH)，2.20(s，3H)，2.20-0.98 (m，9H). MS (ES) m/z416(M+l).In 3-methoxypropionic acid (11 mg, 0.1 mmol), N-phenyl_4,4, _bipyridine-2,2L-amine (26 mg, 0.1 mmol), light base Benzotriazole (14 mg, 0.1 mmol), polystyrene-conjugated diisopropylamine (N, N- (diisopropyl) aminomethylpolybenzylacetamidine), 32 mg, 0.12 mmol Mol) and polystyrene combined carbodiimide (N-cyclohexylcarbodiimide-NL propoxymethyl polystyrene, 1% mg, 0.3 mmol), add 2 ml Dimethylformamide i. The mixture was stirred at 120 C under argon for 48 hours. Filter and evaporate to obtain a brown permanent liquid, place it in a maple (200 microliters), and use an automated preparative HPLC system (waters 2767/2525) on eg-shixijiao. A gradient of 25% acetonitrile in .05M acetic acid was subjected to chromatography. The appropriate fractions were combined 'and concentrated to dryness under vacuum to yield 53 mg of the title compound. The column 'contained a 8.6 minute gradient of trifluoroacetic acid in% methanol. UV_diode array detector, clnd and 89385 -54- 200417546 MSD-ESI detection) showed a single compound with 349 (M + 1). C2OH2〇N4〇2, MW-348.4. Example 75 -85 Compound 75-85 is an N-phenyl 1,4, -bipyridine-2,2 made according to the procedure set forth in Example 74, using an appropriate carboxylic acid and a suitable amine. -Made of diamine. Example ----- 1 -1 "name" MW meaning 厶, 厶--measured value m / z 5L into 0 production yield 9.2 milliF 75 N- (2'-anilino-4,4'- Dioxanthin-2-yl) -4-methoxycyclohexanechitamine 402.5 403 76 N- (2f-aniline-4,4f-dioxanthen-2-yl) -3-methoxypropane Fermented amine 348.4 349 5.3 mg 77 N- (2'-aniline-4,4'-bipyridin-2-yl) tetrahydroanan-3-Seramine 360.4 361 17.4 mg 78 N- (2'- Aniline-4,4f-bipyridine-2 «· yl) -4- (dimethylamino) butamidamine 375.5 376 9.6 mg 79 N_ (2f-aniline-4,4'-bipyridine-2 -Based) Assay amine 367.4 368 9.2 mg 80 N- (2f-aniline-4,4f-bipyridin-2-yl) -4- (dimethylamino) benzamidine 409.5 410 3.8 mg 81 Ν -(2 '· aniline-4,4'-bipyridin-2-yl) -2,6-dimethoxynicotinylamine 427.5 428 3.3 mg 82 Ν- (2'_aniline-4,4 '-Bipyridin-2-yl 丨 Homo-2-rejuvenated amine 405.5 406 3.1 mg 83 N- (2f-anilino-4,4'-bipyridin-2-yl) -5-methylpyridine-2 -Carboxamide 382.4 383 3.9 mg 84 N- (2f-anilino-4,4'-bi-p-pyridin-2-yl) ex 1: pyridin-2-carboxamide 367.4 368 9.2 mg 85 N- (2f-anilino-4,4f-bipyridin-2-yl) -3-carboxamidine 356.4 357 5.5 mg Example 86 89385 -55-200417546 N- (2'_anilino-4 , 4'-bipyridin_2_yl) _N'_phenylurea procedure: for N-phenyl-4,4'-bipyridine-2,2'-diamine (131 mg, 0.5 mmol) In a solution in dioxopropane (5 ml), under nitrogen, add phenyl isocyanate (60 mg, 0.5 mmol) dissolved in dioxopropane (1 ml). Mix the mixture in Stir for 16 hours at room temperature. The precipitated material was filtered off and confirmed to be the title compound (104 mg, 55%) by NMR and HPLC-MS, 96% purity (uv-detection). 1H NMR (DMS 0-D6) ) 5 8.40 (d, J = 5.6 Hz, 1H), 5 8.30 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.30 (m, 5H), 7.15 (s, 1H, NH), 7.04 (m, 2H), 6.92 (t, 7.1 Hz, 1H ). 13 C NMR (DMSO-D6) 5 156.7, 152.1, 148.5, 147.5, 145.9, 141.5, 139.0, 138.9, 128.9, 128.7, 122.6, 120.7, 118.8, 118.7, 118.1, 115.3, 111.8, 108.8, 107.9 · 15NNMR (D MSO-D6) 5 -275.0, -260.4, -269.5, -113.3, 108_1. The chemical shifts and positions of nitrogen atoms are measured using 15NHSQC and 15NHMBC, and measured with 1H-1HCOSY. The 15N chemical shift is given relative to external nitromethane at 0.0 ppm. The 15N experiment was performed on a Brnker DRX600 NMR spectrometer, operating at 600 MHz, providing a proton of 60 MHz for nitrogen-15, and equipped with a 5 mm TXI probe and a Z-gradient. The experiment was performed at 22 ° C. HPLC-MS (Waters Exterra C8-column, 8.6 minute gradient of 0-100% methanol in 0.1% trifluoroacetic acid. UV-diode array detector, CLND and MSD-ESI detection) shows a single compound With m / z 382 (M + 1) · C24H27N50, MW = 381.4. Procedure 5: Phenyl isocyanate (72 μl, 0.5 Μ, in dioxolane, 0.036 millimolar) 89385 -56- 200417546 In a solution in a 2 ml deep well 96-well plate, under nitrogen, add dioxolane (200 μl) &lt; N-phenyl_4,4, -bipyridine_2,2, _di Amine (7.9 mg, 2003 mmol). Place the plate on an orbital shaker and stir at room temperature for 16 hours. The precipitated substance 'I was filtered off and dissolved in dimethylarsine. Product analysis was performed using an Agilent Gil 1100 HPLC-MS system (Waters ExtermC8_ column with 0_1% trifluoride) equipped with UV-diode array detector 'CLND (nitrogen detector) and msd_esi detector. Acetic acid (100% gradient of 86% methanol). Compounds 87-166 were prepared according to the procedure set forth in Procedure B using an appropriate isochlorate derivative and N_phenyl_4, bipyridine diamine prepared as described in Example U. Examples 87-166 Accession number 87 Name N- (2f-aniline_4,4'_bipyridin-2-yl) -N'-phenylurea MW 381.4 Found 382 Yield (mg) 3.6 88 Ν- (2 '-Anilino-4,4'-bipyridin-2-yl) -N'-[l- (4-bromophenyl) ethyl] urea 488.4 488 0.1 89 N- (2'-anilino-4, 4'-bipyridin-2-yl) -N'-thiophene-3-ylurea 387.5 388 2.8 90 N- (2f-aniline-4,4'-bipyridin-2-yl) -Nf- (2_ Methylphenyl) urea 395.5 396 1.9 91 N- (2'-aniline_4,4'_bipyridin-2 ^ yl) -N '-(4-methylphenyl) urea 395.5 396 1.8 92 N- (2'-benzylamino_4,4'_bipyridin_2_yl) -Nf- (3-fluorophenyl) urea 399.4 400 2.9 93 N- (2'-aniline-4,4'-bipyridine 2-yl) -NH2-fluorophenyl) urea 399.4 400 0.4 89385 -57- 200417546 94 N- (2'-aniline-4,4'-bipyridin-2-yl) -NH4-fluorophenyl) Urea 399.4 400 0.1 95 N- (2'-aspartyl_4,4'_bi-p-pyridine-2_yl) · N '_ [4- (chloromethyl) phenyl] urea 429.9 430 2.2 96 Ν -(2'-anilino-4,4'-bipyridin-2-yl) -N '-(3-cyanophenyl) urea 406.4 407 1.7 97 N- (2 ^ amido-4,4f- Bi-rhodido-2_yl) -N '-(4-cyano Phenyl) moon urine 406.4 407 0.3 98 N- (2'-anilino-4,4f-bi-pyridine-2 · yl) -N '-(2-cyanophenyl) urea 406.4 407 0.1 99 N- (2'-aniline-4,4f-bi-pi ratio-2.yl) -N '-(2,3-dimethylphenyl) Moon urine 409.5 410 0.8 100 N- (2f-aniline-4 , 4'-bipyridin-2-yl) -N '-(2,5-dimethylphenyl) urea 409.5 410 0.3 101 N- (2'-anilino-4,4'-bi-peptide- 2 * group) -N '-(4-ethylphenyl) urea 409.5 410 0.7 102 N- (2f-aniline-4,4f-bipyridin-2-yl) -Nf- (3-ethylbenzene Based) Lunar urine 409.5 410 1.6 103 N- (2'-aniline-4,4f-bi-p-pyridine-2_yl) -N '-(4-methoxyphenyl) urea 411.5 412 2.6 104 N- (2 '-Anilino-4,4'-bi-pyridine-2-yl) -N'-(3-methoxyphenyl) urea 411.5 412 0.2 105 N- (2f-anilino-4,4'-linked Pyridin-2-yl) -N '-(2-methoxyphenyl) urea 411.5 412 0.2 106 N- (2'-anilino-4,4'-bi-p-pyridine-2_yl) -NH5-fluoro 2-methylphenyl) menses urine 413.5 414 0.4 107 N- (2'-anilino-4,4f-bi-rhobiazyl-2-yl) -TνΓ- (2-fluorofluorenyl) menses urine 413.5 414 2.7 108 N- (2'-aniline-4,4'-bi-p-butane-2_yl) -N -(2-Gas-5-methylphenyl) urea 413.5 414 0.3 200417546 109 N- (2'-aniline-4,4f-bipyridin-2-yl) -N '-(3-fluoroyl ) Moon urine 413.5 414 1.5 110 N- (2f-aniline-4,4'-bipyridin-2-yl) -N '-(2-chlorophenyl) urea 415.9 416 0.3 111 N- (2'-aniline -4,4'-bipyridin-2-ylchlorophenyl) urea 415.9 416 0.2 112 N- (2f-anilino-4,4'-bi-p-pyridine-2_yl) -N '-(2- Chlorofluorenyl) Moon urine 429.9 430 2.3 113 N- (2f-anilino-4,4'-biyanido-2_yl) -Nl (2,5-difluorophenyl) urea 417.4 418 0.2 114 N- ( 2'-aniline-4,4'-bi-p-pyridyl-2 · yl) -N '_ (2,4-difluorophenyl) urea 417.4 418 0.1 115 N- (2f-aniline-4,4 '-Bi-p-pyridin-2_yl) -N'-(3,4-dichlorobenzyl) urea 464.4 464 1.6 116 N- (4-ethylamidophenyl) -NH2f-aniline-4,4f- Bipyridin-2-yl) urea 423.5 424 0.2 117 N- (3-Ethylfluorenylphenyl) -Nf- (2'-aniline-4,4'-bipyridin-2-yl) urea 423.5 424 3.2 118 N- (2'-benzamino-4,4'-bi-p-pyridine-2_yl) -N '-(4-isopropylphenyl) urea 423.5 424 0.4 119 N- (2'-aniline- 4,4'-bi-ρ ratio lake-2_ radical) -N '-(2-iso Propylphenyl) moon urine 423.5 424 0.9 120 N- (2'-anilino-4,4'-bi-pyridine-2_yl) -N '-(2-ethyl-6-methylphenyl) Urea 423.5 424 0.2 121 N- (2f-anilino-4,4 ^ bi-pyridin-2-yl) -N'-2,4,6-trimethylphenylurea 423.5 424 0.1 122 N- (2f-aniline -4,4'-bi-p-pyridine-2-yl) -N '-(2-propylphenyl) urea 423.5 424 1.0 123 N- (2f-aniline eodo-2-yl) -N'_ [4- (Dimethylamino) phenyl] urea 424.5 425 0.1 89385 -59- 200417546 124 N- (2'-aniline-4,4'-bipyridin-2-yl) -N'-1,3 -Benzodioxol-5-ylurea 425.4 426 0.2 125 N- (2'-anilino-4,4 [bipyridin-2-yl) -N '-(4-methoxy-2- Methylphenyl) urea 425.5 426 0.4 126 N- (2'-aniline-4,4f-bipyridin-2-yl) -N '-(2-methoxy-5-methylphenyl) urea 425.5 426 0.1 127 N- (2 ^ this amine group 1? Than biten-2-yl) -N '-(4-ethoxyphenyl) moon urine 425.5 426 0.9 128 Ν- (2 ^ aniline-4,4 '-Bi-p-pyridine-2_yl) _Nf- (4-methoxyfluorenyl) menses diarrhea 425.5 426 1.6 129 Ν- (2 ^ ligamino-4,4f-bi-p-pyridyl-2-yl)- NH4-nitrophenyl) urea 426.4 427 0.5 130 N- (2f-aniline -4,4f-bi-p-pyridin-2-yl) nitrophenyl) moon urine 426.4 427 0.6 131 N- (2f-aniline-4,4'-bi-p-pyridyl-2_yl) -N'- [3- (methylthio) phenyl] urea 427.5 428 3.3 132 N- (2f-aniline-4,4f-bipyridin-2-yl) -N '-[4- (methylthio) phenyl] Urea 427.5 428 0.4 133 N- (2f-aniline-4,4'-bipyridin-2-yl) -N '-(2-methylbenzyl) urea 409.5 410 2.7 134 N- (2f-aspartyl- 4,4 ^ bi-pyridine-2_yl) -N '-(5-chloro-2-methylphenyl) urea 429.9 430 0.3 135 N- (2L aniline-4,4f-bipyridyl- 2_yl) -Nf- (2-chloro-5-methylphenyl) urea 429.9 430 0.4 136 N- (2f-anilino-4,4'-bi-p-pyridine-2_yl) -N '-( 2-chlorobenzyl) urea 429.9 430 2.1 89385 -60- 200417546 137 N- (2'-aniline-4,4'-bipyridin-2-yl) -N '-(3-chloro-4-fluoro Phenyl) moon urine 433.9 434 0.2 138 N- (2f-aniline-4,4'-bipyridin-2-yl) -N '-(2,3,4-trifluorophenyl) urea 435.4 436 0.1 139 N- (2'-anilino-4,4'-bi-p-pyridine-2_yl) -N '-(4-butylprivate) menses 437.5 438 0.1 140 N- (2'-anilino-4 , 4f-bi-rhodido-2_yl) -N '-(2-isopropyl-6-methylphenyl) urea 437.5 438 0.1 141 N- (2'-anilino-4,4f-biπ ratio lake 2-yl) -N '-(2-second-butylphenyl) moon urine 437.5 438 0.4 142 々- ( {[^ '-Anilino-septa ^^-bi ^ pyridine · ^ -yl) aminotenyl} amino) benzoic acid methyl ester 439.5 440 0.1 143 N- (2f-aniline-4,4'- Bipyridin-2-yl) -1 ^ '-(3,4-dimethoxyphenyl) Luna urine 441.5 442 3.6 144 N- (2f-amido-4,4'-bi-p ratio p- 2_yl) -N '-(3,5-dimethoxyphenyl) urea 441.5 442 0.8 145 N- (2f-anilino-4,4f-bi-peptide-2_yl) -1NΓ- (3- Chloro-4-methoxyphenyl) urea 445.9 446 0.8 146 N- (2'-aniline-4,4f-bipyridin-2-yl) -N '-[4- (difluoromethoxy) benzene Group] urea 447.4 448 0.6 147 N- (2f-benzyl-4,4f-bi-p-pyridine-2_yl) -N '-[2- (trifluoromethyl) phenyl] urea 449.4 450 0.2 148 N -(2f-anilino-4,4f • bi-rhodido-2-yl) -N '-[3- (trifluoromethyl) phenyl] urea 449.4 450 0.1 149 N- (2'-anilino- 4,4f-bipyridin-2-yl) -Nf- [4- (trifluoromethyl) phenyl] urea 449.4 450 0.1 150 N- (2'-anilino-4,4f-bi-rho ratio-2_ ) -NH2,5-dichlorophenyl) urea 450.3 450 0.1 89385 -61-200417546 151 N- (T-aniline-4, renpyridin-2-yl) -Nf- (3,5-dichlorophenyl) urea 450.3 450 0.0 152 N- (2f-aniline-4 , 4f-bipyridin-2-yl) -N '-(3,4-dichlorophenyl) urea 450.3 450 0.3 153 N- (2'-benzyl-4,4f-bi-p-pyridine-2_yl ) -N '-(2,3-dichlorophenyl) urea 450.3 450 0.2 154 N- (2f-amido-4,4f-bi-p-pyridine-2-yl) -N'-(2,4 -Dichlorophenyl) urea 450.3 450 1.2 155 N- (2f-anilino-4,4f-bi-p-pyridine-2_yl) -N '-(4-brookyl-3-methylphenyl) urea 474.4 474 0.1 156 N- (2f-anilino-4,4f-bi-p-pyridin-2-yl) -Nf- (2,6-dichloro p-pyridin-4-yl) Lunar urine 451.3 451 0.1 157 N- (2'-anilino-4,4 ^ bi-pyridine-2_yl) _Nf- (4-butyl-2-methylphenyl) urea 451.6 452 0.0 158 N- (2'-anilino-4, 4f · bipyridin-2-yl) -N45-methyl-2- (trifluoromethyl) -3-furanyl] urea 453.4 454 0.2 159 3-({[(2 \ aniline-4,4'- Bi 1: 7 Biyodo-2-yl) amino] carbonyl} amino) ethyl benzoate 453.5 454 0.2 160 N- (2f-aniline-4,4'-bi-pyrido-2-yl)- Nf- (4-butoxyphenyl) moon urine 453.5 454 0.2 161 N- (2'-aniline-4,4'-diamine p ratio lake-2_yl) -Nf- [4- (trifluoromethoxy) phenyl] urea 465.4 466 0.1 162 N- (2'-anilino-4,4f-biρ ratio lake 2-yl) -N '-(2,6-diisopropylphenyl) urea 465.6 466 0.1 163 N- (2f-aniline-4,4' * bi-peptide-2_yl:)-N '-(4- Methylbenzyl) urea 409.5 410 0.5 89385 -62- 200417546 164 N- (2'-aniline_4,4'_bipyridin_2_yl) _N '-(5-chloro-2,4-dimethoxy Phenyl) urea 475.9 476 1.6 165 N- (2 ^ anilino-4,4'-bipyridin-2-yl) -1 ^ {4-[(trifluoromethyl) thio] phenyl} urea 481.5 482 0.1 166 N- (2'-aniline-4,4f-bipyridin-2-yl) -Nf- [3,5-bis (trifluoromethyl) phenyl] urea 517.4 518 0.1 Example 167 1-B The procedure of Example 14 was as described in Example 14 for phenyl-N- (2'-anilino-4,4'-bi-p-pyridin-2-yl) hexazine p-pyridyl-4-benzylamine. Reaction with 1-acetamidinehexahydropyridine-4-carboxylic acid for 5 days. Purification on silica gel (0 to 10% MeOH in CH2C12) gave 5 mg (5%) of the title compound. The product was treated with 1 equivalent of trifluoroacetic acid and lyophilized to obtain a TFA salt. MS (ES) m / z416 (M + 1). Example 168 N- (2'-Anilino-4,4'_bipyridin-2_yl) -5. Ketoproline amide as in Example 14 . Reaction with D, L-pyroglutamic acid for 5 days gave 12 mg (13%) of the title compound. The product was treated with 1 equivalent of TFA and dried> to obtain trifluoroacetate. 1 H NMR (CD3 OD): δ 8.54-8.48 (m, 2H), 7.98 (d, J = 6.5 Hz, 1Η), 7.56-7.35 (m, 7H), 7.30 (dd, J = 6.5, 2 Hz, 1H), 4.44 (m, 1H), 2.65-2.15 (m, 4H), 1.30 (m, 1H). MS (ES) m / z 374 (M + l). Example 169 89385 -63- 200417546 N3 -Ethyl-N1-(2, -anilino-4,4, -bipyridin-2-yl) -faminopropylamidamine as in Example 14. Reaction with N-acetamido-/?-Alanine for 5 days gave 30 g (31%) of the title compound. The product was treated with 1 equivalent of TFA and lyophilized to obtain trifluoroacetate. 4 NMR (CD3 OD): 8.50-8.46 (m, 2H), 7.96 (d, J = 6.5 Hz, 1H), 7.59-7.39 (m, 7H), 7.33 (dd, J = 6.5, 1.5 Hz, 1H), 3.53 (m, 2H), 2.68 (m, 2H), 1.92 (s, 3H). Example 170 N- (2'-anilino-4,4'-lianedian_2_yl) Hexahydro-n-pyridine-4-benzylamine was used as in Example 14. Reaction with i- (third-butoxycarbonyl) hexahydropyridine glacial carboxylic acid for 8 days. Reverse phase chromatography followed by removal of boc with TFA / CH2Cl2: 1. Second reverse phase chromatography gave 16 mg (17%) of the title compound as a free base. 1H NMR (CD3 OD): 5 8.42 (s, 1H), 8.37 (d, J = 5 Hz, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.54 (m, 2H), 7.37 ( dd, J = 5.5, 1.5 Hz, 1H), 7.29 (m, 2H), 7.10 (s, 1H), 7.03 (dd, J = 5.5, 1.5 Hz, 1H), 6.97 (m, 1H), 3.11 (m, 2H), 2.64 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H). Example 171 3-amino_N_ (2, _anilino-4,4, -bipyridine- 2-Methyl) Butamidamine was as described in Example 14. Reaction with (+/-)-3-[(third-butoxycarbonyl) amino] butanoic acid for 5 days followed by removal of N-boc as for 26757 gave 10 mg (11%) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1 H NMR (CD3 OD): δ 8_43 (s, 1H), 8.36 (d, J = 5 Hz, 1H), 8.19 (d, J = 5 Hz, 1H), 7.53 (m, 2H), 7.36 (dd, J = 5,2 Hz, 1H), 7.28 (m, 2H), 7.09 (s, 1H), 7.02 (dd, J = 5.5, 1.5 Hz, 1H), 6.97 (m , 1H), 3.40 (m, 1H), 3.34 (s, 3H), 2.60-2.43 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H). 89385 -64- 200417546 MS (ES) m / z 348 (M + 1). Example 172 N- (2'-Anilino-4,4'-biyanido-2-yl) _L_proline amine was as in the procedure of Example 14. Reaction with 1- (tertiary-butoxycarbonyl) -L-proline for 8 days followed by removal of N-boc as for 26757 gave 7 mg (9%) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1HNMR (CD3OD): 58_48 (s, 1H), 8.37 (d, J = 5Hz, 1H), 8.20 (d, J = 5.5 Hz, 1Η), 7.53 (m, 2H), 7.40 (dd, J = 5, 1.5 Hz, 1H), 7_29 (m, 2Η) 5 7 · 10 (s, 1H), 7.03 (dd, J = 5, 1.5 Hz, 1H), 6.97 (m, 1H), 3.86 (m, 1H), 3.03 (m, 2H), 2.23 (m, 1H), 1.93 (m, 1H), 1.79 (m, 2H). MS (ES) m / z 360 (M + l). Example 173 N- (2-Anilino-4,4f-bi-p-pyridin-2-yl) ethylamine makes N-phenyl-4,4'-bipyridine-2,2'-diamine (50 mg, (Ϊ́9 mmol) was dissolved in pyridine (2 ml), and acetamidine chloride (14 μl, 0.20 mmol) was added at 0 ° C, and stirred at 25 ° C for 1 hour And then concentrated in vacuo. Purification by reverse phase chromatography 'gave 16 g (27%) of the title compound as a free state test. 1 η NMR (CD3 OD): 5 8.50 (m5 1H)? 8.16 (s? 1H)? 8.01 (d? J = 5 Hz? 1H)? 7.68 (m? 1H)? 7.59 (m, 2H), 7.52 7.44 (m, 4H), 7.36 (m, 1H), 3.22 (s, 3H) · MS (ES) m / z 305 (M + 1). Example 174 2'-anilino-4,4f-bipyridine- The 2-ylaminocarbamate was as described in Example 173. Methyl chloroformate (16 μl, 0.20 mol) was added at 0 ° C, and after 12 hours, a second portion (5 ml) was added, and the mixture was held at 25Qc 89385 -65-200417546, Stir and stir for 2 days. Purification by silica gel chromatography (0 to 10% in EtOAc) gave 5 g (8%) of the title compound. The product was treated with HCi (Water Drop) and lyophilized to obtain HC1 salt. 1 H NMR (CD3 0D): 3 8.45 (m, 1H), 8.13 (s? 1H)? 7.97 (d? J = 6.5 Hz? 1H) 5 7.58 (m3 2H) 5 7.51 (m? 1H) 5 7.48- 7.43 (m9 4H), 7.35 (m5 1H), 3.84 (s, 3H) · MS (ES) m / z 322 (M + 1). Example 175 N- (2f-anilino-4,4'-bipyridine 2-yl) Methanesulfonamide is as described in Example 173. Methanesulfonium chloride (16 µl, 0.20 mmol) was added at 0 ° C, and stirring was continued at 25 ° C for 3 days. Purification by silica gel chromatography (0 to 5% MeOH in EtOAc) followed by reverse phase chromatography gave 2 mg (3%) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1 H NMR (CD3 OD): 5 8.46 (m, 1H), 7.96 (d, J = 6.5 Hz, 1H), 7.56 (m, 2H), 7.47-7.28 (m, 7H), 3.29 ( s, 3H) · MS (ES) m / z 341 (M + l). Example 176 N- (2'-anilino_4,4'_Lian'edian-2_yl) cyclohexyl benzylamine such as Procedure of Example 173. Cyclohexylcarbonyl chloride (28 µl, 0.20 mmol) was added at 0 ° C and stirring was continued at 25 ° C for 12 hours. Purification by reverse phase chromatography gave 4 mg (5%) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1 H NMR (CD3 OD): 5 8.46 (m, 2H), 8.00 (d, J = 6.5 Hz, 1H), 7.55-7.40 (m, 5H), 7.35 (m, 2H), 7.27 (m, 1H), 2.50 (m5 1H), 1.97-1.22 (m5 10H). MS (ES) m / z 373 (M + l). 89385 -66- 200417546 Example 177 1-Ethyl-N- (2 The procedure of '-anilino-4,4'-bipyridin-2-yl) hexahydropyridine-2-carboxamide is as in Example 14. With 1- (second-butoxycarbonyl) ττ nitrogen, i-do-2-acid (described in Costa, Brian R. de; Dominguez, Celia; He, Xiao-shu; Williams, Wanda; Radesca, Lilian; Bowen, Wayne; J. Med. Chem .; 35; 23; 1992; 4334-4343) for 7 days, followed by general treatment, and treated with TFA / CH2C12 1: 1 for 30 minutes. Purified by reverse phase chromatography to obtain 5 mg (13 μmol) of N-boc deprotected product, which was dissolved in CH2C12 (2 mL) with triethylamine (2.1 μl, 15 μmol). And treated with acetic anhydride (1.4 microliters, 14 micromolar). After stirring off at 25 ° C for 12 hours' and evaporating the solvent from true to medium, it was purified by reverse phase chromatography to obtain 2 mg (1%, 3 steps) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1HNMR (CD3OD): 5 8.40 (m, 2H), 8.20 (m, 1H), 7.54 (m, 2H), 7.40 (m, 1H), 7.29 (m, 2H), 7.11 (m, 1H) ), 7_04 (m, lH), 6.97 (m, lH), 2.20 (s, 3H), 2.20-0.98 (m, 9H). MS (ES) m / z416 (M + l).

實例178 1-乙酿基-N-(2’-苯胺基-4,4f•聯p比淀-2-基）六氫峨淀-3-叛酿胺 如實例14之程序。與1-乙驢六氫ρ比咬-3-叛酸（描述於：Zalucky 等人，J· Pharm· Sci·，1965, 54, 687-693中）反應5天。以逆相層析純 化，獲得3毫克（3% )標題化合物。將產物以1當量之HC1 (水 溶液）處理，並凍乾，而得HC1鹽。1HNMR(CD3OD) : 5 8.52- 8.42 (m，2H)，7.95 (d，J = 6.5 Hz，1H)，7.58 (m，3H)，7.51-7.42 (m，4H)，7.34 (dd，J = 7,2 Hz，1H)，4.53 (m5 1H)，4.19 (m，1H)，3.98-3.84 (m，2H)，2.99 (m， 1H)，2·13 (s，3H)，2.13-1.26 (m，4H). 89385 -67- 200417546 MS (ES) m/z416 (M+l). 實例179 4_[(2’·苯胺基_4,4’_聯吡啶-2·基）胺基】_4_酮基丁酸乙酯 於氮大氣下，將4-乙氧基斗酮基丁酸（36毫克，〇25毫莫耳） 與六氟磷酸N-[(二甲胺基三唑并[4,5七]吡啶·3_基氧基） 亞甲基]-Ν-甲基甲銨（142毫克，〇·375毫莫耳）在4毫升無水n，n_ 一甲基甲胺中稀釋。逐滴添加二異丙基乙胺（64毫克，87 微升，0.575耄莫耳）。攪拌1小時後，慢慢添加N_苯基-4,4，-聯 p比淀-2,2 -一胺（65耄克，〇·25毫莫耳）在無水n，N-二甲基甲醯胺 (1毫升）中之溶液，並將混合物於2(TC下攪拌15小時。將混 合物傾倒在飽和NaHC03水溶液（5毫升）上，並以酷酸乙酯 (3x10毫升）萃取。使有機層以硫酸鎂脫水乾燥，過漉，並於 真芝下蒸發’而得粗產物使其藉急驟式層析（酷酸乙酯/甲 醇：98/2)純化。產率：25%(25 毫克）。iHNMR^OOMHz’CDCU) :δ 9.04 (s，1H)，8.45 (s，1H)，8·30 (d，J = 6·1 Hz，1H)，8·25 (d，J = 4·5 Hz， 1Η)，7.43-7.32 (m，5Η)，7.20-7.14 (m，1Η)，7·09-7·05 (m，2Η)，6.96 (d，J = 5·6 Hz，1H)，4.16 (q，J = 7·1 Hz，2H)，2.76-2.66 (m，4H)，1.27-1.22 (t，J = 7.1 Hz， 3H). 13 C NMR (101 MHz, CDC13) ： δ 172.64 (s，1C)，170.50 (s，1C)，156.58 (s，1C)，152.20 (s5 1C)，148.38 (s，1C)，148.08 (s，1C)，147.85 (s，1C)，139.97 (s，1C)，129.40 (s，4C)，123.30 (s，1C)，120.66 (s，1C)，117.56 (s，1C)，113.07 (s，1C)，111.89 (s，1C)，106.39 (s，1C)，60.87 (s，1C)，31.97 (s，1C)，29.03 (s，1C)， 14.15 (s? 1C). MS (TSP) m/z (M+l) ·· 343, 391. 實例180 -68- 89385 200417546 沐(2’-苯胺基-4,4，-聯吡啶：基）四氫呋喃：羧醯胺(幻）與读2) 糸氮大氣下，將四氫吱喃_2—瘦酸（58毫克，〇·25毫莫耳）與 六氟磷酸化[(二甲胺基）(3乩[1，2,3]三唑并[4,5-b风啶各基氧基）亞 甲基]-Ν-甲基甲銨（285毫克，〇·75毫莫耳）在6毫升無水风1^二 甲基甲胺中稀釋。逐滴添加二異丙基乙胺（129毫克，174 從升，1.0笔莫耳）。攪拌1小時後，慢慢添加N_苯基_4,4，_聯吡 啶-2,2’-二胺（131耄克’ 〇.5〇毫莫耳）在無水n，n_二甲基甲醯胺（2 毫升）中之溶液，並將混合物於2(TC下攪拌15小時。將混合 物傾倒在飽和NaHC〇3水溶液（20毫升）上，並以醋酸乙酯（3x2〇 毫升）萃取。使有機層以硫酸鍰脫水乾燥，過濾，並於真空 下蒸發，而得粗產物，使其藉急騾式層析（醋酸乙酯/甲醇 :98/2)純化。產率：44% (81毫克）外消旋物。將兩種對掌異 構物在對掌性管柱上分離，而得：25毫克與22毫克以。 1H NMR (400 MHz，CDC13 )·· 5 9.12 (s，1H)，8.51 (s，1H)，8·36 (d，J = 4.5 Hz， lH)，8.30(d，J = 6.1Hz，lH)，7.42-7.34(m，4H)，7.23(d，J = 3.5Hz，lH)，7.11-7·04 (m，2H)，7.01 (d，J = 5·1 Hz，1H)，6.64 (s，1H)，4.50 (dd，J = 8·6,5.6 Hz， 1H)，4.12-4.03 (m，1H)，4.02-3.92 (m5 1H)，2.44-2.33 (m，1H)，2.19 (td，J = 13.4, 6.1 Hz, 1H)5 2.02-1.90 (m5 2H). 13 C NMR (101 MHz, CDC13) ： 5 172.32 (s，1C)，156.63 (s，1C)，151·55 (s，1C)，149.15 (s，1C)，148.74 (s，1C)，148.62 (s，1C)，140.15 (s，1C)，129.38 (s，2C)，123.10 (s，1C)，120.38 (s，2C)，117.92 (s， 1C)，113.29 (s，1C)，111.51 (s，1C)，106.26 (s，1C)，78.52 (s，1C)，69.76 (s，1C)， 31.87 (s，1C)，25.58 (s，1C). MS(TSP)m/z(M+l) ： 361. 實例181 89385 -69- 200417546 (S)-3N2-乙醯基_Nl _(2，_苯胺基·4,4，_聯吡啶_2•基）甲硫胺醯胺 於氮大氣下，將（S)-N-乙醯基-L-甲硫胺酸（96毫克，〇 5〇毫莫 耳）與六氟磷酸N-[(二甲胺基三唑并[4,5七]吡啶·氧 基）亞甲基]-N-甲基甲銨（285毫克，0.75毫莫耳）在6毫升無水 N，N-二甲基甲醯胺中稀釋。逐滴添加二異丙基乙胺（1四毫克 174彳放升，ΐ·〇耄莫耳）。授拌1小時後，慢慢添加队苯基_4,4，_ 聯晚淀-2,2’-二胺（131毫克，〇.50毫莫耳）在無水凡队二甲基甲 縫胺（2毫升）中之溶液，並將混合物於2〇t：下攪拌15小時。 將混合物傾倒在飽和NaHC〇3水溶液（20毫升）上，並以醋酸乙 酯（3x20毫升）萃取。使有機層以硫酸鎂脫水乾燥，過滤，並 於真空下蒸發，而得粗產物，使其藉急驟式層析（醋酸乙酯 / 甲醇：98/2)純化。產率：25% (54 毫克）。1H NMR (400 MHz，CDC13) ·· 5 9.27 (s，1Η)，8.42 (s，1H)，8·33 (d，J = 5·1 Hz，1H)，8·26 (d，J = 5·6 Hz， 1H)，7.42-7.33 (m，4H)，7.22 (d，J = 5·6 Hz，1H)，7·11-7·05 (m，3H)，6.97 (d，J = 5.6 Hz，1H)，6.44 (d，J = 8.1 Hz，1H)，4.85-4.77 (m，1H)，2.67-2.56 (m，2H)， 2.27-2.18 (m，1H)，2.13 (s，3H)，2.09-2.00 (m，4H)· 13 C NMR (101 MHz， CDC13) ： 5 170.50 (s，1C)，170.20 (s，1C)，156.69 (s，1C)，151.73 (s，1C)， 148.96 (s，1C)，148.89 (s，1C)，148.36 (s，1C)，147.51 (s，1C)，140.08 (s，1C)， 129.40 (s，2C)，123.17 (s，1C)5 120.44 (s，2C)，118.07 (s，1C)，113.11 (s，1C)， 111.95 (s，1C)，106.22 (s，1C)，53.35 (s，1C)，31.20 (s，1C)，30.29 (s，1C)，23.22 (s，1C)，15.38 (s，1C). MS(TSP)m/z(M+l) ： 436. 實例182 N-(2，-苯胺基-4,4’-聯吡啶-2_基）四氫-2H-喊喃-4-羧醯胺 89385 -70- 200417546Example 178 1-Ethyl-N- (2'-aniline-4,4f • bi-p-pyridin-2-yl) hexahydroeodo-3-benzylamine The procedure of Example 14 was used. It reacts with 1-ethyl donkey hexahydro-ratio bitate-3-destroic acid (described in: Zalucky et al., J. Pharm. Sci., 1965, 54, 687-693) for 5 days. Purification by reverse phase chromatography gave 3 mg (3%) of the title compound. The product was treated with 1 equivalent of HC1 (aqueous solution) and lyophilized to give the HC1 salt. 1HNMR (CD3OD): 5 8.52- 8.42 (m, 2H), 7.95 (d, J = 6.5 Hz, 1H), 7.58 (m, 3H), 7.51-7.42 (m, 4H), 7.34 (dd, J = 7 , 2 Hz, 1H), 4.53 (m5 1H), 4.19 (m, 1H), 3.98-3.84 (m, 2H), 2.99 (m, 1H), 2.13 (s, 3H), 2.13-1.26 (m , 4H). 89385 -67- 200417546 MS (ES) m / z416 (M + 1). Example 179 4 _ [(2 '· aniline_4,4'_bipyridin-2 · yl) amino] _4_ Ethyl ketobutyrate Under nitrogen atmosphere, 4-ethoxytetramethyl butyric acid (36 mg, 025 mmol) and N-[(dimethylaminotriazolo [4, Hepta] pyridine · 3-yloxy) methylene] -N-methylmethylammonium (142 mg, 0.375 mmol) was diluted in 4 ml of anhydrous n, n-methylmethylamine. Diisopropylethylamine (64 mg, 87 μl, 0.575 mol) was added dropwise. After stirring for 1 hour, N-phenyl-4,4, -bi-p-pyridine-2,2-monoamine (65 g, 0.25 mmol) was added in anhydrous n, N-dimethyl A solution in formamidine (1 ml), and the mixture was stirred at 2 ° C for 15 hours. The mixture was poured onto saturated aqueous NaHC03 solution (5 ml) and extracted with ethyl picrate (3 x 10 ml). The organic The layer was dried over magnesium sulfate, dried over water, and evaporated under real cheese to obtain a crude product, which was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 25% (25 mg ). IHNMR ^ OOMHz'CDCU): δ 9.04 (s, 1H), 8.45 (s, 1H), 8.30 (d, J = 6.1 Hz, 1H), 8.25 (d, J = 4 · 5 Hz, 1Η), 7.43-7.32 (m, 5Η), 7.20-7.14 (m, 1Η), 7.09-7 · 05 (m, 2Η), 6.96 (d, J = 5.6 Hz, 1H) , 4.16 (q, J = 7.1 Hz, 2H), 2.76-2.66 (m, 4H), 1.27-1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDC13): δ 172.64 (s, 1C), 170.50 (s, 1C), 156.58 (s, 1C), 152.20 (s5 1C), 148.38 (s, 1C), 148.08 (s, 1C), 147.85 (s, 1C), 139.97 (s , 1C), 129.40 (s, 4C), 123.30 (s, 1C ), 120.66 (s, 1C), 117.56 (s, 1C), 113.07 (s, 1C), 111.89 (s, 1C), 106.39 (s, 1C), 60.87 (s, 1C), 31.97 (s, 1C) , 29.03 (s, 1C), 14.15 (s? 1C). MS (TSP) m / z (M + 1) · 343, 391. Example 180 -68- 89385 200417546 Mu (2'-anilino-4, 4, -bipyridine: yl) tetrahydrofuran: carboxamide (phantom) and reading 2) In a nitrogen atmosphere, tetrahydrofuran-2-leptic acid (58 mg, 0.25 mmol) and hexafluorophosphate [(Dimethylamino) (3 乩 [1,2,3] triazolo [4,5-b amidinyloxy) methylene] -N-methylmethylammonium (285 mg, 75 millimolar) was diluted in 6 ml of anhydrous wind 1 ^ dimethylmethylamine. Diisopropylethylamine (129 mg, 174 liters, 1.0 pen mole) was added dropwise. After stirring for 1 hour, N_phenyl_4,4, _bipyridine-2,2'-diamine (131 g '0.5 mg) was added in anhydrous n, n_dimethyl A solution in formamidine (2 ml), and the mixture was stirred at 2 ° C for 15 hours. The mixture was poured onto saturated aqueous NaHC03 (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over hydration sulfate, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 44% (81 Mg) racemate. The two palmar isomers were separated on a palmar column to obtain: 25 mg and 22 mg. 1H NMR (400 MHz, CDC13) · 5 9.12 (s, 1H ), 8.51 (s, 1H), 8.36 (d, J = 4.5 Hz, lH), 8.30 (d, J = 6.1 Hz, lH), 7.42-7.34 (m, 4H), 7.23 (d, J = 3.5Hz, lH), 7.11-7 · 04 (m, 2H), 7.01 (d, J = 5.1 Hz, 1H), 6.64 (s, 1H), 4.50 (dd, J = 8.6, 5.6 Hz , 1H), 4.12-4.03 (m, 1H), 4.02-3.92 (m5 1H), 2.44-2.33 (m, 1H), 2.19 (td, J = 13.4, 6.1 Hz, 1H) 5 2.02-1.90 (m5 2H ). 13 C NM R (101 MHz, CDC13): 5 172.32 (s, 1C), 156.63 (s, 1C), 151.55 (s, 1C), 149.15 (s, 1C), 148.74 (s, 1C), 148.62 (s, 1C), 140.15 (s, 1C), 129.38 (s, 2C), 123.10 (s, 1C), 120.38 (s, 2C), 117.92 (s, 1C), 113.29 (s, 1C), 111.51 (s, 1C) ), 106.26 (s, 1C), 78.52 (s, 1C), 69.76 (s, 1C), 31.87 (s, 1C), 25.58 (s, 1C). MS (TSP) m / z (M + 1): 361. Example 181 89385 -69- 200417546 (S) -3N2-Acetyl_Nl _ (2, _anilino · 4,4, _bipyridine_2 • yl) methanamine in nitrogen atmosphere, (S) -N-Ethyl-L-methionine (96 mg, 0.05 mmol) and N-[(dimethylaminotriazolo [4,5 hepta]] pyridine -Oxy) methylene] -N-methylmethylammonium (285 mg, 0.75 mmol) was diluted in 6 ml of anhydrous N, N-dimethylformamide. Diisopropylethylamine (14 mg 174 彳 L, 彳 〇mol) was added dropwise. After 1 hour of incubation, slowly add phenyl _4,4, _ lianwandian-2,2'-diamine (131 mg, 0.50 mol) in anhydrous vanadyl methanosamine (2 ml) of the solution, and the mixture was stirred at 20 t for 15 hours. The mixture was poured onto saturated aqueous NaHC03 (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layer was dried over magnesium sulfate, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 25% (54 mg). 1H NMR (400 MHz, CDC13) ·· 5 9.27 (s, 1Η), 8.42 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 8.26 (d, J = 5 6 Hz, 1H), 7.42-7.33 (m, 4H), 7.22 (d, J = 5.6 Hz, 1H), 7.11-7 · 05 (m, 3H), 6.97 (d, J = 5.6 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.85-4.77 (m, 1H), 2.67-2.56 (m, 2H), 2.27-2.18 (m, 1H), 2.13 (s, 3H) , 2.09-2.00 (m, 4H) · 13 C NMR (101 MHz, CDC13): 5 170.50 (s, 1C), 170.20 (s, 1C), 156.69 (s, 1C), 151.73 (s, 1C), 148.96 (s, 1C), 148.89 (s, 1C), 148.36 (s, 1C), 147.51 (s, 1C), 140.08 (s, 1C), 129.40 (s, 2C), 123.17 (s, 1C) 5 120.44 ( s, 2C), 118.07 (s, 1C), 113.11 (s, 1C), 111.95 (s, 1C), 106.22 (s, 1C), 53.35 (s, 1C), 31.20 (s, 1C), 30.29 (s , 1C), 23.22 (s, 1C), 15.38 (s, 1C). MS (TSP) m / z (M + 1): 436. Example 182 N- (2, -anilino-4,4'-linked Pyridine-2_yl) tetrahydro-2H-sulfan-4-carboxamidine 89385 -70- 200417546

使四氫-2H-哌喃-4-羧酸（83毫克，0·64毫莫耳）溶於4毫升二 氯化亞硫醯中，並將溶液在室溫下攪拌30分鐘。在真空下 移除溶劑，並使所形成之油溶於1毫升二氯甲烷中。將此溶 液逐滴添加至N-苯基-4,4’-聯吡啶-2,2’-二胺（160毫克，0·61毫莫 耳）在10毫升外b淀中之溶液内。攬拌1小時後，於真空下移 除溶劑，並使粗產物藉HPLC純化：管柱：XTerra®prep MSC8， 梯度液20-80% B，20毫升/分鐘，40°C，(A-0.1 % CH3 CN水溶液中 之0·lMNH4OAc，B-CH3CN)。產率：48%(110毫克）。1HNMR (400 MHz，CDC13): 5 8.49 (s，1H)，8·32 (d，J = 6·1 Hz，1H)，8.28 (d，J = 4·5 Hz, 1H)，8.05 (s，1H)，7.42-7.33 (m，4H)，7.23-7.19 (m，1H)，7.09-7.03 (m，2H)， 6.99 (d，J = 5_6 Hz，1H)，6.71 (s，1H)，4.10-4.02 (m，2H)，3.51-3.41 (m，2H)， 2.59-2.49 (m，1H)，1.95-1.84 (m，4H). 13 C NMR (101 MHz，CDC13) : 5 172.97 (s，1C)，156.66 (s，1C)，152.05 (s，1C)，149.20 (s，1C)，148.43 (s，1C)， 147_38 (s，1C)，140.17 (s，1C)5 129.38 (s，2C), 123.07 (s，1C)，120.35 (s，2C)， 117.82 (s，1C)，113.24 (s，1C)，111.70 (s，1C)，106.29 (s，1C)，67.07 (s，2C)， 43-26(s，lC)，29.01(s，2C)· MS(TSP)m/z(M+l) ： 375. 實例183 3-[(2，_苯胺基_4,4▼聯冲b C基）胺基】-3__基丙酸乙酯 於氮大氣下，將3-乙氧基-3-氧基丙酸（33毫克，0.25毫莫耳） 與六氟磷酸N-[(二甲胺基）(3H-[1，2,3]三唑并[4,5姊比啶-3-基氧基） 亞甲基]-N-甲基甲銨（142毫克，0.375毫莫耳）在4毫升無水N，N-二甲基甲醯胺中稀釋。逐滴添加二異丙基乙胺（64毫克，87 微升，0.575 *莫耳）。攪拌1小時後，慢慢添加N-苯基_4,4’_聯 89385 -71 - 200417546 吡哫-2,2-一胺（65毫克，〇·25毫莫耳）在無水N，N_二甲基甲醯胺 (1毛升）中之落液，並將混合物於2〇艺下攪拌ι5小時。將混 合物傾倒在飽和NaHC〇3水溶液（5毫升）上，並以醋酸乙酯 (3x10笔升）萃取。使有機層以硫酸鎂脫水乾燥，過濾，並於 真空下蒸發，而得粗產物，使其藉急騾式層析（醋酸乙酯/ 甲酉予· 98/2)純化。產率：27%(25 毫克）。lHNMR(4〇〇MHz，CDC13) • ^9.59 (s? 1H)? 8.42 (s? 1H)5 8.35 (d? J = 6.1 Hz? 1H)5 8.28 (d? J = 6.1 Hz? 1H)5 7.41-7.32 (m，4H)，7.23-7.22 (m，1H)，7.10-7.04 (m，2H)，7.01-6.95 (m，1H)， 6.81 (s，1H)，4.27 (q，J = 7·1 Hz，2H)，3.51 (s，2H)，1.32 (t，J = 7·1 Hz，4H). MS (TSP) m/z (M+l) : 377. 實例184 N-(2’_苯胺基_4,4，_聯峨淀_2_基)_3_(甲硫基）丙醯胺 於氮大氣下’將3-硫甲氧基丙酸（33毫克，〇·25毫莫耳）與六 氟磷酸柯(二甲胺基X3H-H3]三唑并[4,5帅比啶各基氧基）亞甲 基]-N-甲基甲銨（142毫克，0.375毫莫耳）在4毫升無水N，N-二 甲基甲酿胺中稀釋。逐滴添加二異丙基乙胺⑦4毫克，87微 升，0.575毫莫耳）。攪拌1小時後，慢慢添加N_苯基_4,4，_聯吡 哫-2,2f-二胺（65毫克，0.25毫莫耳）在無水N，N-二甲基甲醯胺Q 毫升）中之溶液，並將混合物於20°C下攪拌15小時。將混合 物傾倒在飽和NaHC〇3水溶液（5毫升）上，並以醋酸乙酯（3xl〇 毫升）萃取。使有機層以硫fei鎮脫水乾燥，過滤，並於真空 下蒸發，而得粗產物，使其藉急驟式層析（醋酸乙酯/甲醇 :98/2)純化。產率：27% (25 毫克）。iHNMR(400MHz，CDCl3) ·· (5 8.67 (s，1H)，8·47 (s，1H)，8.32 (d，J = 5.1 Hz，1H)，8.28 (d，J = 5·1 Hz，1H)， -72- 89385 200417546 7-42-7.31 (m，4H)，7.20 (d，J = 5·1 Hz，1H)，7.09-7.02 (m，2H)，6.98 (d，J = 5.6 Hz，1H)，2.92-2.85 (m，2H)，2.72 (t，J = 7·1 Hz，2H)，2·15 (s，3H). 13 C NMR (101 MHz, CDC13) : 5 156.63 (s，1C)，149.13 (s，1C)5 148.83 (s，1C)，148.39 (s，1C)，147.36 (s，1C)，147.35 (s，1C)，140.13 (s，1C)，129.34 (s，2C)，122.95 (s，1C)，120.33 (s，1C)，120.19 (s，2C)，117.78 (s，1C)，113.17 (s，1C)，111.75 (s，1C)，106.28 (s，1C)，37·35 (s，1C)，37.32 (s，1C)，29.39 (s，1C)· MS(TSP)m/z(M+l) ： 365. 實例185 (± )N_(2f-苯胺基_4,4’_聯吡啶_2_基)_2-四氫吡咯_2-基乙醯胺 於氮大氣下，將[1-(第三-丁氧羰基）四氫吡咯-2-基]醋酸（163 毫克，〇·75毫莫耳）與六氟磷酸N-[(二甲胺基）(3H-[1，2,3]三唑并 [4,5-b]峨啶-3-基氧基）亞甲基]-N-甲基甲銨（380毫克，1.0毫莫耳） 在4毫升無水N，N-二甲基甲醯胺中稀釋。逐滴添加二異丙基 乙月；（193毫克’ 258微升，1.5毫莫耳）。擾掉1小時後，慢慢 添加N-苯基-4,4f-聯吡啶_2,2，-二胺（131毫克，0.50毫莫耳）在無 水N，N-二甲基甲_胺（2毫升）中之溶液，並將混合物於2〇。〇下 攪拌15小時。將混合物傾倒在飽和NaHC〇3水溶液（2〇毫升）上 ’並以醋酸乙醋（3x20晕升）萃取。使有機層以硫酸鎂脫水乾 燥，過濾，並於真空下蒸發，而得粗產物，使其藉急驟式 層析（醋酸乙酯/甲醇：95/5)純化。產率：87% (207毫克）。 將此化合物（207耄克）於氮大氣下，在1〇毫升二氯甲烷中稀 釋，並使溶液冷卻至0 C。逐滴添加三氟醋酸（2毫升），並將 溶液於20 C下攪拌15小時。於真空下移除溶劑。將所形成之 物質在MeOH(10毫升）中稀釋，並與D〇wex 混合。於過漉後， 89385 -73- 200417546 在真空下濃縮溶液，使粗製物質藉HPLC管柱純化：XTerra® prepMSQ，梯度液 20-80% B 20 毫升 / 分鐘，40°C (Α-0·1% CH3 CN 水 溶液中之 〇.1MNH4OAc，B-CH3CN)。產率：38% (71 毫克）。iHNMR (400 MHz? CDC13 )： (5 8.44 (s? 1H)? 8.34 (d3 J - 4.5 Hz5 1H)5 8.28 (d5 J = 6.1 Hz5 1H)，7.42-7.33 (m，4H)，7.16 (d，J = 3·5 Hz，1H)，7.09-7.02 (m，2H)，6·99 (d，J = 5·1 Hz，1H)，6.77 (s，1H)，3·63-3·51 (m，1H)，3.09-3.02 (m，2H)，2.54-2.42 (m， 2H)，2.05-1.96 (m，1H)，1.94-1.82 (m，1H)，1.76 (ddd，J = 12.6, 9.1，7·1 Hz，1H)， 1.56-1.44 (m，1H). MS (TSP) m/z (M+l) ： 374. 實例186 (3S)-3-胺基-N-(2f-苯胺基-4,4，-聯吡啶-2·基）-4-氰基丁醯胺 於氮大氣下，將（3S)-5-胺基-3-[(第三-丁氧羰基）胺基酮基 戊酸（57耄克，〇·25毫莫耳）與六氟磷酸N-[(二甲胺基乂犯屮又习 一峻并[4,5-b&gt;比啶-3-基氧基）亞甲基]孙甲基甲銨（142毫克， 0.375笔莫耳）在4¾升無水n，N-二甲基甲醯胺中稀釋。逐滴添 加二異丙基乙胺（64毫克，87微升，〇·575毫莫耳）。攪拌工小 時後，杈添加Ν-苯基-4,4’-聯吡啶_2,2，-二胺（65毫克，0.25毫 莫耳）在無水N，N-=甲基甲酸胺（1毫升）中之溶液，並將混合Tetrahydro-2H-piperan-4-carboxylic acid (83 mg, 0.64 mmol) was dissolved in 4 ml of thionyl chloride, and the solution was stirred at room temperature for 30 minutes. The solvent was removed under vacuum and the formed oil was dissolved in 1 ml of dichloromethane. This solution was added dropwise to a solution of N-phenyl-4,4'-bipyridine-2,2'-diamine (160 mg, 0.61 mol) in 10 ml of outer precipitate. After stirring for 1 hour, the solvent was removed under vacuum and the crude product was purified by HPLC: column: XTerra®prep MSC8, gradient 20-80% B, 20 ml / min, 40 ° C, (A-0.1 0.1M NH4OAc (B-CH3CN) in% CH3 CN aqueous solution). Yield: 48% (110 mg). 1HNMR (400 MHz, CDC13): 5 8.49 (s, 1H), 8.32 (d, J = 6.1 Hz, 1H), 8.28 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.42-7.33 (m, 4H), 7.23-7.19 (m, 1H), 7.09-7.03 (m, 2H), 6.99 (d, J = 5_6 Hz, 1H), 6.71 (s, 1H), 4.10 -4.02 (m, 2H), 3.51-3.41 (m, 2H), 2.59-2.49 (m, 1H), 1.95-1.84 (m, 4H). 13 C NMR (101 MHz, CDC13): 5 172.97 (s, 1C), 156.66 (s, 1C), 152.05 (s, 1C), 149.20 (s, 1C), 148.43 (s, 1C), 147_38 (s, 1C), 140.17 (s, 1C) 5 129.38 (s, 2C ), 123.07 (s, 1C), 120.35 (s, 2C), 117.82 (s, 1C), 113.24 (s, 1C), 111.70 (s, 1C), 106.29 (s, 1C), 67.07 (s, 2C) , 43-26 (s, 1C), 29.01 (s, 2C) · MS (TSP) m / z (M + 1): 375. Example 183 3-[(2, _anilino_4,4 ▼ b C group) amino group] ethyl 3--3-propionate under nitrogen, 3-ethoxy-3-oxypropionic acid (33 mg, 0.25 mmol) and N-[( Dimethylamino) (3H- [1,2,3] triazolo [4,5supridin-3-yloxy) methylene] -N-methylmethylammonium (142 mg, 0.375 mmol Ear) in 4 ml of anhydrous N, N-dimethyl Dilute in formamidine. Add diisopropylethylamine (64 mg, 87 μl, 0.575 * mole) dropwise. After stirring for 1 hour, N-phenyl_4,4'_bi 89385 -71-200417546 pyrido-2,2-monoamine (65 mg, 0.25 mmol) was added slowly in anhydrous N, N_ The solution was dropped in dimethylformamide (1 liter), and the mixture was stirred at 20 ° C for 5 hours. The mixture was poured onto a saturated aqueous solution of NaHC03 (5 ml) and extracted with ethyl acetate (3 x 10 pen liters). The organic layer was dried over magnesium sulfate, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / formaldehyde 98/2). Yield: 27% (25 mg). lHNMR (400MHz, CDC13) • ^ 9.59 (s? 1H)? 8.42 (s? 1H) 5 8.35 (d? J = 6.1 Hz? 1H) 5 8.28 (d? J = 6.1 Hz? 1H) 5 7.41 -7.32 (m, 4H), 7.23-7.22 (m, 1H), 7.10-7.04 (m, 2H), 7.01-6.95 (m, 1H), 6.81 (s, 1H), 4.27 (q, J = 7 · 1 Hz, 2H), 3.51 (s, 2H), 1.32 (t, J = 7.1 Hz, 4H). MS (TSP) m / z (M + l): 377. Example 184 N- (2'_ Aniline_4,4, _lianedian_2_yl) _3_ (methylthio) propanamide in a nitrogen atmosphere '3-thiomethoxypropionic acid (33 mg, 0.25 mmol) With hexafluorophosphate (dimethylamino X3H-H3] triazolo [4,5 sapyridinyloxy) methylene] -N-methylmethylammonium (142 mg, 0.375 mmol) Dilute in 4 ml of anhydrous N, N-dimethylformamide. (4 mg, 87 μl, 0.575 mmol) were added dropwise. After stirring for 1 hour, N_phenyl_4,4, _bipyridine-2,2f-diamine (65 mg, 0.25 mmol) was added slowly in anhydrous N, N-dimethylformamide Q Ml), and the mixture was stirred at 20 ° C for 15 hours. The mixture was poured onto saturated aqueous NaHC03 (5 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer was dehydrated and dried over sulfur, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 27% (25 mg). iHNMR (400MHz, CDCl3) ... (5 8.67 (s, 1H), 8.47 (s, 1H), 8.32 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 5.1 Hz, 1H ), -72- 89385 200417546 7-42-7.31 (m, 4H), 7.20 (d, J = 5.1 Hz, 1H), 7.09-7.02 (m, 2H), 6.98 (d, J = 5.6 Hz, 1H), 2.92-2.85 (m, 2H), 2.72 (t, J = 7.1 Hz, 2H), 2.15 (s, 3H). 13 C NMR (101 MHz, CDC13): 5 156.63 (s, 1C), 149.13 (s, 1C) 5 148.83 (s, 1C), 148.39 (s, 1C), 147.36 (s, 1C), 147.35 (s, 1C), 140.13 (s, 1C), 129.34 (s, 2C ), 122.95 (s, 1C), 120.33 (s, 1C), 120.19 (s, 2C), 117.78 (s, 1C), 113.17 (s, 1C), 111.75 (s, 1C), 106.28 (s, 1C) , 37 · 35 (s, 1C), 37.32 (s, 1C), 29.39 (s, 1C) · MS (TSP) m / z (M + 1): 365. Example 185 (±) N_ (2f-aniline group) _4,4'_bipyridine_2_yl) _2-tetrahydropyrrole_2-ylacetamidamine [1- (third-butoxycarbonyl) tetrahydropyrrole-2-yl] under a nitrogen atmosphere Acetic acid (163 mg, 0.75 mol) with N-[(dimethylamino) hexafluorophosphate (3H- [1,2,3] triazolo [4,5-b] eridine-3- Oxy) methylene] -N-methylmethylammonium (380 mmol , 1.0 mM) Diluted in 4 ml of anhydrous N, N-dimethylformamide. Diisopropylethane was added dropwise; (193 mg '258 μl, 1.5 mM). Disturb 1 After hours, slowly add N-phenyl-4,4f-bipyridine_2,2, -diamine (131 mg, 0.50 mmol) in anhydrous N, N-dimethylmethyl_amine (2 ml) Solution, and the mixture was stirred for 15 hours at 2000. The mixture was poured onto a saturated aqueous solution of NaHC03 (20 ml) and extracted with ethyl acetate (3 x 20 ml). The organic layer was sulfuric acid The magnesium was dried, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / methanol: 95/5). Yield: 87% (207 mg). This compound (207 g) was diluted in 10 ml of dichloromethane under a nitrogen atmosphere, and the solution was cooled to 0 ° C. Trifluoroacetic acid (2 ml) was added dropwise, and the solution was stirred at 20 C for 15 hours. The solvent was removed under vacuum. The material formed was diluted in MeOH (10 mL) and mixed with DOwex. After mashing, 89385 -73- 200417546 concentrated the solution under vacuum to purify the crude material by HPLC column: XTerra® prepMSQ, gradient 20-80% B 20 ml / min, 40 ° C (Α-0 · 1 0.1MNH4OAc, B-CH3CN) in% CH3 CN aqueous solution). Yield: 38% (71 mg). iHNMR (400 MHz? CDC13): (5 8.44 (s? 1H)? 8.34 (d3 J-4.5 Hz5 1H) 5 8.28 (d5 J = 6.1 Hz5 1H), 7.42-7.33 (m, 4H), 7.16 (d, J = 3.5 Hz, 1H), 7.09-7.02 (m, 2H), 6.99 (d, J = 5.1 Hz, 1H), 6.77 (s, 1H), 3.63-3 · 51 ( m, 1H), 3.09-3.02 (m, 2H), 2.54-2.42 (m, 2H), 2.05-1.96 (m, 1H), 1.94-1.82 (m, 1H), 1.76 (ddd, J = 12.6, 9.1 , 7.1 Hz, 1H), 1.56-1.44 (m, 1H). MS (TSP) m / z (M + 1): 374. Example 186 (3S) -3-amino-N- (2f-aniline -4,4, -bipyridyl-2 · yl) -4-cyanobutylammonium amine in a nitrogen atmosphere, (3S) -5-amino-3-[(third-butoxycarbonyl) amino Ketovaleric acid (57 g, 0.25 mmol) and N-[(dimethylaminoammonium chloride) [Xi Yijun and [4,5-b &gt; pyridin-3-yloxy] Methylene] sun methylmethylammonium (142 mg, 0.375 moles) was diluted in 4¾ liters of anhydrous n, N-dimethylformamide. Diisopropylethylamine (64 mg, 87 microliters, 0.575 mol). After stirring for several hours, N-phenyl-4,4'-bipyridine_2,2, -diamine (65 mg, 0.25 mol) was added in the absence of Solution in water N, N- = methyl formate (1 ml) and mix

物於2(TC下攪拌15小時。 I 。將混合物傾倒在飽和NaHC03水溶液The mixture was stirred at 2 ° C for 15 hours. I. The mixture was poured into saturated aqueous NaHC03 solution.

89385 -74- 200417546 酸鎂脫水乾燥，過濾，及在真空中濃縮。使粗製物質藉HPLC 純化：管柱·· XTen^prep MSC8，梯度液20-80% B 20毫升/分鐘40 °C，(A-0.1%CH3CN水溶液中之(UMNH4OAc，B-CH3CN)。產率 :12% (11 毫克）。1H NMR (400 MHz，MeOD-d4) : 5 8_44 (s，1H)，8.36 (dd，J = 5.3, 0·8 Hz，1H)，8·18 (dd，J = 5.5, 0·8 Hz，1Η)，7·55-7·51 (m，2H)，7·36 (dd，J = 5.3, 1·6 Hz，1H)，7.31-7.26 (m，3H)，7.09 (dd，J = 1.6, 0·8 Hz，1H)，7·02 (dd，J = 5.4, 1.7 Hz，1H)，6.99-6.94 (m，1H)，3.61-3.53 (m，1H)，2.73-2.63 (m， 4H)· 13 C NMR (101 MHz，MeOD-d4) : 5 171.85 (s，1C)，158·52 (s，1C)， 153.82 (s，1C)，149.88 (s，1C)，149.72 (s，1C)，149.39 (s，1C)，148.64 (s，1C)， 142.40 (s，1C)，129.91 (s，2C)，123.02 (s，1C)，120.63 (s，2C)，119.00 (s，1C)， 118.66 (s，1C)，113.34 (s，1C)，113.01 (s，1C)，109.09 (s，1C)5 46.82 (s，1C)， 43.47 (s，1C)，26.06 (s，1C). MS(TSP)m/z(M+l) ： 373. 實例187 N1 -(2’-苯胺基-4,4’-聯吡啶-2-基）環丙烷-1，1-二羧醯胺 於氮大氣下，將1-(胺基羰基）環丙烷羧酸（32毫克，0.25毫莫 耳）與六氟磷酸N-[(二甲胺基）(3H-[1，2,3]三唑并[4,5-b]吡啶-3-基氧 基）亞甲基]-N-甲基甲銨（142毫克，0.375毫莫耳）在4毫升無水 N，N-二甲基甲醒胺中稀釋。逐滴添加二異丙基乙胺（64毫克 ，87微升，0.575毫莫耳）。攪拌1小時後，慢慢添加N•苯基-4,4，_ 聯吡啶-2,2’-二胺（65毫克，0.25毫莫耳）在無水N，N_二甲基甲醯 胺（1毫升）中之溶液，並將混合物於20°c下攪拌15小時。將 混合物傾倒在飽和NaHC03水溶液（5毫升）上，並以酷酸乙酉旨 (3x10毫升）萃取。使有機層以硫酸鍰脫水乾燥，過遽，並於 89385 -75 - 200417546 真空下蒸發，而得粗產物，使其藉急驟式層析（醋酸乙酯/ 甲醇·· 98/2)純化。產率：48% (45 毫克）。1H NMR (400 MHz，MeOD-d4) :5 8·43 (s，1H)，8.37 (d，J = 5·1 Hz，1H)，8.19 (d，J = 5.6 Hz，1H)，7.53 (d，J = 7.6 Hz，2H)，7.41-7.36 (m，1H)，7.32-7.25 (m，2H)，7.09 (s，1H)，7.03 (d，J = 7·1 Hz，1H)，7.00-6.94 (m，1H)，1.71-1.64 (m5 2H)，1.57-1.48 (m，2H). MS(TSP)m/z(M+l) ： 374. 實例188 (3S)-1-乙醯基-N-(2f-苯胺基-4,4，-聯吡啶-2-基）六氫吡啶-3-叛醯胺 於氮氣及20°C下，將乙基二異丙基胺（129毫克，1·〇毫莫耳） 慢慢添加至四氟酸N，N，N’，N’-四甲基-鄰-(苯并三唑小基）錁 (321毫克，1.0毫莫耳）、羥基苯并三唑（137毫克，1_〇毫莫耳） 及1-乙醯六氫吡啶-3-叛酸（171毫克，1.0毫莫耳）在3毫升DMF 中之溶液内。5分鐘後，於氮氣下，將此溶液添加至N—苯基-4,4M葬吡啶-2,2’-二胺（200毫克，0.76毫莫耳）在2毫升二甲基甲 醯胺中之溶液内。攪拌2天後，以2M碳酸鉀水溶液（5毫升） 使反應淬滅。以二氯甲烷萃取水層。蒸發溶劑後，使所形 成之油藉HPLC純化。產量：53毫克（17%)。iHNMRCMeODO ·· 5 8·52-8·42 (m，2H)，7.95 (d，J = 6·5 Hz，1H)，7.58 (m，3H)，7.51-7.42 (m， 4H)，7.34 (dd，J = 7, 2 Hz，1H)，4.53 (m，1H)，4.19 (m，1H)，3·98_3·84 (m，2H)， 2.99(m，lH)，2.13(s，3H)，2.13-1.26(m，4H). MS(ES)m/z(M+l) ： 416. 實例189 N-(2 -苯胺基-4,4’·聯p比淀-2-基）四氮咬喃-3-叛酿胺(+)與㈠ 於氮大氣下，將1-羥基苯并三唑（104毫克，0.76毫莫耳）、 89385 -76- 200417546 四氟硼酸2-(1Η-苯并三唑-1-基）-1，1，3,3,甲基錁（244毫克，〇·76 毫莫耳）及四氫味喃-3-叛酸（72微升，ο·%毫莫耳）在無水ν，Ν_ 一甲基甲醯胺（4毫升）中稀釋。逐滴添加二異丙基乙胺（264 械升’ 1.52毫莫耳）。攪拌30分鐘後，慢慢添加Ν_苯基-4,4，_聯 吡啶-2,2，-二胺（200毫克，0.76毫莫耳）在無水Ν，Ν-二甲基甲醯 胺（2毫升）中之溶液，並溶液於室溫下攪拌3天。將反應混 合物傾倒在碳酸钾水溶液（2Μ，1〇毫升）上，並以二氯甲燒 萃取。使有機層以硫酸鍰脫水乾燥，過濾，並於真空下蒸 發’而得粗產物，使其藉急驟式層析（醋酸乙酯/甲醇：梯 度液100/0至90/100)純化。產率：21% (59毫克）。藉對掌性層 析分離外消旋混合物，而得1〇毫克（+)對掌異構物與1〇毫克㈠ 對掌異構物。 1H NMR (400 MHz，CDCI3): 5 10.56 (s，1Η)，8.96 (s，1Η)，8·45 (s，1Η)，8.36 (d，J = 5.6 Ηζ，1Η)，8.01 (d，J = 6·1 Ηζ，1Η)，7.49-7.41 (m，2Η)，7·37-7·30 (m， 3H)，7.18 (s，1H)，7.12 (d，J = 4.5 Hz，1H)，7.06 (d，J = 6·1 Hz，1H)，4·05-3·95 (m，3H)，3.87-3.79 (m，lH)，3.25-3.16(m，lH)，2.30-2.21(m，2H)· MS(ES)m/z(M+l) ： 361. 實例190 N_{2’_[(4-氣苯基)胺基】-4,4f•聯峨淀-2-基}四氫吱喃_3_叛醯胺 於氮大氣下，將1-羥基苯并三唑（51毫克，0.38毫莫耳）、 四氟硼酸2-(1Η-苯并三唑-1-基）-ΐ，ι，3,3-四甲基錁（122毫克，0.38 毫莫耳）及四氫呋喃各羧酸（24微升，0.25毫莫耳），在無水n，N-二甲基甲醯胺（3毫升）中稀釋。逐滴添加二異丙基乙胺（87微 升，0.50毫莫耳）。攪拌30分鐘後，慢慢添加N-(4-氟苯基）ά -77- 89385 200417546 聯吡啶-2,2’-二胺（70毫克，〇·25毫莫耳）在無水N，N_二甲基甲醯 胺（2毫升）中之溶液，並將溶液於室溫下攪拌3天。將反應 混合物傾倒在飽和碳酸氫鈉水溶液（1〇毫升）上，並以醋酸乙 酯（3x10毫升）萃取。使有機層以硫酸鎂脫水乾燥，過濾，並 於真空下蒸發，而得粗產物，使其藉急驟式層析（醋酸乙酯 /甲醇：98/2)純化。產率：32%(30毫克）。藉對掌性層析分 離外消旋混合物，而得10毫克㈠對掌異構物與12毫克㈩對 5.1 Hz，1H)，8.12 (d，J = 5·1 Hz，1H)，7.49 (dd，J = 9.1，4.5 Hz，2H)，7.31 (d，J = 5·1 Hz，1H)，7.00-6.94 (m，4H)，3.97 (t，J = 8.1 Hz，1H)，3.92-3.85 (m，2H)，3.81 -3_71 (m，1H)，2.18 (q，J = 7_1 Hz，2H). 19F NMR (376 MHz，MeOD-d4) : 5 -124.05 (m5 IF). MS(ES)m/z(M+l) ： 379. 實例191 N-{2 -[(4_氟苯基)胺基]_4,4’_聯p比淀_2-基}四氮-2H-，底喃-4-羧醯胺89385 -74- 200417546 Magnesium acid is dried, filtered, and concentrated in vacuo. The crude material was purified by HPLC: column XTenprep MSC8, gradient 20-80% B 20 ml / min 40 ° C, (A-0.1% CH3CN in water (UMNH4OAc, B-CH3CN). Yield : 12% (11 mg). 1H NMR (400 MHz, MeOD-d4): 5 8_44 (s, 1H), 8.36 (dd, J = 5.3, 0.8 Hz, 1H), 8.18 (dd, J = 5.5, 0 · 8 Hz, 1Η), 7.55-7 · 51 (m, 2H), 7.36 (dd, J = 5.3, 1.6 Hz, 1H), 7.31-7.26 (m, 3H) , 7.09 (dd, J = 1.6, 0.8 Hz, 1H), 7.02 (dd, J = 5.4, 1.7 Hz, 1H), 6.99-6.94 (m, 1H), 3.61-3.53 (m, 1H) , 2.73-2.63 (m, 4H) · 13 C NMR (101 MHz, MeOD-d4): 5 171.85 (s, 1C), 158 · 52 (s, 1C), 153.82 (s, 1C), 149.88 (s, 1C), 149.72 (s, 1C), 149.39 (s, 1C), 148.64 (s, 1C), 142.40 (s, 1C), 129.91 (s, 2C), 123.02 (s, 1C), 120.63 (s, 2C) ), 119.00 (s, 1C), 118.66 (s, 1C), 113.34 (s, 1C), 113.01 (s, 1C), 109.09 (s, 1C) 5 46.82 (s, 1C), 43.47 (s, 1C) , 26.06 (s, 1C). MS (TSP) m / z (M + 1): 373. Example 187 N1-(2'-aniline-4,4'-bipyridin-2-yl) cyclopropane-1 , 1-dicarboxylic acid Under a nitrogen atmosphere, 1- (aminocarbonyl) cyclopropanecarboxylic acid (32 mg, 0.25 mmol) and N-[(dimethylamino) (3H- [1,2,3] trifluorophosphate) Zolo [4,5-b] pyridin-3-yloxy) methylene] -N-methylmethylammonium (142 mg, 0.375 mmol) in 4 ml of anhydrous N, N-dimethylformamide Diluted in amine. Diisopropylethylamine (64 mg, 87 μl, 0.575 mmol) was added dropwise. After stirring for 1 hour, N • phenyl-4,4, _bipyridine-2, A solution of 2'-diamine (65 mg, 0.25 mmol) in anhydrous N, N-dimethylformamide (1 ml), and the mixture was stirred at 20 ° C for 15 hours. The mixture was poured onto saturated aqueous NaHC03 (5 ml) and extracted with ethyl acetate (3x10 ml). The organic layer was dehydrated and dried with tritium sulfate, dried over tritium, and evaporated under vacuum at 89385 -75-200417546 to obtain a crude product, which was purified by flash chromatography (ethyl acetate / methanol · 98/2). Yield: 48% (45 mg). 1H NMR (400 MHz, MeOD-d4): 5 8 · 43 (s, 1H), 8.37 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.53 (d , J = 7.6 Hz, 2H), 7.41-7.36 (m, 1H), 7.32-7.25 (m, 2H), 7.09 (s, 1H), 7.03 (d, J = 7.1 Hz, 1H), 7.00- 6.94 (m, 1H), 1.71-1.64 (m5 2H), 1.57-1.48 (m, 2H). MS (TSP) m / z (M + 1): 374. Example 188 (3S) -1-ethenyl -N- (2f-anilino-4,4, -bipyridin-2-yl) hexahydropyridine-3-benzidineamine Under nitrogen and 20 ° C, ethyl diisopropylamine (129 mg, 1.0 mmol) slowly added to tetrafluoro acid N, N, N ', N'-tetramethyl-o- (benzotriazole small group) fluorene (321 mg, 1.0 mmol), hydroxyl A solution of benzotriazole (137 mg, 1.0 mmol) and 1-acetamidinehexahydropyridine-3-metanoic acid (171 mg, 1.0 mmol) in 3 ml of DMF. After 5 minutes, this solution was added to N-phenyl-4,4M-pyridine-2,2'-diamine (200 mg, 0.76 mmol) in 2 ml of dimethylformamide under nitrogen. Inside the solution. After stirring for 2 days, the reaction was quenched with 2M aqueous potassium carbonate solution (5 ml). The aqueous layer was extracted with dichloromethane. After evaporation of the solvent, the formed oil was purified by HPLC. Yield: 53 mg (17%). iHNMRCMeODO ·· 5 8 · 52-8 · 42 (m, 2H), 7.95 (d, J = 6.5 Hz, 1H), 7.58 (m, 3H), 7.51-7.42 (m, 4H), 7.34 (dd , J = 7, 2 Hz, 1H), 4.53 (m, 1H), 4.19 (m, 1H), 3.98_3 · 84 (m, 2H), 2.99 (m, 1H), 2.13 (s, 3H), 2.13-1.26 (m, 4H). MS (ES) m / z (M + 1): 416. Example 189 N- (2-aniline-4,4 '· bi-p-pyridin-2-yl) tetrazine Nitra-3-Betamin (+) and plutonium Under nitrogen atmosphere, 1-hydroxybenzotriazole (104 mg, 0.76 mmol), 89385 -76- 200417546 tetrafluoroborate 2- (1fluorene-benzene Benzotriazol-1-yl) -1,1,3,3, methylfluorene (244 mg, 0.76 mmol) and tetrahydrofuran-3-metanoic acid (72 μl, ο ·% mmol) Mol) was diluted in anhydrous v, N-methylformamide (4 ml). Diisopropylethylamine (264 liters' 1.52 mmol) was added dropwise. After stirring for 30 minutes, N_phenyl-4,4, _bipyridine-2,2, -diamine (200 mg, 0.76 mmol) was added slowly in anhydrous N, N-dimethylformamide ( 2 ml), and the solution was stirred at room temperature for 3 days. The reaction mixture was poured onto an aqueous potassium carbonate solution (2M, 10 ml), and extracted with dichloromethane. The organic layer was dehydrated and dried with tritium sulfate, filtered, and evaporated under vacuum to obtain a crude product, which was purified by flash chromatography (ethyl acetate / methanol: gradient solution 100/0 to 90/100). Yield: 21% (59 mg). The racemic mixture was separated by para palmar chromatography to obtain 10 mg (+) para palmar isomers and 10 mg pyrene para palmar isomers. 1H NMR (400 MHz, CDCI3): 5 10.56 (s, 1Η), 8.96 (s, 1Η), 8.45 (s, 1Η), 8.36 (d, J = 5.6 Ηζ, 1Η), 8.01 (d, J = 6.1 Ηζ, 1Η), 7.49-7.41 (m, 2Η), 7.37-7 · 30 (m, 3H), 7.18 (s, 1H), 7.12 (d, J = 4.5 Hz, 1H), 7.06 (d, J = 6.1 Hz, 1H), 4.05-3.95 (m, 3H), 3.87-3.79 (m, lH), 3.25-3.16 (m, lH), 2.30-2.21 (m , 2H) · MS (ES) m / z (M + 1): 361. Example 190 N_ {2 '_ [(4-Gaphenyl) amino] -4,4f • Lianedian-2-yl} Tetrahydroanal_3_benzamine in a nitrogen atmosphere, 1-hydroxybenzotriazole (51 mg, 0.38 mmol), tetrafluoroborate 2- (1fluorene-benzotriazol-1-yl) -pyrene, ι, 3,3-tetramethylpyrene (122 mg, 0.38 mmol) and each carboxylic acid of tetrahydrofuran (24 µl, 0.25 mmol) in anhydrous n, N-dimethylformamide (3 ml). Diisopropylethylamine (87 μl, 0.50 mmol) was added dropwise. After stirring for 30 minutes, N- (4-fluorophenyl) ά -77- 89385 200417546 bipyridine-2,2'-diamine (70 mg, 0.25 mmol) was added in anhydrous N, N_ A solution in dimethylformamide (2 ml), and the solution was stirred at room temperature for 3 days. The reaction mixture was poured onto a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer was dried over magnesium sulfate, filtered, and evaporated under vacuum to obtain the crude product, which was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 32% (30 mg). Separation of racemic mixtures by para-palladium chromatography yielded 10 mg of europium para-isomer and 12 mg of europium versus 5.1 Hz, 1H), 8.12 (d, J = 5.1 Hz, 1H), 7.49 (dd , J = 9.1, 4.5 Hz, 2H), 7.31 (d, J = 5.1 Hz, 1H), 7.00-6.94 (m, 4H), 3.97 (t, J = 8.1 Hz, 1H), 3.92-3.85 ( m, 2H), 3.81 -3_71 (m, 1H), 2.18 (q, J = 7_1 Hz, 2H). 19F NMR (376 MHz, MeOD-d4): 5 -124.05 (m5 IF). MS (ES) m / z (M + l): 379. Example 191 N- {2-[(4_fluorophenyl) amino] _4,4'_bi-p ratio lake_2-yl} tetrazol-2H-, diran -4-carboxamide

使四氲-2H-派喃-4-叛酸（97.5毫克，0.75毫莫耳）溶於5毫升二 氯化亞硫醯中，並將溶液在室溫下攪拌3〇分鐘。在真空下 移除洛劑，並使所形成之油溶於2毫升二氯甲燒中。將此溶 液逐滴添加至N-(4-氟苯基）-4,4f-聯吡啶-2,2，-二胺（70毫克，0.25 耄莫耳）在10毫升ρ比淀中之溶液内。攪拌1小時後，於真空 下移除溶劑，並使粗產物藉HPLC管柱純化：XTerr^prepMSCk 梯度液20-80% B20毫升/分鐘，40°C，(Α-0·1% CH3CN水溶液中 之0·lMNH4OAC，B-CH3CN)。產率：47%(130毫克）。lHNMR (400 MHz，DMS〇-d6): 5 10.63 (s，1H)，9.31 (s5 1H)，8·49 (s，1H)，8.43 (d，J = 89385 -78- 200417546 5.1 Hz，1H)，8.25 (d，J = 5.6 Hz，1H)，7.76-7.69 (m，2H)，7·45-7_40 (m，1H)， 7.14-7.06(m，4H)，3.94-3.87(m，2H)，2.83-2.73 (m，lH)，1.74_1.64(m，4H)_ MS(TSP)m/z(M+l) ： 393. 實例192 4-({2’-[(4-氟苯基）胺基]-4,4’_聯p比淀_2_基}胺基)-4-_基丁酸乙醋 於氮大氣下，將4-乙氧基-4-酮基丁酸（95毫克，0.65毫莫耳） 與六氟磷酸0-(7-氮苯并三唑小基）_n，N，N’，N’-四甲基錁（342毫克 ，〇·90毫莫耳）在6毫升無水N，N-二甲基甲醯胺中稀釋。逐滴 添加二異丙基乙胺（74毫克，1〇〇微升，0.575毫莫耳）。攪;拌1 小時後，慢慢添加N-(4_氟苯基）-4,4’-聯吡啶-2,2，-二胺（140毫克 ，0·50毫莫耳）在無水N，N-二甲基甲醯胺（2毫升）中之溶液， 並將混合物於20 °C下攪拌15小時。將混合物傾倒在飽和 NaHC〇3水溶液（5毫升）上，並以醋酸乙酯（3x10毫升）萃取。使 有機層以硫酸鎂脫水乾燥，過濾，並於真空下蒸發，而得 粗產物，使其藉急騾式層析（醋酸乙酯/甲醇·· 98/2)純化。 產率：35% (72 毫克）。iHNMRGOOMK^DMSOO: 5 10.71 (s，1H)， 9.31 (s，1H)，8.46-8.37 (m，2H)，8.25 (d，J = 5.6 Hz，1H)，7·72 (dd，J = 9.1，5.1 Hz，2H)，7.47-7.37 (m，1H)，7.14-7.04 (m，4H)，4.08-3.98 (m，2H)，2·71 (d，J = 7.1 Hz，2H)，2·60 (d，J = 7.1 Hz，2H)，1.19-1.11 (m，3H). MS(TSP)m/z(M+l) ： 409. 實例193 4-({2 -[(4-氟苯基)胺基】-4,4’_聯p比淀_2-基}胺基）_4·銅基丁酸 將4-({2-[(4-氣冬基）胺基]_4,4^聯ρ比淀-2-基}胺基）-4-嗣基丁酸乙 酉旨（50毫克’ 0.12¾吴耳）在乙醉/水/ THF之混合物（5/5/3毫 89385 -79- 200417546Tetramethylene-2H-pyran-4-metanoic acid (97.5 mg, 0.75 mmol) was dissolved in 5 ml of thionyl chloride, and the solution was stirred at room temperature for 30 minutes. The lotion was removed under vacuum and the resulting oil was dissolved in 2 ml of dichloromethane. This solution was added dropwise to a solution of N- (4-fluorophenyl) -4,4f-bipyridine-2,2, -diamine (70 mg, 0.25 mol) in 10 ml of pH ratio . After stirring for 1 hour, the solvent was removed under vacuum, and the crude product was purified by HPLC column: XTerr ^ prepMSCk gradient solution 20-80% B 20 ml / min, 40 ° C, (Α-0 · 1% CH3CN in water (0.1 MNH4OAC, B-CH3CN). Yield: 47% (130 mg). lHNMR (400 MHz, DMS 0-d6): 5 10.63 (s, 1H), 9.31 (s5 1H), 8.49 (s, 1H), 8.43 (d, J = 89385 -78- 200417546 5.1 Hz, 1H) , 8.25 (d, J = 5.6 Hz, 1H), 7.76-7.69 (m, 2H), 7.45-7_40 (m, 1H), 7.14-7.06 (m, 4H), 3.94-3.87 (m, 2H) , 2.83-2.73 (m, lH), 1.74_1.64 (m, 4H) _ MS (TSP) m / z (M + l): 393. Example 192 4-({2 '-[(4-fluorobenzene Aminyl) amino] -4,4'-bi-p-pyridine_2_yl} amino) -4-_butyric acid ethyl acetate under nitrogen atmosphere, 4-ethoxy-4-ketobutyric acid (95 mg, 0.65 mmol) with 0- (7-azabenzotriazole small hexafluorophosphate) _n, N, N ', N'-tetramethylphosphonium (342 mg, 0.90 mmol) ) Dilute in 6 ml of anhydrous N, N-dimethylformamide. Diisopropylethylamine (74 mg, 100 μl, 0.575 mmol) was added dropwise. Stir; After stirring for 1 hour, slowly add N- (4-fluorophenyl) -4,4'-bipyridine-2,2, -diamine (140 mg, 0.50 mmol) in anhydrous N, A solution in N-dimethylformamide (2 ml), and the mixture was stirred at 20 ° C for 15 hours. The mixture was poured onto a saturated aqueous solution of NaHC03 (5 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer was dried over magnesium sulfate, filtered, and evaporated under vacuum to obtain a crude product, which was purified by flash chromatography (ethyl acetate / methanol · 98/2). Yield: 35% (72 mg). iHNMRGOOMK ^ DMSOO: 5 10.71 (s, 1H), 9.31 (s, 1H), 8.46-8.37 (m, 2H), 8.25 (d, J = 5.6 Hz, 1H), 7.72 (dd, J = 9.1, 5.1 Hz, 2H), 7.47-7.37 (m, 1H), 7.14-7.04 (m, 4H), 4.08-3.98 (m, 2H), 2.71 (d, J = 7.1 Hz, 2H), 2.60 (d, J = 7.1 Hz, 2H), 1.19-1.11 (m, 3H). MS (TSP) m / z (M + l): 409. Example 193 4-({2-[(4-fluorophenyl ) Amine group] -4,4'_bi-p ratio lake 2-yl} amino group) _4 · copperyl butyric acid 4-({2-[(4- Gasoyl) amino group] _4,4 ^ Bi-Hydro-2-yl} amino) -4-Aminobutyric acid ethyl ester (50 mg '0.12 ¾ ur) in acetic acid / water / THF mixture (5/5/3 mmol 89385 -79- 200417546

升）中稀釋。添加2毫升2M氫氧化鋼水溶液，並將反應混合 物於室溫下攪拌1小時。使溶液於真空下濃縮，過遽，並以 醋酸乙酯萃取濾液。以醋酸使水層酸化至pH值4，然後以醋 故乙醋（3x10耄升）萃取。使有機層以硫酸鎂脫水乾燥，過遽 ’並於真空下蒸發，而得酸。產率：88% (40毫克）。1 η NMR (400 MHz，DMSO-d6) ·· 3 11· 14 (s，1Η)，9.34 (s，1Η)，8.46 (s5 1Η)，8.44-8.37 (m，1H)，8·24 (d，J = 5.3 Hz，1H)，7.78-7.67 (m，2H)，7.38 (dd，J = 5.2，1.7 Hz， 1H)，7.15_7.04 (m，4H)，2.65-2.56 (m，2H)，2.46-2.37 (m，2H)· MS(TSP)m/z(M+l) ： 381. 實例194 Ν-{2’·[(4_氟苯基)胺基]-4,4f-聯〃比淀-2-基}-3-(甲硫基）丙酿胺 於氮大氣及0°C下，將3-(甲硫基）丙酸(21毫升，24毫克，〇·25 毫莫耳）慢慢添加至1毫升1Μ氣化草醯在二氣甲烷中之溶液 内。攪拌30分鐘後，於真空下移除溶劑，並將所獲得之油 在〇·5毫升無水二氯甲烷中稀釋。將此溶液逐滴添加至Ν_(4_ 氟冬基）-4,4^聯ρ比淀-2,2f•二胺（70愛克，0.25毫莫耳）在ρ比淀（5毫 升）中之溶液内。於20°C下攪拌1小時後，過濾混合物，並在 真空下蒸發溶劑。使粗製物質藉急·驟式層析（醋酸乙酯/乙 醇 98/2)純化。產率38%(36 毫克）。iHNMRGOOMHz'DClJ: 5 8.46 (s? 1H), 8.34-8.30 (m5 1H)? 8.26 (d? J = 5.3 Hz, 1H)? 8.24 (s? 1H)? 7.40-7.34 (m，2H)，7.20 (dd，J = 5.2, 1.7 Hz，1H)，7.09-7.02 (m，2H)，6.98 (dd，J = 5.3, 1.6Liters). 2 ml of a 2M aqueous solution of steel hydroxide was added, and the reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under vacuum, filtered, and the filtrate was extracted with ethyl acetate. The aqueous layer was acidified to pH 4 with acetic acid, and then extracted with vinegar and ethyl acetate (3x10xL). The organic layer was dehydrated and dried over magnesium sulfate, dried over magnesium sulfate, and evaporated under vacuum to obtain an acid. Yield: 88% (40 mg). 1 η NMR (400 MHz, DMSO-d6) ·· 3 11 · 14 (s, 1Η), 9.34 (s, 1Η), 8.46 (s5 1Η), 8.44-8.37 (m, 1H), 8 · 24 (d , J = 5.3 Hz, 1H), 7.78-7.67 (m, 2H), 7.38 (dd, J = 5.2, 1.7 Hz, 1H), 7.15_7.04 (m, 4H), 2.65-2.56 (m, 2H) , 2.46-2.37 (m, 2H) · MS (TSP) m / z (M + 1): 381. Example 194 N- {2 '· [(4-fluorophenyl) amino] -4,4f-linked Hidayodo-2-yl} -3- (methylthio) propanamine Under nitrogen atmosphere and 0 ° C, 3- (methylthio) propionic acid (21 ml, 24 mg, 0.25 mmol) Ear) was slowly added to 1 ml of a 1M solution of vaporized grasshopper in digas methane. After stirring for 30 minutes, the solvent was removed under vacuum, and the obtained oil was diluted in 0.5 ml of anhydrous dichloromethane. This solution was added dropwise to N_ (4_fluorodongyl) -4,4 ^ bi-rhodido-2,2f • diamine (70 gram, 0.25 mmol) in p-hodno (5 ml) Inside the solution. After stirring for 1 hour at 20 ° C, the mixture was filtered and the solvent was evaporated under vacuum. The crude material was purified by flash chromatography (ethyl acetate / ethanol 98/2). Yield 38% (36 mg). iHNMRGOOMHz'DClJ: 5 8.46 (s? 1H), 8.34-8.30 (m5 1H)? 8.26 (d? J = 5.3 Hz, 1H)? 8.24 (s? 1H)? 7.40-7.34 (m, 2H), 7.20 ( dd, J = 5.2, 1.7 Hz, 1H), 7.09-7.02 (m, 2H), 6.98 (dd, J = 5.3, 1.6

Hz, 1H)5 6.92 (s5 1H)? 6.55 (s? 1H)5 2.89 (t5 J = 6.8 Hz5 2H)5 2.72 (t? J - 6.9 Hz? 2H)，2.17(s，3H). MS(TSP)m/z(M+l) ： 383. 89385 -80- 200417546 實例195 (± )_1_乙醯基-]\_{2’-丨(4-氟苯基）胺基】-4,4’-聯峨淀-2-基}六氫p比淀· 3-叛醯胺 使（± )-1-乙醯六氫吡啶各羧酸（85毫克，0.5毫莫耳）溶於3毫 升二氯化亞硫醯中，並將溶液在室溫下攪拌1小時。在真空 下移除溶劑，並使所形成之油溶於1.0毫升二氯甲烷中。將 此溶液逐滴添加至N-(4-氟苯基&gt;4,4f-聯吡啶-2,2，-二胺（140毫克 ’ 〇·5毫莫耳）在7毫升吡啶中之溶液内。攪拌1〇分鐘後，於 真空下移除溶劑，並使粗產物藉急驟式層析（醋酸乙酯/甲 醇：95/5 至 90/10)純化。產率：17% (38 毫克）。iHNMR(400MHz， CDC13) : 5 8.86 (s，1H)，8·44 (s，1H)，8.33-8.28 (m，1H)，8.26-8.21 (m，1Η)， 7,40-7·34 (m，2H)，7.23-7.15 (m，1H)，7Ό7-7.01 (m，2H)，6.96 (m，2H)，6.92 (s，1H)，4.60-4.50 (m，1H)，3.95-3.70 (m，1H)，3.42-2.70 (m，2H)，2.58-2.52 (m，1H)，2.14-2.06 (m，4H)，2.00-1.80 (m，2H)，1.52 (m，1H). MS(TSP)m/z(M+l) ： 434. 實例196 (3R)-1-乙醯基氟苯基）胺基卜4,4匕聯吡啶基I六氫吡啶《 3-叛醯胺 使（3R)-1-乙驢7T氫p比淀-3-幾酸（75毫克，0.44毫莫耳）溶於5 *升二氯化亞硫醯中，並將溶液在室溫下攪拌丨小時。在真 $下移除溶劑，並使所形成之油溶於15毫升二氯甲烷中。 知此A液逐滴添加至N-(4-氟苯基）_4,4’_聯p比淀-2,2，-二胺（115毫 克’ 0.41毫莫耳）在5毫升吡啶中之溶液内。攪拌1〇分鐘後， 於真空下移除溶劑，並使粗產物藉HPLC管柱純化： 89385 -81 - 200417546 XTerra⑧prep MSC8，梯度液 20-60% B 20 毫升 / 分鐘，40°C，（A-0.1 % CH3CN 水溶液中之 0.1MNH4OAc，B-CH3CN)。產率：46% (82 毫克）。1H NMR (400 MHz，CDC13): 5 8.86 (s，1H)，8_44 (s，1H)，8.33-8.28 (m，1H)，8.26-8.21 (m，1H)，7.40-7.34 (m，2H)，7.23-7.15 (m，1H)，7.07-7.01 (m， 2H)，6_96(m，2H)，6_92(s，lH)，4.60-4.50(m，lH)，3.95-3_70(m，lH)，3.42-2.70(m，2H)，2.58-2.52 (m，lH)，2.14-2.06(m，4H)，2.00-1.80(m，2H)，1.52(m，1H). MS(TSP)m/z(M+l) ： 434. 實例197 (3S)_1_乙醯基-N-{2，-[(4-氟苯基）胺基】-4,4，-聯吡啶-2_基}六氫吡啶-3-羧醯胺 使（3S)小乙醯六氫吡啶-3-羧酸（75毫克，0.44毫莫耳）溶於5 毫升二氯化亞硫醯中，並將溶液在室溫下攪拌1小時。在真 空下移除溶劑，並使所形成之油溶於1.5毫升二氯甲烷中。 將此溶液逐滴添加至N-(4-氟苯基）-4,4’·聯吡啶-2,2f-二胺（115毫 克，0.41毫莫耳）在5毫升吡啶中之溶液内。攪拌10分鐘後， 在真空下移除溶劑，並使粗產物藉HPLC管柱純化：XTerra® prep MSC8，梯度液 20-60% B 20 毫升 / 分鐘，40°C，（A-0.1 % CH3 CN 水溶液中之〇.1^1见140八(：，：6-0130冲。產率：58%(102毫克）。 1H NMR (400 MHz，CDC13) ·· δ 8.86 (s，1H)，8.44 (s，1H)，8.33-8.28 (m，1H)， 8.26-8.21 (m，1Η)，7.40-7.34 (m，2Η)，7.23-7.15 (m，1Η)，7·07-7·01 (m，2Η)， 6.96 (m? 2H)5 6.92 (s? 1H)? 4.60-4.50 (m5 1H), 3.95-3.70 (m? 1H)5 3.42-2.70 (m5 2H)，2.58-2.52 (m，1H)，2.14-2.06 (m，4H)，2.00-1.80 (m，2H)，1.52 (m，1H)· MS(TSP)m/z(M+l) ： 434. 89385 -82- 200417546 t Μ 198 1-乙酿基-N-{2’_[(4-氟苯基）胺基】-4,4，-聯吡啶-2-基}四氳吡咯-3-羧 醯胺(E1)與（E2) 使1-乙醯基四氫吡咯各羧酸（97毫克，0.62毫莫耳）溶於5毫 升二氯化亞硫醯中，並將溶液在室溫下攪拌1小時。在真空 下移除溶劑，並使所形成之油溶於L5毫升二氯甲烷中。將 此溶液逐滴添加至Ν-(ζμ氟苯基）-4,4，-聯吡啶-2,2，-二胺（141毫克 ，〇·51毫莫耳）在5毫升吡啶中之溶液内。攪拌1小時後，於 真芝下移除溶劑，並使粗產物藉HPLC純化：XTerra® prep MSC8， 梯度液20-50% B20毫升/分鐘，40°C，(Α-0·1% CH3CN水溶液中 之 0.1MNH4OAc，B-CH3CN)。產率：37% (80 毫克）。然後，使 此外消旋物於對掌性管柱上純化，而得2種對掌異構物E1 (6 毫克）與 E2 (6 毫克）。1H NMR (400 MHz，CDC13)·· δ 8.67-8.58 (m，1H)， 8.49-8.40 (m，1Η)，8.34-8.28 (m，1Η)，8.28-8.20 (m，1Η)，7.41-7.34 (m，2Η)， 7.25-7.18 (m，1H)，7.09-7.02 (m，2H)，6.99-6.95 (m，1H)，6.95-6.87 (m，2H)， 3.87-3.73 (m，3H)，3.57-3.47 (m，1H)，3.26-3.04 (m，1H)，2.44-2.23 (m，2H)， 2.09-2.05 (m5 3H). MS(TSP)m/z(M+l) ： 420. 實例199 3-(胺基續醯基)善{2，-[(4-氟苯基)胺基】-4,4’_聯吡啶_2_基}苯甲醯胺 將3-(胺基磺醯基）苯甲酸（56毫克，0.28毫莫耳）在二氯化亞 硫醯（5毫升）中稀釋，並將混合物於回流下加熱4小時。蒸 發溶劑，並使粗製物質溶於1毫升二氯甲烷中。將此溶液逐 滴添加至N-(4-氟苯基）-4,4f-聯吡啶-2,二胺（77毫克，〇·27毫莫 89385 &gt;83- 200417546 耳）在5毫升峨啶中之溶液内。攪拌2小時後，於真空中濃縮 所形成之混合物，並使粗製物質藉HPLC純化：XTen^VepMSCb 梯度液20_80% B 20毫升/分鐘，4〇。〇，(A-0.1 % CH3 CN水溶液中 之 0.1MNH4〇Ac，B_CH3CN)。產率：1.5% (2 毫克）。iffNMR (400 MHz，MeOD-d4) : 3 8·58 (s，1H)，8_51 (s，1H)，8·47 (d，J = 5.3 Hz，1H)， 8·23_8·17 (m，2H)，8.13 (d，J = 8.4 Hz，1H)，7·73 (t，J = 7·8 Hz，1H)，7.60-7.52 (m，2H)，7.47 (dd，J = 5.2, 1·5 Hz，1H)，7.11-7.00 (m，4H). MS(TSP)m/z(M+l) : 464. 隹 實例200 2-{【(2’-苯胺基-4,4’-聯吡啶-2-基）胺基】甲基}環丙烷羧酸乙酯 使N-苯基-4,4f-聯p比淀-2,2’-二胺（131毫克，0.50毫莫耳）溶於5 毫升甲醇中，並添加2-甲醯基環丙烷羧酸乙酯（85毫克，〇.6〇 毫莫耳）。於〇°C下冷卻後，添加醋酸直到pH值4為止，並將 反應物在此溫度下攪拌15分鐘。然後添加氰基硼氫化鈉（38 毫克，0.60毫莫耳），並使混合物溫熱至室溫，及藉tlC追蹤 反應直到完成為止。將溶液以飽和NaHC〇3水溶液(20毫升）洗 鲁 滌，並以醋酸乙酯萃取。使有機層以硫酸鎂脫水乾燥，過 濾，並於真空下移除溶劑。使粗產物藉急驟式層析（醋酸乙 酯/甲醇：98/2)純化。產率：62% (120毫克），為黃色粉末。 1H NMR (400 MHz，Me〇D-d4)·· (5 8.10 (d，J = 5.6 Hz，1H)，7.95 (t，J = 5.6 Hz， 1H)，7.45 (d，J = 8.1 Hz，2H)，7·26-7·21 (m，2H)，6.98 (s，1H)，6.94-6.90 (m，2H)， 6.75-6.70 (m，2H)，4.04 (q，J = 7.1 Hz，2H)，3.56-3.19 (m，2H)，1.70-1.64 (m，1H)， 1.61-1.53(m，lH)，1.21-l_15(m，3H)，U3-1.07(m，lH)，0.92-0,84(m，lH)· MS(ES)m/z(M+l) ： 389. 89385 -84- 200417546 實例201 2-{[(2’-苯胺基_4,4’_聯吡啶_2_基）胺基】甲基丨環丙烷羧酸 使2-{[(2’-苯胺基-4,4’-聯吡啶-2-基）胺基]甲基}環丙烷羧酸乙酯 (120毫克，〇·31毫莫耳）溶於thf/H2〇混合物（2: 1)(6毫升）中。 然後添加氫氧化鉀（21毫克，〇·37毫莫耳），並將混合物於20 °C下攪拌20小時。蒸發THF，並以醋酸乙酯（2χ1〇毫升）萃取 水層。將水層稀釋（以5毫升Η20)，並以醋酸酸化直到ρΗ值5 為止。以醋酸乙酯（2x10毫升）萃取酸性混合物。使有機層以 石爪鍰脫水乾燥’過滤’及在真芝下濃縮，而得酸，為純 產物。產率：54% (60 毫克）。iHNMRGOOMHz'DClJ: 5 8.18(d，J = 5·6 Hz，1H)，7.98 (d，J = 5.6 Hz，1H)，7·61 (s，1H)，7.39-7.30 (m，4H)，7.11-7.03 (m，2H)，6.88 (d，J = 4.0 Hz，1H)，6·71 (d，J = 5.6 Hz，1H)，6.52 (s5 1H)，3.50 (dd， J= 13.1，6.1 Hz，1H)，3.00-2.90 (m，1H)，1·78 (d，J = 6·1 Hz，1H)，1.66-1.55 (m， 1H)，1.37-1.28 (m，1H)，0.92-0.85 (m，1H). MS (TSP)m/z(M+l) : 361. 實例202 N-苯基-N4四氫-2H-哌喃_4-基甲基)-4,4，_聯吡啶-2,2，-二胺 使N-(2f-苯胺基-4,4’-聯吡啶-2-基）四氫-2H-哌喃-4-羧醯胺（59毫 克，0.157毫莫耳）在N2大氣下溶於THF(5毫升）中，並使溶液 在0°C下冷卻。逐滴添加DIBAL 1M在己烷中之溶液（2毫升，2.0 毫莫耳），並將溶液攪掉於25°C下15小時。添加H20 (2毫升） ，並持續攪拌30分鐘。於Celite®墊上過濾溶液，並以醋酸乙 酯萃取。於真空下濃縮有機層，並使粗製物質藉HPLC純化 。產率：71% (40 毫克）。1H NMR (400 MHz，CDC13): 5 8.22 (d，J = 5.3 89385 -85- 200417546 Ηζ，1Η)，8·08 (d，J = 5.3 Hz，1H)，7.37-7.27 (m，5H)，7.11-7.02 (m，2H)，6.90 (d， J = 5.3 Hz，1H)，6.71 (d，J = 5.3 Hz，1H)，6.48 (s，1H)，5.24 (s，1H)，3.98 (dd， J= 11.1，3.5 Hz，2H)，3.42-3.33 (m，2H)，3.20 (d，J = 3·5 Hz，2H)，1.91-1.80 (m，1H)，1.70 (dd，J = 13.0, 1.9 Hz，2H)，1.36 (m，2H). 13 C NMR (101 MHz， CDC13): (Π59.20 (s，1C)，156.67 (s，1C)，148.70 (s，1C)，148·61 (s，1C)，148.28 (s，1C)，148.15 (s，1C)，140.09 (s，1C)，129.41 (s，2C)，123.25 (s，1C)，120.68 (s，2C)，113.03 (s，1C)，110.85 (s，1C)，105.70 (s，1C)，104.11 (s，1C)，67.65 (s， 2C)，48.14 (s，1C)，35.07 (s，1C)，30.88 (s，2C). φ MS(ES)m/z(M+l) ： 361. 實例203 N-苯基(四氫呋喃-3_基甲基)-4,4’-聯吡啶-2,2，-二胺 使N-(2’-苯胺基-4,4f-聯吡啶-2-基）四氫呋喃-3-羧醯胺（43毫克， 0·12毫莫耳）在N2大氣下溶於THF (5毫升）中，並使溶液在0°C 下冷卻。逐滴添加DIBAL 1M在己烷中之溶液（2毫升，2.0毫 莫耳），並將溶液攪拌於25°C下15小時。添加H20 (2毫升）， 並持續攪拌30分鐘。於矽藻土墊上過滤溶液，並以醋酸乙 鲁 酯萃取。於真空下濃縮有機層，並使粗製物質藉HPLC純化 。將產物以1當量之HC1 (水溶液）處理，並凍乾，獲得HC1鹽 。產率：61% (28 毫克）。iHNMRGOOMHAMeODO : 5 8.16 (d，J = 5.6 Hz，1H)，7.90 (d，J = 6·6 Hz，1H)，7.47 (d，J = 8.6 Hz，2H)，7.32-7.24 (m，2H)，7_10 (s，1H)，7.06-6.97 (m，3H)，3.91-3.80 (m，2H)，3.77-3.68 (m，1H)， 3.57 (dd，J = 8.6, 5·1 Hz，1H)，3.33 (d，J = 7·6 Hz，2H)，2.60 (s，1H)，2·12 (d，J = 13.1 Hz，1H)，1.68 (s，1H). MS(ES)m/z(M+l) ： 347. 89385 -86- 200417546 縮寫之清單 SPA 閃爍親近檢測 ATP 腺苷三磷酸 ATF 活化轉錄因子 MOPS 3-[N-嗎福啉基】-丙烷磺酸 EGTA 乙二醇_雙（冷_胺基乙醚)四醋酸 DTT 二硫基蘇糖醇 JNK Jun N-末端激酶 MAP 有絲分裂原活化之蛋白質 生物學評估 本發明之化合物可根據下述程序檢測其活性： 以抑制JNK3催化轉移[r-33P]ATP之r-磷酸鹽基團至生物素 化ATF2為基礎之閃燦親近檢測（SPA)已被設立，以鑒定抑制 性化合物。使所形成之33P-標識之生物素化ATF2捕獲在已塗 覆鏈黴胺基酸之SPA珠粒表面上。 檢測係在96-井板中進行。於10 mM下，在DMSO中構成之 待測化合物，及1 : 3連續稀釋液，係在100% DMSO中製成。 然後，將此等連續稀釋液在檢測緩衝液（50 mM MOPS pH 7.2, 150 mM，NaCl，0.1 mM EGTA，1 mM DTT，6.25 mM /3-磷酸甘油酯）中 稀釋1: 10，並將10微升轉移至檢測板（造成檢測中之2% DMSO 最後濃度）中。於具有待測化合物之各井中，添加2.4微升 JNK3/ATP 酵素溶液（1.18 U / 毫升 JNK3, 20 &quot;Μ ATP，2 mM Mg(Ac)2， 0.01% Brij-35在檢測缓衝液中）。使混合物於環境溫度下預培 養10分鐘。接著，將3.6微升[r-33P]ATP-溶液（0.20 //Ci/微升[ 89385 -87- 200417546 r -3 3 Ρ]ΑΤΡ，66·6 mM Mg(Ac)2，1 mM DTT，50 mM MOPS，pH 7.2, 150 mM NaCl，0.1 mM EGTA)添加至各井中，接著是10微升ATF2溶液（在 檢測緩衝液中之60微克/毫升生物素化ATF2)，以起動反應 。使反應於環境溫度下進行10分鐘。然後，藉由每井添加200 微升終止緩衝劑/珠粒混合物（0.4毫克/毫升鏈黴胺基酸塗 覆之SPA-珠粒，在50 mM EDTA，pH 7.6中），以終止反應。將板 以塑膠蓋密封，並離心（2000 rpm，5分鐘），以使珠粒沉澱， 接著在 Wallac 1450 MicrobetaTM 中計數。 IC5〇值係以待測化合物使ATF2磷醯化作用降至對照值50% 下之濃度計算而得。 結果 本發明化合物之典型Ki值係在約0.001至約10,000 nM之範圍 内。其他&amp;數值係在約0.001至約1000 nM之範圍内。另外之&amp; 數值係在約0Ό01 nM至約300 nM之範圍内。 89385 88-Hz, 1H) 5 6.92 (s5 1H)? 6.55 (s? 1H) 5 2.89 (t5 J = 6.8 Hz5 2H) 5 2.72 (t? J-6.9 Hz? 2H), 2.17 (s, 3H). MS (TSP ) m / z (M + l): 383. 89385 -80- 200417546 Example 195 (±) _1_ethylfluorenyl-] \ _ {2'- 丨 (4-fluorophenyl) amino group] -4,4 '-Lianedian-2-yl} hexahydrop-pyridine · 3-benzylamine dissolves (±) -1-acetamidine hexahydropyridine in each carboxylic acid (85 mg, 0.5 mmol) in 3 ml In thionyl chloride, and the solution was stirred at room temperature for 1 hour. The solvent was removed under vacuum and the resulting oil was dissolved in 1.0 ml of dichloromethane. This solution was added dropwise to a solution of N- (4-fluorophenyl> 4,4f-bipyridine-2,2, -diamine (140 mg '0.5 mmol) in 7 ml of pyridine After stirring for 10 minutes, the solvent was removed under vacuum and the crude product was purified by flash chromatography (ethyl acetate / methanol: 95/5 to 90/10). Yield: 17% (38 mg). iHNMR (400MHz, CDC13): 5 8.86 (s, 1H), 8.44 (s, 1H), 8.33-8.28 (m, 1H), 8.26-8.21 (m, 1Η), 7,40-7 · 34 ( m, 2H), 7.23-7.15 (m, 1H), 7Ό7-7.01 (m, 2H), 6.96 (m, 2H), 6.92 (s, 1H), 4.60-4.50 (m, 1H), 3.95-3.70 ( m, 1H), 3.42-2.70 (m, 2H), 2.58-2.52 (m, 1H), 2.14-2.06 (m, 4H), 2.00-1.80 (m, 2H), 1.52 (m, 1H). MS ( TSP) m / z (M + 1): 434. Example 196 (3R) -1-Ethylfluorophenyl) amino group 4,4 dipyridyl I hexahydropyridine 3R) -1-Ethyl 7T hydrogen p-pyridine-3-chinic acid (75 mg, 0.44 mmol) was dissolved in 5 * liters of thionyl dichloride, and the solution was stirred at room temperature for hr. The solvent was removed under real conditions and the resulting oil was dissolved in 15 ml of dichloromethane. This solution A was added dropwise to a solution of N- (4-fluorophenyl) _4,4'_bi-pyridine-2,2, -diamine (115 mg '0.41 mmol) in 5 ml of pyridine Inside. After stirring for 10 minutes, the solvent was removed under vacuum, and the crude product was purified by HPLC column: 89385 -81-200417546 XTerra⑧prep MSC8, gradient 20-60% B 20 ml / min, 40 ° C, (A- 0.1M NH4OAc, B-CH3CN) in a 0.1% CH3CN solution. Yield: 46% (82 mg). 1H NMR (400 MHz, CDC13): 5 8.86 (s, 1H), 8_44 (s, 1H), 8.33-8.28 (m, 1H), 8.26-8.21 (m, 1H), 7.40-7.34 (m, 2H) , 7.23-7.15 (m, 1H), 7.07-7.01 (m, 2H), 6_96 (m, 2H), 6_92 (s, lH), 4.60-4.50 (m, lH), 3.95-3_70 (m, lH) , 3.42-2.70 (m, 2H), 2.58-2.52 (m, 1H), 2.14-2.06 (m, 4H), 2.00-1.80 (m, 2H), 1.52 (m, 1H). MS (TSP) m / z (M + l): 434. Example 197 (3S) _1_Ethyl-N- {2,-[(4-fluorophenyl) amino] -4,4, -bipyridin-2-yl} Hexahydropyridine-3-carboxamidine Dissolve (3S) acetohexahydropyridine-3-carboxylic acid (75 mg, 0.44 mmol) in 5 ml of thionyl dichloride and place the solution in the chamber. Stir at warm for 1 hour. The solvent was removed under vacuum and the resulting oil was dissolved in 1.5 ml of dichloromethane. This solution was added dropwise to a solution of N- (4-fluorophenyl) -4,4'.bipyridine-2,2f-diamine (115 mg, 0.41 mmol) in 5 ml of pyridine. After stirring for 10 minutes, the solvent was removed under vacuum and the crude product was purified by HPLC column: XTerra® prep MSC8, gradient 20-60% B 20 ml / min, 40 ° C, (A-0.1% CH3 CN 0.1 ^ 1 in the aqueous solution is shown in 140 (:,: 6-0130). Yield: 58% (102 mg). 1H NMR (400 MHz, CDC13) · δ 8.86 (s, 1H), 8.44 ( s, 1H), 8.33-8.28 (m, 1H), 8.26-8.21 (m, 1Η), 7.40-7.34 (m, 2Η), 7.23-7.15 (m, 1Η), 7.07-7 · 01 (m , 2Η), 6.96 (m? 2H) 5 6.92 (s? 1H)? 4.60-4.50 (m5 1H), 3.95-3.70 (m? 1H) 5 3.42-2.70 (m5 2H), 2.58-2.52 (m, 1H ), 2.14-2.06 (m, 4H), 2.00-1.80 (m, 2H), 1.52 (m, 1H) · MS (TSP) m / z (M + 1): 434. 89385 -82- 200417546 t Μ 198 1-Ethyl-N- {2 '_ [(4-fluorophenyl) amino] -4,4, -bipyridin-2-yl} tetrapyrrole-3-carboxamide (E1) and ( E2) Dissolve each carboxylic acid (97 mg, 0.62 mmol) of 1-acetamidinetetrahydropyrrole in 5 ml of thionyl dichloride, and stir the solution at room temperature for 1 hour. Move under vacuum The solvent was removed, and the formed oil was dissolved in 5 ml of dichloromethane. Add dropwise to a solution of N- (ζμfluorophenyl) -4,4, -bipyridine-2,2, -diamine (141 mg, 0.51 mmol) in 5 ml of pyridine. Stir for 1 hour After that, the solvent was removed under real cheese, and the crude product was purified by HPLC: XTerra® prep MSC8, gradient solution 20-50% B 20 ml / min, 40 ° C, (0.1% in Α-0 · 1% CH3CN aqueous solution MNH4OAc, B-CH3CN). Yield: 37% (80 mg). Then, the racemate was purified on a palm column to obtain two palm isomers, E1 (6 mg) and E2 ( 6 mg). 1H NMR (400 MHz, CDC13) ... δ 8.67-8.58 (m, 1H), 8.49-8.40 (m, 1Η), 8.34-8.28 (m, 1Η), 8.28-8.20 (m, 1Η) , 7.41-7.34 (m, 2Η), 7.25-7.18 (m, 1H), 7.09-7.02 (m, 2H), 6.99-6.95 (m, 1H), 6.95-6.87 (m, 2H), 3.87-3.73 ( m, 3H), 3.57-3.47 (m, 1H), 3.26-3.04 (m, 1H), 2.44-2.23 (m, 2H), 2.09-2.05 (m5 3H). MS (TSP) m / z (M + l): 420. Example 199 3- (Amino-continuous fluorenyl) sulfanyl {2,-[(4-fluorophenyl) amino] -4,4'_bipyridin-2-yl} benzidine 3- (Aminosulfonyl) benzoic acid (56 mg, 0.28 mmol) Acyl thionyl dichloride diluted (5 ml), and the mixture was heated under reflux for 4 hours. The solvent was evaporated and the crude material was dissolved in 1 ml of dichloromethane. This solution was added dropwise to N- (4-fluorophenyl) -4,4f-bipyridine-2, diamine (77 mg, 0.27 mmol 89385 &gt; 83-200417546 ear) in 5 ml eridine Inside the solution. After stirring for 2 hours, the resulting mixture was concentrated in vacuo and the crude material was purified by HPLC: XTen VepMSCb gradient 20-80% B 20 ml / min, 40. (A-0.1% NH4oAc, B-CH3CN in 0.1% CH3CN in water). Yield: 1.5% (2 mg). iffNMR (400 MHz, MeOD-d4): 3 8 · 58 (s, 1H), 8_51 (s, 1H), 8.47 (d, J = 5.3 Hz, 1H), 8 · 23_8 · 17 (m, 2H ), 8.13 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.60-7.52 (m, 2H), 7.47 (dd, J = 5.2, 1.5 Hz, 1H), 7.11-7.00 (m, 4H). MS (TSP) m / z (M + 1): 464. Example 200 2-{[(2'-anilino-4,4'-bipyridine -2-yl) amino] methyl} cyclopropanecarboxylic acid ethyl ester dissolves N-phenyl-4,4f-bi-peptide-2,2'-diamine (131 mg, 0.50 mmol) In 5 ml of methanol, ethyl 2-formamylcyclopropanecarboxylate (85 mg, 0.60 mmol) was added. After cooling at 0 ° C, acetic acid was added until pH 4 and the reaction was stirred at this temperature for 15 minutes. Then sodium cyanoborohydride (38 mg, 0.60 mmol) was added and the mixture was allowed to warm to room temperature and the reaction was followed by tLC until completion. The solution was washed with saturated aqueous NaHC03 (20 ml) and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (ethyl acetate / methanol: 98/2). Yield: 62% (120 mg) as a yellow powder. 1H NMR (400 MHz, MeOD-d4) ... (5 8.10 (d, J = 5.6 Hz, 1H), 7.95 (t, J = 5.6 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H ), 7.26-7 · 21 (m, 2H), 6.98 (s, 1H), 6.94-6.90 (m, 2H), 6.75-6.70 (m, 2H), 4.04 (q, J = 7.1 Hz, 2H ), 3.56-3.19 (m, 2H), 1.70-1.64 (m, 1H), 1.61-1.53 (m, lH), 1.21-l_15 (m, 3H), U3-1.07 (m, lH), 0.92-0 , 84 (m, lH) · MS (ES) m / z (M + 1): 389. 89385 -84- 200417546 Example 201 2-{[(2'-aniline_4,4'_bipyridine_2 _Yl) amino] methyl 丨 cyclopropanecarboxylic acid makes 2-{[((2'-aniline-4,4'-bipyridin-2-yl) amino] methyl} cyclopropanecarboxylic acid ethyl ester ( 120 mg, 0.31 mmol) was dissolved in a thf / H2O mixture (2: 1) (6 ml). Then potassium hydroxide (21 mg, 0.37 mmol) was added, and the mixture was dissolved in 20 mg. Stir for 20 hours at ° C. Evaporate THF and extract the aqueous layer with ethyl acetate (2 x 10 ml). Dilute the aqueous layer (5 ml Η 20) and acidify with acetic acid until the pH value is 5. Use ethyl acetate ( 2x10 ml) to extract the acidic mixture. The organic layer was dried with stone claws' Filtration and concentration under real cheese gave the acid as a pure product. Yield: 54% (60 mg). IHNMRGOOMHz'DClJ: 5 8.18 (d, J = 5.6 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.39-7.30 (m, 4H), 7.11-7.03 (m, 2H), 6.88 (d, J = 4.0 Hz, 1H), 6.71 (d, J = 5.6 Hz, 1H), 6.52 (s5 1H), 3.50 (dd, J = 13.1, 6.1 Hz, 1H), 3.00-2.90 (m, 1H), 1.78 (d, J = 6 · 1 Hz, 1H), 1.66-1.55 (m, 1H), 1.37-1.28 (m, 1H), 0.92-0.85 (m, 1H). MS (TSP) m / z (M + l): 361. Example 202 N-phenyl-N4 tetrahydro-2H-piperan_4-ylmethyl) -4,4, _bipyridine-2,2, -diamine makes N- (2f-anilino-4,4'- Bipyridin-2-yl) tetrahydro-2H-piperan-4-carboxamide (59 mg, 0.157 mmol) was dissolved in THF (5 ml) under N 2 atmosphere, and the solution was kept at 0 ° C. cool down. A solution of DIBAL 1M in hexane (2 ml, 2.0 mmol) was added dropwise, and the solution was stirred at 25 ° C for 15 hours. Add H20 (2 mL) and continue stirring for 30 minutes. The solution was filtered on a Celite® pad and extracted with ethyl acetate. The organic layer was concentrated under vacuum and the crude material was purified by HPLC. Yield: 71% (40 mg). 1H NMR (400 MHz, CDC13): 5 8.22 (d, J = 5.3 89385 -85- 200417546 Ηζ, 1Η), 8.08 (d, J = 5.3 Hz, 1H), 7.37-7.27 (m, 5H), 7.11-7.02 (m, 2H), 6.90 (d, J = 5.3 Hz, 1H), 6.71 (d, J = 5.3 Hz, 1H), 6.48 (s, 1H), 5.24 (s, 1H), 3.98 (dd , J = 11.1, 3.5 Hz, 2H), 3.42-3.33 (m, 2H), 3.20 (d, J = 3.5 Hz, 2H), 1.91-1.80 (m, 1H), 1.70 (dd, J = 13.0 , 1.9 Hz, 2H), 1.36 (m, 2H). 13 C NMR (101 MHz, CDC13): (Π59.20 (s, 1C), 156.67 (s, 1C), 148.70 (s, 1C), 148 · 61 (s, 1C), 148.28 (s, 1C), 148.15 (s, 1C), 140.09 (s, 1C), 129.41 (s, 2C), 123.25 (s, 1C), 120.68 (s, 2C), 113.03 (s, 1C), 110.85 (s, 1C), 105.70 (s, 1C), 104.11 (s, 1C), 67.65 (s, 2C), 48.14 (s, 1C), 35.07 (s, 1C), 30.88 ( s, 2C). φ MS (ES) m / z (M + 1): 361. Example 203 N-phenyl (tetrahydrofuran-3-ylmethyl) -4,4'-bipyridine-2,2,- Diamine dissolves N- (2'-anilino-4,4f-bipyridin-2-yl) tetrahydrofuran-3-carboxamide (43 mg, 0.12 mmol) in THF (5 Ml), The solution was allowed to cool at 0 ° C. A solution of DIBAL 1M in hexane (2 ml, 2.0 mmol) was added dropwise, and the solution was stirred at 25 ° C for 15 hours. H20 (2 ml) was added, Stirring was continued for 30 minutes. The solution was filtered on a celite pad and extracted with ethyl acetate. The organic layer was concentrated under vacuum and the crude material was purified by HPLC. The product was treated with 1 equivalent of HC1 (aqueous solution) and Lyophilization to obtain HC1 salt. Yield: 61% (28 mg). IHNMRGOOMHAMeODO: 5 8.16 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 6.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.32-7.24 (m, 2H), 7_10 (s, 1H), 7.06-6.97 (m, 3H), 3.91-3.80 (m, 2H), 3.77-3.68 (m, 1H) , 3.57 (dd, J = 8.6, 5.1 Hz, 1H), 3.33 (d, J = 7.6 Hz, 2H), 2.60 (s, 1H), 2.12 (d, J = 13.1 Hz, 1H ), 1.68 (s, 1H). MS (ES) m / z (M + 1): 347. 89385 -86- 200417546 List of abbreviations SPA Scintillation Proximity Detection ATP Adenosine Triphosphate ATF Activated Transcription Factor MOPS 3- [N -Morpholinyl] -propanesulfonic acid EGTA ethylene glycol_bis (cold_amino ether) tetraacetic acid DTT dithiothio Alcohol JNK Jun N-terminal kinase MAP mitogen-activated protein biological evaluation The compounds of the present invention can be tested for their activity according to the following procedure: To inhibit JNK3 catalytic transfer of the r-phosphate group of [r-33P] ATP to biotin ATF2-based Scintillation Proximity Test (SPA) has been established to identify inhibitory compounds. The formed 33P-labeled biotinylated ATF2 was captured on the surface of SPA beads coated with streptavidin. Detection was performed in 96-well plates. The test compound formed in DMSO at 10 mM and a 1: 3 serial dilution were made in 100% DMSO. Then, these serial dilutions were diluted 1:10 in detection buffer (50 mM MOPS pH 7.2, 150 mM, NaCl, 0.1 mM EGTA, 1 mM DTT, 6.25 mM / 3-phosphate glyceride), and 10 Transfer microliters to the test plate (causing 2% of the final DMSO concentration in the test). In each well with the test compound, add 2.4 μl of JNK3 / ATP enzyme solution (1.18 U / ml JNK3, 20 &quot; M ATP, 2 mM Mg (Ac) 2, 0.01% Brij-35 in detection buffer) . The mixture was pre-incubated at ambient temperature for 10 minutes. Next, 3.6 microliters of [r-33P] ATP-solution (0.20 // Ci / microliters [89385 -87- 200417546 r -3 3 P] ATP, 66 · 6 mM Mg (Ac) 2, 1 mM DTT, 50 mM MOPS, pH 7.2, 150 mM NaCl, 0.1 mM EGTA) was added to each well, followed by 10 μl ATF2 solution (60 μg / ml biotinylated ATF2 in detection buffer) to start the reaction. The reaction was allowed to proceed at ambient temperature for 10 minutes. The reaction was then stopped by adding 200 μl of stop buffer / bead mixture (0.4 mg / ml streptavidin-coated SPA-beads in 50 mM EDTA, pH 7.6) per well. The plate was sealed with a plastic lid and centrifuged (2000 rpm, 5 minutes) to pellet the beads and then counted in a Wallac 1450 MicrobetaTM. The IC50 value is calculated from the concentration at which the test compound reduces the phosphorylation of ATF2 to 50% of the control value. Results The typical Ki values of the compounds of the present invention are in the range of about 0.001 to about 10,000 nM. Other &amp; values are in the range of about 0.001 to about 1000 nM. In addition, the &amp; value is in the range of about 0Ό01 nM to about 300 nM. 89385 88-

Claims (1)

200417546 拾、申請專利範園： 1 · 一種通式I化合物200417546 Patent application park: 1 · A compound of general formula I /R2 (I) 其中： R1為芳基或雜芳基，其每一個係視情況被一或多個r3、OR3 、OCOR3、COOR3、COR3、CONR3 R4、nhcorS、NR3 R4、丽s〇2 R3 、S02R3、S02NR3R4、SR3、CN、_ 基及购2取代； R2 為 R5、R6、COR5、COR6、CONHR5、CONHR6、CON(R6)2 、COOR5、COOR6、S02R5 或 S〇2R6 ; R3與R4各獨立為氫、Ch烷基、c26烯基、C26炔基、C3_ 8環燒基、（Cm環烷基）Ci_6烷基、雜環、雜環Cl_6烷基、Cl 6 氟烷基、C卜6三氟烷氧基； R5為芳基或雜芳基，其每一個係視情況被一或多個R7、OR7 、OCOR7、COOR7、COR7、c〇NR7R8、CONHOR7、NHCOR7 、NR7R8、NHS〇2R7、S02R7、s〇2NR7R8、SR7、R7SR8、CN 、鹵基、氧及N〇2取代； R6為氫、Ch烷基、c3_8環烷基、（c3_8環烷基）Ci 6烷基、 雜環、雜環Cl_6烷基、雜芳*Cl_6烷基、芳基Ci_6烷基、 Cl_6烷氧基或C2_6烯基，其中任何Cl_6烷基、C3_8環烷基 、（C3_8環烷基）(^_6烷基、雜環、雜環Cl_6烷基、雜芳基Ci 6 89385 k基、万基Cufe基、Cb6燒氧基及缔s，係視情況 被一或多個A取代； _各獨立為氫〜完基、C3-8環燒基、(C3-8環燒基) Ch燒基、C2.6職、芳基、雜芳基、雜芳基Ci6燒基、 雜環、雜環Cl-6燒基、芳基、Ci6ij燒基及Ci6氯基燒基 ，其中任何Cufe基、（：3_8環烷基、（C3 8環烷基）Ci 6燒基 匸2·6缔基、雜芳基、雜芳基C16烷基、雜環及雜環Cl 6 火元基，係視情況被一或多個B取代； R9與R1G各獨立為氫、Ci·6烷基、C38環烷基、（CH環烷 基）Cw烷基、C2_6烯基、雜環、雜環Ci6烷基、雜芳基、 雜芳基Ci-6燒基、芳基或芳基C16烷基，其中任何烷 基、C3_8環烷基、（C3_8環烷基）Cl_6烷基、c2_6晞基、雜環 、雜環q-6烷基、雜芳基、雜芳*C1_6烷基、芳基或芳基 ci -6燒基，係視情況被一或多個B取代； A 為 R9、〇r9、〇c〇r9、C00R9、COR9、CONR9R1()、CONHOR9 、NHCOR9、NR9R1()、NR9S02R1G、S02R9、S02NR9R1G、SR9 、R9 SR10、CN 或鹵基； 烷基、Ch烷氧基、Ch烷胺基、二（Cm烷基）胺 基或自基； 作為其自由態驗或鹽。 2.根據申請專利範圍第1項之化合物，其中 R1為芳基或雜芳基，視情況被一或多個R3、OR3、nr3r4 、鹵基或no2取代； R2 為 R5、R6、COR5、CQR6、CONHR5、CONHR6、COOR6 或 89385 200417546 so2r6 ； R3與R4各獨立為氫、烷基或Cl_6氟烷基； R5為芳基或雜芳基，其每一個係視情況被一或多個R7、〇R7 、COOR7、COR7、CONHOR7、NR7R8、s〇2R7、S02NR7R8、 SR7、鹵基、氧及N02取代； R6為氫、Cu烷基、（c3_8環烷基）(^_6烷基、雜環、雜環Cl_6 ’元基其中任何Cl - 6 基、（C3 - 8每·燒基）C! _ 6燒基或雜環 係視情況被一或多個A取代； R7與R8各獨立為氫、Cl_6烷基、Cs_8環烷基、芳基、雜環 ’其中任何ci -6烷基係視情況被一或多個B取代； R9與R1G各獨立為氫或Cl_6烷基，其中任何烷基係視 情況被一或多個B取代； A 為 COOR9、COR9、CONR9 R10、NHCOR9、NR9 R10、SR9、R9 SR10 或CN ; B為鹵基或二烷基）胺基。 3·根據申請專利範圍第1或2項之化合物，其中“為芳基， 視情況被一或多個R3、〇R3及NR3 R4取代。 4·根據申請專利範圍第3項之化合物，其中該芳基為苯基。 5·根據申請專利範圍第3項之化合物，其中R3係選自氟 燒基、甲基及_基。 根據申清專利範圍第1或2項之化合物，其中R2係選自R5 、COR5 及 CONHR5。 7·根據申請專利範圍第6項之化合物，其中R5為芳基，視情 /兄被一或多個 r7、OR7、COOR7、COR7、CONHOR7、NR7R8 89385 17546 、scw、S〇2NR7R8、SR7、* 基、氧 8·根據中請專糊第7項之化合物，其中二代 氧、、I6统基、C3-8環垸基、芳基、雜環，其中Ϊ = 係視情況被一或多個Β取代，該β為南基。 卜“ 土 9.根，申請專利範圍第丨或2項之化合物，其中r2 Μ 、C0R6、CONHR6&amp;s〇2R6。 讥根據申請專利範圍第9項之化合物，其中R6係選自氫、Cl 6 烷基、（c3.8環垸基）Cl.6燒基、雜環、雜環c“燒基，其 中任何Cufe基、（c3.8環燒基）u充基及雜環係視情況 被一或多個A取代。 11.根據申請專利範圍第9項之化合物，其中該八係選自c〇〇R9 、COR9、CONR9R1()、NHCOR9、NR9R1()、SR9、R9SRl(^CN ;且妒與rig各獨立為氫或Cl6烷基。 12· —種化合物，其係為 Ν，Ν’-雙[4-(三氟甲基）苯基]-4,4’-聯吡啶-2,2’-二胺； Ν，Ν’-雙（4-氟苯基）-4,4’-聯吡啶-2,2’-二胺； Ν，Ν’-雙（3,4-二氟苯基）-4,4’-聯吡啶-2,2f-二胺； N，N’-雙[3-(三氟甲基）苯基]-4,4’-聯吡啶-2,2’-二胺； N，N’-雙[3-(三氟甲氧基）苯基]-4,4’-聯吡啶-2,2f-二胺； N，Nf-雙（2-氟苯基）-4,4’-聯吡啶-2，T-二胺； Ν，Ν’-雙（2-甲基苯基）-4,4’-聯吡啶-2,2’-二胺； Ν，Ν，-雙（2-胺基苯基）-4,4，-聯吡啶_2,2’-二胺； Ν，Ν，-雙（2-甲氧苯基）-4,4，-聯吡啶-2,2f-二胺； N，N，-雙（2-乙氧苯基）-4,4，-聯吡啶-2,2f-二胺； -4- 89385 200417546 N-(2’-苯胺基-4,4，-聯吡啶-2-基）-反式斗甲氧基環己烷羧醯胺； Ν-(2’-苯胺基4,4，-聯吡啶-2-基）,式_4_甲氧基環己烷羧醯胺； Ν_{2’-[(4-氟苯基）胺基]-4,4’·聯吡淀基卜反式_4_甲氧基-環己 烷羧醯胺； Ν-{2’-[(4-氟苯基）胺基]-4,4’_聯吡啶_2-基}_順式冬甲氧基_環己 烷羧醯胺； Ν-(6-甲基吡啶-2-基）-Ν’-苯基-4,4，-聯吡啶_2,2，-二胺； Ν-苯基-Ν1-峨啶-2-基_4,4’_聯吡啶_2,2，_二胺； Ν-{4-[(4-甲基六氫吡畊小基）績醯基]苯基卜见苯基-，·聯吡 啶-2,2’-二胺； N-苯基-N1·^比淀-3-基-4,4’-聯p比途_2,2，-二胺； N-苯基-N%密淀-2-基-4,4L聯p比食·2,2，_二胺； Ν-苯基-Ν、密淀-5-基-4,4’-聯峨淀_2,2，-二胺； (2Ε)-1-{4-[(2’_苯胺基_4,4，·聯吡啶丨基）胺基]苯基卜3仁甲胺基） 丙-2-晞-1-酉同； 4-[(2’-苯胺基-4,4’-聯吡啶_2·基）胺基]_N_(2_四氫吡咯+基乙基） 苯績驗胺； 4-[(2’-苯胺基-4,心聯吡啶-2_基）胺基]嗎福啉冬基乙基）苯 磺醯胺； N-{4-[(4-乙基六氫吡畊小基）續醯基]苯基卜，苯基_4，聯吡 啶-2,2’-二胺； N-苯基-NWt:啶-4-基-4,4f-聯吡啶_2,2，-二胺； N-(2f-苯胺基-4,4f-聯吡啶-2-基）四氫呋喃氺羧醯胺； N-(2 -苯胺基-4,4f-聯吡哫-2-基&gt;3-六氫吡啶+基丙醯胺； 89385 200417546 N-(2’-苯胺基-4,4’-聯吡啶-2-基）四氫呋喃-3-羧醯胺； N-(2’-苯胺基_4,4’_聯吡啶-2-基）菸鹼醯胺； N-(2’_苯胺基-4,4，-聯吡啶-2-基）-4-(二$胺基）苯甲醯胺； N-(T-苯胺基-4,聯吡啶-2_基）-2,6-二甲氧基菸鹼醯胺； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-1Η-吲哚-2-羧醯胺； N-(2f-苯胺基-4,4’-聯吡啶-2·基）吡啶-2-羧醯胺； N-(2’-苯胺基-4,4f-聯吡啶-2-基）各呋喃醯胺； Ν-(2^苯胺基-4,4f-聯ρ比咬-2-基）-1，2,3-ρ塞二0坐-4-致酿胺； Ν-(2’-苯胺基_4,4’·聯吡啶-2-基）異噚唑-5-羧醯胺； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-5-甲基異哼唑-3-羧醯胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）吡畊-2-羧醯胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-1-甲基-1H-咪唑-4-羧醯胺； Ν-(2^苯胺基-4,4’-聯峨淀-2-基）-2-p失喃酸胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基）冰甲氧基苯甲醯胺； N-(2 -丰胺基-4,4 -聯p比淀-2-基）_5-&gt;臭基_2_咬喃醒胺， N-(2f-苯胺基_4,4’_聯吡啶-2-基）-2-(甲硫基）於鹼醯胺； 4-{[(2’-苯胺基-4,聯吡啶-2-基）胺基]羰基}苯甲酸甲酯； 3-(乙醯胺基）-N-(2f-苯胺基-4,4，-聯吡啶-2-基）苯甲醯胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）-4-酮基-4,5,6,7-四氫-1-苯并呋喃· 3-羧醯胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）-5-[(吡啶-2-基硫基）甲基»夫喃 醯胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基）菸鹼醯胺1-氧化物； N-(2’-苯胺基-4,4f-聯吡啶-2-基）-3-經基吡啶冬羧醯胺； 89385 200417546 N-(2’-苯胺基-4,4f-聯吡啶-2-基）-6-溴基吡啶-2-羧醯胺； N-(2 -冬胺基_4,4f-聯p比淀-2-基）異於驗酸胺1-氧化物； N-(2f-苯胺基-4,4’-聯吡啶-2-基）_2邊基菸鹼醯胺； Ν-(2^苯胺基-4,4’-聯p比淀-2-基基p比淀-2-叛if胺； N-(2’-苯胺基-4,扎聯吡啶-2-基）-3-苯甲醯基吡啶-2-羧醯胺； N-(2 -本胺基_4,4’-聯ρ比淀-2-基）-6-甲基p比淀-2-瘦酸胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基&gt;3,5-二甲基異噚唑-4-羧醯胺； N-(2 -笨胺基-4,4f-聯ρ比淀-2-基）-2-甲氧基於驗醯胺； Ν-(2^苯胺基_4，心聯吡啶-2-基）-4-甲基-1，2,3-遠二唑-5-羧醯胺； N-(2’-苯胺基_4，扎聯吡啶-2-基）-2-氯基異菸鹼醯胺； N-(T-苯胺基-4,聯吡啶-2-基）_5_甲基異噚唑-4_羧醯胺； N-(2’-苯胺基Ά聯吡啶-2-基）各甲基異噚唑-4-羧醯胺； N-(2f-苯胺基-4,聯吡啶-2·基）-1-甲基-1H-吡咯-2-羧醯胺； N-(2 -冬胺基-4,4^聯p比淀-2-基）-2-氯基於驗醯胺； N-(2’-苯胺基_4,4’-聯吡啶-2-基）-5-氯基-1H-吲哚-2-羧醯胺； N-(2 -冬胺基_4,4’_聯ρ比淀_2基）-4-氣基-1Η_ρ比峻-3-叛S盈胺； Ν-Ρ-苯胺基-4,4f-聯吡啶-2-基）-5-甲基-1Η-吡唑-3-羧醯胺； (2E)-N-(2 -本胺基-4,4f聯ρ比淀-2-基）-3-(3-咬喃基）丙錦r驗胺； N_(2 -冬胺基-4,4’-聯p比淀-2-基）-3-(2-嗣基-1，3-苯并p号峻-3(2H)-基） 丙醯胺； N’-(2’-苯胺基-4,4f-聯吡啶-2-基）-N，N-二甲基琥拍醯胺； N-(2 -冬胺基-4,4’-聯p比淀-2-基）-2-[(4-氯苯基）續酸基]乙醯胺； N-(2 -冬胺基-4,4f-聯p比淀-2-基）-5-嗣基膽胺驢胺； N-(2 -冬胺基_4,4’-聯p比淀-2-基）-3-甲氧基丙驢胺； 89385 200417546 Ν-(2·-苯胺基-4,聯吡啶-2-基）-4-甲氧基環己烷羧醯胺； N (2本胺基_4,4 -聯p比淀-2-基）-3-甲氧基丙酸胺； N-(2 -苯胺基-4,4L聯p比淀_2_基）四氫吱喃各叛驢胺； N_(2L苯胺基_4,4，_聯吡啶-2-基）-4-(二甲胺基）丁醯胺； N-(2 -苯胺基Ά聯p比症_2_基）於驗酸胺； N-(2’-苯胺基-4,4，-聯吡啶-2-基）-4-(二甲胺基）苯甲醯胺； N (2本胺基_4,4 -聯p比淀-2-基）-2,6-二甲氧基於驗縫胺； N-(2 -本胺基_4,4f-聯说淀-2-基）-1Η-4丨嗓-2-叛醯胺； N-(2 -私胺基_4,4’-聯？比淀-2-基）-5-甲基峨畊-2-叛Si胺； N-(2’-苯胺基-4,4，-聯吡啶-2-基风啶-2-羧醯胺； N (2冬胺基_4,4 -聯p比淀_2_基）-3-咬喃驢胺； Ν-(2^苯胺基-4,聯吡啶-2-基)-Nf-苯基脲； N-P苯胺基_4,4’-聯吡啶-2-基)-Ν’-苯基脲； Ν-(2’-苯胺基-4,4f_聯吡啶-2-基）-Ν’_[1_(4-溴苯基）乙基]脲； N-(2f-苯胺基-4,4’_聯吡啶-2-基）-Ν’-噻吩各基脲； N-(2f-苯胺基-4,4’-聯吡啶-2_基）-Ν，-(2-甲基苯基)脲； N_(2L苯胺基-4,4’-聯吡啶-2-基&gt;Ν’_(4-甲基苯基）脲； Ν·(2’_苯胺基-4,4’-聯吡啶-2-基）-ΝΗ3-氟苯基）脲； Ν-(Τ-苯胺基_4,4'-聯吡啶·2_基)-Ν，-(2-氟苯基)脲； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-ΝΗ4-氟苯基)脲； N-(2L苯胺基-4,4’-聯吡啶-2-基）-Ν’-[4-(氯基甲基）苯基]脲； Ν-(Α苯胺基_4,4’-聯吡啶么基氰基苯基)脲； Ν-Θ-苯胺基-4,4’-聯吡啶-2-基）-N’-(4-氰基苯基)脲； N-(2’-苯胺基-4,4’-聯吡啶-2-基)-NH2-氰基苯基)脲； 89385 200417546 二甲基苯基）脲 二甲基苯基)脲 基苯基)脲 基苯基：)脲 氧苯基：)脲 氧苯基)脲 氧苯基)脲 N-(2f-苯胺基-4,4f-聯吡啶-2-基）-N，-(2,3-_ N-(2’-苯胺基-4,4’_聯吡啶-2-基）_N，-(2,5-_ N-(2'-苯胺基-4,聯吡啶-2-基）-N’-(4-乙 N-(2f-苯胺基_4,4’-聯吡啶-2-基）-Nf-(3-乙 N-(2f-苯胺基_4,4’-聯吡啶-2-基）-NH4-甲 N-(2’-苯胺基-4,4，-聯吡啶-2-基）-N，-(3-甲 N-(2f-苯胺基4,4’-聯吡啶-2-基）-Nf-(2-甲 N-(2’-苯胺基-4/Γ-聯吡啶-2-基）-N，-(5-氟基-2-甲基苯基)脲； N-(2 -冬胺基_4,4’-聯卩比淀-2_基）-N’-(2_氣基爷基）脉； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-(2-氟基冬甲基苯基)脲； N-(2f-苯胺基-4,聯吡啶-2-基）-N，-(3-氟基苄基)脲； N-(2f-苯胺基_4,4’_聯吡啶-2-基）-N，-(2-氯苯基)脲； N-(2 -本胺基-4,4’-聯ρ比淀-2-基）-N’-(3-氯苯基)服； N-(2f-苯胺基_4,4’-聯吡啶-2-基)-NH2-氯苄基)脲； N-(2’-苯胺基_4,4’-聯吡啶-2-基）-N，-(2,5-二氟苯基)脲；/ R2 (I) where: R1 is aryl or heteroaryl, each of which is optionally one or more of r3, OR3, OCOR3, COOR3, COR3, CONR3 R4, nhcorS, NR3 R4, Lis〇2 R3 , S02R3, S02NR3R4, SR3, CN, _ and 2 are substituted; R2 is R5, R6, COR5, COR6, CONHR5, CONHR6, CON (R6) 2, COOR5, COOR6, S02R5 or S〇2R6; R3 and R4 each Independently are hydrogen, Ch alkyl, c26 alkenyl, C26 alkynyl, C3_8 cycloalkyl, (Cm cycloalkyl) Ci_6 alkyl, heterocyclic ring, heterocyclic Cl_6 alkyl, Cl 6 fluoroalkyl, C 6 Trifluoroalkoxy; R5 is aryl or heteroaryl, each of which is optionally one or more of R7, OR7, OCOR7, COOR7, COR7, coon7R8, CONHOR7, NHCOR7, NR7R8, NHS〇2R7, S02R7, so2NR7R8, SR7, R7SR8, CN, halo, oxygen and No2 substitution; R6 is hydrogen, Chalkyl, c3_8 cycloalkyl, (c3_8 cycloalkyl) Ci 6 alkyl, heterocyclic, hetero Ring Cl_6 alkyl, heteroaryl * Cl_6 alkyl, aryl Ci_6 alkyl, Cl_6 alkoxy, or C2_6 alkenyl, of which any Cl_6 alkyl, C3_8 cycloalkyl, (C3_8 cycloalkyl) (^ _6 alkyl, Heterocyclic, heterocyclic Cl_6 alkyl, heteroaryl C i 6 89385 k-based, 10,000-based Cufe-based, Cb6-based alkoxy, and s are substituted by one or more A, as appropriate; _ each independently is hydrogen ~ endyl, C3-8 cycloalkyl, (C3-8 (Cycloalkyl) Cyloalkyl, C2.6, aryl, heteroaryl, heteroaryl Ci6 alkyl, heterocyclic, heterocyclic Cl-6 alkyl, aryl, Ci6ij alkyl, and Ci6 chloroalkyl , Where any Cufe group, (: 3-8 cycloalkyl, (C3 8 cycloalkyl) Ci 6 alkyl, 2-6 alkenyl, heteroaryl, heteroaryl C16 alkyl, heterocyclic and heterocyclic Cl 6 A radical, which is optionally substituted by one or more B; R9 and R1G are each independently hydrogen, Ci · 6 alkyl, C38 cycloalkyl, (CH cycloalkyl) Cw alkyl, C2-6 alkenyl, heterocyclic, Heterocyclic Ci6 alkyl, heteroaryl, heteroaryl Ci-6 alkyl, aryl or aryl C16 alkyl, of which any alkyl, C3_8 cycloalkyl, (C3_8 cycloalkyl) Cl_6 alkyl, c2_6 晞Group, heterocyclic ring, heterocyclic q-6 alkyl group, heteroaryl group, heteroaryl * C1-6 alkyl group, aryl group or aryl ci-6 alkyl group, which are optionally substituted by one or more B; A is R9, 〇r9, 〇c〇r9, C00R9, COR9, CONR9R1 (), CONHOR9, NHCOR9, NR9R1 (), NR9S02R1G, S02R9, S02NR9R1G , SR9, R9, SR10, CN or halo; alkyl, Chalkoxy, Chalkylamino, di (Cmalkyl) amino or self-group; as its free state test or salt. 2. The compound according to item 1 of the scope of patent application, wherein R1 is aryl or heteroaryl, optionally substituted by one or more R3, OR3, nr3r4, halo or no2; R2 is R5, R6, COR5, CQR6 , CONHR5, CONHR6, COOR6 or 89385 200417546 so2r6; R3 and R4 are each independently hydrogen, alkyl or Cl_6fluoroalkyl; R5 is aryl or heteroaryl, each of which is one or more R7, as appropriate. R7, COOR7, COR7, CONHOR7, NR7R8, SOC2R7, S02NR7R8, SR7, halo, oxygen, and N02 substitution; R6 is hydrogen, Cu alkyl, (c3_8 cycloalkyl) (^ _6 alkyl, heterocyclic, hetero Ring Cl_6 'membered group in which any Cl-6 group, (C3-8 per alkynyl) C! _ 6 alkynyl or heterocyclic ring is optionally substituted by one or more A; R7 and R8 are each independently hydrogen, Cl_6 Alkyl, Cs_8 cycloalkyl, aryl, heterocycle 'where any ci-6 alkyl is optionally substituted by one or more B; R9 and R1G are each independently hydrogen or Cl_6 alkyl, where any alkyl is Cases are substituted with one or more B; A is COOR9, COR9, CONR9 R10, NHCOR9, NR9 R10, SR9, R9 SR10 or CN; B is halo or dialkyl) amino. 3. The compound according to item 1 or 2 of the scope of patent application, wherein "is an aryl group, optionally substituted with one or more R3, OR3 and NR3 R4. 4. The compound according to item 3 of the scope of patent application, wherein Aryl is phenyl. 5. The compound according to item 3 of the scope of the patent application, wherein R3 is selected from the group consisting of fluoroalkyl, methyl and _. The compound according to item 1 or 2 of the scope of the patent application, where R2 is selected. From R5, COR5 and CONHR5. 7. According to the 6th compound of the patent application, where R5 is an aryl group, as appropriate, one or more of r7, OR7, COOR7, COR7, CONHOR7, NR7R8 89385 17546, scw, S〇2NR7R8, SR7, * group, oxygen 8. According to the compound in item 7, please specify the second oxygen group, I6 group, C3-8 cyclofluorenyl group, aryl group, heterocyclic ring, where Ϊ = is It is optionally substituted by one or more Bs, and the β is a South base. [Earth 9. Roots, the compounds in the scope of application patent No. 丨 or 2, wherein r2M, COR6, CONHR6 & so2R6.化合物 The compound according to item 9 of the scope of the patent application, wherein R6 is selected from hydrogen, Cl 6 alkyl, (c3.8 cyclofluorenyl) Cl.6 alkyl, heterocycle, heterocyclic c "alkyl, of which any Cufe Group, (c3.8 ring alkyl group) u charge group and heterocyclic ring are optionally substituted with one or more A. 11. The compound according to item 9 of the scope of patent application, wherein the eight series is selected from the group consisting of 〇R9, COR9, CONR9R1 (), NHCOR9, NR9R1 (), SR9, R9SR1 (^ CN; and jealousy and rig are each independently hydrogen or Cl6 alkyl. 12. A compound, which is Ν, Ν'-bis [4- (Trifluoromethyl) phenyl] -4,4'-bipyridine-2,2'-diamine; Ν, Ν'-bis (4-fluorophenyl) -4,4'-bipyridine-2, 2'-diamine; Ν, Ν'-bis (3,4-difluorophenyl) -4,4'-bipyridine-2,2f-diamine; N, N'-bis [3- (trifluoro (Methyl) phenyl] -4,4'-bipyridine-2,2'-diamine; N, N'-bis [3- (trifluoromethoxy) phenyl] -4,4'-bipyridine -2,2f-diamine; N, Nf-bis (2-fluorophenyl) -4,4'-bipyridine-2, T-diamine; Ν, Ν'-bis (2-methylphenyl) -4,4'-bipyridine-2,2'-diamine; Ν, Ν, -bis (2-aminophenyl) -4,4, -diamine Pyridine_2,2'-diamine; N, N, -bis (2-methoxyphenyl) -4,4, -bipyridine-2,2f-diamine; N, N, -bis (2-ethyl Oxyphenyl) -4,4, -bipyridine-2,2f-diamine; -4- 89385 200417546 N- (2'-anilino-4,4, -bipyridin-2-yl) -trans bucket Methoxycyclohexanecarboxamide; Ν- (2'-aniline 4,4, -bipyridin-2-yl), formula_4_methoxycyclohexanecarboxamide; Ν_ {2'- [(4-Fluorophenyl) amino] -4,4 '· bipyridyl, trans_4-methoxy-cyclohexanecarboxamide; Ν- {2'-[(4-fluorobenzene (Amino) amino] -4,4'_bipyridin_2-yl} _cis-dongmethoxy_cyclohexanecarboxamide; N- (6-methylpyridin-2-yl) -N'- Phenyl-4,4, -bipyridine_2,2, -diamine; N-phenyl-N1-eridin-2-yl_4,4'_bipyridine_2,2, _diamine; Ν -{4-[(4-methylhexahydropyridinyl) phenyl] phenylphenyl see phenyl-, · bipyridine-2,2'-diamine; N-phenyl-N1 · ^ ratio Yodo-3-yl-4,4'-bi p ratio _2,2, -diamine; N-phenyl-N% dense Yodo-2-yl-4,4L bip ratio · 2,2, _Diamine; N-phenyl-N, dense lake-5-yl-4,4'-biyanide_2,2, -diamine; (2Ε) -1- {4-[(2'_aniline Base_4,4 , · Bipyridyl) amino] phenyl] 3-benzylmethylamino) propan-2- 酉 -1-pyridine; 4-[(2'-aniline-4,4'-bipyridine_2 · [Amino] amino] _N_ (2-tetrahydropyrrole + ylethyl) phenylphenamine; 4-[(2'-anilino-4, cardiopyridine-2_yl) amino] morpholinol Ethyl) benzenesulfonamide; N- {4-[(4-ethylhexahydropyridine small group) continyl} phenylphenyl, phenyl-4, bipyridine-2,2'-diamine; N-phenyl-NWt: pyridin-4-yl-4,4f-bipyridine_2,2, -diamine; N- (2f-aniline-4,4f-bipyridin-2-yl) tetrahydrofuran carboxyl Amidoamine; N- (2-anilino-4,4f-bipyridin-2-yl &gt; 3-hexahydropyridine + ylpropylamidine; 89385 200417546 N- (2'-anilino-4,4 ' -Bipyridin-2-yl) tetrahydrofuran-3-carboxamide; N- (2'-anilino-4,4'_bipyridin-2-yl) nicotinamide; N- (2'_aniline -4,4, -bipyridin-2-yl) -4- (di $ amino) benzidine; N- (T-aniline-4, bipyridin-2-yl) -2,6-di Methoxy nicotinamide; N- (2'-aniline_4,4'_bipyridin-2-yl) -1'-indole-2-carboxamide; N- (2f-aniline-4 4'-bipyridin-2-yl) pyridine-2-carboxamide; N -(2'-anilino-4,4f-bipyridin-2-yl) furanamidine; Ν- (2 ^ aniline-4,4f-bi-p-ratio-2-yl) -1,2, 3-rhexidine-0-fermenting amine; Ν- (2'-aniline_4,4 '· bipyridin-2-yl) isoxazole-5-carboxamide; Ν- (2' -Anilino-4,4'-bipyridin-2-yl) -5-methylisohumidazole-3-carboxamide; N- (2'-aniline-4,4'-bipyridine-2- Pyridin-2-carboxamide; N- (2f-anilino-4,4'-bipyridin-2-yl) -1-methyl-1H-imidazole-4-carboxamide; N- ( 2 ^ anilino-4,4'-bienedian-2-yl) -2-p alanate; N- (2f-anilino-4,4'-bipyridin-2-yl) glacial methoxy Benzamidine; N- (2-fungamino-4,4-bi-p-pyridin-2-yl) _5- &gt; odoryl_2_anhydroxanthine, N- (2f-aniline_ 4,4'_bipyridin-2-yl) -2- (methylthio) in amidine; 4-{[(2'-aniline-4, bipyridin-2-yl) amino] carbonyl} Methyl benzoate; 3- (acetamido) -N- (2f-aniline-4,4, -bipyridin-2-yl) benzidine; N- (2'-aniline-4, 4'-bipyridin-2-yl) -4-one-4,5,6,7-tetrahydro-1-benzofuran · 3-carboxamide; N- (2'-aniline-4, 4'-bipyridine-2- ) -5-[(pyridin-2-ylthio) methyl »furanamine; N- (2f-anilino-4,4'-bipyridin-2-yl) nicotinamine 1-oxide Compounds; N- (2'-anilino-4,4f-bipyridin-2-yl) -3-merylpyridolamine; 89385 200417546 N- (2'-anilino-4,4f-bipyridine) 2-yl) -6-bromopyridine-2-carboxamidine; N- (2-aspartyl-4,4f-bi-p-pyridin-2-yl) is different from acid amine 1-oxide; N- (2f-anilino-4,4'-bipyridin-2-yl) _2 side group nicotinamide; N- (2 ^ anilino-4,4'-bi-p-pyridine-2-yl group p-Hyoto-2-amine; N- (2'-anilino-4, bipyridin-2-yl) -3-benzylidenepyridine-2-carboxamide; N- (2-benzyl Amine_4,4'-bi-p-pyridin-2-yl) -6-methyl p-pyridine-2-lepic acid amine; N- (2f-aniline-4,4'-bipyridine-2- &Gt;3,5-dimethylisoxazol-4-carboxamidine; N- (2-benzylamino-4,4f-bi-pyridine-2-yl) -2-methoxy Amine; N- (2 ^ anilino-4, cardiac bipyridin-2-yl) -4-methyl-1,2,3-distadiazol-5-carboxamidine; N- (2'-aniline _4, Bipyridin-2-yl) -2-chloroisonicotinamide; N- (T-anilino-4, bipyridin-2-yl) _5_methyl Oxazole-4_carboxamidin; N- (2'-anilinopyridin-2-yl) each methylisoxazole-4-carboximide; N- (2f-anilino-4, bipyridine -2 · yl) -1-methyl-1H-pyrrole-2-carboxamidine; N- (2-dongamido-4,4 ^ bipyridine-2-yl) -2-chloro Amine; N- (2'-anilino_4,4'-bipyridin-2-yl) -5-chloro-1H-indole-2-carboxamidine; N- (2-aspartyl_4 , 4'_bi-ρ bidian_2yl) -4-amino-1Η_ρ bijun-3-benzylamine; N-P-aniline-4,4f-bipyridin-2-yl) -5- Methyl-1fluorenyl-pyrazole-3-carboxamide; (2E) -N- (2-benzylamino-4,4f-bi-pyridin-2-yl) -3- (3-octyl) propanyl N- (2-hydroxyamido-4,4'-bi-p-pyridine-2-yl) -3- (2-fluorenyl-1,3-benzo-p-jun-3 (2H) -Yl) propylamidine; N '-(2'-anilino-4,4f-bipyridin-2-yl) -N, N-dimethylsuccinimide; N- (2-dongamido- 4,4'-bi-p-pyridin-2-yl) -2-[(4-chlorophenyl) continyl acid] acetamidinium; N- (2-dongamido-4,4f-bi-p-pyridine -2-yl) -5-amidinocholamine donutylamine; N- (2-aspartyl-4,4'-bi-p-pyridin-2-yl) -3-methoxypropyldonylamine; 89385 200417546 Ν- (2 · -aniline-4, bipyridine-2- ) -4-methoxycyclohexanecarboxamide; N (2-benzylamino-4,4-bipyridine-2-yl) -3-methoxypropionic acid amine; N- (2-aniline -4,4L bi-p-pyridine_2_yl) tetrahydroanylamine; N_ (2L aniline_4,4, _bipyridin-2-yl) -4- (dimethylamino) Butanidine; N- (2-aniline-pyridinyl p-pyridin-2-yl) in acid test amine; N- (2'-aniline-4,4, -bipyridin-2-yl) -4- (Dimethylamino) benzamidine; N (2-benzylamino-4,4-bipyridine-2-yl) -2,6-dimethoxybenzylamine; N- (2-benzyl Amino_4,4f-synthetase-2-yl) -1Η-4 丨 Homo-2-benzylamine; N- (2 -private amine_4,4'-linked? Biyodo-2-yl) -5-methyleghen-2-benzylamine; N- (2'-anilino-4,4, -bipyridin-2-ylfengidin-2-carboxamide; N (2-aspartyl-4,4-bi-p-pyridine_2-yl) -3-anhydrodonylamine; N- (2 ^ aniline-4, bipyridin-2-yl) -Nf-phenyl Urea; NPanilino_4,4'-bipyridin-2-yl) -N'-phenylurea; N- (2'-anilino-4,4f_bipyridin-2-yl) -N'_ [1- (4-bromophenyl) ethyl] urea; N- (2f-aniline-4,4'_bipyridin-2-yl) -N'-thiophene-based urea; N- (2f-aniline -4,4'-bipyridin-2-yl) -N,-(2-methylphenyl) urea; N_ (2L anilino-4,4'-bipyridin-2-yl> N '_ ( 4-methylphenyl) urea; Ν · (2'_aniline-4,4'-bipyridin-2-yl) -ΝΗ3-fluorophenyl) urea; Ν- (Τ-aniline_4,4 '-Bipyridine 2-yl) -N,-(2-fluorophenyl) urea; Ν- (2'-aniline-4,4'-bipyridin-2-yl) -NΗ4-fluorophenyl) Urea; N- (2L aniline-4,4'-bipyridin-2-yl) -N '-[4- (chloromethyl) phenyl] urea; Ν- (Αaniline_4,4' -Bipyridinyl cyanophenyl) urea; N-Θ-aniline-4,4'-bipyridin-2-yl) -N '-(4-cyanophenyl) urea; N- (2' -benzene -4,4'-bipyridin-2-yl) -NH2-cyanophenyl) urea; 89385 200417546 dimethylphenyl) ureadimethylphenyl) ureidophenyl) ureidophenyl :) Ureaoxyphenyl:) Ureaoxyphenyl) Ureaoxyphenyl) Urea N- (2f-aniline-4,4f-bipyridin-2-yl) -N,-(2,3-_ N- (2 '-Anilino-4,4'_bipyridin-2-yl) _N,-(2,5-_ N- (2'-aniline-4, bipyridin-2-yl) -N'-(4 -Ethyl N- (2f-anilino_4,4'-bipyridin-2-yl) -Nf- (3-ethyl N- (2f-anilino_4,4'-bipyridin-2-yl)- NH4-methylN- (2'-aniline-4,4, -bipyridin-2-yl) -N,-(3-methylN- (2f-aniline 4,4'-bipyridin-2-yl) ) -Nf- (2-methylN- (2'-aniline-4 / Γ-bipyridin-2-yl) -N,-(5-fluoro-2-methylphenyl) urea; N- ( 2 -Ethylamino_4,4'-bipyridyl-2_yl) -N '-(2_aminoyl) vein; N- (2f-aniline-4,4'-bipyridine- 2-yl) -N '-(2-fluorobenzylmethylphenyl) urea; N- (2f-aniline-4, bipyridin-2-yl) -N,-(3-fluorobenzyl) Urea; N- (2f-aniline_4,4'_bipyridin-2-yl) -N,-(2-chlorophenyl) urea; N- (2-benzylamino-4,4'-linked ρ Biyodo-2-yl) -N '-(3-chlorophenyl); N- (2 f-aniline_4,4'-bipyridin-2-yl) -NH2-chlorobenzyl) urea; N- (2'-aniline_4,4'-bipyridin-2-yl) -N, -(2,5-difluorophenyl) urea; N-(2’-苯胺基_4,4’-聯吡啶-2-基）-N’-(2,4-二氟苯基）脲； N-(2’-苯胺基_4,4，-聯吡啶-2-基）-ΝΗ3,4·二氯芊基)脲； Ν·(4-乙醯基苯基）-ν，-(2，-苯胺基-Μ’-聯吡啶_2_基）月尿； Ν-(3-乙醯基苯基）-Ν’-(2’-苯胺基-4,4f-聯吡啶-2-基）脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N’-(4-異丙基苯基）脲； Ν·(2’_苯胺基-4,4f-聯吡啶-2-基）-N’-(2-異丙基苯基）脲； N-(2’-冬胺基-4,4f-聯π比淀-2-基）-N〔(2-乙基_6_甲基苯基)脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基)-Ν’-三甲苯基脲； Ν-(2’-苯胺基-4,聯吡啶-2-基）-ΝΗ2-丙基苯基）脲； 89385 -9- 200417546 N-(2 -丰胺基-4,4f-聯π比淀-2-基）-N’-[4-(二甲胺基）苯其]服· N-(2’-苯胺基_4,4’_聯吡啶-2-基）-N’-l，3-苯并二氧伍圜烯基脲； N-(2 -冬胺基·4,4’_聯峨淀-2-基）-N’-(4-甲氧基_2_甲基苯其）月尿. N-(2 -木胺基-4,4’-聯外1：淀_2-基）_N’-(2-甲氧基-5-甲基苯基)脲· N-(2 -冬胺基-4,4’-聯ρ比淀-2-基）-N’-(4-乙氧苯基）脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-NH4-甲氧基芊基郷； N-(2 -冬胺基-4,4’-聯ρ比淀-2-基）-N’_(4-硝基苯基）脲； N-(2’-苯胺基-4,4Ί说違-2-基）-N’-(3-硝基苯基）脲； N-(2^苯胺基-4/-聯叶1：淀-2-基）-Nf-[3-(甲硫基）苯基]脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-Nf-[4-(甲硫基）苯基]脲； N-(2 -冬胺基_4,4’_聯ρ比淀-2-基）-N’-(2-甲苹基）脲； N-(2 _冬胺基-4,4f-聯ρ比淀-2-基）-Nf-(5-氯基-2-甲基苯基)脲； N-(2 冬胺基-4,4·-聯ρ比淀-2-基）-N'-(2-氯基-5-甲基苯基)脲； N_(2 -冬胺基_4,4’_聯ρ比淀-2-基）^’-(2_氯爷基）月尿； N-(2’-苯胺基-4,4’-聯p比淀-2-基）-N’-(3_氯基-4-氟苯基)脲； N-(2 _本胺基-4,4f-聯p比淀-2-基）-&gt;1’-(2,3,4-三氟苯基）脲； N-(2 -本胺基-4,4f-聯p比淀-2-基）-N’-(4-丁基苯基）脲； N-(2’-苯胺基-4,4’-聯吡啶-2-基）-NH2-異丙基-6-甲基苯基）脲； N-(2 -冬胺基-4,4’·聯p比岐-2-基）-N’-(2-第三-丁基苯基）脲； 4-({[(2’-苯胺基-4,4’-聯吡啶-2-基）胺基]羰基}胺基）苯甲酸甲酯； N-(2'-苯胺基_4,4’_聯p比淀-；2-基）-N’-(3,4-二甲氧基苯基)脲； N_(2f•苯胺基_4,4’_聯吡啶-2-基）_N’-(3,5-二甲氧基苯基)脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）-NH3-氯基斗甲氧苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-N’-[4-(二氟甲氧基）苯基]脲； 89385 -10- 200417546 N-(2’·苯胺基-4,4f-聯吡啶-2-基）-N42-(三氟甲基）苯基]脲； N-(2 -冬胺基-4,4f-聯p比淀-2-基）-Nf-[3-(二氟甲基）苯基]膽； N-(2 -冬胺基-4,4’-聯峨淀-2-基）-N*-[4-(三氟甲基）苯基]月尿； N-(2f-苯胺基-4,聯吡啶-2-基）-NH2,5-二氯苯基）脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）·Ν’-(3,5-二氯苯基)脲； N-(2f-苯胺基-4,4f-聯吡啶-2-基）·Ν’-(3,4-二氯苯基）脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-Ν’-(2,3-二氯苯基)脲； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-Ν’-(2,4-二氯苯基)脲； Ν-(2’-苯胺基-4,4f-聯吡啶-2_基&gt;ΝΗ4-溴基各甲基苯基)脲； N-(2f-苯胺基-4,4’-聯吡啶-2-基）-ΝΗ2,6-二氯吡啶斗基）脲； Ν-(2’-苯胺基_4,4’_聯吡啶-2-基）-Ν’-(4-丁基-2-甲基苯基）脲； Ν-(2’-苯胺基-4,4’-聯吡啶-2-基）-Ν45-甲基-2-(三氟甲基）各呋喃 基]脲； 3-({[(2 -冬胺基-4,4^聯外1：淀-2-基）胺基]幾基}胺基）苯甲酸乙酉旨； N-(2’-苯胺基·4,4’_聯吡啶-2-基）-N’-(4-丁氧基苯基)脲； N-(2f-苯胺基_4,4’·聯吡啶-2-基）_N’_(2,6-二異丙基苯基）脲； N-(2f-苯胺基_4,4’_聯吡啶-2-基）-N’-(4-甲苄基)脲； N-(2’-苯胺基_4,4’_聯吡啶-2-基）-NH5-氯基-2,4-二甲氧基苯基） 脲； N-(2’-苯胺基-4,4f-聯吡啶-2-基州’-{4-[(三氟甲基)硫基]苯基}脲； N-(2f-苯胺基_4,4’_聯吡啶-2-基）-N43,5_雙（三氟甲基）苯基]脲； 1-乙fe基-N-(2’-苯胺基-4,4’-聯ρ比p定-2-基）六氯p比淀-4-叛酸胺； N-(2 _冬胺基-4,4f-聯ρ比淀-2-基）-5-艱1基舖胺驗胺； N -乙g监基-N1 -(2’-苯胺基-4,4’-聯p比淀-2-基）-/3-胺基丙驢胺； 89385 -11 - 200417546 N-(2’-冬胺基-4,4’-聯外b淀-2-基）六氮p比淀-4-叛S盈胺； 3- 胺基-Ν-(2^苯胺基-4,4’-聯峨淀-2-基）丁酸胺； Ν-(2^苯胺基-4,4L聯吡啶-2-基）-L_脯胺醯胺； N-(2f-苯胺基-4,4’-聯吡啶-2-基）乙醯胺； 2'-苯胺基-4,4’·聯吡啶-2-基胺基甲酸甲酯； N-(2’-苯胺基-4,4’-聯吡啶-2-基）曱烷磺醯胺； N-(2’-苯胺基-4,4’-聯吡啶-2-基）環己烷羧醯胺； 1-乙醒基-Ν-(2·-苯胺基-4Ά聯p比淀-2-基）六氫外(：症-2-瘦S盡胺； ⑩ 1-乙驗基-N-(2f-苯胺基-4,4f-聯ρ比淀-2-基）六氫ρ比淀-3-致S盛胺； 4- [(2’-苯胺基-4,4’-聯吡啶-2-基）胺基]-4-酮基丁酸乙酯； N-(2:苯胺基-4,4’-聯p比淀-2-基）四氫吱喃-2-複醯胺； (S)-3 N2-乙醯基-Nl-(2’-苯胺基-4,4，-聯吡啶-2-基）甲硫胺醯胺； N-(2f-苯胺基-4,心聯吡啶-2-基）四氫-2H-哌喃-4-羧醯胺； 3-[(2’-苯胺基_4,4’_聯吡啶-2-基）胺基]-3-酮基丙酸乙酯； N-(2L冬胺基-4,4^聯p比淀-2_基）-3-(甲硫基）丙酸胺； (± )N-(2’-苯胺基-4,4’-聯吡啶_2-基）-2-四氫吡咯-2-基乙醯胺； _ (3S)-3-胺基-Ν·(2’-苯胺基-4,4，-聯吡啶-2_基）-4-氰基丁醯胺； Nl-(2f-苯胺基-4,4f-聯叶1：淀-2-基）環丙燒-1，1·二致醯胺； (3S)-1-乙酉盈基-N-(2f-苯月安基-4,4’-聯外(：淀-2-基）六氫ρ比淀-3-叛酉盛 胺； N-(2f-苯胺基_4,4’_聯p比淀-2-基）四氫吱喃_3_羧醯胺（+)與㈠； N-{24(4-氟苯基）胺基]·4,4’_聯吡淀-2_基}四氫咬喃-3-複醯胺； Ν_{2’-[(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}四氫-2Η-哌喃冬羧醯 胺； 89385 -12- 200417546 4-({2^[(4-^苯基）胺基]-4,4f-聯p比淀-2-基}胺基）-4-i同基丁酸乙 酯； 4-({2’-[(4-氟苯基）胺基]-4,4|-聯^?比淀-2-基}胺基）-4-嗣基丁酸； N-{2f-[(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}-3-(甲硫基）丙醯胺； (± )小乙醯基-N-{24(4-氟苯基）胺基]-4,4’-聯吡啶-2-基}六氫吡 啶各羧醯胺； (3R)小乙醯基-N_{2，-[(4-氟苯基）胺基]-4,4，-聯吡啶-2-基}六氫吡 淀-3-複醯胺； (3S)小乙醯基-N-{2’_[(4-氟苯基）胺基H，4，-聯吡啶_2_基}六氫外匕 啶各羧醯胺； 1-乙_基-N-{2，-[(4-氟苯基）胺基]_4,4，_聯吡啶-2-基}四氫吡洛各 羧醯胺； 3-(胺基碍醯基）善{2L[(‘氟苯基）胺基]-4,4，_聯吡啶_2_基 &gt; 苯甲 醯胺； 2_{[(2’_笨胺基-4,4，-聯吡啶-2-基）胺基]甲基}環丙烷羧酸乙酯； 2'{[(2f-苯胺基_4,4，_聯吡啶-2-基）胺基]甲基}環丙烷羧酸； N笨基-N，-(四氫_211-喊喃-4-基甲基）-4,4’-聯峨唉_2,2，_二胺； Ν笨基_Ν’-(四氫吱喃-3-基甲基）-4,4f-聯ρ比咬-2,2，_二胺； 作為自由態鹼或鹽。 根據申清專利範圍第1或2項之化合物，其係呈藥學上可 接受鹽之形式。 14. 一種醫藥配方，其包含作為活性成份之治療上有效量之 豕申μ專利範圍第1或2項之化合物，伴隨著藥學上可 接定之載劑或稀釋劑。 89385 -13- 200417546 種醫藥配方，其包含作為活性成份之治療上有效量之 根據申請專利範圍第丨或2項之化合物，用於預防及/或 ’ 口療與JNK活化作用有關聯之症狀。 16.根據申請專利範圍第！或2項之化合物，其係用於治療。 17· —種根據申請專利範圍第丨或2項之化合物在藥劑製造上 芝用途，孩藥劑係用於預防及/或治療與活化作用有 關聯之症狀。 18· —種根據申請專利範圍第丨或2項之化合物在藥劑製造上 之用途，該藥劑係用於預防及/或治療選自以下之症狀 :中樞或末梢神經變性病症，包括阿耳滋海默氏疾病、 認知病症、巴金生氏病、亨丁頓氏疾病、肌萎縮性側索 硬化額3與顧骨疲呆症巴金生氏型、Gaum之巴金生癡 呆症複徵、HIV癡呆症、腎上腺基底變性、拳擊手癡呆症 、Down氏徵候簇、腦炎後巴金生氏徵候簇、進行性核上 麻痺、Pick氏病、Niemann-Pick氏病、癲癇、末梢神經病、 含髓損傷、頭邵損傷；自身免疫疾病，包括多發性硬化 、炎性腸疾病、克隆氏病、風濕性關節炎、氣喘 '敗血 性休克、移植排斥；心與血管疾病，包括中風、動脈硬 化、心肌梗塞、心肌再灌注損傷；癌症，包括乳房、結 腸直腸、胰、前列腺癌。 19·根據申請專利範圍第18項之用途，其中該症狀為阿耳滋 海默氏疾病。 2〇· —種根據申請專利範圍第1或2項之化合物在藥劑製造上 之用途，該藥劑係用於預防及/或治療與抑制可引致預 89385 -14- 200417546 發炎蛋白質之表現有關聯之症狀。 21. -種根據申請專利範圍第⑷嚷之化合物在藥劑製造上 之用途，該藥劑係預防及/或治療症狀，選自水腫 、痛覺缺失、發熱及疼痛，譬如神經與肌肉疼痛、頭痛 、癌症疼痛、牙痛及關節炎疼痛^ 22. —種根據式π化合物 ΗN- (2'-aniline_4,4'-bipyridin-2-yl) -N '-(2,4-difluorophenyl) urea; N- (2'-aniline_4,4, -Bipyridin-2-yl) -NΗ3,4 · dichlorofluorenyl) urea; Ν · (4-ethylamidophenyl) -ν,-(2, -anilino-M'-bipyridine_2_ ) Lunauria; Ν- (3-ethenylphenyl) -N '-(2'-aniline-4,4f-bipyridin-2-yl) urea; N- (2'-aniline_4 , 4'-bipyridin-2-yl) -N '-(4-isopropylphenyl) urea; Ν · (2'_aniline-4,4f-bipyridin-2-yl) -N'- (2-isopropylphenyl) urea; N- (2'-aspartyl-4,4f-bi-pi ratio-2-yl) -N [(2-ethyl-6-methylphenyl) Urea; N- (2f-anilino-4,4f-bipyridin-2-yl) -N'-tricityl urea; N- (2'-anilino-4, bipyridin-2-yl) -NΗ2 -Propylphenyl) urea; 89385 -9- 200417546 N- (2 -pentylamino-4,4f-bi-pi ratio-2-yl) -N '-[4- (dimethylamino) benzyl ] Service · N- (2'-aniline_4,4'_bipyridin-2-yl) -N'-1,3-benzodioxolenylurea; N- (2-dongamido · 4,4'_Lianedian-2-yl) -N '-(4-methoxy_2_methylbenzyl) moon urine. N- (2-lignyl-4,4'-linked Outer 1: Yodo_2-based) _N '-(2-methoxy-5-methylphenyl) urea · N- (2-Deramido-4,4'-bi-p-pyridine-2-yl) -N'-(4-ethyl Oxyphenyl) urea; N- (2f-aniline-4,4f-bipyridin-2-yl) -NH4-methoxyfluorenylfluorene; N- (2-dongamido-4,4'-linked ρ Biyodo-2-yl) -N '_ (4-nitrophenyl) urea; N- (2'-anilino-4,4anhydro-2-yl) -N'-(3-nitro Phenyl) urea; N- (2 ^ anilino-4 / -bifoliate 1: Yodo-2-yl) -Nf- [3- (methylthio) phenyl] urea; N- (2f-aniline- 4,4'-bipyridin-2-yl) -Nf- [4- (methylthio) phenyl] urea; N- (2-dongamido_4,4'_bi-pyridine-2-yl ) -N '-(2-Methylbenzyl) urea; N- (2-_Amino-4,4f-bi-p-pyridin-2-yl) -Nf- (5-chloro-2-methylbenzene ) Urea; N- (2-aspartyl-4,4 · -bi-pyridine-2-yl) -N '-(2-chloro-5-methylphenyl) urea; N_ (2- winter Amine_4,4'_bi-p-pyridin-2-yl) ^ '-(2_chloroethenyl) moon urine; N- (2'-aniline-4,4'-bi-p-pyridine-2 -Yl) -N '-(3-chloro-4-fluorophenyl) urea; N- (2_presentamino-4,4f-bi-p-pyridine-2-yl)-&gt; 1'-( 2,3,4-trifluorophenyl) urea; N- (2-benzyl-4,4f-bi-p-pyridin-2-yl) -N '-(4-butylbenzene ) Urea; N- (2'-aniline-4,4'-bipyridin-2-yl) -NH2-isopropyl-6-methylphenyl) urea; N- (2-dongamido-4 , 4 '· bi-p-biqi-2-yl) -N'-(2-third-butylphenyl) urea; 4-({[((2'-aniline-4,4'-bipyridine- 2-yl) amino] carbonyl} amino) benzoic acid methyl ester; N- (2'-aniline_4,4'_bi-p ratio lake-; 2-yl) -N '-(3,4- Dimethoxyphenyl) urea; N_ (2f • aniline_4,4'_bipyridin-2-yl) _N '-(3,5-dimethoxyphenyl) urea; N- (2f- Aniline-4,4f-bipyridin-2-yl) -NH3-chlorobendomethoxyphenyl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -N ' -[4- (difluoromethoxy) phenyl] urea; 89385 -10- 200417546 N- (2 '· aniline-4,4f-bipyridin-2-yl) -N42- (trifluoromethyl) Phenyl] urea; N- (2-Deramido-4,4f-bi-p-pyridin-2-yl) -Nf- [3- (difluoromethyl) phenyl] gallbladder; N- (2-D Winter Amine-4,4'-biyanido-2-yl) -N *-[4- (trifluoromethyl) phenyl] lunate urine; N- (2f-aniline-4, bipyridine-2- ) -NH2,5-dichlorophenyl) urea; N- (2f-aniline-4,4f-bipyridin-2-yl) · N '-(3,5-dichlorophenyl) urea; N -(2f-aniline- 4,4f-bipyridin-2-yl) · N '-(3,4-dichlorophenyl) urea; N- (2f-aniline-4,4'-bipyridin-2-yl) -N' -(2,3-dichlorophenyl) urea; N- (2'-anilino-4,4'_bipyridin-2-yl) -N '-(2,4-dichlorophenyl) urea; Ν- (2'-anilino-4,4f-bipyridin-2-yl) &gt; ΝΗ4-bromoylmethylphenyl) urea; N- (2f-anilino-4,4'-bipyridyl-2 -Yl) -N'2,6-dichloropyridinyl) urea; Ν- (2'-aniline_4,4'_bipyridin-2-yl) -N '-(4-butyl-2-methyl Phenyl) urea; N- (2'-aniline-4,4'-bipyridin-2-yl) -N45-methyl-2- (trifluoromethyl) furanyl] urea; 3- ( {[(2-Hydroxyamino-4,4 ^ exo-1: Yodo-2-yl) amino] Jinyl} amino) benzoic acid ethyl ester; N- (2'-aniline · 4,4 ' _Bipyridin-2-yl) -N '-(4-butoxyphenyl) urea; N- (2f-aniline_4,4' · bipyridin-2-yl) _N '_ (2,6 -Diisopropylphenyl) urea; N- (2f-aniline-4,4'_bipyridin-2-yl) -N '-(4-methylbenzyl) urea; N- (2'-aniline -4,4'_bipyridin-2-yl) -NH5-chloro-2,4-dimethoxyphenyl) urea; N- (2'-aniline-4,4f-bipyridine-2 -Kee -{4-[(trifluoromethyl) thio] phenyl} urea; N- (2f-aniline_4,4'_bipyridin-2-yl) -N43,5_bis (trifluoromethyl ) Phenyl] urea; 1-Ethyl-N- (2'-anilino-4,4'-bi-p ratio p-deoxy-2-yl) hexachloro p-pyridine-4-metanoic acid amine; N- (2_Deramido-4,4f-bi-p-pyridin-2-yl) -5-diaminopyridine; N-ethylg-monyl-N1-(2'-aniline-4,4 '-Bi-p-pyridin-2-yl)-/ 3-aminopropyl-donkey amine; 89385 -11-200417546 N- (2'-aspartyl-4,4'-bi-exo-b-yl-2-yl) Hexanitro p-pyridine-4-aminobenzylamine; 3-amino-N- (2 ^ aniline-4,4'-biyando-2-yl) butanoic acid amine; Ν- (2 ^ aniline -4,4L bipyridin-2-yl) -L-proline amide; N- (2f-aniline-4,4'-bipyridin-2-yl) acetamide; 2'-aniline-4 , 4 '· Bipyridin-2-ylaminocarbamate; N- (2'-aniline-4,4'-bipyridin-2-yl) methanesulfonamide; N- (2'-aniline -4,4'-bipyridin-2-yl) cyclohexanecarboxamide; 1-Ethyl-N- (2 · -anilino-4pyridinylpyridine-2-yl) hexahydro : Syndrome-2-Lean amine; ⑩ 1-ethynyl-N- (2f-anilino-4,4f-bi-p-pyridin-2-yl) hexahydro p-pyridin-3-induced S-amine 4-[(2'-anilino-4,4'-bipyridin-2-yl) amino] -4-ketobutyric acid ethyl ester; N- (2: anilino-4,4'-bi-p Biyodo-2-yl) tetrahydroquinan-2-fluorenamine; (S) -3 N2-ethylfluorenyl-Nl- (2'-aniline-4,4, -bipyridin-2-yl) Methionamine; N- (2f-anilino-4, cardiac bipyridin-2-yl) tetrahydro-2H-piperan-4-carboxamide; 3-[(2'-anilino-4, 4'-bipyridin-2-yl) amino] -3-ketopropanoic acid ethyl ester; N- (2L winter amino-4,4 ^ bi p-pyridine-2_yl) -3- (methylsulfide ) Propionic acid amine; (±) N- (2'-anilino-4,4'-bipyridin_2-yl) -2-tetrahydropyrrole-2-ylacetamidamine; _ (3S) -3 -Amino-N · (2'-anilino-4,4, -bipyridin-2-yl) -4-cyanobutylamidine; Nl- (2f-anilino-4,4f-bifoliate 1: Yodo-2-yl) cyclopropane-1,1 · dihydrofluorenamine; (3S) -1-ethanesulfonyl-N- (2f-benzylphenyl-4,4'-exo (: Yodo- 2-based) hexahydro ρ biyodo-3-benzylamine; N- (2f-anilino_4,4'_bi p biydan-2-yl) tetrahydrocran_3_carboxyamido ( +) With hydrazone; N- {24 (4-fluorophenyl) amino] · 4,4'_bipyridin-2_yl} tetrahydroanthran-3-amidine; Ν_ {2 '-[ (4-fluorophenyl) amino] -4,4'- Bipyridin-2-yl} tetrahydro-2'-pirandolamide; 89385 -12- 200417546 4-({2 ^ [(4- ^ phenyl) amino] -4,4f-bi-p-pyridine -2-yl} amino) -4-i isobutyric acid ethyl ester; 4-({2 '-[(4-fluorophenyl) amino] -4,4 | -bi ^?-2 -Yl} amino) -4-fluorenylbutanoic acid; N- {2f-[(4-fluorophenyl) amino] -4,4'-bipyridin-2-yl} -3- (methylthio ) Propanamide; (±) Smethylene-N- {24 (4-fluorophenyl) amino] -4,4'-bipyridin-2-yl} hexahydropyridine, each carboxyhydrazine; (3R ) Sm-ethenyl-N_ {2,-[(4-fluorophenyl) amino] -4,4, -bipyridin-2-yl} hexahydropyridine-3-faloxamine; (3S) small Ethyl-N- {2 '_ [(4-fluorophenyl) amino H, 4, -bipyridin_2_yl} hexahydroexocarboxidine, each carboxamidine; 1-Ethyl-N- {2,-[(4-fluorophenyl) amino] -4,4, _bipyridin-2-yl} tetrahydropyrrolidine carboxamide; 3- (amino group hindering group) good {2L [( 'Fluorophenyl) amino] -4,4, _bipyridine_2_yl> benzamidine; 2 _ {[(2'_benzylamino-4,4, -bipyridin-2-yl) Amine] methyl} cyclopropanecarboxylic acid ethyl ester; 2 '{[((2f-aniline_4,4, _bipyridin-2-yl) amino] methyl} cyclopropanecarboxylic acid; N-benzyl- N -(Tetrahydro_211-sulfan-4-ylmethyl) -4,4'-biazepine_2,2, _diamine; ΝBenzyl_N '-(tetrahydroquinan-3-yl Methyl) -4,4f-bi-ratio than bite-2,2, _diamine; as a free state base or salt. The compounds according to claim 1 or claim 2 are in the form of pharmaceutically acceptable salts. 14. A pharmaceutical formulation comprising a therapeutically effective amount of a compound in the scope of patent claims 1 or 2 as an active ingredient, accompanied by a pharmaceutically acceptable carrier or diluent. 89385 -13- 200417546 pharmaceutical formulations which contain, as an active ingredient, a therapeutically effective amount of a compound according to item 丨 or 2 of the scope of patent application, for the prevention and / or ’oral treatment of symptoms associated with JNK activation. 16. According to the scope of patent application! Or 2 compounds, which are used for treatment. 17. · A compound according to item 1 or 2 of the scope of the patent application is used for the manufacture of medicaments, and the medicaments are used to prevent and / or treat symptoms associated with activation. 18. · The use of a compound according to item 1 or 2 of the scope of patent application in the manufacture of a medicament for the prevention and / or treatment of a symptom selected from the group consisting of central or peripheral neurodegenerative disorders, including Alzheimer 'S disease, cognitive disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis 3 and osteoporosis Parkinson's type, Gaum's recurrence of Parkinson's dementia, HIV dementia, adrenal glands Basal degeneration, Boxer dementia, Down's syndrome, Parkinson's syndrome after encephalitis, Progressive supranuclear palsy, Pick's disease, Niemann-Pick's disease, Epilepsy, Peripheral neuropathy, Myeloid injury, Head injury Autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, asthma, septic shock, transplant rejection; heart and vascular diseases, including stroke, arteriosclerosis, myocardial infarction, myocardial reperfusion Injury; cancer, including breast, colorectal, pancreatic, prostate cancer. 19. Use according to item 18 of the scope of patent application, wherein the symptom is Alzheimer's disease. 20 · —The use of a compound according to item 1 or 2 of the scope of patent application in the manufacture of a medicament, the medicament is used for the prevention and / or treatment and inhibition of the expression of the protein that can cause pre-89385 -14-200417546 symptom. 21.-Use of a compound according to the scope of the patent application in the manufacture of a medicament for the prevention and / or treatment of symptoms, selected from the group consisting of edema, analgesia, fever and pain, such as nerve and muscle pain, headache, cancer Pain, toothache and arthritis pain ^ 22. A compound according to formula Η 其中R1為芳基或雜芳基，其每一個係視情況被一或多個 下列 R3、⑽、OCOR3、C00R3、c〇R3、c〇nr3r4、_咖3 、NR3R4、丽SO#、S〇2R3、S〇2Nr3r4、呢、⑶、_ 基 或1^02取代； R3與R4各獨立為氫、_基、Cm烷基，視情況被m3R4取 代之Ci_6烷基，C3_8環烷基、Ο3、烯基，視情況被^^^圮取 代之C3_6烯基，（C3_8環烷基）cw烷基、雜環、雜環6烷 基、Cu氟烷基，或者，nr3r4可形成具有3至7個原子之 環，該環視情況包含一或多個其他雜原子，視情況被一 或多個A取代； 八為q-6烷基或鹵基·， 作為自由態鹼或鹽。 23.—種化合物’其係為 89385 -15- 200417546 N-苯基-4,4f-聯ρ比唉_2,2，-二胺； N-(4-氟苯基）-4,4f-聯吡淀_2,二胺 作為自由態驗或鹽。 24· 一種根據申請專利範圍第22項 叫專利範圍第1或2項之式I化合物之用途 25. —種根據申請專利範圍第Μ項之化 利範圍第1或2項之式I化合物之用途 1旬很據申Wherein R1 is aryl or heteroaryl, each of them is optionally one or more of the following R3, fluorene, OCOR3, C00R3, cO3, conr3r4, _ca3, NR3R4, Li SO #, S. 2R3, S〇2Nr3r4, 呢, ⑶, _ or 1 ^ 02; R3 and R4 are each independently hydrogen, _, Cm alkyl, optionally Ci_6 alkyl substituted by m3R4, C3_8 cycloalkyl, 〇3, Alkenyl, optionally C3_6 alkenyl substituted by ^^^ 圮, (C3_8 cycloalkyl) cw alkyl, heterocyclic, heterocyclic 6alkyl, Cufluoroalkyl, or nr3r4 can be formed with 3 to 7 Atomic ring, which optionally contains one or more other heteroatoms, optionally substituted by one or more A; Eight is q-6 alkyl or halo, as a free state base or salt. 23.—A kind of compound 'its line is 89385 -15- 200417546 N-phenyl-4,4f-bi-ratio 唉 _2,2, -diamine; N- (4-fluorophenyl) -4,4f- Bipyridine_2, diamine is used as a free state test or salt. 24. Use of a compound of formula I according to item 22 of the scope of patent application, which is called item 1 or 2 of the patent scope 25.-Use of compound of formula I according to item scope 1 or 2 of the patent application, scope M It's very well 根據申請專According to application 89385 16- 200417546 柒、指定代表圖： (一) 本案指定代表圖為：第（ ）圖。 (二) 本代表圖之元件代表符號簡單說明： 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式:89385 16- 200417546 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) A brief description of the representative symbols of the components in this representative diagram: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 8938589385
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