TW201202242A - 6-(alkyl-or cycloalkyl-triazolopyridazine-sulfanyl)benzo-thiazole derivatives: preparation, and use as medicaments and as MET inhibitors - Google Patents

6-(alkyl-or cycloalkyl-triazolopyridazine-sulfanyl)benzo-thiazole derivatives: preparation, and use as medicaments and as MET inhibitors Download PDF

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TW201202242A
TW201202242A TW100110835A TW100110835A TW201202242A TW 201202242 A TW201202242 A TW 201202242A TW 100110835 A TW100110835 A TW 100110835A TW 100110835 A TW100110835 A TW 100110835A TW 201202242 A TW201202242 A TW 201202242A
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group
cyclopropyl
triazolo
sulfanyl
alkyl
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TW100110835A
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Chinese (zh)
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Eric Bacque
Dominique Damour
Conception Nemecek
Antonio Ugolini
Sylvie Wentzler
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Sanofi Aventis
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Priority claimed from FR1052367A external-priority patent/FR2958292A1/en
Priority claimed from FR1058393A external-priority patent/FR2966151B1/en
Application filed by Sanofi Aventis filed Critical Sanofi Aventis
Publication of TW201202242A publication Critical patent/TW201202242A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Abstract

The invention relates to the novel products of formula (I): with R1 representing alkyl, cycloalkyl or cycloalkylalkyl; Rb representing a hydrogen atom or a fluorine atom W representing H; alkyl, cycloalkyl, heterocycloalkyl or COR with R representing cycloalkyl, heterocycloalkyl, alkyl; alkoxy, -O-heterocycloalkyl; or NHR2 with R2 representing H, cycloalkyl, heterocycloalkyl or alkyl; all optionally substituted; these products being in any isomer form, and the salts thereof, as medicaments, especially as MET inhibitors.

Description

201202242 六、發明說明: 【發明所屬之技術領域】 本發明係關於新穎6-(烷基-或環烷基_***并嗒畊_硫烷 基)苯并噻唑衍生物、其製備方法、所得新穎中間物、其 作為藥物之用途、含有其之醫藥組合物及該等6_***并塔 哨"·硫烧基苯并〇塞唾衍生物之新穎用途。 本發明更特定言之係關於經由調節蛋白質、尤其激酶之 活性而具有抗癌活性之新穎6·(烷基_或環烷基_***并嗒 p井-硫烧基)苯并。塞〇坐衍生物。 【先前技術】 迄今為止,化學療法中所用之大多數市售化合物具有細 胞毒性,且對患者造成副作用及耐受性之嚴重問題。若所 用藥物選擇性地作用於癌細胞而排除健康細胞,則此等作 用可爻限制。因此,限制化學療法之不適宜作用的一種解 決方案可在於使用作用於代謝路徑或此等路徑中主要表現 在癌細胞中而不會表現或僅少量地表現在健康細胞中的組 成成分的藥物。激酶蛋白為催化特異性蛋白質殘基(諸如 酪胺酸、絲胺酸或蘇胺酸殘基)之羥基磷酸化的酶家族。 該等鱗8文化可在很大程度上改變蛋白質之功能:因此,激 S#蛋白在調節夕種細胞過程(尤其包括細胞代謝及增瘦、 細胞黏著及運動、細胞分化或細胞存活)中起重要作用, 特定激酶蛋白在細胞週期事件之起始、發展及完成中起主 要作用》 在激酶蛋白之活性參與之各種細胞功能中,特定過程提 154635.doc 201202242 疾病之具吸引力之〜可尤其提及之實例包 S纟及控制細胞週期以及細胞增殖,以激酶蛋白 ^主要作用。此等過程為實體腫瘤以及其他疾病之生長 ”必需.誶言之’抑制該等激酶之分子能夠限制不適宜 之細胞增殖(諸如癌症中觀察到之細胞增殖),且可干涉神 經退化性疾病(諸如阿茲海默氏病(Alzhei贿,s…咖)或 神經兀凋亡)之預防、調節或治療。 【發明内容】 本發明之一標的為對激酶蛋白具有抑制作用之新穎衍生 物。因此’本發明之產物可尤其用於預防或治療可藉由抑 制激酶蛋白而調節之疾病。 本發明之產物經由調節激酶活性尤其展示抗癌活性。需 要調節活性之激酶中,MET以及蛋白f ΜΕτ之突變體為較 佳。 本發明亦關於該等衍生物用於製備供治療人類用之藥物 的用途。 因此,本發明之一目的在於提出因尤其作用於激酶而具 有抗癌活性之組合物。需要調節活性之激酶中,MET為較 佳0 在以下藥理學部分中,生物化學測試中及細胞株上展示 本專利申請案之產物因此尤其抑制MET之自體磷酸化活性 及生長取決於MET或其突變形式之細胞的增殖。 MET或肝細胞生長因子受體為具有酪胺酸激酶活性之受 體’其尤其表現在上皮及内皮細胞中。HGF,肝細胞生長 154635.doc 201202242 因子,描述為MET之特異性配位體。HGF由間葉細胞分泌 且活化MET受體,從而使MET受體均二聚。因此,受體在 催化域之酪胺酸Y1230、Y1234及Y1 235上變得自體磷酸 化。 用HGF刺激MET會誘發細胞增殖、擴散(或分散)及運 動、抗凋亡、侵襲及血管生成。 發現MET以及HGF過度表現於許多人類腫瘤及多種癌症 中。亦發現MET在胃腫瘤及膠質母細胞瘤中擴增。亦描述 腫瘤中,尤其激酶域中,以及近膜域及SEMA域中有MET 基因之許多點突變。過度表現、擴增或突變使得受體可經 組成性活化且使其功能去調節。 因此,本發明尤其係關於激酶蛋白MET及其突變體之新 穎抑制劑,其可用於抗增殖及抗轉移治療,尤其腫瘤學 中 〇 本發明亦關於激酶蛋白MET及其突變體之新穎抑制劑, 其可用於抗血管生成治療,尤其腫瘤學中。 本發明之一標的為式(I)產物:201202242 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel 6-(alkyl- or cycloalkyl-triazolo-indole-sulfanyl)benzothiazole derivatives, a process for the preparation thereof, and the like. Novel intermediates, their use as pharmaceuticals, pharmaceutical compositions containing the same, and novel uses of such 6-3-triazolidine sulphur benzopyrene derivatives. More specifically, the present invention relates to novel 6(alkyl- or cycloalkyl-triazoloindole-sulphur-sulfonyl) benzoates having anticancer activity via modulation of the activity of proteins, particularly kinases. The scorpion sits on a derivative. [Prior Art] To date, most of the commercially available compounds used in chemotherapy have been cytotoxic, and have serious problems of side effects and tolerance to patients. If the drug used selectively acts on cancer cells to exclude healthy cells, then these effects can be limited. Thus, one solution to limit the unsuitable effects of chemotherapy may be to use drugs that act on metabolic pathways or components of such pathways that are predominantly expressed in cancer cells without exhibiting or exhibiting only a small amount in healthy cells. A kinase protein is a family of enzymes that catalyze the hydroxy phosphorylation of specific protein residues such as tyrosine, serine or threonine residues. These scale 8 cultures can largely alter the function of proteins: therefore, the S# protein plays a role in the regulation of the germ cell process (especially including cell metabolism and lean, cell adhesion and movement, cell differentiation or cell survival). Important role, specific kinase protein plays a major role in the initiation, development and completion of cell cycle events. Among the various cellular functions involved in the activity of kinase protein, the specific process is 154635.doc 201202242 The attractiveness of the disease~ The examples mentioned include the regulation of cell cycle and cell proliferation, with the main role of kinase protein. These processes are essential for the growth of solid tumors and other diseases. In other words, the molecules that inhibit these kinases can limit inappropriate cell proliferation (such as cell proliferation observed in cancer) and can interfere with neurodegenerative diseases ( Prevention, modulation or treatment of, for example, Alzheimer's disease (Alzhei bribe, s... coffee) or neural crest apoptosis. [Abstract] One of the present invention is a novel derivative having an inhibitory effect on kinase proteins. The product of the present invention is particularly useful for the prevention or treatment of diseases which can be modulated by inhibition of kinase proteins. The products of the present invention, in particular, exhibit anticancer activity via regulation of kinase activity. Among the kinases which require modulation of activity, MET and protein f ΜΕτ Mutants are preferred. The present invention also relates to the use of such derivatives for the preparation of a medicament for the treatment of humans. Accordingly, it is an object of the present invention to provide a composition having anticancer activity by acting particularly on a kinase. Among the kinases that regulate activity, MET is preferred. In the following pharmacology, biochemical tests and cell lines are displayed. The product of the application thus inhibits, inter alia, the autophosphorylation activity and growth of MET depending on the proliferation of cells of MET or its mutated form. MET or hepatocyte growth factor receptor is a receptor with tyrosine kinase activity' It is expressed in epithelial and endothelial cells.HGF, hepatocyte growth 154635.doc 201202242 factor, described as a specific ligand for MET. HGF is secreted by mesenchymal cells and activates the MET receptor, thereby dimerizing the MET receptor. Thus, the receptor becomes autophosphorylated on the tyrosine acids Y1230, Y1234 and Y1 235 in the catalytic domain. Stimulation of MET with HGF induces cell proliferation, proliferation (or dispersion) and movement, anti-apoptosis, invasion and angiogenesis. It has been found that MET and HGF are overexpressed in many human tumors and various cancers. It has also been found that MET is amplified in gastric tumors and glioblastomas. It is also described in tumors, especially in the kinase domain, as well as in the juxtamembrane and SEMA domains. Many point mutations in the MET gene. Excessive expression, amplification or mutation allows the receptor to be constitutively activated and its function to be regulated. Thus, the present invention relates in particular to the kinase protein MET and its Novel inhibitors of the body which are useful in anti-proliferative and anti-metastatic treatments, particularly in oncology. The present invention also relates to novel inhibitors of kinase protein MET and its mutants, which are useful in anti-angiogenic therapy, particularly oncology. One of the objects of the invention is the product of formula (I):

其中 R1表示烷基、環烷基或環烷基烷基;視情況如下所示經 154635.doc 201202242Wherein R1 represents an alkyl group, a cycloalkyl group or a cycloalkylalkyl group; as the case may be as follows: 154635.doc 201202242

Rb表示氫原子或氟原子; w表示氫原子;烷基、環烷基或雜環烷基,視情況經烷 基、烷氧基、雜環烷基或NR3R4基團取代,該等基團自身 視情況如下所示經取代;或基團C〇R,其中R表示: -環院基、雜環烷基或烷基’均視情況經一或多個選自 氫原子、羥基、烷基及烷氧基及環烷基、雜環烷基、 雜芳基、苯基及NR3R4基團之基團取代,該等基團自 身視情況如下所示經取代; -烧氧基,視情況經烷基、雜環烷基或NR3R4取代,該 等基團自身視情況如下所示經取代;或基團_〇_雜環 烷基’視情況如下所示經取代; -或基團NHR2,其中R2表示氫原子或環烷基、雜環烷 基或烷基,均視情況經一或多個可相同或不同且選自 經基及烧氧基及雜環烧基、雜芳基、苯基及Nr3r4基 團之基團取代,該等基團自身視情況如下所示經取 代; -其中R3及R4可相同或不同,選自氫原子及烷基、環 烷基、雜環烷基、雜芳基及苯基,均視情況經一或多 個可相同或不同且選自羥基、烷氧基、NH2、NH烷 基、N(烷基)2、雜環烷基、雜芳基及苯基的基團取 代,該等取代基團自身視情況如下所示經取代;或者 R3及R4與其所連接之氮原子一起形成3至1〇員環狀基 團其視情況含有一或多個選自〇、s、N及NH之其 他雜原子,其中該視情況存在之§可能為8〇或3〇2形 154635.doc 201202242 式’此基團’包括其可能含有之任何NH,視情況如 下所示經取代; 上文定義之所有該等烷基、環烷基、雜環烷基、-0-雜 環烷基、雜芳基及苯基、及R3AR4與其所連接之氮原子 一起可形成之該等環狀基團視情況經一或多個選自以下之 基團取代:鹵素原子、羥基、側氧基(〇χ〇)、烷氧基、-〇_ CO-R5、-COOH、COOR5、-CONH2、CONHR5、ΝΗ2、 NHR5、NR5R5’、-NH-CO-R5 及-S02-烷基-基團、及烷 基、環烷基、雜環烷基、烷基-雜環烷基、CO-雜環烷基、 苯基、CH2-苯基、c〇-苯基、雜芳基及S-雜芳基,使得在 該等取代基團中’該等烷基、烷氧基、環烷基、雜環烷 基、苯基及雜芳基自身視情況經一或多個選自_素原子及 羥基、側氧基、烷基、環烷基、環烷基烷基及含有1至4個 碳原子之烷氧基、ΝΗ2、ΝΗ烷基及Ν(烷基)2的基團取代, 上文定義之所有該等環烷基、雜環烷基、-0-雜環烷 基、雜芳基及苯基亦視情況經基團Si(烷基)3取代; 上文定義之所有該等環烷基及雜環烷基可在環之一個碳 上經螺環烷基或螺雜環烷基取代,或視情況在環之兩個碳 上經稠合之環烷基或雜環烷基取代; R5及R5'可相同或不同,表示烷基或環烷基,視情況經 一或多個選自自素原子及羥基、含有1至4個碳原子之烷基 及烷氧基、NH2、NH烷基及N(烷基)2的基團取代, 該等烷基表示含有1至10個碳原子之烷基; 該等環烷基含有至多3至7個碳原子; 154635.doc 201202242 該等式(!)產物為任何可m肖旋、對映異構或非對映 異構性異構體形式,以及該等式(1)產物與無機及有機酸或 與無機及有機鹼之加成鹽。 本發明之-標的亦為如上文或下文所定義之式⑴產物, 其中 R1表示烷基、環烷基或環烷基烷基;視情況如下所示經 取代;Rb represents a hydrogen atom or a fluorine atom; w represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by an alkyl group, an alkoxy group, a heterocycloalkyl group or an NR3R4 group, and the groups themselves Substituting as shown below; or a group C〇R, wherein R is: - a ring-based group, a heterocycloalkyl group or an alkyl group, as the case may be selected from one or more selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group and Substituted by alkoxy and cycloalkyl, heterocycloalkyl, heteroaryl, phenyl and NR3R4 groups, the groups themselves being substituted as shown below; - alkoxy, optionally via an alkane Substituted, heterocycloalkyl or NR3R4 substituted, such groups are themselves substituted as follows; or the group _〇_heterocycloalkyl' is substituted as follows; or the group NHR2, wherein R2 And a hydrogen atom or a cycloalkyl group, a heterocycloalkyl group or an alkyl group, which may, depending on the case, be one or more selected from the group consisting of a peroxy group and an alkoxy group, a heterocyclic group, a phenyl group and Substituting a group of the Nr3r4 group, the groups themselves are optionally substituted as follows; wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and an alkyl group And a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group and a phenyl group, which may be the same or different one or more selected from the group consisting of a hydroxyl group, an alkoxy group, an NH2, an NH alkyl group, and an N (alkyl group) 2 Substituted with a heterocycloalkyl, heteroaryl and phenyl group, the substituents themselves being substituted as shown below; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 1 ring The group optionally contains one or more other heteroatoms selected from the group consisting of ruthenium, s, N and NH, wherein the § may optionally be 8 〇 or 3 〇 2 154 635.doc 201202242 Formula 'this group' Including any NH which it may contain, as the case may be substituted as follows; all such alkyl, cycloalkyl, heterocycloalkyl,-0-heterocycloalkyl, heteroaryl and phenyl groups, as defined above, And the cyclic group which R3AR4 may form together with the nitrogen atom to which it is attached may be optionally substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group. , -〇_CO-R5, -COOH, COOR5, -CONH2, CONHR5, ΝΗ2, NHR5, NR5R5', -NH-CO-R5 and -S02-alkyl- group, and alkyl, ring Group, heterocycloalkyl, alkyl-heterocycloalkyl, CO-heterocycloalkyl, phenyl, CH2-phenyl, c〇-phenyl, heteroaryl and S-heteroaryl, such that In the substituent group, 'the alkyl group, alkoxy group, cycloalkyl group, heterocycloalkyl group, phenyl group and heteroaryl group are themselves optionally selected from one or more selected from the group consisting of a _ atom and a hydroxy group, a pendant oxy group, and an alkane. a group of a cycloalkyl group, a cycloalkylalkyl group, and an alkoxy group having 1 to 4 carbon atoms, an anthracene 2, a decyl group, and a fluorenyl (alkyl) 2 group, all of which are defined above. Alkyl, heterocycloalkyl,-0-heterocycloalkyl, heteroaryl and phenyl are also optionally substituted by the group Si(alkyl)3; all such cycloalkyl and heterocycloalkyl groups as defined above Substituting a spirocycloalkyl or spiroheterocycloalkyl group on one carbon of the ring or, optionally, a fused cycloalkyl or heterocycloalkyl group on the two carbons of the ring; R5 and R5' may be the same Or different, meaning alkyl or cycloalkyl, optionally with one or more alkyl and alkoxy groups selected from the group consisting of a self atom and a hydroxyl group, having 1 to 4 carbon atoms, NH2, NH alkyl and N (alkane) Substituted by a group of 2), the alkyl group represents 1 An alkyl group of up to 10 carbon atoms; the cycloalkyl group contains up to 3 to 7 carbon atoms; 154635.doc 201202242 The product of the equation (!) is any m-co-rotation, enantiomeric or diastereomeric The conformational isomer form, and the addition salt of the product of the formula (1) with inorganic and organic acids or with inorganic and organic bases. The subject matter of the invention is also a product of formula (1) as defined above or below, wherein R1 represents alkyl, cycloalkyl or cycloalkylalkyl; optionally substituted as indicated below;

Rb表示氫原子或氟原子; W表示氫原子n⑽基或雜環㈣,視情況經烧 基、烷氧基、雜環烷基或NR3R4基團取代,該等基團自身 視情況如下所示經取代;或基團c〇R,其中R表示: -¼烷基、雜環烷基或烷基,視情況經一或多個選自氫 原子、羥基、烷基及烷氧基及環烷基、雜環烷基、雜芳 基、苯基及NR3R4基團之基團取代,該等基團自身視情況 如下所示經取代; 烧氧基,視情況經雜環院基或NR3R4取代,該等基團 自身視情況如下所示經取代;或基團雜環烷基,視情 況如下所示經取代; -或基團NHR2 ’其中R2表示氫原子或環烷基、雜環烷基 . 或烷基,均視情況經一或多個可相同或不同且選自羥基及 烷氧基及雜環烷基、雜芳基、苯基&NR3R4基團之基團取 代,所有該等基團均視情況如下所示經取代; 其中R3及R4可相同或不同,選自氫原子及烷基、環烷 基、雜環烷基及苯基,均視情況經一或多個可相同或不同 154635.doc 201202242 且選自羥基、烷氧基、NH2、NH烷基及N(烷基)2基團、及 雜環烷基、雜芳基及苯基的基團取代,該等取代基團自身 視情況如下所示經取代;或者R3及R4與其所連接之氮原 子一起形成3至10員環狀基團,其視情況含有一或多個選 自Ο、S、N及NH之其他雜原子,其中該視情況存在之S可 能為SO或S02形式’此基團’包括其可能含有之任何 NH ’視情況如下所示經取代; 上文定義之所有該等烷基、環烷基、雜環烷基、_〇_雜 環烷基、雜芳基及苯基、及们及以與其所連接之氮原子 一起可形成之該等環狀基團視情況經一或多個選自以下之 基團取代:鹵素原子、羥基、側氧基、烷氧基、_〇_c〇_ R5、NH2、 NH烷基、N(烷基)2及-S02-烷基、及烷基、環 烷基、雜環烷基、CH2-雜環烷基、苯基、CH2_苯基、c〇_ 苯基、雜芳基及S-雜芳基,使得在該等取代基團中,該等 烷基、烷氧基、環烷基、雜環烷基、苯基及雜芳基自身視 情況經一或多個選自齒素原子及羥基、側氧基、含有丨至4Rb represents a hydrogen atom or a fluorine atom; W represents a hydrogen atom n(10) group or a heterocyclic ring (tetra), and is optionally substituted with an alkyl group, an alkoxy group, a heterocycloalkyl group or an NR3R4 group, and the groups themselves are as follows Substituent; or a group c〇R, wherein R represents: -1⁄4 alkyl, heterocycloalkyl or alkyl, optionally one or more selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group and an alkoxy group, and a cycloalkyl group. Substituted by a heterocycloalkyl, heteroaryl, phenyl and NR3R4 group, the groups themselves being substituted as shown below; alkoxy groups, optionally substituted by a heterocyclic or NR3R4, The group itself is optionally substituted as shown below; or the group heterocycloalkyl, as the case may be substituted; or the group NHR2 ' wherein R 2 represents a hydrogen atom or a cycloalkyl group, a heterocycloalkyl group or Alkyl groups, all optionally substituted by one or more groups which may be the same or different and selected from the group consisting of hydroxy and alkoxy and heterocycloalkyl, heteroaryl, phenyl &NR3R4 groups, all such groups Substituted as follows; wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and an alkyl group, a cycloalkyl group, a heterocycloalkyl group Phenyl group, which may be the same or different, depending on the case, 154635.doc 201202242 and selected from the group consisting of hydroxyl, alkoxy, NH2, NH alkyl and N(alkyl) 2 groups, and heterocycloalkyl, hetero Substituting aryl and phenyl groups, the substituents themselves are optionally substituted as shown below; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 10 membered cyclic group, optionally containing one Or a plurality of other heteroatoms selected from the group consisting of ruthenium, S, N and NH, wherein the optionally present S may be in the form of SO or S02 'this group' includes any NH which may be contained as appropriate All of the alkyl, cycloalkyl, heterocycloalkyl, 〇-heterocycloalkyl, heteroaryl and phenyl groups defined above, and the same may be formed with the nitrogen atom to which they are attached The cyclic group is optionally substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group, _〇_c〇_R5, NH2, an NH alkyl group, and an N group. And 2, -S02-alkyl, and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2_phenyl, c〇_phenyl, heteroaryl S-heteroaryl, such that in the substituents, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups are themselves optionally selected from one or more teeth Atom and hydroxyl, pendant oxy, containing 丨 to 4

烷基及N(烷基)2的基團取代; R5表示烧基或環烧基;a group substituted by an alkyl group and an N(alkyl) 2 group; R5 represents a alkyl group or a cycloalkyl group;

與無機及有機鹼之加成鹽。Addition salts with inorganic and organic bases.

其中R1具有任一 Rb表示 標的亦為如上文或下文所定義之3 ‘一其他技術方案中所定義之意義 154635.doc •】0. 201202242 氫原子或氟原子,且w表示氫原子;烷基、環烷基或雜環 烷基,視情況經視情況如下所示經取代之烷基、雜環烷基 或NR3R4基團取代;或基團c〇r,其中R表示: -%烷基、雜環烷基或烷基,視情況經烷基、雜環烷基 或NR3R4基團取代,該等基團自身視情況如下所示經 取代; -烷氧基,視情況經雜環烷基或NR3R4*團取代,該等 基團自身視情況如下所示經取代;或〇_雜環烷基,視 情況如下所示經取代; -或基團NHR2,其中R2表示氫原子或烷基,視情況經 雜環烷基或NR3R4取代;該等基團自身視情況如下所 示經取代; 其中R3及R4可相同或不同,選自氫原子及烷基、環烷 基及雜環烷基,視情況經一或多個可相同或不同且選自烷 氧基、雜環烷基、NH2、NH烷基及N(烷基)2基團之基團取 代;或者R3及R4與其所連接之氮原子一起形成3至7員環 狀基團,其視情況含有一或多個選自〇及NH之其他雜原 子,此基團,包括其所含之視情況存在之NH,視情況如 下所示經取代; 上文疋義之所有該等烷基、雜環烷基及雜環烷基、 及R3及R4與其所連接之氮原子一起可形成之該等環狀基 團視情況經一或多個選自以下之基團取代:鹵素原子、羥 基、烷氧基、NH2、NH烷基、N(烷基)2及-S02-烷基、及 烷基、壤烷基、雜環烷基、CH2_雜環烷基、苯基、eH2_ 154635.doc • 11 - 201202242 苯基及雜芳基,使得在該等取代基團中,該等烷基、烷氧 基、環烷基、雜環烷基、苯基及雜芳基自身視情況經一或 多個選自鹵素原子及羥基、含有丨至4個碳原子之烷基及烷 氧基、環烷基、環烷基烷基、NH2、NH烷基及N(烷基)2的 基團取代; 該等式(I)產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機鹼之加成鹽。 本發明之一標的亦為如上文所定義之式⑴產物,其中: R1表示烷基、環烷基或環烷基烷基;視情況如下所示經 取代;Wherein R1 has any Rb represents a target and is also defined as defined above or below 3'. The meaning as defined in the other technical schemes 154635.doc • 0. 201202242 Hydrogen or fluorine atom, and w represents a hydrogen atom; a cycloalkyl or heterocycloalkyl group, optionally substituted with an alkyl, heterocycloalkyl or NR3R4 group as indicated below; or a group c〇r, wherein R represents: -% alkyl, a heterocycloalkyl or alkyl group, optionally substituted by an alkyl, heterocycloalkyl or NR3R4 group, which groups are themselves substituted as follows; - alkoxy, optionally heterocycloalkyl or Substituted NR3R4* group, the groups themselves are optionally substituted as follows; or 〇_heterocycloalkyl, as the case may be substituted as follows; - or the group NHR2, wherein R2 represents a hydrogen atom or an alkyl group, The case is substituted with a heterocycloalkyl group or NR3R4; the groups are themselves substituted as follows; wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and an alkyl group, a cycloalkyl group and a heterocycloalkyl group, The one or more may be the same or different and are selected from the group consisting of alkoxy, heterocycloalkyl, NH2, NH alkyl Substituting a group of the N(alkyl) 2 group; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 7 membered cyclic group, optionally containing one or more other impurities selected from the group consisting of hydrazine and NH. Atom, this group, including the NH as it is contained, is optionally substituted as follows; all such alkyl, heterocycloalkyl and heterocycloalkyl groups, and R3 and R4, as defined above The cyclic groups which may be formed together with the nitrogen atom to which they are attached are optionally substituted with one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, alkoxy groups, NH2, NH alkyl groups, N (alkyl groups). 2 and -S02-alkyl, and alkyl, tert-alkyl, heterocycloalkyl, CH2_heterocycloalkyl, phenyl, eH2_ 154635.doc • 11 - 201202242 phenyl and heteroaryl, such that In the substituent group, the alkyl group, the alkoxy group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group and the heteroaryl group are themselves optionally selected from one or more selected from the group consisting of a halogen atom and a hydroxyl group, and containing yttrium to 4 carbons. Substituted by an alkyl group of an atom and an alkoxy group, a cycloalkyl group, a cycloalkylalkyl group, an NH2, an NH alkyl group, and an N(alkyl) 2 group; the product of the formula (I) is any Outside racemic, enantiomeric or diastereomeric isomer forms, as well as the equation ⑴ addition salts with mineral and organic acids or with inorganic and organic bases of. A subject of the invention is also a product of formula (1) as defined above, wherein: R1 represents alkyl, cycloalkyl or cycloalkylalkyl; optionally substituted as indicated below;

Rb表示氫原子或氟原子; —w表不氫原子;烷基、環烷基或雜環烷基,視情況經烷 氧基、雜㈣基或NR3R4錢取代,該等基團自身視情況 如下所示經取代;或基團COR,其中R表示: -環烷基、雜環烷基或烷基(CH3),均視情況經一或多 個選自_素原子、羥基及烷氧基、及環烷基、雜環烷 基雜芳基、苯基及NR3R4基團之基團取代,該等基 團自身視情況如下所示經取代; 烷氧基,視情況經烷基、雜環烷基或NR3R4取代,該 等基團自身視情況如下所示經取代;或基團-0-雜環 烷基,視情況如下所示經取代; -或基團NHR2,其中R2表示氫原子或我基、雜環烧 基或烷基,均視情況經一或多個可相同或不同且選自 154635.doc •12· 201202242 羥基及烷氧基及雜環烷基、雜芳基、苯基及NR3R4基 團之基團取代,該等基團自身視情況如下所示經取 代; -其中R3及R4可相同或不同,選自氫原子及烷基、環 烷基、雜環烷基、雜芳基及苯基,均視情況經一或多 個可相同或不同且選自羥基、烷氧基、NH2、NH烷 基、N(烷基)2、雜環烷基、雜芳基及苯基的基團取 代,該等取代基團自身視情況如下所示經取代;或者 R3及R4與其所連接之氮原子一起形成3至10員環狀基 團(4,5,6),其視情況含有一或多個選自Ο、S、N及NH 之其他雜原子,其中該視情況存在之S可能為SO或 S02形式;此基團,包括其可能含有之任何NH,視情 況如下所示經取代; 上文定義之所有該等烷基、環烷基、雜環烷基、-0-雜 環烷基、雜芳基及苯基、及R3及R4與其所連接之氮原子 一起可形成之該等環狀基團視情況經一或多個選自以下之 基團取代:鹵素原子、羥基、側氧基、烷氧基、-0-(:0-R5、-COOH、C00R5、-C0NH2、CONHR5、NH2、 NHR5、NR5R5'及-NH-C0-R5基團、及烷基、環烷基、雜 環烷基、烷基-雜環烷基、C0-雜環烷基、苯基、CH2-苯 基、C0-苯基、雜芳基及S-雜芳基,使得在該等取代基團 中,該等烷基、環烷基、雜環烷基、苯基及雜芳基自身視 情況經一或多個選自li素原子及羥基、側氧基、含有1至4 個碳原子之烷基、環烷基及烷氧基、NH2、NH烷基及 154635.doc •13· 201202242 N(貌基)2的基團取代, 上文定義之所有該等環烷基、雜環烷基、-Ο-雜環烷 基、雜芳基及苯基亦視情況經基團Si(烷基取代; 上文定義之所有該等環烷基及雜環烷基可在環之一個碳 上經螺環烷基或螺雜環烷基取代,或視情況在環之兩個碳 上經桐合之環烷基或雜環烷基取代; R5及R5’可相同或不同,表示烷基或環烷基,視情況經 一或多個選自齒素原子及羥基、含有丨至4個碳原子之烷基 及烧氧基、NH2、NH烷基及N(烷基)2的基團取代, 該等院基表示含有1至10個碳原子之烷基; 該等環烷基含有至多3至7個碳原子; 該等式⑴產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機鹼之加成鹽。 因此’本發明之一標的為如上文所定義之式⑴產物,其 中: R1表示烷基、環烷基或環烷基烷基;視情況如下所示經 取代;Rb represents a hydrogen atom or a fluorine atom; -w represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by an alkoxy group, a hetero (tetra) group or an NR3R4 group, and the groups themselves are as follows Substituted as shown; or a group COR, wherein R represents: a cycloalkyl, heterocycloalkyl or alkyl (CH3) group, optionally containing one or more selected from the group consisting of a _ s atom, a hydroxy group and an alkoxy group, And a group substituted with a cycloalkyl, heterocycloalkylheteroaryl, phenyl and NR3R4 group, the groups themselves being substituted as shown below; alkoxy, optionally alkyl, heterocycloalkane Substituted or substituted by NR3R4, the groups themselves are optionally substituted as shown below; or the group -0-heterocycloalkyl, as the case may be substituted as follows; - or the group NHR2, wherein R2 represents a hydrogen atom or me a group, a heterocyclic alkyl group or an alkyl group, which may be the same or different, and optionally selected from the group consisting of 154635.doc •12·201202242 hydroxy and alkoxy and heterocycloalkyl, heteroaryl, phenyl and Substituting a group of the NR3R4 group, the groups themselves are optionally substituted as follows; wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and An alkyl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, and a phenyl group, which may be the same or different, and optionally selected from the group consisting of a hydroxyl group, an alkoxy group, an NH2, an NH alkyl group, and an N (alkyl group). 2, a heterocyclic alkyl group, a heteroaryl group, and a phenyl group substituted, the substituent groups themselves being substituted as shown below; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 10 membered ring a group (4, 5, 6), which optionally contains one or more other heteroatoms selected from the group consisting of ruthenium, S, N and NH, wherein the optionally present S may be in the form of SO or S02; this group , including any NH which it may contain, as the case may be substituted as follows; all such alkyl, cycloalkyl, heterocycloalkyl,-0-heterocycloalkyl, heteroaryl and phenyl groups as defined above And the cyclic group which R3 and R4 may form together with the nitrogen atom to which they are attached may be optionally substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group, 0-(:0-R5, -COOH, C00R5, -CONH2, CONHR5, NH2, NHR5, NR5R5' and -NH-C0-R5 groups, and alkyl, cycloalkyl, heterocycloalkyl, alkyl- Heterocyclene , C0-heterocycloalkyl, phenyl, CH2-phenyl, C0-phenyl, heteroaryl and S-heteroaryl, such that among the substituents, the alkyl, cycloalkyl, hetero The cycloalkyl, phenyl and heteroaryl groups, by themselves, are optionally selected from one or more selected from the group consisting of a halogen atom and a hydroxyl group, a pendant oxy group, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group and an alkoxy group, NH2. , NH alkyl and 154635.doc • 13· 201202242 N (Focus) 2 group substitution, all such cycloalkyl, heterocycloalkyl, -Ο-heterocycloalkyl, heteroaryl as defined above And a phenyl group, optionally substituted by a group Si (alkyl; all of the cycloalkyl and heterocycloalkyl groups defined above may be substituted on a carbon of the ring via a spirocycloalkyl or spiroheterocycloalkyl group, Or optionally substituted with a cycloalkyl or heterocycloalkyl group on the two carbons of the ring; R5 and R5' may be the same or different and represent an alkyl or cycloalkyl group, optionally selected from one or more Substituted by a dentate atom and a hydroxyl group, an alkyl group having from 丨 to 4 carbon atoms, and an alkoxy group, NH2, NH alkyl group, and N(alkyl) 2 group, the group representing 1 to 10 carbon atoms Alkyl group There are up to 3 to 7 carbon atoms; the product of the formula (1) is in any possible racemic, enantiomeric or diastereomeric form, and the product of the formula (1) and inorganic and organic acids or Addition salts with inorganic and organic bases. Thus, 'one of the inventions' is a product of formula (1) as defined above, wherein: R1 represents alkyl, cycloalkyl or cycloalkylalkyl; optionally substituted as indicated below;

Rb表示氫原子或氟原子; W表示氫原子;烷基、環烷基或雜環烷基,視情況經烷 氧基、雜環烷基或NR3R4基團取代,該等基團自身視情況 如下所示經取代;或基團COR,其中R表示: -環烧基、雜環烧基或烧基,均視情況經一或多個選自 鹵素原子、羥基及烷氧基、及環烷基、雜環烷基、雜 154635.doc -14- 201202242 芳基、苯基及NR3R4基團之基團取代,該等基團自身 視情況如下所示經取代; _烷氧基,視情況經烷基、雜環烷基或NR3R4取代,該 等基團自身視情況如下所示經取代;或基團-〇_雜環 院基,視情況如下所示經取代; _或基團NHR2,其中R2表示氫原子或環烷基、雜環烷 基或烧基,均視情況經一或多個可相同或不同且選自 羥基及烷氧基及雜環烷基、雜芳基、苯基及NR3R4基 團之基團取代,該等基團自身視情況如下所示經取 代; -其中R3及R4可相同或不同,選自氫原子及烷基、環 烧基、雜環烧基、雜芳基及苯基,均視情況經一或多 個可相同或不同且選自羥基、烷氧基、NH2、NH烷 基、N(烷基)2、雜環烷基、雜芳基及苯基的基團取 代’該等取代基團自身視情況如下所示經取代;或者 R3及R4與其所連接之氮原子一起形成3至1〇員環狀基 團,其視情況含有一或多個選自〇、S、N及NH之其 他雜原子’其中該視情況存在之S可能為s〇或S02形 式;此基團,包括其可能含有之任何NH,視情況如 下所示經取代; 上文所定義之所有該等烷基、環烷基、雜環烷基、_〇_ 雜環烷基、雜芳基及苯基、及R3及R4與其所連接之氮原 子一起可形成之該等環狀基團視情況經一或多個選自以下 之基團取代:鹵素原子、羥基、側氧基、烷氧基、-0-C0- 154635.doc -15· 201202242 R5、-COOH、COOR5、-CONH2、CONHR5、NH2、 NHR5、NR5R5’及_NH-CO_R5基團、及烷基、環烷基、雜 環烧基、烷基-雜環烷基、CO-雜環烷基、苯基、CH2-苯 基、CO-苯基、雜芳基及S-雜芳基,使得在該等取代基團 中,該等烷基、環烷基、雜環烷基、苯基及雜芳基自身視 情況經一或多個選自_素原子及經基、側氧基、烧基及含 有1至4個碳原子之烷氧基、NH2、NH烷基及N(烷基)2的基 團取代, 上文定義之所有該等環烷基、雜環烷基、雜環烷 基、雜芳基及苯基亦視情況經基團Si(烷基)3取代; 上文疋義之所有έ亥等環院基及雜環院基可在環之一個碳 上經螺環烷基或螺雜環烷基取代,或視情況在環之兩個碳 上經稠合之環烷基或雜環烷基取代; R5及R5’可相同或不同’表示烷基或環烷基,視情況經 一或多個選自齒素原子及羥基、含有丨至4個碳原子之烷基 及烧氧基、NH2、NH烷基及N(烷基)2的基團取代, 該等院基表示含有1至1〇個碳原子之烷基; s亥等環院基含有至多3至7個碳原子; 該等式(I)產物使得一或多個氫原子可分別經一或多個氘 原子置換,該等式⑴產物為任何可能之外消旋、對映異構 或非對映異構性異構體形式,以及該等式⑴產物與無機及 有機酸或與無機及有機驗之加成鹽。. 因此,本發明之一標的為如上文所定義之式⑴產物其 不包含任何氘原子。 154635.doc 201202242 因此,本發明之一標的亦為如上文所定義之式(i)產物, 其中一或多個氫原子分別經一或多個氘原子置換。 更特定言之,本發明之一標的亦為如上文所定義之式⑴ 產物,其中如上文所定義之基團w之一或多個氫原子分別 經一或多個氘原子置換。 本發明之一標的亦為如上文或下文所定義之式⑴產物, 其中 R1表示烷基、環烷基或環烷基烷基;視情況如下所示經 取代;Rb represents a hydrogen atom or a fluorine atom; W represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by an alkoxy group, a heterocycloalkyl group or an NR3R4 group, and the groups themselves are as follows Substituted as shown; or a group COR, wherein R represents: - a cycloalkyl, a heterocycloalkyl or an alkyl group, optionally, one or more selected from the group consisting of a halogen atom, a hydroxyl group and an alkoxy group, and a cycloalkyl group. , heterocycloalkyl, hetero- 154635.doc -14- 201202242 substituted groups of aryl, phenyl and NR3R4 groups, which groups themselves are optionally substituted as follows; _alkoxy, optionally via alkane Substituted, heterocycloalkyl or NR3R4 substituted, the groups themselves being substituted as shown below; or the group - oxime-heterocyclic, substituted as appropriate; _ or group NHR2, wherein R2 Represents a hydrogen atom or a cycloalkyl group, a heterocycloalkyl group or a alkyl group, which may, depending on the case, be one or more selected from the group consisting of hydroxy and alkoxy and heterocycloalkyl, heteroaryl, phenyl and NR3R4 Substituting groups of groups, such groups are themselves substituted as follows; - wherein R3 and R4 may be the same or different and are selected from the group consisting of hydrogen And an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group and a phenyl group, which may be the same or different one or more selected from the group consisting of a hydroxyl group, an alkoxy group, an NH2, an NH alkyl group, and a N group, as the case may be. The group of the alkyl group 2, heterocycloalkyl, heteroaryl and phenyl is substituted. The substituent groups are themselves substituted as follows; or R3 and R4 together with the nitrogen atom to which they are attached form 3 to 1 a cyclic group of a member, which optionally contains one or more other heteroatoms selected from the group consisting of ruthenium, S, N and NH, wherein the S which may optionally be in the form of s〇 or S02; this group, including Any NH which may be present, as the case may be substituted; all such alkyl, cycloalkyl, heterocycloalkyl, 〇-heterocycloalkyl, heteroaryl and phenyl, as defined above, and The cyclic groups which R3 and R4 may form together with the nitrogen atom to which they are attached may be optionally substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group, and -0- C0-154635.doc -15· 201202242 R5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5' and _NH-CO_R5 groups, and alkyl, cycloalkyl, a heterocycloalkyl group, an alkyl-heterocycloalkyl group, a CO-heterocycloalkyl group, a phenyl group, a CH2-phenyl group, a CO-phenyl group, a heteroaryl group, and an S-heteroaryl group, such that the substituent groups Wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups, by themselves, are optionally selected from one or more selected from the group consisting of a _ atom and a thiol group, a pendant oxy group, a decyl group, and a 1-4 Substituted by a group of alkoxy groups of carbon atoms, NH2, NH alkyl and N(alkyl) 2, all such cycloalkyl, heterocycloalkyl, heterocycloalkyl, heteroaryl groups as defined above and The phenyl group is also optionally substituted by the group Si(alkyl)3; all of the above-mentioned ring groups and heterocyclic groups may be via a spirocycloalkyl or spiroheterocycloalkyl group on one carbon of the ring. Substituted, or optionally substituted with a fused cycloalkyl or heterocycloalkyl group on two carbons of the ring; R5 and R5' may be the same or different 'indicate alkyl or cycloalkyl, as the case may be one or more Substituted from a dentate atom and a hydroxyl group, an alkyl group having from 丨 to 4 carbon atoms, and an alkoxy group, NH2, NH alkyl group and N(alkyl) 2 group, the hospital group is represented by 1 to 1 〇 An alkyl group of carbon atoms; Up to 3 to 7 carbon atoms; the product of the formula (I) is such that one or more hydrogen atoms can be replaced by one or more deuterium atoms, respectively, and the product of the equation (1) is any possible racemic, enantiomeric Or a diastereoisomeric form, and an addition salt of the product of the formula (1) with an inorganic or organic acid or with an inorganic or organic compound. Thus, one of the present invention is labeled as a product of formula (1) as defined above which does not contain any deuterium atoms. Thus, one of the subject matter of the invention is also a product of formula (i) as defined above wherein one or more hydrogen atoms are replaced by one or more deuterium atoms, respectively. More specifically, one of the objects of the invention is also a product of formula (1) as defined above, wherein one or more hydrogen atoms of the group w as defined above are each replaced by one or more deuterium atoms. A subject of the invention is also a product of formula (1) as defined above or below, wherein R1 represents alkyl, cycloalkyl or cycloalkylalkyl; optionally substituted as indicated below;

Rb表示氫原子或氟原子; W表不氫原子;烷基、環烷基或雜環烷基,視情況經烷 氧基、雜環烷基或NR3R4基團取代,該等基團自身視情況 如下所示經取代;或基團c〇R,其中R表示: •環烷基或烷基,視情況經一或多個選自齒素原子、羥 基及烧氧基、及環炫基、雜環院基、雜芳基、苯基及 NR3R4基團之基團取代,該等基團自身視情況如下所 示經取代; _烷氧基,視情況經雜環烷基或犯^尺4取代,該等基團Rb represents a hydrogen atom or a fluorine atom; W represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by an alkoxy group, a heterocycloalkyl group or an NR3R4 group, which groups are themselves as appropriate Substituted as follows; or a group c〇R, wherein R represents: • a cycloalkyl or alkyl group, optionally containing one or more selected from the group consisting of a dentate atom, a hydroxyl group and an alkoxy group, and a cyclodyl group, Substituted by a group of a ring-based, heteroaryl, phenyl, and NR3R4 group, which groups are themselves substituted as follows; _alkoxy, optionally substituted with a heterocycloalkyl or a ruthenium 4 Such groups

羥基及烷氧基及雜環烷基、雜芳基、 團之基團取代,該等基團均視情況如 苯基及NR3R4基 下所示經取代; 154635.doc •17· 201202242 其中R3及R4可相同或不同,選自氫原子及烷基、環烷 基、雜環烷基及笨基,均視情況經一或多個可相同或不同 且選自羥基、烷氧基、NH2、NH烷基及N(烷基)2基團、及 雜環烧基、雜芳基及苯基的基團取代,該等取代基團自身 視情況如下所示經取代;或者R3及R4與其所連接之氮原 子一起形成3至10員環狀基團,其視情況含有一或多個選 自Ο、S、N及NH之其他雜原子,其中該視情況存在之3可 能為SO或S 02形式,此基團,包括其可能含有之任何 NH,視情況如下所示經取代; 上文所定義之所有該等烧基、環烧基、雜環烧基、 雜環烷基、雜芳基及苯基、及尺3及R4與其所連接之氮原 子一起可形成之該等環狀基團視情況經一或多個選自以下 之基團取代:鹵素原子、經基、側氧基、烧氧基、_〇_C〇_ R5、NH2、NH烷基及N(烷基)2基團、及烷基、環烷基、 雜環烧基、CH2-雜環烷基、苯基、CH2-苯基、C0-苯基、 雜芳基及S-雜芳基,使得在該等取代基團中,該等烷基、 %烷基、雜環烷基、苯基及雜芳基自身視情況經一或多個 選自_素原子及羥基、側氧基、烷基及含有丨至4個碳原子 之院氧基、NH2、NH烧基及N(垸基)2的基團取代; R5表示院基或環烧基; 該等式(I)產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機鹼之加成鹽。 本發明之一標的亦為如上文或下文所定義之式⑴產物, 154635.doc •18- 201202242 其中Substituted by a hydroxyl group and an alkoxy group and a heterocycloalkyl group, a heteroaryl group, or a group of the group, such groups are optionally substituted as shown in the phenyl group and the NR3R4 group; 154635.doc •17·201202242 wherein R3 and R4 may be the same or different and is selected from a hydrogen atom and an alkyl group, a cycloalkyl group, a heterocycloalkyl group and a stupid group, and may be the same or different one or more selected from the group consisting of a hydroxyl group, an alkoxy group, NH2, and NH. a group substituted with an alkyl group and an N(alkyl) 2 group, and a heterocycloalkyl group, a heteroaryl group, and a phenyl group, which are themselves substituted as follows; or R3 and R4 are attached thereto The nitrogen atoms together form a 3 to 10 membered cyclic group, which optionally contains one or more other heteroatoms selected from the group consisting of ruthenium, S, N and NH, wherein the optionally present 3 may be in the form of SO or S 02 This group, including any NH which it may contain, is optionally substituted as follows; all such alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, heteroaryl groups as defined above and The phenyl group, and the cyclic group 3 and R4 together with the nitrogen atom to which they are attached may form the cyclic group as the case may be selected from one or more selected from the group consisting of Group substitution: halogen atom, thiol group, pendant oxy group, alkoxy group, _〇_C〇_R5, NH2, NH alkyl group and N(alkyl) 2 group, and alkyl group, cycloalkyl group, heterocyclic ring a pyridyl group, a CH2-heterocycloalkyl group, a phenyl group, a CH2-phenyl group, a C0-phenyl group, a heteroaryl group and an S-heteroaryl group, such that in the substituent groups, the alkyl group, the % alkyl group a heterocycloalkyl group, a phenyl group and a heteroaryl group, optionally, one or more selected from the group consisting of a sulfonium atom and a hydroxy group, a pendant oxy group, an alkyl group, and an alkoxy group having from 丨 to 4 carbon atoms, NH2, NH Substituted by a group of an alkyl group and N(indenyl) 2; R5 represents a deutero or cycloalkyl; the product of the formula (I) is any possible racemic, enantiomeric or diastereomeric a conformational form, and an addition salt of the product of the formula (1) with inorganic and organic acids or with inorganic and organic bases. One of the subject matter of the invention is also the product of formula (1) as defined above or below, 154635.doc • 18-201202242 wherein

Rb表示氫原子或敗原子; R1具有上文所定義之任何意義,且W表示氫原子;烧 基、環烷基或雜環烷基,視情況經雜環烷基4NR3R4基團 取代’該等基團視情況如下所示經取代;或基團C〇R,其 中R表示: -環烷基或烷基,視情況經雜環烷基或NR3R4基團取 代’該專基團自身視情況如下所示經取代; -烷氧基,視情況經雜環烷基或NR3R4*團取代,該等 基團自身視情況如下所示經取代;或〇_雜環烧基,視 情況如下所示經取代; -或基團NHR2,其中R2表示氫原子或烷基,視情況經 雜環院基或NR3R4取代;該等基團自身視情況如下所 示經取代; 其中们及R4可相同或不同,選自氮原子及院基及雜環 烧基,視情況經-或多個可相同或不W選自院氧基、雜 環絲、卿、崎基及咐基)2基團之基團取代;或者 R3及R4與其所連接之氛廣 &接之氣原子-起形成 ✓、視情況3有一夺客相 '联& 面…0請之其他雜原子,此基 團,匕括其所含之視情況存 取代. 之ΝΗ視情況如下所示經 上文定義之所有該等雜環 R4與其所連接之氮原子之2魏基、及R3及 經-或多個選自《下之基團取:成=狀基團視情- 弋·鹵素原子、羥基、燒氧 154635.doc 201202242 基、NH2、NH烷基及N(烷基)2基團、及烷基、環烷基、雜 環烷基、CH2-雜環烷基、苯基、CH2苯基及雜芳基,使 得在該等取代基團中,該等烷基、雜環烷基、苯基及雜芳 基自身視情況經一或多個選自函素原子及羥基、含有丨至4 個碳原子之烷基及烷氧基、NH2、NH烷基及N(烷基)2的基 團取代; 該等式⑴產物為任何可能之外消旋、對映異構或非對映 異構f生異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機鹼之加成鹽。 在式(I)產物中及在下文中: -術語炫基表示直鏈及適當時分支鏈曱基、乙基、丙 基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊 基、異戊基、己基、異己基以及庚基、辛基、壬基及癸 基,以及其直鏈或分支鏈位置異構體:上述清單中含有1 至6個碳原子之烷基,且更特定言之含有丨至4個碳原子之 烷基為較佳; •術語烧氧基表示直鏈及適當時分支鏈甲氧基、乙氧 基、丙氧基或異丙氧基、第二或第三直鏈丁氧基、戊氧基 或己氧基以及其直鏈或分支鏈位置異構體:上述清單中含 有1至4個碳原子之烷氧基為較佳; -術語鹵素原子表示氣、溴、碘或氟原子,且較佳為 氯、溴或氟原子。 -術語環烷基表示含有3至1〇個碳原子之飽和碳環基團, 且因此尤其表示環丙基、環丁基、環戊基、環己基及環庚 154635.doc •20- 201202242 基; •因此,術語雜環烷基表示雜有一或多個可相同或不同 且選自氧、氮及硫原子之雜原子的3至1〇員單環或雙環碳 環基團:可提及之實例包括嗎琳基、硫代嗎琳基、氣丙唆 基、氮雜環丁烧基、㈣基、㈣基、高^井基、^比㈣ 基、咪唑啶基、吡唑啶基、四氫呋喃基、四氫噻吩基、四 氫哌絲、四氫硫代哌喃基及側氧基二氫嗒畊&、或者氧 雜環丁縣或硫雜環丁统基,所有此#基_視情況經取 代,可注思到,此等雜環院基可包含由兩個環成員形成之 橋以形成例如氧雜_5_氮雜雙環[…]纽或氛雜螺[3,3]庚 烷基團或其他氮雜雙環烷或氮雜螺烷環。 -術語芳基及”基分別表示不飽和或部分不飽和單環 或雙%、奴環及雜環基團,其不超過12員,可能含有 •C⑼環成員’雜環基團含有一或多個可相同或不同且選 自0、N及S之雜原子’其中N在適當時視情況經取代; •因此,術語芳基表示6至12員單環或雙環基團’例如苯 基二萘基、聯苯、節基、第基及慧基,更特定言之為苯基 及萘基甚至更特定言之為苯基。可注意到,含有 -c(0)環成員之碳環基團為例如四氫萘酮基團; 因此,術叩雜芳基表示5至12員單環或雙環基團·單環 雜芳基,例如嚷吩基(諸如2-嚷吩基及3·嗟吩基)、咬喃基 (諸如2-呋喃I、3_呋喃基)、哌喃基、咄咯基、吡咯啉 基、°比吐淋基、.坐基"比絲定基(諸如2_吼。定基、 3-吡啶基及4,啶基)、吡畊基、嘧啶基、嗒喷基、噁唑 154635.doc •21 · 201202242 基、噻唑基、異噻唑基、二唑基、噻二唑基、噻***基、 噁二唑基、異噁唑基(諸如3_異噁唑基或4•異噁唑基)、呋 。占基、游離或鹽化之四唑基,所有此等基團均視情況經取 代,其中更特定言之為噻吩基(諸如2_噻吩基及3噻吩 基)、呋喃基(諸如2-呋喃基)、吡咯基、吡咯啉基、吡唑啉 基、咪唑基、吡唑基、噁唑基、異噁唑基、吡啶基及嗒畊 基,此等基團視情況經取代;雙環雜芳基,例如苯并噻吩 基(諸如3-苯并噻吩基)、苯并噻唑基、喹啉基、異喹啉 基、二氫喹啉基、喹啉酮(quin〇l〇ne)、四氫萘酮、金剛烷 基、苯并呋喃基、異苯并呋喃基、二氫苯并呋喃基、伸乙 基二氧基苯基、噻嗯基、苯并。比咯基、苯并咪唑基、苯并 噁唑基、硫代萘基、巧,朵基、氮雜,嗓基、,唑基嘴呤 基、噻吩并吡唑基、四氫吲唑基、四氫環戊二烯并吡唑 基、二氫呋喃并吡唑基、四氫吡咯并吡唑基、側氧基四氫 ㈣并Μ基、四氫㈣并㈣基、四氫β比咬并吼唾基或 側氧基二氫吡啶并吡唑基’所有此等基團均視情況經取 作為雜芳基或雙環基團之實例,更特定言之可提及痛咬 基、°比咬基、吼洛基、氮雜。弓卜朵基、十坐基或吼唾基,視 情況如上所示經-或多個相同或不同取代基取代。 式⑴產物之m基可用熟習此項技術者已知之各種基團鹽 化或酯化,其中可提及之實例包括: -在鹽化化合物中’無機鹼,諸如一當量鈉、鉀、鋰、 辑、鎮或敍,或有機驗,例如甲胺、.丙胺、三甲胺、二乙 154635.doc •22- 201202242 胺、三乙胺、N,N-二曱基乙醇胺、參(羥基曱基)胺基甲 烷、乙醇胺、吡啶、甲基吡啶、二環己胺、嗎啉、苯甲基 胺、普魯卡因(procaine)、離胺酸、精胺酸、組胺酸或N-甲基還原葡糖胺, •在酯化化合物中,形成烷氧基羰基(例如曱氧基羰基、 乙氧基羰基、第三丁氧基羰基或苯甲氧基羰基)之烷基, 此等烷基可經選自例如鹵素原子及羥基、烷氧基、醯基、 醯氧基、烷基硫基、胺基及芳基之基團取代,例如在氯甲 基、羥基丙基、曱氧基曱基、丙醯氧基甲基、甲基硫基甲 基、二甲基胺基乙基、苯甲基或苯乙基中。 式(I)產物與無機或有機酸之加成鹽可為例如與以下形成 之鹽:鹽酸、氫溴酸、氫埃酸、硝酸、硫酸、填酸、丙 酸、乙酸、三氟乙酸、曱酸、苯甲酸、順丁烯二酸、反丁 烯二酸、丁二酸、酒石酸、檸檬酸、草酸、乙醛酸、天冬 胺酸或抗壞血酸、烷基單磺酸(例如甲烷磺酸、乙烷磺 酸、丙烷磺酸)、烷基二磺酸(例如甲烷二磺酸、α,β_乙烷 二磺酸)、芳基單磺酸(諸如苯磺酸)及芳基二磺酸。 可再次提及,立體異構在其最廣泛意義上可定義為具有 同一結構式但各種基團在空間中之排列不同之化合物的異 構’尤其諸如在取代基可位於軸向或平伏位置之經單取代 之環己烷、及乙烷衍生物之各種可能性旋轉構形中。然 而’由於雙鍵或環上固定取代基的各種空間排列而存在另 一種類型之立體異構’其經常稱作幾何異構或順反異構。 術語「立體異構體」在本專利申請案中以其最廣泛意義使 154635.doc -23- 201202242 用’且因此涉及以上所指示之所有化合物。 本發明之一標的亦為如上文或下文所定義之式⑴產物, 其中R1表示烷基或環烷基或環烷基烷基; 其中烷基含有1至2個碳原子且環烷基含有3至6個碳原 子;Rb represents a hydrogen atom or a deficient atom; R1 has any meaning as defined above, and W represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by a heterocycloalkyl group 4NR3R4 group' The group is optionally substituted as follows; or the group C〇R, wherein R represents: a cycloalkyl or alkyl group, optionally substituted by a heterocycloalkyl group or an NR3R4 group. Substituted as shown; - alkoxy, optionally substituted by heterocycloalkyl or NR3R4* group, which groups are themselves substituted as indicated below; or 〇-heterocyclic alkyl, as the case may be Substituted; - or the group NHR2, wherein R2 represents a hydrogen atom or an alkyl group, optionally substituted by a heterocyclic compound or NR3R4; such groups are themselves substituted as shown below; wherein R4 and R4 may be the same or different, It is selected from the group consisting of a nitrogen atom and a substituent and a heterocyclic group, and optionally substituted with a group which may or may not be selected from the group consisting of an anthracene group, a heterocyclic group, a thiol group, and a fluorenyl group. Or R3 and R4 are connected to the atmosphere and the gas atoms that are connected to form a ✓, as the case 3 has a occupant's joint & Other heteroatoms, such as those contained in the surface, are replaced by the conditions contained therein. All of the heterocyclic rings R4 and the nitrogen atom to which they are attached, as defined above, are as follows. 2 Wei Ke, and R3 and by- or more selected from the group below: the group = like a group - 弋 · halogen atom, hydroxyl, oxygen 154635.doc 201202242 base, NH2, NH alkyl and An N(alkyl) 2 group, and an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a CH2-heterocycloalkyl group, a phenyl group, a CH 2 phenyl group, and a heteroaryl group, such that among the substituent groups, The isoalkyl, heterocycloalkyl, phenyl and heteroaryl groups, by themselves, are optionally one or more selected from the group consisting of a functional atom and a hydroxyl group, an alkyl group having from 丨 to 4 carbon atoms, and an alkoxy group, NH2, NH alkane. a group substituted with a group of N(alkyl) 2; the product of the formula (1) is any possible racemic, enantiomeric or diastereomeric f-isomer form, and the product of the formula (1) Inorganic and organic acids or addition salts with inorganic and organic bases. In the product of formula (I) and hereinafter: - the term leukoname means straight chain and, where appropriate, branched chain fluorenyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third Butyl, pentyl, isopentyl, hexyl, isohexyl and heptyl, octyl, decyl and decyl, and linear or branched positional isomers thereof: 1 to 6 carbon atoms in the above list Alkyl groups, and more particularly alkyl groups having from 丨 to 4 carbon atoms, are preferred; • The term alkoxy represents straight-chain and, where appropriate, branched-chain methoxy, ethoxy, propoxy or isopropoxy a second, third or third straight-chain butoxy group, pentyloxy group or hexyloxy group, and a straight-chain or branched-chain positional isomer thereof: an alkoxy group having 1 to 4 carbon atoms in the above list is preferred; - The term halogen atom means a gas, bromine, iodine or fluorine atom, and is preferably a chlorine, bromine or fluorine atom. - the term cycloalkyl denotes a saturated carbocyclic group containing from 3 to 1 carbon atoms, and thus especially denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptane 154635.doc •20-201202242 Thus, the term heterocycloalkyl denotes a 3 to 1 membered monocyclic or bicyclic carbocyclic group which is heterozygous with one or more heteroatoms which may be the same or different and which are selected from oxygen, nitrogen and sulfur atoms: Examples include morphinyl, thiomorphinyl, apocyanoyl, azetidinyl, (tetra)yl, (tetra)yl, gamma, 1,4-(yl), imidazolidinyl, pyrazolyl, tetrahydrofuran Base, tetrahydrothiophenyl, tetrahydropyridinium, tetrahydrothiopiperidyl and acetohydroindoline & or oxetine or thiohelide, all of which Substituting, it is contemplated that such heterocyclic building groups may comprise a bridge formed by two ring members to form, for example, oxa-5-azabicyclo[...] holly or snail [3,3]heptyl a group or other azabicycloalkane or azaspiro ring. - the term aryl and "yl" respectively denotes an unsaturated or partially unsaturated monocyclic or bis-, n-, and heterocyclic group which is not more than 12 members and may contain a ?C(9) ring member' heterocyclic group containing one or more Heteroatoms which may be the same or different and are selected from 0, N and S 'wherein N is optionally substituted as appropriate; • Thus, the term aryl denotes 6 to 12 membered monocyclic or bicyclic groups 'eg phenyl dinaphthalene a base, a biphenyl, a benzyl group, a benzyl group, and a fluorenyl group, more specifically a phenyl group and a naphthyl group, and more specifically a phenyl group. It is noted that a carbocyclic group containing a -c(0) ring member For example, a tetralone group; therefore, a deuterated aryl group means a 5 to 12 membered monocyclic or bicyclic group monocyclic heteroaryl group, such as a porphinyl group (such as 2-nonyl and 3 porphin) Base), a thiol group (such as 2-furan I, 3-furanyl), piperidyl, fluorenyl, pyrrolinyl, °, spiro group, sit-based "bisome-based (such as 2_吼) Fixation, 3-pyridyl and 4, pyridine), pyridinyl, pyrimidinyl, oxime, oxazole 154635.doc •21 · 201202242 base, thiazolyl, isothiazolyl, oxazolyl, thiadiazole Thiazolozolyl, oxadiazolyl, isoxazolyl (such as 3-isoxazolyl or 4; isoxazolyl), furyl, free or salified tetrazolyl, all such radicals The group is substituted as appropriate, and more specifically, it is a thienyl group (such as 2_thienyl and 3 thienyl), a furyl group (such as 2-furyl), pyrrolyl, pyrrolinyl, pyrazolinyl, imidazole a pyrazole group, an oxazolyl group, an isoxazolyl group, a pyridyl group, and a hydrazine group, such groups being optionally substituted; a bicyclic heteroaryl group such as a benzothienyl group (such as 3-benzothienyl) , benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolinone, tetralone, adamantyl, benzofuranyl, isobenzofuran , dihydrobenzofuranyl, ethylidene dioxyphenyl, thiol, benzo, pyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, clever, Aza, fluorenyl, oxazolylhydrazyl, thienopyrazolyl, tetrahydrocarbazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazole base, Oxytetrahydro (tetra)-indenyl, tetrahydro(tetra)-(tetra)-yl, tetrahydro-β-biting and hydrazino or pendant oxydihydropyridazolyl 'all such groups are taken as heteroaryls as appropriate Examples of a basal or bicyclic group, more specifically, a bite base, a bite base, a fluorenyl group, an aza group, a phenylidene group, a decyl group or a sulfhydryl group, as the case may be - or a plurality of the same or different substituents. The m group of the product of formula (1) can be salted or esterified with various groups known to those skilled in the art, and examples which may be mentioned include: - in the salinating compound 'inorganic a base, such as one equivalent of sodium, potassium, lithium, series, town or Syria, or an organic test, such as methylamine, propylamine, trimethylamine, diethyl 154635.doc • 22-201202242 amine, triethylamine, N, N- Dimercaptoethanolamine, cis (hydroxyindenyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, spermine Acid, histidine or N-methyl reduced glucosamine, • in the esterification compound, form an alkoxycarbonyl group (eg, decyloxycarbonyl, B An alkyl group of a carbonyl group, a third butoxycarbonyl group or a benzyloxycarbonyl group, which may be selected from, for example, a halogen atom and a hydroxyl group, an alkoxy group, a decyl group, a decyloxy group, an alkylthio group, Amine and aryl group substitution, for example, in chloromethyl, hydroxypropyl, decyloxy fluorenyl, propyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzo Base or phenethyl. The addition salt of the product of formula (I) with an inorganic or organic acid may be, for example, a salt formed with hydrochloric acid, hydrobromic acid, hydrous acid, nitric acid, sulfuric acid, acid, propionic acid, acetic acid, trifluoroacetic acid, hydrazine. Acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid or ascorbic acid, alkyl monosulfonic acid (such as methanesulfonic acid, Ethanesulfonic acid, propanesulfonic acid), alkyl disulfonic acid (such as methane disulfonic acid, α, β-ethane disulfonic acid), aryl monosulfonic acid (such as benzenesulfonic acid), and aryl disulfonic acid . It may again be mentioned that stereoisomerism may in its broadest sense be defined as the heterogeneity of a compound having the same structural formula but differing in the arrangement of the various groups in space, especially such that the substituent may be in an axial or blunt position. The various possible rotational configurations of the monosubstituted cyclohexane, and ethane derivatives. However, there is another type of stereoisomerism due to the various spatial arrangements of double bonds or fixed substituents on the ring, which are often referred to as geometric or cis-trans isomerism. The term "stereoisomer" is used in this patent application in its broadest sense to use 154635.doc -23-201202242 and thus all of the compounds indicated above. A subject of the invention is also a product of formula (1) as defined above or below, wherein R1 represents alkyl or cycloalkyl or cycloalkylalkyl; wherein alkyl has 1 to 2 carbon atoms and cycloalkyl contains 3 Up to 6 carbon atoms;

Rb表示氫原子或氟原子; W表不氫原子;烷基、環烷基或雜環烷基,視情況經烷 基、雜環烷基或NR3R4基團取代;或基團c〇R,其中尺表 不 · -環烷基、雜環烷基或烷基,視情況經烷基 '雜環烷基 或NR3R4基團取代’該等基團自身視情況如下所示經 取代; _ 0-雜環烷基,視情況如下所示經取代; -或基團NHR2,其中R2表示氫原子聽基,視情況經 雜環烷基或NR3R4基團取代,該等基團自身視情況如 下所示經取代; 其中R3及R4可相同或不同,表示氫原子或烷基或環烷 基,視情況經基團N(烷基)2取代,或者们及以與其所連接 之氮原子一起形成環狀基團,其視情況含有一或多個選自 Ο及NH之其他雜原子,此基團,包括其所含之視情況存在 之NH,視情況經取代; 上文定義之所有該等烷基、雜環烷基及_〇_雜環烷基、 及R3及R4與其所連接之氮原子一起可形成之該等環狀基 團視情況經-或多個選自以下之基團取代:齒素原子、經 154635.doc •24- 201202242 基、側氧基、院氧基、NH2、NH烧基、N(院基)2及-S02-烷基、及烷基、環烷基、雜環烧基、烷基_雜環烷基、c〇_ 雜環燒基及本基,s亥等取代基團自身視情況經一或多個選 自鹵素原子及羥基、含有1至4個碳原子之烷基、環烷基、 環烷基烷基及烷氧基、NH2、NH烷基及N(烷基)2的基團取 代; 該等式(I)產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及.有機驗之加成鹽。 本發明之一標的尤其為如上文或下文所定義之式⑴產 物,其中 R1表示烧基或環院基或環烧基烧基; 其中烧基含有1至2個碳原子且環烷基含有3至6個碳原 子;Rb represents a hydrogen atom or a fluorine atom; W represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted with an alkyl group, a heterocycloalkyl group or an NR3R4 group; or a group c〇R, wherein The ruler is not a cycloalkyl, heterocycloalkyl or alkyl group, optionally substituted by an alkyl 'heterocycloalkyl group or an NR3R4 group'. These groups are themselves substituted as follows; _ 0-hetero a cycloalkyl group, optionally substituted as follows; or a group NHR2, wherein R2 represents a hydrogen atom listener group, optionally substituted with a heterocycloalkyl group or an NR3R4 group, which groups themselves are as follows Substituent; wherein R3 and R4 may be the same or different and represent a hydrogen atom or an alkyl group or a cycloalkyl group, optionally substituted by a group N(alkyl)2, or together with a nitrogen atom to which they are attached, form a cyclic group. a group, which optionally contains one or more other heteroatoms selected from the group consisting of hydrazine and NH, including the NH as the case may be, optionally substituted; all such alkyl groups as defined above, Heterocycloalkyl and 〇-heterocycloalkyl, and R3 and R4 together with the nitrogen atom to which they are attached may form such cyclic groups The situation is replaced by - or a plurality of groups selected from the group consisting of dentate atoms, 154635.doc •24-201202242 base, pendant oxy group, alkoxy group, NH2, NH alkyl group, N (hospital base) 2 and- S02-alkyl, and alkyl, cycloalkyl, heterocycloalkyl, alkyl-heterocycloalkyl, c〇_heterocyclic alkyl and the same, the substituent group such as shai itself may be one or more a group substituted with a halogen atom and a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group, a cycloalkylalkyl group and an alkoxy group, NH2, NH alkyl group and N(alkyl) 2; The product of the formula (I) is in any form of racemic, enantiomeric or diastereomeric isomers, and the product of the formula (1) and inorganic and organic acids or inorganic and organic Addition salt. A subject of the invention is especially a product of formula (1) as defined above or below, wherein R1 represents an alkyl or a ring-based or a cycloalkyl group; wherein the alkyl group contains 1 to 2 carbon atoms and the cycloalkyl group contains 3 Up to 6 carbon atoms;

Rb表示氩原子或氟原子; W表示氫原子;烷基、環烷基或雜環烷基,視情況經雜 環烧基或NR3R4基團取代;或基團c〇R,其中r表示: -環烧基或烷基’視情況經雜環烷基或NR3R4基團取 代,該等基團自身視情況如下所示經取代; • Ο -雜ί哀烧基’視情況如下所示經取代; -或基團NHR2 ’其中R2表示氫原子或烷基,視情況經 雜環烧基或NR3R4基團取代,該等基團自身視情況如 下所示經取代; 其中R3及R4可相同或不同,表示氫原子或烷基,或者 154635.doc •25· 201202242 R3及R4與其所連接之氮原子一起形成環狀基團,其視情 況含有一或多個選自〇&NH之其他雜原子,此基團,包括 其所含之視情況存在之NH,視情況經取代; 上文定義之所有該等雜環烷基及_〇_雜環烷基、及尺3及 R4與其所連接之氮原子—起可形成之該等環狀基團視情況 經一或多個選自以下之基團取代:齒素原子、羥基、側氧 基、烷氧基、NH2、NH烷基及N(烷基)2基團、及烷基、環 烷基、雜環烷基、烷基-雜環烷基、C〇_雜環烷基及苯基, 该等取代基團自身視情況經一或多個選自鹵素原子及羥 基、含有1至4個碳原子之烷基、環烷基及烷氧基、NH2、 NH烷基及N(烷基)2的基團取代; 該等式(I)產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機驗之加成鹽。 本發明之一標的亦為如上文或下文所定義之式⑴產物, 其中:Rb represents an argon atom or a fluorine atom; W represents a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by a heterocyclic alkyl group or an NR3R4 group; or a group c〇R, wherein r represents: The cycloalkyl or alkyl group is optionally substituted with a heterocycloalkyl group or an NR3R4 group, which groups are themselves substituted as follows; • Ο-heterozyring group is substituted as shown below; Or the group NHR2' wherein R2 represents a hydrogen atom or an alkyl group, optionally substituted by a heterocyclic alkyl group or an NR3R4 group, the groups themselves being substituted as shown below; wherein R3 and R4 may be the same or different, Represents a hydrogen atom or an alkyl group, or 154635.doc •25·201202242 R3 and R4 together with the nitrogen atom to which they are attached form a cyclic group which optionally contains one or more other heteroatoms selected from 〇 &NH; This group, including the optionally present NH, is optionally substituted; all of the heterocycloalkyl and 〇-heterocycloalkyl as defined above, and the nitrogen to which the ruthenium 3 and R4 are attached Atoms - These cyclic groups which may be formed are optionally substituted by one or more groups selected from the group consisting of: a dentate atom, a hydroxyl group, a pendant oxy group, an alkoxy group, an NH2, an NH alkyl group, and an N(alkyl) 2 group, and an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkyl-heterocycloalkyl group, C〇_heterocycloalkyl and phenyl, the substituents themselves, optionally, one or more selected from the group consisting of a halogen atom and a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group and an alkoxy group, Substituting NH2, NH alkyl and N(alkyl) 2 groups; the product of formula (I) is in any form of racemic, enantiomeric or diastereomeric isomers, and The addition product of the product of the formula (1) with inorganic and organic acids or with inorganic and organic compounds. One of the subject matter of the invention is also the product of formula (1) as defined above or below, wherein:

Rb表示氫原子或氟原子; R1表示烷基或環烷基或環烷基烷基; 其中烷基含有1至2個碳原子且環烷基含有3至6個碳原 . 子; W表不氫原子;烷基、環烷基或雜環烷基,視情況經雜 環烷基或NR3R4基團取代;或基團c〇R,其中R表示: -環院基或院基,視情況經基團NR3R4取代,該基團自 身視情況如下所示經取代; 154635.doc -26 - 201202242 -〇-雜環烷基’視情況如下所示經取代; _或基團NHR2,其中R2表示氫原子或烷基,視情況經 雜環烷基或NR3R4基團取代,該等基團自身視情況如 下所示經取代; 其中R3及R4可相同或不同,表示氫原子或烷基,或者 R3及R4與其所連接之氮原子一起形成環狀基團,其視情 況含有一或多個選自〇及ΝΗ之其他雜原子,此基團,包括 其所含之視情況存在之ΝΗ ’視情況經取代; 上文定義之所有該等雜環烷基及_〇_雜環烷基、及幻及 R 4與其所連接之氮原子—起可形成之該等環狀基團視情況 經一或多個選自以下之基團取代:齒素原子、羥基、烷氧 基、ΝΗ2、ΝΗ烧基及Ν(烧基)2基團、及烷基、環烧基、雜 環焼基及苯基,該等取代基團自身視情況經—或多個選自 齒素原子及經基、含有…個碳原子之燒基及院氧基、 ΝΗ2、ΝΗ烷基及Ν(烷基)2的基團取代; 該等式⑴產物為任何可能之外消旋、對映異構或非對映 異構性異構體形式,以及該等式⑴產物與無機及有機酸或 與無機及有機驗之加成鹽。 如上文戟義之雜環燒基尤其表示氮雜環庚烧基、嗎琳 基、料°定基ϋ基及㈣基,其自身視情況如上文或 下文所定義經取代。 在NR3R4如上文所定義形成環時,該胺基環可尤其選自 η対啶基,啉基、派啶基、氮呼基、嗎啉 基及㈣基,此等基團自身視情況如上文或下文所示經取 154635.doc •27· 201202242 代。 更特定言之,基團NR3R4可選自咣咯啶基、嗎啉基、哌 咬基及娘P井基, 適當時視情況在一或多個碳或氮原子上經一或兩個選自 i素原子及環烷基、雜環烷基及烷基之基團取代,該等取 代基團自身視情況經一或多個可相同或不同且選自鹵素原 子及烷基、羥基及烷氧基之基團取代。 詳言之,在式(I)產物中,環烷基可表示環己基或環丙 基。 本發明尤其係關於如上文所定義之式⑴產物,其中Rb 表示氟原子。 本發明尤其係關於如上文所定義之式⑴產物,其中Rb 表不風原子。 因此,本發明之一標的為對應於以下各式之如上文或下 文所定義之式(I)產物: -W6-[(6-環丙基[1,2,4]***并[4,3_6]嗒畊_3_基)硫烷 基]-1,3-笨并售唾冬基卜3·[2_(嗎琳I基)乙基]脲 • 6-[(6-環丙基[1,2,4]***并[4 3_6]嗒畊_3·基)硫烷基]_ 1,3-苯并嗟嗤胺 _ #-{6-[(6-環丙基[1,2,4]***并[4 3_6]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑_2_基卜2_(嗎啉基)乙醯胺 • 2-(4-環丙基哌畊_1_基)_沁{6_[(6環丙基[^,糾***并 [4’3 6]»合畊_3_基)硫烧基]-1,3-苯并0塞唑_2_基}乙酿胺 • #-{6-[(6-環丙基[1,2,4]***并[4,3_y嗒畊_3_基)硫烷 154635.doc •28- 201202242 基]-I,3·苯并°塞°坐。-基丨^^气‘氟派咬-丨-基丨乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4_(嗎啉_4-基)哌啶_ι_基]乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(2-乙氧基乙基)哌畊-丨_基]乙 酿胺 _ N-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-办]嗒畊-3-基] 硫烷基}-1,3-苯并噻唑-2-基)-2-(4-環丙基哌畊·ι_基)乙醯胺 -#-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-6]嗒畊-3-基] 硫院基}-1,3-苯并°塞嗤-2-基)-2-(嗎啦_4-基)乙醯胺 -(3/?)-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并嗟。坐-2-基}胺基甲酸1-甲基η比嘻咬_3_基酯 -(3*S)-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}胺基甲酸1-曱基吡咯啶_3·基酯 -{6-[(6-環丙基[1,2,4]二〇坐并[4,3-办]<»荅p井_3_基)硫烧基]-1,3-苯并°塞°坐-2-基}胺基甲酸1-甲基n底咬-4-基酯 -{6-[(6-環丙基[1,2,4]二唾并[4,3-6]°荅p井-3-基)硫炫基]_ 1,3-苯并噻唑-2-基}胺基曱酸1-(2-氟乙基)哌啶_4-基酯 -(3i?)-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-6]嗒畊-3-基]硫烷基}-1,3-苯并噻唑-2-基)胺基曱酸1-曱基吡咯啶-3-基酯 -(3幻-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-6]嗒畊-3-基]硫烷基}-l,3-苯并噻唑-2-基)胺基曱酸l-甲基吡咯啶·3· 基酯 154635.doc •29· 201202242 • 6-[(6-環丙基[1,2,4]***并[4,3-δ]嗒畊·3-基)硫烷基] [2-(4,4-二氟哌啶-1-基)乙基]-1,3-苯并噻唑-2-胺 -2-(4-環丙基哌畊-1-基)-ΛΜ6-[(6-曱基[1,2,4]***并 [4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 • #-{6-[(6-甲基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}環丙烷曱醯胺 -#-{6-[(6_曱基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3 -苯并°塞°坐-2-基}-2-(嗎琳-4-基)乙酿胺 -1-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-6]嗒畊-3-基] 硫烷基}-1,3-苯并噻唑-2-基)-3-[2-(嗎啉-4-基)乙基]脲 -Ν·(6-{[6-(環己基曱基)[ι,2,4]***并[4,3-b]嗒畊-3-基] 硫院基}·1,3-笨并噻唑-2-基)環丙烷曱醢胺 -Ν-(6-{[6-(環丙基)[1,2,4]***并[4 3_b]嗒畊·3·基]硫烷 基卜1,3-苯并噻唑-2-基)環丙烷甲醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]·1’3-苯并噻唑-2·基卜2-[(2H8)嗎啉·4-基]乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊·3·基)硫烷 基]-5-氟-1,3-苯并噻唑_2-基}-2-(嗎啉_4_基)乙醢胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-乙基哌基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑-2-基}_2-[(2R,6S)-2,6-di甲基嗎啉-4-基] 乙醯胺 _ Ν-{6·[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷 154635.doc •30· 201202242 基]-1,3-苯并噻唑_2-基}-2-(1,4-二氧雜-8-氮雜螺[4,5]癸-8_ 基)乙醯胺 -2-[4-(環丙基甲基)哌畊-1-基]-N-{6-[(6-環丙基[12,4j 三。坐并[4,3-b]。荅》井-3-基)硫烧基]-1,3 -苯并嗔唾-2-基}乙 醯胺 -2-(4-環丁基派p井-1-基)-N- {6-[(6-環丙基[1,2,4]三。坐并 [4,3-b]D荅**井-3-基)硫烧基]-1,3 -苯并°塞°坐-2-基}乙醯胺 -2-(4-環丙基-3,5-di甲基哌ρ井-1-基)-Ν-{6·[(6-環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-笨并噻唑_2_ 基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒呼_3_基)硫烧 基μυ·苯并噻唑-2-基}-2-[(lS,4S)-2-氡雜_5_氮雜雙環 [2,2,1]庚-5-基]乙醯胺 'L ,一 u J %、叮· -丞;办;ίΐ λτο 基…-苯并。塞嗤_2-基}-2-(8_氧雜_3j雜雙環[3,2,^-3_ 基)乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]五D坐并[4,3外答呼_3基)硫烷 基]-5-氟-1,3-苯并㈣-2-基}-2_(4_乙基派啡.卜基)乙醯胺 _ Ν-{6-[(6·環丙基Π,2,4]三唾并[4,3外答喷-3-基)琉烷 基]山3-苯并°塞°坐_2-基}-2例丙I基氧基…定-!•基]乙 醯胺 -N-{6-[(6-環丙基Π,2,4]三唾并[4,3外答喷小基)硫烷 基⑷-苯并㈣-2-基}-2-[4-⑷乙基^井小基)㈣小基] 乙醯胺 154635.doc •31 · 201202242 -:^-{6-[(6-環丙基[1,2,4]***并[4,3-15]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(2-氧雜-6-氮雜螺[3,3]庚-6-基) 乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(1-曱基哌啶-4-基)哌畊-1-基] 乙醢胺 ->1-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-{4-[(4-甲基哌畊-1-基)羰基]哌 啶-1-基}乙醯胺 ->1-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[(3 8)-3-甲基嗎啉-4-基]乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(嗎啉-4-基甲基)哌啶-1-基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-5-氟-1,3-苯并噻唑-2-基}-2-[(lS,4S)-2-氧雜-5-氮雜雙 環[2,2,1]庚-5-基]乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-側氧基哌啶-1-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基)-2-(3-曱氧基氮雜環丁烷-1-基)乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(。比咯啶-1-基)哌啶-1-基]乙 154635.doc -32- 201202242 醯胺 -:^-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯弁°塞°坐-2-基}-2-[4-(2-輕基乙基)π底p井-1 -基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(吡咯啶-1-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-羥基。比咯啶-1-基)乙醯胺 -:^-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3 -苯弁π塞。坐-2-基}-2-(3 -敗π比洛〇定-1 -基)乙酿胺 -2-[(lS,4S)-5-環丙基-2,5-二氮雜雙環[2,2,1]庚-2-基]-Ν-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -2-[4-(4-環丙基哌畊-1-基)哌啶-1-基]-Ν-{6-[(6-環丙基 [1,2,4]***并[4,3-1?]嗒_-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -^[-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯并°塞α坐-2-基}-2-[1-(2,2 -二說乙基)派。定-4-基]乙 醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[1-(2,2,2-三氟乙基)哌啶-4-基] 乙醯胺 -2-(4-環丙基嗎啉-2-基)-N-{6-[(6-環丙基[1,2,4]***并 [4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 154635.doc -33- 201202242 -2-(4-環丙基嗎啉-3-基)-N-{6-[(6-環丙基[ι,2,4]***并 [4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(2-曱基丙_2-基)哌畊-1-基]乙 醯胺 -2-[4-( 丁 -2-基)哌畊-1-基]-N-{6-[(6-環丙基[1,2,4]*** 并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基卜2-[4-(甲基磺醯基)哌畊-1-基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒β井-3-基)硫烷 基]-1,3 -苯并β塞α坐-2-基}_2-[4-(丙-2 -基)略ρ井-1-基]乙酿胺 -N2·環丙基-N-{6-[(6-環丙基[l,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-*}-Ν2-乙基甘胺醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-N2-乙基-N2-丙-2-基甘胺酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}〜2-[2-(二甲基胺基)乙基]-N2-乙 基甘胺醯胺 -2-[4-(1-環丙基哌啶-4_基)哌畊-1-基]-N-{6-[(6-環丙基 [1,2,4]***并[4,3-15]嗒畊-3-基)琉烷基]-1,3-苯并噻唑-2-基}乙酿胺 -2-{4-[1-(環丙基甲基)〇底咬-4-基]π底p井-l-基 }_N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-l,3-苯并噻 154635.doc •34· 201202242 唑-2-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-羥基哌啶-1-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-本并°塞°坐-2-基}-2-(3-曱氧基。比洛。定-1 -基)乙酿胺 -义{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3 -苯弁。塞吐-2-基}-2-[3-(二乙基胺基比略·17定-1-基]乙 醯胺 -:^-{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯并°塞°坐-2-基}-2-[3-(2-乙氧基乙氧基)°比π各咬-1 · 基]乙醯胺 -2-[4-(1-環丙基乙基)哌畊-1-基]-Ν-{6-[(6-環丙基[1,2,4] ***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并°塞β坐-2-基}-2-(1-曱基派。定-4-基)乙酿胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并°塞。坐-2-基}-2-(1-曱基α底β定-2-基)乙酿胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-笨并噻唑-2-基}-2-(1-曱基。比咯啶-3-基)乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-4-曱基嗎啉-2-甲醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-笨并噻唑-2-基}-1-甲基哌啶-3-曱醯胺 154635.doc -35- 201202242 -N-{6-[(6-環丙基[i,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-笨并噻唑基哌啶_4_曱醯胺 -2-[1-(環丙基甲基)哌啶_4_基]·ν_{6 [(6•環丙基[12,4] ***并[4,3-b]嗒啡_3-基)硫烷基卜丨,^苯并噻唑_2_基}乙 醢胺 -N-{6-[(6-環丙基以’2,4]***并[4 3 b]嗒畊_3基)硫烷 基]-1,3-苯并噻唑·2-基卜丨,4_二曱基哌畊_2_甲醯胺 -6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3基)硫烷基卜 N-(l -乙基°比η各咬·3-基)_1,3_苯并嘆唾_2胺 -6-[(6·環丙基[1,2,4]***并[4 3 b]嗒畊_3基)硫烷基]_ Ν-[1·(四氫呋喃-2-基曱基)哌啶_4_基苯并噻唑_2_胺 以及該等式(I)產物與無機及有機酸或與無機及有機鹼之加 成鹽。 本發明之一標的亦為製備如上文所定義之式⑴產物之任 何方法。 本發明之產物可由習知有機化學方法製備。以下流程 1、2、3及4說明用於製備式⑴產物之方法。在此方面其 不應關於製備所主張化合物之方法而對本發明之範嘴構成 限制。 因此’本發明之如上文所;t義之式⑴產物可尤其根據以 下流程1、2、3及4中所述之方法製備。 因此’本發明之一標的亦為根據如下所定義之流程!製 備式⑴產物之方法。 因此’本發明之一標的亦為根據如下所定義之流程2製 154635.doc -36 - 201202242 備式⑴產物之方法。 二二本發明之一標的亦為根據如下所定義之流程3製 備式(I)產物之方法。 因此本發明之一標的亦為根據如下所定義之流程4製 備式⑴產物之方法。 # 的通用途獲 流程1 ·合成通式(j)及(Ia)之化合物Rb represents a hydrogen atom or a fluorine atom; R1 represents an alkyl group or a cycloalkyl group or a cycloalkylalkyl group; wherein the alkyl group has 1 to 2 carbon atoms and the cycloalkyl group contains 3 to 6 carbon atoms. a hydrogen atom; an alkyl group, a cycloalkyl group or a heterocycloalkyl group, optionally substituted by a heterocycloalkyl group or an NR3R4 group; or a group c〇R, wherein R represents: - a ring-based or a hospital base, optionally Substituted by the group NR3R4, the group itself is optionally substituted as follows; 154635.doc -26 - 201202242 - anthracene-heterocycloalkyl group is optionally substituted as follows; _ or a group NHR2, wherein R2 represents hydrogen An atom or an alkyl group, optionally substituted by a heterocycloalkyl or NR3R4 group, wherein the groups are themselves substituted as follows; wherein R3 and R4 may be the same or different and represent a hydrogen atom or an alkyl group, or R3 and R4, together with the nitrogen atom to which it is attached, forms a cyclic group which optionally contains one or more other heteroatoms selected from the group consisting of ruthenium and osmium, including the presence of the oxime as it appears. Substituted; all such heterocycloalkyl groups as defined above and 〇-heterocycloalkyl, and phantom and R 4 are attached thereto The nitrogen atom - such a cyclic group which may be formed, is optionally substituted with one or more groups selected from the group consisting of a dentate atom, a hydroxyl group, an alkoxy group, a ruthenium group 2, a ruthenium group and a ruthenium group (alkyl group) 2 a group, and an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, and a phenyl group, and the substituent groups themselves, as the case may be, or a plurality of alkyl groups selected from the group consisting of dentate atoms and radicals, containing carbon atoms, and Substituted by a group of alkoxy, hydrazine 2, decylalkyl and decyl (alkyl) 2; the product of the formula (1) is in any form of racemic, enantiomeric or diastereomeric isomers, And an addition salt of the product of the formula (1) with an inorganic or organic acid or with an inorganic or organic compound. The heterocyclic alkyl group as defined above particularly denotes azacycloheptyl, morphine, fluorenyl and (iv), which are themselves substituted as defined above or below. When NR3R4 is formed into a ring as defined above, the amino ring may be especially selected from the group consisting of η aridinyl, phenyl, pyridyl, aziryl, morpholinyl and (iv) groups, which are themselves as described above. Or as shown below, take 154635.doc •27·201202242 generation. More specifically, the group NR3R4 may be selected from the group consisting of an oxazolidinyl group, a morpholinyl group, a piperidine group, and a mother P group, and optionally, one or two selected from one or more carbon or nitrogen atoms, as the case may be. Substituting a group of a n atom and a cycloalkyl group, a heterocycloalkyl group and an alkyl group, the substituent groups themselves may be the same or different and may be selected from a halogen atom and an alkyl group, a hydroxyl group and an alkoxy group, as the case may be. Substituted by the group. In particular, in the product of formula (I), a cycloalkyl group may represent a cyclohexyl group or a cyclopropyl group. The invention relates in particular to the product of formula (1) as defined above, wherein Rb represents a fluorine atom. The invention relates in particular to the product of formula (1) as defined above, wherein Rb represents a wind atom. Thus, one of the present invention is directed to the product of formula (I) as defined above or below, corresponding to the following formula: -W6-[(6-cyclopropyl[1,2,4]triazolo[4, 3_6] 嗒 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1,2,4]triazolo[4 3_6]indole _3·yl)sulfanyl]_1,3-benzobenzamide _ #-{6-[(6-cyclopropyl[1, 2,4]triazolo[4 3_6]indole _3_yl)sulfanyl]-1,3-benzothiazole_2_ kib 2_(morpholinyl)acetamide • 2-(4- Cyclopropyl piperazine_1_yl)_沁{6_[(6-cyclopropyl[^, triazol[4'3 6]» ____) thiol]-1,3- Benzooxazole-2-yl}Ethylamine• #-{6-[(6-Cyclopropyl[1,2,4]triazolo[4,3_y嗒嗒_3_yl)sulfane 154635 .doc •28- 201202242 base]-I,3·Benzene °°°. -基丨^^气'Fluorine bite-丨-丨丨乙醯amine-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6] -3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(morpholine-4-yl)piperidine-yl)-acetamide-#-{6 -[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}- 2-[4-(2-ethoxyethyl)piped-indole-yl]ethanoamine_N-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazole [4,3-do] 嗒--3-yl] sulfanyl}-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperidine·ι_yl)acetamide -#-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-6]indole-3-yl]thiol}}-1,3-benzene And °嗤-2-yl)-2-(?啦_4-yl)acetamide-(3/?)-{6-[(6-cyclopropyl[1,2,4]triazole [4,3-6]indol-3-yl)sulfanyl]-1,3-benzindole. Sodium-2-yl}aminocarbamate 1-methyl η than 嘻3_yl ester-(3*S)-{6-[(6-cyclopropyl[1,2,4]triazolo[ 4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}carbamic acid 1-mercaptopyrrolidine_3·yl ester-{6-[( 6-cyclopropyl[1,2,4]dioxins and [4,3-do]<»荅p well_3_yl)thioalkyl]-1,3-benzo-°°°- 2-yl}aminocarbamate 1-methyl n-bottom-4-yl ester-{6-[(6-cyclopropyl[1,2,4]disindol [4,3-6]°荅p Well-3-yl)thione]_1,3-benzothiazol-2-yl}amino decanoic acid 1-(2-fluoroethyl)piperidine-4-yl ester-(3i?)-( 6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-6]indole-3-yl]sulfanyl}-1,3-benzothiazole-2 -yl)amino decanoic acid 1-decylpyrrolidin-3-yl ester-(3 magic-(6-{[6-(cyclohexyldecyl)[1,2,4]triazolo[4,3 -6]嗒耕-3-yl]sulfanyl}-l,3-benzothiazol-2-yl)amino decanoic acid l-methylpyrrolidine·3·yl ester 154635.doc •29· 201202242 • 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-δ]indole-3-yl)sulfanyl][2-(4,4-difluoropiperidine- 1-yl)ethyl]-1,3-benzothiazol-2-amine-2-(4-cyclopropylpiped-1-yl)-indole 6-[(6-fluorenyl[1,2,4 ]three Zoxa[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine • #-{6-[(6-methyl[1] , 2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanedecylamine-#-{6- [(6_Mercapto[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzo-°°°-2-yl} -2-(Mallin-4-yl)ethanoamine-1-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-6] 3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea-Ν·(6-{[6-( Cyclohexyl fluorenyl)[ι,2,4]triazolo[4,3-b]indol-3-yl]sulfenyl}·1,3-1,3-thiazol-2-yl)cyclopropane oxime Amine-Ν-(6-{[6-(cyclopropyl)[1,2,4]triazolo[4 3_b]indole·3·yl]thioalkyl 1,3-benzothiazole-2 -yl)cyclopropanecarbamamine-Ν-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl] 1'3-Benzothiazol-2·kib 2-[(2H8)morpholine-4-yl]acetamidine-Ν-{6-[(6-cyclopropyl[1,2,4]triazole And [4,3_b]嗒耕·3·yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}-2-(morpholine-4-yl)acetamide-oxime -{6-[(6-cyclopropyl[1,2,4]3 And [4,3_b]嗒耕_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(4-ethylpiperidyl)acetamide-N-{6- [(6-Cyclopropyl[1,2,4]triazolo[4,3_b]indole_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}_2-[( 2R,6S)-2,6-dimethylmorpholin-4-yl]acetamide _ {-{6·[(6-cyclopropyl[1,2,4]triazolo[4,3_b]嗒耕_3_基)sulfane 154635.doc •30· 201202242 base]-1,3-benzothiazolyl-2-yl}-2-(1,4-dioxa-8-azaspiro[4 , 5] 癸-8_yl) acetamidine-2-[4-(cyclopropylmethyl)piped-1-yl]-N-{6-[(6-cyclopropyl[12,4j III. Sit and [4,3-b].荅" well-3-yl) thiol group]-1,3-benzoindole-2-yl}acetamido-2-(4-cyclobutyl-p--1-yl)-N- { 6-[(6-cyclopropyl[1,2,4]III. Sodium[4,3-b]D荅** well-3-yl)thioalkyl]-1,3-benzo-pyrene ° sit-2-yl}acetamide-2-(4-cyclopropyl-3,5-dimethylpiperidin-1-yl)-indole-{6·[(6-cyclopropyl[1] , 2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazolyl-2-yl}acetamide-N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole_3_yl)thiol group μυ·benzothiazol-2-yl}-2-[(lS,4S) -2-indene_5_azabicyclo[2,2,1]hept-5-yl]acetamidamine 'L, a u J %, 叮·-丞; do; ΐ λτο 基...-benzo.嗤嗤_2-yl}-2-(8_oxa-3j heterobicyclo[3,2,^-3_yl)acetamide-Ν-{6-[(6-cyclopropyl[1,2, 4]5D sitting and [4,3 outside reply _3 base) sulfanyl]-5-fluoro-1,3-benzo(tetra)-2-yl}-2_(4_ethylpyrylene. Ethylamine _ {-{6-[(6·cyclopropyl hydrazine, 2,4]tris-[4,3-exo- -3-yl) decyl] Sitting 2 - base} - 2 cases of propyl I oxy group ... butyl - ketoamine - N-{6-[(6-cyclopropyl hydrazine, 2, 4] trisporin [4, 3 External reaction small base) sulfanyl (4)-benzo(tetra)-2-yl}-2-[4-(4)ethyl^ well small group) (iv) small group] acetamamine 154635.doc •31 · 201202242 -:^ -{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-15]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- }}-2-(2-oxa-6-azaspiro[3,3]hept-6-yl)acetamido-N-{6-[(6-cyclopropyl[1,2,4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(1-mercaptopiperidin-4- Peptidin-1-yl] acetamidine-> 1-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indole-3-yl Sulfuryl]-1,3-benzothiazol-2-yl}-2-{4-[(4-methylpipedino-1-yl)carbonyl]piperidin-1-yl}acetamide- >1-{6-[(6-cyclopropyl[1] ,2,4]triazolo[4,3-13]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[(3 8)-3- Methylmorpholin-4-yl]acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfide Alkyl]-1,3-benzothiazol-2-yl}-2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]acetamide-N-{6-[( 6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl} -2-[(lS,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-yl]acetamido-N-{6-[(6-cyclopropyl[ 1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(4-lateral oxypermidine Acet-1-yl)acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl] -1,3-benzothiazol-2-yl)-2-(3-decyloxyazetidin-1-yl)acetamide-N-{6-[(6-cyclopropyl[1] , 2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(. Bilobidine-1-yl)piperidin-1-yl]ethyl 154635.doc -32- 201202242 Indoleamine-:^-{6-[(6-cyclopropyl[1,2,4]triazolo[ 4,3-13]嗒耕-3-yl)sulfanyl]-1,3-phenylhydrazine°°°-2-yl}-2-[4-(2-light-ethyl)π bottom p Well-1 -yl]acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl] -1,3-benzothiazol-2-yl}-2-(pyrrolidin-1-yl)acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo [4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(3-hydroxy.pyrrolidin-1-yl)acetamide -:^-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indole-3-yl)sulfanyl]-1,3-benzoquinone π Plug. Sodium-2-yl}-2-(3-definition pipiroxime-1 -yl)ethanoamine-2-[(lS,4S)-5-cyclopropyl-2,5-diazabicyclo [2,2,1]hept-2-yl]-indole-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indole-3-yl) Thioalkyl]-1,3-benzothiazol-2-yl}acetamide-2-[4-(4-cyclopropylpipen-1-yl)piperidin-1-yl]-indole-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1?]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl }Acetamine-^[-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indol-3-yl)sulfanyl]-1,3 -Benzo-insulating α-spin-2-yl}-2-[1-(2,2-di-ethyl). -4--4-yl]acetamide-Ν-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl] -1,3-benzothiazol-2-yl}-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]acetamide-2-(4-cyclopropyl Morpholin-2-yl)-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1 , 3-benzothiazol-2-yl}acetamide 154635.doc -33- 201202242 -2-(4-cyclopropylmorpholin-3-yl)-N-{6-[(6-cyclopropyl) [ι,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide-N-{6- [(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2 -[4-(2-amidinopropionyl-2-yl)piped-1-yl]acetamimid-2-[4-(but-2-yl)piped-1-yl]-N-{6 -[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}B Indoleamine-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzoene Thiazol-2-yl b 2-[4-(methylsulfonyl)piped-1-yl]acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazole And [4,3-b]嗒β well-3-yl)sulfanyl]-1,3-benzo-β-α-yl-2-yl }_2-[4-(Propan-2-yl) slightly ρ well-1-yl]ethidamine-N2·cyclopropyl-N-{6-[(6-cyclopropyl[l,2,4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-*}-indole 2-ethylglycinamide-indole-{6-[ (6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-N2- Ethyl-N2-propan-2-ylglycine amine-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl Sulfuryl]-1,3-benzothiazol-2-yl}~2-[2-(dimethylamino)ethyl]-N2-ethylglycine decylamine-2-[4-( 1-cyclopropylpiperidine-4_yl)piped-1-yl]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-15]fluorene Phenyl-3-yl)nonyl]-1,3-benzothiazol-2-yl}ethenyl-2-{4-[1-(cyclopropylmethyl)indole-4-yl] π bottom p well-l-group}_N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]- l,3-benzothiazepine 154635.doc •34· 201202242 oxazol-2-yl}acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3 -b]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(4-hydroxypiperidin-1-yl)acetamide-N-{6- [(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl) Alkyl-yl] -1,3 ° and plug the present sit ° 2-yl} -2- (3 Yue group. Bilo. -1-1 -yl)ethanoamine-yi{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indol-3-yl)sulfanyl]- 1,3 - benzoquinone.吐 -2--2-yl}-2-[3-(diethylaminopyrano-17-decyl-1-yl)acetamide-:^-{6-[(6-cyclopropyl[1,2 , 4] triazolo[4,3-13]indole-3-yl)sulfanyl]-1,3-benzo-pyran °-2-yl}-2-[3-(2-B Oxyethoxyethoxy)° ratio π each bite-1 ·yl]acetamide-2-[4-(1-cyclopropylethyl)piped-1-yl]-Ν-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide-N -{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzo-pyrene -2-yl}-2-(1-indolyl.dent-4-yl)ethanoamine-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3 -b]嗒耕-3-yl)sulfanyl]-1,3-benzo-pyrene. sit-2-yl}-2-(1-indolyl α-beta-but-2-yl)ethonamide -Ν-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-indotethiazole- 2-yl}-2-(1-indolyl.pyrrolidin-3-yl)acetamido-indole-{6-[(6-cyclopropyl[1,2,4]triazolo[4, 3-b]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-4-mercaptomorpholine-2-carboxamide-N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-] Thiazol-2-yl}-1-methylpiperidin-3-indoleamine 154635.doc -35- 201202242 -N-{6-[(6-cyclopropyl[i,2,4]triazolo[ 4,3-b]indo-3-yl)sulfanyl]-1,3-benzothiazolylpiperidine-4-[indolyl-2-(1-cyclopropylmethyl)piperidine 4_基]·ν_{6 [(6•cyclopropyl[12,4]triazolo[4,3-b]indanyl-3-yl)sulfanyldiazine,^benzothiazole_2_ Acetylamine-N-{6-[(6-cyclopropyl with '2,4]triazolo[4 3 b]indole_3yl)sulfanyl]-1,3-benzothiazole · 2-基卜丨, 4_二曱基培耕_2_Procarbamide-6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]嗒耕_3 base Sulfuryl b. N-(l-ethyl ° ratio η each bite 3-yl)_1,3_benzoxanthene-2-amine-6-[(6·cyclopropyl[1,2,4] Triazolo[4 3 b]indole_3yl)sulfanyl]_Ν-[1·(tetrahydrofuran-2-ylindenyl)piperidine-4-ylbenzothiazole-2-amine and the equation (I) Addition salts of the product to inorganic and organic acids or to inorganic and organic bases. One of the objects of the invention is also any process for the preparation of a product of formula (1) as defined above. The products of the present invention can be prepared by conventional organic chemical methods. The following Schemes 1, 2, 3 and 4 illustrate the process for the preparation of the product of formula (1). In this regard, it should not be construed as limiting the manner in which the claimed compounds are made. Thus, the product of the formula (1) of the present invention as defined above can be prepared in particular according to the methods described in the following Schemes 1, 2, 3 and 4. Therefore, one of the objects of the present invention is also a process according to the following definition! A method of preparing the product of formula (1). Thus, the subject matter of the present invention is also a method of preparing a product of formula (1) according to Scheme 2 as defined below. 154635.doc -36 - 201202242. The subject matter of one of the inventions is also a method of preparing a product of formula (I) according to Scheme 3 as defined below. Thus, one of the objects of the present invention is also a process for preparing a product of formula (1) according to Scheme 4 as defined below. #通通使用过程 1 ·Synthesis of compounds of formula (j) and (Ia)

在上述流程1中,取代基R1及W具有上文對於式(I)產物 所提供之含義。式(D)化合物中之取代基Z表示氫、氰基或 硫基,使得在此情況下,化合物(D)表示對稱二硫化物。 154635.doc •37- 201202242 通式(i)化合物可藉由以下獲得: -途控1 ’將鏈W引入硫氰酸2_胺基-1,3-苯并噻唑_6·基 醋(C)(當Rb=H且Rb=F時,為專利WO 10/007 318中所 述之市售化合物)上’繼而與化合物(B)根據熟習此項 技術者已知、且尤其專利WO 09/056 692中所述之常 用方法或根據下文在流程2、3及4中所述之方法反 rig · /¾ > -途徑2 ’使化合物(b)與硫氰酸2-胺基-1,3_苯并噻唑_6_ 基醋(C)反應,繼而根據熟習此項技術者已知且尤其 專利WO 09/056 692中所述之常用方法或根據下文在 流程2、3及4中所述之方法引入鏈w。 在W為保護基(諸如胺基曱酸酯或第三丁基或者諸如環 丙基甲醯胺之基團)的情況下,通式(la)之2-胺基衍生物亦 可藉由例如在鹽酸介質中脫除衍生物(I)之保護基而獲得。In the above Scheme 1, the substituents R1 and W have the meanings given above for the product of the formula (I). The substituent Z in the compound of the formula (D) represents hydrogen, a cyano group or a thio group, so that in this case, the compound (D) represents a symmetrical disulfide. 154635.doc •37-201202242 The compound of formula (i) can be obtained by the following: - Route 1 'Introduction of chain W into thiocyanate 2-amino-1,3-benzothiazole -6 vinegar (C (when Rb = H and Rb = F, the commercially available compound described in patent WO 10/007 318) is then known to the compound (B) according to the skilled artisan, and in particular the patent WO 09/ The usual method described in 056 692 or the method described in Schemes 2, 3 and 4 below, the compound (b) and the 2-amino-1, thiocyanate, are reversed. 3_benzothiazole-6-based vinegar (C) reaction, followed by conventional methods known to those skilled in the art and especially as described in patent WO 09/056 692 or according to the following in Schemes 2, 3 and 4 The method introduces the chain w. In the case where W is a protecting group such as an amino phthalate or a tributyl group or a group such as cyclopropylcarbamide, the 2-amino derivative of the formula (la) can also be used, for example, by It is obtained by removing the protecting group of the derivative (I) in a hydrochloric acid medium.

化合物(B)可為市售產品,或根據熟習此項技術者已知 之常用方法,經由偶合反應,例如在例如專利WO 05/009 957中所述之條件下,在約70°C之溫度下,在雙(三第三丁 基膦)鈀存在下,在溶劑(諸如四氫呋喃)中使3,6-二氣*** 并嗒畊與式ZnBrRl (其中R1如上文所定義)之溴基鋅偶合而 獲得。 154635.doc -38- 201202242 流程2 :合成通式(la)、(lb)之化合物的途徑Compound (B) may be a commercially available product, or via a coupling reaction, for example, under the conditions described in, for example, WO 05/009957, at a temperature of about 70 ° C, according to conventional methods known to those skilled in the art. Coupling of 3,6-dioxatriazole in a solvent (such as tetrahydrofuran) in the presence of bis(tri-tert-butylphosphine)palladium with a bromozinc zinc of the formula ZnBrR1 (wherein R1 is as defined above) And get. 154635.doc -38- 201202242 Scheme 2: Routes for the synthesis of compounds of formula (la), (lb)

在上述流程2中,取代基R、r 1、R3、R4及Rb具有上文 對於式(I)產物所指示之含義。 通式(lb)之苯并噻唑羧醯胺可由硫氰酸2_胺基_丨,3_苯并 噻唑-6-基酯(C)經由下述途徑1或2製備。In the above Scheme 2, the substituents R, r 1 , R3, R4 and Rb have the meanings indicated above for the product of the formula (I). The benzothiazole carboxamide of the formula (lb) can be produced from 2-amino-thiocyanate, 3-benzothiazol-6-yl ester (C) via the following route 1 or 2.

通式(D1)及(G)之化合物可由硫氰酸2_胺基心》苯并噻 154635.doc •39· 201202242 吐-6-基酯(C)或式(ia)化合物,例如藉由在約60°C之溫度 下’在溶劑(諸如二噁烷)中與氣乙醯氯(E)反應而獲得。The compound of the formula (D1) and (G) may be a compound of the formula (D1) and (G) which may be a compound of the formula (D) or a compound of the formula (ia), for example, by a thiocyanate 2-amino group benzophenone 154635.doc •39·201202242 It is obtained by reacting with ethylene ethoxide (E) in a solvent such as dioxane at a temperature of about 60 °C.

化合物(D2)及(D3)(使得R3及R4不為H)及式(lb)之羧醯胺 可由式(D1)或式(G)之氣乙醯基化合物,例如用以下獲 得: -胺鹽酸鹽(F),在約20°C之溫度下,在溶劑(諸如4-曱 基嗎琳)中,或在二異丙基乙胺存在下,於二氣甲烷 與二噁烷之50/50混合物中,或在約2〇。(:之溫度下, 在溶劑(諸如DMSO)中, -胺(F) ’其自身用作溶劑或於溶劑(諸如dms〇)中,在 約20°C之溫度下。 式(F)之胺為市售產品或經由熟習此項技術者已知之方 法獲得。舉例而言,根據M.L· GiUaspy,B.A. Lefker等人 在[(1-乙氧基環丙基)氧 TL 1995, 36, 41,7399所述之方法, 基](三甲基)矽烷及冰醋酸存在下執行環丙烷化,繼而添加 氰基蝴氫化鈉。 基-1,3·苯并。塞》坐-6-基及式(B)化合物製備。 更特定言之,通式(la)及(lb)之苯并噻唑可在約8〇t之溫 度下,在例如D,L-二硫蘇糖醇及磷酸二氫鉀存在下,於容 劑(諸如乙醇)中由式(D2)或(D3)之化合物或由式(〇之2 = 154635.doc -40. 201202242 通式(if)之苯并噻唑羧醯胺可由通式(Ia)之胺例如藉由與 式(0)之酸反應而製備: -在約20C之溫度下,在;ν-[3-(二甲基胺基)丙基]·#,·乙 基碳化二亞胺鹽酸鹽存在下,於溶劑(諸如吡啶)中, -或在20°C與回流溫度之間的溫度下,在N_乙基二異丙 胺及2,4,6-三氧化2,4,6-三乙基],3,5,2,4,6_三氧雜三亞鱗境 (phosphinane)及催化用N,N_二曱基吡啶_4胺存在下,於溶 劑(諸如2-曱基四氫咬喃)中。 式⑼之酸為市售產品或經由熟習此項技術者已知之方 法獲得。舉例而言,根據M.L. Gillaspv ρι λ Β·Α. Lefker等人 TL 1995, 36, 41,7399所述之方法,在『n ’ u -己氧基環丙基)氧 基](三甲基)矽烷及冰醋酸存在下執行包. 艰S能基之酸的 環丙烧化,繼而添加氰基删氫化納。 154635.doc 41· 201202242 流程3 :合成通式(id)之胺基甲酸酯的途徑The compounds (D2) and (D3) (so that R3 and R4 are not H) and the carboguanamine of the formula (lb) can be obtained from the gas oxime compound of the formula (D1) or (G), for example, by the following: - an amine Hydrochloride (F) at a temperature of about 20 ° C in a solvent such as 4-indolyl or in the presence of diisopropylethylamine in 50 methane and dioxane /50 mixture, or at about 2 〇. (At the temperature, in a solvent such as DMSO, -amine (F)' itself is used as a solvent or in a solvent such as dms〇 at a temperature of about 20 ° C. Amine of formula (F) It is obtained for commercial products or by methods known to those skilled in the art. For example, according to ML Giuaspy, BA Lefker et al. in [(1-ethoxycyclopropyl)oxyl TL 1995, 36, 41, 7399 In the above method, cyclopropanation is carried out in the presence of (trimethyl)decane and glacial acetic acid, followed by the addition of sodium cyanofosate. The base-1,3·benzone. B) Preparation of the compound. More specifically, the benzothiazoles of the formulae (la) and (lb) may be present at a temperature of about 8 Torr, for example, D,L-dithiothreitol and potassium dihydrogen phosphate. In the case of a solvent (such as ethanol), a compound of the formula (D2) or (D3) or a compound of the formula (〇2 = 154635.doc -40. 201202242 formula (if) of benzothiazole carboxamide can be passed The amine of formula (Ia) is prepared, for example, by reaction with an acid of formula (0): - at a temperature of about 20 C, in; ν-[3-(dimethylamino)propyl]·#, · B In the presence of carbodiimide hydrochloride In a solvent such as pyridine, or at a temperature between 20 ° C and reflux temperature, in N-ethyldiisopropylamine and 2,4,6-trioxide 2,4,6-triethyl] , 3,5,2,4,6_trioxatriazine phosphinane and catalyzed in the presence of N,N-dimercaptopyridine-4 amine in a solvent (such as 2-mercaptotetrahydroethylene) The acid of formula (9) is commercially available or obtained by methods known to those skilled in the art. For example, according to the method described in ML Gillaspv ρι λ Β·Α. Lefker et al. TL 1995, 36, 41, 7399. In the presence of "n'u-hexyloxycyclopropyl)oxy](trimethyl)decane and glacial acetic acid, the cyclopropanylation of the acid of the Sonic acid is carried out, followed by the addition of cyano-dehydrogenation. 154635.doc 41· 201202242 Scheme 3: Pathway for the synthesis of urethanes of the general formula (id)

在上述流程3中,取代基R1及Rb具有上文對於式⑴產物 所指示之含義。在式(Id)及(D5)之化合物中,取代基R5使 得OR5表示烷氧基,視情況經烷基、雜環烷基或NR3R4取 代,該等基團自身視情況經取代;或視情況經視情況經取 代之基團0-雜環烷基取代,如通式⑴產物中所示。 在上述流程3中’通式(Id)之苯并噻唑胺基甲酸酯可由硫 氰酸2·胺基-1,3-苯并。塞唾-6-基酯(C)經由下述途徑1或2製 備。In the above Scheme 3, the substituents R1 and Rb have the meanings indicated above for the product of the formula (1). In the compounds of the formulae (Id) and (D5), the substituent R5 is such that OR5 represents an alkoxy group, optionally substituted by an alkyl group, a heterocycloalkyl group or NR3R4, the groups themselves being optionally substituted; or optionally Substituted by a substituted 0-heterocycloalkyl group as shown in the product of formula (1). In the above Scheme 3, the benzothiazolyl carbamate of the formula (Id) may be thiocyanate 2·amino-1,3-benzo. Sesa-6-yl ester (C) is prepared via the following Route 1 or 2.

式(D4)及(Ic)之胺基曱酸酯可由硫氰酸2_胺基],3_笨并 154635.doc •42· 201202242 售唾-6-基酯(C)或由式(ia)化合物,例如根據專利w〇 09/056 692中所述之方法,藉由在約20°C之溫度下,在溶 劑(諸如四氫呋喃)中,在鹼(諸如碳酸氫鈉)存在下與式(N) 之氯碳酸苯酯反應而製備。The amino phthalic acid esters of the formulae (D4) and (Ic) can be obtained from the thiocyanate 2 -amino group, 3 - stupid and 154635.doc • 42· 201202242 sold as a salino-6-yl ester (C) or by the formula (ia) a compound, for example, according to the method described in the patent WO 09/056 692, by means of a formula (in the presence of a base such as sodium hydrogencarbonate) in a solvent such as tetrahydrofuran at a temperature of about 20 ° C ( Prepared by reacting N) chlorocarbonate.

通式(D5)及(Id)之胺基甲酸酯可藉由例如在約7〇〇c之溫 度下’在溶劑(諸如四氫呋喃)中使式(D4)之胺基甲酸笨酯 或式(Ic)化合物與通式(H)之醇(其中R5如上文所定義)反應 而獲得。 更特定言之,通式(Id)之苯并噻唑胺基曱酸酯可在例如 D,L二硫蘇糖醇及磷酸二氫鉀存在下,在溶劑(諸如乙醇) 中且在約80 C之溫度下由式(D5)化合物及式(B)化合物製 備。 154635.doc •43· 201202242 流程4:合成通式(ie)之胺基化合物的途徑The urethanes of the formulae (D5) and (Id) can be obtained by formulating the ester of the aminocarboxylic acid of the formula (D4) or the formula (for example, at a temperature of about 7 〇〇c) in a solvent such as tetrahydrofuran. The compound Ic) is obtained by reacting an alcohol of the formula (H) wherein R5 is as defined above. More specifically, the benzothiazolyl phthalate of the formula (Id) can be present in the presence of, for example, D,L dithiothreitol and potassium dihydrogen phosphate in a solvent such as ethanol and at about 80 C. It is prepared from the compound of the formula (D5) and the compound of the formula (B) at a temperature. 154635.doc •43· 201202242 Scheme 4: Ways to synthesize amine compounds of formula (ie)

在上述流程4中,取代基以及尺化具有上文對於式⑴產 物所指示之含義。在式(Ie)化合物中,取代基尺6表示如通 式(I)產物中所示視情況經取代之烷基、環烷基或雜環烷 基0 通式(Ie)之2-胺基苯并嗔π坐化合物可由硫氰酸2_胺基 1,3-苯并嗟。坐-6-基醋(C)經由下述途徑1或2製備。In the above Scheme 4, the substituent and the sizing have the meanings indicated above for the product of the formula (1). In the compound of the formula (Ie), the substituent base 6 represents an optionally substituted alkyl group, a cycloalkyl group or a heterocycloalkyl group as shown in the product of the formula (I). The 2-amino group of the formula (Ie) The benzofluorene π sitting compound may be 2-aminotriphenylphosphonium thiocyanate. The -6-based vinegar (C) was prepared via the following route 1 or 2.

Br 式(K)及(Μ)之化合物由式(C)之硫氰酸2_胺基_丨,3_苯并噻 J54635.doc 201202242 。坐-6-基酯或由式(Ia)化合物,例如根據專利w〇 09/056 692 中所述之方法,藉由在〇。(:與-20〇C之間的溫度下,在溶劑 (諸如乙腈)中用亞硝酸烷酯及溴化亞銅處理而獲得。The compound of the formula (K) and (Μ) is a compound of the formula (C) 2-amino group 丨 3, 3-benzothiazide J54635.doc 201202242. The -6-yl ester is taken or by a compound of the formula (Ia), for example by the method described in the patent WO 09/056 692, by hydrazine. (: obtained by treatment with an alkyl nitrite and cuprous bromide in a solvent such as acetonitrile at a temperature between -20 TorrC.

(〇6) 通式(D6)及(Ie)之化合物可由式(κ)或式(⑷之^溴_13_ 苯并噻唑-6-基及通式(L)之胺(其中R6如上文所定義)例如 在微波照射下’在溶劑(諸如四氫呋喃)中在約14〇。〇之溫度 下持續約5分鐘而獲得。 更特定言之,通式(Ie)之2-胺基苯并噻唑化合物可例如 在D,L-二硫蘇糖醇及磷酸二氫鉀存在下,在溶劑(諸如乙 醇)中且在約80。(:之溫度下由式(D6)化合物及式(B)化合物 製備。 式(Dl)、(D2)、(D3)、(D4)、(D5)及(D6)之化合物為流 程1中所定義之通式D之產物,其中w表示如上所示之意 義。 式(la)、(lb)、(Ic)、(Id)及(Ie)之化合物為流程丨中所定 義之通式(I)之產物,其中…表示如上所示之意義。 本發明之一標的亦為作為新穎工業產物之如上文所定義 的式(C)、(Dl)、(D2)、(D3)、(D4)、(D5)、(D6)、(G)、 (K)及(M)之合成中間物,其中R1、❿、R3、R4、R5&R6 具有上文所示且下文再次提及之定義: 154635.doc •45- 201202242(〇6) The compound of the formula (D6) and (Ie) may be an amine of the formula (κ) or the formula ((4), a bromo-13 benzothiazole-6-yl group and an amine of the formula (L) (wherein R6 is as above) Definitions) Obtained, for example, under microwave irradiation, in a solvent such as tetrahydrofuran at a temperature of about 14 Torr for about 5 minutes. More specifically, a 2-aminobenzothiazole compound of the formula (Ie) It can be prepared, for example, from a compound of the formula (D6) and a compound of the formula (B) in the presence of D,L-dithiothreitol and potassium dihydrogen phosphate in a solvent such as ethanol and at a temperature of about 80°. The compounds of the formulae (D1), (D2), (D3), (D4), (D5) and (D6) are the products of the formula D as defined in Scheme 1, wherein w represents the meaning as indicated above. The compounds of (la), (lb), (Ic), (Id) and (Ie) are the products of the formula (I) as defined in the scheme, wherein ... represents the meaning as indicated above. Also for the novel industrial products of formula (C), (Dl), (D2), (D3), (D4), (D5), (D6), (G), (K) and (as defined above) a synthetic intermediate of M), wherein R1 ❿, R3, R4, R5 & R6 have the definitions shown above and below mentioned once again: 154635.doc • 45- 201202242

—些為已知的且可購得;此 熟習此項技術者已知之常用 得0 如上所示,在起始物質中, 等產物或其他起始物質可根據 方法’例如由其他市售產品獲 熟習此項技術者應瞭解,為執行前述本發明之方法,^ 能必需為胺基、羧基及醇官能基引入保護基以避免副万 應0 可提及以下保護反應性官能基之實例的非詳盡清單·· -羥基可例如經如下烷基保護,諸如第三丁基、三甲基 石夕烧基、第三丁基二甲基矽烷基、甲氧基曱基、四氫哌喃 基、苯f基或乙醯基, -胺基可例如經乙醯基、三苯曱基、笨甲基、第三丁氧 基幾基、BOC、苯甲氧基羰基或酞醯亞胺基或肽化學中已 知之其他基團保護。 154635.doc • 46- 201202242 酸官能基可例如以酯形式經保護,該等酯由容易裂解之 酯(諸如苯曱酯或第三丁酯或肽化學中已知之酯)形成。 可使用之各種保護基之清單見於熟習此項技術者已知之 手冊及例如專利BF 2 499 995中。 可注意到,必要及必需時,經由以上所示之方法由此獲 得的中間產物或式(I)產物可進行熟習此項技術者已知之一 或多個如下轉化反應以獲得其他中間物或式⑴之其他產 物,例如: a) 酯化酸官能基之反應, b) 使酯官能基皂化為酸官能基之反應, c) 使游離或酯化羧基官能基還原為醇官能基之反應, d) 將燒氧基g能基轉化為經基官能基或者將經基官能基 轉化為烷氧基官能基之反應, e) 移除經保護反應性官能基可帶有之保護基的反應, f) 用無機或有機酸或用鹼獲得相應鹽之鹽化反應, g) 將外消旋形式解析為經解析產物之反應, 該等由此獲得之式(I)產物為任何可能之外消旋、對映異 構或非對映異構性異構體形式。 反應a)至g)可在熟習此項技術者已知之常用條件(例如下 文所示之條件)下執行。 a) 上述產物必要時可在可能之羧基官能基上進行酯化反 應’該等酯化反應可根據熟習此項技術者已知之常用方法 執行。 b) 上述產物之酯官能基可能轉化為酸官能基,必要時可 154635.doc -47· 201202242 在熟習此項技術者已知之常用條件下,尤其藉由酸性或驗 性水解’例如在醇介質中(例如在甲醇中)用氫氧化鈉或氫 氧化卸或者用鹽酸或硫酸執行。 息化反應可根據熟習此項技術者已知之常用方法,例如 在溶劑(諸如甲醇、乙醇、二噁烷或二甲氧基乙烷)中,在 氫氧化鈉或氫氧化鉀存在下執行。 C)上述產物之可能之游離或酯化羧基官能基必要時可經 由熟習此項技術者已知之方法還原為醇官能基:可能之酯 化羧基官能基必要時可經由熟習此項技術者已知之方法且 尤其在溶劑(例如四氫呋喃、二噁烷或***)中用氫化鋰鋁 還原為醇.官能基。 上述產物之可能之游離羧基官能基必要時可尤其用氫化 硼還原為醇官能基。 d)上述產物之可能之烷氧基官能基(尤其諸如甲氧基)必 要時可在熟習此項技術者已知之f用條件下,例如在溶劑 (諸如二氯甲烷)中用三溴化硼,用吡啶氫溴酸鹽或鹽酸 鹽’或者在回流下’在m乙酸中用㈣酸或鹽酸轉 化為羥基官能基。 e)移除保護基(諸如如上所示之保護基)可在熟習此項去 術者已知之f用條件下執行,尤其經由酸性水解用_ 如鹽酸對甲苯續酸、f酸或三氟乙酸)執行, 或者經由催化氫化執行。 酿酿亞胺基可用肼移除。 )上述產物乂要時可例如用無機或有機酸或用無機或有 154635.doc •48- 201202242 機鹼,根據熟習此項技術者已知之常用方法進行鹽化反 應:該鹽化反應可例如在例如鹽酸或酒石酸'檸檬酸或甲 烷磺酸存在下,在醇(例如乙醇或甲醇)中執行。 g)上述產物之可能之光學活性形式可藉由根據熟習此項 技術者已知之常用方法解析外消旋混合物而製備。 如上文所定義之式⑴產物及其酸加成鹽具有適宜藥理學 特性,尤其由於其如上所示之激酶抑制特性。 本發明之產物尤其適用於治療腫瘤。 因此,本發明之產物亦可提高常用抗腫瘤劑之治療作 為筚物的ΓΓ整其治療用途,且本發明之一標的尤其為作 可二、,文所定義之式⑴產物,該等式⑴產物為任何 映異構或非對映異構性異構體形式,以 藥;=產物與醫藥學上可接受之無機及有機酸或與醫 、予上了接又之無機及有機鹼之加成鹽。 各=之,本發明之-標的為作為藥物的對應於以下 基广…三嗤并㈣…⑷硫院 2_基卜3_[2-(嗎啉-4-基)乙基]脲 &笨:環:2基:邮^ .沁{6_[(6·環丙基Π,2,4]三唾并[4 3小 笨并0塞0坐~2·基卜嗎嘛-4.基)乙醯胺土硫燒 4(4·環丙基叫1·基)邻裕環丙基Π,2,4]三唾并 154635.doc •49· 201202242 [4,3-6]嗒畊-3-基)疏炫•基]-1,3-笨并噻唑_2_基)乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3_^嗒畊_3_基)硫烷 基]-1,3-苯并°塞嗤-2-基}-2-(4-^ η底咬_ι·基)乙酿胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3_6]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(嗎啉_4_基)哌啶基]乙醢胺 -#-{6-[(6-環丙基[1,2,4]***并[4 3_6]嗒畊_3基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(2-乙氧基乙基)哌畊_丨_基]乙 醯胺 -Ν-(6-{[6-(環己基甲基)[1,2,4]***并[4,3-ά]嗒畊-3-基] 硫烷基}-1,3·苯并噻唑-2-基)-2-(4-環丙基哌畊-丨-基)乙醯胺 -#-(6-{[6-(環己基甲基)[1,2,4]***并[4,3-6]嗒畊-3-基] 硫烷基}-1,3-苯并噻唑-2-基)-2-(嗎啉-4-基)乙醯胺 -(3i?)-{6-[(6-環丙基[1,2,4]***并[4,3-办]嗒畊-3-基)琉烧 基]-1,3 -苯并"塞11 坐-2-基}胺基曱酸ι_曱基β比p各咬_3_基商旨 -(3<S)-{6-[(6-環丙基[1,2,4]三。坐并[4,3-办]。荅啡-3-基)硫炫 基]-1,3-苯并°塞D坐_2-基}胺基甲酸1-甲基η比洛咬_3_基酯 -{6-[(6-環丙基[1,2,4]二。坐并[4,3-Ζ)]««荅 <»井-3-基)硫炫基]_ 1,3-苯并噻唑-2-基}胺基甲酸1_甲基哌啶-4-基酯 -{6-[(6-環丙基Π,2,4]***并[4,3-Ζ>]嗒畊-3-基)硫烷基]_ 1,3-苯并噻唑-2-基}胺基甲酸1-(2-氟乙基)哌啶-4-基酯 -(3/?)-(6-{[6-(環己基甲基)[1,2,4]***并[4,3-6]嗒畊-3-基]硫烷基}-1,3-苯并嗟唾-2-基)胺基甲酸1-甲基吡咯啶-3-基醋 (35>(6-{[6-(環己基曱基)[1,2,4]***并[4,3-0]嗒畊-3- 154635.doc •50· 201202242 基]硫烷基}-l,3-苯并噻唑_2_基)胺基甲酸l_甲基吡咯啶-3-基酉旨 -6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-#-[2-(4,4-二氟°辰咬-1-基)乙基]-1,3-苯并°塞》坐-2-胺 -2-(4-環丙基哌'*井-1-基)-#-{6-[(6-甲基[1,2,4]***并 [4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -#-{6-[(6-甲基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}環丙烷曱醯胺 -#-{6-[(6-甲基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3 -本并°塞嗤-2-基}-2-(嗎琳-4-基)乙酿胺 -1-(6-{[6-(環己基曱基)[ι,2,4]***并[4,3-6]嗒畊-3-基] 硫烧基}-1,3-苯并噻唑_2·基)-3-[2-(嗎啉-4-基)乙基]腺 _ Ν_(6-{[6·(環己基甲基)[1,2,4]***并[4,3-b]嗒畊-3-基] 硫烷基}-1,3-笨并噻唑基)環丙烷甲醢胺 _ N_(6_{[6-(環丙基)[1,2,4]***并[4,3-b]嗒畊-3-基]硫烷 基}-1,3-笨并噻唑_2_基)環丙烷曱醯胺 -N-{6-[(6-環丙基***并[4,3_b]嗒喷-3_基)硫烷 基]-1,3-苯并》塞唾_2•基卜2[(2H8)嗎啉_4基]乙醯胺 _ N-{6_[(6-環丙基[1,2,4]***并[4,3-b]嗒啫-3-基)硫烷 基]-5-氟-1,3-苯并噻唑_2_基}_2_(嗎啉_4基)乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3_6]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑_2-基}-2-(4-乙基哌畊-1-基)乙醢胺 -#-{6-[(6-環丙基[12 4]***并[4 3_6]嗒喵_3_基)硫烷 基]-1,3-苯并噻唑_2_基}_2_[(2R 6S) 2 6二曱基嗎啉_4_基] 154635.doc -51· 201202242 乙酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒p井_3·基)硫尸 基]-1,3-苯并噻唑-2-基}-2-(1,4-二氧雜_8-氮雜螺[4,5]癸_8 基)乙醯胺 -2-[4-(環丙基曱基)哌畊-1-基]-Ν-{6-[(6·環丙基[12 4] 三0坐并[4,3-b]。荅ρ井-3-基)硫烧基]-1,3 -苯并〇塞唾-2-基}乙 醯胺 -2-(4-環丁基D底ρ井-1-基)-Ν-{6-[(6-環丙基[1,2,4]三。坐并 [4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -2-(4-環丙基-3,5-二甲基哌畊-卜基)-N-{6-[(6-環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2_ 基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊_3-基)硫烷 基]-1,3 -苯并售β坐-2-基}-2-[(lS,4S)-2 -氧雜-5 -氮雜雙環 [2,2,1]庚-5-基]乙酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(8-氧雜-3-氮雜雙環[3,2,1]辛_3· 基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-5-氟-1,3-苯并嘆"坐-2-基}-2-(4·乙基派p井-1-基)乙酿胺 -Ν·{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯并〇塞唾-2-基}-2-[4-(丙-2 -基氧基)派咬基]乙 醯胺 -Ν·{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啡-3-基)硫烷 154635.doc • 52- 201202242 基]-1,3-苯弁°塞。坐-2-基}-2-[4-(4 -乙基娘p井-1 -基)。辰°定-1 -基] 乙醯胺 -义{6-[(6-環丙基[1,2,4]***并[4,3-1)]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(2-氧雜-6-氮雜螺[3,3]庚-6-基) 乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯并α塞β坐-2-基}-2-[4-(1-曱基。底σ定-4-基)派哨 -1 -基] 乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-{4-[(4-曱基哌畊-1-基)羰基]哌 啶-1-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯弁°塞。坐-2-基}-甲基嗎嚇 -4-基]乙酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(嗎啉-4-基甲基)哌啶-1-基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-5-氟-1,3-苯并噻唑-2-基}-2-[(lS,4S)-2-氧雜-5-氮雜雙 環[2,2,1]庚-5-基]乙醯胺 -义{6-[(6-環丙基[1,2,4]***并[4,3-15]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-側氧基哌啶-1-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-曱氧基氮雜環丁烷-1-基)乙 醯胺 154635.doc •53- 201202242 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(°比咯啶-1-基)哌啶-1-基]乙 醢胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(2-羥基乙基)哌啡-1-基]乙 酿胺 -7V-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(。比咯啶-1-基)乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-羥基吡咯啶-1-基)乙醯胺 -#-{6-[(6-環丙基[1,2,4]***并[4,3-δ]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-氟°比咯啶-1-基)乙醯胺 -2-[(lS,4S)-5-環丙基-2,5-二氮雜雙環[2,2,1]庚-2-基] {6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-l,3-苯并噻唑-2-基}乙醯胺 -2-[4-(4-環丙基0底p井-1-基)0底0定-1-基]-N-{6-[(6-環丙基 [1,2,4]***并[4,3-b]嗒啡-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[1-(2,2-二氟乙基)哌啶-4-基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[1-(2,2,2-三氟乙基)哌啶_4_基] 乙醯胺 -54- 154635.doc 201202242 -2-(4-環丙基嗎琳-2-基)-N-{6-[(6-環丙基[i,2,4]***并 [4,3-13]"荅<»井_3-基)硫烧基]-1,3-苯并嘆11坐_2-基}乙醯胺 -2-(4-環丙基嗎淋-3-基)-N-{6-[(6-環丙基[i,2,4]***并 [4,3-b]塔井-3-基)硫烧基]-1,3-苯并塞嗤_2_基}乙醯胺 -Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并嘆唾-2-基}-2-[4-(2-甲基丙_2_基)派p井-1·基]乙 醢胺 -2-[4-(丁 -2-基)派畊-1-基]-N-{6-[(6-環丙基[ι,2,4]*** 并[4,3-b]»荅畊-3-基)硫烧基]-1,3-苯并嚷唾_2_基}乙酿胺 -Ν·{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒'•井-3-基)硫烷 基]-1,3 -苯并》塞唆-2-基} -2-[4-(甲基續醯基)派哨__1_基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啡-3-基)硫烷 基]-1,3 -苯并°塞哇-2-基}-2-[4-(丙-2 -基)n辰呼_1·基]乙酷胺 -N2-環丙基-N-{6-[(6-環丙基[1,2,4]三。坐并[4,3-b]"荅p井_ 3 -基)硫院基]-1,3 -苯并°塞β坐-2-基}-N2 -乙基甘胺酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}^2-乙基-N2-丙-2·基甘胺醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒呼-3-基)硫烷 基]-1,3-苯并噻唑-2-*}-N2-[2-(二甲基胺基)乙基]-N2-乙 基甘胺醯胺 -2-[4-(1-壤丙基娘咬-4-基)派p井-1-基]-N-{6-[(6-環丙基 [1,2,4]***并[4,3-1>]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 154635.doc -55- 201202242 -2-{4-[1-(環丙基甲基)。底。定·4-基]派井-l-基 }-N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻 唑-2-基}乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-羥基哌啶-1-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-甲氧基吡咯啶-1·基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[3-(二乙基胺基)吡咯啶_丨_基]乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[3-(2-乙氧基乙氧基比咯啶—b 基]乙醯胺 -2-[4-(1-環丙基乙基)哌畊·卜基]-N-{6-[(6-環丙基[1,2,4] ***并[4,3-b]嗒畊-3-基)硫烷基l·1,3·苯并噻唑-2-基}乙醯胺 -Ν-{6·[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(1-甲基哌啶-4-基)乙醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3,苯并噻唑-2-基}-2-(1-甲基哌啶-2-基)乙醢胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(1_甲基°比咯啶-3-基)乙酿胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-4-甲基嗎啉-2-曱醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒呼-3-基)硫烷 154635.doc -56- 201202242 基]-1,3-笨并噻唑_2-基卜1-曱基哌啶-3-甲醯胺 • N-{6-[(6-環丙基[1,2,4]***并[4,3-b]塔畊-3-基)硫院 基]-1,3-笨并噻唑_2-基}-1-甲基哌啶-4-甲醯胺 -2-[1-(環丙基曱基)略咬-4-基]-N-{6-[(6-環丙基[1,2,4] 二°坐并[4,3-b]塔p井-3-基)硫烧基]-1,3 -笨并嚷。坐_2_基}乙 醯胺 -N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊_3_基)硫烷 基]-1,3-笨并噻唑_2_基}_1,4-二甲基哌畊_2_曱醯胺 -6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊_3_基)硫烷基卜 N-(l-乙基吡咯啶_3_基)_13_苯并噻唑_2•胺 • 6-[(6-環丙基[丨,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]_ Ν·[1-(四氫呋喃_2_基甲基)哌啶笨并噻唑_2胺 以及該等式(I)產物與醫藥學上可接受之無機及有機酸或與 醫藥學上可接受之無機及有機鹼之加成鹽。 本發明亦關於如下醫藥組合物,其含有如上文所定義之 式(I)產物或此產物之醫藥學上可接受之鹽或此產物之前藥 中之至少一者作為有效成分,及適當時含有醫藥學上可接 受之載劑。 因此,本發明涵蓋如下醫藥組合物,其含有至少一種如 上文所定義之藥物作為有效成分。 本發明之該等醫藥組合物適#時亦可含有其他抗有絲分 裂藥物(尤其諸如基於紫杉醇、順翻、__***劑及其類 似物之抗有絲***藥物)之有效成分。 ’、 此等醫藥组合物可經口投與、非經腸投與或藉由局部施 154635.doc •57- 201202242 用於皮膚及黏膜而局部投與,或經由靜脈内或肌肉内注射 投與。 此等組合物可為固體或液體且可為人類醫藥中常用之任 何醫藥形式,例如簡單錠劑或糖衣錠劑、丸劑、***鍵、 凝膠膠囊、滴劑、顆粒、可注射製劑、軟膏、乳膏或凝膠 劑;其根據常用方法製備。有效成分可與此等醫藥組合物 中常用之如下賦形劑一起併入其中,諸如滑石、*** 膠、乳糖、澱粉、硬脂酸鎂、可可脂、水性或非水性媒 劑、動物或植物來源之脂肪物質、石蠟衍生物、二醇、各 種濕潤劑、分散劑或乳化劑及防腐劑。 對於成人而言,可視所用產物、所治療患者及所研究之 病患而變化的常用劑量可為例如每天0.05至5 g,或較佳每 天0.1至2 g。 本發明之-標的亦為如上文所定義之式⑴產物或此等產 物之醫藥學上可接受之鹽的用途’其係用於製備供抑制激 酶蛋白之活性用的藥物。 本發明之—標的亦為如上文所定義之式⑴產物之用途, 其係用於製備供治療或預防特徵為激酶蛋白之活性去調節 之疾病用的藥物。 該藥物尤其欲用於治療或預防哺乳動物之疾病 本發明之一標的亦為如上文所定義之用途 白為路胺酸激酶蛋白。 其中激酶蛋 其中酪胺酸 本發明之一標的亦為如上文所定義之用途 激酶蛋白為MET或其突變形式。 154635.doc -58· 201202242 本發明之一標的亦為如上文所定義之用途,其中 白在細胞培養物中。 丈 本發明之-標的亦為如上文所定義之用途,其中激酶蛋 白在β南乳動物中β 本發明之-標的尤其為如上文所定義之式⑴產物之用 途,其係用於製備供預防或治療與不受控増殖有關之疾 用的藥物。 、; 本發明之一標的尤其為如上文所定義之式⑴產物之用 途,其係用於製備供治療或預防選自以下群之疾病用的藥 物:血管增生病症、纖維變性病症、「腎隔」細胞增殖病 症、代謝失調、過敏、哮喘、血栓形《、神經系統疾病、 視網膜病、牛皮癬、類風濕性關節炎、糖尿病、肌肉退化 症、細菌感染(尤其單核細胞增多性李氏菌(ζ 感染)及癌症。 因此,最特定言之,本發明之一標的為如上文所定義之 式(I)產物之用途,其係用於製備供治療或預防腫瘤疾病且 尤其治療癌症用之藥物。 在此等癌症中,注意力集中於治療實體或液體腫瘤及治 療抗細胞毒性劑之癌症。 所提及之本發明產物可尤其用於治療原發性腫瘤及/或 轉移,尤其胃癌、肝癌、腎癌、卵巢癌、腸癌或*** 癌、肺癌(NSCLC及SCLC)、膠質母細胞瘤、曱狀腺癌、膀 胱癌或乳癌、黑色素瘤、淋巴或骨髓造血腫瘤、肉瘤、腦 癌、喉癌、淋巴系統癌症、骨癌及胰腺癌。 154635.doc -59- 201202242 本發明之一標的亦為如上文所定義之式(1)產物之用途, 其係用於製備欲用於癌症化學療法之藥物。 欲用於癌症化學療法之該等藥物可單獨或組合使用。 本專利申請案之產物尤其可單獨投與或與化學療法或放 射療法組合投與,或者與例如其他治療劑組合投與。 該等治療劑可為常用抗腫瘤劑。 可提及之激酶抑制劑包括丁内酯、黃酮吡多 (flavopiddol)及2·(2_羥基乙基胺基)_6_苯甲基胺基_9曱基 嗓呤(稱作奥洛母新(〇l〇m〇ucine))。 本發明之一標的亦為作為新穎工業產物之如上文所定義 且下文再次提及之式(c)、(Dl)、(D2)、(D3)、(D4)、 (D5)、(D6)、(G)、(κ)及(M)之合成中間物:Some are known and commercially available; this is commonly known to those skilled in the art. As indicated above, in the starting materials, the equivalent products or other starting materials may be obtained according to the method 'e. Those skilled in the art will appreciate that in order to carry out the foregoing methods of the present invention, it may be necessary to introduce a protecting group for the amine, carboxyl and alcohol functional groups to avoid the use of the following examples of protecting reactive functional groups. OVERVIEW LISTING - The hydroxyl group can be protected, for example, by an alkyl group such as a tert-butyl group, a trimethyl group, a tributyl dimethyl decyl group, a methoxy fluorenyl group, a tetrahydropyranyl group, a benzene f. Or an ethoxy group, the amine group can be, for example, an acetonitrile group, a triphenyl fluorenyl group, a benzyl group, a third butoxy group, a BOC, a benzyloxycarbonyl group or a quinone imine group or a peptide chemistry. Other groups are known to be protected. 154635.doc • 46-201202242 Acid functional groups can be protected, for example, in the form of esters formed from readily cleavable esters such as benzoquinone or tert-butyl ester or esters known in peptide chemistry. A list of the various protecting groups that can be used is found in the manuals known to those skilled in the art and in, for example, the patent BF 2 499 995. It may be noted that, if necessary and necessary, the intermediate product or the product of formula (I) thus obtained via the process indicated above may be subjected to one or more of the following conversion reactions known to the skilled artisan to obtain other intermediates or formulas. (1) Other products, such as: a) reaction of esterifying acid functional groups, b) reaction of saponification of ester functional groups into acid functional groups, c) reaction for reduction of free or esterified carboxyl functional groups to alcohol functional groups, d a reaction for converting an alkoxyg energy group to a transfunctional group or a transfunctional group to an alkoxy group, e) removing a protecting group which may be carried by the protective reactive group, f The salting reaction of the corresponding salt with an inorganic or organic acid or with a base, g) the resolution of the racemic form to the resolved product, the product of formula (I) thus obtained is any possible racemization , enantiomeric or diastereomeric forms. The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art (e.g., the conditions shown below). a) The above products may be subjected to an esterification reaction on a possible carboxyl functional group if necessary. The esterification reaction may be carried out according to a conventional method known to those skilled in the art. b) the ester functional group of the above product may be converted to an acid functional group, if necessary, 154635.doc -47·201202242 under common conditions known to those skilled in the art, especially by acidic or prophylactic hydrolysis 'for example in an alcohol medium It is carried out with sodium hydroxide or hydroxide or with hydrochloric acid or sulfuric acid (for example in methanol). The in vitro reaction can be carried out according to conventional methods known to those skilled in the art, for example, in a solvent such as methanol, ethanol, dioxane or dimethoxyethane in the presence of sodium hydroxide or potassium hydroxide. C) Possible free or esterified carboxyl functional groups of the above products may be reduced to alcohol functional groups, if desired by methods known to those skilled in the art: possible esterification of the carboxyl functional groups, if desired, by those skilled in the art The process is especially reduced to an alcohol. functional group with lithium aluminum hydride in a solvent such as tetrahydrofuran, dioxane or diethyl ether. The possible free carboxyl functional groups of the abovementioned products can, if necessary, be reduced, in particular, with boron hydride to the alcohol functional groups. d) possible alkoxy functional groups of the above products (especially such as methoxy), if necessary, may be used with boron tribromide in the conditions known to those skilled in the art, for example in a solvent such as dichloromethane. Conversion to a hydroxy functional group with a pyridine hydrobromide or hydrochloride 'or under reflux' in m acetic acid with (iv) acid or hydrochloric acid. e) removal of a protecting group (such as a protecting group as indicated above) can be carried out under the conditions known to those skilled in the art, especially via acidic hydrolysis, such as p-toluene hydrochloride, f acid or trifluoroacetic acid. Executed, or performed via catalytic hydrogenation. Brewed imine groups can be removed with hydrazine. The above product may be subjected to a salification reaction, for example, by using an inorganic or organic acid or with an inorganic or organic or 154635.doc • 48-201202242 base, according to a conventional method known to those skilled in the art: For example, in the presence of hydrochloric acid or tartaric acid 'citric acid or methanesulfonic acid, it is carried out in an alcohol such as ethanol or methanol. g) Possible optically active forms of the above products can be prepared by resolution of the racemic mixture according to conventional methods known to those skilled in the art. The product of formula (1) and its acid addition salts as defined above have suitable pharmacological properties, especially due to their kinase inhibiting properties as indicated above. The products of the invention are especially useful for treating tumors. Therefore, the product of the present invention can also enhance the therapeutic use of a conventional anti-tumor agent as a sputum, and one of the objects of the present invention is particularly the product of the formula (1) as defined herein, which is (1) The product is in the form of any of the enantiomeric or diastereomeric isomers; the product is added to the pharmaceutically acceptable inorganic and organic acids or to the medical and inorganic and organic bases. A salt. Each of the present invention is labeled as a drug corresponding to the following bases... 三嗤和(四)...(4) 硫院2_基卜3_[2-(morpholin-4-yl)ethyl]urea & stupid : Ring: 2 base: post ^. 沁 {6_[(6·cyclopropyl Π, 2, 4] three saliva and [4 3 small stupid and 0 plug 0 sit ~ 2 · Kibu?-4. base) Ethylamine sulphide 4 (4·cyclopropyl is 1 yl) o-ring propyl hydrazine, 2, 4] sorrow 154635.doc •49· 201202242 [4,3-6] 嗒耕-3 -based) 疏 • 基 基 基 基 基 基 基 # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # # 3_^嗒耕_3_yl)sulfanyl]-1,3-benzoxanth-2-yl}-2-(4-^ η bottom biting_ι·yl) ethylamine-#-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3_6]indole_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}-2 -[4-(morpholine-4-yl)piperidinyl]acetamidine-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4 3_6]嗒耕_3 Thioalkyl]-1,3-benzothiazol-2-yl}-2-[4-(2-ethoxyethyl)piped-indole-yl]acetamide-indole-(6- {[6-(Cyclohexylmethyl)[1,2,4]triazolo[4,3-indene]indole-3-yl]sulfanyl}-1,3·benzothiazol-2-yl )-2-(4-cyclopropylpiped-indole-yl)acetamide-#-( 6-{[6-(cyclohexylmethyl)[1,2,4]triazolo[4,3-6]indole-3-yl]sulfanyl}-1,3-benzothiazole-2 -yl)-2-(morpholin-4-yl)acetamide-(3i?)-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-do]嗒 -3- -3- 琉 ] ] ] ] ] ] ( ( ( ( ( ( ( ( ( ( ;S)-{6-[(6-cyclopropyl[1,2,4]3. Sit and [4,3-do]. morphine-3-yl) thiophanyl]-1,3-benzene And ° plug D sitting _2-yl} carbamic acid 1-methyl η Bilo bite _3_ carbyl ester -{6-[(6-cyclopropyl[1,2,4] bis. sit and [4 , 3-Ζ)]««荅<» well-3-yl)thione]_1,3-benzothiazol-2-yl}carbamic acid 1-methylpiperidin-4-yl- {6-[(6-Cyclopropylindole, 2,4]triazolo[4,3-indole]]indol-3-yl)sulfanyl]_1,3-benzothiazol-2-yl } 1-(2-Fluoroethyl)piperidin-4-ylcarbamate-(3/?)-(6-{[6-(cyclohexylmethyl)[1,2,4]triazole [4,3-6]indol-3-yl]sulfanyl}-1,3-benzopyrene-2-yl)carbamic acid 1-methylpyrrolidin-3-yl vinegar (35> 6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-0]嗒耕-3- 154635.doc •50· 201202242 base]sulfanyl}-l, 3-benzothiazide _2_yl)carbamic acid l-methylpyrrolidin-3-ylindole-6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3 -yl)sulfanyl]-#-[2-(4,4-difluoro-Ethylene-1-yl)ethyl]-1,3-benzo-pyrene-sodium-2-amine-2-( 4-cyclopropylpiperone '* well-1-yl)-#-{6-[(6-methyl[1,2,4]triazolo[4,3-6]indole-3-yl) Thioalkyl]-1,3-benzothiazol-2-yl}acetamide-#-{6-[(6-methyl[1,2,4]triazolo[4,3-6]fluorene Phenyl-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanylamine-#-{6-[(6-methyl[1,2,4]triazolo [4,3-6]嗒耕-3-yl)sulfanyl]-1,3-iso-β嗤-2-yl}-2-(morphin-4-yl)ethenol-1- (6-{[6-(cyclohexylfluorenyl)[ι,2,4]triazolo[4,3-6]indole-3-yl]thioalkyl}-1,3-benzothiazole_ 2·yl)-3-[2-(morpholin-4-yl)ethyl] gland_Ν_(6-{[6·(cyclohexylmethyl)[1,2,4]triazolo[4, 3-b]嗒耕-3-yl]sulfanyl}-1,3-benzothiazolyl)cyclopropanecarbamide _ N_(6_{[6-(cyclopropyl)[1,2,4] Triazolo[4,3-b]indole-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanoinamide-N-{6-[(6-ring Propyltriazolo[4,3_b]indole-3_yl)sulfide ]]-1,3-Benzene 塞 唾 • • • • [ [ [ [ [ [ [ [ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Triazolo[4,3-b]indol-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}_2-(morpholine-4-yl)acetamide- #-{6-[(6-Cyclopropyl[1,2,4]triazolo[4,3_6]indole_3_yl)sulfanyl]-1,3-benzothiazol-2-yl }-2-(4-ethylpiped-1-yl)acetamide-#-{6-[(6-cyclopropyl[12 4]triazolo[4 3_6]indole_3_yl) Thioalkyl]-1,3-benzothiazolyl-2-yl}_2_[(2R 6S) 2 6 Dimercaptomorpholine_4_yl] 154635.doc -51· 201202242 Ethylamine-N-{6 -[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒p well_3·yl)thio-cadaveryl]-1,3-benzothiazol-2-yl} -2-(1,4-Dioxa-8-azaspiro[4,5]indole-8-yl)acetamide-2-[4-(cyclopropylindolyl)piped-1-yl] -Ν-{6-[(6·cyclopropyl[12 4]三零坐和[4,3-b].荅ρ井-3-yl)thiol group]-1,3-benzoxanthion-2-yl}acetamido-2-(4-cyclobutyl D bottom ρ well-1-yl)-Ν -{6-[(6-cyclopropyl[1,2,4]III. Sodium[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole-2 -yl}acetamide-2-(4-cyclopropyl-3,5-dimethylpipen-bry)-N-{6-[(6-cyclopropyl[1,2,4]3 Zoxa[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamido-N-{6-[(6-cyclopropyl[1] , 2,4]triazolo[4,3-b]indole_3-yl)sulfanyl]-1,3-benzo-suppleral beta-spin-2-yl}-2-[(lS,4S) -2 -oxa-5-azabicyclo[2,2,1]hept-5-yl]ethanoamine-N-{6-[(6-cyclopropyl[1,2,4]triazole [4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(8-oxa-3-azabicyclo[3,2, 1] 辛_3·yl) acetamidine-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfane ]]-5-fluoro-1,3-benzoindole "sitting-2-yl}-2-(4·ethylpi-p--1-yl)ethinamine-Ν·6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzoxanthion-2-yl}-2- [4-(Propan-2-yloxy) ketone] acetamidine-Ν·6-[(6-ring [1,2,4] triazolo [4,3-b] despair morphine-3-yl) sulfane 154635.doc • 52- 201202242 yl] -1,3-benzene ° Bian plug. Sodium-2-yl}-2-[4-(4-ethylanthine p-l-yl). °°定-1 -yl] acetamidine-yi{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1)]indol-3-yl)sulfane ]]-1,3-benzothiazol-2-yl}-2-(2-oxa-6-azaspiro[3,3]hept-6-yl)acetamide-Ν-{6-[ (6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzo-3-insole-β-yl-2-yl} -2-[4-(1-indenyl. oxazepine-4-yl) sentinel-1 -yl] acetamidine-Ν-{6-[(6-cyclopropyl[1,2,4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-{4-[(4-mercaptoploxacin-1 -yl)carbonyl]piperidin-1-yl}acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3- Base) sulfanyl]-1,3-benzoquinone ° plug. -2--2-yl}-methyl 吓-4-yl] ethanoamine-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒Rhen-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]acetamide- N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-5-fluoro-1,3-benzene And thiazol-2-yl}-2-[(lS,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-yl]acetamidamine-yi{6-[( 6-Cyclopropyl[1,2,4]triazolo[4,3-15]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-( 4-oxopiperidin-1-yl)acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3- Thioalkyl]-1,3-benzothiazol-2-yl}-2-(3-decyloxyazetidin-1-yl)acetamide 154635.doc •53- 201202242 -N -{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- }[2-(4-pyrrolidin-1-yl)piperidin-1-yl]acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazole And [4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(2-hydroxyethyl)pipepone-1- Ethylamine-7V-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6] Indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(.pyrrolidin-1-yl)acetamide-#-{6-[(6- Cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(3- Hydroxypyrrolidin-1-yl)acetamide-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-δ]indole-3-yl)sulfane ]]-1,3-benzothiazol-2-yl}-2-(3-fluoropyrrolidin-1-yl)acetamide-2-[(lS,4S)-5-cyclopropyl- 2,5-diazabicyclo[2,2,1]heptan-2-yl] {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6] -3-yl)sulfanyl]-l,3-benzothiazol-2-yl}acetamide-2-[4-(4-cyclopropyl 0 bottom p--1-yl) 0 bottom -1-yl]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3 -benzothiazol-2-yl}acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfur Alkyl]-1,3-benzothiazol-2-yl}-2-[1-(2,2-difluoroethyl)piperidin-4-yl]acetamide-N-{6-[( 6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[ 1-(2,2,2-trifluoroethyl)piperidine-4-yl]acetamide-54- 154635.doc 201202242 -2-( 4-cyclopropylmorphin-2-yl)-N-{6-[(6-cyclopropyl[i,2,4]triazolo[4,3-13]"荅<»井_ 3-yl)thioalkyl]-1,3-benzoindole 11 sitting_2-yl}acetamido-2-(4-cyclopropyl-n--3-yl)-N-{6-[( 6-cyclopropyl[i,2,4]triazolo[4,3-b]t--3-yl)thioalkyl]-1,3-benzoxanthene-2-yl}acetamide -Ν-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzopyrene -2-yl}-2-[4-(2-methylpropan-2-yl)pyr-1-yl]acetamide-2-[4-(but-2-yl)-plowing-1 -yl]-N-{6-[(6-cyclopropyl[ι,2,4]triazolo[4,3-b]»indol-3-yl)thiol]-1,3- Benzopyrene 2 -yl}Ethylamine-Ν6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒'• well-3-yl )sulfanyl]-1,3-benzo"sep-2-yl} -2-[4-(methyl hydrazino) sentinus __1_yl]acetamide-N-{6-[ (6-Cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzo-Sev-2-yl}- 2-[4-(Propan-2-yl)n-n-heptyl-yl]acetamide-N2-cyclopropyl-N-{6-[(6-cyclopropyl[1,2,4]3 . Sit and [4,3-b]"荅p well _ 3 -base) sulphur-based]-1,3-benzo-β-β-yl-2-yl}-N2-ethylglycine-amine-N -{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- }^2-ethyl-N2-propan-2-ylglycine amide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole呼-3-yl)sulfanyl]-1,3-benzothiazol-2-*}-N2-[2-(dimethylamino)ethyl]-N2-ethylglycinamide-2 -[4-(1-Ph-propyl-propyl Nitrile-4-yl)-p--1-yl]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4 , 3-1 >] 嗒-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide 154635.doc -55- 201202242 -2-{4-[1-( Cyclopropylmethyl). bottom.定·4-基]派井-l-基}-N-{6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl) Thioalkyl]-1,3-benzothiazol-2-yl}acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b] Indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(4-hydroxypiperidin-1-yl)acetamide-N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(3 -methoxypyrrolidin-1yl)acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl Sulfuryl]-1,3-benzothiazol-2-yl}-2-[3-(diethylamino)pyrrolidinyl]indolyl-acetamide-N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[3 -(2-ethoxyethoxypyrrolidinyl-b-yl)acetamide-2-[4-(1-cyclopropylethyl)pipedyl]-N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl l·1,3·benzothiazol-2-yl}acetamid-amine -{6·[(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- }}-2-(1-methylpiperidin-4-yl)acetamide-N-{6-[(6- Propyl [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3,benzothiazol-2-yl}-2-(1-A Isopiperidin-2-yl)acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfane ]]-1,3-benzothiazol-2-yl}-2-(1-methylpyrrolidin-3-yl)ethenylamine-N-{6-[(6-cyclopropyl[1] , 2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-4-methylmorpholin-2-indole Indoleamine-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfane 154635.doc -56- 201202242 base] -1,3-benzothiazol-2-ylpyridin-1-mercaptopiperidine-3-carboxamide• N-{6-[(6-cyclopropyl[1,2,4]triazolo[4 , 3-b] tareng-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-1-methylpiperidine-4-carboxamide-2-[1-(ring Propyl fluorenyl) slightly bit -4-yl]-N-{6-[(6-cyclopropyl[1,2,4] bis-[4,3-b]-t-p--3-yl Sulfur-based group -1,3 - stupid and sputum. _2_yl}acetamide-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole_3_yl)sulfanyl] -1,3-benzothiazolyl-2-yl}_1,4-dimethylpiped_2_nonylamine-6-[(6-cyclopropyl[1,2,4]triazolo[4 ,3-b]嗒耕_3_yl)sulfanyl b N-(l-ethylpyrrolidine_3_yl)_13_benzothiazole_2•amine•6-[(6-cyclopropyl[丨,2,4]triazolo[4,3_b]indole _3_yl)sulfanyl]_ Ν·[1-(tetrahydrofuran-2-ylmethyl)piperidine benzothiazol-2-amine and the An addition salt of a product of the formula (I) with a pharmaceutically acceptable inorganic or organic acid or a pharmaceutically acceptable inorganic or organic base. The present invention also relates to a pharmaceutical composition comprising a product of the formula (I) as defined above or a pharmaceutically acceptable salt of the product or a prodrug of the product as an active ingredient, and if appropriate A pharmaceutically acceptable carrier. Accordingly, the present invention encompasses a pharmaceutical composition comprising at least one drug as defined above as an active ingredient. The pharmaceutical compositions of the present invention may also contain other active ingredients which are resistant to mitotic drugs (especially anti-mitotic drugs such as paclitaxel, cisplatin, __inserts and the like). ', these pharmaceutical compositions can be administered orally, parenterally or by topical application 154635.doc •57-201202242 for topical administration to the skin and mucous membranes, or by intravenous or intramuscular injection . Such compositions may be solid or liquid and may be in any pharmaceutical form commonly used in human medicine, such as simple lozenges or dragees, pills, buccal bonds, gel capsules, drops, granules, injectable preparations, ointments, Cream or gel; it is prepared according to conventional methods. The active ingredient may be incorporated with such excipients commonly used in such pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or plant sources Fatty substances, paraffin derivatives, glycols, various wetting agents, dispersing or emulsifying agents and preservatives. For adults, the usual dosage which varies depending on the product used, the patient being treated, and the patient being studied may be, for example, 0.05 to 5 g per day, or preferably 0.1 to 2 g per day. The subject matter of the present invention is also the use of the product of the formula (1) as defined above or a pharmaceutically acceptable salt of such a product, which is used for the preparation of a medicament for inhibiting the activity of a protein. The subject matter of the invention is also the use of a product of formula (1) as defined above for the manufacture of a medicament for the treatment or prevention of a disease characterized by the activity of a kinase protein. The medicament is particularly intended for use in the treatment or prevention of a disease in a mammal. One of the objects of the invention is also the use as defined above. The white is a histidine kinase protein. Wherein the kinase egg is tyrosine, one of the inventions is also the use as defined above. The kinase protein is MET or a mutant form thereof. 154635.doc -58.201202242 One of the subject matter of the invention is also the use as defined above, wherein the white is in the cell culture. The subject matter of the invention is also the use as defined above, wherein the kinase protein is used in beta-south milk animals, and the use of the product of formula (1), as defined above, for the prevention of preparation Or a drug that treats a disease associated with uncontrolled colonization. And the use of a product of formula (1) as defined above, in particular for the manufacture of a medicament for the treatment or prevention of a disease selected from the group consisting of vascular proliferative disorders, fibrotic disorders, "kidney septum" Cell Proliferation, Metabolic Disorders, Allergies, Asthma, Thrombosis, Nervous System Diseases, Retinopathy, Psoriasis, Rheumatoid Arthritis, Diabetes, Muscle Degeneration, Bacterial Infections (especially Listeria monocytogenes ( ζ Infections and cancers. Thus, most particularly, one of the inventions is directed to the use of a product of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of neoplastic diseases and especially for the treatment of cancer. In these cancers, attention is focused on the treatment of solid or liquid tumors and the treatment of cancers against cytotoxic agents. The products of the invention mentioned may be especially useful for the treatment of primary tumors and/or metastases, especially gastric cancer, liver cancer , kidney cancer, ovarian cancer, intestinal or prostate cancer, lung cancer (NSCLC and SCLC), glioblastoma, verrucous adenocarcinoma, bladder or breast cancer, melanin Tumor, lymphoid or bone marrow hematopoietic tumor, sarcoma, brain cancer, laryngeal cancer, lymphatic system cancer, bone cancer and pancreatic cancer. 154635.doc -59- 201202242 One of the objects of the invention is also the product of formula (1) as defined above The use thereof is for the preparation of a medicament for use in cancer chemotherapy. The medicaments to be used in cancer chemotherapy can be used singly or in combination. The products of this patent application can be administered alone or in combination with chemotherapy or radiation. The therapeutic combination is administered or administered in combination with, for example, other therapeutic agents. The therapeutic agents may be commonly used anti-tumor agents. The kinase inhibitors which may be mentioned include butyrolactone, flavopiddol and 2·(2_ Hydroxyethylamino)6-benzylaminoamino-9(曱l新m〇ucine). One of the objects of the present invention is also as a novel industrial product as above. Synthesis of equations (c), (Dl), (D2), (D3), (D4), (D5), (D6), (G), (κ), and (M) defined and mentioned again below Intermediate:

154635.doc -60 - 201202242 其中R1、Rb、R3、R4、R5及R6具有如上文對於式(I)產物 所示之定義。 以下實例為式(I)產物,其說明本發明,但不限制本發 明。 【實施方式】 實驗部分 另外使用之微波為Biotage,Initiator™ 2.0,最大為400 W,2450 MHz機器。 在303 K之溫度下,在Brtiker Avance DRX-400光譜儀上 獲得400 MHz下之1H NMR譜,其中化學位移(δ,以ppm 計)為在用作參照之溶劑二曱亞砜-d6(DMSO-d6)(2.5 ppm) 中之化學位移。 質譜(MS)經由方法A、方法B或方法C獲得:154635.doc -60 - 201202242 wherein R1, Rb, R3, R4, R5 and R6 have the definitions as indicated above for the product of formula (I). The following examples are the products of formula (I) which illustrate the invention but are not intended to limit the invention. [Embodiment] Experimental section The microwave used in addition is Biotage, InitiatorTM 2.0, up to 400 W, 2450 MHz machine. The 1H NMR spectrum at 400 MHz was obtained on a Brtiker Avance DRX-400 spectrometer at a temperature of 303 K, where the chemical shift (δ, in ppm) was the solvent used in the reference disulfoxide-d6 (DMSO- Chemical shift in d6) (2.5 ppm). Mass spectrometry (MS) is obtained via Method A, Method B or Method C:

LC/MS中所用之分析條件 方法A 在Waters UPLC-SQD機器上獲得譜圖 電離:電噴霧,正離子及/或負離子模式(ES+/-) 層析條件: •管柱:AcquityBEHC18-1.7 μπι-2.1 x50 mm •溶劑:A : H2O(0.1%曱酸)B : CH3CN(0.1%甲酸) •管柱溫度:50°C •流速:1 ml/min •梯度(2分鐘):在0·8分鐘内,5%至50% B ; 1.2分鐘: 100% Β ; 1.85分鐘·· 100% Β ; 1.95 ·· 5% Β 154635.doc -61 - 201202242Analytical conditions used in LC/MS Method A Spectral ionization was obtained on a Waters UPLC-SQD machine: electrospray, positive ion and/or negative ion mode (ES+/-) Chromatographic conditions: • Column: AcquityBEHC18-1.7 μπι- 2.1 x50 mm • Solvent: A: H2O (0.1% citric acid) B: CH3CN (0.1% formic acid) • Column temperature: 50 ° C • Flow rate: 1 ml/min • Gradient (2 minutes): at 0·8 minutes Within, 5% to 50% B; 1.2 minutes: 100% Β; 1.85 minutes·· 100% Β; 1.95 ·· 5% Β 154635.doc -61 - 201202242

方法B 在Waters ZQ機器上獲得譜圖 電離:電喷霧,正離子及/或負離子模式(ES+/-) 層析條件: •管柱:XBridge C18-2.5 μηι-3χ50 mm •溶劑:A : H2O(0.1%甲酸)B : CH3CN(0.1% 甲酸) •管柱溫度:70°C •流速:0.9 ml/minMethod B Spectral ionization on a Waters ZQ machine: electrospray, positive ion and/or negative ion mode (ES+/-) Chromatographic conditions: • Column: XBridge C18-2.5 μηι-3χ50 mm • Solvent: A: H2O (0.1% formic acid) B : CH3CN (0.1% formic acid) • Column temperature: 70 ° C • Flow rate: 0.9 ml/min

•梯度(7分鐘):在5.3分鐘内,5%至100% B ; 5·5分鐘: 100% Β ; 6.3分鐘:5% Β 方法C 獲得譜圖: 在 Waters UPLC-SQD機器上 電離:電喷霧,正離子及/或負離子模式(ES+/-) 層析條件: •管柱:Acquity UPLC BEH C18-1.7 μιη-2.1χ30 mm •溶劑:A : Η20(0·10/〇 曱酸)Β : CH3CN(0.10/〇甲酸) •管柱溫度:45°C •流速:0.6 ml/min •梯度(2分鐘) : 時間(分鐘) % A %B 0 95 5 1 50 50 1.30 0 100 154635.doc 201202242 1.45 0 100 1.75 95 5 2 95 5 或在 Waters UPLC- -XEVO/Qtof機器上 電離:電喷霧,正離子模式(ES + ) 層析條件: •□管柱:Acquity UPLC BEH C1 8-1.7 μιη-2· lxioo mm .□溶劑:A : H2O(0.10/o 甲酸)B : CH3CN(0.1〇/〇 甲酸) •□管柱溫度:55°C •□流速:0.55 ml/min• Gradient (7 minutes): 5.3 to 100% B in 5.3 minutes; 5·5 minutes: 100% Β; 6.3 minutes: 5% Β Method C to obtain spectra: ionization on a Waters UPLC-SQD machine: electricity Spray, positive ion and / or negative ion mode (ES+/-) Chromatographic conditions: • Column: Acquity UPLC BEH C18-1.7 μιη-2.1χ30 mm • Solvent: A: Η20 (0·10/capric acid)Β : CH3CN (0.10/〇carboxylic acid) • Column temperature: 45 ° C • Flow rate: 0.6 ml/min • Gradient (2 minutes): Time (minutes) % A %B 0 95 5 1 50 50 1.30 0 100 154635.doc 201202242 1.45 0 100 1.75 95 5 2 95 5 or ionization on a Waters UPLC- -XEVO/Qtof machine: electrospray, positive ion mode (ES + ) Chromatographic conditions: • □ column: Acquity UPLC BEH C1 8-1.7 Ιιη-2· lxioo mm .□ Solvent: A : H2O (0.10/o formic acid) B : CH3CN (0.1 〇 / 〇 formic acid) • □ column temperature: 55 ° C • □ flow rate: 0.55 ml / min

•□梯度(11分鐘):在8.3分鐘内,5%至97% B ; 8.6分鐘: 100% B ; 9分鐘:5% B 實例1 : 1-{6·[(6-環丙基[1,2,4】***并[4,3-b】嗒畊_3_基)硫 烧基]-1,3·笨并嗔唾_2-基}-3-丨2-(嗎琳_4_基)乙基】腺 a) 環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]- 1,3-苯并噻唑_2_基嗎啉_4_基)乙基]脲可以如下方式 製備: 在10 cm3三頸燒瓶中,將〇.217 g Η2·(嗎啉_4基)乙基]_ 3-(6-硫燒基_ι,3_苯并售。坐_2_基)腺及0125 g 3-氯-6-環丙基 [1,2,4]二。坐并[4,3-办]塔ρ井溶解於3.5 cm3正丁醇中。在氛氣 噴射下將所得溶液脫氣約15分鐘。添加n 57 g磷酸鉀於 1.1 cm3水中之溶液,且使混合物在氬氣下回流約2〇小時。 冷卻至約20 C之溫度之後,渡出不溶物質。用5〇 cm3乙 酸乙酯稀釋母液,且用50 cm3水洗滌。用5〇 cm3乙酸乙酯 I54635.doc •63· 201202242 再萃取水相兩次。經硫酸鎂乾燥經合併之有機相,過渡且 在減壓下濃縮至乾。二氧化矽管柱急驟層析[溶離劑:二 氣甲烷/甲醇(95/5,以體積計)]之後,獲得0.061 g呈白色 固體狀之1-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫 烷基]-1,3-苯并噻唑-2-基}-3-[2-(嗎啉-4-基)乙基]脲,其特 徵如下: 炼點:244-246。〇(考夫勒塊(KSflerblock)) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.88至 0.98 (m 2印;1.〇6至1.13(111,2印;2.17至2.26(111,111);2.37至2.46 (m,6 H); 3·25 至 3.35 (部分遮蔽之多重峰,2 H); 3.59 (m,4 H); 6.77 (寬多重峰,1 H); 7 29 (d,J=9 8 Hz,1 H); 7 43 (dd,*/=1.7及 8.6 Hz,1 H); 7.56 (d,J=8.6 Hz,1 H); 8.05 (d, ’1·7 Hz’ 1 H); 8·26 (d,/=9.8 Hz,1 H); 10.89 (寬多重峰, 1 Η) ,• □ gradient (11 minutes): within 8.3 minutes, 5% to 97% B; 8.6 minutes: 100% B; 9 minutes: 5% B Example 1: 1-{6·[(6-cyclopropyl[1] , 2,4] Triazolo[4,3-b]嗒耕_3_基)thiol group]-1,3·笨笨嗔嗔_2-基}-3-丨2-(么琳_ 4_yl)ethyl]gland a) cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazole_ 2_Gimorpholine_4_yl)ethyl]urea can be prepared as follows: In a 10 cm3 three-necked flask, 217.217 g Η2·(morpholine-4-yl)ethyl]_ 3-(6- Sulfur-based _ι, 3_ benzene is sold. Sit 2_g) gland and 0125 g 3-chloro-6-cyclopropyl [1, 2, 4] bis. Sit and [4,3-do] tower p well dissolved in 3.5 cm3 n-butanol. The resulting solution was degassed under atmospheric spray for about 15 minutes. A solution of n 57 g of potassium phosphate in 1.1 cm3 of water was added and the mixture was refluxed under argon for about 2 hours. After cooling to a temperature of about 20 C, insoluble matter is withdrawn. The mother liquor was diluted with 5 〇 cm 3 of ethyl acetate and washed with 50 cm 3 of water. The aqueous phase was extracted twice with 5 〇 cm 3 of ethyl acetate I54635.doc • 63· 201202242. The combined organic phases were dried over MgSO4,EtOAcEtOAc After flash chromatography of ruthenium dioxide column [solvent: di-methane/methanol (95/5 by volume)], 0.061 g of 1-{6-[(6-cyclopropyl) was obtained as a white solid. 1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholine- 4-yl)ethyl]urea, which has the following characteristics: Refining point: 244-246. 〇 (Kfler block) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.88 to 0.98 (m 2 imprint; 1. 〇6 to 1.13 (111, 2 imprint; 2.17 to 2.26 ( 111,111); 2.37 to 2.46 (m,6 H); 3·25 to 3.35 (partially masked multiplet, 2 H); 3.59 (m, 4 H); 6.77 (width multiple, 1 H); 29 (d, J=9 8 Hz, 1 H); 7 43 (dd, */=1.7 and 8.6 Hz, 1 H); 7.56 (d, J=8.6 Hz, 1 H); 8.05 (d, '1 ·7 Hz' 1 H); 8·26 (d, /=9.8 Hz, 1 H); 10.89 (width multiple peak, 1 Η),

質譜:方法A 滞留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 497; [M-H]-: m/z 495 b) 3氣-6-%丙基[12,4]***并[4 3 6]嗒畊可以如下方式製 備: 在氬氣喷射下向0.7 g 3,6·二氯[1,2,4]***并[4,3-6]嗒畊 於1〇 cm3四氫呋喃中之溶液中添加llu⑽3漠(環丙基)辞 於四氣咬喃中之〇·5 M溶液。約15分鐘之後,添加〇 〇95 g 雙(一第二丁基膦)鈀且使混合物回流2小時❶濃縮反應混合 物及一氧化矽營柱急驟層析[溶離劑:二氯甲烷/甲醇 154635.doc •64- 201202242 (98/2,以體積計)]之後’獲得〇 345 g泡沫。將此泡珠溶解 於5 cm —曱氧基乙烷中,添加i em3 i N氫氧化鈉且在 約9(TC之溫度下維持溶液約30分鐘。冷卻至約2〇χ:之溫度 之後,將溶液傾倒於l〇〇cm3水中且用50cm3乙酸乙酿萃取 二次。用50 cm3水洗滌經合併之有機相三次,經硫酸鎂乾 燥,過濾且在減壓下濃縮至乾。獲得〇·299 g呈淺黃色固體 狀之3-氯-6-環丙基Π,2,4]ι唑并[4,3外荅畊,其特徵如 下: m NMR (彻 MHz,s (ppm),DMS〇姆 i 別至 i 22 (m 4 H); 2.17^2.36 7.29 (d, ^9.8 Hz, 1 H); 8.27 (d, •7=9.8 Hz, 1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.57 ; [M+H] + : m/z 195 l-[2-(嗎琳-4-基)乙基]_3·(6_硫院基w•苯并嗟峻·2•基) 脲如專利WO 2009/056 692中所述製備。 實例2 L環丙基fl,2,4】三唾并【4 3_b卜终3基)硫燒 基]-1,3-苯并嘆嗤-2-胺 —6-U6·環丙基Π,2,4]三料[4,3_6則_3基)魏基]H 笨并。塞嗤-2-胺可以如下方式製備. 將〇.451 g硫氰酸2·胺基笨并w_6m4 3_氣_6·環丙基[1,2,4]三唾并[4,3爾_於53 em3乙醇中之 溶液及0.012 g磷酸二氫鉀於2 4 cm3 ^上 — 4 em水中之溶液的懸浮液用 氬氣脫氣約1小時。添加丨.22 1 + S ,4 一硫_dl_穌糖醇且使混 154635.doc -65- 201202242 合物回流約20小時》 冷卻至約20°C之溫度之後,將混合物傾倒於丨〇〇 cm3飽 和碳酸氫鈉溶液中且用1〇〇 cm3二氣甲烷萃取三次。用1〇〇 cm3水及1〇〇 cm3飽和氣化鈉溶液洗滌經合併之有機相三 次’經硫酸鎂乾燥’過濾且在減壓下濃縮^二氧化矽管柱 急驟層析[溶離劑:二氯曱烷/甲醇(95/5,以體積計)]之 後,獲得0.134 g呈白色固體狀之6_[(6_環丙基[124]*** 并[4,3-6]»答°井-3-基)硫院基]_1,3_苯并嗔。坐_2-胺,其特徵如 下: 熔點:218-225。〔:(步奇(Buchi.)) 1H NMR (400 MHz, δ (ppm), DMSO-d6): 0.97 (m, 2 H); 1.11 (m,2 H); 2.23 (m,i h); 7.25至 7.30 (m,2 H); 7.35 (dd,*7=2.0 及 8.6 Hz,1 h); 7.63 (寬單峰,2 H); 7.86 (d, ^=2.0 Hz, 1 H); 8.24 (d, /=9.7 Hz, 1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 497; [MH]-: m/z 495 b) 3 gas-6-% propyl [12,4] Zyzolo[4 3 6] tillage can be prepared as follows: Under argon injection, 0.7 g of 3,6·dichloro[1,2,4]triazolo[4,3-6]嗒 is cultivated in 1〇. Add a solution of llu(10)3 (cyclopropyl) to the solution of cm3 in tetrahydrofuran. After about 15 minutes, 〇〇95 g of bis(a-butylphosphine)palladium was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated and the ruthenium oxide column was flash chromatographed [solvent: dichloromethane/methanol 154635. Doc •64-201202242 (98/2, by volume)] After 'get 〇345 g foam. The beads were dissolved in 5 cm-methoxysilane, i em3 i N sodium hydroxide was added and the solution was maintained at about 9 (TC temperature for about 30 minutes. After cooling to about 2 Torr: temperature, The solution was poured into 1 〇〇 cm 3 of water and extracted twice with 50 cm 3 of EtOAc. The combined organic phases were washed three times with 50 cm of water, dried over magnesium sulfate, filtered and evaporated to dryness g 3-chloro-6-cyclopropyl hydrazine, 2,4]oxazolidine [4,3 exogenous tillage, characterized by the following: m NMR (complete MHz, s (ppm), DMS〇) m i to i 22 (m 4 H); 2.17^2.36 7.29 (d, ^9.8 Hz, 1 H); 8.27 (d, •7=9.8 Hz, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) =0.57 ; [M+H] + : m/z 195 l-[2-(morphin-4-yl)ethyl]_3·(6_thiol-based w•benzoxanthene·2•yl) urea Prepared as described in the patent WO 2009/056 692. Example 2 L cyclopropyl fl, 2, 4] trisporin [4 3_b final 3 base) thiol]] 1,3-benzopyran-2 -amine-6-U6.cyclopropyl hydrazine, 2,4] three materials [4,3_6 _3 yl) Weiyl]H stupid. The sulphate-2-amine can be prepared in the following manner. 〇.451 g thiocyanate 2·amine stupid and w_6m4 3_gas _6·cyclopropyl[1,2,4]tris-[4,3 er A suspension of the solution in 53 em3 ethanol and 0.012 g of potassium dihydrogen phosphate in 2 4 cm 3 ^ - 4 em of water was degassed with argon for about 1 hour. Add 丨.22 1 + S , 4 sulphur _dl_sugar alcohol and reflux 154635.doc -65-201202242 for about 20 hours. After cooling to a temperature of about 20 ° C, pour the mixture into 丨〇 The solution was extracted three times with 〇〇cm3 of saturated sodium bicarbonate solution and with 1 〇〇cm 3 of methane. The combined organic phases were washed three times with 1 〇〇 cm 3 of water and 1 〇〇 cm 3 of saturated sodium carbonate solution. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure. The cerium dioxide column was rapidly chromatographed [solvent: two After chlorodecane/methanol (95/5 by volume)], 0.134 g of 6-[(6-cyclopropyl[124]triazolo[4,3-6]» A well was obtained as a white solid. -3-yl)thiol group]_1,3_benzopyrene. Sitting on a 2-amine, the characteristics are as follows: Melting point: 218-225. 〔:(Buchi.) 1H NMR (400 MHz, δ (ppm), DMSO-d6): 0.97 (m, 2 H); 1.11 (m, 2 H); 2.23 (m, ih); 7.25 To 7.30 (m, 2 H); 7.35 (dd, *7=2.0 and 8.6 Hz, 1 h); 7.63 (wide unimodal, 2 H); 7.86 (d, ^=2.0 Hz, 1 H); 8.24 ( d, /=9.7 Hz, 1 H)

質譜:方法A 滞留時間Tr(分鐘)=〇63 ; [m+h]+: m/z 341; [M H] : m/z 339 實例3 · Ν-{6·[(6-環丙基[12 4】***并[4 3 b】塔ρ井·3•基)硫 基】1’3苯并嗟唾基}·2_(嗎琳_4基)乙醯胺 Μ ^{6·[(6·環丙基Π,2,4]三口坐并[4,3-6]塔口井-3·基)硫烷基]_ ’苯并噻唑-2-基卜2-(嗎啉_4·基)乙醯胺可以如下方式製 備: 氯氣嘴射下’向0·238 g Ν,Ν,-(二硫烷二基二-l,3-苯并 嗟0坐-6,2-二其彳雔Γο —'签’又〖2·(嗎啉·4_基)乙醯胺]及0 15〇 g 3_氣_6-154635.doc • 66 · 201202242 環丙基[1,2,4]***并[4,3-6]嗒畊於i〇 cm3乙酵中之懸浮液 中添加0.004 g鱗酸二氫钟於2.4 cm3水中之溶液。將混合物 在氬氣下脫氣約30分鐘’添加0.432 g l,4-二硫-DL-蘇糖醇 且使混合物回流約20小時。 冷卻至約2 0 C之溫度之後’將混合物傾倒於5 〇 c m3水 中’藉由添加飽和碳酸氫納溶液調節pH值為約9,且用50 cm乙酸乙酯萃取所得混合物三次。用5〇 cm3水及5〇 cm3飽 和氯化納溶液洗條經合併之有機相三次,經硫酸鎖乾燥, 過濾且在減壓下濃縮。二氧化矽管柱急驟層析[溶離劑: 一氯曱烧/曱醇(96/4,以體積計)]之後,獲得〇142 g呈白 色固體狀之#-{6-[(6-環丙基[1,2,4]***并[4,3-办]嗒畊·3_ 基)硫烷基]_1,3_苯并噻唑_2-基}-2-(嗎啉-4-基)乙醯胺,其 特徵如下: 熔點:255。(:(步奇) 1Η NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.88至 0.96 (ηι 2 H); 1·〇2至 1.12 (m,2 H); 2· 18至 2.27 (m,1 H); 2.53 (部分 遮蔽之多重峰,4 H); 3.33 (s,2 H); 3.56 至 3.63 (m,4 H); 7.30 (d,J=9.8 Hz,1 H); 7.48 (dd,《7=2.0&8.5Hz,lH)· 7.69 (d5 J=8.5 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d •/=9.8 Hz,1 H); 12.18 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.66 ; [M+H] + : m/z 468; [M+2H]2+: m/z 234.5 (基峰) [M-H]-: m/z 466 154635.doc -67- 201202242 b) iV,#’-(二硫烷二基二-丨,^苯并噻唑_6,孓二基)雙[2·(嗎啉· 4-基)乙醜胺]可以如下方式製備: 在約2(TC之溫度下搜拌丨g硫氰酸2_[(氣乙酿基)胺基 1,3-苯并噻唑-6-基酯於1〇 cm3嗎啉中之懸浮液約2〇小時。 將所得溶液在減壓下濃縮至乾。二氧化矽管柱急驟層析 [溶離劑:二氯甲烷/甲醇(98/2,以體積計)]之後,獲得 0.634 g呈淡米色泡沫狀之#,#·_(二硫烷二基二— I%苯并噻 唑-6,2-一基)雙[2-(嗎啉-4-基)乙醯胺],其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 〇63; [m+h]+: m/z 341; [MH]: m/z 339 Example 3 · Ν-{6·[(6-cyclopropyl[ 12 4] Triazolo[4 3 b] ρ 井 · 3 • yl) thio] 1 '3 benzoindoles · · _ · } { { { { ^{6·[( 6·Cyclopropyl hydrazine, 2, 4] three-spot and [4,3-6]Takai-3·yl)sulfanyl]_ 'benzothiazol-2-yl b 2-(morpholine_4 · Benzylamine can be prepared as follows: Chlorine gas nozzle shot 'to 0. 238 g Ν, Ν, - (disulfanediyl bis-l, 3-benzopyrene 0 -6, 2- bis彳雔Γο — 'Sign' and 〖2·(morpholine·4_yl) acetamidine] and 0 15〇g 3_gas _6-154635.doc • 66 · 201202242 Cyclopropyl [1,2,4 Add a solution of 0.004 g of dihydrogen hydride in 2.4 cm3 of water to the suspension of triazo[4,3-6] guanidine in i〇cm3, and degas the mixture under argon for about 30 minutes. 'Add 0.432 gl, 4-dithio-DL-threitol and reflux the mixture for about 20 hours. After cooling to a temperature of about 20 C, 'pour the mixture into 5 〇c m3 water' by adding saturated sodium bicarbonate The solution was adjusted to a pH of about 9 and extracted with 50 cm of ethyl acetate. The mixture was washed three times. The combined organic phases were washed three times with 5 〇 cm 3 of water and 5 〇 cm 3 of saturated sodium chloride solution, dried by sulphuric acid, filtered and concentrated under reduced pressure. Separation of ruthenium dioxide column [solvent] : chlorofluorene/sterol (96/4 by volume)], 〇 142 g was obtained as a white solid #-{6-[(6-cyclopropyl[1,2,4]triazole And [4,3-do] 嗒耕·3_yl)sulfanyl]_1,3-benzothiazol-2-yl}-2-(morpholin-4-yl)acetamide, which has the following characteristics: : 255. (: (step) 1 NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.88 to 0.96 (ηι 2 H); 1·〇2 to 1.12 (m, 2 H); 2· 18 To 2.27 (m, 1 H); 2.53 (partially masked multiplet, 4 H); 3.33 (s, 2 H); 3.56 to 3.63 (m, 4 H); 7.30 (d, J = 9.8 Hz, 1 H 7.48 (dd, "7=2.0&8.5Hz, lH)· 7.69 (d5 J=8.5 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d •/=9.8 Hz, 1 H); 12.18 (width multiple peak, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.66; [M+H] + : m/z 468; [M+2H]2+: m/ z 234.5 (base peak) [MH]-: m/z 466 154635.doc -67- 201202242 b) iV,#'-( Sulfoxdiyldi- fluorene, benzothiazole -6, fluorenyldiyl bis[2·(morpholine-4-yl)ethyl uglyamine can be prepared as follows: Mix at a temperature of about 2 (TC) A suspension of _g thiocyanate 2_[( gas ethoxy)amino 1,3-benzothiazol-6-yl ester in 1 〇 cm 3 of morpholine for about 2 hr. The resulting solution was concentrated to dryness under reduced pressure. After flash chromatography of the ruthenium dioxide column [solvent: dichloromethane/methanol (98/2 by volume)], 0.634 g of a light beige foam was obtained ###-(disulfanediyldiyl) — I% benzothiazole-6,2-mono)bis[2-(morpholin-4-yl)acetamide], which is characterized as follows:

Rf—氧化矽TLC=0.19 [溶離劑:二氣甲烷/甲醇(98/2, 以體積計)] 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 2.54 (部分遮蔽 之夕重峰,8 H),3.55 至 3.66 (m,8 H); 3.74 (s,4 H); 7.57 (<1(1,>/-1.7及8.6 112,2 11);7.72(<1,*/=8.6 112,2 11);8.19(£1., •/=1.7 Hz,2 Η) 質譜:方法A 滯留時間Tr(分鐘)=0.74 ; [M+H] + : m/z 617; [M+2H]2+: m/z 309 (基峰) [M-H]-: m/z 615 c)硫氰酸2-[(氯乙醯基)胺基卜丨,;^苯并噻唑_6_基輯可以如 下方式製備: 使2 g硫氰酸2-胺基-1,3-苯并噻唑-6-基酯於25 cm3二嗔 烧中之懸浮液達到約6 0 C之溫度。向所得溶液中逐滴添加 用5 cm3二噁烷稀釋之1 cm3氣乙醯氣溶液。在約6〇〇c ^授 拌混合物4.5小時,隨後添加〇· 1 Cm3氯乙醯氯且在相同溫 154635.doc -68- 201202242 度下再攪拌所得混合物4小時》冷卻至約20°C之後,藉由 抽吸濾出所形成之沈澱物,用20 cm3二噁烷洗滌一次,隨 後用10 cm3***洗滌三次且在空氣中乾燥。 獲得2.77 g呈白色固體狀之硫氰酸2-[(氣乙醯基)胺基]-1,3-苯并噻唑_6_基酯,其特徵如下: 熔點:196-19VC(考夫勒塊) 質譜:方法A 滯留時間Tr(分鐘)=0.82 ; [M+H] + : m/z 284; [M-H]-: m/z 282 實例4 : 2-(4-環丙基哌畊-1-基)_Ν-{6·【(6·環丙基[^4]*** 并[4,3-b]嗒井-3-基)硫烷基】-1,3-苯并噻唑_2-基}乙醯胺 a) 2-(4-環丙基哌畊-1·基環丙基[12 4]***并 [4,3-6]嗒》井-3-基)硫烷基]-1,3-苯并噻唑_2-基}乙醯胺可以 如下方式獲得: 將0.288 g硫氰酸2-{[(4-環丙基哌p井小基)乙醯基]胺基卜 1,3-苯并噻唑-6_基酯、〇.15〇 g 3_氣_6_環丙基***并 [4,3-6]嗒啡於1〇 cm3乙醇中之溶液及〇.〇〇4 g磷酸二氬鉀於 2.4 cm水中之溶液的懸浮液用氬氣脫氣3〇分鐘,繼而添加 0.432 g 1,4-二硫-DL-蘇糖醇。使懸浮液回流約18小時。冷 部至約2(TC之溫度之後,將混合物傾倒於5〇 cm3水中,藉 由添加飽和碳酸氫鈉溶液調節?11值為約9,且用% em3二 氣甲烧萃取所得混合物三次。㈣W水洗祕合併之有 機相三次’經硫酸鎮乾燥,過遽且在減壓下濃縮至乾。二 氧化石夕管柱急驟層析[溶離劑:二氯曱烧/曱醇(95/5,以體 154635.doc •69· 201202242 積計)]之後’獲得0.078 g呈白色固體狀之2_(心環丙基派 畊-1-基)-7V-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊_3_基)硫 烷基]-1,3·苯并噻唑-2-基}乙醯胺,其特徵如下: 熔點:205-210°C(考夫勒塊) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.22至 〇 3〇 (m, 2 H); 0.39 (m,2 H); 0.87至 0.95 (m,2 H); [(^至! 13 (m 2 H); 1.61 (m,1 H); 2.22 (m,1 H); 2.46 至 2.59 (部分遮蔽之 多重峰,8 H); 3.31 (s,2 H); 7.30 (d,·7=9.8 HZ,1 H); 7.48 (dd,>/=2.0&8.4HZ,lH);7.70(d,</=8.4HZ,iH);814(d, •/=2.0 Hz,1 H); 8.28 (d,*7=9.8 Hz,1 H); 12.00 (寬多重峰, 1 Η) 質譜:方法B 滯留時間Tr(分鐘)=2.92 ; [M+H] + : m/z 507; [M+2H]2 + : m/z 254 (基峰) [M-H]-: m/z 505 b)硫氰酸2-{[(4-環丙基哌畊_i_基)乙醯基]胺基卜丨,%笨并 噻唑-6-基酯可以如下方式製備: 向〇.1 g硫氰酸2·[(氯乙醯基)胺基]_1,3_苯并噻唑_6_基酯 於2 cm3 4-甲基嗎啉中之懸浮液中添加〇〇84 g丨·環丙基娘 畊二鹽酸鹽且攪拌懸浮液18小時。在減壓下濃縮至乾及二 氧化石夕管柱急驟層析[溶離劑:二氣甲烷/甲醇(95/5,以體 積計)]之後’獲得0.081 g呈白色固體狀之硫氰酸2_{[(4_環 丙基娘1*井-1-基)乙醯基]胺基}_1,3_苯并<1塞11坐_6_基醋,其特 徵如下: 154635.doc •70· 201202242Rf—yttrium oxide TLC=0.19 [esolvent: di-gas methane/methanol (98/2 by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 2.54 (partially obscured , 8 H), 3.55 to 3.66 (m, 8 H); 3.74 (s, 4 H); 7.57 (<1 (1,>/-1.7 and 8.6 112, 2 11); 7.72 (<1, */=8.6 112,2 11); 8.19 (£1., •==1.7 Hz, 2 Η) Mass Spectrometry: Method A Retention time Tr (minutes) = 0.74; [M+H] + : m/z 617; [M+2H]2+: m/z 309 (base peak) [MH]-: m/z 615 c) thiocyanate 2-[(chloroethyl)aminopurin, benzothiazole _ The 6_base can be prepared as follows: A suspension of 2 g of 2-amino-1,3-benzothiazole-6-yl thiocyanate in 25 cm3 of diterpene is brought to a temperature of about 60 °C. To the resulting solution, a 1 cm 3 gas acetonitrile solution diluted with 5 cm 3 of dioxane was added dropwise. The mixture was stirred at about 6 ° C for 4.5 hours, then 〇·1 Cm3 chloroacetamidine chloride was added and the resulting mixture was stirred for another 4 hours at the same temperature of 154635.doc -68-201202242 °" after cooling to about 20 ° C The precipitate formed was filtered off by suction, washed once with 20 cm3 of dioxane, then three times with 10 cm3 of diethyl ether and dried in air. 2.77 g of 2-[(glymethylene)amino]-1,3-benzothiazole-6-yl thiocyanate as a white solid are obtained, which are characterized by the following: Melting point: 196-19 VC (Coffler) Block) Mass Spectrometry: Method A Retention time Tr (minutes) = 0.82; [M+H] + : m/z 284; [MH]-: m/z 282 Example 4: 2-(4-cyclopropylpiped- 1-yl)_Ν-{6·[(6·cyclopropyl[^4]triazolo[4,3-b]嗒-3-yl)sulfanyl]-1,3-benzothiazole_ 2-yl}acetamide a) 2-(4-cyclopropylpiped-1·ylcyclopropyl[12 4]triazolo[4,3-6]fluorene-3-yl)sulfane The base]-1,3-benzothiazolyl-2-yl}acetamide can be obtained in the following manner: 0.288 g of 2-{[(4-cyclopropylpiperylpyridinyl)ethinyl]amine thiocyanate a solution of 1,3-benzothiazol-6-yl ester, 〇.15〇g 3_gas_6_cyclopropyltriazolo[4,3-6]morphine in 1〇cm3 of ethanol and A suspension of a solution of 4 g of potassium dihydrogen phosphate in 2.4 cm of water was degassed with argon for 3 minutes, followed by the addition of 0.432 g of 1,4-dithio-DL-threitol. The suspension was refluxed for about 18 hours. After the cold portion to about 2 (the temperature of TC, the mixture was poured into 5 〇cm 3 of water, adjusted to a value of about 9 by the addition of a saturated sodium hydrogencarbonate solution, and the resulting mixture was extracted three times with a % em 3 gas. (IV) W The combined organic phase was washed three times with sulphuric acid, dried over hydrazine and concentrated to dryness under reduced pressure. Separation of sulphur dioxide and sulphuric acid column [solvent: dichlorohydrazine/decyl alcohol (95/5, Body 154635.doc •69· 201202242 Accumulation)] After '0.078 g of white solid 2_(heart ring propyl phenyl-1-yl)-7V-{6-[(6-cyclopropyl[1] , 2,4]triazolo[4,3-6]indole_3_yl)sulfanyl]-1,3·benzothiazol-2-yl}acetamide, characterized by the following: Melting point: 205 -210 ° C (Cafele block) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.22 to 〇3〇 (m, 2 H); 0.39 (m, 2 H); 0.87 to 0.95 ( m,2 H); [(^ to! 13 (m 2 H); 1.61 (m,1 H); 2.22 (m,1 H); 2.46 to 2.59 (partially masked multiplet, 8 H); 3.31 ( s, 2 H); 7.30 (d, ·7=9.8 HZ,1 H); 7.48 (dd,>/=2.0&8.4HZ,lH); 7.70 (d, </=8.4HZ, iH) ;814 (d, •==2.0 Hz, 1 H); 8.28 (d, *7 = 9.8 Hz, 1 H); 12.00 (width multiple peak, 1 Η) Mass Spectrum: Method B Retention time Tr (minutes) = 2.92; [M+H] + : m/z 507; [M+ 2H]2 + : m/z 254 (base peak) [MH]-: m/z 505 b) 2-{[(4-cyclopropylpiperidine_i_yl)ethenyl]amino group Dimethoate, % stupid and thiazole-6-yl ester can be prepared as follows: 1 g of thiocyanate 2·[(chloroethenyl)amino]_1,3-benzothiazole-6-yl ester Add 〇〇84 g丨·cyclopropyl maiden dihydrochloride to a suspension of 2 cm3 of 4-methylmorpholine and stir the suspension for 18 hours. Concentrate to dryness and sulphur dioxide column under reduced pressure. Flash chromatography [esolvent: di-methane/methanol (95/5 by volume)] followed by '0.081 g of thiocyanate as a white solid 2_{[(4_cyclopropylniang 1* well-1) -yl)ethinyl]amino}_1,3_benzo<1 plug 11 sitting _6_ vinegar, which is characterized as follows: 154635.doc •70· 201202242

Rf:氧化矽TLC = 0.14[溶離劑:二氯甲烷/曱醇(95/5,以 體積計)] 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.24至 0.30 (m, 2 H); 0.36至 0.44 (m,2 H); 1.61 (m,1 H); 2.48至 2.62 (部分 遮蔽之多重峰,8 H); 3.34 (s,2 H); 7.69 (dd,《7=2.0 及 8.6 Hz, 1 H); 7.84 (d, J=8.6 Hz, 1 H); 8.39 (d, J=2.0 Hz, 1 H); 12·23 (寬多重峰,i H)Rf: cerium oxide TLC = 0.14 [esolvent: dichloromethane / decyl alcohol (95/5 by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.24 to 0.30 (m, 2) H); 0.36 to 0.44 (m, 2 H); 1.61 (m, 1 H); 2.48 to 2.62 (partially masked multiplet, 8 H); 3.34 (s, 2 H); 7.69 (dd, "7= 2.0 and 8.6 Hz, 1 H); 7.84 (d, J=8.6 Hz, 1 H); 8.39 (d, J=2.0 Hz, 1 H); 12·23 (width multiple peak, i H)

質譜:方法A 滯留時間Tr(分鐘)=0.62 ; [M+H] + : m/z 374; [M-H]-: m/z 372 實例5 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒畊-3-基)硫 炫基]-1,3-苯并嘆嗤-2-基}-2-(4-敦旅咬-1-基)乙酿胺 a) #-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-本弁售β坐_2-基}-2-(4-氟η底咬-1-基)乙酿胺可如實例4-a 製備’但以0.246 g硫氰酸2-{[(4-氟哌啶-1-基)乙醯基]胺 基}-1,3-苯并噻唑-6-基酯、0.137 g 3-氣-6-環丙基[1,2,4]三 唑并[4,3-6]嗒畊、0.004 g磷酸二氫鉀於6 cm3水中之溶液 及0.432 g 1,4-二硫-DL-蘇糖醇於8 cm3乙醇中之溶液為起 始物。二氧化石夕管柱急驟層析[溶離劑:二氣曱烧/甲醇 (98/2,以體積計)]之後’獲得0.076 g呈白色固體狀之#· {6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫院基 苯并噻唑-2-基}-2-(4-氟哌啶-1-基)乙醯胺,其特徵如^ : 熔點:207-227°C (步奇) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.89至 0.95 (m 154635.doc -71. 201202242 2 H); 1.03至 1.12 (m,2 H); 1.40至 1.61 (m,2 H); 1.66至 1.90 (m,2 H); 2.16 至 2.26 (m, 1 H); 2.42 至 2.63 (部分遮蔽之多 重峰,3 H); 2.79 至 2.95 (m,1 H); 3.40 (m, 2 H); 4.55 至 4.79 (m,1 H); 7.30 (d,《/=9.8 Hz, 1 H); 7.48 (dd,J=2.0及 8.6 Hz, 1H); 7.70 (d, 7=8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d’《7=9·8 Hz,1 H); 12.11 (宽多重峰,i h) 質譜:方法A 滞留時間Tr(分鐘)=0.63 ; [M+H] + : m/z 484; [M+2H]2 + : m/z 242.5 (基峰) [M-H]-: m/z 482 b)硫氰酸2-{[(4-氟哌啶-^基)乙醯基]胺基卜i,3苯并噻 嗤-6-基酯可以如下方式製備: 向0.3 g硫氰酸2-[(氣乙醯基)胺基]-丨,%苯并噻唑_6_基酯 於5 cm3 N-乙基二異丙胺中之懸浮液中添加〇 163 g 4_氟哌 啶鹽酸鹽。在約20t之溫度下攪拌混合物約18小時。向反 應混合物中添加5 cm3二氣甲烷及5 cm3二噁烷且繼續攪拌2 天。在減壓下濃縮至乾及二氧化矽管柱急驟層析[溶離 劑.一氣甲院/甲醇(98/2,以體積計)]之後,獲得〇 246 g 呈米色固體狀之硫氰酸2-{[(4-氟哌啶q•基)乙醯基]胺基卜 1,3-苯并嘆η坐-6-基醋’其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.62; [M+H] + : m/z 374; [MH]-: m/z 372 Example 5: N-{6-[(6-cyclopropyl) 1,2,4]triazolo[4,3-b]indole-3-yl)thiononyl]-1,3-benzoindole-2-yl}-2-(4-Dun Bite -1-yl)ethinamine a) #-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl] - 1,3-Selling β-sodium 2-yl}-2-(4-fluoro-n-yl-1-yl)ethene can be prepared as in Example 4-a but with 0.246 g of thiocyanate 2- {[(4-Fluoropiperidin-1-yl)ethenyl]amino}-1,3-benzothiazol-6-yl ester, 0.137 g 3- gas-6-cyclopropyl [1,2, 4] Triazolo[4,3-6] arable, 0.004 g potassium dihydrogen phosphate in 6 cm3 water and 0.432 g 1,4-dithio-DL-threitol in 8 cm3 ethanol Starting material. After the separation of the dioxide and the column of sulfur dioxide [solvent: two gas smoldering / methanol (98/2, by volume)], '0.076 g was obtained as a white solid #·{6-[(6-cyclopropyl) [1,2,4]triazolo[4,3-6]indole-3-yl)sulfanylbenzothiazol-2-yl}-2-(4-fluoropiperidin-1-yl) Acetamine, characterized by ^ : melting point: 207-227 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 to 0.95 (m 154635.doc -71. 201202242 2 H ); 1.03 to 1.12 (m, 2 H); 1.40 to 1.61 (m, 2 H); 1.66 to 1.90 (m, 2 H); 2.16 to 2.26 (m, 1 H); 2.42 to 2.63 (multiple masking) Peak, 3 H); 2.79 to 2.95 (m, 1 H); 3.40 (m, 2 H); 4.55 to 4.79 (m, 1 H); 7.30 (d, "/=9.8 Hz, 1 H); 7.48 ( Dd, J = 2.0 and 8.6 Hz, 1H); 7.70 (d, 7 = 8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d' "7=9·8 Hz, 1 H); 12.11 (width multiple peak, ih) Mass Spectrum: Method A Retention time Tr (minutes) = 0.63; [M+H] + : m/z 484; [M+2H]2 + : m/z 242.5 ( Base peak) [MH]-: m/z 482 b) 2-{[(4-Fluoropiperidine-yl)ethyl) thiocyanate i,3 benzothiazepine-6-yl ester Can be prepared as follows Add 〇163 g 4 to a suspension of 0.3 g thiocyanate 2-[(acetomethyl)amino]-oxime, % benzothiazole-6-yl ester in 5 cm3 N-ethyldiisopropylamine. _Flupiridine hydrochloride. The mixture was stirred at a temperature of about 20 t for about 18 hours. 5 cm3 of di-methane and 5 cm3 of dioxane were added to the reaction mixture and stirring was continued for 2 days. After concentrating under reduced pressure to dryness and flash chromatography of ruthenium dioxide column [solvent. A gas institute/methanol (98/2 by volume)], 246 g of thiocyanate was obtained as a beige solid. -{[(4-Fluoropiperidineq•yl)ethylidene]aminopyrim 1,3-benzoindole η--6-yl vinegar' is characterized as follows:

Rf二氧化矽TLC = 0.78 [溶離劑:二氣曱烷/甲醇(9〇/1〇, 以體積計)] 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 1.42至 1.63 (m 2 H); UUmo (m,2 H); 2.43至2別(部分遮蔽之多重峰 154635.doc •72- 201202242 3 H); 2.83至 2·95 (m,1 H); 3.44 (m,2 H); 4.57至 4.79 (m,1 H),7.70 (dd,《/=2.0及 8.6 Hz, 1 H); 7.86 (d, ι/=8·6 Hz,1 H); 8.40 (d,《/=2.0 Hz,1 H); 12.27 (寬多重峰,i h) 質譜:方法A 滯留時間Tr(分鐘)=0.54 ; [M+H] + : m/z 351; [M-H]-: m/z 349 303733v 實例6 : N-{6-[(6-環丙基[1,2,4】***并[4,3_b】嗒畊_3_基)硫 燒基]-1,3-苯并嗔峻-2-基}-2-[4-(嗎琳-4-基)旅唆_i_基】乙 醯胺 a) iV-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1’3-苯并喧唾-2-基}-2-[4-(嗎啭-4-基)娘咬-i_基]乙醢胺可 如實例4-a製備,但以0_3 g硫氰酸2-({[4-(嗎啉-4-基)哌啶-1-基]乙醯基}胺基)-1,3-苯并噻唑-6-基酯、0.140 g 3-氣-6-環丙基[1,2,4]***并[4,3-6]嗒啩於9 cm3乙醇中之溶液及 0.006 g磷酸二氫鉀於4 cm3水中之溶液及0.403 g 1,4-二硫-DL-蘇糖醇為起始物。二氧化矽管柱急驟層析[溶離劑:二 氣甲烷/甲醇(95/5,以體積計)]之後,獲得0 081 g呈白色 固體狀之#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒'•井-3-基) 硫烧基]-1,3-苯并售°坐-2-基}-2-[4-(嗎琳-4-基)娘咬-1-基]乙 醯胺,其特徵如下: 熔點:142-144°C (步奇) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.93 (m, 2 H); 1.08 (m,2 H); 1.37至 1.51 (m,2 H); 1.73 (m,2 H); 2.04至 2.26 (m,4 H); 2.45 (m,4 H); 2_91 (m,2 H); 3.29 (經遮蔽之 I54635.doc -73- 201202242 單♦,2 H); 3.56 (m,4 HV 7 7.30 (dj J=9 s Hz> ! H); 7 46 (dd,l/=1.8&8.6Hz,lHV7fiWd / 65 (d,J==8 6 Hz,! H); 8.10 (寬 單峰,1 H); 8.27 (d,《/=9.8 Hz 1 μ、 . ^ nz’ 1 H); 10.2^^.58 (極寬多 重峰,1 H) 質譜:方法30561 1v 滯留時間Tr(分鐘)=0.56 ; [M+H] + : m/z 551; m/z 549 —, w 4基)〇底啶-1-基]乙醯基}胺基)_1,3- 苯并嗟唑-6-基酯可以如下方式製備. 在约20C之/皿度下攪拌i g硫氰酸2_ [(氣乙醯基)胺基]_ M-苯并㈣-6-基醋、0.9〇2 g 4十底咬4-基)嗎琳及ι〇 ‘ N-乙基二異丙胺於2〇 cm3二氣甲烷及2〇 Gy二噁烷中之溶 液2天。濃縮反應混合物至乾之後,藉由二氧化矽管柱急 驟層析[溶離劑:二氣曱烷/曱醇(95/5,以體積計)]純化殘 餘物,且獲得0.887 g呈白色固體狀之2_({[4_(嗎啉_4基)哌 啶-1-基]乙酿基}胺基)-1,3-苯并噻唑-6-基,其特徵如下:Rf ruthenium dioxide TLC = 0.78 [Eluent: dioxane / methanol (9 〇 / 1 〇, by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.42 to 1.63 (m 2 H); UUmo (m, 2 H); 2.43 to 2 (partially obscured multiple peaks 154635.doc • 72- 201202242 3 H); 2.83 to 2.95 (m, 1 H); 3.44 (m, 2 H); 4.57 to 4.79 (m, 1 H), 7.70 (dd, "/=2.0 and 8.6 Hz, 1 H); 7.86 (d, ι/=8·6 Hz, 1 H); 8.40 (d, /=2.0 Hz, 1 H); 12.27 (width multiple peak, ih) Mass Spectrum: Method A Retention time Tr (minutes) = 0.54; [M+H] + : m/z 351; [MH]-: m/z 349 303733v Example 6: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]indole_3_yl)thiol]-1,3-benzoene嗔君-2-yl}-2-[4-(?琳-4-yl) tourism 唆i_yl] acetamamine a) iV-{6-[(6-cyclopropyl[1,2, 4] Triazolo[4,3-6]indole-3-yl)sulfanyl]-1'3-benzopyrene-2-yl}-2-[4-(indol-4-yl) ) Nitrile-i_yl] acetamidine can be prepared as in Example 4-a, but with 0-3 g of 2-({[4-(morpholin-4-yl)piperidin-1-yl] acetonitrile) Amino]-1,3-benzothiazol-6-yl ester, 0.140 g 3- gas-6-cyclopropyl[1,2,4]triazolo[4,3- 6] A solution of hydrazine in 9 cm3 of ethanol and a solution of 0.006 g of potassium dihydrogen phosphate in 4 cm3 of water and 0.403 g of 1,4-dithio-DL-threitol are used as starting materials. After flash chromatography of ruthenium dioxide column [solvent: di-methane/methanol (95/5 by volume)], 0 081 g of #-{6-[(6-cyclopropyl) was obtained as a white solid. [1,2,4]triazolo[4,3-6]嗒'• well-3-yl) thiol group]-1,3-benzene is sold in °-2-yl}-2-[4 - (Merlin-4-yl) Nitrile-1-yl]acetamide, which has the following characteristics: Melting point: 142-144 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6) : 0.93 (m, 2 H); 1.08 (m, 2 H); 1.37 to 1.51 (m, 2 H); 1.73 (m, 2 H); 2.04 to 2.26 (m, 4 H); 2.45 (m, 4) H); 2_91 (m, 2 H); 3.29 (masked I54635.doc -73- 201202242 single ♦, 2 H); 3.56 (m, 4 HV 7 7.30 (dj J=9 s Hz> ! H); 7 46 (dd,l/=1.8&8.6Hz, lHV7fiWd / 65 (d, J==8 6 Hz, ! H); 8.10 (width unimodal, 1 H); 8.27 (d, "/=9.8 Hz 1 μ, . ^ nz' 1 H); 10.2^^.58 (extremely broad multiplet, 1 H) Mass Spectrum: Method 30561 1v Residence time Tr (minutes) = 0.56; [M+H] + : m/z 551 ; m/z 549 —, w 4 —) decridin-1-yl]ethinyl}amino)-1,3-benzoxazol-6-yl ester can be prepared in the following manner: at about 20C / dish Stir ig sulfur Cyanic acid 2_ [(epiethyl)amino]_ M-benzo(tetra)-6-yl vinegar, 0.9 〇 2 g 4 decend 4-base) 琳琳 and ι〇' N-ethyldiisopropylamine A solution of 2 〇 cm 3 of di-methane and 2 〇 of Gy dioxane was used for 2 days. After concentrating the reaction mixture to dryness, the residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 2_({[4_(morpholine-4-yl)piperidin-1-yl]ethenyl}amino)-1,3-benzothiazole-6-yl, which is characterized as follows:

Rf二氧化矽TLC=0.33 [溶離劑:二氣甲烷/曱醇(9〇/1〇, 以體積計)] 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 1.46 (m,2 H). 1.74(111,2 11);2.11(«,>/=3.5及11.1112,111);2.20(111,2 H); 2.44 (m,4 H); 2.92 (m,2 H); 3.34 (s,2 H); 3.56 (m, 4 H); 7.69 (dd, /=2.0及 8.6 Hz,1 H); 7.84 (d,*7=8.6 Hz, 1 H); 8·39 (d,《/=2.0 Hz, 1 H); 12.12 (寬多重峰,1 H)Rf cerium oxide TLC=0.33 [Eluent: di-methane/decyl alcohol (9 〇/1 〇, by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.46 (m, 2 H). 1.74 (111, 2 11); 2.11 («, >/= 3.5 and 11.1112, 111); 2.20 (111, 2 H); 2.44 (m, 4 H); 2.92 (m, 2 H); 3.34 (s, 2 H); 3.56 (m, 4 H); 7.69 (dd, /=2.0 and 8.6 Hz, 1 H); 7.84 (d, *7=8.6 Hz, 1 H); 8·39 (d , "/=2.0 Hz, 1 H); 12.12 (width multiple peak, 1 H)

質譜:方法A 154635.doc -74- 201202242 滯留時間Tr(分鐘)=0.45 ; [M+H] + : m/z 418; [M-H]-: m/z 416 實例7 : N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫 烧基]-1,3-苯并噻唑-2-基}-2-【4-(2-乙氧基乙基)哌畊-1-基] 乙醯胺 a) #-{6-[(6-環丙基[1,2,4]***并[4,3功]嗒畊-3-基)硫烷基]_ 1,3-苯并噻唑_2-基}-2-[4-(2-乙氧基乙基)哌畊-丨_基]乙醯胺 可如實例4-a製備,但以0.2 g硫氰酸2_({[4-(2-乙氧基乙基) 0底畊-1-基]乙酿基}胺基)_1,3_笨并噻唑_6_基酯、〇 〇96 g 3· 氣-6-環丙基[1,2,4]***并[4,3-6]。荅p井於9 cm3乙醇中之溶 液及0.003 g墻酸二氫斜於4 cm3水中之溶液及〇.274 g 1,4_ 二硫-DL-蘇糖醇為起始物。二氧化矽管柱急驟層析[溶離 劑.一氯甲烷/甲醇(95/5,以體積計)]之後,獲得〇 〇85 g 呈白色固體狀之ΛΓ-{6-[(6-環丙基[ι,2,4]三。坐并[4,3-6]塔畊_ 3-基)硫烷基]-1,3·苯并噻唑_2_基卜2_[4_(2_乙氧基乙基)哌 11 井-1-基]乙醯胺,其特徵如下: 熔點:136°C (步奇) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.06 至 1.12 (m,5 H); 2.22 (m,i H); 2 43 至 2 57 (部分遮蔽 之多重峰,10 H); 3.32 (s,2 H); 3.37 至 3.48 (m,4 H); 7.30 (d,《/=9.8 Hz,1 H); 7.48 (dd,/=2.0及 8.6 Hz,1 H); 7.70 (d, /=8.6 Hz,1 H); 8.14 (d,*/=2.0 Hz, 1 H); 8.28 (d,《7=9.8 Hz, 1 H); 12.11 (寬多重峰,1 h)Mass Spectrometry: Method A 154635.doc -74- 201202242 Retention time Tr (minutes) = 0.45; [M+H] + : m/z 418; [MH]-: m/z 416 Example 7: N-{6-[ (6-Cyclopropyl[1,2,4]triazolo[4,3_b]indole_3_yl)thioalkyl]-1,3-benzothiazol-2-yl}-2-[4 -(2-ethoxyethyl)piped-1-yl]acetamidamine a) #-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3]嗒-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(2-ethoxyethyl)piped-indole-yl]acetamide Prepared as in Example 4-a, but with 0.2 g of thiocyanate 2-({[4-(2-ethoxyethyl) 0 bottom ole-1-yl]ethyl}amino)_1,3_ stupid Thiazole-6-yl ester, 〇〇96 g 3·gas-6-cyclopropyl[1,2,4]triazolo[4,3-6]. The solution of 荅p well in 9 cm3 of ethanol and 0.003 g of dibasic acid dihydrogen in 4 cm3 of water and 274.274 g 1,4_disulfide-DL-threitol were used as starting materials. After flash chromatography of ruthenium dioxide column [solvent. chloroform/methanol (95/5 by volume)], 〇〇85 g was obtained as a white solid-{6-[(6-cyclopropyl) Base [ι,2,4]III. Sit and [4,3-6] Talm _ 3-yl)sulfanyl]-1,3·benzothiazole_2_基卜2_[4_(2_B Oxyethyl)piper 11-ytyl-1-acetamidamine, which has the following characteristics: Melting point: 136 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.06 to 1.12 (m, 5 H); 2.22 (m, i H); 2 43 to 2 57 (multiple peaks partially masked, 10 H); 3.32 (s, 2 H); 3.37 to 3.48 ( m,4 H); 7.30 (d, "/=9.8 Hz, 1 H); 7.48 (dd, /=2.0 and 8.6 Hz, 1 H); 7.70 (d, /=8.6 Hz, 1 H); 8.14 ( d, */= 2.0 Hz, 1 H); 8.28 (d, "7=9.8 Hz, 1 H); 12.11 (width multiple peak, 1 h)

質譜:方法B 154635.doc •75- 201202242 滯留時間Tr(分鐘)=2.94 ; [M+H] + : m/z 539; [M+2H]2 + : m/z 270 (基峰) [M-H]-: m/z 537 b)硫氰酸2-({[4-(2-乙氧基乙基)哌畊q-基]乙醯基丨胺基 1,3·苯并噻唑-6-基酯可如實例6_b製備,但以1 g硫氰酸2-[(氣乙醯基)胺基]-1,3-笨并噻唑·6_基酯、〇·9ΐ8 g 1-(2-乙氧 基乙基)哌畊及10 cm3 N-乙基二異丙胺於2〇 cm3二氣曱烷 及20 cm二°惡烧中之溶液為起始物。二氧化;g夕管柱急驟層 析[溶離劑:二氣曱烷/甲醇(95/5,以體積計)]之後,獲得 0.448 g呈黃色固體狀之硫氰酸2_({[4_(2_乙氧基乙基)哌__ 1-基]乙醯基}胺基)-1,3-苯并嗟唑_6_基酯,其特徵如下: 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.08 (t, J=TΛ Hz,3 H); 2.37至2.5 8 (部分遮蔽之多重峰,10 h); 3.34 (s,2 H); 3·37至 3,51 (m,4 H); 7·69 (dd,J=2.0及 8.6 Hz,1 H); 7.84 (d,/=8.6 Hz, 1 H); 8.39 (d,·7=2.0 Hz,1 H); 12.21 (宽 多重峰,1 H) 質譜:方法A 滞留時間Τι·(分鐘)=0.62 ; [M+H] + : m/z 406; [M-H]-: m/z 404 實例8 : N-(6-{[6-(環己基甲基)[1,2,4]***并【4,3-b]嗒啩-3_ 基1硫烷基}-l,3-苯并噻唑-2-基)-2-(4-環丙基哌哜·1_基)乙 醯胺 a) JV-(6-{[6·(環己基曱基)[1,2,4]***并[4,3-6]嗒啩-3-基]硫 烧基}-1,3-苯并°塞°坐-2-基)-2-(4-環丙基π底π井-1-基)乙酿胺可 154635.doc • 76 - 201202242 如實例4-a製備,但以0 298 g硫氰酸2{[(4_環丙基哌啩卜 基)乙醯基]胺基}-l,3-苯并噻唑-6-基酯、0.2 g 3-氯-6-(環 己基曱基)[1,2,4]***并[4,3-6]嗒畊、〇.〇〇4§磷酸二氫鉀於 2.5 cm水中之溶液及0 447 g 1,4-二硫-DL-蘇糖醇於10 cm3 乙醇中之溶液為起始物。二氧化矽管柱急驟層析[溶離 劑.二氣甲烷/甲醇(95/5 ’以體積計)]之後,獲得〇」22 g 呈白色固體狀之ΛΓ-(6-{[6-(環己基甲基)[12,4]***并[4,3-办]嗒啡-3-基]硫烷基卜ι,3-苯并噻唑_2_基)_2_(4_環丙基哌 畊-1-基)乙酿胺,其特徵如下: 熔點:140-144°C(考夫勒) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.26 (m, 2 H); 0.34至 0.43 (m,2 H); 0.71 至 0.88 (m,2 H); 0.95至 1.12 (m, 3 H); 1.38 至 1.52 (m,5 H); 1.56 至 1.65 (m,2 H); 2.45 至 2.58 (部分遮蔽之多重峰,8 H); 2.65 (d,/=7.1 Hz,2 H); 3.25至 3.35 (部分遮蔽之多重峰,2 H); 7_34 (d,《7=9.5 Hz,1 H); 7.45 (dd,*7=1.5及 8.3 Hz,1 H); 7.66 (d,*7=8.3 Hz,1 H); 8.09 (d, /=1.5 Hz,1 H); 8.31 (d,《7=9.5 Hz,1 H); 12.11 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.84 ; [M+H] + : m/z 563; [M-H]-: m/z 561 b)3-氯-6-(環己基曱基)[1,2,4]***并[4,3·6]嗒畊可如實 例Ι-b製備,但以1.5 g 3,6-二氣[^4]***并[^^嗒。井、 23.8 cm3溴(環己基曱基)鋅於四氫呋喃中之〇 5 M溶液及 154635.doc -77· 201202242 0.203 g雙(二第三丁基膦)鈀於3〇 cm3四氫呋喃中之溶液為 起始物,由此獲得0.686 g呈油狀之3氯_6 (環己基甲 基)Π,2,4]***并[4,3-6]嗒畊,其特徵如下:Mass Spectrometry: Method B 154635.doc •75- 201202242 Retention time Tr (minutes) = 2.94; [M+H] + : m/z 539; [M+2H]2 + : m/z 270 (base peak) [MH ]-: m/z 537 b) 2-({[4-(2-ethoxyethyl) piperidinyl q-yl]ethyl sulfhydryl thiocyanate 1,3·benzothiazole-6- The base ester can be prepared as in Example 6-b, but with 1 g of 2-[(epiethyl)amino]-1,3- benzothiazol-6-yl thiocyanate, 〇·9ΐ8 g 1-(2- Ethoxyethyl) piped and 10 cm3 of N-ethyldiisopropylamine in 2〇cm3 dioxane and 20 cm of digested as a starting material. Dioxide; g-column flash layer After dissolving [solvent: dioxane/methanol (95/5 by volume)], 0.448 g of thiocyanate 2_({[4_(2-ethoxyethyl))) was obtained as a yellow solid. _ 1-yl]ethinyl}amino)-1,3-benzoxazole-6-yl ester, which is characterized as follows: 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.08 (t , J=TΛ Hz, 3 H); 2.37 to 2.5 8 (multiple peaks partially masked, 10 h); 3.34 (s, 2 H); 3·37 to 3, 51 (m, 4 H); 7·69 (dd, J=2.0 and 8.6 Hz, 1 H); 7.84 (d, /=8.6 Hz, 1 H); 8.39 (d, ·7=2.0 Hz, 1 H); 12.21 (wide multiple , 1 H) Mass Spectrum: Method A Retention time Τι·(minutes)=0.62; [M+H] + : m/z 406; [MH]-: m/z 404 Example 8: N-(6-{[6 -(cyclohexylmethyl)[1,2,4]triazolo[4,3-b]indole-3-yl-1sulfanyl}-l,3-benzothiazol-2-yl)-2- (4-cyclopropylpiperidinyl-1-yl)acetamide a) JV-(6-{[6·(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-6] Indole-3-yl]sulfanyl}}1,3-1,3-pyran °°-2-yl)-2-(4-cyclopropylπ-pi-pi-1-yl)etheneamine 154635 .doc • 76 - 201202242 Prepared as in Example 4-a but with 0 298 g of thiocyanate 2{[(4-cyclopropylpiperazinyl)ethenyl]amino}-l,3-benzothiazole -6-yl ester, 0.2 g 3-chloro-6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3-6]indole, 〇.〇〇4§ potassium dihydrogen phosphate A solution of 2.5 cm of water and 0 447 g of 1,4-dithio-DL-threitol in 10 cm3 of ethanol was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent. Dihydromethane/methanol (95/5 'by volume)], 〇" 22 g is obtained as a white solid -(6-{[6-(ring) Hexylmethyl)[12,4]triazolo[4,3-do]morphin-3-yl]sulfanyldiphenyl,3-benzothiazol-2-yl)_2_(4-cyclopropylpiperidine Cultivated -1-yl) ethanoamine, which has the following characteristics: Melting point: 140-144 ° C (Craft) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.26 (m, 2 H); 0.34 to 0.43 (m, 2 H); 0.71 to 0.88 (m, 2 H); 0.95 to 1.12 (m, 3 H); 1.38 to 1.52 (m, 5 H); 1.56 to 1.65 (m, 2 H); 2.45 to 2.58 (partially masked multiplet, 8 H); 2.65 (d, /=7.1 Hz, 2 H); 3.25 to 3.35 (partially masked multiplet, 2 H); 7_34 (d, "7=9.5 Hz , 1 H); 7.45 (dd, *7 = 1.5 and 8.3 Hz, 1 H); 7.66 (d, *7 = 8.3 Hz, 1 H); 8.09 (d, /=1.5 Hz, 1 H); 8.31 ( d, "7 = 9.5 Hz, 1 H); 12.11 (width multiple peak, 1 H) Mass spectrum: Method A residence time Tr (minutes) = 0.84; [M+H] + : m/z 563; [MH]- : m/z 561 b) 3-chloro-6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3·6] arable can be prepared as in the example Ι-b, but at 1.5 g 3, 6-digas [^4] triazole and [^^嗒. Well, 23.8 cm3 bromo(cyclohexylfluorenyl)zinc in tetrahydrofuran and 5 M solution and 154635.doc -77·201202242 0.203 g of bis(di-t-butylphosphine)palladium in 3〇cm3 tetrahydrofuran The starting material thus obtained 0.686 g of oily 3 chloro-6 (cyclohexylmethyl) fluorene, 2,4]triazolo[4,3-6] hydrazine, and its characteristics are as follows:

Rf—氧化矽TLC=0.48 [溶離劑:二氣曱烷/甲醇(95/s, 以體積計)]Rf—yttrium oxide TLC=0.48 [Esolvent: dioxane/methanol (95/s, by volume)]

質譜:方法A 滯留時間Tr(分鐘)=0.98 ; [M+H] + : m/z 251 實例9 . N-(6-{【6-(環己基甲基)【1,2,4]***并[4,3-b】嗒哨·_3-基】硫燒基}-1,3-苯并嘆唑-2-基)-2-(嗎琳-4-基)乙醯胺 #-(6-{[6-(環己基甲基)[i,2,4]***并[43_6]嗒畊_3_基]硫 烷基}-1,3-苯并噻唑-2-基)-2-(嗎啉-4-基)乙醯胺可如實例3_ a製備,但以0.238 g N,N'-(二硫烷二基二_ι,3·苯并噻唑_ 6,2-二基)雙[2-(嗎啉·4_基)乙醯胺]、〇 193 g 3_氣_6_(環己 基甲基)[1,2,4]***并[4,3-6]嗒畊、0.004 g填酸二氫卸於 2.4 cm3水中之溶液及0.432 g 1,4-二硫-DL-蘇糖醇於1〇 cm3 乙醇中之溶液為起始物。二氧化矽管柱急驟層析[溶離 劑:二氣甲烷/甲醇(98/2 ’以體積計)]之後,獲得0.051 g 呈白色固體狀之沁(6-{[6-(環己基甲基)[1,2,4]***并[4,3-办]嗒畊-3-基]硫烷基}-1,3_苯并噻唑基)-2-(嗎啉-4-基)乙 醯胺,其特徵如下: 熔點:200-2〇2°C (考夫勒塊) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.72至 0.87 (m, 2 H); 0.96至 1.12 (m,3 H); 1.39至 1.53 (m,5 H); 1.59 (m,1 154635.doc •78· 201202242 H); 2.52 (部分遮蔽之多重峰,4 H); 2.65 (d,·7=7.1 Hz,2 印;3.32(3,2 11);3.54至3.64(111,4印;7.34((1,7=9.5 1^1 H); 7·45 (dd,·7=2·0及 8.6 Hz,1 H); 7.65 (d,J=8.6 Hz,1 H). B.08 (d, J=2.0 Hz, 1 H); 8.31 (d, J=9.5 Hz, 1 H); 12.18 (χ 多重峰,1 H) 質譜:方法B 滞留時間Tr(分鐘)=3.63 ; [M+H] + : m/z 524; [M-H]-: m/z 522 實例10 : (3R)-{6-[(6-環丙基[1,2,4】***并[4,3_b】„荅呼-3· 基)硫烷基】-1,3-苯并噻唑-2-基}胺基甲酸ι_甲基吡略咬 基酯 a) (3Λ)-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)琉燒 基]-1,3-苯并噻唑_2-基}胺基甲酸1_甲基吡咯啶_3_基酷可如 實例4-a製備,但以〇.2〇 g (3i?)-(6-硫氰基-ΐ,3_苯并噻唑_2_ 基)胺基曱酸1-甲基吡咯啶·3_基酯、0.097 g 3-氣-6-環丙其 [1,2,4]***并[4,3-6]嗒畊、0.003 g磷酸二氫鉀於3 cm3水中 之溶液及0.280 g 1,4-二硫-DL-蘇糖醇於6 cm3乙醇中之溶 液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/ 甲醇(95/5,以體積計)]之後,獲得0.149 g呈白色固體狀之 (3/?)-{6-[(6-環丙基[1,2,4]***并[4,3-Z>]嗒畊_3_基)硫烷基]· 1,3-苯并噻唑-2-基}胺基曱酸卜甲基吡咯啶_3_基酯,其特 徵如下: 熔點:175-192°C (步奇) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.86至 0.96 (m, 154635.doc -79- 201202242 2 H); h〇5 至 m (m,2 H); 1.77至 1·88 (m,1 H); 2.16至 2.36 (m,3 H); 2.29 (s,3 H); 2.62至 2.80 (m,3 H); 5.17至 5.29 (m’ 1 H); 7.29 (d,J=9.8 Hz,! H); 7 46 (dd,J=2 〇及8 6 Hz, 1 H); 7.64 (d, 7=8.6 Hz, 1 H); 8.11 (d, J=2.〇 Hz, 1 H); 8.27 (d,*7=9.8 Hz,1 H); 12.01 (寬多重峰,丄 H) 質譜:方法A 滞留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 468; [M-H]-: m/z 466 b) (3i?)-(6-硫氰基·ι,3·苯并噻唑_2_基)胺基甲酸丨·甲基吡咯 啶-3-基酯可以如下方式製備: 使含2 g (6-硫氰基_ι,3_苯并噻唑_2-基)胺基甲酸苯酯之 20 cm3四氫呋喃及124 g 甲基吡咯啶_3_醇的溶液回 流約1小時。冷卻至約2〇。〇之溫度之後,在減壓下濃縮至 乾且進行二氧化矽管柱急驟層析[溶離劑:二氯甲烷/曱醇 (95/5 ’以體積計)],獲得1 g呈白色固體狀之(3/^)-(6-硫氰 基-1,3-苯并噻唑-2-基)胺基甲酸1-甲基吡咯啶_3-基酯,其 特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.98; [M+H] + : m/z 251 Example 9. N-(6-{[6-(cyclohexylmethyl)[1,2,4]3 Zoxa[4,3-b]嗒 ··_3-yl]thioalkyl}-1,3-benzoindazol-2-yl)-2-(morphin-4-yl)acetamide #- (6-{[6-(cyclohexylmethyl)[i,2,4]triazolo[43_6]indole_3_yl]sulfanyl}-1,3-benzothiazol-2-yl) -2-(morpholin-4-yl)acetamide can be prepared as in Example 3-a, but with 0.238 g of N,N'-(disulfanediyldi-,3·benzothiazole-6,2- Diyl) bis[2-(morpholine-4-yl)acetamide], 〇193 g 3_gas_6_(cyclohexylmethyl)[1,2,4]triazolo[4,3-6 A solution of 0.004 g of dihydrogenated dihydrogen in 2.4 cm3 of water and a solution of 0.432 g of 1,4-dithio-DL-threitol in 1 cm3 of ethanol was used as a starting material. After flash chromatography of ruthenium dioxide column [solvent: di-methane/methanol (98/2 'by volume)], 0.051 g of ruthenium (6-{[6-(cyclohexylmethyl)) was obtained as a white solid. )[1,2,4]triazolo[4,3-do]indol-3-yl]sulfanyl}-1,3-benzothiazolyl)-2-(morpholin-4-yl) Acetamine, which has the following characteristics: Melting point: 200-2 〇 2 ° C (Kauflule block) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.72 to 0.87 (m, 2 H); 0.96 To 1.12 (m,3 H); 1.39 to 1.53 (m,5 H); 1.59 (m,1 154635.doc •78· 201202242 H); 2.52 (partially masked multiplet, 4 H); 2.65 (d, ·7=7.1 Hz, 2 prints; 3.32 (3, 2 11); 3.54 to 3.64 (111, 4 prints; 7.34 ((1,7=9.5 1^1 H); 7·45 (dd,·7=2 · 0 and 8.6 Hz, 1 H); 7.65 (d, J = 8.6 Hz, 1 H). B.08 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.5 Hz, 1 H) ; 12.18 (χ Multiplet, 1 H) Mass Spectrum: Method B Retention time Tr (minutes) = 3.63; [M+H] + : m/z 524; [MH]-: m/z 522 Example 10: (3R) -{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]„荅-3-yl)sulfanyl]-1,3-benzothiazol-2-yl }Amino ι-methylpyrrolidyl Ester a) (3Λ)-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)indole]-1,3- Benzothiazole 2 -yl}aminocarbamic acid 1 -methylpyrrolidinyl _3_yl can be prepared as in Example 4-a, but with 〇.2〇g (3i?)-(6-thiocyano-oxime , 3_benzothiazolyl-2-yl)aminol-decanoic acid 1-methylpyrrolidinyl 3-yl ester, 0.097 g of 3-gas-6-cyclopropane[1,2,4]triazolo[4, 3-6] 嗒耕, a solution of 0.003 g of potassium dihydrogen phosphate in 3 cm 3 of water and a solution of 0.280 g of 1,4-dithio-DL-threitol in 6 cm 3 of ethanol as a starting material. After column flash chromatography [solvent: di-methane/methanol (95/5 by volume)], 0.149 g of (3/?)-{6-[(6-cyclopropyl) was obtained as a white solid. 1,2,4]triazolo[4,3-Z>]嗒 _3_yl)sulfanyl]·1,3-benzothiazol-2-yl}aminopyrrolidine-methylpyrrolidine_3 _ base ester, characterized as follows: Melting point: 175-192 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.86 to 0.96 (m, 154635.doc -79- 201202242 2 H h;5 to m (m,2 H); 1.77 to 1.88 (m,1 H); 2.16 to 2.36 (m,3 H); 2.29 (s,3 H); 2.62 to 2.80 (m, 3 H); 5.17 5.29 (m '1 H); 7.29 (d, J = 9.8 Hz ,! H); 7 46 (dd, J=2 〇 and 8 6 Hz, 1 H); 7.64 (d, 7=8.6 Hz, 1 H); 8.11 (d, J=2.〇Hz, 1 H); 8.27 (d, *7 = 9.8 Hz, 1 H); 12.01 (width multiple peak, 丄H) Mass spectrum: Method A residence time Tr (minutes) = 0.59; [M+H] + : m/z 468; [MH] -: m/z 466 b) (3i?)-(6-Thionanyl·ι,3·benzothiazole-2-yl)carbamic acid oxime·methylpyrrolidin-3-yl ester can be prepared as follows : refluxing a solution containing 20 g of 6-(6-thiocyanato_m,3-benzothiazol-2-yl)carbamic acid phenyl ester in 20 cm3 of tetrahydrofuran and 124 g of methylpyrrolidine-3-ol for about 1 hour . Cool to about 2 〇. After the temperature of hydrazine, it was concentrated to dryness under reduced pressure and subjected to flash chromatography of ruthenium dioxide column [solvent: dichloromethane / methanol (95/5 ' by volume)] to obtain 1 g of a white solid. (3/^)-(6-Thienyl-1,3-benzothiazol-2-yl)carbamic acid 1-methylpyrrolidin-3-yl ester, which is characterized as follows:

Rf二氧化矽TLC=0.39 [溶離劑:二氣曱烷/甲醇(90/10, 以體積計)]Rf cerium oxide TLC=0.39 [Eluent: dioxane/methanol (90/10, by volume)]

1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 1.72至 1.90 (m, 11^;2.17至2.37(111,2 1^;2.26(3,3 11);2.58至2.78(〇1,3 H);5.20(m,iH);7.63(dd,/=1.5&8.8Hz,lH);7.75(d, Hz,1 H); 8.31(寬單峰,1 H); 12.34 (寬多重峰,1 Η) 質譜:方法A 154635.doc -80 - 201202242 滯留時間Tr(分鐘)=〇.54 [M+H] + : m/z 335; [M-H]-: m/z 333 (6-硫氰基-1,3-笨并噻唑_2_基)胺基曱酸苯酯如專利w〇 2009/056 692中所述製備。 實例11 : (3S)-{6-[(6-環丙基[1,2,4】***并[4,3-b】嗒啡_3_ 基)硫烷基】-1,3-苯并噻唑_2-基}胺基甲酸1·甲基吡咯啶·3_ 基酯 a) (3幻-{6-[(6-環丙基[ι,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}胺基曱酸1·甲基吡咯啶_3_基酯可如 實例4-a獲得,但以〇.2〇 g 硫氰基-l,3-苯并噻唑_2_ 基)胺基甲酸1-甲基吡咯啶-3-基酯、0.097 g 3-氯-6-環丙基 [1,2,4]***并[4,3-6]塔啡、0,003 g麟酸二氫鉀於3 cm3水中 之溶液及0.280 g 1,4-二硫-DL-蘇糖醇於6 cm3乙醇中之溶 /夜為起始物。一氧化^夕管柱急驟層析[溶離劑:二氣曱烧/ 曱醇(95/5’以體積5十)]之後’獲得〇·〇70 g呈白色固體狀之 (3«SH6-[(6-環丙基[1,2,4]***并[4,34]嗒畊_3_基)硫烷基]_ 1,3 -苯并嗟唾-2-基}胺基曱酸1 -甲,基υ比η各咬_基g旨,其特 徵如下: 熔點:155-159.8°C (步奇) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.89至 0.96 (m, 2 H); 1.05 至 1.12 (m,2 H); 1.72至 1.88 (m,1 H); 2.1 ό至 2.30 (m,3 H); 2.25 (s,3 H); 2.56至 2.76 (m, 3 H); 5 15至 5 23 (m,1 H),7.29 (d,《7-9.8 Hz,1 H); 7.45 (dd, «/=2.0及 8.6 Hz 1 H); 7.63 (d, 7=8.6 Hz, 1 H); 8.10 (d, J=2.〇 Hz, 1 H); 8 27 154635.doc 201202242 (d,《7=9.8 Hz,1 H); 12.13 (寬多重峰,1 η) 質譜:方法A 滞留時間Tr(分鐘)= 0.61 ; [M+H] + :m/z 468;基峰:m/z367 [M-H]-: m/z 466 b) (35)-(6-硫氰基-1,3-苯并噻唑_2_基)胺基曱酸丨_甲基吡咯 啶-3-基酯可如實例ΙΟ-b製備,但以2 g (6-硫氰基-丨’弘苯并 °塞°坐-2-基)胺基曱酸苯醋於2〇 cm3四氫0夫喃中之溶液及1 24 g (3*S)-1-甲基吡咯啶-3-醇為起始物》二氧化矽管柱急驟層 析[溶離劑:二氣甲烷/甲醇(95/5,以體積計)]之後,獲得 1.2 g呈白色固體狀之(35>(6-硫氰基-1,3-苯并噻唑_2_基)胺 基甲酸1-曱基吡咯啶-3-基酯,其特徵如下:1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.72 to 1.90 (m, 11^; 2.17 to 2.37 (111, 2 1^; 2.26 (3, 3 11); 2.58 to 2.78 (〇1, 3 H); 5.20 (m, iH); 7.63 (dd, /= 1.5 & 8.8 Hz, lH); 7.75 (d, Hz, 1 H); 8.31 (wide singlet, 1 H); 12.34 (wide multiple Peak, 1 Η) Mass Spectrometry: Method A 154635.doc -80 - 201202242 Retention time Tr (minutes) = 〇.54 [M+H] + : m/z 335; [MH]-: m/z 333 (6- Phenyl thiocyano-1,3- benzothiazol-2-yl) phthalic acid phthalate was prepared as described in the patent WO 2009/056 692. Example 11: (3S)-{6-[(6-ring Propyl [1,2,4]triazolo[4,3-b]indolyl-3-ylsulfonyl]-1,3-benzothiazol-2-yl}carbamic acid 1·methylpyrrole Acridine·3_yl ester a) (3 magic-{6-[(6-cyclopropyl[ι,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]- 1,3-Benzothiazol-2-yl}amino decanoic acid 1·methylpyrrolidinyl-3-yl ester can be obtained as in Example 4-a, but with 〇.2〇g thiocyano-l,3- Benzothiazole-2-yl)carbamic acid 1-methylpyrrolidin-3-yl ester, 0.097 g 3-chloro-6-cyclopropyl[1,2,4]triazolo[4,3-6] Talatin, 0,003 g of potassium dihydrogenate in 3 cm3 of water and 0.280 g of 1,4- The dissolution of sulfur-DL-threitol in 6 cm3 of ethanol is the starting material. The oxidation of the sulfur-DL-threitol in the column is carried out. [Eluent: two gas smoldering / sterol (95/5' in a volume of 50 )] After obtaining '〇·〇 70 g as a white solid (3«SH6-[(6-cyclopropyl[1,2,4]triazolo[4,34]嗒耕_3_yl) sulfur Alkyl]_ 1,3 -benzoindole-2-yl}amino decanoic acid 1-methyl, quinone to η each bite _ base g, its characteristics are as follows: Melting point: 155-159.8 ° C (step 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 to 0.96 (m, 2 H); 1.05 to 1.12 (m, 2 H); 1.72 to 1.88 (m, 1 H); 2.30 (m,3 H); 2.25 (s,3 H); 2.56 to 2.76 (m, 3 H); 5 15 to 5 23 (m,1 H), 7.29 (d, "7-9.8 Hz, 1 H 7.45 (dd, «/=2.0 and 8.6 Hz 1 H); 7.63 (d, 7=8.6 Hz, 1 H); 8.10 (d, J=2.〇Hz, 1 H); 8 27 154635.doc 201202242 (d, "7=9.8 Hz, 1 H); 12.13 (width multiple peak, 1 η) mass spectrum: method A residence time Tr (minutes) = 0.61; [M+H] + : m/z 468; base peak :m/z367 [MH]-: m/z 466 b) (35)-(6-Thienyl-1,3-benzothiazol-2-yl)amino decanoate-methylpyrrolidine-3 - the base ester can be as true a solution prepared by ΙΟ-b, but with 2 g (6-thiocyano-oxime 弘 并 ° ° sit-2-yl) amino phthalic acid phenyl vinegar in 2 〇 cm 3 tetrahydro 0 pentane and 1 24 g (3*S)-1-methylpyrrolidin-3-ol as starting material" Chromatography column of ruthenium dioxide column [Esolvent: di-methane/methanol (95/5 by volume)] Thereafter, 1.2 g of (35) (6-thiocyanato-1,3-benzothiazol-2-yl)carbamic acid 1-decylpyrrolidin-3-yl ester was obtained as a white solid, which was characterized as follows :

Rf二氧化矽TLC=0.40 [溶離劑:二氯甲烷/甲醇(90/10, 以體積計)] 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 1.76至 1.89 (m, 1 H); 2·19至 2.34 (m,2 H); 2.27 (s,3 H); 2.61 至 2.81 (m,3 H); 5.12至 5.30 (m,1 H); 7.66 (dd,/=2.0及 8.6 Hz,1 H); 7.78 (d, >7=8.6 Hz,1 H); 8.35 (d,/=2.0 Hz,1 H); 12.17 (寬 多重岭,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.53 ; [M+H] + : m/z 335; [M-H]-: m/z 333 實例12 : {6-[(6-環丙基[1,2,4】***并【4,3-b]嗒畊-3-基)硫烷 基】-1,3-苯并噻唑-2-基}胺基甲酸1-甲基哌啶-4-基酯 154635.doc • 82 - 201202242 a) {6-[(6-環丙基[^,4]***并[4,3_6]嗒畊_3_基)硫烷基]_ Μ-苯并噻唑-2_基}胺基甲酸1-曱基哌啶-4-基酯可如實例 4-a製備,但以0.418 g (6-硫氰基-1,3-苯并噻唑-2-基)胺基 甲酸1-曱基哌啶_4_基酯、0.195 g 3-氣-6-環丙基[H4]三 β坐并[4,3-6]塔p井、0.006 g填酸二氫斜於6 cm3水中之溶液 及0_518 g 1,4-二硫-DL-蘇糖醇於12 cm3乙醇中之溶液為起 始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/甲醇 (90/10 ’以體積計)]之後,獲得0.077 g呈白色固體狀之{6· [(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]_i,3_苯 并噻唑-2-基}胺基甲酸1-曱基哌啶-4-基酯,其特徵如下: 熔點:51.5-51.6°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.87至 0.97 (m,2 H); 1.04至 1.14 (m,2 H); 1.54至 1.71 (m,2 H); 1·82至 1.95 (m,2 H); 2.08至 2.15 (m, 2 H); 2.17 (s,3 H); 2.20至 2.27 (m,1 H); 2.62 (m,2H); 4.69 (m,1 H); 7.29 (d,《7=9.8 Hz,1 H); 7.42 (d,/=8.6 Hz,1 H); 7.57 (寬多重峰,i h); 8.06 (寬單峰,1H); 8.26 (d,*7=9.8 Hz,1 H); 12.07 (寬多重 峰,1 H)Rf ruthenium dioxide TLC=0.40 [Eluent: dichloromethane/methanol (90/10 by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.76 to 1.89 (m, 1 H) 2;19 to 2.34 (m,2 H); 2.27 (s,3 H); 2.61 to 2.81 (m,3 H); 5.12 to 5.30 (m,1 H); 7.66 (dd, /=2.0 and 8.6 Hz,1 H); 7.78 (d, >7=8.6 Hz,1 H); 8.35 (d, /=2.0 Hz, 1 H); 12.17 (width multi-ridge, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) = 0.53; [M+H] + : m/z 335; [MH]-: m/z 333 Example 12: {6-[(6-cyclopropyl[1,2,4]triazole And [4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}carbamic acid 1-methylpiperidin-4-yl ester 154635.doc • 82 - 201202242 a) {6-[(6-Cyclopropyl[^,4]triazolo[4,3_6]嗒耕_3_yl)sulfanyl]_Μ-benzothiazole-2_yl} 1-mercaptopiperidin-4-yl carbamate can be prepared as in Example 4-a but with 0.418 g (6-thiocyano-1,3-1,3-benzothiazol-2-yl)aminocarbamate 1- Hydrylpiperidine _4_yl ester, 0.195 g 3- gas-6-cyclopropyl [H4] tri-β-[4,3-6] tower p well, 0.006 g acid dihydrogen slant in 6 cm3 water Solution and 0_518 g 1,4-disulfide-DL-threose 12 cm3 of ethanol in the solution is a starting material. After flash chromatography of ruthenium dioxide column [solvent: di-methane/methanol (90/10 'by volume)), 0.077 g of {6·[(6-cyclopropyl[1, 2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]_i,3-benzothiazol-2-yl}aminocarbazide 1-mercaptopiperidin-4-yl The ester has the following characteristics: Melting point: 51.5-51.6 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.87 to 0.97 (m, 2 H); 1.04 to 1.14 (m, 2 H); 1.54 to 1.71 (m, 2 H); 1.82 to 1.95 (m, 2 H); 2.08 to 2.15 (m, 2 H); 2.17 (s, 3 H); 2.20 to 2.27 (m, 1 H); 2.62 (m, 2H); 4.69 (m, 1 H); 7.29 (d, "7=9.8 Hz, 1 H); 7.42 (d, /=8.6 Hz, 1 H); 7.57 (wide multiple Peak, ih); 8.06 (width unimodal, 1H); 8.26 (d, *7 = 9.8 Hz, 1 H); 12.07 (width multiple peak, 1 H)

質譜:方法B 滯留時間Tr(分鐘)=2.92 ; [M+H] + : m/z 482; [M-H]-: m/z 480 b) (6·硫氰基-1,3-苯并噻唑-2-基)胺基甲酸基哌啶_4_基 酯可如實例l〇-b製備,但以〇.5 g (6·硫氰基-i,3-苯并噻唑· 2·基)胺基甲酸苯酯於5 cm3四氫呋喃中之溶液及〇35i g ^ 154635.doc •83- 201202242 曱基哌啶-4-醇為起始物。二氧化矽管柱急驟層析[溶離 劑:二氣甲烧/甲醇(95/5,以體積計)]之後,獲得〇 422 g 呈白色固體狀之(6_硫氰基_U-苯并售峻_2_基)胺基甲酸卜 曱基哌啶-4-基酯,其特徵如下:Mass Spectrometry: Method B Retention time Tr (minutes) = 2.92; [M+H] + : m/z 482; [MH]-: m/z 480 b) (6· thiocyano-1,3-benzothiazole 2-yl)aminocarbamic acid piperidinyl-4-yl ester can be prepared as in the case of l-b, but with 〇.5 g (6. thiocyano-i,3-benzothiazol-2-yl) A solution of phenyl carbamate in 5 cm3 of tetrahydrofuran and 〇35i g ^ 154635.doc • 83- 201202242 decylpiperidin-4-ol as starting material. After cerium dioxide column flash chromatography [solvent: two gas aeration / methanol (95/5 by volume)], 〇 422 g was obtained as a white solid (6-thiocyano_U-benzo The product is sold as a hydrazinopiperidin-4-yl carbazide-4-yl ester, which is characterized as follows:

Rf—氧化矽TLC=0.24 [溶離劑:二氣甲烷/甲醇(9〇/1〇, 以體積計)] 1H NMR (400 ΜΗζ, δ (ppm)5 DMSO-d6): 1.60J. 1.74 (m, 2 H),1.94 (m’ 2 H); 2.17 (m,2 H); 2.19 (s,3 H); 2·60至 2.72 (m,2 H); 4.77 (m,1 H); 7.65 (dd, */=2.0及 8.6 Hz,1 H), 7.78 (d, J=8.6 Hz, 1H); 8.35 (d, 7=2.0 Hz, 1 H); 12.11 (寬多重峰,1 H)Rf—yttrium oxide TLC=0.24 [Eluent: di-methane/methanol (9〇/1〇, by volume)] 1H NMR (400 ΜΗζ, δ (ppm) 5 DMSO-d6): 1.60J. 1.74 (m , 2 H), 1.94 (m' 2 H); 2.17 (m, 2 H); 2.19 (s, 3 H); 2·60 to 2.72 (m, 2 H); 4.77 (m, 1 H); 7.65 (dd, */=2.0 and 8.6 Hz, 1 H), 7.78 (d, J=8.6 Hz, 1H); 8.35 (d, 7=2.0 Hz, 1 H); 12.11 (width multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.62 ; [M+H] + : m/z 349; [M-H]-: m/z 347 實例13 : {6-【(6-環丙基[1,2,4]***并[4,3-b】嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}胺基甲酸1-(2_氟乙基)哌啶_4基酯 a) {6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]_ 1,3-苯并噻唑-2-基}胺基甲酸丨-^-氟乙基)哌啶_4_基酯可如 實例4-a製備,但以0.250 g (6-硫氰基_l53_苯并噻唑_2_基) 胺基曱酸1-(2-氟乙基)哌啶·4_基酯、0.128 g 3-氯-6-環丙基 [1,2,4]***并[4,3乃]嗒畊、0.004 g磷酸二氫鉀於6 cm3水中 之溶液及0.370 g 1,4-二硫_DL-蘇糖醇於8 cm3乙醇中之溶 液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/ 曱醇(95/5 ’以體積計)]之後,獲得〇.037 g呈白色固體狀之 154635.doc • 84 - 201202242 {6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2-基}胺基甲酸ι_(2_氟乙基)哌啶_4_基酯,其特 徵如下: 熔點:146-156°C(步奇) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.89至 0,97 (m, 2 H); 1.06至 1.12 (m,2 H); 1.57至 1.69 (m,2 H); 1·87至 1.97 (m,2 H); 2.18至 2.24 (m,1 H); 2.25至 2.34 (m,2 H); 2.63 〇(1,>/=4.9及28.6 1^,2 11);2.72至2.83(111,2 11);4.52(1(!, •7=4.9及 47.7 Hz,2 H); 4.73 (m,1 H); 7.29 (d,*7=9.8 Hz, 1 H); 7.43 (d,《7=8.6 Hz,1 H); 7.60 (寬多重峰,1 H); 8.07 (寬 單峰,1 H); 8.26 (d,《7=9.8 Hz,1 H); 12.10 (寬多重峰,1 Η)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.62; [M+H] + : m/z 349; [MH]-: m/z 347 Example 13: {6-[(6-cyclopropyl[1, 2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}carbamic acid 1-(2-fluoroethyl) Piperidine-4-yl ester a) {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indol-3-yl)sulfanyl]_ 1,3 -Benzothiazol-2-yl}aminocarbamic acid hydrazine-^-fluoroethyl)piperidine-4-yl ester can be prepared as in Example 4-a but at 0.250 g (6-thiocyano-l53_benzo Thiazole-2-yl) 1-(2-fluoroethyl)piperidine-4-yl ester, 0.128 g 3-chloro-6-cyclopropyl[1,2,4]triazolo[4 , 3 is a sloping, a solution of 0.004 g of potassium dihydrogen phosphate in 6 cm 3 of water and a solution of 0.370 g of 1,4-dithio-DL-threitol in 8 cm 3 of ethanol as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: di-methane / sterol (95/5 'by volume)], 〇.037 g was obtained as a white solid 154635.doc • 84 - 201202242 {6- [(6-Cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}amino Formic acid ι_(2_fluoroethyl)piperidine-4-yl ester, which has the following characteristics: Melting point: 146-156 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 to 0,97 (m, 2 H); 1.06 to 1.12 (m, 2 H); 1.57 to 1.69 (m, 2 H); 1.87 to 1.97 (m, 2 H); 2.18 to 2.24 (m, 1 H) ); 2.25 to 2.34 (m, 2 H); 2.63 〇 (1, >/=4.9 and 28.6 1^, 2 11); 2.72 to 2.83 (111, 2 11); 4.52 (1 (!, • 7= 4.9 and 47.7 Hz, 2 H); 4.73 (m, 1 H); 7.29 (d, *7 = 9.8 Hz, 1 H); 7.43 (d, "7=8.6 Hz, 1 H); 7.60 (wide multiple peak , 1 H); 8.07 (width single peak, 1 H); 8.26 (d, "7=9.8 Hz, 1 H); 12.10 (width multiple peak, 1 Η)

質譜:方法A 滯留時間Tr(分鐘)=0.64 ; [M+H] + : m/z 514; [M-H]-: m/z 512 b) (6-硫氰基-l,3_苯并噻唑·2_基)胺基曱酸1-(2氟乙基)哌 啶-4-基酯可如實例i〇_b製備,但以〇5 g (6_硫氰基·13苯 并°塞°坐-2-基)胺基曱酸苯g旨於1〇 cm3四氫吱喃中之溶液及 0.449 g 1-(2-氟乙基)略η定_4_醇為起始物。二氧化石夕管柱急 驟層析[溶離劑:二氯甲烷/甲醇(98/2,以體積計)]之後, 獲得0.198 g呈白色固體狀之(6_硫氰基_13_苯并噻唑。基) 胺基甲酸1-(2-氟乙基)哌啶·‘基酯,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.64; [M+H] + : m/z 514; [MH]-: m/z 512 b) (6-thiocyano-l,3-benzothiazole · 2-(yl)amino-decanoic acid 1-(2fluoroethyl)piperidin-4-yl ester can be prepared as in the example i〇_b, but with 〇5 g (6-thiocyano]13 benzopyrene坐-2-yl)amino phthalic acid Benzene g is a solution of 1 〇cm 3 tetrahydrofuran and 0.449 g of 1-(2-fluoroethyl) succinyl-4-alcohol as a starting material. After quenching the sulfur dioxide column chromatography [solvent: dichloromethane/methanol (98/2 by volume)], 0.198 g of a white solid (6-thiocyano- 13-benzothiazole) was obtained. 1-(2-fluoroethyl)piperidine·'-based carboxylic acid, characterized by the following:

Rf二氧化矽TLO0.44 [溶離劑:二氯甲烷/甲醇(9〇/1〇, 以體積計)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.59^. i.72 (m 154635.doc • 85 - 201202242 2 H); 1.93 (m,2 H); 2.24至 2.38 (m,2 H); 2·63 (td,·7=4.9及 28.6 Hz,2 H); 2·72至 2.85 (m,2 H); 4.53 (td,《7=4.9及 47.9 Hz,2 H); 4.78 (m,1H); 7.66 (dd,J=2.0及 8.3 Hz,1 H); 7.78 (d,*7=8.3 Hz,1 H); 8.35 (d,^/=2.0 Hz, 1 H); 12.22 (寬多重 峰,1 H)Rf cerium oxide TLO0.44 [Eluent: dichloromethane/methanol (9 〇 / 〇, by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.59^. i.72 (m 154635.doc • 85 - 201202242 2 H); 1.93 (m, 2 H); 2.24 to 2.38 (m, 2 H); 2·63 (td, ·7=4.9 and 28.6 Hz, 2 H); · 72 to 2.85 (m, 2 H); 4.53 (td, "7 = 4.9 and 47.9 Hz, 2 H); 4.78 (m, 1H); 7.66 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.78 (d, *7 = 8.3 Hz, 1 H); 8.35 (d, ^/= 2.0 Hz, 1 H); 12.22 (width multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 381; [M-H]-: m/z 379 實例14 : (3R)-(6-{【6-(環己基甲基)【1,2,41***并[4,3-b]嗒 畊-3·基】硫烷基卜苯并噻唑_2_基)胺基甲酸^甲基〇比咯 啶-3-基酯 (3/?)-(6-{[6-(環己基曱基)[ij,4]***并[43功]嗒畊_3_基] 硫烷基}-1,3-苯并噻唑_2_基)胺基甲酸卜曱基吡咯啶_3_基酯 可如實例4-a製備,但以〇.2〇 g 硫氰基-丨,^苯并噻 唑-2-基)胺基曱酸1•曱基吡咯啶·3_基酯、〇 125 g 3_氣_^ (環己基甲基)[1,2,4]***并[4,3-6]嗒畊、〇_〇〇3 g磷酸二氫 鉀於3 cm3水中之溶液及〇.28〇 g 14二硫_DL蘇糖醇於6 cm乙醇中之溶液為起始物。二氧化矽管柱急驟層析[溶離 劑·一氣甲烷/曱醇(95/5,以體積計)]之後,獲得〇 〇24 g -呈白色固體狀之(3/?)-(6-{[6-(環己基曱基)[丨,^]***并 - [4,3-6]〇合啡-3-基]硫烷基笨并噻唑·2_基)胺基甲酸卜 甲基吡咯啶-3-基酯,其特徵如下: 熔點:101-175°C (步奇) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.78J.0.92 154635.doc • 86 - 201202242 2 Η); 0·99至 1.13 (m,3 H); 1 ·43至 1.58. (% 5 η); 1 ·63 (m,1 印;1.79(111,111);2.17至2.29(111,2扣;2.25(3,311);2.58 至 2.73 (m,5 H); 5.17 (m,1 H); 7.33 (d,^/=9.8 Hz, 1 H)_ 7.42 (dd,*7=2.0及 8.6 Hz,1 H); 7.58 (寬二重峰,J=8 6 Hz,丄 H); 8.04 (寬單峰,1 H); 8.30 (d,《7=9.8 jjz,i h); 12.03 (寬 多重峰,1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 381; [MH]-: m/z 379 Example 14: (3R)-(6-{[6-(ring) Hexylmethyl)[1,2,41 triazolo[4,3-b]indole-3·yl]sulfanyl benzothiazol-2-yl)aminocarboxylic acid^methylpyrrolidine- 3-yl ester (3/?)-(6-{[6-(cyclohexylfluorenyl)[ij,4]triazolo[43]]嗒耕_3_yl]sulfanyl}-1,3 -benzothiazolyl-2-yl)carbamic acid dipyridyl pyrrolidine-3-yl ester can be prepared as in Example 4-a, but with 〇.2〇g thiocyano-oxime, benzothiazol-2-yl) Amino decanoic acid 1 • decyl pyrrolidine · 3 yl ester, hydrazine 125 g 3 _ _ ^ (cyclohexylmethyl) [1, 2, 4] triazolo[4, 3-6] ploughing, A solution of 〇_〇〇3 g of potassium dihydrogen phosphate in 3 cm3 of water and a solution of 〇.28〇g of 14 disulfide-DL threitol in 6 cm of ethanol was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent·monomethane/decanol (95/5 by volume)], 〇〇24 g - (3/?)-(6-{ [6-(cyclohexylfluorenyl)[丨,^]triazolo-[4,3-6]indole-3-yl]sulfanyl benzothiazol-2-yl)aminoformic acid methylpyrrolidine 3-yl ester, which has the following characteristics: Melting point: 101-175 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.78 J.0.92 154635.doc • 86 - 201202242 2 Η ); 0·99 to 1.13 (m, 3 H); 1 · 43 to 1.58. (% 5 η); 1 · 63 (m, 1 print; 1.79 (111, 111); 2.17 to 2.29 (111, 2 buckle ; 2.25(3,311); 2.58 to 2.73 (m,5 H); 5.17 (m,1 H); 7.33 (d,^/=9.8 Hz, 1 H)_ 7.42 (dd, *7=2.0 and 8.6 Hz, 1 H); 7.58 (width doublet, J=8 6 Hz, 丄H); 8.04 (width unimodal, 1 H); 8.30 (d, "7=9.8 jjz, ih); 12.03 (width multiple peak, 1 H)

質譜:方法A 滯留時間1^(分鐘)=0.81; [M+H] + : m/z 524; [M-H]-: m/z 522 實例15 : (3S)-(6-{[6-(環己基曱基Ml,2,4】***并[4 3_b]嗒 呼_3-基]硫炫基}-l,3-苯并噻唑-2-基)胺基甲酸1•甲基吼洛 咬-3 -基香旨 (35>(6·{[6·(環己基甲基)[1,2,4]三。| 并 硫烷基}-l,3-苯并噻唑-2-基)胺基曱酸^甲基吡咯啶_3_基酯 可如實例4-a製備,但以0.20 g⑽_(6_硫氛基苯并嗔 。坐-2-基)胺基曱酸!-甲基㈣咬基酯、〇125 ^ %氣-6_ (環己基甲基)Π,2,4]三嗤并[4,3#答n井' 〇 〇〇3 _酸二氫 卸於3⑽3水中之溶液及〇.280 g认二硫-DL-蘇糖醇於6 cm3乙醇中之溶液為起始物。二氧切管柱急驟層析[溶離 劑·一氯曱烷/曱醇(95/5,以體積計)]之後,獲得〇_〇97 g 呈白色固體狀之(3幻-(6-{[6-(環己基甲基)Π,2,4]***并 [4,3功]嗒叫一3-基]硫烷基卜丨’夂笨并噻唑_2_基)胺基甲酸卜 曱基吡咯啶-3-基酯,其特徵如下: 熔點:18(M87°C (步奇) 154635.doc -87- 201202242 lHNMR(400 MHz,δ(ppm),DMSOd6):o,76至0.91(m, 2 H); 0.99至 1.14 (m,3 H); 1.39至 1.55 (m,5 H); 1·61 (m,1 H); 1.79 (m,1 H); 2.17至 2.31 (m,2 H); 2.25 (s,3 H); 2.56 至 2.77 (m,5 H); 5.19 (m,1 H); 7.34 (d,《/=9 5 Hz,1 H); 7.43 (dd,《7=2.0及 8.6 Hz,1 H); 7.61 (d,《/=8.6 Hz, 1 H); 8.06 (d,J=2.0 Hz,1 H); 8.31 (d,/=9.5 Hz,1 h); 12.06 (寬 多重峰,1 H)Mass Spectrometry: Method A Retention time 1 ^ (minutes) = 0.81; [M+H] + : m/z 524; [MH]-: m/z 522 Example 15: (3S)-(6-{[6-( Cyclohexyl fluorenyl Ml, 2, 4] triazolo[4 3_b] oxime _3-yl] thiophanyl}-l, 3-benzothiazol-2-yl) carbamic acid 1 • methyl guanlo咬-3 -基香之(35>(6·{[6·(cyclohexylmethyl)[1,2,4]三。| and sulfanyl}-l,3-benzothiazol-2-yl Amino decanoic acid methylpyrrolidine _3_yl ester can be prepared as in Example 4-a, but with 0.20 g of (10) _(6-thiophenebenzoindole. sit-2-yl)amino decanoic acid! Base (4) dimethyl ester, 〇 125 ^ % gas-6_ (cyclohexylmethyl) hydrazine, 2, 4] triterpene [4, 3 # answer n well ' 〇〇〇 3 _ acid dihydrogen unloaded in 3 (10) 3 water A solution of 280 g of disulfide-DL-threitol in 6 cm3 of ethanol was used as a starting material. Chromatography of dioxane column [solubilizer · chlorodecane / decyl alcohol (95/5) After the volume]), 〇_〇97 g is obtained as a white solid (3 phantom-(6-{[6-(cyclohexylmethyl) fluorene, 2,4] triazole [4,3 gong]嗒 一 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- : Point: 18 (M87 ° C (step) 154635.doc -87- 201202242 lHNMR (400 MHz, δ (ppm), DMSOd6): o, 76 to 0.91 (m, 2 H); 0.99 to 1.14 (m, 3) H); 1.39 to 1.55 (m, 5 H); 1.61 (m, 1 H); 1.79 (m, 1 H); 2.17 to 2.31 (m, 2 H); 2.25 (s, 3 H); To 2.77 (m, 5 H); 5.19 (m, 1 H); 7.34 (d, "/=9 5 Hz, 1 H); 7.43 (dd, "7=2.0 and 8.6 Hz, 1 H); 7.61 ( d, "/=8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 8.31 (d, /=9.5 Hz, 1 h); 12.06 (width multiple peak, 1 H)

質譜:方法B 滯留時間Tr(分鐘)=3.41 ; [M+H] + : m/z 524; [M-H]-: m/z 522 實例16 : 6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊_3·基)硫烷 基]-N-【2-(4,4-二l略咬-1-基)乙基】-1,3 -苯并嗟唾_2_胺 a) 6-[(6-環丙基[1,2,4]***并[4,3-6]。荅畊-3-基)硫炫基]_#- [2-(4,4-二11»底咬-1_基)乙基]_1,3-苯并〇塞嗤_2-胺可如實例 4-a製備,但以〇.297 g硫氰酸2-{[2-(4,4-二氟哌啶_丨·基)乙 基]胺基}-1,3-苯并嗟唑-6-基酯、0.136 g 3-氣-6-環丙基 [1,2,4]***并[4,3-6]嗒畊、0.004 g磷酸二氫鉀於6 cm3水中 之溶液及0.392 g 1,4-二硫-DL-蘇糖醇於8 cm3乙醇中之溶 液為起始物《二氧化矽管柱急驟層析[溶離劑:二氣曱院/ 甲醇(95/5,以體積計)]之後’獲得〇·165 g呈淺黃色固體狀 之6-[(6·環丙基H4]***并[4,3-6]嗒畊-3-基)硫烷基] [2气4,4-二氟哌啶-1-基)乙基]-1,3-苯并噻唑-2-胺,其特徵 如下: 熔點:55°C (考夫勒) 154635.doc -88- 201202242 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.92至 0.99 (m 2 H); 1.06至 1.14 (m,2 H); 1.86至 2.03 (m,4 H); 2.16至 2.30 (m,1 H); 2.53 至 2.63 (m,6 H); 3·48 (q,J=6.2 Hz,2 H); 7.28 (d,《7=9.5 Hz,1H); 7.30至 7.38 (m,2 H); 7.87 (d,J=l.2 Hz,1 H); 8.11 (寬三重峰,/=6.2 Hz, 1 H); 8.24 (d,*7=9.5Mass Spectrometry: Method B Retention time Tr (minutes) = 3.41; [M+H] + : m/z 524; [MH]-: m/z 522 Example 16: 6-[(6-cyclopropyl[1,2 , 4] triazolo[4,3-b]indole _3·yl)sulfanyl]-N-[2-(4,4-dil-l-yl-1-yl)ethyl]-1, 3-Benzene oxime salin-2-amine a) 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6].indol-3-yl)thione] _#- [2-(4,4-II11»Bottom-1_yl)ethyl]_1,3-benzoxanthene-2-amine can be prepared as in Example 4-a, but with 〇.297 g 2-{[2-(4,4-Difluoropiperidinyl)ethyl]amino}-1,3-benzoxazol-6-yl thiocyanate, 0.136 g 3- gas -6-cyclopropyl[1,2,4]triazolo[4,3-6]indole, 0.004 g potassium dihydrogen phosphate in 6 cm3 water and 0.392 g 1,4-disulfide-DL- A solution of threitol in 8 cm3 of ethanol is used as the starting material "Separation of cerium dioxide column [solubilizer: digastric broth / methanol (95/5 by volume)]] after obtaining 〇·165 g 6-[(6·Cyclopropyl H4]triazolo[4,3-6]indole-3-yl)sulfanyl][2 gas 4,4-difluoropiperidine- 1-yl)ethyl]-1,3-benzothiazol-2-amine, which has the following characteristics: Melting point: 55 ° C (Coffre) 154635 .doc -88- 201202242 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 to 0.99 (m 2 H); 1.06 to 1.14 (m, 2 H); 1.86 to 2.03 (m, 4 H) ; 2.16 to 2.30 (m, 1 H); 2.53 to 2.63 (m, 6 H); 3·48 (q, J = 6.2 Hz, 2 H); 7.28 (d, "7=9.5 Hz, 1H); 7.30 To 7.38 (m, 2 H); 7.87 (d, J=l.2 Hz, 1 H); 8.11 (wide triplet, /=6.2 Hz, 1 H); 8.24 (d, *7=9.5

Hz, 1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.64 ; [M+H] + : m/z 488; [M-H]-: m/z 486 b)硫氰酸2-{[2-(4,4-二氟哌啶-丨_基)乙基]胺基卜i,3_苯并 噻。坐-6-基酯可以如下方式製備: 向0.5 g硫氰酸2-溴_1,3-苯并噻唑_6_基酯於5 cm3四氫呋 喃中之溶液中添加0.363 g 2-(4,4-二氟哌啶-1-基)乙胺。將 混合物在微波照射下在約14〇〇c之溫度下維持約5分鐘。在 減壓下濃縮至乾且進行二氧化矽管柱急驟層析[溶離劑: 二氣甲烷/曱醇(98/2,以體積計)]之後,獲得〇·297 g呈橙 色油狀之硫氰酸2-{[2-(4,4-二氟哌啶_ι_基)乙基]胺基卜丨,3_ 笨并噻唑-6-基酯,其特徵如下:Hz, 1 H) Mass Spectrometry: Method A Retention time Tr (minutes) = 0.64; [M+H] + : m/z 488; [MH]-: m/z 486 b) Thiocyanate 2-{[2- (4,4-Difluoropiperidin-indoleyl)ethyl]aminopyridinium i,3-benzothiazide. The -6-yl ester can be prepared as follows: To a solution of 0.5 g of 2-bromo-1,3-benzothiazole-6-yl thiocyanate in 5 cm3 of tetrahydrofuran, 0.363 g of 2-(4,4) is added. -Difluoropiperidin-1-yl)ethylamine. The mixture was maintained under microwave irradiation at a temperature of about 14 ° C for about 5 minutes. After concentrating to dryness under reduced pressure and performing a flash chromatography of ruthenium dioxide column [solvent: di-methane/decanol (98/2, by volume)], 〇·297 g of sulfur in the form of an orange oil was obtained. 2-{[2-(4,4-Difluoropiperidinyl)ethyl]aminoglycolic acid, 3_ benzothiazol-6-yl ester, characterized by the following:

Rf—氧化石夕TLC = 0_40 [溶離劑:二氯甲烷/曱醇(95/5 , " 以體積計)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.88^2.01 (m, 4 H)> 2.57 (m, 4 H); 2.61 (t, J=6.3 Hz, 2 H); 3.51 (m, 2 H); 7.45 (d,Hz,1 H); 7.50 (dd,/=2.0及 8.6 Hz, 1 H); 8.〇6 (d, J-2.〇 Hz,1 H); 8.27 (寬三重峰,/=5.5 Hz,1 H) 154635.doc •89· 201202242Rf—Oxidized oxide eve TLC = 0_40 [Isolator: dichloromethane/decanol (95/5, " by volume)] 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 1.88^2.01 ( m, 4 H)> 2.57 (m, 4 H); 2.61 (t, J = 6.3 Hz, 2 H); 3.51 (m, 2 H); 7.45 (d, Hz, 1 H); 7.50 (dd, /=2.0 and 8.6 Hz, 1 H); 8.〇6 (d, J-2.〇Hz, 1 H); 8.27 (wide triplet, /=5.5 Hz, 1 H) 154635.doc •89· 201202242

質譜:方法A 滯留時間Tr(分鐘)=0.5 5, [M+H] + : m/z 355; [M-H]-: m/z 353 硫氰酸2-漠-1,3-苯并°塞°坐-6-基醋如專利w〇 2009/056 692中所述製備。 實例17 : 2-(4-環丙基哌畊-1-基)-Ν·{6·【(6-甲基丨三唾 并[4,3-b]嗒畊-3-基)硫烷基】-1,3-苯并噻唑_2_基}乙酿胺 2·(4-環丙基旅畊-1-基)-iV-{6-[(6-曱基[1,2,4]***并[4 3_ 办]。荅喷-3-基)硫烷基]-1,3-苯并噻唑_2_基}乙醯胺可如實例 4-a製備,但以0.110 g硫氰酸2-{[(4-環丙基哌畊基)乙醯 基]胺基}-1,3-苯并°塞。坐-6-基酯、0.050 g 3-氣甲基 [1,2,4]二。坐并[4,3-ά]。合11井於5 cm3乙醇中之溶液及〇 〇〇2 g镇 酸二氫鉀於1.2 cm3水中之溶液及0.165 g 14 —二硫_DL_蘇糖 醇為起始物。二氧化矽管柱急驟層析[溶離劑:二氣曱烷/ 曱醇(95/5,以體積計)]之後,獲得0 〇72 g呈白色固韙狀之 2-(4-環丙基哌畊-1-基)-#-{6-[(6-甲基[1,2,4]***并[4,3-6] 。合呼-3-基)硫烧基]-1,3-苯并售〇坐_2-基}乙醯胺,其特徵如 下。 熔點:156-166°C (步奇) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.27 (m, 2 H); 0.39 (m,2 H); 1.59 (m,1 H); 2.45至2.59 (部分遮蔽之多重 峰,11 H); 3.22 (s,2 H); 7.34 (d,J=9.5 Hz,1 H); 7.50 (dd, J-2.0及 8.6 Hz,1 H); 7.69 (d,《/=8.6 Hz,1 H); 8.13 (d, •/=2.0 Hz, 1 H); 8.31 (d,J=9.5 Hz,1 H); 12.50 (極寬多重 154635.doc -90- 201202242 峰,1 Η) 質譜:方法A 滞留時間Tr(分鐘)=0.55 ; [M+H] + : m/z 481; [M-H]-: m/z 479 3-氯-6·甲基[1,2,4]***并[4,3-6]嗒畊為市售產品。 實例IS : N-{6-【(6-甲基[I,2,4】***并【4,3_b】嗒畊_3_基)硫燒 基】-1,3-苯并噻唑-2-基}環丙烷甲醯胺 ^-{6-[(6-曱基[1,2,4]二0坐并[4,3-6]〇荅 〇井-3-基)硫院基] 1,3·苯并噻唑-2-基}環丙烷甲醯胺可如實例4_a製備,但以 0·5〇〇 g硫氰酸2-[(環丙基羰基)胺基]-1,3-苯并噻唾_6基 酉曰、0.306 g 3-氣-6-曱基[1,2,4]三嗤并[4,3-6]。荅口井於22 cm3 乙醇中之溶液及0.010 g磷酸二氫鉀於5.6 cm3水中之溶液及 1.008经1,4-二硫-0!^-蘇糖醇為起始物。獲得〇.144§呈白色 固體狀之#-{6-[(6-曱基[1,2,4]***并[4,3-6]嗒,井基)硫 烷基]-1,3-苯并噻唑-2-基}環丙烷甲醯胺,其特徵如下: 熔點:260°C (考夫勒) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.93 (m,4 jj). 1.96 (m, 1 H); 2.55 (s, 3 H); 7.34 (d5 /=9.5 Hz, 1 H); η 49 (dd,*/=2.0及 8.6 Hz,1 H); 7.68 (d,《7=8.6 Hz, 1 H); 8.10 (d */=2.0 Hz,1 H); 8.31 (d,/=9.5 Hz,1 H); 12.61 (寬多重峰 1 Η) 質譜:方法B 滯留時間Tr(分鐘)=3.44 ; [M+H] + : m/z 383; [M-H]-: m/z 382 154635.doc -91- 201202242 硫氰酸2-[(環丙基幾基)胺基]_1,3_苯并嗟唾_6_基酯如專 利WO 2009/056 692中所述製備。 實例19 : N-{6-[(6-甲基【1,2,4】***并[4,3-b】嗒畊-3-基)硫烷 基】-1,3-苯并噻唑-2-基卜2-(嗎啉-4-基)乙醯胺 甲基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}·2-(嗎啉-4-基)乙醢胺可如實例3_a製 備,但以0.180 g N,N,·(二硫烷二基二_丨,3_苯并噻唑·6,2•二 基)雙[2-(嗎啉-4·基)乙醯胺]及0.098 g 3-氣-6-甲基[1,2,4] ***并[4,3-6]嗒畊於8 cm3乙醇中之溶液、〇.〇〇3 g磷酸二 氫鉀於1.8 cm3水中之溶液及〇.327 g i,4_二硫_DL蘇糖醇為 起始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/甲醇 (95/5,以體積計)]之後,獲得〇 1〇4 8呈白色固體狀之^ {6-[(6-曱基[1,2,4]***并[4,3功]嗒畊-3-基)硫烷基]_!,夂笨 并噻唑-2-基}-2-(嗎啉-4-基)乙醯胺,其特徵如下: 熔點:242-243°C (考夫勒塊) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 2.53 (m, 4 H)· 2.55 (s,3 H); 3.34 (s,2 H); 3.61 (m,4 H); 7.34 (d, «/=9 5 Hz,1 H); 7.50 (dd,J=l.7及 8.6 Hz,1 H); 7.71 (d,《7=8.6 Hz 1 H); 8.14 (d, J=1.7 Hz, 1 H); 8.32 (d, J=9.5 Hz, 1 H); 12.17 (寬多重峰,1 H) ’Mass Spectrometry: Method A Retention time Tr (minutes) = 0.5 5, [M+H] + : m/z 355; [MH]-: m/z 353 thiocyanate 2-di-1,3-benzo-pyrene °S-6-based vinegar was prepared as described in the patent WO 2009/056 692. Example 17: 2-(4-cyclopropylpiped-1-yl)-oxime {6·[(6-methylindoletris[4,3-b]indole-3-yl)sulfane 】]-1,3-benzothiazol-2-yl}Ethylamine 2·(4-cyclopropyl-branched-1-yl)-iV-{6-[(6-fluorenyl[1,2, 4] Triazolo[4 3 — ]]. Indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide can be prepared as in Example 4-a, but at 0.110 g 2-{[(4-cyclopropylpipedyl)ethinyl]amino}-1,3-benzo-thiocyanate. Take 6-yl ester, 0.050 g of 3-methylmethyl [1,2,4]. Sit and [4,3-ά]. A solution of well 11 in 5 cm3 of ethanol and a solution of 2 g of potassium dihydrogen potassium in 1.2 cm3 of water and 0.165 g of 14-dithio-DL-threitol were used as starting materials. After flash chromatography of the ruthenium dioxide column [solvent: dioxane / decyl alcohol (95/5 by volume)], 0 〇 72 g of 2-(4-cyclopropyl) was obtained as a white solid. Piper-1-yl)-#-{6-[(6-methyl[1,2,4]triazolo[4,3-6].-h-yl-3-yl)thiol]-1 3-Benzene is sold as a 2-amino}acetamide, which is characterized as follows. Melting point: 156-166 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.27 (m, 2 H); 0.39 (m, 2 H); 1.59 (m, 1 H) ; 2.45 to 2.59 (multiple peaks partially masked, 11 H); 3.22 (s, 2 H); 7.34 (d, J = 9.5 Hz, 1 H); 7.50 (dd, J-2.0 and 8.6 Hz, 1 H) ; 7.69 (d, "/=8.6 Hz, 1 H); 8.13 (d, •==2.0 Hz, 1 H); 8.31 (d, J=9.5 Hz, 1 H); 12.50 (extremely wide multiple 154635.doc -90- 201202242 Peak, 1 Η) Mass Spectrum: Method A Retention time Tr (minutes) = 0.55; [M+H] + : m/z 481; [MH]-: m/z 479 3-chloro-6·A The base [1,2,4]triazolo[4,3-6] is cultivated as a commercially available product. Example IS: N-{6-[(6-methyl[I,2,4]triazolo[4,3_b]嗒耕_3_yl)thiol]-1,3-benzothiazole-2 -yl}cyclopropanecarbamamine^-{6-[(6-fluorenyl[1,2,4]dioxa[4,3-6]〇荅〇井-3-yl)thiol] 1,3·Benzothiazol-2-yl}cyclopropanecarbamide can be prepared as in Example 4_a, but with 0.5 〇〇g thiocyanate 2-[(cyclopropylcarbonyl)amino]-1,3 - benzothiazepine-6, oxime, 0.306 g of 3-gas-6-fluorenyl [1,2,4]triindole [4,3-6]. A solution of Sakaguchi well in 22 cm3 of ethanol and a solution of 0.010 g of potassium dihydrogen phosphate in 5.6 cm3 of water and 1.008 of 1,4-dithio-O-^-threitol were used as starting materials. Obtaining #.{6-[(6-fluorenyl[1,2,4]triazolo[4,3-6]fluorene, well base)sulfanyl]-1, as a white solid. 3-benzothiazol-2-yl}cyclopropanecarbamide characterized by the following: Melting point: 260 ° C (Cafele) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.93 (m, 4 jj). 1.96 (m, 1 H); 2.55 (s, 3 H); 7.34 (d5 /=9.5 Hz, 1 H); η 49 (dd, */=2.0 and 8.6 Hz, 1 H); 7.68 (d, "7=8.6 Hz, 1 H); 8.10 (d */=2.0 Hz, 1 H); 8.31 (d, /=9.5 Hz, 1 H); 12.61 (width multiple peak 1 Η) mass spectrum: method B retention time Tr (minutes) = 3.44; [M+H] + : m/z 383; [MH]-: m/z 382 154635.doc -91- 201202242 2-[(cyclopropyl) thiocyanate Amino]_1,3_benzoxime-7-yl ester was prepared as described in patent WO 2009/056 692. Example 19: N-{6-[(6-methyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazole 2-yl-2-(morpholin-4-yl)acetamimidylmethyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1 , 3-benzothiazol-2-yl} 2-(morpholin-4-yl)acetamide can be prepared as in Example 3-a, but with 0.180 g of N,N,·(disulfanediyldi-fluorene, 3_benzothiazole·6,2•diyl)bis[2-(morpholin-4-yl)acetamide] and 0.098 g of 3-gas-6-methyl[1,2,4]triazole [4,3-6] 嗒 于 in 8 cm3 of ethanol, 〇.〇〇3 g of potassium dihydrogen phosphate in 1.8 cm3 of water and 〇.327 gi,4_disulfo-DL threitol The original. After the flash chromatography of the ruthenium dioxide column [esolvent: di-methane/methanol (95/5 by volume)], 〇1〇4 8 is obtained as a white solid ^{6-[(6-fluorenyl) [1,2,4]triazolo[4,3 work] 嗒-3-yl)sulfanyl]_!, hydrazine and thiazol-2-yl}-2-(morpholin-4-yl) Acetamine, which has the following characteristics: Melting point: 242-243 ° C (Covre block) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 2.53 (m, 4 H)· 2.55 (s, 3 H); 3.34 (s, 2 H); 3.61 (m, 4 H); 7.34 (d, «/=9 5 Hz, 1 H); 7.50 (dd, J=l.7 and 8.6 Hz, 1 H) ; 7.71 (d, "7=8.6 Hz 1 H); 8.14 (d, J = 1.7 Hz, 1 H); 8.32 (d, J = 9.5 Hz, 1 H); 12.17 (width multiple peak, 1 H) '

質譜:方法A 滯留時間Tr(分鐘)=0.52 ; [M+H] + : m/z 442; [M-H]-: m/z 440 實例20 : l-(6-{[6-(環己基甲基)口,2,4]***并丨七苫吨丨嗒,井、 154635.doc •92- 201202242 3-基】硫燒基卜1,3-苯并嗟唾-2-基嗎琳_4_基)乙基】服 1-(6-{[6_(環己基甲基)[1,2,4]***并[4,3_6]塔畊_3•基]硫 烧基}-1,3-苯并嚷。坐-2-基)-3-[2-(嗎κ基)乙基]腦可如實 例卜&製備,但以〇.2l7 g H2-(嗎啉·4_基)乙基]_3(6_硫烷 基-1,3-苯并售唾-2-基)腺及〇·16〇 g 3_氣_6 (環己基^ 基)Π,2,4]三哇并[4,3-6]塔喷於3 cm3正丁醇中之溶液及 0.157 g磷酸鉀於1_1 cm3水中之溶液為起始物。二氧化矽管 柱急驟層析[溶離劑:二氣甲烷/曱醇(98/2,以體積叶)]之 後,獲得0.074 g呈白色固體狀之(環己基曱 基)[1,2,4]***并[4,3-6]嗒畊·3-基]硫烷基卜丨,3_苯并噻唑 2-基)-3-[2-(嗎淋-4-基)乙基]脲,其特徵如下: 熔點:212-214°C(考夫勒塊) 1H NMR (400 ΜΗζ,δ (ppm),DMSO-d6): 0.75至 〇.9〇 2 H); 1.01 至 1.13 (m,3 H); 1.41 至 1.57 (m,5 H); 1.63 (m ! H); 2.37至 2.44 (m,6 H); 2.67 (m,2 H); 3.26 (部分遮蔽之 多重峰,2 H); 3.59 (m,4 H); 6·76 (寬多重峰,1 H); 7.33 (d •/=9.5 Hz,1 H); 7.40 (dd,*7=2.0及 8.3 Hz,1 H); 7·53 (d /=8.3 Hz,1 H); 8.02 (d,*/=2.0 Hz,1 H); 8.30 (d,《/=9.5 Hz 1 H); 10.87 (寬多重峰,1 H) 質譜:方法A 滞留時間T r (分鐘)=0.7 7 ; [M+H] + :m/z 553;基峰:m/z397 [M-H]-: m/z 551 實例21 : N-(6-{【6-(環己基甲基)[l,2,4]***并[4,3-b】嗒畊 154635.doc -93- 201202242 3-基】硫烷基卜l,3-苯并噻唑_2_基)環丙烷甲醢胺 N-(6-{[6-(環己基甲基)[12 4]***并[4,3_b]嗒畊·3基]硫 烷基}-1,3-苯并噻唑_2_基)環丙烷甲醯胺可如實例A”製 備,但以0_146 g硫氰酸2_[(環丙基羰基)胺基卜丨,%笨并噻 唑_6·基酯、0·110 g 3_氯-6-(環己基甲基)[1,2,4]***并 [4,3-6]嗒畊於6 cm3乙醇中之溶液及0 0025 g磷酸二氫鉀於 1.4 cm3水中之溶液及0 245 g丨,4_二硫_DL_蘇糖醇為起始 物。二氧化矽管柱急驟層析[溶離劑:二氣曱烷/甲醇 (98/2,以體積計)]之後,獲得〇 〇77 §呈白色固體狀之 (6-{[6-(環己基曱基)[u〆]***并[4,3_b]嗒畊·3基]硫烷 基}-1,3-苯并噻唑-2-基)環丙烷甲醯胺,其特徵如下: 熔點:254-258°C (步奇) 1H NMR (400 MHz, δ (ppm), DMSO-d6): 0.82 (m, 2 H); 0.94 (m,4 H); 0.99至 l.ii (m,3 h); 1.39至 1.55 (m,5 H); 1.60 (m,1 H); 1.98 (m,1 H); 2.66 (d,《7=7.1 Hz,2 H); 7.34 (d, «7=9.5 Hz,1 H); 7.45 (dd,J=2.0及 8.6 Hz,1 H); 7.67 (d, */=8.6 Hz, 1 H); 8.09 (d, J=2.0 Hz, 1 H); 8.32 (d, J=9.5 Hz, 1 H); 12.67 (宽多重峰,i h) 質譜:方法A 滯留時間Tr(分鐘)=1.08 ; [M+H] + : m/z 465; [M-H]-: m/z 463 實例22 : N-(6-{[6-(環丙基)丨i,2,4】***并[4,3-b]嗒畊-3-基] 硫燒基}·1,3-苯并噻唑_2-基)環丙烷甲醯胺 Ν-(6-{[6-(環丙基)[1,2,4]***并[4,3-b]嗒啡-3-基]硫烷 154635.doc • 94· 201202242 基}-l,3-苯并噻唑_2_基)環丙烷曱醯胺可如實例4 a製備, 但以0.50 g硫氰酸2_[(環丙基羰基)胺基]_!,3_笨并噻唑·6•基 酯、0.353 g 3_氣_6_(環丙基曱基)[^,划***并[4,3功]嗒〇井 於16 cm3乙醇中之溶液及〇 〇1〇 g磷酸二氫鉀於2 3 cm3水中 之溶液及1_01 g 1,4-二硫-DL-蘇糖醇為起始物。二氧化矽 管柱急驟層析[溶離劑:二氯曱烷/甲醇(98/2,以體積計)] 之後’獲得0.177 g呈白色固體狀之n_(6_{[6_(環丙基甲 基)[1,2,4]***并[4,3-b]嗒畊-3-基]硫烷基}-1,3_苯并噻唑_ 2-基)環丙烧甲醯胺,其特徵如下: 熔點:307-320°C (步奇) 1H NMR (400 ΜΗζ,δ (ppm), DMSO-d6): 0.86至 0.98 (m 6 H); 1.08 (m,2 H); 1.99 (m, 1 H); 2.21 (m, 1 H); 7.29 (d, >9.8 Hz,1 H); 7.47 (dd,《/=2.1 及 8.6 Hz,1 H); 7.69 (d */=8.6 Hz, 1 H); 8.12 (d, /=2.1 Hz, 1 H); 8.27 (d, J=9.8 Hz, 1 H); 12.68 (寬單峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.87 ; [M+H] + : m/z 409; [M-H]-: m/z 407 實例23 : N-{6-[(6-環丙基丨1,2,4]***并【4,3_b】嗒畊-3-基)硫 燒基卜1,3-苯并售唑_2-基}-2-[(2H8)嗎琳-4-基】乙酿胺 a) #-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基卜 1,3-笨并噻唑-2-基}-2-[(2H8)嗎啉_4_基]乙醯胺可以如下方 式製備: 向 0.150 g 2-氣-7V-{6-[(6-環丙基[ι,2,4]***并[4,3-6]嗒 154635.doc -95- 201202242 畊-3-基)硫烷基]-i,3_苯并噻唑_2_基}乙醯胺於5 cm3二氣甲 烷中之懸浮液中添加0.0625 cm3 N_乙基二異丙胺及〇〇38 g (2,2,3,3,5,5,6,6-2118)嗎啉。在約20〇(:之溫度下攪拌混合物1 小時。添加0.055 g (2,2,3,3,5,5,6,6-2118)嗎啉且攪拌約18小 時之後’添加 0.100 g (2,2,3,3,5,5,6,6-2118)嗎啉及0.125(:1113 N-乙基二異丙胺’且用5 cm3二甲亞砜稀釋混合物。 攪拌所得溶液一小時,隨後傾倒於1〇〇 cm3水中且用 cm3二氣甲烷萃取三次。用5〇 水洗滌經合併之有機 相,經硫酸鎂乾燥,過濾且在減壓下濃縮。二氧化矽管柱 急驟層析[溶離劑:二氣曱烷/曱醇(98/2,以體積計)]之 後,獲得0.098 g呈白色固體狀之#環丙基[12 4] 一 唾并[4,3-6]嗒畊-3-基)硫烷基]-i,3-苯并噻唑基} 2 [(2H8)嗎啉-4-基]乙醯胺,其特徵如下: 熔點:247-247.5。(:(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 (m 2 H). 1.09 (m,2 H); 2.21 (m,1 H); 3.33 (s,2 H); 7.30 (d,5 Hz,1 H); 7.47 (dd,/=2.2及 8.6 Hz,1 H); 7.68 (d,7=8 6 Hz 1 H); 8.12 (d,《7=2.2 Hz,1 H); 8.27 (d,《7=9.5 Hz,1 H). 12·16 (寬單峰,1 H) ’Mass Spectrometry: Method A Retention time Tr (minutes) = 0.52; [M+H] + : m/z 442; [MH]-: m/z 440 Example 20: l-(6-{[6-(cyclohexyl) Base), 2,4] triazole 丨 苫 苫 丨嗒, well, 154635.doc •92- 201202242 3-based thiol-based 1,3-benzopyrene-pyrene-2-pyreline _ 4_yl)ethyl] served 1-(6-{[6_(cyclohexylmethyl)[1,2,4]triazolo[4,3_6]tral _3•yl]thiol}}-1 , 3-benzopyrene. Sodium-2-yl)-3-[2-(? k-)ethyl] brain can be prepared as in the example & but with 〇.2l7 g H2-(morpholine·4_ Ethyl]_3 (6-sulfanyl-1,3-benzo-salt-2-yl) gland and 〇·16〇g 3_gas_6 (cyclohexyl) hydrazine, 2,4] A solution of the Sanwa[4,3-6] tower sprayed in 3 cm3 of n-butanol and a solution of 0.157 g of potassium phosphate in 1_1 cm3 of water were used as starting materials. After the flash chromatography of the ruthenium dioxide column [solvent: di-methane/sterol (98/2, by volume)], 0.074 g of (cyclohexylfluorenyl) [1, 2, 4 was obtained as a white solid. Triazolo[4,3-6]indole·3-yl]sulfanyldiazine,3-benzothiazolyl-2-yl)-3-[2-(norlin-4-yl)ethyl] Urea, which has the following characteristics: Melting point: 212-214 ° C (Kauflule block) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.75 to 〇.9〇2 H); 1.01 to 1.13 (m) , 3 H); 1.41 to 1.57 (m, 5 H); 1.63 (m ! H); 2.37 to 2.44 (m, 6 H); 2.67 (m, 2 H); 3.26 (partially masked multiplet, 2 H 3.59 (m,4 H); 6·76 (width multiple peak, 1 H); 7.33 (d •/=9.5 Hz, 1 H); 7.40 (dd, *7=2.0 and 8.3 Hz, 1 H) ; 7·53 (d /=8.3 Hz, 1 H); 8.02 (d, */=2.0 Hz, 1 H); 8.30 (d, "/=9.5 Hz 1 H); 10.87 (width multiple peak, 1 H Mass Spectrometry: Method A Retention time T r (minutes) = 0.7 7 ; [M+H] + : m/z 553; base peak: m/z 397 [MH]-: m/z 551 Example 21: N-(6 -{[6-(cyclohexylmethyl)[l,2,4]triazolo[4,3-b]嗒耕154635.doc -93- 201202242 3-yl]sulfanyl b,3-benzene Thiazol-2-yl) Cyclopropanecarbamide N-(6-{[6-(cyclohexylmethyl)[12 4]triazolo[4,3_b]indole·3yl]sulfanyl}-1,3-benzothiazole _2_yl)cyclopropanecarbamamine can be prepared as in Example A", but with 0-146 g of thiocyanate 2-[(cyclopropylcarbonyl)amine oxime, % benzothiazole -6 ester, 0.110 a solution of g 3_chloro-6-(cyclohexylmethyl)[1,2,4]triazolo[4,3-6]indole in 6 cm3 of ethanol and 0 0025 g of potassium dihydrogen phosphate at 1.4 cm3 A solution of water and 0 245 g 丨, 4_ disulfo-DL_threitol as a starting material. Chromatography of ruthenium dioxide column [solvent: dioxane / methanol (98/2, by volume) After that, 〇〇77 § was obtained as a white solid (6-{[6-(cyclohexylfluorenyl)[u〆]triazolo[4,3_b]indole·3yl]sulfanyl}- 1,3-Benzothiazol-2-yl)cyclopropanecarbamide characterized by the following: Melting point: 254-258 ° C (step) 1H NMR (400 MHz, δ (ppm), DMSO-d6): 0.82 (m, 2 H); 0.94 (m, 4 H); 0.99 to l.ii (m, 3 h); 1.39 to 1.55 (m, 5 H); 1.60 (m, 1 H); 1.98 (m, 1 H); 2.66 (d, "7=7.1 Hz, 2 H); 7.34 (d, «7=9.5 Hz, 1 H); 7.45 (dd, J=2.0 and 8.6 Hz, 1 H); 7.67 (d, */=8.6 Hz, 1 H); 8.09 (d, J=2.0 Hz, 1 H); 8.32 (d, J=9.5 Hz, 1 H); 12.67 (width multiple peak, ih) mass spectrum: Method A Retention time Tr (minutes) = 1.08; [M+H] + : m/z 465; [MH]-: m/z 463 Example 22: N-(6-{[6-(cyclopropyl)fluorene i,2,4]triazolo[4,3-b]indole-3-yl]sulfuryl}}1,3-benzothiazol-2-yl)cyclopropanecarbamamine-(6- {[6-(cyclopropyl)[1,2,4]triazolo[4,3-b]indol-3-yl]sulfane 154635.doc • 94· 201202242 base}-l,3-benzene And thiazol-2-yl)cyclopropanoguanamine can be prepared as in Example 4a, but with 0.50 g of thiocyanate 2-[(cyclopropylcarbonyl)amino]-!, 3- benzothiazolyl-6 ester , 0.353 g 3_gas_6_(cyclopropyl fluorenyl) [^, a solution of triazole and [4,3 work] 嗒〇 well in 16 cm3 of ethanol and 〇〇1〇g potassium dihydrogen phosphate at 2 A solution of 3 cm3 of water and 1_01 g of 1,4-dithio-DL-threitol are used as starting materials. Chromatography of ruthenium dioxide column [solvent: dichloromethane/methanol (98/2 by volume)] followed by 'obtaining 0.177 g of n_(6_{[6_(cyclopropylmethyl) as a white solid [1,2,4]triazolo[4,3-b]indole-3-yl]sulfanyl}-1,3-benzothiazolyl-2-yl)cyclopropenylcarboxamide, The characteristics are as follows: Melting point: 307-320 ° C (step) 1H NMR (400 ΜΗζ, δ (ppm), DMSO-d6): 0.86 to 0.98 (m 6 H); 1.08 (m, 2 H); 1.99 (m , 1 H); 2.21 (m, 1 H); 7.29 (d, > 9.8 Hz, 1 H); 7.47 (dd, "/=2.1 and 8.6 Hz, 1 H); 7.69 (d */= 8.6 Hz , 1 H); 8.12 (d, /=2.1 Hz, 1 H); 8.27 (d, J=9.8 Hz, 1 H); 12.68 (width unimodal, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) =0.87 ; [M+H] + : m/z 409; [MH]-: m/z 407 Example 23: N-{6-[(6-cyclopropyl丨1,2,4]triazolo[ 4,3_b】嗒耕-3-yl) thiopyrazine 1,3-benzoxazole -2-yl}-2-[(2H8)morphin-4-yl]ethinamine a) #-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyldi-1,3-phenylthiazol-2-yl}- 2-[(2H8)morpholine_4_yl]acetamide can be prepared as follows: to 0.150 g 2-gas-7V- {6-[(6-cyclopropyl[ι,2,4]triazolo[4,3-6]嗒154635.doc -95- 201202242 耕-3-yl)sulfanyl]-i,3_ Add 0.0625 cm3 N-ethyldiisopropylamine and 〇〇38 g (2,2,3,3,5,5, to a suspension of benzothiazole-2-yl}acetamide in 5 cm3 of di-methane. 6,6-2118) morpholine. The mixture was stirred at about 20 Torr for 1 hour. Add 0.055 g (2,2,3,3,5,5,6,6-2118) morpholine and stir for about 18 hours, then add 0.100 g (2 , 2,3,3,5,5,6,6-2118)morpholine and 0.125 (:1113 N-ethyldiisopropylamine' and dilute the mixture with 5 cm3 of dimethyl sulfoxide. Stir the resulting solution for one hour, then Pour into 1 〇〇 cm 3 of water and extract three times with cm 3 of methane. The combined organic phases are washed with 5 hr of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. After the agent: dioxane/sterol (98/2 by volume)], 0.098 g of #cyclopropyl [12 4] was expressed as a white solid and [4,3-6] 3-yl)sulfanyl]-i,3-benzothiazolyl} 2 [(2H8)morpholin-4-yl]acetamide, which has the following characteristics: Melting point: 247-247.5. (:(step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m 2 H). 1.09 (m, 2 H); 2.21 (m, 1 H); 3.33 (s, 2 H); 7.30 ( d, 5 Hz, 1 H); 7.47 (dd, /= 2.2 and 8.6 Hz, 1 H); 7.68 (d, 7 = 8 6 Hz 1 H); 8.12 (d, "7=2.2 Hz, 1 H) ; 8.27 (d, "7=9.5 Hz, 1 H). 1 2·16 (wide single peak, 1 H) ’

質譜:方法A 滯留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 476; [M-H]-: m/z 474 b) 2-氣-W-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊_3·基)碎 烷基]-1,3·苯并噻唑-2-基}乙醯胺可如實例3-c製備,彳旦以 154635.doc •96- 201202242 〇·375 g 6_[(6_環丙基π,2,4]***并[4,3_ό]嗒畊冬基)硫烷 基]-1,3-笨并噻唑_2_胺及〇114 cm3氣乙醯氯於i5 em3二噁 烷中之溶液為起始物。獲得0.471 g呈黃色固體狀之2_氣_ …(^⑽-環丙基^”***并^义^嗒喷士基丨硫烷基卜 1,3-苯并噻唑_2_基丨乙醯胺,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 476; [MH]-: m/z 474 b) 2-gas-W-{6-[(6-ring Propyl [1,2,4]triazolo[4,3-6]indole _3.yl)alkylidene]-1,3·benzothiazol-2-yl}acetamide can be as Example 3 -c preparation, 彳旦 to 154635.doc •96- 201202242 〇·375 g 6_[(6_cyclopropyl π,2,4]triazolo[4,3_ό]嗒耕冬基) sulfanyl]- A solution of 1,3-stupothiazole-2-amine and hydrazine 114 cm3 of gas oxime chloride in i5 em3 dioxane is used as a starting material. Obtained 0.471 g of 2_gas_((())-cyclopropyl) triazole and sulfonyl sulfonyl 1,3-benzothiazole 2 _ 丨Indoleamine, which has the following characteristics:

Rf—氧化矽TLC = 0.38 [溶離劑:二氯曱烷/甲醇(95/5 , 以體積計)]Rf—yttrium oxide TLC = 0.38 [dissolving agent: dichlorodecane/methanol (95/5 by volume)]

質譜:方法C 滯留時間Tr(分鐘)=1.17 ; [M+H] + : m/z 417; [M-H]-: m/z 415 c)6-[(6-環丙基[i,2,4]***并[4,34]嗒畊_3_基)硫烷基]_ 1,3-苯并噻唑_2_胺可如對於實例2所示製備或以如下方式 製備: 將 0.585 g N-(6-{[6-(環丙基)^,2,4]***并[4,3-b]嗒畊-3- 基]硫烷基}-1,3-苯并噻唑-2-基)環丙烷甲醯胺於25 cm3 6 N 鹽酸水溶液中之懸浮液在約7 〇 t之溫度下維持約6小時, 繼而添加2 cm3 12 N鹽酸水溶液,且在相同溫度下攪拌所 得混合物約8小時。冷卻至約5°c之溫度之後,藉由添加 30%氫氧化鈉調節PH值為約9_10。藉由抽吸濾出固體,用 水洗滌直至中性且在空氣中乾燥。獲得〇 375 g呈黃色固體 狀之6-[(6-環丙基[1,2,4]***并[4 3功]嗒畊_3_基)硫烷基]· 1,3-苯并售》坐-2-胺,其特徵如下:Mass Spectrometry: Method C Retention time Tr (minutes) = 1.17; [M+H] + : m/z 417; [MH]-: m/z 415 c) 6-[(6-cyclopropyl[i,2, 4] Triazolo[4,34]indole_3_yl)sulfanyl]-1,3-benzothiazole-2-amine can be prepared as shown in Example 2 or prepared as follows: 0.585 g N-(6-{[6-(cyclopropyl)^,2,4]triazolo[4,3-b]indole-3-yl]sulfanyl}-1,3-benzothiazole- A suspension of 2-yl)cyclopropanecarbamide in 25 cm3 of 6 N aqueous hydrochloric acid is maintained at a temperature of about 7 Torr for about 6 hours, followed by the addition of 2 cm3 of 12 N aqueous hydrochloric acid, and the resulting mixture is stirred at the same temperature. About 8 hours. After cooling to a temperature of about 5 ° C, the pH was adjusted to about 9-10 by the addition of 30% sodium hydroxide. The solid was filtered off by suction, washed with water until neutral and dried in air. 6 375 g of 6-[(6-cyclopropyl[1,2,4]triazolo[4 3 work] 嗒3_yl)sulfanyl]·1,3-benzene as a yellow solid And sold "sodium-2-amine, its characteristics are as follows:

Rf二氧化矽TLC=0.07 [溶離劑:二氯曱烷/甲醇(95/5, 以體積計)] 154635.doc -97- 201202242 質譜:方法A 滯留時間Tr(分鐘)=0.64 ; [M+H] + : m/z 341; [M-H]-: m/z 339 實例24 : Ν-{6-[(6·環丙基丨1,2,4】***并[4,3-b]嗒畊_3_基)硫 炫基】-5-氟-1,3-苯并噻唑-2-基}_2_(嗎啉-4-基)乙醯胺 a) N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]_ 5-氟-1,3-苯并噻唑-2-基}-2-(嗎啉-4-基)乙醯胺可以如下方 式製備: 向 0.150 g 2-氣-#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒 _ -3-基)硫烷基]-5-氟-i,3-苯并噻唑_2-基}乙醯胺於5 cm3 一甲亞石風中之溶液中添加0.223 cm3嗎琳。在約20°C之溫度 下攪拌混合物1小時,隨後傾倒於1〇〇 cm3水中且用1〇〇 cm3 一氣甲院萃取二次。用100 cm3水洗務經合併之有機相三 次’經硫酸鎂乾燥,過濾且在減壓下濃縮》二氧化矽管柱 急驟層析[溶離劑:二氣曱烷/曱醇(98/2,以體積計)]之 後’獲得0.2178呈白色固體狀之#_{6-[(6_環丙基[124]三 唑并[4,3功]嗒啡-3-基)硫烷基]_5_氟-1,3-苯并噻唑-2-基}-2-(嗎琳-4-基)乙醢胺,其特徵如下: 熔點:254°C (考夫勒) 1H NMRs普(400 ΜΗζ,δ (ppm),DMSO-d6): 0.89 (m,2 H); 1.07 (m, 2 H); 2.20 (m, 1 H); 2.53 (m, 4 H); 3.35 (s, 2 H); 3.60 (m, 4 H); 7.30 (d5 J=9.8 Hz, 1 H); 7.68 (d, 7=10.3 Hz, 1 H); 8.16 (d, 7=7.3 Hz, 1 H); 8.27 (d, J=9.8 Hz, 1 H); 12.33 (寬多重峰,1 H) 154635.doc • 98 - 201202242Rf ruthenium dioxide TLC=0.07 [Eluent: dichloromethane/methanol (95/5, by volume)] 154635.doc -97- 201202242 Mass spectrometry: Method A residence time Tr (minutes) = 0.64; [M+ H] + : m/z 341; [MH]-: m/z 339 Example 24: Ν-{6-[(6·cyclopropyl 丨1,2,4]triazolo[4,3-b]嗒____) thiophanyl]-5-fluoro-1,3-benzothiazol-2-yl}_2_(morpholin-4-yl)acetamidamine a) N-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]- 5-fluoro-1,3-benzothiazol-2-yl}- 2-(morpholin-4-yl)acetamide can be prepared as follows: to 0.150 g of 2-gas-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4, 3-6]嗒_-3-yl)sulfanyl]-5-fluoro-i,3-benzothiazol-2-yl}acetamidamine added 0.223 cm3 to a solution of 5 cm3 of ketone Ms. Lin. The mixture was stirred at a temperature of about 20 ° C for 1 hour, then poured into 1 〇〇 cm 3 of water and extracted twice with 1 〇〇 cm 3 of a gas chamber. The combined organic phases were washed three times with 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography of ruthenium dioxide column [solvent: dioxane/sterol (98/2, Volumetric))] after obtaining 0.2178 as a white solid #_{6-[(6_cyclopropyl[124]triazolo[4,3]] morphine-3-yl)sulfanyl]_5_ Fluorine-1,3-benzothiazol-2-yl}-2-(morphin-4-yl)acetamide, which has the following characteristics: Melting point: 254 ° C (Cafele) 1H NMR s (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 (m, 2 H); 1.07 (m, 2 H); 2.20 (m, 1 H); 2.53 (m, 4 H); 3.35 (s, 2 H); 3.60 (m, 4 H); 7.30 (d5 J=9.8 Hz, 1 H); 7.68 (d, 7=10.3 Hz, 1 H); 8.16 (d, 7=7.3 Hz, 1 H); 8.27 (d, J=9.8 Hz, 1 H); 12.33 (width multiple peak, 1 H) 154635.doc • 98 - 201202242

質譜:方法A 滞留時間Tr(分鐘)=0.67 ; [M+H] + : m/z 486; [M-H]-: m/z 484 b) 2-氣-#-{6-[(6-環丙基[i,2,4]***并[4,3_6]嗒畊_3基)硫 烷基]-5-氟-1,3-苯并噻唑_2-基}乙醯胺可如實例3_c製備, 但以0.320 g 6-[(6-環丙基[^4]***并[4 3 6]嗒畊_3基)硫 烷f ]-5-氟-1,3-苯并噻唑_2_胺及〇 〇93 cm3氯乙醯氯於$ cm二噁烷中之溶液為起始物。獲得〇 372 g呈黃色固體狀 之2-氣-iV-{6-[(6-環丙基Π,2,4]***并[4 3_6]嗒畊基)硫 烷基]-5-氟-1,3·苯并噻唑_2_基}乙醯胺,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.67; [M+H] + : m/z 486; [MH]-: m/z 484 b) 2-gas-#-{6-[(6-ring Propyl [i,2,4]triazolo[4,3_6]indole_3yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide can be as an example Prepared by 3_c, but with 0.320 g of 6-[(6-cyclopropyl[^4]triazolo[4 3 6]indole_3yl)sulfane f]-5-fluoro-1,3-benzothiazole A solution of _2_amine and 〇〇93 cm3 chloroacetamidine chloride in $cm dioxane was used as the starting material. Obtained 372 g of 2- gas-iV-{6-[(6-cyclopropylindole, 2,4]triazolo[4 3_6]indole)sulfanyl]-5-fluoro -1,3·benzothiazole_2-yl}acetamide, which is characterized as follows:

Rf二氧化矽TLC = 0.29 [溶離劑:二氣甲烷/甲醇(95/5, 以體積計)]Rf ruthenium dioxide TLC = 0.29 [Eluent: two gas methane / methanol (95/5, by volume)]

質譜:方法A 滯留時間Tr(分鐘)=〇.9〇 ; [M+H] + : m/z 435; [M-H]-: m/z 433 c)6-[(6-環丙基[i,2,4]***并[4,3功]嗒畊_3_基)硫烷基]-5_ 敦+3-笨并。塞。坐_2-胺如實例23_c製備,但以〇4 g n-(6-{[6-(環丙基)[1,2,4]三唾并[4,3_b]。荅,井-3_基]硫院基}_5_氟_ 1,3_笨并嗟。坐_2·基)環丙烷曱醯胺於16 cm3 6 N鹽酸水溶液 中之'合液為起始物。獲得0.33 g呈黃色固體狀之6-[(6-環丙 基Π’2,4]二唑并[4,3_6]嗒畊·3_基)硫烷基卜5_氟-i,3苯并噻 唑胺,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.9 〇; [M+H] + : m/z 435; [MH]-: m/z 433 c) 6-[(6-cyclopropyl[i] , 2, 4] triazolo[4,3 work] 嗒 _ _3_ base) sulfanyl]-5_ 敦+3- stupid. Plug. Sit 2-amine prepared as in Example 23_c, but with 〇4 g n-(6-{[6-(cyclopropyl)[1,2,4]tris-[4,3_b].荅, well-3 _ base] sulfur hospital base}_5_ fluorine_ 1,3_ stupid and 嗟. sit 2 · base) cyclopropanolamine in 16 cm3 6 N hydrochloric acid aqueous solution of the 'liquid mixture as a starting material. Obtaining 0.33 g of 6-[(6-cyclopropylΠ'2,4]diazolo[4,3_6]indole·3_yl)sulfanyl b-5-fluoro-i,3 benzene as a yellow solid And thiazolyl, which has the following characteristics:

Rf-氧化矽TLC = 〇.15 [溶離劑:二氯曱烷/曱醇(95/5, 以體積計)] i54635.doc -99- 201202242 質譜:方法A 滯留時間Tr(分鐘)= 0.73 ; [M+H] + : m/z 359; [M-H]-: m/z 357 d) Ν-(6·{[6-(環丙基)[l,2,4]***并[4,3-b]嗒畊-3-基]硫烷 基}-5-氟-1,3-苯并噻唑-2-基)環丙烷曱醯胺可如實例4-a製 備’但以0.50 g硫氰酸2-[(環丙基羰基)胺基]5-氟-1,3-苯并 嗟峰-6-基酯、0.365 g 3-氣-6-(環丙基曱基)[1,2,4]***并 [4,3-6]嗒畊於15 cm3乙醇中之溶液及0.010 g磷酸二氫鉀於 2 cm3水中之溶液及0.954 g 1,4-二硫-DL-蘇糖醇為起始 物。獲得0.400 g呈黃色固體狀之N-(6-{[6-(環丙基甲 基)[1,2,4]***并[4,3-b]嗒畊-3-基]硫烷基}-5-氟-1,3-苯并 °塞嗤-2-基)環丙烷甲醯胺,其特徵如下:Rf-矽 矽 TLC = 〇.15 [dissolving agent: dichlorodecane / decyl alcohol (95/5, by volume)] i54635.doc -99- 201202242 Mass spectrometry: Method A residence time Tr (minutes) = 0.73; [M+H] + : m/z 359; [MH]-: m/z 357 d) Ν-(6·{[6-(cyclopropyl)[l,2,4]triazolo[4, 3-b] indole-3-yl]sulfanyl}-5-fluoro-1,3-benzothiazol-2-yl)cyclopropanoguanamine can be prepared as in Example 4-a but with 0.50 g sulfur 2-[(cyclopropylcarbonyl)amino]5-fluoro-1,3-benzopyrene-6-yl cyanate, 0.365 g 3- gas-6-(cyclopropylindenyl)[1, 2,4]Triazolo[4,3-6] hydrazine in 15 cm3 ethanol and 0.010 g potassium dihydrogen phosphate in 2 cm3 water and 0.954 g 1,4-dithio-DL-threitol The alcohol is the starting material. Obtained 0.400 g of N-(6-{[6-(cyclopropylmethyl)[1,2,4]triazolo[4,3-b]indole-3-yl]sulfane as a yellow solid a group of 5-5-fluoro-1,3-benzox-indol-2-yl)cyclopropanecarbamide characterized by the following:

Rf二氧化矽TLC = 0.26 [溶離劑:二氣曱烧/甲醇(95/5, 以體積計)] 質譜:方法C 滯留時間Tr(分鐘)=1.24 ; [M+H] + : m/z 427; [M-H]-: m/z 425 硫氰酸2-[(環丙基羰基)胺基]5-氟-1,3-苯并噻唑基酷 可如專利WO 09/056 692中所述製備。 實例25 : #-{6-[(6-環丙基[1,2,4】***并[4,3-6】嗒畊-3-基)硫 烧基]-1,3 -苯并嗟吐-2-基}-2-(4_乙基旅**井-1·基)乙酿胺 #-{6-[(6-環丙基[I,2,4]***并[4,3功]嗒畊-3-基)硫烷基]· 1,3 -本并嘆β坐_2-基}-2-(4-乙基略*•井-1-基)乙醯胺可如實例 24製備,但以〇.2 g 2-氣-iV-{6-[(6-環丙基[1,2,4]三唾并 154635.doc -100- 201202242 [4,3-6]嗒畊-3-基)硫烷基]-i,3-苯并噻唑_2_基丨乙醯胺及 0.120 g 1-乙基哌畊於6 cm3二甲亞砜中之溶液為起始物。 二氧化矽管柱急驟層析[溶離劑:二氣甲烷/甲醇(9〇/1〇, 以體積計)]之後’獲得0.138 g呈白色固體狀之#_{6_[(6_環 丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-i,3-苯并噻唑_ 2-基}-2-(4-乙基旅p井-1-基)乙酿胺,其特徵如下: 熔點:186°C (考夫勒) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 0.98 (t, /=7.2 Hz, 3 H); 1.09 (m, 2H); 2.21 (m, 1 H); 2.27 至2.5 8 (部分遮蔽之多重峰,i〇H); 2.30 (q,/=7.2 Hz,2 H); 7.30 (d,/=9.8 Hz.l H); 7.48 (dd,·7=2.0及 8.6 Hz,1 H); 7·69 (d,/=8.6 Hz,1 H); 8.13 (d,《7=2.0 Hz, 1 H); 8.27 (d,《7=9.8 Hz,l H); 12.06 (寬多重峰,1 H)Rf cerium oxide TLC = 0.26 [Eluent: two gas smoldering / methanol (95/5, by volume)] Mass spectrometry: Method C Retention time Tr (minutes) = 1.24; [M+H] + : m/z [MH]-: m/z 425 2-[(cyclopropylcarbonyl)amino]5-fluoro-1,3-benzothiazolylthiocyanate as described in patent WO 09/056 692 preparation. Example 25: #-{6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)thiol]-1,3-benzo嗟 -2--2-yl}-2-(4_ethyl Brigade ** well-1·yl) Ethylamine #-{6-[(6-cyclopropyl[I,2,4]triazolo[ 4,3 work] 嗒耕-3-yl)sulfanyl]·1,3 Å and ββ sit_2-yl}-2-(4-ethyl **• well-1-yl) acetamidine The amine can be prepared as in Example 24, but with 〇.2 g 2-gas-iV-{6-[(6-cyclopropyl[1,2,4]trisole and 154635.doc-100-201202242 [4,3 -6]嗒耕-3-yl)sulfanyl]-i,3-benzothiazol-2-ylhydrazide and 0.120 g of 1-ethylpiperidine in 6 cm3 of dimethyl sulfoxide Starting material. Chromatography of ruthenium dioxide column [solvent: di-methane/methanol (9 〇 / 1 〇, by volume)] after '0.138 g of white solid was obtained #_{6_[(6_cyclopropyl) [1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-i,3-benzothiazole-2-yl}-2-(4-ethyl brit P--1-yl)ethinylamine, characterized as follows: Melting point: 186 ° C (Craft) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 0.98 (t, /=7.2 Hz, 3 H); 1.09 (m, 2H); 2.21 (m, 1 H); 2.27 to 2.5 8 (multiple peaks partially masked, i〇H); 2.30 (q, /= 7.2 Hz, 2 H); 7.30 (d, /=9.8 Hz.l H); 7.48 (dd, ·7=2.0 and 8.6 Hz, 1 H); 7·69 (d, /=8.6 Hz, 1 H) ; 8.13 (d, "7=2.0 Hz, 1 H); 8.27 (d, "7=9.8 Hz, l H); 12.06 (width multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0_60 ; [M+H] + : m/z 495; [M-H]-: m/z 493 實例26 : ΛΓ-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒啩-3-基)硫 烷基】-1,3-苯并噻唑-2-基}-2-[(211,68)-2,6-二甲基嗎啉-4-基]乙醯胺 #-{6-[(6-環丙基[1,2,4]***并[4,3功]嗒畔-3-基)硫烷基]-1,3-苯并噻唑-2-基}_2-[(2R,6S)-2,6-二曱基嗎啉_4_基]乙醯 胺可如實例24製備,但以0.3 g 2-氯-#-{6-[(6-環丙基 [1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]_1,3-苯并噻唑-2-基}乙醯胺及0.182 g (2R,6S)-2,6-二曱基嗎淋於6 cm3二甲 154635.doc -101- 201202242 亞砜中之溶液為起始物。二氧化矽管柱急驟層析[溶離 劑:二氣曱烷/曱醇(98/2,以體積計之後,獲得〇〇83 g 呈白色固體狀之仏{6-[(6-環丙基Π,2,4]***并[4,3_ft]嗒畊· 3-基)硫烷基]-1,3-苯并噻唑-2-基}_2-[(2R,6S)-2,6-二曱基嗎 啉-4-基]乙醯胺,其特徵如下: 溶點.218-221 C(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m, 2 H); 1.04 (d, J=6A Hz, 6 H); 1.09 (m, 2 H); 1.89 (t, J=li.9 Hz, 2 H); 2.21 (m,1 H); 2.77 (寬二重峰,J=11.9 Hz,2 H); 3 35 至3.45 (經遮蔽之多重峰,2 H); 3 62 (m,2 H); 7 (d, •/=9.8 Hz,1 H); 7.47 (dd,/=2.2及 8.3 Hz,1 H); 7.68 (d, /=8.3 Hz, 1 H); 8.13 (d, J=2.2 Hz, 1 H); 8.27 (d5 J=9.8 Hz, 1 H); 12.06 (極寬多重峰,i h) 質譜:方法A 滯留時間Tr(分鐘)= 0.67 ; [M+H] + : m/z 496; [M-H]-: m/z 494 實例27 : N_{6](6-環丙基口以】三嗤并[4,3-b】.荅併_3_基)硫 烷基】-1,3·苯并嘆唾_2_基}·2_(Μ_二氧雜_8兔雜螺[45】癸_ 8-基)乙醯胺 Ν-{6·[(6-環丙基[U 4]三啥并[4 3帅答呼·3·基)硫院基]_ 1,3-苯并噻唑-2-基}·2_(1,4_二氧雜_8氮雜螺[4,5]癸基) 乙酿胺可如實例24製備,但以〇.3 g 2•氣環丙基 [1,2’4]三°坐并Κ3·6]°荅喷·3·基)硫院基]_1,3·苯并嗟。坐_2_ 基}乙酿胺及0.227 g κ二氧雜·8_氮雜螺[4,5]癸烧於6 ^ 154635.doc -102. 201202242 一甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析[溶 離劑.二氣甲烷/曱醇(95/5,以體積計之後,獲得〇 112 g呈白色固體狀之N-{6-[(6-環丙基以又糾***并[4,3_b]嗒 畊_3-基)硫烷基]-1,3-苯并噻唑_2-基卜2_(1,4_二氧雜_8_氮雜 螺[4,5]癸-8-基)乙醯胺,其特徵如下: 熔點:216-216.5°C(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m’ 2 H); 1·〇9 (m,2 H); 1.65 (m,4 H); 2.21 (m,i h); 2.60 (m,4 H); 3·35 (s,2 H); 3.86 (s,4 H); 7.30 (d,《7=9.8 Hz,1 H); 7.48 (dd,*7=2.0及 8.6 Hz,1 H); 7.69 (d,*7=8.6 Hz, 1 H); 8.13 (d, J=2.〇 Hz,1 H); 8.28 (d,·7=9.8 Hz,1 H); 12.08 (極寬多重 峰,1 Η)Mass Spectrometry: Method A Retention time Tr (minutes) = 0_60; [M+H] + : m/z 495; [MH]-: m/z 493 Example 26: ΛΓ-{6-[(6-cyclopropyl[ 1,2,4]triazolo[4,3-6]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[(211,68)- 2,6-Dimethylmorpholin-4-yl]acetamidine #-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3]]嗒-3- The thioalkyl]-1,3-benzothiazol-2-yl}_2-[(2R,6S)-2,6-dimercaptomorpholine-4-yl]acetamide can be prepared as in Example 24. But with 0.3 g 2-chloro-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]_1 , 3-benzothiazol-2-yl}acetamidamine and 0.182 g (2R,6S)-2,6-dimercapto-methyl lysate in 6 cm3 dimethyl 154635.doc -101- 201202242 Starting material. Chromatography of ruthenium dioxide column [Eluent: dioxane / decyl alcohol (98/2, after volume, 〇〇83 g is obtained as a white solid 仏{6-[(6-cyclopropyl) Π,2,4]triazolo[4,3_ft] 嗒耕·3-yl)sulfanyl]-1,3-benzothiazol-2-yl}_2-[(2R,6S)-2,6 - Dimercaptomorpholin-4-yl]acetamide, which has the following characteristics: melting point. 218-221 C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m , 2 H); 1.04 (d, J=6A Hz, 6 H); 1.09 (m, 2 H); 1.89 (t, J=li.9 Hz, 2 H); 2.21 (m,1 H); 2.77 (Wide doublet, J=11.9 Hz, 2 H); 3 35 to 3.45 (shaded multiplet, 2 H); 3 62 (m, 2 H); 7 (d, •/=9.8 Hz, 1 H); 7.47 (dd, /=2.2 and 8.3 Hz, 1 H); 7.68 (d, /=8.3 Hz, 1 H); 8.13 (d, J=2.2 Hz, 1 H); 8.27 (d5 J=9.8 Hz, 1 H); 12.06 (extremely wide multiplet, ih) Mass Spectrometry: Method A Retention time Tr (minutes) = 0.67; [M+H] + : m/z 496; [MH]-: m/z 494 Example 27 : N_{6](6-cyclopropyl sulfonate) triterpene [4,3-b]. 荅 and _3_yl)sulfanyl]-1,3·benzoindole_2_yl }·2_(Μ_二氧_8 rabbit snail [45] 癸 _ 8-yl) acetamidine Ν-{6· [(6-Cyclopropyl[U 4]triindole[4 3 handsome answer ·3·yl)thiol]] 1,3-benzothiazol-2-yl}·2_(1,4_2 Oxa-8 azaspiro[4,5]fluorenyl) Ethylamine can be prepared as in Example 24, but with 〇.3 g 2 • gas cyclopropyl [1,2'4] three-degree sitting and Κ3·6 ] ° 荅 · · 3 · base) sulfur yards] _1,3 · benzopyrene. The solution of 2-bromoamine and 0.227 g κ dioxa-8-azaspiro[4,5] was calcined in 6 ^ 154635.doc -102. 201202242 monosulfoxide was used as a starting material. Chromatography of ruthenium dioxide column [Seluent. Dihydromethane/sterol (95/5, after volume, obtained 〇112 g as a white solid N-{6-[(6-cyclopropyl Also corrected triazo[4,3_b]嗒耕_3-yl)sulfanyl]-1,3-benzothiazole_2-yl b 2_(1,4_dioxa-8-azaspiro[ 4,5]癸-8-yl)acetamide, which has the following characteristics: Melting point: 216-216.5 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m' 2 H); 1·〇9 (m, 2 H); 1.65 (m, 4 H); 2.21 (m, ih); 2.60 (m, 4 H); 3·35 (s, 2 H); 3.86 ( s, 4 H); 7.30 (d, "7 = 9.8 Hz, 1 H); 7.48 (dd, *7 = 2.0 and 8.6 Hz, 1 H); 7.69 (d, *7 = 8.6 Hz, 1 H); 8.13 (d, J=2.〇Hz, 1 H); 8.28 (d,·7=9.8 Hz, 1 H); 12.08 (extremely wide multiplet, 1 Η)

質譜:方法A 滯留時間1>(分鐘)=0.61; [M+H] + : m/z 524; [M-H]-: m/z 522 實例28 : 2-[4-(環丙基甲基)哌畊-l-基】-N-{6-[(6-環丙基 [1,2,4]***并[4,3_b]嗒畊_3_基)硫烷基】^孓苯并噻唑_2_ 基}乙醢胺 2·[4-(環丙基甲基)派畊-i_基]-Ν-{6-[(6-環丙基[1,2,4]三 嗤并[4,3-b]嗒啩基)硫烷基]-1,3-笨并噻唑-2-基}乙醯胺 可如實例24製備,但以〇.3 g 2-氣·ΑΜ6-[(6-環丙基 二咕并[4,3-6]嗒畊·3-基)疏烷基]-1,3-苯并噻唑-2-基}乙醯 胺及0.222 g 1·(環丙基甲基)哌畊於6 cm3二曱亞颯中之溶 液為起始物。二氧化矽管柱急驟層析[溶離劑:二氯曱烷/ 154635.doc • 103- 201202242 甲醇(95/5,以體積計)]之後,獲得0.069 g呈白色固體狀之 2-[4·(環丙基曱基)哌畊_1_基]-N-{6-[(6-環丙基三嗤 并[4,3-b]嗒畊“3-基)硫烷基]-1,3-苯并噻唑_2_基}乙醢胺, 其特徵如下: 熔點:217°C (步奇) 1H NMR譜(400 ^41^,5(??111),0?480-(16):〇.〇5(1112 11)· 0.44 (m,2 H); 0.80 (m, 1 H); 0.91 (m,2 H); ΐ·〇8 (m 2 H); 2.17 (d,《/=6.6 Hz,2 H); 2.21 (m,1 H); 2.41 至 2.5 8 (部分遮 蔽之多重峰,8 H); 3.32 (s,2 H); 7.30 (d,《7=9.8 Hz,! H); 7.48 (dd,《7=2.0及 8.6 Hz,1 H); 7.70 (d,*7=8.6 Hz,! H); 8.14 (d,*/=2.0 Hz,1 H); 8.28 (d,*7=9.8 Hz,1 H); 12.09 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.63 ; [M+H] + : m/z 521; [M+2H]2 + : m/z 261 (基峰) [M-H]-: m/z 5 19 實例29 : 2-(4-環丁基哌畊-1-基)·Ν-{6-[(6-環丙基[H4]三 嗅并[4,3-b]塔哨^-3-基)硫燒基】-1,3-苯并嗟唾-2-基}乙酿胺 2-(4-環丁基υ底井-1-基)-Ν-{6-[(6 -環丙基[1,2,4]三0坐并 [4,3-b]塔井-3-基)硫烧基]-1,3-苯并β塞唾-2-基}乙醯胺可如 實例24製備’但以0.3 g 2-氣-iV-{6-[(6-環丙基[ι,2,4]三0坐 并[4,3-ό]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、 0.200 g 1-環丁基哌畊二鹽酸鹽及0.442 cm3 Ν-乙基二異丙 胺於6 cm3二甲亞礙中之溶液為起始物。二氧化石夕管枉急 -104- 154635.doc 201202242 驟層析[溶離劑:二氯甲烷/甲醇(95/5 ’以體積計)]之後’ 獲得0.089 g呈白色固體狀之2-(4-環丁基哌畊-1-基)-N-{6_ [(6-環丙基[1,2,4]***并[4,3-b]嗒啩-3-基)硫烷基l·1,3·苯 并噻唑-2-基}乙醯胺,其特徵如下: 熔點:102.4°C(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 〇, 2 H); 1.09 (m,2 H); 1.60 (m,2 H); 1·74 (m,2 H); 1·89至 1·98 (m, 2 H); 2.21 (m,1 H); 2.27 (m,4 H); 2.54 (部分遮蔽之多重 峰,4 H); 2.69 (m,1 H); 3.23 (s,2 H); 7.30 (d,/=9.7 Hz,1 H); 7.47 (dd,·7=2.0及 8.6 Hz, 1 H); 7.69 (d,/=8.6 Hz,1 H); 8.13 (d,*7=2.0 Hz,1 H); 8.28 (d,J=9.7 Hz,1 H); 12.04 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)= 0.63 ; [M+H] + : m/z 521; [M+2H]2 + : m/z 261 [M-H]-: m/z 519 實例30 : 2-(4-環丙基-3,5-二甲基哌畊-1-基)-N-{6-[(6-環丙 基[1,2,4】***并[4,3-b]嗒畊-3-基)硫烷基】-1,3-苯并噻峻-2-基}乙醯胺 2-(4-環丙基-3,5 -二曱基哌_ _ι_基)_N-{6-[(6-環丙基 [1,2,4]***并[4,3-1)]嗒畊_3-基)硫烷基]-1,3-苯并嘍唑-2-基}乙醯胺可如實例24製備,但以〇 3 g 2-氯-#-{6-[(6-環丙 基[1,2,4]***并[4,3-6]嗒畊_3_基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、0.213 g 1·環丙基_2,6_二甲基哌畊二鹽酸鹽及 154635.doc -105- 201202242 0.442 cm3 N-乙基二異丙胺於6 cm3二曱亞砜中之溶液為起 始物。二氧化石夕管柱急驟層析[溶離劑:二氣甲烧/曱醇 (95/5 ’以體積計)]之後’獲得0.047 g呈白色固體狀之2_(4· 環丙基-3,5-二曱基娘p井-1-基)-N-{6-[(6-環丙基[12,4]三》坐 弁[4,3-b]。荅喷_3 -基)硫烧基]-1,3 -本并°塞唾-2 -基丨乙酿胺, 其特徵如下: 熔點:173-196°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.38 (m,2 H); 0.52 (m,2 H); 0.91 (m,2 H); 1.09 (m,2 H); l.io (d, J=6.5Mass Spectrometry: Method A Retention Time 1 > (minutes) = 0.61; [M+H] + : m/z 524; [MH]-: m/z 522 Example 28: 2-[4-(cyclopropylmethyl) Piper-l-yl]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]indole_3_yl)sulfanyl] Thiazole-2_yl}acetamide 2·[4-(cyclopropylmethyl)-cultivation-i_yl]-Ν-{6-[(6-cyclopropyl[1,2,4]trimium [4,3-b]decyl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide can be prepared as in Example 24, but with 〇.3 g 2-gas·ΑΜ6-[ (6-Cyclopropyldiindolo[4,3-6]indole·3-yl)alkyl]-1,3-benzothiazol-2-yl}acetamide and 0.222 g 1·(ring A solution of propylmethyl) pipetine in 6 cm3 of diterpenoids was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: methylene chloride / 154635.doc • 103-201202242 methanol (95/5 by volume)], 0.069 g of a white solid was obtained as 2-[4· (cyclopropyl fluorenyl) piperidine_1_yl]-N-{6-[(6-cyclopropyltriazino[4,3-b]indole "3-yl)sulfanyl]-1 , 3-benzothiazolyl-2-yl}acetamide, which has the following characteristics: Melting point: 217 ° C (step) 1H NMR spectrum (400 ^ 41 ^, 5 (?? 111), 0? 480- (16 ):〇.〇5(1112 11)· 0.44 (m,2 H); 0.80 (m, 1 H); 0.91 (m, 2 H); ΐ·〇8 (m 2 H); 2.17 (d, /=6.6 Hz, 2 H); 2.21 (m, 1 H); 2.41 to 2.5 8 (multiple peaks partially masked, 8 H); 3.32 (s, 2 H); 7.30 (d, "7=9.8 Hz, H); 7.48 (dd, "7=2.0 and 8.6 Hz, 1 H); 7.70 (d, *7=8.6 Hz, ! H); 8.14 (d, */=2.0 Hz, 1 H); 8.28 ( d, *7 = 9.8 Hz, 1 H); 12.09 (width multiple peak, 1 H) Mass spectrum: Method A residence time Tr (minutes) = 0.63; [M+H] + : m/z 521; [M+2H ]2 + : m/z 261 (base peak) [MH]-: m/z 5 19 Example 29: 2-(4-cyclobutylpiped-1-yl)·Ν-{6-[(6- Cyclopropyl[H4]triseno[4,3-b]tasin-3-yl)thiol 】-1,3-benzoindole-2-yl}Ethylamine 2-(4-cyclobutylhydrazine--1-yl)-indole-{6-[(6-cyclopropyl[1, 2,4]Tris(<>>[4,3-b]Tajing-3-yl)sulfanyl]-1,3-benzo[beta]propan-2-yl}acetamide can be prepared as in Example 24 However, with 0.3 g of 2-gas-iV-{6-[(6-cyclopropyl[ι,2,4]三零和[4,3-ό]嗒-3-yl)sulfanyl]- a solution of 1,3-benzothiazol-2-yl}acetamide, 0.200 g of 1-cyclobutylpiperidine dihydrochloride and 0.442 cm3 of hydrazine-ethyldiisopropylamine in 6 cm3 of dimethyl sulfoxide Starting material: SiO2 枉 枉 - -104- 154635.doc 201202242 After chromatography [dissolving agent: dichloromethane / methanol (95/5 'by volume)]] after obtaining 0.089 g as a white solid 2-(4-cyclobutylpiped-1-yl)-N-{6_[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl Sulfuryl l·1,3·benzothiazol-2-yl}acetamide, which has the following characteristics: Melting point: 102.4 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6 ): 0.91 〇, 2 H); 1.09 (m, 2 H); 1.60 (m, 2 H); 1·74 (m, 2 H); 1·89 to 1.98 (m, 2 H); 2.21 (m,1 H); 2.27 (m,4 H); 2.54 (partially masked multiplet 4 H); 2.69 (m, 1 H); 3.23 (s, 2 H); 7.30 (d, /=9.7 Hz, 1 H); 7.47 (dd, ·7=2.0 and 8.6 Hz, 1 H); 7.69 (d, /=8.6 Hz, 1 H); 8.13 (d, *7 = 2.0 Hz, 1 H); 8.28 (d, J = 9.7 Hz, 1 H); 12.04 (width multiple peak, 1 H) Mass spectrum: Method A Retention time Tr (minutes) = 0.63; [M+H] + : m/z 521; [M+2H]2 + : m/z 261 [MH]-: m/z 519 Example 30: 2-( 4-cyclopropyl-3,5-dimethylpipen-1-yl)-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒--3-yl)sulfanyl]-1,3-benzothiathio-2-yl}acetamidamine 2-(4-cyclopropyl-3,5-dimercaptopipeto-yl) _N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1)]indole-3-yl)sulfanyl]-1,3-benzoxazole 2-yl}acetamide can be prepared as in Example 24, but with 〇3 g 2-chloro-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3- 6] 嗒耕_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide, 0.213 g of 1·cyclopropyl-2,6-dimethylpiperidine dihydrochloride Salt and 154635.doc -105- 201202242 0.442 cm3 A solution of N-ethyldiisopropylamine in 6 cm3 of disulfoxide is the starting material. After the sulfur dioxide column chromatography (dissolving agent: two gas-burning / decyl alcohol (95/5 'by volume)]] then obtained 0.047 g of 2_(4·cyclopropyl-3, as a white solid. 5-曱曱基娘 p well-1-yl)-N-{6-[(6-cyclopropyl[12,4]三" sit 弁[4,3-b].荅喷_3 -基) Sulfur-based group -1,3 - escapazine - thiophene-2-ylamine, characterized by the following: Melting point: 173-196 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.38 (m, 2 H); 0.52 (m, 2 H); 0.91 (m, 2 H); 1.09 (m, 2 H); l.io (d, J = 6.5

Hz, 6 H); 1.38 (m, 1 H); 2.03 (m, 2 H); 2.21 (ms χ H); 2.53 (部分遮蔽之多重峰,2 H); 2.69 (m,2 H); 3.22至3.35 (部分 遮蔽之多重峰,2 H); 7.30 (d,>9.5 Hz,1 h); 7.47 (dd, 2.1 及 8.4 Hz,1 H); 7.67 (d,*7=8.4 Hz,1 h); 8.12 (d, >2.1 Hz,1 H); 8.27 (d,J=9.5 Hz,1 H); 12.01 (寬多重峰, 1 Η)Hz, 6 H); 1.38 (m, 1 H); 2.03 (m, 2 H); 2.21 (ms χ H); 2.53 (multiple peaks partially masked, 2 H); 2.69 (m, 2 H); To 3.35 (partially masked multiplet, 2 H); 7.30 (d, > 9.5 Hz, 1 h); 7.47 (dd, 2.1 and 8.4 Hz, 1 H); 7.67 (d, *7 = 8.4 Hz, 1 h); 8.12 (d, > 2.1 Hz, 1 H); 8.27 (d, J = 9.5 Hz, 1 H); 12.01 (width multiple peak, 1 Η)

質譜:方法A 滞留時間Tr(分鐘)=0.65 ; [M+H] + : m/z 535; [M-H]-: m/z 533 實例31 : N-{6-[(6-環丙基口’2,4]三㈣【43b]塔呼_3基)硫 炫基】-1’3-苯并嗟峻-2-基卜2_[(18,48)·2·氧雜·5氮雜雙環 [2,2,1]庚-5-基]乙醯胺 Ν·{6-[(6-環丙基[…]三唾并[4,3外荅咯3_基)硫炫基]_ 苯并㉝ϋ基}_2_[(1S傅2_氧雜_5_氮雜雙環[…] 庚-5-基]乙醯胺可如實例24製備,但以〇3。·氣善㈣& 154635.doc -106 - 201202242 環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻 唑-2-基}乙醯胺、0.127 g (lS,4S)-2·氧雜-5-氮雜雙環 [2,2,1]庚院鹽酸鹽及0.295 cm3 N-乙基二異丙胺於6 cm3二 甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析[溶離 劑:二氣曱烷/甲醇(95/5,以體積計)]之後,獲得〇〇43 g 呈白色固體狀之N-{6-[(6-環丙基[1,2,4]三唾并[4,3-b]。荅《•井_ 3-基)硫烷基]-1,3-苯并噻唑-2-基}-2-[(lS,4S)-2-氧雜-5_氮 雜雙環[2,2,1]庚-5-基]乙酿胺,其特徵如下: 熔點:217-218°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1·〇9 (m,2 H); 1.60 (寬二重峰,/=9.5 Hz,1 H); 1.82 (寬二 重峰,《7=9.5 Hz,1 H); 2.21 (m,1 H); 2·54 (d,/=10.1 Hz,1 H); 2·94 (dd,·7=1·8及 10.1 Hz, 1 H); 3.53 (m,3 H); 3.58 (寬 單峰,1 H); 3.86 (d,*7=7.6 Hz,1 H); 4.35 (寬單峰,1 H); 7.30 (d,J=9.5 Hz,1 H); 7.47 (dd,·7=2.1 及 8.4 Hz, 1 H); 7.67 (d, 7=8.4 Hz, 1 H); 8.12 (d, /=2.1 Hz, 1 H); 8.27 (d, •/=9.5 Hz,1 H); 12.08 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.56 ; [M+H] + : m/z 480; [M-H]-: m/z 478 實例32 : N-{6-[(6-環丙基【1,2,4】***并【4,3-b]嗒啩-3-基)硫 烷基】-1,3·苯并噻唑-2-基}-2-(8-氧雜-3-氮雜雙環[3,2,1】辛_ 3-基)乙醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]· 154635.doc •107· 201202242 1,3-苯并噻唑-2-基}-2-(8-氧雜-3-氮雜雙環[3,2,1]辛、基) 乙醯胺可如實例24製備,但以〇.4 g 2_氣-浴{6-[(6-環丙基 [1,2,4]***并[4,3-6]嗒,井-3-基)硫烷基]-1,3-苯并噻唑、入 基}乙醯胺、0.187 g 8-氧雜-3-氮雜雙環[3,2,1]辛烷鹽酸鹽 及0.362 cm3 N-乙基二異丙胺於6 cm3二甲亞砜中之溶液為 起始物。二氧化矽管柱急驟層析[溶離劑:二氣曱烷/甲醇 (98/2,以體積計)]之後,獲得〇 1〇5 g呈白色固體狀之… {6-[(6·環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3· 苯并噻唑-2-基}-2-(8-氧雜-3-氮雜雙環[3,2,ι]辛_3_基)乙醯 胺,其特徵如下: 熔點:193-195°C (步奇) 1H NMRsf (400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.09 (m, 2 H); 1.72 (m, 2 H); 1.92 (m, 2 H); 2.22 (m, 1 H); 2.45 (寬二重峰,7=10.5 Hz,2 H); 2.59 (寬二重峰,7=10.5 Hz, 2 H); 3.27 (s, 2 H); 4.21 (m, 2 H); 7.31 (d, 7=9.8 Hz, 1 H); 7.47 (dd,/=2.0及 8.3 Hz,1 H); 7_69 (d,《/=8.3 Hz,1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.29 (d, 7=9.8 Hz, 1 H); 12.12 (% 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.72 ; [M+H] + :m/z 494;基峰:m/z341 [M-Η]-: m/z 492 實例33 : N-{6-【(6·環丙基u,2,4]***并【4,3_b】嗒啡_3基)硫 烷基】-5-氟·1,3-苯并噻唑·2_*}_2·(4-乙基哌畊·i基)乙 154635.doc • 108 · 201202242 醢胺 N-{6-[(6-% 丙基[1,2,4]二唑并[4,3-b]嗒哜-3-基)硫烷基]_ 5-氟-1,3·苯并噻唑-2-基}-2-(4-乙基哌畊_丨_基)乙醯胺可如 實例24製備’但以〇·2 g 2-氯-#-{6-[(6-環丙基[ι,2,4]*** 并[4,3乃]嗒畊-3-基)硫烷基]-5·氟-i,3_苯并噻唑_2•基}乙醯 胺及0.140 cm3 1-乙基哌啡於3 em3二曱亞砜中之溶液為起 始物。二氧化矽管柱急驟層析[溶離劑:二氯甲烷/甲醇 (90/10,以體積計)]之後,獲得(jug g呈白色固體狀之义 {6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啼-3-基)硫烷基]^-氟― 1,3-苯并噻唑-2-基}-2-(4-乙基哌啩-i_基)乙醯胺,其特徵 如下: 熔點:226°C (考夫勒) 1H NMR譜(400 ΜΗζ,δ (ppm), DMSO-d6): 0.90 (m,2 H); 0.98 (t,《7=7.2 Hz,3 H); 1.08 (m,2 H); 2.20 (m, 1 H); 2.30 (q,*7=7.2 Hz,2 H); 2.39 (寬多重峰,4 H); 2.54 (寬多重峰, 4 H); 3.26 (部分遮蔽之多重峰,2 H); 7.31 (d,·7=9.5 Hz,1 H); 7.68 (d, 7=10.3 Hz, 1 H); 8.16 (d, J=1 Λ Hz, 1 H); 8.28 (d,/=9.5 Hz,1 H); 12.27 (寬多重峰,1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.65; [M+H] + : m/z 535; [MH]-: m/z 533 Example 31: N-{6-[(6-cyclopropyl) '2,4]three (four) [43b] tower _3 base) thiophanyl]-1'3-benzopyrene-2-yl b 2_[(18,48)·2·oxa·5 aza Bicyclo[2,2,1]hept-5-yl]acetamidamine·{6-[(6-cyclopropyl[...]tris-[4,3-exo-pyrrole-3-yl)thione] _Benzo 33 fluorenyl}_2_[(1S Fu 2_oxa-5-azabicyclo[...]hept-5-yl]acetamide can be prepared as in Example 24, but with 〇3.·Gashan (4) & 154635 .doc -106 - 201202242 Cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl} Acetamine, 0.127 g (lS,4S)-2.oxa-5-azabicyclo[2,2,1]geptane hydrochloride and 0.295 cm3 N-ethyldiisopropylamine in 6 cm3 dimethyl The solution in the sulfone is the starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dioxane/methanol (95/5 by volume)], N-{6-[(6-ring) was obtained as a white solid. Propyl [1,2,4]tris-[4,3-b].荅••井_3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[ (lS,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-yl]ethinylamine, characterized by the following: Melting point: 217-218 ° C (step) 1H NMR Spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1·〇9 (m, 2 H); 1.60 (width doublet, /=9.5 Hz, 1 H); 1.82 (width doublet, "7=9.5 Hz, 1 H); 2.21 (m,1 H); 2·54 (d, /=10.1 Hz, 1 H); 2·94 (dd,·7=1 ·8 and 10.1 Hz, 1 H); 3.53 (m,3 H); 3.58 (width unimodal, 1 H); 3.86 (d, *7=7.6 Hz, 1 H); 4.35 (width unimodal, 1 H 7.30 (d, J=9.5 Hz, 1 H); 7.47 (dd, ·7=2.1 and 8.4 Hz, 1 H); 7.67 (d, 7=8.4 Hz, 1 H); 8.12 (d, /= 2.1 Hz, 1 H); 8.27 (d, •==9.5 Hz, 1 H); 12.08 (width multiple peak, 1 H) Mass Spectrum: Method A Residence time Tr (minutes) = 0.56; [M+H] + : m/z 480; [MH]-: m/z 478 Example 32: N-{6-[(6-cyclopropyl[1,2,4]triazole [4,3-b]indol-3-yl)sulfanyl]-1,3·benzothiazol-2-yl}-2-(8-oxa-3-azabicyclo[3,2, 1] oct-3-yl)acetamidamine-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl ]· 154635.doc •107· 201202242 1,3-benzothiazol-2-yl}-2-(8-oxa-3-azabicyclo[3,2,1]octyl) acetylamine Prepared as in Example 24, but with 〇.4 g 2_gas-bath {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole, well-3-yl Sulfuryl]-1,3-benzothiazole, benzylamine, 0.187 g 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride and 0.362 cm3 N- A solution of ethyldiisopropylamine in 6 cm3 of dimethyl sulfoxide was used as the starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dioxane/methanol (98/2 by volume)], 〇1〇5 g is obtained as a white solid... {6-[(6·环Propyl [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3·benzothiazol-2-yl}-2-(8-oxo Hetero-3-azabicyclo[3,2,ι] octyl-3-yl)acetamide characterized by the following: Melting point: 193-195 ° C (step) 1H NMRsf (400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.09 (m, 2 H); 1.72 (m, 2 H); 1.92 (m, 2 H); 2.22 (m, 1 H); 2.45 (width double Peak, 7=10.5 Hz, 2 H); 2.59 (width doublet, 7=10.5 Hz, 2 H); 3.27 (s, 2 H); 4.21 (m, 2 H); 7.31 (d, 7=9.8 Hz, 1 H); 7.47 (dd, /=2.0 and 8.3 Hz, 1 H); 7_69 (d, "/=8.3 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.29 ( d, 7=9.8 Hz, 1 H); 12.12 (% multiplet, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.72; [M+H] + : m/z 494; base peak: m/ Z341 [M-Η]-: m/z 492 Example 33: N-{6-[(6·cyclopropyl u,2,4]triazolo[4,3_b]morphine-3-yl)sulfanyl 】-5-fluoro·1,3-benzothiazole·2_*}_2·(4-ethyl peptin·i base) B 154635.doc • 108 · 201202242 Indoleamine N-{6-[(6-% propyl[1,2,4]diazolo[4,3-b]indol-3-yl)sulfanyl]_ 5-fluoro- 1,3·Benzothiazol-2-yl}-2-(4-ethylpiperidin-yl)acetamide can be prepared as in Example 24 but with 〇·2 g 2-chloro-#-{6 -[(6-cyclopropyl[ι,2,4]triazolo[4,3-indolino-3-yl)sulfanyl]-5-fluoro-i,3-benzothiazole_2• A solution of acetaminophen and 0.140 cm3 of 1-ethylpiperin in 3 em3 disulfoxide was used as a starting material. After flash chromatography of ruthenium dioxide column [solvent: dichloromethane / methanol (90/10 by volume)], (jug g is obtained as a white solid {6-[(6-cyclopropyl) 1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]^-fluoro-1,3-benzothiazol-2-yl}-2-(4-ethyl Lysohydrin-i-yl acetamide characterized by the following: Melting point: 226 ° C (Cafele) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.90 (m, 2 H) ; 0.98 (t, "7=7.2 Hz, 3 H); 1.08 (m, 2 H); 2.20 (m, 1 H); 2.30 (q, *7 = 7.2 Hz, 2 H); 2.39 (width multiple , 4 H); 2.54 (width multiple peak, 4 H); 3.26 (partially masked multiplet, 2 H); 7.31 (d, ·7 = 9.5 Hz, 1 H); 7.68 (d, 7 = 10.3 Hz, 1 H); 8.16 (d, J=1 Λ Hz, 1 H); 8.28 (d, /=9.5 Hz, 1 H); 12.27 (width multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.62 ; - [M+H] + : m/z 513; [M+2H]2+: m/z 257 [M-H]-: m/z 511 實例34 : N-{6-【(6-環丙基[1,2,4】***并[4,3-b】嗒畊-3-基)硫 烷基】-l,3-苯并噻唑-2-基}-2-[4-(丙-2-基氧基)哌啶-1-基]乙 154635.doc -109· 201202242 酿胺 Ν-{6·[(6-環丙基[1,2,4]三唾并[4,3-b]。荅味-3-基)硫烷基]- I,3-苯并嗟。坐ι基卜2_[4_(丙_2基氧基)娘啶卜基]乙醯胺 可如實例24製備,但以〇.3 g 2_氣_#_{6_[(6環丙基[ι24] 一坐并[4,3-办]"答〃井-3-基)硫烧基μι%苯并售嗤_2_基丨乙醯 胺、0.168 g 4-(丙-2-基氧基)哌啶鹽酸鹽及〇 3〇7 em3 \_乙 基二異丙胺於8 cm3二甲亞砜中之溶液為起始物。二氧化 矽管柱急驟層析[溶離劑:二氣曱烷/曱醇(95/5,以體積 什)]之後,獲得0.147 g呈白色固體狀之N-{6-[(6-環丙基 [1’2,4]***并[4,3-1)]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2- 基}-2-[4-(丙-2-基氧基)〇底咬_ι_基]乙醯胺,其特徵如下: 熔點:148-149。(:(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.05 (d, J=6.4 Hz, 6 H); 1.09 (m, 2 H); 1.42 (m, 2 H); 1.78 (m, 2 H); 2.22 (m, 1 H); 2.31 (m, 2 H); 2.73 (m, 2 H); 3.31 (s,2 H); 3.35 (部分遮蔽之多重峰,1 H); 3.67 (m,1 H); 7.30 (d,*/=9.8 Hz,1 H); 7.48 (dd, /=2.0及 8.6 Hz,1 H); 7.70 (d, 7=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, •/=9.8 Hz, 1 H); 12.14 (寬多重峰,1 H) 質譜:方法A 滞留時間Tr(分鐘)=0.68 ; [M+H] + : m/z 524; [M-H]-: m/z 522 實例35 : N-{6-[(6-環丙基丨1,2,4】***并[4,3-b】嗒畊-3-基)硫 烷基]-1,3-苯并噻唑-2-基}-2-[4-(4-乙基哌畊-1-基)哌啶-1- 154635.doc •110· 201202242 基】乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3 -苯并0塞0坐-2-基}-2-[4-(4-乙基派p井-1-基)η底咬-1-基]乙 醯胺可如實例24製備,但以〇.3 g 2-氯-iV-{6-[(6-環丙基 [1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]·1,3-苯并噻唑-2-基}乙醯胺、0.185 g 1-乙基-4-(娘咬-4-基)娘》•井及0.123 cm3 N-乙基二異丙胺於8 cm3二曱亞颯中之溶液為起始物。二 氧化矽管柱急驟層析[溶離劑:二氣甲烧/甲醇(90/10,以 體積計)]之後,獲得0.089 g呈白色固體狀之N-{6-[(6-環丙 基[1,2,4]***并[4,3-b]嗒啩-3-基)硫烷基]-1,3-苯并噻唑 基}-2-[4-(4-乙基哌畊-1-基)哌啶-1-基]乙醯胺,其特徵如 下: 熔點:160_165°C (步奇) 1H NMR譜(400]\11^,5(卩卩111),〇]^8〇-(16):0.92(111,2^1)· 0.98 (t, J=7.3 Hz, 3 H); 1.08 (m, 2 H); 1.47 (m, 2 H); l.7l (m,2 H); 2_07 至 2.55 (部分遮蔽之多重峰,14 H); 2.90 2 H); 3.31 (s, 2 H); 7.30 (d, 7=9.5 Hz, 1 H); 7.48 (dd J=2.0及 8.6 Hz,1 H); 7.70 (d, «7=8.6 Hz, 1 H); 8.14 〇 •/=2.0 Hz,1 H); 8.28 (d,《7=9.5 Hz,1 H); 12.01 (寬多重峰 1 Η) 質譜:方法A 滯留時間Tr(分鐘)=0.48 ; [M+H] + : m/z 578; [M+2H]2+: m/z 289.5 [M-H]-: m/z 576 154635.doc 201202242 實例 36 : N-{6-[(6-環 炫基】-1,3-苯并售唾 基)乙醯胺 丙基[1,2,4】***并【4,3_b】嗒哜·3基)硫 •2-基}-2-(2-氧雜-6-氮雜螺【3,3]庚_6_ Ν刺6·環丙基Π,2,4]三蝴4,3b則·3基)硫烧基]- 1,3-本并噻唑-2_基}_2_(2氧雜冬氮雜螺[3,3]庚冬基)乙醯 胺可如實例24製備,如 取備但以〇.3 g 2-氣-iV-{6_[(6_環丙基 [1’2’4]三嗤并[4,3#荅基)硫烧基卜^•苯并售吐_2_ 基}乙酿胺、0.104 e 9签X*产 g 氣雜-6-氮雜螺[3,3]庚烷草酸鹽(2:1) 及(K310 em 3 乙基二異丙胺於8 cm3二曱亞硬中之溶液 為起始物。一氧化矽管柱急驟層析[溶離劑:二氯曱烷/甲 醇(95/5 ’以體積叶)]之後,獲得0.031 g呈白色固體狀之N- {6-[(6-環丙基[1,2,4]***并[4,3_b]。荅_ -3_基)硫烷基]山% 苯并噻唑-2-基}-2-(2-氧雜·6·氮雜螺[3,3]庚_6_基)乙醯胺, 其特徵如下: 溶點· 178-188C(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); l‘〇9 (m,2 H); 2.21 (m,i h); 3.30 至 3·40 (部分遮蔽之多重 峰,2 H); 3.46 (s,4 H); 4.61 (s,4 H); 7·30 (d,·7=9·8 Ηζ,1 H); 7.47 (dd,《7=2.2及 8.6 Hz, 1 H); 7.67 (d,*7=8.6 Hz, 1 H); 8.12 (d,*/=2.2 Hz,1 H); 8.29 (d,/=9.8 Hz,1 H); 12.15 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)= 0.56 ; [M+H] + : m/z 480; [M-H]-: m/z 478 I54635.doc -112- 201202242 2-氧雜_6-氮雜螺 .1τ ’]庚烧草酸鹽(2:1)如 AngewandteMass Spectrometry: Method A Retention time Tr (minutes) = 0.62; - [M+H] + : m/z 513; [M+2H]2+: m/z 257 [MH]-: m/z 511 Example 34: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-l,3-benzothiazole-2 -yl}-2-[4-(propan-2-yloxy)piperidin-1-yl]ethyl 154635.doc -109· 201202242 Amine oxime-{6·[(6-cyclopropyl[1, 2,4]tris-[4,3-b]. azet-3-yl)sulfanyl]-I,3-benzopyrene. Sitting on the ibu kibu 2_[4_(prop-2-yloxy) stilbene] acetamidine can be prepared as in Example 24, but with 〇.3 g 2_gas_#_{6_[(6-cyclopropyl [ Ι24] sit and [4,3-do]" answer 〃-3-yl) sulphur-burning μι% benzene and sell 嗤_2_yl acetamide, 0.168 g 4-(propan-2-yl) A solution of oxy) piperidine hydrochloride and 〇3〇7 em3 \-ethyl diisopropylamine in 8 cm 3 of dimethyl sulfoxide was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dioxane / decyl alcohol (95/5, by volume)], 0.147 g of N-{6-[(6-cyclopropane) was obtained as a white solid. Base [1'2,4]triazolo[4,3-1)]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-( Propyl-2-yloxy) anthraquinone, which is characterized by the following melting points: 148-149. (:(step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.05 (d, J = 6.4 Hz, 6 H); 1.09 (m, 2 H ); 1.42 (m, 2 H); 1.78 (m, 2 H); 2.22 (m, 1 H); 2.31 (m, 2 H); 2.73 (m, 2 H); 3.31 (s, 2 H); 3.35 (Multiple peaks partially masked, 1 H); 3.67 (m, 1 H); 7.30 (d, */=9.8 Hz, 1 H); 7.48 (dd, /=2.0 and 8.6 Hz, 1 H); 7.70 (d, 7=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, •==9.8 Hz, 1 H); 12.14 (width multiple peak, 1 H) Mass spectrum: Method A Retention time Tr (minutes) = 0.68; [M+H] + : m/z 524; [MH]-: m/z 522 Example 35: N-{6-[(6-cyclopropyl丨1, 2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(4-ethylperidyl) Plant-1-yl) piperidine-1- 154635.doc •110· 201202242 base] acetaminophen N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3- b]嗒耕-3-yl)sulfanyl]-1,3-benzo-3-oxo-2-yl}-2-[4-(4-ethylpyp--1-yl) Benton-1-yl]acetamide can be prepared as in Example 24, but with 〇.3 g 2-chloro-iV-{6-[(6-cyclopropyl[1,2,4]triazolo[4, 3-6]嗒耕-3-yl)sulfanyl]·1,3-benzothiazole-2 -Based on the solution of acetamidine, 0.185 g of 1-ethyl-4-(Nymphote-4-yl) Niang" well and 0.123 cm3 of N-ethyldiisopropylamine in 8 cm3 of diterpenoid The starting material. Chromatography of the ruthenium dioxide column [solvent: two gas toluene / methanol (90/10 by volume)], after obtaining 0.089 g of N-{6-[(6- Cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazolyl}-2-[4-(4- Ethyl piperazine-1-yl)piperidin-1-yl]acetamide, which has the following characteristics: melting point: 160_165 ° C (step) 1H NMR spectrum (400) \11^, 5 (卩卩 111), 〇]^8〇-(16): 0.92(111,2^1)·0.98 (t, J=7.3 Hz, 3 H); 1.08 (m, 2 H); 1.47 (m, 2 H); l. 7l (m, 2 H); 2_07 to 2.55 (partially masked multiplet, 14 H); 2.90 2 H); 3.31 (s, 2 H); 7.30 (d, 7=9.5 Hz, 1 H); 7.48 ( Dd J=2.0 and 8.6 Hz, 1 H); 7.70 (d, «7=8.6 Hz, 1 H); 8.14 〇•/=2.0 Hz,1 H); 8.28 (d, "7=9.5 Hz, 1 H ); 12.01 (width multiple peak 1 Η) mass spectrum: method A residence time Tr (minutes) = 0.48; [M+H] + : m/z 578; [M+2H]2+: m/z 289.5 [MH] -: m/z 576 154635.doc 201202242 Example 36 : N-{6-[(6-Cyclodextrin)-1,3-Benzene-salt-sodium)-acetamidopropyl [1,2,4]triazolo[4,3_b]嗒哜·3 Sulfur-2-yl}-2-(2-oxa-6-azaspiro[3,3]hept_6_ Ν6.cyclopropyl hydrazine, 2,4] three-female 4,3b-d3 Thiosulfonyl]-1,3-benzisothiazole-2_yl}_2_(2oxasoazaspiro[3,3]heptylyl)acetamide can be prepared as in Example 24, such as 〇.3 g 2-gas-iV-{6_[(6_cyclopropyl[1'2'4]triindole[4,3# fluorenyl) sulphur-based keb ^• Benzene sold spit_2_ Ethylamine, 0.104 e 9-labeled X* produced g gas-6-azaspiro[3,3]heptane oxalate (2:1) and (K310 em 3 ethyldiisopropylamine in 8 cm3 The solution in the diterpene is the starting material. After flash chromatography of the ruthenium oxide column [solvent: dichloromethane/methanol (95/5 'by volume)), 0.031 g of N-{6-[(6-cyclopropyl) as a white solid was obtained. [1,2,4]triazolo[4,3_b].荅_-3_yl)sulfanyl]Molar % Benzothiazol-2-yl}-2-(2-oxa-6.aza Spiro[3,3]heptyl-6-yl)acetamide, which has the following characteristics: Melting point · 178-188C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m , 2 H); l'〇9 (m, 2 H); 2.21 (m, ih); 3.30 to 3.40 (multiple peaks partially masked, 2 H); 3.46 (s, 4 H); 4.61 (s , 4 H); 7·30 (d, ·7=9·8 Ηζ, 1 H); 7.47 (dd, "7=2.2 and 8.6 Hz, 1 H); 7.67 (d, *7=8.6 Hz, 1 H); 8.12 (d, */=2.2 Hz, 1 H); 8.29 (d, /=9.8 Hz, 1 H); 12.15 (width multiple peak, 1 H) Mass spectrum: Method A Residence time Tr (minutes) = [M+H] + : m/z 480; [MH]-: m/z 478 I54635.doc -112- 201202242 2-oxa-6-azaspiro.1τ '] heptanoic acid oxalate ( 2:1) like Angewandte

Chemical Int. Ed. 2〇η» . 7,4512·4515中所述製備。 實例 37 · 1^-{6-[(6_環农 * 丙基[1,2,4】***并[4,3-b】嗒畊-3-基)硫 燒基]-1,3-苯并嗟唾 叹_2-基卜2_[4_(1_甲基哌啶_4基 畊 基】乙醢胺 N {6 [(6 ^ ^ ^[1,2,4]^^ 4 [4,3-b]^^-3-^)^L^^]-1,3苯并嗟! 2-基卜2_[4_(1_甲基旅咬_4_基)派味卜基]乙 醯胺可如實例24製備,但以〇3 g 2_氣_^(6_[(6_環丙基 [1,2,4]***并[4,3-6]嗒畊_3_基)硫烷基]·丨,3苯并噻唑_2_ 基}乙醯胺、0.185 g 1_(1_甲基哌啶_4_基)哌畊及〇 123 cm3 N-乙基二異丙胺於8 cm3二曱亞砜中之溶液為起始物。二 氧化石夕管柱急驟層析[溶離劑:二氣甲烧/甲醇(8〇/2〇,以 體積計)]之後’獲得0.179 g呈白色固體狀之N-{6-[(6-環丙 基[1,2,4]***并[4,3-b]嗒啩-3-基)硫烷基]-1,3-苯并噻唑-2-基}-2-[4-(1-甲基n底咬-4-基)派畔-1-基]乙醯胺,其特徵如 下: 熔點:202-247, 6°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 (m,2 H); 1.08 (m, 2 H); 1.39 (m, 2 H); 1.69 (m, 2 H); 1.81(m, 2 H); 2.09 (m,1 H); 2.12 (s, 3 H); 2.21 (m,1 H); 2.45至 2.55 (部 分遮蔽之多重峰,8 H); 2_76 (m, 2 H); 3.35至3.45 (經遮蔽 之單峰,2 H); 7.30 (d,/=9.8 Hz,1 H); 7.48 (dd,·7=2.0及 8.6 Hz, 1 H); 7.70 (d, /=8.6 Hz, 1 H); 8.14 (ds J=2.0 Hz, 1 H); 8.27 (d,/=9.8 Hz,1 H); 11.94 (寬多重峰,1 H) 154635.doc •113- 201202242 質譜:方法A 滞留時間Tr(分鐘)=〇.5(); [M+H] + : m/z 564;基峰:m/z 467 [M-H]-: m/z 562 實例38 : N-{6-[(6-環兩基丨H4】***并【43b】塔呼_3·基)琉 烷基]-1,3-苯并噻唑-2-基卜2_{4_[(4_甲基哌畊4 —基)羰基]哌 啶-l-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]_ 1’3-苯并隹峻-2-基卜2-{4-[(4-曱基哌畊-1_基)羰基]哌啶_1_ 基}乙醯胺可如實例24製備,但以ο ] g 2_氣_#_{6_[(6·環丙 基[1,2,4]二唑并[4,3-6]嗒p井-3_基)硫烷基]·13_苯并噻唑_2_ 基}乙醯胺、〇.266 g (4_曱基哌畊-1-基)(哌啶-4-基)曱酮二 鹽酸鹽及0.442 cm3 N-乙基二異丙胺於8 cm3二甲亞砜中之 溶液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣甲 烷/甲醇(90/10 ’以體積計之後’獲得〇 〇8i g呈砂色固體 狀之N-{6-[(6-環丙基[124]***并[43b]嗒畊_3基)硫烷 基]-1,3-苯并"塞唾-2-基卜2-{4-[(4-甲基哌畊-1-基)羰基]哌 啶-l-基}乙醯胺,其特徵如下: 熔點:251°C (步奇) 1H NMRf#(40〇 MHz, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 109 (m,2 H); i·52至 1.73 (m,4 H); 2.19 (寬單峰,3 H); 2.20至 2.36 (m,7 H); 2.55 (m,1 H); 2.88 (m,2 H); 3.33 (s, 2 H); 3.47 (寬多重峰,4 H); 7 3〇 (d,J=9 5 Hz,i H); 7 48 (dd, 7=2.0^8.6 Hz, 1 H); 7.70 (ds 7=8.6 Hz, 1 H); 8.14 (d, 154635.doc -114· 201202242 •/=2.0 Hz,1 H); 8.28 (d,/=9.5 Hz,1 H); l2.〇6 (寬多重峰, 1 Η) 質譜:方法A 滯留時間Tr(分鐘)=0.48 ; [M+H] + : m/z 592; [M+2H]2+: m/z 296_5 (基峰^ [M-H]-: m/z 590 實例39 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒哨·3_基)硫 烧基】-1,3-苯并噻唑-2-基}-2-[(3S)-3-甲基嗎琳_4_基]乙 醯胺 Ν·{6-[(6-環丙基[1,2,4]三唾并[4,3-b]°荅畊_3_基)硫院基]-1,3-苯并嗟唑-2-基}-2-[(3S)-3-甲基嗎琳-4-基]乙醯胺可如 貫例24製備,但以0.3 g 2_氯-_/v_{6-[(6-環丙基[ι,2,4]三嗤 并[4,3-办]〇合p井-3-基)硫烧基]_ι,3_苯并售唾_2_基丨乙醯胺、 0.095 g (3S)-3-甲基嗎啉及0.123 cm3 Ν-乙基二異丙胺於8 cm 一甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析 [>谷離劑:二氯曱烷/曱醇(95/5,以體積計)]之後,獲得 〇·170 g呈白色固體狀之Ν·{6_[(6_環丙基[12 4]***并[4 3_ bp合畊-3-基)硫烷基]-1,3_笨并噻唑_2_基卜2_[(3S)_3_曱基嗎 啉-4-基]乙醯胺,其特徵如下: 熔點:143°C (步奇) 1H NMR4(400 ΜΗζ,δ (ppm),DMSO-d6): 0.87至 0.95 (m, 5 H), 1.08 (m, 2 H); 2.22 (m, 1 H); 2.531.2.64 (m, 2 H); 2.74 (td, ^=2.7^π.5 Hz, 1 H); 3.13 (dd, /=9.0^ 11.〇 Hz,1 H); 3.34 (〇16.4 Hz,i H); 3 55 ⑼,J=2 7及 u 5 154635.doc -115- 201202242 Ηζ,1Η);3.58((!,·/=16·4Ηζ,1Η);3.62((1ί1,*/=2.7&11.〇 Hz, 1 H); 3.69 (td,《7=2.7及 11.5 Ηζ,1 H); 7.29 (d, *7=9.5 Hz,1 H); 7.49 (dd,/=2.0及 8.6 Hz,1 H); 7.71 (d,*7=8.6 Hz, 1 H); 8.14 (d, 7=2.0 Hz, 1 H); 8.28 (d, /=9.5 Hz, 1 H); 12.06 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)= 0,64 ; [M+H] + :m/z 482;基峰:m/z341 [M-H]-: m/z 480 實例40 : Ν·{6-[(6_環丙基[i,2,4]***并[4,3-b]嗒啡-3-基)硫 炫基】-1,3-苯并隹嗤-2-基卜2_【4-(嗎啉-4-基甲基)哌啶-1-基】 乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]_ 1,3-苯并噻唑-2-基}-2-[4-(嗎啉-4-基甲基)哌啶-1-基]乙醯 胺可如實例24製備,但以〇 3 g 2_氣環丙基 [1’2,4]二唾并[4,3-6]嗒唯·3·基)硫烷基]·丨,3•苯并噻唑_2_ 基}乙醯胺、0.241 g 4-(哌啶-4-基甲基)嗎啉二鹽酸鹽及 0.442 cm N-乙基二異丙胺於8cm3二曱亞砜中之溶液為起 始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/曱醇 (90/10 ’以體積計)]之後,獲得〇 198 g呈極淺粉色固體狀 之Ν-^·[(6_環丙基Π,24]三唾并[4,3罐基)硫炫朴 1’3-苯并嗟唾-2_基}_2_[4_(嗎淋冰基甲基)略咬-卜基]乙醯 胺,其特徵如下: 炫點.189-191°C (步奇) 154635.doc • 116 - 201202242 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.90 (m,2 H); 1.08 (m, 2 H); 1.15 (m, 2 H); 1.49 (m, 1 H); 1.65 (m, 2 H); 2.08至 2.26 (m,5 H); 2.30 (m,4 H); 2.86 (m,2 H); 3.20至 3.40 (部分遮蔽之多重峰,2 H); 3.55 (m,4 H); 7.30 (d, •/=9.5 Hz,1 H); 7.48 (dd,J=2.0及 8.6 Hz,1 H); 7.69 (d, J=8.6 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H); 11.88 (寬多重峰,1 H)Prepared as described in Chemical Int. Ed. 2〇η» . 7, 4512·4515. Example 37 · 1^-{6-[(6_环农*propyl[1,2,4]triazolo[4,3-b]indol-3-yl)thiol]-1,3 -benzopyrene sputum _2-kib 2_[4_(1_methylpiperidine _4 based cultivating base) acetaminophen N {6 [(6 ^ ^ ^[1,2,4]^^ 4 [ 4,3-b]^^-3-^)^L^^]-1,3 benzopyrene! 2-kib 2_[4_(1_methyl brigade bite_4_base) Acetamide can be prepared as in Example 24, but with 〇3 g 2_gas_^(6_[(6_cyclopropyl[1,2,4]triazolo[4,3-6]嗒耕_3_ ) 硫 ] ] 3 3 3 3 3 3 3 3 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 The solution in 8 cm3 of disulfoxide was used as the starting material. After the separation of the silica dioxide column [solvent: two gas aeration / methanol (8 〇 / 2 〇, by volume)] - obtained 0.179 g N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3- as a white solid Benzothiazol-2-yl}-2-[4-(1-methyln-bottom-4-yl)pyran-1-yl]acetamide, which has the following characteristics: Melting point: 202-247, 6° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.08 (m, 2 H); 1.39 (m, 2 1.) (m, 2 H); Multiple peaks, 8 H); 2_76 (m, 2 H); 3.35 to 3.45 (shaded singlet, 2 H); 7.30 (d, /=9.8 Hz, 1 H); 7.48 (dd, ·7=2.0 And 8.6 Hz, 1 H); 7.70 (d, /=8.6 Hz, 1 H); 8.14 (ds J=2.0 Hz, 1 H); 8.27 (d, /=9.8 Hz, 1 H); 11.94 (width multiple Peak, 1 H) 154635.doc •113- 201202242 Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.5(); [M+H] + : m/z 564; base peak: m/z 467 [MH ]-: m/z 562 Example 38: N-{6-[(6-cyclic two-based 丨H4]triazolo[43b] ta _3·yl)decyl]-1,3-benzothiazole -2- kib 2_{4_[(4_methylpipedino-4-yl)carbonyl]piperidine-1-yl}acetamidamine N-{6-[(6-cyclopropyl[1,2,4 Triazolo[4,3_b]嗒耕_3_yl)sulfanyl]_ 1'3-benzopyrene-2-ylbu 2-{4-[(4-曱基培耕-1_ The carbonyl]piperidinyl-1 yl}acetamide can be prepared as in Example 24, but with ο ] g 2 — gas _#_{6_[(6·cyclopropyl[1,2,4]diazolo[ 4,3-6]嗒p well-3_yl)sulfanyl]·13_benzothiazol-2-yl}acetamide, 〇.266 g (4_曱基piped-1-yl) 4-yl) Yue dihydrochloride and 0.442 cm3 N- ethyldiisopropylamine in 8 cm3 of dimethyl sulfoxide solution as a starting material. Chromatography of ruthenium dioxide column [dissolving agent: di-methane/methanol (90/10 'after volume' to obtain -8i g of a sand-colored solid N-{6-[(6-cyclopropyl) [124]Triazolo[43b]indole_3yl)sulfanyl]-1,3-benzo"sodium-2-yl-2-{4-[(4-methylpiped-1 -yl)carbonyl]piperidine-1-yl}acetamide characterized by the following: Melting point: 251 ° C (step) 1H NMRf# (40 〇 MHz, δ (ppm), DMSO-d6): 0.91 (m , 2 H); 109 (m, 2 H); i·52 to 1.73 (m, 4 H); 2.19 (wide unimodal, 3 H); 2.20 to 2.36 (m, 7 H); 2.55 (m, 1 H); 2.88 (m, 2 H); 3.33 (s, 2 H); 3.47 (width multiplet, 4 H); 7 3 〇 (d, J = 9 5 Hz, i H); 7 48 (dd, 7=2.0^8.6 Hz, 1 H); 7.70 (ds 7=8.6 Hz, 1 H); 8.14 (d, 154635.doc -114· 201202242 •/=2.0 Hz, 1 H); 8.28 (d, /= 9.5 Hz, 1 H); l2. 〇6 (width multiple peak, 1 Η) Mass spectrum: Method A residence time Tr (minutes) = 0.48; [M+H] + : m/z 592; [M+2H]2 +: m/z 296_5 (base peak ^ [MH]-: m/z 590 Example 39: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b ]嗒哨·3_基)thiol]-1,3-benzothiazol-2-yl}-2-[(3S)-3-methyl琳_4_基]Acetamine Ν·{6-[(6-cyclopropyl[1,2,4]tris-[4,3-b]°荅____)) -1,3-benzoxazol-2-yl}-2-[(3S)-3-methylmorphin-4-yl]acetamide can be prepared as in Example 24, but with 0.3 g of 2-chloro -_/v_{6-[(6-cyclopropyl[ι,2,4]三嗤[4,3-办]〇合p-3-yl)thioalkyl]_ι,3_benzo A solution of salino-2_yl acetamide, 0.095 g (3S)-3-methylmorpholine and 0.123 cm3 Ν-ethyldiisopropylamine in 8 cm of sulfoxide was used as a starting material. After flash column chromatography [>column: chloroformane/sterol (95/5 by volume)], 〇·170 g was obtained as a white solid.·{6_[(6_ Cyclopropyl[12 4]triazolo[4 3_ bp oxa-3-yl)sulfanyl]-1,3_ benzothiazolyl-2-yl-2-yl[2(3S)_3_decylmorpholine- 4-yl]acetamide, which has the following characteristics: Melting point: 143 ° C (step) 1H NMR 4 (400 ΜΗζ, δ (ppm), DMSO-d6): 0.87 to 0.95 (m, 5 H), 1.08 (m) , 2 H); 2.22 (m, 1 H); 2.531.2.64 (m, 2 H); 2.74 (td, ^=2.7^π.5 Hz, 1 H); 3.13 (dd, /=9.0^ 11. 〇Hz,1 H); 3.34 (〇16.4 Hz, i H); 3 55 (9), J=2 7 and u 5 154635.doc -115 - 201202242 Ηζ,1Η);3.58((!,·/=16·4Ηζ,1Η); 3.62((1ί1,*/=2.7&11.〇Hz, 1 H); 3.69 (td, “7=2.7 And 11.5 Ηζ,1 H); 7.29 (d, *7=9.5 Hz, 1 H); 7.49 (dd, /=2.0 and 8.6 Hz, 1 H); 7.71 (d, *7=8.6 Hz, 1 H) ; 8.14 (d, 7=2.0 Hz, 1 H); 8.28 (d, /=9.5 Hz, 1 H); 12.06 (width multiple peak, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) = 0,64 ; [M+H] + : m/z 482; base peak: m/z 341 [MH]-: m/z 480 Example 40: Ν·{6-[(6_cyclopropyl[i,2,4] Triazolo[4,3-b]indol-3-yl)thione]-1,3-benzoindole-2-yl b-2-[4-(morpholin-4-ylmethyl)per Acridine-1-yl] acetamidine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]indole _3_yl)sulfanyl]_ 1, 3-Benzothiazol-2-yl}-2-[4-(morpholin-4-ylmethyl)piperidin-1-yl]acetamide can be prepared as in Example 24, but with 〇3 g 2 qi Cyclopropyl[1'2,4]disitado[4,3-6]indole-3-yl)sulfanyl]·丨,3•benzothiazol-2-yl}acetamide, 0.241 g 4 A solution of -(piperidin-4-ylmethyl)morpholine dihydrochloride and 0.442 cm of N-ethyldiisopropylamine in 8 cm3 of disulfoxide was used as a starting material. After the cerium dioxide column flash chromatography [solvent: di-methane/sterol (90/10 'by volume)], 〇 198 g is obtained as a very pale pink solid Ν-^·[(6_环Propyl hydrazine, 24] trisporin [4,3 cans) sulphur turmeric 1'3-benzopyrene-salt-2-yl}_2_[4_(? 冰冰基基 methyl) slightly bite-buki] B Indoleamine, which has the following characteristics: Hyun point. 189-191 ° C (step) 154635.doc • 116 - 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.90 (m, 2 H) 1.08 (m, 2 H); 1.15 (m, 2 H); 1.49 (m, 1 H); 1.65 (m, 2 H); 2.08 to 2.26 (m, 5 H); 2.30 (m, 4 H) ; 2.86 (m, 2 H); 3.20 to 3.40 (multiple peaks partially masked, 2 H); 3.55 (m, 4 H); 7.30 (d, •==9.5 Hz, 1 H); 7.48 (dd, J =2.0 and 8.6 Hz,1 H); 7.69 (d, J=8.6 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H); 11.88 (wide multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0·48 ; [M+H] + : m/z 565; [Μ-Η]-: m/z 563 實例41 : Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫 烷基】-5-氟-1,3-苯并噻唑-2-基卜2-[(lS,4S)-2-氧雜-5-氮雜 雙環[2,2,1】庚-5·基】乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]_ 5-氟-1,3-苯并噻唑-2-基卜2-[(lS,4S)-2-氧雜_5_氮雜雙環 [2,2,1]庚基]乙醯胺可如實例24製備,但以〇 255 g 2_氣_ #-{6-[(6·環丙基[1,2,4]***并[4,3功]嗒畊_3_基)硫烷基]_5_ 氟-1,3-苯并噻唑-2-基}乙醯胺、〇1〇3 g (1S,4S)_2氧雜_5_ 氮雜雙環[2,2,1]庚烷鹽酸鹽及〇 24〇 cm3 Ν·乙基二異丙胺 於6 cm 一甲亞硬中之溶液為起始物。二氧化矽管柱急驟 層析[溶離劑:二氯甲烷/甲醇(98/2,以體積計)]之後,獲 得0.123 g呈白色固體狀之义{6_[(6_環丙基[I,]〆]***并 [4,3-b]令畊-3-基)硫烷基]·5_敗],3_苯并噻唑_2_基}·2_ [(lS,4S)-2-氧雜_5_氮雜雙環⑽⑴庚:以乙醯^其特 154635.doc -117- 201202242 徵如下: 熔點:206°C (考夫勒) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.89 (m,2 H); 1·〇7 (m,2 H); 1.61 (寬二重峰,《7=9.7 Hz,1 H); 1.83 (寬二 重峰,7=9.7 Hz,1 H); 2·21 (m,1 H); 2.53 (寬二重峰, •/=10.2 Hz,1 H); 2.94 (dd,《7=1.8及 10.2 Hz,1 H); 3.51 至 3.63 (m, 4 H); 3.86 (d, 7=7.8 Hz, 1 H); 4.35 (t, J=2.2 Hz, 1 H); 7.30 (d,《7=9.5 Hz, 1 H); 7.68 (d,/=10.3 Hz,1 H); 8.17 (d,·7=7.3 Hz,1 H); 8.27 (d,*7=9.5 Hz,1 H); 12.01 (寬多重 峰,1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.48; [M+H] + : m/z 565; [Μ-Η]-: m/z 563 Example 41: Ν-{6-[(6- Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl-2- [(lS,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-yl]acetamidamine N-{6-[(6-cyclopropyl[1,2, 4] Triazolo[4,3_b]嗒耕_3_yl)sulfanyl]_ 5-fluoro-1,3-benzothiazol-2-ylbu 2-[(lS,4S)-2-oxo Hetero-5-azabicyclo[2,2,1]heptyl]acetamide can be prepared as in Example 24, but with 〇255 g 2_gas_#-{6-[(6·cyclopropyl[1, 2,4]triazolo[4,3 work] plowing _3_yl)sulfanyl]_5_fluoro-1,3-benzothiazol-2-yl}acetamide, 〇1〇3 g (1S , 4S) _2 oxa _5_ azabicyclo[2,2,1]heptane hydrochloride and 〇24〇cm3 Ν·ethyldiisopropylamine in 6 cm of a melon hard solution as a starting material. After flash chromatography of the ruthenium dioxide column [solvent: dichloromethane/methanol (98/2 by volume)], 0.123 g of a white solid was obtained {6_[(6_cyclopropyl[I, ]〆]Triazolo[4,3-b] tern-3-yl)sulfanyl]·5_ defeat], 3_benzothiazolyl-2-yl}·2_ [(lS,4S)-2 -oxa-5-azabicyclo(10)(1)g: as acetonitrile 154635.doc -117-201202242 as follows: Melting point: 206 ° C (Cafele) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 (m, 2 H); 1·〇7 (m, 2 H); 1.61 (width doublet, "7=9.7 Hz, 1 H); 1.83 (width doublet, 7= 9.7 Hz, 1 H); 2·21 (m, 1 H); 2.53 (width doublet, •/10.2 Hz, 1 H); 2.94 (dd, “7=1.8 and 10.2 Hz, 1 H); 3.51 to 3.63 (m, 4 H); 3.86 (d, 7 = 7.8 Hz, 1 H); 4.35 (t, J = 2.2 Hz, 1 H); 7.30 (d, "7 = 9.5 Hz, 1 H); 7.68 (d, / = 10.3 Hz, 1 H); 8.17 (d, ·7 = 7.3 Hz, 1 H); 8.27 (d, *7 = 9.5 Hz, 1 H); 12.01 (width multiple peak, 1 H)

質譜:方法A 滞留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 498; [M-H]-: m/z 496 實例42 : N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫 烧基]-1,3-苯并噻唑-2-基}-2-(4-側氧基哌啶-1-基)乙酿胺 n_{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2-基}_2_(4_側氧基哌啶-1-基)乙醯胺可如實 例24製備,但以0.3 g 2-氣-#-{6-[(6-環丙基[1,2,4]***并 [4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、 0.144 g哌啶_4_酮鹽酸鹽及0.283 cm3 N-乙基二異丙胺於8 cm _甲亞颯中之溶液為起始物。二氧化石夕管柱急驟層析 [溶離劑:二氣甲烷/曱醇(98/2,以體積計乃之後,獲得 0.16〇呂呈白色固體狀之1^-{6-[(6-環丙基[1,2,4]***并[4,3-b]。荅畊-3-基)硫烷基]-i,3_苯并噻唑_2-基}-2-(4-側氧基哌 154635.doc •118· 201202242 咬-1 -基)乙醯胺’其特徵如下: 熔點:143。(:(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.08 (m, 2 H); 2.22 (m, 1 H); 2.40 (t, 7=6.1 Hz, 4 H); 2.88 (t, J=6.1 Hz, 4 H); 3.52 (s, 2 H); 7.30 (d, J=9.8 Hz, 1 H); 7.48 (dd,J=2.0及 8.6 Hz,1 H); 7_70 (d,《7=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, /=9.8 Hz, 1 H); 12.24 (% 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.55 ; [M+H] + : m/z 480 實例43 : N-{6-[(6-環丙基ny***并【4 3_b】嗒畊_3基)硫 烷基】-l,3-苯并噻唑_2_基}_2_(3_甲氧基氮雜環丁烷“基)乙 醯胺 N-{6-[(6-環丙基[υ〆]***并[4 3_b]嗒畊_3·基)硫烷基]_ 1’3-苯并嗟唾基卜2·(3_曱氧基氮雜環丁烷_丨·基)乙醯胺 可如實例24製備,但以〇3 g 2_氯環丙基 二唑并[4,34]嗒畊_3_基)硫烷基]_丨,3苯并噻唑_2_基丨乙醯 胺、〇.116 g 3·甲氧基氮雜環丁烷鹽酸鹽及0.295 cm3 N-乙 基二異丙胺於8 cm3二甲亞砜中之溶液為起始物。二氧化 矽官柱急驟層析[溶離劑:二氯甲烷/曱醇(95/5,以體積 计)]之後,獲得0.159 g呈白色固體狀之冰{6_[(6·環丙基 [1,2,4]***并[4,3_b]嗒喑_3_基)硫烷基卜以-苯并噻唑·2· 基}-2-(3_甲氧基氮雜環丁燒-1-基)乙醯胺,其特徵如下: 154635.doc -119· 201202242 炼點· 156-161°C (步奇) 1H NMRtf(400 MHz, δ (ppm), DMSO-d6): 〇.92 (m, 2 H); 1.08 (m,2 H); 2.21 (m,丄 H); 3.01 (m,2 H); 3.15 (s, 3 H); 3.42 (s, 2 H); 3.63 (m, 2 H); 4.01 (m, 1 H); 7.3〇 (d, 7=9.8Mass Spectrometry: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 498; [MH]-: m/z 496 Example 42: N-{6-[(6-cyclopropyl) 1,2,4]triazolo[4,3-b]indole-3-yl)thioalkyl]-1,3-benzothiazol-2-yl}-2-(4-lateral oxypermidine Acridine-1-yl)ethinyl n_{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1 , 3-benzothiazolyl-2-yl}_2_(4_p-oxypiperidin-1-yl)acetamide can be prepared as in Example 24, but with 0.3 g 2-gas-#-{6-[(6 -cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine, 0.144 A solution of g piperidine-4-one hydrochloride and 0.283 cm3 of N-ethyldiisopropylamine in 8 cm of thymidine was used as the starting material. Chromatography of sulphur dioxide cerium column [dissolving agent: di-methane/sterol (98/2, after volume, obtained 0.16 〇 呈 呈 white solid 1^-{6-[(6-ring Propyl [1,2,4]triazolo[4,3-b].indol-3-yl)sulfanyl]-i,3-benzothiazol-2-yl}-2-(4- Side oxypiperone 154635.doc •118· 201202242 bite-1 -yl) acetamamine's characteristics are as follows: Melting point: 143. (: (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6 ): 0.92 (m, 2 H); 1.08 (m, 2 H); 2.22 (m, 1 H); 2.40 (t, 7 = 6.1 Hz, 4 H); 2.88 (t, J = 6.1 Hz, 4 H 3.52 (s, 2 H); 7.30 (d, J=9.8 Hz, 1 H); 7.48 (dd, J=2.0 and 8.6 Hz, 1 H); 7_70 (d, "7=8.6 Hz, 1 H 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, /=9.8 Hz, 1 H); 12.24 (% multiplet, 1 H) Mass spectrum: Method A residence time Tr (minutes) = 0.55; [M+H] + : m/z 480 Example 43: N-{6-[(6-cyclopropylnytriazolo[4 3_b]嗒耕_3yl)sulfanyl]-l,3-benzene And thiazol-2-yl}_2_(3-methoxyazetidine "yl"acetamide N-{6-[(6-cyclopropyl[υ〆]triazolo[4 3_b] _3·yl)sulfanyl]_ 1'3-benzopyrene · (3_Hydroxyazetidinyl)-acetamide can be prepared as in Example 24, but with 〇3 g 2 -chlorocyclopropyldiazolo[4,34] 嗒3__ ) 硫 ] ] 3 3 3 3 3 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 116 A solution of 8 cm3 of dimethyl sulfoxide was used as a starting material. After flash chromatography of ruthenium dioxide column [solvent: dichloromethane / decyl alcohol (95/5 by volume)], 0.159 g of a white solid was obtained. Shaped ice {6_[(6·cyclopropyl[1,2,4]triazolo[4,3_b]indole-3-yl)sulfanyl b-benzothiazole·2·yl}-2 -(3_methoxyazetidin-1-yl)acetamide, which has the following characteristics: 154635.doc -119· 201202242 Refining point · 156-161°C (step) 1H NMRtf (400 MHz, δ (ppm), DMSO-d6): 〇.92 (m, 2 H); 1.08 (m, 2 H); 2.21 (m, 丄H); 3.01 (m, 2 H); 3.15 (s, 3 H ); 3.42 (s, 2 H); 3.63 (m, 2 H); 4.01 (m, 1 H); 7.3 〇 (d, 7=9.8

Hz,1 H); 7.47 (dd,《/=2.0及 8·6 Hz,1 H); 7.68 (d,*/=8.6 Hz, 1 H); 8.13 (d, 7=2.0 Hz, 1 H); 8.27 (d, y=9.8 Hz, 1 H); U.IO (寬多重峰,i h) 質譜:方法A 滯留時間Tr(分鐘)=〇.58 ; [M+H] + : m/z 468; [M-H]-: m/z 466 實例44 : N-{6-[(6-環丙基μ’2,4】***并[4,3-b】嗒畊-3-基)硫 烷基]-1,3-苯并噻唑_2-基}-2-【4-(吼咯啶-1-基)哌啶基】乙 酿胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒喑-3·基)硫烷基]· 1 ’3本并°塞唾-2-基} -2-[4-( >»比u各B定_丨_基)。底咬_ι_基]乙酿胺 可如實例24製備,但以〇.3 g 2_氯项_{6_[(6_環丙基[124] 一 0坐并[4,3-0]〇合喷-3-基)硫烧基]_ι,3·苯并η塞。坐_2_基}乙 醯、0.213 g 4-(吡咯啶-1-基)哌啶二鹽酸鹽及〇 455 cm3 Ν_ 乙基二異丙胺於8 cm3二曱亞砜中之溶液為起始物。二氣 化矽管柱急驟層析[溶離劑:二氯甲烷/甲醇(8〇/2〇,以體 積計)]之後’獲得0.132 g呈白色固體狀之N-{6-[(6-環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2· 基}-2-[4-(吡咯啶-1-基)哌啶_ι_基]乙醯胺,其特徵如下: 熔點:144-148.8°C (步奇) 154635.doc •120- 201202242 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0_92 (m,2 H); 1.08 (m, 2 H); 1.44 (m, 2 H); 1.65 (m, 4 H); 1.80 (m, 2 H); 1.95 (m, 1 H); 2·16至 2.27 (m,3 H); 2.46 (m,4 H); 2.84 (m, 2 11);3.20至3.40(部分遮蔽之多重峰,2印;7.30((1,>/=9.7 Hz,1 H); 7.48 (dd,《7=2.0及 8.3 Hz,1 H); 7.69 (d,/=8.3 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d, J=9.7 Hz, 1 H); 12.00 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.52 ; [M+H] + : m/z 535; [M-H]-: m/z 533 實例45 : N-{6-【(6-環丙基[1,2,4】***并【4,3-b】嗒畊-3-基)硫 烷基】-1,3-苯并噻唑-2-基}-2-[4-(2-羥基乙基)哌啩-1-基]乙 醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3_基)硫烷基]-1,3-苯并噻唑-2-基}-2-[4-(2-羥基乙基)哌畊-1-基]乙醯胺可 如實例24製備’但以0.3 g 2-氣i-{6-[(6-環丙基[H4]三 。坐并[4,34]嗒畊-3-基)硫烷基]_1,3_苯并噻唑·2_基}乙醯 胺、0.122 g 2-(哌畊-1-基)乙醇及〇.123 cm3 N-乙基二異丙 胺於8 cm3二曱亞砜中之溶液為起始物。二氧化石夕管柱系 驟層析[溶離劑:二氣曱烷/甲醇(90/10,以體積計)]之隻 獲得0.185邑呈白色固體狀之]^-{6-[(6-環丙基[124]_ [4,3-b]嗒畊-3-基)硫烷基]-1,3·笨并噻唑基丨ο 丞 W-[4-(2-羥 基乙基)°底11 井-1-基]乙醯胺,其特徵如下: 熔點:177-178.5°C (步奇) 154635.doc -121. 201202242 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.90 (m,2 H); 1.08 (m, 2 H); 2.21 (m, 1 H); 2.37 (t, 7=6.4 Hz, 2 H); 2.40 至 2.58 (部分遮蔽之多重峰,8 H); 3.31 (s,2 H); 3.48 (t, •7=6.4 Hz,2 H); 4.33 (寬多重峰,1 H); 7.30 (d,J=9.8 Hz,i H); 7.48 (dd,/=2.0及 8.6 Hz,1 H); 7.69 (d,*7=8.6 Hz,1 H); 8.13 (d,>7=2.0 Hz,1 H); 8.27 (d,/=9.8 Hz,1 H); 12.03 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.58 ; [M+H] + : m/z 511; [M-H]-: m/z 509 實例46 : iV-{6-[(6-環丙基[1,2,4】***并[4,3乃】嗒啡_3_基)硫 烷基]-1,3-苯并噻唑-2-基}-2-(吡咯啶-1-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3功]嗒畊-3-基)硫烷基]_ 1,3 -苯并°塞°坐-2-S}-2_(e比洛咬-1-基)乙酿胺可如實例24製 備’但以0.3 g 2-氣-#-{6-[(6-環丙基[1,2,4]***并[4,3-办] 嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、0.060 cm3 吡咯啶及0.123 cm3 N-乙基二異丙胺於8 cm3二甲亞砜中之 溶液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣曱 烷/曱醇(95/5 ’以體積計)]之後,獲得0.091 g呈白色固體 狀之iV-{6-[(6-環丙基[1,2,4]***并[4,3_6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(。比咯啶-1-基)乙醯胺,其特徵 如下: 熔點:237-239°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0·92 (m,2 H); 154635.doc •122· 201202242 1.08 (m,2 H); 1.72 (m,4 H); 2.22 (m,1 H); 2·62 (m, 4 H); 3.46 (s,2 H); 7.30 (d, *7=9.8 Hz,1 H); 7.47 (dd,J=2.0及 8.3 Hz,1 H); 7.68 (d,《7=8.3 Hz,1 H); 8.13 (d,《/=2.0 Hz, 1 H); 8.27 (d,J=9.8 Hz,1 H); 11.81 (寬多重峰,1 H) 質譜:方法A 滞留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 452; [M-H]-: m/z 450 實例47 : TV-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒哨_3_基)硫 烷基】-l,3-苯并噻唑-2-基}-2_(3-羥基吡咯啶·1_基)乙醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-6]塔〇井-3-基)硫烧基]_ 1,3 -苯并》塞β坐-2-基}-2-(3-輕基°比洛咬-1-基)乙酿胺可如實 例24製備,但以〇.3 g 2-氯-#-{6-[(6-環丙基[1,2,4]***并 [4,3-6]塔<»井-3 -基)硫院基]-1,3-苯并嗟嗤-2-基}乙醯‘胺、 0.107 cm3吡咯啶-3-醇及0.123 cm3 Ν-乙基二異丙胺於8 cm3 二曱亞砜中之溶液為起始物。二氧化矽管柱急驟層析[溶 離劑:二氣甲烷/曱醇(95/5,以體積計)]之後,獲得0.099 g呈白色固體狀之ΛΓ-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒 畊-3-基)硫烷基]-1,3-苯并噻唑_2-基}_2-(3-羥基吡咯啶-ΐ_ 基)乙醯胺,其特徵如下: 熔點:219-221°C (步奇) 1H NMRIt(400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); W (m,2 H); L60 (m,1 H); 2.01 (m,1 H); 2.21 (m,1 H); 2.56 (寬多重峰,2 H); 2.80 (寬多重峰,2 H); 3.50 (寬多重 峰,2 H); 4.20 (寬多重峰,i H); 4 87 (寬多重峰,i H); 7 3ι 154635.doc •123- 201202242 (d,/=9.8 Hz,1 H); 7.48 (dd,《7=2.0及 8.6 Hz,1 H); 7.70 (d, J=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.29 (d, /=9.8 Hz, 1 H); 12.13 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.56 ; [M+H] + : m/z 468; [M-H]-: m/z 466 實例48 : iV-{6-【(6-環丙基[1,2,4]***并[4,3-A】嗒畊-3-基)碰 烷基]-1,3-苯并噻唑-2-基}-2-(3-氟吡咯啶-1-基)乙醢胺 >1-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}-2-(3-氟吡咯啶-1-基)乙醯胺可如實例 24製備,但以0.3 g 2-氣-7V-{6-[(6-環丙基[1,2,4]***并 [4,3-6]嗒畊-3-基)硫烷基]_1,3_苯并噻唑-2-基}乙醯胺、 0.157 g 3-氟吡咯啶鹽酸鹽及〇·4〇 cm3 N-乙基二異丙胺於8 cm3二曱亞砜中之溶液為起始物。二氧化矽管柱急驟層析 [溶離劑:二氣曱烷/甲醇(95/5,以體積計)]之後,獲得 0.214 g呈白色固體狀之#_{6-[(6_環丙基[12 4]***并[4 3· ά]塔p井-3-基)硫烷基]-13·苯并噻唑_2_基氟吡咯啶· 卜基)乙醯胺,其特徵如下: 熔點:143。(:(步奇) 1H NMRtf(400 MHz, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.07 (m,2 H); 1.82至 2.00 (m,1 H); 2.05 至 2.18 (m, 1 H); 2.21 (m,1 H); 2.54 (m,1 H); 2.82 (m,1 H); 2.86至 2.99 (m, 2 H); 3.51 (m} 2 H); 5.22 (dm, /=55.8 Hz, 1 H); 7.30 (d, •/=9.8 Hz,1 H); 7.48 (dd,^/=2.0及 8.3 Hz,1 H); 7.70 (d, 154635.doc -124· 201202242 ^=8.3 Hz, 1 H); 8.14 (d, 7=2.0 Hz, 1 H); 8.27 (d, 7=9.8 Hz, 1 H); 12_20 (寬多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 470; [M-H]-: m/z 468 實例49 : 2-【(lS,4S)-5-環丙基-2,5-二氮雜雙環[2,2,1】庚-2-基]環丙基[1,2,4】***并[4,3-6】嗒畊-3-基)硫烷 基】-1,3-苯并噻唑-2-基}乙醯胺 a) 2-[(lS,4S)-5-環丙基-2,5-二氮雜雙環[^:^庚-之-基] {6-[(6-環丙基[1,2,4]***并[4,3-W嗒畊-3-基)硫烷基]-1,3-苯并噻唑_2_基}乙醯胺可如實例24製備,但以0.3 g 2-氣-#-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、〇·129 g (iS,4S)_2_環丙基_2,5_ 二氮雜雙環[2,2,1]庚烷及0.307 cm3 N_乙基二異丙胺於8 cm3二甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析 [溶離劑:二氣甲烷/甲醇(95/5,以體積計)]之後,獲得 0.053 g呈白色固體狀之2_[(18,48)_5•環丙基_2,5_二氮雜雙 環[2,2’1]庚-2-基]1{6_[(6_環丙基[12 4]三。坐并[4 3朴答 畊-3-基)硫烷基]-1’3_苯并噻唑_2_基}乙醯胺,其特徵如 下: 熔點:145-171°C(步奇) 1H NMR譜(400 MHz 、τλλ/tc〜 V ηζ,δ (PPm),DMSO-d6): 0.27 (m,2 H); 〇.48 (m,2 H); 〇.91 (m,2 H); 1.08 (m,2 H); 1.60 (d,J=9.8Hz,1 H); 7.47 (dd, "/=2.0 and 8·6 Hz, 1 H); 7.68 (d, */=8.6 Hz, 1 H); 8.13 (d, 7=2.0 Hz, 1 H) ; 8.27 (d, y=9.8 Hz, 1 H); U.IO (width multiple peak, ih) Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.58 ; [M+H] + : m/z 468 ; [MH]-: m/z 466 Example 44: N-{6-[(6-cyclopropylμ'2,4]triazolo[4,3-b]indole-3-yl)sulfane ]]-1,3-benzothiazolyl-2-yl}-2-[4-(indolyl-1-yl)piperidinyl]ethinylamine-{6-[(6-cyclopropyl) 1,2,4]triazolo[4,3-b]indole-3·yl)sulfanyl]· 1 '3 this and °sept-2-yl} -2-[4-( > »Compared with u each B _ _ _ base). Bottom bite _ι_基] Ethylamine can be prepared as in Example 24, but with 〇.3 g 2_chloro term _{6_[(6_cyclopropyl[124]-0 sit and [4,3-0] 〇 喷 -3-yl) thiol group]_ι, 3 · benzo η 塞. Start with a solution of _2_yl}acetamidine, 0.213 g of 4-(pyrrolidin-1-yl)piperidine dihydrochloride and 〇455 cm3 Ν_ethyldiisopropylamine in 8 cm3 of disulfoxide Things. 2 gasification cartridge column flash chromatography [solvent: dichloromethane / methanol (8 〇 / 2 〇, by volume)] after 'obtaining 0.132 g of N-{6-[(6-ring) Propyl [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole_2·yl}-2-[4-( Pyrrrolidin-1-yl)piperidine-yl]acetamide, which has the following characteristics: Melting point: 144-148.8 ° C (step) 154635.doc • 120- 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm) ), DMSO-d6): 0_92 (m, 2 H); 1.08 (m, 2 H); 1.44 (m, 2 H); 1.65 (m, 4 H); 1.80 (m, 2 H); 1.95 (m , 1 H); 2·16 to 2.27 (m, 3 H); 2.46 (m, 4 H); 2.84 (m, 2 11); 3.20 to 3.40 (multiple peaks partially masked, 2 imprints; 7.30 (1 ,>/=9.7 Hz,1 H); 7.48 (dd, "7=2.0 and 8.3 Hz, 1 H); 7.69 (d, /=8.3 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d, J = 9.7 Hz, 1 H); 12.00 (width multiple peak, 1 H) Mass spectrum: Method A residence time Tr (minutes) = 0.52; [M+H] + : m/z 535 ; [MH]-: m/z 533 Example 45: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfide Alkyl]-1,3-benzothiazol-2-yl}-2-[4-(2-hydroxyethyl) Piperidin-1-yl]acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl ]-1,3-Benzothiazol-2-yl}-2-[4-(2-hydroxyethyl)piped-l-yl]acetamide can be prepared as in Example 24 but with 0.3 g 2-gas I-{6-[(6-cyclopropyl[H4]III. Sodium[4,34]indol-3-yl)sulfanyl]_1,3-benzothiazol-2-yl}acetamide 0.122 g of 2-(peptidin-1-yl)ethanol and 〇.123 cm3 N-ethyldiisopropylamine in 8 cm3 of disulfoxide as starting material. Separate layer of sulphur dioxide Analysis of [esolvent: dioxane/methanol (90/10 by volume)] obtained only 0.185 邑 as a white solid]^-{6-[(6-cyclopropyl[124]_[4 ,3-b]嗒耕-3-yl)sulfanyl]-1,3· benzothiazolyl 丨ο 丞W-[4-(2-hydroxyethyl)° bottom 11 well-1-yl]B Indoleamine, which has the following characteristics: Melting point: 177-178.5 ° C (step) 154635.doc -121. 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.90 (m, 2 H); 1.08 (m, 2 H); 2.21 (m, 1 H); 2.37 (t, 7 = 6.4 Hz, 2 H); 2.40 to 2.58 (partially masked multiplet, 8 H); 3.31 (s, 2 H) ; 3.48 (t, •7=6.4 Hz, 2 H); 4 .33 (width multiple peak, 1 H); 7.30 (d, J = 9.8 Hz, i H); 7.48 (dd, /=2.0 and 8.6 Hz, 1 H); 7.69 (d, *7=8.6 Hz, 1 H); 8.13 (d, > 7 = 2.0 Hz, 1 H); 8.27 (d, / = 9.8 Hz, 1 H); 12.03 (width multiple peak, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) =0.58 ; [M+H] + : m/z 511; [MH]-: m/z 509 Example 46: iV-{6-[(6-cyclopropyl[1,2,4]triazolo[ 4,3 is] morphine _3_yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(pyrrolidin-1-yl)acetamide N-{6-[( 6-cyclopropyl[1,2,4]triazolo[4,3 work]嗒耕-3-yl)sulfanyl]_ 1,3 -benzo-pyrene °°-2-S}-2_ (e is more than l-yl) Ethylamine can be prepared as in Example 24 but with 0.3 g of 2-gas-#-{6-[(6-cyclopropyl[1,2,4]triazolo[ 4,3-do] 嗒--3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide, 0.060 cm3 pyrrolidine and 0.123 cm3 N-ethyldiisopropylamine at 8 The solution in cm3 dimethyl sulfoxide is the starting material. After flash chromatography of ruthenium dioxide column [solvent: dioxane / decyl alcohol (95/5 'by volume)], 0.091 g of iV-{6-[(6-cyclopropyl) was obtained as a white solid. [1,2,4]triazolo[4,3_6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(.Byrrolidine-1 -yl) acetamamine, which has the following characteristics: Melting point: 237-239 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0·92 (m, 2 H); 154635 .doc •122· 201202242 1.08 (m,2 H); 1.72 (m,4 H); 2.22 (m,1 H); 2·62 (m, 4 H); 3.46 (s,2 H); 7.30 ( d, *7=9.8 Hz, 1 H); 7.47 (dd, J=2.0 and 8.3 Hz, 1 H); 7.68 (d, "7=8.3 Hz, 1 H); 8.13 (d, "/=2.0 Hz , 1 H); 8.27 (d, J = 9.8 Hz, 1 H); 11.81 (width multiple peak, 1 H) Mass spectrum: Method A residence time Tr (minutes) = 0.59; [M+H] + : m/z 452; [MH]-: m/z 450 Example 47: TV-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]嗒 ____) Sulfuryl]-l,3-benzothiazol-2-yl}-2_(3-hydroxypyrrolidinyl-1-yl)acetamidamine-{6-[(6-cyclopropyl[1,2, 4] Triazolo[4,3-6] 〇 〇-3-yl) thiol group] _ 1,3 - benzo" -2-yl}-2-(3-light-based piroxime-1-yl)ethanoamine can be prepared as in Example 24, but with 〇.3 g 2-chloro-#-{6-[(6- Cyclopropyl[1,2,4]triazolo[4,3-6][<» well-3-yl)thiol]]1,3-1,3-benzoin-2-yl}acetamidine A solution of 'amine, 0.107 cm3 pyrrolidin-3-ol and 0.123 cm3 Ν-ethyl diisopropylamine in 8 cm3 of disulfoxide was used as a starting material. After flash chromatography of ruthenium dioxide column [solvent: di-methane/decanol (95/5 by volume)], 0.099 g of ruthenium-{6-[(6-cyclopropyl) was obtained as a white solid. [1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}_2-(3-hydroxypyrrolidine- Ethylamine, which is characterized by the following: Melting point: 219-221 ° C (step) 1H NMR It (400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); W (m, 2 H); L60 (m, 1 H); 2.01 (m, 1 H); 2.21 (m, 1 H); 2.56 (width multiple peak, 2 H); 2.80 (width multiple peak, 2 H); 3.50 ( Wide multiplet, 2 H); 4.20 (width multiple peak, i H); 4 87 (width multiple peak, i H); 7 3ι 154635.doc • 123- 201202242 (d, /=9.8 Hz, 1 H); 7.48 (dd, "7=2.0 and 8.6 Hz, 1 H); 7.70 (d, J=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.29 (d, /=9.8 Hz , 1 H); 12.13 (width multiple peak, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.56; [M+H] + : m/z 468; [MH]-: m/z 466 Example 48 : iV-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-A]indole-3-yl)-trialkyl]-1,3-benzothiazole- 2-yl}-2-(3-fluoropyrrolidin-1-yl)acetamidine Amines> 1-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzox Thiazol-2-yl}-2-(3-fluoropyrrolidin-1-yl)acetamide can be prepared as in Example 24, but with 0.3 g of 2-gas-7V-{6-[(6-cyclopropyl) 1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]_1,3-benzothiazol-2-yl}acetamide, 0.157 g 3-fluoropyrrolidine A solution of the hydrochloride and 〇·4〇cm3 N-ethyldiisopropylamine in 8 cm3 of disulfoxide was used as the starting material. After flash chromatography of the ruthenium dioxide column [solvent: dioxane/methanol (95/5 by volume)], 0.214 g of ##{-[(6_cyclopropyl) was obtained as a white solid. [12 4] Triazolo[4 3· ά] p p -3-yl) sulfanyl]-13 benzothiazole 2 yl fluoropyrrolidine yl acetamide, which is characterized as follows: Melting point: 143. (:(step) 1H NMRtf (400 MHz, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.07 (m, 2 H); 1.82 to 2.00 (m, 1 H); 2.18 (m, 1 H); 2.21 (m, 1 H); 2.54 (m, 1 H); 2.82 (m, 1 H); 2.86 to 2.99 (m, 2 H); 3.51 (m} 2 H); 5.22 (dm, /=55.8 Hz, 1 H); 7.30 (d, •==9.8 Hz, 1 H); 7.48 (dd,^/=2.0 and 8.3 Hz, 1 H); 7.70 (d, 154635.doc -124· 201202242 ^=8.3 Hz, 1 H); 8.14 (d, 7=2.0 Hz, 1 H); 8.27 (d, 7=9.8 Hz, 1 H); 12_20 (width multiple peak, 1 H) Mass spectrum: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 470; [MH]-: m/z 468 Example 49: 2-[(lS,4S)-5-cyclopropyl- 2,5-diazabicyclo[2,2,1]hept-2-yl]cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfane -1,3-1,3-thiathiazol-2-yl}acetamidamine a) 2-[(lS,4S)-5-cyclopropyl-2,5-diazabicyclo[[::g- -yl] {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-W嗒-3-yl)sulfanyl]-1,3-benzothiazole_2 Acetylamine can be prepared as in Example 24, but with 0.3 g 2-gas-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]fluorene Phenyl-3-yl)sulfanyl]-1,3-benzoene Thiazol-2-yl}acetamide, 〇·129 g (iS,4S)_2_cyclopropyl-2,5-diazabicyclo[2,2,1]heptane and 0.307 cm3 N_ethyl diiso A solution of propylamine in 8 cm3 of dimethyl sulfoxide was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: di-methane/methanol (95/5 by volume)], 0.053 g of 2_[(18,48)_5•cyclopropyl_ as a white solid was obtained. 2,5-diazabicyclo[2,2'1]hept-2-yl]1{6_[(6-cyclopropyl[12 4]III. Sit and [4 3 Pak -3-K) Sulfoalkyl]-1'3_benzothiazol-2-yl}acetamide, which has the following characteristics: Melting point: 145-171 ° C (step) 1H NMR spectrum (400 MHz, τλλ/tc~V ηζ, δ (PPm), DMSO-d6): 0.27 (m, 2 H); 〇.48 (m, 2 H); 〇.91 (m, 2 H); 1.08 (m, 2 H); 1.60 (d, J=9.8

Hz, 1 H); 1.67 (d, J=9.8 Hz, 1 H); 2.00 (m, ! H); 2.22 (m, 1 154635.doc -125- 201202242 H); 2.69至2.83 (m,4 H); 3.25至3.42 (部分遮蔽之多重峰 H); 3.50 (m, 2 H); 7.29 (d, J=9.5 Hz, 1 H); 7.48 (dd, jJ2 2 及 8.6 Hz, 1 H); 7.69 (d, */=8.6 Hz,1 H); 8.13 (d,j=2」 1 H); 8.28 (d,J=9.5 Hz,1 H); 12.85 (寬多重峰,! H)、Hz, 1 H); 1.67 (d, J=9.8 Hz, 1 H); 2.00 (m, ! H); 2.22 (m, 1 154635.doc -125- 201202242 H); 2.69 to 2.83 (m, 4 H 3.25 to 3.42 (multiple peak H for partial shading); 3.50 (m, 2 H); 7.29 (d, J = 9.5 Hz, 1 H); 7.48 (dd, jJ2 2 and 8.6 Hz, 1 H); 7.69 (d, */=8.6 Hz, 1 H); 8.13 (d, j=2" 1 H); 8.28 (d, J = 9.5 Hz, 1 H); 12.85 (width multiple peak, ! H),

質譜:方法A 滯留時間丁1'(分鐘)=〇.61; [M+H] + : m/z 519; m/z sly b) (lS,4S)-2-環丙基-2,5_二氮雜雙環[2,2,1;]庚貌可以如 方式製備: 向1.63 g (lS,4S)-5·環丙基-2,5-二氮雜雙環[^丨]庚烷一 2-甲酸2-甲基丙·2_基酯於! 5 cm3二氣曱烷中之溶液中逐滴 添加7.85 cm3三氟乙酸。在約2〇。〇之溫度下攪拌溶液約a 小時。在減壓下濃縮至乾之後,將殘餘物溶解於15 cy水 中且藉由逐滴添加3〇%氫氧化鈉調節pH值同時維持溫度 在約〇°C下。用1〇〇 cm3二氯曱烷萃取水相三次。用i〇〇 em3 水洗滌經合併之有機相兩次,經硫酸鎂乾燥,過濾且在減 壓下濃縮。獲得0.633 g呈黃色油狀之(is,4S)-2-環丙基-2,5_二氮雜雙環[2,2,1]庚烷,其特徵如下: 1H NMR譜(4〇〇 ΜΗζ,δ (ppm), DMSO-d6): 0.21 至 0.41 (m,4 H); 1.38 (寬二重峰,j=9.8 Hz,1 H); 1.59 (寬二重峰, •/=9·8 Hz,1 H); 1·94 (m,1 H); 2·4ό (寬二重峰,J=9 3 Hz,! H); 2.66 (dd,/=2.4及 9.8 Hz,1 H); 2.82 (dd,/=2.4及 9.3 Hz’ 1 H); 2.99 (寬二重峰,/=9.8 Hz,1 H); 3.27 至 3.35 (部 分遮蔽之多重峰,1 H); 3.40 (m,1 Η) 154635.doc _ 126· 201202242Mass Spectrometry: Method A Retention time 丁1' (minutes) = 〇.61; [M+H] + : m/z 519; m/z sly b) (lS,4S)-2-cyclopropyl-2,5 The _diazabicyclo[2,2,1;]glycan can be prepared as follows: to 1.63 g (lS,4S)-5·cyclopropyl-2,5-diazabicyclo[h丨]heptane 2-Dimethyl 2-methylpropan-2-yl ester in! To the solution in 5 cm3 of dioxane, 7.85 cm3 of trifluoroacetic acid was added dropwise. At about 2 baht. The solution was stirred at a temperature of about one hour. After concentration to dryness under reduced pressure, the residue was dissolved in 15 y water and pH was adjusted by dropwise addition of 3 % sodium hydroxide while maintaining the temperature at about 〇 ° C. The aqueous phase was extracted three times with 1 〇〇 cm 3 of dichloromethane. The combined organic phases were washed twice with EtOAc EtOAc (EtOAc)EtOAc. 0.633 g of (is, 4S)-2-cyclopropyl-2,5-diazabicyclo[2,2,1]heptane as a yellow oil was obtained, which was characterized as follows: 1H NMR spectrum (4 〇〇ΜΗζ , δ (ppm), DMSO-d6): 0.21 to 0.41 (m, 4 H); 1.38 (width doublet, j = 9.8 Hz, 1 H); 1.59 (width doublet, •==9·8 Hz,1 H); 1·94 (m,1 H); 2·4ό (width doublet, J=9 3 Hz, ! H); 2.66 (dd, /=2.4 and 9.8 Hz, 1 H); 2.82 (dd, /=2.4 and 9.3 Hz' 1 H); 2.99 (width doublet, /=9.8 Hz, 1 H); 3.27 to 3.35 (partially masked multiplet, 1 H); 3.40 (m,1 Η) 154635.doc _ 126· 201202242

質譜:方法A 滯留時間Tr(分鐘)=〇.ι3 ; [M+H] + : m/z 139 C) (1S’4S)_5_f丙基·2’5·二氮雜雙環[如麻·2·甲酸2. 甲基丙-2-基醋可以如下方式製備. 向⑽8(18,48)-2,5_二氮雜雙環[2,21]庚烧_2_甲酸2_甲 基丙-2-基醋於18 W甲醇中之溶液中添加8i8 g仏 基環丙基)氧基Κ三甲基)钱、5·37 cm3冰醋酸幻g从分 子篩。在約2(TC之溫度下攪拌溶液約3〇分鐘之後,添加 2.36 g氰基硼氫化鈉且將混合物維持在回流下約2小時。冷 卻至約20°C之後,將混合物傾倒於100 cm3水中且藉由添 加碳酸氫鈉使pH值達到約9。用1 〇〇 cm3二氯曱烷萃取混合 物三次。用100 cm3水洗滌經合併之有機相三次,經硫酸 鎂乾燥,過濾且在減壓下濃縮至乾。二氧化矽管柱急驟層 析[溶離劑:二氣曱烷/甲酵(98/2 ’以體積計)]之後,獲得3 g呈無色油狀之(lS,4S)-5-環丙基-2,5-二氮雜雙環[2,2,1]庚 烷-2-曱酸2-曱基丙-2-基酯,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.ι3; [M+H] + : m/z 139 C) (1S'4S)_5_fpropyl·2'5·diazabicyclo[[2] · Formic acid 2. Methyl propan-2-yl vinegar can be prepared as follows. To (10) 8 (18,48)-2,5-diazabicyclo[2,21]heptan-2-formic acid 2-methylpropyl- To the solution of 2-based vinegar in 18 W of methanol was added 8i8 g of mercaptocyclopropyl)oxyindole trimethyl)methanol, 5.37 cm3 of glacial acetic acid to the molecular sieve. After stirring the solution for about 3 minutes at a temperature of about 2 (TC), 2.36 g of sodium cyanoborohydride was added and the mixture was maintained at reflux for about 2 hours. After cooling to about 20 ° C, the mixture was poured into 100 cm3 of water. And the pH was brought to about 9 by the addition of sodium bicarbonate. The mixture was extracted three times with 1 〇〇 cm 3 of dichloromethane. The combined organic phases were washed three times with 100 cm of water, dried over magnesium sulfate, filtered and evaporated Concentrate to dryness. After flash chromatography of the ruthenium dioxide column [esolvent: dioxane/methyl leaven (98/2 'by volume)], 3 g of (lS, 4S)-5 is obtained as a colorless oil. - cyclopropyl-2,5-diazabicyclo[2,2,1]heptane-2-furoate 2-mercaptopropan-2-yl ester, which is characterized as follows:

Rf二氧化矽TLC = 0.21 [溶離劑:二氣曱烷/曱醇(95/5, 以體積計)] 質譜:方法A 滯留時間1>(分鐘)=0.31; [M+H] + : m/z 239 實例50 : 2-[4-(4-環丙基哌畊·1-基)哌啶_1-基]-N-{6-【(6-環 丙基[1,2,4】***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑- 154635.doc -127· 201202242 2-基}乙酿胺 a) 2-[4-(4-環丙基哌畊卜基)哌啶“基] n_{6_[(6環丙基 [1,2,4]二"坐并[4,3、b]嗒畊·3-基)硫烷基]-1,3-苯并噻唑 基}乙酿胺可如實例24製備,但以0.3 g 2-氣-#-{6-[(6-環兩 基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙酿胺、0.3 g丨·環丙基_4_(哌啶_4_基)哌畊三氟乙酸自旨 及0.43 cm N-乙基二異丙胺於8 cm3二曱亞砜中之溶液為 起始物。二氧化矽管柱急驟層析[溶離劑:二氯曱烷/曱醇 (90/10,以體積計)]之後,獲得0.088 g呈白色固體狀之2-[4-(4_環丙基哌。井-1-基)哌啶-1-基]-Ν-{6-[(6-環丙基[1,2,4] 二。坐并[4,3-b]塔啡_3_基)硫烷基卜込弘苯并噻唑_2_基丨乙醯 胺,其特徵如下: 熔點:143°C (步奇) 1H NMRIf(400 MHz, δ (ppm), DMSO-d6): 0.25 (m, 2 H); 0.38 (m, 2 H); 0.92 (m, 2 H); l.〇9 (m, 2 H); 1.46 (m, 2 H); 1.54 (m,1 H); 1.69 (m,2 H); 2.05至 2.26 (m,4 H); 2.36至 2.58 (部分遮蔽之多重峰,8 H); 2 89 (m, 2 H); 3 2〇至3 4〇 (經遮蔽之多重峰,2 H); 7.30 (d,/=9.5 Hz,1 H); 7.48 (dd, •7=2.1 及 8.6 Hz,1 H); 7.69 (d,/=8.6 Hz,1 H); 8.13 (d, J=2.1 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H)Rf ruthenium dioxide TLC = 0.21 [Eluent: dioxane / decyl alcohol (95/5 by volume)] Mass spectrometry: Method A Retention time 1 > (minutes) = 0.31; [M+H] + : m /z 239 Example 50: 2-[4-(4-cyclopropylpipedyl-1-yl)piperidin-1-yl]-N-{6-[(6-cyclopropyl[1,2,4 Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole- 154635.doc -127· 201202242 2-based}ethylamine a) 2-[ 4-(4-cyclopropylpiperidinyl) piperidine "yl" n_{6_[(6-cyclopropyl[1,2,4]二"Sitting and [4,3,b]嗒耕·3 -yl)sulfanyl]-1,3-benzothiazolyl}ethinylamine can be prepared as in Example 24, but with 0.3 g of 2-gas-#-{6-[(6-ringed two groups [1,2] , 4] Triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}ethinamide, 0.3 g 丨·cyclopropyl_4_ (Piperidin-4-yl) piperidine trifluoroacetic acid and a solution of 0.43 cm N-ethyldiisopropylamine in 8 cm3 of disulfoxide as starting material. Chromatography of ruthenium dioxide column [dissolution] After the reagent: methylene chloride / decyl alcohol (90/10 by volume)], 0.088 g of 2-[4-(4-cyclopropanepiperidin-1-yl)piperidine was obtained as a white solid. -1-yl]-Ν-{6-[(6-cyclopropyl[1] , 2,4] II. Sit and [4,3-b] taphthyl _3_yl) sulfanyl hydrazine benzothiazole _2 hydrazinamide, which has the following characteristics: Melting point: 143 ° C (step) 1H NMRIf (400 MHz, δ (ppm), DMSO-d6): 0.25 (m, 2 H); 0.38 (m, 2 H); 0.92 (m, 2 H); l.〇9 (m) , 2 H); 1.46 (m, 2 H); 1.54 (m, 1 H); 1.69 (m, 2 H); 2.05 to 2.26 (m, 4 H); 2.36 to 2.58 (partially masked multiplet, 8 H); 2 89 (m, 2 H); 3 2〇 to 3 4〇 (shaded multiplet, 2 H); 7.30 (d, /=9.5 Hz, 1 H); 7.48 (dd, •7= 2.1 and 8.6 Hz, 1 H); 7.69 (d, /=8.6 Hz, 1 H); 8.13 (d, J=2.1 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.52 ; [M+H] + : m/z 590; [M-H]-: m/z 5gg b) 1-環丙基-4-(哌啶-4-基)哌畊可以如下方式獲得: 154635.doc -128- 201202242 向1 g 4-(4-環丙基哌畊_l_基)哌啶_丨_曱酸2_曱基丙_2_基 醋於10 cm3二氣曱烷中之溶液中逐滴添加3 7 cm3三氟乙 酸。在約20 C之溫度下授拌約1小時之後,在減壓下濃縮 溶液至乾。獲得1.2 g呈白色固體狀之丨_環丙基_4_(哌啶_4_ 基)哌畊三氟乙酸酯,其特徵如下: 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.65 (m,4 H); 1.55 (m, 1 H); 1.70 (m, 2 H); 2.10 (m, 2 H); 2.32 (m, 1 H); 2.815.2.97 (m, 2 H); 2.99^.3.24 (m, 8 H); 3.40 (m, 2 H); 8.37至8_83〇,2 11) 質譜:方法A 滯留時間丁1*(分鐘)=0.11; [M+H] + : m/z 210 c) 4-(4-環丙基哌畊_i_基)哌啶_i_甲酸2_甲基丙_2_基酯可如 貫例49-c製備,但以3 g 4-〇底畊-1-基)痕咬·ΐ·曱酸2-甲基 丙-2-基酯、11.15 cm3 [(1·乙氧基環丙基)氧基](三甲基)矽 烧、6.37 cm3冰醋酸、2.8 g氰基硼氫化鈉於21 cm3曱醇中 之溶液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣 甲院/甲醇(95/5 ’以體積計)]之後,獲得3.05 g呈白色固體 狀之4-(4-環丙基哌畊·ι_基)哌啶_丨_甲酸2_甲基丙_2_基酯, 其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.52; [M+H] + : m/z 590; [MH]-: m/z 5gg b) 1-cyclopropyl-4-(piperidin-4- The base piper can be obtained as follows: 154635.doc -128- 201202242 to 1 g of 4-(4-cyclopropylpiperidinyl-1) piperidine_丨_capric acid 2_mercaptopropenyl-2-yl 3 7 cm 3 of trifluoroacetic acid was added dropwise to a solution of vinegar in 10 cm 3 of dioxane. After mixing for about 1 hour at a temperature of about 20 C, the solution was concentrated to dryness under reduced pressure. 1.2 g of 丨-cyclopropyl_4_(piperidine-4-yl) piperidine trifluoroacetate was obtained as a white solid, which was characterized as follows: 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6) : 0.65 (m, 4 H); 1.55 (m, 1 H); 1.70 (m, 2 H); 2.10 (m, 2 H); 2.32 (m, 1 H); 2.815.2.97 (m, 2 H) ; 2.99^.3.24 (m, 8 H); 3.40 (m, 2 H); 8.37 to 8_83〇, 2 11) Mass Spectrometry: Method A Residence time D 1* (minutes) = 0.11; [M+H] + : m/z 210 c) 4-(4-cyclopropylpiperidine _i_yl)piperidine _i-formic acid 2-methylpropan-2-yl ester can be prepared as in Example 49-c but at 3 g 4-〇 bottom cultivating-1-yl) bite, ΐ·2-methylpropan-2-yl phthalate, 11.15 cm3 [(1·ethoxycyclopropyl)oxy](trimethyl)anthracene A solution of 6.37 cm3 of glacial acetic acid and 2.8 g of sodium cyanoborohydride in 21 cm of methanol was used as the starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dioxin/methanol (95/5 'by volume)], 3.05 g of 4-(4-cyclopropylpitricin·white) was obtained as a white solid. _ base) piperidine_丨_carboxylic acid 2_methylpropan-2-yl ester, which is characterized as follows:

Rf二氧化矽TLC=0.21 [溶離劑:二氯曱烷/甲醇(95/5, 以體積計)] 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.25 (m,2 H); 0.39 (m, 2 H); 1.23 (m, 2 H); 1.39 (s, 9 H); 1.58 (m, 1 H); 154635.doc -129- 201202242 1·7〇 (m,2 H); 2.31 (m, 1 H); 2.39 至 2.54 (部分遮蔽之多重 峰,8 H); 2.70 (m, 2 H); 3.92 (m,2 Η) 質譜:方法A 滯留時間Tr(分鐘)=0.43 ; [M+H] + : m/z 310 實例51 : N-{6-【(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫 炫基】-1,3-苯并噻唑_2j}_2-[M2,2_二氟乙基)哌啶_4_基】 乙醯胺 Ν-{6-[(6·環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-笨并噻唑_2_基}_2-[i-(2,2-二氟乙基)哌啶_4-基]乙醯胺 可以如下方式製備: 向〇·4 g 6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑_2_胺於10 cm3吡啶中之溶液中添加2 25 g # [3 ( —曱基胺基)丙基]-V -乙基碳化二亞胺鹽酸鹽及ο.?〗 S [1-(2,2-一氟^乙基)°底咬-4-基]乙酸。在約2〇°c之溫度下揽 拌約4小時之後,在減壓下濃縮混合物至乾,溶解於“ cm3水中且用100 cm3二氯甲烷萃取三次。用i〇〇 Gy水及 100cm3飽和氣化鈉溶液洗滌經合併之有機相三次,經硫酸 鎂乾燥,過濾且在減壓下濃縮至乾。二氧化 析[溶離劑:二氣甲坑/甲醇州,以體積計)]之後 b]°合畊-3-基)硫烷基]-i,3-苯并噻唑_2_基卜2•[丨_(2,2_二氟乙 基)派啶-4-基]乙醯胺,其特徵如下: 熔點:264-266°C (步奇) I54635.doc •130- 201202242 1H NMR譜(400 ΜΗζ,δ (ppm), DMSO-d6): 0.92 (m,2 H); 1.09 (m, 2 H); 1.22 (m, 2 H); 1.61 (m, 2 H); 1.78 (m, 1 H); 2.13 (m, 2 H); 2.22 (m, 1 H); 2.40 (d, J=6.S Hz, 2 H); 2.67 (此1/=4.5及15.7出,2 11);2.85(111,2 11);6.09(«,>/=4.5及 55.8 Hz,1 H); 7.29 (d,7=9.5 Hz,1 H); 7.47 (dd,*7=2.0及 8.6 Hz, 1 H); 7.67 (d, 7=8.6 Hz, 1 H); 8.11 (d, 7=2.0 Hz, 1 H); 8.27 (d,/=9.5 Hz,1 H); 12.32 (寬多重峰,1 H)Rf ruthenium dioxide TLC=0.21 [Eluent: dichloromethane/methanol (95/5 by volume)] 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.25 (m, 2 H 0.39 (m, 2 H); 1.23 (m, 2 H); 1.39 (s, 9 H); 1.58 (m, 1 H); 154635.doc -129- 201202242 1·7〇(m, 2 H 2.31 (m, 1 H); 2.39 to 2.54 (partially masked multiplet, 8 H); 2.70 (m, 2 H); 3.92 (m, 2 Η) Mass Spectrometry: Method A Residence Time Tr (minutes) = 0.43 ; [M+H] + : m/z 310 Example 51 : N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒耕-3- Thiophanyl]-1,3-benzothiazole_2j}_2-[M2,2-difluoroethyl)piperidine _4_yl] acetamidine oxime-{6-[(6·cyclopropyl) [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}_2-[i-(2, 2-Difluoroethyl)piperidine-4-yl]acetamide can be prepared as follows: 〇·4 g 6-[(6-cyclopropyl[1,2,4]triazolo[4,3 -6]Indole-3-yl)sulfanyl]-1,3-benzothiazol-2-amine in a solution of 10 cm3 pyridine was added 2 25 g #[3 (-decylamino)propyl ]-V-ethylcarbodiimide hydrochloride and ο.?〗 S [1-(2,2-fluoroethyl)ethyl 4-yl] acetic acid. After stirring for about 4 hours at a temperature of about 2 ° C, the mixture was concentrated to dryness under reduced pressure, dissolved in "cm3 water and extracted three times with 100 cm3 of dichloromethane. With i〇〇Gy water and 100 cm3 of saturated gas The combined organic phases were washed three times with sodium sulphate, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Dioxides [solvent: two gas pits/methanol state, by volume)] b]° Co-cultivated 3-yl)sulfanyl]-i,3-benzothiazol-2-yldi-2-[[2,2-difluoroethyl)pyridin-4-yl]acetamidamine, Its characteristics are as follows: Melting point: 264-266 ° C (step) I54635.doc • 130- 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.09 (m , 2 H); 1.22 (m, 2 H); 1.61 (m, 2 H); 1.78 (m, 1 H); 2.13 (m, 2 H); 2.22 (m, 1 H); 2.40 (d, J =6.S Hz, 2 H); 2.67 (this 1/=4.5 and 15.7, 2 11); 2.85 (111, 2 11); 6.09 («, >/= 4.5 and 55.8 Hz, 1 H); 7.29 (d,7=9.5 Hz,1 H); 7.47 (dd,*7=2.0 and 8.6 Hz, 1 H); 7.67 (d, 7=8.6 Hz, 1 H); 8.11 (d, 7=2.0 Hz , 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.32 (width multiple peak, 1 H)

質譜:方法A 滞留時間Tr(分鐘)=0.64 ; [M+H] + : m/z 530;基峰:m/z 341 [M-H]-: m/z 528 實例52 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒畊-3-基)硫 烷基]-1,3-苯并噻唑-2-基卜2-[l-(2,2,2_三氟乙基)哌啶-4-基】乙醜胺 N-{6-[(6-環丙基[u〆]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并嘆唾-2-基}-2-[1-(2,2,2-三氟乙基)哌啶-4-基]乙醯 胺可如實例51製備,但以〇·4 g 6-[(6-環丙基[1,2,4]***并 [4’3_6]°荅"井·3·基)硫烷基]-1,3-苯并噻唑-2-胺、2.25 g #-[3-(—甲基胺基)丙基]乙基碳化二亞胺鹽酸鹽及〇 73 g [1 二氟乙基)π底咬_4_基]乙酸於1〇 cm3。比β定中之溶液 為起始物。二氧化矽管柱急驟層析[溶離劑:二氯曱烷/曱 "° 以體積汁)]之後’獲得0.176 g呈白色固體狀之 {6_[(6_環丙基[H4]***并[4,3-b]嗒畊-3-基)硫烷基卜丨,3_ 本并塞圭_2-基}_2_[1_(2,2,2-三氟乙基)娘咬_4-基]乙醯胺, 154635.doc _131· 201202242 其特徵如下: 熔點:265-274°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 (m, 2 H); 1- 09 (m, 2 H); 1.25 (m, 2 H); 1.62 (m, 2 H); 1.78 (m, 1 H); 2- 21 (m, 1 H); 2.30 (m5 2 H); 2.41 (d, 7=6.8 Hz, 2 H); 2.89 (m, 2 H); 3.11 (q, J=l〇.3 Hz, 2 H); 7.29 (d, 7=9.5 Hz, 1 H); 7.47 (dd,/=2.0及 8.3 Hz,1 H); 7.68 (d,J=8.3 Hz, 1 H); 8.12 (d,*7=2.0 Hz,1 H); 8.27 (d,*7=9.5 Hz,1 H); 12.35 (寬 多重峰,1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.64; [M+H] + : m/z 530; base peak: m/z 341 [MH]-: m/z 528 Example 52: N-{6-[ (6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl-2--[ L-(2,2,2-trifluoroethyl)piperidin-4-yl]ethyl acetamide N-{6-[(6-cyclopropyl[u〆]triazolo[4,3-b] Indole-3-yl)sulfanyl]-1,3-benzoindole-2-yl}-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl] Acetamide can be prepared as in Example 51, but with 4 g 6-[(6-cyclopropyl[1,2,4]triazolo[4'3_6]°荅" well·3·yl) sulfur Alkyl]-1,3-benzothiazol-2-amine, 2.25 g #-[3-(-methylamino)propyl]ethylcarbodiimide hydrochloride and 〇73 g [1 difluoro Ethyl) π bottom bite _4_yl] acetic acid at 1 〇 cm 3 . The solution than the β solution is the starting material. Chromatography of ruthenium dioxide column [solvent: chloroformane / 曱 " ° by volume of juice]] after 'obtaining 0.176 g of white solid {6_[(6_cyclopropyl[H4]triazole And [4,3-b]嗒耕-3-yl)sulfanyldiazine,3_本塞塞圭_2-yl}_2_[1_(2,2,2-trifluoroethyl) Ninjabita_4 -yl]acetamide, 154635.doc _131· 201202242 Its characteristics are as follows: Melting point: 265-274 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1- 09 (m, 2 H); 1.25 (m, 2 H); 1.62 (m, 2 H); 1.78 (m, 1 H); 2- 21 (m, 1 H); 2.30 (m5 2 H); 2.41 (d, 7=6.8 Hz, 2 H); 2.89 (m, 2 H); 3.11 (q, J=l〇.3 Hz, 2 H); 7.29 (d, 7=9.5 Hz, 1 H); 7.47 (dd, /= 2.0 and 8.3 Hz, 1 H); 7.68 (d, J = 8.3 Hz, 1 H); 8.12 (d, *7 = 2.0 Hz, 1 H); 8.27 (d, *7=9.5 Hz, 1 H); 12.35 (width multiple peak, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.82 ; [M+H] + : m/z 548; [M-H]-: m/z 546 實例53 . 2-(4-環丙基嗎淋-2-基)-N-{6-[(6-環丙基丨i,2,4]三 嗤并[4,3-b]嗒畊-3-基)硫烷基]-I,3-苯并噻唑_2_基}乙酿胺 a) 2-(4-環丙基嗎琳-2-基)-N-{6-[(6-環丙基[ι,2,4]三β坐并 [4,3-b]塔11井-3-基)硫烧基]-1,3 -苯并°塞°坐-2-基}乙酿胺可如 實例51製備,但以0.4 g 6-[(6-環丙基[1,2,4]***并[4,3-έ] 嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-胺、2.25 g沁[3-(二曱 基胺基)丙基]乙基碳化二亞胺鹽酸鹽及0.87 g (4_環丙 基嗎啉-2-基)乙酸鹽酸鹽於10 cm3吡啶中之溶液為起始 物。二氧化石夕管柱急驟層析[溶離劑:二氣甲烧/曱醇 (95/5’以體積計)]之後,獲得〇.1〇6§呈白色固體狀之2_(4_ 環丙基嗎嚇·j -基)-N-{6-[(6-環丙基[1,2,4]三。坐并[4,3-b]»又 p井-3-基)硫烧基]-1,3-苯并**塞峻-2-基}乙醯胺,其特徵如 154635.doc -132- 201202242 下: 熔點:231-244°C (步奇) 1H NMR譜(400 ^1出,3咖111),〇]^80-(16):〇.32〇,2 11)· 0.41 (m, 2 H); 0.91 (m, 2 H); 1.09 (m, 2 H); 1.64 (m, 1 H); 2.08 (m,1 H); 2.17至 2.30 (m,2 H); 2.62至 2.72 (m,3 H); 2.87 (m,1 H); 3.39 (m,1 H); 3.72 (m,1 H); 3.82 (m,1 H); 7.69 (d, /=8.6 Hz, 1 H); 8.13 (d, 7=2.2 Hz, 1 H); 8.27 (d, •/=9·8 Hz,1 H); 12.40 (寬多重峰,i h) 質譜:方法A 滯留時間Tr(分鐘)= 0.62 ; [M+H] + : m/z 508; [M-H]-: m/z 506 b) (4-環丙基嗎啉_2-基)乙酸可以如下方式獲得: 向0.567 g (4-環丙基嗎啉-2-基)乙酸曱酯於5 cm3甲醇中 之溶液中逐滴添加4.3 cm3 1 N氫氧化鈉水溶液。在約2〇β(: 之溫度下攪拌混合物約2小時。在減壓下濃縮至乾之後, 將殘餘物溶解於1G em3水中且藉由添加5 N鹽酸水溶液使 PH值達到約在減壓下濃縮混合物至乾且獲得〇 87〇 g呈 白色固體狀之(4-環丙基嗎啉-2-基)乙酸鹽酸鹽,其特徵如 下: 、主 質譜:方法A 滯留時間Tr(分鐘)= 0.12 ; [M+H] + : m/z 186 Ο (4-環丙基嗎啉_2_基)乙酸曱酯可如實例49_c製備,伸以 154635.doc •133- 201202242 1 g嗎啉-2-基乙酸甲酯、5.78 cm3 [(1•乙氧基環丙基)氧 基](三甲基)石夕烧、3·3 cm3冰醋酸及^5 g氰基硼氫化鈉於 7 cm曱醇中之溶液為起始物。二氧化矽管柱急驟層析[溶 離劑:二氣甲烷/曱醇(98/2,以體積計)]之後,獲得〇 567 g呈無色油狀之乙酸(4-環丙基嗎啉基)酯,其特徵如 下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.82; [M+H] + : m/z 548; [MH]-: m/z 546 Example 53. 2-(4-cyclopropyl hydrazine-2- -N-{6-[(6-cyclopropyl丨i,2,4]triazino[4,3-b]indole-3-yl)sulfanyl]-I,3-benzo Thiazole-2-yl}ethylamine a) 2-(4-cyclopropylmorphin-2-yl)-N-{6-[(6-cyclopropyl[ι,2,4]tri-[beta] [4,3-b]Tail 11 well-3-yl)thiol group]-1,3-benzo-pyrene ° sit-2-yl}ethinylamine can be prepared as in Example 51, but with 0.4 g 6- [(6-Cyclopropyl[1,2,4]triazolo[4,3-indene]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-amine, 2.25 g沁[3-(Dimercaptoamino)propyl]ethylcarbodiimide hydrochloride and a solution of 0.87 g (4-cyclopropylmorpholin-2-yl)acetic acid hydrochloride in 10 cm3 pyridine As a starting material. After quenching the sulfur dioxide column chromatography [solvent: two gas aeration / sterol (95/5' by volume)], 2_(4_cyclopropyl) was obtained as a white solid.吓) j-based)-N-{6-[(6-cyclopropyl[1,2,4]III. Sodium[4,3-b]»又 p--3-yl)thiol ]-1,3-Benzo-oxen-2-yl}acetamidamine, characterized by 154635.doc -132-201202242 Bottom: Melting point: 231-244°C (step) 1H NMR spectrum (400^ 1 out, 3 coffee 111), 〇]^80-(16): 〇.32〇, 2 11)· 0.41 (m, 2 H); 0.91 (m, 2 H); 1.09 (m, 2 H); 1.64 (m, 1 H); 2.08 (m, 1 H); 2.17 to 2.30 (m, 2 H); 2.62 to 2.72 (m, 3 H); 2.87 (m, 1 H); 3.39 (m, 1 H) 3.72 (m,1 H); 3.82 (m,1 H); 7.69 (d, /=8.6 Hz, 1 H); 8.13 (d, 7=2.2 Hz, 1 H); 8.27 (d, •/ =9·8 Hz,1 H); 12.40 (width multiple peak, ih) Mass Spectrum: Method A Retention time Tr (minutes) = 0.62; [M+H] + : m/z 508; [MH]-: m/ z 506 b) (4-cyclopropylmorpholine-2-yl)acetic acid can be obtained as follows: to a solution of 0.567 g of (4-cyclopropylmorpholin-2-yl)acetic acid decyl ester in 5 cm3 of methanol A 4.3 cm 3 1 N aqueous solution of sodium hydroxide was added dropwise. The mixture was stirred at a temperature of about 2 〇β (: about 2 hours. After concentration to dryness under reduced pressure, the residue was dissolved in 1G EtOAc water and pH was brought to about under reduced pressure by adding 5 N aqueous hydrochloric acid. The mixture was concentrated to dryness to give (4-cyclopropylmorpholin-2-yl)acetic acid hydrochloride as a white solid. mp. [M+H] + : m/z 186 曱 (4-cyclopropylmorpholine-2-yl) decyl acetate can be prepared as in Example 49_c, 154635.doc • 133-201202242 1 g morpholine- Methyl 2-methylacetate, 5.78 cm3 [(1•ethoxycyclopropyl)oxy](trimethyl) zebra, 3·3 cm3 glacial acetic acid and 5 g of sodium cyanoborohydride at 7 cm The solution in sterol is the starting material. After flash chromatography of the ruthenium dioxide column [solvent: di-methane/sterol (98/2 by volume)], 〇567 g is obtained as a colorless oil. (4-Cyclopropylmorpholinyl) ester, which is characterized as follows:

Rf二氧化矽TLC = 0.68 [溶離劑:二氣甲烷/甲醇(9〇/1〇, 以體積計)] 1H NMR譜(400 ΜΗζ,δ (ppm),DMS〇-d6): 0.30 (m,2 H); 0.40 (m, 2 H); 1.62 (m, 1 H); 2.02 (m, 1 H); 2.24 (td, /=3.4 及 11.4 Hz,1 H); 2.40 (dd,《7=8.1 及 15.4 Hz,1 H); 2.49 (dd, •/=5.1 及 15.4 Hz,1 H); 2.70 (m,1 H); 2.83 (m,1 H); 3.39 〇(1,</=2.7及11.2 1^,111);3.61(3,3 1^);3.64至3.75(111,2 H)Rf ruthenium dioxide TLC = 0.68 [Eluent: di-gas methane / methanol (9 〇 / 1 〇, by volume)] 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMS 〇-d6): 0.30 (m, 2 H); 0.40 (m, 2 H); 1.62 (m, 1 H); 2.02 (m, 1 H); 2.24 (td, /=3.4 and 11.4 Hz, 1 H); 2.40 (dd, "7= 8.1 and 15.4 Hz, 1 H); 2.49 (dd, •/=5.1 and 15.4 Hz, 1 H); 2.70 (m,1 H); 2.83 (m,1 H); 3.39 〇(1,</= 2.7 and 11.2 1^, 111); 3.61 (3, 3 1^); 3.64 to 3.75 (111, 2 H)

質譜:方法A 滞留時間丁1*(分鐘)=0.11; [M+H] + : m/z 200 實例54 : 2-(4-環丙基嗎啉-3-基)-N-{6-【(6-環丙基[1,2,4]三 唑并[4,3-b]嗒畊-3-基)硫烷基]-I,3-苯并噻唑-2-基}乙醯胺 a) 2-(4-環丙基嗎啉-3-基)-N-{6-[(6-環丙基[1,2,4]***并 [4,3-b]嗒叫· -3-基)硫烷基]-1,3-苯并噻唑-2_基}乙醯胺可如 實例Μ製備,但以0.4 g 6-[(6-環丙基[1,2,4]***并[4,3-6] 嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-胺、2.25 g #-[3-(二曱 基胺基)丙基]-ΛΓ'-乙基碳化二亞胺鹽酸鹽及0.782 g (4-環丙 154635.doc .134- 201202242 基嗎淋-3-基)乙酸鹽酸鹽於i〇 cm3 °比咬中之溶液為起始 物。二氧化矽管柱急驟層析[溶離劑:二氯甲烷/甲醇 (95/5,以體積計)]之後,獲得0.153 g呈白色固體狀之2_(4_ 環丙基嗎淋-3-基)-Ν-{6·[(6-環丙基[1,2,4]三。坐并[4,3-b]。荅 啡-3-基)硫烧基]-1,3-笨并嘆峻-2-基}乙酿胺,其特徵如 下: 熔點:229-234°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.22 (m,1 H); 0.31 至 0.47 (m,3 H); 0.91 (m, 2 H); 1.08 (m,2 H); 1.69 (m, 1 H); 2.22 (m,1 H); 2.40 (m,1 H); 2.49 (部分遮蔽之多重 峰,1 H); 2.79 (m,1 H); 2.96 (m,1 H); 3.05 (m,1 H); 3.23 (m, 1 H); 3.49 (m, 1 H); 3.62 (m, 2 H); 7.29 (d, J=9.8 Hz, 1 H); 7.48 (dd, J=2.0及 8.3 Hz,1 H); 7.69 (d,/=8.3 Hz, 1 H); 8.12 (d,《7=2.0 Hz,1 H); 8.27 (d,《7=9.8 Hz,1 H); 12.46 (寬 多重峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)= 0.64 ;Mass Spectrometry: Method A Retention time 丁1*(min)=0.11; [M+H] + : m/z 200 Example 54: 2-(4-cyclopropylmorpholin-3-yl)-N-{6- [(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-I,3-benzothiazol-2-yl}acetamidine Amine 2-) 2-(4-cyclopropylmorpholin-3-yl)-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b] nickname · -3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide can be prepared as in the example, but with 0.4 g of 6-[(6-cyclopropyl[1,2, 4] Triazolo[4,3-6]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-amine, 2.25 g #-[3-(didecylamino) Propyl]-ΛΓ'-ethylcarbodiimide hydrochloride and 0.782 g (4-cyclopropane 154635.doc .134- 201202242 quinol-3-yl)acetic acid hydrochloride salt at i〇cm3 ° The solution in the middle is the starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dichloromethane/methanol (95/5 by volume)], 0.153 g of 2-(4-cyclopropyl-n--3-yl) was obtained as a white solid. -Ν-{6·[(6-cyclopropyl[1,2,4]三. Sit and [4,3-b]. morphine-3-yl)thiol]-1,3-stupid The sulphate-2-yl} amine can be characterized as follows: Melting point: 229-234 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.22 (m, 1 H) 0.31 to 0.47 (m, 3 H); 0.91 (m, 2 H); 1.08 (m, 2 H); 1.69 (m, 1 H); 2.22 (m, 1 H); 2.40 (m, 1 H) ; 2.49 (Multiple peaks partially masked, 1 H); 2.79 (m, 1 H); 2.96 (m, 1 H); 3.05 (m, 1 H); 3.23 (m, 1 H); 3.49 (m, 1 H); 3.62 (m, 2 H); 7.29 (d, J = 9.8 Hz, 1 H); 7.48 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.69 (d, /=8.3 Hz, 1 H 8.12 (d, "7=2.0 Hz, 1 H); 8.27 (d, "7=9.8 Hz, 1 H); 12.46 (width multiple peak, 1 H) Mass spectrometry: method A residence time Tr (minutes) = 0.64 ;

[M+H] + : m/z 508; [M-H]-: m/z 506 b) (4-環丙基嗎啉-3-基)乙酸可如實例53_b製備,但以丨29 g (4-環丙基嗎啉-3-基)乙酸乙酯及9 〇7 cm3 i N氫氧化鈉水 /谷液於10 cm曱醇中之溶液為起始物。獲得239 g呈白色 固體狀之(4-環丙基嗎啉-3-基)乙酸鹽酸鹽,其特徵如下: 質譜:方法A 滞留時間Tr(分鐘)=0.12 ; 154635.doc -135- 201202242 [M+H] + :m/zl86;基峰:m/zl79 c) (4-環丙基嗎啉-3-基)乙酸乙酯可如實例49_e製備,但以 1 g嗎琳-3-基乙酸乙酯、5.78 cm3 [(1-乙氧基環丙基)氧 基](三甲基μ夕烷、3.3 cm3冰醋酸及1.45 g氰基硼氫化鈉於 7 cm3甲醇中之溶液為起始物。獲得ι·29 g呈無色油狀之(4_ 環丙基嗎啉-3-基)乙酸乙酯,其特徵如下:[M+H] + : m/z 508; [MH]-: m/z 506 b) (4-cyclopropylmorpholin-3-yl)acetic acid can be prepared as in Example 53_b, but 丨29 g (4 -cyclopropylmorpholine-3-yl)acetate and a solution of 9 〇7 cm3 i N sodium hydroxide water/guar solution in 10 cm of methanol as starting material. 239 g of (4-cyclopropylmorpholin-3-yl)acetic acid hydrochloride as a white solid are obtained as follows: Mass Spectrum: Method A Retention time Tr (minutes) = 0.12; 154635.doc -135-201202242 [M+H] + :m/zl86; base peak: m/zl79 c) (4-cyclopropylmorpholin-3-yl)acetate can be prepared as in Example 49_e, but with 1 g of lining-3- Ethyl acetate, 5.78 cm3 [(1-ethoxycyclopropyl)oxy] (trimethylheptane, 3.3 cm3 glacial acetic acid and 1.45 g of sodium cyanoborohydride in 7 cm3 of methanol The title compound was obtained as a colorless oily (4-cyclopropylmorpholin-3-yl)acetate as a colorless oil.

Rf二氧化矽TLC=0.5 8 [溶離劑:二氯甲烷/甲醇(90/10, 以體積計)] 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 〇.〇9至 0.46 (m, 4 H); 1.10 (t, 7=7.3 Hz, 3 H); 1.59 (m, 1 H); 2.21 (dd, «/=7.3及 15.9 Hz,1 H); 2.30 (m,1 H); 2.60至 2.74 (m,2 H); 2.76至 2.88 (m, 1 H); 3.10 (m, 1 H); 3.37 (m, 1 H); 3.51 (m, 2 H); 3.98 (q, /=7.3 Hz, 2 H) 質譜:方法A 滯留時間Tr(分鐘)=0.24 ; [M+H] + : m/z 214 實例55 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒哜-3·基)硫 烷基】-1,3-苯并噻唑_2_基卜2-[4-(2-甲基丙_2·基)哌畊·i基] 乙醯胺 N-{6_[(6-環丙基[^,4]***并[4,3-b]嗒畊·3_基)硫烷基]-1,3-本并嘆吐-2-基}_2-[4-(2-甲基丙-2-基)〇辰Ρ井_ι_基]乙醯 胺可如實例24製備,但以〇.4 g 2-氣-7V-{6-[(6-環丙基 [1,2,4]二。坐并[4,3-6] 〇荅畊-3-基)硫烧基]_ι,3·苯并嗟吐-2-基}乙酿胺、0.177 g 1-(2-甲基丙-2-基)0底p井及0.180 cm3 N- 154635.doc -136- 201202242 乙基二異丙胺於8 cm3二甲亞硬中之溶液為起始物。二氧 化矽管柱急驟層析[溶離劑:二氣曱烷/甲醇(95/5,以體積 計)]之後,獲得0.120 g呈白色固體狀之ν-{6-[(6-環丙基 [1,2,4]三°坐并[4,3-1)]'1荅'1井-3-基)硫烧基]-1,3-苯并嗟1>坐_2- 基}-2-[4-(2-甲基丙-2-基)〇底ρ井-1-基]乙醯胺,其特徵如 下: 熔點:146-149°C(步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.00 (s,9 H); 1.09 (m,2 H); 2.22 (m,1 H); 2.54 (經遮蔽之 多重峰,4 H); 3.33 (經遮蔽之多重峰,6 H); 7.30 (d,《7=9.5Rf ruthenium dioxide TLC = 0.5 8 [Eluent: dichloromethane / methanol (90/10 by volume)] 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 〇.〇9 to 0.46 (m, 4 H); 1.10 (t, 7=7.3 Hz, 3 H); 1.59 (m, 1 H); 2.21 (dd, «/=7.3 and 15.9 Hz, 1 H); 2.30 (m, 1 H) 2.60 to 2.74 (m, 2 H); 2.76 to 2.88 (m, 1 H); 3.10 (m, 1 H); 3.37 (m, 1 H); 3.51 (m, 2 H); 3.98 (q, /=7.3 Hz, 2 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.24; [M+H] + : m/z 214 Example 55: N-{6-[(6-cyclopropyl[1, 2,4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole_2_ylbu 2-[4-(2-methylpropane_ 2·base) piperidine·i group] acetamamine N-{6_[(6-cyclopropyl[^,4]triazolo[4,3-b]indole·3_yl)sulfanyl] -1,3-Benzyl oxazol-2-yl}_2-[4-(2-methylpropan-2-yl)〇辰Ρ井_ι_基] acetamidine can be prepared as in Example 24, but 4.4 g 2-gas-7V-{6-[(6-cyclopropyl[1,2,4]二. Sit and [4,3-6] 〇荅-3-yl) thiol] _ι,3·Benzoindole-2-yl}Ethylamine, 0.177 g 1-(2-methylpropan-2-yl)0 bottom p well and 0.180 cm3 N- 154635.doc -136- 201202242 Ethyl Diisopropyl A solution of the amine in 8 cm3 of dimethyl sulfoxide was used as the starting material. After flash chromatography of ruthenium dioxide column [solvent: dioxane / methanol (95/5 by volume)], 0.120 g of ν-{6-[(6-cyclopropyl) was obtained as a white solid. [1,2,4] three-degree sitting and [4,3-1)] '1荅'1 well-3-yl) sulfur-based group]-1,3-benzopyrene 1> sitting_2-based} -2-[4-(2-methylpropan-2-yl)indole ρ well-1-yl]acetamide, which has the following characteristics: Melting point: 146-149 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.00 (s, 9 H); 1.09 (m, 2 H); 2.22 (m, 1 H); 2.54 (shadowed multiple Peak, 4 H); 3.33 (multiple peaks obscured, 6 H); 7.30 (d, "7=9.5

Hz, 1 H); 7.48 (dd,*/=2.0及 8·6 Hz,1 H); 7.69 (d,《7=8.6 Hz, 1 H); 8.13 (d, /=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H)Hz, 1 H); 7.48 (dd, */=2.0 and 8·6 Hz, 1 H); 7.69 (d, "7=8.6 Hz, 1 H); 8.13 (d, /=2.0 Hz, 1 H) ; 8.27 (d, 7=9.5 Hz, 1 H)

質譜:方法A 滯留時間Tr(分鐘)= 0.62 ; [M+H] + : m/z 523; [M-H]-: m/z 521 實例56 : 2_[4-(丁 -2-基)哌畊基卜N_{6_【(6·環丙基丨12 4] ***并[4,3-b]嗒畊-3-基)硫烷基】-u-苯并噻唑_2_基}乙 醢胺 2-[4-(丁-2-基)哌畊·1_基]·Ν·{6_[(6_環丙基[12 4]***并 [4,3-b]嗒喷-3-基)硫烷基卜丨,;^苯并噻唑_2_基}乙醯胺可如 實例24製備,但以〇·4 g 2_氯_#_{6_[(6_環丙基[丨又糾*** 并[4,3-δ]嗒畊-3-基)硫烷基]-丨,3•笨并噻唑_2_基}乙醯胺、 0.177 g 1_(丁 _2-基)哌畊及〇 18〇 cm3 N乙基二異丙胺於8 cm 一甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析 154635.doc -137- 201202242 [溶離劑:二氣曱烷/曱醇(95/5,以體積計)]之後,獲得 〇.l43 g呈白色固體狀之2-[4-( 丁-2-基)哌畊-1-基]-N-{6-[(6-環丙基[1,2,4]二。坐并[4,3-b]»»荅p井-3-基)硫炫基]-1,3 -笨并0塞 唑-2-基}乙醯胺,其特徵如下: 熔點:222-237°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.84 (t,《/=7.5 Hz,3 H); 0.92 (m,5 H); 1.08 (m,2 H); 1.24 (m,1 H); 1.46 (111,111);2.22(«,>/=4.9及8.2 1^,111);2.34至2.46(111,1 H); 2.53 (經遮蔽之多重峰,4 h); 3·33 (經遮蔽之多重峰,6 H); 7_30 (d,J=9.5 Ηζ,1 H); 7·48 (dd,J=2.0及 8.6 Ηζ,1 H); 7.70 (d, 7=8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d, •/=9.5 Hz,1 H) 質谱.方法A 滯留時間Tr(分鐘)= 0.65 ; [M+H] + : m/z 523; [M-H]-: m/z 521 實例57 : N-{6-[(6-環丙基[i,2,4]***并[4,3-b]嗒畊-3-基)硫 烷基]-l,3-笨并噻唑·2_基卜2-[4-(甲基磺酿基)哌畊-1-基]乙 •Όχ JJSs N-{6-[(6-環丙基[i,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-^3-笨并噻唑-2-基}-2-[4-(甲基磺醯基)哌畊-1-基]乙醯胺可 如實例24製備,但以0.4 g 2-氯-#-{6-[(6-環丙基[1,2,4]三 唾并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醢 ·250 g 1-(甲基續醯基)η底畊鹽酸鹽及0.442 cm3 Ν-乙 基一異丙胺於8 cm3二曱亞颯中之溶液為起始物。二氧化 154635.doc 201202242 矽管柱急驟層析[溶離劑:二氣曱烷/曱醇(98/2,以體積 計)]之後,獲得〇.244 g呈白色固體狀之Ν-{6·[(6-環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并嘆„坐 基}-2-[4-(甲基續酿基)D底p井-1-基]乙酿胺,其特徵如下: 熔點:233-240°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m 2 H); 1.08 (m, 2 H); 2.20 (m, 1 H); 2.65 (t, 7=4.9 Hz, 4 H); 2.88 (s, 3 H); 3.14 (m, 4 H); 3.42 (s, 2 H); 7.30 (d, J=9.5 Hz, 1 H); 7.48 (dd, ·7=2·0及 8.6 Hz, 1 H); 7.69 (d,/=8.3 Hz,1 H); 8.13 (d,/=2.0 Hz,1 H); 8.27 (d,/=9.5 Hz,1 H); 12.17 (寬 單峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)= 0.72 ; [M+H] + : m/z 545; [M-H]-: m/z 543 實例58 : N-{6-[(6-環丙基[1,2,4]***并[4,3_b】嗒畊_3_基)硫 烷基]-1,3·苯并噻唑-2_基卜2_[4_(丙-2-基)哌畊4基】乙醢胺 N-{6-[(6-環丙基[^4]***并[4,3_b]嗒啩·3_基)硫烷基]_ 1,3_苯并噻唑_2_基}_2_[4_(丙_2_基)哌畊“-基]乙醯胺可如 實例24製備,但以0_4 g 2-氯-AM6-K6-環丙基[^川*** 并[4,3-6]嗒畊_3·基)硫烷基]_i,3_苯并噻唑_2_基)乙醯胺、 〇·\60 § 1-(丙-2-基)派呼及0.180 cm3 乙基二異丙胺於8 cm 一甲亞硬中之溶液為起始物。二氣化碎管柱急驟層析 [溶離劑:二氣曱烷/甲醇(95/5,以體積計)]之後,獲得 0.174 g呈白色固體狀之Ν·{6_[(6_環丙基[12 4]***并[4 3· 154635.doc •139· 201202242 b]嗒畊-3-基)硫烷基]-1,3-笨并噻唑_2_基}_2-[4-(丙-2-基)哌 p井-1-基]乙醯胺,其特徵如下: 熔點:207-210°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.89 (m,2 H); 0.96 (d,*7=6.6 Hz, 6 H); 1.08 (m,2 H); 2.21 (m,1 H); 2.45 (m,4 H); 2.5 3 (m,4 H); 2.61 (m,1 H); 3.32 (經遮蔽之多重 峰,2 H); 7.30 (d,《7=9.5 Hz,1 H); 7.48 (dd,·7=2.1 及 8.4 Hz, 1 H); 7.69 (d, 7=8.6 Hz, 1 H); 8.13 (d, J=2.0 Hz, 1 H); 8.27 (d,7=9.5 Hz,1 H); 12.08 (寬單锋,i h) 質譜:方法A 滯留時間Tr(分鐘)=0.62 ; [M+H] + : m/z 509; [M-H]-: m/z 507 實例59 : N2-環丙基-N-{6_[(6·環丙基[1,2,4】***并[4,3-b】 嗒畊-3-基)硫烷基苯并噻唑-2-*}-N2-乙基甘胺醯胺 N2-環丙基-N-{6-[(6-環丙基[1,2,4]三嗤并[4,3-b]°荅p井- 3-基)硫炫*基]·1,3_本并隹°坐-2-基}-N -乙基甘胺酿胺可如貫例 24製備,但以〇.4 g 2-氣-#-{6-[(6-環丙基[1,2,4]***并 [4,3-6]嗒哨^3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺、 0.106 g N-乙基環丙胺及0.180 cm3 N-乙基二異丙胺於8 cm3二甲亞砜中之溶液為起始物。二氧化矽管柱急驟層析 [溶離劑:二氣曱烷/曱醇(95/5,以體積計)]之後,獲得 0.110 g呈白色固體狀之N2-環丙基-N-{6-[(6-環丙基Π,2,4] 三0坐并[4,3-b]°荅**井-3-基)硫烧基]-1,3 -苯并β塞u坐_2-基}以-乙基甘胺醯胺,其特徵如下: 154635.doc •140· 201202242 熔點:194-203°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm), DMSO-d6): 0.40 (m,4 H); 0.91 (m,2 H); 1.02 (t,J=7.2 Hz,3 H); 1.09 (m,2 H); 2.11 (m, 1 H); 2.23 (m, 1 H); 2.77 (q, 7=7.3 Hz, 2 H); 3.52 (s, 2 H); 7.30 (d,《7=9.5 Hz,1 H); 7.47 (dd,/=2.1 及 8.4 Hz, 1 H); 7.68 (d, 7=8.6 Hz, 1 H); 8.12 (d, J=1.5 Hz, 1 H); 8.27 (d, •/=9.5 Hz,1 H); 12.04 (寬單峰,i h)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.62; [M+H] + : m/z 523; [MH]-: m/z 521 Example 56: 2_[4-(but-2-yl) piped Keb N_{6_[(6·cyclopropyl丨12 4]triazolo[4,3-b]indole-3-yl)sulfanyl]-u-benzothiazole_2-yl}acetamidine Amine 2-[4-(but-2-yl)pipedyl 1·yl]·Ν·6_[(6-cyclopropyl[12 4]triazolo[4,3-b]indole-3 -yl)sulfanyldiazine, ;benzothiazole-2-yl}acetamide can be prepared as in Example 24, but with 〇·4 g 2_chloro_#_{6_[(6_cyclopropyl [丨 and triazole [4,3-δ] 嗒-3-yl) sulfanyl]- 丨, 3 • benzothiazol-2-yl} acetamidine, 0.177 g 1 _ (but 2 -yl) A solution of piperene and 〇18〇cm3 Nethyldiisopropylamine in 8 cm of sulfoxide was used as a starting material. After the cerium dioxide column flash chromatography 154635.doc -137- 201202242 [solvent: dioxane / decyl alcohol (95/5, by volume)], 〇.l43 g is obtained as a white solid 2- [4-( Butan-2-yl)piped-1-yl]-N-{6-[(6-cyclopropyl[1,2,4] bis. Sodium[4,3-b]»»荅p well-3-yl) thiophanyl]-1,3-stupid0-oxazole-2-yl}acetamidamine, which has the following characteristics: Melting point: 222-237 ° C (step) 1H NMR spectrum ( 400 ΜΗζ, δ (ppm), DMSO-d6): 0.84 (t, "/=7.5 Hz, 3 H); 0.92 (m, 5 H); 1.08 (m, 2 H); 1.24 (m, 1 H) 1.46 (111,111); 2.22 («,>/=4.9 and 8.2 1^,111); 2.34 to 2.46 (111,1 H); 2.53 (multiple peaks obscured, 4 h); 3·33 (Multiple peaks obscured, 6 H); 7_30 (d, J = 9.5 Ηζ, 1 H); 7·48 (dd, J = 2.0 and 8.6 Ηζ, 1 H); 7.70 (d, 7 = 8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d, •==9.5 Hz, 1 H) Mass Spectrometry. Method A Residence Time Tr (minutes) = 0.65; [M+H] + : m/z 523; [MH]-: m/z 521 Example 57: N-{6-[(6-cyclopropyl[i,2,4]triazolo[4,3-b] 3-yl)sulfanyl]-l,3- benzothiazol-2-yl 2-2-[4-(methylsulfanyl)per Plough-1-yl]B•Όχ JJSs N-{6-[(6-cyclopropyl[i,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl] -^3- benzothiazol-2-yl}-2-[4-(methylsulfonyl)piped-1-yl]acetamide can be prepared as in Example 24, but with 0.4 g of 2-chloro-# -{6-[(6-cyclopropyl[1,2,4]trisino[4,3-6]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- A solution of 2-(methyl hydrazino) η bottom tillage hydrochloride and 0.442 cm3 Ν-ethyl monoisopropylamine in 8 cm3 of diterpenoids was used as a starting material. Dioxide 154635.doc 201202242 After the column chromatography (dissolving agent: dioxane / decyl alcohol (98/2 by volume)], 〇.244 g was obtained as a white solid-{6· [(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzoindole s-sitting}-2- [4-(Methyl aryl) D bottom p--1-yl] ethylamine, which has the following characteristics: Melting point: 233-240 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m 2 H); 1.08 (m, 2 H); 2.20 (m, 1 H); 2.65 (t, 7 = 4.9 Hz, 4 H); 2.88 (s, 3 H); (m, 4 H); 3.42 (s, 2 H); 7.30 (d, J=9.5 Hz, 1 H); 7.48 (dd, ·7=2·0 and 8.6 Hz, 1 H); 7.69 (d, /=8.3 Hz,1 H); 8.13 (d, /=2.0 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.17 (wide unimodal, 1 H) Mass Spectrometry: Method A Residence Time Tr (minutes) = 0.72; [M+H] + : m/z 545; [MH]-: m/z 543 Example 58: N-{6-[(6-cyclopropyl[1,2,4] Triazolo[4,3_b]嗒耕_3_yl)sulfanyl]-1,3·benzothiazole-2_yl b 2_[4_(prop-2-yl)piped 4 base] acetamidine N-{6-[(6-cyclopropyl[^4]triazolo[4,3_b]indole-3-yl)sulfanyl]_ 1,3_benzo Thiazole-2_yl}_2_[4_(prop-2-yl)piperidine "-yl"acetamide can be prepared as in Example 24, but with 0-4 g 2-chloro-AM6-K6-cyclopropyl [^ Chuansan Azolo[4,3-6]indole_3·yl)sulfanyl]_i,3_benzothiazol-2-yl)acetamide, 〇·\60 § 1-(propan-2-yl) A solution of 0.180 cm3 of ethyl diisopropylamine in 8 cm of a hardened medium was used as the starting material. After flash chromatography of the second gasification column [solvent: dioxane/methanol (95/5 by volume)], 0.174 g of a white solid was obtained. {6_[(6_cyclopropyl) [12 4] Triazolo[4 3· 154635.doc •139· 201202242 b]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}_2-[4-( Prop-2-yl)piperidin-1-yl]acetamide, which has the following characteristics: Melting point: 207-210 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.89 (m, 2 H); 0.96 (d, *7 = 6.6 Hz, 6 H); 1.08 (m, 2 H); 2.21 (m, 1 H); 2.45 (m, 4 H); 2.5 3 (m , 4 H); 2.61 (m, 1 H); 3.32 (multiple peaks obscured, 2 H); 7.30 (d, "7=9.5 Hz, 1 H); 7.48 (dd, ·7=2.1 and 8.4 Hz , 1 H); 7.69 (d, 7 = 8.6 Hz, 1 H); 8.13 (d, J = 2.0 Hz, 1 H); 8.27 (d, 7 = 9.5 Hz, 1 H); 12.08 (width single front, Ih) Mass Spectrum: Method A Retention time Tr (minutes) = 0.62; [M+H] + : m/z 509; [MH]-: m/z 507 Example 59: N2-cyclopropyl-N-{6_[ (6·cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanylbenzothiazole-2-*}-N2-ethylglycinamide N2-cyclopropyl-N-{6-[(6-cyclopropyl[1,2,4]triindole[ 4,3-b]°荅p well-3-base) sulphur*yl]·1,3_this 隹° sit-2-yl}-N-ethylglycine ethamine can be prepared as in Example 24 , but with 〇.4 g 2-gas-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl a solution of 1-1,3-benzothiazol-2-yl}acetamide, 0.106 g of N-ethylcyclopropylamine and 0.180 cm3 of N-ethyldiisopropylamine in 8 cm3 of dimethyl sulfoxide . After flash chromatography of the ruthenium dioxide column [solvent: dioxane / decyl alcohol (95/5 by volume)], 0.110 g of N2-cyclopropyl-N-{6- [(6-cyclopropylhydrazine, 2,4] tris(s) and [4,3-b]°荅** well-3-yl)thioalkyl]-1,3-benzo-β-u sitting_ 2-Base}-ethylglycine decylamine, which has the following characteristics: 154635.doc •140· 201202242 Melting point: 194-203°C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6 ): 0.40 (m, 4 H); 0.91 (m, 2 H); 1.02 (t, J = 7.2 Hz, 3 H); 1.09 (m, 2 H); 2.11 (m, 1 H); 2.23 (m , 1 H); 2.77 (q, 7 = 7.3 Hz, 2 H); 3.52 (s, 2 H); 7.30 (d, "7=9.5 Hz, 1 H); 7.47 (dd, /=2.1 and 8.4 Hz , 1 H); 7.68 (d, 7=8.6 Hz, 1 H); 8.12 (d, J=1.5 Hz, 1 H); 8.27 (d, •==9.5 Hz, 1 H); 12.04 (wide single peak , ih)

質譜:方法A 滯留時間Tr(分鐘)=〇.67 ; [M+H] + : m/z 466; [M-H]-: m/z 464 實例60 : Ν-{6·[(6·環丙基[H4】***并[4,3_b]嗒畊_3基)硫 烷基】·1,3-苯并噻唑-2-基卜N2_乙基_N2_丙·2_基甘胺醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒,井-3-基)硫烷基]_ 1,3-苯并噻唑-2-基} ·Ν2_乙基_N2_丙·2_基甘胺醯胺可如實例 24製備,但以〇·4 g 2_氣_沁{6_[(6_環丙基[^4]***并 [4,3-6]嗒畊-.3-基)硫烷基H,3_苯并噻唑_2_基}乙醯胺、 ⑽N-乙.基二異丙胺於8 。二氧化矽管柱急驟層析 ,以體積計)]之後,獲得 0.108 g N-乙基丙-2-胺及 0.180 cm3二曱亞砜中之溶液為起始物 [溶離劑:二氣曱烷/曱醇(95/5 0.060 g呈白色固體狀2N_{6_[(6_環丙基[124]***并 b]嗒畊-3-基)硫烷基并噻唑_2_基}七2_乙基π、丙 2-基甘胺醯胺,其特徵如下: 熔點:128-158°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 (m,2 H) 154635.doc 201202242 0-99 (m, 9 H); 1.09 (m, 2 H); 2.22 (m, 1 H); 2.59 (q, /=7.1 Hz,2H);3.02(dt,J=6.6&13.2Hz,lH);3.35(s,2H); 7.30 (d,J=9.5 Hz,1 H); 7.48 (dd,*7=2.0及 8.3 Hz,1 H); 7.69 (d, J=8.6 Hz, 1 H); 8.13 (d, 7=2.0 Hz, 1 H); 8.27 (d, •/=9·8 Hz,1 H); 11.55 (寬單峰,1 H) 質谱·方法A 滯留時間1>(分鐘)=〇.61; [M+H] + : m/z 468; [M-H]-: m/z 466 實例61 : N-{6-[(6-環丙基丨1,2,4]***并[4,3-b]嗒畊-3-基)硫 烷基】-1,3-苯并噻唑-2j}_N2-[2-(二甲基胺基)乙基]-N2-乙 基甘胺醯胺 N-{6-[(6-環丙基[ι,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]_ 1,3-苯并噻唑·2_基}_Ν2·[2_(二甲基胺基)乙基]_N2乙基甘胺 醯胺可如實例24製備,但以04 g 2_氣·環丙基 [1’2’4]***并[4,3功]嗒畊_3_基)硫烷基]_i,3苯并噻唑_2_ 基}乙醯胺、0.145 g N·-乙基_N,N-二甲基乙_12_二胺及 0.180 cm N-乙基二異丙胺於8 cm3二甲亞砜中之溶液為起 始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/曱醇 (9〇/10以體積5十之後,獲得0.037 g呈米色固體狀之N-{6-[(6-環丙基H4]三嗤并[4 3 b]塔呼 苯并塞坐2基卜N -[2-(二甲基胺基)乙基]·N2_乙基甘胺醯 胺,其特徵如下: 溶點.260-261。〇 (步奇) 1H 醒R4(4G() ΜΗζ,δ (ppm), dms〇·柳㈣(叫 2 取 154635.doc 201202242 0·98 (t,J=7.3 Hz,3 H); 1.09 (m,2 H); 2.21 (m,1 H); 2.34 (s’ ό H); 2.48 (m,2 H); 2.68 (m,4 H); 3.37 (經遮蔽之多重 峰,2 H); 7.29 (d,j=9.8 Hz,i H); 7 45 (dd,/=2 2及 8 6 Hz, 1 H); 7.65 (d, 7=8.3 Hz, 1 H); 8.10 (d, J=2.0 Hz, 1 H); 8.27 (d, J=9.3 Hz, 1 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.67; [M+H] + : m/z 466; [MH]-: m/z 464 Example 60: Ν-{6·[(6·Cyclopropyl Base [H4]triazolo[4,3_b]indole_3yl)sulfanyl]1,3-1,3-benzothiazol-2-ylbu-N2_ethyl_N2_propan-2-ylglycine Amidoxime-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole, well-3-yl)sulfanyl]-1,3-benzothiazole -2-yl}·Ν2_ethyl_N2_propan-2-glycidylamine can be prepared as in Example 24, but with 〇·4 g 2_gas_沁{6_[(6_cyclopropyl[^ 4] Triazolo[4,3-6]indole-.3-yl)sulfanyl H,3-benzothiazol-2-yl}acetamide, (10) N-ethyldiisopropylamine. After the flash chromatography of the ruthenium dioxide column, by volume,], a solution of 0.108 g of N-ethylpropan-2-amine and 0.180 cm3 of disulfoxide was obtained as a starting material [solvent: dioxane /nonanol (95/5 0.060 g in the form of a white solid 2N_{6_[(6_cyclopropyl[124]triazolo b]indol-3-yl)thioalkylthiazole_2_yl}7 2 _Ethyl π, propyl 2-glycine decylamine, which has the following characteristics: Melting point: 128-158 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H) 154635.doc 201202242 0-99 (m, 9 H); 1.09 (m, 2 H); 2.22 (m, 1 H); 2.59 (q, /=7.1 Hz, 2H); 3.02 (dt, J =6.6 & 13.2 Hz, lH); 3.35 (s, 2H); 7.30 (d, J = 9.5 Hz, 1 H); 7.48 (dd, *7 = 2.0 and 8.3 Hz, 1 H); 7.69 (d, J=8.6 Hz, 1 H); 8.13 (d, 7=2.0 Hz, 1 H); 8.27 (d, •==9·8 Hz, 1 H); 11.55 (wide unimodal, 1 H) mass spectrometer· Method A Retention time 1 > (minutes) = 〇.61; [M+H] + : m/z 468; [MH]-: m/z 466 Example 61: N-{6-[(6-cyclopropyl)丨1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazole-2j}_N2-[2-(dimethylamino) )ethyl]-N2-ethylglycine decylamine N-{6-[(6-ring Propyl [ι, 2, 4] triazolo[4,3-b]indole-3-yl)sulfanyl]_1,3-benzothiazolyl-2-yl}_Ν2·[2_(dimethyl The aminoamino)ethyl]_N2 ethylglycine decylamine can be prepared as in Example 24, but with 04 g 2 qi·cyclopropyl[1'2'4]triazolo[4,3 work] 3_yl)sulfanyl]_i,3 benzothiazole_2_yl}acetamide, 0.145 g N·-ethyl_N,N-dimethylethyl-12-diamine and 0.180 cm N-ethyl A solution of diisopropylamine in 8 cm3 of dimethyl sulfoxide was used as a starting material. Chromatography of ruthenium dioxide column [dissolving agent: di-methane/sterol (9 〇/10 in a volume of 50 deg, obtaining 0.037 g of N-{6-[(6-cyclopropyl H4) as a beige solid嗤三嗤[4 3 b] ta benzophene sit 2 kib N-[2-(dimethylamino)ethyl]·N2_ethylglycine decylamine, which has the following characteristics: melting point. 260-261.〇(步奇) 1H Wake up R4(4G() ΜΗζ,δ (ppm), dms〇·Liu (4) (call 2 take 154635.doc 201202242 0·98 (t, J=7.3 Hz, 3 H) ; 1.09 (m, 2 H); 2.21 (m, 1 H); 2.34 (s' ό H); 2.48 (m, 2 H); 2.68 (m, 4 H); 3.37 (multiple peaks obscured, 2 H); 7.29 (d, j = 9.8 Hz, i H); 7 45 (dd, /= 2 2 and 8 6 Hz, 1 H); 7.65 (d, 7 = 8.3 Hz, 1 H); 8.10 (d , J=2.0 Hz, 1 H); 8.27 (d, J=9.3 Hz, 1 H)

質譜:方法A 滯留時間Tr(分鐘)=0.64 ; [M+H] + : m/z 497; [M-H]-: m/z 495 實例62 : 2-[4-(l·環丙基哌啶_4基)哌畊小基卜N_{6_[(6環 丙基[1,2,4]***并[4,3-b]嗒畊_3_基)硫烷基】-1,3-苯并噻唑-2-基}乙醯胺 a) 2-[4_(1-環丙基哌啶_4•基)娘畊_丨基]·N_{6_[(6_環丙基 [1’2,4]三》坐并[4,3-|3]嗒唯_3_基)硫烷基]_1,3-苯并噻唑_2- 基}乙醯胺可如實例24製備,但以〇·4 g 2-氣-iV-{6-[(6-環丙 基[1,2,4]三吐并[4,3-6]嗒。井_3_基)硫烷基]_ι,3-苯并噻唑-2- 基}乙醯胺、0.465 g 1_(丨_環丙基哌啶_4_基)哌。井三氟乙酸 醋及0.820 cm3 N-乙基二異丙胺於8 cm3二甲亞颯中之溶液 為起始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/甲 醇(90/10 ’以體積計)]之後,獲得〇 195 §呈白色固體狀之 2-[4-(1-環丙基哌啶基)哌〇井_丨_基卜N-{6_[(6_環丙基 [1,2,4]***并[4,3-b]嗒畊_3_基)硫烷基]-1,3-苯并噻唑-2- 基}乙醯胺,其特徵如下·· 熔點:196-200°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.24 (m,2 H); 154635.doc •143- 201202242 0.38 (m,2 H); 0.90 (m,2 H); 1.09 (m,2 H); 1.30 (m,2 H); 1.54 (m,1 H); 1.69 (m,3 h); 2.09 (m,6 H); 2.23 (m,1 h); 2.56 (經遮蔽之多重峰,4 H); 2 93 (山 /=12.0 Hz,2 H); 3.29 (經遮蔽之單峰,2 h); 7 3〇 (d,/=9.8 Hz,1 H); 7.48 (dd,/=2.1 及 8.4 Hz,1 H); 7.70 (d,*7=8.3 Hz, 1 H); 8.M (d, •/=2.0 Hz’ 1 H); 8.28 (d,/=9.5 Hz,1 H); 12.07 (寬單峰,工 H)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.64; [M+H] + : m/z 497; [MH]-: m/z 495 Example 62: 2-[4-(l·cyclopropylpiperidine) _4 base) pipetine small base N_{6_[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole _3_yl)sulfanyl]-1,3 -benzothiazol-2-yl}acetamide a) 2-[4_(1-cyclopropylpiperidine-4)-based 娘_丨基]·N_{6_[(6_cyclopropyl[1] '2,4]三" sit and [4,3-|3]嗒only _3_yl)sulfanyl]-1,3-1,3-benzothiazole_2-yl}acetamide can be prepared as in Example 24, but 〇·4 g 2-gas-iV-{6-[(6-cyclopropyl[1,2,4]trido[4,3-6]嗒.well_3_yl)sulfanyl] _ι, 3-benzothiazol-2-yl}acetamide, 0.465 g of 1_(丨_cyclopropylpiperidine-4-yl)pipeper. A solution of well trifluoroacetic acid vinegar and 0.820 cm3 of N-ethyldiisopropylamine in 8 cm3 of dimethyl hydrazine was used as a starting material. After the flash chromatography of the ruthenium dioxide column [eluent: di-methane/methanol (90/10 'by volume)], 2-[4-(1-cyclopropyl) was obtained as a white solid. Pyridyl) piperidine well_丨_基卜 N-{6_[(6_cyclopropyl[1,2,4]triazolo[4,3-b]indole_3_yl)sulfanyl] -1,3-benzothiazol-2-yl}acetamide, which is characterized by the following melting point: 196-200 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.24 (m,2 H); 154635.doc •143- 201202242 0.38 (m,2 H); 0.90 (m,2 H); 1.09 (m,2 H); 1.30 (m,2 H); 1.54 (m , 1 H); 1.69 (m, 3 h); 2.09 (m, 6 H); 2.23 (m, 1 h); 2.56 (multiple peaks obscured, 4 H); 2 93 (mountain/=12.0 Hz, 2 H); 3.29 (shaded single peak, 2 h); 7 3 〇 (d, /=9.8 Hz, 1 H); 7.48 (dd, /=2.1 and 8.4 Hz, 1 H); 7.70 (d, *7=8.3 Hz, 1 H); 8.M (d, •==2.0 Hz' 1 H); 8.28 (d, /=9.5 Hz, 1 H); 12.07 (wide unimodal, work H)

質譜:方法A 滯留時間1>(分鐘)=〇.51; [M+H] + : m/z 590; [M-H]-: m/z 588 b) 1-(1-環丙基哌啶-4-基)哌畊可如實例50-b中所述製備, 但以1 g 4-(1-環丙基哌啶_4、基)哌畊―卜甲酸2-甲基丙_2_基 酯及3.7 cm3三氟乙酸於10 cm3二氯甲烷中之溶液為起始 物。獲得1.3 g呈白色固體狀之•環丙基哌啶_4_基)哌畊 三氟乙酸酯,其特徵如下:Mass Spectrometry: Method A Retention Time 1 > (minutes) = 〇.51; [M+H] + : m/z 590; [MH]-: m/z 588 b) 1-(1-cyclopropylpiperidine- 4-Based Pipeline can be prepared as described in Example 50-b, but with 1 g of 4-(1-cyclopropylpiperidine-4,yl)piperidin-benzoic acid 2-methylpropan-2-yl A solution of the ester and 3.7 cm3 of trifluoroacetic acid in 10 cm3 of dichloromethane was used as the starting material. Obtained 1.3 g of a cyclopropylpiperidine _4_yl) piperidine trifluoroacetate as a white solid, which is characterized as follows:

Rf二氧化矽TLC=0.08 [溶離劑:二氣甲烷/曱醇/28〇/〇氨 水(80/10/1,以體積計)]Rf ruthenium dioxide TLC=0.08 [Eluent: two gas methane / decyl alcohol / 28 〇 / 〇 ammonia water (80/10/1, by volume)]

質譜:方法A 滯留時間Tr(分鐘)=0.09 ; [M+H] + : m/z 210 c) 4-(1-環丙基哌啶·4_基)哌畊曱酸2_曱基丙_2_基酯可如 實例49-c製備,但以i g 4-(哌啶基)哌畊_丨_甲酸2_甲基 丙-2-基酿、3.71 cm3 [(1_乙氧基環丙基)氧基](三曱基)石夕 烷、2.10 cm3冰醋酸、0.93 g氰基堋氣化鈉及〇 5 g 3A分子 154635.doc •144· 201202242 篩於7 cm3甲醇中之溶液為起始物。二氧化石夕管柱急驟層 析[溶離劑:二氯甲烷/曱醇(95/5,以體積計)]之後,獲得 1.01 g呈白色固體狀之4-(1_環丙基哌啶·‘基”底畊卜甲酸 2-甲基丙·2-基酯,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.09; [M+H] + : m/z 210 c) 4-(1-cyclopropylpiperidine·4_yl)pipelinic acid 2_mercaptopropyl _2_base ester can be prepared as in Example 49-c, but is ig 4-(piperidinyl) piperene_丨-formic acid 2-methylpropan-2-yl, 3.71 cm3 [(1-ethoxylated ring) Propyl)oxy](trimethylene) oxalate, 2.10 cm3 glacial acetic acid, 0.93 g sodium cyanohydrazide and 〇5 g 3A molecule 154635.doc •144· 201202242 The solution in sieved in 7 cm3 of methanol is Starting material. After quenching the sulfur dioxide column chromatography [solvent: dichloromethane / methanol (95/5 by volume)], 1.01 g of 4-(1-cyclopropylpiperidine) was obtained as a white solid. 'Base' bottom cultivating 2-methylpropan-2-yl ester, characterized by the following:

Rf二氧化石夕TLC=0_36 [溶離劑:二氣曱燒/甲醇(9〇/1〇, • 以體積計)]Rf dioxide dioxide TLC=0_36 [Eluent: two gas smoldering / methanol (9 〇 / 1 〇, • by volume)]

質谱:方法A 滯留時間Tr(分鐘)=〇.25 ; [M+H] + : m/z 310 實例63 ·· 2-{4-[1-(環丙基甲基)旅咬_4_基】娘味小基卜N{6_ [(6-環丙基[1,2,4]***并[4,3_b】嗒畊_3_基)硫烷基】-13笨 并噻唑_2-基}乙醯胺 &)2-{4-[1-(環丙基曱基)哌啶_4_基]哌啡_1_基卜1^_{6_[(6_環 丙基[1,2,4]***并[4,3-b]嗒畊_3_基)硫烷基卜^·苯并噻唑-2-基}乙醯胺可如實例24製備,但以〇4 g 2_氣项_{6_[(6_環 丙基[1,2,4]***并[4,3-6]嗒畊_3_基)硫烷基]_13_笨并噻唑_ 2-基}乙醯胺、0.485 g i_tl_(環丙基甲基)哌啶_4基]哌畊三 氟乙酸酯及0.820 cm3 N—乙基二異丙胺於8 cm3二甲亞颯中 之溶液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣 甲烷/甲醇/28%氨水(8〇/10/1,以體積計)]之後,獲得〇 〇5〇 g呈白色固體狀之2-{4-[1-(環丙基曱基)哌啶·4_基]哌畊 基}-Ν·{6_[(6-環丙基[1,2,4]三唾并[4,3_b]。荅_小基)硫烷 基]-1,3-笨并》塞。坐-2-基}乙酿胺,其特徵如下: 熔點:200-203°C (步奇) 154635.doc -145· 201202242 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.08 (m,2 H); 0- 46 (m, 2 H); 0.80 (m, 1 H); 0.92 (m, 2 H); 1.07 (m, 2 H); 1- 42 (m, 2 H); 1.72 (m, 2 H); 1.95 (m, 2 H); 2.17 (m, 4 H); 2.53 (經遮蔽之多重峰,8 H); 3.02 (d,《7=10.8 Hz,2 H); 3.31 (經遮蔽之多重峰,2 H); 7.30 (d,/=9.8 Hz,1 H); 7.48 (dd,·7=2·0及 8.6 Hz,1 H); 7.70 (d,/=8.3 Hz,1 H); 8.14 (d, •/=2.0 Hz,1 H); 8.28 (d,/=9.5 Hz,1 H); 11.99 (寬單峰,i H) 質譜:方法A 滯留時間Tr(分鐘)=0.52 ; [M+H] + : m/z 604; [M-H]-: m/z 602 b) i-n-(環丙基曱基)哌啶-4-基]哌畊可如實例5〇_b中所述 製備’但以0.499 g 4-[1-(環丙基甲基)哌啶基]哌畊甲 酸2-甲基丙-2-基酯及1.77 cm3三氟乙酸於5 cm3二氣甲院中 之浴液為起始物。獲得〇72 g呈白色固體狀之卜丨丨气環丙基 甲基)哌啶-4-基]哌畊三氟乙酸酯,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.25; [M+H] + : m/z 310 Example 63 ····{{2-[1-(cyclopropylmethyl) brigade bite_4 _基】娘味小基卜 N{6_ [(6-cyclopropyl[1,2,4]triazolo[4,3_b]嗒耕_3_yl)sulfanyl]-13 stupid thiazole _ 2-yl}acetamide &) 2-{4-[1-(cyclopropylindolyl)piperidine-4-yl]piperidin-1_ylbu 1^_{6_[(6_cyclopropyl The base [1,2,4]triazolo[4,3-b]indole_3_yl)sulfanyl bromide-2-benzoyl-2-yl}acetamide can be prepared as in Example 24, but 〇4 g 2_gas _{6_[(6_cyclopropyl[1,2,4]triazolo[4,3-6]嗒耕_3_yl)sulfanyl]_13_stupidylthiazole _ 2-yl}acetamide, 0.485 g i_tl_(cyclopropylmethyl)piperidine-4-yl] piperazine trifluoroacetate and 0.820 cm3 N-ethyldiisopropylamine in 8 cm3 dimethyl hydrazine The solution is the starting material. After the flash chromatography of the ruthenium dioxide column [esolvent: di-methane/methanol/28% ammonia (8 〇/10/1 by volume)], 2-5〇g is obtained as a white solid 2-{ 4-[1-(cyclopropylindenyl)piperidin-4-yl]pipedyl}-Ν·{6_[(6-cyclopropyl[1,2,4]tris-[4,3_b]荅_小基)sulfanyl]-1,3-stupid. Ethyl-2-amine}, characterized by the following: Melting point: 200-203 ° C (step) 154635.doc -145· 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.08 (m, 2 H); 0-46 (m, 2 H); 0.80 (m, 1 H); 0.92 (m, 2 H); 1.07 (m, 2 H); 1- 42 (m, 2 H) 1.72 (m, 2 H); 1.95 (m, 2 H); 2.17 (m, 4 H); 2.53 (multiple peaks obscured, 8 H); 3.02 (d, "7 = 10.8 Hz, 2 H) ; 3.31 (Multiple peaks obscured, 2 H); 7.30 (d, /=9.8 Hz, 1 H); 7.48 (dd, ·7=2·0 and 8.6 Hz, 1 H); 7.70 (d, /= 8.3 Hz,1 H); 8.14 (d, •==2.0 Hz, 1 H); 8.28 (d, /=9.5 Hz, 1 H); 11.99 (wide unimodal, i H) Mass Spectrometry: Method A Residence Time Tr (minutes)=0.52; [M+H] + : m/z 604; [MH]-: m/z 602 b) in-(cyclopropylindolyl)piperidin-4-yl]piped can be as an example Prepared as described in 5〇_b, but with 0.499 g of 4-[1-(cyclopropylmethyl)piperidinyl]piped formic acid 2-methylpropan-2-yl ester and 1.77 cm3 of trifluoroacetic acid in 5 The bath in the cm3 second gas institute is the starting material. Obtained 72 g of p-oxacyclopropylmethyl)piperidin-4-yl]pitricin trifluoroacetate as a white solid with the following characteristics:

Rf —氧化矽TLC=0.32 [溶離劑:氯仿/甲醇/28〇/〇氨水 (72/18/3,以體積計)]Rf - yttrium oxide TLC = 0.32 [Eluent: chloroform / methanol / 28 〇 / 〇 ammonia (72 / 18 / 3, by volume)]

質譜:方法A 滞留時間Tr(分鐘)= 0·10 ; [M+H] + : m/z 224 勾(環丙基甲基)哌啶_4_基]哌畊甲酸2_甲基丙_2-基 酯可以如下方式製備: 向0.5 g 4-(哌啶_4_基)哌畊_丨_甲酸2_甲基丙基酯於1〇 154635.doc -146 - 201202242 cm3乙腈t之溶液中添加0.3 8 g (溴甲基)環丙烷及2 42 g碳 酸絶。在約20°C之溫度下攪拌所得懸浮液約18小時。過濾 且在減壓下濃縮之後,藉由二氧化矽管柱急驟層析[溶離 劑:二氯甲烷/甲醇(90/10,以體積計)]純化殘餘物,且獲 得0.499 g呈白色固體狀之4_Π_(環丙基甲基)哌啶_4_基]哌 畊-1-甲酸2-甲基丙-2-基酯,其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0·10; [M+H] + : m/z 224 Hook (cyclopropylmethyl) piperidine_4_yl] Piper formic acid 2_Methylpropyl_ The 2-based ester can be prepared as follows: 0.5 g of 4-(piperidine-4-yl) piperazine_丨-formic acid 2-methylpropyl ester in 1〇154635.doc -146 - 201202242 cm3 acetonitrile t solution 0.3 8 g (bromomethyl)cyclopropane and 2 42 g of carbonic acid were added. The resulting suspension was stirred at a temperature of about 20 ° C for about 18 hours. After filtration and concentrating under reduced pressure, the residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 4_Π_(cyclopropylmethyl)piperidine-4-yl]piperidine-1-carboxylic acid 2-methylpropan-2-yl ester, which is characterized as follows:

Rf二氧化矽TLC=0_27 [溶離劑:二氯曱烷/甲醇(9〇/1〇, 以體積計)]Rf ruthenium dioxide TLC=0_27 [Eluent: dichloromethane/methanol (9 〇 / 1 〇, by volume)]

質譜:方法A 滯留時間Tr(分鐘)=0.26 ; [M+H] + : m/z 324 實例64 : N-{6-[(6-環丙基[H4】***并[4 3 b】嗒畊·3•基)硫 烷基卜1,3-苯并噻唑-2-基}_2_(4_羥基哌啶^基)乙醢胺 N-{6-[(6-環丙基⑴以]三。坐并[4,3外荅喷·3·基)硫烷基]_ 1,3-苯并噻唑-2-基}-2-(4-羥基哌啶-ΐ_基)乙醯胺可如實例 24製備,但以〇·4 g 2_氯项_{6_[(6_環丙基[124]***并 [4,3-6]嗒呼-3-基)硫烷基苯并噻唑_2_基}乙醯胺、 0.172 g哌啶-4-醇鹽酸鹽及〇.40 cm3 N_乙基二異丙胺於8 cm 一甲亞砜中之 >谷液為起始物。二氧化矽管柱急驟層析 [溶離劑:二氯曱烷/甲醇(95/5,以體積計)]之後,獲得 0.277 g呈白色固體狀之沁{6_[(6_環兩基***并[4,3_ b]嗒畊-3-基)硫烷基苯并噻唑基卜2_(4羥基哌啶-1-基)乙醯胺,其特徵如下: 熔點:181-192°c(步奇) 154635.doc -147- 201202242 1H NMR譜(400 ΜΗζ,δ (ppm), DMSO-d6): 0.91 (m,2 H); 1.09 (m, 2 H); 1.44 (m, 2 H); 1.71 (m, 2 H); 2.26 (m, 3 H); 2.76 (m,2 H); 3.3 0 (經遮蔽之多重峰,2 H); 3.46 (m,1 H); 4.53 (寬單峰,1 H); 7.30 (d,《7=9.8 Hz,1 H); 7.48 (dd, •/=2.0及 8.6 Hz,1 H); 7.70 (d,/=8.6 Hz,1 H); 8.13 (d, «/=2.0 Hz,1 H); 8.27 (d,/=9.5 Hz,1 H); 12.00 (寬單峰,1 Η) 質譜:方法A 滯留時間Tr(分鐘)= 0.56 ; [M+H] + : m/z 482; [M-H]-: m/z 480 實例6S : N-{6-【(6-環丙基【1,2,4】***并【4,3-b】嗒畊-3-基)硫 烷基】-1,3-苯并噻唑-2-基卜2-(3-曱氧基吡咯啶-1-基)己醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]· 1,3-苯并噻唑-2-基}-2-(3 -曱氧基吡咯啶-1-基)乙醯胺可如 實例24製備’但以〇.4 g 2-氣-#-{6-[(6-環丙基[1,2,4]*** 并[4,3-6]嗒呻-3-基)硫烷基]·ι,3·苯并噻唑-2-基}乙醯胺、 0.172 g 3-曱氧基吡咯啶鹽酸鹽及〇 4〇 cm3 Ν-乙基二異丙胺 於8 cm3二甲亞砜中之溶液為起始物。二氧化矽管柱急驟 層析[溶離劑:二氣甲烷/曱醇(95/5,以體積計)]之後,獲 得0.228 g呈白色固體狀之Ν-{6_[(6·環丙基[1,2,4]***并 [4,3-b]嗒畊-3·基)硫烷基]·1,3-笨并噻唑基)-2-(3-曱氧基 。比咯啶-1-基)乙醯胺,其特徵如下: 熔點:212-229。(:(步奇) 1Η NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m, 2 H); 154635.doc •148· 201202242 1.07 (m, 2 H); 1.68 (m, 1 H); 1.99 (m, 1 H); 2.22 (m, 1 H); 2.0 (m,2 H); 2.72 (m, 1 H); 2.86 (dd,J=6.1 及 10.0 Hz, 1 H); 3.18 (s, 3 H); 3.45 (s, 2 H); 3.89 (m, 1 H); 7.30 (d, >9.5 Hz,1 H); 7.48 (dd,*7=2.0及 8.3 Hz,1 H); 7.70 (d, ^=8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d, J=9.5 Hz, 1 H); 12.03 (寬單峰,! h) 質譜:方法A 滯留時間Tr(分鐘)=〇.6〇 ; [M+H] + : m/z 482; [M-H]-: m/z 480 實例66 : N-{6-[(6-環丙基丨1,2,4】***并[4,3_b】嗒畊-3·基)琉 烷基]-1,3-苯并噻唑_2-基}-2-[3-(二乙基胺基)吡咯啶基】 乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}_2-[3-(二乙基胺基)吡咯啶_丨_基]乙醯胺 可如實例24製備’但以〇.4 g 2-氣-iV-{6-[(6-環丙基H4] 一 0坐并[4,3-ά]。合p井-3-基)硫烧基]-ΐ,3·苯并〇塞。坐_2_基丨乙醯 胺、0.177§队:^-二乙基吡咯啶-3-胺及〇.18〇(;1113>^乙基二 異丙胺於8 cm3二甲亞颯中之溶液為起始物。二氧化矽管 柱急驟層析[溶離劑:二氣甲烷/曱醇(80/20,以體積計之 後,獲得0.157§呈白色固體狀之1^{6_[(6_環丙基[1,2,4]三 唾并[4,3-b]塔畊-3 -基)硫烧基]-1,3 -苯并σ塞唆_2_基 (二乙基胺基)吡咯啶-1-基]乙醯胺,其特徵如下: 熔點:128-162°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm), DMSO-d6): 〇 91 (m 8 H)· 154635.doc -149- 201202242 1.08 (m, 2 H); 1.62 (m, 1 H); 1.94 (m, 1 H); 2.21 (m, 1 H); 2·53 (經遮蔽之多重蜂,6 H); 2.65 (m, 2 H); 2.76 (t,《7=8.1 Hz, 1 H); 3.43 (m, 2 H); 7.30 (d, /=9.5 Hz, 1 H); 7.48 (dd, •7=2.0及 8.6 Hz, 1 H); 7.69 (d, *7=8.6 Hz,1 H); 8.13 (d, •/=2.0 Hz,1 H); 8.27 (d,*7=9.5 Hz,1 H); 12.10 (寬單峰,1 Η)Mass Spectrometry: Method A Retention time Tr (minutes) = 0.26; [M+H] + : m/z 324 Example 64: N-{6-[(6-cyclopropyl[H4]triazolo[4 3 b]嗒耕·3•yl)sulfanyldiphenyl 1,3-benzothiazol-2-yl}_2_(4-hydroxypiperidinyl)acetamidamine N-{6-[(6-cyclopropyl(1) ]. Sit and [4,3 outer oxime ·3·yl)sulfanyl]_1,3-benzothiazol-2-yl}-2-(4-hydroxypiperidin-indole-yl)acetamidine The amine can be prepared as in Example 24, but with 〇·4 g 2_chloro term _{6_[(6-cyclopropyl[124]triazolo[4,3-6]indole-3-yl)sulfanyl Benzothiazole-2-yl}acetamide, 0.172 g piperidin-4-ol hydrochloride and 40.40 cm3 N-ethyldiisopropylamine in 8 cm monothyl sulfoxide> The original. After flash chromatography of ruthenium dioxide column [solvent: dichloromethane (methanol, 95/5 by volume)], 0.277 g of ruthenium {6_[(6-cyclo-bis-triazole) was obtained as a white solid. And [4,3_b]indole-3-yl)sulfanylbenzothiazolyl 2_(4-hydroxypiperidin-1-yl)acetamide, which has the following characteristics: melting point: 181-192 °c (step奇) 154635.doc -147- 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.09 (m, 2 H); 1.44 (m, 2 H); 1.71 (m, 2 H); 2.26 (m, 3 H); 2.76 (m, 2 H); 3.3 0 (shaded multiple peak, 2 H); 3.46 (m, 1 H); 4.53 (wide single peak , 1 H); 7.30 (d, "7=9.8 Hz, 1 H); 7.48 (dd, •/=2.0 and 8.6 Hz, 1 H); 7.70 (d, /=8.6 Hz, 1 H); 8.13 ( d, «/=2.0 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.00 (width single peak, 1 Η) Mass Spectrometry: Method A Residence time Tr (minutes) = 0.56 ; [M+ H] + : m/z 482; [MH]-: m/z 480 Example 6S: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒--3-yl)sulfanyl]-1,3-benzothiazol-2-yl-2-(3-decyloxypyrrolidin-1-yl)hexylamine N-{6-[(6 -cyclopropyl[1,2,4]triazolo[ 4,3-b]indol-3-yl)sulfanyl]·1,3-benzothiazol-2-yl}-2-(3-methoxypyrrolidin-1-yl)acetamide Prepared as in Example 24 but with 〇.4 g 2-gas-#-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6]indol-3-yl Sulfoalkyl]·ι,3·benzothiazol-2-yl}acetamide, 0.172 g 3-methoxypyrrolidine hydrochloride and 〇4〇cm3 Ν-ethyldiisopropylamine in 8 cm3 The solution in sulfoxide is the starting material. After flash chromatography of the ruthenium dioxide column [solvent: di-methane/decanol (95/5 by volume)], 0.228 g of ruthenium-{6_[(6·cyclopropyl) was obtained as a white solid. 1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]·1,3- benzothiazolyl)-2-(3-decyloxy.pyrrolidine -1-yl) acetamamine, which has the following characteristics: Melting point: 212-229. (:(step) 1Η NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 154635.doc •148· 201202242 1.07 (m, 2 H); 1.68 (m, 1 H); 1.99 (m, 1 H); 2.22 (m, 1 H); 2.0 (m, 2 H); 2.72 (m, 1 H); 2.86 (dd, J=6.1 and 10.0 Hz, 1 H) 3.18 (s, 3 H); 3.45 (s, 2 H); 3.89 (m, 1 H); 7.30 (d, > 9.5 Hz, 1 H); 7.48 (dd, *7=2.0 and 8.3 Hz, 1 H); 7.70 (d, ^=8.6 Hz, 1 H); 8.14 (d, /=2.0 Hz, 1 H); 8.27 (d, J=9.5 Hz, 1 H); 12.03 (wide unimodal,! h) Mass Spectrometry: Method A Retention time Tr (minutes) = 〇.6〇; [M+H] + : m/z 482; [MH]-: m/z 480 Example 66: N-{6-[(6 -cyclopropyl hydrazine 1,2,4]triazolo[4,3_b]indole-3·yl)decyl]-1,3-benzothiazole_2-yl}-2-[3-( Diethylamino)pyrrolidinyl] acetamidine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfide Alkyl]-1,3-benzothiazol-2-yl}_2-[3-(diethylamino)pyrrolidinyl-yl]acetamide can be prepared as in Example 24 but with 〇.4 g 2-gas-iV-{6-[(6-cyclopropylH4]- 0 sits and [4,3-ά]. p--3-yl)thioalkyl]-ΐ,3·benzopyrene塞. Sitting_2_基丨乙Amine, 0.177 § team: ^-diethylpyrrolidine-3-amine and 〇.18〇 (;1113>^ethyldiisopropylamine in 8 cm3 of dimethyl hydrazine as a starting material. Column flash chromatography [solvent: di-methane/decyl alcohol (80/20, after volume, obtained 0.157 § as a white solid 1^{6_[(6_cyclopropyl[1,2,4 Trisin[4,3-b]tung-3-yl)thiol]-1,3-benzo-xetazine-2-yl (diethylamino)pyrrolidin-1-yl] Acetamine, which has the following characteristics: Melting point: 128-162 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 〇91 (m 8 H)· 154635.doc -149- 201202242 1.08 (m, 2 H); 1.62 (m, 1 H); 1.94 (m, 1 H); 2.21 (m, 1 H); 2·53 (masked multiple bees, 6 H); 2.65 (m , 2 H); 2.76 (t, "7=8.1 Hz, 1 H); 3.43 (m, 2 H); 7.30 (d, /=9.5 Hz, 1 H); 7.48 (dd, •7=2.0 and 8.6 Hz, 1 H); 7.69 (d, *7=8.6 Hz, 1 H); 8.13 (d, •==2.0 Hz, 1 H); 8.27 (d, *7=9.5 Hz, 1 H); 12.10 ( Wide single peak, 1 Η)

質譜:方法A 滯留時間Tr(分鐘)=〇·59 ; [M+H] + : m/z 523; [M-H]-: m/z 521 實例67 : N-{6-[(6-環丙基丨1,2,4]***并[4,3-b]嗒畊-3·基)硫 烷基】-1,3-苯并噻唑-2-基}-2-[3-(2-乙氧基乙氧基)吼咯啶-1 -基]乙酿胺 >^-{6-[(6-環丙基[1,2,4]***并[4,3-15]嗒畊-3-基)硫烷基]· I,3-苯并噻唑_2-基}_2-[3-(2-乙氧基乙氧基)°比咯啶-1-基]乙 酿胺可如實例24製備,但以〇.4 g 2-氯-AM6-K6-環丙基 [1,2,4]***并[4,3-6]嗒《»井-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醢胺、0.244 g 3-(2-乙氧基乙氧基)吡咯啶鹽酸鹽及 0.4〇0 cm3 N-乙基二異丙胺於8 cm3二曱亞砜中之溶液為起 始物。二氧化矽管柱急驟層析[溶離劑:二氣甲烷/曱醇 (95/5,以體積計)]之後,獲得〇179 g呈白色固體狀之n_ {6-[(6-環丙基Π,2,4]***并[4,3_b]嗒啡_3基)硫烷基w,% 苯并噻唑-2-基}-2-[3-(2-乙氧基乙氧基)吡咯啶_丨_基]乙醯 胺,其特徵如下: 熔點:128-134°C (步奇) 154635.doc 201202242 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.90 (m,2 H); 1.08 (m, 5 H); 1.68 (m, 1 H); 2.02 (m, 1 H); 2.23 (m, 1 H); 2.60 (m,2 H); 2.73 (q,J=8.3 Hz,1 H); 2.86 (dd,《7=6.1 及 10.0 Hz,1 H); 3.37至 3·53 (m,8 H); 4.03 (m,1 H); 7.30 (d, /=9.8 Hz,1 H); 7.48 (dd,《7=2.0及 8.6 Hz, 1 H); 7.69 (d, •7=8.6 Hz, 1 H); 8.13 (d,>7=2.0 Hz,1 H); 8.27 (d, «/=9.5 Hz, 1 H); 12.12 (寬單峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.65 ; [M+H] + : m/z 540; [M-H]-: m/z 538 實例68:2-【4-(1-環丙基乙基)哌畊_1-基】_1^_{6_【(6_環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基】-l,3_苯并噻唑_2_ 基}乙醯胺 2-[4-(1-環丙基乙基)哌畊_丨_基]環丙基[124] ***并[4,3-b]嗒畊-3-基)硫烷基卜丨,%苯并噻唑_2•基}乙醯 胺可如實例24製備,但以0.4 g 2_氣劣_{6_[(6環丙基 [1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基卜丨,%苯并噻唑·2_ 基}乙醯胺、0.283 g 1-(1-環丙基乙基)哌畊二鹽酸鹽及〇.6〇 cm3 N-乙基二異丙胺於8 cm3二曱亞砜中之溶液為起始物。 二氧化矽管柱急驟層析[溶離劑:二氯曱烷/甲醇(95/5,以 體積計)]之後,獲得0‘187 g呈白色固體狀之2_[4_(1_環丙基 乙基)旅畊-1-基]-N-{6-[(6-環丙基⑴以]***并[4,3_b]塔 畊-3-基)硫烷基]-1,3-苯并噻唑_2_基}乙醯胺,其特徵如 154635.doc •151· 201202242 熔點:156-176°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): -0.02 (m,1 H); 0.23 (m,1 H); 0.38 (m,l H); 0.51 (m,1 H); 0.71 (m,1 H); 0.92 (m, 2 H); 1.04 (d, J=6.6 Hz, 3 H); 1.08 (m, 2 H); 1.68 (m, 1 H); 2.22 (m,1 H); 2.52至 2.58 (m,6 H); 2.66 (m, 2 H); 3.31 (寬單峰,2 H); 7.30 (d,/=9.5 Hz,1 H); 7.48 (dd, •7=2.0及 8.3 Hz,1 H); 7.70 (d,*7=8.6 Hz,1 H); 8.14 (d, •7=2.0 Hz, 1 H); 8.27 (d,《/=9.5 Hz,1 H); 12.00 (寬單峰,i H) 質譜:方法A 滞留時間Tr(分鐘)=3.42 ; [M+H] + : m/z 535 實例69 : N-{6-[(6-環丙基[i,2,4]***并[4,3-b】嗒畊-3-基)硫 燒基】-1,3-苯并嗟嗤-2-基}-2-(1-甲基旅咬-4-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}-2·(1-甲基哌咬-4-基)乙醯胺可以如下 方式製備: 向0.4 g 6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫燒 基]-1,3-苯并噻唑-2-胺、0.273 g (1-甲基哌啶-4-基)乙酸鹽 酸鹽、0.014 g N,N-二甲基吡啶-4-胺及0.96 cm3 N-乙基二 異丙胺於1 _5 cm3 2-甲基四氫呋喃中之懸浮液中逐滴添加 1.35 g 2,4,6-二氧化2,4,6-三乙基-1,3,5,2,4,6-三氧雜三亞膦 烧。在約70°C之溫度下加熱所得橙色溶液約1小時。 冷卻至約20°C之後’將混合物傾倒於50 cm3水中且藉由 154635.doc •152- 201202242 添加1 N碳酸氫鈉使pH值達到約8-9。用50 cm3二氣曱烷萃 取混合物三次。用50 cm3水及50 cm3飽和氯化納水溶液洗 滌經合併之有機相三次,經硫酸鎂乾燥,過濾且在減壓下 濃縮至乾。二氧化矽管柱急驟層析[溶離劑:二氣曱烷/甲 酵/28%氨水(80/10/1,以體積計)]之後,獲得0.121 g呈白 色固體狀之N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒喷-3-基)硫烧基]-1,3 -苯并售"坐-2 -'基}-2-(1-曱基d底咬_4_基)乙醯 胺,其特徵如下: 熔點:235-257°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.08 (m,2 H); 1.23 (dt,《7=3.9及 12.0及 12.2 Hz,2 H); 1.60 (d,*/=14.2 Hz, 2 H); 1.73 (m,1 H); 1·83 (td,/=2.0及 11.7 Hz,2 H); 2.12 (s,3 H); 2.22 (tt,《7=4.9及 8.2 Hz,1 H); 2·41 (d, J=1 Λ Hz, 2 H); 2.71 (d, 7=11.7 Hz, 2 H); 7.30 (d, 7=9.5Mass Spectrometry: Method A Retention time Tr (minutes) = 〇·59; [M+H] + : m/z 523; [MH]-: m/z 521 Example 67: N-{6-[(6-cyclopropyl) Base 1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[3-(2 -ethoxyethoxy)pyrrolidin-1 -yl]ethanoamine>^-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-15] Indole-3-yl)sulfanyl]·I,3-benzothiazol-2-yl}_2-[3-(2-ethoxyethoxy)°-pyrrolidin-1-yl] The amine can be prepared as in Example 24, but with 4 g of 2-chloro-AM6-K6-cyclopropyl[1,2,4]triazolo[4,3-6]indole» well-3-yl) Sulfoalkyl]-1,3-benzothiazol-2-yl}acetamide, 0.244 g 3-(2-ethoxyethoxy)pyrrolidine hydrochloride and 0.4〇0 cm3 N-ethyl A solution of isopropylamine in 8 cm3 of disulfoxide was used as a starting material.二 〇 〇 〇 急 急 急 急 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Π,2,4]triazolo[4,3_b]indanyl-3-yl)sulfanyl w,% benzothiazol-2-yl}-2-[3-(2-ethoxyethoxy) Pyrrolidine 丨 基 yl acetamide, which has the following characteristics: Melting point: 128-134 ° C (step) 154635.doc 201202242 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.90 (m , 2 H); 1.08 (m, 5 H); 1.68 (m, 1 H); 2.02 (m, 1 H); 2.23 (m, 1 H); 2.60 (m, 2 H); 2.73 (q, J =8.3 Hz,1 H); 2.86 (dd, "7=6.1 and 10.0 Hz, 1 H); 3.37 to 3.53 (m,8 H); 4.03 (m,1 H); 7.30 (d, /= 9.8 Hz,1 H); 7.48 (dd, "7=2.0 and 8.6 Hz, 1 H); 7.69 (d, •7=8.6 Hz, 1 H); 8.13 (d,>7=2.0 Hz, 1 H 8.27 (d, «/=9.5 Hz, 1 H); 12.12 (width unimodal, 1 H) Mass Spectrum: Method A residence time Tr (minutes) = 0.65; [M+H] + : m/z 540; [MH]-: m/z 538 Example 68: 2-[4-(1-cyclopropylethyl)piped-1-yl]_1^_{6_[(6_cyclopropyl[1,2, 4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-l,3_ Benzothiazole_2_yl}acetamide 2-[4-(1-cyclopropylethyl)piped-indole-yl]cyclopropyl[124]triazolo[4,3-b] 3-yl)sulfanyldiazine,%benzothiazole-2-yl}acetamide can be prepared as in Example 24, but with 0.4 g 2 _ _{6_[(6 cyclopropyl [1, 2, 4] Triazolo[4,3-6]indole-3-yl)sulfanyldiazine,%benzothiazole·2_yl}acetamidamine, 0.283 g 1-(1-cyclopropylethyl) A solution of piperazine dihydrochloride and 〇.6〇cm3 N-ethyldiisopropylamine in 8 cm3 of disulfoxide was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dichloromethane (methanol) (95/5 by volume)], 2'[4_(1_cyclopropyl) was obtained as a white solid. ))-Lungry-1-yl]-N-{6-[(6-cyclopropyl(1)-]triazolo[4,3_b]-tata-3-yl)sulfanyl]-1,3-benzene And thiazol-2-yl}acetamide, which is characterized by 154635.doc • 151·201202242 Melting point: 156-176°C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): - 0.02 (m,1 H); 0.23 (m,1 H); 0.38 (m,l H); 0.51 (m,1 H); 0.71 (m,1 H); 0.92 (m, 2 H); d, J = 6.6 Hz, 3 H); 1.08 (m, 2 H); 1.68 (m, 1 H); 2.22 (m, 1 H); 2.52 to 2.58 (m, 6 H); 2.66 (m, 2 H); 3.31 (width unimodal, 2 H); 7.30 (d, /=9.5 Hz, 1 H); 7.48 (dd, •7=2.0 and 8.3 Hz, 1 H); 7.70 (d, *7=8.6 Hz,1 H); 8.14 (d, •7=2.0 Hz, 1 H); 8.27 (d, “/=9.5 Hz, 1 H); 12.00 (wide unimodal, i H) Mass Spectrometry: Method A Residence Time Tr (minutes) = 3.42; [M+H] + : m/z 535 Example 69: N-{6-[(6-cyclopropyl[i,2,4]triazolo[4,3-b]嗒Tung-3-yl)thiol]-1,3-benzoindole-2-yl}-2-(1-methyl咬-4-yl) acetamamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]- 1,3-Benzothiazol-2-yl}-2·(1-methylpiperidin-4-yl)acetamide can be prepared as follows: to 0.4 g of 6-[(6-cyclopropyl[1, 2,4]triazolo[4,3-6]indole-3-yl)thioalkyl]-1,3-benzothiazol-2-amine, 0.273 g (1-methylpiperidin-4- Add 1.35 g dropwise to a suspension of acetic acid hydrochloride, 0.014 g of N,N-dimethylpyridin-4-amine and 0.96 cm3 of N-ethyldiisopropylamine in 1 _5 cm3 of 2-methyltetrahydrofuran. 2,4,6-Dioxide 2,4,6-triethyl-1,3,5,2,4,6-trioxatriphosphonazo. The resulting orange solution was heated at a temperature of about 70 ° C for about 1 hour. After cooling to about 20 ° C, the mixture was poured into 50 cm 3 of water and the pH was brought to about 8-9 by the addition of 1 N sodium bicarbonate by 154635.doc • 152-201202242. The mixture was extracted three times with 50 cm3 of dioxane. The combined organic phases were washed with EtOAc EtOAc EtOAc. After the flash chromatography of the ruthenium dioxide column [solvent: dioxane / methyl ester / 28% ammonia (80/10/1, by volume)], 0.121 g of N-{6- was obtained as a white solid. [(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)thiol]-1,3-benzo-selling "sitting-2 -' The base -2-(1-indolyl d bottom _4_yl) acetamidine, which has the following characteristics: Melting point: 235-257 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO -d6): 0.92 (m, 2 H); 1.08 (m, 2 H); 1.23 (dt, "7=3.9 and 12.0 and 12.2 Hz, 2 H); 1.60 (d, */=14.2 Hz, 2 H ); 1.73 (m,1 H); 1·83 (td, /=2.0 and 11.7 Hz, 2 H); 2.12 (s,3 H); 2.22 (tt, "7=4.9 and 8.2 Hz, 1 H) ; 2·41 (d, J=1 Λ Hz, 2 H); 2.71 (d, 7=11.7 Hz, 2 H); 7.30 (d, 7=9.5

Hz,1 H); 7·47 (dd,·7=2·0及 8.3 Hz,1 H); 7.68 (d,《7=8.6 Hz, 1 H); 8.12 (d, y=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H); 1236 (寬單峰,i h) 質譜:方法A 滯留時間Tr(分鐘)=0.60 ; [M+H] + : m/z 480; [M-H]-: m/z 478 實例70 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒畊-3-基)硫 烷基1-1,3-苯并噻唑-2-基卜2-(1-甲基哌啶-2-基)乙酿胺 Ν·{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊_3_基)硫烷基]-1,3-笨并噻唑_2_基}_2_(ι_曱基派咬_2-基)乙醯胺可如實例 154635.doc -153- 201202242 69製備’但以0.4 g 6-[(6-環丙基[1,2,4]***并[4,3-6]塔啡-3-基)硫烧基]-1,3-苯并0塞0坐-2-胺、0.22 g (1-曱基〇底咬_2_ 基)乙酸、0.014 g Ν,Ν-二甲基0比咬-4-胺、0.723 cm3 Ν-乙 基二異丙胺及1.35 g 2,4,6-三氧化2,4,6-三乙基-1,3,5,2,4,6- 三氧雜三亞膦烧為起始物。二氧化矽管柱急驟層析[溶離 劑:二氣甲烷/曱醇(95/5 ’以體積計)]之後,獲得〇 186 g 呈白色固體狀之N-{6-[(6-環丙基[1,2,4]***并[4,3-b]。荅_ -3-基)硫烧基]-1,3 -苯并°塞°坐-2-基}-2-(1-曱基π底咬_2_基)乙 醯胺,其特徵如下: 熔點:209-214°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.08 (m,2 H); 1.28 (m,2 H); 1.38至 1.66 (m,4 H); 2.10 (td, •/=2.7及11.〇沿,111);2.21(111,4 11);2_55(經遮蔽之多重 峰,2 H); 2.74 (m,2 H); 7.29 (d,*7=9.5 Hz,1 H); 7.47 (dd, J_2.1 及 8.4 Hz, 1 H); 7.68 (d,7=8.6 Hz,1 h); 8 11 (d, •7=1.5 Hz,1 H); 8.27 (d,7=9.5 Hz,1 H); 12.49 (寬單蜂,i Η) 質譜:方法A 滯留時間Tr(分鐘)=0.63 ; [M+H] + : m/z 480; [M-H]-: m/z 478 實例71 : N-{6-[(6-環丙基[1,2,4]***并[4,3-b】嗒畊_3_基)硫 烧基]-1,3-苯并嗟嗅-2-基}-2-(1-甲基π比洛咬-3·基)乙酿胺 1^-{6-[(6-環丙基[1,2,4]三〇坐并[4,3-1)]。荅《>井_3_基)硫烧基]_ 1,3 -笨并售嗤-2-基}-2-(1-甲基β比洛咬-3-基)乙酿胺可如實 154635.doc -154- 201202242 例69製備’但以(Μ g 6_[(6_環丙基[124]***并[43_h嗒 ’-3-基)硫烷基]-1,3-苯并噻唑_2-胺、0.202 g (1-甲基吡咯 咬-3-基)乙酸、0.014 g N,N-二甲基吡啶-4-胺、0.723 cm3 N-乙基二異丙胺及1.35 g 2,4,.6-三氧化2,4,6-三乙基· 1,3,5,2,4,6-三氧雜三亞膦烧於1.5 cm3 2 -曱基四氫吱喃中之 溶液為起始物《二氧化矽管柱急驟層析[溶離劑:二氣甲 烧/甲醇(80/20,以體積計)]之後,獲得0125 g呈白色固體 狀之N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(1-甲基。比咯啶基)乙醯胺,其 特徵如下: 熔點:216-222°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1·〇8 (m, 2 H); 1.41 (m, 1 H); 1.97 (m, 1 H); 2.21 (m, 5 H); 2-45 (m, 2 H); 2.57 (m, 3 H); 2.65 (m, 1 H); 7.30 (d, 7=9.5Hz, 1 H); 7·47 (dd, ·7=2·0 and 8.3 Hz, 1 H); 7.68 (d, "7=8.6 Hz, 1 H); 8.12 (d, y=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H); 1236 (width unimodal, ih) Mass Spectrum: Method A Retention time Tr (minutes) = 0.60; [M+H] + : m/z 480; MH]-: m/z 478 Example 70: N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl 1-1,3-benzothiazol-2-yl-2-(1-methylpiperidin-2-yl)ethinylamine·{6-[(6-cyclopropyl[1,2,4] Triazolo[4,3-b]indole_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}_2_(ι_曱基派咬_2-yl)acetamide Can be prepared as in Example 154635.doc -153- 201202242 69 but with 0.4 g of 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6] talyn-3-yl) Sulfur-based]-1,3-benzox0-oxan-2-amine, 0.22 g (1-mercaptopurine base 2_) acetic acid, 0.014 g hydrazine, Ν-dimethyl 0 ratio bite-4 -amine, 0.723 cm3 Ν-ethyldiisopropylamine and 1.35 g 2,4,6-trioxide 2,4,6-triethyl-1,3,5,2,4,6-trioxatriphosphine Burn as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: di-methane/sterol (95/5 'by volume)], N-{6-[(6-cyclopropyl) was obtained as a white solid in 〇 186 g. [1,2,4]triazolo[4,3-b].荅_-3-yl)thiol]-1,3-benzo-°°°-2-yl}-2-( 1-indenyl π-bottom _2-yl) acetamamine, which has the following characteristics: Melting point: 209-214 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 ( m,2 H); 1.08 (m,2 H); 1.28 (m,2 H); 1.38 to 1.66 (m,4 H); 2.10 (td, •/=2.7 and 11. 〇, 111); 2.21 (111, 4 11); 2_55 (multiple peaks obscured, 2 H); 2.74 (m, 2 H); 7.29 (d, *7 = 9.5 Hz, 1 H); 7.47 (dd, J_2.1 and 8.4 Hz, 1 H); 7.68 (d, 7 = 8.6 Hz, 1 h); 8 11 (d, • 7 = 1.5 Hz, 1 H); 8.27 (d, 7 = 9.5 Hz, 1 H); 12.49 (width Single bee, i Η) Mass spectrum: Method A Retention time Tr (minutes) = 0.63; [M+H] + : m/z 480; [MH]-: m/z 478 Example 71: N-{6-[( 6-cyclopropyl[1,2,4]triazolo[4,3-b]indole_3_yl)thioalkyl]-1,3-benzoindole-2-yl}-2- (1-Methyl π 洛洛 bit-3·yl) Ethylamine 1^-{6-[(6-cyclopropyl[1,2,4] 三〇 And [4, 3-1)].荅 "> well _3_ base) sulphide] _ 1,3 - stupid and sold 嗤-2-yl}-2-(1-methylβ piroxime-3-yl) 154635.doc -154- 201202242 Example 69 Preparation 'but with (Μ g 6_[(6-cyclopropyl[124]triazolo[43_h嗒'-3-yl)sulfanyl]-1,3-benzo) Thiazole-2-amine, 0.202 g (1-methylpyrrole-3-yl)acetic acid, 0.014 g N,N-dimethylpyridin-4-amine, 0.723 cm3 N-ethyldiisopropylamine and 1.35 g 2 ,4,.6-a solution of 2,4,6-triethyl·1,3,5,2,4,6-trioxatriphosphine in 1.5 cm3 2 -mercaptotetrahydrofuran After the starting material "cerium dioxide column flash chromatography [solvent: two gas aeration / methanol (80 / 20, by volume)], obtained 0125 g as a white solid N-{6-[( 6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-( 1-Methyl.pyrrolidyl)acetamide, which has the following characteristics: Melting point: 216-222 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1·〇8 (m, 2 H); 1.41 (m, 1 H); 1.97 (m, 1 H); 2.21 (m, 5 H); 2-45 (m, 2 H); 2.57 (m, 3 H); 2.65 (m, 1 H); 7.30 (d , 7=9.5

Hz,1 H); 7.48 (dd,/=2.0及 8.6 Hz,1 H); 7.69 (d,*7=8.6 Hz, 1 H); 8.13 (d, /=2.0 Hz, 1 H); 8.27 (d, 7=9.5 Hz, 1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.59 ; [M+H] + :m/z 466; [M-H]-: m/z 464 實例72 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b]嗒畊·3-基)硫烷基]_ 1,3-苯并噻唑_2-基}-4-甲基嗎啉-2-甲醯胺 n_{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3_基)硫烷基]_ 1,3 -本并"塞唾-2-基}-4-甲基嗎琳-2-甲醯胺可如實例69製 154635.doc •155· 201202242 備,但以0.4 g 6-[(6-環丙基***并[43_0]嗒畊_3_基) 硫烷基]-1,3-苯并噻唑_2·胺、〇·256 g 4•甲基嗎啉_2_甲酸鹽 酸鹽、0.014 g N,N-二甲基吡啶_4_胺、〇 963 cm3 N乙基二 異丙胺及1.35 g 2,4,6-三氧化2,4,6-三乙基_1,3,5,2,4,6-三氧 雜三亞膦烷於1.5 cm3 2-曱基四氫呋喃中之溶液為起始 物。二氧化矽管柱急驟層析[溶離劑:二氣曱烷/甲醇 (95/5,以體積計)]之後,獲得0.136 g呈白色固體狀之义 {6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]_13· 笨并β塞》坐-2-基}-4-曱基嗎琳_2-曱醯胺,其特徵如下: 熔點:179°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.91 (m,2 H); 1.0B (m, 2 H); 2.17 (m, 6 H); 2.54 (m, 1 H); 2.85 (dd, J=1.7 &11.5Hz,lH);3.61(ddd,《/=2.7&10.0&11.2Hz,lH); 3.91 (dt,《7=3.1 及 11·3 Hz,1 H); 4.32 (dd,/=2.9及 9.0 Hz,1 H); 7.30 (d,*7=9.5 Hz,1 H); 7.48 (dd,/=2.0及 8.6 Hz,1 H); 7.71 (d, J=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, •/=9.5 Hz,1 H); 12.22 (寬單峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 468; [M-H]-: m/z 466 實例73 : N-{6-【(6-環丙基[1,2,4】***并丨4,3-b】嗒畊-3-基)硫 烷基卜1,3-苯并噻唑-2-基}-1-甲基哌啶-3-甲醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫炫基]_ 1,3_笨并噻唑-2-基}-1-甲基哌啶-3-曱醯胺可如實例69製 154635.doc -156- 201202242 備,但以0.4 g 6-[(6-環丙基[ι,2,4]***并[4,3-6]嗒。井基) 硫烷基]-1,3-苯并噻唑-2-胺、0 253 g丨_甲基哌啶_3_甲酸鹽 酸鹽、0.014 g N,N-二甲基吡啶_4_胺、〇 963 cm3 N_乙基二 異丙胺及1.35 g 2,4,6-三氧化2,4,6-三乙基-1,3,5,2,4,6-三氧 雜二亞膦烷於1.5 cm3 2-甲基四氫呋喃中之溶液為起始 物。二氧化矽管柱急驟層析[溶離劑:二氯甲烷/甲醇 (90/10,以體積計)]之後,獲得〇 212 §呈白色固體狀之ν· {6-[(6-環丙基[l,2,4]***并[4,3_b]嗒畊_3_基)硫烷基]13_ 苯并噻唑-2-基}-1-甲基哌啶_3-甲醯胺,其特徵如下: 熔點:248-25 1°C (步奇) 1H NMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 0.92 (m,2 H); 1.08 (m, 2 H); 1.47 (m, 2 H); 1.67 (m, 1 H); 1.84 (m, 1 H); 1.94 (t, 7=10.3 Hz, 1 H); 2.13 (ts J=l〇.〇 Hz, 1 H); 2.21 (m, 4 H); 2.63 (d, 7=11.5 Hz, 1 H); 2.80 (m, 2 H); 7.30 (d, */=9.8 Hz,1 H); 7.47 (dd,*7=2.0及 8.6 Hz,1 H); 7.69 (d, ^=8.3 Hz, 1 H); 8.12 (d, J=2.0 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.42 (寬單峰,1 H) 質譜:方法A 滯留時間丁1*(分鐘)=0.61; [M+H] + : m/z 466; [M-H]-: m/z 464 實例74 : N-{6-[(6-環丙基[1,2,4】***并[4,3-b】嗒畊-3-基)硫 烷基】-1,3-苯并噻唑-2-基}-1-甲基哌啶-4-甲醯胺 >^-{6-[(6-環丙基[1,2,4]***并[4,3-1)]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基} -1 -曱基哌啶-4-曱醯胺可如實例69製 154635.doc -157- 201202242 備’但以0‘4 g 6-[(6·環丙基[1,2,4]***并[4,3-6]嗒啩-3-基) 硫烷基]-1,3-苯并噻唑胺、〇 253 g卜曱基哌啶甲酸鹽 酸鹽、0.014 g N,N_二曱基吡啶·4_胺、ο.%〗cm3 N_乙基二 異丙胺及1,35 g 2,4,6-三氧化2,4,6-三乙基-1,3,5,2,4,6-三氣 雜三亞膦烷於丨.5 cm3 2_曱基四氫呋喃中之溶液為起始 物。一氧化矽管柱急驟層析[溶離劑:二氣甲烷/甲醇 (9〇/1〇,以體積計)]之後,獲得0.210 g呈白色固體狀之Ν· {卜以-環丙基以又^***并^义心荅命小基㈣烷基卜^· 苯并噻唑-2-基}-1_曱基哌啶·4_甲醯胺,其特徵如下: 熔點:261_270°C(步奇) 1H NMRtf(400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1·〇8 (m,2 H); 1.64 (qd,/=3.2及 13.0 Hz,2 H); 1.84 (m,4 H); 2.16 (s, 3 H); 2.22 (m, 1 H); 2.46 (m, 1 H); 2.81 (d, ^=11.7 Hz, 2 H); 7.30 (dj y=9.5 Hz, 1 H); 7.47 (dd, 7=2.0 及 8.3 Hz, 1 H); 7.69 (d,J=8.6 Hz,1 H); 8.13 (d,*/=2.0 Hz, 1 H); 8.27 (d,J=9.5 Hz,1 H); 12.36 (寬單峰,1 H) 質譜:方法A 滞留時間Tr(分鐘)=0.59 ; [M+H] + : m/z 466; [M-H]-: m/z 464 實例75 : 2-[l-(環丙基甲基)旅咬-4-基】-N-{6· [(6-環丙基 【1,2,4】***并[4,3-b]嗒畊-3-基)硫烷基】_1,3-笨并嗟唑_2_ 基}乙酿胺 a)2-[l_(環丙基甲基)哌啶_4_基]-N-{6-[(6-環丙基[12 4] 三。坐并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯 -158- 154635.doc 201202242 胺可如實例69製備,但以〇·4 g 6_[(6_環丙基[^,糾***并 [4,3 6]荅井-3-基)硫烧基]_ 1,3_苯并嘆唾胺、〇 330 g [1_ (環丙基曱基)哌啶_4_基]乙酸鹽酸鹽、〇 〇14 g n,n_二甲基 吡咬-4-胺、0.963 cm3 N-乙基二異丙胺及135 g 2,4,6_三氧 化2,4,6-三乙基mw—三氧雜三亞膦烷於15⑽3 2_甲 基四氫呋喃中之溶液為起始物。二氧化矽管柱急驟層析 [溶離劑:二氣甲烷/甲醇(90/10,以體積計)]之後,獲得 0.069 g呈白色固體狀之(環丙基曱基)哌啶_4基]N_ {6-[(6-環丙基[i’2,4]***并[4,3_b]嗒畊_3基)硫烷基]_13· 苯并噻唑-2-基}乙醯胺,其特徵如下: 熔點:229-233°C (步奇) 1H 1NJMR譜(400 ΜΗζ,δ (ppm),DMSO-d6): 〇.〇4 (m,2 H); 0.43 (m, 2 H); 0.79 (m, 1 H); 0.93 (m, 2 H); 1.08 (m, 2 H); 1.22 (m, 2 H); 1.63 (d, J=12.5 Hz, 2 H); 1.75 (m, 1 H); 1.89 (t, /=11.0 Hz, 2 H); 2.13 (d, J=6.6 Hz, 2 H); 2.22 (m, 1 H); 2.41 (d, J=6.8 Hz, 2 H); 2.91 (d, J=11.2 Hz, 2 H); 7.29 (d, •7=9.8 Hz,1 H); 7.47 (dd,*7=2.1 及 8.4 Hz,1 H); 7.67 (d, 7=8.8 Hz, 1 H); 8.11 (d, /=1.1 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.28 (寬單峰,1 H) 質譜:方法A 滯留時間Tr(分鐘)=0.66 ; [M+H] + : m/z 520; [M-H]-: m/z 518 b)[l-(環丙基甲基)哌啶-4-基]乙酸可如實例53-b製備, 但以0.509 g [1-(環丙基甲基)哌啶-4-基]乙酸乙酯及3.39 154635.doc -159- 201202242 cm 1 N氫氧化鈉水溶液於丨〇 cm3乙醇中之溶液為起始物。 獲得0.760 g呈白色固體狀之[丨_(環丙基甲基)哌啶_4基]乙 酸鹽酸鹽,其特徵如下:Hz,1 H); 7.48 (dd, /=2.0 and 8.6 Hz, 1 H); 7.69 (d, *7=8.6 Hz, 1 H); 8.13 (d, /=2.0 Hz, 1 H); 8.27 ( d, 7=9.5 Hz, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 466; [MH]-: m/z 464 Example 72: N-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]_1,3-benzothiazol-2-yl} 4-methylmorpholine-2-carboxamide n_{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3_yl)sulfane Base]_1,3-Ben and "Seda-2-yl}-4-methylmorphin-2-carboxamide can be prepared as in Example 69, 154635.doc • 155·201202242, but with 0.4 g 6 -[(6-cyclopropyltriazolo[43_0]嗒耕_3_yl) sulfanyl]-1,3-benzothiazolyl-2-amine, 〇·256 g 4•methylmorpholine_2 _Acetate, 0.014 g N,N-dimethylpyridine_4_amine, 〇963 cm3 Nethyldiisopropylamine and 1.35 g 2,4,6-trioxide 2,4,6-triethyl A solution of the base 1,3,5,2,4,6-trioxatriphosphinane in 1.5 cm3 of 2-decyltetrahydrofuran was used as a starting material. After flash chromatography of the ruthenium dioxide column [solvent: dioxane/methanol (95/5 by volume)], 0.136 g of a white solid was obtained as {6-[(6-cyclopropyl) 1,2,4]triazolo[4,3_b]indole _3_yl)sulfanyl]_13· stupid beta-supplement-2-yl}-4-mercaptoline_2-曱醯Amine, characterized by the following: Melting point: 179 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.91 (m, 2 H); 1.0B (m, 2 H); (m, 6 H); 2.54 (m, 1 H); 2.85 (dd, J=1.7 & 11.5 Hz, lH); 3.61 (ddd, "/=2.7&10.0&11.2 Hz, lH); 3.91 (dt, "7=3.1 and 11·3 Hz, 1 H); 4.32 (dd, /=2.9 and 9.0 Hz, 1 H); 7.30 (d, *7=9.5 Hz, 1 H); 7.48 (dd, /=2.0 and 8.6 Hz,1 H); 7.71 (d, J=8.6 Hz, 1 H); 8.14 (d, J=2.0 Hz, 1 H); 8.28 (d, •==9.5 Hz, 1 H) ; 12.22 (Wide single peak, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 468; [MH]-: m/z 466 Example 73: N-{ 6-[(6-cyclopropyl[1,2,4]triazoloindole 4,3-b]indol-3-yl)sulfanyldi-1,3-benzothiazol-2-yl}- 1-methylpiperidine-3-carboxamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4, 3-b] indole-3-yl)sulfanyl]_ 1,3_ benzothiazol-2-yl}-1-methylpiperidin-3-indanamine can be prepared as in Example 69 154635.doc - 156-201202242 Preparation, but with 0.4 g of 6-[(6-cyclopropyl[ι,2,4]triazolo[4,3-6]嗒. well base) sulfanyl]-1,3-benzene Thiazol-2-amine, 0 253 g 丨-methylpiperidine _3_formate, 0.014 g N,N-lutidine 4-amine, 〇963 cm3 N-ethyldiisopropylamine And 1.35 g of 2,4,6-trioxide 2,4,6-triethyl-1,3,5,2,4,6-trioxadiphosphine in 1.5 cm3 of 2-methyltetrahydrofuran The solution is the starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dichloromethane/methanol (90/10 by volume)], 〇212 § §·6-[(6-cyclopropyl) was obtained as a white solid. [l,2,4]triazolo[4,3_b]indole_3_yl)sulfanyl]13_benzothiazol-2-yl}-1-methylpiperidine-3-carbamide The characteristics are as follows: Melting point: 248-25 1 ° C (step) 1H NMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1.08 (m, 2 H); 1.47 ( m, 2 H); 1.67 (m, 1 H); 1.84 (m, 1 H); 1.94 (t, 7 = 10.3 Hz, 1 H); 2.13 (ts J=l〇.〇Hz, 1 H); 2.21 (m, 4 H); 2.63 (d, 7=11.5 Hz, 1 H); 2.80 (m, 2 H); 7.30 (d, */=9.8 Hz, 1 H); 7.47 (dd, *7= 2.0 and 8.6 Hz, 1 H); 7.69 (d, ^=8.3 Hz, 1 H); 8.12 (d, J=2.0 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.42 ( Broad single peak, 1 H) Mass spectrum: Method A residence time din 1* (minutes) = 0.61; [M+H] + : m/z 466; [MH]-: m/z 464 Example 74: N-{6 -[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}- 1-methylpiperidine-4-carboxamide>^-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1)]indole-3-yl Sulfox ]]-1,3-benzothiazol-2-yl}-1 -mercaptopiperidin-4-decylamine can be prepared as in Example 69 154635.doc -157- 201202242 备'but with 0'4 g 6- [(6·Cyclopropyl[1,2,4]triazolo[4,3-6]indol-3-yl)sulfanyl]-1,3-benzothiazolidine, 〇253 g Pyridinium hydrochloride, 0.014 g N,N-dimercaptopyridine·4_amine, ο.%〗 cm3 N-ethyldiisopropylamine and 1,35 g 2,4,6-trioxide 2,4 A solution of 6-triethyl-1,3,5,2,4,6-tris-heterotriphosphinane in cm.5 cm3 2 -mercaptotetrahydrofuran was used as a starting material. After flash chromatography of ruthenium oxide column [solvent: di-methane/methanol (9 〇/1 〇, by volume)], 0.210 g of ruthenium was obtained as a white solid. ^ Triazole and ^ 荅 荅 小 小 ( 四 四 四 四 四 四 四 ( ( · · · · · · · · · · · 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 261 Odd) 1H NMRtf (400 MHz, δ (ppm), DMSO-d6): 0.92 (m, 2 H); 1·〇8 (m, 2 H); 1.64 (qd, /=3.2 and 13.0 Hz, 2 H 1.84 (m,4 H); 2.16 (s, 3 H); 2.22 (m, 1 H); 2.46 (m, 1 H); 2.81 (d, ^=11.7 Hz, 2 H); 7.30 (dj y=9.5 Hz, 1 H); 7.47 (dd, 7=2.0 and 8.3 Hz, 1 H); 7.69 (d, J=8.6 Hz, 1 H); 8.13 (d, */=2.0 Hz, 1 H) ; 8.27 (d, J = 9.5 Hz, 1 H); 12.36 (wide unimodal, 1 H) Mass Spectrum: Method A Retention time Tr (minutes) = 0.59; [M+H] + : m/z 466; [MH ]-: m/z 464 Example 75: 2-[l-(cyclopropylmethyl)bend-4-yl]-N-{6·[(6-cyclopropyl[1,2,4]3 Azolo[4,3-b]indole-3-yl)sulfanyl]_1,3-benzoxazole-2-yl}ethylamine a)2-[l_(cyclopropylmethyl)piperidine _4_基]-N-{6-[(6-cyclopropyl[12 4] III. Sit and [4 ,3-b]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidine-158- 154635.doc 201202242 Amine can be prepared as in Example 69, but with 〇·4 g 6_[(6_cyclopropyl[^, triazolo[4,3 6]荅井-3-yl)thiol]_ 1,3_benzoxanthene, 〇330 g [1_ ( Cyclopropyl hydrazino)piperidine-4-yl]acetate hydrochloride, hydrazine 14 gn, n-dimethylpyridin-4-amine, 0.963 cm3 N-ethyldiisopropylamine and 135 g 2,4 A solution of 6_3,4,6-triethylmw-trioxatriphosphinane in 15(10)3-dimethyltetrahydrofuran is used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: di-methane/methanol (90/10 by volume)], 0.069 g of (cyclopropylindenyl)piperidine-4 base was obtained as a white solid. N_ {6-[(6-cyclopropyl[i'2,4]triazolo[4,3_b]indole_3yl)sulfanyl]_13·benzothiazol-2-yl}acetamidamine, Its characteristics are as follows: Melting point: 229-233 ° C (step) 1H 1NJMR spectrum (400 ΜΗζ, δ (ppm), DMSO-d6): 〇.〇4 (m, 2 H); 0.43 (m, 2 H) ; 0.79 (m, 1 H); 0.93 (m, 2 H); 1.08 (m, 2 H); 1.22 (m, 2 H); 1.63 (d, J = 12.5 Hz, 2 H); 1.75 (m, 1 H); 1.89 (t, /=11.0 Hz, 2 H); 2.13 (d, J=6.6 Hz, 2 H); 2.22 (m, 1 H); 2.41 (d, J=6.8 Hz, 2 H) 2.91 (d, J=11.2 Hz, 2 H); 7.29 (d, •7=9.8 Hz, 1 H); 7.47 (dd, *7=2.1 and 8.4 Hz, 1 H); 7.67 (d, 7= 8.8 Hz, 1 H); 8.11 (d, /=1.1 Hz, 1 H); 8.27 (d, /=9.5 Hz, 1 H); 12.28 (wide unimodal, 1 H) Mass Spectrometry: Method A Residence Time Tr ( Minutes) = 0.66; [M+H] + : m/z 520; [MH]-: m/z 518 b) [l-(cyclopropylmethyl)piperidin-4-yl]acetic acid as in Example 53 -b prepared, but with 0.509 g of [1-(cyclopropylmethyl)piperidin-4-yl]acetic acid 3.39 154635.doc -159- 201202242 cm and 1 N aqueous sodium hydroxide solution in ethanol Shu billion cm3 of solution as a starting material. 0.760 g of [丨_(cyclopropylmethyl)piperidin-4-yl]acetate was obtained as a white solid, which was characterized as follows:

Rf二氧化矽TLC=0.43 [溶離劑:氣仿/甲醇/28%氨水 (60/30/5,以體積計)]Rf cerium oxide TLC=0.43 [Eluent: gas imitation / methanol / 28% ammonia (60/30/5, by volume)]

質譜:方法A 滯留時間Tr(分鐘)=0.15 ; [M+H] + : m/z 198 c)U-(環丙基曱基)哌啶-4-基]乙酸乙酯可如實例63_〇製 備,但以0.500 g哌啶_4_基乙酸乙酯、〇 59 g (溴曱基)環丙 烷及3.80 g碳酸鉋於1〇 cm3乙腈中之溶液為起始物。二氧 化矽管柱急驟層析[溶離劑:二氯甲烷/甲醇(9〇/1〇,以體 積計)]之後,獲得0.509 g呈無色油狀之π_(環丙基曱基)哌 °定-4 -基]乙酸乙酯’其特徵如下:Mass Spectrometry: Method A Retention time Tr (minutes) = 0.15; [M+H] + : m/z 198 c) U-(cyclopropylindolyl)piperidin-4-yl]ethyl acetate as in Example 63_ Prepare, but start with a solution of 0.500 g of piperidinyl-4-ethyl acetate, hydrazine 59 g (bromomethyl)cyclopropane and 3.80 g of carbonic acid in 1 〇 cm 3 of acetonitrile. After flash chromatography of ruthenium dioxide column [solvent: dichloromethane / methanol (9 〇 / 1 〇, by volume)], 0.509 g of π_(cyclopropyl fluorenyl) piperidine was obtained as a colorless oil. -4 -yl]ethyl acetate' is characterized as follows:

Rf二氧化矽TLC=0.24 [溶離劑:氣仿/曱醇(9〇/1〇,以體 積計)] 質譜:方法A 滯留時間Tr(分鐘)=0.28 ; [M+H] + : m/z 226 實例76 : Ν·{6-[(6-環丙基[i,2,4]***并[43b】嗒畊·3•基)硫 烷基]-1,3-苯并噻唑-2-基}-1,4_二曱基哌啡_2_甲醯胺 a)N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒啼_3_基)硫烷 基]-1,3-苯并噻唑-2_基}-1,4_二曱基哌畊_2_曱醯胺可如實 例69製備,但以0.4 g 6-[(6-環丙基[丨又糾***并嗒 154635.doc _ 160- 201202242 畊-3-基)硫烷基]·13·笨并噻唑·2胺、〇33〇 g 二甲基 哌呼I甲酸鹽酸鹽、0.014 g N,N-二曱基吡咬|胺、12〇 咖3 N-乙基二異丙胺及1.35 g 2,4,6-三氧化2,4,6_三乙基_ 1,3’5,2,4,6-三氧雜三亞膦烷於15 cm3 2_曱基四氫呋喃中之 溶液為起始物。二氧化矽管柱急驟層析[溶離劑:二氣曱 烷/甲醇(9W5 ’以體積計)]之後,獲得〇⑶g呈米色固體 狀之N-{6-[(6-環丙基***并[4,3_b]嗒啩_3基)硫烷 基]_1,3_苯并噻唑-2-基}_1,4_二曱基哌畊_2_甲醯胺,其特 徵如下: 熔點:165-166。(:(步奇) 1H NMR譜(300 ΜΗζ,δ (ppm),DMSO-d6): 0.93 (m,2 H); 1.08 (m,2 H); 2.18 (s,3 H); 2.19 (s,3 H); 2.20至 2.37 (m,4 H); 2.53 (m,1 H); 2.69 (dd,/=4.3及 11.2 Hz, 1 H); 2 83 (m, 1 H); 3.13 (dd,/=3.5及 8·6 Hz,1 H); 7.30 (d,《/=9 6 Hz,! H); 7.47 (dd,《7=1·9及 8.5 Hz,1 H); 7.69 (d, /=8.5 Hz, 1 H); 8.12 (d,》/=2.0 Hz, 1 H); 8.28 (d,《7=9.6 Hz,1 H); 12 21 (寬 單峰,1 H)Rf cerium oxide TLC=0.24 [Eluent: gas imitation/sterol (9 〇/1 〇 by volume)] Mass spectrometry: Method A Retention time Tr (minutes) = 0.28; [M+H] + : m/ z 226 Example 76: Ν·{6-[(6-cyclopropyl[i,2,4]triazolo[43b]indole·3•yl)sulfanyl]-1,3-benzothiazole- 2-yl}-1,4-dimercaptopipen-2-carbamidine a) N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]fluorene啼_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}-1,4-diindolylpiped-2-amine can be prepared as in Example 69, but at 0.4 g 6 -[(6-cyclopropyl[丨和纠***嗒嗒154635.doc _ 160- 201202242 耕-3-基)sulfanyl]·13· benzothiazol-2-amine, 〇33〇g dimethyl Piper I acid hydrochloride, 0.014 g N,N-dimercaptopyridine|amine, 12 33 3 N-ethyldiisopropylamine and 1.35 g 2,4,6-trioxide 2,4,6 A solution of triethyl _ 1,3'5,2,4,6-trioxatriphosphinane in 15 cm3 of 2-indenyltetrahydrofuran was used as a starting material. After the flash chromatography of the ruthenium dioxide column [solvent: dioxane / methanol (9W5 'by volume)], N-{6-[(6-cyclopropyltriazole) is obtained as a beige solid in 〇(3)g. And [4,3_b]嗒啩_3yl)sulfanyl]_1,3_benzothiazol-2-yl}_1,4_didecylpiperidine-2-mercaptoamine, which has the following characteristics: 165-166. (:(step) 1H NMR spectrum (300 ΜΗζ, δ (ppm), DMSO-d6): 0.93 (m, 2 H); 1.08 (m, 2 H); 2.18 (s, 3 H); 2.19 (s , 3 H); 2.20 to 2.37 (m, 4 H); 2.53 (m, 1 H); 2.69 (dd, /=4.3 and 11.2 Hz, 1 H); 2 83 (m, 1 H); 3.13 (dd , /= 3.5 and 8·6 Hz, 1 H); 7.30 (d, "/=9 6 Hz, ! H); 7.47 (dd, "7=1·9 and 8.5 Hz, 1 H); 7.69 (d , /=8.5 Hz, 1 H); 8.12 (d, ”/=2.0 Hz, 1 H); 8.28 (d, “7=9.6 Hz, 1 H); 12 21 (width unimodal, 1 H)

質譜:方法A ' 滯留時間Tr(分鐘)=0.58 ; [M+H] + : m/z 481; [M-H]-: m/z 479 實例77 : 6-[(6-環丙基【1,2,4】***并[4,3-b】嗒畊-3·基)硫烷 基】-Ν-(1-乙基吡咯啶-3-基)-1,3·苯并噻唑-2-胺 a)6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基卜 N-(l-乙基。比η各咬-3-基)-1,3-苯并。塞《圭-2-胺可以如下方式製 154635.doc •161· 201202242 備: 在20°C下將162 mg 3-[(2-溴-l,3-苯并噻唑-6-基)硫烷基]-6-環丙基[l,2,4]***并[4,3·b]嗒畊於2cm3N-曱基吡咯啶 酮、1 cm3三乙胺及274 kL 1-乙基吡咯啶-3-胺之混合物中 之溶液置於微波管中。在30秒之預攪拌時間之後,在8〇°c 下於^波反應益中擾掉反應混合物3 X 5分鐘。在減壓下濃 縮反應混合物至乾。藉由於25 g Merck二氧化石夕桶上層 析’藉由固體沈積繼而用99:1至80:20二氣曱烷/(二氣甲 院.38/甲醇.17/氨水:2)之梯度稀釋來純化殘餘物β由 此獲得136 mg呈米色固體狀之6-[(6-環丙基[1,2,4]三峻并 [4,3-b]〇荅ρ井-3 -基)硫烧基]-N-(l -乙基》»比哈°定-3-基)_ι,3 -苯并 噻唑-2-胺,其特徵如下: 1H NMR譜 NMR (400 MHz, DMSO-d6) δ (ppm): 0 96 (m, 2 H); 1.01 (t, 7=7.2 Hz, 3 H); 1.11 (m, 2 H); 1.66 (m, 1 H); 2.15至2.27(!〇,2 11);2.34(111,111);2_414,1/=7.2112,2 H); 2.52 (部分遮蔽之多重峰,1 H); 2_61至2.76 (m,2 H); 4.29 (m, 1 H); 7.28 (d, 7=9.5 Hz, 1 H); 7.34 (m, 2 H); 7.86 (t, 7=1.3 Hz, 1 H); 8.24 (d, J=9.5 Hz, 1 H); 8.34 (d, /=6.6 Hz, 1 H) 質譜: 滞留時間Tr(分鐘)=3.09 ; [M+H] + : m/z 438 ; b)3-[(2-溴-1,3-苯并噻唑-6-基)硫烷基]-6-環丙基nq ***并[4,3-b]嗒畊: 154635.doc -162· 201202242 在20°c下將8 cm3乙腈、8 cm3 N-甲基吼嘻。定酮及624 pL 含2.5 g溴化亞銅之亞硝酸第三丁酯及丨12 g 6_[(6_環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-胺 之混合物分配於四個微波管中。在3 〇秒之預攪拌時間之 後’在80°C下於微波反應器中攪拌混合物5分鐘。將反應 介質傾倒於20 cm3水中。添加5 cm3 28%氨水溶液且隨後用 3x70 cm3乙酸乙酯萃取混合物。用3〇 cm3水,隨後用30 cm3鹽水依次洗滌有機相,經硫酸鎂乾燥,過濾,隨後在 減壓下蒸發至乾》藉由於丨丨7 g Merck二氧化石夕桶上層析, 藉由固體沈積繼而用99.5 :〇.5至98:2二氣曱烷/甲醇之梯度 稀釋而純化所得棕色固體。由此獲得56〇 mg呈淺黃色固體 狀之3-[(2-漠-U3-苯并噻哇_6基)硫烷基]6-環丙基[124] 二嗤并[4,3-b]嗒畊’其特徵如下: 質譜: 滯留時間Tr(分鐘)=〇.98 ; [M+H] + : m/z 404 ; 實例78 : 6-[(6-環丙基Μ,μ , ^ 丞U,2,4】***并[4,3-b]嗒畊-3-基)硫烷 基]-Ν·【1-(四氫吱味 2基甲基)哌啶-4-基]-1,3-苯并噻唑- 2-胺 6-1(6-環丙基[1,2,41 = „也 # 坐并[4,3-b]嗒呼-3-基)硫烷基]-N- [1-(四氫呋喃-2-基甲基λ w χ )底咬·4-基]-1,3-笨并噻唑-2-胺可以 類似於實例77之方式製偌 衣爾’但以162 mg 3-[(2-漠-1,3-苯并 0塞0坐-6-基)硫院基]-6 -環岛甘r 衣兩基[1,2,4]***并[4,3-b]嗒畊77b 於2 cm3 N-曱基吡咯啶獅 3 1 c m三乙胺及6 3 6 m g 1 -(四氮 154635.doc • 163 · 201202242 呋喃-2-基甲基)哌啶-4-胺二鹽酸鹽半水合物之混合物中之 溶液為起始物。由此獲得104 mg呈白色固體狀之6_[(6_環 丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-Ν-[ι·(四氫0夫 喃-2-基甲基)哌啶-4-基]-1,3-苯并噻唑-2-胺,其特徵如 下: 1Η NMR譜NMR (400 MHz,DMSO-d6) δ (ppm): 0 97 (m 2 H); 1.10 (m,2 H); 1.39至 1.54 (m,3 H); 1.691183 (m,2 H); 1.86至 1.97 (m,3 H); 2.01 至 2.17 (m,2 H); 2·23 (m,i 11);2.35((1,*/=5.9 112,2 11);2.76至2.96(〇1,2幵);3.55至 3.76 (m, 3 H); 3.90 (m, 1 H); 7.28 (d, J=9.5 Hz, l H); η 33 (m,2 H); 7.85 (t,《7=1.3 Hz,1 H); 8.13 (d,*7=7.6 Hz,1 H). 8.24 (d, J=9.5 Hz, 1 H) 質譜: 滯留時間Tr(分鐘)= 0.63 ; [M+H] + : m/z 508; [M+2H]2 + : m/z 254.5 (基峰) [M-H]-: m/z 506 實例79 :醫藥組合物 製備對應於下式之錢劑: 實例1之產物.......................〇.2 g 最終錠劑之賦形劑..........重1 g (賦形劑之詳情:乳糖、滑石、派粉、硬脂酸鎂)。 實例80 :醫藥組合物 製備對應於下式之錠劑: 0.2 g 實例15之產物 154635.doc 201202242 最終錄:劑之賦形劑...... (賦形劑之詳情:乳糖、 實例81 :醫藥組合物 •jig 滑石、澱粉、硬脂酸鎂)。 製備對應於下式之錠劑: 實例25之產物.................. . g 最終錠劑之賦形劑.........重j g (賦形劑之詳情:乳糖、滑石、澱粉、硬脂酸鎂)。 實例1及15被視為醫藥製備之實例,必要時此製備可能 用本專利申請案中所說明之其他產物執行。 藥理學部分: 實驗方案 I) MET細胞質域之表現及純化 表現為桿狀病毒: 將 pFastBac(Invitrogen)中之重組 DNA His-Tev-MET(956- 1390)轉染於昆蟲細胞中’且在數個病毒擴增步驟之後, 測試最終桿狀病毒儲備液中相關蛋白質之表現。 在27C下用重組病毒感染72小時之後,藉由離心收集 S F 21細.胞培養物,且在-8 0 C下儲存細胞離心塊。 純化: 將細胞離心塊再懸浮於溶解緩衝液(緩衝液A [50 mM HEPES,pH 7.5,250 mM NaCl,甘油 l〇〇/0,TECP 1 mM] ; + Roche Diagnostics無EDTA蛋白酶抑制劑混合液, 參考1873580)中,在4°C下攪拌直至均質,隨後使用「杜 恩斯(Dounce)」機器以機械方式溶解。 154635.doc > • 165· 201202242 離心之後,將溶解上清液在4°C下與鎳螯合樹脂(出3-Trap 6 Fast FlowTM,GE Healthcare)— 起培育 2小時。用 20 體積緩衝液A洗滌之後,將懸浮液裝填於管柱中,用緩衝 液B(緩衝液A+ 290 mM咪唑)之梯度溶離蛋白質。 彙集根據電泳分析(SDS PAGE)含相關蛋白質之溶離份, 藉由超濾(10 kDa截留)濃縮,且注射於用緩衝液A平衡之 排阻層析管柱(SuperdexTM 200,GE Healthcare)上。 酶法裂解組胺酸標記之後,將蛋白質再注射於用緩衝液 A平衡之新IMAC鎳螯合層析管柱(His-Trap 6 Fast F1owtm, GE Healthcare)上。最終將用緩衝液B之梯度溶離且電泳 (SDS PAGE)之後含有相關蛋白質之早期溶離份彙集且儲存 在-80°C下。 為製備自體磷酸化之蛋白質,在添加ATP 2 mM、MgCl2 2 mM及Na3V04 4 mM之後將前述溶離份在室溫下培育1小 時。用5 mM EDTA使反應停止之後,將反應混合物注射於 用緩衝液A + Na3V04 4 mM預平衡之HiPrep去鹽管柱(GE Healthcare)上,且彙集含相關蛋白質之溶離份(SDS PAGE 分析)且儲存在-80°C下。藉由質譜(LC-MS)且藉由肽圖譜 檢驗磷酸化程度。Mass Spectrometry: Method A 'Retention time Tr (minutes) = 0.58; [M+H] + : m/z 481; [MH]-: m/z 479 Example 77: 6-[(6-cyclopropyl[1, 2,4]triazolo[4,3-b]indole-3·yl)sulfanyl]-indole-(1-ethylpyrrolidin-3-yl)-1,3·benzothiazole-2 -amine a) 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl b-N-(l-ethyl. η each bit-3-yl)-1,3-benzo. Seco-2-amine can be prepared as follows: 154635.doc •161· 201202242 Preparation: 162 mg of 3-[(2-bromo-l,3-benzothiazol-6-yl)sulfane at 20 °C 6-cyclopropyl[l,2,4]triazolo[4,3·b]indole in 2cm3N-decylpyrrolidone, 1 cm3 triethylamine and 274 kL 1-ethylpyrrolidine The solution in the mixture of 3-amines was placed in a microwave tube. After a pre-mixing time of 30 seconds, the reaction mixture was disturbed for 3 X for 5 minutes at 8 °C. The reaction mixture was concentrated to dryness under reduced pressure. By chromatography on 25 g Merck dioxide on the eve of the bucket 'by solid deposition followed by a gradient of 99:1 to 80:20 dioxane / (digastric.38 / methanol.17 / ammonia: 2) Diluted to purify the residue β to obtain 136 mg of 6-[(6-cyclopropyl[1,2,4]tris[4,3-b]〇荅ρ well-3-yl as a beige solid. Sulfur-based]-N-(l-ethyl)»Bihadent-3-yl)-m,3-benzothiazol-2-amine characterized by the following: 1H NMR spectrum NMR (400 MHz, DMSO- D6) δ (ppm): 0 96 (m, 2 H); 1.01 (t, 7 = 7.2 Hz, 3 H); 1.11 (m, 2 H); 1.66 (m, 1 H); 2.15 to 2.27 (! 〇, 2 11); 2.34 (111, 111); 2_414, 1/= 7.2112, 2 H); 2.52 (partially masked multiplet, 1 H); 2_61 to 2.76 (m, 2 H); 4.29 (m, 1 H); 7.28 (d, 7=9.5 Hz, 1 H); 7.34 (m, 2 H); 7.86 (t, 7=1.3 Hz, 1 H); 8.24 (d, J=9.5 Hz, 1 H) ; 8.34 (d, /=6.6 Hz, 1 H) Mass Spectrum: Retention time Tr (minutes) = 3.09; [M+H] + : m/z 438 ; b) 3-[(2-bromo-1,3- Benzothiazole-6-yl)sulfanyl]-6-cyclopropyl nq Triazolo[4,3-b]嗒耕: 154635.doc -162· 201202242 8 cm3 acetonitrile, 8 at 20 °c Cm3 N-methyl oxime. Ketone and 624 pL of tert-butyl nitrite containing 2.5 g of cuprous bromide and 丨12 g 6_[(6_cyclopropyl[1,2,4]triazolo[4,3-b] A mixture of -3-yl)sulfanyl]-1,3-benzothiazol-2-amine was partitioned into four microwave tubes. The mixture was stirred in a microwave reactor at 80 ° C for 5 minutes after a pre-stirring time of 3 sec. Pour the reaction medium into 20 cm3 of water. A 5 cm3 28% aqueous ammonia solution was added and then the mixture was extracted with 3 x 70 cm3 of ethyl acetate. The organic phase was washed successively with 3 〇 cm 3 of water, followed by 30 cm 3 of brine, dried over magnesium sulfate, filtered, and then evaporated to dryness under reduced pressure, by chromatography on 丨丨 7 g Merck dioxide. The solid precipitate was then purified by gradient dilution of 99.5: 至.5 to 98:2 dioxane/methanol to afford a brown solid. Thus, 56 [mu]mg of 3-[(2-di-U3-benzothiazol-6-yl)sulfanyl]6-cyclopropyl[124]diindole[4,3- b] 嗒耕' has the following characteristics: Mass spectrum: residence time Tr (minutes) = 〇.98; [M+H] + : m/z 404; Example 78: 6-[(6-cyclopropyl Μ, μ, ^ 丞U,2,4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-Ν·[1-(tetrahydroanthracene 2-ylmethyl)piperidin-4- ]]-1,3-benzothiazol-2-amine 6-1 (6-cyclopropyl [1,2,41 = „also #坐和[4,3-b]嗒呼-3-yl)sulfur Alkyl]-N-[1-(tetrahydrofuran-2-ylmethylλ w χ ) bottom bit 4-yl]-1,3- benzothiazol-2-amine can be made in a manner similar to that of Example 77. Er's with 162 mg 3-[(2- desert-1,3-benzox0-o-s-6-yl) sulphur-based]-6-ring gans-li-[2,2,4] Triazolo[4,3-b]indole 77b in 2 cm3 N-mercaptopyrrolidinium 3 1 cm triethylamine and 6 3 6 mg 1 -(tetrazo 154635.doc • 163 · 201202242 furan-2- A solution of a mixture of methylmethyl)piperidin-4-amine dihydrochloride salt hemihydrate is the starting material. Thus, 104 mg of 6-[(6-cyclopropyl[1,2, 4] Triazolo[4,3-b]indole-3-yl Sulfoalkyl]-indole-[ι·(tetrahydrofuro-2-ylmethyl)piperidin-4-yl]-1,3-benzothiazol-2-amine, which has the following characteristics: 1Η NMR spectrum NMR (400 MHz, DMSO-d6) δ (ppm): 0 97 (m 2 H); 1.10 (m, 2 H); 1.39 to 1.54 (m, 3 H); 1.691183 (m, 2 H); 1.97 (m,3 H); 2.01 to 2.17 (m,2 H); 2·23 (m,i 11); 2.35 ((1,*/=5.9 112,2 11); 2.76 to 2.96 (〇1, 2幵); 3.55 to 3.76 (m, 3 H); 3.90 (m, 1 H); 7.28 (d, J=9.5 Hz, l H); η 33 (m, 2 H); 7.85 (t, “7 =1.3 Hz,1 H); 8.13 (d,*7=7.6 Hz,1 H). 8.24 (d, J=9.5 Hz, 1 H) Mass Spectrum: Residence time Tr (minutes) = 0.63 ; [M+H] + : m/z 508; [M+2H]2 + : m/z 254.5 (base peak) [MH]-: m/z 506 Example 79: Preparation of a pharmaceutical composition corresponding to the following formula: Example 1 Product.......................〇2g The excipient of the final tablet..........重重1g Details of the agent: lactose, talc, pie powder, magnesium stearate). Example 80: Pharmaceutical Composition Preparation A lozenge corresponding to the following formula: 0.2 g Product of Example 15 154635.doc 201202242 Final Record: Excipients for the Agent... (Excipient Details: Lactose, Example 81 : Pharmaceutical composition • jig talc, starch, magnesium stearate). Preparation of a tablet corresponding to the following formula: Product of Example 25.................. g Excipient of the final tablet .... Jg (details of excipients: lactose, talc, starch, magnesium stearate). Examples 1 and 15 are considered to be examples of pharmaceutical preparations which may be carried out, if desired, with other products described in this patent application. Pharmacological part: Experimental protocol I) Expression and purification of MET cell plastids as baculovirus: Recombinant DNA His-Tev-MET (956-1390) in pFastBac (Invitrogen) was transfected into insect cells' After the virus amplification step, the performance of the relevant protein in the final baculovirus stock was tested. After 72 hours of infection with the recombinant virus at 27C, the S F 21 fine cell culture was collected by centrifugation, and the cell pellet was stored at -8 0 C. Purification: Resuspend the cell pellet in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, glycerol l〇〇/0, TECP 1 mM]; + Roche Diagnostics EDTA-free protease inhibitor cocktail) , refer to 1873580), stir at 4 ° C until homogenization, and then mechanically dissolve using a "Dounce" machine. 154635.doc > • 165·201202242 After centrifugation, the dissolved supernatant was incubated with nickel chelating resin (3-Trap 6 Fast FlowTM, GE Healthcare) at 4 °C for 2 hours. After washing with 20 volumes of buffer A, the suspension was loaded into a column and the protein was eluted with a gradient of buffer B (buffer A + 290 mM imidazole). The fractions containing the relevant proteins were pooled according to electrophoresis analysis (SDS PAGE), concentrated by ultrafiltration (10 kDa cut-off), and injected onto an exclusion chromatography column (SuperdexTM 200, GE Healthcare) equilibrated with buffer A. After enzymatic cleavage of histidine labeling, the protein was re-injected onto a new IMAC nickel chelate chromatography column (His-Trap 6 Fast F1owtm, GE Healthcare) equilibrated with buffer A. Eventually, the gradient of buffer B was used to dissolve and electrophoresis (SDS PAGE) followed by early dissociation of the relevant protein and stored at -80 °C. To prepare autophosphorylated protein, the aforementioned fractions were incubated for 1 hour at room temperature after addition of ATP 2 mM, MgCl 2 2 mM and Na3V04 4 mM. After the reaction was stopped with 5 mM EDTA, the reaction mixture was injected onto a HiPrep desalting column (GE Healthcare) pre-equilibrated with buffer A + Na3V04 4 mM, and the fractions containing the relevant proteins were pooled (SDS PAGE analysis) and Store at -80 °C. The degree of phosphorylation was examined by mass spectrometry (LC-MS) and by peptide mapping.

II)測試A、B及C A)測試A: 96孔形式中之HTRFMET測試 在室溫下,在於DMSO 4.3%(νο1/νο1)中濃度範圍為14.3 μΜ至0.24 ηΜ(增量為3)之欲評估分子或其溶劑(DMSO 4.3°/。)(對於陽性對照組)存在下,將MET 7.1 ηΜ預培育於 154635.doc • 166· 201202242 35 μΐ 體積之反應緩衝液(MOPS 10 mM(pH 7.0)、Tween 20 0.01%(重量/體積)、1^^0:125 111]^、01'丁1111]^)中30分鐘。 亦製備陰性對照組,其無酶且無抑制劑,但在分子之溶劑 (反應緩衝液及DMSO 4.3%)存在下。預培育30分鐘之後, 藉由在反應缓衝液中添加兩種受質poly (GAT)及ATP之15 μΐ混合物起始酶促反應。則反應培養基中之濃度為poly (GAT) 1 pg/ml、ATP 10 μΜ、酶 5 nM、抑制劑 10 μΜ 至 0.17 ηΜ及DMSO 3%(vol/vol)。在室溫下培育5分鐘之後, 用每孔 30 μΐ MOPS 10 mM(pH 7.0)、氣化鉀 400 mM、BSA 0.1%、EDTA 133 mM、80 ng抗生蛋白鏈菌素 61SAXLB Cis-Bio Int.及18 ng抗磷酸酪胺酸Mab PT66-銪穴狀化合物 之混合物使反應停止。在4°C下擱置隔夜之後,使用專用 於時差式螢光傳遞量測之讀取器在兩個波長(620 nm及665 nm)下進行讀數。由所得665/620比率計算相對於無抑制劑 之對照組的抑制百分比。 此測試A中對於實驗部分中所說明之式(I)產物獲得之結 果為IC5〇值低於500 ιιΜ且尤其100 nM。 Β)測試Β :對MET自體磷酸化之抑制;ELISA技術 (pppY1230, 1234, 1235) a)細胞溶解物:將MKN45細胞以每孔20 000個細胞接種 於96孔培養板(Cell coat BD polylysine)中之 200 μΐ RPMI + 10% FCS +1% L-麩醯胺酸之混合物中,隨後在37°C下置 於培育箱中24小時以使其黏著。 接種次日,用六種濃度之產物單次(monoplicate)處理細 154635.doc •167- 201202242 胞1小時。用相同最終量之DMSO處理六個對照孔。 產物稀釋:以10 mM於純DMSO中之儲備液為起始物, 用純DMSO製備1 mM至3 μΜ之範圍(增量交替地為3.3及 3)。用培養基製備1/50中間稀釋液,且隨後向細胞(200 μΐ) 中直接添加10 μΐ此等稀釋液。最終範圍為1000至3 ηΜ。 在培育結束時,小心地移除上清液且用200 μΐ PBS沖洗 細胞。直接向孔中添加1〇〇 μΐ溶解緩衝液且在4°C下培育培 養板30分鐘。 溶解緩衝液:10 mM Tris HCl(pH 7.4)、100 mM NaCl、 1 mM EDTA、1 mM EGTA、1% Triton X-100、10%甘油、 0.1% SDS、0.5%去氧膽酸鹽,向其中每10 mL緩衝液臨時 添加抗蛋白酶錠劑及抗磷酸酶錠劑(Roche)。 將100 μΐ溶解物轉移至V形底聚丙烯培養板中,且立即 執行ELISA,或將培養板冷凍於-80°C下。 b) ELISA 磷酸化 MET BioSource/Invitrogen 套組 KHO0281 向套組培養板之各孔中添加80 μΐ套組稀釋緩衝液+20 μί 細胞溶解物或20 μΐ溶解緩衝液(對於空白組)。在室溫下, 在緩和攪拌下培育培養板2小時。 用400 μΐ套組洗滌緩衝液沖洗孔四次。隨後在室溫下與 100 μΐ抗磷酸化MET抗體一起培育培養板1小時。 用400 μΐ套組洗滌緩衝液再次沖洗孔四次。隨後在室溫 下與100 μΐ抗兔HRP抗體一起培育培養板30分鐘(除僅含色 素原之孔以外)。 再用400 μΐ套組洗滌緩衝液沖洗孔四次之後,添加100 154635.doc •168- 201202242 pL色素原且在室溫下在黑暗中培育培養板3〇分鐘。 用100 μΐ停止溶液使反應停止。在45〇 ηΜ下以〇丨秒於 Wallac Victor板讀取器上進行讀數0 此測试B中對於貫驗部分中所說明之式(I)產物獲得之結 果為IC5〇值低於500 nM且尤其1〇〇 nM。 C)測試C :用14C-胸苦脈衝量測細胞增殖 在37C及5% C〇2下,以每孔10 〇〇〇個細胞之比率將18〇 μΐ MKN45細胞接種於96孔Cytostar培養板中RPMI +1〇〇/0胎 牛血清+ 1% L·麩醯胺酸之混合物中4小時。此4小時培育之 後’添加10 μΐ根據對於ELISA提及之稀釋方法呈20倍濃縮 溶液形式的產物。在1〇個濃度下自1〇〇〇 nM至0.03 nM(增 量交替地為3,3及3)雙重複測試產物。 處理72小時之後’添加1〇 μι 10 gCi/ml "c_胸苷以每孔 獲得0.1 pCi。24小時脈衝及96小時處理之後,於Micr〇_ Beta機器(perkin-Elmer)上量測14C-胸苷之併入量。 所有測s式步驟均在Bio mek 2000或Tec an站上自動完成。 此測試C中對於實驗部分中所說明之式⑴產物獲得之結 果為IC5〇值低於500 nM且尤其低於1〇〇 nM。 以下藥理學結果表中提供對於上述實驗部分中所說明之 產物獲得的結果,如下: 對於測試A ’+符號對應於低於5 〇〇 nM且++符號對應於 低於100 nM, 對於測試B,+符號對應於低於500 nM且++符號對應於 低於100 nM, 154635.doc -169- 201202242 對於測試C,+符號對應於低於500 nM且++符號對應於 低於100 nM。 藥理學結果表: 實例編號 測試A 測試B 測試C 1 ++ ++ ++ 2 ++ -I-+ 3 ++ ++ -H- 4 -H- ++ -f+ 5 ++ ++ 6 ++ ++ ++ 7 ++ ++ ++ 8 ++ + + 9 + + -Η- 10 ++ ++ ++ 11 ++ ++ ++ 12 ++ ++ 13 ++ ++ 14 + ++ + 15 + + + 16 ++ ++ ++ 17 + + 18 -H- HH- -Η- 19 ++ + + 20 ++ -H- ++ 21 + ++ 22 ++ ++ ++ 23 ++ -Η- 24 ++ ++ ++ 25 -H- -Η- 26 -H- ++ 27 ++ -Η- 28 ++ 29 ++ ++ ++ 30 ++ ++ ++ 31 ++ ++ -Η- 32 ++ ++ ++ 33 ++ ++ ++ 34 ++ ++ ++ 35 ++ ++ ++ 36 ++ ++ ++ 37 -H- 4-+ ++ 38 ++ ++ 39 -H- ++ -Η- 40 ++ ++ ++ 41 -Η- 154635.doc •170- 201202242 42 -Η- -Η- ++ 43 ++ ++ ++ 44 -Η- ++ 45 ++ ++ ++ 46 ++ -Η- ++ 47 ++ ++ ++ 48 Η· ++ ++ 49 ++ -Η- ++ 50 ++ ++ ++ 51 ++ ++ -Η- 52 -Η- -Η- 53 ++ 4-+ ++ 54 ++ -Η- ++ 55 ++ ++ ++ 56 ++ ++ -Η- 57 ++ ++ 58 -Η- +-l· 59 ++ -Η- ++ 60 -Η- + + 61 -Η- ++ ++ 62 ++ -Η- ++ 63 ++ -h+ -Η- 64 ++ ++ -Η- 65 -Η- -Η- ++ 66 -Η- -Η- ++ 67 ++ -Η- ++ 68 ++ ++ -h-h 69 ++ ++ ++ 70 ++ ++ -Η- 71 ++ ++ -hh 72 + + + 73 ++ -Η- ++ 74 ++ 75 ++ -Η- ++ 76 + + - 77 + + + 78 ++ ++ -171 - 154635.docII) Tests A, B and CA) Test A: The HTRFMET test in the 96-well format is at room temperature in a concentration range of 14.3 μΜ to 0.24 ηΜ (increment of 3) in DMSO 4.3% (νο1/νο1) MET 7.1 ηΜ was pre-incubated in 154635.doc • 166· 201202242 35 μΐ volume of reaction buffer (MOPS 10 mM (pH 7.0) in the presence of the assay molecule or its solvent (DMSO 4.3°/.) (for the positive control) Tween 20 0.01% (w/v), 1^^0:125 111]^, 01' Ding 1111]^) 30 minutes. A negative control group was also prepared which was enzyme-free and no inhibitor, but in the presence of a molecular solvent (reaction buffer and 4.3% DMSO). After 30 minutes of pre-incubation, the enzymatic reaction was initiated by the addition of two 15 μΐ mixtures of poly(GAT) and ATP in the reaction buffer. The concentration in the reaction medium was poly (GAT) 1 pg/ml, ATP 10 μΜ, enzyme 5 nM, inhibitor 10 μΜ to 0.17 ηΜ, and DMSO 3% (vol/vol). After incubation for 5 minutes at room temperature, 30 μM MOPS 10 mM (pH 7.0) per well, potassium hydride 400 mM, BSA 0.1%, EDTA 133 mM, 80 ng of streptavidin 61SAXLB Cis-Bio Int. A mixture of 18 ng of anti-phosphotyrosine Mab PT66-铕 cryptate stopped the reaction. After overnight at 4 ° C, readings were taken at two wavelengths (620 nm and 665 nm) using a reader dedicated to time-lapse fluorescence transmission measurements. The percent inhibition relative to the control without inhibitor was calculated from the resulting 665/620 ratio. The results obtained in this test A for the product of formula (I) illustrated in the experimental section are IC5 〇 below 500 Μι and especially 100 nM. Β) Test Β: inhibition of MET autophosphorylation; ELISA technique (pppY1230, 1234, 1235) a) Cell lysate: MKN45 cells were seeded in 96-well culture plates at 20,000 cells per well (Cell coat BD polylysine) In a mixture of 200 μΐ RPMI + 10% FCS +1% L-glutamic acid, it was then placed in an incubator at 37 ° C for 24 hours to adhere. On the next day of inoculation, the cells of the six concentrations were treated with a monoplicate of 154635.doc •167-201202242 for 1 hour. Six control wells were treated with the same final amount of DMSO. Product dilution: starting from 10 mM stock in pure DMSO, prepared in pure DMSO from 1 mM to 3 μΜ (incrementally alternately 3.3 and 3). A 1/50 intermediate dilution was prepared from the medium, and then 10 μM of these dilutions were directly added to the cells (200 μM). The final range is 1000 to 3 ηΜ. At the end of the incubation, the supernatant was carefully removed and the cells were washed with 200 μΐ PBS. 1 μ μ μ μ dissolved buffer was added directly to the wells and the plates were incubated at 4 ° C for 30 minutes. Lysis buffer: 10 mM Tris HCl (pH 7.4), 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, to which Anti-protease tablets and anti-phosphatase lozenges (Roche) were temporarily added per 10 mL of buffer. 100 μL of the lysate was transferred to a V-bottom polypropylene culture plate, and the ELISA was immediately performed, or the plate was frozen at -80 °C. b) ELISA phosphorylation MET BioSource/Invitrogen kit KHO0281 Add 80 μM kit dilution buffer + 20 μί cell lysate or 20 μM lysis buffer (for blank) to each well of the kit culture plate. The plates were incubated for 2 hours at room temperature with gentle agitation. The wells were rinsed four times with 400 μΐ kit wash buffer. The plates were then incubated with 100 μM anti-phosphorylated MET antibody for 1 hour at room temperature. Rinse the wells four more times with 400 μΐ kit wash buffer. The plates were then incubated with 100 μM anti-rabbit HRP antibody for 30 minutes at room temperature (except for wells containing only chromogens). After rinsing the wells four more times with 400 μM kit wash buffer, add 100 154635.doc •168- 201202242 pL chromogen and incubate the plates for 3 minutes at room temperature in the dark. Stop the reaction with 100 μΐ stop solution. Readings were taken at 45 〇ηΜ on the Wallac Victor plate reader in leap seconds. The results obtained for the product of formula (I) described in the test section in test B are IC5 〇 below 500 nM and Especially 1〇〇nM. C) Test C: Cell proliferation was measured by 14C-chest pulse pulse. 18〇μΐ MKN45 cells were seeded in 96-well Cytostar culture plates at a ratio of 10 cells per well at 37C and 5% C〇2. RPMI +1 〇〇 / 0 fetal calf serum + 1% L · glutamic acid in a mixture for 4 hours. After this 4 hour incubation, 10 μΐ of the product in the form of a 20-fold concentrated solution according to the dilution method mentioned for the ELISA was added. The test product was repeated from 1 〇〇〇 nM to 0.03 nM (alternatively 3, 3 and 3 in increments) at 1 concentration. After 72 hours of treatment, '1 μl of 10 gCi/ml " c_thymidine was added to obtain 0.1 pCi per well. After 24 hours of pulse and 96 hours of treatment, the amount of 14C-thymidine incorporation was measured on a Micr(R)_beta machine (perkin-Elmer). All s steps were automated on the Bio mek 2000 or Tec an station. The results obtained in this test C for the product of formula (1) illustrated in the experimental section are IC5 〇 values below 500 nM and especially below 1 〇〇 nM. The results obtained for the products described in the experimental section above are provided in the following pharmacological results table as follows: For test A '+ symbol corresponds to less than 5 〇〇 nM and ++ symbol corresponds to less than 100 nM, for test B The + symbol corresponds to less than 500 nM and the ++ symbol corresponds to less than 100 nM, 154635.doc -169 - 201202242 For test C, the + symbol corresponds to less than 500 nM and the ++ symbol corresponds to less than 100 nM. Pharmacological Results Table: Example Number Test A Test B Test C 1 ++ ++ ++ 2 ++ -I-+ 3 ++ ++ -H- 4 -H- ++ -f+ 5 ++ ++ 6 + + ++ ++ 7 ++ ++ ++ 8 ++ + + 9 + + - Η - 10 ++ ++ ++ 11 ++ ++ ++ 12 ++ ++ 13 ++ ++ 14 + + + + 15 + + + 16 ++ ++ ++ 17 + + 18 -H- HH- -Η- 19 ++ + + 20 ++ -H- ++ 21 + ++ 22 ++ ++ ++ 23 ++ -Η- 24 ++ ++ ++ 25 -H- -Η- 26 -H- ++ 27 ++ -Η- 28 ++ 29 ++ ++ ++ 30 ++ ++ ++ 31 + + ++ -Η- 32 ++ ++ ++ 33 ++ ++ ++ 34 ++ ++ ++ 35 ++ ++ ++ 36 ++ ++ ++ 37 -H- 4-+ ++ 38 ++ ++ 39 -H- ++ -Η- 40 ++ ++ ++ 41 -Η- 154635.doc •170- 201202242 42 -Η- -Η- ++ 43 ++ ++ ++ 44 - Η- ++ 45 ++ ++ ++ 46 ++ -Η- ++ 47 ++ ++ ++ 48 Η· ++ ++ 49 ++ -Η- ++ 50 ++ ++ ++ 51 + + ++ -Η- 52 -Η- -Η- 53 ++ 4-+ ++ 54 ++ -Η- ++ 55 ++ ++ ++ 56 ++ ++ -Η- 57 ++ ++ 58 -Η- +-l· 59 ++ -Η- ++ 60 -Η- + + 61 -Η- ++ ++ 62 ++ -Η- ++ 63 ++ -h+ -Η- 64 ++ ++ -Η- 65 -Η- -Η- ++ 66 -Η- -Η- ++ 67 ++ -Η- ++ 68 ++ ++ -hh 69 ++ ++ ++ 70 ++ ++ -Η- 71 ++ ++ -hh 72 + + + 73 ++ -Η- ++ 74 ++ 75 ++ -Η- ++ 76 + + - 77 + + + 78 + + ++ -171 - 154635.doc

Claims (1)

201202242 七、申請專利範圍: 1. 一種式(I)產物,201202242 VII. Patent application scope: 1. A product of formula (I), 其中: R1表不烧基、環烷基或環烷基烷基;視情況如下所示 經取代; Rb表示氫原子或氟原子; W表示氫原子;烷基、環烷基或雜環烷基,視情況經 烷基、烷氧基、雜環烷基或NR3R4基團取代,該等基團 自身視情況如下所示經取代;或基團COR,其中R表 示: 環烷基、雜環烷基或烷基’均視情況經一或多個選 自氫原子、經基、烷基及烷氧基及環烷基、雜環烷 基、雜芳基、苯基及NR3R4基團之基團取代,該等基 團自身視情況如下所示經取代; 烷氧基,視情況經烷基、雜環烷基或NR3R4取代, 該等基團自身視情況如下所示經取代;或基團_〇雜環 烷基’視情況如下所示經取代; 或基團NHR2,其中R2表示氫原子或環烷基、雜環 烷基或烷基,均視情況經一或多個可相同或不同且選 自經基及烧氧基及雜環烷基、雜芳基、笨基及NR3R4 154635.doc 201202242 基團之基團取代,該等基團自身視情況如下所示經取 代; 其中R3及R4可相同或不同,選自氫原子及烷基、環 烷基、雜環烷基、雜芳基及苯基,均視情況經一或多 個可相同或不同且選自羥基、烷氧基、NH2、NH烷 基、N(烷基)2、雜環烷基、雜芳基及苯基的基團取 代,該等取代基團自身視情況如下所示經取代;或者 R3及R4與其所連接之氮原子一起形成3至10員環狀基 團,其視情況含有一或多個選自〇、S、N及NH之其他 雜原子,其中該視情況存在之S可能為SO或S02形 式;此基團,包括其可能含有之任何NH,視情況如下 所示經取代; 上文所定義之所有該等烷基、環烷基、雜環烷基、-〇-雜環烷基、雜芳基及苯基、及R3及R4與其所連接之氮原 子一起可形成之該等環狀基團視情況經一或多個選自以 下之基團取代:鹵素原子、羥基、側氧基、烷氧基、-〇-C0-R5、-C00H、COOR5、-C0NH2、C0NHR5、NH2、 NHR5、NR5R5,、-NH-C0-R5 及-S02-烷基-基團、及烷 基、環烷基、雜環烷基、烷基-雜環烷基、C0-雜環烷 基、苯基、CH2-苯基、C0-苯基、雜芳基及S-雜芳基, 使得在該等取代基團中,該等烷基、烷氧基、環烷基、 雜環烷基、苯基及雜芳基自身視情況經一或多個選自鹵 素原子及羥基、側氧基、含有1至4個碳原子之烷基、環 烷基、環烷基烷基及烷氧基、NH2、NH烷基及N(烷基)2 154635.doc 201202242 的基團取代, 上文所定義之所有該等環烷基、雜環烷基、-〇·雜環烷 基、雜芳基及笨基亦視情況經基團Si(烷基)3取代; 上文所定義之所有該等環烷基及雜環烷基可在環之一 個碳上經螺環烷基或螺雜環烷基取代,或視情況在環之 兩個碳上經調合之環烷基或雜環烷基取代; R5及R5’可相同或不同,表示烷基或環烷基,視情況 經一或多個選自鹵素原子及羥基、含有1至4個碳原子之 烷基及烷氧基、NH2、NH烷基及N(烷基)2的基團取代, 該等烧基表示含有丨至⑺個碳原子之烷基; 該等環烷基含有至多3至7個碳原子; 該等式(I)產物為任何可能之外消旋、對映異構或非對 映異構性異構體形式,以及該等式⑴產物與無機及有機 酉义或與無機及有機驗之加成鹽。 2.如請求項1之式(I)產物,其中 Ri表示燒基、環烷基或環烷基烷基;視情況如下所示 經取代; Rb表示風原子或氟原子; W表示氫原子;烷基、環烷基或雜環烷基,視情況經 烷基、烷氧基、雜環烷基或NR3R4基團取代,該等基團 自身視情況如下所示經取代;或基團C〇r,其中R表 不 · 環烧基 '雜環烷基或烷基’視情況經一或多個選自 氫原子、羥基、烷基及烷氧基及環烷基、雜環烧基、 154635.doc , 201202242 雜芳基、苯基及NR3R4基團之基團取代,該等基團自 身視情況如下所示經取代; 烷氧基,視情況經雜環烷基或]^113114取代,該等基 團自身視情況如下所示經取代;或基團_〇_雜環烷基, 視情況如下所示經取代; 或基團NHR2 ’其中R2表示氫原子或環烷基、雜環 烧基或烧基,均視情況經一或多個可相同或不同且選 自羥基及烷氧基及雜環烷基、雜芳基、苯基及NR3R4 基團之基團取代,所有該等基團均視情況如下所示經 取代; 其中R3及R4可相同或不同,選自氫原子及烷基、環烷 基、雜環烷基及苯基,均視情況經一或多個可相同或不 同且選自羥基、烷氧基、NH2、NH烷基及N(烷基)2基 團、及雜環烷基、雜芳基及苯基的基團取代,該等取代 基團自身視情況如下所示經取代;或者R3及尺4與其所連 接之氮原子一起形成3至1〇員環狀基團,其視情況含有 一或多個選自〇、S、N及NH之其他雜原子,其中該視情 況存在之S可能為SO或S02形式,此基團,包括其可能 含有之任何NH,視情況如下所示經取代; 上文所定義之所有該等烷基、環烷基、雜環烷基、 雜環烷基、雜芳基及苯基、及R3&R4與其所連接之氮原 子一起可形成之該等環狀基團視情況經一或多個選自以 下之基團取代:鹵素原子、羥基、侧氧基、烷氧基、 C0-R5、NH2、NH烷基、N(烷基)2及-S02-烷基、及烷 154635.doc 201202242 基、環烷基、雜環烷基、CH2_雜環烷基、苯基、CH2j 基、co-苯基、雜芳基及s•雜芳基,使得在該等取代基 團中,該等烷基、烷氧基、環烷基、雜環烷基、苯基及 雜芳基自身視情況經一或多個選自齒素原子及羥基、側 氧基、含有1至4個碳原子之烷基、環烷基、雜環烷基及 烷氧基、NH2、NH烷基及N(烷基)2的基團取代; R5表示烧基或環炫基; .該等式(I)產物為任何可能之外消旋、對映異構或非對 映異構性異構體形式,以及該等式⑴產物與無機及有機 酸或與無機及有機鹼之加成鹽。 3.如其他請求項中任一項之式(I)產物,其中R1具有其他請 求項中任一項中所定義之意義,Rb表示氫原子或氟原 子,且W表示氫原子;烷基、環烷基或雜環烷基,視情 況經烷基、雜環烷基或NR3R4基團取代,該等基團視情 況如下所示經取代;或基團COR,其中r表示: 環烷基、雜環烷基或烷基,視情況經烷基、雜環烧基 或NR3R4基團取代,該等基團自身視情況如下所示經取 代; 烷氧基,視情況經雜環烷基或NR3R4基團取代,該等 基團自身視情況如下所示經取代;或〇_雜環烷基,視情 況如下所示經取代; 或基團NHR2,其中R2表示氫原子或烧基,視情況經 雜%烧基或NR3R4取代;該等基團自身視情況如下所示 經取代; 154635.doc 201202242 其中R3及R4可相同或不同,選自氫原子及烷基、環烷 基及雜環烷基,視情況經一或多個可相同或不同且選自 烷氧基、雜環烷基、NH2、NH烷基及N(烷基)2基團之基 團取代;或者R3及R4與其所連接之氮原子一起形成3至7 員環狀基團,其視情況含有一或多個選自〇及NH之其他 雜原子,此基團,包括其所含之視情況存在之NH,視情 況如下所示經取代; 上文所疋義之所有該等烷基、雜環烷基及_0_雜環烷 基、及R3及R4與其所連接之氮原子一起可形成之該等環 狀基團視情況經一或多個選自以下之基團取代:齒素原 子、羥基、烷氧基、NH2、NH烷基' N(烷基)2及-S02-烷基、及烷基、環烷基、雜環烷基、CH2_雜環烷基、苯 基、CH2-苯基及雜芳基,使得在該等取代基團中,該等 烷基、烷氧基、環烷基、雜環烷基、苯基及雜芳基自身 視情況經一或多個選自齒素原子及羥基、含有丨至4個碳 原子之烷基及烷氧基、環烷基、環烷基烷基、NH2、nh 烷基及N(烷基)2的基團取代; 該等式(I)產物為任何可能之外消旋、對映異構或非對 映異構性異構體形式,以及該等式⑴產物與無機及有機 酸或與無機及有機鹼之加成鹽。 4.如其他凊求項中任一項之式(I)產物,其中: R1表示烧基或環烷基或環烷基烷基; 其中烧基含有1至2個碳原子且環院基含有3至6個碳原 子; 154635.doc -6 - 201202242 Rb表示氫原子或氟原子; W表不虱原子;烧基、環院基或雜環烧基,視情況經 烷基、雜環烷基或NR3R4基團取代;或基團COR,其中 R表示: 環烷基、雜環烷基或烷基,視情況經烷基' 雜環烷 基或NR3R4基團取代,該等基團自身視情況如下所示 經取代; 〇-雜環院基’視情況如下所示經取代; 或基團NHR2,其中R2表示氫原子或烷基,視情況 經雜環烷基或NR3R4基團取代,該等基團自身視情況 如下所示經取代; 其中R3及R4可相同或不同,表示氫原子或烷基或環烷 基,視情況經基團N(烷基)2取代,或者们及尺4與其所連 接之氮原子一起形成環狀基團,其視情況含有一或多個 選自Ο及NH之其他雜原子,此基團,包括其所含之視情 況存在之NH,視情況經取代; 上文所定義之所有該等烧基、雜環烧基及_〇_雜環烧 基、及R3及R4與其所連接之氮原子一起可形成之該等環 狀基團視情況經一或多個選自以下之基團取代:齒素原 子、羥基、側氧基、烷氧基、NH2、NH烷基、N(烧基)2 及-S02-烷基、及烷基、環烷基、雜環烷基、烧基_雜環 烧基、CO-雜環烧基及笨基,該等取代基團自身視情況 經一或多個選自鹵素原子及羥基、含有1至4個碳原子之 烧基、環烧基、環烧基烧基及烧氧基、NH2、NH烧基及 154635.doc 201202242 N(烷基)2的基團取代; 該等式⑴產物為任何可能之外消旋、對映異構或非 映異構性異構㈣式,以及料式⑴產物與無機及 酸或與無機及有機驗之加成鹽。 5•如其他請求項中任一項之式⑴產物,其對應於 式: 環丙基U,2,4b唑并[4 3斗荅味_3基)硫烷 基]-1,3·苯并嗟唾-2_基}_3_[2_(嗎琳冬基)乙基]脲 6 [(6環丙基[u〆]三。坐并[4 3_0]塔_ _3基)硫烷基]_ 1,3-苯并嗟唾-2-胺 則6-[(6-環丙基π,2,4]三唆并[4,3斗荅呼_3•基)硫烷 基]1,3本并塞唾_2_基}-2-(嗎琳_4-基)乙酿胺 2-(4-環丙基哌畊_丨_基)_沁{6_[(6環丙基[12 4]***并 [4,3-6]嗒畊-3-基)硫烷基]_ι,3·苯并噻唑_2•基}乙醯胺 ΑΜ6-[(6-環丙基[^4]***并[4,3_6]嗒畊_3_基)硫烷 基]-1,3·苯并噻唑_2_基卜2_(4_氟哌啶·卜基)乙醯胺 #-{6-[(6-環丙基[i’2,4]***并[4,3_6]嗒畊_3_基)硫烷 基]-1,3-苯并噻唑_2_基}_2_[4_(嗎啉_4基)哌啶卜基]乙 醯胺 #-{6_[(6-環丙基[^4]***并[4 3 6]嗒畊·3•基)硫烷 基]-1,3-苯并噻唑_2•基卜2_[4_(2-乙氧基乙基)哌畊_丨_基] 乙醯胺 N-(6-{[6-(環己基甲基)[1,2,4]***并[43·6]嗒畊_3_基] 硫烷基卜1,3·苯并噻唑-2-基)-2-(4-環丙基哌畊_1_基)乙 154635.doc 201202242 醯胺 iV-(6-{[6-(環己基曱基)[1,2,4]***并[4,3功]嗒畊-3-基] 硫烷基}-1,3-苯并噻唑-2-基)-2-(嗎啉基)乙醯胺 (3i?)-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊_3·基)硫烷 基]-1,3-苯并嚷0坐-2-基}胺基甲酸1·甲基„比略咬_3_基酯 (3<S)-{6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷 基]-1,3 -苯并嗟°坐-2-基}胺基甲酸ι_曱基n比略咬_3_基酉旨 {6-[(6-環丙基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]_ 1,3-苯并°塞°坐-2-基}胺基甲酸1-甲基派咬_4-基酯 {6-[(6-% 丙基[1,2,4]二。坐并[4,3-6]β荅p井-3-基)硫炫>基]·· l,3-苯并°塞唑-2-基}胺基甲酸l-(2-氟乙基)β底咬·4-基酯 (3及)-(6-{[6-(環己基曱基)[1,2,4]***并[4,3-Ζ>]嗒畊-3-基]硫烷基}-1,3 -苯并噻唑-2-基)胺基甲酸1·甲基吡洛啶-3-基醋 (3<S)-(6-{[6-(環己基曱基)[1,2,4]三》坐并[4,3-6]塔 ρ井-3· 基]硫院基}-1,3-苯并嘆。坐-2-基)胺基曱酸ι_曱基。比η各咬-3-基酯 6-[(6-環丙基[I,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-#-[2·(4,4-二氟哌啶-1-基)乙基]·1,3-笨并噻唑-2-胺 2-(4-環丙基哌畊-1-基)-#-{6-[(6-曱基[1,2,4]***并 [4,3-6]〇荅畊-3-基)硫烧基]-1,3-苯并噻唾-2-基}乙酿胺 #-{6-[(6-曱基[1,2,4]***并[4,3-6]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}環丙烷甲醯胺 #-{6-[(6-曱基[1,2,4]***并[4,34]嗒啡-3-基)硫烷基]- 154635.doc -9- 201202242 1,3-苯并噻唑-2-基}-2-(嗎啉_4-基)乙醯胺 1-(6-{[6-(環己基甲基)[124]***并[43办]嗒__3基] 硫烷基}-1,3-苯并噻唑_2·基)_3_[2_(嗎啉_4_基)乙基]脲 N-(6-{[6-(環己基甲基)[12,4]***并[4 3 b]嗒畊_3基] 硫烷基}-1,3-苯并噻唑_2_基)環丙烷甲醯胺 N-(6-{[6-(環丙基***并[4,3 b]嗒畊_3•基]硫烷 基}-1,3-苯并噻唑_2_基)環丙烷甲醯胺 N-{6-[(6-環丙基[^4]***并[4 3_b]嗒畊_3基)硫烷 基]-1,3-苯并噻唑_2-基}-2-[(2118)嗎啉_4_基]乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3基)硫烷 基]-5-氟-1,3-苯并噻唑-2-基}-2-(嗎啉基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3_b]嗒畊_3基)硫烷 基]-1,3-本并嗓嗤-2-基}-2-(4 -乙基0底p井-i_基)乙酿胺 Ν-{6·[(6-環丙基[1,2,4]***并[4,3-b]嗒啩_3_基)硫院 基]-1,3-本并嗟〇坐-2-基}-2-[(211,68)-2,6-二甲基嗎琳_4 基]乙醯胺 N-{6-[(6-環丙基[1,2,4]三。坐并[4,3-b]嗒畊_3·基)硫燒 基]-1,3 -本并售。坐-2-基}-2-(1,4 -一氧雜_8_氮雜螺[4,5]癸_ 8-基)乙酿胺 2-[4-(環丙基甲基)哌畊-1-基]-N-{6-[(6-環丙基[i,2,4] 二0坐并[4,3-b]。荅17井-3-基)硫院基]_ 1,3-苯并〇塞。坐_2_基)乙 酿胺 2-(4-環丁基略p井-1-基)-N-{6-[(6-環丙基[丨,2,4]三。坐并 [4,3-b]。荅”井-3-基)硫烧基]-1,3-苯并°塞唾-2-基}乙醯胺 154635.doc • 10- 201202242 2-(4-環丙基-3,5-二甲基哌畊-1-基)-N-{6-[(6-環丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒0井-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[(lS,4S)-2-氧雜-5-氮雜雙環 [2,2,1]庚-5-基]乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(8-氧雜-3-氮雜雙環[3,2,1]辛-3-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-5 -氣-1,3 -苯并°塞°坐-2-基}-2-(4 -乙基派11井-1 -基)乙酿胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒呼-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(丙-2-基氧基)哌啶-1-基]乙 醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啫-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(4-乙基哌畊-1-基)哌啶-1-基]乙醯胺 义{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(2-氧雜-6-氮雜螺[3,3]庚-6-基) 乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(1-曱基哌啶-4-基)哌畊-1-基]乙醯胺 义{6-[(6-環丙基[1,2,4]***并[4,3-1?]嗒畊-3-基)硫烷 154635.doc -11 - 201202242 基]-1,3-苯并噻嗦-2-基}-2-{4-[(4-甲基哌畊-1-基)羰基]哌 啶-1-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[(38)-3-曱基嗎啉-4-基]乙醢胺 ]^-{6-[(6-環丙基[1,2,4]***并[4,3-1)]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(嗎啉-4-基甲基)哌啶-1-基] 乙醢胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-5-氟-1,3-苯并噻唑-2-基}-2-[(lS,4S)-2-氧雜-5-氮雜 雙環[2,2,1]庚-5-基]乙醯胺 义{6-[(6-環丙基[1,2,4]***并[4,3-1)]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(4-側氧基哌啶-1-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-甲氧基氮雜環丁烷-1-基)乙 醯胺 义{6-[(6-環丙基[1,2,4]***并[4,3-13]嗒畊-3-基)硫烷 基]-1,3 -苯并°塞σ坐-2-基}-2-[4-(。比洛°定-1 -基)°底°定-1 -基]乙 醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(2-羥基乙基)哌畊-1-基]乙 醢胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(吡咯啶-1-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 154635.doc -12- 201202242 基]-1,3-苯并噻唑-2-基丨-2-(3-羥基吡咯啶-1-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啩-3-基)硫烷 基]-1,3-笨并噻唑-2-基}-2-(3-氟吼咯啶-卜基)乙醯胺 2-[(13,43)-5-環丙基-2,5-二氮雜雙環[2,2,1]庚-2-基]-^^ {6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]_ 1,3-苯并噻唑-2-基}乙醯胺 2-[4-(4-環丙基哌畊-1-基)哌啶-1-基]-N-{6-[(6-環丙基 [1,2,4]***并[4,3-b]嗒啩-3-基)硫烷基]-1,3-笨并噻唑-2-基}乙醯胺 >^-{6-[(6-環丙基[1,2,4]***并[4,3-1)]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[1-(2,2-二氟乙基)哌啶-4-基] 乙醯胺 1^-{6-[(6-環丙基[1,2,4]***并[4,3-1>]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[1-(2,2,2-三氟乙基)哌啶-4-基] 乙醯胺 2-(4-環丙基嗎啉-2-基)-Ν-{6·[(6-環丙基[1,2,4]***并 [4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 2-(4·環丙基嗎啉-3-基)-N-{6-[(6-環丙基[1,2,4]***并 [4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]_1,3_本弁嗟0坐-2-基}-2-[4-(2-曱基丙-2 -基)〇底**井-1-基] 乙醯胺 2-[4-( 丁 -2-基)哌畊-1-基]-N-{6-[(6-環丙基[1,2,4]*** 并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 154635.doc -13- 201202242 N-{6-[(6-環丙基[1,2,4]三0坐并[4,3-b]塔p井-3-基)硫烧 基]-1,3-苯并噻唑-2-基}-2-[4-(甲基磺醯基)哌畊-1-基]乙 醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[4-(丙-2-基)哌畊-1-基]乙醯胺 N2-環丙基-N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-*}-N2-乙基甘胺醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3·基)硫烷 基]-1,3-苯并噻唑-2-基}·Ν2-乙基-N2-丙-2-基甘胺醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-笨并噻唑-2-基}-N242-(二甲基胺基)乙基]-N2-乙 基甘胺醯胺 2-[4-(1-環丙基哌啶-4-基)哌畊-1-基]-N-{6-[(6-環丙基 [1,2,4]***并[4,3-1>]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 2-{4-[1-(環丙基曱基)哌啶基]哌畊-l-基 }-N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并 噻唑-2-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -本并°塞嗤-2-基}·_2-(4 -經基派π定-1-基)乙酿胺 Ν-{6-[(6_環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(3-甲氧基"比咯啶-1-基)乙醯胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[3-(二乙基胺基)咕咯啶-1-基] 154635.doc • 14 - 201202242 乙酿胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒啡-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-[3-(2-乙氧基乙氧基)。比咯啶-1-基]乙醯胺 2-[4-(1- ί哀丙基乙基)痕啡-1 -基]-N -{6-[(6-壤丙基 [1,2,4]***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯并°塞0坐-2-基}-2-(1-曱基派咬-4-基)乙酿胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯并喔嗤-2-基}-2-(1-曱基旅咬-2-基)乙酿胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-2-(1-甲基。比咯啶-3-基)乙醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-4-甲基嗎啉-2-曱醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯弁°塞α圭-2 -基} -1 -甲基〇底。定-3 -曱酿胺 Ν-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3 -苯弁°塞°坐-2-基}-1-甲基派0定-4-甲酿胺 2-[1-(環丙基曱基)哌啶-4-基]-N-{6-[(6-環丙基[1,2,4] ***并[4,3-b]嗒畊-3-基)硫烷基]-1,3-苯并噻唑-2-基}乙 醯胺 N-{6-[(6-環丙基[1,2,4]***并[4,3-b]嗒畊-3-基)硫烷 基]-1,3-苯并噻唑-2-基}-1,4-二曱基哌畊-2-曱醯胺 154635.doc -15- 201202242 6-[(6-環丙基Π,2,4]三。坐并[4,3外Η·]』)硫烧基]_ N-(l-乙基°比嘻啶-3-基)-1,3·苯并噻唾_2_胺 Μ(6·環丙基[1,2,4]三㈣[4,3姻__3基)硫烧基]_ Ν-Π-(四氫吱喃-2·基曱基…定+基⑴苯并嗟嗤冬胺 以及該等式(I)產物與無機及有機酴 ,機奴或與無機及有機鹼之 加成鹽。 6. 一種製備如其他請求項申任一項 W <式⑴產物的方法,其 具有以下流程I : 流程1 :Wherein: R1 represents a non-alkyl group, a cycloalkyl group or a cycloalkylalkyl group; as the case may be substituted as follows; Rb represents a hydrogen atom or a fluorine atom; W represents a hydrogen atom; alkyl group, cycloalkyl group or heterocycloalkyl group Substituted by an alkyl, alkoxy, heterocycloalkyl or NR3R4 group, the groups themselves being substituted as shown below; or a group COR wherein R represents: cycloalkyl, heterocycloalkane Or alkyl group, as the case may be, by one or more groups selected from the group consisting of a hydrogen atom, a transalkyl group, an alkyl group and an alkoxy group, and a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group, a phenyl group and a NR3R4 group. Substituting, such groups are themselves substituted as follows; alkoxy groups, optionally substituted by alkyl, heterocycloalkyl or NR3R4, which groups themselves are substituted as indicated below; or groups _ The hydrazine heterocycloalkyl group is optionally substituted as shown below; or the group NHR2, wherein R 2 represents a hydrogen atom or a cycloalkyl group, a heterocycloalkyl group or an alkyl group, which may be the same or different by one or more a group selected from the group consisting of a peroxy group and an alkoxy group and a heterocycloalkyl group, a heteroaryl group, a strepyl group, and a NR3R4 154635.doc 201202242 group And the groups are themselves substituted as follows; wherein R3 and R4 may be the same or different and are selected from the group consisting of a hydrogen atom and an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group and a phenyl group, as the case may be. Substituted by one or more groups which may be the same or different and are selected from the group consisting of hydroxyl, alkoxy, NH2, NH alkyl, N(alkyl) 2, heterocycloalkyl, heteroaryl and phenyl, such substitutions The group itself is optionally substituted as shown below; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 10 membered cyclic group, optionally containing one or more selected from the group consisting of ruthenium, S, N and NH. Other heteroatoms wherein the optionally present S may be in the form of SO or S02; this group, including any NH which it may contain, is optionally substituted as follows; all such alkyl groups, rings as defined above Alkyl, heterocycloalkyl, -fluorenyl-cycloalkyl, heteroaryl and phenyl, and R3 and R4 may be formed together with the nitrogen atom to which they are attached, optionally by one or more Substituted by a group selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group, -〇-C0-R5, -C00H, COOR5, -CONH2, C 0NHR5, NH2, NHR5, NR5R5, -NH-C0-R5 and -S02-alkyl- groups, and alkyl, cycloalkyl, heterocycloalkyl, alkyl-heterocycloalkyl, C0-heterocyclic An alkyl group, a phenyl group, a CH2-phenyl group, a C0-phenyl group, a heteroaryl group and an S-heteroaryl group, such an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic ring in the substituent groups The alkyl group, the phenyl group and the heteroaryl group are themselves optionally one or more selected from the group consisting of a halogen atom and a hydroxyl group, a pendant oxy group, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group, a cycloalkylalkyl group and an alkane. Substituents of oxy, NH2, NH alkyl and N(alkyl) 2 154635.doc 201202242, all such cycloalkyl, heterocycloalkyl, -〇·heterocycloalkyl, heterocycles as defined above The aryl and stupid groups are also optionally substituted by the group Si(alkyl)3; all such cycloalkyl and heterocycloalkyl groups as defined above may be spirocycloalkyl or spiro on one carbon of the ring. Substituted by a cycloalkyl group, or optionally substituted with a cycloalkyl or heterocycloalkyl group on two carbons of the ring; R5 and R5' may be the same or different and represent an alkyl or cycloalkyl group, optionally a plurality of selected from halogen atoms and hydroxyl groups, including Substituted with an alkyl group of 1 to 4 carbon atoms and a group of an alkoxy group, NH2, NH alkyl group and N(alkyl) 2, the alkyl group represents an alkyl group having from 丨 to (7) carbon atoms; The alkyl group contains up to 3 to 7 carbon atoms; the product of the formula (I) is in any possible racemic, enantiomeric or diastereomeric form, and the product of the formula (1) and the inorganic And organic derogatory or additive salts with inorganic and organic tests. 2. The product of the formula (I) of claim 1, wherein Ri represents a decyl group, a cycloalkyl group or a cycloalkylalkyl group; as the case may be substituted as follows; Rb represents a wind atom or a fluorine atom; W represents a hydrogen atom; An alkyl, cycloalkyl or heterocycloalkyl group, optionally substituted by an alkyl, alkoxy, heterocycloalkyl or NR3R4 group, the groups themselves being substituted as indicated below; or a group C〇 r, wherein R represents a cycloalkyl group 'heterocycloalkyl or alkyl group', optionally, one or more selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group and an alkoxy group, and a cycloalkyl group, a heterocyclic alkyl group, 154635 .doc , 201202242 Substituent substitution of heteroaryl, phenyl and NR3R4 groups, the groups themselves being substituted as shown below; alkoxy, optionally substituted by heterocycloalkyl or ]113114, The group itself is optionally substituted as shown below; or the group _〇_heterocycloalkyl, as the case may be substituted as follows; or the group NHR2 'wherein R 2 represents a hydrogen atom or a cycloalkyl group, a heterocyclic group Or a base, which may be the same or different, and may be selected from the group consisting of hydroxy and alkoxy and heterocycloalkyl, heteroaryl, benzene, as the case may be. Substituted with a group of the NR3R4 group, all of which are substituted as follows; wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and an alkyl group, a cycloalkyl group, a heterocycloalkyl group, and A phenyl group, which may be the same or different, and optionally selected from the group consisting of a hydroxyl group, an alkoxy group, an NH2, an NH alkyl group, and an N(alkyl) 2 group, and a heterocycloalkyl group, a heteroaryl group, and a benzene group, as the case may be. Substituted by a group, the substituents are themselves substituted as follows; or R3 and 4 together with the nitrogen atom to which they are attached form a 3 to 1 member cyclic group, which optionally contains one or more Other heteroatoms selected from the group consisting of ruthenium, S, N and NH, wherein the S present optionally may be in the form of SO or S02, and this group, including any NH which it may contain, is optionally substituted as follows; All such alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkyl, heteroaryl and phenyl groups as defined herein, and R3&R4 together with the nitrogen atom to which they are attached may form such cyclic groups The group is optionally substituted with one or more groups selected from the group consisting of a halogen atom, a hydroxyl group, a pendant oxy group, an alkoxy group, and C0-R. 5. NH2, NH alkyl, N(alkyl)2 and -S02-alkyl, and alkane 154635.doc 201202242, cycloalkyl, heterocycloalkyl, CH2_heterocycloalkyl, phenyl, CH2j , co-phenyl, heteroaryl and s.heteroaryl, such that in the substituents, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl groups themselves Depending on the case, one or more selected from the group consisting of a dentate atom and a hydroxyl group, a pendant oxy group, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group, a heterocycloalkyl group and an alkoxy group, NH2, NH alkyl group and N Substituted by a group of (alkyl) 2; R5 represents an alkyl or cyclodole; the product of the formula (I) is any possible racemic, enantiomeric or diastereomeric form And an addition salt of the product of the formula (1) with inorganic and organic acids or with inorganic and organic bases. 3. The product of formula (I) according to any one of the claims, wherein R1 has the meaning defined in any of the other claims, Rb represents a hydrogen atom or a fluorine atom, and W represents a hydrogen atom; a cycloalkyl or heterocycloalkyl group, optionally substituted by an alkyl group, a heterocycloalkyl group or an NR3R4 group, which groups are optionally substituted as follows; or a group COR, wherein r represents: a cycloalkyl group, a heterocycloalkyl or alkyl group, optionally substituted by an alkyl group, a heterocyclic alkyl group or an NR3R4 group, which groups are themselves substituted as follows; alkoxy groups, optionally heterocycloalkyl or NR3R4 Substituted, the groups themselves are optionally substituted as follows; or 〇-heterocycloalkyl, as the case may be substituted as follows; or the group NHR2, wherein R2 represents a hydrogen atom or a burnt group, as the case may be a hetero-alkyl group or a NR3R4 group; these groups are themselves substituted as follows; 154635.doc 201202242 wherein R3 and R4 may be the same or different and are selected from a hydrogen atom and an alkyl group, a cycloalkyl group and a heterocycloalkyl group. , as the case may be the same or different and selected from alkoxy, heterocycloalkyl Substituting a group of NH2, NH alkyl and N(alkyl) 2 groups; or R3 and R4 together with the nitrogen atom to which they are attached form a 3 to 7 membered cyclic group, optionally containing one or more selected from the group consisting of one or more And other heteroatoms of NH, including the NH as it is contained, optionally substituted as follows; all such alkyl, heterocycloalkyl and _0_ as defined above A heterocycloalkyl group, and R3 and R4, which may be formed together with the nitrogen atom to which they are attached, are optionally substituted with one or more groups selected from the group consisting of a dentate atom, a hydroxyl group, an alkoxy group, NH2, NH alkyl 'N(alkyl) 2 and -S02-alkyl, and alkyl, cycloalkyl, heterocycloalkyl, CH 2 heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl In such a substituent group, the alkyl group, the alkoxy group, the cycloalkyl group, the heterocycloalkyl group, the phenyl group and the heteroaryl group are themselves optionally selected from one or more selected from the group consisting of a dentate atom and a hydroxyl group, a group having an alkyl group having up to 4 carbon atoms and an alkoxy group, a cycloalkyl group, a cycloalkylalkyl group, an NH2, an nh alkyl group, and an N(alkyl) 2 group; the product of the formula (I) is Any possibility Racemic, enantiomeric or diastereomeric isomer forms, as well as the equation ⑴ addition salts with mineral and organic acids or with inorganic and organic bases of. 4. The product of formula (I) according to any one of the preceding claims, wherein: R1 represents an alkyl or cycloalkyl or cycloalkylalkyl group; wherein the alkyl group contains 1 to 2 carbon atoms and the ring contains 3 to 6 carbon atoms; 154635.doc -6 - 201202242 Rb represents a hydrogen atom or a fluorine atom; W represents a halogen atom; an alkyl group, a ring-based group or a heterocyclic group, optionally an alkyl group or a heterocycloalkyl group Or a NR3R4 group substituted; or a group COR, wherein R represents: a cycloalkyl, heterocycloalkyl or alkyl group, optionally substituted with an alkyl 'heterocycloalkyl group or an NR3R4 group, which groups are themselves as appropriate Substituted as follows; fluorene-heterocyclic compound 'substituted as shown below; or group NHR2, wherein R2 represents a hydrogen atom or an alkyl group, optionally substituted with a heterocycloalkyl group or an NR3R4 group, The group itself is optionally substituted as shown below; wherein R3 and R4 may be the same or different and represent a hydrogen atom or an alkyl or cycloalkyl group, optionally substituted by the group N(alkyl)2, or The attached nitrogen atoms together form a cyclic group which optionally contains one or more other heterogeneous species selected from the group consisting of ruthenium and NH. , the group, including the optionally present NH, as the case may be substituted; all such alkyl, heterocycloalkyl and hydrazine-heterocyclic groups, and R3 and R4, as defined above The cyclic groups which may be formed together with the nitrogen atom to which they are attached are optionally substituted with one or more groups selected from the group consisting of a dentate atom, a hydroxyl group, a pendant oxy group, an alkoxy group, an NH2, an NH alkyl group, N (alkyl) 2 and -S02-alkyl, and alkyl, cycloalkyl, heterocycloalkyl, alkyl-heterocyclic, CO-heterocyclic, and stupid, the substituents themselves Optionally, one or more selected from the group consisting of a halogen atom and a hydroxyl group, a alkyl group having 1 to 4 carbon atoms, a cycloalkyl group, a cycloalkyl group, an alkoxy group, an NH2 group, an NH group, and a 154635.doc 201202242 N Substituted by a group of (alkyl) 2; the product of the formula (1) is any possible racemic, enantiomeric or diastereomeric (4) formula, and the product of the formula (1) with inorganic and acid or with inorganic And organic test addition salts. 5. A product of formula (1) according to any one of the claims, which corresponds to the formula: cyclopropyl U, 2, 4b oxazo[4 3 oxo _3 yl) sulfanyl]-1,3 benzene And 嗟 -2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1,3-benzoindole-2-amine is 6-[(6-cyclopropyl π,2,4]triazino[4,3 荅 荅 _ 3 _ _ ] ] ] ]]]] Benzosin-2-yl}-2-(Merlinyl-4-yl)ethenylamine 2-(4-cyclopropylpiperidine_丨_yl)_沁{6_[(6-cyclopropyl[12] 4] Triazolo[4,3-6]indole-3-yl)sulfanyl]_ι,3·benzothiazole_2•yl}acetamidamine 6-[(6-cyclopropyl[^4] Triazolo[4,3_6]嗒耕_3_yl)sulfanyl]-1,3·benzothiazole_2_kib 2_(4_fluoropiperidinyl)ethylamine #-{ 6-[(6-cyclopropyl[i'2,4]triazolo[4,3_6]indole_3_yl)sulfanyl]-1,3-benzothiazol-2-yl}_2_[ 4-((morpholine-4-yl)piperidinyl]acetamidine #-{6_[(6-cyclopropyl[^4]triazolo[4 3 6]indole·3•yl)sulfanyl] -1,3-benzothiazole_2•基卜2_[4_(2-ethoxyethyl)piped_丨_yl] acetamidine N-(6-{[6-(cyclohexylmethyl)) [1,2,4] Triazolo[43.6]嗒耕_3_基] sulfanyl group 1,3·benzothiazol-2-yl)-2-(4-cyclopropylpipedyl-1-yl)ethyl 154635. Doc 201202242 Indole iV-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3 work]嗒耕-3-yl]sulfanyl}-1,3 -benzothiazol-2-yl)-2-(morpholinyl)acetamide (3i?)-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3- 6]嗒耕_3·yl)sulfanyl]-1,3-benzopyrene0-yl-2-yl}aminocarboxylic acid 1·methyl „比略____yl ester (3<S)- {6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzopyrene ° sitting-2 -基}Aminoguanidine ι_曱-yl n ratio slightly bite _3_基酉 { {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-6] 嗒耕- 3-yl)sulfanyl]-1,3-1,3-benzo-°-yl-2-yl}aminocarbamate 1-methylpyrazine _4-yl ester {6-[(6-% propyl[1] , 2,4] II. Sit and [4,3-6]β荅p well-3-yl) sulphonic > base]··· l,3-benzo-pyrazol-2-yl} carbamic acid L-(2-fluoroethyl)β bottom bite 4-yl ester (3 and)-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4,3- Ζ>]嗒-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamic acid 1·methylpyrrolidine 3-yl vinegar (3<S)-(6-{[6-(cyclohexylfluorenyl)[1,2,4]three" sits and [4,3-6] tower ρ well-3· ki] Sulfur yard base}-1,3-benzene sigh. Sodium-2-yl)amino phthalic acid ι_ fluorenyl. 6-[(6-cyclopropyl[I,2,4]triazolo[4,3-6]indol-3-yl)sulfanyl]-#-[ 2·(4,4-Difluoropiperidin-1-yl)ethyl]·1,3- benzothiazol-2-amine 2-(4-cyclopropylpiped-1-yl)-#-{ 6-[(6-fluorenyl[1,2,4]triazolo[4,3-6]indole-3-yl)thioalkyl]-1,3-benzothiasin-2-yl }乙含胺#-{6-[(6-Mercapto[1,2,4]triazolo[4,3-6]indole-3-yl)sulfanyl]-1,3-benzox Thiazol-2-yl}cyclopropanecarbamamine #-{6-[(6-fluorenyl[1,2,4]triazolo[4,34]indol-3-yl)sulfanyl]- 154635 .doc -9- 201202242 1,3-benzothiazol-2-yl}-2-(morpholine-4-yl)acetamide 1-(6-{[6-(cyclohexylmethyl)[124] Triazolo[43]]嗒__3yl]sulfanyl}-1,3-benzothiazolyl-2-yl)_3_[2_(morpholin-4-yl)ethyl]urea N-(6-{ [6-(cyclohexylmethyl)[12,4]triazolo[4 3 b]indole_3yl]sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide N-(6-{[6-(cyclopropyltriazolo[4,3 b]indole _3•yl]sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamidine Amine N-{6-[(6-cyclopropyl[^4]triazolo[4 3_b]indole_3yl)sulfanyl]-1,3-benzothiazole_2-yl}-2- [ (2118) morpholine _4_yl] acetamamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3_b]indole _3yl)sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl}-2-(morpholinyl)acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo [4,3_b]嗒耕_3基)sulfanyl]-1,3-benzin-2-yl}-2-(4-ethyl 0 bottom p-i-yl) -{6·[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)thiol]-1,3-this squat- 2-yl}-2-[(211,68)-2,6-dimethylmorphin_4yl]acetamide N-{6-[(6-cyclopropyl[1,2,4]3 Sit and [4,3-b] sorghum _3·yl) sulphide]-1,3 - this is sold. Sit-2-yl}-2-(1,4-oxo_8_ Azaspiro[4,5]indole-3-yl)ethanoyl 2-[4-(cyclopropylmethyl)piped-l-yl]-N-{6-[(6-cyclopropyl[ i,2,4] 2 sit-and-[4,3-b]. 荅17 well-3-yl) sulphur-based]_1,3-benzopyrene. sit _2_base) -(4-Cyclobutyl succin-1-yl)-N-{6-[(6-cyclopropyl[丨,2,4]三. Sit and [4,3-b].荅"well-3-yl) thiol group]-1,3-benzox-sodium-2-yl}acetamide 154635.doc • 10- 201202242 2-(4-cyclopropyl-3,5- Dimethylpipen-1-yl)-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl ]-1,3-Benzothiazol-2-yl}acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒0 well- 3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[(lS,4S)-2-oxa-5-azabicyclo[2,2,1]heptane- 5-yl]acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1, 3-benzothiazol-2-yl}-2-(8-oxa-3-azabicyclo[3,2,1]oct-3-yl)acetamide N-{6-[(6-cyclo) Propyl [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-5-gas-1,3-benzo-°°°-2-yl} -2-(4-ethylpyrene-11-l-yl)ethenylamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]嗒3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(propan-2-yloxy)piperidin-1-yl]acetamide N-{ 6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl} -2-[4-(4-ethylpiped-1-yl)piperidin-1-yl]acetamide {6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-13]indole-3-yl)sulfanyl]-1,3-benzothiazole-2- }}-2-(2-oxa-6-azaspiro[3,3]hept-6-yl) acetamidine N-{6-[(6-cyclopropyl[1,2,4]3 Zoxa[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(1-mercaptopiperidin-4-yl) Piperidin-1-yl]acetamid {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1?]indol-3-yl)sulfane 154635 .doc -11 - 201202242 ]]-1,3-benzothiazin-2-yl}-2-{4-[(4-methylpipelin-1-yl)carbonyl]piperidin-1-yl} Acetamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzoyl Thiazol-2-yl}-2-[(38)-3-indolylmorpholin-4-yl]acetamide]^-{6-[(6-cyclopropyl[1,2,4]triazole And [4,3-1)]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(morpholin-4-ylmethyl)peri Acridine-1-yl]acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]- 5-fluoro-1,3-benzothiazol-2-yl}-2-[(lS,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-yl]B Indole {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1)]indol-3-yl)sulfane ]]-1,3-benzothiazol-2-yl}-2-(4-oxopiperidin-1-yl)acetamide N-{6-[(6-cyclopropyl[1,2] , 4] Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(3-methoxyazetidine Alkyl-1-yl)acetamid {6-[(6-cyclopropyl[1,2,4]triazolo[4,3-13]indol-3-yl)sulfanyl]-1 , 3 - benzo-β σ sit-2-yl}-2-[4-(.比洛°定-1 -基)°底定定-1 -yl]acetamidamine-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b] Indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(2-hydroxyethyl)piped-1-yl]acetamidamine N-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl} -2-(pyrrolidin-1-yl)acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl) Sulfane 154635.doc -12- 201202242 base]-1,3-benzothiazol-2-ylindole-2-(3-hydroxypyrrolidin-1-yl)acetamide N-{6-[(6- Cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-indolothiazol-2-yl}-2-(3- Fluoropyrrolidine-diylacetamide 2-[(13,43)-5-cyclopropyl-2,5-diazabicyclo[2,2,1]hept-2-yl]-^^ {6-[(6-Cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]_1,3-benzothiazol-2-yl Ethylamine 2-[4-(4-cyclopropylpiped-1-yl)piperidin-1-yl]-N-{6-[(6-cyclopropyl[1,2,4]3 Zizo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine>^-{6-[(6-cyclopropyl) [1,2,4]triazolo[4,3-1)]indole-3-yl Thioalkyl]-1,3-benzothiazol-2-yl}-2-[1-(2,2-difluoroethyl)piperidin-4-yl]acetamide 1^-{6-[ (6-Cyclopropyl[1,2,4]triazolo[4,3-1>]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2 -[1-(2,2,2-trifluoroethyl)piperidin-4-yl]acetamide 2-(4-cyclopropylmorpholin-2-yl)-indole-{6·[(6 -cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine 2- (4. cyclopropylmorpholin-3-yl)-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl) Thioalkyl]-1,3-benzothiazol-2-yl}acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole Phenyl-3-yl)sulfanyl]_1,3_benzin-2-ylidene-2-yl}-2-[4-(2-mercaptopropan-2-yl)indole ** well-1-yl Acetylamine 2-[4-(butyl-2-yl)piped-1-yl]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3] -b]嗒耕-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine 154635.doc -13- 201202242 N-{6-[(6-cyclopropyl[ 1,2,4]Three-position and [4,3-b]T-p--3-yl)thioalkyl]-1,3-benzothiazol-2-yl}-2-[4-(A Sulfosyl) piperidin-1-yl]acetamide N-{6-[(6-cyclopropyl) [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-[4-(propyl- 2-based) piperidin-1-yl]acetamide N2-cyclopropyl-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole Tung-3-yl)sulfanyl]-1,3-benzothiazol-2-*}-N2-ethylglycinamide N-{6-[(6-cyclopropyl[1,2,4 Triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}·Ν2-ethyl-N2-propan-2-ylglycine Amidoxime-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-indotethiazole -2-yl}-N242-(dimethylamino)ethyl]-N2-ethylglycinamide 2-[4-(1-cyclopropylpiperidin-4-yl)piped-1- ]-N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-1>]indol-3-yl)sulfanyl]-1,3-benzene And thiazol-2-yl}acetamide 2-{4-[1-(cyclopropylindolyl)piperidinyl]piped-l-yl}-N-{6-[(6-cyclopropyl[ 1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine N-{6-[( 6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-iso-β嗤-2-yl}·_2 -(4 - keto-pyridin-1-yl) ethylamine Ν-{6-[(6_cyclopropyl[ 1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(3-methoxy&quot ;birridin-1-yl)acetamidamine-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfane ]]-1,3-benzothiazol-2-yl}-2-[3-(diethylamino)pyridin-1-yl] 154635.doc • 14 - 201202242 Ethylamine N-{6 -[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}- 2-[3-(2-ethoxyethoxy). Bilobidine-1-yl]acetamide 2-[4-(1- lysylpropyl)norphin-1 -yl]-N -{6-[(6-platinylpropyl[1,2 , 4] Triazolo[4,3-b]indol-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamidamine N-{6-[(6-ring Propyl [1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzo[0]-2-yl}-2-( 1-曱基派乙-4-基)Ethylamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl) Thioalkyl]-1,3-benzoin-2-yl}-2-(1-indenyl bun-2-yl)ethenylamine N-{6-[(6-cyclopropyl[1] , 2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(1-methyl. Acridine-3-yl)acetamide N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]- 1,3-benzothiazol-2-yl}-4-methylmorpholin-2-indoleamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4, 3-b] indole-3-yl)sulfanyl]-1,3-benzoquinone °A-gu 2 -yl} -1 -methylindole. -3-6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indol-3-yl)sulfanyl]-1, 3-Benzene 塞°°?-2-yl}-1-methyl-pyrene-4-butane-2-[1-(cyclopropylindolyl)piperidin-4-yl]-N-{ 6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzothiazol-2-yl} Acetamine N-{6-[(6-cyclopropyl[1,2,4]triazolo[4,3-b]indole-3-yl)sulfanyl]-1,3-benzoyl Thiazol-2-yl}-1,4-dimethylpiperidine-2-guanamine 154635.doc -15- 201202242 6-[(6-cyclopropylhydrazine, 2,4] III. Sit and [4 , 3 outer Η ·] 』) thiol group] _ N-(l-ethyl ° than acridine-3-yl)-1,3·benzothiazepine-2-amine Μ (6·cyclopropyl [ 1,2,4]three (four) [4,3 marriage __3 base) thiol group] Ν Π-Π-(tetrahydrofuran-2. fluorenyl group ... fixed + group (1) benzoanthracene and the The product of the formula (I) with an inorganic or organic hydrazine, a machine slave or an addition salt with an inorganic or an organic base. 6. A method for preparing a W <formula (1) product as claimed in other claims, having the following scheme I : Process 1: 在以上流程1中’取代基R1及W具有如請求項1至4中 154635.doc -16· 201202242 任一項中對於該等式⑴產物所提供之含義,且式化 合物中之取代基Z表示氫、氰基或硫基,使得化入物(〇) 表示對稱二硫化物。 7. —種製備如請求項1至5中任一項之式(I)產物的方法,其 具有以下流程2 : ' 流程2 :In the above Scheme 1, the substituents R1 and W have the meanings provided for the product of the formula (1) in any of claims 154635.doc -16 201202242, and the substituent Z in the compound of the formula represents Hydrogen, cyano or thio, such that the hydride (〇) represents a symmetrical disulfide. 7. A method of preparing a product of formula (I) according to any one of claims 1 to 5, having the following Scheme 2: 'Process 2: 在流程2中’取代基Rl、R3、R4及Rb具有如請東 至4中任一項中對於該等式⑴產物所提供之含義。 8, 一種製備如其他請求項中任一項之式(I)產物的方法 ,其 154635.doc •17· 201202242 具有以下流程4 : 流程4 :In Scheme 2, the substituents R1, R3, R4 and Rb have the meanings provided for the product of the formula (1) as set forth in any one of the above. 8. A method of preparing a product of formula (I) according to any of the other claims, 154635.doc • 17· 201202242 having the following Scheme 4: Scheme 4: R' (la) (D6)R' (la) (D6) XjCV-ΒΓ 'r, m 在M上流程4中,取代基^及扑具有如請求項1至4中 任人項中對於該等式⑴產物所提供之含義,且在式(Ie) 化《物中,取代基尺6表示視情況經取代之烷基、環烷基 或雜環烷基,如該等通式⑴產物所示。 9. 10. =:求項1至5中任—項之式⑴產物以及該等式⑴產物與 4藥學上可接文之無機及有機酸或與醫藥學上可接受之 無機及有機驗之加成鹽,其係作為藥物。 如請求項5之式⑴產物以及該等式⑴產物與醫藥學上可 接受之無機及有機酸或與醫藥學上可接受之無機及有機 鹼之加成鹽,其係作為藥物。 154635.doc -18- 201202242 η. —種醫藥組合物,其含有如請求項1至5中任—項之式⑴ 產物或此產物之醫藥學上可接受之鹽或此產物之前藥中 之至少一者作為有效成分,及醫藥學上可接受之載劑。 12. —種如請求項i至5中任一項之式⑴產物或此等產物之醫 藥學上可接受之鹽的用途,其係用於製備供抑制激酶蛋 白MET及其突變形式之活性用的藥物。 13· —種如請求項1至5中任一項之式⑴產物之用途,其係用 於製備供治療或預防選自以下群之疾病用的藥物:血管 增生病症、纖維變性病症、「腎隔」細胞增殖病症、代 謝失調、過敏、哮喘、血栓形成、神經系統疾病、視網 膜病、牛皮癬、類風濕性關節炎、糖尿病、肌肉退化 症、細菌感染(尤其單核細胞增多性李氏菌(Ιζ·ίί6η·α 感染)及癌症。 14. 一種如請求項1至5中任一項之式(I)產物之用途,其係用 於製備供治療癌症用之藥物。 15. 如請求項14之用途,其係用於治療實體或液體腫瘤。 16·如請求項14或15之用途,其係用於治療抗細胞毒性劑之 癌症。 17.如請求項14至16中一或多項之用途’其係用於治療原發 性腫瘤及/或轉移,尤其胃癌、肝癌、腎癌、卵巢癌、腸 癌或***癌、肺癌(NSCLC及SCLC) '膠質母細胞瘤、 甲狀腺癌、膀胱癌或乳癌、黑色素瘤、淋巴或骨髓造血 腫瘤、肉瘤、腦癌、喉癌、淋巴系統癌症、骨癌及騰腺 癌0 154635.doc 19- 201202242 種如吻求項1至5之式⑴產物之用途,其係用於製備用 於癌症化學療法之藥物。 19· ^如D月求項!至5之式⑴產物之用途,其係用於製備用 於單獨或組合癌症化學療法之藥物。 2〇·如請求項1至5中任一項之式⑴產物,其係作為激酶抑制 劑。 21.如請求項⑴中任—項之式⑴產物,其係作為赠抑制 劑。 .種口成中間物’其具有如請求項6至8中所定義且下文 中再次提及之式(C)、(Dl)、(D2)、(D3)、(D4)、(D5)、 (D6)、(G)、(K)及(Μ),其係作為新穎工業產物:XjCV-ΒΓ 'r, m In Scheme 4, the substituents have the meanings provided for the product of the equation (1) in any of claims 1 to 4, and are expressed in the formula (Ie) In the above, the substituent base 6 represents an optionally substituted alkyl group, a cycloalkyl group or a heterocycloalkyl group as shown by the products of the above formula (1). 9. 10. =: Product of formula (1) in any of items 1 to 5 and the product of the formula (1) and 4 pharmaceutically acceptable inorganic and organic acids or pharmaceutically acceptable inorganic and organic tests An addition salt is used as a drug. The product of the formula (1) of claim 5 and the addition salt of the product of the formula (1) with a pharmaceutically acceptable inorganic or organic acid or a pharmaceutically acceptable inorganic or organic base are used as a medicament. 154635.doc -18-201202242 η. A pharmaceutical composition comprising the product of formula (1) as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt of the product or at least one of the prodrugs of the product One is an active ingredient and a pharmaceutically acceptable carrier. 12. Use of a product of formula (1) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt of such a product, for the preparation of an activity for inhibiting kinase protein MET and mutant forms thereof Drug. 13. Use of the product of formula (1) according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of a disease selected from the group consisting of vascular proliferative disorders, fibrotic disorders, "kidney" Cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, neurological diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, bacterial infections (especially Listeria monocytogenes ( 14. The use of a product of formula (I) according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of cancer. Use for the treatment of solid or liquid tumors. 16. The use of claim 14 or 15 for the treatment of cancers against cytotoxic agents. 17. Use of one or more of claims 14 to 16. 'It is used to treat primary tumors and / or metastasis, especially gastric cancer, liver cancer, kidney cancer, ovarian cancer, intestinal or prostate cancer, lung cancer (NSCLC and SCLC) 'glioblastoma, thyroid cancer, bladder cancer or Breast cancer, black Pigmentoma, lymphoid or bone marrow hematopoietic tumor, sarcoma, brain cancer, laryngeal cancer, lymphatic cancer, bone cancer and adenocarcinoma 0 154635.doc 19- 201202242 The use of the product of formula (1), such as Kiss 1 to 5, It is used to prepare drugs for cancer chemotherapy. 19· ^ For the purpose of D month! The use of the product of formula (1) to 5, for the preparation of drugs for cancer chemotherapy alone or in combination. The product of the formula (1) according to any one of items 1 to 5, which is a kinase inhibitor. 21. The product of the formula (1) according to any one of the items (1), which is used as a gift inhibitor. It has the formulas (C), (Dl), (D2), (D3), (D4), (D5), (D6), (G) as defined in claims 6 to 8 and mentioned again below. , (K) and (Μ), which are novel industrial products: (Κ) 其中Rl、Rb、R3、R4、R5及R6具有對於如請求項1至 4中任一項之式(I)產物所示之定義。 154635.doc -20- 201202242 四、 指定代表圖: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件符號簡單說明: 五、 本案若有化學式時,請揭示最能顯示發明特徵的化學式:(Κ) wherein R1, Rb, R3, R4, R5 and R6 have the definitions indicated for the product of the formula (I) according to any one of claims 1 to 4. 154635.doc -20- 201202242 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If the case has a chemical formula, please reveal the best display. Chemical formula of the inventive feature: 154635.doc154635.doc
TW100110835A 2010-03-30 2011-03-29 6-(alkyl-or cycloalkyl-triazolopyridazine-sulfanyl)benzo-thiazole derivatives: preparation, and use as medicaments and as MET inhibitors TW201202242A (en)

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FR1052367A FR2958292A1 (en) 2010-03-30 2010-03-30 New 6-triazolopyridazine-sulfanyl benzothiazole compounds are met kinase inhibitors useful for treating e.g. metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, diabetes and cancers
FR1058393A FR2966151B1 (en) 2010-10-14 2010-10-14 6- (ALKYL- OR CYCLOALKYL-TRIAZOLOPYRIDAZINE-SULFANYL) BENZOTHIAZOLES DERIVATIVES: PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS MET INHIBITORS
FR1151138 2011-02-11

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MX2015012062A (en) 2013-03-14 2016-05-05 Tolero Pharmaceuticals Inc Jak2 and alk2 inhibitors and methods for their use.
CA3084809A1 (en) * 2017-12-07 2019-06-13 The Regents Of The University Of Michigan Nsd family inhibitors and methods of treatment therewith
JP2021530554A (en) 2018-07-26 2021-11-11 スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド Methods and ACVR1 Inhibitors for Treatment of Diseases with Abnormal ACVR1 Expression
BR112021018168B1 (en) 2019-03-21 2023-11-28 Onxeo PHARMACEUTICAL COMPOSITION, COMBINATION AND KIT COMPRISING A DBAIT MOLECULE AND A KINASE INHIBITOR FOR THE TREATMENT OF CANCER
EP4054579A1 (en) 2019-11-08 2022-09-14 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
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PA8792501A1 (en) 2007-08-09 2009-04-23 Sanofi Aventis NEW DERIVATIVES OF 6-TRIAZOLOPIRIDACINA-SULFANIL BENZOTIAZOL AND BENCIMIDAZOL, ITS PREPARATION PROCEDURE, ITS APPLICATION AS MEDICATIONS, PHARMACEUTICAL COMPOSITIONS AND NEW MAIN USE AS MET INHIBITORS.
FR2933982A1 (en) 2008-07-18 2010-01-22 Sanofi Aventis NOVEL IMIDAZO-1,2-A! PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS MET INHIBITORS

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