TW201040187A

TW201040187A - 6-(6-o-cycloalkyl-or 6-NH-cycloalkyl-triazolopyridazine-sulfanyl) benzothiazole and benzimidazole derivatives: preparation, and use as medicaments and as MET inhibitors

Info

Publication number: TW201040187A
Application number: TW099103558A
Authority: TW
Inventors: Eric Bacque; Conception Nemecek; Antonio Ugolini; Sylvie Wentzler
Original assignee: Sanofi Aventis
Priority date: 2009-02-06
Filing date: 2010-02-05
Publication date: 2010-11-16
Also published as: BRPI1011354A2; EP2393790A1; SG173558A1; MA33102B1; FR2941949A1; CN102388029A; EA201171010A1; AR075248A1; AU2010212231A1; FR2941949B1; MX2011008312A; KR20110126660A; IL214407A0; CO6400222A2; UY32419A; JP2012517407A; CA2751525A1; WO2010089506A1

Abstract

The invention relates to the novel products of formula (I): in which represents a single or double bond; Ra represents -O-cycloalkyl or -NH-cycloalkyl; X represents S, SO or SO2; A represents NH or S; W represents H, alkyl or COR with R representing cycloalkyl; alkyl; alkoxy; O-phenyl; -O- (CH2)n-phenyl with n = 1 to 4; or NR1R2 with R1 representing H or alk and R2 represents H, cycloalkyl, heterocycloalkyl or alkyl; or alternatively R1 and R2 form with N a ring optionally containing O, S, N and/or NH; all these radicals being optionally substituted; these products being in any isomeric form, and the salts, as medicaments, especially as MET inhibitors.

Description

201040187 六、發明說明：【發明所屬之技術領域】本發明係關於新額6 、' 烷基-或6-NH-環烷基_***并嗒二土开心及笨并°米嗤衍生物，製備彼等之方法，所二中間物’其作為藥物之用途，含有彼等之醫藥生:之新Γ種6_三嗤并。终硫基苯并❹及苯并味吐衍生物之新病用途。201040187 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a novel 6 , 'alkyl- or 6-NH-cycloalkyl-triazolo-p-dioxin happy and stupid ° 嗤 derivative, In the preparation of these methods, the two intermediates' use as medicines, including their medical students: the new species 6_三嗤. The use of terminal thiobenzindole and benzo-flavored organisms for new diseases.

或==彻 6_Q_W 物，經由調編=，并…苯輸衍生贫白#(知·別是激酶）之活性。【先前技術】胞2 ’在化學療法中所使用之大部份市售化合物係為細用:藥物現副作用及病患耐藥性之主要問題。若所使柰物έ選擇性地作用於癌细則此等作用可受到m '’上’而排除健康細胞，之解決辦法之制。用於限制化學療法之不想要作用 — 可因此包括使用會作用於代謝途徑或此等返棱之組成構件之藥物，主要hH飞此4 或僅節制w αI 表見衣癌細胞中，而不表現族群11:健康細胞中。激酶蛋白質為-種酵素如-胺酸、絲胺酸或蘇胺酸=:基_化作用，譬地修改蛋白質之功能：因：：：種卿作用可廣泛細胞過程中扮演一項重要角色節極多種作用及增生、細胞黏連與能動性，。括、"胞新陳代謝某此、生、、細胞分化或、細胞存活， '…考蛋白貝係在細胞循環事件之引發、發展及完成上 145862 201040187 扮演一項中樞角色。在其中係涉及激酶蛋白質之些過程係代表用於治療某歧：性之各種細胞功能中，某及之實例包括血管一矢病之吸引人標的。可特別提 ❹ ❹ 其中激酶蛋白質可H = ^環以及細胞增生之控制，是固態腫瘤以及其他疾病之=角色。此等過程係為尤其此種激酶之分子係能夠限制不：所必須.特定言之’抑制症中所發現者，且可 ==胞增生’譬如在癌療，譬如阿耳滋_^ 疾病之預防、謂節或治本發明之！氏病或神經元細辑。乃之一項主題係為對於新賴衍生物。根據本發明之產物蛋白貝賦與抑制作用之治療可藉由抑制激酶蛋白質可因此尤其是用於預防或根據本發明之產物尤其是：:周制之疾病。癌活性。在對1需：疋、…敫酶活性之調制’顯示抗贿之突變體係為=制之激酶中’肅以及蛋白質 =明=於該衍生物製備供治療人類之物之—係為提出具有抗癌… 激酶二::酶發生作用。在對其需要活性調制之在下文藥理學段兹+ . y^ 胞系*正實本鼻刹由物化學試驗中及對於細碟酿化，w 案之產物係因此尤其是抑制贿之自增+生/’及其生長係依賴贈或其突變形式之細胞之贈或肝細胞心子受輯―種具㈣胺酸激酶活 145862 201040187 性之受體’其係特別表現於上皮與内皮細胞中。hgf，肝細胞生長因子，係被描述為met之專一配位體。HGF係藉由間葉細胞分泌，且會使met受體活化，其會均二聚化。因此’該受體變成自磷醯基化於催化功能部位之酪胺酸 Y1230、Y1234 及 Y1235 上。 MET藉由HGF之刺激會引致細胞增生、擴散（或分散）及能動性’對細胞凋零之抵抗性、侵入及血管生成。已發現MET及同樣為HGF係被過度表現於許多人類腫瘤及極多種癌症中。亦已發現MET係在胃腫瘤與神經膠質母細胞瘤中被放大。MET基因之許多點突變亦已被描述於腫瘤中’特別是在激酶功能部位中，而且亦在近細胞膜功能部位與SEMA功能部位中。過度表現 '放大或突變會造成受體之構成活化作用，及其功能之失調。本&明因此尤其是關於激酶蛋白質MET及其突變體之新 :抑制劑，其可用於抗增生與抗轉移治療，尤其是在腫瘤学上。質MET及其突變體之新穎抑制療’尤其是在腫瘤學上。本發明亦關於激酶蛋白Or == complete 6_Q_W, through the modulation =, and ... benzene to derive the activity of poor white # (known as a kinase). [Prior Art] Most of the commercially available compounds used by the cells in chemotherapy are used in detail: the main side effects of the drug and the main problem of drug resistance. If the mites are selectively acted upon by cancer, these effects can be taken by m '' and exclude healthy cells. Used to limit the unwanted effects of chemotherapy – it may therefore include the use of drugs that act on metabolic pathways or components of such returning edges, primarily hH fly 4 or only control w αI in cancer cells without expression Ethnic group 11: in healthy cells. The kinase protein is an enzyme such as -amine acid, serine acid or threonine =: basal-chemical action, which modifies the function of the protein: because::: The role of the seed can play an important role in a wide range of cellular processes. A variety of effects and proliferation, cell adhesion and motility. Included, "cell metabolism, this, life, cell differentiation or cell survival, '...The protein shellfish plays a central role in the initiation, development and completion of cell cycle events 145862 201040187. Among the processes involved in the involvement of kinase proteins are representative of various cellular functions for the treatment of certain traits, and some examples include the attractiveness of vascular disease. Special mention can be made ❹ 激酶 where the kinase protein can be controlled by H = ^ loop and cell proliferation, which is the role of solid tumors and other diseases. These processes are particularly limited to the molecular structure of such a kinase: it is necessary. Specifically, it is found in the 'inhibition disease, and can be == cell proliferation', such as in cancer therapy, such as Alzheimer's disease Prevention, predation or treatment of the invention! A series of diseases or neurons. One of the themes is for the new Lai derivatives. The treatment of the product protein and inhibition according to the invention can be used, in particular, for the prevention or according to the invention, in particular by: inhibition of the kinase protein. Cancer activity. In the case of the need for: 疋, ... 敫 enzyme activity modulation 'shows that the anti-bribery mutation system is the system of the = system of the 'supplement and protein = Ming = the preparation of the derivative for the treatment of humans - is proposed to have resistance Cancer... Kinase II:: Enzymes work. In the following pharmacology section: y ^ cell line * positive real-time nasal brake chemical test and for the fine-disc brewing, the product of the w case is therefore especially inhibiting the increase of bribes + Health/' and its growth depend on the gift of the cell or the mutant form of the hepatocyte heart--the species (4) Amino acid kinase 145862 201040187 The receptor of the sex's line is particularly expressed in the epithelium and endothelial cells. Hgf, a hepatocyte growth factor, is described as a specific ligand for met. HGF is secreted by mesenchymal cells and activates the met receptor, which dimerizes. Therefore, the receptor becomes self-phosphorylated at the catalytic functional sites of tyrosine Y1230, Y1234 and Y1235. MET stimulation by HGF causes cell proliferation, spread (or dispersion), and motility to resist, invade, and angiogenesis. MET and the same HGF line have been found to be overexpressed in many human tumors and in many cancers. The MET system has also been found to be amplified in gastric tumors and glioblastomas. Many point mutations in the MET gene have also been described in tumors, particularly in the functional sites of kinases, and in the functional sites near the cell membrane and in the functional sites of SEMA. Excessive performance 'Amplification or mutation causes activation of the receptor and its function. This & Ming is therefore particularly relevant to the kinase protein MET and its mutants: inhibitors, which are useful in anti-proliferative and anti-metastatic treatments, especially in oncology. The novel inhibition of MET and its mutants is especially in oncology. The invention also relates to kinase protein

其可用於抗血管生成治【發明内容】个赞明之It can be used for anti-angiogenesis treatment [invention content]

J、主題為式（I)產物其中 145862 201040187 表示單或雙鍵；J, the subject is the product of formula (I) wherein 145862 201040187 represents a single or double bond;

Ra表示基團-〇-環烧基或基團-NH-環烧基，兩者均視情況經取代； X表示S、SO或S02 ; * A表示NH或S ; • W表示氫原子；視情況被烷氧基、雜環烷基或NR3R4取代之烷基；或基團COR，其中R表示： ❽ 烧基或烧基’視情況被鹵原子或基團環烧基、 NR3R4、烷氧基、羥基、苯基、雜芳基或雜環烷基取代，取代基本身係視情況經取代； - 烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基取代；基團0-苯基或基團0-(CH2)n-苯基，其中笨基視情況經取代，且η表示1至4之整數； -或基團NR1R2，其中R1與R2係致使R1與R2中之—表示氫原子、環烷基或烷基，而R1與R2中之另一個表 Q 示氫原子、環烷基、雜環烷基或烷基，視情況被一或多個可為相同或不同之基團取代，選自下列基團：羥基、烷氧基、雜芳基、雜環烷基、NR3R4、苯 * 基’視情況經取代，或者’ R1與R2和彼等所連接之 ’ 氮原子形成3-至10-員環狀基團，視情況含有一或多個其他雜原子，選自〇、S、N及ΝΗ，其中選用之S 可能里SO或S02形式；此基團’包括其含有之可能 NH ’係視情況經取代；其中R3與R4，其可為相同或不同，係表示氫原子、烷 145862 201040187 基、環烷基、雜環烷基、雜芳基或苯基，全部均視情況被一或多個可為相同或不同之基團取代，選自下列基團··羥基、烷氧基、雑芳基、雜環烷基、Nm、 NHAik、N(Alk)2或笨基，視情況經取代；或者，汜與斛和彼等所連接之氮原子形成3_至1〇_員環狀基團，視情況含有一或多個其他雜原子，選自〇、s、，其中選用之S可能呈S0或s〇2形式；此基團，包括其含有之可能NH ’係視情況經取代；上文定義之所有烷基、環烷基、雜環烷基、雜芳基及笨基，以及可藉由R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自函原子與下列基團：經基、酮基、烷氧基、_〇_c: R5、-COOH、C00R5、_c〇腦、c〇NHR5、臟順％、 NR5R5、-NH-C0-R5及院基、環烧基、雜環院基、⑽-雜環烷基苯基、CH2-苯基、C0-苯基、雜芳基及s雜芳基，以致在後述基ffi巾，歸、環院基、雜環絲、苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自鹵原子與下列基團：Μ基、酮基、含有i至4個碳原子之烧基與烷氧基、NH2、NHalk 及 N(alk)2，上文定義之所有環烷基、雜環烷基、雜芳基及苯基係進— 步視情況被基團Si(alk)3取代；上文定義之所有環烷基與雜環烷基可視情況在該環之其中一個碳上被螺環烷基或螺雜環烷基取代，或視情況在該環之兩個喊上被稍合之環烧基或雜環院基取代； 145862 201040187 R5與R5,，其可為相同或不同，表示含有不超過ό個碳原子之烷基或環烷基； alk表示含有不超過4個碳原子之烷基；應明瞭的是，當A表示S，X表示S，Ra表示未經取代之〇_ 環己基或未經取代之NH-環己基，且二二表示雙鍵時，w 不表示Η，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’以及該式（I)產物與礦酸及有機酸類或與礦鹼及 ® 有機鹼類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，其中 ——表示單或雙鍵；Ra represents a group - anthracene-cycloalkyl group or a group -NH-cycloalkyl group, both of which are optionally substituted; X represents S, SO or S02; * A represents NH or S; • W represents a hydrogen atom; An alkyl group substituted with an alkoxy group, a heterocycloalkyl group or NR3R4; or a group COR, wherein R represents: an anthracenyl group or an alkyl group, optionally a halogen atom or a cyclic group, NR3R4, alkoxy group Substituted by a hydroxy, phenyl, heteroaryl or heterocycloalkyl group, the substituent is optionally substituted; - alkoxy, optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl; group 0 a phenyl group or a group 0-(CH2)n-phenyl, wherein the stupid group is optionally substituted, and η represents an integer from 1 to 4; or the group NR1R2, wherein R1 and R2 are such that R1 and R2 are — represents a hydrogen atom, a cycloalkyl group or an alkyl group, and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group or an alkyl group, which may be the same or different by one or more Substituted by a group selected from the group consisting of hydroxy, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl*, as appropriate, or 'R1 and R2, and the nitrogen to which they are attached The atom forms a 3- to 10-membered cyclic group, optionally containing one or more other heteroatoms, selected from the group consisting of ruthenium, S, N and oxime, wherein the S may be in the form of SO or S02; this group includes It may contain NH's as appropriate; wherein R3 and R4, which may be the same or different, represent a hydrogen atom, an alkane 145862 201040187 group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group or a phenyl group, All are optionally substituted by one or more groups which may be the same or different, selected from the group consisting of hydroxyl, alkoxy, fluorenyl, heterocycloalkyl, Nm, NHAik, N(Alk)2 Or a stupid base, as the case may be substituted; or, a nitrogen atom to which the hydrazine and hydrazine are attached form a 3 to 1 〇 member cyclic group, optionally containing one or more other heteroatoms, selected from hydrazine, s, wherein the selected S may be in the form of S0 or s〇2; this group, including the possible NH's contained therein, is optionally substituted; all alkyl, cycloalkyl, heterocycloalkyl, as defined above, a heteroaryl group and a stupid group, and a cyclic group which may be formed by a nitrogen atom to which R1 and R2 or R3 and R4 are bonded to each other, as the case may be. Substituted by one or more groups, the substituent is selected from the group consisting of a radical, a keto group, an alkoxy group, _〇_c: R5, -COOH, C00R5, _c camphor, c〇NHR5, dirty Cis%, NR5R5, -NH-C0-R5 and affinyl, cycloalkyl, heterocyclic, (10)-heterocycloalkylphenyl, CH2-phenyl, C0-phenyl, heteroaryl and s Therefore, in the following description, the base ffi, the ring, the heterocyclic, the phenyl and the heteroaryl are optionally substituted by one or more groups selected from a halogen atom and the following groups: a ketone group, a ketone group having from 1 to 4 carbon atoms and an alkoxy group, NH2, NHalk and N(alk)2, all cycloalkyl, heterocycloalkyl, heteroaryl and phenyl groups as defined above Typing - stepwise substitution by the group Si(alk)3; all cycloalkyl and heterocycloalkyl groups as defined above may optionally be spirocycloalkyl or spiroheterocycloalkyl on one of the carbons of the ring Substituted, or optionally substituted with a slightly cyclized or heterocyclic, in the two rings of the ring; 145862 201040187 R5 and R5, which may be the same or different, meaning no more than one carbon atom Alkyl or cycloalkyl; Alk denotes an alkyl group containing no more than 4 carbon atoms; it should be understood that when A represents S, X represents S, and Ra represents unsubstituted 〇-cyclohexyl or unsubstituted NH-cyclohexyl, and two In the case of a double bond, w does not represent hydrazine, and the product of formula (I) is in any possible racemic, para-isomeric or diastereomeric form 'and the product of formula (I) with mineral acid and organic An acid or an addition salt with a mineral base and an organic base. A subject of the invention is a product of formula 1 as defined above or below, wherein - represents a single or double bond;

Ra表不視情況經取代之基團_〇_環烷基或基團_ΝΗ_^烷基； X表示S、so或so2 ; A表示NH或S ; 〇 W表不氫原子’視情況被烷氧基、雜環烷基或NR3R4取代之烷基；或基團.C0R，其中R表示： "燒基或燒基’視情況被鹵原子或基團環烷基、 NR3R4、烧氧基、羥基、苯基、雜芳基或雜環烷基取代’取代基本身係視情況經取代； -烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基取代；基團0-苯基或基團0_(CH2)n_苯基，其中苯基視情况經取代，且η表示1至4之整數； _或基團NR1R2 ,其中R1與R2係致使R1與R2中之一表 145862 201040187 一、气原子 '環炫*基或^元基，而R1與R2中之另一個表不氫原子、環烷基、雜環烷基或烷基，視情況被一或多個可為相同或不同之基團取代，選自下列基團羧基、烷氧基、雜芳基、雜環烷基、NR3R4、苯基，視情況經取代，或者，則與们和彼等所連接之氮原子形成3-至10-員環狀基團’視情況含有一或多個其他雜原子，選自〇、s、MNH，其中選用之s 可能呈so或S02形式，此基團’包括其含有之可能 NH ’係視情況經取代； -中R3與R4 ’其可為相同或不同’係表示氯原子、烧 2T烷基、雜環烷基、雜芳基或苯基，全部均視情況被 —或多」固可為相同或不同之基團取代，選自下列基團：羥基/完氧基、雜芳基、雜環烷基、NH2、NHAlk、N_2 $笨基，視情況經取代；或者，R3與R4和彼等所連接之 ί原子开v成3-至1〇_員環狀基團’視情況含有一或多個其他雜原子、’選自〇、s、N&NH，其中選用之s可能呈犯或 S02形式，此基團，包括其含有之可能NH，係視情況經取代；上文定義之所有烷基、環烷基、雜環烷基、雜芳基及苯基，以及可藉由R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自鹵原子與下列基團：羥基、酮基、烷氧基、-0-C0-R5、NH2、NHalk、N(alk)2 及烷基、環烷基、雜環烧基、CH2-雜環烷基、苯基、CH2- 145862 -10- 201040187 本基c〇本基、雜^•基及s-雜芳基，以致在後述基團中，烷基、環烷基、雜環烷基、苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自鹵原子與下列基團：羥基、酮基、含有丨至4個碳原子之院基與烧氧基、NH2、NHalk及N(alk)2 ; R5表示含有不超過6個碳原子之烷基或環烷基；該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機驗類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，八中、Ra及X具有其他請求項之任一項中所定義之意義，且： A表示NH或S ; w表示氫原子；視情況被烷氧基、雜環烷基或NR3R4取代之烧基；或基團COR，其中R表示： Q '環烧基或烷基，視情況被鹵原子或基團環烷基、 NR3R4、烷氧基、羥基、苯基或雜環烷基取代，取代基本身係視情況經取代； ' 烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基、取代；基團0-苯基或基團〇-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至4之整數； -或基團NR1R2，其中R1與R2係致使R1與R2中之一表示氫原子或烷基，而R1與R2中之另一個表示氫原子、環烷基、雜環烷基或烷基，視情況被烷氧基或 145862 201040187 雜環烧基或職4取代；或者，R_和彼等所連接之氮原子形成3-至10-員環狀基團，視情況含有〆或多個其他雜原子，選自〇'S、N及丽，此基團，包括其含有之可能NH，係視情況經取代； -其中NR3R4，致使汜與恥，其可為相同或不同，係表示氫原子或烷基或雜環烷基，全部均視情況被一或多個可為相同或不同之基團取代，取代基選自烷氧基或雜環烷基或NH2、NHA1htN(Alk)2;或者，R3 與R4和彼等所連接之氮原子形成3_至1〇_員環狀基團，視情況含有一或多個其他雜原子，選自〇、s、n及 NH ’此基團’包括其含有之可能NH，係視情況經取代；上文所定義之所有環烷基、雜環烷基及苯基，以及可藉由 R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自原子與下列基團.羥基、烷氧基、NH2、NHalk、及烷基、雜％烷基、CH2-雜環烷基' 苯基、CH2_苯基及雜芳基，以致在後述基團中，烷基、雜環烷基' 苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自鹵原子及羥基、含有1至4個碳原子之烷基與烷氧基、NH2、NHaik及 N(alk)2 ； π玄式（I)產物係呈任何可能之外消旋、對掌異構或非對块異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。 145862 201040187 至於可藉由R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團’此等基團視情況含有一或多個其他雜原子，璉自Ο、S、N及NH，其中選用之s可能呈SO或S02形式；此等基團，包括其含有之選用NH，可因此視情況尤其是被選自烷基、烷氧基' 環烷基及雜環烷基之基團取代’其本身係視情況被一或多個基團取代，取代基選自鹵原子與基團烷基、烷氧基、NH2、NHAIk及N(Alk)2 ;The Ra table is irreplaceed by the substituted group _〇_cycloalkyl or the group _ΝΗ_^alkyl; X represents S, so or so2; A represents NH or S; 〇W represents a hydrogen atom 'as appropriate An oxy group, a heterocycloalkyl group or an alkyl group substituted with NR3R4; or a group .C0R, wherein R represents: "alkyl or alkyl group as the case may be a halogen atom or a group cycloalkyl group, NR3R4, alkoxy group, A hydroxy, phenyl, heteroaryl or heterocycloalkyl substituted 'substitution is optionally substituted as appropriate; - an alkoxy group, optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl; group 0- Phenyl or a group 0-(CH2)n_phenyl, wherein phenyl is optionally substituted, and η represents an integer from 1 to 4; _ or a group NR1R2 wherein R1 and R2 form one of R1 and R2 145862 201040187 1. A gas atom is a ring or a group, and the other of R1 and R2 is not a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group or an alkyl group, as the case may be one or more. Substituted by the same or different groups, selected from the group consisting of a carboxyl group, an alkoxy group, a heteroaryl group, a heterocycloalkyl group, an NR3R4, a phenyl group, optionally substituted, or a nitrogen to which they are attached The atom forms a 3- to 10-membered cyclic group 'optionally containing one or more other heteroatoms selected from the group consisting of hydrazine, s, MNH, wherein the selected s may be in the form of so or S02, and the group 'includes It is possible that NH ' is substituted as appropriate; - R3 and R4 'which may be the same or different' means a chlorine atom, a 2T alkyl group, a heterocycloalkyl group, a heteroaryl group or a phenyl group, all of which are optionally — or more” may be substituted by the same or different groups selected from the group consisting of hydroxy/peroxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N 2 $, and optionally substituted; Alternatively, R3 and R4 and the ί atom to which they are attached are opened to form a 3- to 1 〇 member cyclic group ' optionally containing one or more other heteroatoms, 'selected from 〇, s, N&NH, Wherein the selected s may be in the form of S02 or in the form of S02, which includes the possible NH, which may be substituted as appropriate; all alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and benzene as defined above a group, and a cyclic group which may be formed by a nitrogen atom to which R1 and R2 or R3 and R4 are bonded to each other, optionally substituted by one or more groups The substituent is selected from a halogen atom and the following groups: hydroxy, keto, alkoxy,-0-C0-R5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl, CH2 -heterocycloalkyl, phenyl, CH2- 145862 -10- 201040187 benzyl, hydrazino, s-heteroaryl, and s-heteroaryl, such as alkyl, cycloalkyl, heterocycle in the groups described below The alkyl, phenyl and heteroaryl basic groups are optionally substituted by one or more groups selected from the group consisting of a halogen atom and the following groups: a hydroxyl group, a ketone group, a hospital group containing from 丨 to 4 carbon atoms, and a burnt group. Oxyl, NH2, NHalk and N(alk)2; R5 represents an alkyl or cycloalkyl group containing not more than 6 carbon atoms; the product of formula (I) is in any possible racemization, palmar isomerism or a diastereomeric form, and an addition salt of the product of the formula 1 with a mineral acid and an organic acid or with a mineral base and an organic test. A subject of the invention is a product of formula 1 as defined above or below, wherein VIII, Ra and X have the meanings as defined in any of the other claims, and: A represents NH or S; w represents a hydrogen atom An alkyl group substituted by an alkoxy group, a heterocycloalkyl group or NR3R4, or a group COR, wherein R represents: Q 'cycloalkyl or alkyl group, optionally a halogen atom or a cycloalkyl group, NR3R4 , alkoxy, hydroxy, phenyl or heterocycloalkyl substituted, the substituent is optionally substituted; 'alkoxy, optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl; group; 0-phenyl or the group 〇-(CH2)n-phenyl, wherein phenyl is optionally substituted, and η represents an integer from 1 to 4; or the group NR1R2, wherein R1 and R2 are such that R1 and R2 are One represents a hydrogen atom or an alkyl group, and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group or an alkyl group, optionally substituted by an alkoxy group or 145862 201040187 heterocycloalkyl or valence 4 Or, R_ and the nitrogen atom to which they are attached form a 3- to 10-membered cyclic group, optionally containing hydrazine or a plurality of other heteroatoms, selected from hydrazine 'S, N and Li, this group, including its possible NH, is substituted as appropriate; - where NR3R4, which causes sputum and shame, which may be the same or different, means a hydrogen atom or an alkyl or heterocyclic ring Alkyl groups, all optionally substituted by one or more groups which may be the same or different, the substituents being selected from alkoxy or heterocycloalkyl or NH2, NHA1htN(Alk)2; or, R3 and R4 and The nitrogen atom to be attached forms a 3 to 1 membered cyclic group, optionally containing one or more other heteroatoms, selected from the group consisting of hydrazine, s, n and NH 'this group' includes the possible NH Substituted as appropriate; all cycloalkyl, heterocycloalkyl and phenyl groups as defined above, and cyclic groups which may be formed by R1 and R2 or R3 and R4 and the nitrogen atom to which they are attached , optionally substituted by one or more groups selected from the group consisting of an atom and the following groups: hydroxy, alkoxy, NH2, NHalk, and alkyl, heteroalkyl, CH2-heterocycloalkyl' benzene a group, a CH 2 —phenyl group and a heteroaryl group, such that in the groups described below, the alkyl group, the heterocycloalkyl group, the phenyl group and the heteroaryl group are optionally taken by one or more groups. Substituents, the substituent is selected from the group consisting of a halogen atom and a hydroxyl group, an alkyl group having 1 to 4 carbon atoms and an alkoxy group, NH2, NHaik, and N(alk)2; the π-formula (I) product is in any possible elimination. Cyclone, palmomere or non-block isomer form, and addition salts of the product of formula 1 with mineral acids and organic acids or with mineral bases and organic bases. 145862 201040187 As for a cyclic group which may be formed by a nitrogen atom to which R1 and R2 or R3 and R4 are bonded to each other, such groups optionally contain one or more other heteroatoms, from Ο, S, N And NH, wherein the selected s may be in the form of SO or S02; such groups, including the NH selected therein, may therefore be selected, inter alia, from alkyl, alkoxy'cycloalkyl and heterocycloalkyl groups. The group substitution 'is itself substituted by one or more groups, the substituent being selected from the group consisting of a halogen atom and a group alkyl group, an alkoxy group, NH2, NHAIk and N(Alk) 2 ;

其中 '一表示單或雙鍵；如表示基團_〇_環烷基或基團_NH_環烷基，兩者均視情況經取代；〇 X 表示 s、so 或 S02 ; A表示NH或S ; . w表示氫原子；視情況被烷氧基、雜環烷基或N幻財取代之烷基；或基團C0R，其中R表示： '環烧基或烷基，視情況被基團NR3R4、烷氧基、經基、本基、雜芳基或雜環院基取代，取代基本身係視情況經取代； -烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基 145862 -13- 201040187 取代；基團0-苯基或基團〇-(CH2)n-笨基，其中苯基視情況經取代，且n表示1至4之整數； -或基團NR1R2，其中R1與R2係致使R1與R2中之一表示氫原子' 環烷基或烷基，而R1與R2中之另一個表示虱原子、環烧基或院基’視情況被一或多個可為相同或不同之基團取代’選自下列基團：羥基、烧氧基、雜芳基、雜環烧基、NR3R4、苯基，視情況經取代，或者，R1與R2和彼等所連接之氮原子形成3_ 至10-員環狀基團’視情況含有一或多個其他雜原子，選自0、S'N及ΝΗ，此基團，包括其含有之可能NH ’係視情況經取代；其中R3與R4 ’其可為相同或不同，係表示氫原子、院基、環烧基 '雜^基或苯基，全部係視情況經取代，戋者，R3與R4和彼等所連接之氮原子形成3_至1〇_員環狀基團，視情況含有一或多個其他雜原子，選自〇、s、N及 NH，此基團，包括其含有之可能NH ,係視情況經取代；上文定義之所有烷基、環烷基、雜環烷基、雜芳基及苯基’以及可藉由R1與R2或R3與R4和彼等所連接之氮原子开> 成之環狀基團，係視情況被一或多個基團取代，取代美述自ΐ原子與下列基團··經基、酮基、燒氧基、〇 R5、-COOH、COOR5、-CONH2、CONHR5、ΝΗ2、NHR5、 NR5R5'、-NH-CO-R5及烷基、環烷基、CH2-雜環烷基 '苯基、CH2-苯基、CO-苯基 '雜芳基及S_雜芳基，以致在後述基團中，烷基、環烷基、雜環烷基、苯基及雜芳基本身係 145862 -14- 201040187 視情況被一或多個基團取代，取代基選自由原子與下列基團：羥基、酮基、含有…個碳原子之烷基與烷氧基、 NH2、NHalk 及 N(alk)2， . i文定義之所有環炫基、雜環烧基、雜芳基及苯基係進一步視情況被基團Si(alk)3取代； R5與R5 ’其可為相同或不同，係表示含有不超過6個碳原子之烷基或環烷基； alk表示含有不超過4個碳原子之烷基；〇應明瞭的是’ tA表示S，X表示S，Ra表示未經取代之〇_ 環己基或未經取代之NH_環己基，且二二表示雙鍵時，w 不表示Η，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機驗類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物， ^ ^ t ❹ ——表示單或雙鍵；Wherein 'one represents a single or double bond; as indicated by a group _〇_cycloalkyl or a group _NH_cycloalkyl, both are optionally substituted; 〇X represents s, so or S02; A represents NH or S ; . w represents a hydrogen atom; an alkyl group optionally substituted by an alkoxy group, a heterocycloalkyl group or an N-tide; or a group C0R, wherein R represents: 'cycloalkyl or alkyl group, optionally as a group Substituted by NR3R4, alkoxy, thiol, benzyl, heteroaryl or heterocyclic, substituted as such, optionally substituted; - alkoxy, optionally NR3R4, alkoxy, hydroxy or heterocycloalkane Substituent 145862 -13- 201040187 substituted; group 0-phenyl or group 〇-(CH2)n-phenyl, wherein phenyl is optionally substituted, and n represents an integer from 1 to 4; - or group NR1R2, Wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom 'cycloalkyl or alkyl group, and the other of R1 and R2 represents a halogen atom, a cycloalkyl group or a hospital base', as the case may be one or more Substituting the same or different groups for the group selected from the group consisting of hydroxy, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted, or R1 and R2 and their The nitrogen atom to be bonded forms a 3 to 10-membered cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of 0, S'N and hydrazine, and the group, including the possible NH's Substituted; wherein R3 and R4' may be the same or different, and represent a hydrogen atom, a hospital group, a cycloalkyl group, or a phenyl group, all of which are substituted as appropriate, and R3 and R4 and their The nitrogen atom to which it is attached forms a 3 to 1 membered cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of ruthenium, s, N and NH, including the possible NH, Substituted as appropriate; all alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl' as defined above and may be opened by R1 and R2 or R3 and R4 and the nitrogen atom to which they are attached > A cyclic group which is optionally substituted by one or more groups, replacing the hydrazine atom with the following groups: thiol, keto, alkoxy, oxime R5, -COOH, COOR5 , -CONH2, CONHR5, ΝΗ2, NHR5, NR5R5', -NH-CO-R5 and alkyl, cycloalkyl, CH2-heterocycloalkyl 'phenyl, CH2-phenyl, CO-phenyl'heteroaryl And S_ heterofang a group such that an alkyl group, a cycloalkyl group, a heterocycloalkyl group, a phenyl group, and a heteroaryl group 145862 -14- 201040187 are optionally substituted by one or more groups in the group described below, and the substituent is selected from an atom. And all of the following groups: a hydroxy group, a ketone group, an alkyl group having a carbon atom and an alkoxy group, NH2, NHalk, and N(alk)2, . The base and the phenyl group are further substituted by the group Si(alk)3; R5 and R5' may be the same or different, and represent an alkyl group or a cycloalkyl group having not more than 6 carbon atoms; alk means no An alkyl group having more than 4 carbon atoms; 〇 should be clear that 'tA represents S, X represents S, Ra represents unsubstituted 〇_cyclohexyl or unsubstituted NH_cyclohexyl, and when two represents double bond , w does not denote Η, the product of formula (I) is in any possible racemic, para-isomeric or diastereomeric form, and the product of formula 1 with mineral acids and organic acids or with minerals and Addition salts of organic tests. A subject of the invention is a product of formula 1 as defined above or below, ^^t ❹ - representing a single or double bond;

Ra表示基團_〇_環烷基或基團_NH_環烷基，兩者均視情況經 '取代； , X 表示 S、so 或 so2 ; A表示NH或S ; w表示氫原子，視情況被烷氧基、雜環烷基或NR3R4取代之烧基；或基團C0R，其中r表示： -環烷基或烷基，視情況被基團NR3R4、烷氡基、羥 145862 -15- 201040187 基苯基'雜芳基或雜環烷基取代，取代基本身係視情況經取代；烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基取代’基團α苯基或基團〇_(CH2)n_苯基，其中笨基視情況經取代，且η表示1至4之整數；或基團NR1R2，其中R1與R2係致使R1與R2中之一表不氫原子、環烷基或烷基，而R1與R2中之另—個表示氫原子、環烷基或烷基，視情況被一或多個可為相同或不同之基團取代，選自下列基團：羥基、烷氧基、雜芳基、雜環烷基、NR3R4 '苯基，視情況經取代，或者，R1與R2和彼等所連接之氮原子形成3_ 員裒狀基團，視情況含有一或多個其他雜原子，選自〇、S ' N及NH，此基團，包括其含有之可能NH ’係視情況經取代；中R3與R4，其可為相同或不同，係表示氫原子、烧基、環烧基' 雜芳基或苯基，其係視情況經取代，或者， R3與R4和彼等所連接之氮原子形成3_至1〜員環狀基團，視情況含有-或多個其他雜原子，選自Ο、S、N及NH，此基團’包括其含有之可能NH，係視情況經取代；上文定義之所有烷基、環烷基、雜環烷基、雜芳基及笨基’、以及可藉由RWR2或R3與叫彼等所連接之氣原子〈成之％狀基團’係視情況被—或多個基團取代，取代基選自齒原子與下列基團：羥基、_基、烷氧基、_〇_〇> R5、_、NHalk、N(alk)2及烧基、環燒基、雜環烧基、 145862 201040187 CH2-雜環烷基、苯基、CH2_苯基、c〇_苯基、雜芳基及^雜芳基，以致在後述基團中，烷基、環烷基、雜環烷基、苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自南原子與下列基團：羥基、酮基、含有1至4個碳原子之烷基與烷氧基、NH2、NHalk及N(alk)2 ; R5表示含有不超過6個碳原子之烷基或環烷基；該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式（I)產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，其中——、Ra及X具有其他請求項之任一項中所定義之音義，且： A表示NH或S ; w表示氫原子；視情況被烷氧基、雜環烷基或NR3R4取代之烷基；或基團COR，其中R表示： -環烧基或炫基，視情況被基團NR3R4、；)：完氧基、_ 基、苯基或雜環烷基取代，取代基本身係視情況經取代； -烷氧基’視情況被NR3R4、烷氧基、羥基或雜環烷基取代；基團〇-苯基或基團0-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至4之整數； -或基團NR1R2 ’其中R1與R2係致使幻與中之一表示氫原子或烧基’而R1與R2中之另一個表示氫原子、環烧基或烷基’視情況被烷氧基或雜環烷基或NR3R4取代.或者，R1與R2和彼等所連接之氮原子形成3_至1〇_員環狀基 145862 201040187 團，視情況含有一或多個其他雜原子，選自〇、s、N& NH，此基團，包括其含有之可能NH，係視情況經取代；其中NR3R4，致使R3與R4，其可為相同或不同，係表示氫原子或烷基，或者，们與似和彼等所連接之氮原子形成 3-至10-員環狀基團，視情況含有一或多個其他雜原子，選自Ο、S、N及NH ’此基團’包括其含有之可能NH ,係視情況經取代；上文定義之所有環烷基、雜環烷基及苯基，以及可藉由 R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自鹵原子與下列基團：經基、烧氧基、NH2、NHalk、N(alk)2及院基、雜環烷基、CH2-雜環烷基、苯基、CH2_苯基及雜芳基，以致在後述基时，烧基、料⑥基 '笨基及料基本身係視情況被一或多個基團取代，取代基選自齒原、子及經基、含有1至4個碳原子之烷基與烷氧基、NH2、NHaik及 N(alk)2 ；該式(I)產物係、呈任何可能之外消旋、對掌異構或非對映異構物形 <，以及該式①產物與礦酸及冑機酸類或與礦驗及有機鹼類之加成鹽。本發明之-項主題為如前文或下文所定義之式①產物，其中—、Ra及X具有其他請求項之任—項中所定義之意義，且： A表示NH或S ; w表示氫原子；視情況被雜環烷基或nr3r4取代之烷基； 145862 201040187 或基團COR，其中R表示： -環烷基或烷基’視情況被基團NR3R4或烷氧基取代； -基團0-苯基或a(CH2)n-苯基，其中苯基視情況經取代，且η表示1至2之整數； -或基團NR1R2，其中R1與R2係致使R1與R2中之一表示氫原子、環烷基或烷基，而則與尺2中之另一個表示氫原子、視情況被雜環基或NR3R4取代之烧基，或者，ri與把和彼等所連接之氮原子形成環狀基團，視情況含有一或多個其他雜原子’選自〇、S、Ν及ΝΗ，此基團，包括其含有之可能ΝΗ，係視情況經取代；其中NR3R4，致使R3與R4，其可為相同或不同，係表示氫原子或烷基，或者，R3與R4和彼等所連接之氮原子形成環狀基團，視情況含有—或多個其他雜原子，選自〇、 S、N及NH，此基團，包括其含有之可能NH，係視情況經取代； Q 上文所疋義之所有環烷基、雜環族及苯基，以及可藉由 R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自_原子與 ‘ 下列基IS :經基、燒氧基、NH2、NHalk、N(alk)2|m基及 ‘苯基’後述基團本身係視情況被―或多個基團取代，取代基選自函原子及經基、+有個碳原子之烧基與烧氧基、NH2、NHalk 及 N(alk)2 ; 該式①產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’卩及該< (I)產#與礦酸及有機酸類《與礦驗及 145S62 •19- 201040187 有機鹼類之加成鹽。本發明之一項主題為如前文或下文所定義之式（I)產物其中A表示NH，取代基=、Ra'X&w係 1乐選自其他請求項之任一項中關於此等基團所定義之所有意義，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物二式’以及該式(I)產物與礦酸及有機酸類或與礦驗二類之加成鹽。驗本發明之-項主題為如前文或下文戟義之式⑴產物，其中A表示S ’取代基=、Ra'M係選自其他請求項之任-項中關於此等基團所定義之所有意^，該式①產物係呈任何可能之外消旋、對掌異構或非對映異構、以及該式（I)產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。、本發明之一項主題為如前文或下文所定義之式①產物，其係相應於式（la)或（Ib):Ra represents a group _〇_cycloalkyl or a group _NH_cycloalkyl, both of which are optionally substituted; X represents S, so or so2; A represents NH or S; w represents a hydrogen atom, a group substituted with an alkoxy group, a heterocycloalkyl group or NR3R4; or a group C0R, wherein r represents: a cycloalkyl group or an alkyl group, optionally a group NR3R4, an alkano group, a hydroxy group 145862-15- 201040187 Phenylphenyl 'heteroaryl or heterocycloalkyl substituted, substituted subunits as appropriate; alkoxy, optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl' group αphenyl Or a group 〇_(CH2)n_phenyl, wherein the stupid group is optionally substituted, and η represents an integer from 1 to 4; or the group NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents hydrogen An atom, a cycloalkyl or an alkyl group, and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl group or an alkyl group, optionally substituted by one or more groups which may be the same or different, selected from the group consisting of a group: a hydroxy group, an alkoxy group, a heteroaryl group, a heterocycloalkyl group, an NR3R4 'phenyl group, optionally substituted, or a nitrogen atom to which R1 and R2 are bonded to form a 3 member-like group. Optionally containing one or more other heteroatoms selected from the group consisting of hydrazine, S'N and NH, the group including the possible NH's which may be substituted as appropriate; and R3 and R4, which may be the same or different, Is a hydrogen atom, a pyridyl group, a cycloalkyl group 'heteroaryl group or a phenyl group, which may be substituted as appropriate, or R3 and R4 and the nitrogen atom to which they are attached form a 3_ to 1 to a cyclic group. , optionally containing - or a plurality of other heteroatoms selected from the group consisting of hydrazine, S, N and NH, the group 'including the possible NH which may be substituted as appropriate; all alkyl, cycloalkyl groups as defined above , a heterocycloalkyl group, a heteroaryl group, and a stylyl group, and a gas atom which may be attached to the ring by RWR2 or R3 (the % group formed) is optionally substituted with a plurality of groups, The substituent is selected from the group consisting of a tooth atom and the following groups: hydroxy, _ group, alkoxy, _〇_〇> R5, _, NHalk, N(alk) 2 and alkyl, cycloalkyl, heterocycloalkyl, 145862 201040187 CH2-Heterocycloalkyl, phenyl, CH 2 —phenyl, c〇—phenyl, heteroaryl and heteroaryl, such that in the groups described below, alkyl, cycloalkyl, heterocycloalkyl , The basic and heteroaromatic basic bodies are optionally substituted by one or more groups selected from the group consisting of a south atom and the following groups: a hydroxyl group, a ketone group, an alkyl group having 1 to 4 carbon atoms and an alkoxy group, NH2. , NHalk and N(alk)2; R5 represents an alkyl or cycloalkyl group containing no more than 6 carbon atoms; the product of formula (I) is in any possible racemization, palmar isomerization or diastereoisomerism a form of the structure, and an addition salt of the product of the formula (I) with a mineral acid and an organic acid or with a mineral base and an organic base. A subject of the invention is a product of formula 1 as defined above or below, wherein -, Ra and X have the meaning as defined in any of the other claims, and: A represents NH or S; w represents hydrogen An atom; an alkyl group optionally substituted by an alkoxy group, a heterocycloalkyl group or NR3R4; or a group COR, wherein R represents: a cycloalkyl or a leuco group, optionally a group NR3R4, ;): an oxy group Substituted by a phenyl group, a phenyl group or a heterocycloalkyl group, the substituent is optionally substituted; the alkoxy group is optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl; group 〇-phenyl Or a group 0-(CH2)n-phenyl, wherein the phenyl group is optionally substituted, and η represents an integer from 1 to 4; or the group NR1R2 'where R1 and R2 are one of the phantoms and one represents a hydrogen atom Or a calcining group' and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl group or an alkyl group, optionally substituted by an alkoxy or heterocycloalkyl group or NR3R4. Alternatively, R1 and R2 and the nitrogen to which they are attached The atom forms a 3_ to 1〇 member cyclic group 145862 201040187 group, optionally containing one or more other heteroatoms, selected from 〇, s, N& NH, this group, Including NR3R4, which may be R3 and R4, which may be the same or different, represent a hydrogen atom or an alkyl group, or may form a nitrogen atom to which they are attached. a 3- to 10-membered cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of hydrazine, S, N and NH '. This group includes the possible NH which may be substituted as appropriate; All cycloalkyl, heterocycloalkyl and phenyl as defined herein, and cyclic groups which may be formed by R1 and R2 or R3 and R4 and the nitrogen atom to which they are attached, are optionally one or more Substituted by a group, the substituent is selected from a halogen atom and the following groups: a trans group, an alkoxy group, NH2, NHalk, N(alk)2, and a phenyl group, a heterocycloalkyl group, a CH2-heterocycloalkyl group, a phenyl group, CH2_phenyl and heteroaryl, such that in the latter group, the alkyl group, the 6-based group and the basic body are optionally substituted by one or more groups selected from the group consisting of dentogen, sub- and a group having an alkyl group having 1 to 4 carbon atoms and an alkoxy group, NH2, NHaik, and N(alk)2; wherein the product of the formula (I) is in any possible racemization or palmar isomerism Diastereomeric addition salts isomeric form thereof of formula <, and ① product with a mineral acid or acids and the helmet machine mineral and organic bases of the test. The subject matter of the invention is a product of formula 1 as defined above or below, wherein -, Ra and X have the meanings defined in any of the other claims, and: A represents NH or S; w represents a hydrogen atom An alkyl group substituted by a heterocycloalkyl group or nr3r4; 145862 201040187 or a group COR, wherein R represents: - a cycloalkyl group or an alkyl group 'optionally substituted with a group NR3R4 or an alkoxy group; - a group 0 -phenyl or a(CH2)n-phenyl, wherein phenyl is optionally substituted, and η represents an integer from 1 to 2; or the group NR1R2, wherein R1 and R2 are such that one of R1 and R2 represents hydrogen An atom, a cycloalkyl group or an alkyl group, and the other one of the sizing 2 represents a hydrogen atom, optionally substituted by a heterocyclic group or NR3R4, or ri forms a ring with the nitrogen atom to which they are attached. a group, optionally containing one or more other heteroatoms, selected from the group consisting of ruthenium, S, osmium and iridium. This group, including the possible oxime contained therein, is optionally substituted; wherein NR3R4, which results in R3 and R4, They may be the same or different and represent a hydrogen atom or an alkyl group, or R3 and R4 and the nitrogen atom to which they are attached form a ring. a group, as the case may be - or a plurality of other heteroatoms selected from the group consisting of ruthenium, S, N and NH. This group, including the possible NH, may be substituted as appropriate; Q All of the rings as defined above An alkyl group, a heterocyclic group and a phenyl group, and a cyclic group which may be formed by a nitrogen atom to which R1 and R2 or R3 and R4 are bonded to each other, optionally substituted by one or more groups, a substituent a group selected from the group consisting of _ atoms and 'subunits IS': a radical, an alkoxy group, an NH2, a NHalk, an N(alk) 2|m group, and a 'phenyl group, the group described below is itself substituted with one or more groups, The substituent is selected from the group consisting of a functional atom and a transradical, a calcining group having a carbon atom and an alkoxy group, NH2, NHalk and N(alk)2; the product of the formula 1 is in any possible racemization and palmar isomerism. Or diastereomeric forms '卩 and the < (I) produced # with mineral acids and organic acids "with minerals and 145S62 • 19- 201040187 addition of organic bases. A subject of the invention is a product of formula (I) as defined above or below wherein A represents NH, substituent =, Ra'X&w is a property selected from any of the other claims. In all senses defined by the group, the product of formula (I) is in any possible racemic, para-isomeric or diastereomeric form II and the product of formula (I) with mineral acids and organic acids or Addition salts with the second type of mineral test. The subject matter of the present invention is a product of the formula (1) as hereinbefore or hereinafter defined, wherein A represents S 'substituent =, and Ra'M is selected from any of the claims of the other claims. Meaning, the product of formula 1 is in any possible racemization, palmar isomerization or diastereomerization, and the product of formula (I) with mineral acid and organic acid or with mineral and organic test A salt. A subject of the invention is a product of formula 1 as defined above or below, which corresponds to formula (la) or (Ib):

龜《 a LITurtle "a LI

/ w (la)/ w (la)

意義、如及μ選自其他請求項之任_項中所指示之該式㈣與⑽產物係呈任何可能之外消旋、對掌異構或非 145862 •20- 201040187 對映異構物形式，以及該式（la)與（lb)產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，The meanings, such as and the μ, are selected from any of the other claims, and the products of formulas (4) and (10) are in any possible racemization, palmar isomerism or non-145862 •20- 201040187 enantiomeric forms. And addition salts of the products of formula (la) and (lb) with mineral acids and organic acids or with mineral bases and organic bases. A subject of the invention is a product of formula 1 as defined above or below,

取代基Ra、X、A及W具有其他請求項之任一項中所指示之意義，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。本發明之-項主題為如前文或下文所定義之式①產物，Substituents Ra, X, A and W have the meaning indicated in any of the other claims, and the product of formula (I) is in any possible racemic, para-isomeric or diastereomeric form And an addition salt of the product of the formula 1 with mineral acids and organic acids or with mineral bases and organic bases. The subject matter of the present invention is a product of formula 1 as defined above or below,

其中取代基Ra、X、a及w具有其他請求項之任—項指示之意義，映異鹼及該式(I)產物係呈任何可能之外消旋、對掌異構或非對構物形式，以及該式（I)產物與礦酸及有機酸類或與礦有機鹼類之加成鹽。 / 其::::::題 145862 21 201040187Wherein the substituents Ra, X, a and w have the meaning of any of the other claims, and the pheno-alkali and the product of formula (I) are in any possible racemization, palmar isomerism or non-conversion. Form, and addition salts of the product of formula (I) with mineral acids and organic acids or with mineral organic bases. / Its::::::title 145862 21 201040187

d'a) 其中Ra與W係選自其他請求項之任一項中所指示之意義，該式（I'a)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式（I，a)產物與礦酸及有機酸類或與礦鹼及有機驗類之加成鹽。本發明之一項主題為如前文或下文所定義之式（1)產物，其中一表不雙,$，其係相應於式（I”a)產物： ΗD'a) wherein Ra and W are selected from the meanings indicated in any of the other claims, the product of formula (I'a) being in any possible racemization, palmar isomerism or diastereomeric The form of the structure, and the addition salt of the product of the formula (I, a) with mineral acid and organic acid or with mineral alkali and organic. A subject of the invention is a product of formula (1) as defined above or below, wherein one of the formulas is not double, $, which corresponds to the product of formula (I"a):

Η ΝΗ Ν

W 0"a) 其中Ra與W係選自其他請求項之任一項中所指示之意義，該式（I"a)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’以及該式（I"a)產物與礦酸及有機酸類或與礦鹼及有機驗類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，表不單鍵，其係相應於式（I，b)產物：W 0"a) where Ra and W are selected from the meanings indicated in any of the other claims, and the product of the formula (I"a) is in any possible racemization, palmar isomerism or diastereoisomerism. The isomeric form 'and the addition salts of the product of the formula (I" a) with mineral acids and organic acids or with mineral bases and organic tests. A subject of the invention is a product of formula 1 as defined above or below, which represents a single bond, which corresponds to the product of formula (I, b):

w d'b)w d'b)

Ra 其中Ra與W係選自其他請求項之任—項中所指示之意義，該式（I'b)產物係呈任何可能之外消旋、對掌異構或非對映 145862 •22· 201040187 異構物形式，以及該式（I’b)產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。本發明之一項主題為如前文或下文所定義之式①產物，其中—了表示雙鍵’其係相應於式（I”b)產物：Ra wherein Ra and W are selected from the meanings indicated in the claims of other claims, the product of formula (I'b) is in any possible racemization, palmar isomerism or diastereoinization 145862 •22· 201040187 Isomer form, and addition salts of the product of formula (I'b) with mineral acids and organic acids or with mineral and organic tests. A subject of the invention is a product of formula 1 as defined above or below, wherein - represents a double bond which corresponds to the product of formula (I"b):

ΟΟ

其中Ra與W係選自其他請求項之任一項中所指示之意義，該式G，，b)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式（I”b)產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。、在式（I)產物卡，及在以下本文中： -烧基（或Aik) —詞表示線性及在適當情況下為分枝狀甲基、乙基、丙基、異丙基、丁基、異丁基、第二_ 丁基、第二-丁基、戊基、異戊基、己基、異己基，以及庚基、辛基壬基及癸基’以及其線性或分枝狀位置異構物：含有⑴個碳原子之烧基，且更特別是上文清單之含^至 4個碳原子之烷基係為較佳； ^氧基—詞表示線性及在適當情況下為分枝狀甲氧基、乙虱基、丙氧基或異丙氧基’第二或第三線性丁氧基、戊氧基或己减，以及其線性或分枝狀位置異構物：上文产單之含有1至4個碳原子之烷氧基係為較佳； /月 1原子-詞表示氯、m氟科，或氟原子。早乂住為氯、溴 145862 •23· 201040187 -環烧基-詞表示含有3至1()個碳原子之飽和礙環族基圈，且因此尤其是表示環丙基、環丁基、環戊基及環己基，而最特別是環丙基、環丁基、環戊基、環己基及環庚基； -雜環烧基-詞因此係表示3_至㈣單環狀或雙環狀碳環族基團:被-或多個雜原子***，其可為相同或不同，選 '氧氮及羧原子‘可指出之實例包括嗎福啉基、硫代嗎祸啉基、ll丙啶基、一氮四圜基、六氫吡畊基、六氣吡啶基、高六氫則基、四氫t各基、四氣味唾基、四氣心〇基、四氫吱喃基、四氫,塞吩基、四氫味喃基 '四氣硫代喊喃基及酮基二氫忒畊其，—、土 je, ^ 虱。井基，或者，裱虱丙烷基或環硫丙烷田所有此等基團係視情況經取代；可指出的是，此等雜 %烷基可包含由兩個環員所形成之橋基，以形成例如氧彳，雙環并庚烧或氮螺[3.3]庚烧基團或其他氮雙環氮螺垸環。一係視情況經取代；。方基，雜芳基術語個別表示不飽和或部份不飽和翠環狀 ^雙被狀、碳環族與雜環族基團，其係不大於d可能含有’環員’此雜環族基團含有—或多個雜原子，: 可為相同或不同，選自〇、NAS’其中在適當情況下，： :方基-詞因此表示6-至12-員單環狀或雙環狀基團，例如本基、萘基、聯苯基、茚基、第基及茵鱼^ -弗丞及恩基，更特別是苯基，、奈基，而又更特別是苯基。。^ 土」导日出的疋，含有-C(O)環貝之私環族基團係為例如四氫茶酮基團； -雜芳基-詞因此表示5-至12-員單環狀或雙環狀基團：單 145862 -24- 201040187 環狀雜芳基’例如嘍吩基，譬如2-嘍吩基與3_嘍吩基，呋喃基，譬如2-呋喃基、呋喃基，哌喃基、吡咯基、二氫 p比°各基、二虱p比唾基、_ „坐基、p比唾基，峨σ定基，譬如2_ 吡啶基、3-吡啶基及4-吡啶基，吡畊基、嘧啶基、嗒啡 . 基、噚唑基、嘧唑基、異噻唑基、二唑基、嘧二唑基、嘧 ' ***基、哼二唑基，異噚唑基，譬如3-或4-異噚唑基，呋咕基，自由態或經鹽化之四唑基，所有此等基團係視情況經取代，其中更特別是噻吩基，譬如2_ρ塞吩基與3_噻吩〇基，吱喃基’譬如2·吱喃基，吡咯基、二氫峨咯基、二氫吡唑基、咪唑基、吡唑基、噚唑基、異噚唑基、吡啶基及嗒畊基，此等基團係視情況經取代；雙環狀雜芳基，例如苯并嘧吩基，譬如3_苯并嘧吩基、苯并噻唑基、喳啉基、異喳啉基、二氫喹啉基、喹啉酮、四氫莕酮、金剛烷基、苯并呋喃基、異苯并呋喃基、二氫苯并呋喃基、伸乙二氧基苯基、嘧嗯基、苯并吡咯基、苯并咪唑基、苯并噚唑〇基、硫苯基、呻哚基、氮啕哚基、4唑基、嘌呤基、嘧吩并峨°坐基、四氫+坐基、四氫環戊峨唾基、二氫吱喃并,比唑基、四氫吡咯并吡唑基、酮基四氫吡咯并吡唑基、四氫 * •哌喃并吡唑基、四氫吡啶并吡唑基或酉同基二氫吡啶并吡唑基’所有此等基團均視情況經取代。作為雜芳基或雙環狀基團之實例，可更特別地指出喷。定基、吹°定基、^各基、氮+朵基、+坐基或峨哇基，視情況被-或多個如上文所指出之相同或不同取代基取代。式（I)產物之《可以熟諸此藝者所已知之各種基團鹽化 145862 -25- 201040187 或酿化’其中可指出之實例包括： -在鹽化作用化合物中’礦物鹼，例如一當量鈉、鉀、經、鈣、錤或錢，或有機驗，例如甲胺、丙胺、三甲胺、一乙胺二乙胺、N,N_二甲基乙醇胺、參（經甲基）_胺基甲烷、乙醇胺、吡啶、甲基吡啶、二環己基胺、嗎福啉、芊胺、普魯卡因、離胺酸、精胺酸、組胺酸或队甲：糖胺， j甸 :在醋化作用化合物中’烷基以形成烷氧羰基，例如数基、乙氧幾基、第三_丁氧録或亨氧徵基，此等 :被基團取代’例如選自㈣子，以及經基、峨二土、醯乳基、烧硫基、胺基及芳基，例如在氣基甲基 :基、甲氧基甲基、丙醯氧基甲基、甲硫基甲基、；基乙基、芊基或苯乙基中。女酸酸酸酸酸基所St:與礦酸或有機酸之加成鹽’可為例如以下述酸酸：丙二鹽酸、氫漠酸、氫峨酸'硝酸、硫酸、碟 -文、酷酸、三氟醋酸、甲酸、苯甲酸、順丁歸二反丁烯二酸、琥珀酸、酒石酸、檸檬酸、草酸、乙: 天門冬胺酸或抗壞血酸，烧基單石黃酸類，例如甲燒供 =續酸、丙繼，炫基二續酸類，例如甲二 %尽乙烷二磺酸，芳基單磺酸類，、磺酸類。“本石頁酸’及芳廣意義被定義為但其各種基團係單取代之環己烷可回憶的是，立體異構現象可以其最寬、S物之異構現象，其具有相同結構式，以不同方式排列於空間中，尤其是譬如在 145862 -26- 201040187 中，其中取代基可在軸向或赤道位置上，及乙烷衍生物之各種可忐旋轉構形。但是，另一種類型之立體異構現象係由於固定取代基之不同空間排列，而存在於雙鍵上或於環上，其係經常被稱為幾何異構現象或順_反異構現象。立 . 體異構物一詞係以其最寬廣意義使用於本專利申請案中， ' 且因此係關於所有上文所示之化合物。環狀基團，其可一方面藉由R1與R2和彼等所連接之氮原子，而另一方面藉由R3與R4和彼等所連接之氮原子所形成，係視情況被一或多個基團取代，選自此等上文關於雜環烷基上之可能取代基所示者，意即一或多個基團，選自鹵原子與下列基團：羥基、酮基、烷氧基、nh2 ; NHalk、N(alk)2及烷基、雜環烷基、cm#環烷基、苯基、 CH2-苯基、雜芳基及c〇_苯基，以致在後述基團中，烷基、雜環烷基及苯基本身係視情況被一或多個基團取代，取代基選自㈣子與下列基:&基、喊、含有〇個碳原子之烷基與烷氧基、NH2; NHalk及N(alk)2。一方面可藉由R1與R2和彼等所連接之氮原子而另一方面藉由R3與R4和彼等所連接之氮原子所形成之環狀基團，係尤其是視情況被-或多個相同或不同基團取代，取 • 代基選自_原子與烷基、羥基、烷氧基、CH2_W氫吡咯 f、CH2-笨基、雜芳基及苯基，#中烷基、四氫吡咯基及苯基本身係視情況被一或多個相同或不同基團取代，取代基選自鹵原子與烷基、羥基、酮基及烷氧基。士上文所疋義之雜環烷基尤其是表示一氮七圜烷基、嗎 145862 -27- 201040187 才田林基、四氫吡咯基、六氫吡啶基及六氫吡畊基，其本身係視h况如前文或下文所定義經取代。田NR1R2或NR3R4形成如上文所定義之環時，此種胺環可尤疋選自四虱p比°各基 '四氫P比α坐基、二氫P比唾基 '六 '疋基氮七園烯基、嗎福ρ林基及六氫ρ比呼基，此等基團本身係視情況如上文或下文所指示經取代：例如被— 或多個可為相同或不同之基團，選自鹵原子與烷基、羥基，、烷氧基、苯基及CH2_苯基，該烷基或苯基本身係視情况被一或多個相同或不同基團取代，取代基選自齒原子與垸基、羥基及烷氧基。衣NR1R2 $ NR3R4可更特別是選自日氮叶匕略基與嗎福淋基’視情況被-或兩個烧基取代，或六氫峨p井基，視情況在第一個氮原子上被烷基、苯基或CH2-苯基取代，其本身係視情況被一或多個相同或不同基團取代，取代基選自鹵原子與烷基、羥基及烷氧基。本毛明之一項主題為如前文或下文所定義之式①產物，其中 =表示單或雙鍵Wherein Ra and W are selected from the meanings indicated in any of the other claims, and the products of formula G, b) are in any form of racemic, para-isomeric or diastereomeric forms, And an addition salt of the product of the formula (I"b) with mineral acids and organic acids or with mineral and organic tests. In the product card of formula (I), and in the following: - an alkyl group (or Aik) - the word indicates linear and, where appropriate, branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, second-butyl, pentyl, isuf a base, a hexyl group, an isohexyl group, and a heptyl group, an octyl decyl group and a fluorenyl group, and linear or branched positional isomers thereof: a group containing (1) carbon atoms, and more particularly the above list Alkyl groups of one carbon atom are preferred; ^oxy-word means linear and, where appropriate, branched methoxy, ethoxylated, propoxy or isopropoxy' second or third linear a butoxy group, a pentyloxy group or a hexanyl group, and a linear or branched positional isomer thereof: an alkoxy group having 1 to 4 carbon atoms in the above-mentioned single product is preferred; 1 atom-word means chlorine, m-fluorine, or fluorine atom. Early residence is chlorine, bromine 145862 •23· 201040187 -cycloalkyl-words indicate saturated ring-containing ring containing 3 to 1 () carbon atoms And thus especially denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and most particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; -heterocycloalkyl- The term thus denotes a 3 to to (tetra)monocyclic or bicyclic carbocyclic group: inserted by - or a plurality of heteroatoms, which may be the same or different, and examples of which 'oxygen nitrogen and a carboxyl atom' may be indicated include Morpholinoyl, thio-indolyl, ll-propidyl, nitro-tetradecyl, hexahydropyrrole, hexapyridine, high hexahydro, tetrahydron, tetrasyl , tetracentric fluorenyl, tetrahydrofuranyl, tetrahydro, secantyl, tetrahydrofuranyl 'four gas thiopyranyl and keto dihydroanthraquinone, -, soil je, ^ 虱. Well base, or all of these groups in the oxime or thiopropane field are optionally substituted; it may be noted that such heteroalkyl groups may comprise a bridging group formed by two ring members, Forming, for example, oxygen彳, bicyclo and heptane or snail [3.3] heptane group or other nitrogen bicycloazepane ring. One system is substituted as appropriate; square, heteroaryl terminology individually means unsaturated or partially unsaturated a cyclic ring, a carbocyclic group and a heterocyclic group, which is not greater than d may contain a 'ring member'. The heterocyclic group contains - or a plurality of heteroatoms, which may be the same or different, selected Since 〇, NAS' where appropriate, :: square-word thus means 6- to 12-membered monocyclic or bicyclic groups, such as benzyl, naphthyl, biphenyl, fluorenyl, Base and squid ^ - Fructus and Enki, more particularly phenyl, neptyl, and more particularly phenyl. ^^""", the sunrise of the 疋, containing the private -C(O) ring The cyclocyl group is, for example, a tetrahydrotanone group; the heteroaryl-word thus represents a 5- to 12-membered monocyclic or bicyclic group: 145862 -24- 201040187 cyclic heteroaryl For example, a porphinyl group, such as a 2-nonylphenyl group and a 3-brenyl group, a furyl group, such as a 2-furyl group, a furyl group, a piperidyl group, a pyrrolyl group, a dihydrop-pyrylene group, a diterpene-p-salt Base, _ „sitting base, p than saliva , 峨σ定基, such as 2_ pyridyl, 3-pyridyl and 4-pyridyl, pyridinyl, pyrimidinyl, morphine, carbazolyl, pyrazolyl, isothiazolyl, diazolyl, pyrimidine Azyl, pyrido-triazolyl, oxadiazolyl, isoxazolyl, such as 3- or 4-isoxazolyl, furazyl, free or salted tetrazolyl, all such groups Substituting, as appropriate, more particularly thienyl, such as 2_ρ exemplyl and 3 thiophene fluorenyl, fluorenyl ', such as 2, fluorenyl, pyrrolyl, dihydrofuranyl, dihydropyrazolyl , imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl and hydrazine, these groups are optionally substituted; bicyclic heteroaryls, such as benzopyrhenyl, such as 3 Benzene pyrimenyl, benzothiazolyl, porphyrinyl, isoindolyl, dihydroquinolyl, quinolinone, tetrahydrofurfurone, adamantyl, benzofuranyl, isobenzofuranyl , dihydrobenzofuranyl, ethylenedioxyphenyl, pyrimido, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thiophenyl, decyl, hydrazino, 4 azolyl, fluorenyl , thiophene oxime, tetrahydrogen + sityl, tetrahydrocyclopentanyl sulphate, dihydrofuran, pyrazolyl, tetrahydropyrrolopyrazolyl, ketotetrahydropyrrolopyrazolyl , tetrahydro*·piperazopyrazolyl, tetrahydropyridopyrazolyl or fluorenyldihydropyridopyrazolyl 'all such groups are optionally substituted. As an example of a heteroaryl or bicyclic group, the spraying can be more particularly indicated. The base, the blowing base, the base, the nitrogen + a phenyl group, the aryl group or the oxime group are optionally replaced by - or a plurality of the same or different substituents as indicated above. The products of the formula (I) can be salted with various groups known to those skilled in the art. 145862 - 25 - 201040187 or brewing. Examples which may be mentioned include: - in the salinating compound 'mineral base, for example one Equivalent to sodium, potassium, potassium, strontium or money, or organic tests such as methylamine, propylamine, trimethylamine, monoethylamine diethylamine, N,N-dimethylethanolamine, ginseng (methyl)-amine Methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morphine, guanamine, procaine, lysine, arginine, histidine or team: glycosamine, j: in An alkyl group in the acetalization compound to form an alkoxycarbonyl group, such as a number group, an ethoxy group, a third-butoxy-ox or a henyl group, such as: substituted by a group 'for example, selected from (d), and a base, a bismuth, a thiol, a thiol group, an amine group, and an aryl group, for example, a methyl group: a methoxymethyl group, a methoxymethyl group, a methyl thiomethyl group; In the ethyl group, decyl group or phenethyl group. The acid-acidic acid group St: the addition salt with mineral acid or organic acid can be, for example, the following acid acids: malonic acid hydrochloric acid, hydrogen desert acid, hydroquinone acid nitric acid, sulfuric acid, dish-text, cool Acid, trifluoroacetic acid, formic acid, benzoic acid, cis-butyl dimaleic acid, succinic acid, tartaric acid, citric acid, oxalic acid, B: aspartic acid or ascorbic acid, pyridyl monolithic acid, such as formazan For the acid, the propyl group, the thiol and the second acid, such as methyl oxadisulfonic acid, aryl monosulfonic acid, sulfonic acid. The meaning of "this shale acid" and the meaning of Fangguang is defined as the cyclohexane in which various groups are monosubstituted. It can be recalled that the stereoisomerism can be the widest and the heterogeneous phenomenon of S, which has the same structural formula. , arranged in different ways in space, especially in 145862 -26- 201040187, where the substituents can be in the axial or equatorial position, and various rotatable configurations of ethane derivatives. However, another type Stereoisomerism is often referred to as geometric isomerism or cis-trans isomerism due to the different spatial arrangement of fixed substituents on the double bond or on the ring. The term is used in its broadest sense in this patent application, and is therefore related to all of the compounds shown above. A cyclic group which can be linked to the nitrogen by R1 and R2 on the one hand. An atom, on the other hand, formed by R3 and R4 and the nitrogen atom to which they are attached, optionally substituted by one or more groups selected from the above-mentioned possible substituents on the heterocycloalkyl group As shown, meaning one or more groups, selected a halogen atom and the following groups: hydroxy, keto, alkoxy, nh2; NHalk, N(alk)2 and alkyl, heterocycloalkyl, cm#cycloalkyl, phenyl, CH2-phenyl, heteroaryl And a c〇-phenyl group, such that in the groups described below, the alkyl group, the heterocycloalkyl group and the phenyl group are themselves optionally substituted by one or more groups selected from the group consisting of (iv) and the following groups: & Base, shout, alkyl and alkoxy groups containing one carbon atom, NH2; NHalk and N(alk) 2. On the one hand, R1 and R2 and the nitrogen atom to which they are attached, and on the other hand, R3 The cyclic group formed by R4 and the nitrogen atom to which they are attached is, in particular, optionally substituted by - or a plurality of the same or different groups, and the substituent is selected from the group consisting of an atom and an alkyl group, a hydroxyl group, and an alkane. Oxyl, CH 2 —W hydropyrrole f, CH 2 -phenyl, heteroaryl and phenyl, # alkyl, tetrahydropyrrolyl and phenyl are themselves optionally substituted by one or more identical or different groups, substituents It is selected from a halogen atom and an alkyl group, a hydroxyl group, a ketone group, and an alkoxy group. The heterocycloalkyl group as defined above, especially, represents a nitrogen sulfenyl group, 145862 -27- 201040187 Hydropyrrolyl, hexahydropyridyl and hexahydropyridinyl, which are themselves as defined above or as defined below. When the NR1R2 or NR3R4 forms a ring as defined above, such an amine ring may It is selected from the group consisting of tetrakis-p-specific groups, 'tetrahydro-P ratio, α-sitting group, dihydro-P-saltyl-s-hexyl nitrogen, hepta-alkenyl, phenanthroline, and hexahydro-p-butyl. The group itself is optionally substituted as indicated above or below: for example, one or more groups which may be the same or different, selected from a halogen atom and an alkyl group, a hydroxyl group, an alkoxy group, a phenyl group and a CH2_ group. Phenyl, the alkyl or phenyl itself is optionally substituted by one or more identical or different groups selected from the group consisting of a tooth atom and a fluorenyl group, a hydroxyl group and an alkoxy group. NR1R2 $ NR3R4 may be more particularly selected from the group consisting of Nitrogen sulphate and whalamide, as appropriate - or two alkyl groups, or hexahydropyrene, or as appropriate on the first nitrogen atom Substituted by an alkyl group, a phenyl group or a CH2-phenyl group, which is itself optionally substituted by one or more identical or different groups selected from the group consisting of a halogen atom and an alkyl group, a hydroxyl group and an alkoxy group. A subject of Benjamin is a product of formula 1 as defined above or below, where = represents a single or double bond

Ra表示基團環烧基或基團姻.環燒基，視情況被經基、燒氧基或-0-C0-R5基團取代； X表示S ; A表示S ; W表示氫原子，或視情況被雜環燒基取代之烧基，或基團 COR，其中R表示： U5862 •28- 201040187 -環烷基或烷基’視情況被基團NR3R4或烷氧基取代； -基團0-苯基； -或基團NR1R2，其中R1與R2係致使一個表示氫原子，而另一個表示視情況被雜環烷基取代之烷基；其中NR3R4，致使R3與R4，其可為相同或不同，係表示氫原子或炫》基； R5表示含有至多6個碳原子之烷基或環烷基；〇該式（1)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機驗類之加成鹽。尤其是在式（I)產物中，環烷基可表示環庚基、環已基、裱戊基、環丁基或環丙基；尤其是在式①產物中，雜環烷基可表示嗎福琳基或四氫P比P各基。本發明之一項主題係因此為如前文或下文所定義之式（工）產物’其係相應於下列化學式： Ο _ 環己基氧基）[丨，2,4]***并[4,3-b]嗒畊-3-基]硫基}- 1，3-苯并嘍唑_2_基）環丙烷羧醯胺 -1-(6-{[6-(環己基氧基）[以斗]***并[4,3七]嗒畊_3基]硫基H，3_ 苯并嘧唑_2-基）各[2-(嗎福啉-4-基）乙基]脲 1-(6-丨[6_(環戊氧基）[以4]5 °坐并[4,3-b]塔呼-3-基]硫基}-1，3-苯并11塞11 坐-2-基）_3_[2_(嗎福淋_4_基）乙基膊 1 (6他侦庚基氧基肌2,4]三°坐并[4,3-b]嗒畊-3-基]硫基}-1，3-表并遠唾-2-基)_3_[2_(嗎福啉_4-基）乙基]脲 -队(6-{[6-(環己胺基）[u，4]***并[4,3七]嗒畊各基]硫基h，3_ 145862 -29- 201040187 笨并嘧唑-2-基）乙醯胺 • 1-(6-{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜1，3~笨并遠。坐-2-基）各[2-(四氫吡咯-1-基）乙基]脲 -N|{[6-(環己胺基）[U，4]***并[4,3七]嗒，井；基]硫基h，3_ 苯并嘧唑-2-基）環丙烷羧醯胺 -N-[6-({6-[(反式_4_羥基環己基）胺基][U4]***并[4,3七]塔啡_ 3基Kil基）-1，3_苯并Vi塞峻-2-基]環丙炫叛醯胺 • Ν·(6-{[6-(環丙胺基）[1，2,4]***并[4,3-b]塔_各基]硫基苯并4。坐-2-基）環丙烷羧醯胺 _ 1-(6-{[6-(環己胺基肌以***并[4 3七]嗒畊_3基]硫基卜u笨并漆唾-2-基）_3_[2-(嗎福啉_4_基）乙基]脲 -1-(6-{[6-(環丙胺基^，训王唑并[4,3卻荅„井各基]硫基}_u苯 #。塞。坐-2-基）_3_[2_(嗎福啉冰基）乙基]脲 • N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}_ 1，3-苯并嚷唾_2_基）乙醯胺 (6 {[6-(環己基氧基）[1，2,4]三嗤并[4,3-b]塔啡-3-基]硫基}-1，3_ 笨并塞。坐-2-基）胺基曱酸苯酯 _ 1-(6-{[6-(環己基氧基）[U，4]***并[4,3-b]塔畊-3-基]硫基笨并違唾-2-基）各[2_(四氳吡咯基）乙基]脲 6 ([6-(環己基氧基）[1，2,4]三。坐并[4,3-b]。荅畊-3-基]硫基}-Ν-[2· (四氫Ρ比略'1-基）乙基]-1,3-苯并嘧唑-2-胺 _ Ν'(6_{[6·(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}_ 1’3-苯并噻唑_2_基）_2_甲氧基乙醯胺 _ N_(6_{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒啡-3-基]硫基卜 145862 -30- 201040187 1，3-苯并噻唑冬基）_N2，N2_二甲基甘胺醯胺 _ Ν·(Μ[6·(環己基氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基}_ U_笨并嘍唑-2-基）-3-甲基丁醯胺 _ N_(6][6'(環己基氧基）[1，2,4]***并[4,3七]嗒畊-3-基]硫基卜 1，3-笨并嘧唑：基）_3_甲氧基丙醯胺 6 {[6-(¾戊氧基氾训***并[4,3-b]嗒呼-3-基]硫基H，3-笨并嘧唑-2-胺 ❹ -N-(6-{[6-(環戊氧基氾训***并[4 3 b]嗒畊各基]硫基Η)· 笨并p塞唾-2-基）環丙烷羧醯胺 -N-(6-U6-(環戊氧基瓜，“]***并[4,3 b]嗒畊各基]硫基卜^ 苯并p塞°坐-2-基）乙醯胺 6 {[6-(環庚基氧基）[12 4]***并[4,3七]塔畊各基]硫基卜笨并嘧唑-2-胺 -N-(6-{[6-(環庚基氧基）[^4]***并[4,3 b]嗒畊_3基]硫基卜 1，3-苯并p塞唾-2-基）乙醯胺〇 -環丙烧缓酸反式-4-{[3-({2-[(環丙基羰基）胺基H，3_苯并嘍。坐-6-基卜硫基）[丨训***并[4,3-b]嗒畊各基]胺基丨環己酯 -N-[6-({6-[(反式_4_羥基環己基）胺基]|；1，2,4]三喹并[4 3_b]塔呼_ 3-基}硫基)-1,3-苯并P塞唑_2_基]乙醯胺 -3-[(2-胺基-i，3-苯并噻唑_6_基）硫基]_N_環丙基[以^***并 [4,3-b]嗒畊-6-胺 -N-(6-{[6-(環丙胺基）[12,4]三。坐并[4,3七]嗒啡-3-基]硫基H，3-苯并嘧唑-2-基）乙醯胺 -N-(6-{[6-(環丙胺基）[ι，2,4]***并[4,3-b]嗒4 -3-基]硫基卜1，3- 145862 -31 - 201040187 笨并魂嗅-2-基）-3-曱氧基丙醯胺 N-(6-{[6-(環丙胺基）[i，2,4]***并[4,3七]嗒畊_3_基]硫基卜n 笨并4。生_2-基）-N2，N2 -二曱基甘胺醯胺 • 3-[(2-胺基·笨并嘧唑·6_基)硫基]_N_環己基_7,8二氫[丨义外二唾并[4,3-b]塔畊-6-胺 • (6-{[6-(環己基氧基氾划***并[4,3 b]嗒畊各基]硫基卜n 笨并。坐_2-基）胺基曱酸乙酯 -2-氯-N-(6-{[6-(環己基氧基）⑴训***并[4,3_b]嗒畊_3基]硫基}-1，3-笨并嘧唑_2_基）乙醯胺 Ν-(6·{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3苯并p塞唑_2_基）_N2 _環丙基甘胺醯胺 6 [(6丨[4'(二氟甲基）環己基]氧基}[1,2,4]***并[4,3-b>答畊-3-基)硫基]-1，3_苯并p塞唑_2_胺 ' N'(6_{[6-(環丁基氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基}- ’笨并p塞唾_2-基）-2-(4-乙基六氫p比畊小基）乙醯胺 —N_(M[6_(環丁基氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基}-1,3笨并屢。坐-2'基）-N2，N2 -二乙基甘胺醯胺 Ν'(6'{[6·(環庚基氧基）Π，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1’3笨并屢嗤_2_基）環丙烧羧醯胺 (6 (核己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘍唑基）—3~[3-(嗎福啉-4-基）丙基]脲 —1 (6-{[6·(環己基氧基）Π，2,4]***并[4,3-b]嗒畊-3-基]琉基}-1,3-笨并P塞啥'2·基）_3-[3-(嗎福啉-4-基）丙基]脲 (6 被丁基氧基）[1又4]***并[4,3-b]塔畊-3-基]硫基}-1,3- 145862 -32- 201040187 笨并嘧唑-2-基）各[2_(嗎福啉冰基）乙基]脲 -1-[2-(嗎福啉冰基）乙基]_3_{6_[(6_{[4 (三氟曱基）環己基]氧基m，2,4]二唾并[4,3_b]嗒畊各基)硫基]_u-苯并嘧唑_2_基}膽 -N-(6-{[6-(環己基氧基）[u，4]***并[4,3七]嗒畊_3基]硫基卜 1，3-苯并嘧唑_2-基）_2-環丙基乙醯胺 -N-(6-{[6-(環丁基氧基）[12,4]***并[4,3_b]嗒畊各基]硫基卜 1,3-苯并違唑·2_基）環丙烷羧醯胺 -外消旋-順/反_Ν_{4_[(3_{[2_({[2_(嗎福啉斗基）乙基]胺曱酿基}胺基）-1，3-苯并嘧唑各基]硫基}[1，2,4]***并[4,3_b]嗒畊-& 基）氧基]環己基卜乙醯胺 N {6 [(6 {[4-(二氟曱基）環己基]氧基}[1，2,4]三。坐并[4,3_b]n荅 _ -3-基）硫基]_1，3_苯并嘍唑_2_基丨環丙烷羧醯胺 -H6-({6-[(反式-4-羥基環己基）氧基][1，2,4]***并[4,3-b]。荅畊_ 3-基}-硫基）-1，3-苯并嘍唑_2_基]各[2-(嗎福啉-4-基）乙基脈 -6-{[6-(雙環并[3丄〇]己_3_基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并噻唑-2-胺 -3-[(2-胺基-1，3-苯并嘧唑-6-基）硫基]-N-環丁基[1，2,4]***并 [4,3-b]-嗒畊-6-胺 -N-(6-{[6-(雙環并[3.1.0]己-3-基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]-硫基}-1，3-苯并嘧唑-2-基）環丁烷羧醯胺 -外消旋-6-({6-[(反式-2-氟基環己基）氧基][1，2,4]***并[4,3-b] 嗒畊-3-基}-硫基)-1,3-苯并p塞唑-2-胺 -外消旋-N-{6-[(6-{[(反式-2-氟基環己基]氧基}[1,2,4]***并 [4,3-b]嗒畊-3-基）硫基]-1，3-苯并嘧唑-2-基}環丙烷羧醯胺 145862 -33- 201040187 _ N_(6_{[6-(環丁基胺基）[1，2,4]三唾并[4,3-b]嗒味！基]硫基}· 1，3-苯并4唾-2-基）環丙烷羧醯胺 _ Ν_(6_ί[6-(雙環并[3.1.0]己-3-基氧基）[1，2,4]***并[4,3补荅畊各基]-硫基}-1，3-苯并嘧唑_2_基）環丙烷羧醯胺 -外消旋祁妒-二乙基-Ν-[6-({6-[(反式-2-氟基環己基）氧基][1，2,4]二唾并⑽钟荅畊_3_基}硫基）_1，3_笨并嘧唑_2_基]甘胺醯胺 _外消旋'2·(4~乙基六氫吡畊-1-基）-N-{6-[(6-{[反式_2-氟基環己基]氧基}[1，2,4]***并[4,3七]嗒畊-3-基）硫基]-1,3-苯并嘍唑_2_ 基}乙醯胺 -外消旋-N-{6-[(6-{[反式-2-氟基環己基]氧基犯，^]***并 [4,3_b]°答唯_3-基)硫基Η，3·苯并嘍唑-2-基}-2-(嗎福啉-4-基）乙醯胺 -N-(6-{[6-(環丁基氧基）[12,4]***并[4,3_b]嗒畊_3基]硫基卜 U_苯并P塞唾-2-基）-2-(嗎福啉-4-基）乙醯胺 -外消旋-2-(4-環丙基六氫吡畊小基）_N_{6_[(6_{[反式_2氟基環-己基]氧基}[丨，2,4]***并[4,3-b]嗒畊-3-基）硫基]-1，3-苯并嘍。坐-2-基卜乙酸胺 -Ν_(6_ί[6·(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}_ 1,3-笨并*^塞σ坐_2_基）_2_(4_環丙基六氫吡畊小基）乙醯胺 _ Ν_(6_{[6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}_ 1，3笨并遠唾_2_基）_2~(1，1_二氧化硫代嗎福淋冰基）乙醯胺 -N-(6-{[6_(環丁基氧基）[u，4]***并[4,3 b]嗒畊各基]硫基} U_苯并嚷唾-2-基）：(1,4-氧氮七圜-4-基）乙醯胺 _ Ν·(6_{[6'(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基} 145862 -34- 201040187 1，3-苯并嘆唾_2_基）各甲氧基丙醯胺 _ Ν·(6~{[6'(環丁基氧基）[1,2,4]***并[4,3-b]嗒畊-3-基]硫基}- 1，3-苯并嘴唾_2•基）_2_(3,3_二氟六氫吡啶小基）乙醯胺 _外消旋 '順/反-l-{6-[(6-{[3-甲基環己基]氡基}[1，2,4]***并 [4’3—b]嗒口井基)硫基H，3-苯并嘧唑-2-基}-3-[2-(嗎福啉-4-基)乙基]脲 '外’肖旋-順/反-N_{6-[(6-{[3-曱基環己基]氧基}[1，2,4]***并 0 [4’3-b]4^井各基）硫基H^-苯并噻唑么基丨環丙烷羧醯胺 -外消旋-順/反-1-[6-({6-[(4-甲基環己基）氧基][1，2,4]***并 [4’3卻合呼~3_基}硫基H，3-苯并4唑-2-基]-3-[2-(嗎福啉-4-基）乙基]脲 _ 環己基氧基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基}- 1，3-苯并嘍唑_2_基）各(六氫吡啶小基）一氮四圜小羧醯胺 —外’肖旋-順/反-N-[6-({6-[(4-甲基環己基）氧基][ι，2,4]***并 [4,3_b]°合啩基}硫基H，3-苯并4唑-2-基]環丙烷羧醯胺 © N'(6-{[6'(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}- 1’3笨并嘍唑—2_基）_2_氧各氮螺[3.3]庚烷各羧醯胺 N_(6-{[6-(環己基氧基）***并[4,3七]嗒啩_3基]硫基卜 1，3苯并噻唑_2_基）_3_(嗎福啉_4_基）一氮四圜+羧醯胺 •外 >肖旋-N-{6-[(6-{[反式_2_曱基環戊基]氧基丨H4]***并 [4,3-1)>合畊冬基）硫基]4,3_苯并嘧唑冬基}環丙烷羧醢胺 -外消旋小{6-[(6-{[反式-2-曱基環戊基]氧基丨[丨乂斗]***并 [4’3_b]°合唯各基）硫基]-1，3-笨并4唾-2-基}-3_[2-(嗎福淋-4-基）乙基]脲 145862 •35- 201040187 -N (M[6-(環己基氧基）[12,4]***并[4,3七]嗒畊_3基]疏基卜 1，3-苯并嘍唑_2_基）_3·曱氧基一氮四園小羧醯胺 1 (6丨[6'(環己基氧基凡1，2，々]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并P塞唉-2-基）各環氧丙烷各基脲外肩％ -順/反小丨6_[(6_{[3_曱基環戊基]氧基丨以，2,4]***并 [4’3七]°答P井^基）硫基H，3_苯并口塞4 -2-基}-3-[2-(嗎福啉-4-基）乙基]月尿 -外消旋-順/反_Ν_ί6_[(6_{[3_甲基環戊基]氧基}[以⑷***并 [4’3 b]荅°井基）硫基]-1，3—苯并ρ塞唑-2-基}環丙烷羧醯胺以及該式（I)產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。本龟明之一項主題亦為製備如上文定義之式①產物之任何方法。本發明之一項主題係因此為製備如上文所定義之式①產物之任何方法，其中Α表示ΝΗ。本發明之一項主題係因此為製備如上文所定義之式①產物之任何方法，其中A表示S。根據本發明之產物可製自習用有機化學方法。下文圖式 1 2 3、4、5及6係說明用於製備式①產物之方法。在此方面，其將不構成關於製備所請求化合物方法之範圍之限制。 $ 根據本發明如上文所定義之式⑴產物可因此尤其是根摅下文圖式卜2、施、3、4、5及6中所述之方法製成: 本發明之一項主題因此亦為關於根據如下文定義之圖式 145862 -36、Ra represents a group of a cycloalkyl or a group of a cycloalkyl group, optionally substituted by a transradical, alkoxy or -O-C0-R5 group; X represents S; A represents S; W represents a hydrogen atom, or An alkyl group substituted by a heterocyclic alkyl group, or a group COR, wherein R represents: U5862 • 28- 201040187 - a cycloalkyl or alkyl group is optionally substituted by a group NR3R4 or an alkoxy group; a phenyl group; or a group NR1R2, wherein R1 and R2 are such that one represents a hydrogen atom and the other represents an alkyl group optionally substituted by a heterocycloalkyl group; wherein NR3R4, such that R3 and R4, which may be the same or Different, means a hydrogen atom or a Hyun group; R5 represents an alkyl group or a cycloalkyl group containing up to 6 carbon atoms; 〇 The product of the formula (1) is in any possible racemization, palmar isomerism or non-pair The form of the imide, and the addition salt of the product of the formula 1 with mineral acids and organic acids or with minerals and organics. Particularly in the product of the formula (I), the cycloalkyl group may represent a cycloheptyl group, a cyclohexyl group, a decyl group, a cyclobutyl group or a cyclopropyl group; especially in the product of the formula 1, can the heterocycloalkyl group be represented? Folinyl or tetrahydro P is more specific than P. A subject of the invention is therefore a product (form) as defined above or below which corresponds to the following chemical formula: Ο _ cyclohexyloxy) [丨, 2, 4] triazolo[4,3 -b]嗒耕-3-yl]thio}-1,3-benzoxazole-2-yl)cyclopropanecarboxamide-1-(6-{[6-(cyclohexyloxy)[斗]Triazolo[4,37]嗒耕_3 base]thio group H,3_benzopyrazole_2-yl)[2-(morpholine-4-yl)ethyl]urea 1- (6-丨[6_(cyclopentyloxy)[4]5 ° sit and [4,3-b] tau-3-yl]thio}-1,3-benzo-11 plug 11 sit-2 -基)_3_[2_(?福淋_4_基)Ethyl 1 (6 he detected heptyloxy muscle 2,4] three-degree sitting and [4,3-b] 嗒-3-yl] Thio}-1,3-pheno-deso-2-yl)_3_[2_(morpholine-4-yl)ethyl]urea-team (6-{[6-(cyclohexylamino)[u , 4] triazolo[4,3-7] sorghum base] sulphate h,3_ 145862 -29- 201040187 benzopyrazol-2-yl)acetamamine• 1-(6-{[6-( Cyclohexylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thiolbu 1,3~ stupid and far. sit-2-yl) each [2- (tetrahydropyrrol-1-yl)ethyl]urea-N|{[6-(cyclohexylamino)[U,4]triazolo[4,3-7]indole, well; thiol h, 3_ benzene Pyrazol-2-yl)cyclopropanecarboxamide-N-[6-({6-[(trans-4_hydroxycyclohexyl))amino][U4]triazolo[4,3-7]ratin _ 3 -Kilyl)-1,3_benzo-Visin-2-yl]cyclopropane tetamine · Ν·(6-{[6-(cyclopropylamino)[1,2,4] three Azolo[4,3-b]pyrene-yl]thiobenzo-4-ision-2-yl)cyclopropanecarboxamide _ 1-(6-{[6-(cyclohexylamine-based muscle triazole) And [4 3 7] 嗒 _ 3 base] thio ke b u stupid and varnish-2-yl) _3_[2-(morpholine _4_ yl)ethyl]urea-1-(6-{[ 6-(cyclopropylamine^, schizozolium [4,3 荅井井基 ] ] ] } } } } } } } 坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐坐Urea • N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}_ 1,3- Benzopyrene_2_yl)acetamide (6 {[6-(cyclohexyloxy)[1,2,4]triazino[4,3-b]tyn-3-yl]thio }-1,3_ Stupid and plug. Sodium-2-yl)aminophenyl phthalate _ 1-(6-{[6-(cyclohexyloxy)[U,4]triazolo[4,3- b] Tatricin-3-yl]thio is stupid and defen-2-yl) each [2_(tetrapyrrolidinyl)ethyl]urea 6 ([6-(cyclohexyloxy)[1,2,4 ]three. Sit and [4,3-b].荅耕-3-yl]thio}-Ν-[2·(tetrahydroindole ratioo-1'-yl)ethyl]-1,3-benzopyrazol-2-amine _ Ν' (6_{[ 6·(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indol-3-yl]thio}_ 1'3-benzothiazole_2_yl)_2_ Methoxyethylamine _ N_(6_{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indol-3-yl]thiopyr 145862 -30 - 201040187 1,3-benzothiazolyl)-N2,N2_dimethylglycinamide _ Μ·(Μ[6·(cyclohexyloxy)[1,2,4]triazolo[4, 3 VII] 嗒 -3--3-yl]thio}_ U_ benzoxazol-2-yl)-3-methylbutyramine _ N_(6][6'(cyclohexyloxy)[1, 2,4]triazolo[4,3-7]indole-3-yl]thiol 1,3- benzopyrimidine: yl)_3_methoxypropionamide 6 {[6-(3⁄4 戊Oxygen-training triazolo[4,3-b]indole-3-yl]thio H,3- benzopyrazol-2-amine oxime -N-(6-{[6-(cyclopentyloxy) Base-training triazole [4 3 b] 嗒各 ] ] ] ] ] · · · p p p p p p p -2- -2- - - - - - - - - - - - - - - - - - - - - , "] Triazolo[4,3 b] 嗒各 each base] thiol b ^ benzo p plug ° sit-2-yl) acetamamine 6 {[6-(cycloheptyloxy) [12 4 Triazo[4,3-7] towering base] thiol b stupid Pyrazol-2-amine-N-(6-{[6-(cycloheptyloxy)[^4]triazolo[4,3 b]indole_3yl]thiol 1,3-benzene And p-sodium-2-yl)acetamidoxime-cyclopropanone acid-trans-trans-4-{[3-({2-[(cyclopropylcarbonyl))amine H,3_benzoindole. -6-yl-thio-)[丨-triazolo[4,3-b]indole]amino-cyclohexanyl-N-[6-({6-[(trans-_4_hydroxy) Cyclohexyl)amino]|; 1,2,4]triquino[4 3_b] ta _ 3-yl}thio)-1,3-benzo-pyrazole-2-yl]acetamide- 3-[(2-Amino-i,3-benzothiazolyl-6-yl)thio]_N_cyclopropyl[^^Triazolo[4,3-b]indole-6-amine-N -(6-{[6-(cyclopropylamino)[12,4] III. Sodium [4,3-7] morphine-3-yl]thio H,3-benzopyrazol-2-yl) Acetamine-N-(6-{[6-(cyclopropylamino)[ι,2,4]triazolo[4,3-b]嗒4-3-yl]thiopyran 1,3- 145862 -31 - 201040187 笨魂 -2- 基基基基基基 N N N-(6-{[6-(cyclopropylamino)[i,2,4]triazolo[4,3 VII] 嗒 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6_yl)thio]_N_cyclohexyl_7,8 dihydrogen [丨义外二唾和[4,3-b]塔耕-6-amine• ( 6-{[6-(cyclohexyloxy pan-triazolo[4,3 b] 嗒各 each base] thio-bu n stupid. _22-amino)ethyl decanoate-2-chloro-N-(6-{[6-(cyclohexyloxy)(1)triazolo[4,3_b]indole_3yl]thio }-1,3- benzopyrimidine-2-yl)acetamidamine-(6·{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b] Indole-3-yl]thio}-1,3 benzopyrazole-2-yl)_N2_cyclopropylglycine indoleamine 6 [(6丨[4'(difluoromethyl)cyclohexyl] Oxy}}[1,2,4]triazolo[4,3-b>Aging-3-yl)thio]-1,3_benzop-pyrazole-2-amine 'N' (6_{ [6-(cyclobutyloxy)[U,4]triazolo[4,3-b]indole-3-yl]thio}- 'stupid p-salt-2-yl)-2- (4-ethylhexahydro-p-ratio small base) acetamidine-N_(M[6_(cyclobutyloxy)[U,4]triazolo[4,3-b]indole-3-yl Sulfyl}-1,3 stupid and repeated. sit -2'-)-N2,N2-diethylglycine amidoxime' (6'{[6·(cycloheptyloxy)), 2, 4] Triazolo[4,3-b]indole-3-yl]thio}-1'3 stupid and 嗤_2_yl)cyclopropanol carboxamide (6 (nuclear hexylamino) [ 1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzoxazolyl)-3~[3-(morpholin-4- Propyl]urea-1 (6-{[6·(cyclohexyloxy)anthracene, 2,4]triazolo[4,3-b]indol-3-yl]indenyl}-1, 3- And P 啥 '2·yl)_3-[3-(morpholine-4-yl)propyl]urea (6-butyloxy)[1·4]triazolo[4,3-b] Tatric-3-yl]thio}-1,3-145862-32- 201040187 benzopyrimidin-2-yl) each [2_(morpholine yl)ethyl]urea-1-[2-( Morpholine-based)ethyl]_3_{6_[(6_{[4(trifluoromethyl)cyclohexyl]oxy) m,2,4]disindol [4,3_b] ]_u-benzopyrimidin-2-yl}choline-N-(6-{[6-(cyclohexyloxy)[u,4]triazolo[4,3-7]嗒耕_3 base] sulfur Kib 1,3-benzopyrazole-2-yl)_2-cyclopropylacetamide-N-(6-{[6-(cyclobutyloxy)[12,4]triazolo[4 ,3_b]嗒耕各基]thiol 1,3-benzoxazole·2_yl)cyclopropanecarboxamide-racemic-cis/reverse_Ν_{4_[(3_{[2_({[ 2_(Morfosinyl)ethyl]amine oxime}amino)-1,3-benzopyrazoleyl]thio}[1,2,4]triazolo[4,3_b]嗒Plough-& yl)oxy]cyclohexylacetamide N {6[(6 {[4-(difluoroindolyl)cyclohexyl)oxy}[1,2,4] III. Sit and [4 ,3_b]n荅_ -3-yl)thio]_1,3_benzoxazole-2-ylcyclopropanecarboxamide-H6-({6-[(trans-4-hydroxycyclohexyl)) Oxy][1,2,4]triazolo[4, 3-b].荅耕_3-基}-thio)-1,3-benzoxazole-2-yl][2-(morpholine-4-yl)ethyl -6-{[6-(bicyclic) And [3丄〇]hexyl-3-yloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzothiazole- 2-Amine-3-[(2-amino-1,3-1,3-benzopyrazole-6-yl)thio]-N-cyclobutyl[1,2,4]triazolo[4,3- b]-嗒耕-6-amine-N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3- b] 嗒-3-yl]-thio}-1,3-benzopyrazol-2-yl)cyclobutane carbamide-racemic-6-({6-[(trans-2) -fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-b]indol-3-yl}-thio)-1,3-benzo-pyrazole-2- Amine-racemic-N-{6-[(6-{[(trans-2-fluorocyclohexyl)oxy}[1,2,4]triazolo[4,3-b] -3-yl)thio]-1,3-benzopyrazol-2-yl}cyclopropanecarboxamide 145862 -33- 201040187 _ N_(6_{[6-(cyclobutylamino)[1, 2,4]Trisin and [4,3-b] astringent! Base]thio]·1,3-1,3-benzo-4-sial-2-yl)cyclopropanecarboxamide _ Ν_(6_ί[6-(double ring And [3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3 荅荅各]]]]]]]]] Base) cyclopropane carboxamide - external Cyclodecyl-diethyl-indole-[6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]disindol (10) 荅荅 _3_ base }thio)_1,3_ benzopyrimidine_2_yl]glycineamine_racemic '2·(4~ethylhexahydropyrylene-1-yl)-N-{6-[( 6-{[trans-2-hexylcyclohexyl]oxy}[1,2,4]triazolo[4,3-7]indole-3-yl)thio]-1,3-benzoene Carbazole_2_yl}acetamide-racemic-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy), ^]triazolo[4,3_b]°唯 _3-yl)thio sulfonium, 3 · benzoxazol-2-yl}-2-(morpholine-4-yl)acetamide-N-(6-{[6-(cyclobutane)氧基oxy)[12,4]triazolo[4,3_b]indole_3yl]thio-bu-U_benzo-Peda-2-yl)-2-(morpholine-4-yl) Acetamide-racemic-2-(4-cyclopropylhexahydropyrazine)_N_{6_[(6_{[trans-2-fluorocyclo-hexyl]oxy}[丨,2,4 Triazolo[4,3-b]indole-3-yl)thio]-1,3-benzopyrene. sit-2-ylacetic acid amine-Ν_(6_ί[6·(cyclobutyloxy) Base)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}} 1,3-stupid*^ plug σ sitting_2_yl)_2_(4_ Cyclopropylhexahydropyrazine small base) acetamidine _ Ν_(6_{[6-(cyclobutyloxy)[1,2,4]triazolo[ 4,3-b]嗒耕-3-yl]thio}_ 1,3 stupid and far salivary_2_yl)_2~(1,1_dithiocarbamate thiophenate) acetamide-N- (6-{[6_(cyclobutyloxy)[u,4]triazolo[4,3 b]indole]]thio]U_benzoindole-2-yl): (1, 4-oxo-7-yl-4-yl)acetamidine _ Ν·(6_{[6'(cyclobutyloxy)[1,2,4]triazolo[4,3-b] 3-yl]thio] 145862 -34- 201040187 1,3-benzoxanthene_2_yl) methoxypropionamide _ Ν·(6~{[6'(cyclobutyloxy)[ 1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-1,3-benzoindole_2•yl)_2_(3,3-difluorohexahydro Pyridine small group) acetamidine _ racemic 'cis/trans-l-{6-[(6-{[3-methylcyclohexyl]fluorenyl}[1,2,4]triazolo[4' 3-b] Sakaguchi base) thio-based H,3-benzopyrazol-2-yl}-3-[2-(morpholine-4-yl)ethyl]urea 'outside' /trans-N_{6-[(6-{[3-indolylcyclohexyl]oxy}[1,2,4]triazolo[4'3-b]4^ well)thiol H ^-Benzothiazolidinylcyclopropanecarboxamide-racemic-cis/trans-1-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4] Triazolo[4'3 is combined with ~3_yl}thio H,3-benzo-4-oxazol-2-yl]-3-[2-( 4-yl)ethyl]urea_cyclohexyloxy)[1,2,4]triazolo[4,3-b]tac-3-yl]thio}-1,3-benzoindole Oxazol-2-yl) each (hexahydropyridine small group)-azatetraindole small carboxamide-external 'xift-cis/trans-N-[6-({6-[(4-methylcyclohexyl)) Oxy][ι,2,4]triazolo[4,3_b]°indenyl}thio-H,3-benzo-4-oxazol-2-yl]cyclopropanecarboxamide © N'(6-{ [6'(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}- 1'3 benzoxazole-2_yl)_2 _ Oxygen nitrogen snail [3.3] heptane each carboguanamine N_(6-{[6-(cyclohexyloxy)triazolo[4,3-7] 嗒啩3 base] thio phenyl 1,3 benzene And thiazol-2-yl)_3_(morpholine_4_yl)-azatetraindole+carboxycarboxamide•external>Xiaoxuan-N-{6-[(6-{[trans-_2_曱 base) Cyclopentyl]oxyanthracene H4]triazolo[4,3-1)>Homodishyl)thio]4,3-benzopyrazolylyl}cyclopropanecarboxamide-racemic small {6-[(6-{[trans-2-indolylcyclopentyl]oxyindole[丨乂斗]Triazolo[4'3_b]°合基基)thio]-1,3- Stupid and 4-sial-2-yl}-3_[2-(moffa-4-yl)ethyl]urea 145862 •35- 201040187 -N (M[6-(cyclohexyloxy)[12,4] Triazo[4,3-7] _3 base] succinyl 1,3-benzoxazole_2_yl)_3·decyloxy-nitrogen tetracarboxamide Carboxamide 1 (6丨[6'(cyclohexyloxygen 1,2,々) Triazolo[4,3-b]indole-3-yl]thio}-1,3-benzopyrene-2-yl) propylene oxide various urea shoulders %-cis/reverse Small 丨6_[(6_{[3_曱-ylcyclopentyl]oxyindole, 2,4]triazolo[4'3-7]°P Well II)thio-based H,3_benzo-block 4--2-yl}-3-[2-(morpholine-4-yl)ethyl]urea-racemic-cis/trans_Ν_ί6_[(6_{[3_methylcyclopentyl]oxy) Base}[(4)triazolo[4'3 b]荅井)thio]-1,3-benzo-pyrazol-2-yl}cyclopropanecarboxamide and the product of the formula (I) Mineral acid and organic acids or addition salts with mineral bases and organic bases. One of the themes of this Guiming is also any method of preparing the product of formula 1 as defined above. A subject of the invention is therefore any method of preparing a product of formula 1 as defined above, wherein Α represents hydrazine. A subject of the invention is therefore any method of preparing a product of formula 1 as defined above, wherein A represents S. The products according to the invention can be prepared from conventional organic chemistry methods. The following schemes 1 2 3, 4, 5 and 6 illustrate the process for the preparation of the product of formula 1. In this regard, it will not constitute a limitation as to the scope of the method of preparing the claimed compound. The product of the formula (1) as defined above according to the invention may thus be produced, in particular, by the method described in the following figures 2, 3, 4, 5 and 6: a subject of the invention is therefore also Regarding the drawing 145862-36 as defined below,

201040187 1製備式（i)產物之方法。本發明之~ jf 士 3S m , i 2製備式(I)產物之方法。4關於根據如下文定義之圖式 / ^項主題因此亦為關於根據如下文定# 2bls製備式（I)產物之方法。卜文又義之圖式本發明之—項主題因此亦為關於 3製備式①產物之方法。下文疋義之圖式 4製主題因此亦為關於根據如下文定義之圖式表備式（I)產物之方法。 ,本發明之—項主題因此亦為關於根據如下文定義之圖式 t備式（I)產物之方法。本發明之—項主題因此亦為關於根據如下文定義之圖式 6製備式（I)產物之方法。同樣地，在如上文所定義之式（I)產物中，其中=表示單或雙鍵，式（Γ)產物係經定義，其係表示其中二二表示單、建之式（I)產物’及式（Γ)產物’其係表示其中二二表示雙鏠之式（I)產物’且同樣地’關於如下文定義之式⑻、 ⑼、（C)、⑹、⑹及（f)合成中間物，其中=表示單或雙鍵’式（a，）、（b，）、（c，）、（d，）、⑹及（f)化合物係經定義，其中表示單鍵’及式（a")、（b")、（c")、（d")、（e")及（Π化合物’其中=表示雙鍵。 -37- 201040187 圖式 1 :式（la”）、（lb”）、（l”c)、（Id”）、（1〇、（la，）' (lb’) (lc’）、（Id')及（le〇苯并咪唑衍生物之合成201040187 1 Method for preparing a product of formula (i). The method of the present invention for preparing a product of the formula (I) is the use of ~jf 3S m , i 2 . 4 Regarding the subject of the formula /^ according to the definition below, it is therefore also a method for preparing the product of the formula (I) according to # 2bls as follows. BRIEF DESCRIPTION OF THE INVENTION The subject matter of the present invention is therefore also a method for the preparation of the product of Formula 1. The subject matter of the following formula 4 is therefore also a method for preparing the product of the formula (I) according to the schema defined below. The subject matter of the present invention is therefore also a method for preparing a product of formula (I) according to the formula defined below. The subject matter of the present invention is therefore also a method for preparing a product of formula (I) according to Scheme 6 as defined below. Similarly, in the product of formula (I) as defined above, wherein = represents a single or double bond, the product of formula (Γ) is defined to mean that the product of formula (I) is represented by two or two. And the product of the formula (Γ) is a product of the formula (I) in which two or two represent a biguanide, and likewise 'in the middle of the synthesis of the formulae (8), (9), (C), (6), (6) and (f) as defined below , wherein = represents a single or double bond 'a (a,), (b,), (c,), (d,), (6) and (f) compounds are defined, which represent a single bond 'and formula (a&quot ;), (b"), (c"), (d"), (e"), and (Π compound 'where = indicates double bond. -37- 201040187 Figure 1: formula (la)), (lb) , (l"c), (Id"), (1〇, (la,)' (lb') (lc'), (Id') and (le) synthesis of benzimidazole derivatives

NCNC

OCOC

市耩Market

還原作用Reduction

在上文圖式1中，取代基似可採取上文關於式⑺與產物所予之意義，在式⑺、（la，）及（la”）化合物中之取代基 R5表示烧基’而在式（〇)、（ld，）及（1(Γ)化合物中之取代基 R6表示烷基，視情況被NR3R4 (_(CH2)n_NR3R4基團）、烷氧基 '經基、雜環烷基、苯基或_(012)11_苯基取代，其中苯基係視情況經取代，且η表示！至4之整數。在式（P)與 (le〇/(le”）化合物中之取代基R7表示環烷基或烷基，視情況被NR3R4、烷氧基、羥基、苯基、雜芳基或雜環烷基取代’取代基本身視情況經取代。 145862 -38 - 201040187 在上文圖式1中，當w关Η時，構成W之基團c〇NR1R2 ' C02R6及COR7可採取如上文關於式（Γ)與（Γ)產物所定義貿之意義。在上文圖式1 中，通式（la")、（lb")、（lc")、（ld,·)及（le”）苯并咪唑，以及其通式（la〇、（lbi)、（lc，）、（ld，）及（le,)之經還原類似物，可製自市購之式⑸3,6_二氣[u，4^唑并[4,3_b]塔In the above formula 1, the substituents may take the meanings given above for the formula (7) and the product, and the substituent R5 in the compounds of the formulae (7), (la,) and (la") represents the alkyl group. The substituent R6 in the formula (〇), (ld,) and (1(Γ) compound represents an alkyl group, optionally a NR3R4 (_(CH2)n_NR3R4 group), an alkoxy group, a heterocycloalkyl group , phenyl or _(012)11-phenyl substituted, wherein phenyl is optionally substituted, and η represents an integer from ! to 4. Substitution in compounds of formula (P) and (le〇/(le") The group R7 represents a cycloalkyl group or an alkyl group, which is optionally substituted by NR3R4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl substituted 'substituents. 145862 -38 - 201040187 In Scheme 1, when w is closed, the groups c 〇 NR1R2 'C02R6 and COR7 constituting W may take the meaning as defined above for the products defined by the formulas (Γ) and (Γ). In the above Scheme 1 , general formula (la"), (lb"), (lc"), (ld, ·), and (le") benzimidazole, and its general formula (la〇, (lbi), (lc,), ( Ld,) and (le,) Also like the original, it can be prepared from commercially available two gas ⑸3,6_ of formula [u, 4 ^ oxazolo [4,3_b] column

化合物（E)可例如經由醇類或胺類，於鹼存在或不存在下，在化合物⑸上之反應而獲得。反應係例如在2(TC至80 °C區域中之溫度下進行。The compound (E) can be obtained, for example, by reacting an alcohol or an amine with a compound (5) in the presence or absence of a base. The reaction is carried out, for example, at a temperature of 2 (TC to 80 °C).

化合物（G)可例如經由使式（F) 3_胺基斗硝基笨硫醇與式 (E)化合物反應而獲得。式（F)化合物係經由硫氰酸3_胺基冬硝基苯S旨（Q)(市購化合物），例如於硼氫化鈉存在下，在溶劑中，譬如N，N-二甲基曱醯胺，於20°C區域中之溫度下之當场遷原作用而獲得。Compound (G) can be obtained, for example, by reacting a compound of formula (F) 3-amino phenyl thiol with a compound of formula (E). The compound of the formula (F) is via thiocyanate 3-aminobutyryl benzene S (Q) (commercially available compound), for example in the presence of sodium borohydride in a solvent such as N,N-dimethylhydrazine Indoleamine is obtained by on-the-spot migration at a temperature in the region of 20 °C.

145862 -39· 201040187 致使二表示雙鍵之化合物肝，）可例士〇經由以鐵⑼，於式（G)化合物上，在溶劑中’譬如甲醇，於醋酸存在下，在70 C區域中之溫度下之還原作用而獲得。致使二表示單鍵之化合物（H，）可例如經由以⑽）化合物之鋅⑼’於醋酸存在下’在2〇t區域中之溫度下之還原作用而獲得。更特定言之，通式⑽與（la”）胺基甲酸醋类員可尤其是按專利WO 03/028721 A2中所述，個別以式（H，）與（H„)硫化3,木二胺基苯開始，且使用式（J)擬硫脲，於醋酸存在下，及在質子性溶劑中，譬如甲醇，於8〇〇c區域中之溫度下製成。更特定言之，通式（lb，）與（lb”）苯并咪唑可個別經由式⑻ 胺NHR1R2 (其中R1與R2如上文所定義），與式似，）及山"）胺基甲酸酯，例如於非質子性溶劑譬如丨_甲基冬四氫吡咯酮存在下之反應而製成。反應係例如在120。(：區域中之溫度下，於密封管中，在微波下進行。、更特定言之，通式（1c，）與（lc”）2_胺基苯并咪唑可例如經由使溴化氰，個別與式（H，）及（H”）化合物，於質子性溶劑譬如乙醇存在下反應而製成。反應係在8〇。〇區域中之溫度下進行。更特定言之’通式（Id')與（Id”）胺基甲酸酯類可經由使式 (〇)氣碳酸酯（X = C1)，與通式（lc，）及（lc")化合物，例如在溶劑中，譬如四氫呋喃’於鹼存在下，譬如碳酸氫鈉，在20 °C區域中之溫度下反應而獲得。更特定言之’羧醯胺類（le，）與（le")可個別得自通式（Ic，）與 145862 -40- 201040187 (lc”）胺類 _藉由使胺類（ic，）和（ic，，），與式（p)氣化醯（χ = α)，於例如溶劑存在下，譬如吡啶，在20。〇區域中之溫度下反應； -藉由使胺類（lc')和（lc")，與式（Ρ)酸酐（χ = 〇c〇R7)，於例如溶劑存在下，譬如吡啶，在2(rc區域中之溫度下反應； -藉由使胺類（lc’）和（1c”），與式（P)酸(X = 〇H)，在例如由D D.145862 -39· 201040187 The compound liver which causes two double bonds, can be obtained by using iron (9) on the compound of formula (G) in a solvent such as methanol in the presence of acetic acid in the 70 C region. Obtained by reduction at temperature. The compound (H,) which causes two to represent a single bond can be obtained, for example, by reduction of zinc (9)' of the compound (10) in the presence of acetic acid at a temperature in the 2 〇t region. More specifically, the general formula (10) and (la") amino carboxylic acid vinegar members can be specifically vulcanized by the formula (H,) and (H „3, as described in the patent WO 03/028721 A2. Aminobenzene is initiated and prepared using the formula (J) pseudothiourea in the presence of acetic acid and in a protic solvent such as methanol at a temperature in the 8 〇〇c region. More specifically, the general formulas (lb,) and (lb") benzimidazoles may be individually via the formula (8) amine NHR1R2 (wherein R1 and R2 are as defined above), and analogously, and "mountain" The acid ester is prepared, for example, by the reaction in the presence of an aprotic solvent such as hydrazine-methyltetrahydropyrrolidone. The reaction is carried out, for example, at a temperature of 120 in a sealed tube under microwave. More specifically, the general formulae (1c,) and (lc") 2-aminobenzimidazoles can be protonated, for example, by reacting cyanogen bromide with the compounds of formula (H,) and (H"). The solvent is prepared by reacting in the presence of ethanol, for example. The reaction is carried out at a temperature of 8 Torr in the oxime region. More specifically, the 'Formula(Id') and (Id)) urethanes can be obtained by 〇) gas carbonate (X = C1), and compounds of the formula (lc,) and (lc", for example in a solvent such as tetrahydrofuran in the presence of a base, such as sodium bicarbonate, in the region of 20 ° C More specifically, 'carboxy amides (le,) and (le") can be obtained from the general formula (Ic, And 145862 -40- 201040187 (lc") amines - by reacting amines (ic,) and (ic,,) with formula (p), hydrazine (χ = α), for example in the presence of a solvent, For example, pyridine, reacting at a temperature in the oxime region; - by making amines (lc') and (lc"), and formula (Ρ) anhydride (χ = 〇c〇R7), for example, in the presence of a solvent , for example, pyridine, reacting at 2 (the temperature in the rc region; - by making the amines (lc') and (1c"), and the formula (P) acid (X = 〇H), for example by D D.

DesMarteau ; V· Montanari (Chem· Lett·，2000 ⑼.1052)所述之條件下，於1-羥基苯并***與μ(3_二曱胺基丙基）_3_乙基碳化二亞胺存在下，且於鹼存在下，譬如三乙胺，在4〇。〇區域中之溫度下偶合。圖式 2 ·式（2a)、（2b，）、（2c，）、（2d，）、（2a”）、（2b")、（2c”）及 (2d")笨并p塞唾衍生物之合成 ❹Under the conditions described by DesMarteau ; V· Montanari (Chem· Lett., 2000 (9). 1052), 1-hydroxybenzotriazole and μ(3-diaminopropylpropyl)_3_ethylcarbodiimide In the presence and in the presence of a base, such as triethylamine, at 4 Torr. Coupling at the temperature in the helium region. Figure 2 · Equations (2a), (2b,), (2c,), (2d,), (2a"), (2b"), (2c"), and (2d") stupid and p-saliva derivatives Synthetic ❹

在上文圖式2中，取代基尺 a可採取上文關於式（Γ)與（Γ) 145862 41 201040187 產物所示之意義。在上文圖式2中，當W关Η時’構成W之基團CONR1R2、 C02R6及COR7可採取上文關於式(Γ)與(I”）產物所定義w之意義。在上文圖式2中，通式（2a”）、（2b”）、（2C”）及(2d，，）苯并喳。坐 ’及其通式（2a’）、（2b1)、（2c')及（2d’）之經還原類似物，可製自硫氰酸2-胺基-1,3-笨并嘧唑-6-基酯（K)(市購化合物）。In the above Scheme 2, the substituent base a can take the meanings indicated above for the products of the formula (Γ) and (Γ) 145862 41 201040187. In the above Scheme 2, when W is closed, the groups constituting W, CONR1R2, C02R6 and COR7, may take the meaning of w defined above for the products of the formulae (Γ) and (I"). In 2, the general formula (2a"), (2b"), (2C") and (2d,,) benzofluorene. The sitting and 'reduced analogs of the formulae (2a'), (2b1), (2c') and (2d') can be prepared from 2-amino-1,3-benzopyrimidine thiocyanate- 6-yl ester (K) (commercially available compound).

通式（L1)胺基曱酸酯類可例如經由使式（〇)氣碳酸酯（χ = C1) ’與硫氰酸2-胺基-1,3-苯并p塞σ坐基g旨（κ)，在溶劑中，譬如四氫呋喃，於驗存在下，譬如碳酸氫鈉，在2〇°c區域中之溫度下反應而獲得。The amine phthalate of the formula (L1) can be prepared, for example, by reacting a gas of the formula (χ = C1) with a 2-amino-1,3-benzopyranyl thiocyanate group. (κ), obtained by reacting in a solvent, such as tetrahydrofuran, in the presence of a test, such as sodium hydrogencarbonate, at a temperature in the region of 2 ° C.

通式（L2)化合物可例如經由使式（L1)胺基甲酸酯類，其中R6 =苯基’與式（R)胺類NHR1R2 (其中R1與R2如上文所定義）’於非質子性〉谷劑存在下，譬如四氫吹喃，在2〇。〇區域中之溫度下反應而獲得。脲類（2b)與（2b”）可例如個別得自胺基甲酸醋類（2a，）與 (2a”），其中R6 =苯基，以如同脲類（L2)係經由使類型（L1)胺基曱酸酯類上之胺類反應而獲得之方式。The compound of the formula (L2) can be, for example, via the aproticity of the formula (L1) urethane, wherein R6 = phenyl ' and the formula (R) amine NHR1R2 (wherein R1 and R2 are as defined above) In the presence of a granule, such as tetrahydrofuran, at 2 〇. Obtained by reaction at a temperature in the helium region. The ureas (2b) and (2b") may, for example, be obtained individually from the amino carboxylic acid vinegars (2a,) and (2a"), wherein R6 = phenyl, as in the urea (L2) system via the type (L1) The manner in which the amines on the amine phthalates are reacted.

145862 -42- 201040187 可獲得通式（L3)化合物，例如： -藉由使式（P)氣化醯(χ = α)，與硫氰酸2_胺基4,3_苯并嘧唑_ 6-基酯（Κ)，於例如溶劑存在下，譬如吡啶，在2〇t區域中之溫度下反應， -藉由使式（P)酸酐（X = OCOR7)，與硫氰酸2_胺基4,3_笨并嘧唑-6-基酯（K)，於例如溶劑存在下，譬如峨啶，在2〇χ：區域中之溫度下反應， -藉由使硫氰酸2-胺基-1，3-苯并嘧唑_6_基酯（κ)，與式（?)酸(X ® = OH) ’ 在例如由 D.D. DesMarteau ; v M_nafi &hem Utt 5 ⑼.1052)所述之條件下，於丨_羥基苯并***與H3_:甲胺基丙基）-3-乙基碳化二亞胺存在下，且於鹼存在下，譬如三乙胺，在40°C區域中之溫度下偶合。以羧醯胺類（L3)可經由胺（K)之醯化作用而獲得之相同方式，羧醯胺類（2c’）與（2c")可個別得自胺類（2d，）與（2d")，其方式是與式（P)酸（X = OH)，在例如由N· Xi等人，Bi〇〇rg. Med. Q Chem. Lett. 15 (2005) 5211-5217 所述之條件下，於六氟磷酸〇_(7_ 氮苯并***-1-基）-N，N，N，，N，-ra甲基錁（HATU)存在下，在溶劑中，譬如N，N-二甲基曱醯胺，於鹼存在下，譬如二異丙基 - 乙胺，在20°C區域中之溫度下偶合。 145862 -43- 201040187 圖式2bis :關於合成甘胺醯胺衍生物（2c')與（2c”）之途徑145862 -42- 201040187 A compound of the formula (L3) can be obtained, for example: - by gasification of the formula (P) with hydrazine (χ = α), with 2 -amino thiocyanate 4,3-benzopyrazole _ 6-yl ester (oxime), in the presence of, for example, a solvent such as pyridine, reacted at a temperature in the 2 〇t region, - by making the anhydride of formula (P) (X = OCOR7), with 2-amine thiocyanate Base 4,3_ benzopyrazine-6-yl ester (K), for example in the presence of a solvent, such as acridine, reacted at a temperature in the 2:: region, - by subjecting thiocyanate to 2-amine -1,3-benzopyrazole _6-yl ester (κ), and formula (?) acid (X ® = OH) ' in, for example, by DD DesMarteau; v M_nafi & hem Utt 5 (9). 1052) Under the conditions described, in the presence of hydrazine-hydroxybenzotriazole and H3_:methylaminopropyl)-3-ethylcarbodiimide, and in the presence of a base, such as triethylamine, in the region of 40 ° C Coupling at medium temperature. In the same manner as the carboxamide (L3) can be obtained by the deuteration of the amine (K), the carboxamides (2c') and (2c" can be obtained individually from the amines (2d,) and (2d";) in the same manner as the formula (P) acid (X = OH), as described, for example, by N. Xi et al., Bi〇〇rg. Med. Q Chem. Lett. 15 (2005) 5211-5217 In the presence of ruthenium hexafluorophosphate _(7-azabenzotriazol-1-yl)-N,N,N,,N,-ramethylhydrazine (HATU) in a solvent such as N, N- Dimethylguanamine is coupled in the presence of a base such as diisopropyl-ethylamine at a temperature in the region of 20 °C. 145862 -43- 201040187 Scheme 2bis: pathway for the synthesis of glycine derivatives (2c') and (2c")

在上文圖式2bis中，取代基R7可採取胺基甲基之意義。此等甘胺醯胺（2c72c")可藉由使胺類（2d，）和（2d”），與縮水甘油酸（F) ’使用上文關於酸類（p) (X = 〇H)所述之方法偶合而獲得。縮水甘油酸類（P)可在類似由D. T. Witiak等人；_1.]\^(1· Chem. 1985，28，1228所述之條件下’製自演醋酸與胺類 HNR3R4 〇或者’可將胺類（2d’）與（2d”）’以氟基氯化乙醯，於鹼存在下，譬如吡啶、三乙胺或N-曱基嗎福啉，在溶劑中，譬如一氣曱烧，於0C至20 C區域中之溫度下處理。如此形成之氣基乙醢胺（2e/2e )可與如上文所定義之類型hnr3R4 胺類，在溶劑中，譬如吡啶，於2(rc區域中之溫度下反應，而得如上文圖式2bis中所定義之衍生物（2c,/2c”）。通式（Ml)、（M2)及（M3)化合物可例如藉由通式（L1)、（L2) 或（L3)化合物，以DL-二硫基蘇糖醇，於碳酸氫鈉存在下，在溶劑中，譬如乙醇’且於8(TC區域中之溫度下之還原作用而獲得。 145862 -44 - 201040187 通式（N)化合物可當場經由式（κ)化合物’例如以硼氫化納，在溶劑中，譬如Ν，Ν_二甲基甲酿胺，於驗存在下，譬如二乙胺，且在95。(：之區域中或在2(rc與95C>c間之溫度下之還原作用而製成。 & 更特定言之，通式（2d，）與（2d”）苯并噻唑亦可藉由例如與三氟醋酸，在溶劑中’譬如二氯甲烷，於坑區域中之溫度下之反應，個別製自式（2a，）與（2a")胺基甲酸酯類，其中 R6 =第三-丁基。In the above formula 2bis, the substituent R7 may take the meaning of an aminomethyl group. Such glycosides (2c72c" can be used by using the amines (2d,) and (2d") with glycidic acid (F)' as described above for the acid (p) (X = 〇H) The method is obtained by coupling. The glycidic acid (P) can be self-actuated with acetic acid and amine HNR3R4 under the conditions described by DT Witiak et al.; _1.]\^(1·Chem. 1985, 28, 1228). Or 'the amines (2d') and (2d") can be fluorinated with ethyl acetate in the presence of a base, such as pyridine, triethylamine or N-mercapto porphyrin, in a solvent, such as a gas The calcination is carried out at a temperature in the region from 0 C to 20 C. The gas acetamide (2e/2e) thus formed may be of the type hnr3R4 amine as defined above, in a solvent such as pyridine, at 2 ( The reaction is carried out at a temperature in the rc region to obtain a derivative (2c,/2c" as defined in the above formula 2bis. The compounds of the formulae (M1), (M2) and (M3) can be, for example, by the formula ( a compound of L1), (L2) or (L3) in the presence of DL-dithiothreitol in the presence of sodium bicarbonate in a solvent such as ethanol and at a temperature of 8 (the temperature in the TC region) 145862 -44 - 201040187 The compound of the formula (N) can be present in the field via a compound of the formula (κ), for example in the form of sodium borohydride, in a solvent such as hydrazine, hydrazine dimethyl ketoamine. , for example, diethylamine, and is produced in the region of 95. (or in the region between 2 and rc and 95C > c. & more specifically, the formula (2d,) and ( 2d") benzothiazole can also be independently prepared from the formula (2a,) and (2a" amine groups by reaction with trifluoroacetic acid in a solvent such as dichloromethane at a temperature in the pit region. Formate, wherein R6 = third-butyl.

反向地，通式（2a，）與（2a")苯并噻唑亦可例如藉由與式（〇) 氣碳酸酯（X = C1) ’在溶劑中，譬如四氫呋喃，於鹼存在下，譬如碳酸氫鈉，在2(TC區域中之溫度下之反應，個別製自式（2d')與（2d")苯并噻唑。更特定言之，可製備通式（2a”）、（2b”）、（2c”）及⑽”）苯并嘧唑，及其通式（2a，）、（2b1)、（2c1)及（2d，）之經還原類似物，例如： ""~~ 一 ------------- 1) 經由使式（E)化合物，與衍生物（M1)、（M2)及（M3)以及（N) 偶合，其係當場藉由衍生物（LI)、（L2)、（L3)及（K)，以硼氮化納’在溶劑中，譬如N，N_二曱基曱醯胺，且於鹼存在下’譬如三乙胺，在95°C之區域中或在5(TC與95。(：間之溫度下之還原作用而產生； 2) 或經由使經單離之衍生物（M1)、（M2)及（M3)與式（扮化合物’於硼氫化鈉存在下，在溶劑中，譬如N，N_二曱基曱醯胺’且於驗存在下’譬如三乙胺，在95。〇區域中之溫度下偶合； 145862 -45- 201040187 3) 或經由使經單離之衍生物（M1)、（M2)及（M3)與式（E)化合物，在例如由 U. Schopfer 等人(Tetrahedron，2001，57, 3069)所述之條件下，於正-三丁基膦 '第三_丁醇鉀、參（二笨亞甲基丙酮）-一鈀（0)及雙（2-二苯基膦基苯基）醚存在下，在溶劑中，譬如甲苯，於ll〇°C區域中之溫度下偶合； 4) 或絰由使式（E)化合物，與衍生物（M1)、（M2)及（M3)以及 (N)偶合，其係當場藉由衍生物叫）、（L2)、（L3)及⑹，於 DL-二硫基蘇糖醇與碳酸氫鈉存在下，在溶劑中，譬如乙醇，且於80°C區域中之溫度下之還原作用而產生。吁 A(Za)、（2b)、（2c)及（2d)產物，而條件3)與4)獲得式（2a)、⑽）、還原性條件1)與2)可獲得式（2a) 致使——表示單或雙鍵，而條件' (2c)及（2d)產物，致使二二表示雙鍵。Conversely, the general formulae (2a,) and (2a") benzothiazole can also be obtained, for example, by reacting with a gas carbonate (X = C1) in a solvent such as tetrahydrofuran in the presence of a base, for example Sodium bicarbonate, in the reaction at 2 (the temperature in the TC region, is prepared separately from the formula (2d') and (2d") benzothiazole. More specifically, the formula (2a"), (2b) can be prepared. , (2c") and (10)") benzopyrazole, and reduced analogs of the formulae (2a,), (2b1), (2c1) and (2d,), for example: ""~~ I------------- 1) By coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N), it is derived on the spot. (LI), (L2), (L3), and (K), in the form of sodium borohydride in a solvent, such as N,N-didecyl decylamine, and in the presence of a base such as triethylamine, In the region of 95 ° C or at 5 (TC and 95 (reduced by the reduction of temperature; 2) or via the isolated derivatives (M1), (M2) and (M3) a compound (in the presence of sodium borohydride in a solvent such as N, N_ di Indoleamine 'and in the presence of 'such as triethylamine, coupled at a temperature in the 95. 〇 region; 145862 -45- 201040187 3) or via the isolated derivatives (M1), (M2) and (M3) with a compound of the formula (E), under the conditions described, for example, by U. Schopfer et al. (Tetrahedron, 2001, 57, 3069), in n-tributylphosphine 'third potassium butoxide, ginseng ( Coupling in the presence of a palladium (0) and bis(2-diphenylphosphinophenyl)ether in a solvent such as toluene at a temperature in the region of ll ° ° C; Or 偶 by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N), which are on the spot by derivatives, (L2), (L3) and (6) It is produced by reduction in the presence of DL-dithiothreitol and sodium hydrogencarbonate in a solvent such as ethanol at a temperature in the region of 80 °C. Calling A (Za), (2b), (2c), and (2d) products, while conditions 3) and 4) obtaining formulas (2a), (10)), reducing conditions 1) and 2) yielding formula (2a) - indicates a single or double bond, and the conditions ' (2c) and (2d) produce, causing the two to represent a double bond.

(E)***并嗒犄气迮(E) Triazole and anthraquinone

在上文圖式3中，物所示之意義。文關於式（I)產物所定取代基R8表示環烷基，譬如上義。中所指示，得自市購之式（E)化合物可例如按上文圖式3 式⑻3,6-二氯[1，2,4]***并[4,3-b>荅p井 145862 -46- 201040187 更特定言之，式（E)化合物’其中Ra表示基團〇R8，可以下述方式獲得，將3,6-二氯[1，2,4]***并[4,3-b]嗒畊（S)，在20 C至80 C區域中之溫度下，且於溶劑中，譬如四氫p夫喃，以式（U)烷氧化物處理，其本身係經由將醇（H0R8)，以例如氳化鈉，在溶劑中，譬如四氫呋喃，於〇。〇至2〇。〇區域中之溫度下處理而獲得。更特定言之，式（E)化合物，其中Ra表示R8NH基團，可藉由將3,6-二氣[1，2,4]***并[4,3-b]-嗒畊（S)，以式（R8NH2)胺，In the above Figure 3, the meaning of the object. The substituent R8 represents a cycloalkyl group, and the hydrazine is as defined above. As indicated in the above, the commercially available compound of the formula (E) can be, for example, according to the above formula 3, formula (8) 3,6-dichloro[1,2,4]triazolo[4,3-b>荅p well 145862 -46- 201040187 More specifically, the compound of the formula (E) wherein Ra represents a group 〇R8 can be obtained in the following manner, 3,6-dichloro[1,2,4]triazolo[4,3 -b] arable (S), at a temperature in the region of 20 C to 80 C, and in a solvent such as tetrahydropyrene, treated with an alkoxide of the formula (U), which itself is via an alcohol ( H0R8), for example, sodium hydride, in a solvent such as tetrahydrofuran, in hydrazine. 〇 to 2〇. Obtained by processing at temperatures in the helium region. More specifically, a compound of the formula (E) wherein Ra represents an R8NH group can be obtained by 3,6-diox[1,2,4]triazolo[4,3-b]-indole (S) ), with the formula (R8NH2) amine,

在20°C至50°C區域中之溫度下，且於溶劑譬如N，N_二甲基甲醯胺中處理而獲得。It is obtained by treatment in a solvent such as N,N-dimethylformamide at a temperature in the region of 20 ° C to 50 ° C.

❹ 根據上文圖式4，通式（2e，）與（2e")苯并嘧唑可個別製自式 (2a1)與（2a")化合物。在上文圖式4中，取代基〇R6較佳係表示〇-第三_ 丁基。取代基R9表示院基或環烧基，視情況被院氧基或雜環烧基或NR3R4 (R3與R_4如上文所定義）取代。 145862 -47- 201040187❹ According to the above formula 4, the general formula (2e,) and (2e") benzoxazole can be independently prepared from the compounds of the formulae (2a1) and (2a". In the above Scheme 4, the substituent 〇R6 preferably represents 〇-third butyl. The substituent R9 represents a deutero or cycloalkyl group, optionally substituted with a oxy or heterocycloalkyl group or NR3R4 (R3 and R_4 are as defined above). 145862 -47- 201040187

通式（τ)與（τ”）胺基甲酸酯類可個田使通式（2a')盥 (2a1·)胺基曱酸酯類，其中R6較佳 ” 例如與式（W)烷基i化物，在溶劑中，譬如N N_二 T丞甲醯胺，於氫化鈉存在下，在20與90t間之溫度下反應而獲得。通式（2e')與（2e”）苯并噻唑亦可經由式（τ,)與（τ,)化合物，製自式（L1)化合物’其中R6較佳=tBu。更特定言之’通式帽(2e”)化合物可個別藉由將經單離之化合物（T，）與cn，例如以三氟醋酸，在溶劑中，譬如二氣甲烷，於20°c區域_之溫度下處理而獲得。或者，通式（2〇化合物可直接經由使式（u)與⑻化合物，經由當場形成之化合物（T，，），例如於DL_二硫基蘇糖醇與碳酸氫鈉存在下，在溶劑中，譬如乙醇，且於8(rc區域中之溫度下反應而獲得，若必要，則視情況接著以三氟醋酸，於20°C下之當場處理。The general formula (τ) and (τ") urethanes can be used to formulate the general formula (2a') oxime (2a1.) amino phthalate, wherein R6 is preferably "for example, with a formula (W) alkyl group. The compound is obtained by reacting in a solvent such as N N_di-T-carbamidine in the presence of sodium hydride at a temperature between 20 and 90 t. The general formula (2e') and (2e") benzothiazole can also be obtained from the compound of the formula (L1) via the formula (τ,) and (τ,), wherein R6 is preferably = tBu. More specifically, The compound of the cap (2e") can be treated individually by treating the isolated compound (T,) with cn, for example with trifluoroacetic acid, in a solvent such as di-methane at a temperature of 20 ° C. obtain. Alternatively, the compound of the formula (2〇 can be directly passed through the compound of formula (u) and (8), via the compound (T, ,) formed in the field, for example, in the presence of DL-dithiothreitol and sodium hydrogencarbonate in a solvent For example, ethanol is obtained by reaction at a temperature of 8 (the rc region), and if necessary, it is then treated with trifluoroacetic acid at 20 ° C on the spot.

L4 通式（L4)胺基甲酸酯類可藉由使通式（L1)胺基甲酸酯類，例如與式（W)烷基鹵化物，在溶劑中，譬如n，N-二甲基曱醯胺，於氫化鈉存在下，在20與90。(：間之溫度下反應而獲得。 145862 -48- 201040187 圖式S:細)與(2e”）苯并㈣衍生物之合成L4 of the formula (L4) urethane can be obtained by using a urethane of the formula (L1), for example with an alkyl halide of the formula (W), in a solvent such as n,N-dimethylhydrazine Indoleamine, in the presence of sodium hydride, at 20 and 90. (: 145862 -48- 201040187 Scheme S: fine) and (2e") synthesis of benzo (tetra) derivatives

與（E)化合物，例如於甘―& (Μ) 、L_—奴基穌糖醇與碳酸氫鈉存在下：在溶劑譬如乙醇，且載區域中之溫度下。通式（2e·)苯并4唾可根據下文關於自化合物⑺製備化合物（Γ)所述之方法，製自式（2e”）化合物。口式（L6)化合物可藉由以衍生物NH2R9，例如在溶劑中，譬如四氫呋喃，於2〇t區域中之溫度下之處理，製自2_溴基苯并嘧唑衍生物（L5)。取代基R9表示烷基或環烷基，視情況被烷氧基或雜環烷基或NR3R4 (R3與R4如上文所定義）取代。式（L5)化合物可例如經由以亞硝酸烷酯與溴化亞銅，在溶劑中，譬如乙腈，於〇_2〇。(：區域中之溫度下，根據由 Jagabandhu Das 等人在 J. Med. Chem. 2006, 49, 6819-6832 中所述之方法處理，製自硫氰酸2-胺基-U-苯并嘧唑-6-基酯（K)(市購化合物）。 145862 -49- 201040187With (E) a compound, for example, in the presence of gan-&(R), L--n-sulphanol and sodium bicarbonate: in a solvent such as ethanol, and at a temperature in the loading zone. The benzohethane of the formula (2e.) can be prepared from the compound of the formula (2e") according to the method described below for the preparation of the compound (Γ) from the compound (7). The compound of the formula (L6) can be obtained by the derivative NH2R9. For example, in a solvent such as tetrahydrofuran, it is treated at a temperature in the 2 〇t region from a 2-bromobenzoimidazole derivative (L5). The substituent R9 represents an alkyl group or a cycloalkyl group, as the case may be. Alkoxy or heterocycloalkyl or NR3R4 (R3 and R4 are as defined above). The compound of formula (L5) can be, for example, via alkyl nitrite and cuprous bromide in a solvent such as acetonitrile, in 〇 2: (: at a temperature in the region, according to the method described by Jagabandhu Das et al., J. Med. Chem. 2006, 49, 6819-6832, from 2-amino-thio-cyanate-U- Benzopyrazole-6-yl ester (K) (commercially available compound) 145862 -49- 201040187

在基明 W上之反應 A^xxh (η 茳 ΧΧ>Λ A· (r> cr Μ 根據上文圖式6 ’通式(Γ)苯并嘍唑亦可製自式(Γ)化合物，經由例如以硼氫化鈉，在溶劑中，譬如乙醇，於區域中之溫度下之還原作用，或經由以鋅(〇)，於醋酸存在 20°c區域中之溫度下之還原作用。或者，化合物（I，）亦可製自式（E,)化合物，其方式是舆以中間物獲得之類型M1、M2、M3U之化合物偶合，經由化合物LI、L2、L3或κ當場之還原作帛，如前文在圖式2 中所述者。類型M1、M2或M3化合物亦可被單離，且用於與（E，）偶合。化合物（E，）可藉由例如以鋅⑼，於醋酸存在下，在20。。區域中之溫度下之還原作用，得自式⑻化合物。或者，化合物（I，）亦可製自其他化合物（Γ)，經由基團w 之轉化成相同性質之基團w，，如上文關於w所定義，且根據圖式2 . 2d/2d之轉化成為2a，/2a”及成為2c，/2c”，2a，/2a，，之轉中所定義反應之類型J_ 在如上文所疋義之通式（J)化合物中，硫s可根據熟諳此藝者已知之方法被氧化成亞颯so或颯S02 ,若必要，則以適虽保濩基保護任何反應性基團。 145862 -50- 201040187 K 0、？、（^、1^、3、1；、\^及\¥起始物質中，一些係為已知，且可市購或根據熟諳此藝者常用方法獲得，例如得自市售產物。、、熟阳此藝者應明瞭的是，為實現根據前述本發明之方法，可能必須引進關於胺基、缓基及醇官能基之保護其，以避免副反應。 ❹ ❹ 扣可指出保護反應性官能基之實例之下列非毫無遺漏清單. -經基可例如以燒基保€，譬如第三 Α ^ Τ基矽烷丁基二甲基鶴、甲氧基甲基、四氫派喃基、卞基或乙醯基， -胺基可例如以乙醯基、三苯甲基、苄基、第三_ 其、Rnr1 -+Λ- ^ 丁氧 Ik 土、卞虱羰基或鄰苯二曱醯亞胺基或肽化學之其他基團保護。酸官能基可例如經保護，呈以易於***8旨_ 類形式’譬如芊基或第三_丁基酯類 . 類。予甲已知之酯可被使用之各種保護基之清單係在熟諳此藝者手冊中及例如在專利BF 2 499 995中發現。可指出的是，經由上文所示方法如物或產物，若需尊日—，卞< 式（1)中間產他產物，料^ a 切)^他^物或其應，例如或多種熟諳此藝者所已知之轉變反幻關於酸官能基之_化作用之反應’ 145862 201040187 b) 關於I旨官能基之皂化成酸官能基之反應， c) 關於自由態或經酯化之羧基官能基還原成醇官能基之反應， d) 關於燒氧基官能基之轉化成經官能基或者經官能基之轉化成烷氧基官能基之反應， e) 關於移除可藉由經保護之反應性官能基所帶有保護基之反應， ί)與礦酸或有機酸或與鹼之鹽化作用反應，以獲得豆相應之鹽，〜幻關於外消旋形式之解析成經解析產物之反應， ”亥如此獲得之式（1)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式。反應a陶可在熟諳此藝者所已知之一般條件下進行，例如下文所示者。 3)若需要，則上述產物可在可能之減官能基上進行醒化反應，其可根據熟諳此藝者所已知之常用方法進行。 b) 上述產物之酯官能其基之了靶轉化成為酸官能基，若兩要，可在熟諳此藝者所已知而巳知之常用條件下施行，尤其是藓由酸性或鹼性水解，例士n枯、曰 J如使用虱氧化鈉或氫氧化鉀，在醢性媒質中，例如在甲醇中， Ύ 或者，使用鹽酸或硫酸。皂化反應可根據熟諸U蔹| ^ 、口曰此藝者所已知之常用方法進行，如在溶劑中，譬如甲醆、 -手乙醇、二氧陸圜或二甲氧烷，於氫氧化鈉或氫氧化鉀存在下。土乙 c) 上述產物之可能自由能曰由態或酯化羧基官能基，若需要， 145862 •52- 201040187 可經由熟諳此藝者已知之方法，被還原成醇官能基：可能之西曰化敌基吕能基，若需要，可經由熟諳此藝者已知之方法，被還原成醇官能基’且尤其是使用氫化鋰銘，在溶劑 • 中’譬如四氫吱喃、二氧陸圜或***。 >若需要’可使上述產物之可能自由態縣官能基還原成醇s月匕基，尤其是使用氫化石朋。 Φ上述產物之可能燒氧基官能基，尤其是譬如甲氧基，〇 =要’可在熟諳此藝者所已知之一般條件下，被轉：成，輕官能基，例如使用三溴化硼，在溶劑巾，嬖如二氯曱烧，使用㈣氫漠酸鹽或鹽酸鹽，或者，使用氮_或鹽西欠，在水或二氣醋酸中，於回流下。 e)保護基，例如上文所示者，其移除可在熟諳此蔽者所已知之-般條件下進行，尤其是經由以酸進行之酸性水解，譬如鹽酸、苯石黃酸或對-甲苯石黃酸、甲酸或三說醋酸，或者，經由催化氫化作用。 Q 鄰苯二曱醯亞胺基可以肼移除。 "上述產物，若需要’可接受鹽化反應，例如使用礦酸或有機酸或使用㈣或有㈣’根據熟諳此藝者戶斤已知之 • f用方法：此種鹽化反應可例如於譬如鹽酸或酒石酸'檸 . 檬酸或甲烷磺酸存在下，在醇例如乙醇或曱醇中進行。 g)上述產物之可能光學活性形式，可根據熟諳此:者所已知之常用方法，藉由解析外消旋混合物而製成。如上文所定義之式（1)產物及其酸加成鹽具有有利理學性質，尤其是由於其如上文所指出之激酶抑制性質:、 145862 -53- 201040187 本發明之產物尤其是可用於治療腫瘤本發明之產物亦可因此增加常用抗_1治療作用。此專性質餘明其治㈣途，且切明之域係特別是如上文所定義之式①產物作為藥物，該式①產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式 ?產物”藥于上可接文之礦酸及有機酸類或與藥學上可接觉之礦驗及有機驗類之加成鹽。本發明之主題最特別是相應於下列化學式之產物，作藥物： ‘ N (6-{[6-(乂己基氧基）[以…王唑并[4,3_外答_ _3_基]硫基卜 1，3-苯并嘧唑_2_基）環丙烷羧醯胺 :WM[6-(環己基氧基）^4]***并[4 3 b]嗒畊各基]硫基H,3· 笨并嘧唑-2-基）各[2-(嗎福淋_4_基）乙基]脲 _叫孤(環戊氧基氾，2,4]***并[4,3-b]嗒命-3-基]硫基}-1,3-苯并<*塞°坐-2-基）-3-[2-(嗎福淋-4-基）乙基]脎 • H6-{[6-(環庚基氧基）[丨训***并[4 3_b]嗒畊_3基]硫基}13_ 苯并邊唾-2-基)-3-[2-(嗎福啉-4-基）乙基]脲 • Nl{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基H，3_ 笨并p塞嗤-2-基）乙醯胺 1 (6-{[6~(環己胺基）[1，2,4]三唾并[4,3_b]塔p井-3-基]硫基}_ι，3_苯并"塞。坐基）-3-[2-(四氫吡咯-1-基）己基]脲 -N-(6-{[6-(環己胺基）⑴训***并[4,3七]嗒，井各基]硫基}_u_ 笨并P塞唾-2-基）環丙烷羧醯胺 _ N_[6-({6-[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b]塔畊-145862 -54- 201040187 3-基}硫基笨并嘍唑_2_基;1環丙烷羧醯胺 -N-(6_{[6-(環丙胺基）[1，2,4]***并[4,3-b]嗒啩-3-基]硫基H，3-苯并遠唾-2-基）環丙烷羧醯胺 -1-(6-{[6-(環己胺基）[12,4]***并[4,3-b]塔p井-3-基]硫基}-U-苯并喧。坐-2-基）各[2_(嗎福啉_4_基）乙基]脲 _ 1_(6-{[6-(環丙胺基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基}-1,3-笨并0塞唾-2-基）_3-[2-(嗎福啉-4-基）乙基]脲 0 ' Ν-(6-{[6·(環己基氧基肌以]***并[4,3七]嗒p井各基]硫基卜 1，3-苯并P塞唑_2_基）乙醯胺 ' (6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒4 -3-基]硫基H，3-笨并違嗤-2-基）胺基曱酸苯酯 -1-(6-{[6-(環己基氧基）[124]***并[4,3 b]塔畊各基]硫基卜13_ 笨并嘧唑-2-基）-3-[2-(四氫吡咯_1_基）乙基]脲 ' 6'丨[6'(環己基氧基）[1，2,4]***并[4,3-b]塔_ -3-基]硫基}-N-[2-(四氫吡咯-1-基）乙基H，'3-苯并噻唑冬胺；〇 N-(6-{[6-(環己基氧基）[124]***并[4 3 b]嗒畊_3基]硫基卜 U-苯并嘍唑·2_基）_2_甲氧基乙醯胺 NK[6'(環己基氧基）[1，2,4]***并[4,3-b]嗒畊73-基]硫基}-1，3笨并嘍唑_2_基）_n2，n2_二甲基甘胺醯胺 N (6-{[6-(環己基氧基狀2,4]三嗤并阳补答畊各基]硫基卜 1，3-笨并嘧唑_2_基）各甲基丁醯胺 Ν'(6_ί[6_(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-U-笨并嘍唑_2_基）各曱氧基丙醯胺 6_ί[6-(%戊氧基瓜，2，々]***并[4,3-b]嗒畊-3-基]疏基}-1，3-苯并 145862 -55- 201040187 遠唾-2-胺 -队(6-丨[6-(環戊氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基卜1，3-笨并p塞唑-2-基）環丙烷羧醯胺 •队(6_{[6-(環戊氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基卜1，3-苯并嘧唑-2-基）乙醯胺 -M[6-(環庚基氧基）[i，2,4]***并[4,3-b]塔畊-3-基]硫基}-1,3-苯并ϋ塞σ全-2-胺 -Ν-(6-{[6-(環庚基氧基肌2,4]***并[4,3-b]嗒呼-3-基]硫基卜 1,3-苯并喳唑_2_基）乙醯胺 -環丙烧羧酸反式_4-{[3·({2-[(環丙基羰基）胺基]4,3_苯并嘧。坐_6·基卜硫基）[丨，2,4]***并[4,3-b]嗒畊-6-基]胺基}環己酯 -N-[6-({6-[(反式_4_羥基環己基）胺基][ι，2,4]***并[4,3-b]嗒畊-3-基}硫基）-1，3_苯并噻唑_2_基]乙醯胺 -3-[(2-胺基巧}苯并嘍唑各基）硫基]善環丙基⑴2 4]***并 [4,3-b]塔畊-6-胺 N-(6-{[6-(環丙胺基）[uj]***并[43七]嗒畊_3基]硫基笨并'•塞嗤-2-基）乙醯胺丙胺基）[i，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯并遠σ坐-2-基）-3-曱氧基丙醯胺 Ν_(6'丨[6'(裱丙胺基犯，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）_N2，N2_二曱基甘胺醯胺 -3-[(2-胺基义^苯并嘍唑各基）硫基]善環己基二氫[ι，2,仆三。垒并[4,3-b]嗒畊_6_胺 (6_{[6-(%己基氧基儿1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-145862 201040187 苯并P塞唑基）胺基曱酸乙酯 2_氯_N~(6'{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-笨并嘍唑4基）乙醯胺 N""(6’{[6'(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 ’本并塞唾-2-基）_n2 _環丙基甘胺醯胺 _ 6_[(6_{[4~(三氟甲基）環己基]氧基}[1，2,4]***并[4,3-b]嗒畊基）硫基]-1，3-苯并p塞唑_2_胺 ❹ N-(6_{[6'(環丁基氧基）[1二4]***并[4,3七]嗒畊-3-基]硫基卜 ’笨并嚷嗅_2_基）__2_(4_乙基六氫峨畊小基）乙醯胺 N-(6-{[6-(環丁基氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基}_ 1，3苯并嘍唑_2_基）_Ν2 ,ν2 _二乙基甘胺醯胺 • Ν_(6—{[6~(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 ’本并塞。坐_2_基）環丙烧竣酿胺 1 (6丨[6_(環己胺基）[12,4]***并[4,3-b]嗒p井-3-基]硫基}-1，3_笨并嘍唑-2-基）_3_[3_(嗎福啉斗基）丙基]膽〇 + 1_(6-{[6'(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基丨Ί 笨并嘧唑'2·基）-3_[3-(嗎福啉-4-基）丙基]脲 1 (6 {[6你丁基氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基卜n 苯并嘧唑-2-基）各[2_(嗎福啉_4_基）乙基]脲 . 1 [2 (馬揭啉斗基）乙基]各丨6-[(6-{[4-(三氟曱基）環己基]氧基}[1，2,4]二唑并[4,3七]嗒畊-3-基)硫基]-1,3-苯并嘧唑-2-基}膽 Ν+(6·ί[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 I，3-苯并嘍唑-2-基）-2-環丙基乙醯胺 N (6-{[6'(環丁基氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基卜 145862 -57- 201040187 1,3-苯并p塞吐-2-基）環丙烧缓醯胺 -外消旋-順/反-Ν-{4-[(3-{[2-({[2-(嗎福啉-4-基）乙基]胺曱醯基}胺基）-1，3-笨并嘍唑-6-基]硫基}[1，2,4]***并[4,3-b]嗒畊-6-基）氧基]環己基}-乙醯胺 N-{6-[(6-{[4-(三氟甲基）環己基]氧基丨[ι，2,4]***并[4,3-b]嗒畊-3-基)硫基]-1,3-笨并4唑-2-基}環丙烷羧醯胺 -H6-({6-[(反式-4-羥基環己基）氧基][1，2,4]***并[4,3七]嗒畊-3-基}-硫基）-1,3-苯并嘧唑-2-基]-3-[2-(嗎福啉-4-基）乙基]脲 -6-{[6-(雙環并[3丄〇]己各基氧基）[1,2,4]***并[4,3七]嗒啩-3-基]硫基}-1，3-苯并遠哇-2-胺 -3-[(2-胺基-1，3-苯并喳唑_6_基）硫基]-N-環丁基[1,2,4]***并 [4,3七]-塔p井-6-胺 -N-(6-{[6-(雙環并[3丄〇]己-3-基氧基）[1，2,4]***并[4,3-b]塔畊-3-基]-硫基}-1，3-苯并嘧唑-2-基）環丁烷羧醯胺 _外消旋-6-({6-[(反式-2-氟基環己基）氧基][1,2,4]***并[4,3七] 嗒畊-3-基}-硫基）_ι，3—苯并嘧唑_2_胺 "外消旋-N-{6-[(6-{[(反式-2-氟基環己基]氧基}[1，2,4]***并 [4,3-b]嗒畊-3-基）硫基]-1，3-苯并P塞唑-2-基}環丙烷羧醯胺 -N-(6-{[6-(環丁基胺基）[l52,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并喳唑_2_基）環丙烷羧醢胺 -Ν-(6-{[6-(雙環并[3.1.0]己-3-基氧基）[1,2,4]***并[4,3-b]嗒畊-3-基]-硫基}-1，3-笨并嘧唑-2-基）環丙烷羧醯胺 •外消旋-N2，N2-二乙基-N-[6-({6-[(反式-2-氟基環己基）氧基][1，2,4]***并[4,3-b]嗒畊各基}硫基H，3-苯并嘧唑-2-基]甘胺 145862 -58· 201040187 醯胺 -外消旋-2-(4-乙基六氫吡畊小基）_N_{6_[(6_{[反式_2·氟基環己基]氧基}[1，2,4]***并[4,3-b]嗒畊-3-基）硫基]_ι，3_苯并嘧唑_2_ 基}乙醯胺 -外消旋-N-{6-[(6-{[反式-2-氟基環己基]氧基K1，24]***并 [4,3-b]嗒啩冬基)硫基Η，3_苯并噻唑_2_基}_2_(嗎福啉斗基）乙醢胺 -Ν-(6-{[6-(環丁基氧基）[u，4]***并[4,3 b]嗒畊_3基]硫基}_ @ 1，3-苯并噻唑_2_基）_2_(嗎福啉斗基）乙醯胺 -外消旋-2-(4-環丙基六氫吡畊小基）_ν_{6_[(μ[反式_2_氟基壤_己基]氧基}[1，2,4]***并[4,3七]嗒畊-3-基）硫基>1，3-苯并嘍唾-2-基}-乙酿胺 —N-(6-{[6-(環丁基氡基）[12,4]***并[43七]嗒畊_3基]硫基卜 1.3- 苯并噻唑_2_基）_2_(4_環丙基六氫吡畊小基）乙醯胺 N (6 {[6~(環丁基氧基）[1，2,4]***并[4,3-b]嗒啩-3-基]硫基}_ 1’3-苯并嘍唑冬基）_2_(u_:氧化硫代嗎福啉斗基）乙醯胺〇 N-(6-{[6-(環丁基氧基）[u，4]***并[4,3-b]嗒畊-3-基]硫基}- 本并p塞唾_2-基）-2-(1，4-氧氮七圜-4-基）乙醯胺 -N-(6-{[6-(環丁基氧基犯，“]***并[4,3七]嗒畊各基]硫基卜 1.3- 苯并嗜唾_2基）_3•甲氧基丙醯胺 Ν·(Μ[6-(環丁基氧基）[12,4]***并[4 3 b]嗒畊_3基]硫基卜 ’笨并噻唑_2_基）_2_(3,3_二氟六氫吡啶+基）乙醯胺外’肖旋-順/反甲基環己基]氧基}***并 [4’3 b]合井基）硫基]-L3-苯并p塞唑-2-基}-3-[2-(嗎福啉-4-基）乙基]脲 145862 -59- 201040187 -外消旋-順/反_N-{6-[(6-{[3-甲基環己基]氧基丨以二斗]***并 [4,3-b>合啩_3_基）硫基]^苯并嘍唑冬基丨環丙烷羧醯胺 -外消旋-順/反小[6_({6_[(4_曱基環己基）氧基][12 4]***并 [4,3-bh荅啡各基）硫基）4,3_苯并ρ塞唑_2_基]3—[2_(嗎福啉冰基）乙基]脲 _ Ν_(6-{[6<環己基氧基）[丨，2,4]***并[4,3-b]嗒畊-3-基]硫基}_ 1，3-苯并嘍唑_2_基）_3_(六氫吡啶_丨_基）一氮四圜小羧醯胺 -外消旋-順/反_N_[6_({6_[(4_甲基環己基）氧基***并 [4’3 b]合P井~3-基丨硫基）_1，3_苯并3塞唑-2-基]環丙烷羧醯胺 -n-(m[6_(環己基氧基）[u，4]***并[4,3 b]嗒畊各基]硫基}_ 1，3-苯并喳唑_2•基）_2_氧_6_氮螺[3 3]庚烷_6羧醯胺 -N-(6-{[6、(環己基氧基似又…***并…3_別嗒畊各基]硫基卜 1,3笨并p塞唾_2_基）_3_(嗎福p林冰基）一氮四圜—1_叛酿胺 -外消旋-N-{6-[(6-{[反式-2-曱基環戊基]氧基}[1,2,4]***并 [4’3 b>合畊各基）硫基]-1,3-笨并嘧唑_2_基丨環丙烷羧醯胺 -外消旋-1_{6_[(6_{[反式·2_甲基環戊基]氧基}[1，2,4]***并 [4,3抝合畊基）硫基]_1，3_苯并嘧唑冬基}-3-[2-(嗎福啉-4-基）乙基]脲 N 環己基氧基）***并[4,3七]嗒畊各基]硫基卜 1,3苯并喧„坐_2_基）_3_甲氧基一氮四圜小欺醯胺 1 (6 {[6-(環己基氧基）[ι，2,4]***并[4,3七]嗒畊·3基]硫基卜13_ 苯并4唾-2-基）-3-環氧丙烷-3-基脲 -外消旋-順/反小{6_[(6_{[3_甲基環戊基]氧基}[1,2,4]***并 [4,3补荅51井_3·基）硫基]―1，3·苯并嘍唑-2-基}-3-[2-(嗎福啉_4_基）乙 145862 201040187 基]脲 -外消旋-順/反-Ν-{6-[(Μ[3_甲基環戊基]氧基似邮吐并 ⑽則各基)硫基Η}苯并嘆唾·2_基}環丙錢酿胺 :及該式(1)產物與藥學上可接受之礦酸及有機酸類或與藥予上可接受之礦鹼及有機鹼之加成鹽。本發明亦關於醫藥組合物’其含有至少—種如上文所定義之式ω產物或此產物或此產物之前體藥物之藥學上可接 ❹ 〇The reaction on gemin W A^xxh (η 茳ΧΧ > Λ A· (r> cr Μ according to the above formula 6 'General formula (Γ) benzoxazole can also be prepared from the formula (Γ) compound, via For example, sodium borohydride, in a solvent such as ethanol, reduction at a temperature in the region, or via reduction with zinc (〇) in the presence of acetic acid in the region of 20 ° C. Alternatively, the compound ( I,) can also be prepared from a compound of the formula (E), which is a coupling of a compound of the type M1, M2, M3U obtained by the intermediate, and a reduction of the compound LI, L2, L3 or κ on the spot, as in the foregoing The compound of the type M1, M2 or M3 may also be isolated and used for coupling with (E,) in the formula 2. The compound (E,) may be, for example, in the presence of acetic acid in the presence of zinc (9). 20. The reduction at a temperature in the region is obtained from a compound of the formula (8). Alternatively, the compound (I,) may be prepared from another compound (Γ), converted to a group of the same nature via the group w, As defined above for w, and according to the pattern 2. 2d/2d, the transformation becomes 2a, /2a" and becomes 2c, /2c" 2a, /2a,, the type of reaction defined in the transition J_ In the compound of the formula (J) as defined above, the sulfur s can be oxidized to the azulene or 飒S02 according to a method known to the art. If necessary, protect any reactive groups with a suitable sulfhydryl group. 145862 -50- 201040187 K 0,?, (^,1^,3,1;, \^ and \¥ starting materials, some systems It is known and commercially available or obtained according to the usual methods known to those skilled in the art, for example, from commercially available products. It is understood by those skilled in the art that in order to implement the method according to the present invention, it may be necessary to introduce The amine, sulfhydryl and alcohol functional groups are protected from side reactions. ❹ 扣扣 can indicate the following non-exhaustive list of examples of protecting reactive functional groups. The third Α ^ mercapto butyl dimethyl dimethyl crane, methoxymethyl, tetrahydropyranyl, decyl or ethyl, the amine group can be, for example, ethyl hydrazino, trityl, benzyl , third _, Rnr1 - + Λ - ^ butoxy 1k soil, hydrazine carbonyl or phthalimide or a peptide chemistry The acid functional group can be protected, for example, in a form that is easy to split, such as a mercapto group or a third-butyl ester. The list of various protecting groups to which the known esters can be used is It is found in the handbook of this artist and found, for example, in the patent BF 2 499 995. It can be pointed out that, via the method or product described above, if it is necessary to respect the day -, 卞 < The product, the material, or the saponification of the functional group, 145862 201040187 b) Reaction of an acid-forming functional group, c) reaction for the reduction of a free or esterified carboxyl functional group to an alcohol functional group, d) conversion of an alkoxy functional group to a functional group or a functional group for conversion to an alkane Reaction of an oxy-functional group, e) reaction for removing a protecting group carried by a protected reactive functional group, ί) reacting with a mineral acid or an organic acid or with a base to obtain a bean Corresponding salt, ~ illusion about the resolution of the racemic form into a solution The reaction product, "(1) the product of formula thus obtained based Hai than in any possible racemic, on the palm isomers or diastereomeric forms. The reaction a can be carried out under the general conditions known to those skilled in the art, such as those shown below. 3) If desired, the above products may be subjected to a wake-up reaction on a possible depressing functional group, which can be carried out according to the usual methods known to those skilled in the art. b) the ester function of the above product is converted to an acid functional group by a target, and if desired, it can be carried out under the usual conditions known to those skilled in the art, especially by acid or alkaline hydrolysis. For example, if sodium sulphate or potassium hydroxide is used, in an inert medium, for example, in methanol, hydrazine or hydrochloric acid or sulfuric acid may be used. The saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as in a solvent such as formazan, -ethanol, dioxane or dimethoxygen, in sodium hydroxide. Or in the presence of potassium hydroxide.乙乙乙) The possible free energy of the above products, or esterification of carboxyl functional groups, if desired, 145862 • 52- 201040187 can be reduced to alcohol functional groups by methods known to the art: possible The enantiyl group can, if desired, be reduced to an alcohol functional group by methods known to those skilled in the art, and in particular using lithium hydride, in a solvent such as tetrahydrofuran, dioxane or diethyl ether. > If desired, the possible free state functional groups of the above products can be reduced to the alcohol sulphate group, especially using hydrogenated stone. Φ Possible alkoxy functional groups of the above products, especially such as methoxy, 〇 = can be converted to light functional groups, for example using boron tribromide, under the general conditions known to those skilled in the art In a solvent towel, such as dichlorohydrazine, use (iv) hydrogen oxalate or hydrochloride, or, using nitrogen or salt, in water or di-acetic acid, under reflux. e) a protecting group, such as the one shown above, may be removed under the conditions known to those skilled in the art, especially via acidic hydrolysis with an acid such as hydrochloric acid, benzinic acid or p- Toluene acid, formic acid or tri-acetic acid, or via catalytic hydrogenation. The Q phthalimide group can be removed. "The above products, if it is required to 'accept salting reaction, such as using mineral acid or organic acid or using (4) or (4) 'according to the skill of the artisan, the method is known: f such salting reaction can be, for example, 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 decyl alcohol. g) A possible optically active form of the above product, which can be prepared by resolving a racemic mixture according to the usual methods known to those skilled in the art. The product of formula (1) and its acid addition salt as defined above have advantageous properties, in particular due to its kinase inhibiting properties as indicated above: 145862 - 53 - 201040187 The product of the invention is especially useful for the treatment of tumors The products of the invention may thus also increase the usual anti-_1 therapeutic effects. This specific property is described in the fourth paragraph, and the domain of the invention is specifically the product of formula 1 as defined above as a drug, and the product of formula 1 is in any possible racemization, palmar isomerization or diastereoisomerism. The form of the structure, and the addition of the "product" drug to the mineral acid and organic acid or the pharmaceutically pharmaceutically acceptable mineral and organic test. The subject matter of the present invention most particularly corresponds to The product of the following chemical formula, as a drug: ' N (6-{[6-(乂 hexyloxy) [to... oxazolo[4,3_外答_ _3_yl]thiol 1,3-benzoyl Pyrazole-2-ylcyclopropanecarboxamide: WM[6-(cyclohexyloxy)^4]triazolo[4 3 b]indole]thiol H,3· benzopyrimidine- 2-yl) each [2-(moffa- 4-yl)ethyl]urea_called orphan (cyclopentyloxy, 2,4]triazolo[4,3-b]deutero-3- ]]thio]}1,3-1,3-benzo<*sodium-2-yl)-3-[2-(moffa-4-yl)ethyl]anthracene • H6-{[6-( Cycloheptyloxy)[丨训***和[4 3_b]嗒耕_3基]thio}13_ benzo-p-ylidene-2-yl)-3-[2-(morpholin-4-yl) Ethyl]urea • Nl{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thio H 3_ stupid and p-purin-2-yl) acetam 1 (6-{[6~(cyclohexylamino)[1,2,4]tris-[4,3_b]-p--3-yl Sulfyl}_ι,3_benzo" stopper. Sodium)-3-[2-(tetrahydropyrrol-1-yl)hexyl]urea-N-(6-{[6-(cyclohexylamino) (1) Training triazolo[4,3-7]嗒, well each]]thio}_u_ stupid and P-sept-2-yl)cyclopropanecarboxamide _ N_[6-({6-[(trans) -4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]tower-145862-54- 201040187 3-yl}thio-phenyl oxazol-2-yl; 1-cyclopropane carboxamide-N-(6_{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]indol-3-yl]thio H,3- Benzo-p-rhen-2-yl)cyclopropanecarboxamide-1(6-{[6-(cyclohexylamino)[12,4]triazolo[4,3-b]-t-p-3 -yl]thio}-U-benzopyrene. sit-2-yl) each [2_(morpholine-4-yl)ethyl]urea_ 1_(6-{[6-(cyclopropylamino)[ 1,2,4]triazolo[4,3-b]tac-3-yl]thio}-1,3-indolo-oxo-2-yl)_3-[2-(morphine -4-yl)ethyl]urea 0 ' Ν-(6-{[6·(cyclohexyloxy muscle to] triazolo[4,3-7] 嗒p well base] thiodi 1,3- Benzo-P-pyrazole-2-yl)acetamide '(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[ 4,3-b]嗒4-3-yl]thio H,3-stupidyl-2-yl)aminophenyl phthalate-1-(6-{[6-(cyclohexyloxy)) [124] Triazolo[4,3 b]Talvestine base]thiochab 13_ benzopyrazol-2-yl)-3-[2-(tetrahydropyrrole_1-yl)ethyl]urea 6'丨[6'(cyclohexyloxy)[1,2,4]triazolo[4,3-b]t-7-3-yl]thio}-N-[2-(tetrahydropyrrole- 1-yl)ethyl H, '3-benzothiazolamide; 〇N-(6-{[6-(cyclohexyloxy)[124]triazolo[4 3 b]indole _3 base] Sulfur-based U-benzoxazole·2_yl)_2-methoxyacetamide NK[6'(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole Plowing 73-yl]thio}-1,3 stupid and oxazol-2-yl)_n2,n2_dimethylglycinamide N (6-{[6-(cyclohexyloxy) 2,4]嗤嗤阳阳 ] ] ] ] ] ] ] ] ] ] ] ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (6_ί[6_(cyclohexyloxy)[1,2,4 Triazolo[4,3-b]indole-3-yl]thio}-U- benzoxazole-2-yl) methoxy propylamine 6_ί[6-(% pentyloxy ,2,々]Triazolo[4,3-b]indol-3-yl]sulfanyl}-1,3-benzo-145862-55- 201040187 far-salt-2-amine-team (6-丨[ 6-(cyclopentyloxy)[1,2,4]triazolo[4,3-7] Tung-3-yl]thiol 1,3- phenyl p-pyrazol-2-yl)cyclopropane carboxamide; group (6_{[6-(cyclopentyloxy)[1,2,4] three Zoxa[4,3-7]indole-3-yl]thiol1,3-1,3-pyrazol-2-yl)acetamide-M[6-(cycloheptyloxy)[i,2 , 4] Triazolo[4,3-b]tac-3-yl]thio}-1,3-benzoxanthene σ-all-2-amine-Ν-(6-{[6-(环Heptyloxy muscle 2,4]triazolo[4,3-b]indole-3-yl]thiopyranyl 1,3-benzoxazole-2-yl)acetamide-cyclopropanone Acid trans _4-{[3·({2-[(cyclopropylcarbonyl))amino] 4,3-benzopyrimidine. _6·Kipylthio)[丨,2,4]triazolo[4,3-b]indole-6-yl]amino}cyclohexyl ester-N-[6-({6-[ (trans_4_hydroxycyclohexyl)amino][ι,2,4]triazolo[4,3-b]indole-3-yl}thio)-1,3_benzothiazole_2 _ ] 醯 -3- [ [ [ [ [ [ [ 善善善善善善善善善善善善善善善善善善善善善善善善善善善善善善善善善善N-(6-{[6-(cyclopropylamino)[uj]triazolo[437]indole_3yl]thio-p-and-sept-2-yl)acetamidamine) i,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzo-indenyl-yl-2-yl)-3-decyloxypropionamide Ν_(6'丨[6'(裱propylamine, 2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzopyrazole-2- Base)_N2,N2_didecylglycine indoleamine-3-[(2-amino-based benzoxazole)thio]N-cyclohexyldihydro[ι,2, servant III. 4,3-b]嗒耕_6_amine (6_{[6-(%-hexyloxyl 1,2,4]triazolo[4,3-b]indole-3-yl]thio]} -1,3-145862 201040187 Benzo-P-pyrazolyl)amino decanoate 2_Chloro_N~(6'{[6-(cyclohexyloxy)[1,2,4]triazolo[ 4,3-b]嗒耕-3-yl]thio}-1,3-indolocarbazole-4-yl)acetamidamine N"& Quo(6'{[6'(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio-bu-b- Base)_n2 _cyclopropylglycine amide _ 6_[(6_{[4~(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]嗒Plough based] thio]-1,3-benzo-pyrazole-2-amine ❹ N-(6_{[6'(cyclobutyloxy)[1 2 4]triazolo[4,3-7]嗒耕-3-yl]thio-bu'b] and 嚷 sniffing _2_yl)__2_(4_ethylhexahydroindole small base) acetaminophen N-(6-{[6-(cyclobutyloxy) [U,4]triazolo[4,3-b]indole-3-yl]thio}_ 1,3 benzoxazole_2_yl)_Ν2, ν2 _diethylglycine Amine • Ν_(6—{[6~(cycloheptyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio-bu-b. _2_基) Cyclopropanol amide 1 (6丨[6_(cyclohexylamino)[12,4]triazolo[4,3-b]嗒p well-3-yl]thio}- 1,3_stupidoxazol-2-yl)_3_[3_(ffofolin)yl]propyl]cholinyl-1_(6-{[6'(cyclohexyloxy)[1,2,4] Triazolo[4,3-b]indole-3-yl]thio sulfonium benzopyrimidine '2·yl)-3_[3-(morpholine-4-yl)propyl]urea 1 ( 6 {[6-butyloxy)[U,4]triazolo[4,3-b]indole-3-yl]sulfur卜 n benzopyrazol-2-yl) each [2_(morpholine-4-yl)ethyl]urea. 1 [2 (Mamarufensyl) ethyl] 丨6-[(6-{ [4-(Trifluoromethyl)cyclohexyl]oxy}[1,2,4]diazolo[4,3-7]indole-3-yl)thio]-1,3-benzopyrazole -2-yl}cholesterol+(6·ί[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thiopyran I 3-benzoxazol-2-yl)-2-cyclopropylacetamide N (6-{[6'(cyclobutyloxy)[U,4]triazolo[4,3-b]嗒耕-3-yl]thiopyr 145862 -57- 201040187 1,3-benzo-p-propen-2-yl)cyclopropanol hydrazide-racemic-cis/trans-Ν-{4-[ (3-{[2-({[2-(morpholine-4-yl)ethyl]amine)}amino)-1,3-indolocarbazyl-6-yl]thio} 1,2,4]triazolo[4,3-b]indole-6-yl)oxy]cyclohexyl}-acetamide N-{6-[(6-{[4-(trifluoromethyl) Cyclohexyl]oxyindole [ι,2,4]triazolo[4,3-b]indole-3-yl)thio]-1,3-cyclo-4azo-2-yl} ring Propane carboxamide-H6-({6-[(trans-4-hydroxycyclohexyl)oxy][1,2,4]triazolo[4,3-7]indole-3-yl}-sulfur ))-1,3-benzopyrazol-2-yl]-3-[2-(morpholine-4-yl)ethyl]urea-6-{[6-(bicyclo[3丄〇] Have each Oxy)[1,2,4]triazolo[4,3-7-indol-3-yl]thio}-1,3-benz-indol-2-amine-3-[(2-amine -1,3-benzoxazole-6-yl)thio]-N-cyclobutyl[1,2,4]triazolo[4,3-7]-t-p--6-amine-N -(6-{[6-(bicyclo[3丄〇]hex-3-yloxy)[1,2,4]triazolo[4,3-b]tac-3-yl]-sulfur }}-1,3-benzopyrazol-2-yl)cyclobutanecarboxyguanamine_racemic-6-({6-[(trans-2-fluorocyclohexyl)oxy][1 , 2,4]triazolo[4,3-7] 嗒耕-3-yl}-thio)_ι,3-benzopyrazole-2-amine "racemic-N-{6-[( 6-{[(trans-2-fluorocyclohexyl)oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]-1,3- Benzo-P-pyrazol-2-yl}cyclopropanecarboxamide-N-(6-{[6-(cyclobutylamino)[l52,4]triazolo[4,3-b] 3-yl]thio}-1,3-benzoxazole-2-yl)cyclopropanecarboxamide-Ν-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy) (1,2,4)triazolo[4,3-b]indole-3-yl]-thio}-1,3-benzoxazol-2-yl)cyclopropanecarboxamide racemic-N2,N2-diethyl-N-[6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3 -b] 嗒耕基基}thio-H,3-benzopyrazole- 2-yl]glycine 145862 -58· 201040187 guanamine-racemic-2-(4-ethylhexahydropyrazine)_N_{6_[(6_{[trans-2-hexylcyclohexyl]] Oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]_ι,3_benzopyrazole-2-yl}acetamide-racemic- N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy K1,24]triazolo[4,3-b]indoleyl)thiopurine, 3_benzo Thiazole-2-yl}_2_(ffofolin)-acetamid-indole-(6-{[6-(cyclobutyloxy)[u,4]triazolo[4,3 b] _3基]thio}_ @1,3-benzothiazolyl-2-yl)_2_(ffofolin)-acetamido-racemic-2-(4-cyclopropylhexahydropyrazole Base)_ν_{6_[(μ[trans-2-_2-fluoro-based-hexyl]oxy}[1,2,4]triazolo[4,3-7]indole-3-yl)thio] 1,3-benzopyrene-2-yl}-ethonamine-N-(6-{[6-(cyclobutylindolyl)[12,4]triazolo[437]嗒耕_3 Isothiol 1.3-benzothiazol-2-yl)_2_(4_cyclopropylhexahydropyrazine) acetamide N (6 {[6~(cyclobutyloxy)[1,2 , 4] Triazolo[4,3-b]indol-3-yl]thio}_ 1'3-benzoxazole winter base)_2_(u_: oxythiofosfosin) Amine 〇N-(6-{[6-(ring) Butyloxy)[u,4]triazolo[4,3-b]indole-3-yl]thio}-bens p-salt-2-yl)-2-(1,4-oxo Nitrosyl-7-yl)acetamido-N-(6-{[6-(cyclobutyloxy), "]triazolo[4,3-7] sorghum base] thiophene 1.3- Benzo-indan-2-yl)_3•methoxypropanol Ν·(Μ[6-(cyclobutyloxy)[12,4]triazolo[4 3 b]嗒耕_3 base] sulfur Keb 'stupidyl thiazol-2-yl}_2_(3,3-difluorohexahydropyridinium + yl) acetamidine outside 'spin-cis/transmethylcyclohexyl]oxy} triazolo[4' 3 b] well base) thio]-L3-benzo-pyrazol-2-yl}-3-[2-(morpholine-4-yl)ethyl]urea 145862 -59- 201040187 - external elimination Spin-cis/trans_N-{6-[(6-{[3-methylcyclohexyl]oxyindole as difluide] triazolo[4,3-b> 啩_3_yl)thio Benzene carbazole, carbazinylcyclopropane, carbamide, racemic-cis/anti-small [6_({6_[(4-fluorenylcyclohexyl)oxy][12 4]triazolo[4, 3-bh morphine each) thio) 4,3_benzoheptazole-2-yl]3-[2_(morpholine yl)ethyl]urea _ Ν_(6-{[6< Hexyloxy)[丨,2,4]triazolo[4,3-b]indole-3-yl]thio}_1,3-1,3-benzoxazole-2-yl)_3_(hexahydropyridine _丨_一-tetrazepine small carboxamide-racemic-cis/trans_N_[6_({6_[(4_methylcyclohexyl)oxytriazolo[4'3 b]P well~3- Thiothio)_1,3_benzo-3-pyrazol-2-yl]cyclopropanecarboxamide-n-(m[6_(cyclohexyloxy)[u,4]triazolo[4,3 b嗒各 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫硫6, (cyclohexyloxy similar to ... triazole and ... 3 _ 嗒嗒各 ] ] ] ] ] ] ] ] ] ] ] ] 硫硫硫硫硫硫硫硫 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1_Reductive amine-racemic-N-{6-[(6-{[trans-2-indolylcyclopentyl]oxy}[1,2,4]triazolo[4'3 b&gt ; 耕各 ) ) ) ) ) ) ) ) ) ) ) ) 硫硫外外外外外外外外 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Alkyloxy][1,2,4]triazolo[4,3 hydrazine]thio]_1,3_benzopyrazolyl]-3-[2-(morpholin-4 -yl)ethyl]urea N-cyclohexyloxy)triazolo[4,3-7]indoles]thiocha 1,3 benzopyrene „sit_2_yl)_3_methoxy-nitrogen Tetracetinamine 1 (6 {[6-(cyclohexyloxy)[ι,2,4]triazolo[4,3-7]嗒耕·3基]thiobub 13_ benzo-4 saliva- 2- )-3-epoxypropan-3-ylurea-racemic-cis/anti-small {6_[(6_{[3_methylcyclopentyl]oxy}[1,2,4]triazolo[ 4,3 荅荅 51 well _3· yl) thio]-1,3·benzoxazol-2-yl}-3-[2-(morpholine_4_yl)ethyl 145862 201040187 base]urea - racemic-cis/trans-indole-{6-[(Μ[3_methylcyclopentyl]oxy) is like vomiting and (10) is thiol Η} benzo sin. Cyclopropylamine: and the addition salt of the product of the formula (1) with a pharmaceutically acceptable mineral acid and an organic acid or a pre-acceptable mineral base and an organic base. The invention also relates to a pharmaceutical composition which contains at least one of the formula ω products as defined above or a pharmaceutically acceptable pharmaceutically acceptable product of the product or the prodrug of the product.

支鹽，作為活性成份，及在適♦ _I 牡週田ft况下，藥學上可接受之戰體。本發明因此涵蓋醫藥組合物，之藥物，作為活性成份。3有至種如上文定義有：!=種醫藥組合物亦可在適當情況下含有其他抗有4W樂物之活性主要成份，尤其是譬如以紅豆杉醇、順氯胺鉑、：DNA-***劑等為基礎者。此專醫藥組合物可以口士 4 ,^ 了❹服方式，麵腸方式，或局部方式’局概至皮膚與黏膜，或經由行投藥。 X肌内左射進此寺組合物可為固體或液體，且可呈常用於人類醫藥之任何醫藥形式，例如單純或糖塗覆 :； :滕膠囊、滴劑、顆粒、可注射製劑、軟二；膠；其係根據常用方法製成。活性成份：二或；被使用於此等醫膠、乳糖、澱粉、硬… 。如-石、*** 硬月曰酸鎂、可可豆脂、水性岑# hi 劑、動物或植物來#> 次非水性媒物來源之脂肪物質、石蠟衍生物、二醇類、 145862 -6J · 201040187 各種潤濕劑、分散劑或乳化劑及防腐劑。苇用幻里，其可根據所使用之產物、所治療之病患及在考量下之病苦而改變，對成人可為例如每天0.05至5克，或較佳為每天0.1至2克。本發明之一項主題亦為如上文所定義之式①產物或此等產物之藥學上可接受鹽製備藥物之用it，該藥物係抑制激酶蛋白質之活性。本發明之-項主題亦為如上文所定義之式①產物製備藥物之用途’該藥物係治療或㈣錢為激酶蛋自質活調之疾病。此種樂物可尤其是欲供 _〜巾札勒物τ <妖炳發明之-項主題亦為上文所定義之用途，其中激酶白質係為路胺酸激酶蛋白質。本發明之一項主題亦為上文所定義之用途激酉母蛋白質係為met或其突變形式。 ' 本發明之-項主題亦為上文所定義之用途白枭係在細胞培養物中。 ’、其中赂胺酸其中激酶蛋本發明之一項主題亦為上文所定義白質係在哺乳動物中。Branch salt, as an active ingredient, and a pharmaceutically acceptable warfare under the condition of _I. The invention thus encompasses pharmaceutical compositions, medicaments, as active ingredients. 3There are as defined above: !=The pharmaceutical composition may also contain other active ingredients which are resistant to 4W of music, as appropriate, such as, for example, taxol, cisplatin, DNA-insertion Based on the agent. This special pharmaceutical composition can be administered as a veterinarian, in a face-lifting manner, or in a partial manner, to the skin and mucous membranes, or via a drug. The X intramuscular left injection into the temple composition may be solid or liquid, and may be in any medical form commonly used in human medicine, such as simple or sugar coating:; Teng capsules, drops, granules, injectable preparations, soft Second; glue; it is made according to common methods. Active ingredients: two or; used in this medicine, lactose, starch, hard... Such as - stone, Arabian hard magnesium citrate, cocoa butter, water-based hi # hi agent, animal or plant to #> 副 non-aqueous media source of fatty substances, paraffin derivatives, glycols, 145862 -6J · 201040187 Various wetting agents, dispersing or emulsifying agents and preservatives. The illusion may vary depending on the product used, the patient being treated, and the condition under consideration, and may be, for example, 0.05 to 5 grams per day for an adult, or preferably 0.1 to 2 grams per day. A subject of the invention is also the use of a product of formula 1 as defined above or a pharmaceutically acceptable salt of such a product for the preparation of a medicament which inhibits the activity of the kinase protein. The subject matter of the present invention is also the use of the product of formula 1 as defined above. The drug is a therapeutic or (d) money which is a self-regulating activity of the kinase egg. Such a musical substance may especially be used for the purpose defined above, wherein the kinase white matter is a glutamate kinase protein. A subject of the invention is also the use as defined above. The stimulating parent protein line is met or a mutant form thereof. The subject matter of the present invention is also the use as defined above. Cretaceous is in cell culture. ', wherein citric acid, a kinase egg, a subject of the invention is also defined above as a white matter line in a mammal.

之用途其中激酶蛋本發明之一項製備藥物之用途有關聯之疾病。叱我之式該藥物係預防或治療與未經控制文所定義之式(I)產物防選自下列組群之疾 ,本發明之一項主題係為特別是如上製備藥物之用it ’該藥物係治療或預 145862 -62- 201040187 病：血管增生病症、纖維變性病症、" 辦生竑、片,κ 腎小球％間膜"細胞曰生病症代謝病症、過敏反應备綠r*· e 、礼而灰栓开，成、神經系統疾病、視網膜病、牛皮癣肌肉退化及癌症。錄關即炎、糖尿病、本發明之一項主題係因此最 ^ Mm miin ^ m ^ σ上文所定義式（I)產物t備樂物之用途，該藥物尤其是治療癌症。戈預防腫瘤學疾病’及在此專癌症中，注音六技奎Uses of the kinase egg One of the inventions The use of a medicament for the treatment of a disease associated therewith.叱之该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该该Drug treatment or pre-145862 -62- 201040187 disease: vascular proliferative disorders, fibrotic disorders, "surgical sputum, tablets, κ glomerular% intermembrane" cell-proliferative disorders metabolic disorders, allergic reactions prepared green r* · e, ritual and gray sputum, into, nervous system diseases, retinopathy, psoriasis muscle degeneration and cancer. Recording is inflammation, diabetes, and a subject of the present invention is therefore the use of the formula (I) of the formula (I) defined above, which is especially for the treatment of cancer. Go to prevent oncological diseases' and in this special cancer, the phonetic six skills

意力係'專注於固態或液態腫瘤之治療’及對細胞毒劑具抗M性之癌症之治療。The intention is to focus on the treatment of solid or liquid tumors and the treatment of cancers with anti-M properties of cytotoxic agents.

本發明所引述之產物可+甘B 、 ’、疋被使用於治療原發性腫瘤及/或轉移，制是在胃、肝臟、腎臟、卵巢、腸或前列腺癌、肺癌(NSCLC嫩)、神經膠質母細胞瘤、甲狀腺、膀胱或乳癌、I色素瘤、淋巴樣或趙樣造血腫瘤、肉瘤、腦癌、喉癌、淋巴系統癌、骨癌及姨癌上。本發明之-項主題亦為如上文所定義之式①產物製備藥物之用途，該藥物係欲供癌症化學療法使用。此種欲供癌症化學療法用之藥物可單獨或合併使用。本專利申凊案之產物可尤其是單獨投藥，或併用化學療法或放射療法，或者，併用例如其他治療劑。此種治療劑可為常用抗腫瘤劑。可指出之激酶抑制劑包括丁内酯、黃酮吡啶醇及2_(2_羥乙基胺基)-6-节胺基-9-甲基嘌呤，稱為歐羅莫辛(〇1〇m〇udne)。本發明之一項主題亦為如上文所定義及下文所回憶之式 K、Ml、M2、M3及N合成中間物，作為新穎工業產物： 145862 -63· 201040187The products cited in the present invention can be used to treat primary tumors and/or metastases in the stomach, liver, kidney, ovary, intestine or prostate cancer, lung cancer (NSCLC tender), nerves. Glioblastoma, thyroid, bladder or breast cancer, I tymoma, lymphoid or Zhao-like hematopoietic tumor, sarcoma, brain cancer, laryngeal cancer, lymphatic system cancer, bone cancer and sputum cancer. The subject of the invention is also the use of a product of formula 1 as defined above for the preparation of a medicament for cancer chemotherapy. Such drugs for cancer chemotherapy may be used singly or in combination. The product of this patent application may, in particular, be administered alone, or in combination with chemotherapy or radiation therapy, or together with, for example, other therapeutic agents. Such a therapeutic agent can be a commonly used antitumor agent. The kinase inhibitors which may be mentioned include butyrolactone, flavonol and 2-(2-hydroxyethylamino)-6-amino-9-methyl hydrazine, which are called uromoxine (〇1〇m〇). Udne). A subject of the invention is also a K, Ml, M2, M3 and N synthesis intermediate as defined above and hereinafter recalled as a novel industrial product: 145862 - 63· 201040187

其中構成W之基團CONR1R2、C02R6及COR7可採取如上文關於式（I)產物所定義，當W关Η時之W意義，且取代基Ra 可採取上文關於式（I)產物所示之意義。_ 下文實例，其係為式（I)產物，係說明本發明，但非限制之。【貫施方式】實驗段落本發明化合物之命名法係以ACDLABS軟體10.0版與11版產生。所使用之微波爐：The groups CONR1R2, C02R6 and COR7 constituting W may take the meaning of W as defined above for the product of formula (I), when W is concerned, and the substituent Ra may be as indicated above for the product of formula (I) significance. The following examples, which are products of formula (I), illustrate the invention, but are not limiting. [Comprehensive application method] Experimental paragraph The nomenclature of the compounds of the present invention was produced using ACDLABS software versions 10.0 and 11. Microwave oven used:

Biotage，引發器 EXP-EU, 300 W 最大值，2450 MHz 400 MHz 與 300 MHz 1H NMR 光譜係使用 Briiker Avance DRX-400 或BrUker Avance DPX-300光議儀獲得，其中化學位移（(5，以 ppm表示），在溶劑二曱亞颯-d6(DMSO-d6)中，係參考2.5 ppm，於303 K之溫度下。質譜係藉由分析以下之任一種而獲得： -LC-MS-DAD-ELSD (MS = Waters ZQ) -LC-MS-DAD-ELSD (MS =平台 II Waters Micromass) -UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters) 145862 -64- 201040187 -UPLC-SQD (Waters) DAD波長係考慮叉=210-400毫微米 ELSD : Sedere SEDEX 85 ;霧化作用溫度=坑；霧化作用壓力=3.7巴實例1 : 環己基氧基氾，“]***并[4,3_b]嗒呼_3基]硫基}·u-苯并嚙唑-2-基）環丙烷羧醯胺 ’ a) Ν-(6·{ [6_(環己基氧基Xl，2,4]***并[4,3七]嗒哜各基]硫基卜 1,3-本并Ρ塞α坐-2-基）環丙烧緩酿胺可以下述方式製成· 將75毫克6-{[6-(環己基氧基）[u，4]***并[4 3 b]嗒畊冬基]硫基}-1，3-苯并噻唑冬胺與20微升環丙烷氯化醯於2〇t下添加至2立方公分吡啶中。3小時後，添加另外2〇微升環丙烷氯化醯，並將混合物攪拌18小時。添加另外20微升環丙烷氯化醯，且使混合物再留置反應一小時。使反應混合物濃縮至乾涸，並使固體殘留物於Bi〇tage Quad藥筒12/25 (κρ_ SIL，60Α; 32-63 //Μ)上，藉固體沉積而層析，以二氣甲烷/ 甲醇之99.5/0.5至90/10梯度液溶離。將所獲得之固體以*** 洗滌。因此，獲得66毫克Ν_(6_{[6_(環己基氧基犯，^]***并 [4,3-b]。合畊-3-基]硫基卜ι，3_苯并嘧唑基）環丙烷羧醯胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（4〇〇 MHz，觀抓士）5 ppm 〇 881 〇1 (m，4H) i 131 % (m, 6H) 1.52-1.66 (m, 2H) 1.71-1.86 (m, 2H) 1.92-2.04 (m, 1H) 4.61-4.74 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.0, 2.0 Hz, 1H) 7.67 (d, J = 8.0Biotage, initiator EXP-EU, 300 W maximum, 2450 MHz 400 MHz and 300 MHz 1H NMR spectra were obtained using a Briiker Avance DRX-400 or BrUker Avance DPX-300 optical nebulizer with chemical shift ((5 in ppm) In the solvent diterpenoid-d6 (DMSO-d6), reference is made to 2.5 ppm at a temperature of 303 K. Mass spectrometry is obtained by analyzing any of the following: -LC-MS-DAD-ELSD (MS = Waters ZQ) -LC-MS-DAD-ELSD (MS = Platform II Waters Micromass) - UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters) 145862 -64- 201040187 -UPLC-SQD (Waters) DAD wavelength is considered for the fork = 210-400 nm ELSD: Sedere SEDEX 85; atomization temperature = pit; atomization pressure = 3.7 bar Example 1: cyclohexyloxy pan, "] triazolo[4,3_b]嗒 _ 3 _ _ _ _ _ _ _ _ _ _ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( And [4,3 VII] 嗒哜 each base] thiol 1,3- and Ρ α α sit-2-yl) cyclopropanthine can be made in the following manner · 75 mg 6-{[ 6-(cyclohexyloxy)[u,4]triazolo[4 3 b]indole winter base]thio}}1,3-benzothiophene Azolamide and 20 microliters of cyclopropane chloride were added to 2 cubic centimeters of pyridine at 2 Torr. After 3 hours, another 2 liters of microliters of cyclopropane ruthenium chloride were added and the mixture was stirred for 18 hours. 20 microliters of cyclopropane ruthenium chloride, and the mixture was left to react for one hour. The reaction mixture was concentrated to dryness and the solid residue was placed on a Bi〇tage Quad cartridge 12/25 (κρ_ SIL, 60 Α; 32-63 / / Μ), by solid deposition and chromatography, eluting with a gradient of 99.5/0.5 to 90/10 of methane/methanol. The obtained solid was washed with diethyl ether. Thus, 66 mg of Ν_(6_{[6_ (cyclohexyloxy oxime, ^] triazolo[4,3-b]. cultivative-3-yl]thiophenyl, 3-benzopyrazolyl)cyclopropanecarboxamide, in the form of a white powder The characteristics are as follows: 1H NMR spectrum (4〇〇MHz, Guanshi) 5 ppm 〇881 〇1 (m,4H) i 131 % (m, 6H) 1.52-1.66 (m, 2H) 1.71-1.86 (m , 2H) 1.92-2.04 (m, 1H) 4.61-4.74 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.0, 2.0 Hz, 1H) 7.67 (d, J = 8.0

Hz’ 1H) 8.05 (d, J = 2,0 Hz, 1H) 8.28 (d，J = 10.0 Hz, 1H) 12.67 (寬廣 s” 145862 -65 - 201040187 1H) 質譜：UPLC-SQD ·· MH+ m/z = 467+ ; ΜΗ- = 465-。 b) 6-丨[6-(環己基氧基）[1，2,4]***并[4,3-b]。荅畊-3-基]硫基卜ι，3-笨并嘍唑-2-胺可以下述方式製成·· 使氬氣流起泡經過149毫克硫氰酸2-胺基_ι,3-苯并嘍唑各基醋（市購）在20立方公分乙醇中之溶液，歷經5分鐘。然後添加0.2立方公分水中之4毫克磷酸二氫鉀、333毫克dl_ 一硫基蘇糖醇及182毫克3-氣基-6-(環己基氧基）[丨,2,4]三σ坐并 [4,3-b]嗒畊。將反應混合物於80它下加熱23小時，接著在真空下濃縮至乾涸。使殘留物於矽膠上藉固體沉積純化，以 100%二氣甲烷至80/20二氯曱烷/(38二氯甲烷/：17甲醇/2氨水）之梯度液溶離。因此，獲得130毫克6_{[6_(環己基氧基 ***并[4,3-b]嗒畊-3-基]硫基H，3_苯并噻唑冬胺，呈帶黃色粉末形式，其特徵如下：質譜：LC/MS 電噴霧於 Waters UPLC_SQD 上：MH+ 讀=399+ ; MH- = 397- c) 3-氣基-6-(環己基氧基）[^4]三哇并[4,3七]嗒畊可以下述方式製成：於(TC及氬氣下，將762毫克在6〇%下於油中之氫化鈉添加至3.18克環己醇在30立方公分四氫吱π南中之溶液内。在擾拌15分鐘後，添加3克3,6_二氯[以]三嗤并[4,3钟答叫（市購）。將褐色懸浮液擾拌22小時，同時使其逐漸回復至2〇 t。然後，將反應媒質倒入冰水中，&以醋酸乙酿萃取混合物。使有機相於真空下濃縮至乾酒後，獲得褐色油。使 145862 -66- 201040187 油狀殘留物在Biotage Quad 12/25藥筒上層析（Kp_SIL，60人； 32-63 /Μ)，以95/5至65/35環己烷/醋酸乙酯梯度液溶離。因此，獲得2.7克3-氯基-6-(環己基氧基）[ι,2,4]***并[4,3-b]嗒畊’呈帶黃色粉末形式，其特徵如下：質譜·· LC/MS 電噴霧於 Waters UPLC-SQD 上：MH+ = 253+ 實例2 : 1-(6-{[6-(環己基氧基）[H4]***并[4,3_b]嗒畊各基]硫基}1，3苯并嘧唑-2-基)-3.[2-(嗎福啉-4-基）乙基脈 O a) 1-(6_{[6_(環己基氧基）[1，2,4]***并[4,3-1)]嗒畊-3-基]硫基}- 1，3-苯并噻唑-2-基）-3-[2-(嗎福啉-4-基）乙基]脲可以下述方式製成：Hz' 1H) 8.05 (d, J = 2,0 Hz, 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.67 (broad s" 145862 -65 - 201040187 1H) Mass Spectrometer: UPLC-SQD ·· MH+ m/ z = 467+ ; ΜΗ- = 465-. b) 6-丨[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]. 荅-3-yl] Thioyl ι, 3- benzoxazole-2-amine can be prepared in the following manner: • argon gas stream is bubbled through 149 mg of 2-amino thiocyanate _ι,3-benzoxazole vinegar (commercially available) solution in 20 cubic centimeters of ethanol, after 5 minutes. Then add 4 mg of potassium dihydrogen phosphate, 333 mg of dl_monothiothreitol and 182 mg of 3-sulfo-6- in 0.2 cubic centimeters of water. (cyclohexyloxy)[丨,2,4]tris[sigma][4,3-b] tillage. The reaction mixture was heated at 80 ° for 23 hours, then concentrated under vacuum to dryness. The ruthenium was purified by solid deposition and dissolved in a gradient of 100% di-methane to 80/20 dichloromethane/(38 dichloromethane/:17 methanol/2 ammonia). Thus, 130 mg of 6_{[6_( Cyclohexyloxytriazolo[4,3-b]indole-3-yl]thio H,3-benzothiazolamide, in the form of a yellow powder, characterized by Mass spectrometry: LC/MS electrospray on Waters UPLC_SQD: MH+ read = 399+; MH- = 397- c) 3-carbyl-6-(cyclohexyloxy)[^4]triwax[4,3-7 The ploughing can be made in the following manner: Under TC and argon, 762 mg of sodium hydride in oil at 6〇% is added to 3.18 g of cyclohexanol in 30 cubic centimeters of tetrahydroanthracene π south. Within the solution, after stirring for 15 minutes, add 3 g of 3,6-dichloro [to] triterpene and [4, 3 call (commercially available). The brown suspension was spoiled for 22 hours while gradually allowing it to gradually Return to 2 〇t. Then, the reaction medium is poured into ice water, & extract the mixture with acetic acid. The organic phase is concentrated under vacuum to dry wine to obtain a brown oil. 145862 - 66 - 201040187 oily residue Chromatography on a Biotage Quad 12/25 cartridge (Kp_SIL, 60 persons; 32-63 / Μ), eluting with a 95/5 to 65/35 cyclohexane/ethyl acetate gradient. Thus, 2.7 g of 3 was obtained. -Chloro-6-(cyclohexyloxy)[ι,2,4]triazolo[4,3-b]indole" is in the form of a yellow powder with the following characteristics: Mass Spectrometry·· LC/MS Electrospray On Waters UPLC-SQD: MH+ = 253+ Example 2: 1-(6-{[6-(cyclohexyl) Base][H4]triazolo[4,3_b]indole]thio]},3 benzopyrazol-2-yl)-3.[2-(morpholine-4-yl)ethyl Pulse O a) 1-(6_{[6_(cyclohexyloxy)[1,2,4]triazolo[4,3-1)]indol-3-yl]thio}- 1,3- Benzothiazol-2-yl)-3-[2-(morpholine-4-yl)ethyl]urea can be prepared in the following manner:

使1氣流起泡經過339毫克1-[2-(嗎福啉_4_基）乙基]-3-(6-硫基-1，3-苯并p塞唾-2-基）脲在2〇立方公分乙醇中之溶液，歷經 5分鐘。接著添加0.2立方公分水中之5毫克磷酸二氫鉀、 463宅克DL-二硫基蘇糖醇及253毫克3氣基_6 (環己基氧 Q 基）[1，2’4]二。坐并[4,3七]嗒畊（k)。然後，將反應混合物於8(TC 下加熱47小時，接著，使帶白色溶液在真空下蒸發至乾涸。使殘留物於矽膠上藉固體沉積純化，以1〇〇%二氯甲烷至 . 85/15二氯甲烷7(38二氣甲烷/17曱醇/2氨水）之梯度液溶離。 • 因此’獲得246毫克1-(6-{[6-(環己基氧基）[1,2,4]***并[4,3-13] 嗒畊-3-基]硫基}-1，3-苯并嘍唑_2_基）冬[2_(嗎福啉_4_基）乙基] 脲’呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMS0-d6) 5 ppm 1.00-1.55 (m，6H) 1.62 (m， 2H) 1.73-1.90 (m, 2H) 2.29-2.47 (m, 6H) 3.19-3.28 (m, 2H) 3.59 (m, 4H) 145862 •67- 201040187 4.57-4.80 (m，1H) 6.77 (寬廣 s” 1H) 7.02 (d，J = 9.8 Hz，1H) 7_36 (dd，J = 8.5, 1.5 Hz, 1H) 7.54 (d, J = 8.5 Hz, 1H) 7.99 (d, J = 1.5 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 10·% (寬廣 s·，1H) 質譜：UPLC-SQD : MH+ m/z = 555+ ; MH- = 553- b) l-[2-(嗎福淋-4·-基）乙基]-3-(6-硫基-1，3-苯并p塞。圭-2-基）腺可以下述方式製成：於20°C下，使氬氣流起泡經過900毫克硫氰酸2-{[(2-嗎福淋-4-基乙基）胺曱酿基]胺基}-1，3-苯并p塞。坐-6-基S旨與40立方公分乙醇之混合物’歷經5分鐘。然後添加0.4立方公分水中之11毫克磷酸二氫鉀與1.1克DL-二硫基蘇糖醇。將混合物在80°C下加熱3.5小時。使反應媒質冷卻至20。(：，接著倒入水中。將此懸浮液攪拌45分鐘，同時保持以氬溫和起泡。藉抽氣滤出所形成之沉澱物，並以3x10立方公分水洗滌’然後於真空及20°C下乾燥。因此，獲得633毫克1_(2_嗎福琳-4-基乙基）-3-(6-硫基-1，3-苯并〇塞。坐-2-基）脲，呈白色固體形式，其特徵如下：質譜：LC-MS-DAD-ELSD : MH+ m/z = 339+ ; (M-H)- = 337- c) 硫氰酸2-{[(2-嗎福啉-4-基乙基）胺曱醯基]胺基卜苯并嘧唑-6-基酯可以下述方式製成：將0.44立方公分2-嗎福p林-4-基乙胺於20 C下添加至1克（6 氰硫基4,3-苯并嘍唑-2-基）胺基甲酸苯酯在30立方公分四氯吃喃中之20°C下溶液内。24小時後，使反應混合物蒸發至乾酒’並使所得之殘留物在Merck 70克藥筒上層析（固體沉積；以二氣甲烷’接著以90/10二氣曱烷/曱醇之梯度液溶 145862 -68- 201040187 離）。因此，回收902毫克硫氰酸2-{[(2-嗎福啉_4_基乙基）胺曱醯基]胺基}-1，3-笨并嘍唑-6-基酯，呈無色泡珠物形式，其特徵如下：質譜：UPLC-MS-DAD-ELSD: MH+m/z：=364+ d) (6-氰硫基-1，3-苯并p塞唾-2-基）胺基曱酸苯酯以下述方式製成：將7.5克氣碳酸苯S旨’接著為4.05克碳酸氫鈉與9.4立方公分水，於20°C下添加至2.5克市購硫氰酸2_胺基d，}苯并噻唑-6-基酯在94立方公分四氫咬喃中之溶液内。然後，將所形成之混合物於20°C下攪拌20小時，接著以2χ15()立方公分醋酸乙酯萃取。合併有機相’然後以3x50立方公分飽和碳酸氫鈉水溶液洗滌。使所獲得之有機相以硫酸鎂脫水乾燥，接著在減壓下濃縮至乾涸。使殘留物溶於5〇立方公分水中’然後藉由抽氣濾出’並在真空及2〇。〇下乾燥。因此’獲得3.45克（6-氰硫基-1,3-苯并違吐_2_基）胺基曱酸苯酯，呈淡黃色固體形式，其特徵如下：質谱· LC-MS-DAD-ELSD : MH+ m/z = 328+ ; (M-H)- = 326- 實例3 : Ν-(6-{[6·(環己基氧基似以仨唑并[4,3补荅畊-3·基]硫基卜;ι，3_苯并ρ塞唑-2·基）乙醯胺 Ν-(6-{[6-(環己基氡基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-笨并噹唑-2-基）乙醯胺可以下述方式製成：將0.276立方公分醋酸酐與160亳克6-{[6_(環己基氧基）[ι，2,4] 二嗤并[4,3-b]°荅畊-3-基]硫基}-1，3-笨并逢吐_2_胺⑽）於20°C下 145862 -69· 201040187 添加至2立方公分吡啶中。5小時後，添加另外〇·3立方公分醋酸酐，並將混合物留置攪拌17小時。使反應混合物在真空下濃縮至乾涸。使帶黃色固體殘留物於m〇tage Quad 12/25 藥筒上層析（KP_SIL，60人；32_63 ，以 1〇〇% 二氣曱烧至97.5/2.5二氯甲烧/甲醇之梯度液溶離。因此，獲得宅克N-(6-{[6-(環己基氧基）[1，2,4]三唾并[4,3-b]塔味-3-基]硫基}_ 1,3-笨并噻唑_2_基）乙醯胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（4〇〇 MHz, DMSO-d6) <5 ppm 1.05-1.53 (m, 6H) 1.52-1.68 (m, 2H) 1.71-1.85 (m, 2H) 2.19 (s, 3H) 4.56-4.73 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.40 (dd, J = 8.5, 2.0 Hz, 1H) 7.66 (d, J = 8.5 Hz, 1H) 8.06 (d, J = 2.0The 1 gas stream was bubbled through 339 mg of 1-[2-(morpholine-4-yl)ethyl]-3-(6-thio-1,3-benzo-p-sp-2-yl)urea. A solution of 2 〇 cubic centimeters of ethanol, after 5 minutes. Next, 5 mg of potassium dihydrogen phosphate, 463 gram of DL-dithiothreitol, and 253 mg of 3 gas-based -6 (cyclohexyloxy Q-based) [1,2'4] were added in 0.2 cubic centimeters of water. Sit and [4, 3 seven] ploughing (k). Then, the reaction mixture was heated at 8 (TC) for 47 hours, then the white solution was evaporated to dryness in vacuo. The residue was purified on a silica gel eluted with solids, from 1% to dichloromethane. 15 Dichloromethane 7 (38 dioxane methane / 17 decyl alcohol / 2 ammonia) gradient solution. • Therefore 'obtained 246 mg 1-(6-{[6-(cyclohexyloxy)[1,2,4 Triazolo[4,3-13] indole-3-yl]thio}-1,3-benzoxazole-2-yl) winter [2_(morpholine-4-yl)ethyl] Urea' is in the form of a white powder and is characterized as follows: 1H NMR spectrum (400 MHz, DMS0-d6) 5 ppm 1.00-1.55 (m, 6H) 1.62 (m, 2H) 1.73-1.90 (m, 2H) 2.29-2.47 ( m, 6H) 3.19-3.28 (m, 2H) 3.59 (m, 4H) 145862 •67- 201040187 4.57-4.80 (m,1H) 6.77 (broad s) 1H) 7.02 (d, J = 9.8 Hz, 1H) 7_36 (dd, J = 8.5, 1.5 Hz, 1H) 7.54 (d, J = 8.5 Hz, 1H) 7.99 (d, J = 1.5 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 10·% (wide s·,1H) Mass Spectrum: UPLC-SQD: MH+ m/z = 555+; MH- = 553- b) l-[2-(moffa-4-yl)ethyl]-3-(6- The thio-1,3-benzo-p-plug. guan-2-yl) gland can be made in the following manner: The argon gas stream was bubbled at 900 ° C through a solution of 900 mg of 2-{[(2-)-hydroxy-4-ylethyl) thiocyanate]amino}-1,3-benzop Plug. Take a mixture of -6-based S and 40 cubic centimeters of ethanol' for 5 minutes. Then add 11 mg of potassium dihydrogen phosphate and 1.1 g of DL-dithiothreitol in 0.4 cubic centimeters of water. Mix the mixture at 80 The mixture was heated for 3.5 hours at ° C. The reaction medium was cooled to 20. (:, then poured into water. The suspension was stirred for 45 minutes while maintaining blistering with argon. The precipitate formed was filtered off with suction and 3x10 cubic centimeters of water was washed 'then and then dried under vacuum at 20 ° C. Thus, 633 mg of 1_(2_wufolin-4-ylethyl)-3-(6-thio-1,3-benzene was obtained. 〇。. sit-2-yl)urea, in the form of a white solid, characterized as follows: Mass spectrum: LC-MS-DAD-ELSD: MH+ m/z = 339+; (MH)- = 337- c) Thiocyanate 2-{[(2-Morfolin-4-ylethyl)amine oxime]aminobenzicilazole-6-yl ester can be prepared in the following manner: 0.44 cubic centimeters 2-? Lin-4-ylethylamine is added to 1 gram (6 cyanothio 4,3-benzoxazol-2-yl)amine A at 20 C The phenyl ester was in a solution at 20 ° C in 30 cubic centimeters of tetrachloromethane. After 24 hours, the reaction mixture was evaporated to dryness' and the residue obtained was chromatographed on a Merck 70 gram cartridge (solid deposition; di-methane methane followed by a gradient of 90/10 dioxane/decyl alcohol) Liquid soluble 145862 -68- 201040187 off). Therefore, 902 mg of 2-{[(2-norfosin-4-yl)ethyl fluorenyl]amino}-1,3- benzoxazole-6-yl thiocyanate was recovered as a colorless color. The form of the bead, characterized by the following: Mass spectrum: UPLC-MS-DAD-ELSD: MH+m/z:=364+ d) (6-cyanothio-1,3-benzo-p-sp-2-onyl) Amino phthalic acid phenyl ester was prepared in the following manner: 7.5 g of gas carbonate benzene S was then followed by 4.05 g of sodium hydrogencarbonate and 9.4 cubic centimeters of water, and added to 2.5 g of commercially available thiocyanate 2 at 20 ° C _Amino d,} benzothiazole-6-yl ester in a solution of 94 cubic centimeters of tetrahydroanthracene. Then, the resulting mixture was stirred at 20 ° C for 20 hours, followed by extraction with 2 χ 15 () cubic centimeters of ethyl acetate. The combined organic phases were then washed with 3 x 50 cubic centimeters of saturated aqueous sodium bicarbonate. The obtained organic phase was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was dissolved in 5 cubic centimeters of water 'and then filtered off by suction' and placed under vacuum and 2 Torr. Dry under the armpits. Therefore, '3.45 g (6-cyanothio-1,3-benzoindol-2-yl) phenyl decanoate was obtained as a pale yellow solid with the following characteristics: Mass Spectrometry· LC-MS-DAD -ELSD : MH+ m/z = 328+ ; (MH)- = 326- Example 3: Ν-(6-{[6·(cyclohexyloxy is similar to carbazole [4,3 荅荅 -3 Isothiophene-(6-{[6-(cyclohexylfluorenyl)[1,2,4]triazolo[4] , 3-b] indole-3-yl]thio}-1,3-indolocarbazol-2-yl)acetamide can be prepared in the following manner: 0.276 cubic centimeters of acetic anhydride and 160 grams of 6 -{[6_(cyclohexyloxy)[ι,2,4] diindolo[4,3-b]°荅耕-3-yl]thio}-1,3- stupid and spit_2_ The amine (10)) was added to 2 cubic centimeters of pyridine at 20 ° C at 145862 - 69 · 201040187. After 5 hours, another 3 cubic centimeters of acetic anhydride was added, and the mixture was left to stir for 17 hours. The reaction mixture was concentrated to dryness in vacuo. The residue with yellow solids was chromatographed on a m〇tage Quad 12/25 cartridge (KP_SIL, 60 persons; 32_63, immersed in 1% by weight of dioxane to 97.5/2.5 dichloromethane/methanol gradient solution Therefore, Necker N-(6-{[6-(cyclohexyloxy)[1,2,4]trisino[4,3-b]pyran-3-yl]thio}_ 1 is obtained. , 3- benzothiazol-2-yl)acetamide, in the form of a white powder, characterized by the following: 1H NMR spectrum (4 〇〇 MHz, DMSO-d6) <5 ppm 1.05-1.53 (m, 6H) 1.52 -1.68 (m, 2H) 1.71-1.85 (m, 2H) 2.19 (s, 3H) 4.56-4.73 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.40 (dd, J = 8.5, 2.0 Hz , 1H) 7.66 (d, J = 8.5 Hz, 1H) 8.06 (d, J = 2.0

Hz，1H) 8.28 (d, J =： 10.0 Hz, 1H) 12.37 (寬廣 s, 1H) 質 s晋.UPLC-SQD : MH+ m/z = 441+ ; MH- = 439-實例4 : (Η[6·(環己基氧基狀训王唑并[4,3_b]塔畊-3_基]硫基H，3苯并嘍唑-2-基）胺基甲酸苯酯 (6-{[6-(環己基氧基）[丨二斗]***并[4,3-b]嗒畊-3-基]硫基}-1，3-笨并噻嗤-2-基）胺基甲酸苯酯可以下述方式製成：將0.13立方公分氯碳酸苯醋於2〇°c下添加至5立方公分p比咬中之200毫克6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并噻唑-2-胺（lb)内。4小時後，使黃色懸浮液在真空下濃縮至乾涸。使殘留物於Bi〇tage Quad 12/25藥筒上層析（KP-SIL，60人；32-63 //Μ)，以 100% 二氣曱烷至 92.5/ 7.5 一乳甲院/甲醇之梯度液溶離。因此’獲得224毫克 145862 -70- 201040187 {[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-l，3-苯并嘍唑-2-基）胺基甲酸苯酯，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz，DMSO-d6) 5 ppm 1.13-1.42 (m，5H) 1.43-1.66 (m, 3H) 1.72-1.85 (m, 2H) 4.63-4.74 (m, 1H) 7.03 (d, J = 10.0 Hz, 1H) 7.25-7.35 (m, 3H) 7.40-7.50 (m, 3H) 7.69 (d, J = 9.0 Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d，J = 10.0 Hz，1H) 12.66 (寬廣 s，1H) 質譜：UPLC-SQD: MH+m/z = 519+; MH- = 517-❹實例5 : l-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]塔畊·3_基]硫基}·1，3-苯并噻唑-2-基)-3-[2·(四氳吡咯-1-基）乙基脲 a) H6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}- 1，3-苯并嘧唑—2-基）-3-[2-(四氫吡咯-1-基）乙基]脉可以下述方式製成：將0.06立方公分2-(四氫吡咯-1-基）乙胺與〇14立方公分三 Q 乙胺，於20°C下，添加至200毫克（6-{[6-(環己基氧基）[ι，2,4] ***并[4,3-b]嗒嗜-3-基]硫基丨-1，3-苯并嘍唑_2_基）胺基曱酸苯酯⑷在5立方公分四氫呋喃中之溶液内。於2(Γ(：下2小時後，將反應媒質在6(TC下加熱3小時。使黃色溶液於減壓下蒸發至乾涸。使殘留物在Biotage Quad 12/25藥筒上層析 (KP-SIL，60A ; 32-63 幽，以 99/1 至 50/50 二氣甲烷 / 曱醇梯度液溶離。因此，獲得171毫克H6-{[6-(環己基氧基）唑并[4,3-b]嗒畊各基]硫基H，3_笨并噹唑冬基)_3_[2_(四氫吡咯_ 1-基）乙基姆，呈白色粉末形式，其特徵如下： 145862 -71 - 201040187 1H NMR 光譜（400 MHz, DMSO-d6) 5 ppm 1.08-1.87 (m，14H) 2.52-2.63 (經遮蔽之 m，6H) 3.32-3.38 (經遮蔽之 m，2H) 4.57-4.80 (m, 1H) 6.82 (寬廣 s，1H) 7.02 (d，J = 10.0 Hz，1H) 7.36 (dd, J = 8.5, 2.0 Hz，1H) 7.55 (d, J = 8.5 Hz, 1H) 8.00 (d, J = 2.0 Hz, 1H) 8.27 (d, J = l〇.〇 Hz, 1H) 10.78 (s, 1H) 質譜：UPLC-SQD : MH+ m/z = 539+ ; MH- = 537-實例6 : 6-{[6-(環己基氧基）[l，2,4]***并[4,3-b]嗒畊-3-基]硫基}.N-[2-(四氫吡咯-1_基）乙基]-1，3-苯并嘧唑-2-胺 a) 6-{[6~(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜N- [2-(四氫吡口各-1-基）乙基]_ι，3_苯并嘧唑_2_胺可以下述方式製成：將686毫克2-(四氫吡咯-i_基）乙胺添加至534毫克硫氰酸2_ 溴基-1，3-苯并嘍唑-6-基酯在7立方公分四氫呋喃中之溶液内。將反應媒質於20t下攪拌18小時’然後，使此懸浮液在減壓下濃縮至乾涸。使所獲得之油狀褐色殘留物溶於立方公分乙醇中。使混合物藉由於2(rc下以氬噴射5分鐘而脫氣，然後添加0.2立方公分水中之5毫克磷酸二氫鉀，接者添加617毫克DL-二硫基蘇糖醇與253毫克3_氣基_6_(環己基乳基）[1，2,4]***并[4,3-b]嗒畊（ic)。於回流下23小時後，使紅色懸浮液在減壓下濃縮至乾涸。使殘留物於q— 25M (KP-SIL ’ 60人；32-63 _上藉乾燥沉積純化，以95/5至 5二氣甲烧/(二氯甲烧：38/甲醇：17/氨水：2)之梯度液溶離。將所獲得之黃色固體以醚與戊烷洗滌。因此，獲得 145862 -72- 201040187 218毫克6-{[6-(環己基氧基）[ι，2,4]***并[4,3-b]嗒啡-3-基]-硫基}-N-[2-(四氫吡咯-1-基）乙基]4,3-苯并，塞唑-2-胺，呈黃色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) 5 ppm 1.17-1.59 (m，7H) 1.60-1.73 (m，7H) 1.79-1.94 (m，2H) 2.45 (經遮蔽之 m，2H) 2.55-2.71 (m，2H) 3.47 (q, J = 6.0 Hz, 2H) 4.68-4.81 (m, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.24-7.35 (m, 2H) 7.82 (d, J = 1.5 Hz, 1H) 8.15 (t, 1H) 8.25 (d, J = 10.0 Hz, 1H) 質譜：UPLC-SQD : MH+ m/z = 496+ ; MH- = 494_ g% b) 硫氰酸2-溴基-1，3-苯并嘧。坐-6-基酯可以下述方式製成：將6_5克漠化亞銅在666立方公分乙腈中之溶液以氬滌氣 5分鐘。使所形成之溶液冷卻至〇_5t，然後添加4 3立方公分亞確酸第三-丁酯。接著’在〇〇c下分次引進5克硫氰酸2_ 胺基-1,3-苯并p塞峻_6_基酯（市購）。將反應混合物於2(rc下擾掉3小時’然後在減壓下濃縮至乾涸。使殘留物溶於醋酸乙酯中，接著，將所獲得之溶液以飽和碳酸氫鈉溶液洗 Q 滌。將有機相以硫酸鎂脫水乾燥，然後在真空下濃縮至乾涸。因此，獲得5 05克硫氰酸2溴基-U苯并噻唑冬基酯，呈金頁色粉末形式，其特徵如下：質譜：UPLC-SQD: MH+m/z = 271+ 實例7 : N-(6-{[6-(環己基氧基）|；1，2,4]***并[4,3七]嗒畊各基]硫基卜^苯并嘧唑·2_基)_2·曱氧基乙醯胺 (6 {[6 (¼己基氧基）[1，2,4]***并[4,3七]塔畊-3-基]硫基}-1,3· 苯并噻唑-2-基）-2-甲氧基乙醯胺可以類似實例la之方式， 145862 -73- 201040187 但以200毫克6-{[6-(環己基氧基氾#]***并[4,3_b]嗒畊·3_基] 硫基}-U-苯并4唾-2-胺（lb)在5立方公分吡啶與0.165立方公分氣化甲氧基乙醯中開始，於2〇°c下反應23小時後製成。因此，獲得196亳克Ν·(6_ί[6_(環己基氧基）[12,4]***并[4 3_b] 塔11 井-3-基]硫基}-l，3-苯并嘍唑_2_基）_2_甲氧基乙醯胺，呈白色粉末形式，其特徵如下： 1H NMR 光谱（400 MHz, DMSO-d6) 5 ppm 1.09-1.40 (m, 5H) 1.41-1_65 (m, 3H) 1.72-1.86 (m, 2H) 3.36 (s, 3H) 4.19 (s, 2H) 4.61-4.72 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5, 2.0 Hz, 1H) 7.68 (d, J = 8.5 Hz, 1H) 8.O7 (d, J = 2.0 Hz，1H) 8.28 (d, J = 10.0 Hz, 1H) 12.32 (寬廣 s, 1H) 質譜· UPLC-SQD: MH+m/z = 469+; MH- = 471· 實例8 : Ν-(6-{[6·(環己基氧基^，以]***并[4,3_b]嗒畊_3·基]硫基}1，3苯并嘧唑-2-基）-N2，N2-二甲基甘胺醯胺 N-(6-{[6-(環己基氧基）[丨’以]***并[4,3七]嗒畊各基]硫基}1，3_ 苯并嘍唑-2-基）-N2，N2-二曱基甘胺醯胺可以類似實例la之方式，但以100毫克6-{[6-(環己基氧基）[12,4]***并[4 3七]嗒畊_ 3-基]硫基}-1，3-苯并噻唑胺（lb)，在1〇立方公分二氣甲烷中，使用300毫克氣化n，N-二甲基甘胺醯、〇 33立方公分三乙胺及11毫克4-N，N-二甲胺基吡啶開始，於2〇。〇下反應27小時後製成。因此，獲得75毫克N-(6-{[6-(環己基氧基）[1，2,4]三唑并[4,3-b]。合畊-3-基]硫基卜ι，3_苯并嘍唑_2_基）_N2，N2_二曱基甘胺醯胺’呈帶黃色粉末形式，其特徵如下： 1H NMR 光 s晋（400 MHz, DMSO-d6) δ ppm UO-1.64 (m，8H) 1.69-1.87 145862 -74- 201040187 (m, 2H) 2.29 (s, 6H) 3.37-3.52 (m, 2H) 4.52-4.75 (m, 1H) 7.02 (d, J = l〇.〇 Hz, 1H) 7.41 (dd, J = 8.5, 2.0 Hz, 1H) 7.67 (d, J = 8.5 Hz, 1H) 8.07 (d, J = 2.0Hz,1H) 8.28 (d, J =: 10.0 Hz, 1H) 12.37 (broad s, 1H) quality sigma. UPLC-SQD: MH+ m/z = 441+ ; MH- = 439-example 4: (Η[ 6·(Cyclohexyloxy-like oxazolidine [4,3_b] Tatricin-3_yl]thio-H,3 benzoxazol-2-yl)carbamic acid phenyl ester (6-{[6- (cyclohexyloxy)[丨二斗]triazolo[4,3-b]indol-3-yl]thio}-1,3-benzothiazin-2-yl)carbamic acid phenyl ester It can be made in the following manner: 0.13 cubic centimeters of chloroacetic acid benzene vinegar is added to 2 cubic centimeters of p-bit 200 mg 6-{[6-(cyclohexyloxy)[1,2, at 2 ° C. 4] Triazolo[4,3-b]indole-3-yl]thio}-1,3-benzothiazol-2-amine (lb). After 4 hours, the yellow suspension was allowed to dry under vacuum. Concentrate to dryness. Chromatography of the residue on a Bi〇tage Quad 12/25 cartridge (KP-SIL, 60 persons; 32-63 //Μ), with 100% dioxane to 92.5/ 7.5 The hospital/methanol gradient solution is dissolved. Therefore 'obtained 224 mg 145862 -70- 201040187 {[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]嗒耕-3- Phenyl]thio]-l,3-benzoxazol-2-yl)carbamic acid phenyl ester, as a white powder, characterized by : 1H NMR spectrum (400 MHz, DMSO-d6) 5 ppm 1.13-1.42 (m, 5H) 1.43-1.66 (m, 3H) 1.72-1.85 (m, 2H) 4.63-4.74 (m, 1H) 7.03 (d, J = 10.0 Hz, 1H) 7.25-7.35 (m, 3H) 7.40-7.50 (m, 3H) 7.69 (d, J = 9.0 Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.66 (broad s, 1H) Mass spectrum: UPLC-SQD: MH+m/z = 519+; MH- = 517-❹ Example 5: l-(6-{[6-(cyclohexyloxy) Base)[1,2,4]triazolo[4,3-b]tral,3_yl]thio}·1,3-1,3-thiathiazol-2-yl)-3-[2·(four氲pyrrol-1-yl)ethylurea a) H6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio }- 1,3-benzopyrazole-2-yl)-3-[2-(tetrahydropyrrol-1-yl)ethyl] vein can be prepared in the following manner: 0.06 cubic centimeter 2-(tetrahydrogen) Pyrrol-1-yl)ethylamine and hydrazine 14 cubic centimeters of tri-Q-ethylamine, added to 200 mg (6-{[6-(cyclohexyloxy)[ι,2,4] triazole at 20 ° C And [4,3-b]oxazol-3-yl]thioguanidine-1,3-benzoxazole-2-yl)amino decanoate (4) in a solution of 5 cubic centimeters of tetrahydrofuran. After 2 hours (after 2 hours, the reaction medium was heated at 6 (TC for 3 hours). The yellow solution was evaporated to dryness under reduced pressure. The residue was chromatographed on a Biotage Quad 12/25 cartridge (KP -SIL, 60A; 32-63 secluded, eluted with a 99/1 to 50/50 dioxane/sterol gradient. Thus, 171 mg of H6-{[6-(cyclohexyloxy)oxazole [4, 3-b] sorghum base] thiol H,3_ stupid and oxazolamide)_3_[2_(tetrahydropyrrole-1-yl)ethylm, in the form of a white powder, characterized by the following: 145862 -71 - 201040187 1H NMR spectrum (400 MHz, DMSO-d6) 5 ppm 1.08-1.87 (m, 14H) 2.52-2.63 (masked m, 6H) 3.32-3.38 (masked m, 2H) 4.57-4.80 (m , 1H) 6.82 (broad s, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.5, 2.0 Hz, 1H) 7.55 (d, J = 8.5 Hz, 1H) 8.00 (d, J = 2.0 Hz, 1H) 8.27 (d, J = l〇.〇Hz, 1H) 10.78 (s, 1H) Mass Spectrum: UPLC-SQD: MH+ m/z = 539+ ; MH- = 537-Example 6 : 6- {[6-(Cyclohexyloxy)[l,2,4]triazolo[4,3-b]indole-3-yl]thio}.N-[2-(tetrahydropyrrole-1_ Ethyl]-1,3-benzopyrazol-2-amine a) 6-{[6~(cyclohexyloxy) [1,2,4]triazolo[4,3-b]indole-3-yl]thiopyranyl N-[2-(tetrahydropyridin-1-yl)ethyl]_ι,3_ Benzopyrazole-2-amine can be prepared in the following manner: 686 mg of 2-(tetrahydropyrrole-i-yl)ethylamine is added to 534 mg of 2-bromo-1,3-benzoxazole thiocyanate. The solution of the 6-yl ester in 7 cubic centimeters of tetrahydrofuran. The reaction medium was stirred at 20 t for 18 hours. Then, the suspension was concentrated to dryness under reduced pressure. The obtained oily brown residue was dissolved. Cubic centimeters of ethanol. The mixture was degassed by spraying 2 rc under argon for 5 minutes, then adding 5 mg of potassium dihydrogen phosphate in 0.2 cubic centimeters of water, followed by 617 mg of DL-dithiothreitol. 253 mg of 3_gas-based _6_(cyclohexyl lactyl)[1,2,4]triazolo[4,3-b]indole (ic). After 23 hours under reflux, the red suspension was reduced. Concentrate to dryness by pressing. Allow the residue to be purified by q- 25M (KP-SIL '60 person; 32-63 _ by dry deposition, with 95/5 to 5 gas-fired / (dichloromethane: 38/ Methanol: 17 / ammonia: 2) gradient solution is dissolved. The yellow solid obtained was washed with ether and pentane. Thus, 145862 -72 - 201040187 218 mg of 6-{[6-(cyclohexyloxy)[ι,2,4]triazolo[4,3-b]indol-3-yl]-thio} -N-[2-(tetrahydropyrrol-1-yl)ethyl]4,3-benzo,pyrazol-2-amine, as a yellow powder, characterized as follows: 1H NMR spectrum (400 MHz, DMSO- D6) 5 ppm 1.17-1.59 (m,7H) 1.60-1.73 (m,7H) 1.79-1.94 (m,2H) 2.45 (masked m,2H) 2.55-2.71 (m,2H) 3.47 (q, J = 6.0 Hz, 2H) 4.68-4.81 (m, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.24-7.35 (m, 2H) 7.82 (d, J = 1.5 Hz, 1H) 8.15 (t, 1H) 8.25 (d, J = 10.0 Hz, 1H) Mass Spectrum: UPLC-SQD: MH+ m/z = 496+; MH- = 494_ g% b) 2-bromo-1,3-benzopyrimidine thiocyanate. The -6-yl ester can be prepared in the following manner: 6 to 5 grams of a solution of desertified cuprous copper in 666 cubic centimeters of acetonitrile is scrubbed with argon for 5 minutes. The resulting solution was cooled to 〇_5t, and then 4 3 cubic centimeters of tri-butyl phthalate was added. Next, 5 g of 2-amino-1,3-1,3-benzopyran-6-yl thiocyanate (commercially available) was introduced in portions under 〇〇c. The reaction mixture was quenched at 2 (rc for 3 hrs) then concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate, and then the obtained solution was washed with saturated sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated to dryness in vacuo. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; UPLC-SQD: MH+m/z = 271+ Example 7: N-(6-{[6-(cyclohexyloxy)|; 1,2,4]triazolo[4,3-7] Thiothiophene benzopyrazole 2_yl)_2·decyloxyacetamide (6 {[6 (1⁄4 hexyloxy)[1,2,4]triazolo[4,3-7] Tatricin-3-yl]thio}-1,3·benzothiazol-2-yl)-2-methoxyacetamide can be similar to the method of Example la, 145862 -73- 201040187 but with 200 mg 6- {[6-(cyclohexyloxypan #]triazolo[4,3_b]indole·3_yl]thio}-U-benzo-4-sal-2-amine (lb) in 5 cubic centimeters of pyridine 0.165 cubic centimeters of gasified methoxyacetamide was started and reacted at 2 ° C for 23 hours. Therefore, 196 g of Ν·(6_ί[6_(cyclohexyloxy)[12,4] was obtained. Zoxa[4 3_b] column 11 well-3-yl]thio}-l,3-benzoxazole-2-yl)_2-methoxyacetamide, in the form of a white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) 5 ppm 1.09-1.40 (m, 5H) 1.41-1_65 (m, 3H) 1.72-1.86 (m, 2H) 3.36 (s, 3H) 4.19 (s, 2H) 4.61- 4.72 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5, 2.0 Hz, 1H) 7.68 (d, J = 8.5 Hz, 1H) 8.O7 (d, J = 2.0 Hz,1H) 8.28 (d, J = 10.0 Hz, 1H) 12.32 (broad s, 1H) Mass Spectrum · UPLC-SQD: MH+m/z = 469+; MH- = 471· Example 8: Ν-(6- {[6·(cyclohexyloxy^,]triazolo[4,3_b]嗒耕_3·yl]thio}1,3 benzopyrazol-2-yl)-N2,N2-dimethyl Glycine decylamine N-(6-{[6-(cyclohexyloxy)[丨']]triazolo[4,3-7] sorghum base]thio}1,3_benzoxazole- 2-yl)-N2,N2-dimercaptoguanamine can be similar to the procedure of Example la, but with 100 mg of 6-{[6-(cyclohexyloxy)[12,4]triazolo[4 3 VII] 嗒__ 3-yl] thio}-1,3-benzothiazolylamine (lb), using 300 mg of vaporized n,N-dimethylglycinamine in 1 〇 cubic centimeter of di-methane 〇33 cubic centimeters Triethylamine and 11 mg of 4-N, N- dimethylaminopyridine begins at 2〇. The underarm reaction was made after 27 hours. Thus, 75 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]. 3_Benzocarbazole_2_yl)_N2,N2_dimercaptoamineamine is in the form of a yellow powder with the following characteristics: 1H NMR light sigma (400 MHz, DMSO-d6) δ ppm UO- 1.64 (m,8H) 1.69-1.87 145862 -74- 201040187 (m, 2H) 2.29 (s, 6H) 3.37-3.52 (m, 2H) 4.52-4.75 (m, 1H) 7.02 (d, J = l〇. 〇Hz, 1H) 7.41 (dd, J = 8.5, 2.0 Hz, 1H) 7.67 (d, J = 8.5 Hz, 1H) 8.07 (d, J = 2.0

Hz, ；IH) 8.28 (d，J = 10.0 Hz, 1H) 11.92 (寬廣 s，ih) 質譜：Waters-ZQ: MH+m/z = 484+; MH- = 482- 實例9 : Ν-(6·{[6-(環已基氧基）[^4]***并[4>b]嗒畊各基]硫基丨以·苯并嘧唑-2-基)-3-甲基丁醯胺队(6-{[6-(環己基氧基）[1，2,4]三嗤并[4,3卻荅啡-3-基]硫基}-1，3-苯并違吐-2-基）-3-甲基丁醯胺可以類似實例la之方式，但以102毫克6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-胺（lb)在5立方公分吡啶與〇 437立方公分氣化3-曱基丁醯中開始’於2〇°C下反應46小時後製成。因此’獲得98毫克N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒 _ -3-基]硫基}-1，3-苯并嚷〇坐-2-基）-3-甲基丁醯胺，呈白色粉末形式，其特徵如下： 1Η NMR 光譜（40〇]\41^，〇]\^0-<16)<5?卩111〇.93((^ = 6.81^，611)1.〇8- 1.63 (m, 8H) 1.71-1.82 (m, 2H) 2.03-2.17 (m, 1H) 2.36 (d, J = 7.1 Hz, 2H) 4.56-4.69 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.4, 1.8 Hz, 1H) 7.66 (d, J = 8.6 Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 9.8 Hz, 1H) 12.34 (寬廣s, 1H) 質譜：UPLC-SQD: MH+m/z = 483+; MH- = 481_ 實例10 : Ν-(6·{[6-(環己基氧基)[1，2,4]***并[4,3-b]嗒井-3-基]硫基苯并p塞嗅-2-基)-3-甲氧基丙醢胺 145862 -75- 201040187 N-(6-{[6-(環己基氧基）[12,4]***并[4 3七]嗒畊各基]硫基}_13_ 苯并碟唾-2-基）-3-曱氧基丙醯胺可以類似實例la之方式，但以146毫克6-{[6-(環己基氧基）[12,4]***并[4,3-b]嗒畊-3·基] 硫基}-1，3-笨并p塞唑_2_胺（此）在5立方公分吡啶與〇.19ι立方公分氯化3-甲氧基丙醯中開始，於2〇^下反應23小時後製成。因此’獲得132毫克N-(6-{[6-(環己基氧基）[1,2,4]***并 [4,3-b>荅畊-3-基]硫基卜ι，3_苯并魂唑_2_基）_3甲氧基丙醯胺，呈白色粉末形式’其特徵如下： 1H NMR 光譜（4〇〇 MHz，DMSO-d6) (5 ppm 1.11-1.65 (m，8H) 1.74-1.83 (m, 2H) 2.72 (t, J = 6.1 Hz, 2H) 3.23 (s, 3H) 3.64 (t, J = 6.1 Hz, 2H) 4.62-4.72 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.41 (dd, J = 8.3, 2.0 Hz, 1H) 7.66 (d, J = 8.6Hz, ;IH) 8.28 (d, J = 10.0 Hz, 1H) 11.92 (broad s, ih) Mass Spectrum: Waters-ZQ: MH+m/z = 484+; MH- = 482- Example 9: Ν-(6 ·{[6-(cyclohexyloxy)[^4]triazolo[4>b] 嗒各 each base] thio 丨 benzopyrazol-2-yl)-3-methylbutanthene Amine team (6-{[6-(cyclohexyloxy)[1,2,4]triazino[4,3 quinone-3-yl]thio}-1,3-benzo-anti-vomiting- 2-yl)-3-methylbutyramine can be similar to the manner of Example la, but with 102 mg of 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3- b] indole-3-yl]thio}-1,3-benzopyrazol-2-amine (lb) begins in 5 cubic centimeters of pyridine and 〇453 cubic centimeters of gasified 3-mercaptobutylpyrene It was prepared after reacting at 2 ° C for 46 hours. Thus 'obtained 98 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1, 3-Benzoindolo-2-yl)-3-methylbutyramine, in the form of a white powder, characterized by the following: 1 NMR spectrum (40 〇]\41^, 〇]\^0-<16 )<5?卩111〇.93((^ = 6.81^,611)1.〇8- 1.63 (m, 8H) 1.71-1.82 (m, 2H) 2.03-2.17 (m, 1H) 2.36 (d, J = 7.1 Hz, 2H) 4.56-4.69 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.4, 1.8 Hz, 1H) 7.66 (d, J = 8.6 Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 9.8 Hz, 1H) 12.34 (broad s, 1H) Mass spectrum: UPLC-SQD: MH+m/z = 483+; MH- = 481_ Example 10 : Ν-(6·{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]嗒-3-yl]thiobenzopyrene-2 3-methoxypropionamide 145862 -75- 201040187 N-(6-{[6-(cyclohexyloxy)[12,4]triazolo[4 3-7] The base}_13_benzoxan-2-yl)-3-decyloxypropionamide can be similar to the method of the example la, but with 146 mg of 6-{[6-(cyclohexyloxy)[12,4] three Azolo[4,3-b]indole-3·yl]thio}-1,3-cyclop-pyrazole-2-amine (this) in 5 cubic The pyridine was started in 19.19 Ω cubic centimetres of 3-methoxypropene fluorinated and reacted at 2 〇^ for 23 hours. Thus, '132 mg of N-(6-{[6-(cyclohexyloxy) was obtained) [1,2,4]triazolo[4,3-b>indole-3-yl]thiophenyl, 3-benzoxazole-2-yl)-3-methoxypropanamide In the form of a white powder, the characteristics are as follows: 1H NMR spectrum (4 〇〇 MHz, DMSO-d6) (5 ppm 1.11-1.65 (m, 8H) 1.74-1.83 (m, 2H) 2.72 (t, J = 6.1 Hz, 2H) 3.23 (s, 3H) 3.64 (t, J = 6.1 Hz, 2H) 4.62-4.72 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.41 (dd, J = 8.3, 2.0 Hz, 1H ) 7.66 (d, J = 8.6

Hz，1H) 8.06 (d，J = 2.0 Hz, 1H) 8.28 (d, J == 9.8 Hz, 1H) 12.37 (寬廣 s，1H) 質譜：Waters-ZQ: MH+m/z = 485+; MH- = 483- 實例11 : M[6-(環戊氧基似训三唾并[4,3_b]嗒畊·3·基]硫基H，3_苯并嘧唑-2-胺 a) 6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-i，3-苯并噻唑-2-胺可以類似實例比之方式，但以3〇立方公分經脫氣乙醇中之889毫克3-氣基-6_(環戊氧基）[12 4]***并[4 3 b] 嗒畊、0.3立方公分水中之17毫克磷酸二氫鉀、172克1)1^ 二硫基蘇糖醇及772毫克硫氰酸2_胺基义^苯并噻唑_6_基酯開始，於80t下24小時後製成。因此，獲得1〇4克6_丨[6_(環戍氧基）[1，2,4]三唾并[4,3-b]塔畊_3-基]硫基Η，〗·苯并嘍„坐_2_ 月女’呈白色粉末形式’其特徵如下： 145862 -76- 201040187 1H NMR 光谱（400 MHz, DMSO-d6) (5 ppm 1.49-1.76 (m，6H) 1.83-1.97 (m, 2H) 5.12-5.22 (m, 1H) 6.99 (d, J = 9.8 Hz, 1H) 7.28 (d, J = 8.6 Hz, 1H) 7.34 (dd, J = 8.3, 2.0 Hz, 1H) 7.61 (s, 2H) 7.90 (d, J = 2.0 Hz, 1H) 8.23 (d, J = 9.8 Hz, 1H) 質譜：UPLC-SQD: MH+m/z = 385+ b) 3-氯基-6-(環戊氧基）[i，2,4]***并[4,3-b]嗒p井可以類似貫例lc之方式’但以20立方公分四氩咬„南中之914毫克環 0 戊醇、254毫克在60%下於油中之氫化鈉及1克3 6_二氯[丨义斗] 二嗤并[4,3-b]嗒畊（市購）開始’於反應6小時3〇分鐘後製成。因此’獲得896毫克3-氯基-6-(環戊氧基）[1，2,4]***并 [4,3-b]嗒畊’呈無色油形式，其係結晶，其特徵如下：質譜：Waters UPLC-SQD : MH+ m/z = 239+ 實例12 : N-(6-{[6-(環戊氧基）^4]***并[4,3_b]嗒畊_3_基]硫基苯并嘍唑-2-基）環丙烷羧醯胺〇 N-(6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜1,3-苯并"塞°坐基）環丙烷羧醯胺可以類似實例la之方式，但以 3〇〇毫克6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 1,3-苯并p塞唑_2-胺（ua)在5立方公分吡啶與〇 14〇立方公分環丙院氯化醯中開始，於2(TC下反應3小時後製成。因此，獲得277毫克N-(6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基] 硫基卜1，3-苯并嘧唑_2-基）環丙烷羧醯胺，呈白色粉末形式’其特徵如下： 1H NMR 光譜（4〇0 MHz，DMS〇d6) 5 ppm 〇 84巧〇〇 (m，4H) i 441 71 145862 -77- 201040187 (m, 6H) 1.73-1.88 (m, 2H) 1.92-2.04 (m, 1H) 5.04-5.17 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.4,1.8 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.13 (d, J = 2.0 Hz，1H) 8.26 (d, J = 9.8 Hz, 1H) 12.67 (寬廣 s，1H) 質譜：Waters UPLC-SQD: MH+m/z = 453+; MH- = 451-實例13 : N-(6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒啡·3·基]硫基}-l，3-苯并嘍唑·2·基）乙酿胺 Ν-(6-{[6-(環戊氧基）[1，2,4]三。坐并[4,3-b]塔ρ井-3-基]硫基}_1，3_苯并p塞β坐-2-基）乙醯胺可以類似實例la之方式，但以250毫克 6-{[6-(環戊氧基）[1，2,4]三峻并[4,3-b>荅1^ -3-基]疏基}-i，3-苯并違。坐-2-胺11a在5立方公分p比咬與2.5立方公分醋酸酐中開始，於20°C下反應48小時後製成。因此，獲得255毫克n_(6_{[6_ (環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]-硫基卜ι，3-苯并噻唑_ 2-基）乙醯胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) δ ppm 1.44-1.71 (m, 6H) 1.71-1.88 (m, 2H) 2.19 (s, 3H) 5.04-5.15 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.6, 2.0 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.14 (d, J = 2.0 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 12.37 (s, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 427+ ; MH_ = 實例14 : l-(6-{[6-(環戊氧基）[1，2,4]三嗤并[4,3-b>荅畊-3-基]硫基}·1，3-苯并嘧唑-2-基)-3_[2-(嗎福啉_4·基）乙基脈 a) 1-(6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯并魂咬-2-基）-3-[2-(嗎福ρ林-4-基）乙基]服可以類似實例5a 145862 -78- 201040187 之方式，但於20°C下以778毫克（6-{[6-(環戊氧基）[1,2,4]*** 弁[4,3-b]e荅p井-3-基]硫基}-1，3-苯弁》»塞α坐-2-基）胺基甲酸苯醋與 (6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基苯并嘧唑-2-基）醯亞胺基二碳酸二苯酯之混合物在1〇立方公分四氫呋喃、0.32立方公分2-(嗎福啉-1-基）乙胺及1.04立方公分三乙胺中開始而製成。因此，獲得127毫克1-(6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]塔p井-3-基]硫基卜1，3-苯并嘧唑-2-基）-3-[2-(嗎福淋-4-基）乙基]脉’呈白色粉末形式，其特徵如下： 1H NMR 光譜（500 MHz，DMSO-d6) 5 ppm 1.48-1.71 (m，6H) 1.78-1.92 (m, 2H) 2.32-2.46 (m, 6H) 3.27 (q, J = 5.9 Hz, 2H) 3.54-3.64 (m, 4H) 5.09- 5.17 (m，1H) 6.80 (寬廣 s，1H) 7.01 (d，J = 9.6 Hz，1H) 7.41 (dd，J = 8.5, 1.6Hz,1H) 8.06 (d,J = 2.0 Hz, 1H) 8.28 (d, J == 9.8 Hz, 1H) 12.37 (broad s, 1H) Mass Spectrum: Waters-ZQ: MH+m/z = 485+; MH - = 483- Example 11: M[6-(cyclopentyloxy-tris-tris[4,3_b]indole·3·yl]thio H,3-benzopyrazol-2-amine a) 6 -{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]indol-3-yl]thio}-i,3-benzothiazol-2-amine Similar to the example, but in a 3〇 cubic centimeter degassed ethanol, 889 mg 3-carbyl-6-(cyclopentyloxy)[12 4]triazolo[4 3 b] 17 mg of potassium dihydrogen phosphate in water, 172 g of 1) 1 dithiothreitol and 772 mg of 2-amino benzothiazole -6-yl thiocyanate, 24 hours after 80 t production. Thus, 1 〇 4 g of 6_丨[6_(cyclodecyloxy)[1,2,4]tris-[4,3-b]tral- _3-yl]thio ruthenium, benzo·benzo喽„坐_2_月女' in white powder form's characteristics are as follows: 145862 -76- 201040187 1H NMR spectrum (400 MHz, DMSO-d6) (5 ppm 1.49-1.76 (m,6H) 1.83-1.97 (m, 2H) 5.12-5.22 (m, 1H) 6.99 (d, J = 9.8 Hz, 1H) 7.28 (d, J = 8.6 Hz, 1H) 7.34 (dd, J = 8.3, 2.0 Hz, 1H) 7.61 (s, 2H 7.90 (d, J = 2.0 Hz, 1H) 8.23 (d, J = 9.8 Hz, 1H) Mass Spectrum: UPLC-SQD: MH+m/z = 385+ b) 3-Chloro-6-(cyclopentyloxy) The base [[i,2,4]triazolo[4,3-b]嗒p well can be similar to the method of the example lc' but with 20 cubic centimeters of tetra-argon biting 914 mg of cyclopentanol, 254 mM at 60% sodium hydride in oil and 1 gram of 3 6 _ dichloro [丨义斗] 嗤[4,3-b] 嗒耕 (commercially available) began 'after 6 hours and 3 minutes after reaction production. Therefore, '896 mg of 3-chloro-6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]indole was obtained as a colorless oil, which was crystallized and characterized as follows : Mass Spectrum: Waters UPLC-SQD: MH+ m/z = 239+ Example 12: N-(6-{[6-(cyclopentyloxy)^4]triazolo[4,3_b]嗒耕_3_基Thiobenzo-3-oxazol-2-yl)cyclopropanecarboxamide 〇N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]嗒--3-yl]thio-p-1,3-benzo- "suthenyl-cyclopropanecarboxamide can be similar to the method of the example la, but with 3 〇〇 mg 6-{[6-(cyclopentyl) Oxy))[1,2,4]triazolo[4,3-b]indole-3-yl]thiol1,3-1,3-benzopyrazole-2-amine (ua) at 5 cm3 Pyridine was started in ruthenium chloride with 14 〇 cubic centimeters of cyanoguanidine, and was prepared at 2 (TC) for 3 hours. Thus, 277 mg of N-(6-{[6-(cyclopentyloxy)[1] was obtained. , 2,4]triazolo[4,3-b]indole-3-yl]thiocha 1,3-benzopyrazole-2-yl)cyclopropanecarboxamide, in the form of a white powder The characteristics are as follows: 1H NMR spectrum (4〇0 MHz, DMS〇d6) 5 ppm 〇84巧巧(m,4H) i 441 71 145862 -77- 201040187 (m, 6H) 1.73-1.88 (m, 2 H) 1.92-2.04 (m, 1H) 5.04-5.17 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.4, 1.8 Hz, 1H) 7.67 (d, J = 8.6 Hz , 1H) 8.13 (d, J = 2.0 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 12.67 (broad s, 1H) Mass Spectrum: Waters UPLC-SQD: MH+m/z = 453+; MH- = 451-Example 13: N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]indolyl·3yl]thio}-l , 3-benzoxazole·2·yl)Ethylamine-(6-{[6-(cyclopentyloxy)[1,2,4]III. Sit and [4,3-b] Tower ρ Well-3-yl]thio}_1,3_benzo-p-beta-pyridyl-2-ylacetamide can be similar to the example la, but with 250 mg of 6-{[6-(cyclopentyloxy) [1,2,4]三峻和[4,3-b>荅1^ -3-yl] thiol}-i,3-benzo-inhibited. Sodium-2-amine 11a in 5 cubic centimeters p bite It was prepared by reacting with 2.5 cubic centimeters of acetic anhydride at 48 ° C for 48 hours. Thus, 255 mg of n_(6_{[6_(cyclopentyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]-thiophenyl,3-benzene was obtained. And thiazol-2-yl)acetamide, in the form of a white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) δ ppm 1.44-1.71 (m, 6H) 1.71-1.88 (m, 2H) 2.19 (s, 3H) 5.04-5.15 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.6, 2.0 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.14 ( d, J = 2.0 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 12.37 (s, 1H) Mass Spectrum: Waters UPLC-SQD: MH+ m/z = 427+ ; MH_ = Example 14: l-(6 -{[6-(cyclopentyloxy)[1,2,4]triazino[4,3-b>indole-3-yl]thio}·1,3-benzopyrazole-2- -3_[2-(morpholine-4-yl)ethyl a) 1-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3 -b]嗒耕-3-yl]thio}-1,3-benzophenan-2-yl)-3-[2-(i-fusin)-yl)ethyl] can be similarly 5a 145862 -78- 201040187 by 778 mg (6-{[6-(cyclopentyloxy)[1,2,4]triazolium [4,3-b]e荅 at 20 °C P-jing-3-yl]thio}-1,3-benzoquinone»»αα-yl)aminobenzoic acid phenylacetic acid with (6-{[6-(cyclopentyloxy) a mixture of [1,2,4]triazolo[4,3-b]indole-3-yl]thiobenzopyrazol-2-yl)indenidodicarbonate in 1 〇 It was prepared by starting with tetrahydrofuran, 0.32 cubic centimeters of 2-(morpholin-1-yl)ethylamine and 1.04 cubic centimeters of triethylamine. Thus, 127 mg of 1-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]t-p--3-yl]thiopyran 1, 3-Benzopyrazole-2-yl)-3-[2-(moffa-4-yl)ethyl]mai' is in the form of a white powder characterized by the following: 1H NMR spectrum (500 MHz, DMSO-d6) 5 ppm 1.48-1.71 (m, 6H) 1.78-1.92 (m, 2H) 2.32-2.46 (m, 6H) 3.27 (q, J = 5.9 Hz, 2H) 3.54-3.64 (m, 4H) 5.09- 5.17 ( m,1H) 6.80 (broad s, 1H) 7.01 (d, J = 9.6 Hz, 1H) 7.41 (dd, J = 8.5, 1.6

Hz, 1H) 7.55 (d, J = 8.5 Hz, 1H) 8.08 (d, J = 1.6 Hz, 1H) 8.26 (d, J = 9.6 Hz, 1H) 10.93 (寬廣 s，1H) 質譜：Waters UPLC-SQD: MH+m/z = 541+; MH- = 539-b) (6-{[6-(環戊氧基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基}-l，3- 苯并噻唑-2-基）胺基甲酸苯酯與（6_{[6_(環戊氧基*** 并[4,3七]°合0井-3-基]硫基}_1，3_笨并p塞唑_2_基）醯亞胺基二碳酸二苯醋之混合物可以類似實例4a之方式，但以326毫克6_ {[6-(環戊氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜ι，3-苯并p塞唑-2-胺（11a)與0.21立方公分氣碳酸苯酯在5立方公分吡啶中開始而製成。因此，獲得892毫克米黃色粉末之（6_{[6_(環戊氧基）[1’2’4]二唑并[4,3-b]-嗒畊_3_基]硫基卜i，3_笨并嘧唑_2_基）胺基甲酸苯酿與（6-{[6·(環戊氧基氾二4]***并[4,3_b]塔畊各基]硫基}-1，3-苯并喳唑_2_基）醯亞胺基二碳酸二苯酯之混合 145862 -79- 201040187 物，將其產物使用於下述步驟中，無需進—步純化：質譜：Waters UPLC_SQD : MH+ _ = 5〇5+ ;應=5〇3 實例1S : 1制[6-(環庚基氧基)⑽这唾# [4,3-b]n荅料基]硫基} ι，3_苯并遠《坐-2-基)·3·[2-(嗎福琳-4-基）乙基贩 a) L(6][6-(環庚基氧基）[U，4]***并[4,3_b],荅味冬基]硫基} 1,3笨并喧唑_2_基）_3-[2-(嗎福琳_4_基）乙基]脲可以類似實例lb之方式，但以305毫克(嗎福啉斗基）乙基]各硫基— 1，3-苯并嘍唑么基）脲（2b)、5立方公分經脫氣乙醇、〇1立方❹ 公分水中之4毫克磷酸二氫鉀、347毫克£^_二硫基蘇糖醇及202毫克3-氯基-6-(環庚基氧基）^4]***并[4,3_b]嗒畊開始而製成。因此，獲得253毫克1-(6-{[6-(環庚基氧基）[口⑷*** 并[4,3-b]嗒畊-3-基]硫基}_1，3_苯并嘍唑_2_基）各[2—(嗎福啉斗基）乙基]脲’呈白色粉末形式’其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) <5 ppm 1.24-1.40 (m，2H) 1.42-1.58 (m, 6H) 1.58-1.70 (m, 2H) 1.78-1.93 (m, 2H) 2.36-2.45 (m, 6H) 3.22-3.28 (m, 2H) 3.59 (t，J = 4.4 Hz，4H) 4.81-4.91 (m，1H) 6.77 (寬廣 s，1H) 7.01 (d，J = ^Hz, 1H) 7.55 (d, J = 8.5 Hz, 1H) 8.08 (d, J = 1.6 Hz, 1H) 8.26 (d, J = 9.6 Hz, 1H) 10.93 (broad s, 1H) Mass Spectrometer: Waters UPLC-SQD : MH+m/z = 541+; MH- = 539-b) (6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b] Phenyl 3-yl]thio}-l,3-benzothiazol-2-yl)carboxylate with (6_{[6_(cyclopentyloxytriazolo[4,3-7]°0 well- A mixture of 3-yl]thio}_1,3_stuppy p-pyrazole-2-yl) quinone dicarbonate diphenyl vinegar can be similar to the method of Example 4a, but with 326 mg 6_ {[6-(ring) Pentyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thiophenyl, 3-benzopyrazole-2-amine (11a) with 0.21 cubic The benzene carbonate was started in 5 cubic centimeters of pyridine. Thus, 892 mg of a beige powder was obtained (6_{[6-(cyclopentyloxy)[1'2'4]diazolo[4,3 -b]-嗒耕_3_基]thiol i,3_ benzopyrimidine_2_yl) phenyl carboxylic acid benzene and (6-{[6·(cyclopentyloxypana-2) three a mixture of oxazolo[4,3_b]tungonic]thiol}-1,3-benzoxazole-2-yl)diphenyldicarbonate diphenyl ester 145862 -79- 201040187 Used in the following In the step, no further purification is required: Mass spectrometer: Waters UPLC_SQD: MH+ _ = 5〇5+; should be =5〇3 Example 1S: 1 system [6-(cycloheptyloxy)(10) This saliva # [4,3 -b]n荅基]thiol} ι,3_benzoin "sit-2-yl"·3·[2-(moffin-4-yl)ethyl vendor a) L(6][ 6-(cycloheptyloxy)[U,4]triazolo[4,3_b], astringent winter base]thio} 1,3 benzoxazole_2_yl)_3-[2-(? Fulin _4_yl)ethyl]urea can be similar to the method of the example lb, but with 305 mg (fosfosin) ethyl] thio-1,3-1,3-benzoxazolyl) urea (2b ), 5 cubic centimeters of degassed ethanol, 〇1 cubic ❹ 4 mg of potassium dihydrogen phosphate in water, 347 mg of dimethyl dithionitol and 202 mg of 3-chloro-6-(cycloheptyloxy) Base) ^4] Triazolo[4,3_b] was prepared by cultivating. Thus, 253 mg of 1-(6-{[6-(cycloheptyloxy)[(4)triazolo[4,3-b]indole-3-yl]thio}_1,3-benzoyl) was obtained.喽 _2 _ _ _ 各 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 (m, 2H) 1.42-1.58 (m, 6H) 1.58-1.70 (m, 2H) 1.78-1.93 (m, 2H) 2.36-2.45 (m, 6H) 3.22-3.28 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 4.81-4.91 (m, 1H) 6.77 (broad s, 1H) 7.01 (d, J = ^

10.0 Hz, 1H) 7.36 (dd, J = 8.6, 2.0 Hz, 1H) 7.55 (d, J = 8.6 Hz, 1H) 8.00 (d, J =1.7 Hz’ 1H) 8.26 (d，J = 9.8 Hz，1H) 10.87 (寬廣 s, 1H) . 質譜：Waters UPLC-SQD: MH+m/z = 569+; MH- = 567- b) 3-氯基-6-(環庚基氧基）[1，2,4]***并[4,3-b]塔p井可以類似貫例lc之方式’但以15立方公分四氫咬喃中之1.21克環庚醇、254毫克在60%下於油中之氫化鈉及1克3,6-二氯[1，2,4] ***并[4,3-b]嗒畊（市購）開始而製成。因此，獲得453毫克 145862 -80- 201040187 3-氯基-6-(環庚基氧基）[1，2,4]***并[4,3_b]嗒畊，呈無色油形式，其係結晶，其特徵如下：質譜：Waters ZQ : MH+ m/z = 267+ 實例16 : H[6-(環庚基氧基）[1，2,4]***并[4,3.b]嗒畊·3-基]硫基}_1，3-苯并噻唑·2-胺 6-{[6-(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-ΐ,3-苯并雀唾-2-胺可以類似實例lb之方式，但以5立方公分經脫〇氣乙醇中之249毫克3_氯基各(環庚基氧基）[1，2,4]***并[4,3七] 。答味（15b)、0.1立方公分水中之5毫克磷酸二氫鉀、432毫克DL-二硫基蘇糖醇及193毫克硫氰酸2-胺基_i，3_苯并噻唑_6_ 基酯開始’於80°C下24小時後製成。因此，獲得26〇毫克6_ {[6-(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-i,3-苯并嘍唑-2-胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) δ ppm 1.29-1.74 (m, 10H) 1.86-1.97 0 (m» 2H) 4.87-4.99 (m, 1H) 7.00 (d, J = 9.8 Hz, 1H) 7.23-7.31 (m, 2H) 7.60 (s, 2H) 7.80-7.85 (m, 1H) 8.24 (d, J = 9.8 Hz, 1H) 質譜：Waters ZQ: MH+m/z = 413+; MH- = 411-實例17 : Ν-(6-{[6·(環庚基氧基)[1，2,4]三唾并[4,3-b]嗒井-3·基]硫基}-l，3-苯并嘧唑-2_基）乙醢胺 Ν-(6-{[6-(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯并p塞吐-2·•基）乙醯胺可以類似實例ia之方式，但以85毫克6-{[6-(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯10.0 Hz, 1H) 7.36 (dd, J = 8.6, 2.0 Hz, 1H) 7.55 (d, J = 8.6 Hz, 1H) 8.00 (d, J =1.7 Hz' 1H) 8.26 (d, J = 9.8 Hz, 1H 10.87 (broad s, 1H) . Mass Spectrum: Waters UPLC-SQD: MH+m/z = 569+; MH- = 567- b) 3-Chloro-6-(cycloheptyloxy)[1,2 , 4] Triazolo[4,3-b] tower p well can be similar to the method of the example lc 'but in the case of 15 cubic centimeters tetrahydronethane, 1.21 g of cycloheptanol, 254 mg at 60% in oil It was prepared by starting sodium hydride and 1 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]indole (commercially available). Therefore, 453 mg 145862 -80- 201040187 3-chloro-6-(cycloheptyloxy)[1,2,4]triazolo[4,3_b] is obtained as a colorless oil, which is crystallized. , characterized by the following: Mass Spectrum: Waters ZQ: MH+ m/z = 267+ Example 16: H[6-(cycloheptyloxy)[1,2,4]triazolo[4,3.b] 3-yl]thio}_1,3-benzothiazolyl 2-amine 6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]indole Benz-3-yl]thio}-indole, 3-benzoxan-2-amine can be similar to the method of the example lb, but in the 5 cubic centimeters of 249 mg of 3-chloro group in the deuterium ethanol (ring Heptyloxy)[1,2,4]triazolo[4,3-7]. Answer (15b), 5 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 432 mg of DL-dithiothreitol and 193 mg of 2-amino thiocyanate _i,3-benzothiazole-6-yl ester Start 'made at 24 ° C after 24 hours. Thus, 26 mg of 6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-i,3- Benzooxazole-2-amine, in the form of a white powder, is characterized as follows: 1H NMR spectrum (400 MHz, DMSO-d6) δ ppm 1.29-1.74 (m, 10H) 1.86-1.97 0 (m» 2H) 4.87- 4.99 (m, 1H) 7.00 (d, J = 9.8 Hz, 1H) 7.23-7.31 (m, 2H) 7.60 (s, 2H) 7.80-7.85 (m, 1H) 8.24 (d, J = 9.8 Hz, 1H) Mass Spectrum: Waters ZQ: MH+m/z = 413+; MH- = 411 - Example 17: Ν-(6-{[6·(cycloheptyloxy)[1,2,4]tris-[4] ,3-b]嗒井-3·yl]thio}-l,3-benzopyrazol-2-yl)acetamidoxime-(6-{[6-(cycloheptyloxy)[1 , 2,4]triazolo[4,3-b]indol-3-yl]thio}-1,3-benzoxepoxi-2·•yl)acetamid can be similar to the example ia But with 85 mg of 6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3- benzene

145862 -8N 201040187 并嘧唾-2-胺（16a)在5立方公分吡啶與0.160立方公分醋酸針中開始，於20°C下反應24小時後製成。因此，獲得9〇毫克 N-(M[6-(環庚基氡基）[1，2,4]***并[4,3七]嗒畊！基]_硫基}1，3_ 笨并嘧唑-2-基）乙醯胺，呈黃色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz，DMSCM6) δ ppm 1.20-1.35 (m，2H) 1.40-1.55 (m, 6H) 1.54-1.66 (m, 2H) 1.76-1.89 (m, 2H) 2.19 (s, 3H) 4.78-4.88 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.6, 2.0 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.06 (d, J = 2.0 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 12.38 ( % ^ s, 1H) 質譜：Waters ZQ : MH+ m/z = 455+ ; MH- = 453-實例18 : Ν-(6·{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-l，3-苯并嘍唑-2-基）乙醯胺 a) N-(6-{[6-(環己胺基）[1，2,4]三。坐并[4,3-1>]°答17井-3-基]硫基卜 1,3-本并p塞。坐-2-基）乙酿胺可以類似實例la之方式，但以150 毫克3-[(2-胺基-1，3-苯并嘧唑-6-基）硫基]-N-環己基[1,2,4]三唾并[4,3-b]嗒畊-6-胺在1立方公分吡啶與0.5立方公分醋酸趼中開始’於20°C下反應18小時後製成。因此，獲得65毫克N-(6-{[6-(環己胺基）[1,2,4]***并[4,3七]嗒畊-3-基]-硫基卜1，3-笨并嘧唑-2-基）乙醯胺，呈淡米黃色粉末形式，其特徵如下·· 1H NMR 光譜（300 MHz, DMSO-d6) δ ppm 0.95-1.32 (m, 5H) 1.45-1.67 (m, 3H) 1.68-1.84 (m, 2H) 2.19 (s, 3H) 3.35-3.45 (m, 1H) 6.79 (d, J = i〇.〇 Hz, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.38 (dd, J = 8.5, 2.0 Hz, 1H) 7.64 (d, J = g.5 Hz, 1H) 7.92 (d, J = 10.0 Hz, 1H) 8.05 (d, J = 2.0 Hz, 1H) 12.35 (寬廣 s， 1H) 145862 -82- 201040187 質譜：Waters UPLC_SQD: MH+m/z = 44〇+; mh=438_ b) 3-[(2·胺基-U-苯并4唑-6-基）硫基]-N-環己基[l，2,4]*** 并[4,3-b]塔呼-6_胺可以類似實例比之方式，但以ι〇立方公分經脫氣乙醇中之607毫克3-氯-N-環己基[1，2,4]***并[4,3-b] 嗒畊-6-胺、1立方公分水中之12毫克磷酸二氫鉀、ι ΐ2克 DL-二硫基蘇糖醇及5〇〇毫克硫氰酸2_胺基-笨并噻唑各基酯開始，於8(TC下24小時後製成。因此’獲得7邰毫克3_[(2_ 胺基-1，3-苯并噻唑-6-基）硫基]環己基***并[4,3_切嗒畊-6-胺，呈白色粉末形式，其特徵如下：吳譜.Waters UPLC-SQD : MH+ m/z = 398+ ; MH- = 396. c) 3_氯-N-環己基[1，2,4]***并[4,3七]嗒嗜-6-胺可以下述方式製成：將2.3立方公分環己胺與3 7立方公分三乙胺添加至5克市購 3,6-一氣[1，2,4]二唑并[4,3-b]嗒畊在50立方公分N，N-二甲基甲醯胺中之溶液内。將反應物於2〇。〇下攪拌18小時。然後添加另外1.1立方公分環己胺與7 5立方公分三乙胺，並將反應物在50 C下攪拌4小時。使反應混合物冷卻至2〇它，接著添加60立方公分水。藉抽氣濾出白色沉澱物，然後以水與醚連續洗蘇。因此，獲得3克3_氯_N_環己基[12,4]***并 [4,3-b>荅4 -6-胺，呈白色粉末形式。在留下過夜後，將上文獲得之最初濾液中所形成之沉澱物藉抽氣濾出，並以 N，N-二曱基曱醢胺，以脫礦質水，及以曱醇連續洗滌。因此，獲得第二份收取之1.42克3-氣-N-環己基[1，2,4]***并[4,3-b>荅畊-6-胺’呈黃色粉末形式，其特徵如下： 145862 -83- 201040187 質 β普.Waters UPLC-SQD : MH+ m/z = 252+ ; ΜΗ- = 250- 實例19 : 1- (6·{[6-(環己胺基）^4]***并[4,3.b]嗒畊_3基]硫基}1，3_苯并嘧唑-2-基)·3-[2-(四氫吡咯小基）乙基雕 a) H6-{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]琉基}-1,3-苯并嘧唑-2-基）-3-[2-(四氫吡咯-1-基）乙基]脲可以類似實例 lb之方式’但以6立方公分經脫氣乙醇中之3〇〇毫克硫氰酸 2- {[(2-四氫吡咯基乙基）胺甲醯基]胺基H，3_苯并p塞嗤_6基酉旨、0.6立方公分水中之4毫克填酸二氫鉀' 4〇〇毫克DL-二硫基蘇糖醇及240毫克3-氯-N-環己基[1，2,4]***并[4,3-b]塔畊-6-胺（18c)開始，於8〇。(：下18小時後製成❶因此，獲得193毫克1-(6-{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）-3-[2-(四氫吡咯-1-基）乙基]脲，呈淡黃色粉末形式’其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) <5 ppm 1.00-1.34 (m, 6H) 1.46-1.74 (m，6H) 1.75-1.86 (m，2H) 2.40-2.57 經遮蔽（m，6H) 3.21-3.28 (m，2H) 3.39-3.49 (m, 1H) 6.79 (d, J = 10.0 Hz, 1H) 6.81-6.88 (m, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.35 (dd, J = 8.5, 2.0 Hz, 1H) 7.52 (d, J = 8.5 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 2.0 Hz, 1H) 10.81 (寬廣 s, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 538+ ; MH- = 536- b) 硫氰酸2-{[(2-四氳吡咯基乙基）胺曱醯基]胺基卜1,3-苯并嘧唑-6-基酯可以下述方式製成：將1.4立方公分2-四氫p比略基乙胺於20 °C下添加至3克（6-氰硫基-1,3-苯并嘧唑-2-基）胺基曱酸笨酯在90立方公分四氫呋 145862 -84- 201040187 °南中之溶液内。24小時後，使反應混合物在減壓下濃縮至乾涸。將***添加至所獲得之油狀黃色殘留物中。藉抽氣遽出所形成之沉澱物。因此，獲得3 33克硫氰酸2_{[(2_四氫 p比11各基乙基）胺甲醯基]胺基}_u_苯并嘧唑_6_基酯，呈帶黃色粉末形式’其特徵如下：質譜：Waters ZQ : MH+ m/z = 348+ ; MH- = 346- c) (6_氰硫基-1，3-苯并喳唑-2-基）胺基曱酸笨酯以下述方式製成：將7.5克氯碳酸苯酿，接著為4 〇5克碳酸氫鈉及9 4立方公分水’於20°C下，添加至2.5克市購硫氰酸2-胺基-1,3-苯并噻。坐-6-基酿在94立方公分四氫呋喃中之溶液内。然後，將所形成之混合物於2(TC下攪拌20小時，接著以2x150立方公分醋酸乙酯萃取。合併有機相’然後以3Χ5〇立方公分飽和碳酸氫鈉水溶液洗滌。使所獲得之有機相以硫酸鎂脫水乾燥’接著在減壓下濃縮至乾涸。使殘留物溶於5〇立方公分水中，然後藉抽氣濾出，並在真空及2〇°c下乾燥。因此，獲得3.45克（6-氛硫基-1，3-苯并p塞唾_2_基）胺基曱酸苯酯，呈淡黃色固體形式，其特徵如下·· 質譜：LC-MS-DAD-ELSD : MH+ m/z = 328+ ; MH- = 326-實例20 : 環丙烷羧酸反式-4-{[3-({2-[(環丙基羰基)胺基]苯并噻唑各基l·硫基）[1，2,4]三峻并[4,3_b]塔畊·6-基]胺基}環己酯 a)環丙烷羧酸反式-Μ[3·({2-[(環丙基羰基）胺基Η}苯并遠°坐-6-基卜硫基）[1，2,4]二》坐并[4,3-b]»荅p井-6-基]胺基}環己酯可 145862 85· 201040187 以類似實例la之方式，但以300毫克反式-4-({3-[(2-胺基-l，3_ 苯并嘧唑-6-基）硫基][1，2,4]***并[4,3-b]嗒畊-6-基}胺基）環己醇在2.1立方公分吡啶與0.133立方公分環丙烷氣化醯中開始’於20°C下反應18小時後製成。因此，獲得303毫克環丙烧叛酸反式-4-{[3-({2-[(環丙基羧基）胺基]_ι，3-苯并p塞。坐基}硫基）[1，2,4]***并[4,3-b>荅啡-6-基]胺基}環己酯，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) 6 ppm 0.76-1.01 (m，8H) 1.06-1.32 (m, 4H) 1.51-1.65 (m, 1H) 1.67-1.81 (m5 4H) 1.93-2.05 (m, 1H) 3.30-3.38 (m, 1H) 4.44-4.61 (m, 1H) 6.78 (d, J = 9.8 Hz, 1H) 7.20-7.34 (m, 2H) 7.62 (d, J = 8.6 Hz’ 1H) 7.93 (d，J = 9.8 Hz, 1H) 8.05 (d，J = 2.0 Hz，1H) 12.64 (寬廣 s， 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 550+ ; MH- = 548-b) 反式_4-({3-[(2-胺基-1，3-苯并嘧唑-6-基）硫基Π1,2,4]*** 并[4,3-b]。合11井-6-基}胺基）環己醇可以類似實例ib之方式，但以20立方公分經脫氣乙醇中之1克硫氰酸2_胺基_u_苯并嘍唾-6-基醋、2立方公分水中之23毫克磷酸二氫鉀、2.32克 01"二硫基蘇糖醇及1.29克反式-4-[(3-氯基[1,2,4]***并[4,3-13] °荅p井-6-基）胺基]環己醇開始，於8〇t下18小時後製成。因此’獲得1.8克反式_4_({3-[(2-胺基-1,3-苯并嘧唑各基）硫基][1’2,4]三。全并[4,3七]嗒畊_6·基丨胺基）環己醇，呈乳白色粉末形式’其特徵如下：質譜：Waters ZQ: MH+m/z = 414+; MH- = 412- C) 反式々[(I氯基[1，2,4]***并[4,3-b>荅畊-6-基）-胺基]環己 145862 201040187 醇可以類似實例18c之方式，但以50立方公分摩二甲基甲醯胺中之5克市構3,6-二氣[⑵]三吐并[4,3七>^井、6克反式_ 4_胺基環己醇鹽酸鹽及17立方公分三乙胺開始，於抓下 . 48小時及在50艺下4小時後製成。因此，獲得35克反式斗 [(3-氯基[1，2,4]***并[4,3-b]嗒畊_6_基）胺基]環己醇，呈白色粉末形式，其特徵如下：質譜：Waters UPLC-S® : MH+ m/z = 268+ ; MH- = 266- 實例21 : 〇 Ν-(6-{[6·(環己胺基）H4]***并[4,3_b]嗒畊_3_基]硫基}1，3_苯并嘧唑-2-基）環丙烷羧醯胺 N-(6-{[6-(環己胺基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基}-i，3-苯并0塞吐-2-基）環丙烷羧醯胺可以類似實例la之方式，但以 3〇〇窀克3-[(2-胺基-1,3-苯并峰吐-6-基）硫基]-N-環己基[ι，2,4]三峻并[4,3-b]嗒p井-6-胺（18b)在2.1立方公分吡啶與0.14立方公分環丙烷氯化醯中開始，於2(TC下反應18小時後製成。因 Q 此’獲得268毫克N-(6-{[6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并噹唑-2-基）-環丙烷羧醯胺，呈乳白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz，DMSO-d6) (5 ppm 0.86-1.00 (m, 4H) 1.01-1.28 • (m, 5H) 1.48-1.66 (m, 3H) 1.70-1.83 (m, 2H) 1.92-2.04 (m, 1H) 3.36-3.45 (m, 1H) 6.79 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.39 (d, J = 8.6 Hz, 1H) 7.65 (d，J = 8.3 Hz，1H) 7.91 (d，J = 9.8 Hz，1H) 8.03 (s，1H) 12.65 (寬廣 s， 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 466+ ; MH- = 464- 145862 • 87- 201040187 實例22 : N-[6-({6-[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b]嗒畊-3-基}硫基)-1，3-苯并tr塞吐-2-基]乙醯胺 a) N-[6-({6-[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b]嗒畊-3-基}硫基）-1,3-苯并嘍唑-2-基]乙醯胺可以下述方式製成：將0.08立方公分氣化乙醯與0.16立方公分三乙胺添加至 114毫克反式-4-({3-[(2-胺基-1，3-苯并嘧唑-6-基）硫基][1,2,4]*** 并[4,3-b]嗒畊-6-基}胺基）環己醇（20b)在2立方公分二氯甲烷中之溶液内。18小時後，使反應媒質在減壓下濃縮至乾涸。使殘留物溶於水中。藉抽氣濾出所形成之黃白色沉澱物’並以水洗務，然後於Biotage Quad 25M (KP-SIL，60入；32-63 //Μ)上藉乾燥沉積純化，以95/5至70/30二氣甲烷/(二氯曱烷：38/曱醇：17/氨水：2)之梯度液溶離。因此，獲得 46毫克N-[6-({6-[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b] 嗒畊-3-基}硫基）-1,3-苯并嘧唑-2-基]乙醯胺，呈米黃色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz，DMS0-d6) (5 ppm 1.01-1.27 (m，4H) 1.68-1.86 (m, 4H) 2.19 (s, 3H) 3.35-3.44 (m, 2H) 4.51 (d, J = 4.6 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 6.8 Hz, 1H) 7.42 (dd, J = 8.4, 1.8 Hz, 1H) 7.65 (d, J = 8.3 Hz, 1H) 7.92 (d, J = 9.8 Hz, 1H) 8.01 (d, J = 1.7 Hz, 1H) 12.34 ( ^ s, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 456+ ; MH- = 454-實例23 : 145862 -88- 201040187 Ν-[6-({6·[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b]嗒呼-3-基}硫基)-1,3-苯并崦唑-2-基]環丙烷羧醯胺 N-[6-({6-[(反式-4-羥基環己基）胺基][1,2,4]***并[4,3-b]塔_-3-基}硫基）-1，3-苯并碟嗤-2-基]環丙烧叛醢胺可以類似實例ia 之方式，但以300毫克反式-4-({3-[(2-胺基-1,3-苯并嘧唑-6-基）硫基][1，2,4]***并[4,3-b]嗒畊-6-基}胺基）環己醇（20b)在3立方公分吡啶與0.235立方公分環丙烷氣化醯中開始，於2〇°c下反應16小時後製成。因此，獲得51毫克N-[6-({6-[(反式-4-羥基環己基）胺基][1，2,4]***并[4,3-b]嗒畊-3-基}硫基）-1，3-苯并嘧唑-2-基]環丙烷羧醯胺，呈米黃色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) 6 ppm 0.89-0.99 (m，4H) 1.02-1.27 (m, 4H) 1.68-1.87 (m, 4H) 1.92-2.03 (m, 1H) 3.31-3.45 (m, 2H) 4.51 (d, J = 4.4 Hz, 1H) 6.77 (d，J = 9.8 Hz，1H) 7.25 (d，J = 7.1 Hz，1H) 7.43 (dd,J = 8.6, 2.0 Hz, 1H) 7.65 (d, J = 8.6 Hz, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.00 (d, J = 1.7 Hz，1H) 12.64 (寬廣 s，1H) 質譜：Waters UPLC-SQD : MH+ m/z = 482+ ; MH- = 480-實例24 : 3_[(2·胺基-1，3-苯并n塞唾-6-基）硫基]-N-環丙基[1，2,4]三也并[4,3-b]e荅p井-6-胺 a) 3-[(2-胺基-1,3-苯并嘧唑-6-基）硫基]-N-環丙基[1，2,4]*** 并[4,3-b]嗒畊-6-胺可以類似實例lb之方式，但以41立方公分經脫氣乙醇中之1.4克硫氰酸2-胺基-1，3-笨并嘧唑-6-基酯、4立方公分水中之32毫克磷酸二氫鉀、3.13克DL-二硫 145862 -89- 201040187 基蘇糖醇及1.42克3-氣-N-環丙基[1，2,4]***并[4,3-b]嗒畊-6-胺開始，於80°C下18小時後製成。因此，獲得122克3-[(2-胺基-1，3-苯并嘧唑-6-基）硫基]-N-環丙基[1，2,4]***并[4,3-b]塔4 -6-胺，呈乳白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz，DMSO-d6) <5 ppm 0.41-0.48 (m，2H) 0.71-0.79 (m, 2H) 2.56-2.65 (m, 1H) 6.76 (d, J = 9.8 Hz, 1H) 7.27 (d, J = 8.3 Hz, 1H) 7.42 (dd，J = 8.3, 2.0 Hz, 1H) 7.67 (寬廣 s，3H) 7.92 (d, J = 9.8 Hz，1H) 7.95 (d,J=1.7 Hz, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 356+ ; ΜΗ- = 354_ b) 3-氣-N-環丙基[1,2,4]三嗤并[4,3七]塔畊-6-胺DPN1.150可以類似實例18c之方式’但以2克市購3,6-二氣[1，2,4]***并 [4,3-b]嗒畊在20立方公分n，N-二甲基曱醯胺、U立方公分環丙基胺及3立方公分三乙胺中開始，於2〇。〇下18小時及在 50 C下3小時後製成。因此，獲得153克3_氣_N_環丙基以，2,4] 三峻并[4,3-b]嗒畊-6-胺，呈白色粉末形式，其特徵如下：質譜：Waters ZQ: MH+m/z = 210+; MH- = 208- 實例25 : N-(6-{[6-(環丙胺基）tl，2,4]***并[4,3-b]嗒畊-3-基]硫基}·;ι，3_苯并 ρ塞唾-2-基）乙醯胺 a) N_(6_{[6-(環丙胺基）[U，4]***并[4,3-b]塔_ -3-基]硫基}_ 1,3-苯并嘍唑-2-基）乙醯胺可以類似實例la之方式，但以3〇〇毫克3-[(2-胺基-i，3-笨并，塞唑-6-基）硫基]環丙基[丨二冽*** 并[4,3七]嗒畊-6-胺（24a)在2_1立方公分吡啶與ι·〇4立方公分醋酸酐中開始，於2(TC下反應18小時後製成。因此，獲得 145862 -90- 201040187 100毫克N-(6-{[6-(環丙胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）乙醢胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) δ ppm 0.34-0.45 (m，2H) 0.61-0.74 (m, 2H) 2.19 (s, 3H) 2.53-2.58 (m, 1H) 6.77 (d, J = 9.5 Hz, 1H) 7.53 (d, J = 8.3 Hz, 1H) 7.62-7.73 (m, 2H) 7.94 (d, J = 9.8 Hz, 1H) 8.19 (s, 1H) 12.38 (寬廣s，1H) 質譜：Waters UPLC-SQD : MH+ m/z = 398+ ; MH- = 396- 〇實例26 : N-(6-{[6-(環丙胺基）[i，2,4]***并[4,3-b]塔哜-3·基]硫基}-l，3_苯并 <»塞°坐-2-基)環丙烧叛醮胺 a) N-(6-{[6-(環丙胺基）[ι，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）環丙烷羧醯胺可以類似實例之方式，但以300毫克3-[(2-胺基-1,3-苯并嘧唑-6-基）硫基]-N-環丙基 [1，2,4]***并[4,3-b]塔畊-6-胺（24a)在3立方公分吡啶與0.16立〇方公分環丙烷氣化醯中開始，於20°c下反應18小時後製成。因此’獲得208毫克N-(6-{[6-(環丙胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜1，3-苯并嘍唑-2-基）環丙烷羧醯胺，呈白色粉末形式，其特徵如下： 1H NMR 光譜（400 MHz, DMSO-d6) δ ppm 0.34-0.44 (m，2H) 0.62-0.73 (m, 2H) 0.89-1.01 (m, 4H) 1.93-2.03 (m, 1H) 2.52-2.61 (m, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.53 (dd, J = 8.6, 1.7 Hz, 1H) 7.61-7.71 (m, 2H) 7.94 (d, J = 9.8145862 -8N 201040187 The pyrimidine-2-amine (16a) was prepared in 5 cubic centimeters of pyridine and 0.160 cubic centimeters of acetic acid needle and reacted at 20 ° C for 24 hours. Thus, 9 mg of N-(M[6-(cycloheptyldecyl)[1,2,4]triazolo[4,3-7]嗒[!]]]]thiol}1,3_ stupid Pyrazole-2-yl)acetamide, in the form of a yellow powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSCM6) δ ppm 1.20-1.35 (m, 2H) 1.40-1.55 (m, 6H) 1.54-1.66 (m, 2H) 1.76-1.89 (m, 2H) 2.19 (s, 3H) 4.78-4.88 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.6, 2.0 Hz, 1H ) 7.67 (d, J = 8.6 Hz, 1H) 8.06 (d, J = 2.0 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 12.38 ( % ^ s, 1H) Mass Spectrum: Waters ZQ : MH+ m/ z = 455+ ; MH- = 453 - Example 18: Ν-(6·{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]嗒耕-3- ]]thio]-l,3-benzoxazol-2-yl)acetamidamine a) N-(6-{[6-(cyclohexylamino)[1,2,4] III. [4,3-1>]°A17 well-3-yl]thiol 1,3-benz and p-plug. Sodium-2-yl) Ethylamine can be similar to the example la, but with 150 mg 3 -[(2-Amino-1,3-benzopyrazol-6-yl)thio]-N-cyclohexyl[1,2,4]tris-[4,3-b]嗒耕-6 -Amine starts in 1 cubic centimeter of pyridine and 0.5 cubic centimeter of yttrium acetate. 'Reacts at 20 ° C for 18 hours. After made. Thus, 65 mg of N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-7]indole-3-yl]-thio-bub 1,3 was obtained. - benzopyrazol-2-yl)acetamide, in the form of a pale beige powder, characterized by 1H NMR spectrum (300 MHz, DMSO-d6) δ ppm 0.95-1.32 (m, 5H) 1.45-1.67 (m, 3H) 1.68-1.84 (m, 2H) 2.19 (s, 3H) 3.35-3.45 (m, 1H) 6.79 (d, J = i〇.〇Hz, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.38 (dd, J = 8.5, 2.0 Hz, 1H) 7.64 (d, J = g.5 Hz, 1H) 7.92 (d, J = 10.0 Hz, 1H) 8.05 (d, J = 2.0 Hz, 1H) 12.35 (broad s, 1H) 145862 -82- 201040187 Mass: Waters UPLC_SQD: MH+m/z = 44〇+; mh=438_ b) 3-[(2·Amino-U-benzotetrazole-6- The thio]]-N-cyclohexyl[l,2,4]triazolo[4,3-b] tacho-6-amine can be similarly exemplified by the method, but degassed by ι〇cubic centimeters 607 mg of 3-chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]indole-6-amine, 12 mg of potassium dihydrogen phosphate in 1 cm 2 of water, ι ΐ2克 DL-dithiothreitol and 5 mg of 2-amino- benzothiazolyl thiocyanate were started and made at 8 (TC) 24 hours later. Mg 3_[(2_Amino-1,3-benzothiazol-6-yl)thio]cyclohexyltriazolo[4,3_cutin-6-amine, in the form of a white powder, characterized as follows: Wu Li. Waters UPLC-SQD: MH+ m/z = 398+ ; MH- = 396. c) 3_Chloro-N-cyclohexyl[1,2,4]triazolo[4,3-7] The 6-amine can be prepared in the following manner: 2.3 cubic centimeters of cyclohexylamine and 3 7 cubic centimeters of triethylamine are added to 5 grams of commercially available 3,6-mono-[1,2,4]diazoles [4,3 -b] tillage in a solution of 50 cubic centimeters of N,N-dimethylformamide. The reaction was taken at 2 Torr. Stir under the arm for 18 hours. An additional 1.1 cubic centimeters of cyclohexylamine and 75 cubic centimeters of triethylamine were then added and the reaction was stirred at 50 C for 4 hours. The reaction mixture was allowed to cool to 2 Torr, followed by the addition of 60 cubic centimeters of water. The white precipitate was filtered off with suction and then continuously washed with water and ether. Thus, 3 g of 3-chloro-N-cyclohexyl[12,4]triazolo[4,3-b>荅4-6-amine was obtained in the form of a white powder. After leaving overnight, the precipitate formed in the initial filtrate obtained above was filtered off with suction and washed successively with N,N-didecylamine, demineralized water, and with methanol. Thus, a second portion of 1.42 g of 3- gas-N-cyclohexyl[1,2,4]triazolo[4,3-b>indole-6-amine was obtained in the form of a yellow powder, which is characterized as follows : 145862 -83- 201040187 质β普.Waters UPLC-SQD : MH+ m/z = 252+ ; ΜΗ- = 250- Example 19 : 1- (6·{[6-(cyclohexylamino)^4]3 Zoxa[4,3.b]嗒耕_3yl]thio}1,3_benzopyrazol-2-yl)·3-[2-(tetrahydropyrrole small)ethyl an) H6 -{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]indol-3-yl]fluorenyl}-1,3-benzopyrazole-2- Benzyl-3-(2-(tetrahydropyrrol-1-yl)ethyl]urea can be similar to the method of Example lb 'but 3 gram of thiocyanate 2-{ in 6 cubic centimeters of degassed ethanol (2-tetrahydropyrrolylethyl)amine-methylmethyl]amino H,3_benzopyrene- 6-based hydrazine, 4 mg of potassium dihydrogenate in 0.6 cm 3 of water ' 4 〇〇 ML DL - Dithiothreitol and 240 mg of 3-chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]tac-6-amine (18c), starting at 8 Torr. (: After the next 18 hours, ❶ was obtained, thus obtaining 193 mg of 1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]indole-3 -yl]thio}-1,3-benzopyrazol-2-yl)-3-[2-(tetrahydropyrrol-1-yl)ethyl]urea, in the form of a pale yellow powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) <5 ppm 1.00-1.34 (m, 6H) 1.46-1.74 (m, 6H) 1.75-1.86 (m, 2H) 2.40-2.57 Masked (m, 6H) 3.21 -3.28 (m,2H) 3.39-3.49 (m, 1H) 6.79 (d, J = 10.0 Hz, 1H) 6.81-6.88 (m, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.35 (dd, J = 8.5, 2.0 Hz, 1H) 7.52 (d, J = 8.5 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 2.0 Hz, 1H) 10.81 (broad s, 1H) Mass Spectrum: Waters UPLC-SQD : MH+ m/z = 538+ ; MH- = 536- b) 2-{[(2-tetrapypyrrylethyl)amine thiol]aminophenyl 1,3-benzene The pyrimido-6-yl ester can be prepared in the following manner: 1.4 cubic centimeters of 2-tetrahydro-p-pyridylethylamine is added to 3 g (6-thiocyanato-1,3-benzene) at 20 °C. And pyrimidin-2-yl)amino decanoic acid ester in a solution of 90 cubic centimeters of tetrahydrofuran 145862-84-201040187 ° South. After 24 hours, the reaction mixture was concentrated to dryness under reduced pressure. Ethyl ether was added to the obtained oily yellow residue. Use the pumping gas to extract the precipitate formed. Thus, 3 33 g of thiocyanate 2_{[(2_tetrahydrop to 11 ethylideneethyl)amine indenyl]amino}_u_benzopyrazole-6-yl ester was obtained in the form of a yellow powder 'Characteristics are as follows: Mass spectrometry: Waters ZQ: MH+ m/z = 348+; MH- = 346-c) (6-cyanothio-1,3-benzoxazol-2-yl)amine decanoic acid The ester is prepared in the following manner: 7.5 g of chlorocarbonate is brewed, followed by 4 〇 5 g of sodium hydrogencarbonate and 94 gm of water 'at 20 ° C, added to 2.5 g of commercially available 2-amino group thiocyanate -1,3-benzothiazepine. Sit in a solution of -6-base in 94 cubic centimeters of tetrahydrofuran. Then, the resulting mixture was stirred at 2 (TC for 20 hours, then with 2 x 150 cubic centimeters of ethyl acetate. The combined organic phases were then washed with 3 Χ 5 〇 cubic centimeter of saturated aqueous sodium hydrogencarbonate. The obtained organic phase was The dried magnesium sulfate was dried and then concentrated to dryness under reduced pressure. The residue was dissolved in 5 s of cubic centi of water, then filtered off with suction and dried under vacuum at 2 ° C. Thus, 3.45 g (6) was obtained. - thio-yl-1,3-benzo-pyrrolidino-2-yl) phenyl decanoate, in the form of a pale yellow solid, characterized by the following: MS: LC-MS-DAD-ELSD: MH+ m/ z = 328+ ; MH- = 326 - Example 20: cyclopropanecarboxylic acid trans-4-{[3-({2-[(cyclopropylcarbonyl)amino)]benzothiazoleyl l-thio) [1,2,4]Sanjun and [4,3_b] Tagging·6-yl]amino}cyclohexyl ester a) cyclopropanecarboxylic acid trans-Μ[3·({2-[(cyclopropyl) Carbonyl)amine hydrazide}benzoyl sylylene-6-yl thio)[1,2,4]di" and [4,3-b]»荅p well-6-yl]amino} ring Hexyl ester can be 145862 85· 201040187 in a similar manner to the example la, but with 300 mg of trans-4-({3-[(2-amino-l,3_benzopyrazole-6-yl) )thio][1,2,4]triazolo[4,3-b]indole-6-yl}amino)cyclohexanol starts in 2.1 cubic centimeters of pyridine and 0.133 cubic centimeters of cyclopropane gasification hydrazine 'Prepared after reacting at 20 ° C for 18 hours. Thus, 303 mg of ciprofloxacin trans-trans-4-{[3-({2-[(cyclopropylcarboxy)amino]], 3-benzopyran. sylylene}thio)[1 , 2,4]triazolo[4,3-b>indolyl-6-yl]amino}cyclohexyl ester, in the form of a white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) 6 Ppm 0.76-1.01 (m,8H) 1.06-1.32 (m, 4H) 1.51-1.65 (m, 1H) 1.67-1.81 (m5 4H) 1.93-2.05 (m, 1H) 3.30-3.38 (m, 1H) 4.44- 4.61 (m, 1H) 6.78 (d, J = 9.8 Hz, 1H) 7.20-7.34 (m, 2H) 7.62 (d, J = 8.6 Hz' 1H) 7.93 (d, J = 9.8 Hz, 1H) 8.05 (d , J = 2.0 Hz, 1H) 12.64 (broad s, 1H) Mass Spectrum: Waters UPLC-SQD : MH+ m/z = 550+ ; MH- = 548-b) Trans _4-({3-[(2- Amino-1,3-benzopyrazol-6-yl)thiolΠ1,2,4]triazolo[4,3-b].11-11-6-yl}amino)cyclohexanol Similar to the method of the example ib, but in a 20 cubic centimeter degassed ethanol, 1 g of thiocyanate 2-amino- _u_benzopyrene-6-yl vinegar, 23 mg of potassium dihydrogen phosphate in 2 cubic centimeters of water , 2.32 g of 01"dithiothreitol and 1.29 g of trans-4-[(3-chloro[1,2,4]triazolo[4,3-13] °荅 well-6-based Amine] Hexanol begins to 8〇t made after 18 hours. Therefore, '1.8 g of trans-_4_({3-[(2-amino-1,3-benzopyrazole))thio][1'2,4] III is obtained. ] 嗒 _ _ -6 丨丨 ) ) ) ) , , , , , , , 环环环环环环 Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water Water I-chloro[1,2,4]triazolo[4,3-b>荅耕-6-yl)-amino]cyclohexyl 145862 201040187 Alcohol can be similar to the method of Example 18c, but with 50 cubic centimeters 5 grams of methylformamide 3,6-digas [(2)] tri- ox[4,3-7] well, 6 g of trans- 4_aminocyclohexanol hydrochloride and 17 Starting from cubic centimeters of triethylamine, it was taken at 48 hours and 4 hours after 50 art. Thus, 35 g of trans-bucket [(3-chloro[1,2,4]triazolo[4,3-b]indole_6-yl)amino]cyclohexanol was obtained in the form of a white powder. The characteristics are as follows: Mass spectrometry: Waters UPLC-S®: MH+ m/z = 268+; MH- = 266- Example 21: 〇Ν-(6-{[6·(cyclohexylamino)H4]triazolo[ 4,3_b]嗒耕_3_yl]thio}1,3_benzopyrazol-2-yl)cyclopropanecarboxamide N-(6-{[6-(cyclohexylamino)[1, 2,4]triazolo[4,3-b]tac-3-yl]thio}-i,3-benzoxepoxi-2-yl)cyclopropanecarboxamide can be similar to the example la , but with 3 g of 3-[(2-amino-1,3-benzo-p--6-yl)thio]-N-cyclohexyl [ι, 2, 4] Sanjun [4 , 3-b] 嗒p well-6-amine (18b) was started in 2.1 cubic centimeters of pyridine and 0.14 cubic centimeters of cyclopropane ruthenium chloride, and was prepared after 2 hours of reaction at 2 (TC). Mg N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzoene When oxazol-2-yl)-cyclopropanecarboxamide is in the form of a milky white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) (5 ppm 0.86-1.00 (m, 4H) 1.01-1.28 • ( m, 5H) 1.48-1.66 (m, 3H) 1.70-1.83 (m, 2H) 1.92-2.04 (m, 1H) 3.36-3.45 (m, 1H) 6.79 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.39 ( d, J = 8.6 Hz, 1H) 7.65 (d, J = 8.3 Hz, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.03 (s, 1H) 12.65 (broad s, 1H) Mass Spectrometer: Waters UPLC-SQD : MH+ m/z = 466+ ; MH- = 464- 145862 • 87- 201040187 Example 22: N-[6-({6-[(trans-4-hydroxycyclohexyl))amino][1,2, 4] Triazolo[4,3-b]indole-3-yl}thio)-1,3-benzoxep-2-yl]acetamidamine a) N-[6-({6 -[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]indole-3-yl}thio)-1,3-benzopyrene Zin-2-yl]acetamide can be prepared in the following manner: 0.08 cubic centimetres of vaporized acetamidine and 0.16 cubic centimeters of triethylamine are added to 114 mg of trans-4-({3-[(2-amino) -1,3-benzopyrazol-6-yl)thio][1,2,4]triazolo[4,3-b]indole-6-yl}amino)cyclohexanol (20b) In a solution of 2 cubic centimeters of dichloromethane. After 18 hours, the reaction medium was concentrated to dryness under reduced pressure. The residue is dissolved in water. The resulting yellow-white precipitate was filtered off with suction and washed with water, then purified by dry deposition on a Biotage Quad 25M (KP-SIL, 60 in; 32-63 // Μ), 95/5 to 70/ 30 dioxane methane / (dichlorodecane: 38 / decyl alcohol: 17 / ammonia: 2) gradient solution. Thus, 46 mg of N-[6-({6-[(trans-4-hydroxycyclohexyl))amino][1,2,4]triazolo[4,3-b]indole-3- a thiol)-1,3-benzopyrazol-2-yl]acetamide in the form of a beige powder characterized by the following: 1H NMR spectrum (400 MHz, DMS0-d6) (5 ppm 1.01-1.27 (m,4H) 1.68-1.86 (m, 4H) 2.19 (s, 3H) 3.35-3.44 (m, 2H) 4.51 (d, J = 4.6 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 6.8 Hz, 1H) 7.42 (dd, J = 8.4, 1.8 Hz, 1H) 7.65 (d, J = 8.3 Hz, 1H) 7.92 (d, J = 9.8 Hz, 1H) 8.01 (d, J = 1.7 Hz, 1H) 12.34 ( ^ s, 1H) Mass Spectrum: Waters UPLC-SQD : MH+ m/z = 456+ ; MH- = 454 - Example 23: 145862 -88- 201040187 Ν-[6-({6· [(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]indole-3-yl}thio)-1,3-benzoxazole -2-yl]cyclopropanecarboxamide N-[6-({6-[(trans-4-hydroxycyclohexyl))amino][1,2,4]triazolo[4,3-b] The -3--3-yl}thio)-1,3-benzoxan-2-yl]cyclopropanol ruthenium can be similar to the ia exe, but with 300 mg trans-4-({3- [(2-Amino-1,3-benzopyrazol-6-yl)thio][1,2,4]triazolo[4,3-b]嗒耕-6 -Amino}amino)cyclohexanol (20b) was started in 3 cubic centimeters of pyridine and 0.235 cubic centimeters of cyclopropane gasification ruthenium, and was reacted at 2 ° C for 16 hours. Thus, 51 mg of N-[ 6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]indole-3-yl}thio)-1, 3-benzopyrazol-2-yl]cyclopropanecarboxamide, in the form of a beige powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) 6 ppm 0.89-0.99 (m, 4H) 1.02- 1.27 (m, 4H) 1.68-1.87 (m, 4H) 1.92-2.03 (m, 1H) 3.31-3.45 (m, 2H) 4.51 (d, J = 4.4 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.43 (dd, J = 8.6, 2.0 Hz, 1H) 7.65 (d, J = 8.6 Hz, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.00 ( d, J = 1.7 Hz, 1H) 12.64 (broad s, 1H) Mass Spectrum: Waters UPLC-SQD: MH+ m/z = 482+; MH- = 480-Example 24: 3_[(2·Amino-1,3 -benzon-sept-6-yl)thio]-N-cyclopropyl[1,2,4]tris[4,3-b]e荅p well-6-amine a) 3-[ (2-Amino-1,3-benzopyrazol-6-yl)thio]-N-cyclopropyl[1,2,4]triazolo[4,3-b]indole-6- The amine can be similar to the example lb, but with 41 Divided into 1.4 g of 2-amino-1,3-benzoxazole-6-yl thiocyanate in degassed ethanol, 32 mg of potassium dihydrogen phosphate in 4 cubic centimeters of water, 3.13 g of DL-disulfide 145862 -89- 201040187 base of threitol and 1.42 g of 3-gas-N-cyclopropyl[1,2,4]triazolo[4,3-b]indole-6-amine at 80 ° C Made after 18 hours. Thus, 122 g of 3-[(2-amino-1,3-benzopyrazol-6-yl)thio]-N-cyclopropyl[1,2,4]triazolo[4,3 was obtained. -b]Tower 4-6-amine, in the form of a milky white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) <5 ppm 0.41-0.48 (m, 2H) 0.71-0.79 (m, 2H) 2.56-2.65 (m, 1H) 6.76 (d, J = 9.8 Hz, 1H) 7.27 (d, J = 8.3 Hz, 1H) 7.42 (dd, J = 8.3, 2.0 Hz, 1H) 7.67 (broad s, 3H) 7.92 (d, J = 9.8 Hz, 1H) 7.95 (d, J = 1.7 Hz, 1H) Mass Spectrum: Waters UPLC-SQD: MH+ m/z = 356+ ; ΜΗ- = 354_ b) 3-Gas-N-ring Propyl [1, 2, 4] triterpene [4, 3 seven] tar pitch-6-amine DPN 1.150 can be similar to the way of example 18c 'but commercially available 3,6-two gas [1, 2 , 4] Triazolo[4,3-b] sorghum started in 20 cubic centimeters of n,N-dimethyl decylamine, U cubic centicyclopropylamine and 3 cubic centimeters of triethylamine, at 2〇 . It was made 18 hours after squatting and 3 hours after 50 C. Thus, 153 g of 3_gas_N_cyclopropyl was obtained as 2,4]tris[4,3-b]indole-6-amine in the form of a white powder which was characterized as follows: Mass Spectrum: Waters ZQ : MH+m/z = 210+; MH- = 208- Example 25: N-(6-{[6-(cyclopropylamino)tl,2,4]triazolo[4,3-b] -3-yl]thio}·;ι,3_benzox-sodium-2-yl)acetamidamine a) N_(6_{[6-(cyclopropylamino)[U,4]triazolo[ 4,3-b]t-7-3-yl]thio}_1,3-1,3-oxazol-2-yl)acetamide can be similar to the method of the example la, but with 3 〇〇 mg 3-[( 2-Amino-i,3-abido,yrazole-6-yl)thio]cyclopropyl[indenyl triazolo[4,3-7]indole-6-amine (24a) in 2_1 cubic The pyridine was started in iv·〇4 cubic centimeters of acetic anhydride and was prepared after 2 hours of reaction at 2 (TC). Thus, 145862-90-201040187 100 mg N-(6-{[6-(cyclopropylamino)) was obtained. [1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzopyrazol-2-yl)acetamide, in the form of a white powder. The characteristics are as follows: 1H NMR spectrum (400 MHz, DMSO-d6) δ ppm 0.34-0.45 (m, 2H) 0.61-0.74 (m, 2H) 2.19 (s, 3H) 2.53-2.58 (m, 1H) 6.77 (d , J = 9.5 Hz, 1H) 7 .53 (d, J = 8.3 Hz, 1H) 7.62-7.73 (m, 2H) 7.94 (d, J = 9.8 Hz, 1H) 8.19 (s, 1H) 12.38 (broad s, 1H) Mass Spectrometer: Waters UPLC-SQD : MH+ m/z = 398+ ; MH- = 396- 〇 Example 26: N-(6-{[6-(cyclopropylamino)[i,2,4]triazolo[4,3-b]哜-3·yl]thio}-l,3_benzo<» 塞 ° sit-2-yl) cyclopropanol ruthenium a) N-(6-{[6-(cyclopropylamino)[ ι,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzopyrazol-2-yl)cyclopropanecarboxamide can be similarly exemplified , but with 300 mg of 3-[(2-amino-1,3-benzopyrazol-6-yl)thio]-N-cyclopropyl[1,2,4]triazolo[4,3 -b] Tatricin-6-amine (24a) was prepared in 3 cubic centimeters of pyridine and 0.16 cubic centimeter of cyclopropane gasification ruthenium, and reacted at 20 ° C for 18 hours. Therefore 'obtained 208 mg of N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thiol 1,3- Benzooxazol-2-yl)cyclopropanecarboxamide, in the form of a white powder, characterized by the following: 1H NMR spectrum (400 MHz, DMSO-d6) δ ppm 0.34-0.44 (m, 2H) 0.62-0.73 (m , 2H) 0.89-1.01 (m, 4H) 1.93-2.03 (m, 1H) 2.52-2.61 (m, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.53 (dd, J = 8.6, 1.7 Hz, 1H ) 7.61-7.71 (m, 2H) 7.94 (d, J = 9.8)

Hz’ 1H) 8.19 (d, J = 1.5 Hz, 1H) 12.66 (寬廣 s, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 424+ ; MH- = 422- 145862 •91 - 201040187 實例27 : (環己胺基）***并[4,3_b]嗒畊各基]硫基}1，3笨并邊。坐-2-基)-3-[2-(嗎福啉_4_基）乙基獅 a) 1(6+6-(環己胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并4唾_2_基）各[2_(嗎福啉冰基）乙基]脲可以類似實例 lb之方式，但以3〇〇毫克H2_(嗎福啉_4基）乙基]各(6硫基-1，3-苯并4唾_2_基）脲（2b)、7 5立方公分經脫氣乙醇、〇.7立方公分水中之6毫克磷酸二氫鉀、552毫克DL_二硫基蘇糖醇及403毫克3-氣-N-環己基[1,2,4]***并[4,3-b]嗒畊-6-胺（18c) 開始而製成。因此’獲得370毫克1-(6-{[6-(環己胺基）[1，2,4]三。坐并[4,3-b]嗒畊-3-基]硫基卜1，3-苯并嘧唑_2_基）_3_[2-(嗎福啉-4-基）乙基]脲’呈白色粉末形式，其特徵如下： 1H NMR 光譜（4〇〇 MHz，DMSO-d6) <5 ppm 1.08-1.30 (m，5H) 1.47-1.70 (m，3H) 1.71-1.89 (m，2H) 2.32-2.46 (m，6H) 3.22-3.28 (經遮蔽之 m，2H) 3.36-3.52 (m, 1H) 3.59 (t, J = 4.3 Hz, 4H) 6.69-6.93 (m, 2H) 7.25 (d, J = 7.1 Hz, 1H) 7.35 (dd, J = 8.3, 2.0 Hz, 1H) 7.52 (d, J = 8.3 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d，J = 1.7 Hz, 1H) 10.90 (寬廣 s，1H) 質譜：Waters ZQ : MH+ m/z = 554+ ; MH- = 552-實例28 : N-(6-{[6-(環丙胺基)[1，2,4]***并[4,3-b]嗒畊-3·基]硫基}-l，3-苯并 p塞嗅-2-基)-3-曱氧基丙酿胺 a) 1^-(6-{[6-(環丙胺基）[1，2,4]***并[4,3七]嗒畊-3-基]硫基}-1,3-苯并碟唑-2-基）-3-曱氧基丙醯胺可以類似實例ia之方式，但以220毫克3-[(2-胺基-1，3-苯并嘍唑-6-基）硫基]-N-環丙 145862 -92- 201040187 基[1，2,4]***并[4,3-b]塔畊-6-胺（24a)在7立方公分吡啶與0.2立方公分氯化3-甲氧基丙酿中開始，於2〇。〇下反應18小時後製成。因此’獲得81毫克N-(6-{[6-(環丙胺基）[1,2,4]***并 [4,3-b]嗒畊-3-基]硫基}-l，3-苯并噻唑_2_基）_3_曱氧基丙醯胺，呈淡米黃色粉末形式，其特徵如下： 1H NMR 光譜（4〇〇 MHz，DMSO-d6) <5 ppm 0.33-0.43 (m, 2H) 0.62-0.73 (m, 2H) 2.53-2.59 (m, 1H) 2.73 (t, J = 6.1 Hz, 2H) 3.24 (s, 3H) 3.64 (t, J = 6.0 〇 Hz, 2H) 6.77 (d, J = 9.5 Hz, 1H) 7.53 (dd, J = 8.4,1.6 Hz, 1H) 7.68 (d, J = 8.6Hz' 1H) 8.19 (d, J = 1.5 Hz, 1H) 12.66 (broad s, 1H) Mass Spectrum: Waters UPLC-SQD: MH+ m/z = 424+; MH- = 422- 145862 •91 - 201040187 Example 27: (Cyclohexylamino)triazolo[4,3_b]indoles]thiol}1,3 stupid. Sodium-2-yl)-3-[2-(morpholine-4-yl)ethyl lion a) 1(6+6-(cyclohexylamino)[1,2,4]triazolo[4 , 3-b] indole-3-yl]thio}-1,3-benzo-4-salt-2-yl) each [2_(morpholineyl)ethyl]urea can be similar to the method of the example lb, But with 3 〇〇 mg of H 2 _ (morpholine _ 4 yl) ethyl] each (6 thio-1,3-benzo-4-salt-2-yl) urea (2b), 7 5 cubic centimeters of degassed ethanol , 毫克.7 cubic centimeters of water, 6 mg of potassium dihydrogen phosphate, 552 mg of DL-dithiothreitol and 403 mg of 3-gas-N-cyclohexyl[1,2,4]triazolo[4,3 -b] Made from sorghum-6-amine (18c). Thus 'obtained 370 mg of 1-(6-{[6-(cyclohexylamino)[1,2,4] tris. Sodium[4,3-b]indole-3-yl]thiopyran 1, 3-benzopyrazole-2-yl)_3_[2-(morpholine-4-yl)ethyl]urea' is in the form of a white powder which is characterized as follows: 1H NMR spectrum (4 〇〇 MHz, DMSO-d6) <5 ppm 1.08-1.30 (m,5H) 1.47-1.70 (m,3H) 1.71-1.89 (m,2H) 2.32-2.46 (m,6H) 3.22-3.28 (masked m, 2H) 3.36- 3.52 (m, 1H) 3.59 (t, J = 4.3 Hz, 4H) 6.69-6.93 (m, 2H) 7.25 (d, J = 7.1 Hz, 1H) 7.35 (dd, J = 8.3, 2.0 Hz, 1H) 7.52 (d, J = 8.3 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 1.7 Hz, 1H) 10.90 (broad s, 1H) Mass Spectrum: Waters ZQ : MH+ m/z = 554 + ; MH- = 552 - Example 28: N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thio }-l,3-Benzo-p-s-ol-2-yl)-3-decyloxypropanol a) 1^-(6-{[6-(cyclopropylamino)[1,2,4]3 Zizo[4,3-7]indole-3-yl]thio}-1,3-benzoxazol-2-yl)-3-decyloxypropionamide can be similar to the example ia, but 220 mg 3-[(2-Amino-1,3-benzoxazol-6-yl)thio]-N-cyclopropene 145862 -92- 20 1040187-based [1,2,4]triazolo[4,3-b]tung-6-amine (24a) begins in 7 cubic centimeters of pyridine with 0.2 cubic centimeters of 3-methoxypropyl chloride. 2〇. The underarm reaction was made after 18 hours. Thus 'obtained 81 mg of N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-l,3 -Benzothiazole-2-yl)_3_decyloxypropionamide, in the form of a pale beige powder, characterized by the following: 1H NMR spectrum (4 〇〇 MHz, DMSO-d6) <5 ppm 0.33-0.43 ( m, 2H) 0.62-0.73 (m, 2H) 2.53-2.59 (m, 1H) 2.73 (t, J = 6.1 Hz, 2H) 3.24 (s, 3H) 3.64 (t, J = 6.0 〇Hz, 2H) 6.77 (d, J = 9.5 Hz, 1H) 7.53 (dd, J = 8.4, 1.6 Hz, 1H) 7.68 (d, J = 8.6

Hz, 1H) 7.72 (d, J = 2.7 Hz, 1H) 7.96 (d, J = 9.8 Hz, 1H) 8.22 (d, J = 1.5 Hz, 1H) 12.46 (寬廣 s，ih) 質譜：Waters UPLC-SQD : MH+ m/z = 442+ 實例29 : H6-{[6-(環丙胺基）队训***并[4,3_b]嗒畊各基]硫基}1，3•苯并嘧唑-2-基)-3-[2-(嗎福啉-4·基）乙基爾 a) 1_(6_{[6-(環丙胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}- ❹ 1，3_苯并嘍唑-2-基）-3-[2-(嗎福啉-4-基）乙基]脲可以類似實例 lb之方式，但以3〇〇毫克嗎福啉*基）乙基]_3 (6硫基_ 1,3-苯并嘍唑_2_基）脲（2b) ' 12立方公分經脫氣乙醇、12立方公分水中之5毫克磷酸二氫鉀、41〇毫克DL_二硫基蘇糖醇及187毛克3-氣環丙基[ι，2,4]三唾并[4,3七>荅p井-6-胺（24b) 開始，於8(TC下18小時後製成。因此，獲得133毫克h6_ {[6-(環丙胺基）[^4]***并[4,3七]嗒P井各基]硫基H 3苯并嘧唑-2-基嗎福啉氺基）乙基]脲，呈乳白色粉末形式，其特徵如下： 145862 -93- 201040187 1H NMR 光 §普（400 MHz, DMSO-d6CD3COOD) δ ppm 0.36-0.49 (m, 2H) 0.65-0.82 (m, 2H) 2.57-2.65 (m, 1H) 2.96-3.16 (m, 6H) 3.50 (t, J = 5.7 Hz, 4H) 3.79 (寬廣 s, 2H) 6.79 (d, J = 9.8 Hz, 1H) 6.90-7.05 (m, 1H) 7.48-7.63 (m，2H) 7.66 (寬廣 s, 1H) 7.91 (d, J = 9.8 Hz，1H) 8.16 (s, 1H) 質譜：WatersUPLC-SQD·· MH+m/z = 512+; MH- = 510-實例30 : N-(6-{[6-(環丙胺基)[l，2,4]***并[4,3-b]嗒畊.3·基]硫基}·1，3-苯并嘧唑-2-基)-Ν2，Ν2 -二甲基甘胺醯胺 a) 义(6-{[6-(環丙胺基）[1，2,4]***并[4,3-13]嗒畊-3-基]硫基}-1,3-苯并噻唑-2-基）-N2,N2-二曱基甘胺醯胺可以類似實例ia 之方式’但以220毫克3-[(2-胺基-1,3-苯并嘧唑-6-基）硫基]-N-環丙基[1，2,4]***并[4,3-b]塔畊-6-胺（24a)，在8立方公分二氣甲烧中，使用197毫克氣化N，N-二甲基甘胺醯鹽酸鹽與0.26 立方公分三乙胺開始’於2〇。〇下反應18小時後製成。因此，獲得167毫克N-(6-{[6-(環丙胺基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并p塞唾-2-基）-N2，N2 -二曱基甘胺醯胺，呈淡米育色粉末形式，其特徵如下： 1H NMR 光譜（500 MHz, DMSO-d6) (5 ppm 0.39 (寬廣 s，2H) 0.69 (d，J =5.2 Hz，2H) 2.29 (s，6H) 2.52-2.59 (m，1Η) 3.10-3.25 (經遮蔽之 m，2H)Hz, 1H) 7.72 (d, J = 2.7 Hz, 1H) 7.96 (d, J = 9.8 Hz, 1H) 8.22 (d, J = 1.5 Hz, 1H) 12.46 (broad s, ih) Mass Spectrometer: Waters UPLC-SQD : MH+ m/z = 442+ Example 29: H6-{[6-(cyclopropylamino) team-trained triazolo[4,3_b] sorghum base]thio}1,3•benzopyrazole-2 -yl)-3-[2-(morpholin-4-yl)ethyler a) 1_(6_{[6-(cyclopropylamino)[1,2,4]triazolo[4,3- b] 嗒-3-yl]thio]- ❹ 1,3_benzoxazol-2-yl)-3-[2-(morpholine-4-yl)ethyl]urea can be similar to the example lb Way, but with 3 〇〇 mg of morpholinol* yl)ethyl]_3 (6 thio-1,3-1,3-benzoxazole-2-yl)urea (2b) '12 cubic centimeters by degassed ethanol, 5 mg of potassium dihydrogen phosphate, 41 〇 mg of DL-dithiothreitol and 187 g of 3-cyclohexyl propyl [1,3,7] in 12 cubic centimeters of water荅p well-6-amine (24b) was started and made at 8 (TC) after 18 hours. Therefore, 133 mg of h6_{[6-(cyclopropylamino)[^4]triazolo[4,3-7 was obtained.嗒P well base] thio-based H 3 benzopyrazol-2-ylmorpholine fluorenyl)ethyl]urea, in the form of a milky white powder, characterized as follows: 145862 -93- 201040187 1H NMR Light § Pu (400 MHz, DMSO-d6CD3COOD) δ ppm 0.36-0.49 (m, 2H) 0.65-0.82 (m, 2H) 2.57-2.65 (m, 1H) 2.96-3.16 (m, 6H) 3.50 (t, J = 5.7 Hz, 4H) 3.79 (broad s, 2H) 6.79 (d, J = 9.8 Hz, 1H) 6.90-7.05 (m, 1H) 7.48-7.63 (m, 2H) 7.66 (broad s, 1H) 7.91 (d , J = 9.8 Hz, 1H) 8.16 (s, 1H) Mass Spectrum: WatersUPLC-SQD·· MH+m/z = 512+; MH- = 510-Example 30: N-(6-{[6-(Cyclopropylamine) Base)[l,2,4]triazolo[4,3-b]indole.3·yl]thio}·1,3-1,3-pyrazol-2-yl)-Ν2,Ν2-dimethyl Glysamine amide a) Sense (6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-13]indole-3-yl]thio}-1, 3-Benzothiazol-2-yl)-N2,N2-dimercaptoamine amide can be similar to the procedure of Example ia' but with 220 mg of 3-[(2-amino-1,3-benzopyrazole) -6-yl)thio]-N-cyclopropyl[1,2,4]triazolo[4,3-b]tac-6-amine (24a), in 8 cm ^ 2 gas Using 197 mg of gasified N,N-dimethylglycine hydrazine hydrochloride with 0.26 cubic centimeters of triethylamine began at 2 Torr. The underarm reaction was made after 18 hours. Thus, 167 mg of N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3 was obtained. -Benzo-p-sial-2-yl)-N2,N2-diglycidylguanamine, in the form of a light beige coloring powder, characterized by the following: 1H NMR spectrum (500 MHz, DMSO-d6) (5 ppm 0.39 (broad s, 2H) 0.69 (d, J = 5.2 Hz, 2H) 2.29 (s, 6H) 2.52-2.59 (m, 1Η) 3.10-3.25 (masked m, 2H)

6.77 (d, J = 9.6 Hz, 1H) 7.53 (d, J = 8.2 Hz, 1H) 7.61-7.74 (m, 2H) 7.95 (d, J =9.6 Hz, 1H) 8.20 (s，1H) 12.06 (寬廣 s，1H) 質譜：WatersUPLC-SQD: MH+m/z = 441+; MH- = 439-實例31 : 3-[(2·胺基-1，3-苯并嚓唑_6-基）硫基]·Ν_環己基-7,8-二氫[1，2,4]三 -94- 145862 201040187 唑并[4,3-b]嗒畊-6-胺 a) 3-[(2·胺基-1，3-苯并嘧唑-6-基）硫基]-N-環己基-7,8-二氫 [U，4]二唾并[4,3-b]塔啡-6-胺可以類似實例lb之方式，但以 250毫克硫氰酸2-胺基_1，3_苯并嘍唑_6_基酯、8立方公分經脫氣乙醉、0.8立方公分水中之6毫克磷酸二氫鉀、66〇毫克DL-二硫基蘇糖醇及3〇6毫克3_氯_N_環己基***并 [4,3-b]嗒畊-6-胺開始而製成《因此，獲得2〇2毫克3_[(2_胺基_ 1，3-苯并P塞唾-6-基）硫基]-N-環己基_7,8_二氫[U4]***并[4,3_b] ❹ 嗒畊各胺，呈乳白色粉末形式，其特徵如下： 1H NMR 光譜（4〇〇 MHz, DMSO-d6) 6 ppm 1.00-1,35 (m，5H) 1.48-1.74 (m, 3H) 1.78-1.90 (m, 2H) 2.56 (t, J = 7.7 Hz, 2H) 2.96 (t, J = 7.7 Hz, 2H) 3.45-3.55 (m，1H) 7.08 (d，J = 7.6 Hz，1H) 7.16-7.37 (m，2H) 7.66 (寬廣 s， 2H) 7.81 (s, 1H) 質譜：Waters UPLC-SQD : MH+ m/z = 400+ ; MH- = 398- b) 3_氣-N-環己基-7,8-二氫[1，2,4]***并[4,3-b]嗒畊-6-胺可以下述方式製成：將1.3克鋅粉於20°C下添加至16立方公分冰醋酸中之5〇〇毫克3-氣-N-環己基[1，2,4]***并[4,3-b]»荅啡-6-胺（18c)内。在攪拌 • 2小時後’使此懸浮液經過濾紙過濾，並使濾液於減壓下 .濃縮至乾酒。所獲得之固體殘留物係藉乾燥沉積於Bi〇tage6.77 (d, J = 9.6 Hz, 1H) 7.53 (d, J = 8.2 Hz, 1H) 7.61-7.74 (m, 2H) 7.95 (d, J = 9.6 Hz, 1H) 8.20 (s, 1H) 12.06 (wide) s,1H) Mass Spectrum: WatersUPLC-SQD: MH+m/z = 441+; MH- = 439-Example 31: 3-[(2·Amino-1,3-benzoxazole-6-yl)sulfide ]]·Ν_cyclohexyl-7,8-dihydro[1,2,4]tri-94- 145862 201040187 oxazo[4,3-b]indole-6-amine a) 3-[(2· Amino-1,3-benzopyrazol-6-yl)thio]-N-cyclohexyl-7,8-dihydro[U,4]disialo[4,3-b] talactin-6 - The amine can be similar to the example lb, but with 250 mg of 2-amino-1,3-benzoxazole-6-yl thiocyanate, 8 cubic centimeters of degassed, and 6 cubic centimeters of water Made from milligrams of potassium dihydrogen phosphate, 66 mg of DL-dithiothreitol and 3〇6 mg of 3-chloro-N-cyclohexyltriazolo[4,3-b]indole-6-amine "Therefore, 2 〇 2 mg of 3_[(2_amino-1 1,3-benzo-Pessa-6-yl)thio]-N-cyclohexyl_7,8-dihydro[U4]triazole was obtained. And [4,3_b] ❹ 各各、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、 m, 3H) 1.78-1.90 (m, 2H) 2.56 (t, J = 7.7 Hz, 2H) 2.96 (t, J = 7.7 Hz, 2H) 3.45-3.55 (m, 1H) 7.08 (d, J = 7.6 Hz, 1H) 7.16-7.37 (m, 2H) 7.66 (broad s, 2H) 7.81 (s, 1H) Mass Spectrometry: Waters UPLC-SQD: MH+ m/z = 400+ ; MH- = 398- b) 3_Gas-N-Cyclohexyl-7,8-II Hydrogen [1,2,4]triazolo[4,3-b]indole-6-amine can be prepared in the following manner: 1.3 g of zinc powder is added to 16 cubic centimeters of glacial acetic acid at 20 ° C. 5 mg of 3-oxo-N-cyclohexyl[1,2,4]triazolo[4,3-b]»indan-6-amine (18c). After stirring for 2 hours, the suspension was filtered through a filter paper, and the filtrate was concentrated under reduced pressure to dryness. The solid residue obtained is deposited by dry deposition on Bi〇tage

Quad 12/25藥筒（KP-SIL ’ 6〇Α ; 32·63 #M)上，於石夕膠上藉層析純化，以二氯甲烷/甲醇之95/5至90/10梯度液溶離。因此，獲得317毫克3-氯-N-環己基-7,8-二氫[1，2,4]***并[4,3-b]。荅畊-6-胺’呈白色粉末形式，其特徵如下： 145862 •95- 201040187 質譜：Waters UPLC-SQD : MH+ m/z = 254+ ; ΜΗ- = 252-實例32 : (6-{[6·(環己基氧基Π1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）胺基甲酸乙酯 a) (6-{[6-(環己基氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基卜 1,3-苯并嘧唑-2-基）胺基甲酸乙酯可以下'述方式製成：於20°C下，將7立方公分乙醇中之320毫克硫氰酸2-[(嗎福啉-4-基羰基）胺i ]-1,3-苯并嘧唑-6-基酯（32b)放置在裝有攪拌器之10立方公分微波小玻瓶中。使氧氣流起泡經過混合物，歷經5分鐘，接著添加0.25立方公分水中之408毫克磷酸二氫鉀、463毫克DL-二硫基蘇糖醇及252毫克3-氯基-6-(環己基氧基）[U，4]***并[4,3-b]嗒畊（lc)。將混合物在微波爐中於120°C下攪拌1小時。然後，使反應混合物在真空下濃縮至乾涸，接著，固體殘留物係藉固體沉積，於Merck矽膠藥筒上，藉二次連續層析純化，以二氣曱烷/曱醇之99/1至 97/3梯度液溶離。因此，獲得77毫克（6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）胺基甲酸乙酯，呈白色固體形式，其特徵如下：質譜：LC/MS電喷霧於Waters UPLC-SQD上：滯留時間Rt (分鐘）=1.06 ; [M+H]+ : m/z471 ; [M-H]- : m/z469 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 1.15 至 1.40 (m， 8H) ; 1.42 至 1.64 (m，3H) ; 1.79 (d，J = 13.2 Hz, 2H) ; 4.24 (q，J = 7.1 Hz, 2H) ; 4.67 (m，1H) ; 7.02 (d，J = 9,8 Hz, 1H) ; 7.39 (dd，J = 1.8 與 8.2 Hz, 1H) ； 7.62 (d, J = 8.6 Hz, 1H) ； 8.05 (s, 1H) ； 8.28 (d, J = 9.8 Hz, 145862 -96- 201040187 1H); 12.06(寬廣 S，1H) b)硫氰酸2_[(嗎福啉-4-基羰基）胺基]_1，3_苯并嘍唑各基酯可以類似實例2c之方式，但以2 29克（6氰硫基u苯并噻口坐-2-基）胺基甲酸苯酿⑽在7〇立方公分四氫咬喃與幢立方公分嗎福琳之混合物中開始，於贼下製成，歷經則、蚪。因此，獲和*2.12克硫氰酸2_[(嗎福啉斗基羰基）胺基]n 苯并嘧唑-6-基酯，呈白色固體形式，其特徵如下： f 譜：Waters UPLC-SQD :滞留時間 Rt (分鐘）=0.73 ; [m+h]+ : m/z 321 ； [M-H]-： m/z319 實例33 : 2-氣具(6-{[6-(環己基氧基）[咖王吐并[4,3.吵荅p井各基]硫基卜 1，3-苯并《«塞唑-2-基）乙醯胺 a) 2·氣-N_(6-{[6-(環己基氡基）[12,4]***并[4,3 b]嗒畊冬基] 硫基}-1’3-苯并噻唑_2-基）乙醯胺可以下述方式製成：於〇-5°C下，將〇.1立方公分氣化氯乙醯逐滴添加至2立方〇公分二氯甲烷與〇.5立方公分吡啶中之200毫克6-{[6-(環己基氧基）[1，2,4]***并[4,3七]嗒畊各基]硫基H，3_.并嘍唑_2_胺 (lb)内。將所形成之溶液在2〇它下攪拌3〇分鐘，然後，使媒質於氬氣及20。(：下蒸發至乾涸。殘留物係藉固體沉積，於Merck矽膠藥筒上，藉層析純化，以1〇〇%二氣甲烷至92/8 二氯甲烷/(二氯甲烷：38/曱醇：17/氨水：2)之梯度液溶離。於醚中配成漿液及在真空下乾燥後，獲得1〇2毫克孓氯_ N-(6-{[6-(環己基氧基）[nq***并[4,3七]嗒畊各基]硫基卜I)苯并嘧唑-2-基）乙醯胺，呈白色固體形式，其特徵如下： 145862 -97- 201040187 質譜：Waters UPLC-SQD :滯留時間 Rt (分鐘）=1.03 ; [M+H]+ : m/z 475 [M-H]- *· m/z 473 1H NMR 光譜（400 MHz, 6 以 ppm 表示，DMSO-d6) : 1.10 至 1.38 (m， 5H) ; 1·41 至 1.65 (m，3H) ; 1.77 (m，J = 12.2 Hz，2H) ; 4.44 (s，2H); 4.66 (m, 1H) ； 7.03 (d, J = 9.8 Hz, 1H) ； 7.42 (dd, J = 2.0 ^ 8.6 Hz, 1H)； 7.70 (d, J = 8.6 Hz, 1H) ； 8.08 (d, J = 2.0 Hz, 1H) ； 8.29 (d, J = 10.0 Hz, 1H) ; 12.75 (寬廣 s，1H) 實例34 : Ν-(6·{[6-(環己基氧基)[1，2,4]三也并[4,3-b]。答，井-3-基]硫基}·1，3-苯并嘧唑-2-基）-Ν2·環丙基甘胺醯胺 a) 叫6-{[6-(環己基氧基）[1，2,4]***并[4,3-1)]塔畊-3-基]硫基}- 1.3- 苯并違唾-2-基）-N2-環丙基甘胺醯胺可以下述方式製成：於20°C下’將0.35立方公分環丙基胺添加至4立方公分吡啶中之280毫克2-氯-N-(6-{[6-(環己基氧基似,2,4]***并[4,3-b] 塔啩-3-基]硫基卜1,3-苯并嘧唑-2-基）乙醯胺（33)内。在攪拌5 小時後’使反應媒質於20 C下蒸發至乾涸。殘留物係藉固體沉積’於Merck石夕膠藥筒上’藉層析純化，以二氣曱烧至97/3 一氯曱烧/曱醇之梯度液溶離。因此，獲得n〇毫克N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3七]嗒畊-3-基]硫基}_ 1.3- 苯并塞唑-2-基）-N2-環丙基甘胺醯胺，呈黃色固體形式，其特徵如下：貝 s善.Waters UPLC-SQD .滯留時間 Rt (分鐘）=0.74 ; [M+H]+ : m/z 496 ； [M-H]- ： m/z 494 1H NMR 光譜（400 ΜΗζ，ά 以 ppm 表示，DMSad6) ·· 〇 19 至〇 4〇 (m 145862 -98 - 201040187 4H) ; U4 至 1.26 (m，3H) ; 1.33 (m，2H) ; 1.41 至 1.66 (m，3H) ; 1.78 (m，2H) ; 2.17 (m，1H) ; 3.51 (s，2H) ; 4.60 至 4.72 (m，1H) ; 7.03 (d，J = 9.8 Hz, 1H) ; 7.41 (dd, J = 1.5 與 8.3 Hz，1H) ; 7,68 (d，J = 8.8 Hz，1H); 8.08 (s, 1H) ； 8.28 (d, J = 9.8 Hz, 1H) 實例35 : 6-{[6-(環丁基氧基）H4]***并[4,3-b]嗒畊-3-基]硫基}-l，3-苯并嘍唑·2-胺The Quad 12/25 cartridge (KP-SIL '6〇Α; 32·63 #M) was purified by chromatography on Shixia gel and dissolved in a gradient of 95/5 to 90/10 of dichloromethane/methanol. . Thus, 317 mg of 3-chloro-N-cyclohexyl-7,8-dihydro[1,2,4]triazolo[4,3-b] was obtained.荅耕-6-amine' is in the form of a white powder with the following characteristics: 145862 • 95- 201040187 Mass: Waters UPLC-SQD: MH+ m/z = 254+; ΜΗ- = 252-Example 32: (6-{[6 ·(Cyclohexyloxyindole 1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3-benzopyrazol-2-yl)carbamic acid Ester a) (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-7]indole-3-yl]thiopyrim 1,3-benzopyrazole -2-yl)ethyl carbamate can be prepared as follows: 320 mg of 2-[(hofolin-4-ylcarbonyl)amine thiocyanate in 7 cubic centimeters of ethanol at 20 °C i]-1,3-benzopyrazole-6-yl ester (32b) was placed in a 10 cm3 microwave vial equipped with a stirrer. The oxygen stream was bubbled through the mixture over 5 minutes, followed by 408 mg of potassium dihydrogen phosphate, 463 mg of DL-dithiothreitol and 252 mg of 3-chloro-6-(cyclohexyloxy) in 0.25 cubic centimeters of water. Base) [U,4]triazolo[4,3-b]indole (lc). The mixture was stirred in a microwave oven at 120 ° C for 1 hour. Then, the reaction mixture was concentrated under vacuum to dryness. Then, the solid residue was deposited on a Merck gel cartridge and purified by a second continuous chromatography to a mixture of dioxane / methanol to 99/1. The 97/3 gradient was dissolved. Thus, 77 mg (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3- Ethyl benzopyrazol-2-yl)carbamate, as a white solid, characterized as follows: Mass Spectrum: LC/MS electrospray on Waters UPLC-SQD: retention time Rt (minutes) = 1.06; [M +H]+ : m/z471 ; [MH]- : m/z469 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.15 to 1.40 (m, 8H); 1.42 to 1.64 (m, 3H) ; 1.79 (d, J = 13.2 Hz, 2H); 4.24 (q, J = 7.1 Hz, 2H); 4.67 (m, 1H); 7.02 (d, J = 9,8 Hz, 1H); 7.39 (dd , J = 1.8 and 8.2 Hz, 1H); 7.62 (d, J = 8.6 Hz, 1H); 8.05 (s, 1H); 8.28 (d, J = 9.8 Hz, 145862 -96- 201040187 1H); 12.06 (wide S,1H) b) 2 -[(hhofolin-4-ylcarbonyl)amino] _1,3-benzoxazole thiocyanate can be similar to the method of Example 2c, but with 2 29 g (6 cyanide) Sulphur-based thiobenzopyranoyl-2-yl) carbamic acid benzene (10) is started in a mixture of 7 〇 cubic centimeters of tetrahydroanthene and a cubic centimeter of whallin, made under the thief, after the thief, 蚪. Thus, *2.12 g of thiocyanate 2-[(fofolin phenylcarbonyl)amino]n benzopyrazole-6-yl ester was obtained as a white solid with the following characteristics: f Spectrum: Waters UPLC-SQD : residence time Rt (minutes) = 0.73; [m+h]+: m/z 321 ; [MH]-: m/z319 Example 33: 2-gas (6-{[6-(cyclohexyloxy)) [Cai Wang spit and [4,3. 荅荅井各 ] ] ] ] 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- 1,3- « 1,3- 1,3- 1,3- 1,3- · · · · · · · · · · · · · · · · · 6-(cyclohexylfluorenyl)[12,4]triazolo[4,3 b]indole winter base]thio}-1'3-benzothiazol-2-yl)acetamide can be obtained in the following manner Manufactured: Add 〇.1 cubic centimeter of gasified chloroacetate dropwise to 2 cubic centimeters of methylene chloride and 200.5 cubic centimeters of pyridine 200 mg 6-{[6- at 〇-5 °C (Cyclohexyloxy)[1,2,4]triazolo[4,3-7]indolyl]thiol H,3_. and carbazole-2-amine (lb). The resulting solution was stirred under 2 Torr for 3 Torr, and then the medium was allowed to pass argon and 20. (: Evaporate to dryness. The residue is deposited by solids on a Merck gel cartridge, purified by chromatography, with 1% di-methane to 92/8 dichloromethane/(dichloromethane: 38/曱) Alcohol: 17/Ammonia: 2) Gradient solution is dissolved. After slurring in ether and drying under vacuum, 1 2 mg of chloro-N-(6-{[6-(cyclohexyloxy)[ Nq triazolo[4,3-7] 嗒各】 thiophene I) benzopyrazol-2-yl)acetamide, in the form of a white solid, characterized as follows: 145862 -97- 201040187 Mass Spectrometry: Waters UPLC-SQD: residence time Rt (minutes) = 1.03; [M+H]+: m/z 475 [MH]-*· m/z 473 1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6) : 1.10 to 1.38 (m, 5H) ; 1·41 to 1.65 (m, 3H); 1.77 (m, J = 12.2 Hz, 2H); 4.44 (s, 2H); 4.66 (m, 1H) ; 7.03 (d , J = 9.8 Hz, 1H); 7.42 (dd, J = 2.0 ^ 8.6 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1H); 8.29 (d , J = 10.0 Hz, 1H); 12.75 (broad s, 1H) Example 34: Ν-(6·{[6-(cyclohexyloxy)[1,2,4]tri-[4,3-b Answer, well-3-yl]thio}·1,3-benzopyrazole -2-yl)-Ν2·cyclopropylglycine amide a) is called 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-1)] -3-yl]thio}-1.3-benzoin-2-yl)-N2-cyclopropylglycine decylamine can be prepared in the following manner: '0.35 cubic centimeters of cyclopropyl group at 20 ° C The amine is added to 280 mg of 2-chloro-N-(6-{[6-(cyclohexyloxy-like, 2,4]triazolo[4,3-b] tau-3- in 4 cubic centimeters of pyridine In the thiol 1,3-benzopyrazol-2-yl)acetamide (33). After stirring for 5 hours, the reaction medium was evaporated to dryness at 20 C. The residue was deposited by solids. Purified by chromatography on Merck's gelatin cartridge, and immersed in a gas chromatographic solution of 97/3 chlorohydrazine/sterol. Thus, n 〇 mg N-(6-{[6- (cyclohexyloxy)[1,2,4]triazolo[4,3-7]indole-3-yl]thio}_ 1.3-benzoxazol-2-yl)-N2-cyclopropyl Glycineamine, in the form of a yellow solid, has the following characteristics: Bes Shan. Waters UPLC-SQD. Retention time Rt (minutes) = 0.74; [M+H]+: m/z 496 ; [MH]- : m /z 494 1H NMR spectrum (400 ΜΗζ, ά expressed in ppm, DMSad6) ·· 〇19 to 〇4〇(m 145862 -98 - 201040187 4H) ; U4 to 1.26 (m,3H) ; 1.33 (m,2H) ; 1.41 to 1.66 (m,3H) ; 1.78 (m,2H) ; 2.17 (m,1H) ; 3.51 (s , 2H); 4.60 to 4.72 (m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.41 (dd, J = 1.5 and 8.3 Hz, 1H); 7,68 (d, J = 8.8 Hz, 1H); 8.08 (s, 1H); 8.28 (d, J = 9.8 Hz, 1H) Example 35: 6-{[6-(cyclobutyloxy)H4]triazolo[4,3-b]indole Phenyl-3-yl]thio}-l,3-benzoxazole·2-amine

a) 6-{[6-(環丁基氧基）[1，2,4]***并[4,3七]嗒畊-3-基]硫基}-Q 1,3-苯并噻唑_2_胺可以類似實例lb之方式，但以1〇7克硫氰酸2-胺基-1，3-苯并嚓唑_6-基酯、15立方公分經脫氣乙醇、 0.1立方公分水中之2〇毫克構酸二氫鉀、〖99克DL_二硫基蘇糖醇及964毫克3-氯基-6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒 11井開始而製成。因此，獲得u克6_丨[6_(環丁基氧基儿^^三 11 坐并[4,3-b]塔畊-3-基]硫基卜ι，3_苯并噻唑_2_胺，呈帶白色粉末形式，其特徵如下： Q 質譜：Waters ZQ :滯留時間 Rt (分鐘）=3.39 ; [M+H]+ : m/z 371 ； [M-H]- ： m/z369 1H NMR 光譜（400 ΜΗζ，δ 以 ppm 表示，DMSO-d6) ·· 1.66 (m，1H); 1.80 (m，1H) ; 2.01 至 2.13 (m，2H) ; 2.31 至 2.40 (m，2H) ; 4.96 (qd，J = . 7.1 與 7.3 Hz, 1H) ; 7.04 (d，Jf = 9.8 Hz，1H) ; 7.29 (d，J = 8.3 Hz, 1H); 7.34 (dd，J = 2.0 與 8.6 Hz，1H) ; 7.62 (s，2H) ; 7.88 (d，J = 1.7 Hz，1H); 8.26 (d, J = 9.8 Hz, 1H) b) 3-氯基-6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊可以類似實例1C之方式，但以1〇立方公分四氫呋喃中之954毫克 145862 •99- 201040187 環丁醇、317毫克在60%下於；由中之氯化納及m6_二氣 [1，2,4]***开[4’3-b]嗒啡（市購）開始而製成。因此，獲得1〇3 克3-氣基-6-(環丁 ^氧基）[咖王嗤并[4,3补答呼，呈米黃色粉末形式，其特徵如下：爾MR光譜（彻廳，d以鹏表示，DMS〇d6): 163至i96(m， 2H) ; 2.07 至 2.24 (m，2H) ; 2.41 至 2 52 (經部份遮蔽之取 2H); 4.95 至 5.34 (m，1H) ; 7.10 (d，J = 9.8 Hz，1H) ; 8.28 (d，J = 9.8 Hz，1H) 實例36 : N-(6-{[6-(環丁基氧基）[i，2,4]***并[4,3叫嗒畊_3_基]硫基} ^-苯并嘧唑-2-基）-2-(4-乙基六氫吡畊小基）乙醯胺 a) N-(6-U6-(環丁基氧基）[U，4]***并[4 3_b]嗒畊各基]硫基}_ 1，3-苯并嘧唑_2_基）-2-(4-乙基六氫吡啡+基）乙醯胺可以下述方式製成：將273毫克（4-乙基六氫吡畊小基）醋酸（市購）、〇28立方公分二異丙基乙胺及411毫克六氟磷酸〇_(7_氮苯并***小基）_ Ν’Ν，Ν|，Ν|-四曱基錁（HATU)在3立方公分凡队二曱基曱醯胺中之20 C下之合物於20 C下授拌1小時。將2〇〇毫克6-{[6-(環丁基氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基}_1，3_苯并，塞唑_2_ 胺（35a)添加至反應媒質中。18小時後，將溶液倒入冰水中及;慮出〉儿殿物。使經早離之黃色糊劑溶於90/10醋酸乙酉曰/曱醇混合物中。將所獲得之溶液以硫酸鎂脫水乾燥，過濾，然後在真空下濃縮至乾涸。使油狀殘留物於Sp〇T n 上’在矽膠藥筒（SVF D26 Si60 ; 15-40 //Μ ; 25克）上藉層析純化’以％/4二氣曱烷/曱醇至100%甲醇之梯度液溶離。因 145862 •100· 201040187 此’獲得127毫克N-(6-{[6-(環丁基氧基）[HA***并[4,3_b]嗒畊-3-基]硫基}-1，3-苯并噏唑_2_基）_2_(4_乙基六氮吡畊小基）乙醯胺’呈黃色粉末形式’其特徵如下：質譜.Waters ZQ滯留時間Rt (分鐘卜3 1〇 ; [M+H]+ : _仍； [M-H]- ： m/z 523 1H NMR 光 §晋（400 ΜΗζ，δ 以 ppm 表示，DMS〇_d6):丄〇〇 (t，j = 7 2 Hz, 3H)，1.59 (m，1H) ; 1.73 (m，1H) ; 1.94 至 2.09 (m, 2H) ; 2.20 至 ◎ 2.31 (m，2H) ’ 2.32 至 2.58 (經部份遮蔽之 m, 1〇H) ; 3.34 (s，2H); 4.90 (m, 1H) ’ 7.06 (d，J = 9.8 Hz，1H) ; 7.48 (dd，J = 1.8 與 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H) ； 8.14 (d, J =： 1.8 Hz, 1H) ； 8.30 (d, J = 9.8 Hz, 1H) ; 12.12 (極寬廣 m，1H) 實例37 : N-(6-{[6-(環丁基氧基）[“⑷***并[4,3_b]嗒畊·3_基]硫基}#苯并p塞吐-2-基）-N2，N2 _二乙基甘胺酿胺 a) 環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 Ο I，3笨并P塞唑_2_基）_N2，N2_二乙基甘胺醯胺可以下述方式製成：將827毫克（二乙胺基）醋酸鈉（市購）在5.5立方公分氯化氫在醚中之2N溶液内之混合物於20它下攪拌i小時。使所形成之懸浮液在真空下蒸發至乾涸。將8立方公分毗啶、2〇〇毫克6-{[6-(環丁基氧基）[ι，2,4]***并[4,3七]嗒畊_3_基戚基卜n 苯并嘍唑-2-胺（35a)及1.03克N-(3-二甲胺基丙基）N._乙基碳化一亞胺鹽酸鹽，於20°c下，添加至所獲得之白色殘留物中。5小時後，使褐色反應媒質蒸發至乾涸。使殘留物溶 145862 201040187 於甲苯中，並使混合物在真空下再一次蒸發至乾涸。使殘留物溶於水中，且以醋酸乙酯萃取混合物’然後蒸發至乾涸。將殘留物於矽膠上藉乾燥沉積純化’並在Biotase Quad 12/25藥筒（KP-SIL，6〇A ; 32-63 //Μ)上層析’以二氯甲烷/甲醇之100/0至98/2梯度液溶離。因此，獲得135毫克N-(6-{[6-(環丁基氧基）[1,2,4]***并[4,3-b]嗒畊各基]硫基}-l，3-苯并嘧唑-2-基）-N2，N2-二乙基甘胺醯胺，呈米黃色粉末形式，其特徵如下：質譜：Waters UPLC-SQD :滯留時間 Rt (分鐘）=〇.72 ; [M+H]+ : m/z 484 ; [M+2H]2+ : m/z 242.5 (基峰）；[M-H]- : m/z 482 1H NMR 光譜（400 ΜΗζ，δ 以 ppm 表示，DMSO-d6) : 1.00 (t，J = 7.2 Hz, 6H) ; 1.52 至 1.66 (m，1H) ; 1·68 至 1·80 (m，1H) ; 1.95 至 2.09 (m， 2H) ; 2.20 至 2.31 (m，2H) ; 2.62 (q，J = 7.2 Hz，4H) ; 3.40 (s，2H) ; 4.90 (m，1H) ; 7.06 (d，J = 9·8 Hz，1H) ; 7.47 (dd，J = 1.9 與 8.5 Hz, 1H) ; 7.69 (d, J = 8.5 Hz, 1H) ； 8.13 (d, J = 1.9 Hz, 1H) ； 8.29 (d, J = 9.8 Hz, 1H)； 11.54(極寬廣 m，lH) 藉由類似上文實例所製成之其他實例及其中間物係描述於下表：實例名稱類似以下實例製備：以下列開始：經單離之量 ----— 38 --------- N-(6-{[6-(環庚基氧基） 3·基]硫基丨-1，3-苯并噻°坐_ la 86毫克6-{[6-(環庚基氧基） [1，2,4]三0坐并[4,3七]°荅畊-3-基] 硫基} -1,3-苯并嘧唑-2-胺(16a) 52毫克基)環丙院缓醯胺與44毫克環丙坑氣化醯 145862 • 102- 201040187 39 H6-{[6-(環己胺基)[i，2,4] ***并[4,3-1>]»荅》井-3-基]硫基卜1，3-笨并喳唑-2-基)·3-[3-(嗎福淋斗基)丙基姆 lb 105毫克3-氣-N-環己基[1,2,4] ***并[4,3-b]嗒畊-6-胺(18c)與 155毫克硫氱酸2-({[3-(嗎福啉-4-基)丙基]胺曱醯基}胺基)-1,3-苯并嘧唑-6-基酯(39b) 168毫克 39b 硫氰酸2-({ [3-(嗎福琳-4-基)丙基]胺曱醯基}胺基)_ 1,3-苯并遠。全-6-基酯 2c 500毫克(6-氱硫基-1,3-苯并嘧唑-2-基)胺基甲酸苯酯(2d)與 264毫克N-(3-胺基丙基)嗎福啉(市購） 634毫克 40 1-(6-{[6-(環己基氡基） :1，2,4]***并[4,3七]。荅口井-3-基]硫基卜1，3-苯并v)墓。坐_ 2_基)-3-[3-(嗎福Φ4-基)丙基]脲 lb 200毫克3-氣基-6-(環己基氧基)[1，2,4]***并[4,3-b]嗒畊 (lc)與299毫克硫氰酸2-({[3-(嗎福啉-4-基)丙基]胺曱醯基} 胺基)-1,3-苯并嘧唑-6-基酯 (39b) 149毫克 41 1- (6-{[6-(環丁基氧基） [1，2,4]***并[4,3-b>荅畊-3-基]絲H，3-苯并魂嗤_ 2- 基)-3-[2-(嗎福參4-基)乙基]脲 2a 200毫克3-氣基-6-(環丁基氧基)[1，2,4]***并[4,3-b]嗒畊 (3Sb)與422毫克1-[2-(嗎福淋-4-基)乙基]-3-(6-硫基-1,3-苯并嘧唑-2-基)脲(2b) 245毫克 42 外消旋-1 -〇(嗎福〇林-4-基）乙基]-3-{6-[(6-{[反式-4-(三氟曱基)環己基]氧基} [1，2,4]***并[4,3-b]嗒畊-3-基)硫基]-1，3-苯并》塞唑-2-基}脲 2a 200毫克外消旋-3-氣基-6- {[反式-4-(三氟甲基)環己基]氧基}[1，2,4]***并[4,3-b]嗒畊 (42b)與295毫克1-[2-(嗎福淋-4_基)乙基]-3-(6-硫基-1，3-苯并嘧唑-2-基)脲(2b) 199毫克 42b 外消旋-3-氣基-6-{[反式-4-(三氟曱基)環己基]氧基} [1，2,4]***并[4,3-b]塔畊 lc 1 克3,6-二氣[1，2,4]***并[Μ-ΐ?] 嗒畊(市購)與2.19克外消旋-反式-4-(三氟曱基)環己-1-醇 (市購） 997毫克 43 N-(6-{[6-(環己基氧基） [1，2,4]***并[4,3-b]塔畊-3-基]硫基}-1，3-笨并嘧唑-2-基)-2-環丙基乙醯胺 32a 252毫克3-氣基-6-(環己基氧基)[1，2,4]***并[4,3-b]嗒畊 (lc)與289毫克硫氰S曼2-[(環丙基乙醯基)胺基]-1,3-苯并噻唑-6-基酯(43b) 110毫克 43b 硫氰酸2-[(環丙基乙醯基）胺基]-1,3-苯并嘧唑-6-基酯 la 830毫克硫氰酸2-胺基-1，3-笨并嘧唑-6-基酯與1當量氣化環丙基乙醯溶液(43c) 383毫克 43c 氯化環丙基乙醯 1克環丙基醋酸與0.75立方公分S0C12，在類似由Kreimeyer 等人 J. Med. Chem. 1999,42， 4394所述之條件下直接使用之溶液 145862 -103- 201040187 44 N-(6-{[6-(環丁基氧基） [1,2,4]***并[4,3七]嗒畊-3-基]硫基H，3-苯并》塞唑-2-基)環丙烷羧醯胺 la 70毫克6-{ [6-(環丁基氧基） [1，2,4]***并[4,3-b]嗒啩-3-基] 琉基}-l，3-苯并p墓啥-2-胺(35a) 與0.037立方公分環丙烷氣化醯 64毫克 0 〇 45 外消旋-順式/反式-N-{4-[(3-{[2-({[2-(嗎福啉冰基）乙基]胺曱醯基}胺基)-1,3-苯并嘧唑-6-基]硫基} [1，2,4]***并[4,3-b]嗒畊-6-基)氧基]環己基}乙醯胺 2a 200毫克外消旋-順式/反式-N-{4-[(3-氣基[1，2,4]***并[4,3-b]嗒'•井-6-基)氧基]環己基}乙醯胺(45b)與306毫克1-[2-(嗎福琳-4-基)乙基]-3-(6-硫基-1，3-苯并嘧唑基)脲(2b) 89毫克異構物 (30/70順式/反式）之混合物 45b 外消旋-順式/反式-N-H-[(3-氣基[1，2,4]***并[4,3-b]嗒畊-6-基)氧基]環己基} 乙醯胺 lc 1 克3,6-二氣[1，2,4]***并[4,3-b]嗒p井(市購)與2.04克N-(4-羥基環己基)乙醯胺(市購） 2.49克異構物 (30/70順式/反式）之混合物 46 N-{6-[(6-{[4-(三氟曱基)環己基]氧基KU,4]***并 [4,3-b]嗒畊-3-基)硫基]-1，3-笨并'塞唑-2-基}環丙烷羧醯胺 la 440毫克6-[(6-{[4-(三氟曱基）環己基]氧基} [1，2,4]***并井-3-基)硫基]-1,3-苯并嘧唑-2-胺(46b)與197毫克環丙烷氣化碳醯 330毫克 46b 6-[(6-{[4-(三氟甲基)環己基]氧基}[1，2,4]***并[4,3-b]嗒畊-3-基)硫基]-1,3-笨并》塞唑-2-胺 lb 323毫克硫氰酸2-胺基-1，3-笨并嘧唑-6-基酯與500毫克3-氣基-6_ {[4-(三敗曱基)環己基]氧基} [1,2,4]***并[4,3七]嗒啼 (42b) 496毫克 47 1-[6-(丨6-[(反式-4-羥基環己基)氧基][1,2,4]***并[4,3-b]嗒畊-3-基}硫基)-1,3-苯并嘍唑-2-基]-3-[2-(嗎福啉-4-基)乙基]脲 2a 250毫克反式-4-[(3-氣基[1，2,4] ***并[4,3-b]嗒啡-6-基)氧基] 環己醇(47b)與378毫克1-[2-(嗎福啉-4-基)乙基]-3-(6-硫基-1，3-苯并嘍唑-2-基)脲(2b) 232毫克 47b 反式-4_[(3-氣基[1，2,4]*** 并[4,3七]嗒"井-6-基)氧基] 環己醇 lc 1 克3,6-二氣[l,2,4]***并[4,3-b]嗒畊(市購)與3,07克l，4-環己二醇(順式/反式混合物） 256毫克反式(與 214毫克順式） 48 6-{[6-(雙環并[3.1.0]己-3-基氧基)[1,2,4]***并[4,3-b]嗒啡-3-基]硫基卜ι，3-苯并喳唑-2-胺 lb 550毫克6-(雙環并[3.1.0]己-3-基氧基)-3-氣基[1，2,4]***并 [4,3-b]嗒畊(48b)與455毫克硫氰酸2-胺基-1,3-苯并噻唑-6-基醋 574毫克 145862 -104- 201040187 48b 6_(雙環并[3.1.0]己-3-基氧基)-3-氣基[1，2,4]***并 [4,3-b]塔啩 lc 1 克 3,6-二氣[1,2,4]***并[4,3-b]嗒畊(市購)與1.04克雙環并 [3.1.0]己烧-3-醇 968毫克 49 3-[(2-胺基],3-苯并喳峻-6-基)硫基]-N-環丁基[ι，2,4] ***并[4,3_b]嗒喑-6-胺 lb 500毫克 3-氣-N-環丁基[1，2,4] ***并[4,3七]嗒p井-6-胺(49b) 與463毫克硫氰酸2-胺基-1，3-笨并嘍唑-6-基酯 417毫克 49b 3-氣-N-環丁基[1,2,4]*** 并[4,3-b] 口荅口井-6-胺 18c 2 克3,6-二氣[1，2,4]***并[Μ-ΐ?] 嗒畊 (市購) 與 1.17 立方公分環丁基胺 2.14 克 50 N-(6-{[6-(雙環并[3.1.0]己-3-基氧基)[1,2,4]***并 [4,3-b]嗒喷-3·基]硫基卜 I，3-苯并嘧唑-2—基)環丁烷叛醯胺 la 530毫克 6-{[6-(雙環并[3.1.0] 己-3-基氧基)[1,2,4]***并 [4,3-b]嗒畊-3-基]硫基}-1,3-苯并嘧唑-2-胺(48)與0.24立方公分環丁烷氣化碳醯 568毫克 51 外消旋-6-({6-[(反式-2-氟基環己基)氧基][1，2,4]*** 并[4,3七]嗒畊-3-基}硫基)-1，3-苯并1»塞唑-2-胺 lb 550毫克外消旋-3-氣基-6-[(反式-2-氟基環己基)氧基][1,2,4] ***并[4,3-b]嗒畊(51b)與421 毫克硫氰酸2-胺基-1，3-苯并p塞唑-6-基酯 249毫克 51b 外消旋-3-氣基-6-[(反式-2-氟基環己基)氧基][1，2,4]三唑并[4,3-b]嗒畊 lc 650毫克3,6-二氣[1,2,4]***并 [4,3-b]嗒畊與813毫克外消旋-反式-2-氣基環己醇(市購） 829毫克 52 外消旋-N-{6-[(6-{[(反式-2-氟基環己基]氧基}[1，2,4]三唑并[4,3七>荅_-3-基)硫基]-1,3-苯并-塞唑-2-基}環丙烷羧醯胺 la 195毫克外消旋_6-({6-[(反式-2-氟基環己基)氧基][1，2,4]三唑并[4,3-b]命井-3-基}硫基)-1，3-苯并嘍唑-2-胺(51)與0.085 立方公分環丙烷氣化碳醯 103毫克 53 N-(6-{[6-(環丁基胺基） [1，2,4]***并[4,3-b]。荅畊-3-基]硫基}-1，3-苯并嘧吐-2-基)環丙烷羧醯胺 la 120毫克3-[(2-胺基-1，3-苯并u塞唑-6,基)硫基]-N-環丁基[1,2,4] ***并[4,3-b]嗒畊-6,胺(49)與 0.06立方公分環丙烷氣化碳^ 87毫克 54 N-(6-{[6-(雙環并[3.1.0]己-3-基氧基)[1，2,4]***并 [4,3七]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基)環丙烷羧醯胺 la 11〇毫克6-{[6-(雙環并[3丄〇] 己-3-基氧基）[ι,2,4]***并 [4,3七]嗒畊各基]硫基卜1，3-苯并嘧唑-2-胺(48)與0.051立方公分環丙烷氣化碳醯 112毫克 145862 -105- 201040187 55 外消旋-N2，N2-j^ 6 基-N-反式-2-氟基環己基)氧基][1，2,4]三。坐并[4,3-b]。荅畊-3-基}硫基)-ΐ，3·笨并塞唑-2-基]甘胺醯胺 37a 200毫克外消旋-6-({6-[(反式-2-氣基環己基)氧基][l,2,4]三唑并[4,3-b]嗒呼-3-基}硫基)-1，3-笨并嘧唑-2-胺(51)與735毫克(二乙胺基)醋酸納(市購） 164毫克 56 外消旋-2-(4-乙基六氫p比畊-1-基)-N-{6-[(6-{[反式-2-氟基環己基]氧基m，2,4] 三嗤并[4,3-b]嗒畊·3-基)硫基Η，3-笨并嘧唑-2-基}乙醯胺 37a 300毫克6-({ 6-[(反式-2-氟基環己基)氧基][1，2,4]***并[4,3-b]嗒嗜-3-基丨硫基)-1,3-苯并嘍唑-2-胺(51)與1.82克(4-乙基六氫吡畊-1-基)醋酸氫溴酸鹽 (市購） 120毫克 57 外消旋-Ν-{6-[(6-{[反式-2-氟基環己基]氧基}[1，2,4]三唑并[4,3七]嗒喷-3_基)硫基]-1，3-苯并嘍坐-2-基}-2- (嗎福啉-4-基)乙醯胺 37a 300毫克6-({6-[(反式-2-氟基環己基)氧基][1，2,4]***并[4,3-b]嗒啩-3-基}硫基)-1,3-苯并嘍唑-2-胺(51)與1.05克嗎福<#-4-基醋酸(市購） 156毫克 58 N-(6-U6-(環丁基氧基） [1,2,4]***并[4,3七]嗒畊-3-基]硫基}-1，3-笨弁p塞。坐· 2-基)-2-(嗎福琳-4-基)乙酿胺 37a 200毫克6-{[6-(環丁基氧基） [1，2,4]***并[4,3-b]。荅 °井-3-基] 硫基}-1，3-苯并魂。圭-2-胺(35a) 與784毫克嗎福κ林-4-基醋酸 (市購） 96毫克 59 外消旋-2-(4-環丙基六氫吡畊-1-基)-N-{6-[(6-{[反式-2-氟基環己基]氧基}[1，2,4] ***并[4,3-b]塔畊-3-基)硫基]-1,3-苯并嘧唑-2-基}乙醯胺 37a 200毫克6-({6-[(反式-2-氟基環己基)氧基][1，2,4]***并[Μι)]0荅p 井各基} 硫基 )-l，3-苯并 p 塞唑-2-胺(51)與990毫克(4-環丙基六氫吡畊-1-基)醋酸鉀(59b) 98毫克 59b (4-環丙基六氫p比畊-1 -基）醋酸鉀 2· 1克溴醋酸與3克4-環丙基六氫吡畊.HC1，在類似由D.T. Witiak 等人；j. Med. Chem. 1985, 28, 1228所述之條件下 2.66 克 60 N-(6-{[6-(環丁基氧基） tl，2,4]***并[4,3-b]嗒嗜-3-基]硫基H,3-笨并p塞°圭-2-基)-2-(4-環丙基六氫吡 σ井-1-基)乙酿胺 37a 15〇毫克6-{[6-(環丁基氧基） [1，2,4]***并[4,3-b]嗒畊-3-基] 硫基}-1，3-苯并嘧唑-2-胺(35a) 與418毫克(4-環丙基六氫被吨-1-基)醋酸鉀(59b) 143毫克 61 Ν-(6-{[6-(環丁基氧基） [1,2,4]三嗤并[4,3-1)]塔11井-3-基]硫基}-1，3-笨并嘧。坐-2-基)-2-(U-二氧化硫代嗎福0林-4-基)乙酿胺 37a 15〇毫克6-{[6-(環丁基氧基） [1，2,4]***并[4,3-bR畊-3-基] 硫基H,3-笨并嘧唑-2-胺(35a) 與391毫克(1，1_二氧化硫代嗎福啉-4-基)醋酸(市購） 109毫克 145862 -106- 201040187 62 N-(6-{[6-(環丁基氧基） [1,2,4]***并[4,3-1)]嗒啡-3-基]硫基卜1,3-苯弁p塞唆-2-基)-2-(1,4-氧氮七圜-4-基)乙醯胺 37a 200毫克6-{[6-(環丁基氧基） [1,2,4]***并[4,3-1)]嗒畊-3-基] 硫基}-1，3-本弁”塞嗅-2-胺(35a) 與489毫克1，4-氧氮七園-4-基醋酸卸(62b) 152毫克 62b 1,4-氧氮七圜-4-基醋酸鉀 2.32克溴醋酸與2.3克1,4-氧氮七圜鹽酸鹽，在類似由D. T. Witiak 等人；<1.1^(1.0^111· 1985, 28, 1228所述之條件下 2.77 克 63 N-(6-{[6-(環丁基氧基） [1，2,4]***并[4,3七]嗒啡-3-基]硫基}-1，3-苯并嘍唑-2-基)-3-甲氧基丙醯胺 la 300毫克6-{[6-(環丁基氧基） [1,2,4]***并[4,3七]嗒畊-3-基] 硫基}-1，3-笨并噻唑-2-胺(35a) 與200毫克氣化3-曱氧基丙醯 (市購） 101毫克 64 N-(6-{[6-(環丁基氧基） [1，2,4]***并[4,3-b]嗒畊-3-基]破基}-1，3-笨弁墓吐-2-基)-2-(3,3-二氟六氫吡啶-1-基)乙醯胺 37a 200毫克6-{[6-(環丁基氧基） [1,2,4]***并[4,3七]嗒畊-3-基] 硫基} -1,3-笨并嘧唑-2-胺(35a) 與484毫克(3,3-二氟六氫吡啶-1-基)醋酸鉀(64b) 183毫克 64b (3,3-二氟六氫吡啶-1-基)醋酸鉀 1.6克溴醋酸與1.8克3,3-二氟六氫p比咬，在類似由D. T. Witiak 等人；】.？^(1.0^111· 1985, 28, 1228所述之條件下 1.16 克上表產物之特徵如下：實例 SM RMN 38 滯留時間 Tr (分鐘）=1.09 ; [M+H]+ ： m/z481 ； [M-H]- ： m/z 479 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 0.88 至 0.98 (m， 4H) ; 1.16 至 1.35 (m, 2H) ; 1.39 至 1.54 (m，6H) ; 1.55 至 1.69 (m，2H); 1.74 至 1.89 (m，2H) ; 1.93 至 2.04 (m， 1H) ; 4.73 至 4.90 (m, 1H) ; 7.01 (d，J =9.8 Hz，1H) ; 7.41 (dd，J = 2.1 與 8.4 Hz, 1H) ； 7.67 (d, J = 8.6 Hz, 1H)； 8.05 (d, J = 2.0 Hz, 1H) ； 8.27 (d, J = 9.8 Hz，1H) ; 12.67 (寬廣 s，1H) 145862 107· 201040187 39 滞留時間 Tr(分鐘）=3,03 ; [M+H]+ ： m/z 568 ； [M-H]- ： m/z 566 1H NMR 光譜（400 MHz, δ 以 ppm 表示，DMSO-d6) : 0.97 至 1.32 (m， 5H) ; 1.47 至 1.68 (m，5H) ; 1.80 (m， 2H) ; 2.25 至 2.37 (m, 6H) ; 3.13 至 3.23 (m，2H) ; 3.37 至 3.49 (m，1H); 3.57 (m，4H) ; 6.71 至 6.82 (m，1H); 6.79 (d, J = 10.0 Hz, 1H) ； 7.25 (d, J = 7.1 Hz，1H) ; 7.35 (dd，J = 2.0 與 8.6 Hz, 1H) ； 7.52 (d, J = 8.6 Hz, 1H)； 7.91 (d, J = 10.0 Hz, 1H) ； 7.98 (d, J = 2.0 Hz，1H) ; 10.80 (寬廣 m, 1H) 39b 1H NMR 光譜（400 MHz, d 以 ppm 表示，DMSO-d6) : 1.53 至 1.70 (m, 2H); 2.28 至 2.37(m,6H); 3.15 至 3.24 (m, 2H) ; 3.52 至 3.63 (m，4H); 6.76 至 6.82 (m，1H) ; 7.48 (dd，J = 2.0 M 8.6 Hz, 1H) ； 7.58 (d, J = 8.6 Hz, 1H) ； 8.08 (d, J = 2.0 Hz, 1H) ； 10.86 (寬廣m, 1H) 40 滯留時間 Tr (分鐘）=0.73 ; [M+H]+ ： m/z 569 ； [M-H]- ： m/z 567 1 H NMR 光譜（400 MHz，<5 以 ppm 表示，DMSO-d6) : 1.15 至 1.43 (m， 5H) ; 1.45 至 1.53 (m，1H) ; 1.57 至 1.66 (m，4H) ; 1.78 至 1.86 (m，2H); 2.27 至 2.37 (m，6H) ; 3.19 (q，J = 5.6 Hz, 2H) ； 3.57 (t, J = 4.8 Hz, 4H)； 4.66 至 4.75 (m，1H) ; 6.77 (寬廣 s, 1H) ； 7.02 (d, J = 9.8 Hz, 1H) ； 7.36 (dd，J = 2.0 與 8.6 Hz, 1H) ; 7.54 (d，J = 8.3 Hz, 1H) ； 8.00 (d, J = 2.0 Hz, 1H)； 8.27 (d，J = 9.8 Hz, 1H) ; 10.81 (寬廣 s, 1H) 、 145862 108- 201040187 41 滯留時間 Tr (分鐘）=2.98 ; [M+H]+ ： m/z 527 ； [M-H]- ： m/z 525 1HNMR光譜（400MHz，（5以ppm 表示，DMSO-d6) : 1.62 (m，1H); 1.76 (m, 1H) ； 2.04 (m, 2H) ； 2.30 (m, 2H) ; 2.37 至 2.45 (m，6H) ; 3.23 至 3.28 (經遮蔽之 m, 2H) ; 3.59 (t，J = 4.6 Hz, 4H) ; 4.92 (qd,J = 7.1 與 7.3 Hz，1H) ; 6.77 (寬廣 s，1H) ; 7.05 (d， J = 9.8 Hz，1H) ; 7.42 (dd，J = 2.1 與 8.4 Hz, 1H) ； 7.57(d,J=8.6Hz, 1H)； 8.06 (d, J = 2.2 Hz, 1H) ； 8.28 (d, J = 9.8 Hz，1H) ; 10.89 (寬廣 s，1H) 42 滯留時間 Tr(分鐘）= 0.75 ; [M+H]+ ： m/z 623 ； [M-H]- · m/z 621 1H NMR 光譜（400 MHz, 6 以 ppm 表示，DMSO-d6) : 1·22 (m，2H); 1.33 (m, 2H) ； 1.75 (d, J = 13.2 Hz, 2H) ； 1.94 (d, J = 11.5 Hz, 2H) ； 2.19 至 2.35 (m，1H) ; 2.36 至 2.45 (m, 6H) ; 3.23至3.28 (經遮蔽之m， 2H) ； 3.59 (t, J = 4.8 Hz, 4H) ； 4.65 (m, 1H) ; 6.76 (寬廣 s，1H) ; 7.03 (d，J = 9.8 Hz，1H) ; 7.32 (dd，J = 2.0 與 8.6 Hz, 1H) ； 7.52 (d, J = 8.6 Hz, 1H)； 7.96 (d, J = 2.0 Hz, 1H) ； 8.30 (d, J = 9.8 Hz，1H) ; 10.87 (寬廣 s，1H) 42b 1H NMR 光譜（400 MHz, <5 以 ppm 表示，DMSO-d6) : 1.32 至 1.66 (m, 4H) ； 1.99 (m, 2H) ； 2.30 (m, 2H)； 2.37 至 2.45 (m，1H) ; 4.91 至 5.04 (m, 1H) ； 7.09 (d, J = 9.8 Hz, 1H) ； 8.28 (d, J = 9.8 Hz, 1H) 145862 109- 201040187 43 滯留時間 Tr(分鐘）= 4.56 ; [M+H]+ : m/z481 ; [M-H]- ： m/z 479 1 H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 0.20 (m, 2H); 0.49 (m，2H) ; 1.06 (m, 1H) ; 1.14 至 1·40 (m，5H) ; 1.42 至 1.65 (m, 3H); 1.72 至 1.84 (m, 2H) ; 2.37 (d，J = 7.1 Hz, 2H) ; 4.60 至 4.73 (m，1H) ; 7.02 (d，J = 9.8 Hz，1H) ; 7.41 (dd，J = 2.0 與 8.6 Hz，1H) ; 7.66 (d，J = 8.6 Hz, 1H); 8.06 (d, J = 2.0 Hz, 1H) ； 8.28 (d, J = 9.8 Hz，1H) ; 12.30 (寬廣 s，1H) 43b 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : -0.03 至 0.03 (m， 2H) ; 0.27 至 0.32 (m，2H) ; 0.81 至 0.93 (m, 1H) ； 2.20 (d, J = 7.1 Hz, 2H) ; 7.48 (dd, J = 2.0 與 8.6 Hz, 1H); 7.63 (dd, J = 0.5 H 8.6 Hz, 1H) ； 8.18 (dd，J = 0.5 與 2.0 Hz，1H) ; 12.24 (寬廣 m，1H) 44 滯留時間 Tr (分鐘）=0.97 ; [M+H]+ : m/z 439 ； [M-H]- : m/z 437 1H NMR 光譜（400 MHz，δ 以 ppm 表示，DMSO-d6) : 0.92 至 0.98 (m， 4H); 1.60 (m，lH); 1.75 (m，lH); 2.01 (m，3H) ; 2.27 (m，2H) ; 4·90 (五重峰，J = 7.3 Hz, 1H) ; 7.06 (d,J = 9.8 Hz, 1H) ; 7.47 (dd, J = 2,0 與 8.6 Hz, 1H) ； 7.69 (d, J = 8.6 Hz, 1H) ； 8.11 (d, J = 2.0 Hz, 1H) ； 8.29 (d, J = 9.8 Hz, 1H) ; 12.67 (寬廣 s, 1H) 145862 Π0* 201040187 45 滯留時間 Tr (分鐘）=ο.% ; :M+H]+: m/z612; -M-H]- : m/z 610 1l·lNMR光譜（400MHz,δ以ppm 表示，DMSO-d6)異構物70%反式 30%順式之混合物：1.12至1.65 (m，4H) ; 1.67 至 1.85 (m, 5H) ; 1.87 至 1.97 (m，2H) ; 2.35 至 2.45 (m， 6H) ; 3.26 (經遮蔽之 m，2H) ; 3.51 至 3.68 (m, 5H) ; 4.66 (m, 0.7H) ; 4.98 (m，0.3H) ; 6.77 (寬廣 s，1H) ; 6.98 至 7·06 (m, 1H) ; 7.39 (m，1H) ; 7.56 (m, 1H) ； 7.66 (d, J = 8.6 Hz, 0.7H)； 7.74(d,J = 8.1Hz,0.3H) ； 7.95 (d,J = 2.0 Hz, 0.7H) ； 8.03 (d, J = 2.0 Hz, 0.3H) ； 8.28 (d, J = 9.5 Hz, 1H) ； 10.88 (寬廣s，1H) 45b 1H NMR 光譜（400 MHz, (5 以 ppm 表示，DMSO~d6)異構物70%反式 (雙軸向）與30%順式（CHN ax-CHO eq)之混合物具有：1.29至2.23 (m，8H); 1.78 (s，0.9H); 1.80 (s， 2.1H) ; 3.50 至 3.72 (m，1H) ; 4.94 (tt， J = 4·2 與 10.3 Hz，0.7H) ; 5.14 (m, 0.3H) ; 7.03 至 7.13 (m, 1H) ; 7.79 至 7.90 (m，1H) ; 8.21 至 8.30 (m，1H) 46 滯留時間丁1*(分鐘）=1.〇5; [M+H]+ ： m/z 535 ； [M-H]- ： m/z 533 1H NMR 光譜（400 MHz，δ 以 ppm 表示，DMSO-d6) : 0.90 至 0.98 (m， 4H) ； 1.14 (m, 2H) ； 1.31 (m, 2H)； 1.69 (d, J = 12.2 Hz, 2H) ； 1.87 (d, J = 10.5 Hz, 2H) ； 1.98 (m, 1H) ； 2.24 (m, 1H) ； 4.51 (m,lH) ； 7.03 (d,J = 9.8 Hz, 1H) ； 7.35 (dd, J = 2.0 ^ 8.6 Hz, 1H) ； 7.64 (d, J = 8.6 Hz, 1H) ； 8.02 (d, J = 2.0 Hz, 1H) ； 8.31 (d, J = 9.8 Hz, 1H) ; 12.66 (寬廣 s, 1H) 46b 滯留時間 Tr (分鐘）=3.86 ; [M+H]+ ： m/z 467 1 [M-H]- * m/z 465 145862 -Ill - 201040187 47 滯留時間 Tr(分鐘）= 0.51 ; [M+H]+ ： m/z 571 ；；M-H]- ： m/z 569 1H NMR 光譜（400 MHz, 5 以 ppm 表示，DMSO-d6) : 1.24 (m，2H); 1.36 (m, 2H) ； 1.75 (m, 2H) ； 1.91 (m, 2H) ; 2.35 至 2.45 (m，6H) ; 3.23 至 3.29 (經遮蔽之 m, 2H) ; 3.47 (m, 1H) ； 3.59 (t, J = 4.6 Hz, 4H) ； 4.57 (d, J = 4.2 Hz, 1H) ； 4.72 (m, 1H) ； 6.79 (寬廣 s，lH); 7.01(d，J = 9.8Hz， 1H) ; 7.40 (dd，J = 2.1 與 8.4 Hz, 1H); 7.56 (d, J = 8.6 Hz, 1H) ； 7.96 (d, J = 2.0 Hz, 1H) ； 8.27 (d, J = 9.8 Hz, 1H)； 10.87 (寬廣 s，1H) 47b 1H NMR 光譜（400 MHz, 5 以 ppm 表示，DMSO-d6) : 1.29 至 1.43 (m， 2H) ; 1.49 至 1.63 (m, 2H) ; 1.82 至 1.92 (m，2H) ; 2.09 至 2.22 (m，2H); 3.58 (m, 1H) ； 4.59 (d, J = 3.9 Hz, 1H) ； 4.98 (m, 1H) ； 7.07 (d, J = 10.0 Hz, 1H) ； 8.26 (d, J = 10.0 Hz, 1H) 48 滯留時間 Tr (分鐘）=3.65 ; [M+H]+ ： m/z 397 ； [M-H]- ： m/z 395 1H NMR 光譜（400 MHz, 6 以 ppm 表示，DMSO-d6) : 0.38 (q，J = 4.2 Hz， 1H) ； 0.49 (m, 1H) ； 1.32 (m, 2H)； 1.86 (m, 2H) ； 2.20 (m, 2H) ； 5.25 (t, J =6.7 Hz, 1H) ； 6.96 (d, J = 9.8 Hz, 1H) ； 7.28 (d, J = 8.3 Hz, 1H) ； 7.33 (dd，J = 2.0 與 8.6 Hz, 1H) ; 7.62 (s， 2H) ； 7.90 (d, J = 2.0 Hz, 1H) ； 8.22 (d, J = 9.8 Hz, 1H) 48b 1 H NMR 光譜（400 MHz，<5 以 ppm 表示，DMSO-d6) : 0.44 (q，J = 4.2 Hz， 1H) ; 0_53 (m，1H) ; 1.33 至 1.44 (m, 2H) ； 1.99 (d, J = 14.9 Hz, 2H) ； 2.23 至 2.37 (m，2H) ; 5.44 (t，J = 6.7 Hz， 1H) ； 7.03 (d, J = 9.8 Hz, 1H) ； 8.24 (d, J = 9.8 Hz, 1H) 145862 -112- 201040187 49 滞留時間 Tr (分鐘）=〇,68 ; [M+H]+ : m/z 370 ； [M-H]- : m/z 368 1H NMR 光譜（400 MHz，（5 以 ppm 表示，DMSO-d6) : 1.66 至 1.78 (m， 2H) ; 1.80 至 1.96 (m，2H) ; 2.16 至 2.31 (m，2H) ; 3.95 至 4.18 (m，1H); 6.76 (d, J = 9.8 Hz, 1H) ； 7.31 (d, J = 8.6 Hz, 1H) ; 7.37 (dd，J = 1.8 與 8,6 Hz， 1H) ; 7.72 (寬廣 d，J = 7.0 Hz，1H); 7.87 至 7.95 (m，2H) ; 8.04 (寬廣 m， 2H) 49b 滯留時間 Tr (分鐘）=〇.7〇 ; [M+H]+ : m/z 224 ； [M-H]- : m/z 222 50 滯留時間 Tr (分鐘）= 1.08 ; [M+H]+ ： m/z 479 ； [M-H]- : m/z 477 WNMR 光譜（400 MHz，（5 以 ppm 表示，DMSO-d6) : 0.35 (q，J = 3.9 Hz， 1H) ; 0.47 (m，1H) ; 1.27 (m, 2H); 1.72 至 2.03 (m, J = 14.9 Hz，4H) ; 2.07 至 2.33 (m, 6H) ; 3.35 至 3.47 (經遮蔽之 m，1H) ; 5.21 (t’ J = 6.8 Hz, 1H) ； 6.98 (d, J = 9.8 Hz, 1H) ； 7.45 (dd，J = 2.1 與 8.4 Hz，1H) ; 7.67 (d，J = 8.3 Hz, 1H) ； 8.16 (d, J = 2.0 Hz, 1H)； 8.25 (d，J = 9.8 Hz, 1H) ; 12.25 (寬廣 s，lH) 51 滯留時間 Tr (分鐘）=0.76 ; [M+H]+： m/z 417； [M-H]- : m/z 415 1H NMR 光譜（400 MHz，占以 ppm 表示，DMSO-d6) : 1.29 (d，J = 8.6 Hz， 3H); 1,43 至 1.76(m,3H); 1.90 至 2.18 (m，2H) ; 4.50 至 4.88 (m, 2H); 7.07 (d, J = 9.8 Hz, 1H) ； 7.27 (d, J = 8.6 Hz，1H) ; 7.31 (dd，J = 1.7 與 8.3 Hz, 1H) ； 7.61 (s, 2H) ； 7.83 (d, J = 2.0 Hz, 1H) ； 8.29 (d, J = 10.0 Hz, 1H) 145862 -113- 201040187 51b 1HNMR光譜（400MHz，δ以ppm 表示，DMSO-d6) : 1.32 至 1.53 (m， 3H) ; 1.56 至 1.79 (m，3H) ; 2.12 (m， 1H) ; 2.30 (m, 1H) ; 4.61 至 4.87 (m， 1H) ; 5.01 至 5.17 (m, 1H) ; 7.14 (d，J =9.8 Hz, 1H) ； 8.30 (d, J = 9.8 Hz, 1H) 52 滯留時間 Tr (分鐘）=0.97 ; [M+H]+ ： m/z 485 ； [M-H]- ： m/z 483 1H NMR 光譜（400 MHz, 5 以 ppm 表示，DMSO-d6) : 0.95 (m，4H); 1.07 至 1.33 (m，3H) ; 1.43 (m，2H); 1.62 (m, J = 15.7 Hz, 1H) ； 1.85 (m, 1H) ; 1.93 至 2.12 (m，2H) ; 4.46 至 4.78 (m, 2H) ； 7.08 (d, J = 9.8 Hz, 1H) ; 7.44 (dd，J = 2.0 與 8.3 Hz, 1H); 7.68 (d, J = 8.3 Hz, 1H) ； 8.08 (d, J = 2.0 Hz, 1H) ； 8.32 (d, J = 9.8 Hz, 1H)； 12.67 (寬廣 s, 1H) 53 滯留時間 Tr (分鐘）=0.89 ; [M+H]+ ： m/z 438 ； [M-H]- ： m/z 436 1H NMR 光譜（400 MHz, ¢5 以 ppm 表示，DMSO-d6) : 0,90 至 0.99 (m， 4H) ; 1.61 至 1.73 (m，2H) ; 1.77 至 1.90 (m，2H) ; 1.94 至 2.04 (m，1H); 2.12 至 2.24 (m，2H) ; 3.95 至 4.07 (m， 1H) ； 6.75 (d, J = 9.8 Hz, 1H) ； 7.45 (dd，J = 1.8 與 8.4 Hz, 1H) ; 7.63 至 7.72 (m, 2H) ； 7.93 (d, J = 9.8 Hz, 1H) ； 8.12 (d, J = 1.8 Hz, 1H) ； 12.66 (寬廣m，1H) 54 滯留時間 Tr (分鐘）=1.03 ; [M+H]+ ： m/z 465 ； [M-H]- ： m/z 463 1H NMR 光譜（400 MHz，δ 以 ppm 表示，DMSO-d6) : 0.34 (q，J = 4.3 Hz, 1H) ； 0.47 (m, 1H) ； 0.95 (m, 4H)； 1.27 (m，2H) ; 1.72 至 1.84 (m, 2H); 1.98 (m, 1H) ； 2.12 (m, 2H) ； 5.20 (t, J =6.7 Hz, 1H) ； 6.98 (d, J = 9.8 Hz, 1H) ; 7.45 (dd，J = 2.0 與 8.6 Hz，1H); 7.68(d,J = 8.6Hz, 1H) ； 8.13 (d,J = 2.0 Hz, 1H) ； 8.24 (d, J = 9.8 Hz, 1H)； 12.66 (寬廣 s，1H) 201040187a) 6-{[6-(Cyclobutyloxy)[1,2,4]triazolo[4,3-7]indole-3-yl]thio}-Q 1,3-benzothiazole _2_amine can be similar to the method of the example lb, but with 1 〇 7 g of 2-amino-1,3-benzoxazole _6-yl thiocyanate, 15 cubic centimeters of degassed ethanol, 0.1 cubic centimeter 2 mg of potassium dihydrogenate in water, 99 g of DL-dithiothreitol and 964 mg of 3-chloro-6-(cyclobutyloxy)[1,2,4]triazolo[ 4,3-b] 嗒11 well started. Therefore, u g 6_丨[6_(cyclobutyloxy^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The amine, in the form of a white powder, is characterized as follows: Q mass spectrum: Waters ZQ: residence time Rt (minutes) = 3.39; [M+H]+: m/z 371; [MH]-: m/z369 1H NMR spectrum (400 ΜΗζ, δ expressed in ppm, DMSO-d6) ·· 1.66 (m,1H); 1.80 (m,1H); 2.01 to 2.13 (m,2H); 2.31 to 2.40 (m,2H) ; 4.96 (qd , J = . 7.1 and 7.3 Hz, 1H); 7.04 (d, Jf = 9.8 Hz, 1H); 7.29 (d, J = 8.3 Hz, 1H); 7.34 (dd, J = 2.0 and 8.6 Hz, 1H); 7.62 (s, 2H) ; 7.88 (d, J = 1.7 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H) b) 3-chloro-6-(cyclobutyloxy)[1,2 , 4] triazolo[4,3-b] arable can be similar to the method of Example 1C, but in 1 〇 cubic centimeters of tetrahydrofuran 954 mg 145862 • 99- 201040187 cyclobutanol, 317 mg at 60%; It is made from sodium chloride and m6_diox [1,2,4]triazole [4'3-b] morphine (commercially available). Therefore, 1 〇 3 g of 3-gasyl-6-(cyclobutoxy) is obtained [Cafwang 嗤 [4, 3 replies, in the form of a beige powder, which is characterized as follows: , d is expressed as Peng, DMS〇d6): 163 to i96(m, 2H); 2.07 to 2.24 (m, 2H); 2.41 to 2 52 (taken by partial masking 2H); 4.95 to 5.34 (m, 1H) 7.10 (d, J = 9.8 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H) Example 36: N-(6-{[6-(cyclobutyloxy)[i,2,4 Triazolo[4,3 is called 嗒3_yl]thio}^-benzopyrazol-2-yl)-2-(4-ethylhexahydropyrazine) acetaminophen a) N-(6-U6-(cyclobutyloxy)[U,4]triazolo[4 3_b]indole]thio]_1,3-1,3-pyrimidin-2-yl)-2 -(4-Ethylhexahydropyrone + yl)acetamide can be prepared in the following manner: 273 mg (4-ethylhexahydropyrrolidine) acetic acid (commercially available), 〇28 cm 2 dichotomous Propylethylamine and 411 mg bismuth hexafluorophosphate _ (7-nitrobenzotriazole small base) _ Ν 'Ν, Ν |, Ν | - tetradecyl hydrazine (HATU) in 3 cubic centimeters The 20 C compound in guanamine was stirred at 20 C for 1 hour. 2〇〇 mg of 6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-7]indole-3-yl]thio}_1,3_benzo The azole-2_amine (35a) is added to the reaction medium. After 18 hours, pour the solution into ice water and consider the children. The early yellow paste was dissolved in a 90/10 ethyl acetate/sterol mixture. The obtained solution was dried over magnesium sulfate, filtered, and then concentrated to dryness in vacuo. The oily residue was purified by chromatography on a sputum cartridge (SVF D26 Si60; 15-40 // Μ; 25 g) on SpST n to %/4 dioxane/sterol to 100 % methanol gradient solution was dissolved. 145862 •100· 201040187 This 'obtained 127 mg of N-(6-{[6-(cyclobutyloxy)[HA triazolo[4,3_b]indol-3-yl]thio}-1, 3-benzoxazole_2_yl)_2_(4_ethylhexanitropyrrolidinyl)acetamide 'in yellow powder form' is characterized as follows: Mass spectrometry. Waters ZQ retention time Rt (minutes 3 1〇) ; [M+H]+ : _ still; [MH]- : m/z 523 1H NMR light § Jin (400 ΜΗζ, δ in ppm, DMS〇_d6): 丄〇〇(t,j = 7 2 Hz, 3H), 1.59 (m, 1H); 1.73 (m, 1H); 1.94 to 2.09 (m, 2H); 2.20 to ◎ 2.31 (m, 2H) ' 2.32 to 2.58 (partially masked m, 1 〇H) ; 3.34 (s,2H); 4.90 (m, 1H) ' 7.06 (d, J = 9.8 Hz, 1H); 7.48 (dd, J = 1.8 and 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H); 8.14 (d, J =: 1.8 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.12 (extremely broad m, 1H) Example 37: N-(6-{[6 -(cyclobutyloxy)["(4)triazolo[4,3_b]indole·3_yl]thio}#benzoxep-2-yl)-N2,N2 _diethylglycine Amine amine a) cyclobutyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thiopyridinium I,3 stupid P-pyrazole-2-yl ) _N2, N2_diethylglycine decylamine can be prepared in the following manner: a mixture of 827 mg of sodium (diethylamino)acetate (commercially available) in a solution of 5.5 cubic centimeters of hydrogen chloride in 2N of ether at 20 it Stir for 1 hour. Evaporate the resulting suspension to dryness under vacuum. 8 cubic centimeters of pyridinium, 2 mg of 6-{[6-(cyclobutyloxy)[ι,2,4]3 Azolo[4,3-7] 嗒_3_ 戚戚卜b benzoxazol-2-amine (35a) and 1.03 g of N-(3-dimethylaminopropyl) N.-ethyl carbonation The monoimine hydrochloride was added to the obtained white residue at 20 ° C. After 5 hours, the brown reaction medium was evaporated to dryness. The residue was dissolved in 145862 201040187 in toluene and the mixture was vacuum Evaporate to dryness again. Dissolve the residue in water and extract the mixture with ethyl acetate and then evaporate to dryness. Purify the residue on a silica gel by dry deposition and in a Biotase Quad 12/25 cartridge (KP- SIL, 6〇A; 32-63 //Μ)) was chromatographed on a gradient of 100/0 to 98/2 in dichloromethane/methanol. Thus, 135 mg of N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]indole]thio]-l,3 was obtained. - benzopyrazol-2-yl)-N2,N2-diethylglycinamide, in the form of a beige powder, characterized by the following: Mass Spectrum: Waters UPLC-SQD: residence time Rt (minutes) = 〇.72 ; [M+H]+ : m/z 484 ; [M+2H]2+ : m/z 242.5 (base peak); [MH]- : m/z 482 1H NMR spectrum (400 ΜΗζ, δ in ppm , DMSO-d6): 1.00 (t, J = 7.2 Hz, 6H); 1.52 to 1.66 (m, 1H); 1.68 to 1.80 (m, 1H); 1.95 to 2.09 (m, 2H); 2.20 To 2.31 (m, 2H); 2.62 (q, J = 7.2 Hz, 4H); 3.40 (s, 2H); 4.90 (m, 1H); 7.06 (d, J = 9·8 Hz, 1H); 7.47 ( Dd, J = 1.9 and 8.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 1H); 8.13 (d, J = 1.9 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1H); 11.54 ( Very broad m, lH) Other examples made by similar examples above and their intermediates are described in the following table: Example names are similar to the following examples: Start with the following: singly----- 38 --------- N-(6-{[6-(cycloheptyloxy) 3 yl]thio sulfonium- 1,3-benzothiazepines sitting _ la 86 mg 6-{[6-(cycloheptyloxy) [1,2,4] tris(s) and [4,3-7]°荅-3-yl ] thio}}1,3-benzopyrazol-2-amine (16a) 52 mg) Cyclopropylamine hydrazine and 44 mg Cyclopropanol gasification 醯醯 145862 • 102- 201040187 39 H6-{[6 -(cyclohexylamino)[i,2,4]triazolo[4,3-1>]»荅"-3-yl]thiol 1,3- benzoxazol-2-yl) ·3-[3-(?)-propyl propyl 105 lb 3-mg-N-cyclohexyl[1,2,4] Triazolo[4,3-b]indole-6-amine (18c) with 155 mg of 2-({[3-(morpholine-4-yl)propyl]amino)}amino)-1,3-benzopyrazole-6-yl thiocyanate (39b) 168 mg of 39b thiocyanate 2-({[3-(moffin-4-yl)propyl]amino]amino}amino)_1,3-benzoin. Benz-6-yl ester 2c 500 mg (6-fluorenyl-1,3-benzopyrazol-2-yl) phenyl carbamate (2d) with 264 mg of N-(3-aminopropyl) Morpholine (commercially available) 634 mg 40 1-(6-{[6-(cyclohexyldecyl):1,2,4]triazolo[4,3-7].荅口-3-yl] Sulfur-based 1,3-benzo-v) tomb. Sit _ 2_yl)-3-[3-(TM- Φ4-yl)propyl]urea lb 200 mg 3-carbyl-6-(cyclohexyloxy)[1,2,4]triazolo[ 4,3-b] 嗒耕(lc) and 299 mg of 2-({[3-(morpholine-4-yl)propyl]amine sulfhydryl}amino)-1,3-benzene thiocyanate And pyrimidin-6-yl ester (39b) 149 mg 41 1-(6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-b> 3-Based]S,H,3-Benzothymidine-2-yl)-3-[2-(N-Fushen-4-yl)ethyl]urea 2a 200 mg 3-Alkyl-6-(cyclobutyl Oxy)[1,2,4]triazolo[4,3-b]indole (3Sb) with 422 mg of 1-[2-(moffa-4-yl)ethyl]-3-(6 -thio-1,3-benzopyrazol-2-yl)urea (2b) 245 mg 42 racemic-1 - hydrazine (morphinein-4-yl) ethyl]-3-{6- [(6-{[trans-4-(trifluoromethyl)cyclohexyl]oxy} [1,2,4]triazolo[4,3-b]indole-3-yl)thio] -1,3-Benzo-conazole-2-yl}urea 2a 200 mg of racemic-3-yl-6-{[trans-4-(trifluoromethyl)cyclohexyl]oxy}[ 1,2,4]triazolo[4,3-b]indole (42b) with 295 mg of 1-[2-(ifolin-4-yl)ethyl]-3-(6-thio- 1,3-benzopyrazol-2-yl)urea (2b) 199 mg 42b racemic-3-yl-6-{[trans-4-(trifluoromethyl) ring ]]oxy} [1,2,4]triazolo[4,3-b]tung lc 1 g 3,6-digas [1,2,4]triazolo[Μ-ΐ?] 嗒Plowing (commercially available) with 2.19 g of racemic-trans-4-(trifluoromethyl)cyclohexan-1-ol (commercially available) 997 mg 43 N-(6-{[6-(cyclohexyloxy) [1,2,4]triazolo[4,3-b]tac-3-yl]thio}-1,3-benzoxazol-2-yl)-2-cyclopropylethylhydrazine Amine 32a 252 mg 3-carbyl-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole (lc) with 289 mg thiocyanate Sman 2-[( Cyclopropylethyl hydrazino)amino]-1,3-benzothiazol-6-yl ester (43b) 110 mg 43b 2-[(cyclopropylethylhydrazinyl)amino]-1,3 thiocyanate - benzopyrazole-6-yl ester la 830 mg 2-amino-1,3-benzopyrazol-6-yl thiocyanate and 1 equivalent of gasified cyclopropyl acetam solution (43c) 383 mg 43c Cyclopropylacetate chloride 1 gram of cyclopropylacetic acid and 0.75 cubic centimeters of S0C12, in a solution similar to that used by Kreimeyer et al. J. Med. Chem. 1999, 42, 4394, 145862-103- 201040187 44 N-(6-{[6-(Cyclobutyloxy) [1,2,4]triazolo[4,3-7]indole-3-yl]thio H,3-benzo" Retoxazol-2-yl)cyclopropanecarboxamide la 70 mg 6 -{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]indol-3-yl]indenyl}-l,3-benzo-p tomb- 2-Amine (35a) with 0.037 cubic centimeters of cyclopropane gasification 醯64 mg 0 〇45 racemic-cis/trans-N-{4-[(3-{[2-({[2-() Fulinium) Amino]aminoindenyl}amino)-1,3-benzopyrazole-6-yl]thio}[1,2,4]triazolo[4,3-b]嗒耕-6-yl)oxy]cyclohexyl}acetamidamine 2a 200 mg racemic-cis/trans-N-{4-[(3-carbyl[1,2,4]triazole [4,3-b]嗒'• Well-6-yl)oxy]cyclohexyl}acetamide (45b) with 306 mg of 1-[2-(moffin-4-yl)ethyl]-3 -(6-thio-1,3-benzopyrazolyl)urea (2b) 89 mg isomer (30/70 cis/trans) mixture 45b racemic-cis/trans-NH -[(3-carbyl[1,2,4]triazolo[4,3-b]indole-6-yl)oxy]cyclohexyl}acetamide lc 1 g 3,6-diox [ 1,2,4] Triazolo[4,3-b]嗒p well (commercially available) with 2.04 g of N-(4-hydroxycyclohexyl)acetamide (commercially available) 2.49 g of isomer (30/ a mixture of 70 cis/trans) 46 N-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy KU,4]triazolo[4,3-b] -3-yl)thio]-1,3-stupid -2-yl}cyclopropanecarboxamide la 440 mg 6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy} [1,2,4]triazolo--3-yl )thio]-1,3-benzopyrazol-2-amine (46b) with 197 mg of cyclopropane gasified carbon hydrazine 330 mg 46b 6-[(6-{[4-(trifluoromethyl)cyclohexyl) ]oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]-1,3-indigo-conazole-3-amine lb 323 mg thiocyanate Acid 2-amino-1,3- benzopyrazole-6-yl ester with 500 mg of 3-alkyl-6-{[4-(disindolyl)cyclohexyl]oxy} [1,2,4 Triazolo[4,3-7]indole (42b) 496 mg 47 1-[6-(丨6-[(trans-4-hydroxycyclohexyl)oxy][1,2,4]triazole And [4,3-b]嗒耕-3-yl}thio)-1,3-benzoxazol-2-yl]-3-[2-(morpholin-4-yl)ethyl] Urea 2a 250 mg trans-4-[(3-carbyl[1,2,4]triazolo[4,3-b]indolino-6-yl)oxy]cyclohexanol (47b) with 378 Mg 1-[2-(morpholine-4-yl)ethyl]-3-(6-thio-1,3-benzoxazol-2-yl)urea (2b) 232 mg 47b trans- 4_[(3-Alkyl[1,2,4]triazolo[4,3-7]嗒" Well-6-yl)oxy]cyclohexanol lc 1 g 3,6-digas [l, 2,4]triazolo[4,3-b]indole (commercially available) with 3,07 g of 1,4-cyclohexanediol (shun) /trans mixture) 256 mg trans (with 214 mg cis) 48 6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[ 4,3-b]morphin-3-yl]thiophenyl, 3-benzoxazol-2-amine lb 550 mg 6-(bicyclo[3.1.0]hex-3-yloxy)- 3-Alkyl[1,2,4]triazolo[4,3-b]indole (48b) with 455 mg of 2-amino-1,3-benzothiazol-6-yl vinegar 574 Mg 145862 -104- 201040187 48b 6_(bicyclo[3.1.0]hex-3-yloxy)-3-carbyl[1,2,4]triazolo[4,3-b]talc lc 1 3,6-diox[1,2,4]triazolo[4,3-b]indole (commercially available) with 1.04 g of bicyclo[3.1.0]hexan-3-ol 968 mg 49 3 -[(2-amino),3-benzoxanthene-6-yl)thio]-N-cyclobutyl[ι,2,4]triazolo[4,3_b]indole-6-amine Lb 500 mg 3-gas-N-cyclobutyl[1,2,4]triazolo[4,3-7]嗒p well-6-amine (49b) with 463 mg 2-amino-1 thiocyanate , 3- benzoxazole-6-yl ester 417 mg 49b 3- gas-N-cyclobutyl [1,2,4]triazolo[4,3-b] 荅荅 well-6-amine 18c 2 grams of 3,6-diox [1,2,4]triazolo[Μ-ΐ?] 嗒耕 (commercially available) with 1.17 cubic centimeters of cyclobutylamine 2.14 grams of 50 N-(6-{[6- (Bicyclo[3.1.0]hex-3-氧基))[1,2,4]triazolo[4,3-b]indole-3·yl]thiol I,3-benzopyrazole-2-yl)cyclobutane retinoin La 530 mg 6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]sulfur }}-1,3-benzopyrazol-2-amine (48) with 0.24 cubic centimeters of cyclobutane gasified carbon 醯 568 mg 51 racemic-6-({6-[(trans-2-fluoro) Ethylcyclohexyl)oxy][1,2,4]triazolo[4,3-7]indole-3-yl}thio)-1,3-benzox»-pyrazol-2-amine lb 550 Mg of racemic-3-yl-6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-b]indole (51b) and 421 mg 2-amino-1,3-benzo-pyrazole-6-yl thiocyanate 249 mg 51b racemic-3-yl-6-[(trans-2-fluorocyclohexyl) Oxy][1,2,4]triazolo[4,3-b]indole 650 mg 3,6-diox[1,2,4]triazolo[4,3-b] With 813 mg of racemic-trans-2-cyclohexanol (commercially available) 829 mg 52 rac-N-{6-[(6-{[(trans-2-fluorocyclohexyl)] Oxy}[1,2,4]triazolo[4,3?>indole-3-yl)thio]-1,3-benzo-pyrazol-2-yl}cyclopropanecarboxamide La 195 mg racemic _6-({6-[(trans-2-fluoro) ring Alkyloxy][1,2,4]triazolo[4,3-b]hom-3-yl}thio)-1,3-benzoxazol-2-amine (51) with 0.085 Cubic-part cyclopropane gasification carbon hydrazine 103 mg 53 N-(6-{[6-(cyclobutylamino) [1,2,4]triazolo[4,3-b]. Indole-3-yl]thio}-1,3-benzopyraz-2-yl)cyclopropanecarboxamide la 120 mg 3-[(2-amino-1,3-benzo-u-[- -6,yl)thio]-N-cyclobutyl[1,2,4]triazolo[4,3-b]indole-6,amine (49) and 0.06 cubic centimeters of cyclopropane gasification carbon^ 87 mg 54 N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-7]indole-3-yl ]thio]-1,3-benzopyrazol-2-yl)cyclopropanecarboxamide la 11〇mg 6-{[6-(bicyclo[3丄〇]hex-3-yloxy)[ ι,2,4]triazolo[4,3-7] 嗒耕基基]thiophenyl 1,3-benzopyrazol-2-amine (48) with 0.051 cubic centimeters of cyclopropane gasification carbon 醯 112 mg 145862 -105- 201040187 55 racemic-N2,N2-j^6-N-trans-2-fluorocyclohexyl)oxy][1,2,4]tri. Sit and [4,3-b].荅 -3--3-yl}thio)-indole, 3 · benzoxazol-2-yl]glycinamide 37a 200 mg racemic-6-({6-[(trans-2-) Cyclohexyl)oxy][l,2,4]triazolo[4,3-b]indole-3-yl}thio)-1,3-benzopyrazol-2-amine (51) 735 mg (diethylamino)acetic acid sodium (commercially available) 164 mg 56 racemic-2-(4-ethylhexahydrop than tiller-1-yl)-N-{6-[(6-{[ Trans-2-fluorocyclohexyl]oxym,2,4] triazino[4,3-b]indole 3-yl)thio sulfonium, 3-benzopyrazol-2-yl} Acetamide 37a 300 mg 6-({ 6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-b]indole-3-yl丨thio)-1,3-benzoxazol-2-amine (51) with 1.82 g (4-ethylhexahydropyrrolidin-1-yl)acetic acid hydrobromide (commercially available) 120 mg 57 Racemic-Ν-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-7]indole-3_yl) Thio]-1,3-benzoindole-2-yl}-2-(morpholine-4-yl)acetamide 37a 300 mg 6-({6-[(trans-2-fluoro) Cyclohexyl)oxy][1,2,4]triazolo[4,3-b]indol-3-yl}thio)-1,3-benzoxazol-2-amine (51) 1.05 g of sulphate <#-4-based acetic acid (commercially available) 156 mg 58 N-(6-U6-(cyclobutene) Oxy) [1,2,4]triazolo[4,3-7]indole-3-yl]thio}-1,3-alumpy p. Sit·2-base)-2-( Folin-4-yl) Ethylamine 37a 200 mg of 6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-b].荅 ° well-3-yl] thio}}-1,3-benzone. Gye-2-amine (35a) with 784 mg of whf-kallin-4-yl acetic acid (commercially available) 96 mg of 59 racemic-2-(4-cyclopropylhexahydropyrrol-1-yl)-N -{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]tagon-3-yl)thio] -1,3-benzopyrazol-2-yl}acetamide 37a 200 mg 6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazole And [Μι)]0荅p well base} thiol)-l,3-benzo-pyrazole-2-amine (51) and 990 mg (4-cyclopropylhexahydropyrrol-1-yl) Potassium Acetate (59b) 98 mg 59b (4-cyclopropylhexahydrop to plough-1 -yl) Potassium Acetate 2·1 g of bromoacetic acid and 3 g of 4-cyclopropylhexahydropyrazine. HC1, in a similar manner DT Witiak et al; j. Med. Chem. 1985, 28, 1228 under conditions of 2.66 g of 60 N-(6-{[6-(cyclobutyloxy) tl,2,4]triazolo[ 4,3-b]嗒--3-yl]thio H,3-stuppy p-°-Guidin-2-yl)-2-(4-cyclopropylhexahydropyridin-1-yl)B Amine amine 37a 15〇 mg 6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3 - benzopyrazole-2-amine (35a) with 418 mg (4-cyclopropylhexahydropyran-1-yl)acetate potassium (59b) 143 mg 61 Ν-(6-{[6-( Butyloxy) [1,2,4] and laugh [4,3-1)] column 11 wells 3-yl] thio} -1,3 stupid and ethyl. Sodium-2-yl)-2-(U-dithiocarbamate 0 -4-yl) Ethylamine 37a 15 〇 mg 6-{[6-(cyclobutyloxy) [1,2,4] Triazolo[4,3-bR -3-yl]thio H,3- benzopyrazol-2-amine (35a) with 391 mg (1,1-dithioxofenofolin-4-yl) Acetic acid (commercially available) 109 mg 145862 -106- 201040187 62 N-(6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-1)] morphine- 3-yl]thiol1,3-1,3-phenylindole p-indole-2-yl)-2-(1,4-oxo-7-yl-4-yl)acetamide 37a 200 mg 6-{[6- (cyclobutyloxy) [1,2,4]triazolo[4,3-1)]indol-3-yl]thio}}1,3-1,3-indole" 35a) with 489 mg of 1,4-oxo-7-octanyl-4-acetic acid unloaded (62b) 152 mg of 62b 1,4-oxo-7-hydroxy-4-phenylacetate 2.32 g of bromoacetic acid and 2.3 g of 1,4- Oxynitride heptahydrochloride hydrochloride, similar to that described by DT Witiak et al; <1.1^ (1.0^111· 1985, 28, 1228) 2.77 g 63 N-(6-{[6-(cyclobutane)氧基oxy) [1,2,4]triazolo[4,3-7]indol-3-yl]thio}-1,3-benzoxazol-2-yl)-3-methoxy Propylamine la 300 mg 6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-7]indole-3-yl]thio}-1,3- Stupid Thiazol-2-amine (35a) with 200 mg of gasified 3-decyloxypropionate (commercially available) 101 mg 64 N-(6-{[6-(cyclobutyloxy) [1,2,4] Triazolo[4,3-b]indole-3-yl]degradation}-1,3-alum tomb-2-yl)-2-(3,3-difluorohexahydropyridine-1- Acetylamine 37a 200 mg 6-{[6-(cyclobutyloxy) [1,2,4]triazolo[4,3-7]indole-3-yl]thio}}, 3- benzopyrimidine-2-amine (35a) with 484 mg (3,3-difluorohexahydropyridin-1-yl)acetic acid potassium (64b) 183 mg 64b (3,3-difluorohexahydropyridine - 1-base) potassium acetate 1.6 g of bromoacetic acid and 1.8 g of 3,3-difluorohexahydro-p bite, similar to those described by DT Witiak et al;;.^^ (1.0^111· 1985, 28, 1228 The characteristics of the 1.16 g of the above product are as follows: Example SM RMN 38 Retention time Tr (minutes) = 1.09; [M+H]+: m/z481; [MH]-: m/z 479 1H NMR spectrum (400 MHz) , 5 in ppm, DMSO-d6): 0.88 to 0.98 (m, 4H); 1.16 to 1.35 (m, 2H); 1.39 to 1.54 (m, 6H); 1.55 to 1.69 (m, 2H); 1.74 to 1.89 (m, 2H); 1.93 to 2.04 (m, 1H); 4.73 to 4.90 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.41 (dd, J = 2.1 8.4 Hz, 1H); 7.67 (d, J = 8.6 Hz, 1H); 8.05 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 12.67 (broad s, 1H) 145862 107· 201040187 39 Residence time Tr (minutes) = 3,03 ; [M+H]+ : m/z 568 ; [MH]- : m/z 566 1H NMR spectrum (400 MHz, δ in ppm, DMSO- D6) : 0.97 to 1.32 (m, 5H); 1.47 to 1.68 (m, 5H); 1.80 (m, 2H); 2.25 to 2.37 (m, 6H); 3.13 to 3.23 (m, 2H); 3.37 to 3.49 ( m,1H); 3.57 (m,4H); 6.71 to 6.82 (m,1H); 6.79 (d, J = 10.0 Hz, 1H); 7.25 (d, J = 7.1 Hz, 1H); 7.35 (dd, J = 2.0 and 8.6 Hz, 1H); 7.52 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 10.0 Hz, 1H); 7.98 (d, J = 2.0 Hz, 1H); 10.80 (broad m, 1H) 39b 1H NMR spectrum (400 MHz, d in ppm, DMSO-d6): 1.53 to 1.70 (m, 2H); 2.28 to 2.37 (m, 6H); 3.15 to 3.24 (m, 2H); 3.52 to 3.63 (m, 4H); 6.76 to 6.82 (m, 1H); 7.48 (dd, J = 2.0 M 8.6 Hz, 1H); 7.58 (d, J = 8.6 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1H) ; 10.86 (broad m, 1H) 40 residence time Tr (minutes) = 0.73; M+H]+ : m/z 569 ; [MH]- : m/z 567 1 H NMR spectrum (400 MHz, <5 expressed in ppm, DMSO-d6): 1.15 to 1.43 (m, 5H); To 1.53 (m, 1H); 1.57 to 1.66 (m, 4H); 1.78 to 1.86 (m, 2H); 2.27 to 2.37 (m, 6H); 3.19 (q, J = 5.6 Hz, 2H); 3.57 (t , J = 4.8 Hz, 4H); 4.66 to 4.75 (m, 1H); 6.77 (broad s, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.36 (dd, J = 2.0 and 8.6 Hz, 1H 7.54 (d, J = 8.3 Hz, 1H); 8.00 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 10.81 (broad s, 1H), 145862 108- 201040187 41 residence time Tr (minutes) = 2.98; [M+H]+: m/z 527 ; [MH]- : m/z 525 1H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.62 (m , 1H); 1.76 (m, 1H); 2.04 (m, 2H); 2.30 (m, 2H); 2.37 to 2.45 (m, 6H); 3.23 to 3.28 (masked m, 2H); 3.59 (t, J = 4.6 Hz, 4H); 4.92 (qd, J = 7.1 and 7.3 Hz, 1H); 6.77 (broad s, 1H); 7.05 (d, J = 9.8 Hz, 1H); 7.42 (dd, J = 2.1 and 8.4 Hz, 1H); 7.57 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 2.2 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H); 10.89 (broad s, 1H) 42 Residence time Tr (minutes) = 0.75 ; [M+H]+ : m/z 623 ; [MH]- · m/z 621 1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6): 1·22 (m, 2H); 1.33 (m, 2H); 1.75 (d, J = 13.2 Hz, 2H); 1.94 (d, J = 11.5 Hz, 2H); 2.19 to 2.35 (m, 1H); 2.36 to 2.45 (m, 6H); 3.23 to 3.28 (masked m, 2H); 3.59 (t, J = 4.8 Hz, 4H); 4.65 (m, 1H); 6.76 (broad s, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.32 (dd, J = 2.0 and 8.6 Hz, 1H); 7.52 (d, J = 8.6 Hz, 1H 7.96 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 10.87 (broad s, 1H) 42b 1H NMR spectrum (400 MHz, <5 expressed in ppm, DMSO- D6): 1.32 to 1.66 (m, 4H); 1.99 (m, 2H); 2.30 (m, 2H); 2.37 to 2.45 (m, 1H); 4.91 to 5.04 (m, 1H); 7.09 (d, J = 9.8 Hz, 1H) ; 8.28 (d, J = 9.8 Hz, 1H) 145862 109- 201040187 43 Residence time Tr (minutes) = 4.56 ; [M+H]+ : m/z481 ; [MH]- : m/z 479 1 H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.20 (m, 2H) 0.49 (m, 2H) ; 1.06 (m, 1H); 1.14 to 1.40 (m, 5H); 1.42 to 1.65 (m, 3H); 1.72 to 1.84 (m, 2H); 2.37 (d, J = 7.1 Hz, 2H); 4.60 to 4.73 (m, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.41 (dd, J = 2.0 and 8.6 Hz, 1H); 7.66 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 2.0 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H); 12.30 (broad s, 1H) 43b 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6 ) : -0.03 to 0.03 (m, 2H) ; 0.27 to 0.32 (m, 2H); 0.81 to 0.93 (m, 1H); 2.20 (d, J = 7.1 Hz, 2H); 7.48 (dd, J = 2.0 with 8.6 Hz, 1H); 7.63 (dd, J = 0.5 H 8.6 Hz, 1H); 8.18 (dd, J = 0.5 and 2.0 Hz, 1H); 12.24 (broad m, 1H) 44 Residence time Tr (minutes) = 0.97 ; [M+H]+ : m/z 439 ; [MH]- : m/z 437 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.92 to 0.98 (m, 4H); m,lH); 1.75 (m,lH); 2.01 (m,3H) ; 2.27 (m,2H) ; 4·90 (five-peak, J = 7.3 Hz, 1H); 7.06 (d, J = 9.8 Hz , 1H) ; 7.47 (dd, J = 2,0 and 8.6 Hz, 1H); 7.69 (d, J = 8.6 Hz, 1H); 8.11 (d, J = 2.0 H z, 1H) ; 8.29 (d, J = 9.8 Hz, 1H); 12.67 (broad s, 1H) 145862 Π0* 201040187 45 Residence time Tr (minutes) = ο.% ; :M+H]+: m/z612 ; -MH]- : m/z 610 1l·l NMR spectrum (400 MHz, δ expressed in ppm, DMSO-d6) isomer 70% trans 30% cis mixture: 1.12 to 1.65 (m, 4H); 1.67 To 1.85 (m, 5H); 1.87 to 1.97 (m, 2H); 2.35 to 2.45 (m, 6H); 3.26 (masked m, 2H); 3.51 to 3.68 (m, 5H); 4.66 (m, 0.7) H); 4.98 (m, 0.3H); 6.77 (broad s, 1H); 6.98 to 7.06 (m, 1H); 7.39 (m, 1H); 7.56 (m, 1H); 7.66 (d, J = 8.6 Hz, 0.7H); 7.74 (d, J = 8.1 Hz, 0.3H); 7.95 (d, J = 2.0 Hz, 0.7H); 8.03 (d, J = 2.0 Hz, 0.3H); 8.28 (d, J = 9.5 Hz, 1H); 10.88 (broad s, 1H) 45b 1H NMR spectrum (400 MHz, (5 in ppm, DMSO~d6) isomer 70% trans (biaxial) and 30% cis The mixture of (CHN ax-CHO eq) has: 1.29 to 2.23 (m, 8H); 1.78 (s, 0.9H); 1.80 (s, 2.1H); 3.50 to 3.72 (m, 1H); 4.94 (tt, J = 4·2 with 10.3 Hz, 0.7H); 5.14 (m, 0.3H); 7.03 to 7.13 (m, 1H); 7.79 to 7.90 (m,1H) ; 8.21 to 8.30 (m,1H) 46 residence time 11*(minutes)=1.〇5; [M+H]+ : m/z 535 ; [MH]- : m/z 533 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.90 to 0.98 (m, 4H); 1.14 (m, 2H); 1.31 (m, 2H); 1.69 (d, J = 12.2 Hz, 2H ; 1.87 (d, J = 10.5 Hz, 2H); 1.98 (m, 1H); 2.24 (m, 1H); 4.51 (m, lH); 7.03 (d, J = 9.8 Hz, 1H); 7.35 (dd , J = 2.0 ^ 8.6 Hz, 1H); 7.64 (d, J = 8.6 Hz, 1H); 8.02 (d, J = 2.0 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.66 (wide) s, 1H) 46b residence time Tr (minutes) = 3.86; [M+H]+: m/z 467 1 [MH]- * m/z 465 145862 -Ill - 201040187 47 residence time Tr (minutes) = 0.51 ; [M+H]+ : m/z 571 ; ;MH]- : m/z 569 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.24 (m, 2H); 1.36 (m, 2H ; 1.75 (m, 2H); 1.91 (m, 2H); 2.35 to 2.45 (m, 6H); 3.23 to 3.29 (masked m, 2H); 3.47 (m, 1H); 3.59 (t, J = 4.6 Hz, 4H); 4.57 (d, J = 4.2 Hz, 1H); 4.72 (m, 1H); 6.79 (broad s, lH); 7.01 (d J = 9.8 Hz, 1H); 7.40 (dd, J = 2.1 and 8.4 Hz, 1H); 7.56 (d, J = 8.6 Hz, 1H); 7.96 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 10.87 (broad s, 1H) 47b 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.29 to 1.43 (m, 2H); 1.49 to 1.63 (m, 2H) ; 1.82 to 1.92 (m, 2H); 2.09 to 2.22 (m, 2H); 3.58 (m, 1H); 4.59 (d, J = 3.9 Hz, 1H); 4.98 (m, 1H) ; 7.07 (d, J = 10.0 Hz, 1H) ; 8.26 (d, J = 10.0 Hz, 1H) 48 Residence time Tr (minutes) = 3.65; [M+H]+ : m/z 397 ; [MH]- : m/z 395 1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6): 0.38 (q, J = 4.2 Hz, 1H); 0.49 (m, 1H); 1.32 (m, 2H); 1.86 (m, 2H); (m, 2H); 5.25 (t, J = 6.7 Hz, 1H); 6.96 (d, J = 9.8 Hz, 1H); 7.28 (d, J = 8.3 Hz, 1H); 7.33 (dd, J = 2.0 with 8.6 Hz, 1H); 7.62 (s, 2H); 7.90 (d, J = 2.0 Hz, 1H); 8.22 (d, J = 9.8 Hz, 1H) 48b 1 H NMR spectrum (400 MHz, <5 in ppm Represents DMSO-d6): 0.44 (q, J = 4.2 Hz, 1H); 0_53 (m, 1H); 1.33 to 1.44 (m, 2H); 1.99 (d, J = 14.9 Hz, 2H); 2.23 to 2.37 (m, 2H); 5.44 (t, J = 6.7 Hz, 1H); 7.03 (d, J = 9.8 Hz, 1H) 8.24 (d, J = 9.8 Hz, 1H) 145862 -112- 201040187 49 Residence time Tr (minutes) = 〇, 68 ; [M+H]+ : m/z 370 ; [MH]- : m/z 368 1H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.66 to 1.78 (m, 2H); 1.80 to 1.96 (m, 2H); 2.16 to 2.31 (m, 2H); 3.95 to 4.18 (m ,1H); 6.76 (d, J = 9.8 Hz, 1H); 7.31 (d, J = 8.6 Hz, 1H); 7.37 (dd, J = 1.8 and 8,6 Hz, 1H); 7.72 (broad d, J = 7.0 Hz, 1H); 7.87 to 7.95 (m, 2H); 8.04 (broad m, 2H) 49b Residence time Tr (minutes) = 〇.7〇; [M+H]+ : m/z 224 ; [MH ]- : m/z 222 50 residence time Tr (minutes) = 1.08; [M+H]+ : m/z 479 ; [MH]- : m/z 477 W NMR spectrum (400 MHz, (5 in ppm, DMSO-d6) : 0.35 (q, J = 3.9 Hz, 1H); 0.47 (m, 1H); 1.27 (m, 2H); 1.72 to 2.03 (m, J = 14.9 Hz, 4H); 2.07 to 2.33 (m , 6H); 3.35 to 3.47 (masked m, 1H); 5.21 (t' J = 6.8 Hz, 1H); 6.98 (d, J = 9.8 Hz, 1H); 7.45 (dd, J = 2.1 and 8.4 Hz, 1H); 7.67 (d, J = 8.3 Hz, 1H); 8.16 (d, J = 2.0 Hz, 1H); 8.25 (d, J = 9.8 Hz, 1H); 12.25 (broad s, lH) 51 Residence time Tr (minutes) = 0.76; [M+H]+: m/z 417; [MH]- : m/z 415 1H NMR spectrum (400 MHz, expressed in ppm, DMSO-d6): 1.29 (d, J = 8.6 Hz, 3H); 1,43 to 1.76 (m, 3H); 1.90 to 2.18 (m, 2H); 4.50 To 4.88 (m, 2H); 7.07 (d, J = 9.8 Hz, 1H); 7.27 (d, J = 8.6 Hz, 1H); 7.31 (dd, J = 1.7 and 8.3 Hz, 1H); 7.61 (s, 2H) ; 7.83 (d, J = 2.0 Hz, 1H); 8.29 (d, J = 10.0 Hz, 1H) 145862 -113- 201040187 51b 1H NMR spectrum (400 MHz, δ expressed in ppm, DMSO-d6): 1.32 to 1.53 (m, 3H); 1.56 to 1.79 (m, 3H); 2.12 (m, 1H); 2.30 (m, 1H); 4.61 to 4.87 (m, 1H); 5.01 to 5.17 (m, 1H); 7.14 (d , J = 9.8 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H) 52 Retention time Tr (minutes) = 0.97; [M+H]+ : m/z 485 ; [MH]- : m/z 483 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.95 (m, 4H); 1.07 to 1.33 (m,3H) ; 1.43 (m,2H); 1.62 (m, J = 15.7 Hz, 1H); 1.85 (m, 1H); 1.93 to 2.12 (m, 2H); 4.46 to 4.78 (m, 2H) ; 7.08 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and 8.3 Hz, 1H); 7.68 (d, J = 8.3 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1H) ; 8.32 (d, J = 9.8 Hz, 1H); 12.67 (broad s, 1H) 53 Residence time Tr (minutes) = 0.89; [M+H]+ : m/z 438 ; [MH]- : m/z 436 1H NMR spectrum (400 MHz, ¢5 in ppm, DMSO-d6): 0,90 to 0.99 (m, 4H); 1.61 to 1.73 (m, 2H); 1.77 to 1.90 (m, 2H); 1.94 to 2.04 (m,1H); 2.12 to 2.24 (m,2H); 3.95 to 4.07 (m, 1H); 6.75 (d, J = 9.8 Hz, 1H); 7.45 (dd, J = 1.8 and 8.4 Hz, 1H) ; 7.63 to 7.72 (m, 2H); 7.93 (d, J = 9.8 Hz, 1H); 8.12 (d, J = 1.8 Hz, 1H); 12.66 (broad m, 1H) 54 Residence time Tr (minutes) = 1.03 ; [M+H]+ : m/z 465 ; [MH]- : m/z 463 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.34 (q, J = 4.3 Hz, 1H) ; 0.47 (m, 1H); 0.95 (m, 4H); 1.27 (m, 2H); 1.72 to 1.84 (m, 2H); 8 (m, 1H) ; 2.12 (m, 2H) ; 5.20 (t, J = 6.7 Hz, 1H); 6.98 (d, J = 9.8 Hz, 1H); 7.45 (dd, J = 2.0 and 8.6 Hz, 1H 7.68 (d, J = 8.6 Hz, 1H); 8.13 (d, J = 2.0 Hz, 1H); 8.24 (d, J = 9.8 Hz, 1H); 12.66 (broad s, 1H) 201040187

55 ---— 滯留時間 Tr (分鐘）=0 71 ; :M+H]+ : m/z 530 ; [M+2H]2+： m/z 265.5 (基峰）[M-H]- : m/z 528 — 1H NMR 光譜（400 MHz，δ 以 ppm 表示，DMSO-d6) : 0·99 (t，J = 7.2 Hz， 6H) ; 1.04 至 1.33 (m，3H) ; 1.34 至 1.50 (m，2H) ; 1.56 至 1.70 (m, 1H); 1,85 (d，J = 6.1 Hz，lH); 1.95 至 2.10 (m, 1H) ； 2.62 (q, J = 7.1 Hz, 4H)； 3.40 (s，2H) ; 4.42 至 4.76 (m，2H); 7.08 (d, J = 9.8 Hz, 1H) ； 7.43 (dd, J = 1.8 與 8.4 Hz，1H) ; 7.67 (d，J = 8.4 Hz， 1H); 8.10 (d，J = 1.8 Hz，lH); 8.32 (d， J = 9‘8 Hz，1H) ; 10.73 至 12.94 (極寬廣 m，1H) 56 -一滯留時間 Tr (分鐘）=0,70 ; [M+H]+ : m/z 571 ； [M+2H]2+ : m/z 286 (基峰）[M-H]- : m/z 569 -—-- iHNMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 0.98 (t，J = 7.1 Hz， 3H); 1.08 至 1.33(m，3H); 1.35 至 1.50 (m, 2H) ； 1.63 (m, 1H) ； 1.84 (m, 1H) ; 2.04 (m，1H) ; 2.20 至 2.58 (經部份遮蔽之m，10H) ; 3.20至3.40 (經部份遮蔽之m，2H) ; 4.45至 4.76 (m, 2H) ； 7.08 (d, J = 9.8 Hz, 1H) ; 7.44 (dd，J = 1.7 與 8.8 Hz，1H); 7.68(d,J = 8.8Hz, 1H) ； 8.10 (d,J= 1.7 Hz, 1H) ； 8.32 (d, J = 9.8 Hz, 1H)； 12.09 (寬廣 m, 1H) 57 滯留時間 Tr (分鐘）=0.71 ; [M+H]+ : m/z 544 ; [M+2HJ2+ ： m/z 272.5 (基峰）[M-H]- : m/z 542 1H NMR 光譜（400 MHz, 5 以 ppm 表示，DMSO-d6) : 1.10 至 1.32 (m， 3H) ; 1.34 至 1.51 (m，2H) ; 1.58 至 1.68 (m，1H) ; 1.81 至 1.92 (m，1H); l. 96 至 2.11 (m，1H) ; 2.45 至 2.55 (經部份遮蔽之 m，4H) ; 3.34 (s，2H); 3.56 至 3.66 (m，4H) ; 4.48 至 4.78 (m， 2H) ； 7.08 (d, J = 9.8 Hz, 1H) ； 7.44 (dd，J = 2.0 與 8.6 Hz, 1H) ; 7.68 (d，J = 8.6 Hz, 1H) ； 8.10 (d, J = 2.0 Hz, 1H)； 8.32(d，J = 9.8Hz，lH); 12.15(寬廣 m, 1H) 145862 115 - 201040187 58 滯留時間 Tr (分鐘）=0.71 ; [M+H]+ ： m/z 498 ； [M+2H]2+ ： m/z 249.5 (基峰）[M-H]- : m/z 496 1H NMR 光譜（400 MHz, (5 以 ppm 表示，DMSO-d6) : 1.61 (m，1H); l. 74 (m，1H) ; 1.95 至 2.09 (m，2H); 2.20 至 2.31 (m，2H) ; 2.53 (m，4H); 3.33 (s, 2H) ； 3.60 (m, 4H) ； 4.90 (m, 1H) ； 7.06 (d, J = 9.8 Hz, 1H) ； 7.47 (dd，J = 2.0 與 8.8 Hz，1H) ; 7.70 (d，J 二 8.8 Hz, 1H) ； 8.13 (d, J = 2.0 Hz, 1H)； 8.30 (d，J = 9.8 Hz，1H) ; 12.14 (寬廣 m, 1H) 59 滯留時間 Tr (分鐘）=〇,72 ; [M+H]+ ： m/z 583 ； [M+2HJ2+ ： m/z 292 (基峰）[M-H]- : m/z 581 1H NMR 光譜（400 MHz, <5 以 ppm 表示，DMSO-d6) : 0.26 (m，2H); 0.39 (m，2H) ; 1.02 至 1.33 (m，3H); 1.35 至 1.50 (m，2H); 1.61 (d，J = 3.2 Hz, 2H) ; 1.79 至 1.92 (m，1H) ; 2.04 (m，1H) ; 2.45至2.59 (經部份遮蔽之 m, 8H) ; 3.37 至 3.41 (m，2H); 4.46 至 4.75 (m，2H) ; 7·08 (d，J = 9.8 Hz, 1H) ; 7.44 (寬廣 d, J = 8.7 Hz, 1H) ； 7.68 (d, J = 8.7 Hz, 1H) ； 8.10 (寬廣 s，1H) ; 8.32 (d，J = 9·8 Hz, 1H) ; 12.12(寬廣 m,lH) 59b 滯留時間 Tr (分鐘）= 0.10 ; [M+H]+ ： m/z 185 ； 201040187 60 滯留時間 Tr (分鐘）= 0.71 ; [M+H]+ ： m/z 537 ； [M+2H]2+ ： mlz 269 (基峰）[M-H]- : m/z 535 ^NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 0.20 至 0.30 (m, 2H) ; 0.36 至 0.45 (m, 2H) ; 1.54 至 1.66 (m，2H) ; 1.69 至 1.81 (m，1H); 1.96 至 2.09 (m，2H) ; 2.22 至 2.31 (m, 2H) ; 2.42至2.60 (經部份遮蔽之 m，8H) ; 3.18至3.46 (經部份遮蔽之 m，2H) ; 4·90 (m，1H) ; 7.06 (d，J = 9.8 Hz，1H) ; 7.47 (dd，J = 1.9 與 8.6 Hz, 1H) ； 7.70 (d, J = 8.6 Hz, 1H)； 8.13 (d，J = 1.9 Hz，1H) ; 8.29 (d，J = 9.8 Hz, 1H) ; 11.23 至 13.22 (極寬廣 m, 1H) 61 滯留時間 Tr(分鐘）= 0,86 ; [M+H]+ ： m/z 546 ； [M-H]- ： m/z 544 1H NMR 光譜（400 MHz，（5 以 ppm 表示，DMSO-d6) : 1.60 (m，1H); 1.75 (m，1H) ; 1.96 至 2.10 (吼 2H); 2.23 至 2.34 (m，2H) ; 3.03 至 3.19 (m， 8H) ； 3.58 (s, 2H) ； 4.91 (m, 1H)； 7.06 (d, J = 9.8 Hz, 1H) ； 7.48 (dd, J = 2.0 與 8.6 Hz, 1H) ; 7.71 (d，J = 8.6 Hz, 1H) ； 8.14 (d, J = 2.0 Hz, 1H) ； 8.30 (d, J = 9.8 Hz，1H) ; 12.23 (寬廣 m，1H) 62 滯留時間 Tr(分鐘）= 3.10 ; [M+H]+： m/z 512； [M-H]-： m/z 510 1H NMR 光譜（400 MHz, (5 以 ppm 表示，DMSO-d6) : 1.54 至 1.66 (m， 1H); 1.68 至 l,78(m，lH); 1.82(五重峰，J = 5.9Hz，2H); 1.95 至 2.10 (m，2H) ; 2.22 至 2.32 (m, 2H) ; 2.75 至 2.85 (m, 4H) ; 3.53 (s，2H) ; 3.60 至 3.65 (m，2H) ; 3.69 (t，J = 5.9 Hz, 2H) ； 4.90 (m, 1H) ； 7.06 (d, J = 9.8 Hz，1H) ; 7.47 (dd，J = 2.0 與 8.6 Hz, 1H) ； 7.70 (d, J = 8.6 Hz, 1H) ； 8.13 (d, J = 2.0 Hz, 1H) ； 8.30 (d, J = 9.8 Hz, 1H); 12.12(寬廣 m，lH) 145862 •117· 201040187 62b 滯留時間 Tr (分鐘）= 0.13 ; [M+H]+ : m/z 160 ; [M-H]- ： m/z 158 63 滯留時間 Tr (分鐘）=0.91 ; [M+H]+ : m/z 457 ; [M-H]- * m/z 455 1 H NMR 光譜（400 MHz, (5 以 ppm 表示，DMSO-d6) : 1.61 (m，1H); 1.74 (m，1H) ; 1.92 至 2.09 (m，2H); 2.22 至 2.32 (m，2H) ; 2.73 (t，J = 6.1 Hz, 2H) ； 3.23 (s, 3H) ； 3.65 (t, J = 6.1 Hz, 2H) ； 4.90 (m, 1H) ； 7.06 (d, J = 10.0 Hz，1H) ; 7.47 (dd，J = 2.0 與 8.6 Hz, 1H) ； 7.69 (d, J = 8.6 Hz, 1H)； 8.12 (d, J = 2.0 Hz，lH); 8.29 (d，J = 10.0 Hz，1H) ; 12.41 (寬廣 m，1H) 64 滯留時間 Tr (分鐘）=1.04 ; [M+H]+ : m/z 532 ; [M-H]- ： m/z 530 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 1.51 至 1.80 (m， 4H) ; 1.82 至 1.94 (m, 2H) ; 1.96 至 2.10 (m，2H) ; 2.22 至 2.31 (m，2H); 2.62 (m, 2H) ； 2.90 (t, J = 11.7 Hz, 2H) ； 3.50 (s, 2H) ； 4.90 (m, 1H)； 7.06 (d, J = 9.8 Hz, 1H) ； 7.48 (dd, J = 2.0 與 8.6 Hz，1H) ; 7.71 (d，J = 8.6 Hz, 1H) ； 8.14 (d, J = 2.0 Hz, 1H) ； 8.30 (d, J = 9.8 Hz, 1H) ; 12.19 (寬廣 m, 1H) 64b 滯留時間 Tr (分鐘）= 0.13 ; [M+H]+ ： m/z 180 ； [M-H]- : m/z 178 實例65 : 外消旋-1·{6-[(6-{[3-曱基環己基]氧基}[1，2,4]三《坐并[4,3-b]"荅喷· 3-基)硫基]_1，3·苯并嘧唑-2-基}-3_[2-(嗎福啉-4-基）乙基]g尿，順式與反式異構物（主要）之15/85混合物 a) l-{6-[(6-{[3-曱基環己基]氧基川又4]***并[4,3_b]嗒畊各基）&基]-1，3-笨并p塞。坐-2-基}-3-[2-(嗎福淋_4_基）乙基]脲可以類 145862 -118- 201040187 似關於實例2a中所述之方式製成，但使用〇 24〇克外消旋順式-與反式-3-氯基-6-{[3-甲基環己基]氧基}[ι，2,4]***并[4,3-b] 。合畊之1/1混合物，溶於12立方公分乙醇中，接著，在2〇。〇區域中之溫度下’添加0.457克1-[2-(嗎福淋-4-基）乙基]-3-(6-硫基-1，3-苯并嘧唑-2-基)脲（2b)、0.416克DL-二硫基蘇糖醇及 0.061克磷酸二氫鉀在〇 6〇〇立方公分蒸餾水中之溶液。於回流下擾拌8小時後’使反應媒質在減壓（2.7 kPa)下濃縮至乾〇涵。使殘留物溶於40立方公分二氯曱烷中，並將所獲得之混合物以30立方公分蒸餾水與15立方公分飽和氣化鈉溶液連續洗滌兩次，然後以無水硫酸鎂脫水乾燥，過濾，及在減壓（2.7 kPa)下濃縮至乾涸，而得0.370克橘色泡沫物。使此橘色泡沫物於矽膠上藉急驟式層析純化[溶離劑：二氣甲烷/曱醇/乙腈（90/5/5體積比+ 0.1% v/v20%氨水溶液）]。於減壓下濃縮溶離份後，獲得0.121克外消旋順式-與反式小 {6-[(6-{[3-曱基環己基]氧基丨[1，2,4]***并[4,3-b]嗒畊-3-基）硫〇基H，3-苯并p塞唑-2-基}-3-[2-(嗎福啉-4-基）乙基]脲之15/85混合物，呈白色固體形式，在197.6°C下熔解，其特徵如下： 1H NMR 光譜（400 MHz, 6 以 ppm 表示，DMSO-d6)異構物 85% H1-ax 15% Hl-eq 之混合物具有 0.71 (d, J = 6.3 Hz，0.45H) ; 0.81 (d，J = ‘ 6.6 Hz，2.55H) ; 0.72 至 1.80 (m，7H) ; 1.85 至 1.94 (m，2H) ; 2.36 至 2.44 (m，6H) ; 3.26 (經部份遮蔽之 m，2H) ; 3.59 (m，4H) ; 4.64 (m， 0.85H) ; 5.07 (m，0.15H) ; 6.78 (寬廣 t，J = 6.1 Hz，1H) ; 7.01 (d，J = 10.0 Hz，0.85H) ; 7.03 (d，J = 10.0 Hz，0.15H) ; 7.34 (dd，J = 2.0 與 8.6 Hz, 0.85H) ； 7.37 (dd, J = 2.0 # 8.6 Hz, 0.15H) ； 7.54 (d, J = 8.6 Hz, 1H)； U5862 201040187 7.96 (d, J - 2.0 Hz, 0.85H) ； 8.03 (d, J = 2.0 Hz, 0.15H) ； 8.25 (d, J = 10.0 Hz, 0.15H) ; 8·27 (d, J = 10.0 Hz，〇 85H) ; 1〇 9〇 (寬廣 m，1H)。質譜 ES+/- : [M+H]+ : m/z 569 ; [m-η]- : m/z 567。 b)外消旋順式·與反式-3-氯基-6-{[3-甲基環己基]氧基}[1，2,4]***并[4,3-b]嗒畊之m混合物可以類似實例lc中所述之方式製成，但在氬氣流下，以已溶於6立方公分四氫呋喃中之0.628克外消旋順式_與反式各甲基_環己醇之m混合物開始，在o°c區域中之溫度下’於其中添加〇 22〇克在 60%下於油中之氫化鈉。使反應媒質在區域中之溫度下保持15分鐘，接著添加0_650克3 6_二氣[12 4]***并[4 3七]嗒畊。於20°C區域中之溫度下攪拌24小時後，添加1〇立方公分飽和氣化銨水溶液與20立方公分醋酸乙酯。在分離兩相後，將有機相以10立方公分蒸餾水與15立方公分飽和氯化鈉溶液連續洗滌兩次，然後以無水琉酸鎂脫水乾燥，過濾，及在減壓（2.7 kPa)下濃縮至乾涸，而得〇 95〇克外消旋順式-與反式-3-氣基-6-{[3-曱基環己基]氧基}[12 4]***并[4,3_ b]嗒畊之1/1混合物，呈褐色油形式，其特徵如下：質譜 ES+ : [M+H]+ : m/z 267。實例66 : 外消旋-N-{6-[(6-{[3_甲基環己基]氧基似，：^]***并[4,3 b]塔畔· 3-基）硫基]-1，3-苯并嘧唑-2-基}環丙烷羧醯胺，順式與反式異構物（主要）之15/85混合物 a)外消旋N-{6-[(6-{[3-曱基環己基]氧基}[1，2,4]三。坐并[4,3_ b]嗒畊-3-基）硫基]-1,3-苯并p塞唑-2-基}環丙烷羧醯胺之順式與 145862 •120- 201040187 反式異構物之15/85混合物可以類似關於實例2a中所述之方式製成，但以0.500克N-(6-硫基-1，3-笨并嘧唑-2-基）環丙烷缓醯胺、0.616克DL-二硫基蘇糖醇、0.090克磷酸二氫鉀在1立方公分蒸餾水中之溶液、0.355克外消旋順式-與反式_3_氣基-6-{[3-甲基環己基]氧基}[1，2,4]***并[4,3-b]嗒畊之1/1混合物（65b)及18立方公分乙醇開始》於回流下擾拌8小時，接著處理及在石夕膠上藉急驟式層析純化[溶離劑：二氣甲烧/ 甲醇/乙腈(90/5/5體積比）]後，獲得(U98克外消旋N-{6-[(6-{[3-甲基環己基]氧基} [1,2,4]***并[4,3-b]嗒畊-3-基)硫基]4,3-苯并嘧吐-2-基}環丙烷羧醯胺之順式與反式異構物之15/85混合物’呈白色固體形式’在216.5°C下熔解，其特徵如下： 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6)異構物 85% H1-ax-15% Hl-eq 之混合物具有〇·7〇 (d，J = 6.4 Hz, 0.45H) ; 0.78 (d J = 6.4 Hz, 2.55H)，0.72 至 1.78 (m，11H) ; 1.85 (m，2H) ; 1.97 (m, iH);55 ---— Residence time Tr (minutes)=0 71 ; :M+H]+ : m/z 530 ; [M+2H]2+: m/z 265.5 (base peak)[MH]- : m/ z 528 — 1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0·99 (t, J = 7.2 Hz, 6H); 1.04 to 1.33 (m, 3H); 1.34 to 1.50 (m, 2H) ; 1.56 to 1.70 (m, 1H); 1,85 (d, J = 6.1 Hz, lH); 1.95 to 2.10 (m, 1H); 2.62 (q, J = 7.1 Hz, 4H); 3.40 (s, 2H) ; 4.42 to 4.76 (m, 2H); 7.08 (d, J = 9.8 Hz, 1H); 7.43 (dd, J = 1.8 and 8.4 Hz, 1H); 7.67 (d, J = 8.4 Hz, 1H); 8.10 (d, J = 1.8 Hz, lH); 8.32 (d, J = 9'8 Hz, 1H); 10.73 to 12.94 (extremely broad m, 1H) 56 - one residence time Tr (minutes) = 0, 70; [M+H]+ : m/z 571 ; [M+2H]2+ : m/z 286 (base peak) [MH]- : m/z 569 ---- iHNMR spectrum (400 MHz, 5 ppm) DMSO-d6): 0.98 (t, J = 7.1 Hz, 3H); 1.08 to 1.33 (m, 3H); 1.35 to 1.50 (m, 2H); 1.63 (m, 1H); 1.84 (m, 1H) 2.04 (m,1H); 2.20 to 2.58 (partially masked m, 10H); 3.20 to 3.40 (partially masked m, 2H); 4.45 to 4.76 (m, 2H); .08 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 1.7 and 8.8 Hz, 1H); 7.68 (d, J = 8.8 Hz, 1H); 8.10 (d, J = 1.7 Hz, 1H) ; 8.32 (d, J = 9.8 Hz, 1H); 12.09 (broad m, 1H) 57 Residence time Tr (minutes) = 0.71; [M+H]+ : m/z 544 ; [M+2HJ2+ : m/z 272.5 (base peak) [MH]- : m/z 542 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.10 to 1.32 (m, 3H); 1.34 to 1.51 (m, 2H); 1.58 To 1.68 (m, 1H); 1.81 to 1.92 (m, 1H); l. 96 to 2.11 (m, 1H); 2.45 to 2.55 (partially masked m, 4H); 3.34 (s, 2H); 3.56 To 3.66 (m, 4H); 4.48 to 4.78 (m, 2H); 7.08 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and 8.6 Hz, 1H); 7.68 (d, J = 8.6 Hz, 1H); 8.10 (d, J = 2.0 Hz, 1H); 8.32 (d, J = 9.8 Hz, lH); 12.15 (broad m, 1H) 145862 115 - 201040187 58 residence time Tr (minutes) = 0.71; [M+H]+ : m/z 498 ; [M+2H]2+ : m/z 249.5 (base peak) [MH]- : m/z 496 1H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.61 (m, 1H); l. 74 (m, 1H); 1.95 to 2.09 (m, 2H); 2.20 to 2.31 (m, 2H) ; 2.53 (m, 4H); 3.33 (s, 2H) ; 3.60 (m, 4H) ; 4.90 (m, 1H) ; 7.06 (d, J = 9.8 Hz, 1H) ; 7.47 (dd, J = 2.0 With 8.8 Hz, 1H); 7.70 (d, J two 8.8 Hz, 1H); 8.13 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.14 (broad m, 1H) 59 Residence time Tr (minutes) = 〇, 72 ; [M+H]+ : m/z 583 ; [M+2HJ2+ : m/z 292 (base peak) [MH]- : m/z 581 1H NMR spectrum ( 400 MHz, <5 expressed in ppm, DMSO-d6): 0.26 (m, 2H); 0.39 (m, 2H); 1.02 to 1.33 (m, 3H); 1.35 to 1.50 (m, 2H); 1.61 (d , J = 3.2 Hz, 2H); 1.79 to 1.92 (m, 1H); 2.04 (m, 1H); 2.45 to 2.59 (partially masked m, 8H); 3.37 to 3.41 (m, 2H); 4.46 to 4.75 (m, 2H) ; 7·08 (d, J = 9.8 Hz, 1H); 7.44 (broad d, J = 8.7 Hz, 1H); 7.68 (d, J = 8.7 Hz, 1H); 8.10 (broad s , 1H); 8.32 (d, J = 9·8 Hz, 1H); 12.12 (broad m, lH) 59b residence time Tr (minutes) = 0.10; [M+H]+ : m/z 185 ; 201040187 60 Time Tr (minutes) = 0.71; [M+H]+ : m/z 537 ; [M+2H]2+ : mlz 269 (base peak) [MH]- : m/z 535 ^ NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.20 to 0.30 (m, 2H); 0.36 to 0.45 (m, 2H); 1.54 to 1.66 (m, 2H); 1.69 to 1.81 (m) , 1H); 1.96 to 2.09 (m, 2H); 2.22 to 2.31 (m, 2H); 2.42 to 2.60 (partially masked m, 8H); 3.18 to 3.46 (partially masked m, 2H); 4·90 (m,1H) ; 7.06 (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 1.9 and 8.6 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H); 8.13 (d , J = 1.9 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1H); 11.23 to 13.22 (extremely wide m, 1H) 61 Residence time Tr (minutes) = 0,86 ; [M+H]+ : m/z 546 ; [MH]- : m/z 544 1H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.60 (m, 1H); 1.75 (m, 1H); 1.96 to 2.10 (吼2H); 2.23 to 2.34 (m, 2H); 3.03 to 3.19 (m, 8H); 3.58 (s, 2H); 4.91 (m, 1H); 7.06 (d, J = 9.8 Hz, 1H); 7.48 ( Dd, J = 2.0 and 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H); 8.14 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.23 ( Wide m, 1H) 62 Residence time Tr (minutes) = 3.10 ; [M+H]+: m/z 512; [MH]-: m/z 510 1H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.54 to 1.66 (m, 1H); 1.68 to 1,78 (m, lH); 1.82 (Five peaks, J = 5.9 Hz, 2H); 1.95 to 2.10 (m, 2H); 2.22 to 2.32 (m, 2H); 2.75 to 2.85 (m, 4H); 3.53 (s, 2H); 3.60 to 3.65 (m, 2H); 3.69 (t, J = 5.9 Hz, 2H); 4.90 (m, 1H); 7.06 (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 2.0 and 8.6 Hz, 1H) ;770 (d, J = 8.6 Hz, 1H); 8.13 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.12 (broad m, lH) 145862 •117· 201040187 62b Retention time Tr (minutes) = 0.13 ; [M+H]+ : m/z 160 ; [MH]- : m/z 158 63 Residence time Tr (minutes)=0.91 ; [M+H]+ : m/z 457 ; [MH]- * m/z 455 1 H NMR spectrum (400 MHz, (5 in ppm, DMSO-d6): 1.61 (m, 1H); 1.74 (m, 1H); 1.92 to 2.09 (m, 2.H (2H); 7.06 (d, J = 10.0 Hz, 1H); 7.47 (dd, J = 2.0 and 8.6 Hz, 1H); 7.69 (d, J = 8.6 Hz, 1H); 8.12 (d, J = 2.0 Hz, lH); 8.29 (d, J = 10.0 Hz, 1H); 12.41 (wide m, 1H) 64 Residence time Tr (minutes) = 1.04; [M+H]+ : m/ z 532 ; [MH]- : m/z 530 1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.51 to 1.80 (m, 4H); 1.82 to 1.94 (m, 2H); 1.96 to 2.10 (m, 2H); 2.22 to 2.31 (m, 2H); 2.62 (m, 2H); 2.90 (t, J = 11.7 Hz, 2H); 3.50 (s, 2H); 4.90 (m, 1H); 7.06 ( d, J = 9.8 Hz, 1H); 7.48 (dd, J = 2.0 and 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H); 8.14 (d, J = 2.0 Hz, 1H); 8.30 ( d, J = 9.8 Hz, 1H); 12.19 (broad m, 1H) 64b Residence time Tr (minutes) = 0.13; [M+H]+ : m/z 180 ; [MH]- : m/z 178 Example 65 : racemic-1·{6-[(6-{[3-indolylcyclohexyl]oxy}[1,2,4] three "sit and [4,3-b]"荅喷·3 -yl)thio]_1,3·benzopyrazol-2-yl}-3_[2-(morpholine-4-yl)ethyl]g urinary, cis and trans isomers (mainly) 15/85 mixture a) l-{6-[(6-{[3-indolylcyclohexyl]oxychuan 4]triazolo[4,3_b]indole)& base]-1, 3- Stupid and p plug. Sodium-2-yl}-3-[2-(ifosin-4-yl)ethyl]urea can be made in the manner described in Example 2a, but using 〇24 gram. Racemic cis-and trans-3-chloro-6-{[3-methylcyclohexyl]oxy}[ι,2,4]triazolo[4,3-b]. A 1/1 mixture of ploughed, dissolved in 12 cubic centimeters of ethanol, and then at 2 Torr. Adding 0.457 g of 1-[2-(norfos-4-yl)ethyl]-3-(6-thio-1,3-benzopyrazol-2-yl)urea at the temperature in the hydrazine region (2b), a solution of 0.416 g of DL-dithiothreitol and 0.061 g of potassium dihydrogen phosphate in 〇6 〇〇 cubic centimeter of distilled water. After stirring for 8 hours under reflux, the reaction medium was concentrated under reduced pressure (2.7 kPa) to dry culvert. The residue is dissolved in 40 cubic centimeters of dichloromethane, and the obtained mixture is continuously washed twice with 30 cubic centimeters of distilled water and 15 cubic centimeters of saturated sodium carbonate solution, and then dried over anhydrous magnesium sulfate, filtered, and Concentration to dryness under reduced pressure (2.7 kPa) gave 0.370 g of orange foam. This orange foam was purified by flash chromatography on silica gel [solvent: di-methane/methanol/acetonitrile (90/5/5 volume ratio + 0.1% v/v 20% aqueous ammonia solution)]. After concentrating the fractions under reduced pressure, 0.121 g of racemic cis- and trans-small {6-[(6-{[3-indolylcyclohexyl]oxyindole[1,2,4]triazole were obtained. And [4,3-b]indole-3-yl)thiol H,3-benzo-pyrazol-2-yl}-3-[2-(morpholine-4-yl)ethyl] The 15/85 mixture of urea, in the form of a white solid, melts at 197.6 ° C and is characterized as follows: 1H NMR spectrum (400 MHz, 6 ppm, DMSO-d6) isomer 85% H1-ax 15% Hl The mixture of -eq has 0.71 (d, J = 6.3 Hz, 0.45H); 0.81 (d, J = '6.6 Hz, 2.55H); 0.72 to 1.80 (m, 7H); 1.85 to 1.94 (m, 2H); 2.36 to 2.44 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.64 (m, 0.85H); 5.07 (m, 0.15H); 6.78 (broad t, J = 6.1 Hz, 1H); 7.01 (d, J = 10.0 Hz, 0.85H); 7.03 (d, J = 10.0 Hz, 0.15H); 7.34 (dd, J = 2.0 and 8.6 Hz, 0.85H); 7.37 ( Dd, J = 2.0 # 8.6 Hz, 0.15H) ; 7.54 (d, J = 8.6 Hz, 1H); U5862 201040187 7.96 (d, J - 2.0 Hz, 0.85H) ; 8.03 (d, J = 2.0 Hz, 0.15 H) ; 8.25 (d, J = 10.0 Hz, 0.15H); 8·27 (d, J = 10.0 Hz, 〇85H) ; 1〇 9〇 (wide m, 1H). Mass Spectrum ES+/-: [M+H]+: m/z 569; [m-η]-: m/z 567. b) racemic cis-and trans-3-chloro-6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b] The m mixture can be prepared in a manner similar to that described in Example lc, but under a stream of argon, 0.628 g of racemic cis- and trans-methyl-cyclohexanol dissolved in 6 cubic centimeters of tetrahydrofuran. The m mixture begins with the addition of 22 g of sodium hydride in 60% oil in the temperature at the temperature in the o°c region. The reaction medium was maintained at the temperature in the zone for 15 minutes, followed by the addition of 0-650 grams of 3 6_diox [12 4]triazole [4 3 7]. After stirring at a temperature in the region of 20 ° C for 24 hours, 1 〇 cubic centimeter of saturated aqueous ammonium sulfate solution and 20 cubic centimeters of ethyl acetate were added. After separating the two phases, the organic phase was washed twice with 10 cubic centimeters of distilled water and 15 cubic centimeters of saturated sodium chloride solution, then dehydrated with anhydrous magnesium citrate, filtered, and concentrated under reduced pressure (2.7 kPa). Drying, and yielding 95 g of racemic--trans--3-ylyl-6-{[3-indolylcyclohexyl]oxy}[12 4]triazolo[4,3_b] A 1/1 mixture of sorghum, in the form of a brown oil, characterized as follows: Mass Spectrum ES+: [M+H]+: m/z 267. Example 66: Racemic-N-{6-[(6-{[3_methylcyclohexyl]oxy],:^]triazolo[4,3 b]taan·3-yl)thio ]-1,3-Benzopyrazole-2-yl}cyclopropanecarboxamide, 15/85 mixture of cis and trans isomers (mainly) a) racemic N-{6-[(6) -{[3-indolylcyclohexyl]oxy}[1,2,4]III. Sodium[4,3_b]indole-3-yl)thio]-1,3-benzo-pyrazole The cis-form of -2-yl}cyclopropanecarboxamide and the 15/85 mixture of 145862 •120-201040187 trans isomers can be made in a manner similar to that described in Example 2a, but with 0.500 g N-(6 -thio-1,3- benzopyrazol-2-yl)cyclopropanolamine, 0.616 g of DL-dithiothreitol, 0.090 g of potassium dihydrogen phosphate in 1 cubic centimeter of distilled water, 0.355克外消顺式-与反式_3_气基-6-{[3-Methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b] The 1/1 mixture (65b) and 18 cubic centimeters of ethanol were initially spoiled under reflux for 8 hours, followed by treatment and purification by flash chromatography on Shishi gum. [Solution: Digestion / Methanol / Acetonitrile (90 /5/5 by volume)], obtained (U98 g of racemic N-{6-[(6-{[3-methylcyclohexane [1,2,4]triazolo[4,3-b]indole-3-yl)thio]4,3-benzopyrazin-2-yl}cyclopropanecarboxamide The 15/85 mixture of cis and trans isomers 'as a white solid' melted at 216.5 ° C and was characterized as follows: 1H NMR spectrum (400 MHz, 5 ppm, DMSO-d6) isomer A mixture of 85% H1-ax-15% Hl-eq has 〇·7〇 (d, J = 6.4 Hz, 0.45H); 0.78 (d J = 6.4 Hz, 2.55H), 0.72 to 1.78 (m, 11H) ; 1.85 (m, 2H) ; 1.97 (m, iH);

4.62 (m, 0.85H) » 5.03 (m, 0.15H) ) 7.01 (d, J = 9.8 Hz, 0.85H) i 7 03 (d J =9.8 Hz，0.15H) ; 7.39 (dd，J = 2.0 與 8,6 Hz，0.85H) ; 7.41 (dd，J = 2.0 與 8.6 Hz, 0.15H) ； 7.66 (d, J = 8.6 Hz, 1H) ； 8.02 (d, J = 2.0 Hz, 0.85H)； 8.09 (d, J = 2.0 Hz, 0.15H) ； 8.26 (d, J = 9.8 Hz, 0.15H) ； 8.28 (d J = 9 8 Hz, 0.85H) ; 12.67 (寬廣 m，m)。質譜 ES+/- : [M+H]+ : m/Z48i ; [m-H]- : m/z479。 b) N-(6-硫基-1，3-苯并嘧唑_2_基）環丙烷羧醯胺可以類似實例2b中所述之方式製成，但以14·〇克硫氰酸2_[(環丙基羰基）胺基]-U-苯并嘧唑各基酯、22.44克DL-二硫基蘇糖醇、 0.235克磷酸二氫鉀在60立方公分蒸餾水中之溶液及45〇立 145862 • 121 - 201040187 方公分乙醇開始。&回流下攪拌5小時後，將反應媒質在氬氣流下倒入700立方公分冰水中。於VF3上濾出所形成之頁色固體，以70立方公分冰水洗滌兩次，然後在減壓7 kPa)下，於40 C下經棋箱乾燥24小時，而得12 74克n_(6_硫基-1,3-苯并嘧唑-2-基）環丙烷羧醯胺，呈黃色固體形式，其特徵如下：質譜 ES+/- : [M+H]+ : m/z251 ; [M-H]- : m/z249。 c)硫氰酸2-[(環丙基羰基）胺基H,3_苯并嘧唑_6_基酯可以類似實例la中所述之方式製成，但以15〇克硫氰酸2_胺基_ 1’3-苯并噻唑_6_基酯、7‘88立方公分環丙烷氣化醯及立方公分吡啶開始。在2〇。(：區域中之溫度下攪拌5小時後，將反應媒質倒入500立方公分冰水中。在VF3濾器上濾出所形成之固體，然後以70立方公分冰水洗滌5次，接著於減壓（2.7 kPa)下，在4(TC下經烘箱乾燥10小時，而得19克硫氰酸2-[(環丙基羰基）胺基^义苯并嘧唑各基酯，呈粉紅色固體形式，其特徵如下：質譜 ES+/- : [M+H]+ : m/z 276 ; [M-H]- : m/z 274。實例67 : 1-[6-({6-[(4-甲基環己基）氧基似’2,4]***并[4,3_b]嗒畊各基}_硫基）-1，3-苯并違嗤·2·基]_3·[2-(嗎福淋_4·基）乙基脈，順式與反式異構物（主要）之15/85混合物 a)順式-與反式-丨啪-⑼-⑼-甲基環己基懷基叩又…*** 并[4,3-b]塔呼-3-基}硫基)-1,3-苯并p塞唾-2-基]-3-[2-(嗎福琳-4-基）乙基]脲之15/85混合物可以類似關於實例2a中所述之方式 145862 -122- 201040187 製成，但以0.876克1-[2-(嗎福啉-4-基）_乙基]_3_(6_硫基心-苯并嘍唑-2-基)脉(2b)、0.798克DL-二硫基蘇糖醇、01 η克磷酸二氫鉀在1.15立方公分蒸餾水中之溶液、〇 46〇克順式與反式-3-氣基各(4-甲基環己基氧基Η，2,4_***并[4,3 b]嗒畊之1Α 混合物及23立方公分乙醇開始。於回流下攪拌16小時，接著處理及在矽膠上藉急驟式層析純化[溶離劑：二氯甲烷/ 曱醇/乙腈（90/5/5體積比+ 〇·ΐ% ν/ν2〇%氨水溶液）]後，獲得 0.261克外消旋順式-與反式甲基環己基）氧 ® 基][1，2,4]二♦并[4,3七]塔畊-3-基}硫基）-ΐ，3-苯并ρ塞嗤-2-基]-3-|> (嗎福-4-基）乙基]脲之15/85混合物，呈白色固體形式，在 155.9°C下熔解，其特徵如下： 1 H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6)異構物 85% H1- ax-15% Hl-eq 之混合物具有：0.86 (d，j = 6 4 Hz，3H) ; 〇 88 至〇 93 (m，2H) ; 1.17 至 1.63 (m，5H) ; 1.76 至 1.93 (m，2H) ; 2.35 至 2.45 (m, 6H) ; 3.26 (經部份遮蔽之 m，2H) ; 3.59 (m，4H) ; 4.40 至 4.57 (m, q 1H) ; 6.78 (寬廣 m，1H) ; 7.00 (d，J = 9.8 Hz，0.85H) ; 7.04 (d，J = 9.84.62 (m, 0.85H) » 5.03 (m, 0.15H) ) 7.01 (d, J = 9.8 Hz, 0.85H) i 7 03 (d J =9.8 Hz, 0.15H); 7.39 (dd, J = 2.0 with 8,6 Hz, 0.85H); 7.41 (dd, J = 2.0 and 8.6 Hz, 0.15H); 7.66 (d, J = 8.6 Hz, 1H); 8.02 (d, J = 2.0 Hz, 0.85H); 8.09 (d, J = 2.0 Hz, 0.15H); 8.26 (d, J = 9.8 Hz, 0.15H); 8.28 (d J = 9 8 Hz, 0.85H); 12.67 (broad m, m). Mass spectrum ES+/-: [M+H]+: m/Z48i; [m-H]-: m/z479. b) N-(6-thio-1,3-benzopyrazol-2-yl)cyclopropanecarboxamide can be prepared in a manner similar to that described in Example 2b, but with 14 gram thiocyanate 2 _ [(cyclopropylcarbonyl)amino]-U-benzopyrazole ester, 22.44 g DL-dithiothreitol, 0.235 g potassium dihydrogen phosphate in 60 cm cm distilled water and 45 〇 145862 • 121 - 201040187 The start of the centimeters of ethanol. After stirring for 5 hours under reflux, the reaction medium was poured into 700 cubic centimeters of ice water under a stream of argon. The formed color solid was filtered out on VF3, washed twice with 70 cubic centimeters of ice water, and then dried at 40 C for 24 hours under a reduced pressure of 7 kPa to obtain 12 74 g of n_(6_ Thio-1,3-benzopyrazol-2-yl)cyclopropanecarboxamide, in the form of a yellow solid, characterized as follows: Mass Spectrum ES+/-: [M+H]+: m/z 251; [MH] - : m/z249. c) 2-[(cyclopropylcarbonyl)amino H,3-benzopyrazol-6-yl thiocyanate can be prepared in a manner similar to that described in Example la, but with 15 g of thiocyanate 2 Starting with _amino- 1'3-benzothiazole-6-yl ester, 7'88 cubic centimeters of cyclopropane gasified ruthenium and cubic centi pyridine. At 2 〇. (: After stirring for 5 hours at the temperature in the zone, the reaction medium was poured into 500 cubic centimeters of ice water. The solid formed was filtered off on a VF3 filter, and then washed 5 times with 70 cubic centimeters of ice water, followed by decompression (2.7 Under kPa), it was dried in an oven at 4 (TC) for 10 hours to obtain 19 g of 2-[(cyclopropylcarbonyl)amine-based benzopyrazole ester in the form of a pink solid. The characteristics are as follows: Mass spectrum ES+/-: [M+H]+: m/z 276; [MH]-: m/z 274. Example 67: 1-[6-({6-[(4-methylcyclohexyl) )oxy-like '2,4]triazolo[4,3_b]indoles}}-thiol-1,3-benzo-inhibited·2·yl]_3·[2-(? 4·yl) Ethyl vein, a 15/85 mixture of cis and trans isomers (mainly) a) cis- and trans-丨啪-(9)-(9)-methylcyclohexyl-kilyzinium...three Zoxao[4,3-b]toxa-3-yl}thio)-1,3-benzox-sial-2-yl]-3-[2-(moffin-4-yl) B The 15/85 mixture of ureas can be prepared similarly to the manner described in Example 2a 145862 - 122 - 201040187, but with 0.876 g of 1-[2-(morpholin-4-yl)-ethyl]_3_( 6_thio-heart-benzoxazol-2-yl) pulse (2b), 0.798 a solution of DL-dithiothreitol, 01 ηg of potassium dihydrogen phosphate in 1.15 cubic centimeters of distilled water, 〇46 g of cis and trans-3-carbyl (4-methylcyclohexyloxyindole) , 2,4_triazolo[4,3 b] 嗒之之 Α 混合物及及及及及及及及及及及及及及及 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 After methyl chloride/nonanol/acetonitrile (90/5/5 volume ratio + 〇·ΐ% ν/ν2〇% ammonia solution)], 0.261 g of racemic cis- and trans-methylcyclohexyl)oxy® were obtained. Base][1,2,4]two ♦[4,3-7]tung-3-yl}thio)-indole, 3-benzoxoxin-2-yl]-3-|> A 15/85 mixture of sulphon-4-yl)ethyl]urea, as a white solid, was melted at 155.9 ° C and characterized as follows: 1 H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6) The mixture of the isomers 85% H1-ax-15% Hl-eq has: 0.86 (d, j = 6 4 Hz, 3H); 〇88 to 〇93 (m, 2H); 1.17 to 1.63 (m, 5H) 1.76 to 1.93 (m, 2H); 2.35 to 2.45 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.40 to 4.57 (m, q 1H); 6.78 (broad m, 1H); 7.00 (d, J = 9.8 Hz, 0.85H); 7.04 (d, J = 9.8

Hz，0.15H) ; 7.31 (dd，J = 2.0 與 8.6 Hz，0.85H) ; 7.40 (dd，J = 2.0 與 8.6Hz, 0.15H); 7.31 (dd, J = 2.0 and 8.6 Hz, 0.85H); 7.40 (dd, J = 2.0 and 8.6)

Hz, 0.15H) > 7.53 (d, J =： 8.6 Hz, 0.85H) » 7.55 (d, J = 8.6 Hz, 0.15H)； 8.00 (d, J = 2.0 Hz, 0.85H) ； 8.04 (d, J = 2.0 Hz, 0.15H) ； 8.25 (d, J = 9.8Hz, 0.15H) > 7.53 (d, J =: 8.6 Hz, 0.85H) » 7.55 (d, J = 8.6 Hz, 0.15H); 8.00 (d, J = 2.0 Hz, 0.85H); 8.04 (d , J = 2.0 Hz, 0.15H); 8.25 (d, J = 9.8

Hz, 0.15H) ; 8.27 (d，J = 9.8 Hz，0.85H) ; 10.91 (寬廣 m，1H)。質譜 ES+/- : [M+H]+ : m/z 569 ; [M-H]- : m/z 567。 b)順式-與反式-3-氯基-6-(4-甲基環己基氧基）-1,2,4-*** 并[4,3-b]嗒畊之1/1混合物可以類似實例ic中所述之方式製成，但以0.628克外消旋順式-與反式_4_曱基環己醇之m混 145862 -123- 201040187 合物、6立方公分四氫呋喃、〇22〇克在6〇%下於油中之氫化納及0.650克3,6-二氣叫啦㈣[4,3补荅㈣始。在赃區域中之溫度下攪拌24小時，接著處理後，獲得〇88〇克順式-與反式-3-氯基-6-(4-甲基環己基氧基H,2,4_***并[4,3七]嗒畊之1/1混合物，呈褐色油形式，其係固化，其特徵如下：質譜 ES+ : [M+H]+ : m/z 267。實例68 : N-(6-{[6-(環己基氧基）[ι，2,4]***并[4,3_b]嗒畊_3-基]硫基}-i，3-苯并*»塞°坐-2-基）-3-(六風p比咬-1-基）一氮四園叛醯胺 N-(6-{[6-(%己基氧基）[1，2,4]***并[4,3七]嗒啡_3-基]硫基}-1，3· 笨并4唾-2-基）-3-(六氫p比啶-1-基）一氮四圜+羧醢胺可以類似實例5之方式，但以185毫克（6_{[6_(環己基氧基取，^]*** 并[4,3-bh合喷-3-基]硫基丨-1，3-苯并嘧唑_2_基）胺基曱酸苯酯 (4) ’在10立方公分THF與10立方公分DMF中，使用75毫克 1-(一氮四圜-3-基）六氫吡啶二鹽酸鹽與〇.16〇立方公分三乙月女開始’於20 C下反應66小時後製成。因此，獲得I%毫克N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基卜i，3_ 苯并嘧唑-2-基）-3-(六氫吡啶-1-基）一氮四圜小羧醯胺，呈淡黃色固體形式，其特徵如下： 1 H NMR 光譜（400 MHz，DMSO-d6, δ ppm) : 1.13 至 1.67 (m，14H); U1 (m，2H) ; 2.24 (寬廣 m，4H) ; 2.99 至 3.20 (寬廣 m，1H) ; 3.70 至 4.15 (寬廣 m，4H) ; 4.64 至 4.74 (m, 1H) ; 7.01 (d，J = 9.8 Hz，1H) ; 7.37 (dd，J = 2.0 與 8.3 Hz，1H) ; 7_55 (d，J = 8.3 Hz，1H) ; 8.00 (寬廣 s， 145862 -124- 201040187 1H); 8.27(d，J = 9.8Hz，1H); 11.32(寬廣 m，m)。質譜（電喷霧於 Waters UPLC-SQD 上）：[M+H]+ : m/z 565 ; [M_H]. :m/z 563。實例69 : N-[6-({H(4-甲基環己基）氧基】丨i，2,4】***并【4,3_b丨塔啩_3基卜碗基)-l，3-苯并嘧唑-2-基】環丙烷羧酿胺，順式與反式異構物（主要）之15/85混合物順式-與反式-N-[6-({6-[(4-曱基環己基）氧基][丨，2,4]三嗤并 [4,3_b]塔p井_3-基}硫基）_；[，3_苯并噻唑_2_基]環丙烷羧醯胺之 15/85混合物可以類似關於實例2a中所述之方式製成，但以 0.592克N-(6-硫基-1，3-苯并嘧唑_2_基）_環丙烷羧醢胺（66b)、 0.729克DL-二硫基蘇糖醇、〇.ι〇7克磷酸二氫斜在丨〇5立方公分蒸餾水中之溶液、0.420克3-氣基-6-(4-曱基環己基氧基）_ 1，2,4-***并[4,3-b]嗒畊之1/1混合物（67b)及20立方公分乙醇開始。於回流下攪拌16小時，接著處理及在矽膠上藉急驟式層析純化[溶離劑：二氯曱烷/甲醇/乙腈（9〇/5/5體積比）] 後’獲得0,336克N-[6-({6-[(4-甲基環己基）氧基][1，2,4]***并 [4,3-b]塔畊-3-基}硫基）·ι，3_苯并P塞唑_2_基]環丙烷羧醯胺之順式與反式異構物之15/85混合物，呈白色固體形式，在230 °C下熔解，其特徵如下： 1H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6)異構物 850/〇出-ax-15% Hl-eq 之混合物具有：0 72 至〇 99 (m，6H) ; 〇 82 (d，J = 6·6 Hz’2.55H); 0.88(cl，J = 6.6Hz，0.45H); 1.06 至 1.59(m, 5H); 1.82(d，J =9.0 Hz，2H) ; 1.94 至 2.04 (m，1H) ; 4.35 至 4.51 (m，1H) ; 7.00 (d，J = 145862· -125- 201040187 9.8 Hz, 0.85H) ; 7.04 (d，J = 9.8 Hz，0.15H) ; 7.35 (dd，J = 2.0 與 8.6 Hz， 0.85H); 7.45(dd，J = 2.0 與 8·6Ηζ,0.15Η); 7.66(d，J = 8.6Hz，〇.85H); 7.68 (d, J - 8.6 Hz, 0.15H) ； 8.06 (d, J = 2.0 Hz, 0.B5H) ； 8.11 (d, J = 2.0 Hz, 0.15H) ； 8.26 (d, J = 9.8 Hz, 0.15H) ； 8.28 (d, J = 9.8 Hz, 0.85H)； 12.68 (寬廣 m，1H)。質譜 ES+/- ·· [M+H]+ : m/z481 ; [M-H]- : m/z479 〇實例70 : N-(6-{【6-(環己基氧基）[1，2,4】***并丨43-b】嗒畊-3-基】硫基苯并嘧唑-2-基）-2-氧·6-氮螺丨3.3】庚烷-6-羧醢胺 Ν-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜1,3-苯并峰吨-2-基）-2-氧-6-氮螺[3.3]庚烧-6-叛醯胺可以類似實例 5中所述之方式製成’但以150毫克（6-{[6-(環己基氧基）[丨又斗] 三唾并[4,3-b]嗒畊-3-基]-硫基}-1，3-苯并嘍唑-2-基）胺基甲酸苯醋⑷、65毫克2-氧-6-氮螺[3.3]庚烷單草酸鹽、0.144立方公分三乙胺及10立方公分四氫呋喃開始。在2〇°c區域中之溫度下攪拌15小時，接著處理後，獲得〇.〇56克N_(6_{[6_(環己基氧基）[1，2,4]三哇并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘍嗤_2_ 基）-2-氧-6-氮螺[3.3]庚烷-6-羧醯胺，呈白色固體形式，其特徵如下：質譜 ES+Λ : [M+H]+ : m/z 524 ; [M-H]- : m/z 522。 1 H NMR 光譜（4〇〇 mhz，占以 ppm 表示，DMS〇_d6) : i 15 至 j 42 (m, 5H)，1‘49 (m，1H) ; 1.61 (m，2H) ; 1.81 (m，2H) ; 4.20 (寬廣 s, 4H) ; 4·66 (s，4H) ; 4.68 至 4.74 (m，1H) ; 7.01 (d，J = 9.8 Hz, 1H) ; 7.37 (dd，J = 2.0 與 8.6 Hz, 1H) ; 7·55 (寬廣 d，J = 8.6 Hz，1H) ; 8,00 (d, J = 145862 •126· 201040187 2.0 Hz，1H) ; 8.27 (d，J = 9·8 Hz，1H) ; 11.36 (寬廣 m，1H)。 2-氧-6-氣螺[3.3]庚烧單草酸鹽可如由Georg Wuitschik，Mark Rogers-Evans, Andreas Buckl, Maurizio Bernasconi, Moritz Marki, Thierry Godel, Holger Fischer, Bjiirn Wagner, Isabelle Parrilla，Franz Schuler, Josef Schneider，Andre Alker, W. Bernd Schweizer, Klaus Muller 及 Erick M. Carreira，Angew. Chem. Int. Ed. 2008, 47,4512-4515 所述製成。實例71 : Ν·(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3·基]硫基}-l，3-苯并《•塞唑-2-基)-3-(嗎福淋-4-基）一氮四圓-1-羧醯胺 N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜1,3-苯并p塞11 坐-2-基）-3-(嗎福琳-4-基）一氣四圜-1-緩隨胺可以類似實例5之方式，但以10立方公分THF中之182毫克（6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘍唑-2-基）胺基甲酸苯酯⑷、106毫克4-(一氮四園-3-基）嗎福p林二鹽酸鹽及0.167立方公分三乙胺開始，於20°C下反應22小時後製成。因此，獲得60毫克N-(6-{[6-(環己基氧基）[1，2,4]***并 [4,3-b]塔11 井-3-基]硫基}-1，3-苯并u塞嗤-2-基）-3-(嗎福p林-4-基）一氮四圜-1-羧醯胺，呈白色固體形式，其特徵如下： 1 H NMR 光譜（400 MHz, DMSO-d6，<5 ppm) : 1.11 至 1.42 (m，5H); 1.50 (m，1H) ; 1.62 (m，2H) ; 1.82 (m，2H) ; 2.31 (m，4H) ; 3.09 至 3.19 (m，1H) ; 3.59 (m，4H) ; 3.85 (m，2H) ; 4.04 (m，2H) ; 4.63 至 4.78 (m， 1H) ; 7.01 (d，J = 9.8 Hz, 1H) ; 7.36 (dd，J = 2Ό 與 8.6 Hz, 1H) ; 7.52 (寬廣 d，J = 8.6 Hz, 1H)，7.98 (d，J = 2.0 Hz, 1H) ; 8.26 (d，J = 9.8 Hz, 1H) ; 11.38(寬廣 m，1H)。 145862 -127- 201040187 質譜（電噴霧 Waters ZQ) : [M+H]+ : m/z 567 ; [M-H]- : m/z 565。實例72 : 外消旋-N-{6-[(6_{[反式·2-曱基環戊基]氧基}[ι，2,4]***并[4,3-b] °荅畊-3-基)硫基]_1，3_苯并嘍唑.2_基}環丙烷羧醯胺 a) 外消旋-N-{6-[(6-{[反式-2-甲基環戊基]氧基}[1，2,4]*** 并[4,3-b]嗒呼-3-基）硫基]-i，3-苯并嘧唑-2-基}環丙烷羧醯胺可以類似關於實例2a中所述之方式製成，但以0.636克N-(6-硫基-1,3-苯并噻唑-2-基）環丙烷羧醯胺（66b)、0.784克DL-二硫基蘇糖醇、0.115克磷酸二氫鉀在1.27立方公分蒸餾水中之溶液、0.428克外消旋順式-與反式-3-氣基-6-(2-甲基-環戊氧基）_ 1，2,4-***并[4,3-b]嗒畊之1/1混合物及23立方公分乙醇開始。於回流下攪拌16小時，接著處理及在矽膠上藉急驟式層析純化[溶離劑：二氯甲烷/曱醇/乙腈（90/5/5體積比）] 後’獲得0.260克外消旋-N-{6-[(6-{[反式-2-甲基環戊基]氧基}[1，2,4]***并[4,3-b]塔畊-3-基）硫基H，3-苯并嘧唑-2-基μ裒丙烷羧醢胺’呈白色固體形式，在197.7°C下熔解，其特徵如下： 1 H NMR 光譜（400 MHz，5 以 ppm 表示，DMSO-d6) : 0.89 (d，J = 7.1 Hz，3H) ; 0·92 至 1.00 (m，4H) ; 1.06 至 1.21 (m，1H) ; 1.46 至 1.69 (m, 3H) ; 1.78 至 2.12 (m，4H) ; 4.45 至 4.56 (m，1Η) ; 7.03 (d，J = 9.8 Hz， 1H) ； 7.43 (dd, J = 2.0 # 8.6 Hz, 1H) ； 7.68 (d, J = 8.6 Hz, 1H) ； 8.09 (d, J =2.0 Hz, 1H) ; 8.27 (d, J = 9.8 Hz, 1H) ; 12.67 (寬廣 m，1H)。質譜 ES+/- : [M+H]+ : m/z 467 ; [M-H]- : m/z 465。 b) 外消旋順式-與反式-3-氣基-6-(2-曱基環戊氧基）_i，2,4_ 145862 -128- 201040187 二唾并[4,3-b]°荅p井之1/1混合物可以類似實例中所述之方式製成’但以0.678克順式-與反式_2-甲基環戊醇之I/〗混合物、10立方公分四氫呋喃、0,271克在60%下於油中之氫化納及0.800克3,6-—氯[1，2,4]二唾并[4,3-b]*^ p井開始。在2〇°c區域中之溫度下授拌24小時，接著處理後，獲得ί ο%克外消旋順式-與反式-3-氣基-6-(2-甲基-環戊氧基）_ι，2,4-***并[4,3_ b]嗒畊之1/1混合物，呈褐色油形式，其特徵如下： ^ 質譜 ES+ : [M+H]+ : m/z 253。 Ό 實例73 : 外消旋·1-{6-[(6-{[反式·2·甲基環戊基]氧基似，2,4]***并[4,3七] 塔呼-3-基)硫基]-1，3-苯并嘧唑.2-基}·3·[2·(嗎福啉《4-基）乙基娜外消旋-1-{6-[(6-{[反式-2-曱基環戊基]氧基丨似⑷***并[4,3_ b]塔呼-3-基）硫基]-1，3-苯并嘧唑_2_基卜3-[2-(嗎福啉冰基）乙基] 脲可以類似關於實例2a中所述之方式製成，但以〇·6〇9克^ [2-(嗎福淋-4-基）乙基]-3-(6-硫基-l，3-苯并ρ塞唾_2_基）脲（2b)、 Ο 0·555克DL-二硫基蘇糖醇、〇·〇8ΐ克磷酸二氫鉀在0.85立方公勿蒸顧水中之溶液、0.303克外消旋順式_與反式各氯_6_(2_ 曱基-¾戊氧基）-1，2,4-***并[4,3-b]嗒畊之1/1混合物（72b)及17 立方公分乙醇開始。於回流下攪拌16小時，接著處理及在矽膠上藉急驟式層析純化[溶離劑：二氯曱烷/甲醇/乙腈 (90/5/5體積比+ oj% v/v2〇%氨水溶液）]後，獲得〇 223克外消方疋-1-{6-[(6-{[反式-2-甲基環戊基]氧基}[ι，2,4]三吐并[4,3七]塔喷_ 3-基）硫基H，3-笨并嘧唑_2_基丨_3_[2_(嗎福啉斗基）乙基]脲，呈淡黃色固體形式，在203.3T：下熔解，其特徵如下： 145862 -129- 201040187 1H NMR 光譜（4〇〇 MHz, (5 以 ppm 表示，DMSO-d6) : 0.92 (d, J = 7.1 Hz，3H) ; 1.16 (m, 1H) ; 1.50 至 1.69 (m, 3H) ; 1.79 至 2.12 (m, 3H); 2.37 至 2.44 (m, 6H) ; 3·26 (經部份遮蔽之 m，2H) ; 3.59 (m，4H); 4.52 至 4.60 (m，1H) ; 6.79 (寬廣 m，1H) ; 7.03 (d，J = 9.8 Hz，1H) ; 7.37 (dd，J = 2.0 與 8.5 Hz, 1H) ; 7.55 (d，J = 8.5 Hz, 1H) ; 8.03 (d，J = 2.0 Hz， 1H) ; 8.26 (d，J = 9.8 Hz, 1H) ; 10.90 (寬廣 m，iH)。質譜 ES+/- : [M+H]+ : m/z 555 ; [M-H]- : m/z 553。實例74 : 1^-(6-{[6-(環己基氧基）[1,2,4]***并[4,3-1)]嗒畊-3-基]硫基}-1，3-苯并f塞嗤-2-基)-3-甲氧基一氮四圜羧醯胺 N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3_ 苯并噻唑-2-基）-3-甲氧基一氮四圜小羧醯胺可以類似實例$ 之方式，但以5立方公分二甲基甲醯胺中之192毫克 (%己基氧基）[1，2,4]***并[4,3-b]嗒畊各基]硫基卜a苯并噻唑-2-基）胺基曱酸苯酯⑷' 69毫克3_甲氧基一氮四園鹽酸鹽及0.078立方公分三乙胺開始，於2(rc下反應2〇小時後製成。因此，獲得120毫克N-(6-{[6-(環己基氧基）[^4]***并 [4’3-b>合畊-3-基]硫基卜ι，3-苯并p塞唑_2_基）_3_甲氧基一氮四圜_ 1-羧醯胺，呈灰白色固體形式，其特徵如下： NMR 光譜(4〇〇 MHz，DMSO-d6, δ ppm):⑶至 142 (m，5H); 1.44 至 1.53 (m，1H) ; 1.61 (m，2H) ; 1.81 (m，2H) ; 3.21 (s, 3H) ; 3.83 (m, 2H) ; 4.13 至 4.30 (m，3H) ; 4.64 至 4.74 (m，1H) ; 7.02 (d, j = 9 8Hz, 0.15H); 8.27 (d, J = 9.8 Hz, 0.85H); 10.91 (broad m, 1H). Mass Spectrum ES+/-: [M+H]+: m/z 569; [M-H]-: m/z 567. b) 1/1 mixture of cis- and trans-3-chloro-6-(4-methylcyclohexyloxy)-1,2,4-triazolo[4,3-b] It can be prepared in a manner similar to that described in the example ic, but with 0.628 g of racemic cis-mixed with trans-_4_nonylcyclohexanol 145862-123-201040187, 6 cubic centimeters of tetrahydrofuran, hydrazine 22 grams at 6〇% in the oil in the hydrogenation and 0.650 grams of 3,6-two gas called (four) [4,3 supplement (four) began. After stirring for 24 hours at the temperature in the hydrazine zone, followed by treatment, 〇88 克 cis- and trans-3-chloro-6-(4-methylcyclohexyloxy H, 2, 4_3 were obtained. A 1/1 mixture of oxazolo[4,3-7] tillage, in the form of a brown oil, which is solidified and characterized as follows: Mass Spectrum ES+: [M+H]+: m/z 267. Example 68: N-( 6-{[6-(cyclohexyloxy)[ι,2,4]triazolo[4,3_b]indole_3-yl]thio}-i,3-benzo-*»塞°- 2-yl)-3-(hexaphos-p-but-1-yl)-nitrogen-tetramine rebel amine N-(6-{[6-(%hexyloxy)[1,2,4]triazole [4,3-7] morphine _3-yl]thio}-1,3· benzo-4-pyry-2-yl)-3-(hexahydrop-pyridin-1-yl)-azatetraindole+carboxylate The guanamine can be similar to the method of Example 5, but with 185 mg (6_{[6-(cyclohexyloxy), triazolo[4,3-bh-pyran-3-yl]thioguanidine-1,3 - benzopyrazole-2-yl) phenyl decanoate (4) 'In 10 cubic centimeters of THF and 10 cubic centimeters of DMF, 75 mg of 1-(azatetradec-3-yl)hexahydropyridine was used. The dihydrochloride salt was prepared with a 〇.16 〇 cubic centimeter of a tri-monthly female start to react at 66 C for 66 hours. Thus, I% mg of N-(6-{[6-(cyclohexyloxy) was obtained. [1,2,4]triazolo[4,3-b]tac-3-yl]thio-pi i,3_benzopyrazol-2-yl)-3-(hexahydropyridin-1-yl Nitrotetradecylcarbazone, in the form of a pale yellow solid, characterized by the following: 1 H NMR spectrum (400 MHz, DMSO-d6, δ ppm): 1.13 to 1.67 (m, 14H); U1 (m, 2H) ; 2.24 (broad m, 4H); 2.99 to 3.20 (broad m, 1H); 3.70 to 4.15 (broad m, 4H); 4.64 to 4.74 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H) 7.37 (dd, J = 2.0 and 8.3 Hz, 1H); 7_55 (d, J = 8.3 Hz, 1H); 8.00 (broad s, 145862 -124- 201040187 1H); 8.27 (d, J = 9.8Hz, 1H 11.32 (broad m, m) Mass spectrum (electrospray on Waters UPLC-SQD): [M+H]+: m/z 565 ; [M_H]. : m/z 563. Example 69: N- [6-({H(4-methylcyclohexyl)oxy] 丨i, 2, 4] triazolo[4,3_b丨啩_3 kibyl)-l,3-benzopyrazole -2-yl]cyclopropanecarboxylamine, a 15/85 mixture of cis and trans isomers (mainly) cis- and trans-N-[6-({6-[(4-mercapto) Hexyl)oxy][丨,2,4]triazino[4,3_b]t-p well_3-yl}thio)_;[,3-benzothiazol-2-yl]cyclopropane The 15/85 mixture of guanamine can be made in a similar manner as described in Example 2a, but with 0.592 g of N-(6-thio-1,3-benzopyrazole-2-yl)-cyclopropanecarboxylate. Amine (66b), 0.729 g of DL-dithiothreitol, 〇.ι 7 g of dihydrogen phosphate in 丨〇5 cm cm of distilled water, 0.420 g of 3-gas -6-(4-曱Start with a 1/1 mixture of 1,2,4-triazolo[4,3-b]indole (67b) and 20 cubic centimeters of ethanol. Stirring under reflux for 16 hours, followed by treatment and purification by flash chromatography on silica gel [solvent: dichloromethane (methanol / acetonitrile (9 〇 / 5 / 5 by volume)] - then obtained 0,336 g of N-[ 6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]tac-3-yl}thio)·ι,3_ A 15/85 mixture of cis and trans isomers of benzopyrazole-2-ylcyclopropanecarboxamide as a white solid, which melts at 230 ° C and is characterized by the following: 1H NMR spectrum ( 400 MHz, 5 in ppm, DMSO-d6) isomer 850 / sputum - ax-15% Hl-eq mixture has: 0 72 to 〇 99 (m, 6H); 〇 82 (d, J = 6 ·6 Hz '2.55H); 0.88 (cl, J = 6.6 Hz, 0.45H); 1.06 to 1.59 (m, 5H); 1.82 (d, J = 9.0 Hz, 2H); 1.94 to 2.04 (m, 1H) 4.35 to 4.51 (m, 1H); 7.00 (d, J = 145862· -125- 201040187 9.8 Hz, 0.85H); 7.04 (d, J = 9.8 Hz, 0.15H); 7.35 (dd, J = 2.0 with 8.6 Hz, 0.85H); 7.45 (dd, J = 2.0 and 8.6 Ηζ, 0.15 Η); 7.66 (d, J = 8.6 Hz, 〇.85H); 7.68 (d, J - 8.6 Hz, 0.15H); 8.06 (d, J = 2.0 Hz, 0.B5H); 8.11 (d, J = 2.0 Hz, 0.15H) ; 8.26 (d, J = 9.8 Hz, 0.15H); 8.28 (d, J = 9.8 Hz, 0.85H); 12.68 (broad m, 1H). Mass Spectrum ES+/- ·· [M+H]+ : m/z481 ; [MH]- : m/z479 〇 Example 70 : N-(6-{[6-(cyclohexyloxy)[1,2,4 Triazolopyrene 43-b] 嗒--3-yl]thiobenzopyrazol-2-yl)-2-oxo-6-azaspiroline 3.3]heptane-6-carboxyguanamine oxime-( 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thiol 1,3-benzoxanthene-2- ))-2-oxo-6-azaspiro[3.3]heptane-6-treazone can be made in the same manner as described in Example 5 but with 150 mg (6-{[6-(cyclohexyloxy) )[丨又斗] 三唾和[4,3-b]嗒耕-3-yl]-thio}-1,3-benzoxazol-2-yl)carbamic acid phenylacetic acid (4), 65 mg Starting with 2-oxo-6-azaspiro[3.3]heptane monooxalate, 0.144 cubic centimeters of triethylamine and 10 cubic centimeters of tetrahydrofuran. After stirring for 15 hours at a temperature in the region of 2 ° ° C, and then treating, 〇.〇 56 g of N_(6_{[6_(cyclohexyloxy)[1,2,4]triwax[4,3 was obtained. -b]嗒耕-3-yl]thio}-1,3-benzoindole_2_yl)-2-oxo-6-azaspiro[3.3]heptane-6-carboxamide, as a white solid Form, characterized by the following mass spectrum: ES+Λ: [M+H]+: m/z 524; [MH]-: m/z 522. 1 H NMR spectrum (4 〇〇 mhz, expressed in ppm, DMS 〇 _d6): i 15 to j 42 (m, 5H), 1'49 (m, 1H); 1.61 (m, 2H); 1.81 ( m, 2H); 4.20 (broad s, 4H); 4·66 (s, 4H); 4.68 to 4.74 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 With 8.6 Hz, 1H); 7·55 (broad d, J = 8.6 Hz, 1H); 8,00 (d, J = 145862 •126· 201040187 2.0 Hz, 1H); 8.27 (d, J = 9·8 Hz, 1H); 11.36 (wide m, 1H). 2-Oxo-6-spiro[3.3] heptanoic acid monooxalate can be obtained by Georg Wuitschik, Mark Rogers-Evans, Andreas Buckl, Maurizio Bernasconi, Moritz Marki, Thierry Godel, Holger Fischer, Bjiirn Wagner, Isabelle Parrilla, Franz Made by Schuler, Josef Schneider, Andre Alker, W. Bernd Schweizer, Klaus Muller and Erick M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4512-4515. Example 71: Ν·(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3·yl]thio}-l,3- Benzo-<"""""""""""""""" ,2,4]triazolo[4,3-b]indole-3-yl]thiol1,3-1,3-benzopyran 11-yl-2-yl)-3-(fofofene-4- The base gas can be used in the same manner as in Example 5, but in the form of 182 mg (6-{[6-(cyclohexyloxy)[1,2,4]triazole in 10 cubic centimeters of THF. And [4,3-b] phenyl-3-yl]thio}-1,3-benzoxazol-2-yl)carbamic acid phenyl ester (4), 106 mg 4-(nitrogen tetragen-3 -Based on the base of the chlorinated dihydrochloride and 0.167 cubic centimeters of triethylamine, the reaction was carried out at 20 ° C for 22 hours. Thus, 60 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]t-l[pi]-3-yl]thio}-1 was obtained. , 3-Benzou-indole-2-yl)-3-(i-fos-p-lin-4-yl)-azatetraindole-1-carboxamide, in the form of a white solid, characterized by the following: 1 H NMR spectrum (400 MHz, DMSO-d6, <5 ppm): 1.11 to 1.42 (m, 5H); 1.50 (m, 1H); 1.62 (m, 2H); 1.82 (m, 2H); 2.31 (m, 4H) ; 3.09 to 3.19 (m, 1H) ; 3.59 (m, 4H) ; 3.85 (m, 2H) ; 4.04 (m, 2H) ; 4.63 to 4.78 (m, 1H) ; 7.01 (d, J = 9.8 Hz, 1H ; 7.36 (dd, J = 2Ό and 8.6 Hz, 1H); 7.52 (broad d, J = 8.6 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H); 11.38 (wide m, 1H). 145862 -127- 201040187 Mass Spectrum (electrospray Waters ZQ): [M+H]+: m/z 567 ; [M-H]-: m/z 565. Example 72: Racemic-N-{6-[(6_{[trans-2-indolylcyclopentyl]oxy}[ι,2,4]triazolo[4,3-b] °荅Rhen-3-yl)thio]_1,3-benzoxazole.2_yl}cyclopropanecarboxamide a) racemic-N-{6-[(6-{[trans-2-) Cyclopentyl]oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]-i,3-benzopyrazol-2-yl} ring Propane carboxamide can be prepared in a manner similar to that described in Example 2a, but with 0.636 grams of N-(6-thio-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (66b), 0.784 g of DL-dithiothreitol, 0.115 g of potassium dihydrogen phosphate in 1.27 cubic centimeters of distilled water, 0.428 g of racemic cis- and trans-3-ylyl-6-(2-methyl Start with a 1/1 mixture of cyclopentyloxy)-1 1,2,4-triazolo[4,3-b]indole and 23 cubic centimeters of ethanol. Stirring under reflux for 16 hours, followed by treatment and purification by flash chromatography on silica gel [solvent: dichloromethane / methanol / acetonitrile (90 / 5 / volume ratio)] - obtained 0.260 g of racemic - N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]tagon-3-yl)sulfur The base H,3-benzopyrazol-2-ylpyrrolidinecarboxamide' is in the form of a white solid which melts at 197.7 ° C and is characterized as follows: 1 H NMR spectrum (400 MHz, 5 in ppm, DMSO -d6) : 0.89 (d, J = 7.1 Hz, 3H); 0·92 to 1.00 (m, 4H); 1.06 to 1.21 (m, 1H); 1.46 to 1.69 (m, 3H); 1.78 to 2.12 (m , 4H); 4.45 to 4.56 (m, 1Η); 7.03 (d, J = 9.8 Hz, 1H); 7.43 (dd, J = 2.0 # 8.6 Hz, 1H); 7.68 (d, J = 8.6 Hz, 1H) ; 8.09 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 12.67 (broad m, 1H). Mass Spectrum ES+/-: [M+H]+: m/z 467; [M-H]-: m/z 465. b) racemic-and trans-3-methyl-6-(2-indolylcyclopentyloxy)_i, 2,4_ 145862 -128- 201040187 disax[4,3-b]° The 1/1 mixture of the 荅p well can be made in the same manner as described in the example 'but with 0.678 g of cis- and trans-2-methylcyclopentanol I/〗 mixture, 10 cm ^ 4 tetrahydrofuran, 0,271 g Starting at 60% sodium hydride in oil and 0.800 g of 3,6--chloro[1,2,4]disindol [4,3-b]*^ p. The mixture was stirred for 24 hours at a temperature in the region of 2 ° ° C. After the treatment, ί ο 克克克克克克克克克克克克克克克克克克克克克克克克克克克克克克克克A 1/1 mixture of ι,2,4-triazolo[4,3_b] sorghum, in the form of a brown oil, characterized as follows: ^ Mass Spectrum ES+: [M+H]+: m/z 253. Ό Example 73: Racemic·1-{6-[(6-{[trans-2-methylcyclopentyl]oxy), 2,4]triazolo[4,3-7] 3-yl)thio]-1,3-benzopyrazole. 2-yl}·3·[2·(morphine "4-yl)ethylna racemic-1-{6-[( 6-{[trans-2-indolylcyclopentyl]oxy oxime (4) triazolo[4,3_b] tau-3-yl)thio]-1,3-benzopyrazole_2 _Kibu 3-[2-(morpholine yl)ethyl]urea can be prepared in a manner similar to that described in Example 2a, but with 〇·6〇9 g^ [2-(? -yl)ethyl]-3-(6-thio-l,3-benzox-sodium-2-yl)urea (2b), Ο 0·555 g DL-dithiothreitol, 〇· 〇8ΐg potassium dihydrogen phosphate in 0.85 cubic meters of non-distilled water solution, 0.303 g of racemic cis _ and trans chloro-6_(2_ fluorenyl-3⁄4 pentyloxy)-1,2,4- Start with a 1/1 mixture of triazolo[4,3-b]indole (72b) and 17 cubic centimeters of ethanol. Stirring under reflux for 16 hours, followed by treatment and purification by flash chromatography on silica gel [solvent: dichloromethane/methanol/acetonitrile (90/5/5 volume ratio + oj% v/v2% ammonia solution) After that, 〇223 g of the exo- 疋-1-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[ι,2,4] three spit and [4, 3 7] tower spray _ 3-yl) thio-based H, 3- benzopyrimidine 2 yl hydrazine _3_[2_(fofolin phenyl)ethyl]urea, in the form of a pale yellow solid, at 203.3T : Lower melting, the characteristics are as follows: 145862 -129- 201040187 1H NMR spectrum (4 〇〇 MHz, (5 in ppm, DMSO-d6): 0.92 (d, J = 7.1 Hz, 3H); 1.16 (m, 1H ; 1.50 to 1.69 (m, 3H); 1.79 to 2.12 (m, 3H); 2.37 to 2.44 (m, 6H); 3·26 (partially masked m, 2H); 3.59 (m, 4H); 4.52 to 4.60 (m, 1H); 6.79 (broad m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.5 Hz, 1H); 7.55 (d, J = 8.5 Hz, 1H); 8.03 (d, J = 2.0 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H); 10.90 (broad m, iH) Mass Spectrometry ES+/- : [M+H]+ : m /z 555 ; [MH]- : m/z 553. Example 74: 1^-(6-{[6-(cyclohexyloxy)[1 , 2,4]triazolo[4,3-1)]indol-3-yl]thio}-1,3-benzof-indol-2-yl)-3-methoxy-nitrogen Carboxyguanamine N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3_ Benzothiazol-2-yl)-3-methoxy-azinotetraminecarboxamide can be similar to the example of the example, but with 192 mg (% hexyloxy) in 5 cubic centimeters of dimethylformamide [1,2,4]triazolo[4,3-b]indoles]thiol-benzothiazol-2-yl)aminophenyl phthalate (4)' 69 mg 3-methoxyl Starting from nitrogen tetrahydrochloride hydrochloride and 0.078 cubic centimeters of triethylamine, it was prepared after 2 hours of reaction at 2 rc. Thus, 120 mg of N-(6-{[6-(cyclohexyloxy)[^ 4] Triazolo[4'3-b>gt.-3-yl]thiophenyl, 3-benzo-pyrazole-2-yl)_3_methoxy-nitrotetramethylene-1-carboxylate The amine, in the form of an off-white solid, is characterized as follows: NMR spectrum (4 〇〇 MHz, DMSO-d6, δ ppm): (3) to 142 (m, 5H); 1.44 to 1.53 (m, 1H); 1.61 (m, 2H) ; 1.81 (m, 2H); 3.21 (s, 3H); 3.83 (m, 2H); 4.13 to 4.30 (m, 3H); 4.64 to 4.74 (m, 1H); 7.02 (d, j = 9 8

Hz, 1H) ; 7.37 (dd，J = 2.0 與 8.6 Hz, 1H) ; 7.54 (寬廣 d，J = 8.6 Hz， 1H) ’· 8.00 (d，J = 2·0 Hz，1H) ; 8.27 (d，J = 9‘8 HZ, 1H) ; 11.36 (寬廣 m， 145862 -130- 201040187 1H)。質譜（電喷霧 Waters ZQ) : [M+H]+ : m/z 512 ; [M-H]- : m/z 510。實例75 : 1·(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]嗒畊基]硫基M，3•苯并噻唑_2_基)-3-環氧丙烷-3·基脲 1-(6-{[6-(環己基氧基）[1，2,4]三唾并[db]塔呼_3胃基]硫基卜n 苯并噻唑-2-基）-3-環氧丙烷-3-基脉可以類似實例5之方式，但以3立方公分二甲基甲酿胺中之191毫克（6_{[6_(環己基氧基）[1’2,4]二嗤并[4,3-1>]°答ρ井-3-基]硫基}-i，3-苯并癌嗅_2_基）_胺基甲@文本Sa (4)、40宅克壤氧丙院-3-胺開始，於2〇°c下反應 20小時後製成。因此，獲得95毫克1-(6-{[6-(環己基氧基）[1，2,4]***并[4,3-b]塔畊-3-基]硫基卜l，3-苯并„塞唑_2-基）_3_環氧丙烧-3-基脲，呈白色固體形式，其特徵如下： 4 NMR 光譜（400 MHz, DMSO-d6, 5 ppm) : 1.12 至 1.43 (m，5H); 1.47 至 1.54 (m，1H) ; 1.62 (m，2H) ; 1.83 (m，2H) ; 4.47 (t，J = 6.4 Hz， 2H) ; 4.67 至 4.76 (m，3H) ; 4.77 至 4.86 (m，1H) ; 7.01 (d，J = 9.8 Hz, 1H) ·’ 7.35 (dd，J = 1.8 與 8.4 Hz, 1H) ; 7.52 (寬廣 m，2H) ; 7.97 (寬廣 s，1H) ; 8.26 (d，J = 9.8 Hz，1H) ; 10_99 (寬廣 m，1H)。質譜（電喷霧於 Waters UPLC-SQD 上）：[M+H]+ : m/z 498 ; [M-H]- :m/z496。實例76 : 外消旋-l-{6-[(6-{[3-甲基環戊基]氧基}[1，2,4]三唾并[4,3七]塔ττ井-3-基)硫基]-1,3-苯并ρ塞唾-2-基}-3_[2-(嗎福淋-4·基）乙基脈，外消旋順式與反式異構物（主要）之2/3混合物 145862 201040187 )(6 [(6 ί[3_甲基環戊基]氧基}[1，2,4]三唾并[4,3帅荅啡_3_ ^ ^ ^ _2^ }.3,2,,% ^ ^ _4_^ ^ ^ ^ 旋順式與反式異構物之2/3混合物可以類似關於實例^中所述之方式製成，但㈣643克H6l苯并❹絲）各& 嗎福4 -4-基-乙幻-脲⑽、〇·586克二硫基蘇糖醇、〇 _ 克麟酸二氫鉀在〇.95立方公分蒸館水中之溶液、〇·32〇克3_ 氯基婚甲基-環戊氧基>u，4_三哇并[4,3卻荅ρ井之外消旋順式與反式異構物之m混合物及19立方公分乙醇開始。於回流下授拌16小時’接著處理及在石夕膠上藉急驟式層析純化[溶離劑：二氣甲烷/甲醇/乙腈（9〇/5/5體積比，具有〇1% v/v20%氨水溶液）]後，獲得〇〇65克1{6_[(6_{[3甲基環戊基]氧基}[1，2,4]***并[4,3_b]嗒畊各基）硫基]巧}苯并喧唑_2_基丨各& (嗎福啉-4-基）乙基]脲之外消旋順式與反式異構物之2/3混合物，呈白色固體形式，在174.7。(：下熔解，其特徵如下： H NMR 光譜（4〇〇 MHz, <5 以 ppm 表示，DMSO-d6)異構物之 2/3-1/3 混合物具有：〇.9〇 (d，J = 6.8 Hz，1H) ; 0.94 (d, J = 6.6 Hz, 2H); 1.00 至 1.35 (m，2H) ; 1.57 至 2.16 (m，5H) ; 2.36 至 2.44 (m，6H) ; 3·26 (經部份遮蔽之 m，2H) ; 3.59 (m，4H) ; 5.05 (m, 0.66H) ; 5.11 (m， 0.34H) ; 6.79 (寬廣 m，1H) ; 7.00 (d，J = 9.8 Hz, 0.34H) ; 7.02 (d，J = 9.8 Hz, 0.66H) ; 7.38 (***之 dd, J = 2.0 與 8.6 Hz, 1H) ; 7.54 (d, J = 8.6Hz, 1H); 7.37 (dd, J = 2.0 and 8.6 Hz, 1H); 7.54 (broad d, J = 8.6 Hz, 1H) '· 8.00 (d, J = 2·0 Hz, 1H); 8.27 (d , J = 9'8 HZ, 1H); 11.36 (broad m, 145862 -130- 201040187 1H). Mass Spectrum (electrospray waters ZQ): [M+H]+: m/z 512; [M-H]-: m/z 510. Example 75: 1·(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]indole]thiol M,3•benzothiazole_2 _ yl)-3-epoxypropan-3-ylurea 1-(6-{[6-(cyclohexyloxy)[1,2,4]tris-[db]tahu_3 gastric base]sulfur Keb n benzothiazol-2-yl)-3-epoxypropan-3-yl group can be similar to the method of Example 5, but with 191 mg of 3 cubic centimeters of dimethylamine (6_{[6_( Cyclohexyloxy)[1'2,4]diindolo[4,3-1>]° answer ρ -3-yl]thio}-i,3-benzocarcinoma olfactory_2_yl) The amine group A @ text Sa (4), 40 home grams of oxy-propanol-3-amine began, and was reacted at 2 ° C for 20 hours. Thus, 95 mg of 1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]tac-3-yl]thiol b,3 was obtained. - benzoxepazole-2-yl)_3_glycidyl-3-ylurea, as a white solid, characterized as follows: 4 NMR spectrum (400 MHz, DMSO-d6, 5 ppm): 1.12 to 1.43 (m, 5H); 1.47 to 1.54 (m, 1H); 1.62 (m, 2H); 1.83 (m, 2H); 4.47 (t, J = 6.4 Hz, 2H); 4.67 to 4.76 (m, 3H); 4.77 to 4.86 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H) · ' 7.35 (dd, J = 1.8 and 8.4 Hz, 1H); 7.52 (broad m, 2H); 7.97 (broad s, 1H) ; 8.26 (d, J = 9.8 Hz, 1H); 10_99 (broad m, 1H) Mass spectrometry (electrospray on Waters UPLC-SQD): [M+H]+ : m/z 498 ; [MH] - : m/z 496. Example 76: rac-l-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]tris-[4,3-7 ]Taττ well-3-yl)thio]-1,3-benzo-oxetan-2-yl}-3_[2-(moffa-4)yl-ethyl, racemic cis 2/3 mixture with trans isomer (mainly) 145862 201040187 )(6 [(6 ί[3_methylcyclopentyl]oxy}[1,2,4]three saliva[4,3 handsome荅 _3_ ^ ^ ^ _2^ }.3,2,,% ^ ^ _4_^ ^ ^ ^ The 2/3 mixture of the cis-trans and trans isomers can be made in a similar manner as described in the example ^, but (iv) 643 g of H6l benzofluorene) each & 福福 4 -4- Base-Ethyl-urea (10), 〇·586g dithiothreitol, 〇_Kilamine dihydrogen potassium in 〇.95 cubic centimeters of steamed water, 〇·32〇g 3_ chloro-methylene -cyclopentyloxy>u,4_triwax[4,3 but 荅ρ well starting with a mixture of racemic cis and trans isomers and 19 cubic centimeters of ethanol. Mixing under reflux 16 Hour' subsequent treatment and purification by flash chromatography on Shishijiao [esolvent: di-gas methane / methanol / acetonitrile (9 〇 / 5 / 5 by volume, with 〇 1% v / v 20% aqueous ammonia solution)] , obtained 〇〇65 g 1{6_[(6_{[3methylcyclopentyl]oxy}[1,2,4]triazolo[4,3_b] 嗒各 each base) thio] 】 benzene And a 2/3 mixture of the racemic cis and trans isomers of the carbazole 2 _ 丨 & & amp & & 。。。。。。。。。。。。。。。。。。。。。 (: under melting, the characteristics are as follows: H NMR spectrum (4 〇〇 MHz, < 5 in ppm, DMSO-d6) 2/3-1/3 of the mixture of isomers: 〇.9 〇 (d, J = 6.8 Hz, 1H); 0.94 (d, J = 6.6 Hz, 2H); 1.00 to 1.35 (m, 2H); 1.57 to 2.16 (m, 5H); 2.36 to 2.44 (m, 6H); (partially obscured by m, 2H); 3.59 (m, 4H); 5.05 (m, 0.66H); 5.11 (m, 0.34H); 6.79 (broad m, 1H); 7.00 (d, J = 9.8 Hz , 0.34H) ; 7.02 (d, J = 9.8 Hz, 0.66H); 7.38 (divided dd, J = 2.0 and 8.6 Hz, 1H); 7.54 (d, J = 8.6

Hz，1H) ; 8.04 (d，J = 2.0 Hz, 1H) ; 8.25 (***之 d，J = 9.8 Hz，1H); 10.92 (寬廣 m, 1H)。質譜 ES+/- : [M+H]+ ·· m/z 555 ; [M-H]- ·· m/z 553。 b) 3-氯基-6-(3-曱基-環戊氧基）-l，2,4-***并[4,3-b]嗒畊之 145862 -132- 201040187 卜肩疑川員式與反式異構物之1八混合物可以類似實例ic中所述之方式製成’但以0.678克外消旋順式與反式_3_甲基環戊醇異構物之丨/1混合物、10立方公分四氫呋喃、0.271克在6〇%下於油中之氫化鈉及0.800克3,6-二氣[1，2,4]***并[4 3_ b]°合畊開始。在20°C區域中之溫度下攪拌24小時，接著處理後，獲得0.860克3-氯基-6-(3-曱基-環戊氧基）4,2,4_***并 [4,3_b]嗒畊之外消旋順式與反式異構物之1/1混合物，呈褐色油形式，其特徵如下：〇質譜 ES+/- : [M+H]+ : m/z 253。實例77 : 外消旋-Ν·{6-[(6·{[3-曱基環戊基]氧基H1，2,4]***并[4,3七]嗒畊_ 3-基）硫基]-1，3_苯并嘍唑·2•基}環丙烷羧醯胺，外消旋順式與反式異構物（主要）之2/3混合物 N-{6-[(6-{[3-曱基環戊基]氧基m，2,4]***并[4 3七]嗒畊_3基）硫基]-1,3-苯并嘧唑_2_基}環丙烷羧醯胺之外消旋順式與反 ❹ 式異構物之2/3混合物可以類似關於實例2a中所述之方式製成，但以0.505克N-(6-硫基-1,3-苯并嘧唑-2-基）環丙烷羧醯胺（66b)、0_622克DL-二硫基蘇糖醇、0.091克磷酸二氫鉀在 1.01立方公分蒸餾水中之溶液、〇 34〇克3_氣基_6 (3甲基環戊氧基）-1，2’4-二峻并[4,3-b]塔畊之外消旋順式與反式異構物之1/1此合物（76b)及23立方公分乙醇開始。於回流下授掉 16小時，接著處理及在矽膠上藉急驟式層析純化[溶離劑.二氣曱烧/甲醇/乙腈（90/5/5體積比）]後，獲得〇172克N_ {6-[(6-{[3-甲基環戊基]氧基}tl，2,4]***并[4,3-b]嗒畊-3-基）硫 145862 -133- 201040187 基]-1,3-苯并嘍唑-2-基}環丙烷羧醯胺之外消旋順式與反式異構物之2/3混合物’呈白色固體形式，在98°C下熔解，其特徵如下： 1 H NMR 光譜（400 ΜΗζ, δ 以 ppm 表示，DMSO-d6)異構物之 2/3-1/3 混合物具有：0.84 至 0.97 (m，7H) ; 0.99 至 1.30 (m，2H) ; 1.54 至 2.14 (m，6H) ; 5.03 (m，0.66H) ; 5.10 (m，0.34H) ; 7.00 (d, J = 9.8 Hz, 〇·34Η) ; 7.02 (d, J = 9.8 Hz，0.66H) ; 7.41 (***之 dd，J = 2·0 與 8.6 Hz， 1H) ; 7.65 (寬廣 d，J = 8·6 Hz，1H) ; 8.08 (寬廣 s, 1H) ; 8.26 (*** 之 d，J = 9.8 Hz，1H) ; 12.64 (寬廣 m，1H)。質譜 ES+/- : [M+H]+ : ra/z467 ; [M-H]- : m/z465。實例78 :醫藥組合物製備相應於下列配方之片劑：實例1之產物.......................〇.2克賦*形劑’提供最後完成之片劑重量..........1克 (蛛形劑之細節：乳糖、滑石、澱粉、硬脂酸鎂）。實例79 :醫藥組合物製備相應於下列配方之片劑：實例4之產物.......................〇·2克 _形劑，提供最後完成之片劑重量..........1克 (賦形劑之細節：乳糖、滑石、澱粉、硬脂酸鎂）。實例1與4係被取為醫藥製劑之實例，此製劑若泰、碎要可以本專利申請案中所示之其他產物進行。藥理學段落：實驗擬案 145862 -134- 201040187 I) MET細胞質功能部位之表現與純化以桿狀病毒之表現：在 pFastBac (Invitrogen)中之重組 DNA His-Tev-MET (956-1390)係被轉染至昆蟲細胞中，且於數個病毒放大步驟後，將最後桿狀病毒儲備液測試關於吾人感興趣蛋白質之表現。 ' 在27°C下以重組病毒感染72小時後，藉離心採集SF21細胞培養物，並將細胞丸粒儲存於-80°C下。純化：〇 w 使細胞丸粒再懸浮於溶胞緩衝劑（缓衝劑A [50 mM HEPES， pH 7·5, 250 mM NaCl，甘油 10%，TECP 1 mM] ; + Roche Diagnostics 不含EDTA之蛋白酶抑制劑混合藥液，參考號碼1873580)中，於4°C下攪拌直到均勻為止，然後使用"Dounce”機器，以機械方式溶解。於離心後，將溶解上層清液於4°C下與鎳螯合樹脂〇^-Trap 6 Fast FlowTM，GE保健）一起培養2小時。在以20體積之 q 緩衝劑A洗滌後，將此懸浮液裝填至管柱，並以缓衝劑B (緩衝劑A+ 290 mM咪唑）之梯度液溶離蛋白質。按照電泳分析（SDS PAGE)，將含有吾人感興趣蛋白質之溶離份匯集，藉由超過濾濃縮（10 kDa截止值），並注射至 ' 以緩衝劑A平衡之排阻層析管柱（SuperdexTM200, GE保健）上。在組胺酸標記之酵素***後，將蛋白質再注射至以緩衝劑A平衡之新IMAC錄螯合層析管柱(His-Trap 6 Fast FlowTM，GE 保健）上。以缓衝劑B之梯度液溶離且於電泳（SDS PAGE)之 145862 -135 - 201040187 後含有吾人感興趣蛋白質之溶離份，係於最後匯集並儲存於-80°C下。關於自磷醯基化蛋白質之產生，係將前述溶離份於添加 ATP 2 mM，MgCl22 mM及Na3 V044 mM後，在室溫下培養1小時。在以5 mM EDTA使反應停止之後，將反應混合物注射至以緩衝劑A + Na3 V044 mM預先達成平衡之HiPr印脫鹽管柱 (GE保健）上，並將含有吾人感興趣蛋白質之溶離份（SDS PAGE分析）匯集，且儲存於-80°C下。磷醯化作用之程度係藉由質量光譜法（LC-MS)及藉由肽定圖譜法確認。Hz, 1H); 8.04 (d, J = 2.0 Hz, 1H); 8.25 (divided d, J = 9.8 Hz, 1H); 10.92 (broad m, 1H). Mass Spectrum ES+/- : [M+H]+ ·· m/z 555 ; [M-H]- ·· m/z 553. b) 3-Chloro-6-(3-indolyl-cyclopentyloxy)-l,2,4-triazolo[4,3-b]嗒耕之145886-132- 201040187 The mixture of the formula and the trans isomer can be made in a manner similar to that described in the example ic 'but with 0.678 g of the racemic cis and the trans-3-methylcyclopentanol isomer/1 The mixture, 10 cubic centimeters of tetrahydrofuran, 0.271 grams of sodium hydride in oil at 6% by weight and 0.800 grams of 3,6-diox[1,2,4]triazolo[4 3_b]° were started. After stirring for 24 hours at a temperature in the region of 20 ° C, followed by treatment, 0.860 g of 3-chloro-6-(3-indolyl-cyclopentyloxy) 4,2,4-triazolo[4, 3_b] 1/1 mixture of racemic and trans isomers in the form of a brown oil, characterized by the following: 〇 mass spectrum ES+/- : [M+H]+ : m/z 253. Example 77: Racemic-Ν·{6-[(6·{[3-indolylcyclopentyl]oxylH1,2,4]triazolo[4,3-7]嗒耕_3-base) Thio]-1,3_benzoxazole·2•yl}cyclopropanecarboxamide, a 2/3 mixture of racemic cis and trans isomers (mainly) N-{6-[(6) -{[3-indolylcyclopentyl]oxy m,2,4]triazolo[4 3-7]indole_3yl)thio]]1,3-1,3-pyrimidazole_2_yl} A 2/3 mixture of racemic cis and ruthenium isomers of cyclopropanecarboxamide can be prepared in a manner similar to that described in Example 2a, but with 0.505 grams of N-(6-thio-1, 3-benzopyrazol-2-yl)cyclopropanecarboxamide (66b), 0-622 grams of DL-dithiothreitol, 0.091 grams of potassium dihydrogen phosphate in 1.01 cubic centimeters of distilled water, 〇34 grams 3_ gas-based _6 (3methylcyclopentyloxy)-1,2'4-disino[4,3-b] ploughing 1/1 of the racemic cis and trans isomers This compound (76b) and 23 cubic centimeters of ethanol were started. After being subjected to reflux for 16 hours, followed by treatment and purification by flash chromatography on a silica gel [solvent. Dioxane/methanol/acetonitrile (90/5/5 by volume)], 172 g of N_{ 6-[(6-{[3-methylcyclopentyl]oxy}tl,2,4]triazolo[4,3-b]indole-3-yl)sulfide 145862-133- 201040187 base] -1,3-benzoxazol-2-yl}cyclopropanecarboxamide, a 2/3 mixture of racemic cis and trans isomers, as a white solid, melted at 98 ° C, The characteristics are as follows: 1 H NMR spectrum (400 ΜΗζ, δ in ppm, DMSO-d6) 2/3-1/3 mixture of isomers: 0.84 to 0.97 (m, 7H); 0.99 to 1.30 (m, 2H) ; 1.54 to 2.14 (m, 6H); 5.03 (m, 0.66H); 5.10 (m, 0.34H); 7.00 (d, J = 9.8 Hz, 〇·34Η); 7.02 (d, J = 9.8 Hz, 0.66H) ; 7.41 (divided dd, J = 2·0 and 8.6 Hz, 1H); 7.65 (broad d, J = 8·6 Hz, 1H); 8.08 (broad s, 1H); 8.26 (split d , J = 9.8 Hz, 1H); 12.64 (wide m, 1H). Mass Spectrum ES+/-: [M+H]+: s/z467; [M-H]-: m/z465. Example 78: Pharmaceutical Composition A tablet corresponding to the following formulation was prepared: Product of Example 1 ....................... 克. 2g 'Provides the final finished tablet weight..... 1 gram (details of arachid: lactose, talc, starch, magnesium stearate). Example 79: Pharmaceutical Compositions Tablets corresponding to the following formulations were prepared: Product of Example 4.................... 〇 2 g _ shaped agent, Provide the final finished tablet weight.... 1 gram (details details: lactose, talc, starch, magnesium stearate). Examples 1 and 4 are taken as examples of pharmaceutical preparations which may be carried out by other products as shown in the present patent application. Pharmacological Paragraph: Experimental Proposal 145862 -134- 201040187 I) Expression and Purification of MET Cytoplasmic Functional Sites by Baculovirus: Recombinant DNA His-Tev-MET (956-1390) in pFastBac (Invitrogen) Transfection into insect cells, and after several viral amplification steps, the final baculovirus stock is tested for performance of the protein of interest to us. After 72 hours of infection with recombinant virus at 27 ° C, SF21 cell cultures were collected by centrifugation and the cell pellets were stored at -80 °C. Purification: 〇w Resuspend cell pellets in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, glycerol 10%, TECP 1 mM]; + Roche Diagnostics without EDTA The protease inhibitor mixed solution, reference number 1873580), was stirred at 4 ° C until uniform, and then mechanically dissolved using a "Dounce" machine. After centrifugation, the supernatant was dissolved at 4 ° C. Incubate for 2 hours with Nickel Chelate Resin -^-Trap 6 Fast FlowTM, GE Healthcare. After washing with 20 volumes of q Buffer A, the suspension is loaded onto the column and buffered with buffer B (buffering) Dissolve the protein in a gradient of the agent A + 290 mM imidazole. According to electrophoresis analysis (SDS PAGE), the fractions containing the protein of interest are collected, concentrated by ultrafiltration (10 kDa cutoff), and injected into the buffer. A balanced exclusion chromatography column (SuperdexTM 200, GE Healthcare). After the histidine-labeled enzyme is split, the protein is re-injected into a new IMAC-labeled chromatography column equilibrated with buffer A (His- Trap 6 Fast FlowTM, GE Healthcare) with buffer The gradient solution of B is dissolved and contains the soluble fraction of the protein of interest after electrophoresis (SDS PAGE) 145862 -135 - 201040187, which is finally collected and stored at -80 ° C. About the production of self-phosphorylated protein The above fractions were incubated for 1 hour at room temperature after addition of ATP 2 mM, MgCl22 mM and Na3 V044 mM. After stopping the reaction with 5 mM EDTA, the reaction mixture was injected to buffer A + Na3 V044 mM pre-equilibrated HiPr imprinted desalting column (GE Healthcare), and the fractions containing our protein of interest (SDS PAGE analysis) were pooled and stored at -80 ° C. The degree of phosphorylation was borrowed. Confirmed by mass spectrometry (LC-MS) and by peptide mapping.

II)試驗A與B A)試驗A:在96-井格式中之HTRFMET試驗在50微升最後體積之酵素反應物中，將最後MET 5 nM於試驗分子存在下（對於最後濃度範圍0.17 nM至10 //M，DMSO 3% 最後），在 MOPS 10 mM pH 7.4, DTT 1 mM，0.01% Tween 20 缓衝劑中培養。反應係以受質溶液引發，以獲得最後濃度為聚-(GAT) 1微克/毫升、ATP 10 及MgCl25 mM。在室溫下培養10分鐘之後，以30微升混合物使反應停止，以獲得最後溶液為 Hepes 50 mM pH 7.5，氟化鉀 500 mM，0.1% BSA 及 EDTA 133 mM，於每井80毫微克鏈黴胺基酸61SAXLB Cis-Bio Int.與 18毫微克抗-磷酸酪胺酸Mab PT66-销隱性物存在下。在室溫下培養2小時後，讀數係在兩個波長620毫微米與665毫微米下，於關於TRACE/HTRF技術之讀取器上取得，而抑制百分比係計算自665/620比例。於實驗段落中所示，經由此試驗A對於式（I)產物所獲得 145862 -136- 201040187 之結果，係致使IC50係低於500 nM，且尤其是低於100 nM ° B)試驗B : MET之自磷醯化作用之抑制；ELISA技術 (pppY1230,1234,1235) a)細胞溶胞產物：將MKN45細胞接種於96-井板（細胞塗層BD聚離胺酸）中，在200微升RPMI培養基+ 10% FCS + 1% L-麩醯胺中，至20,000個細胞/井之比率。在培養器中留置黏連24小時。在接種之後當天，以產物，在六種濃度下，將細胞以重複方式處理1小時。將至少三個對照井以相同量之最後 DMSO處理。產物稀釋液：於10 mM下，在純DMSO中之儲備液-範圍為10 mM至30 ，在純DMSO中以3之增量-中間50倍稀釋液，在培養物培養基中，接著移除10微升，直接添加至細胞（200微升）中：最後範圍為10000至30 nM。II) Test A and BA) Test A: HTRFMET test in 96-well format In the final volume of 50 μl of the enzyme reaction, the final MET 5 nM is in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 //M, DMSO 3% final), cultured in MOPS 10 mM pH 7.4, DTT 1 mM, 0.01% Tween 20 buffer. The reaction was initiated with a substrate solution to obtain a final concentration of poly-(GAT) 1 μg/ml, ATP 10 and MgCl 25 mM. After incubation for 10 minutes at room temperature, the reaction was stopped with 30 μl of the mixture to obtain a final solution of Hepes 50 mM pH 7.5, potassium fluoride 500 mM, 0.1% BSA and EDTA 133 mM at 80 ng per well. Moldy amino acid 61SAXLB Cis-Bio Int. with 18 ng of anti-phosphotyrosinate Mab PT66-pin recessive. After 2 hours of incubation at room temperature, the readings were taken at two wavelengths of 620 nm and 665 nm on a reader for the TRACE/HTRF technique, and the percent inhibition was calculated from the 665/620 ratio. As shown in the experimental paragraphs, the results obtained by this test A for the product of formula (I) 145862 - 136 - 201040187 resulted in an IC50 system of less than 500 nM, and especially less than 100 nM ° B) Test B: MET Inhibition of phosphorylation; ELISA technique (pppY1230, 1234, 1235) a) Cell lysate: MKN45 cells were seeded in 96-well plates (cell coated BD poly-glycolic acid) at 200 μl RPMI medium + 10% FCS + 1% L-bromoamide, to a ratio of 20,000 cells per well. Leave the adhesive in the incubator for 24 hours. On the day after inoculation, the cells were treated in a repeated manner for 1 hour at the six concentrations with the product. At least three control wells were treated with the same amount of final DMSO. Product dilution: stock solution in pure DMSO at 10 mM - ranging from 10 mM to 30 in 3-fold increments - 3 fold intermediate in pure DMSO, in culture medium, followed by removal of 10 Microliters, added directly to cells (200 microliters): the final range is 10,000 to 30 nM.

於培養結束時，精緻地移除上層清液，並以200微升PBS 沖洗。接著，將100微升溶胞緩衝劑直接放置在井中，於冰上，且於4°C下培養30分鐘。溶胞緩衝劑：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，20 mM NaF, 2 mM Na3 V04，1 mM PMSF及抗蛋白酶混合藥液。將100微升溶胞產物轉移至V-型底之聚丙烯板中，且直接進行ELISA，或將板在-80°C下冷凍。 b) ELISA PhosphoMET BioSource 套件 KHO0281 145862 201040187 添加70微升套件稀緩衝液+ 3〇微升細胞溶胞產物或3〇微升溶胞緩衝劑至套件板之各井，供空白試驗用。在室溫下培養2小時’伴隨著溫和擺動。將井以400微升套件洗滌緩衝劑沖洗四次。在室溫下，以100微升抗-填醯基MET抗體培養1小時。將井以400微升套件洗滌緩衝劑沖洗四次。在室溫下，以100微升抗-兔子HRP抗體培養30分鐘（惟單獨具有色原之井除外）。將井以400微升套件洗滌緩衝劑沖洗四次。引進1〇〇微升色原，且在黑暗中，於室溫下培養3〇分鐘。以100微升終止溶液，使反應停止。在450 nM下，〇1 秒’於WallacVictor板讀取器上，採取讀數而未延遲。 C)試驗C :細胞增生經由mc-胸腺核苷脈衝之度量將細胞接種於Cytostar 96-井板中，在18〇微升中，於37〇c 及5% C〇2下，歷經4小時：HCT116細胞，於每井2500個細胞之比率下，在DMEM培養基+ 1〇%牛胎兒血清+ 1% L_麩醯胺中，及MKN45細胞，於每井75〇〇個細胞之比率下，在 RPMI培養基+ 10%牛胎兒血清+ 1% L_麵醯胺。於此等4小時之培養後，將產物以ίο微升添加，根據ELISA所引述之稀釋法’作成20倍濃溶液。產物係在10種濃度下，以重複方式測試，從10,000 nM至0.3 nM，具有3之增量。於處理72小時後’添加10微升14C_胸腺核芬，在1〇 ^α/ 毫升下，以獲得每井0.1 。14C-胸腺核苷之摻入量係於 24小時脈衝及96小時處理後’在Micr〇_卢機器（perkin_Eimer') 145862 -138- 201040187 上度量。所有試驗步驟係於BIOMEK 2000或TECAN工作站上自動化。於實驗段落中所示，經由此試驗B對於式（I)產物所獲得之結果，係致使IC50係低於10 //M，且尤其是低於1 //M。於實驗段落中所示，對於產物所獲得之結果，係示於下文藥理學結果之表中，如下述：At the end of the culture, the supernatant was carefully removed and rinsed with 200 μl of PBS. Next, 100 μl of the lysis buffer was placed directly in the well, on ice, and 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, 20 mM NaF, 2 mM Na3 V04, 1 mM PMSF and anti-protease mixed solution. One hundred microliters of the lysate was transferred to a V-type polypropylene plate and either directly subjected to ELISA or the plate was frozen at -80 °C. b) ELISA PhosphoMET BioSource Kit KHO0281 145862 201040187 Add 70 μl of kit dil buffer + 3 〇 microliters of cell lysate or 3 μl of lysing buffer to each well of the kit plate for blank assay. Incubation at room temperature for 2 hours' accompanied by gentle swing. The well was rinsed four times with 400 microliters of kit wash buffer. The cells were incubated with 100 μl of anti-primer MET antibody for 1 hour at room temperature. The well was rinsed four times with 400 microliters of kit wash buffer. Incubate with 100 μl of anti-rabbit HRP antibody for 30 minutes at room temperature (except for wells with chromogen alone). The well was rinsed four times with 400 microliters of kit wash buffer. One microliter of chromogen was introduced and cultured in the dark for 3 minutes at room temperature. The solution was stopped with 100 microliters to stop the reaction. At 450 nM, 〇1 sec. on the WallacVictor plate reader, taking readings without delay. C) Test C: Cell proliferation Cells were seeded in a Cytostar 96-well plate by mc-thymidine pulse, in 18 〇 microliters at 37 ° C and 5% C 〇 2 for 4 hours: HCT116 cells, at a ratio of 2500 cells per well, in DMEM medium + 1% fetal calf serum + 1% L_ branamide, and MKN45 cells at a ratio of 75 cells per well, RPMI medium + 10% fetal bovine serum + 1% L-faceamine. After 4 hours of incubation, the product was added in ίο μL, and a 20-fold concentrated solution was prepared according to the dilution method quoted by ELISA. The product was tested in a repeating manner at 10 concentrations from 10,000 nM to 0.3 nM with an increment of 3. After treatment for 72 hours, 10 microliters of 14C_thymidine was added at 1 〇 ^α/ml to obtain 0.1 per well. The amount of 14C-thymidine incorporation was measured on a Micr® machine (perkin_Eimer') 145862-138-201040187 after 24 hours of pulse and 96 hours of treatment. All test procedures are automated on BIOMEK 2000 or TECAN workstations. As shown in the experimental paragraphs, the results obtained for this product of formula (I) via this test B resulted in an IC50 of less than 10 //M, and especially less than 1 //M. As shown in the experimental paragraphs, the results obtained for the product are shown in the table below for pharmacological results, as follows:

關於試驗A，+符號係相應於低於500 nM，而++符號係相應於低於100 nM，關於試驗B，+符號係相應於低於500 nM，而++符號係相應於低於100 nM，關於試驗C，+符號係相應於低於10 //Μ，而++符號係相應於低於1 /iM。藥理學結果之表：實例編號試驗A 試驗B 試驗C 1 ++ ++ ++ 2 ++ ++ ++ 3 ++ ++ ++ 4 ++ + ++ 5 ++ ++ 十+ 6 ++ ++ 7 ++ ++ ++ 8 ++ ++ 9 ++ ++ ++ 10 ++ ++ ++ 11 ++ ++ ++ 12 ++ ++ ++ 145862 -139- 201040187 13 ++ ++ ++ 14 ++ ++ ++ 15 ++ ++ ++ 16 ++ + ++ 17 ++ ++ ++ 18 ++ ++ ++ 19 ++ ++ ++ 20 ++ + ++ 21 ++ ++ ++ 22 ++ ++ 23 ++ ++ ++ 24 ++ ++ ++ 25 ++ ++ ++ 26 ++ ++ ++ 27 ++ ++ ++ 28 ++ ++ ++ 29 ++ ++ ++ 30 ++ ++ ++ 31 ++ ++ 32 ++ ++ ++ 33 ++ + ++ 34 ++ ++ ++ 35 ++ ++ ++ 36 ++ ++ ++ 37 ++ + ++ 38 ++ ++ ++ 39 ++ ++ ++ 40 ++ ++ ++ 41 ++ ++ + + 42 ++ ++ ++ 43 ++ ++ ++ 145862 -140- 201040187Regarding test A, the + symbol corresponds to less than 500 nM, and the ++ 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, with regard to test C, the + symbol corresponds to less than 10 // Μ, and the ++ symbol corresponds to less than 1 / iM. Table of Pharmacological Results: Example Number Test A Test B Test C 1 ++ ++ ++ 2 ++ ++ ++ 3 ++ ++ ++ 4 ++ + ++ 5 ++ ++ Ten + 6 + + ++ 7 ++ ++ ++ 8 ++ ++ 9 ++ ++ ++ 10 ++ ++ ++ 11 ++ ++ ++ 12 ++ ++ ++ 145862 -139- 201040187 13 + + ++ ++ 14 ++ ++ ++ 15 ++ ++ ++ 16 ++ + ++ 17 ++ ++ ++ 18 ++ ++ ++ 19 ++ ++ ++ 20 ++ + ++ 21 ++ ++ ++ 22 ++ ++ 23 ++ ++ ++ 24 ++ ++ ++ 25 ++ ++ ++ 26 ++ ++ ++ 27 ++ ++ ++ 28 ++ ++ ++ 29 ++ ++ ++ 30 ++ ++ ++ 31 ++ ++ 32 ++ ++ ++ 33 ++ + ++ 34 ++ ++ ++ 35 ++ ++ ++ 36 ++ ++ ++ 37 ++ + ++ 38 ++ ++ ++ 39 ++ ++ ++ 40 ++ ++ ++ 41 ++ ++ + + 42 ++ ++ ++ 43 ++ ++ ++ 145862 -140- 201040187

44 ++ ++ ++ 45 ++ + 46 + ++ ++ 47 ++ ++ 48 ++ + ++ 49 ++ ++ ++ 50 ++ ++ ++ 51 ++ ++ ++ 52 ++ ++ ++ 53 ++ ++ ++ 54 ++ ++ ++ 55 ++ ++ ++ 56 ++ ++ ++ 57 ++ ++ ++ 58 ++ ++ ++ 59 ++ ++ ++ 60 ++ ++ ++ 61 ++ + ++ 62 ++ ++ ++ 63 ++ ++ ++ 64 ++ ++ ++ 65 ++ ++ ++ 66 ++ ++ ++ 67 ++ ++ ++ 68 ++ + ++ 69 ++ ++ ++ 70 ++ + ++ 71 + + ++ 72 ++ ++ ++ 73 ++ ++ ++ 74 ++ + ++ 145862 201040187 75 ++ ++ ++ 76 ++ ++ + + 77 ++ ++ ++ 145862 142-44 ++ ++ ++ 45 ++ + 46 + ++ ++ 47 ++ ++ 48 ++ + ++ 49 ++ ++ ++ 50 ++ ++ ++ 51 ++ ++ ++ 52 ++ ++ ++ 53 ++ ++ ++ 54 ++ ++ ++ 55 ++ ++ ++ 56 ++ ++ ++ 57 ++ ++ ++ 58 ++ ++ ++ 59 + + ++ ++ 60 ++ ++ ++ 61 ++ + ++ 62 ++ ++ ++ 63 ++ ++ ++ 64 ++ ++ ++ 65 ++ ++ ++ 66 ++ + + ++ 67 ++ ++ ++ 68 ++ + ++ 69 ++ ++ ++ 70 ++ + ++ 71 + + ++ 72 ++ ++ ++ 73 ++ ++ ++ 74 + + + ++ 145862 201040187 75 ++ ++ ++ 76 ++ ++ + + 77 ++ ++ ++ 145862 142-

Claims

201040187 七、申請專利範圍： 1. 一種式（I)產物：201040187 VII. Patent application scope: 1. A product of formula (I):

=表示單或雙鍵； Ra表示基團-〇-環烷基或基團烷基， U w有均視情況經取代； X表示S、SO或S02 ; A表示NH或S ; w表示氫原子；視情況被烷氧基、雜環烷基或nr3r4取代之烷基；或基團C0R，其中R表示： -環烷基或烷基，視情況被顧原子或基團環烷基、 NR3R4、烷氧基、羥基、苯基、雜芳基或雜環烷基〇取代’取代基本身係視情況經取代； -烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基取代，基團Ο-苯基或基團〇-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至4之整數； -或基團NR1R2，其中R1與R2係致使R1與R2中之一表示氫原子、環烷基、雜環烷基或烷基，而Ri與R2中之另一個表示氫原子、環烷基或烷基，視情況被一或多個可為相同或不同之基團取代，取代基選自下 ’ 列基團：羥基、烷氧基、雜芳基、雜環烷基、 145862 201040187 _、笨基，視情況經取代，或者，ri_和彼等所連接之氮原子形成3_至10_員環狀基團，視情況含有一或多個其他雜原子，選自〇、s、n&nh, 其中選用之S可能呈S0或S02形式；此基團，包括其含有之可能NH ’係視情況經取代；其中R3與R4 ’其可為相同或不同’係表示氣原子、炫基、環歸、雜我基、雜芳基或苯基，全部均視情況被一或多個可為相同或不同之基團取代，取代基選自下列基團：視情況經取代之經基、燒氧基、雜芳基、雜環烷基、NH2、舰止、_k)2或笨基；或者，幻與財和彼等所連接之氮原子形成3_至10_員環狀基團，視情況含有一或多個其他雜原子，選自〇、5、1^及1^1，其中選用之 S可能呈SO或S02形式；此基團，包括其含有之可能 NH ’係視情況經取代；上文定義之所有烷基、環烷基、雜環烷基、雜芳基及苯基，以及可藉由R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自_原子與下列基團：羥基、酮基、烷氧基、_〇_c〇_ R5、-C00H、C00R5、-C0NH2、C〇NHR5、Nm、NHR5、 NR5R5、-NH-C0-R5與烧基、環烧基、雜環烧基、cH2-雜環烷基、苯基、CH2-苯基、C0-笨基、雜芳基及s_雜芳基，以致在後述基團中，烷基、環烷基、雜環烷基 '笨基及雜芳基本身係視情況被一或多個基團取代，取代基選自_原子與下列基團：羥基、酮基、含有丨至4個碳原 145862 201040187 子之烷基與烷氧基、NH2、NHalk及N(alk)2，上文定義之所有環烷基、雜環烷基、雜芳基及苯基係進一步視情況被基團Si(alk)3取代；上文定義之所有環烷基與雜環烷基可視情況在該環之其中一個碳上被螺環烷基或螺雜環烷基取代，或視情況在該環之兩個碳上被稠合之環烷基或雜環烷基取代；. R5與R5' ’其可為相同或不同，係表示含有不超過6個碳原子之烧基或環炫基；〇 alk表不含有不超過4個碳原子之烷基；應明瞭的是，當A表示S，X表示s ’ Ra表示未經取代之〇-環己基或未經取代之NH_環己基，且二二表示雙鍵時， W不表示η，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式（I)產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。〇 2·如請求項1之式（I)產物，其中 ~表示單或雙鍵； Ra表示視情況經取代之基團_〇_環烷基或基團_ΝΗ-環烷 ’基； X表示S、so或so2 ; A表示NH或S ; w表示氫原子，視情況被烷氧基、雜環烷基或NR3R4取代之烷基；或基團C0R ’其中R表示： -環烧基或院基，視情況被齒原子或基團環烷基、 145862 201040187 NR3R4、烷氧基、羥基、苯基、雜芳基或雜環烧基取代，取代基本身係視情況經取代； -烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷基取代；基團0-苯基或基團〇-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至4之整數； -或基團NR1R2 ’其中R1與R2係致使R1與R2中之一表示氫原子、環烷基或烷基，而R1與R2中之另—個表示氫原子、環烷基、雜環烷基或烷基，視情況被一或多個可為相同或不同之基團取代，取代基選自下列基團.經基、烧氧基、雜芳基、雜環烧基、 NR3R4、苯基’視情況經取代，或者’ R1與R2和彼等所連接之氮原子形成3-至10-員環狀基團，視情況含有一或多個其他雜原子，選自〇、S、N&NH，其中選用之S可能呈so或S02形式，此基團，包括其含有之可能NH ’係視情況經取代；其中R3與R4 ’其可為相同或不同，係表示氫原子、烧基、環烷基、雜環烷基、雜芳基或苯基，全部均視情況被一或多個可為相同或不同之基團取代，取代基選自下列基團.羥基、烧氧基、雜芳基、雜環烷基、NH2、 NHAlk、N(Alk)2或苯基，視情況經取代；或者，R3與R4 和彼等所連接之氮原子形成3_至1〇_員環狀基團，視情況含有一或多個其他雜原子，選自〇、S、n及NH，其中選用之S可能呈SO或S02形式，此基團，包括其含有之可能 NH，係視情況經取代； 145862 201040187 上文定義之所有烷基、環烷基、雜環烷基'雜芳基及苯基’以及可藉由R1與R2或R3與R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自函原子與下列基團：經基、酉同基、烧氧基、-0-CO-R5、NH2、NHalk、N(alk)2 與烷基、環烷基、雜環烷基、CH2-雜環烷基、苯基、 CH2-苯基' CO-苯基、雜芳基及s_雜芳基，以致在後 ❹ 述基團中，烷基、環烷基、雜環烷基、苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自 _原子與下列基團：羥基、酮基、含有1至4個碳原子之烧基與烷氧基、NH2、NHalk及N(alk)2 ; R5表示含有不超過6個碳原子之烷基或環烷基； 3亥式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’以及該式①產物與礦酸及有機酸類或與礦驗及有機鹼類之加成鹽。〇 3.如叫求項1或2之式（1)產物，其中^二、Ra及X具有請求項1或2中所定義之意義，且： A表示NH或S ; W表不氫原子；視情況被烷氧基、雜環烷基或NR3R4取代之烧基；或基團COR，其中R表示：環燒基或烧基，視情況被鹵原子或基團環烷基、 NR3R4、燒氧基、羥基、笨基或雜環烷基取代，取代基本身係視情況經取代；烷氧基，視情況被NR3R4、烷氧基、羥基或雜環烷 145862 201040187 基取代；基團0-苯基或基團〇-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至4之整數； -或基團NR1R2，其中R1與R2係致使ri與R2中之一表示氫原子或烷基，而R1與R2中之另一個表示氫原子、環烷基、雜環烷基或烷基，視情況被烷氧基或雜％烧基或NR3R4取代；或者，ri與R2和彼等所連接之氮原子形成3-至10-員環狀基團，視情況含有一或多個其他雜原子，選自〇、S、N及NH，此基團’包括其含有之可能NH，係視情況經取代； -其中NR3R4，致使幻與斛，其可為相同或不同，係表示氫原子或烷基或雜環烷基，全部均視情況被一或多個可為相同或不同之基團取代，取代基選自烷氧基或雜環烧基或NH2、NHAlk或N(Alk)2 ;或者，R3 與R4和彼等所連接之氮原子形成3-至10-員環狀基團，視情況含有一或多個其他雜原子，選自〇、 S、N及NH，此基團，包括其含有之可能NH，係視情況經取代；上文所定義之所有環烷基、雜環烷基及苯基，以及可藉由R1與R2或_R4和彼等所連接之氮原子形成之環狀基團，係視情況被一或多個基團取代，取代基選自_原子 ”下列基團·羥基、烷氧基、NH2、NHaik、N(aik)2與烷基、雜環烷基、CH2-雜環烷基、苯基、cm_笨基及雜芳基’以致在後述基團中，统基、雜我基、苯基及雜芳基本身係視情況被一或多個基團取代，取代基選自齒原 145862 201040187 子及經基、含有1至4個碳原子之烷基與烷氧基、NH2、 NHalk 及 N(alk)2 ; 該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式（I)產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。 4.如請求項1或2之式①產物，其中=、Ra及χ具有請求項1或2中所定義之意義，且： A表示NH或S ; 〇 _ w表示氳原子；視情況被雜環烷基或NR3R4取代之烷基；或基團COR，其中R表示： -環烷基或烷基’視情況被基團NR3R4或烷氧基取代； -基團0-苯基或〇-(CH2)n-苯基，其中苯基視情況經取代，且η表示1至2之整數； -或基團NR1R2 ’其中R1與R2係致使R1與r2中之一表〇示氫原子、環烷基或烷基，而R1與R2中之另一個表示氫原子、視情況被雜環基或NR3R4取代之烷基，或者，R1 與R2和彼等所連接之氮原子形成環狀基團，視情況含有一或多個其他雜原子，選自〇、S、N及NH’此基團，包括其含有之可能NH，係視情況經取代；其中NR3R4，致使R3與R4，其可為相同或不同，係表示氫原子或烷基，或者，R3與R4和彼等所連接之氮原子形成環狀基團，視情況含有一或多個其他雜原子，選自〇、S ' N及NH，此基團，包括其含有之可能NH，係視 145862 201040187 情況經取代；上文所定義之所有環烷基、雜環族及苯基，以及可藉由 R1與R2或R3與R4和彼等所連接之氮原子形成之環^基團’係視情況被-或多個基團取代，取代基選自齒原子與下列基團：經基、燒氧基 '聰'Ν·、峨)2及院基與苯基，後述基團本身係視情況被一或多個基團取代，取代基選自蟲原子及經基、含有個碳原子之烧基與烷氧基、NH2、NHalk及N(alk)2 ; 該式①產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式(1)產物與礦酸及有機酸類或與礦驗及有機鹼類之加成鹽。 5. ^求項1或2之式①產物，其中A表示，取代基〜 Ra、X及W係選自請求項1或2中關於此等基團所疋義之所有意義，該式（1)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式，以及該式①產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。月长項1或2之式（I)產物，其中a表示s，取代基二二、及W係遥自请求項1或2中關於此等基團所定義之斤有忍義，該式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’以及該式（I)產物與礦酸及有機酸類或與確鹼及有機鹼類之加成鹽。月求項1或2之式①產物，其係相應於式（la)或（lb): 145862 201040187= represents a single or double bond; Ra represents a group - anthracene-cycloalkyl or a group alkyl group, U w is substituted as appropriate; X represents S, SO or S02; A represents NH or S; w represents a hydrogen atom An alkyl group optionally substituted by an alkoxy group, a heterocycloalkyl group or an nr3r4 group; or a group C0R, wherein R represents: a cycloalkyl group or an alkyl group, optionally a cycloalkyl group or a cycloalkyl group, NR3R4, Alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl hydrazine substituted 'substituent dynasties as appropriate; - alkoxy, optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl a group Ο-phenyl or a group 〇-(CH 2 ) n-phenyl, wherein phenyl is optionally substituted, and η represents an integer from 1 to 4; or a group NR1R 2 wherein R 1 and R 2 are such that R 1 And one of R2 represents a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group or an alkyl group, and the other of Ri and R2 represents a hydrogen atom, a cycloalkyl group or an alkyl group, which may be the same as one or more Or a different group substituted, the substituent is selected from the group consisting of: hydroxy, alkoxy, heteroaryl, heterocycloalkyl, 145862 201040187 _, stupid, as the case may be Or, ri_ and the nitrogen atom to which they are attached form a 3 to 10-membered cyclic group, optionally containing one or more other heteroatoms, selected from 〇, s, n&nh, wherein S may be in the form of S0 or S02; this group, including its possible NH', may be substituted as appropriate; wherein R3 and R4 'may be the same or different' means gas atom, dazzle, ring, miscellaneous a group, a heteroaryl group or a phenyl group, all of which are optionally substituted by one or more groups which may be the same or different, the substituent being selected from the group consisting of a substituted group, an alkoxy group, a heteroaryl group a base, a heterocycloalkyl group, an NH2, a saponin, a _k) 2 or a stupid group; or, a phantom and a nitrogen atom to which they are attached form a 3 to 10 membered cyclic group, optionally containing one or more Other heteroatoms selected from the group consisting of ruthenium, 5, 1^ and 1^1, wherein the selected S may be in the form of SO or S02; this group, including the possible NH's contained therein, is optionally substituted; All alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl, and nitrogen atom which may be attached via R1 and R2 or R3 to R4 and to them The cyclic group is optionally substituted by one or more groups selected from the group consisting of a _ atom and the following groups: hydroxy, keto, alkoxy, _〇_c〇_ R5, -C00H, C00R5 , -C0NH2, C〇NHR5, Nm, NHR5, NR5R5, -NH-C0-R5 with alkyl, cycloalkyl, heterocycloalkyl, cH2-heterocycloalkyl, phenyl, CH2-phenyl, C0- a silly group, a heteroaryl group and an s_heteroaryl group, such that in the groups described later, the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the stupyl group and the heteroaryl group are optionally substituted by one or more groups. a substituent selected from the group consisting of a _ atom and the following groups: a hydroxy group, a keto group, an alkyl group having a fluorene to 4 carbon atoms 145862 201040187, an alkoxy group, NH2, NHalk, and N(alk)2, all defined above The cycloalkyl, heterocycloalkyl, heteroaryl and phenyl groups are further optionally substituted by the group Si(alk)3; all of the cycloalkyl and heterocycloalkyl groups defined above may be in one of the rings Substituted by a spirocycloalkyl or spiroheterocycloalkyl group, or optionally substituted with a fused cycloalkyl or heterocycloalkyl group on the two carbons of the ring; R5 and R5'' may be the same Or different An alkyl or cyclosyl group having no more than 6 carbon atoms; 〇alk does not contain an alkyl group of not more than 4 carbon atoms; it should be understood that when A represents S, X represents s 'Ra represents unsubstituted 〇-cyclohexyl or unsubstituted NH_cyclohexyl, and when two represents a double bond, W does not represent η, and the product of formula (I) is in any possible racemization, palmar isomerization or diastereomeric An isomeric form, and an addition salt of the product of formula (I) with mineral acids and organic acids or with mineral and organic tests. 〇2. The product of formula (I) of claim 1, wherein ~ represents a single or double bond; Ra represents a optionally substituted group _〇_cycloalkyl or a group of ΝΗ-cycloalkane'; X represents S, so or so2; A represents NH or S; w represents a hydrogen atom, optionally substituted by an alkoxy group, a heterocycloalkyl group or an NR3R4 group; or a group C0R 'wherein R represents: - a cycloalkyl group or a hospital a group, optionally substituted by a tooth atom or a group of a cycloalkyl group, 145862 201040187 NR3R4, an alkoxy group, a hydroxyl group, a phenyl group, a heteroaryl group or a heterocycloalkyl group, and the substituted basic body is optionally substituted; - alkoxy group , optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkyl; group 0-phenyl or the group 〇-(CH2)n-phenyl, wherein phenyl is optionally substituted and η represents 1 to An integer of 4; or a group NR1R2 'wherein R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl group or an alkyl group, and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl group, Heterocycloalkyl or alkyl, optionally substituted by one or more groups which may be the same or different, the substituent being selected from the group consisting of a benzyl group, an alkoxy group, a heteroaryl group, a heterocyclic ring. The group, NR3R4, phenyl' is optionally substituted, or 'R1 and R2 and the nitrogen atom to which they are attached form a 3- to 10-membered cyclic group, optionally containing one or more other heteroatoms, selected from 〇, S, N & NH, wherein S may be in the form of so or S02, and this group, including its possible NH', may be substituted as appropriate; wherein R3 and R4' may be the same or different, The hydrogen atom, alkyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group or phenyl group are all optionally substituted by one or more groups which may be the same or different, and the substituent is selected from the group consisting of the following groups. Alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N(Alk)2 or phenyl, optionally substituted; or R3 and R4 and the nitrogen atom to which they are attached form 3_ to 1 a cyclic group, optionally containing one or more other heteroatoms, selected from the group consisting of ruthenium, S, n and NH, wherein the selected S may be in the form of SO or S02, including the possible NH , as appropriate; 145862 201040187 All alkyl, cycloalkyl, heterocycloalkyl 'heteroaryl and phenyl' as defined above And a cyclic group which may be formed by a nitrogen atom to which R1 and R2 or R3 and R4 are bonded to each other, optionally substituted by one or more groups selected from a functional group and the following groups: Base, fluorenyl, alkoxy, -0-CO-R5, NH2, NHalk, N(alk)2 with alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2 -phenyl 'CO-phenyl, heteroaryl and s-heteroaryl, such that in the latter group, alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are as appropriate. Substituted by one or more groups, the substituent is selected from the group consisting of a hydroxy group, a keto group, an alkyl group having 1 to 4 carbon atoms and an alkoxy group, NH2, NHalk and N(alk)2; R5 represents an alkyl group or a cycloalkyl group having not more than 6 carbon atoms; 3 the product of the formula (I) is in any possible racemic, para-isomeric or diastereomeric form 'and the formula 1 The addition of products to mineral acids and organic acids or to minerals and organic bases. 〇 3. The product of formula (1), wherein, 2, Ra, and X have the meanings defined in claim 1 or 2, and: A represents NH or S; W represents a hydrogen atom; An alkyl group substituted by an alkoxy group, a heterocycloalkyl group or NR3R4, or a group COR, wherein R represents: a cycloalkyl group or a alkyl group, optionally a halogen atom or a cycloalkyl group, NR3R4, oxygenated Substituted by a hydroxy group, a phenyl group or a heterocycloalkyl group, the substituent is optionally substituted; the alkoxy group is optionally substituted by NR3R4, alkoxy, hydroxy or heterocycloalkane 145862 201040187; group 0-benzene Or a group of 〇-(CH2)n-phenyl, wherein phenyl is optionally substituted, and η represents an integer from 1 to 4; or a group NR1R2, wherein R1 and R2 are such that one of ri and R2 is represented a hydrogen atom or an alkyl group, and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl group, a heterocycloalkyl group or an alkyl group, optionally substituted by an alkoxy group or a heteroalkyl group or NR3R4; or, ri and R2 And the nitrogen atom to which they are attached form a 3- to 10-membered cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of ruthenium, S, N and NH. It may contain NH, which may be substituted as appropriate; - wherein NR3R4, which causes phantom and deuterium, which may be the same or different, represents a hydrogen atom or an alkyl or heterocycloalkyl group, all of which are optionally one or more Substituted for the same or different groups, the substituent is selected from alkoxy or heterocycloalkyl or NH2, NHAlk or N(Alk)2; or R3 and R4 and the nitrogen atom to which they are attached form 3-to a 10-membered cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of hydrazine, S, N and NH, and the group, including the possible NH thereof, is optionally substituted; as defined above All of the cycloalkyl, heterocycloalkyl and phenyl groups, and cyclic groups which may be formed by R1 and R2 or _R4 and the nitrogen atom to which they are attached, are optionally substituted by one or more groups The substituent is selected from the group consisting of _ atoms", the following groups, hydroxy, alkoxy, NH2, NHaik, N(aik)2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, cm_styl And a heteroaryl group such that in the groups described below, the basic group, the hetero group, the phenyl group and the heteroaryl group are optionally substituted by one or more groups, and the substituent is selected from the group consisting of 145862 201040187 Sub and perylene group, alkyl group having 1 to 4 carbon atoms and alkoxy group, NH2, NHalk and N(alk)2; the product of formula (I) is in any possible racemization and palmar a conformational or diastereomeric form, and an addition salt of the product of formula (I) with a mineral acid and an organic acid or with a mineral base and an organic base. 4. A product of the formula 1 of claim 1 or 2, wherein =, Ra and χ have the meanings as defined in claim 1 or 2, and: A represents NH or S; 〇_w represents a halogen atom; an alkyl group optionally substituted by a heterocycloalkyl group or NR3R4; or a group COR Wherein R represents: - a cycloalkyl or alkyl group 'optionally substituted by a group NR3R4 or an alkoxy group; - a group 0-phenyl or fluorenyl-(CH2)n-phenyl, wherein the phenyl group is optionally substituted And η represents an integer from 1 to 2; or a group NR1R2 'wherein R1 and R2 are such that one of R1 and r2 represents a hydrogen atom, a cycloalkyl group or an alkyl group, and the other of R1 and R2 represents a hydrogen atom, an alkyl group optionally substituted by a heterocyclic group or NR3R4, or a nitrogen atom to which R1 and R2 are bonded to form a cyclic group, optionally containing one or more other impurities a group selected from the group consisting of hydrazine, S, N and NH', including the possible NH, which may be substituted as appropriate; wherein NR3R4, such that R3 and R4, which may be the same or different, represent a hydrogen atom or an alkane Or, R3 and R4 and the nitrogen atom to which they are attached form a cyclic group, optionally containing one or more other heteroatoms selected from the group consisting of hydrazine, S'N and NH, including the group thereof. Possible NH, as in the case of 145862 201040187; all cycloalkyl, heterocyclic and phenyl groups as defined above, and rings which may be formed by the nitrogen atom to which R1 and R2 or R3 and R4 are attached ^The group ' is substituted by a group or a plurality of groups, and the substituent is selected from the group consisting of a tooth atom and the following groups: a thiol group, an alkoxy group, a genus, a ruthenium, a phenyl group, and a phenyl group, which will be described later. The group itself is optionally substituted by one or more groups selected from the group consisting of a worm atom and a thiol group containing a carbon atom and an alkoxy group, NH2, NHalk and N(alk)2; The product is in any possible racemic, para-isomeric or diastereomeric form, and the product of formula (1) with mineral acid and organic acid Class or addition salts with minerals and organic bases. 5. The product of formula 1 of claim 1 or 2, wherein A represents that the substituents ~Ra, X and W are selected from all of the meanings of claim 1 or 2 with respect to such groups, which is (1) The product is in any possible racemic, palmeomeric or diastereomeric form, and addition salts of the product of formula 1 with mineral acids and organic acids or with mineral bases and organic bases. The product of formula (I) of the term 1 or 2, wherein a represents s, the substituents are two, and the W system is remotely claimed from claim 1 or 2, and the formula is I) the product is in any possible racemic, para-isomeric or diastereomeric form 'and the addition salts of the product of formula (I) with mineral acids and organic acids or with caustic and organic bases . The product of formula 1 or 2, which corresponds to formula (la) or (lb): 145862 201040187

ΗΗ

Ν Ό ΟΝ Ό Ο

W (lb) /、中觔及w係選自請求項1或2中所指示之意義，該式_Ib)產物係呈任何可能之外消旋、對掌異構或非對映異構物形汰再物心式，以及忒式（邱與（lb)產物與礦酸及有機酸類或與礦鹼及有機鹼類之加成鹽。 8·如請求項1或2之式①產物，1 ψ 表不雙鍵，其係相應於式（Γ)產物： X、/X、Α Α Η -Ν 、Ν· Nw (η 其中取代基Ra、χ、八及…呈右咬七、s 丄音義，具有凊求項1或2中所指示之 =1)產物係呈任何可能之外消旋、對掌異構或非對映驗=式，以及該式(1)產物與礦酸及有機驗及有機鹼類之加成鹽。、< 士 D月求項1或2之式①產物 W座物其中一'表示雙鍵，其係相應於式（I”a)產物： ”你相 145862 201040187W (lb) /, medium ribs and w are selected from the meaning indicated in claim 1 or 2, and the product of formula _Ib) is in any possible racemization, palmomere or diastereomer Re-centering, and 忒 (Qi and (lb) products with mineral acid and organic acids or with minerals and organic bases. 8 · Product 1 of claim 1 or 2, 1 ψ The table does not have a double bond, which corresponds to the product of the formula (Γ): X, /X, Α Η Η -Ν, Ν·Nw (η where the substituents Ra, χ, 八, and ... are right bite seven, s 丄义, Having the product indicated in claim 1 or 2 = 1) is any possible racemization, palmar isomerization or diastereoselection = formula, and the product of formula (1) and mineral acid and organic detection Addition salt of an organic base. < 士 D月求1 or 2 of the product of the formula W, where one ' represents a double bond, which corresponds to the product of the formula (I"a): "You phase 145862 201040187

其中如與w係選自請求項⑴中該式（I，，a)產物係呈任何可At /π之思義，了此之外消旋、對掌显構戍非異構物形式，以及兮切，、^ 對旱，、稱次非對映 .« ^ + ^式（I a)產物與礦酸及有機酸類或盘礦鹼及有機鹼類之加成鹽。碾其中表示雙鍵’其係相 10.如請求項1或2之式①產物應於式（I"b)產物：Wherein, if w is selected from the claim (1), the product of the formula (I, a) is in the sense of At / π, and the racemization, the palmarization, and the non-isomer form, and兮切,,^对干,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Milled where represents a double bond 'the phase of the phase 10. The product of formula 1 of claim 1 or 2 is to be a product of formula (I"b):

(r，b) :::與W係選自請求項“戈2中所指示之意義，。亥式（I b)產物係呈任 t 映異槿物w 仃了此之外消旋、對掌異構或非對 .. ^ ^，以及該式（rb)產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。 4 1L =求項1或2之式①產物，其中一表示單或雙鍵表不基團-〇-環烷基或基團_NH-環烷基；視情況被羥基、烷氧基或-aC0_R5基團取代； X表示s; A表示S ; γ.，塔 7 '、風原子或視情況被雜環烷基取代之烷基，或基團 COR ’其中R表示： 145862 -10- 201040187 -環烧基或烷基，視情況被基團NR3R4或烷氧基取代； -基團〇-苯基； -或基團NR1R2，其中R1與R2係致使一個表示氫原子’而另一個表示視情況被雜環烷基取代之烷基；其中NR3R4，致使R3與R4，其可為相同或不同，係表示氫原子或烧基； R5表示含有至多6個碳原子之烷基或環烷基； (01 上 β亥式（I)產物係呈任何可能之外消旋、對掌異構或非對映異構物形式’以及該式①產物與礦酸及有機酸類或與礦驗及有機驗類之加成鹽。 12.如請求項丨或2之式①產物，其係相應於下列化學式： -Ν-(6-{[6-(環己基氧基）[12,4]***并[4 3 b]嗒畊_3基]硫基卜 1’3_苯并嘧唑-2-基）環丙烷羧醯胺 -1-(6-{[6-(環己基氡基）[U4]***并[4,3 b]嗒畊_3基]硫基卜 φ 1，3-苯并嘍唑_2_基）·3_[2_(嗎福啉_4基）乙基]脲 -1-(6-{[6-(環戊氧基）[12 4]***并[4 3 b]嗒畊_3基]硫基卜13_ 笨并p塞唾-2-基）-3-[2-(嗎福啉_4-基）乙基]脲 1_(6'{[6·(環庚基氧基）[丨，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3 ^并屢唑_2_基)_3_[2_(嗎福κ基）乙基]腺 N-(M[6-(環己胺基似，2,4]***并[4,3补荅畊_3基]硫基卜1；3_ 苯并Ρ塞唑-2-基）乙醯胺 :環己胺基）[u，4^唑并[4,3七]嗒畊各基]硫基}1，3_ 笨并"塞唾·2_基）-3-[2_(四氫吡咯-1-基）乙基]脲 145862 -11 - 201040187 _ N|丨[1-(環己胺基）[U，4]***并[4,3-b]塔畊-3-基]硫基H，3_ 苯并遠唑-2-基）環丙烷羧醯胺 -N46-({6-[(反式_4_羥基環己基）胺基][u，4]***并[4 3卻答呼-3-基}硫基）4,3_苯并嘍唑_2_基]環丙烷羧醯胺 -N-(6-丨[6_(環丙胺基）[u，4]***并[4,3_b]嗒畊_3·基]硫基丨^-苯并嚷°全-2-基）環丙烷羧醯胺 -W-UM環己胺基）[H4]***并[4,3_b]嗒畊_3_基]硫基}1，3_ 苯并€唾-2-基)-3-[2-(嗎福啉-4-基）乙基]脉 _ W-UM環丙胺基）[丨灿***并[4,3七]嗒畊各基]硫基η，3_ 〇苯并'*墓°坐-2_基）-3-[2-(嗎福啉-4-基）乙基獅 Ν (1~{[1_(環己基氧基）[1二4]***并[4,3-b]嗒畊-3-基]硫基卜 U-笨并嘍唑_2_基）乙醯胺 L (1-U6-(環己基氧基）[以々]***并[4 3 b]嗒畊_3基]硫基卜13_ 苯并隹唾I基）胺基甲酸苯酯 1 (1 {[6-(裱己基氧基儿1，2,4]***并[4,3-b]塔畊-3-基]硫基}_ U苯并嘍唑_2_基）冬[2_㈣氫吡咯_ι_基）乙基]脈 -12- 1 {[6咖己基氧基狀2,4]***并[4,3-b]嗒畊-3-基]硫基}-N-[2-❹ (四氣"比°各小基）乙基H，3-苯并嘧唑-2-胺 • 環己基氧基）[12,4]***并[4 3 b]嗒畊各基]硫基卜 ’3笨并嘧唑_2-基）_2_甲氧基乙醯胺 (1 己基氧基）[以⑴***并[4,3七]嗒畊各基]硫基卜认笨并4唾絲）_N2，N2二甲基甘胺醯胺 (1 {[6-(¾己基氧基）[以#]***并[4,3_b]嗒畊_3基]硫基卜 1,3笨并噻唑-2-基）-3-甲基丁醢胺 Ϊ45862 201040187 -N-(6-{[6-(環己基氧基）[U4]***并[4,3_b]嗒畊_3_基]硫基}_ 1，3-苯并嘍唑_2_基）_3_曱氧基丙醯胺 ‘ 6-{[6-(環戊氧基犯，2,4]***并[4,3_b]嗒畊·3基]硫基卜〗，3-苯并遠σ坐-2-胺 _ Ν-(6·{[6-(環戊氧基）[U，4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-本并屢唾-2-基）環丙貌缓醯胺 -Ν-(6-{[6-(環戊氧基狀2,4]***并[4,3 b]嗒畊_3_基]硫基} n ❾ 苯并p塞唑-2-基）乙醯胺 6 {[6-(環庚基氧基）[丨，2,4]三唾并[4,3七]。荅畊_3-基]硫基卜ι，3_ 苯并遠唑-2-胺 • N-(6-{[6'(環庚基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯并噻唑_2_基）乙醯胺 -環丙烧瘦酸反式_4-{[3-({2-[(環丙基羰基）胺基Η，、苯并嘧。坐-6-基}-硫基）tl，2,4]***并[4,3-b]嗒畊-6-基]胺基}環己酯 -N-[6-({6-[(反式斗羥基環己基）胺基肌㈣***并[4,3七]嗒響畊-3-基}硫基)_ι，3_苯并雀π坐_2_基]乙醯胺 -3-[(2-胺基_ι，3_苯并，塞„坐_6_基）硫基環丙基叩⑷***并_ [4,3-b]*7答畊-6-胺 -N-(6-{[6-(環丙胺基犯二斗]***并[4,3-b]嗒畊-3-基]硫基卜n 苯并嘧唑-2-基）乙醯胺 -N-(6-{[6-(環丙胺基）[ι，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3-苯并嘧唑-2-基）-3-甲氧基丙醯胺 ' N-(6_{[6-(環丙胺基）[U，4]***并[4,3-b]嗒畊-3-基]硫基}-1,3-苯并違°坐-2-基）-N2,N2:甲基甘胺醯胺 145862 -13- 201040187 -3-[(2-胺基_4,3_苯并嘧唑_6基）硫基]_N環己基—7,8_二氫_ [1，2,4]二唾并[4,3七]塔u井各胺 _ (6_{[6-(環己基氧基）[U,4]***并[4,3-b]嗒畊-3-基]硫基}-1，3- 本并遠。坐-2-基）胺基甲酸乙酯 -2-氣-N-(6-{[6_(環己基氧基讥，24]***并[4,3 b]嗒畊_3基]硫基}-1，3-笨并噻唑_2_基）乙醯胺 -N-(6-{[6-(環己基氧基）***并[4,3切嗒畊各基]硫基卜 1,3_苯并噻唑~2-基）-N2-環丙基甘胺醯胺 6 [(6丨[4-(二氟曱基）環己基]氧基}[1，2,4]***并[4,3-b]。荅畊-3- ^ 基)琉基]_1，3-苯并嘧唑_2_胺 —N-(6-{[6-(環丁基氧基犯二^***并[4,3 b]塔_各基]硫基卜 1,3笨并p塞唑_2_基）_2_(4_乙基六氫被p井小基）乙醯胺 N-(6-{[6-(環丁基氧基）Π，2,4]***并[4,3-b]。荅啡各基]硫基}-1，3-苯并噻唑冬基）_N2，N2 _二乙基甘胺醯胺 —队(6_{[6'(環庚基氧基）[1，2,4]***并[4,3-b>荅喷各基]硫基}_ 1’3-苯并嘍唑_2_基）環丙烷羧醯胺 ' 1-(6-{[6-(環己胺基）[12,4]***并[4,3 b]嗒畊各基]硫基} 笨并喧》坐_2-基)_3-[3-(嗎福琳-4-基）丙基]脲 —環己基氧基）[w’4]***并[4,3_b]嗒畊_3基]硫基卜 1，3-苯并喧唑·2_基)各[3_(嗎福啉冰基）丙基]脲 W-UM環丁基氧基）[U，4]***并[4 3—b]嗒畊_3·基]硫基卜 H苯并π塞唑-2-基）-3-[2-(嗎福啉-4-基）乙基]脲 • Η2-(嗎福啉-4-基）乙基]-3-{6-[(6-丨[4-(三氟甲基）環己基]氧基丨[1，2,4]***并[4,3七]嗒畊各基)硫基]_Uj并噻唑冬基爾 145862 -14- 201040187 -义(6-丨[6-(環己基氧基）[1,2,4]***并[4,3七]嗒畊-3-基]硫基}_ 1.3- 苯并嘍唑_2-基）-2-環丙基乙醯胺 -N-(6-{[6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基卜 1.3- 苯并嘍唑_2_基）環丙烷羧醯胺 '外消旋-順/反-N-{4-[(3-{[2-({[2-(嗎福啉-4-基）乙基]胺曱醯 ’ 基}胺基H，3-苯并噻唑-6-基]硫基}[1，2,4]***并[4,3-b]。荅畊-6- 基）氧基]環-己基}乙醯胺 -N-{6-[(6-{[4-(三氟曱基）環己基]氧基丨[1，2,4]***并[4,3-b]塔 ◎ 啡-3-基）硫基]-i，3-苯并噻唑-2-基}環丙烷羧醯胺 -H6-({6-[(反式-4-羥基環己基）氧基][1，2,4]***并[4,3-b]嗒畊-3-基}硫基)-1，3-苯并嘍唑-2-基]-3-[2-(嗎福啉-4-基）乙基]脲 -6_{[6_(雙環并[3丄0]己-3-基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]-硫基}-1,3-苯并嘧唑-2-胺 -3-[(2-胺基-1,3-苯并噻唑-6-基）硫基]-N-環丁基[1，2,4]***并-[4,3-b]嗒畊-6-胺 φ — N-(6-{[6_(雙環并[3.1.0]己-3-基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]-硫基}-1，3-苯并嘍唑-2-基）環丁烷羧醯胺 •外消旋_6-({6-[(反式-2-氟基環己基）氧基][1，2,4]***并[4,3-b] • 嗒畊各基}硫基）-1,3-苯并嚓唑-2-胺、 -外消旋-N-{6-[(6-{[(反式-2-氟基環己基]氧基}[1，2,4]***并 [4,3-b]嗒畊-3-基）硫基]-i，3-苯并嘍唑-2-基μ裒丙烷羧醯胺 -Ν-(6-{[6-(環丁基胺基）[ι，2,4]***并[4,3-b>荅畊-3-基]硫基}-1，3-笨并4唑-2-基）環丙烷羧醯胺 -N-(6-{[6-(雙環并[3丄0]己_3_基氧基似义斗]***并[4,3_b]。荅畊- 145862 -15- 201040187 3-基]-硫基}-l，3-苯并嘍唑-2-基）環丙烷羧醯胺 -外消旋-Ν2，Ν2^乙基-N-[6-({6-[(反式_2-氟基環己基）氧基][1,2,4]***并-[4,3七]塔畊-3-基}硫基）-1，3_苯并嘍唾_2_基]甘胺醯胺 •外消旋-2-(4-乙基六氫p比畊-1-基）-N-{6-[(6-{[反式_2_氣基考己基]氧基}-[1，2,4]三嗤并[4,3-b]嗒畊-3-基）硫基苯并嗓哇_ 2-基}乙醯胺 -外消旋善{6-[(6-{[反式-2-氟基環己基]氧基}[1，2,4]***并 [4,3七>荅P井_3·基）硫基Η，3·苯并嘍唑-2-基}-2-(嗎福啉冰基）乙醯胺 -Ν-(6-{[6-(環丁基氧基）[丨划***并[4,3 b]嗒畊_3_基]硫基卜 1,3-笨并〇塞。坐-2-基）-2-(嗎福p林-4-基）乙醯胺 -外消旋-2-(4-環丙基六氫吡畊_丨_基）善丨6—[(6_{[反式_2_氟基 %己基]-氧基}[1，2,4]***并[4,3-b]嗒畊-3-基）硫基]-i，3-苯并嘧嗤-2-基}乙醢胺 N-(6-{[6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3苯并嚷唑_2-基）_2_(4_環丙基六氫吡畊小基）乙醯胺 N (6-丨[6-(每丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-1,3笨并噻唑基）-2-(U-二氧化硫代嗎福啉-4-基）乙醯胺 _ N_(6_{[6-(環丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}-,笨并皇4 基）_2-(ι，4_氧氮七圜_4_基）乙醯胺 (6 衣丁基氧基）[1，2,4]***并[4,3-b]嗒畊-3-基]硫基}- 1，3-苯弁p塞唯9 | 是1基>3-曱氧基丙醯胺 (晨丁基氣基）[1，2,4]三。圭并[4,3七>荅_ -3-基]硫基卜 145862 -16- 201040187 1.3- 苯并嚷唾-2-基）-2-(3,3-二氟六氫？比唆小基）乙醯胺 -外消旋-順/反-l-{6-[(6-{[3-甲基環己基]氧基}[ι，2,4]***并 [4,3-13]-°合1(1井-3-基）硫基]-1，3-苯弁p塞唾_2—基卜3-[2-(嗎福淋-4-基）乙基]脲 -外消旋-順/反-N-{6-[(6-{[3-曱基環己基]氧基叩又斗]***并 [4,3-b]-°合呻-3-基）琉基]-1，3-苯并遠峻_2_基}環丙烧羧醯胺外消旋-順/反-l-[6-({6-[(4-甲基環己基）氧基][丨二斗]***并 [4,3-b]-«合。井各基}硫基）-1,3-苯并噻。坐_2_基]_3-[2-(嗎福琳-4-基） ^ 乙基]脲 -N-(6-{[6-(環己基氧基）[1，2,4]***并[4,3_b]嗒畊各基]硫基卜 1，3-笨并p塞唑_2_基）_3-(六氫吡啶小基）一氮四圜小羧醯胺 -外消旋-順/反-N-[6-({6-[(4-曱基環己基）氧基]^4]***并 [4’3-b]-哈畊各基丨硫基）^苯并噻唑_2_基]環丙烷羧醯胺 -N-(6-{[6-(環己基氧基）[丨二々]***并[43 b]嗒畊各基]硫基卜 1.3- 苯并嘍唑_2_基）_2_氧_6_氮螺[3 3]庚烷各羧醯胺 Φ _ Ν_(6-ί[6-(環己基氧基）[丨，2,4]***并[4,3-b]嗒畊-3-基]硫基卜，本并p塞。坐_2_基）各(嗎福。林_4_基）一氮四圜小緩醯胺 —外消旋-N-丨6-[(6-丨[反式-2-甲基環戊基]氧基}[1，2 4]***并 [4’3 b>合畊_3_基）硫基]'3—苯并嘧唑么基丨環丙烷羧醯胺外消％小{6-[(6-{[反式_2-曱基環戊基]氧基丨[12,4]***并 [4,3吵合畊I基）硫基]-1，3-苯并嘍唑-2-基丨-3-[2-(嗎福啉-4-基）乙基脈 -環己基氧基）[12,4]***并[4,3卻答_各基]硫基卜 1’3-苯并噻唑么基）各曱氧基一氮四圜小羧醯胺 145862 -17- 201040187 -1-(6-{[6、(環己基氧基）^4]***并[4,3 b]嗒畊_3基]硫基卜 1’3-苯并嘍唑_2_基)各環氧丙烷各基脲 -外消旋-順/反-l-{6-[(6-{[3-甲基環戊基]氧基}[1，2,4]***并 [4,3七]_嗒哜基）硫基]-1，3·苯并嘧唑冬基}-3-[2-(嗎福啉斗美）乙基]脲 -外消旋-順/反-N-{6-[(6-{[3_曱基環戊基]氧基m,2,4]***并 [4,3-b]-嗒畊各基）硫基卜丨头苯并嘍唑_2_基}環丙烷羧醯胺以及該式（I)產&與賴及錢酸類或與石錄及有機驗類之加成鹽。、 13. 14. 15. 16. 17. 18. 19. 一種製備如請求項i至12中任—項之式（1)產物之方法。一種製備如請求項1至12中任-項之式(I)產物之方法，其中A表示NH。一種製備如請求項i至12中任—項之式（1)產物之方法，其中A表示;§。種藥物，其係為如請求項1或2之式（I)產物，以及該式 (I)產物與藥學上可接受之石廣酸及有機酸類或與藥學上可接叉之礦鹼與有機鹼類之加成鹽。種樂物，其係為如請求項12之式①產物’以及該式① 產物與萬學上可接受之礦酸及有機酸類或與藥學上可接受之礦鹼與有機鹼類之加成鹽。一種醫藥組合物’其含有至少-種如請求項1至12中任一頁之式Φ產物，或此產物或此產物之前體藥物之藥學上可接叉鹽，作為活性成份，及藥學上可接受之载體。種如明求項1至12中任一項之式⑴產物或此等產物之藥 145862 -18- 201040187 藥物係用於抑制學上可接受鹽於藥物製備上之用途，該激酶蛋白質MET及其突變形式之活性。X 20.如請求項19之用途中。其中激酶蛋白質係在細胞培養物(r,b)::: and W are selected from the meaning of the request item "Go 2," and the hai (I b) product is a t 槿槿 w 之外之外之外之外Isomerization or non-pair: ^ ^, and the addition of the product of the formula (rb) to mineral acids and organic acids or to mineral and organic tests. 4 1L = product of formula 1 or 2, One of which represents a single or double bond represents a group - 〇-cycloalkyl or a group -NH-cycloalkyl; optionally substituted by a hydroxy, alkoxy or -aC0_R5 group; X represents s; A represents S; γ., column 7 ', a wind atom or an alkyl group optionally substituted by a heterocycloalkyl group, or a group COR ' wherein R represents: 145862 -10- 201040187 - a cycloalkyl group or an alkyl group, optionally a group NR3R4 Or alkoxy substituted; - group 〇-phenyl; - or group NR1R2, wherein R1 and R2 are such that one represents a hydrogen atom and the other represents an alkyl group optionally substituted by a heterocycloalkyl group; wherein NR3R4, R3 and R4, which may be the same or different, represent a hydrogen atom or a burnt group; R5 represents an alkyl group or a cycloalkyl group having up to 6 carbon atoms; (01) is a product of any of the formula (I) May be racemic, palmomeric or diastereomeric forms' and addition salts of the product of formula 1 with mineral acids and organic acids or with mineral and organic tests. a product of formula 1 which corresponds to the following chemical formula: -Ν-(6-{[6-(cyclohexyloxy)[12,4]triazolo[4 3 b]indole_3yl]thio Bu 1'3_benzopyrazol-2-yl)cyclopropanecarboxamide-1(6-{[6-(cyclohexylfluorenyl)[U4]triazolo[4,3 b]嗒耕_ 3-yl]thiocha φ 1,3-benzoxazole-2-yl)·3_[2_(morpholine-4-yl)ethyl]urea-1-(6-{[6-(cyclopentyloxy) ))[12 4]triazolo[4 3 b]indole _3 yl]thiosyl 13_ phenyl p-pyran-2-yl)-3-[2-(morpholine-4-yl) Urea]urea-1_(6'{[6·(cycloheptyloxy)[丨,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3^ And oxazol-2-yl)_3_[2_(fukufuyl)ethyl]glycol N-(M[6-(cyclohexylamine-like, 2,4]triazolo[4,3 3-yl]thiolbu 1;3_benzoxazol-2-yl)acetamide:cyclohexylamine)[u,4^oxadol[4,3-7]indolyl]thio]}1 ,3_ 笨和"塞塞·2_基)-3-[2_(tetrahydropyrrol-1-yl)ethyl]urea 145862 -11 - 201040187 _ N|丨[1-(cyclohexylamino)[U,4]triazolo[4,3-b]tac-3-yl]thio H,3_benzoxazole-2 -yl)cyclopropanecarboxamide-N46-({6-[(trans-4_hydroxycyclohexyl))amino][u,4]triazolo[4 3 but OH-3-yl}thio 4,3_benzoxazole-2-yl]cyclopropanecarboxamide-N-(6-丨[6_(cyclopropylamino)[u,4]triazolo[4,3_b]嗒耕_3 · thiol 丨^-benzoxene all-2-yl)cyclopropanecarboxamide-W-UM cyclohexylamine)[H4]triazolo[4,3_b]嗒耕_3_基] Thio}1,3_benzoxan-2-yl)-3-[2-(morpholine-4-yl)ethyl] vein_W-UMcyclopropylamino)[丨灿***[4 ,3七]嗒耕各基]thiol η,3_ 〇 benzo[* tomb ° sit-2_yl)-3-[2-(morpholine-4-yl)ethyl griffin (1~{ [1_(cyclohexyloxy)[1 2 4]triazolo[4,3-b]indole-3-yl]thio-bu-U- benzoxazole-2-yl)acetamide L (1) -U6-(cyclohexyloxy)[in oxime]triazolo[4 3 b]indole _3 base]thiol 13_benzopyrene-I-) phenyl carbamate 1 (1 {[6- (裱hexyloxy 1,2,4]triazolo[4,3-b]tac-3-yl]thio}_ Ubenzoxazole_2_yl) winter [2_(tetra)hydropyrrole_ι _base) Base] vein-12-1 {[6 hexyloxy 2,4]triazolo[4,3-b]indole-3-yl]thio}-N-[2-❹ (four gas &quot ; ratio of each small group) ethyl H,3-benzopyrazol-2-amine • cyclohexyloxy) [12,4] triazolo[4 3 b] 嗒各 each base] thio pu '3 Stupid pyrimidazole-2-yl)_2-methoxyacetamide (1 hexyloxy) [(1) triazolo[4,3-7] 嗒各】 thio] _N2, N2 dimethylglycine decylamine (1 {[6-(3⁄4 hexyloxy)[#]triazolo[4,3_b] 嗒 _3 base] thio phenyl 1,3 stupid thiazole - 2-yl)-3-methylbutyramine hydrazine 45862 201040187 -N-(6-{[6-(cyclohexyloxy)[U4]triazolo[4,3_b]indole _3_yl]thio }_ 1,3-benzoxazole_2_yl)_3_decyloxypropionamide '6-{[6-(cyclopentyloxy, 2,4]triazolo[4,3_b]嗒Plowing · 3 bases > thiol b, 3-benzo- far-yttrium-2-amine _ Ν-(6·{[6-(cyclopentyloxy)[U,4]triazolo[4,3- b] 嗒 -3--3-yl]thio}-1,3-benzol and repeats succinyl-2-yl)cyclopropanoid hydrazide-Ν-(6-{[6-(cyclopentyloxy 2, 4] Triazolo[4,3 b]indole _3_yl]thio} n 苯benzop-pyrazol-2-yl)acetamide 6 {[6-(cycloheptyloxy)[丨2,4] three saliva and [4,3 seven].荅耕_3-yl]thio-based ι,3_benzoxazol-2-amine• N-(6-{[6'(cycloheptyloxy)[1,2,4]triazolo[4 ,3-b]嗒耕-3-yl]thio}-1,3-benzothiazol-2-yl)acetamidamine-cyclopropane-skinny trans-_4-{[3-({2- [(cyclopropylcarbonyl)aminopurine, benzopyrimidine. Sodium-6-yl}-thio)tl,2,4]triazolo[4,3-b]indole-6-yl]amine Cyclohexyl ester-N-[6-({6-[(trans) hydroxycyclohexyl)amine-based muscle (tetra)-triazolo[4,3-7] oxime-3-yl}thio)_ι, 3_Benzene π sitting _2_yl] acetamidine-3-[(2-amino-based, 3-benzoic, s-supphonyl-6-yl)thiocyclopropyl hydrazide (4) triazole _ [4,3-b]*7 Augmentation-6-amine-N-(6-{[6-(cyclopropylamino)-triazole]triazolo[4,3-b]indole-3-yl Thiophene b benzopyrazol-2-yl)acetamide-N-(6-{[6-(cyclopropylamino)[ι,2,4]triazolo[4,3-b]indole Rhen-3-yl]thio}-1,3-benzopyrazol-2-yl)-3-methoxypropionamide 'N-(6_{[6-(cyclopropylamino)[U,4 Triazolo[4,3-b]indole-3-yl]thio}-1,3-benzo-indolyl-2-yl)-N2,N2:methylglycineamide 145862 -13 - 201040187 -3-[(2-Amino-4,3-benzopyrazole-6-yl)thio]_Ncyclohexyl-7,8_2 _ [1,2,4]Disaphthene[4,3-7] Tower u wells _ (6_{[6-(cyclohexyloxy)[U,4]triazolo[4,3-b] Indole-3-yl]thio}-1,3-benzent. Sodium-2-yl)ethyl carbamate-2-gas-N-(6-{[6_(cyclohexyloxyindole, 24] Triazolo[4,3 b]indole_3yl]thio}-1,3-benzothiazol-2-yl)acetamido-N-(6-{[6-(cyclohexyloxy) Base) triazolo[4,3 cut sorghum base] thiopyrib 1,3_benzothiazolyl~2-yl)-N2-cyclopropylglycine decylamine 6 [(6丨[4-(二) Fluorofluorenyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b].indolizin-3-^yl)indenyl]-1,3-benzopyrazole_2_ Amine-N-(6-{[6-(cyclobutyloxy) oxadiazolo[4,3 b]-[individual]thiol, 1,3 stupid and p-pyrazole-2-yl) _2_(4_ethylhexahydro was p-base small) acetaminophen N-(6-{[6-(cyclobutyloxy)indole, 2,4]triazolo[4,3-b].荅各 ] ] 硫硫硫 } } } } } ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 6 6 6 6 6 6 6 4] Triazolo[4,3-b>荅各 ]]]thio}_ 1'3-benzoxazole-2-yl)cyclopropanecarboxamide ' 1-(6-{[6-( Cyclohexylamino)[12,4]triazolo[4,3 b]indole Base] stupid and 喧" sitting 2 - base) _3-[3-(moffin-4-yl)propyl]urea-cyclohexyloxy)[w'4]triazolo[4,3_b]嗒Plowing _3 yl] thio phenyl 1,3-benzoxazole · 2 yl) each [3_ (morpholine yl) propyl] urea W-UM cyclobutyloxy) [U, 4] three Zoxa[4 3 -b]嗒耕_3·yl]thiochab H benzopyrazole-2-yl)-3-[2-(morpholine-4-yl)ethyl]urea•Η2 -(morpholine-4-yl)ethyl]-3-{6-[(6-indole[4-(trifluoromethyl)cyclohexyl]oxyindole[1,2,4]triazolo[ 4,3-7] 嗒耕基基)thio]_Uj-thiazole winter il 145862 -14- 201040187 -yi (6-丨[6-(cyclohexyloxy)[1,2,4]triazolo[ 4,3-7]嗒耕-3-yl]thio}} 1.3-benzoxazole-2-yl)-2-cyclopropylacetamide-N-(6-{[6-(cyclobutyl) Oxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thiol-1.3-benzoxazole-2-yl)cyclopropanecarboxamide-racemic -cis/trans-N-{4-[(3-{[2-({[2-(morpholine-4-yl)ethyl)amine 曱醯' yl) amide H,3-benzothiazole -6-yl]thio}[1,2,4]triazolo[4,3-b].荅--6-yl)oxy]cyclo-hexyl}acetamide-N-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxyindole [1,2,4] Triazolo[4,3-b] oxazol-3-yl)thio]-i,3-benzothiazol-2-yl}cyclopropanecarboxamide-H6-({6-[(trans) 4-hydroxycyclohexyl)oxy][1,2,4]triazolo[4,3-b]indole-3-yl}thio)-1,3-benzoxazol-2-yl ]-3-[2-(morpholine-4-yl)ethyl]urea-6_{[6-(bicyclo[3丄0]hex-3-yloxy)[1,2,4]triazole And [4,3-b]indol-3-yl]-thio}-1,3-benzopyrazol-2-amine-3-[(2-amino-1,3-benzothiazole- 6-yl)thio]-N-cyclobutyl[1,2,4]triazolo-[4,3-b]indole-6-amine φ-N-(6-{[6_(bicyclo- [3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]-thio}-1,3-benzoxazole -2-yl)cyclobutane carboxy guanamine • racemic _6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4, 3-b] • 嗒各 each base} thio)-1,3-benzoxazol-2-amine, - racemic-N-{6-[(6-{[(trans-2-fluorine) Cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]-i,3-benzoxazol-2-ylpyridinium propane Carboxylamidine-Ν-(6-{[6-( Butylamino)[ι,2,4]triazolo[4,3-b>indole-3-yl]thio}-1,3-indolo-4oxa-2-yl)cyclopropanecarboxylate Amine-N-(6-{[6-(bicyclo[3丄0]hexyl-3-yloxy-like ox]triazolo[4,3_b]. 荅耕- 145862 -15- 201040187 3-based ]-thio}-l,3-benzoxazol-2-yl)cyclopropanecarboxamide-racemic-Ν2,Ν2^ethyl-N-[6-({6-[(trans) 2-fluorocyclohexyl)oxy][1,2,4]triazolo-[4,3-7]-tower-3-yl}thio)-1,3_benzopyrene-_2 ]Glycidamine · Racemic-2-(4-ethylhexahydrop-ratio-1-yl)-N-{6-[(6-{[trans-_2_ gas-based hexyl]oxy] }}-[1,2,4]triazino[4,3-b]indole-3-yl)thiobenzopyrene w_ 2-yl}acetamide-racemic good {6-[ (6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-7]荅P well_3·yl)thio sulfonium, 3·benzene And oxazol-2-yl}-2-(morpholine yl) acetamide-indole-(6-{[6-(cyclobutyloxy)[丨三三和和[4,3 b]嗒耕_3_基]thiol 1,3- stupid and choking. Sodium-2-yl)-2-(ifuplin-4-yl)acetamide-racemic-2-(4-cyclopropylhexahydropyrazine_丨_yl)Shenzhen 6-[( 6_{[trans-2-p-fluoro-hexyl]-oxy}[1,2,4]triazolo[4,3-b]indole-3-yl)thio]-i,3-benzene And pyrimidin-2-yl}acetamide N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl ]thio]-1,3 benzoxazole_2-yl)_2_(4_cyclopropylhexahydropyrazine) acetamide N (6-丨[6-(per butyloxy)[ 1,2,4]triazolo[4,3-b]indole-3-yl]thio}-1,3 benzothiazolyl)-2-(U-dithiopentazolin-4-yl) Ethylamine _ N_(6_{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]indole-3-yl]thio}-, stupid Emperor 4 base)_2-(ι,4_oxazepine-7_yl)acetamide (6-butyloxy)[1,2,4]triazolo[4,3-b] -3-yl]thio}-1,3-phenylindole p-serazine 9 | is a 1-based > 3-decyloxypropionamide (butyl butyl group) [1, 2, 4] III.圭和[4,3七>荅_ -3-yl]thiopyr 145862 -16- 201040187 1.3- Benzopyrene-2-yl)-2-(3,3-difluorohexahydro? Small base) acetamidine-racemic-cis/trans-l-{6-[(6-{[3-methylcyclohexyl]oxy}[ι,2,4]triazolo[4,3 -13]-°1 (1 well-3-yl)thio]-1,3-benzoquinone p-salt-2-yl-4-(2-(2-norfos-4-yl)ethyl] Urea-racemic-cis/trans-N-{6-[(6-{[3-indolylcyclohexyl]oxyanthracene] triazolo[4,3-b]-°呻呻-3 -yl) fluorenyl]-1,3-benzophenanthrene-2-yl}cyclopropanone carboxy oxime racemic-cis/trans-l-[6-({6-[(4-methyl ring) Hexyl)oxy][丨二斗]Triazolo[4,3-b]-«合. Wells each base}thio)-1,3-benzothiazyl. Sit_2_基]_3-[2 -(fofolin-4-yl) ^ethyl]urea-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3_b] Thiophenyl 1,3- phenyl p-pyrazole-2-yl) 3-(hexahydropyridine small) nitro-tetradecyl carboximine-racemic-cis/trans-N-[6-( {6-[(4-Mercaptocyclohexyl)oxy]^4]triazolo[4'3-b]-hacoming thiol](benzothiazole-2-yl)cyclopropanecarboxylate Amine-N-(6-{[6-(cyclohexyloxy)[indenyl]triazolo[43 b嗒各各 ] ] ] ] ] ] 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Hexyloxy)[丨,2,4]triazolo[4,3-b]indole-3-yl]thio-bu,benz and p. sit _2_base) each (ifu.lin_ 4_yl)-azatetraindole small sulfhydryl-racemic-N-丨6-[(6-丨[trans-2-methylcyclopentyl]oxy}[1,2 4]triazole And [4'3 b>gt. _3_yl)thio]'3-benzopyrazolidinylcyclopropanecarboxamide has a small external %{6-[(6-{[trans _2- Mercaptocyclopentyl]oxyindole [12,4]triazolo[4,3 argon-based I)thio]-1,3-benzoxazol-2-ylindole-3-[2- (morpholine-4-yl)ethyl-p-cyclohexyloxy)[12,4]triazolo[4,3 but OH]thiol 1'3-benzothiazolyl) each曱一氮 145 145 145 145 145862 -17- 201040187 -1-(6-{[6,(cyclohexyloxy)^4]triazolo[4,3 b]嗒耕_3 base] Thiobubu 1'3-benzoxazole-2-yl) propylene oxide perurea-racemic-cis/trans-l-{6-[(6-{[3-methylcyclopentyl) ]oxy}[1,2,4]triazolo[4,3-7]-mercapto)thio]-1,3·benzopyrazole winter base}-3-[2-(斗美) Ethyl]urea-racemic-cis/trans-N-{6-[(6-{[3_indolylcyclopentyl]oxy m,2,4]triazolo[4,3 -b]- 嗒各 ) ) ) ) ) ) ) ) 苯以及以及以及以及以及以及以及以及和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和和Addition of salt. 13. 14. 15. 16. 17. 18. 19. A process for the preparation of the product of formula (1) as claimed in any one of claims i to 12. A process for the preparation of the product of formula (I) according to any one of claims 1 to 12, wherein A represents NH. A method of preparing a product of the formula (1) according to any one of the claims i to 12, wherein A is represented; A drug of the formula (I) according to claim 1 or 2, and a product of the formula (I) and a pharmaceutically acceptable polychloric acid and an organic acid or a pharmaceutically acceptable ore and an organic base Addition salts of the class. An item of music, which is the product of formula 1 of claim 12 and the addition salt of the product of formula 1 with a pharmaceutically acceptable mineral acid and an organic acid or with a pharmaceutically acceptable mineral base and an organic base. . A pharmaceutical composition comprising at least one product of the formula Φ as claimed in any one of claims 1 to 12, or a pharmaceutically acceptable salt of the product or a precursor drug of the product, as an active ingredient, and pharmaceutically acceptable Accepted carrier. A product of the formula (1) according to any one of items 1 to 12, or a drug of the same, 145862 -18- 201040187, a drug for inhibiting the use of a physiologically acceptable salt for the preparation of a medicament, the kinase protein MET and The activity of the mutant form. X 20. In the use of claim 19. Kinase protein line in cell culture

21·如清求項19或20之用途，中。其中激酶蛋白質係在哺乳動物 22. —種如請求項1至12中任一、 T仕項之式（I)產物於藥物製備上之用途，3亥樂劑係用於治療或箱卩六、g 6 0 卜口縻及預防選自下列組群之疾病：血管增生病症、纖維變性病症、"腎小球環間膜”細胞增生病症、代謝病症、過敏反應、氣喘、血栓形成、神經系統疾病、視網膜症、车由、应 η、β ,. J胰炳午皮癬、風濕性關節炎、糖尿病、肌肉退化及癌症。 23. 種如哨求項!至12中任一項之式①產物於藥劑製備上之用途’該藥劑係用於治療癌症。 24. 如請求項23之用途’其係用於治療固態或液態腫瘤。 _ 25.如％求項23或24之用it ’其係用於治療對細胞毒劑具抗藥性之癌症。 26. 如請求項23或24之用途，其係用於治療原發性腫瘤及/或轉移，特別是在胃、肝臟、腎臟、卵巢、腸或*** 癌、肺癌（NSCLC與SCLC)、神經膠質母細胞瘤、甲狀腺、膀胱或乳癌、黑色素瘤、淋巴樣或髓樣造血腫瘤、肉瘤、細癌、喉癌、淋巴系統癌、骨癌及騰癌中。 27. —種如請求項】至12中任一項之式①產物於藥劑製備上之用途，該藥劑係用於癌症化學療法。 145862 -19- t 201040187 28. '種如往本用逹，：L項1至12中任一項之式(ι)產物於藥劑製備上之 29. 二劑係用於癌症化學療法，單獨或併用。 30. 如=項1或2之式①產物，其係作為激酶抑制劑。月項1或2之式（1)產物，其係作為MET抑制劑。 31· —種新穎. 成中間物產物，其係為式Η1、搬、祀及N之合 -CI21·If the use of item 19 or 20 is clear, medium. Wherein the kinase protein is used in the preparation of a medicament for the preparation of a medicament of the formula (I) according to any one of claims 1 to 12, and the method of the invention is for the treatment or the kit. g 6 0 縻縻 and prevention of diseases selected from the group consisting of: vascular proliferative disorders, fibrotic disorders, "glomerular internuclear membrane" cell proliferative disorders, metabolic disorders, allergic reactions, asthma, thrombosis, nervous system Disease, retinopathy, car, η, β, J pancreas, rheumatoid arthritis, diabetes, muscle degeneration and cancer. 23. Kind of sacred item! Use of the product in the preparation of a medicament for the treatment of cancer. 24. The use of claim 23 is for the treatment of solid or liquid tumors. _ 25. If % is used for 23 or 24 it' Used to treat cancers that are resistant to cytotoxic agents. 26. For use in claim 23 or 24, for the treatment of primary tumors and/or metastases, particularly in the stomach, liver, kidneys, ovaries, intestines Or prostate cancer, lung cancer (NSCLC and SCLC), nerve Maternal blastoma, thyroid, bladder or breast cancer, melanoma, lymphoid or myeloid hematopoietic tumors, sarcoma, carcinoma, laryngeal cancer, lymphatic system cancer, bone cancer and cancer. 27. — as required] to Use of the product of formula 1 according to any one of 12 for the preparation of a medicament for use in cancer chemotherapy. 145862 -19- t 201040187 28. 'As used herein, any of L items 1 to 12 The product of the formula (1) is used in the preparation of the medicament. 29. The second dose is for cancer chemotherapy, either alone or in combination. 30. The product of formula 1 as = 1 or 2, which is used as a kinase inhibitor. Or the product of formula (1), which is a MET inhibitor. 31· a novel. An intermediate product, which is a combination of formula 搬 1, moving, hydrazine, and N-CI

E·E·

M1 M2 0 r2 M3 N 其中R6表示院基’視情況被服测（ (CH2)n N贿基團卜烷氧基、羥基、雜環烷基、苯基或糊n_苯基取代，1 中苯基係視情況經取代，且n表示之整數，以致⑽ 表示如上文所定義R之相應意義；幻表示環院基或院基’視情況被NR3R4、烷氧基或羥基或笨基、雜芳基或雜環烷基取代，取代基本身視情況如請求項丨中所指示經取代·，且^把及似具有請求们中所指示:意義。 145862 -20、 201040187 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：M1 M2 0 r2 M3 N where R6 represents the hospital base's conditional test ((CH2)n N bridging group alkoxy, hydroxy, heterocycloalkyl, phenyl or paste n_phenyl substituted, 1 benzene The base system is optionally substituted, and n represents an integer such that (10) represents the corresponding meaning of R as defined above; the phantom represents a ring-based or hospital-based 'as appropriate NR3R4, alkoxy or hydroxy or stupid, heteroaryl Substituted or heterocycloalkyl substituted, substituted for the basic circumstance as indicated in the request 丨, and ^ and seems to have the meaning indicated in the request: 145862 -20, 201040187 IV. Designated representative map: ( a) The representative representative of the case is (·) (2) A brief description of the symbol of the representative figure·· 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

145862145862