药、蒽、咕吨、二苯并环庚酮和吖啶的衍生物及其用途 Medicine, anthracene, xanthene, dibenzosuberan one and acridine derivatives and their use

[0001] 本申请要求2007年5月10日提交的美国临时申请60/928， 592和2007年10月15日提交的60/999， 153的优先权，其公开通过引用完全结合到本文中。 [0001] This application claims the United States May 10, 2007 filed provisional application 60/928, 592 priority and October 15, 2007 filed 60/999, 153, the disclosure of which is incorporated herein by reference in its entirety in.

发明领域 Field of the Invention

[0002] 本发明涉及用于治疗癌症的新化合物及其使用方法的领域。 [0002] The present invention relates to the field of new compounds and methods of use for the treatment of cancer. [0003] 发明背景 [0003] Background of the Invention

[0004] Wnt/P _联蛋白信号途径被认为是癌症的主要信号途径之一，被视为许多肿瘤类型特别是结肠肿瘤的治疗干预的有效目标。 [0004] Wnt / P _] -catenin signaling pathway is considered to be one of the major signaling pathways of cancer, the target is considered valid many tumor types particularly colon cancer therapeutic intervention.

[0005] 多细胞生物体的细胞具有相互识别和传递信号的能力，有时距离相当远。 [0005] multicellular organism cells have the ability to recognize and transmit signals to each other, sometimes quite far distance. 通过产生由一个细胞产生的信号分子然后与不同细胞上的特异性受体结合，可完成此类信号传递。 By generating a signal molecule produced by one cell and bind to specific receptors on different cells, can accomplish such signal transmission. 此类信号途径涉及各种疾病过程，包括癌症。 Such signaling pathways involved in various disease processes, including cancer. 通过受体结合然后增加细胞内P-联蛋白的Wnt信号传递被称为经典（canonical)途径。 By receptor binding and increases intracellular Wnt signaling P- catenin is known as the classic (canonical) pathway. Wnt蛋白形成高度保守的分泌信号分子家族，所述分子调节细胞与细胞相互作用，涉及癌症的发病机制。 Wnt proteins form a highly conserved family of secreted signaling molecules, the molecular regulation of cell-cell interactions involved in the pathogenesis of cancer. Wnt蛋白与细胞表面的Frizzled和LRP家族的受体结合。 Wnt Frizzled protein on the cell surface and LRP receptor family. 通过几种胞质中继组分，将信号转导至P-联蛋白，然后进入细胞核，与TCF形成复合物以激活Wnt靶基因的转录。 Through several cytoplasmic relay components, the signal transduction associated protein to P-, and then into the nucleus, forming a complex with TCF to activate transcription of Wnt target genes.

[0006] 在这种途径中，Wnt多肽存在于信号细胞表面上，或由细胞释放并最终接触另一个细胞的特异性细胞表面受体。 [0006] In this pathway, Wnt polypeptide signal present on the cell surface or released by the cell and ultimately contacting another specific cell surface receptors of cells. 在靶细胞上的此类受体包括Frizzled/LRP受体（LRP = LDL-受体-相关蛋白），它们将信号传递至细胞内蛋白，如13 _联蛋白，其通过连续降解（通常由蛋白体介导）通常保持在相当低的稳态水平。 Such receptors on target cells include Frizzled / LRP receptor (LRP = LDL- receptor - related protein), which transmit signals to intracellular proteins, such as 13 _-catenin, which by continuous degradation (usually by the protein mediated) normally maintained at a relatively low steady-state level. 这由含有蛋白GSK-3/APC/Axin(GSK-3 二糖原合成酶激酶和APC二腺瘤性结肠息肉病）的复合物控制。 This composition containing protein GSK-3 / APC / Axin (GSK-3 two glycogen synthase kinase and APC two adenomatous polyposis coli) composite control. Wnt结合在靶细胞表面上的结果是抑制P _联蛋白降解，从而使后者蓄积，进入细胞核内，与转录调节剂结合以打开基因。 Wnt binding on the surface of target cells is the result of inhibition of P _ -catenin degradation, so that the accumulation of the latter into the nucleus, bind to gene transcriptional regulatory agents to open.

[0007] 业已发现促进Wnt信号途径组成型激活的突变可导致癌症。 [0007] It has been found to promote constitutive activation of Wnt signaling pathway mutations can lead to cancer. [综述参阅Logan和Nusse， 〃 The Wnt Signaling Pathway in Development andDisease (在发育禾口疾病中的Wnt信号途径），"在Ann. Rev. Cell Dev. Biol. , 20 :781-810 (2004)中]例如，Axin2突变使个体容易患结肠癌（Lammi等，Am. J. Hum. Genet. ，74 :1043-50 (2004))。再例如，家族性腺瘤性息肉病（FAP)，一种以结肠和直肠多发息肉为特征的遗传性疾病，通常由APC(另一种Wnt信号途径蛋白）切断引起，其促进Wnt途径的畸变激活[参阅：Kinzler等，Science, 253:661-665(1991)]在结肠癌及其它肿瘤类型中也已发现APC和P-联蛋白突变（综述参阅Giles等，Biochim. Biophys. Acta, 1653 :1-24 (2003))。此外，导致功能丧失的Axin突变可见于肝细胞癌。[参阅:Satoh等，Nat. Genet. ，24 :245-50(2000)]因此，使Wnt信号和P _联蛋白调控中断的任何突变或其它细胞事件对于癌症的发生很重要。 [0008] 因为此类致癌事件与13 -联蛋白水平提高有关（S卩13 -联蛋白水平独立于Wnt)， 所以重新建立这种连接或减少P-联蛋白的小的有机化合物或其它药物将有助于减轻癌性过程，可用作抗肿瘤剂。本发明提供降低肿瘤细胞中P-联蛋白水平的采用芴、蒽、咕吨、 二苯并环庚酮和吖啶的二磺酰胺衍生物形式的此类药物。[0009] 本领域已知具有被芳族胺取代的磺酰胺基的结构上相关的芴和蒽衍生物（参阅如US 2004/0019042)是包含P2X3和P2X2/3的受体的抑制剂，可用于治疗和预防疾病如膀胱过度活动症、遗尿或尿痛。但是，本文显示，可制备新的结构上相关的化合物，用作Wnt/P-联蛋白途径的调节剂。已知P-联蛋白是Wnt信号途径调节剂（参阅Willert 禾口Nusse， Current Opinion in Genetics and Development (遗4专禾口发育的新3见点)，8 : 95-102(1998)。 [0010] 发明简述 [For review see Logan and Nusse, 〃 The Wnt Signaling Pathway in Development andDisease (Wnt signaling pathway in the development of Wo mouth disease), "in Ann Rev. Cell Dev Biol, 20:... 781-810 (2004) in] For example, Axin2 mutation makes the individual susceptible to colon cancer (Lammi et, Am J. Hum Genet, 74:... 1043-50 (2004)) and then, for example, familial adenomatous polyposis (FAP), a colon. and rectal polyps is characterized by multiple genetic disease, usually caused by cutting APC (another Wnt signaling pathway proteins), which promotes distortions Wnt pathway activation [see: Kinzler, etc., Science, 253: 661-665 (1991)] In colon cancer and other tumor types have also been found and P- APC mutations associated protein (for review see Giles, etc., Biochim Biophys Acta, 1653:.. 1-24 (2003)). In addition, Axin mutations cause loss of function can be found in hepatocellular carcinoma [See:. Satoh et, Nat Genet, 24:. 245-50 (2000)]. Thus, the Wnt signal and P _ -catenin regulation or interruption of any other cell mutation event is very important for cancer. [0008] For these oncogenic events 13-- associated protein levels increase related to (S Jie 13-- associated protein level is independent of the Wnt), so re-establish this connection or reduce P- -catenin small organic compounds or other drugs will help to reduce the cancerous processes, useful as anti-tumor agents. The present invention provides methods for reducing tumor cell associated protein level using P- fluorene, anthracene, xanthene, dibenzo cycloheptanone and the two acridine sulfonamide derivative The form of these drugs. [0009] known in the art has been substituted on an aromatic amine sulfonamide group of structurally related fluorene and anthracene derivatives (see e.g. US 2004/0019042) containing P2X3 and P2X2 / 3 of receptor inhibitors useful in the treatment and prevention of diseases such as overactive bladder, urinary incontinence or painful urination. However, this article shows that the new structurally related compounds can be prepared for use as Wnt / P- catenin pathway modulators Known P- catenin Wnt signaling pathway is regulating agent (see Willert Hekou Nusse, Current Opinion in Genetics and Development (left 4 development of new special Hekou see point 3), 8: 95-102 (1998) [. 0010] SUMMARY

[0011] 本发明提供干扰Wnt信号途径和减低癌细胞中P-联蛋白水平的用于治疗癌症的 [0011] The present invention provides an interference Wnt signaling pathway in cancer cells and reduce P- catenin levels for the treatment of cancer

新化合物，及其合成方法。 The new compounds, methods for their synthesis. 在具体实施方案中，这些化合物包括降低肿瘤细胞中P-联蛋白 In a particular embodiment, these compounds reduce tumor cells comprising Annexin P-

水平的芴、蒽、咕吨、二苯并环庚酮和吖啶的二磺酰胺衍生物。 Level fluorene, anthracene, xanthene, dibenzo cycloheptanone and the two acridine sulfonamide derivatives.

[0012] 本发明化合物具有式I结构：<formula>formula see original document page 8</formula> [0012] The compounds of the present invention has the structure of formula I: <formula> formula see original document page 8 </ formula>

[0013] [0013]

[0014] 式I [0014] Formula I

[0015] 其中n = 0-2，其中当n = 1时，X选自CH2、 0、 NRA、 CO禾口C = NORa，其中当n = 2 时，X = CH2 [0015] where n = 0-2, wherein when n = 1, X is selected from CH2, 0, NRA, CO Hekou C = NORa, wherein when n = 2, X = CH2

[0016] Y = 0、S、NORa或NRa [0016] Y = 0, S, NORa or NRa

[0017] 其中Ra逸自H、烷基、杂烷基、烯基、炔基、环烷基、-C( = 0)RB、-C( = 0)0RB、_C(= 0)NRBRc、-C( = NRB)R。 [0017] wherein Ra Yi from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -C (= 0) RB, -C (= 0) 0RB, _C (= 0) NRBRc, - C (= NRB) R. -NRBRc、杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷基芳基[0018] 其中所述RB和R。 -NRBRc, A heterocyclic group, an aromatic group or an aryl, heteroaryl, arylalkyl and alkyl aryl groups [0018] wherein RB and R. 各自独立是H、烷基或杂烷基， They are each independently H, alkyl or heteroalkyl,

[0019] U和V各自独立选自C二0禾P0二S二O，其中当U是C = 0时，V不是C = 0， [0020] &、 R2、 &和1?4各自独立选自H、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基，所述&、 R2和所述R3、 R4可各自独立结合以形成杂环烷基， [0021] Rs和Re各自独立选自H、 0H、 SH、烷氧基、硫代烷氧基、烷基、卤素、CN、 CF3、 N02、 C00RD、 C0NRDRE、 NRDRE、 NRDC0RE、 NRDS02RE和NRFC0NRDRE ; [0019] U and V each independently selected from C 20 Wo P0 = S two O, wherein when U is C = 0 时, V instead of C = 0, [0020] &, R2, & and 1? 4 are each independently selected from from H, alkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, &, R2 and the R3, R4 can is independently combined to form a heterocyclic group, [0021] Rs and Re are each independently selected from H, 0H, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, N02, C00RD, C0NRDRE , NRDRE, NRDC0RE, NRDS02RE and NRFC0NRDRE;

[0022] 其中R。 [0022] wherein R. 、I^和RF独立是H、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基或杂环烷基； , I ^ and RF is independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

[0023] 其中如果X是0、Y是0且U和V都是0 = S = 0，则NR^和NR3R4不相同，其中R丄和R3各自独立选自H和低级烷基，其中R2和R4各自独立选自低级烷氧基（低级烷基）、二(低级）烷基氨基（低级）烷基、卤代节基、吗啉代（低级）烷基，或者NR^和NR3R4独立选自哌啶子基、吗啉代、哌嗪-l-基（piperazino)、 N-苯基哌嗪-l-基、乙氨基或取代的甘氨酸， [0023] wherein if X is 0, Y is 0 and U and V are 0 = S = 0, then the NR ^ and NR3R4 are not the same, wherein R Shang and R3 are each independently selected from H and lower alkyl, wherein R2 and R4 is independently selected from lower alkoxy (lower alkyl), di (lower) alkylamino (lower) alkyl, halo section group, morpholino (lower) alkyl, or NR ^ and NR3R4 are independently selected from piperidino, morpholino, piperazinyl -l- yl (piperazino), N- phenylpiperazine -l- group, an ethylamino group or a substituted glycine,

[0024] 其中当X是(CH2) 2、 Y是0或NOH且U和V各自是0 = S = 0时，则R2、 R3和R4 [0024] wherein when X is (CH2) 2, Y is 0 = S = 0 0 or NOH and U and V are each, then R2, R3 and R4

无一是甲基， No one is methyl,

[0025] 其中当n = 0、 Y是0或N0H且U禾PV各自是0 = S = 0时，贝U ，2和NR3R4不相同，且和R4各自独立选自C「C5烷基、Q。烷基丄16烷基丄17烷基、苯基、苄基、萘基、哌嗪-l-基（piperizino)、吡啶基、妣唑基、苯并咪唑基、三唑基；或者NR凡和NR3R4独立是哌啶子基、吗啉代或哌嗪-1-基， [0025] wherein when n = 0, Y is 0 or N0H and U Wo PV are each 0 = S = 0, the shell U, 2 and NR3R4 are not the same, and and R4 are each independently selected from C "C5 alkyl, Q Alkyl C16 alkyl Shang Shang 17 alkyl, phenyl, benzyl, naphthyl, piperazinyl -l- yl (piperizino), pyridyl, oxazolyl deceased mother, benzimidazolyl, triazolyl; or NR where and NR3R4 independently piperidino, morpholino or piperazin-1-yl,

[0026] 其中当X是CO、Y是0且U和V各自是0二S二0时，则NI^I^和NR3R4不一样，其中Ri、 R2、 R3和R4各自独立选自甲基、乙基、羟基-Q-Cf烷基、SH、 R0、 C00H、 S0、NH2和苯基； NR凡和NR3R4独立选自未被取代的哌啶子基J-甲基哌嗪-1-基或N-甲基高哌嗪-1-基， [0027] 其中当X是C二0或C二N0H， Y是0或N0H， U禾PV各自是0二S二0，I^或R2其中之一和R3或R4其中之一是苯基时，则&或R2和R3或R4中的另一个不是H或烷基， [0028] 包括其所有药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、溶剂化物或前药。 [0026] wherein when X is CO, Y is 0 and U and V are each 0 = S 20, then NI ^ I ^ and NR3R4 are not the same, wherein Ri, R2, R3 and R4 are each independently selected from methyl, ethyl group, a hydroxyl group -Q-Cf alkyl, SH, R0, C00H, S0, NH2 and phenyl; NR NR3R4 where and are independently selected from unsubstituted piperidino J- methyl-piperazin-1-yl or N- methyl-piperazin-1-yl high, [0027] wherein when X is a C 20 or C = N0H, Y is 0 or N0H, U are independently 0 Wo PV two S diglycidyl 0, I ^ or R2 of which It and one of R3 or R4 is phenyl which is & or R2 and R3 or R4 of the other is not H or alkyl, [0028] including all pharmaceutically acceptable salts, esters, amides, stereoisomers isomers, geometrical isomers, solvates or prodrugs.

[0029] 在具体实施方案中，本发明化合物包括表2-13的那些化合物，所述化合物各自或以任何组合构成本发明。 [0029] In a particular embodiment, the compounds of the present invention include those compounds shown in Table 2-13, each of the compounds or any combination thereof of the present invention.

[0030] 本发明还提供本发明的任何化合物如表1-13的化合物的治疗组合物。 [0030] Any compound of the present invention, the present invention also provides therapeutic compositions comprising a compound of Table 1-13.

[0031] 本发明还涉及改善哺乳动物癌或肿瘤转移的方法，包括给予所述哺乳动物有效量 [0031] The present invention further relates to a mammalian cancer or improving cancer metastasis, comprising administering to said mammal an effective amount of

的本发明化合物。 The compounds of the invention. 特别是表1-13化合物的用途。 In particular the use of compounds in Table 1-13.

[0032] 定义 [0032] defines

[0033] 除非另外明确表示，否则以下术语各自具有所示含义： [0033] Unless otherwise expressly indicated otherwise, the following terms have the meanings of each follows:

[0034]"酰基"或"羰基"是羧酸脱除羟基形成的基团（即RC( = 0)-)。 [0034] "acyl" or "carbonyl" is a carboxylic acid formed by removing a hydroxyl group (ie, RC (= 0) -). 优选酰基包括(例如）乙酰基、甲酰基和丙酰基。 Preferably acyl groups include (for example) acetyl, formyl, and propionyl.

[0035] 术语"碳链"包括任何烷基、烯基、炔基或杂烷基、杂烯基或杂炔基，为直链、环状或其任何组合。 [0035] The term "carbon chain" includes any alkyl, alkenyl, alkynyl or heteroalkyl, heteroaryl alkenyl or heteroaryl alkynyl group, a straight-chain, cyclic or any combination thereof. 如果该链是连接体的一部分且该连接体包含一个或多个环作为核心主链的一部分，为了计算链长，"链"只包括组成指定环的底部或顶部（并非两者都是）的那些碳原子，当环的顶部和底部长度不等时，应当用较短的距离确定链长。 If the chain is connected to the connector body part and contains one or more rings as a core part of the backbone, in order to calculate chain length, "chain" includes only the specified ring consisting of the bottom or top (but not both) of Those carbon atoms, when the top and bottom of the unequal length of the loop, should be used to determine the chain length shorter distance. 如果链包含杂原子作为主链的一部分，那些原子不算碳链长的一部分。 If the chain contains heteroatoms as part of the backbone, those atoms is not part of the carbon chain length.

[0036]"烷基"指具有1-15个碳原子、优选1-10个碳原子的饱和烃链。 [0036] "Alkyl" means having 1 to 15 carbon atoms, preferably a saturated hydrocarbon chain of 1 to 10 carbon atoms. 无论单独或组合使用，它都指具有1-约30个碳、更优选1-12个碳的任选取代的直链或任选取代的支链饱和烃基。 Whether alone or in combination, which all mean a branched having 1 to about 30 carbons, more preferably 1 to 12 carbon atoms or an optionally substituted straight chain saturated hydrocarbon group optionally substituted. 烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、叔戊基、戊基、己基、庚基、辛基等。 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl group.

[0037] 单独或组合的术语"烯基"指任选取代的直链或任选取代的支链烃基，具有一个或多个碳_碳双键且具有2-约30个碳原子，更优选2-约18个碳。 [0037] alone or in combination, the term "alkenyl" refers to an optionally substituted straight or branched chain hydrocarbon group optionally substituted, _ having one or more carbon-carbon double bonds and having 2 to about 30 carbon atoms, more preferably 2 to about 18 carbons. 烯基的实例包括乙烯基、 丙烯基、丁烯基、1 ， 3- 丁二烯基等。 Examples of alkenyl groups include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like.

[0038] 单独或组合的术语"炔基"指任选取代的直链或任选取代的支链烃基，具有一个或多个碳_碳三键且具有2-约30个碳原子，更优选2-约12个碳原子、2_约6个碳原子以及具有2-约4个碳原子。 [0038] alone or in combination, the term "alkynyl" refers to an optionally substituted straight or branched chain hydrocarbon group optionally substituted with one or more carbon-carbon triple bond and _ having from 2 to about 30 carbon atoms, more preferably 2 to about 12 carbon atoms, 2_ about 6 carbon atoms and having 2 to about 4 carbon atoms. 炔基的实例包括乙炔基、2_丙炔基、2_ 丁炔基、1，3_ 丁二炔基等。 Examples of alkynyl groups include ethynyl, propynyl 2_, 2_ butynyl, 1,3_ diacetylene group. [0039]"烯烃"是具有至少1个（优选仅1个）碳_碳双键且具有2-15个碳原子、优选2-10个、更优选2-5个碳原子的烃链。 [0039] "olefin" having at least one (preferably only one) carbon-carbon double bond and _ having 2-15 carbon atoms, preferably 2 to 10, more preferably 2-5 carbon atoms, the hydrocarbon chain.

[0040]"炔烃"是具有至少1个（优选仅1个）碳_碳三键且具有2-15个碳原子、优选2-10个、更优选2-5个碳原子的烃链。 [0040] "alkyne" having at least one (preferably only one) carbon-carbon triple bond and _ having 2-15 carbon atoms, preferably 2 to 10, more preferably 2-5 carbon atoms, the hydrocarbon chain.

[0041] 烷基、烯烃和炔烃链（总称为"烃链"）可以是直链或支链，可以未被取代或被取代。 [0041] The alkyl, alkene and alkyne chains (referred to as "hydrocarbon chains") may be straight or branched chain, may be unsubstituted or substituted. 优选支链烷基、烯烃和炔烃链具有1或2个分支，优选1个分支。 Preferably branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. 优选链是烷基。 Preferably is an alkyl chain. 烷基、烯烃和炔烃链各自可未被取代或被1-4个取代基取代；当被取代时，优选链被单-、二-或三-取代。 Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with 1-4 substituents; when substituted, preferred chains sheets -, two - or three - substituted. 烷基、烯烃和炔烃链各自可被卤代基、羟基、芳氧基（如苯氧基）、杂芳氧基、酰氧基（如乙酰氧基）、羧基、芳基（如苯基）、杂芳基、环烷基、杂烷基、杂环烷基、螺环、氨基、酰氨基（amido)、酰基氨基（acylamino)、酮基、硫酮基、氰基或其任何组合取代。 Alkyl, alkene and alkyne hydrocarbon chains each may be halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g. acetoxy), carboxy, aryl (e.g. phenyl ), heteroaryl, cycloalkyl, heteroalkyl, heterocycloalkyl, spiro, amino, acylamino (amido), acylamino (acylamino), a ketone group, a thione group, a cyano group, or any combination of substituents . 优选烃基包括甲基、乙基、丙基、异丙基、丁基、乙烯基、烯丙基、丁烯基和exomethylenyl。 Preferably a hydrocarbon group include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl. [0042]"低级烷基"是较短的烷基，如含有1-约6个碳原子的烷基。 [0042] "lower alkyl" is a shorter alkyl group, such as an alkyl group containing from 1 to about 6 carbon atoms.

[0043] 而且，本文提到的"低级"烷基、烯烃或炔烃部分（如"低级烷基"）在烷基情况下是由l-10、优选l-8个碳原子组成的链，在烯烃和炔烃情况下是由2-10、优选2-8个碳原子组成的链。 [0043] Further, referred to herein, "lower" alkyl, alkene or alkyne moiety (e.g., "lower alkyl") is made in the case of alkyl l-10, preferably l-8 carbon atoms in the chain, In the case of alkenes and alkynes by 2-10, preferably 2-8 carbon atoms in the chain.

[0044]"烷氧基"指具有烃链取代基的氧基团，其中烃链是烷基或烯基（即-0-烷基或-o-烯基）。 [0044] "alkoxy" refers to alkoxy groups having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -0- alkyl or alkenyl group -o-). 烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、烯丙氧基等。 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, allyloxy and the like.

[0045]"芳基"是芳族烃环。 [0045] "Aryl" is an aromatic hydrocarbon ring. 芳环是单环或稠合双环的环系统。 The aromatic ring is a single ring or a fused bicyclic ring system. 单环芳环的环中包含6个碳原子。 Monocyclic aromatic ring containing 6 ring carbon atoms. 单环芳环也称为苯环。 Monocyclic aromatic ring is also known as a benzene ring. 双环芳环的环中包含8-17个碳原子，优选9-12个碳原子。 Bicyclic aromatic ring containing 8-17 ring carbon atoms, preferably 9-12 carbon atoms. 双环芳环包括其中一个环是芳基且另一个环是芳基、环烷基或杂环烷基的环系统。 Bicyclic aryl rings include those wherein one ring is aryl and the other ring is aryl, cycloalkyl or heterocycloalkyl ring system. 优选双环芳环包含与5-、6_或7-元环稠合的5-、6_或7-元环。 Preferably bicyclic aromatic ring contains 5-, 6_ or 7-membered rings fused to 5-, 6_ or 7-membered ring. 芳环可以未被取代或在环上被1-4个取代基取代。 The aromatic ring may be unsubstituted or substituted with 1-4 substituents on the ring. 芳基可以被卣代基、氰基、硝基、羟基、羧基、氨基、酰基氨基、烷基、杂烷基、卤代烷基、苯基、芳氧基、烷氧基、杂烷氧基、氨基甲酰基、卤代烷基、亚甲基二氧基、杂芳氧基或其任何组合取代。 Aryl substituent may be wine container, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroaryl alkoxy, amino formyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination of substituents. 优选芳环包括萘基、甲苯基、二甲苯基和苯基。 Preferably aromatic rings include naphthyl, tolyl, xylyl, and phenyl. 最优选芳环基是苯基。 The most preferred aryl ring radical is phenyl.

[0046]"芳氧基"是具有芳基取代基的氧基团（即-o-芳基）。 [0046] "Aryloxy" is an aryl group having substituent groups (i.e., aryl -o-). 优选芳氧基包括（例如） 苯氧基、萘氧基、甲氧基苯氧基和亚甲基二氧基苯氧基。 An aryloxy group preferably comprises (e.g.) phenoxy, naphthyloxy, methoxyphenoxy, and methylenedioxy phenyl group.

[0047]"环烷基"指非芳族的饱和或不饱和烃环。 [0047] "Cycloalkyl" means a non-aromatic saturated or unsaturated hydrocarbon ring. 环烷基环是单环，或是稠合、螺或桥接双环或多环的环系统。 Cycloalkyl ring is a single ring, or fused, spiro or bridged bicyclic or polycyclic ring system. 单环的环烷基环在环中包含约3-约12个碳原子，优选3-7个碳原子。 Monocyclic cycloalkyl rings contain from about 3 to about 12 carbon atoms in the ring, preferably 3-7 carbon atoms. 双环的环烷基环在环中包含7-17个碳原子，优选7-12个碳原子。 Bicyclic cycloalkyl rings contain 7-17 carbon atoms in the ring, preferably 7-12 carbon atoms. 优选双环环烷基环包含与5-、6-或7-元环稠合的4-、5-、6-或7-元环。 Preferably bicyclic cycloalkyl ring contains 5-, 6- or 7-membered ring fused 4-, 5-, 6- or 7-membered ring. 环烷基环可以未被取代或在环上被1_4 个取代基取代。 Cycloalkyl ring may be unsubstituted or substituted with 1_4 substituents on the ring. 环烷基可被卣代基、氰基、烷基、杂烷基、卣代烷基、苯基、酮基、羟基、羧基、 氨基、酰基氨基、芳氧基、杂芳氧基或其任何组合取代。 Cycloalkyl substituents may be wine container, cyano, alkyl, heteroalkyl, wine container substituted alkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combinations thereof. 优选环烷基环包括环丙基、环戊基、 环己基、环庚基、环辛基和环壬基环。 Preferably cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and nonyl ring.

[0048] 术语"环烷基"还包括环状烷基，包括单环、双环、三环和高级多环烷基，其中各环状部分具有3-约12个碳原子，是3-12元环。 [0048] The term "cycloalkyl" also includes cyclic alkyl group, including monocyclic, bicyclic, tricyclic and higher polycyclic group, wherein each cyclic moiety has from 3 to about 12 carbon atoms, a 3-12 membered ring. 环烷基的实例包括环丙基、环丁基、环戊基、 环己基等。 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0049] 术语"环炔基"指环状炔基，包括单环、双环、三环和高级多环炔基，其中各环状部分具有3-约8个碳原子。 [0049] The term "cycloalkynyl group" refers to a cyclic alkynyl group, including monocyclic, bicyclic, tricyclic and higher polycyclic alkynyl group, wherein each cyclic moiety has from 3 to about 8 carbon atoms. "低级炔基"指具有2-约6个碳的炔基。 "Lower alkynyl" refers to alkynyl group having from 2 to about 6 carbon atoms.

[0050]"卤代基"或"卤素"是氟代基、氯代基、溴代基或碘代基。 [0050] "halo" or "halogen" is fluoro, chloro, bromo or iodo group. 优选卤代基是氟代基、氯代基和溴代基；通常最优选氯代基和氟代基，特别是氟代基。 Preferably halo is fluoro, chloro and bromo; chloro group and generally most preferably fluoro, especially fluoro.

[0051]"卤代烷基"是被一个或多个卤代取代基取代的直链、支链或环状烃。 [0051] "Haloalkyl" is substituted with one or more halo substituted straight chain, branched chain or cyclic hydrocarbon. 优选QC^ 卤代烷基；更优选Q-Ce卣代烷基；还更优选卣代烷基。 Preferably QC ^ haloalkyl; Q-Ce wine container is more preferably alkyl group; still more preferably substituted alkyl wine container. 优选卣代取代基是氟代基和氯代基。 Wine container on behalf of the substituent is preferably fluoro and chloro. [0052]"杂原子"是氮、硫或氧原子。 [0052] "Heteroatom" is a nitrogen, sulfur or oxygen atom. 包含不止一个杂原子的基团可包含不同的杂原子。 Contains more than one hetero atom may contain different heteroatoms. [0053] 术语"杂烷基（heteroalkyl)、杂烯基和杂炔基"包括任选取代的如上所述烷基、烯基和炔基结构，其中一个或多个骨架链原子选自非碳原子，如氧、氮、硫、磷或其组合。 As described above alkyl, alkenyl and alkynyl structures [0053] The term "heteroalkyl (heteroalkyl), heteroaryl alkenyl and alkynyl heteroaryl" includes an optionally substituted, wherein the one or more skeletal chain atoms selected from carbon non- atoms, such as oxygen, nitrogen, sulfur, phosphorus or combinations thereof. [0054]"杂烷基（heteroalkyl)"是包含碳和至少一个杂原子的饱和或不饱和链，其中没有两个杂原子相邻。 [0054] "heteroalkyl (heteroalkyl)" containing carbon and at least one heteroatom in a saturated or unsaturated chain wherein no two adjacent heteroatoms. 杂烷基链的链中包含2-15、优选2-10、更优选2-5个成员原子（碳和 Miscellaneous alkyl chain which contains 2-15, preferably 2-10, more preferably 2-5 member atoms (carbon and

杂原子）。 Hetero atom). 例如，烷氧基（即-o-烷基或-o-杂烷基）可包含在杂烷基中。 For example, alkoxy (i.e. -o- -o- alkyl or heteroalkyl) may be included in the hetero alkyl. 杂烷基链可为 Heteroalkyl chains may be

直链或支链。 Straight or branched chain. 优选支链杂烷基具有1或2个分支，优选1个分支。 Preferably branched heteroalkyl have one or two branches, preferably one branch. 优选饱和杂烷基。 Preferably a saturated heteroalkyl. 不饱和杂烷基具有一个或多个碳_碳双键和/或一个或多个碳_碳三键。 Unsaturated heteroalkyl have one or more carbon-carbon double bond and _ / _ or one or more carbon-carbon triple bond. 优选不饱和杂烷基具有1或2个双键或三键，更优选1个双键。 Preferably the unsaturated heteroalkyl having 1 or 2 double or triple bonds, more preferably one double bond. 杂烷基链可以未被取代或被1-4个取代基取代。 Heteroalkyl chains may be unsubstituted or substituted with 1-4 substituents. 优选取代的杂烷基被单_、二_或三_取代。 Preferably substituted heteroalkyl _ mono-, di- or tri-_ _-substituted. 杂烷基可被低级烷基、卤代烷基、卤代基、羟基、 芳氧基、杂芳氧基、酰氧基、羧基、单环芳基、杂芳基、环烷基、杂烷基、杂环烷基、螺环、氨基、 酰基氨基、酰氨基、酮基、硫酮基、氰基或其任何组合取代。 Heteroaryl alkyl may be lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycloalkyl, spiro, amino, acylamino, amido, keto, thione group, a cyano group, or any combinations thereof. 当将一种基团描述为例如烷基衍生物如"-乙基吡啶"时，破折号"-"表示取代基的连接点。 When one group is described, for example, alkyl derivatives, such as - when "ethylpyridinium" dash "-" indicates a substituent connection point. 因此，"-乙基吡啶"指通过基团的乙基段连接乙基吡啶，而"乙基吡啶指通过吡啶环连接。 Thus, "- ethylpyridinium" means connection ethylpyridinium segment by ethyl group, and "ethylpyridinium that connects through the pyridine ring.

[0055]"杂芳基"是在环中包含碳原子和1-约6个杂原子的芳环。 [0055] "Heteroaryl" is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. 杂芳环是单环或稠合的双环环系统。 Heteroaromatic ring is a single ring or a fused bicyclic ring system. 单环杂芳环在环中包含约5-约9个成员原子（碳和杂原子），优选5或6 个成员原子。 Monocyclic heteroaryl rings contain about 5 to about 9 member atoms (carbon and hetero atoms) in the ring, preferably 5 or 6 member atoms. 双环杂芳环在环中包含8-17个成员原子，优选8-12个成员原子。 Bicyclic heteroaromatic rings contain 8-17 member atoms in the ring, preferably from 8 to 12 member atoms. 双环杂芳环包括其中一个环是杂芳基且另一个环是芳基、杂芳基、环烷基或杂烷基、杂环烷基的环系统。 Bicyclic heteroaryl rings include those wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heteroalkyl, heterocycloalkyl ring system. 优选双环杂芳基环系统包含与5-、6-或7-元环稠合的5-、6-或7-元环。 Preferably bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered ring. 杂芳环可以未被取代或在环上被l-4个取代基取代。 Heteroaromatic ring may be unsubstituted or ring is l-4 substituents. 杂芳基可被卣代基、氰基、硝基、羟基、羧基、氨基、 酰基氨基、烷基、杂烷基、卤代烷基、苯基、烷氧基、芳氧基、杂芳氧基或其任何组合取代。 Heteroaryl substituent may be wine container, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy or replace any combination thereof. 优选杂芳环包括但不限于以下杂芳环： [0056] Preferred heteroaryl rings include, but are not limited to, the following heteroaryl ring: [0056]

<formula>formula see original document page 11</formula><formula>formula see original document page 12</formula> <Formula> formula see original document page 11 </ formula> <formula> formula see original document page 12 </ formula>

[0058] 稠合杂芳基可包含2-4个稠环，连接的环是杂芳环，稠环系统内的其它各环可以是芳族环、杂芳族环、脂族环或杂环族环。 [0058] The fused heteroaryl groups may contain 2-4 fused ring, the ring is a heteroaromatic ring connected to each other rings fused ring system may be an aromatic ring, heteroaromatic ring, alicyclic or heterocyclic aromatic ring. 术语杂芳基还包括具有5-约12个骨架环原子以及具有5-约10个骨架环原子的单-杂芳基或稠合杂芳基。 The term heteroaryl also includes a 5 to about 12 skeletal ring atoms and having a single 5 to about 10 skeletal ring atoms, - heteroaryl or fused heteroaryl. 术语"低级杂芳基"指具有5-约10个骨架环原子的杂芳基，如吡啶基、噻吩基、嘧啶基、吡嗪基、吡咯基或呋喃基。 The term "lower heteroaryl" refers to a 5 to about 10 skeletal ring atoms, heteroaryl such as pyridyl, thienyl, pyrimidinyl, pyrazinyl, pyrrolyl or furyl. [0059]"杂芳氧基"是具有杂芳基取代基的氧基团（即-0-杂芳基）。 [0059] "heteroaryloxy" is a heteroaryl substituent groups (ie -0- heteroaryl). 优选杂芳氧基包括(例如）吡啶氧基、呋喃氧基、（噻吩）氧基、（噁唑）氧基、（噻唑）氧基、（异噁唑）氧基、 嘧啶氧基、吡嗪氧基和苯并噻唑氧基。 Preferred heteroaryl groups include (for example) pyridyloxy, furanyloxy, (thiophene) oxy, (oxazole) oxy, (thiazole) oxy, (isoxazole) oxy, pyrimidinyl group, pyrazinyl group and benzothiazole group.

[0060]"杂环烷基"是环内包含碳原子和1_4(优选1-3)个杂原子的饱和或不饱和环。 [0060] "heterocycloalkyl" is a ring that contains carbon atoms and 1_4 (preferably 1-3) heteroatoms, saturated or unsaturated ring. 杂环烷基环并非芳环。 Heterocycloalkyl ring is not an aromatic ring. 杂环烷基环是单环，或是稠合、桥接或螺双环的环系统。 Heterocycloalkyl ring is a monocyclic, or fused, bridged or spiro bicyclic ring system. 单环杂环烷基环在环中包含约3-约9个成员原子（包括碳和杂原子），优选5-7个成员原子。 Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (including carbon and hetero atoms) in the ring, preferably from 5-7 member atoms. 双环杂环烷基环在环中包含7-17个成员原子，优选7-12个成员原子。 Bicyclic heterocycloalkyl rings contain 7-17 ring member atoms, preferably 7 to 12 member atoms. 双环杂环烷基环包含约7-约17个环原子，优选7-12个环原子。 Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. 双环杂环烷基环可以是稠合、螺或桥接的环系统。 Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. 优选双环杂环烷基环包含与5-、6-或7-元环稠合的5-、6-或7-元环。 Bicyclic heterocycloalkyl rings preferably comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered ring. 杂环烷基环可以未被取代（即包含氢作为环原子的取代基）或被l-4个取代基取代（在碳或杂原子上或两者皆 Heterocycloalkyl ring may be unsubstituted (i.e., containing a hydrogen atom as ring substituent) or l-4 substituents (on carbon or heteroatoms or both

可），所述取代基选自甲基、卣代基、卣代烷基、氰基、羟基、羧基、酮基、硫酮基、氨基、酰基氨 May be), the substituents are selected from methyl, substituents wine container, wine container alkyl group, a cyano group, a hydroxyl group, a carboxyl group, a ketone group, thione group, amino group, acylamino

基、酰基、酰氨基、烷基（除甲基以外）、杂烷基、卣代烷基、苯基、烷氧基、芳氧基或其任何组 Group, an acyl group, an acylamino group, an alkyl (other than methyl), heteroalkyl, wine container substituted alkyl, phenyl, alkoxy, aryloxy or any group

合。 Co. 优选杂环烷基上的取代基包括甲基、乙氧基、卣代基和卣代烷基。 Preferably substituents on heterocycloalkyl include methyl, ethoxy, wine container wine container and substituted alkyl substituents. 杂环烷基环可通过所 Heterocycloalkyl ring can be through the

述杂环烷基环的任何化学上合适的原子连接成更大结构的取代基。 Any suitable atom chemically said heterocycloalkyl ring is connected to a substituent larger structure. 优选杂环烷基环包括但 Preferably heterocycloalkyl rings include, but are

不限于以下杂环烷基环： Heterocycloalkyl rings is not limited to the following:

[0061] [0061]

〉—□。 > - □. cr 0 0 CO cr 0 0 CO

环氧乙烷氮丙夂环氧丙烷氮杂环丁烷四氢呋喃吡咯烷3H-吲哚 Fan ethylene oxide-propylene oxide nitrogen azetidine tetrahydrofuran pyrrolidine 3H- indole

[0062]<formula>formula see original document page 14</formula> [0062] <formula> formula see original document page 14 </ formula>

<formula>formula see original document page 14</formula>[0063] 术语"元环"可包括任何环状结构，包括芳族、杂芳族、脂环族、杂环和多环的稠合环系统，如下描述。 <Formula> formula see original document page 14 </ formula> [0063] The term "membered ring" may include any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring system , as described below. 术语"元"指构成环的骨架原子数。 The term "dollars" refers to the number of atoms constituting the ring skeleton. 因此，例如吡啶、吡喃和嘧啶是6-元环，吡咯、四氢呋喃和噻吩是5-元环。 Thus, for example, pyridine, pyran and pyrimidine 6-membered ring, pyrrole, tetrahydrofuran and thiophene are 5-membered ring. [0064] 单独或组合的术语"芳基"指6-约20个环原子的任选取代的芳族烃基，包括单-芳环和稠合芳环。 [0064] alone or in combination, the term "aryl" means 6 to about 20 ring atoms, optionally substituted aromatic hydrocarbon, including single - aromatic ring and fused aromatic rings. 稠合芳环基包含2-4个稠环，其中连接的环是芳环，稠环内的其他各环可以是芳族环、杂芳族环、脂环族或杂环族环。 Fused aromatic ring group comprises 2-4 fused ring, wherein the ring is connected to an aromatic ring, each other rings fused ring may be an aromatic ring, heteroaromatic ring, alicyclic or heterocyclic ring. 而且，术语芳基包括含有6-约12个碳原子以及含有6-约10个碳原子的单_芳环和稠合芳环。 Moreover, the term aryl groups include 6 to about 12 carbon atoms and a single _ aromatic ring and fused aromatic ring containing 6 to about 10 carbon atoms. 芳基的实例包括但不限于苯基、萘基、蒽基、篇基和苯并芘基环系统。 Examples of aryl groups include but are not limited to, phenyl, naphthyl, anthryl, articles yl group, and benzopyrene ring system. 术语"低级芳基"指具有6-约IO个骨架环碳的芳基，如苯基和萘基环系统。 The term "lower aryl" refers to an aryl group having from 6 to about IO skeletal ring carbons, such as phenyl and naphthyl ring system.

[0065] 术语"杂环基"指含有5-约20个环原子的任选取代的饱和或不饱和非芳环基团， 其中一个或多个环原子是杂原子如氧、氮、硫和磷。 [0065] The term "heterocyclic group" means a 5 to about 20 ring atoms, optionally substituted saturated or unsaturated non-aromatic ring groups, in which one or more ring atoms is a heteroatom such as oxygen, nitrogen, sulfur, and phosphorus. 术语脂环基包括单_杂环和稠合杂环基。 The term alicyclic group include single _ heterocyclic and fused heterocyclic group. 稠合杂环基可包含2-4个稠环，其中连接环是杂环，稠合杂环基内的其它各环可以是芳族、杂芳族、脂环族或杂环族。 Condensed heterocyclic group may contain 2 to 4 fused rings, wherein the connection is a heterocyclic ring, fused heterocyclic ring each other within the group may be aromatic, hetero aromatic, alicyclic or heterocyclic. 术语杂环族还包括具有5-约12个骨架环原子以及具有5-约10个骨架环原子的单_杂环族和稠合脂环族基团。 The term heterocyclic also includes a 5 to about 12 skeletal ring atoms and having 5 to about 10 skeletal ring atoms single _ heterocyclic and fused alicyclic group. 杂环族的实例包括但不限于四氢呋喃基、苯二氮杂草基、四氢吲唑基、二氢喹啉基等。 Examples of the heterocyclic group include, but are not limited to, tetrahydrofuran, benzene diazepine-yl, tetrahydro-indazolyl, quinolyl dihydro the like. 术语"低级杂环族"指具有5-约IO个骨架环原子的杂环系统，如二氢吡喃基、吡咯烷基、吲哚基、哌啶基、哌嗪基等。 The term "lower heterocyclic" refers to heterocyclic ring system having 5 to about IO skeletal ring atoms, such as dihydropyran, pyrrolidinyl, indolyl, piperidinyl, piperazinyl and the like. [0066] 单独或组合使用的术语"烷基芳基"指其中1个H原子被如上文限定的烷基代替的如上文限定的芳基，如甲苯基、二甲苯基等。 [0066] alone or in combination, the term "alkyl aryl" means wherein an H atom is replaced by an alkyl group as defined above for an aryl group as defined above, such as tolyl, xylyl and the like.

[0067] 单独或组合的术语"芳基烷基"或"芳烷基"指其中1个H原子被如上文限定的芳基代替的如上文限定的烷基，如苄基、2_苯基乙基等。 [0067] alone or in combination, the term "arylalkyl" or "aralkyl" means a group where one H atom is an aryl group as defined above in place of the above defined alkyl group, such as benzyl, phenyl 2_ ethyl and the like.

[0068] 术语"杂芳基烷基"指其中1个H原子被如上文限定的杂芳基代替的如上文限定的烷基，其各自可被任选取代，但其中芳基连接于较大的核心结构，烷基为末端部分。 [0068] The term "heteroaryl group" means a group where one H atom is as hereinbefore defined heteroaryl replaced by an alkyl group as defined above, each of which may be optionally substituted, wherein the aryl group is connected to but larger The core structure, the alkyl is a terminal portion. [0069] 术语"烷基杂芳基"指其中1个H原子被如上文限定的杂芳基代替的如上文限定的烷基，其各自可被任选取代，但其中烷基连接于较大的核心结构，杂芳基为末端部分。 [0069] The term "alkyl heteroaryl" refers to an H atom which is as hereinbefore defined heteroaryl replaced by an alkyl group as defined above, each of which may be optionally substituted, wherein the alkyl group is attached to a larger but core structures, heteroaryl end portion. [0070] 单独或组合的术语"芳氧基"指其中术语芳基如上文限定的芳基醚基。 [0070] alone or in combination, the term "aryloxy" refers to wherein the term aryl as hereinbefore defined aryl ether group. 芳氧基的实例包括苯氧基、苄氧基等。 Examples of aryloxy include phenoxy, benzyloxy and the like.

[0071] 单独或组合的术语"烷硫基"指烷硫基，烷基-S-，其中术语烷基如上文限定。 [0071] alone or in combination, the term "alkylthio" means an alkylthio group, an alkyl group -S-, wherein the term alkyl as defined above.

[0072] 单独或组合的术语"芳硫基"指芳硫基，芳基-S-，其中术语芳基如上文限定。 [0072] alone or in combination, the term "arylthio" means an arylthio group, an aryl group -S-, wherein the term aryl as defined above.

[0073] 术语"杂芳硫基"指基团杂芳基-S-，其中术语杂芳基如上文限定。 [0073] The term "heteroaryl group" refers to the group heteroaryl -S-, wherein the term heteroaryl as defined above.

[0074] 术语"酰基"指基团-C(O)R，其中R包括烷基、烯基、炔基、芳基、杂芳基、脂环基、杂 [0074] The term "acyl" refers to the group -C (O) R, wherein R comprises an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an alicyclic group, a hetero

环基、芳基烷基或杂芳基烷基，其中烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷 Cycloalkyl group, aryl group or heteroaryl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl

基或杂芳基烷基可被任选取代。 Group or heteroaryl group may be optionally substituted.

[0075] 术语"酰氧基"指酯基-OC(0)R，其中R是H、烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、芳基烷基或杂芳基烷基，其中烷基、烯基、炔基、芳基、杂芳基、脂环基、杂环基、 芳基烷基或杂芳基烷基可被任选取代。 [0075] The term "acyloxy" refers to the ester group -OC (0) R, wherein R is H, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an alicyclic group, a heterocyclic group, an aryl group alkyl or heteroaryl group, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl group may be optionally substituted.

[0076] 术语"羧基酯"指-C(0)OR，其中R是烷基、芳基或芳基烷基，其中烷基、芳基和芳基烷基可被任选取代。 [0076] The term "carboxy esters" refers to -C (0) OR, wherein R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.

[0077] 术语"氨甲酰基"指结构-C(O)NRR'，其中氮连接于羰基碳，R和R'各自独立选 [0077] The term "carbamoyl" refers to the structure -C (O) NRR ', wherein the nitrogen attached to the carbonyl carbon, R and R' are each independently selected from

自H、烷基、芳基、杂芳基、脂环基、杂环基、芳基烷基和杂芳基烷基，其中烷基、芳基、杂芳基、 From H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl,

脂环基、杂环基或芳基烷基可被任选取代。 An alicyclic group, a heterocyclic group or arylalkyl group may be optionally substituted.

[0078] 术语"氧代基"指双键合的氧，以=O表示。 [0078] The term "oxo" means a double-bonded oxygen, in order to represent = O.

[0079] 术语"卣素"包括F、 Cl 、 Br禾口I 。 [0079] The term "wine container element" includes F, Cl, Br Hekou I. [0080] 使用"卤代烷基、卤代烯基、卤代炔基和卤代烷氧基"包括被一个或多个氟、氯、溴或碘或其组合取代的如上描述的烷基、烯基、炔基和烷氧基结构。 [0080] Use "haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy" includes one or more fluorine, chlorine, bromine or iodine, or combinations thereof as described above substituted alkyl, alkenyl, alkynyl, and alkoxy structures.

[0081 ] 术语"全卤代烷基、全卤代烷氧基和全卤代酰基"指所有H原子都被氟、氯、溴或碘或其组合取代的如上描述的烷基、烷氧基和酰基。 [0081] The term "perhaloalkyl, perhaloalkoxy and perhaloalkyl acyl" refers to all H atoms are fluorine, alkyl, alkoxy and acyl chlorine, bromine or iodine, or combinations thereof substituted as described above.

[0082] 术语"环烷基、芳基烷基、芳基、杂芳基、脂环基、杂环基、烷基、炔基、烯基、卤代烷基和杂烷基"包括任选取代的环烷基、芳基烷基、芳基、杂芳基、脂环基、杂环基、烷基、炔基、 烯基、卤代烷基和杂烷基。 [0082] The term "cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl" includes optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl.

[0083] 术语"烷基氨基"指基团-NHR、其中R独立选自烷基。 [0083] The term "alkylamino" refers to the group -NHR, wherein R is independently selected from alkyl. [0084] 术语"二烷基氨基"指基团-NRR'，其中R和R'是烷基。 [0084] The term "dialkylamino" refers to the group -NRR ', wherein R and R' is alkyl.

[0085] 术语"硫醚"指与2个原子共价结合的硫原子；所述硫的正式（formal)氧化状态是（11)。 [0085] The term "thioether" refers to a sulfur atom and two atoms covalently bonded; official (formal) oxidation state of said sulfur is (11). 术语"硫代醚"可与术语"硫醚"互换使用。 The term "thioether" may use the term "sulfide" interchangeably.

[0086] 术语"亚砜"指与3个原子共价结合的硫原子，其中至少1个原子是氧原子；所述硫原子的正式氧化状态是（IV)。 [0086] The term "sulfoxide" refers to a sulfur atom covalently bonded to three atoms in which at least one atom is an oxygen atom; a sulfur atom in the formal oxidation state (IV).

[0087] 术语"砜"指与4个原子共价结合的硫原子，其中至少2个原子是氧原子；所述硫原子的正式氧化状态是（VI)。 [0087] The term "sulfone" refers to a sulfur atom covalently bonded to 4 atoms, wherein at least two atoms is an oxygen atom; a sulfur atom in the formal oxidation state (VI).

[0088] 术语"任选的"或"任选地"指接着描述的事件或状态可以但不一定发生，该描述既包括该事件或状态发生的情况也包括不发生的情况。 [0088] The term "optional" or "optionally" means subsequently described event or condition may but need not occur, that the description includes both the case of the occurrence of an event or condition also includes the case it does not. 例如，"被烷基任选单_或二_取代的芳基"指该烷基可以但不一定存在，或者可能存在1或2个烷基，该描述包括芳基被1或2个烷基取代的情况和芳基不被烷基取代的情况。 For example, "is an alkyl group optionally mono- or di-_ _ substituted aryl" means that the alkyl may but need not be present, or there may be one or two alkyl groups, the aryl group is described comprising 1 or 2 alkyl groups substituted aryl group is not the case and the case of substituted alkyl.

[0089]"任选取代的"基团可被取代或未被取代。 [0089] "optionally substituted" group may be substituted or unsubstituted. "任选取代的"基团的取代基可包括但不限于独立选自以下基团或其特定亚类的一个或多个取代基：低级烷基、低级烯基、低级炔基、低级芳基、杂芳基、脂环基、杂环基、芳基烷基、杂芳基烷基、低级烷氧基、低级芳氧基、氨基、烷基氨基、二烷基氨基、二芳基烷基氨基、烷硫基、芳硫基、杂芳硫基、氧代基、 氧杂基、羰基（-C(0))、羧基酯（-C(0)0R)、氨甲酰基（-C(0)叫）、羧基、酰氧基、-H、卤代基、-CN、 -N02 、 -N3 、 -SH、 -OH、 -C (0) CH3 、全卤代烷基、全卤代烷氧基、全卤代酰基、胍、吡啶基、 噻吩、呋喃基、吲哚、吲唑、S旨、酰胺、膦酸酯、膦酸、磷酸酯、磷酰胺、磺酸酯、砜、硫酸酯、磺酰胺、氨基甲酸酯、脲、硫脲和硫代酰胺、硫烷基。 Substituent "optionally substituted" group may include, but are not limited to, an independently selected group or specific subclass or more substituents: lower alkyl, lower alkenyl, lower alkynyl, lower aryl , heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, alkyl diaryl amino, alkylthio, arylthio, heteroarylthio, oxo, oxa group, a carbonyl group (-C (0)), carboxyl ester (-C (0) 0R), carbamoyl group (-C ( 0) is called), carboxy, acyloxy, -H, halo, -CN, -N02, -N3, -SH, -OH, -C (0) CH3, perhaloalkyl, perhaloalkoxy, whole haloacyl, guanidino, pyridyl, thienyl, furanyl, indole, indazole, S purpose, amides, phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulfonamide, carbamate, urea, thiourea and thioamides, thioalkyl. 任选取代的基团可以未被取代（如-C4CH》、 完全取代（如<&0&)、单取代（如-CH2CH2F)或在完全取代与单取代之间的任何水平取代(如_CH2CF3)。 Optionally substituted group may be unsubstituted (such as -C4CH ", completely replaced (such as <& 0 &), mono-substituted (such as -CH2CH2F) or completely replace and supersede any level between mono-substituted (such as _CH2CF3).

[0090] 本发明的一些化合物可包含一个或多个手性中心，因此可存在对映体和非对映体 [0090] Some of the compounds of the present invention may contain one or more chiral centers and therefore can exist as enantiomers and diastereomers

形式。 Form. 本发明的范围预计包括所有异构体本身，以及顺式和反式异构体混合物、非对映体混 The scope of the invention is expected to include all isomers themselves, as well as cis and trans isomeric mixture of diastereomers mixed

合物和对映体（旋光异构体）的外消旋混合物，可以用众所周知的方法分离各种形式，本发 Outside the compound and enantiomers (optical isomers) of the racemic mixture, it can be isolated by methods well known in various forms, the present

明一些实施方案的特征可以是指定对映体或非对映体的纯化或富集物。 Ming features some embodiments may be designated enantiomer or enantiomer purification or enrichment.

[0091]"药理组合物"指本文所述一种或多种化合物或其药学上可接受的盐与其它化学 [0091] "pharmacological composition" refers to the one or more of the compounds herein, or a pharmaceutically acceptable salt thereof, with other chemical

组分（如药学上可接受的载体和/或赋形剂）的混合物。 Mixture components (such as a pharmaceutically acceptable carrier and / or excipient) is. 药理组合物的目的是便于将化合 Objective pharmacological composition is to facilitate the compound

物给予生物体。 Was given organism.

[0092] 短语"药学上可接受的载体"用于本文指药学上可接受的材料、组合物或溶媒，如液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料，用于将主药从一种器官或机体的一部分携带或转运至另一种器官或机体的一部分。 [0092] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, for The main drug from an organ or body part in carrying or transporting to another organ or body part. 每种载体必须"可被接受"指与制剂的其它成分相容且对患者无害。 Each carrier must be "acceptable" means compatible with the other ingredients of the formulation and injurious to the patient. 可作为药学上可接受的载体的一些材料实例包括：（l)糖，如乳糖、葡萄糖和蔗糖；（2)淀粉，如玉米淀粉和马铃薯淀粉；（3)纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和乙酸纤维素；(4)黄蓍胶粉；（5)麦芽；(6)明胶；（7)滑石粉；（8) 赋形剂，如可可豆油和栓蜡；（9)油，如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；（IO) 二醇，如丙二醇；（ll)多元醇，如甘油、山梨醇、甘露醇和聚乙二醇；（12)酉旨， 如油酸乙酯和月桂酸乙酯；（13)琼脂；（14)缓冲剂，如氢氧化镁和氢氧化铝；（15)海藻酸; (16)无热原水;(17)等渗盐水;(18)林格氏液;(19)乙醇;(20)磷酸盐缓冲液；和(21)用于药用制剂中的其它非毒性相容性物质。 Some examples of materials can be used as pharmaceutically acceptable carriers include: (l) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powder tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (IO) glycols, such as propylene glycol; (ll) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) unitary purpose, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) used in pharmaceutical formulations with other non-toxic Capacitive substances. 生理学上可接受的载体应当对生物体不产生明显剌激性并且不消除给予的化合物的生物活性和特性。 Physiologically acceptable carrier organisms should not have a significant irritant and does not abrogate the biological activity and properties of the compound administered.

[0093] 术语"赋形剂"指加至药理学组合物以进一步便于化合物给药的惰性物质。 [0093] The term "excipient" refers to the pharmacological composition is added to further facilitate administration of a compound to an inert substance. 赋形 Shaped

剂的实例包括但不限于碳酸钙、磷酸钙、各种糖类和淀粉类型、纤维素衍生物、明胶、植物油和聚乙二醇。 Examples of agents include, but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0094] 用于本文时，术语"治疗作用"包括但不限于抑制（完全或部分）增殖性疾病如结肠癌的特征细胞的生长。 [0094] As used herein, the term "therapeutic effect" includes, but is not limited to, inhibiting (completely or partially) proliferative diseases such as colon cancer cell growth characteristics. 治疗作用还可包括改善疾病的一种或多种症状（除了细胞团块的细胞生长或大小之外），可包括l)减少细胞数目；2)减小细胞大小；3)抑制（即减慢，优选停止）细胞浸润（即转移）入周围器官内；3)抑制或减慢细胞生长；和/或4)缓解与疾病如癌有关的一种或多种症状。 Therapeutic effect may also include ameliorating one or more symptoms of the disease (in addition to the cell pellet or cell growth beyond the size), may comprise l) reduce the number of cells; 2) reduced cell size; 3) inhibition (i.e., slowing preferably stop) cellular infiltration (i.e., metastasis) into the surrounding organs; 3) inhibiting or slowing down cell growth; and / or 4) relieving one or more symptoms associated with diseases such as cancer. 产生此类治疗作用的本文公开化合物的任何剂量视为所述化合物的"治疗有效剂量"或"治疗有效量"。 Any such doses produce a therapeutic effect of the compounds disclosed herein as a "therapeutically effective amount" or "therapeutically effective amount" of the compound.

[0095] 当涉及癌症时，短语"有效量"指在转移或原发性肿瘤进展、大小或生长方面，足以产生所需效应或改善症状或体征的量。 [0095] When it comes to cancer, the phrase "effective amount" refers to metastasis or primary tumor progression, size, or growth aspect, the amount of the desired effect, or ameliorate symptoms or signs sufficient to produce. 代表性的哺乳动物治疗接受者包括小鼠、大鼠、猫、 狗和灵长类，包括人。 Representative mammals treatment recipients include mice, rats, cats, dogs, and primates, including humans. 对于具体患者的有效量可不同，取决于以下因素，如正在治疗的疾病、 患者的全身健康状况、给药方法、途径和剂量以及副作用的严重度。 For an effective amount of a particular patient may vary, depending on such factors as the disease being treated, the patient's general health, administration method, dose and route and severity of side effects. 优选该作用将导致定量改变至少约10 % ，优选至少20 % 、 30 % 、 50 % 、 70 %或甚至90 %或更多。 Preferably, the effect will lead to quantitative change of at least about 10%, preferably at least 20%, 30%, 50%, 70% or even 90% or more. 当组合时，有效量与组分的组合成比例，其作用不限于各组分单独使用时的作用。 When combined, the combination of an effective amount is proportional to the component, and its role is not limited to the role of each component when used alone.

[0096]"溶剂化物"是溶质（如金属蛋白酶抑制剂）和溶剂（如水）组合形成的复合物。 [0096] "solvate" is a solute (such as metalloproteinase inhibitor) and a solvent (water) composition of complex formation.

参阅J. Honig等，The Van Nostrand Chemist' s Dictionary, p. 650 (1953)。 See J. Honig, etc., The Van Nostrand Chemist 's Dictionary, p. 650 (1953).

[0097] 术语"旋光异构体"、"几何异构体"（如顺式和/或反式异构体）、"立体异构体" [0097] The term "optical isomer", "geometric isomers" (such as cis and / or trans isomer), "stereoisomer"

禾口"非对映体，，具有公认含义（参阅如Hawley' s CondensedChemical Dictionary, 11th Hekou "diastereomer ,, have accepted meanings (see, for example Hawley 's CondensedChemical Dictionary, 11th

Ed.)。 Ed.). 举例说明的本发明化合物的具体被保护形式及其它衍生物预计非限制性。 Specific forms of protection are compounds of the invention illustrated and other derivatives expected non-limiting. 其它有用 Other useful

的保护基团、盐形式、前药等的应用在技术人员能力范围之内。 Application protecting groups, salt forms, prodrugs and other technical staff in the capacity range.

[0098]"前药"是在变为活化或完全活化的药物之前必须通过代谢过程发生化学转化的药物形式。 [0098] "Prodrugs" is activated prior to or become fully activated form of the drug must occur pharmaceutical chemical conversion by metabolic processes. 前药在其摄入或吸收形式或给药形式时无活性，或活性较小。 Inactive prodrug ingested or absorbed when it is administered in the form or forms, or less active. 例如，前药可被消化系统中的细菌分解为产物，其中至少一种将活化成为药物。 For example, prodrugs can be decomposed by bacteria in the digestive system for the products, wherein at least one of the drug will become activated. 或者，它可通过全身例如静脉内注射给药，接着代谢为一种或多种活性分子。 Alternatively, it may be by systemic administration such as intravenous injection, followed by one or more metabolic active molecules.

[0099] 用于本文时，术语"1(:5。"指在测量此类效应的测定中，获得最大效应50%抑制的具体测试化合物的量、浓度或剂量。在本发明的一些方法实施方案中，本发明化合物对正常细胞的"1(:5。"值可大于对表现增殖性疾病的细胞，如乳癌细胞的"1(:5。"值。该数值取决于所用测定法。 [0099] As used herein, the term "1 (: 5" refers to the measurement of the effect of such measurement, the maximum amount to obtain 50% inhibition of the specific effects of the test compounds, concentrations or doses in some methods of the present invention is implemented. , a compound of the present invention to normal cells "1 (: 5 'may be greater than the value of cell proliferative disease manifestations, such as breast cancer cells" 1 (: 5 "depending on the value of the assay values.

[0100]"标准"指阳性或阴性对照。 [0100] "Standard" means a positive or negative control. 阴性对照在这里指与癌细胞相反的正常对照，如具有正常细胞相关的Wnt/ |3 _联蛋白途径活性的样品。 Negative control here refers to the opposite of the normal control of cancer, such as having a normal cell-associated Wnt / | _ Sample 3-catenin pathway activity. 阴性对照还可包括不含有此类途径的样品。 Negative control may also include a sample does not contain such a way. 相反，阳性对照含有优选为增殖性疾病如乳癌中所见过度表达相关量的此类途径。 In contrast, the positive control containing preferably proliferative disease such as breast cancer seen in excessive amount of expression pathways associated. 对照物可来自细胞或组织样品，或可包含纯化、固定等的配体（或不含配体）。 Controls may be derived from a cell or tissue sample, or may comprise purified, fixation of the ligand (or ligand-free). 在一些实施方案中，一种或多种对照物可采用诊断"测量杆（dipstick)"的形式。 In some embodiments, one or more controls can diagnose "measuring rod (dipstick)" form.

[0101]"选择性靶向"指对一种类型细胞的作用超过另一种，如对于癌细胞和对于非癌细 [0101] "selective targeting" refers to the action of a type of cell over another, such as for cancer and a fine for non-cancerous

胞的情况下。 Cellular situation under.

[0102] 发明详述 [0102] DETAILED DESCRIPTION

[0103] 本发明提供具有式I结构的化合物[0104] [0103] The present invention provides a compound having the structure of formula I [0104]

Y<formula>formula see original document page 18</formula> Y <formula> formula see original document page 18 </ formula>

[0105] 式I [0105] Formula I

[0106] 其中n = 0-2，其中当n = 1时，X选自CH2、 0、 NRA、 CO禾口C = NORa，其中当n = 2 时，X = CH2 [0106] where n = 0-2, wherein when n = 1, X is selected from CH2, 0, NRA, CO Hekou C = NORa, wherein when n = 2, X = CH2

[0107] Y = 0、S、NORa或NRa， [0107] Y = 0, S, NORa or NRa,

[0108] 其中Ra逸自H、烷基、杂烷基、烯基、炔基、环烷基、-C( = 0)RB、-C( = 0)0RB、_C(= 0)NRBRc、 -C( = NRB)RC、 ^&1^、杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷基芳基其中所述RB和Rc各自独立是H、烷基或杂烷基， [0108] wherein Ra Yi from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, -C (= 0) RB, -C (= 0) 0RB, _C (= 0) NRBRc, - C (= NRB) RC, ^ & 1 ^, a heterocyclic group, an aromatic group or an aryl, heteroaryl, arylalkyl and alkyl aryl groups wherein the RB and Rc each independently is H, alkyl or heteroalkyl,

[0109] U和V各自独立选自C二0禾P0二S二O，其中当U是C = 0时，V不是C = 0， [0110] &、 R2、 &和1?4各自独立选自H、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基，所述NR^和NR3R4可各自独立形成杂环烷基， [0109] U and V each independently selected from C 20 Wo P0 = S two O, wherein when U is C = 0 时, V instead of C = 0, [0110] &, R2, & and 1? 4 are each independently selected from from H, alkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, NR3R4 and NR ^ each independently may form a heterocyclic ring alkyl,

[0111] Rs和Re各自独立选自H、 0H、 SH、烷氧基、硫代烷氧基、烷基、卤素、CN、 CF3、 N02、 C00R。 [0111] Rs and Re are each independently selected from H, 0H, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, N02, C00R. 、 C0NRDRE、 NRDRE、 NRDC0RE、 NRDS02RE和NRFC0NRDRE ; , C0NRDRE, NRDRE, NRDC0RE, NRDS02RE and NRFC0NRDRE;

[0112] 其中R。 [0112] wherein R. 、I^和RF独立是H、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基或杂环烷基； , I ^ and RF is independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

[0113] 前提是如果X是0、Y是0且U和V都是0 = S = 0，则NR凡和NR3R4不相同，其中&和R3各自独立选自H和低级烷基，其中R2和R4各自独立选自低级烷氧基（低级烷基）、 二（低级）烷基氨基（低级）烷基、卤代节基、吗啉代（低级）烷基，或者NRA和NR3R4独立选自哌啶子基、吗啉代、哌嗪-1-基、N-苯基哌嗪-1-基、乙氨基或取代的甘氨酸，如果X 是（CH2)2、 Y是0或NOH且U和V各自是0 = S = 0，则R2、 R3和R4不全是甲基， [0114] 如果n = 0、 Y是0或NOH且U和V各自是0 = S = 0，则NR^和NR3R4不相同， 且R2、 R3和R4各自独立选自C「Cs烷基、C1Q烷基、C16烷基、C17烷基、苯基、节基、萘基、哌嗪-1-基、妣啶基、妣唑基、苯并咪唑基、三唑基；或者NR凡和NR3R4独立是哌啶子基、吗啉代或哌嗪-1-基， [0113] provided that if X is 0, Y is 0 and U and V are 0 = S = 0, where the NR and NR3R4 are not the same, where & and R3 are each independently selected from H and lower alkyl, wherein R2 and R4 is independently selected from lower alkoxy (lower alkyl), di (lower) alkylamino (lower) alkyl, halo section group, morpholino (lower) alkyl, or NRA and NR3R4 are independently selected from piperazine piperidino, morpholino, piperazin-1-yl, N- phenyl-piperazin-1-yl, or substituted amino ethyl glycine, if X is (CH2) 2, Y is O or NOH, and U and V each is 0 = S = 0, then R2, R3 and R4 are not all methyl, [0114] if n = 0, Y is 0 or NOH and U and V are each 0 = S = 0, then the NR ^ and NR3R4 not the same, and R2, R3 and R4 are each independently selected from C "Cs alkyl, C1Q alkyl, C16 alkyl, C17 alkyl, phenyl, section group, a naphthyl group, piperazin-1-yl, piperidinyl deceased mother, deceased mother oxazolyl, benzimidazolyl, triazolyl; or NR where and NR3R4 independently piperidino, morpholino or piperazin-1-yl,

[0115] 如果X是CO、Y是0且U和V各自是O = S = 0，则NR^和NR3R4不相同，其中&、 R2、 R3和R4各自独立选自甲基、乙基、羟基-Q-Cf烷基、SH、 R0、 C00H、 S0、 NH2和苯基，或者其不相同的NRA和NR3R4其中之一或两者是未被取代的哌啶子基J-甲基哌嗪-1-基或N-甲基高哌嗪-l-基， [0115] If X is CO, Y is 0 and U and V are independently O = S = 0, it is not the same as NR3R4 and NR ^, wherein &, R2, R3 and R4 are each independently selected from methyl, ethyl, hydroxy -Q-Cf alkyl, SH, R0, C00H, S0, NH2 and phenyl, or a different NRA and NR3R4 wherein one or both are unsubstituted piperidino J- methylpiperazine - 1- yl or N- methyl homopiperazine -l- yl,

[0116] 其中当X是C = 0或C = N0H， Y是0或N0H，U禾PV各自是0 = S = 0， &或R2其中之一和R3或R4其中之一是苯基时，则&或R2和R3或R4中的另一个不是H或烷基， [0117] 包括其所有药学上可接受的盐、S旨、酰胺、立体异构体、几何异构体、溶剂化物或前药。 [0116] wherein when X is C = 0 or C = N0H, Y is 0 or N0H, U Wo PV are each 0 = S = 0, &, or R2 and R3 or one in which one of R4 is phenyl, the & or R2 and R3 or R4 of the other is not H or alkyl, [0117] includes all pharmaceutically acceptable salt thereof, S purpose, amide, stereoisomer, geometric isomer, solvate or before drugs.

[0118] 在另一个实施方案中，本发明提供具有式II结构的化合物[0119] [01] In another embodiment, the present invention provides a compound having the structure of formula II [0119]

[0120] 式II [0120] Formula II

[0121] 其中R7和R8独立选自H和S02NR3R4， R7或R8其中之一是氢，或式III化合物[0122] [0121] wherein R7 and R8 are independently selected from H and S02NR3R4, wherein one of R7 or R8 is hydrogen, or a compound of formula III [0122]

[0123] 式III [0123] Formula III

[0124] 其中R7和R8独立选自H和S02NR3R4，其中R7和R8其中之一是氢，其中在每个所述式II和III中，其它取代基具有如式I限定的含义。 [0124] wherein R7 and R8 are independently selected from H and S02NR3R4, wherein one of R7 and R8 is hydrogen, wherein in each of the formulas II and III, the other substituents having the meaning as defined in formula I.

[0125] 在本发明的具体实施例中，式I化合物是此类结构，其中A是NR"或其中A是 [0125] In a particular embodiment of the invention, the compound of Formula I is such a structure, in which A is NR "or where A is

(CR凡）迈，m = l，或其中A是(CR^2)m， m = 2， &和R2如本文其它地方限定。 (CR Van) Mai, m = l, or where A is (CR ^ 2) m, m = 2, & and R2 are as defined elsewhere herein.

[0126] 在本发明的具体实施例中，式I化合物是此类结构，其中B是，或其中B是 [0126] In a particular embodiment of the invention, the compound of Formula I is such a structure, wherein B is or wherein B is

(CR凡）迈，m = l，或其中B是(CR^2)m， m = 2， &和R2如本文其它地方限定。 (CR Van) Mai, m = l, or where B is (CR ^ 2) m, m = 2, & and R2 are as defined elsewhere herein.

[0127] 在本发明的其它具体实施例中，式I化合物是此类结构，其中C是，或其中C是 [0127] In other embodiments of the present invention, such a structure is a compound of formula I, wherein C is or is wherein C

(CR凡）m， m = 1或m = 2， &和R2如本文其它地方限定。 (CR where) m, m = 1 or m = 2, & and R2 are as defined elsewhere herein.

[0128] 在本发明的其它具体实施例中，式I化合物是此类结构，其中D是，或其中D是(CR凡）m， m = 1或m = 2， &和R2如本文其它地方限定。 [0128] In another embodiment of the present invention, the compound of Formula I is such a structure wherein D is or where D is (CR where) m, m = 1 or m = 2, & and R2 specific embodiments as described elsewhere Limited.

[0129] 在本发明的另外的具体实施例中，式I化合物是此类结构，其中n二O，使得中间含X的环为5-元环。 [0129] In a further embodiment of the present invention, the compounds of formula I are such a structure, in which n = O, making the middle of the ring containing X is 5-membered ring.

[0130] 在本发明的其它具体实施例中，式I化合物是此类结构，其中X是0且n = 1或其中X是O且n = 2。 [0130] In another particular embodiment of the present invention, the compound of Formula I is such a structure, wherein X is 0 and n = 1 or wherein X is O and n = 2.

[0131] 在本发明的具体实施例中，式I化合物是此类结构，其中X是NR"n二l，或其中X 是CO且n = l，或其中X是C = NOR" n = 1， &如本文其它地方限定。 [0131] In a particular embodiment of the invention, the compound of Formula I is such a structure, wherein X is NR "n two l, or wherein X is CO and n = l, or wherein X is C = NOR" n = 1 , & as defined elsewhere herein. [0132] 在本发明的具体实施例中，式I化合物是此类结构，其中X是CR凡，n = 1或其中X是CR凡，n = 2，其中&和R2如本文其它地方限定。 [0132] In a particular embodiment of the invention, the compound of Formula I is such a structure, wherein X is CR where, n = 1, or wherein X is CR where, n = 2, wherein & elsewhere and R2 are as defined herein.

[0133] 在本发明的具体实施例中，式I化合物是此类结构，其中Y是0，或其中Y是或其中Y是，其中&如本文其它地方限定。 [0133] In a particular embodiment of the invention, the compound of Formula I is such a structure, wherein Y is 0, or wherein Y is or wherein Y is wherein & such as defined elsewhere herein. [0134] 在式I的一个实施方案中，当Y是0时，X不是C = 0，当X是C = 0时，Y不是0。 [0134] In one embodiment of Formula I, when Y is 0, X is not C = 0, when X is C = 0, Y is not zero. 在单独的实施方案中，Y是O且X是C = 0。 In a separate embodiment, Y is O and X is C = 0.

[0135] 在式I的另一个实施方案中，当E是O或NRi时，Y不是NOH或n不是1。 [0135] In another embodiment of formula I, or NRi when E is O, Y is not NOH or n is not 1. 在后者的单独实施方案中，当E是0或时，n是1且Y是N0H。 In the latter alone embodiment, when E is 0 or, n is 1 and Y is N0H.

[0136] 在式I化合物的具体实施例中，U和V各自是O = S = 0。 [0136] In a particular embodiment of the compounds of formula I, U and V are independently O = S = 0. 后者的另外实施例是其中X是CH2、n二l或2且Y是0或S的化合物，或其中X是CH2、n二l或2且Y是NORA或NRA的化合物，或X是O且Y是O或S的化合物，或其中X是0且Y是NORA或NRA的化合物， 或其中X是NRa且Y是O或S的化合物，或其中X是NRA且Y是NORA或NRA的化合物，或其中X是CO且Y二O的化合物，或其中X是CO且Y是NORA或NRA的化合物，或其中X是C = N0RA且Y是0的化合物，或其中X是C = N0RA且Y是N0RA的化合物。 The latter is another embodiment wherein X is CH2, n two l or 2 and Y is 0 or S, compound, or wherein X is CH2, n two l or 2 and Y is a compound or NORA NRA or X is O and Y is O or S, compound, or a compound wherein X is NRA or NORA and Y is 0, or wherein X is NRa and Y is O or S, compound, or wherein X is NRA and Y is a compound or the NRA NORA or compounds wherein X is CO and Y = O or wherein X is CO and Y is a compound NORA or the NRA, or compounds wherein X is 0 and Y is C = N0RA, or where X and Y is C = N0RA N0RA of a compound.

[0137] 在式I的所有实施方案中，当X是C = O或C = N0H，Y是0或N0H，且U和V各自是0二S二0且Ri或I^其中之一和R3或R4其中之一是苯基时，则&或R2和R3或R4中的另一个不是H或烷基。 [0137] In all embodiments of formula I, when X is C = O or C = N0H, Y is 0 or N0H, and U and V are each 0 = S 20 and Ri or I ^ one and R3 or one in which R4 is a phenyl group, or R2 and R3 is & another or R4 is not H or alkyl. 因此， 一种非限制性实施例是如果X是C = 0， Y是NOH， U和V各自是0 = s = 0， Ri和r4各自是苯基时，则r2不是h或烷基，r3不是h或烷基。 Thus, a non-limiting example is if X is C = 0, Y is NOH, U and V are each 0 = s = 0, when Ri and r4 each are phenyl, alkyl or h is not r2, r3 h or not alkyl. [0138] 在式II的一个实施方案中，HI^和R4各自独立选自H、烷基、环烷基、烯基和炔基。 [0138] In one embodiment of Formula II, HI ^ and R4 are each independently selected from H, alkyl, cycloalkyl, alkenyl and alkynyl groups. 在另一个此类实施方案中，RA是氢，R2、 R3和R4各自独立选自H、烷基、环烷基、烯基和炔基。 In another such embodiment, RA is hydrogen, R2, R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkenyl and alkynyl groups. 在其它此类实施方案中，NR^和NR3R4各自独立是6-至15-元杂环，优选杂环院基。 In other such embodiments, NR ^ and NR3R4 are each independently a 6- to 15-membered heterocyclic ring, preferably a heterocyclic group homes.

[0139] 在式II的具体实施方案中，HI^和R4各自独立选自H、烷基、环烷基、烯基或炔基。 [0139] In the formula II embodiments, HI ^ and R4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, or alkynyl group. 在其它此类实施例中，RA是氢，&、 R2、 R3和R4各自独立选自H、烷基、环烷基、烯基或炔基。 In other such embodiments, RA is hydrogen, &, R2, R3 and R4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, or alkynyl group. 在其它实施例中，NR凡和NR3R4独立是6-至15-元杂环，优选在环中含有1个氮的杂环烷基。 In other embodiments, NR and NR3R4 where independence is a 6- to 15-membered heterocyclic ring, preferably a nitrogen-containing heterocyclic group in the ring.

[0140] 在其它实施方案中，本发明化合物是以下环系统其中一种的衍生物，特别是其二 [0140] In other embodiments, the compounds of the present invention are the following ring systems wherein one derivatives, especially second

磺酰胺衍生物： [0141] Sulfonamide derivatives: [0141]

[0142] 此类化合物可被适当取代。 [0142] Such compounds can be substituted appropriately.

[0143] 本发明还涉及包括表1-13中化合物在内的化合物的组合物，所述化合物具有式I [0143] The present invention further relates to compounds included in Table 1-13 of the composition comprising a compound, the compound having the formula I

结构，以治疗有效量存在于药学上可接受的载体中。 Structure, a therapeutically effective amount in a pharmaceutically acceptable carrier. [0144]Y [0144] Y

[0145] 式I [0145] Formula I

[0146] 其中X = CH2且n = 0-2 ;或0、 NRA、 CO或C = NORA且n = 1Y = 0、 S、 NORA或NRA [0147] 其中RA独立选自氢、烷基、杂烷基、烯基、炔基、环烷基、-C( = 0)RB、 -C( = 0) 0RB、 -C( = 0)NRBRc、 -C( = NRB)Re、-服^。 [0146] wherein X = CH2 and n = 0-2; or 0, NRA, CO or C = NORA and n = 1Y = 0, S, NORA, or NRA [0147] wherein RA is independently selected from hydrogen, alkyl, heteroalkyl alkyl, alkenyl, alkynyl, cycloalkyl, -C (= 0) RB, -C (= 0) 0RB, -C (= 0) NRBRc, -C (= NRB) Re, - ^ service. 杂环烷基、芳基或多芳族、杂芳基、芳基烷基和烷 Heterocycloalkyl, an aryl group or an aromatic, aryl, heteroaryl, arylalkyl and alkylaryl

基方基 Group party group

[0148] 其中所述RB和Rc各自独立是H、烷基、杂烷基， [0148] wherein the RB and Rc are each independently H, alkyl, heteroalkyl,

[0149] U和V各自独立选自C二0禾P0二S二O，如果U是C = 0， V不可以是C = 0， [0150] &、 R2、 R3和R4各自独立选自氢、烷基、杂烷基、环烷基、芳基环烷基、烯基、炔基、芳基、杂芳基、杂环烷基，所述NR^和NR3R4各自可独立形成杂环烷基， [0149] U and V are each independently selected from C 20 S Wo P0 two two O, if U is C = 0, V is not C = 0, [0150] &, R2, R3 and R4 are each independently selected from hydrogen , alkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, NR3R4 and NR ^ wherein each may independently form a heterocyclic group ,

[0151] &和Re选自氢、羟基、巯基、烷氧基、硫代烷氧基（thioalkoxy)、烷基、卣素、CN、 CF3、 N02、 C00RD、 C0NRDRE、 NRDRE、 NRDC0RE、 NRDS02RE和NRFC0NRDRE ; [0151] & and Re selected from hydrogen, hydroxyl, mercapto, alkoxy, thioalkoxy (thioalkoxy), alkyl, wine container elements, CN, CF3, N02, C00RD, C0NRDRE, NRDRE, NRDC0RE, NRDS02RE and NRFC0NRDRE ;

[0152] 其中RD、 &和1^独立是氢、烷基、杂烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基和杂环烷基； [0152] wherein RD, & and 1 ^ are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

[0153] 包括其所有药学上可接受的盐、S旨、酰胺、立体异构体、几何异构体、溶剂化物或前药。 [0153] including all pharmaceutically acceptable salts, S purpose, amide, stereoisomer, geometric isomer, solvate or prodrug thereof.

[0154] 所述组合物的化合物还可包含多环环烷基或杂环烷基桥结构（如表所示），所述结构含有总计至多12个原子和至多4个选自N和0的杂原子。 [0154] The compound of the composition may also include polycyclic cycloalkyl or heterocycloalkyl bridge structure (as shown in the table), the structure containing a total of up to 12 and up to four atoms selected from N and 0 heteroatoms. [0155] 本发明还提供本发明的任何化合物如表1-13的化合物的治疗组合物。 Any compound [0155] The present invention also provides a therapeutic composition of the present invention, such as compounds of Table 1-13. [0156] 本发明的化合物可采用其药学上可接受的盐、酯、酰胺、立体异构体、几何异构体、 溶剂化物或前药的形式。 Compound [0156] of the present invention can be pharmaceutically acceptable salts, esters, amides, stereoisomers, geometric isomers, solvates or prodrugs. 当本发明化合物是立体异构体时，可以是对映体或非对映体。 When the compounds of the invention are stereoisomers, it may be enantiomers or enantiomers. 当所述化合物是对映体（或包含手性中心，如手性碳原子）时，用于药用目的的化合物形式可包括对映体或外消旋体，但可优选所述对映体中的一种（例如当对映体中的一种是活化形式或比其它对映体更有活性的情况下）。 When the compound is enantiomerically (or contain chiral centers, such as chiral carbon atoms), the form of the compound used for medicinal purposes may include enantiomers or racemates, but preferably the enantiomers one (for example, when one enantiomer is an activated form or more than the other enantiomer under active case). 当所述本发明化合物是几何异构体（如包含以顺式_或反式_构型连接取代基的碳对）时，虽然顺式_形式或反式_形式可优选药用，但顺式_和反式形式的混合物也可用于本发明的方法以达到它们具有所需药效的程度。 When the compounds of the present invention is a geometric isomer (such as those containing in cis or trans _ _ connection configuration substituted carbon pairs) when, although the cis or trans form _ _ preferably in the form of a pharmaceutically acceptable, but cis and mixtures of formula _ trans forms of the method of the present invention may also be used to achieve a desired degree of efficacy they have. [0157]"药学上可接受的盐"是在任何酸性（如羧酸）基团形成的阳离子盐，或在任何碱性（如氨基）基团形成的阴离子盐。 [0157] "Pharmaceutically acceptable salt" is any acidic (e.g. carboxylic acid) cationic salt group formation, or anionic salt any basic (e.g., amino) group is formed. 本领域已知许多此类盐，如描述于WO 87/05297 (Johnston等，1987年9月11日公布，通过引用结合到本文中）。 Many such salts are known in the art, as described in WO 87/05297 (Johnston et al., Published September 11, 1987, herein incorporated by reference). 合适的酸式盐实例包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、 柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、乙醇酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2_羟基乙磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐；棕榈酸盐（palmoate)、果胶酯酸盐（pectinate)、过硫酸盐、 3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。 Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric salt, camphorsulfonate, cyclopentane-propionate, di gluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2_ isethionate, lactate, maleate, malonate salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate; palmitate (palmoate), pectin ester salt (pectinate), persulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. 其它酸如草酸虽然本身并非为药学上可接受，但可用于制备盐，所述盐可作为获得本发明化合物及其药学上可接受的酸加成盐的中间体。 Other acids such as oxalic acid, although it is not a pharmaceutically acceptable, but can be used to prepare the salt, the salt can be used in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts. 优选阳离子盐包括碱金属盐（如钠和钾），和碱土金属盐（如镁和f丐）和有机盐。 Preferably cationic salts include alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and f hack) and organic salts. 优选阴离子盐包括卤化物（如氯化物盐）、磺酸盐、羧酸盐、磷酸盐等。 Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates and the like.

[0158] 含有一个或多个酸性官能团的本发明化合物能够与药学上可接受的碱形成药学上可接受的盐。 [0158] The compound of the present invention contain one or more acidic functional groups capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. 术语"药学上可接受的盐"在这些情况下指本发明化合物的相对无毒性、无机和有机碱加成盐。 The term "pharmaceutically acceptable salts" in these cases refers to the relatively non-toxic compounds of the invention, inorganic and organic base addition salts. 同样这些盐可在最终分离和纯化化合物时原位制备，或者通过使游离酸形式的纯化化合物单独与合适的碱（如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐）、与氨或与药学上可接受的有机伯、仲或叔胺反应制备。 These same salts can be prepared in situ during the final isolation and purification of the compounds, or by reacting the free acid form of the purified compound alone with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate ), with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine acid. 代表性碱盐或碱土盐包括锂、钠、钾、*丐、镁和铝盐等。 Representative alkali or alkaline earth salts include salts of lithium, sodium, potassium, * beggar, magnesium and aluminum salts and the like. 可使用的一些碱的例示性实例包括氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、N^C卜4烷基）4等。 Some illustrative examples of bases that may be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N ^ C 4 alkyl Bu) 4 and the like. 可用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。 It can be used to form base addition salts Representative organic amines include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. 本发明还预计使本文公开的化合物的任何碱性含氮基团季铵化。 The compounds of the invention disclosed herein is also expected to make any basic nitrogen-containing quaternary ammonium groups. 通过这样季铵化可获得可溶解或分散在水或油中的产物。 By such quaternization obtained dissolved or dispersed in water or oil product. [0159] 技术人员熟知此类盐，技术人员能够用专业知识制备任何数目的盐。 [0159] Such salts are well known in the art, the art of salt can be prepared by any number of specialized knowledge. 而且，应理解技术人员可能由于溶解度、稳定性、配制方便性等原因而优选一种盐而不选另一种。 Moreover, it should be understood the art may be due to solubility, stability, ease of preparation and other reasons and not a salt is preferably selected from another. 对此类盐的确定和优化在技术人员的技能范围内。 To determine and optimize such salts within the skill of the technical staff.

[0160] 另一方面，本发明涉及本发明任何化合物的组合物，优选其中此类化合物以治疗有效量存在于药学上可接受的载体中。 [0160] another aspect, the present invention relates to compositions of the present invention, any compound, preferably wherein such compound is present in a therapeutically effective amount of a pharmaceutically acceptable carrier. 此类组合物将通常包含非毒性量（即对治疗而言为安全的量）的此类化合物。 Such compositions will generally comprise a non-toxic amount (i.e., the treatment is safe in terms of the amount) of such compounds.

[0161] 本发明化合物的选择性实例包括但不限于表2-13的任何或所有化合物。 Selective examples [0161] compounds of the invention include, but are not limited to any or all of the compounds in Table 2-13. 任何和 Any and

所有此类化合物因其在任何和所有本发明方法中的用途而被特别要求保护。 All of these compounds for their use in any and all methods of the present invention are particularly claimed. 在每种所示结 Results shown in each

构中，通过标记星号（*)的原子连接配体。 Configuration through marked with an asterisk (*) atom of the ligand. 例如，在表l中，核心结构的硫原子在表中R列 For example, in Table l, the sulfur atoms in the core structure of the columns in the table R

标记星号的氮处连接所示R基团。 Marked with an asterisk are connected as shown at the nitrogen R group.

[0162] 表l [0162] Table l

[0163]<formula>formula see original document page 22</formula><table>table see original document page 23</column></row> <table><table>table see original document page 24</column></row> <table><table>table see original document page 25</column></row> <table><table>table see original document page 26</column></row> <table><table>table see original document page 27</column></row> <table><table>table see original document page 28</column></row> <table><table>table see original document page 29</column></row> <table>[0171] [0163] <formula> formula see original document page 22 </ formula> <table> table see original document page 23 </ column> </ row> <table> <table> table see original document page 24 </ column> < / row> <table> <table> table see original document page 25 </ column> </ row> <table> <table> table see original document page 26 </ column> </ row> <table> <table> table see original document page 27 </ column> </ row> <table> <table> table see original document page 28 </ column> </ row> <table> <table> table see original document page 29 </ column> < / row> <table> [0171]

<formula>formula see original document page 30</formula> <Formula> formula see original document page 30 </ formula>

[0172] 表2 [0173] [0172] Table 2 [0173]

<table>table see original document page 30</column></row> <table> <Table> table see original document page 30 </ column> </ row> <table>

[0174] [0174]

<table>table see original document page 30</column></row> <table><table>table see original document page 31</column></row> <table><table>table see original document page 32</column></row> <table><table>table see original document page 33</column></row> <table><table>table see original document page 34</column></row> <table><table>table see original document page 35</column></row> <table>[0180] <Table> table see original document page 30 </ column> </ row> <table> <table> table see original document page 31 </ column> </ row> <table> <table> table see original document page 32 < / column> </ row> <table> <table> table see original document page 33 </ column> </ row> <table> <table> table see original document page 34 </ column> </ row> <table> <table> table see original document page 35 </ column> </ row> <table> [0180]

<table>table see original document page 36</column></row> <table><table>table see original document page 37</column></row> <table><table>table see original document page 38</column></row> <table><table>table see original document page 39</column></row> <table>[0188]<formula>formula see original document page 40</formula> <Table> table see original document page 36 </ column> </ row> <table> <table> table see original document page 37 </ column> </ row> <table> <table> table see original document page 38 < / column> </ row> <table> <table> table see original document page 39 </ column> </ row> <table> [0188] <formula> formula see original document page 40 </ formula>

<table>table see original document page 40</column></row> <table><table>table see original document page 41</column></row> <table><table>table see original document page 42</column></row> <table><table>table see original document page 43</column></row> <table><table>table see original document page 44</column></row> <table><table>table see original document page 45</column></row> <table><table>table see original document page 46</column></row> <table><table>table see original document page 47</column></row> <table><table>table see original document page 48</column></row> <table><table>table see original document page 49</column></row> <table>[0207] 表8 [0208] <Table> table see original document page 40 </ column> </ row> <table> <table> table see original document page 41 </ column> </ row> <table> <table> table see original document page 42 < / column> </ row> <table> <table> table see original document page 43 </ column> </ row> <table> <table> table see original document page 44 </ column> </ row> <table> <table> table see original document page 45 </ column> </ row> <table> <table> table see original document page 46 </ column> </ row> <table> <table> table see original document page 47 < / column> </ row> <table> <table> table see original document page 48 </ column> </ row> <table> <table> table see original document page 49 </ column> </ row> <table> [0207] Table 8 [0208]

<formula>formula see original document page 50</formula> <Formula> formula see original document page 50 </ formula>

<table>table see original document page 50</column></row> <table><table>table see original document page 51</column></row> <table><table>table see original document page 52</column></row> <table><table>table see original document page 53</column></row> <table><table>table see original document page 54</column></row> <table><table>table see original document page 55</column></row> <table><table>table see original document page 56</column></row> <table> <Table> table see original document page 50 </ column> </ row> <table> <table> table see original document page 51 </ column> </ row> <table> <table> table see original document page 52 < / column> </ row> <table> <table> table see original document page 53 </ column> </ row> <table> <table> table see original document page 54 </ column> </ row> <table> <table> table see original document page 55 </ column> </ row> <table> <table> table see original document page 56 </ column> </ row> <table>

<formula>formula see original document page 56</formula><table>table see original document page 57</column></row> <table><table>table see original document page 58</column></row> <table><table>table see original document page 59</column></row> <table><table>table see original document page 60</column></row> <table><table>table see original document page 61</column></row> <table> <Formula> formula see original document page 56 </ formula> <table> table see original document page 57 </ column> </ row> <table> <table> table see original document page 58 </ column> </ row> <table> <table> table see original document page 59 </ column> </ row> <table> <table> table see original document page 60 </ column> </ row> <table> <table> table see original document page 61 </ column> </ row> <table>

[0235] 如上所述，本发明涉及本发明化合物作为药物、特别是作为用于治疗肿瘤的药物的活性成分的用途。 [0235] As described above, the present invention relates to compounds of the present invention as a pharmaceutical, particularly as an active ingredient of a medicament for the treatment of tumors of use. 因此本发明化合物将存在于药用组合物中，所述药用组合物含有式I或II化合物作为活性成分，与其混合的是药学上可接受的载体和赋形剂，包括本身不诱导产生对接受组合物的个体有害的抗体的任何药物，其给药可不产生过度毒性。 Thus compounds of the present invention will be present in a pharmaceutical composition, said pharmaceutical composition comprising a compound of formula I or II as active ingredient, in admixture with pharmaceutically acceptable carriers and excipients, including itself does not induce the production of harmful to the individual receiving the composition of any drug antibodies, which may be administered undue toxicity. 药学上可接受的载体包括但不限于液体如水、盐水、甘油和乙醇等，包括可用于形成鼻腔及其它呼吸道喷雾剂或递药至眼部系统的载体。 Pharmaceutically acceptable carriers include, but are not limited to liquids such as water, saline, glycerol, ethanol and the like, may be used including forming a spray or nasal and other respiratory tract delivery system of the eye to the carrier. 关于药学上可接受的载体、稀释剂及其它赋形剂的全面讨论可参阅REMINGTON' S PHARMACEUTICAL SCIENCES (Mack Pub. Co. ， NJ currentedition)。 About a pharmaceutically acceptable carrier, diluent, and other excipients full discussion can be found in REMINGTON 'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ currentedition). 本领域技术人员熟知此类载体的用途，在本文将不再讨论。 Well known to those skilled in the use of such vectors, we will not be discussed in this article. [0236] 如上所述，本发明还涉及预防或治疗与哺乳动物具体基因集合（set)表达水平改变有关的疾病的方法，包括给予所述哺乳动物有效量的本发明化合物。 [0236] As described above, the present invention also relates to a method of changing the expression level of disease associated with a mammal for preventing or treating a specific gene sets (set), comprising administering to said mammal an effective amount of a compound of the present invention.

[0237] 本发明化合物在需要这样治疗的哺乳动物特别是人中，将具有减少肿瘤特别是原发性肿瘤大小和数量的作用。 Compound [0237] The present invention particularly humans in a mammal in need of such treatment, will have to reduce tumors, especially primary tumor size and number of role. 原发性肿瘤或转移细胞数量的统计学显著性改变将通常为至少约10%、优选20%、30%、50%、70%、90%或更多。 Primary tumor or metastatic cells of a statistically significant number of changes will generally be at least about 10%, preferably 20%, 30%, 50%, 70%, 90% or more.

[0238] 根据本发明，可将本文所述药物与本文所述疾病的其它疗法结合，如其它化疗、放疗、免疫疗法、手术治疗等。 [0238] According to the present invention, the drug and the disease in combination with other therapies article herein, such as other chemotherapy, radiotherapy, immunotherapy, surgical treatment. 还可将本发明化合物与其它药物联合给药，如止痛药、利尿剂、抗利尿剂、抗病毒剂、抗生素、营养补充剂、贫血疗法、凝血疗法、骨疗法，以及精神病学和心 The compound may also be administered in combination with other drugs of this invention, such as analgesics, diuretics, anti-diuretics, antivirals, antibiotics, nutritional supplements, anemia therapy, coagulation therapy, osteopathy, as well as psychiatric and heart

理学疗法。 Physical Therapy. [0239] 由临床医生（如使用本领域已知可完成治疗或预计将完成治疗的参数或因素）确定合适的治疗剂量。 [0239] by a clinician (such as known in the art can be done to treat or expected to be completed treatment parameters or factors) determine the appropriate treatment dose. 通常，开始的剂量比最佳剂量小一些，然后逐渐小量增加，直至获得与任何不良副作用相比而言所需或最佳的作用。 Typically, smaller than the optimum dose of the beginning of a number of doses, and then increased by small increments until the desired purposes of comparison with any adverse side effects, or the best effect.

[0240] 当然，给予本发明化合物以获得治疗和/或预防作用的具体剂量将由具体情况决定，包括例如给予的具体化合物、给药途径、待治疗疾病和待治疗个体。 [0240] Of course, the administration of the compounds of the present invention to obtain therapeutic and / or prophylactic effect of a specific dose will be determined by the specific circumstances, including the specific compound administered, for example, the route of administration, the condition being treated and the individual being treated. 通常日剂量（单次或分次给药）将包含约0. 01mg/kg-约50-100mg/kg体重的本发明活性化合物的剂量水平。 A typical daily dose (in single or divided doses) will contain about 0. 01mg / kg- about 50-100mg / dosage levels of the active compounds of the present invention kg body weight. 优选日剂量通常将为约0. 05mg/kg-约25mg/kg，最理想的是约0. lmg/kg-约10mg/kg。 Preferred daily doses generally will be from about 0. 05mg / kg- about 25mg / kg, and most preferably from about 0. lmg / kg- about 10mg / kg. 虽然本文没有明确叙述，但本领域技术人员用标准程序将很容易确定因素如清除率、半衰期 Although not explicitly described herein, those skilled in the art will readily using standard procedures to determine factors such as clearance, half-life

和最大耐受剂量（MTD)。 And the maximum tolerated dose (MTD).

[0241] 治疗的有效量将通常使症状控制至少约10%;通常至少约20%;优选至少约30%; An effective amount of [0241] Treatment will generally control the symptoms of at least about 10%; usually at least about 20%; preferably at least about 30%;

更优选至少约50%。 More preferably at least about 50%. 或者，迁移的控制将指各种癌细胞类型的迁移或转运受影响。 Alternatively, the migration control will refer to various types of cancer cell migration or transport affected. 这样将 This will

导致例如受影响细胞的数量发生统计学显著性和可定量的改变。 Cause such as the number of affected cells occurs statistically significant and quantifiable changes. 这可以是在一段时间或靶 This may be a period of time or target

区域内吸引的靶细胞数减少。 The number of target cells in the region to attract reduced. 还可监测原发性肿瘤进展的速率、大小或生长。 It may also monitor the rate of primary tumor progression, size, or growth.

[0242] 另一方面，本发明涉及预防或治疗由改变的基因表达调控的疾病的方法，其中所 [0242] On the other hand, the present invention relates to a method of gene expression and regulation of disease prevention or treatment by the change, in which the

述疾病选自癌、心血管疾病、关节炎、骨质疏松症、炎症、牙周病和皮肤病，包括给予需要这 Said disease is selected from cancer, cardiovascular disease, arthritis, osteoporosis, inflammation, periodontal disease and skin diseases, which comprises administering

样治疗或预防的哺乳动物治疗有效量的本发明化合物。 The compounds of the invention, like the treatment or prevention of a mammal a therapeutically effective amount.

[0243] 在优选实施方案中，本发明涉及在哺乳动物中预防、治疗或改善癌或肿瘤转移的方法，包括给予所述哺乳动物有效量的本发明化合物，优选其中所述哺乳动物是人。 [0243] In a preferred embodiment, the present invention relates to a mammal in preventing, treating or ameliorating cancer or tumor metastasis the method comprising administering to said mammal an effective amount of a compound of the present invention, preferably wherein the mammal is a human. [0244] 本发明化合物通常通过调控出现于细胞特别是哺乳动物细胞中的一个或多个基因将发挥治疗作用，所述细胞如癌细胞，优选结肠癌，最优选腺癌。 [0244] The compound of the present invention is generally in particular mammalian cells by regulating one or more genes will play a therapeutic role in the cell such as cancer, preferably colon cancer, most preferably adenocarcinoma occurs in cells. 因此，通过确定本发明的一种或多种化合物对基因集合的调控，可用本发明的一种或多种化合物测定或区分这样的基因集合。 Therefore, such gene sets by determining regulation of one or more compounds of the present invention to the gene set, the present invention can be used one or more measured or distinguish compounds. 例如，当发现某基因集合在癌细胞比在其它正常细胞特别是与癌细胞相同组织或器官的正常细胞中上调时，可通过用本发明的一种或多种化合物接触此类基因或含有此类基因的细胞，通过其共同的被调控的特性测定基因集合（基于基因表达的改变，如转录RNA的比率或量或者由所述表达产生的多肽量的改变）。 For example, when a certain set of genes found in cancer cells than in normal cells, especially when other normal cells and cancer cells raised the same tissue or organ, and can be treated with one or more compounds of the present invention comprises contacting such genes or this cellular genes, gene sets was measured by their common characteristic is regulated (based on changes in gene expression, such as a ratio or amount of transcription of RNA or altered by the amount of expression of the polypeptide produced). 当然，此类调控的程度可与用于接触的所述一种或多种化合物的量有关。 Of course, the extent of such regulation may be one or more related to the amount of the compound for the contact. 此类调控可包括所有测定基因（即该集合的基因） 的表达增加，所有该集合基因的表达减少，或该集合基因中一些表达增加而其它表达减少。 Such regulation may include increasing all measured genes (that is, the set of genes) expression, the expression of all genes in the set reduction, or the collection of gene expression is increased while reducing some other expression. 因此，测试化合物（用于接触基因或含有它们的细胞的化合物）不调控的基因视为非该集合成员。 Therefore, (for contacting genes or their cell containing compound) is not regulated gene test compound treated as non-members of the collection.

[0245] 因此，本发明涉及基因集合，其中所述基因集合与本发明化合物接触的结果是调控所述基因集合各成员的表达。 [0245] Accordingly, the present invention relates to a collection of genes, wherein said set of genes results in contact with a compound of the present invention is the regulation of gene expression of each member of the set. 在具体实施方案中，所述接触的结果是所述基因集合各成员的表达增加或者所述接触的结果是表达减少。 In a particular embodiment, the contact is the result of gene expression of each member of the set of results is increased or reduced expression of said contact. 在另一个优选实施方案中，基因集合存在于细胞中。 In another preferred embodiment, the set of genes present in the cell. 此类基因集合将通常与具体疾病过程有关，如其中所有基因都由本发明化合物调控的基因集合，其中此类化合物具有具体治疗作用，如作为抗肿瘤剂。 Such gene sets will generally related to specific disease processes, such as by the present invention wherein all the genes regulated gene sets compound, wherein such compound that has a specific therapeutic effect, such as an antitumor agent. [0246] 本发明还涉及在哺乳动物中改善癌或肿瘤转移的方法，包括给予所述哺乳动物有效量的本发明化合物。 [0246] The present invention further relates to a method of improving the cancer or tumor metastasis in a mammal, comprising said mammal an effective amount of a compound of the present invention is administered. 特别是表l化合物的用途。 In particular, the table uses l compounds. 在选择的实施方案中，所述癌是肉瘤或所述癌是癌瘤。 In selected embodiments, the cancer or the cancer is a sarcoma cancer. 本发明方法针对的具体癌包括但不限于结肠癌、腺癌、直肠癌、结直肠癌、乳癌、肺癌、卵巢癌、腺瘤性息肉病和肝细胞癌中的一种或多种。 The method of the present invention is directed to a specific cancer, including but not limited to colon cancer, cancer, colorectal cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, adenomatous polyposis and hepatocellular carcinoma in one or more.

[0247] 本发明还提供根据流程1所示通用合成途径合成式I化合物的便利方法。 [0247] The present invention also provides a convenient method for the synthesis of the compounds of general synthetic route shown in formula I according to the process. 可通过使相应的芳环系统直接氯磺酰化或通过使合适的磺酸衍生物氯化获得原料磺酰氯1。 By reacting the corresponding aromatic ring system directly or obtain raw materials chlorosulfonylating chloride 1 by reacting the appropriate acid chloride derivative. 使化合物1与6或7-元环胺反应以得到仲磺酰胺2。 Compound 1 is reacted with 6 or 7-membered cyclic amine to give the secondary sulfonamide 2. 另外可将化合物2转换为衍生物3，其有时可充当前药，所述前药具有改良的物理-化学和药理学特性如水溶性、改良的蛋白结合特性、在血桨中的稳定性、毒性等。 Further compounds may be converted to derivatives 3 2, which sometimes charge current drugs, prodrugs with improved physical - chemical and pharmacological properties such as water solubility, improved binding characteristics, stability in plasma can, toxicity and so on.

实施例 Example

[0248] 根据流程1所示通用合成途径用相应的磺酰氯衍生物制备本文公开的大部分化合物。 [0248] Most of the compounds with the appropriate sulfonyl chloride derivative was prepared according to the process herein disclosed general synthetic route shown in Figure 1.

[0249] 流程1 [0250] <formula>formula see original document page 63</formula> [0249] Process 1 [0250] <formula> formula see original document page 63 </ formula>

[0251] 以下流程和实施例预计用于举例说明，不限制在附属权利要求书中限定的本发明范围。 [0251] The following schemes and examples intended for illustration, not limitation in the appended claims of the present invention.

[0252]、流禾呈2 [0253] [0252], flow Wo was 2 [0253]

[0254] 实施例1 [0254] Example 1

[0255] 2， 7- 二（氮杂环辛烷-1-基磺酰基）蒽_9， 10- 二酮（1-27) [0256] 使蒽醌-2， 7- 二磺酰氯（1215mg， 3mmole)溶于100mL DCM中。 [0255] 2, 7-bis (diazabicyclo octane-1-ylsulfonyl) anthracene _9, 10- dione (1-27) [0256] anthraquinone -2, 7-sulfonyl chloride (1215mg , 3mmole) was dissolved in 100mL DCM. 将溶液冷却至-5(TC。向该溶液内加入lmL(8mmole)七亚甲亚胺（h印tamethyleneimine)，接着加入lmL二异丙基乙胺。将反应混合物在室温下搅拌4小时。蒸发溶剂，将残留物用1N HC1处理，滤除，用水洗涤和干燥。使粗材料从氯仿-己烷中结晶，得到1.014g(91X)黄色化合物1-27。 tf-腿（CDCl3) :8. 70(2H， d， Cl和C8) ，8. 47 (2H， d， C4和C5) ，8. 22 (2H， dd， C3和C6) ，3. 22(8H， m) ， 1. 70 (20H， m)。 [025" 实施例2 The solution was cooled to -5 (TC. To this solution was added lmL (8mmole) seven methylene imine (h printed tamethyleneimine), followed by addition of lmL of diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hours. Evaporated the solvent, the residue was treated with 1N HC1, filtered, washed with water, and the crude material dried from chloroform - hexane to afford 1.014g (91X) yellow compound 1-27 tf- leg (CDCl3):. 8.. 70 (2H, d, Cl and C8), 8. 47 (2H, d, C4 and C5), 8. 22 (2H, dd, C3 and C6), 3. 22 (8H, m), 1. 70 ( 20H, m). [025 "Example 2

[0258] 2， 7- 二（氮杂环辛烷-1-基磺酰基）蒽_9， 10- 二酮二肟（2-22) [0258] 2, 7-bis (diazabicyclo octane-1-ylsulfonyl) anthracene _9, 10- dione dioxime (2-22)

[0259] 将实施例1的产物（1. Og， 1. 706mmole) 、5mL吡啶和盐酸羟胺（1. 5g，21. 5mmole)在95t:搅拌36小时。 [0259] The product of (1. Og, 1. 706mmole) of Example 1, 5mL of pyridine and hydroxylamine hydrochloride (1. 5g, 21 5mmole.) In the 95t: stirred for 36 hours. 蒸发吡啶，将残留物用IN HCl(50mL)搅拌几分钟。 Pyridine was evaporated, and the residue was stirred with IN HCl (50mL) minutes. 将白色产物过滤收集，用水洗涤和干燥。 The white product was collected by filtration, washed with water and dried. 然后用DCM-己烷使粗材料结晶，得到970mg(97X)白色化合物2-22。 Then DCM- hexane crude material crystallized to give 970mg (97X) white compound 2-22. tfNMR(CDCl3) :9. 05(1H，dd) ，8. 75(1H，dd) ，8. 35(1H，dd) ，8. 05(1H，dd) ，7. 90(2H，m)， 3. 20(8H， m) ， 1. 70 (20H， m)。 tfNMR (CDCl3):..... 9 05 (1H, dd), 8 75 (1H, dd), 8 35 (1H, dd), 8 05 (1H, dd), 7 90 (2H, m), 3. 20 (8H, m), 1. 70 (20H, m). [0260] 实施例3 [0260] Example 3

[0261] 2，7_二（氮杂环辛烷-l-基磺酰基）蒽-9，10-二酮二肟二钠盐（2-22 x 2Na) [0262] 将化合物2-22 (620mg， 1. Ommole) 、35mL DCM和2. 2mL 1M乙醇钠/乙醇的混合物加热搅拌，直至形成澄清溶液。 [0261] 2,7_ di (cyclooctane -l- aza-ylsulfonyl) anthracene-9,10-dione dioxime disodium salt (2-22 x 2Na) [0262] Compound 2-22 ( 620mg, 1. Ommole), a mixture of 35mL DCM and 2. 2mL 1M sodium ethoxide / ethanol was heated with stirring until a clear solution. 向溶液内加入100mL醚，对混合物声处理5分钟。 100mL ether was added to the solution, the mixture was sonicated for 5 minutes. 将黄色固体产物过滤收集，用醚洗涤和干燥以得到660mg(100X )标题化合物。 The yellow solid product was collected by filtration, washed with ether and dried to give 660mg (100X) of the title compound. [0263] 实施例4 [0263] Example 4

[0264] 9，10-二（N' _(3-(二甲基氨基）丙基）_N_乙基氨基甲亚氨酰基氧基亚氨基）_2， 7_二（氮杂环辛烷-l-基磺酰基）-9，10-二氢-蒽四盐酸盐（3-18) [0264] 9,10-bis (N '_ (3- (dimethylamino) propyl) _N_ ethylcarbamoyl group imino-imino) 2, 7_ bis (aza cyclooctane - l- ylsulfonyl) -9,10-dihydro - anthracene tetrahydrochloride (3-18)

[0265] 将化合物2-22 (442mg， 0. 75mmole) 、4mL无水氯仿和400mgEDAC在6(TC搅拌1小时。将反应混合物浓縮和用HPLC层析。加入5mL IN HC1使含有所需产物（MH+ = 899)的合并流分酸化并蒸发至干。使产物溶于蒸馏水中，冻干得到530mg(68X )白色标题化合物。 [0266] 流程3 [0267]4M HCl/二氧己环 [0265] Compound 2-22 (442mg, 0. 75mmole), 4mL of anhydrous chloroform and 400mgEDAC in 6 (TC was stirred for 1 hour. The reaction mixture was concentrated and chromatographed by HPLC. Add 5mL IN HC1 containing the desired product (MH + = 899) of the combined fractions was acidified and evaporated to dryness. The product was dissolved in distilled water and lyophilized to give 530mg (68X) of white title compound. [0266] Process 3 [0267] 4M HCl / dioxane

[0268] 实施例5 [0268] Example 5

[0269] 9， 10- 二[ (3-氨基丙基）氧基亚氨基]-2， 7- 二（氮杂环辛烷-1-基磺酰基）_9， 10- 二氢-蒽（3-24) [0269] 9,10-bis [(3-aminopropyl) imino] -2, 7-di (diazabicyclo octane-1-ylsulfonyl) [9, 10-dihydro-- anthracene (3 -twenty four)

[0270] 向化合物2-22 x 2Na(320mg，0. 5mmole)在DMS0(2mL)中的溶液内加入3-溴代丙基氨基甲酸叔丁酯（180mg，0. 75mmole)，将混合物在室温下搅拌1小时。 [0270] To compound 2-22 x 2Na (320mg, 0. 5mmole) in DMS0 added to (2mL) was added 3-bromo-propyl carbamic acid tert-butyl ester (180mg, 0. 75mmole), and the mixture was at room temperature under stirring for 1 hour. 将水加入反应混合物内，用乙酸乙酯提取沉淀产物。 Water was added to the reaction mixture, the precipitated product was extracted with ethyl acetate. 将提取物用硫酸钠干燥，蒸发，用4N HCl/二氧己环（5mL) 将残留物搅拌l小时。 The extract was dried over sodium sulfate, and evaporated with 4N HCl / dioxane (5mL) and the residue was stirred for l hour. 蒸发溶剂，使残留物溶于甲醇中，用制备HPLC纯化。 The solvent was evaporated, the residue was dissolved in methanol and purified by preparative HPLC. 将含有主产物的流分用盐酸酸化和蒸发。 The stream containing the main product were acidified with hydrochloric acid and evaporated. 使残留物溶于水中和冻干以得到标题化合物，为二盐酸盐（170mg， 2步骤收率为44% ) 。 The residue was dissolved in water and lyophilized to give the title compound as the dihydrochloride salt (170mg, 2 step yield 44%). MS703 (MH")。 [0271] 实施例6 MS703 (MH "). [0271] Example 6

[0272] 10-(3-氨基丙基）氧基亚氨基-9-羟基亚氨基-2，7-二（氮杂环辛烷-l-基磺酰基）-9，10-二氢-蒽（3-24) [0272] 10- (3-aminopropyl) -9-hydroxy-imino-2,7-imino (aza cyclooctane -l- ylsulfonyl) -9,10-dihydro - anthracene (3-24)

[0273] 将实施例5的第二种主产物分离为标题化合物。 [0273] The second embodiment of the primary separation of the product of Example 5 the title compound. 收率：2步骤后为20 % . MS 646 (MH+)。 Yield: after 2 steps 20% MS 646 (MH +).. [0274] 流程4 [0275] [0274] Scheme 4 [0275]

[0276] 实施例7 [0276] Example 7

[0277] 10-甲基-9-氧代-9， 10- 二氢吖啶-2， 7_ 二磺酰二氯 [0277] 10-methyl-9-oxo -9, 10-dihydro-acridine -2, 7_ disulfonyl dichloride

[0278] 将10-甲基吖啶-9 (10H)-酮（4. 2g， 20mmole)和氯磺酸（100mL， 1. 5mole)的混合物回流加热5小时。 [0278] The 10-methyl-acridine -9 (10H) - one (4. 2g, 20mmole) and chlorosulfonic acid (100mL, 1. 5mole) was heated under reflux for 5 hours. 然后使反应混合物浓縮，冷却至室温，小心地倒在500g冰上。 The reaction mixture was concentrated, cooled to room temperature, carefully poured onto 500g ice. 将黄色沉淀产物过滤收集，用水洗涤，干燥以得到8. lg标题化合物。 The yellow precipitated product was collected by filtration, washed with water, and dried to give the title compound 8. lg. 该材料不需纯化用于下一步。 The material used in the next step without purification. [0279] 实施例8 [0279] Example 8

[0280] 2，7_二(3，5-二甲基哌啶-1-基磺酰基）-10_甲基吖啶_9 (10H)-酮(11-4) [0281] 向来自实施例7的10-甲基-9-氧代-9，10-二氢吖啶-2，7-二磺酰二氯（810mg， 2mmole)在THF(20mL)中的溶液内加入3， 5-二甲基哌啶（2mL， 15mmole)，将反应混合物在室温下搅拌6小时。 [0280] 2,7_-bis (3,5-dimethyl-piperidin-1-ylsulfonyl) methyl acridine -10_ _9 (10H) - one (11-4) [0281] from the embodiment Example 10-methyl-9-oxo-9,10-dihydro-7-sulfonyl-2,7-dichloro-acridine (810mg, 2mmole) was added 3, 5 in THF (20mL) was dimethyl-piperidine (2mL, 15mmole), and the reaction mixture was stirred at room temperature for 6 hours. 蒸发溶剂，将残留物用1N HCl(50mL)处理和搅拌10分钟。 The solvent was evaporated, the residue (50mL) was stirred for 10 minutes and treated with 1N HCl. 将黄色产物过滤收集，用水和甲醇洗涤并干燥。 The yellow product was collected by filtration, washed with water and methanol and dried. 使粗材料从氯仿_乙醇中结晶以得到900mg(80% ) 黄色11-4。 The crude material was crystallized from chloroform _ ethanol to give 900mg (80%) yellow 11-4. MS 560(MH+)。 MS 560 (MH +). [0282] 实施例9 [0282] Example 9

[0283] 2，7_二（3，5-二甲基哌啶-1-基磺酰基）-10_甲基吖啶-9(10H)-硫酮 [0283] 2,7_-bis (3,5-dimethyl-piperidin-1-ylsulfonyl) -10_ methyl acridine -9 (10H) - thione

[0284] 将化合物11-4(560mg， lmmole)、无水甲苯（10mL)和Lawesson' s试剂（820mg， [0284] Compound 11-4 (560mg, lmmole), anhydrous toluene (10mL) and Lawesson 's reagent (820mg,

2mmole)的混合物回流4小时。 2mmole) was refluxed for 4 hours. 蒸发除去甲苯。 Toluene was removed by evaporation. 向残留物内加入甲醇（20mL)，在室温下搅拌几分钟，将产物过滤收集和干燥以得到500mg标题化合物。 To the residue was added methanol (20mL), stirred for several minutes at room temperature, the product was collected by filtration and dried to give 500mg of the title compound. MS 576(MH+)。 MS 576 (MH +). [0285] 实施例10 [0285] Example 10

[0286] 2，7_二（3，5-二甲基哌啶-l-基磺酰基）-9-羟基亚氨基-10-甲基-(9H，10H)-吖啶（12-4) [0286] 2,7_-bis (3,5-dimethyl-piperidin -l- yl sulfonyl) -9-hydroxyimino-10-methyl - (9H, 10H) - acridine (12-4)

[0287] 向2，7-二（3，5-二甲基哌啶-l-基磺酰基）-10-甲基吖啶-9(10H)-硫酮（290mg， 0，5mmole)在吡啶（5mL)中的溶液内加入盐酸羟胺（210mg， 30mmole)，将混合物在IO(TC搅拌8小时。除去溶剂，用水处理残留物以除去过量羟胺。使粗材料从甲醇-水中结晶以得到245mg(85% )标题化合物。MS 575 (MH")。 [0288] 实施例11 [0287] To a 2,7-bis (3,5-dimethyl-piperidin -l- yl sulfonyl) 10-methyl-acridine -9 (10H) - thione (290mg, 0,5mmole) in pyridine was added to the (5mL) was added hydroxylamine hydrochloride (210mg, 30mmole), the mixture IO (TC stirred for 8 hours the solvent was removed, the residue was treated with water to remove excess hydroxylamine The crude material from methanol -. water crystallized to give 245mg ( 85%) of the title compound .MS 575 (MH "). [0288] Example 11

[0289] 2，7_二（3，5-二甲基哌啶-1-基磺酰基）-9-(3-二甲基氨基丙基）亚氨基-10-甲基-(9H，10H)-吖啶(12-5) [0289] 2,7_-bis (3,5-dimethyl-piperidin-1-ylsulfonyl) -9- (3-dimethylaminopropyl) imino-10-methyl - (9H, 10H ) - acridine (12-5)

[0290] 将2，7-二（3，5-二甲基哌啶-1-基磺酰基）-10_甲基吖啶-9(10H)硫酮（145mg， 0. 25mmole)、吡啶(5mL)和二甲氨基丙胺（0. 125mL， lmmole)的混合物在10(TC搅拌4小时。 部份蒸发溶剂，加入甲醇使反应产物沉淀。将沉淀物过滤收集，用甲醇洗涤和干燥以得到137mg(85%)标题化合物。MS 644(MH+)。 [0291] 流程5 [0292] [0290] 2,7-bis (3,5-dimethyl-piperidin-1-ylsulfonyl) -10_ methyl acridine -9 (10H) thione (145mg, 0. 25mmole), pyridine ( 5mL) and dimethylaminopropylamine (0. 125mL, lmmole) in a mixture of 10 (TC was stirred for 4 hours. The solvent was evaporated portion, so that the reaction product is precipitated by addition of methanol. The precipitate was collected by filtration, washed with methanol and dried to give 137mg (85%) of the title compound .MS 644 (MH +). [0291] Scheme 5 [0292]

[0293] 实施例12 [0293] Example 12

[0294] N2， N7-二（4-叔丁基环己基）-9，10-二氧代-9，10-二氢蒽-2，7-二磺酰胺(1-36): [0294] N2, N7- Bis (4-t-butylcyclohexyl) anthracene-9,10-dihydro-9,10-dioxo-2,7-sulfonamide (1-36):

[0295] 使蒽醌-2，7-二磺酰氯（10g，24. 7mmo1)溶于200mL DCM中。 [0295] anthraquinone-2,7-chloride (10g, 24. 7mmo1) was dissolved in 200mL DCM. 将溶液冷却至_50°C 。 The solution was cooled to _50 ° C. 向该溶液内加入4-叔丁基环己胺（8.43g，54mmol)，接着加入三乙胺（8. 6ml，61. 7mmo1)。 To this solution was added 4-tert-butyl-cyclohexylamine (8.43g, 54mmol), followed by addition of triethylamine (8. 6ml, 61. 7mmo1). 将反应混合物在室温下搅拌4小时。 The reaction mixture was stirred at room temperature for 4 hours. 蒸发溶剂，将残留物用MeOH处理，滤除，干燥以得到15g(95% )产物（l-36)，为黄色粉状物。 The solvent was evaporated, and the residue was treated with MeOH, filtered, and dried to give 15g (95%) product (l-36), as a yellow powder. [0296] 实施例13 [0296] Example 13

[0297] N2，N7-二（4-叔丁基环己基）-N2-(3-(二甲基氨基）丙基）_9， 10-二氧代_9， 10- 二氢蒽-2， 7- 二磺酰胺（13-1)和[0298] N2， NL二（4-叔丁基环己基）-N2， N7-二（3-(二甲基氨基）丙基）-9，10-二氧代-9， 10- 二氢蒽-2， 7- 二磺酰胺（1-70) [0297] N2, N7- Bis (4-t-butylcyclohexyl) -N2- (3- (dimethylamino) propyl) [9, 10-dioxo [9, 10-dihydro-anthracene -2, 7- two sulfonamides (13-1) and [0298] N2, NL-di (4-t-butylcyclohexyl) -N2, N7- bis (3- (dimethylamino) propyl) -9,10-dioxo - 9, 10-dihydro-anthracene -2, 7-sulfonamide (1-70)

[0299] 在氩气下向磺酰胺（1-36，6. 82g， 10. 61mmo1)在无水DMF(100ml)中的冰冷溶液内加入NaH(95. 0%，697mg，27. 58mmol)。 Was added NaH inner [0299] Under argon sulfonamide (1-36,6. 82g, 10. 61mmo1) in dry DMF (100ml) in ice-cold solution of (95. 0%, 697mg, 27. 58mmol). 将溶液搅拌5分钟，然后加入3-氯代-N，N- 二甲基丙-1-胺盐酸盐（2. 18g， 13. 8mmo1) 。 The solution was stirred for 5 minutes, followed by addition of 3-chloro -N, N- dimethyl-propan-1-amine hydrochloride (2. 18g, 13. 8mmo1). 10分钟后，将反应混合物转移至4(TC预热油浴中，搅拌3天。LCMS显示存在单烷基化和二烷基化产物（比率，65 : 25)，以及未反应的原料。冷却后，将1N NaOH加入反应混合物内，用乙酸乙酯提取。用无水硫酸镁干燥有机相，减压蒸发滤液。将粗混合物用硅胶柱层析纯化。用40XEtOAc/己烷洗脱该柱，回收未反应的原料。单用EtOAc洗脱时获得纯的单烷基化产物（13-1， LCMS， MS 728. 0 (MH+))，用5%三乙胺/EtOAc作为洗脱剂时分离二烷基化产物（1-70， LCMS， MS 813. 2(MH+))。将收集的流分减压蒸发至干以得到13-1(3. 02g，53% )和1-70(1. 10g，17% )。 [0300] 流程6 [0301]<formula>formula see original document page 68</formula>[0302] 实施例14 After 10 minutes, the reaction mixture was transferred to a 4 (TC preheated oil bath and stirred for 3 days .LCMS shows the presence of monoalkylated and dialkylated product (ratio 65: 25), was cooled and unreacted starting material After the reaction mixture was added 1N NaOH, extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, the filtrate was evaporated under reduced pressure. The crude mixture was purified by chromatography on a silica gel column. with 40XEtOAc / hexane The column, recover unreacted starting material. monoalkylated obtain pure single product eluting with EtOAc (13-1, LCMS, MS 728. 0 (MH +)), washed with 5% triethylamine / EtOAc as eluent dialkylated product (1-70, LCMS, MS 813. 2 (MH +)). The fractions were collected and evaporated to dryness to give 13-1 (3. 02g, 53%) and 1-70 (1 . 10g, 17%). [0300] Process 6 [0301] <formula> formula see original document page 68 </ formula> [0302] Example 14

[O303] N、W-二（4-叔丁基环己基）-W-(3-(二甲基氨基）丙基）-9，10-二（羟基亚氨基）-9，10-二氢蒽-2，7-二磺酰胺（6-1) [O303] N, W--bis (4-t-butylcyclohexyl) -W- (3- (dimethylamino) propyl) -9,10-bis (hydroxyimino) -9,10-dihydro-anthracene - 2,7-sulfonamide (6-1)

[0304] 用36小时在95t:按照通用程序用单烷基化磺酰胺（13_1， 2g， 2. 7mmo1)、过量盐酸羟胺（2.7g，27.5mmo1)和吡啶(50ml)制备二月亏(6-1)。 [0304] 36-hour 95t: Following the general procedure with a single alkylated sulfonamide (13_1, 2g, 2. 7mmo1), excess hydroxylamine hydrochloride (2.7g, 27.5mmo1) and pyridine (50ml) prepared in February deficit (6 -1). 冷却后，将过量羟胺过滤除去，用吡啶洗涤，将滤液减压蒸发至干。 After cooling, the excess hydroxylamine was removed by filtration, washed with pyridine, and the filtrate was evaporated to dryness under reduced pressure. 向其内加入过量1N HC1水溶液，使肟沉淀，过滤以收集无色沉淀物和干燥。 Thereto was added an excess of 1N HC1 solution, the oxime precipitated colorless precipitate was collected by filtration to and dried. 通过结晶或HPLC进一步纯化以得到作为无色HC1盐的肟（6-1) (1.42g， 65% )。 Further purified by crystallisation or HPLC to give the oxime as a colorless HC1 salt (6-1) (1.42g, 65%).

[0305] NMR(400MHz， DMS0-d6) S :13. 04-13. 01 (m， 1H) ， 12. 94-12. 89 (m， 1H) ， 10. 48 (br [0305] NMR (400MHz, DMS0-d6) S:... 13 04-13 01 (m, 1H), 12. 94-12 89 (m, 1H), 10. 48 (br

s， 1H) ， 9. 18-9. 07 (m， 1H) ， 8. 87-8. 78 (m， 1H) ， 8. 40-7. 78 (m， 4H) ， 3. 75-3. 05 (m， 16H)， 2. 72 (s， 6H) ， 1. 96-0. 76 (m， 28H)。 s, 1H), 9. 18-9. 07 (m, 1H), 8. 87-8. 78 (m, 1H), 8. 40-7. 78 (m, 4H), 3. 75-3. 05 (m, 16H), 2. 72 (s, 6H), 1. 96-0. 76 (m, 28H). [0306] 实施例15 [0306] Example 15

[0307] N2， N7- 二（4-叔丁基环己基）-N2， N7- 二（3_( 二甲基氨基）丙基）_9， 10- 二（羟基亚氨基）_9， 10- 二氢蒽-2， 7- 二磺酰胺（2-65) [0307] N2, N7- Bis (4-t-butylcyclohexyl) -N2, N7- bis (3_ (dimethylamino) propyl) [9, 10-di (hydroxyimino) [9, 10-dihydro-anthracene - 2, 7-sulfonamide (2-65)

[0308] 按照上文描述的通用程序，用36小时在95。 [0308] Following the general procedure described above, with 36 hours on 95. C用相应的蒽醌衍生物（1_70， lg， 1. 23mmo1)、过量盐酸羟胺（1. 2g， 12. 3mmo1)和妣啶（25ml)制备作为HC1盐的二后（2-65) (0. 710g，63% )。 C using the corresponding anthraquinone derivatives (1_70, lg, 1. 23mmo1), excess hydroxylamine hydrochloride (1. 2g, 12. 3mmo1) and deceased mother pyridine (25ml) was prepared as a HC1 salt after two (2-65) (0 . 710g, 63%).

[0309] 4匪R(400MHz， DMS0-d6) S : 13. 09-13. 07 (m， 1H) ， 12. 98-12. 95 (m， 1H)， 9. 14-9. 08 (m， 1H) ， 8. 89-8. 82 (m， 1H) ， 8. 35-7. 92 (m， 4H) ， 3. 75-3. 04 (m， 16H) ， 2. 72-0. 77 (m， [0309] 4 bandits R (400MHz, DMS0-d6) S:... 13. 09-13 07 (m, 1H), 12. 98-12 95 (m, 1H), 9. 14-9 08 (m , 1H), 8. 89-8. 82 (m, 1H), 8. 35-7. 92 (m, 4H), 3. 75-3. 04 (m, 16H), 2. 72-0. 77 (m,

46H)。 46H).