TW201125566A

TW201125566A - Antimicrobial compounds and methods of making and using the same

Info

Publication number: TW201125566A
Application number: TW99135286A
Authority: TW
Inventors: Erin M Duffy; Ashoke Bhattacharjee
Original assignee: Rib X Pharmaceuticals Inc
Priority date: 2009-10-16
Filing date: 2010-10-15
Publication date: 2011-08-01
Also published as: MY161870A; JP2018024653A; CN105646370A; NZ623384A; NZ713357A; TW201622725A; KR20120099436A; TWI612048B; TWI589294B; JP2018039784A; KR20120101392A; TW201124417A; SG10201406635QA; TW201731849A; AR080559A1; SG10201406634VA; CN107266470A; TW201825495A; KR20120099435A; SG10201406631TA

Abstract

The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and/or reducing the risk of microbial infections in humans and animals.

Description

201125566 六、發明說明：相關申請案本申請案主張在2009年10月16曰提出申請之美國臨時申請案第61/252,478號、在2010年3月16日提出申請之美國臨時申請案第61/314,287號及在2010年6月 24日提出申請之美國臨時申請案第6 1 /3 5 8,20 1號之利益。將前述申請案的內容以其全文倂入本文以供參考。【發明所屬之技術領域】本發明槪括關於抗微生物性化合物領域及其製造與使用方法。該等化合物有用於治療、預防及減低在人類和動物中的微生物感染風險。【先前技術】自從在1 920年代發現青黴素及在1 940年代發現鏈黴素以來，已發現或尤其設計用作爲抗生素的許多新型化合物。曾經認爲使用該等治療劑可使感染性疾病完全受到控制或根除。然而，此看法受到挑戰，因爲對抗目前有效的治療劑之細胞株或微生物持續進化。幾乎每一種經開發出臨床用途的抗生素最終遭遇抗藥性細菌出現的問題。例如 ’已發展出抗藥性革蘭氏（Gram)陽性菌株，諸如抗二甲苯青黴素（methicillin)之葡萄球菌、抗青黴素之鏈球菌及抗萬古黴素之腸球菌。抗藥性細菌可使感染之病患引起嚴重且甚至致命的結果。參見 Lowry, F. D. “Antimicrobial -5- 201125566201125566 VI. INSTRUCTIONS: RELATED APPLICATIONS This application claims US Provisional Application No. 61/252,478, filed on October 16, 2009, and US Provisional Application No. 61/ filed on March 16, 2010. Benefits No. 314,287 and U.S. Provisional Application No. 6 1 /3 5 8,20 1 filed on June 24, 2010. The content of the aforementioned application is incorporated herein by reference in its entirety. TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of antimicrobial compounds and methods of making and using same. These compounds are useful for treating, preventing and reducing the risk of microbial infections in humans and animals. [Prior Art] Since the discovery of penicillin in the 1950s and the discovery of streptavidin in the 1940s, many novel compounds have been discovered or especially designed for use as antibiotics. It has been thought that the use of such therapeutic agents can completely control or eradicate infectious diseases. However, this view is challenged because cell lines or microorganisms that fight the currently effective therapeutic agents continue to evolve. Almost every antibiotic developed for clinical use eventually suffers from problems with drug-resistant bacteria. For example, drug-resistant Gram-positive strains such as Staphylococcus against methicillin, Streptococcus against penicillin, and Enterococcus against vancomycin have been developed. Drug-resistant bacteria can cause serious and even fatal results in infected patients. See also Lowry, F. D. "Antimicrobial -5- 201125566

Resistance : The Example of Staphylococcus aureus’’，J. Clin. Invest., vo 1. 111, no. 9, pp. 1 265 - 1 273 (2003 )；及 Gold, H. S. and Moellering, R. C., Jr., 'Antimicrobial-Drug Resistance55, N. Engl. J. Med., vol. 335, pp. 1 4 4 5-53 (1996)° 新型抗細菌劑的發現及開發已爲許多醫藥公司數十年來的主要重點。但是，在最近幾年已有醫藥公司從此硏究及藥物開發領域退出。此退出的結果使得非常少的新型抗生素進入市場。此新型抗生素的缺乏特別感到不安，尤其是在對目前醫療法的細菌抗藥性正於醫院及社區兩者環境中增加。在新型抗生素的探索中，硏究員嘗試組合或連結各種部分的抗生素分子，以創造多功能或混成化合物。其他的硏究員嘗試製造已知的抗生素類別之衍生物，例如以商標 Ketek®銷售之泰利黴素（telithromycin)爲紅黴素之衍生物。然而，該等方法取得有限的成功。開發新型抗微生物性化合物之方法爲設計細菌核糖體功能之調節劑，例如抑制劑。此等抗微生物性化合物可藉由調節或抑制細菌核糖體功能而千擾基本過程，諸如 RNA轉譯及蛋白質合成，藉此提供抗微生物效果。事實上’已知一些抗生素化合物與核糖體結合，諸如紅黴素、克林達黴素（clindamycin)及利奈唑德（linezolid)。本發明利用以結構爲基準之藥物設計方法來發現及開發新型抗微生物劑。此方法係以核糖體的高解析X-射線 -6- 201125566 晶體開始’以設計具有特殊的化學結構、核糖體結合特徵及抗微生物活性之抗微生物性化合物的新分類。此以結構爲基準之藥物發現方法說明於以下發表中：Franceschi, F. and Duffy，Ε. Μ., “Structure-based drug design meets the ribosome”，Biochemical Pharmacology, vol. 71，pp. 10 16-1025 (2006) ° 基於此以結構爲基準之藥物設計方法，本發明說明有用於治療在人類和動物中的細菌感染之抗微生物性化合物的新化學分類。不受理論的限制，咸信該等化合物係藉由與核糖體結合來抑制細菌核糖體功能。本發明的抗微生物性化合物可利用該等核糖體結合位置來提供比目前的抗生素化合物更好的活性，尤其對抗抗藥性細菌株。本發明利用以結構爲基準之藥物設計方法來發現及開發新型抗微生物劑。此方法係以核糖體的高解析X-射線晶體開始，以設計具有特殊的化學結構、核糖體結合特徵及所欲抗微生物活性之抗微生物性化合物的新分類。此以結構爲基準之藥物發現方法說明於以下發表中： Franceschi, F. and Duffy, Ε. Μ., Structure-based drug design meets the ribosome”，Biochemical Pharmacology, vol. 71，pp. 1 0 1 6- 1 02 5 (2006)。本發明因此滿足了提供新型抗微生物劑之重要的持續需求，特別爲具有對抗抗藥性病原細菌有機體的活性之抗微生物劑。 201125566 【發明內容】製造與使人類和動物在醫藥本發明槪括關於抗微生物性化合物領域及用方法。該等化合物有用於治療、預防及減低物中的微生物感染風險。本發明亦提供該等化上可接受之鹽、酯、N-氧化物及前藥。本發明提供具有以下結構之化合物：Resistance : The Example of Staphylococcus aureus'', J. Clin. Invest., vo 1. 111, no. 9, pp. 1 265 - 1 273 (2003); and Gold, HS and Moellering, RC, Jr., ' Antimicrobial-Drug Resistance55, N. Engl. J. Med., vol. 335, pp. 1 4 4 5-53 (1996) ° The discovery and development of new antibacterial agents has been a major focus for many pharmaceutical companies for decades. However, in recent years, pharmaceutical companies have withdrawn from the field of research and drug development. The result of this withdrawal made very few new antibiotics enter the market. The lack of this new type of antibiotic is particularly disturbing, especially as the bacterial resistance to current medical practices is increasing in both hospital and community settings. In the exploration of new antibiotics, researchers try to combine or link various parts of antibiotic molecules to create multifunctional or mixed compounds. Other researchers have tried to make derivatives of known antibiotic classes, such as telithromycin, sold under the trademark Ketek®, as a derivative of erythromycin. However, these methods have had limited success. A method of developing novel antimicrobial compounds is to design modulators of bacterial ribosome functions, such as inhibitors. Such antimicrobial compounds can interfere with basic processes, such as RNA translation and protein synthesis, by modulating or inhibiting bacterial ribosome functions, thereby providing an antimicrobial effect. In fact, some antibiotic compounds are known to bind to ribosomes, such as erythromycin, clindamycin, and linezolid. The present invention utilizes a structure-based drug design method to discover and develop novel antimicrobial agents. This method begins with a high-resolution X-ray -6-201125566 crystal of ribosomes to design a new classification of antimicrobial compounds with specific chemical structures, ribosome binding characteristics, and antimicrobial activity. This structure-based drug discovery method is described in the following publication: Franceschi, F. and Duffy, Ε. Μ., "Structure-based drug design meets the ribosome", Biochemical Pharmacology, vol. 71, pp. 10 16- 1025 (2006) ° Based on this structure-based drug design method, the present invention describes a new chemical classification of antimicrobial compounds for the treatment of bacterial infections in humans and animals. Without being bound by theory, it is believed that these compounds inhibit bacterial ribosome function by binding to ribosomes. The antimicrobial compounds of the present invention can utilize these ribosome binding sites to provide better activity than current antibiotic compounds, particularly against drug resistant bacterial strains. The present invention utilizes a structure-based drug design method to discover and develop novel antimicrobial agents. This method begins with a high resolution X-ray crystal of ribosomes to design a new classification of antimicrobial compounds with specific chemical structures, ribosome binding characteristics, and desired antimicrobial activity. This structure-based drug discovery method is described in the following publication: Franceschi, F. and Duffy, Ε. Structure., Structure-based drug design meets the ribosome", Biochemical Pharmacology, vol. 71, pp. 1 0 1 6 - 1 02 5 (2006). The present invention thus satisfies an important continuing need to provide novel antimicrobial agents, particularly antimicrobial agents having activity against drug-resistant pathogenic bacterial organisms. 201125566 [Invention] Manufacturing and making humans Animals in Medicine The present invention encompasses the field of antimicrobial compounds and methods of use thereof for the treatment, prevention, and reduction of the risk of microbial infections. The present invention also provides such acceptable salts, esters, and Ns. - Oxides and prodrugs. The present invention provides compounds having the following structure:

其中0爲選自下式之化學部分：Where 0 is a chemical moiety selected from the group consisting of:

，另一選擇地兩個R3 —起形成羰基， V係獨立選自-CR4a-或-N-: 其中vg)代表稠合之5至7員飽和、不飽和或芳環系環系統； W爲O'NR^'NOR1或S，另一選擇地W =係的碳原子連接之HO·與H-二者之組合或與相連接之（Ch烷基）0-與H-二者之組合；、C = NOR3 碳環或雜自與相同的碳原子 201125566 χ二二γ代表單鍵或雙鍵，使得當χ=γ爲單鍵時，則X係選自0、NR2及S(0)ns Y爲C-R3，而當X二爲雙鍵時，則X爲Ν且Υ爲碳原子， Ζ係選自0、NR4或S(0)n， R1係選自Η及C!_8烷基， R2係選自Η及（^.8烷基， R3係選自Η及Cm烷基， R4係選自Η及Cu烷基， R4a係選自Η及（^.8烷基， η爲0、1或2，另一選擇地，-G-H-J係選自下式：Alternatively, two R3 together form a carbonyl group, and the V system is independently selected from -CR4a- or -N-: wherein vg) represents a fused 5- to 7-membered saturated, unsaturated or aromatic ring system; W is O'NR^'NOR1 or S, another combination of a combination of HO and H- of a carbon atom of the W = system or a combination of (Ch alkyl) 0- and H-; , C = NOR3 Carbocyclic or heterozygous with the same carbon atom 201125566 χ22 γ represents a single bond or double bond, so that when χ = γ is a single bond, then X is selected from 0, NR2 and S(0) ns Y is C-R3, and when X is a double bond, X is Ν and Υ is a carbon atom, lanthanide is selected from 0, NR4 or S(0)n, and R1 is selected from Η and C!_8 alkyl R2 is selected from the group consisting of ruthenium and (^.8 alkyl, R3 is selected from the group consisting of ruthenium and Cm alkyl, R4 is selected from ruthenium and Cu alkyl, R4a is selected from ruthenium and (^.8 alkyl, η is 0) , 1 or 2, alternatively, the -GHJ system is selected from the following formula:

其中Rx係選自CH2、ΝΗ、ΝΝ,-β烷基）、S或0; 1^及Rz 爲C或CH，各自獨立以一或多個F、CH3、CF3、OH& OCH3取代；或Rx、Ry及Rz各自獨立選自CH2或CRaRb ，其中Ra及Rb —起形成C3-5碳環； J 係選自 NH2、NH(C丨-8烷基）、N(C丨.8烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ；其中n爲0、1或2 ; 另一選擇地，-G-H-J係選自： -9- 201125566Wherein Rx is selected from the group consisting of CH2, ruthenium, osmium, -beta alkyl), S or 0; 1^ and Rz are C or CH, each independently substituted with one or more of F, CH3, CF3, OH &OCH3; or Rx , Ry and Rz are each independently selected from CH2 or CRaRb, wherein Ra and Rb together form a C3-5 carbocyclic ring; J is selected from the group consisting of NH2, NH(C丨-8 alkyl), N(C丨.8 alkyl) 2. NHC(=0)CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; where n is 0, 1 or 2; alternatively, the -GHJ is selected from: -9- 201125566

其中Rx係選自CHz'NH'NiCw烷基）、S或0; Rz 一或多個CH3取代之C或CH ’或Rz爲CRaRb ’其q 及Rb —起形成C3_5碳環；其中m爲1、2或3 ; J 係選自 NH2、NH(C丨·8烷基）、N(C丨.8烷基 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 NHC( = NH)H ； C-B-A-、-D-E-F及-G_H-J爲化學部分，其中 A、D及G係獨立選自： (a)單鍵，（b)-(C,.8 烷基）-，（c)-(C2.8 烯基）-， (d)-(C2.8炔基）_，其中 i) 前文（b)-(d)中任一者中的〇_4個碳原子隨以選自-0-、_s(0)p.、.NR6-、-(C = 〇)- ' -S(0)PNR6-、 _Nr6s(0)p 及-NR6S(0)pNR6-之部分代替， ii) 前文（b)-(d)中任一者隨意地以一或多個B 團取代，及 iii) 前文（b)-(d)中任一者隨意地以-(C丨-8烷基基團取代； (e)-〇- > (f)-NR6- . (g)-S(〇)P- > (h)-C(〇)-' C(〇)〇-，（j)-OC(O)-，（k)-0c(0)0-，⑴-C(0)NR6- ’ NR CO- ’ (n)-NR6C(0)NR6- ， (o)-C( = NR6)- ’ 爲以 μ Ra )2 ' 意地 .5基 )-R5 (i)- (m)- (p)· 201125566 C( = NR6)〇- , (q)-OC( = NR6)- ， (r)-C( = NR6)NR6- ， (s)-NR6C( = NR6)- ， (t)-C( = S)- ’ (u)-C( = S)NR6- ， (v)- NR6C( = S)-，（w)-C(0)S-，（x)-SC(0)-，（y)-0C( = S)-，（z)-C( = S)0- > (aa)-NR6(CNR6)NR6- > (b b) - C R6 R6 C ( O) - - (cc)-C(0)NR6(CR6R6)t-，（dd)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（ee) 3-14員飽和、不飽和或芳族碳環，及（ff)-(CR6R6)t-，其中（dd)或（ee)隨意地以一或多個R5基團取代； B、E及Η係獨立選自·· (a) 單鍵， (b) 含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環， (c) 3-14員飽和、不飽和或芳族碳環，其中（b)或（c)隨意地以—或多個R5基團取代； (d) -(C|.8 院基）_，（e)_(C2.8 嫌基）-’（f)-(C2-8 块基）_，其中 i) 前文（d)-(f)中任一者中的0-4個碳原子隨意地以選自-0- ' -S(0)P、_NR6-、-(C = 0)- ' -C( = NR6)-、-S(0)pNR6-、-NR6s(〇)p 及-NR6S(0)pNR6-之部分代替， ii) 前文（d)-(f)中任一者隨意地以一或多個r5基團取代，及Wherein Rx is selected from CHz 'NH'NiCw alkyl), S or 0; Rz one or more CH3 substituted C or CH' or Rz is CRaRb ', q and Rb together form a C3_5 carbon ring; wherein m is 1 , 2 or 3; J is selected from the group consisting of NH2, NH(C丨8 alkyl), N(C丨.8 alkyl NHC(=0)CH3, NHC(=0)NH2, NHC(=NH)NH2 NHC ( = NH)H ; CBA-, -DEF and -G_H-J are chemical moieties, wherein A, D and G are independently selected from: (a) single bond, (b)-(C, .8 alkyl)- , (c)-(C2.8 alkenyl)-, (d)-(C2.8 alkynyl)_, wherein i) 〇_4 carbon atoms in any of the foregoing (b)-(d) It is selected from the group consisting of -0-, _s(0)p., .NR6-, -(C = 〇)- ' -S(0)PNR6-, _Nr6s(0)p and -NR6S(0)pNR6- Alternatively, ii) any of the foregoing paragraphs (b)-(d) are arbitrarily replaced by one or more B groups, and iii) any of the foregoing (b)-(d) optionally with -(C丨- VIII alkyl group substitution; (e)-〇- > (f)-NR6- . (g)-S(〇)P- > (h)-C(〇)-' C(〇)〇- , (j)-OC(O)-, (k)-0c(0)0-,(1)-C(0)NR6- ' NR CO- ' (n)-NR6C(0)NR6- , (o)- C( = NR6)- ' is in μ Ra )2 'Ideland .5 base)-R5 (i)- (m)- (p)· 201125566 C( = NR6)〇 - , (q)-OC( = NR6)- , (r)-C( = NR6)NR6- , (s)-NR6C( = NR6)- , (t)-C( = S)- ' (u) -C( = S)NR6- , (v)- NR6C( = S)-,(w)-C(0)S-,(x)-SC(0)-,(y)-0C( = S) -, (z) - C ( = S) 0 - > (aa) - NR6 (CNR6) NR6 - > (bb) - C R6 R6 C ( O) - - (cc) - C (0) NR6 ( CR6R6)t-, (dd) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (ee) 3-14 member saturated, unsaturated or An aromatic carbocyclic ring, and (ff)-(CR6R6)t-, wherein (dd) or (ee) is optionally substituted with one or more R5 groups; B, E and anthracene are independently selected from (a) a single bond, (b) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (c) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring. , wherein (b) or (c) is optionally substituted with — or a plurality of R 5 groups; (d) —(C|.8 院基)_, (e)_(C2.8 suspicion)-'(f )-(C2-8 block group)_, wherein i) 0-4 carbon atoms in any of the foregoing (d)-(f) are optionally selected from -0' '-S(0)P, _NR6-, -(C = 0)- ' -C( = NR6)-, -S(0)pNR6-, -NR6s(〇)p and -NR6S( 0) a partial replacement of pNR6-, ii) any of the foregoing (d)-(f) is optionally substituted with one or more r5 groups, and

Ui)前文（d)-(f)中任一者隨意地以-(Cm烷基）-R5 基團取代；及（g)-(CR6R6)t·, -11 - 201125566 <：、？及]係獨立選自： (a)氫，（c)F，（d)Cl，（e)Br，（f)I，（g)-CF3，（h)-CN ，⑴·Ν3，（j)-N02，（k)-NR6(CR6R6)tR8，（l)-OR8， (m)-S(0)p(CR6R6),R8，（n)-C(0)(CR6R6)tR8， (o)-OC(0)(CR6R6),R8 - (p)-SC(0)(CR6R6),R8 > (q)-C(0)0(CR6R6)tR8，（r)-NR6C(0)(CR6R6)tR8， (s)-C(0)NR6(CR6R6)tR8，（t)-C( = NR6)(CR6R6)tR8， (u)-C( = NNR6R6)(CR6R6)tR8，（v)-C( = NNR6C(0)R6)( CR6R6)tR8 > (w)-C( = NOR8)(CR6R6),R8 > (x)-NR6C(0)0(CR6R6)tR8，（y)-0C(0)NR6(CR6R6)tR8，（z)_ NR6C(0)NR6(CR6R6),R8，（aa)-NR6S(0)p(CR6R6)tR8，（bb)-S(0)pNR6(CR6R6),R8 > (cc)-NR6S(0)pNR6(CR6R6),R8 > (dd)-NR6R8，（ee)-NR6(CR6R6)R8，（ff)-OH，（gg)-NR8R8， (hh)-OCH3 ’（ii)-S(0)pR8，（jj)-NC(0)R8， (кк) -NR6C(NR6)NR6R8，（11)(^.8 烷基，（mm)C2.8 烯基， (nn)C2.8炔基，（0〇)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（pp)3-14員飽和、不飽和或芳族碳環，（qq)-(CR6R6)tNR6(CR6R6)tR8，（rr)- N[(CR6R6)tR8][C = 0(CR6R6)tR8] , (s s) - (C R6 R6), N [ (C R6 R6 ),R8] [(CR6R6)tR8] ’ (tt)-(CR6R6),NR6(C = 0)(CR6R6),R8 > (uu)-鹵烷基，（vv)-C(0)(CR6)[(CR6R6)tR8]R8 ，（ww)- (CR6R6)tC(0)NR8R8 > (xx)-(CR6R6)tC(0)0(CR6R6),R8 - (yy)-NR6C(0)CR8R8R8，（zz)-N[(CR6R6)tR8]C(0)R8，及 (ааа) -S(0)pNR8R8 ； 201125566 其中（11)至（PP)隨意地以一或多個R7基團取代； R5 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)_ CN，（h)-N3，（i)-N02 , (j) -NR6R6 ’ （k)-OR8，（i)_ NR6(CNR6)NR6R6，（m)-Cl.8 烷基，（n)-Ch8 烯基，（0)-(:,.8 炔基，烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（qMChs烷基 )-(3-14員飽和、不飽和或芳族碳環），（〇·鹵烷基，（s)_ SR6，（t)含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環，及（u)3-14員飽和、不飽和或芳族碳環；另一選擇地兩個R5基團一起形成碳環，其中（m)至⑴及⑴至（u)隨意地以—或多個R8取代； R6係選自（a)氫’（bhCu烷基，或另一選擇地兩個r6基團一起形成碳環，（c)-鹵烷基，（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (e)3-14員飽和、不飽和或芳族碳環；其中（b)至（e)隨意地以一或多個r8取代； R7 係選自（a)氫 ’（b)F ’（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN ，（h)-N3 ’ （i)-N02 ，（j)_NR6R6 ，（k)-OR6 ，（1)- nr6(cnr6)nr6r6’（m)-Cl.8 烷基，（n)_Cl.8 烯基，（0)-C| 8 炔基，（Ρ)-(<^·8院基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Ci8烷基 )-(3-14員飽和、不飽和或芳族碳環）’（r)_鹵烷基，（s)_ NR6R8 - (t)-OR8 - (u)-(CR6R6)tNR6Rs , (v).CR6R8R8 , (w)- SR6 ’（x)含有一或多個選自氮、氧及硫之雜原子的4 201125566 員飽和、不飽和或芳族雜環，（y)3-14員飽和、不飽和或芳族碳環，（z)-(CR6R6)tC(0)NR8R8，（aa)-S(0)pR8，（bb)-NR6C(0)NR6R6，（cc)-NR6C(0)R6，及（dd)-C( = NR6)NR6R6 > 其中（m)至（q)及（x)至（y)隨意地以一或多個R9取代： R8 係選自（a)氫 ’（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN ’ （h)-N3 ’ （i)-N02 ，（j)-NR6R9，（k)-OR9，（1)- NR6(CNR6)NR6R6，（m)-C 卜 8 烷基，（n)-C 卜 8 烯基，（cO-Cu 炔基’（pidC!·8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Cl8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)含有—或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’（s)3-14員飽和、不飽和或芳族碳環，（t)_鹵烷基， (u)-C(0)(CR6R6)tR9，（V)-SR6，（w)-0C(0)(CR6R6)tR9， (x)-NR6C(0)NR6R9 > (y)-NR6C(0)R9，(z)-N R6 (C N R9)( NR6R6)，（aa)-ONR6(CNR6)NR6R6，（bb)-C( = NR9)NR6R6， (cc)-S(0)pR9 > (dd)-(CR6R6),C(0)NR6R9 -(ee)-(CR6R6)丨OR9 ’ 及（ff)_(CR6R6)tNR6R9 ; 其中（m)至（s)隨意地以一或多個R9取代； R9 係選自（a)氫，（b)F’（c)Cl> (d)Br，（e)I，（f)-CF3，（g)-CN > (h)-N3 ’ （i)-N02，（j)-NR6R10，（k)-〇R6，（1)- nr6(cnr6)nr6r6’（m)-C(0)(CR6R6)丨nR6R6, u)-c丨·8 烷基 ’（0)-(2,-8烯基’（phCy炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， -14- 201125566 (r)3-14員飽和、不飽和或芳族碳環，（s)_鹵烷基，〇)_ (CR6R6)tOR6 - (u)-〇(CR6R6)tNR6R10 - (v)-C(0)R6 . (w). SR6，（x)-C(0)0R1Q，（y)-S(0)pR6’（zHCu 烷基）·（含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（aa^C!.*烷基）-(3-14員飽和、不飽和或芳族碳環），（bb)-0(CR6R6)t0R6，（cc)-C( = NR6)NR6R6 , (dd)-ONR6R6 - (ee)-NR6C(0)NR6R6 - (f f) - Ο ( C R6 R 6), 〇 R 6 , (gg)-NR6C(0)R6，及（hh)-(CR6R6)tNR6R10 ; 其中（n)至（r)及（z)至（aa)隨意地以一或多個取代； R10 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3， (g)-CN ’（h)-N3，（i)-N02，（j)-NR6R6，（k)-〇R6，（1)_ nr6(cnr6)nr6r6，（m)_c(〇)(CR6R6)tNR6R6，（n) C| 8 烷基 ’（cO-Cm烯基’（p)-C】-8炔基’（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (〇3-14員飽和、不飽和或芳族碳環，（s)_鹵烷基，（〇_ (CR6R6)tOR6 * (u)-〇(CR6R6)tNR6R6 - (v)-C(〇)R6 , (w)-SR6 ’（x)-C(0)0R6 ’（y)-S(0)pR6，⑴-(Ci 8 烷基）_(含有—或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環）’（aa)-(Cl_8烷基）-(3-14員飽和、不飽和或芳族 ONR6R6，（ee).NR6C(〇)NR6R6，（ff)-〇(CR6R6)t〇R6，（gg)_ NR6C(0)R6’ 及（hh)-(CR6R6)tNR6R6; 隨意地’其中基團-D-E-F或基團-G-H-J不存在（例如，基團D-E-F或基團- G- H- J代表氫）’但是- D- E- F及- G- H- J二 -15- 201125566 者不同時不存在； P爲〇、1或2 ;及 t 爲〇、1、2 或 3，或其醫藥上可接受之鹽、酯' 互變異構物或前藥。另外，本發明提供合成前述化合物之方法。在合成之後，可將化合物中之一或多者以治療有效量與醫藥上可接受之載劑調配，用作爲抗微生物劑，特別爲抗細菌劑投於人類或動物。在特定的具體例中，本發明化合物有用治療、預防或減低微生物感染風險或製造供治療、預防或減低微生物感染風險之藥劑。據此，化合物或調配物例如可經口服、非經腸、耳、眼、鼻或局部途徑投予，以提供有效量化合物予人類或動物》本發明的前述及其他觀點及具體例可藉由參考以下的詳細說明和申請專利範圍更完整了解。本發明的詳細說明本發明提供可用作爲抗微生物劑，更特別用作爲抗細菌劑之化合物家族。本發明包括該化合物在醫藥上可接受之鹽、酯、互變異構物、N -氧化物及前藥。本文所述化合物可具有不對稱中心。含有不對稱取代原子之本發明化合物可以光學活性或外消旋形式分離。在本技藝中熟知如何製備光學活性形式，諸如藉由分解外消旋形式或藉由從光學活性起始材料合成。烯烴、C=N雙鍵 ⑧ -16 - 201125566 及類似物的許多幾何異構物亦可存在於本文所述化合物中 ’且將所有此等穩定的異構物涵蓋於本發明中。本發明化合物的順式和反式幾何異構物係經說明且可分離成異構物混合物或單獨的異構物形式。意欲涵蓋結構的所有手性、非鏡像、外消旋及幾何異構物形式，除非特定標示特殊的立體化學或異構物形式。用於製備本發明化合物的所有方法及其中所製備之中間物被認爲是本發明的一部分。所顯示或所述之化合物的所有互變異構物亦被認爲是本發明的一部分。此外，本發明亦包括本文所述化合物的代謝物。本發明意欲包括出現在本發明化合物中之原子的所有同位素。同位素包括那些具有相同的原子數，但是不同的質量數之原子。以一般的實例方式而非限制的氫同位素包括氚及氘。碳同位素包括C-13及C-14。當任何變體（例如，R6)在化合物的任何構造或化學式中出現一次以上時，則其在各出現場合的定義與其在每次其他出現場合的定義無關。因此，例如若基團經顯示被一或多個R6部分取代時，則R6在各出現場合係獨立選自 R6之定義。取代基及/或變體的組合亦受到許可，但僅在若此等組合導致在特許之原子正常價數內的穩定化合物時〇以點線圖像顯示化學鍵的化學結構標示鍵可隨意地存 & °例如’緊鄰實線單鍵所繪製之點線標示該鍵可爲單鍵或雙鍵。當至取代基的鍵經顯示與連接環中的兩個原子之鍵交 -17- 201125566 叉時，則此取代基可與環上的任何原子鍵結。當取代基經陳列而未標示此取代基係經由何原子與既定化學式之化合物的其餘部分鍵結時，則此取代基可經由此式中任何原子鍵結。取代基及/或變體的組合受到許可，但僅在若此等組合導致穩定的化合物時。在其中本發明化合物有氮原子的情況中，若適當時，該等氮原子可藉由以氧化劑（例如，MCPBA及/或過氧化氫）處理而轉化成N-氧化物。因此，若適當時，所顯示且主張之氮原子被認爲包括所顯示之氮及其N-氧化物（N — 〇 )衍生物二者。一種開發出改進之抗增殖劑及抗感染劑之方法係提供核糖體功能調節劑（例如，抑制劑）。核糖體爲存在於原核生物及真核生物二者中的核糖核蛋白。核糖體爲負貴蛋白質合成之細胞器》在基因表現期間，核糖體轉錄在信使RNA中編碼之遺傳訊息至蛋白質中（Garrett 等人之（2000)” The Ribosome: Structure, Function, Antibiotics and Cellular Interactions”， American Society for Microbiology, Washington, D. C.) ° 核糖體包含非對等核糖核蛋白次單元。較大的次單元 (亦稱爲"大核糖體次單元〃）具有約2倍較小的次單元（亦稱爲"小核糖體次單元〃）尺寸。小核糖體次單元結合信使RNA(mRNA)且介導在mRNA與轉送RNA(tRNA)反密碼子之間的交互作用，轉錄保真性係取決於此交互作用。大核糖體次單元催化肽鍵形成，亦即蛋白質合成的肽基轉 -18- 201125566 移酶反應，且包括至少三個不同的t RN A結合位置，已知爲胺醯基、肽基及出口位置。胺醯基或A -位置容納進來的胺醯基-tRN A，有助於其胺基酸至生長肽鏈。A-位置的 A空間亦重要。肽基位置或P -位置容納肽基-1RN A複合物，亦即具有其胺基酸的t RN A，其爲生長肽鏈的一部分。出口或E-位置係在給予其胺基酸至生長聚肽鏈之後容納去醯化tRN A。 1 .定義 "異構現象"意謂具有相同的分子式，但是彼等原子的鍵結順序或彼等原子在空間中排列不同的化合物。彼等原子在空間中排列不同的異構物被稱爲'^立體異構物〃。彼此不爲鏡像的立體異構物被稱爲 '' 非鏡像異構物〃，而彼此鏡像不可重疊的立體異構物被稱爲"鏡像異構物〃或有時被稱爲光學異構物。與四個不相同的取代基鍵結之碳原子被稱爲、手性中心〃。 "手性異構物〃意謂具有至少一個手性中心的化合物。其具有兩個對立手性的鏡像異構物形式且可以單獨的鏡像異構物或以鏡像異構物之混合物存在。含有等量的對立手性之個別鏡像異構物形式的混合物被稱爲'、外消旋性混合物〃。具有超過一個手性中心的化合物具有2 n ·1個鏡像異構物對’其中η爲手性中心數量。具有超過—個手性中心的化合物可以個別的非鏡像異構物或以稱爲、非鏡像異構物混合物〃的非鏡像異構物之混合物存在。當有—個手 -19- 201125566 性中心存在時，則立體異構物可以該手性中心的絕對組態 (R或S)特徵化。絕對組態係指與手性中心連接的取代基之空間排列》與手性中心連接的取代基之考量係依照Ui) Any of the foregoing (d)-(f) is optionally substituted with a -(Cm alkyl)-R5 group; and (g)-(CR6R6)t·, -11 - 201125566 <:,? And] are independently selected from: (a) hydrogen, (c)F, (d)Cl, (e)Br, (f)I, (g)-CF3, (h)-CN, (1)·Ν3, (j )-N02, (k)-NR6(CR6R6)tR8, (l)-OR8, (m)-S(0)p(CR6R6), R8, (n)-C(0)(CR6R6)tR8, (o )-OC(0)(CR6R6), R8 - (p)-SC(0)(CR6R6), R8 > (q)-C(0)0(CR6R6)tR8,(r)-NR6C(0)( CR6R6)tR8, (s)-C(0)NR6(CR6R6)tR8,(t)-C( = NR6)(CR6R6)tR8, (u)-C( = NNR6R6)(CR6R6)tR8,(v)- C( = NNR6C(0)R6)( CR6R6)tR8 > (w)-C( = NOR8)(CR6R6), R8 > (x)-NR6C(0)0(CR6R6)tR8,(y)-0C (0) NR6(CR6R6)tR8, (z)_NR6C(0)NR6(CR6R6), R8, (aa)-NR6S(0)p(CR6R6)tR8, (bb)-S(0)pNR6(CR6R6) , R8 > (cc)-NR6S(0)pNR6(CR6R6), R8 > (dd)-NR6R8, (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh )-OCH3 '(ii)-S(0)pR8,(jj)-NC(0)R8, (кк) -NR6C(NR6)NR6R8,(11)(^.8 alkyl, (mm)C2.8 Alkenyl, (nn) C2.8 alkynyl, (0) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (pp)3 -14-membered saturated, unsaturated or aromatic carbocyclic ring, (qq)-(CR6R6)tNR6(CR6R6)tR8, Rr)- N[(CR6R6)tR8][C = 0(CR6R6)tR8] , (ss) - (C R6 R6), N [ (C R6 R6 ),R8] [(CR6R6)tR8] ' (tt) -(CR6R6), NR6(C = 0)(CR6R6), R8 > (uu)-haloalkyl, (vv)-C(0)(CR6)[(CR6R6)tR8]R8 , (ww)- ( CR6R6)tC(0)NR8R8 > (xx)-(CR6R6)tC(0)0(CR6R6), R8 - (yy)-NR6C(0)CR8R8R8,(zz)-N[(CR6R6)tR8]C( 0) R8, and (ааа) -S(0)pNR8R8; 201125566 wherein (11) to (PP) are optionally substituted with one or more R7 groups; R5 is selected from (a) hydrogen, (b)F, (c) Cl, (d) Br, (e) I, (f)-CF3, (g) _ CN, (h)-N3, (i)-N02, (j) -NR6R6 ' (k)-OR8 , (i) _ NR6(CNR6)NR6R6, (m)-Cl.8 alkyl, (n)-Ch8 alkenyl, (0)-(:,.8 alkynyl, alkyl)-(containing one or more a 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from nitrogen, oxygen and sulfur heteroatoms, (qMChs alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), 〇.haloalkyl, (s)_SR6, (t) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) 3-14 Saturated, unsaturated or aromatic carbon ring; another option The R5 groups together form a carbocyclic ring, wherein (m) to (1) and (1) to (u) are optionally substituted with - or a plurality of R8; R6 is selected from (a) hydrogen' (bhCu alkyl, or alternatively The two r6 groups together form a carbocyclic ring, (c)-haloalkyl, (d) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. And (e) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring; wherein (b) to (e) are optionally substituted with one or more r8; R7 is selected from (a) hydrogen '(b)F '(c)Cl,(d)Br,(e)I,(f)-CF3,(g)-CN , (h)-N3 ' (i)-N02 , (j)_NR6R6 , (k)-OR6 , (1)- nr6(cnr6)nr6r6'(m)-Cl.8 alkyl, (n)_Cl.8 alkenyl, (0)-C| 8 alkynyl, (Ρ)-(<^·8 (base) - (3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), (q)-(Ci8 alkyl)-(3-14 A saturated, unsaturated or aromatic carbocyclic ring) '(r)_haloalkyl, (s)_ NR6R8 - (t)-OR8 - (u)-(CR6R6)tNR6Rs , (v).CR6R8R8 , (w) - SR6 '(x) contains one or more heteroatoms selected from nitrogen, oxygen and sulfur 4 201125 566 saturated, unsaturated or aromatic heterocyclic ring, (y) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (z)-(CR6R6)tC(0)NR8R8, (aa)-S(0) pR8, (bb)-NR6C(0)NR6R6, (cc)-NR6C(0)R6, and (dd)-C(=NR6)NR6R6 > where (m) to (q) and (x) to (y Optionally substituted with one or more R9: R8 is selected from (a) hydrogen '(b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)- CN ' (h)-N3 ' (i)-N02 , (j)-NR6R9, (k)-OR9, (1)- NR6(CNR6)NR6R6, (m)-C b 8 alkyl, (n)- C 8 alkenyl, (cO-Cu alkynyl '(pidC!·8 alkyl)-(3-14 member saturated, unsaturated or aromatic containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) Heterocycle), (q)-(Cl8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r) containing - or a plurality of heteroatoms selected from nitrogen, oxygen and sulfur -14-membered saturated, unsaturated or aromatic heterocyclic ring '(s) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (t)-haloalkyl, (u)-C(0)(CR6R6)tR9 , (V)-SR6, (w)-0C(0)(CR6R6)tR9, (x)-NR6C(0)NR6R9 > (y)-NR6C(0)R9,(z)-N R6 (CN R9 ) ( NR6R6), (aa)-ONR6 ( CNR6)NR6R6, (bb)-C(=NR9)NR6R6, (cc)-S(0)pR9 > (dd)-(CR6R6), C(0)NR6R9 -(ee)-(CR6R6)丨OR9 ' And (ff)_(CR6R6)tNR6R9; wherein (m) to (s) are optionally substituted with one or more R9; R9 is selected from (a) hydrogen, (b) F'(c)Cl> (d) Br,(e)I,(f)-CF3,(g)-CN > (h)-N3 ' (i)-N02,(j)-NR6R10,(k)-〇R6,(1)- nr6 (cnr6)nr6r6'(m)-C(0)(CR6R6)丨nR6R6, u)-c丨·8 alkyl '(0)-(2,-8 alkenyl'(phCy alkynyl, (q)-containing a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring selected from one or more of the heteroatoms of nitrogen, oxygen and sulfur, -14-201125566 (r) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl, 〇)_(CR6R6)tOR6 - (u)-〇(CR6R6)tNR6R10 - (v)-C(0)R6 . (w). SR6,(x)-C(0) 0R1Q, (y)-S(0)pR6'(zHCu alkyl)·(3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), (aa^C!.*alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (bb)-0(CR6R6)t0R6, (cc)-C( = NR6)NR6R6 , (dd )-ONR6R6 - (ee)-NR6C(0)NR6R6 - (ff) - Ο ( C R6 R 6), 〇R 6 , (gg)-NR6C(0)R6, and (hh)-(CR6R6)tNR6R10; wherein (n) to (r) and (z) to (aa) optionally Or a plurality of substitutions; R10 is selected from the group consisting of (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)-CN '(h)- N3, (i)-N02, (j)-NR6R6, (k)-〇R6, (1)_nr6(cnr6)nr6r6, (m)_c(〇)(CR6R6)tNR6R6,(n) C| 8 alkane a radical '(cO-Cm alkenyl'(p)-C)-8 alkynyl' (q) containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, 3-14 members saturated, unsaturated or aromatic Heterocycle, (〇3-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl, (〇_(CR6R6)tOR6 * (u)-〇(CR6R6)tNR6R6 - (v)-C (〇)R6 , (w)-SR6 '(x)-C(0)0R6 '(y)-S(0)pR6,(1)-(Ci 8 alkyl)_(containing - or more selected from nitrogen, 3-14 member saturated, unsaturated or aromatic heterocyclic ring of oxygen and sulfur heteroatoms) '(aa)-(Cl_8 alkyl)-(3-14 member saturated, unsaturated or aromatic ONR6R6, (ee). NR6C(〇)NR6R6,(ff)-〇(CR6R6)t〇R6,(gg)_NR6C(0)R6' and (hh)-(CR6R6)tNR6R6; optionally 'where a group-DEF or group- GHJ does not exist ( For example, the group DEF or the group - G-H-J represents hydrogen) 'but - D- E-F and - G-H-J II-15- 201125566 do not exist at the same time; P is 〇, 1 or 2 And t is 〇, 1, 2 or 3, or a pharmaceutically acceptable salt, ester 'tautomer or prodrug thereof. Additionally, the invention provides methods of synthesizing the foregoing compounds. After synthesis, one or more of the compounds can be formulated in a therapeutically effective amount with a pharmaceutically acceptable carrier for administration as an antimicrobial agent, particularly an antibacterial agent, to humans or animals. In a particular embodiment, the compounds of the invention are useful for treating, preventing or reducing the risk of microbial infection or for the manufacture of a medicament for treating, preventing or reducing the risk of microbial infection. Accordingly, the compound or formulation can be administered, for example, orally, parenterally, otic, ocularly, nasally or topically to provide an effective amount of the compound to a human or animal. The foregoing and other aspects and specific examples of the invention may be Refer to the detailed description below and the scope of the patent application for a more complete understanding. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a family of compounds useful as antimicrobial agents, more particularly as antibacterial agents. The invention includes pharmaceutically acceptable salts, esters, tautomers, N-oxides and prodrugs of the compounds. The compounds described herein can have asymmetric centers. The compounds of the invention containing asymmetrically substituted atoms can be separated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by decomposition of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefin, C=N double bonds 8-16-201125566 and the like may also be present in the compounds described herein' and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the invention are illustrated and can be separated into isomer mixtures or individual isomer forms. It is intended to cover all chiral, non-mirrored, racemic, and geometric isomer forms of the structure, unless a particular stereochemistry or isomeric form is specifically indicated. All methods for preparing the compounds of the invention and intermediates prepared therein are considered to be part of the invention. All tautomers of the compounds shown or described are also considered to be part of the invention. In addition, the invention also includes metabolites of the compounds described herein. The invention is intended to include all isotopes of atoms occurring in the compounds of the invention. Isotopes include those atoms that have the same number of atoms but different mass numbers. Hydrogen isotopes, which are by way of general example and not limitation, include strontium and barium. Carbon isotopes include C-13 and C-14. When any variant (e.g., R6) occurs more than once in any configuration or formula of a compound, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R6 moieties, then R6 is independently selected from the definition of R6 in each occurrence. Combinations of substituents and/or variants are also permitted, but only if such combinations result in stable compounds within the normal valence of the licensed atom, the chemical structure labeling of the chemical bonds in dotted lines can be optionally stored. & ° For example, the dotted line drawn by the solid line single button indicates that the key can be a single button or a double button. When a bond to a substituent is shown to cross a bond with two atoms in a linker, the substituent may be bonded to any atom on the ring. When a substituent is shown to indicate that the substituent is bonded via the atom to the remainder of the compound of the formula, then the substituent may be bonded via any atom of the formula. Combinations of substituents and/or variants are permissible, but only if such combinations result in stable compounds. In the case where the compound of the present invention has a nitrogen atom, if appropriate, the nitrogen atom can be converted to an N-oxide by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxide). Thus, if appropriate, the nitrogen atoms shown and claimed are considered to include both the nitrogen and its N-oxide (N- 〇) derivatives. One method of developing improved anti-proliferative and anti-infective agents is to provide modulators of ribosome function (e.g., inhibitors). Ribosomes are ribonucleoproteins found in both prokaryotes and eukaryotes. Ribosomes are organelles of negative protein synthesis. During gene expression, ribosomes transcribe the genetic information encoded in messenger RNA into proteins (Garrett et al. (2000)” The Ribosome: Structure, Function, Antibiotics and Cellular Interactions ", American Society for Microbiology, Washington, DC) ° Ribosomes contain non-equal ribonucleoprotein subunits. The larger subunit (also known as "large ribosome subunit 〃) has about 2 times smaller subunit (also known as "small ribosome subunit 〃) size. The small ribosomal subunit binds to messenger RNA (mRNA) and mediates the interaction between mRNA and the trans-RNA (tRNA) anti-closed code, and transcriptional fidelity depends on this interaction. The large ribosome subunit catalyzes the formation of peptide bonds, ie, the peptidyl group of protein synthesis, -18-201125566, and includes at least three different t RN A binding sites, known as amine sulfhydryl, peptidyl and export. position. The amine sulfhydryl-tRN A is contained in the amine sulfhydryl group or the A-position to facilitate its amino acid to the growing peptide chain. The A space of the A-position is also important. The peptidyl position or P-position accommodates the peptidyl-1 RN A complex, i.e., t RN A with its amino acid, which is part of the growing peptide chain. The export or E-position accommodates deuterated tRN A after administration of its amino acid to the growing polypeptide chain. 1. Definitions "Isomerism" means compounds having the same molecular formula, but the order of bonding of their atoms or the arrangement of their atoms in space. The isomers in which the atoms are arranged in space are called '^ stereoisomers. Stereoisomers that are not mirror images of each other are called ''non-mirrored isomers', and stereoisomers that are non-superimposable mirror images of each other are called "image isomers〃 or sometimes called optical isomerism Things. A carbon atom bonded to four different substituents is referred to as a chiral center enthalpy. "Chiral isomers mean compounds having at least one chiral center. It has two opposite chiral mirror image isomer forms and may be present as a separate mirror isomer or as a mixture of mirror image isomers. A mixture of individual mirror image isomer forms containing equal amounts of opposite chirality is referred to as the ', racemic mixture oxime. A compound having more than one chiral center has 2 n · 1 mirror isomer pair 'where n is the number of chiral centers. Compounds having more than one chiral center may be present as individual non-image isomers or as a mixture of non-mirromeric isomers known as non-mirromeric isomers. When there is a hand -19- 201125566 sex center, the stereoisomer can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. The considerations for the substituents attached to the chiral center are in accordance with

Sequence Rule of Cahn，Ingold and Prelog· (Cahn 等人之 Angew. Chem. Inter. Edit. 1 966, 5, 3 8 5; errata 511 ； Cahn 等人之 Angew. Chem. 1 966, 7 8，413 ； Cahn and In go 1 d, J Chem. Soc. 19 5 1 (London), 6 12； Cahn 等人之 Experientia 1 956，12,8 1; Cahn, J Chern. Educ. 1 964，41，116)分等級 o "幾何異構物〃意謂彼等的存在歸因於雙鍵周圍旋轉受阻的非鏡像異構物。該等組態係根據 Cahn-Ingold-Prelog規則在名字上以字首順式和反式，或Z和E區別，其標示基團係在分子雙鍵的相同面或對立面上。另外，在本申請案中所討論的結構及其他化合物包括所有的其限制構形異構物。”限制構形異構物〃爲其中兩種異構物的原子在空間排列不同的立體異構物類型。限制構形異構物的存在歸因於大基團在中心鍵周圍旋轉受阻所引起的限制旋轉。此等限制構形異構物典型地以混合物存在，然而，由於層析技術的新近進展，已有可能在選擇性情況下分離兩種限制構形異構物之混合物。 %互變異構物〃係指其結構的原子排列顯著不同，但是其輕易且快速平衡存在的化合物。應了解可將式I化合物描述爲不同的互變異構物。亦應了解當化合物具有互變異構物形式時，意欲以所有的互變異構物形式在本發明的 -20- 201125566 範疇內，且化合物的命名不排除任何互變異構物形式。本發明的一些化合物可以互變異構物形式存在，亦意欲將其包含在本發明的範疇內。本發明的化合物、鹽及前藥可以數種互變異構物形式存在，包括烯醇及亞胺形式及酮基及烯胺形式，與其幾何異構物及混合物。所有的此等互變異構物形式包括在本發明的範疇內。互變異構物係以互變異構物組於溶液中的混合物存在。在固體形式中，經常以一種互變異構物佔優勢。雖然可以一種互變異構物說明，但是本發明包括本發明化合物的所有互變異構物。互變異構物爲平衡存在且可輕易地從一種異構物形式轉化成另一種形式的二或多種結構異構物中之一。此反應導致伴隨有相鄰的共軛雙鍵轉換的氫原子正式遷移。在其中可能有互變異構化作用的溶液中，可達成互變異構物的化學平衡。互變異構物的真實比率係取決於許多因素而定，包括溫度、溶劑及pH。以互變異構化作用可互相轉化的互變異構物之槪念被稱爲互變異構現象。在有可能的互變異構現象的各種類型之中，常觀察到兩種類型。在酮基-烯醇互變異構現象中發生電子及氫原子的同步位移。環-鏈互變異構現象係以葡萄糖展現。其係由於糖鏈分子中的醛基（-CHO)與相同分子中的羥基（-OH)中之一反應而出現，得到環（成環狀）形式的葡萄糖。互變異構化作用可藉由鹼：1.去質子化；2.形成非定域陰離子（例如，烯醇鹽）；3.在陰離子的不同位置上質子 -21 - 201125566 化；酸：1.質子化；2.形成非定域陽離子；3.在與陽離子相鄰的不同位置上去質子化而催化。常見的互變異構物對爲：酮-烯醇、醯胺-腈、內醯胺-內醯亞胺、在雜環系環中的醯胺-醯亞胺酸互變異構現象（例如，在核鹼基中的鳥嘌呤、胸腺嘧啶及胞嘧啶）' 胺-烯胺及烯胺-烯胺。以例證爲目的包括以下實例，旦本發明不限於此實例： 0〆 ΗΟ" 、Ν- 術語π晶體多形物"或^多形物〃或"晶體形式〃意謂其中化合物（或其鹽或溶劑合物）可以不同的晶體堆積排列而結晶的晶體結構，所有的結構皆具有相同的元素組成。不同的晶體形式經常具有不同的X -射線繞射圖案、紅外線光譜、熔點 '密度硬度、晶體形狀、光學和電性質、穩定性及溶解度。再結晶溶劑、結晶速度、貯存溫度及其他因素可引起一種晶體形式成爲優勢。化合物的晶體多形物可藉由在不同的條件下結晶而製備。如本文所使用之術語％經取代之"意謂在特許原子上 (經常爲碳、氧或氮原子）的任何一或多個氫被選自指定的基團置換，其先決條件係不超過特許原子的正常價數，且取代導致穩定的化合物。當取代基爲酮基（亦即=0)時，則置換在原子上的2個氫原子。如本文所使用之環雙鍵爲在兩個相鄰的環原子之間形成的雙鍵（例如，C = C、C = N或 N = N)。 -22- 201125566 如本文所使用之術語"變旋異構碳〃意謂醣苷之縮醛碳。如本文所使用之術語"醣苷〃爲環系縮醛。如本文所使用之"烷基"意欲包括具有指定的碳原子數之直鏈或支鏈飽和脂族烴基二者。例如，C,.6烷基意欲包括c,、c2、C3、C4、（：5及c6烷基。烷基的一些實例包括（但不限於此）甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基、第二戊基、正己基、正庚基及正辛基。如本文所使用之''烯基〃意欲包括直鏈或支鏈組態及可出現在沿著鏈的任何穩定點的一或多個不飽和碳-碳鍵之烴鏈’諸如乙烯基及丙烯基。例如，C2-6烯基意欲包括 c2、c3、c4、c5 及 c6 烯基。如本文所使用之 > 炔基〃意欲包括直鏈或支鏈組態及可出現在沿著鏈的任何穩定點的一或多個碳-碳參鍵之烴鏈，諸如乙炔基及丙炔基。例如，C 2.6炔基意欲包括C 2 、C3 ' c4、c5 及 c6 炔基。此外，”烷基〃、w烯基〃及 ''炔基"意欲包括爲二基團的部分，亦即具有兩個連接點，在本發明的實例爲D 係選自該等化學基團時。此烷基部分爲二基團的非限制性實例爲-CH2CΗ2-，亦即經由各末端碳原子與分子其餘部分共價鍵結的 C2烷基。烷二基亦被稱爲 > 伸烷基 (alkylenyl)^ 。嫌二基亦被稱爲 Μ申燃基（alkenylenyl)" 。炔二基亦被稱爲Μ申炔基（alkynylenyl)"。 -23- 201125566 如本文所使用之"環烷基〃意欲包括飽和環基團，諸如環丙基、環丁基或環戊基。c3-8環烷基意欲包括c3、 C4、c5、c6、c7 及 c8 環烷基。如本文所使用之"相對離子〃係用於意謂與相反電荷之離子共同存在的正或負荷電物種。相對離子的非限制性實例爲抗衡有機化合物上的電荷或電荷類而存在的離子或離子類。相對離子的非限制性實例包括氯化物、溴化物、氫氧化物、乙酸鹽' 硫酸鹽及銨。如本文所使用之^鹵基"或〜鹵素〃係指氟基、氯基、溴基及碘基取代基。如本文所使用之"鹵烷基"意欲包括以1或多個鹵素取代之具有標示的碳原子數之直鏈及支鏈飽和脂族烴基二者（例如，-CVFW，其中v=l至3及w=l至（2V+1))。鹵烷基的實例包括（但不限於此）三氟甲基、三氯甲基、五氟乙基及五氯乙基。如本文所使用之 '、烷氧基〃係指經由氧橋連接之具有標示的碳原子數量的如上述定義之烷基。Ci.6烷氧基意欲包括c,、c2、C3、C4、C5及C6烷氧基。烷氧基意欲包括c,、c2、c3、c4、c5、c6、c7及c8烷氧基。烷氧基的實例包括（但不限於此）甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第二丁氧基、第三丁氧基、正戊氧基、第二戊氧基、正庚氧基及正辛氧基。如本文所使用之"烷硫基"係指經由硫橋連接之具有標示的碳原子數量的如上述定義之烷基。C,.6烷硫基意欲 -24- 201125566 包括c,、c2、C3、C4、C5及C6烷硫基。C丨-8烷硫基意欲包括 c,、c2、c3、c4、c5、c6、c7 及（：8烷硫基。如本文所使用之A碳環"或"碳環系環〃意欲意謂（除非另有其他指定）任何穩定的 3、4、5、6、7、8、9、 10、11或12_員單環、雙環或三環系環，任何該等環可爲飽和、不飽和（包括部分及完全不飽和）或芳族。此等碳環的實例包括（但不限於此）環丙基、環丁基、環丁烯基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環庚烯基、金剛烷基、環辛基、環辛烯基、環辛二烯基、[3.3.0]雙環辛烷、[4.3.0]雙環壬烷、[4.4.0]雙環癸烷、[2·2·2]雙環辛烷、蕗基、苯基、萘基、二氫茚基、金剛烷基及四氫萘基。如上所示，橋連環亦包括在碳環的定義中（例如， [2.2.2]雙環辛烷）。當一或多個碳原子連結兩個不相鄰的碳原子時，則發生橋連環。較佳的橋具有1或2個碳原子。應注意橋總是將單環系環轉化成三環系環。當環被橋連時’以環引述之取代基亦可出現在橋上。亦包括稠合環（例如，萘基及四氫萘基）及螺旋環。如本文所使用之術語 '、雜環〃意謂（除非另有其他陳述）穩疋的3、4、5、6、7、8、9、10、1丨或12·員單環、雙環或三環系環，其爲飽和、不飽和（包括部分及完全不飽和）或芳族，且由碳原子及一或多個環雜原子所組成，例如1或1-2或1·3或I-4或1-5或1-6個獨立選自氮' 氧及硫的雜原子’且包括任何雙環或三環基團，其中將上述定義之雜環系環中任一者稠合或與第二個環（例如，苯 -25- 201125566 環）連接。氮及硫雜原子可隨意地被氧化（亦即N— 0及 S(0)p，其中p=i或2)。當氮原子包括在環中時，其爲Ν 或NH，其係取決是否其與環中的雙鍵連接（亦即若有必要維持氮原子的三價數時，則有氫原子的存在）。氮原子可被取代或未被取代（亦即N或NR，其中R爲Η或如定義之另一取代基）。可將雜環系環在任何雜原子或碳原子上與其側基團連接，其導致穩定的結構。本文所述之雜環系環可在碳上或在氮原子上被取代，假設所得化合物是穩定的。在雜環中的氮可隨意地四級化。橋連環亦包括在雜環的定義中。當一或多個原子（亦即C、0、Ν或S)連結兩個不相鄰的碳或氮原子時，則發生橋連環。較佳的橋包括（但不限於此）1個碳原子，2個碳原子，1個氮原子，2個氮原子及碳-氮基團。當環被橋連時，以環引述之取代基亦可出現在橋上。亦包括螺旋環及稠合環。如本文所使用之術語a芳族雜環〃或 ''雜芳基〃意欲意謂穩定的5、6、7、8' 9、10、11或12 -員單環或雙環芳族環’其係由碳原子及一或多個雜原子所組成，例如1 或1-2或1-3或1-4或1-5或1-6個獨立選自氮、氧及硫的雜原子。在雙環雜環芳族環的情況中，兩個環之中僅一個必須爲芳族（例如’ 2，3 -二氫吲哚），雖然兩個皆可爲芳族（例如’喹啉）。可將第二個環稠合或橋連，如上述就雜環所定義。氮原子可被取代或被經取代（亦即N或NR，其中R爲Η或如定義之其他取代基）。氮及硫雜原子可隨意地被氧化（亦即Ν— 0及S(0)p，其中p=i或2)。在特定的 201125566 具體例中，s與0原子在芳族雜環中的總數不超過1個以上。雜環的實例包括（但不限於此）吖啶基、氮雜雙環辛醯基、四氫吖唉基、氮雜環辛四烯基（azocinyl)、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻唑基、苯並***基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、苯並二噁唑基、苯並噁二唑基、咔唑基、4 aH -咔唑基、咔啉基、色滿基、色烯基、噌啉基、環庚基、十氫喹啉基、二氫苯並二噁哄基、2只，6^1-1，5,2-二噻畊基、二氫呋並[2,3· b]四氫呋喃、呋喃基、呋咕基、咪唑啶基、咪唑啶基亞胺、咪唑啉基、咪唑基、咪唑酮基、1H-吲唑基、吲哚烯基 (indolenyl)、吲哚啉基、吲哚畊基、吲哚基、3H-吲哚基 '靛紅醯基（isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異 B惡哩基、甲二氧基苯基、甲基苯並三哩基、甲基咲喃基、甲基咪唑基、甲基噻唑基、嗎啉基、萘啶基、八氫異唾啉基、D惡二哩基、1，2，3 -嚼二Π坐基、1，2，4 -嚼二D坐基' 1 , 2，5 -噁二唑基、1 ,3，4-噁二唑基 '噁唑啶基、噁唑啶酮基、嚼唑基、羥吲哚基、啡啶基、啡啉基、啡阱基、啡噻哄基、啡噁噻基、啡嚼哄基、酞哄基、哌明:基、峨π井酮基、哌陡基、哌陡酮基、4 -脈D定酮基、胡椒基、蝶陡基、曝吟基、口比喃基、啦明1基、吡Π坐陡基、吡哩琳基、耻π坐基、塔明；基、啦陡並噪哩基、吡陡並咪哗基、耻D定並噻哗基、卩比陡基 -27- 201125566 (pyridinyl)、吡啶酮基、吡啶基（pyridyl)、嘧啶基、吡咯酮基、吡咯啶基、吡咯啶酮基、吡咯啉基、2 Η -吡咯基、吡咯基、喹唑啉基、喹啉基、4 Η -喹啉哄基、喹噁啉基、奎寧環基、四氫呋喃基、四氫異唾啉基、四氫唾啉基、四唑基、6Η-1，2,5 -噻二畊基、1，2,3 -噻二唑基、1，2,4 -噻二唑基、1，2,5·噻二唑基、1，3,4-噻二唑基、噻嗯基、噻唑基、噻吩基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、硫代嗎啉基二噁啶基、三哄基、***並嘧啶基、1，2,3-***基、l，2,4-***基、1，2,5-***基、1，3,4-三唑基及二苯並哌喃基。如本文所使用之慣用語”醫藥上可接受〃係指在健全的醫學判斷範圍內適合與人類和動物組織接觸使用而沒有過度毒性、刺激性、過敏反應或其他問題或倂發症，具有相稱合理的利益/風險比的該等化合物、材料、組成物、載劑及/或劑型。如本文所使用之"醫藥上可接受之鹽〃係指所揭示之化合物的衍生物’其中親體化合物係藉由製成其酸或鹼鹽而予以修改。醫藥上可接受之鹽的實例包括（但不限於此）鹼性殘基（諸如胺）之無機或有機酸鹽；酸性殘基之鹼或有機鹽（諸如羧酸）；及類似物。醫藥上可接受之鹽包括例如從無毒性無機或有機酸所形成之親體化合物的習知之無毒性鹽或四級敍鹽。例如，此等習知的無毒性鹽包括（但不限於此）該等從選自下列的無機和有機酸所衍生者：2 -乙醯氧基苯甲酸、2-羥基乙烷磺酸、乙酸、抗壞血酸、苯磺 • 28 - 201125566 酸、苯甲酸、雙碳酸、碳酸、檸檬酸、乙二胺四乙烷二磺酸、乙烷磺酸、反丁烯二酸、葡萄庚酸、葡、麩胺酸、乙醇酸 '乙二醇對胺苯胂酸、己基間苯、哈胺酸（hydrabamic)、氫溴酸、氫氯酸、氫碘酸順丁烯二酸、羥萘酸、羥乙磺酸、乳酸、乳糖醛酸基磺酸、順丁烯二酸、蘋果酸、杏仁酸、甲烷磺酸酸（napsylic) '硝酸 '草酸、雙羥萘酸、泛酸、苯、磷酸、聚半乳糖酸、丙酸、水楊酸、硬脂酸、鹽酸（subacetic)、琥拍酸、胺橫酸、擴胺酸、硫酸、、酒石酸及甲苯磺酸。本發明的醫藥上可接受之鹽可從含有鹼性或酸之親體化合物藉由習知的化學方法合成。此等鹽通由該等化合物的游離酸或鹼形式與化學劑量之適當酸在水或有機溶劑中或在兩種之混合物中反應而製常以非水性介質較佳，如醚、乙酸乙酯、乙醇、異乙腈。適合的鹽名單於 Remington’s Pharma< Sciences, 18 th e d., Mack Publishing Company, PA, USA, p. 1 44 5 (1990)中發現。因爲已知前藥會增強藥劑的許多所欲品質（例解度、生物利用率、製造等），所以本發明化合物藥形式輸送。因此’本發明意欲涵蓋目前主張之化前藥、輸送前藥之方法及含有前藥之組成物。、前欲包括任何共價鍵結之載劑，在此等前藥投予哺乳象時於活體內釋出本發明的活性親體藥物。本發明酸、乙萄糖酸二酚酸、羥基、月桂、萘磺基乙酸基性酢單寧酸性部分常係藉的鹼或備；通丙醇或 :e u t i c a I Easton, 如，溶可以前合物的藥〃意動物對的前藥 -29- 201125566 係藉由修改在化合物中存在的官能基而製備，以此方式使修改物按慣例操作或於活體內裂解成親體化合物。前藥包括其中羥基、胺基或氫硫基與任何基團鍵結的本發明化合物，當本發明前藥投予哺乳動物對象時，該前藥裂解，分別形成游離羥基、游離胺基或游離氫硫基。前藥的實例包括（但不限於此）在本發明化合物中的醇及胺官能基之乙酸酯、甲酸酯和苯甲酸酯衍生物。如本文所使用之a穩定的化合物"及"穩定的結構" 意胃具有足夠的強度從反應混合物得以分離爲有用的純度且調配成有效力的治療劑之化合物。如本文所使用之術語、'病患〃意謂可能承受外科或侵入性醫學程序之人類或動物（在動物的情況中，更典型爲哺乳動物）對象。由於外科程序或侵入性醫學程序而可能認爲此等病患或對象有需要減低感染風險或預防感染之方法。此等病患或對象亦可被認爲有需要手術期間的預防。如本文所使用之術語A治療〃意謂提供治療干預，使感染痊癒或改善。如本文所使用之術語"預防〃意謂完全或幾乎完全停止感染發生，例如當病患或對象易受感染或易在接觸感染的風險下時。預防亦可包括抑制，亦即遏阻感染發生。如本文所使用之術語"減低風險〃意謂降低感染發生的可能性或或然性’例如當病患或對象易受感染或易在接觸感染的風險下時。如本文所使用之、不飽和〃係指具有至少一種不飽和 ⑧ -30- 201125566 程度（例如，至少一個多重鍵）之化合物且包括部分及完全不飽和化合物。如本文所使用之術語 ''有效量"係指當作爲抗微生物劑單獨或組合投予時有效的本發明化合物或化合物組合量。例如，有效量係指給予接受病患或對象足以誘出生物活性（例如，抗感染活性，諸如抗微生物活性 '抗細菌活性、抗真菌活性、抗病毒活性或抗寄生蟲活性）的組成物中、調配物中或醫學裝置上存在的化合物量。術語"預防有效量〃意謂用於預防由於外科程序或侵入性醫學程序之感染或減低其風險而投予之本發明化合物或化合物類的有效量。應進一步了解'v氫鍵受體-氫鍵受體-氫鍵施體〃及，氫鍵受體·氫鍵受體-氫鍵受體〃之表述意謂表明氫鍵受體與施體的相對定位，並不意謂限制此等基團直接連接在一起，預期額外的原子或原子之基團可包括在該等基團之間 0 在說明書中，單數形式亦包括複數，除非在上下文中另有其他明確的指定。除非另有其他定義，在本文所使用之所有技術及科學術語皆具有與熟諳屬於本發明技藝者— 般了解的意義。在有抵觸的情況下，將對照本發明說明書。如本文所使用之 '、哺乳動物〃係指人類和非人類病患。如本文所使用之術語"治療有效量〃係指以足以誘出生物活性（例如，抗微生物活性、抗真菌活性 '抗病毒活性、抗寄生蟲活性、抗腹瀉活性及/或抗增殖活性）之量存 -31 - 201125566 在於接受者中或上的本發明化合物或化合物組合。化合物的組合較佳爲協乘性組合物。當以組合投予時的化合物效果比以單一試劑單獨投予時更大的化合物加成效果時，則發生協乘性，如由例如Chou and Talalay，Adv. Enzyme Regul. ν〇1·22，pp.27-55 ( 1 984)所述。通常在化合物的次優濃度下最明確地證明出協乘效果。協乘性可以較低的細胞毒性或增加的抗增殖效果或與各個組份相比的一些其他有利的組合效應爲角度。如本文所使用之術語w RNA微螺旋結合位置〃係指由式III之RN A微螺旋佔據之大核糖體次單元的核糖功能所在地。RNA微螺旋結合位置限定至少一部分與E-位置的重疊。如本文所使用之術語> A-位置〃係指在其參與肽鍵形成反應之前立即由胺醯基-tRNA分子佔據之核糖功能所在地》如本文所使用之術語％ E-位置〃係指在其參與肽鍵形成反應之後由去醯化tRNA分子佔據之核糖功能所在地。如本文所使用之術語"P-位置〃係指在其參與肽鍵形成反應的同時由肽基-tRNA佔據之核糖功能所在地。如本文所使用之術語"A-空間〃係指在肽基轉移酶中心內結合胺醯化-tRNA之胺基酸部分的一部分A-位置，或另一選擇係指結合利奈唑德之噁唑啶酮環的一部分A-位置》應了解如本文所使用及關於核糖體或核糖體次單元之 -32- 201125566 術語 '、一部分〃或、立體結構的一部分〃意謂藉由核糖體或核糖體次單元的至少3個，更佳爲至少3至10個’而最佳爲至少1 〇個胺基酸殘基及/或核苷酸殘基所形成之核糖體或核糖體次單元之立體結構的一部分，包括電荷分布及親水性/疏水性特徵。形成此一部分的殘基可爲例如（i) 以例如核糖體RN A或核糖體蛋白質的第一序列爲基準之連續殘基’（Π)形成核糖體或核糖體次單元之立體結構的連續部分之殘基，或（c)其組合。應了解如本文所使用及關於RN A微螺旋之術語 '、一部分〃或'•、立體結構的一部分〃意謂藉由式ΙΠ之一或多個核心殘基的至少3個，更佳爲至少3至1 0個原子所形成之RNA微螺旋之立體結構的一部分，包括電荷分布及親水性/疏水性特徵。形成此一部分的原子可爲例如（i)埋藏在RNA微螺旋核心內之溶劑不可及原子，（ii)RNA微螺旋之溶劑可及原子，或（iii) 其組合。本文所使用之所有百分比及比値係以重量計，除非另有其他標示。在整個說明中，在以具有、包括或包含特殊的組份說明組成物時，或在以具有、包括或包含特殊的方法步驟說明方法時’預期本發明組成物基本上亦由或由所引述之組份所組成，且本發明方法基本上亦由或由所引述之處理步驟所組成。再者’應了解步驟的次序或執行特定作用的次序不重要’只要本發明仍維持爲可操作。而且，可同時進行二或多個步驟或作用。 -33- 201125566 2.本發明化合物在一個觀點中，本發明關於具有以下結構之化合物：Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1 966, 5, 3 8 5; errata 511; Cahn et al., Angew. Chem. 1 966, 7 8, 413; Cahn and In go 1 d, J Chem. Soc. 19 5 1 (London), 6 12; Experientia of Cahn et al. 1 956,12,8 1; Cahn, J Chern. Educ. 1 964,41,116) Grade o " Geometric isomers mean that their existence is due to non-mirrored isomers that are blocked by rotation around the double bond. These configurations are distinguished by the word cis and trans, or Z and E, according to the Cahn-Ingold-Prelog rule, which indicates that the group is on the same or opposite side of the molecular double bond. Additionally, the structures and other compounds discussed in this application include all of their restricted conformational isomers. "Restricted conformation isomers" are stereoisomer types in which the atoms of the two isomers are arranged differently in space. The presence of restricted conformational isomers is attributed to the resistance of large groups around the central bond. Restricted rotation. These restricted conformational isomers are typically present as a mixture, however, due to recent advances in chromatography techniques, it has been possible to separate mixtures of two restricted conformational isomers under selective conditions. An isomer lanthanum refers to a compound whose structure has a significantly different atomic arrangement, but which readily and rapidly balances the compounds present. It is understood that the compounds of formula I can be described as different tautomers. It should also be understood that when the compounds have tautomers Forms are intended to be in the form of all tautomers within the scope of -20-201125566 of the present invention, and the nomenclature of the compounds does not exclude any tautomeric forms. Some of the compounds of the present invention may exist as tautomeric forms, It is intended to be included within the scope of the invention. The compounds, salts and prodrugs of the invention may exist in several tautomeric forms, including enol and imine And keto and enamine forms, as well as geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the invention. Tautomers are mixtures of tautomeric groups in solution. In the solid form, it is often dominated by one tautomer. Although one tautomer can be illustrated, the invention includes all tautomers of the compounds of the invention. Tautomers exist in equilibrium and can be easily Converting from one isomeric form to one of two or more structural isomers of another form. This reaction results in a formal migration of a hydrogen atom accompanied by an adjacent conjugated double bond transition. There may be tautomerism therein. The chemical equilibrium of tautomers can be achieved in the solution. The true ratio of tautomers depends on many factors, including temperature, solvent and pH. Mutual transformation can be converted by tautomerization. The commemoration of the structure is called tautomerism. Among the various types of possible tautomerism, two types are often observed. In the keto-enol mutual mutation The simultaneous shift of electrons and hydrogen atoms occurs in the phenomenon. The cyclo-chain tautomerism is exhibited by glucose, which is due to the aldehyde group (-CHO) in the sugar chain molecule and one of the hydroxyl groups (-OH) in the same molecule. The reaction occurs to give a ring (ring-forming) form of glucose. The tautomerization can be by base: 1. deprotonation; 2. formation of a delocalized anion (eg, enolate); Protons at different positions - 201125566; acid: 1. protonation; 2. formation of delocalized cations; 3. catalysis by deprotonation at different positions adjacent to the cation. Common tautomer pairs are : keto-enol, guanamine-nitrile, indoleamine-indole imine, guanamine-oxime acid tautomerism in a heterocyclic ring (eg, guanine in nucleobases, Thymine and cytosine) 'amine-enamine and enamine-enamine. The following examples are included for illustrative purposes, and the invention is not limited to this example: 0〆ΗΟ", Ν- the term π crystal polymorph" ^ Polymorph or "crystal form" means a compound (or a salt or solvate thereof) thereof A crystal structure that can be crystallized by different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms often have different X-ray diffraction patterns, infrared spectra, melting point 'density hardness, crystal shape, optical and electrical properties, stability and solubility. The recrystallization solvent, crystallization rate, storage temperature and other factors can cause a crystal form to be advantageous. Crystalline polymorphs of compounds can be prepared by crystallization under different conditions. The term "substituted by" as used herein means that any one or more hydrogens on a licensed atom (often a carbon, oxygen or nitrogen atom) are replaced by a group selected from the specified group, the prerequisites of which are not exceeded. The normal valence of a licensed atom and the substitution of a compound that results in stability. When the substituent is a keto group (i.e., =0), then two hydrogen atoms on the atom are replaced. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C = C, C = N or N = N). -22- 201125566 The term "cyclonic isomeric carbon" as used herein means acetal carbon of a glycoside. The term "glucoside is used herein as a cyclic acetal. "Alkyl" as used herein is intended to include both straight-chain or branched saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C,.6 alkyl is intended to include c,, c2, C3, C4, (:5 and c6 alkyl. Some examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso Propyl, n-butyl, t-butyl, tert-butyl, n-pentyl, second pentyl, n-hexyl, n-heptyl and n-octyl. As used herein, 'alkenyl" is intended to include straight Chain or branched configuration and hydrocarbon chains such as vinyl and propylene groups that may occur at one or more unsaturated carbon-carbon bonds along any stable point of the chain. For example, C2-6 alkenyl is intended to include c2. C3, c4, c5 and c6 alkenyl. As used herein, alkynyl is intended to include a straight or branched chain configuration and one or more carbon-carbon bonds that may occur at any stable point along the chain. a hydrocarbon chain such as an ethynyl group and a propynyl group. For example, a C 2.6 alkynyl group is intended to include C 2 , C 3 ' c 4 , c 5 and c 6 alkynyl groups. Further, "alkyl fluorene, w alkenyl hydrazine and ' 'alkynyl group" It is intended to include a moiety that is a di-group, that is, has two points of attachment, in the case of an example of the invention where D is selected from such chemical groups. This alkyl moiety is a non-limiting group of di-groups. For example, -CH2CΗ2-, that is, a C2 alkyl group covalently bonded to the rest of the molecule via each terminal carbon atom. The alkanediyl group is also referred to as >alkylenyl^. The dibasic group is also known as Alkenylenyl " alkynediyl is also known as alkynylenyl" -23- 201125566 As used herein, "cycloalkylfluorene is intended to include saturated cyclic groups, such as Cyclopropyl, cyclobutyl or cyclopentyl. The c3-8 cycloalkyl group is intended to include c3, C4, c5, c6, c7 and c8 cycloalkyl. As used herein, "relative ion lanthanide is used to mean A positive or load electrical species coexisting with oppositely charged ions. A non-limiting example of a relative ion is an ion or ion species that exists to counteract a charge or charge on an organic compound. Non-limiting examples of relative ions include chloride, Bromide, hydroxide, acetate 'sulfate and ammonium. As used herein, halo" or "halogen" refers to fluoro, chloro, bromo and iodo substituents. "haloalkyl" is intended to include having one or more halogens substituted Both a straight chain and a branched saturated aliphatic hydrocarbon group of a carbon number are shown (for example, -CVFW, wherein v = 1 to 3 and w = 1 to (2V + 1)). Examples of haloalkyl include (but not Limited to this) trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl. As used herein, alkoxy hydrazine refers to the number of carbon atoms indicated by an oxygen bridge, as described above. The alkyl group is defined. The Ci.6 alkoxy group is intended to include c, c2, C3, C4, C5 and C6 alkoxy groups. The alkoxy group is intended to include c, c2, c3, c4, c5, c6, c7 and c8. Alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, tert-butoxy, n-pentyloxy Base, second pentyloxy, n-heptyloxy and n-octyloxy. "alkylthio" as used herein refers to an alkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge. C, .6 alkylthio is intended to be -24- 201125566 includes c, c2, C3, C4, C5 and C6 alkylthio groups. The C丨-8 alkylthio group is intended to include c, c2, c3, c4, c5, c6, c7 and (:8 alkylthio. As used herein, A carbon ring " or "carbocyclic ring is intended Means (unless otherwise specified) any stable 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered monocyclic, bicyclic or tricyclic ring, any such ring may be saturated Unsaturated (including partial and fully unsaturated) or aromatic. Examples of such carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0] Bicyclodecane, [4.4.0]bicyclodecane, [2·2·2]bicyclooctane, indenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. The bridging ring is also included in the definition of a carbocyclic ring (for example, [2.2.2] bicyclooctane). When one or more carbon atoms are bonded to two non-adjacent carbon atoms, a bridging ring occurs. The bridge has 1 or 2 carbon atoms. It should be noted that the bridge is always The monocyclic ring is converted to a tricyclic ring. When the ring is bridged, the substituents quoted by the ring may also be present on the bridge. Also included are fused rings (for example, naphthyl and tetrahydronaphthyl) and helical rings. The term ', heterocyclic ring as used herein, means (unless otherwise stated) a stable 3, 4, 5, 6, 7, 8, 9, 10, 1 or 12 member monocyclic, bicyclic or a tricyclic ring which is saturated, unsaturated (including partially and fully unsaturated) or aromatic, and consists of a carbon atom and one or more ring heteroatoms, such as 1 or 1-2 or 1-3 or I. -4 or 1-5 or 1-6 heteroatoms independently selected from nitrogen 'oxygen and sulfur' and includes any bicyclic or tricyclic group wherein any of the heterocyclic ring defined above is fused or The second ring (for example, benzene-25-201125566 ring) is attached. The nitrogen and sulfur heteroatoms can be arbitrarily oxidized (ie, N-0 and S(0)p, where p=i or 2). When included in the ring, it is Ν or NH depending on whether it is attached to the double bond in the ring (ie, if it is necessary to maintain the trivalent number of the nitrogen atom, there is a hydrogen atom). Be replaced Unsubstituted (i.e., N or NR, wherein R is deuterium or another substituent as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom, which results in a stable structure. The heterocyclic ring described herein can be substituted on carbon or on a nitrogen atom, assuming that the resulting compound is stable. The nitrogen in the heterocyclic ring can be optionally quaternized. The bridged ring is also included in the definition of the heterocyclic ring. A bridging ring occurs when one or more atoms (ie, C, 0, Ν, or S) join two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon Atom, 2 carbon atoms, 1 nitrogen atom, 2 nitrogen atoms and a carbon-nitrogen group. When the ring is bridged, the substituents quoted by the ring may also be present on the bridge. Also included are spiral rings and fused rings. The term a-aromatic heterocyclic or ''heteroaryl" as used herein is intended to mean a stable 5, 6, 7, 8' 9, 10, 11 or 12-membered monocyclic or bicyclic aromatic ring' It consists of a carbon atom and one or more heteroatoms, for example 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. In the case of a bicyclic heterocyclic aromatic ring, only one of the two rings must be aromatic (e.g., ' 2,3 -dihydroanthracene), although both may be aromatic (e.g., 'quinoline). The second ring can be fused or bridged as defined above for the heterocycle. The nitrogen atom may be substituted or substituted (i.e., N or NR, wherein R is deuterium or other substituents as defined). The nitrogen and sulfur heteroatoms are optionally oxidized (i.e., Ν-0 and S(0)p, where p = i or 2). In a specific example of 201125566, the total number of s and 0 atoms in the aromatic heterocyclic ring does not exceed one or more. Examples of heterocyclic rings include, but are not limited to, acridinyl, azabicyclooctyl, tetrahydroindenyl, azacinyl, benzimidazolyl, benzofuranyl, benzosulfonyl Dehydrofuranyl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazole Benzomidazolinyl, benzobisoxazolyl, benzooxadiazolyl, oxazolyl, 4 aH-carbazolyl, porphyrinyl, chromanyl, chromenyl, porphyrinyl, ring Heptyl, decahydroquinolyl, dihydrobenzodioxin, 2, 6^1-1,5,2-dithiophenyl, dihydrofuro[2,3·b]tetrahydrofuran, furan Base, furazinyl, imidazolidinyl, imidazolidinyl imide, imidazolinyl, imidazolyl, imidazolidinyl, 1H-carbazolyl, indolenyl, porphyrinyl, hydrazine , fluorenyl, 3H-fluorenyl 'isatinoyl, isobenzofuranyl, isochroman, isoxazolyl, isoindolyl, isodecyl, isoquinolyl, Isothiazolyl, iso-B-decyl, methyldioxyphenyl Methylbenzotrimethyl, methylfuranyl, methylimidazolyl, methylthiazolyl, morpholinyl, naphthyridinyl, octahydroisophyllinyl, Doxadiyl, 1,2,3 - chewed scorpion, 1,2,4 - chewed two D-sodium ' 1, 2,5-oxadiazolyl, 1,3,4-oxadiazolyl'oxazolidinyl, oxazolidinone Base, oxazolyl, hydroxydecyl, phenanthryl, morpholinyl, morphine, thioxanthyl, phenothiaphthyl, morphyl, sulfhydryl, phenanthrenyl, hydrazine Keto group, piperazine, piperhenidone, 4-deoxydextrin, piperonyl, pterene, thiol, phenanthyl, phenanthyl, pyridinium, pyridoxine Base, shame π-sitting, towering; base, steep and noisy thiol, pyridinium and imipenyl, pubic stilbenylthiophene, fluorene steep -27- 201125566 (pyridinyl), pyridone, Pyridyl, pyrimidinyl, pyrrolidone, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, 2 Η-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4 Η-quinolinium Base, quinoxaline, quinuclidinyl, tetrahydrofuranyl, tetrahydroisophyllinyl, tetrahydrosallinyl, tetrazole , 6Η-1,2,5-thiadipine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 4-thiadiazolyl, thienyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thiomorpholinyldioxaridinyl, tridecyl , triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and dibenzo Piperidyl. As used herein, the term "pharmaceutically acceptable" means that it is suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications. A reasonable benefit/risk ratio of such compounds, materials, compositions, carriers, and/or dosage forms. As used herein, "pharmaceutically acceptable salts are derivatives of the disclosed compounds, wherein the parent compound It is modified by making it an acid or a base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; bases of acidic residues or An organic salt such as a carboxylic acid; and the like. The pharmaceutically acceptable salt includes, for example, a conventional non-toxic salt or a quaternary salt of a parent compound formed from a non-toxic inorganic or organic acid. For example, such conventional Non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-ethoxyethoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid. Benzene sulfonate 28 - 201125566 acid, benzoic acid, dicarbonic acid, carbonic acid, citric acid, ethylenediaminetetraethane disulfonic acid, ethanesulfonic acid, fumaric acid, grape heptanoic acid, hydrochloric acid, glutamic acid, Glycolic acid 'ethylene glycol to benzoic acid, hexyl benzene, hydrabamic, hydrobromic acid, hydrochloric acid, hydroiodic acid maleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid , lactanoic acid sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid (napsylic) 'nitric acid' oxalic acid, pamoic acid, pantothenic acid, benzene, phosphoric acid, polygalacturic acid, propionic acid , salicylic acid, stearic acid, subacetic, succinic acid, amine acid, alanine, sulfuric acid, tartaric acid and toluenesulfonic acid. The pharmaceutically acceptable salts of the present invention may be derived from alkaline or Acidic parent compounds are synthesized by conventional chemical methods. These salts are prepared by reacting the free acid or base form of the compound with a suitable amount of a suitable acid in water or an organic solvent or a mixture of the two. Preferred as non-aqueous medium, such as ether, ethyl acetate, ethanol, isoacetonitrile. Suitable salts Found in Remington's Pharma < Sciences, 18 th e d., Mack Publishing Company, PA, USA, p. 1 44 5 (1990). Because prodrugs are known to enhance many of the desired qualities of the agent (examples, Bioavailability, manufacture, etc., so that the compound of the present invention is delivered in a pharmaceutical form. Therefore, the present invention is intended to cover the prodrugs currently claimed, the methods of delivering the prodrugs, and the compositions containing the prodrugs. a carrier for releasing the active parent drug of the present invention in the living body when the prodrug is administered to the mammal. The acid, glucosinolate, hydroxy, laurel, naphthalene sulfoacetate of the present invention Alkaloids of the tannic acid moiety often used; or propionol or: eutica I Easton, eg, prodrug-producing drug prodrugs -29- 201125566 by modifying the presence in the compound The functional groups are prepared in such a way that the modifications are routinely manipulated or cleaved in vivo into the parent compound. Prodrugs include compounds of the invention wherein a hydroxy, amine or thiol group is bonded to any group, and when a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amine group, or a free Hydrogenthio group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. As used herein, a stable compound "stable structure" is a compound having sufficient strength to be separated from the reaction mixture into a useful purity and formulated into an effective therapeutic agent. The term "patient" as used herein refers to a human or animal (in the case of an animal, more typically a mammal) subject that may be subjected to a surgical or invasive medical procedure. Due to surgical procedures or invasive medical procedures, it may be considered that such patients or subjects have a need to reduce the risk of infection or prevent infection. Such patients or subjects may also be considered to be in need of prevention during surgery. The term A treatment as used herein means providing a therapeutic intervention to heal or improve the infection. The term "prevention" as used herein means completely or almost completely stopping the occurrence of an infection, such as when the patient or subject is susceptible to infection or at risk of exposure to infection. Prevention can also include inhibition, which is to prevent infection from occurring. The term "reducing risk" as used herein means reducing the likelihood or likelihood that an infection will occur', e.g., when the patient or subject is susceptible to infection or is at risk of being exposed to the infection. As used herein, unsaturated oxime refers to a compound having at least one degree of unsaturation 8-30 to 201125566 (e.g., at least one multiple bond) and includes partially and fully unsaturated compounds. The term "effective amount" as used herein refers to a compound or combination of compounds of the invention that is effective when administered as an antimicrobial agent, alone or in combination. For example, an effective amount refers to a composition that is administered to a subject or subject sufficient to elicit biological activity (eg, anti-infective activity, such as antimicrobial activity 'antibacterial, antifungal, antiviral, or antiparasitic activity'). The amount of compound present in the formulation or on the medical device. The term "prophylactically effective amount" is meant to mean an effective amount of a compound or compound of the invention administered to prevent infection or reduce the risk of a surgical procedure or an invasive medical procedure. It should be further understood that the expression of 'v hydrogen bond acceptor-hydrogen bond acceptor-hydrogen bond donor 〃 and hydrogen bond acceptor hydrogen bond acceptor-hydrogen bond acceptor 表明 means hydrogen bond acceptor and donor body Relative positioning does not mean that these groups are directly linked together, and it is contemplated that additional atoms or groups of atoms may be included between the groups. In the specification, the singular forms also include the plural, unless There are other clear assignments. All technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined. In case of conflict, the description of the present invention will be made. As used herein, 'mammalian mites are human and non-human patients. The term "therapeutically effective amount" as used herein means sufficient to induce biological activity (eg, antimicrobial activity, antifungal activity 'antiviral activity, antiparasitic activity, antidiarrheal activity, and/or antiproliferative activity). Amounts - 31 - 201125566 are compounds or combinations of compounds of the invention in or on the recipient. The combination of compounds is preferably a synergistic composition. Co-multiplicative occurs when the compound effect when administered in combination is greater than the compound addition effect when administered alone as a single agent, as by, for example, Chou and Talalay, Adv. Enzyme Regul. ν〇1·22, Proced in pp. 27-55 (1 984). The synergistic effect is most clearly demonstrated at suboptimal concentrations of the compound. The synergistic effect can be at a lower cytotoxicity or an increased anti-proliferative effect or some other advantageous combined effect compared to each component. The term w RNA microhelical binding position 如 as used herein refers to the location of the ribose function of the large ribosome subunit occupied by the RN A microhelix of Formula III. The RNA microhelical binding position defines an overlap of at least a portion of the E-position. The term > A-position 〃 as used herein refers to the location of the ribofunction occupied by the amine thiol-tRNA molecule immediately prior to its participation in the peptide bond formation reaction. The term % E-position 〃 as used herein refers to It participates in the peptide bond formation reaction and is home to the ribose function occupied by the deuterated tRNA molecule. The term "P-position" as used herein refers to the locus of ribo functions occupied by peptidyl-tRNA while participating in the peptide bond formation reaction. The term "A-space 〃 as used herein refers to a portion of the A-position of the amino acid moiety of the amine deuterated-tRNA in the peptidyl transferase center, or another selection refers to the combination of linozide A portion of the A-position of the oxazolidinone ring. It is to be understood that as used herein and with respect to ribosome or ribosome subunits, the term ', part of 〃 or a part of a steric structure is meant to be by ribosome or ribose. At least 3, more preferably at least 3 to 10 ', and optimally at least 1 胺 amino acid residues and/or nucleotide residues formed by the ribosome or ribosome subunit Part of the structure, including charge distribution and hydrophilic/hydrophobic characteristics. The residue forming this portion may be, for example, (i) a contiguous portion of a ribosome or ribosome subunit formed by a contiguous residue '(Π) based on, for example, the first sequence of ribosomal RN A or ribosomal protein. a residue, or (c) a combination thereof. It should be understood that the term ', a part of 〃 or '•, a part of a steric structure as used herein and with respect to the RN A microhelix, means at least 3, or preferably at least 3, of one or more core residues of the formula 更A portion of the three-dimensional structure of the RNA microhelix formed by 3 to 10 atoms, including charge distribution and hydrophilic/hydrophobic characteristics. The atom forming this portion may be, for example, (i) a solvent inaccessible atom buried in the core of the RNA microhelix, (ii) a solvent accessible atom of the RNA microhelix, or (iii) a combination thereof. All percentages and ratios used herein are by weight unless otherwise indicated. Throughout the description, when the composition is described as having, including or comprising a particular component, or when the method is described as having, including or comprising a particular method step, the composition of the invention is expected to be substantially or by reference. The components are composed of, and the method of the invention consists essentially of or consists of the processing steps recited. Further, it should be understood that the order of the steps or the order in which the specific actions are performed is not critical as long as the present invention remains operable. Moreover, two or more steps or functions can be performed simultaneously. -33- 201125566 2. Compounds of the Invention In one aspect, the invention relates to compounds having the structure:

E——F 其中爲選自下式之化學部分E——F where is the chemical part selected from the following formula

其中 u 係選自 CR3R3 ' Ο、NR4 或 S(0)n、C = 0、C = NOR3 ，另一選擇地兩個R3 —起形成羰基， V係獨立選自-CR4a-或-N-; 其中vg)代表稠合之5至7員飽和、不飽和或芳族碳環或雜環系環系統； W爲O'NRhNOR1或S’另一選擇地w =係選自與相同的碳原子連接之HO -與H·二者之組合或與相同的碳原子連接之（C^8烷基）0-與H-二者之組合；代表單鍵或雙鍵，使得當X二二Y爲單鍵時，則X係選自0、NR2及S(0)n且Υ爲C-R3 ’而當X二二γ爲雙鍵時 ’則X爲N且Y爲碳原子， z係選自0、NR4或S(0)n， ⑧ -34- 201125566 R1係選自Η R2係選自Η R3係選自Η R4係選自Η R4a係選自Η η爲0、1或另一選擇地，及C 1 - 8院基1 及C I - 8院基’ 及C | - 8院基’ 及Ci.8烷基，及C 1 - 8院基’ 2， -G-H-J係選自下式：Wherein u is selected from the group consisting of CR3R3 'Ο, NR4 or S(0)n, C=0, C=NOR3, and alternatively two R3 together form a carbonyl group, and V is independently selected from -CR4a- or -N-; Wherein vg) represents a fused 5- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system; W is O'NRhNOR1 or S', alternatively w= is selected from the same carbon atom a combination of HO - and H · or a combination of (C 8 alkyl) 0- and H- linked to the same carbon atom; represents a single bond or a double bond, such that when X 2 Y is a single When the bond is selected, X is selected from 0, NR2 and S(0)n and Υ is C-R3'. When X bis is γ is double bond, then X is N and Y is a carbon atom, and z is selected from 0. NR4 or S(0)n, 8 -34- 201125566 R1 is selected from Η R2 is selected from Η R3 is selected from Η R4 is selected from Η R4a is selected from Η η is 0, 1 or alternatively. And C 1 - 8 yard base 1 and CI-8 yard base 'and C | - 8 yard base' and Ci.8 alkyl, and C 1-8 yard base ' 2, -GHJ are selected from the following formula:

其中Rx係選爲C或CH OCH3取代；，其中Ra及 J係選自 NHC( = 0)CH3 NHC( = NH)H 其中η爲0、另一選擇地，自 CH2、NH、院，各自獨立以一或多個或Rx、Ry及Rz各自獨 Rb —起形成C3.5碳環； NH2、NHCCm 烷基）、 NHC( = 0)NH2 、 1或2 ; -G-H-J係選自：基）、S或Ο ; Ry及Rz F、CH3、CF3、OH 及立選自CH2或CRaRb 、N(C丨-8烷基）2 、 NHC( = NH)NH2 、Wherein Rx is selected as C or CH OCH3 substituted; wherein Ra and J are selected from NCC(=0)CH3 NHC(=NH)H wherein η is 0, alternatively, from CH2, NH, and are independent Forming a C3.5 carbocyclic ring by one or more of Rx, Ry and Rz, respectively; R2, NH2, NHCCm alkyl), NHC(=0)NH2, 1 or 2; -GHJ is selected from: S or Ο; Ry and Rz F, CH3, CF3, OH and are selected from CH2 or CRaRb, N(C丨-8 alkyl)2, NHC(=NH)NH2,

其中Rx係選自 CH2、NH、N(Ch8 烷基）、S或0 ; R z爲以 -35- 201125566 一或多個CH3取代之C或CH，或1爲CRaRb，其中Ra 及Rb —起形成C3.5碳環；其中m爲1、2或3 ; J 係選自 NH2、NH(C,.8 烷基）、N(Cl.8 烷基）2、 NHC( = 0)CH3 ' NHC( = 〇)NH2 ' NHC( = NH)NH2 ' NHC( = NH)H ； C-B-A-、-D-E-F及- G- H- J爲化學部分，其中 A、D及G係獨立選自： (a)單鍵，（b)-(C 丨·8 烷基）-，（c)-(c2.8 烯基）-， (d)-(C2-8炔基）·，其中 i) 前文（b)-(d)中任一者中的0-4個碳原子隨意地以選自-0-、-S(〇)p、-NR6-、-(C = 0)·、-S(0)pNR6·、-nr6s(〇)p 及-NR6S(〇)pNR6-之部分代替， ii) 前文（b)-(d)中任一者隨意地以一或多個R5基團取代，及 iii)前文（b)-(d)中任一者隨意地以-(Cu烷基）-R5 基團取代； (e)-〇- ’ （f)-NR6-，（g)-s(0)p-，（h)-C(O)-，⑴- C(0)0- , (j).〇C(〇). . (k)-0C(0)0- > (1)-C(0)NR6- > (m)- NK L〇· ’ (n)-NR6C(0)NR6- ’ (o)-C( = NR6)- ’ (p)- C( = NR6)〇- ’ (q).〇c( = NR6)-，(r)-C( = NR6)NR6-，(s)-NR6C( = NR6).，(t)-C( = S)-，(u)-C( = S)NR6-，（v)-NR6C( = S)- . (w)-C(0)S- > (x)-SC(O)- > (y)-0C( = S)- - (z)-C( = S)〇. , (aa)-NR6(CNR6)NR6- > (bb)-CR6R6C(0)- > (cc)- 201125566 C(0)NR6(CR6R6)t-，（dd)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，口 _i 4員飽和、不飽和或芳族碳環，及（ffXCRl6；^，其中（dd)或（ee)隨意地以一或多個R5基團取代； B、 E及Η係獨立選自： (a) 單鍵， (b) 含有一或多個選自氮、氧及硫之雜原子的3_i4員飽和、不飽和或芳族雜環， (c) 3-14員飽和、不飽和或芳族碳環，其中（b)或（c)隨思地以一或多個R5基團取代； (dHCu 烷基）-’（e)_(C2 8 烯基）·，（f)_(C2 8 炔基）_，其中 i)前文（d)-(f)中任一者中的〇_4個碳原子隨意地以選自-0-、-S(〇)p、-nr6-、-(c = 0)-、-C( = NR6)-、- S(0)pNR6-、-NR6S(〇)p-及·ΝΚ63(〇)ρΝΙι6_ 之部分代替， Π)前文（d)-(f)中任一者隨意地以—或多個r5基團取代，及 iii)前文（d)-(f)中任一者隨意地以_(Cl_8烷基）_R5 基團取代；及（g)，（CR6R6)t-， C、 F及J係獨立選自： (a)氫 ’（c)F ’（d)Cl，（e)Br，（f)I，（g)-CF3，（h)-CN ，（i)-N3，（j)-N〇2，(k)-NR6(CR6R6)tR8 ' (l)-〇R8，(m)-S(0)p(CR6R6)tR8 ， (n)-C(0)(CR6R6),R8 ， (〇)- -37- 201125566 0C(0)(CR6R6)tR8 > (p)-SC(0)(CR6R6)tR8 > (q)- C(0)0(CR6R6)tR8 ， (r)-NR6C(0)(CR6R6)tR8 ， (s)- C(0)NR6(CR6R6),R8 ， (t)-C( = NR6)(CR6R6)«R8 · (u)· C( = NNR6R6)(CR6R6)tR8，(v)-C (= NNR6C (O)R6) (CR6R6)tR8 ’（w)-C( = NOR8)(CR6R6)tR8，（x)_NR6C(0)0(CR6R6)tR8， (y)-0C(0)NR6(CR6R6)tR8 , (z)-NR6C(0)NR6(CR6R6),R8 · (aa)-NR6S(0)p(CR6R6)tR8 , (b b) - S (0) PN R6 (C R6R6), R8 > (cc)-NR6S(0)pNR6(CR6R6),r8 , (dd)-NR6R8 ， (ee)- NR6(CR6R6)R8 > (ff)-OH - (gg)-NR8R8 - (hh)-OCH3 > (ii)-S(0)pR8 - (jj)-NC(0)R8 - (kk)-NR6C(NR6)NR6R8 - (11)C,.8 垸基，（mm)C2-8嫌基’（nn)C2-8诀基’（oo)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’（pp)3-14員飽和、不飽和或芳族碳環，（qq)_ (CR6R6)tNR6(CR6R6)tR8，(rr)-N[(CR6R6)tR8][C = 0(CR6R6 )tR8]，(ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8]，(tt)-(CR6R6)tNR6(C = 0)(CR6R6)tR8 , (uu)-鹵烷基，（〇)- C(0)(CR6)[(CR6R6)tR8]R8 ’ (ww)-(CR6R6)tC(0)NR8R8 » (xx)-(CR R )tC (0)0(CR6R6)tR8 > (yy)-NR6C(〇)CR8R8R8 » (zz)-N[(CR6R6)tR8]C(0)R8，及（aaa)_s(〇)pNR8R8 ; 其中（11)至（PP)隨意地以一或多個R7基團取代； R5 係選自（a)氫，（b)F’（c)Cl’（d)Br，（e)I，（f)-CF3，（g)· CN ’ (h)-N3 ' (i)-N02 > (j) -NR6R6 , (k)-〇R8 · (1). NR6(CNR6)NR6R6,（nO-Cn 院基，（n)_u 基，（〇)_Ci i 炔基’（PhiC!·8院基）-(含有一或多個選自氮、氧及硫之雜 -38· 201125566 原子的3-14員飽和、不飽和或芳族雜環），（9)-((^.8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)_鹵烷基，（s)_ SR6，（t)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及（u)3-14員飽和、不飽和或芳族碳環；另一選擇地兩個R5基團一起形成碳環，其中（m)至（〇及⑴至（u)隨意地以一或多個R8取代； R6係選自（a)氫’（bhCu烷基，或另一選擇地兩個R6基團一起形成碳環’（c) -鹵烷基，（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (e) 3 - 1 4員飽和、不飽和或芳族碳環；其中（b)至（e)隨意地以一或多個r8取代； R7 係選自（a)気 ’（b)F’（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN，（h)-N3 > (i)-N02，(j)-NR6R6，(k)-OR6 , (1)- NR6(CNR6)NR6R6 ’（n^-Cu 院基，（n)-Cl 8 稀基，（〇)_Cu8 炔基’（P)-(C ,-8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Ci 8烷基 )-(3-14員飽和、不飽和或芳族碳環），（〇_鹵烷基，（s)_ NR R 1 (t)-OR8 » (u)-(CR6R6)tNR6R8 , (V)-CR6R8R8 ( (w)-5116’（\)含有一或多個選自氮、氧及硫之雜原子的3_14 貝飽和、不飽和或芳族雜環，（y)3_14員飽和、不飽和或 NR C(0)NR R ，（cc)_nr6C(0)R6，及（dd) c( = NR6)NR6R6 ♦ 其中（m)至（q)及（x)至（y)隨意地以〜或多個R9取代； -39- 201125566 R8 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)_CF3，（g)-CN，(h)-N3，(i)-N02，（j)-NR6R9，（k)-OR9，（1)-NR6(CNR6)NR6R6，（nO-Cu 烷基，（tO-C】.8 烯基，（〇)-(：,.8 炔基，（P)-(Ci_8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’（s)3-14員飽和、不飽和或芳族碳環，（t)-鹵烷基， (u)-C(0)(CR6R6)tR9，（v)-SR6，（w)-〇C(0)(CR6R6)tR9， (x)-NR6C(0)NR6R9 - (y)-NR6C(0)R9 ， (z)-NR6(CNR9)( NR6R6) . (aa)-ONR6(CNR6)NR6R6 > (bb)-C( = NR9)NR6R6 -(cc)-S(0)pR9，（dd)-(CR6R6)tC(0)NR6R9， (ee)-(CR6R6)tOR9，及（ff)-(CR6R6)tNR6R9 ; 其中（m)至（s)隨意地以一或多個R9取代； r9 係選自（a)氫 ’（b)F，（c)Cl，（d)Br，（e)I，（f)_CF3，（g)_ CN ’ (h)-N3 > (i)-N02 . (j)-NR6R10 . (k)-〇R6 . (1). NR6(CNR6)NR6R6,（m)-C(0)(CR6R6)tNR6R6,（n)_Ci 8 烷基 ’（〇)-C|-8嫌基’（p)-Ci-8炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (03-14員飽和、不飽和或芳族碳環，（s)_鹵院基，（t)_ (CR6R6)t〇R6 , (u)-0(CR6R6)tNR6R10 > (v)-C(〇)R6 , (w). SR6 ’（^o-cucoor1。’（y)-S(〇)pR6 ’（z)_(Ci 8 烷基）（含有 ~或多個選自氮、氧及硫之雜原子的3·14員飽和、不飽和或方族雜環），（a a)-(Cm烷基）-(3-14員飽和、不飽和或 -40- 201125566 芳族碳環）’（bb)-0(CR6R6)t0R6 ’（cc)-C(=NR6)NR6R6， (dd)-ONR6R6 - (ee)-NR6C(0)NR6R6 > (f f) - 0 ( C R6 R6), 0 R6 , (gg)-NR6C(0)R6，及（hh)-(CR6R6)tNR6R10 ; 其中（n)至（r)及（z)至（aa)隨意地以一或多個R1Q取代； R10 係選自（a)氫 ’（b)F ’（c)Cl ’（d)Br，（e)I，（f)-CF3， (g)-CN，（h)-N3，（i)-N02，⑴-NR6R6，（k)-OR6，⑴-NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（n)-C 丨·8 烷基，（o)-Ci-8燃基，（p)-Ci.8炔基，（q)含有一或多個選自氣、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (03-14員飽和、不飽和或芳族碳環，（s)-鹵烷基，⑴_ (CR6R6)t〇R6 > (u)-0(CR6R6)tNR6R6 > (v)-C(0)R6 - (w)-SR6 ，（x)-C(0)0R6 ’（y)-S(0)pR6 ’（^-(Cu 烷基）-(含有—或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（aaXC,.8烷基）-(3-14員飽和、不飽和或芳族碳環），（1^)-0(〇116116)10116，（“）-(：( = \116"116116,(刊）-ONR6R6 > (ee)-NR6C(0)NR6R6 - (f f) - 0 (C R6 R6), 0 R6 , (gg). NR6C(0)R6，及（hh)-(CR6R6)tNR6R6; 隨意地，其中基團- D- E- F或基團- G- H- J不存在，但是.D_ E-F及- G-H-J二者不同時不存在； p爲0、1或2 ;及 t 爲 0、1、2 或 3，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中進一·步· -41 - 201125566 包含氫鍵施體部分或額外的氫鍵受體部分。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、醋、互變異構物或前藥，其中医〕爲包含至少兩個氫鍵受體部分及至少一個氫鍵施體部分之化學部分。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽'酯、互變異構物或前藥，其中氫鍵受體部分及氫鍵施體部分係呈氫鍵受體-氫鍵受體-氫鍵施體之定向。如上述所使用之術語 >呈定向"不意謂氫鍵施體或受體部分必然直接連接在一起，因爲可以有其他干預原子或原子之基團在氫鍵施體或受體部分之間。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中氫鍵受體部分彼此係在5埃之內及氫鍵施體部分係在氫鍵受體部分的 5埃之內。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中氫鍵受體部分彼此係在3埃之內及氫鍵施體部分係在氫鍵受體部分的 3埃之內。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中氫鍵受體部分係包含於環結構內，其中該環結構爲單環結構或稠合之多環結構。在一些具體例中，本發明係關於一種化合物或其醫藥 -42- 201125566 上可接受之鹽、酯、互變異構物或前藥’其中ΡΠ爲包含至少三個氫鍵受體部分之化學部分。在一些具體例中’本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥’其中氫鍵受體部分係呈氫鍵受體-氫鍵受體-氫鍵受體之定向。如上述所使用之術語"呈定向〃不意謂氫鍵施體或受體部分必然直接連接在一起，因爲可以有其他干預原子或原子之基團在氫鍵受體部分之間。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中各氫鍵受體部分係在至少一個其他的氫鍵受體部分的約5埃之內。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中各氫鍵受體部分係在至少一個其他的氫鍵受體部分的約3埃之內。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中氫鍵受體部分中之至少二者係包含於環結構內，其中該環結構爲單環結構或稠合之多環結構。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中該氫鍵受體部分係獨立選自羰基、硫代羰基、亞胺基、經烷基取代之亞胺基、亞颯基、颯基、肟基、經烷基取代之肟基、腙基、經單烷基或二烷基取代之腙基、氧醚（-〇-)基、硫化物 ’亦稱爲硫醚基（-S-)、羥基、烷氧基、胺基、經單烷基或 -43- 201125566 二烷基取代之胺基及硝基。在一些具體例中’本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中該氫鍵施體部分係選自羥基、硫醇基、胺基及經單取代之胺基。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中|□包含下式之結構部分：Wherein Rx is selected from the group consisting of CH2, NH, N(Ch8 alkyl), S or 0; Rz is C or CH substituted with -35-201125566 one or more CH3, or 1 is CRaRb, wherein Ra and Rb are together Forming a C3.5 carbocyclic ring; wherein m is 1, 2 or 3; J is selected from the group consisting of NH2, NH(C, .8 alkyl), N(Cl.8 alkyl) 2, NHC(=0)CH3 'NHC ( = 〇) NH2 ' NHC( = NH)NH2 ' NHC( = NH)H ; CBA-, -DEF and - G- H- J are chemical moieties, of which A, D and G are independently selected from: (a) Single bond, (b)-(C 丨·8 alkyl)-, (c)-(c2.8 alkenyl)-, (d)-(C2-8 alkynyl)·, where i) (b) 0-4 carbon atoms in any of -(d) are optionally selected from -0-, -S(〇)p, -NR6-, -(C=0)·, -S(0)pNR6 -, -nr6s(〇)p and -NR6S(〇)pNR6- are replaced by a part, ii) any of the foregoing (b)-(d) is optionally substituted with one or more R5 groups, and iii) Any one of (b)-(d) is optionally substituted with a -(Cualkyl)-R5 group; (e)-〇- ' (f)-NR6-, (g)-s(0)p- , (h)-C(O)-, (1)- C(0)0-, (j).〇C(〇). . (k)-0C(0)0- > (1)-C(0 )NR6- > (m)- NK L〇· ' (n)-NR6C(0)NR6- ' (o)-C( = NR6)- ' (p)- C( = NR6)〇- ' (q).〇c( = NR6)-, (r)-C( = NR6)NR6-,(s)-NR6C( = NR6).,(t)-C( = S)-, (u)-C(=S)NR6-, (v)-NR6C(=S)- . (w)-C(0)S- > (x)-SC(O)- > (y)-0C( = S)- - (z)-C( = S)〇. , (aa)-NR6(CNR6)NR6- > (bb)-CR6R6C(0)- > (cc)- 201125566 C(0)NR6(CR6R6)t-, (dd) a 3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, port _i 4 members a saturated, unsaturated or aromatic carbocyclic ring, and (ffXCRl6; ^, wherein (dd) or (ee) is optionally substituted with one or more R5 groups; B, E and anthracene are independently selected from: (a) a bond, (b) a 3- to 4-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, (c) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring, Wherein (b) or (c) is optionally substituted with one or more R5 groups; (dHCu alkyl)-'(e)_(C2 8 alkenyl)·, (f)_(C2 8 alkynyl) _, wherein i) 〇_4 carbon atoms in any of the foregoing (d)-(f) are optionally selected from -0-, -S(〇)p, -nr6-, -(c = 0 )-, -C( = NR6)-, - S(0)pNR6-, -NR6S(〇)p- and Substituting ΝΚ63(〇)ρΝΙι6_, Π) Any of the foregoing (d)-(f) is optionally substituted with — or a plurality of r5 groups, and iii) any of the foregoing (d)-(f) Optionally substituted with a _(Cl_8 alkyl)-R5 group; and (g), (CR6R6)t-, C, F and J are independently selected from: (a) hydrogen '(c)F '(d)Cl, (e) Br, (f) I, (g)-CF3, (h)-CN, (i)-N3, (j)-N〇2, (k)-NR6(CR6R6)tR8 ' (l)- 〇R8,(m)-S(0)p(CR6R6)tR8 , (n)-C(0)(CR6R6),R8 , (〇)- -37- 201125566 0C(0)(CR6R6)tR8 > ( p)-SC(0)(CR6R6)tR8 > (q)- C(0)0(CR6R6)tR8 , (r)-NR6C(0)(CR6R6)tR8 , (s)- C(0)NR6( CR6R6), R8, (t)-C( = NR6)(CR6R6)«R8 · (u)· C( = NNR6R6)(CR6R6)tR8,(v)-C (= NNR6C (O)R6) (CR6R6) tR8 '(w)-C( = NOR8)(CR6R6)tR8,(x)_NR6C(0)0(CR6R6)tR8, (y)-0C(0)NR6(CR6R6)tR8 , (z)-NR6C(0 ) NR6(CR6R6), R8 · (aa)-NR6S(0)p(CR6R6)tR8 , (bb) - S (0) PN R6 (C R6R6), R8 > (cc)-NR6S(0)pNR6( CR6R6), r8, (dd)-NR6R8, (ee)- NR6(CR6R6)R8 > (ff)-OH - (gg)-NR8R8 - (hh)-OCH3 > (ii)-S(0)pR8 - (jj)-NC(0)R8 - (kk)-NR6C(NR6)NR6R8 - (11) C,.8 fluorenyl, (mm) C2-8 nickyl '(nn)C2-8 fluorenyl' (oo) contains one or more heteroatoms selected from nitrogen, oxygen and sulfur 3-14 a saturated, unsaturated or aromatic heterocyclic ring '(pp) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (qq)_(CR6R6)tNR6(CR6R6)tR8,(rr)-N[(CR6R6) tR8][C = 0(CR6R6 )tR8],(ss)-(CR6R6)tN[(CR6R6)tR8][(CR6R6)tR8],(tt)-(CR6R6)tNR6(C = 0)(CR6R6)tR8 , (uu)-haloalkyl, (〇)- C(0)(CR6)[(CR6R6)tR8]R8 ' (ww)-(CR6R6)tC(0)NR8R8 » (xx)-(CR R )tC (0)0(CR6R6)tR8 > (yy)-NR6C(〇)CR8R8R8 » (zz)-N[(CR6R6)tR8]C(0)R8, and (aaa)_s(〇)pNR8R8; where (11 To (PP) optionally substituted with one or more R7 groups; R5 is selected from (a) hydrogen, (b) F'(c)Cl'(d)Br, (e)I, (f)- CF3,(g)· CN ' (h)-N3 ' (i)-N02 > (j) -NR6R6 , (k)-〇R8 · (1). NR6(CNR6)NR6R6,(nO-Cn , (n)_u base, (〇)_Ci i alkynyl' (PhiC!·8 yard base)-(containing one or more selected from nitrogen, oxygen and sulfur -38· 201125566 atomic 3-14 member saturation , unsaturated or aromatic heterocyclic ring), (9)-((^.8 alkyl)-(3-14 member saturation Unsaturated or aromatic carbocyclic ring), (r)-haloalkyl, (s)_SR6, (t) 3-14 member saturated or unsaturated containing one or more heteroatoms selected from nitrogen, oxygen and sulfur Or an aromatic heterocyclic ring, and (u) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring; alternatively another two R5 groups are taken together to form a carbocyclic ring, wherein (m) to (〇 and (1) to (u Optionally substituted with one or more R8; R6 is selected from (a) hydrogen' (bhCu alkyl, or alternatively two R6 groups together form a carbocyclic ring '(c)-haloalkyl, (d a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (e) 3 - 14 membered saturated, unsaturated or aromatic carbocyclic ring; Wherein (b) to (e) are optionally substituted with one or more r8; R7 is selected from (a) 気'(b)F'(c)Cl, (d)Br, (e)I, (f) -CF3, (g)-CN, (h)-N3 > (i)-N02, (j)-NR6R6, (k)-OR6, (1)-NR6(CNR6)NR6R6 '(n^-Cu Base, (n)-Cl 8 dilute, (〇)_Cu8 alkynyl '(P)-(C ,-8 alkyl)-(3- containing one or more heteroatoms selected from nitrogen, oxygen and sulfur 14 members of saturated, unsaturated or aromatic heterocyclic rings), q) _(Ci 8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (〇_haloalkyl, (s)_NR R 1 (t)-OR8 » (u)- (CR6R6)tNR6R8, (V)-CR6R8R8 ((w)-5116'(\) a saturated or unsaturated or aromatic heterocyclic ring containing 3 or 14 shells of one or more heteroatoms selected from nitrogen, oxygen and sulfur, (y) 3_14 member saturated, unsaturated or NR C(0)NR R , (cc)_nr6C(0)R6, and (dd) c( = NR6)NR6R6 ♦ where (m) to (q) and (x) to ( y) optionally substituted with ~ or more R9; -39- 201125566 R8 is selected from (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f)_CF3, (g)-CN, (h)-N3, (i)-N02, (j)-NR6R9, (k)-OR9, (1)-NR6(CNR6)NR6R6, (nO-Cu alkyl, (tO-) C].8 alkenyl, (〇)-(:, .8 alkynyl, (P)-(Ci_8 alkyl)- (3-14 members containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) a saturated, unsaturated or aromatic heterocyclic ring), an alkyl group - (3-14 membered saturated, unsaturated or aromatic carbocyclic ring), (r) containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 3-14 member saturated, unsaturated or aromatic heterocyclic ring '(s) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (t)-halogen Base, (u)-C(0)(CR6R6)tR9,(v)-SR6,(w)-〇C(0)(CR6R6)tR9, (x)-NR6C(0)NR6R9 - (y)-NR6C (0) R9 , (z)-NR6(CNR9)( NR6R6) . (aa)-ONR6(CNR6)NR6R6 > (bb)-C( = NR9)NR6R6 -(cc)-S(0)pR9,( Dd)-(CR6R6)tC(0)NR6R9, (ee)-(CR6R6)tOR9, and (ff)-(CR6R6)tNR6R9; wherein (m) to (s) are optionally substituted with one or more R9; r9 Is selected from (a) hydrogen '(b)F, (c)Cl, (d)Br, (e)I, (f)_CF3, (g)_CN ' (h)-N3 > (i)- N02 . (j)-NR6R10 . (k)-〇R6 . (1). NR6(CNR6)NR6R6,(m)-C(0)(CR6R6)tNR6R6,(n)_Ci 8 alkyl '(〇)- C|-8 stimulant '(p)-Ci-8 alkynyl, (q) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (03-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)_halogen compound, (t)_(CR6R6)t〇R6, (u)-0(CR6R6)tNR6R10 > (v)-C (〇) R6, (w). SR6 '(^o-cucoor1. '(y)-S(〇)pR6 '(z)_(Ci 8 alkyl) (3,14-membered saturated, unsaturated or aromatic complex containing ~ or more heteroatoms selected from nitrogen, oxygen and sulfur Ring), (aa)-(Cm alkyl)-(3-14 member saturated, unsaturated or -40-201125566 aromatic carbocyclic ring) '(bb)-0(CR6R6)t0R6 '(cc)-C(= NR6)NR6R6, (dd)-ONR6R6 - (ee)-NR6C(0)NR6R6 > (ff) - 0 ( C R6 R6), 0 R6 , (gg)-NR6C(0)R6, and (hh)- (CR6R6)tNR6R10; wherein (n) to (r) and (z) to (aa) are optionally substituted with one or more R1Q; R10 is selected from (a) hydrogen '(b)F '(c)Cl ' (d) Br, (e) I, (f)-CF3, (g)-CN, (h)-N3, (i)-N02, (1)-NR6R6, (k)-OR6, (1)-NR6 (CNR6) NR6R6, (m)-C(0)(CR6R6)tNR6R6, (n)-C 丨·8 alkyl, (o)-Ci-8 aldehyde, (p)-Ci.8 alkynyl, (q) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring selected from one or more of heteroatoms of gas, oxygen and sulfur, (03-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkane Base, (1)_(CR6R6)t〇R6 > (u)-0(CR6R6)tNR6R6 > (v)-C(0)R6 - (w)-SR6 ,(x)-C(0)0R6 '(y )-S(0)pR6 '(^-(Cu alkyl)-(including a 3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring having one or more heteroatoms selected from nitrogen, oxygen and sulfur, (aaXC, .8 alkyl)-(3-14 member saturated, unsaturated or Aromatic carbon ring), (1^)-0(〇116116)10116,(")-(:( = \116"116116,(刊)-ONR6R6 > (ee)-NR6C(0)NR6R6 - (ff ) - 0 (C R6 R6), 0 R6 , (gg). NR6C(0)R6, and (hh)-(CR6R6)tNR6R6; optionally, wherein the group - D-E-F or group - G- H-J is absent, but neither .D_EF and -GHJ are not present at the same time; p is 0, 1 or 2; and t is 0, 1, 2 or 3, or a pharmaceutically acceptable salt, ester thereof, a tautomer or a prodrug. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the further comprises: -41 - 201125566 comprising hydrogen The bond donor moiety or additional hydrogen bond acceptor moiety. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, vinegar, tautomer or prodrug thereof, wherein the method comprises at least two hydrogen bond acceptor moieties and at least one hydrogen bond The chemical part of the body part. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt thereof, an ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety and the hydrogen bond donor moiety are hydrogen bond acceptors - Hydrogen bond acceptor - the orientation of the hydrogen bond donor. The term "orientation" as used above does not mean that the hydrogen bond donor or acceptor moiety is necessarily directly joined together because there may be other groups of interfering atoms or atoms between the hydrogen bond donor or acceptor moiety . In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 5 angstroms of each other and the hydrogen bond donor moiety It is within 5 angstroms of the hydrogen bond acceptor moiety. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is within 3 angstroms of each other and the hydrogen bond donor moiety It is within 3 angstroms of the hydrogen bond acceptor moiety. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is contained within a ring structure, wherein the ring structure is a single Ring structure or fused multi-ring structure. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the oxime is a chemical moiety comprising at least three hydrogen bond acceptor moieties . In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof wherein the hydrogen bond acceptor moiety is a hydrogen bond acceptor-hydrogen bond acceptor-hydrogen The orientation of the bond receptor. The term "orientation" as used above does not mean that the hydrogen bond donor or acceptor moiety is necessarily directly joined together because there may be other groups of interfering atoms or atoms between the hydrogen bond acceptor moieties. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein each hydrogen bond acceptor moiety is attached to at least one other hydrogen bond acceptor moiety Within about 5 angstroms. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein each hydrogen bond acceptor moiety is attached to at least one other hydrogen bond acceptor moiety Within about 3 angstroms. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein at least two of the hydrogen bond acceptor moieties are contained within a ring structure, wherein The ring structure is a single ring structure or a fused multi-ring structure. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond acceptor moiety is independently selected from the group consisting of a carbonyl group, a thiocarbonyl group, and an imine Alkyl, alkyl substituted imido, fluorenylene, fluorenyl, fluorenyl, alkyl substituted fluorenyl, fluorenyl, monoalkyl or dialkyl substituted fluorenyl, oxyether (-hydrazine -) A group, a sulfide 'also known as a thioether group (-S-), a hydroxyl group, an alkoxy group, an amine group, an amine group substituted with a monoalkyl group or a -43-201125566 dialkyl group, and a nitro group. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the hydrogen bond donor moiety is selected from the group consisting of a hydroxyl group, a thiol group, an amine group, and A monosubstituted amine group. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein |□ comprises a moiety of the formula:

W爲0、NR1、NOR1或S，另一選擇地W =係選自與相同的碳原子連接之HO-與H-二者之組合或與相同的碳原子連接之（Ci.8烷基）0-與H-二者之組合； X二iY代表單鍵或雙鍵，使得當X=Y爲單鍵時，則X係選自0、NR2及S(0)n且Υ爲C-R3，而當X二二Υ爲雙鍵時，則X爲N且Y爲碳原子， Z係選自0、NR4或S(0)n， ΤΊ係選自CH或N， R1係選自Η及Cu烷基， R2係選自Η及Cu烷基， R3係.選自Η及Cu烷基， R3a係選自H及C,.8烷基，或另一選擇地兩個R3a基團一起形成羰基， R4係選自Η及Cu烷基， R“係選自Η及Cu烷基， -44- 201125566 η爲0、1或2。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中 W爲0、 NR1、NOR1 或 S。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中0¾含下式之結構部分：W is 0, NR1, NOR1 or S, and alternatively W = is selected from a combination of both HO- and H- linked to the same carbon atom or to the same carbon atom (Ci.8 alkyl) a combination of 0- and H-; X di iY represents a single bond or a double bond, such that when X=Y is a single bond, then X is selected from 0, NR2 and S(0)n and Υ is C-R3 And when X dioxin is a double bond, then X is N and Y is a carbon atom, Z is selected from 0, NR 4 or S(0) n, lanthanide is selected from CH or N, and R 1 is selected from lanthanum and Cu alkyl, R2 is selected from the group consisting of hydrazine and Cu alkyl, R3 is selected from hydrazine and Cu alkyl, R3a is selected from H and C, .8 alkyl, or alternatively two R3a groups are formed together. a carbonyl group, R4 is selected from the group consisting of hydrazine and Cu alkyl, R" is selected from the group consisting of hydrazine and Cu alkyl, and -44-201125566 η is 0, 1 or 2. In some embodiments, the invention relates to a compound or a medicament thereof An acceptable salt, ester, tautomer or prodrug wherein W is 0, NR1, NOR1 or S. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester thereof, A tautomer or prodrug, wherein 03⁄4 contains the moiety of the formula:

..L..L

其中Z係選自0、NR4或S(0)n ; R4係選自Η及Cm烷基，及 η爲0、1及2。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中〇包含下式之結構部分：Wherein Z is selected from the group consisting of 0, NR4 or S(0)n; R4 is selected from the group consisting of hydrazine and Cm alkyl, and η is 0, 1 and 2. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein the oxime comprises a moiety of the formula:

其中R4係選自Η及C,.6烷基。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中其中R4爲 Η。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中含胞 -45 - 201125566 嘧啶或異胞嘧啶部分或其衍生物。在一些具體例中’本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中包含下式之結構部分：Wherein R4 is selected from the group consisting of hydrazine and C,.6 alkyl. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein R4 is hydrazine. In some embodiments, the invention relates to a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, which comprises a cell-45 - 201125566 pyrimidine or isocytosine moiety or a derivative thereof. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, which comprises a moiety of the formula:

其中 u 係選自 CR3R3、Ο、NR4 或 S(0)n、C = 〇、C=NOR3 ’另一選擇地兩個R3 —起形成羰基， V係獨立選自-CR4a-或-N-; 其中⑧代表稠合之5至7員飽和、不飽和或芳族碳環或雜環系環系統； W爲〇、NR1、NOR1或S，另一選擇地W =係選自與相同的碳原子連接之HO -與H -二者之組合或與相同的碳原子連接之（Cu烷基）〇 -與H -二者之組合； X二二Y代表單鍵或雙鍵，使得當X二二γ爲單鍵時，則X係選自0、NR2及S(0)n且Y爲C-R3，而當X二爲雙鍵時 ’則X爲Ν且Υ爲碳原子， Ζ係選自0、NR4或S(0)n， R係選自Η及C|.8院基’ R2係選自Η及Cm烷基， R3係選自Η及Cu烷基， -46 - 201125566 R4係選自11及Ci.8院基， R4a係選自Η及Cm烷基， η爲0、1或2。在一些具體例中’本發明係關於一種具有下式之化合物：Wherein u is selected from the group consisting of CR3R3, hydrazine, NR4 or S(0)n, C=〇, C=NOR3' alternatively another two R3 together form a carbonyl group, and the V system is independently selected from -CR4a- or -N-; Wherein 8 represents a fused 5 to 7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system; W is deuterium, NR1, NOR1 or S, and alternatively W = is selected from the same carbon atom a combination of HO- and H-, or a combination of (Cu alkyl) 〇- and H-, which are bonded to the same carbon atom; X bis represents a single bond or a double bond, such that when X is two When γ is a single bond, X is selected from 0, NR2 and S(0)n and Y is C-R3, and when X is a double bond, 'X is Ν and Υ is a carbon atom, and Ζ is selected from 0, NR4 or S(0)n, R is selected from Η and C|.8院基' R2 is selected from Η and Cm alkyl, R3 is selected from Η and Cu alkyl, -46 - 201125566 R4 From 11 and Ci.8, R4a is selected from the group consisting of hydrazine and Cm alkyl, and η is 0, 1, or 2. In some embodiments, the invention relates to a compound having the formula:

另一選擇地兩個R3 —起形成羰基， V係獨立選自-CR4a-或-Ν-; 其中⑧代表稠合之5至7員飽和、不飽和或芳族碳環或雜環系環系統； W爲〇、NR1、NOR1或S，另一選擇地W =係選自與相同的碳原子連接之H0 -與H -二者之組合或與相同的碳原子連接之（C ,. 8烷基）〇 -與Η -二者之組合； X二二Υ代表單鍵或雙鍵，使得當X二二Υ爲單鍵時，則X係選自0、NR2及8(0)„且Υ爲C-R3’而當X---Υ爲雙鍵時 ’則X爲Ν且Υ爲碳原子， Ζ係選自〇、NR4或S(0)n， R1係選自Η及Cy烷基， R2係選自Η及C,.8烷基， R3係選自Η及Cu烷基， R3a係選自Η及（^.8烷基，或另一選擇地兩個R3a基團一 -47 - 201125566 起形成羰基， R4係選自Η及Cu烷基， H4a係選自Η及Cu烷基， η爲0、1或2，另一選擇地，-G-H_J係選自：其中各個Η及J係獨立選擇，另一選擇地，-G-H-J係選自：Alternatively, two R3 together form a carbonyl group, and the V system is independently selected from -CR4a- or -Ν-; wherein 8 represents a fused 5 to 7 member saturated, unsaturated or aromatic carbocyclic or heterocyclic ring system W is 〇, NR1, NOR1 or S, and alternatively W = is selected from the group consisting of H0- and H--linked to the same carbon atom or linked to the same carbon atom (C, .8 alkane) Base) 〇-and Η - a combination of the two; X dioxin represents a single bond or a double bond, such that when X dioxin is a single bond, then X is selected from 0, NR 2 and 8 (0) „ and Υ For C-R3' and when X---Υ is a double bond, then 'X is Ν and Υ is a carbon atom, Ζ is selected from 〇, NR4 or S(0)n, and R1 is selected from Η and Cy alkyl. R2 is selected from the group consisting of hydrazine and C, .8 alkyl, R3 is selected from the group consisting of hydrazine and Cu alkyl, and R3a is selected from the group consisting of hydrazine and (.8 alkyl, or alternatively two R3a groups -47 - 201125566 to form a carbonyl group, R4 is selected from the group consisting of hydrazine and Cu alkyl group, H4a is selected from the group consisting of hydrazine and Cu alkyl group, η is 0, 1 or 2, and alternatively, -G-H_J is selected from the group consisting of: And J series independent selection, another option, -GHJ is selected from:

其中Rx係選自CH2、ΝΗ、ΝΚ,-β烷基）、S或0; 1^及Rz 爲C或CH，各自獨立以一或多個？、（：1^'€?3、（^及 OCH3取代；或Rx、Ry& Rz各自獨立選自CH2或CRaRb ，其中Ra及Rb —起形成C3.5碳環； J 係選自 NH2、NHiCus烷基）、N(C丨.8烷基）2、 NHC( = 0)CH3 ' NHC( = 0)NH2、NHC( = NH)NH2、NHC( = NH )H ; 其中n爲0、1或2 ; 另一選擇地，-G-H-J係選自： 201125566 其中Rx係選自CH2、NH、N(C丨-8烷基）、S或0; Rz爲以 —或多個CH3取代之c或CH ;或爲CRaRb，其中Ra 及Rb —起形成C3-5碳環：其中m爲1、2或3 ; J係選自 NH2、NH(C丨.8烷基）、N(C丨.8烷基）2、 NHC( = 0)CH3 、 NHC( = 〇)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ； C-B-A-、-D-E-F及- G- H- J爲化學部分，其中 A、D及G係獨立選自： (a)單鍵 ’（bKCH 烷基）-，（c)-(C2-8 烯基）-， (d)-(C2.8炔基）-，其中 i) 前文（b)-(d)中任一者中的0-4個碳原子隨意地以選自-0-、-S(0)p-、-NR6-、-(C = 0)- ' -S(0)pNR6-、-NR6S(〇)p-及-NR6s(〇)pNR6_之部分代替， ii) 前文（b)-(d)中任一者隨意地以一或多個R5基團取代，及 iii) 前文（b)-(d)中任一者隨意地以-(C,.8烷基）-R5 基團取代； (e)-〇. , (f)-NR6- . (g)-S(0)p- > (h)-C(O)- C(0)0- , (j).〇C(0)- - (k)-0C(0)0- 1 (1)-C(0)NR6-NR6C〇- , (n)-NR6C(〇)NR6- ’ (o)-C( = NR6)-， C( = NR6)〇. , (q)-〇C( = NR6)-，(r)-C( = NR6)NR6- NR6C( = Mr6 (u)-C( = S)NR(Wherein Rx is selected from the group consisting of CH2, hydrazine, hydrazine, -beta alkyl), S or 0; 1^ and Rz are C or CH, each independently of one or more? , (:1^'€?3, (^ and OCH3 substituted; or Rx, Ry& Rz are each independently selected from CH2 or CRaRb, wherein Ra and Rb together form a C3.5 carbocyclic ring; J is selected from NH2, NHiCus Alkyl), N(C丨.8 alkyl)2, NHC(=0)CH3 'NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; where n is 0, 1 or 2; Alternatively, -GHJ is selected from: 201125566 wherein Rx is selected from CH2, NH, N(C丨-8 alkyl), S or 0; Rz is c or CH substituted with - or multiple CH3 Or CRaRb, wherein Ra and Rb together form a C3-5 carbocycle: wherein m is 1, 2 or 3; J is selected from NH2, NH(C丨.8 alkyl), N(C丨.8 alkane Base) 2, NHC(=0)CH3, NHC(=〇)NH2, NHC(=NH)NH2, NHC(=NH)H; CBA-, -DEF and -G-H-J are chemical moieties, of which A , D and G are independently selected from: (a) a single bond '(bKCH alkyl)-, (c)-(C2-8 alkenyl)-, (d)-(C2.8 alkynyl)-, wherein i The 0-4 carbon atoms in any of the foregoing (b)-(d) are optionally selected from the group consisting of -0-, -S(0)p-, -NR6-, -(C=0)-' -S(0)pNR6-, -NR6S(〇)p- and -NR6s(〇)pNR6_ are replaced by a part, ii) any of the foregoing (b)-(d) optionally Substituting one or more R5 groups, and iii) any of the foregoing (b)-(d) is optionally substituted with a -(C,.8 alkyl)-R5 group; (e)-〇. (f)-NR6- . (g)-S(0)p- > (h)-C(O)- C(0)0- , (j).〇C(0)- - (k)- 0C(0)0- 1 (1)-C(0)NR6-NR6C〇- , (n)-NR6C(〇)NR6- ' (o)-C( = NR6)-, C( = NR6)〇. , (q)-〇C( = NR6)-, (r)-C( = NR6)NR6- NR6C( = Mr6 (u)-C( = S)NR(

NR C( = S)-，（w)-C(〇)S-，（x)-SC(O)-，（y)-〇C( = S)- ⑴· (m)- (p)- (s)- (v)- (z)- -49- 201125566 C( = S)0-，（aa)-NR6(CNR6)NR6-，（bb)-CR6R6c(〇)_，（cc). C(0)NR6(CR6R6)t- ’（dd)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（ee)3_l4員飽和、不飽和或芳族碳環，及（ff)-(CR6R6)t_，其中（dd)或（ee)隨意地以一或多個R5基團取代； B、 E及Η係獨立選自： (a) 單鍵， (b) 含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環， (c) 3-14員飽和、不飽和或芳族碳環，其中（b)或（c)隨意地以一或多個R5基團取代； (d) -(C,.8 垸基）·，（e)-(C2 8 烯基）·，（f) (C2 8 炔基）_，其中 1)則文（d)-(f)中任—者中的0_4個碳原子隨意地以選自-〇-、-s(0)p-、-NR6-、（c = 0)·、 c(=nr6) 、_ S(0)pNR6-、-NR6S(〇)p-及 _NR6s(〇)pNR6 之部分代替， ii)前文（d)-(f)中任—者隨意地以一或多個r5基團取代，及NR C( = S)-,(w)-C(〇)S-,(x)-SC(O)-,(y)-〇C( = S)- (1)· (m)- (p)- (s)- (v)- (z)- -49- 201125566 C( = S)0-,(aa)-NR6(CNR6)NR6-,(bb)-CR6R6c(〇)_,(cc). C (0) NR6(CR6R6)t- '(dd) a 3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (ee) 3_l4 saturated, An unsaturated or aromatic carbocyclic ring, and (ff)-(CR6R6)t_, wherein (dd) or (ee) is optionally substituted with one or more R5 groups; B, E and anthracene are independently selected from: (a a single bond, (b) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (c) 3-14 member saturated, unsaturated or aromatic carbon a ring, wherein (b) or (c) is optionally substituted with one or more R5 groups; (d) -(C,.8 fluorenyl)·, (e)-(C2 8 alkenyl)·, (f (C2 8 alkynyl)_, wherein 1) 0-4 carbon atoms in any of (d)-(f) are optionally selected from -〇-, -s(0)p-, -NR6- Substituting (c = 0)·, c(=nr6), _S(0)pNR6-, -NR6S(〇)p- and _NR6s(〇)pNR6, ii) (d)-(f) Incumbent Substituted with one or more r5 groups, and

Hi)前文（d)-(f)中任—者隨意地以_(Ci8烷基）_r5 基團取代；及（g)-(CR6R6),-， C、 F及J係獨立選自： ⑷氫，（c)F，⑷C1，（e)Br，（f)I , (g) CF3，⑻·cn '(i)-N3 5 (j)-N〇2 , (k)-NR6(CR6R6)tR8 - (l)-〇R8 , (m). -50- 201125566 (n)-C(0)(CR6R6)tR8 (p)-SC(0)(CR6R6)tR8 (r)-NR6C(0)(CR6R6),R8 (t)-C( = NR6)(CR6R6),Ri S(0)p(CR6R6)tR8 ，㈧）、 (s)_ 0C(0)(CR6R6),R8 ， C(0)0(CR6R6),R8 ， (v)-C( = NNR6C(0)R6)(CR6R6)(R1 C(0)NR6(CR6R6)tR8 C( = NNR6R6)(CR6R6)tR ，（w)-C( = NOR8)(CR6R6)tR8，（x)-NR6C(0)0(CR6R6)tR8 (y)-0C(0)NR6(CR6R6),R8 . (z) - N R6 C (O) N R6 (C R6 R6), ^ 8 (aa)-NR6S(0)p(CR6R6),R8 ， (b b) - S (0) p N R6 (C R6 R6) t r 8 )- ，⑴）- (cc)-NR6S(0)pNR6(CR6R6)tR8 ， (dd)-NR6R8 ， ( NR6(CR6R6)R8，（ff)-OH，（gg)-NR8R8，（hh)-OCH S(0)pR8 ’（jj)-NC(0)R8，（kk)-NR6C(NR6)NR6R8，（U)c 院基’（mm)C2.8稀基’（nn)C2-8炔基，（〇〇)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（pp)3-14員飽和、不飽和或芳族碳環，（qq)_ (CR6R6)tNR6(CR6R6)tR8，(r r) - N [ (C R6 R6) t R8 ] [ C = 0 (C R6 R6 ).R8] ’ (ss)-(CR6R6)tN[(CR6R6),R8][(CR6R6)tR8] , (tt)- (CR6R6),NR6(C = 0)(CR6R6)tR8 ，（uu)-鹵烷基，（vv)_ C(0)(CR6)[(CR6R6)tR8]R8，（ w w) - ( C R 6 R6 ), C ( 0 ) N R8 R8， (xx)-(CR6R6),C(0)0(CR6R6)tR8，（yy)-NR6C(〇)CR8R8R8， (zz)-N[(CR6R6),R8]C(0)R8，及（aaa)-S(0)pNR8R8 : 其中（11)至（pp)隨意地以一或多個R7基團取代； R5 係選自（a)氫 ’（b)F’（c)Cl’（d)Br’（e)I，（f)-CF3，（g)-Hi) (a)-(f) are optionally substituted with _(Ci8 alkyl)_r5 groups; and (g)-(CR6R6), -, C, F and J are independently selected from: (4) Hydrogen, (c)F, (4)C1, (e)Br, (f)I, (g) CF3,(8)·cn '(i)-N3 5 (j)-N〇2 , (k)-NR6(CR6R6) tR8 - (l)-〇R8 , (m). -50- 201125566 (n)-C(0)(CR6R6)tR8 (p)-SC(0)(CR6R6)tR8 (r)-NR6C(0)( CR6R6), R8 (t)-C( = NR6)(CR6R6), Ri S(0)p(CR6R6)tR8 , (8)), (s)_ 0C(0)(CR6R6), R8, C(0)0 (CR6R6), R8, (v)-C( = NNR6C(0)R6)(CR6R6)(R1 C(0)NR6(CR6R6)tR8 C( = NNR6R6)(CR6R6)tR ,(w)-C( = NOR8)(CR6R6)tR8,(x)-NR6C(0)0(CR6R6)tR8 (y)-0C(0)NR6(CR6R6),R8 . (z) - N R6 C (O) N R6 (C R6 R6), ^ 8 (aa)-NR6S(0)p(CR6R6), R8 , (bb) - S (0) p N R6 (C R6 R6) tr 8 )- , (1))- (cc)-NR6S( 0) pNR6(CR6R6)tR8, (dd)-NR6R8, (NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH S(0)pR8 '(jj)-NC( 0) R8, (kk)-NR6C(NR6)NR6R8, (U)c 院基' (mm) C2.8 dilute base (nn) C2-8 alkynyl group, (〇〇) containing one or more selected from 3-14 members of nitrogen, oxygen and sulfur heteroatoms saturated, unsaturated or aromatic Heterocycle, (pp) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (qq)_(CR6R6)tNR6(CR6R6)tR8, (rr) - N [ (C R6 R6) t R8 ] [ C = 0 (C R6 R6 ).R8] ' (ss)-(CR6R6)tN[(CR6R6),R8][(CR6R6)tR8] , (tt)- (CR6R6),NR6(C = 0)(CR6R6)tR8 , (uu)-haloalkyl, (vv)_ C(0)(CR6)[(CR6R6)tR8]R8,( ww) - ( CR 6 R6 ), C ( 0 ) N R8 R8, (xx)- (CR6R6), C(0)0(CR6R6)tR8, (yy)-NR6C(〇)CR8R8R8, (zz)-N[(CR6R6), R8]C(0)R8, and (aaa)-S(0 pNR8R8: wherein (11) to (pp) are optionally substituted with one or more R7 groups; R5 is selected from (a) hydrogen '(b)F'(c)Cl'(d)Br'(e) I, (f)-CF3, (g)-

CNCN

(h)-N (i)-N02 (j) -NR6R( (k)-〇R: (D-(h)-N (i)-N02 (j) -NR6R( (k)-〇R: (D-

NR6(CNR6)NR6R6’（n^-CH 院基，（iO-CM 稀基，（0)-C -51 - 201125566 炔基’（p)-(C^8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環），（q)_(Cl_8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)_鹵烷基，（s)· SR6’（t)含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環，及（u )3-14員飽和、不飽和或芳族碳環；其中（m)至（〇及（t)至（u)隨意地以—或多個r8取代； RM系選自（a)氫’（bhC!.8烷基，或另一選擇地兩個R6基團一起形成碳環，（c) -鹵烷基’（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (e)3-14員飽和、不飽和或芳族碳環；其中（b)至（e)隨意地以一或多個R8取代； R7 係選自（a)氫 ’（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)· CN ’（h)-N3，（i)_N〇2 ’ ⑴-NR6R6，（k)-OR6，（1)_ nr6(cnr6)nr6r6，（m)-C|.8 烷基，（n)_Ci 8 烯基，（〇)_C| 8 炔基’ 4)-((2, ·8烷基）_(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Ci8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r) _鹵烷基’（3)_ NR6R8 > (t)-OR8 . (u)-(CR6R6)tNR6R8 > (v)-CR6R8R8 > (w)-SR6’（x)含有一或多個選自氮、氧及硫之雜原子的3_14 員飽和：不飽和或芳族雜環，（y)3_14員飽和、不飽和或芳族碳環’（z)-(CR6R6)tC(0)NR8R8，（aa).S(0)pR8，（bb)_ nr6c(o)nr6r6 ’（cc)_NR6C(0)r6，及（dd) c(=NR6)NR6R6 -52- 201125566 其中（m)至（q)及（x)至（y)隨意地以一或多個R9取代； R8 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN ’ （h)-N3，（i)-N02，（j)-NR6R9，（k)-〇R9，（l)_ NR6(CNR6)NR6R6，（m)-Ch8 烷基，（rO-Chs 烯基，（0)-0,.8 炔基’烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（s)3-14員飽和、不飽和或芳族碳環，（t)-鹵烷基， (u)-C(0)(CR6R6),R9 - (v)-SR6 > (w)-0C(0)(CR6R6)tR9 , (x)-NR6C(0)NR6R9 > (y)-NR6C(0)R9 ， (z) - N R 6 ( CN R9)( NR6R6)，（aa)-〇NR6(CNR6)NR6R6，（bb)-C( = NR9)NR6R6， (cc)-S(0)pR9 - (dd)-(CR6R6),C(0)NR6R9 > (ee)-(CR6R6)tOR9，及（ff)-(CR6R6)tNR6R9 ; 其中（m)至（s)隨意地以一或多個R9取代； R9 係選自（a)氫，（b)F，（c)Cl，（d)Br ’（e)I，（f)_CF3，（g). CN，（h)-N3，（i)-N02，（j)-NR6R10 ’ （k)-〇R6，（1)- NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（nXhs 院基，（0)-(^-8烧基，（p)-C|-8炔基，（q)含有一或多個選自氮 '氧及硫之雜原子的3-14員飽和 '不飽和或芳族雜環， (r)3-14員飽和、不飽和或芳族碳環’（s)-鹵烷基，（〇_ (CR6R6),OR6 ' (u)-0(CR6R6),NR6R10 > (v)-C(〇)R6 , (w). SR6 ’（x)-C(0)0R1()，（y)-S(0)pR6 ’（zHCu 烷基）_(含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽 -53- 201125566 和或芳族雜環）’（aa^C,-8烷基）-(3-14員飽和、不飽和或芳族碳環）’（bb)-0(CR6R6)t0R6，（cc).c( = NR6)NR6R6， (dd)-ONR6R6 . (ee)-NR6C(0)NR6R6 , (ff)-0(CR6R6)t0R6 , (gg)-NR6C(0)R6，及（hh)-(CR6R6)tNR6R10 ; 其中（n)至（r)及（z)至（aa)隨意地以—或多個rig取代； R10 係選自（a)氫，（b)F ’（c)Cl，（d)Br，（e)I，（f)-CF3， (g)-CN’（h)-N3，（i)-N02’（j)-NR6R6，（lc)-〇R6，（i)_ NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（n)_Cl_8 院基，（o)-Ci-8烯基’（pj-C^s炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14貝飽和、不飽和或芳族雜環， (r)3-14員飽和、不飽和或芳族碳環，（s)_鹵院基，（t)_ (CR6R6)tOR6 ’（u)-0(CR6R6)tNR6R6，⑺-C(0)R6，（w).sr6 ’（x)-C(0)0R6’（y)-S(0)pR6，（2)-((:,.8 烷基）-(含有—或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和j $ 芳族雜環），（aa^Cu烷基）-(3-14員飽和、不飽和或芳族碳環），（bb)-0(CR6R6)t0R6，（cc)C( = NR6)NR6R6，（dd) ONR6R6 > (ee)-NR6C(0)NR6R6 - (ff)-0(CR6R6)t〇R6 , (gg)_ NR6C(0)R6，及（hh)-(CR6R6)tNR6R6; 隨意地，其中基團-D-E-F或基團-G-H-J不存在，但是_D_ E-F及- G- H- J二者不同時不存在； p爲〇、1或2 ;及 t 爲 0、1 ' 2 或 3，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種根據式丨、u、 -54- 201125566 III、IV、V、VI、VII或VIII之化合物，其中A係選自： (a) 含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (b) 3-14員飽和、不飽和或芳族碳環， (Ο單鍵，其中（a)或（b)隨意地以一或多個R5基團取代； B 係選自（a)-(Ci-8 院基）-，（b)-(C2-8 稀基）-，（c)-(C2-8 炔基）-’（d)單鍵，其中 i) 前文（a)-(c)中任一者中的〇-4個碳原子隨意地以選自 _0-、-S(0)p-、-NR6-、-(C = 0)-、-C( = NR6)- ' - S(〇)PNR6-及-NR6S(〇)pNR6_ 之部分代替， ii) 前文（a)-(c)中任一者隨意地以—或多個r5基團取代，及 in)則文（a)-(c)中任一者隨意地以_(c18垸基）_R5 基團取代，及 C 係選自（a)NH2，（b)-NHC( = NH)NH2 及（c)氫，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在—些具體例中，本發明係關於—種根據式〖、π、 III IV、V、VI、VII或VIII之化合物，其中A係選自： (a) 含有一或多個選自氮 '氧及硫之雜原子的4_7員飽和、不飽和或芳族雜環， (b) 4-7員飽和、不飽和或芳族碳環， (c) 單鍵，其中（a)或（b)隨意地以—或多個R5基團取代； -55- 201125566 或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，其中A係選自氮雜環庚烷基（azepanyl)、環丁基、環戊基、環己基、環庚基、苯基、吡啶基、環己烯基、環己二烯基、二氫吡陡基、呋喃基、四氫肤喃基、四氣吡卩定基、四氫吖唉基、卩比略啶基、哌啶基及哌啶烯基；其中前文A中任一者隨意地以一或多個R5基團取代NR6(CNR6)NR6R6'(n^-CH, based on (iO-CM, (0)-C-51 - 201125566 alkynyl'(p)-(C^8 alkyl)-(containing one or more a 3 to 14 membered saturated, unsaturated or aromatic heterocyclic ring selected from the group consisting of nitrogen, oxygen and sulfur, (q)-(Cl_8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring) , (r)-haloalkyl, (s)·SR6'(t) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring; wherein (m) to (〇 and (t) to (u) are optionally substituted with - or more than r8; RM is selected from (a) hydrogen' (bhC !.8 alkyl, or alternatively two R6 groups together form a carbocyclic ring, (c)-haloalkyl'(d) contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. a 14-membered saturated, unsaturated or aromatic heterocyclic ring, and (e) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring; wherein (b) to (e) are optionally substituted with one or more R8; Selected from (a) hydrogen '(b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)· CN '(h)-N3, (i)_N〇 2 ' (1)-NR6R6, (k)-OR6, ( 1) _ nr6(cnr6)nr6r6, (m)-C|.8 alkyl, (n)_Ci 8 alkenyl, (〇)_C| 8 alkynyl ' 4)-((2, ·8 alkyl)_ (3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), (q)-(Ci8 alkyl)-(3-14 member saturated, not Saturated or aromatic carbocyclic ring), (r) _haloalkyl '(3)_ NR6R8 > (t)-OR8 . (u)-(CR6R6)tNR6R8 > (v)-CR6R8R8 > (w)- SR6'(x) is a 3-14 member saturated with one or more heteroatoms selected from nitrogen, oxygen and sulfur: an unsaturated or aromatic heterocyclic ring, (y) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring (z) )-(CR6R6)tC(0)NR8R8,(aa).S(0)pR8,(bb)_ nr6c(o)nr6r6 '(cc)_NR6C(0)r6, and (dd) c(=NR6)NR6R6 -52- 201125566 wherein (m) to (q) and (x) to (y) are optionally substituted with one or more R9; R8 is selected from the group consisting of (a) hydrogen, (b)F, (c)Cl, ( d) Br, (e) I, (f)-CF3, (g)-CN ' (h)-N3, (i)-N02, (j)-NR6R9, (k)-〇R9, (l)_ NR6(CNR6)NR6R6, (m)-Ch8 alkyl, (rO-Chs alkenyl, (0)-0,.8 alkynyl 'alkyl)- (containing one or more selected from the group consisting of nitrogen, oxygen and sulfur Hetero atom 3-14 membered saturated, unsaturated or aromatic heterocyclic ring), alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r) containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a hetero atom of a 3-14 member saturated, unsaturated or aromatic heterocyclic ring, (s) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (t)-haloalkyl, (u)-C (0) )(CR6R6), R9 - (v)-SR6 > (w) - 0C(0)(CR6R6)tR9 , (x)-NR6C(0)NR6R9 > (y)-NR6C(0)R9 , (z ) - NR 6 ( CN R9)( NR6R6), (aa)-〇NR6(CNR6)NR6R6, (bb)-C( = NR9)NR6R6, (cc)-S(0)pR9 - (dd)-(CR6R6 C(0)NR6R9 > (ee)-(CR6R6)tOR9, and (ff)-(CR6R6)tNR6R9; wherein (m) to (s) are optionally substituted with one or more R9; R9 is selected from (a) hydrogen, (b)F, (c)Cl, (d)Br '(e)I, (f)_CF3, (g). CN, (h)-N3, (i)-N02, (j )-NR6R10 ' (k)-〇R6,(1)- NR6(CNR6)NR6R6,(m)-C(0)(CR6R6)tNR6R6,(nXhs 院基,(0)-(^-8 alkyl, (p)-C|-8 alkynyl, (q) a 3-14 membered saturated 'unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen 'oxygen and sulfur, (r) 3-14 Saturated, unsaturated or aromatic carbon ring '(s)-halogen Base, (〇_ (CR6R6), OR6 ' (u)-0(CR6R6), NR6R10 > (v)-C(〇)R6 , (w). SR6 '(x)-C(0)0R1() , (y)-S(0)pR6 '(zHCu alkyl)_(3-14-membered saturated, unsaturated-53-201125566 or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur )'(aa^C,-8-alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring)'(bb)-0(CR6R6)t0R6,(cc).c( = NR6)NR6R6, (dd)-ONR6R6. (ee)-NR6C(0)NR6R6, (ff)-0(CR6R6)t0R6, (gg)-NR6C(0)R6, and (hh)-(CR6R6)tNR6R10; where (n) To (r) and (z) to (aa) optionally substituted with - or multiple rigs; R10 is selected from (a) hydrogen, (b) F '(c)Cl, (d)Br, (e)I , (f)-CF3, (g)-CN'(h)-N3, (i)-N02'(j)-NR6R6, (lc)-〇R6, (i)_NR6(CNR6)NR6R6,(m )-C(0)(CR6R6)tNR6R6, (n)_Cl_8, (o)-Ci-8 alkenyl' (pj-C^s alkynyl, (q) containing one or more selected from nitrogen, oxygen And 3 to 14 moles of saturated, unsaturated or aromatic heterocyclic rings of sulfur heteroatoms, (r) 3-14 members of saturated, unsaturated or aromatic carbocyclic rings, (s)_halogenyl, (t)_ ( CR6R6)tOR6 '(u)-0(CR6R6)tNR6R6,(7) -C(0)R6,(w).sr6 '(x)-C(0)0R6'(y)-S(0)pR6,(2)-((:,.8 alkyl)-(contains- Or a plurality of 3-14 membered saturated, unsaturated j$ aromatic heterocyclic rings selected from nitrogen, oxygen and sulfur heteroatoms, (aa^Cualkyl)-(3-14 member saturated, unsaturated or aromatic) Carbocycle), (bb)-0(CR6R6)t0R6, (cc)C( = NR6)NR6R6, (dd) ONR6R6 > (ee)-NR6C(0)NR6R6 - (ff)-0(CR6R6)t〇 R6 , (gg)_ NR6C(0)R6, and (hh)-(CR6R6)tNR6R6; optionally, wherein the group -DEF or the group -GHJ is absent, but _D_EF and -G-H-J Does not exist at the same time; p is 〇, 1 or 2; and t is 0, 1 ' 2 or 3, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound according to formula 丨, u, -54- 201125566 III, IV, V, VI, VII or VIII, wherein A is selected from: (a) one or more selected a 3-14 member saturated, unsaturated or aromatic heterocyclic ring of a hetero atom of nitrogen, oxygen and sulfur, (b) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (Ο a single bond, wherein (a) Or (b) optionally substituted with one or more R5 groups; B is selected from (a)-(Ci-8)-, (b)-(C2-8)-, (c)- (C2-8 alkynyl)-'(d) single bond, wherein i) 〇-4 carbon atoms in any of the foregoing (a)-(c) are optionally selected from _0-, -S ( 0) partial replacement of p-, -NR6-, -(C = 0)-, -C( = NR6)- ' - S(〇)PNR6- and -NR6S(〇)pNR6_, ii) (a)- Any one of (c) is optionally substituted with - or a plurality of r5 groups, and in) any of (a)-(c) is optionally substituted with a _(c18 fluorenyl)-R5 group, and C It is selected from the group consisting of (a) NH2, (b)-NHC(=NH)NH2 and (c) hydrogen, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some specific embodiments, the invention relates to a compound according to formula 〖, π, III IV, V, VI, VII or VIII, wherein A is selected from the group consisting of: (a) containing one or more selected from the group consisting of nitrogen a 4-7-membered saturated, unsaturated or aromatic heterocyclic ring of a hetero atom of oxygen and sulfur, (b) a 4-7 membered saturated, unsaturated or aromatic carbocyclic ring, (c) a single bond, wherein (a) or (b) Optionally substituted with - or a plurality of R5 groups; -55-201125566 or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, VI, VII or VIII, wherein A is selected from the group consisting of azepanyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, cyclohexadienyl, dihydropyridyl, furyl, tetrahydrofuranyl, tetrapyridinyl, tetra Hydroquinone, anthrapyridyl, piperidinyl and piperidinyl; wherein any of the foregoing A is optionally substituted with one or more R5 groups

I 另一選擇地，A爲單鍵； B係選自（3)-((:,-8烷基）-，其中 i) 前文（a)中的0-4個碳原子隨意地以選自_〇_、 S(0)p-、-NR6-、-(C = 0)-、-S(0)pNR6-及-NR6S(0)pNR6·之部分代替， ii) 前文（a)隨意地以一或多個R5基團取代，及 iii) 前文（a)隨意地以-(Cm烷基）-R5基團取代. 及另一選擇地，B爲單鍵； c 係選自（a)NH2 ’（b)-NHC( = NH)NH2，及（c)氫；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於—種根據式I、π、 III、IV、V、VI、VII或VIII之化合物，G係選自： (a)單鍵 ’（!)）-((：,.8 烷基）-，（c)-(C2.8 烯基）-， (d)-(C2-8炔基）-，其中 -56- 201125566 1)前文（b)_(d)中任一者中的〇_4個碳原子隨意地以进自-0-、-S(0)p-、-nr6-、-(c = 0)-、-C( = NR6)-、. S(0)pNH6-、-NR6S(〇)p_ 及 _NR6s(〇)pNR6·之部分代替， H)前文（b)-(d)中任—者隨意地以一或多個R5基團取代，及 iii)前文（b)-(d)中任一者隨意地以_(Cl.8烷基）_Rs 基團取代； (e) 含有一或多個選自氮、氧及硫之雜原子的3_丨4員飽和、不飽和或芳族雜環，及 (f) 3-14員飽和、不飽和或芳族碳環，其中（e)或（f)隨意地以—或多個R5基團取代；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中’本發明係關於一種根據式〗、II、 ΙΠ、IV、V、VI、Vn或VIII之化合物’ G係選自： (a)單鍵 ’（b)-(C,-8 烷基）_，（c)_(C2 8 烯基）_， (d)-(c2_8炔基）-，其中 i)前文（b)-(d)中任一者中的〇_4個碳原子隨意地以選自 _〇_、_s(〇)P、-NR6-、-(c = 0)-、-C( = NR6)-、-S(〇)pNR6_、·ΝΚ6δ(〇)ρ_ 及 _NR6s(〇)pNR6•之部分代替， H)前文（b)-(d)中任一者隨意地以一或多個R5基團取代，及 iii)前文（b)-(d)中任一者隨意地以-(c丨-8烷基）_r5 基團取代；其中P爲0、1或2， -57- 201125566 或其醫; 在 III ' IV 係選自5Q. 或其醫; 在 III、IV 係選自異構物] 在 III、IV 自：上可接受之鹽、酯、互變異構物或前藥。些具體例中，本發明係關於一種根據式I、Π、Further alternatively, A is a single bond; B is selected from (3)-((:,-8-alkyl)-, wherein i) 0-4 carbon atoms in (a) above are optionally selected from Partial replacement of _〇_, S(0)p-, -NR6-, -(C = 0)-, -S(0)pNR6-, and -NR6S(0)pNR6·, ii) (a) arbitrarily Substituted with one or more R5 groups, and iii) (a) optionally substituted with a -(Cm alkyl)-R5 group. And alternatively, B is a single bond; c is selected from (a) NH2 '(b)-NHC(=NH)NH2, and (c) hydrogen; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound according to formula I, π, III, IV, V, VI, VII or VIII, wherein G is selected from the group consisting of: (a) a single bond '(!))-(( :, .8 alkyl)-, (c)-(C2.8 alkenyl)-, (d)-(C2-8 alkynyl)-, wherein -56- 201125566 1) (b)_(d) The 〇_4 carbon atoms in any of them are optionally taken from -0-, -S(0)p-, -nr6-, -(c = 0)-, -C(= NR6)-,. Substituting S(0)pNH6-, -NR6S(〇)p_ and _NR6s(〇)pNR6·, H) Any of the foregoing (b)-(d) is optionally substituted with one or more R5 groups And iii) any of the foregoing (b)-(d) is optionally substituted with a _(Cl.8 alkyl)_Rs group; (e) one or more heteroatoms selected from nitrogen, oxygen and sulfur a 3 丨 4 member of a saturated, unsaturated or aromatic heterocyclic ring, and (f) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring, wherein (e) or (f) optionally consists of - or a plurality of R 5 a group substituted; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, 'the invention relates to a compound according to formula, II, ΙΠ, IV, V, VI, Vn or VIII' G is selected from the group consisting of: (a) a single bond '(b)-(C,- 8 alkyl)_, (c)_(C2 8 alkenyl)_, (d)-(c2_8 alkynyl)-, wherein i) 〇_4 of any of the foregoing (b)-(d) The carbon atom is optionally selected from the group consisting of _〇_, _s(〇)P, -NR6-, -(c = 0)-, -C(= NR6)-, -S(〇)pNR6_, ·ΝΚ6δ(〇)ρ_ And _NR6s(〇)pNR6• is replaced by a part, H) any of the foregoing (b)-(d) is optionally substituted with one or more R5 groups, and iii) in the foregoing (b)-(d) Either optionally substituted with a -(c丨-8 alkyl)_r5 group; wherein P is 0, 1 or 2, -57-201125566 or its physician; and III' IV is selected from 5Q. or its physician; In III, IV is selected from the isomers] in III, IV from: acceptable salts, esters, tautomers or prodrugs. In some specific examples, the present invention relates to a formula I, Π,

V VI、 VII或VIII之化合物，其中a compound of V VI, VII or VIII, wherein

上可接受之鹽、酯、互變異構物或前藥。些具體例中，本發明係關於一種根據式I、II、、V、VI、VII或VIII之化合物，其中An acceptable salt, ester, tautomer or prodrug. In some embodiments, the invention relates to a compound according to formula I, II, V, VI, VII or VIII, wherein

Η_J 或其醫藥上可接受之鹽、酯、互變 ζ前藥。 -些具體例中，本發明係關於一種根據式I、II、、V、VI、VII或VIII之化合物，其中- G- H- J係選 -58- 201125566Η_J or its pharmaceutically acceptable salts, esters, tautomeric prodrugs. In some embodiments, the invention relates to a compound according to formula I, II, V, VI, VII or VIII, wherein -G-H-J is selected from -58 to 201125566

或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-D-E-F、-G-H-J、K、U、V、W、X、Y 及Wherein C-B-A-, -D-E-F, -G-H-J, K, U, V, W, X, Y and

C一 B— A W 人 \Ν’ z係如前文式（I)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種化合物或其醫藥上可接又之鹽、酯、互變異構物或前藥，其中❿代表稠合之6員飽和、不飽和或芳族碳環或雜環系環系統。在~些具體例中’本發明係關於一種具有下式之化合物： -59- 201125566C-B-A W human \Ν' z is as defined in the above formula (I), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein ❿ represents a fused 6-membered saturated, unsaturated or aromatic carbocyclic ring or Heterocyclic ring system. In some specific examples, the present invention relates to a compound having the formula: -59- 201125566

其中 C-B-A-、-D-E-F、-G-H-J、U、V、W、X、Y 及 Z 係如式（I)中所定義，其中Qi、Q2、Q3及Q4係獨立選自氮原子、碳原子或CH’其中當有- D-E-F或- G-H-J存在時，其係與碳連接，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中’本發明係關於一種具有下式之化合物：Wherein CBA-, -DEF, -GHJ, U, V, W, X, Y and Z are as defined in formula (I), wherein Qi, Q2, Q3 and Q4 are independently selected from nitrogen, carbon or CH 'When there is -DEF or - GHJ, it is attached to carbon, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-G_H-J、U、V、W、X、Y 及 Z 係如式（I)中所定義，其中Qla、Q2a& Q4a係獨立選自氮原子、碳原子或CH，或其醫藥上可接受之鹽 '酯、互變異構物或前藥。在一些具體例中’本發明係關於—種具有下式之化合物：Wherein CBA-, -G_H-J, U, V, W, X, Y and Z are as defined in formula (I), wherein Qla, Q2a & Q4a are independently selected from nitrogen, carbon or CH, or A pharmaceutically acceptable salt 'ester, tautomer or prodrug. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-D-E-F、-G-H-J、U、V、W、X、Y 及 z 係 -60- 201125566 如式（11)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中必代表稠合之6員飽和、不飽和或芳族碳環或雜環系環系統。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -DEF, -GHJ, U, V, W, X, Y and z--60-201125566 are as defined in formula (11), or a pharmaceutically acceptable salt, ester or tautomer thereof Or a prodrug. In some embodiments, the invention relates to a compound or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, which must represent a fused 6-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic Ring system. In some embodiments, the invention relates to a compound having the formula:

/E _F D，/E _F D,

其中 C-B-A-、-D-E-F、-G-H-J、U、V、W、X、γ 及 Z 係如式（II)中所定義，其中Q1、Q2、Q3及Q4係獨立選自氮原子、碳原子或CH’其中當有- D-E-F或- G-H-J存在時，其係與碳連接，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -DEF, -GHJ, U, V, W, X, γ and Z are as defined in formula (II), wherein Q1, Q2, Q3 and Q4 are independently selected from nitrogen, carbon or CH 'When there is -DEF or - GHJ, it is attached to carbon, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-G-H-J、U · V、W、X、Y 及 Z 係如式（II) 中所定義，其中Q1' Q2及Q4係獨立選自氮原子、碳原子或其醫藥上可接受之鹽、醋、互變異構物或前藥。 -61 - 201125566 在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -GHJ, U · V, W, X, Y and Z are as defined in formula (II), wherein Q1' Q2 and Q4 are independently selected from nitrogen atoms, carbon atoms or pharmaceutically acceptable thereof Salt, vinegar, tautomers or prodrugs. -61 - 201125566 In some embodiments, the invention relates to a compound having the formula:

其中C-B-A-、-G-H-J、V、W、X及Y係如式（I)中所定義，其中T1爲CH或NH，其先決條件係當T1爲NH時，則-D-E-F不存在，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -GHJ, V, W, X and Y are as defined in formula (I), wherein T1 is CH or NH, and the prerequisite is that when T1 is NH, then -DEF is absent, or its medicine An acceptable salt, ester, tautomer or prodrug. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-D-E-F 、-G-H-J、1(、乂、\¥、乂、丫及 z 係如式（I)或式（11)中所定義，或其醫藥上可接受之鹽'酯'互變異構物或前藥。在一些具體例中’本發明係關於一種具有式（I)或（II) 之化合物，其中代表稠合之6員芳族碳環或雜環系環系統；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中’本發明係關於一種具有下式之化合物：Wherein CBA-, -DEF, -GHJ, 1 (, 乂, \¥, 乂, 丫, and z are as defined in formula (I) or formula (11), or a pharmaceutically acceptable salt thereof; Or a prodrug. In some embodiments, the invention relates to a compound of formula (I) or (II), which represents a fused 6 membered aromatic carbocyclic or heterocyclic ring system; A pharmaceutically acceptable salt, ester, tautomer or prodrug. In some embodiments, the invention relates to a compound having the formula:

;-h—J (la)或;-h-J (la) or

其中 C-B-A-、-D-E-F、-G-H-J、U、V、W、X、Y 及 z 係 201125566 如式（I)或式（II)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -DEF, -GHJ, U, V, W, X, Y and z are 201125566 as defined in formula (I) or formula (II), or a pharmaceutically acceptable salt, ester or tautomer thereof Structure or prodrug. In some embodiments, the invention relates to a compound having the formula:

其中 C-B-A-、-D-E-F、-G-H-J、U、V、W、X、Y 及 Z 係如式（I)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有式V、VI、 V 11或V 111之化合物：Wherein C-B-A-, -D-E-F, -G-H-J, U, V, W, X, Y and Z are as defined in formula (I), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula V, VI, V 11 or V 111:

其中C-B-A-、-D-E-F及-G-H-J係如式（I)中所定義，或其 (VII)，或醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有式V之化合物：Wherein C-B-A-, -D-E-F and -G-H-J are as defined in formula (I), or (VII) thereof, or a pharmaceutically acceptable salt, ester, tautomer or prodrug. In some embodiments, the invention relates to a compound of formula V:

其中C-B-A-、-D — E-F及-G-H-J係如式（I)中所定義，或其 201125566 醫藥上可接受之鹽、酯、互變異構物或前藥° 在一些具體例中，本發明係關於一種具有下式之化合物：Wherein CBA-, -D-EF and -GHJ are as defined in formula (I), or its 201125566 pharmaceutically acceptable salt, ester, tautomer or prodrug. In some embodiments, the invention is Regarding a compound having the formula:

其中D及E爲單鍵’且F爲氫；其中C-B-A-及- G-H-J係如式（I)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein D and E are a single bond ' and F is hydrogen; wherein C-B-A- and -G-H-J are as defined in formula (I), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

其中C-B-A-及-G-H-J係如式（I)中所定義，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Wherein C-B-A- and -G-H-J are as defined in formula (I), or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

G—Η—J (Ic), 其中C-B-A -及- G- H- J係如式（I)中所定義，或其醫藥上可接受之鹽、醋、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物： -64 - ⑧ 201125566G-Η-J (Ic), wherein C-B-A- and -G-H-J are as defined in formula (I), or a pharmaceutically acceptable salt, vinegar, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula: -64 - 8 201125566

或or

其中A係選自 (a) 含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (b) 3-14員飽和、不飽和或芳族碳環， (c) 單鍵，其中（a)或（b)隨意地以一或多個R5基團取代； B 係選自（aMCu 烷基）_ ’（b)_(C2-8 烯基）-，（c)-(c2.8 炔基）-，（d)單鍵，其中 i) 前文（a)-(c)中任一者中的個碳原子隨意地以選自-0-、-S(〇)P-、-nr6·、-(c = 0).、-C( = NR6)-、· S(0)pNR6-及-NR6S(〇)PNR6-之部分代替’ ii) 前文（a)-(c)中任—者隨意地以一或多個R5基團取代，及川）前文（3)-((：)中任一者隨意地以-(匚1-8烷基）-115 基團取代；及 C 係選自（a)NH2，（b)-NHC( = NH)NH2 及（C)氫；或其醫藥上可接受之鹽 '醋' 互變異構物或前藥。在一些具體例中’本發明係關於一種具有下式之化合物：Wherein A is selected from the group consisting of (a) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (b) 3-14 member saturated, unsaturated Or an aromatic carbocyclic ring, (c) a single bond, wherein (a) or (b) is optionally substituted with one or more R5 groups; B is selected from (aMCu alkyl)_ '(b)_(C2- 8 alkenyl)-, (c)-(c2.8 alkynyl)-, (d) a single bond, wherein i) one of the carbon atoms of any of the foregoing (a) to (c) is optionally selected from -0-, -S(〇)P-, -nr6·, -(c = 0)., -C( = NR6)-, ·S(0)pNR6-, and -NR6S(〇)PNR6- ' ii) in the preceding paragraphs (a)-(c) - optionally substituted with one or more R5 groups, and Chuan) Any of the preceding (3)-((:) is optionally -(匚1- And the C system is selected from the group consisting of (a) NH2, (b)-NHC(=NH)NH2 and (C) hydrogen; or a pharmaceutically acceptable salt thereof, 'vinegar' tautomerism Or a prodrug. In some embodiments, the invention relates to a compound having the formula:

-65- 201125566 其中 A係選自氮雜環庚烷基、環丁基、環戊基、環己基、環庚基、苯基、吡啶基、環己烯基 '環己二烯基、二氫吡啶基、呋喃基、四氫呋喃基、四氫吡啶基、四氫吖唉基、吡咯啶基、哌啶基及哌啶烯基；其中前文A中任一者隨意地以一或多個R5基團取代；另一選擇地，A爲單鍵； B係選自（a)-(C|.8烷基）_，其中 i)前文（a)中的〇-4個碳原子隨意地以選自-〇-、-S(〇)P-、-NR6-、-(c = 〇)-、_s(〇)pNR6-及-NR6S(0)pNR6-之部分代替， ii) 前文（a)隨意地以—或多個R5基團取代，及 iii) 前文（a)隨意地以- (Cu烷基）-R5基團取代：另一選擇地，B爲單鍵； C 係選自（a)NH2，（b)-NHC( = NH)NH2 及（c)氫；或其醫藥上可接受之鹽、醋、互變異構物或前藥。在一些具體例中’本發明係關於一種具有下式之化合物：-65- 201125566 wherein A is selected from the group consisting of azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl'cyclohexadienyl, dihydrogen Pyridyl, furyl, tetrahydrofuranyl, tetrahydropyridyl, tetrahydroindenyl, pyrrolidinyl, piperidinyl and piperidinyl; wherein any of the foregoing A is optionally one or more R5 groups Alternatively, A is a single bond; B is selected from (a)-(C|.8 alkyl)_, wherein i) the 〇-4 carbon atoms in (a) above are optionally selected from -〇-, -S(〇)P-, -NR6-, -(c = 〇)-, _s(〇)pNR6- and -NR6S(0)pNR6- are replaced by partial, ii) (a) arbitrarily Substituting - or a plurality of R5 groups, and iii) (a) optionally substituted with a -(Cualkyl)-R5 group: Alternatively, B is a single bond; C is selected from (a) NH2 (b)-NHC(=NH)NH2 and (c) hydrogen; or a pharmaceutically acceptable salt, vinegar, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

-66- 201125566-66- 201125566

-67- 201125566-67- 201125566

或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中’本發明係關於一種具有下式之化合物：Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

(a)單鍵 ’（bXCu 烷基）_，（c)-(C28 烯基）_， (d)-(C2.8炔基）-，其中 i) 前文（b)-(d)中任—者中的〇-4個碳原子隨意地以選自-0-、-S(〇)p-、_Nr6_、（c = 〇)-、-C( = nr6)_、- S(0)pNR6-、-NR6S(0)p-及·NR6s(〇)pNR6_之部分代替， ii) 前文（b)-(d)中任—者隨意地以—或多個r5基團取代，及(a) a single bond '(bXCu alkyl)_, (c)-(C28 alkenyl)_, (d)-(C2.8 alkynyl)-, wherein i) any of the foregoing (b)-(d) - 〇-4 carbon atoms in the person are optionally selected from -0-, -S(〇)p-, _Nr6_, (c = 〇)-, -C( = nr6)_, -S(0)pNR6 -, -NR6S(0)p- and ·NR6s(〇)pNR6_ are replaced by a part, ii) in the above (b)-(d), optionally substituted with - or a plurality of r5 groups, and

Hi)前文（b)-(d)中任—者隨意地以_(Cl 8烷基）基團取代： (e)含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環，及 -68- 201125566 (f)3-14員飽和、不飽和或芳族碳環，其中（e)或（f)隨意地以一或多個R5基團取代；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有下式之化合物：Hi) in the preceding paragraphs (b)-(d) - optionally substituted with a _(Cl 8 alkyl) group: (e) a 3-14 member saturated with one or more heteroatoms selected from nitrogen, oxygen and sulfur , an unsaturated or aromatic heterocyclic ring, and -68- 201125566 (f) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring wherein (e) or (f) is optionally substituted with one or more R5 groups Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound having the formula:

令或基）-’（d ) - ( C 2 . 8炔基）-，其中 i)前文（b)-(d)中任一者中的〇-4個碳原子隨意地以選自-0-、-S(0)p-、-NR6-、-(C = 0)-、-C( = NR6)- ' -S(〇)pNR6-、-NR6S(0)p-及-NR6S(0)pNR6-之部分代替， ii)前文（b)-(d)中任一者隨意地以—或多個r5基團取代，及 111)則文（b) - (d)中任一者隨意地以_ (c丨_ 8烷基）-R 5 基團取代；其中P爲0、1或2，或其醫藥上可接受之鹽、酯、互變異構物或前藥。Or the group -'(d) - (C 2 .8 alkynyl)-, wherein i) the 〇-4 carbon atoms in any of the foregoing (b)-(d) are optionally selected from -0 -, -S(0)p-, -NR6-, -(C = 0)-, -C( = NR6)- ' -S(〇)pNR6-, -NR6S(0)p- and -NR6S(0 a part of pNR6-, ii) any one of (b)-(d) above is optionally substituted with - or a plurality of r5 groups, and 111) any one of (b) - (d) is optionally Substituted with a _(c丨_ 8 alkyl)-R 5 group; wherein P is 0, 1 or 2, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

-69- 201125566-69- 201125566

或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種具有式Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a possessive

係選自： -70- 201125566Line from: -70- 201125566

201125566 其中Rx係選自CH2、NH、NKhs烷基）、S或0; 1^及Rz 爲C或CH，各自獨立以一或多個F、CH3、CF3、OH及 OCH3取代；或Rx、Ry及Rz各自獨立選自CH2或CRaRb ，其中Ra及Rb —起形成C3-5碳環； J係選自 NH2、NH(C丨·8烷基）' NiCi-s烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ；其中n爲〇、1或2 ; 另一選擇地，-G-H-J係選自：201125566 wherein Rx is selected from CH2, NH, NKhs alkyl), S or 0; 1^ and Rz are C or CH, each independently substituted with one or more of F, CH3, CF3, OH and OCH3; or Rx, Ry And Rz are each independently selected from CH2 or CRaRb, wherein Ra and Rb together form a C3-5 carbocycle; J is selected from NH2, NH(C丨8 alkyl) 'NiCi-s alkyl) 2, NHC (= 0) CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; where n is 〇, 1 or 2; alternatively, GHJ is selected from:

其中Rx係選自CH2、NH、NCCm烷基）、S或0; Rz爲以一或多個CH3取代之（：或CH;或1爲CRaRb，其中Ra 及Rb —起形成C3.5碳環；其中m爲1、2或3 ; J係選自 NH2、NH(Cu8烷基）、NiCu烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種含有R5之化合物，其中 R5 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN，(h)-N3 > (i)-N02 > (j)-NH2，（k)-OR6， (1)NHC( = NH)NH2’（πΟ-C,.8 烷基，烯基，（0)-(:,.8 •72- 201125566 炔基，（P)-(C 烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（qMC^s烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)-鹵烷基，（s)-SR6，（t)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及（u)3-14員飽和、不飽和或芳族碳環；另一選擇地’兩個R5基團一起形成碳環；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種含有R6之化合物，其中R6係選自（a)氫，（bhCu烷基，或另一選擇地兩個R6基團一起形成碳環，（c) -鹵院基，（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’及（e)3-14員飽和、不飽和或芳族碳環；或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中’本發明係關於一種根據式I、π、 III、IV、V、VI、VII或VIII之化合物’或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中- D- E- F代表氫。在一些具體例中’本發明係關於一種根據式I、π、 III、IV、V、VI、VII或νπι之化合物，或其醫藥上可接受之鹽、醋、互變異構物或前藥，其中當有你存在時，其爲 Ο、NR1、NOR1 或 S。在一些具體例中，本發明係關於一種根據式I、„、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中當有Χ1^γ存在時 ’其爲雙鍵’且X爲Ν及γ爲碳原子。 -73- 201125566 在一些具體例中，本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中當有1148存在時，其爲Η。在一些具體例中’本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯 '互變異構物或前藥，其中當有Ζ存在時，其爲 NR4。在一些具體例中，本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中R4爲Η。在一些具體例中，本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，其係與核糖體結合。在一些具體例中，本發明係關於一種根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，其係與核糖體結合，其中核糖體爲細菌核糖體。在一些具體例中，本發明係關於一種根據表1中之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥。在一些具體例中，本發明係關於一種醫藥組成物，其包含本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，及醫藥上可接受之載劑。在一些具體例中，本發明係關於一種治療、預防或減 -74- 201125566 低在人類或動物中的疾病狀態風險之方法，其包含以有效量之本發明化合物’或其醫藥上可接受之鹽、酯、互變異構物或則藥投予需要其之人類或動物。在一些具體例中’本發明係關於一種治療在人類或動物中的微生物感染之方法，其包含以有效量之本發明化合物’或其醫藥上可接受之鹽、醋、互變異構物或前藥投予人類或動物。在一些具體例中’本發明係關於本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療在人類或動物中的微生物感染之藥劑的用途。在一些具體例中’本發明係關於一種治療、預防或減低在人類或動物中的微生物感染風險之方法，其包含以有效量之本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低微生物感染風險之藥劑的用途，其中該微生物感染係選自：皮膚感染、革蘭氏陽性感染、革蘭氏陰性感染、院內感染肺炎、社區型感染肺炎、病毒後感染肺炎、醫院型感染肺炎/呼吸器相關肺炎、呼吸道感染，諸如CRTI(慢性呼吸道感染）、急性骨盆感染、倂發性皮膚及皮膚結構感染、皮膚及軟組織感染（SSTI)，包括無倂發性皮膚及軟組織感染（uSSTI)與倂發性皮膚及軟組織感染、腹部感染、倂發性腹腔內感染、尿道感染、菌血症、敗血症、心內膜炎、心室心房分流感染、血管通路感染、 -75- 201125566 腦膜炎、預防性手術感染、腹膜感染、骨感染、關節感染、抗二甲苯青黴素金黃葡萄球菌感染、抗萬古黴素腸球菌感染、抗利奈唑德有機體感染、炭疽桿菌（Bacillus anthracis)感染、兔熱病桿菌（Francisella tularensis)感染、鼠疫耶氏菌（Yersinia pestis)感染及結核病。在一些具體例中，本發明係關於一種方法或用途，其中本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥係經耳、眼、鼻、口服、非經腸、局部或靜脈內投予。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的倂發性腹腔內感染風險之方法，其包含以有效量之根據式I、II、III、IV、V、VI、VII或VIII 之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、II、III、IV、V、 VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低倂發性腹腔內感染風險之藥劑的用途，其中倂發性腹腔內感染係選自由於大腸桿菌、梭狀梭菌（Clostridium clostridioforme) 、遲緩真桿菌（Eubacterium lentum)、消化鏈球菌屬 (Peptostreptococcus spp.)、脆弱擬桿菌（Bacteroides fragilis)、狄氏擬桿菌（Bacteroides distasonis)、卵形擬桿菌（Bacteroides ovatus)、多形擬桿菌（Bacteroides thetaiotaomicron)、單形擬桿菌（Bacteroides uniformis)、咽峽炎鏈球菌（Streptococcus anginosus)、星座鏈球菌 -76- ⑧ 201125566 (Streptococcus constellatus)、糞腸球菌、奇異變型桿菌 (Proteus mirabilis)或產氣莢膜桿菌（Clostridium perfringens)之多種微生物感染，諸如膿腫。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的倂發性皮膚及皮膚結構感染風險之方法，其包含以有效量之根據式I、II、III、IV、V、VI、 VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、Π、III 、IV、V、VI、VII或vm之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低倂發性皮膚及皮膚結構感染風險之藥劑的用途，其中倂Wherein Rx is selected from CH2, NH, NCCm alkyl), S or 0; Rz is substituted with one or more CH3 (: or CH; or 1 is CRaRb, wherein Ra and Rb together form a C3.5 carbocycle Wherein m is 1, 2 or 3; J is selected from the group consisting of NH2, NH(Cu8 alkyl), NiCu alkyl) 2, NHC(=0)CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a compound containing R5 wherein R5 is selected from the group consisting of (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f)- CF3, (g)-CN, (h)-N3 > (i)-N02 > (j)-NH2, (k)-OR6, (1) NHC(=NH)NH2'(πΟ-C,. 8 alkyl, alkenyl, (0)-(:,.8 •72- 201125566 alkynyl, (P)-(C alkyl)-(containing one or more heteroatoms selected from nitrogen, oxygen and sulfur 3-14 member saturated, unsaturated or aromatic heterocyclic ring), (qMC^s alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r)-haloalkyl group, (s) -SR6, (t) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) 3-14 member saturated, unsaturated or aromatic a family carbocycle; alternatively, the two R5 groups together form a carbocyclic ring; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a a compound of R6, wherein R6 is selected from the group consisting of (a) hydrogen, (bhCu alkyl, or alternatively two R6 groups together form a carbocyclic ring, (c) - a halogen-based group, (d) containing one or more a 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from nitrogen, oxygen and sulfur heteroatoms and (e) 3-14 member saturated, unsaturated or aromatic carbocyclic ring; or pharmaceutically acceptable thereof a salt, ester, tautomer or prodrug. In some embodiments, 'the invention relates to a compound according to formula I, π, III, IV, V, VI, VII or VIII' or pharmaceutically acceptable thereof a salt, ester, tautomer or prodrug wherein -D-E-F represents hydrogen. In some embodiments, the invention relates to a formula I, π, III, IV, V, VI, VII or a compound of νπι, or a pharmaceutically acceptable salt, vinegar, tautomer or prodrug thereof, wherein when present, it is Ο, NR1, NOR1 or S. In some embodiments, the invention relates to A compound according to formula I, „, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein when Χ1^γ is present, Is a double bond 'and X is Ν and γ is a carbon atom. -73- 201125566 In some embodiments, the invention relates to a formula I, II, III, IV, V a compound of, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, wherein when 1148 is present, it is hydrazine. In some embodiments, the invention relates to a A compound according to formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester 'tautomer or prodrug thereof, wherein in the presence of hydrazine it is NR4. In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, Where R4 is Η. In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, It is associated with ribosomes. In some embodiments, the invention relates to a compound according to formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, It binds to ribosomes, which are bacterial ribosomes. In some embodiments, the invention relates to a compound according to Table 1, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of a disease state in a human or an animal, comprising an effective amount of a compound of the invention' or a pharmaceutically acceptable compound thereof Salts, esters, tautomers or drugs are administered to humans or animals in need thereof. In some embodiments, the invention relates to a method of treating a microbial infection in a human or animal comprising an effective amount of a compound of the invention 'or a pharmaceutically acceptable salt thereof, vinegar, tautomer or pre- The drug is administered to humans or animals. In some embodiments, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment of a microbial infection in a human or animal. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of microbial infection in a human or animal comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, or mutual An isomer or prodrug administered to a human or animal, or a pharmaceutical composition of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of microbial infection The use of the microbial infection is selected from the group consisting of: skin infection, Gram-positive infection, Gram-negative infection, nosocomial infection pneumonia, community-type pneumonia, post-virus pneumonia, hospital-type pneumonia/respirator-associated pneumonia, Respiratory infections, such as CRTI (chronic respiratory infection), acute pelvic infections, hairy skin and skin structure infections, skin and soft tissue infections (SSTI), including no skin and soft tissue infections (uSSTI) and hairy skin and Soft tissue infection, abdominal infection, idiopathic intra-abdominal infection, urinary tract infection, bacteremia, sepsis, endocarditis, Atrial diverticulum infection, vascular access infection, -75- 201125566 meningitis, preventive surgical infection, peritoneal infection, bone infection, joint infection, anti-xanthin penicillin, staphylococcus aureus infection, vancomycin-resistant enterococci infection, anti-linazole German organism infection, Bacillus anthracis infection, Francisella tularensis infection, Yersinia pestis infection and tuberculosis. In some embodiments, the invention relates to a method or use wherein a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, is otic, ocular, nasal, oral, non-essential Intestinal, topical or intravenous administration. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of idiopathic intra-abdominal infection in a human or animal, comprising an effective amount according to formulas I, II, III, IV, V, a compound of VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formula I, II, III, IV, V, VI, VII or Use of a compound of VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of idiopathic intra-abdominal infection, wherein a secondary intra-abdominal infection Is selected from Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus spp., Bacteroides fragilis, Bacteroides distasonis Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Streptococcus angin Osus), Streptococcus faecalis -76- 8 201125566 (Streptococcus constellatus), Enterococcus faecalis, Proteus mirabilis or Clostridium perfringens, such as abscesses. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of idiopathic skin and skin structure infection in a human or animal comprising an effective amount according to formulas I, II, III, IV, a compound of V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with formula I, Π, III, IV, V, VI, Use of a compound of VII or vm, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of idiopathic skin and skin structure infections, wherein

甲苯青黴素敏感性及抗藥性分離物）、無乳鏈球菌 (Streptococcus agalactiae)、化膿性鏈球菌（Streptococcus pyogenes)、大腸桿菌、克雷伯氏肺炎桿菌（Klebsiella pneumoniae)、奇異變型桿菌（Proteus mirabilis)、脆弱擬桿菌、消化鏈球菌屬、不解糖卟啉單胞菌（Porphyromonas asaccharolytica)或二路普雷沃爾菌（Prevotella bivia)的無骨髓炎之糖尿病足感染。在一些具體例中’本發明係關於一種治療、預防或減低在人類或動物中的社區型感染肺炎風險之方法，其包含以有效量之根據式I、II、III、IV、V、VI、VII或VIII 之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、II、III、IV、V、 -77- 201125566 VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低社區型感染肺炎風險之藥劑的用途，其中社區型感染肺炎係由於包括合倂菌血症之病例的肺炎鏈球菌（青黴素敏感性及抗藥性分離物）、流感嗜血桿菌（Haemophilus influenzae)(包括冷-內醯胺酶陽性分離物）、卡他莫拉菌（Moraxella catarrhalis)或非典型細菌，如黴漿菌屬。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的倂發性尿道感染風險之方法，其包含以有效量之根據式I、II、III、IV、V、VI、VII或VIII 之化合物’或其醫藥上可接受之鹽 '酯、互變異構物或前藥投予人類或動物，或關於根據式I、II、III、IV、V、 VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低倂發性尿道感染風險之藥劑的用途，其中倂發性尿道感染係選自由於大腸桿菌、合倂菌血症或克雷伯氏肺炎桿菌之腎盂腎炎 0 在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的急性骨盆感染風險之方法，其包含以有效量之根據式I、II、III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、II、III、IV、V、VI 、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低急性骨盆感 -78- 201125566 染風j食之藥劑的用途，其中包括產後子宮內膜炎、敗血性流產及手術後婦科感染之急性骨盆感染係由於無乳鍵球菌、大腸桿菌、脆弱擬桿菌、不解糖卟啉單胞菌、消化鍵球菌屬或二路普雷沃爾菌。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的醫院型感染肺炎/呼吸器相關肺炎風險之方法’其包含以有效量之根據式I、II、Ul、IV、V ' VI、VII或νπΐ2化合物，或其醫藥上可接受之鹽、醋、互變異構物或前藥投予人類或動物，或關於根據式I、 II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低醫院型感染肺炎/呼吸器相關肺炎風險之藥劑的用途，其中醫院型感染肺炎/呼吸器相關肺炎係由於肺炎鏈球菌（青黴素敏感性及抗藥性分離物）、金黃色葡萄球菌 (二甲苯青黴素敏感性及抗藥性分離物）、克雷伯氏肺炎桿菌、綠膿桿菌（Pseudomonas aeruginosa)、不動桿菌屬 (Acinetobacter spp.)、嗜麥芽窄食單胞菌 (Stenotrophomonas maltophilia)、流感嗜血桿菌（包括內醯胺酶陽性分離物）或肺炎退伍軍人菌（Legionella pneumophila) ° 在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的與好氧性革蘭氏陽性微生物有關的微生物感染風險之方法’其包含以有效量之根據式1、11、 III、 IV、V、VI、VII或VIII之化合物，或其醫藥上可接 -79- 201125566 受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式 I、II、III、IV、V、VI、VII 或 VIII 之化合物’ 或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低與好氧性革蘭氏陽性微生物有關的微生物感染風險之藥劑的用途，其中好氧性革蘭氏陽性微生物係選自：金黃色葡萄球菌（二甲苯青黴素敏感性及抗藥性分離物）、肺炎鏈球菌（青黴素敏感性及抗藥性分離物）、腸球菌屬（萬古黴素敏感性及抗藥性分離物）、無乳鏈球菌、化膿性鏈球菌或上皮葡萄球菌（Staphylococcus epidermidis)(二甲苯青黴素敏感性及抗藥性分離物）。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的與好氧性革蘭氏陰性微生物有關的微生物感染風險之方法，其包含以有效量之根據式I、II、 III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、Π、III、IV、V、VI、VII或 VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥在製造用於治療、預防或減低與好氧性革蘭氏陰性微生物有關的微生物感染風險之藥劑的用途，其中好氧性革蘭氏陰性微生物係選自：大腸桿菌（包括ESBL及KPC產生之分離物）、流感嗜血桿菌（包括Θ -內醯胺酶陽性分離物）、克雷伯氏肺炎桿菌（包括ESBL及KPC產生之分離物）、弗氏檸檬酸桿菌（Citrobacter freundii)、產氣腸桿菌（Enterobacter aerogenes)、陰溝腸桿菌（Enterobacter cloacae)、摩氏摩 201125566 根菌（Morganella morganii)、沙雷氏桿菌（Serratia marcescens)、綠膿桿菌、鮑氏不動桿菌（Acinetobacter baumannii)、卡他莫拉菌、奇異變型桿菌、克氏檸檬酸桿菌（Citrobacter koseri)、副流感嗜血桿菌（Haemophilus parainfluenzae)、產酸克雷伯士菌（Klebsiella oxytoca)(包括ESBL及KPC產生之分離物）、普通變形桿菌（Proteus vulgaris)、雷氏普羅威登斯菌（Providencia rettgeri)或普羅非登斯菌（Providencia stuartii)。在一些具體例中，本發明係關於一種治療、預防或減低在人類或動物中的與厭氧性微生物有關的微生物感染風險之方法，其包含以有效量之根據式I、II、III、IV、V 、VI ' VII或VIII之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥投予人類或動物，或關於根據式I、 II、III、IV、V、VI、VII或VIII之化合物，或其醫藥上可接受之鹽'酯、互變異構物或前藥在製造用於治療、預防或減低與厭氧性微生物有關的微生物感染風險之藥劑的用途’其中厭氧性微生物係選自：脆弱擬桿菌、狄氏擬桿菌、卵形擬桿菌、多形擬桿菌、單形擬桿菌 '梭狀梭菌、遲緩真桿菌、消化鏈球菌屬、不解糖卟啉單胞菌、二路普雷沃爾菌、普通擬桿菌（Bacteroides vulgatus)、產氣莢膜丰干囷或梭桿菌屬（Fusobacterium spp)。在一些具體例中，本發明係關於一種方法或用途，其中本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥係經耳、眼、鼻、口服、非經腸、局部或靜脈內 -81 - 201125566 投予。在一些具體例中’本發明係關於一種合成本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥之方法。在一些具體例中’本發明係關於一種含有本發明化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥之醫學裝置。在一些具體例中’本發明係關於一種含有本發明化合物之醫學裝置，其中裝置爲支架。 3.本發明化合物之合成本發明提供用於製造本發明化合物之方法。下列流程 lc-2c描述用於合成本發明化合物的槪括來說之禾例途徑。更特殊的化學細節提供於實例中。流程lc-[6,6,6]胞嘧口定 -82 201125566Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis An osteomyelitis-free diabetic foot infection of Bacteroides fragilis, Peptostreptococcus, Porphyromonas asaccharolytica or Prevotella bivia. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of community-type infection pneumonia in a human or an animal, comprising an effective amount according to formulas I, II, III, IV, V, VI, a compound of VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formulas I, II, III, IV, V, -77-201125566 VI, Use of a compound of VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of community-type pneumonia, wherein a community-type infection is due to pneumonia Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Haemophilus influenzae (including cold-endoprolinase-positive isolates), and Moraxella catarrhalis (including isolates of sputum bacilli) Moraxella catarrhalis) or atypical bacteria, such as the genus Mycoplasma. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of idiopathic urinary tract infection in a human or animal comprising an effective amount according to formulas I, II, III, IV, V, VI a compound, a VII or a VIII, or a pharmaceutically acceptable salt thereof, an ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with Formula I, II, III, IV, V, VI, VII or VIII Use of a compound, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of idiopathic urinary tract infection, wherein the urinary tract infection is selected from Due to Escherichia coli, sputum bacteremia or pyelonephritis of Klebsiella pneumoniae 0 In some embodiments, the present invention relates to a method of treating, preventing or reducing the risk of acute pelvic infection in humans or animals, Including administration of an effective amount of a compound according to formula I, II, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, to a human or animal, or About according to formulas I, II, III, IV a compound of V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for use in the treatment, prevention or reduction of acute pelvic sensation -78-201125566 The use of pharmaceutical agents, including postpartum endometritis, septic abortion and postoperative gynecological infections in acute pelvic infections due to no lactococcus, Escherichia coli, Bacteroides fragilis, P. gingivalis, Peptostococcus Genus or two-way Prevobacter. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of hospital-type pneumonia/respirator-associated pneumonia in a human or animal, which comprises an effective amount according to formulas I, II, Ul, IV a compound of V ' VI, VII or νπ ΐ 2, or a pharmaceutically acceptable salt, vinegar, tautomer or prodrug thereof, administered to a human or animal, or according to formulas I, II, III, IV, V, VI, Use of a compound of VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for the manufacture of a medicament for the treatment, prevention or reduction of the risk of nosocomial pneumonia/respirator-associated pneumonia, wherein the hospital Type of pneumonia/respirator-associated pneumonia due to Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Staphylococcus aureus (xylene penicillin-sensitive and drug-resistant isolates), Klebsiella pneumoniae, P. aeruginosa Pseudomonas aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia, Haemophilus influenzae (including endogenous prolylase-positive separation) (Legionella pneumophila) ° In some embodiments, the present invention relates to a method of treating, preventing or reducing the risk of microbial infection associated with aerobic Gram-positive microorganisms in humans or animals 'It contains an effective amount of a compound according to formula 1, 11, III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. Administration to humans or animals, or for the manufacture of a compound according to formula I, II, III, IV, V, VI, VII or VIII or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof The use of a medicament for treating, preventing or reducing the risk of microbial infection associated with aerobic Gram-positive microorganisms, wherein the aerobic Gram-positive microorganism is selected from the group consisting of: Staphylococcus aureus (xylene penicillin sensitivity and resistance) Separation), Streptococcus pneumoniae (penicillin-sensitive and drug-resistant isolates), Enterococcus (vancomycin-sensitive and drug-resistant isolates), Streptococcus agalactiae, Streptococcus pyogenes or Staphylococcus (Staphylococcus epidermidis) (xylene and sensitivity to penicillin resistant isolates). In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of microbial infection associated with aerobic Gram-negative microorganisms in humans or animals, comprising an effective amount according to formulas I, II a compound of III, IV, V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or in accordance with formula I, Π, III, IV a compound of V, VI, VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, for use in the manufacture, prevention or reduction of microorganisms associated with aerobic Gram-negative microorganisms Use of an agent at risk of infection, wherein the aerobic Gram-negative microorganism is selected from the group consisting of Escherichia coli (including ESBL and KPC-derived isolates), Haemophilus influenzae (including sputum-endoprostase-positive isolates), Klebsiella pneumoniae (including isolates produced by ESBL and KPC), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Mohs 201125566 Rootella (Morganella morganii), Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Moraxella catarrhalis, Phytophthora bacillus, Citrobacter koseri, Haemophilus parainfluenzae, Klebsiella oxytoca (including ESBL and KPC isolates), Proteus vulgaris, Providencia rettgeri ) or Providencia stuartii. In some embodiments, the invention relates to a method of treating, preventing or reducing the risk of microbial infection associated with anaerobic microorganisms in a human or animal, comprising an effective amount according to formulas I, II, III, IV a compound of V, VI ' VII or VIII, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, administered to a human or animal, or according to formulas I, II, III, IV, V, VI Use of a compound of VII, VIII or VIII, or a pharmaceutically acceptable salt thereof, ester, tautomer or prodrug for the manufacture of a medicament for the treatment, prevention or reduction of the risk of microbial infection associated with anaerobic microorganisms The anaerobic microorganisms are selected from the group consisting of: Bacteroides fragilis, Bacteroides bisporus, Bacteroides ovum, Bacteroides variabilis, Bacteroides bisporus, Clostridium fusiformis, Lactobacillus brevis, Peptidotrophus, and non-lyolysin Porphyromonas, two-way Prevobacter, Bacteroides vulgatus, capsular sputum or Fusobacterium spp. In some embodiments, the invention relates to a method or use wherein a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, is otic, ocular, nasal, oral, non-essential Intestine, local or intravenous -81 - 201125566 cast. In some embodiments, the invention relates to a method of synthesizing a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a medical device comprising a compound of the invention, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. In some embodiments, the invention relates to a medical device comprising a compound of the invention, wherein the device is a stent. 3. Synthesis of Compounds of the Invention The invention provides methods for making the compounds of the invention. The following scheme lc-2c describes a pathway for the synthesis of the compounds of the present invention. More specific chemical details are provided in the examples. Process lc-[6,6,6] cytosine-82 201125566

BrBr

G 一 H_JG a H_J

-►-►

G-H-JG-H-J

G-H—JG-H-J

NHNH

流程2 c - [ 6,6,6 ]異胞嘧啶 C、B' ΟScheme 2 c - [ 6,6,6 ]Isocytosine C, B' Ο

4 .本發明化合物的特徵以上述方法設計、選擇及/或最優化之化合物在一經生產時可使用那些熟諳本技藝者已知的各種檢定法特徵化 ’以測定化合物是否具有生物活性。例如，可將分子以包括（但不限於此）那些下述檢定法的習知檢定法特徵化，以 -83- 201125566 測定該等分子是否具有預期的活性、結合活性及/或結合特異性。此外，可使用高產出量篩選加速使用此等檢定法之分析。結果有可能快速篩選本文所述之分子作爲例如抗癌症、抗細菌、抗真菌、抗寄生蟲或抗病毒劑之活性。亦有可能使用本技藝中已知的技術檢定化合物如何與核糖體或核糖體次單元交互作用及/或有效作爲蛋白質合成之調節劑（例如，抑制劑）。用於執行高產出量篩選的通用方法說明於例如 Devlin (1998) High Throughput Screening, Marcel Dekker;及美國專利第5,763,263號中。高產出量檢定法可使用一或多種不同的檢定技術，包括（但不限於此）那些下述者。 (1)表面結合硏究。各種結合檢定法可用於篩選新型分子的其結合活性。一種方法包括表面電漿子共振（SPR) ，可使用其評估關注之分子與有關的核糖體、核糖體次單元或其片段之結合性質。 SPR方法係在即時經由量子-機械表面電漿子的產生來測量在二或多種巨分子間的交互作用。一種裝置（來自 Pharmacia Biosensor, P i scatawy , N . J .之 BIAcore4. Characteristics of the Compounds of the Invention Compounds designed, selected and/or optimized in the above manner can be characterized, upon production, using various assays known to those skilled in the art to determine whether a compound is biologically active. For example, molecules can be characterized by conventional assays including, but not limited to, those assays described below, which determine whether the molecules have the desired activity, binding activity, and/or binding specificity, as -83-201125566. In addition, high throughput screening can be used to speed up the analysis using these assays. As a result, it is possible to rapidly screen the molecules described herein as, for example, anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. It is also possible to characterize how a compound interacts with a ribosome or ribosome subunit and/or as a modulator of protein synthesis (e.g., an inhibitor) using techniques known in the art. General methods for performing high throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High throughput assays may use one or more different assay techniques including, but not limited to, those described below. (1) Surface bonding research. Various binding assays can be used to screen for the binding activity of novel molecules. One method involves surface plasmon resonance (SPR), which can be used to assess the binding properties of the molecule of interest to the associated ribosome, ribosome subunit or fragment thereof. The SPR method measures the interaction between two or more macromolecules in real time via the generation of quantum-mechanical surface plasmons. A device (from Pharmacia Biosensor, P i scatawy , N. J. BIAcore)

Biosensor RTM)提供多色光之聚焦光束至金膜（提供作爲可棄式生物感應器''晶片〃）與緩衝間隔（可由使用者調整 )之間的界面。由提供關注之分析物共價固定的基質之羧基化聚葡萄糖所組成的100奈米厚"水凝膠〃與金膜連接。當聚焦光與金膜的游離電子團交互作用時，則增強電漿 -84 - 201125566 子共振。使所得反射光於光譜上耗損波長，最優化地釋放出共振。藉由分離反射之多色光成爲其組份波長（利用稜鏡）且測定經耗損之頻率，以BIAcore建立光學界面，其精確地記述所產生之表面電漿子共振表現。當設計係如上所述時，則電漿子共振（且因此耗損光譜）對逐漸消失區域 (其大致相對應於水凝膠的厚度）之質量具敏感性。若交互作用配對的一種組份係固定至水凝膠，且交互作用夥伴係經由緩衝間隔提供，則在兩種組份之間的交互作用可以在逐漸消失區域中的質量累積及其相對應之電漿子共振效應 (如以耗損光譜所測量）爲基準即時測量。此系統容許快速且敏感的分子交互作用即時測量，不需要標記任一種組份〇 (2)螢光極化。螢光極化（FP)爲一種可輕易地應用於蛋白質-蛋白質、蛋白質-配位體或RNA-配位體交互作用之測量技術，俾以導出兩種分子之間的聯合反應之IC5Q及 Kd。在此技術中，將關注之分子中之一與螢光團共軛》此通常爲系統中較小的分子（在此情況中爲關注之化合物）。將含有配位體-探針共軛物及核糖體、核糖體次單元或其片段二者之樣品混合物以垂直的極化光激發。光係由探針螢光團吸收，且在短時間之後再發射。測量發射光之極化程度。發射光之極化係取決於許多因素而定，但是最重要在於溶液之黏度及螢光團之視分子量。以適當之控制使發射光之極化程度的變化僅取決於螢光團之視分子量的變化，其依次取決於探針-配位體共軛物是否不存於溶液中 -85- 201125566 ，或與受體結合。以FP爲基準之結合檢定法具有許多重要的優勢，包括在確實的均相平衡條件下測量IC5()及Kd ，分析速度與自動化之便利設施，及在混濁懸浮液與有色溶液中的篩選能力。 (3) 蛋白質合成。除了以前述的生化檢定法特徵化以外，預期關注之化合物亦可以核糖體或核糖體次單元之功能活性的調節劑（例如，蛋白質合成抑制劑）特徵化。此外，更特殊的蛋白質合成抑制檢定法的執行可藉由將化合物投予整個有機體、組織、器官、細胞器、細胞、細胞或次細胞萃取物、或純化之核糖體製劑且藉由測定例如其抑制蛋白質合成之抑制常數（IC5G)來觀察其藥理及抑制性質。可執行倂入3H白胺酸或35s甲硫胺酸或類似的實驗來硏究蛋白質合成活性。在關注之分子存在下的細胞中之蛋白質合成量或速度的變化表明分子爲蛋白質合成調節劑。蛋白質合成速度及量的減少表明分子爲蛋白質合成抑制劑。 (4) 抗微生物檢定法及其他評估。此外，可以細胞水平檢定化合物的抗增殖或抗感染性質。例如，當目標有機體爲微生物時，關注之化合物活性可藉由關注之微生物在含有或缺少化合物之培養基中的生長來檢定。生長抑制可表示分子可作爲蛋白質合成抑制劑起作用。更特別地，關注之化合物對抗細菌病原體的活性可藉由化合物抑制限定之人類病原體菌株生長的能力來證明。就此目的而言，可將細菌株培養盤聚集，以包括各種目標病原體物種，一些 -86- 201125566 含有已特徵化之抗藥機制。使用此有機體培養盤容許不僅關於效力及光譜，且亦以排除抗藥機制之觀點來測定結構-活性關係。最小抑制濃度（MIC)係根據臨床及實驗室標準協會 (Clinical and Laboratory Standards Institute)[CLSI ;以前爲美國臨床實驗室標準委員會（National Committee for Clinical Laboratory Standards (NCCLS)]所槪述之模式以微稀釋法測定，典型係以100微升之最終體積。參見 CLSI ： Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne，PA; NCCLS; 2000。檢定法亦可根據由CLSI所發表之習知方法於微滴定盤中執行。參見 CLSI : Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-S eventh Edition. CLSI Document M7-A7 [ISBN 1 -5 623 8-5 87-9] CLSI, 940 West Valley Road, Suite 1 400，Wayne Pennsylvania 1 9087- 1 898 USA, 2006) o 化合物的抗微生物及其他藥物性質可在各種活體內哺乳動物檢定法中進一步評估，諸如小鼠或兔腹膜炎感染模式、皮膚及軟骨組織模式（常被稱爲大腿模式）或小鼠肺炎模式。有那些熟諳本技藝者已知的敗血症或器官感染模式。該等效力模式可用作爲評估方法的一部分且可用作爲在人類中的潛在效力之指南。端點可從減少細菌量改變至殺 -87- 201125566 傷率。就後者的終點而言，結果常以P D 5 〇値或防護5 0 % 之動物免於死亡之藥物劑量表示。爲了進一步評定化合物的似藥物性質，亦可使用重組的人類酵素系統或更複雜的系統（如人類肝微粒體）測量細胞色素Ρ450酵素及第Π期代謝酵素活性之抑制量度。再者’亦可就化合物作爲該等代謝酵素活性之基質予以評定。該等活性有用於測定化合物引起藥物·藥物交互作用或產生保留或不具有用的抗微生物活性之代謝物的潛力。爲了得到化合物對口服生物利用率的潛在性評估，亦可執行溶解度及Caco·2檢定法。後者爲來自人類上皮的細胞株，其允許測量穿過常在配備有1微米薄膜的24槽孔微滴定盤之槽孔內生長之Caco-2細胞單層的藥物攝取及通過。可在單層的底側面上測量游離藥物濃度，以評定可通過腸單層的藥物量。有必要適當的控制，以確保單層完整性及裂隙接點的緊密性。可使用此相同的系統得到以 P-糖蛋白質介導之流出量的評估。P-糖蛋白質爲局限至細胞頂膜的幫浦，形成極化單層。此幫浦可取消跨越Caco-2細胞膜的主動或被動攝取，造成較少的藥物通過腸上皮層。該等結果常與溶解度測量一起進行且已知該兩種因素促成在哺乳動物中的口服生物利用率。使用傳統的藥物動力學實驗在動物及最終在人類中的口服生物利用率之測量係測定絕對口服生物利用率。亦可使用實驗結果發展有助於預測促成似藥物性質之物理-化學參數的模式。當此模式經證明屬實時’可歸納 -88- 201125566 出實驗方法，增加對模式可預測性的可信度。 5 .調配及投藥本發明化合物可用於預防或治療各種人類 (包括哺乳動物及非哺乳動物）之病症，包括例、真菌感染、病毒感染、腹瀉、寄生蟲疾病及鑑證時’預期本發明的活性分子可在使用之前當的載劑中。活性分子的劑量、投予模式及適用係取決於意欲之接受者及目標有機體而定。的化合物之調配物（用於獸醫學及人類醫學二q 括與醫藥上可接受之載劑結合的此等化合物。載劑應爲^可接受之"，具有與調配物的相容且不對接受者有害之意義。關於此點，醫之載劑意欲包括與醫藥投予可相容的任何及所分散介質、包膜、抗細菌與抗真菌劑、等張與及類似物。用於醫藥活性物質的此等介質及劑已知。除了在任何習知的介質或劑與活性化合的範圍以外，可預期其他在組成物中的用途。的活性化合物（根據本發明及/或在本技藝中已或經設計者）倂入組成物中。調配物可方便以現且可以藥學/微生物學技藝中熟知的任何方常一些調配物可藉由將化合物與液體載劑或細劑或與二者達成結合且接著若必要時將產物定配物而製備。或其他動物如細菌感染癌症。一經倂入任何適合的載劑使根據本發明 I )典型地包其他成分可藥上可接受有的溶劑、吸收延遲劑爲本技藝中物不可相容亦可將補充知的經鑑證單位劑型呈法製備。通碎的固體載形成所欲調 -89- 201125566 應將本發明的醫藥組成物調配成與其意欲之投予途徑可相容。投予途徑的實例包括經口服、耳、眼、鼻或非經腸（例如，靜脈內、皮0內、吸入、穿透皮0 (局部）' 穿透黏膜及直腸）投予。用於非經腸、皮0內或皮下施予之溶液或懸浮液可包括下列組份：無菌稀釋劑，諸如注射用水、食鹽水溶液、固定油、聚乙二醇、甘油、丙二醇或其他合成溶劑；抗細菌劑，諸如苄醇或對羥基苯甲酸甲酯；抗氧化劑，諸如抗壞血酸或亞硫酸氫鈉；螯合劑，諸如乙二胺四乙酸；緩衝劑，諸如乙酸鹽、檸檬酸鹽或磷酸鹽，及張力調節劑，諸如氯化鈉或葡萄糖。pH可以酸或鹼調整，諸如鹽酸或氫氧化鈉。有用於口服或非經腸投予之溶液可以醫藥技藝中熟知的任何方法製備，例如在 Remington’s Pharmaceutical Sciences, (Gennaro，A.，ed.), Mack Pub·，（1990)中所描。用於非經腸投予之調配物亦可包括用於頰內投予之甘膽酸鹽、用於直腸投予之甲氧基水楊酸鹽或用於***投予之檸檬酸。非經腸製劑可封裝於玻璃或塑膠所製成之安瓶、可棄式注射器或多劑小瓶中。用於直腸投予之栓劑可藉由將藥物與無刺激性賦形劑（諸如在室溫下爲固體及在體溫下爲液體之可可奶油、其他甘油酯或其他組成物）混合而製備。調配物亦可包括例如聚伸烷二醇（諸如聚乙二醇）、蔬菜來源之油類及氫化萘。用於直接投予之調配物可包括甘油及其他高黏度組成物。其他潛在有用於該等藥物的非經腸載劑包括乙烯-乙酸乙烯酯共聚物粒子、滲透幫浦、可 -90- 201125566 植入之灌注系統及脂質體。用於吸入投予之調配物可含有如賦形劑（例如，乳糖），或可爲含有例如聚氧基伸乙基-9 -月桂醚、甘膽酸鹽及去氧膽酸鹽之水溶液，或以鼻滴劑形式投予之油性溶液，或爲經鼻內塗抹之凝膠。留滞型灌腸劑亦可用於直腸輸送。適合於口服投於予之本發明調配物可呈以下形式：個別單元，諸如膠囊、明膠膠囊、小藥囊、錠劑、菱形錠或喉糖錠，每個含有預定量之藥物；粉末或顆粒組成物；在水性液體或非水性液體中的溶液或懸浮液；或油水型乳液或水油型乳液。藥物亦可以大藥九、糖果劑或糊劑形式投予。錠劑可藉由將藥物隨意地與一或種多種附屬成分壓縮或模製而製得。經壓縮之錠劑可藉由將呈自由流動形式之藥物（諸如粉末或顆粒）在適合的機器中壓縮且隨意地與黏合劑、潤滑劑、惰性稀釋劑、表面活性或分散劑混合而製備。經模製之錠劑可藉由將粉末狀藥物與以惰性液體稀釋劑弄濕之適合的載劑之混合物在適合的機器中模製而製得〇口服組成物通常包括惰性稀釋劑或可食用載劑。以口服治療投予爲的目，可將活性化合物與賦形劑合倂。使用液體載劑所製備而用作爲漱口水之口服組成物包括在流體載劑中的化合物，且經口施予，並漱口且吐出或吞下。醫藥上可相容之黏合劑及/或佐劑材料可包括爲組成物的一部分。錠劑、九劑、膠囊 '菱形錠及類似物可含有任何下列成分或類似本性之化合物：黏合劑，諸如微結晶纖維素 -91 - 201125566 、黃蓍膠或明膠；賦形劑，諸如澱粉或乳糖；崩散劑，諸如藻酸、普姆膠（Primogel)或玉米澱粉；潤滑劑，諸如硬脂酸鎂或史特羅（Sterotes);助滑劑，諸如膠體二氧化矽 ;甜味劑，諸如蔗糖或糖精；或調味劑，諸如薄荷、水楊酸甲酯或柳橙口味。適合於注射使用的醫藥組成物包括無菌水性溶液（於此可溶於水）或分散液及即席製備無菌可注射溶液或分散液的無菌粉末。適合於靜脈內投予的載劑包括生理食鹽水、制菌水、Cremophor ELTM(BASF，Parsippany，N.J·)或磷酸鹽緩衝食鹽水（PBS)。其在製造及貯存條件下應該爲穩定的且應該以對抗微生物（諸如細菌和真菌）的污染作用予以保存。載劑可爲含有例如水、乙醇、多元醇（例如，甘油、丙二醇及液體聚乙二醇）及其適合的混合物之溶劑或分散介質。適當的流動性可例如藉由使用包膜（諸如卵磷脂），藉由在分散液的情況中維持必需的粒徑及藉由使用界面活性劑來維持。在許多情況中，較佳的是在組成物中包括等張劑（例如，糖）、多元醇（諸如甘露醇、山梨醇）或氯化鈉。延長可注射組成物的吸收可藉由在組成物中包括延遲吸收之劑而引起，例如單硬脂酸鋁及明膠。無菌可注射溶液可藉由將活性化合物以必需的量與若必需時的上述列舉之成分中之一或其組合倂入適當的溶劑中及接著過濾滅菌而製備。通常分散液係藉由將活性化合物倂入含有基本分散介質及來自那些上述列舉之必需的其他成分的無菌媒劑中而製備。在用於製備無菌可注射溶液 ⑧ -92- 201125566 之無菌粉末的情況中’製備方法包括真空乾燥及凍乾’得到活性成分加上來自先前其經無菌過濾之溶液的任何額外所欲成分之粉末。適合於關節內投予之調配物可呈藥物的無菌水性製劑形式，其可呈微結晶形式，例如呈水性微結晶懸浮液形式。亦可使用脂質體調配物或可生物降解之聚合物系統，以提供用於關節內及眼部投予二者之藥物。適合於局部投予（包括眼部治療）之調配物包括液體或半液體製劑，諸如擦劑、洗劑、凝膠、敷劑、油水型或水油型乳液（諸如乳霜、軟膏或糊劑）；或溶液或懸浮液（諸如滴劑）。用於局部投予皮膚表面之調配物可藉由將藥物以皮膚學上可接受之載劑（諸如洗劑、乳霜、軟膏或肥皂）分散而製備。特別有用的載劑爲能夠在皮膚上形成膜或層之載劑，以局限施予且禁止移除。可將用於局部投予內部組織表面之劑分散在液體組織黏著劑或已知的其他物質中，以增強吸附至組織表面。例如，可有利於使用羥丙基纖維素或纖維蛋白原/凝血酶溶液。另一選擇地，可使用組織塗佈溶液，諸如含果膠之調配物。可使用以噴霧罐、噴灑器或霧化器配送之粉末吸入（自行-推進或噴霧調配物）用於吸入治療。此等調配物可從粉末吸入裝置或自行-推進粉末-配送調配物而呈用於肺部投予的細粉末形式。在自行-推進溶液及噴霧調配物之情形中，此效果可藉由選擇具有所欲噴霧特徵之閥（亦即能夠產生具有所欲粒徑之噴霧）或藉由倂入活性成分作爲粒 -93- 201125566 徑受控制之懸浮粉末而達成。以吸入投予之化合物亦可以氣溶膠噴霧形式從含有適合的推進劑（例如，氣體，諸如二氧化碳）或噴灑劑之加壓容器或配送器輸送。全身性投予亦可以穿透黏膜或穿透皮0的方式。以適合於穿透障壁的穿透劑用於穿透黏膜或穿透皮廚投予的調配物中。此等穿透劑通常爲本技藝中已知，且包括例如用於穿透黏膜投予的清潔劑及膽鹽。穿透黏膜投予可經由使用鼻噴霧劑或栓劑而實現。穿透皮膚投予的活性化合物典型地調配成通常爲本技藝中已知的軟脊、油膏、凝膠或乳霜。活性化合物可以防護化合物免於從身體快速消除的醫藥上可接受之載劑製備，諸如控制釋放調配物，包括植入劑及微囊封輸送系統。可使用可生物降解且可生物相容之聚合物，諸如乙烯乙酸乙烯酯、聚酐、聚乙醇酸、膠原蛋白、聚原酸酯及聚乳酸。此等調配物之備製方法爲那些熟諳本技藝者顯而易見。微脂體懸浮液亦可用作爲醫藥上可接受之載劑。該等可根據那些熟諳本技藝者已知的方法製備，例如在美國專利案第4,5 22，81 1號中所述。口服或非經腸組成物可調配成容易投予且劑量均勻的單位劑型。單位劑型係指適合作爲用於欲治療之對象的單一劑量的物理分立單位：每個單位含有與必需之醫藥載劑結合的經計算以產生所欲療效之預定量活性化合物。本發明的單位劑型規格係由且直接取決於活性化合物的獨特特徵及欲達成之特別療效而指定，且取決於在化合用於治療 ⑧ -94- 201125566 個體的此活性化合物之技藝中的固有限制。此外，投予可爲以大藥九之定期注射，或可從外部儲存器（例如，靜脈注射袋）更連續以靜脈內、肌肉內或腹腔內投予而達成。在希望黏附於組織表面處，組成物可包括分散於纖維蛋白原/凝血酶組成物或其他生物黏著劑中的藥物。接著可將化合物塗敷、噴灑或以另外方式塗抹於所欲組織表面。另一選擇地，藥物可經調配而以例如治療有效量經耳、眼、鼻、非經腸或口服投予人類或其他動物，例如該有效量提供適當的藥物濃度至目標組織，經足夠的時間誘發所欲效果。在活性化合物欲用作爲移植程序的一部分時，其可在組織或器官自捐贈者移出之前先提供至欲移植之活組織或器官。可將化合物提供至捐贈宿主。另一選擇地或另外，一經自捐贈者移出時，可將器官或活組織放入含有活性化合物的保存溶液中。在所有情況中，可將活性化合物直接投予所欲組織，如藉由注射至組織中，或可使用本文所述及/或本技藝中已知的任何方法及調配物經全身提供，例如藉由耳、眼、鼻、口服或非經腸投予。在藥物包含組織或器官保存溶液的一部分時，可有利於使用任何市售可取得的保存溶液。例如，在本技藝中已知的有用溶液包括可林（Collins)溶液、威斯康辛（Wisconsin)溶液、貝爾惹 (Belzer)溶液、優可林（Eurocollins)溶液及乳酸化之林格 (Ringer)溶液。本發明化合物可藉由將化合物施加在與組織接觸安置 -95- 201125566 的醫學裝置中而直接投予組織所在地。醫學裝置的實例爲支架，其含有或被塗以一或多種本發明化合物。例如，可將活性化合物施加在血管受傷位置的支架中。支架可以醫藥技術中熟知的任何方法製備。參見例如 Fattori, R. and Piva, T., 44Drug-Eluting Stents in Vascular Intervention," Lancet, 2003, 361, 247-249 ； Morice, M. C., “A New Era in the Treatment of Coronary Disease?” European Heart Journal, 2003, 24， 209-211 ;及Biosensor RTM) provides an interface between the focused beam of multi-colored light to the gold film (provided as a disposable biosensor ''chip') and the buffer interval (adjustable by the user). A 100 nm thick "hydrogel" consisting of a carboxylated polydextrose that provides a covalently immobilized matrix of the analyte of interest is attached to the gold film. When the focused light interacts with the free electron cluster of the gold film, it enhances the plasma resonance of -84 - 201125566. The resulting reflected light is spectrally depleted in wavelength, optimally releasing resonance. By separating the reflected polychromatic light into its component wavelength (using a prism) and measuring the frequency of the loss, an optical interface is established with BIAcore, which accurately describes the surface plasmon resonance performance produced. When the design is as described above, the plasmon resonance (and therefore the loss spectrum) is sensitive to the quality of the fading region, which roughly corresponds to the thickness of the hydrogel. If one component of the interaction pair is immobilized to the hydrogel and the interaction partner is provided via a buffer interval, the interaction between the two components can be mass accumulation in the fading region and its corresponding The plasmon resonance effect (as measured by the loss spectrum) is measured on the fly. This system allows for fast and sensitive molecular interactions for immediate measurement without the need to label any component 〇 (2) Fluorescence polarization. Fluorescence Polarization (FP) is a measurement technique that can be easily applied to protein-protein, protein-ligand or RNA-ligand interactions to derive IC5Q and Kd for the joint reaction between two molecules. . In this technique, one of the molecules of interest is conjugated to a fluorophore. This is usually the smaller molecule in the system (in this case the compound of interest). A sample mixture containing a ligand-probe conjugate and a ribosome, a ribosome subunit or a fragment thereof is excited with vertical polarized light. The light system is absorbed by the probe fluorophore and re-emitted after a short time. Measure the degree of polarization of the emitted light. The polarization of the emitted light depends on many factors, but the most important is the viscosity of the solution and the apparent molecular weight of the fluorophore. The change in the degree of polarization of the emitted light with appropriate control depends only on the change in the apparent molecular weight of the fluorophore, which in turn depends on whether the probe-ligand conjugate is not present in the solution -85-201125566, or Binds to the receptor. The FP-based binding assay has many important advantages, including IC5() and Kd under reliable homogeneous equilibrium conditions, analytical speed and automation facilities, and screening capabilities in turbid suspensions and colored solutions. . (3) Protein synthesis. In addition to being characterized by the aforementioned biochemical assays, compounds of interest are also characterized by modulators of functional activity of ribosomes or ribosomal subunits (e.g., protein synthesis inhibitors). In addition, more specific protein synthesis inhibition assays can be performed by administering the compound to an entire organism, tissue, organ, organelle, cell, cell or subcellular extract, or purified ribosome preparation and by measuring, for example, The inhibitory constant (IC5G) of protein synthesis was inhibited to observe its pharmacological and inhibitory properties. The activity of protein synthesis can be investigated by injecting 3H leucine or 35s methionine or the like. A change in the amount or rate of protein synthesis in a cell in the presence of a molecule of interest indicates that the molecule is a protein synthesis regulator. A decrease in the rate and amount of protein synthesis indicates that the molecule is a protein synthesis inhibitor. (4) Antimicrobial assays and other assessments. In addition, the anti-proliferative or anti-infective properties of the compounds can be assayed at the cellular level. For example, when the target organism is a microorganism, the activity of the compound of interest can be assayed by growth of the microorganism of interest in a medium containing or lacking the compound. Growth inhibition can indicate that a molecule can act as a protein synthesis inhibitor. More particularly, the activity of a compound of interest against a bacterial pathogen can be demonstrated by the ability of the compound to inhibit the growth of a defined human pathogen strain. For this purpose, bacterial strain plates can be aggregated to include a variety of target pathogen species, and some -86-201125566 contain a characterized resistance mechanism. The use of this organism culture plate allows the determination of the structure-activity relationship not only with respect to potency and spectrum, but also from the viewpoint of eliminating the drug resistance mechanism. The minimum inhibitory concentration (MIC) is based on the model described by the Clinical and Laboratory Standards Institute [CLSI; formerly the National Committee for Clinical Laboratory Standards (NCCLS)] Determined by the dilution method, typically in a final volume of 100 μl. See CLSI: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-fifth edition. Wayne, PA; NCCLS; 2000. The assay can also be based on CLSI The published conventional methods are performed in a microtiter plate. See CLSI: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-S eventh Edition. CLSI Document M7-A7 [ISBN 1 -5 623 8-5 87 -9] CLSI, 940 West Valley Road, Suite 1 400, Wayne Pennsylvania 1 9087- 1 898 USA, 2006) o Antimicrobial and other pharmaceutical properties of compounds can be further evaluated in various in vivo mammalian assays, such as mice Or rabbit peritonitis infection pattern, skin and cartilage Weave pattern (often called thigh mode) or mouse pneumonia model. There are those patterns of sepsis or organ infection known to those skilled in the art. These modes of effectiveness can be used as part of the assessment method and can be used as a guide to potential efficacy in humans. The endpoint can be changed from reducing the amount of bacteria to killing -87-201125566 injury rate. For the latter endpoint, the results are often expressed as P D 5 〇値 or a drug dose that protects 50% of the animals from death. To further assess the medicinal properties of the compounds, recombinant human enzyme systems or more complex systems (such as human liver microsomes) can also be used to measure the inhibition of cytochrome 450 enzymes and the metabolic activity of the third metabolite. Further, the compound can also be evaluated as a substrate for the activity of such metabolic enzymes. Such activities have the potential to be used to determine whether a compound causes a drug-drug interaction or produces a metabolite with or without antimicrobial activity. In order to obtain a potential assessment of the compound's oral bioavailability, solubility and Caco 2 assays can also be performed. The latter is a cell line derived from human epithelium that allows for the measurement of drug uptake and passage through a Caco-2 cell monolayer that is often grown in a well of a 24-well microtiter plate equipped with a 1 micron membrane. The free drug concentration can be measured on the bottom side of the monolayer to assess the amount of drug that can pass through the intestinal monolayer. Appropriate control is necessary to ensure single layer integrity and tightness of the crack joints. This same system can be used to obtain an assessment of P-glycoprotein mediated outflow. The P-glycoprotein is a pump that is localized to the apical membrane of the cell, forming a polarized monolayer. This pump can eliminate active or passive uptake across the Caco-2 cell membrane, resulting in less drug passing through the intestinal epithelium. These results are often performed along with solubility measurements and these two factors are known to contribute to oral bioavailability in mammals. Absolute oral bioavailability was determined using conventional pharmacokinetic experiments to measure oral bioavailability in animals and ultimately in humans. Experimental results can also be used to develop patterns that help predict physico-chemical parameters that contribute to drug-like properties. When this model is proven to be a real-time 'inductive-88-201125566 experimental method, the credibility of the model predictability is increased. 5. Formulation and Administration The compounds of the present invention are useful for the prevention or treatment of various human (including mammalian and non-mammalian) conditions including, for example, fungal infections, viral infections, diarrhea, parasitic diseases and at the time of verification 'expected activity of the present invention The molecule can be used as a carrier before use. The dosage, mode of administration, and availability of the active molecule will depend on the intended recipient and the target organism. Formulations of the compounds (for veterinary medicine and human medicine, including such compounds in combination with pharmaceutically acceptable carriers. The carrier should be acceptable ", compatible with the formulation and not correct The recipient's harmful meaning. In this regard, the medical carrier is intended to include any and dispersion medium, envelope, antibacterial and antifungal agents, isotonic and analogous compatible with pharmaceutical administration. Such media and agents of the active materials are known, except for the use of any of the conventional media or agents in combination with the active ingredients. The active compounds are contemplated (in accordance with the present invention and/or in the art) Incorporating into the composition. The formulation may be conveniently prepared by any of the usual formulations which are well known in the art of pharmacy/microbiology, by the compound and liquid carrier or fine agent or Prepare a combination and then prepare the product formulation if necessary. Or other animal such as a bacterium that infects cancer. Once incorporated into any suitable carrier, I) typically encapsulates other ingredients in accordance with the present invention. Some acceptable solvent, absorption delaying agents was not compatible with the present techniques may also be supplemented by known forensic unit dosage form was prepared. The comminuted solids are formed to form the desired tone. -89- 201125566 The pharmaceutical composition of the present invention should be formulated to be compatible with the intended route of administration. Examples of routes of administration include administration via oral, otic, ocular, nasal or parenteral (e.g., intravenous, intradermal, inhalation, penetrating skin 0 (local) 'transmucosal and rectal) administration. Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: sterile diluents, such as water for injection, aqueous saline, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents. An antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium hydrogen sulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate , and a tonicity modifier such as sodium chloride or glucose. The pH can be adjusted with an acid or a base such as hydrochloric acid or sodium hydroxide. Solutions for oral or parenteral administration can be prepared by any of the methods well known in the art of pharmacy, for example, as described in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration may also include glycocholic acid for buccal administration, methoxysalicylate for rectal administration or citrate for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration can be prepared by mixing the drug with non-irritating excipients such as cocoa butter, other glycerides or other compositions which are solid at room temperature and liquid at body temperature. Formulations may also include, for example, polyalkylene glycols (such as polyethylene glycol), oils derived from vegetable sources, and hydrogenated naphthalenes. Formulations for direct administration may include glycerin and other high viscosity compositions. Other non-enteric carriers which are potentially useful for such drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, perfusion systems and liposomes that can be implanted in -90-201125566. The formulation for administration by inhalation may contain, for example, an excipient (for example, lactose), or may be an aqueous solution containing, for example, polyoxyethylidene-9-lauryl ether, glycocholate, and deoxycholate, or An oily solution administered as a nasal drop, or a gel applied intranasally. A stasis enema can also be used for rectal delivery. Formulations suitable for oral administration can be in the form of individual units, such as capsules, gelatin capsules, sachets, lozenges, lozenges or lozenges, each containing a predetermined amount of the drug; powder or granules a composition; a solution or suspension in an aqueous liquid or a non-aqueous liquid; or an oil-water emulsion or a water-oil emulsion. The drug can also be administered in the form of a large drug, a candy or a paste. Tablets can be prepared by compressing or molding the drug with one or more accessory ingredients. The compressed lozenge can be prepared by compressing a free-flowing form of the drug (such as a powder or granules) in a suitable machine and optionally mixing with a binder, lubricant, inert diluent, surface active or dispersing agent. The molded tablet can be prepared by molding a mixture of the powdered drug and a suitable carrier which is moistened with an inert liquid diluent in a suitable machine. The oral compositions usually comprise an inert diluent or are edible. Carrier. The active compound can be combined with excipients for oral administration. An oral composition prepared as a mouthwash using a liquid carrier is included in a fluid carrier and administered orally, and rinsed and spit or swallowed. Pharmaceutically compatible adhesives and/or adjuvant materials can be included as part of the composition. Tablets, nine doses, capsules, diamond-shaped tablets and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose-91 - 201125566, tragacanth or gelatin; excipients such as starch or Lactose; a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Strotes; a slip agent such as colloidal cerium oxide; a sweetener such as Sucrose or saccharin; or a flavoring agent such as mint, methyl salicylate or orange flavor. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (wherein they are soluble in water) or dispersions and sterile powders in the preparation of sterile injectable solutions or dispersions. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of an envelope (such as lecithin), by the maintenance of the necessary particle size in the case of dispersions, and by the use of surfactants. In many cases, it is preferred to include an isotonic agent (e.g., a sugar), a polyhydric alcohol (such as mannitol, sorbitol) or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption in the compositions, such as aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount, together with one or a combination of the above-mentioned ingredients, if necessary, in a suitable solvent, followed by filter sterilization. Typically, the dispersion is prepared by incorporating the active compound into a sterile vehicle containing the base dispersion medium and other ingredients necessary from those enumerated above. In the case of a sterile powder for the preparation of a sterile injectable solution 8-92-201125566, the method of preparation comprises vacuum drying and lyophilization to obtain an active ingredient plus a powder of any additional desired ingredients from a previously sterilely filtered solution thereof. . Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the drug, which may be in a microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to provide drugs for both intra-articular and ocular administration. Formulations suitable for topical administration, including ocular treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, dressings, oil-water or water-oil emulsions (such as creams, ointments or pastes). ); or a solution or suspension (such as drops). Formulations for topical administration to the skin surface can be prepared by dispersing the drug in a dermatologically acceptable carrier such as lotion, cream, ointment or soap. A particularly useful carrier is a carrier capable of forming a film or layer on the skin for localized administration and forbidden removal. The agent for topical administration to the surface of the internal tissue can be dispersed in a liquid tissue adhesive or other known substance to enhance adsorption to the surface of the tissue. For example, it may be advantageous to use a hydroxypropylcellulose or a fibrinogen/thrombin solution. Alternatively, a tissue coating solution, such as a formulation containing pectin, can be used. Powder inhalation (self-propelled or spray formulations) delivered in a spray can, sprinkler or nebulizer can be used for inhalation therapy. Such formulations may be in the form of a fine powder for pulmonary administration from a powder inhalation device or a self-propelled powder-delivery formulation. In the case of self-propelled solutions and spray formulations, this effect can be achieved by selecting a valve having the desired spray characteristics (i.e., capable of producing a spray having the desired particle size) or by injecting the active ingredient as a granule-93. - 201125566 Achieved with a controlled suspension of powder. The compound administered by inhalation may also be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide) or a spray. Systemic administration can also penetrate the mucosa or penetrate the skin 0. A penetrant suitable for penetrating the barrier is used to penetrate the mucosa or penetrate the formulation administered by the kitchen. Such penetrants are generally known in the art and include, for example, detergents and bile salts for penetrating mucosal administration. Penetrating mucosal administration can be accomplished by the use of nasal sprays or suppositories. The active compound administered through the skin is typically formulated into a soft ridge, ointment, gel or cream which is generally known in the art. The active compound can protect the compound from pharmaceutically acceptable carrier preparations which are rapidly eliminated from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. The preparation of such formulations is apparent to those skilled in the art. The liposome suspension can also be used as a pharmaceutically acceptable carrier. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,5,22,81. The oral or parenteral compositions can be formulated in unit dosage forms for ease of administration and uniformity. Unit dosage form refers to a physically discrete unit suitable as a single dose for the subject to be treated: each unit contains a predetermined amount of active compound in association with the required pharmaceutical carrier, calculated to produce the desired therapeutic effect. The unit dosage form of the present invention is specified by and directly depending on the unique characteristics of the active compound and the particular therapeutic effect desired, and is dependent upon the inherent limitations in the art of compounding the active compound for treatment of the individual from 8 to 94 to 201125566. . Further, the administration may be carried out by regular injection of a large drug, or may be administered continuously, intravenously, intramuscularly or intraperitoneally from an external reservoir (e.g., an intravenous bag). Where it is desired to adhere to the surface of the tissue, the composition may include a drug dispersed in a fibrinogen/thrombin composition or other bioadhesive. The compound can then be applied, sprayed or otherwise applied to the desired tissue surface. Alternatively, the medicament may be formulated to be administered to a human or other animal, for example, in a therapeutically effective amount, by ear, eye, nose, parenteral or oral administration, for example, the effective amount provides the appropriate drug concentration to the target tissue, sufficient Time induces the desired effect. Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of the tissue or organ from the donor. The compound can be provided to a donor host. Alternatively or additionally, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, such as by injection into a tissue, or can be provided systemically, for example, by any of the methods and formulations described herein and/or as known in the art. It is administered by ear, eye, nose, orally or parenterally. Where the drug comprises a portion of the tissue or organ preservation solution, it may be advantageous to use any commercially available preservation solution. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eucollins solution, and lactated Ringer solution. The compounds of the present invention can be administered directly to the site of the tissue by applying the compound to a medical device that is placed in contact with the tissue and placed in -95-201125566. An example of a medical device is a scaffold that contains or is coated with one or more compounds of the invention. For example, the active compound can be applied to a stent at the site of the vessel injury. The stent can be prepared by any method well known in the art of medicinal techniques. See, for example, Fattori, R. and Piva, T., 44 Drug-Eluting Stents in Vascular Intervention, " Lancet, 2003, 361, 247-249; Morice, MC, "A New Era in the Treatment of Coronary Disease?" European Heart Journal, 2003, 24, 209-211; and

Toutouzas，K.等人之”Sirolimus-Eluting Stents : A Review of Experimental and Clinical Findings,Z. Kardiol.，2002, 91(3), 49-57。支架可由不銹鋼或其他生物可相容之金屬製作，或其可以生物可相容之聚合物製得。活性化合物可與支架表面連結，嵌入塗佈在支架上的聚合物材料且從該材料釋放，或由塗佈或跨橋支架之載劑圍繞且經由該載劑釋放。可使用支架投予單一或多重活性化合物至鄰近於支架之組織。可將如本文所述之方法鑑證且設計之活性化合物可投予個體以治療病症（預防或治療）。可將藥物基因學（亦即硏究個體基因型與個體對外來化合物或藥物的反應之間的關係）與此治療一起考慮。治療法的代謝差異可藉由改變藥理活性藥物的劑量與血液濃度之間的關係而造成嚴重的毒性或治療失敗。因此，醫師或臨床醫師可考慮應用在測定是否投予藥物以及修改以藥物治療的劑量及/或治療系統之相關藥物基因學硏究中所獲得的知識。 -96- 201125566 在治療或對抗哺乳動物中的細菌感染之治療用途中，將化合物或其醫藥組成物以獲得及維持濃度的劑量經耳、眼、鼻、口服、非經腸及/或局部投予，亦即該濃度爲活性組份在進行治療之動物中的抗微生物有效量或血液或組織水平。活性組份劑量的有效量通常係在從約0 .丨至約 100 ’更佳爲從約ΐ·〇至約50毫克/公斤體重/天之範圍內。所投予之量亦同樣取決於諸如欲治療之疾病或徵兆類型和程度 '特殊病患的整體健康狀態、所輸送之化合物的相關生物效力、藥物的調配、調配物中的賦形劑存在和類型及投予途徑之變數而定。亦應了解所投予之初劑量可增加超越上述的上水平，俾以快速達到所欲血液水平或組織水平’或初劑量可小於最優値且日劑量可在治療期間取決於特殊狀況而循序增加。若有要求時，亦可將日劑量分成多重劑量投予，例如每天2至4次。在人類和其他哺乳動物中的各種疾病狀態或症狀經發現係由無意義或錯義突變所引起或介導。該等突變係由於例如蛋白質合成、摺疊、運輸及/或功能受到不利影響而引起或介導疾病狀態或症狀。疾病狀態或症狀（其中相當高百分比的疾病症狀咸信係由無意義或錯義突變所造成）的實例包括血友病（因子V 111基因）、神經纖維瘤病（N F 1 和NF2基因）、色素沉著性視網膜炎（人類USH2A基因）、大皰性皮膚病，如大皰性表皮鬆解症（COL7A 1基因）、囊性纖維變性（囊性纖維變性透膜調節基因）、乳癌和卵巢癌 (BRCA1和BRCA2基因）、裘馨氏肌肉萎縮症（肌肉萎縮蛋 -97- 201125566 白基因）、結腸癌（誤配基因，以M L Η 1和M S Η 2佔優勢）及溶小體醣脂類儲積症，諸如尼曼匹克症（Niemann-Pick disease)(酸性鞘磷脂酶基因）。參見Sanders CR, Myers J K. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004; 33 ： 25-51 ；Toutouzas, K. et al., "Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings, Z. Kardiol., 2002, 91(3), 49-57. Stents can be made of stainless steel or other biocompatible metals, Or it may be made of a biocompatible polymer. The active compound may be attached to the surface of the stent, embedded in and released from the polymeric material coated on the stent, or surrounded by a carrier coated or bridged and Release via the carrier. A single or multiple active compound can be administered to the tissue adjacent to the stent using a stent. The active compound ascertained and designed as described herein can be administered to an individual to treat the condition (prophylaxis or treatment). The pharmacogenetics (that is, the relationship between the individual genotype and the response of an individual to a foreign compound or drug) can be considered together with this treatment. The metabolic difference in the treatment can be changed by changing the dose and blood concentration of the pharmacologically active drug. The relationship between them causes severe toxicity or treatment failure. Therefore, the physician or clinician may consider applying whether to administer the drug and modify it. Knowledge obtained from the dose of the therapeutic agent and/or related pharmacological studies of the therapeutic system. -96- 201125566 In the therapeutic use of treating or combating bacterial infections in mammals, the compound or its pharmaceutical composition is obtained. And maintaining the concentration of the dose by ear, eye, nose, oral, parenteral and/or topical administration, that is, the concentration is an antimicrobially effective amount or blood or tissue level of the active ingredient in the animal being treated. The effective amount of the component dose is usually in the range of from about 0.1 to about 100', more preferably from about 毫克·〇 to about 50 mg/kg of body weight per day. The amount administered also depends on, for example, The type and extent of the disease or condition being treated depends on the overall health status of the particular patient, the biological effectiveness of the compound being delivered, the formulation of the drug, the presence and type of excipients in the formulation, and the variables of the route of administration. It should be understood that the initial dose administered may increase beyond the above-mentioned upper level, and the sputum may quickly reach the desired blood level or tissue level' or the initial dose may be less than optimal and the daily dose may be taken during the treatment period. Depending on the particular condition, it may be added sequentially. If required, the daily dose may be divided into multiple doses, for example 2 to 4 times a day. Various disease states or symptoms in humans and other mammals are found to be meaningless. Caused or mediated by a missense mutation that causes or mediates a disease state or symptom due to, for example, adverse effects on protein synthesis, folding, trafficking, and/or function. A disease state or symptom (a relatively high percentage of the disease) Examples of symptomatic salty signals caused by meaningless or missense mutations include hemophilia (factor V 111 gene), neurofibromatosis (NF 1 and NF2 genes), pigmented retinitis (human USH2A gene), Bullous skin diseases such as bullous epidermolysis (COL7A 1 gene), cystic fibrosis (cystic fibrosis transmembrane regulatory gene), breast and ovarian cancer (BRCA1 and BRCA2 genes), and muscles Atrophy (muscle-deficient egg-97- 201125566 white gene), colon cancer (mismatched gene, dominated by ML Η 1 and MS Η 2) and lytic glycolipid accumulation, such as Man Pick disease (Niemann-Pick disease) (acid sphingomyelinase gene). See Sanders CR, Myers J K. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct. 2004; 33: 25-51;

National Center for Biotechnology Information (U.S.) Genes and Disease Bethesda， MD; NCBI， NLM ID : 1 0 1 1 3 8 5 60 ;及 Rask0，Istv^n; Downes，C S Genes in medicine : molecular biology and human genetic disorders 1st ed. London; New York; Chapman & Hall，1 995. NLM ID : 95 02 4 04。可使用本發明化合物治療或預防在哺乳動物中由此等無意義或錯義突變所引起或介導之疾病狀態，其係藉由將有效量之本發明化合物投予需要其之哺乳動物，以抑制涉入疾病狀態中的無意義或錯義突變。【實施方式】 6.實例核磁共振（NMR)光譜係在 Bruker Avance 300或 Avance 500分光計上獲得，或在一些情況中於GE-Nicolet 3 00分光計上獲得。常見的反應溶劑具有高性能液相層析術（HPLC)等級或美國化學學會（American Chemical S〇Ciety)(ACS)等級，且此爲從製造商所獲得的無水物，除非另有其他註明。a層析術〃或、以矽膠純化〃係指使用矽膠（EM Merck，Silica Gel 60，23 0-400 篩網）之快速管柱 201125566 層析術，除非另有其他註明。本發明化合物可使用適應於手邊的特殊情況之已知的化學轉變來製備。在下列實例合成的實驗細節中所使用的一些縮寫係定義如下：h或hr =小時；min =分鐘；m〇l =莫耳；mm〇i =毫莫耳；M =莫耳；μΜ =微莫耳；g =公克；pg =微克；η =室溫 ;L =公升；mL =毫生；Et2 =二***；THF =四氫呋喃； DMSO=二甲亞颯；EtOAc=乙酸乙酯；Et3N=三乙胺；i-Pr2NEt或 DIPEA=二異丙基乙胺；CH2C丨2=二氯甲院； CHC13 =氯仿；CDC13 =氘化氯仿；CC14 =四氯化碳；MeOH = 甲醇；CD3OD =氘化甲醇；EtOH =乙醇；DMF =二甲基甲醯胺；BOC =第三丁氧基羰基；CBZ =苯甲氧基羰基；TBS =第三丁基二甲基矽烷基；TBSC1 =第三丁基二甲基矽烷基氯 ;TFA二三氟乙酸；DBU=二氮雜雙環十一·烯；TBDPSC1 = 第三丁基二苯基氯砂院；胡尼格氏（Hunig’s)驗=N，N -二異丙基乙胺；DMAP = 4-二甲基胺基吡啶；Cul=碘化銅（I); MsCl=甲院磺醯氯；NaN3=疊氮化鈉；Na2S04=硫酸鈉； NaHC〇3 =碳酸氫鈉；NaOH=氫氧化鈉；MgS〇4 =硫酸鎂； K2C03=碳酸鉀；KOH=氫氧化鉀；NH4OH=氫氧化銨； NH4C1=氯化銨；Si02=二氧化矽；Pd-C=鈀/碳： Pd(dppf)Cl2 =二氯[1，1’-雙（二苯膦基）二茂鐵]鈀（II)。將依照本發明所合成之示例化合物陳列於表1中。所顯示之黑體鍵或虛線鍵係標示在手性中心的特殊立體化學，而波形鍵標示取代基可在定位上或化合物爲其混合物。 -99- 201125566 亦應知道爲了節省空間而將一些化合物的化學結構***成具有兩個連接點的兩個部分，每個連接點以波形線交叉的鍵標示。參見例如化合物9 5 6，將其繪製成如以下的兩個部分：National Center for Biotechnology Information (US) Genes and Disease Bethesda, MD; NCBI, NLM ID: 1 0 1 1 3 8 5 60 ; and Rask0, Istv^n; Downes, CS Genes in medicine : molecular biology and human genetic disorders 1st Ed. London; New York; Chapman & Hall, 1 995. NLM ID: 95 02 4 04. The compounds of the invention may be used to treat or prevent a disease state caused or mediated by such nonsense or missense mutations in a mammal by administering an effective amount of a compound of the invention to a mammal in need thereof Inhibition of meaningless or missense mutations involved in disease states. [Embodiment] 6. Examples Nuclear magnetic resonance (NMR) spectroscopy was obtained on a Bruker Avance 300 or Avance 500 spectrometer or, in some cases, on a GE-Nicolet 00 spectrometer. Common reaction solvents are high performance liquid chromatography (HPLC) grades or American Chemical S(Ciety) (ACS) grades, and this is an anhydride obtained from the manufacturer unless otherwise noted. a Chromatography or purification with tannin refers to the use of tantalum (EM Merck, Silica Gel 60, 23 0-400 mesh) fast column 201125566 chromatography, unless otherwise noted. The compounds of the present invention can be prepared using known chemical transformations adapted to the particular conditions at hand. Some of the abbreviations used in the experimental details of the synthesis of the following examples are defined as follows: h or hr = hours; min = minutes; m〇l = mol; mm〇i = millimolar; M = mol; μΜ = micro Mohr; g = gm; pg = microgram; η = room temperature; L = liter; mL = millis; Et2 = diethyl ether; THF = tetrahydrofuran; DMSO = dimethyl hydrazine; EtOAc = ethyl acetate; Et3N = three Ethylamine; i-Pr2NEt or DIPEA = diisopropylethylamine; CH2C丨2 = dichlorocarbyl; CHC13 = chloroform; CDC13 = deuterated chloroform; CC14 = carbon tetrachloride; MeOH = methanol; CD3OD = deuterated Methanol; EtOH = ethanol; DMF = dimethylformamide; BOC = third butoxycarbonyl; CBZ = benzyloxycarbonyl; TBS = third butyl dimethyl decyl; TBSC1 = tertiary butyl Dimethyl decyl chloride; TFA ditrifluoroacetic acid; DBU = diazabicyclo undecene; TBDPSC1 = third butyl diphenyl chloride sand; Hunig's test = N, N - Diisopropylethylamine; DMAP = 4-dimethylaminopyridine; Cul = copper iodide (I); MsCl = sulfonium chloride; NaN3 = sodium azide; Na2S04 = sodium sulfate; NaHC〇3 = sodium bicarbonate; NaOH = sodium hydroxide; MgS〇4 = magnesium sulfate; K2C03 = potassium carbonate; KOH = potassium hydroxide; NH4OH = ammonium hydroxide; NH4C1 = ammonium chloride; SiO2 = cerium oxide; Pd-C = palladium / carbon: Pd (dppf) Cl2 = dichloro [ 1,1'-bis(diphenylphosphino)ferrocene]palladium (II). Exemplary compounds synthesized in accordance with the present invention are shown in Table 1. The black or dashed key shown is indicative of a particular stereochemistry at the chiral center, while the wavy bond indicates that the substituent can be positioned or the compound is a mixture thereof. -99- 201125566 It should also be understood that in order to save space, the chemical structure of some compounds is split into two parts with two connection points, each of which is indicated by a wavy line crossing key. See, for example, Compound 9.5, which is drawn as two parts as follows:

但是對應於以下完整的化學結構： ΝΗ υιαχ^0〇可將本發明化合物製備、調配成鹽、酯及前藥且以其輸送。爲方便起見，通常顯示化合物而不標示特殊的鹽、酯或前藥形式。將本發明化合物顯示於表1中。提供可取得的 LCMS(液相層析術質譜）數據。當不可取得數據時，則以 % ΝΑ"標示。LCMS數據係使用具有格式[Μ + Η] +之m/z 爲常規提供，除非另有其他標示。 ⑧ 表1 化合物編號結構 LCMS 392 、Χ〇 Η 385.10 -100- 201125566 393 Η 458.00 396 H2N^^N^rj^ 442.00 400 ，丫 Ό Η 527.00 402 458.00 440 0^Ν次 0〇 527.00 442 ^ΑΝ/·γ°γ^ΒΓ 442.00 460 H^Tx^ry^yF 入W 482.00 201125566 528 5χ〇 Η 341.90 529 ΝΗ Η2Ν 人〇ANAKAy 383.90 543 H 356.10 544 4x〇 H 384.10 557 H 370.20 558 oix^y H 486.10 575 NH H2N^f HN^ 398.20 576 NH H 3x〇 H 426,10 -102- ⑧ 201125566 578 Η 285.00 579 407.00 592 464.10 595 Η〇。人人 Η 298.90 598 厂Ο Η 355.90 603 -卜，χο Η 398.10 604 Η/°ϊΧ：〇 Η 370.30 606 νη2 。人乂 och3 400.10 -103- 201125566 614 ^^ν^Τ°ΊΡΊ 0ΑνΑνΛ^Α^ν Η ch3 463.00 615 ^^Ν^γ0γ^| 入人 F 466.10 627 ΝΗ 0Ανγ^Ν Η 1 Λ .CH3 Ν V ch3 505.20 638 ΝΗ Η 0 596.90 639 ΝΗ Η Η 0人Ν人㈡人入|^NVCF3 0 509.20 64】 ΝΗ Η2Ν 人 Η \^Ν^°γΝ η 。人人 571.10 -104- 201125566 642 NH 554.30 643 NH h2n 人 Jf"T〇X^i H H 0 559.10 651 NH oiax^Q 573.10 656 NH H2N 人 539.20 657 NH h2n^n-"^^n^ 553.10 658 NH h2n^ n^^1 ^ιχα,^ο O 568.10 -105- 201125566 659 NH H2N 人 i^T°T^L H cAN人^ 549.10 660 1^T°T^1 h 〇入 n人! 507.20 664 Τ-^-Λ AH: Π W^N--=Y〇Y^. 。人 559.30 667 H 543.10 669 NH H οΐαχι,^ο O 540.20 671 Η2ΝγΝν^/χ/Νν^^ ^ U-.n^y〇y^ 0人人 H XaCFs 543.10 ⑧ -106- 201125566 672 N·^、N H 'Uc, 501.10 674 NH H2N 人 H 〇xy：^v^t> H 8 552.10 675 NH H2N 义 Χ^Ύ Ύ^Ι h iCf：3 5871.10 676 HN _/^{^) y~N<r HzN o^n^n^^^Y-cn 499.10 681 NH h2n人卩八八^ ^"Ν^Τ〇Ύ) 。人乂>-CH3 Ί'、。、 611.20 685 NH H2N 人 Ν"^| F 557.10 -107- 201125566 686 494.10However, it corresponds to the following complete chemical structure: ΝΗ υιαχ^0〇 The compounds of the present invention can be prepared, formulated into salts, esters and prodrugs and delivered therewith. For convenience, the compounds are usually shown without the particular salt, ester or prodrug form. The compounds of the invention are shown in Table 1. Available LCMS (liquid chromatography mass spectrometry) data are available. When data is not available, it is marked with % ΝΑ". The LCMS data is routinely provided using the format [Μ + Η] + m/z unless otherwise indicated. 8 Table 1 Compound numbering structure LCMS 392, Χ〇Η 385.10 -100- 201125566 393 Η 458.00 396 H2N^^N^rj^ 442.00 400 , 丫Ό Η 527.00 402 458.00 440 0^Ν次0〇527.00 442^ΑΝ/· γ°γ^ΒΓ 442.00 460 H^Tx^ry^yF into W 482.00 201125566 528 5χ〇Η 341.90 529 ΝΗ Η2Ν 〇ANAKAy 383.90 543 H 356.10 544 4x〇H 384.10 557 H 370.20 558 oix^y H 486.10 575 NH H2N ^f HN^ 398.20 576 NH H 3x〇H 426,10 -102- 8 201125566 578 Η 285.00 579 407.00 592 464.10 595 Η〇. Everyone Η 298.90 598 Factory Η 355.90 603 - Bu, χο Η 398.10 604 Η / ° ϊΧ: 〇 Η 370.30 606 νη2.人乂och3 400.10 -103- 201125566 614 ^^ν^Τ°ΊΡΊ 0ΑνΑνΛ^Α^ν Η ch3 463.00 615 ^^Ν^γ0γ^| Entering F 466.10 627 ΝΗ 0Ανγ^Ν Η 1 Λ .CH3 Ν V ch3 505.20 638 ΝΗ Η 0 596.90 639 ΝΗ Η Η 0 person (人(二)人入|^NVCF3 0 509.20 64】 ΝΗ Η2Ν People Η \^Ν^°γΝ η. Everyone 571.10 -104- 201125566 642 NH 554.30 643 NH h2n People Jf"T〇X^i HH 0 559.10 651 NH oiax^Q 573.10 656 NH H2N People 539.20 657 NH h2n^n-"^^n^ 553.10 658 NH H2n^ n^^1 ^ιχα,^ο O 568.10 -105- 201125566 659 NH H2N 人i^T°T^LH cAN人^ 549.10 660 1^T°T^1 h Enter n people! 507.20 664 Τ- ^-Λ AH: Π W^N--=Y〇Y^. Person 559.30 667 H 543.10 669 NH H οΐαχι,^ο O 540.20 671 Η2ΝγΝν^/χ/Νν^^ ^ U-.n^y〇y^ 0人H XaCFs 543.10 8 -106- 201125566 672 N·^, NH 'Uc, 501.10 674 NH H2N Human H 〇xy:^v^t> H 8 552.10 675 NH H2N Χ Χ Ύ Ι ^ Ι h iCf: 3 5871.10 676 HN _/^{^) y~N<r HzN o ^n^n^^^Y-cn 499.10 681 NH h2n people 卩八八^ ^"Ν^Τ〇Ύ). People 乂>-CH3 Ί',. 611.20 685 NH H2N People Ν"^| F 557.10 -107- 201125566 686 494.10

689 553.10689 553.10

691 552.40691 552.40

-108 201125566 695 NH H2N 人入入 η 1 580.20 696 NH h2n^^ H 〇X^：X\wOH H l 567.10 707 NH 0 入 N入 H 0 hL/ 535.20 708 NH οΧΧΐΧ^γ^-^ 552.30 714 丫、〇ΑΝΑ^Α>γ^ H ^NY^nh2 482.20 715 NH H2N 人 ^^n^y°y"s 566.30 -109- 201125566 718 NH H2N 人〇λνληλα^ 广 ^Νγ^ΝΗ2 0 554.30 729 NH Η2Ν 人 Η [χ^Ν^Υ〇Υ%ι cA^Ap Η 654.40 730 ΝΗ Η2Ν·^'Ν^ν^^Ν^ν| \^n-^V^°'v^S 〇^Ν人 Η Uy^ 638.30 731 0XXj\^^OH 0 525.10 732 Η2ΝγΝ^^ί3^^ ^ςα〇Η ο 567.30 733 人h_/=Vf ^ΝγΝ-ν^/ 604.20 -110- 201125566 738 NH H K/ a 608.30 740 J!^T iPl h 。人Άν—〇η 509.10 741 NHi ^Tr°'T\ H 。人次 553.10 748 h2n/^^^n^N j^^NH H 。"a: 691.30 749 NH H2N 人卩 N^^| O人次H人人广I 「NH H .° Vx 733.40 -111 - 201125566 750 H2N 丫 NH ^^N^T〇Y^] k/N'-〇>^/N'CH3 A 625.30 751 Η,ΝγΝν^-^ΝΝ^^ o^n^n-^N^, H ^NV^l"CHj 0 CHS 566.30 752 h2n 丫 NH NH H ^NY^^NHj 580.30 753 L \^VN^Y°Y^ 〇人人 H 。"a: 747.40 754 H O人次广 IJIH 。Sa: 705.40 -112- 201125566 763 NHz h 〇 535.10 765 〇人人 H 4¾ 618.20 774 nh2 |^n，CH3 c^n 0 581.00 776 叫 ^Ν-γ〇^ 人〜八 0 564.30 777 Ην^Ν^Γτ°γχ H2N 。人人 0 592.30 781 ΗΝ 丫^ ΝΗ2 0 568.30 -113- 201125566 782 NH H2N 又㈡ H 1^s'n^t〇Y^i H、A F 640.20 783 。人V^O% 592.30 792 HN >-NH H2N '〇。人Ί^、 "Τ^Ί f ^NY^nAnh2 580.30 793 HN /~^N | 〇x7：XX^ ^NY^nh2 538.40 794 HN >-NH 〇xm H H *^Νγ^/ΝγΝΗ 0 nh2 594.30 114- 201125566-108 201125566 695 NH H2N Human access η 1 580.20 696 NH h2n^^ H 〇X^:X\wOH H l 567.10 707 NH 0 Enter N into H 0 hL/ 535.20 708 NH οΧΧΐΧ^γ^-^ 552.30 714 丫〇ΑΝΑ^Α>γ^ H ^NY^nh2 482.20 715 NH H2N person^^n^y°y"s 566.30 -109- 201125566 718 NH H2N 人〇λνληλα^ 广^Νγ^ΝΗ2 0 554.30 729 NH Η2Ν person Η [χ^Ν^Υ〇Υ%ι cA^Ap Η 654.40 730 ΝΗ Η2Ν·^'Ν^ν^^Ν^ν| \^n-^V^°'v^S 〇^Ν人Η Uy^ 638.30 731 0XXj\^^OH 0 525.10 732 Η2ΝγΝ^^ί3^^ ^ςα〇Η ο 567.30 733 people h_/=Vf ^ΝγΝ-ν^/ 604.20 -110- 201125566 738 NH HK/ a 608.30 740 J!^T iPl h. Person Άν—〇η 509.10 741 NHi ^Tr°'T\ H . People 553.10 748 h2n/^^^n^N j^^NH H . "a: 691.30 749 NH H2N 人卩N^^| O people H everyone wide I "NH H .° Vx 733.40 -111 - 201125566 750 H2N 丫NH ^^N^T〇Y^] k/N'- 〇>^/N'CH3 A 625.30 751 Η,ΝγΝν^-^ΝΝ^^ o^n^n-^N^, H ^NV^l"CHj 0 CHS 566.30 752 h2n 丫NH NH H ^NY^^ NHj 580.30 753 L \^VN^Y°Y^ 〇人人H."a: 747.40 754 HO person wide IJIH. Sa: 705.40 -112- 201125566 763 NHz h 〇535.10 765 〇人H 43⁄4 618.20 774 nh2 | ^n,CH3 c^n 0 581.00 776 Called ^Ν-γ〇^ 人~八0 564.30 777 Ην^Ν^Γτ°γχ H2N. Everyone 0 592.30 781 ΗΝ 丫^ ΝΗ2 0 568.30 -113- 201125566 782 NH H2N (2) H 1^s'n^t〇Y^i H, AF 640.20 783. Person V^O% 592.30 792 HN >-NH H2N '〇.人Ί^, "Τ^Ί f ^NY^nAnh2 580.30 793 HN /~^N | 〇x7:XX^ ^NY^nh2 538.40 794 HN >-NH 〇xm HH *^Νγ^/ΝγΝΗ 0 nh2 594.30 114- 201125566

-115- 201125566 832 h2n νη Η ^ΝΥ^ν^νη2 538.60 833 ΗΝ >-ΝΗ ν^ΛΝ^/〇γ^ Η k/Nv^NH2 523.40 858 一〇- 0 415.20 859 ΗΝ >-ΝΗ ΗίΝ V-^nxN^°'v^N Ί Η Ιν^^ν、οη, 552.30 868 Η2Ν\^\^ΝΚ^\ υ、^γ〇γ^ 0人、Λ^ί 0 r^^NH U^anXj "α; 706.30 -116- ⑧ 201125566 869 Η Η ΝΗ 〇人人A^k Η ο r^^NH "a; 747.50 870 H,N O 482.40 888 h2n .xXj^aNH2 O 482.40 889 h r^r 0 499.20 890 HN--X .X5C：^wOH 0 468.10 891 HN--X O 425.10 -117- 201125566 903 Η Η Ονη 482.30 904 Η Η 〇ΛνΑνΛ^ Η Η Ο- 581.10 908 ΗΝ\ 0 425.10 909 Η2Ν/ν^\ jT^T ΊΡΐ Η r^jH 0 425.20 916 Η Η L υ^.Ν^〇^ ο人人 ΝΗ, 538.30 917 Η Η 0人乂 Η r ’ MpH 538.30 ⑧ -118- 201125566 919 ch3 一 Onh H 386.20 920 HN-\ H 455.10 921 HN—^^ 455.20 929 k 丄 n^y°o o人n次 H 347.90 938 NHz 〇人又 H ^nh 479.30 941 Η H 〇人人 Η 0 f^^NH 566.30 -119- 201125566 942 入人Λ^/ Η 538.30 950 ΝΗ η2ν-^ '°χχχν5 0 524.00 953 〇人人 Η Η Οη 539.30 954 、/Αη〜^νη2 498.20 955 Η H2N\/^\^NV^\ 〇人人Χ^Η： Η 498.30 ⑧ -120- 201125566 956 h2n Ν\^Ί 〇人人 Η 511.40 972 H2Nv^. 382.00 973 H2N*y^\ ο人人^V、 Η 0 Γ^^-ΝΗ 648.50 976 ν-^-Ν·^γ°-γ^] ΛΛΝΐν、〆〇又Ο "α; 648.60 993 Η2Ν 丫 ΝΗ Η k^NH 481.80 -121 - 201125566 1006 〇人次 Η tXAO Η 522.80 1007 Η2Ν«^^ Η 536.70 ’〇αΝ〇 in3 1008 H2Nvr^ U"，.N^Y〇 H 454.80 1014 。人人Λ^〆 Η Γ 、’〇又〇 602.60 -122- ⑧ 201125566-115- 201125566 832 h2n νη Η ^ΝΥ^ν^νη2 538.60 833 ΗΝ >-ΝΗ ν^ΛΝ^/〇γ^ Η k/Nv^NH2 523.40 858 一〇- 0 415.20 859 ΗΝ >-ΝΗ ΗίΝ V -^nxN^°'v^N Ί Η Ιν^^ν, οη, 552.30 868 Η2Ν\^\^ΝΚ^\ υ, ^γ〇γ^ 0 people, Λ^ί 0 r^^NH U^anXj &quot ;α; 706.30 -116- 8 201125566 869 Η Η ΝΗ 〇人人 A^k Η ο r^^NH "a; 747.50 870 H,NO 482.40 888 h2n .xXj^aNH2 O 482.40 889 hr^r 0 499.20 890 HN--X .X5C:^wOH 0 468.10 891 HN--XO 425.10 -117- 201125566 903 Η Η Ονη 482.30 904 Η Η 〇ΛνΑνΛ^ Η Ο Ο- 581.10 908 ΗΝ\ 0 425.10 909 Η2Ν/ν^\ jT^ T ΊΡΐ Η r^jH 0 425.20 916 Η Η L υ^.Ν^〇^ ο人人ΝΗ, 538.30 917 Η Η 0人乂Η r ' MpH 538.30 8 -118- 201125566 919 ch3 An Onh H 386.20 920 HN- \ H 455.10 921 HN—^^ 455.20 929 k 丄n^y°oo people n times H 347.90 938 NHz 〇人又 H ^nh 479.30 941 Η H 〇人人Η 0 f^^NH 566.30 -119- 201125566 942人Λ^/ Η 538.30 950 ΝΗ η2ν-^ '°χχχν5 0 524.00 953 〇人人Η Η 539.30 954 , /Αη~^νη2 498.20 955 Η H2N\/^\^NV^\ 〇人人Χ^Η: Η 498.30 8 -120- 201125566 956 h2n Ν\^Ί 〇人人Η 511.40 972 H2Nv^ 382.00 973 H2N*y^\ ο人人^V, Η 0 Γ^^-ΝΗ 648.50 976 ν-^-Ν·^γ°-γ^] ΛΛΝΐν, 〆〇又Ο "α; 648.60 993 Η2Ν 丫ΝΗ Η k^NH 481.80 -121 - 201125566 1006 〇人Η tXAO Η 522.80 1007 Η2Ν«^^ Η 536.70 '〇αΝ〇in3 1008 H2Nvr^ U",.N^Y〇H 454.80 1014 . Everyone Λ^〆 Η Γ , '〇又〇 602.60 -122- 8 201125566

-123- 201125566 1031 。人&义4 ΌαΝ〇 k/CHa ^CF, 646.30 1032 ο人·^ 495.20 1033 Qh 0 ο人次 "α: 761.30 1041 Η2Ν4γ^\ 人工《haXr h3co 580.40 1042 h2n、^ V 612.40 ⑧ -124- 201125566-123- 201125566 1031 .人&义4 ΌαΝ〇 k/CHa ^CF, 646.30 1032 ο人·^ 495.20 1033 Qh 0 ο人次 "α: 761.30 1041 Η2Ν4γ^\ Artificial "haXr h3co 580.40 1042 h2n, ^ V 612.40 8 -124- 201125566

-125- 201125566-125- 201125566

-126- 201125566-126- 201125566

-127- 201125566 1096 H2Nv^^ 人 \ ΝΗ Ν=-/ 652.30 1133 N、^\s〆 531.20 1134 Η2Ν Η Τ〇〇人次 552.30 1135 ΗιΝ\^νη ΗΝ Η y° L kJ-.N-w〇Y^ H Oh 594.40 1145 HjN\^NH HN H2N^^^NK^\ · o人人 H XJh 552.30 ⑧ -128- 201125566 1146 h2n V 510.30 1147 o人人 H Oh 489.00 1192 HI〇 h 0 υ'Ν/^γΟγ^ H Oh 522.10 1193 H0 H 〇人次㈡ H k/NH 508.20 1197 〇人次 H Uh 504.10 1198 HjC-^fTl °\ J~\ 1 h3c-^\〇/'\^^,nv^^ 626.30 -129 - 201125566 1212 Η 491.10 1213 r~\ η 0 ^，Ν^Γ°Υ^ι Η Οη 509.20 1234 θ Η 507.50 1235 0 η!ν八^人〇<^ Η k/NH 467.00 1236 ΝΗ 〇 Η2Ν 人 Η Η 509.20 1237 η 3 Η,Ν ν!η Η 495.20 ⑧ -130- 201125566 1238 H H k/NH 453.10 1244 h2n o人次 496.50 1269 o人次 H k/NH 452.80 1270 NH 。人"s% '"Oh 495.20 1271 h/一瓜欲， Η Η Η ΝΗ 495.60 1368 k^NH 396.3 1369 リ,,..N^^^ϊγ。^^ Η U 396.2 -131 - 201125566 1370 510.1 1421 Η λ Ν. Η〆 CH3 414.1 1426 ΗίΝ"Ύ^ 〇ΧΧ^9 V. 413.9 1427 HjN^V^j .1XX? X 371.9 1441 olXl? Ηλ 0 .n 455.6 ⑧ -132- 201125566 1449 h2n"^V^ Λ nh2 386.3 1450 H2N^V^j 〇X?：Xp Cl 405.4 1464 NH 0 H2N 又 2 H 〇lXX^ X. 485.0 1465 NH h2n^n^^s^ \ 471.9 -133- 201125566 1466 NH H2N 人 N 八 V . HjN^NH 〇χχχρ X 570.4 1467 Η2Ν·^γ^| 419.0 362 F 入乂兔 F 456.10 377 Η!Ν^^Ό^Λ 。人Ύ ^^OCF, 486.10 378 ，〜丫。人Ύ Sdck 432.10 379 0人认 ifV^T〇CH3 γ^〇〇Η3 OCH, 492.10 380 hXVAx〇 460.10 -134- 201125566 390 Η2Ν^γχνΛ ΓΙ 470.00 391 H U^A ^^、CF, 470.10 426 OCF, 500.10 430 H〆〜ίΓγ^ g 484.00 447 w、hH s H 2 461.10 469 Η^όαχ Η 471.10 568 h2N^/、H F 425.00 569 o^'n^nh \ F 368.00 570 χγιΝ O^N^n-nn^ V2 F 368.10 4000c 342.90 -135- 201125566 〇I?：Xp 〇CH3 4001c \ o^nh2 415.10 4002c \ NH 505.20 4003c H2N^V^N H \ 、JD 477.30 4004c Η H H2N oixx? V 457.90 4005c H2NV^^ olXX? V 358.10 ⑧ -136- 201125566 4006c ίΓ ° η2ν X 485,30 4007c 0 Η °\ νη2 443.30 4008c ΝΗ 0 η2ν 〇ϊ?：^0 、νη2 483.4 在進一步的具體例中，本發明化合物不包含具有以下結構之化合物：-127- 201125566 1096 H2Nv^^ 人\ ΝΗ Ν=-/ 652.30 1133 N,^\s〆531.20 1134 Η2Ν Η Τ〇〇人552.30 1135 ΗιΝ\^νη ΗΝ Η y° L kJ-.Nw〇Y^ H Oh 594.40 1145 HjN\^NH HN H2N^^^NK^\ · o Everyone H XJh 552.30 8 -128- 201125566 1146 h2n V 510.30 1147 o Everyone H Oh 489.00 1192 HI〇h 0 υ'Ν/^γΟγ^ H Oh 522.10 1193 H0 H 〇人次(二) H k/NH 508.20 1197 〇人次 H Uh 504.10 1198 HjC-^fTl °\ J~\ 1 h3c-^\〇/'\^^,nv^^ 626.30 -129 - 201125566 1212 Η 491.10 1213 r~\ η 0 ^,Ν^Γ°Υ^ι Η 509 509.20 1234 θ Η 507.50 1235 0 η!ν八^人〇<^ Η k/NH 467.00 1236 ΝΗ 〇Η2Ν 人Η 509 509.20 1237 η 3 Η, Ν ν!η Η 495.20 8 -130- 201125566 1238 HH k/NH 453.10 1244 h2n o person 496.50 1269 o person H k/NH 452.80 1270 NH. People "s% '"Oh 495.20 1271 h/一瓜欲, Η Η Η 495 495.60 1368 k^NH 396.3 1369 リ,,..N^^^ϊγ. ^^ Η U 396.2 -131 - 201125566 1370 510.1 1421 Η λ Ν. Η〆CH3 414.1 1426 ΗίΝ"Ύ^ 〇ΧΧ^9 V. 413.9 1427 HjN^V^j .1XX? X 371.9 1441 olXl? Ηλ 0 .n 455.6 8 -132- 201125566 1449 h2n"^V^ Λ nh2 386.3 1450 H2N^V^j 〇X?:Xp Cl 405.4 1464 NH 0 H2N 2 H 〇lXX^ X. 485.0 1465 NH h2n^n^^s^ \ 471.9 -133- 201125566 1466 NH H2N Person N Eight V. HjN^NH 〇χχχρ X 570.4 1467 Η2Ν·^γ^| 419.0 362 F Into the rabbit F 456.10 377 Η!Ν^^Ό^Λ. People Ύ ^^OCF, 486.10 378, ~丫.人Ύ Sdck 432.10 379 0 people recognize ifV^T〇CH3 γ^〇〇Η3 OCH, 492.10 380 hXVAx〇460.10 -134- 201125566 390 Η2Ν^γχνΛ ΓΙ 470.00 391 HU^A ^^, CF, 470.10 426 OCF, 500.10 430 H〆~ίΓγ^ g 484.00 447 w, hH s H 2 461.10 469 Η^όαχ Η 471.10 568 h2N^/, HF 425.00 569 o^'n^nh \ F 368.00 570 χγιΝ O^N^n-nn^ V2 F 368.10 4000c 342.90 -135- 201125566 〇I?:Xp 〇CH3 4001c \ o^nh2 415.10 4002c \ NH 505.20 4003c H2N^V^NH \ , JD 477.30 4004c Η H H2N oixx? V 457.90 4005c H2NV^^ olXX? V 358.10 8 -136- 201125566 4006c ίΓ ° η2ν X 485,30 4007c 0 Η °\ νη2 443.30 4008c ΝΗ 0 η2ν 〇ϊ?: ^0, νη2 483.4 In a further specific example, the compound of the present invention does not comprise a compound having the following structure :

本發明化合物可使用那些熟諳本技藝者熟知的合成化學技術製得。實例1 -5 92之合成法本發明化合物可使用那些熟諳本技藝者熟知的合成化學技術（包括本文槪述之流程）製得。以例證爲目的，化合物5 9 2的合成法說明於下。 -137- 201125566The compounds of the invention can be prepared using synthetic chemistry techniques well known to those skilled in the art. EXAMPLES 1-5 Synthesis of the Compounds The compounds of the present invention can be prepared using synthetic chemistry techniques well known to those skilled in the art, including the schemes described herein. For the purpose of illustration, the synthesis of the compound 5 9 2 is described below. -137- 201125566

4-苯甲氧基羰基胺基-哌啶-i_羧酸第三丁酯將碳酸氫鈉飽和溶液（200毫升）添加在23。(：下在 THF(80毫升）中的4-胺基-哌啶-1-羧酸第三丁酯（11.98公克’ 58.4毫莫耳，丨當量）之溶液中，接著添加氯甲酸苯甲酯（9.19毫升，64.2毫莫耳，1.1當量）。將反應攪拌55 分鐘’接著分溶在乙酸乙酯（200毫升）與水（1〇〇毫升）之間。將有機層分開，以飽和食鹽水溶液（200毫升）清洗，乾燥（MgS04) ’過濾且濃縮，得到20.4公克黃褐色固體。將此材料以未進一步純化而用於下一步驟中。4-Benzyloxycarbonylamino-piperidine-i-carboxylic acid tert-butyl ester A saturated solution of sodium hydrogencarbonate (200 ml) was added at 23. (: a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.98 g '58.4 mmol, 丨 equivalent) in THF (80 ml) followed by benzyl chloroformate (9.19 ml, 64.2 mmol, 1.1 eq.). The reaction was stirred for 55 min. then partitioned between ethyl acetate (200 mL) and water (1 mL). (200 mL), EtOAc (EtOAc)EtOAc.

哌啶-4-基-胺甲酸苯甲酯將三氟乙酸（40毫升）添加在23 °C下在二氯甲烷（100 毫升）中的4-苯甲氧基羰基胺基-哌啶-1-羧酸第三丁酯 (20.4公克，來自先前步驟的粗產物）之溶液中。在攪拌45 分鐘之後，將反應混合物濃縮。將殘餘物溶解在水（100 毫升）中，接著經由添加碳酸鉀固體鹼化成pH 1 1。將所得溶液以二氯甲烷（2x50毫升）萃取。有機萃取物非常混濁，將彼等乾燥（Na2S04)，過濾且濃縮。將殘餘物溶解/懸浮在氯仿（70毫升）中且經由通過玻璃熔料過濾.來移除觀察到的微粒。將溶液濃縮，得到1 5公克棕色油。將此材料以未進一步純化而用於後續步驟中。 HBr.H2Nx*Vx^'Br -► BocHN^^'Br ⑧ -138- 201125566 (3-溴丙基）-胺甲酸第三丁酯將三乙胺（10.2毫莫耳，73.6毫莫耳，1.26當量）添加在23 °C下在二氯甲烷（200毫升）中的3 -溴丙基胺氫溴化物 (12.8公克，58.4毫莫耳，1當量）中，接著添加二碳酸二第三丁酯（12.8公克，58.4毫莫耳，1當量）。在攪拌〗小時之後，將反應混合物以水（200毫升）及接著以飽和食鹽水溶液（200毫升）連續清洗；接著乾燥（MgS04)，過濾且濃縮，得到成爲澄清油的1 3.9公克所欲產物。將此材料立即用於下一步驟中。Piperidine-4-yl-carbamic acid benzyl ester Trifluoroacetic acid (40 ml) was added to 4-benzyloxycarbonylamino-piperidine-1 in dichloromethane (100 mL) at 23 °C. a solution of a third butyl carboxylate (20.4 g, from the crude product of the previous step). After stirring for 45 minutes, the reaction mixture was concentrated. The residue was dissolved in water (100 mL) then basified to pH 1 1 by addition of potassium carbonate. The resulting solution was extracted with dichloromethane (2×50 mL). The organic extracts were very turbid, they were dried (Na2SO4), filtered and concentrated. The residue was dissolved/suspended in chloroform (70 ml) and the observed particles were removed by filtration through a glass frit. The solution was concentrated to give 15 g of a brown oil. This material was used in the next step without further purification. HBr.H2Nx*Vx^'Br -► BocHN^^'Br 8 -138- 201125566 (3-Bromopropyl)-aminocarboxylic acid tert-butyl ester triethylamine (10.2 mmol, 73.6 mmol, 1.26 Equivalent) added to 3-bromopropylamine hydrobromide (12.8 g, 58.4 mmol, 1 eq.) in dichloromethane (200 mL) at 23 ° C followed by dibutyl succinate (12.8 grams, 58.4 millimoles, 1 equivalent). After stirring for a small period of time, the reaction mixture was washed successively with water (200 ml) and then with saturated aqueous sodium chloride (200 ml); then dried (MgS04), filtered and concentrated to give 1 3.9 g of desired product as a clear oil. Use this material immediately in the next step.

[1-(3-第三丁氧基羰基胺丙基）-哌啶-4-基]-胺甲酸苯甲酯將碳酸鉀（12.1公克，87.6毫莫耳，1.5當量）、碘化鉀（4.85公克，29.2毫莫耳，0.5當量）及（3-溴丙基）-胺甲酸第三丁酯（13.9公克，58.4毫莫耳，1當量）添加在23 °C 下在二甲基甲醯胺（60毫升）中的哌啶-4-基-胺甲酸苯甲酯 (15公克，58.4毫莫耳，來自Boc·去保護步驟之粗產物）之溶液中。將所得混合物溫熱至60°C (油浴）。在60t下 90分鐘之後，將反應混合物冷卻至23 °C，接著分溶在乙酸乙酯與水（各1 00毫升）之間。將有機層分開，以飽和食鹽水溶液（150毫升）清洗，乾燥（MgS04)，過濾且濃縮。將產物使用I s c 〇 C 〇 m b i F1 a s h自動化層析術系統純化。將在二氯甲烷（25毫升）中的殘餘物溶液裝載在3 3 0公克矽膠管柱上’接著以在二氯甲烷中的甲醇中的2M氨溶析（0- -139- 201125566 1 2 · 5 %之甲醇中的2 Μ氣線性梯度，經1 2個管柱體積’以 100毫升/分鐘之流速），得到成爲澄清油的16.9公克（43.2 毫莫耳，經3步驟的74% )標題化合物。[1-(3-Tertiaryoxycarbonylaminopropyl)-piperidin-4-yl]-carbamic acid benzyl ester potassium carbonate (12.1 g, 87.6 mmol, 1.5 eq.), potassium iodide (4.85 g) , 29.2 mmol, 0.5 eq.) and (3-bromopropyl)-carbamic acid tert-butyl ester (13.9 g, 58.4 mmol, 1 eq.) were added at 23 ° C in dimethylformamide ( A solution of piperidin-4-yl-carbamic acid benzyl ester (15 g, 58.4 mmol, from the crude product of the Boc. deprotection step) in 60 ml). The resulting mixture was warmed to 60 ° C (oil bath). After 90 minutes at 60 t, the reaction mixture was cooled to 23 ° C and then partitioned between ethyl acetate and water (100 ml each). The organic layer was separated, washed with EtOAc EtOAc m. The product was purified using an Is cho C 〇 m b i F1 a s h automated chromatography system. The residue solution in dichloromethane (25 ml) was loaded onto a 300 g 矽矽 ' ' column followed by 2 M ammonia in methanol in dichloromethane (0--139-201125566 1 2 · A linear gradient of 2 helium in 5% methanol over a volume of 12 column 'at a flow rate of 100 ml/min." gives 16.9 g (43.2 mmol, 74% over 3 steps) as a clear oil. Compound.

[3-(4-胺基-哌啶-1-基）-丙基]-胺甲酸第三丁酯將鈀/碳（2.25公克’1〇重量％’濕式’1^811353型）添加在23°C下在乙醇（200毫升）中的[1-(3-第三丁氧基羰基胺丙基）-哌啶-4-基]-胺甲酸苯甲酯（16.9公克，43.2毫莫耳’ 1當量）之溶液中。將反應容器安置在氫氣（氣球）下且攪拌〗4小時。在此期間，tic分析顯示反應不完全，將混合物經由以乙醇（1 0 0毫升）清洗的矽藻土墊過濾。將所得溶液以新鮮鈀觸媒（2.25公克）處理，接著安置在5(TC的氫氣（氣球）下。在7小時之後，分析顯示起始材料完全消耗。將反應混合物冷卻至23 °C ’且接著經由以乙醇（200毫升）清洗的矽藻土墊過濾。將濾液濃縮，得到1 1 · 1公克 (43.2毫莫耳，1〇〇% )所欲化合物。[3-(4-Amino-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester added palladium/carbon (2.25 g '1 〇 wt% 'wet type '1 811 353)) [1-(3-Tertiaryoxycarbonylaminopropyl)-piperidin-4-yl]-carbamic acid benzyl ester (16.9 g, 43.2 mmol) in ethanol (200 mL) at 23 °C '1 equivalent) in solution. The reaction vessel was placed under hydrogen (balloon) and stirred for 4 hours. During this time, tic analysis indicated that the reaction was incomplete, and the mixture was filtered through a pad of Celite washed with ethanol (100 mL). The resulting solution was treated with fresh palladium catalyst (2.25 g) followed by 5 (TC of hydrogen (balloon). After 7 hours, analysis showed complete consumption of starting material. The reaction mixture was cooled to 23 °C. It was then filtered through a pad of celite washed with ethanol (200 mL). The filtrate was concentrated to give 11.1 g (43.2 mmol, 1%) of desired compound.

[3-(4-脲基-哌啶-i_基）_丙基]-胺甲酸第三丁酯將三乙胺（5.97毫升’ 42.9毫莫耳’ 1.5當量）添加在〇°C下在二氯甲烷中的[3-(4-胺基-哌啶-1-基）_丙基]-胺甲酸第三丁醋（7·34公克，28.6毫莫耳，1當量）之溶液中，接著添加氯甲酸苯酯（3.97毫升’ 31.4毫莫耳，當量） ⑤ -140- 201125566 。將反應混合物在〇 °C下攪拌2.5小時，接著分溶在二氯甲烷（200毫升）與碳酸氫鈉飽和水溶液（2 50毫升）之間。將有機層分開。將水層以二氯甲烷（5〇毫升）再萃取。將合倂的有機層乾燥（MgS04) ’過濾且濃縮，得到成爲白色半固體的1 0.5公克胺甲酸苯酯。將粗殘餘物溶解在甲醇（60毫升）中，接著以氫氧化銨水溶液（28%氨，60毫升）處理。在23 °C下攪拌1 5小時之後，將反應混合物濃縮。將殘餘物以***（3 〇 0毫升）處理，得到沉澱物。在2 3 °C下放置2 小時之後，經由通過中孔玻璃熔料過濾來收集沉澱物。將收集的白色固體在真空中乾燥，得到6.23公克（2 0.8毫莫耳，73% )所欲尿素。[3-(4-Urytyl-piperidine-i-yl)-propyl]-carbamic acid tert-butyl ester Triethylamine (5.97 ml '42.9 mmol' 1.5 equivalent) was added at 〇 ° C a solution of [3-(4-amino-piperidin-1-yl)-propyl]-aminecarboxylic acid terpene vinegar (7·34 g, 28.6 mmol, 1 eq.) in dichloromethane, Then add phenyl chloroformate (3.97 ml '31.4 mmol, equivalent) 5 -140-201125566. The reaction mixture was stirred at 0<0>C for 2.5 h then partitioned between EtOAc (EtOAc) Separate the organic layers. The aqueous layer was re-extracted with dichloromethane (5 mL). The combined organic layers were dried (MgS04) and filtered and concentrated to afford <RTI ID=0.0>> The crude residue was dissolved in MeOH (60 mL) thenEtOAcEtOAcEtOAc After stirring at 23 ° C for 15 hours, the reaction mixture was concentrated. The residue was taken up in diethyl ether (3 mL) to give a crystal. After standing at 2 3 °C for 2 hours, the precipitate was collected by filtration through a mesoporous glass frit. The collected white solid was dried in vacuo to give 6.23 g (2 0.8 mmol, 73%) of desired.

(4-溴-2-硝苯甲基）·乙酸乙酯將碳酸鉀（4.14公克，30毫莫耳，2當量）添加在23 °C 下在二甲基甲醯胺（40毫升）中的4-溴-2-硝酚（3.28公克， 15.0毫莫耳，1當量）之溶液中，接著添加溴乙酸乙酯 (1.84毫升，16.6毫莫耳，1.1當量）。將所得混合物溫熱至60°C (油浴）經90分鐘，接著冷卻至23t。將反應混合物分溶在乙酸乙酯：庚烷（1 : 1)與水（各1〇〇毫升）之間。將有機層分開且以水及飽和食鹽水溶液（各1 〇〇毫升）連續清洗，接著乾燥（MgS04)，過濾且濃縮，得到成爲黃色油的4.50公克（11.5毫莫耳，77%)產物。 -141 - 201125566(4-Bromo-2-nitrobenzyl) ethyl acetate Potassium carbonate (4.14 g, 30 mmol, 2 eq.) was added at 23 ° C in dimethylformamide (40 mL) A solution of 4-bromo-2-nitrophenol (3.28 g, 15.0 mmol, 1 eq.) followed by ethyl bromoacetate (1.84 mL, 16.6 mmol, 1.1 eq.). The resulting mixture was warmed to 60 ° C (oil bath) for 90 minutes and then cooled to 23t. The reaction mixture was partitioned between ethyl acetate: heptane (1:1) and water (1 mL). The organic layer was separated and washed successively with water and a saturated aqueous brine (1 mL) and then dried (MgS04), filtered and concentrated to give 4.50 g (11.5 mmol, 77%) product as a yellow oil. -141 - 201125566

[4-(3-氟苯基乙炔基）-2-硝苯氧基]-乙酸乙酯將三乙胺（4.05毫升，29.1毫莫耳，3當量）、碘化銅 (55毫克，0.29毫莫耳，0.03當量）及反式-二氯雙（三-鄰· 甲苯膦）鈀（Π)(152毫克，0.19毫莫耳，〇.〇2當量）添加在微波反應器容器中的二甲基甲醯胺（15毫升）中的（4-溴-2-硝苯甲基）-乙酸乙酯（2.95公克，9.70毫莫耳，1當量）及 1-乙炔基-3-氟苯（1.34毫升，11.6毫莫耳，1.2當量）之溶液中。將反應安置在氬氣下，接著在微波反應器中加熱至 80°C經30分鐘。接著將反應混合物分溶在乙酸乙酯：庚烷（1 : 1)與1.0N水性氫氯酸（各100毫升）之間。將有機層分開且以飽和水性碳酸氫鈉、1 : 1之飽和水性碳酸氫鈉 :飽和水性氯化銨、飽和食鹽水溶液（各1 00毫升）連續清洗，接著乾燥（MgS04)，過濾且濃縮。將產物使用Isco Combi Flash自動化層析術系統純化。將在二氯甲烷（5毫升）中的殘餘物溶液裝載在120公克矽膠管柱上，接著以在庚烷中的乙酸乙酯溶析（0-40%之乙酸乙酯線性梯度，經1 6個管柱體積，以8 5毫升/分鐘之流速），得到成爲棕色油的1 .72公克（5.01毫莫耳，52% )標題化合物。[4-(3-Fluorophenylethynyl)-2-nitrophenoxy]-acetic acid ethyl ester triethylamine (4.05 ml, 29.1 mmol, 3 equivalents), copper iodide (55 mg, 0.29 m Molar, 0.03 equivalents) and trans-dichlorobis(tri-o-tolylphosphine) palladium (Π) (152 mg, 0.19 mmol, 〇.〇2 equivalent) added to the microwave in the microwave reactor vessel (4-Bromo-2-nitrobenzyl)-acetic acid (2.95 g, 9.70 mmol, 1 eq.) and 1-ethynyl-3-fluorobenzene (1.34) in carbamide (15 mL) In milliliters, 11.6 millimoles, 1.2 equivalents) in solution. The reaction was placed under argon and then heated to 80 ° C for 30 minutes in a microwave reactor. The reaction mixture was then partitioned between ethyl acetate:heptane (1:1) and 1.0N aqueous hydrochloric acid (100 mL). The organic layer was separated and washed with saturated aqueous sodium hydrogen sulfate, 1:1 saturated aqueous sodium hydrogen carbonate: saturated aqueous ammonium chloride, brine (100 ml each), and then dried (MgSO4), filtered and concentrated. The product was purified using an Isco Combi Flash automated chromatography system. The residue solution in dichloromethane (5 mL) was loaded onto a 120 gram hydrazine column, followed by elution with ethyl acetate in heptane (0-40% ethyl acetate linear gradient, 1 6 The column volume, at a flow rate of 85 ml/min, gave 1.72 g (5.01 mmol, 52%) of the title compound as a brown oil.

-142- 201125566 6-[2-(3 -氟苯基）-乙基]-4H-苯並Π，4]噁哄-3-酮將鈀/碳（500毫克，10重量％ ’濕式，Degussa型）添加在乙酸乙酯（50毫升）中的[4-(3 -氟苯基乙炔基）-2 -硝苯氧基]-乙酸乙酯（1.72公克’ 5.01毫莫耳，1當量）之溶液中。將反應容器安置在氫氣（氣球）下且在23 °C下攪拌15 小時。在此期間，L C M S分析顯不反應含有所欲苯並嚼哄酮產物（主要）與未環化之苯胺（少許）的混合物。將混合物經由以乙酸乙酯（1 00毫升）清洗的矽藻土墊過濾。將溶液濃縮，接著再溶解在乙酸乙酯（100毫升）中且回流2小時。：L CMS分析顯示未改進環化：未環化之比値。添加對-甲苯磺酸酐（1 1 1毫克）且將所得溶液再回流1小時。將溶液冷卻至23 °C，接著以水、1 .0N水性氫氯酸、飽和水性食鹽水（各100毫升）連續清洗，乾燥（MgS04)，過濾且濃縮。將產物使用Isco CombiFlash自動化層析術系統純化。將在二氯甲烷（5毫升）中的殘餘物溶液裝載在80公克矽膠管柱上，接著以在二氯甲烷中的甲醇溶析（0-5%之甲醇線性梯度，經1 8個管柱體積，以60毫升/分鐘之流速），得到成爲黃褐色固體的1.15公克（4.24毫莫耳，85%)標題化合物。-142- 201125566 6-[2-(3-Fluorophenyl)-ethyl]-4H-benzopyrene, 4]oxan-3-one palladium/carbon (500 mg, 10% by weight 'wet, Degussa type) [4-(3-Fluorophenylethynyl)-2-nitrophenoxy]-acetic acid (1.72 g, 5.01 mmol, 1 eq.) in ethyl acetate (50 mL) In the solution. The reaction vessel was placed under hydrogen (balloon) and stirred at 23 ° C for 15 hours. During this time, the L C M S analysis showed no reaction with a mixture containing the desired benzoxanthone product (mainly) and uncyclized aniline (a little). The mixture was filtered through a pad of Celite, washed with ethyl acetate (100 mL). The solution was concentrated, then redissolved in ethyl acetate (100 mL). : L CMS analysis showed no improved cyclization: uncyclized ratio 値. p-Toluenesulfonic anhydride (11 1 mg) was added and the resulting solution was refluxed for additional 1 hour. The solution was cooled to 23 ° C, and then successively washed with water, 1.0 N aqueous hydrochloric acid, and saturated aqueous sodium chloride (100 ml each), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue solution in dichloromethane (5 ml) was loaded onto an 80 g ruthenium tube column, followed by methanol elution in dichloromethane (0-5% linear gradient of methanol over 18 column) The volume, at a flow rate of 60 ml/min, gave 1.15 g (4.24 mmol, 85%) of the title compound as a tan solid.

{3-氯-6-[2-(3-氟苯基）-乙基]-苯並[1，4]亞噁哄-2-基甲基}- 二甲胺將磷（V)醯氯（0.78毫升，8.49毫莫耳，2當量）添加在 -143- 201125566 〇 °C下在氯仿（10毫升）中的二甲基甲醯胺（0.82毫升’ 1〇·6 毫莫耳，2.5當量）之溶液中。在〇°C下攪拌10分鐘之後，將反應容器溫熱至23 °C經1〇分鐘，接著再冷卻至〇°C 。添加在氯仿（7毫升）中的6-[2-(3-氟苯基）·乙基]-4H-苯並[1,4]噁哄-3-酮之溶液。在〇°C下再攪拌5分鐘之後，將反應溫熱至回流（油浴）經4小時，接著冷卻至23 °C，且分溶在二氯甲烷與水（各1〇〇毫升）之間。將水層以5N水性氫氧化鈉調整至pH 12，且接著將有機層分開。將有機層以食鹽水（1 00毫升）清洗且放到一邊。將原來的水層以二氯甲烷（100毫升）再萃取。將兩個有機萃取物合倂，乾燥 (MgS04)，過濾且濃縮。將產物使用ISC0 CombiFlash自動化層析術系統純化。將在二氯甲烷（5毫升）中的殘餘物溶液裝載在80公克矽膠管柱上，接著以在庚烷中的乙酸乙酯溶析（0-40%之乙酸乙酯線性梯度，經16個管柱體積 ’以60毫升/分鐘之流速），得到成爲橘/棕色油的985毫克（2.86毫莫耳，67 % )標題化合物。{3-chloro-6-[2-(3-fluorophenyl)-ethyl]-benzo[1,4]-oxan-2-ylmethyl}-dimethylamine will be phosphorus (V) ruthenium chloride (0.78 ml, 8.49 mmol, 2 eq.) dimethylformamide (0.82 mL '1 〇·6 mmol, 2.5 eq.) in chloroform (10 mL) at -143 - 201125566 〇 °C ) in the solution. After stirring at 〇 ° C for 10 minutes, the reaction vessel was warmed to 23 ° C for 1 Torr and then cooled to 〇 ° C. A solution of 6-[2-(3-fluorophenyl)ethyl]-4H-benzo[1,4]oxan-3-one in chloroform (7 mL) was added. After stirring for an additional 5 minutes at 〇 ° C, the reaction was warmed to reflux (oil bath) over 4 h then cooled to 23 ° C and partitioned between dichloromethane and water (1 mL) . The aqueous layer was adjusted to pH 12 with 5N aqueous sodium hydroxide and then the organic layers were separated. The organic layer was washed with brine (100 ml) and set aside. The original aqueous layer was re-extracted with dichloromethane (100 mL). The two organic extracts were combined, dried (MgSO4), filtered and concentrated. The product was purified using an ISC0 CombiFlash automated chromatography system. The residue solution in dichloromethane (5 mL) was loaded onto an 80 gram hydrazine column, followed by elution with ethyl acetate in heptane (0-40% ethyl acetate linear gradient over 16 Column volume 'at a flow rate of 60 ml/min) gave 985 mg (2.86 mmol, 67%) of the title compound as an orange/brown oil.

{3-[4-(3-{2-二甲胺基亞甲基-6-[2-(3·氟苯基）-乙基]-2H-苯並[1，4]噁哄-3-基}-脲基）-哌啶-1-基]•丙基}-胺甲酸第三丁酯將乙酸鈀（Π)(3·2毫克，0.0145毫莫耳，〇.〇1當量）、 4,5-雙（二苯膦基）-9,9-二甲基二苯並哌喃（xantphos，17毫 ⑧ -144- 201125566 克，0.02 9毫莫耳，〇_〇2當量）及碳酸鉋（709毫克’ 2.18 毫莫耳，1.5當量）添加在二噁烷（15毫升）中的{3-氯- 6- [2-(3-氟苯基）-乙基]-苯並[1,4]亞噁哄-2-基甲基}-二甲胺（5〇〇毫克，：1.45毫莫耳，1當量）及[3-(4-脲基-哌啶-1-基）·丙基]-胺甲酸第三丁酯（435毫克’ 1.45毫莫耳’ 1當量）之溶液中。將反應混合物以氣氣噴灑，接著將反應谷器松、封（螺旋蓋）且安置在1 〇〇 °c之油浴中。在1 0 0 °C下1 4小時之後，將反應冷卻至23 °C，且接著分溶在乙酸乙酯與水（各 1 〇〇毫升）之間。將有機層分開且以飽和食鹽水溶液（1 〇〇毫升）清洗，接着乾燥（MgS04)，過濾且濃縮。將產物使用 I s c 〇 C 〇 m b i F 1 a s h自動化層析術系統純化。將在二氯甲院 (5毫升）中的殘餘物溶液裝載在80公克矽膠管柱上，接著以在二氯甲烷中的甲醇中的2M氨溶析（0-8%之甲醇中的 2M氨線性梯度，經1 8個管柱體積，以60毫升/分鐘之流速），得到成爲黃/棕色固體的313毫克（0.5 15毫莫耳，36 % )標題化合物。{3-[4-(3-{2-Dimethylaminomethylene-6-[2-(3.fluorophenyl)-ethyl]-2H-benzo[1,4]oxan-3 -butyl-ureido)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester palladium acetate (Π3) (0.35 mg, 0.0145 mmol, 〇.〇1 equivalent), 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (xantphos, 17 mM -144 - 201125566 g, 0.02 9 mmol, 〇〇 2 equivalent) and carbonic acid Planing (709 mg ' 2.18 mmol, 1.5 eq.) of {3-chloro-6-[2-(3-fluorophenyl)-ethyl]-benzo[1] in dioxane (15 mL) , 4] oxaidino-2-ylmethyl}-dimethylamine (5 〇〇 mg,: 1.45 mmol, 1 equivalent) and [3-(4-ureido-piperidin-1-yl)· A solution of propyl]-tert-butyl carbamate (435 mg ' 1.45 mmol' 1 equivalent). The reaction mixture was sprayed with air, then the reaction bar was loosened, sealed (screw cap) and placed in an oil bath of 1 〇 ° °C. After 14 hours at 10 °C, the reaction was cooled to 23 °C and then partitioned between ethyl acetate and water (1 mL). The organic layer was separated and washed with a saturated aqueous solution of brine (1 mL), then dried (MgS04), filtered and concentrated. The product was purified using an automated tomography system using I s c 〇 C 〇 m b i F 1 a s h. The residue solution in the dichlorocarbyl (5 ml) was loaded on an 80 g crucible tube column followed by 2 M ammonia in methanol in dichloromethane (2M ammonia in 0-8% methanol) A linear gradient of 13 mL column volumes at a flow rate of 60 mL/min gave 313 mg (0.515 mmol, 36%) of the title compound as a yellow/brown solid.

[3-(4-{7-[2-(3-氟苯基）-乙基]-2-酮基-2,9-二氫-1〇-氧雜-1，3,9-三氮雜蒽-3-基}-吡啶-1-基）-丙基]-胺甲酸第三丁酯將在乙酸（15毫升）中的{3-[4-(3-{2-二甲胺基亞甲基-6-[2-(3-氟苯基）-乙基]-2H-苯並[1,4]噁畊-3-基}-脲基）-哌啶-1-基]-丙基卜胺甲酸第三丁酯（310毫克，0.510毫莫耳，1當量）之溶液安置在微波反應器容器中。將反應安置 -145 - 201125566 在氬氣下，接著在微波反應器容器中加熱至100°c經90 分鐘。LCMS分析顯示獲得所欲產物，但是發生Boc的部分損失。將乙酸溶液濃縮，接著將殘餘物溶解在四氫呋喃 (25毫升）中且以碳酸鉀（600毫克’ 4.34毫莫耳’ 8.5當量 )及二碳酸二第三丁酯（190毫克，0.872毫莫耳，1.7當量）處理。在23 °C下攪拌30分鐘之後，將反應混合物分溶在乙酸乙酯與水（各60毫升）之間。將有機層分開且以飽和食鹽水溶液（50毫升）清洗，接著乾燥（MgS04)，過濾且濃縮。將殘餘物溶解/懸浮在1: 1之乙酸乙酯：庚烷（1〇毫升，熱）中。在冷卻之後，經由過濾收集固體。將固體吸附在矽膠（5公克）上，接著使用Isco CombiFlash自動化層析術系統純化。將產物在40公克矽膠匣中經由在二氯甲烷中的甲醇中的2M氨溶析（0-8%之甲醇中的2M氨線性梯度，經24個管柱體積，以40毫升/分鐘之流速），得到成爲淡黃色固體的94毫克（0.167毫莫耳，33%)標題化合物。[3-(4-{7-[2-(3-Fluorophenyl)-ethyl]-2-keto-2,9-dihydro-1〇-oxa-1,3,9-triazole <RTIgt;(3-(4-(2-{2-dimethylamino)</RTI> <RTIgt; </RTI> 3-(3-(4-{2-dimethylamino) in the acetic acid (15 ml) Methylene-6-[2-(3-fluorophenyl)-ethyl]-2H-benzo[1,4]cain-3-yl}-ureido)-piperidin-1-yl]- A solution of butyl propyl methacrylate (310 mg, 0.510 mmol, 1 eq.) was placed in a microwave reactor vessel. The reaction was placed -145 - 201125566 under argon and then heated to 100 ° C in a microwave reactor vessel for 90 minutes. LCMS analysis showed that the desired product was obtained, but a partial loss of Boc occurred. The acetic acid solution was concentrated, then the residue was dissolved in tetrahydrofuran (25 mL) eluted with potassium carbonate (600 mg <RTI ID=0.0>>> 1.7 equivalents) Treatment. After stirring at 23 ° C for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water (60 ml each). The organic layer was separated and washed with a saturated aqueous solution of brine (50 ml), then dried (MgS04), filtered and concentrated. The residue was dissolved/suspended in 1:1 ethyl acetate: heptane (1 Torr, hot). After cooling, the solids were collected via filtration. The solid was blotted onto silicone (5 grams) and then purified using an Isco CombiFlash automated layering system. The product was dissolved in 40 g of hydrazine oxime via 2 M ammonia in methanol in dichloromethane (linear gradient of 2M ammonia in 0-8% methanol over 24 column volumes at a flow rate of 40 ml/min) There was obtained 94 mg (0.167 mmol, 33%) of title compound as pale yellow solid.

3-[1-(3-胺丙基）-哌啶-4-基]-7-[2-(3-氟苯基）-乙基]-3H，9H-10-氧雜-1，3,9-三氮雜蒽-2-酮將三氟乙酸（4.0毫升）添加在23 t下在二氯甲烷（10 毫升）中的[3-(4-{7-[2-(3-氟苯基乙基]·2_氧代- 2,9·二氫_ 10 -氧雜-1,3,9-三氮雜蒽-3-基卜吡陡-丨-基）_丙基]_胺甲酸第三丁酯（94毫克，0.167毫莫耳，1當量）之溶液中。將 ⑧ -146- 201125566 反應攪拌3 0分鐘，接著濃縮。將殘餘物溶解在水（1 〇毫升）中，接著以1.0Ν水性氫氯酸（2.0毫升）處理。將所得溶液濃縮，且接著將殘餘物再溶解在水（1 0毫升）中，以氫氯酸（2.0毫升）處理且濃縮。將殘餘物溶解在水（1〇毫升）中且接著將所得溶液冷凍及接著凍乾，得到成爲黃色固體的88毫克（0.165毫莫耳，99% )所欲產物（二鹽酸鹽）。 LCMS (ΕΙ) ： 464.1 (Μ + Η)+。3-[1-(3-Aminopropyl)-piperidin-4-yl]-7-[2-(3-fluorophenyl)-ethyl]-3H,9H-10-oxa-1,3 , 9-triazaindole-2-one added trifluoroacetic acid (4.0 ml) in [3-(4-{7-[2-(3-fluoro) in dichloromethane (10 mL)) Phenylethyl]·2_oxo-2,9·dihydro-10-oxa-1,3,9-triazaindole-3-ylpyridyl-pyridyl-yl)-propyl]_ A solution of the butyl carbamic acid ester (94 mg, 0.167 mmol, 1 eq.). The reaction was stirred for 30 minutes, then concentrated. The residue was dissolved in water (1 mL). This was followed by aq. EtOAc (EtOAc (EtOAc)EtOAc. Dissolved in water (1 mL) and the resulting solution was chilled and then lyophilized to give 88 mg (0.165 mmol, 99%) of desired product (dihydrochloride) as a yellow solid. LCMS (ΕΙ) : 464.1 (Μ + Η)+.

3-氯-2-二甲胺基亞甲基- 3,4-二氫- 2Η-苯並[1,4]噁畊-6·羧酸甲酯（2) 將4.05毫升DMF(52.5毫莫耳，2.5當量）添加至 CHC13(100毫升）中，將所得溶液冷卻至〇°C ’然後以三氯磷酸鹽（6.43公克’ 42毫莫耳’ 2.0當量）處理，將反應溶液溫熱至RT且攪拌20分鐘，然後再冷卻至0°C且在0°C 下添加3-酮基-3,4-二氫- 2H-苯並[1,4]噁哄-6-羧酸甲酯 (1)(4.36公克，21毫莫耳’ 1.0當量）’且將所得反應混合物加熱至回流經6小時。當TLC及LCMS顯示反應完全 -147- 201125566 時，將反應混合物冷卻至RT且分溶在二氯甲烷與水之間，且將水層以5N NaOH鹼化成pH 12 ’且以二氯甲烷 (3 X 1 0 0毫升）萃取，將合倂的有機層濃縮且以管柱層析術 (Si02，20-50%之EtOAc /庚烷梯度溶析）純化，以供給成爲黃色固體的所欲3-氯-2-二甲胺基亞甲基-3，4-二氫- 2H-苯並[1，4]噁畊-6-羧酸甲酯（2)(4· 13公克，理論値5.9公克，70% )。 3-{3-[1·(3-第三丁氧基羰基胺基-丙基）-哌啶-4-基]-脲基}-2-二甲胺基亞甲基- 3,4-二氫-2Η-苯並[1，4]噁哄-6-羧酸甲酯（4)及3-[ 1-(3-第三丁氧基羰基胺基-丙基）·哌啶-4-基]-2· 酮基-2,3,9,以-四氫-111-10-氧雜-1，3,9-三氮雜蒽-7-羧酸甲酯（5) 將在二噁烷（20.0毫升）中的3 -氯-2·二甲胺基亞甲基-3,4·二氫-2H-苯並[1，4]噁畊-6-羧酸甲酯（2)(1.28公克，4.6 毫莫耳’ 1.0當量）及[3-(4-脲基-哌啶-1-基）-丙基]_胺甲酸第三丁酯（3)(1.37公克，4.6毫莫耳，1.0當量）之溶液以 Pd(OAc)2 (20.6 毫克，0.092 毫莫耳，0.02 當量）、 Xantphos (10.6 毫克，0·18 毫莫耳，〇.〇4 當量）及 Cs2C03 (2.25公克，6.9毫莫耳，1.5當量）處理，且將所得反應混合物加熱至90°C經6小時。當TLC及MS顯示反應完全時’以在l〇〇°C下攪拌的乙酸（8毫升）經1小時直接添加至反應混合物中’未從反應混合物分離出3-{3-[1-(3 -第三丁氧基羰基胺基-丙基）-哌啶-4-基]-脲基}-2-二甲胺基亞甲 "148 - 201125566 基-3,4-二氫- 2H -苯並[1，4]噁哄-6-羧酸甲酯（4)。將反應溶液在真空中濃縮，且將殘餘物以管柱層析術（Si 02，0-5 % 之MeOH/CH2Cl2梯度溶析）直接純化，以供給成爲棕色油性材料的3-[1 - (3-第三丁氧基羰基胺基-丙基）-哌啶-4-基]- 2- 酮基- 2,3,9,9a-四氫-1H-10-氧雜-1，3,9-三氮雜蒽-7-羧酸甲酯（5)(760毫克，理論値2295.4毫克’ 33%)。關於4: C27H40N6O6，LCMS (El) m/e 545 (M + + H)。關於 5 : C25H33N5〇6，LCMS (El) m/e 500 (M + + H)。 3- [l-(3-第三丁氧基羰基胺基-丙基）-哌啶-4-基]-2·酮基-2,9-二氫-3^10-氧雜-1，3,9-三氮雜蒽-7-羧酸（6) 將1M LiOH水溶液（4_5毫升，3當量）及3-[1·(3-第三丁氧基羰基胺基-丙基）-哌啶基]-2-氧代-2,3，9,9a·四氫· 1H-10-氧雜-1，3,9·三氮雜蒽-7-羧酸甲酯（5，760毫克， 1.52毫莫耳，1.0當量）添加至THF(5毫升），溫熱至50°C 且攪拌，直到LCMS顯示沒有留下起始材料爲止。將反應溶液冷卻至RT且以EtOAc萃取。將水層酸化至pH 2，並將所欲產物沉澱且過濾，得到成爲淺棕色固體的3-[ 1-(3-第三丁氧基羰基胺基-丙基）-哌啶-4-基]-2-酮基-2,9-二氫-3H-10-氧雜-1,3,9-三氮雜蒽-7-羧酸（412毫克，理論値738 毫克，56%)。關於 6: C24H31N 506，LCMS (El) m/e 486 (M++H)。 4- [3-({3-[l-(3-第三丁氧基羰基胺基-丙基）·哌啶-4-基]-2- -149- 201125566 酮基-2,9-二氫-3Η·10·氧雜-三氮雜蒽_7_羰基卜胺基 )·丙基]-哌畊-1-羧酸第三丁酯（7) 將在DMF(5毫升）中的3-[1-(3-第三丁氧基羰基胺基-丙基）-哌啶-4-基]-2-酮基- 2,9-二氫- 3H-10-氧雜-1，3,9-三氮雜蒽-7-羧酸（6)(150毫克，0.31毫莫耳，1當量）及4-(3-胺丙基）-哌哄-1-羧酸第三丁酯（150毫克，0.62毫莫耳， 2.0當量）之溶液以HATU(2 3 5毫克，0.62毫莫耳，2.0當量）及胡尼格氏鹼處理。將所得溶液在RT下攪拌6小時。當TLC及LCMS顯示反應完全時，將反應溶液在真空中濃縮且將殘餘物以管柱層析術（Si〇2，0-10 %之 MeOH/CH2Cl2梯度溶析）直接純化，以供給所欲4-[3-({3-[1-(3-第三丁氧基羰基胺基-丙基）·哌啶-4-基]-2-酮基-2,9-二氫- 3H-10-氧雜-1，3,9-三氮雜蒽-7-羰基}-胺基）-丙基]-哌哄-1-羧酸第三丁酯（106毫克，理論値220毫克，48%)，將其以在二噁烷中的4M HC1處理，以供給最終產物3-[1-(3-胺丙基）-哌啶-4-基]-2-酮基-2,9-二氫-3 H-10-氧雜-1，3,9-三氮雜蒽-7-羧酸（3-哌畊-1-基丙基）-醯胺（8)。關於7 :C36H54Ns07，LCMS (El) m/e 711 (M + + H)。關於 8 : C26H38N803，LCMS (El) m/e 511 (M + + H)。實例2-抗微生物活性測試本發明化合物的抗微生物活性。該等數數呈現於表3中。化合物係使用標準的微稀釋檢定法進行抗大腸桿菌株ATCC25922，以測定最小抑制濃度（MIC)。數據呈現 -150- 201125566 於此，藉此以、+ 〃標示化合物具有1 6微克/毫升或更低的MIC値及以"-〃標示化合物大於16微克/毫升的M1C 値。、' N/A 〃意謂未取得數據。熟諳本技藝者應承認可進行化合物對抗其他的細菌有機體的評定且對抗大腸桿菌的活性之數據呈現係作爲例證’並意欲不以任何方式限制本發明的範疇。可取決於所欲收集之性能活性來進行本發明化合物對抗其他微生物範圍的評定。此外，''+〃、"-〃及N / A "的呈現及1 6微克/毫升之分界値的選擇亦作爲例證，並意欲不以任何方式限制本發明的範疇。例如， 1 - 〃不意謂標示化合物必定缺乏活性或利用性，但寧可以其對抗標示之微生物的MIC値大於16微克/毫升。表2 化合物編號大腸桿菌 ATCC25922 MIC 392 — 393 — 396 — -151 - 201125566 化合物編號大腸桿菌 ATCC25922 MIC 400 - 402 - 440 — 442 - 460 — 528 — 529 — 543 - 544 - 557 - 558 - 575 - 576 - 578 - 579 - 592 + 595 - 598 — 603 + 604 - 606 - 614 - 615 - 627 + 638 — 639 - 641 - 642 - 643 - 651 - 656 - 657 - 658 - 659 — 660 - 664 — 667 - 669 一 671 — 672 - 674 — 675 - 676 - 681 - 685 — 686 - -152 201125566 化合物編號大腸桿菌 ATCC25922 MIC 689 + 690 — 691 — 694 - 695 + 696 + 707 + 708 + 714 - 715 + 718 — 729 + 730 - 731 + 732 + 733 - 738 — 740 + 741 + 748 - 749 + 750 - 751 + 752 + 753 + 754 + 763 - 765 + 774 + 776 + 777 + 781 + 782 - 783 + 792 + 793 + 794 + 795 - 798 — 811 + 812 - 818 + 832 + 833 + 858 - 859 + -153- 201125566 化合物編號大腸桿菌 ATCC25922 MIC 868 + 869 + 870 - 888 ~ 889 - 890 ~ 891 - 903 - 904 + 908 ~ 909 - 916 + 917 + 919 - 920 ~ 921 ~ 929 - 938 4* 941 + 942 + 950 953 954 + 955 + 956 + 972 - 973 - 976 - 993 + 1006 - 1007 — 1008 - 1014 — 1016 一 1025 - 1026 - 1030 一 1031 - 1032 + 1033 + 1041 - 1042 - 1055 — 1056 一 1058 ~ 1070 ~ -154 201125566 化合物編號大腸桿菌 ATCC25922 MIC 1071 — 1072 — 1073 - 1082 — 1083 — 1084 — 1086 + 1096 — 1133 + 1134 + 1135 + 1145 + 1146 + 1147 — 1192 — 1193 — 1197 — 1198 — 1212 — 1213 - 1234 + 1235 + 1236 + 1237 + 1238 1244 + 1269 + 1270 + 1271 + 362 — 377 — 378 — 379 — 380 — 390 — 391 — 426 - 430 - 447 — 469 — 568 - 569 — 570 - 1368 — 1369 - 1370 + 201125566 化合物編號大腸桿菌 ATCC25922 MIC 1421 - 1426 - 1427 - 1441 - 1449 一 1450 - 1464 - 1465 + 1466 + 1467 — 4000c — 4001c — 4002c - 4003c - 4004c + 4005c - 4006c + 4007c - 4008c - 倂入以供參考將本文所述及的每個專利文件及科學論文的整個揭示內容就所有的目的倂入本文以供參考。等效物本發明可以不違背其精神或基本特徵的其他特定形式具體化。前述具體例因此被視爲在所有方面作爲對本文所述之發明的例證而非限制。本發明的範疇因此係藉由所附之申請專利範圍而非前述的說明予以標示，且意欲將達到在申請專利範圍的等效意義及範圍內的所有變化包含於本發明中。 ⑧ -156-3-Chloro-2-dimethylaminomethylene-3,4-dihydro-2Η-benzo[1,4]caco-6-carboxylic acid methyl ester (2) 4.05 ml DMF (52.5 mmol) Ears, 2.5 equivalents) were added to CHC13 (100 mL), the resulting solution was cooled to 〇 ° C ' and then treated with trichlorophosphate (6.43 g '42 mAh '2.0 eq) and the reaction solution was warmed to RT And stirring for 20 minutes, then cooling to 0 ° C and adding 3-keto-3,4-dihydro-2H-benzo[1,4]oxan-6-carboxylic acid methyl ester (at 0 ° C) 1) (4.36 g, 21 mmoles 1.0 equivalent) and the resulting reaction mixture was heated to reflux for 6 hours. When TLC and LCMS showed the reaction was completely -147 - 201125566, the reaction mixture was cooled to RT and partitioned between dichloromethane and water, and the aqueous layer was basified to pH 12 s with 5N NaOH and dichloromethane (3) X 1 0 0)), the combined organic layer was concentrated and purified by column chromatography (SiO 2 , 20-50% EtOAc /Heptane gradient) to afford the desired solid as a yellow solid. Chloro-2-dimethylaminomethylene-3,4-dihydro-2H-benzo[1,4]cain-6-carboxylic acid methyl ester (2) (4·13 g, theory 値5.9 g , 70%). 3-{3-[1·(3-Tertioxycarbonylamino-propyl)-piperidin-4-yl]-ureido}-2-dimethylaminomethylene-3,4- Dihydro-2-indole-benzo[1,4]oxo-6-carboxylic acid methyl ester (4) and 3-[1-(3-t-butoxycarbonylamino-propyl)-piperidine-4 -yl]-2·keto-2,3,9,-tetrahydro-111-10-oxa-1,3,9-triazaindole-7-carboxylic acid methyl ester (5) will be in two 3-Chloro-2·dimethylaminomethylene-3,4·dihydro-2H-benzo[1,4]cain-6-carboxylic acid methyl ester in methane (20.0 ml) (2) (1.28 grams, 4.6 millimolar '1.0 equivalents) and [3-(4-ureido-piperidin-1-yl)-propyl]-aminocarboxylic acid tert-butyl ester (3) (1.37 g, 4.6 mmol) The solution of the ear, 1.0 eq.) was Pd(OAc)2 (20.6 mg, 0.092 mmol, 0.02 eq.), Xantphos (10.6 mg, 0·18 mmol, 〇.〇4 eq.) and Cs2C03 (2.25 g, Treated at 6.9 millimolar, 1.5 equivalents, and the resulting reaction mixture was heated to 90 °C for 6 hours. When TLC and MS showed the reaction was complete, 'acetic acid (8 ml) stirred at 10 ° C was added directly to the reaction mixture over 1 hour 'not isolated from the reaction mixture 3-{3-[1-(3 -Tertibutoxycarbonylamino-propyl)-piperidin-4-yl]-ureido}-2-dimethylamino"" 148 - 201125566 yl-3,4-dihydro-2H - Benzo[1,4]oxo-6-carboxylic acid methyl ester (4). The reaction solution was concentrated in vacuo, and the residue was purified directly by column chromatography (Si02, 0-5 % MeOH/CH2Cl2 gradient) to afford 3-[1 - ( 3-tert-butoxycarbonylamino-propyl)-piperidin-4-yl]-2-one keto-2,3,9,9a-tetrahydro-1H-10-oxa-1,3, Methyl 9-triazaindole-7-carboxylate (5) (760 mg, theory 値 2295.4 mg '33%). Regarding 4: C27H40N6O6, LCMS (El) m/e 545 (M + + H). About 5 : C25H33N5〇6, LCMS (El) m/e 500 (M + + H). 3-[l-(3-Tertioxycarbonylamino-propyl)-piperidin-4-yl]-2.keto-2,9-dihydro-3^10-oxa-1, 3,9-triazaindole-7-carboxylic acid (6) 1M aqueous solution of LiOH (4-5 ml, 3 equivalents) and 3-[1·(3-tert-butoxycarbonylamino-propyl)-peri Pyridyl]-2-oxo-2,3,9,9a·tetrahydro-1H-10-oxa-1,3,9·triazaindole-7-carboxylic acid methyl ester (5,760 mg, 1.52 mmol, 1.0 eq.) was added to THF (5 mL), warmed to 50 <0>C and stirred until LCMS showed no starting material left. The reaction solution was cooled to RT and extracted with EtOAc. The aqueous layer was acidified to pH 2, and the desired product was crystallised and filtered to give 3-[1-(3-t-butoxycarbonylamino-propyl)-piperidin-4-yl as a light brown solid. ]-2-keto-2,9-dihydro-3H-10-oxa-1,3,9-triazaindole-7-carboxylic acid (412 mg, theory 値 738 mg, 56%). About 6: C24H31N 506, LCMS (El) m/e 486 (M++H). 4-[3-({3-[l-(3-Tertoxycarbonylamino-propyl)-piperidin-4-yl]-2-yl------- Hydrogen-3Η·10·oxa-triazaindole_7-carbonyl-amino)propyl]-piperidine-1-carboxylic acid tert-butyl ester (7) 3 in DMF (5 ml) -[1-(3-Tertioxycarbonylamino-propyl)-piperidin-4-yl]-2-keto-2,9-dihydro-3H-10-oxa-1,3 , 9-triazaindole-7-carboxylic acid (6) (150 mg, 0.31 mmol, 1 equivalent) and 4-(3-aminopropyl)-piperazine-1-carboxylic acid tert-butyl ester ( A solution of 150 mg, 0.62 mmol, 2.0 eq.) was treated with HATU (2 3 5 mg, 0.62 mmol, 2.0 eq.) and H. s. The resulting solution was stirred at RT for 6 hours. When TLC and LCMS showed the reaction was completed, the reaction solution was concentrated in vacuo and the residue was purified directly by column chromatography (Si 〇 2, 0-10% MeOH/CH 2 Cl 2 gradient) to supply 4-[3-({3-[1-(3-Tertoxycarbonylamino-propyl)-piperidin-4-yl]-2-one-2,9-dihydro-3H- 3-oxo-1,3,9-triazaindole-7-carbonyl}-amino)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (106 mg, theory 値 220 mg, 48 %), which was treated with 4M HCl in dioxane to provide the final product 3-[1-(3-aminopropyl)-piperidin-4-yl]-2-keto-2,9- Dihydro-3 H-10-oxa-1,3,9-triazaindole-7-carboxylic acid (3-pipen-1-ylpropyl)-decylamine (8). Regarding 7 : C36H54Ns07, LCMS (El) m/e 711 (M + + H). About 8 : C26H38N803, LCMS (El) m/e 511 (M + + H). Example 2 - Antimicrobial Activity The antimicrobial activity of the compounds of the invention was tested. These numbers are presented in Table 3. The compound was subjected to the anti-Escherichia coli strain ATCC25922 using a standard microdilution assay to determine the minimum inhibitory concentration (MIC). Data Presentation -150- 201125566 Hereby, the compound has a MIC of 16 μg/ml or less and a M1C 値 of the compound of greater than 16 μg/ml with "-〃. , 'N/A 〃 means no data is obtained. Those skilled in the art will recognize that data can be evaluated against other bacterial organisms and that the data against E. coli activity is presented as an illustration and is not intended to limit the scope of the invention in any way. The evaluation of the compounds of the invention against other microbial ranges can be carried out depending on the performance activity desired to be collected. In addition, the choice of ''+〃,"-〃 and N / A " and the choice of a boundary of 16 μg/ml are also exemplified and are not intended to limit the scope of the invention in any way. For example, 1 - 〃 does not mean that the labeled compound must be inactive or useful, but rather the MIC 其 against the labeled microorganism is greater than 16 μg/ml. Table 2 Compound No. E. coli ATCC25922 MIC 392 — 393 — 396 — -151 - 201125566 Compound No. E. coli ATCC25922 MIC 400 - 402 - 440 — 442 - 460 — 528 — 529 — 543 - 544 - 557 - 558 - 575 - 576 - 578 - 579 - 592 + 595 - 598 - 603 + 604 - 606 - 614 - 615 - 627 + 638 - 639 - 641 - 642 - 643 - 651 - 656 - 657 - 658 - 659 - 660 - 664 - 667 - 669 671 — 672 - 674 — 675 - 676 - 681 - 685 — 686 - -152 201125566 Compound number E. coli ATCC25922 MIC 689 + 690 — 691 — 694 - 695 + 696 + 707 + 708 + 714 - 715 + 718 — 729 + 730 - 731 + 732 + 733 - 738 — 740 + 741 + 748 - 749 + 750 - 751 + 752 + 753 + 754 + 763 - 765 + 774 + 776 + 777 + 781 + 782 - 783 + 792 + 793 + 794 + 795 - 798 — 811 + 812 - 818 + 832 + 833 + 858 - 859 + -153- 201125566 Compound number E. coli ATCC25922 MIC 868 + 869 + 870 - 888 ~ 889 - 890 ~ 891 - 903 - 904 + 908 ~ 909 - 916 + 917 + 919 - 920 ~ 921 ~ 929 - 938 4* 941 + 942 + 950 953 954 + 955 + 956 + 972 - 973 - 976 - 993 + 1006 - 1007 - 1008 - 1014 - 1016 - 1025 - 1026 - 1030 - 1031 - 1032 + 1033 + 1041 - 1042 - 1055 - 1056 - 1058 ~ 1070 ~ -154 201125566 Compound number E. coli ATCC25922 MIC 1071 — 1072 — 1073 - 1082 — 1083 — 1084 — 1086 + 1096 — 1133 + 1134 + 1135 + 1145 + 1146 + 1147 — 1192 — 1193 — 1197 — 1198 — 1212 — 1213 - 1234 + 1235 + 1236 + 1237 + 1238 1244 + 1269 + 1270 + 1271 + 362 — 377 — 378 — 379 — 380 — 390 — 391 — 426 - 430 - 447 — 469 — 568 - 569 — 570 - 1368 — 1369 - 1370 + 201125566 Compound No. E. coli ATCC25922 MIC 1421 - 1426 - 1427 - 1441 - 1449 A 1450 - 1464 - 1465 + 1466 + 1467 — 4000c — 4001c — 4002c - 4003c - 4004c + 4005c - 4006c + 4007c - 4008c - For reference, please refer to this article. Patent documents and scientific papers of the entire disclosure for all purposes Merger incorporated herein by reference. Equivalents The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics. The foregoing specific examples are to be considered in all respects The scope of the invention is therefore intended to be embraced by the scope of the appended claims 8 -156-

Claims

201125566 七、申請專利範圍： 1. 一種具有下式之化合物：201125566 VII. Patent application scope: 1. A compound with the following formula:

其中-G_H-j 一選擇地選自下式： Η—J -G j， Η— 其中各個Η及J係獨立選擇，或-G-H-J係選自：Wherein -G_H-j is selectively selected from the group consisting of: Η-J - G j, Η - wherein each Η and J are independently selected, or -G-H-J is selected from:

其中Rx係選自CH2、NH、N(Ci-8烷基）、S或0; 1^及Rz 爲C或CH，各自獨立以一或多個F、CH3、CF3、OH及 OCH3取代；或Rx、Ry及Rz各自獨立選自CH2或CRaRb ，其中Ra及Rb —起形成C3.5碳環； J係選自NH2、NHd.s烷基）、烷基）2、 NHC( = 0)CH3、NHC( = 0)NH2、NHC( = NH)NH2、 NHC( = NH)H ；其中n爲0、1或2 ; -157- 201125566 另一選擇地，-G_H-J係選自：Wherein Rx is selected from the group consisting of CH2, NH, N(Ci-8 alkyl), S or 0; 1^ and Rz are C or CH, each independently substituted with one or more of F, CH3, CF3, OH and OCH3; Rx, Ry and Rz are each independently selected from CH2 or CRaRb, wherein Ra and Rb together form a C3.5 carbocyclic ring; J is selected from the group consisting of NH2, NHd.s alkyl), alkyl) 2, NHC (= 0) CH3 , NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; wherein n is 0, 1 or 2; -157- 201125566 Alternatively, -G_H-J is selected from:

其中Rx係選自CH2、NH、烷基）、S或0; 1^爲C 或CH’以一或多個CH3取代；或1^爲CRaRb，其中Ra 及Rb —起形成C3.5碳環；其中m爲1、2或3 ; J係選自NH2、NH(CU8烷基）、Νγ,.β烷基）2、 NHC( = 0)CH3 ' NHC( = 〇)NH2 ' NHC( = NH)NH2 ' NHC( = NH)H ； C-B-A·、-D-E-F及-G-H-J爲化學部分，其中 A、D及G係獨立選自： (a)單鍵 ’（b)-(C 丨·8 烷基）-，（c)-(C2 —8 烯基）-，（d)-(C2· 8炔基）_，其中 i)前文（b)_(d)中任一者中的0-4個碳原子隨意地以選自-0-、-S(〇)p·、-nr6-、-(c = 0)-、-S(0)pNR6.、-nr6S(0)p-及-NR6S(〇)pNR6-之部分代替， H)前文（b)-(d)中任一者隨意地以一或多個R5基團取代，及 ⑴）前文（b)-(d)中任一者隨意地以-(Ci-8烷基）-r5 基團取代； (e)-〇-，(f)-NR6-，(g)-S(0)p-，(h)-C(0)-，(i)- C(0)0-，⑴· 0c(0)-’(k)_0C(0)0•，⑴_c(〇)NR6-，(m)-NR6c〇_， -158- 201125566 (n)-NR6C(0)NR6-，（〇)-C( = NR6)-，（p)-C( = NR6)〇_， (q)-OC( = NR6)-,(r)-C( = NR6)NR6-,(s)-NR6C( = NR6)-, (t)-C( = S)-,(u)-C( = S)NR6-,(v)-NR6C( = S)-,(w)-C(0)S-, (x)-SC(0)-，（y)-0C( = S)-，（z)-C( = S)0-,(aa)-NR6(CNR6)NR6· ,(bb)-CR6R6C(0)-，（cc)-C(0)NR6(CR6R6)t-，（dd)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’（ee)3-14員飽和、不飽和或芳族碳環，及（ff)_ (CR6R6),- > 其中（dd)或（ee)隨意地以一或多個R5基團取代； B、E及Η係獨立選自： (a) 單鍵， (b) 含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環， (c) 3-14員飽和、不飽和或芳族碳環，其中（b)或（c)隨意地以—或多個R5基團取代； (cO-CCu 烷基）-’（ε)-((：2·8 烯基）_，（f)_((：28 炔基）_，其中 1)即文（d)-(f)中任—者中的〇_4個碳原子隨意地以選自-0·、-s(0)P-、-NR6-、-(C = 0)-、-C(=NR6)- —— S(0)pNR6-、-NR6S(〇)p_&-NR6s(〇)pNR6_ 之部分代替， ii) 前文（d)-(f)中任—者隨意地以一或多個r5基團取代，及 iii) 前文（d)-(f)中任—者隨意地以_(ci8烷基）_r5 基團取代； -159- 201125566 及（g)-(CR6R6)t-， C、F及J係獨立選自： (a)氫，（c)F，（d)Cl，（e)Br，（f)I，（g)-CF3，（h)-CN， (i) -N3，（j)-N02，（k)-NR6(CR6R6)tR8，（l)-〇R8，（m)-S(0)p(CR6R6),R8，（n)-C(0)(CR6R6)tR8， (o)-OC(0)(CR6R6)tR8，（p)-SC(0)(CR6R6),R8， (q)-C(0)0(CR6R6)tR8，（r)-NR6C(0)(CR6R6)tR8， (s)-C(0)NR6(CR6R6)tR8，（t)-C( = NR6)(CR6R6)tR8， (u)-C( = NNR6R6)(CR6R6)tR8，（v)-C( = NNR6C(0)R6)( CR6R6)tR8 ， (w)-C( = NOR8)(CR6R6),R8 ，(x)-NR6C(0)0( CR6R6)tR8，（y)-0C(0)NR6(CR6R6)tR8，（z)-NR6C(0)NR6( CR6R6)tR8，(aa)-NR6S(0)p(CR6R6)tR8 > (b b) - S (O) PN R6 ( CR6R6)tR8 > (cc)-NR6S(0)pNR6(CR6R6)tR8，（dd)-NR6R8， (ee)-NR6(CR6R6)R8，（ff)-OH，（gg)-NR8R8，（hh)-OCH3， (ii) -S(0)pR8 - (jj)-NC(0)R8 - (kk)-NR6C(NR6)NR6R8 - (11)(:,.8 烷基，（mm)C2.8 烯基，（nn)C2.8 炔基，（00)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（ρρ)3·14員飽和、不飽和或芳族碳環，（qq)-(CR6R6)tNR6(CR6R6),R8- > (rr)-N[(CR6R6)tR8][C = 0( CR6R6)tR8] . (ss)-(CR6R6),N[(CR6R6),R8][(CR6R6),R8] > (tt)-(CR6R6),NR6(C = 0)(CR6R6)tR8 > (uu)-鹵烷基，（vv)- C(0)(CR6)[(CR6R6)tR8]R8 ， (ww)-(CR6R6)tC(0)NR8R8 ， (xx)-(CR6R6)tC(0)0(CR6R6)tR8，（yy)-NR6C(0)CR8R8R8， (zz)-N[(CR6R6)tR8]C(0)R8，及（aaa)-S(0)pNR8R8 ; -160- 201125566 其中（11)至（PP)隨意地以一或多個R7基團取代； R5 係選自（a)氫 ’（b)F’（c)Cl’（d)Br，（e)i，（f)-CF3，（g)-CN ’ (h)-N3 > (i)-N02 ' (j)-NR6R6 , (k)-OR8 > (1)- N R6 (C N R6) N R6 R6，（ m) - C i · 8 院基，（n) · C !. 8 烯基，（o ) - C ,. 8 炔基，（Ρ)-((^_8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Cl_8烷基 )-(3-14員飽和、不飽和或芳族碳環），（Γ)_鹵院基，（s)_ SR6’（t)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’及（u)3-14員飽和、不飽和或芳族碳環；另一選擇地兩個R5基團一起形成碳環，其中（m)至⑴及⑴至（u)隨意地以一或多個R8取代； R6係選自（a)氫，（b)-C】.8烷基’或另一選擇地兩個R6基團一起形成碳環，（c)-鹵烷基’（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (e)3-14員飽和、不飽和或芳族碳環；其中（b)至（e)隨意地以一或多個R8取代·， R7 係選自（a)氫，（b)F，（c)Cl ’（d)Br，（e)I，（f)-CF3，（g)-CN ，（h)-N3 ，（i)-N〇2 ’ （j)-NR6R6 ，（k)-OR6 ，（1)- NR6(CNR6)NR6R6，（nO-C,.8 院基，（nhCu 烯基，（οχ】」炔基，0)-(6-8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)-(Ci.8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r) -鹵烷基，。）-NR6R8 > (t)-OR8 - (U)-(CR6R6),NR6R8 - (v)-CR6R8R8 ' (w)-SR6，Ο)含有一或多個選自氮、氧及硫之雜原子的3_14員 -161 - 201125566 飽和、不飽和或芳族雜環，（y )3-14員飽和、不飽和或芳族碳環，（z)-(CR6R6)tC(0)NR8R8 ’ （aa)-S(0)pR8 ’ （bb)- NR6C(0)NR6R6，（cc)-NR6C(0)R6，及（dd)-C( = NR6)NR6R6 t 其中（m)至（q)及（x)至（y)隨意地以~或多個R9取代； R8 係選自（a)氫，（b)F，（c)Cl ’（d)Br ’（e)I ’（f)-CF3，（g)- CN，（h)-N3，(i)-N02，(j)-NR6R9，（k)-OR9 ’ (1)- NR6(CNR6)NR6R6，（nO-Cu 院基，（n)-Ci-8 烯基，（〇)-C 卜 8 炔基，（ρ)-((^.8烷基）_(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)-(C^8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（s)3-14員飽和、不飽和或芳族碳環，（〇-鹵烷基， (u)-C(0)(CR6R6),R9 > (v)-SR6 > (w)-0C(0)(CR6R6),R9 > (x)-NR6C(0)NR6R9 ， (y)-NR6C(0)R9 ， (z)-NR6(CNR9)( NR6R6)，（aa)-ONR6(CNR6)NR6R6，（bb)-C ( = NR9)NR6R6， (cc)-S(0)pR9，（dd)-(CR6R6)tC(0)NR6R9， (ee)-(CR6R6)tOR9，及（ff)-(CR6R6)tNR6R9 ; 其中（m)至（s)隨意地以一或多個R9取代； R9 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN，(h)-N3 ’ (i)-N02 ’ (j)-NR6R10，(k)-OR6 > (1)- NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（iO-Cw 烷基，（ohCu烯基，（pi-Cu炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， ⑧ -162- 201125566 (r)3-14員飽和、不飽和或芳族碳環，（s)-鹵院基，（〇-(CR6R6)t〇R6，（u)-O(CR6R6)tNR6Rl0，（v)-C(O)R6，（w)-SR6，^)-(:(0)0111 G ’（y)-S(0)pR6，（z)-(Cl.8 烷基）_(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（aaHCM烷基）-(3-14員飽和、不飽和或芳族碳環），（bb)-0(CR6R6)t0R6，（cc)-C( = NR6)NR6R6， (dd)-ONR6R6，（ee)-NR6C(0)NR6R6，（ff)-〇(CR6R6)t〇R6， (gg)-NR6C(0)R6，及（hh)-(CR6R6)tNR6R10 ; 其中（n)至（r)及（z)至（aa)隨意地以一或多個Rl()取代； R10 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3， (g)-CN，（h)-N3，（i)-N02，（j)-NR6R6，（k)-OR6，（i)_ NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（rO-Cw 院基，（0)-(:,.8烯基，（phCy炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (r)3-14員飽和、不飽和或芳族碳環，（s) -鹵院基，⑴_ (CR6R6)tOR6 > (u)-0(CR6R6)tNR6R6 - (v)-C(0)R6 - (w)-SR6 ，（x)-C(0)0R6 ’（y)-S(0)pR6，烷基）-(含有—或多個選自氮、氧及硫之雜原子的3-14員飽和 '不飽和或芳族雜環），（aa)-(Cr8烷基）-(3-14員飽和、不飽和或芳族碳環），（bb)-0(CR6R6)t0R6，（cc)-C( = NR6)NR6R6，（dd)_ ONR6R6，（ee)-NR6C(0)NR6R6，（ff)-0(CR6R6)t0R6，（gg)_ NR6C(0)R6，及（hh)-(CR6R6)tNR6R6; 隨意地，其中基團-D-E-F或基團不存在，但是基團- D-E-F及基團- G-H-J二者不同時不存在； -163- 201125566 p爲0、1或2 ;及 t 爲 0、1、2 或 3，或其醫藥上可接受之鹽、酯、互變異構物或前藥。 2.根據申請專利範圍第1項之化合物，其具有下式：Wherein Rx is selected from CH2, NH, alkyl), S or 0; 1^ is C or CH' substituted with one or more CH3; or 1^ is CRaRb, wherein Ra and Rb together form a C3.5 carbocyclic ring Wherein m is 1, 2 or 3; J is selected from the group consisting of NH2, NH(CU8 alkyl), Νγ, .β alkyl)2, NHC(=0)CH3 'NHC( = 〇)NH2 'NHC( = NH NH2 'NHC( = NH)H ; CBA·, -DEF and -GHJ are chemical moieties, wherein A, D and G are independently selected from: (a) single bond '(b)-(C 丨·8 alkyl ), -(c)-(C2-8 alkenyl)-, (d)-(C2.8 alkynyl)_, wherein i) 0-4 of any of the foregoing (b)-(d) The carbon atom is optionally selected from the group consisting of -0-, -S(〇)p·, -nr6-, -(c=0)-, -S(0)pNR6., -nr6S(0)p-, and -NR6S ( 〇) a partial replacement of pNR6-, H) any of the foregoing (b)-(d) is optionally substituted with one or more R5 groups, and (1)) any of the foregoing (b)-(d) Substituted with a -(Ci-8 alkyl)-r5 group; (e)-〇-, (f)-NR6-, (g)-S(0)p-, (h)-C(0)- , (i)- C(0)0-,(1)· 0c(0)-'(k)_0C(0)0•,(1)_c(〇)NR6-,(m)-NR6c〇_, -158- 201125566 ( n)-NR6C(0)NR6-,(〇)-C( = NR6)-,(p)-C( = NR6) 〇_, (q)-OC( = NR6)-, (r)-C( = NR6)NR6-,(s)-NR6C( = NR6)-, (t)-C( = S)-,(u )-C( = S)NR6-,(v)-NR6C( = S)-,(w)-C(0)S-, (x)-SC(0)-,(y)-0C( = S ),, (z)-C( = S)0-, (aa)-NR6(CNR6)NR6· , (bb)-CR6R6C(0)-, (cc)-C(0)NR6(CR6R6)t- , (dd) a 3-14 member saturated, unsaturated or aromatic heterocyclic ring of '(ee) 3-14, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, a saturated, unsaturated or aromatic carbocyclic ring. And (ff)_(CR6R6), - > wherein (dd) or (ee) is optionally substituted with one or more R5 groups; B, E and anthracene are independently selected from: (a) single bond, ( b) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (c) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring, wherein (b) Or (c) optionally substituted with - or a plurality of R5 groups; (cO-CCu alkyl)-'(ε)-((:2·8 alkenyl)_, (f)_((:28 alkyne) )), where 1) 〇_4 carbon atoms in any of the texts (d)-(f) are optionally selected from -0, -s(0)P-, -NR6-, - (C = 0)-, -C(=NR6)- —— S(0)pNR6-, -NR6S(〇)p_&-NR6s(〇)pNR6_ Substituting, ii) in the preceding paragraphs (d)-(f) - optionally substituted with one or more r5 groups, and iii) in the preceding paragraphs (d)-(f) - optionally _(ci8 Alkyl)_r5 group substitution; -159- 201125566 and (g)-(CR6R6)t-, C, F and J are independently selected from: (a) hydrogen, (c)F, (d)Cl, (e )Br,(f)I,(g)-CF3,(h)-CN, (i) -N3,(j)-N02,(k)-NR6(CR6R6)tR8,(l)-〇R8,( m)-S(0)p(CR6R6), R8, (n)-C(0)(CR6R6)tR8, (o)-OC(0)(CR6R6)tR8,(p)-SC(0)(CR6R6 ), R8, (q)-C(0)0(CR6R6)tR8, (r)-NR6C(0)(CR6R6)tR8, (s)-C(0)NR6(CR6R6)tR8,(t)-C ( = NR6)(CR6R6)tR8, (u)-C( = NNR6R6)(CR6R6)tR8,(v)-C( = NNR6C(0)R6)( CR6R6)tR8 , (w)-C( = NOR8) (CR6R6), R8, (x)-NR6C(0)0(CR6R6)tR8, (y)-0C(0)NR6(CR6R6)tR8,(z)-NR6C(0)NR6(CR6R6)tR8,(aa )-NR6S(0)p(CR6R6)tR8 > (bb) - S (O) PN R6 ( CR6R6)tR8 > (cc)-NR6S(0)pNR6(CR6R6)tR8,(dd)-NR6R8, ( Ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NR8R8, (hh)-OCH3, (ii) -S(0)pR8 - (jj)-NC(0)R8 - (kk) -NR6C(NR6)NR6R8 - (11)(:,.8 alkyl, Mm) C2.8 alkenyl, (nn) C2.8 alkynyl, (00) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (ρρ)3·14 member saturated, unsaturated or aromatic carbocyclic ring, (qq)-(CR6R6)tNR6(CR6R6), R8- > (rr)-N[(CR6R6)tR8][C = 0(CR6R6 )tR8] . (ss)-(CR6R6), N[(CR6R6), R8][(CR6R6), R8] > (tt)-(CR6R6), NR6(C = 0)(CR6R6)tR8 > ( Uu)-haloalkyl, (vv)-C(0)(CR6)[(CR6R6)tR8]R8 , (ww)-(CR6R6)tC(0)NR8R8 , (xx)-(CR6R6)tC(0) 0(CR6R6)tR8, (yy)-NR6C(0)CR8R8R8, (zz)-N[(CR6R6)tR8]C(0)R8, and (aaa)-S(0)pNR8R8 ; -160- 201125566 where 11) to (PP) optionally substituted with one or more R7 groups; R5 is selected from (a) hydrogen '(b)F'(c)Cl'(d)Br, (e)i, (f) -CF3,(g)-CN ' (h)-N3 > (i)-N02 ' (j)-NR6R6 , (k)-OR8 > (1)- N R6 (CN R6) N R6 R6,( m) - C i · 8 院, (n) · C !. 8 alkenyl, (o ) - C ,. 8 alkynyl, (Ρ)-((^_8 alkyl)-(containing one or more 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from heteroatoms of nitrogen, oxygen and sulfur), (q)_(Cl_ 8-alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (Γ)_halogen compound, (s)_SR6'(t) containing one or more selected from the group consisting of nitrogen, oxygen and sulfur a hetero atom of a 3-14 member saturated, unsaturated or aromatic heterocyclic ring' and (u) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring; alternatively another two R5 groups are taken together to form a carbocyclic ring, Wherein (m) to (1) and (1) to (u) are optionally substituted with one or more R8; R6 is selected from (a) hydrogen, (b)-C].8 alkyl' or alternatively two R6 The groups together form a carbocyclic ring, and (c)-haloalkyl group (d) contains one or more 3-14 membered saturated, unsaturated or aromatic heterocyclic rings selected from heteroatoms of nitrogen, oxygen and sulfur, and e) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring; wherein (b) to (e) are optionally substituted by one or more R8, and R7 is selected from (a) hydrogen, (b)F, ( c) Cl '(d)Br, (e)I, (f)-CF3, (g)-CN, (h)-N3, (i)-N〇2 ' (j)-NR6R6 , (k)- OR6 , (1)- NR6(CNR6)NR6R6, (nO-C, .8 fen, (nhCu alkenyl, (οχ) alkynyl, 0)-(6-8 alkyl)-(contains one or more 3-14 selected from heteroatoms of nitrogen, oxygen and sulfur a saturated, unsaturated or aromatic heterocyclic ring), (q)-(Ci.8 alkyl)-(3-14 membered saturated, unsaturated or aromatic carbocyclic ring), (r)-haloalkyl. )-NR6R8 > (t)-OR8 - (U)-(CR6R6),NR6R8 - (v)-CR6R8R8 ' (w)-SR6,Ο) contains one or more heteroatoms selected from nitrogen, oxygen and sulfur 3_14 member-161 - 201125566 saturated, unsaturated or aromatic heterocyclic ring, (y) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (z)-(CR6R6)tC(0)NR8R8 ' (aa) -S(0)pR8 ' (bb)- NR6C(0)NR6R6, (cc)-NR6C(0)R6, and (dd)-C( = NR6)NR6R6 t where (m) to (q) and (x To (y) optionally substituted with ~ or more R9; R8 is selected from (a) hydrogen, (b)F, (c)Cl '(d)Br '(e)I '(f)-CF3, (g)-CN, (h)-N3, (i)-N02, (j)-NR6R9, (k)-OR9 ' (1)- NR6(CNR6)NR6R6, (nO-Cu, based on (n) -Ci-8 alkenyl, (〇)-C 卜 8 alkynyl, (ρ)-((^.8 alkyl)_ (3-14 containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) a saturated, unsaturated or aromatic heterocyclic ring), (q)-(C^8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r) containing one or more selected from 3-14 member saturated, unsaturated or aromatic heterocyclic ring of nitrogen, oxygen and sulfur heteroatoms, (s) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (〇) -haloalkyl, (u)-C(0)(CR6R6), R9 > (v)-SR6 > (w)-0C(0)(CR6R6), R9 > (x)-NR6C(0) NR6R9 , (y)-NR6C(0)R9 , (z)-NR6(CNR9)( NR6R6), (aa)-ONR6(CNR6)NR6R6,(bb)-C ( = NR9)NR6R6, (cc)-S (0) pR9, (dd)-(CR6R6)tC(0)NR6R9, (ee)-(CR6R6)tOR9, and (ff)-(CR6R6)tNR6R9; wherein (m) to (s) are optionally one or Multiple R9 substitutions; R9 is selected from (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)-CN, (h)- N3 ' (i)-N02 ' (j)-NR6R10, (k)-OR6 > (1)- NR6(CNR6)NR6R6, (m)-C(0)(CR6R6)tNR6R6, (iO-Cw alkyl , (ohCu alkenyl, (pi-Cu alkynyl, (q) a 3- to 14-membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, 8 -162- 201125566 (r) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-halogen compound, (〇-(CR6R6)t〇R6, (u)-O(CR6R6)tNR6Rl0, (v)- C(O)R6,(w)-SR6,^)-(:(0)0111 G '(y)-S(0)pR6,(z)-(Cl.8 alkyl)_(containing one or more a 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from heteroatoms of nitrogen, oxygen and sulfur), aaHCM alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (bb)-0(CR6R6)t0R6, (cc)-C(=NR6)NR6R6, (dd)-ONR6R6, (ee -NR6C(0)NR6R6, (ff)-〇(CR6R6)t〇R6, (gg)-NR6C(0)R6, and (hh)-(CR6R6)tNR6R10; where (n) to (r) and z) to (aa) optionally substituted with one or more R1(); R10 is selected from (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f) -CF3, (g)-CN, (h)-N3, (i)-N02, (j)-NR6R6, (k)-OR6, (i)_NR6(CNR6)NR6R6, (m)-C(0 (CR6R6)tNR6R6, (rO-Cw), (0)-(:,.8 alkenyl, (phCy alkynyl, (q) containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) -14-membered saturated, unsaturated or aromatic heterocyclic ring, (r) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-halogen compound, (1)_(CR6R6)tOR6 > (u)-0 (CR6R6)tNR6R6 - (v)-C(0)R6 - (w)-SR6 ,(x)-C(0)0R6 '(y)-S(0)pR6,alkyl)-(contains - or more 3-14 member saturated 'unsaturated or aromatic heterocyclic ring selected from heteroatoms of nitrogen, oxygen and sulfur, (aa)-(Cr8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbon) Ring), (bb)-0(CR6R6)t0R6 , (cc)-C( = NR6)NR6R6, (dd)_ ONR6R6, (ee)-NR6C(0)NR6R6, (ff)-0(CR6R6)t0R6, (gg)_ NR6C(0)R6, and Hh)-(CR6R6)tNR6R6; Optionally, wherein the group -DEF or group is absent, but the group - DEF and the group - GHJ are not present at the same time; -163- 201125566 p is 0, 1 or 2 And t is 0, 1, 2 or 3, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 2. A compound according to item 1 of the scope of the patent application having the following formula:

或其醫藥上可接受之鹽、酯、互變異構物或前藥。 3 .根據申請專利範圍第2項之化合物，其具有下式：Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 3. A compound according to item 2 of the scope of the patent application having the following formula:

其中D及E爲單鍵，且F爲氫；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 4.根據申請專利範圍第3項之化合物，其具有下式：Wherein D and E are single bonds and F is hydrogen; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 4. A compound according to item 3 of the scope of the patent application having the following formula:

或其醫藥上可接受之鹽、酯、互變異構物或前藥。 5.根據申請專利範圍第4項之化合物，其具有下式：Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 5. A compound according to item 4 of the scope of the patent application having the following formula:

或其醫藥上可接受之鹽、酯、互變異構物或前藥。 6.根據申請專利範圍第4項之化合物，其中 A係選自 ⑧ -164- 201125566 U)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (b) 3-14員飽和、不飽和或芳族碳環，及 (c) 單鍵，其中（a)或（b)隨意地以一或多個R5基團取代； B 係選自（a)-(C,_8 烷基）-，（b)-(C2-8 烯基）-，（c)-(C2.8 炔基 )-’及（d)單鍵，其中 i) 前文（a)-(c)中任一者中的0-4個碳原子隨意地以選自-0-、-S(0)p-、-NR6-、-(C = 0)·、-C( = NR6)-、-S(〇)pNR6-及-NR6S(〇)pNR6-之部分代替， ii) 前文（a)-(c)中任一者隨意地以一或多個R5基團取代，及 iii) 前文（a)-(c)中任一者隨意地以- (CU8院基）_r5 基團取代；及 C 係選自（a)NH2，（b)-NHC( = NH)NH2，及（c)氫；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 7 ·根據申請專利範圍第6項之化合物，其中a g g 氮雜環庚院基（azepanyl)、環丁基、環戊基、環己基、環庚基、苯基、吡啶基、環己烯基、環己二烯基、一翁nu 〜氮吡啶基、呋喃基、四氫呋喃基、四氫吡啶基、四氫吖唉基、Μ 咯啶基、哌啶基及哌啶烯基；其中前文Α中任一者隨意地以一或多個R5基團取代·，另一選擇地，A爲單鍵； B係選自烷基）-’其中 -165- 201125566 i) 前文（a)中的〇·4個碳原子隨意地以選自-〇-、-s(0)p-、-NR6-、-(c = 0)-、-S(0)PNR6-及-NR6S(0)pNR6-之部分代替， ii) 前文（a)隨意地以—或多個R5基團取代，及 iii) 前文（a)隨意地以_(ci·8院基）-R5基團取代及另一選擇地，B爲單鍵； C 係選自（a)NH2 ’（b)-NHC( = NH)NH2 ’ 及（c)氫；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 8.根據申請專利範圍第7項之化合物，其中^ r A -体選自：氫， οOr a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 6. A compound according to claim 4, wherein A is selected from the group consisting of 8 - 164 - 201125566 U) 3-14 members containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, saturated, unsaturated or aromatic a heterocyclic ring, (b) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring, and (c) a single bond, wherein (a) or (b) is optionally substituted with one or more R5 groups; Selected from (a)-(C,_8 alkyl)-, (b)-(C2-8 alkenyl)-, (c)-(C2.8 alkynyl)-' and (d) single bond, wherein i The 0-4 carbon atoms in any of the foregoing (a)-(c) are optionally selected from the group consisting of -0-, -S(0)p-, -NR6-, -(C=0)·, Substituting -C( = NR6)-, -S(〇)pNR6- and -NR6S(〇)pNR6-, ii) Any of the foregoing (a)-(c) optionally with one or more R5 groups Substituted, and iii) any of the foregoing paragraphs (a)-(c) are optionally substituted with the - (CU8-based) _r5 group; and the C-system is selected from (a) NH2, (b)-NHC (= NH NH2, and (c) hydrogen; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 7. A compound according to claim 6 of the scope of the patent application, wherein agg azepanyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, cyclohexenyl, a cyclohexadienyl group, a nu nu azo azide group, a furyl group, a tetrahydrofuranyl group, a tetrahydropyridyl group, a tetrahydroindenyl group, an anthranylene group, a piperidinyl group, and a piperidinyl group; One is optionally substituted with one or more R5 groups, and alternatively, A is a single bond; B is selected from an alkyl group)-' wherein -165- 201125566 i) 〇·4 in (a) above The carbon atoms are optionally replaced by a moiety selected from the group consisting of -〇-, -s(0)p-, -NR6-, -(c = 0)-, -S(0)PNR6-, and -NR6S(0)pNR6- , ii) (a) optionally substituted with — or a plurality of R 5 groups, and iii) (a) optionally substituted with _(ci·8 yards)-R5 groups and alternatively, B is Single bond; C is selected from the group consisting of (a) NH2 '(b)-NHC(=NH)NH2' and (c) hydrogen; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 8. A compound according to claim 7 wherein the ^ r A - body is selected from the group consisting of: hydrogen, ο

-166- 201125566-166- 201125566

167- 201125566167- 201125566

或其醫藥上可接受之鹽、酯、互變異構物或前藥。 9.根據申請專利範圍第4項之化合物，其中〇係選自 (a)單鍵，（b)-(C|.8 烷基）·，（c)_(C2 8 烯基）·， (d)-(C2-8炔基）-，其中 1)前文（b)-(d)中任一者中的〇_4個碳原子隨意地以選自-〇·、-S(0)P-、-NR6-、-(c = 〇)_、-c( = nr6)-、- S(0)pNR6·、-NR6S(0)p-及 _NR6s(0)pNR6_ 之部分代替， ii)前文（b)-(d)中任一者隨意地以—或多個r5基團取代，及 iii)前文（b)-(d)中任一者隨意地以_(Cl.8烷基）_R5 基團取代； (e) 含有一或多個選自氮、氧及硫之雜原子的3_14員飽和、不飽和或芳族雜環，及 (f) 3-14員飽和、不飽和或芳族碳環，其中（e)或⑴隨意地以一或多個R5基團取代；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 1 0·根據申請專利範圍第6項之化合物，其中R5係選 ③ -168- 201125566 自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN， (h)-N3，（i)-N02，⑴-NH2，（k)-OR6，（1)NHC(=NH)NH2， (m)-Ci.8 院基 ’（n)-Ci.8 傭基 ’（〇)-Ci.8 块基，（p)-(C|-8 院基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或方族雜環），（q)-(Ci.s院基）-(3-14員飽和、不飽和或芳族碳環），（r)-鹵烷基，（s)-SR6，（t)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’及（u)3-14員飽和、不飽和或芳族碳環；另一選擇地，兩個R5基團一起形成碳環；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 1 1 ·根據申請專利範圍第6項之化合物，其中R6係選自（a)氫’（bhCu烷基，或另一選擇地兩個R6基團—起形成碳環’（〇-鹵烷基，（d)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及（e)3_14員飽和、不飽和或芳族碳環；或其醫藥上可接受之鹽、酯、互變異構物或前藥。 1 2.根據申請專利範圍第9項之化合物，其中G係選自（a)單鍵 ’（bXCu 烷基）_，（c).(c2.8 烯基）-，（d)-(C2-8 炔基）-，其中〇前文（b)-(d)中任一者中的〇_4個碳原子隨意地以選自-〇-、-S(〇)P-、-NR6- > -(C = 0)-、-C( = NR6)-、-S(0)pNR6-、-NR6S(0)p-及 _.NR6s(〇)p：NR6-之部分代替， H)前文（b)-(d)中任一者隨意地以—或多個r5基團取代，及 -169- 201125566 iii)前文（b)-(d)中任一者隨意地以- (Cm烷基）-R5 基團取代；其中P爲〇、1或2 ; 或其醫藥上可接受之鹽、酯、互變異構物或前藥。 1 3.根據申請專利範圍第 2項之化合物，其中Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 9. A compound according to claim 4, wherein the lanthanide is selected from the group consisting of (a) a single bond, (b)-(C|.8 alkyl), (c)-(C2 8 alkenyl), ( d)-(C2-8 alkynyl)-, wherein 1) the 〇_4 carbon atoms in any of the foregoing (b)-(d) are optionally selected from -〇·, -S(0)P -, -NR6-, -(c = 〇)_, -c( = nr6)-, -S(0)pNR6·, -NR6S(0)p- and _NR6s(0)pNR6_ are replaced by part, ii) Any of the foregoing (b)-(d) is optionally substituted with - or a plurality of r5 groups, and iii) any of the foregoing (b)-(d) is optionally _(Cl.8 alkyl) a _R5 group substituted; (e) a 3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (f) 3-14 member saturated, unsaturated or aromatic a carbocyclic ring wherein (e) or (1) is optionally substituted with one or more R5 groups; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 1 0. A compound according to item 6 of the patent application, wherein R5 is selected from 3 - 168 to 201125566 from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f )-CF3,(g)-CN, (h)-N3,(i)-N02,(1)-NH2,(k)-OR6,(1)NHC(=NH)NH2, (m)-Ci.8 Base '(n)-Ci.8 maid' (〇)-Ci.8 block base, (p)-(C|-8 yard base)-(containing one or more selected from nitrogen, oxygen and sulfur 3-14 members of the atom are saturated, unsaturated or tetracyclic, (q)-(Ci.s)-(3-14-membered saturated, unsaturated or aromatic carbocyclic), (r)-halogen Alkyl, (s)-SR6, (t) 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u)3-14 members A saturated, unsaturated or aromatic carbocyclic ring; alternatively, the two R5 groups together form a carbocyclic ring; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 1 1 · A compound according to claim 6 wherein R6 is selected from (a) hydrogen' (bhCu alkyl, or alternatively two R6 groups - to form a carbocycle' (〇-haloalkyl) (d) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (e) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring; Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 1 2. A compound according to claim 9 wherein G is selected from the group consisting of (a) a single bond '(bXCu alkyl)), (c). (c2.8 alkenyl)-, (d)-(C2-8 alkynyl)-, wherein the 〇_4 carbon atoms in any of the preceding paragraphs (b)-(d) are optionally Selected from -〇-, -S(〇)P-, -NR6- > -(C = 0)-, -C( = NR6)-, -S(0)pNR6-, -NR6S(0)p -and _.NR6s(〇)p: a partial replacement of NR6-, H) any of the foregoing (b)-(d) is optionally substituted with - or a plurality of r5 groups, and -169- 201125566 iii) Any one of (b)-(d) optionally substituted with a -(Cmalkyl)-R5 group; wherein P is hydrazine, 1 or 2; or a pharmaceutically acceptable salt, ester or tautomer thereof Or prodrug thereof. 1 3. A compound according to item 2 of the scope of the patent application, wherein

或其醫藥上可接受之鹽、酯、互變異構物或前藥。 14.根據申請專利範圍第1 3項之化合物，其中Or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 14. A compound according to claim 13 of the scope of the patent application, wherein

係選自： -170- 201125566Line from: -170- 201125566

或-G-H-J係選自 201125566Or -G-H-J is selected from 201125566

其中Rx係選自CH2、NH、N(Ci.8烷基）、S或0;、及Rz 爲C或CH，各自獨立以一或多個F、CH3、CF3、OH及 OCH3取代；或Rx、Ry及Rz各自獨立選自Ch2或CRaRb ’其中Ra及Rb —起形成C3.5碳環； J 係選自 NH2、ΝΗπ,.β烷基）、NiChs烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ；其中n爲〇、1或2 ; 另一選擇地，-G-H-M系選自：Wherein Rx is selected from the group consisting of CH2, NH, N(Ci.8 alkyl), S or 0; and Rz is C or CH, each independently substituted with one or more of F, CH3, CF3, OH and OCH3; or Rx , Ry and Rz are each independently selected from Ch2 or CRaRb 'where Ra and Rb together form a C3.5 carbocyclic ring; J is selected from the group consisting of NH2, ΝΗπ, .β alkyl), NiChs alkyl) 2, NHC (= 0) CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; where n is 〇, 1 or 2; alternatively, -GHM is selected from:

其中Rx係選自CH2、ΝΗ、Ν((^·8烷基）、S或0; Rz爲以一或多個CH3取代之C或CH ;或Rz爲CRaRb，其中Ra 及Rb —起形成C3.5碳環；其中m爲1、2或3 ; J 係選自 NH2、NHiCu烷基）、N(C丨.8烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ;或其醫藥上可接受之鹽、酯、互變異構物或前藥。 -172- ⑧ 201125566 1 5 .根據申請專利範圍第1至1 4項中任一項之化合物，其係與核糖體結合。 1 6.根據申請專利範圍第1 5項之化合物，其中該核糖體爲細菌核糖體。 17.—種根據表1中之化合物中任一者之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥。 1 S · —種醫藥組成物’其包含根據申請專利範圍第i _ 17項中任一項之化合物，或其醫藥上可接受之鹽、酯、互變異構物或前藥，及醫藥上可接受之載劑。 1 9 · 一種用於治療、預防或減低人類或動物疾病狀態風險之醫藥組成物’其包含有效量之根據申請專利範圍第 1-17項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥。 2 0. —種根據申請專利範圍第1 _ 1 7項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥之用途’係用來製造用於治療 '預防或減低人類或動物疾病狀態風險之藥劑。 21.—種用於治療人類或動物微生物感染之醫藥組成物，其包含有效量之根據申請專利範圍第1 -1 7項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥。 2 2 · —種根據申請專利範圍第1 -1 7項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥之用途 ’係用來製造用於治療人類或動物微生物感染之藥劑。 •173- 201125566 23.—種用於治療、預防或減低人類或動物微生物感染風險之醫藥組成物，其包含有效量之根據申請專利範圍第1_17項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥，其中該微生物感染係選自：皮膺感染、革蘭氏（Gram)陽性菌感染、革蘭氏陰性菌感染、院內感染肺炎、社區型感染肺炎、病毒後感染肺炎、醫院型感染肺炎/呼吸器相關肺炎、呼吸道感染（諸如CRTI)、急性骨盆感染、倂發性皮膚及皮膚結構感染、皮膚及軟組織感染（SSTI)(包括無倂發性皮膚及軟組織感染（USSTI)與倂發性皮膚及軟組織感染）、腹部感染、倂發性腹腔內感染、尿道感染、菌血症、敗血症、心內膜炎、心室心房分流感染、血管通路感染、腦膜炎、預防性手術感染、腹膜感染、骨感染、關節感染、抗二甲苯青黴素金黃葡萄球菌感染、抗萬古黴素腸球菌感染、抗利奈唑德（linezolid)有機體感染、炭痕桿菌（Bacillus anthracis)感染、兔熱病桿菌 (Francisella tularensis)感染、鼠疫耶氏菌（Yersinia pestis) 感染及結核病。 24· —種根據申請專利範圍第1 -1 7項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥之用途’係用來製造用於治療、預防或減低人類或動物微生物感染風險之藥劑，其中該微生物感染係選自：皮膚感染、革蘭氏（Gram)陽性菌感染、革蘭氏陰性菌感染、院內感染肺炎、社區型感染肺炎、病毒後感染肺炎、醫院型感染肺炎/呼吸器相關肺炎、呼吸道感染（諸如CRTI)、急性骨盆 -174- 201125566 感染、倂發性皮膚及皮膚結構感染、皮膚及軟組織感染 (SSTI)(包括無倂發性皮膚及軟組織感染（USSTI)與倂發性皮膚及軟組織感染）、腹部感染、倂發性腹腔內感染、尿道感染、菌血症、敗血症、心內膜炎、心室心房分流感染、血管通路感染、腦膜炎、預防性手術感染、腹膜感染、骨感染、關節感染、抗二甲苯青黴素金黃葡萄球菌感染、抗萬古黴素腸球菌感染、抗利奈唑德（linezolid)有機體感染、炭疽桿菌（Bacillus an thracis)感染、兔熱病桿菌 (Francisellatularensis)感染、鼠疫耶氏菌（Yersinia pestis) 感染及結核病。 2 5 ·根據申請專利範圍第1 9、2 1、及2 3項中任一項之醫藥組成物，其係經耳、眼、鼻、口服、非經腸、靜脈內或局部方式投予。 26·如申請專利範圍第20、22及24項中任一項之用途’其中該藥劑係經耳、眼、鼻、口服、非經腸、靜脈內或局部方式投予。 2 7 · —種含有根據申請專利範圍第1 - 1 7項中任一項之化合物或其醫藥上可接受之鹽、酯、互變異構物或前藥之醫學裝置。 2 8.根據申請專利範圍第27項之醫學裝置，其中該裝置爲支架。 29·—種具有下式之化合物： -175-Wherein Rx is selected from the group consisting of CH2, hydrazine, hydrazine ((^.8 alkyl), S or 0; Rz is C or CH substituted with one or more CH3; or Rz is CRaRb, wherein Ra and Rb together form C3 .5 carbon ring; wherein m is 1, 2 or 3; J is selected from NH2, NHiCu alkyl), N(C丨.8 alkyl) 2, NHC(=0)CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. The compound according to any one of claims 1 to 4, which binds to a ribosome. 1 6. The compound according to claim 15 wherein the ribosome is a bacterial ribosome. 17. A compound according to any one of the compounds of Table 1, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 1 S - a pharmaceutical composition comprising a compound according to any one of the claims i--17, or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof, and pharmaceutically acceptable Accepted carrier. A pharmaceutical composition for treating, preventing or reducing the risk of a human or animal disease state, which comprises an effective amount of a compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof , ester, tautomer or prodrug. 2 0. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof for use in the manufacture of a ' An agent that prevents or reduces the risk of disease in humans or animals. 21. A pharmaceutical composition for treating a human or animal microbial infection, comprising an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, ester or mutual thereof An isomer or prodrug. 2 2 - The use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof for use in the manufacture of a human Or an agent for animal microbial infection. • 173- 201125566 23. A pharmaceutical composition for treating, preventing or reducing the risk of microbial infection in humans or animals, comprising an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable compound thereof a salt, ester, tautomer or prodrug, wherein the microbial infection is selected from the group consisting of: skin infection, Gram-positive infection, Gram-negative infection, nosocomial infection, pneumonia, community-type infection , post-virus pneumonia, hospital-type pneumonia/respirator-associated pneumonia, respiratory infections (such as CRTI), acute pelvic infections, hairy skin and skin structure infections, skin and soft tissue infections (SSTI) (including no acne skin) And soft tissue infections (USSTI) and hairy skin and soft tissue infections), abdominal infections, idiopathic intra-abdominal infections, urinary tract infections, bacteremia, sepsis, endocarditis, ventricular atrial shunt infection, vascular access infections, meninges Inflammation, preventive surgical infection, peritoneal infection, bone infection, joint infection, anti-xylene penicillin, Staphylococcus aureus infection, anti-Wanggu Su enterococcal infections, anti linezolid Germany (linezolid) organism infection, charcoal marks bacillus (Bacillus anthracis) infection, tularemia bacilli (Francisella tularensis) infection, Y. pestis (Yersinia pestis) infection and tuberculosis. 24. The use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof for use in the treatment or prevention Or an agent that reduces the risk of microbial infection in humans or animals, wherein the microbial infection is selected from the group consisting of: skin infection, Gram-positive bacterial infection, Gram-negative bacterial infection, nosocomial infection pneumonia, community-type pneumonia, and virus Pneumonia, hospital-type pneumonia/respirator-associated pneumonia, respiratory infections (such as CRTI), acute pelvic-174-201125566 infection, hairy skin and skin structure infections, skin and soft tissue infections (SSTI) (including no claudication) Skin and soft tissue infections (USSTI) and idiopathic skin and soft tissue infections, abdominal infections, idiopathic intra-abdominal infections, urinary tract infections, bacteremia, sepsis, endocarditis, ventricular atrial shunt infection, vascular infection, Meningitis, preventive surgical infection, peritoneal infection, bone infection, joint infection, anti-xanthin penicillin, Staphylococcus aureus infection, vancomycin resistance Enterococcus infection, resistance to linezolid organisms, infection with Bacillus anthracis, infection with Francisellatularensis, infection with Yersinia pestis, and tuberculosis. The pharmaceutical composition according to any one of claims 1, 9 and 21, which is administered by ear, eye, nose, oral, parenteral, intravenous or topical administration. The use of any one of claims 20, 22 and 24 wherein the agent is administered by ear, eye, nose, oral, parenteral, intravenous or topical. A medical device comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof. 2 8. The medical device according to claim 27, wherein the device is a stent. 29·—a compound of the formula: -175-

201125566201125566

其中 u 係選自 cr3r3、o、nr4 或 s(o)n、c ’另一選擇地兩個R3 —起形成羰基， v係獨立選自-CR4a-或-N-; 其中vg)代表經稠合之5至7員飽和、不飽和| 或雜環系環系統： W爲〇、NR1、NOR1或S，另一選擇地W =保碳原子連接之H0-與H-二者之組合或與同一碳 (C!.8烷基）0-與H-二者之組合； X=Y代表單鍵或雙鍵，使得當Χ---Υ爲單鍵選自0、NR2及S(0)n且Υ爲C-R3，而當X二 ’則X爲N且Y爲碳原子， Z係選自Ο、NR4或S(0)„， R1係選自Η及C,.8烷基， R2係選自Η及Cm烷基， R3係選自Η及（^.8烷基， R係選自Η及C|.8院基’ R4a係選自Η及C|.8烷基， η爲〇、1或2，另~選擇地，-G-H-J係選自下式： Η一J H—J， -176- -Ε一F - H_J ⑼，〆〇—E—F Ϊ 、G-H—J(IV)， =0 ' C=N〇r3 :芳族碳環系 :選自與同一 ί原子連接之時，則X係爲雙鍵時 201125566 其中各個Η及J係獨立選擇，Wherein u is selected from the group consisting of cr3r3, o, nr4 or s(o)n, c'. Alternatively, two R3 together form a carbonyl group, and v is independently selected from -CR4a- or -N-; wherein vg) represents thick 5 to 7 member saturated, unsaturated | or heterocyclic ring system: W is 〇, NR1, NOR1 or S, and alternatively W = a combination of H0- and H- of the carbon-bonding bond or The same carbon (C!.8 alkyl) combination of 0- and H-; X=Y represents a single bond or a double bond, such that when Χ---Υ is a single bond selected from 0, NR2 and S(0) n and Υ is C-R3, and when X ′′, X is N and Y is a carbon atom, Z is selected from Ο, NR 4 or S(0) „, and R 1 is selected from Η and C, .8 alkyl, R2 is selected from the group consisting of hydrazine and Cm alkyl, R3 is selected from the group consisting of hydrazine and (^.8 alkyl, R is selected from fluorene and C|.8). The R4a is selected from the group consisting of hydrazine and C|.8 alkyl, η. For 〇, 1 or 2, another choice, -GHJ is selected from the following formula: Η一JH—J, -176- -Ε一F - H_J (9), 〆〇—E—F Ϊ , GH—J(IV ), =0 ' C=N〇r3 : aromatic carbocyclic ring system: when it is selected from the same ί atom, when X is a double bond, 201125566, each of which is independently selected,

其中Rx係選自CH2、NH、N(C,-8烷基）、S或0; %及Rz 爲C或CH，各自獨立以一或多個F、CH3、CF3、OH及 OCH3取代；或Rx、Ry及Rz各自獨立選自CH2或CRaRb ，其中Ra及Rb —起形成C3_5碳環； J 係選自 NH2、NH(C丨.8烷基）、N(C丨.8烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 NHC( = NH)H ；其中n爲0、1或2 ; 另一選擇地，-G-H-J係選自：Wherein Rx is selected from the group consisting of CH2, NH, N(C,-8-alkyl), S or 0; % and Rz are C or CH, each independently substituted with one or more of F, CH3, CF3, OH and OCH3; Rx, Ry and Rz are each independently selected from CH2 or CRaRb, wherein Ra and Rb together form a C3_5 carbon ring; J is selected from NH2, NH(C丨.8 alkyl), N(C丨.8 alkyl)2 , NHC(=0)CH3, NHC(=0)NH2, NHC(=NH)NH2, NHC(=NH)H; where n is 0, 1 or 2; alternatively, the -GHJ is selected from:

其中Rx係選自CH2、NH、烷基）、S或0; Rz爲以一或多個CH3取代之C或CH，或Rz爲CRaRb，其中Ra 及Rb —起形成C3.5碳環；其中m爲1、2或3 ; J 係選自 NH2、NH(Ci-8 烷基）、Ν((^-8 烷基）2、 NHC( = 0)CH3 、 NHC( = 0)NH2 、 NHC( = NH)NH2 、 -177- 201125566 NHC( = NH)H ； C-B-A-' -D-E-F及-G-Η·】爲化學部分，其中 A、 D及G係獨立選自： (a)單鍵’（b)-(Cu8 烷基）-，（c)-(C2.8 烯基）·，（d)-(C2. 8炔基）-，其中 i) 前文（b)-(d)中任一者中的〇·4個碳原子隨意地以選自-0-、-S(0)P-、-nr6-、-(c = 〇)-、-S(0)pNR6-、-NR6S(0)p 及-NR6S(〇)pNR6-之部分代替， ii) 前文（b)-(ci)中任一者隨意地以一或多個R5基團取代，及 iii) 前文（b)-(d)中任一者隨意地以- (Cu烷基）-R5 基團取代； (e)-0-，（f)-NR6-，（g)-s(〇)p-，（h)-C(0)-，（i)-C(0)0-，（j)-OC(O)·，（k)-OC(〇)〇-，（i)-C(0)NR6-，（m)- NR6C0- ’ (n)-NR6C(0)NR6- ， (〇)-C( = NR6)- ， (p)- C( = NR6)0- ，（q)-0C(=NR6)- ，(r)-C( = NR6)NR6- ’ (s)-NR6C( = NR6)- ’ (t)-C( = S)- ， (u)-C( = S)NR6- ， (v)- NR6C( = S)- > (w)-C(0)S- > (x)-SC(O)- . (y).〇C( = S)- · (z)-C( = S)0- > (aa)-NR6(CNR6)NR6- , (b b) - C R6 R ^ C (0) - - (cc)-C(0)NR6(CR6R6)t- ’（dd)含有一或多個選自氮 '氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（ee)3_M員飽和、不飽和或芳族碳環，及（ff)-(CR6R6)t-，其中（dd)或（ee)隨意地以一或多個R5基團取代； B、 E及Η係獨立選自： -178- 201125566 (a) 單鍵， (b) 含有一或多個選自氮 '氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (0 3-14員飽和、不飽和或芳族碳環，其中（b)或（c)隨意地以一或多個R5基團取代； (dXCu 院基）_ ’（e)_(C2 8 烯基）· ’（f)-(C2-8 炔基）_，其中 i)前文（d)-(f)中任一者中的〇-4個碳原子隨意地以選自-0-、_S(〇)p_、„NR6_、_(C=〇)_、_C( = NR6)_、_ S(0)pNR6-、-NR6S(0)p-及-NR6s(0)pNR6-之部分代替， Π)前文（d)-(f)中任一者隨意地以一或多個R5基團取代，及 iii)前文（d)-(f)中任一者隨意地以_(Cl.8烷基）_R5 基團取代；及（g)-(CR6R6)t-， C、F及J係獨立選自： (a)氫 ’（c)F、（d)Cl、（e)Br，（f)I、（g)-CF3，（h)-CN， (i)-N3 ’（j)-N02，（k)-NR6(CR6R6)|R8，（1)-0R8， (m)-S(0)p(CR6R6)tR8 . (n)-C(0)(CR6R6)tR8 > (o)-OC(0)(CR6R6)tR8 - (p)-SC(0)(CR6R6),R8 > (q)-C(0)0(CR6R6)tR8 > (r) - N R6 C (0) (C R6 R6), R8 ' (s)-C(0)NR6(CR6R6),R8 - (t)-C( = NR6)(CR6R6),R8 -(u)-C( = NNR6R6)(CR6R6)tR8 - (v) - C (= NN R6 C (0) R6)( CR6R6)tR8 ' (w)-C( = NOR8)(CR6R6),R8 > (x) - N R6 C (0) 0 ( -179- 201125566 CR6R6),R8 > (y)-0C(0)NR6(CR6R6)tR8 - (z)-NR6C(0)NR6( CR6R6),R8 ' (aa)-NR6S(0)p(CR6R6)tR8 > (b b) - S (O) PN R6 ( CR6R6),R8 > (cc)-NR6S(0)pNR6(CR6R6),R8 > (dd)-NR6R8 > (ee)-NR6(CR6R6)R8，（ff)-OH，（gg)-NRsR8，（hh)-OCH3， (ii)-S(0)pR8 ' (jj)-NC(0)R8 > (kk)-NR6C(NR6)NR6R8 · (11)C 丨-8 烷基，（mm)C2-8 烯基，（nn)C2.8 炔基，（oo)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（ΡΡ)3·14員飽和、不飽和或芳族碳環，（qq)-(CR6R6)tNR6(CR6R6),R8 > (rr)-N [(CR6R6)tR8] [C = 0( CR6R6),R8] > (ss)-(CR6R6),N[(CR6R6),R8][(CR6R6),R8] > (tt)-(CR6R6),NR6(C = 0)(CR6R6),R8 - (uu)-鹵烷基，（”）- C(0)(CR6)[(CR6R6)tR8]R8 ’ (ww)-(CR6R6)tC(0)NR8R8 ， (xx)-(CR6R6),C(0)0(CR6R6),R8 - (yy)-NR6C(〇)CR8R8R8 » (zz)-N[(CR6R6)tR8]C(0)R8 ’ 及（aaa)-S(0)pNR8R8 ; 其中（11)至（pp)隨意地以一或多個R7基團取代； R5 係選自（a)氫 ’（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN，（h)-N3，（i)-N02，（j)-NR6R6，（k)-OR8，（l)-NR6(CNR6)NR6R6，（m)-Cr8 烷基，（n)-C 丨·8 烯基，（〇)-C,.8 炔基，0)-(6.8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（q)_(Cl_8烷基 )-(3-14員飽和、不飽和或芳族碳環），（r)-鹵烷基，（8)_ SR6，（t)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及（u)3-14員飽和、不飽和或芳族碳環：另一選擇地兩個R5基團一起形成碳環， -180- 201125566 其中（m)至⑴及⑴至（u)隨意地以—或多個R8取代； R6係選自（a)氫，（bhCu烷基，或另一選擇地兩個R6基團一起形成碳環，（c)-鹵烷基，（d)含有一或多個選自氮' 氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，及 (e)3-14員飽和、不飽和或芳族碳環；其中（b)至（e)隨意地以一或多個R8取代； R7 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN ，（h)-N3 ，（i)-N02 ，（j)-NR6R6 ，（k)-OR6 ，（1)- NR6(CNR6)NR6R6 ’（nO-Cus 烷基，（11)-(:,-8 烯基，（0)-(:,.8 炔基，（？）-(<^_8烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），烷基 )-(3-14員飽和、不飽和或芳族碳環），（〇-鹵烷基，（s)-NR6R8 > (t)-OR8 - (u)-(CR6R6),NR6R8 - (v)-CR6R8R8 > (w)-SR6，（x)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環，（y)3-14員飽和、不飽和或芳族碳環，（z)-(CR6R6)tC(0)NR8R8，（aa)-S(0)pR8 ’ （bb)- NR6C(0)NR6R6，（cc)-NR6C(0)R6，及（dd)-C( = NR6)NR6R6 » 其中（m)至（q)及（x)至（y)隨意地以一或多個R9取代； R8 係選自（a)氫，（b)F ’（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN，（h)-N3，（i)-N02，（j)-NR6R9 ’ （k)-〇R9 ’ （1)- NR6(CNR6)NR6R6，（m)-C 卜 8 烷基’（n)-C 卜 8 烯基，（〇)-C 卜 8 炔基，0)-(6.8烷基）·（含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環）’（q)-(Cl·8烷基 -181 - 201125566 )-(3-14員飽和、不飽和或芳族碳環），（r)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環’（s) 3-14員飽和、不飽和或芳族碳環，（t)_鹵烷基， (u)-C(0)(CR6R6)tR9 ’（V)-SR6，（w)-〇C(0)(CR6R6)tR9， (x)-NR6C(0)NR6R9 ，（y)-NR6C(0)R9 ， (z)-NR6(CNR9)( NR6R6)，(aa)-ONR6(CNR6)NR6R6 - (bb)-C( = NR9)NR6R6 -(cc)-S(0)pR9，（dd)-(CR6R6)tC(0)NR6R9，（ee)-(CR6R6)t〇R9，及（ff)-(CR6R6)tNR6R9 ; 其中（m)至（s)隨意地以一或多個R9取代； R9 係選自（a)氫，（b)F ’（c)Cl，（d)Br，（e)I，（f)-CF3，（g)-CN ’ (h)-N3 ’ (i)-N02 ，（j)-NR6R10，(k)-OR6 > (1)- NR6(CNR6)NR6R6，（m)-C(0)(CR6R6)tNR6R6，（M-Cm 院基 ’（0)-Ci-8嫌基’（p)-Ci.8炔基’（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (03-14員飽和、不飽和或芳族碳環，（s)_鹵烷基，（〇_ (CR6R6)tOR6，（u)-O(CR6R6),NR6R10，（v)-C(O)R6，（w)-SR6 ’（x)-C(0)0R1()，（y)-S(0)pR6，烷基）-(含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環），（33)-((^.8烷基）-(3-14員飽和、不飽和或芳族碳環），（bb)-0(CR6R6)t0R6，（cc)-C( = NR6)NR6R6， (dd)-〇NR6R6 > (ee)-NR6C(0)NR6R6 > (ff)-0(CR6R6)t〇R6 , (gg)-NR6C(0)R6，及（hh)-(CR6R6)tNR6R10 ; 其中（n)至（r)及（z)至（aa)隨意地以一或多個RIQ取代； R10 係選自（a)氫，（b)F，（c)Cl，（d)Br，（e)l，（f).CF3 , -182- 201125566 (g)-CN，（h)-N3，（i)-N〇2，（j)-NR6R6，（k)-〇R6，（l)_ NR6(CNR6)NR6r6 , (m)_c(0)(CR6R6)tNR6R6，（n)-C^8 烷基 ’（0)·(：】-8烯基，（p)_C|8炔基，（q)含有一或多個選自氮、氧及硫之雜原子的3-14員飽和、不飽和或芳族雜環， (r)3-14員飽和、不飽和或芳族碳環，（s)_鹵烷基，“卜 (CR6R6)tOR6 - (u)-〇(CR6R6),NR6R6 - (v)-C(〇)R6 > (w)，sr6 ，⑴-C(0)0R6 ’（y)-S(0)pR6，⑴.（Ci 8 烷基）·（含有〜或多個選自氮、氧及硫之雜原子的Π4員飽和、不飽和或芳族雜環），（aaMC,·8烷基）-(3-14員飽和、不飽和或芳族碳環）’ （bb)-0(CR6R6)t〇R6，（cc)_c( = NR6)NR6R6，（dd) 〇NR6R6 > (ee)-NR6C(0)NR6R6 , ( f f) - 〇 ( C R6 R6) t O R6 , (gg^ NR6C(0)R6，及（hh)-(CR6R6)tNR6R6; 隨意地，其中基團-D-E-F或基團不存在，但是_D E-F及-G-H-J二者不同時不存在； p爲〇 ' 1或2 ;及 t 爲〇、1、2 或 3，或其醫藥上可接受之鹽、酯、互變異構物或前藥。 -183- 201125566 四、指定代表圖： (一）本案指定代表圖為：無。 (二）本代表圖之元件符號簡單說明：無 201125566 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Wherein Rx is selected from the group consisting of CH2, NH, alkyl), S or 0; Rz is C or CH substituted with one or more CH3, or Rz is CRaRb, wherein Ra and Rb together form a C3.5 carbocyclic ring; m is 1, 2 or 3; J is selected from the group consisting of NH2, NH(Ci-8 alkyl), Ν((^-8 alkyl)2, NHC(=0)CH3, NHC(=0)NH2, NHC( = NH)NH2, -177- 201125566 NHC( = NH)H ; CBA-'-DEF and -G-Η·] are chemical parts, of which A, D and G are independently selected from: (a) single bond '( b) -(Cu8 alkyl)-, (c)-(C2.8 alkenyl)·, (d)-(C2.8 alkynyl)-, wherein i) any of the foregoing (b)-(d) The 〇·4 carbon atoms in the arbitrarily are selected from -0-, -S(0)P-, -nr6-, -(c = 〇)-, -S(0)pNR6-, -NR6S(0 a part of p and -NR6S(〇)pNR6-, ii) any of the foregoing (b)-(ci) optionally substituted with one or more R5 groups, and iii) (b)-(d) Any of them optionally substituted with a -(Cualkyl)-R5 group; (e)-0-, (f)-NR6-, (g)-s(〇)p-, (h)-C (0)-, (i)-C(0)0-, (j)-OC(O)·, (k)-OC(〇)〇-, (i)-C(0)NR6-, (m )- NR6C0- ' (n)-NR6C(0)NR6- , (〇)-C( = NR6 ), , (p)- C( = NR6)0- , (q)-0C(=NR6)- , (r)-C( = NR6)NR6- ' (s)-NR6C( = NR6)- ' ( t)-C( = S)- , (u)-C( = S)NR6- , (v)- NR6C( = S)- > (w)-C(0)S- > (x)- SC(O)- . (y).〇C( = S)- · (z)-C( = S)0- > (aa)-NR6(CNR6)NR6- , (bb) - C R6 R ^ C (0) - - (cc)-C(0)NR6(CR6R6)t- '(dd) 3-14 members containing one or more heteroatoms selected from nitrogen 'oxygen and sulfur, saturated, unsaturated or aromatic a heterocyclic ring, (ee) 3_M member saturated, unsaturated or aromatic carbocyclic ring, and (ff)-(CR6R6)t-, wherein (dd) or (ee) is optionally substituted with one or more R5 groups; B, E and oxime are independently selected from: -178- 201125566 (a) single bond, (b) 3-14 member saturated, unsaturated or aromatic containing one or more heteroatoms selected from nitrogen 'oxygen and sulfur Heterocyclic ring, (0 3-14 membered saturated, unsaturated or aromatic carbocyclic ring, wherein (b) or (c) is optionally substituted with one or more R 5 groups; (dXCu 院基)_ '(e)_ (C2 8 alkenyl)· '(f)-(C2-8 alkynyl)_, wherein i) 〇-4 carbon atoms in any of the foregoing (d)-(f) are optionally selected from - 0-, _S(〇)p_, „NR6_, _(C=〇)_ _C( = NR6)_, _ S(0)pNR6-, -NR6S(0)p- and -NR6s(0)pNR6- are replaced by a part, Π) any of the foregoing (d)-(f) optionally Substituting one or more R5 groups, and iii) any of the foregoing (d)-(f) is optionally substituted with a _(Cl.8 alkyl)-R5 group; and (g)-(CR6R6)t -, C, F and J are independently selected from: (a) hydrogen '(c)F, (d)Cl, (e)Br, (f)I, (g)-CF3, (h)-CN, ( i)-N3 '(j)-N02,(k)-NR6(CR6R6)|R8,(1)-0R8, (m)-S(0)p(CR6R6)tR8 . (n)-C(0) (CR6R6)tR8 > (o)-OC(0)(CR6R6)tR8 - (p)-SC(0)(CR6R6), R8 > (q)-C(0)0(CR6R6)tR8 > ( r) - N R6 C (0) (C R6 R6), R8 ' (s)-C(0)NR6(CR6R6), R8 - (t)-C( = NR6)(CR6R6), R8 -(u) -C( = NNR6R6)(CR6R6)tR8 - (v) - C (= NN R6 C (0) R6)( CR6R6)tR8 ' (w)-C( = NOR8)(CR6R6),R8 > (x) - N R6 C (0) 0 ( -179- 201125566 CR6R6), R8 > (y)-0C(0)NR6(CR6R6)tR8 - (z)-NR6C(0)NR6( CR6R6),R8 ' (aa )-NR6S(0)p(CR6R6)tR8 > (bb) - S (O) PN R6 (CR6R6), R8 > (cc)-NR6S(0)pNR6(CR6R6), R8 > (dd)- NR6R8 > (ee)-NR6(CR6R6)R8, (ff)-OH, (gg)-NRsR8,(hh)-OCH3, ( Ii)-S(0)pR8 ' (jj)-NC(0)R8 > (kk)-NR6C(NR6)NR6R8 · (11)C 丨-8 alkyl, (mm) C2-8 alkenyl, ( Nn) C2.8 alkynyl, (oo) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (ΡΡ) 3·14 member saturated, Unsaturated or aromatic carbocyclic ring, (qq)-(CR6R6)tNR6(CR6R6), R8 > (rr)-N [(CR6R6)tR8] [C = 0(CR6R6),R8] > (ss)- (CR6R6), N[(CR6R6), R8][(CR6R6), R8] > (tt)-(CR6R6), NR6(C = 0)(CR6R6), R8 - (uu)-haloalkyl, ( ”)- C(0)(CR6)[(CR6R6)tR8]R8 ' (ww)-(CR6R6)tC(0)NR8R8 , (xx)-(CR6R6),C(0)0(CR6R6),R8 - (yy)-NR6C(〇)CR8R8R8 »(zz)-N[(CR6R6)tR8]C(0)R8 ' and (aaa)-S(0)pNR8R8; where (11) to (pp) optionally Or substituted with a plurality of R7 groups; R5 is selected from (a) hydrogen '(b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)-CN, ( h)-N3, (i)-N02, (j)-NR6R6, (k)-OR8, (l)-NR6(CNR6)NR6R6, (m)-Cr8 alkyl, (n)-C 丨·8 ene Base, (〇)-C, .8 alkynyl, 0)-(6.8 alkyl)-(3-14 member saturated with one or more heteroatoms selected from nitrogen, oxygen and sulfur , unsaturated or aromatic heterocyclic ring), (q)-(Cl_8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r)-haloalkyl, (8)_SR6, (t) a 3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, and (u) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring. Another alternative is to form a carbocyclic ring together with two R5 groups, -180-201125566 wherein (m) to (1) and (1) to (u) are optionally substituted with - or more than R8; R6 is selected from (a) hydrogen, (bhCu alkyl, or alternatively two R6 groups together form a carbocyclic ring, (c)-haloalkyl, (d) 3-14 containing one or more heteroatoms selected from nitrogen 'oxygen and sulfur a saturated, unsaturated or aromatic heterocyclic ring, and (e) a 3-14 membered saturated, unsaturated or aromatic carbocyclic ring; wherein (b) to (e) are optionally substituted with one or more R8; From (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)I, (f)-CF3, (g)-CN, (h)-N3, (i)-N02, (j)-NR6R6, (k)-OR6, (1)-NR6(CNR6)NR6R6 '(nO-Cus alkyl, (11)-(:,-8 alkenyl, (0)-(:,.8 Alkynyl, (? )-(<^_8 alkyl)-(3-14 membered saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur), alkyl)-(3- 14-membered saturated, unsaturated or aromatic carbocyclic ring), (〇-haloalkyl, (s)-NR6R8 > (t)-OR8 - (u)-(CR6R6), NR6R8 - (v)-CR6R8R8 > (w)-SR6, (x) a 3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, (y) 3-14 member saturated, unsaturated Or an aromatic carbocyclic ring, (z)-(CR6R6)tC(0)NR8R8, (aa)-S(0)pR8 ' (bb)- NR6C(0)NR6R6, (cc)-NR6C(0)R6, and (dd)-C(=NR6)NR6R6» wherein (m) to (q) and (x) to (y) are optionally substituted with one or more R9; R8 is selected from (a) hydrogen, (b)F '(c)Cl,(d)Br,(e)I,(f)-CF3,(g)-CN,(h)-N3,(i)-N02,(j)-NR6R9 ' (k)- 〇R9 ' (1)- NR6(CNR6)NR6R6,(m)-C 卜8 alkyl '(n)-C b 8 alkenyl, (〇)-C b 8 alkynyl, 0)-(6.8 alkyl (3-14 member saturated, unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulfur) '(q)-(Cl·8 alkyl-181 - 201125566 )-(3-14 member saturated, unsaturated or aromatic carbocyclic ring), (r) 3-14 member saturated, unsaturated or aromatic heteropoly containing one or more heteroatoms selected from nitrogen, oxygen and sulfur Ring '(s) 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (t)-haloalkyl, (u)-C(0)(CR6R6)tR9 '(V)-SR6,(w)- 〇C(0)(CR6R6)tR9, (x)-NR6C(0)NR6R9, (y)-NR6C(0)R9, (z)-NR6(CNR9)(NR6R6), (aa)-ONR6(CNR6) NR6R6 - (bb)-C( = NR9)NR6R6 -(cc)-S(0)pR9,(dd)-(CR6R6)tC(0)NR6R9,(ee)-(CR6R6)t〇R9, and (ff (-) is substituted with one or more R 9; e) I, (f)-CF3, (g)-CN ' (h)-N3 ' (i)-N02 , (j)-NR6R10, (k)-OR6 > (1)- NR6(CNR6)NR6R6 , (m)-C(0)(CR6R6)tNR6R6, (M-Cm 院基'(0)-Ci-8 stimuli'(p)-Ci.8 alkynyl'(q) contains one or more a 3-14 member saturated, unsaturated or aromatic heterocyclic ring of a hetero atom of nitrogen, oxygen and sulfur, (03-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl, (〇_ (CR6R6)tOR6, (u)-O(CR6R6), NR 6R10,(v)-C(O)R6,(w)-SR6 '(x)-C(0)0R1(),(y)-S(0)pR6,alkyl)-(containing one or more 3-14 member saturated, unsaturated or aromatic heterocyclic ring selected from heteroatoms of nitrogen, oxygen and sulfur, (33)-((^.8 alkyl)-(3-14 member saturated, unsaturated or aromatic Family carbocycle), (bb)-0(CR6R6)t0R6, (cc)-C(=NR6)NR6R6, (dd)-〇NR6R6 > (ee)-NR6C(0)NR6R6 > (ff)-0 (CR6R6)t〇R6 , (gg)-NR6C(0)R6, and (hh)-(CR6R6)tNR6R10; wherein (n) to (r) and (z) to (aa) optionally one or more RIQ is substituted; R10 is selected from (a) hydrogen, (b)F, (c)Cl, (d)Br, (e)l, (f).CF3, -182- 201125566 (g)-CN, (h )-N3, (i)-N〇2, (j)-NR6R6, (k)-〇R6, (l)_NR6(CNR6)NR6r6, (m)_c(0)(CR6R6)tNR6R6,(n) -C^8 alkyl '(0)·(:]-8 alkenyl, (p)_C|8 alkynyl, (q) 3-14 containing one or more heteroatoms selected from nitrogen, oxygen and sulfur a saturated, unsaturated or aromatic heterocyclic ring, (r) a 3-14 member saturated, unsaturated or aromatic carbocyclic ring, (s)-haloalkyl, "Bu(CR6R6)tOR6 - (u)-〇 (CR6R6 ), NR6R6 - (v)-C(〇)R6 > (w),sr6 ,(1)-C(0) 0R6 '(y)-S(0)pR6,(1).(Ci 8 alkyl)·(a 4 member-saturated, unsaturated or aromatic heterocyclic ring containing ~ or more heteroatoms selected from nitrogen, oxygen and sulfur) , (aaMC, ·8 alkyl)-(3-14 member saturated, unsaturated or aromatic carbocyclic ring)' (bb)-0(CR6R6)t〇R6,(cc)_c( = NR6)NR6R6,(dd 〇NR6R6 > (ee)-NR6C(0)NR6R6 , ( ff) - 〇( C R6 R6) t O R6 , (gg^ NR6C(0)R6, and (hh)-(CR6R6)tNR6R6; Wherein the group -DEF or group is absent, but _D EF and -GHJ are not present at the same time; p is 〇' 1 or 2; and t is 〇, 1, 2 or 3, or it is pharmaceutically acceptable Accepted salts, esters, tautomers or prodrugs. -183- 201125566 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 201125566 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

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