TW200410956A

TW200410956A - Proline derivatives

Info

Publication number: TW200410956A
Application number: TW092123113A
Authority: TW
Inventors: Masahiro Fujita; Masato Sakamoto; Nobuhiko Horiuchi; Takayoshi Yamamoto; Kyoji Tomita; Mizuno Kazuhiro; Niga Toshiyuki; Ito Hideaki; Kashimoto Shigeki
Original assignee: Dainippon Pharmaceutical Co
Priority date: 2002-08-23
Filing date: 2003-08-22
Publication date: 2004-07-01
Also published as: WO2004018453A1; AU2003257637A1

Abstract

The present invention provides proline derivatives (I) represented by the following formula and their salts, which are used as antimicrobial for polydrug resistant bacteria. In formula (I), ring A is a 5- to 6- membered heterocyclic group which may be condensed with an benzene ring being optionally substituted by halogen; p1, p2, p3 is 0 or 1; R1, R2 and R3 are H, an optionally substituted lower alkyl group, or a saturated or unsaturated 5- to 6- membered cyclic group (a), etc., T is a single bond, methylene group or carbonyl group, R4 and R5 are H or lower alkyl group, etc., n, m is 1 or 2, R6 and R7 are H, OH, halogen, etc., X is C, S or O, Y is H or an amino protection group, or a group represented by formula (b), R8 is alkyl group or cycloalkyl lower alkyl group, R9 is H or a hydroxy protection group etc., and when Y is H or an amino protection group, said compound is an intermediate of the compound wherein Y is (b).

Description

410956 坎、發明說明：【發明所屬之技術領域】本發明係有關可作為醫藥品使用_酸衍生物及/、衣&中間體。詳言之，本發明為尤其對於多劑耐性菌具有，越抗菌作用之脯氨酸衍生物或其鹽、其製造中間體、醫藥及藥學上之組成物。【先前技術】簡％為MRS A之新青黴素耐性黃色葡萄球菌 (Meth1Cillin_Resistant㈣⑽⑽罐⑽）於丄州年從英國對於其存在首先提出之報告得知為難隸術後感染症、呼吸器或消化器感染症之起因菌。mrsa感染症從⑽ 年代後半至1970年代後半在歐美流行，在曰本，於19肋年代認為是院内感染之主要起因菌而廣受世間之注意， 1990年代後半期蔓延至全國。現在，遣sa已為多劑高度耐性化，對於作為MRSA感染症之抗菌劑之萬古黴素。又 (VanC〇myCin)或阿貝卡辛（Arbekacin)亦已出現耐性菌株。於醫療界’吸引高度關心之多劑耐性菌已知除了上述之MRSA外還有青黴素耐性肺炎球菌㈣pRSp)或萬古黴素耐性腸球菌 (VwC〇myCin-Resistani h,er〇c〇ccw 介％，·謂，vre)。肺炎球囷之毒性強，為肺炎起因菌，腸球菌與mrsa同時為臨床分離之全身感染症及/或尿道感染症之起因菌。對於因該等多劑耐性菌引起之感染症使用新蒽醌系、 (newquinolone)抗菌劑或噁唑烷酮（〇xaz〇lidin〇ne)系抗菌 314976 7 200410956 劑，但有報告指出該等之抗菌活性不夠強，且亦出現對該等抗菌劑之耐性菌株。於國際公開第99/ 39704號說明書申請專利範圍第工項揭示下述式所不之通式。410956 Description of invention: [Technical field to which the invention belongs] The present invention relates to acid derivatives and / or clothing & intermediates which can be used as pharmaceuticals. Specifically, the present invention is a proline derivative or a salt thereof having a more antibacterial effect, especially for multi-drug resistant bacteria, and an intermediate, a pharmaceutical and a pharmaceutical composition thereof. [Prior art] The new penicillin-resistant Staphylococcus aureus (Meth1Cillin_Resistant) is MRS A. It was first reported from the United Kingdom for its existence in Luzhou in the year of 2016. It is known as postoperative infection, respirator or digestive infection. The cause of bacteria. The mrsa infection was prevalent in Europe and the United States from the second half of the 19th century to the second half of the 1970s. In Japan, it was considered to be the main cause of nosocomial infections in the 19th century and it attracted worldwide attention. It spread throughout the country in the second half of the 1990s. Currently, SA has been highly resistant to multiple doses of vancomycin as an antibacterial agent for MRSA infections. Also VancomyCin or Arbekacin have emerged tolerant strains. The multi-dose resistant bacteria that have attracted high attention in the medical field are known to include penicillin-resistant pneumococcus pRSp or vancomycin-resistant enterococci (VwCommyCin-Resistani h, eroccoccw) in addition to the MRSA mentioned above · Predicate, vre). Pneumococcus is highly toxic and is the cause of pneumonia. Enterococci and mrsa are the cause of clinically isolated systemic infections and / or urinary tract infections. For an infectious disease caused by these multi-dose resistant bacteria, a new anthraquinone-based, (newquinolone) antibacterial agent or an oxazolidone (〇xazolidinone) antibacterial 314976 7 200410956 agent is used, but there are reports that the The antibacterial activity was not strong enough, and resistant strains to these antibacterial agents also appeared. The item in the scope of patent application for the specification of International Publication No. 99/39704 discloses a general formula other than the following formula.

R-j Ο 於後述本發明化合物中，若檢視上述通式中各取代基之定義則可能推論係構造與本發明化合物稍為相近之化合物，但是，於後述本發明化合物中，就八環不存在之點而言即與本發明化合物不同^該國際公開公報之說明書具體揭示之脯氨酸衍生物只有其實施例12所揭示之下述曰化合物Α。 °Rj Ο In the compounds of the present invention described below, if the definition of each substituent in the above formula is examined, it may be inferred that the structure of the compounds is slightly similar to that of the compounds of the present invention. In other words, it is different from the compound of the present invention. The only proline derivative specifically disclosed in the specification of this International Publication is the following compound A disclosed in Example 12. °

CH, Ν ch3 【發明内容】 MRS^r月人等進行對於該等多劑耐性菌，尤其是對於 S A具強大抗菌力之务人铷夕柊各脯氨酸街生物，因選擇後述之丁生物，因而完成本發明。鹽。亦印，本發明係有關下述式所示之脯氨酸衍生物或其 314976 8 200410956CH, Ν ch3 [Summary of the invention] MRS ^ r Yueren et al. Carried out these multi-dose resistant bacteria, especially those who have a strong antibacterial effect on SA. The proline street creatures, because of the selection of Ding Thus, the present invention has been completed. salt. It is also printed that the present invention relates to a proline derivative represented by the following formula or its 314976 8 200410956

(式中’ A環為具有壞構成原子之1至4個雜原子，可與可經鹵素原子取代之笨環進行縮合之5至6員雜環基）。 pi為〇或1之整數，p2為〇或1之整數，？3為0或 1之整數。 R!、R2及R3結合於A環上之任何位置，可相同或不同，為可經1至3個i素原子或羥基（該羥基亦可用醯基保護）取代之低級烷基、氫原子、低級烷氧基、低級烷硫基、鹵素原子、羥基、胺基或胺基羰基（該胺基可經保護或以低級烷基單或二取代）、羥基低級烷胺基 '羧基、低級烷氧基罗厌基、低級烧基^基氧基、可經1至3個鹵素原子取代之低級烧基續驢氧基或氰基，p 1 =p 2 = 1時，同一碳原子所結合之^及R2 —起形成氧代基或pl=p2=p3 = i時，|^及為氫原子，R3為5至6員飽和或不飽和環狀基（a)，此係與 A壞直接結合或藉由羰基、亞胺基低級伸烷基或氧基低級伸烷基結合，環狀基（a)之構成原子可含有1至2個雜原子，環狀基（a)亦可經_素原子取代之低級烷基或鹵素原子取代。 T為單鍵，伸曱基或羰基。 h及h可相同或不同，為氫原子或低級烷基’或結口方；同一奴原子之二者亦可一同形成氧代基。 314976 9 200410956 m為1或2之整數。 R0及R?可相同或不同，為氫原子、羥基、鹵素原子、低級炫基、笨基、低級烷氧基、苯基低級烷氧基、可經保護之胺基，亦可二者一同形成飽和環狀基。 X為碳原子（CH2、CH或C)、硫原子或氧原子，n為i 或2之整數。 Y為氫原子、胺基保護基或下述式所示之基（b)(In the formula, the 'A ring is a 1 to 4 heteroatom having a bad constituent atom, and a 5 to 6-membered heterocyclic group which can be condensed with a stupid ring which may be substituted with a halogen atom). pi is an integer of 0 or 1, and p2 is an integer of 0 or 1. 3 is an integer of 0 or 1. R !, R2, and R3 are bonded to any position on the A ring, which may be the same or different, and are lower alkyl groups, hydrogen atoms, Lower alkoxy, lower alkylthio, halogen atom, hydroxyl, amine or aminocarbonyl (the amine may be protected or mono- or di-substituted with lower alkyl), hydroxy-lower alkylamino 'carboxyl, lower alkoxy Aryl, alkynyl, lower alkynyloxy, lower alkynyl or cyano which may be substituted by 1 to 3 halogen atoms, when p 1 = p 2 = 1, the same carbon atom is bonded ^ And R2 together form an oxo group or pl = p2 = p3 = i, | ^ and is a hydrogen atom, R3 is a 5- to 6-membered saturated or unsaturated cyclic group (a), which is directly bonded to A or By combining carbonyl, imino-lower alkylene, or oxy-lower alkylene, the constituent atoms of cyclic group (a) may contain 1 to 2 heteroatoms, and the cyclic group (a) may also contain Substituted lower alkyl or halogen atoms. T is a single bond, fluorenyl or carbonyl. h and h may be the same or different, and they are a hydrogen atom or a lower alkyl 'or an interface; both of the same slave atom may form an oxo group together. 314976 9 200410956 m is an integer of 1 or 2. R0 and R? May be the same or different, and they are hydrogen atom, hydroxyl group, halogen atom, lower alkyl, benzyl, lower alkoxy, phenyl lower alkoxy, protected amine, or both Saturated cyclic group. X is a carbon atom (CH2, CH or C), a sulfur atom or an oxygen atom, and n is an integer of i or 2. Y is a hydrogen atom, an amine-protecting group, or a group represented by the following formula (b)

此處，Rs為烷基或環烷基低級烷基，r9為氫原子、經基保 5蔓基或 R9a。1^93為 R9al-C〇-、R9a2-〇-C〇-、r -ΓCΗ )- > ha 1為低級烧基（该低級烧基可經1種或2種選自苯基、妒保護之胺基及羧基之基取代）、單低級烷基取代胺基或將6 員之飽和環狀胺基亦可經取代之6員飽和環狀胺基、可經 • 羥基取代之C6-C】G芳基或可與苯環進行縮合之5至6員飽和或不飽和雜環基。 R~9 a2為低級烧基、可經低級烧基取代之考烧某或了妒低級烷基取代之5員飽和環狀酯殘基。Here, Rs is an alkyl group or a cycloalkyl lower alkyl group, and r9 is a hydrogen atom, an alkyl group, or R9a. 1 ^ 93 is R9al-C〇-, R9a2-〇-C〇-, r -ΓCΗ)-> ha 1 is a lower alkyl group (the lower alkyl group may be selected from one or two kinds selected from phenyl and protected by jealousy) Amine and carboxyl group substitution), mono-lower alkyl substituted amine group or 6-membered saturated cyclic amine group can also be substituted 6-membered saturated cyclic amine group, C6-C which can be substituted by hydroxyl group] Garyl may be a 5- to 6-membered saturated or unsaturated heterocyclic group which can be condensed with a benzene ring. R ~ 9 a2 is a lower alkyl group, which can be substituted by a lower alkyl group or a 5-membered saturated cyclic ester residue substituted with a lower alkyl group.

Rw為經低級烷基取代、亦可與苯環飨人々ς。耶D之5貝飽和或不飽和環狀酯殘基或環狀碳酸酯殘基，P為〇或 4 i之整數）。【實施方式】 [實施本發明之最佳形態] 314976 10 200410956 本發明化合物（i)係主要構造共同但依特性不同而分成二組。第一組為Y為取代基w(氫原子或胺基保護基）之下述式（Ι-A)所示之脯氨酸衍生物或其鹽。 R，Rw is substituted with a lower alkyl group and can also be substituted with a benzene ring. Y 5 D saturated or unsaturated cyclic ester residues or cyclic carbonate residues, P is an integer of 0 or 4 i). [Embodiment] [Best mode for carrying out the present invention] 314976 10 200410956 The compound (i) of the present invention is mainly divided into two groups with common structures but different characteristics. The first group is a proline derivative represented by the following formula (I-A) or a salt thereof in which Y is a substituent w (a hydrogen atom or an amine protecting group). R,

(式中，W為氫原子或胺基保護基，其他取代基或符號之定義與上述者同意義）第一組為Y為式（b)所示之脯氨酸衍生物（ΙβΒ)或其鹽。 ^(In the formula, W is a hydrogen atom or an amine protecting group, and the definitions of other substituents or symbols have the same meaning as the above.) The first group is Y is a proline derivative (IβB) represented by formula (b) or salt. ^

/ 士 σ付號及取代基之定義與上述者同意義） β)中化Λ物（Ι-Α)為化合物（Ι_Β)之製造中間體。化合物（] 具W Γ風原子或R9a之化合物[以下亦稱為化合物（Ι-ί 几囷作用，尤其是對於以MRSA為代具有強力之卜“ ⑽表之多劑耐性抗囷作用，可作為抗菌劑使用。上述化合物（I-B)構造上之特徵為具有⑴存在有a 314976 11 200410956 環、（Π)具有至少3個 ".·、田Α每、Β環及C環組成之雜環基、 (m)A環與β環藉由τ έ士八、”Q B、（iv)具有Ν-甲醯基-N-〇R9-胺 (v)# u取代基κ及以該等組合存在，尤其以⑴、 ⑻及㈣’特別是⑴為特徵之本質。本發明化合物（、占 .. )〒作為抗菌劑之理想化合物為通式（1-8)之R9為氫原子，一、 A 3展為A!環之下述通式（Ι-C)所示之脯氨酸衍生物或其鹽。/ The definition of σ and the number of substituents have the same meaning as above. Β) Sinochem Λ (Α-Α) is a manufacturing intermediate of compound (Ι_Β). Compound [] A compound having a W Γ wind atom or R9a [hereinafter also referred to as a compound (Ι-ί), especially for MRSA, which has a powerful effect of "multi-dose resistance and anti-knock effect, which can be used as Antibacterial agent is used. The above-mentioned compound (IB) is structurally characterized by having a 314976 11 200410956 ring, (Π) having at least three " .., a heterocyclic group consisting of each of A, B and C rings. (M) A ring and β ring through ττ, 士, QB, (iv) have N-methylamino-N-OR9-amine (v) # u substituent κ and exist in these combinations, In particular, it is characterized by ⑴, ⑻, and ㈣ ', especially ⑴. The compound of the present invention (, account ..) is an ideal compound as an antibacterial agent. R9 is a hydrogen atom of general formula (1-8). A proline derivative or a salt thereof represented by the following general formula (I-C) exhibiting the A! Ring.

RW6a1 c / NRW6a1 c / N

fN—Z1 ^，x,/pifN—Z1 ^, x, / pi

AN, —z3 U p2 (式中，、R2、r3、R 與别述式⑴之定義相同和5至6員單環雜環基之苯環縮合，此處，z ^Wp3 k R5、η、P1、p2、p3 及 R8 之定義 A】環為具有i至3個雙鍵之不飽該雜環基亦可與經鹵素原子取代 -4、冗3及Z4可相同或不同，為备广次C)、鼠原子（NH或氮原子）、硫原子及氧原子之原子。但是，亦有&、乙、乙及中任何〆们不存在之丨月况’ Ri、R2及&係與構成〜環之任何一個石炭原子或氣原子結合。目同或不同，為氫原子、低級烧基、i素原子或低級燒氧基，為峻原子（eh、 CH或C)或氧原子）。本發明化合物（I_C)中作為抗菌劑之最理想化合物為下述通式(Ι-D)所示之脯氨酸衍生物或其鹽。 12 314976 200410956AN, —z3 U p2 (wherein, R2, r3, R have the same definitions as those of formula ⑴ and a benzene ring condensation of a 5- to 6-membered monocyclic heterocyclic group. Definitions of P1, p2, p3, and R8 A] The ring is unsaturated with i to 3 double bonds. The heterocyclic group may also be the same as or different from the -4, redundant 3, and Z4 substituted by halogen atoms. C), atom of rat atom (NH or nitrogen atom), sulfur atom and oxygen atom. However, there are also cases where &, B, B, and any of them do not exist. Ri, R2, and & are bonded to any one of the carbon atoms or gas atoms constituting a ~ ring. The heads are the same or different, they are hydrogen atom, lower alkyl group, i element atom or lower alkyloxy group, and they are jue atom (eh, CH or C) or oxygen atom). Among the compounds (I-C) of the present invention, the most preferable compound as an antibacterial agent is a proline derivative represented by the following general formula (I-D) or a salt thereof. 12 314976 200410956

Rla為氮原子、低級烷基、低級烷氧基或鹵素原子，二二為早鍵、雙鍵或鍵不存在，Ala環為5員或6員）為鍵不存在時，A! a環為如下所示：Rla is a nitrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom, two or two is an early bond, a double bond, or a bond does not exist, and the Ala ring is 5 or 6 members) When the bond does not exist, the A! A ring is As follows:

本毛月化合物（I-B)中，I為之化合物（PE)及其鹽亦具有優越之抗菌活性。Among the hairy moon compounds (I-B), the compounds (PE) and salts thereof which I is also have superior antibacterial activity.

^n^p2〇-E) P3 式中“Η及取代基之定義與上述者同意義）本《月化合物中可作為抗菌劑使用之化合物之且體可列舉如下。化合物D -1 -1 々（2S) M211)-3^戊基·2_[(Ν·甲醒基-N·經基胺基）甲 3J4976 13 200410956 化合物D - 2 -1 (2S)小{(2R)-2-[(N-甲醯基*經基胺基）曱基]己醯基} -2-{[4-(2-嘧啶基）-1-六氫吡哄基]羰基丨吡咯烷；化合物D - 3 -1 (2S)-卜{(2R)-3-環戊基_2_[(N_甲醯基_N_經基胺基）甲基]丙 1藍基}-2_{[4-(2-噻唾基）小六氫吼哄基]幾基}吼咯烷；化合物D - 4 -1 籲（2S)-l-{(2R)-2-[(N_曱酿基_N_經基胺基）曱基]己酿基} -2-{[4-(2-噻唑基）-1-六氫吡哄基]羰基}吡咯烷；化合物D-5 (2S)-l-{(2R)-2-[(N-甲醯基_N-經基胺基）甲基]己醯基} -2-{[4-(4-甲基-2-噻唑基）-^六氫吡啡基]羰基}吡咯烷；化合物D-6 (lS，2S，5R)-3-氮雜-3-{(2R)-2-[(N_甲醯基善經基胺基）甲基]庚醯基}-2-{[4-(2-嘧啶基）-丨_六氫吡哄基]羰基}二環 _ [3·1·0]己烷；化合物D - 7 -1 (2S)-l-{(2R)-2-[(N-曱醯基羥基胺基）甲基]庚醯基} -2-{[4-(2-噻唑基）-1-六氫吡哄基]羰基}吡咯烷；化合物D-8 (2S)小{(2R)-2-[(N-曱驢基_N_經基胺基）曱基]庚醯基} -2-{ [4-(4-曱基-2-噻唑基）-1_六氫吡哄基]羰基}吼咯烷；化合物D-9 (2S)-2-{[4-(5-溴I-噻唑基•六氫吡哄基]羰基卜^ 314976 14 200410956 {(2R)-2-[(N-甲醯基羥基胺基）甲基]庚醯基}吡咯烷；化合物D-10 (2 S)_2_ {[4-(2-笨并噻唑基六氫吡哄基]羰基卜卜 {(2R)_2-[(N-甲醯基-N-羥基胺基）甲基]庚醯基}吡咯烷；化合物D-11-1 (2S)-l-{(2R)-3-環戊基_2_[(N-甲醯基·Ν_羥基胺基）甲基]丙醯基}-2-{[4-(4-甲基-2-噻唑基卜；^六氫吡啡基]羰基} 吡咯烷；化合物D-12 (23,3 3)-1-{(211)-2-[(1^曱醯基-1羥基胺基）甲基]庚醯基}-3 -曱基-2-{[4-(2-嘧啶基）-1_六氫吡哄基]羰基y比咯烷；化合物1>13 (23)-4,4-二氟-1-{(211)-2-[(1^-曱醯基->^羥基胺基）曱基]庚醯基}-2-{ [4-(2-嘧啶基）-1_六氫卩比畊基]羰基丨吼咯烷；化合物D-14 (2S)-l-{(2R)-2-[(N-曱醯基-N-羥基胺基）曱基]庚醯基} -2 - {[ 4 - (6 -曱氧基-2 -吼σ定基）-1 -六氫□比啡基]獄基}吼洛烧；化合物D-15 (2S)-2-{[4-(6-氯-2-吼哄基）-1_六氫吡哄基]羰基卜卜 {(2R)-2-[(N-曱驢基-N-羥基胺基）曱基]庚醯基p比咯烷；化合物D -1 6 -1 (28)-1-{(211)-3-環己基-2-[(>^曱醯基_义羥基胺基）曱 314976 15 200410956 基]丙a服基卜2-{[4·(2鲁坐基）小六氫哦哄基]幾基咯烧。其次’對於各取代基或符號加以說明。合物⑴中之為具有1至4個雜原子作為原子’亦可與㈣素原子取代之笨環進行縮合之5 貝雜環基。此處之雜原子以選自例如氮原子、硫原子 ^乳原子*至少含有1個氮原子者較理想。A環可為飽 ^旦以不飽和較佳。A環及3環藉由τ結合，但以Μ 人、,，” Α %之石厌原子之間以直接鍵結(以下稱為、、Ν-5 。此時τ為單鍵）結合者較佳。衣所不5至6員雜環基之具體例並未限制，可列舉 η定基、％喃基、噻吩基、咲喃f基、㈣啉 :、=，、六氯卩比咬基、四氯咲嗔基等具有丨個雜原之卓雜玉衣基，如穷令装 Πί-ί- n4f -Η* 〜 W Ρ疋基、吡哄基、噠畊基、咪唑基、啡1:且：唑基、異噻哇基、噁唾基、異噁唑基、六氫吡一 '"寻八2個雜原子之單環雜環基，·如四唑基、^ n ^ p20-E) P3 In the formula, "the definition of Η and substituents has the same meaning as the above." In this "Moon Compound, compounds which can be used as antibacterial agents are listed below. Compound D -1 -1 々 (2S) M211) -3 ^ pentyl · 2 _ [(N · methylpentyl-N · mercaptoamino) methyl 3J4976 13 200410956 compound D-2 -1 (2S) small {(2R) -2-[( N-formamyl group * Aminoamino) fluorenyl] hexyl} -2-{[4- (2-pyrimidinyl) -1-hexahydropyridinyl] carbonyl-1-pyrrolidine; Compound D-3- 1 (2S) -Bu {(2R) -3-cyclopentyl_2 _ [(N_methylamido_N_alkylamino) methyl] propanyl 1 cyano} -2 _ {[4- (2- Thiasalyl) small hexahydrocarbyl] several groups} aryl; compound D-4 -1 (2S) -l-{(2R) -2-[(N_ 曱 Vinyl_N_ Jingji Amine) fluorenyl] hexyl} -2-{[4- (2-thiazolyl) -1-hexahydropyridyl] carbonyl} pyrrolidine; Compound D-5 (2S) -l-{(2R ) -2-[(N-methylamidino_N-methylamino) methyl] hexyl}}-2-{[4- (4-methyl-2-thiazolyl)-^ hexahydropyridine Group] carbonyl} pyrrolidine; compound D-6 (1S, 2S, 5R) -3-aza-3-{(2R) -2-[(N_methylsulfanylamino) methyl] heptyl Fluorenyl} -2-{[4- (2-pyrimidinyl)-丨 _hexahydropyridyl] carbonyl } Bicyclo_ [3 · 1 · 0] hexane; Compound D-7 -1 (2S) -1-{(2R) -2-[(N-fluorenylhydroxyamino) methyl] heptanyl } -2-{[4- (2-thiazolyl) -1-hexahydropyridyl] carbonyl} pyrrolidine; compound D-8 (2S) small {(2R) -2-[(N- 曱 donyl _N_Ethylamino) fluorenyl] heptanyl} -2- {[4- (4-fluorenyl-2-thiazolyl) -1_hexahydropyridyl] carbonyl} hyrrolidine; Compound D -9 (2S) -2-{[4- (5-Bromo I-thiazolyl hexahydropyridyl) carbonyl ^ 314976 14 200410956 {(2R) -2-[(N-methylaminohydroxylamino ) Methyl] heptyl} pyrrolidine; Compound D-10 (2 S) _2_ {[4- (2-Benzothiazolylhexahydropyridyl) carbonyl group {(2R) _2-[(N- Formamyl-N-hydroxyamino) methyl] heptyl} pyrrolidine; Compound D-11-1 (2S) -1-{(2R) -3-cyclopentyl_2 _ [(N-formamidine N-hydroxyamino) methyl] propanyl} -2-{[4- (4-methyl-2-thiazolyl; hexahydropyridinyl] carbonyl} pyrrolidine; Compound D-12 (23,3 3) -1-{(211) -2-[(1 ^ fluorenyl-1hydroxyamino) methyl] heptanyl} -3 -fluorenyl-2-{[4- (2 -Pyrimidinyl) -1_hexahydropyridinyl] carbonyl y than pyrrolidine; Compound 1 > 13 (23) -4,4-difluoro-1-{(211) -2-[(1 ^-曱醯Base- > ^ Hydroxyamino) fluorenyl] heptanyl} -2- {[4- (2-pyrimidinyl) -1_hexahydrofluorenylpyridyl] carbonyl group sirrolidine; compound D-14 (2S)- l-{(2R) -2-[(N-fluorenyl-N-hydroxyamino) fluorenyl] heptanyl} -2-{[4-(6 -fluorenyloxy-2 -sigma stilbyl) -1 -Hexahydropyridinyl] hexyl} Hellozyl; compound D-15 (2S) -2-{[4- (6-chloro-2-hizyl) -1_hexahydropyridyl ] Carbonyl group {(2R) -2-[(N- 曱 donyl-N-hydroxyamino) fluorenyl] heptanyl p-pyrrolidine; compound D -1 6 -1 (28) -1- { (211) -3-Cyclohexyl-2-[(> ^-Methyl-sensehydroxyamino) 曱 314976 15 200410956 group] Propyl 2-([4 · (2 Roryl) Primary Six Hydrogen coaxed] A few bases burned. Next, each substituent or symbol is described. The compound VII is a 5-heterocyclyl group having 1 to 4 heteroatoms as atoms and also condensing with a stupid ring substituted with a halogen atom. The heteroatom here is preferably selected from, for example, a nitrogen atom, a sulfur atom, a milk atom *, and at least one nitrogen atom. The A ring may be saturated, preferably unsaturated. The A ring and the 3 ring are connected by τ, but the direct binding between the anaerobic atoms of Α%, (hereinafter referred to as, and N-5. At this time, τ is a single bond) Specific examples of 5- to 6-membered heterocyclic groups are not limited, and examples include η-Amino,% sulfanyl, thienyl, sulfanyl f, oxoline:, =, hexachloropyridyl, Tetrachloropyrrolyl and other complex jade clothes bases with a number of heterogeneous elements, such as poor order equipment Π-ί- n4f -Η * ~ W Ρ, pyridyl, pyridyl, imidazolyl, brown 1: And: azolyl, isothiyl, isoxalyl, isoxazolyl, hexahydropyridine '" looking for eight heterocyclic monocyclic heterocyclic groups, such as tetrazolyl,

—畊基、1，2,4-三啡基、四哄基、噻二唑基等具有3至4 個雜原子之單環雜择：I 入„ |%基及该等皁環雜環基與苯環縮合之縮 3雜環基。此種縮八略卢f π τ丨扣口雜％、基可列舉例如異喹啉基、嗤_、萘錠、笨并嚷唾基、苯并喔哇基等。 Α壞所不之兮楚 c ^ 至6貝雜環基中亦以如通式（lc)之 ^環’更具體而言如通式㈣之AIa環，Ν-C結合之C側 ^部位ί旁邊存在有作為雜原子之氮原子者較佳。該等 “衣基之取理想例可列舉嘧啶基或噻唑基。 314976 16—Phenyl, 1,2,4-triphyl, tetrazyl, thiadiazolyl, and other monocyclic heterocycles with 3 to 4 heteroatoms: I into the% group and these soap ring heterocyclic groups 3 heterocyclic groups condensed with a benzene ring. Such condensed f π τ 丨% of heterocyclic groups, examples of the groups include isoquinolinyl, fluorene, naphthyl, benzopyridyl, benzo Wowyl et al. Α is not good, c ^ to 6-heterocyclyl also has a ^ ring such as the general formula (lc), more specifically, such as the AIa ring of the general formula ㈣, N-C bound C It is preferable that a nitrogen atom as a hetero atom exists beside the side portion ί. Examples of the "coating group" include pyrimidyl or thiazolyl. 314976 16

yjyjO 本發明化合物（I)中之取任何一個位f 、土 1、R2或R3可在A環之yjyjO Among the compounds (I) of the present invention, any one of the positions f, R 1, R 2 or R 3 may be in the A ring.

置1灯取代，作吾如ϋ # A 合。R、R e D 瓦奴好係與Α環上之碳原子結 1 R2及R3所含之一個取抑其炎-Γ 原子或羥美…1 们取代基為可經1至3個鹵素明童「低幼m 土保叹）取代之低級烷基。本說美邱八夕山 …打別之限制，賦予該用語之基其烴土。刀之石反原子數為i至6。「乙基、丙基、里丙A 丁其低、.及说基」可列舉例如甲基、兴内基、丁基、显丁其、一己基等直鏈狀或支鍵狀Ai弟二-丁基、戊基、氣肩子1! 齒素原子」用語係指氟原子、乳原子、溴原子、碘原子。低纺11 、、 1至J個鹵素原子取代之低級k基」可列舉例如三識「土 fe基」可列舉例如乙醯土 i 土、二甲基乙醯基等低級脂肪族醯基。本說明書中「低級烷氧基」為具有低級烷基述者同意義之低級烧氧基，灣例如甲氧基、乙氧基、丙乳基、丁氧基、戊氧基、己氧基等。本說明書中「低級烧硫基」為其低級烧基部分盘上述者同意義之低級烧硫基，可列舉甲硫基、乙硫基、丙硫基、異丙硫基、丁硫基、異丁硫基、第三_丁硫基、戊硫基、己硫基等直鏈狀或支鏈狀基。、本說明書中「單低級烧胺基」為其低級烧基部分與上述者同意義之單低級烷胺基，可列舉例如甲胺基、乙胺基、丙胺基、異丙胺基、丁胺基、異丁胺基、第三_ 丁胺基、戊胺基、己胺基等直鏈狀或支鏈狀基。本說明書中「二低級烷胺基」為其低級烷基部分與上述者同思“之一低級烧胺基，可列舉例如二甲胺基、一 314976 17 200410956 胺基、二丙胺基、二異丙胺基、二丁胺棊、二異丁胺基、二-第三-丁胺基、二戊胺基、二己胺基等直鏈狀或支鏈狀基。本說明書中「單低級烷胺基羰基」為其低級烷基部分與上述者同意義之單低級烷胺基羰基，可列舉例如甲胺基羰基、乙胺基羰基、丙胺基羰基、異丙胺基羰基、丁胺基羰基、異丁胺基羰基、第三-丁胺基羰基、戊胺基羰基、己胺基羰基等直鏈狀或支鏈狀基。本說明書中「二低級烷胺基羰基」為其低級烷基部分與上述者同意義之二低級烷胺基羰基，可列舉例如二甲胺基羰基、二乙胺基羰基、二丙胺基羰基、二異丙胺基羰基、二丁胺基羰基、二異丁胺基羰基、二-第三-丁胺基羰基、二戊胺基羰基、二己胺基羰基等直鏈狀或支鏈狀基。本說明書中「羥基低級烷胺基」為其低級烷基部分與上述者同意義之羥基低級烷胺基，可列舉例如羥基甲胺基、2-羥基乙胺基、3-羥基丙胺基、2-羥基-1-曱基-1-乙胺基、4 -沒基丁胺基、2 -經基-1 -曱基-1 -丙胺基、2 -經基-1，1 _ 二曱基-卜乙胺基、5-羥基戊胺基、6-羥基己烷胺基等直鏈狀或支鏈狀基。本說明書中「低級烷氧基羰基」為其低級烷基部分與上述者同意義之低級烷氧基羰基，可列舉例如甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙氧基羰基、丁氧基羰基、異丁氧基羰基、第三-丁氧基羰基、戊氧基羰基、己氧基羰基等直鏈狀或支鏈狀基。 18 314976 200410956 ,、、兒明書中「低級烷基羰基氧基」為其低級烷基部分與上述去ΡΠ立 * ^ 冋思義之低級烷基羰基氧基，可列舉例如甲基幾 " 乙基羰基氧基、丙基羰基氧基、異丙基羰基氧基、二蚊，氧基、異丁基羰基氧基、第三_丁基羰基氧基、戊基羰基氧基、己基羰基氧基等直鏈狀或支鏈狀基。盥2說明書中「低級烷基磺醯氧基」為其低級烷基部分二2述者同意義之低級烷基磺醯氧基，可列舉例如曱基磺醯氧基、乙基磺醯氧基、丙基磺醯氧基、異丙基磺醯氧基、/、丁基續酸氧基、異丁基績醯氧基、第三—丁基磺酿氧基、戊基磺醯氧基、己基磺醯氧基等直鏈狀或支鏈狀基。「可經！至们1δ素原子取代之低級烷基續醯氧基」可列舉三氟甲基續醯氧基。本°兒明書中「亞胺基低級伸烷基」可列舉-Νίί((：ϋ2) _ (q為1至6之整數），以亞胺基伸曱基較佳。本說明書中「氧基低級伸烷基」可列舉_〇（Ch2v(q為 1至6之整數），以氧基伸甲基較佳。本說明書中「苯基低級烷氧基」為其低級烷基部分與上述者同意義之苯基低級烷氧基，可列舉苄氧基、苯乙氧基、3-苯基丙氧基等直鏈狀或支鏈狀基。 R6與R7 —同形成之飽和環狀基可列舉環丙基、環丁基、壞戊基、環己基。本說明書t使用「該胺基係經保護者」'「可經保護之胺基」或「胺基保護基」等用語，該等用語之任何一種均可總括於作為有關「胺基之保護基」之說明。本說明書^ 314976 ]9 200410956 「胺基之保護基」可使用在化學領域，尤其是在肽化學領域常用者。 • 「胺基之保護基」為可將保護基還原脫離者及可水解『脫離者。可還原脫離之「胺基保護基」可列舉如對_甲苯磺醯基等芳基磺醯基；如苄基、三苯甲基、苄氧基甲基等經苯基或T氧基取代之甲基；如〒氧基羰基或對_甲氧基〒氧基羰基等芳基甲氧基幾基；如2,2,2-三氯乙氧基羰基、碘乙氧基羰基等鹵化乙氧基羰基等。另一方面，可水解脫離之「胺基保護基」可列舉如乙氧基羰基或簡稱為b〇c之第三-丁氧基羰基、苄氧基羰基、對-甲氧基〒氧基羰基、乙烯氧基羰基、2-對甲苯磺醯基乙氧基羰基等含有氧基羰基之基，如曱醯基、乙醯基、三氟乙醯基等醯基，此外亦可列舉鄰-硝基苯磺醯基、三甲基矽烷基、四氫吡喃基、二苯基膦基等。同刀子内有2個胺基存在時，以採用一為可水解脫 ♦綠之「胺基保護基」，另一為可還原脫離之「胺基保護基」者為上策。t例如於Ri、R2或h令「胺基或胺基羰基（該胺 * 基為經保s隻者）」之「胺基保護基」以採用可還原脫離者， ,γ之胺基保護基選擇·^水解脫離之「胺基保冑基」較佳。 I中「5至6員飽和或不飽和環狀基（a)」並無限制，可列舉苯基、金剛烧基、吼咬基、六氯〇比哄基、嗎琳基、嗎啉代基、D比哄基、四氫咲。南基等，該等環狀基⑷亦可經如曱基或乙基％•低級烧基或函素原子取代。該等環狀基⑷ 為經由直接結合幾基、亞胺基伸甲基等亞胺基低級伸烷 314976 20 200410956 基、氧基伸甲基等氧基低級伸烷基與A環結合。 R8所定我之「烷基」，其碳原子數只要是2至1 〇即可，可為直鏈狀或支鏈狀之任何_種，但以直鏈狀較佳。理想之烷基碳原子數為4至7，X以正丁基或正戊基更佳所疋義之「壞烷基低級烷基」中之環烷基可列舉碳原子為 4至7個者，較好為5或6個者，低級烷基可列舉碳原子為1至4個者，較好為甲基或乙基。因此，理想之「環烷基低級烷基」之具體例可列舉環戊基甲基或環己基甲基等。土 R9所疋義之「备基保護基」只要經由化學方法可脫離者即了，並然知別之限制，可列舉例如节基、2，4·-二甲氧基苯基甲基。其中以容易脫離之2,‘二甲氧基苯基甲基較佳。又’具有羥基保護基之化合物（Ι-Β)不具抗菌活性。所定義之「低級烷基（該低級烷基可經1種或2種選自苯基、經保護之胺基及羧基之基取代）」之具體例可列舉曱基、第三-丁基、3-羧基丙基、2-苯基-1-(第三-丁氧基幾基）胺基乙基等。R9ai中「單低級烷基取代胺基」或「可將6員飽和環狀胺基取代之6員飽和環狀胺基」之具體例了列舉正丁爿女基、4 -六鼠卩比σ定基-1 -六氮吼°定基等。R 9 a t中「可經羥基取代之C6-CiG芳基」之具體例可列舉苯基、2-經基苯基、1-或2-萘基等，「可與苯環縮合之5至6員飽和或不飽和雜環基」之具體例可列舉3-吡啶基、2-吡咯基、 3-喹啉基、2-吲哚基、2-噻吩基、3-呋喃基、嗎啉代基等。中「低級烷基」、「可經低級烷基取代之環烷基」 21 314976 200410956 之具體例可列舉異丙基、環丁基、環戊基、環己基、2-異丙基―5-曱基環己基。又，R9a2中「可經低級烷基取代之5Set a light to replace it. R, R e D Vanuatu is connected to the carbon atom on the A ring. One of R2 and R3 contains its inflammation-Γ atom or hydroxymeta ... The substituents are 1 to 3 halogenated children "Low young m Tu Baotan) substituted lower alkyl. Originally said that the Qiuqibaxi Mountain ... hit other restrictions, given the base of this term to its hydrocarbon soil. The anti-atomic number of the sword is i to 6." Ethyl Examples include linear, branched, or branched Ai-di-butyl, such as methyl, xenyl, butyl, succinyl, and hexyl. The term "pentyl, gas shoulder 1! Tooth element atom" means fluorine atom, milk atom, bromine atom, iodine atom. Low-spinning 11, 1 to J halogen atom-substituted lower k-groups "may include, for example, three-sense" earth fe-based "may include, for example, acetofluorene i, dimethylacetamyl and other lower aliphatic fluorenyl groups. The "lower alkoxy group" in this specification is a lower alkoxy group having the same meaning as the lower alkyl group, and examples thereof include methoxy, ethoxy, propionyl, butoxy, pentyloxy, and hexyloxy. The "lower thiol group" in this specification refers to the lower thiol group which has the same meaning as above, and includes methylthio, ethylthio, propylthio, isopropylthio, butylthio, and isobutyl. Linear or branched groups such as thio, tertiary-butylthio, pentylthio, and hexylthio. In the present specification, "mono-lower alkylamine" refers to a mono-lower alkylamino group whose lower alkyl group has the same meaning as the above, and examples thereof include methylamino, ethylamino, propylamino, isopropylamine, butylamine, Linear or branched groups such as isobutylamino, tertiary-butylamino, pentylamino, and hexylamine. In this specification, "di-lower alkylamino" is a lower alkyl group whose lower alkyl moiety is the same as the above, and examples thereof include dimethylamino, -314976 17 200410956 amino, dipropylamino, and diisopropyl. Linear or branched chain groups such as propylamino, dibutylamino, diisobutylamino, di-tertiary-butylamino, dipentylamino, and dihexylamino groups. In this specification, "mono-lower alkylamines" "Aminocarbonyl" is a mono-lower alkylaminocarbonyl group having the same meaning as the lower alkyl portion, and examples thereof include methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, isobutyl Linear or branched groups such as aminocarbonyl, tertiary-butylaminocarbonyl, pentaminocarbonyl, and hexylaminocarbonyl. The "di-lower alkylaminocarbonyl group" in this specification is a di-lower alkylaminocarbonyl group whose lower alkyl portion has the same meaning as the above, and examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, diamino Linear or branched groups such as isopropylaminocarbonyl, dibutylaminocarbonyl, diisobutylaminocarbonyl, di-third-butylaminocarbonyl, dipentylaminocarbonyl, and dihexylaminocarbonyl. The "hydroxy lower alkylamino group" in this specification refers to a hydroxy lower alkylamino group having a lower alkyl portion having the same meaning as the above, and examples thereof include hydroxymethylamino, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- Hydroxy-1-fluorenyl-1-ethylamino, 4-mercaptobutylamino, 2-mercapto-1 -fluorenyl-1 -propylamino, 2-mercapto-1,1_diamidino-bu Linear or branched groups such as ethylamino, 5-hydroxypentylamino, and 6-hydroxyhexaneamine. The "lower alkoxycarbonyl group" in this specification is a lower alkoxycarbonyl group whose lower alkyl portion has the same meaning as the above, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, and an isopropoxycarbonyl group. , Butoxycarbonyl, isobutoxycarbonyl, tertiary-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl and other linear or branched groups. 18 314976 200410956, "lower alkylcarbonyloxy" in the book of Ming and Qing Dynasty, its lower alkyl moiety and the above-mentioned lower alkylcarbonyloxy group, which can be exemplified by methyl group " ethyl Carbonylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, dimosquito, oxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy Etc. linear or branched. The "lower alkylsulfonyloxy" in the specification of the lower alkyl is a lower alkylsulfonyloxy having the same meaning as described in the lower alkyl part. Examples include sulfonylsulfonyloxy, ethylsulfonyloxy, Propylsulfonyloxy, isopropylsulfonyloxy, /, butylcontinyloxy, isobutylsulfonyloxy, tert-butylsulfonyloxy, pentylsulfonyloxy, hexylsulfonyl Linear or branched groups such as oxy. The "lower alkyl fluorenyloxy group which can be substituted by 1 δ prime atom" includes trifluoromethyl fluorenyloxy group. The "imino-lower alkylene group" in this book can be listed as -Νίί ((:) 2) _ (q is an integer from 1 to 6), and an imino-alkylene group is preferred. In this specification, "oxyl group" Examples of "lower alkylene" include _〇 (Ch2v (q is an integer from 1 to 6), and oxymethyl is preferred. In the present specification, "phenyl lower alkoxy" is a lower alkyl portion thereof and agrees with the above Examples of the phenyl lower alkoxy group include straight-chain or branched-chain groups such as benzyloxy, phenethyloxy, and 3-phenylpropoxy. R6 and R7 —Saturated cyclic groups formed together include a ring Propyl, cyclobutyl, badpentyl, cyclohexyl. In this specification, the terms "the amine group is protected", "protectable amine group" or "amino group protecting group" are used. Any of them can be summarized as the description about "protecting group of amine group". This specification ^ 314976] 9 200410956 "protecting group of amine group" can be used in the field of chemistry, especially those commonly used in the field of peptide chemistry. "Amine The "protective group of the base" is a person that can reduce the protective group and can be hydrolyzed. Examples include arylsulfonyl groups such as p-toluenesulfonyl; methyl groups such as benzyl, trityl, benzyloxymethyl substituted with phenyl or Toxy; such as fluorenyloxycarbonyl or P-methoxymethoxy oxycarbonyl and other arylmethoxycarbonyl groups; such as 2,2,2-trichloroethoxycarbonyl, iodoethoxycarbonyl and other halogenated ethoxycarbonyl groups. On the other hand, may Examples of the "amino-protecting group" which can be removed by hydrolysis include ethoxycarbonyl or tertiary-butoxycarbonyl, benzyloxycarbonyl, p-methoxyfluorenyloxycarbonyl, and vinyloxycarbonyl , 2-p-toluenesulfonylethoxycarbonyl and other groups containing oxycarbonyl groups, such as fluorenyl groups such as fluorenyl, ethylfluorenyl, trifluoroethylfluorenyl, etc. In addition, o-nitrobenzenesulfonyl , Trimethylsilyl, tetrahydropyranyl, diphenylphosphine, etc. When there are 2 amine groups in the same knife, one is used to hydrolyze the green "amine protecting group", and the other It is the best policy if it is a reducible "amino protecting group". For example, in "Ri, R2, or h", "amino protecting group of" amino group or aminocarbonyl group (the amine * group is protected) " With For those who can reduce the detachment, the amine protecting group of γ is preferably selected. The amine protecting group which is detached by hydrolysis is better. The "5 to 6-membered saturated or unsaturated cyclic group (a)" is not limited in I Examples include phenyl, adamantyl, sulfonyl, hexachloro, biroxy, morpholinyl, morpholinyl, D biroxy, and tetrahydropyrene. Southyl and the like It can be substituted by fluorenyl or ethyl% · lower alkynyl or halo atoms. These cyclic radicals ⑷ are imino-lower alkylenes such as imino and iminomethyl, which are directly bonded 314976 20 200410956, oxygen A lower alkylene group such as a methyl group is bonded to the ring A. The "alkyl group" defined by R8 need only have 2 to 10 carbon atoms, and may be any of a straight or branched chain. , But linear is better. Ideally, the number of carbon atoms of the alkyl group is 4 to 7, and the cycloalkyl group in the "bad alkyl lower alkyl group" where X is n-butyl or n-pentyl is more preferable. Examples include 4 to 7 carbon atoms. Five or six are preferred, and examples of the lower alkyl group include one to four carbon atoms, and methyl or ethyl is more preferred. Therefore, specific examples of the ideal "cycloalkyl lower alkyl" include cyclopentylmethyl or cyclohexylmethyl. As long as the "protective group for protecting group" as defined in R9 is chemically detachable, and other limitations are known, for example, benzyl, 2,4 · -dimethoxyphenylmethyl, and the like can be mentioned. Among them, 2, 'dimethoxyphenylmethyl which is easily detached is preferred. Furthermore, the compound (I-B) having a hydroxyl protecting group has no antibacterial activity. Specific examples of the "lower alkyl group (the lower alkyl group may be substituted with one or two groups selected from a phenyl group, a protected amine group, and a carboxyl group)" include fluorenyl, tertiary-butyl, 3-carboxypropyl, 2-phenyl-1- (tertiary-butoxychiyl) aminoethyl, and the like. Specific examples of "mono-lower alkyl-substituted amino groups" or "6-membered saturated cyclic amino groups that can be substituted by 6-membered saturated cyclic amino groups" in R9ai include n-butylamidine, 4-6-hexamidine ratio σ Definite-1-Hexazine ° Definite and so on. Specific examples of the "C6-CiGaryl group which may be substituted by a hydroxyl group" in R 9 at include phenyl, 2-alkylphenyl, 1- or 2-naphthyl, and "5 to 6 which can be condensed with a benzene ring" Specific examples of the "membered saturated or unsaturated heterocyclic group" include 3-pyridyl, 2-pyrrolyl, 3-quinolinyl, 2-indolyl, 2-thienyl, 3-furyl, and morpholinyl Wait. Middle "lower alkyl", "cycloalkyl which may be substituted with lower alkyl" 21 314976 200410956 Specific examples include isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-isopropyl-5- Fluorenyl cyclohexyl. Also, in R9a2, "5

員飽和環狀|g殘基」之例可列舉下述式（C)所示之基，RW 之「經低級烧基取代、可與苯環縮合之5員飽和或不飽和環狀酷殘基或環狀碳酸酯殘基」之例可列舉下述式（〇1)及（e) 所示之基。Examples of the member-saturated cyclic | g residue "include the group represented by the following formula (C), and the" 5-membered saturated or unsaturated cyclic cool residue which is substituted with a lower alkyl group and can be condensed with a benzene ring " Examples of the "or cyclic carbonate residue" include groups represented by the following formulae (〇1) and (e).

本兔明化合物（I)在分子中之驗性氮原子與酸之間可形成酸付加鹽。此處之酸付加鹽可列舉如與酒石酸、富馬 " 乙酉文乳酉欠、號ίό酸、曱石黃酸、馬來酸、丙二酸、葡糖酸或如天冬胺酸等胺基酸等有機酸形成之鹽或與鹽酸、磷酸等無機酸形成之鹽。於本發明化合物之Ν-甲醯基羥基胺部位可形成鈉、鉀、鈣等金屬鹽。本务明化合物（I)偶而以水合物或溶劑合物存在，更有以如光學異構體之立體異構物或該等之混合物存在，這些全都包含於本發明中。接著’對於本發明化合物（I)之製造方法加以說明。本發明化合物根據例如以下所示之反應式，即可有利地製造。下述之反應式中w，為胺基保護基，IV為羥基之^護基。其他之取代基或符號與上述者同意義。 H製造方法丄· 314976 22 200410956The present rabbit compound (I) can form an acid addition salt between the experimental nitrogen atom in the molecule and the acid. The acid salt here can be exemplified with tartaric acid, Fumar " acetic acid, acetic acid, luteine, luteol, maleic acid, malonic acid, gluconic acid or amines such as aspartic acid Salts formed from organic acids such as basic acids or salts formed with inorganic acids such as hydrochloric acid and phosphoric acid. Metal salts such as sodium, potassium, and calcium can be formed at the N-formamyl hydroxylamine site of the compound of the present invention. The present compound (I) is sometimes present as a hydrate or a solvate, and more preferably as a stereoisomer such as an optical isomer or a mixture of these, all of which are included in the present invention. Next, a method for producing the compound (I) of the present invention will be described. The compound of the present invention can be advantageously produced according to the reaction formula shown below, for example. In the following reaction formula, w is an amine-protecting group, and IV is a hydroxy-protecting group. Other substituents or symbols have the same meaning as the above. H manufacturing method 丄 314976 22 200410956

吨2 (丨-A-2)Ton 2 (丨 -A-2)

P2 P2 (l-E) 200410956 步驟1 步驟1為使化合物（1)及化合物（2)進行反應（醯胺化反應），成為新穎化合物（KA-1)之步驟。本步驟可根據肽製造之常法實施。例如，本步驟可在如1-乙基-3-(3-二甲胺基丙基）碳化二亞胺鹽酸鹽（wsc)之縮合劑及如^羥基苯并三吐之反應促進劑存在下，於如二氣甲烷之溶劑中將兩原料化合物混合攪拌而實施。化合物（2)形成酸付加鹽時，以在如三乙胺之鹼存在下進行較佳。本步驟在_i(rc至45。〇進行1小時至3日。又，化合物（1)為公知，化合物（2)也幾乎為公知，從公知之化合物，使用公知之方法，即可容易地調製。步驟 2P2 P2 (l-E) 200410956 Step 1 Step 1 is a step of reacting compound (1) and compound (2) (amidation reaction) to become a novel compound (KA-1). This step can be carried out according to a conventional method for peptide production. For example, this step may be in the presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (wsc) and a reaction accelerator such as ^ hydroxybenzotrityl Then, the two raw material compounds are mixed and stirred in a solvent such as digas methane. When the compound (2) forms an acid addition salt, it is preferably carried out in the presence of a base such as triethylamine. This step is performed at _i (rc to 45.0) for 1 hour to 3 days. In addition, compound (1) is known and compound (2) is almost known. From known compounds, known methods can be easily used. Modulation Step 2

y知-為使步驟1所製造之化合物（j_A_ 1)之胺基保错基W’脫離，成為化合物(I_A_2)之步驟。脫離可根據胺基：護基W，之特性進行還原或水解。通常，以水解，較好以酸 :解進仃k理想’而以選擇適用於酸分解之胺基保護基較佳。適用於酸分解之w，以B〇c(第三丁氧羰基，^ butoxycarbonyi)較理想。經由酸分解之胺基保護& w，之脫離可在溶劑中，於销至喊，較好於（TCS室溫使化合物（Ι·Α·1)與酸接觸而實施。此處之酸可列舉氯化氮、三氟乙酸等，溶劑可列舉乙酸乙§旨、M_n二氣甲^ 等。兀用所獲得之化合物（I-A-2)可作為下一步驟3之原料使 314976 24 200410956 步驟3 步驟3可使化合物（3)及上述 I化合物（I-A-2)進行盥步驟1同樣之反應（醯胺化反應），而向成為化合物Hi)。化合物（3)可根據後述參考例所揭示基準之方法即可有利地製造步驟4 厂足方法，或是以該方法為步驟4為將化合物（1各im基之保護基^，脫離，成為化合物（H2)之步驟。本步驟可經由在如：氯曱烧之溶劑中，於化合物（I-B-1)中加入如二蠢7> 於、 ,τ / 又一鼠乙酸之酸，於-10〇C至 45 C攪拌混合1至20小時而實施。步驟5 步驟5為將（I-B-2)之羥基加以修飾，成為化合物（I_E) 之步驟。本步驟可在如吼啶之驗存在下，於（112)中加入例如 R9al-CO-Cl、R9a2-0_CO_Cl、R9a3_(CH2)p_cl(R9ai、R9a2、 R9a3及P係如上述所定義）之醯化劑或如烧基鹵化物之烧基化劑’於-1 0°c至45 °c攪拌1至3 0小時而實施。如此所製造之本發明化合物亦可適當地變換為其他之本發明化合物。例如，於、I、&、1或存在有「經保‘之胺基」、低級烧氧基戴基、低級烧基幾基氧基時可將其變換為胺基、緩基、羥基，亦可為逆變換。又，獲得如光學異構體之立體異構體混合物時，可根據常法將該等分離。生成物之精製可藉由溶劑洗淨或矽膠管柱層析法而實施。實施例 25 314976 200410956 接著，列舉製造實施例或參考例對本發明作更詳細之說明。以下之製造實施例或參考例係由系列A :原料（2)及其Boc體之製造、系列B :中間體（PH)之製造、系列C :原料（3)之製造及系列D :本發明化合物（I-B)等之製造構成，各步驟所製造之化合物經由300MHziH-NMR可明瞭籲其物性。系列D所製造之化合物若未特別註明，則為非結晶體，於以下之條件，根據高速液體層析法之滯留時間（從於石夕膠管枉注入本發明化合物至排出為止之時間）亦可明瞭其物性。滯留時間（Tr)之測疋條件：將濃度調整為5 〇毫克/毫y is known-a step for removing the amine group error-protecting group W 'of the compound (j_A_1) produced in step 1 to become compound (I_A_2). The detachment can be reduced or hydrolyzed according to the characteristics of the amine group: the protecting group W. In general, it is preferred to use hydrolysis, preferably acid: decomposition, and to select an amine protecting group suitable for acid decomposition. For w used for acid decomposition, Boc (third butoxycarbonyi) is preferred. The protection of the amine group through acid decomposition & w, the release can be carried out in a solvent, and is better than (TCS room temperature, the compound (I · A · 1) is contacted with the acid to be implemented. The acid here may be Examples include nitrogen chloride, trifluoroacetic acid, and the like, and solvents include ethyl acetate, M_n, and the like. The obtained compound (IA-2) can be used as a raw material for the next step 3, so that 314976 24 200410956 step 3 In step 3, the compound (3) and the above-mentioned compound I (IA-2) can be subjected to the same reaction (amidation reaction) as in step 1 to become the compound Hi). The compound (3) can be advantageously manufactured according to the method disclosed in the reference examples described below, and can be manufactured step 4 factory foot method, or using this method as step 4 to remove the compound (1 im protecting group ^, to become a compound) (H2) step. This step can be added to the compound (IB-1) in a solvent such as chlorosulfuric acid, such as dibenzyl 7 > C to 45 C is stirred and mixed for 1 to 20 hours. Step 5 Step 5 is a step of modifying the hydroxyl group of (IB-2) to become compound (I_E). (112) Adding, for example, R9al-CO-Cl, R9a2-0_CO_Cl, R9a3_ (CH2) p_cl (R9ai, R9a2, R9a3 and P are as defined above) or a halogenating agent such as a halogenated halogenated halogenated agent 'It is carried out by stirring at -10 ° C to 45 ° c for 1 to 30 hours. The compound of the present invention thus produced can also be appropriately converted into other compounds of the present invention. For example, Yu, I, &, 1 or When there are "protected amine groups", lower alkynyl groups, lower alkynyl groups can be converted to amine groups , Retardation, hydroxyl, can also be inverse transformation. In addition, when obtaining stereoisomer mixtures such as optical isomers, these can be separated according to conventional methods. The product can be purified by solvent washing or silicone tube Column chromatography was used. Example 25 314976 200410956 Next, the present invention will be described in more detail with reference to manufacturing examples or reference examples. The following manufacturing examples or reference examples consist of series A: raw material (2) and its Boc body. Production, series B: production of intermediates (PH), series C: production of raw materials (3), and series D: production of the compound (IB) of the present invention, etc. The compounds produced in each step can be clarified by 300 MHz iH-NMR Call for its physical properties. Compounds produced in series D are non-crystalline unless otherwise specified. The retention time (the time from the injection of the compound of the present invention to the discharge of the compound in the Shixi tube) is the following: ) The physical properties can also be clarified. Measurement conditions of residence time (Tr): the concentration is adjusted to 50 mg / milli

升之化合物之二甲亞碉溶液0·1/ζ 1注入管柱CApCELL PAC C18SG 12〇(4.6mm0 X 250mni，資生堂（股）公司 (Sh1Seid〇Co.，Ltd)製造），在測定溫度為奶下以流速為丄The liter of the compound dimethylarsin solution 0.1 · / ζ 1 was injected into a column CApCELL PAC C18SG 120 (4.6 mm 0 x 250 mni, manufactured by Shiseido Co., Ltd.), and the temperature was determined as milk Flow velocity

毫升/min流入乙腈：0.05%三氟乙酸水=35: 65之溶劑，於檢測波長254nm進行分析，卡p W衣件源自化合物之高峰出現時間作為滯留時間（7>)。又，為 J 在5亥條件下甲醇之滯留時間 (Τι·)為 2·89 分。於以下之製造實施例中所使用之簡稱之定義如下述亞胺鹽酸鹽 WSC. 1-乙基- 3- (3-二甲胺基丙基）碳 DMAP : 4-(N，N-二甲胺基）π比啶 THF :四氫咲口南Ml / min flow into acetonitrile: 0.05% trifluoroacetic acid water = 35: 65 solvent, analysis was performed at a detection wavelength of 254 nm, the peak time of the card-derived clothing-derived compound was taken as the residence time (7>). In addition, the residence time (Tm ·) of methanol under the conditions of 5 为 is 2.89 minutes. The abbreviations used in the following production examples are defined as the following imine hydrochloride WSC. 1-ethyl-3- (3-dimethylaminopropyl) carbon DMAP: 4- (N, N-di Methylamino) pi-pyridine THF:

Me :甲基 314976 26 200410956Me: methyl 314976 26 200410956

Et :乙基 B u : 丁基 Ph :苯基 Ac :乙醯基Et: ethyl Bu: butyl Ph: phenyl Ac: ethyl

Boc :第三-丁氧基羰基 η-:正 t-或tert- ··第三 k列A ·原料化合物（2)及其b 0 c體之製造參考例A -1 4-[2-(4,6-一氯-1，3,5-三哄基）]六氫吡畊_1_羧酸第三_丁酯Boc: Third-butoxycarbonyl group η-: n-t- or tert- ··· The third k column A · Production of raw material compound (2) and its b 0 c body Reference Example A -1 4- [2- ( 4,6-monochloro-1,3,5-trioxo)] hexahydropyridine_1_carboxylic acid third_butyl ester

於 2,4,6-二氯-1,3, 溶液100毫升中滴下含有六氫吡哄_丨_羧酸第三_丁醋i 9 公克（1 0.6匪〇1)及三乙胺η公克（25 之乙腈溶液 6〇毫升’在室溫授拌3小時。濃縮後用氯仿抽出，獲得珠製結晶3 · 7公克後經由矽膠管柱層析法(氯仿，曱醇κ /1)精製’獲得 4-[2-(4,6 -二氯一 1 3 - π卄讨、1 乳i，3，t二哄基）]六氫吡羧酸第三-丁酯1.44公克（收率41%)。 1H — NMR (CDC13) : 6/PPm x 4〇iQW 、 4 8 (9H, s), 3. 5 1 (4 Η, t, J = 5. 1Hz), 3. 86 (4H) t> j = 5. lHz). 參考例A-2及A-7 與參考例A -1揭示之方法同 ^ 1」极刼作，後得以下之化乂 314976 27 410956 物。表1原料化合物（2)Boc體之製造參考例 N=Zi Boc - νΓ^Ν-^ ,、Ζ2 NMR (CDCls, ppm) Ζι z2 z4 Α-2 C.CF3 C-H N 1.49 (9H, s), 3.46-3.60 (4H, m), 3.80-3.92 (4H, m), 6.78 (lH, d, J = 4.8 Hz), 8.50 (1H, d, J = 4.8 Hz). Α-3 C-CI N C，H • Α-4 N C-CI C-H 1·49 (9H, s), 3·51 (4¾ t，J 二 5·1 Hz), 3.86 (4H, t, J = 5.lHz). Α-5 C-F C-F C-F 1.48 (9H, s), 3.36*3.40 (4H, m), 3.51-3.56 (4H, m), 7.24-7.33 (1H, m). Α·6 R 1.49 (9H, s), 3.55 (3H, s), 5.74 (lH, d, J - 7.3 Hz), 6.35 (1H, d, J = 9.0 Hz). Α-7 Me 1.48 (9H, s), 3.00-3.03 (4H, m), 3.50 (3H, s), 3.54-3.58 (4H, m), 6.68 (lH, d, J = 1.5 Hz), 6.78 (lH, d, J = 1.5 Hz).In 100 ml of 2,4,6-dichloro-1,3, solution, hexahydropyridine was added dropwise. 9 g (1 0.6 mg) of tricarboxylic acid and 1 g of triethylamine (60 ml of 25 acetonitrile solution 'Stir at room temperature for 3 hours. After concentrating, extract with chloroform to obtain 3 · 7 g of bead crystals, then refine via silica gel column chromatography (chloroform, methyl alcohol κ / 1)' Obtained 4- [2- (4,6-dichloro-1 3-π 卄, 1 milk i, 3, t dioxo)] hexahydropyridine tertiary-butyl ester 1.44 g (41% yield) 1H — NMR (CDC13): 6 / PPm x 40iQW, 4 8 (9H, s), 3. 5 1 (4 Η, t, J = 5. 1Hz), 3. 86 (4H) t > j = 5. lHz). The methods disclosed in Reference Examples A-2 and A-7 and Reference Example A -1 are the same as ^ 1 ″, and the following chemical compounds are obtained: 314976 27 410956. Table 1 Reference examples for the production of the raw material compound (2) Boc body N = Zi Boc-νΓ ^ N- ^ ,, Z2 NMR (CDCls, ppm) Zil z2 z4 Α-2 C.CF3 CH N 1.49 (9H, s), 3.46-3.60 (4H, m), 3.80-3.92 (4H, m), 6.78 (lH, d, J = 4.8 Hz), 8.50 (1H, d, J = 4.8 Hz). Α-3 C-CI NC, H • Α-4 N C-CI CH 1.49 (9H, s), 3.51 (4¾ t, J = 5.1 Hz), 3.86 (4H, t, J = 5.lHz). Α-5 CF CF CF 1.48 (9H, s), 3.36 * 3.40 (4H, m), 3.51-3.56 (4H, m), 7.24-7.33 (1H, m). Α · 6 R 1.49 (9H, s), 3.55 ( 3H, s), 5.74 (lH, d, J-7.3 Hz), 6.35 (1H, d, J = 9.0 Hz). Α-7 Me 1.48 (9H, s), 3.00-3.03 (4H, m), 3.50 (3H, s), 3.54-3.58 (4H, m), 6.68 (lH, d, J = 1.5 Hz), 6.78 (lH, d, J = 1.5 Hz).

參考例A-8 4-[2-(1，3,5-三哄基）]六氫吡哄羧酸第三-丁酯Reference Example A-8 4- [2- (1,3,5-trisyl)] hexahydropyridinecarboxylic acid tert-butyl ester

將麥考例A-1所獲得之化合物144公克（4·3πιηι〇〇之 M-二噁烷溶液70毫升冰冷後加入1〇%鈀-碳〇·43公克及 28 314976 200410956 二乙胺 ι·ο 公克（10mm〇1)，還原。過濾，除去觸媒後將4:大氣下於室溫進行接觸製物經切膠㈣得粗製物。將粗 4-[2-(1，3,5-三哄基）]六氫w1QQ//l)精製’獲得 (收率82%)。井-1-竣酸弟三-丁醋0.94公克 iH —NMR (CDC 1. s /η , PPm l 49 (9H，s)，3. 46-3. UH，< 3· 8〇 —3· 90 (4Η, m)，8. 54 (2Η，s). 參考例A - 9免A -1 0 與茶考例A-8揭示之方法同樣操作，獲得以下之化合物0 表2原料化合物（2)boc體之製造參考例 H—Z. NMR (CDC13, ppm) Zi ζ2 A-9 C-H Ν 1.49 (9Η，s)，3.48-3.58 (4Η，m)，3.60.3.70 (4H, m), 6.50 (lH, d, J = 6.2 Hz), 8.23 (1H, d, J = 6.2 Hz), 8.61 (1H, s). A-10 Ν C-H 1.49 (9H, s), 3.48-3.74 (8H, m), 6.90 (1H, dd, J=1.3, 9.2 Hz), 7.23 (lH, dd, J = 4.5, 9.2 Hz), 8.61 (1H, dd, J=1.3, 4.5 Hz). 參考例A-11 2-[4-(第三-丁氧基羰基）-1-六氫吡畊基]-5-嗎啉代基-1，3,4-σ惡二唾 Ν-Ν 29 314976 200410956 (1)將2 -胺基-5 -嗎啉代基-1，3，4 -σ惡二嗤1公克（5.9 m m ο 1)之乙腈〉谷液冰冷後加入漠化亞銅1 · 5 9公克（7.1 m m ο 1)及亞石肖酸第三-丁酯〇·92公克（8.9mmol)，攪拌30分鐘。回復到至/里，授拌1小時後於反應液中加入稀鹽酸水及氯仿，將 ^物從有機層抽，用飽和食鹽水洗淨❹無水硫酸鎮乾無，過濾，將濾液濃縮後用矽膠管，柱層析法（氣仿/曱醇144 g of the compound obtained from McCorley A-1 (70 ml of a M-dioxane solution of 4.3 m) was ice-cold, and 10% palladium-carbon 0.43 g and 28 314976 200410956 diethylamine were added. οg (10mm〇1), reduction. After filtering, removing the catalyst, contact the product at 4: atmospheric temperature at room temperature and cut the gel to obtain the crude product. The crude 4- [2- (1, 3, 5- Trio group)] Hexahydro w1QQ // l) Refined 'obtained (82% yield). Well-1-Juncid tri-butyric acid 0.94 g iH-NMR (CDC 1. s / η, PPm l 49 (9H, s), 3. 46-3. UH, < 3.80--3 · 90 (4Η, m), 8. 54 (2Η, s). Reference examples A-9 and A -1 0 were performed in the same manner as in Tea Test Example A-8 to obtain the following compounds. Table 2 Raw compound (2 ) Boc body production reference example H-Z. NMR (CDC13, ppm) Zi ζ 2 A-9 CH Ν 1.49 (9Η, s), 3.48-3.58 (4Η, m), 3.60.3.70 (4H, m), 6.50 (lH, d, J = 6.2 Hz), 8.23 (1H, d, J = 6.2 Hz), 8.61 (1H, s). A-10 Ν CH 1.49 (9H, s), 3.48-3.74 (8H, m) , 6.90 (1H, dd, J = 1.3, 9.2 Hz), 7.23 (lH, dd, J = 4.5, 9.2 Hz), 8.61 (1H, dd, J = 1.3, 4.5 Hz). Reference example A-11 2- [4- (Third-butoxycarbonyl) -1-hexahydropyridyl] -5-morpholino-1,3,4-σoxadiazine N-N 29 314976 200410956 (1) -Amino-5 -morpholino-1,3,4 -σoxadiamidone 1 g (5.9 mm ο 1) of acetonitrile> Valley ice was added after ice-cold desertification 1.59 g (7.1 mm ο 1) and tertiary-butyl stilbite acid 0.92 g (8.9 mmol), stirred for 30 minutes. Return to / Li, after 1 hour of stirring in the reaction solution Dilute hydrochloric acid water and chloroform were added to the solution, and the residue was extracted from the organic layer, washed with saturated brine, dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated, and then a silica gel tube was used.

=3〇/1)精製，獲得2-溴_5-嗎啉代基，3，心噁二唑73〇毫克（收率53%)。 iH — NMR (CDCl3):5/ppm 3 47 76 — 3. 83 (4H，m). 3· 54 (4H, m), 3· (2)與參考例A-l揭示之方法同樣操作 — 獲传2-[4-(笫二丁氧基羰基）-1-六氫吡畊基嗎啉一八基-1，3，心噁二唑。 'Η-NMR (CDCl3):5/pPm 1,48 42 (8H，m), 3. 4 9 - 3. 5 7 (4H, m) m). (9汽，s), 3· 3 2 —3· 3· 7 5-3· 8 1 (4Η, 兔度至 Α-13 獲得以下之化與參考例A-11揭示之方法同樣操作合物。 314976 30 200410956 表3原料化合物（2)Boc體之製造參考例 Boc一N N—\ ||1 Nf \-^Z2 NMR (CDC13, ppm) Zi z2 Α·12 C-SIVIe N 1.48 (9H, s), 2.59 (3H, s), 3.45-3.60 (8H, m). A-13 N C-H 1.49 (9H, s), 3.50-3.65 (8H, m), 8.49 (lH, s). 參考例A-1 4 4-{2-[4-(3-吼啶基）噻唑基]}六氫吡哄-丨_羧酸第三-丁酯= 3〇 / 1) was purified to obtain 2-bromo-5-morpholino, 3, oxadiazole 7300 mg (53% yield). iH — NMR (CDCl3): 5 / ppm 3 47 76 — 3. 83 (4H, m). 3 · 54 (4H, m), 3 · (2) The same operation as the method disclosed in Reference Example Al — Obtained 2 -[4- (fluorenedibutoxycarbonyl) -1-hexahydropyridylmorpholine-octayl-1,3, dioxadiazole. 'Η-NMR (CDCl3): 5 / pPm 1,48 42 (8H, m), 3. 4 9-3. 5 7 (4H, m) m). (9 vapor, s), 3 · 3 2 — 3 · 3 · 7 5-3 · 8 1 (4Η, rabbit degree to A-13) The following compounds were obtained in the same manner as the method disclosed in Reference Example A-11. 314976 30 200410956 Table 3 Raw compound (2) Boc form Manufacturing reference example Boc-NN— \ || 1 Nf \-^ Z2 NMR (CDC13, ppm) Zi z2 Α · 12 C-SIVIe N 1.48 (9H, s), 2.59 (3H, s), 3.45-3.60 ( 8H, m). A-13 N CH 1.49 (9H, s), 3.50-3.65 (8H, m), 8.49 (lH, s). Reference example A-1 4 4- {2- [4- (3- Carryl) thiazolyl]} Hydroxypyridine- 丨 _carboxylic acid third-butyl ester

在由文獻公知之4-硫代胺基甲醯基六氫吡啡_丨_羧酸第二-丁酯1.31公克（5.3mm〇1)、二異丙基乙胺186毫升 (10.7mm〇l)及乙醇24毫升組成之混合物中加入3_(溴乙醯基）吼σ疋氫溴酸鹽1·5公克（5·3mmol)，於室溫攪拌丨小時。將反應液減壓濃縮後加水並用乙酸乙酯抽鎮乾燥後減壓蒸罐溶劑，獲得4佩(3:二基]}六氫吡哄-1-羧酸第三-丁酯186公克（收率1〇〇%)。 H-NMR (CDCl3):5/pPm 1· 49 (9H, s), 3 50-3 66 (8H, m), 6. 89 (1 H, s), 7. 30 (1 H, dd T-4 R 7. 9Hz), 8. 11 (1H, ddd, 5, 1. 8, 7.^2)/8/ 52 (1H, dd, J = l. 5, 4 8Hz)，9·〇6 (1H, d 了=工 8Hz)· ’ ’ · 314976 31 200410956 曼支教^-15至A-17 與參考例A-1 4揭示之方法同樣操作，獲得以下之化合物。表4原料化合物（2)Boc體之製造參考例構造式 NMR (CDC13, ppm) A-15 Boc-N^N^ jj 1.49 (9H, s), 3.53-3.63 (8H, m), 6.71 (lH, s), 7.02-7.11 (2H, m), 7·77-7·84 (2H, m). A-16 Boc，N、，Ν—JJ 1.49 (9H, s), 3.54-3.61 (8H, m), 6.78 (lH, s), 7.47-7.51 (2H7 m), 7.68*7.73 (2H, m). A*17 --—— Boc-N^N-C^Tf^^ 1.48 (9H, s), 1.74 (6H, br s), 1.91 (6H, br s), 2.04 (3H, br s), 3.44 (4H, br s), 3.50-3.59 (4H, m), 6.11 (lH, s). ^Aj^LA-18 4 —[2-(4-氯-6-乙氧基-1，3,5·三啡基）]六氫吡啡-1-羧酸第三 -丁 S旨In the literature, 4-thioaminomethylamidinohexahydropyridine _ _ carboxylic acid second-butyl ester 1.31 g (5.3 mm), diisopropylethylamine 186 ml (10.7 mm) ) And ethanol (24 ml) was added with 1.5 g (5.3 mmol) of 3- (bromoethylfluorenyl) hydrozine hydrobromide and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, the mixture was dried with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 4 gram (3: diyl)} hexahydropyridine-1-carboxylic acid third-butyl ester (186 g). Rate 100%). H-NMR (CDCl3): 5 / pPm 1.49 (9H, s), 3 50-3 66 (8H, m), 6. 89 (1 H, s), 7. 30 (1 H, dd T-4 R 7. 9Hz), 8. 11 (1H, ddd, 5, 1. 8, 7. ^ 2) / 8/52 (1H, dd, J = l. 5, 4 8Hz ), 9 · 06 (1H, d = 8Hz) · '· · 314976 31 200410956 Manchuria ^ -15 to A-17 The same operations as those disclosed in Reference Example A-1 4 were performed to obtain the following compounds. Table 4 Raw material compound (2) Reference example for production of Boc body Structural formula NMR (CDC13, ppm) A-15 Boc-N ^ N ^ jj 1.49 (9H, s), 3.53-3.63 (8H, m), 6.71 (lH, s), 7.02-7.11 (2H, m), 7.77-7 · 84 (2H, m). A-16 Boc, N ,, N—JJ 1.49 (9H, s), 3.54-3.61 (8H, m ), 6.78 (lH, s), 7.47-7.51 (2H7 m), 7.68 * 7.73 (2H, m). A * 17 ------ Boc-N ^ NC ^ Tf ^^ 1.48 (9H, s), 1.74 (6H, br s), 1.91 (6H, br s), 2.04 (3H, br s), 3.44 (4H, br s), 3.50-3.59 (4H, m), 6.11 (lH, s). ^ Aj ^ LA-18 4 — [2- (4-chloro-6-ethoxy-1,3,5 · triphyl)] hexa Hydropyridine-1-carboxylic acid tertiary

在由 2,4,6-三氯-1，3,5-三畊 1.98 公克（10.8mmol)、碳酉文氫鈉2.57公克（30.6mmol)及乙醇25毫升組成之混合物中加入六氫吡哄羧酸第三-丁酯1.94公克（i〇.4mlTlol) 之乙醇溶液80毫升，於室溫攪拌一晚。加入水，將結晶過濾’以異丙醇、二異丙醚之順序洗淨，獲得‘[2兴心氯-6_ 乙氧基-1，3,5-三哄基）]六氫吡哄-1-羧酸第三-丁酯2.12公克（收率61%)。 314976 200410956 ’Η〜NMR (CDC 1 3) ·· δ/ρ pm 1 . 4 0 ( 3 H，t，J ：= 7 · 5 ·Η z ), 1. 48 (9H，s), 3. 46 - 3. 55 (4H，m)，3· 77 — 3· 90 (4 H, m), 4. 41 (2H, q, J = 7. 5Hz). 兔^例A-1 9 4·[2-(4-乙氧基-1，3,5-三畊基）]六氫吡哄-1-羧酸第三-丁酯Hexahydropyridine was added to a mixture consisting of 2,4,6-trichloro-1,3,5-tricotine 1.98 g (10.8 mmol), sodium carbohydrogen 2.57 g (30.6 mmol) and 25 ml of ethanol. 80 ml of an ethanol solution of 1.94 g (0.4 ml of Tlol) of the third-butyl carboxylic acid was stirred at room temperature overnight. Water was added and the crystals were filtered and washed 'in the order of isopropanol and diisopropyl ether to obtain' [2Xingxin chloride-6_ethoxy-1,3,5-trioxo)] hexahydropyridine- Tertiary-butyl 1-carboxylic acid 2.12 g (61% yield). 314976 200410956 'Η ~ NMR (CDC 1 3) ·· δ / ρ pm 1. 4 0 (3 H, t, J: = 7 · 5 · Η z), 1. 48 (9H, s), 3. 46 -3. 55 (4H, m), 3.77 — 3.90 (4 H, m), 4. 41 (2H, q, J = 7. 5Hz). Rabbit ^ A-1 9 4 · [2 -(4-ethoxy-1,3,5-trigenyl)] hexahydropyridine-1-carboxylic acid tert-butyl ester

與參考例A-8揭示之方法同樣操作，使參考例a-18 所獲得之化合物進行接觸還原，獲得標題化合物。 XH-NMR (CDCl3)：5/ppm 1.42(3H, t,J = 7.1Hz), 1· 49 (9H, s), 3· 43 - 3. 57 (4H, m), 3· 73 - 3· 93 (4 b r s ), 4. 3 9 (2Η, q, J = 7. 1 Η ζ )，8 · 3 5 (1 Η, s )· 例A-20 4-[2-(4-T氧基嘧啶基）]六氫吡畊-丨_羧酸第三-丁酯及4_ [4-(2-〒氧基嘧啶基六氫吡畊-丨-羧酸第三-丁酯In the same manner as in the method disclosed in Reference Example A-8, the compound obtained in Reference Example a-18 was subjected to contact reduction to obtain the title compound. XH-NMR (CDCl3): 5 / ppm 1.42 (3H, t, J = 7.1Hz), 1.49 (9H, s), 3.43-3.57 (4H, m), 3.73-3 · 93 (4 brs), 4. 3 9 (2Η, q, J = 7. 1 Η ζ), 8 · 3 5 (1 Η, s) · Example A-20 4- [2- (4-Toxy Pyrimidinyl]] Hydroxypyridine- 丨 _carboxylic acid third-butyl ester and 4_ [4- (2-Methoxypyrimidylhexahydropyridine- 丨 -carboxylic acid third-butyl ester

(1)在冰冷下，於苄醇10.8公克（O.lmol)之THF 200毫升溶液中加入60%氫化納4.4公克（〇·11 mol)，搜拌之。在冰冷下’將該反應懸濁液慢慢加至2，4 -二氯。密。定1 5公克（0 · 1 m ο 1) 之THF 2 00毫升溶液中，在室溫攪拌一晚。將該反應液用 314976 200410956 乙酸水中和，減壓濃縮。殘渣中加入氣仿及水，將目的物從有機層抽出，用無水硫酸鎂乾燥後減壓蒸餾除去溶劑，獲得4-〒氧基_2_氯嘧啶及其位置異構體氧基氯嘧 σ定之混合物2 5 · 0公克。 (2)在上述所獲得之混合物25()公克中加入六氫吡哄_1_魏酸第三-丁酯22·35公克（012m〇l)及碳酸氫鈉16·8公克 (〇.2mol)，在乙醇中，於⑽它攪拌一晚。將反應液減壓濃鲁縮後於㈣加人氯仿及水，將目的物從有機層抽出。用無水硫酸鎂乾燥，減壓蒸餾除去溶劑後殘渣用矽膠管柱層析法（乙酸乙酯/己烷=1//2至i /丄）精製，獲得4·[2_(4_ 卞氧基％'啶基）]六氫吡哄_丨_羧酸第三_ 丁酯2丨·丨公克（收率57/。）及其位置兴構體4-[4_(2-节氧基。密。定基）]六氫卩比口井 -1-羧酸第三-丁酯14·4公克（收率39%)。 4-[2_(4 -卞氧基嘧啶基）]六氫吡畊―丨―羧酸第三_丁酯 1Η —NMR (CDCl3)：6//ppm 1. 49 (9H, s), 3. 45-~3 _ 49 (4H, m), 3. 7 6 — 3. 8 0 (4H, m), 5. 34 (2H, s), 6 42 (1H，d，J = 5· 7Hz), 7· 30 - 7· 44 (5H，m), 8·〇7 (1H, d, J = 5. 7Hz). 4-[4-(2-苄氧基嘧啶基）]六氫吡啡-卜羧酸第三-丁酯 ^-NMR (CDCl3)：5//ppm χ. 48 (9 H, s), 3. 47-3. 50 (4Η, m), 3· 6 0 —3. 6 4 (4Η, m), 5· 36 (2Η, s), 6· 16 (1H, d, J^6. 1Hz), 7. 2 5 - 7. 5 0 (5H, m), 8. 〇5 (1H, d, J = 6. 1Hz). . 參者例A-21 314976 34 200410956 4-[2-(4-羥基嘧啶基）]六氫吡畊羧酸第三-丁酯(1) Under ice-cooling, 60% sodium hydride 4.4 g (0.11 mol) was added to a 200 ml solution of 10.8 g (0.1 mol) of THF in benzyl alcohol, and the mixture was searched and mixed. This reaction suspension was slowly added to 2,4-dichloro under ice-cooling. dense. Into a solution of 15 g (0 · 1 m ο 1) of THF in 200 ml, stir at room temperature overnight. The reaction solution was neutralized with 314976 200410956 acetic acid, and concentrated under reduced pressure. After adding gas imitation and water to the residue, the target substance was extracted from the organic layer, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4-methoxy-2-chloropyrimidine and its positional isomer oxychloropyrimidine σ. Set the mixture to 2 5 · 0 g. (2) To 25 () grams of the mixture obtained above, hexahydropyridine_1-weieric acid third-butyl ester 22.35 grams (012 ml) and sodium bicarbonate 16.8 grams (0.2 mol) were added. ), In ethanol, stir it overnight. The reaction solution was concentrated under reduced pressure, and the mixture was condensed with chloroform and water, and the target substance was extracted from the organic layer. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1 // 2 to i / 丄) to obtain 4 · [2_ (4_ fluorenyloxy%). 'Pyridyl)] Hexahydropyridine _ 丨 _ Carboxylic Acid Tertiary Butyl Esters 2 丨 · gram (yield 57 /.) And its positional isomer 4- [4_ (2-benzyloxy. Dense. (Base group)] Hexahydropyrene 14.4 g (the yield of 39%) of the third-butyl tert-butyl carboxylic acid. 4- [2_ (4 -Methoxypyrimidinyl)] hexahydropyridine --- tertiary-butyl carboxylic acid 1Η-NMR (CDCl3): 6 // ppm 1. 49 (9H, s), 3. 45- ~ 3 _ 49 (4H, m), 3. 7 6 — 3. 8 0 (4H, m), 5. 34 (2H, s), 6 42 (1H, d, J = 5. · 7Hz), 7.30-7.44 (5H, m), 8.07 (1H, d, J = 5. 7Hz). 4- [4- (2-benzyloxypyrimidinyl)] hexahydropyridine-bu Tertiary-butyl carboxylic acid ^ -NMR (CDCl3): 5 // ppm χ. 48 (9 H, s), 3. 47-3. 50 (4Η, m), 3. 6 0 —3. 6 4 (4Η, m), 5.36 (2Η, s), 6.16 (1H, d, J ^ 6.1 Hz), 7. 2 5-7. 5 0 (5H, m), 8. 〇5 ( 1H, d, J = 6. 1Hz) .. Participant Example A-21 314976 34 200410956 4- [2- (4-hydroxypyrimidinyl)] hexahydropyridinecarboxylic acid tert-butyl ester

將參考例A-20所獲得4-[2-(4-苄氧基嘧啶基）]六氫吡哄-卜羧酸第三-丁酯14.8公克（4Ommol)之乙醇溶液300 毫升冰冷後，加入10%鈀-碳〇·5公克，於室溫在氫氣大氣下進行接觸還原。反應完成後於所析出結晶中加入氯仿，溶解後過濾除去觸媒。將濾液減壓濃縮，獲得4-[2-(4-羥基。密咬基）]六氫吡哄-1-羧酸第三-丁酯13.2公克（100%)。 'H-NMR (CDCl3)：6/ppm 1· 49 (9H, s), 3· 52 - 3· 5 5 (4Η, m), 3. 7 2- 3. 7 5 (4 H，m), 5 . 7 7 (1 H, d , J 二 6· 2H z), 7. 7 6 (1 H, d, J =6. 2Hz), 1 2. 05 (1H, br s). 參考例A-22 4_(l，3，+5-三甲基吼唑基）六氫吡哄-丨_羧酸第三-丁酯300 ml of an ethanol solution of 14.8 g (40 mmol) of 4- [2- (4-benzyloxypyrimidinyl)] hexahydropyridine-tricarboxylic acid, obtained in Reference Example A-20, was added to the solution, and the mixture was ice-cooled and added 10% palladium-carbon 0.5 g was contact-reduced at room temperature under a hydrogen atmosphere. After the reaction was completed, chloroform was added to the precipitated crystals, and the catalyst was removed by filtration after dissolution. The filtrate was concentrated under reduced pressure to obtain 13.2 g (100%) of 4- [2- (4-hydroxy. Octyl)] hexahydropyridine-1-carboxylic acid tert-butyl ester. 'H-NMR (CDCl3): 6 / ppm 1.49 (9H, s), 3.52-3.55 (4Η, m), 3. 7 2- 3. 7 5 (4 H, m), 5. 7 7 (1 H, d, J 2 6. 2H z), 7. 7 6 (1 H, d, J = 6.2 Hz), 1 2. 05 (1H, br s). Reference example A- 22 4_ (l, 3, + 5-trimethyloxazolyl) hexahydropyridine- 丨 _carboxylic acid third-butyl ester

U)在由雙（2-氯乙基）胺鹽酸鹽1〇公克（56 0rnm〇i)、二氯甲 k 84宅升及1 〇%氫氧化鈉水溶液$ 6毫升組成之混合溶液中加入二-第三-丁基二碳酸酯12.9毫升（56.0毫升），攪拌晚。分取有機層’用飽和食鹽水洗淨後用硫酸鈉乾燥。洛餾除去溶劑，獲得第三~丁基N，N-雙（2-氯乙基）胺基甲 314976 200410956 酸酿13 ·8公克（收率100%)。 H NMR (CDC 1 3) ： δ/ρ pm 1. 47 (9 Η, s), 3. 6 6 (8 (2)將由上述生成物3 〇4公克（12 6mm〇 * 子基^.43公克⑴.4 —、三乙胺3.5毫升叫及1，4 一噁烷1 8耄升組成之混合物加熱回流一晚。蒸餾除去溶劑，加入水、乙酸乙酯，分液，有機層用飽和食鹽水 :淨後用硫酸納乾燥。蒸德除去溶劑，粗製物用鹼性” 吕桎層析法（乙酸乙酯/正己烷=丄）精製，獲得4一 (j，3,5-三曱基吼唑基）六氫吡哄-1-羧酸第三-丁酯58() 毫克（收率17%) 〇 ^-NMR (CDCI3)： δ/ppm I- 3 3, 1. 4 8 (tota 1 9 H. b〇th s), 1. 63 (3H, s), 2. χ6 (3H, s), 2. 21 (3 s), 2.8 9 (4H, m), 3. 4·8 (4H, m). A-23U) To a mixed solution consisting of 10 g (560 nm) of bis (2-chloroethyl) amine hydrochloride, dimethyl chloride 84 liters, and 10% aqueous sodium hydroxide solution 6 ml Di-third-butyl dicarbonate 12.9 ml (56.0 ml), stirred late. The organic layer was separated and washed with saturated brine, and then dried over sodium sulfate. The solvent was removed by distillation, and the third to butyl N, N-bis (2-chloroethyl) aminomethyl 314976 200410956 acid brewing 13.8 g (yield 100%) was obtained. H NMR (CDC 1 3): δ / ρ pm 1. 47 (9 Η, s), 3. 6 6 (8 (2) will be obtained from the above-mentioned product 3.04 g (12 6 mm 0 * subunit ^. 43 g ⑴.4—3.5 ml of triethylamine and 1,8 liters of 1-8 oxane are heated and refluxed overnight. The solvent is distilled off, water, ethyl acetate are added, the solution is separated, and the organic layer is saturated with brine. : After cleaning, it was dried with sodium sulfate. The solvent was removed by distillation, and the crude product was purified by basic chromatography (Ethyl acetate / n-hexane = hydrazone) to obtain 4- (j, 3,5-trimethylamino) Oxazolyl hexahydropyridine-1-carboxylic acid tertiary-butyl ester 58 () mg (17% yield) 〇-NMR (CDCI3): δ / ppm I- 3 3, 1. 4 8 (tota 1 9 H. b〇th s), 1. 63 (3H, s), 2. χ6 (3H, s), 2. 21 (3 s), 2.8 9 (4H, m), 3. 4 · 8 (4H , m). A-23

4_[2-(4-胺基甲醯基噻唑基）]六氫吡哄_丨_羧酸第三_丁酯及4_[2-(4-氰基噻唑基）]六氫吡哄-^羧酸第三_ 丁醋曰4_ [2- (4-Aminomethylamidothiazolyl)] hexahydropyridines Carboxylic Acid Tertiary

(1)與參考例A-1揭示之方法同樣操作，獲得2_u_[4_(第三 • 丁氣基羰基）六氯吼哄基]}噻唾羧酸乙醋4 65公克率 92%)。 314976 36 200410956 H-NMR(CDCl3):5/ppm 1· 37 (3Η, t，J = 7. 1Hz), 1· 48 (9H，s)，3· 4 8-3. 62 (8H, m), 4· 36 (2H, q J = 7· 1Hz), 7. 4 7 (1H，s)· (2) 將2-{l-[4-(第三-丁氧基羰基）六氫吡哄基]}噻唑基一叛酸乙醋2·23公克（6.5mmol)溶解於甲醇20毫升中，慢慢加入1N氫氧化鈉水溶液1 3 · 1毫升，在室溫攪拌1 7小時後減壓濃縮。在冰冷下加入丨〇%鹽酸水溶液使pH值為2，用乙酸乙酯抽出。用飽和食鹽水洗淨後用無水硫酸鎂乾燥，減壓濃縮。加入己烷，濾取所析出之結晶，乾燥，獲得2-[4-(第三-丁氧基羰基）六氫吡畊基]噻唑_4 —羧酸 1 ·89公克（收率92%)。 'H-NMR (CDC13)： δ/ppm 1. 49 (9 H, s), 3. 46~3. 6 1 (8H, m), 7. 5 5 (1 H, s). (3) 將由2-[4-(第三-丁氧基羰基）六氫吡哄基]噻唑羧酸 1·〇公克（3.2mmol)、WSC 734 毫克（3.8mmol)、卜羥基苯并一唑1水合物474毫克（3.5mmol)及DMF 10毫升組成之此6物在至溫攪拌丨小時後加入2 8 %氨水溶液2.9毫升，(1) In the same manner as the method disclosed in Reference Example A-1, 2_u_ [4_ (Third • Butanylcarbonyl) hexachloromethyl]] ethyl thiasialcarboxylate (65 g, 92%) was obtained. 314976 36 200410956 H-NMR (CDCl3): 5 / ppm 1.37 (3Η, t, J = 7. 1Hz), 1.48 (9H, s), 3. 4 8-3. 62 (8H, m) , 4 · 36 (2H, q J = 7.1 Hz), 7. 4 7 (1H, s) · (2) 2- {l- [4- (third-butoxycarbonyl) hexahydropyridine 2.23 g (6.5 mmol) of thiazolyl monoethyl acetate in 20 ml of methanol, slowly added 1 1 · 1 ml of a 1N sodium hydroxide aqueous solution, stirred at room temperature for 17 hours, and concentrated under reduced pressure. . A 10% aqueous hydrochloric acid solution was added under ice-cooling to bring the pH to 2, and the mixture was extracted with ethyl acetate. It was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane was added, and the precipitated crystals were collected by filtration and dried to obtain 2- [4- (third-butoxycarbonyl) hexahydropyridyl] thiazole-4-carboxylic acid 1.89 g (92% yield). . 'H-NMR (CDC13): δ / ppm 1. 49 (9 H, s), 3. 46 ~ 3. 6 1 (8H, m), 7. 5 5 (1 H, s). (3) will be determined by 2- [4- (Third-butoxycarbonyl) hexahydropyridyl] thiazolecarboxylic acid 1.0 g (3.2 mmol), WSC 734 mg (3.8 mmol), hydroxybenzobenzoazole 1 hydrate 474 After 6 milligrams (3.5 mmol) and 10 ml of DMF were stirred at room temperature for 丨 hours, 2.9 ml of a 28% aqueous ammonia solution was added.

於室溫攪拌14小時。於反應液中加入乙酸乙酯，以水、1N =虱化鈉水溶液、水之順序洗淨，用無水硫酸鎂乾燥。減壓蒸餾除去溶劑，用矽膠管柱層析法（乙‘酸乙酯/己烷=3 / 7至1/〇)精製。經由乙酸乙酯-己烷再結晶，獲得4-[2-(4- 安基甲I基Q藥唑基）]六氫吡哄_丨_魏酸第三-丁酯92〇毫克 (收率92%)。 314976 200410956 iH-NMR (CDCl3):5/ppm ι· 49 (9H，s)，3· 43 〜3 62 (8H，m)，5· 52 (1H, br)，6· 99 (1H, br), 7· 4 (1H，s)·Stir at room temperature for 14 hours. Ethyl acetate was added to the reaction solution, and the reaction solution was washed with water, a 1N = sodium lactate aqueous solution, and water in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl'ethyl acetate / hexane = 3/7 to 1/0). Recrystallization from ethyl acetate-hexane to obtain 4- [2- (4-Aminomethyl I-Q drug oxazolyl)] hexahydropyridine --- Weiwei acid third-butyl ester 92 mg 92%). 314976 200410956 iH-NMR (CDCl3): 5 / ppm i 49 (9H, s), 3.43 to 3 62 (8H, m), 5.52 (1H, br), 6.99 (1H, br) , 7 · 4 (1H, s) ·

(4)在冰冷下，於由4-[2-(4-胺基甲醯基噻唑基）]六氫吡啡卜羧酸第二-丁酯914毫克（2·9mmol)、三乙胺1 ·35毫升 (9·7mmol)及二氯甲烷30毫升組成之混合物中滴下三氟甲磺酸酐811 # l(4.8mmol)，在冰冷下攪拌3〇分鐘，在室溫攪拌4日。於反應液中加入冰水，分取有機層，以飽和= 酸氫鈉水溶液及飽和食鹽水之順序洗淨。用無水硫酸鎂乾燥後減壓蒸餾除去溶劑，經由矽膠管柱層析法（乙酸乙酯/(4) Under ice-cooling, 914 mg (2.9 mmol) of 4- [2- (4-aminomethylamidothiazolyl)] hexahydropyridinecarboxylic acid second-butyl ester, triethylamine 1 · Trifluoromethanesulfonic anhydride 811 # 1 (4.8 mmol) was dropped into a mixture consisting of 35 ml (9.7 mmol) and 30 ml of dichloromethane, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 4 days. Ice water was added to the reaction solution, and the organic layer was separated and washed in the order of saturated = sodium hydrogen acid aqueous solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate /

己烷=1/4至2/3)精製。經由乙酸乙酯-己烷再結得4-[2-(4-氰基噻唑基）]六氫吡畊-；1_羧酸第三_ 丁酯毫克（收率85%)。 NMR (CDC 1 3) : δ/ρ pm 1· 4 8 (9H，s), 3. 4 6-3 6 1 ( 8 H, m). 參考例A-24 2-(1·六氫吡畊基）-4-(三氟甲基）嘧啶2鹽酸鹽Hexane = 1/4 to 2/3). 4- [2- (4-Cyanothiazolyl)] hexahydropyridine-; 1-carboxylic acid tertiary-butyl ester mg (yield 85%) was obtained through ethyl acetate-hexane. NMR (CDC 1 3): δ / ρ pm 1. 4 8 (9H, s), 3. 4 6-3 6 1 (8 H, m). Reference Example A-24 2- (1 · Hydroxypyridine ) -4- (trifluoromethyl) pyrimidine 2 hydrochloride

3 2HCI 在冰冷下，於參考例A-2所獲得之化合物〇5公克中力―口^ 4莫耳/1〇〇〇毫升HC1之乙酸乙6旨溶液1〇毫升，於至/皿攪拌3小時後濃縮，獲得2_(1_六氫吡哄基）_々_(三氣甲朴密啶2鹽酸鹽之粗製物。該化合物不經過精製，：接用 314976 38 200410956 於下一個步驟。參考例A-25至A-41 與參考例A-24揭示之方法同樣操作，獲得以下之化合物。該等化合物不經過精製，直接用於下一個步驟。表5原料化合物（2)鹽酸鹽之製造3 2HCI Under ice-cooling, the compound obtained in Reference Example A-2 was 0. 5 g of Zhongli-mouth ^ 4 mol / 100 ml of HC1 in ethyl acetate solution of ethyl acetate, 10 ml, and stirred at / dish 3 After concentrating for hours, a crude product of 2_ (1_hexahydropyridyl) _々_ (tris-methylpyrimidine 2 hydrochloride) was obtained. This compound was not purified: 314976 38 200410956 was used in the next step. Reference Examples A-25 to A-41 were performed in the same manner as the method disclosed in Reference Example A-24 to obtain the following compounds. These compounds were used directly in the next step without purification. Table 5 Raw material compounds (2) hydrochloride Made

參考例 /-Λ /Ν==Ζ1 HNwN-<\ /2 Zi Z2 A-25 C_H N A-26 C-OEt N A-27 OOH C-HReference example / -Λ / Ν == Z1 HNwN- < \ / 2 Zi Z2 A-25 C_H N A-26 C-OEt N A-27 OOH C-H

參考例 N-/ V2 Z1 z2 z4 A-28 C-OCH2Ph N C-H A-29 C-H N C-H A-30 N C-H C-H A-31 C-F C-F C-F 39 314976 200410956 表6原料化合物（2)鹽酸鹽之製造Reference Example N- / V2 Z1 z2 z4 A-28 C-OCH2Ph N C-H A-29 C-H N C-H A-30 N C-H C-H A-31 C-F C-F C-F 39 314976 200410956 Table 6 Production of Raw Compound (2) Hydrochloride

參考例㈠時 Ζι z3 Α·32 N C-N^〇 \—y 〇 A-33 C-SMe H s A-34 N C-H s Α·35 C-H s Α-36 C-H s Α-37 C_H s Α-38 C-H s Α*39 C-CN C-H s 2 - (1 -六氫D比哄基）煙驗酸乙酉旨參考例構造式 A-40 0¾ A，41 Me .. HfO^ MeReference Example ιι3 Α · 32 N CN ^ 〇 \ —y 〇A-33 C-SMe H s A-34 N CH s Α · 35 CH s Α-36 CH s Α-37 C_H s Α-38 CH s Α * 39 C-CN CH s 2-(1 -Hexahydro D ratios) Acetyl nicotinic acid Reference example Structural formula A-40 0¾ A, 41 Me .. HfO ^ Me

將六氫咄〇井3.74公克⑷.5mmol)、2'氯煙鹼酸乙g| 1 ·86公克（1 0.0mm〇1)及正丁醇1 〇〇毫升組成之混合物於 1 j 0 C加熱2日。濃縮後加入飽和碟酸氣鈉水溶液，用氯抽出。有機層用餘和食鹽水洗淨後用硫酸鎂乾燥，^ & 314976 40 200410956 粗製物經由矽膠管柱層析法（氣仿/曱醇=8〇/丨至2〇/ 〇精製，獲得目的物2-(1-六氫吡哄基）煙鹼酸乙酯ι.68公克（收率72%) 〇 H —NMR (CDC 1 3) ： δ y p pm 1.39(3 H, t,J = 7. 1Hz), 2· 90 - 3.10 (4 H, m), 3· 30 - 3· 5 0 (4 H，m), 4· 3 5(2 H, q, J = 7. 1Hz), 6. 7 3 (1 H, d d, J=4. 7, 7. 6 Hz),A mixture consisting of 3.74 g of hexahydrogen (0.5 mmol), 2 'of chloronicotinic acid, 1.86 g (1 0.0 mm), and 100 ml of n-butanol was heated at 1 j 0 C. 2nd. After concentration, a saturated aqueous solution of sodium bisulfate and sodium chloride was added, and the mixture was extracted with chlorine. The organic layer was washed with brine and dried over magnesium sulfate, and the crude product was purified by silica gel column chromatography (aerosol / methanol = 80 / 丨 to 20 / 〇) to obtain the target product. 2- (1-hexahydropyridyl) ethyl nicotinate. 68 g (yield 72%) OH-NMR (CDC 1 3): δ yp pm 1.39 (3 H, t, J = 7. 1Hz), 2.90-3.10 (4 H, m), 3.30-3.50 (4 H, m), 4.3.5 (2 H, q, J = 7. 1Hz), 6. 7 3 (1 H, dd, J = 4, 7, 7. 6 Hz),

7· 97 (1H, dd, J = l· 8, 7· 6Hz), 8. 27 (1H, dd, J =1 · 8，4 · 7 H z ) · 參考例A-43至A-45 與參考例A-42揭示之方法同樣操作，獲得以下之化合物。表7原料化合物（2)之製造參考例 N=Z1 HNV_VN~<\ /2 Z4-Z3 NMR (CDCI3, ppm) Ζι z2 Z3 z4 A-43 C-H C-H N C-CN 3.02 (4H, t, J = 5.0 Hz), 3.79 (4H, t, J = 5.0 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 2.2 Hz). A-44 c-nh2 C-F C-H N 2.89 (4H, t, J = 5.0 Hz), 3.65 (4H, t, J = 5.0 Hz), 4.76 (2H, br s), 7.83 (1H, d, J = 2.9Hz). A-45 HN〇i〇 3.00 (4H, m), 3.62 (4H, m), 7.07 (1H, t, J = 7.9 Hz), 7.29 (lH, t, J = 7.9 Hz), 7.54 (1H, d, J = 7.9 Hz), 7.58 (1H, d, J = 7.9 Hz). 參考例A-46 4-苯基-2-(1 -六氫吡啡基）噻唑 4】 314976 2004109567.97 (1H, dd, J = 1.8, 7.6 Hz), 8. 27 (1H, dd, J = 1. 8, 4, 7 Hz) Reference examples A-43 to A-45 and The method disclosed in Reference Example A-42 was operated in the same manner to obtain the following compounds. Table 7 Reference examples for the production of the raw material compound (2) = 5.0 Hz), 3.79 (4H, t, J = 5.0 Hz), 8.00 (1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 2.2 Hz). A-44 c-nh2 CF CH N 2.89 (4H, t, J = 5.0 Hz), 3.65 (4H, t, J = 5.0 Hz), 4.76 (2H, br s), 7.83 (1H, d, J = 2.9Hz). A-45 HN〇i 〇3.00 (4H, m), 3.62 (4H, m), 7.07 (1H, t, J = 7.9 Hz), 7.29 (lH, t, J = 7.9 Hz), 7.54 (1H, d, J = 7.9 Hz) , 7.58 (1H, d, J = 7.9 Hz). Reference Example A-46 4-phenyl-2- (1-hexahydropyridyl) thiazole 4] 314976 200410956

在一齐丙胺不存在下，眉土仕卜原科使用溴代苯乙酮，以參考例A-1 4揭示之方法為基準彳f彳*通化合物。In the absence of azipromine, Meibo Shibuyuanke uses bromoacetophenone, based on the method disclosed in Reference Example A-14, as a reference compound.

7 δ4 —7 8i (2H m), 7 3 9- 7. 2 4 (3H, m)> 6. 76(lH> s)> 3. 5 3-3. 5 0 (4H, m)，3. 0 2- 2. 9 8 (4H, m)，1_ 7〇 (1H，s)7 δ4 —7 8i (2H m), 7 3 9- 7. 2 4 (3H, m) > 6. 76 (lH > s) > 3. 5 3-3. 5 0 (4H, m), 3. 0 2-2. 9 8 (4H, m), 1_ 7〇 (1H, s)

差考J^LA-47 至 A-4Q 原料使用六氫吡哄，以參考例A_ u揭示之方法為基準’獲得以下之化合物。表8原料化合物（2)之製造參考例 Η〇 VZ2 NMR (CDCla, ppm) 2ι Z2 Α·47 C-H C-Me 1.70 (1H, s), 2.30 (3H, d, J = 1.3 Hz), 2·95·2·98 (4H，m), 3.37-3.40 (4H, m), 6.81 __ (1H, d, J = 1.3 Hz). Α·48 C-Me C-Me 1.67 (1H, s), 2.14 (3H, s), 2.19 (3H, s), 2.94-2.97 (4H, m), 3.33-3.37 (4H, m). Α-49 N c-cf3 3.01 (4H, m), 3.58 (4H, m). 參考例^^ 1 -苯基-5 - (1 -六氫吡哄基）四唑 42 314976 200410956Poorly tested J ^ LA-47 to A-4Q The raw materials used hexahydropyridine. The following compounds were obtained based on the method disclosed in Reference Example A_u. Table 8 Production reference examples of the raw material compound (2): OVZ2 NMR (CDCla, ppm) 2mZ2 Α · 47 CH C-Me 1.70 (1H, s), 2.30 (3H, d, J = 1.3 Hz), 2 · 95 · 2 · 98 (4H, m), 3.37-3.40 (4H, m), 6.81 __ (1H, d, J = 1.3 Hz). Α · 48 C-Me C-Me 1.67 (1H, s), 2.14 (3H, s), 2.19 (3H, s), 2.94-2.97 (4H, m), 3.33-3.37 (4H, m). Α-49 N c-cf3 3.01 (4H, m), 3.58 (4H, m ). Reference example ^^ 1-phenyl-5-(1-hexahydropyridyl) tetrazole 42 314976 200410956

0 將市售之5-[4-(卜苄基.六氫吡哄基笨基四唑i 〇公克 (S.Ummol)、5%鈀-碳100毫克、四氫呋喃ΐ5毫升及"古 15笔升之混合物在氫氣大氣下，於室溫授拌7小時。、尚= 後蒸餾除去溶劑，粗製物用鹼性碎膠管柱層析法(氣仿〕：醇= 2G/1)精製’獲得i•笨基巧仆六氫_啡基）四哇例耄克（收率68%) 〇 H — NMR (CDC 1 3) : δ/ρ pm 〇 Q1 …丁、。 3 y pm 9 1 (4H, m), 3· 2 2 (4 H, m), 7. 5 0 - 7. 6 3 (5H，m)·0 Will be commercially available 5- [4- (bubenzyl. Hexahydropyridylbenzyl tetrazolium i. 0 g (S.Ummol), 5% palladium-carbon 100 mg, tetrahydrofuran hydrazone 5 ml and 15 ancient The mixture was stirred for 7 hours at room temperature under a hydrogen atmosphere. After the solvent was distilled off, the crude product was purified by alkaline gel column chromatography (aerosol): alcohol = 2G / 1. Benzene hexahydro-phynyl) tetrahydroglycerol (yield 68%) 〇H — NMR (CDC 1 3): δ / ρ pm 〇Q1…, Ding. 3 y pm 9 1 (4H, m), 3 · 2 2 (4 H, m), 7. 5 0-7. 6 3 (5H, m) ·

例 A-51 $ A-W 與參考例A - 1 4揭示之方半ρη n ^ ^ ^ /去冋樣操作，獲得以下之化合物。 314976 43 200410956 表8-2原料化合物（2)B〇c體之製造參考例構造式 NMR (CDCls, ppm) A'5l Boc-N^N-C^]TCF3 w S 1.48 (9H, s), 3.47-3.60 (8H, m), 7.00 (1H, s). A-52 Boc-Hif 1.48 (9H, s), 3.45-3.60 (8H, m), 6.65 (1H, s), 6.96-7.04 (lH, m), 7.16-7.24 (1H, m), 7.31-7.38 (lH, m). A-53 Βο〇-Ν_Ν-<^ 1.48 (9H, s), 3.47-3.61 (8H, m), 6.62 (1H, s), 7.25-7.32 (1H, m), 7.34-7.39 (1H, m), 7.65-7.70 (1H, m). A'54 ^ nJ3 Boc-N^N^ Tj (DMSO-碑：1·43 (9H, s), 3.49 (8H，.s), 7.26-7.33 (1H, m), 7.51 (lH, s), 7.80-7.97 (2H, m), 8.53-8.59 (1H, m). A-55 r-\ Boc-NwNK，J (DMSO-^： 1.43 (9H, s), 3.50 (8H, s), 7.66 (1H, s), 7.72-7.78 (1H, m), 8.51-8.59 (1H, m), 8.62-8.68 (1H, m), 9.15-9.20 (1H, m). A-56 …>F3 Boc-N^r 1.42 (9H, s), 3.61 (8H, s), 7.62 (1H, s), 7.63 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz). * 參考例A - 5 7 獲得以下之化合與參考例A-1揭示之方法同樣操作物。Example A-51 $ A-W and the square half ρη n ^ ^ ^ ^ / removed from Reference Example A-14 were obtained to obtain the following compounds. 314976 43 200410956 Table 8-2 Reference Example for Production of Raw Compound (2) Boc Form Structural Formula NMR (CDCls, ppm) A'5l Boc-N ^ NC ^] TCF3 w S 1.48 (9H, s), 3.47- 3.60 (8H, m), 7.00 (1H, s). A-52 Boc-Hif 1.48 (9H, s), 3.45-3.60 (8H, m), 6.65 (1H, s), 6.96-7.04 (lH, m ), 7.16-7.24 (1H, m), 7.31-7.38 (lH, m). A-53 Βο〇-Ν_Ν- < ^ 1.48 (9H, s), 3.47-3.61 (8H, m), 6.62 (1H , s), 7.25-7.32 (1H, m), 7.34-7.39 (1H, m), 7.65-7.70 (1H, m). A'54 ^ nJ3 Boc-N ^ N ^ Tj (DMSO- tablet: 1 · 43 (9H, s), 3.49 (8H, .s), 7.26-7.33 (1H, m), 7.51 (lH, s), 7.80-7.97 (2H, m), 8.53-8.59 (1H, m). A -55 r- \ Boc-NwNK, J (DMSO- ^: 1.43 (9H, s), 3.50 (8H, s), 7.66 (1H, s), 7.72-7.78 (1H, m), 8.51-8.59 (1H , m), 8.62-8.68 (1H, m), 9.15-9.20 (1H, m). A-56… > F3 Boc-N ^ r 1.42 (9H, s), 3.61 (8H, s), 7.62 ( 1H, s), 7.63 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz). * Reference Example A-5 7 The following compound is obtained in the same way as disclosed in Reference Example A-1 Operator.

ΝΗΒη Ρ NMR (CDCl3):6/ppm 1‘ 46 (9H, s), 3· 24-3· 28 (4Η, m)，3. 45 - 3· 50 (4Η，m), 4· 57 - 4· 59 (2Η, m), 4. 6 9 (1 H, b r s), 6. 9 6 - 7 · 〇 3 (1 H, m)，7 · 18. 7. 3 3 (5H, m). 參考例A-58 44 314976 200410956 與參考例A-23(3)揭示之方法同樣操作，獲得以下之化合物。ΝΗΒη Ρ NMR (CDCl3): 6 / ppm 1 '46 (9H, s), 3.24-3.28 (4Η, m), 3.45-3.50 (4Η, m), 4.57-4 · 59 (2Η, m), 4. 6 9 (1 H, brs), 6. 9 6-7 · 〇3 (1 H, m), 7 · 18. 7. 3 3 (5H, m). Reference Example A-58 44 314976 200410956 The same procedure as described in Reference Example A-23 (3) was performed to obtain the following compound.

Bo MS (m/z) : 3 6 7 (MH+). !H —NMR (CDCl3): 5/ppm l· 48 (9H，s)，1· 82-1· 99 (4H，m)，3· 4 2 - 3. 6 8 (1 0H, m), 3. 83 —3· 93 (2 H, m), 7. 3 3 (1 H, s). 參考例A-59 使用參考例A-23(l)所獲得之化合物，在氯化鈣共存下用硼氫化鈉還原，獲得以下之化合物。 MS (m/z) :3 0 0 (ΜΗ4). ΧΗ —NMR (CDC13)· δ /ppm 1. 48 (9Η, s), 3. 4 5 — 3. 60 (8Η, m), 4. 55 (2Η, d, J = 5. 3Hz), 6. 44 (1 H, t, J=0. 9Hz). 參考例A-60至A-69 與參考例A-24揭示之方法同樣操作，獲得以下之化合物。該等化合物不經過精製，直接用於下一個步驟。 45 314976 200410956 表8_3原料化合物（2)之製造Bo MS (m / z): 3 6 7 (MH +).! H —NMR (CDCl3): 5 / ppm l · 48 (9H, s), 1 · 82-1 · 99 (4H, m), 3 · 4 2-3. 6 8 (1 0H, m), 3. 83 —3 · 93 (2 H, m), 7. 3 3 (1 H, s). Reference example A-59 Use reference example A-23 (1) The obtained compound was reduced with sodium borohydride in the presence of calcium chloride to obtain the following compound. MS (m / z): 3 0 0 (ΜΗ4). ΧΗ —NMR (CDC13) · δ / ppm 1. 48 (9Η, s), 3. 4 5 — 3. 60 (8Η, m), 4. 55 (2Η, d, J = 5. 3Hz), 6. 44 (1 H, t, J = 0. 9Hz). Reference Examples A-60 to A-69 were operated in the same manner as the method disclosed in Reference Example A-24 to obtain The following compounds. These compounds were used directly in the next step without purification. 45 314976 200410956 Table 8_3 Manufacture of raw material compound (2)

參考例構造式 A-60 /~^ N/CF3 HN U A-61 HN IJ A-62 门 Νγ^δ A-63 一;0 HNWNV A-64 HNwNVReference example Structural formula A-60 / ~ ^ N / CF3 HN U A-61 HN IJ A-62 Gate Νγ ^ δ A-63 I; 0 HNWNV A-64 HNwNV

參考例構造式 A-65 A-66 NHBn F Α·67 K^〇NH2 H〇^ A-68 A-69 h〇^〇H 參考例A-70至A-72 與參考例A-42揭示之方法同樣操作，獲得以下之化合物。表8-4原料化合物（2)之製造參考例構造式 NMR (CDC13, ppm) A-70 Me〆 h〇^D> 1.13 (3H, d, J = 6.4 Hz), 2.50-2.59 (1H, m), 2.77-3.14 (4H, m), 4.58*4.63 (2H, m), 6.47 (lH, t, J = 4.8 Hz), 8.30 (2H, d, J 二 4.7 Hz). Α·71 Me 1.13 (3H, d, J = 6.4 Hz), 2.50-2.59 (1H, m), 2.77-3.14 (4H，m), 4·58·4·63 (2H, m), 6.47 (lH, t, J = 4.8 Hz), 8.30 (2H, d, J = 4.7Hz). A-72 Η〇^Γ 2.93-3.03 (4H, m), 3.40-3.51 (4H, m), 6.42 (1H, s).Reference Example Structural Formula A-65 A-66 NHBn F A · 67 K ^ 〇NH2 H〇 ^ A-68 A-69 h〇 ^ 〇H Reference Examples A-70 to A-72 and Reference Example A-42 In the same manner, the following compounds were obtained. Table 8-4 Manufacturing reference examples of raw material compound (2) Structural formula NMR (CDC13, ppm) A-70 Me〆h〇 ^ D > 1.13 (3H, d, J = 6.4 Hz), 2.50-2.59 (1H, m ), 2.77-3.14 (4H, m), 4.58 * 4.63 (2H, m), 6.47 (lH, t, J = 4.8 Hz), 8.30 (2H, d, J 4.7 Hz). Α · 71 Me 1.13 ( 3H, d, J = 6.4 Hz), 2.50-2.59 (1H, m), 2.77-3.14 (4H, m), 4.58 · 4 · 63 (2H, m), 6.47 (lH, t, J = 4.8 Hz), 8.30 (2H, d, J = 4.7Hz). A-72 Η〇 ^ Γ 2.93-3.03 (4H, m), 3.40-3.51 (4H, m), 6.42 (1H, s).

系列B :化合物（I-A-1)之製造實施例B-1 46 314976 200410956 (2S)小（第三-丁氧基幾基）-Μ[4♦以基）+六氮吼啡基] 羰基}吼咯烷Series B: Production Example of Compound (IA-1) Example B-1 46 314976 200410956 (2S) Small (third-butoxyquinyl) -M [4 aryl] + hexaaziridinyl] carbonyl} Sallane

將N-(第三-丁氧基羰基）丄·脯氨酸15 〇公克 (69.8mm〇l)、WSC16.0 公克（83.5mmol)、卜羥基苯并*** i 水合物9.4公克（61.4mmol)及二氯曱烷15〇毫升組成之混合物於室溫攪拌30分鐘後，在冰冷下加入2—六氫吡哄基嘧啶12·6公克（76.7mmol)，於室溫攪拌2日。加入水，過濾不溶物後將濾液分液，有機層以飽和碳酸氫鈉水溶液、飽和食鹽水之順序洗淨，用硫酸鎂乾燥、濃縮，將所獲得之粗製結晶付諸矽膠管柱層析（乙酸乙酯），再經由再結晶 (乙酸乙酯-正己烷），獲得（2S)-1-(第三-丁氧基羰基）_2一 {[4-(2-嘧啶基六氫吡畊基]羰基丨吼咯烷2〇·9公克（收率 83%) 〇 H-NMR (CDCl3):5/ppm 1· 40 (〇· 5Χ9Η, s), l 46 (〇· 5X9H, s), ι· 76 —2· 29 (4H, m), 3. 30 —4. 〇 5 (10H，m), 4· 5 5 - 4. 8 0 (1 H, m), 6· 48 - 6· 60 (1H， m)，8· 32 (0. 5X2H, d, J=4· 6Hz)，8· 34 (0· 5X2H， d，1=4. 6 H z ) ·N- (third-butoxycarbonyl) 丄 · proline 15 gram (69.8mm), WSC 16.0 grams (83.5mmol), hydroxybenzobenzotriazole i hydrate 9.4 grams (61.4mmol ) And 150 ml of dichloromethane were stirred at room temperature for 30 minutes, and then 2-hexahydropyridylpyrimidine 12.6 g (76.7 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 days. Water was added, the insoluble matter was filtered, and the filtrate was separated. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated brine in that order, dried over magnesium sulfate, and concentrated. The obtained crude crystals were subjected to silica gel column chromatography ( Ethyl acetate), and then recrystallized (ethyl acetate-n-hexane) to obtain (2S) -1- (third-butoxycarbonyl) _2-{[4- (2-pyrimidinylhexahydropyridyl) ] Carbonyl 丨 Holidine 20.9 g (83% yield) 〇H-NMR (CDCl3): 5 / ppm 1.40 (〇 × 5 × 9Η, s), l 46 (〇 × 5X9H, s), ι · 76 —2 · 29 (4H, m), 3. 30 —4. 〇5 (10H, m), 4.5 5-4. 8 0 (1 H, m), 6.48-6.60 ( 1H, m), 8.32 (0.5X2H, d, J = 4.6 Hz), 8.34 (0.5X2H, d, 1 = 4.6 Hz) ·

iH B-2 S 將糸列A之參考例所製造之化合物以與實施例b _丨揭不之方法同樣處理，獲得以下之化合物。 314976 200410956iH B-2 S treated the compound produced in the reference example of queue A in the same manner as that disclosed in Example b _ 丨 to obtain the following compound. 314976 200410956

表9化合物（I-A-l)之製造實施例 Boc N=Z-| NMR (CDCls, ppm) Ζι z2 B-2 C-OMe C-H 3.37-4.00 (10H, m), 3.87 (3H, m)3 6.10-6.26 (2H, m), 7.36-7.53 (lH, m). B-3 C-H C-H 3.33-3.90 (10H, m), 6.58-6.76 (2H, m), 7.46-7.60 (1H, m), 8.13-8.27 (lH, m). Β·4 C-Wle C-H 2.40 (0.5 x 3H, s), 2.41(0.5 x 3H, s), 3.35*3.89 (10H, m), 6.39*6.49 (lH, m), 6.54 (1H, t, J = 7.4 Hz), 7.35-7.47 (1H, m). Β-5 C-H C_C1 3.33-3.89 (10H, m), 6.52*6.65 (1H, m), 7.39-7.52 (1H, m), 8.07-8.17 (1H, m). Β·6 Ν C-H 1.40, 1.45 (9H, s), 1.79^2.26 (4H, m), 2.60 (3H, s), 3.37-3.97 (10H, m), 4.50-4.76 (1H, m). 表10化合物（Ι-A- 1)之製造、/ 實施例 0^^ KZ4) NMR (CDCla, ppm) ζ4 Β-7 C-C02Et 1.26-1.57 (12H, m), 3.23*3.90 (10H, m), 4.20-4.42 (2H, m), 6.74-6.88 (lH, m), 7.96*8.12 (1H, m), 8.25-8.36 (lH, m). Β-8 C-CN 3.37-3.93 (10H, m), 6.76-6.90 (lH, m), 7.75-7.90 (1H, in), 8.30-8.42 (1H, m). Β-9 c-conh2 3.07-4.00 (10H, m), 7.07*7.17 (lH, m), 8.28 (1H, d, J =- 7.8 Hz), 8.37-8.43 (lH, m). 48 314976 200410956 表11化合物（I-A-l)之製造實施例令〇2 NMR (CDCls, ppm) Zi z2 B-10 N C-H 3· 10-3.94 (10H，m)，7.12-7.27 (2H，m)， 8.07-8.23 (1H, m), 8.32 (lH, br s). B11 C-H N 3.27- 3.93 (10H, m), 6.60*6.73 (2H, m), 8.27- 8.40 (2H, m). 表12化合物（I-A-1)之製造實施例 Βοο"Νγ N=Z^ N—^ NMR (CDCls, ppm) Zi Z2 B-12 c-cf3 C-H 3.37-4.07 (10H, m), 6.75-6.90 (lH, m), 8.48-8.58 (1H, m). Β·13 c-nh2 C-H 1.40 (0.5 x 9H; s), 1.46 (0.5 x 9H, s), 3.39-3.97 (10H, m), 5.77-5.83 (lH, m), 7.91-7.97 (1H, m). B-14 c_nh2 C-F 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 3.37-3.95 (10H，m), 7.81-7.86 (1H, m). B-15 C-OH C-H 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 5.77-5.83 (1H, m), 7.75-7.80 (lH, m). 49 314976 200410956Table 9 Production Example of Compound (IAl) Boc N = Z- | NMR (CDCls, ppm) Z 2 B-2 C-OMe CH 3.37-4.00 (10H, m), 3.87 (3H, m) 3 6.10-6.26 (2H, m), 7.36-7.53 (lH, m). B-3 CH CH 3.33-3.90 (10H, m), 6.58-6.76 (2H, m), 7.46-7.60 (1H, m), 8.13-8.27 (lH, m). Beta · 4 C-Wle CH 2.40 (0.5 x 3H, s), 2.41 (0.5 x 3H, s), 3.35 * 3.89 (10H, m), 6.39 * 6.49 (lH, m), 6.54 (1H, t, J = 7.4 Hz), 7.35-7.47 (1H, m). Β-5 CH C_C1 3.33-3.89 (10H, m), 6.52 * 6.65 (1H, m), 7.39-7.52 (1H, m ), 8.07-8.17 (1H, m). Beta · 6 Ν CH 1.40, 1.45 (9H, s), 1.79 ^ 2.26 (4H, m), 2.60 (3H, s), 3.37-3.97 (10H, m), 4.50-4.76 (1H, m). Table 10 Production of compound (I-A-1), Example 0 ^^ KZ4) NMR (CDCla, ppm) ζ4 Β-7 C-C02Et 1.26-1.57 (12H, m ), 3.23 * 3.90 (10H, m), 4.20-4.42 (2H, m), 6.74-6.88 (lH, m), 7.96 * 8.12 (1H, m), 8.25-8.36 (lH, m). Β-8 C-CN 3.37-3.93 (10H, m), 6.76-6.90 (lH, m), 7.75-7.90 (1H, in), 8.30-8.42 (1H, m). Β-9 c-conh2 3.07-4.00 (10H , m), 7.07 * 7.17 (lH, m), 8.28 (1H, d, J =-7.8 Hz), 8.37-8.43 (lH, m). 48 314976 200410956 Table 11 Production Example of Compound (IAl) Order 02 NMR (CDCls, ppm) Zi z2 B-10 N CH 3 · 10-3.94 (10H, m), 7.12-7.27 (2H, m ), 8.07-8.23 (1H, m), 8.32 (lH, br s). B11 CH N 3.27- 3.93 (10H, m), 6.60 * 6.73 (2H, m), 8.27- 8.40 (2H, m). Table Production Example of Compound 12 (IA-1) Bοο " Nγ N = Z ^ N- ^ NMR (CDCls, ppm) Zi Z2 B-12 c-cf3 CH 3.37-4.07 (10H, m), 6.75-6.90 (lH , m), 8.48-8.58 (1H, m). Beta · 13 c-nh2 CH 1.40 (0.5 x 9H; s), 1.46 (0.5 x 9H, s), 3.39-3.97 (10H, m), 5.77-5.83 (lH, m), 7.91-7.97 (1H, m). B-14 c_nh2 CF 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 3.37-3.95 (10H, m), 7.81-7.86 (1H, m). B-15 C-OH CH 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 5.77-5.83 (1H, m), 7.75-7.80 (lH, m). 49 314976 200410956

表13化合物（I-A-l)之製造實施例 Boc 丫^ Ν=Ζι °^〇·Λ /2 Z4—Z3 NMR (CDC13, ppm) Zi z2 z3 z4 B-16 C-H N C-H C-H B-17 C-OCH2Ph N C-H C-H 1.39 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 3.35-3.88 (10H, m), 5.37 (2H, s), 6.15-6.21 (1H, m), 7.27-7.48 (5H,m)，8.05-8.12 (lH，m)· B-18 C-CI C-H N C-H 1.75-2.3 (4H, m), 3.38-3.9 (10H, m), 4.54-4.62 and 4.66-4.73 (total 1H, both m), 7.88 (1H, d, J = 9.2 Hz), 7.99 (1H, d, J = 7.1Hz). B-19 C-H C-H N C-H B-20 C-H C-H N C-CN B-21 C-H N C-H N B-22 C-OEt N C-H N 1.40 (3H, t, J = 7 Hz), 3.40-4.00 (10H, m), 4.40 (2H, q, J = 7 Hz), 8.35 (1H, s). B-23 N C-H C-H N 3.40-4.17 (10H, m), 8.16*8.18 (lH, m), 8.56-8.58 (lH, m). B-24 C-F C-F C-H C-F 1.41 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 3.40-3.72 (10H, m), 4.55-4.72 (1H, m), 7.25-7.36 (lH, m). 50 314976 200410956 表14化合物（I-A-l)之製造實施例 Boc’N? n NMR (CDCb, ppm) Zi z2 Z3 B-25 C-H C-H s 3.30*3.93 (10H, m), 6.58-6.66 (1H, m), 7.16-7.25 (1H, m). B-26 N C-Me s 2.60 (3H, br s), 3.23-3.95 (10H, m)· B-27 C-H C-Br s 1.40 and 1.46 (total 9H, both s), 1.80-2.29 (4H,m)，3·25·3·90 (10H, m), 4.51-4.72 (1H, m), 7.09 and 7.10 (total 1H, both s). B-28 C-Me C-H s 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 1.78-2.25 (4H, m), 2.26 (3H, s), 3.30-3.93 (10H, m), 4.53-4.73 (lH, m), 6.16 (0.5 x 1H, s), 6.19 (0.5 x 1H, s). Β·29 C-H C-Me s 1.39, 1·45 (9H, s)，1.66-2.30 (4H,瓜)， 2.31 (3H, s), 3.33-3.93 (10H, m), 4.54-4.71 (1H, m), 6.80-6.86 (1H, m). B-30 C-Me C-Me s 1.39, 1.45 (9H, s), 1.76-2.26 (4H, m), 2.14 (3H, s), 2.20 (3H, s), 3.26-3.73 (10H, m), 4.53-4.70 (1H, m). B-31 C-Ph C-H s 1.40, 1.46 (9H, s), 1.80*2.29 (4H, m), 3.38-3.93 (10H, m), 4.56*4.73 (lH, m), 6.80, 6.82 (1H, s), 7.26-7.40 (3H, m), 7.81-7.83 (2H, m). Β·32 N C-H s 1.40, 1.46 (9H7 s), 1.65-2.29 (4H, m), 3.38-3.94 (10H，m)，4.53-4.74 (lH,m), 8.51, 8.53 (1H, s). Β-33 C-SMe N s 1.40，1.45 (9H, s)，1.79-2.26 (4H, m), 2.60 (3H, s), 3.37-3.97 (10H, m), 4.50*4.76 (1H, m). Β-34 N c_cf3 s 1.26, 1.48 (total 9H, both s), 1.98*2.15 (4H, m), 3.48-3.68 (10H, m), 4.72 (lH,j m). | 51 200410956Table 13 Production Examples of Compound (IAl) Boc ^ N = Zι ° ^ 〇 · Λ / 2 Z4-Z3 NMR (CDC13, ppm) Zi z2 z3 z4 B-16 CH N CH CH B-17 C-OCH2Ph N CH CH 1.39 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 3.35-3.88 (10H, m), 5.37 (2H, s), 6.15-6.21 (1H, m), 7.27-7.48 (5H , m), 8.05-8.12 (lH, m) · B-18 C-CI CH N CH 1.75-2.3 (4H, m), 3.38-3.9 (10H, m), 4.54-4.62 and 4.66-4.73 (total 1H , both m), 7.88 (1H, d, J = 9.2 Hz), 7.99 (1H, d, J = 7.1Hz). B-19 CH CH N CH B-20 CH CH N C-CN B-21 CH N CH N B-22 C-OEt N CH N 1.40 (3H, t, J = 7 Hz), 3.40-4.00 (10H, m), 4.40 (2H, q, J = 7 Hz), 8.35 (1H, s) . B-23 N CH CH N 3.40-4.17 (10H, m), 8.16 * 8.18 (lH, m), 8.56-8.58 (lH, m). B-24 CF CF CH CF 1.41 (0.5 x 9H, s) , 1.46 (0.5 x 9H, s), 3.40-3.72 (10H, m), 4.55-4.72 (1H, m), 7.25-7.36 (lH, m). 50 314976 200410956 Table 14 Production Examples of Compounds (IAl) Boc'N? N NMR (CDCb, ppm) Zi z2 Z3 B-25 CH CH s 3.30 * 3.93 (10H, m), 6.58-6.66 (1H, m), 7.16-7.25 (1H, m). B-26 N C-Me s 2.60 (3H, br s), 3.23-3.95 (10H, m) · B-27 CH C-Br s 1.40 and 1.46 (total 9H, both s), 1.80-2.29 (4H, m), 3.25 · 3 · 90 (10H, m), 4.51-4.72 (1H, m), 7.09 and 7.10 (total 1H, both s). B-28 C-Me CH s 1.40 (0.5 x 9H, s), 1.46 (0.5 x 9H, s), 1.78-2.25 (4H, m), 2.26 (3H, s), 3.30-3.93 (10H, m), 4.53-4.73 (lH, m), 6.16 (0.5 x 1H, s), 6.19 (0.5 x 1H, s). Beta 29 CH C-Me s 1.39, 1.45 (9H, s), 1.66-2.30 (4H, melons), 2.31 (3H, s), 3.33-3.93 (10H, m), 4.54 -4.71 (1H, m), 6.80-6.86 (1H, m). B-30 C-Me C-Me s 1.39, 1.45 (9H, s), 1.76-2.26 (4H, m), 2.14 (3H, s ), 2.20 (3H, s), 3.26-3.73 (10H, m), 4.53-4.70 (1H, m). B-31 C-Ph CH s 1.40, 1.46 (9H, s), 1.80 * 2.29 (4H, m), 3.38-3.93 (10H, m), 4.56 * 4.73 (lH, m), 6.80, 6.82 (1H, s), 7.26-7.40 (3H, m), 7.81-7.83 (2H, m). Β · 32 N CH s 1.40, 1.46 (9H7 s), 1.65-2.29 (4H, m), 3.38-3.94 (10H, m), 4.53-4.74 (lH, m), 8.51, 8.53 (1H, s). Β- 33 C-SMe N s 1.40, 1.45 (9H, s), 1.79-2.26 (4H, m), 2.60 (3H, s), 3.37-3.97 (10H, m), 4.50 * 4.76 (1H, m). Β -34 N c_cf3 s 1.26, 1.48 (total 9H, both s), 1.98 * 2.15 (4H, m), 3.48-3.68 (10H, m), 4.72 (lH, j m). | 51 200410956

B-35 C-H S 1.41 and 1.46 (total 9H, both s), 1.80-2.30 (4H, m), 3.40-3.95 (10H, m), 4.56-4.75 (1H, m), 6.90 and 6.92 (total 1H, both s), 7.27-7.34 (1H, dd，J = 4.8, 7.9 Hz), 8.10 (1H, ddd, J = 1.8, 2.0, 7.9 Hz), 8.52 (lHr dd, J = 1.8, 4.8 Hz), 9.06 (1H, br). B-36 N ONw〇〇 1.40, 1.46 (9H, s), 1.76-2.26 (4H, m), 3.26*3.89 (18H, m), 4.50*4.72 (lH, m). B-37 N N N-Ph 1.39, 1.44 (total 9H, both s), 1.83-2.17 (4H, m), 3.17-3.76 (10H, m), 4.51-4.64 (1H, m), 7.52-7.60 (5H, m). B-38 C-H S 1.29 (9H, s), 1.48 (9H, s), 3.48 (4H, br s), 3.56 (4H, br s), 6.16 (lH, s). B-39 C-Et C-H S 1.24 (3H, t, J = 7.5 Hz), 1.48 (9H, s), 2.63 (2H, q, J = 7.5Hz), 3.42-3.52 (4H, m), 3.51*3.60 (4H, m), 6.16 (lH, s) B-40 ch^-f C-H S 1.49 (9H, s), 3.53-3.63 (8H, m), 6.71 (1H, s), 7.02-7.11 (2H, m), 7.77-7.84 (2H, m). B-41 C-H S 1.49 (9H, s), 3.54-3.61 (8H, m), 6.78 (lH, s), 7.47-7.51 (2H, m), 7.68-7.73 (2H, m). B-42 c焱 C-H S L48 (9H, s), 1.74 (6H, br s), 1.91 .(6H, br s), 2.04 (3H, br s), 3.44 (4H, br s), 3.50-3.59 (4H, m), 6.11 (1H, s). B-43 C-CN C-H s 1.40 and 1.46 (total 9H, both s), 1.82-2.29 (4H, m), 3.35-3.95 (10H, m), 4.53-4.73 (1H, m). 52 314976 200410956 表15化合物（I-A-l)之製造實施例 0人R NMR (CDCla, ppm) R B-44 3.40-4.07 (10H, m), 6.95-7.03 (lH, m), 7.50-7.76 (3H, m), 7.88-7.98 (lH, m). B-45 1.40, 1.46 (total 9H, both s), 1.85-2.22 (4H, m), 3.41-3.84 (10H, m), 4.57-4.72 (1H, m), 7.11 (lH, m), 7.32 (1H, m), 7.55-7.64 ClH, m). B-46 Β·47 -0^¾) 3·33·3·97 (10H, m), 7.00-7.43 (4H, m). Β-48 1.43, 1.47 (total 9H, both s), 1.86-2.21 (4H, m), 2.75-3.20 (4H, m), 3.40-3.61 (9H, m), 4.56-4.71 (1H, m), 5.74 (1H, d, J = 7.1 Hz), 6.37 (lH, d, J = 8.8 Hz), 7.27 (1H, m). Β·49 _〇Ve Me 1.31 (9H, s), 1.63-1.93 (2H, m), 2.01 (3H, s), 2 .03 (3H, s), 2.04 (3H, s), 2.64-2.88 (3H, m), 3.25-3.67 (9H, m), 4.53-4.57 (lH, m). Β·50 Μς ·〇〇 Β-51 〇々 3.20-4.30 (10H; m), 6.33-6.53 (lH, m), 8.07-8.33 (2H, m). Β·52 Me 2.77-4.00 (6H, m), 4.33-4.83 (3H, m), 6.47*6.63 (1H, m), 8.27-8.43 (2H, m). Β-53 Me 2.90-4.93 (9H, m), 6.47-6.63 (lH, m), 8.23*8.50 (2H, m). Β·54 53 3J4976 200410956B-35 CH S 1.41 and 1.46 (total 9H, both s), 1.80-2.30 (4H, m), 3.40-3.95 (10H, m), 4.56-4.75 (1H, m), 6.90 and 6.92 (total 1H, both s), 7.27-7.34 (1H, dd, J = 4.8, 7.9 Hz), 8.10 (1H, ddd, J = 1.8, 2.0, 7.9 Hz), 8.52 (lHr dd, J = 1.8, 4.8 Hz), 9.06 (1H, br). B-36 N ONw00.40, 1.46 (9H, s), 1.76-2.26 (4H, m), 3.26 * 3.89 (18H, m), 4.50 * 4.72 (lH, m). B -37 NN N-Ph 1.39, 1.44 (total 9H, both s), 1.83-2.17 (4H, m), 3.17-3.76 (10H, m), 4.51-4.64 (1H, m), 7.52-7.60 (5H, m). B-38 CH S 1.29 (9H, s), 1.48 (9H, s), 3.48 (4H, br s), 3.56 (4H, br s), 6.16 (lH, s). B-39 C- Et CH S 1.24 (3H, t, J = 7.5 Hz), 1.48 (9H, s), 2.63 (2H, q, J = 7.5Hz), 3.42-3.52 (4H, m), 3.51 * 3.60 (4H, m ), 6.16 (lH, s) B-40 ch ^ -f CH S 1.49 (9H, s), 3.53-3.63 (8H, m), 6.71 (1H, s), 7.02-7.11 (2H, m), 7.77 -7.84 (2H, m). B-41 CH S 1.49 (9H, s), 3.54-3.61 (8H, m), 6.78 (lH, s), 7.47-7.51 (2H, m), 7.68-7.73 (2H , m). B-42 c 焱 CH S L48 (9H, s), 1.74 (6H, br s), 1.91. (6H, br s), 2.04 (3H, br s), 3.44 (4H, br s ), 3.50-3.59 (4H, m), 6.11 (1H, s). B-43 C-CN CH s 1.40 and 1.46 (total 9H, both s), 1.82-2.29 (4H, m), 3.35-3.95 ( 10H, m), 4.53-4.73 (1H, m). 52 314976 200410956 Table 15 Production Example of Compound (IAl) 0 Human R NMR (CDCla, ppm) R B-44 3.40-4.07 (10H, m), 6.95 -7.03 (lH, m), 7.50-7.76 (3H, m), 7.88-7.98 (lH, m). B-45 1.40, 1.46 (total 9H, both s), 1.85-2.22 (4H, m), 3.41 -3.84 (10H, m), 4.57-4.72 (1H, m), 7.11 (lH, m), 7.32 (1H, m), 7.55-7.64 ClH, m). B-46 Β · 47 -0 ^ ¾) 3.333.97 (10H, m), 7.00-7.43 (4H, m). Β-48 1.43, 1.47 (total 9H, both s), 1.86-2.21 (4H, m), 2.75-3.20 (4H , m), 3.40-3.61 (9H, m), 4.56-4.71 (1H, m), 5.74 (1H, d, J = 7.1 Hz), 6.37 (lH, d, J = 8.8 Hz), 7.27 (1H, m). Β49_〇Ve Me 1.31 (9H, s), 1.63-1.93 (2H, m), 2.01 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.64 -2.88 (3H, m), 3.25-3.67 (9H, m), 4.53-4.57 (lH, m). Β50 Μς · 〇〇Β-51 〇3.20-4.30 (10H; m), 6.33-6.53 (lH, m), 8.07-8.33 (2H, m). Β52 Me 2.77-4.00 (6H, m), 4.33-4.83 (3H, m), 6.47 * 6.63 (1H, m), 8.27-8.43 (2H, m). Β-53 Me 2.90-4.93 (9H, m), 6.47-6.63 (lH, m), 8.23 * 8.50 (2H, m ). Β54 53 3J4976 200410956

表16化合物（I-A-l)之製造實施例 NMR (CDC13, ppm) Re B-55 4 •""OH 3·13·3·91 (9H，m), 4.24 (1H, br), 4.67·4·78 (1H， m), 5.02 (1H, br), 6.64-6.72 (1H, m), 8.39 (2H, d, J = 4.6 Hz). B-56 4 —OH 3.48-4.14 (9H, m), 4.28-4.41 (lH, m), 4.67-4.78 (1H, m), 5.72 (lH, d, J = 11.9 Hz), 6.54 (1H, t, J =4.8 Hz), 8.33 (2H，d，J 二 4.8 Hz). B-57 乙F 1.42 and 1.48 (both 0.5 x 9H, s), 4.68 and 4.80 (both 0.5 x 1H, br d, J = 9.0 Hz), 5.09-5.17 and 5.26-5.35 (both 0.5 x 1H, m), 6.50-6.58 (1H, m), 8.28-8.36 (1H, m). B-58 4 "川 0-CH2Ph 1.40 (0.5 x 9H, s), 1·45 (0.5 x 9H, s)，6.50-6.58 (1H, m), 7.25-7.39 (5H, m), 8.30-8.36 (lH, m). Β·59 4 ""iph 3.33-4.23 (11H, m), 6·48_6·62 (1H, * m), 7.20-7.38 (5H, m), 8.28-8.38 (2H, m). Β-60 3 ""Me 1·07-1·27 (3H, m), 3.404.07 (10H, m), 6.50-6.67 (1H, 1x1), 8.27*8.43 (2H, m). 54 3]4976 200410956 表17化合物（I-A-l)之製造實施例 (CH2)n-fx^R7 Β〇Ί -X 0 NMR (CDCI3, ppm) X 尺6, R7 n B-61 ch2 4^F ^/p 1 3.43-4.07 (10H, m), 6.50-6.63 (1H, m), 8.27-8.43 (2H, m). B-62 ch2 a/%3 1 0.49 (1H, dt, J = 4.9, 4.2 Hz), 0.63 (1H, dt, J = 7.9, 4.9 Hz), 2·98 (1¾ d，J 二 9.7 Hz), 3.30 (1H, dd, J = 9.7, 3.8 Hz), 3.64-3.76 (4H, m), 3.83-3.92 (4H, m), 3.94 (lH, s)7 6.54 (1H, t, J = 4.7 Hz), 8.33 (2H, d, J = 4.7 Hz). B-63 s -H，-H 1 2.77 (1H, dd, J = 10.1, 9.1 Hz), 3.19 (lH, dd, J = 10.1, 6.8 Hz), 3.57-3.89 (9H, m), 4·13 (1H, d, J = 9·5 Hz)，4.48 (1¾ d; J 二 9.5 Hz). B-64 ch2 -Η, -H 2 3.20-3.33 (2H, m), 3.70-4.00 (9H, m), 6.54 (1H, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). B-65* o -Η, -H 2 1.46 (9H, s), 3.40-4.20 (14H, m), 3.63-3.90 (1H, br), 6.55 (1H, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). *消旋體實施例 (28,411)-1-(第三-丁氧基羰基）-4-甲氧基：2-{[4_(2-嘧啶基）-1-六氫吡哄基]羰基}吡咯烷Table 16 Production Examples of Compound (IAl) NMR (CDC13, ppm) Re B-55 4 • " " OH 3 · 13 · 3 · 91 (9H, m), 4.24 (1H, br), 4.67 · 4 78 (1H, m), 5.02 (1H, br), 6.64-6.72 (1H, m), 8.39 (2H, d, J = 4.6 Hz). B-56 4 —OH 3.48-4.14 (9H, m) , 4.28-4.41 (lH, m), 4.67-4.78 (1H, m), 5.72 (lH, d, J = 11.9 Hz), 6.54 (1H, t, J = 4.8 Hz), 8.33 (2H, d, J Two 4.8 Hz). B-57 B F 1.42 and 1.48 (both 0.5 x 9H, s), 4.68 and 4.80 (both 0.5 x 1H, br d, J = 9.0 Hz), 5.09-5.17 and 5.26-5.35 (both 0.5 x 1H, m), 6.50-6.58 (1H, m), 8.28-8.36 (1H, m). B-58 4 " Chuan 0-CH2Ph 1.40 (0.5 x 9H, s), 1.45 (0.5 x 9H , s), 6.50-6.58 (1H, m), 7.25-7.39 (5H, m), 8.30-8.36 (lH, m). Β · 59 4 " " iph 3.33-4.23 (11H, m), 6 48_6 · 62 (1H, * m), 7.20-7.38 (5H, m), 8.28-8.38 (2H, m). Β-60 3 " " Me 1.07-1 · 27 (3H, m) , 3.404.07 (10H, m), 6.50-6.67 (1H, 1x1), 8.27 * 8.43 (2H, m). 54 3] 4976 200410956 Table 17 Production Example of Compound (IAl) (CH2) n-fx ^ R7 Β〇Ί -X 0 NMR (CDCI3, ppm) X feet 6, R7 n B-61 ch2 4 ^ F ^ / p 1 3.43-4.07 (10H, m), 6.50-6.63 (1H, m), 8.27-8.43 (2H, m). B-62 ch2 a /% 3 1 0.49 (1H , dt, J = 4.9, 4.2 Hz), 0.63 (1H, dt, J = 7.9, 4.9 Hz), 2.98 (1¾ d, J = 9.7 Hz), 3.30 (1H, dd, J = 9.7, 3.8 Hz ), 3.64-3.76 (4H, m), 3.83-3.92 (4H, m), 3.94 (lH, s) 7 6.54 (1H, t, J = 4.7 Hz), 8.33 (2H, d, J = 4.7 Hz) B-63 s -H, -H 1 2.77 (1H, dd, J = 10.1, 9.1 Hz), 3.19 (lH, dd, J = 10.1, 6.8 Hz), 3.57-3.89 (9H, m), 4. · 13 (1H, d, J = 9.5 Hz), 4.48 (1¾ d; J 9.5 Hz). B-64 ch2 -Η, -H 2 3.20-3.33 (2H, m), 3.70-4.00 (9H, m), 6.54 (1H, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). B-65 * o -Η, -H 2 1.46 (9H, s), 3.40-4.20 (14H , m), 3.63-3.90 (1H, br), 6.55 (1H, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). * Racemate Example (28,411) -1- ( Third-butoxycarbonyl) -4-methoxy: 2-{[4_ (2-pyrimidinyl) -1-hexahydropyridyl] carbonyl} pyrrolidine

55 314976 200410956 在實施例B_55所獲得化合物900毫克（2.4mmol)之 DMF 30 *升溶液中加入60%氫化鈉114毫克（2.9mmol)，於室溫攪拌3 0分鐘後，在冰冷下加入甲基碘222 g (^•57mmol) ’於室溫攪拌一晚。將反應液減壓濃縮後於殘 /查中加入乙酸乙酯及水，將目的物從有機層抽出。用無水 & ^鎂乾燥後減壓蒸餘除去溶劑，殘渣用石夕膠管柱層析法 •(氯仿/曱醇=1/〇至20/ 1)精製，獲得（2S，4R)-l-(第三-丁氧基羰基）-4-甲氧基_2_{[4_(2_嘧啶基六氫吡啡基]羰基}吼p各烧7 6 0毫克（收率8 2 %)。 H—*NMR (CDC13)： h / ppm 1· 40(0. 5 X 9 Η, s ), 1 . 4 5 (〇. 5 X 9 Η, s)，1. 97 — 2· 3 2 ( 2 Η, m), 3 · 3 3 ( 3 Η， s)，3· 50 - 4· 15 (11Η, m), 4· 6 8 —4. 8 8 (1 Η，m)，6. 50 - 6· 5 9 (1 Η, m), 8. 3 3 (2Η, t , J =4. 7Ηζ)· ί施例Β-67 (2S54S)-4-乙醯胺基-ΐ_(第三-丁氧基羰基嘧啶 _ 基）-1-六氫吡哄基]羰基}吼咯烷 Η N-Ac55 314976 200410956 To a solution of 900 mg (2.4 mmol) of the compound obtained in Example B_55 in 30 * liter of DMF was added 114 mg (2.9 mmol) of 60% sodium hydride, and the mixture was stirred at room temperature for 30 minutes. Iodine 222 g (^ • 57mmol) was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the target substance was extracted from the organic layer. After drying over anhydrous magnesium, the solvent was removed under reduced pressure and the solvent was removed. The residue was purified by column chromatography on spore gel column ((chloroform / methanol = 1/0 to 20/1)) to obtain (2S, 4R) -l- (Third-butoxycarbonyl) -4-methoxy_2 _ {[4_ (2-pyrimidinylhexahydropyridinyl] carbonyl}) each 760 mg (yield 82%). H — * NMR (CDC13): h / ppm 1.40 (0.5 X 9 Η, s), 1. 4 (0.5 X 9 Η, s), 1. 97 — 2. 3 2 (2 Η , m), 3 · 3 3 (3 Η, s), 3 · 50-4 · 15 (11Η, m), 4 · 6 8 —4. 8 8 (1 Η, m), 6. 50-6 · 5 9 (1 Η, m), 8. 3 3 (2Η, t, J = 4. 7Ηζ) · Example B-67 (2S54S) -4-acetamido- 醯 _ (third-butoxy Carbonylpyrimidinyl) -1-hexahydropyridinyl] carbonyl} hyrrolidine N-Ac

(1)將由實施例B-55所獲得之化合物7.11公克 (18.8 m mol)、三乙胺 4.0 毫升（28.7 mmol)、DMAP 460 毫克 (3.77mmol)及二氣曱炫120毫升組成之混合物在冰冷下加入對-曱基石黃酸氯4 · 3 1公克（2 2.6 m m ο 1 )，於室溫搜拌4曰。 314976 56 200410956 在減壓下蒸餾除去溶劑，於所獲得之殘渣中加入乙酸乙酯’以冰冷稀鹽酸、稀食鹽水、餘和碳酸氫鈉水、飽和食鹽水之順序洗淨。用無水硫酸納乾燥後減屢蒸館除去溶劑，獲得（2S，4R)小（第：丁氧基幾基）|{[4 ♦密。定訂 1”、風哏哄基]幾基卜4-對甲苯磺醯氧基唯洛烷9.83公克 (收率98%)。士_ (CDCmppm L 38,卫 41 (t〇tai 9 Η- both s), 2. 46 (3H, s), 3. 5-4. 0 (l〇H; m)( 4 7 7 ( 〇 . 5 X 1 H t T 〜7 v tt 、 n，t，j —7· 7Hz)，4 8 4 (◦· 5χ ih 七 =4. 8 H z ), 4 98 — 5 n ,- / n ’ , 5· 05 (〇· 5χ1Η，m), 5· 08 — 5· 16 (0. 5 X 1 H, m), 6 . 5 4 (〇 5 x τ ττ . τ . 7 (0. 5Χ!Η t J-4 8HZ)，6· 5 1M, t, J-^4. 8Hz), 7. 37 (2H, br d, J = 8 3Hz), 7. 8 0 (2H, br d 卜只 qw、〇 · d> J-8. 3Hz), 8. 32 (〇. 5X2 Η- d, J=4. 8HZ), 8. 34 CO. 5X2H, d, J = 4. 8Hz). ⑺在前項所獲得之化合物中加入迭氮化納i 8〇公克 (27·7_01)及DMF70毫升，於机加熱擾拌4曰，接著於80 C加熱搜拌3小時後在減壓下蒸德除去溶劑。殘法中加入乙酸乙醋’以水、餘和食鹽水之順序洗淨後用無:硫酸鈉乾燥。減壓蒸餾除去溶劑 ^ 合W獲付（2S，4S)-4-迭氮基-1-(第 -丁氧基叛基）-2-{[4-(2-σ密唆基）小六氫〇比啡基]幾基}吡咯烷之粗製物8 · 5 5公克。 ™R(cDCl3)：5/ppm , 4 0,, 4 6 (t〇tai 9 ；3〇 3, S；，' 9'2' 〇1 (1H> m)> 2· 5~2· 65 m), 3. 35-4. 15 (l〇H, m), 4. 62 (〇 5χ 6. 6, 8. ΐΗζ), 4. 73 (〇 5Χ1Η ,η r · 5 Χ 1Η，d d，J = 6· 〇, 8· 4Η Ζ)，6_ 5 —6· 6 (1Η，^ δ. 29-8. 36 (2Η, m)· 314976 57 200410956 (3)方、鈉項所獲得之化合物中加入5%鈀-碳800毫克及乙醇 1 〇〇也升’於4〇°c進行常壓接觸還原5小時。加入活性碳，過滤’將濾液減壓濃縮，獲得結晶性之殘渣。加入二異丙醚，濾取結晶後以乙酸乙酯-二異丙醚之丨：丨混合物洗淨並乾燥之’獲得（2S，4S)_4_胺基(第三-丁氧基羰基）_2_(1) A mixture consisting of 7.11 g (18.8 m mol) of the compound obtained in Example B-55, 4.0 ml (28.7 mmol) of triethylamine, 460 mg (3.77 mmol) of DMAP, and 120 ml of dioxamine was ice-cold Add 4 · 3 1 g (2 2.6 mm ο 1) of p-fluorenyl lutein chloride and search for 4 days at room temperature. 314976 56 200410956 The solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solution was washed with ice-cold dilute hydrochloric acid, dilute saline, residual sodium bicarbonate water, and saturated saline. After drying with anhydrous sodium sulfate, the solvent was removed in a distillate oven to obtain a small (2S, 4R) (No .: butoxyline) | {[4 ♦ dense. Ordering 1 ", wind hydrazine] Jijibu 4-p-toluenesulfonyloxychlorinane 9.83 g (yield 98%). _ (CDCmppm L 38, Wei 41 (t〇tai 9 Η- both s), 2. 46 (3H, s), 3. 5-4. 0 (lOH; m) (4 7 7 (0. 5 X 1 H t T ~ 7 v tt, n, t, j — 7 · 7Hz), 4 8 4 (◦ · 5χ ih VII = 4. 8 H z), 4 98 — 5 n,-/ n ', 5 · 05 (〇 · 5χ1Η, m), 5 · 08 — 5 · 16 (0. 5 X 1 H, m), 6. 5 4 (〇5 x τ ττ. Τ. 7 (0.5 ×! Η t J-4 8HZ), 6. 5 1M, t, J- ^ 4 8Hz), 7. 37 (2H, br d, J = 8 3Hz), 7. 8 0 (2H, br d only qw, 〇d > J-8. 3Hz), 8. 32 (〇. 5X2 Η- d, J = 4.8HZ), 8.34 CO. 5X2H, d, J = 4. 8Hz). 加入 Add sodium azide i 80g (27 · 7_01) and the compound obtained in the previous item and 70ml DMF, stir in the machine for 4 hours, then heat and stir at 80 C for 3 hours, and then evaporate the solvent under reduced pressure. Add ethyl acetate in the residual method, wash it in the order of water, residue and brine, and then use None: Drying with sodium sulfate. The solvent was distilled off under reduced pressure to obtain (2S, 4S) -4-azido-1- (s-butoxyalkyl) -2-{[4- (2-σ Myitky Hexahydropyridinyl] quinyl} pyrrolidine crude product 8.55 g. ™ R (cDCl3): 5 / ppm, 40, 4, 46 (t〇tai 9; 3 03, S ;, '9'2' 〇1 (1H > m) > 2.5-5 ~ 65m), 3. 35-4. 15 (l〇H, m), 4. 62 (〇5χ 6. 6, 8 ΐΗζ), 4. 73 (〇5χ1Η, η r · 5 χ 1Η, dd, J = 6. 0, 8. · 4Η Zn), 6_ 5 —6 · 6 (1Η, ^ δ. 29-8. 36 ( 2Η, m) · 314976 57 200410956 (3) The compound obtained from the formula (3) and sodium was added with 5% palladium-carbon 800 mg and ethanol 100 liters, and subjected to normal pressure contact reduction at 40 ° C for 5 hours. Activated carbon is filtered and the filtrate is concentrated under reduced pressure to obtain a crystalline residue. Diisopropyl ether was added, and the crystals were filtered and washed with ethyl acetate-diisopropyl ether. The mixture was washed and dried to obtain (2S, 4S) _4_amino group (third-butoxycarbonyl) _2_.

{[心（2-"治°定基）4-六氫吡啡基]羰基}吼咯烷4·81公克（從曱苯績驗體之收率6 1 %)。 'H-NMR (CDCl3)：5/ppm 1.40, 1. 46(total 9 H, both s), l. 6-1. 8 (1H, m), 2. 40-2. 54 (ih, m)，3· 3 —3· 45 (1H，m), 3· 4 5 —4. 0 5 (1 0H, m), 4. 61 (〇. 5X1H, dd, J-4. 8, 9. 3Hz), 4. 72 (0. 5X1 H，dd，J=4· 2, 9· 4Hz), 6· 51-6· 59 (1H, m)，8· 3 —8· 3 6 (2H，m)· (4)將由前項所獲得之化合物2〇〇毫克（〇 53mm〇1)、乙酸酐 6〇//l(〇.636mm〇l)、三乙胺 111//1(〇 796mm〇1)及二氯曱烷 5.〇毫升組成之混合物於室溫攪拌18小時。減壓蒸餾除去溶劑，所獲得之殘渣經由矽膠管柱層析法（氣仿/乙醇=4〇 /1至2〇/1)精製，獲得（23,48)-4_乙醯胺基_1_(第三-丁氧基幾基）-2_{[4-(2+定基）小六氫吼D井基]戴基}批略烷⑽ 毫克（收率100%)。 xH-NMR (CDC 1 3) ： δ/ρ pm 1 · 4 5 (total 9 H, both s), 1.93, 1 . 2 · 3 3 - 2 · 5 3 (1 H, m), 3· 4· 84 (2Η，m)，6· 52 - 6· d, J = 9. OH ζ), 8. 3 0-8. 9 6 ( t 0 t a 1 3H，b o t h s)， 4 5-4· 〇 (1 〇H，m)，4· 6 4-6 2 (1H，m), 7. 8 2 (1 H, b r 36 (2H，m). 實施例B-68 $ B-81 314976 58 200410956 與實施例B-1揭示之方法同樣操作，獲得以下之化合物。表I7·2化合物（I-A-l)之製造實施例構造式 NMR (CDC13, ppm) B-68 1.40 and 1.46 (total 9H, both s), 1.76-2.29 (4H, m), 3.34-3.93 (10H, m), 4.53-4.74 (lH, m), 7.02 and 7.04 (total 1H, both s). B-69 BocN^O^i^ 1.40 and 1.46 (total 9H, both s), 1.74-2.26 (4H, m), 3.34-4.03 (10H, m), 4.54*4.75 (lH, m), 6.65 and 6.68 (total 1H, both s), 7.00-7.11 (1H, m), 7.21-7.32 (1H, m), 7.54 (1H, br s). B-70 B〇C，5〇^S 1.41 and 1.46 (total 9H, both s), 1.79-2.30 (4H, m), 3.38.3,95 (10H, m), 4.53-4.79 (lH, m), 6.65, 6.67 (1H, s), 7.24-7.45 (2H, m), 7.74 (1H, br s). B-71 Β。今〇令^ 1.41 and 1.46 (total 9H, both s), 1.79-2.29 (4H, m), 3.35-3.94 (10H, m), 4.56-4.76 (1H, m), 7.22-7.32 (1H, m), 7.62*7.72 (lH, m), 7.78-7.88 (lH, m), 8.02-8.10 (1H, m), 8.56-8.65 (lH, m). B-72 bocN^n^n^TT^ 1.41 and 1.46 (total 9H, both s), 1.79-2.29 (4H, m), 3.40*3.94 (lOH, m), 4.56-4.76 (lH, m), 6.98 and 6.99 (total 1H, both s), 7.43-7.50 (1H, m), 8.21-8.31 (lH, m), 8.51-8.57 (lH, m), 9.14 (lH, br s). B-73 〇 ^ 1.41 and 1.46 (total 9H, both s), 1.79-2.32 (4H, m), 3.03-3.18 (lH, m), 3.38-3.94 (9H, m), 4.56-476 (lH, m), 6.90 and 6.93 (total 1H, both s), 7.64 (2H, d, J = 8.2Hz), 7.95 (2H, d, J = 8.2Hz). B-74 Boc^NY ΝΗΒη 〇丄 O^F F 1.41 (0.5 x 9H, s), 1.47 (0.5 x 9H, s), 4.58-4.61 (2H, m), 4.70-4.72 (2H, m), 7.00-7.05 (1H, m), 7.31-7.34 (5H, m)· B-75 Boc^^O ?β 1.11-2.17 (16H, m), 3.01-3.50 (6H, m), 4.33-4.80 (4H, m), 6.506.55 (1H, m), 8.308.33 (2H, m). B-76 0^NwN^J> 1.40 (0.5 x 9H, s), 1.45 (0.5 x 9H, s), 3.08-3.74 (6H, m), 4.35-4.83 (4H, m), 6.52-6.55 (1H，m), 8.30-8.33 (2H, m). 59 314976 200410956 B-77 boc5〇^ONH2 1.40 and 1.46 (total 9H, both s), 4.54-4.74 (lH, m), 5.57 (lH, br), 6.98 (1H, br), 7.47 and 7.49 (total lH, both s). Β·78 BocS〇^0 1.40 and 1.46 (total 9H, both s), 3.37-3.93 (14H, m), 4.53*4.74 (lH, m), 7.33 and 7.35 (total 1H, both s). Β-79 1.40 and 1.46 (total 9H, both s), 3.34-3.91(10¾ m), 4.50*4.74 (3H, m), 6.46 and 6.49 (total 1H, both s). Β-80 B0CS〇^r 1.40 and 1.46 (total 9H，both s), 3.34-3.91(10H, m), 4.52-4.73 (1H, m), 6.47 and 6.50 (total 1H, both s). Β-81 Boc^O 1.45 (9H, s), 3.45-4.12 (14H, m), 4.61-4.83 (1H, m), 6.62 (lH, d, J = 3.6 Hz), 7.21 (1H, d, J=3.6Hz). 系列C :原料（3)之製造參考例C-1 (2R)-N-[(2,4-二甲氧基苯基）甲氧基]-2-(羥基甲基）己醯胺{[心 (2- " 治 ° 定基) 4-hexahydropyridinyl] carbonyl} glutaridine 4.81 g (the yield of phenylbenzene test body is 61%). 'H-NMR (CDCl3): 5 / ppm 1.40, 1. 46 (total 9 H, both s), 1. 6-1. 8 (1H, m), 2. 40-2. 54 (ih, m) , 3 · 3 —3 · 45 (1H, m), 3 · 4 5 —4. 0 5 (1 0H, m), 4. 61 (〇. 5X1H, dd, J-4. 8, 9. 3Hz) , 4. 72 (0. 5X1 H, dd, J = 4 · 2, 9 · 4Hz), 6 · 51-6 · 59 (1H, m), 8 · 3 —8 · 3 6 (2H, m) · (4) The compound obtained in the preceding item is 200 mg (〇53mm〇1), acetic anhydride 60 // l (0.6636mm), triethylamine 111 // 1 (〇796mm〇1), and two A mixture of 5.0 ml of chloromethane was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (aerosol / ethanol = 4〇 / 1 to 2〇 / 1) to obtain (23,48) -4_acetamido_1_ (Third-butoxyalkyl) -2 _ {[4- (2 + Axyl) small hexahydrozyl D well-based] Daiji} Lanthane ⑽ mg (yield 100%). xH-NMR (CDC 1 3): δ / ρ pm 1 · 4 5 (total 9 H, both s), 1.93, 1.2. 3 3-2 · 5 3 (1 H, m), 3 · 4 · 84 (2Η, m), 6.52-6 · d, J = 9. OH ζ), 8. 3 0-8. 9 6 (t 0 ta 1 3H, both), 4 5-4 · 〇 (1 〇H, m), 4 · 6 4-6 2 (1H, m), 7. 8 2 (1 H, br 36 (2H, m). Example B-68 $ B-81 314976 58 200410956 and Examples The method disclosed in B-1 was performed in the same manner to obtain the following compounds: Table I7 · 2 Production Examples of Compounds (IAl) Structural Examples NMR (CDC13, ppm) B-68 1.40 and 1.46 (total 9H, both s), 1.76- 2.29 (4H, m), 3.34-3.93 (10H, m), 4.53-4.74 (lH, m), 7.02 and 7.04 (total 1H, both s). B-69 BocN ^ O ^ i ^ 1.40 and 1.46 (total 9H, both s), 1.74-2.26 (4H, m), 3.34-4.03 (10H, m), 4.54 * 4.75 (lH, m), 6.65 and 6.68 (total 1H, both s), 7.00-7.11 (1H, m), 7.21-7.32 (1H, m), 7.54 (1H, br s). B-70 B〇C, 5〇S 1.41 and 1.46 (total 9H, both s), 1.79-2.30 (4H, m) , 3.38.3, 95 (10H, m), 4.53-4.79 (lH, m), 6.65, 6.67 (1H, s), 7.24-7.45 (2H, m), 7.74 (1H, br s). B-71 Β. Order of this day ^ 1.41 and 1.46 (total 9H, both s), 1.79-2.29 (4H, m), 3.35-3.94 (10H, m), 4.56-4.76 (1H, m), 7.22-7.32 (1H, m), 7.62 * 7.72 (lH, m), 7.78-7.88 (lH, m), 8.02-8.10 (1H, m), 8.56-8.65 (lH, m). B-72 bocN ^ n ^ n ^ TT ^ 1.41 and 1.46 (total 9H, both s ), 1.79-2.29 (4H, m), 3.40 * 3.94 (lOH, m), 4.56-4.76 (lH, m), 6.98 and 6.99 (total 1H, both s), 7.43-7.50 (1H, m), 8.21 -8.31 (lH, m), 8.51-8.57 (lH, m), 9.14 (lH, br s). B-73 〇 1.41 and 1.46 (total 9H, both s), 1.79-2.32 (4H, m), 3.03-3.18 (lH, m), 3.38-3.94 (9H, m), 4.56-476 (lH, m), 6.90 and 6.93 (total 1H, both s), 7.64 (2H, d, J = 8.2Hz), 7.95 (2H, d, J = 8.2Hz). B-74 Boc ^ NY ΝΗΒη 〇丄 O ^ FF 1.41 (0.5 x 9H, s), 1.47 (0.5 x 9H, s), 4.58-4.61 (2H, m) , 4.70-4.72 (2H, m), 7.00-7.05 (1H, m), 7.31-7.34 (5H, m) B-75 Boc ^^ O? Β 1.11-2.17 (16H, m), 3.01-3.50 ( 6H, m), 4.33-4.80 (4H, m), 6.506.55 (1H, m), 8.308.33 (2H, m). B-76 0 ^ NwN ^ J > 1.40 (0.5 x 9H, s), 1.45 (0.5 x 9H, s), 3.08-3.74 (6H, m), 4.35-4.83 (4H, m), 6.52-6.55 (1H, m), 8.30-8.33 (2H, m). 59 3 14976 200410956 B-77 boc50〇 ONH2 1.40 and 1.46 (total 9H, both s), 4.54-4.74 (lH, m), 5.57 (lH, br), 6.98 (1H, br), 7.47 and 7.49 (total lH, both s). Β · 78 BocS〇 ^ 0 1.40 and 1.46 (total 9H, both s), 3.37-3.93 (14H, m), 4.53 * 4.74 (lH, m), 7.33 and 7.35 (total 1H, both s) Β-79 1.40 and 1.46 (total 9H, both s), 3.34-3.91 (10¾ m), 4.50 * 4.74 (3H, m), 6.46 and 6.49 (total 1H, both s). Β-80 B0CS〇 ^ r 1.40 and 1.46 (total 9H, both s), 3.34-3.91 (10H, m), 4.52-4.73 (1H, m), 6.47 and 6.50 (total 1H, both s). Β-81 Boc ^ O 1.45 (9H, s), 3.45-4.12 (14H, m), 4.61-4.83 (1H, m), 6.62 (lH, d, J = 3.6 Hz), 7.21 (1H, d, J = 3.6Hz). Series C: Raw materials ( 3) Production Reference Example C-1 (2R) -N-[(2,4-dimethoxyphenyl) methoxy] -2- (hydroxymethyl) hexamidine

• (1)於公知化合物（4S)-4-T基-3-[(2R)-2-(〒氧基甲基）己醯基]-2-噁唑烷酮240公克（606mmol)中加入5%鈀-碳25.0公克、乙醇1 600毫升，於40°C邊加溫邊在氫氣大氣下進行接觸還原。過濾除去觸媒後將濾液濃縮，獲得固體殘渣。加入己烧3 0 0毫升，暫且加溫後邊攪拌邊慢慢冷卻。經由過濾收集結晶，用己烷洗淨、乾燥，獲得（4S)-4-T基-3-[(2R)-2-(羥基甲基）己醯基]-2-噁唑烷酮177.9公克（收率 96〇/〇)。 60 314976 200410956 'H-NMR (CDC13)： δ/ppm 〇.89(3H，t,J = 7.0Hz)， 1.0-1. 8 (6H, m)，2. 15 - 2· 3 (1H, br s), 2· 81 (1 H, d d, J = 9. 3, 13. 5Hz), 3· 30 (1H, dd，J 二 3. 3, 13· 4Hz), 3· 7 5-4· 0 (2H, m), 4. 1 一 4· 3 (2H，m)， 4. 65 - 4· 7 5 (1 H, m), 7· 1 — 7· 5 (5H，m)· (2) 於前項所獲得之化合物中加入30至35.5%過氧化氫水 226毫升、水350毫升及THF 1400毫升，於冰冷下滴下氫氧化鋰1水合物48.9公克（1.1 7mol)之水溶液（3 50毫升）後在室溫下攪拌2小時。在冰冷下於反應液中以1.5小時加入亞硫酸鈉3 3 0公克，在室溫攪拌3小時，蒸餾除去溶劑。所獲得之殘渣中加入水，用氣仿洗淨4次後用濃鹽酸使pH 值為4，遊離之目的化合物用乙酸乙酯抽出3次。有機層用飽和食鹽水洗淨，用硫酸鈉乾燥後蒸餾除去溶劑，獲得 (2R)-2-(羥基甲基）己酸78.2公克（收率92%)。 ^-NMR (CDCl3)：5/ppm 0·91(3Η, t，J = 7.〇Hz)， I. 25 —1· 48 (4H, m), 1. 48 — 1· 77 (2H, m)，2· 62 (1 3 Η, quint, J=6. 4Hz), 3. 8 0 (2Η, d, J = 6· 2H z). (3) 於由前項所獲得之化合物77.3公克（529mmol)、公知化合物〇-[(2，4-二甲氧基苯基）曱基]羥基胺η 9.7公克 (5 5 5mmol)及吡啶750毫升組成之混合物中，於冰冷下加入 WSC 121.7公克（63 5mmol)。在室溫下攪拌一晚後將反應液減壓濃縮，所獲得之殘渣中加入乙酸乙酯，以丨〇%檸檬酸水浴液、飽和被1氫納水溶液、飽和食鹽水之順序洗淨。有機層用硫酸納乾燥，蒸餾除去溶劑，於所獲得之粗製物 314976 61 200410956 1 72么克中加人乙酸乙g旨及二異丙_之混合溶劑，渡取所析出之結晶。所獲得之結晶從乙酸乙酯及二異丙醚之混合溶劑中再結晶’獲得(2R)善[(2,4_二甲氧基苯基）甲氧^ 2-(¾基曱基）己fe胺119.7公克（收率73%)。 ^-NMR (CDC 1 3) : 5/p pm 0.8 8 (3H, t, J-6. 8Hz), 1· 2-1. 75 (6H，m)，2· 0 - 2. 6 (1H，m)，3. 6-3· 8 (2 H, m), 3· 81 (3H, s), 3. 8 3 〇H> s), 4 · 7 7 - 5 · 0 (2 H, m), 6. 4 2- 6. 5 2 (2 H, m), 7. 1 一 7· 35 (1H, m). 參考例C-2至C-4 與參考例C- 1揭示之方法同樣操作，獲得表丨8之化合物。表18化合物（3)原料之製造參考例 §8 H ?Me HMe NMR (CDCls, ppm) Re 02 Me / 0.87 (3H, br t), 1.17-1.77 (8H,. m), 2.33*2.66 (1H, br), 3.57-3.83 (2H, m), 3.81 (3H, s), 3.83 (3H, s), 4.77-5.00 (2H, m), 6.40-6.53 (2H, m), 7.24 (1H, br s), 8.25-8.50 (1H, br). 03 r° 0.95-1.90 (11H, m), 3.52-4.00 (2H, m), 3.82 (3H, s), 3·84 (3H, s), 4.80-5.02 (2H, m), 6.39-6.55 (2H, m), 8.13-8.26 (1H, br). 04 3.56-3.76 (2H, m), 3.81 (3H, s), 3.83 (3H, s), 4.89 (1H, d, J = 11.0 Hz), 4.96 (lH, d, J =11.0 Hz). 62 3]4976 200410956 參考伤 (2幻_2{{1[(2,4-二甲氧基苯基）甲氧基]胺基}曱基}己酸• (1) To 240 g (606 mmol) of the well-known compound (4S) -4-Tyl-3-[(2R) -2- (fluorenylmethyl) hexyl] -2-oxazolidinone 25.0 g of 5% palladium-carbon and 1,600 ml of ethanol were subjected to contact reduction under hydrogen atmosphere while heating at 40 ° C. After the catalyst was removed by filtration, the filtrate was concentrated to obtain a solid residue. Add 300 ml of sautéed food. After heating, cool slowly while stirring. The crystals were collected by filtration, washed with hexane, and dried to obtain 177.9 g of (4S) -4-Tyl-3-[(2R) -2- (hydroxymethyl) hexyl) -2-oxazolidinone. (Yield: 96/0). 60 314976 200410956 'H-NMR (CDC13): δ / ppm 0.89 (3H, t, J = 7.0Hz), 1.0-1. 8 (6H, m), 2. 15-2.3 (1H, br s), 2 · 81 (1 H, dd, J = 9. 3, 13. 5Hz), 3 · 30 (1H, dd, J 2 3. 3, 13 · 4Hz), 3 · 7 5-4 · 0 (2H, m), 4. 1-4. 3 (2H, m), 4. 65-4 · 7 5 (1 H, m), 7 · 1 — 7 · 5 (5H, m) · (2) To the compound obtained in the preceding item, 226 ml of 30 to 35.5% hydrogen peroxide water, 350 ml of water and 1400 ml of THF were added, and an aqueous solution of 48.9 g (1.1 7 mol) of lithium hydroxide monohydrate was dropped under ice-cooling (3 50 ml). It was then stirred at room temperature for 2 hours. Under ice cooling, 330 grams of sodium sulfite was added to the reaction solution over 1.5 hours, followed by stirring at room temperature for 3 hours, and the solvent was distilled off. Water was added to the obtained residue, and the mixture was washed 4 times with gas imitation, and then the pH value was adjusted to 4 with concentrated hydrochloric acid. The free target compound was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to obtain 78.2 g of (2R) -2- (hydroxymethyl) hexanoic acid (yield 92%). ^ -NMR (CDCl3): 5 / ppm 0 · 91 (3Η, t, J = 7.〇Hz), I. 25 — 1. 48 (4H, m), 1. 48 — 1. 77 (2H, m ), 2.62 (1 3 Η, quint, J = 6.4 Hz), 3. 8 0 (2 Η, d, J = 6. 2H z). (3) 77.3 g (529 mmol) of the compound obtained from the previous item ), A well-known compound 0-[(2,4-dimethoxyphenyl) fluorenyl] hydroxylamine η 9.7 g (55 5 mmol) and 750 ml of pyridine in a mixture consisting of WSC 121.7 g (63 5mmol). After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the solution was washed in the order of 10% citric acid aqueous bath solution, saturated aqueous sodium hydrogen solution, and saturated brine. The organic layer was dried over sodium sulfate, and the solvent was distilled off. A crude solvent of 314976 61 200410956 1 72 g was added with a mixed solvent of ethyl acetate and diisopropoxide, and the precipitated crystals were collected. The obtained crystals were recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain (2R) san [(2,4-dimethoxyphenyl) methoxy ^ 2- (¾ylfluorenyl) hexyl Fe amine 119.7 g (73% yield). ^ -NMR (CDC 1 3): 5 / p pm 0.8 8 (3H, t, J-6. 8Hz), 1. · 2-1.75 (6H, m), 2 · 0-2. 6 (1H, m), 3. 6-3 · 8 (2 H, m), 3. 81 (3H, s), 3. 8 3 〇H > s), 4 · 7 7-5 · 0 (2 H, m) , 6. 4 2-6. 5 2 (2 H, m), 7. 1-7.35 (1H, m). Reference examples C-2 to C-4 are the same as the methods disclosed in reference example C-1 To obtain the compounds of Table 丨 8. Table 18 Reference examples for the production of compound (3) raw materials § 8 H? Me HMe NMR (CDCls, ppm) Re 02 Me / 0.87 (3H, br t), 1.17-1.77 (8H, .m), 2.33 * 2.66 (1H , br), 3.57-3.83 (2H, m), 3.81 (3H, s), 3.83 (3H, s), 4.77-5.00 (2H, m), 6.40-6.53 (2H, m), 7.24 (1H, br s), 8.25-8.50 (1H, br). 03 r ° 0.95-1.90 (11H, m), 3.52-4.00 (2H, m), 3.82 (3H, s), 3.84 (3H, s), 4.80 -5.02 (2H, m), 6.39-6.55 (2H, m), 8.13-8.26 (1H, br). 04 3.56-3.76 (2H, m), 3.81 (3H, s), 3.83 (3H, s), 4.89 (1H, d, J = 11.0 Hz), 4.96 (lH, d, J = 11.0 Hz). 62 3] 4976 200410956 Reference injury (2 Magic_2 {{1 [(2,4-dimethoxybenzene Group) methoxy] amino} fluorenyl} hexanoic acid

(1) 於參考例CM所獲得之化合物128·2公克（412mrn〇l)中加入三笨膦118.8公克（453mmol)、THF 1200毫升，冰冷之’慢慢添加二異丙基偶氮二羧酸酯85.4毫升（4 1 2 mmol)。在室溫下攪拌1小時後將反應液減壓濃縮，於所獲得之油狀粗製物中加入二異丙醚，慢慢攪拌，濾取所析出之結晶。將該濾液減壓濃縮，於所獲得之殘渣中加入二異丙醚及己烷之混合溶劑，邊冰冷邊慢慢攪拌，濾取所析出之結晶。將濾液減壓濃縮，獲得13 8.4公克之粗製物。 (2) 於前項所獲得之粗製物9.73公克及THF-水（3 : 1)之混合溶劑120毫升之混合物中，添加氫氧化鋰1水合物1.58 公克（3 7.5mmol)，在室溫擾拌一晚後在減壓下蒸鶴除去 THF。殘渣用乙酸乙酯洗淨後水層用鹽酸使呈酸性，用氯仿抽出。有機層用飽和食鹽水洗淨，用硫酸鈉乾燥。蒸鶴除去溶劑，獲得（211)-2{{^[(2,4-二甲氧基苯基）曱氧基]胺基}曱基}己酸7.14公克（2步驟之收率79%)。 63 314976 200410956 ΧΗ —NMR (CDCl3)：5/ppm 0· 89 (3H，t，J = 7. 1Hz)， 1· 2 5 — 1 . 4 (6 H，m)，1. 4—1· 6 (1 H, m), 1. 6 3 — 1. 8 (lH，m)，2. 65 — 2. 78 (lH，m)，3. 02 - 3. 18 (2H, m)， 3. 81 ( 3 H, s ), 3. 8 2 ( 3 H, s ), 4. 7 0 (1 H, d , J = 1 1 . OHz)，4. 7 6 (1H，d, J = ll· OHz)，6. 4 - 6. 5 (2H，m)， 7.18 — 7. 2 3 (1H, d). 參考例C-6至C-8 與參考例C-5揭示之方法同樣操作，獲得表1 9之化合(1) To the compound obtained in Reference Example CM (128. 2 g (412 mrnoll)) was added triphenylphosphine (118.8 g (453 mmol) and 1200 ml of THF), and diisopropylazodicarboxylic acid was slowly added under ice-cooling 85.4 ml of ester (4 1 2 mmol). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Diisopropyl ether was added to the obtained crude oil, and the mixture was stirred slowly, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure, a mixed solvent of diisopropyl ether and hexane was added to the obtained residue, and the mixture was slowly stirred while cooling on ice, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure to obtain 13 8.4 g of a crude product. (2) To a mixture of 9.73 g of the crude product obtained in the preceding paragraph and 120 ml of a mixed solvent of THF-water (3: 1), add 1.58 g (3 7.5 mmol) of lithium hydroxide monohydrate, and stir at room temperature After one night, the THF was removed under reduced pressure. After the residue was washed with ethyl acetate, the aqueous layer was made acidic with hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off to obtain (211) -2 {{^ [(2,4-dimethoxyphenyl) fluorenyl] amino} fluorenyl} hexanoic acid 7.14 g (yield of 79% in 2 steps) . 63 314976 200410956 X-NMR (CDCl3): 5 / ppm 0 · 89 (3H, t, J = 7. 1Hz), 1 · 2 5-1. 4 (6 H, m), 1. 4-1 · 6 (1 H, m), 1. 6 3 — 1. 8 (lH, m), 2. 65 — 2. 78 (lH, m), 3. 02-3. 18 (2H, m), 3. 81 (3 H, s), 3. 8 2 (3 H, s), 4. 7 0 (1 H, d, J = 1 1. OHz), 4. 7 6 (1H, d, J = ll · OHz ), 6. 4-6. 5 (2H, m), 7.18 — 7. 2 3 (1H, d). Reference Examples C-6 to C-8 The same operation as the method disclosed in Reference Example C-5, to obtain the table 1 of 9

表19化合物（3)前驅體之製造參考例 OMe Me〇"^> Rs ΗΝνχΛ〇〇〇Η NMR (CDCls, ppm) r8 06 Me / 0.90 (3H, t, J = 7.0 Hz), 1.20Ί.83 (8H, m), 2.67-2.78 (lH, m), 3.00*3.20 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.70 (lH, d, J =10.0 Hz), 4.76 (1H, d, J = 10.0 Hz), 6.37-6.53 (2H, m), 7.20 (lH, d, J = 8.8 Hz)· 07 0.99-2.00 (11H, m), 2.67*2.80 (iH, m), 2.99-3.22 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.72 and 4.78 (2H, AB-q, J = 11.2 Hz), 6.40-6.57 (2H, m), 7.21 (lH, d, J = 8.8 Hz). 08 2.98-3.15 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.71 (1H, d, J = 11.0 Hz), 4.76 (1H, d, J 二 11.0 Hzk 64 314976 200410956 參考例C-9 (2R)-2{{>H(2,4-二T氧基苯基）甲氧基]-Ν-甲醯基胺基}f 基}己酸Table 19 Reference examples for production of the compound (3) precursor OMe Me〇 " ^ > Rs ΗΝνχΛ〇〇〇Η NMR (CDCls, ppm) r8 06 Me / 0.90 (3H, t, J = 7.0 Hz), 1.20Ί .83 (8H, m), 2.67-2.78 (lH, m), 3.00 * 3.20 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.70 (lH, d, J = 10.0 Hz ), 4.76 (1H, d, J = 10.0 Hz), 6.37-6.53 (2H, m), 7.20 (lH, d, J = 8.8 Hz) 07 0.99-2.00 (11H, m), 2.67 * 2.80 (iH , m), 2.99-3.22 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.72 and 4.78 (2H, AB-q, J = 11.2 Hz), 6.40-6.57 (2H, m ), 7.21 (lH, d, J = 8.8 Hz). 08 2.98-3.15 (2H, m), 3.81 (3H, s), 3.82 (3H, s), 4.71 (1H, d, J = 11.0 Hz), 4.76 (1H, d, J di 11.0 Hzk 64 314976 200410956 Reference example C-9 (2R) -2 {{> H (2,4-diToxyphenyl) methoxy] -N-formamyl Amine} f group} caproic acid

於參考例C-5所獲得之（2R)_2 {{N-[(2,4·二甲氧基笨基）甲氧基]胺基}甲基}己酸丨.50公克（48mm〇l)中加入甲酸乙酯25 ^:升（3 lOmmol)，加熱回流24小時。減壓濃縮，所獲得之殘渣經由矽膠管柱層析法（氯仿/甲醇=1〇〇/ 製，獲得目的物（2R)-2{{N-[(2,4-二曱氧基苯基）曱氧基]_义甲醯基胺基}甲基}己酸1.3 5公克（收率82%)。 ^-NMR (CDC13)： δ/ppm 〇-88(3H,t,J = 7.〇Hz), 1· 2 - 1 . 7 5 (6 H, m), 2· 75 - 3· Ο (1 Η, m), 3· 75 - 3. 9 (2Η, m), 3. 8 1 (3 Η, s), 3. 8 3 (3Η, s), 4. 7-5. Ο (2Η, m), 6· 42 —6· 5 (2Η, m), 7· ΐ — 7· 2 (1Η, m), 8· 1 Ο (1H, b r s). t考例C-10至C-12 與參考例C-9揭示之方法同樣操作，獲得表2〇之化合 314976 65 200410956 表20化合物（3)之製造參考例 OMe Μθ〇"^〇 Ra o^n^Acooh NMR (CDCls, ppm) Re C-10 Me / 0.88 (3H, t, J=7.0 Hz), 1.16-1.77 (8H, m), 2.73-3.00 (1H, m), 3.50-3.97 (2H, br), 3.81 (3H, s), 3.83 (3H, s), 4.70*5.07 (1H, br), 6.33-6.55 (2H, m), 7.13 (lH, br s), 8.10 (1H, br s). C-11 r° 0.97-2.10 (11H, m), 2.83 (lH, br), 3.81 (3H, s), 3.83 (3H, s), 4.81 (2H, br), 6.43-6.53 (2H，m), 7.107.20 (1H，m), 8.10 (1H, br). 012 3.81 (3H, s), 3.82 (3H, s), 4.77-4.90 (2H, br s), 8.03-8.13 (lH, br s).(2R) _2 {{N-[(2,4 · dimethoxybenzyl) methoxy] amino} methyl} hexanoic acid} .50 g (48 mm) obtained in Reference Example C-5 ) 25 liters of ethyl formate (3 lOmmol) was added and heated under reflux for 24 hours. It was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (made by chloroform / methanol = 100 /) to obtain the target compound (2R) -2 {{N-[(2,4-dioxoxyphenyl) ) Methoxy] -s-methylaminoamino} methyl} hexanoic acid 1.35 g (82% yield). ^ -NMR (CDC13): δ / ppm 0-88 (3H, t, J = 7. 〇Hz), 1.2-1. 7 5 (6 H, m), 2.75-3 · Ο (1 Η, m), 3.75-3. 9 (2Η, m), 3. 8 1 (3 Η, s), 3. 8 3 (3Η, s), 4. 7-5. 〇 (2Η, m), 6.42 —6 · 5 (2Η, m), 7. ΐ — 7 · 2 (1Η, m), 8.1 · 10 (1H, brs). TCases C-10 to C-12 operate in the same manner as disclosed in Reference Example C-9 to obtain the compound of Table 20 314976 65 200410956 Table 20 compounds (3) Manufacturing reference example OMe Μθ〇 " ^ 〇Ra o ^ n ^ Acooh NMR (CDCls, ppm) Re C-10 Me / 0.88 (3H, t, J = 7.0 Hz), 1.16-1.77 (8H, m), 2.73-3.00 (1H, m), 3.50-3.97 (2H, br), 3.81 (3H, s), 3.83 (3H, s), 4.70 * 5.07 (1H, br), 6.33-6.55 (2H, m), 7.13 (lH, br s), 8.10 (1H, br s). C-11 r ° 0.97-2.10 (11H, m), 2.83 (lH, br), 3.81 (3H, s), 3.83 (3H , s), 4.81 (2H, br), 6.43-6.53 (2H, m), 7.107.20 (1H, m) , 8.10 (1H, br). 012 3.81 (3H, s), 3.82 (3H, s), 4.77-4.90 (2H, br s), 8.03-8.13 (lH, br s).

系列D :化合物（I-B)之製造例 D _ 1 _ 1 (2 3)-1-{(211)-3-環戊基-2-[(1^甲醯基_;^羥基胺基）曱基]丙醯基}-2-{[4-(2-嘧啶基）-1-六氫吡哄基]羰基}Π比咯烷Series D: Production Example of Compound (IB) D _ 1 _ 1 (2 3) -1-{(211) -3-cyclopentyl-2-[(1 ^ methylamidino_; ^ hydroxyamino) 曱Propyl] propionyl} -2-{[4- (2-pyrimidinyl) -1-hexahydropyridyl] carbonyl} Πpyrrolidine

⑴於實施例W之化合物582毫克(l 6mm〇i)中加入4莫 X觸毫升HC1之乙酸乙酷溶液8毫升，在室溫搜掉2 日H咸壓了蒸館除去溶劑，獲得叫2-{卜（2_。密。定基） 314976 66 200410956 -1-六氫吼D井基]羰基}吼咯烷2鹽酸鹽之粗製物。 (2) 於所項所獲得之粗製物中加入參考例u所獲得之化合物588毫克（1.6mmol)、三乙胺ΐ·ι2毫升（8.0mm〇i)、卜羥基笨并二唑1水合物217毫克〇 4min〇丨）及二氯曱烷2〇毫升’在冰冷下添加WSC 370毫克（19mm〇1)。在室溫攪拌1 8小時後加入水，分取有機層。用飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，用硫酸鎂乾燥、濃縮，經由矽膠管柱層析法（乙酸乙酯/丙酮=10/丨至丨）精製，獲得— 1-{(2ΙΌ-3-環戊基-2_{αΝ_[(2,4-二曱氧基苯基）曱氧基]^一曱L基月女基}甲基}丙驢基} -2- { [4-(2-。密咬基）-1 -六氫π比哄基]羰基}吼咯烷668毫克（收率68%)。 ^-NMR (CDC13) ： δ/ppm 0. 98-2. 20 (1 7H, m), .2. 8 7-3. 17 (1H, m), 3. 4 6-4. 12 (16H, m), 4. 6 8 一 5· 03 (3H, m)，6· 47 (2H，br s), 6. 53 (1H, t, j —4· 8Hz) ,7.17(1 H，br s), 7· 83(0· 5 5X1 H, br s) 8. 11 (0. 45X1H, br s), 8. 32 (2H, d, J-4. 8Hz). (3) 於上述生成物666毫克（l.lmmol)中加入3%三氟乙酸二氯曱烷溶液12毫升，在室溫攪拌丨7小時。在冰冷下加入飽和碳酸氫鈉水溶液，分取有機層，用飽和食鹽水洗淨後用硫酸鎂乾燥，濃縮，所獲得之粗製物經由矽膠管桎層析法（一虱曱烷/曱醇=2〇/ i至13/ υ精製，獲得目的物 (2S)-l-{(2R)-3-環戊基-2_[(Ν_甲醯基•羥基胺基）甲基]丙酿基卜2-{[4-(2“密啶基）+六氫吼哄基]幾基}[]比咯烷⑽毫克（收率77%)。 t 314976 67 200410956 MS (m/z) :4 5 9 (MH+). 'H-NMR (DM SO - c/6) ： δ/ρ Pm 〇·9〇 —2·26(18Η, m)， 3. 20 - 4· 13 (10H，m)，4· 77 —4. 96 (1H，m), 6. 67 (1H, t, J=4. 8Hz), 8. 3 9 (2H, d, J=4. 8Hz), 9. 6 8 (0· 7 x 1 H, s ), 1 0. 〇 3 (〇· 3 x 1 h，s)· 化合物（I-B-2)之鹽之製造實施例 D-l-1-1 : D-l-1 之麵 (2S) -1 - {(2R)-3-環戊基- 2-[(N-甲酿基經基胺基）甲基]丙醯基}-2-{[4-(2-嘧啶基卜六氫吡哄基]羰基}D比咯烷之鈉鹽在室溫，於實施例D-1·1之化合物2.0公克（4.36mmol) 中加入甲基異丁基甲_ 20毫升、42.8(w/ w)%氫氧化鈉水溶液〇· 1 5毫升後過濾。將濾液在室溫攪拌一晚，濾取所析出之結晶。用二異丙醚洗淨後乾燥，獲得標題化合物丨68 公克（79%、結晶體）° 融點 1 2 8— 1 3 2。(：· MS (m/z) :4 5 9 (MH+).加入 To 582 mg (16 mm) of the compound of Example W was added 4 ml X contact ml 8 ml of acetic acid ethyl acetate solution of HC1, searched at room temperature for 2 days. -{Bu (2_. Dense. Ding base) 314976 66 200410956 -1-Hydrogenol D Jingji] carbonyl} crude crude of hydrochloride 2 hydrochloride. (2) Add 588 mg (1.6 mmol) of the compound obtained in Reference Example u, triethylamine ι · 2 ml (8.0 mm), and hydroxybenzodiazole 1 hydrate to the crude obtained in the item. 217 mg (4 min) and 20 ml of dichloromethane '(370 mg (19 mm)) were added under ice-cooling. After stirring at room temperature for 18 hours, water was added and the organic layer was separated. It was washed with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate / acetone = 10 / 丨 to 丨) to obtain — 1-{(2ΙΌ- 3-cyclopentyl-2_ {αN _ [(2,4-dioxophenyl) fluorenyloxy] ^ monomethyl L-methyl} {methyl} propanyl} -2- {[4- ( 2-. Dense group) -1-Hexahydropi ratio [carbonyl] carbonyl} sparrolane 668 mg (68% yield). ^ -NMR (CDC13): δ / ppm 0. 98-2. 20 (1 7H, m), 2. 8 7-3. 17 (1H, m), 3. 4 6-4. 12 (16H, m), 4. 6 8-5.03 (3H, m), 6 · 47 (2H, br s), 6. 53 (1H, t, j — 4 · 8Hz), 7.17 (1 H, br s), 7.83 (0 · 5 5X1 H, br s) 8. 11 (0 45X1H, br s), 8. 32 (2H, d, J-4. 8Hz). (3) To the above product 666 mg (l.l mmol) was added 12% 3% trifluoroacetic acid dichloromethane solution Stir at room temperature for 7 hours. Add a saturated sodium bicarbonate aqueous solution under ice cooling, separate the organic layer, wash with saturated brine, dry over magnesium sulfate, and concentrate. The obtained crude product is subjected to silica gel tube chromatography. (Monoxane / Methanol = 2〇 / i to 13 / υ refined to obtain the target product (2S ) -l-{(2R) -3-Cyclopentyl-2 _ [(N_methylamido • hydroxyamino) methyl] propanyl 2-{[4- (2 "melidinyl) + six Hydroxyl group] several groups} [] than pyrrolidine mg (yield 77%). T 314976 67 200410956 MS (m / z): 4 5 9 (MH +). 'H-NMR (DM SO-c / 6): δ / ρ Pm 0.90-2.26 (18Η, m), 3. 20-4.13 (10H, m), 4.77-4.96 (1H, m), 6.67 (1H, t, J = 4.8 Hz), 8. 3 9 (2H, d, J = 4.8 Hz), 9. 6 8 (0.7 x 1 H, s), 1 0. 〇3 (〇 · 3 x 1 h, s) · Production Example of Salt of Compound (IB-2) Dl-1-1: Face of Dl-1 (2S) -1-{(2R) -3-cyclopentyl-2 -[(N-methylaminomethyl) methyl] propanyl} -2-{[4- (2-pyrimidinylhexahydropyridyl] carbonyl} D than sodium salt of pyrrolidine in the chamber To 2.0 g (4.36 mmol) of the compound of Example D-1 · 1, 20 ml of methyl isobutyl formamide and 42.8 (w / w)% aqueous sodium hydroxide solution of 0.15 ml were added and filtered. The filtrate was stirred at room temperature overnight, and the precipitated crystals were collected by filtration. After washing with diisopropyl ether and drying, 68 g (79%, crystals) of the title compound were obtained. Melting point 1 2 8— 1 3 2. (: · MS (m / z): 4 5 9 (MH +).

元素分析 C46H67Nl2Na〇8 · 2H2〇理論值（％) : c，5 6. 6 6 ; Η, 7. 3 4 ; Ν, 17. 2 4 ; N a , 2. 3 6.測定值（％) : C, 5 6 · 53; Η, 7. 22 ;Ν, 17. 15;Na, 2. 42. 'H-NMR (CDC 13):δ/ρρπι 0·97 — 2·30(16Η, m), 3. 17 - 4. 〇5(ι 2 Η, m), 4 · 8 9 - 5 · 0 〇 (1 Η, m)，6 · 5 2 (1 Η, t, J = 4 . 7Elemental analysis C46H67Nl2Na〇8 · 2H2O Theoretical value (%): c, 5 6. 6 6; Thallium, 7. 3 4; N, 17. 2 4; Na, 2. 3 6. Measured value (%): C, 5 6 · 53; Η, 7. 22; N, 17. 15; Na, 2. 42. 'H-NMR (CDC 13): δ / ρρπι 0 · 97 — 2 · 30 (16Η, m), 3. 17-4. 〇5 (ι 2 Η, m), 4 · 8 9-5 · 0 〇 (1 Η, m), 6 · 5 2 (1 Η, t, J = 4.7

Hz), 7. 65 (1 H, s)，8· 31 (2 H, d, J=4. 7Hz). 以實施例D-l-l-l揭示之方法為基準，製造以下之鹽 ° 314976 68 200410956 表21化合物（I-B-2)之鹽之製造實施例金屬鹽/試藥融點、MS、元素分析 NMR (CDCla, ppm) D-1-1-2 D-1-1之K鹽 (結晶體） /K2C〇3 融點：136-139°C. MS (m/z): 459 (MH+). 元素分析·· α6Η67ΚΝ12〇8·Η2〇理論值(％): C, 56.77; Η, 7·15; Κ，4.02; Ν，17.27. 測定值(％): C, 56·57; Η, 7.21; Κ, 4.03; Ν, 17.25. NMR: 0.97-2.26 (16Η，m), 3.15-3.35 (2Η, m), 3.44-4.09 (10Η, m), 4.88-4.98 (1H, m), 6.52 (lH, t, J =4.8 Hz), 7.64 (1H, s), 8.33 (2H, d, J = 4.8Ήζ). D-1-1-3 D-1-1之 C a 鹽 (結晶體） /Ca(OH)2 融點：178-181°C. MS (m/z)： 459 (MH+). 元素分析：C46H6eCaN12CV4H2〇理論值(％): C, 53·78; H, 7.26; N, 16.36; Ca, 3.90. 測定值(％): C, 53·69; H, 7.28; N, 16.28; Ca，3.90. NMR： 0.97-2.43 (16H, m), 3.37-4.17 (12H, m), 6.51 (1H, t, J = 4.7 Hz), 7.46 (lH, s), 8.31 (2H, d, J = 4.7 Hz). 實施例D-1-1-4 (2S)-l-{(2R)-3-環戊基-2-[(N-甲醯基-N-羥基胺基）甲基]丙醯基}-2-{[4-(2_嘧啶基）-1-六氫吡啡基]羰基}吼咯烷鹽酸Hz), 7. 65 (1 H, s), 8.31 (2 H, d, J = 4.7 Hz). Based on the method disclosed in Example D111, the following salts were produced ° 314976 68 200410956 Table 21 Compounds Production Examples of (IB-2) Salts Metal salt / Reagent melting point, MS, Elemental analysis NMR (CDCla, ppm) D-1-1-2 D-1-1 K salt (crystal) / K2C. 3 Melting point: 136-139 ° C. MS (m / z): 459 (MH +). Elemental analysis ·· α6Η67ΚΝ12〇8 · Η20 Theoretical value (%): C, 56.77; Η, 7.15; Κ, 4.02; Ν, 17.27. Measured value (%): C, 56 · 57; Η, 7.21; Κ, 4.03; Ν, 17.25. NMR: 0.97-2.26 (16Η, m), 3.15-3.35 (2Η, m), 3.44-4.09 (10Η, m), 4.88-4.98 (1H, m), 6.52 (lH, t, J = 4.8 Hz), 7.64 (1H, s), 8.33 (2H, d, J = 4.8Ήζ). D -1-1-3 D-1-1 Ca salt (crystal) / Ca (OH) 2 Melting point: 178-181 ° C. MS (m / z): 459 (MH +). Elemental analysis: C46H6eCaN12CV4H2. Theoretical value (%): C, 53 · 78; H, 7.26; N, 16.36; Ca, 3.90. Measured value (%): C, 53 · 69; H, 7.28; N, 16.28; Ca, 3.90. NMR: 0.97-2.43 (16H, m), 3.37-4.17 (12H, m), 6.51 (1H, t, J = 4.7 Hz), 7.46 (lH, s), 8.31 (2H, d, J = 4.7 Hz ). Example D-1-1-4 (2S) -l-{(2R) -3-Cyclopentyl-2-[(N-formamyl-N-hydroxyamino) methyl] propanyl } -2-{[4- (2_pyrimidinyl) -1-hexahydropyridinyl] carbonyl} sylrolidine hydrochloride

將實施例D -1 -1之化合物9 0 3毫克（2 · 0 m m ο 1)溶解於乙酸乙酯60毫升，在冰冷下加入4莫耳/ 1 000毫升HC1之乙酸乙酯溶液1 · 2毫升。減壓濃縮後加入***，濾取析出物，乾燥，獲得目的物9 1 4毫克（9 1 %)。 69 314976 200410956 MS (m/z) :4 5 9 (MH+).元素分析 C 2 3h3 5 C 1 N6 〇 4 · 0 · 8 H2〇理論值（％) C，5 4· 2 3 ; H, 7· 2 4 ; N，1 6. 5 〇；C 1 , 6· 9 6.測定值（％) C，5 4. 4 7 ; H, 7· 1 8 ; N, 1 6. 1 5 ; C 1 , 7.06· 'H-NMR (DM SO- d 6) : δ/ρ pm 〇· 97 —2· 21 (15H, m), 2· 90 - 4· 60 (13H, m), 4. 75 —4· 95 (1H， m), 6. 7 0 (1 H, t, 1=4. 8Hz), 7. 76 and 7. 85 (t otal 1H, both s )，8 · 4 1 ( 2 H, d , J = 4 · 8 H z ) · 化合物（I-E)之製造實施例D-1-2 (2S)-1-{(2R)-3-環戊基-2-{[N-曱醯基萘醯氧基）胺基] 曱基}丙醯基}-2_{[4-(2-嘧啶基）-1-六氫吡畊基]羰基}[]比咯烷903 mg (2.0 mm) of the compound of Example D -1 -1 was dissolved in 60 ml of ethyl acetate, and 4 mol / 1 000 ml of an ethyl acetate solution of HC1 was added under ice-cooling 1 · 2 Ml. After concentration under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration and dried to obtain 914 mg (91%) of the target compound. 69 314976 200410956 MS (m / z): 4 5 9 (MH +). Elemental analysis C 2 3h3 5 C 1 N6 〇 4 · 0 · 8 H 2 0 Theoretical value (%) C, 5 4 · 2 3; H, 7 · 2 4; N, 16. 5 0; C 1, 6 · 9 6. Measured value (%) C, 5 4. 4 7; H, 7. 1 8; N, 1 6. 1 5; C 1 , 7.06 · 'H-NMR (DM SO- d 6): δ / ρ pm 〇 97 —2 · 21 (15H, m), 2 · 90-4 · 60 (13H, m), 4. 75 —4 · 95 (1H, m), 6. 7 0 (1 H, t, 1 = 4.8 Hz), 7. 76 and 7. 85 (t otal 1H, both s), 8 · 4 1 (2 H, d , J = 4 · 8 H z) · Production Example of Compound (IE) D-1-2 (2S) -1-{(2R) -3-cyclopentyl-2-{[N-fluorenylnaphthalene Alkoxy) amino] fluorenyl} propanyl} -2 _ {[4- (2-pyrimidinyl) -1-hexahydropyridyl] carbonyl} [] pyrrolidine

將声、施例D-1 -1之化合物2 3 0笔克（〇 ·5 mm〇 1)溶解於口啶5毫升，在室溫加入h萘醯氯1〇5毫克（〇.55mm〇i)，在同溫度搜拌2G小時。纟机減壓蒸鶴除去反應液後將殘匕/主入矽取g柱層析儀（氯仿/甲醇=1 / 〇至2 0 / 1)，溶出物用曱醇-水結晶化。濾取所析出之結晶後將結晶用水洗甲所獲付之結晶在8(Γ(：乾燥5小時，獲得目的物外 ((2R) J衣戊基·2][Ν-曱醯基~N-(2·萘醯氧基）胺基]曱基；丙L基；2-{[4-(2-嘧啶基六氫吡哄基]羰基丨吼咯烷 314976 70 200410956 237毫克（77%，結晶體）。融點 16 2〜16 3°C· MS (m/z ) :613 (MH+). 元素分析 C34H40N6〇5 理論值（％) : C，6 6· 6 5 ; H，6· 5 8 ; N， 13. 7 2.測定值（％) ·· C, 6 6· 5 4 ; H，6. 5 9 ; N, 1 3. 6 7. lH~NMR (CDC 1 3) : δ/ρ pm 1.00—1.30 (2H，m)，l· 35 - 2. 25 (13H，m), 2.75 - 3· 20 (1H，m), 3. 30 - 4· 05 (llH，m), 4. 10 — 4· 30 (1H, m), 4· 7 0 —4.80 (1 H, b r s), 6. 53 (1H, t, J=4. 8Hz), 7. 6 0 - 7. 8 0 (2 H，m), 7. 80 — 8. 05 (4H, m), 8· 10 —8· 45 (1H, br s), 8.3 2 (2H, d, J=4. 8Hz), 8.6 8 (1 H, s). 實施例D-1-3至D-1-9 與實施例D-1 -2揭示之方法同樣操作，獲得以下之化合物。表22化合物（i_e)之製造實施例構造式融點、MS、元素分析 NMR (CDCla, ppm) D-1-3 Η? P 結晶體融點：227〜228°C. MS (m/z): 602 (MH+)· 元素分析：C32H39N7〇5 理論值(％): C，63.88; Η, 6.53; Ν, 16·30· 測定值(％): C, 63.61; Η, 6·55; Ν, 16.17. NMR： 0.95-1.30 (2Η, m), 1.30*2.25 (13Η, m), 2,80-3.20 (1Η, m), 3.25.4.05 (llH, m), 4.05*4.40 (1H, m), 4.60*4.75 (iH, br s), 6.53 (1H, t, J = 4.8 Hz), 7.05-7.50 (4H, m), 7.70 (1H, d, J = 8.3 Hz), 8.15-8.40 (lH, m), 8.32 (2H, d, J = 4.8 Hz), 9.35-9.70 (lH, br s). D'l-4 Me f〇〇。工〇{》結晶體融點：94-96°C. MS (m/z): 641 (MH+)· 元素分析：〇34Η52Ν6〇6·〇.75ΪΪ2〇理論值(％): C, 62·41; Η, 8.24; Ν, 12·84. 測定值(％)·· C, 62.34; Η, 8.34; Ν, 12.91. NMR*· 0·80·1·26 (17Η, m), 1.41-2.21 (16Η, m), 3.03 (1Η, m), 3.46-4.14 (12H, m), 4.63 (1H, m), 4.89 (iH, m), 6.54 (lH, t, J = 4.8 Hz), 7.98 (1H, s), 8.32 (2H, d, J = 4.8 Hz). 71 314976 200410956 ϋΊ·5 s? 〇r"o o〇 NMR： 0.86-2.18 (15H, m), 4.85-4.88 (lH, m), 6.54 (1H, d, J = 4.8 Hz), 7.21 (lH, m), 7.72 (1H, d, J = 4.8 Hz), 7.95 (lH, d, J = 3.3 Hz), 8.32 (2H, d, J = 4.8 Hz). D*1'6 ?sj& NMR： 0.88-2.18 (15H, m), 4.86*4.89 (lH, m), 6.54 (1H, d, J = 4.8 Hz), 6.61-6.63 (lH, m), 7.38 (1H, d, J = 3.5 Hz), 7.69 (lH, m), 8.32 (2H, d, J = 4.8 Hz). D-l-7 0*^9 NMR： 1.10-2.18 (19H, m), 4.86-4.91 (1H, m), 6.54 (1H, d, J = 4.7 Hz), 8.32 (2H, d, J = 4.7 Hz). D-l-8 NMR: 1.10-2.18 (21H, m〉，4.87-4.93 (1H, m), 6.54 (1H, d, J = 4.8 Hz), 8.32 (2H, d, J = 4.8 Hz)· D-l-9 2 NMR： 1.10-2.19 (19H, m), 4.86*4.90 (1H, m), 6.54 (1H, d, J = 4.8 Hz), 8.32 (2H, d, J = 4.8 Hz). 實施例D-l-10 Φ (23)-1-{(21〇-3-環戊基-2-{[>^甲醯基->^(1-萘醯氧基）胺基] 甲基}丙醯基}-2-{[4-(2-嘴。定基）-1-六氫[|比。定基]羰基”比17各烧Dissolve 230 grams (0.5 mm) of the compound of Example D-1 -1 in 5 ml of pyridine, and add 105 mg (0.55 mm) of naphthalene chloride at room temperature. ), Search for 2G hours at the same temperature. After removing the reaction solution by using a decompression steamer, the residual solution / mainly passed through a silica gel column chromatography (chloroform / methanol = 1/0 to 20/1), and the eluate was crystallized with methanol-water. The precipitated crystals were collected by filtration, and the crystals obtained by washing the crystals with water were dried at 8 ° (Γ (: dried for 5 hours to obtain the target compound ((2R) J-amyl · 2) [N-fluorenyl ~ N -(2 · naphthyloxy) amino] fluorenyl; propanyl; 2-{[4- (2-pyrimidinylhexahydropyridinyl) carbonyl; n-pyrrolidine 314976 70 200410956 237 mg (77%, Crystal) Melting point 16 2 ~ 16 3 ° C · MS (m / z): 613 (MH +). Elemental analysis C34H40N6 05 Theoretical value (%): C, 6 6 · 6 5; H, 6 · 5 8 N, 13. 7 2. Measured value (%) ·· C, 6 6 · 5 4; H, 6. 5 9; N, 1 3. 6 7. lH ~ NMR (CDC 1 3): δ / ρ pm 1.00—1.30 (2H, m), l · 35-2. 25 (13H, m), 2.75-3. · 20 (1H, m), 3. 30-4. 05 (llH, m), 4. 10 — 4 · 30 (1H, m), 4. 7 0 —4.80 (1 H, brs), 6. 53 (1H, t, J = 4.8 Hz), 7. 6 0-7. 8 0 (2 H M), 7. 80 — 8. 05 (4H, m), 8.10 — 8.45 (1H, br s), 8.3 2 (2H, d, J = 4.8 Hz), 8.6 8 (1 H s). Examples D-1-3 to D-1-9 were carried out in the same manner as the method disclosed in Example D-1-2, and the following compounds were obtained. Table 22 Production Example of Compound (i_e) Structural Formula Melting Point , MS, element Analytical NMR (CDCla, ppm) D-1-3 Η? P Crystal melting point: 227 ~ 228 ° C. MS (m / z): 602 (MH +) · Elemental analysis: C32H39N705 Theoretical value (%): C , 63.88; Η, 6.53; Ν, 16.30 · Measured value (%): C, 63.61; Η, 6.55; Ν, 16.17. NMR: 0.95-1.30 (2Η, m), 1.30 * 2.25 (13Η, m), 2,80-3.20 (1Η, m), 3.25.4.05 (llH, m), 4.05 * 4.40 (1H, m), 4.60 * 4.75 (iH, br s), 6.53 (1H, t, J = 4.8 Hz), 7.05-7.50 (4H, m), 7.70 (1H, d, J = 8.3 Hz), 8.15-8.40 (lH, m), 8.32 (2H, d, J = 4.8 Hz), 9.35-9.70 ( 1H, br s). D'l-4 Me f〇〇.工〇 {"Crystal melting point: 94-96 ° C. MS (m / z): 641 (MH +) · Elemental analysis: 〇34Η52N6〇〇.75ΪΪ20 Theoretical value (%): C, 62 · 41; Η, 8.24; Ν, 12.84. Measured value (%) · C, 62.34; Η, 8.34; Ν, 12.91. NMR * · 0 · 80 · 1 · 26 (17Η, m), 1.41-2.21 (16Η , m), 3.03 (1Η, m), 3.46-4.14 (12H, m), 4.63 (1H, m), 4.89 (iH, m), 6.54 (lH, t, J = 4.8 Hz), 7.98 (1H, s), 8.32 (2H, d, J = 4.8 Hz). 71 314976 200410956 ϋΊ · 5 s? 〇r " oo〇NMR: 0.86-2.18 (15H, m), 4.85-4.88 (lH, m), 6.54 ( 1H, d, J = 4.8 Hz), 7.21 (lH, m), 7.72 (1H, d, J = 4.8 Hz), 7.95 (lH, d, J = 3.3 Hz), 8.32 (2H, d, J = 4.8 Hz). D * 1'6? Sj & NMR: 0.88-2.18 (15H, m), 4.86 * 4.89 (lH, m), 6.54 (1H, d, J = 4.8 Hz), 6.61-6.63 (lH, m ), 7.38 (1H, d, J = 3.5 Hz), 7.69 (lH, m), 8.32 (2H, d, J = 4.8 Hz). Dl-7 0 * ^ 9 NMR: 1.10-2.18 (19H, m) , 4.86-4.91 (1H, m), 6.54 (1H, d, J = 4.7 Hz), 8.32 (2H, d, J = 4.7 Hz). Dl-8 NMR: 1.10-2.18 (21H, m>, 4.87- 4.93 (1H, m), 6.54 (1H, d, J = 4.8 Hz), 8.32 (2H, d, J = 4.8 Hz) Dl-9 2 NMR: 1.10-2.19 (19H, m), 4.86 * 4.90 (1H, m), 6.54 (1H, d, J = 4.8 Hz), 8.32 (2H, d, J = 4.8 Hz). Example Dl-10 Φ (23) -1-{(21〇-3-cyclopentyl-2-{[> ^ methylamido- > ^ (1-naphthalenyloxy) amino] methyl} propanyl} -2-{[4- (2-mouth. (Fixed base) -1-hexahydro [| ratio. Fixed group] carbonyl "than 17 each

於實施例D-1-1之化合物23〇毫克（O^mmoi；)、^蔡曱酸104毫克（0.5mmol)及氯仿1 0毫升之混合物中加入Wsc 314976 72 200410956 115笔克（0.5111111〇1)、〇]\4八？31毫克（〇.5111111〇1)，在室溫授拌j小時。將反應液減壓濃縮，所獲得之殘渣注入石夕膠管柱層析儀（氯仿/甲醇=1/0至1〇/ υ，溶出物用甲醇-水結晶化。濾取所析出之結晶後將結晶用水洗淨後乾燥，獲得標題化合物274毫克（89%，結晶體）。融點 1 5 6 〜1 5 7 C. M S (m/ z ) : 6 1 3 (MH + ) 元素分析 C34H4()N605 理論值（％) :c, 66· 65;Η，6· 58;N， 1 3· 7 2‘ 測定值（％):(：,6 6.4 4;反6.62;队13.7〇· ^-NMR (CDC13) ： δκρρπι 1. 0 0-1. 3 0 (2H, m)； 1. 35 - 2· 25 (13H, m), 2· 75 —3· 20 (2H, m), 3· 30 - 4· 05 (11Η, m)，4· 10 —4. 30 (1Η, m), 4· 70 —4· 80 (1 Η, br s), 6· 54 (1Η, t，J=4. 8Ηζ), 7· 45 - 7· 75 (3 Η, m), 7· 8 5 - 8. 0 5 (1 Η, m)，8· 10一8· 2〇 (1Η, m), 8· 20 — 8· 40 (1Η，m) 8. 32 (2Η, d, J=4· 8Ηζ), 8· 7 5-8· 8 5 (1Η, m). 實施例D-l-1 1至D-1-h 與貫施例D-1 -1 〇揭示之方法同樣操作，獲得以下之化合物。 3)4976 73 200410956 表23化合物（I-E)之製造實施例構造式融點、MS、元素分析 NMR (CDC13, ppm)Wsc 314976 72 200410956 115 pens (0.5111111〇1) was added to a mixture of 23 mg (Ommoi;) of the compound of Example D-1-1, 104mg (0.5mmol) of ceramic acid and 10ml of chloroform ), 〇] \ 4 八? 31 mg (0.5111111〇1), and stirred at room temperature for j hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was injected into a Shixi gel column chromatography (chloroform / methanol = 1/0 to 10 / υ, and the eluate was crystallized with methanol-water. The precipitated crystals were collected by filtration and The crystals were washed with water and dried to obtain 274 mg (89%, crystals) of the title compound. Melting point 1 5 6 ～ 1 5 7 C. MS (m / z): 6 1 3 (MH +) Elemental analysis C34H4 () N605 Theoretical value (%): c, 66 · 65; Η, 6. 58; N, 1 3 · 7 2 'Measured value (%): (:, 6 6.4 4; trans 6.62; team 13.7〇 ^ -NMR ( CDC13): δκρρπι 1. 0 0-1. 3 0 (2H, m); 1. 35-2.25 (13H, m), 2.75 — 3.20 (2H, m), 3.30-4 · 05 (11Η, m), 4.10 — 4. 30 (1Η, m), 4.70 — 4.80 (1 Η, br s), 6.54 (1Η, t, J = 4. 8Ηζ) , 7.45-7.75 (3 Η, m), 7. 8 5-8. 0 5 (1 Η, m), 8.10-8.20 (1Η, m), 8.20 — 8 · 40 (1Η, m) 8. 32 (2Η, d, J = 4 · 8Ηζ), 8. 7 5-8 · 8 5 (1Η, m). Examples Dl-1 1 to D-1-h and The method disclosed in Example D-1 -1 was performed in the same manner to obtain the following compounds: 3) 4976 73 200410956 Table 23 Production of Compound (IE) Constructed of formula melting point, MS, elemental analysis NMR (CDC13, ppm)

結晶體融點·· 126〜127°C. MS (m/z): 614 (MH+). 元素分析：C33H39N7O5 理論值(％): C, 64·58; Η, 6·41; N，15.98. 測定值(％): C，63.37; H, 6.23; N, 15.76. NMR： 0.95Ί.26 (2H, m), 1.27-2.25 (13H, m), 2.90-3.20 (1H, m), 3.30-4.00 (llH, m), 4.20-4.30 (1H, m), 4.70-4.80 (lH, br s), 6.53 (1H, t, J = 4.8 Hz), 7.60*7.75 (lH, m), 7.80-8.05 (2H, m), 8.10-8.45 (4H, m), 8.94 (lH, s), 9.30*9.50 (lH, br s). . D-1-12Crystal melting point · 126 ~ 127 ° C. MS (m / z): 614 (MH +). Elemental analysis: C33H39N7O5 Theoretical value (%): C, 64 · 58; Thallium, 6.41; N, 15.98. Determination Value (%): C, 63.37; H, 6.23; N, 15.76. NMR: 0.95Ί.26 (2H, m), 1.27-2.25 (13H, m), 2.90-3.20 (1H, m), 3.30-4.00 (llH, m), 4.20-4.30 (1H, m), 4.70-4.80 (lH, br s), 6.53 (1H, t, J = 4.8 Hz), 7.60 * 7.75 (lH, m), 7.80-8.05 ( 2H, m), 8.10-8.45 (4H, m), 8.94 (lH, s), 9.30 * 9.50 (lH, br s) ... D-1-12

結晶體融點：144〜146°C. MS (m/z): 579 (MH+). 元素分析：C3〇H38N6〇6 理論值(％): C, 62.27; H, 6.62; N, 14.52. 測定值(％): C, 62.28; H, 6.51; N, 14.54. NMR： 0.95-1.30 (2H, m), 1.30*2.25 (13H, m), 2.90-3.20 (lH，m)，3.30-4.10 (11H, m), 4.15-4.40 (1H, m), 4.70-4.80 (1H, br s), 6.54 (1H, t, J = 4.8 Hz), 6.97 (1H, t, J = 7.8 Hz), 7.07 (lH, t, J = 8.3 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.87 (lH, t, J = 8.3 Hz), 8.1-8.4 (1H, br s), 8.32 (2H, d, J = 4.8 Hz), 9.70-10.20 (1H, br s)._ D-1-13Crystal melting point: 144 ~ 146 ° C. MS (m / z): 579 (MH +). Elemental analysis: C30H38N6〇6 Theoretical value (%): C, 62.27; H, 6.62; N, 14.52. Measured value (%): C, 62.28; H, 6.51; N, 14.54. NMR: 0.95-1.30 (2H, m), 1.30 * 2.25 (13H, m), 2.90-3.20 (lH, m), 3.30-4.10 (11H , m), 4.15-4.40 (1H, m), 4.70-4.80 (1H, br s), 6.54 (1H, t, J = 4.8 Hz), 6.97 (1H, t, J = 7.8 Hz), 7.07 (lH , t, J = 8.3 Hz), 7.58 (1H, t, J = 7.8 Hz), 7.87 (lH, t, J = 8.3 Hz), 8.1-8.4 (1H, br s), 8.32 (2H, d, J = 4.8 Hz), 9.70-10.20 (1H, br s) ._ D-1-13

結晶體融點：156〜157°C. MS (m/z): 613 (MH+). 元素分析：C34H4GN6〇5 理論值(％): C, 66.65; H, 6.58; N, 13.72. 測定值(％): C, 66.44; H, 6.62; N, 13.70. NMR： 1.00-1.30 (2H, m), 1.35-2.25 (13H, m), 2.75-3.20 (2H, m), 3.30-4.05 (llH, m), 4.10-4.30 (lH, m), 4.70-4.80 (lH, br s), 6.54 (lH, t, J = 4.8 Hz), 7.45-7.75 (3H, m), 7.85-8.05 (lH, m), 8.10-8.20 (1H, m), 8.208.40 (1H, m), 8·32 (2H, d, J - 4.8 Hz), 8.75~8.85 (lH, m)._Crystal melting point: 156 ~ 157 ° C. MS (m / z): 613 (MH +). Elemental analysis: C34H4GN6O5 Theoretical value (%): C, 66.65; H, 6.58; N, 13.72. Measured value (% ): C, 66.44; H, 6.62; N, 13.70. NMR: 1.00-1.30 (2H, m), 1.35-2.25 (13H, m), 2.75-3.20 (2H, m), 3.30-4.05 (llH, m ), 4.10-4.30 (lH, m), 4.70-4.80 (lH, br s), 6.54 (lH, t, J = 4.8 Hz), 7.45-7.75 (3H, m), 7.85-8.05 (lH, m) , 8.10-8.20 (1H, m), 8.208.40 (1H, m), 8.32 (2H, d, J-4.8 Hz), 8.75 ~ 8.85 (lH, m) ._

D-1-14 ocA〇<p> 結晶體融點：180〜183°C. MS (m/z): 552 (MH+). 元素分析·· C28H37N7O5 理論值(％): C, 60.96; Η, 6·76; N, 17.77. 測定值(％):(3,60.81;11，6.78;；^，17.85· NMR： 0.95-1.30 (2H, m), 1.30-2.25 (13H, m), 2.90-3.20 (1H, m), 3.30-4.05 (llH, m), 4.05-4.30 (1H, m), 4.70-4.80 (lH, br s), 6.25-6.45 (lH, br s), 6.53 (1H, t, J = 4.8 Hz), 6.80-7.20 (2H, m), 8.10 (0.65 x 1H, s), 8.25 (0.35 x 1H, s), 8.32 (2H, d, J = 4.8 Hz), 9.56 (0.65 x 1H，s)，9.79 (0.35 x 1H，s). 74 3]4976 200410956 實施例D-l-15 (28)-1-{(211)-3-環戊基-2-{{1^-{[(3 8)-253,4,5-四氫-4,4-二甲基-2-氧代基-3-咲喃基]氧基羰基氧基卜义甲醯胺基）甲基}丙醯基>2-{[4-(2-嘧咬基）-1_六氫吡哄基]羰基丨吡咯烷D-1-14 ocA〇 < p > Crystal melting point: 180 ~ 183 ° C. MS (m / z): 552 (MH +). Elemental analysis · C28H37N7O5 Theoretical value (%): C, 60.96; Η, 6.76; N, 17.77. Measured value (%): (3,60.81; 11,6.78 ;; ^, 17.85 · NMR: 0.95-1.30 (2H, m), 1.30-2.25 (13H, m), 2.90- 3.20 (1H, m), 3.30-4.05 (llH, m), 4.05-4.30 (1H, m), 4.70-4.80 (lH, br s), 6.25-6.45 (lH, br s), 6.53 (1H, t , J = 4.8 Hz), 6.80-7.20 (2H, m), 8.10 (0.65 x 1H, s), 8.25 (0.35 x 1H, s), 8.32 (2H, d, J = 4.8 Hz), 9.56 (0.65 x 1H, s), 9.79 (0.35 x 1H, s). 74 3] 4976 200410956 Example Dl-15 (28) -1-{(211) -3-cyclopentyl-2-{{1 ^-{[ (3 8) -253,4,5-tetrahydro-4,4-dimethyl-2-oxo-3-fluoranyl] oxycarbonyloxy (methylformamido) methyl) propyl Amidino > 2-{[4- (2-pyrimidinyl) -1_hexahydropyridyl] carbonylcarbonylpyrrolidine

(1) 於（L)-泛酸内酯645毫克（4.96mmol)中加入[[比。定1〇毫升、二氯曱烧20毫升、氯曱酸4-硝基笨酯1 ·〇〇公克 (4.96mmol)及 DMAP 61 毫克（〇.496mmol)，在室溫攪拌一晚。在減壓下蒸館除去溶劑後加入水、乙酸乙酯，分取有機層，用飽和食鹽水洗淨後用硫酸鈉乾燥，濃縮，所獲得之粗製物經由矽膠管柱層析法（乙酸乙酯/正己烷=丨〆4) 精製，獲得（3S)-2,3,4,5-四氫-4,4-二甲基-3-[(4-硝基笨氧基） .基氧基]-2 -氧代D夫喃8 3 0毫克（收率5 7 %)。 ^-NMR (CDC13) ： δ/ppm 1. 23 (3 H, s), 1. 32 (3 H，s)，4·〇6 —4. 15 (2H, m), 5· 25 (1H，s)，7· 46 (2 H, d，了二9. 3H z), 8. 3 1 (2H, d, J = 9. 3Hz)· (2) 於上述生成物193毫克（〇 654rnni〇i)中加入實施例n 1所獲仔之化合物200毫克（0.43 6mmol)、D比α定2毫升及 DMAP 5.3毫克（〇.〇43 6mmol) ’在室溫攪拌一晚。在減厣下蒸餘除去溶劑，加入水、乙酸乙酯，分取有機層，用釣矛食鹽水洗淨後用硫酸鈉乾燥，濃縮，所獲得之粗製物細由石夕膠管柱層析法（乙酸乙酯/正己烷=4/ 1至氯 314976 75 200410956 υ精製’用水-甲醇再結晶’獲得目的物（叫小 {(2R)-3-環戊基-2-{{N_{[(3S)_2,3,4,5_ 四氫 _4,4_二甲基 j 氧代基-3-呋喃基]氧基羰基氧基}_N_甲醯胺基}甲基^丙酿基} 2-{ [4-(2-¾啶基）_丨_六氫吼哄基]羰基丨卩比咯烷22〇毫克 (收率82%、結晶體）。峡點！55-157。。· MS (m/ z ) : 6 1 5 (MH+).(1) To (L) -pantolactone 645 mg (4.96 mmol) was added [[ratio. 10 ml, 20 ml of dichloromethane, 1.0 g (4.96 mmol) of 4-nitrobenzyl chloroacetate and 61 mg (0.496 mmol) of DMAP were stirred and stirred at room temperature overnight. After removing the solvent under reduced pressure, water and ethyl acetate were added. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate Esters / n-hexane = 丨〆4) Refined to obtain (3S) -2,3,4,5-tetrahydro-4,4-dimethyl-3-[(4-nitrobenzyloxy) .oxy Benzyl] -2-oxo-D-furan 830 mg (yield 57.7%). ^ -NMR (CDC13): δ / ppm 1. 23 (3 H, s), 1. 32 (3 H, s), 4.0 · 4-15.15 (2H, m), 5.25 (1H, s), 7.46 (2 H, d, 2.9.3 H z), 8. 3 1 (2H, d, J = 9. 3 Hz) · (2) 193 mg (〇654rnni〇i) of the above product ) Add 200 mg (0.43 6 mmol) of the compound obtained in Example n1, 2 mL of D ratio α and 5.3 mg (0.043 6 mmol) of DMAP, and stir at room temperature overnight. The solvent was removed under reduced pressure, and water and ethyl acetate were added. The organic layer was separated, washed with fishing spear brine, dried over sodium sulfate, and concentrated. The crude product obtained was purified by Shixi column chromatography (Ethyl acetate / n-hexane = 4/1 to chlorine 314976 75 200410956 υ Refined 'water-methanol recrystallization' to obtain the target substance (called small {(2R) -3-cyclopentyl-2-{{N _ {[( 3S) _2,3,4,5_tetrahydro_4,4_dimethylj oxo-3-furanyl] oxycarbonyloxy} _N_formamido} methyl ^ propanyl} 2 -{[4- (2-¾pyridyl) _ 丨 _Hexahydrocarbyl] carbonylcarbonylpyrrolidine 22 mg (82% yield, crystal). Gap point! 55-157 ... · MS ( m / z): 6 1 5 (MH +).

711 素分析（330Η42Ν6〇8·0· 2 5H2〇理論值（％):C, 5 8· 19; Η， 6* 9 2 ; Ν, 13. 4 3.測定值（％) : C, 5 8. Ο Ο ; Η，6 · 9 0 ; Ν，1 3· 9 7· 'H-NMR (CDCl3)：5//ppm 1. 20(6 Η，m)> 1· 30 (3Η, s), 1· 4 7-1. 6 1 (6Η, m), 1· 7 1 - 2 * 17 (6Η, m), 3. 05 (1Η, m), 3. 69-4. 12 (14 H, m), 4· 9 5 (1 H, m)，5· 1 5 (1Η, m), 6. 5 3 (1 H, t, J = 4. 8 Hz)，8. 0 5 (1 H, s), 8· 32 (2H，d, J=4. 8Hz). D-l-16 至 D小 18 與實施例D-1 -1 5揭示之方法同樣操作，獲得以下之化合物。711 voxel analysis (330Η42N60.8 · 2 5H2O theoretical value (%): C, 5 8 · 19; Η, 6 * 9 2; Ν, 13. 4 3. Measured value (%): C, 5 8 Ο Ο; Η, 6 · 9 0; Ν, 1 3 · 9 7 · 'H-NMR (CDCl3): 5 // ppm 1. 20 (6 Η, m) > 1 · 30 (3Η, s) , 1 · 4 7-1. 6 1 (6Η, m), 1 · 7 1-2 * 17 (6Η, m), 3. 05 (1Η, m), 3. 69-4. 12 (14 H, m), 4 · 9 5 (1 H, m), 5.1 · 5 (1Η, m), 6. 5 3 (1 H, t, J = 4. 8 Hz), 8. 0 5 (1 H, s), 8.32 (2H, d, J = 4.8 Hz). Dl-16 to Dmin. 18 were carried out in the same manner as the method disclosed in Example D-1 to 15 to obtain the following compounds.

76 314976 200410956 表24化合物（Ι-E)之製造實施例構造式融點、MS、元素分析 NMR (CDC13, ppm) D-1-16 °〇Χ<：φ 結晶體融點：103.105°C. MS (m/z): 557 (MH+)，元素分析：C28H4〇N6(V0.50H2〇理論值(％): C, 59.45; H，7.31; N，14.86. 測定值(％): C，59.24; Η, 7·27; N，14.77. NMR： 1.12 (2H, m), 1.40-2.01 (12H, m), 2.37 (4H, m), 2.43 (2H, m), 3.02 (lH, m), 3.45-4.08 (13H, m), 4.89 (1H, m), 5.02 (lH, m), 6.54 (1H, t, J = 4.8 Hz), 7.97 (lH, s), 8.32 (2H, d, J=4.8Hz). D-1-17 °5j& 結晶體融點：93-96°C. MS (m/z): 571 (MH+).. 元素分析：〇29Η42Ν6〇6·〇.5〇Η2〇理論值(％)·· C, 60.09; Η, 7.48; N, 14·50. 測定值(％): C, 59·97; Η, 7·52; Ν, 14.57. NMR： 1.12 (2Η, m), 1.39-1.97 (19Η, m), 2.15 (2Η, m), 2.93 (2Η, m)，3.39-4.15 (12Η, m), 4.88 (lH, m), 6.54 (lH, t, J = 4.7 Hz), 8.00 (1H, s), 8.32 (2H, d, J = 4.7 Hz). ΌΊΊ8 °5j& 結晶體融點：85-88°C. MS (m/z): 585 (MH+). 元素分析.〇34ΪΪ52Ν6〇6·〇.75Η2〇 · 理論值(％)·· C, 62·41; Η, 8.24; N, 12·84· 測定值(％): C, 62.34; Η, 8.34; Ν, 12.91. NMR： 1.13-2.24 (22Η, m), 2.65-3.18 (4H, m), 3.47-4.14 (12H, m), 4.74 (1Π, m), 4.90 (1H, m), 6.54 (1H, t, J - 4.8 Hz), 7.98 (0.5 x 1H, s), 8.02 (0.5 x 1H, s), 8.32 (2H, d, J = 4.8 Hz). 實施例D-2-1至D-2-10 與實施例D-1-1或實施例D-1-2揭示之方法同樣操作，獲得以下之化合物。實施例D-2-1 -1之化合物以實施例D-1 -1-1揭示之方法為基準製造。 77 3】4976 200410956 表25化合物（Ι-B)’之製造實施例構造式融點、MS、元素分析 NMR (CDC13, ppm) D-2-1 Me nH'9 f ΓΛ MS (m/z)： 433 (MH+). NMR： 0.91 (3H, t, J = 7.2 Hz), 1.20*2.3 (10H, m), 2.9-3.0, 3.1-3.25 (total 1H, both m), 3.4-4.05 (12H, m), 4.74 (0.35 x 1H, dd, J = 2.7, 9.0 Hz), 4.84-4.98 (0.65 x 1H, m), 6.51*6.61 (1H, m), 8.3-8.36 (2H, m). D-2-1-1 D-2-1之K鹽結晶體融點：128-mt：· MS (m/z): 433 (MHO· 元素分析：〇42Η63ΚΝ12〇8·2.5Η2〇理論值(％): C，53.20; H，7·23; K, 4.12; N, 17.73. 測定值(％):〇,53.35;11,7.06;1^4.28;1^，17.81· NMR： 0.90 (3H, t, J = 6.9 Hz), 1.18-2.32 (11H, m), 3.12-3.35 (2H; m), 3.47*4.06 (10H, m), 4.87-4.97 (1H, m), 6.52 (lH, t, J = 4.6 Hz), 7.66 (1H, s), 8.31 (2H, d, J = 4.6 Hz). D-2-2 Me JMe MS (m/z): 475 (MH+). NMR： 0.91 (3H, m), 1.34-1.46 (4H, m), 1.88*2.19 (4H, m), 2.24 (3H, s), 2.93 (1H, m), 3.38-4.18 (14H, m), 4.89 (1H, m), 6.54 (1H, t, J =4.8 Hz), 8.00 (1H, s), 8.32 (2H, d, J = 4.8 Hz). D-2-3 MeJ^le Me MS (m/z)： 517 (MH+). NMR： 0.91 (3H, m), 1.24-1.42 (3H, m), 1.34 (9H, s), 1.56-1.69 (3H, m), 1.88-2.17 (4H, m), 2.87 (1H, m), 3.35-4.16 (12H, m), 4.90 (lH, m), 6.54 (1H, t, J = 4.7 Hz), 8.00 (lH, s), 8.33 (2H, d, J = 4.7 Hz). D-2-4 D Me Λ f ΓΛ . °<>NV^VNV> Hod MS (m/z)： 537 (MH+). NMR： 0.89 (3H, m), 1.24-1.47 (3H, m), 1.70-2.26 (7H, m), 2.98 (lH, m), 3.53-3.95 (11H, m), 4.22 (1H, m), 4.81 (lH, m), 6.53 (lH, t, J = 4.8 Hz), 7.43-7.54 (2H, m), 7.66 (1H, m), 8.03-8.13 (3H, m), 8.32 (2H, d, J = 4.8 Hz).76 314976 200410956 Table 24 Production example of compound (I-E) Structural formula Melting point, MS, Elemental analysis NMR (CDC13, ppm) D-1-16 ° 〇 × <: φ Crystal melting point: 103.105 ° C. MS (m / z): 557 (MH +), elemental analysis: C28H4ON6 (V0.50H2O theoretical value (%): C, 59.45; H, 7.31; N, 14.86. Measured value (%): C, 59.24; Tritium, 7.27; N, 14.77. NMR: 1.12 (2H, m), 1.40-2.01 (12H, m), 2.37 (4H, m), 2.43 (2H, m), 3.02 (lH, m), 3.45 -4.08 (13H, m), 4.89 (1H, m), 5.02 (lH, m), 6.54 (1H, t, J = 4.8 Hz), 7.97 (lH, s), 8.32 (2H, d, J = 4.8 Hz). D-1-17 ° 5j & Crystal melting point: 93-96 ° C. MS (m / z): 571 (MH +) .. Elemental analysis: 〇29Η42N6〇6 · 0.5〇2〇Theoretical value (%) · C, 60.09; Η, 7.48; N, 14.50. Measured value (%): C, 59 · 97; Η, 7.52; Ν, 14.57. NMR: 1.12 (2Η, m), 1.39-1.97 (19Η, m), 2.15 (2Η, m), 2.93 (2Η, m), 3.39-4.15 (12Η, m), 4.88 (lH, m), 6.54 (lH, t, J = 4.7 Hz) , 8.00 (1H, s), 8.32 (2H, d, J = 4.7 Hz). ΌΊΊ8 ° 5j & Crystal melting point: 85-88 ° C. MS (m / z): 585 (MH +). Elemental analysis.〇 34 ΪΪ52N6〇6.0.75Η2〇Theoretical value (%) C, 62 · 41; Η, 8.24; N, 12.84Measured value (%): C, 62.34; Η, 8.34; Ν, 12.91. NMR: 1.13-2.24 (22Η, m), 2.65-3.18 (4H, m), 3.47-4.14 (12H, m), 4.74 (1Π, m), 4.90 (1H, m), 6.54 (1H, t, J -4.8 Hz), 7.98 (0.5 x 1H, s), 8.02 (0.5 x 1H, s), 8.32 (2H, d, J = 4.8 Hz). Examples D-2-1 to D-2-10 and implementation The method disclosed in Example D-1-1 or Example D-1-2 was performed in the same manner, and the following compounds were obtained. The compound of Example D-2-1 -1 was produced based on the method disclosed in Example D-1 -1-1. 77 3] 4976 200410956 Table 25 Production Example of Compound (I-B) 'Structural formula Melting point, MS, Elemental analysis NMR (CDC13, ppm) D-2-1 Me nH'9 f ΓΛ MS (m / z) : 433 (MH +). NMR: 0.91 (3H, t, J = 7.2 Hz), 1.20 * 2.3 (10H, m), 2.9-3.0, 3.1-3.25 (total 1H, both m), 3.4-4.05 (12H, m), 4.74 (0.35 x 1H, dd, J = 2.7, 9.0 Hz), 4.84-4.98 (0.65 x 1H, m), 6.51 * 6.61 (1H, m), 8.3-8.36 (2H, m). D- 2-1-1 D-2-1 K salt crystal melting point: 128-mt: · MS (m / z): 433 (MHO · Elemental analysis: 〇42Η63ΚΝ12〇8 · 2.5Η2〇 Theoretical value (%): C, 53.20; H, 7.23; K, 4.12; N, 17.73. Measured value (%): 〇, 53.35; 11, 7.06; 1 ^ 4.28; 1 ^, 17.81 · NMR: 0.90 (3H, t, J = 6.9 Hz), 1.18-2.32 (11H, m), 3.12-3.35 (2H; m), 3.47 * 4.06 (10H, m), 4.87-4.97 (1H, m), 6.52 (lH, t, J = 4.6 Hz), 7.66 (1H, s), 8.31 (2H, d, J = 4.6 Hz). D-2-2 Me JMe MS (m / z): 475 (MH +). NMR: 0.91 (3H, m), 1.34-1.46 (4H, m), 1.88 * 2.19 (4H, m), 2.24 (3H, s), 2.93 (1H, m), 3.38-4.18 (14H, m), 4.89 (1H, m), 6.54 ( 1H, t, J = 4.8 Hz), 8.00 (1H, s), 8.32 (2H, d, J = 4.8 Hz). D-2-3 MeJ ^ le Me MS (m / z): 517 (MH +). NMR: 0.91 (3H, m), 1.24-1.42 (3H, m), 1.34 (9H, s), 1.56 -1.69 (3H, m), 1.88-2.17 (4H, m), 2.87 (1H, m), 3.35-4.16 (12H, m), 4.90 (lH, m), 6.54 (1H, t, J = 4.7 Hz ), 8.00 (lH, s), 8.33 (2H, d, J = 4.7 Hz). D-2-4 D Me Λ f ΓΛ. ° < > NV ^ VNV > Hod MS (m / z): 537 (MH +). NMR: 0.89 (3H, m), 1.24-1.47 (3H, m), 1.70-2.26 (7H, m), 2.98 (lH, m), 3.53-3.95 (11H, m), 4.22 (1H , m), 4.81 (lH, m), 6.53 (lH, t, J = 4.8 Hz), 7.43-7.54 (2H, m), 7.66 (1H, m), 8.03-8.13 (3H, m), 8.32 ( 2H, d, J = 4.8 Hz).

78 314976 200410956 D-2-578 314976 200410956 D-2-5

MS (m/z): 538 (MH+). NMR： 0.88 (3H,m), 1.25-2.17 (11H, m), 2.99 (lH, m), 3.55-3.96 (10H, m), 4.28 (lH, m), 4.85 (1H, m), 6.54 (lH, t, J = 4.8 Hz), 7.48 (lH, dd, J = 5.0, 7.7 Hz), 8.14 (lH, s), 8.31-8.37 (3H, m), 8.89 (1H, m), 9.26 (lH, s). D-2-6MS (m / z): 538 (MH +). NMR: 0.88 (3H, m), 1.25-2.17 (11H, m), 2.99 (lH, m), 3.55-3.96 (10H, m), 4.28 (lH, m), 4.85 (1H, m), 6.54 (lH, t, J = 4.8 Hz), 7.48 (lH, dd, J = 5.0, 7.7 Hz), 8.14 (lH, s), 8.31-8.37 (3H, m ), 8.89 (1H, m), 9.26 (lH, s). D-2-6

結晶体融点：86·88 °C. NMR： 0.80-2.18 (23H, m), 4.87-4.90 (lH, m), 6.54 (1H, d, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). 以實施例D-1 -2揭示之方法為基準，獲得以下之化合物。表26化合物（Ι-E)之製造實施例 R <Me 9a\〇 / 融點、MS、元素分析 . NMR (CDCI3, ppm) R9a/試藥 D-2-7 We / Me Me人j / Me人2 0人/ 〇Me Cl MS (m/z)： 519 (MH+). NMR： 0.91 (3H, m), 1.37 (3H, s), 1.39 (3Hy s), 1,34.1.45 (5H, m), 1.60 (lH, m)? 1.86-2.23 (4H, m), 3.00 (1H, m), 3.42*4.11 (12H, m), 4.87-5.02 (2H, m), 6.54 (1H, t, J =4.8 Hz), 7.98 (1H, br s), 8.32 (2H, d, J = 4.8 Hz). D-2-8 COOH V/4 0 MS (m/z)： 547 (MH+). NMR： 0.90 (4H, m), 1.26-1.42 (2H, m), 2.00-2.17 (7H, m), 2.48-2.56 (4H，s)，2.91 (lH, m), 3.45*4.09 (14H, m), 4.91 (1H, m), 6.54 (1H, m), 8.02 (0.6 x 1H, s), 8.10 (0.4 x 1H), 8.33 (2H, d, J = 4.7Hz). 79 314976 200410956 D-2-9 /Me^0 MS (m/z)· 545 (MH+). NMR： 0.91 (3H, m), 1.26Ί.50 (5H, m), 1.65 (2H, m), 1.86-2.16 (3H, m), 2.26 (3H, s), 2,41 (1H, s), 3.63-3.98 (12H, m), 4.74 (lH, m), 4.90 (1H, m), 6.55 (lH, t, J = 4.8 Hz), 7.92 (1H, br s), 8.32 (2H, d, J = 4.8 Hz). D-2-10 MS (m/z)： 565 (MH+). NMR： 0.86-0.93 (4H, m), 1.26Ί.71 (5H, m), 1.87-2· 17 (4H, m), 3.18-3.99 (14H，m), 4.90 (lH, m), 6.51-6.56 (lH, m), 6.63-6.72 (1H，m), 7.64-7.76 (2H, m)，7.90-8.02 (2H， m), 8.32 (2H, m).Crystal melting point: 86 · 88 ° C. NMR: 0.80-2.18 (23H, m), 4.87-4.90 (lH, m), 6.54 (1H, d, J = 4.8 Hz), 8.33 (2H, d, J = 4.8 Hz). Based on the method disclosed in Example D-1-2, the following compounds were obtained. Table 26 Production Example of Compound (I-E) R < Me 9a \ 〇 / Melting point, MS, Elemental analysis. NMR (CDCI3, ppm) R9a / Reagent D-2-7 We / Me Me Human j / Me person 20 person / 〇Me Cl MS (m / z): 519 (MH +). NMR: 0.91 (3H, m), 1.37 (3H, s), 1.39 (3Hy s), 1,34.1.45 (5H , m), 1.60 (lH, m)? 1.86-2.23 (4H, m), 3.00 (1H, m), 3.42 * 4.11 (12H, m), 4.87-5.02 (2H, m), 6.54 (1H, t , J = 4.8 Hz), 7.98 (1H, br s), 8.32 (2H, d, J = 4.8 Hz). D-2-8 COOH V / 4 0 MS (m / z): 547 (MH +). NMR : 0.90 (4H, m), 1.26-1.42 (2H, m), 2.00-2.17 (7H, m), 2.48-2.56 (4H, s), 2.91 (lH, m), 3.45 * 4.09 (14H, m) , 4.91 (1H, m), 6.54 (1H, m), 8.02 (0.6 x 1H, s), 8.10 (0.4 x 1H), 8.33 (2H, d, J = 4.7Hz). 79 314976 200410956 D-2- 9 / Me ^ 0 MS (m / z) · 545 (MH +). NMR: 0.91 (3H, m), 1.26Ί.50 (5H, m), 1.65 (2H, m), 1.86-2.16 (3H, m ), 2.26 (3H, s), 2,41 (1H, s), 3.63-3.98 (12H, m), 4.74 (lH, m), 4.90 (1H, m), 6.55 (lH, t, J = 4.8 Hz), 7.92 (1H, br s), 8.32 (2H, d, J = 4.8 Hz). D-2-10 MS (m / z): 565 (MH +). NMR: 0.86-0.93 (4H, m) , 1.26Ί.71 (5H, m ), 1.87-2 · 17 (4H, m), 3.18-3.99 (14H, m), 4.90 (lH, m), 6.51-6.56 (lH, m), 6.63-6.72 (1H, m), 7.64-7.76 (2H, m), 7.90-8.02 (2H, m), 8.32 (2H, m).

實施例D-3-1至D-16-3 與實施例D-1 -1或實施例D-1- 1 0揭示之方法同樣操作，獲得以下之化合物。但是D-4-3係根據D-l-15、D-16-3 係根據D-1 -2揭示之方法製造。又，金屬鹽化合物係以實施例D-1 -1 -1揭示之方法為基準製造。Examples D-3-1 to D-16-3 were performed in the same manner as the method disclosed in Example D-1 -1 or Example D-1- 1 0, and the following compounds were obtained. However, D-4-3 is manufactured according to the methods disclosed in D-1-15 and D-16-3 according to D-1-2. The metal salt compound was produced based on the method disclosed in Example D-1 -1 -1.

80 314976 200410956 表27化合物（Ι-B)’之製造實施例構造式融點、MS、元素分析 NMR (CDC13, ppm) and Tr (min.) D-3-1 Ρ 60工〇气3 MS (m/z): 464 (MH+)， NMR (DMSO-Je)： 0.92-2.23 (15H, m), 2.87-3.96 (13H, m), 4.73^4.99 (1H, m), 6.89 (1H, d, J = 3.6 Hz), 7.19 (1H, d, J = 3.6 Hz). Tr = 3.71. D-3-1-1 D-3-1 之C a 鹽結晶體融點：171-174°C. MS (m/z): 464 (MH+). 元素分析：C44He4CaN1(>08S2*4H2〇理論值(％): C, 50·95; Η, 7.00; Ca，3·86; N, 13·50·測定值(％)·· C，50.66; Η, 6.95; Ca， 3.95； Ν, 13.47. , NMR： 0.97-2.30 (16Η, m), 3.23*4.06 (12Η, m), 6·61 (1Η, d, J = 3.6 Hz), 7.20 (1H, d, J = 3.6 Hz), 7.44 (1H, s). D-3-2 結晶體融點：166〜167°C. MS (m/z): 557 (MH+). 元素分析：C27H3eN6〇5S理論值(％): C, 58.25; H, 6.52; N, 15.10; S, 5·76.測定值 (%)： C, 58.38； H, 6.59； N, 15.23； S, 5.51. NMR： 0.92-1.26 (2H,m), 1.27-2.25 (13H, m), 2.45-3.15 (1H, m), 3.25-3.90 (llH, m), 4.00-4.28 (lH, m), 4.30-4.45 (0.35 x 1H, br s), 4.70-4.85 (0.65 x 1H, br s), 6.34 (1H, br s), 6.61 (lH, d, J = 3.6 Hz), 6.80-7.18 (2H, m), 7.20 (1H, d, J = 3.6 Hz), 8.00-8.15 (0.65 x 1H, br), 8.15-8.30 (0.35 x 1H, br s), 9.50-9.65 (0.65 x 1H, br s), 9.65-9.80 (0.35 x 1H, br s). D-3-3 ^〇Ρ νΝχ〇結晶體融點：162〜163°C. MS (m/z): 618 (MH十元素分析：C33H39N5〇5S理論值(％)·· C， 64.16; H，6.36; Ν, 11.34; S, 5.19.測定值 (°/〇)： C, 63.93； H,6.37； N, 11.33； S, 5.05. NMR: 1.0O1.30 (2H, m), 1.40-2.25 (13H, m), 2.80-3.20 (2H, m), 3.25-3.80 (llH, m), 3.80-4.00 (0.4 x 1H, m), 4.00-4.15 (0.4 x 1H, m), 4.15*4.40 (0.6 x 1H, m), 4.60-4.80 (0.6 x 1H, m), 6.61 (1H, d, J = 3.6 Hz), 7.20 (1H, d，J 二 3.6 Hz), 7.50-7.75 (2H, m), 7.80-8.15 (4H, m), 8.07 (0.6 x 1H, s), 8.17 (0.4 x 1H, s), 8.68 (1H, s). 81 314976 20041095680 314976 200410956 Table 27 Production Example of Compound (I-B) 'Example Structural formula Melting point, MS, Elemental analysis NMR (CDC13, ppm) and Tr (min.) D-3-1 Ρ 60 Working gas 3 MS ( m / z): 464 (MH +), NMR (DMSO-Je): 0.92-2.23 (15H, m), 2.87-3.96 (13H, m), 4.73 ^ 4.99 (1H, m), 6.89 (1H, d, J = 3.6 Hz), 7.19 (1H, d, J = 3.6 Hz). Tr = 3.71. D-3-1-1 D-3-1 C a salt crystal melting point: 171-174 ° C. MS ( m / z): 464 (MH +). Elemental analysis: C44He4CaN1 (> 08S2 * 4H2〇Theoretical value (%): C, 50 · 95; Η, 7.00; Ca, 3.86; N, 13 · 50 · Determination Value (%) · C, 50.66; Η, 6.95; Ca, 3.95; Ν, 13.47., NMR: 0.97-2.30 (16Η, m), 3.23 * 4.06 (12Η, m), 6.61 (1Η, d , J = 3.6 Hz), 7.20 (1H, d, J = 3.6 Hz), 7.44 (1H, s). D-3-2 Crystal melting point: 166 ~ 167 ° C. MS (m / z): 557 ( MH +). Elemental analysis: C27H3eN605S theoretical value (%): C, 58.25; H, 6.52; N, 15.10; S, 5.76. Measured value (%): C, 58.38; H, 6.59; N, 15.23 S, 5.51. NMR: 0.92-1.26 (2H, m), 1.27-2.25 (13H, m), 2.45-3.15 (1H, m), 3.25-3.90 (llH, m), 4.00-4.28 (lH, m ), 4.30-4.45 (0.35 x 1H, br s), 4.70-4.85 (0.65 x 1H, br s), 6.34 (1H, br s), 6.61 (lH, d, J = 3.6 Hz), 6.80-7.18 (2H, m), 7.20 (1H, d, J = 3.6 Hz), 8.00-8.15 (0.65 x 1H, br), 8.15-8.30 (0.35 x 1H, br s), 9.50-9.65 (0.65 x 1H, br s), 9.65-9.80 (0.35 x 1H, br s). D-3-3 ^ 〇Ρ νΝχ〇 crystal melting point: 162 ~ 163 ° C. MS (m / z): 618 (MH ten element analysis: C33H39N50S theoretical value (% ) · C, 64.16; H, 6.36; N, 11.34; S, 5.19. Measured value (° / 〇): C, 63.93; H, 6.37; N, 11.33; S, 5.05. NMR: 1.0O1.30 ( 2H, m), 1.40-2.25 (13H, m), 2.80-3.20 (2H, m), 3.25-3.80 (llH, m), 3.80-4.00 (0.4 x 1H, m), 4.00-4.15 (0.4 x 1H , m), 4.15 * 4.40 (0.6 x 1H, m), 4.60-4.80 (0.6 x 1H, m), 6.61 (1H, d, J = 3.6 Hz), 7.20 (1H, d, J two 3.6 Hz), 7.50-7.75 (2H, m), 7.80-8.15 (4H, m), 8.07 (0.6 x 1H, s), 8.17 (0.4 x 1H, s), 8.68 (1H, s). 81 314976 200410956

D-4-1 Me MS (m/z): 438 (MH+)， NMR (CDaOD)： 0.93 (3H, t, J = 6.9 Hz), 1.20-2.73 (11H, m), 3.00-4.00 (12H, m), 4.80*5.10 (1H, m), 6.78 (lH, d, J = 3.7 Hz), 7.17 (1H, d, J = 3.7 Hz), 7.81 (0.6 x 1H, s), 7.90 (0.4 x 1H, s). D-4-2 HN^ Me 0^0 f r\ 〇 Λ r-\ N-. °O^Nw^jl 結晶體融點：167〜169°C. MS (m/z): 581 (MH+). 元素分析：C29H36N6〇5S 理論值(％〉： C, δ9.98; Η, 6.25; N, 14.47; S，5·52.測定值(％) :C， 59.88； Η, 6.26； N, 14.47； S, 5.36. NMR： 0.89 (3H, t, J = 7.2 Hz) 1.25-2.25 (10H, m), 2.75-3.80 (12H, m), 3.803.90 (0·4 x 1H, m), 3.90-4.05 (0.4 x 1H, m), 4.15-4.35 (0.6 x 1H, m), 4.60-4.70 (0.6 x 1H, m), 6.61 (lH, d, J = 3.6 Hz), 7.20-7.55 (5H, m), 7.60-7.75 (lH, br s), 8.17 (0.6 x 1H, s), 8.30 (0.4 x 1H, s), 9.44 (1H, br s). D-4-3 CX Me 〇^9 f ΓΛ 〇〇Ν^Λ^Νγ> 〇Λ〇<^ι 結晶體融點：103-106°C. NMR： 0.89 (3H, t, J = 6.8 Hz), 4.84-5.05 (2H, m), 6.62 (1H, d, J = 3.7 Hz), 7.21 (1H，d, J = 3.7 Hz). D-5 Me nHV f r\ MS (m/z): 452 (MH+) NMR (CDsOD)： 0.93 (3H, t, J = 6.8 Hz), 1.20-2.16 (10H, m), 2.21 (3H, s), 3.06-4.00 (13H, m), 4.73-5.07 (lH, m), 6.32 (lH, s), 7.81 (0.5 x 1H, s), 7.90 (0.5 x 1H, s). D_6 Me NMR： 0.28-0.32 (lH, m), 0.86 (3H, t, J = 6.9 Hz), 6.56 (1H, t, J = 4.7 Hz), 8.34 (2H, d, J = 4.7 Hz). Tr = 6.30. D-7-1 Me H o /r\ 〇丄3^]] NMR： 0.86 (3H, t, J = 6.1 Hz), 6.85-6.93 (lH, m), 7.14-7.25 (lH, m). Tr 二 3.75. 82 14976 200410956 D-7-1-1 D-7-1 之 C a 鹽 MS (m/z)： 452 (MH+). 元素分析：C42H64N1()CaO8S2,0.5H2〇理論值 (%)： C, 53.09； H, 6.89； Ca, 4.22； N, 14.74； S, 6.75. ^J^i(%)： C, 52.95； H, 6.85； Ca, 4.20； N, 14.68； S, 6.53. (CDsOD)： 0.91 (3H, t, J 6.9 Hz), 1.21-2.32 NMR： (13H, m)，3.24-3.97 (12H, m), 4.76-4.97 (1H, m), 6.78 (1H, d, J = 3.7 Hz), 7.17 (1H, d, J = 3.7 Hz), 7.56 (1H, s). D-8 Me MS (m/z)： 466 (MH+). NMR： 0.88 (3¾ t, J = 6.8 Hz), 1.00-2.25 (13H, m), 2.25 (3H, s), 2.86-4.00 (12H, m), 4.33*4.97 (1H, m), 6.17 (0.6 x 1H, s), 6.18 (0.4 x 1H, s), 7.80 (0.6 x 1H, s), 8.34 (0.4 x 1H, s). D-9 Me NMR： 0.89 (3H, br t), 1.20-2.28 (12H, m), 2.90-3.22 (1H, m), 3.25-4.05 (13H, m)，7.09 (lH, s), 7.84 and 8.35 (total 1H, both s). D-10 Me Q^n^^nO 0。工〇切 MS (m/z)： 502 (MH+). NMR (CD3〇D): 0.91(lH,m), 1·34·1.62 (8H, m), 1.85-2.05 (3H, m), 2.27 (lH, m), 3.07 (lH, m), 3.59-3.87 (13H, m), 4.90 (lH； m), 7.11 (lH, t, J = 7.9 Hz), 7.30 (lH, t, J = 7.9 Hz), 7.49 (1H, d, J = 7.9 Hz), 7.67 (lH, d, J = 7.9 Hz), 7.82 (0.6 x 1H, s), 7.90 (0.4 x 1H, s). D-ll-1 η ό Ργλ MS (m/z)： 478 (MH+) NMR (CD3OD)： 1.03-2.16 (15H, m), 2.21 (3H, s), 3.38-4.00 (13H, m), 4.80 (lH, m), 6.32 (1H, s), 7.80 (0.5 x 1H, s), 7.90 (0.5 x 1H, s). D-ll-1-1 D-11-1之 C a 鹽結晶體融點：162-167°C. MS (m/z): 478 (MH+)· 元素分析：C46H68CaN1()08S2-4.25H2〇理論值 (%)： C, 51.64； H, 7.21； Ca, 3.86； N, 13.09； S, 5.99·測定值(％): C, 51.38; H, 7.01; Ca, 3.87; N, 13.03； S, 5.81. NMR： 0.97-2.24 (16H, m), 2.25 (3H, s), 3.26-3.94 (12H, m), 6.16 (lH, s), 7.45 (lH, br s). D-12 Me NMR： 0.88 (3H, t, J = 6,9Hz), 1.11Ί.21 (3H, m), 6.51-6.60 (lH, m), 8.31-8.35 (2H, m). Tr = 6.56. 83 3]4976 200410956 D-13 Me NMR: 0.86-0.91 (3H，m)，6.53-6.63 (1H, m), 8.32-8.36 (2H，m). Tr = 8.61. D-14 Me 〜A NMR: 0.86-0.91 (3H，m)，1.40 (3H, t，J = 6.7 Hz), 4.39 (2H, q, J = 6.7 Hz), 8.35 (lH, br s). Tr = 16.05. D-15 Me c, Ο〇χ〇-〇 NMR： 0.89 (3H, t, J = 6.8 Hz), 4.70-4.95 (lH, m), 7.80-8.05 (2H, m). Tr = 14.06. D-16-1 o^Jbb °O^N^N-^j] NMR： 0.76-2.20 (17H, m), 6.89 (lH, t, J = 3.7 Hz), 7.19 (1H, t, J = 3.7Hz). Tr = 4.47. D-16-1-1 D-16-1之 K 鹽結晶體融點：120-123°C. MS (m/z): 478 (MH+). 元素分析：C46H69KN10〇8S2.1·5Η2〇理論值(％): C, 54.15; Η, 7.11; K, 3.83; N, 13.73; S, 6.28.測定值(％):〇,54.53;氏7.10; K, 4.22； Ν, 13.73； S, 5.91. NMR： 0.79-2.26 (18Η, m), 3.18-3.94 (12Η, m), 4.87-4.97 (lH, m), 6.61 (lH, d, J = 3.7 Hz), 7.20 (1H, d, J = 3.7 Hz), 7.65 (lH, s). D-16-2 9 BocHN.J 〇c^CKb MS (m/z): 725 (MH+)· NMR： 0.75-1.05 (2H, m), 1.05*2.25 (24H, m), 2.90-3.20 (1H, m), 3.25-3.85 (14H, m), 4.05*4.25 (1¾ m), 4.50-4.65 (lH7 m); 4.75-5.00 (1H, m), 6.61 (lH, d, J = 3.6 Hz), 7.15-7.45 (6H, m), 8.04 (lH, s). D-16.3 MS (m/z): 672 (MH+)· NMR： 0.8-2.25 (27H, m), 2.37-3.13 (8H, m), 3.37^3.89 (12H, m), 4.03-4.25 (2H, m), 4.88 (1H, dd, J = 4.2, 7.5 Hz), 6.62 (lH, d, J = 3.7 Hz), 7.21 (1H, d, J= 3.7 Hz), 7.98 (0.7 H, s), 8.15 (0.3H, s). Tr = 3.95.D-4-1 Me MS (m / z): 438 (MH +), NMR (CDaOD): 0.93 (3H, t, J = 6.9 Hz), 1.20-2.73 (11H, m), 3.00-4.00 (12H, m), 4.80 * 5.10 (1H, m), 6.78 (lH, d, J = 3.7 Hz), 7.17 (1H, d, J = 3.7 Hz), 7.81 (0.6 x 1H, s), 7.90 (0.4 x 1H , s). D-4-2 HN ^ Me 0 ^ 0 fr \ 〇Λ r- \ N-. ° O ^ Nw ^ jl Crystal melting point: 167 ~ 169 ° C. MS (m / z): 581 ( MH +). Elemental analysis: C29H36N6O5S theoretical value (%>: C, δ9.98; Η, 6.25; N, 14.47; S, 5.52. Measured value (%): C, 59.88; Η, 6.26; N , 14.47; S, 5.36. NMR: 0.89 (3H, t, J = 7.2 Hz) 1.25-2.25 (10H, m), 2.75-3.80 (12H, m), 3.803.90 (0.4 x 1H, m) , 3.90-4.05 (0.4 x 1H, m), 4.15-4.35 (0.6 x 1H, m), 4.60-4.70 (0.6 x 1H, m), 6.61 (lH, d, J = 3.6 Hz), 7.20-7.55 ( 5H, m), 7.60-7.75 (lH, br s), 8.17 (0.6 x 1H, s), 8.30 (0.4 x 1H, s), 9.44 (1H, br s). D-4-3 CX Me 〇 ^ 9 f ΓΛ 〇〇ΝΝΛ ^ Νγ > 〇Λ〇 < ^ ι Crystal melting point: 103-106 ° C. NMR: 0.89 (3H, t, J = 6.8 Hz), 4.84-5.05 (2H, m) , 6.62 (1H, d, J = 3.7 Hz), 7.21 (1H, d, J = 3.7 Hz). D-5 Me nHV fr \ MS (m / z): 452 (MH +) NMR (CDsOD): 0.93 (3H, t, J = 6.8 Hz), 1.20-2.16 (10H, m), 2.21 (3H, s), 3.06-4.00 (13H, m), 4.73-5.07 ( lH, m), 6.32 (lH, s), 7.81 (0.5 x 1H, s), 7.90 (0.5 x 1H, s). D_6 Me NMR: 0.28-0.32 (lH, m), 0.86 (3H, t, J = 6.9 Hz), 6.56 (1H, t, J = 4.7 Hz), 8.34 (2H, d, J = 4.7 Hz). Tr = 6.30. D-7-1 Me H o / r \ 〇丄 3 ^]] NMR: 0.86 (3H, t, J = 6.1 Hz), 6.85-6.93 (lH, m), 7.14-7.25 (lH, m). Tr 3.75. 82 14976 200410956 D-7-1-1 D-7- Ca salt of 1 MS (m / z): 452 (MH +). Elemental analysis: C42H64N1 () CaO8S2, 0.5H20 Theoretical value (%): C, 53.09; H, 6.89; Ca, 4.22; N, 14.74; S, 6.75. ^ J ^ i (%): C, 52.95; H, 6.85; Ca, 4.20; N, 14.68; S, 6.53. (CDsOD): 0.91 (3H, t, J 6.9 Hz), 1.21-2.32 NMR: (13H, m), 3.24-3.97 (12H, m), 4.76-4.97 (1H, m), 6.78 (1H, d, J = 3.7 Hz), 7.17 (1H, d, J = 3.7 Hz), 7.56 (1H, s). D-8 Me MS (m / z): 466 (MH +). NMR: 0.88 (3¾ t, J = 6.8 Hz), 1.00-2.25 (13H, m), 2.25 (3H, s ), 2.86-4.00 (12H, m), 4.33 * 4.97 (1H, m), 6.17 (0.6 x 1H, s), 6.18 (0.4 x 1H, s), 7.80 (0.6 x 1H, s), 8.34 (0.4 x 1H, s). D-9 Me NMR: 0.89 (3H, br t), 1.20-2.28 (12H, m), 2.90-3.22 ( 1H, m), 3.25-4.05 (13H, m), 7.09 (lH, s), 7.84 and 8.35 (total 1H, both s). D-10 Me Q ^ n ^^ nO 0. I-cut MS (m / z): 502 (MH +). NMR (CD3〇D): 0.91 (lH, m), 1.34 · 1.62 (8H, m), 1.85-2.05 (3H, m), 2.27 (lH, m), 3.07 (lH, m), 3.59-3.87 (13H, m), 4.90 (lH; m), 7.11 (lH, t, J = 7.9 Hz), 7.30 (lH, t, J = 7.9 Hz), 7.49 (1H, d, J = 7.9 Hz), 7.67 (lH, d, J = 7.9 Hz), 7.82 (0.6 x 1H, s), 7.90 (0.4 x 1H, s). D-ll-1 η ργλ MS (m / z): 478 (MH +) NMR (CD3OD): 1.03-2.16 (15H, m), 2.21 (3H, s), 3.38-4.00 (13H, m), 4.80 (lH, m) , 6.32 (1H, s), 7.80 (0.5 x 1H, s), 7.90 (0.5 x 1H, s). D-ll-1-1 D-11-1 C a salt crystal melting point: 162-167 ° C. MS (m / z): 478 (MH +) Elemental analysis: C46H68CaN1 () 08S2-4.25H2〇Theoretical value (%): C, 51.64; H, 7.21; Ca, 3.86; N, 13.09; S, 5.99 · Measured value (%): C, 51.38; H, 7.01; Ca, 3.87; N, 13.03; S, 5.81. NMR: 0.97-2.24 (16H, m), 2.25 (3H, s), 3.26-3.94 (12H , m), 6.16 (lH, s), 7.45 (lH, br s). D-12 Me NMR: 0.88 (3H, t, J = 6,9Hz), 1.11Ί.21 (3H, m), 6.51- 6.60 (lH, m), 8.31-8.35 (2H, m). Tr = 6.56. 83 3] 4976 200410956 D-13 Me NMR: 0.86-0.91 (3H, m), 6.53-6.63 (1H, m), 8.32-8.36 (2H, m). Tr = 8.61. D-14 Me ~ A NMR: 0.86-0.91 (3H, m), 1.40 (3H, t, J = 6.7 Hz), 4.39 (2H, q, J = 6.7 Hz), 8.35 (lH, br s). Tr = 16.05. D-15 Me c, 〇〇χ〇-〇NMR: 0.89 (3H, t, J = 6.8 Hz), 4.70-4.95 (lH, m), 7.80-8.05 (2H, m). Tr = 14.06. D-16-1 o ^ Jbb ° O ^ N ^ N- ^ j] NMR: 0.76-2.20 ( 17H, m), 6.89 (lH, t, J = 3.7 Hz), 7.19 (1H, t, J = 3.7Hz). Tr = 4.47. D-16-1-1 D-16-1 K salt crystal melts Point: 120-123 ° C. MS (m / z): 478 (MH +). Elemental analysis: C46H69KN10〇8S2.1 · 5Η2〇 Theoretical value (%): C, 54.15; Η, 7.11; K, 3.83; N , 13.73; S, 6.28. Measured value (%): 〇, 54.53; 7.10; K, 4.22; N, 13.73; S, 5.91. NMR: 0.79-2.26 (18Η, m), 3.18-3.94 (12Η, m ), 4.87-4.97 (lH, m), 6.61 (lH, d, J = 3.7 Hz), 7.20 (1H, d, J = 3.7 Hz), 7.65 (lH, s). D-16-2 9 BocHN. J 〇c ^ CKb MS (m / z): 725 (MH +) · NMR: 0.75-1.05 (2H, m), 1.05 * 2.25 (24H, m), 2.90-3.20 (1H, m), 3.25-3.85 ( 14H, m), 4.05 * 4.25 (1¾ m), 4.50-4.65 (lH7 m); 4.75-5.00 (1H, m), 6.61 (lH, d, J = 3.6 H z), 7.15-7.45 (6H, m), 8.04 (lH, s). D-16.3 MS (m / z): 672 (MH +) · NMR: 0.8-2.25 (27H, m), 2.37-3.13 (8H , m), 3.37 ^ 3.89 (12H, m), 4.03-4.25 (2H, m), 4.88 (1H, dd, J = 4.2, 7.5 Hz), 6.62 (lH, d, J = 3.7 Hz), 7.21 ( 1H, d, J = 3.7 Hz), 7.98 (0.7 H, s), 8.15 (0.3H, s). Tr = 3.95.

實施例D-16-4 84 314976 200410956 (2 3)-1-{(211)-3-環己基-2-{[>^甲醯基-1^(1^丁基胺基甲酸氧基）胺基]曱基}丙醯基}-2-{ [4-(2-噻唑基）-1-六氫tj比哄基] 羰基}吼咯烷Example D-16-4 84 314976 200410956 (2 3) -1-{(211) -3-cyclohexyl-2-{[> ^ methylamido-1 ^ (1 ^ butylaminocarbamyloxy ) Amine] fluorenyl} propanyl} -2- {[4- (2-thiazolyl) -1-hexahydrotj ratio carbonyl] carbonyl} hyrrolidine

在室溫下，於由實施例D-16-1之化合物丨50毫克 (0.314111111〇1)、三乙胺88/(/1(0.63111111〇1)及甲苯2.0毫升組成之混合物中加入丁基異氰酸酯43 /z 1(0.3 8mmol)，於同溫度撥掉2 3小時。在減懕下策顧略土、、办丸丨.^ 。t .At room temperature, butyl isocyanate was added to a mixture consisting of the compound of Example D-16-1, 50 mg (0.314111111〇1), triethylamine 88 / (/ 1 (0.63111111〇1), and 2.0 ml of toluene. 43 / z 1 (0.3 8mmol), set aside for 23 hours at the same temperature. Under the circumstances, we will take care of the soil, and the pill. ^. T.

羰基}哦咯烧93毫克（收率51 % )。 MS (m/z) :5 7 7 (MH〇. ^H-NMR (CDC 1 3) : δ/ppm 〇 · 8 — 2 · 2 5 ( 2 1 H，m), 0 · 94 (3H, t，J = 7. 2Hz)，3· 〇〇〜3· 32 (3H，m)，3· 32 一 3.9 (12H，m), 4·82 (1H, dd, j 二 3.3, 7 2Hz)、5· i 3 (1H, br s), 6.6 1 (1H, d, J^3> 7Hz), 7. 21 (1H, d, J — 3. 7Hz), 8. 00 (1H, br $)Carbonyl group] 93 mg (51% yield). MS (m / z): 5 7 7 (MH〇. ^ H-NMR (CDC 1 3): δ / ppm 〇 8 — 2 · 2 5 (2 1 H, m), 0 · 94 (3H, t , J = 7. 2 Hz), 3. · 00 ～ 3. 32 (3H, m), 3.32-3.9 (12H, m), 4.82 (1H, dd, j 2.3.3, 7 2Hz), 5 I 3 (1H, br s), 6.6 1 (1H, d, J ^ 3 > 7Hz), 7. 21 (1H, d, J — 3. 7Hz), 8. 00 (1H, br $)

Tr:=17. 4min. 實施例D-17至D-79 1-1-4揭示之方法同樣操 D_25-l-l之化合物係以實與實施例D-l-1或實施例— b 作，獲得以下之化合物。實施例£) _ 7 5 314976 85 200410956 施例D-1 -1 -1揭示之方法為基準製造。表28化合物（I-B-2)之製造實施例 Me NMR(CDCl3，ppm)及 Tr(min.) Ζι z2 D-17 C-H C-H 0.86-0.91 (3H, m), 4.85-4.96 (lH, m), 6.63-6.69 (2H, m), 7.47-7.58 (1H, m), 8.19-8.21 (1H, m). Tr 二 3.43· D-18 C-Me C-H 0.85 (3H, t, J = 6.3Hz), 6.53 (lH, d, J =7.3 Hz), 6.61 (lH, d, J = 8.4 Hz), 7.43 (1H, t, J = 7.8 Hz). D-19 C-H C-CI 0.86 (3H, t, J - 6.2 Hz), 6.90 (lH, d, J = 9.2 Hz), 7.63 (1H, dd, J = 2.6 Hz, 9.2 Hz), 8.13 (lH, d, J = 2.7 Hz). 表29化合物（I-B-2)之製造實施例 Me NMR (CDCI3, ppm) Z4 D-20 C-C02Et 0.86-0.91 (3H, m), 4.29-4.39 (2H, m), 6.77-6.89 (1H, m), 8.01-8.11 (lH, m), 8.24-8.34 (1H, m). D*21 C-CN 0.86-0.90 (3¾ m), 4.85·4.94 (1H, m)， 6.79-6.91 (1H, m), 7.78-7.87 (lH, m), 8.35-8.40 (1H, m). D-22 c-conh2 0.86Ό.90 (3H, m), 7.07*7.13 (lH, m), 8.22-8.28 (1H，m)，8.34-8.38 (1H，m). 86 314976 200410956Tr: = 17. 4min. The methods disclosed in Examples D-17 to D-79 1-1-4. The same compounds as those in D_25-11 were used in practice with Examples D1-1 or Example-b to obtain Compounds. Example £) _ 7 5 314976 85 200410956 The method disclosed in Example D-1 -1 -1 is benchmarked. Table 28 Production Examples of Compound (IB-2) Me NMR (CDCl3, ppm) and Tr (min.) Z 2 D-17 CH CH 0.86-0.91 (3H, m), 4.85-4.96 (lH, m), 6.63-6.69 (2H, m), 7.47-7.58 (1H, m), 8.19-8.21 (1H, m). Tr 2.34 · D-18 C-Me CH 0.85 (3H, t, J = 6.3Hz), 6.53 (lH, d, J = 7.3 Hz), 6.61 (lH, d, J = 8.4 Hz), 7.43 (1H, t, J = 7.8 Hz). D-19 CH C-CI 0.86 (3H, t, J -6.2 Hz), 6.90 (lH, d, J = 9.2 Hz), 7.63 (1H, dd, J = 2.6 Hz, 9.2 Hz), 8.13 (lH, d, J = 2.7 Hz). Table 29 Compounds (IB- 2) Production Examples Me NMR (CDCI3, ppm) Z4 D-20 C-C02Et 0.86-0.91 (3H, m), 4.29-4.39 (2H, m), 6.77-6.89 (1H, m), 8.01-8.11 (lH, m), 8.24-8.34 (1H, m). D * 21 C-CN 0.86-0.90 (3¾ m), 4.85 · 4.94 (1H, m), 6.79-6.91 (1H, m), 7.78-7.87 (lH, m), 8.35-8.40 (1H, m). D-22 c-conh2 0.86Ό.90 (3H, m), 7.07 * 7.13 (lH, m), 8.22-8.28 (1H, m), 8.34 -8.38 (1H, m). 86 314976 200410956

表30化合物（I-B-2)之製造實施例 Me NMR (CDCI3, ppm) Zi z2 1>23 N C-H 0.86-0.90 (3H，m)，4·82-4·91 (1H， m), 7.18-7.21 (2H, m), 8.10-8.16 (1H, m), 8.29-8.33 (lH, m). D-24 C-H N 0.85-0.90 (3H, m), 4.80*4.93 (lH, m), 6.62-6.72 (2H, m), 8.25-8:35 (2H, m).Table 30 Production Examples of Compound (IB-2) Me NMR (CDCI3, ppm) Zi z2 1> 23 N CH 0.86-0.90 (3H, m), 4 · 82-4 · 91 (1H, m), 7.18- 7.21 (2H, m), 8.10-8.16 (1H, m), 8.29-8.33 (lH, m). D-24 CH N 0.85-0.90 (3H, m), 4.80 * 4.93 (lH, m), 6.62- 6.72 (2H, m), 8.25-8: 35 (2H, m).

87 14976 200410956 表31化合物（I-B-2)之製造87 14976 200410956 Table 31 Manufacture of compound (I-B-2)

實施例 Η / J也严融點、MS、元素分析 NMR(CDCl3，ppm)及 Tr(min·) Ζι Z2 D-25-1 C-H C-H NMR： 0.89 (3H, br t), 4.72-4.98 (iH, m), 6.54 (lH, t, J = 4.8 Hz), 8.28-8.40 (2H, m). Tr 二 5.54. D-25-1-1 D-25-1之 C a 鹽結晶體融點：148-152°C, MS (m/z): 447 (MH+). 元素分析：C44H66N12CaOr4.75H20理論值 (%): C, 51.98; Η, 7·49; Ca，3.94; Ν，16·5& 測定值（％): C, 52.34; Η，7.39; Ca，4·07; Ν, 15.98. NMR： 0.86 (3Η, t, J = 6.7 Hz), 1.15-2.26 (13H, m), 3.26-4.13 (12H, m), 5.11 (lH, br), 6.51 (1H, t, J = 4.7 Hz), 7.47 (1H, br s), 8.31 (2H, d, J = 4.7Hz). D-25-1-2 D-25.1 之 HC1 鹽 MS (m/z)： 477 (MH+). NMR (DMSO-Λ)： 0.81-0.90 (3H, m), 1.12*2.21 (13H, m), 4.76-5.00 (lH, m), 6.66-6.73 (1H, m), 8.39-8.44 (1H, m). D-26 c-cf3 C-H NMR： 0.86-0.91 (3H, m), 4.82-4.91 (lH, m), 6.80*6.87 (1H, m), 8.50-8.54 (1H, m). D-27 c-nh2 C-H NMR： 0.82-0.97 (3H, m), 5.77*5.79 (1H, m), 7.88-8·00 (1H, m)· D-28 c-nh2 C-F NMR： 0.77-0.97 (3H, m), 7.79-7.85 (lH, m). TV = 3.42· D-29 C-OH C-H NMR (CDaOD)： 0.80-0.94 (3H, m), 5.78 and 5.80 (total 1H, both d, J = 6.0 Hz), 7.76 (1H, d, J = 6.4 Hz). 88 14976 200410956 表32化合物（I-B-2)之製造實施例 fyie Z4-Z3 NMR (CDCI3, ppm) Z1 z2 z3 z4 D-30 C-H N C-H C-H 0.86Ό.92 (3H, m), 6.75 (lH, d, J =7.1 Hz), 8.32 (1H, d, J = 7.1 Hz), 8.70 (lH, br s). D-31 C-OCH2Ph N C-H C-H 0.77-0.94 (3H, m), 5.37 (2H, s), 6.13-6.26 (1H, m), 7.23-7.50 (5H, m), 8.05-8.14 (iH, m). D-32 C-H C-H N C-H 0.86-0.90 (3H, m), 4.80-4.93 (1H, m), 7.79-7.93 (lH, m), 8.09-8.22 (1H, m). D-33 C-H C-H N C-CN 0.86Ό.91 (3H, m), 4.83-4.91 (1H, m), 8.07-8.10 (lH, m), 8.28-8.33 (1H, m). D-34 C-OEt N C-H N 0.86*0.91 (3H, m), 3.86.(3H, s), 6.10-6.20 (2H, m), 7.39-7.48 (lH, m). D-35 N C-H C-H N 0.86Ό.91 (3H, m), 4.86-4.94 (lH, m), 8.15*8.20 (lH, m), 8.55-8.57 (1H, m). 89 14976 200410956Example Η / J also has strict melting point, MS, elemental analysis NMR (CDCl3, ppm) and Tr (min ·) Z2 D-25-1 CH CH NMR: 0.89 (3H, br t), 4.72-4.98 (iH , m), 6.54 (lH, t, J = 4.8 Hz), 8.28-8.40 (2H, m). Tr di 5.54. D-25-1-1 D-25-1 C a salt crystal melting point: 148 -152 ° C, MS (m / z): 447 (MH +). Elemental analysis: C44H66N12CaOr4.75H20 theoretical value (%): C, 51.98; Europium, 7.49; Ca, 3.94; Ν, 16.5 & determination Value (%): C, 52.34; Η, 7.39; Ca, 4.07; Ν, 15.98. NMR: 0.86 (3Η, t, J = 6.7 Hz), 1.15-2.26 (13H, m), 3.26-4.13 ( 12H, m), 5.11 (lH, br), 6.51 (1H, t, J = 4.7 Hz), 7.47 (1H, br s), 8.31 (2H, d, J = 4.7Hz). D-25-1- 2 D-25.1 HC1 salt MS (m / z): 477 (MH +). NMR (DMSO-Λ): 0.81-0.90 (3H, m), 1.12 * 2.21 (13H, m), 4.76-5.00 (lH, m), 6.66-6.73 (1H, m), 8.39-8.44 (1H, m). D-26 c-cf3 CH NMR: 0.86-0.91 (3H, m), 4.82-4.91 (lH, m), 6.80 * 6.87 (1H, m), 8.50-8.54 (1H, m). D-27 c-nh2 CH NMR: 0.82-0.97 (3H, m), 5.77 * 5.79 (1H, m), 7.88-8 · 00 (1H , m) · D-28 c-nh2 CF NMR: 0.77-0.97 (3H, m), 7.79-7.8 5 (lH, m). TV = 3.42 · D-29 C-OH CH NMR (CDaOD): 0.80-0.94 (3H, m), 5.78 and 5.80 (total 1H, both d, J = 6.0 Hz), 7.76 ( 1H, d, J = 6.4 Hz). 88 14976 200410956 Table 32 Production Example of Compound (IB-2) fyie Z4-Z3 NMR (CDCI3, ppm) Z1 z2 z3 z4 D-30 CH N CH CH 0.86Ό.92 (3H, m), 6.75 (lH, d, J = 7.1 Hz), 8.32 (1H, d, J = 7.1 Hz), 8.70 (lH, br s). D-31 C-OCH2Ph N CH CH 0.77-0.94 (3H, m), 5.37 (2H, s), 6.13-6.26 (1H, m), 7.23-7.50 (5H, m), 8.05-8.14 (iH, m). D-32 CH CH N CH 0.86-0.90 (3H, m), 4.80-4.93 (1H, m), 7.79-7.93 (lH, m), 8.09-8.22 (1H, m). D-33 CH CH N C-CN 0.86Ό.91 (3H, m ), 4.83-4.91 (1H, m), 8.07-8.10 (lH, m), 8.28-8.33 (1H, m). D-34 C-OEt N CH N 0.86 * 0.91 (3H, m), 3.86. 3H, s), 6.10-6.20 (2H, m), 7.39-7.48 (lH, m). D-35 N CH CH N 0.86Ό.91 (3H, m), 4.86-4.94 (lH, m), 8.15 * 8.20 (lH, m), 8.55-8.57 (1H, m). 89 14976 200410956

表33化合物（I-B-2)之製造實施例 Me ηό /γλ 〇^Ν^Λ^Νγ> 〇〇丄R 300MHz NMR (CDC13, ppm) 及 Tr (min·) R D-36 0.83Ό.93 (3H, m), 6.94-7.04 (1H, m), 7.57-7.80 (3H, m), 7·83·8.01 (1H，m). Tr = 4.48. D-37 -N0<Klcl 0.86 (3H, t, J = 6.4 Hz), 6.90 (lH, dd, J = 2.2, 8.4 Hz), 7.46 (lH, d, J = 8.6 Hz), 7.94 (1H, d, J = 2.2 Hz). D-38 0.86-0.90 (3H, m), 4.84-4.93 (lH, m), 7.02-7.40 (4H, m). D-39 ·〇*〇 0.80*0.93 (3H, m), 6.43-6.60 (1H, m), 8.27-8.37 (2H, m). D-40 Me 0.86*0.92 (3H, m), 6.30-6.58 (lH, m), 8.25-8.35 (2H, m). D-41 Me 0.86-0.91 (3H, m), 6.30-6.58 (1H, m), 8.25-8.33 (1H, m). D-42 -N^N-f 0.88 (3H, br t), 1.17-2.27 (12¾ m), 2.87-3.23 (1H, m), 3.43^4.07 (12H, m), 4.63- 5.00 (1H, m), 7.33*7.43 (lH, m), 7.63- 7.93 (2H, m), 8.58 (lH, d, J = 3Hz), 8.20, 9.57 (total 1H, both s). D.43 0.88 (3H, br t), 1.17*2.73 (16H, m), 2.90-3.23 (1H, m), 3.43-4.07 (10H, m), 4.63-4.97 (1H, m), 7.17-7.27 (1H, m), 7.33*7.47 (1H, m), 7.60.7.77 (1H, m), 8.53-8.67 (1H, m), 8.35, 9.71 (total 1Π, both s). 90 314976 200410956 表34化合物（I-B-2)之製造實施例 Me NMR (CDC13, ppm) Re D-44 丨丨丨OH 0.86 (3H, br), 6.67 (lH, t, J = 4.8 Hz), 8.39 (2H, d, J = 4.8Hz). D-45 —OH 0.85 (3H, t, J = 7.1 Hz), 6.66 (1H, t, J = 4.8 Hz), 8.38 (2H, d, J = 4.8 Hz). D-46 —F 0.74-0.97 (3H，m), 4·93 (1H, dd, J = 9.5, 61.1 Hz), 6.51-6.62 (lH, m), 8.30*8.37 (2H, m). D-47 ""i〇-CH2Ph 0.77-0.94 (3H, m), 6.51-6.62 (lH, m), 7.28-7.41 (5H, m), 8.30*8.36 (lH, m). D-48 •|〇Me 0.77-0.97 (3H，m), 3·36 (3H, s), 6.51-6.62 (1H, m), 8.31-8.37 (2H, m). D-49 丨丨Ph 0.86-0.90 (3H, m), 6.51*6.60 (lH, m), 7.22-7.36 (5H, m), 8.28-8.37 (lH, m). D-50 —NH-Ac 0.89 (3H, t, J = 7.0 Hz), 1·97 (3H, s), 4.58-5.02 (2H, m), 6.52-6.64 (1H, m), 8.33 (2H, br d, J = 4.7 Hz). 91 314976 200410956 表35化合物（I-B-2)之製造實施例 Me ΗΌ f(CH2)rr-X MS 及 NMR(CDCl3，ppm) X n D-51 s 1 0.86 (3H, t, J = 6.9 Hz), 4.69 (lH, d, J = 8.4 Hz), 4.95 (1H, d, J = 8.4 Hz), 5.32 (2H, m), 6.54 (1H, t, J = 4.5 Hz), 8.32 (2H, d, J = 4.5 Hz). D-52 ch2 2 0.76Ό.91 (3H, m), 6.65 (lH, t, J = 4.8 Hz), 8.37 (2H, d, J = 4.8Hz). D-53 o 2 MS (m/z)： 463 (MH+). 0.88 (3H, t, J = 6.9 Hz), 1.20-2.10 (9H, m), 3.40-4.20 (16H, m), 5.29 (lH, d, J = 4.0 Hz), 6.54 (1H, t, J = 4.8 Hz), 7.80 (lH, s), 8.32 (2H, d, J = 4.8 Hz), 9.00-9.16 (lH, br).Table 33 Production Example of Compound (IB-2) Me ηό / γλ 〇 ^ Ν ^ Λ ^ Νγ > 〇〇丄 R 300MHz NMR (CDC13, ppm) and Tr (min ·) R D-36 0.83Ό.93 ( 3H, m), 6.94-7.04 (1H, m), 7.57-7.80 (3H, m), 7.83 · 8.01 (1H, m). Tr = 4.48. D-37 -N0 < Klcl 0.86 (3H, t , J = 6.4 Hz), 6.90 (lH, dd, J = 2.2, 8.4 Hz), 7.46 (lH, d, J = 8.6 Hz), 7.94 (1H, d, J = 2.2 Hz) .D-38 0.86- 0.90 (3H, m), 4.84-4.93 (lH, m), 7.02-7.40 (4H, m). D-39 · 〇 * 〇0.80 * 0.93 (3H, m), 6.43-6.60 (1H, m), 8.27-8.37 (2H, m). D-40 Me 0.86 * 0.92 (3H, m), 6.30-6.58 (lH, m), 8.25-8.35 (2H, m). D-41 Me 0.86-0.91 (3H, m), 6.30-6.58 (1H, m), 8.25-8.33 (1H, m). D-42 -N ^ Nf 0.88 (3H, br t), 1.17-2.27 (12¾ m), 2.87-3.23 (1H, m), 3.43 ^ 4.07 (12H, m), 4.63- 5.00 (1H, m), 7.33 * 7.43 (lH, m), 7.63- 7.93 (2H, m), 8.58 (lH, d, J = 3Hz), 8.20, 9.57 (total 1H, both s). D.43 0.88 (3H, br t), 1.17 * 2.73 (16H, m), 2.90-3.23 (1H, m), 3.43-4.07 (10H, m), 4.63 -4.97 (1H, m), 7.17-7.27 (1H, m), 7.33 * 7.47 (1H, m), 7.60.7.77 (1H, m), 8.53-8.67 (1H, m), 8.35, 9.71 (total 1Π, both s). 90 314976 200410956 Table 34 Production Example of Compound (IB-2) Me NMR (CDC13, ppm) Re D-44 丨丨丨 OH 0.86 (3H, br) , 6.67 (lH, t, J = 4.8 Hz), 8.39 (2H, d, J = 4.8Hz). D-45 —OH 0.85 (3H, t, J = 7.1 Hz), 6.66 (1H, t, J = 4.8 Hz), 8.38 (2H, d, J = 4.8 Hz). D-46 —F 0.74-0.97 (3H, m), 4.93 (1H, dd, J = 9.5, 61.1 Hz), 6.51-6.62 ( lH, m), 8.30 * 8.37 (2H, m). D-47 " " i〇-CH2Ph 0.77-0.94 (3H, m), 6.51-6.62 (lH, m), 7.28-7.41 (5H, m ), 8.30 * 8.36 (lH, m). D-48 • | MeMe 0.77-0.97 (3H, m), 3.36 (3H, s), 6.51-6.62 (1H, m), 8.31-8.37 (2H , m). D-49 丨丨 Ph 0.86-0.90 (3H, m), 6.51 * 6.60 (lH, m), 7.22-7.36 (5H, m), 8.28-8.37 (lH, m). D-50 — NH-Ac 0.89 (3H, t, J = 7.0 Hz), 1.97 (3H, s), 4.58-5.02 (2H, m), 6.52-6.64 (1H, m), 8.33 (2H, br d, J = 4.7 Hz). 91 314976 200410956 Table 35 Production Example of Compound (IB-2) Me ΗΌ f (CH2) rr-X MS and NMR (CDCl3, ppm) X n D-51 s 1 0.86 (3H, t, J = 6.9 Hz), 4.69 (lH, d, J = 8.4 Hz), 4.95 (1H, d, J = 8 .4 Hz), 5.32 (2H, m), 6.54 (1H, t, J = 4.5 Hz), 8.32 (2H, d, J = 4.5 Hz). D-52 ch2 2 0.76Ό.91 (3H, m) , 6.65 (lH, t, J = 4.8 Hz), 8.37 (2H, d, J = 4.8Hz). D-53 o 2 MS (m / z): 463 (MH +). 0.88 (3H, t, J = 6.9 Hz), 1.20-2.10 (9H, m), 3.40-4.20 (16H, m), 5.29 (lH, d, J = 4.0 Hz), 6.54 (1H, t, J = 4.8 Hz), 7.80 (lH, s), 8.32 (2H, d, J = 4.8 Hz), 9.00-9.16 (lH, br).

表36化合物（I-B-2)之製造實施例構造式 NMR (CDCls, ppm) D-54 H-〇P〇 0.82-1.05 (2H, m), 1.05-2.30 (15H, m), 4.63-5.0 (1H, m), 6·5·6.63 (1H, m)，8.27-8.40 (2H, m). D.55 Me H'〇〇/錢e 0.86 (3H，t, J = 6.6Hz)，2.82-4.00 (11H，m). 92 14976 200410956 表37化合物（I-B-2)之製造實施例構造式 MS (m/z) NMR (CDCls, ppm) D-56 NMR (CD30D): 1.03-2.35 (15H，m)，3.01.4.00 (13H, m), 4.78-5.05 (lH, m), 7.26 (lH, s), 7.45 (1H, dd, J = 4.8, 8.1 Hz), 7.81 (lH, s), 8.27 (lH, ddd, J = 1.5, 1.8, 8.1 Hz), 8.43 (lH, dd, J = 1.5, 4.8 Hz), 9.03 (1H, br d). D-57 NMR (CDsOD)： 1.05-2.34 (15H, m), 3.04-4.00 (13H, m), 4.81-5.03 (lH, m), 7.30 (lH, dd, J = 4.6, 8.4 Hz), 7.44 (1H, ddd, J = 1.3, 2.4, 8.4 Hz), 7.80 and 7.90 (total 1H, both s), 8.00 (lH, dd, J = 1.3, 4.6 Hz), 8.26 (1H, d, J = 2.4 Hz). D-58 Me MS (m/z)： 476 (MH+). NMR： 0.87-0.90 (4H, m), 1.25Ί.66 (10H, m), 1.85-2.15 (4H, m), 2.94-3.16 (5H, m), 3.49 (3H, s), 3.52-4.06 (6H, m), 4.74-4.86 (lH, m), 5.75 (lH, d, J = 6.2 Hz), 6.38 (1H, d, J = 9.1 Hz), 7.27 (lH, m), 7.84 (0.6 x 1H, br s), 8.35 (0.4 x 1H, br s). D-59 Me 〇λ〇，Κ> MS (m/z)： 522 (MH+). NMR (CD3OD)： 0.91(3H, t, J = 6.5 Hz), 1.18-2.32 (13H, m), 3.00-3.97 (20H, m). D-60 Me MS (m/z)： 514 (MH+). NMR (CDsOD)： 0.93 (3H, t, J = 6.8 Hz), 1.26-2.36 (10H, m), 3.03-3.96 (13H, m), 4.83-4.96 (lH, m), 7.02 (1H, s), 7·23·7.38 (3H, m), 7.82-7.84 (2H, m), 7.89 (1H, s). D-61 Me ho /r\ SMe MS (m/z)： 499 (MH+). NMR： 0.88 (3H, t, J = 6.2 Hz), 1.16*2.32 (13H, m), 2.59 (3H, s), 2.87-4.00 (12H, m), 4.65-4.90 (lH, m). D-62 Me °〇X0^ MS (m/z): 453 (MH+)· NMR (CDsOD)： 0.79-L00 (3H, m), 1.18.2.74 (13H, m), 3.00-4.03 (12H, m), 8.74 (lH, s). 93 314976 200410956Table 36 Production Examples of Compound (IB-2) Structural formula NMR (CDCls, ppm) D-54 H-〇PO〇 0.82-1.05 (2H, m), 1.05-2.30 (15H, m), 4.63-5.0 ( 1H, m), 6.5.56.63 (1H, m), 8.27-8.40 (2H, m). D. 55 Me H'〇〇 / 钱 e 0.86 (3H, t, J = 6.6Hz), 2.82- 4.00 (11H, m). 92 14976 200410956 Table 37 Production Example of Compound (IB-2) Structural formula MS (m / z) NMR (CDCls, ppm) D-56 NMR (CD30D): 1.03-2.35 (15H, m), 3.01.4.00 (13H, m), 4.78-5.05 (lH, m), 7.26 (lH, s), 7.45 (1H, dd, J = 4.8, 8.1 Hz), 7.81 (lH, s), 8.27 (lH, ddd, J = 1.5, 1.8, 8.1 Hz), 8.43 (lH, dd, J = 1.5, 4.8 Hz), 9.03 (1H, br d). D-57 NMR (CDsOD): 1.05-2.34 (15H , m), 3.04-4.00 (13H, m), 4.81-5.03 (lH, m), 7.30 (lH, dd, J = 4.6, 8.4 Hz), 7.44 (1H, ddd, J = 1.3, 2.4, 8.4 Hz ), 7.80 and 7.90 (total 1H, both s), 8.00 (lH, dd, J = 1.3, 4.6 Hz), 8.26 (1H, d, J = 2.4 Hz). D-58 Me MS (m / z): 476 (MH +). NMR: 0.87-0.90 (4H, m), 1.25Ί.66 (10H, m), 1.85-2.15 (4H, m), 2.94-3.16 (5H, m), 3.49 (3H, s) , 3.52-4.06 (6H, m), 4.74-4.86 (lH, m), 5.75 (lH , d, J = 6.2 Hz), 6.38 (1H, d, J = 9.1 Hz), 7.27 (lH, m), 7.84 (0.6 x 1H, br s), 8.35 (0.4 x 1H, br s). D- 59 Me 〇λ〇, K > MS (m / z): 522 (MH +). NMR (CD3OD): 0.91 (3H, t, J = 6.5 Hz), 1.18-2.32 (13H, m), 3.00-3.97 ( 20H, m). D-60 Me MS (m / z): 514 (MH +). NMR (CDsOD): 0.93 (3H, t, J = 6.8 Hz), 1.26-2.36 (10H, m), 3.03-3.96 (13H, m), 4.83-4.96 (lH, m), 7.02 (1H, s), 7.23.7.38 (3H, m), 7.82-7.84 (2H, m), 7.89 (1H, s) .D -61 Me ho / r \ SMe MS (m / z): 499 (MH +). NMR: 0.88 (3H, t, J = 6.2 Hz), 1.16 * 2.32 (13H, m), 2.59 (3H, s), 2.87-4.00 (12H, m), 4.65-4.90 (lH, m). D-62 Me ° 〇X0 ^ MS (m / z): 453 (MH +) · NMR (CDsOD): 0.79-L00 (3H, m ), 1.18.2.74 (13H, m), 3.00-4.03 (12H, m), 8.74 (lH, s). 93 314976 200410956

D-63 % Pry 〇A〇<^ MS (m/z): 466 (MH十 NMR: 0·88 (3H, t，J = 6.9 Hz), 1.06-2.56 (12H, m)， 2.31 (3H, s), 2.88-4.03 (13H, m), 4.78-4.97 (1H, m), 6.82-6.84 (1H, m), 7.89, 8.34 (lH, s). D-64 K。jP。飞Χ〇^χ: MS (m/z): 480 (MH+). NMR: 0.88 (3H, t, J = 6.9 Hz), 1.20.2.46 (12H, m), 2.13 (3H, s), 2.20 (3H, s), 2.93^4.01 (13H, m), 4.78-4.96 (1H, m), 7.79, 8.34 (lH, s). D-65 Me MS (m/z)： 447 (MH+). NMR： 0.77-0.97 (3H, m), 1.19*2.58 (13H, m), 2.39-4.10 (12H, m), 4.72-5.00 (lH, m), 6.85-7.00 (1H, m), 7.21-7.33 (1H, m), 8.60-8.69 (1H, m). D-66 Me Me MS (m/z)： 477 (MH+). NMR： 0.88 (3H, m), 1.22-1.73 (6H, m), 1.93-2.05 (1H, m), 2.16-2.21 (9H, m), 2.95-3.01 (5H，m), 3.47-3.72 (11H, m), 3.93 (lH, m), 4.71-4.93 (1H, m), 7.85 (0.6 x 1H), 8.36 (0.4 x 1H).. D-67 Me NMR (CDaOD)： 0.90 (3H, m), 1.32-1.61 (10H, m), 1.84-2.07 (3H, m), 2.26 (lH, m), 3.62-3.89 (10H, m), 467 (2H, m), 7.89 (0.8 x 1H, br s), 8.25 (0.2 x 1H, br s). D-68 fyie oX^? °〇XC^S 6 NMR： 0.88 (3H, m), 1.30Ί.63 (8H, m), 1.76-2.25 (4H, m), 3.23-3.82 (13H, m), 4.81 (lH, m), 7.56-7.69 (5H, m), 7.89 (0.75 x 1H), 8.23 (0.25 x 1H). D-69 MS (m/z)： 520 (MH+). NMR： 1.32 (9H, s), 4.74-4.95 (1H, m), 6.15*6.24 (1H, m). D-70 MS (m/z)： 492 (MH+). NMR： 1.25 (3H, t, J = 7.3 Hz), 2.67 (2H, q, J = 7.3 Hz), 4.73-4.94 (1H, m), 6.16-6.24 (1H, m). 94 314976 200410956 D-71 MS (m/z)： 558 (MH+). NMR： 4.74-4.97 (lH, m), 6.70-6.79 (lH, m), 7.01-7.14 (2H, m)，7.75-7.86 (2H，m). D-72 MS (m/z): 620 (MH+). NMR： 4.76-4.97 (lH, m), 6.74-6.85 (1H, m), 7.47-7.55 (2H, m), 7.66-7.78 (2H, m). D-73 ‘9n4n?<k^ MS (m/z): 598 (MH+). NMR： 1.75 (6H, s), 1.93 (6H, s), 2.05 (3H, s), 4.74-4.94 (1H, m), 6.12-6.18 (1H, m)· D-74 MS (m/z)： 527 (MH+). NMR： 0.90 (2H, m), 4.70-5.00 (1H, m), 6.75-6.90 (1H, m), 8.45-8.55 (1H, m). D-75 ^^Rr-Λ n-YCN 〇〇表 dii NMR： 0.89 (3H, br t), 4.70-4.93 (1H, m), 7.27 and 7.28 (total 1H, both s). D-76 0 入CKO NMR： 1.15-2.31 (15H, m), 4.86-4.93 (lH, m), 7.11 (1H, t, J = 7.6 Hz), 7.30 (1H, t, J = 7.6 Hz), 7.50 (1H，d, J = 7.6 Hz), 7.67 (1H, d, J = 7.6 Hz). D-77 XAc， NMR： 1.10-2.35 (15H, m), 4.86*4.95 (lH, m), 6.70 (1H, d, J 二 1.6 Hz), 6.85 (1H，d, J = 1.6 Hz). D-78 F 〇〇工〇»0h= F厂 NMR (CD3〇D)： 1.15-2.25 (15H, m), 4.83-4.90 (1H, m), 7.62-7.72 (lH, m). D-79 Me HO f f-χ 0〇X〇^ NMR： 0.86-0.92 (3H, m), 6.75 (iH, d, J = 7.1 Hz), 8.32 (1H, d, J = 7.1 Hz), 8.70 (lH, br s). 95 314976 200410956 實感例D - 8 0 (23)-1-{(211)-2-{[1^甲醯基->^羥基胺基）甲基]庚醯基卜2-{ [4-(4-乙氧基-2-嘧啶基>1-六氫吡啡基]羰基}吼咯烷D-63% Pry 〇A〇 < ^ MS (m / z): 466 (MH NMR: 0.88 (3H, t, J = 6.9 Hz), 1.06-2.56 (12H, m), 2.31 (3H , s), 2.88-4.03 (13H, m), 4.78-4.97 (1H, m), 6.82-6.84 (1H, m), 7.89, 8.34 (lH, s). D-64 K.jP. Fly 〇〇 ^ χ: MS (m / z): 480 (MH +). NMR: 0.88 (3H, t, J = 6.9 Hz), 1.20.2.46 (12H, m), 2.13 (3H, s), 2.20 (3H, s ), 2.93 ^ 4.01 (13H, m), 4.78-4.96 (1H, m), 7.79, 8.34 (lH, s). D-65 Me MS (m / z): 447 (MH +). NMR: 0.77-0.97 (3H, m), 1.19 * 2.58 (13H, m), 2.39-4.10 (12H, m), 4.72-5.00 (lH, m), 6.85-7.00 (1H, m), 7.21-7.33 (1H, m) , 8.60-8.69 (1H, m). D-66 Me Me MS (m / z): 477 (MH +). NMR: 0.88 (3H, m), 1.22-1.73 (6H, m), 1.93-2.05 (1H , m), 2.16-2.21 (9H, m), 2.95-3.01 (5H, m), 3.47-3.72 (11H, m), 3.93 (lH, m), 4.71-4.93 (1H, m), 7.85 (0.6 x 1H), 8.36 (0.4 x 1H): D-67 Me NMR (CDaOD): 0.90 (3H, m), 1.32-1.61 (10H, m), 1.84-2.07 (3H, m), 2.26 (lH, m), 3.62-3.89 (10H, m), 467 (2H, m), 7.89 (0.8 x 1H, br s), 8.25 (0.2 x 1H, br s). D-68 fyie oX ^? ° 〇XC ^ S 6 NMR: 0.88 (3H, m), 1.30Ί .63 (8H, m), 1.76-2.25 (4H, m), 3.23-3.82 (13H, m), 4.81 (lH, m), 7.56-7.69 (5H, m), 7.89 (0.75 x 1H), 8.23 (0.25 x 1H). D-69 MS (m / z): 520 (MH +). NMR: 1.32 (9H, s), 4.74-4.95 (1H, m), 6.15 * 6.24 (1H, m). D- 70 MS (m / z): 492 (MH +). NMR: 1.25 (3H, t, J = 7.3 Hz), 2.67 (2H, q, J = 7.3 Hz), 4.73-4.94 (1H, m), 6.16- 6.24 (1H, m). 94 314976 200410956 D-71 MS (m / z): 558 (MH +). NMR: 4.74-4.97 (lH, m), 6.70-6.79 (lH, m), 7.01-7.14 (2H , m), 7.75-7.86 (2H, m). D-72 MS (m / z): 620 (MH +). NMR: 4.76-4.97 (lH, m), 6.74-6.85 (1H, m), 7.47- 7.55 (2H, m), 7.66-7.78 (2H, m). D-73 '9n4n? &Lt; k ^ MS (m / z): 598 (MH +). NMR: 1.75 (6H, s), 1.93 (6H , s), 2.05 (3H, s), 4.74-4.94 (1H, m), 6.12-6.18 (1H, m) · D-74 MS (m / z): 527 (MH +). NMR: 0.90 (2H, m), 4.70-5.00 (1H, m), 6.75-6.90 (1H, m), 8.45-8.55 (1H, m). D-75 ^^ Rr-Λ n-YCN 〇〇 table dii NMR: 0.89 (3H , br t), 4.70-4.93 (1H, m), 7.27 and 7.28 (total 1H, both s). D-76 0 CKO NMR: 1.15-2.31 (15H, m), 4.86-4.93 (lH, m) , 7.11 (1 H, t, J = 7.6 Hz), 7.30 (1H, t, J = 7.6 Hz), 7.50 (1H, d, J = 7.6 Hz), 7.67 (1H, d, J = 7.6 Hz). D-77 XAc , NMR: 1.10-2.35 (15H, m), 4.86 * 4.95 (lH, m), 6.70 (1H, d, J 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz). D-78 F 〇〇工〇 »0h = F-factor NMR (CD3〇D): 1.15-2.25 (15H, m), 4.83-4.90 (1H, m), 7.62-7.72 (lH, m). D-79 Me HO f f- χ 0〇X〇 ^ NMR: 0.86-0.92 (3H, m), 6.75 (iH, d, J = 7.1 Hz), 8.32 (1H, d, J = 7.1 Hz), 8.70 (lH, br s). 95 314976 200410956 Real sense example D-8 0 (23) -1-{(211) -2-{[1 ^ methylamidino- > ^ hydroxyamino) methyl] heptylbiphenyl 2- {[4- ( 4-ethoxy-2-pyrimidinyl group> 1-hexahydropyridinyl] carbonyl group

(1)於實施例D-29中途過程所獲得之（2S)-l-{(2R)-2-{{N-[(2,4-二曱氧基苯基）曱氧基]-N-曱醯胺基}甲基}庚醯基卜 2_{[4-(4-羥基-2-嘧啶基）-1-六氫吡哄基]羰基}吼咯烷4〇〇毫克（0.6 5mmol)及甲基碘78# l(l.〇mm〇l)之THF溶液中加入碳酸鉀180毫克（ΐ·3mm〇l)，於6〇t：攪拌一晚。將反應液減壓濃縮，於殘渣中加入氯仿及水，將目的物從有機層抽出，用無水硫酸鎂乾燥後減壓蒸餾除去溶劑，獲得（2S)(1) (2S) -l-{(2R) -2-{{N-[(2,4-dimethoxyphenyl) fluorenyloxy] -N obtained in the middle of Example D-29 -Fluorenylamino} methyl} heptanylmethyl 2-{[4- (4-hydroxy-2-pyrimidinyl) -1-hexahydropyridinyl] carbonyl} hyrrolidine 400 mg (0.6 5 mmol) To a solution of methyl iodide 78 # 1 (1.0 mmmol) in THF was added 180 mg of potassium carbonate (ΐ · 3 mmmol), and the mixture was stirred at 60 t for one night. The reaction solution was concentrated under reduced pressure, chloroform and water were added to the residue, and the target substance was extracted from the organic layer. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain (2S).

羰基}口比咯烷380毫克（收率91〇/〇)。Carbonyl} ratio of 380 mg of pyrrolidine (yield 91/0).

、十〇虱丞-2·嘧啶基卜六氫吡哄基]羰基}吼咯烷。 314976 96 200410956 XH-NMR (CDC13): δ/ppm 0· 77 — 0· 94 (3H，m), 1. 2-2.3(1 2H, m), 1. 3 8 (3H, t, J = 7.1Hz), 2. 9-3. 0，3. 12 — 3. 2 3 (total 1 H, both m), 3.4 — 4. 0 5 (12H，m), 4. 34 (2H，d，J二 7. 1Hz)，4. 7 — 4. 77 (0. 3 0 X 1 H, b r d), 4. 8 4 -4. 9 6 (0. 7 0 X 1 H, m), 5. 98 一 6. 0 6 (1H, m), 8. 0 3-8. 10 (1H，m)· 實施例D-81 (2 8)-1-{(211)-2-[(>1-曱醯基->1-羥基胺基）曱基]庚醯基}-2-{[4-(4-甲氧基-2-嘧啶基）-1-六氫吡畊基]羰基}吼咯烷, 丞丞 · -2 · pyrimidinyl hexahydropyridinyl] carbonyl} arrolidine. 314976 96 200410956 XH-NMR (CDC13): δ / ppm 0 · 77 — 0 · 94 (3H, m), 1. 2-2.3 (1 2H, m), 1. 3 8 (3H, t, J = 7.1 Hz), 2. 9-3. 0, 3. 12 — 3. 2 3 (total 1 H, both m), 3.4 — 4. 0 5 (12H, m), 4. 34 (2H, d, J 2 7. 1Hz), 4. 7 — 4. 77 (0. 3 0 X 1 H, brd), 4. 8 4 -4. 9 6 (0. 7 0 X 1 H, m), 5. 98 — 6 0 6 (1H, m), 8. 0 3-8. 10 (1H, m) · Example D-81 (2 8) -1-{(211) -2-[(> 1- 曱醯-&Gt; 1-hydroxyamino) fluorenyl] heptanyl} -2-{[4- (4-methoxy-2-pyrimidinyl) -1-hexahydropyridyl] carbonyl} hyridine

以實施例D-80揭示之方法為基準，獲得標題化合物。 'H-NMR (COC I 3) : δ /p vm 0 . 8 9 ( 3 H, t , J = 6 . 9 Η z ), 3. 89(3 H，s) ,6.00 — 6.09(1 H, m)，8.02 — 8. 12(1 H, m). Trz=4. 08min. 實施例D-82 (2S)-l-{(2R)-2-{{N-[(2,4-二曱氧基苯基）甲氧基]-N-甲醯胺基}甲基}庚醯基}-2-{[4-(4-三氟甲磺醯氧基-2-嘧啶基）-1 -六氫吡畊基]羰基}吼咯烷Based on the method disclosed in Example D-80, the title compound was obtained. 'H-NMR (COC I 3): δ / p vm 0. 8 9 (3 H, t, J = 6.9 Η z), 3. 89 (3 H, s), 6.00 — 6.09 (1 H, m), 8.02 — 8. 12 (1 H, m). Trz = 4.08min. Example D-82 (2S) -l-{(2R) -2-{{N-[(2,4- 二(Methoxyphenyl) methoxy] -N-formamido} methyl} heptyl} -2-{[4- (4-trifluoromethanesulfonyloxy-2-pyrimidinyl) -1 -Hexahydropyridyl] carbonyl

97 314976 200410956 在冰冷下，於含有實施例D-29中途過程所獲得之 (2S)小{(2R)-2-{{N 一 [(2,4__二甲氧基笨基）甲氧基]善甲酿胺基}甲基}庚醯基}|{[4-(4·經基密啶基）小六氫吡哄基]徵基}哦洛烧610毫克（lmm〇i)及三乙胺&以（3_〇1) 之二氣甲烷12毫升溶液中加入三氟甲磺酸酐202#^ (1·2ΠΠΏ〇1)，攪拌4小時。於反應液中加入氯仿及水，將目的物從有機層抽出後用飽和碳酸氫鈉水溶液洗淨，用無水硫酸鎂乾燥。減壓蒸餾除去溶劑，殘渣經由矽膠管柱層析法（氣仿/甲醇=I/O至25/1)精製，獲得（23)」_{(211)_ 二-^^^^肛二甲氧基苯基”氧基卜^甲醯胺基^甲基^庚 &基}-2-{[4-(4-二氟甲績醯氧基_2-嘧啶基）_1_六氫吡哄基] 獄基}哦17各烧3 00毫克（收率4〇0/〇)。 W-NMR (CDCl3):5/ppm 〇· 65 —0· 97 (3H, m), 4· 71 - 4. 88 (2H, m), 6. 41-6· 53 (2H, m), 6· 55 (1H, d, J = 5. OHz), 7. 85 (〇. 5X1H, s), 8. 12 (0. 5 X 1 H, s), 8. 1 7 (1H, d, J = 5. 〇Hz). 實施例D - 8 3 (2S)-l-{(2R)-2-[(N-甲醯基經基胺基）甲基]庚醯基卜2-{[4-(4-嗎琳代基-2-嘧啶基卜六氫吡啡基]羰基}吼咯烷97 314976 200410956 (2S) small {(2R) -2-{{N 1 [(2,4__dimethoxybenzyl) methoxy) methoxy obtained in the middle of Example D-29 under ice cooling ] Synmethylamine} Methyl} heptyl} | {[4- (4 · Aminopyrimidinyl) Hexahydropyridyl] Hydroxyl 610 mg (lmm〇i) and three Ethylamine & was added with trifluoromethanesulfonic anhydride 202 # ^ (1. 2ΠΠΏ〇1) in a 12 ml solution of methane gas (3_〇1) and stirred for 4 hours. Chloroform and water were added to the reaction solution, and the target substance was extracted from the organic layer, washed with a saturated sodium bicarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (aerosol / methanol = I / O to 25/1) to obtain (23) ″ _ {(211) _ di-^^^^ Oxyphenyl "oxymethyl ^ methylaminoamino ^ methyl ^ heptyl} -2-{[4- (4-difluoromethylphenoxy_2-pyrimidinyl) _1_hexahydropyridine基基] 基} OH 17 each burned 300 mg (yield 400 / 〇). W-NMR (CDCl3): 5 / ppm 〇 65 — 0 · 97 (3H, m), 4. 71- 4. 88 (2H, m), 6. 41-6 · 53 (2H, m), 6.55 (1H, d, J = 5. OHz), 7. 85 (〇. 5X1H, s), 8. 12 (0. 5 X 1 H, s), 8. 1 7 (1H, d, J = 5. 0 Hz). Example D-8 3 (2S) -l-{(2R) -2-[( N-methylamidomethylamino) methyl] heptylbiphenyl 2-{[4- (4-morpholinyl-2-pyrimidinylhexahydropyridinyl] carbonyl} hyrrolidine

(1)將實施例D-82所獲得之化合物46〇毫克（〇.62mmol)及 98 314976 200410956 嗎啉218// l(2.5mmol)之乙醇l〇毫升溶液於7〇t：邊加煞邊攪拌一晚。將反應液減壓濃縮，於殘渣中加入氣仿及水，將目的物從有機層抽出，用無水硫酸鎂乾燥後減壓蒸鶴除去溶劑’獲得（28)-1-{(2尺）-2-{[义[(2，心二甲氧基苯基）甲氧基]曱醯胺基}甲基}庚醯基}-2-{[4-(4-嗎琳代基-2_。密σ定基）-1 -六氫吼哄基]戴基}吼洛烧450毫克（收率1〇〇%)。 1H —NMR (CDCl3):5/ppm 0. 79~0. 94(3H, m), 4. 7 1 - 4 · 8 8 ( 2 H, m), 5 · 8 7 (1 H, d，J = 6 · 〇 Η ζ ), β · 4 1 —6. 53 (2Η, m)，7· 85 (0· 5 X 1 Η, s), 7· 9 6 (1 Η, d, J = 6. OH ζ), 8. 10 (0. 5 X 1 Η, s) ⑺與貫施例D -1 -1之（3)揭示之方法同樣操作，獲得（2S)-l-{(2R)-2-[(N-曱醯基-N-經基胺基）甲基]庚酸基卜2-{[4_ (4-嗎啉代基-2-嘧啶基）-1-六氫吡哄基]羰基}吼,各烷。 ^-NMR (CDC 1 3) ： δ/ppm 〇 . 8 1 - 〇. 9 7 (3H, m), 1. 2 0 —2· 3 0 (1 2H, m)，2. 9 5-3· 〇〇，3· 1 7 — 3. 22 (t 〇tal 1 H, both m), 3. 30-4. 〇5 (20H, m), 4. 70 ~~4. 76 (〇. 30X1H, br d), 4. 82 — 4. gg (〇 7 〇 x 1 H, m)，5· 8 6 - 5. 9 4 (1 H, m), 7. 97 (1H，d, J=5· 9Hz)· 實施例D-84至D-92 與貫施例D - 8 3揭示之方法同樣操作，獲得以下之化合物。 314976 99 200410956(1) A solution of 46 mg (0.62 mmol) of the compound obtained in Example D-82 and 98 314976 200410956 10 ml of morpholine 218 / l (2.5 mmol) in ethanol was added to 70 t: Stir overnight. The reaction solution was concentrated under reduced pressure, and aerosol and water were added to the residue. The target substance was extracted from the organic layer, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (28) -1-{(2 feet)- 2-{[meaning [(2, cardiodimethoxyphenyl) methoxy] fluorenylamino} methyl} heptanyl} -2-{[4- (4-morpholinyl-2_. Dense stilbene group)-1 -Hexahydrosynthesis group] Daiji} Hou Luo burning 450 mg (100% yield). 1H —NMR (CDCl3): 5 / ppm 0. 79 ~ 0. 94 (3H, m), 4. 7 1-4 · 8 8 (2 H, m), 5 · 8 7 (1 H, d, J = 6 · 〇Η ζ), β · 4 1 — 6.53 (2Η, m), 7.85 (0 · 5 X 1 Η, s), 7. 9 6 (1 Η, d, J = 6. OH ζ), 8. 10 (0. 5 X 1 Η, s) ⑺ is the same as the method disclosed in (3) of Example D -1 -1, and (2S) -l-{(2R) -2 -[(N-fluorenyl-N-mercaptoamino) methyl] heptanoate 2-{[4_ (4-morpholino-2-pyrimidinyl) -1-hexahydropyridyl] Carbonyl}, each alkane. ^ -NMR (CDC 1 3): δ / ppm 0.8 1-0.9 7 (3H, m), 1. 2 0 —2 · 3 0 (1 2H, m), 2. 9 5-3 · 〇〇, 3. 17 — 3. 22 (t 〇tal 1 H, both m), 3. 30-4. 〇5 (20H, m), 4. 70 ~ 4.76 (〇. 30X1H, br d), 4. 82 — 4. gg (〇7 〇x 1 H, m), 5.86-5. 9 4 (1 H, m), 7. 97 (1H, d, J = 5.9 Hz ). Examples D-84 to D-92 were carried out in the same manner as in the method disclosed in Example D-8 3 to obtain the following compounds. 314976 99 200410956

表38化合物（I-B-2)之製造實施例 Me R1 NMR (CDCls, ppm) Ri D-84 -NHMe 0.86-0.92 (3H, m), 2.91 (3H, d, J = 2.6 Hz), 5.68-5.78 (1H, m), 7.86*7.94 (lH, m). D-85 0.87-0.90 (3H, m), 2.35 (3H, s), 5.88-5.94 (1H, m), 7.94 (1H, d, J = 6.1 Hz). D-86 Η 0.87-0.90 (3H, m), 4.71 (2H, d, J = 5.3 Hz), 5.81-5.88 (1H, m), 7.90 (lH, d, J = 5.7 Hz), 8.49-8.53 (1H, m). D-87 0.87-0.90 (3H, m), 5.70-5.76 (lH* m), 7.84-7.89 (1H, m). D-88 -NHCH2Ph 0.79-0.94 (3H, m), 5.72-5.79 (1H, m), 7.21-7.41 (5H, m), 7.85-7.94 (1H, m). D-89 H 0.77-0.94 (3H, m), 1.16-2.58 (13H, m), 2.87-4.03 (16H, m), 4.68-4.97 (lH, m), 5.16-5.32 (1H, m), 5.71-5.84 (lH, m), 7.77-7.90 (1H, m). D-90 -SMe 0.77Ί.00 (3H, m), 1.16*2.45 (13H, m), 2.49 (3H, s), 2.90-4.10 (12H, m), 4.68-5.00 (1H, m), 6.39*6.55 (1H, m), 7.90-8.03 (1H, m). D-91 0.68-0.97 (3H, m)，1.18-2.56 (13H, m〉， 2.88-4.06 (12H, m), 4.52 (2H, d, J = 5.3 Hz), 4.71-5.09 (2H, m), 5.71-5.85 (lH, m), 6.18-6.26 (lH, m), 6.29*6.35 (lH, m), 7.36 (1H, s), 7.86-7.93 (lH, m). D-92 -NMe2 0.82-0.94 (3H, m), 1.16-2.55 (13H, m), 2.87*4.06 (12H, m), 3.01-3.09 (6H, m), 4.68-4.94 (1H，m), 5.80-5.90 (1H, m), 7.87-4.94 (1H, m). 100 3]4976 200410956 實施例D-93 (23) + {(211)-2-[(>^曱醯基4_經基胺基）曱基]庚醯基卜2-{[4-(3-羧基-2·吼啶基）—i_六氫吡畊基]羰基}吼咯烷Table 38 Production Examples of Compound (IB-2) Me R1 NMR (CDCls, ppm) Ri D-84 -NHMe 0.86-0.92 (3H, m), 2.91 (3H, d, J = 2.6 Hz), 5.68-5.78 (1H, m), 7.86 * 7.94 (lH, m). D-85 0.87-0.90 (3H, m), 2.35 (3H, s), 5.88-5.94 (1H, m), 7.94 (1H, d, J = 6.1 Hz). D-86 Η 0.87-0.90 (3H, m), 4.71 (2H, d, J = 5.3 Hz), 5.81-5.88 (1H, m), 7.90 (lH, d, J = 5.7 Hz) , 8.49-8.53 (1H, m). D-87 0.87-0.90 (3H, m), 5.70-5.76 (lH * m), 7.84-7.89 (1H, m). D-88 -NHCH2Ph 0.79-0.94 (3H , m), 5.72-5.79 (1H, m), 7.21-7.41 (5H, m), 7.85-7.94 (1H, m). D-89 H 0.77-0.94 (3H, m), 1.16-2.58 (13H, m), 2.87-4.03 (16H, m), 4.68-4.97 (lH, m), 5.16-5.32 (1H, m), 5.71-5.84 (lH, m), 7.77-7.90 (1H, m). D- 90 -SMe 0.77Ί.00 (3H, m), 1.16 * 2.45 (13H, m), 2.49 (3H, s), 2.90-4.10 (12H, m), 4.68-5.00 (1H, m), 6.39 * 6.55 (1H, m), 7.90-8.03 (1H, m). D-91 0.68-0.97 (3H, m), 1.18-2.56 (13H, m>), 2.88-4.06 (12H, m), 4.52 (2H, d , J = 5.3 Hz), 4.71-5.09 (2H, m), 5.71-5.85 (lH, m), 6.18-6.26 (lH, m), 6.29 * 6.35 (lH, m), 7.36 (1H, s), 7.86 -7.93 (lH, m). D-92 -NMe2 0.82-0.94 (3H, m), 1.16-2.55 (13H, m), 2.87 * 4.06 (12H, m), 3.01-3.09 (6H, m), 4.68 -4.94 (1H, m), 5.80-5.90 (1H, m), 7.87-4.94 (1H, m). 100 3] 4976 200410956 Example D-93 (23) + ((211) -2-[(> ^ Amidyl 4-amylamino) Amidyl] heptyl] 2-{[4- (3-carboxy-2 · armidinyl) -i_hexahydropyridyl] carbonyl} arrolidine

於實施例D-20化合物〇·27公克（〇.52mm〇1)之乙醇溶液1毫升中加入1莫耳/ 1000毫升氫氧化鈉丨毫升，於室 /m攪:拌一日，〉辰細’除去乙醇後加入水、1 〇 %乙酸，用氯仿抽出。有機層用飽和食鹽水洗淨，用硫酸鎂乾燥後濃縮，獲得粗製物0.22公克。將粗製物經由矽膠管柱層析法（氯仿/曱醇= 30/1至6 /1)精製，獲得目的物 -2-[(N-甲醯基-N-羥基胺基）曱基]庚醯基卜2][4_(弘鲮基 2-□比啶基）-1 -六氫吡哄基]羰基}吼咯烷8〇毫克（收率 3 1%) 〇 MS (m/z) : 4 9 Ο (MH+)， 0. 89 (3H， br t), i· 〇! 4· 50 (13H，m)，4· —5 S)? 8* 50^8. 7〇 (2H, m). VH — NMR (CDC 1 3) : δ/ρ pm —2. 5 0 (1 2 H, m), 2. 5 0 — Ο Ο (1H, m), 7. 3 7 (1H, b r 實施例D-94 羰基}吼咯烷 (2S)-l-{(2R)-2-[(N-曱醯基，-經基胺基）甲基]庚酿基卜2_ {{4-[3-(N，N-二甲基胺基甲酿基）“六氫吼哄基 3】4976 101 2004109561 mol / 1000 ml of sodium hydroxide was added to 1 ml of the ethanol solution of the compound of Example D-20 (27.27 g (0.52 mm)), and stirred in a chamber / m: mix for one day,> Chen fine 'After removing ethanol, water and 10% acetic acid were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain 0.22 g of a crude product. The crude product was purified by silica gel column chromatography (chloroform / methanol = 30/1 to 6/1) to obtain the target compound 2-[(N-formamyl-N-hydroxyamino) fluorenyl] heptyl.醯基布 2] [4_ (Hong 鲮 yl 2- □ pyridinyl) -1 -hexahydropyridinyl] carbonyl} yrrolidine 80 mg (yield 31 1%) 〇MS (m / z): 4 9 Ο (MH +), 0.89 (3H, br t), i · 〇! 4 · 50 (13H, m), 4 · -5 S)? 8 * 50 ^ 8. 7〇 (2H, m) VH — NMR (CDC 1 3): δ / ρ pm — 2. 5 0 (1 2 H, m), 2. 5 0 — Ο Ο (1H, m), 7. 3 7 (1H, br) Example D-94 carbonyl} Horrolidine (2S) -l-{(2R) -2-[(N-fluorenyl, -alkylamino) methyl] heptyl 2_ {{4- [3- (N, N-dimethylaminomethylamino) "Hexyl 3" 4976 101 200410956

CO - _e2 (1) 在於實施例D-2〇中途過程所獲得之 {{N-[(2,4-二曱氧基苯基）曱氧基]曱醯胺基}曱基）庚醯基}-2-{[4-(3 -乙氧基羰基比啶基六氫吡哄基]羰基）吡咯烷1.25公克（i.87mm〇1)之乙醇溶液2毫升中加入1莫耳/ 1 0 0 0宅升氫氧化納4毫升，於室溫攪拌4日，濃縮，加入乙酸、水’用氯仿抽出。有機層用飽和食鹽水洗淨，用硫酸鎂乾燥後濃縮，獲得（2s)-i-{(2R)-2-{{N-[(2,4-二曱氧基笨基）曱氧基;μΝ_甲醯胺基}甲基）庚醯基}_2_{[4_(3_羧基-2-吼咬基）-1-六氫吡哄基]羰基}吼咯烷之粗製物1.08公克。 (2) 在㈤項所獲传化合物〇· 1 9公克（0.30mmol)之二氯曱烧溶液12毫升中加入50%二甲胺水溶液9〇毫克〇〇mm〇1) 及WSC 90毫克（〇.4 7mmol)，於室溫攪拌丨i曰後濃縮。加入飽和碳酸氫鈉水溶液，用氯仿抽出。有機層用飽和食鹽水洗淨，用硫酸鎂乾燥，濃縮，將所獲得之粗製結晶〇.23 公克經由矽膠管柱層析法（氯仿/曱醇=5〇/ 1至2〇/ 〇精製，獲得（2S)-l-{(2R)-2-{{N-[(254-二曱氧基苯基）甲氧基]-]^甲醯胺基}甲基}庚醯基卜2」4>[3_(}^，]^二甲基胺基甲醯基）-2-吡啶基六氫吡畊基]羰基}吼咯烷〇 ]3公克 (2步驟之收率66%)。 102 314976 200410956 ()將上述化合物與實施例…之⑺揭示之方法同樣處理，獲得甲酸基養經基胺基）甲基]庚酿基}-2-{{4-[3-(N,N_二甲基胺基甲酿基）n定小六氯吼哄基}羰基}D比咯烷41毫克（收率41%)。 MS (m/z) :517 (MH+), ^-NMR (CDC13) ： δ/ppm 〇. 88(3Ή, brt) 1 〇〇 -2. 27 (14H, m), 2. 86 (3H> s), 3. n (3H, s) 2 5 0-4. 0 0 (1 2H, m), 4. 73-5. 〇〇 (1H, m); 6. 93-6. 77 (1H, m), 7. 4 7- 7. 6 0 (1H, d, J = 7. 5Hz), 8. 17 一8· 3 Ο (1H, m). 實施例D-95 (2S)-l-{(2R)-2-[(N-甲醯基-N-經基胺基）曱基]庚醯基}一2-{{4-[3-(1-吡咯烷基羰基）-2-吡啶基]-1-六氫吡哄基]羰基} 吡咯烷CO-_e2 (1) is {{N-[(2,4-dimethoxyoxyphenyl) fluorenyl] fluorenyl} fluorenyl) heptanyl obtained in the middle of Example D-20. } -2-{[4- (3-ethoxycarbonyl group than pyridylhexahydropyridyl] carbonyl) pyrrolidine 1.25 g (i.87mm〇1) in 2 ml of ethanol solution was added 1 mole / 1 0 4 milliliters of sodium hydroxide 4 ml, stirred at room temperature for 4 days, concentrated, added acetic acid, water 'and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain (2s) -i-{(2R) -2-{{N-[(2,4-dimethoxyoxybenzyl) fluorenyl). μN_formamidinyl} methyl) heptyl} _2 _ {[4_ (3_carboxy-2-crotyl) -1-hexahydropyridyl] carbonyl} crude crude 1.08 g. (2) To 12 ml of the dichloromethane solution of 0.19 g (0.30 mmol) of the compound obtained in item (2), a 50% aqueous solution of dimethylamine (90 mg, 0 mm) and WSC 90 mg ( .4 7 mmol), stirred at room temperature, and then concentrated. A saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated, and the obtained crude crystals, 0.23 g, were purified by silica gel column chromatography (chloroform / methanol = 50/1 to 2〇 / 〇, (2S) -l-{(2R) -2-{{N-[(254-dimethoxyphenyl) methoxy]-] ^ methylamino} methyl} heptyl-2- 4 > [3 _ (} ^,] ^ dimethylaminomethylamidino) -2-pyridylhexahydropyridyl] carbonyl} hyrrolidine 3] g (yield 66% in 2 steps). 102 314976 200410956 () The above compounds were treated in the same manner as the method disclosed in Example ⑺ to obtain formic acid-based amidoamino) methyl] heptyl} -2-{{4- [3- (N, N_ (Dimethylaminomethyl), n-Hexachlor, carbonyl} D, 41 mg (41% yield) of pyrrolidine. MS (m / z): 517 (MH +), ^ -NMR (CDC13): δ / ppm 0.88 (3Ή, brt) 1 〇〇-2. 27 (14H, m), 2. 86 (3H > s ), 3. n (3H, s) 2 5 0-4. 0 0 (1 2H, m), 4. 73-5. 〇〇 (1H, m); 6. 93-6. 77 (1H, m ), 7. 4 7- 7. 6 0 (1H, d, J = 7. 5Hz), 8. 17-8. 3 〇 (1H, m). Example D-95 (2S) -l-{( 2R) -2-[(N-methylamino-N-methylamino) fluorenyl] heptanyl} -2-{{4- [3- (1-pyrrolidinylcarbonyl) -2-pyridyl ] -1-hexahydropyridyl] carbonyl} pyrrolidine

與實施例D-94揭示之方法同樣操作，獲得標題化合物。 ]H*^NMR (CDCI3) ： δ / ppm 0. 8 9 (3 H, b r t), 1.00 一 2· 2 7 (1 8H, m), 3. 0 7-4. 0 0 (1 6 H, m), 4. 7 3-5. 〇 0 (1 H, m)，6. 7 7 — 7· 〇〇 (1 H, m), 7. 5 0 — 7. 6 3 ( 1 H， dd，J = l· 83，7 . 3 0Hz), 8. 17-8. 3 0 (1 H, m). 103 314976 200410956 實施例D-96 (2 8)-1-{(211)-2-[(>^甲醯基-1^羥基胺基）曱基；]庚醯基卜2- {[4-(4-三甲基乙醯氧基-2-嘧啶基卜丨-六氫吡哄基）羰基}吡咯烷The title compound was obtained in the same manner as the method disclosed in Example D-94. ] H * ^ NMR (CDCI3): δ / ppm 0.8 9 (3 H, brt), 1.00-2. 2 7 (1 8H, m), 3. 0 7-4. 0 0 (1 6 H, m), 4. 7 3-5. 〇0 (1 H, m), 6. 7 7 — 7 · 〇〇 (1 H, m), 7. 5 0 — 7. 6 3 (1 H, dd, J = 1.83, 7. 30 Hz), 8. 17-8. 3 0 (1 H, m). 103 314976 200410956 Example D-96 (2 8) -1-{(211) -2- [ (> Methylpentyl-1 ^ hydroxyamino) fluorenyl;] heptanyl 2-([4- (4-trimethylethoxy-2-pyrimidinyl)-hexahydropyridine ) Carbonyl} pyrrolidine

(1)在冰冷下，於實施例D_29中途過程所獲得之 {(2R)-2-{{N-[(2,4-二曱氧基苯基）曱氧基]_N_甲醯胺基}曱基}庚醯基}-2_{[4-(4-羥基-2-嘧啶基）_；!_六氫吡哄基]羰基} 吡咯烷307毫克（0.5mmol)及三乙胺211//1〇 5mm〇1)之二氯曱烷溶液中加入三甲基乙醯氯74 # 1(〇.6mm〇1)，於室溫(1) {(2R) -2-{{N-[(2,4-Dimethoxyphenyl) fluorenyloxy] _N_formamidine group obtained in the middle of Example D_29 under ice cooling } Fluorenyl} heptanyl} -2 _ {[4- (4-hydroxy-2-pyrimidinyl) _;! _ Hexahydropyridyl] carbonyl} pyrrolidine 307 mg (0.5 mmol) and triethylamine 211 / / 1〇5mm〇1) in dichloromethane solution was added trimethylacetamido chloride 74 # 1 (0.6mm〇1), at room temperature

及水’將目的物從有機層抽出後用無水硫酸鎂乾燥。減壓蒸餾除去溶劑，殘渣經由矽膠管柱層析法(氯仿/曱醇=1/〇至25/1)精製，獲得 (23)小{(211)_2_{{叫（2,4_二甲氧基苯基）甲氧基叫甲醯胺幻甲基}庚醯基}-2-{ [4-(4-三曱基乙酿氧基〜密啶基）_ 卜六氫吡啡基]羰基}吡咯烷34〇毫克（收率丄〇〇%)。 ^H-NMR (CDC13): δ/ppm 0. 79-0. 9? (3H m) 4 7卜心 88 (2H，m)，6· 29 (1H，d，J = 5 3Hz)，6 38 -6. 56 (2H, m), 7. 85 (0. 5 X 1 H, s); 8. 12 (〇_ 5χι H，s)，8· 32 (1H，d，J = 5. 3Hz). (2)將上述化合物與實施例D—h】之（3)揭示之方法同樣處 3J4976 104 200410956 理，獲得（2S)-l-{(2R)-2-[(N-曱醯基-N-羥基胺基）曱基}庚醯基}-2-{ [4-(4-三曱基乙醯氧基-2-嘧啶基）-1-六氫吡畊基] 羰基}吡咯烷。 ΧΗ~ΝΜΚ (CDC13)： δ/ppm 0.8 9 (3H, t, J = 6. 9Hz), 1. 3 6 (9H，s), 6. 2 6 -6. 3 9 (1 H，m), 8. 2 9 — 8. 3 9 (1 H，m) · 實施例D-97至D-110 與實施例D-1-1揭示之方法同樣操作，獲得以下之化合物。表38-2化合物（I-B)之製造實施例構造式 MS (m/z) NMR (CDC13, ppm) D-97 MS (m/z)： 480 (MH+). NMR (CD3OD): 1.03-1.87 (12H，m)， 3.37-4.12 (16H, m), 5.27-5.32 (lH, m), 6.78 (1H, d, J = 3.6 Hz), 7.16 (1H, d, J =3.6 Hz). D-98 ^-οΡγλ 〇〇工0^ MS (m/z)： 493 (MH+). NMR (CDaOD)： 1.06-2.32 (16H； m), 3.08*3.90 (12H, m), 4.85-4.93 (lH, m), 7.80 (1H, s), 8.13 (lH, s). D-99 0：〇^Ϊ〇^Ρ3 MS (m/z)： 532 (MH+). NMR： 4.71-5.00 (lH, m), 7.01^7.09 (1H, m). D-100 u U S」 MS (m/z)： 546 (MH+). NMR： 4.74^4.97 (lH, m), 6.59-6.74 (1H, m), 7.04 (lH, br s), 7.21-7.26 (1H, m), 7.53 (lH, br s). D-101 〇 MS (m/z)： 546 (MH+). NMR： 4.74-4.98 (lH, m), 6.6Γ6.71 (1H, m)，7.28-7.42 (2H， m)} 7.83 (1H, br s). D-102 MS (m/z)： 541 (MH+). NMR： 4.74-4.97 (1H, m)， 7,36-7.46 (1H，m)，7.85.8.22 (3H， m). 8.65~8.76 (lH; m). 105 314976 200410956 D-103 MS (m/z)： 541 (MH+). NMR： 4.75*4.98 (lH, m), 7.00-7.10 (1H, m), 7.42*7.60 (1H, m), 8.23·8.40 (1H，m)，8.56 (1H， br s), 9.15 (lH, br s). D-104 MS (m/z)： 608 (MH+). NMR: 4.72-4.98 (1H，m)，6.89-6.98 (1H, m)3 7.63 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 8.2 Hz). D-105 NMR： 1.10-1.37 (6H, m), 6.61 (lH, t, J = 4.7 Hz), 8.33 (2H, d, J = 4.7 Hz). D-106 NMR： 1.13-1.37 (6H, m), 6.61 (lH, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.7 Hz). D-107 °^£〇^_2 NMR： 4.74-4.95 (lH, m)3 5.78 (1H, br), 7.00 (lH, br), 7.47 and 7.48 (total 1H, both s). D-108 NMR： 3.41-3.93 (16H, m), 4.73-4.96 (1H, m), 7*34 and 7.36 (total 1H, both s). D-109 NMR： 4.55 (2H, s), 4.73-4.95 (lH, m), 6.46, 6.48 and 6.52 (total 1H, each s). D-110 〇 9H f ΝΗΒη 〇o:NO0-F F NMR： 1.17-2.23 (15H? m), 4.56 (2H, m), 7.14*7.35 (6H, m). 實施例D-lll 使用實施例B-80所獲得之化合物，與實施例D-l-1 揭示之方法同樣操作，獲得以下之化合物。 ]〇6 314976 200410956And water ', the target substance was extracted from the organic layer, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 1 / 〇 to 25/1) to obtain (23) small {(211) _2 _ {{called (2,4_dimethyl) Oxyphenyl) methoxy is called methylamidomethyl} heptyl} -2- {[4- (4-trimethylethylacetoxy ~ melidinyl) _ hexahydropyridinyl] Carbonyl} pyrrolidine (340 mg, 100% yield). ^ H-NMR (CDC13): δ / ppm 0. 79-0. 9? (3H m) 4 7 Bu Xin 88 (2H, m), 6.29 (1H, d, J = 5 3Hz), 6 38 -6. 56 (2H, m), 7. 85 (0.5 X 1 H, s); 8. 12 (〇_ 5χ H, s), 8.32 (1H, d, J = 5. 3Hz) (2) The method described in Example D-h] (3) is the same as the method disclosed in (3) 3J4976 104 200410956, and (2S) -l-{(2R) -2-[(N-fluorenyl- N-hydroxyamino) fluorenyl} heptanyl} -2-{[4- (4-trimethylethylethoxy-2-pyrimidinyl) -1-hexahydropyridyl] carbonyl} pyrrolidine. ΧΗ ～ NMK (CDC13): δ / ppm 0.8 9 (3H, t, J = 6. 9Hz), 1. 3 6 (9H, s), 6. 2 6 -6. 3 9 (1 H, m), 8. 2 9 — 8. 3 9 (1 H, m) · Examples D-97 to D-110 were carried out in the same manner as the method disclosed in Example D-1-1 to obtain the following compounds. Table 38-2 Production Examples of Compound (IB) Structural formula MS (m / z) NMR (CDC13, ppm) D-97 MS (m / z): 480 (MH +). NMR (CD3OD): 1.03-1.87 ( 12H, m), 3.37-4.12 (16H, m), 5.27-5.32 (lH, m), 6.78 (1H, d, J = 3.6 Hz), 7.16 (1H, d, J = 3.6 Hz). D-98 ^ -οΡγλ 〇〇工 0 ^ MS (m / z): 493 (MH +). NMR (CDaOD): 1.06-2.32 (16H; m), 3.08 * 3.90 (12H, m), 4.85-4.93 (lH, m ), 7.80 (1H, s), 8.13 (lH, s). D-99 0: 0 ^ Ϊ〇 ^ P3 MS (m / z): 532 (MH +). NMR: 4.71-5.00 (lH, m), 7.01 ^ 7.09 (1H, m). D-100 u US "MS (m / z): 546 (MH +). NMR: 4.74 ^ 4.97 (lH, m), 6.59-6.74 (1H, m), 7.04 (lH , br s), 7.21-7.26 (1H, m), 7.53 (lH, br s). D-101 〇MS (m / z): 546 (MH +). NMR: 4.74-4.98 (lH, m), 6.6 Γ6.71 (1H, m), 7.28-7.42 (2H, m)} 7.83 (1H, br s). D-102 MS (m / z): 541 (MH +). NMR: 4.74-4.97 (1H, m ), 7,36-7.46 (1H, m), 7.85.8.22 (3H, m). 8.65 ~ 8.76 (lH; m). 105 314976 200410956 D-103 MS (m / z): 541 (MH +). NMR ： 4.75 * 4.98 (lH, m), 7.00-7.10 (1H, m), 7.42 * 7.60 (1H, m), 8.23 · 8.40 (1H, m), 8.56 (1H, br s), 9.15 (lH, br s). D-104 MS (m / z): 608 (MH +). NMR: 4.72-4.98 (1H, m), 6.89-6.98 (1H, m) 3 7.63 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 8.2 Hz). D-105 NMR: 1.10-1.37 (6H, m), 6.61 (lH, t, J = 4.7 Hz), 8.33 (2H, d, J = 4.7 Hz). D-106 NMR: 1.13-1.37 (6H, m), 6.61 (lH, t, J = 4.8 Hz), 8.33 (2H, d, J = 4.7 Hz). D-107 ° ^ £ 〇 ^ _2 NMR: 4.74-4.95 (lH, m) 3 5.78 (1H, br), 7.00 (lH, br), 7.47 and 7.48 (total 1H, both s). D-108 NMR: 3.41-3.93 (16H, m), 4.73-4.96 (1H, m), 7 * 34 and 7.36 (total 1H, both s). D-109 NMR: 4.55 (2H, s), 4.73-4.95 (lH, m ), 6.46, 6.48 and 6.52 (total 1H, each s). D-110 〇9H f ΝΗΒη 〇o: NO0-F F NMR: 1.17-2.23 (15H? M), 4.56 (2H, m), 7.14 * 7.35 (6H, m). Example D-11 The compound obtained in Example B-80 was used in the same manner as the method disclosed in Example D1-1 to obtain the following compound. ] 〇6 314976 200410956

MS (m/z) :4 8 0 (MH+). W — NMR (CDCl3):5/ppm 〇· 97 —2. 30 (15H，m)，2· 9 0 — 4. 3 2 (1 5 H, m), 4 . 71-4. 92 (1 H, m). 實施例D-l 12MS (m / z): 4 8 0 (MH +). W — NMR (CDCl3): 5 / ppm 〇 97 — 2. 30 (15H, m), 2. 9 0 — 4. 3 2 (1 5 H , m), 4. 71-4. 92 (1 H, m). Example Dl 12

於實施例D-l 10所獲得之化合物150毫克（0.25 1 mmol) 中加入乙醇5毫升、20%Pd(〇H)2-C 30毫克，在氫氣大氣下’在室溫攪拌7小時。將反應液過濾、濃縮，粗製物經由鹼性矽膠管柱層析法（氯仿/甲醇=20/ 1)精製，獲得目的物（2S)-l-{(2R)-3-環戊基-2-[(N-曱醯基羥基胺基）曱基}丙St基}-2-{[4-(2胺基- 3,5-二農-6-吼σ定基）-卜六氫吼哄基]獄基} D比洛：):完4 0毫克（收率3 1 %)。 MS (m/z) 5 〇 9 (ΜΗ+). 'H-NMR (CD3〇D) : δ/ρ pm 〇. 87-2. 22 ( 15 H, m), 3. 2 8 — 3. 7 8 (1 3H, m), 4. 8 2 — 4. 8 5 (1 H, m), 7. 16 -7. 23 (1H, m), 7. 80 (〇. 7 5 X 1 H, br s), 8. 26 (0. 2 5 X 1 H, b r s). 實施例D-1 13至D-143 根據上述參考例及貫施例揭示之方法或以該等方法為 3)4976 200410956 基準之方法可製造以下之化合物。表39化合物（I-B-2)之製造To 150 mg (0.25 1 mmol) of the compound obtained in Example D-11 was added 5 ml of ethanol and 30% of 20% Pd (OH) 2-C, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction solution was filtered and concentrated, and the crude product was purified by basic silica gel column chromatography (chloroform / methanol = 20/1) to obtain the target compound (2S) -1-{(2R) -3-cyclopentyl-2 -[(N-fluorenylhydroxyamino) fluorenyl} propyl Styl} -2-{[4- (2 amino-3,5-dinon-6-rho stilbyl) -buhexahydro Base] prison base} D Billow :): End 40 mg (yield 31%). MS (m / z) 5 〇9 (ΜΗ +). 'H-NMR (CD3〇D): δ / ρ pm 〇. 87-2. 22 (15 H, m), 3. 2 8 — 3. 7 8 (1 3H, m), 4. 8 2 — 4. 8 5 (1 H, m), 7. 16 -7. 23 (1H, m), 7. 80 (〇. 7 5 X 1 H, br s), 8. 26 (0. 2 5 X 1 H, brs). Examples D-1 13 to D-143 are based on the methods disclosed in the above reference examples and examples, or are based on these methods 3) 4976 200410956 benchmark This method can produce the following compounds. Table 39 Production of Compound (I-B-2)

108 314976 200410956108 314976 200410956

]〇9 314976 200410956] 〇9 314976 200410956

no 314976 200410956no 314976 200410956

由此所獲得之本發明化合物（ι_Β)，具有優越之抗菌作用，可作為抗菌劑使用。接著，揭示本發明化合物（I-B)，之抗菌作用。實驗例1 :於體外之抗菌活性（MIC(Minimal Ihibition Concentration) ·•微克 / 毫升）：以國際協會之臨床實驗標準（The National Committee for Clinical Laboratory Standards，NCCLS)所訂定之標準法為基準，測定最小發育阻止濃度（MIC :微克/毫升），獲得表40之結果。 ]]] 314976 200410956The compound (ι_B) of the present invention thus obtained has an excellent antibacterial effect and can be used as an antibacterial agent. Next, the antibacterial effect of the compound (I-B) of the present invention is disclosed. Experimental Example 1: In vitro antibacterial activity (MIC (Minimal Ihibition Concentration) · • μg / ml): Based on the standard method set by The National Committee for Clinical Laboratory Standards (NCCLS) The minimum developmental inhibitory concentration (MIC: microgram / ml) was obtained as shown in Table 40. ]]] 314976 200410956

表40於體外之抗菌活性（MIC :微克/毫升）菌株 MIC (微克/毫升） D小1 D-3-1 D-4-1 D-5 D-6 A 0.25 0.5 0.25 0.125 0.25 0.5 B 0.125 0.25 0.125 0.125 0.125 0.25 C 0.125 0.25 0.125 0.125 0.125 0.25 D 0.25 0.5 0.25 0.25 0.25 0.5 E 0.25 0.5 0.25 0.25 0.25 0.5, F 0.25 0.5 0.25 0.25 0.25 0.5 G 0.03 0.125 0.06 0.06 0.06 0.125 Η 0.25 0.5 0.125 0.25 0.25 1 1 0.5 1 0.25 1 2 0.5 J 0.125 0.5 0.125 0.5 025 1 K 1 2 0.25 2 1 1 L 0.5 2 0.5 2 1 2 Μ 0.125 0.5 0·125 1 0.5 0.125Table 40 Antibacterial activity in vitro (MIC: microgram / ml) Strain MIC (microgram / ml) D small 1 D-3-1 D-4-1 D-5 D-6 A 0.25 0.5 0.25 0.125 0.25 0.5 B 0.125 0.25 0.125 0.125 0.125 0.25 C 0.125 0.25 0.125 0.125 0.125 0.25 D 0.25 0.5 0.25 0.25 0.25 0.5 E 0.25 0.5 0.25 0.25 0.25 0.5, F 0.25 0.5 0.25 0.25 0.25 0.5 G 0.03 0.125 0.06 0.06 0.06 0.06 0.125 Η 0.25 0.5 0.125 0.25 0.25 1 1 0.5 1 0.25 1 2 0.5 J 0.125 0.5 0.125 0.5 025 1 K 1 2 0.25 2 1 1 L 0.5 2 0.5 2 1 2 Μ 0.125 0.5 0 · 125 1 0.5 0.125

1 !2 314976 200410956 表40(續）於體外之抗菌活性（MIC :微克/毫升）菌株 MIC{微克/亳升} D-7-1 D-8 D-9 D-10 D-11-1 D-12 A 0.25 0.25 0.125 0.5 0.25 0.5 B 0.125 0.125 0.125 0.25 0.06 0.25 C 0.25 0.125 0.125 0.25 0.125 0.25 D 0.25 0.25 0.25 0.5 0.125 0.5 E 0.5 0.25 0.25 0.5 0.125 1 F 0.25 0.25 0.25 0.5 0.125 0.5 G 0·06 0.06 0.06 0.06 0·03 0.125 Η 0.25 0.25 0.125 0.06 0.125 0.5 1 0.5 0.5 0.5 0.25 0.25 1 J 0.25 0.25 0.25 0-125 0.125 0,5 κ 0.5 0.5 0.5 0.25 0.125 2 L 2 1 1 2 0.25 2 Μ 0.25 0.125 0.25 0.5 0.125 0.125 113 314976 2004109561! 2 314976 200410956 Table 40 (continued) Antibacterial activity in vitro (MIC: μg / ml) Strain MIC {μg / ml} D-7-1 D-8 D-9 D-10 D-11-1 D -12 A 0.25 0.25 0.125 0.5 0.25 0.5 B 0.125 0.125 0.125 0.25 0.06 0.25 C 0.25 0.125 0.125 0.25 0.125 0.25 D 0.25 0.25 0.25 0.5 0.125 0.5 E 0.5 0.25 0.25 0.5 0.125 1 F 0.25 0.25 0.25 0.5 0.125 0.5 G 0.06 0.06 0.06 0.06 0 · 03 0.125 Η 0.25 0.25 0.125 0.06 0.125 0.5 1 0.5 0.5 0.5 0.25 0.25 1 J 0.25 0.25 0.25 0-125 0.125 0,5 κ 0.5 0.5 0.5 0.25 0.125 2 L 2 1 1 2 0.25 2 M 0.25 0.125 0.25 0.5 0.125 0.125 113 314976 200410956

表40(續）於體外之抗菌活性(MIC :微克/毫升）菌株 WHC (微克/毫升） D-13 D-14 D-15 D-16-1 化合物A%1 化合物Bx2 A 0,5 1 0.5 0.25 2 0.125 B 0.25 0.25 0.125 0.125 1 64 C 0.25 0.25 0.25 0.125 1 16 D 0.5 0.5 0.5 0.25 1 >128 E 0.5 0.5 0.5 0.25 2 0.125 F 0.5 0.5 0,5 0.25 1 >128 G 0.06 0.125 0.06 0.06 0.5 0.25 H 0.5 0.25 0.5 0.125 4 1 1 1 0.5 1 0.25 8 16 J 0.25 0.25 0.5 0.125 4 0.5 K 1 0.5 1 0.125 8 0.25 L 2 2 2 1 16 4 M 0.125 1 1 0.125 0.5 0.06 菌株 A :金黃色葡萄球菌菌株B:金黃色葡萄球菌㈣rews) KT0150 (MRSA)*3 菌株C :金黃色葡萄球菌（57a/?/73；/wcz^⑽7yz^)KT0130 (MRSA)*3 菌株 D :金黃色葡萄球菌（ί/7);/ococ⑶s azyreι/s)KT0 ]. 1 6 (MRSA)*3Table 40 (continued) Antibacterial activity in vitro (MIC: μg / ml) Strain WHC (μg / ml) D-13 D-14 D-15 D-16-1 Compound A% 1 Compound Bx2 A 0,5 1 0.5 0.25 2 0.125 B 0.25 0.25 0.125 0.125 1 64 C 0.25 0.25 0.25 0.125 1 16 D 0.5 0.5 0.5 0.25 1 > 128 E 0.5 0.5 0.5 0.25 2 0.125 F 0.5 0.5 0,5 0.25 1 > 128 G 0.06 0.125 0.06 0.06 0.5 0.25 H 0.5 0.25 0.5 0.125 4 1 1 1 0.5 1 0.25 8 16 J 0.25 0.25 0.5 0.125 4 0.5 K 1 0.5 1 0.125 8 0.25 L 2 2 2 1 16 4 M 0.125 1 1 0.125 0.5 0.06 Strain A: Staphylococcus aureus Strain B: S. aureus ㈣rews) KT0150 (MRSA) * 3 Strain C: S. aureus (57a /? / 73; / wcz ^ ⑽7yz ^) KT0130 (MRSA) * 3 Strain D: S. aureus (ί / 7); / ococ⑶s azyreι / s) KT0]. 1 6 (MRSA) * 3

菌株 E :金黃色葡萄球菌（iSVap/iv/ococds 209P Π4 314976 200410956 菌株F :金黃色葡萄球菌（57叩办⑽rew)KMP9 (MRSA)*3 囟株G ·表皮葡萄球菌（a叩印以以”对油、） ATCC12228 囷株Η ·肺k葡萄球菌（心叩六少/wew :以） ATCC49619 菌株 1 :肺炎葡萄球菌pW 777 0；7Z.W)KT2524 (PRSP)*3 ΐί株J ·肺乂葡萄球菌广⑽㈣?⑽ζ·ββ)ΚΤ2534 (PRSP)*3 囷株K ·釀版葡萄球菌（&叩/7y/〇e〇CCWtSI么Y义αα) ATCC12344 菌株L ··腸球菌（五;謂）ATCC19434 fe 株 Μ : Λ/〇Γ(3<Χ6//α(〜氺4 * ]化合物A :為具有本說明書第2項揭示之構造，揭示於國際公開第99/ 3 9704號說明書實施例12之比較對照化合物。 *2化合物B :為具有下述構造之市售吡啶酮羧酸系抗菌劑 (基晋沙辛（Ciprofl〇xacin))Strain E: Staphylococcus aureus (iSVap / iv / ococds 209P Π4 314976 200410956 Strain F: Staphylococcus aureus (57) rewrew) KMP9 (MRSA) * 3 Strain G · Staphylococcus epidermidis (a) For oil,) ATCC12228 Bacillus spp. Lung k. Staphylococcus pneumoniae (heart sacrifice six / wew: to) ATCC49619 Strain 1: Staphylococcus pneumoniae pW 777 0; 7Z.W) KT2524 (PRSP) * 3 株 J Strain L. Staphylococcus aureus ⑽ζ · ββ) Κ2534 (PRSP) * 3 strain K · brewed staphylococcus (& 叩 / 7y / 〇e〇CCWtSI Mody Yαα) ATCC12344 strain L · Enterococcus (five; said ) ATCC19434 fe Strain M: Λ / 〇Γ (3 < × 6 // α (~ 氺 4 *) Compound A: It has a structure disclosed in the second item of this specification, and is disclosed in Examples of International Publication No. 99/3 9704 Comparative control compound of 12. * 2 Compound B: a commercially available pyridonecarboxylic acid-based antibacterial agent (Ciprofloxacin) having the following structure

本株為臨床分離株。本株為革蘭氏陰性菌，其他為革蘭氏陽性菌。 314976 )]5 200410956 菌株Η至K可經由微量液體稀釋法可經由瓊脂平板稀釋法測定。、，/、他之菌株實驗例2 :對於老鼠全身感染症之效果· 對於老鼠全身感染症之效果（叫。半數有效劑量獅重…幻每隻由腹腔内投予^ 里約5〇倍量之上述病原菌(A至C)之生菌：木致死時後2次皮下投予㈣，從感染7日後老氧生存^ 小德法异出。其結果如表41所示率以晋必This strain is a clinical isolate. This strain is Gram-negative bacteria, the others are Gram-positive bacteria. 314976)] 5 200410956 Strains Η to K can be determined by micro liquid dilution method can be determined by agar plate dilution method. 、 / 、 His strains Experimental example 2: Effect on mouse systemic infection · Effect on mouse systemic infection The bacteria of the above pathogenic bacteria (A to C): 2 times subcutaneously administered to the salamander after the death of the wood, and survived from the oxygen 7 days after the infection

驗化合物溶解於生理食鹽水之溶液於感染】^ ，將試 Π6 314976 200410956 由上仔知，本發明化合物中R9為氫原子或R之化合物（I-B)，或其生理上所容 h之化其毒性亦低。例如，如表40所一編之“作用，且表4〇所示之本發明化合物，於具有比化合物A更優越之> ^ 、版外棱越之抗困活性，於體内之抗菌作用亦強。又，例如 D-1-i、D-3 1 τλ 1 U 3]、D_7]、D_14、D] 1、D-17、D-25-1 及 “… 之化合物對於老鼠之急性毒性值 (LD50，Le ehal dose Hfty，丰齡鉍沉…曰.、 y牛數致死劑夏π)都大於1〇〇毫克/公斤，該等為益卷松―、主 …毋性或毒性極低之化合物。因此，本發明化合物（I-B)，吱J：吐裡u α〜 4 上所容許之鹽可作為人類物之抗菌劑使用。本發明化合物（I _ B )，之;曰> _Ln 7 卜 1 )之杈予篁依投予方法、症狀、年齡寺而異，通常每日每6f)八冷 △斤重投予約2至5000毫克，較好約5至500臺吉，话從从。Λ 毛克，更好約30至3〇〇毫克。投予途徑可為經口投予，但是軔始笛非疋軏推薦非經口投予，尤其是靜脈内投予。本^月化口物〜B)’ 一般以製劑形態投予。該等製劑可將化合物（I-B)與製劑化成分配合而調製。例如，於非經口权予衣』之液剡中之製劑化成分，水、生理食鹽水等溶劑為必須成分，除此之外亦可適當配合等張化劑、無痛化劑、 PH調節劑、緩衝劑、保存劑等辅助成分。如注射劑之液劑可經由將化合物（I-B)，溶解於注射用生理食鹽水等溶， ^ ^ a ^ 視而要，方; >谷解前或溶解後與其他輔助成分配合而調製。康結乾燥製劑可將該等液劑;東結乾燥而調製，於投予時再加以溶解。 [產業上利用之可能性] in Π4976 200410956The test compound was dissolved in a physiological saline solution for infection] ^, test Π 6 314976 200410956 from the above, R9 in the compounds of the present invention is a hydrogen atom or a compound (IB) of R, or its physiological content h The toxicity is also low. For example, as shown in Table 40, the "actions" and the compounds of the present invention shown in Table 40 have superior anti-drowsiness activity than Compound A, ^, anti-drowsiness outside the plate, and antibacterial effect in vivo. Also strong. Also, for example, acute toxicity to rats of compounds D-1-i, D-3 1 τλ 1 U 3], D_7], D_14, D] 1, D-17, D-25-1 and "... The values (LD50, Le ehal dose Hfty, bismuth at high age…, y number of lethal agents Xia π) are all greater than 100 mg / kg, these are Yiwansong——, the main ... Of compounds. Therefore, the compound (I-B) of the present invention can be used as an antibacterial agent for human beings as the salt allowed in J: Turi u α ~ 4. The compound of the present invention (I_B), which is called > _Ln 7 bl 1), varies depending on the method of administration, symptoms, and age, and is usually administered about 2 to 8 times per day at 6f) 5000 milligrams, preferably about 5 to 500 Taiwan dollars, from the beginning. Λ gram, more preferably about 30 to 300 mg. The route of administration can be oral, but 轫 Shi Di Fei 疋軏 recommends non-oral administration, especially intravenous administration. This product is usually administered in the form of a preparation. These preparations can be prepared by compounding the compound (I-B) with a formulation component. For example, for liquid formulations in parenteral clothing, solvents such as water and physiological saline are essential components. In addition to this, an isotonicity agent, an analgesic agent, and a pH adjuster may be appropriately added. , Buffering agents, preservatives and other auxiliary ingredients. For example, the liquid preparation of an injection can be prepared by dissolving the compound (I-B) in physiological saline for injection, etc. ^ ^ a ^ Depending on the formula, > Compounding with other auxiliary ingredients before or after dissolution. Kangjie dried preparations can be prepared with these liquid preparations; Dongjie dried and prepared, and then dissolved when administered. [Possibility of Industrial Use] in Π4976 200410956

本發明化合物（Ι-B)’或其生理上所容許之鹽對於多劑耐性菌具有優越之作用，可作為抗菌劑使用。又，本發明化合物（Ι-A)或其鹽可作為化合物（I-B)之直接製造中間體使用。 ]]8 314976The compound (I-B) 'of the present invention or a physiologically acceptable salt thereof has an excellent effect on multi-dose resistant bacteria and can be used as an antibacterial agent. The compound (I-A) or a salt thereof of the present invention can be used as an intermediate for the direct production of the compound (I-B). ]] 8 314976

Claims

拾、申請專利範圍： 1· 一種通式- )斤不之脯氨酸衍生物或其鹽：Scope of patent application: 1. A general formula-) Proline derivative or its salt:

可舁可I _素原子取代之苯環進行縮合之5至6員雜琿基， " Pi為〇或1之整數，p2為〇或i之整數，p3為〇或1之整數， R]、尺2及Rs結合於A環上之任何位置，可相同或不同’為可經1至3個鹵素原子或羥基（該羥基亦可用醯基保護）取代之低級烷基、氫原子、低級烷氧基、低級烷硫基、il素原子、羥基、胺基或胺基羰基（該胺基可經保瘦或以低級烷基單或二取代）、羥基低級烷胺基、羧基、低級烷氧基羰基、低級烷基羰基氧基、可經 1至3個i素原子取代之低級烷基磺醯氧基或氰基， pl=P2=l時，同一碳原子所結合之心及& 一起形成氧代基或pl=p2 = p3：=l時，Ri及r2為氫原子，&為5至6 員飽和或不飽和環狀基（a)，其係與A環直接結合或藉由戴基、亞胺基低級伸烧基或氧基低級伸垸基結合，環狀基（a)之構成原子可含有1至2個雜原子，環狀基（a) Π9 314976 亦可經鹵素原子取代之低級烷基或ii素原子取代， τ為單鍵，為伸曱基或羰基， r4及r5可相同或不同，為氫原子或低級烷基，或是結合於同一碳原子之二者一同形成氧代基， m為1或2之整數， R6及R7可相同或不同，為氫原子、羥基、鹵素原子、低級烷基、苯基、低級烷氧基、苯基低級烷氧基、可經保護之胺基’亦可一者一同形成飽和環狀基， X為喊原子（CH2、CH、C)、硫原子或氧原子，η為 1或2之整數， Υ為下述式所示之基（b)A 5- to 6-membered heterofluorenyl group which can be condensed by a benzene ring substituted by a prime atom, " Pi is an integer of 0 or 1, p2 is an integer of 0 or i, p3 is an integer of 0 or 1, R] , Chi 2 and Rs can be combined at any position on the A ring, which may be the same or different. 'It is a lower alkyl group, hydrogen atom, lower alkyl group which may be substituted by 1 to 3 halogen atoms or a hydroxyl group (the hydroxyl group may also be protected by a fluorenyl group). Oxy, lower alkylthio, il element, hydroxy, amine or amine carbonyl (the amine can be thinned or mono- or di-substituted with lower alkyl), hydroxy lower alkylamino, carboxyl, lower alkoxy Carbonyl group, lower alkylcarbonyloxy group, lower alkylsulfonyloxy group or cyano group which can be substituted by 1 to 3 i element atoms, when pl = P2 = 1, the heart of the same carbon atom and & together When an oxo group is formed or pl = p2 = p3: = 1, Ri and r2 are hydrogen atoms and & is a 5- to 6-membered saturated or unsaturated cyclic group (a), which is directly bonded to the A ring or through Diyl, imino-lower alkynyl or oxy-lower fluorenyl are combined. The constituent atoms of the cyclic group (a) may contain 1 to 2 heteroatoms. The cyclic group (a) Π9 314976 It can be substituted by a lower alkyl or ii element atom substituted by a halogen atom, τ is a single bond, is a fluorenyl group or a carbonyl group, r4 and r5 may be the same or different, are a hydrogen atom or a lower alkyl group, or are bonded to the same carbon atom The two together form an oxo group, m is an integer of 1 or 2, R6 and R7 may be the same or different, and are a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a phenyl group, a lower alkoxy group, and a phenyl lower alkyl group. Oxygen, the amine group that can be protected may also form a saturated cyclic group together, X is a yell atom (CH2, CH, C), a sulfur atom or an oxygen atom, η is an integer of 1 or 2, and Υ is the following The base shown in the formula (b)

此處’ Rs為烧基或環烧基低級烷基，&為氫原子、經基保護基或 R9a。R9a 為 R9a】-C〇-、R9a2_〇_CC) 、R ” (CH2_)p- ’ Rw為低級烧基（該低級烧基可經1種戋2種選自苯基、經保護之胺基及羧基之基取代）、單低級烷基取代胺基、可將6 H和環狀胺基取代之6員飽和環狀胺基、可經羥基取代之c^c】g芳基或可與苯迨進行縮合之5至6員飽和或不飽和雜環基，、仃可 Rw為低級烷基、可經低級烷基取代之環烷美經低級烷基取代之5員飽和環狀酯殘基，兀土，飽和為經低級烷基取代、可與苯環縮合之$ 3M976 120 或不飽和環狀酯殘基或環狀碳酸酯殘基，P為0或1之整數）。如申請專利範圍第1項之脯氨酸衍生物或其鹽，其中，通式（I)所示之脯氨酸衍生物或其鹽中： pi 及 ρ2 為 1 ’ ρ3 為〇， R〗及I可相同或不同，為可經1至3個鹵素原子取代之低級烧基、氫原子、低級烷氧基、鹵素原子、羥基、胺基或胺基羰基（該胺基可經保護或以低級烷基單或二取代）、羧基、低級烷氧基羰基、低級烷基羰基氧基、可經1至3個_素原子取代之低級烷基磺醯氧基或氛基，R]為氫原子，R2為5至6員飽和或不飽和環狀基（a)與Α ϊ展直接結合或是藉由亞胺基低級伸烷基或氧基低級伸烧基結合，環狀基（a)之構成原子可含有1至2 個雜原子’環狀基（a)可經低級烧基取代， T為單鍵， R4及在B環上之任意位置結合，可相同或不同，為氣原子或低級烧基，或結合於同一碳原子之二者一同形成氧代基， m為1或2之整數，反6及R7可相同或不同，為氫原子、羥基、鹵素原子、低級烷基、笨基、低級烷氧基、苯基低級烷氧基、可經保墁之胺基，亦可二者一同形成飽和環狀基， X為碳原子（CH2、CH、C)、硫原子或氧原子，η為 1或2之整數， 314976 200410956 Y為下述式所示之基（b)Here, Rs is a lower alkyl group or a lower alkyl group, and & is a hydrogen atom, a protective group for a radical, or R9a. R9a is R9a] -C〇-, R9a2_〇_CC), R "(CH2_) p- 'Rw is a lower alkyl group (the lower alkyl group may be selected from 1 type, 2 types selected from phenyl, protected amine Group and carboxyl group substitution), mono-lower alkyl-substituted amine group, 6-membered saturated cyclic amine group which can be substituted with 6 H and cyclic amine group, c ^ c] g aryl group which can be substituted with hydroxyl group or 5- to 6-membered saturated or unsaturated heterocyclic group with phenylhydrazone condensed, Rw may be lower alkyl, cycloalkyl may be substituted with lower alkyl, 5-membered saturated cyclic ester residue substituted with lower alkyl , Wutu, saturated with lower alkyl substituted, can be condensed with benzene ring $ 3M976 120 or unsaturated cyclic ester residues or cyclic carbonate residues, P is an integer of 0 or 1). The proline derivative or its salt according to item 1, wherein in the proline derivative or its salt represented by the general formula (I): pi and ρ2 are 1 ′, ρ3 is 0, and R} and I may be the same or Different, it is a lower alkyl group, a hydrogen atom, a lower alkoxy group, a halogen atom, a hydroxyl group, an amine group, or an amine carbonyl group which may be substituted by 1 to 3 halogen atoms (the amine group may be protected Mono- or di-substituted with lower alkyl), carboxyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylsulfonyloxy or aryl group which may be substituted by 1 to 3 atoms, R] is A hydrogen atom, R2 is a 5 to 6-membered saturated or unsaturated cyclic group (a) which is directly bonded to Aϊ, or is bonded through an imino-lower alkylene group or an oxy-lower alkylene group, and the cyclic group (a The constituent atom of) may contain 1 to 2 heteroatoms. The cyclic group (a) may be substituted by a lower alkyl group, T is a single bond, R4 and any position on the B ring are combined, and may be the same or different, and are gas atoms. Or a lower alkyl group, or two bonded to the same carbon atom together to form an oxo group, m is an integer of 1 or 2, trans 6 and R7 may be the same or different, and are a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, Benzyl, lower alkoxy, phenyl lower alkoxy, amine group that can be protected, or both can form a saturated cyclic group, X is carbon atom (CH2, CH, C), sulfur atom or oxygen Atom, η is an integer of 1 or 2, 314976 200410956 Y is a base (b) represented by the following formula

此處，R8為烷基或環烷基低級烷基，R9為氫原子或羥基保護基。Here, R8 is an alkyl group or a cycloalkyl lower alkyl group, and R9 is a hydrogen atom or a hydroxy protecting group.

3. —種通式（Ι-B)所示之脯氨酸衍生物或其鹽，3. a proline derivative represented by the general formula (I-B) or a salt thereof,

P2 (式中，各符號及取代基之定義與申請專利範圍第1項之定義者同意義）。 4.如申請專利範圍第3項之脯氨酸衍生物或其鹽，其中，該化合物為式（Ι-C)所示者：P2 (In the formula, the definition of each symbol and substituent is the same as the definition of item 1 in the scope of patent application). 4. The proline derivative or its salt according to item 3 of the scope of application for a patent, wherein the compound is represented by formula (I-C):

H〇' OHC (式中，R]、R2、R3、R4、R5、η、p 1、p2、p3 及之定義與申請專利範圍第1項之定義者同意義，A]環為具有1至3個雙鍵之不飽和5至6員單環雜環基，該雜 122 314976 200410956 環基可與可經_素原子取代之 Z、Z、7 尽衣進仃縮合，此處， c…3及4可相同或不同，為選自碳原子(ch7、子二)、氮原子(丽或氮原子)、硫原子及氧原子之原二?：，亦有21、22〜24之任何-個不存在之 % 6 Rl、I及1與構成八】環之任仿义门山原子結合，R及R可相nk 碳原子或氮 an 631及731叮相同或不同，為氫原子、低級 /兀暴鹵素原子或低級烷氧基，X，為石山店7 或C)或氧原子）。 “為奴原子（CH2、CH 5.如申請專利範圍第4項之脯氨酸衍生物或其鹽该化合物為下述式（Ι-D)所示者· ’、H〇 'OHC (where R], R2, R3, R4, R5, η, p1, p2, p3 and the definitions have the same meaning as the definition in item 1 of the scope of patent application, the A] ring is Unsaturated 5- to 6-membered monocyclic heterocyclic group of 3 double bonds, the hetero 122 314976 200410956 ring group can be condensed with Z, Z, 7 which can be substituted by a prime atom, here, c ... 3 And 4 may be the same or different, and are the first two selected from the group consisting of a carbon atom (ch7, a second atom), a nitrogen atom (a nitrogen atom or a nitrogen atom), a sulfur atom, and an oxygen atom: there are also any one of 21, 22 ~ 24 The non-existent% 6 Rl, I and 1 are combined with any imitation Yimenshan atom that constitutes the eight ring. R and R can be the same or different from nk carbon atom or nitrogen an 631 and 731. They are hydrogen atom, lower / violent halogen. Atomic or lower alkoxy, X, is Shishandian 7 or C) or oxygen atom). "It is a slave atom (CH2, CH5. The proline derivative or its salt as described in item 4 of the scope of the patent application. The compound is represented by the following formula (I-D).

s _ ………么、必、叹坑虱暴或滷素原子，〗a <中為單鍵、雙鍵或鍵不存在）。 6.:申凊專利範圍第3項或第4項之脯氨酸衍鹽，其中HI及汉3均為氮原子者。 Λ 7·如申料利範圍第3項之脯氨酸衍生物或其鹽，其中， :A環為吡啶基、吡喃基、噻吩基、呋喃基、吡咯基、基、吡哄基、噠畊基、咪唑基、吡唑基、噻唑^、錢。坐一基、。惡吃基、異嚼唾基、四。坐基、US三哄基' U，4-三啡基、四啡基、噻二錢、異嗤啉基、笨并嚷唑基、笨并噁唑基之任一基者。 314976 123 9. 碰 ” ％乐5項之脯氨酸衍生物或其骚，其中，該A】環岑a 但& A AIa %為嘧啶基或噻唑基者。如申請專利範圍第3項、筮Λ ^ , 、弟4或弟5項之脯氨酸衍生物或其鹽’其中，該汉為不 , 8為正戊基、正丁基、環戊基甲基 10 或環己基曱基之任~基者。 .如申請專利範圍第3項或 Μ Α弟4項之脯氨酸衍生物或其极’其中，該化合物為下、+ 乃局下述任一種者，化合物D-1-1 (2S) H(2R)-3-環戊基j[(N_曱酿基喜經基胺基）土]丙1基} 2 {[4、（2“密咬基）小六氫吼哄基憤基^比各垸；化合物D-2-1 其（）1 {(2R) 2 [(N-甲醯基|經基胺基）曱基]己醯〜2-{[4-(21义基）小六氫吼哄基]獄基丨吼咯烷·，化合物D-3-1 (S) 1 {(2R) 3-環戊基_2_[(N•曱醯基_N_經基胺基）曱基]丙基卜2-{[4-(2-噻.坐基）小六氫吼哄基]幾基}吼 u各烷；化合物D-4-1 (2S)-l-U2R)-2-[(N-甲醯基_N_經基胺基）甲基]己醯基}-2-{[4-(2-噻唑基）-l-六氫吡哄基]羰基丨吡咯烷； 4匕合物D-5 (2S)-] - {(2R)-2-[(N-甲g|基I經基胺基）甲基]己醯基}，2-{[4-(4-曱基-2-噻唑基六氫吡畊基]羰基）^比咯 314976 124 200410956 少完；化合物D>6 (lS，2S，5R)-3-氮雜-3_{(2R卜入[(N_曱醯基羥基胺基）曱基]庚醯基}-2-{[4-(2-嘧啶基;μ!·六氫吡哄基]羰基}二環[3·1·0]己烷; 化合物D-7 -1 (2S)-l-{(2R)-2-[(N-曱醯基養經基胺基）曱基]庚醯基卜2-{ [4-(2-噻唑基）-1_六氫吡哄基]羰基}吡咯烷；化合物D-8 (2S)-l-{(2R)-2-[(N-·曱醯基-N—羥基胺基）甲基]庚醯基}-2_{[4-(4-曱基-2-噻唑基六氫吡畊基]羰基y比咯烷；化合物D-9 (2S)-2-{[4-(5-溴-2-噻唑基兴^六氫吡哄基]羰基卜 l-{(2R)-2-[(N-曱酿基羥基胺基）曱基]庚醯基}〇比口各烧；參化合物D-10 (2S)-2-{[4-(2-苯并噻唑基广六氫吡畊基]羰基卜， l-{(2R)-2-[(N-曱醯基-Ν-羥基胺基）曱基;|庚醯基}D比咯」烷；化合物D-11-1 (2S)-l-{(2R)-3-環戊基- 2-[(N-曱醯基羥基胺基）甲基]丙醯基}-2-{[4-(4 -甲基-2-噻唑基）-1-六氫吡π井基] 羰基}%咯烷； 314976 125 200410956 化合物em 2 US’3S)+{(2R) j[(N•甲酉藍基養經基胺基）甲基] 庚酉皿基} 3甲基_2_{[4♦嗜u定基）小六氫购基]魏基} 吡咯烷；化合物D-13 (2外4,4-二II小{(2R)I[(N-T酸基1經基胺基） • 曱基]庚1基卜2」[4，(2“密"定基）-1-六氫口比哄基]魏基}吼咯烷；化合物D -1 4 (){(2R) 2·[(Ν-甲醯基-N-經基胺基）曱基]庚酸基i 2 {[4 (6-曱氧基_2』比啶基）小六氫吡哄基]魏基^比咯烷；化合物D -1 5 (2S)-2-{[4-(6-m比哄基）小六氫Q比哄基]敷基}_ 1-{(2R)_2-[(N_曱酸基-N-經基胺基）曱基]庚醯基}吼咯 — 烷；化合物D-16-1 、（2S)]-{(2R)-3、環己基_2_[(1曱醯基·队羥基胺基） 1曱基]丙酉&基}-2-{[4-(2-噻唑基）-卜六氫吼哄基]羰基}[]比咯烷。 11.如申請專利範圍第1項至第1〇項任何_項之脯氨酸衍生物，其鹽為酸付加鹽或金屬鹽者。 1 2· —種醫藥，係以申請專利範圍第3項之式（Ι-Β)所示之脯氨酸衍生物或其生理上所容許之鹽作為有效成分，其 126 314976 200410956 13. 14. 15. 16. 17. 18. 19 一種醫藥組成物，所示之脯氨酸衍生成分組成，其中，如申請專利範圍第組成物之形態為液中’式（I-B)之I為氫原子或者。 ^申晴專利範圍第12項之醫藥，係以申專利範圍第斗員之式(1-(：)所不之脯氨酸衍生物或其生理上所鹽作為有效成分者。 ° =料利1_12項之醫藥，係_請專利範圍第5 鹽作所不之辅氨酸衍生物或其生理上所容許之 I作為有效成分者。 ::請專利範圍第12項、第13項或第14項之醫荜， :物戈：Γ成分為申請專利範圍第10項之脯氨酸衍生物或其生理上所容許之鹽者。如申請專利範圍第13 笼頁至弟15項任何一項之醫藥，其甲该醫樂為抗菌劑者。如申晴專利範圍第1 ,,.. 6項之面樂，其中，該抗菌劑為多剤耐性菌之抗菌劑者。係由申請專利範圍第3項之式（ρΒ) 物或其生理上所容許之鹽及製劑化式（Ι-Β)之&為氫原子或者。 1 8項之醫藥組成物，其中，該醫藥狀製劑或使用時溶解型製劑者。 314976 】27 200410956 柒、指定代表圖： (一）本案指定代表圖為：第（）圖。 (二) 本代表圖之元件代表符號簡單說明：本案無圖式。捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式：s _………,…, sigh, or a halogen atom, in a < a single bond, double bond, or bond does not exist). 6 .: Proline derivative salt of item 3 or item 4 of the patent application, in which HI and Han 3 are nitrogen atoms. Λ 7: The proline derivative or its salt according to item 3 of the claim, wherein: A ring is pyridyl, pyranyl, thienyl, furanyl, pyrrolyl, phenyl, pyridyl, pyridyl Ploughyl, imidazolyl, pyrazolyl, thiazole ^, and money. Take a base ,. Eating base, chewing salivary base, four. Any one of a base group, a US trisyl group, U, 4-triphthyl group, tetraphthyl group, thiazepine, isofluorinyl group, benzopyrazolyl group, and benzooxazolyl group. 314976 123 9. Touch the "proline derivative of item 5" or its expression, in which A] cyclozena but & A AIa% is pyrimidinyl or thiazolyl. For example, if the scope of patent application is No. 3,筮 Λ ^, Pro, 4 or 5 proline derivatives or salts thereof, wherein the han is no, 8 is n-pentyl, n-butyl, cyclopentylmethyl 10 or cyclohexylfluorenyl Any one of the following: For example, if the proline derivative of item 3 of the scope of patent application or item 4 of ΑΑ or its pole is used, wherein the compound is any of the following, + is one of the following, compound D-1- 1 (2S) H (2R) -3-Cyclopentyl j [(N_Phenylyloxetylamino) earth] propanyl} 2 {[4, (2 "dense bite) small hexahydrol Compound D-2-1: Compound D-2-1 its () 1 {(2R) 2 [(N-methylamido | alkylamino) amido] hexyl ~ 2-{[4- ( 21 Sense) Hexahydroxyl] Hexyl 丨 Hyrrolidine, Compound D-3-1 (S) 1 {(2R) 3-cyclopentyl_2 _ [(N • fluorenyl_N_ Ethylamino) fluorenyl] propyl] 2-{[4- (2-thia.xyl) small hexahydroxanzyl] Hexyl} each alkane; compound D-4-1 (2S)- l-U2R) -2-[(N-formamyl_N_mercaptoamino ) Methyl] hexyl} -2-{[4- (2-thiazolyl) -l-hexahydropyridyl] carbonylcarbonylpyrrolidine; D-5 (2S)-]-{( 2R) -2-[(N-methylg | yl I via aminoamino) methyl] hexyl}}, 2-{[4- (4-fluorenyl-2-thiazolylhexahydropyridyl) carbonyl ) ^ Complete less than 314976 124 200410956; Compound D > 6 (lS, 2S, 5R) -3-aza-3 _ {(2R into [(N_fluorenylhydroxyamine) fluorenyl] heptyl} } -2-{[4- (2-pyrimidinyl; μ! · Hexahydropyridyl] carbonyl} bicyclo [3 · 1 · 0] hexane; compound D-7 -1 (2S) -l- { (2R) -2-[(N-fluorenylaminoamino) fluorenyl] heptylbiphenyl 2- {[4- (2-thiazolyl) -1-hexahydropyridyl] carbonyl} pyrrole Alkane; compound D-8 (2S) -l-{(2R) -2-[(N- · fluorenyl-N-hydroxyamino) methyl] heptyl} -2 _ {[4- (4- Fluorenyl-2-thiazolylhexahydropyridyl] carbonyl y than pyrrolidine; compound D-9 (2S) -2-{[4- (5-bromo-2-thiazolyl hexafluoropyridyl) Carbonyl group l-{(2R) -2-[(N-fluorenylhydroxyamino) fluorenyl] heptanyl}; each compound is burned; reference compound D-10 (2S) -2-{[4- (2-benzothiazolylhexylpyridyl) carbonylcarbonyl, l-{(2R) -2-[(N-fluorenyl-N-hydroxyamine ) Fluorenyl; | heptylfluorenyl} D than pyrrolidine; compound D-11-1 (2S) -1-{(2R) -3-cyclopentyl- 2-[(N-fluorenylhydroxyamine ) Methyl] propanyl} -2-{[4- (4-methyl-2-thiazolyl) -1-hexahydropyridyl] carbonyl}% pyrrolidine; 314976 125 200410956 compound em 2 US ' 3S) + {(2R) j [(N • formamidinelanylaminomethyl) methyl] heptylmethyl} 3methyl_2 _ {[4 ♦ Uthionyl) Hexyl]] Wei } Pyrrolidine; compound D-13 (2 outer 4,4-diII small {(2R) I [(NT acid group 1 alkylamino group) • fluorenyl] heptyl 1 gib 2 ”[4, (2 "Dense " denyl) -1-Hexahydropyridyl] Weiji} Horrolidine; Compound D -1 4 () {(2R) 2 · [(N-formamyl-N-methylamino) ) Fluorenyl] heptanoyl i 2 {[4 (6-fluorenyloxy_2 ′ is smaller than pyridyl) hexahydropyridyl] Weiyl ^ pyrrolidine; compound D -1 5 (2S) -2- {[4- (6-m than thiol) smaller hexahydro Q than thiol] aryl} _ 1-{(2R) _2-[(N_fluorenyl-N-methylamino) fluorenyl] Heptyl} hexyl — alkane; compound D-16-1, (2S)]-{(2R) -3, cyclohexyl_2 _ [(1fluorenyl · hydroxylamino) 1fluorenyl] propanyl & yl} -2-{[4- (2-thiazolyl) -buliu Hydrocarbyl] carbonyl} [] than pyrrolidine. 11. If the proline derivative of any one of items 1 to 10 in the scope of the patent application, its salt is an acid addition salt or a metal salt. 1 2 · —A kind of medicine, which uses the proline derivative represented by formula (I-B) or the physiologically acceptable salt thereof as the active ingredient in item 3 of the patent application scope, which is 126 314976 200410956 13. 14. 15. 16. 17. 18. 19 A medicinal composition comprising a proline-derived component as shown, wherein if the form of the composition in the scope of the patent application is in liquid, I of formula (IB) is a hydrogen atom or. ^ The medicine in item 12 of Shen Qing's patent scope is based on the formula (1- (:) proline derivative or its physiologically acceptable salt as the active ingredient.) The medicine of item 1_12 is _ please use the 5th salt of the patent scope as a co-amino acid derivative or a physiologically acceptable I as an active ingredient. :: Please request the patent scope of the 12th, 13th or 14th Physician's item of the item,: Ge: The Γ component is the proline derivative or the physiologically acceptable salt of the item 10 of the patent application scope. For example, any one of item 13 to 15 of the patent application scope Medicine, whose medical music is an antibacterial agent. For example, Shenqing's patent scope No. 1, 6, ..., face music, in which the antibacterial agent is an antibacterial agent of multi-resistant bacteria. It belongs to the scope of patent application. The compound of formula (ρΒ) in item 3, or a physiologically acceptable salt thereof, and the formula (I-B) are hydrogen atoms or. 18 The pharmaceutical composition of item 18, wherein the pharmaceutical preparation or when used Dissolved preparations. 314976】 27 200410956 柒, designated representative map: (a) The designated representative map in this case is: () Figure. (II) Simple description of the element representative symbols of this representative diagram: There is no schema in this case. 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention:

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