TW200526606A

TW200526606A - Substituted triazole derivatives as oxytocin antagonists

Info

Publication number: TW200526606A
Application number: TW093128603A
Authority: TW
Inventors: Alan Daniel Brown; David Ellis; Christopher Ronald Smith
Original assignee: Pfizer
Priority date: 2003-09-22
Filing date: 2004-09-21
Publication date: 2005-08-16
Also published as: UY28524A1; WO2005028452A9; NL1027084A1; AR045791A1; PE20050950A1; BRPI0414663A; EP1673355A1; CA2539297A1; MXPA06003158A; JP2007505888A; PA8613001A1; WO2005028452A1; NL1027084C2; CA2539297C

Abstract

The present invention relates to a class of substituted 1,2,4-triazoles of formula (I) with activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E.).

Description

200526606 九、發明說明：【發明所屬之技術領域】本發明係關於一類具有作為催產素拮抗劑活性之經取代 1，2,4_二唑、其用途、其製備之方法及含該等抑制劑之組合物。此等抑制劑在多種治療領域（包括性功能障礙，尤其於早洩（P.E·))具有效用。【先前技術】200526606 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a class of substituted 1,2,4-diazoles having activity as oxytocin antagonists, their uses, methods for their preparation, and containing such inhibitors Of the composition. These inhibitors have utility in a variety of therapeutic areas, including sexual dysfunction, especially premature ejaculation (P.E.). [Prior art]

Eur. J· Med· Chem. 1985, 20(3)，第 257-266頁，提及具有止痛及抗炎性質之***衍生物。界〇〇3/〇53437提^具有作為催產素拮抗劑活性之。Ep 提及具有甘胺酸輸送劑抑制性質之丨，2,4_***衍生物。【發明内容】本發明之第一態樣提供式⑴之化合物、其互變異構體、或該化合物或互變異構體之醫藥上可接受之鹽、溶合物或多形體（polymorph);Eur. J. Med. Chem. 1985, 20 (3), pp. 257-266, mentions triazole derivatives having analgesic and anti-inflammatory properties. Boundary 03 / 53,437 37 has activity as an oxytocin antagonist. Ep mentions 1,2,4-triazole derivatives with inhibitory properties of glycine transporters. [Summary of the invention] A first aspect of the present invention provides a compound of formula (I), a tautomer thereof, or a pharmaceutically acceptable salt, solvate or polymorph of the compound or tautomer;

其中代表C-R6或N ; V、W、X及Y，其可係相同或不同 Z係C-H或N ; R1係選自：該等取代 ⑴經二個或二個以上取代基取代之苯基環 95339.doc 200526606 基可相同或不同，每一取代基獨立選自鹵素、（ClO 烷基、（CVC6)烷氧基、氰基、C(0)NR7R8、NR7R8、 NR7C(〇)R1G及 N[C(0)R1G]2 ;及 (ii) 含1-3個雜原子之五至七員芳香雜環，該等雜原子係選自N、〇及S及其N-氧化物；該環視情況經二個或二個以上取代基取代，該等取代基可係相同或不同’選自鹵素、（Ci-CO烷基、（CVC6)烷氧基、氰基、 c(o)nr7r8、NR7R8、NVc^COR1。及N[C(0)R1〇]2 ; R2係選自： (l) Η、OH、OR9、NR7R8、NR7C(0)R10及 N[C(O)R10]2 ; (η)含1-3個雜原子之5_7員N-連接雜環，該等雜原子選自N、〇及S ;該環視情況經一或多個基團取代，該等基團選自（cvc6)烷基、（Cl_C6)烷氧基及 c(o)nr7r8 ;及 (iii) 視情況經N-連接5-7員雜環取代之（Cl_c6)烷基，該雜環含1-3個選自N、〇及S之雜原子； R3係選自Η及（CVC6)烷基； R4係選自Η、（CVC6)烷基及〇R9 ; R5係選自i素、（CVC6)烷基、（Cl_c6)烷氧基、NR7R8、 NR7C(0)R1()及NfC^COR1。;^ ; R係選自Η、鹵素、（Ci_C6)烷基、（Ci_c心烷氧基、氰基、 NR7R8、nr7c(o)ri〇、n[c(〇)r10]2AC(〇)nr7r8 ; R及R，其可係相同或不同，係選自H&(CrC6)烷基； R係（Ci-C6)烷基，其視情況可經一或多個基團取代，每〆 95339.doc 200526606 基團係獨立地選自（q-C6)烷氧基及含“3個選自N、〇及8之雜原子之N-連接之5-7員雜環；且 R1G係選自（CVC6)烷基及（C〗_C6)規氧基；其附加條件為式（I)之化合物非為： 3-乙基-5-(4-咪唑-1-基笨基）_4_(4_甲氧基苯基）-4Η-[1，2,4] .一-口坐， 3-(3’，5’-二氯聯苯_心基）_4-(2_甲氧基苯基）_5_甲基 -4Η-[1，2,4]***， 3_(3’，5’_雙_三氟曱基聯苯_4_基）_4_(1氟苯基）_5_甲基 _4Η-[1，2,4]***，或 3 (3 ,5 -雙-二氟甲基聯苯基）曱基_4_(3_三氣甲基苯基）-4Η-[1，2,4]***。除非另外指示，烷基及烷氧基可係直鏈或支鏈且含1至6 個碳原子且較佳含1至4個碳原子。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、戊基及己基。烷氧基之實例包括甲氧基、乙氡基、異丙氧基及正丁氧基。 ΐ素意為狀、氯、漠或峨且較佳係氟。雜環可係飽和、部分飽和或芳香性。雜環基之實例係硫戊環基、吼咯啶基、吼咯啉基、咪唑烷基、咪唑啉基、噻吩燒基㈣f〇lanyl)、二氧戊環基、二氫m、四氯⑽ 基”瓜。定基、D比峻淋H圭燒基、：氧雜環己烧基、嗎 :基:二硫雜環己烧基、硫代嗎琳基”瓜嗓基、氣雜卓基、氧代氮雜卓基（〇xazepinyl)、硫代氮雜卓基（如㈣^州、嗟 95339.doc 200526606 唾琳基（thiazolinyi)及二氮雜環庚烷基（diazapanyl)。芳香雜環基之貫例係呋喃基、噻吩基、吧嘻基、噁吐基、噻唑基、味峻基、ϋ比唑基、異噁唑基、異噻唑基、噁二唑基、*** 基、嗟重氮基、吼u定基、ρ密淀基、ρ比嗪基、噠唤基、三嗪基。除非另外指示，術語經取代意為藉由一或多個界定之基團取代。於基團係可選自諸多替代基團之狀況下，經選擇之基團可係相同或不同。下文界定了本發明之較佳態樣。鲁在一較佳態樣中，本發明包含式⑴之化合物、其互變異構體、或該化合物或互變異構體之醫藥上可接受之鹽、溶合物或多形體，其中當其餘代表C-R6時，基團V、W、X&Y中之丨或2個代表ν; Ζ係C-H或Ν ; R1係選自：Wherein C-R6 or N; V, W, X and Y, which may be the same or different Z is CH or N; R1 is selected from: these substituted phenyl groups substituted by two or more substituents The ring 95339.doc 200526606 may be the same or different, and each substituent is independently selected from halogen, (ClO alkyl, (CVC6) alkoxy, cyano, C (0) NR7R8, NR7R8, NR7C (〇) R1G, and N [C (0) R1G] 2; and (ii) a five- to seven-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from the group consisting of N, 0, and S and their N-oxides; In the case of substitution by two or more substituents, these substituents may be the same or different 'selected from halogen, (Ci-COalkyl, (CVC6) alkoxy, cyano, c (o) nr7r8, NR7R8 , NVc ^ COR1, and N [C (0) R1〇] 2; R2 is selected from: (l) Η, OH, OR9, NR7R8, NR7C (0) R10, and N [C (O) R10] 2; ( η) a 5-7 member N-linked heterocyclic ring containing 1-3 heteroatoms selected from N, 0 and S; the ring is optionally substituted with one or more groups selected from (cvc6 ) Alkyl, (Cl_C6) alkoxy and c (o) nr7r8; and (iii) optionally (Cl_c6) alkyl substituted by N-linked 5-7 membered heterocyclic ring, which Heterocycle contains 1-3 heteroatoms selected from N, 0 and S; R3 is selected from fluorene and (CVC6) alkyl; R4 is selected from fluorene, (CVC6) alkyl and OR9; R5 is selected from i Element, (CVC6) alkyl, (Cl_c6) alkoxy, NR7R8, NR7C (0) R1 (), and NfC ^ COR1 .; ^; R is selected from fluorene, halogen, (Ci_C6) alkyl, (Ci_c axane Oxy, cyano, NR7R8, nr7c (o) ri0, n [c (〇) r10] 2AC (〇) nr7r8; R and R, which may be the same or different, and are selected from H & (CrC6) alkyl ; R-based (Ci-C6) alkyl, which may be substituted by one or more groups as appropriate, each 〆 95339.doc 200526606 group is independently selected from (q-C6) alkoxy and contains "3 N-linked 5-7 membered heterocyclic ring selected from heteroatoms of N, 0 and 8; and R1G is selected from (CVC6) alkyl and (C〗 _C6) ethoxy; its additional condition is formula (I) The compounds are not: 3-ethyl-5- (4-imidazol-1-ylbenzyl) _4_ (4-methoxyphenyl) -4Η- [1,2,4]. 1-mouthed, 3 -(3 ', 5'-dichlorobiphenyl_cardiyl) _4- (2_methoxyphenyl) _5_methyl-4fluorene- [1,2,4] triazole, 3_ (3', 5 '_Bis_trifluorofluorenylbiphenyl_4_yl) _4_ (1fluorophenyl) _5_methyl_4fluorene- [1,2,4] triazole Or 3 (3, 5 - bis - difluoromethyl-biphenylyl) Yue group _4_ (3_ three gas-methylphenyl) -4Η- [1,2,4] triazole. Unless otherwise indicated, alkyl and alkoxy groups can be straight or branched and contain 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, pentyl, and hexyl. Examples of alkoxy include methoxy, ethenyl, isopropoxy and n-butoxy. Haoxin means form, chlorine, desert, or eel and is preferably fluorine. Heterocyclic rings can be saturated, partially saturated, or aromatic. Examples of heterocyclyl are thiopentyl, suldinyl, suldinyl, imidazolidinyl, imidazolinyl, thienyl) (diolyl), dioxolyl, dihydromethane, tetrachlorophosphonium "Melon. Dingyl, D, Bi, H, Alkyl ,: oxetanyl, molybdenum: dithiocyclohexanyl, thiomorphinyl" guaryl, oxalyl, Oxazepinyl (oxazepinyl), thioazepine (such as ㈣州, 嗟 95339.doc 200526606 thiazolinyi) and diazapanyl (diazapanyl). Aromatic heterocyclyl The conventional examples are furyl, thienyl, barthyl, oxetyl, thiazolyl, amidyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, hydrazone Nitrogen, hydrazine, p-mylide, p-pyrazinyl, p-pyrazinyl, triazinyl. Unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the group system In the case of many alternative groups, the selected groups may be the same or different. The preferred aspects of the present invention are defined below. In a preferred aspect, the present invention includes the formula Compounds, tautomers thereof, or pharmaceutically acceptable salts, solvates, or polymorphs of the compounds or tautomers, wherein when the rest represent C-R6, the groups V, W, X & Y丨 or 2 represents ν; Z is CH or N; R1 is selected from:

⑴二個或二個以上取代基取代之苯基環，該等取代基可係相同或不同，每一取代基係獨立選自鹵素、烷基、（cvc6)烷氧基、氰基、c(〇)Nr7r8、nr7r8、 NR7C(0)R1Q及N[C(0)R1G]2 ;及 (ii)含1-3個雜原子之五至七員芳香雜搢货濰％，該等雜原子自Ν、0及S及其Ν-氧化物，該環禎悴 /衣说It况經二個或二, 以上取代基取代，該等取代基可俏相」你相冋或不同，選i 鹵素、（CVC6)烷基、（cvc6)烷氧基、| n 半、丞鼠基、c(o)NR7R8 95339.doc 200526606 nr7r8、nr7c(o)r1C)及 n[c(o)r10]2 ; R2較佳係選自： (i) H、（CVC6)烷氧基、（cvc6)烷氧基-((VC6)烷氧基、 nr7r8、nr7c(o)r1g及 n[c(o)r1()]2 ;及 (ii) 含1-3個雜原子之5-7員N-連接雜環，該等雜原子選自 N、Ο及S ;該環視情況經選自（(VC6)烷基、烷氧基及C(0)NR7R8之一或多個基團取代； R3係選自Η及（CVC6)烷基； R4係選自Η、（CVC6)烷基及OR9 ; R5係（CVC3)烧基、（CVC3)烧氧基或NR7R8 ; R6係Η、鹵素、（CVQ)烷基、（CVC6)烷氧基、氰基或 nr7r8 ； R7及R8，其可相同或不同，係選自h&(Ci_C6)烷基； R9係（Ci-c：6)烷基，其可視情況經（(：1-(：6)烷氧基取代；且 R10係選自（CVC6)烷基及（Cl-C6)烷氧基。在另一較佳態樣中，本發明包含式⑴之化合物、其互變異構體、或該化合物或互變異構體之醫藥上可接受之鹽、溶合物或多形體，其中當其餘代表C-R6且X係CH時，基團v、w、及γ中之個代表N ; Z係C-H或N ; R1係選自： ⑴H取代基取代之笨基環，該等取代基可係相同或 • 不同’每一取代基獨立選自i素、（Cl-C3)烧基、（Cl-c3) 95339.doc -10- 200526606 烧氧基、及氰基；及 (ii)。比啶基環或其N-氧化物，各自經兩個取代基取代，該 #取代基可係相同或不π > / ^ 母個獨立選自鹵素、（crc3) 文元基、（CVC3)烷氧基、及氰基； R2係選自： (C〗-C3)院氧基_(Ci_c3)院氧基及 (i) Η、（CVC3)烷氧基、 Ν(((^-(：3)烷基）2 ;及 (ii)含1-3個氮原子之5 C(0)NR7R8取代；員連接雜環該環視情況經 R3係選自Η及（CVC6)烷基； R4係選自Η、（Ci-C^)烧基及〇汉9 ; R5係（CVC3)烧基、（CVC3)院氧基 *nr7r8 ; R6係Η、（CVCd烷基、（c广c6)烷氧基或1^7化8 ; R7及R8,其可係相同或不同，係選自叫。〜烷基；且 R9係（C「C6)烧基，其視情況經甲氧基取代。在另-較佳態樣中，本發明包含式⑴之化合物、其互變異構體、或該化合物或互變異構體之醫藥上可接受之鹽、溶合物或多形體，其中 W及Y各自獨立地係CH或N，且X及V各自係CH ; Z係N ;苯基 Phenyl ring substituted with two or more substituents, these substituents may be the same or different, each substituent is independently selected from halogen, alkyl, (cvc6) alkoxy, cyano, c ( 〇) Nr7r8, nr7r8, NR7C (0) R1Q and N [C (0) R1G] 2; and (ii) five to seven-membered aromatic heterogeneous products containing 1-3 heteroatoms. Ν, 0 and S and its N-oxide, the ring 祯悴 / yi said that it is replaced by two or more substituents, these substituents can be similar. "You are different or different, choose i halogen, (CVC6) alkyl, (cvc6) alkoxy, | n-half, molesyl, c (o) NR7R8 95339.doc 200526606 nr7r8, nr7c (o) r1C) and n [c (o) r10] 2; R2 Preferred are selected from: (i) H, (CVC6) alkoxy, (cvc6) alkoxy-((VC6) alkoxy, nr7r8, nr7c (o) r1g, and n [c (o) r1 () ] 2; and (ii) a 5-7 member N-linked heterocyclic ring containing 1-3 heteroatoms selected from N, O and S; the ring is optionally selected from ((VC6) alkyl, Alkoxy and one or more groups of C (0) NR7R8 are substituted; R3 is selected from fluorene and (CVC6) alkyl; R4 is selected from fluorene, (CVC6) alkyl and OR9; R5 is (CVC3) Base, (CVC3) Oxy or NR7R8; R6 is fluorene, halogen, (CVQ) alkyl, (CVC6) alkoxy, cyano or nr7r8; R7 and R8, which may be the same or different, are selected from h & (Ci_C6) alkyl; R9 is (Ci-c: 6) alkyl, which may be optionally substituted with ((: 1-(: 6) alkoxy); and R10 is selected from (CVC6) alkyl and (Cl-C6) alkoxy. In another preferred aspect, the present invention comprises a compound of formula (I), a tautomer thereof, or a pharmaceutically acceptable salt, solvate or polymorph of the compound or tautomer, wherein when the rest represents When C-R6 and X is CH, one of the groups v, w, and γ represents N; Z is CH or N; R1 is selected from the group consisting of: 笨 a phenyl ring substituted with a H substituent, and these substituents may be the same Or • different 'each substituent is independently selected from the group consisting of iin, (Cl-C3) alkyl, (Cl-c3) 95339.doc -10- 200526606 alkyl, and cyano; and (ii). Pyridyl The ring or its N-oxide is each substituted with two substituents, and the # substituents may be the same or not π > / ^ each independently selected from halogen, (crc3) motif group, (CVC3) alkoxy group , And cyano; R2 is selected from: (C〗 -C3) 院 oxy_ (C i_c3) oxo and (i) hydrazone, (CVC3) alkoxy, N (((^-(: 3) alkyl) 2; and (ii) 5C (0) containing 1-3 nitrogen atoms NR7R8 is substituted; the member is connected to a heterocyclic ring. The ring is optionally selected from fluorene and (CVC6) alkyl via R3 series; R4 is selected from fluorene, (Ci-C ^) alkyl and 0-9; R5 is (CVC3) alkyl, (CVC3) oxy group * nr7r8; R6 is fluorene, (CVCd alkyl, (c-c6) alkoxy or 1 ^ 7) 8; R7 and R8, which may be the same or different, are selected from the group consisting of. ~ Alkyl; and R9 is (C "C6) alkyl, which is optionally substituted with methoxy. In another preferred embodiment, the present invention comprises a compound of formula VII, its tautomer, or the compound Or tautomers, pharmaceutically acceptable salts, solvates or polymorphs, wherein W and Y are each independently CH or N, and X and V are each CH; Z is N;

Ri係經二個以上取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自氟、氣、曱基、甲氧基、及氰基； R2係選自Η、曱氧基、乙氧基、2-曱氧基乙氧基、二曱基 95339.doc -11 - 200526606 胺基、1，2,3-***-2-基及吡咯啶基，後者視情況經CONH2 取代； r3係選自Η及（CrC6)烷基； R4係Η ;且 R5係曱氧基。根據以上態樣之式（I)之化合物之較佳實施例係彼等併入有二個或二個以上下列優先選擇之實施例。較佳地，當其餘代表C-R6時，基團V、W、X及Υ中之1或 2個代表N。在一較佳實施例中，X係CH。在一較佳實施例中，當其餘代表〇：_116且又係（：11時，基團 V、W及Y中之1或2個代表n ; Y較佳係N或CR6。更佳地’ V、W及Y各自獨立地為CH、C_〇CH3或N。最佳地，W及Y各自獨立地為CH或N。在最佳實施例中，W及Y各自獨立地為CH或N，且每一 X 及V係CH。在一較佳實施例中，z係N。在另一較佳實施例中，Z係CH。 R1較佳係選自： (i)經二個或二個以上取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自鹵素、烷基、（CVC6)烷氧基、氰基、C(〇)NR7R8、Nr7r8、 NR7C(0)R1G及 N[C(0)R1G]2 ;及 95339.doc -12- 200526606 (ii)含1-3個雜原子之五至七員芳香雜環，該等雜原子選自N、〇及S及其N-氧化物；該環視情況經二個或二個以上取代基取代，該等取代基可係相同或不同選自鹵素、（cvc6)烷基、（cvco烷氧基、氰基、c(〇)nr7r8、 nr7r8、nr7c(0)r1()及n[c(o)r10]2 ; R1更佳係選自： (i)經二個取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自鹵素、（Ci_c6)烷基、烷氧基、氰基、c(o)nr7r8、NR7R8、nr7c(())r1(^ n[c(o)r1q]2 ;及 (11)吼唆基環或其N-氧化物，各自經兩個取代基取代，该等取代基可係相同或不同，各自獨立選自鹵素、（Ci 烧基、（CVC6)烧氧基、氰基、c(0)NR7R8、NW、 NR7C(0)R1()及N[C(O)R10]2。 R1更佳係選自： (i)經二個取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自_素、（Cl-C3)烷基、（Ci_C3) 烧氧基及氰基；及 (11)吼唆基環或其N-氧化物，各自經兩個取代基取代，該專取代基可係相同或不同，各自獨立選自鹵素、（ciec3) 烧基、（CrCO烷氧基及氰基。在一較佳實施例中，R1係經二個取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自氟、氯、甲基、曱氧基及氰基。 95339.doc -13- 200526606 在另一較佳實施例中，R1係經兩個甲某敌从签取代之吡啶-N-氧化物。 R2較佳係選自： ⑴H、（Cl-C6)院氧基、（Cl-C6)烧氧基_(Ci_C6m氧基、 NR7R8、NR7C(0)R1G及 N[C(0)R1()]2 ;及 (ii)含1-3個雜原子之5-7員N-連接雜環，該等雜原子選自 N、0及S ;該環視情況經一或多個選自（C〗_C6)烷某、 (Ci-C6)烧氧基及c(o)nr7r8之取代基取代。 R2更佳係選自： ⑴H、（Cl-C3)烧氧基、（Cl-C3)院氧基_(Ci_c3)烧氧基及 Ν((^ν(：3)烷基）2 ;及 (ii)含1-3個氮原子之5員Ν_連接雜環，該環視情況經 c(o)nr7r8取代。 R2更佳係選自H、甲氧基、乙氧基、2·甲氧基乙氧基、二甲基胺基、1，2,3-三嗤-2-基及対D定基，後者視情況經 conh2取代。 R2最佳係選自Η及甲氧基。 R3較佳係Η或（CVC3)烷基。 R3最佳係Η。 R4較佳係Η、（(VC3)烷基或OR9。 R更佳係H、（CVC3)烷基或（cvc3)烷氧基。 R4最佳係Η、曱基或甲氧基。在一較佳實施例中，R4係Η。車乂仏係（eve：3)烷基、（cvc：3)烷氧基*NR7R8。 95339.doc 200526606 R更佳係（C1-C3)烷氧基或NR7R8。 r5最佳係甲氧基或nhch3。在一較佳實施例中，R5係甲氧基。 R6較佳係Η、鹵素、（Cl_c6)烷基、（Cl_c6)烷氧基、氰基或 NR7R8。 R6更佳係Η、（CVC6)烷基、（CVC6)烷氧基、或NR7R8。 R6更佳係H、（CVC3)烷基或（CVC3)烷氧基。 R6最佳係Η、曱基或曱氧基。在一較佳實施例，R6係Η或甲基。在一最佳實施例中，R6係Η。 R7較佳係Η或（C^CJ烷基。 R7最佳係Η或曱基。 R8較佳係Η或（CVC3)烧基。 R8最佳係Η或甲基。 R9較佳係視情況經（C「C6)烷氧基取代之（CrCd烷基。 R9更佳係視情況經甲氧基取代之（CrCd烷基。 R9最佳係甲基。較佳的式（I)之化合物係： 2-(4 -氟-2-曱基苯基）-5-(5 -曱氧基甲基- 4- (6-曱氧基°比淀-3-基）-4H-[ 1，2,4]三 σ坐-3-基）_ntb σ定， 2-(2,3-二甲基苯基）-5-(5-甲氧基甲基-4-(6-甲氧基咐啶_3_ 基）-4Η_[1，2,4]三 0坐-3-基）-ϋ比 σ定， 5-(4-氟-2-曱基苯基）-2-(5-甲氧基甲基-4-(6-曱氧基吨啶-3-基）-4Η_[1，2,4]三 0坐-3-基）-11 比 σ定， 95339.doc -15- 200526606 5-(2，3-二甲基苯基）-2-(5-甲氧基曱基-4-(6-甲氧基ϋ比咬-3-基）-4Η-[1，2,4]***-3-基）-吡啶； 1- [5-[5-(2,3-二甲基苯基）-。比啶-2_基]-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基甲基]-吡咯啶-(2S)-2-羧酸醯胺； 5-(2,3-二甲基苯基）-2-(5-吼咯啶-1-基曱基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基）-吡啶； 2- (4 -氣-2-甲基苯基）-5-[5·甲氧基曱基-4-(6-甲乳基ϋ比咬-3_ 基）-4Η-[1，2,4]***-3-基]-吡嗪； 2-(2,3-二甲基苯基）-5-[5-甲氧基曱基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吼嗪； 2-(4-氣-2-甲基苯基）-5-[4-(6-甲氧基σ比σ定-3 -基）-5-甲基 -4H_[1，2,4]***-3-基]-吡嗪； 2-(2,3-二曱基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(4-鼠基-2-甲基苯基）-5-[4-(6-甲氧基-基）· 5 -甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(5-氟-2-甲氧基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(4-氣基-2-曱基苯基）-5-[5-甲氧基甲基- 4- (6-甲氧基°比°定 -3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 5-(4-氰基-2-甲基苯基）-2-[5-甲氧基甲基-4-(6-甲氧基吼啶 -3-基）-4Η-[1，2,4]***-3-基]-吼啶； 2-(5-氟-2-甲氧基苯基）-5-[5-甲氧基甲基-4-(6-曱氧基吼啶 -3-基）-4Η-[1，2,4]***-3-基]-吡啶； 95339.doc -16- 200526606 2-(2-氟-5-甲氧基苯基）-5-[4-(6-曱氧基吨啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]_ 吼嗪； 2-(2-氣-5-甲基苯基）_5-[4-(6-甲氧基^比口定-3 -基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,5-二氟苯基）-5-[4-(6-甲氧基吼啶-3-基）_5_甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2·(3,5-二甲基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,5-二甲基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]•吡嗪； 2-(2，5-二氣苯基）-5-[4-(6-曱乳基°比σ定-3-基）-5-甲基 -411-[1，2,4]***-3-基]_吡嗪； 2-(2-氣-5-曱氧基苯基）-5-[4-(6-甲氧基吼。定-3 -基）-5 -曱基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(3,5-二氟-苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H_[1，2,4]***-3-基]-吼嗪； 2-(2,3-二曱基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4-(6-甲氧基°比°定-3-基）-4Η· 1，2,4 -二°坐-3-基]°比σ定， 2-(5-氣-2-甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4-(6-甲氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吡啶； 2-(4 -氣-2-甲氧基苯基）-5-[5-[(2-曱氧基乙氧基）甲基]-4-(6-曱氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吼啶； 2-(5-氟-2-甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲]-4-(6-甲氧基吡啶-3-基）-4Η-1，2,4-***-3·基]吼啶； 95339.doc -17- 200526606 2-(5 -氟-2-甲基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]_4_(6_甲氧基°比咬-3-基）-4H-1，2,4·三唾_3_基]吼咬； 2 -曱氧基- 5-{3-[(2-甲氧基乙氧基）甲基]_5_[6-(2_甲氧其5 甲基苯基）吡咬-3-基]-4Η·1，2,4-***-4-基}吡^定； 2-(2-氟-3-甲氧基苯基）-5-[5_[(2_曱氧基乙氧基）甲基]_4·(6· 甲乳基°比〇定-3 -基）_411-1，2,4-三〇坐-3-基]吼11定； 2-(3,5-二氟苯基）-5-[5-[(2-甲氧基乙氧基）甲基]_4-(6_甲氧 2-(2,5-二甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4_(6_ 甲氧基σ比11 定_3_基）-4H_1，2,4 -三11 坐-3-基]η比η定； 2-(3-氣-4-氟苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4-(6 -甲氧 2-(3-氟-2-甲氧基苯基）-5-[5 -曱氧基甲基-4-(6-甲氧基吼。定 -3-基 2_(3_氟-2_曱氧基-苯基）_5-[4-(6-甲氧基-π比咬_3_基）_5-甲基 4-Η·[1，2,4]三唾-3-基]-η 比 cr秦；及其互變異構體及該化合物或互變異構體之醫藥上可接受之鹽、溶合物及多形體。最佳之式（I)之化合物係： 2-(4-氟-2-曱基苯基）-5-(5-甲氧基甲基-4-(6-甲氧基吼唆-3_ 基）-4Η-[1，2,4]三。坐-3-基）比咬； 2-(2,3 - 一甲基苯基）-5-(5_曱氧基甲基-4-(6-曱氧基外匕。定_3_ 基）-4Η-[1，2,4]三唾-3_ 基）_σ 比咬； 5-(4 -氟-2-甲基本基）-2-(5 -甲氧基甲基- 4- (6 -甲氧基吼。定_3_ 95339.doc -18- 200526606 基）-4Η-[1，2,4]***-3-基）-吡啶； 5-(2，3 -二甲基苯基）-2-(5 -甲氧i基甲基-4-(6-甲乳基σ比咬-3_ 基）-4Η-[1，2,4]***-3-基）-吡啶； 1- [5-[5-(2,3-二甲基苯基）-口比啶-2-基]-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基甲基]-吡咯啶-(2S)-2-羧酸醯胺； 5-(2,3-二甲基苯基）-2-(5-吼咯啶-1-基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基）-吡啶； 2- (4-氟-2-甲基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吼嗪； 2-(2,3-二甲基苯基）-5-[5-甲氧基甲基-4-(6-曱氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吼嗪； 2-(4-亂-2-甲基苯基）_5-[4-(6-曱氧基11比°定-3-基）-5-曱基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2，3-二甲基苯基）-5-[4-(6-甲氧基°比σ定-3-基）-5-曱基 -4Η-[1，2,4]***-3-基]-吡嗪； 2-(4-來》基-2-甲基苯基）-5-[4-(6-甲氧基σ比唆-3 -基）-5 -甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(5 -亂-2-甲氧基苯基）-5-[4-(6-甲乳基0比°定-3 -基）-5 -曱基 -4H-[1,2,4]***-3-基]-吡嗪； 2-(4-亂基-2-甲基苯基）·5-[5-甲氧基甲基- 4- (6-甲氧基utb ϋ定 -3-基）-4Η-[1，2,4]***-3-基]^ 比嗪； 5-(4-亂基-2-甲基苯基）·2-[5-甲氧基甲基- 4- (6-甲乳基ntb °定 -3-基）-4Η-[1，2,4]***-3-基]-吡啶； 2-(5-氟-2-曱氧基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基吼啶 95339.doc -19- 200526606 -3-基）-4Η-[1，2,4]***_3_基]-吼啶；及 2(3氟2甲氧基苯基）_5_[5_甲氧基甲基_4_(6_曱氧基。比啶 -3-基）-4H-[l，2,4]*** _3_ 基]-吼嗪； 2-(3-氟-2-甲氧基_苯基）_5_[4_(6_甲氧基_π比啶_3_基）巧_甲基 -4-Η-[1，2,4]***吡嗪；及其互變異構體及該化合物或互變異構體之醫藥上可接受之鹽、溶合物及多形體。式（I)之化合物之醫藥上可接受之鹽包含其酸加成鹽。適當之酸加成鹽係自形成非毒性鹽之酸形成。實例包括乙酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽（besylate)、碳酸氫鹽/¾酸鹽、硫酸氫鹽/硫酸鹽、硼酸鹽、右旋樟腦磺酸鹽、檸檬酸鹽、乙二磺酸鹽、乙磺酸鹽、甲酸鹽、反式丁烯一酸、葡庚糖酸鹽（gluceptate)、葡糖酸鹽、葡糖醛酸鹽、六氟磷酸鹽、hibenzate、氫氯化物/氣化物、氫溴化物/溴化物、氫蛾化物/碘化物、羥乙基磺酸鹽（isethi〇nate)、乳酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸、甲磺酸鹽、曱基硫酸鹽、萘酸鹽（naphthylate)、2-萘磺酸鹽、菸鹹酸鹽 (nicotinate)、硝酸鹽、乳清酸鹽（orotate)、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、糖酸鹽、硬脂酸鹽、琥珀酸鹽、酒石酸鹽、甲苯磺酸鹽及三氟乙酸鹽0 亦可形成酸之半鹽，例如，半硫酸鹽。對適當鹽之綜述，見 Stahl及 Wermuth (Wiley-VCH，Weinheim，德國 ’ 2002) 之 Handbook of Pharmaceutical Salts: Prop^llies，翏electi〇n， 95339.doc -20- 200526606 and Use 〇可藉由三種方法中之一或多種來製備式（I)之化合物之醫藥上可接受之鹽： (1)藉由將式（I)之化合物與所需之酸反應； (ii) 藉由使用所需之酸自式⑴之化合物之適當前驅體移除酸不安定保護基；或 (iii) 藉由與合適酸反應或藉由適當離子交換柱將式⑴之化合物之一種鹽轉化為另一種鹽。所有三種反應通常皆於溶液中進行。所得鹽可沈澱出且藉由過濾收集或可藉由蒸發溶劑來回收。所得鹽之離子化程度可自完全離子化至幾乎非離子化之間變化。本發明之化合物可以未溶劑化及溶劑化形態兩者存在。本文使用術語”溶合物”來描述包含本發明之化合物及化學汁I或非化學計量之量之一或多種醫藥上可接受之溶劑分子（例如，乙酵）的分子複合物。當該溶劑係水時採用術語 π水合物’’。例如籠形物之複合物、内含藥物-主體複合物（其中藥物及主體以化學計量或非化學計量之量存在）包括於本發明之乾圍内。亦包括含兩種或兩種以上有機及/或無機組份之藥物的複合物，該等組份可為化學計量或非化學計量之罝。所得複合物可係離子化、部分離子化、或非離子化。對該等複合物之綜述，見Haleblian之J Pharm Sci，64⑻， ^69-1288(1975年 8 月）。 ’ 下文中式（I)之化合物之所有參考包括對其鹽、溶合物及 95339.doc -21 - 200526606 複合物及對其鹽之溶合物及複合物之參考。本發明之化合物包括如上文所界定之式（I)之化合物（包括其全部多形體及晶體慣態）、如下文界定之其前藥及異構體（包括光學、幾何及互變異構體）及經同位素標記之式（I) 之化合物。如所指示，所謂的式（I)之化合物之”前藥”亦包含於本發明之範圍内。因此，當投藥至體内或體上時，本身具有很少或無醫藥活性之式（I)之化合物之特定衍生物可（例如）藉由水解***而轉化為具有所需之活性的式（I)之化合物。該等衍生物被稱為π前藥’’。關於前藥之使用的進一步之資訊可見於 Pro-drugs as Novel Delivery Systems，第 14卷，ACS Symposium Series (T. Higuchi及 W. Stella)及 Bioreversible Carriers in Drug Design? Pergamon 出版社，1 987(Ε· B· Roche 編著，美國醫藥協會）。可（例如）藉由以描述於例如Η· Bundgaard (Elsevier，1985) 之Design of Prodrugs中之熟習此項技術者所知之稱作n前-部分’’之特定部分置換呈現於式（I)之化合物中之合適官能度，從而製造根據本發明之前藥。根據本發明之前藥之一些實例包括 (i) 當式（I)之化合物含醇官能度（-OH)時，其醚，例如，其中式（I)之化合物之醇官能度之氫經（CrCd烷醯基氧甲基置換之化合物；及 (ii) 當式（I)之化合物含第一或第二胺基官能度（-NH2或 -NHR，其中R#H)時，其醯胺，例如，其中（情形可 95339.doc -22- 200526606 為）式⑴之化合物之胺基官能度之一或全部兩個氫經（Ci-C1G)烷醯基置換之化合物。根據前述實例之置換基團之進一步實例及其它前藥類型之實例可見於上述文獻。此外，式（I)之特定化合物自身可作為其他式⑴之化合物之前藥。式（I)之化合物之代謝物亦包括於本發明之範圍内，意即，在藥物投藥於活體内時所形成之化合物。根據本發明之代謝物之一些實例包括 (0 當式（I)之化合物含甲基時，其羥甲基衍生物〇CH3->_CH2OH); (i〇當式（I)之化合物含烧氧基時，其經基衍生物 (-OR->-〇H); (iii) 當式（I)之化合物含第三胺基時，其第二胺基衍生物 (-NR^R^s-NHR1 或-NHR2); (iv) 當式（I)之化合物含第二胺基時，其第一胺基衍生物 (-NHR1->-NH2)； (v) 當式（I)之化合物含苯基部分時，其苯紛衍生物 (-Ph->-PhOH);且 (vi) 當式（I)之化合物含醯胺基時，其羧酸衍生物 (-CONH2->COOH)。含一或多個不對稱碳原子之式⑴之化合物可作為兩個或兩個以上立體異構體存在。當式（I)之化合物含烯基或块基時，可能為幾何順/反（或Z/E)異構體。當結構異構體可藉由 95339.doc -23- 200526606 低能障相互轉化時，可發生互變異構體異構現象（互變異構現象）。於含例如亞胺基、酮基、或肟基之式⑴之化合物中可以負子互變異構現象為形態，或於含芳香族部分之化合物中可以所謂的化合價互變異構現象為形態。由此可見單一化合物可展示多種類型之異構現象。匕括於本發明之範圍内係式⑴之化合物之所有立體異構體、幾何異構體及互變異構體形態，包括展示多種類型之異構現象的化合物，及其一或多種之混合物”亦包括酸加成孤其中平衡離子係光學活性，例如，d-乳酸鹽、或外消旋（例如）dM酉石酸鹽。可藉由熟習此項技術者所熟知之習知技術來分離順/反異構體’例如，層析法及分步結晶。製備/分離個別對映異構體之習知技術包括自適當之光子、、、屯刚驅體之手性合成或使用（例如）手性高壓液相層析法 (HPLC)分解外消旋物（或鹽或衍生物之外消旋物）。或者，外消旋物（或外消旋前驅體）可與適當光學活性化 e物（例如，醇，或於式⑴之化合物含酸性或鹼性部分之狀況下，與鹼或酸，例如丨_苯基乙胺或酒石酸）反應。可藉由層析法及/或分步結晶分離所得非對映異構體混合物，且藉由熟練操作者所熟知之方法將一或全部兩種非對映異構體轉化為相應純對映異構體。可使用層析法（通常為HPLC)於不對稱樹脂上以由含〇至 50體積％之異丙醇（通常為自2%至2〇%)及〇至5體積％烷基胺（通常為0.1❶/◦二乙胺）之烴（通常為庚烷或己烷）組成之流 95339.doc -24- 200526606 動相彳乂得對映異構體富集形態的本發明之手性化合物（及其手性前驅體）。溶離液之濃縮提供經富集之混合物。可藉由熟習此項技術者已知的習知技術分離立體異構體之聚集體〜參看，例如，E· L_扭⑷及s. H· wn⑶之丛迎㈣幽·迪x„of Orsani[CompcmndL(Wiley，New York 1994) 〇，本發明包括所有醫藥上可接受之經同位素標記之式⑴之化合物，其中一或多個原子經具有相同原子序數但具有與天然中占主導地位之原子質量或質量數不同之原子質量或質量數之原子置換。適於包涵於本發明之化合物中之同位素之實例包括下列兀素之同位素··氫（例如2H及3H)、碳（例如"c、！3C及14C)、氯（例如36ci)、敦（例如#)、碘（例如1231及1251卜氮（例如％及15N)、氧（例如Μ、％及18〇)、碟（例如32p)及硫⑼如35s)。特疋經同位素標記之式⑴之化合物，例如，彼等併入有放射性同位素之化合物，可有效用於藥物及/或基質組織分佈研究。由於其易於併入及檢測方法容易，放射性同位素氣（思即H)、及碳_ 14(意即14c)特別有效於此目的。例如氘（意即2H)之較重同位素之取代可提供特定治療優勢，其來自更高之新陳代謝安定性，例如增加之活體内半衰期或降低之計量要求，且因此於一些環境中為較佳。正電子發射同位素（例如nC、％、"〇及πΝ)之取代，可有效用於檢查基質受體佔有率之正電子發射斷層掃描（ρΕΤ) 研究。 95339.doc -25- 200526606 一般可藉由熟習此項技術者已知之習知方法或藉由類似於彼等描述於附加之實例及製備中之方法使用適當同位素標記試劑置換先前採用之非標記試劑來製備同位素標記之式（I)之化合物。根據本發明之醫藥上可接受之溶合物包括其中結晶化之溶劑可經同位素取代（例如，〇2〇、丙酮、d0_DMs〇)之溶合物。亦包含於本發明之範圍内係如下文中所定義之中間體化合物、其所有的鹽、溶合物及複合物及如上文中對式⑴之化合物所定義之其鹽之所有溶合物及複合物。本發明包括所有前述種類之多形體及其晶體慣態。當製備根據本發明之式⑴之化合物時，對於熟習此項技術者可公開例行地選擇中間體形態，該等中間體提供用於此目的之特徵的最佳組合。此等特徵包括熔點、溶解度、加工性及中間體形態之產量且產物基於分離之純化的戶I得簡易性。【實施方式】藥物產物意欲用於醫藥料之本發明之化合物可以結晶態或非晶 2產物投藥。其可藉由例如沈殿、結晶化、冷;東乾燥、喷族乾、或療發乾燥之方法而（例如）作為固體栓劑、散劑、或薄膜來獲得。微波或射頻乾燥可用於此目的。其可單獨投藥或與-或多種其他本發明之化合物組合投藥或與-或多種其他藥物(或作為其任何組合物)組合投 95339.doc -26- 200526606 藥。一般，其可作為與一或多合之碉配4種两本上可接受之賦形劑聯 ; = =: 用之術語，，賦形劑”用以描述除本久之任何成份。賦形劑之選擇报大程度上將依 =於例如投樂之特定模式、該賦形劑對溶解度及安定性之影響、及劑型之性質。熟習此項技術者將易於瞭解適於本發明之化合物之傳遞的醫藥組合物及其製備之方法。該等組合物及其製備之方法可見於’例如，^第B 版（a c k出版公司，19 9 5 )。口服投藥可口服投藥本發明之化合物。口服投藥可涉及吞齋以使該化合物進入胃腸道，或可採用口腔或舌下投藥藉此使該化合物直接自嘴進入血流。適於口服投藥之調配物包括固體調配物（例如錠劑、含微粒之膠囊、液體、或散劑、***劑（包括液體填充）、咀嚼劑、多-及奈米-微粒、凝膠、固體溶液、脂質體、薄膜、胚珠、喷霧）及液體調配物。液體調配物包括懸浮液、溶液、糖漿及酒劑。可作為軟或硬膠囊中之填充劑來採用該等調配物且一般包含載劑 (例如，水、乙醇、聚乙二醇、丙二醇、甲基纖維素、或適當之油）及一或多種乳化劑及/或懸浮劑。亦可藉由固體之復水（例如，自小袋（sachet))來製備液體調配物。本發明之化合物亦可用於快速溶解、快速崩解之劑型，例如描述於Liang 及 Chen 之 Expert Opinion in Therapeutic 95339.doc -27- 200526606Ri is a phenyl ring substituted with two or more substituents, and the substituents may be the same or different, and each substituent is independently selected from fluorine, gas, fluorenyl, methoxy, and cyano; R2 is selected from Fluorene, fluorenyloxy, ethoxy, 2-fluorenylethoxy, difluorenyl 95339.doc -11-200526606 amino, 1,2,3-triazol-2-yl and pyrrolidinyl, the latter Optionally substituted with CONH2; r3 is selected from fluorene and (CrC6) alkyl; R4 is fluorene; and R5 is fluorenyloxy. Preferred embodiments of the compound of formula (I) according to the above aspects are those which incorporate two or more of the following preferred embodiments. Preferably, when the rest represent C-R6, one or two of the groups V, W, X and Υ represent N. In a preferred embodiment, X is CH. In a preferred embodiment, when the rest represent 0: _116 and are (: 11, one or two of the groups V, W, and Y represent n; Y is preferably N or CR6. More preferably, ' V, W, and Y are each independently CH, C_CH3, or N. Optimally, W and Y are each independently CH or N. In the preferred embodiment, W and Y are each independently CH or N And each X and V is CH. In a preferred embodiment, z is N. In another preferred embodiment, Z is CH. R1 is preferably selected from: (i) two or two Phenyl ring substituted with more than one substituent, these substituents may be the same or different, each substituent is independently selected from halogen, alkyl, (CVC6) alkoxy, cyano, C (〇) NR7R8, Nr7r8, NR7C (0) R1G and N [C (0) R1G] 2; and 95339.doc -12- 200526606 (ii) five to seven-membered aromatic heterocycles containing 1-3 heteroatoms selected from N , 0 and S and their N-oxides; the ring is optionally substituted with two or more substituents, which may be the same or different and are selected from halogen, (cvc6) alkyl, (cvcoalkoxy, Cyano, c (〇) nr7r8, nr7r8, nr7c (0) r1 () and n [c (o) r10] 2; more preferably R1 is selected from (i) a phenyl ring substituted with two substituents, which may be the same or different, each substituent is independently selected from halogen, (Ci_c6) alkyl, alkoxy, cyano, c (o) nr7r8, NR7R8, nr7c (()) r1 (^ n [c (o) r1q] 2; and (11) a hydrazone ring or its N-oxide, each of which is substituted with two substituents, and these substituents may be Are the same or different and are each independently selected from halogen, (Ci alkyl, (CVC6) alkyl, cyano, c (0) NR7R8, NW, NR7C (0) R1 (), and N [C (O) R10] 2. R1 is more preferably selected from: (i) a phenyl ring substituted with two substituents, which substituents may be the same or different, and each substituent is independently selected from the group consisting of _ prime, (Cl-C3) alkyl (Ci_C3) alkoxy group and cyano group; and (11) Ranyl ring or its N-oxide, each of which is substituted with two substituents, the specific substituents may be the same or different, and each is independently selected from halogen, (Ciec3) alkyl, (CrCO alkoxy, and cyano. In a preferred embodiment, R1 is a phenyl ring substituted with two substituents, and these substituents may be the same or different. Each substituent Independently selected from fluorine, chlorine, methyl, methyloxy and cyano. 95339. doc -13- 200526606 In another preferred embodiment, R1 is a pyridine-N-oxide substituted with two formates. R2 is preferably selected from: ⑴H, (Cl-C6) oxy (Cl-C6) alkyloxy_ (Ci_C6moxy, NR7R8, NR7C (0) R1G and N [C (0) R1 ()] 2; and (ii) 5-7 containing 1-3 heteroatoms N-linked heterocyclic ring, the heteroatoms are selected from N, 0 and S; the ring is optionally selected from (C〗 _C6) alkane, (Ci-C6) alkoxy and c (o) nr7r8 is substituted with a substituent. R2 is more preferably selected from the group consisting of: ⑴H, (Cl-C3) alkyloxy, (Cl-C3) yloxy_ (Ci_c3) alkyloxy, and N ((^ ν (: 3) alkyl) 2; and ( ii) A 5-membered N-linked heterocyclic ring containing 1-3 nitrogen atoms, which ring is optionally substituted by c (o) nr7r8. R2 is more preferably selected from H, methoxy, ethoxy, and 2 · methoxy Ethoxy, dimethylamino, 1,2,3-trifluoren-2-yl and fluorenyl D, the latter being optionally substituted with conh2. R2 is preferably selected from fluorene and methoxy. R3 is preferably Η or (CVC3) alkyl. R3 is preferably Η. R4 is preferably Η, ((VC3) alkyl, or OR9. R is more preferably H, (CVC3) alkyl, or (cvc3) alkoxy. R4 is most Preferred is fluorene, fluorenyl, or methoxy. In a preferred embodiment, R4 is fluorene. Car fluorene is (eve: 3) alkyl, (cvc: 3) alkoxy * NR7R8. 95339.doc 200526606 R is more preferably (C1-C3) alkoxy or NR7R8. R5 is most preferably methoxy or nhch3. In a preferred embodiment, R5 is methoxy. R6 is preferably hafnium, halogen, (Cl_c6) Alkyl, (Cl_c6) alkoxy, cyano or NR7R8. R6 is more preferably fluorene, (CVC6) alkyl, (CVC6) alkoxy, or NR7R8. R6 is more preferably H, (CVC3) alkyl or ( CVC 3) Alkoxy. R6 is preferably fluorene, fluorenyl or fluorenyl. In a preferred embodiment, R6 is fluorene or methyl. In a preferred embodiment, R6 is fluorene. R7 is preferably fluorene. Or (C ^ CJ alkyl. R7 is preferably fluorene or fluorenyl. R8 is preferably fluorene or (CVC3) alkyl. R8 is preferably fluorenyl or methyl. R9 is preferably C (C6) Alkoxy substituted (CrCd alkyl. R9 is more preferably optionally substituted with methoxy (CrCd alkyl. R9 is most preferably methyl. Preferred compound of formula (I) is 2- (4- Fluoro-2-fluorenylphenyl) -5- (5 -fluorenyloxymethyl-4-(6-fluorenyloxy ratio ratio-3-yl) -4H- [1,2,4] trisigma -3-yl) _ntb σ fixed, 2- (2,3-dimethylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridine_3_yl) -4Η_ [1,2,4] trio-3-methyl) -fluorene ratio σ, 5- (4-fluoro-2-fluorenylphenyl) -2- (5-methoxymethyl-4- ( 6-fluorenyloxytidin-3-yl) -4Η_ [1,2,4] trioloxan-3-yl) -11 ratio σ, 95339.doc -15- 200526606 5- (2,3-di (Methylphenyl) -2- (5-methoxyfluorenyl-4- (6-methoxyfluorenyl-3-yl) -4fluorene- [1,2,4] triazol-3-yl) -Pyridine; 1- [5- [5- (2,3-dimethylphenyl)-. Pyridin-2_yl] -4- (6-methoxypyridin-3-yl) -4 '-[1,2,4] triazol-3-ylmethyl] -pyrrolidin- (2S)- 2-carboxylic acid amidoamine; 5- (2,3-dimethylphenyl) -2- (5-salrolidin-1-ylfluorenyl-4- (6-methoxyspardin-3-yl) ) -4Η- [1,2,4] triazol-3-yl) -pyridine; 2- (4-Gas-2-methylphenyl) -5- [5 · methoxyfluorenyl-4- ( 6-methyllactylpyrene than bite-3_yl) -4Η- [1,2,4] triazol-3-yl] -pyrazine; 2- (2,3-dimethylphenyl) -5- [ 5-methoxyfluorenyl-4- (6-methoxypyridin-3-yl) -4hydrazone- [1,2,4] triazol-3-yl] -oxazine; 2- (4-Ga 2-methylphenyl) -5- [4- (6-methoxyσσσ-3-yl) -5-methyl-4H_ [1,2,4] triazol-3-yl] -Pyrazine; 2- (2,3-diamidinophenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2,4 ] Triazol-3-yl] -pyrazine; 2- (4-muryl-2-methylphenyl) -5- [4- (6-methoxy-yl) · 5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxypyridine-3- ) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (4-amino-2-fluorenylphenyl) -5- [5-methyl Oxymethyl- 4- (6-methoxy °°°° -3-yl) -4Η- [1,2,4] Azol-3-yl] -pyrazine; 5- (4-cyano-2-methylphenyl) -2- [5-methoxymethyl-4- (6-methoxypyrimidine-3- Yl) -4Η- [1,2,4] triazol-3-yl] -pyridine; 2- (5-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl- 4- (6-Aminopyridin-3-yl) -4）-[1,2,4] triazol-3-yl] -pyridine; 95339.doc -16- 200526606 2- (2-fluoro-5 -Methoxyphenyl) -5- [4- (6-fluorenoxolidine-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] _ Azine; 2- (2-Gas-5-methylphenyl) _5- [4- (6-methoxy ^ pyridine-3 -yl) -5-methyl-4H- [1,2,4 ] Triazol-3-yl] -pyrazine; 2- (2,5-difluorophenyl) -5- [4- (6-methoxypyridin-3-yl) _5_methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2 · (3,5-dimethylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (2,5-dimethylphenyl) -5- [4- (6-methoxy N-methylpyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] • pyrazine; 2- (2,5-difluorophenyl) -5- [ 4- (6-fluorenyllactyl ° ratio σ-determin-3-yl) -5-methyl-411- [1,2,4] triazol-3-yl] _pyrazine; 2- (2-Gas- 5-Methoxyphenyl) -5- [4- (6-methoxyhexyl. Amine-3 -yl) -5 -fluorenyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (3,5-difluoro-phenyl) -5- [4 -(6-methoxypyridin-3-yl) -5-methyl-4H_ [1,2,4] triazol-3-yl] -pyrazine; 2- (2,3-difluorenylbenzene Group) -5- [5-[(2-methoxyethoxy) methyl] -4- (6-methoxy °°°° -3-yl) -4Η1,2,4 -di ° Sat-3-yl] ° Sigma, 2- (5-Gas-2-methoxyphenyl) -5- [5-[(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4Η-1,2,4-triazol-3-yl] pyridine; 2- (4-gas-2-methoxyphenyl) -5- [5 -[(2-fluorenylethoxy) methyl] -4- (6-fluorenyloxypyridin-3-yl) -4fluorene-1,2,4-triazol-3-yl] pyridine; 2 -(5-fluoro-2-methoxyphenyl) -5- [5-[(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4Η -1,2,4-triazol-3.yl] oxanidine; 95339.doc -17- 200526606 2- (5-fluoro-2-methylphenyl) -5- [5-[(2-methoxy Ethoxy) methyl] _4_ (6_methoxy ° ratio-3-yl) -4H-1,2,4 · trisal_3_yl] snake; 2 -fluorenyl-5- {3-[(2-methoxyethoxy) methyl] _5_ [6- (2_methoxy its 5 methylphenyl) pyridin-3-yl] -4Η · 1,2,4-tri Azol-4-yl} pyridine 2- (2-fluoro-3-methoxyphenyl) -5- [5 _ [(2_methoxyoxyethoxy) methyl] _4 · (6 · methyllactyl ) _411-1,2,4-triazolyl-3-yl] 11-11; 2- (3,5-difluorophenyl) -5- [5-[(2-methoxyethoxy) Methyl] _4- (6_methoxy-2- (2,5-dimethoxyphenyl) -5- [5-[(2-methoxyethoxy) methyl] -4_ (6_ methoxy The radical σ is more than 11 and the _3_ group) -4H_1,2,4 -tri 11 cylo-3-yl] η is more than η; 2- (3-Ga-4-fluorophenyl) -5- [5- [ (2-methoxyethoxy) methyl] -4- (6-methoxy-2- (3-fluoro-2-methoxyphenyl) -5- [5-methoxymethyl-4- (6-Methoxyl. Din-3-yl 2_ (3-fluoro-2_fluorenyloxy-phenyl) _5- [4- (6-methoxy-π-ratio_3_yl) _5- Methyl 4-Η · [1,2,4] trisial-3-yl] -η than cr Qin; and tautomers thereof, and pharmaceutically acceptable salts and fusions of the compounds or tautomers And polymorphs. The best compound of formula (I) is 2- (4-fluoro-2-fluorenylphenyl) -5- (5-methoxymethyl-4- (6-methoxy). Roar 唆 -3_ 基) -4Η- [1,2,4] III. Sit-3-yl) specific bite; 2- (2,3-monomethylphenyl) -5- (5_methoxymethyl-4- (6-methoxyoxy outer dagger. Definite_3_yl) -4Η- [1,2,4] trisalyl-3_yl) _σ specific bite; 5- (4-fluoro-2-methylbenzyl) -2- (5-methoxymethyl-4- (6- Methoxyl. _3_ 95339.doc -18- 200526606 group) -4 Η- [1,2,4] triazol-3-yl) -pyridine; 5- (2,3-dimethylphenyl) -2- (5-methoxyi-methyl-4- (6-methyllactyl σ-ratio-3_yl) -4Η- [1,2,4] triazol-3-yl) -pyridine; 1- [5- [5- (2,3-Dimethylphenyl) -pyridin-2-yl] -4- (6-methoxypyrimidin-3-yl) -4Η- [1,2, 4] triazol-3-ylmethyl] -pyrrolidin- (2S) -2-carboxylic acid sulfonamide; 5- (2,3-dimethylphenyl) -2- (5-arrolidine-1 -Ylmethyl-4- (6-methoxypyridin-3-yl) -4 '-[1,2,4] triazol-3-yl) -pyridine; 2- (4-fluoro-2-methyl Phenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4Η- [1,2,4] triazol-3-yl]- Azine; 2- (2,3-dimethylphenyl) -5- [5-methoxymethyl-4- (6-methoxyoxypyrimidin-3-yl) -4Η- [1,2, 4] triazol-3-yl] -oxazine; 2- (4-chaos-2-methylphenyl) _5- [4- (6-fluorenyloxy 11-ratio-3-yl) -5- Amidin-4 H- [1,2,4] triazol-3-yl] -pyrazine; 2- (2,3-dimethylphenyl) -5- [4- (6-methoxy °° σ- 3-yl) -5-fluorenyl-4fluorenyl- [1,2,4] triazol-3-yl] -pyrazine; 2- (4-lai "yl-2-methylphenyl) -5- [ 4- (6-methoxyσ than fluorene-3 -yl) -5 -methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (5-disorder-2 -Methoxyphenyl) -5- [4- (6-methyllactyl 0 ratio ° -3 -yl) -5 -fluorenyl-4H- [1,2,4] triazol-3-yl] -Pyrazine; 2- (4-Ranyl-2-methylphenyl) · 5- [5-methoxymethyl- 4- (6-methoxyutb fluoren-3-yl) -4Η- [1,2,4] triazol-3-yl] ^ biazine; 5- (4-arsyl-2-methylphenyl) · 2- [5-methoxymethyl-4- (6- Methyllactyl ntb ° den-3-yl) -4Η- [1,2,4] triazol-3-yl] -pyridine; 2- (5-fluoro-2-fluorenyloxyphenyl) -5- [ 5-methoxymethyl-4- (6-methoxypyrimidine 95339.doc -19- 200526606-3-yl) -4pyridine- [1,2,4] triazol-3-yl] -pyrimidine ; And 2 (3fluoro2methoxyphenyl) _5_ [5_methoxymethyl_4_ (6_fluorenyloxy. Bipyridin-3-yl) -4H- [l, 2,4] triazol-3-yl] -oxazine; 2- (3-fluoro-2-methoxy_phenyl) _5_ [4_ (6_methyl Oxy_πbipyridine_3_yl) quinone_methyl-4-fluorene- [1,2,4] triazopyrazine; and tautomers thereof and the pharmacologically acceptable compounds or tautomers thereof Accepted salts, solvates and polymorphs. A pharmaceutically acceptable salt of a compound of formula (I) includes its acid addition salt. Appropriate acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / ¾ salt, bisulfate / sulfate, borate, d-camphorsulfonate, lemon Acid salt, ethanesulfonate, ethanesulfonate, formate, trans-butenoic acid, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / gas, hydrobromide / bromide, hydromoth / iodide, isethionate, lactate, malate, maleate, propylene Diacid, mesylate, sulfamate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, Palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, sugar salt, stearate, succinate, tartrate, tosylate and trifluoroacetate 0 Hemi-salts of acids are formed, for example, hemi-sulphates. For a review of suitable salts, see Stahl and Wermuth (Wiley-VCH, Weinheim, Germany '2002) Handbook of Pharmaceutical Salts: Prop ^ llies, 翏 election, 95339.doc -20- 200526606 and Use 〇 There are three One or more of the methods to prepare a pharmaceutically acceptable salt of a compound of formula (I): (1) by reacting a compound of formula (I) with a desired acid; (ii) by using a desired compound The acid removes the acid labile protecting group from a suitable precursor of the compound of formula IX; or (iii) converts one salt of the compound of formula IX to another salt by reaction with a suitable acid or by a suitable ion exchange column. All three reactions are usually performed in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized. The compounds of the present invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules (e.g., acetic acid) in a non-stoichiometric amount or in a stoichiometric amount. When the solvent is water, the term? Hydrate is used. For example, clathrate complexes, drug-host complexes (where the drug and host are present in stoichiometric or non-stoichiometric amounts) are included in the scope of the present invention. Also included are pharmaceutical complexes containing two or more organic and / or inorganic components, which may be stoichiometric or non-stoichiometric. The resulting complex may be ionized, partially ionized, or non-ionized. For a review of these complexes, see J Pharm Sci, 64⑻, ^ 69-1288 by Haleblian (August 1975). ‘All references to compounds of formula (I) below include references to their salts, solvates, and 95339.doc -21-200526606 complexes, and references to their salts and solvates and complexes. The compounds of the present invention include compounds of formula (I) as defined above (including all polymorphs and crystalline inertias thereof), their prodrugs and isomers (including optical, geometric, and tautomers) as defined below And isotope-labeled compounds of formula (I). As indicated, so-called "prodrugs" of compounds of formula (I) are also included within the scope of the invention. Therefore, when administered into or on the body, a specific derivative of a compound of formula (I) that has little or no medicinal activity in itself can be converted, for example, to a formula with the desired activity by hydrolytic cleavage ( I) compounds. These derivatives are called π prodrugs ''. Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design? Pergamon Press, 1 987 (E Edited by B. Roche, American Medical Association). This can be presented, for example, in formula (I) by substituting a specific part described as "n-pre-part" known to those skilled in the Design of Prodrugs such as Η Bundgaard (Elsevier, 1985). Suitable functionality in the compounds to make prodrugs according to the invention. Some examples of prodrugs according to the present invention include (i) when a compound of formula (I) contains alcohol functionality (-OH), its ether, for example, where the hydrogen functionality of the compound of formula (I) Alkyloxymethyl substituted compounds; and (ii) when a compound of formula (I) contains a first or second amine functionality (-NH2 or -NHR, where R # H), its amines, such as In which (case may be 95339.doc -22- 200526606) a compound in which one or both of the amine functionalities of the compound of the formula (I) are replaced by (Ci-C1G) alkyl groups. The replacement groups according to the previous examples Further examples and examples of other types of prodrugs can be found in the above literature. In addition, the specific compound of formula (I) itself can be used as a prodrug of other compounds of formula (I). Metabolites of compounds of formula (I) are also included in the present invention. Within the meaning, that is, compounds formed when the drug is administered in vivo. Some examples of metabolites according to the present invention include (0) when the compound of formula (I) contains a methyl group, its methylol derivative OH3 ->_CH2OH); (i. When the compound of formula (I) contains a thiol group, Meridian derivative (-OR- >-OH); (iii) When the compound of formula (I) contains a third amine group, its second amine derivative (-NR ^ R ^ s-NHR1 or- NHR2); (iv) when the compound of formula (I) contains a second amine group, its first amine derivative (-NHR1- >-NH2); (v) when the compound of formula (I) contains a phenyl group In some cases, its benzene derivative (-Ph- >-PhOH); and (vi) when the compound of the formula (I) contains an amidino group, its carboxylic acid derivative (-CONH2- > COOH). Compounds of formula ⑴ with one or more asymmetric carbon atoms may exist as two or more stereoisomers. When compounds of formula (I) contain alkenyl or bulk groups, they may be geometrically cis / trans (or Z / E) isomers. When structural isomers can be converted into each other through low energy barriers, tautomer isomerism (tautomerism) can occur. For example, containing imine The compounds of the formula (I) in the form of a radical, keto, or oxime group can be in the form of negative tautomerism, or in a compound containing an aromatic moiety, the so-called valence tautomerism can be in the form. It can be seen that a single compound can be Show multiple types Isomerism: All stereoisomers, geometric isomers, and tautomer forms of compounds of formula (i) within the scope of the present invention include compounds that exhibit multiple types of isomerism, and one or more "Mixtures of various types" also include acid additions in which the counterion is optically active, for example, d-lactate, or racemic (eg, dM vermiculite). It can be understood by those skilled in the art. Techniques to separate cis / trans isomers' eg chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from appropriate photons, chitosan, or the decomposition of racemates using, for example, chiral high pressure liquid chromatography (HPLC) (Or racemates of salts or derivatives). Alternatively, a racemate (or a racemic precursor) may be reacted with an appropriate optically active substance (for example, an alcohol, or in the case where the compound of formula ⑴ contains an acidic or basic moiety, and a base or acid, such as 丨_Phenylethylamine or tartaric acid). The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to skilled operators. isomer. Chromatography (typically HPLC) can be used on asymmetric resins from 0 to 50% by volume isopropyl alcohol (typically from 2% to 20%) and 0 to 5% by volume alkylamines (typically 0.1❶ / ◦diethylamine) hydrocarbon (usually heptane or hexane) 95339.doc -24- 200526606 mobile phase to obtain enantiomerically enriched chiral compounds of the present invention ( And its chiral precursors). Concentration of the eluate provides an enriched mixture. Aggregates of stereoisomers can be separated by conventional techniques known to those skilled in the art ~ see, for example, E.L. and s. [CompcmndL (Wiley, New York 1994). The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I), in which one or more atoms have the same atomic number but have a predominant atom in nature. Masses or mass numbers with different atomic masses or mass atomic substitutions. Examples of isotopes suitable for inclusion in the compounds of the invention include the isotopes of the following elements: hydrogen (eg 2H and 3H), carbon (eg " c , 3C and 14C), chlorine (such as 36ci), tun (such as #), iodine (such as 1231 and 1251 nitrogen (such as% and 15N), oxygen (such as M,% and 180), dish (such as 32p) And sulfur compounds such as 35s). Compounds of formula ⑴, which are specifically labeled with isotopes, for example, compounds which incorporate radioisotopes, can be effectively used in the study of drug and / or matrix tissue distribution. Because they are easy to incorporate and detect Easy method, radioisotopes Qi (think H) and carbon-14 (meaning 14c) are particularly effective for this purpose. For example, the replacement of heavier isotopes of deuterium (meaning 2H) can provide specific therapeutic advantages, which come from higher metabolic stability, For example, increased in vivo half-life or reduced metering requirements, and therefore better in some environments. Substitution of positron emission isotopes (such as nC,%, " 0 and πN) can be effectively used to check matrix receptor occupancy Rate positron emission tomography (ρΕΤ) studies. 95339.doc -25- 200526606 In general, it can be done by methods known to those skilled in the art or by methods similar to those described in additional examples and preparations. The isotope-labeled compound of formula (I) is prepared by replacing the previously used unlabeled reagent with an appropriate isotope-labeled reagent. Pharmaceutically acceptable solvates according to the present invention include solvents in which crystallization can be substituted with isotopes (eg, 20, acetone, d0_DMs 0). Also included within the scope of the present invention are intermediate compounds, all their salts, solvates, and Complexes and all solvates and complexes of their salts as defined above for the compound of formula (I). The present invention includes all of the aforementioned species of polymorphs and their crystal inertia. When preparing compounds of formula (I) according to the present invention For those skilled in the art, it is possible to routinely select intermediate forms publicly, and these intermediates provide the best combination of features for this purpose. These features include melting point, solubility, processability, and yield of intermediate forms, and The simplicity of the product is based on the isolated purified household I. [Embodiment] The pharmaceutical product of the present invention is intended to be used as a pharmaceutical compound. The compound can be administered in crystalline or amorphous form. It can be obtained, for example, as a solid suppository, powder, or film by methods such as Shen Dian, crystallization, cold; Dong drying, spray drying, or hair drying. Microwave or RF drying can be used for this purpose. It can be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or as any of its compositions) 95339.doc -26- 200526606. Generally, it can be used in combination with one or more combinations of 4 two acceptable excipients; = =: The term used, "excipient" is used to describe any ingredient other than Benjiu. Excipients The choice will depend to a large extent on, for example, the particular mode of Tokor, the effect of the excipient on solubility and stability, and the nature of the dosage form. Those skilled in the art will readily understand the delivery of compounds suitable for the present invention. Pharmaceutical compositions and methods of making them. These compositions and methods of making them can be found in, for example, ^ version B (ack publishing company, 195 5). Oral administration The compounds of the present invention can be administered orally. Oral administration It may involve fasting to allow the compound to enter the gastrointestinal tract, or oral or sublingual administration may be used to allow the compound to enter the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations (e.g., lozenges, microparticles) Capsules, liquids, or powders, buccal preparations (including liquid fillings), chews, multi- and nano-particles, gels, solid solutions, liposomes, films, ovules, sprays) and liquid formulations. Formulations include suspensions, solutions, syrups, and liquors. These formulations can be used as fillers in soft or hard capsules and generally include a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methyl Cellulose, or suitable oil) and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by rehydration of solids (for example, from sachets). The compounds of the present invention can also be used in Fast dissolving and fast disintegrating dosage forms, such as described in Liang and Chen's Expert Opinion in Therapeutic 95339.doc -27- 200526606

PatentS，U(6)，981_986,2〇〇1 中之劑型。對錠劑劑型，視劑量而定’該藥物可構成該劑型之i重量 :至80重量。/。’更通常為該劑型之5重量％至6〇重量％。除該藥物之外，I定劑通當合—# ώ ώ 種朋解劑。朋解劑之實例包括羥基乙酸澱粉納、幾1甲其祕：‘ , 羧γ基纖維素鈉、羧甲基纖維素鈣、交聯緩甲纖維素鈉、交聯聚乙稀料m稀料相、甲基纖維素、微晶纖維素、經低碳數烧基取代之㈣基纖維素、澱粉、預膠凝殿粉及海藻酸納。通常，崩解劑將包含该劑型之1重量％至25重量％，較佳為5重量％至2〇重量％。黏合劑通常用於賦予錠劑調配物黏著品質。適當之黏合齊^包括微晶纖維素、明膠、糖、聚乙二醇、天然及合成樹膠、聚乙烯料咬嗣、預膠凝殿粉、經丙基纖維素及經丙基甲基纖維素。錠劑亦可含稀釋劑，例如乳糖（單水合物、經喷霧乾燥之單水合物、無水物及其類似物）、甘露醇、木糖醇、葡萄糖、餘、山㈣、微晶纖維素”殿粉及二水合磷酸氫二鈣。錠劑視情況亦可包含表面活性劑（例如十二烷基磺酸鈉及聚山梨醇酯80)及助流劑（例如二氧化矽及滑石）。當存在時，表面活性劑可包含錠劑之〇·2重量％至5重量 0/〇，且助流劑可包含錠劑之〇.2重量％至1重量％。錠劑通常亦含潤滑劑，例如硬脂酸鎂、硬脂酸鈣、硬脂 fee辞、硬脂醯基反式丁烯二酸鈉、及硬脂酸鎂與十二烷基磺酸鈉之混合物。潤滑劑通常包含錠劑之0 25重量％至10 重1 °/〇，較佳為0 · 5重量％至3重量％。 95339.doc -28- 200526606 其他可能之成份包括抗氧化劑、著色劑、芳香劑、防腐劑及掩味劑。例示性键劑含多達約80%之藥物、自約10重量％至約至約 90重量％之黏合劑、自約〇重量％至約85重量％之稀釋劑、自約2重S %至約10重量％之崩解劑、及自約〇 25重量％至約 1 0重量％之潤滑劑。可將錠劑摻合物直接或藉由滾筒壓縮從而形成錠劑。或者，錠劑摻合物或摻合物之部分在錠劑化前可經濕_、乾_、或熔化-粒化、熔化-凍結、或擠壓。最終調配物可包含一或多層且可經塗覆或未經塗覆；其甚至可被裝入膠囊。PatentS, U (6), 981-986, 2001. For lozenge dosage forms, depending on the dosage ', the drug may constitute the weight of the dosage form: up to 80 weights. /. 'Is more usually from 5 to 60% by weight of the dosage form. In addition to the drug, I 定剂通当合 — # ώ Kind of friends. Examples of solubilizers include sodium starch glycolate, several methyl esters: ', sodium carboxygamma cellulose, calcium carboxymethyl cellulose, crosslinked sodium methylcellulose, crosslinked polyethylene thin phase, Methylcellulose, microcrystalline cellulose, fluorenyl cellulose substituted with low carbon number burning group, starch, pregelatinized powder and sodium alginate. Generally, the disintegrant will contain from 1% to 25% by weight of the dosage form, preferably from 5% to 20% by weight. Binders are often used to impart sticky qualities to lozenge formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyethylene bites, pregelatinized powder, propyl cellulose and propyl methyl cellulose . Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, glucose, residual, behenic acid, microcrystalline cellulose "Powder powder and dicalcium phosphate dihydrate. Lozenges may optionally contain surfactants (such as sodium dodecyl sulfonate and polysorbate 80) and glidants (such as silicon dioxide and talc). When present, the surfactant may comprise 0.2 to 5 wt.% Of the lozenge, and the glidant may comprise 0.2 to 1 wt.% Of the lozenge. The lozenges will usually also contain a lubricant , Such as magnesium stearate, calcium stearate, fatty stearate, sodium stearate trans-butenoate, and a mixture of magnesium stearate and sodium dodecyl sulfonate. Lubricants usually include tablets 0 25% to 10% 1 ° / 〇 of the agent, preferably 0.5 to 3% by weight. 95339.doc -28- 200526606 Other possible ingredients include antioxidants, colorants, fragrances, preservatives And taste-masking agents. Exemplary bonding agents contain up to about 80% of the drug, from about 10% to about 90% by weight Agent, from about 0% to about 85% by weight of a diluent, from about 2% by weight of S% to about 10% by weight of a disintegrant, and from about 025% to about 10% by weight of a lubricant. Compress the lozenge blend directly or through a roller to form a lozenge. Alternatively, the lozenge blend or a portion of the blend may be wet-, dry-, or melt-granulated, melted before being lozenged. -Frozen, or squeezed. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be filled into capsules.

Lachman 之Lachman

旋劑之調配於H. Lieberman及The formulation of the revolving agent is in H. Lieberman and

Pharmaceutical Dosage For^c 钕、丄〜、， -•弟一卷（Marcel Dekker，NewPharmaceutical Dosage For ^ c Neodymium, Thallium ~ ,,,-• 一一卷（Marcel Dekker, New

York，1980)中討論。York, 1980).

用於人類或獸用途之可消耗口服膜通常係柔性水溶性可水膨脹之薄膜劑型，其可快速溶解或黏膜黏 (muc〇adhesive)且通常包含式⑴之化合物、成膜聚合物、； ^劑、溶劑、濕潤劑、增塑劑、安定劑或乳化劑、黏度; 良劑及溶劑。調配物之—些組份可執行多種功能。勺^)之化合物可係水溶性或不可溶。水溶性化合物^ :::心%至80重量%、更通常為自2。重量⑽重量, 之洛貝。較不可溶之化合物常多達88重量㈣質。戍者，二S物之更大部分4 小球之形態。一式⑴之化合物可係多顆未成模聚合物可選自天然多糖、蛋白質、或合成水膠體』 95339.doc •29- 200526606 更通常為30至80重量通常呈現於0.01至99重4%之範圍内 %之範圍内。其他可能之成份包括括翁 — 乳化剑、者色劑、調味料或增香劑、防腐劑、唾液刺激劑、冷部劑、助溶劑（包括油）、軟化劑、膨化劑、防泡劑、介面活性#丨及掩味劑。通常藉由塗覆於可剥離之㈣支架（baeking叫卿）或氏上的3水4膜之⑧發乾燥來製備根據本發明之膜。此可於乾燥爐或隧道中完成’通常於組合塗布機乾燥機中，或藉由冷凍乾燥或真空處理來完成。可調配口服投藥之固體調配物以使其立即釋放及/或改性釋放。改性釋放調配物包括延緩_、持續_、脈衝_、控制_、目標化及程式化釋放。用於本發明之目的之適當改性釋放調配物描述於美國專利第6,1〇6,864號中。其他適當釋放技術（例如高能力分散及滲透性及經塗覆之顆粒）之細節見於Verma等人之 ^ilMinaceutical Technology On-line，25(2)，1-14 (2001)。口香糖之使用以達成控制釋放描述於WO 00/35298中。腸胃外投藥亦可將本發明之化合物直接投藥入血流、肌肉、或内部為官中。腸胃外投藥之適當方法包括靜脈内、動脈内、腹膜内、鞘内、心室内、尿道内、膜内、顱内、肌肉内及皮下投藥。腸胃外投藥之適合的元件包括針（包括微針）注射器、無針注射器及灌輸技術。腸胃外調配物通常係水溶液，其可含賦形劑，例如鹽、 95339.doc • 30- 200526606 物及緩衝劑(較佳為自3至9之pH)，但是對於—此應用，其可更適於調配為盔、二能以用；4人 .、、、函非水/合液，或調配為乾燥形心於與適合之媒劑（例如無菌、無熱原水）聯合。二菌，件下腸胃外調配物之製備(例如藉由繼)可於{用热自此項技術者所熟知之標準醫藥技術來完成。可藉由合適之調配物技術（例如溶解度增強劑之併入）之使用來增加用於腸胃外溶液之製備中之式⑴之化合物之溶解度。可調配用於腸胃外投藥之調配物以使其立即及/或改性釋放。改性釋放調配物包括延緩_、持續_、脈衝_、控制_、目標化及程式化釋放。因此將本發明之化合物調配為固體、半㈣、或觸變液體以作為植入庫（―咖以心㈣投藥以提供該活性化合物之改性釋放。此等調配物之實例包括經藥物塗覆之血管支架（stent)及聚（d/_乳酸_共羥基乙酸）酸（PGLA)微球。局部投藥亦可將本發明之化合物局部投藥至皮膚或黏膜，意即，表皮上或經表皮。用於此目的之典型調配物包括凝膠、水凝膠、洗液、溶液、霜劑、藥膏、粉劑、敷料、泡沫、膜、皮膚貼片、圓片、植入物、海綿體、纖維、繃帶及微乳劑。亦可使用脂質體。典型之載劑包括醇、水、礦物油、液體礦脂、白礦脂、丙三醇、聚乙二醇及丙二醇。可併入滲透增強劑一參看，例如，Finnin 及 Morgan 之 J Pharm Sci，88 (1〇)， 955-958 (1999年 10月）。 95339.doc -31 - 200526606 士局部投藥之其他方法包括藉由電穿孔、離子電滲療法、耳波透入療法、超曰波透入療法（s〇n〇ph〇resis)及微針或無針（例如，Powderject™、Bi〇jectTMf)注射傳遞。可調配腸胃外投藥之調配物以使其立即及/或改性釋放。改性釋放調配物包括延緩_、持續_、脈衝、控制-、目標化及程式化釋放。吸入/鼻内投藥Consumable oral films for human or veterinary use are generally flexible, water-soluble, water-swellable film dosage forms that can be quickly dissolved or mucoadhesive, and typically contain a compound of formula (I), a film-forming polymer, ^ Agents, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity; good agents and solvents. Formulations—Some components can perform multiple functions. The compounds in the spoon may be water-soluble or insoluble. Water-soluble compound: ^ ::% to 80% by weight, more usually from 2. Weight ⑽ weight, Lobe. The less soluble compounds often weigh up to 88 weight. Whoever is, the larger part of the two S things is in the form of 4 small balls. A compound of the formula (I) can be a plurality of unmolded polymers. It can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids. "95339.doc • 29- 200526606 More usually 30 to 80 weights Usually present in the range of 0.01 to 99 weight 4% Within the range of%. Other possible ingredients include Emulsions—emulsifying swords, toners, seasonings or flavoring agents, preservatives, saliva stimulants, cold-keeping agents, solubilizers (including oils), softeners, bulking agents, antifoaming agents, Interface activity # 丨 and taste masking agent. The film according to the present invention is usually prepared by drying the 3 water 4 film coated on a peelable tritium holder (baeking). This can be done in a drying oven or tunnel ', usually in a combination coater dryer, or by freeze drying or vacuum processing. Orally administered solid formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed_, sustained_, pulsed_, controlled_, targeted and programmed release. Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies (such as high-capacity dispersion and permeability and coated particles) can be found in Verma et al. Minaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. Parenteral administration The compounds of the present invention can also be administered directly into the bloodstream, muscle, or internal organs. Suitable parenteral administration methods include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intraperitoneal, intracranial, intramuscular, and subcutaneous administration. Suitable components for parenteral administration include needle (including microneedle) injectors, needleless syringes, and infusion techniques. Parenteral formulations are usually aqueous solutions, which may contain excipients such as salts, 95339.doc • 30-200526606 and buffers (preferably at a pH from 3 to 9), but for this application, it can be more Suitable for deployment as a helmet and dual use; 4 persons. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, and, The combination with a suitable vehicle (such as sterile, pyrogen-free water). The preparation of two parenteral, parenteral formulations (e.g., by relaying) can be accomplished {using heat from standard medical techniques well known to those skilled in the art. The solubility of the compound of formula (I) in the preparation of parenteral solutions can be increased by the use of suitable formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration may be formulated for immediate and / or modified release. Modified release formulations include delayed_, sustained_, pulsed_, controlled_, targeted and programmed release. The compounds of the present invention are therefore formulated as solid, semi-aqueous, or thixotropic liquids for use as an implantation library (―Ca is administered with a heart palate to provide modified release of the active compound. Examples of such formulations include drug coating Stent and poly (d / _lactic acid_co-glycolic acid) acid (PGLA) microspheres. Topical administration The compounds of the present invention can also be administered topically to the skin or mucosa, that is, on the epidermis or transepidermis. Typical formulations used for this purpose include gels, hydrogels, lotions, solutions, creams, salves, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, Bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. May be incorporated into penetration enhancers. See also For example, J Pharm Sci of Finnin and Morgan, 88 (10), 955-958 (October 1999). 95339.doc -31-200526606 Other methods of topical administration include electroporation, iontophoresis , Oto-penetration therapy, Chao Yue Penetration therapy (sonaphresis) and microneedle or needleless (eg, Powderject ™, Biojectmf) injection delivery. Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed_, sustained_, pulsed, controlled-, targeted, and programmed release. Inhalation / intranasal administration

亦可將本發明之化合物鼻内或藉由吸入投藥通常幻乾燥散劑吸人器之乾燥散劑形態（單獨或作為混合物& $之任一者，例如，於與乳糖之乾燥掺合物中，或作為矣混合之組份顆粒’例如’與磷脂混合，例如翻醯膽驗^ 作為自加壓容器、杲、嘴射器㈣叫、噴霧器（atomiser)(幸佳為使用流體力學之喷霧器以製造精細薄霧}、或霧^ (nebullser)中之氣噴霧溶勝，使用或不使用適當之推進劑例如U，2,2-四氟乙烷或Μ，1，2,3,3，〗-六氟丙烷。對鼻内仓用’該散劑可包含生物附著劑’例如，殼聚糖或環糊精。力I谷益、栗、喷射器、喷霧器、或霧化器中含本發明之化合物之溶液或懸浮液，其包含，例如，乙醇、含水乙醇、或用於活性成份之分散、溶解、或擴展釋放之適當替代試劑、作為溶劑之推進劑及視情況之介面活性劑，例如二油酸山梨聚糖醋、油酸、或寡聚乳酸。在用於乾燥散劑或懸浮液調配物之前，將藥物產物微粉匕至適於藉由吸入來傳遞之尺寸（通常低於5微米此可藉何口適之私碎方法來達成，例如螺旋喷射研磨、流體 95339.doc -32- 200526606 臨界流體處理、高壓床喷射研磨、用於形成奈米顆粒之超均化、或噴霧乾燥。可將用於吸入器或吹入器中之膠囊(例如由明膠或經丙土甲基纖維素製得）、發泡藥及藥筒調配成含與本發明之化合物之混合散劑、適當散劑基質（例如乳糖或澱粉）及效能改性劑如/_亮胺酸、甘露醇、或硬脂酸鎂)。乳糖可為無水或為單水σ物形悲，較佳為後者。其他適當賦形劑包括右旋㈣、葡萄糖、麥芽糖、山梨醇、木糖醇、果糖、蔗糖及海藻糖。用於使用電水動力學以製造精細薄霧之喷霧器之適當溶液調配物每致動可含自！叫至2() mg本發明之化合物且致動體積可自i μ1至100μ1變化。典型之調配物可包含式⑴之化合物、丙二醇、無菌水、乙醇及氣化鈉。可用於替代丙二醇之替代性溶劑包括丙三醇及聚乙二醇。可將適當芳香劑（例如薄荷醇及左旋薄荷醇 (levomenthol))、或甜味劑（例如糖精或糖精鈉）加入彼等意欲用於吸入/鼻内投藥的本發明之調配物。可使用（例如）PGLA來調配用於吸入/鼻内投藥之調配物以使其立即及/或改性釋放。改性釋放調配物包括延緩_、持續-、脈衝-、控制-、目標化及程式化釋放。在乾燥散劑吸入器及氣溶膠之狀況下，劑量單位藉由傳遞經量測之量之閥決定。通常配置根據本發明之單位以投藥經量測之劑量或含自2至30 mg式（I)之化合物之，，噴煙”。總曰劑量通常將介於50至100 mg之範圍内，其可以單劑量 95339.doc -33- 200526606 或更通常以貫穿全天之分劑量來投藥。直勝内/***内投藥可將本發明之化合物直腸内或***内投藥，例如，以栓劑、***拴劑、或灌腸劑之形態。可可油係傳統栓劑基質，但亦可適當使用多種替代物。可凋配直腸/***投藥之調配物以使其立即及/或改性釋放。改性釋放調配物包括延緩_、持續_、脈衝_、控制_、目標化及程式化釋放。眼/耳投藥亦可將本發明之化合物直接投藥至眼或耳，通常為等滲、經pH調節、無菌生理食鹽水中之經微粉化之懸浮液或 ,液液滴之形態。適於眼及耳投藥之其他調配物包括藥賞、可生物降解（例如，可吸收之凝膠海綿體、勝原質）及不可生物降解（例如聚⑦氧）灌輸液、圓片、晶狀體及微粒或囊狀體系例如囊泡（m〇s〇me)或脂質體。可將聚合物（例如交聯聚丙烯酸1乙烯醇、透明質酸）、纖維素聚合物（例如声丙f甲基纖維素、經乙基纖維素、或甲基纖維素）、或雜多 =聚合物（例如結蘭膠（geUn gum))與防腐麵如，殺藻錢） I併入亦可藉由離子電滲療法傳遞此等調配物。 °周-&耳才又藥之調配物以使其立即及/或改性釋放。改性釋放調配物包括延緩·、持續_、脈衝·、控制_、程式化釋放。其他技術本發明之化合物可與可溶大分子實體（例如環糊精及其 95339.doc -34- 200526606 適畜衍生物或含聚乙二醇之聚合物）組合以改良其、容解度、溶解速率、掩味、生物湘率及/或詩任何前述投藥模式之安定性。藥物-環糊精複合物，例如，被發現通常可有效用於絕大多數劑型及投藥途徑。可使用包含及非包含複合物中之兩者。作為與藥物直接複合之替代，可使用環糊精作為輔助 4加劑，意即，作為載劑、稀釋劑、或增溶劑。最常用於The compounds of the present invention can also be administered intranasally or by inhalation into the dry powder form of a conventional dry powder inhaler (alone or as a mixture & $, for example, in a dry blend with lactose, Or as a component of 矣 mixed with particles such as 混合 mixed with phospholipids, such as biliary biliary test ^ as a self-pressurized container, 杲, mouthpiece howl, atomizer (fortunately, the use of hydrodynamic atomizer to Make fine mists}, or gas sprays in mists (nebullser), with or without the use of appropriate propellants such as U, 2,2-tetrafluoroethane or M, 1,2,3,3, -Hexafluoropropane. For intranasal storage, 'the powder may contain bioadhesives', for example, chitosan or cyclodextrin. Liyi Guyi, chestnut, sprayer, sprayer, or atomizer contains this A solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for the dispersion, dissolution, or extended release of the active ingredient, a propellant as a solvent, and optionally a surfactant, E.g. sorbitan dioleate, oleic acid, or oligomeric Lactic acid. Prior to use in drying powders or suspension formulations, finely powder the drug product to a size suitable for delivery by inhalation (usually less than 5 microns. This can be achieved by suitable sparing methods such as spiral Jet milling, fluid 95339.doc -32- 200526606 critical fluid treatment, high-pressure bed jet milling, super-homogenization for nanoparticle formation, or spray drying. Capsules used in inhalers or insufflators (for example Manufactured from gelatin or via propionate methylcellulose), foaming drugs and cartridges formulated with a mixed powder containing a compound of the invention, a suitable powder base (such as lactose or starch), and performance modifiers such as Amine acid, mannitol, or magnesium stearate). Lactose can be anhydrous or monohydrate, preferably the latter. Other suitable excipients include dextrose, glucose, maltose, sorbitol, xylose Alcohol, fructose, sucrose, and trehalose. Suitable solution formulations for sprayers that use electrohydrodynamics to create fine mists can contain from 1 to 2 () mg of a compound of the invention and actuate per actuation Volume from i μ1 to 100μ 1. Variations. A typical formulation may include a compound of formula VII, propylene glycol, sterile water, ethanol, and sodium gasification. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Appropriate fragrances such as Menthol and levomenthol), or sweeteners (such as saccharin or sodium saccharin) are added to the formulations of the present invention which they intend to use for inhalation / intranasal administration. For example, PGLA can be used for formulation for Inhaled / intranasal formulations for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In dry powder inhalers and In the case of aerosols, the dosage unit is determined by a valve that delivers the measured quantity. Usually the unit according to the invention is configured to measure the dose by administration or contains from 2 to 30 mg of the compound of formula (I), Smoke. " The total daily dose will usually be in the range of 50 to 100 mg, which can be administered in a single dose of 95339.doc -33-200526606 or more often in divided doses throughout the day. Intrinsic / intravaginal administration The compound of the present invention can be administered intrarectally or intravaginally, for example, in the form of suppositories, vaginal suppositories, or enemas. Cocoa butter is a traditional suppository base, but multiple alternatives may be used as appropriate. Rectal / vaginal formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed_, sustained_, pulsed_, controlled_, targeted and programmed release. Eye / ear administration The compounds of the present invention can also be administered directly to the eyes or ears, usually in the form of isotonic, pH-adjusted, micronized suspension or sterile liquid in sterile physiological saline. Other formulations suitable for eye and ear administration include medicinal rewards, biodegradable (eg, absorbable gel sponges, protoplasts) and non-biodegradable (eg polyoxygen) infusions, discs, lenses, and particles Or sac-like systems such as vesicles or liposomes. Polymers (such as cross-linked polyacrylic acid 1 vinyl alcohol, hyaluronic acid), cellulose polymers (such as acrylic methyl cellulose, ethyl cellulose, or methyl cellulose), or heteropoly = The incorporation of polymers (such as geUn gum) with preservatives such as algicidal money I can also deliver these formulations by iontophoresis. ° Chou- & auricular and pharmaceutical formulations for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, and programmed release. Other technologies The compounds of the present invention can be combined with soluble macromolecular entities (such as cyclodextrin and its 95339.doc -34- 200526606 suitable animal derivatives or polyethylene glycol-containing polymers) to improve their solubility, Dissolution rate, taste masking, bioavailability, and / or stability of any of the foregoing modes of administration. Drug-cyclodextrin complexes, for example, have been found to be effective in most dosage forms and routes of administration. Both contained and unincluded complexes can be used. As an alternative to direct compounding with drugs, cyclodextrin can be used as an auxiliary 4 adjuvant, that is, as a carrier, diluent, or solubilizer. Most commonly used

此等目的係、α-、β-、γ_環糊精，其實例可見於國際專利申請案 WO 91/11172、W〇 94/〇2518及界〇 98/55148 中。各部分之套組（Kit_c>f-parts) 广；（例如）出於治療特定疾病或病症之目的可能需要投藥活眭化合物之組合，因此兩種或兩種以上醫藥組合物（其中至夕一種含根據本發明之化合物）可以適於組 ’、、、且之形態而便利地組合，此包含於本發明之範圍内。因此本發明之套組包含兩種或兩種以上獨物，置中5 W、你人」面果、、且合二夕一種έ根據本發明之式（I)之化合物及獨立地These objects are α-, β-, and γ-cyclodextrin, examples of which can be found in International Patent Applications WO 91/11172, WO 94 / 〇2518, and Boundary 98/55148. Kit_c > f-parts are extensive; (for example) a combination of active compounds may be required for the purpose of treating a particular disease or condition, so two or more pharmaceutical compositions Containing the compound according to the present invention) can be conveniently combined in a form suitable for the group ',, and, and this is included in the scope of the present invention. Therefore, the set of the present invention includes two or more kinds of unique objects, including 5 W in the center, noodles, and a combination of the compounds of formula (I) according to the present invention and independently

包…亥等組合物之構件(例如容器、分開之瓶或分開之箔此—套組之實例係與用於錠劑、膠囊及其類似物之封裝類似之發泡包裝。対腸：：明之套組特別有效於投藥不同劑型，例如，口服 ^月外’用於以不同劑量間隔投藥獨立的組合物，或用 1 ^獨立的組合物。為輔助順應性，該套組通常 "又樂說明且可具有所謂的記憶輔助物。劑量 95339.doc •35- 200526606 為投藥至人類患者，本發明之化合物總每日劑量通常介於50 mg至1〇〇 mg之範圍内，當然視投藥模式及功效而定。例如’口服投藥可需要自50 mg至100 mg之總每日劑量。可以單獨或分開之劑量投藥該總每日劑量，且於醫師之判斷下該總每日劑量可超出本文所給出的通常範圍。此等劑量係基於具有約6〇 4至7〇 kg之重量的平均人類受檢者。醫師可易於確定體重超出此範圍之受檢者（例如幼兒及老年人）之劑量。為避免疑惑，本文對，，治療"之參考包括對治癒、減輕及鲁預防治療之參考。方法可根據反應流程1製備其中！^係H、R3係Η且R1、R4、R5、 R6、X、V、W、Υ及Ζ如本文所述之通式⑴之化合物。Packages of components such as containers (such as containers, separate bottles, or separate foils)-Examples of sets are blister packs similar to those used for tablets, capsules, and the like. The kit is particularly effective for administration of different dosage forms, for example, for oral administration of separate compositions at different dose intervals, or for use of independent compositions. To aid compliance, the kits are generally " youle Description and may have so-called memory aids. Dose 95339.doc • 35- 200526606 For administration to human patients, the total daily dose of the compound of the present invention is usually in the range of 50 mg to 100 mg, of course depending on the mode of administration Depending on the effect. For example, 'oral administration may require a total daily dose from 50 mg to 100 mg. The total daily dose may be administered alone or in separate doses, and the total daily dose may exceed this article in the judgment of the physician. Typical ranges given. These dosages are based on average human subjects with a weight of about 604 to 70 kg. Physicians can easily identify subjects whose weights exceed this range (such as young children and the elderly) In order to avoid doubt, the reference to "treatment" in this article includes references to cure, alleviation, and preventive treatment. Methods can be prepared according to Reaction Scheme 1! ^ Is H, R3, and R1, R4, R5 , R6, X, V, W, Y and Z are compounds of the general formula IX as described herein.

流程1 式（II)之化合物可獲自市售或可藉由類似於/少义c/^w , 66(2)，605-608; 2001及英國專利申請案第2219793號，1989 95339.doc -36 - 200526606 年1 2月2 0曰中所述之方法製備。或者，當V、W、X或y=cr60_，可自市售化合物使践6 之標準化學反應及轉化製備式（Π)之化合物。當R6㈣氧基且較佳為甲氧基時，藉由官能基（較佳為氯）之取代併入R6，如製備84-86中所例示。可自式（π)之化合物藉由方法步驟（丨）製備式（hi)之化合物忒步驟包含於適當溶劑（例如甲醇或乙醇）中於_丨〇ο。及 =流之間與肼單水合物之反應。典型條件包含於甲醇中回机加熱1 S篁之芳基酯（11)及12·3當量之肼單水合物小時。可自式（III)之化合物藉由方法步驟（ii)製備式（ιν)之化合物，該步驟包含於適當溶劑（例如取_二甲基甲酿胺、Ν_ 甲基η比洛咬或甲苯）中與Ν，Ν_二甲基乙醯胺二甲基乙縮醛 (=AUidch購得）反應，繼而加入適當酸觸媒（例如三氣乙敲、對甲苯㈣、樟M酸、或氫氯 •二甲基甲醯胺中相。C加熱lt量之芳基醯 1:量之N，N_二甲基乙酿胺二甲基乙縮搭2小時，繼而於真空中濃縮，加入甲苯及0.02#量之對甲苯項酸，隨後將其加熱至回流2小時。可^式（iv)之化合物藉由方法步驟（iii)製備式之化合物為步驟包含於在15〇t下加熱之適當溶劑（例如二甲苯）適田fee (例如二氟乙酸、對甲苯磺酸、樟腦磺酸、或氫二）之存在下與適當笨胺或3 -胺基口比ϋ定反應。典型條件包 a於—甲苯中於15Gt加熱1#量之㈣、2_3 95339.doc 200526606 當量之苯胺或胺基吡啶及0.04-0.1當量之對甲苯磺酸18-23 小時。可自式（V)之化合物藉由方法步驟（iv)製備式（I)之化合物，該步驟包含於適當溶劑中於鹼及鈀觸媒（例如[2-[(二甲基胺基-κΝ)曱基]苯基-kC](三環己基膦）（三氟醋酸根 -K〇-(SP-4-3)-l巴，如中所述製備，2003,22 (5)，987_999)之存在下與適當硼酸（例如2,3-二曱基苯基硼酸（市售））之Suzuki偶合反應。可如文獻 Suzuki，A- Pwre 1985，57，1749及其中所包含之參考文獻；gew· C/zem· /扯五(i. 2002，41， 4176-4211及其中所包含之參考文獻中所述來執行Suzuki偶合反應。典型條件包含於1，4-二噁烷中於120°C加熱1當量之芳基溴（V)、2·5當量之硼酸、3當量之碳酸鈽、0.06當量之來自製備3之鈀觸媒4小時。可根據反應流程2製備其中R3係Η且其中R1、R2、R4、R5、 R6、X、V、W、Υ及Ζ如本文所述、除R2#H外之通式（I)之化合物。 95339.doc 38- 200526606Scheme 1 Compounds of formula (II) can be obtained from the market or can be obtained by analogous to / less meaning c / ^ w, 66 (2), 605-608; 2001 and British Patent Application No. 2219793, 1989 95339.doc -36-200526606 Prepared by the method described in February 20, 2005. Alternatively, when V, W, X, or y = cr60_, a standard chemical reaction and conversion of commercially available compounds can be used to prepare a compound of formula (Π). When R6 is methoxy and preferably methoxy, R6 is incorporated by substitution of a functional group, preferably chlorine, as exemplified in Preparation 84-86. A compound of formula (hi) can be prepared from a compound of formula (π) by method step (丨). The step is comprised in a suitable solvent (for example, methanol or ethanol). And = reaction between the stream and hydrazine monohydrate. Typical conditions include reheating the aryl ester (11) of 1S hydrazone in methanol and 12.3 equivalents of hydrazine monohydrate for 1 hour. A compound of formula (ιν) can be prepared from a compound of formula (III) by method step (ii), which step is included in a suitable solvent (for example, dimethylformamide, N_methyl η bilobit, or toluene) With Ν, Ν_dimethylacetamidine dimethyl acetal (available from AUidch), and then add an appropriate acid catalyst (such as trigas ethyl acetate, p-toluene, camphor M acid, or hydrogen chloride) • The phase of dimethylformamide. C heating the amount of aryl fluorene 1: the amount of N, N_dimethyl ethyl amine dimethyl ethyl condensation for 2 hours, then concentrated in vacuo, add toluene and An amount of 0.02 # of p-toluene acid is then heated to reflux for 2 hours. The compound of formula (iv) can be prepared by the method step (iii) as a suitable solvent containing the step of heating at 15 ° t. (E.g., xylene) In the presence of Shida fee (e.g., difluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, or hydrogendi), it is reacted with an appropriate benzylamine or 3-amino group. Typical conditions include —1 # of fluorene, 2_3 95339.doc 200526606 equivalents of aniline or aminopyridine and 0.04-0.1 equivalents of p-toluenesulfonic acid in toluene heated at 15Gt 18-23 hours. A compound of formula (I) can be prepared from a compound of formula (V) by method step (iv), which step includes a base and a palladium catalyst in a suitable solvent (such as [2-[(dimethylformate) Aminoamino-κN) fluorenyl] phenyl-kC] (tricyclohexylphosphine) (trifluoroacetate-KO- (SP-4-3) -1 bar, prepared as described in, 2003, 22 ( 5), 987_999) in the presence of a Suzuki coupling reaction with an appropriate boric acid (for example, 2,3-diamidinophenylboronic acid (commercially available)). It can be as described in the literature Suzuki, A-Pwre 1985, 57, 1749 and contained therein References; gew · C / zem · / Wuwu (i. 2002, 41, 4176-4211 and the references contained therein to perform the Suzuki coupling reaction. Typical conditions include 1,4-dioxane Heat 1 equivalent of aryl bromide (V), 2.5 equivalents of boric acid, 3 equivalents of europium carbonate, and 0.06 equivalents of palladium catalyst from Preparation 3 for 4 hours at 120 ° C. R3 can be prepared according to Reaction Scheme 2. A compound of the general formula (I) in which R1, R2, R4, R5, R6, X, V, W, Y, and Z are as described herein, except R2 # H. 95339.doc 38- 200526606

流程2 可自式（III)之芳基醯肼藉由方法步驟⑺製備式（VI)之化合物’該步驟包含於鹼（例如三乙胺、甲基嗎啉、碳酸鈉或氳氧化鉀）之存在下與醯基氯（例如甲氧基乙醯基氯（對於 2 R =OCH3))反應。典型條件包含於二氣甲烷中於〇-25〇c加熱 1_〇當量之芳基醯肼（III)、1·(Μ·3當量之醯基氯、ι·2_2 〇當量之Ν-甲基嗎啉3-18小時。可自化合物（vi)藉由方法步驟（vi)製備式（νπ)之化合物，該步驟包含於25。(：及1HTC之間與適當脫水劑（例如氧氯化磷、三氟甲磺酸酐、或五氯化磷）反應。典型條件包含於***中於11〇。(：加熱1.0當量之（VI)4小時。可自式（VII)之化合物藉由方法步驟（iii)製備式之化合物，該步驟包含於15(TC下加熱之適當溶劑（例如二甲 95339.doc -39- 200526606 苯）中在適當酸（例如三氟乙酸、對甲苯磺酸、樟腦磺酸、或氫氯酸）之存在下與適當苯胺或3-胺基。比啶反應。典型條件包含於二甲苯中於15〇°C加熱1當量之1，2,4_噁二唑（VII)、3 當量之苯胺/胺基吡啶及〇·〇4-〇·ι當量之對甲苯磺酸18_22小時。可自式（VIII)之化合物藉由方法步驟（iv)製備式⑴之化合物’該步驟包含如流程丄中所述之Suzuki偶合反應。可根據反應流程3製備其中R4sNR7R8或如本文所述之 5-7 員 N·連接雜環、R3 係 η且其中 Rl、r4、r5、r6、r7、r8、 φ x、v、w、y及z如本文所述之通式⑴之化合物。Scheme 2 A compound of formula (VI) can be prepared from aryl hydrazine of formula (III) by method step 'This step is included in a base (such as triethylamine, methylmorpholine, sodium carbonate or potassium oxide). React with fluorenyl chloride (eg, methoxyethylfluorenyl chloride (for 2 R = OCH3)) in the presence. Typical conditions include heating 1 to 0 equivalents of aryl hydrazine (III), 1 · (M · 3 equivalents of fluorenyl chloride, ι · 2_2 〇 equivalents of N-methyl group in methane at 0-25 ° C. Morpholine 3-18 hours. A compound of formula (νπ) can be prepared from compound (vi) by method step (vi), which step is comprised between 25. (: and 1HTC and a suitable dehydrating agent (such as phosphorus oxychloride) , Trifluoromethanesulfonic anhydride, or phosphorus pentachloride). Typical conditions are contained in phosphorus oxychloride at 110. (: Heating (1.0) equivalent of (VI) for 4 hours. Available from the compound of formula (VII) by Method step (iii) prepare a compound of formula, which step comprises 15 (suitable solvent heated at TC (eg dimethyl 95339.doc -39- 200526606 benzene) in a suitable acid (eg trifluoroacetic acid, p-toluenesulfonic acid, Camphor sulfonic acid, or hydrochloric acid) in the presence of an appropriate aniline or 3-amino group. Bipyridine. Typical conditions include xylene heated at 15 ° C for 1 equivalent of 1,2,4-oxadiazole (VII), 3 equivalents of aniline / aminopyridine, and 0.004 to 0.005 equivalents of p-toluenesulfonic acid for 18-22 hours. It can be obtained from the compound of formula (VIII) by Step (iv) to prepare a compound of formula '' This step includes a Suzuki coupling reaction as described in Scheme 。. R4sNR7R8 or 5-7 member N · linked heterocycle, R3 as described herein can be prepared according to Reaction Scheme 3. A compound of the formula η and wherein R1, r4, r5, r6, r7, r8, φ x, v, w, y and z are as described herein under general formula (I).

流程3 可式（III)之芳基醯肼藉由方法步驟（v)製備式（IX)之化 95339.doc -40. 200526606 合物’该步驟包含於鹼（例如三乙胺、N_曱基嗎啉、碳酸鈉或氮氧化鉀）之存在下與適當醯基氯（例如氯乙醯基氣）反應。典型條件包含於二氯曱烷中於25^下與1〇當量之芳基酉&肼（III)、1·(Μ·3當量之氯乙醯基氯、12_2 〇當量之N-甲基嗎琳反應。可自式（IX)之化合物藉由方法步驟卜〇製備式之化合物，該步驟包含於25°C與ll〇°C之溫度之間與適當脫水劑 (例如***、三氟曱磺酸酐、或五氣化磷）反應。典型條件包含於氧氯化麟中於1 下加熱！ ·〇當量之化合物（Ιχ)4 小時。可自式（X)之烷基氣藉由方法步驟（vii)製備式（χι)之化合物，該步驟包含於適當溶劑（例如乙腈或Ν，Ν_二曱基甲醯胺）中視情況於鹼（例如碳酸鉀、碳酸鈉或碳酸鈽）之存在下藉由於25-5(TC下加熱2-18小時與適當第一或第二胺（hnr7r8) 或5-7員N-連接雜環反應。典型條件包含於乙腈中於以艺下使1當量之烷基氣（X)、1.5當量之胺（HNF7R8)或5_7員N-連接雜環及2當量之碳酸鉀反應18小時。可自式（XI)之化合物藉由步驟（Hi)製備式（XH)之化合物，該步驟包含於在15CTC下加熱之適當溶劑（例如二甲苯）中於適當酸（例如三氟乙酸、對甲苯磺酸、樟腦磺酸、或氫氣酸）之存在下與適當苯胺或3-胺基吨啶反應。典型條件包含於二曱苯中於150它加熱1當量之l52,4_噁二唑（χι)、3當量之苯胺/胺基吨咬及0.04-0· 1當量之對曱笨磺酸丨8_24小時。可自式（XII)之化合物藉由方法步驟（iv)製備式⑴之化合 95339.doc -41 - 200526606 物’該步驟包含於適當溶劑中於如流程1所述之適當驗及姜巴觸媒之存在下與適當硼酸（例如2,3_二甲基苯基硼酸（市隹）) 反應。或者可根據反應流程4製備其中R1、R2、R3、R4、r5、r6、 X、V、w、Y及z如本文所述之通式⑴之化合物。Scheme 3 The aryl hydrazine of formula (III) can be prepared by the method step (v) of the formula (IX) 95339.doc -40. 200526606 Compound 'This step is included in a base (such as triethylamine, N_fluorene Morpholine, sodium carbonate or potassium oxynitride) in the presence of a suitable fluorenyl chloride (such as chloroethenyl). Typical conditions include dichloromethane at 25 ^ with 10 equivalents of aryl hydrazine & hydrazine (III), 1 · (M · 3 equivalents of chloroethenyl chloride, 12_2 〇 equivalents of N-methyl Morin reaction. Compounds of formula can be prepared from compounds of formula (IX) by method step B0, which step comprises between 25 ° C and 110 ° C and a suitable dehydrating agent (such as phosphorus oxychloride, Trifluorophosphonium sulfonic anhydride, or phosphorus pentafluoride) reaction. Typical conditions include heating in oxychlorinate at 1! • 0 equivalent of compound (Ιχ) for 4 hours. Available from alkyl gas of formula (X) A compound of formula (χι) is prepared from method step (vii), which step is comprised in a suitable solvent (such as acetonitrile or N, N-dimethylformamide), optionally a base (such as potassium carbonate, sodium carbonate or rhenium carbonate) In the presence of 25-5 (heating under TC for 2-18 hours with the appropriate first or second amine (hnr7r8) or 5-7 member N-linked heterocyclic ring. Typical conditions are contained in acetonitrile under the following conditions: 1 equivalent of alkyl gas (X), 1.5 equivalents of amine (HNF7R8) or 5-7 member N-linked heterocyclic ring and 2 equivalents of potassium carbonate can be reacted for 18 hours. It can be expressed by formula (XI) Compounds Compounds of formula (XH) are prepared by step (Hi), which step comprises the use of a suitable solvent (such as xylene) heated at 15 CTC in a suitable acid (such as trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, Or hydrogen acid) in the presence of an appropriate aniline or 3-aminoxanthene. Typical conditions are contained in dibenzobenzene at 150 which is heated by 1 equivalent of l52,4_oxadiazole (χι), 3 equivalents of aniline / Amine ton and 0.04-0 · 1 equivalent of p-ammonium sulfonic acid 丨 8-24 hours. The compound of formula (XII) can be prepared by method step (iv) 95339.doc -41-200526606 This step involves reacting with an appropriate boric acid (for example, 2,3-dimethylphenylboronic acid (market)) in an appropriate solvent in the presence of a suitable assay and the Zingba catalyst as described in Scheme 1. Alternatively, it can be based on the reaction Scheme 4 prepares compounds of general formula (I) wherein R1, R2, R3, R4, r5, r6, X, V, w, Y, and z are as described herein.

流程4 如流程1中所述製備式（Π)之化合物。可自通式（II)之化合物藉由如流程1中所述之方法步驟（iv) 製備通式（XIII)之化合物。可自通式（XIII)之化合物藉由如流程1中所述之方法步驟 ⑴製備通式（XIV)之化合物。當R2=H時，可自通式（XIV)之化合物藉由方法步驟 (viii)，使用類似於如流程1中所述之方法步驟（ϋ)之方法製備通式（XV)之化合物。當RbH時，可自通式（XIV)之化合物藉由方法步驟 (viii)，使用類似於如流程2中所述之步驟（v)及（vi)、或如流程3中所述之步驟（v)、（vi)及（vii)之方法製備通式（χν)之化 95339.doc -42- 200526606 合物。可自通式（XV)之化合物藉由如流程1中所述之方法步驟 (iii)製備通式⑴之化合物。或者可根據反應流程5製備其中X係C-R6、R3係η且R1、 R、R4、R5、R6、V、W、丫及乙如本文所述之通式⑴之化合物。Scheme 4 A compound of formula (Π) is prepared as described in Scheme 1. Compounds of general formula (XIII) can be prepared from compounds of general formula (II) by method step (iv) as described in Scheme 1. Compounds of general formula (XIV) can be prepared from compounds of general formula (XIII) by method step ⑴ as described in Scheme 1. When R2 = H, a compound of the general formula (XV) can be prepared from a compound of the general formula (XIV) by method step (viii) using a method similar to the method step (i) described in Scheme 1. When RbH, a compound of the general formula (XIV) can be used by method step (viii), similar to steps (v) and (vi) as described in Scheme 2 or as described in Scheme 3 ( v), (vi) and (vii) to prepare a compound of the general formula (χν) 95339.doc -42- 200526606. Compounds of general formula (XV) can be prepared from compounds of general formula (XV) by method step (iii) as described in Scheme 1. Alternatively, compounds of general formula (I) wherein X is C-R6, R3 is η and R1, R, R4, R5, R6, V, W, Y, and B are as described herein can be prepared according to Reaction Scheme 5.

流程5 如流程1中所述製備式（ΙΠ)之化合物。當R2=H時，可自通式（ΠΙ)之化合物藉由方法步驟（viii)，使用類似於如流程1中所述之方法步驟（ii)之方法製備通式 (IV)之化合物。當RkH時，可自通式（1„)之化合物藉由方法步驟（viii)，使用類似於如流程2中所述之步驟（v)及（vi)、及如流程3中所述之步驟（V)、（Vi)及（vii)之方法製備通式（IV)之化合物。可自通式（IV)之化合物藉由如流程1中所述之方法步驟 (iv)製備通式（XV)之化合物。可自通式（XV)之化合物藉由如流程i中所述之方法步驟 95339.doc -43- 200526606 (iii)製備通式（i)之化合物。可根據反應流程6製備其中R1、R2、R4、R5、V、W、X 及Y如本文所述且R、H之通式⑴及（VIII)之化合物。Scheme 5 A compound of formula (III) is prepared as described in Scheme 1. When R2 = H, the compound of the general formula (IV) can be prepared from the compound of the general formula (III) by method step (viii) using a method similar to the method step (ii) as described in Scheme 1. When RkH, the compounds of the general formula (1 „) can be used by method step (viii), similar to steps (v) and (vi) as described in Scheme 2 and steps as described in Scheme 3 (V), (Vi) and (vii) to prepare compounds of general formula (IV). Compounds of general formula (IV) can be prepared from compound of general formula (IV) by method step (iv) as described in Scheme 1. ) Compounds. Compounds of general formula (i) can be prepared from compounds of general formula (XV) by method steps 95339.doc -43- 200526606 (iii) as described in Scheme i. They can be prepared according to Reaction Scheme 6. R1, R2, R4, R5, V, W, X and Y are as described herein and the compounds of the general formulae VII and (VIII) of R, H.

流程6 可分別自式（XIV)及（III)之化合物藉由方法步驟（ix)製備式⑴及（VIII)之化合物，該步驟包含於在55-60°C下加熱之適當溶劑（例如四氫呋喃或乙酸）中與二甲基乙醯胺二曱基乙縮酸之連續反應，繼而於在9〇-l〇(TC下加熱之適當酸（例如乙酸）之存在下與適當苯胺或胺基吼σ定反應。典型條件包含於THF中於55 °C下加熱1.0當量之醯基酿肼、當量之二甲基乙醯胺二甲基乙縮醛（Aldrich)2小時，繼而加入i」當量之2-曱氧基-5-胺基吡啶（Aldrich)且於乙酸中於9(rc下加熱 5小時。所有以上反應及揭示於前述方法中之新賴起始材料之製从 H S13 L· - t /Scheme 6 Compounds of formulae IX and (VIII) can be prepared from compounds of formula (XIV) and (III), respectively, by method step (ix). This step includes an appropriate solvent (eg, tetrahydrofuran) heated at 55-60 ° C. Or acetic acid) in a continuous reaction with dimethylacetamide difluorenylacetic acid, followed by the presence of a suitable aniline or amino group in the presence of a suitable acid (such as acetic acid) heated at 90-10 (TC) σ determination reaction. Typical conditions include heating 1.0 equivalent of hydrazone hydrazine, equivalent of dimethylacetamide dimethyl acetal (Aldrich) in THF at 55 ° C for 2 hours, and then adding i "equivalent of 2-Methoxy-5-aminopyridine (Aldrich) and heated in acetic acid at 9 (rc for 5 hours. All the above reactions and the preparation of the Xinlai starting material disclosed in the aforementioned method from H S13 L ·- t /

95339.doc -44- 200526606 需產物之過程的適當試劑及反應條件。效用本發明之化合物由於其在哺乳動物（包括人類）中具有醫藥活性而有效。更特定言之，其可有效用於其中產素含量之調節可提供有益效應的病症之治療或預防。可提及之疾病狀態包括性功能障礙，尤其於早洩、早期分娩（prete加 labour)、分娩併發症、食慾及攝食病症、***良性增生、早產、痛經、充血性心力衰竭、動脈性高血壓、肝硬化、月咼血壓（nephrotic hypertensi〇n)、眼部高血壓㈣扣 hypertension)、強迫症（〇bsessive c〇mpulsive 叫及神經性精神病症（neuropsychiatric disorder)。性功能障礙（SD)係可影響男性及女性兩者之重要臨床問 ?€ 之起因可係器質性以及心理性兩者。sd之器質性態樣通常由潛在之血管疾病（例如彼等與高血壓或糖尿病相聯繫之疾病）引起、由處方藥療法（prescripti〇n medicati〇n) 及/或由精神疾病（例如抑鬱）引起。精神因素包括恐懼、操作焦慮及人際衝突。SD削弱性能力、降低自尊心、且破壞人際關係因此誘導個人苦惱。臨床中，SD病症已被分為女性 ί生功此障礙（FSD)病症及男性性功能障礙（以奶）病症 (Melman等人，乂〜‘狀 1999,姐，5_u)。 FSD可被疋義為女性難以或無法於性表達中得到滿足。 FSD係對右干不同女性性功能病症之集體術語 S.R. (1998) ^ Definition and classification of female sexual disorders ^ Int. J. Impotence Res., l〇? S104-S106; Berman, 95339.doc -45- 200526606 J.R·，Berman，L· & Goldstein，Ι· (1999)，Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options，t/ro/〇g;;,M，385_391)。女性可能具有慾望缺失、喚起或高潮困難、***疼痛或此等問題之組合。若干種類型之疾病、藥物、傷害或心理問題可導致FSD。發展中之治療係以治療FSD之具體亞型、主要以慾望及喚起病症為目標。 FSD之種類藉由將其與正常女性性反應階段（慾望、喚起及咼潮）對照而得以最佳定義（Leiblum，S.R. (1998)， Definition and classification of female sexual disorders » Int. /· 10, S104-S1〇6)。慾望或性慾係性表達之驅動力。其表現通常包括當陪伴感興趣之伴侣或暴露於其他性慾刺激時之性想法。喚起係對性刺激之血管反應，其一重要組份係生殖器充血且包括增加之***潤滑度、*** 延長及增加之生殖器感覺/敏感度。高潮係於喚起過程中已達到定點之性緊張之釋放。因此，當女性於任何此等階段（通常為慾望、喚起或高潮）中具有不充分或不滿意反應時，發生FSD。FSD種類包括機月b衣減之性慾病症、性喚起病症、高潮病症及***疼痛病症。儘管本發明之化合物將改良對性刺激之生殖器反應（如於女性性喚起病症中），於進行此過程中，其亦改良相關聯之疼痛、與***相關聯之痛苦及不適，且因此治療其他女性性功能病症。因此，根據本發明進一步之態樣，提供本發明之化合物 95339.doc -46- 200526606 在用於機能衰減性慾病症、性喚起病症、高潮病症及*** 疼痛病症之治療或㈣、更佳用於性喚起病症、高潮病症、 ***疼痛病症之治療及預防、且最佳用於性喚起病症之治療或預防的藥物之製備中之用途。若女1*生不具有或很少具有對性之慾望，且不具有或很少八有f生心法或幻想時’則呈現機能衰減性慾病症。此類型之FSD可藉由低睪固酉同含量導致，其由於自然絕經或手術絕經中之任一者導致。其他起因包括疾病、藥物、疲勞、抑鬱及焦慮。女性性喚起病症（FSAD)以對性刺激之不充分生殖器反應為特徵。生殖器並未經歷為正常性喚起之特徵之充血。陰道壁潤滑較差，以至於***疼痛。可能阻礙高潮。喚起病症可由絕經期時或分娩後及哺乳期之降低之***以及由疾病（具有血管組份，例如糖尿病及動脈硬化症）引起。其他起因來自以利尿劑、抗組胺劑、抗抑鬱劑（例如SSRI)或抗高血壓試劑治療。性父疼痛病症（包括***困難及***痙攣）以來自***之疼痛為特徵且可由降低潤滑度之藥物、子宮内膜異位、骨盆炎症性疾病、炎症性腸病或尿道問題導致。由於術語FSD涵蓋數種類型之問題，其中一些難以量測，且由於對治療FSD之關注相對較晚，因此FSD之流行難以規格化。許多女性之性問題係直接與女性老齡化過程或與慢性疾病（例如糖尿病或高血壓）中之任一者相關聯。由於FSD由數種於性反應循環之獨立階段中表達症狀之 95339.doc -47- 200526606 亞型組成，因此不存在單一療法。當前對之治療主要集中於心理或關係問題上。FSD之治療逐漸發展成更為臨床且基礎科學研究專注於此醫學問題之研究。女性性抱怨於病理生理學上並非完全心理問題，尤其對於彼等可能具有促成總體女性性抱怨之血管生成功能障礙（例如嶋咐組份的個體。目前尚無藥物被許可為用於FSD之治療。經驗藥物療法包㈣激素投藥（局部或作為激素替代療法）、雄激素或情緒改變藥物（例如丁螺旋酮或曲拉唑酮 > 此等治療功能由於低效力或不可接受之副作用而常常非為令人滿意。美國精神病學協會之診斷及統計手冊（Dsm)…定義女性性喚起病症（FSAD)如下： π直至性行為結束仍不能達到或保持性興奮之充分潤滑_ 腫脹反應的持續或復發性無能。該障礙須導致顯著之痛苦或人際關係困難。" 喚起反應由骨盆中血管充血、***潤滑及膨脹及外生殖器腫脹組成。該障礙導致顯著之痛苦或人際關係困難。 FSAD係高度流行之性功能病症，其影響絕經期㈣rt) 前、中、及後之女性。其與伴隨之病症（例如抑鬱、心血管疾病、糖尿病及UG病症）相關聯。 FSAD之主要結果係缺乏充血/腫脹、#乏潤滑及缺乏生殖器快感。FSAD之次要結果係降低之性慾望、***中之疼痛及達到南潮之困難。男性性功能障礙（MSD)通常與***功能障礙（亦稱為男性 95339.doc -48 - 200526606 ***功能障礙（MED))及/或***病症（例如早沒、性快感缺乏（無法達到高潮））或您望病症（例如機能衰減性慾病症（缺乏對性之興趣））中之一者相關聯。 PE係男性中相對常見之性功能查甘a a ^ rp Κ I土刀月匕丨早礙。其已被以數種不同方式定義但最為廣泛接受之定差95339.doc -44- 200526606 Appropriate reagents and reaction conditions for processes that require products. Effectiveness The compounds of the present invention are effective because of their medical activity in mammals, including humans. More specifically, it can be effectively used for the treatment or prevention of a condition in which adjustment of the vegetative content can provide a beneficial effect. Disease states that can be mentioned include sexual dysfunction, especially premature ejaculation, early delivery (prete plus labor), birth complications, appetite and feeding disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, Liver cirrhosis, nephrotic hypertension (hypertension), ocular hypertension (hypertension), obsessive-compulsive disorder (obsessive compulsive) and neuropsychiatric disorder. Sexual dysfunction (SD) can affect Important clinical questions for both men and women? The cause can be both organic and psychological. The organic appearance of SD is usually caused by underlying vascular diseases (such as those associated with hypertension or diabetes). , Caused by prescription medication (prescripti〇n medicati〇n) and / or caused by mental illness (such as depression). Psychological factors include fear, operational anxiety and interpersonal conflicts. SD weakens sexual ability, reduces self-esteem, and disrupts personal relationships and thus induces individuals Distress. Clinically, SD disease has been divided into female and male sexual function disorder (FSD) and male sexual function. Disorders (to milk) disorders (Melman et al., 乂 ~ '1999, elder sister, 5_u). FSD can be interpreted as difficult or impossible for women to be satisfied in sexual expression. FSD is one of the different sexual sexual disorders of women in the right stem. Collective term SR (1998) ^ Definition and classification of female sexual disorders ^ Int. J. Impotence Res., 10? S104-S106; Berman, 95339.doc -45- 200526606 JR., Berman, L. & Goldstein, I. (1999), Female sexual dysfunction: Incidence, pathophysiology, evaluations and treatment options, t / ro / 〇g ;;, M, 385_391). Women may have a lack of desire, difficulty arousing or orgasm, painful intercourse, or a combination of these problems. Several types of illness, drugs, injuries, or psychological problems can cause FSD. Developing therapies are aimed at treating specific subtypes of FSD, primarily with desire and arousal disorders. The type of FSD is best defined by comparing it with normal female sexual response stages (desire, arousal, and high tide) (Leiblum, SR (1998), Definition and classification of female sexual disorders »Int. / · 10, S104 -S106). Desire or sexual desire is the driving force for sexual expression. This usually includes sexual thoughts when accompanying an interested partner or being exposed to other sexual desire stimuli. Arousal is a vascular response to sexual stimuli. An important component is genital congestion and includes increased vaginal lubrication, vaginal elongation, and increased genital sensation / sensitivity. The orgasm is the release of sexual tension that has reached a fixed point during the arousal process. Therefore, FSD occurs when a woman has an inadequate or unsatisfactory response at any of these stages (usually desire, arousal, or orgasm). FSD types include sexual desire disorders, sexual arousal disorders, orgasmic disorders, and painful sexual intercourse disorders. Although the compounds of the present invention will improve the genital response to sexual stimuli (as in female sexual arousal disorders), in doing so, they will also improve the associated pain, the pain and discomfort associated with sexual intercourse, and therefore treat other Female sexual dysfunction. Therefore, according to a further aspect of the present invention, it is provided that the compound of the present invention is 95339.doc -46- 200526606, which is used for the treatment or dysfunction of sexually attenuated sexual desire disorder, sexual arousal disorder, orgasmic disorder and painful sexual intercourse, and is more preferably used for sex Use in the treatment and prevention of arousal disorders, orgasmic disorders, painful sexual intercourse disorders, and the preparation of drugs optimal for the treatment or prevention of sexual arousal disorders. If the female 1 * born does not have or has little desire for sex, and does not have or rarely has a mind or fantasies, then it presents a sexually attenuated sexual desire disorder. This type of FSD can be caused by a low solid content, which is caused by either natural menopause or surgical menopause. Other causes include illness, drugs, fatigue, depression, and anxiety. Female sexual arousal disorder (FSAD) is characterized by an insufficient genital response to sexual stimulation. The genitals have not experienced congestion that is characteristic of normal sexual arousal. The walls of the vulva are poorly lubricated, causing pain during intercourse. May hinder orgasm. Arousal disease can be caused by decreased estrogen during menopause or after childbirth and lactation, as well as by diseases (with vascular components such as diabetes and arteriosclerosis). Other causes come from treatment with diuretics, antihistamines, antidepressants (such as SSRI) or antihypertensive agents. Paternal disorders of sexual fathers (including dyspareunia and vaginal spasms) are characterized by pain from insertion and can be caused by drugs that reduce lubricity, endometriosis, pelvic inflammatory disease, inflammatory bowel disease, or urethral problems. Since the term FSD covers several types of problems, some of which are difficult to measure, and because of the relatively late focus on treating FSD, the popularity of FSD is difficult to standardize. Many women's sexual problems are directly related to any of the women's aging processes or to chronic diseases such as diabetes or hypertension. Because FSD consists of several 95339.doc -47- 200526606 subtypes that express symptoms in separate stages of the sexual response cycle, there is no monotherapy. Current treatments focus on psychological or relationship issues. The treatment of FSD has gradually evolved into a more clinical and basic scientific research focused on this medical issue. Female sexual complaints are not a complete psychological problem in pathophysiology, especially for individuals who may have an angiogenic dysfunction that contributes to overall female sexual complaints (such as individuals who command components). No drugs are currently licensed for the treatment of FSD .Empirical drug therapies include hormonal administration (topical or as hormone replacement therapy), androgen or mood-changing drugs (such as buspirone or trazodone) > These therapeutic functions are often non-functional due to low efficacy or unacceptable side effects Satisfactory. Diagnostic and Statistical Manual of the American Psychiatric Association (Dsm) ... defines female sexual arousal disorder (FSAD) as follows: π Sufficient lubrication cannot be achieved or maintained until sexual activity ends _ Sustained or recurrent swelling response Incompetence. The disorder must cause significant pain or interpersonal difficulties. &Quot; The arousal response consists of vascular congestion in the pelvis, vaginal lubrication and swelling, and swelling of the external genitals. The disorder causes significant pain or interpersonal difficulties. FSAD is highly prevalent Sexual dysfunction, which affects menopause (rt) before, during, and after women . It is associated with accompanying conditions (such as depression, cardiovascular disease, diabetes, and UG conditions). The main results of FSAD are lack of congestion / swelling, #lack of lubrication, and lack of genital pleasure. The secondary results of FSAD are reduced sexual desire Pain during sexual intercourse and difficulty in reaching the South Tide. Male sexual dysfunction (MSD) is often associated with erectile dysfunction (also known as male 95339.doc -48-200526606 erectile dysfunction (MED)) and / or ejaculation disorders (eg Premature absence, lack of sexual pleasure (unable to reach orgasm)), or one of your desired conditions (such as reduced sexual desire (lack of sexual interest)). PE is a relatively common sexual function in men. rp κ I soil knife moon dagger 丨 early obstacle. It has been defined in several different ways but the most widely accepted difference

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Statistical Manual 〇fMental Dis〇rders Iv中之一定義其規定：係於***前、***時或***後較短時間且於患者希望之前在最小性刺激下之終身持續或復發性***。臨床醫師必須考慮影響興奮階段之持續時間之因素，例如年齡、性# 伴侣或刺激之新穎性、及性耔盔 ^ f生仃為之頻率。該障礙導致顯著人際關係困難之痛苦。”One of the Statistical Manual's Mental Disorders Iv defines its provisions: a lifelong continuous or recurrent ejaculation with minimal sexual stimulation before, during, or shortly after insertion, and before the patient desires it. Clinicians must consider factors that affect the duration of the excitement phase, such as age, the novelty of the sexual partner or stimulus, and the frequency of sexual activity. This barrier causes significant pain in interpersonal difficulties. "

International Classification τ^· Μη of Diseases 10(疾病國際分類 l〇)定義規定： :不能充分延遲***以享受性愛，表現為下列中之任一者⑴於I*生又開始之月ij或之後極短時間發生***（若需要時間限制·則於性父開始之前或15秒内）；⑺缺乏足夠***以使***可能之狀況下發峰斛牲馨〜生***。泫問題並非來自性行為之長期節制之結果。，，已使用之其他定義包括以下標準上之分類·· 涉及伴侣之高潮 ***與***之間之持續時間抽插數及隨意控制能力、PE中可涉及心理因素，其中關係問題、焦慮、抑營、先前性失敗均起作用。 95339.doc -49- 200526606 /射知依賴於父感神經及副交感神經系統。藉由交感神經系、先對輸知吕及附睪之傳出衝動製造平滑肌收縮，將*** 私動至後尿道内。精囊、***及尿道球腺之類似收縮增加***之體積及流體含量。***之排出藉由自腰龍脊髓内之原木脊骨退丘腦細胞spin〇thalamic ce⑴增加而產生之傳出衝動調節（c〇〇len & Truitt，&ζ·μW 2〇〇2, 1566)，其穿過副交感神經且導致球狀海綿狀 (bu^b〇cavr_s)、坐骨海綿狀ο·。請⑽似）及骨盆底肌肉之即律性收縮。於人類中***之皮質控制（cortical control) · 仍於f論中。於大鼠中，下丘腦之視前區及室旁核似乎涉及於***。 ***包含兩種冑立白勺組份—遺精及***。遺精係來自^ 端附睪、輸精管、精囊之***流體及***之沈積且衰竭方尿道***部中。此沈積之後係自尿道中強制性排出精浓成伤***不同於高潮，高潮係純粹之大腦事件。通常说等兩過程同時發生。International Classification τ ^ · Μη of Diseases 10 (International Classification of Diseases 10) definitions:: can not sufficiently delay ejaculation in order to enjoy sex, manifested as any one of the following in the month of I * birth and the month ij or short Ejaculation occurs at the time (if a time limit is required, or before the start of the sexual father or within 15 seconds);泫 The problem is not the result of long-term temperance of sexual activity. Other definitions that have been used include the following standard classifications: • The number of duration interpolations and the ability to control arbitrarily between the orgasm insertion and ejaculation of a partner, and psychological factors that can be involved in PE, including relationship problems, anxiety, depression , Previous failures work. 95339.doc -49- 200526606 / Shezhi relies on paternal and parasympathetic nervous systems. By using the sympathetic nervous system, first, the outgoing impulses of Zhizhi Lu and Fu Zhi create smooth muscle contraction, and the semen is moved into the posterior urethra. Similar contractions of seminal vesicles, prostate, and urethral bulbs increase semen volume and fluid content. Semen excretion is regulated by spinal thalamic cells that increase in spinal thalamic cells from the spinal cord of the spinosaurus spinosa (c〇len & Truitt, & z · μW 2000, 1566). It passes through the parasympathetic nerves and leads to globular sponges (bu ^ b0cavr_s) and sciatic sponges. Please)) and the pelvic floor muscles contract regularly. Cortical control of ejaculation in humans · Still in f. In rats, the preoptic zone and paraventricular nucleus of the hypothalamus appear to be involved in ejaculation. Ejaculation consists of two types of components-nocturnal emission and ejaculation. Nocturnal emission is from the esophagus, vas deferens, seminal fluid and the deposition and failure of sperm in the urethra and prostate. After this deposition, the ejaculation is forcibly discharged from the urethra. Injury ejaculation is different from orgasm. Orgasm is a pure brain event. It is usually said that the two processes occur simultaneously.

在甫乳動物中’周邊血清中之催產素之脈衝伴隨***。性中，***時或***前後催產素但並非後葉加壓素土聚濃度顯著上升。催產素自身並不誘導***；此過程100〇/ 處於藉由自脊髓之腰部區域產生之α1_腎上腺素受體/交感神經之神經控制下。催產素之f、統脈衝可於周邊***反應中/、有作用。其可用於調節遍及男性生殖道之導管及腺小茱之濃度，因此（例如）影響不同***組份之流體體積。中央釋放至腦部中之催產素可影響性舉止、喚起(高潮)之主觀_ 95339.doc -50- 200526606 定及後續***之潛伏時間。因此’本發明之一態樣提在用於性功能障礙初…、限制條件地刀月^早礙、較佳男性性功能障礙、最佳防或治療之藥物的製備巾之用途。為之預於科學文獻中已證明子宮中催產素受體數目於懷孕上升，分娩開始前最為顯著(Gimpl & ρ—〇ΐζ :: 户㈣⑽⑺，心叫。不受任何理切制，吾人已知催產素之抑制可有助於預防早期分娩及解、：分娩併發症。醉决不發明之另思像提供式（I)之化合物無限制條地在用於早期分娩及分娩併發症之預防或治療之藥備中之用途。衣催產素於攝食中具有作用，其降低食慾⑽灿等人，如，测，m 89)。藉由抑制催產素，可能增加食您。因此催產素抑制劑有效於治療食慾及攝食病症。因此’本發明之另—態樣提供式⑴之化合物無限制條件地在用於食愁及攝食病症之預防或治療之藥物的製備中之催產素被暗示為***良性增生（BPH)之一原因。*** 組織之分析已顯示具有BPH之患者具有增加之催產素含量 (Nicholson & Jenkin, Adv. Exp. Med. & Biol., 1995, 395 529)。催產素拮抗劑可幫助治療此疾病。 ’ 因此，本發明之另一態樣提供式⑴之化合物無限制條件地在用於***良性増生之預防或治療的藥物之製備中之 95339.doc •51 - 200526606 用途。由於其作為子宮血管收縮劑之活性，催產素在痛已因中具有作用（Akerlund,如1994 47)。催產素拮抗劑於此疾病上可具有治療效果。因此’本發明之另一態樣提供式⑴之化合物無限制條件地在用於痛經之預防或治療的藥物之製備中之用途。應瞭解’本文中對治療之所有參考包括治癒性、減輕性及預防性治療。可與選自下列各物中之一或多種試劑共投藥本發明之化合物： 1) 一或多種選擇性血清素再攝取抑制劑（SSRI)，例如達泊西、/丁（dapoxetine)、帕羅西、汀（paroxetine)、3_[(二甲基胺美）甲基]-4-[4-(甲基硫基）苯氧基]苯石黃醯胺（實例28，Wq 0172687)、3-[(二甲基胺基）甲基]_4_[3_甲基_4_(甲基硫基）苯氧基]苯磺醯胺（實例12，WO 0218333)、，甲基χ{3-[3-甲基- 4-(甲基硫基）苯氧基]_4_。比咬基}甲基）胺（實例π, pct 申請案號PCT/IB02/01032)。 2) —或多種局部麻醉劑； 3) —或多種α-腎上腺素受體拮抗劑（亦稱為^腎上腺素受體阻斷劑、α·受體阻斷劑、α-阻斷劑）；適當腎上腺素受體拮抗劑包括：S分妥拉明、派u坐唤、g分妥拉明曱確酸鹽、曲拉唑酮、醛酶質、吲哚呱胺、萘派地爾（naftopidil)、坦洛新（tamsulosin)、苯氧苄胺、蘿芙木鹼（rauwolfa alkaloid)、洛佳德大（Recordati)15/2739、SNAP 1069、SNAP 5089、 95339.doc -52- 200526606 RS 17053、SL 89.0591、多沙^(doxazosin)、W09830560實例19、特拉唑嗪及阿巴諾喹（abanoquil);適當α2-腎上腺素受體结抗劑包括雙苄胺、托拉佐林、曲馬唾嗪、依法克生 (efaroxan)、育亨賓、口米 σ坐克生可樂定（idazoxan clonidine) 及雙苄胺（dibenarnine);適當非選擇性α-腎上腺素受體拮抗劑包括諾黴素；進一步之α-腎上腺素受體拮抗劑描述於出版於1998年6月14日之PCT申請案WO 99/30697及美國專利：4，18 8,3 90; 4,026,894; 3,511，836; 4,315,007; 3,527,761 ; 3,997,666 ; 2,503,059 ; 4,703,063 ; 3,381，009 ; 4,252,721 及 2，599,000，其中之每一者均以引用之方式併入本文； 4) 一或多種膽固醇降低劑，例如抑制素（例如阿伐他、;丁 (atorvastatin)/Lipitor _商標）及纖維酸自旨（fibrate); 5) —或多種血清素受體促效劑、拮抗劑或調節劑，更具體言之為例如 5HT1A、5HT2A、5HT2C、5HT3、5HT6及 / 或5HT7受體之促效劑、拮抗劑或調節劑，包括彼等描述於 WO-09902159、WO-00002550及 /或 WO-00028993之物質； 6) —或多種NEP抑制劑，較佳為其中該NEP係EC 3.4.24.11且更佳係其中該NEP抑制劑係對EC 3.4.24.11之選擇性抑制劑，更佳為選擇性NEP抑制劑係對EC3.4.24.11之選擇性抑制劑，其具有低於100 nM之IC5G(例如奥帕曲拉 (ompatrilat)、山帕曲拉（sampatrilat))，適當之NEP抑制劑化合物描述於EP-A-1097719中；可使用描述於已公開之專利申請案EP1097719-A1段落[0368]至[0376]之方法來測定對 NEP及 ACE之 IC50值； 95339.doc •53- 200526606 7) —或多種後葉加壓素受體拮抗劑或調節劑，例如瑞科維丹（relcovaptan)(SR 49059)、科尼維丹（conivaptan)、阿托西班（atosiban)、VPA-985、CL-385004、加壓催產素 (Vasotocin) 〇 8) 阿樸嗎啡一阿樸嗎啡作為醫藥使用之教示可見於 US-A-5945117中； 9) 多巴胺促效劑（詳言之選擇性D2、選擇性D3、選擇性 D4及類選擇性D2試劑）例如普拉克索 (Pramipexole)(Pharmacia Upjohn化合物號 PNU95666)、羅匹尼洛（ropinirole)、阿樸嗎13非、蘇嗎尼洛（surmanirole)、喧洛雷（quinelorane)、PNU-142774、漠麥角環肽、卡麥角林 (carbergoline)、麥角乙脲（Lisuride); 10) 黑色皮質素（Melanocortin)受體促效劑（例如 Melanotan II及PT141)及選擇性MC3及MC4促效劑（例如 THIQ)； 11) 單胺傳輸抑制劑，尤其係去甲腎上腺素再攝取抑制劑 (NRI)(例如瑞波西汀（Reboxetine))，其他血清素再攝取抑制劑（SRI)(例如帕羅西汀、達泊西汀）或多巴胺再攝取抑制劑 (DRI)； 12) 5-11丁1八拮抗劑（例如若巴佐丹（1*(^312(^311));及 13) PDE抑制劑，例如PDE2(例如赤-9-(2-羥基-3-壬基）-腺嘌呤及藉由引用併入本文之EP 0771799之實例100)及尤其為PDE5抑制劑例如揭示於EP-A-0463756中之吡唑並[4,3-d] 嘧啶-7-酮；揭示於EP-A-0526004中之吡唑並[4,3-d]嘧啶-7- 95339.doc -54- 200526606 酮；揭示於公開之國際專利申請案w〇93/〇6i〇4中之。比吐並The pulse of oxytocin in the peripheral blood of the lactating animal is accompanied by ejaculation. In sex, the concentration of oxytocin but not the vasopressin increased significantly during or after ejaculation. Oxytocin itself does not induce ejaculation; this process is 100 / under the nerve control of α1_adrenergic receptors / sympathetic nerves produced from the lumbar region of the spinal cord. The oxytocin f and pulse can play a role in the peripheral ejaculation response. It can be used to regulate the concentration of ducts and glandular jujube throughout the male reproductive tract, and therefore, for example, affect the fluid volume of different ejaculation components. The oxytocin released into the brain by the central can affect the subjective behavior of sexual behavior, arousal (orgasm) _ 95339.doc -50- 200526606 and the latency of subsequent ejaculation. Therefore, one aspect of the present invention is directed to the use of a towel for preparing sexual dysfunction at the beginning of ..., restricted conditions, premature dysfunction, early male dysfunction, better male sexual dysfunction, or the best preventive or therapeutic drug. It is foreseen that the number of oxytocin receptors in the uterus has increased in pregnancy before pregnancy, and is most significant before the start of labor (Gimpl & ρ—〇ΐζ :: Husband, heart call. Without any rational control, I have already It is known that the inhibition of oxytocin can help prevent early delivery and resolution: complications of childbirth. The drunk never invents another idea to provide the compound of formula (I) without limitation for the prevention of early delivery and childbirth complications. Or the use in the preparation of treatment. The oxytocin has a role in ingestion, which reduces appetite, such as Cancan et al. (M, 89). By inhibiting oxytocin, you may eat more. Therefore, oxytocin inhibitors are effective in treating appetite and feeding disorders. Therefore, 'another aspect of the present invention provides the compound of formula (I) in an unrestricted manner in the preparation of a medicament for the prevention or treatment of anxiety and ingestion disorders. Oxytocin has been implicated as a cause of benign prostatic hyperplasia (BPH) . Analysis of prostate tissue has shown that patients with BPH have increased levels of oxytocin (Nicholson & Jenkin, Adv. Exp. Med. &Amp; Biol., 1995, 395 529). Oxytocin antagonists can help treat this disease. Therefore, another aspect of the present invention provides the use of the compound of formula (I) in the preparation of a medicament for the prevention or treatment of benign prostatic benign disease without restriction. 95339.doc • 51-200526606 use. Due to its activity as a uterine vasoconstrictor, oxytocin has a role in the cause of pain (Akerlund, eg, 1994 47). Oxytocin antagonists may have a therapeutic effect on this disease. Therefore, another aspect of the present invention provides the use of the compound of formula (I) in the preparation of a medicament for the prevention or treatment of dysmenorrhea without limitation. It is understood that 'all references to treatment herein include curative, alleviative, and prophylactic treatments. The compounds of the invention can be co-administered with one or more agents selected from the following: 1) One or more selective serotonin reuptake inhibitors (SSRI), such as dapoxetine, dapoxetine, paro Pycnoxetine, paroxetine, 3 _ [(Dimethyamine) methyl] -4- [4- (methylthio) phenoxy] benzoflavin (Example 28, Wq 0172687), 3- [(Dimethylamino) methyl] _4_ [3_methyl_4_ (methylthio) phenoxy] benzenesulfonamide (Example 12, WO 0218333), methyl χ {3- [3 -Methyl- 4- (methylthio) phenoxy] _4_. Specific methyl} methyl) amine (example π, pct application number PCT / IB02 / 01032). 2) —or multiple local anesthetics; 3) —or alpha-adrenergic receptor antagonists (also known as adrenergic receptor blockers, alpha-receptor blockers, alpha-blockers); appropriate Adrenergic receptor antagonists include: S-partial tolamine, piezine, g-totolamine, trazolidone, aldolase, indoleamine, and naftopidil. , Tamsulosin, phenoxybenzylamine, rauwolfa alkaloid, Recordati 15/2739, SNAP 1069, SNAP 5089, 95339.doc -52- 200526606 RS 17053, SL 89.0591 , Doxazosin, W09830560 Example 19, terazosin and abanoquil; suitable α2-adrenergic receptor antagonists include dibenzylamine, torazolin, tramazine, efalazine Efaroxan, yohimbine, Izoxan clonidine and dibenarnine; suitable non-selective alpha-adrenergic receptor antagonists include noromycin; further alpha -Adrenergic receptor antagonists are described in PCT application WO 99/30697 published on June 14, 1998 and US Patent: 4 18 8,3 90; 4,026,894; 3,511,836; 4,315,007; 3,527,761; 3,997,666; 2,503,059; 4,703,063; 3,381,009; 4,252,721 and 2,599,000, each of which is incorporated herein by reference; 4) one or A variety of cholesterol lowering agents, such as statins (such as atorvastatin, atorvastatin / Lipitor _ trademark) and fibrate; 5) — or more serotonin receptor agonists, antagonists or modulators Agents, more specifically agonists, antagonists or modulators of, for example, 5HT1A, 5HT2A, 5HT2C, 5HT3, 5HT6, and / or 5HT7 receptors, including those described in WO-09902159, WO-00002550, and / or WO -00028993 substance; 6) — or more NEP inhibitors, preferably wherein the NEP is EC 3.4.24.11 and more preferably wherein the NEP inhibitor is a selective inhibitor of EC 3.4.24.11, more preferably a choice NEP inhibitors are selective inhibitors of EC3.4.24.11 with IC5G (eg, ompatrilat, sampatrilat) of less than 100 nM, suitable NEP inhibitor compounds Described in EP-A-1097719; use can be made of published patents Application EP1097719-A1 paragraphs [0368] to [0376] to determine IC50 values for NEP and ACE; 95339.doc • 53- 200526606 7) — or more vasopressin receptor antagonists or modulators, such as Relcovaptan (SR 49059), conivaptan, atosiban, VPA-985, CL-385004, Vasotocin 〇8) apomorphine a The teaching of apomorphine as a medicine can be found in US-A-5945117; 9) Dopamine agonists (selective D2, selective D3, selective D4 and similar selective D2 agents in detail) such as pramipexole ( (Pramipexole) (Pharmacia Upjohn compound number PNU95666), ropinirole, apomorphine 13fei, surmanirole, quinelorane, PNU-142774, ergocycline, card Ergoline (carbergoline), Lisuride; 10) Melanocortin receptor agonists (such as Melanotan II and PT141) and selective MC3 and MC4 agonists (such as THIQ); 11 ) Monoamine transport inhibitors, especially norepinephrine reuptake inhibitors (NRI) (eg Reboxetine), other serotonin reuptake inhibitors (SRI) (e.g. paroxetine, dapoxetine) or dopamine reuptake inhibitors (DRI); 12) 5-11 but 18 antagonists (e.g. Rubozodane (1 * (^ 312 (^ 311)); and 13) PDE inhibitors, such as PDE2 (eg, eryth-9- (2-hydroxy-3-nonyl) -adenine and incorporated by reference Example 100 of EP 0771799 herein) and especially PDE5 inhibitors such as the pyrazolo [4,3-d] pyrimidin-7-ones disclosed in EP-A-0463756; the pyridines disclosed in EP-A-0526004 Zolo [4,3-d] pyrimidine-7- 95339.doc -54- 200526606 ketone; disclosed in published international patent application WO09 / 〇6IO04. Than

[4’3_d] ;揭示於公開之國際專利申請案WO 93/07149中之異構體^坐並[3,4_小密^定_4·酮；揭示於公開之國際專射請93/12G95中之㈣琳韻；揭示於公開之國際專利申請案W〇 94/〇5661中之吡啶並[3,2令密夂-4-酮，揭不於公開之國際專利申請案w〇 94/⑼々Η中之 %呤-6-酮，揭不於公開之國際專利申請案〜〇 98/49166中之吡唑並[4,3-d]嘧啶_7_酮；揭示於公開之國際專利申請案 WO 99/54333中之η比唑並[4,3_d]嘧啶_7_酮；揭示於 EP-A-0995751中之吡唑並[4,3·(ΐ]嘧啶-7-酮；揭示於公開之國際專利申請案WO 〇〇/24745中之吡唑並[4,3-d]嘧啶-7-酮；揭示於EP-A-0995750中之吡唑並[4,3_d]嘧啶_7_酮；揭示於公開之國際專利申請案w〇 95/19978中之化合物；揭示於公開之國際專利申請案WO 99/24433中之化合物及揭示於公開之國際專利申請案WO 93/07124中之化合物；揭示於公開之國際專利申請案WO 01/27112中之吡唑並[4,3-d]。密 °定-7-酮；揭示於公開之國際專利申請案w〇 01/27113中之 °比唑並[4,3-d]嘧啶-7-酮；揭示於EP-A-1092718中之化合物及揭示於EP-A-1092719之化合物。用於本發明之較佳PDE抑制劑係： 5-[2 -乙氧基- 5-(4-甲基-1-呱嗪基績醯）苯基]_1_甲基·3·正丙基-1，6_二氫-7Η_ σ比唾並[4,3-d]癌咬-7-酮（威而剛 (sildenafil))，亦稱為 1-[[3-(6,7-二氫-1-甲基-7-氧-3-丙基 -111-吡唑並[4,3-引嘧啶-5-基）-4-乙氧基苯基]磺醯]-4-甲基 95339.doc -55- 200526606 呱嗪（參看 EP-A-0463756); 5-(2-乙氧基-5-嗎啉並乙醯基苯基）_ι_甲基-3-正丙基-1，6-二氫-7H-吡唑並[4,3-d]嘧啶-7-酮（參看 EP-A-0526004); 3-乙基乙基狐嗅-1 -基石黃酿）-2-正丙乳基本基]-2-(吡啶-2-基）甲基-2,6-二氫-7H-吡唑並[4,3_d]嘧啶-7-酮（參看 WO 98/49166); 3-乙基-5-[5-(4-乙基呱嗪-1-基磺醯）-2-(2-曱氧基乙氧基） °比咬-3-基]-2-(°比唆-2-基）甲基-2,6-二氫- 7H-°比唾並[4,3-d] 嘧啶-7-酮（參看 WO 99/54333); ( + )-3-乙基-5-[5-(4-乙基呱嗪-1-基磺醯）-2-(2-甲氧基甲基乙氧基）吼啶-3_基]-2-甲基-2,6-二氫-7H-吡唑並 [4,3-d]嘧啶-7-酮，亦稱為3-乙基·5-{5-[4-乙基呱嗪-1-基磺醯]-2-([(1ΙΙ)_2-甲氧基-1-甲基乙基]氧基）吡啶-3-基}-2-甲基-2,6-二氫-7Η-吡唑並[4,3-d]嘧啶-7-酮（參看WO 99/54333)； 5-[2 -乙氧基- 5-(4 -乙基狐嗪-1-基石黃醯）。比π定-3-基]-3 -乙基 _2-[2-曱氧基乙基]-2,6_二氫-7H-咣唑並[4,3-d]嘧啶-7-酮，亦稱為1-{6_乙氧基-5-[3-乙基-6,7-二氫-2_(2-曱氧基乙基）-7-氧-2H-吡唑並[4,3-d]嘧啶-5-基]-3-吡啶基績醯}-4-乙基呱嗪（參看WO 01/27113，實例8); 5-[2-異-丁氧基-5-(4-乙基呱嗪-1-基磺醯）吼啶-3-基]-3-乙基-2-(1-曱基呱啶-4-基）-2,6-二氫-7H-吡唑並[4,3-d]嘧啶 -7-酮（參看 WO 01/27113，實例 15); 5-[2 -乙氧基- 5- (4 -乙基狐嘻-1-基石黃醢）σ比U定-3-基]-3 -乙基 95339.doc -56- 200526606 -2-苯基-2,6-二氫-7H-吡唑並[4,3-d]嘴咬-7-酮（參看w〇 01/27113，實例66);[4'3_d]; The isomers disclosed in the published international patent application WO 93/07149 and the [3,4_ 小密 ^ 定 _4 · ketone; disclosed in the published international special shooting please 93 / Lin Linyun in 12G95; Pyrido [3,2 Ling Mi-4-one, disclosed in published international patent application WO94 / 〇5661, unpublished international patent application WO94 / The% pyridin-6-one in hydrazone is disclosed in the unpublished international patent application ~ Pyrazolo [4,3-d] pyrimidin_7_one in 098/49166; disclosed in the published international patent Η Biazolo [4,3_d] pyrimidin_7_one in application WO 99/54333; pyrazolo [4,3 · (ΐ) pyrimidin-7-one; disclosed in EP-A-0995751; disclosed Pyrazolo [4,3-d] pyrimidin-7-one in published international patent application WO 00/24745; Pyrazolo [4,3_d] pyrimidine_7 disclosed in EP-A-0995750 Ketones; compounds disclosed in published international patent application WO 95/19978; compounds disclosed in published international patent application WO 99/24433 and compounds disclosed in published international patent application WO 93/07124 Compounds; pyridine disclosed in published international patent application WO 01/27112 And [4,3-d]. Mido-7-one; disclosed in the published international patent application WO01 / 27113 ° bizolo [4,3-d] pyrimidin-7-one; revealed Compounds in EP-A-1092718 and compounds disclosed in EP-A-1092719. Preferred PDE inhibitors for use in the present invention are: 5- [2-ethoxy-5- (4-methyl-1) -Pyrazinyl group 醯) phenyl] _1_methyl · 3 · n-propyl-1,6_dihydro-7Η_ σ than sialo [4,3-d] cancer bite-7-one (viagra (sildenafil)), also known as 1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-111-pyrazolo [4,3-primazine-5 -Yl) -4-ethoxyphenyl] sulfonyl] -4-methyl 95339.doc -55- 200526606 oxazine (see EP-A-0463756); 5- (2-ethoxy-5-? (Porphyrinethyl) phenyl-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see EP-A-0526004 ); 3-ethylethyl foxolol-1-cornerstone yellow brewed)-2-n-propyl milk basic group] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazole And [4,3_d] pyrimidin-7-one (see WO 98/49166); 3-ethyl-5- [5- (4-ethylpyrazine-1-ylsulfonyl) -2- (2-fluorene Oxyethoxy) ° Specific-3-yl] -2- (° Specific fluoren-2-yl) methyl-2,6-dihydro- 7H- ° than sialo [4,3-d] pyrimidin-7-one (see WO 99/54333); (+)-3-ethyl-5- [5- (4-ethylpyrazine-1- Sulfosulfonyl) -2- (2-methoxymethylethoxy) pyridin-3_yl] -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d ] Pyrimidin-7-one, also known as 3-ethyl · 5- {5- [4-ethylpyrazine-1-ylsulfonium] -2-([(1ΙΙ) _2-methoxy-1- Methylethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7fluorene-pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333 ); 5- [2-ethoxy-5- (4-ethylfoxazin-1-yl scutellarin). Than π-A-3-yl] -3 -ethyl_2- [2-methoxyoxyethyl] -2,6_dihydro-7H-oxazolo [4,3-d] pyrimidin-7-one , Also known as 1- {6_ethoxy-5- [3-ethyl-6,7-dihydro-2_ (2-fluorenylethyl) -7-oxy-2H-pyrazolo [4 , 3-d] pyrimidin-5-yl] -3-pyridinylsulfanyl} -4-ethylpyrazine (see WO 01/27113, Example 8); 5- [2-iso-butoxy-5- (4-Ethylpyrazine-1-ylsulfonyl) sulfanil-3-yl] -3-ethyl-2- (1-fluorenylpyridin-4-yl) -2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-ethoxy- 5- (4-ethylhuoxine-1-ylsulfur yellow Ii) σ ratio U-determinyl-3-yl] -3 -ethyl 95339.doc -56- 200526606 -2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] -7-one (see WO01 / 27113, Example 66);

5-(5 -乙酷基-2 -丙氧基-3 -°比°疋基）-3 -乙基異丙基_3_ 吖丁啶基）-2,6-二氫-7//^比吐並[4,3-dp密唆-7-類!（參看WO 01/27112，實例 124);5- (5 -Ethyl-2 -propoxy-3-° ratio ° fluorenyl) -3 -ethylisopropyl_3_azetidinyl) -2,6-dihydro-7 // ^ And [4,3-dp Secret-7-class! (See WO 01/27112, Example 124);

5-(5-乙醯基_2_ 丁氧基比11 定基）_3-乙基-2-(丨-乙基-3-吖丁啶基）-2,6-二氫-7H-吡唑並[4,3-d；h密咬-7·酮（參看WO 01/27112，實例 132); (611，12&11)-2,3,6,7，12，12&-六氫-2_甲基-6-(354-亞甲二氧基苯基）-吼嗪並[2，，1，：6，1] °比啶並[3,4-b]吲哚-1，4-二酮 (IC-351)，意即，公開之國際專利申請案W095/19978之實例78及95之化合物，以及實例1、3、7及8之化合物； 2-[2-乙氧基-5-(4-乙基-呱嗪-1-基-1-磺醯）-苯基]-5-甲基 -7-丙基-3H-咪唑幷[5，l-f][l，2,4]三嗪-4-酮（伐地那非 (vardenafil))，亦稱為 1-[[3-(3,4-二氫-5-甲基 _4_ 氧-7-丙基咪唑幷[5, l-f]-as-三嗪-2-基）-4-乙氧基苯基]磺醯]-4-乙基呱嗪，意即公開之國際專利申請案WO 99/24433之實例20、 19、337及336之化合物；及公開之國際專利申請案WO 93/〇7124(EISAI)之實例11之化合物；及來自 Rotella D P，J. Md C/2謂2000, 43，1257之化合物 3 及14。用於本發明之又進一步之PDE5抑制劑包括： 4-溴-5-(吼啶基曱基胺基）_6_[3_(4_氯苯基）_丙氧基]_3(2H) 95339.doc -57- 200526606 噠嗪酮，卜[4-[(l，3-苯幷二氧雜戊環_5_基甲基）胺基卜6_氯 -2-喹唑啉基]-4-呱啶-羧酸，單鈉鹽；（+：Μ|_5,6α，7,9,9，％_ 六氫-2-[4-(二氟甲基）-苯基甲基_5_甲基_環戊基_4,5]咪唑幷 [2，l-b]嘌呤-4(3H)酮；呋喃吖西林（furazl〇cimn);順 _2_己基-5_甲基_3,4,5,6&，7,8,9,9&_八氫環戊基[4,5]_咪唑幷[2，1讣] 嘌呤-4-酮；3-乙醯基-；u(2_氣苄基）_2_丙基吲哚_6_羧酸酯； 3-乙醯基-1-(2-氣苄基）-2-丙基朵魏酸酯；4_溴-5-(3 吼啶基甲基胺基）-6-(3-(4-氯苯基）丙氧基）_3_(2H)噠嗪_ ; 1-甲基-5(5-嗎琳並乙醯基-2-正丙氧基苯基）_3_正丙基_1，6_ 二氫-7H-吡唑並（4,3-d)嘧啶-7-酮；l-[4-[(l，3-苯幷二氧雜戊環-5-基甲基）胺基]-6-氯-2-喧嗤琳基]_4_狐。定魏酸，單納鹽；Pharmaprojects 第 4516 號（Giaxo Wellcome);5- (5-ethylfluorenyl_2_ butoxy than 11 adenyl) _3-ethyl-2- (丨 -ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4 , 3-d; h dense bite-7 · one (see WO 01/27112, Example 132); (611,12 & 11) -2,3,6,7,12,12 & -hexahydro-2_a -6- (354-methylenedioxyphenyl) -oxazino [2,, 1 :: 6,1] ° pyrido [3,4-b] indole-1,4-dione (IC-351), meaning the compounds of Examples 78 and 95 of the published International Patent Application W095 / 19978, and the compounds of Examples 1, 3, 7 and 8; 2- [2-ethoxy-5- ( 4-ethyl-fluorazin-1-yl-1-sulfofluorene) -phenyl] -5-methyl-7-propyl-3H-imidazolium [5, lf] [l, 2,4] triazine -4-one (vardenafil), also known as 1-[[3- (3,4-dihydro-5-methyl_4_oxy-7-propylimidazolium [5, lf] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpyrazine, meaning examples 20, 19, 337 of the published international patent application WO 99/24433 and Compound 336; and compound 11 of the published international patent application WO 93 / 〇7124 (EISAI); and compounds 3 and 14 from Rotella DP, J. Md C / 2, 2000, 43, 1257. Still further PDE5 inhibitors for use in the present invention include: 4-bromo-5- (crotylamidinylamino) _6_ [3_ (4_chlorophenyl) _propoxy] _3 (2H) 95339.doc -57- 200526606 Pyridazinone, [4-[(l, 3-phenylhydrazone dioxolane-5-ylmethyl) amino group 6-chloro-2-quinazolinyl] -4- 呱Pyridine-carboxylic acid, monosodium salt; (+: M | _5,6α, 7,9,9,% _ hexahydro-2- [4- (difluoromethyl) -phenylmethyl_5_methyl _Cyclopentyl_4,5] imidazolium [2, lb] purin-4 (3H) one; furazolcim; cis_2_hexyl-5_methyl_3,4,5, 6 &, 7,8,9,9 & _octahydrocyclopentyl [4,5] _imidazolium [2,1 讣] purin-4-one; 3-ethylamyl-; u (2_gas benzyl ) _2_propylindole-6_carboxylic acid ester; 3-ethylfluorenyl-1- (2-airbenzyl) -2-propyldocoroate; 4-bromo-5- (3amidine Methylamino) -6- (3- (4-chlorophenyl) propoxy) _3_ (2H) pyridazine_; 1-methyl-5 (5-morpholinoacetamido-2-n Propoxyphenyl) _3_n-propyl_1,6_dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-one; l- [4-[(l, 3-phenylhydrazine Oxapenta-5-ylmethyl) amino] -6-chloro-2-oxalinyl] _4_fox. Dingweiic acid, mononaphthalate; Pharmaprojects No. 4516 (Giaxo Wellcome);

Pharmaprojects 第 5051 號（Bayer) ; Pharmaprojects 第 5064號 (Kyowa Hakko ;見 WO 96/26940) ; Pharmaprojects 第 5069 號（Sphering Plough) ; GF-196960 (Glaxo Wellcome) ; E-8010 及 E-4010 (Eisai) ; Bay-38-3045 & 38-9456 (Bayer)及 Sch-51866 。公開之專利申請案及期刊論文之内容且尤其申請專利範圍中之治療活性化合物及例示化合物之通式以全文引用方式併入本文。用於本發明之更佳PDE5抑制劑選自由以下各物組成之群： 5_[2-乙氧基-5-(4-甲基-1-呱嗪基磺醯）苯基]-i-甲基-3-正丙基-1，6-二氫-7H-吼唑並[4,3-d]嘧啶-7-酮（威而剛）； 95339.doc -58- 200526606 (6R, 12aR)-2,3,6,7,12,12a-六氮-2-甲基-6-(3,4-亞甲一？ '一氣基苯基）-°比嗓並[2’，Γ··6，1] σ比咬並[3,4-b],峰_ι 一 — (IC-351); 2-[2-乙氧基-5-(4-乙基-呱嗪-卜基―^磺醯）_苯基]_5_甲美 -7_丙基-3H-咪唾幷[5，l-f][l，2,4]三嗪-4- g同（伐地那非 (vardenafil));及 5-[2_乙氧基- 5-(4-乙基n瓜嗪_ι •基績醢）σ比咬_3_基]·乙美 -2-[2 -甲氧基乙基]-2,6-二氫- 7Η-σ比唾並[4,3-d]喷ϋ定_7 _七 5-(5 -乙醯基-2-丁氧基-3-吼咬基）-3 -乙基-2-(1-乙基σ丫丁咬基）·2,6-二氫-7Η_^σ坐並[4,3-d],咬-7-酮及其醫藥上可接受之鹽。尤佳之PDE5抑制劑係5-[2·乙氧基-5-(4-甲基-丨-呱嗪基磺醯）苯基]-1-甲基-3-正丙基·u•二氫-7H•吡唑並[4,3_^嘧啶 -7-酮（威而剛）（亦稱為1-[[3-(6,7·二氫-1-曱基_7_氧_3_丙某 -1Η-吡唑並[4,3-d]嘧啶-5_基）_4_乙氧基苯基]磺醯]_4•甲2 呱嗪）及其醫藥上可接受之鹽。威而剛檸檬酸鹽係一較佳鹽 ° 與本發明之化合物共投藥之較佳試劑係如前述之pDE5 抑制劑、選擇性血清素再攝取抑制劑（SSRI)、後葉加壓素 V〗a拮抗劑、α-腎上腺素受體拮抗劑、NEp抑制劑、多巴胺促效劑及黑色皮貪素受體促效劑。共投藥之尤佳試劑係如本文所述之PDE抑制劑、SSRI、及via拮抗劑。檢定下文詳述了用於測定化合物之催產素拮抗活性之適當檢 95339.doc -59- 200526606 定。催產素受艎P-内醯胺酶檢定 . 材料：細胞培養/試劑 A :細胞培養營養素混合物 F12 Ham’s 胎牛血清（FBS) 遺傳黴素（Geneticin)Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Sphering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai) Bay-38-3045 & 38-9456 (Bayer) and Sch-51866. The contents of published patent applications and journal articles, and in particular the general formulae for therapeutically active compounds and exemplified compounds within the scope of the patent application, are incorporated herein by reference in their entirety. A more preferred PDE5 inhibitor for use in the present invention is selected from the group consisting of 5- [2-ethoxy-5- (4-methyl-1-fluorazinylsulfonyl) phenyl] -i-methyl Propyl-3-n-propyl-1,6-dihydro-7H-oxazolo [4,3-d] pyrimidin-7-one (viagra); 95339.doc -58- 200526606 (6R, 12aR) -2,3,6,7,12,12a-hexaaza-2-methyl-6- (3,4-methylene-??-monophenyl)-° specification [2 ', Γ ··· 6,1] σ bite [3,4-b], peak _ι a — (IC-351); 2- [2-ethoxy-5- (4-ethyl-pyrazine-butyl — ^ Sulfonium) _phenyl] _5_Memet-7_propyl-3H-amisalazine [5, lf] [l, 2,4] triazine-4-g Same as (vardenafil) ); And 5- [2-ethoxy- 5- (4-ethyln guarazine_ι • base 醢) σ ratio bite_3_yl] · Emei-2- [2-methoxyethyl Radical] -2,6-dihydro-7Η-σ than sialo [4,3-d] pentanidine_7 _seven 5- (5-ethylfluorenyl-2-butoxy-3-carbinyl ) -3 -Ethyl-2- (1-ethylσγbutylene), 2,6-dihydro-7Η_ ^ σ sitting and [4,3-d], bite-7-one and its medical use Acceptable salt. A particularly good PDE5 inhibitor is 5- [2 · ethoxy-5- (4-methyl- 丨 -pyrazinosulfonyl) phenyl] -1-methyl-3-n-propyl · u · di Hydrogen-7H • pyrazolo [4,3_ ^ pyrimidin-7-one (viagra) (also known as 1-[[3- (6,7 · dihydro-1-fluorenyl_7_oxy_3 _ Bing-1 -1Η-pyrazolo [4,3-d] pyrimidin-5_yl) _4_ethoxyphenyl] sulfofluorene] _4 • methyl 2 hydrazine) and its pharmaceutically acceptable salts. Viagra citrate is a preferred salt. The preferred agents for co-administration with the compounds of the present invention are the aforementioned pDE5 inhibitors, selective serotonin reuptake inhibitors (SSRI), and vasopressin V〗 a Antagonists, alpha-adrenergic receptor antagonists, NEp inhibitors, dopamine agonists and melanthorrel receptor agonists. Particularly preferred agents for co-administration are PDE inhibitors, SSRIs, and via antagonists as described herein. Assays Appropriate assays for determining the oxytocin antagonistic activity of a compound are detailed in the following 95339.doc -59- 200526606. Oxytocin is tested by P-lactamase. Materials: Cell culture / reagent A: Cell culture Nutrient mixture F12 Ham ’s Fetal bovine serum (FBS) Geneticin

ZeocinZeocin

胰蛋白酶/EDTA PBS(磷酸緩衝生理食鹽水） HEPES B :試劑催產素 OT受體-特定拮抗劑分子級二甲亞砜（DMSO) 錐蟲藍溶液0.4% CCF4-AM(溶液 A) 聚丙二醇與環氧乙烷加聚物F127s(溶液B) 24% PEG，18% TR40(溶液 C) 丙磺舒（以200 mM溶解於200 mMNaOH中，溶液D) 方法 - 細胞培養 95339.doc -60· 200526606 所用細胞係CHO-OTR/NFAT-β-内醯胺酶。轉染NFAT-β-内醯胺酶表現構造至CHO-OTR細胞系且藉由螢光活化細胞分類術（FACS)分離純系種群。選擇合適純系以展開檢定。生長媒介Trypsin / EDTA PBS (phosphate-buffered saline) HEPES B: Reagent oxytocin OT receptor-specific antagonist molecular grade dimethyl sulfoxide (DMSO) Trypan blue solution 0.4% CCF4-AM (solution A) polypropylene glycol and Ethylene oxide addition polymer F127s (solution B) 24% PEG, 18% TR40 (solution C) probenecid (dissolved in 200 mM in 200 mM NaOH, solution D) Method-Cell Culture 95339.doc -60 · 200526606 The cell line used was CHO-OTR / NFAT-β-lactamase. NFAT-β-lactamase was transfected into the CHO-OTR cell line and the pure line population was isolated by fluorescence activated cell sorting (FACS). Select the appropriate pure line to carry out the test. Growth media

90%F12營養素混合物，15mMHEPES 10% FBS 400 gg/ml遺傳黴素 200 pg/ml Zeocin 2 mM L-穀胺醯胺檢定媒劑90% F12 nutrient mixture, 15mMHEPES 10% FBS 400 gg / ml geneticin 200 pg / ml Zeocin 2 mM L-glutamine

99.5%F12營養素混合物，15mMHEPES 0.5% FBS 細胞之回收一迅速於37°C水浴中解凍一瓶經冷凍之細胞且轉移該細胞懸浮液至一具有50 ml新鮮生長媒介之T225 燒瓶中且於培養器中於37°C、5% C02培養直至細胞附著於燒瓶。第二天以50 ml新鮮媒劑置換原媒劑。培養細胞一於生長媒介中生長CHO-OTR-NFAT-β内醯胺酶細胞。當其達到80-90%融合時採集細胞，移除媒介且以經預溫之PBS洗滌。隨後移除PBS且加入胰蛋白酶/EDTA(對 T225 cm2燒瓶為3 ml)，繼而於37°C/5% C02培養器中培養5 分鐘。當細胞被分離時，加入經預溫之生長媒介（對T225 cm2 燒瓶為7 ml)且重懸浮細胞且藉由移液操作輕輕混合以達成單細胞懸浮液。以35 ml生長媒介中之1:10(對3天生長）及 1:30(對5天生長）之比率將細胞分入T225燒瓶。 95339.doc -61 - 200526606 ρ-内醯胺酶檢定方法第1天細胞板製備採集以8G，％融合生長之細胞料數。製備生長媒介中以2χ105細胞/ml濃度之細胞懸浮液且將3〇 μΐ細胞懸浮液添加至384-孔、黑色透明底板中。使用含來自每一試劑之稀釋液的空白板以使背景減少。於37 C、5% C02中培養板隔夜。第2天細胞刺激 •加入10 μΐ拮抗劑/化合物（稀釋於含125% DMS〇之檢定媒劑中=拮抗劑稀釋液）至合適孔中且於37〇c、5〇/() c〇2 培養1 5分鐘。 •加入於檢定媒劑中組成之1〇 (^催產素至所有孔中且於 37°C、5% C02培養4小時。 •使用獨立的3 8 4 -孔細胞板以產生催產素劑量反應曲線。（將10 μΐ拮抗劑稀釋液添加至每一孔。隨後加入1〇 μΐ催產素。隨後根據拮抗劑/化合物細胞板來處理細胞）。 •精由增強載入協議（Enhanced Loading Protocol)製備1 ml之6x載入緩衝液（此需要根據待篩選之板之數量按比例放大） •將12 μΐ溶液A(乾燥DMS0中之1 mM CCF4-AM)添加至 60 μΐ溶液B(DMS0中之100 mg/ml聚丙二醇與環氧乙 95339.doc -62- 200526606 烷之加聚物-F127 + 0.1%乙酸）中且渦旋。 •將所得溶液添加至925 μΐ溶液C(24%重量/重量 PEG400、水中18% TR40體積/體積）中。 •力口入75 μΐ溶液D(200 mM NaOH中之200 mM丙磺舒）。 •將10 μΐ 6x載入緩衝液添加至所有孔中且於黑暗中於室溫培養1.5小時-2小時。 •讀取該等板，使用LJL分析儀、激發405 nm、發射450 及53 0 nm、增益最佳、滞後時間0.40 整合、4次閃光，底部讀數。使用上述檢定，所有本發明之化合物均展示催產素拮抗活性，表現為低於500 ηΜ之Ki值。較佳實例具有低於200 ηΜ 之Ki值且尤佳之實例具有低於50ηΜ之Ki值。實例8之化合物具有3 ηΜ之Ki值。本發明藉由下列非限制實例闡明，在該等實例中使用下列縮寫及定義：99.5% F12 nutrient mixture, 15mMHEPES 0.5% FBS cell recovery-quickly thaw a bottle of frozen cells in a 37 ° C water bath and transfer the cell suspension to a T225 flask with 50 ml fresh growth medium and place in an incubator Incubate at 37 ° C and 5% CO2 until cells attach to the flask. Replace the original vehicle with 50 ml fresh vehicle the next day. Culture cells-CHO-OTR-NFAT-β-lactamase cells are grown in a growth medium. Cells were harvested when they reached 80-90% confluence, the medium was removed and washed with pre-warmed PBS. The PBS was then removed and trypsin / EDTA (3 ml for a T225 cm2 flask) was added, followed by incubation in a 37 ° C / 5% CO2 incubator for 5 minutes. When the cells are separated, add pre-warmed growth medium (7 ml for T225 cm2 flasks) and resuspend the cells and mix gently by pipetting to achieve a single cell suspension. Cells were divided into T225 flasks at a ratio of 1:10 (for 3 days of growth) and 1:30 (for 5 days of growth) in 35 ml of growth medium. 95339.doc -61-200526606 ρ-lactamase assay method Day 1 Cell plate preparation Collect the number of cells growing at 8G,% confluence. A cell suspension at a concentration of 2x105 cells / ml in the growth medium was prepared and 30 μΐ of the cell suspension was added to a 384-well, black transparent bottom plate. Use a blank plate containing diluent from each reagent to reduce background. The plates were incubated overnight at 37 C, 5% C02. Day 2 Cell Stimulation • Add 10 μΐ antagonist / compound (diluted in assay vehicle with 125% DMS〇 = antagonist dilution) into appropriate wells at 37 ° C, 50 / () c〇2 Incubate for 15 minutes. • Add 10% of oxytocin to the wells in the test vehicle and incubate for 4 hours at 37 ° C, 5% CO2. • Use a separate 3 8 4-well cell plate to generate the oxytocin dose-response curve. (Add 10 μΐ antagonist dilution to each well. Then add 10 μΐ oxytocin. Cells are then processed according to the antagonist / compound cell plate.) • Preparing by the Enhanced Loading Protocol 1 ml of 6x loading buffer (this needs to be scaled up according to the number of plates to be screened) • Add 12 μΐ of solution A (1 mM CCF4-AM in dry DMS0) to 60 μΐ of solution B (100 mg in DMS0) / ml polypropylene glycol and ethylene oxide 95339.doc -62- 200526606 alkane addition polymer-F127 + 0.1% acetic acid) and vortex. • Add the resulting solution to 925 μΐ solution C (24% w / w PEG400, 18% TR40 volume / volume in water). • Force 75 μΐ solution D (200 mM probenecid in 200 mM NaOH). • Add 10 μ10 6x loading buffer to all wells and place in the dark. Incubate at room temperature for 1.5 hours to 2 hours. • Read the plates, use an LJL analyzer, and excite 40 5 nm, 450 and 5300 nm emission, best gain, 0.40 lag time integration, 4 flashes, bottom reading. Using the above assay, all compounds of the present invention exhibit oxytocin antagonistic activity, exhibiting less than 500 ηΜ Ki value. Preferred examples have Ki values below 200 nM and particularly preferred examples have Ki values below 50 nM. The compound of Example 8 has a Ki value of 3 nM. The invention is illustrated by the following non-limiting examples, in which Examples use the following abbreviations and definitions:

Arbocel® 過濾、劑，來自 J· Rettenmaier & Sohne，德國 APC1 + 大氣壓力化學離子化（正掃描） CDC13 氣仿-dl d 雙重 dd 雙重之雙重 DMSO 二甲亞砜 ES + 電喷霧離子化正掃描。 eq 當量 ]H NMR 質子核磁共振譜 95339.doc -63- 200526606 MS (低解析率）質譜 m 多重 m/z 質譜峰 q 四重 s 單重 t 三重 δ 化學位移製備1 雙[2-[(二甲基胺基-κΝ)甲基]苯基-kC】雙[μ-(三氟醋酸根 _κΟ: κΟ，）]-鈀Arbocel® filter, agent from J. Rettenmaier & Sohne, Germany APC1 + Atmospheric pressure chemical ionization (positive scan) CDC13 Aeroform-dl d dual dd dual dual DMSO dimethyl sulfoxide ES + electrospray ionization positive scanning. eq equivalent] H NMR proton nuclear magnetic resonance spectrum 95339.doc -63- 200526606 MS (low resolution) mass spectrum m multiple m / z spectrum peak q quadruple s singlet t triple δ chemical shift preparation 1 double [2-[(two Methylamino-κN) methyl] phenyl-kC] bis [μ- (trifluoroacetate_κΟ: κΟ,)]-palladium

於甲醇（200 mL)中之氣化鈀43 g 中，於氮氣氛中於室溫下藉由注射器加入N，N•二甲基苄胺 (5.82 mL，38.7 mmol)。於室溫下攪拌所得紅色/棕二一 24小時。於真空中濃縮如今之綠色/棕色懸浮液C憨浮液醇，再溶解於二氯甲烷（1 50 mL)中且使其穿竭之以移除甲由二氯甲烷洗滌。於真空中濃縮所得嫩戈石夕膠墊藉 (CDC13, 300 ΜΗζ) δ: 2·86 (s，6 H)，2.89(s，6 3。 H 6.84-7.24 (m，8 Η)。 ’ .95(s，盥備2 氯甲烷：***中重結晶以得所需之產物，4 66 目 § 4 Η) 95339.doc -64- 200526606 雙[2-[(二甲基胺基-κΝ)甲基]苯基(三氟醋睃根 -κΟ: κΟ’）]-把In 43 g of vaporized palladium in methanol (200 mL), N, N • dimethylbenzylamine (5.82 mL, 38.7 mmol) was added via a syringe in a nitrogen atmosphere at room temperature. The resulting red / brown 211 was stirred at room temperature for 24 hours. The current green / brown suspension, C. buoyantum, was concentrated in vacuo, re-dissolved in dichloromethane (150 mL) and allowed to pass through to remove formic acid. Concentrate the obtained Nengosite cushion pad in vacuum (CDC13, 300 ΜΗζ) δ: 2.86 (s, 6 H), 2.89 (s, 6 3. H 6.84-7.24 (m, 8 Η). '. 95 (s, reparation 2 methyl chloride: diethyl ether to obtain the desired product, 4 66 mesh § 4 Η) 95339.doc -64- 200526606 bis [2-[(dimethylamino-κΝ) 甲Phenyl] phenyl (trifluoroacetamidine-κΟ: κΟ ')]-

於丙酮（30 mL)中之三氟乙酸銀（4·48 g，2〇·3 mmol)之溶液中，於氮氣氛中於室溫下加入二氯甲烷（l〇〇 mL)中之製備1之複合物（5·60 g ’ 10.15 mmol)之溶液。於添加過程中出現黏稠白色沈澱物。攪拌懸浮液15分鐘，且隨後藉由一石夕膠墊過濾，以二氯甲烷洗滌。於真空中濃縮得嫩黃色粉末，將其自二氯甲烷：***中重結晶以得所需之產物，7.〇6 g。 iNMR (CDC13, 300 ΜΗζ) δ: 2.05 (s，6 H)，2.88 (s，6 H)， 3·18 (d，2 Η)，3·63 (d，2 Η)，6.89-6.97 (m，6 Η)，7.00-7.10 (m， 2 Η)。 ’ 製備3 【2-[(二甲基胺基-κΝ)甲基】苯基-KC](三環己基膦）（三氟醋酸根-K〇-(SP-4-3)-把 (Xr 於二氣甲烷（50 mL)中之製備2之產物（6·43 g，9.10 mmol) 之溶液中，於氮氣氛中於室溫下加入二氯甲烷（2〇 mL)中之 95339.doc -65- 200526606 二環己基膦（6.89 g，24.5 mmol)之溶液。攪拌丨小時後，將溶液通過一矽膠栓塞（7 cmx2 cm)以二氯甲烷（4〇〇 mL)洗滌，且於真空中濃縮淺黃色濾液。自二氯曱烷：***中重結晶以得所需之複合物，10.53 g。 ^NMR (CDC13? 300 MHz) δ: 1.05-2.30 (m5 3 3 Η), 2.57(s? 3 Η)，2.58 (s，3 Η)，3.93 (s，2 Η)，6.86-6.98 (m，3 η)， 7.10-7.12 (m，1 Η)。製備4 2-(4-溴-苯基）_5_甲基·[nq噁二唑Preparation 1 in a solution of silver trifluoroacetate (4.48 g, 20.3 mmol) in acetone (30 mL) and the addition of dichloromethane (100 mL) at room temperature under a nitrogen atmosphere 1 Of the complex (5 · 60 g '10.15 mmol). A thick white precipitate appeared during the addition. The suspension was stirred for 15 minutes, and then filtered through a pad of silica gel and washed with dichloromethane. Concentrated in vacuo to give a bright yellow powder, which was recrystallized from dichloromethane: diethyl ether to give the desired product, 7.06 g. iNMR (CDC13, 300 ΜΗζ) δ: 2.05 (s, 6 H), 2.88 (s, 6 H), 3.18 (d, 2 Η), 3.63 (d, 2 Η), 6.89-6.97 (m , 6 Η), 7.00-7.10 (m, 2 Η). '' Preparation 3 [2-[(Dimethylamino-κN) methyl] phenyl-KC] (tricyclohexylphosphine) (trifluoroacetate-K〇- (SP-4-3)- In a solution of the product of Preparation 2 (6.43 g, 9.10 mmol) in methane (50 mL), 95395.doc in dichloromethane (20 mL) was added at room temperature under a nitrogen atmosphere- 65- 200526606 A solution of dicyclohexylphosphine (6.89 g, 24.5 mmol). After stirring for one hour, the solution was washed through a silica plug (7 cm x 2 cm) with dichloromethane (400 mL) and concentrated in vacuo. Light yellow filtrate. Recrystallized from dichloromethane: diethyl ether to obtain the desired complex, 10.53 g. NMR (CDC13? 300 MHz) δ: 1.05-2.30 (m5 3 3 Η), 2.57 (s? 3 Η), 2.58 (s, 3 Η), 3.93 (s, 2 Η), 6.86-6.98 (m, 3 η), 7.10-7.12 (m, 1 Η). Preparation 4 2- (4-bromo-phenyl) ) _5_methyl · [nqoxadiazole

將溴-苯曱酸醯肼（12.90 g，60 mmol)及N，N-二甲基乙醯胺二甲基乙縮醛（12 mL，82.0 mmol)溶解於n，N-二甲基甲醯胺（100 mL)中且將該溶液於6(rc加熱2小時。於真空中濃縮該溶液且將殘餘物溶解於甲苯（8〇 mL)中且以對甲苯磺酸單水合物（200 mg，1_50 mmol)處理。加熱混合物至回流2 小時，冷卻，產物自溶液中結晶且藉由過濾收集。以醚洗務粗產物且於真空中乾燥以得白色固體。於真空中漢縮遽液且將殘餘物與白色固體組合，將其溶解於甲苯（5〇且以對甲苯磺酸單水合物（100 mg，〇·75 mm〇1)處理。加熱混合物至回流3小時，冷卻且於真空中濃縮。藉由管柱層析法於矽膠上以80:20至40:60之戊烷：乙酸乙酯洗提來純化殘餘物以得標題產物，12.0 〇 g。 1 腿MR (CDC13, 400 ΜΗζ) δ: 2.61 (s，3 H)，7.62 (d，2 H)， 95339.doc -66- 200526606 7.88 (d，2 Η)。MS ES+ m/z 239 [ΜΗ] 製備5 3-(4_漠.苯基）-4_(4_甲氧基_苯基）_5-甲基4Η-[1，2 4】***Dissolve hydrazine bromide-phenylacetate (12.90 g, 60 mmol) and N, N-dimethylacetamidodimethylacetal (12 mL, 82.0 mmol) in n, N-dimethylformamidine Amine (100 mL) and the solution was heated at 6 (rc for 2 hours. The solution was concentrated in vacuo and the residue was dissolved in toluene (80 mL) and treated with p-toluenesulfonic acid monohydrate (200 mg, 1-50 mmol) treatment. The mixture was heated to reflux for 2 hours, cooled, the product crystallized from the solution and collected by filtration. The crude product was washed with ether and dried in vacuo to obtain a white solid. The residue was combined with a white solid, which was dissolved in toluene (50 and treated with p-toluenesulfonic acid monohydrate (100 mg, 0.75 mm)). The mixture was heated to reflux for 3 hours, cooled and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with pentane: ethyl acetate 80:20 to 40:60 to give the title product, 12.0 g. 1 leg MR (CDC13, 400 μ ζ) δ: 2.61 (s, 3 H), 7.62 (d, 2 H), 95339.doc -66- 200526606 7.88 (d, 2 Η). MS ES + m / z 239 [ΜΗ] Preparation 5 3- (4_ desert . Yl) -4_ (4_ _ methoxy phenyl) methyl _5- 4Η- [1,2 4] triazolo

於製備4之產物（5.00 g，20.9 mmol)中，加入二甲苯（150 mL)中之對甲苯磧酸單水合物（1〇〇 mg，〇·75 mmol)及4-甲氧 _ 基苯基胺（7.70 g，62_5 mmol)之溶液，且於150°C加熱反應混合物22小時。於真空中濃縮反應混合物且將殘餘物溶解於二氯甲烷中且藉由管柱層析法於矽膠上以1 〇〇:〇:〇至 97:3:0.3之二氯甲烷：甲醇：〇·88氨水洗提來純化以得標題產物，7.05 g 〇 ^NMR (DMSO-D6? 400 MHz) δ: 2.20 (s? 3 Η), 3.81 (s5 3 H)，7·07 (m，2 H)，7·28 (m，2 H)，7·34 (m，2 H)，7.56 (m，2 H)。 MS APCI+ m/z 344 [MH]+ 參製備6 5-溴-吡啶-2-羧酸醯肼To the product of Preparation 4 (5.00 g, 20.9 mmol), p-toluenic acid monohydrate (100 mg, 0.75 mmol) and 4-methoxy-phenylphenyl in xylene (150 mL) were added. A solution of amine (7.70 g, 62-5 mmol), and the reaction mixture was heated at 150 ° C for 22 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and purified by column chromatography on silica with 100: 00: 00 to 97: 3: 0.3: dichloromethane: methanol: 88 ammonia was eluted to purify to give the title product, 7.05 g NMR (DMSO-D6? 400 MHz) δ: 2.20 (s? 3 Η), 3.81 (s5 3 H), 7.07 (m, 2 H) , 7.28 (m, 2 H), 7.34 (m, 2 H), 7.56 (m, 2 H). MS APCI + m / z 344 [MH] + Reference Preparation 6 5-Bromo-pyridine-2-carboxylic acid hydrazine

將5-溴-吡啶-2-羧酸甲基酯（J. (9rg· 2001，66(2)， 605-608，化合物 4)(18.10 g，83 mmol)及肼單水合物（12,5 mL，25 0 mmol)溶解於曱醇（400 mL)中，且將反應混合物加 95339.doc -67- 200526606 熱至回流48小時。隨後過濾反應混合物且於真空中乾燥收集之沈澱物以得標題產物，15.40 g。 !ΗΝΜΚ (DMSO-D65 400 MHz) δ: 4.57 (d? 2 Η)5 7 91 (m 1 Η)，8·22 (m，1 Η)，8·72 (m，1 Η)，9·98 (m，1 Η)。MS ES + m/z 217 [ΜΗ] + 製備7 5-氣_吡嗪-2-羧酸醯肼5-Bromo-pyridine-2-carboxylic acid methyl ester (J. (9rg. 2001, 66 (2), 605-608, compound 4) (18.10 g, 83 mmol) and hydrazine monohydrate (12,5 mL, 25 0 mmol) was dissolved in methanol (400 mL), and the reaction mixture was heated to reflux at 95339.doc -67- 200526606 for 48 hours. The reaction mixture was then filtered and the collected precipitate was dried in vacuo to give the title Product, 15.40 g.! ΗNMK (DMSO-D65 400 MHz) δ: 4.57 (d? 2 Η) 5 7 91 (m 1 Η), 8.22 (m, 1 Η), 8.72 (m, 1 Η) ), 9.98 (m, 1 Η). MS ES + m / z 217 [ΜΗ] + Preparation 7 5-Gas_pyrazine-2-carboxylic acid hydrazine

藉由製備6之方法使用5-氯-吡嗪-2-羧酸甲基酯製備標題化合物。製得5.01 g、50%產率之所需產物。 hNMR (CDC13, 400 ΜΗζ) δ: 4.09 (d，2 H)，8.52 (S，1 H)， 8·66 (bs，1 Η)，9_14 (s，1 Η)。微量分析：c5h5CIN4〇，要求： C 34·80，Η 2.92; N 32·47 ;實驗值 C 34.89; Η 2.91，N 32.32。 MS APCI+ m/z 173 [MH] +The title compound was prepared by the method of Preparation 6 using 5-chloro-pyrazine-2-carboxylic acid methyl ester. The desired product was obtained in 5.01 g and 50% yield. hNMR (CDC13, 400 MΗζ) δ: 4.09 (d, 2 H), 8.52 (S, 1 H), 8.66 (bs, 1 Η), 9_14 (s, 1 Η). Microanalysis: c5h5CIN4〇, requirements: C 34 · 80, Η 2.92; N 32 · 47; experimental value C 34.89; Η 2.91, N 32.32. MS APCI + m / z 173 [MH] +

製備f 5-溴-吡啶羧酸N，_(2_甲氧基_乙醯基）醯肼Preparation of f 5-bromo-pyridinecarboxylic acid N, _ (2_methoxy_ethylfluorenyl) hydrazine

BrBr

ch3 將製備6之產物（2·〇 g，9·3 mm〇i)&N•甲基嗎啉（13 ， 12·〇 mmol)溶解於二氯曱烷（6〇 mL)中且以甲氧基乙醯氣 (868 μί ’ 9.50 mmol)處理該溶液。將反應混合物於室温攪掉5小時且隨後以水洗滌且於真空中濃縮以得2·41 g，90產 95339.doc -68 - 200526606 率之標題產物。 1HNMR (CDC13, 400 ΜΗζ) δ: 3.46 (s，3 Η)，4·07 (s，2 H)， 7.98 (dd，1 Η)，8.02 (dd，1 Η)，8.61 (d，1 Η)，8·89 (d，1 Η)， 9·95 (d，1 Η)。MS ES+ m/z 289 [ΜΗ] + 製備9 6-氣-煙酸Ν’-(2-甲氧基-乙醯基）-醯肼ch3 The product of Preparation 6 (2.0 g, 9.3 mmi) & N • methylmorpholine (13, 12 · mmol) was dissolved in dichloromethane (60 mL) and The solution was treated with oxyacetamidine (868 μL '9.50 mmol). The reaction mixture was stirred at room temperature for 5 hours and then washed with water and concentrated in vacuo to give 2.41 g of the title product with a yield of 95339.doc -68-200526606. 1HNMR (CDC13, 400 ΜΗζ) δ: 3.46 (s, 3 Η), 4.07 (s, 2 H), 7.98 (dd, 1 Η), 8.02 (dd, 1 Η), 8.61 (d, 1 Η) , 8.89 (d, 1 Η), 9.95 (d, 1 Η). MS ES + m / z 289 [ΜΗ] + Preparation 9 6-Gas-nicotinic acid N ′-(2-methoxy-ethylfluorenyl) -hydrazine

藉由製備8之方法使用6-氯煙酸醯肼製備標題產物。製得 19.0 g、90%產率之所需產物。 ]HNMR (CDC13? 400 ΜΗζ) δ: 3.36 (s? 3 Η)? 3.97 (s5 2 Η)? 7.68 (d，1 Η)，8.26 (dd，1 Η)，8.84 (s，1 Η)，9.99 (s，1 Η)， 10.61 (s，1 Η)。MS ES+ m/z 246 [ΜΗ] + 製備10 5-氣-吡嗪-2-羧酸Nf-(2-甲氧基-乙醯基）·醯肼The title product was prepared by the method of Preparation 8 using hydrazine 6-chloronicotinate. 19.0 g of the desired product were obtained in 90% yield. ] HNMR (CDC13? 400 ΜΗζ) δ: 3.36 (s? 3 Η)? 3.97 (s5 2 Η)? 7.68 (d, 1 Η), 8.26 (dd, 1 Η), 8.84 (s, 1 Η), 9.99 (s, 1 Η), 10.61 (s, 1 Η). MS ES + m / z 246 [ΜΗ] + Preparation 10 5-Gas-pyrazine-2-carboxylic acid Nf- (2-methoxy-ethylamyl) · hydrazine

藉由製備8之方法使用製備7之醯肼來製備標題產物。製得3.90 g，70%產率之所需產物。 MS APCI+ m/z 245 [MH] + 製備11 5-氣-吡嗪·2-羧酸Ν’-乙醯基-醯肼 95339.doc -69- 200526606 ΟThe title product was prepared by the method of Preparation 8 using the hydrazine of Preparation 7. This gave 3.90 g of the desired product in 70% yield. MS APCI + m / z 245 [MH] + Preparation 11 5-Gas-Pyrazine · 2-Carboxylic Acid N′-Ethyl-Hydrazine 95339.doc -69- 200526606 Ο

ίτγ cr 藉由製備8之方法使用製備7之醯肼及乙醯氯來製備襟題產物。製得4.0g、64%產率之所需產物。不、 MS APCI+ m/z 215 [MH] + 製備12 5_溴·吡啶_2-羧酸N，-(2-氣-乙醯基）-醯肼Γτγ cr The title product was prepared by the method of Preparation 8 using the hydrazine and acetamidine of Preparation 7. 4.0 g of the desired product were obtained in 64% yield. No, MS APCI + m / z 215 [MH] + Preparation of 12 5_bromo · pyridine_2-carboxylic acid N,-(2-gas-ethylfluorenyl) -hydrazine

BrBr

藉由製備8之方法使用製備6之醯肼及氯乙醯氯來製備標題產物。製得4·3〇 g、π。/。產率之所需產物。 HNMR (CDC13, 400 ΜΗζ) δ: 4.20 (s，2 H)，8.00 (d，1 H)， 8·30 (d，1 H)，8·80 (s，1 H)，10.40 (s，1 H)，10·70 (s5 1 h)。 MS APCI+ m/z 293 [MH] + 製備liThe title product was prepared by the method of Preparation 8 using hydrazine and chloroacetamidine chloride of Preparation 6. 4.30 g, π were obtained. /. Yield of desired product. HNMR (CDC13, 400 ΜΗζ) δ: 4.20 (s, 2 H), 8.00 (d, 1 H), 8.30 (d, 1 H), 8.80 (s, 1 H), 10.40 (s, 1 H), 10 · 70 (s5 1 h). MS APCI + m / z 293 [MH] + Preparation

5e>臭_2-(5·甲氧基甲基-[1，3,4】噁二唑-2-基）-吡啶5e > Odor_2- (5 · methoxymethyl- [1,3,4] oxadiazol-2-yl) -pyridine

SCH, 將製備8之產物（2·41 g，8.4 mmol)與***（7 mL)組合且於ΠΟΧ：加熱4小時。於真空中濃縮反應混合物且將殘餘物’谷解於乙酸乙酯及水中。藉由添加10%碳酸鈉溶液中和混合物且將各相分離。以乙酸乙酯萃取水相且於硫酸鎂上乾燥經組合之有機物且於真空中濃縮。藉由管柱層析法於 95339.doc -70- 200526606 矽膠柱上以乙酸乙酯洗提來純化殘餘物以得標題產物， 1.01 g，45%產率。 iHNMR (CDC13, 400 ΜΗζ) δ: 3.48 (s，3 H)，4.73 (s，2 H)， 8.01 (dd5 1 Η), 8·12 (dd，1 Η)，8·81 (dd，1 Η)。MS APCI+ m/z 272 [ΜΗ] + 製備14 2-氣_5_(5·甲氧基甲基[1，3,4】噁二唑-2-基）-吡啶SCH, the product of Preparation 8 (2.41 g, 8.4 mmol) was combined with phosphorus oxychloride (7 mL) and heated at ΙΟχ: for 4 hours. The reaction mixture was concentrated in vacuo and the residue was triturated in ethyl acetate and water. The mixture was neutralized by adding a 10% sodium carbonate solution and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a 95339.doc -70- 200526606 silica gel column with ethyl acetate to give the title product, 1.01 g, 45% yield. iHNMR (CDC13, 400 ΜΗζ) δ: 3.48 (s, 3 H), 4.73 (s, 2 H), 8.01 (dd5 1 Η), 8.12 (dd, 1 Η), 8.81 (dd, 1 Η) ). MS APCI + m / z 272 [ΜΗ] + Preparation 14 2-Gas_5_ (5 · methoxymethyl [1,3,4] oxadiazol-2-yl) -pyridine

藉由製備13之方法使用製備9之產物來製備標題產物，得到7.93 g、40%產率之作為鏽棕色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 3.52 (S，3 Η)，4·74 (s，2 H)， 7.50 (d，1 Η)，8.32 (dd，1 Η)，9·06 (d，1 Η)。微量分析： C9H8C1N302需要：C 47.91; Η 3_57; Ν 18.62 ;實驗值C 47·75; Η 3.50, Ν 18.46。MS APCI+ m/z 226 [ΜΗ] + 製備15 2-氣_5-(5-甲氧基甲基-[^4]噁二唑基 > 吡嗓The title product was prepared by the method of Preparation 13 using the product of Preparation 9 to obtain 7.93 g of the title compound as a rusty brown solid in 40% yield. iHNMR (CDC13, 400 ΜΗζ) δ: 3.52 (S, 3 Η), 4.74 (s, 2 H), 7.50 (d, 1 Η), 8.32 (dd, 1 Η), 9.06 (d, 1 Η). Microanalysis: C9H8C1N302 requires: C 47.91; Η 3_57; Ν 18.62; experimental value C 47 · 75; Η 3.50, Ν 18.46. MS APCI + m / z 226 [ΜΗ] + Preparation 15 2-Gas 5- (5-methoxymethyl-[^ 4] oxadiazolyl >

藉由製備13之方法使用製備10之產物來製備標題產物。製仟1_38 g、38%產率的作為淺棕色固體之所需產物。 'HNMR (CDC13, 400 ΜΗζ) δ: 3.52(s, 3 Η), 4.78 (s, 2 Η) (s, 1 Η), 9.25 (s, 1 Η) ° MS APCI+ m/z 227 [ΜΗ] + 95339.doc -71 - 200526606 製備16 2-氣_5_(5-甲基·μ)，*]噁二唑_2基）比嗪The product of Preparation 10 was used to prepare the title product by the method of Preparation 13. The desired product was prepared as a light brown solid in a yield of 1-38 g, 38%. 'HNMR (CDC13, 400 ΜΗζ) δ: 3.52 (s, 3 Η), 4.78 (s, 2 Η) (s, 1 Η), 9.25 (s, 1 Η) ° MS APCI + m / z 227 [ΜΗ] + 95339.doc -71-200526606 Preparation 16 2-Gas_5_ (5-methyl · μ), *] oxadiazole_2yl) biazine

’ u 製備13之方法使用製備11之產物來製備標題產物。 1^30 g、35%產率之作為棕色固體之所需產物。 HNMR (CDCl3,伽 ΜΗζ) δ·· 2·68 (s，3 H)，8 7 9-22 (s, 1 Η) 〇 MS APCI+ m/z 197 [MH]+ ’The method of Preparation 13 uses the product of Preparation 11 to prepare the title product. 1 ^ 30 g, 35% yield of the desired product as a brown solid. HNMR (CDCl3, gamma ΜΗζ) δ ·· 68 · (s, 3 H), 8 7 9-22 (s, 1 Η) 〇 MS APCI + m / z 197 [MH] + ’

製備17 5溴2-(5-氣甲基_[1，3,4】噁二唑_2基）吼啶Preparation of 17 5Br 2- (5-Gasmethyl_ [1,3,4] oxadiazole_2yl) pyridine

/曰藉由製備13之方去使用製備12之產物來製備標題產物。付到2·3 §、57%產率的作為白色固體之所需產物。 HNMR (DMSO-D6) 400 MHz) δ: 4.80(s? 2 Η), 8.05 (d5 1 ΗUse the product of Preparation 12 to prepare the title product by the method of Preparation 13. The desired product was obtained as a white solid in a 2.3% §, 57% yield. HNMR (DMSO-D6) 400 MHz) δ: 4.80 (s? 2 Η), 8.05 (d5 1 Η

(d, 1 H)，8.85 (s，1 η)。MS APCI+ m/z 276 [MH] + 製備1} /臭2 [5-(甲氧基甲基)_4气6甲氧基吡啶基Mu# ***-3-基】吡咬(d, 1 H), 8.85 (s, 1 η). MS APCI + m / z 276 [MH] + Preparation 1} / Smell 2 [5- (methoxymethyl) _4 gas 6methoxypyridyl Mu # triazol-3-yl] pyridine

95339.doc -72- 200526606 將製備13之產物（1.01 g，3.74 mmol)、5-胺基-2-甲氧基吡啶（1·40 g，11·3 mmol)及對甲苯磺酸單水合物（5〇mg，〇37 mm〇1)溶解於二甲苯（25mL)中，且於15〇t：加熱反應混合物 23小日守。於真空中濃縮反應混合物且藉由管柱層析法於矽膠上以100··0至90:10之二氯甲烷··甲醇洗提來純化殘餘物以仟作為紫色膠狀物之標題產物，1 · 〇 g，72 %產率，。 ^NMR (CDC13? 400 MHz) δ: 3.32 (s? 3 Η)5 3.99 (s? 3 Η)5 4.46 (s，2 Η)，6.82 (d，1 Η)，7.54 (dd，1 Η)，7.90 (dd，1 Η)， 8.05 (d? 1 Η)? 8.13 (d, 1 Η)? 8.37 (d? 1 Η) 〇 MS ES+ m/z 398 · [ΜΗ] + 製備19 2-(4-氟-2-甲基-苯基）·5-(5_ψ氧基甲基β[1，3,4】噁二唑_2_ 基）-°比咬95339.doc -72- 200526606 The product of Preparation 13 (1.01 g, 3.74 mmol), 5-amino-2-methoxypyridine (1.40 g, 11.3 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.37 mm) was dissolved in xylene (25 mL), and at 150 t: the reaction mixture was heated for 23 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel with 100 ·· 0 to 90:10 dichloromethane ·· methanol to purify the residue as the title product of purple gum, 1.0 g, 72% yield. ^ NMR (CDC13? 400 MHz) δ: 3.32 (s? 3 Η) 5 3.99 (s? 3 Η) 5 4.46 (s, 2 Η), 6.82 (d, 1 Η), 7.54 (dd, 1 Η), 7.90 (dd, 1 Η), 8.05 (d? 1 Η)? 8.13 (d, 1 Η)? 8.37 (d? 1 Η) 〇MS ES + m / z 398 · [ΜΗ] + Preparation 19 2- (4- Fluoro-2-methyl-phenyl) · 5- (5_ψoxymethylβ [1,3,4] oxadiazole_2_yl)-° specific bite

苯基侧酸（3 61 mg，2.65 mmol)、製備3之鈀複合物（1〇 mg，觸媒）及碳酸铯（2.16 g，6.66 mmol)溶解於ι，4-二噁烷（1〇 mL) 且將反應混合物加熱至回流2小時。加入額外之鈀複合物 (1 〇 mg)且使反應混合物回流進一步之丨小時。於真空中濃細反應混合物且將殘餘物溶解於乙酸乙酯及水中。分離各相且以鹽水洗滌乙酸乙酯相、於硫酸鎂上乾燥且於真空中濃縮以得標題產物，690 mg，以定量產率。將製備14之氣化合物（500 mg，2·22 mm〇1)、4_氟_2_甲基 95339.doc -73- 200526606 MS APCI+ m/z 300 [MH] + 製備20 2-(2,3-二甲基-苯基）_s_(5_甲氧基甲基丨13 4】噁二唑基比咬Phenyl pentic acid (3 61 mg, 2.65 mmol), the palladium complex of Preparation 3 (10 mg, catalyst) and cesium carbonate (2.16 g, 6.66 mmol) were dissolved in ι, 4-dioxane (10 mL ) And the reaction mixture was heated to reflux for 2 hours. Additional palladium complex (10 mg) was added and the reaction mixture was refluxed for a further hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title product, 690 mg, in quantitative yield. The gas compound of Preparation 14 (500 mg, 2.22 mm〇1), 4-fluoro_2_methyl 95339.doc -73- 200526606 MS APCI + m / z 300 [MH] + Preparation 20 2- (2, 3-dimethyl-phenyl) _s_ (5_methoxymethyl 丨 13 4) oxadiazolyl ratio

藉由製備19之方法使用2,3_二甲基苯基硼酸（399 mg，12 ⑷及製備14之產物（500 mg，2.22 mm〇1)來製備標題產物。製得712 mg、定量產率之所需產物。The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid (399 mg, 12 ⑷, and the product of Preparation 14 (500 mg, 2.22 mm). 712 mg, quantitative yield Rate of desired product.

MS APCI+ m/z 296 [MH] + 製備21 2-(2,3-二甲基_苯基）_5_(5-甲氧基甲基丨噁二唑_2_ 基）-«比嗪MS APCI + m / z 296 [MH] + Preparation 21 2- (2,3-dimethyl_phenyl) _5_ (5-methoxymethyl 丨 oxadiazole_2_yl)-«biazine

ch3 藉由製備19之方法使用2,3-二甲基苯基硼酸及製備15之氯化合物來製備標題產物。製得466 ing、定量產率之所需產物。 ]HNMR (CDC13) 400 MHz) δ: 2.29 (s5 3 Η)? 2.39 (s5 3 Η) 3.52 (s，3 Η)，4.78 (s，2 Η)，7·23-7·37 (m，3 Η)，8·84 (s，1 η) 9·54 (s，1 η) 〇 MS APCI+ m/z 297 [ΜΗ] + 95339.doc -74- 200526606 製備22 2_(4_氟甲基-苯基）-5-(5-甲氧基甲基_[1，3,4]噁二唑基）-吼唤ch3 The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid and the chlorine compound of Preparation 15. The desired product was obtained in 466 ing, quantitative yield. ] HNMR (CDC13) 400 MHz) δ: 2.29 (s5 3 Η)? 2.39 (s5 3 Η) 3.52 (s, 3 Η), 4.78 (s, 2 Η), 7.23-7 · 37 (m, 3 Η), 8.84 (s, 1 η) 9.54 (s, 1 η) 〇MS APCI + m / z 297 [ΜΗ] + 95339.doc -74- 200526606 Preparation 22 2_ (4_fluoromethyl-benzene ) -5- (5-methoxymethyl_ [1,3,4] oxadiazolyl)-roar

藉由製備19之方法使用4-氟-2-甲基-苯基硼酸及製備15 之氯化合物來製備標題產物。製得450 mg、97%之所需產物。 MS APCI+ m/z 3〇1 [MH] + 製備八(2,3·二子基·苯基）-5_(5-甲基-[1，3,4】噁二唑-2-基）-吡嗪The title product was prepared by the method of Preparation 19 using 4-fluoro-2-methyl-phenylboronic acid and the chlorine compound of Preparation 15. 450 mg, 97% of the desired product was obtained. MS APCI + m / z 3〇1 [MH] + Preparation of octa (2,3 · dionyl · phenyl) -5_ (5-methyl- [1,3,4] oxadiazol-2-yl) -pyridine Azine

藉由製備19之方法使用2,3-二甲基苯基硼酸及製備16之氯化合物來製備標題產物。製得404 mg、定量產率之所需產物。MS APCI+ m/z 267 [MH] + 2_(4-氟-2-甲基-苯基）_5_(5•甲基β[1，3,4】噁二唑基）吡嗪The title product was prepared by the method of Preparation 19 using 2,3-dimethylphenylboronic acid and the chlorine compound of Preparation 16. The desired product was obtained in a quantitative yield of 404 mg. MS APCI + m / z 267 [MH] + 2_ (4-fluoro-2-methyl-phenyl) _5_ (5 • methylβ [1,3,4] oxadiazolyl) pyrazine

稭由製備19之方法使用4-氟-2-甲基-苯基硼酸及製備16 95339.doc 200526606 之氯化合物來製備標題產物。製得377 mg、定量產率之所需產物。 MS APCI+ m/z 271 [MH] + 製備25 1-[5-(5-溴-吡啶基）_[1，3,4】噁二唑_2-基甲基】-吡咯啶 _(2S)-2-羧酸醯胺The title product was prepared by the method of Preparation 19 using 4-fluoro-2-methyl-phenylboronic acid and the chlorine compound of Preparation 16 95339.doc 200526606. The desired product was obtained in a quantitative yield of 377 mg. MS APCI + m / z 271 [MH] + Preparation 25 1- [5- (5-Bromo-pyridyl) _ [1,3,4] oxadiazol_2-ylmethyl] -pyrrolidine_ (2S) Sulfanilamide

將製備17之氯化合物（5〇〇 mg，182 mm〇1)及（s)_脯胺酸酉如胺（3 12 mg，2.73 mmol)溶解於乙腈（1〇 mL)且以碳酸鉀 (503 mg，3·64 mmol)處理混合物。於室溫攪拌反應混合物 18小B守且隨後於5〇〇c攪拌2小時。於真空中濃縮反應混合物且將殘餘物分隔於乙酸乙酯與水之間。濾出形成之沈澱物且以水、1 Μ氫氧化鈉溶液及鹽水洗滌濾出液之有機層。隨後灰真空中濃縮有機層以得標題產物，540 mg，84❶/〇產率。 HNMR (DMSO-D6, 400 ΜΗζ) δ: 1.70 (m，3 H)，2.00 (m， 1 H)，2·60 (m，1 H)，3·1〇 (m，1 H)，3.20 (m，1 H)，4.00 (d， 1 H)，4.20 (d，1 H)，7.〇〇-7·2〇 (d，2 H)，8.10 (d，1 H)，8.30 (d， 1 H)，8.90 (s，i H)。製備26 5-溴-2-(5-吡咯啶el_基甲基噁二唑_2基卜吡啶The chlorine compound (500 mg, 182 mm) and (s) -proline amine (3 12 mg, 2.73 mmol) in Preparation 17 were dissolved in acetonitrile (10 mL) and potassium carbonate (503 mg, 3.64 mmol). The reaction mixture was stirred at room temperature for 18 hours and then stirred at 500c for 2 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The formed precipitate was filtered off and the organic layer of the filtrate was washed with water, 1 M sodium hydroxide solution and brine. The organic layer was then concentrated in ash vacuum to give the title product, 540 mg, 84❶ / 0 yield. HNMR (DMSO-D6, 400 ΜΗζ) δ: 1.70 (m, 3 H), 2.00 (m, 1 H), 2.60 (m, 1 H), 3.10 (m, 1 H), 3.20 ( m, 1 H), 4.00 (d, 1 H), 4.20 (d, 1 H), 7.0-7.2-2.0 (d, 2 H), 8.10 (d, 1 H), 8.30 (d, 1 H), 8.90 (s, i H). Preparation 26 5-bromo-2- (5-pyrrolidine el_ylmethyloxadiazole_2ylpyridine

95339.doc 200526606 於室溫下將吡咯啶（324 mg，0.3 8 mL，4.56 mmol)添加至乙腈（15 mL)中之製備17之氯化合物（500 mg，1.82 mmol) 之經授拌之溶液中。攪拌18小時後，於真空中濃縮反應混合物且將殘餘物溶解於乙酸乙酯（5〇中且以2 Μ氫氧化納水溶液洗滌，繼而以水繼而以鹽水洗滌。經硫酸鈉乾燥有機相、過濾且於真空中濃縮以得4〇7 mg、72%產率之標題化合物。 ^NMR (CDC135 400 MHz) δ: 1.90 (m, 4 Η), 2.70 (m, 4 Η)? 4·〇〇 (s，2 Η)，8.00 (d，1 Η)，8·20 (d，1 Η)，8.80 (s，1 Η)。製備27 ^[5-(5-漠比唆 _2-基）-4-(6_ 甲氧基-吼唆-3-基）-4Η·[1，2,4] 二唾_3_基甲基]·吡咯啶_(2S)-2-羧酸醯胺95339.doc 200526606 Add pyrrolidine (324 mg, 0.3 8 mL, 4.56 mmol) to an acetonitrile (15 mL) prepared solution of the 17-chlorine compound (500 mg, 1.82 mmol) in acetonitrile (15 mL) at room temperature. . After stirring for 18 hours, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 and washed with 2M aqueous sodium hydroxide solution, followed by water and then brine. The organic phase was dried over sodium sulfate, filtered And concentrated in vacuo to give 407 mg, 72% yield of the title compound. ^ NMR (CDC135 400 MHz) δ: 1.90 (m, 4 Η), 2.70 (m, 4 Η)? 4.〇〇 ( s, 2 Η), 8.00 (d, 1 Η), 8.20 (d, 1 Η), 8.80 (s, 1 Η). Preparation 27 ^ [5- (5- 漠比唆 _2- 基)- 4- (6_Methoxy-methyl-3-yl) -4Η [[1,2,4] disialyl-3-ylmethyl] · pyrrolidine_ (2S) -2-carboxylic acid sulfonamide

將製傷25之產物（5〇〇 mg，1.20 mmol)及5-胺基-2-甲氧基吡啶（224 mg，1.81 mmol)溶解於二曱苯（15 mL)中且以觸媒性對甲苯磺酸單水合物處理該溶液且將其加熱至回流18小時。於真空中濃縮反應混合物且將殘餘物溶解於乙酸乙酯中且以水、2 Μ檸檬酸溶液、2 Μ氫氧化鈉溶液洗滌，於硫 &L鎂上乾燥且於真空中濃縮。藉由管柱層析法於矽膠上以 100:0至95:5之二氯曱烷··甲醇洗提來純化殘餘物以得標題 95339.doc -77- 200526606 產物，252 mg，46°/。產率。 !HNMR (CDC13, 400 MHz) 5: 1.80 (m，2 H)，2.20(m，1 H)， 2.60 (m，1 H)，3.10(m，1 H)，3.20 (m，1 H)，3_90 (m，2 H)， 4.00 (s，3 H)，5.00 (s，l h)，6.70 (s，1 H)，6.90 (d，1 H)，7.90 (d，1 H)，8.05 (d，1 H)，8.20 (d，1 H)，8·40 (s，1 H)。MS ES + m/z 458 [MH] + 製備28 5-溴-2_(((5_吡咯啶基甲基）-‘(6_甲氧基吡啶-3-基））·4Η-[1，2,4】***-3_基）-吼啶The product from wound 25 (500 mg, 1.20 mmol) and 5-amino-2-methoxypyridine (224 mg, 1.81 mmol) were dissolved in diphenylbenzene (15 mL) and the catalyst was used as a catalyst. This solution was treated with tosylate monohydrate and heated to reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with water, 2M citric acid solution, 2M sodium hydroxide solution, dried over sulfur & L magnesium and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane · methanol 100: 0 to 95: 5 to give the title 95339.doc -77- 200526606 product, 252 mg, 46 ° / . Yield. ! HNMR (CDC13, 400 MHz) 5: 1.80 (m, 2 H), 2.20 (m, 1 H), 2.60 (m, 1 H), 3.10 (m, 1 H), 3.20 (m, 1 H), 3_90 (m, 2 H), 4.00 (s, 3 H), 5.00 (s, lh), 6.70 (s, 1 H), 6.90 (d, 1 H), 7.90 (d, 1 H), 8.05 (d , 1 H), 8.20 (d, 1 H), 8.40 (s, 1 H). MS ES + m / z 458 [MH] + Preparation 28 5-bromo-2 _ (((5-pyrrolidinylmethyl)-'(6-methoxypyridin-3-yl)) · 4Η- [1, 2,4] triazol-3_yl) -amidine

藉由製備27之方法使用製備26之產物製備412 mg、77% 產率之標題化合物。 MS ES+ m/z 417 [MH] + 製備29 甲基_4-(4,4,5,5_四甲基_[1，3,2】二氧硼_2_基）_苄腈The title compound was prepared by the method of Preparation 27 using the product of Preparation 26 in 412 mg, 77% yield. MS ES + m / z 417 [MH] + Preparation 29 Methyl_4- (4,4,5,5_tetramethyl_ [1,3,2] dioxoboro_2_yl) _benzonitrile

將乙酸鈀（II) (224 mg，5 mol%)、乙酸鉀（3.68 g，61.2 mmol) 及雙（戊醯）二硼添加至N，N-二甲基甲醯胺（40 mL)中之1-溴 95339.doc -78- 200526606 -4-氰基-2-甲基苯（4〇 g，2〇 4 mm〇i)之溶液中，且於阶加熱18小時”匕時間後冷卻該混合物且藉由一。出，墊過 /慮以乙&乙®曰及水洗膝。分離有機相，經硫酸納乾燥且於真空中Hx得棕色固體。藉由於戊炫中研磨來純化該固體/慮及乾無以得作為米色固體之標題化合物（2別g ，54%產率）。 HNMR (CDC135 400 MHz) δ: 1.35 (s? 12 Η), 2.55 (s5 3 H)3 7.41-7.45 (m5 2 H)，7·82 (d，1 H)。MS APCI+ m/z 261 [MNH4] + 製備30 2_ 氣-5·[4_(6- T 氧基比唆-3-基）-5-甲基-4H-[1，2,4】***·3-基】-β比嗓Add palladium (II) acetate (224 mg, 5 mol%), potassium acetate (3.68 g, 61.2 mmol) and bis (pentamidine) diboron to N, N-dimethylformamide (40 mL) 1-bromo 95339.doc -78- 200526606 in a solution of 4-cyano-2-methylbenzene (40 g, 204 mm), and the mixture was cooled after 18 hours of stage heating. And by one, the pads were washed / washed with B & B®, and the knees were washed with water. The organic phase was separated, dried over sodium sulfate, and Hx in vacuum to obtain a brown solid. The solid was purified by trituration in pentamine The title compound was obtained as a beige solid (2 g, 54% yield) taking into account dryness. HNMR (CDC135 400 MHz) δ: 1.35 (s? 12 Η), 2.55 (s5 3 H) 3 7.41-7.45 ( m5 2 H), 7.82 (d, 1 H). MS APCI + m / z 261 [MNH4] + Preparation of 30 2_ GA-5 · [4_ (6- T oxobi-3-yl) -5- Methyl-4H- [1,2,4] triazole · 3-yl] -β

藉由製備18之方法使用製備丨6之噁二唑化合物及5-胺基 -2-曱氧基吡啶製備標題產物。製得4.3 g、44%產率之作為米色固體之所需產物。 lHNMR (CDC13? 400 MHz) δ: 2.36 (s? 3 Η)? 3.99 (s, 3 Η), 6·86 (d，1 Η)，7.45 (dd，1 Η)，8·02 (d，1 Η)，8.27 (d，1 Η), 9.23(d，1 Η)。製備31 2-氣-5-[5_甲氧基甲基_4_(6_甲氧基^比啶_3_基）-4Η_[1，2,4] 95339.doc 200526606 二唾_3_基卜n比嗓The title product was prepared by the method of Preparation 18 using the oxadiazole compound of Preparation 6 and 5-amino-2-methoxypyridine. The desired product was obtained as a beige solid in 4.3 g, 44% yield. lHNMR (CDC13? 400 MHz) δ: 2.36 (s? 3 Η)? 3.99 (s, 3 Η), 6.86 (d, 1 Η), 7.45 (dd, 1 Η), 8.02 (d, 1 Η), 8.27 (d, 1 Η), 9.23 (d, 1 Η). Preparation 31 2-Gas-5- [5_methoxymethyl_4_ (6_methoxy ^ pyridin_3_yl) -4Η_ [1,2,4] 95339.doc 200526606 disial Kibble

H3C - 〇藉由製備1 8之方法使用製備15之噁二唑化合物及胺基 -2-甲氧基吡啶製備標題產物。製得1〇·5 g、59%產率之作為米色固體之所需產物。 ^NMR (CDC135 400 MHz) δ: 3.33 (s? 3 Η), 3.99 (s? 3 Η), 4·47 (s，2 Η)，6·83 (d，1 Η)，7.53 (dd，1 Η)，8·06 (d，1 Η)， 8·30 (d，1 Η)，9.25 (d，1 Η)。MS APCI+ m/z 333 [ΜΗ] + 製備32 2-(5-敗-2-甲氧基-苯基）_5-(5_甲氧基甲基413,4]噁二唑基）-β比唆H3C-〇 The title product was prepared by the method of Preparation 18 using the oxadiazole compound of Preparation 15 and amine-2-methoxypyridine. 10.5 g of 59% yield of the desired product was obtained as a beige solid. ^ NMR (CDC135 400 MHz) δ: 3.33 (s? 3 Η), 3.99 (s? 3 Η), 4.47 (s, 2 Η), 6.83 (d, 1 Η), 7.53 (dd, 1 Η), 8.06 (d, 1 Η), 8.30 (d, 1 Η), 9.25 (d, 1 Η). MS APCI + m / z 333 [ΜΗ] + Preparation 32 2- (5-Meta-2-methoxy-phenyl) _5- (5-methoxymethyl413,4] oxadiazolyl) -β ratio instigate

藉由製備19之方法使用5-氟-2-甲氧基-苯基硼酸（565 mg’3.33 mol)及來自製備14之氣化合物（500 mg，2.22 mmol) 製備標題產物。製得669 mg、96%產率之所需產物。】HNMR (CDC13, 400 ΜΗζ) δ: 3.51 (s，3 H)，3.88 (s，3 H)， 4·75 (s，2 Η)，6.97 (d，1 Η)，7.11 (m，1 Η)，7.70 (dd，1 Η)， 8·11 (d，1 Η)，8.37 (dd，1 Η)，9·34 (d，1 Η)。 95339.doc -80- 200526606 MS APCI+ m/z 316[MH] + 製備33 6-氣-煙酸N’-(2-氣-乙醯基醯肼The title product was prepared by the method of Preparation 19 using 5-fluoro-2-methoxy-phenylboronic acid (565 mg'3.33 mol) and the gaseous compound from Preparation 14 (500 mg, 2.22 mmol). The desired product was obtained in 669 mg, 96% yield. HNMR (CDC13, 400 ΜΗζ) δ: 3.51 (s, 3 H), 3.88 (s, 3 H), 4.75 (s, 2 Η), 6.97 (d, 1 Η), 7.11 (m, 1 Η) ), 7.70 (dd, 1 Η), 8.11 (d, 1 Η), 8.37 (dd, 1 Η), 9.34 (d, 1 Η). 95339.doc -80- 200526606 MS APCI + m / z 316 [MH] + Preparation 33 6-Gas-nicotinic acid N ’-(2-Gas-ethylfluorenylhydrazine

將氯乙醯氯（2.8 mL，34·9 mmol)逐滴添加至二氯甲烷 (100 mL)中之6-氯煙酸醯肼（5 g，29 ^ mm〇1)及仁甲基嗎啉 (4.8mL，43_7mm〇l)之冰***液中，且於室溫下攪拌反應3 小時。隨後濾出所得沈澱物，與二氣曱烷形成漿液，重過濾，以二氯甲烷（x3)洗滌並乾燥以得57%產率、41 g之作為米色固體之標題化合物。 !HNMR (DMSO-D6j 400 MHz) δ: 4.20 (s? 2 Η)? 7.68 (d? 1 Η)，8·23 (d，1 Η)，8.84 (m，1 Η)，1G.5G (s5 1 Η)，1G.83 (s，1 Η). MS APCI+ m/z 248/250 [ΜΗ] + 製備34 5·氣-吡嗪-2·羧酸氣-乙醯基）_醯肼Chloroacetylammonium chloride (2.8 mL, 34.9 mmol) was added dropwise to methylene hydrazine 6-chloronicotinate (5 g, 29 ^ mm〇1) and renmethylmorpholine in dichloromethane (100 mL). (4.8 mL, 43-7 mm) in an ice-cold solution, and the reaction was stirred at room temperature for 3 hours. The resulting precipitate was then filtered off, slurried with dioxane, refiltered, washed with dichloromethane (x3) and dried to give 57 g of the title compound as a beige solid in a yield of 41 g. ! HNMR (DMSO-D6j 400 MHz) δ: 4.20 (s? 2 Η)? 7.68 (d? 1 Η), 8.23 (d, 1 Η), 8.84 (m, 1 Η), 1G.5G (s5 1 Η), 1G.83 (s, 1 Η). MS APCI + m / z 248/250 [ΜΗ] + Preparation 34 5 · Ga-Pyrazine-2 · Carboxylic Acid-Acetyl) _Hydrazine

使用製備33之方法，自製備7之產物及氯乙醯氣製備作為固體之標題產物，3 7 %產率。 MS APCI+ m/z 249/251 [MH] + 製備35 6-氣-煙酸Ν’-乙醯基-醯肼 95339.doc -81 - 200526606Using the method of Preparation 33, the title product was prepared as a solid from the product of Preparation 7 and chloroacetamidine in a 37% yield. MS APCI + m / z 249/251 [MH] + Preparation 35 6-Gas-Nicotinic Acid N′-Ethyl-Hydrazine 95339.doc -81-200526606

使用製備33之方法，自6-氯煙酸醯肼及乙醯氯製備作為白色固體之標題產物，64%產率。 iHNMR (DMSO-D6, 400 ΜΗζ) δ·· 1.91 (s，3 H)，7.68 (d， 1 Η)? 8.24 (dd5 1 Η), 8.82 (d? 1 Η)? !〇.〇〇 (s> ! Η)? 1〇.58 (s5 1 Η) MS APCI+ m/z 214 [ΜΗ] + 製備36 氣-煙酸]V，-[2-(2-甲氧基·乙氧基）_乙醯基卜醯肼Using the method of Preparation 33, the title product was prepared as a white solid from hydrazine 6-chloronicotinate and acetamidine in 64% yield. iHNMR (DMSO-D6, 400 ΜΗζ) δ ·· 1.91 (s, 3 H), 7.68 (d, 1 Η)? 8.24 (dd5 1 Η), 8.82 (d? 1 Η)?! 〇.〇〇 (s >! Η)? 1 10.58 (s5 1 Η) MS APCI + m / z 214 [ΜΗ] + Preparation 36 gas-nicotinic acid] V,-[2- (2-methoxy · ethoxy) _ethyl Hydrazine

將（2-甲氧基-乙氧基）_乙醯氯（2l3g，13 99 rnm〇1)添加二氣甲烧（60 mL)中之6_氯煙酸醯耕（2 g，u 66麵叫及】甲基嗎琳（1.92 mL，17.49 mmol)之冰***液中，且於室; 下擾σ物1 8小時。隨後以碳酸氫納溶液處理該混^ 物且於真空中漢縮n甲院（χ2)萃取含水殘餘物且以】水^条經組合之有機溶液且經硫酸納乾燥且於真空中心、>夂《歹欠餘物。奴後於***中攪拌殘餘物2小時，過濾立乾燥以得51%產率、Ug作為淺黃固體之標題化合物/ 'HNMR (CDC13, 400 ΜΗζ) δ:3.46 (s, 3 Η), 3.62 (m, 2 Η； (，2 Η)，4.21 (S，2 Η)，7.42 (d，1 Η), 8.07 (dd，1 Η: (d, 1 Η) 9.28 (brs，ι η)，9.83 (brs，1 Η)。MS APCI+ m/ 288 [ΜΗ] + 製備37 95339.doc -82- 200526606 6-氣-煙酸N，-(2_乙氧基-乙醯基）_醯肼 C1(2-Methoxy-ethoxy) -acetamidine (2l3g, 13 99 rnm〇1) was added to 6-chloronicotinic acid plough (2 g, u 66 noodles) in digas methane (60 mL). Called] Methylmorphine (1.92 mL, 17.49 mmol) in an ice-cold solution, and stirred in the chamber for 18 hours. The mixture was then treated with sodium bicarbonate solution and reduced in a vacuum. (Χ2) extract the aqueous residue and extract the combined organic solution with water and dry with sodium sulfate and dry in a vacuum center, and then 歹歹 remaining residue. After that, stir the residue in ether for 2 hours and filter Drying immediately to obtain the title compound with 51% yield and Ug as a pale yellow solid / 'HNMR (CDC13, 400 ΜΗζ) δ: 3.46 (s, 3 Η), 3.62 (m, 2 Η; (, 2 Η), 4.21 (S, 2 Η), 7.42 (d, 1 Η), 8.07 (dd, 1 Η: (d, 1 Η) 9.28 (brs, ι η), 9.83 (brs, 1 Η). MS APCI + m / 288 [ ΜΗ] + Preparation 37 95339.doc -82- 200526606 6-Gas-nicotinic acid N,-(2-ethoxy-ethenyl) _hydrazine C1

CH 將（2-乙氧基）-乙醯氯[(172 g，13 99 mm〇1)，35, (39)，7269; 1994]添加至二氯甲烷（6〇 mL)中之6_氯煙酸醯肼（2 g，11.66 mmol)及N-曱基嗎啉（1.92 mL，17 49 mm〇1) 之冰***液中且於室溫下攪拌該混合物18小時。隨後以擰檬酸、碳酸氫鈉溶液及鹽水洗滌該混合物且於減壓下蒸發溶劑以得880 mg作為白色固體之一些標題產物。以乙酸乙酯（x2)萃取經組合之含水洗滌液且經硫酸鈉乾燥經組合之有機溶液且於真空中濃縮以得16 §作為淺黃固體之進一步批量之標題化合物（總產率為83%)。 ^NMR (CDC13, 400 MHz) δ: 1.21 (t, 3 Η), 3.55(ς, 2 Η), 4.06 (s, 2 Η), 7.38 (d, 1 Η), 8.00 (dd, 1 Η), 8.77(d, 1 Η) 8 99 (brs5lH),9.15(brs,lH)〇MSAPCI+ ^ 258/260 ^ 製備38至42 藉由製備13之方法使用適當醯肼（製備33_37)及*** 製備下文所示之通式之以下化合物。 αCH Add (2-ethoxy) -acetamidine chloride [(172 g, 13 99 mm 〇1), 35, (39), 7269; 1994] to 6-chloro in dichloromethane (60 mL) The mixture was stirred in an ice-cold solution of hydrazine nicotinate (2 g, 11.66 mmol) and N-fluorenylmorpholine (1.92 mL, 17 49 mm) at room temperature for 18 hours. The mixture was then washed with citric acid, sodium bicarbonate solution and brine and the solvent was evaporated under reduced pressure to give 880 mg of some of the title product as a white solid. The combined aqueous washings were extracted with ethyl acetate (x2) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo to give 16 § a further batch of the title compound as a pale yellow solid (total yield 83% ). ^ NMR (CDC13, 400 MHz) δ: 1.21 (t, 3 Η), 3.55 (ς, 2 Η), 4.06 (s, 2 Η), 7.38 (d, 1 Η), 8.00 (dd, 1 Η), 8.77 (d, 1 Η) 8 99 (brs5lH), 9.15 (brs, 1H) 〇MSAPCI + ^ 258/260 ^ Preparations 38 to 42 Prepared by the method of Preparation 13 using appropriate hydrazine (Preparation 33_37) and phosphorus oxychloride The following compounds of the general formula shown below. α

R2 95339.doc -83 - 200526606 序號 R2 Y 資料產率 38 C1 CH ^MRCCDCls, 400MHz) δ: 4.80(s，2H)，7.52(d，1H)，8.35(dd， 1H)，9.08(d，1H)· MS APCI+ m/z 230/232 [MH]+ 55% 39 C1 N 1HNMR(CDC13, 400MHz) δ: 4.83(s，2H)，8.76(s，1H)，9.36(s， 1H). MS APCI+ m/z 231/233 [MH]+ 38% 40 Η CH !HNMR(CDC13, 400MHz) δ: 2.66(s，3H)，7.51(d，1H)，8.31(d， lH)，9.02(s, 1H)_ 微量分析： C8H6CIN30 0.25 H20 需要：C 48.02; H 3.27; N 21.00 ;見：C 47.89; H 3.23, N 20.95. 77% 41 CH ^MRCCDCls, 400MHz) δ: 3.39(s? 3H)? 3.59-3.61(m? 2H)? 3.78-3.80(m? 2H)? 4.86(s5 2H)5 7.52(d，1H)，8.33(dd，1H)， 9.07(d，1H)· MS APCI+ m/z 270/272 [MH]+ 68% 42 h3c〆〜 CH ^MRCCDCls, 400MHz) δ: 1.28(t，3H)，3.69(q，2H)，4.77(s， 2H)，7.49(d，1H)，8.34(dd，1H)， 9.07(d，1H). MS ES+ m/z 262 [MNa]+ 75% 藉由管柱層析法於矽膠上以100:0至90:10之戊烷：乙酸乙酯洗提來純化製備42。製備43 2-氣-5-(5_[1，2,3】***-2-基甲基-[1，3,4】噁二唑-2-基）-吡啶R2 95339.doc -83-200526606 No. R2 Y Data yield 38 C1 CH ^ MRCCDCls, 400MHz) δ: 4.80 (s, 2H), 7.52 (d, 1H), 8.35 (dd, 1H), 9.08 (d, 1H ) · MS APCI + m / z 230/232 [MH] + 55% 39 C1 N 1HNMR (CDC13, 400MHz) δ: 4.83 (s, 2H), 8.76 (s, 1H), 9.36 (s, 1H). MS APCI + m / z 231/233 [MH] + 38% 40 Η CH! HNMR (CDC13, 400MHz) δ: 2.66 (s, 3H), 7.51 (d, 1H), 8.31 (d, lH), 9.02 (s, 1H ) _ Trace analysis: C8H6CIN30 0.25 H20 Need: C 48.02; H 3.27; N 21.00; see: C 47.89; H 3.23, N 20.95. 77% 41 CH ^ MRCCDCls, 400MHz) δ: 3.39 (s? 3H)? 3.59- 3.61 (m? 2H)? 3.78-3.80 (m? 2H)? 4.86 (s5 2H) 5 7.52 (d, 1H), 8.33 (dd, 1H), 9.07 (d, 1H) · MS APCI + m / z 270 / 272 [MH] + 68% 42 h3c〆 ~ CH ^ MRCCDCls, 400MHz) δ: 1.28 (t, 3H), 3.69 (q, 2H), 4.77 (s, 2H), 7.49 (d, 1H), 8.34 (dd , 1H), 9.07 (d, 1H). MS ES + m / z 262 [MNa] + 75% Eluted by column chromatography on silica gel with 100: 0 to 90:10 pentane: ethyl acetate To purify and prepare 42. Preparation 43 2-Ga-5- (5_ [1,2,3] triazol-2-ylmethyl- [1,3,4] oxadiazol-2-yl) -pyridine

95339.doc -84- 200526606 將 1H-1，2,3-二唾（264 mg，3·85 mmol)添加至 N，N-二甲基甲醯胺（15 mL)中之製備38之氯化合物（800 mg，3.5 mmol)、及碳酸鉀（1.4g，7mm〇l)之懸浮液中且於室溫下攪拌混合物1 8小時。隨後將反應混合物分隔於乙酸乙酯與水之間且分離有機層、以鹽水洗滌、經硫酸鈉乾燥且於真空中濃縮以得71%產率、650 mg之作為黃色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 6.08 (s，2 H)，7.66 (d，1 H)， 7·80 (s，2 Η)，8·38 (dd，1 Η)，8·99 (d，1 Η)。MS APCI+ m/z 263 [ΜΗ] + 盤備44至45 使用製備43之方法自製備38及39之產物製備下文所示之通式之以下化合物。95339.doc -84- 200526606 Chlorine compound of Preparation 38 by adding 1H-1,2,3-disial (264 mg, 3.85 mmol) to N, N-dimethylformamide (15 mL) (800 mg, 3.5 mmol), and a suspension of potassium carbonate (1.4 g, 7 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and water and the organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 71% yield of 650 mg of the title compound as a yellow solid. iHNMR (CDC13, 400 ΜΗζ) δ: 6.08 (s, 2 H), 7.66 (d, 1 H), 7.80 (s, 2 Η), 8.38 (dd, 1 Η), 8.99 (d , 1 Η). MS APCI + m / z 263 [ΜΗ] + Plates 44 to 45 The following compounds of the general formula shown below were prepared from the products of Preparations 38 and 39 using the method of Preparation 43.

序號 R2 Υ 資料產率 44 rssH | Ν MS APCI+ m/z 264 [MH] + 40% 45 Η〆 CH ^NMRCCDCls, 400MHz) δ: 2.34(s，6H)，3.78(s，2H)， 7.43(d，lH)，8.28(dd，1H)，9.01 (d，1H)。MS APCI+ m/z 239/241 [MH] + 82% 製備46至52 藉由製備18之方法使用適當噁二唑（製備14及40-45)及5- 95339.doc -85- 200526606 胺基-曱氧基吡啶製備下文所示之通式之以下化合物。No. R2 Υ Data yield 44 rssH | Ν MS APCI + m / z 264 [MH] + 40% 45 Η〆CH ^ NMRCCDCls, 400MHz) δ: 2.34 (s, 6H), 3.78 (s, 2H), 7.43 (d 1H), 8.28 (dd, 1H), 9.01 (d, 1H). MS APCI + m / z 239/241 [MH] + 82% Preparation 46 to 52 Using the appropriate oxadiazole (Preparations 14 and 40-45) and 5- 95339.doc -85- 200526606 Amine- The methoxypyridine produces the following compounds of the general formula shown below.

序號 R2 Υ 資料產率 46 rn CH ^NMRCCDCls, 400ΜΗζ) δ: 3.97(s，3Η)，5.75(s，2Η)， 6.78(d，1Η)，7.24(d，1Η)， 7.34(d，1H)，7.56(s，2H)， 7.90(dd，1H)，7.94(m，1H)， 8.30(d, 1H) MS APCI+ m/z 369 [MH] + 25% 47 严气 Ν MS APCI+ m/z 370 [MH] + 29% 48 η/ CH iHNMR(CDCl3, 400MHz) δ: 2.25(s，6H)，3.46(s，2H)， 3.99(s，3H)，6.85(d，1H)， 7.34(d，1H)，7.60(dd，1H)， 7.88(dd，1H)，8.10(d，1H)， 8.34(d，1H) MS APCI+ m/z 345/347[MH] + 36% 49 och3 CH ，HNMR(CDC13, 400MHz) δ: 3.35(s，3H)，3.99(s，3H)， 4.48(s，2H)，6.88(d，1H)， 7.34(d，1H)，7.50(m，1H)， 7.88(m，1H)，8.10(d，1H)， 8.35(m5 1H) MS APCI+ m/z 332 [MH] + 50% 50 Η CH 'HNMR(CDC13? 400MHz) δ: 2.38(s，3H)，4.00(s，3H)， 6.90(d? 1H)? 7.35(d? 1H)3 7.40(dd，1H)，7.88(dd，1H)， 8.06(d，1H)，8.31(d，1H) MS APCI+ m/z 302/304 [MH] + 33% 95339.doc -86- 200526606 51 CH iHNMRCCDCl，400MHz) δ: 3.33(s，3Η)，3.48(m，2Η)， 3.64(m，2H)，3.99(s，3H)， 4.60(s，2H)，6.86(d，1H)， 7.35(d，1H)，7.60(dd，1H)， 7.88(dd，1H)，8.09(d，1H)， 8.35(d5 1H). MS APCI+ m/z 376/378 [MH] + 62% 52 h3c〆 CH iNMRCCDCh，400MHz) δ: 1.14(t，3H)，3.50(q，2H)， 4.00(s，3H)，4.52(s，2H)， 6.86(d，1H)，7.34(d，1H)， 7.51(dd，1H)，7.90(dd，1H)， 8.11(d，1H)，8.36(d，1H). MS APCI+ m/z 346 [MH] + 藉由管柱層析法於矽膠上以25 :75至50:50至75:25之乙酸乙酯:戊烷洗提來純化製備46 〇藉由管柱層析法於石夕膠上以99:1 ··〇· 1至97:3 :0· 1之二氯甲烧：甲醇：0· 88氨水洗提來純化製備48，繼而以乙喊研磨。藉由管柱層析法於矽膠上以10:90至1〇〇:〇之乙酸乙酯：戊烷洗提來純化製備49，繼而以***研磨。藉由自乙酸乙酯重結晶來純化^ 50。藉由管柱層析法於矽膠上以1〇〇:〇:〇至99:ι:〇·ι·之二氯甲烷：曱醇：0·88氨水洗提來純化製備51。製備53 4_演_2,3_二甲基-11比咬1-氧化物No. R2 Υ Data yield 46 rn CH ^ NMRCCDCls, 400MΗζ) δ: 3.97 (s, 3Η), 5.75 (s, 2Η), 6.78 (d, 1Η), 7.24 (d, 1Η), 7.34 (d, 1H) , 7.56 (s, 2H), 7.90 (dd, 1H), 7.94 (m, 1H), 8.30 (d, 1H) MS APCI + m / z 369 [MH] + 25% 47 Strict gas MS APCI + m / z 370 [MH] + 29% 48 η / CH iHNMR (CDCl3, 400MHz) δ: 2.25 (s, 6H), 3.46 (s, 2H), 3.99 (s, 3H), 6.85 (d, 1H), 7.34 (d, 1H), 7.60 (dd, 1H), 7.88 (dd, 1H), 8.10 (d, 1H), 8.34 (d, 1H) MS APCI + m / z 345/347 [MH] + 36% 49 och3 CH, HNMR ( CDC13, 400MHz) δ: 3.35 (s, 3H), 3.99 (s, 3H), 4.48 (s, 2H), 6.88 (d, 1H), 7.34 (d, 1H), 7.50 (m, 1H), 7.88 ( m, 1H), 8.10 (d, 1H), 8.35 (m5 1H) MS APCI + m / z 332 [MH] + 50% 50 Η CH 'HNMR (CDC13? 400MHz) δ: 2.38 (s, 3H), 4.00 ( s, 3H), 6.90 (d? 1H)? 7.35 (d? 1H) 3 7.40 (dd, 1H), 7.88 (dd, 1H), 8.06 (d, 1H), 8.31 (d, 1H) MS APCI + m / z 302/304 [MH] + 33% 95339.doc -86- 200526606 51 CH iHNMRCCDCl, 400MHz) δ: 3.33 (s, 3Η), 3.48 (m, 2Η), 3.64 (m, 2H), 3.99 (s, 3H), 4.60 (s, 2 H), 6.86 (d, 1H), 7.35 (d, 1H), 7.60 (dd, 1H), 7.88 (dd, 1H), 8.09 (d, 1H), 8.35 (d5 1H). MS APCI + m / z 376 / 378 [MH] + 62% 52 h3c〆CH iNMRCCDCh, 400MHz) δ: 1.14 (t, 3H), 3.50 (q, 2H), 4.00 (s, 3H), 4.52 (s, 2H), 6.86 (d, 1H), 7.34 (d, 1H), 7.51 (dd, 1H), 7.90 (dd, 1H), 8.11 (d, 1H), 8.36 (d, 1H). MS APCI + m / z 346 [MH] + by Purification by column chromatography on silica gel with 25:75 to 50:50 to 75:25 ethyl acetate: pentane elution to prepare 46. Column chromatography on Shixi gel at 99: 1 ··· 1 to 97: 3: 0: 1 bischloromethane: methanol: 0.88 aqueous ammonia to purify and prepare 48, and then triturated with ethyl acetate. Preparation 49 was purified by column chromatography on silica gel eluting with ethyl acetate: pentane from 10:90 to 100: 0, followed by trituration with ether. ^ 50 was purified by recrystallization from ethyl acetate. Purification by column chromatography on silica gel with 100: 00: 00 to 99: ι: 〇. Dichloromethane: methanol: 0. 88 ammonia water to purify Preparation 51. Preparation 53 4_ 演 _2,3_dimethyl-11 ratio bite 1-oxide

95339.doc •87 200526606 於100°C加熱2,3_二曱基-4-硝基吡啶N-氧化物（5 g，29.7 mmol)及溴化氫（乙酸中30重量％，1〇〇 mL)之混合物48小時。隨後過遽混合物’藉由2 Μ氫氧化鈉洗條且以二氯甲烧 (χ3)萃取濾出液。以鹽水洗滌經組合之有機溶液，經硫酸鈉乾燥且於真空中濃縮。藉由管柱層析法於矽膠上以5〇:5〇之乙酸乙酯：戊烷洗提來純化殘餘物以得作為淺黃色固體之標題產物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.44 (s，3 Η)，2.58 (s，3 Η)， 7.30 (d? 1 Η)3 8.01 (d? 1 Η) MS APCI+ m/z 202/204 [MH] + 製備54 4-(2，3_^一甲基_1-氣比咬_4-基）笨甲酸甲醋95339.doc • 87 200526606 heated at 100 ° C 2,3_diamidino-4-nitropyridine N-oxide (5 g, 29.7 mmol) and hydrogen bromide (30% by weight in acetic acid, 100 mL ) For 48 hours. The permeate mixture was then washed with 2M sodium hydroxide and the filtrate was extracted with dichloromethane (χ3). The combined organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 50:50 ethyl acetate: pentane to give the title product as a pale yellow solid. iHNMR (CDC13, 400 ΜΗζ) δ: 2.44 (s, 3 Η), 2.58 (s, 3 Η), 7.30 (d? 1 Η) 3 8.01 (d? 1 Η) MS APCI + m / z 202/204 [MH ] + Preparation 54 4- (2,3_ ^ monomethyl_1-gas ratio bite_4-yl) methyl benzoate

於110°c加熱1，4-二噁烷（20 mL)中之製備53之產物（765 mg，3·78 mmol)、4-甲氧基羰基苯基硼酸（750 mg，4.16 mmol)、碳酸铯（3·7 g，11.3 4 mmol)及製備 3之產物（5〇 mg，觸媒）3小時。隨後將該混合物分隔於乙酸乙酯與水之間且分離含水層且藉由二氣甲烷（X3)萃取。以鹽水洗滌經組合之有機溶液，經硫酸鈉乾燥且於真空中濃縮以得暗黃色固體。以***研磨該固體以得87%產率之作為淺棕色固體之標題化合物。 95339.doc -88- 200526606 'HNMR (CDC13? 400 MHz) δ: 2.24 (s5 3 H)3 2.60 (s5 3 H)5 3·95 (s，3 H)，7.02 (d，1 H)，7.35 (m，2 H)，8.12 (m，2 H)， 8.22 (d，1 H)。MS APCI+ m/z 258 [MH] + 製備55 4-(2,3-—甲基-1 ·氧-”比咬-4 -基）-苯甲酸酿胖The product of Preparation 53 (765 mg, 3.78 mmol), 4-methoxycarbonylphenylboronic acid (750 mg, 4.16 mmol), carbonic acid was heated at 110 ° C in 1,4-dioxane (20 mL). Cesium (3.7 g, 11.4 mmol) and the product of Preparation 3 (50 mg, catalyst) for 3 hours. The mixture was then partitioned between ethyl acetate and water and the aqueous layer was separated and extracted with methane (X3). The combined organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give a dark yellow solid. This solid was triturated with ether to give the title compound as a light brown solid in 87% yield. 95339.doc -88- 200526606 'HNMR (CDC13? 400 MHz) δ: 2.24 (s5 3 H) 3 2.60 (s5 3 H) 5 3.95 (s, 3 H), 7.02 (d, 1 H), 7.35 (m, 2 H), 8.12 (m, 2 H), 8.22 (d, 1 H). MS APCI + m / z 258 [MH] + Preparation 55 4- (2,3-—methyl-1 · oxy- ”than bite-4 -yl) -benzoic acid

於回流下加熱甲醇（15 mL)中之製備54之產物（85〇 mg， 3·3 mmol)及肼單水合物（482叫，99mm〇1)3小時。隨後將進-步之置的肼單水合物(482 pL，9.9 mmol)添加至反應混合物中且加熱持續18小時。隨後藉由CeHte<g)過濾混合物，藉由甲醇洗務且於真空中濃縮瀘出液以得白色固體。於乙酸乙醋中使固體形成隸、滤出、以乙叫2)絲且真空乾燥以得94%產率、800 mg之作為白色固體之標題化合物。 'HNMR (CDC13, 400 ΜΗζ) δ: 2.18 (s, 3 Η), 2.41 (s, 3 Η), 4·58 (m, 2 Η), 7.14 (d, 1 Η), 7.42 (d, 2 Η), 7.96 (d, 2 Η), 1 Η), 9.85 (s, 1 Η) 〇 MS APCI+ m/z 258 [ΜΗ] + 製備56 1，1，1，2-四甲氧基-乙烷 95339.doc -89- 200526606 H3C^0The product of Preparation 54 (85 mg, 3.3 mmol) and hydrazine monohydrate (482 mg, 99 mmol) in methanol (15 mL) were heated under reflux for 3 hours. Further hydrazine monohydrate (482 pL, 9.9 mmol) was then added to the reaction mixture and heated for 18 hours. The mixture was then filtered through CeHte < g), washed with methanol, and the decanted solution was concentrated in vacuo to give a white solid. The solid was formed in ethyl acetate, filtered off, washed with silk 2) and dried in vacuo to give 94% yield of 800 mg of the title compound as a white solid. 'HNMR (CDC13, 400 ΜΗζ) δ: 2.18 (s, 3 Η), 2.41 (s, 3 Η), 4.58 (m, 2 Η), 7.14 (d, 1 Η), 7.42 (d, 2 Η) ), 7.96 (d, 2 Η), 1 Η), 9.85 (s, 1 Η) 〇MS APCI + m / z 258 [ΜΗ] + Preparation 56 1,1,1,2-tetramethoxy-ethane 95339 .doc -89- 200526606 H3C ^ 0

將甲乳基乙腈（50.0 g，704 mni〇l)溶解於曱醇（34 mL)與 ***（210 mL)之混合物中且冷卻該混合物至〇〇c。使氯化氯氣體起泡穿過該溶液20分鐘且於室溫下攪拌反應混合物2 小時。隨後使氯化氫氣體第二次起泡穿過該混合物且使其於室溫下靜置1 8小時。過濾該混合物且以乙驗洗條所得白色固體，將其溶解於甲醇（340 mL)中且攪拌90分鐘。隨後以醚（3 70 mL)稀釋該溶液，於回流加熱6小時且將其於室温下靜置1 8小時。加入額外之醚（200 mL)且濾出混合物。以 10%碳酸鈉溶液洗滌濾出液、於硫酸鎂上乾燥且於真空中濃縮以得標題產物，34.5 g。 ]HNMR (CDC13? 400 MHz) δ: 3.29 (s? 9 Η)5 3.39 (s5 3 Η) 3.50 (s，2 Η) 製備57 4-[4-(5-甲氧基甲基-[1，3,4]嚼二嗅-2·基）-苯基]-2,3-二甲基 -吡啶1-氧化物Methyl milk acetonitrile (50.0 g, 704 mL) was dissolved in a mixture of methanol (34 mL) and diethyl ether (210 mL) and the mixture was cooled to 0 ° C. Chlorine chloride gas was bubbled through the solution for 20 minutes and the reaction mixture was stirred at room temperature for 2 hours. Hydrogen chloride gas was then bubbled through the mixture a second time and allowed to stand at room temperature for 18 hours. The mixture was filtered and the resulting white solid was washed with ethyl acetate, dissolved in methanol (340 mL) and stirred for 90 minutes. The solution was then diluted with ether (3 70 mL), heated at reflux for 6 hours and allowed to stand at room temperature for 18 hours. Additional ether (200 mL) was added and the mixture was filtered off. The filtrate was washed with 10% sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo to give the title product, 34.5 g. ] HNMR (CDC13? 400 MHz) δ: 3.29 (s? 9 Η) 5 3.39 (s5 3 Η) 3.50 (s, 2 Η) Preparation 57 4- [4- (5-methoxymethyl- [1, 3,4] Chlodinyl-2-yl) -phenyl] -2,3-dimethyl-pyridine 1-oxide

將對甲苯績酸（20 mg，觸媒）添加至曱醇（8 mL)中之製備 55 之產物（400 mg，1.56 mmol)及 56 之產物（470 mg，3 I〕 95339.doc -90- 200526606 mmol)之混合物中且於回流下加熱該混合物1 〇小時。隨後以碳酸氫鈉溶液處理該混合物且以乙酸乙酯（χ3)萃取該含水混合物。以鹽水洗滌經組合之有機溶液、經硫酸鈉乾燥且於真空中》辰縮以得25%產率、122 mg之作為黃色油狀物之標題產物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.25 (s，3 H)，2.62 (s，3 H)， 3·52 (s，3 Η)，4·70 (s，2 Η)，7.04 (d，1 Η)，7.41 (d，2 Η)，8·16 (d，2 Η)，8·25 (d，1 Η)。MS APCI+ m/z 312 [ΜΗ] + 製備58 6-氣-噠嗪-3-羧酸甲酯The product of Preparation 55 (400 mg, 1.56 mmol) and the product of 56 (470 mg, 3 I) were added p-toluene acid (20 mg, catalyst) to methanol (8 mL) 95339.doc -90- 200526606 mmol) and the mixture was heated under reflux for 10 hours. The mixture was then treated with a sodium bicarbonate solution and the aqueous mixture was extracted with ethyl acetate (x3). The combined organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title product as a yellow oil in a yield of 122% in a 25% yield. iHNMR (CDC13, 400 ΜΗζ) δ: 2.25 (s, 3 H), 2.62 (s, 3 H), 3.52 (s, 3 Η), 4.70 (s, 2 Η), 7.04 (d, 1 Η), 7.41 (d, 2 Η), 8.16 (d, 2 Η), 8.25 (d, 1 Η). MS APCI + m / z 312 [ΜΗ] + Preparation 58 6-Ga-pyridazine-3-carboxylic acid methyl ester

將乙二醢氯（1.14 mL ’ 13.09 mmol)逐滴添加至二氯曱烧 (50 mL)與N，N-二甲基甲醯胺（1滴）之混合物中之卜氯-噠嗪 -3-羧酸[(1·9 g，11.9 mmol)，《/· /7此 c/2em· 29(6)，1583-92; 1992]之冰冷懸浮液中，且於室溫下攪拌該混合物1小時。隨後於減壓下蒸發該反應混合物且以二氣甲烧（3〇 mL)稀釋殘餘物且冷卻至0°C。加入甲醇（485 μΐ^，11.9mm〇l)且於〇 C祝拌邊混合物1小時。隨後將碳酸氫納溶液添加至反應混合物中且分離水層且以二氯曱烷（x2)萃取。以鹽水洗條經組合之有機溶液、經硫酸納乾燥且於真空中濃縮以得65〇/〇產率、1.33 g之作為白色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 4.09 (S，3 H)，7.67 (d，1 H)， 95339.doc -91 - 200526606 8.16 (d，1 Η)。MS APCI+ m/z 173 [ΜΗ] 製備59 6-(4-氟-2_甲基-苯基）噠嗪_3_羧酸甲酯Add ethylenedichloride (1.14 mL '13 .09 mmol) dropwise to dichloropyridazine-3 in a mixture of dichloropyrene (50 mL) and N, N-dimethylformamide (1 drop) -Carboxylic acid [(1 · 9 g, 11.9 mmol), "/ · / 7this c / 2em · 29 (6), 1583-92; 1992] in an ice-cold suspension, and the mixture was stirred at room temperature 1 hour. The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30 mL) and cooled to 0 ° C. Methanol (485 μΐ, 11.9 mm) was added and the mixture was stirred at 0 ° C for 1 hour. The sodium bicarbonate solution was then added to the reaction mixture and the aqueous layer was separated and extracted with dichloromethane (x2). The combined organic solution was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 650/0 yield, 1.33 g of the title compound as a white solid. iHNMR (CDC13, 400 ΜΗζ) δ: 4.09 (S, 3 H), 7.67 (d, 1 H), 95339.doc -91-200526606 8.16 (d, 1 Η). MS APCI + m / z 173 [ΜΗ] Preparation 59 6- (4-fluoro-2_methyl-phenyl) pyridazine_3_carboxylic acid methyl ester

使用製備54之方法自製備58之產物及4-氟-2-甲基苯基硼酸製備標題化合物。藉由管柱層析法於矽膠上以75:25」至 50:50:1之戊烷：乙酸乙酯··甲醇洗提來純化粗產物以得16% 產率之作為米色固體之所需產物。 iHNMR(CDCl3, 400 ΜΗζ) δ: 2.44 (s，3 Η)，4·11 (s，3 Η)， 7·〇6 (m，2 Η)，7·47 (dd，1 Η)，7·71 (d，1 Η)，8·26 (d，1 Η)。 MS APCI+ m/z 247 [ΜΗ] + 製備60 6-(4-氟-2-曱基-苯基）-噠嗪-3-羧酸醯肼The title compound was prepared from the product of Preparation 58 and 4-fluoro-2-methylphenylboronic acid using the method of Preparation 54. The crude product was purified by column chromatography on silica gel with pentane: ethyl acetate · methanol 75:25 "to 50: 50: 1 to obtain 16% yield as a beige solid. product. iHNMR (CDCl3, 400 ΜΗζ) δ: 2.44 (s, 3 Η), 4.11 (s, 3 Η), 7.06 (m, 2 Η), 7.47 (dd, 1 Η), 7. · 71 (d, 1 Η), 8.26 (d, 1 Η). MS APCI + m / z 247 [ΜΗ] + Preparation 60 6- (4-fluoro-2-fluorenyl-phenyl) -pyridazin-3-carboxylic acid hydrazine

將肼單水合物（69 μί，1.42 mmol)添加至曱醇（5 mL)中之製備59之產物（290 mg，1·18 mmol)之懸浮液中且於室溫搜拌戎混合物1 8小時。濾出所得沈澱物且乾燥以得μ %產率、240 mg之作為桃色固體之標題化合物。 95339.doc -92- 200526606 iNMR (CDC13, 400 MHz) δ: 2.42 (s，3 H)，4.18 (brs，2 H)， 7.06 (m，2 H)，7.46 (dd，1 H)，7.75 (d，1 H)，8·33 (d，1 H)， 9.18 (brs，1 H)。MS APCI+ m/z 247 [MH] + 數備61 6-(4-氟-2-甲基-苯基）-噠嗪-3-羧酸Ν’·(2·甲氧基-乙醯基）-醯肼Hydrazine monohydrate (69 μL, 1.42 mmol) was added to a suspension of the product of Preparation 59 (290 mg, 1.18 mmol) in methanol (5 mL) and the mixture was stirred at room temperature for 18 hours . The resulting precipitate was filtered off and dried to give a yield of 240% of the title compound as a peach-colored solid. 95339.doc -92- 200526606 iNMR (CDC13, 400 MHz) δ: 2.42 (s, 3 H), 4.18 (brs, 2 H), 7.06 (m, 2 H), 7.46 (dd, 1 H), 7.75 ( d, 1 H), 8.33 (d, 1 H), 9.18 (brs, 1 H). MS APCI + m / z 247 [MH] + Data preparation 61 6- (4-fluoro-2-methyl-phenyl) -pyridazine-3-carboxylic acid N '· (2 · methoxy-acetamyl) -Hydrazine

使用製備8之方法自製備60之產物及曱氧基乙醯氯製備作為米色泡沫狀物之標題化合物，95Q/◦產率。 ]HNMR (CDC13, 400 ΜΗζ) δ: 2.43 (s，3 H)，3.52 (s5 3 H)， 4.14 (s，2 Η)，7·06 (m，2 Η)，7_46 (m，1 Η)，7·76 (d，1 Η)， 8·33 (d，1 Η)，8·80 (brs，1 Η)，10.06 (brs，1 Η)。MS APCI+ m/z 319 [ΜΗ] + 製備62 3-(4-象-2-甲基-苯基）-6-(5-Τ氧基甲基-[ι，3,4】_ n惡二嗤_2_ 基）-建嗓The title compound was prepared as a beige foam using the method of Preparation 8 from the product of Preparation 60 and methoxyethyridine chloride in a yield of 95Q / ◦. ] HNMR (CDC13, 400 ΜΗζ) δ: 2.43 (s, 3 H), 3.52 (s5 3 H), 4.14 (s, 2 Η), 7.06 (m, 2 Η), 7_46 (m, 1 Η) , 7.76 (d, 1 Η), 8.33 (d, 1 Η), 8.80 (brs, 1 Η), 10.06 (brs, 1 Η). MS APCI + m / z 319 [ΜΗ] + Preparation 62 3- (4-Xan-2-methyl-phenyl) -6- (5-Toxymethyl- [ι, 3,4] _ noxadi嗤 _2_ based)-Jian voice

使用製備13之方法自製備61之產物及氧氯化鱗製備_ θ 95339.doc •93- 200526606 化合物。藉由管柱層析法於石夕膠上以99:1至98:2之二氯甲烧: 甲醇洗提來純化粗產物，以得作為米色固體之所需化合物，15%產率。 !HNMR (CDC13, 400 ΜΗζ) δ: 2_43(s，3 H)，3.53 (s，3 H)， 4·80 (s，2 Η)，7.06 (m，2 Η)，7.46 (m，1 Η)，7·74 (d，1 Η) 8.43 (d，1 Η) 〇 MS APCI+ m/z 301 [ΜΗ] + Μ備63 5-溴-嘧啶-2-腈The method of Preparation 13 was used to prepare _θ 95339.doc • 93-200526606 compounds from the product of Preparation 61 and oxychlorinated scale. The crude product was purified by column chromatography on Shixi gum with dichloromethane: methanol from 99: 1 to 98: 2 to obtain the desired compound as a beige solid, 15% yield. ! HNMR (CDC13, 400 ΜΗζ) δ: 2_43 (s, 3 H), 3.53 (s, 3 H), 4.80 (s, 2 Η), 7.06 (m, 2 Η), 7.46 (m, 1 Η) ), 7.74 (d, 1 Η) 8.43 (d, 1 Η) 〇MS APCI + m / z 301 [ΜΗ] + Μ63 63 5-Bromo-pyrimidine-2-carbonitrile

將二甲亞砜（26 mL)中之5-溴_2_氯嘧啶（1〇g，51·8 mm〇][) 之/谷液添加至一甲亞石風（14 mL)及水中之氰化納（2^9 g， 51·8 mmol)及三伸乙基二胺（1.2 g，1〇 4 mm〇1)之混合物中。於至/凰下攪拌所得混合物1 8小時。隨後以水（丨3 〇 mL) 稀釋該混合物且以***（3xl50 mL)萃取。經硫酸鈉乾燥經組合之有機溶液且於真空中濃縮以得淺黃色固體。自熱二氣甲烷重結晶固體得99%產率、9.4 g之標題產物。】HNMR (CDC13, 400 ΜΗζ) δ: 8.84 (s，2 H)。製備64 5-溴-嘯咬-2-叛酸5-Bromo-2-chloropyrimidine (10 g, 51.8 mm)] in dimethyl sulfoxide (26 mL) was added to monomethyl sulfite (14 mL) and water In a mixture of sodium cyanide (2 ^ 9 g, 51.8 mmol) and triethylenediamine (1.2 g, 104 mm). The resulting mixture was stirred for 18 hours at 1500 rpm. The mixture was then diluted with water (30 mL) and extracted with diethyl ether (3 x 150 mL). The combined organic solution was dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. The solid was recrystallized from autothermal methane to give the title product in 99% yield, 9.4 g. HNMR (CDC13, 400 ΜΗζ) δ: 8.84 (s, 2 H). Preparation 64 5-Bromo-sounding 2-acid acid

於6(TC加熱水（122 mL)中之氫氧化納（4 88 g，】2〇匪叫 95339.doc -94· 200526606 及製備63之產物（7·5 g，40.8 mmol)之混合物1小時。隨後以 1 Μ氫氯酸酸化该混合物、以乙酸乙酯及二氯甲统萃取且於真空中濃縮以得一些作為白色固體之標題化合物， mg。亦於減壓下蒸發水溶液且將殘餘物萃取9〇:1〇之二氯甲烷：甲醇中。濾出殘餘物且於真空中濃縮濾出液以得作為白色固體之進一步之標題化合物，5 5 g。 iHNMR (DMSO-D6, 400 MHz) δ: 9.10 (s，2 H)，13.8 (brs 1 H)。MS APCI+ m/z 203 [MH] + 製備65 5-溴-嘧啶-2-羧酸甲酯A mixture of sodium hydroxide (4 88 g,) 2 in 60 (TC heated water (122 mL)) 95953.doc -94 · 200526606 and the product of Preparation 63 (7.5 g, 40.8 mmol) for 1 hour The mixture was then acidified with 1 M hydrochloric acid, extracted with ethyl acetate and dichloromethane and concentrated in vacuo to give some of the title compound as a white solid, mg. The aqueous solution was also evaporated under reduced pressure and the residue was Extract 90:10 in dichloromethane: methanol. The residue was filtered off and the filtrate was concentrated in vacuo to give the further title compound as a white solid, 5 5 g. IHNMR (DMSO-D6, 400 MHz) δ: 9.10 (s, 2 H), 13.8 (brs 1 H). MS APCI + m / z 203 [MH] + Preparation of 65 5-bromo-pyrimidine-2-carboxylic acid methyl ester

BrHry^f 使發煙氫氯酸穿過曱醇（50 mL)中之製備64之產物（5.5 g ，27 mmol)的冰***液中直至飽和。將反應混合物溫至室溫且攪拌18小時。隨後於減壓下蒸發溶劑且將殘餘物溶解於二氯甲烧中、以水及碳酸氫鈉溶液洗滌、經硫酸鎂乾燥且於真空中濃縮以得57%產率、3.5 g的作為黃色固體之標題化合物。 iNMR (CDC13, 400 ΜΗζ) δ: 4.05 (s，3 H)，9.00 〇, 2 H)。 MS APCI+ m/z 218 [ΜΗ] + 製備66 5-溴-嘧啶-2-羧酸醯肼 95339.doc -95- 200526606BrHry ^ f was passed through an ice-cold solution of the product of Preparation 64 (5.5 g, 27 mmol) in methanol (50 mL) until saturated. The reaction mixture was warmed to room temperature and stirred for 18 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water and sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to give 57% yield, 3.5 g as a yellow solid Title compound. iNMR (CDC13, 400 ΜΗζ) δ: 4.05 (s, 3 H), 9.00, 2 H). MS APCI + m / z 218 [ΜΗ] + Preparation 66 5-Bromo-pyrimidine-2-carboxylic acid hydrazine 95339.doc -95- 200526606

BrBr

使用製備6之方法自製備65之產物及肼單水合物以定量產率製備作為黃色固體之標題化合物。 ]HNMR (CDC135 400 MHz) δ: 4.20 (s5 2 Η)5 8.90 (m5 3 Η) 〇 MS APCI+ m/z 217 [MH] + 製備67 5U啶_2_羧酸N，-(2-甲氧基-乙醯基）_醯肼The title compound was prepared as a yellow solid in quantitative yield from the product of Preparation 65 and the hydrazine monohydrate using the method of Preparation 6. ] HNMR (CDC135 400 MHz) δ: 4.20 (s5 2 Η) 5 8.90 (m5 3 Η) 〇MS APCI + m / z 217 [MH] + Preparation 67 5U pyridine_2_carboxylic acid N,-(2-methoxy -Ethenyl) _hydrazine

BrBr

使用製備8之方法自製備66之產物及甲氧基乙醯氯以 45%產率製備作為白色固體之標題化合物。 •HNMR (DMSO-D6, 400 MHz) δ: 3.32 (s, 3 Η), 3.98 (s, 2 Η), 9.20 (s, 2 Η), 10.02 (S, 1 Η), 10.66 (s, 1 H) 〇 MS APCK m/z 290 [MH] + 製備68 5-溴-2-(5-甲氧基甲基·【ny噁二唑_2基）_嘧啶The title compound was prepared as a white solid in 45% yield from the product of Preparation 66 and methoxyacetamidine using the method of Preparation 8. HNMR (DMSO-D6, 400 MHz) δ: 3.32 (s, 3 Η), 3.98 (s, 2 Η), 9.20 (s, 2 Η), 10.02 (S, 1 Η), 10.66 (s, 1 H ) 〇MS APCK m / z 290 [MH] + Preparation 68 5-Bromo-2- (5-methoxymethyl · [nyoxadiazol_2yl) _pyrimidine

使用製備13之方法自製備67產物製備標題化合物。藉由管柱層析法於矽膠上以99.5:0.5至99.1 + 斤曰曰王外.1之二氣甲烷··甲醇洗提來純化粗產品以得45%產率之作氣&々座手之作為白色固體之所需化合物。 95339.doc -96- 200526606 1HNMR (CDC13, 400 MHz) δ: 3.52 (s，3 H)，4.78 (s，2 H)， 9.02 (s，2 H)。MS APCI+ m/z 271 [MH] + 製備69 5-(4-氣_2-甲基-苯基）-2-(5-甲氧基甲基-[1，3,4】鳴二唾-2_ 基）-癌咬The title compound was prepared from the Preparation 67 product using the method of Preparation 13. The crude product was purified by column chromatography on silica gel with 99.5: 0.5 to 99.1 + catty king. 1 2 gas methane · methanol elution to obtain 45% yield of gas & block Hand as the desired compound as a white solid. 95339.doc -96- 200526606 1HNMR (CDC13, 400 MHz) δ: 3.52 (s, 3 H), 4.78 (s, 2 H), 9.02 (s, 2 H). MS APCI + m / z 271 [MH] + Preparation 69 5- (4-Gas_2-methyl-phenyl) -2- (5-methoxymethyl- [1,3,4] Ningosal- 2_ base)-cancer bite

將水（3 mL)中之碳酸鈉（295 mg，2.78 mmol)溶液添加至 1，2-二甲氧基乙烷（3 mL)中之製備68之產物（376 mg，1.39 mmol)、4·氟-2-甲基苯基石朋酸（320 mg，2.08 mmol)及三苯基膦鈀（48 mg，觸媒）之溶液中且於回流下加熱該混合物2 小時。隨後於減壓下蒸發該反應混合物且將該殘餘物分隔於水及乙酸乙酯之間。濾出所得沈澱物，以水、乙酸乙^ 及乙鍵洗丨條’且乾無以付59%產率、332 mg之作為乎色口體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.33 (s，3 H)，3.53 (s 3 H)Add a solution of sodium carbonate (295 mg, 2.78 mmol) in water (3 mL) to the product of Preparation 68 (376 mg, 1.39 mmol) in 1,2-dimethoxyethane (3 mL), 4. · The mixture was heated in a solution of fluoro-2-methylphenyllithium acid (320 mg, 2.08 mmol) and triphenylphosphine palladium (48 mg, catalyst) under reflux for 2 hours. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The resulting precipitate was filtered off, and the strip was washed with water, ethyl acetate and ethyl bond, and dried to afford a 59% yield, 332 mg of the title compound as a color mouthpiece. iHNMR (CDC13, 400 ΜΗζ) δ: 2.33 (s, 3 H), 3.53 (s 3 H)

4·81 (s，2 Η)，7.09 (m，2 Η) 7·25 (m，1 Η)，8.90 (s，2 Η)。MS APCI+ m/z 301 [MH] + 製備70 5-演·2_(5-甲基-[1，3,4]嚼二嗤-2-基）-啦咬4.81 (s, 2 Η), 7.09 (m, 2 Η), 7.25 (m, 1 Η), 8.90 (s, 2 Η). MS APCI + m / z 301 [MH] + Preparation 70 5-Generation · 2_ (5-Methyl- [1,3,4] Chlodiazin-2-yl) -biting

95339.doc -97· 200526606 使用製備4之方法自製備6之產物及n，N-二曱基乙醯胺二曱基乙縮醛以47%產率製備作為白色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.65 (s，3 H)，8.01 (m，1 H)， 8.12 (m, 1 Η)，8.80 (m, 1 Η)。MS APCI+ m/z 240/242 [ΜΗ] + 製備71 3·[3-(5- >臭“比咬-2-基）-5-甲基-[1，2,4】三峻-4-基】-2,6-二甲氧基-σ比唆95339.doc -97 · 200526606 Using the method of Preparation 4 to prepare the title compound as a white solid from the product of Preparation 6 and n, N-diamidinoacetamidinyl acetal in 47% yield. iHNMR (CDC13, 400 MΗζ) δ: 2.65 (s, 3 H), 8.01 (m, 1 H), 8.12 (m, 1 Η), 8.80 (m, 1 Η). MS APCI + m / z 240/242 [ΜΗ] + Preparation 71 3 · [3- (5- > Omega-2-yl) -5-methyl- [1,2,4] Sanjun-4 -Yl] -2,6-dimethoxy-σ ratio 唆

使3-胺基-2,6-二甲氧基吡啶單氫氣化物（2 g，13 mmol) 於碳酸鈉溶液及乙酸乙酯之間分配。分離有機層，以鹽水洗滌，經硫酸鈉乾燥且於真空中濃縮以得游離鹼。隨後將該鹼溶解於二甲苯（30 mL)中且加入製備70之產物（1.8 g， 7.5 mmol)及對甲苯績酸（50 mg，觸媒）。於回流下加熱所得混合物1 8小時。於真空中濃縮反應混合物且藉由管柱層析法於矽膠上以100:0至98:2之二氣曱烷：曱醇洗提來純化該殘餘物，以得23%產率、628 mg之作為紫色固體之標題產物。 lHNMR (CDC135 400 MHz) δ: 2.49 (s, 3 Η)? 3.80 (s5 3 Η)5 3.98 (s，3 Η)，6.41 (d，1 Η)，7·45 (d，1 Η)，7.92 (dd5 1 Η)， 8.11 (d，1 Η)，8·37 (d，1 Η)。MS APCI+ m/z 377 [ΜΗ] + 95339.doc • 98 - 200526606 製備72 5-(4-氟-2-甲基·苯基）-2-(5·甲基-[1，3,4]噁二唑-2-基）-吡啶Partition 3-amino-2,6-dimethoxypyridine monohydrogen (2 g, 13 mmol) between sodium carbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the free base. This base was then dissolved in xylene (30 mL) and the product of Preparation 70 (1.8 g, 7.5 mmol) and p-toluene acid (50 mg, catalyst) were added. The resulting mixture was heated under reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica with 100: 0 to 98: 2 dioxane: methanol to obtain 23% yield, 628 mg As the title product of a purple solid. lHNMR (CDC135 400 MHz) δ: 2.49 (s, 3 Η)? 3.80 (s5 3 Η) 5 3.98 (s, 3 Η), 6.41 (d, 1 Η), 7.45 (d, 1 Η), 7.92 (dd5 1 Η), 8.11 (d, 1 Η), 8.37 (d, 1 Η). MS APCI + m / z 377 [ΜΗ] + 95339.doc • 98-200526606 Preparation 72 5- (4-fluoro-2-methyl · phenyl) -2- (5 · methyl- [1,3,4] Oxadiazol-2-yl) -pyridine

於回流下加熱1，4-二噁烷（25 mL)中之製備40之產物（545 mg，2.79 mmol)、4-氟-2-甲基苯基 W 酸（643 mg，4.18 mmol)、碳酸铯（2.7 g，8.29 mmol)及製備 3之產物（1〇 mg，觸媒）之混合物4小時。隨後冷卻反應混合物至室溫，藉由 Celite®過濾且於真空中濃縮以得定量產率之作為淺黃色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.40 (s，3 Η)，2·66 (s，3 H)， 7.00 (m，2 Η)，7.43 (dd，1 Η)，7.53 (d，1 Η)，8·37 (d，1 Η) 9.29 (d，1 Η)。MS APCI+ m/z 270 [ΜΗ] + 製備73 $ si 糟由製備72之方法使用適當噁二唑（製備14_16)及硼酸以定量產率製備下文所示之通式之以下化合物。精由tic分析監測該反應之進行且於回流下加熱該等混合物直至已消耗所有起始材料。The product of Preparation 40 (545 mg, 2.79 mmol) in 1,4-dioxane (25 mL) was heated under reflux, 4-fluoro-2-methylphenyl W acid (643 mg, 4.18 mmol), carbonic acid A mixture of cesium (2.7 g, 8.29 mmol) and the product of Preparation 3 (10 mg, catalyst) for 4 hours. The reaction mixture was then cooled to room temperature, filtered through Celite® and concentrated in vacuo to give the title compound as a pale yellow solid in quantitative yield. iHNMR (CDC13, 400 ΜΗζ) δ: 2.40 (s, 3 Η), 2.66 (s, 3 H), 7.00 (m, 2 Η), 7.43 (dd, 1 Η), 7.53 (d, 1 Η) , 8.37 (d, 1 Η) 9.29 (d, 1 Η). MS APCI + m / z 270 [ΜΗ] + Preparation 73 $ si The method of Preparation 72 uses the appropriate oxadiazole (Preparation 14-16) and boric acid to prepare the following compounds of the formula shown below in quantitative yield. The reaction was monitored by tic analysis and the mixture was heated under reflux until all starting materials had been consumed.

95339.doc 200526606 序號 R1 R2 Y 資料 73 9C CHS H N iHNMRCCDCh，400MHz) δ: 2.29(s，3H)，2.37(s，3H)， 2.70(s，3H), 7.21-7.34(m，3H)， 8.81(d，1H)，9.51(d，1H)· MS ES+ m/z 289 [MNa] + 74 双 H N ^NMRCCDCb, 400MHz) δ. 2.46(s，3H)，2.70(s，3H)， 7.06(m，2H)，7.50(m，1H)， 8.82(d，1H)，9.49(d，1H). MS ES+ m/z 293 [MNa] + 75 双 och3 CH iHNMRCCDCl^OOMHz”： 2.41(s，3H)，3.52(s，3H)， 4_75(s，2H)，6.94-7.04(m，2H)， 7.44(dd，1H)，7.55(dd，1H)， 8.42(d，1H)，9.35(dd，1H). MS APCI+ m/z 300 [MH] + 76 双 och3 N iHNMRCCDCh，400MHz) δ: 2.46(s，3H)，3.53(s，3H)， 4.79(s，2H)，7.06(m，2H)， 7.51(m，1H)，8.84(d，1H)， 9.51(d，1H)· MS APCI+ m/z 301 [MH] + 77 och3 N ^NMRCCDCh，400MHz) δ: 2.40(d，3H)，3.52(s，3H)，4.51 (s，2H)，7.23-7.30(m，3H)， 9.06(s，lH)，9_40(s，lH). MS ES+ m/z 433 [MCs] + 78 ch3 f och3 N ^NMRCCDCls, 400MHz) δ: 3.78(s，3H)，4.09(s，3H)， 4.80(s，2H)，7.01-7.18(m, 2H)， 7.54-7.72(m，1H)，9.26(s，1H), 9.57(s，1H)· MS ES+ m/z 449 [MCs] + 95339.doc 100- 200526606 79 ch3 och3 N ^NMRCCDCls, 400MHz) δ: 2.37(s，3H)，3.52(s，3H)， 3.89(s，3H)，4.78(s，2H)， 6.95(d，1H)，7.25(m，1H)， 7.77(m，1H)，9.35(d，1H)， 9.49(d，1H)· MS ES+ m/z 445 [MCs] + 80 0爲 φτ F och3 N ^NMRCCDCl，400MHz) δ: 3.52(s，3H)，3.91 (s，3H)， 4.78(s，2H)，6.99(m，1H)， 7.17(m，1H)，7.77(m，1H)， 9.41(d，lH)，9.50(d，lH)· MS ES+ m/z 461 [MCs] + 81 CH. ά： och3 N ^NMRCCDCh，400MHz) δ: 2.39(s，3H)，2.40(s，3H)， 3.53(s，3H)，4.79(s，2H)， 7.03-7.41 (m? 2H)5 8.86(s5 1H)，9.52(d，1H). MS ES+ m/z 429 [MCs] + 製備82 甲基-(5 -场基-0比- 2 -基）-胺〇、、〆〇95339.doc 200526606 No. R1 R2 Y Data 73 9C CHS HN iHNMRCCDCh, 400MHz) δ: 2.29 (s, 3H), 2.37 (s, 3H), 2.70 (s, 3H), 7.21-7.34 (m, 3H), 8.81 (d, 1H), 9.51 (d, 1H) · MS ES + m / z 289 [MNa] + 74 double HN ^ NMRCCDCb, 400MHz) δ. 2.46 (s, 3H), 2.70 (s, 3H), 7.06 (m , 2H), 7.50 (m, 1H), 8.82 (d, 1H), 9.49 (d, 1H). MS ES + m / z 293 [MNa] + 75 double och3 CH iHNMRCCDCl ^ OOMHz ": 2.41 (s, 3H) , 3.52 (s, 3H), 4_75 (s, 2H), 6.94-7.04 (m, 2H), 7.44 (dd, 1H), 7.55 (dd, 1H), 8.42 (d, 1H), 9.35 (dd, 1H) ). MS APCI + m / z 300 [MH] + 76 double och3 N iHNMRCCDCh, 400MHz) δ: 2.46 (s, 3H), 3.53 (s, 3H), 4.79 (s, 2H), 7.06 (m, 2H), 7.51 (m, 1H), 8.84 (d, 1H), 9.51 (d, 1H) · MS APCI + m / z 301 [MH] + 77 och3 N ^ NMRCCDCh, 400MHz) δ: 2.40 (d, 3H), 3.52 ( s, 3H), 4.51 (s, 2H), 7.23-7.30 (m, 3H), 9.06 (s, lH), 9_40 (s, lH). MS ES + m / z 433 [MCs] + 78 ch3 f och3 N ^ NMRCCDCls, 400MHz) δ: 3.78 (s, 3H), 4.09 (s, 3H), 4.80 (s, 2H), 7.01-7.18 (m, 2H), 7.54-7.72 (m, 1H), 9.2 6 (s, 1H), 9.57 (s, 1H) · MS ES + m / z 449 [MCs] + 95339.doc 100- 200526606 79 ch3 och3 N ^ NMRCCDCls, 400MHz) δ: 2.37 (s, 3H), 3.52 ( s, 3H), 3.89 (s, 3H), 4.78 (s, 2H), 6.95 (d, 1H), 7.25 (m, 1H), 7.77 (m, 1H), 9.35 (d, 1H), 9.49 (d ， 1H) · MS ES + m / z 445 [MCs] + 80 0 is φτ F och3 N ^ NMRCCDCl, 400MHz) δ: 3.52 (s, 3H), 3.91 (s, 3H), 4.78 (s, 2H), 6.99 (m, 1H), 7.17 (m, 1H), 7.77 (m, 1H), 9.41 (d, lH), 9.50 (d, lH) · MS ES + m / z 461 [MCs] + 81 CH. ά: och3 N ^ NMRCCDCh, 400MHz) δ: 2.39 (s, 3H), 2.40 (s, 3H), 3.53 (s, 3H), 4.79 (s, 2H), 7.03-7.41 (m? 2H) 5 8.86 (s5 1H) , 9.52 (d, 1H). MS ES + m / z 429 [MCs] + Preparation of 82 methyl- (5-field group-0 ratio-2-yl) -amine 〇, 〆〇

.NH H〆於室溫下使甲胺氣體起泡穿過二氯甲烷（60 mL)中之2-氣 -5-硝基吡啶（4 g，25.2 mmol)之經攪拌之溶液直至已發生飽和。隨後濾出所得黃色沈澱物，以二氯曱烷洗滌且於真空下乾燥以得80%產率、3.07 g之作為黃色固體之標題化合物。 ]HNMR (CDC135 400 MHz) δ: 3.05 (d5 3 Η)3 5.41 (bs? 1 Η)5 95339.doc -101 - 200526606 6.37 (d，1 H)，8.21 (d，1 H)，9.03 (d，1 Η)。MS APCI+ m/z 154 [MH] + 製備83 甲基-吡啶-2,5-二胺.NH H〆 Bubble methylamine gas through a stirred solution of 2-gas-5-nitropyridine (4 g, 25.2 mmol) in dichloromethane (60 mL) at room temperature until saturation has occurred . The resulting yellow precipitate was then filtered off, washed with dichloromethane and dried under vacuum to give 80% yield of 3.07 g of the title compound as a yellow solid. ] HNMR (CDC135 400 MHz) δ: 3.05 (d5 3 Η) 3 5.41 (bs? 1 Η) 5 95339.doc -101-200526606 6.37 (d, 1 H), 8.21 (d, 1 H), 9.03 (d , 1 Η). MS APCI + m / z 154 [MH] + Preparation of 83 methyl-pyridine-2,5-diamine

於6〇 Psi之氫氣體下於乙醇（150 mL)中攪拌製備82之產物（3.〇g’ 19.5 mmol)及 1 〇% Pd/C (300 mg，觸媒）18小時。隨後藉由Celite®過濾該反應混合物且於真空中濃縮濾出液以付17%產率、4〇〇 mg之標題產物。The product 82 (3.0 g ' 19.5 mmol) and 10% Pd / C (300 mg, catalyst) were prepared by stirring in ethanol (150 mL) under a hydrogen gas of 60 Psi for 18 hours. The reaction mixture was then filtered through Celite® and the filtrate was concentrated in vacuo to give 17% yield of 400 mg of the title product.

!HNMR (CDC13? 400 MHz) δ: 2.85 (s, 3 Η), 3.19 (s? 2 Η)3 (s，1 Η)，6·31 (d，1 Η)，6·97 (dd，1 Η)，7·69 (d，1 Η)· MS APCI+ m/z 269 [MNa] + 製備84 二氣_煙酸甲酯! HNMR (CDC13? 400 MHz) δ: 2.85 (s, 3 Η), 3.19 (s? 2 Η) 3 (s, 1 Η), 6.31 (d, 1 Η), 6.97 (dd, 1 Η), 7.69 (d, 1 Η) · MS APCI + m / z 269 [MNa] + Preparation of 84 digas_methyl nicotinate

將3 比疋緩酸[(27 g，160 mm〇l)，汄胸· C/zem，20，1363; 83]逐知添加至氧氣化碟（⑽社）中且於回流下加熱該混口物7 J日夺且方；S溫檀拌18小時。隨後於真空中濃縮該混合 95339.doc •102- 200526606 物至低體積且以水驟冷殘餘物。以碳酸氫鈉溶液中和含水混合物且以氯仿（3x150 mL)萃取。以鹽水洗滌經組合之有機溶液，經硫酸鈉乾燥且於真空中濃縮以得83%產率、27.2g 之作為紅色油狀物之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 3.96 (s，3 H)，7.47 (s，1 H)， 8_85 (s，1 Η) 〇 MS APCI+ m/z 206 [ΜΗ] + 製備85及86 將甲醇鈉（甲醇中0.5 Μ，48.6 mL，24·3 mmol)逐滴添加至曱醇（20 mL)中之製備84之產物（5.0 g，24.3 mmol)的冰*** 鲁液中。將混合物溫至室溫且攪拌2小時。隨後於減壓下蒸發溶劑且將殘餘物分隔於水（50 mL)及氯仿（5〇 mL)之間。分離各層且以氯仿（2x75mL)萃取水層。隨後經硫酸鈉乾燥經組合之有機溶液且於真空中濃縮以得橙色油狀物。藉由管柱層析法於石夕膠上以二氣甲烷（100%)洗提來純化該油狀物以得7·6°/〇產率、370 mg的作為白色固體之製備85之產物。以二氣甲烷進一步之洗提隨後分離出27%產率、1·32 g之作為白色固體的製備86之產物。 · 製備85 4_氣-6-甲氧基-煙酸甲酯Add 3 ratios of tartaric acid [(27 g, 160 mm0l), topless chest · C / zem, 20, 1363; 83] to the oxygenated dish (Hanasha) and heat the mixture under reflux. 7th day won the square; S Wentan mixed for 18 hours. The mixture was then concentrated in vacuo 95339.doc • 102-200526606 to a low volume and the residue was quenched with water. The aqueous mixture was neutralized with sodium bicarbonate solution and extracted with chloroform (3x150 mL). The combined organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 83% yield of 27.2 g of the title compound as a red oil. iHNMR (CDC13, 400 ΜΗζ) δ: 3.96 (s, 3 H), 7.47 (s, 1 H), 8_85 (s, 1 Η) 〇MS APCI + m / z 206 [ΜΗ] + Preparations 85 and 86 Sodium methoxide (0.5 M in methanol, 48.6 mL, 24.3 mmol) was added dropwise to the ice-cold solution of the product of Preparation 84 (5.0 g, 24.3 mmol) in methanol (20 mL). The mixture was warmed to room temperature and stirred for 2 hours. The solvent was then evaporated under reduced pressure and the residue was partitioned between water (50 mL) and chloroform (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (2x75 mL). The combined organic solution was then dried over sodium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by column chromatography on Shixi gum with digas methane (100%) to give 7.6 ° / 0 yield, 370 mg of the product of Preparation 85 as a white solid. . Further elution with digas methane followed by isolation of the product of Preparation 86 as a white solid in a yield of 27% and 1.32 g. Preparation of 85 4_Ga-6-methoxy-nicotinic acid methyl ester

6·81 (s，1 Η)，8.71 (s，1 η)。MS APCI+ m/z 202 [ΜΗ] + 'HNMR (CDC13j 400 MHz) δ: 3.90 (s5 3 Η)? 3.96 (s5 3 Η)? 95339.doc -103- 200526606 製備86 6_氣-4-甲氧基-煙酸甲醋6.81 (s, 1 Η), 8.71 (s, 1 η). MS APCI + m / z 202 [ΜΗ] + 'HNMR (CDC13j 400 MHz) δ: 3.90 (s5 3 Η)? 3.96 (s5 3 Η)? 95339.doc -103- 200526606 Preparation 86 6_ 气 -4-methoxy Methyl-nicotinate

!HNMR (CDC13, 400 ΜΗζ) δ: 3.87 (s，3 H)，3.94 (s，3 H)， 6.90 (s，1 Η)，8·68 (s，1 Η). MS APCI+ m/z 202 [ΜΗ] + 製備87 6-氣-4-甲氧基-煙酸醯肼! HNMR (CDC13, 400 ΜΗζ) δ: 3.87 (s, 3 H), 3.94 (s, 3 H), 6.90 (s, 1 Η), 8.68 (s, 1 Η). MS APCI + m / z 202 [ΜΗ] + Preparation 87 6-Ga-4-methoxy-nicotinic acid hydrazine

將肼單水合物（690 pL，14.2 mmol)添加至甲醇（35 mL)中之製備86之產物（2.7 g，13.4 mmol)之懸浮液中，冷卻至-5 C，且攪拌該混合物3小時。隨後將該混合物溫至室溫且攪拌18小時。濾出所得沈澱物且乾燥以得99〇 mg作為白色固體之一些標題化合物。濾出液之tlc分析顯示並非所有起始材料已消耗且因此加入進一步之肼單水合物（267 ，5 51Hydrazine monohydrate (690 pL, 14.2 mmol) was added to a suspension of the product of Preparation 86 (2.7 g, 13.4 mmol) in methanol (35 mL), cooled to -5 C, and the mixture was stirred for 3 hours. The mixture was then warmed to room temperature and stirred for 18 hours. The resulting precipitate was filtered off and dried to give 990 mg of some of the title compound as a white solid. Tlc analysis of the filtrate showed that not all starting material was consumed and therefore further hydrazine monohydrate (267, 5 51

合物。组合。 The compound.

95339.doc •104- 200526606 247 [MH] + 製備88 6-氣-4-甲氧基-煙酸Ν’-(2·甲氣基-乙酿基）-醜骄95339.doc • 104- 200526606 247 [MH] + Preparation 88 6-Ga-4-methoxy-nicotinic acid N ’-(2 · methylamino-ethyl) -ugly

將甲氧基乙醯氯（733 μι ’ 8 ·02 mmol)添加至二氯甲烧（2〇 mL)及三乙胺（1.2 mL，8.61 mmol)中之製備87之產物（1.16 g，5.73 mmol)的冰冷懸浮液中且於室溫下攪拌該混合物18 小時。隨後以水及鹽水洗滌反應混合物，經硫酸納乾燥且於真空中濃縮以得淺黃色膠狀物。藉由管柱層析法於石夕膠上以100:0至95:5之二氯曱烷：甲醇洗提來純化該膠狀物以得3 1%產率、480 mg之作為透明玻璃狀物之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ·· 3.48 (s，3 H)，4.08 (s，3 H)， 4·1〇 (s5 2 Η)，6·96 (s，1 Η)，9·03 (s，1 Η)，9.25 (d，1 Η)，9·99 (d，1 Η) 〇 MS APCI+ πι/ζ 274/276 [ΜΗ] + 製備89 氣-4-甲氧基_5_(5_甲氣基甲基_[1，3,4】嚼二嗅-2-基）-ι»比咬The product of Preparation 87 (1.16 g, 5.73 mmol) was added to dichloromethane (20 mL) and triethylamine (1.2 mL, 8.61 mmol) with methoxyacetamidine chloride (733 μm '8.02 mmol). ) In an ice-cold suspension and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give a pale yellow gum. The gel was purified by column chromatography on Shixi gum with 100: 0 to 95: 5 dichloromethane: methanol to obtain 31% yield, 480 mg as a transparent glass. Title compound. iHNMR (CDC13, 400 ΜΗζ) δ · 3.48 (s, 3 H), 4.08 (s, 3 H), 4.10 (s5 2 Η), 6.96 (s, 1 Η), 9.03 ( s, 1 Η), 9.25 (d, 1 Η), 9.99 (d, 1 Η) 〇MS APCI + π / ζ 274/276 [ΜΗ] + Preparation 89 GA-4-methoxy_5_ (5_ Methoxymethyl_ [1,3,4] chewing diol-2-yl) -ι »specific bite

使用製備1 3之方法自製備88之產物及***以定量產率製備作為黃色油狀物之標題化合物。 95339.doc -105- 200526606 iHNMR (CDCI3，40〇 MHz) δ: 3.49 (s，3 Η)，4·04 (s，3 H)， 4 73 (s 2H)?7.01(s?l H)? 8.83 (s? 1 H) 0 MS APCI+ m/z 25 6 [MH] + 製備90 2-氣-4-甲氧基-5-[5-甲氧基甲基-4-(6-甲氧基-吼咬-3· 基）_4H-[1，2,4]***-3-基】-吡啶The title compound was prepared as a yellow oil from the product of Preparation 88 and phosphorus oxychloride in quantitative yield using the method of Preparation 13. 95339.doc -105- 200526606 iHNMR (CDCI3, 400MHz) δ: 3.49 (s, 3 Η), 4.04 (s, 3 H), 4 73 (s 2H)? 7.01 (s? L H)? 8.83 (s? 1 H) 0 MS APCI + m / z 25 6 [MH] + Preparation 90 2-Ga-4-methoxy-5- [5-methoxymethyl-4- (6-methoxy) -Ball-3.yl) _4H- [1,2,4] triazol-3-yl] -pyridine

使用製備18之方法自製備89之產物及5-胺基-2-甲氧基吡啶以29°/。產率製備作為淺黃色泡沫狀物之標題化合物。 ]HNMR (CDC135 400 MHz) δ: 3.37(s, 3 Η), 3.61 (s, 3 Η)? 3.93 (s，3 Η)，4.49 (s5 2 Η)，6·76 (m，2 Η)，7·43 (dd，1 Η)， 7.98 (d，1 Η)，8.42 (s，1 Η) 〇 MS APCI+ m/z 362 [ΜΗ] + 製備91 5-(4-氟_2 -甲基-苯基比嗅-2_叛酸甲酯Using the method of Preparation 18 from the product of Preparation 89 and 5-amino-2-methoxypyridine at 29 ° /. The title compound was prepared as a pale yellow foam. ] HNMR (CDC135 400 MHz) δ: 3.37 (s, 3 Η), 3.61 (s, 3 Η)? 3.93 (s, 3 Η), 4.49 (s5 2 Η), 6.76 (m, 2 Η), 7.43 (dd, 1 Η), 7.98 (d, 1 Η), 8.42 (s, 1 Η) 〇MS APCI + m / z 362 [ΜΗ] + Preparation 91 5- (4-fluoro_2 -methyl- Methylphenyl

將4-氟-2-曱基苯基硼酸（17·36 g，112 7 mm〇1)、碳酸鉋 (70.8 g ’ 216.8 mm〇1)及製備 3 之產物（1 5 叫，8 67 咖〇1) 95339.doc -106- 200526606 添加至1，4-二噁烷（2 L)中之5-氣吡嗪_2_甲基羧酸酯（15 g， 86.7 mmol)的溶液中且於回流下加熱混合物2小時。隨後過濾反應混合物且於真空中濃縮以得99%產率、21.33 g之標題化合物。 iNMR (CDC13, 400 ΜΗζ) δ: 2.40 (s，3 H)，4.05 (s，3 H)， 7_05 (m，2 Η)，7.45 (m，1 Η)，8·80 (1，i η)，9.35 (s，1 Η)。 MS APCI+ m/z 247 [ΜΗ] + 製備92 5·(4-氟·2-甲基-苯基）吼嗪-2-羧酸醯肼Add 4-fluoro-2-fluorenylphenylboronic acid (17.36 g, 112 7 mm), carbonate shavings (70.8 g '216.8 mm), and the product of Preparation 3 (15, 8 67 coffee). 1) 95339.doc -106- 200526606 was added to a solution of 5-pyrazine-2-methylcarboxylate (15 g, 86.7 mmol) in 1,4-dioxane (2 L) and refluxed The mixture was heated for 2 hours. The reaction mixture was then filtered and concentrated in vacuo to give 99% yield of 21.33 g of the title compound. iNMR (CDC13, 400 ΜΗζ) δ: 2.40 (s, 3 H), 4.05 (s, 3 H), 7_05 (m, 2 Η), 7.45 (m, 1 Η), 8.80 (1, i η) , 9.35 (s, 1 Η). MS APCI + m / z 247 [ΜΗ] + Preparation 92 5 · (4-fluoro · 2-methyl-phenyl) oxazine-2-carboxylic acid hydrazine

於回流下加熱甲醇（600 mL)中之製備91之產物（42.5 g， 172.8 mmol)與肼單水合物（9.46 mL，207.3 mmol)之混合物 30小時。隨後冷卻反應混合物至室溫且濾出沈澱物且於真二中乾無以得75%產率、7.10 g之標題化合物。 iHNMR (DMSO, 400 ΜΗζ) δ: 2.35 (s，3 H)，4.60 (S，2 H)， 7.20 (m，2 Η)，7.60 (m，1 Η)，8·80 (s，1 Η)，9·15 (s，1 Η)， 1〇·2 (s，1 Η)。實例1-4 95339.doc 107- 200526606A mixture of the product of Preparation 91 (42.5 g, 172.8 mmol) and hydrazine monohydrate (9.46 mL, 207.3 mmol) in methanol (600 mL) was heated under reflux for 30 hours. The reaction mixture was then cooled to room temperature and the precipitate was filtered off and dried in Shinji to give 75% yield of 7.10 g of the title compound. iHNMR (DMSO, 400 ΜΗζ) δ: 2.35 (s, 3 H), 4.60 (S, 2 H), 7.20 (m, 2 Η), 7.60 (m, 1 Η), 8.80 (s, 1 Η) , 9.15 (s, 1 Η), 10.2 (s, 1 Η). Examples 1-4 95339.doc 107- 200526606

將製備5之溴化合物（100 mg，0.29 mmol)、製備3之鈀複合物（10 mg，觸媒）、碳酸铯（440 mg，1.3 5 mmol)及適當硼酸（0.73 mmol)懸浮於1，4-二噁烷（5 mL)中且於120°C加熱反應混合物90分鐘。加入額外之1，4-二噁烷（4 mL)且於100°C 加熱反應混合物進一步之4小時。於真空下過濾反應混合物，藉由二氯曱烷洗滌。於真空中濃縮濾出液且藉由管柱層析法於矽膠上以95 :5:0.5之二氣甲烷：甲醇：0.88氨水洗提來純化殘餘物以得所需產物。序號 R1 資料產率 1 MS ES+ m/z 390 [MH] + 9% 2 bNMRCCDCh，400MHz) δ: 2.01(s，3H)，2.22(s，3H)，2.26(s， 3H)，3.75(s，3H)，6.87(d5 1H)， 7.02(m，4H)，7.20(m，2H)， 7_24(m，2H)，7.39(m，2H) MS APCI+ m/z 370 [MH] + 10% 3 MS APCI+ m/z 370 [MH] + 36% C^CHS 4 h3c、〇人， ^NMRCCDCls, 400MHz) δ: 2.31 (s，3H)，3.79(s，3H)， 3.83(s，3H)，7.02(m，3H)， 7.27(m，2H)，7.34(d，2H)， 7_41(d，2H)，7.57(d，2H)· MS APCI+ m/z 390 [MH] + 52% 95339.doc -108- 200526606 實例5 2-(4-氟-2-甲基苯基）_5_(5-甲氧基甲基-4-(6-甲氧基”比啶-3 基）-4Η-[1，2,4]***-3-基）^比啶The bromine compound (100 mg, 0.29 mmol) from Preparation 5, the palladium complex (10 mg, catalyst) from Preparation 3, cesium carbonate (440 mg, 1.3 5 mmol), and appropriate boric acid (0.73 mmol) were suspended in 1,4. -Dioxane (5 mL) and heated the reaction mixture at 120 ° C for 90 minutes. An additional 1,4-dioxane (4 mL) was added and the reaction mixture was heated at 100 ° C for a further 4 hours. The reaction mixture was filtered under vacuum and washed with dichloromethane. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel with 95: 5: 0.5 gaseous methane: methanol: 0.88 ammonia to purify the residue to give the desired product. Serial number R1 Data yield 1 MS ES + m / z 390 [MH] + 9% 2 bNMRCCDCh, 400MHz) δ: 2.01 (s, 3H), 2.22 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 6.87 (d5 1H), 7.02 (m, 4H), 7.20 (m, 2H), 7_24 (m, 2H), 7.39 (m, 2H) MS APCI + m / z 370 [MH] + 10% 3 MS APCI + m / z 370 [MH] + 36% C ^ CHS 4 h3c, 0 people, ^ NMRCCDCls, 400MHz) δ: 2.31 (s, 3H), 3.79 (s, 3H), 3.83 (s, 3H), 7.02 ( m, 3H), 7.27 (m, 2H), 7.34 (d, 2H), 7_41 (d, 2H), 7.57 (d, 2H) · MS APCI + m / z 390 [MH] + 52% 95339.doc -108 -200526606 Example 5 2- (4-fluoro-2-methylphenyl) _5_ (5-methoxymethyl-4- (6-methoxy "pyridin-3yl) -4Η- [1,2 , 4] triazol-3-yl) ^ pyridine

藉由製備18之方法使用製備19之產物及5-胺基-2-甲氧基 "比ϋ定製備標題產物。製得14〇 mg、15%產率之所需產物。 !HNMR (CDC135 400 MHz) δ: 2.36 (s5 3 Η), 3.38 (s? 3 Η), 4.〇1 (s，3 Η)，4.51 (s，2 Η)，6·88 (d，1 Η)，6.93-7.00 (m，2 Η)， 7·36 (dd，1 Η)，7.40 (d，1 Η)，7.56 (dd，1 Η)，8·00 (dd，1 Η), 8·15 (d，1 Η)，8.64 (d，1 Η)。微量分析：C22h2〇FN5〇2需要： C 65.18, Η 4.97, N 17.27 ;實驗值 c 65.01，Η 4.96, N 17.27. MS APCI+ m/z 406 [MH] + 實例4 2-(2,3-二甲基苯基）-s_(s·甲氧基甲基_4_(6_甲氧基吡啶_3_ 基）_4H-[i，2,4]***-3_基）_吡啶The title product was prepared by the method of Preparation 18 using the product of Preparation 19 and 5-amino-2-methoxy " biridine. The desired product was obtained in 14 mg, 15% yield. ! HNMR (CDC135 400 MHz) δ: 2.36 (s5 3 Η), 3.38 (s? 3 Η), 4.〇1 (s, 3 Η), 4.51 (s, 2 Η), 6.88 (d, 1 Η), 6.93-7.00 (m, 2 Η), 7.36 (dd, 1 Η), 7.40 (d, 1 Η), 7.56 (dd, 1 Η), 8.00 (dd, 1 Η), 8 15 (d, 1 Η), 8.64 (d, 1 Η). Microanalysis: C22h2〇FN502 requires: C 65.18, Η 4.97, N 17.27; experimental value c 65.01, Η 4.96, N 17.27. MS APCI + m / z 406 [MH] + Example 4 2- (2,3-II Methylphenyl) -s_ (s · methoxymethyl_4_ (6_methoxypyridine_3_yl) _4H- [i, 2,4] triazol-3-yl) _pyridine

藉由製備18之方法使用製備20之產物及5_胺基_2_甲氧基 95339.doc -109. 200526606 °比σ定製備標題產物。製得325 mg、36%產率之所需產物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.21 (S，3 H)，2.34 (s，3 H)， 3·38 (s，3 Η)，4.0G (s，3 Η)，4.52 (s，2 Η)，6·88 (d，1 Η)， 7.13-7.22 (m，3 Η)，7·40 (d，1 Η)，7.55 (d，1 Η)，7·99 (dd，1 Η)，8·16 (d，1 Η)，8·64 (d，1 Η)。微量分析：〇：23112况〇2_〇·! Η2〇要求；C 68.50，H5.80，N 17.37;實驗值 C 68.24, Η 5·90, Ν 17.05。MS APCI+ m/z 402 [ΜΗ] + 實例7 5_(4_氟_2_甲基苯基）-:2-(((5-甲氧基甲基_4_(6_甲氧基”比啶 -3-基））_411-[1，2,4】三峻_3-基）-«比咬The title product was prepared by the method of Preparation 18 using the product of Preparation 20 and 5-amino_2_methoxy 95339.doc -109. 200526606 ° ratio σ. The desired product was obtained in 325 mg, 36% yield. iHNMR (CDC13, 400 MΗζ) δ: 2.21 (S, 3 H), 2.34 (s, 3 H), 3.38 (s, 3 Η), 4.0G (s, 3 Η), 4.52 (s, 2 Η) ), 6.88 (d, 1 Η), 7.13-7.22 (m, 3 Η), 7.40 (d, 1 Η), 7.55 (d, 1 Η), 7.99 (dd, 1 Η), 8.16 (d, 1 Η), 8.64 (d, 1 Η). Microanalysis: 〇: 23112, 〇2_〇 ·! Η20 requirements; C 68.50, H5.80, N 17.37; experimental value C 68.24, Η 5.90, N 17.05. MS APCI + m / z 402 [ΜΗ] + Example 7 5_ (4_fluoro_2_methylphenyl)-: 2-(((5-methoxymethyl_4_ (6_methoxy) pyridine -3-base)) _ 411- [1,2,4] Sanjun_3-base)-«than bite

將製備1 8之漠化合物（250 mg，0.66 mmol)、2 -甲基-4-氟-苯基硼酸（23 5 mg，1.53 mmol)、製備3之鈀複合物（1〇 mg，觸媒）及碳酸铯（1 ·00 g，3.07 mmol)添加至1，4_二嗔燒（5 mL) 且於110 C加熱反應混合物4小時。藉由Arbocel®過濾反應混合物，藉由二氯曱烷洗滌且於真空中濃縮濾出液。藉由管柱層析法於矽膠上以100:0至95:5之二氣甲烷：甲醇洗提來純化殘餘物以得作為淺桃紅色固體之標題產物，丨28 mg， 4 8 %產率。 HNMR (DMS〇-D6，400 ΜΗζ) δ: 2.21 (s，3 H)，3.18 (s， 95339.doc -110- 200526606 3 Η)，3·89 (s，3 Η)，4·44 (s，2 Η)，6·94 (m5 1 H)，7.09 (m，1 H)， 7.19 (m，1 H)，7.28 (m，1 H)，7.81 (m，！ H)，7·94 (m，（ H)， 8.15 (m，i H)，8·23 (m，i H)，8·32 (m，1 H)。ms Apci+ 油 406 [MH] + 實例8 5-(2,3-二甲基苯基）-2例甲氧基甲基）冰(6•甲氧基㈣冬基）-4Η-1，2,4-***-3-基】吡啶Preparation of a desert compound (250 mg, 0.66 mmol), 2-methyl-4-fluoro-phenylboronic acid (23 5 mg, 1.53 mmol), and a palladium complex of preparation 3 (10 mg, catalyst) And cesium carbonate (1.00 g, 3.07 mmol) were added to 1,4-dioxane (5 mL) and the reaction mixture was heated at 110 C for 4 hours. The reaction mixture was filtered through Arbocel®, washed with dichloromethane and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica with 100: 0 to 95: 5 methane: methanol to obtain the title product as a pale pink solid, 28 mg, 48% yield . HNMR (DMS〇-D6, 400 ΜΗζ) δ: 2.21 (s, 3 H), 3.18 (s, 95339.doc -110- 200526606 3 Η), 3.89 (s, 3 Η), 4.44 (s , 2 Η), 6.94 (m5 1 H), 7.09 (m, 1 H), 7.19 (m, 1 H), 7.28 (m, 1 H), 7.81 (m,! H), 7.94 ( m, (H), 8.15 (m, i H), 8.23 (m, i H), 8.32 (m, 1 H). ms Apci + oil 406 [MH] + Example 8 5- (2,3 -Dimethylphenyl) -2 examples of methoxymethyl) ice (6 • methoxyfluorenyl) -4Η-1,2,4-triazol-3-yl] pyridine

藉由實例7之方法使m二甲基苯基㈣製備標題產物。製得132 mg、49%產率之作為淺桃紅色固體之所需產物。 iHNMR (DMSO-D6, 400 ΜΗζ) δ: 2.07 (s，3 H)，2.38 (s，3 H)， 3.17 (s，3 Η)，3.89 (s，3 Η)，4·44 (s，2 Η)，6.94 (m，1 Η)，7·04 (m，1 Η)，7.15 (m，1 Η)，7.22 (m，1 Η)，7.82 (m，1 Η)，7·90 (m， 1 Η)，8·15 (m，1 Η), 8.24 (m，1 Η)，8·28 (m，1 Η) 〇 MS APCI+ m/z 402 [ΜΗ] + 實例9 1-[5-[5-(2,3-二甲基苯基）-吡啶-2_基卜4_(6_甲氡基吡啶·3-基ΜΗ-ιι，2,4]^·3-基甲基Ρ比咯啶-(2S)-2令睃醯胺 95339.doc -111 - 200526606The title product was prepared from m-dimethylphenylphosphonium by the method of Example 7. 132 mg, 49% yield of the desired product was obtained as a light pink solid. iHNMR (DMSO-D6, 400 ΜΗζ) δ: 2.07 (s, 3 H), 2.38 (s, 3 H), 3.17 (s, 3 Η), 3.89 (s, 3 Η), 4.44 (s, 2 Η), 6.94 (m, 1 Η), 7.04 (m, 1 Η), 7.15 (m, 1 Η), 7.22 (m, 1 Η), 7.82 (m, 1 Η), 7.90 (m , 1 Η), 8.15 (m, 1 Η), 8.24 (m, 1 Η), 8.28 (m, 1 Η) 〇MS APCI + m / z 402 [ΜΗ] + Example 9 1- [5- [5- (2,3-dimethylphenyl) -pyridine-2_yl_4- (6_methylpyridine · 3-yl MΗ-ιι, 2,4] ^ · 3-ylmethyl P ratio Pyridine- (2S) -2 fluorenamine 95339.doc -111-200526606

將製備27之溴化合物（丨25 mg，0.27 mmol)、2,3-二曱基苯基蝴酸（61 mg，〇·41 mmol)及製備3之鈀複合物（10 mg)溶解於1，2 -二甲氧基乙烧（4 mL)中且以碳酸納（5 8 mg，0.55 mmol)處理該溶液。將反應混合物加熱至回流1小時且隨後於真空中濃縮。將殘餘物溶解於乙酸乙酯（25 mL)中且以水 (25 mL)、2 Μ氫氧化鈉溶液（25 mL)及鹽水（25 mL)洗滌。於硫酸鎂上乾燥該溶液且於真空中濃縮。藉由管柱層析法於石夕膠上以100:0:0至97:3:0.3之二氯甲烷：甲醇：〇.88氨水洗提來純化殘餘物以得標題產物，95 mg，72%產率。 ^NMR (CDC13? 400 MHz) δ. 1.80 (m, 2 Η)5 2.00 (m5 1 Η), 2·10 (s，3 Η)，2.20 (m，1 Η)，2.40 (s，3 Η)，2.60 (m，1 Η)， 3·20 (m，2 Η)，3.80 (m，2 Η)，4.00 (s，3 Η)，5.00 (s，1 Η)， 6·80 (s，1 Η)，6·90 (d，1 Η)，7·00 (d，1 Η)，7·1〇 (d，1 Η)，7.20 (d，1 Η)，7·60 (d，1 Η)，7.70 (d，1 Η)，8.80 (s，ι Η)，8.20 (m， 2 Η)。MS ES+ m/z 484 [ΜΗ] + 實例10 5-(2,3-二甲基苯基）_2-(5-咕洛咬-1-基甲基-4-(6-甲氧基|1比啶-3-基）-4Η_[1，2,4]***-3-基）-吡啶 95339.doc -112- 200526606The bromine compound of Preparation 27 (25 mg, 0.27 mmol), 2,3-difluorenylphenyl butterfly acid (61 mg, 0.41 mmol) and the palladium complex of Preparation 3 (10 mg) were dissolved in 1, The solution was treated with 2-dimethoxyethane (4 mL) and sodium carbonate (58 mg, 0.55 mmol). The reaction mixture was heated to reflux for 1 hour and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL) and washed with water (25 mL), 2M sodium hydroxide solution (25 mL), and brine (25 mL). The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on Shixi gum with 100: 0: 0 to 97: 3: 0.3 dichloromethane: methanol: 0.88 aqueous ammonia to obtain the title product, 95 mg, 72 %Yield. ^ NMR (CDC13? 400 MHz) δ. 1.80 (m, 2 Η) 5 2.00 (m5 1 Η), 2.10 (s, 3 Η), 2.20 (m, 1 Η), 2.40 (s, 3 Η) , 2.60 (m, 1 Η), 3.20 (m, 2 Η), 3.80 (m, 2 Η), 4.00 (s, 3 Η), 5.00 (s, 1 Η), 6.80 (s, 1 Η), 6.90 (d, 1 Η), 7.00 (d, 1 Η), 7.10 (d, 1 Η), 7.20 (d, 1 Η), 7.60 (d, 1 Η) ), 7.70 (d, 1 Η), 8.80 (s, ι Η), 8.20 (m, 2 Η). MS ES + m / z 484 [ΜΗ] + Example 10 5- (2,3-dimethylphenyl) _2- (5-gulobit-1-ylmethyl-4- (6-methoxy | 1 | Pyridin-3-yl) -4Η_ [1,2,4] triazol-3-yl) -pyridine 95339.doc -112- 200526606

乃次使用製備28之溴化合物製備80 mg、藉由實例9之方、太技 3 8 %產率之標韻姦仏 '、產物。HNMR (CDC13, 400 ΜΗζ) δ: 1.80 (s， 4 Η)，2·1〇 (s 3 m ’ J，厶4〇 (s，3 H)，2.50 (s，4 H)，3·70 (s，2 H)， 4.00 (s，3 “rwj ? · 〇 (d，1 H)，7.00 (d，1 H)，7.20 (m，2 H)，7.70 (t，2 H)，8·1〇 (d 】Λ 、，丄 H)，8_20 (d5 1 H)，8.30 (s，1 H)。MS ES+ m/z 441 [MH]4* 實例11 2 (4氣_2_甲基苯基）_5-[5-甲氧基甲基-4-(6-甲氧基咐咬-3-基）_4H-[1，2,4]***_3-基】_π比嗪This time, 80 mg of bromine compound of Preparation 28 was used to prepare the product, which was the standard rhizome of Taiji in 38% yield. HNMR (CDC13, 400 ΜΗζ) δ: 1.80 (s, 4 Η), 2.10 (s 3 m 'J, 厶 4〇 (s, 3 H), 2.50 (s, 4 H), 3.70 ( s, 2 H), 4.00 (s, 3 "rwj? · 〇 (d, 1 H), 7.00 (d, 1 H), 7.20 (m, 2 H), 7.70 (t, 2 H), 8.1 〇 (d) Λ, 丄 H), 8-20 (d5 1 H), 8.30 (s, 1 H). MS ES + m / z 441 [MH] 4 * Example 11 2 (4-Gas_2_methylphenyl) ) _5- [5-methoxymethyl-4- (6-methoxymethoxy-3-yl) _4H- [1,2,4] triazole_3-yl] _πbiazine

將製備22之產物（45〇 mg，1.5〇 mmol)、對甲苯石黃酸單水合物及5-胺基-2-曱氧基吡啶（2〇5 mg，1.65 mmol)添加至二甲本（8 mL)中且於145。(3加熱反應混合物1 8小時。於真空中 ί辰縮反應混合物且藉由管柱層析法於石夕膠上以1 〇〇: 〇: 〇至 99.5:0.5:0.05至99:1:0.1之二氯曱烷：甲醇：〇·88氨水洗提來純化殘餘物以得作為綠色固體之標題產物，300 mg，49% 95339.doc -113- 200526606 產率。 hNMR (CDC13, 400 MHz) δ: 2.38 (s，3 H)，3.34 (s，3 H)， 3.99 (s，3 H)，4.50 (s，2 H)，6.85 (d，1 H)，6.95-7.03 (m，2 H)， 7.36-7.42 (m，1 H)，7.60 (dd，1 H)，8.12 (d，1 H)，8.40 (s，1 H)， 9.48 (s，1 H)。MS APCI+ m/z 407 [MH] + 實例12 2_(2,3 -二甲基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基η比咬_3-基）_4H_[1，2,4]三嗤-3-基]-«比口秦The product of Preparation 22 (45 mg, 1.50 mmol), p-toluene lutein acid monohydrate, and 5-amino-2-methoxypyridine (205 mg, 1.65 mmol) were added to dimethylbenzidine ( 8 mL) and 145. (3 The reaction mixture was heated for 18 hours. The reaction mixture was shrunk in vacuo and subjected to column chromatography on Shixi gum at 100: 0: 0 to 99.5: 0.5: 0.05 to 99: 1: 0.1. Dichloromethane: methanol: 0.88 aqueous ammonia was used to purify the residue to give the title product as a green solid, 300 mg, 49% 95339.doc -113- 200526606 yield. HNMR (CDC13, 400 MHz) δ : 2.38 (s, 3 H), 3.34 (s, 3 H), 3.99 (s, 3 H), 4.50 (s, 2 H), 6.85 (d, 1 H), 6.95-7.03 (m, 2 H) , 7.36-7.42 (m, 1 H), 7.60 (dd, 1 H), 8.12 (d, 1 H), 8.40 (s, 1 H), 9.48 (s, 1 H). MS APCI + m / z 407 [ MH] + Example 12 2_ (2,3-Dimethylphenyl) -5- [5-methoxymethyl-4- (6-methoxyη specific ratio_3-yl) _4H_ [1,2 , 4] 三嗤 -3- 基]-«Bekouqin

h3c - 0 藉由貫例11之方法使用製備21之產物製備42 mg、7%產率之標題產物。 2.23 (s，3 Η)，2·34 (s，3 Η)， (m，2 Η)，6·86 (d, 1 Η)，7·19 1 Η)，7_62 (dd，1 Η)5 8.14 (d， )· MS APCI+ m/z 403 [ΜΗ] + ]HNMR (CDC13? 400 MHz) δ： 2 3.36 (s，3 Η)，4.00 (s，3 Η), 4·5〇 ( (d，1 Η)，7.20 (s，1 Η)，7.24 (m，丄 1 Η)，8.41 (d，1 Η)，9.49 (d，1 Η)· •甲氧基吡啶-3-基）-5-甲基 2-(2,3-二甲基苯基）_5-[4_(6_ 甲 -4Η_[1，2,4]***-3-基]•咄嗅 95339.doc -114- 200526606h3c-0 The title product of 42 mg, 7% yield was prepared by the method of Example 11 using the product of Preparation 21. 2.23 (s, 3 Η), 2.34 (s, 3 Η), (m, 2 Η), 6.86 (d, 1 Η), 7.19 1 Η), 7_62 (dd, 1 Η) 5 8.14 (d,) MS APCI + m / z 403 [ΜΗ] +] HNMR (CDC13? 400 MHz) δ: 2 3.36 (s, 3 Η), 4.00 (s, 3 Η), 4.50 ((d , 1 Η), 7.20 (s, 1 Η), 7.24 (m, 丄 1 Η), 8.41 (d, 1 Η), 9.49 (d, 1 Η) · • methoxypyridin-3-yl) -5 -Methyl 2- (2,3-dimethylphenyl) _5- [4_ (6_methyl-4Η_ [1,2,4] triazol-3-yl] • 咄 ol 95339.doc -114- 200526606

藉由實例11之方法使用製備23之產物製備標題產物，製得23.14 mg、3%產率之作為白色固體之所需產物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.22 (s，3 H)，2.34 (s，3 H)， 2.39 (s，3 Η)，4·01 (s，3 Η)，6.88(d，1 Η)，7.18-7.25 (m，3 Η)， 7·52 (dd，1 Η)，8.09 (d，1 Η)，8·37 (s，1 Η)，9.49 (s，1 Η)。 MS APCI+ m/z 373 [ΜΗ] + 實例14 2-(4•氟_2-甲基苯基）-5·[4_(6_甲氧基n比咬_3_基）-5•甲基 -4H-[1，2,4]***-3-基】吡嗪The title product was prepared by the method of Example 11 using the product of Preparation 23 to obtain 23.14 mg of the desired product as a white solid in 3% yield. iHNMR (CDC13, 400 ΜΗζ) δ: 2.22 (s, 3 H), 2.34 (s, 3 H), 2.39 (s, 3 Η), 4.01 (s, 3 Η), 6.88 (d, 1 Η) , 7.18-7.25 (m, 3 Η), 7.52 (dd, 1 Η), 8.09 (d, 1 Η), 8.37 (s, 1 Η), 9.49 (s, 1 Η). MS APCI + m / z 373 [ΜΗ] + Example 14 2- (4 • fluoro_2-methylphenyl) -5 · [4_ (6_methoxyn specific ratio_3_yl) -5 • methyl -4H- [1,2,4] triazol-3-yl] pyrazine

將製備30之氯化合物（80〇叫，2.6〇111111〇1)、4_氟_2_曱基苯基蝴酸⑽瓜^^瓜⑽…製❸之把複合⑽㈣及碳酸铯（2.50 g，7.90 mmol)添加至i，4_二π惡烧（8〇叫中且將反應混合物加熱至回流2小時。藉由過濾管過濾該混合物且隨後藉由-石夕石整過濾以96:4之二氣甲烧：曱醇洗提。於真空中濃縮濾出液且藉由管柱層析法於矽膠上以丄〇〇: 〇至吵5 95339.doc -115- 200526606 之二氯甲烷：甲醇洗提純化以得66%產率、646 mg作為白色固體之標題產物。】HNMR (CDC13, 400 ΜΗζ) δ: 2.39 (s，3 H)，2.41 (s，3 H) 4.01 (s，3 H)，6.89 (d，1 H)，6.95-7.03 (m，2 H)，7.38 (dd，1 Η) 7.54 (dd，1 H)，8.09 (d，1 H)，8·38 (d，1 H)，9.49 (d，l H)。 MS APCI+ m/z 377 [MH] + 替代方法將二甲基乙醯胺二曱基乙縮醛（28 mL，192.1 mmol)添加至冰醋酸（315 mL)中之製備92之產物（31 ·5 g，127.9 mmol) 籲的懸浮液中且於6 0 C加熱混合物5小時。加入5 -胺基-2 "曱氧基吡啶（23.9 g，192 mmol)且於l〇〇°C加熱混合物進一步之6 小時。隨後冷卻混合物至室溫且於減壓下蒸發。將殘餘物洛解於二氣甲烷（750 mL)中且以飽和碳酸氫鈉溶液（丨L)洗滌。於硫酸鎂上乾燥有機溶液且於真空中濃縮。隨後自熱丙酮中重結晶殘餘物得31%產率、14·81 g作為白色固體之標題化合物。實例15 · 2·(4_氦基-2-甲基苯基）_5_[4_(6_甲氧基，比啶_3基广$甲基 -4Η·[1，2,4】***基卜吡嗪Chlorine compound (80 °, 2.6〇111111〇1), 4_fluoro_2_fluorenylphenyl acetic acid, melons, etc., which are prepared in 30, are made of hydrazone and cesium carbonate (2.50 g, 7.90 mmol) was added to i, 4-diπ oxalic acid (80 ° C. and the reaction mixture was heated to reflux for 2 hours. The mixture was filtered through a filter tube and then filtered through -Shi Xi Shi whole filter at 96: 4 Dichloromethane: Ethanol extraction. Concentrate the filtrate in vacuo and use column chromatography on silica gel with 丄 00: 〇 to No. 5 95339.doc -115- 200526606 in dichloromethane: methanol. Elution and purification to give the title product in 66% yield and 646 mg as a white solid.] HNMR (CDC13, 400 ΜΗζ) δ: 2.39 (s, 3 H), 2.41 (s, 3 H) 4.01 (s, 3 H ), 6.89 (d, 1 H), 6.95-7.03 (m, 2 H), 7.38 (dd, 1 Η) 7.54 (dd, 1 H), 8.09 (d, 1 H), 8.38 (d, 1 H), 9.49 (d, 1 H). MS APCI + m / z 377 [MH] + Alternative method Add dimethylacetamide difluorenyl acetal (28 mL, 192.1 mmol) to glacial acetic acid (315 mL ) Of product 92 (31 · 5 g, 127.9 mmol) in suspension and the mixture was heated at 60 ° C 5 hours. 5-Amino-2 " methoxypyridine (23.9 g, 192 mmol) was added and the mixture was heated at 100 ° C for a further 6 hours. The mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was digested in digas methane (750 mL) and washed with saturated sodium bicarbonate solution (丨 L). The organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was then recrystallized from hot acetone to obtain 31% yield, 14.81 g of the title compound as a white solid. Example 15 · 2 · (4_helyl-2-methylphenyl) _5_ [4_ (6_methoxy, broader than pyridine_3 $ Methyl-4Η · [1,2,4] triazolylpyrazine

h3c^〇 95339.doc -116- 200526606 藉由實例14之方法使用製備30之氯化合物（200 mg，0.66 mmol)及製備29之產物_ mg，Q 99匪叫製備標題產物，製付68 mg、27%產率之作為白色固體之標題產物。 ^NMR (CDC135 400 MHz) δ: 2.40 (s? 3 Η)5 2.43 (s? 3 Η)5 4·01 (s，3 Η)，6.90 (d，1 Η)，7.50-7.55 (m，2 Η), 7.57 (s，1 Η)， 7.60 (s，1 Η)，8.08 (d，1 Η)，8.41 (d，1 Η)，9.55 (d，1 Η)。微量分析·· C21H17N7〇〇·1 η2〇要求；c 65.79, Η 4.47, Ν 25.57 ; 實驗值 C 65.23, Η 4.48, Ν 25.09。MS APCI+ m/z 384 [ΜΗ] + 實例16 2-(5·氟-2-甲氧基苯基甲氧基„比啶_3基）5曱基 -4H_[1，2,4]三嗤·3·基】比唤h3c ^ 〇95339.doc -116- 200526606 By the method of Example 14 using the chlorine compound of preparation 30 (200 mg, 0.66 mmol) and the product of preparation 29_ mg, Q 99 called the title product to prepare 68 mg, 27% yield of the title product as a white solid. ^ NMR (CDC135 400 MHz) δ: 2.40 (s? 3 Η) 5 2.43 (s? 3 Η) 5 4.01 (s, 3 Η), 6.90 (d, 1 Η), 7.50-7.55 (m, 2 Η), 7.57 (s, 1 Η), 7.60 (s, 1 Η), 8.08 (d, 1 Η), 8.41 (d, 1 Η), 9.55 (d, 1 Η). Microanalysis · C21H17N7 0 0 1 η 2 0 requirements; c 65.79, Η 4.47, Ν 25.57; experimental value C 65.23, Η 4.48, Ν 25.09. MS APCI + m / z 384 [ΜΗ] + Example 16 2- (5 · Fluoro-2-methoxyphenylmethoxy „pyridine_3yl) 5fluorenyl-4H_ [1,2,4] trifluorene · 3 · Base

FF

藉由實例14之方法使用製備30之氯化合物（2〇〇 mg，〇 66 mmol)及5 -氟-2-甲氧基苯基石朋酸（168 mg，〇·99 mmol)努備標題產物’製得1 50 mg、58%產率之作為膏狀固體之標題產物。】HNMR (CDC13, 400 ΜΗζ) δ: 2.37 (s，3 H)，3.85 (s，3 H) 4·00 (s，3 Η)，6.88 (d，1 Η)，6.92 (dd，1 Η)，7.09 (m，1 η) 7·50 (dd，1 Η)，7·68 (dd，1 Η)，8.07 (d，1 Η)，8·93 (d，1 Η) 9·46 (d，1 Η)。 -117- 95339.doc 200526606 製備17 2-(4-氰基-2-甲基苯基)_S_ [5甲氧基甲基_4 (6甲氧基吡啶 -3-基）-4H_丨1，2,4]三嗤_3_基】-ϋ比嗓The title product was prepared by the method of Example 14 using the chloro compound of Preparation 30 (200 mg, 066 mmol) and 5-fluoro-2-methoxyphenyllithium benzoate (168 mg, 0.99 mmol). The title product was obtained as a paste-like solid at 150 mg, 58% yield. ] HNMR (CDC13, 400 ΜΗζ) δ: 2.37 (s, 3 H), 3.85 (s, 3 H) 4.00 (s, 3 Η), 6.88 (d, 1 Η), 6.92 (dd, 1 Η) , 7.09 (m, 1 η) 7.50 (dd, 1 Η), 7.68 (dd, 1 Η), 8.07 (d, 1 Η), 8.93 (d, 1 Η) 9.46 (d , 1 Η). -117- 95339.doc 200526606 Preparation 17 2- (4-cyano-2-methylphenyl) _S_ [5methoxymethyl_4 (6methoxypyridin-3-yl) -4H_ 丨 1 ， 2,4] 三嗤 _3_ 基】 -ϋ 比声

藉由實例14之方法使用製備31之氣化合物（1〇 §，3〇 mm〇1)及製備29之氣化合物⑽2 g，4·2 mmGl)製備標題產物，製得814 mg、66〇/〇產率之作為淺黃色固體之所需產物。 ]HNMR (CDC135 400 MHz) δ: 2.35 (s5 3 Η)? 3.15 (s5 3 Η), 3.80 (s，3 Η)，4.45 (s，2 Η)，6.95 (d，1 Η)，7.65-7.90 (m，4 η)。 MS APCI+ m/z 414[ΜΗ] + 實例18 5-(4-氰基-2-甲基苯基）_2-[5-甲氧基甲基-4 (6甲氧基吼啶 -3-基）-4Η-[1，2,4]***-3-基卜吡咬The title product was prepared by the method of Example 14 using the gas compound of Preparation 31 (10§, 30 mm) and the gas compound of Preparation 29 (2 g, 4.2 mm Gl) to obtain 814 mg, 66 ° / °. Yield as the desired product as a pale yellow solid. ] HNMR (CDC135 400 MHz) δ: 2.35 (s5 3 Η)? 3.15 (s5 3 Η), 3.80 (s, 3 Η), 4.45 (s, 2 Η), 6.95 (d, 1 Η), 7.65-7.90 (m, 4 η). MS APCI + m / z 414 [ΜΗ] + Example 18 5- (4-Cyano-2-methylphenyl) _2- [5-methoxymethyl-4 (6methoxypyridin-3-yl) ) -4Η- [1,2,4] triazol-3-ylbip

藉由貫例7之方法使用製備29之產物（1〇〇 mg，0.41 mmol) 及製備18之溴化合物ο” mg，〇⑷mm〇1)製備標題產物， 95339.doc 200526606 製得作為白色固體之67 mg、39%產率之所需產物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.28 (s，3 H)，3.35(s，3 H)， 3·99 (s，3 Η), 4.50 (s，2 Η)，6.85 (d，1 Η)，7·28 (d，！ Η)， 7.52-7.58 (m，2 Η)，7.62 (dd，1 Η)，7.74 (dd，ι η)，8 11 (d 1 Η)，8·28 (dd，1 Η)，8·33 (1 Η，d)。微量分析：C23H2〇N6〇2[：]〇.5The title product was prepared by the method of Example 7 using the product of Preparation 29 (100 mg, 0.41 mmol) and the bromine compound of Preparation 18 (mg), 100 mm), and 95339.doc 200526606 was prepared as a white solid. 67 mg, 39% yield of the desired product. IHNMR (CDC13, 400 MΗζ) δ: 2.28 (s, 3 H), 3.35 (s, 3 H), 3.99 (s, 3 Η), 4.50 (s , 2 Η), 6.85 (d, 1 Η), 7.28 (d,! Η), 7.52-7.58 (m, 2 Η), 7.62 (dd, 1 Η), 7.74 (dd, ι η), 8 11 (d 1 Η), 8.28 (dd, 1 Η), 8.33 (1 Η, d). Microanalysis: C23H2〇N6〇2 [:] 0.5

H20 需要：c 66.55, Η 5.02, N 19·94 ;見c 66.02, Η 4.90, N 19.83。MS APCI+ m/z 413 [MH] + 實例19 2-(5-氟-2-甲氧基苯基）-5-[5-甲氧基甲基_4_(6甲氧基e比咬 -3-基）-4Η-[1，2,4]***-3_ 基]-吡啶H20 requires: c 66.55, Η 5.02, N 19.94; see c 66.02, Η 4.90, N 19.83. MS APCI + m / z 413 [MH] + Example 19 2- (5-Fluoro-2-methoxyphenyl) -5- [5-methoxymethyl_4_ (6methoxye specific ratio-3) -Yl) -4fluorene- [1,2,4] triazole-3_yl] -pyridine

h3c-〇藉由實例11之方法使用製備32之噁二唑化合物及5-胺基 -2-曱氧基吡啶製備作為淺綠色固體（325 mg，30%)之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 3.36 (s，3 H)，3.84 (s，3 H)， 3·98 (s，3 Η)，4·49 (s，2 Η)，6·87 (d，1 Η)，6·92 (dd，1 Η)，7·06 (m，1 Η)，7.54 (dd，1 Η)5 7.58 (dd，1 Η)，7.96-8.00 (m，2 Η)， 8·14 (d，1 Η)，8.60 (d，1 η)。MS APCI+ m/z 422 [ΜΗ] + 實例20-22 藉由製備1-4之方法使用製備46或47之產物及適當硼酸 95339.doc -119- 200526606 製備下文所示之通式之以下化合物。首先藉由官柱層析法於矽膠上以1〇〇:〇_〇至qmi至 95:5:0.5之乙酸乙酯：曱醇：0.88氨水洗提來純化粗產品，繼而藉由HPLC 使用 phen〇menex Lima C18系統以 95:5 至5:95 之水/乙腈/三氟乙酸（5:95:〇·1):乙腈洗提來純化。h3c-〇 The title compound was prepared as a pale green solid (325 mg, 30%) by the method of Example 11 using the oxadiazole compound of Preparation 32 and 5-amino-2-methoxypyridine. iHNMR (CDC13, 400 ΜΗζ) δ: 3.36 (s, 3 H), 3.84 (s, 3 H), 3.98 (s, 3 Η), 4.49 (s, 2 Η), 6.87 (d , 1 Η), 6.92 (dd, 1 Η), 7.06 (m, 1 Η), 7.54 (dd, 1 Η) 5 7.58 (dd, 1 Η), 7.96-8.00 (m, 2 Η) , 8 · 14 (d, 1 Η), 8.60 (d, 1 η). MS APCI + m / z 422 [ΜΗ] + Examples 20-22 The following compounds of the general formula shown below were prepared by the method of Preparation 1-4 using the product of Preparation 46 or 47 and appropriate boric acid 95339.doc -119- 200526606. The crude product was first purified by column chromatography on silica gel with ethyl acetate: methanol: 0.88 ammonia in the range of 100: 00 to 0 to 95: 5: 0.5, and then phen was used by HPLC The Omenex Lima C18 system was purified by elution with 95: 5 to 5:95 water / acetonitrile / trifluoroacetic acid (5: 95: 〇 · 1): acetonitrile.

序號「 R1 Y 資料產率 20 — η， CH ^NMRCCDCls, 400MHz) δ: 2.37(s， 3H)，3.97(s，3H)， 5.77(s，2H)，6.80(d， 1H)，7.31(dd，1H)， 7.45(m，2H)，7.56(m， 4H)，7.99(d，1H)， 8.04(dd，1H)， 8.66(dd? 1H). MS APCI+ m/z 450 [MH] + 21%^ 21 XC N ^NMRCCDCh, 400MHz) δ: 2.40(s， 3H)，3.97(s，3H)， 5.77(s，2H)，6.75(d， 1H)，7.35(dd，1H)， 7.50(d，1H)， 7.54-7.67(m，4H)， 7.95(d，1H)，8.41 (s， 1H)，9.58(s，1H). MS APCI+ m/z 450 [MH] + 15% 95339.doc -120- 200526606 22Serial number "R1 Y Data yield 20 — η, CH ^ NMRCCDCls, 400MHz) δ: 2.37 (s, 3H), 3.97 (s, 3H), 5.77 (s, 2H), 6.80 (d, 1H), 7.31 (dd , 1H), 7.45 (m, 2H), 7.56 (m, 4H), 7.99 (d, 1H), 8.04 (dd, 1H), 8.66 (dd? 1H). MS APCI + m / z 450 [MH] + 21 % ^ 21 XC N ^ NMRCCDCh, 400MHz) δ: 2.40 (s, 3H), 3.97 (s, 3H), 5.77 (s, 2H), 6.75 (d, 1H), 7.35 (dd, 1H), 7.50 (d , 1H), 7.54-7.67 (m, 4H), 7.95 (d, 1H), 8.41 (s, 1H), 9.58 (s, 1H). MS APCI + m / z 450 [MH] + 15% 95339.doc- 120- 200526606 22

CH ^NMRCCDCls, 400MHz) δ: 2.34(s， 3H)，3.97(s，3H)， 5.77(s，2H)，6.78(d， 1H)，6.95(m，2H)， 7.30(dd，1H)， 7.35(dd5 1H)? 7.42(dd，1H)，7.57(s， 2H)，8.00(m，2H)， 8.60(d，1H) MS APCI+ m/z 443 [MH] + 43% 實例23 4_{5_[5·(甲氧基甲基）_4-(6•甲氧基吡啶_3_基）-4H-l，2,4-三嗅-3-基]吼啶_2-基}-3-甲基苄腈CH ^ NMRCCDCls, 400MHz) δ: 2.34 (s, 3H), 3.97 (s, 3H), 5.77 (s, 2H), 6.78 (d, 1H), 6.95 (m, 2H), 7.30 (dd, 1H), 7.35 (dd5 1H)? 7.42 (dd, 1H), 7.57 (s, 2H), 8.00 (m, 2H), 8.60 (d, 1H) MS APCI + m / z 443 [MH] + 43% Example 23 4_ {5_ [5 · (methoxymethyl) _4- (6 • methoxypyridin_3_yl) -4H-1,2,4-triol-3-yl] pyridin-2-yl} -3- Methylbenzonitrile

將製備49之氣化合物（170 mg，0.87 mmol)、製備3之鈀複合物（5 mg ’觸媒）、碳酸絶（847 mg，2.6 1 mmol)及製備29 之產物（317 mg，1·31 mmol)懸浮於l，4-二噁烷（5 mL)中且於 11 〇 °C加熱反應混合物2小時。以乙酸乙酯稀釋反應混合物，且藉由Celite®過濾。分離濾出液層且以乙酸乙酯（χ2) 重萃取水溶液。隨後以鹽水洗滌經組合之有機溶液，經硫酸鈉乾燥且於真空中濃縮。藉由管柱層析法於矽膠上以 100:0:0至97.5:2.5:0.25之二氯甲烷：甲醇：〇.88氨水洗提來純化以得45°/。產率、160 mg作為白色泡沫狀物之標題化合物。 1HNMR (CDC13, 400 ΜΗζ) δ: 2.38 (s，3 H)，3.38 (S，3 H)， 95339.doc -121 - 200526606 4.00 (s, 3 Η), 4.51 (s, 2 Η), 6.90 (d, 1 Η), 7.45 (d, 1 Η), 7.48 (d, 1 Η), 7.55-7.60 (m, 3 Η), 8.03 (dd, 1 H), 8.15 (d, j H), 8.70 (dd，1 H)。MS APCI+ m/z 413 [MH] + 實例24至28 藉由實例23之方法使用適當***化合物（製備31及5〇_51) 及硼酸製備下文所示之通式之以下化合物。The gas compound of Preparation 49 (170 mg, 0.87 mmol), the palladium complex of Preparation 3 (5 mg 'catalyst), carbonic acid (847 mg, 2.6 1 mmol), and the product of Preparation 29 (317 mg, 1.31 mmol) was suspended in 1,4-dioxane (5 mL) and the reaction mixture was heated at 110 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite®. The filtered layer was separated and the aqueous solution was re-extracted with ethyl acetate (x2). The combined organic solution was then washed with brine, dried over sodium sulfate and concentrated in vacuo. Purify by column chromatography on silica gel with 100: 0: 0 to 97.5: 2.5: 0.25 dichloromethane: methanol: 0.88 ammonia water to obtain 45 ° /. Yield, 160 mg of the title compound as a white foam. 1HNMR (CDC13, 400 ΜΗζ) δ: 2.38 (s, 3 H), 3.38 (S, 3 H), 95339.doc -121-200526606 4.00 (s, 3 Η), 4.51 (s, 2 Η), 6.90 ( d, 1 Η), 7.45 (d, 1 Η), 7.48 (d, 1 Η), 7.55-7.60 (m, 3 Η), 8.03 (dd, 1 H), 8.15 (d, j H), 8.70 ( dd, 1 H). MS APCI + m / z 413 [MH] + Examples 24 to 28 The following compounds of the formula shown below were prepared by the method of Example 23 using the appropriate triazole compound (Preparations 31 and 50-51) and boric acid.

序號 R1 Y R2 產率 24 CH H 3 7% 資料 ^NMRCCDCls, 400MHz) δ: 2.38(; 3H)，2·41 (s，3H)，4.00(s，3H)，6.9 1H)，7.45(m，3H)，7.55(s，1H)，7.5 1H)，8.02(dd，1H)，8.12(d，1H)，8· 1H)·微量分析：C22H18N60需要； 69.10, Η 4.74, N 21.98 實驗值 C 6ί Η 4.75, Ν 21.83. MS APCI+ m/z 3 [ΜΗ] + s，丨 2(d， 8(s， 66(d， C ;.74， 83 25 CH, CH H 83% 資料 ^NMRCCDCls, 400MHz) δ: 2.39(s? 3H)，3.83(s，3H)，3.99(s，3H)， 6.88-6.94(m，2H)，7.05(m，1H)， 7.45(dd，1H)，7.58(s，1H)，7.97(m，2H)， 8.11(d，1H)，8.57(d，1H). MS APCI + m/z 392 [MH] + 95339.doc -122- 200526606 26 ch3 N 〇CH3 35% 資料 ^NMRCCDCb, 400MHz) δ: 3.35(s5 3H)，3.86(s，3H)，4.00(s，3H)，4_49(s， 2H)，6.71 (dd，1H)，6.80(m，1H)，6.85(d， 1H)，7.59(dd，1H)，7.91 (dd，1H)， 8.12(d，1H)，8.88(d，1H)，9.44(d，1H). MS APCI+ m/z423[MH] + 27 XC CH 31% 資料 ^NMRCCDCls, 400MHz) δ: 2.38(s? 3H), 3.34(s，3H)，3.50(m，2H)，3.66(m， 2H)，3.99(s，3H)，4.62(s，2H)，6.88(d， 1H)，7.44(d，1H)，7.48(d，1H)，7.56(d， 2H)，7.66(dd，1H)，8.02(dd，1H)， 8.15(d，1H)，8.70(d，1H)。微量分析： C25H24N6〇3 0.5H2O需要；C 64.50, Η 5.41，N 18.05 ;實驗值 C 64·71，Η 5·33, Ν 17.94. MS APCI+ m/z 457 [ΜΗ] + 28 双 CH 叩，0Ν/%〆 90% 資料 ^NMRCCDCls, 400MHz) δ. 2.35(s? 3H)，3.34(s，3H)，3.50(m，2H)，3.66(m， 2H)，3.98(s，3H)，4.62(s，2H)，6.87(d， 1H)，6_93-7.00(m，2H)，7.36(dd，1H)， 7.41 (d，1H)，7.65(dd，1H)，7.97(dd， 1H)，8.15(d，1H)，8.64(d，1H). MS APCI+ m/z 450 [MH] + 實例29 [5-[6-(4-氟-2-甲基-苯基）-吼啶-3-基]-4-(6-甲氧基-口比啶_3_ 基）-4Η-[1，2,4]***-3-基甲基]-二甲基-胺 95339.doc -123 - 200526606No. R1 Y R2 Yield 24 CH H 3 7% Data ^ NMRCCDCls, 400MHz) δ: 2.38 (; 3H), 2.41 (s, 3H), 4.00 (s, 3H), 6.9 1H), 7.45 (m, 3H), 7.55 (s, 1H), 7.5 1H), 8.02 (dd, 1H), 8.12 (d, 1H), 8.1 · H) · Micro analysis: required for C22H18N60; 69.10, Η 4.74, N 21.98 experimental value C 6ί Η 4.75, Ν 21.83. MS APCI + m / z 3 [ΜΗ] + s, 丨 2 (d, 8 (s, 66 (d, C; .74, 83 25 CH, CH H 83% data ^ NMRCCDCls, 400MHz) δ: 2.39 (s? 3H), 3.83 (s, 3H), 3.99 (s, 3H), 6.88-6.94 (m, 2H), 7.05 (m, 1H), 7.45 (dd, 1H), 7.58 (s, 1H), 7.97 (m, 2H), 8.11 (d, 1H), 8.57 (d, 1H). MS APCI + m / z 392 [MH] + 95339.doc -122- 200526606 26 ch3 N 〇CH3 35% Data ^ NMRCCDCb, 400MHz) δ: 3.35 (s5 3H), 3.86 (s, 3H), 4.00 (s, 3H), 4_49 (s, 2H), 6.71 (dd, 1H), 6.80 (m, 1H), 6.85 ( d, 1H), 7.59 (dd, 1H), 7.91 (dd, 1H), 8.12 (d, 1H), 8.88 (d, 1H), 9.44 (d, 1H). MS APCI + m / z423 [MH] + 27 XC CH 31% data ^ NMRCCDCls, 400MHz) δ: 2.38 (s? 3H), 3.34 (s, 3H), 3.50 (m, 2H), 3.66 (m, 2H), 3.99 (s, 3H) 4.62 (s, 2H), 6.88 (d, 1H), 7.44 (d, 1H), 7.48 (d, 1H), 7.56 (d, 2H), 7.66 (dd, 1H), 8.02 (dd, 1H), 8.15 (d, 1H), 8.70 (d, 1H). Microanalysis: C25H24N6〇3 0.5H2O required; C 64.50, Η 5.41, N 18.05; experimental value C 64 · 71, Η 5.33, Ν 17.94. MS APCI + m / z 457 [ΜΗ] + 28 double CH 叩, ON /% 〆90% Data ^ NMRCCDCls, 400MHz) δ. 2.35 (s? 3H), 3.34 (s, 3H), 3.50 (m, 2H), 3.66 (m, 2H), 3.98 (s, 3H), 4.62 ( s, 2H), 6.87 (d, 1H), 6_93-7.00 (m, 2H), 7.36 (dd, 1H), 7.41 (d, 1H), 7.65 (dd, 1H), 7.97 (dd, 1H), 8.15 (d, 1H), 8.64 (d, 1H). MS APCI + m / z 450 [MH] + Example 29 [5- [6- (4-Fluoro-2-methyl-phenyl) -pyridine-3- Yl] -4- (6-methoxy-pyridinyl_3_yl) -4fluorene- [1,2,4] triazol-3-ylmethyl] -dimethyl-amine 95339.doc -123- 200526606

H3cr0 CHa 使用實例1-4之方法自製備48之產物及4-氟_2_甲基苯基硼酸以70%產率製備作為白色泡沫狀物之標題化合物。】HNMR (CDC13, 400 ΜΗζ) δ: 2.25 (s5 6 H)，2.34 (s，3 H)， 3·47 (s，2 Η)，3.99 (s，3 Η)，6.86 (d，1 Η)，6.93-7.00 (m5 2 Η)， 7·38 (m，2 Η)，7·64 (dd，1 Η)，8.00 (dd，1 Η)，8·16 (d，1 Η)， 8.63 (d，1 Η)。微量分析：C23H23FN60 0.25 Η20需要；C 65.31， Η 5.60, Ν 19·87實驗值 C 65.19, Η 5.63, Ν 19.58。MS APCI+ m/z 419 [ΜΗ] + 實例30 5-{3-(乙氧基甲基）-5-[6-(4-氟-2-甲基苯基）”比啶-3-基]·4Η-1，2,4•***_4_基卜2·甲氧基吡啶H3cr0 CHa The title compound was prepared as a white foam in 70% yield from the product of Preparation 48 and 4-fluoro-2-methylphenylboronic acid using the method of Examples 1-4. HNMR (CDC13, 400 ΜΗζ) δ: 2.25 (s5 6 H), 2.34 (s, 3 H), 3.47 (s, 2 Η), 3.99 (s, 3 Η), 6.86 (d, 1 Η) , 6.93-7.00 (m5 2 Η), 7.38 (m, 2 Η), 7.64 (dd, 1 Η), 8.00 (dd, 1 Η), 8.16 (d, 1 Η), 8.63 ( d, 1 Η). Microanalysis: C23H23FN60 0.25 Η20 required; C 65.31, Η 5.60, Ν 19.87 experimental values C 65.19, Η 5.63, Ν 19.58. MS APCI + m / z 419 [ΜΗ] + Example 30 5- {3- (ethoxymethyl) -5- [6- (4-fluoro-2-methylphenyl) "pyridin-3-yl] 4Η-1,2,4 • triazole_4_kib 2.methoxypyridine

將製備52之氣化合物（230 mg，0.67 mmol)、製備3之I巴複合物（10 mg，觸媒）、碳酸铯（648 mg，2.01 mmol)及 4 -氣- 2-曱基苯基石朋酸（143 mg，0.94 mmol)懸浮於1，4-二17惡烧（4 mL) 中且於110°C加熱反應混合物2小時。加入進一步之量之製備3之產物（5 mg)且繼續加熱3.5小時。隨後將混合物分隔於 95339.doc -124- 200526606 乙酸乙酯及水之間，且分離有機層，經硫酸鈉乾燥且於真空中濃縮。藉由HPLC使用Phenomenex Luna C18系統以95:5 至5:95之水/乙腈/三氟乙酸（5:95:0.1):乙腈洗提來純化殘餘物以得16%產率、44 mg作為白色粉末之標題化合物。 'HNMR (CDC135 400 MHz) δ: 1.16 (t5 3 H)? 2.35 (s? 3 H)5 3.54 (q，2 H)，3·99 (s，3 H)，4.55 (s，2 H)，6.88 (d，1 H)， 6.93-7.00 (m，2 H)，7.34-7.42 (m，2 H)，7.56 (dd，1 H)，8.00 (dd，1 H)，8.16 (d，1 H)，8.65 (d，1 H)。微量分析： C23H22FN502 0·5 H20需要；C 64.48, Η 5.41，N 16.35實驗值 C 64.46, Η 5.27, N 16.40。MS APCI+ m/z 420 [MH] + 實例31 4-{5-[5_(乙氧基甲基）-4-(6-甲氧基吡啶-3_基）-411-1，2,4-三唑-3-基]啦啶-2_基}-3-罗基苄腈The gas compound of Preparation 52 (230 mg, 0.67 mmol), the I-bar complex of Preparation 3 (10 mg, catalyst), cesium carbonate (648 mg, 2.01 mmol), and 4-gas- 2-fluorenylphenyl stone The acid (143 mg, 0.94 mmol) was suspended in 1,4-di-17 oxalate (4 mL) and the reaction mixture was heated at 110 ° C for 2 hours. A further amount of the product of Preparation 3 (5 mg) was added and heating was continued for 3.5 hours. The mixture was then partitioned between 95339.doc -124- 200526606 ethyl acetate and water, and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by HPLC elution using a Phenomenex Luna C18 system with 95: 5 to 5:95 water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile to give 16% yield, 44 mg as white The title compound as a powder. 'HNMR (CDC135 400 MHz) δ: 1.16 (t5 3 H)? 2.35 (s? 3 H) 5 3.54 (q, 2 H), 3.99 (s, 3 H), 4.55 (s, 2 H), 6.88 (d, 1 H), 6.93-7.00 (m, 2 H), 7.34-7.42 (m, 2 H), 7.56 (dd, 1 H), 8.00 (dd, 1 H), 8.16 (d, 1 H ), 8.65 (d, 1 H). Microanalysis: C23H22FN502 0.5 H20 required; C 64.48, Η 5.41, N 16.35 experimental value C 64.46, Η 5.27, N 16.40. MS APCI + m / z 420 [MH] + Example 31 4- {5- [5_ (ethoxymethyl) -4- (6-methoxypyridin-3-yl) -411-1,2,4- Triazol-3-yl] eradin-2-yl} -3-rocylbenzonitrile

使用實例30之方法自製備52之產物及製備29之產物以 15%產率製備作為米色固體之標題化合物。 ^NMR (CDC135 400 MHz) δ: 1.16 (t? 3 Η)? 2.38 (s5 3 Η)5 3.52 (q，2 Η)，4·00 (s，3 Η)，4.55 (s，2 Η)，6·89 (d，1 Η)，7.43 (d，1 Η)，7.49 (d，1 Η)，7.58 (m，3 Η)，8.02 (dd，1 Η)，8.17 (d， 1 Η)，8.70 (d，1 Η)。微量分析：C24H22N602 0·5 Η20需要； 95339.doc -125- 200526606 C 66.19, Η 5.32, Ν 19·30 實驗值 C 66.57, Η 5.17, N 19.53。 MS ES+ m/z 427 [MH] + 實例32 2-(3,4-二甲基-苯基）-5-[5-甲氧基甲基-4-(6-甲氧基-«比啶-3-基）-4Η·[1，2,4]***-3_基]-吡嗪The title compound was prepared as a beige solid in 15% yield from the product of Preparation 52 and the product of Preparation 29 using the method of Example 30. ^ NMR (CDC135 400 MHz) δ: 1.16 (t? 3 Η)? 2.38 (s5 3 Η) 5 3.52 (q, 2 Η), 4.00 (s, 3 Η), 4.55 (s, 2 Η), 6.89 (d, 1 Η), 7.43 (d, 1 Η), 7.49 (d, 1 Η), 7.58 (m, 3 Η), 8.02 (dd, 1 Η), 8.17 (d, 1 Η), 8.70 (d, 1 Η). Microanalysis: C24H22N602 0 · 5 Η20 required; 95339.doc -125- 200526606 C 66.19, Η 5.32, Ν 19 · 30 Experimental values C 66.57, Η 5.17, N 19.53. MS ES + m / z 427 [MH] + Example 32 2- (3,4-dimethyl-phenyl) -5- [5-methoxymethyl-4- (6-methoxy- «pyridine -3-yl) -4Η · [1,2,4] triazol-3_yl] -pyrazine

使用實例30之方法自製備31之產物及3,4-二甲基苯硼酸製備標題化合物。藉由管柱層析法於石夕膠上以9 6:4:0.4之二氣曱烷：甲醇：0.88氨水繼而以100%之乙酸乙酯洗提來純化粗化合物以得68%產率之作為米色固體之所需化合物。 ^NMR (CDC13? 400 MHz) δ: 2.31 (s5 3 Η)5 2.33 (s, 3 Η)? 3.35 (s，3 Η)，4.00 (s，3 Η)，4·50 (s，2 Η)，6·85 (d，1 Η)，7·23 (s，1 Η)，7.58 (dd，1 Η)，7·71 (dd, 1 Η)，7.80 (s，1 Η), 8.11 (d， 1 Η)，8·71 (d，1 Η)，9.42 (d，1 Η)。MS APCI+ m/z 403 [ΜΗ] + 實例33 4-{4·[5-甲氧基曱基·4_(6-甲氧基比啶基）-4Η-[1，2,4]三唑·3_基卜苯基}-2,3·二甲基-吡啶1-氧化物 95339.doc -126- 200526606The title compound was prepared from the product of Preparation 31 and 3,4-dimethylphenylboronic acid using the method of Example 30. The crude compound was purified by column chromatography on Shi Xijiao with 9 6: 4: 0.4 dioxane: methanol: 0.88 ammonia and then elution with 100% ethyl acetate to obtain a 68% yield. The desired compound as a beige solid. ^ NMR (CDC13? 400 MHz) δ: 2.31 (s5 3 Η) 5 2.33 (s, 3 Η)? 3.35 (s, 3 Η), 4.00 (s, 3 Η), 4.50 (s, 2 Η) , 6.85 (d, 1 Η), 7.23 (s, 1 Η), 7.58 (dd, 1 Η), 7.71 (dd, 1 Η), 7.80 (s, 1 Η), 8.11 (d , 1 Η), 8.71 (d, 1 Η), 9.42 (d, 1 Η). MS APCI + m / z 403 [ΜΗ] + Example 33 4- {4 · [5-methoxyfluorenyl · 4- (6-methoxybipyridyl) -4Η- [1,2,4] triazole · 3-kibylphenyl} -2,3 · dimethyl-pyridine 1-oxide 95339.doc -126- 200526606

於回流下加熱二甲苯（4 mL)中之製備57之產物（230 mg， 0.74 mmol)、5-胺基-2-甲氧基吡啶（1〇〇 mg，0.81 mmol)及對甲苯磺酸（3 0 mg，觸媒）之混合物18小時。隨後以1 μ氫氯酸酸化該混合物且以乙酸乙酯洗滌且丟棄有機層。以1Μ氫乳化納浴液驗化水溶液且以乙酸乙g旨（χ2)萃取。以鹽水洗務經組合之有機萃取物，經硫酸納乾燥且於真空中濃縮以得棕色油狀物。藉由管柱層析法於矽膠上以1〇〇:〇:〇至98:2:〇·ι 之一氣甲烧：甲醇：0 · 8 8氨水洗提來純化該油狀物以得24%產率、74 mg之米色泡沫狀物之標題化合物。 iNMR (CDC13, 400 ΜΗζ) δ: 2.16 (s，3 H)，2.53 (s，3 H)， 3.31 (s，3 Η)，3·94 (s，3 Η)，4·43 (s，2 Η)，6.81 (d，1 Η)，6·94 (d，1 Η)，7·19 (m，2 Η)，7.49 (m，3 Η)，8·08 (d，1 Η)，8.16 (d， 1Η)。MS APCI+ m/z 418 [ΜΗ] + 實例34 2-(4-氟-2-甲基苯基）-5-【4-(6•甲氧基吡啶-3_基广5-甲基 -4H-1，2,4-***-3-基]吡啶 95339.doc -127- 200526606The product of Preparation 57 (230 mg, 0.74 mmol) in xylene (4 mL), 5-amino-2-methoxypyridine (100 mg, 0.81 mmol) and p-toluenesulfonic acid ( 30 mg, catalyst) for 18 hours. The mixture was then acidified with 1 μ hydrochloric acid and washed with ethyl acetate and the organic layer was discarded. The aqueous solution was assayed with 1M hydrogen-emulsified nanobath and extracted with ethyl acetate (χ2). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The oil was purified by column chromatography on silica gel with one of 100: 00: 0 to 98: 2: 0 · m gas elution: methanol: 0 · 8 8 ammonia water to obtain 24% Yield, 74 mg of the title compound as a beige foam. iNMR (CDC13, 400 ΜΗζ) δ: 2.16 (s, 3 H), 2.53 (s, 3 H), 3.31 (s, 3 Η), 3.94 (s, 3 Η), 4.43 (s, 2 Η), 6.81 (d, 1 Η), 6.94 (d, 1 Η), 7.19 (m, 2 Η), 7.49 (m, 3 Η), 8.08 (d, 1 Η), 8.16 (d, 1Η). MS APCI + m / z 418 [ΜΗ] + Example 34 2- (4-fluoro-2-methylphenyl) -5- [4- (6 • methoxypyridin-3-ylyl-5-methyl-4H -1,2,4-triazol-3-yl] pyridine 95339.doc -127- 200526606

使用實例33之方法自製備72之產物及5-胺基-2-曱氧基吡啶以70%產率製備作為棕色固體之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.34 (s5 3 H)，2.39 (s，3 H)， 3.99 (s，3 Η)，6.87-7.01 (m，3 Η)，7.35 (dd，1 Η)，7.39 (dd， 1 Η)，7·45 (dd，1 Η)，7·97 (dd，1 Η)，8·11 (d，1 Η)，8·59 (d，1 Η)。 MS APCI+ m/z 376 [ΜΗ] + 實例35至45 "定製備下文所示之通式之以下化合物。藉由實例34之方法使用適當噁二唑（製備73_8ΐ)及胺基吡回流下加熱該等混合藉由tic分析監測該反應之進行且於物直至已消耗所有起始材料。The title compound was prepared as a brown solid in 70% yield from the product of Preparation 72 and 5-amino-2-methoxypyridine using the method of Example 33. iHNMR (CDC13, 400 ΜΗζ) δ: 2.34 (s5 3 H), 2.39 (s, 3 H), 3.99 (s, 3 Η), 6.87-7.01 (m, 3 Η), 7.35 (dd, 1 Η), 7.39 (dd, 1 Η), 7.45 (dd, 1 Η), 7.97 (dd, 1 Η), 8.11 (d, 1 Η), 8.59 (d, 1 Η). MS APCI + m / z 376 [ΜΗ] + Examples 35 to 45 " The following compounds of the general formula shown below were prepared. The mixtures were heated by refluxing with appropriate oxadiazole (Preparation 73-8H) and aminopyridine by the method of Example 34. The progress of the reaction was monitored by tic analysis and all the starting materials had been consumed.

95339.doc 200526606 V H3(T〇序號 R1 R2 Y 資料產率 35 双 och3 CH ^NMRCCDCh，400MHz) δ: 2.07(s，3H)，2.34(s，3H)， 3.32(s，3H)，3.97(s，3H)， 4.38(d，1H)，4.49(d，1H)， 6.74(d，1H)，6.95(m，2H)， 7.35(dd，1H)，7.39(d，1H)， 7.50(d，1H)，8.02(d，1H)， 8.65(d5 1H). MS APCI+ m/z 420 [MH] + 25% 36 双 och3 N ^NMRCCDCls, 400MHz) δ: 2.12(s，3H)，2.38(s，3H)， 3.32(s，3H)，3.99(s，3H)， 4.39(d，1H)，4.49(d，1H)， 6.66(d，1H)，6.99(m，2H)， 7.37(d，1H)，7.39(d，1H)， 8.39(d，1H)，9.52(d，1H). MS APCI+ m/z 421 [MH] + 33% 37 双 H N ^HNMRCCDCh，400MHz) δ: 2.17(s，3H)，2.23(s，3H)， 2.44(s? 3H)? 4.00(s5 3H)? 6.64(d，1H)，7.01 (m，2H)， 7.37(m，2H)，8.37(s，1H)， 9.43(s5 1H). MS APCI+ m/z 390 [MH] + 50% 38 PC ch5 H N ^NMRCCDCls, 400MHz) δ: 2.15(s，3H)，2.21(s，3H)， 2.31(s，3H)，2.33(s，3H)， 3.99(s，3H)，6.68(d，1H)， 7.18(m，2H)，7.24(m，1H)， 7.33(d，1H)，8.35(d，1H)， 9.50(d5 1H). MS APCI+ m/z 387[MH] + 36% 95339.doc -129- 200526606 ν Ν-Ν Λ φτ。、 η3ο^° 序號 R1 R2 Y 資料產率 39 成 H N iHNMRCCDCh，400MHz) δ: 2.33(s, 3H)，2.38(s，3H)， 3.82(s，3H)，3.98(s，3H)， 6.41(d，1H)，6.99(m，2H)， 7.38(dd，1H)，7.43(d，1H)， 8.38(d，1H)，9.45(d，1H)· MS APCI+ m/z 407 [MH] + 69% 40 9C CH, H N ^NMRCCDCls, 400MHz) δ: 2.21(s，3H)，2.33(m，6H)， 3.82(s，3H)，3_98(s，3H)， 6.41(s，1H)，7.21(m，3H)， 7.44(d，1H)，8.37(d，1H)， 9.44(d，lH). MS APCI+ m/z 403 [MH] + 49% Φ H^C"0 序號 R1 Y 資料產率 41 CH, och3 N ^NMRCCDCh，400MHz) δ: 2.34(d，3H)，3.35(s，3H)， 4.00(s，3H)，4.50(s，2H)， 6.85(d，lH)，7.10(dd，1H)， 7.58(dd，1H)，7.79(m，1H)， 7.87(dd，1H)，8.11(d， 1H)，8.69(d，H)，9.44(d， 1H). MS APCI+ m/z 407 [MH] + 33% 95339.doc -130- 20052660695339.doc 200526606 V H3 (TO No. R1 R2 Y data yield 35 double och3 CH ^ NMRCCDCh, 400MHz) δ: 2.07 (s, 3H), 2.34 (s, 3H), 3.32 (s, 3H), 3.97 ( s, 3H), 4.38 (d, 1H), 4.49 (d, 1H), 6.74 (d, 1H), 6.95 (m, 2H), 7.35 (dd, 1H), 7.39 (d, 1H), 7.50 (d , 1H), 8.02 (d, 1H), 8.65 (d5 1H). MS APCI + m / z 420 [MH] + 25% 36 double och3 N ^ NMRCCDCls, 400MHz) δ: 2.12 (s, 3H), 2.38 (s , 3H), 3.32 (s, 3H), 3.99 (s, 3H), 4.39 (d, 1H), 4.49 (d, 1H), 6.66 (d, 1H), 6.99 (m, 2H), 7.37 (d, 1H), 7.39 (d, 1H), 8.39 (d, 1H), 9.52 (d, 1H). MS APCI + m / z 421 [MH] + 33% 37 double HN ^ HNMRCCDCh, 400MHz) δ: 2.17 (s, 3H), 2.23 (s, 3H), 2.44 (s? 3H)? 4.00 (s5 3H)? 6.64 (d, 1H), 7.01 (m, 2H), 7.37 (m, 2H), 8.37 (s, 1H) , 9.43 (s5 1H). MS APCI + m / z 390 [MH] + 50% 38 PC ch5 HN ^ NMRCCDCls, 400MHz) δ: 2.15 (s, 3H), 2.21 (s, 3H), 2.31 (s, 3H) , 2.33 (s, 3H), 3.99 (s, 3H), 6.68 (d, 1H), 7.18 (m, 2H), 7.24 (m, 1H), 7.33 (d, 1H), 8.35 (d, 1H), 9.50 (d5 1H). MS APCI + m / z 387 [MH] + 36% 95339.doc -129- 200526606 ν Ν-Ν Λ φτ. , Η3ο ^ ° Serial number R1 R2 Y Data yield 39 HN iHNMRCCDCh, 400MHz) δ: 2.33 (s, 3H), 2.38 (s, 3H), 3.82 (s, 3H), 3.98 (s, 3H), 6.41 ( d, 1H), 6.99 (m, 2H), 7.38 (dd, 1H), 7.43 (d, 1H), 8.38 (d, 1H), 9.45 (d, 1H) · MS APCI + m / z 407 [MH] + 69% 40 9C CH, HN ^ NMRCCDCls, 400MHz) δ: 2.21 (s, 3H), 2.33 (m, 6H), 3.82 (s, 3H), 3_98 (s, 3H), 6.41 (s, 1H), 7.21 (m, 3H), 7.44 (d, 1H), 8.37 (d, 1H), 9.44 (d, lH). MS APCI + m / z 403 [MH] + 49% Φ H ^ C " 0 Serial number R1 Y Rate 41 CH, och3 N ^ NMRCCDCh, 400MHz) δ: 2.34 (d, 3H), 3.35 (s, 3H), 4.00 (s, 3H), 4.50 (s, 2H), 6.85 (d, 1H), 7.10 ( dd, 1H), 7.58 (dd, 1H), 7.79 (m, 1H), 7.87 (dd, 1H), 8.11 (d, 1H), 8.69 (d, H), 9.44 (d, 1H). MS APCI + m / z 407 [MH] + 33% 95339.doc -130- 200526606

och3och3

N WNMRCCDCh，400MHz) l 3.36(s，3H)，3.93(s，3H)， 4.01(s，3H)，4.51(s，2H)， 6.86(d，1H)，7.06(dd，1H)， 7.21(dd，1H)，7.57(m，2H)， 8.11(d，1H)，8.79(d，1H)， 9.51(d，lH)· MSAPCI+ m/z 423 [MH] + 40% 43N WNMRCCDCh, 400MHz) 3.36 (s, 3H), 3.93 (s, 3H), 4.01 (s, 3H), 4.51 (s, 2H), 6.86 (d, 1H), 7.06 (dd, 1H), 7.21 ( dd, 1H), 7.57 (m, 2H), 8.11 (d, 1H), 8.79 (d, 1H), 9.51 (d, 1H) · MSAPCI + m / z 423 [MH] + 40% 43

och3och3

N iNMRCCDCh，400MHz) δ: 2.34(s，3H)，3.35(s，3H)， • 83(s，3H)，4.00(s，3H)， 4.50(s，2H)，6.85(d，1H)， 6.89(d，1H)，7.19-7.26(m， 1H)，7.59(dd，1H)，7.68(s， 1H)，8.12(d，1H)，8.91 (s， 1H)，9.44(d，1H)· MS APCI+ m/z 419 [MH] + 31% 44N iNMRCCDCh, 400MHz) δ: 2.34 (s, 3H), 3.35 (s, 3H), • 83 (s, 3H), 4.00 (s, 3H), 4.50 (s, 2H), 6.85 (d, 1H), 6.89 (d, 1H), 7.19-7.26 (m, 1H), 7.59 (dd, 1H), 7.68 (s, 1H), 8.12 (d, 1H), 8.91 (s, 1H), 9.44 (d, 1H) MS APCI + m / z 419 [MH] + 31% 44

OCH3OCH3

N HNMR(CDC13, 400MHz) δ 3.35(s，3H)，3.85(s，3H)， 4.00(s，3H)，4.50(s，2H)， 6.85(d，1H)，6.93(d，1H)， 7.10(m，1H)，7.59(dd，1H)， 7.69(s，1H)，8.12(d，1H)， 8.96(s，1H)，9.47(d，1H)· MS APCI+ m/z 423[MH] + 39% 45N HNMR (CDC13, 400MHz) δ 3.35 (s, 3H), 3.85 (s, 3H), 4.00 (s, 3H), 4.50 (s, 2H), 6.85 (d, 1H), 6.93 (d, 1H), 7.10 (m, 1H), 7.59 (dd, 1H), 7.69 (s, 1H), 8.12 (d, 1H), 8.96 (s, 1H), 9.47 (d, 1H) · MS APCI + m / z 423 [MH ] + 39% 45

och3och3

N HNMR(CDC13, 400MHz) δ 2.33(s，3H)，2.34(s，3H)， 3.35(s，3H)，4.00(s，3H)， 4.50(s，2H)，6.85(d，1H)， 7.17(dd，2H)，7.24(m，1H)， 7.60(dd，1H)，8.13(d，1H)， 8.43(d，1H)，9.48(d，1H). MS APCI+ m/z 403 [MH] + 41% 實例42 :藉由管柱層析法於矽膠上以98:2之乙酸乙酯：甲醇洗提重來純化粗產物。實例35、37 > 38、41、43、44及45 :藉由以***研磨來純化粗產物。實例46 95339.doc -131 - 200526606 5-{3-[5-(4·氟-2-甲基-苯基）-吼嗪基卜5_甲基-[I，2,4】*** -4-基}·^比啶-2-基）-曱基-胺N HNMR (CDC13, 400MHz) δ 2.33 (s, 3H), 2.34 (s, 3H), 3.35 (s, 3H), 4.00 (s, 3H), 4.50 (s, 2H), 6.85 (d, 1H), 7.17 (dd, 2H), 7.24 (m, 1H), 7.60 (dd, 1H), 8.13 (d, 1H), 8.43 (d, 1H), 9.48 (d, 1H). MS APCI + m / z 403 [MH ] + 41% Example 42: The crude product was purified by column chromatography on silica gel with 98: 2 ethyl acetate: methanol. Examples 35, 37 > 38, 41, 43, 44 and 45: The crude product was purified by trituration with diethyl ether. Example 46 95339.doc -131-200526606 5- {3- [5- (4 · Fluoro-2-methyl-phenyl) -oxazinyl 5-methyl- [I, 2,4] triazole- 4-yl} · ^ pyridin-2-yl) -fluorenyl-amine

於回流下加熱二甲苯（10 rnL)中之製備74之產物（437 mg，1.62 mm〇G及製備 83 之產物（434 mg，3_52 mmol)及對甲苯磺酸之混合物100小時。隨後藉由Celite®過濾該混合物，藉由二氯乙烷洗滌且於真空中濃縮濾液。藉由管柱層析法於石夕膠上以98:2:0.2之二氣甲烷：甲醇：〇88氨水、繼而以98:2之乙酸乙醋：甲醇洗提來純化，得9%產率、57爪^乍為米色固體之標題化合物。 'HNMR (CDC13j 400 ΜΗζ) δ: 2.38(m, 6 Η), 2.98 (d, 3 Η), 4.89 (m, 1 Η), 6.47 (d, 1 H), 6.94-7.02 (m, 2 H), 7.36 (m, 2 H), 7.97 (d,lH) 8.43 (s, 1 H), 9.41 (d, ! H) 〇 MS APCI+m/z 376 [MH] + 實例47 3-(4-氟-2-甲基-苯基）·6_[5_甲氧基甲基邻甲氧基吼唆 -3-基）-4Η-[1，2,4]***-3-基】-建嗅 95339.doc -132- 200526606The product of Preparation 74 (437 mg, 1.62 mmOG and Preparation 83 (434 mg, 3-52 mmol) and p-toluenesulfonic acid) in xylene (10 rnL) was heated at reflux for 100 hours. Subsequently by Celite The mixture was filtered, washed with dichloroethane, and the filtrate was concentrated in vacuo. Column chromatography was performed on Shi Xijiao with 98: 2: 0.2 gas of methane: methanol: 〇88 ammonia, and 98: 2 ethyl acetate: methanol elution and purification, the title compound was obtained in 9% yield, 57 claws as a beige solid. 'HNMR (CDC13j 400 ΜΗζ) δ: 2.38 (m, 6 Η), 2.98 ( d, 3 Η), 4.89 (m, 1 Η), 6.47 (d, 1 H), 6.94-7.02 (m, 2 H), 7.36 (m, 2 H), 7.97 (d, lH) 8.43 (s, 1 H), 9.41 (d,! H) 〇MS APCI + m / z 376 [MH] + Example 47 3- (4-fluoro-2-methyl-phenyl) · 6_ [5_methoxymethyl O-methoxyl-methyl-3-yl) -4Η- [1,2,4] triazol-3-yl]-Jianol 95339.doc -132- 200526606

〇〜CH- 將製備62之產物（40 mg，0_ i 3 mm〇1)、5_胺基_2_甲氧基吡啶（16mg，0.13mmol)及對甲苯磺酸單水合物（5mg，觸媒）溶解於二曱苯（2 mL)中且於回流下加熱反應混合物3小時。隨後將反應混合物分隔於二氣曱烷與碳酸氫鈉溶液之間且以鹽水洗條有機溶液，經硫酸納乾燥且於真空中濃縮。藉由 HPLC使用 Phenomenex Luna C18 系統以 95:5至 5:95 之水/乙腈/三氟乙酸（5 :95:0.1):乙腈洗提來純化殘餘物以得 8%產率、4 mg之作為黃色油狀物之標題化合物。 !HNMR (CDC13? 400 MHz) δ: 2.33(s5 3Η)? 3.36 (s? 3 Η)? 3·94 (s，3 Η)，4.52 (s，2 Η)，6·83 (d，1 Η)，7·02 (m，2 Η)，7.39 (d，1 Η)，7·70 (m，2 Η) 8·11 (s，1 Η)，8.46 (d，1 Η) 〇實例48 5-(4-氟-2-甲基-苯基）-2-[5-甲氧基甲基-4-(6-甲氧基比啶 -3-基）_4H-[1，2,4】***-3-基卜嘧啶〇 ~ CH- The product of Preparation 62 (40 mg, 0_i 3 mm〇1), 5-amino-2-methoxypyridine (16 mg, 0.13 mmol) and p-toluenesulfonic acid monohydrate (5 mg, contact Solution) Dissolved in xylene (2 mL) and heated the reaction mixture at reflux for 3 hours. The reaction mixture was then partitioned between dioxane and sodium bicarbonate solution and the organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by HPLC using a Phenomenex Luna C18 system with 95: 5 to 5:95 water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile to obtain 8% yield, 4 mg as The title compound as a yellow oil. ! HNMR (CDC13? 400 MHz) δ: 2.33 (s5 3Η)? 3.36 (s? 3 Η)? 3.94 (s, 3 Η), 4.52 (s, 2 Η), 6.83 (d, 1 Η) ), 7.02 (m, 2 Η), 7.39 (d, 1 Η), 7.70 (m, 2 Η), 8.11 (s, 1 Η), 8.46 (d, 1 Η). Example 48 5 -(4-fluoro-2-methyl-phenyl) -2- [5-methoxymethyl-4- (6-methoxybipyridin-3-yl) _4H- [1,2,4] Triazol-3-ylpyrimidine

H〆 95339.doc -133- 200526606H〆 95339.doc -133- 200526606

將製備69之產物（80 mg，〇·27 mmol)、5-胺基-2-甲氧基吡啶（50 mg，〇·3 9 mmol)及對甲苯磺酸單水合物（10 mg，觸媒）溶解於二甲苯（3 mL)中且於回流下加熱反應混合物丨8小時。加入額外之對甲苯磺酸單水合物（1 〇 mg，觸媒）且繼續加熱進一步之18小時。隨後於減壓下蒸發反應混合物且將殘餘物浴解於乙酸乙S旨’以1 Μ氫氯酸、碳酸氫納溶液及鹽水洗滌，經硫酸鎂乾燥且於真空中濃縮。藉由管柱層析法使用矽膠以97:3之二氯甲烷：甲醇洗提來純化殘餘物，得 46%產率、49.3 mg之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2.23 (s，3 H)，3_32 (s，3 H)， 3.99 (s，3 Η)，4·51 (s，2 Η)，6.82 (d，1 Η)，6·98 (m，2 Η)，7·17The product of Preparation 69 (80 mg, 0.27 mmol), 5-amino-2-methoxypyridine (50 mg, 0.39 mmol) and p-toluenesulfonic acid monohydrate (10 mg, catalyst ) Dissolved in xylene (3 mL) and heated the reaction mixture under reflux for 8 hours. Add additional p-toluenesulfonic acid monohydrate (10 mg, catalyst) and continue heating for a further 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was bathed in ethyl acetate, washed with 1 M hydrochloric acid, sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel eluting with 97: 3 dichloromethane: methanol to obtain 46% yield of 49.3 mg of the title compound. iHNMR (CDC13, 400 ΜΗζ) δ: 2.23 (s, 3 H), 3_32 (s, 3 H), 3.99 (s, 3 Η), 4.51 (s, 2 Η), 6.82 (d, 1 Η) , 6.98 (m, 2 Η), 7.17

(d’ 1 Η)，7·60 (d，1 Η)，8.11 (s，1 Η)，8·67 (s，2 Η)· MS APCI+ m/z 407 [ΜΗ] + 货例49 $ S7 藉由實例48之方法使用製備71之產物及適當硼酸製備下文所示之通式之以下化合物。(d '1 Η), 7.60 (d, 1 Η), 8.11 (s, 1 Η), 8.67 (s, 2 Η) · MS APCI + m / z 407 [ΜΗ] + Case 49 $ S7 The following compound of the formula shown below was prepared by the method of Example 48 using the product of Preparation 71 and appropriate boric acid.

95339.doc -134- 200526606 序號 R1 資料產率 49 双 ^NMRCCDCls, 400MHz) δ: 2.20(s，3H)，2.30(s，3H)，3.79(s5 3H)，3.95(s，3H)，6.38(d，1H)， 6.88-6.98(m，2H)，7.10(dd，1H)， 7.42(d，1H)，7.65(dd，1H)， 8.19(d，1H)，8.21 (d，1H). MS APCI+ m/z 406 [MH] + 50% 50 9C ^NMRCCDCls, 400MHz) δ: 2.09(s，3H)，2.30(s，3H)，2.39(s， 3H)，3.80(s，3H)，3.96(s，3H)， 6.39(d，1H)，6.98(d，1H)， 7.09-7.02(m，2H)，7.46(d，1H)， 7.68(d，1H)，8.19(d，1H)， 8.24(d，1H). MS APCI+ m/z 402 [MH] + 50% 51 Fxx k MS APCI+ m/z 422 [MH] + 69% 52 CH, MS APCI+ m/z 406 [MH] + 46% 實例53 3-{5-[4_(6-甲氧基-吡啶-3_基）-5-甲基-4H-[1，2,4]***-3-基】 0比嗓-2-基}-4 -甲基-节猜95339.doc -134- 200526606 No. R1 Data yield 49 double ^ NMRCCDCls, 400MHz) δ: 2.20 (s, 3H), 2.30 (s, 3H), 3.79 (s5 3H), 3.95 (s, 3H), 6.38 ( d, 1H), 6.88-6.98 (m, 2H), 7.10 (dd, 1H), 7.42 (d, 1H), 7.65 (dd, 1H), 8.19 (d, 1H), 8.21 (d, 1H). MS APCI + m / z 406 [MH] + 50% 50 9C ^ NMRCCDCls, 400MHz) δ: 2.09 (s, 3H), 2.30 (s, 3H), 2.39 (s, 3H), 3.80 (s, 3H), 3.96 ( s, 3H), 6.39 (d, 1H), 6.98 (d, 1H), 7.09-7.02 (m, 2H), 7.46 (d, 1H), 7.68 (d, 1H), 8.19 (d, 1H), 8.24 (d, 1H). MS APCI + m / z 402 [MH] + 50% 51 Fxx k MS APCI + m / z 422 [MH] + 69% 52 CH, MS APCI + m / z 406 [MH] + 46% Example 53 3- {5- [4_ (6-methoxy-pyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -4 -methyl-section guess

95339.doc -135- 200526606 於回流下加熱1，‘二噁烷（5〇 mL)中之弘氣甲基苄腈〇 g，6·6 mmo1)、雙（戊醯）二硼（1.8 g，7.0 mmol)、碳酸鉋（6·4 g ’ 19.8 mmol)及製備3之產物（5 mg，觸媒）之混合物4小時。隨後冷卻該反應混合物至室溫，藉由Celite®過濾且於真空中濃縮。隨後將一部分殘餘物（145 mg，0_6 mmol)、製備30之產物 (90 mg，0.3 mmol)、碳酸絶（293 mg，0.9 mmol)及製備 3 之產物（2 mg，觸媒）溶解於i，4-二噁烷中且於回流下加熱混合物18小時。隨後冷卻該混合物至室溫，藉由celite®過濾、且於真空中濃縮。藉由管柱層析法於矽膠上以100:0至97:3之二氯甲烷：甲醇洗提來純化殘餘物，得3%產率、3 mg之作為白色固體之標題化合物。 1HNMR (CDC13, 400 ΜΗζ) δ: 2.41 (s，3 H)，2.46 (s，3 H)， 4·02 (s，3 Η)，6·90 (d，1 Η)，7·43 (d，1 Η)，7.53 (dd，1 Η)， 7·63 (dd，1 Η)，7·70 (d，1 Η)，8·09 (d，1 Η)，8·41 (d，1 Η)， 9·55 (d5 1 Η) 〇 S APCI+ m/z 383 [ΜΗ] + 實例54 2-(4-氟-2-甲基-苯基）-4-甲氧基-5-[5-甲氧基甲基-4-(6-甲氧基-啦啶-3-基）·4Η·[1，2,4】***·3·基】-吡啶95339.doc -135- 200526606 heated under reflux, Hongqi methylbenzonitrile 0g, 6.6 mmo1), bis (pentamidine) diboron (1.8 g, 7.0 mmol), carbonate shavings (6.4 g '19 .8 mmol) and the product of Preparation 3 (5 mg, catalyst) for 4 hours. The reaction mixture was then cooled to room temperature, filtered through Celite® and concentrated in vacuo. A portion of the residue (145 mg, 0-6 mmol), the product of Preparation 30 (90 mg, 0.3 mmol), carbonic acid (293 mg, 0.9 mmol) and the product of Preparation 3 (2 mg, catalyst) were then dissolved in i, The mixture was heated in 4-dioxane under reflux for 18 hours. The mixture was then cooled to room temperature, filtered through celite®, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol from 100: 0 to 97: 3 to obtain the title compound as a white solid in 3% yield and 3 mg. 1HNMR (CDC13, 400 ΜΗζ) δ: 2.41 (s, 3 H), 2.46 (s, 3 H), 4.02 (s, 3 Η), 6.90 (d, 1 Η), 7.43 (d , 1 Η), 7.53 (dd, 1 Η), 7.63 (dd, 1 Η), 7.70 (d, 1 Η), 8.09 (d, 1 Η), 8.41 (d, 1 Η), 9.55 (d5 1 Η) 〇S APCI + m / z 383 [ΜΗ] + Example 54 2- (4-fluoro-2-methyl-phenyl) -4-methoxy-5- [5 -Methoxymethyl-4- (6-methoxy-ladin-3-yl) · 4Η · [1,2,4] triazole · 3 · yl] -pyridine

95339.doc -136- 200526606 於回流下加熱二噁烷（4 mL)中之製備9〇之產物（6〇 mg， 0.17 mmol)及製備3之產物（1〇 mg，觸媒）、扣氟冬曱基苯硼酸（3 3 mg，0.21 mmol)及碳酸铯（110 mg，0.3 4 mmol)之混合物16小時。隨後將觸媒量之4_氟甲基苯硼酸及製備3之產物添加至反應混合物中且持續加熱進一步之3小時。以二氯甲烧稀釋該混合物且直接藉由管柱層析法於石夕膠上以 100:0至96:4之二氣甲烷：甲醇洗提來純化以得54%產率、39 mg之作為白色泡沫狀物之標題化合物。 iHNMR (CDC13, 400 ΜΗζ) δ: 2·34 (s5 3 H)，3.39 (s，3 H) 3.62 (s，3 Η)，3.94 (s，3 Η)，4·51 (s，2 Η)，6·77 (m，2 Η)，6·96 (m，2 Η)，7.33 (dd，1 Η)，7·50 (dd，1 Η)，8.05 (d，1 Η)，8.70 (d，1 Η) 〇 S APCI+ m/z 436 [ΜΗ] + 實例55 2-(5-氟-2-甲氧基-苯基）-4_甲氧基_5_[5-甲氧基甲基_4 (6_甲氧基-”比咬基）_4H-[1，2,4]三唾-3-基]比唆95339.doc -136- 200526606 Heat the product of Preparation 90 (60 mg, 0.17 mmol) and the product of Preparation 3 (10 mg, catalyst), fluoxandol in dioxane (4 mL) under reflux. A mixture of fluorenylphenylboronic acid (33 mg, 0.21 mmol) and cesium carbonate (110 mg, 0.3 4 mmol) for 16 hours. The catalyst amount of 4-fluoromethylphenylboronic acid and the product of Preparation 3 were then added to the reaction mixture and heating was continued for a further 3 hours. The mixture was diluted with dichloromethane and purified directly by column chromatography on Shixijiao with a gaseous methane: methanol of 100: 0 to 96: 4 to obtain 54% yield, 39 mg of The title compound as a white foam. iHNMR (CDC13, 400 ΜΗζ) δ: 2.34 (s5 3 H), 3.39 (s, 3 H) 3.62 (s, 3 Η), 3.94 (s, 3 Η), 4.51 (s, 2 Η) , 6.77 (m, 2 Η), 6.96 (m, 2 Η), 7.33 (dd, 1 Η), 7.50 (dd, 1 Η), 8.05 (d, 1 Η), 8.70 (d , 1 Η) 〇S APCI + m / z 436 [ΜΗ] + Example 55 2- (5-fluoro-2-methoxy-phenyl) -4_methoxy_5_ [5-methoxymethyl_ 4 (6-Methoxy- "specific octyl group) _4H- [1,2,4] trisialyl-3-yl] ratio

使用實例54之方法自製備90之產物及5-氟-2-甲氧基苯苯曱酸以53%產率製備作為黃色泡沫狀物之標題化合物。 ]HNMR (CDC13? 400 MHz) δ: 3.39 (s, 3 Η)5 3.63 (s 3 Η) 3.83 (s，3 η)，3.93 (s，3 Η)，4·51 (s，2 Η)，6.76 (d，！ Η)， 95339.doc -137- 200526606 6.93(dd，1 H)，7.07 (m，1 Η)，7·41 (s，1 Η)，7·49 (dd5 1 H)， 7.63 (dd，1 H)，8.04 (d，1 H)，8·70 (s，1 H)。S APCI+ m/z 452 [MH] + 實例56 2-(3 -氣-2_甲氧基-苯基）-5-[4-(6-甲氧基-ϋ比咬-3-基）-5-甲基 -4-Η_[1，2,4]***-3-基]-吡嗪The title compound was prepared as a yellow foam from the product of Preparation 90 and 5-fluoro-2-methoxyphenylphenylarsinic acid in the yield of 53% using the method of Example 54. ] HNMR (CDC13? 400 MHz) δ: 3.39 (s, 3 Η) 5 3.63 (s 3 Η) 3.83 (s, 3 η), 3.93 (s, 3 Η), 4.51 (s, 2 Η), 6.76 (d ,! Η), 95339.doc -137- 200526606 6.93 (dd, 1 H), 7.07 (m, 1 Η), 7.41 (s, 1 Η), 7.49 (dd5 1 H), 7.63 (dd, 1 H), 8.04 (d, 1 H), 8.70 (s, 1 H). S APCI + m / z 452 [MH] + Example 56 2- (3 -Ga-2_methoxy-phenyl) -5- [4- (6-methoxy-fluorenyl-3-yl)- 5-methyl-4-fluorene_ [1,2,4] triazol-3-yl] -pyrazine

H3C^° 藉由實例14之方法使用製備30之氯化合物（108 mg，0.32 mmol)及2 -甲氧基- 3-IL-苯石朋酸（72 mg，0.48 mmol)製備標題產物。製得107 mg、79%產率之作為白色固體之標題產物。 !ΗΝΜΙΙ (CDC13, 400 ΜΗζ) δ: 3.35 (s，3 H)，3.85 (s，3 H)， 4.00 (s，3 Η)，4.5 (s，2 Η)，6.85 (d，1 Η)，7.20 (m，2 Η)，7.60 (m，2 Η)，8·15 (s，1 Η)，8·85 (s，1 Η)，9.50 (s，1 Η)。量分析： C21H19FN603 0.2 Η20需要；C 59.21，Η 4.59, Ν 19.73 ;實驗值 C 59.27, Η 4.69, Ν 19.33。S APCI+ m/z 423 [ΜΗ]+。 95339.doc 138·H3C ^ The title product was prepared by the method of Example 14 using the chloro compound of Preparation 30 (108 mg, 0.32 mmol) and 2-methoxy-3-IL-benzopenic acid (72 mg, 0.48 mmol). The title product was obtained as a white solid in 107 mg, 79% yield. ! ΗΝΜΙΙ (CDC13, 400 ΜΗζ) δ: 3.35 (s, 3 H), 3.85 (s, 3 H), 4.00 (s, 3 Η), 4.5 (s, 2 Η), 6.85 (d, 1 Η), 7.20 (m, 2 Η), 7.60 (m, 2 Η), 8.15 (s, 1 Η), 8.85 (s, 1 Η), 9.50 (s, 1 Η). Quantitative analysis: C21H19FN603 0.2 Η20 required; C 59.21, Η 4.59, Ν 19.73; experimental value C 59.27, Η 4.69, Ν 19.33. S APCI + m / z 423 [ΜΗ] +. 95339.doc 138 ·

Claims

200526606 十、申請專利範圍： 1 · 一種式（I)之化合物、其互變異構體或該化合物或互變異構體之醫藥上可接受之鹽、溶劑合物或多形體；200526606 10. Scope of patent application: 1. A compound of formula (I), a tautomer thereof, or a pharmaceutically acceptable salt, solvate or polymorph of the compound or tautomer;

其中 V、W、X及Y，其可係相同或不同，代表C_R0&N; Z係C-H或N ; R1係選自： (I) 經二個或二個以上取代基取代之苯基環，該等取代基可係相同或不同，每一取代基獨立選自齒基、（c广G) 烷基、（CVC6)烷氧基、氰基、c(〇)nr7r8、nr7r8、 NR7C(0)R1G及 NfCCCOR1。]〗；及 (⑴含^個選自N、0及s之雜原子之五至七員芳族雜環及其N-氧化物；該環視情況經二個或二個以上取代基取代，該等取代基可係相同或不同，選自鹵基、（Ci_C6) 烷基、（CVC6)烷氧基、氰基、c(〇)nr7r8、nr7r8、 NR7C(0)R1()及柯(：（〇)1^〇；|2 ; R2係選自： ⑴ Η、OH、OR9、NR7R8、NR7C(〇)R10及 n[C(0)R1()]2 ; (II) 含1-3個雜原子之5-7員N-連接雜環，該等雜原子係選自N、Ο及S ;該環視情況經一或多個基團取代，該等 95339.doc 200526606 基團選自（CVC6)烷基' (Cl-C6)烷氧基及c(o)NR7R8;及 (出）視情況經一 N-連接之5-7員雜環取代之（CVC6)烷基，該雜環含1_3個選自N、〇及S之雜原子； R3係選自Η及（CVC6)烷基； R4係選自Η、（CVC6)烷基及OR9 ; R5係選自鹵基、（CrCe)烷基、（CVC6)烷氧基、NR7R8、 NR7C(〇)R10及n[c(o)r10]2 ; R6係選自Η、鹵基、（CVC6)烷基、（Cl_c6)烷氧基、氰基、 nr7r8、nr7c(0)r1()、N[C(0)R，2&C(0)NR7R8 ; R及R ’其可係相同或不同，係選自Η及（Ci_c6)烷基； R係（c^c：6)烷基，其可視情況經一或多個基團取代，每基團係獨立選自（Ci-C6)烷氧基及一含i_3個選自N、〇及S之雜原子之N_連接之5_7員雜環；且 R 0係選自（Cl-c6)烷基及（Ci_c6)烷氧基；其限制條件為式⑴之化合物並非為·· 3^·乙基-5-(4-咪唑-；u基苯基）_4·(4_甲氧基苯基 ***， (’5 - —氯聯苯-4-基）-4·(2-甲氧基苯基）_5_甲基一 4Η-[1，2,4]***， 3-Γ3，s，姚 ^ ’雙-二氟甲基聯苯-4-基）-4-(2-氟苯基）_5·甲基 -4Η-[1，2,4]***，或 (，又_二氟甲基聯苯-4-基）-5 -甲基-4-(3-三氟甲基苯基）_4Η·[1，2,4]***。 2·如％求項1之化合物，其中X係CH。 95339.doc 200526606 3.如請求項1或請求項2之化合物，其中V、W&Y各自獨立地為 CH、C-OCH3或 N。 4·如請求項1至3中任一項之化合物，其中買及γ各自獨立地為CH或N且X及V各自為CH。 5 ·如清求項1至4中任一項之化合物，其中2係N。 6. 如請求項1至4中任一項之化合物，其中2係CH。 7. 如请求項1至6中任一項之化合物，其中Ri係選自·· (I) 經二個取代基取代之苯基環，該等取代基可係相同或不同，各自獨立地選自鹵基、（Ci_c6)烷基、（Ci_c6) 烷氧基、氰基、C(0)NR7R8、NR7R8、 nr7c(o)r10 及n[c(o)r，2 ;及 (II) 吡啶基環或其N-氧化物，各自經兩個取代基取代，該等取代基可係相同或不同，各自獨立地選自鹵基、 (CrD烧基、烧氧基、氰基、c(〇)NR7R8、 NR7R8、NR7C(〇)R10及 N[C(〇)R1()]2。 8·如w求項7之化合物，其中Ri係經二個取代基取代之苯基環’該等取代基可係相同或不同，各自獨立地選自氟基、氣基、曱基、甲氧基及氰基。 9·如請求項7之化合物’其fRl係經二個甲基取代之^定善氧化物。 10·如請求項1至9中任一項之化合物，其中r2係選自： ⑴H、（Cl-c3)烧氧基、（Ci_c3)燒氧基院氧基、及 n((cvc3)烷基）2;及 ⑼含“個氮原子之5員N-連接雜環，視情況經 95339.doc 200526606 c(o)nr7r8取代。 11 ·如請求項1 o之化合物，其中r2係選自H、甲氧基、乙氧義、 2-甲氧基乙氧基、二甲基胺基、1，2,3-***-2-基及吡咯啶基，後者視情況經CONH2取代。 12·如請求項11之化合物，其中R2係選自Η及甲氧基。 13.如請求項1至12中任一項之化合物，其中R3係η。 14·如請求項1至13中任一項之化合物，其中R4係η、甲基或甲氧基。 15·如請求項14之化合物，其中R4係Η。 16·如請求項1至15中任一項之化合物，其中R5係甲氧基或 nhch3 〇 17·如"月求項16之化合物，其中R5係甲氧基。 18·如喷求項1之化合物，其係選自： 2_(心氟、2-甲基苯基）-5-(5-甲氧基曱基-4-(6-甲氧基。比啶基）、4H-[1，2,4]***-3-基）-吡啶； 2-(21 _ 二甲基苯基）-5-(5-甲氧基甲基-4-(6-曱氧基啦啶-3-基）-411、[1，2,4]***-3-基）-吡啶； 5_(心氣、2-甲基苯基）-2_(5-甲氧基甲基_4_(6_甲氧基吼啶基〇、4H-[l，2,4]三。坐-3-基）-σ 比咬； 5-(23 — 〜曱基苯基）-2-(5-甲氧基甲基-4-(6-甲氧基。比啶-3-基）-4也[1，2,4]***-3-基）-咕啶； 1-[515、（2,3-二甲基苯基吡啶_2•基]·4-(6-曱氧基叱啶-3- 基）_4Η、[1，2,4]***-3-基甲基]-吡咯啶-(2S)-2-羧酸醯胺； 5-(2 3 一〜甲基苯基）-2-(5-吼咯啶-1-基甲基-4-(6-曱氧基吡 95339.doc 200526606 啶-3-基）-4Η-[1，2,4]***-3-基）-吡啶； 2-(4 -氣-2-甲基苯基）-5-[5-甲乳基甲基-4-(6-甲乳基σ比17疋 -3-基）-4Η-[1，2,4]***-3-基]-吼嗪； 2-(2,3-二甲基苯基）-5-[5-甲氧基曱基-4-(6-甲氧基1?比11定-3-基）-4Η-[ 1，2,4]二 σ坐-3_基]-°比嗓， 2-(4-氟-2-甲基苯基）-5-[4-(6-曱氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,3-二曱基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吼嗪； 2-(4-氰基-2-甲基苯基）-5-[4-(6-甲氧基。比啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(5-氟-2-甲氧基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(4-氰基-2-甲基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基批啶-3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 5-(4-氰基-2-甲基苯基）-2-[5-甲氧基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吡啶； 2-(5-氟-2-甲氧基苯基）-5-[5-曱氧基甲基-4-(6-甲氧基吼啶-3·基）-4Η-[1，2,4]***-3-基]-吡啶； 2-(2-氟-5-甲氧基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2-氣-5-曱基苯基）-5-[4-(6-曱乳基°比σ定-3 -基）-5 -甲基 -4Η-[1，2,4]***-3-基]-吡嗪； 2-(2,5-二氟苯基）-5-[4-(6-甲氧基。比啶-3-基）-5-甲基 95339.doc 200526606 -4H-[1，2,4]***-3-基]-吡嗪； 2-(3,5-二曱基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,5-二甲基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,5-二氯苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]·吡嗪； 2-(2-氟-5-甲氧基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-曱基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(3,5-二氟-苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,3-二甲基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4-(6-甲氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吡啶； 2-(5-氣-2-曱氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-4-(6-甲氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吡啶； 2-(4-氟-2-甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]—4-(6-甲氧基吡啶-3·基）_4H-1，2,4-***-3-基]吼啶； 2-(5-氟-2-甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]-‘（6-曱氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吼啶； 2-(5-氟-2-甲基苯基）-5-[5-[(2-甲氧基乙氧基）曱基]-4-(6-甲氧基吡啶-3-基）-4Η-1，2,4-***-3-基]吡啶； 2-甲氧基-5-{3-[(2-甲氧基乙氧基）甲基]-5-[6-(2-甲氧基 -5-曱基苯基）吼啶-3-基]-4H-1，2,4-***-4-基}吨啶； 2-(2-氟-3-曱氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲 95339.doc -6- 200526606 基]-4-(6-甲氧基π比咬_3_基）-4Η-1，2,4-***_3-基]π比啶； 2-(3,5-二氟苯基）_5-[5-[(2-甲氧基乙氧基）甲基]_‘(6_甲氧基吡啶-3-基）-4Η-1，2,4-彡唑-3·基]吡啶； 2-(2,5-二甲氧基苯基）-5-[5-[(2-甲氧基乙氧基）甲基]_心（6-甲氧基。比淀·3_基）-4Η-1，2,4-三唾-3-基]。比。定； 2-(3-氯+氟苯基）_5_[5_[(2-甲氧基乙氧基）甲基]-4_(6_甲氧基。比啶_3_基彡唑_3_基]吡啶；及 2-(3-氟甲氧基苯基甲氧基甲基-4-(6·甲氧基吡 0定_3-基）-411-[1，2,4]***-3-基]-吡嗪； 2-(3-氟甲氧基-苯基—[4-(6-甲氧基-吡啶-3·基）-5-甲基_4_H、[1，2,4]***-3-基]，比嗪；及其互變異構體及該化合物或互變異構體之醫藥上可接文之鹽、溶劑合物及多形體。 19·如請求項18之化合物，其係選自： ‘賊甲基苯基）-5-(5-甲氧基甲基-4-(6-甲氧基吡啶基广411·^，2,4]***-3-基）-吡啶； 2 (2’3、一甲基苯基）_^(5_甲氧基甲基甲氧基吡啶_3一基）-4H4l，2,4]***_3·基卜比啶； 5 (4·氟^甲基苯基）·2_(5·曱氧基甲基冬（6_曱氧基〇比啶小基Μ^1，2,4]***-3-基卜比。定； 5 (2’3、一甲基苯基）_2_(5_甲氧基甲基-Μ·甲氧基。比啶I 基）-4Η·[ΐ，2,4]***-3-基）“比啶； ^[5 [%(2,3-二甲基苯基）_比啶_2_基]_4_(6_甲氧基吡啶_3· 土）4&[1’2,4]二唾-3-基甲基比咯啶_(2S)-2邊酸醯胺； 95339.doc 200526606 5-(2,3-二曱基苯基）-2-(5 j比咯啶-1-基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基）-吡啶； 2-(4-氟-2-曱基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基吼啶 -3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 2-(2,3-二甲基苯基）-5-[5-曱氧基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 2-(4-氟-2-甲基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(2,3-二甲基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-甲基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(4-氰基-2-曱基苯基）-5-[4-(6-甲氧基处啶-3-基）-5-曱基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(5-氟-2-甲氧基苯基）-5-[4-(6-甲氧基吼啶-3-基）-5-曱基 -4H-[1，2,4]***-3-基]-吡嗪； 2-(4-氣基-2-甲基苯基）-5-[5-甲氧基甲基-4-(6-甲乳基ϋ比啶-3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 5-(4-氰基-2-甲基苯基）-2-[5-甲氧基甲基-4-(6-甲氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吡啶； 2-(5-氟-2-甲氧基苯基）-5-[5-甲氧基甲基-4-(6-甲氧基吼啶-3_基）-4Η-[1，2,4]***-3-基]•吡啶；及 2-(3-氟-2_曱氧基苯基）-5-[5-曱氧基甲基-4-(6-曱氧基吼啶-3-基）-4Η-[1，2,4]***-3-基]-吡嗪； 2-(3 -氣-2 -甲氧基-苯基）-5-[4-(6-甲氧基-°比咬-3 -基）-5 -曱基- 4- Η- [1，2,4]二 °坐-3-基]比嗓；及其互變異構體及該化合物或互變異構體之醫藥上可接 95339.doc 200526606 文之鹽、溶劑合物及多形體。 2〇· 一種醫藥組合物，其包含如請求項1至19中任一項之式⑴ 之化合物，或其醫藥上可接受之鹽' 溶劑合物或多形體，及西条上可接受之稀釋劑或載劑。 21·如請求項1至19中任一項之式⑴之化合物，或其醫藥上可接受之鹽、溶劑合物或多形體，其用作一藥物。 22. —種治療哺乳動物中的其中已知或可顯示對催產素之抑制可產生有益效果之病症或疾病之方法，該方法包含無限制條件地向该哺乳動物投給一治療有效量之如請求項 1至19中任一項之式⑴之化合物，或其醫藥上可接受之鹽、溶劑合物或多形體。 23. -種如請求項u19中任一項之式⑴之化合物、或其醫藥 j可接受之鹽、溶劑合物或多形體無限制條件地在用於 m療其中已知或可顯示對催產素之抑制可產生有益效果之病症或疾病之藥物的製備中之用途。 24·如請求項22之方法或如請求項23之用途，其中該病症或 =病係選自性功能障礙、男性性功能障礙、女性性功能 P早礙、性慾減低病症、性唤起病症、高潮病症、***疼痛病症、早鴻、早期分娩、分娩併發症、食慾及攝食失調、***良性增生、早產、痛經、充血性心力衰竭、動脈性高血麼、肝硬化、腎高血壓、眼部高血壓、強迫症及神經性精神病症。 25.如凊求項24之方法或用途，其中該病症或疾病係選自性喚起病症、高潮病症、***疼痛病症及早洩。 95339.doc 200526606 七、指定代表圖： (一)本案指定代表圖為：（無） .(二)本代表圖之元件符號簡單說明：八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：V, W, X and Y, which may be the same or different, represent C_R0 &N; Z is CH or N; R1 is selected from: (I) a phenyl ring substituted with two or more substituents, The substituents may be the same or different, and each substituent is independently selected from the group consisting of acyl, (c-G) alkyl, (CVC6) alkoxy, cyano, c (〇) nr7r8, nr7r8, NR7C (0) R1G and NfCCCOR1. ]; And (⑴ five to seven membered aromatic heterocycles containing ^ heteroatoms selected from N, 0, and s and their N-oxides; the ring is optionally substituted with two or more substituents, the The equivalent substituents may be the same or different, and are selected from halo, (Ci_C6) alkyl, (CVC6) alkoxy, cyano, c (〇) nr7r8, nr7r8, NR7C (0) R1 (), and Ke (:( 〇) 1 ^ 〇; | 2; R2 is selected from: Η Η, OH, OR9, NR7R8, NR7C (〇) R10 and n [C (0) R1 ()] 2; (II) contains 1-3 impurities A 5-7 member N-linked heterocyclic ring of atoms, the heteroatoms are selected from N, 0 and S; the ring is optionally substituted by one or more groups, and the 95339.doc 200526606 group is selected from (CVC6) Alkyl '(Cl-C6) alkoxy and c (o) NR7R8; and (out) optionally (CVC6) alkyl substituted with an N-linked 5-7 membered heterocyclic ring, the heterocyclic ring containing 1-3 A heteroatom selected from N, 0 and S; R3 is selected from fluorene and (CVC6) alkyl; R4 is selected from fluorene, (CVC6) alkyl and OR9; R5 is selected from halo, (CrCe) alkyl, (CVC6) alkoxy, NR7R8, NR7C (〇) R10 and n [c (o) r10] 2; R6 is selected from fluorene, halo, (CVC6) alkyl, (Cl_c6) alkoxy, cyano, nr7r8, nr 7c (0) r1 (), N [C (0) R, 2 & C (0) NR7R8; R and R 'may be the same or different, and are selected from Η and (Ci_c6) alkyl; R is (c ^ c: 6) alkyl, which may be optionally substituted by one or more groups, each group is independently selected from (Ci-C6) alkoxy and a hetero atom containing i_3 selected from N, 〇 and S 5_7 membered heterocyclic ring of N_; and R 0 is selected from (Cl-c6) alkyl and (Ci_c6) alkoxy; the limitation is that the compound of formula 并非 is not ·· 3 ^ · ethyl-5 -(4-imidazole-; u-phenylphenyl) -4 · (4-methoxyphenyltriazole, ('5-chlorobiphenyl-4-yl) -4 · (2-methoxyphenyl) _5_Methyl-4 '-[1,2,4] triazole, 3-Γ3, s, Yao ^' bis-difluoromethylbiphenyl-4-yl) -4- (2-fluorophenyl) _5 · Methyl-4 '-[1,2,4] triazole, or (, __ difluoromethylbiphenyl-4-yl) -5 -methyl-4- (3-trifluoromethylphenyl) _4Η · [1,2,4] triazole. 2. Compounds such as% seeking item 1, wherein X is CH. 95339.doc 200526606 3. Compounds of claim 1, or claim 2, wherein V, W & Y Each is independently CH, C-OCH3 or N. 4. The compound according to any one of claims 1 to 3, wherein Mai and γ are each independently CH or N and X and V are each CH. 5. The compound of any one of items 1 to 4 as described above, wherein 2 is N. 6. A compound according to any one of claims 1 to 4, wherein 2 is CH. 7. The compound according to any one of claims 1 to 6, wherein Ri is selected from the group consisting of (I) a phenyl ring substituted with two substituents, and these substituents may be the same or different and each is independently selected From halo, (Ci_c6) alkyl, (Ci_c6) alkoxy, cyano, C (0) NR7R8, NR7R8, nr7c (o) r10, and n [c (o) r, 2; and (II) pyridyl The ring or its N-oxide is each substituted with two substituents, and these substituents may be the same or different, and each is independently selected from halo, (CrD alkyl, alkoxy, cyano, and c (〇) NR7R8, NR7R8, NR7C (〇) R10 and N [C (〇) R1 ()] 2. 8. The compound of item 7 as w, wherein Ri is a phenyl ring substituted with two substituents. It may be the same or different, and each is independently selected from a fluoro group, an amino group, a fluorenyl group, a methoxy group, and a cyano group. 9. The compound of claim 7, wherein its fR1 is substituted by two methyl groups. 10. The compound according to any one of claims 1 to 9, wherein r2 is selected from the group consisting of: ⑴H, (Cl-c3) alkyloxy, (Ci_c3) alkyloxy, and n ((cvc3) Alkyl) 2; and ⑼ containing a 5-membered N-linked heterocyclic ring of "nitrogen atoms, The situation is replaced by 95339.doc 200526606 c (o) nr7r8. 11 · The compound of claim 1 o, wherein r2 is selected from the group consisting of H, methoxy, ethoxy, 2-methoxyethoxy, dimethyl Amine, 1,2,3-triazol-2-yl and pyrrolidinyl, the latter optionally substituted with CONH2. 12. The compound of claim 11, wherein R2 is selected from the group consisting of fluorene and methoxy. 13.such as The compound according to any one of claims 1 to 12, wherein R3 is η. 14. The compound according to any one of claims 1 to 13, wherein R4 is η, methyl, or methoxy. 15. According to claim 14 Compound of which R4 is fluorene. 16. The compound of any one of claims 1 to 15, wherein R5 is methoxy or nhch3 〇17. The compound of " month seeking item 16, wherein R5 is methoxy 18. The compound according to item 1, which is selected from the group consisting of 2- (cardiofluoro, 2-methylphenyl) -5- (5-methoxyfluorenyl-4- (6-methoxy.) (Pyridyl), 4H- [1,2,4] triazol-3-yl) -pyridine; 2- (21_dimethylphenyl) -5- (5-methoxymethyl-4- (6 -Pyroxypyridin-3-yl) -411, [1,2,4] triazol-3-yl) -pyridine; 5_ (heart gas, 2-methylphenyl) -2_ (5-methoxymethyl_4_ (6-methoxymethoxypyridinyl group 0, 4H- [l, 2,4] tris.-3-methyl group) -σ specific bite; 5- (23 — ~ 曱Phenyl) -2- (5-methoxymethyl-4- (6-methoxy. Bipyridin-3-yl) -4 is also [1,2,4] triazol-3-yl) -guridine; 1- [515, (2,3-dimethylphenylpyridin-2-yl] · 4- (6-methoxyoxypyridin-3-yl) -4, [1,2,4] triazol-3-ylmethyl] -pyrrolidin- (2S) -2-carboxylic acid fluorenamine; 5- (2 3 mono ~ methylphenyl) -2- (5-salrolidin-1-ylmethyl-4- (6-methoxypyridine 95339.doc 200526606 pyridin-3-yl) -4Η- [1 , 2,4] triazol-3-yl) -pyridine; 2- (4-Ga-2-methylphenyl) -5- [5-methyllactylmethyl-4- (6-methyllactyl σ Than 17 疋 -3-yl) -4Η- [1,2,4] triazol-3-yl] -oxazine; 2- (2,3-dimethylphenyl) -5- [5-methoxy Sulfonyl-4- (6-methoxyl-l-11-l-3-yl) -4fluorene- [1,2,4] bissigma-3-yl]-° specification, 2- (4- Fluoro-2-methylphenyl) -5- [4- (6-methoxyoxazidin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -Pyrazine; 2- (2,3-diamidinophenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2,4 ] Triazol-3-yl] -oxazine; 2- (4-cyano-2-methylphenyl) -5- [4- (6-methoxy.pyridin-3-yl) -5- Methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxy Azidin-3-yl) -5-methyl -4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (4-cyano-2-methylphenyl) -5- [5-methoxymethyl-4- (6-methoxypyridin-3-yl) -4 '-[1,2,4] triazol-3-yl] -pyrazine; 5- (4-cyano-2-methylphenyl)- 2- [5-methoxymethyl-4- (6-methoxypyrimidin-3-yl) -4 '-[1,2,4] triazol-3-yl] -pyridine; 2- (5 -Fluoro-2-methoxyphenyl) -5- [5-Methoxymethyl-4- (6-methoxypyrimidin-3 · yl) -4 {-[1,2,4] triazole -3-yl] -pyridine; 2- (2-fluoro-5-methoxyphenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (2-Gas-5-fluorenylphenyl) -5- [4- (6-fluorenyl °° -Yl) -5 -methyl-4fluorene- [1,2,4] triazol-3-yl] -pyrazine; 2- (2,5-difluorophenyl) -5- [4- (6- Methoxy.pyridin-3-yl) -5-methyl 95339.doc 200526606 -4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (3,5-difluorene Phenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2 -(2,5-dimethylphenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2,4] triazole-3 -Yl] -pyrazine; 2- (2,5-dichlorophenyl) -5- [4- (6-methyl N-methylpyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] · pyrazine; 2- (2-fluoro-5-methoxyphenyl)- 5- [4- (6-methoxypyrimidin-3-yl) -5-fluorenyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (3,5 -Difluoro-phenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazol-3-yl] -pyridine Hydrazine; 2- (2,3-dimethylphenyl) -5- [5-[(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3-yl) -4Η-1,2,4-triazol-3-yl] pyridine; 2- (5-Gas-2-methoxyphenyl) -5- [5-[(2-methoxyethoxy) Methyl] -4- (6-methoxypyridin-3-yl) -4Η-1,2,4-triazol-3-yl] pyridine; 2- (4-fluoro-2-methoxyphenyl ) -5- [5-[(2-methoxyethoxy) methyl] -4- (6-methoxypyridin-3 · yl) _4H-1,2,4-triazol-3-yl ] Pyridine; 2- (5-fluoro-2-methoxyphenyl) -5- [5-[(2-methoxyethoxy) methyl]-'(6-methoxypyridine-3 -Yl) -4′-1,2,4-triazol-3-yl] pyridine; 2- (5-fluoro-2-methylphenyl) -5- [5-[(2-methoxyethyl Oxy) fluorenyl] -4- (6-methoxypyridin-3-yl) -4fluorene-1,2,4-triazol-3-yl] pyridine; 2-methoxy-5- {3- [(2-methoxyethoxy) methyl] -5- [6- (2-methoxy-5-fluorenylphenyl) cycloid-3-yl] -4H-1,2,4-triazol-4-yl} toxidine; 2- (2 -Fluoro-3-methoxyphenyl) -5- [5-[(2-methoxyethoxy) methyl 95339.doc -6- 200526606 group] -4- (6-methoxyπ specific bite _3_yl) -4Η-1,2,4-triazol_3-yl] π-pyridine; 2- (3,5-difluorophenyl) _5- [5-[(2-methoxyethyl (Oxy) methyl]-'(6-methoxypyridin-3-yl) -4'-1,2,4-oxazole-3 · yl] pyridine; 2- (2,5-dimethoxybenzene Group) -5- [5-[(2-methoxyethoxy) methyl] -oxo (6-methoxy. Hiyodo · 3_yl) -4Η-1,2,4-trisialyl-3-yl]. ratio. Fixed; 2- (3-chloro + fluorophenyl) _5_ [5 _ [(2-methoxyethoxy) methyl] -4_ (6_methoxy. Than pyridine_3_yloxazole_3_ Yl] pyridine; and 2- (3-fluoromethoxyphenylmethoxymethyl-4- (6.methoxypyridin-3-yl) -411- [1,2,4] triazole -3-yl] -pyrazine; 2- (3-fluoromethoxy-phenyl- [4- (6-methoxy-pyridine-3 · yl) -5-methyl_4_H, [1,2 , 4] triazol-3-yl], biazine; and tautomers thereof, and pharmaceutically acceptable salts, solvates and polymorphs of the compounds or tautomers. 19. If requested in item 18 Compound, which is selected from the group consisting of: 'Spitomethylphenyl) -5- (5-methoxymethyl-4- (6-methoxypyridyl) 411 · ^, 2,4] triazole-3 -Yl) -pyridine; 2 (2'3, monomethylphenyl) _ ^ (5-methoxymethylmethoxypyridine_3-yl) -4H4l, 2,4] triazol_3 · yl Bibidin; 5 (4 · fluoro ^ methylphenyl) · 2-(5 · 曱 methoxymethyl dong (6-曱〇 oxidine small group M ^ 1, 2, 4,] triazole-3- Gibby. Ding; 5 (2'3, monomethylphenyl) _2_ (5-methoxymethyl-M · methoxy. Pyridinyl) -4Η [[ΐ, 2,4] tri Azole-3-yl) "pyridine; ^ [5 [% (2,3-bis Phenyl) _pyridine_2_yl] _4_ (6_methoxypyridine_3 · ter) 4 & [1'2,4] disialyl-3-ylmethylpyrrolidine_ (2S)- 2-Amino acid amine; 95339.doc 200526606 5- (2,3-Difluorenylphenyl) -2- (5 j than pyrrolidin-1-ylmethyl-4- (6-methoxypyridine- 3-yl) -4Η- [1,2,4] triazol-3-yl) -pyridine; 2- (4-fluoro-2-fluorenylphenyl) -5- [5-methoxymethyl- 4- (6-methoxypyrimidin-3-yl) -4 '-[1,2,4] triazol-3-yl] -pyrazine; 2- (2,3-dimethylphenyl)- 5- [5-Methoxymethyl-4- (6-methoxypyridin-3-yl) -4 '-[1,2,4] triazol-3-yl] -pyrazine; 2- ( 4-fluoro-2-methylphenyl) -5- [4- (6-methoxypyridin-3-yl) -5-methyl-4H- [1,2,4] triazole-3- -] Pyrazine; 2- (2,3-dimethylphenyl) -5- [4- (6-methoxypyrimidin-3-yl) -5-methyl-4H- [1,2 , 4] triazol-3-yl] -pyrazine; 2- (4-cyano-2-amidinophenyl) -5- [4- (6-methoxypyridin-3-yl) -5 -Fluorenyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (5-fluoro-2-methoxyphenyl) -5- [4- (6-methoxy Amidin-3-yl) -5-fluorenyl-4H- [1,2,4] triazol-3-yl] -pyrazine; 2- (4-amino-2-methylphenyl)- 5- [5-methoxymethyl-4- (6-methyl milk Amidinopyridin-3-yl) -4Η- [1,2,4] triazol-3-yl] -pyrazine; 5- (4-cyano-2-methylphenyl) -2- [5 -Methoxymethyl-4- (6-methoxypyridin-3-yl) -4 '-[1,2,4] triazol-3-yl] -pyridine; 2- (5-fluoro-2 -Methoxyphenyl) -5- [5-methoxymethyl-4- (6-methoxypyrimidin-3-yl) -4Η- [1,2,4] triazol-3-yl ] • pyridine; and 2- (3-fluoro-2_methoxyoxyphenyl) -5- [5-methoxyoxy-4--4- (6-methoxyoxypyridin-3-yl) -4Η- [1,2,4] triazol-3-yl] -pyrazine; 2- (3-Gas-2-methoxy-phenyl) -5- [4- (6-methoxy- ° specific bite -3 -yl) -5 -fluorenyl-4- 4-fluorenyl- [1,2,4] di ° sit-3-yl] ratio; and its tautomers and the compounds or tautomers in medicine It can be used as the salt, solvate and polymorph of 95339.doc 200526606. 20. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof 'solvate or polymorph, and an acceptable diluent on Saijo Or carrier. 21. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or polymorph thereof, for use as a medicine. 22. A method of treating a condition or disease in a mammal in which the inhibition of oxytocin is known or can show beneficial effects, the method comprising administering to the mammal a therapeutically effective amount such as A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or polymorph thereof, according to any one of claims 1 to 19. 23. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph of any one of the claims u19, which is used in m therapy without limitation and is known or may show an effect on oxytocin Inhibition of vegetative use in the manufacture of a medicament that produces a beneficial effect on a condition or disease. 24. The method of claim 22 or the use of claim 23, wherein the disorder or disease is selected from the group consisting of sexual dysfunction, male sexual dysfunction, premature impairment of female sexual function, reduced sexual desire, sexual arousal disorder, orgasm Illness, pain during sexual intercourse, Zaohong, early childbirth, childbirth complications, appetite and feeding disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertensive disease, cirrhosis, renal hypertension, high eye Blood pressure, obsessive-compulsive disorder, and neuropsychiatric disorders. 25. The method or use of claim 24, wherein the disorder or disease is selected from the group consisting of sexual arousal disorders, orgasmic disorders, painful intercourse disorders, and premature ejaculation. 95339.doc 200526606 VII. Designated representative map: (1) The designated representative map of this case is: (none). (II) Brief description of the component symbols of this representative map: 8. If there is a chemical formula in this case, please disclose the features that best show the invention Chemical formula:

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