TW200410970A

TW200410970A - Heteroaryl-ethanolamine derivatives as antiviral agents

Info

Publication number: TW200410970A
Application number: TW092124467A
Authority: TW
Inventors: Mark E Schnute; Michele M Cudahy; Marijean Eggen; David J Anderson; Thomas M Judge; J Kim Euibong; A Collier Sarah
Original assignee: Upjohn Co
Priority date: 2002-09-04
Filing date: 2003-09-04
Publication date: 2004-07-01
Also published as: AU2003304151A8; WO2004106345A3; AU2003304151A1; WO2004106345A2

Abstract

The present invention provides a compound of formula as described herein, which are useful as antiviral agents, in particular, as agents against viruses of the herpes family.

Description

200410970 玖、發明說明：【發明所屬之技術領域】本發明係揭示五-(5)員雜芳基乙醇胺衍生物，尤其是提供以下所述式（I)之化合物。此等化合物係用作抗病毒劑，尤其是用作抗皰疹族病毒之藥劑。【先前技術】皰疹病毒包括一大族群之雙股DNA病毒。其亦為人類大部分普通病毒疾病之來源。跑療病毒、單純皰奢病毒1型及 2型（HSV-1及HSV-2)、帶狀皰疹病毒（VZV)、人類細胞巨大型病毒（HCMV)、EB病毒（Epstein-Barr virus)(EBV)、及人類皰疹病毒6、7及8(HHV-6、HHV-7、及HHV-8)已經顯示會感染人類。 HSV-1及HSV-2分另ij會造成嘴唇及生殖器之皰疹性受損。其亦偶爾會造成眼睛及腦炎之感染。HCMV造成嬰兒之分娩缺陷以及各種免疫不全病患之疾病，如視網膜炎、肺炎、及胃腸疾病。VZV為水痘及帶狀皰疹之成因劑。EBV 造成感染性單核白血球增多症。其亦造成免疫不全病患中之淋巴瘤，且已經與伯奇（Burkitt’s)淋巴瘤、鼻咽癌、及或奇今氏症有關。HHV-6為玫瑰疹之成因劑，且可能伴隨多發性硬化及慢性疲乏併發症。HHV-7伴隨之疾病並不清楚，但其可能包含於玫瑰疹之某些情況中。HHV-8與卡普西（Karposi’s)内瘤、以淋巴瘤為主之身體空隙及多發性骨髓炎有關。受皰疹病毒感染或皰疹病毒之再復活會伴隨宿主之許多 200410970 新血管疾病或症狀，如動脈硬化及因冠狀血管壁造成之再狹窄。相仏許多罹患再狹窄之病患，以下冠狀動脈硬塊切除病毒感染，尤其是CMV感染對於疾病之增生扮演重要角色動脈硬化相仏係因宿主罹患整體感染疾病造成，尤其疋皰療病毒’如HS V、CMV及EB V。動物族群（家畜及伴信）受皰療病毒菌株之感染係區域性的包含牛（牛皰療病毒U，BHV)、羊⑽羊跑療病毒U2)、狗（犬皰疹病毒1)、馬（馬皰疹病毒丨_8，EHv)、貓（貓科皰疹漓母1 FHV)、豬（擬狂犬病毒，pRV)、及許多類型之家禽。⑩ 若為牛皰療病毒’則動物可能罹患眼晴、呼吸或消化性疾病梃狂犬病為感染許多物種（如牛、馬、狗、貓、羊及山平），導致快速死亡之極度接觸性傳染病#病原體。該病毒，於成豬無菩’然而’其仍為接觸性感染且在三週内造成而度死亡率。馬受到馬皰療病毒之感染會造成神經性併發 =、呼吸運疾病及新生動物之疾病。雜之皰療病毒感染會 k成縫科病毒氣管炎（FVR)，其特徵為鼻炎、氣管炎、及結膜炎。、 ❿ 由於五-(5)員雜芳基取代基在以下戶斤述式I上之獨特位置’因此本發明化合物證明對上述參考之跑療病毒感染具 =出乎思料《外的活性’尤其是人類細胞巨大型病毒之感【資料揭示】皰疹病毒感染之化合物美國專利第6,239，142號揭示治療及其應用。 87731 200410970 WO 02/065 13揭示篩選4-羥基喹啉、4-氧代-二氫喹啉及4- 氧代-二氫嘧吩吡啶衍生物作為核甘酸皰疹病毒DNA多酶抑制劑之方法。200410970 (ii) Description of the invention: [Technical field to which the invention belongs] The present invention discloses a penta- (5) -membered heteroarylethanolamine derivative, and particularly provides a compound of formula (I) described below. These compounds are used as antiviral agents, especially as agents against herpes virus. [Prior art] Herpes virus includes a large group of double-stranded DNA viruses. It is also the source of most common viral diseases in humans. Runaway virus, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), herpes zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (Epstein-Barr virus) ( EBV), and human herpesviruses 6, 7 and 8 (HHV-6, HHV-7, and HHV-8) have been shown to infect humans. HSV-1 and HSV-2 can cause herpes damage to the lips and genitals. It also occasionally causes eye and encephalitis infections. HCMV causes birth defects in infants and various diseases of immunocompromised patients, such as retinitis, pneumonia, and gastrointestinal disorders. VZV is the causative agent of chickenpox and shingles. EBV causes infectious mononuclear leukocytosis. It also causes lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and / or Kijn disease. HHV-6 is a causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue complications. The diseases that accompany HHV-7 are not clear, but they may be included in some cases of roseola. HHV-8 is associated with Karposi's intratumor, lymphoid body voids, and multiple osteomyelitis. Herpes virus infection or reactivation of the herpes virus can accompany many of the host's 200410970 neovascular diseases or symptoms, such as arteriosclerosis and restenosis due to coronary vessel walls. In relation to many patients suffering from restenosis, the following coronary sclerosis virus infections, especially CMV infections play an important role in the proliferation of the disease. The arteriosclerosis phase is caused by the host's overall infection, especially the herpes treatment virus, such as HS V, CMV and EB V. Animal herds (livestock and associated animals) infected with herpes virus strains include bovine (bovine herpes virus U, BHV), sheep and sheep running virus U2), dog (canine herpes virus 1), and horse ( Equine herpes virus 丨 _8, EHv), felines (feline herpes litter 1 FHV), pigs (rabies pseudovirus, pRV), and many types of poultry. ⑩ In the case of bovine herpes therapy virus, animals may suffer from clear eye, respiratory or digestive diseases. 梃 Rabies is an extreme contact infectious disease that infects many species (such as cattle, horses, dogs, cats, sheep, and mountain flats) and causes rapid death. # 病原体. The virus, which is not found in adult pigs, however, is still a contact infection and caused a mortality rate within three weeks. Horses infected with equine herpes virus can cause neurological complications, respiratory diseases, and neonatal diseases. Miscellaneous herpes treatment for viral infections can cause suture virus bronchitis (FVR), which is characterized by rhinitis, tracheitis, and conjunctivitis. ❿ Because of the unique position of the five- (5) -membered heteroaryl substituent on the formula I below, the compound of the present invention proves that the reference to the above-mentioned running virus infection has an unexpected activity, especially "external activity", especially It is the feeling of megalovirus in human cells. [Data Revealing] U.S. Patent No. 6,239,142, a compound for herpes virus infection, discloses treatment and its application. 87731 200410970 WO 02/065 13 discloses a method for screening 4-hydroxyquinoline, 4-oxo-dihydroquinoline, and 4-oxo-dihydropyridinepyridine derivatives as inhibitors of ribosomal herpes virus DNA .

Tetrahedron Lett. 1983, 24, 3233-3236敘述將N-苄基胺轉化成苄基氯之條件。 WO 95/28405揭示雙環嘧吩衍生物及其用作與荷爾蒙拮抗劑有關之***。 EP 443568揭示嘧吩衍生物，其製造及應用。 WO 02/04445揭示各種三環蕊結構，其具有對抗皰疹病毒之抗病毒活性。 wo 02/04444、WO 02/04443、及 WO 02/04422揭示各種雙環蕊結構，其具有對抗皰齋病毒之抗病毒活性。美國專利第6,248,739揭示蕊結構為喹啉，且用作對抗皰療病毒之抗病毒劑之化合物。 WO 00/53178，WO 00/53179，WO 00/53180，WO 00/53181 ，WO 00/53185及WO 00/53602揭示作為釋出荷爾蒙之促性腺激素之拮抗劑之6-氮雜啕哚化合物。美國專利第6,346,534及WO 00/69859揭示作為釋出促性腺激素荷爾蒙受體拮抗劑之咪峻并-及p比哇并[1，2-a] p密淀 -4-酮0 WO 94/12461揭示用作可能治療AIDS、氣喘、關節炎及其他發炎疾病之雙環蕊結構。【發明内容】本發明提供一種式I之化合物，其對映體、非立體異構物 200410970 或互變體異構物，或其醫藥接受性鹽Tetrahedron Lett. 1983, 24, 3233-3236 describes the conditions for converting N-benzylamine to benzyl chloride. WO 95/28405 discloses bicyclic pyrimidine derivatives and their use as gonadotropins related to hormone antagonists. EP 443568 discloses pyrimidine derivatives, their manufacture and applications. WO 02/04445 discloses various tricyclic stamen structures having antiviral activity against herpes virus. wo 02/04444, WO 02/04443, and WO 02/04422 disclose various bicyclic stamen structures that have antiviral activity against herpes virus. U.S. Patent No. 6,248,739 discloses a compound having a quinoline structure and used as an antiviral agent against herpes virus. WO 00/53178, WO 00/53179, WO 00/53180, WO 00/53181, WO 00/53185 and WO 00/53602 disclose 6-azapyridine compounds which are antagonists of gonadotropins that release hormones. U.S. Patent No. 6,346,534 and WO 00/69859 disclose miconazole as a gonadotropin hormone receptor antagonist- and p-biwa [1,2-a] p-metid-4-one 0 WO 94/12461 Reveal the structure of bicyclina as a possible treatment for AIDS, asthma, arthritis and other inflammatory diseases. [Summary of the Invention] The present invention provides a compound of Formula I, its enantiomer, non-stereoisomer 200410970 or tautomer, or a pharmaceutically acceptable salt thereof

其中 1 R1為 ⑷C1， (b) Br， (c) F ，或 (d) CN ； R2為 (a) 視情況以一或多個戎Cu占备廿 '夕Lm或d.4砭乳基取代之Cm烷基’或 (b) (CH2)mOCH2CH2OH ； R為C 1 _ 2燒基； R4為經由4員子鍵結之具有卜2或3個選自〇、_^n_w 組成之群組之雜原子之五⑺員雜芳基，其中r4係視情況融合於苯環或吡啶環上，且視情況以一或多個Μ取代；其中w為不存在、11或Cm烷基； R5為 (a) Η ，或 (b)視情況以OH取代之Cu烷基； R6為 (a)齒基， 87731 200410970 (b) OCF3， (c) 氰基， (d) 硝基， (e) CONR7R8， (f) NR7R8， (g) C1-7虎基’其係視情況部分不飽和，且視情況以一或多個R9取代， (h) 0(CH2CH20)nR10， (i) OR10 , (j) C02R10 ;或 (k) 視情況以自基、Cl-7烷基或Cl7烷氧基取代之苯基； R7及R8獨立為 (a) Η， (b) 視情況以_基、Cl_7烷基或Cw烷氧基取代之苯基， (c) 視情況以一或多個〇r1g、苯基或_基取代基取代之 C 1 - 7燒基， (d) 03-8環燒基， (e) (OO)R11，或 (f) R及R與其所附接之氮一起形成het，其中het為具有 ~ (1)、二（2)或三（3)個選自由氧、硫或氮組成之雜原子之五 _(5)或六-(6)員雜環，其中het係視情況以Cw烷基取代； R9為 (a) 氧代， (b) 視情況以齒基、Cl_7烷基或Cw烷氧基取代之苯基， 87731 200410970 (c) OR10， (d) 0(CH2CH2)OR10， (e) SR10， (f) NR7R8， (g) iS 基， (h) C02R10， (i) CONR10R10，或 (j) 視情況以OR10取代之（：3-8環燒基， R10為 (a) Η， (b) C1 - 7 fe 基， (C) C3_8環烷基，或 (d)視情況以（¾基、cN7烷基或Cw烷氧基取代之苯基 R"為 (a) CN7烷基， (b) C3.8環烷基，或 (c) 視情況以卣基、Cl-7烷基或Cw烷氧基取代之苯基， η為 1、2、3、4或 5 ;且 m為1或2。本發明另一目的亦提供如下：包括醫藥可接受性載劑及有效量之式I化合物之醫藥組合物，治療或預防哺乳動物皰疹病毒感染之方法，包括對哺乳動物依其需求投與式I之化合物，或其醫藥可接受性鹽， 87731 -11 - 200410970 種抑制病毒DNA聚合物酶之方法，包括在活體内或活骨豆外使聚合物酶與有效抑制量之式！化合物或其醫藥可接受性鹽接觸，治療或預防哺乳動物皰疹病毒感染之醫藥用之式丨化合物或其醫藥可接受性鹽。本發明亦提供新穎中間物及本文中所揭示用於製備式I 化合物之方法。【實施方式】針對本發明（目的’各種含烴基團之碳原子含量係以字Φ 首表7JT基團中最小及最大碳原子數，亦即字首表示整數 "1”至整數Ί”碳原子數之基團。因此，例如（Ci7)燒基係指一至七個礙原子之燒基’包含甲基、乙基、丙基、丁基、戊基、己基及庚基，其直鏈或支鏈形式。 "齒基"或"南素"一詞係指元素氟（F)、氯（C1)、溴（Br)及碘 ⑴。 ’、 "c3.8環燒基”―詞係具有3至8個碳原子之非芳系碳環。 ’’燒氧基”―詞係指R0·’其中R為之㈣之燒基或環垸基。 ’’雜芳基’’ 一詞係指芳系雜環基。熟習本技藝者應了解具有對掌中心之本發明化合物可以光學活性及消旋形式存在且分離。部分化合物可呈現多態。需:解本發明包含本發明化合物之任何消旋、光學活 Ί i變IS或立體異構物形式或其混合物’均具有本文中所述有用之性質，且製備光學活性形式為技❹習 87731 -12- ‘uu^fujy7〇知（，如’藉由再結晶技術溶解消旋形式、藉由光活化起始質。成、藉由對掌性合成或藉由使用對掌性靜態相之層析刀離）’及如何使用本文中所述標準試驗或使用技藝中習知之其他類似試驗測定抗病毒活性。本發明足化合物通常係依據IUPAC或CAS命名系統命名。 ’’醫藥可接受性鹽”係指帶有母體化合物之生化效力及性質，且不具有生化或其他不必要性之鹽。哺乳動物’’係指人類及動物。動物尤其指例如食用動物或寵物。籲視情況’’或’’可能為，’意指隨後所述之狀況或環境可能（但並非一定）發生，且該敘述包含狀況或環境發生之情況及並未發生之情況。醫藥可接受性載劑”意指通常為安全、無毒且沒有生化或其他不必要作用之用於製備醫藥組合物之載劑，且該載劑包含獸醫用途以及人類醫藥用途上均可接受之載劑。說明書及申請專利範圍中所用之”醫藥可接受性載劑”包含一 g 種或超過一種之載劑二者。尤其，本發明之式I具有式IA中所示之立體中心：Where 1 R1 is ⑷C1, (b) Br, (c) F, or (d) CN; R2 is (a) optionally substituted with one or more Ron Cu 夕夕 Lm or d.4 砭 lactyl substitution Cm alkyl 'or (b) (CH2) mOCH2CH2OH; R is a C 1 _ 2 alkyl group; R 4 is a group having 2 or 3 groups selected from 0 and _ ^ n_w bonded through a 4-member bond A five-membered heteroaryl group of a heteroatom, in which r4 is optionally fused to a benzene ring or a pyridine ring, and optionally substituted with one or more M; wherein w is absent, 11 or Cm alkyl; R5 is ( a) Η, or (b) Cu alkyl substituted with OH as appropriate; R6 is (a) dentyl, 87731 200410970 (b) OCF3, (c) cyano, (d) nitro, (e) CONR7R8, (f) NR7R8, (g) C1-7 tiger-based 'It is partially unsaturated and optionally substituted with one or more R9, (h) 0 (CH2CH20) nR10, (i) OR10, (j) C02R10; or (k) phenyl substituted with self-radical, Cl-7 alkyl, or Cl7 alkoxy, as appropriate; R7 and R8 are independently (a) Η, (b) optionally with _yl, Cl_7 alkyl, or Cw alkoxy-substituted phenyl, (c) C 1 -7 alkyl, optionally substituted with one or more OR1g, phenyl, or — substituents, (d) 03-8 A radical, (e) (OO) R11, or (f) R and R together with the nitrogen to which they are attached form a het, where het is a group having ~ (1), two (2) or three (3) selected from the group consisting of oxygen Five- (5) or six- (6) -membered heterocyclic heteroatoms consisting of, sulfur or nitrogen, where het is optionally substituted with Cw alkyl; R9 is (a) oxo, (b) optionally , Cl_7 alkyl or Cw alkoxy substituted phenyl, 87731 200410970 (c) OR10, (d) 0 (CH2CH2) OR10, (e) SR10, (f) NR7R8, (g) iS group, (h) C02R10, (i) CONR10R10, or (j) optionally substituted with OR10 (: 3-8 ring alkyl, R10 is (a) fluorene, (b) C1-7 fe group, (C) C3_8 cycloalkyl group, Or (d) a phenyl group substituted with (¾yl, cN7 alkyl or Cw alkoxy) as appropriate (a) CN7 alkyl, (b) C3.8 cycloalkyl, or (c) as appropriate Fluorenyl, Cl-7 alkyl or Cw alkoxy substituted phenyl, η is 1, 2, 3, 4 or 5; and m is 1 or 2. Another object of the present invention also provides the following: including pharmaceutically acceptable Sex carrier and an effective amount of a pharmaceutical composition of a compound of formula I, a method for treating or preventing mammalian herpes virus infection, It is required to administer a compound of formula I, or a pharmaceutically acceptable salt thereof, 87731 -11-200410970 methods for inhibiting viral DNA polymerases, including polymerases and effective inhibitory amounts of the formulae in vivo or outside live bone beans. !! The compound or a pharmaceutically acceptable salt thereof is a compound of the formula or a pharmaceutically acceptable salt thereof for use in medicine for the treatment or prevention of a herpes virus infection in a mammal. The invention also provides novel intermediates and methods disclosed herein for preparing compounds of formula I. [Embodiment] In accordance with the present invention (the purpose 'the carbon atom content of various hydrocarbon-containing groups is represented by the word Φ at the beginning and the minimum and maximum carbon atoms in the 7JT group, that is, the prefix represents the integer " 1 "to the integer Ί" carbon Atomic number group. Therefore, for example, (Ci7) alkyl refers to one to seven atom-blocking alkyl groups including methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl. Branched form. The term " dentate " or " Southern " refers to the elements fluorine (F), chlorine (C1), bromine (Br), and iodine. ', &Quot; c3.8 Cycloalkyl "" Word is a non-aromatic carbocyclic ring having 3 to 8 carbon atoms. "" Oxyl "-the word refers to R0 · 'where R is an alkyl or cyclofluorenyl group.' 'Heteroaryl' The term refers to an aromatic heterocyclic group. Those skilled in the art should understand that the compounds of the present invention with opposite centers can exist and be separated in optically active and racemic forms. Some compounds can exhibit polymorphisms. Needs: The present invention includes the present invention Any of the racemic, optically active, or IS or stereoisomeric forms of the compounds of the invention, or mixtures thereof, has the properties described herein. Nature, and the preparation of optically active forms is a technical practice 87731 -12- 'uu ^ fujy7〇 know (such as' dissolve the racemic form by recrystallization technology, activate the starting material by light. Into, by the palm Anti-viral activity can be determined synthetically or by the use of a chromatographic separation of the palm-like static phase) 'and how to measure the antiviral activity using standard tests described herein or other similar tests known in the art. The compounds of this invention are generally based on IUPAC or CAS nomenclature. "Pharmaceutically acceptable salt" refers to a salt that has the biochemical potency and properties of the parent compound, and does not have biochemical or other unnecessary properties. Mammals "refers to humans and animals. Animals, especially For example, food animals or pets. "Appealing to the situation" or "may be," means that the condition or environment described later may (but not necessarily) occur, and the narrative includes the condition or environment that occurred and did not occur. "Pharmaceutically acceptable carrier" means a carrier that is generally safe, non-toxic, and has no biochemical or other unwanted effects for the preparation of a pharmaceutical composition, and that the carrier package Veterinary and human medicinal acceptable carriers. "Pharmaceutically acceptable carriers" used in the specification and patent applications include both g or more than one carrier. In particular, Formula I of the present invention With the stereo center shown in Formula IA:

IA. 尤其，包括超過51%式IA化合物之組合物。尤其，包括超過75%式IA化合物之組合物。 87731 -13- 200410970 尤其，包括超過90%式ΙΑ化合物之組合物。尤其，包括超過98%式ΙΑ化合物之組合物。尤其，R1為氣，尤其，以2為Cw烷基，尤其，R2為甲基、乙基或正丙基，尤其，R2為甲基，尤其，R2為以一或二個羥基取代之C1-3烷基，尤其，R2為2-羥基乙基、3-羥基丙基或2,3_二經基丙基，尤其，R2為以Cw烷氧基取代之Cl-4烷基，尤其，R2為以甲氧基取代之C!_4烷基，尤其，R2為2_甲氧基乙基，尤其，R2 為 CH2CH2OCH2CH2OH，尤其，R3為甲基，尤其，R3為乙基，尤其’ R為經由碳原子鍵結之具有一（1)或二（2)個選自由〇、S及N-W組成之群組之雜原子之五_(5)員雜芳基· 尤其，W係不存在；尤其，W為Η ; 尤其，W為甲基、乙基、丙基、丁基、2•甲基丙基；尤其，R4為2-呋喃基、3-呋喃基、嘧吩_2、基 '噻吩基、 1Η_吡唑_2_基、1Η_，比唑_3_基、1Η-咪唑基、ιη_味唑_2_ 基、1，3〜塞吨_2_基、1Η4唑-5_基、1-甲基^沁吡唑冬基、 1-乙基-1Η-吡唑-2-基、1-丙基-1Η-吡唑-2-基、卜甲基]η 咪唑-4-基、卜甲基-1Η-咪唑_2_基、丨_乙基、ιη_咪唑_4_基、 87731 -14- 200410970 1-乙基-1H_咪唑_2_基。尤其，R4為經由碳原子鍵結之具有一（丨）或二（2)個選自由 0、S及N-W組成之群組之雜原子之五_(5)員雜芳基，其中 R4係以R6取代。尤其，R4為5-甲基-2-呋喃基、2,5-二甲基-3-呋喃基、4,5-二甲基-2-呋喃基、4-甲基-2-呋喃基、5-羥基甲基-2-呋喃基、5-((二f基胺基）甲基）-2-呋喃基、5-乙基-2-呋喃基、5-溴-2-呋喃基' 4,5-二溴-2-呋喃基、5-氯呋喃基、5_三氟甲基-2-呋喃基、5-苯基-2-呋喃基、4-苯基_2_呋喃基、5-(2_ · 氣苯基）-2-呋喃基、5-(3-氯苯基）-2-呋喃基、5-(4-氯苯基）-2-吱喃基、5-(2,4-二氯苯基）-2-吱喃基、5_(2,5_二氯苯基）_2_ 呋喃基、5-(2,4,6-三氯苯基）-2-呋喃基、5-氰基嘧吩-2-基、塞吩-2_基、或5-氯p塞吩-2-基。尤其，R4為經由碳原子鍵結之具有一（丨）或二（2)個選自由〇、S及N-W組成之群組之雜原子之五_(5)員雜芳基，其中 R4係與苯或峨咬環稠合。尤其R為苯并呋喃_2_基、苯并呋喃基、苯并嘧吩_2_ 基、苯并噻吩-3-基、ΙΗ-啕哚_3_基、1H_啕哚-2-基、1，3-苯并嘧唑-2-基、呋喃并[2,3_b]吡啶_2•基、呋喃并[2,3_c]吡啶 -2-基、呋喃并[3,2_c]吡啶基、呋喃并[3,2_^吡啶基、咬喃并[2,3_b]P比啶_3-基、呋喃并[2,3-c]峨啶-3-基、呋喃并 [3,2-c]吡啶-3_基、呋喃并[3,2_b]吡啶基、卜甲基_1札吲哚_2_基、丨_乙基_1H-吲哚-2-基。尤其，R4為經由碳原子键結之具有一（1)或二（2)個選自由 87731 -15- 200410970 0、S及Ν-W組成之群組之雜原子之五_(5)員雜芳基，其中 R4係與苯或吡啶環稠合，且以一或多個R6取代。尤其R4為3-氣-1-苯并呋喃-2-基、2-苯基-1H-喇哚-3-基、 2_(4_氟苯基）-1Η-啕哚-3_基、5_氟-1H_吲哚_3_基、2-甲基-1H_ 吲哚_3_基、5-甲基-1H-吲哚-3_基、6·甲基-1H-吲哚-3_基、 7-甲基_1Η·蚓哚-3-基、3-甲基-1-苯并嘧吩_2-基、3_苯基_1H_ 吡唑-4-基、或1，3_二甲基_1H-吡唑-4-基。尤其’ R為1-甲基-1H-1，2,4 -三峻-5-基。尤其，R5為氫。尤其，R5為甲基或乙基。尤其，R5為羥基甲基、1-羥基乙基或2-羥基乙基。尤其，R6為OH、鹵基、Cm烷基、Cm烷氧基、氰基、硝基、OCF3、NRV、苯基或c〇NR7R8。尤其，R6為視情況以一或多個R9取代之Cw烷基。尤其，R6為甲基、乙基、羥基甲基、二甲胺基甲基、三敦甲基或爷基。尤其，R6為視情況以鹵基、Cl_7烷基或Ci-7烷氧基取代之苯基。尤其，R6為嗎啉、哌啶、哌畊或毗咯啉啶。本發明之實例包含（但不限）下列： (1) 消旋-N-(‘氯芊基）-2-(((2-(2-吹喃基經基乙基） (甲基）胺基）_甲基）-7-甲基-4-氧代二氫12塞吩并[2,3-b]吡淀-5 -叛酸胺， (2) (+)_N-(4-氯苄基）-2-((((R)_2-(2-呋喃基）_2_羥基乙基） 87731 -16- 200410970 (甲基）胺基）甲基）-7·甲基-4_氧代_4,7_二氯口塞吩并[2,3帅比淀-5 -幾酸胺， (3)消旋-Μ-氯节基）·2·(((2，基邻-甲基_2_味喃基）乙基)(甲基)胺基)-甲基”·甲基_4_氧代_4,7_二氫嘆吩并 [2,3-b]p比淀-5_叛酸胺， ⑷消旋-Ν·(4-氯爷基）_2·(((2_(3_峡喃基）_2_幾基乙基） (甲基）胺基）-甲基）-7-甲基-4·氧代·4,7_二氫”塞吩并[2,3_化比淀-5-幾酸胺’ (5) 消旋1(((2-(1-苯并呋喃_2•基“省基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-甲基-4-氧代—4,7-二氫嘧吩并 [2,3-bp比淀-5-叛酸胺， (6) 消旋-N-(4-氯苄基）-2-(((2-羥基-2w塞吩_2_基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7-二氫嘧吩并[2,3-b]吡啶 -5 -叛胺， (7) 消旋-Ν-(4·氯苄基）-2-(((2-羥基_2-(lH_吡咯_2_基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7_二氫嘧吩并[2,3-b] 吡啶-5-羧醯胺， (8) 消旋-N-(4-氯苄基）-2-(((2_幾基_2-(i -甲基^仏吡p各 -2-基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫峰吩并[2,3-b]吡啶-5-羧醯胺， (9) 消旋-N-(4-氯宇基）-2_(((2-禮基-2-(1-甲基-1H_咪唆 -4-基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫V»塞吩并[2,3-b]吡啶-5-羧醯胺， (10) 消旋_N-(4-氯爷基）-2-(((2-經基-2-(1 H-咪峻-4-基） 87731 •17- 200410970 乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并 [2,3-b]吡啶-5-羧醯胺， (11) 消旋- N-(4 -氯爷基）-2-(((2-超基-2_(1 Η_ 4卜朵-3-基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b] 叶匕淀-5-幾醯胺， (12) 消旋-N-(4_ 氯苄基）-2-(((2-(2,5-二甲基·3-呋喃基）-2-起基乙基）（甲基）胺基）-甲基）-7-甲基-4 -氧代-4,7 -二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (13) 消旋-2-(((2-(2-苯并嘧吩-2·基）-2-羥基乙基）（甲基）® 胺基）-甲基）-N-(4 -氯卞基）-7 -甲基-4 -氧代-4,7 -二氫p塞吩并 [2,3-b]吡啶-5-羧醯胺， (14) 消旋_N-(4 -氯卞基）-2-(((2-每基-2-(1-甲基-1 Η- 卜朵 -2-基）乙基）（甲基）胺基）-甲基）-7-甲基-4 -氧代-4,7-二氮π塞吩并[2,3-b]吡啶-5-羧醯胺， (1 5)消旋-N-(4-氯苄基）-2-(((2-(5-氰基嘧吩-2-基）-2•羥基乙基）（甲基）胺基）-甲基）-7 -甲基-4-氧代-4,7_二氫π塞吩并 g [2,3-b]吡啶-5-羧醯胺， (16) 消旋-N-(4-氯苄基）-2-(((2•羥基-2-(1，3_嘧唑-2-基）乙基）（甲基）胺基甲基）-7-甲基-4 -氧代-4,7 -二氫π塞吩并 [2,3-b]吡啶-5-羧醯胺， (17) 消旋-2-(((2-(1,3-苯并嘧唑-2-基）-2-羥基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-甲基-4-氧代-4,7-二氫嘧吩并 [2,3-b]p比淀-5-叛酸胺’ (18) 消旋-N-(4-氯苄基）-2-(((2-羥基 _2-(111_吡唑-5-基） 87731 -18- 200410970 乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并 [2,3-b]吡啶-5-羧醯胺， (19) N-(4-氯苄基）-2-((((2R)_2-#i 基 _2·(1Η_吨吐基）乙基）（甲基）胺基）·甲基）-7-甲基-4-氧代·4,7·二氫嘧吩并[2,3-b] 外匕淀-5 -複酸胺’ (20) N-(4-氯芊基）·7_ 乙基 _2-((((2R)-2-(2_吱喃基）_2_經基乙基）（甲基）胺基）-甲基）-4-氧代_4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (21) N-(4-氣罕基）-2-((((2R)_2-(2-呋喃基）-2-羥基乙籲基）（甲基）胺基）-甲基）-7-(2-甲氧基乙基）_4_氧代_4,7_二氫 p塞吩并[2，3 - b ] p比淀-5 -叛酿胺， (22) 消旋-2-(((2-(1-苯并吱喃_2_基）_2_羥基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）_7_乙基-4-氧代_4,7_二氫違吩并 [2,3-b]吡啶-5-羧醯胺， (23) 消旋-2-(((2-(1-苯并呋喃_2_基）-2-羥基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-丙基-4-氧代-4,7-二氫嘧吩并 _ [2,3-b]吡啶-5-羧醯胺， (24) 消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲基）胺基）-甲基）-N-(4-氯芊基）-7-(2-甲氧基乙基）-4-氧代-4,7-二氣p塞吩并[2,3-b]p比淀-5-叛酿胺， (25) 消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-(2,3-二羥基丙基）-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (26) Ν_(4·氯苄基）-7-(2,3-二羥基丙基）-2-((((2R)-2-(2-呋 87731 -19- 200410970 喃基）-2-羥基乙基）（甲基）胺基）-甲基）-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (27) N-(4-氯芊基）-2-((()2R)-2_(呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-7-(3-蠢基丙基）-4 -氣代-4,7 -二氫p塞吩并 [2,3-b]吡啶-5-羧醯胺， (28) 消旋-2-(( (2 _(1_苯并吱喃-2 -基）-2-經基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）·7-(3-羥基丙基）-4-氧代·4,7-二氮魂吩并[2,3-b]p比淀-5-叛醯胺， (29) 消旋- 2-(((2-(1-苯并吱喃_2·基）-2·經基乙基）（甲基）胺基）-甲基）-N-(4 -氯爷基）-7-(2-經基乙基）-4-氧代-4 7--氣 p塞吩并[2，3 - b ] p比淀-5 -獲酸胺， (30) 消旋-N-(4-氣宇基）-2-(((2-(4,5·二甲基 _2 p夫南基）-2-羥基乙基）（甲基）胺基）-甲基）-7_甲基氧代_4 ，, ·ι 氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (31)消旋-N-(4_氯芊基）-2_(((2-(5_苯基-2_,夫喃基）_2與基乙基）（甲基）胺基）_甲基）-7-甲基-4_氧代_4,7_二f ，工，一氧嗤吩并 [2,3-b>比啶-5-叛醯胺，基X-羥基乙 _4,7-二氫噻吩 (32) N-(4_ 氯苄基）-2-((((2R)-2-(2-呋喃基）（甲基）胺基）-甲基）-4_氧代-7·丙基-4·氧代并[2,3-b]吡啶-5-羧醯胺， (33) Ν-(4·氣卞基）-2-(((2-(5-氯-2-呋喃基）_2_幾基乙基）（甲基）胺基）-甲基）-7-曱基-4-氧代-4,7·二氣遠吩并^乙匕吡啶_5_羧醯胺， ’ (34) N_(4_ 氯爷基）_2_((((2Κ)·2_(2_ 呋喃基龜基乙 87731 -20 - 200410970 基）（甲基）胺朴甲基）-7-(2幾基乙基）·4_氧代7二… 吩并[2,3-b]吡啶_5·羧醯胺，，-—虱嘍 (35) N♦氯¥基）_2_(((叫2仆咬喃基）_ 基X甲基）胺基）-甲基）-7仰韻乙氧基）乙基 _4,7-二氫嘧吩并[2,3沁]吡啶_5-羧醯胺， (36)消旋-N_(4_,氯字基）：(((2_幾基_2仙-味吐乙基）（甲基）胺基）甲基）_7_甲基_4_氧代_4,7_二氫口塞吩土并 [2,3-b]吡哫-5-羧醯胺，及其醫藥可接受性鹽。圖A-Ο敘述本發明式⑴化合物之製備。:有起始物質均可由此等圖中所述之程序，以熟習有機化學者習知之程序製備，或謂得。时本發明最終化合物均可由此等圖所述之程序或以熟習有機化學者習知之類似程序製備。式（I)化合物可如圖A中所述般製備。式A.k化合物（其中 X為離去基（例如甲燒韻鹽、氣化物或溴化物）)均在非親核性驗(例如二異丙基乙胺)存在了，於極性溶劑(例如DMF) 中以式R R C(〇H)CH2NH(R3)i二級胺處理，獲得式a 2 之產物A白本技蟄者應了解，在某些情況下r4r5c(⑽)现 ()中存在之&基及其他路易斯驗性或酸性官能度可能而要過度性保護’以協助圖A中已經完全建立之程序 (Greene，T. W.，Wuts，p. G. M•有機合成中之保護基 (Protective Groups in 〇rganic Synihesis)，1999)所述之偶合。 87731 -21- 200410970IA. In particular, compositions comprising more than 51% of a compound of formula IA. In particular, compositions comprising more than 75% of a compound of formula IA are included. 87731 -13- 200410970 In particular, a composition comprising more than 90% of a compound of formula IA. In particular, compositions comprising more than 98% of a compound of Formula IA. In particular, R1 is a gas, in particular, 2 is a Cw alkyl group, in particular, R2 is a methyl group, an ethyl group, or an n-propyl group, in particular, R2 is a methyl group, and in particular, R2 is a C1- group substituted with one or two hydroxyl groups. 3 alkyl, in particular, R2 is 2-hydroxyethyl, 3-hydroxypropyl, or 2,3-diacrylpropyl, in particular, R2 is Cl-4 alkyl substituted with Cw alkoxy, in particular, R2 Is a methoxy-substituted C! _4 alkyl group, in particular, R2 is 2-methoxyethyl, in particular, R2 is CH2CH2OCH2CH2OH, especially R3 is methyl, especially R3 is ethyl, and especially R is via Five- (5) -membered heteroaryl groups having one (1) or two (2) heteroatoms selected from the group consisting of 0, S, and NW bonded to a carbon atom. In particular, W is absent; in particular, W is fluorene; in particular, W is methyl, ethyl, propyl, butyl, 2 • methylpropyl; in particular, R4 is 2-furanyl, 3-furanyl, pyrimidine_2, and radical 'thienyl , 1Η_pyrazol_2_yl, 1Η_, biazole_3_yl, 1Η-imidazolyl, ιη_ 味 azole_2_yl, 1,3 ~ xetazol_2_yl, 1Η4azole-5-yl, 1-methyl ^ pyrimidol, 1-ethyl-1Η-pyrazol-2-yl, 1-propyl-1Η-pyrazol-2-yl, methyl ] η imidazol-4-yl, p-methyl-1H-imidazol-2-yl, ethyl, ethyl, imidazol-4-yl, 87731-14-200410970 1-ethyl-1H_imidazol-2-yl. In particular, R4 is a five- (5) -membered heteroaryl group having one (丨) or two (2) heteroatoms selected from the group consisting of 0, S, and NW bonded via a carbon atom, wherein R4 is based on R6 is substituted. In particular, R4 is 5-methyl-2-furyl, 2,5-dimethyl-3-furyl, 4,5-dimethyl-2-furyl, 4-methyl-2-furyl, 5-hydroxymethyl-2-furanyl, 5-((dif-aminoamino) methyl) -2-furanyl, 5-ethyl-2-furanyl, 5-bromo-2-furanyl '4 , 5-dibromo-2-furyl, 5-chlorofuryl, 5-trifluoromethyl-2-furyl, 5-phenyl-2-furyl, 4-phenyl-2-furyl, 5 -(2-Phenylphenyl) -2-furanyl, 5- (3-chlorophenyl) -2-furanyl, 5- (4-chlorophenyl) -2-caranyl, 5- (2, 4-dichlorophenyl) -2-creanyl, 5_ (2,5_dichlorophenyl) _2_furanyl, 5- (2,4,6-trichlorophenyl) -2-furanyl, 5 -Cyanopyrimin-2-yl, thiophen-2-yl, or 5-chlorop-thiophen-2-yl. In particular, R4 is a five- (5) -membered heteroaryl group having one (丨) or two (2) heteroatoms selected from the group consisting of 0, S, and NW bonded through a carbon atom, wherein R4 is related to Benzene or epineurene is fused. In particular, R is benzofuran-2-yl, benzofuranyl, benzopyrimyl-2-yl, benzothiophen-3-yl, 1Η-pyridin-3-yl, 1H_pyridin-2-yl, 1,3-benzopyrazol-2-yl, furano [2,3_b] pyridin-2-yl, furano [2,3_c] pyridin-2-yl, furano [3,2_c] pyridyl, furan Benzo [3,2_ ^ pyridyl, benzo [2,3_b] P than pyridin-3-yl, furo [2,3-c] eridin-3-yl, furo [3,2-c] Pyridine-3_yl, furo [3,2_b] pyridyl, p-methyl_1zaindole_2_yl, _ethyl_1H-indole-2-yl. In particular, R4 is a five-membered hetero atom having one (1) or two (2) heteroatoms selected from the group consisting of 87731 -15-200410970 0, S, and N-W bonded via a carbon atom. Aryl, where R4 is fused to a benzene or pyridine ring and is substituted with one or more R6. In particular, R4 is 3-gas-1-benzofuran-2-yl, 2-phenyl-1H-raldol-3-yl, 2- (4-fluorophenyl) -1fluorenyl-3, 3-yl, 5 _Fluoro-1H_indole_3_yl, 2-methyl-1H_indole_3_yl, 5-methyl-1H-indole-3_yl, 6.methyl-1H-indole-3 _Yl, 7-methyl_1pyridinol-3-yl, 3-methyl-1-benzopyrimin_2-yl, 3-phenyl_1H_pyrazol-4-yl, or 1,3 _Dimethyl_1H-pyrazol-4-yl. In particular, 'R is 1-methyl-1H-1,2,4-trisam-5-yl. In particular, R5 is hydrogen. In particular, R5 is methyl or ethyl. In particular, R5 is hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl. In particular, R6 is OH, halo, Cm alkyl, Cm alkoxy, cyano, nitro, OCF3, NRV, phenyl, or coNR7R8. In particular, R6 is a Cw alkyl group optionally substituted with one or more R9. In particular, R6 is methyl, ethyl, hydroxymethyl, dimethylaminomethyl, trimethyl or trimethyl. In particular, R6 is a phenyl group optionally substituted with a halogen group, a Cl_7 alkyl group or a Ci-7 alkoxy group. In particular, R6 is morpholine, piperidine, piperin, or pyrrolidin. Examples of the present invention include (but are not limited to) the following: (1) Racemic-N-('chloroamidino) -2-((((2- (2-pyranylethyl)) (methyl) amine (Methyl) -7-methyl) -7-methyl-4-oxodihydro 12 seleno [2,3-b] pyridine-5 -metaamine, (2) (+) _ N- (4-chloro Benzyl) -2-(((((R) _2- (2-furanyl) _2_hydroxyethyl) 87731 -16- 200410970 (methyl) amino) methyl) -7 · methyl-4_oxy __4,7_Dichloroorthopheno [2,3Saipido-5-citric acid amine, (3) meso-M-chlorobenzyl) · 2 (((2, Group_2_weiranyl) ethyl) (methyl) amino) -methyl "· methyl_4_oxo_4,7_dihydropheno [2,3-b] p ratio -5_ ammonium amine, ⑷-N · (4-chloroethenyl) _2 · ((((2_ (3_xanyl) _2_Ethylethyl) (methyl) amino) -methyl ) -7-Methyl-4 · oxo · 4,7_dihydro "cepheno [2,3_Chemical ratio-5-chimonic acid amine '(5) Racemic 1 (((2- (1 -Benzofuran-2-yl "provinylethyl) (methyl) amino) -methyl) -N- (4-chlorobenzyl) -7-methyl-4-oxo-4,7- Dihydropyrido [2,3-bp biyodo-5-metanoic acid amine, (6) racemic-N- (4-chlorobenzyl) -2-(((2-hydroxy-2w thiophene_2 _Ylethyl) (methyl) ) -Methyl) -7-methyl-4-oxo_4,7-dihydropyrido [2,3-b] pyridine-5 -resamine, (7) racemic-N- (4 · Chlorobenzyl) -2-(((2-hydroxy_2- (lH_pyrrole_2_yl) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo _4,7_dihydropyridino [2,3-b] pyridine-5-carboxamide, (8) racemic-N- (4-chlorobenzyl) -2-(((2_ _2- (i -methyl ^ pyridine p-2-yl) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydro peak Benzo [2,3-b] pyridine-5-carboxamidine, (9) Racemic-N- (4-chlorocarbyl) -2 _ (((2-Limethyl-2- (1-methyl- 1H_imidino-4-yl) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydro V »cepheno [2,3- b] pyridine-5-carboxamidine, (10) racemic_N- (4-chloroethenyl) -2-(((2-meryl-2- (1H-imid-4-yl) 87731 • 17- 200410970 ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxy Hydrazine, (11) meso-N- (4-chloroethenyl) -2-(((2-superyl-2_ (1 Η_4budol-3-yl) ethyl) (methyl) amino ) -Methyl) -7-methyl-4-oxo-4,7-dihydropyridino [2,3-b] Amine, (12) racemic-N- (4-chlorobenzyl) -2-((((2- (2,5-dimethyl · 3-furyl) -2-methylidylethyl) (methyl) (Amino) -methyl) -7-methyl-4 -oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxamide, (13) racemic-2- (((2- (2-benzopyrimin-2 · yl) -2-hydroxyethyl) (methyl) ® amino) -methyl) -N- (4-chlorofluorenyl) -7-form -4-oxo-4,7-dihydrop-sedeno [2,3-b] pyridine-5-carboxamidine, (14) racemic_N- (4-chlorofluorenyl) -2- (((2-peryl-2- (1-methyl-1 Η-budol-2-yl) ethyl) (methyl) amino) -methyl) -7-methyl-4 -oxo -4,7-diazepine [2,3-b] pyridine-5-carboxamidine, (1 5) racemic-N- (4-chlorobenzyl) -2-(((2- (5-cyanopyrimidin-2-yl) -2 • hydroxyethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7_dihydroπthiophene And g [2,3-b] pyridine-5-carboxamide, (16) racemic-N- (4-chlorobenzyl) -2-((((2 • hydroxy-2- (1,3-pyrimidine Azol-2-yl) ethyl) (methyl) aminomethyl) -7-methyl-4 -oxo-4,7 -dihydroπ-pheneno [2,3-b] pyridine-5- Carboxamide, (17) racemic-2-(((2- (1,3-benzopyrazol-2-yl) -2-hydroxyethyl (Methyl) amino) -methyl) -N- (4-chlorobenzyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] p ratio Yodo-5-amidoamine '(18) meso-N- (4-chlorobenzyl) -2-(((2-hydroxy_2- (111_pyrazol-5-yl) 87731 -18- 200410970 (Ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxamide, ( 19) N- (4-chlorobenzyl) -2-(((((2R) _2- # i group_2 · (1Η_tonyl) ethyl) (methyl) amino) · methyl)- 7-Methyl-4-oxo · 4,7 · Dihydropyrido [2,3-b] Outer hydrazine-5-double acid amine '(20) N- (4-chlorofluorenyl) · 7_ Ethyl_2-(((((2R) -2- (2_creanyl) _2_Ethylethyl) (methyl) amino) -methyl) -4-oxo_4,7-di Hydropyrimido [2,3-b] pyridine-5-carboxamidamine, (21) N- (4-Gaunyl) -2-(((((2R) _2- (2-furyl) -2 -Hydroxyethoxy) (methyl) amino) -methyl) -7- (2-methoxyethyl) _4_oxo_4,7_dihydrop-pheno [2,3-b ] p-Yodo-5-a benzamine, (22) racemic-2-((((2- (1-benzocrean_2_yl) _2_hydroxyethyl) (methyl) amino)- Methyl) -N- (4-chlorobenzyl) _7_ethyl-4-oxo_4,7_ Hydrogenated benzo [2,3-b] pyridine-5-carboxamide, (23) racemic-2-(((2- (1-benzofuran_2_yl) -2-hydroxyethyl) (Methyl) amino) -methyl) -N- (4-chlorobenzyl) -7-propyl-4-oxo-4,7-dihydropyridino_ [2,3-b] pyridine -5-carboxamide, (24) racemic-2-((((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) -methyl)- N- (4-chlorofluorenyl) -7- (2-methoxyethyl) -4-oxo-4,7-digas p-penepheno [2,3-b] p ratio lake-5- Betamine, (25) racemic-2-(((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) -methyl) -N- ( 4-chlorobenzyl) -7- (2,3-dihydroxypropyl) -4-oxo-4,7-dihydropyrimido [2,3-b] pyridine-5-carboxamide, ( 26) Ν_ (4.chlorobenzyl) -7- (2,3-dihydroxypropyl) -2-(((((2R) -2- (2-furan 87731 -19- 200410970 uranyl) -2- Hydroxyethyl) (methyl) amino) -methyl) -4-oxo-4,7-dihydropyrimido [2,3-b] pyridine-5-carboxamidine, (27) N- (4-chlorofluorenyl) -2-((() 2R) -2- (furanyl) -2-hydroxyethyl) (methyl) amino) -methyl) -7- (3-pyridylpropyl ) -4 -Gas-4,7-dihydrop-pheneno [2,3-b] pyridine-5-carboxamide , (28) racemic-2-((((2_ (1-benzobenzo-2-yl) -2-merylethyl) (methyl) amino) -methyl) -N- (4 -Chlorobenzyl) · 7- (3-hydroxypropyl) -4-oxo · 4,7-diazinopheno [2,3-b] p biyodo-5-benzidine, (29) Racemic-2-(((2- (1-Benzoran_2 · yl) -2 · Ethylethyl) (methyl) amino) -methyl) -N- (4-chloromethyl ) -7- (2-Ethylethyl) -4-oxo-4 7--Ga p-pheneno [2,3-b] p ratio-5-to obtain acid amines, (30) racemic- N- (4-Azoyl) -2-((((2- (4,5 · dimethyl_2 pfnanyl) -2-hydroxyethyl) (methyl) amino) -methyl)- 7_Methyloxo_4,, 1m Hydropyrimido [2,3-b] pyridine-5-carboxamidine, (31) racemic-N- (4_chlorofluorenyl) -2 _ (( (2- (5-Phenyl-2_, furanyl) _2 and phenylethyl) (methyl) amino) _methyl) -7-methyl-4_oxo_4,7_dif, Dioxobenzo [2,3-b > pyridine-5-benzylamine, the group X-hydroxyethyl-4,7-dihydrothiophene (32) N- (4-chlorobenzyl) -2- (((((2R) -2- (2-furanyl) (methyl) amino) -methyl) -4_oxo-7 · propyl-4 · oxo [2,3-b] pyridine -5-carboxamidine, (33) Ν- (4 · airino) -2-(((2- (5 -Chloro-2-furanyl) _2_Ethylethyl) (methyl) amino) -methyl) -7-fluorenyl-4-oxo-4,7. _5_ Carboxamide, '(34) N_ (4_Chloroyl) _2 _ (((((2Κ) · 2_ (2_furylpyridylethyl 87731 -20-200410970 group) (methyl) amine methyl))-7 -(2-Chloroethyl) · 4_oxo 7 di ... Benzo [2,3-b] pyridine_5 · Carboxamidine, ——- (喽) (35) N ♦ Chloroyl) _2 _ (( (Called 2 sulfanyl) _ group X methyl) amino) -methyl) -7 Yang Yun ethoxy) ethyl_4,7-dihydropyrido [2,3qin] pyridine_5 -Carboxamide, (36) racemic-N_ (4_, chloro group): ((((2_Jiji_2sen-weitoethyl) (methyl) amino) methyl) _7_methyl _4_oxo_4,7_dihydroorthophene [2,3-b] pyridine-5-carboxamide, and its pharmaceutically acceptable salts. Figures A-O illustrate the preparation of compounds of formula VII of the invention. : The starting materials can be prepared by the procedures described in these figures and by the procedures familiar to those who are familiar with organic chemistry. In this case, the final compound of the present invention can be prepared according to the procedures described in the drawings or similar procedures known to those skilled in organic chemistry. Compounds of formula (I) can be prepared as described in Figure A. Compounds of formula Ak (where X is a leaving group (such as methyl salt, gaseous or bromide)) are present in non-nucleophilic tests (such as diisopropylethylamine), and in polar solvents (such as DMF) Treatment with a secondary amine of formula RRC (〇H) CH2NH (R3) i to obtain product A of formula a 2 The skilled person should understand that in some cases r4r5c (⑽) now exists in () & Radicals and other Lewis functionalities or acidic functionalities may need to be overprotected 'to assist with the procedures already established in Figure A (Greene, TW, Wuts, p. G. M • Protective Groups in Organic Synthesis) Rganic Synihesis), 1999). 87731 -21- 200410970

或者’如圖B中所述般製備式⑴化合物係。式a. 1之化合物（其中X為離去基（例如甲烷磺酸鹽、氯化物或溴化物））係在非親核性鹼（例如二異丙基乙胺）存在下，於極性溶劑（例如DMF)中，以式R4r5c(〇h)CH2Nh2之一級胺處理，獲得式 Β·1之產物。所得二級胺再藉由熟習本技藝者一般已知之反應，如（1)使Β.1與相對應之烷基_化物、二烷基磺酸酯或烷基芳基-磺酸酯反應，或（2)式Β·1與醛（例如甲醛或乙醛）在還原劑（例如氰基硼氫化鈉或三乙氧基硼氫化鈉）存在下反應燒化’獲得一般式Α.2之化合物。Alternatively, a compound system of formula (I) is prepared as described in Figure B. The compound of formula a. 1 (where X is a leaving group (such as methanesulfonate, chloride or bromide)) is in the presence of a non-nucleophilic base (such as diisopropylethylamine) in a polar solvent ( For example, DMF), treatment with a primary amine of the formula R4r5c (Oh) CH2Nh2 to obtain the product of the formula B · 1. The obtained secondary amine is then reacted by those skilled in the art, such as (1) reacting B.1 with the corresponding alkylate, dialkylsulfonate or alkylaryl-sulfonate, Or (2) formula B · 1 reacts with an aldehyde (such as formaldehyde or acetaldehyde) in the presence of a reducing agent (such as sodium cyanoborohydride or sodium triethoxyborohydride) to obtain a compound of general formula A.2. .

或者，如圖C中所述般製備式（I)化合物。式Α·1之化合物 (其中X為離去基（例如甲烷磺酸鹽、氯化物或溴化物係在非親核性驗（例如二異丙基乙胺）存在下，於極性溶劑（例如 DMF)中，以烷基一級胺（例如甲基胺或乙胺）處理，獲得式 C.1之產物。所得二級胺再於非親核性鹼（例如二異丙基乙胺） 87731 -22- 200410970 存在下，於極性溶劑（例如DMF)中，以式R4R5C(OH)CH2X(其中X為Cl、Br)之親核基處理，或以還氧化物處理，獲得式 A_2之產物。或者，式c.l之化合物依據圖d，以式 R C(0)CH2X(其中X為Cl、Br)之2-鹵基酮燒化，獲得式d」之產物。所得胺基嗣再與適用之非對掌性或對掌性改質之還原劑（例如NaBH4或二異皮諾肯苯基氯硼烷（diis〇_ pinocamphenylchloroborane))還原，獲得式 a.2之化合物。Alternatively, a compound of formula (I) is prepared as described in Figure C. Compounds of formula A · 1 (where X is a leaving group (such as methanesulfonate, chloride or bromide) in the presence of a non-nucleophilic test (such as diisopropylethylamine) in a polar solvent (such as DMF ), Treatment with an alkyl primary amine (such as methylamine or ethylamine) to obtain the product of formula C.1. The obtained secondary amine is then treated with a non-nucleophilic base (such as diisopropylethylamine) 87731 -22 -In the presence of 200410970, in a polar solvent (such as DMF), treated with a nucleophilic group of the formula R4R5C (OH) CH2X (where X is Cl, Br), or treated with an oxide to obtain a product of the formula A_2. Or, The compound of formula cl is calcined with 2-halo ketone of formula RC (0) CH2X (where X is Cl, Br) according to figure d to obtain the product of formula d ". Or reduction of palm-modified reducing agents (such as NaBH4 or diisopinokine phenylchloroborane) to obtain a compound of formula a.2.

圖C A.1Figure C A.1

R1 R2 C.1 A.2 w驅物Α·1係自相對應之醇（γ=〇Η)，藉由在有機鹼（例如、或2,4,6_可力淀）及若需要之活化劑（例如DMAp)，圖ε，下以甲心、醯氣處理製備。或者，式A. 1之化合物係二由在適“谷劑（例如氣仿、：氯甲燒、^ >二氯乙燒或苯）中以氯甲酸乙酯處理三級胺基衍生物（例如Y==N(CH )成仁嗎啉基）製備。 87731 -23- 200410970R1, R2, C.1, A.2, and A.1 are the corresponding alcohols (γ = 〇Η). An activator (such as DMAp), Figure ε, is prepared by treatment with nail core and thoron. Alternatively, the compound of formula A. 1 is obtained by treating a tertiary amine derivative with ethyl chloroformate in a suitable cereal (for example, aerosol, chloroform, dichloroethane, or benzene) ( For example, Y == N (CH) into renmorpholinyl) 87731 -23- 200410970

圖EFigure E

E.1 A.1 Y = OH, NR2 X = OMs, Cl 接著，依據美國專利第6,239，142號中所述或下圖F、〇及 Η中列舉之程序製備一般式Ε· 1之化合物。如圖F中所述，係在四氫呋喃及低溫中，以二異丙基酿胺鋰使3-溴-2-氯噻吩（F.1)金屬化，接著添加仲甲酸獲得醇 F.2。游離羥基使用慣用之方法（Greene，T. W.; Wut% Ρ« 〇 μ Protective Groups in Organic Synthesis, 1999)保護，如笋由以相對應之石夕坑基氯化物及弱驗（例如咪唆）在極性溶劑（例如DMF)中處理之第三丁基二甲基矽烷基醚（TBS)。F3以正丁基鋰金屬化，接著添加N-甲氧基甲基乙醯胺，獲得甲基酮F·4。在強驗（例如氫化鋼）存在下，使ρ·4與碳酸二曱酉旨縮合’獲得酮酯F.5。化合物F.5再於乙酸酐及三乙基原甲酸酯之混合物中回流，獲得中間物烯醇醚，其再以一級胺或苯胺（例如R2NH2)縮合，獲得式F.6之化合物。所得烯胺再藉由於鹼（例如氫化鈉、碳酸鉀或第三丁氧化鉀）存在下，於適當溶劑（例如THF'DMF或第三丁醇）中加熱環化，獲得F7。式F.7之酯藉由（a)已經取代之苄基胺（例如4_氯苄基胺、氟卞基胺或4-溴苄基胺），在高溫下處理，或以無機鹼如氫氧化鈉扈化，獲得相對應之羧酸，其再與以M，_羰基二咪唑（或其他適用之羧酸活化劑）調節之經取代苄基胺偶 87731 -24- 200410970 合’轉化成一般式F.8之醯胺，幾基保護基後續去保護獲得 E · 1係經由一般私序元成，如右為秒坑基酸保護，則以四丁基銨氟化物處理。E.1 A.1 Y = OH, NR2 X = OMs, Cl Next, the compound of general formula E · 1 was prepared according to the procedures described in US Patent No. 6,239,142 or listed in Figures F, 0, and IX below. As shown in Figure F, 3-bromo-2-chlorothiophene (F.1) was metalized with lithium diisopropylamine in tetrahydrofuran and low temperature, and then secondary formic acid was added to obtain alcohol F.2. Free hydroxyl groups are protected using conventional methods (Greene, TW; Wut% Ρ «〇 Protective Groups in Organic Synthesis, 1999). Tertiary butyldimethylsilyl ether (TBS) treated in a solvent such as DMF. F3 was metallized with n-butyllithium, followed by addition of N-methoxymethylacetamide, to obtain methyl ketone F · 4. In the presence of a strong test (such as hydrogenated steel), ρ · 4 is condensed with dioxin carbonate 'to obtain ketoester F.5. Compound F.5 is then refluxed in a mixture of acetic anhydride and triethyl orthoformate to obtain an intermediate enol ether, which is then condensed with a primary amine or aniline (e.g., R2NH2) to obtain a compound of formula F.6. The resulting enamine is further cyclized by heating in a suitable solvent (such as THF'DMF or third butanol) due to the presence of a base (such as sodium hydride, potassium carbonate or potassium third butoxide) to obtain F7. The ester of formula F.7 is treated with (a) a substituted benzylamine (such as 4-chlorobenzylamine, fluorofluorenylamine, or 4-bromobenzylamine) at elevated temperature, or with an inorganic base such as hydrogen Sodium oxide is tritiated to obtain the corresponding carboxylic acid, which is then converted into a general benzylamine couple 87731 -24- 200410970 which is adjusted with M, _carbonyldiimidazole (or other suitable carboxylic acid activator). The amidine of formula F.8, followed by deprotection of several protecting groups to obtain E · 1, is formed by a general private sequence. If the right is protected by a second acid, it is treated with tetrabutylammonium fluoride.

圖FFigure F

式化合物（Y=NR2)可如圖G中所述般製備。在四氫呋喃中及低溫下，以二異丙基醯胺鋰使3_溴·2_ 屬化，且與Ν,Ν·二甲基甲酿胺縮合，獲得二。(G:以胺(例如嗎啉)、乙酸及適當還原劑(例如三乙醯氧基硼氫化納）處理還原性胺化，獲得式G.2之嘍吩。G2以正丁基链金屬化’接著添加N-甲氧基-N•甲基乙酿胺，獲得甲基嗣G.3。使G.3與碳酸二甲酯在強鹼（例如氫化鈉）存在下縮合，獲得 87731 -25- 200410970 酮=.4。所得_再於回流之二甲苯中，以爷基胺（例如 4乳下基胺、4·氟竿基胺或4·漠节基胺）處理，獲得式G.5之酮酿胺。式G.5再於乙酸肝及三乙基原甲酸酯之混合物中回 :’獲：中間物烯醇’其再與'級胺或苯胺(例如R、)縮口獲彳于式G，6<化合物。所得烯胺再藉由於鹼（例如氫化納&酸卸或第二丁氧化神）存在下，於適當溶劑（例如 THF、DMF或第三丁醇）中加熱環化。Compounds of formula (Y = NR2) can be prepared as described in Figure G. In tetrahydrofuran and at a low temperature, the 3-bromo · 2_ is chemically substituted with lithium diisopropylammonium amine, and condensed with N, N · dimethylformamide to obtain di. (G: Reductive amination is treated with an amine (such as morpholine), acetic acid, and an appropriate reducing agent (such as sodium triethoxylate borohydride) to obtain a phenanthrene of formula G.2. G2 is metalized with an n-butyl chain. Add N-methoxy-N • methyl ethyl amine to obtain methyl hydrazone G.3. G.3 is condensed with dimethyl carbonate in the presence of a strong base (such as sodium hydride) to obtain 87731 -25- 200410970 Ketone = .4. The obtained _ is then treated with unylamine (such as 4 lactylamine, 4.fluroylamine or 4.mobenzylamine) in refluxing xylene to obtain a ketone of formula G.5 Stuffed amine. Formula G.5 is then returned in a mixture of liver acetate and triethyl orthoformate: 'obtained: intermediate enol' which is then obtained with a 'grade amine or aniline (such as R,). A compound of formula G. 6 <. The resulting enamine is cyclized by heating in a suitable solvent (such as THF, DMF, or tertiary butanol) in the presence of a base (such as sodium hydride & acid or second butoxylate). .

圖GFigure G

或者，如圖Η中所述般製備式Ε·1(γ：=〇Η)之化合物。‘羥基嚙吩并p，3-b]吡啶-5-羧酸乙酯（j· Heter〇cydie Chem· 7’ 14，807)以二至六當量之二異丙基醯胺鋰在低溫下金屬化，接著與二甲基甲醯胺反應，獲得化合物Η·2。於極性 (例如乙醇）中，以適當還原劑（例如^沾仏)處理Η·2，獲侍醇Η·3。所得酯再於高溫下或在熟習本技藝者習知之其他一般醯胺形成條件下，與經取代之-基胺（例如，4_氯苄基 87731 -26- 200410970 胺、4-氟苄基胺或4-溴苄基胺）反應，獲得式Η·4之化合物。化合物Η.4藉由以選用之經取代烷基鹵化物或烷基續酸酯，在鹼（例如碳酸鉀）存在下處理，或在Mitsunobu條件下，藉由與選用之經取代烷醇反應，於環氮處烷化，獲得一般式Ε· 1之化合物。本反應中所用該烷基_化物之特定實例包含（但不限）硤甲烷、破乙烷、1-碘丙烷、1-碘丁烷及丨_溴_2_ 甲氧基乙烷。熟習本技藝者應了解，某些情況下，上述步驟中所用之R2X(X=鹵基或績酸醋）或r2〇h試劑中存在之經基官能度之過度性保護可能必要，以協助圖Η中或圖A-E中 _ 所述後續化學中所述之偶合。本反應中所用該經保護經基烷基自化物之特定實例包含（但不限）2-(2-溴乙氧基）四氫 -2H-吡喃、2_(2_碘乙氧基）四氫-2H_吡喃、2-(3-溴丙氧基）四氫-2H-卩比喃、2-(3·琪丙氧基）四氫_2H-峨喃、4-(溴曱基）-2,2-二甲基-1，3-二噚茂烷、2_(2-(2-氯乙氧基）乙氧基）四氫- 2H-外1;喃、及2-(鼠甲氧基）乙基苯甲酸酯。在最終或中間階段處使此等情況去保護之程序已經充分建立（Greene，τ. _ W·; Wuts，P. G. Μ·有機合成中之保護基（Pr〇tective Gr〇ups in Organic Synthesis)，1999)。圖ΗAlternatively, a compound of formula E · 1 (γ: = 0%) is prepared as described in FIG. 'Hydroxypheno p, 3-b] pyridine-5-carboxylic acid ethyl ester (j. Heterocydie Chem. 7' 14,807) with two to six equivalents of lithium diisopropylamidamine at low temperature metal And then reacted with dimethylformamide to obtain compound Η · 2. In a polar (such as ethanol), Η · 2 is treated with an appropriate reducing agent (such as 仏) to obtain Η · 3. The resulting ester is then reacted with a substituted-based amine (e.g., 4-chlorobenzyl 87731 -26- 200410970 amine, 4-fluorobenzylamine at high temperature or under other general amidine formation conditions known to those skilled in the art). Or 4-bromobenzylamine) to obtain a compound of formula Η · 4. Compound Η.4 is treated by the selected substituted alkyl halide or alkyl ester in the presence of a base (such as potassium carbonate), or under Mitsunobu conditions, by reacting with the selected substituted alkanol, Alkylation at a ring nitrogen yields a compound of general formula E · 1. Specific examples of the alkylates used in this reaction include, but are not limited to, rhenium methane, ethane ethane, 1-iodopropane, 1-iodobutane, and __bromo_2_methoxyethane. Those skilled in the art should understand that in some cases, the excessive protection of the radical functionality present in the R2X (X = halo or acetic acid) or r2oh reagent used in the above steps may be necessary to assist the figure Couplings described in the following chemistry, or in Figure AE. Specific examples of the protected alkylalkylated compounds used in this reaction include, but are not limited to, 2- (2-bromoethoxy) tetrahydro-2H-pyran, 2_ (2_iodoethoxy) tetra Hydrogen-2H_pyran, 2- (3-bromopropoxy) tetrahydro-2H-fluoranpyran, 2- (3-Qipropoxy) tetrahydro_2H-eran, 4- (bromofluorenyl) ) -2,2-Dimethyl-1,3-dioxocene, 2- (2- (2-chloroethoxy) ethoxy) tetrahydro-2H-exo-1; ran, and 2- (rat (Methoxy) ethyl benzoate. The procedures for deprotection of these situations at the final or intermediate stage have been fully established (Greene, τ._W ·; Wuts, PG M. Protective Groups in Organic Synthesis), 1999 ). Figure Η

87731 -27- 20041097087731 -27- 200410970

H.4 圖A中之胺R4R5C(OH)CH2NH(R3)可購得，可藉由熟習本技藝者已知之程序製備，或可由圖1-0中說明之方法製備。如圖I中所示，市售甲基酮1.1可經鹵化（X=C1、Br)獲得式1.2 之鹵基酮。所得自基酮可經還原，獲得用於非對掌性（例如 NaBH4/CeCl3)使用或對掌性還原條件（例如Hamada，T·; Torii， Τ·; Izawa，Κ·; Noyori，R·; Ikariya，Τ· Org· Lett· 2002，4, 4373-4376)使用之相對應鹵代醇1.3。所得鹵代醇再以一級胺（例如甲基胺或乙胺）處理，獲得式1.5之胺。或者，鹵基酮可以一級胺（例如甲基胺或乙胺）直接處理，獲得胺基酮 1.4，其可再於非對掌性或對掌性還原條件（Ohkuma，T·; Ishii， D.; Takeno, H.; Noyori，R. J. Am. Chem. Soc. 2000，122, 6510-6511; Kawamoto, A.; Wills, M. Tetrahedron: Asymmetry 2000，11，3257-3261)下還原，獲得式1.5之化合物。此情況下，鹼性氮可能需經過度性保護（例如胺基甲酸第三丁酯），以協助還原。前驅物N-Boc胺基酮J.2可如圖J中所述般製備，其中Weinreb醯胺衍生物（Y=N(CH3)(OCH3)(以文獻中習知之方法製備，例如 Sibi，M. Org. Prep. Proc. Int. 1993, 25, 15-40)係在四甲基乙二胺存在下於低溫下與金屬化二甲基胺基甲酸第三丁酯反應。亦經過該還原之其他式J. 1化合物包含羧醯胺（其中Y=4-嗎啉）及硫醇酯（例如Y=SPh)。 87731 -28 - 200410970 圖iH.4 The amine R4R5C (OH) CH2NH (R3) in Figure A is commercially available, can be prepared by procedures known to those skilled in the art, or can be prepared by the method illustrated in Figure 1-0. As shown in FIG. 1, commercially available methyl ketone 1.1 can be halogenated (X = C1, Br) to obtain a haloketone of formula 1.2. The obtained self-derived ketones can be reduced to obtain non-palladium (for example, NaBH4 / CeCl3) use or palm-reducing conditions (for example, Hamada, T ·; Torii, T ·; Izawa, K ·; Noyori, R ·; Ikariya, T. Org. Lett. 2002, 4, 4373-4376) corresponds to the halogenated alcohol 1.3. The resulting halohydrin is then treated with a primary amine such as methylamine or ethylamine to obtain an amine of formula 1.5. Alternatively, the halogenated ketone can be directly treated with a primary amine (such as methylamine or ethylamine) to obtain the amine ketone 1.4, which can then be used in non-palladium or palmar reducing conditions (Ohkuma, T .; Ishii, D. Takeno, H .; Noyori, RJ Am. Chem. Soc. 2000, 122, 6510-6511; Kawamoto, A .; Wills, M. Tetrahedron: Asymmetry 2000, 11, 3257-3261). Compounds. In this case, basic nitrogen may require a degree of protection (such as tert-butyl aminoformate) to assist in the reduction. The precursor N-Boc amine ketone J.2 can be prepared as described in J, in which the Weinreb amide derivative (Y = N (CH3) (OCH3) (prepared by methods known in the literature, such as Sibi, M Org. Prep. Proc. Int. 1993, 25, 15-40) was reacted with the third metal dimethylaminoformate in the presence of tetramethylethylenediamine at low temperature. Other compounds of formula J. 1 include carboxamide (where Y = 4-morpholine) and a thiol ester (eg Y = SPh). 87731 -28-200410970 Figure i

CJ.3 Z = BOC 1.5 Z=H 口或者如圖K中所不，式之特定胺可由平售或以熟習本技藝者習知之方法製備之羧酸K · 1製備K.1以锍化物（例如三甲基锍碘）環氧化，獲得式K.2之環氧化物，ί哀氧化物以一級胺（例如甲基胺或乙基胺）處理，獲得式1.5之化合物。圖K 人4 — —i>^r4 K.1 K.2 R3 1.5 如圖L中所示，式r4r5c(0H)CH2NH(r3)之特定胺亦可由羰基衍生物，藉由在四甲基二胺存在下及低溫下，與金屬化二甲基胺基甲酸第三丁酯反應，獲得經BOC-保護之胺基 87731 -29- 200410970 醇L.2。接著於酸性條件（例如三氟乙酸或鹽酸）下斷鏈，或於驗性條件（例如氫化鈉）下嘮唑啉啶酮環化，接著鹼水解，獲得式L.3之化合物。當R5為羥基甲基、2-羥基乙基或丨_羥基乙基時，羥基係使用慣用之保護基（Greene，T. W.; Wuts，P. G. M. Protective Groups in Organic Synthesis，1999)過度性保護’在如圖A中所述般於偶合之前或之後去保護。CJ.3 Z = BOC 1.5 Z = H or as shown in Figure K, the specific amine of the formula can be sold on the market or prepared by carboxylic acid K · 1 prepared by methods known to those skilled in the art. For example, trimethylphosphonium iodide) is epoxidized to obtain the epoxide of formula K.2, and the oxalate is treated with a primary amine (such as methylamine or ethylamine) to obtain a compound of formula 1.5. Figure K Human 4 — i> ^ r4 K.1 K.2 R3 1.5 As shown in Figure L, the specific amine of formula r4r5c (0H) CH2NH (r3) can also be derived from a carbonyl derivative by In the presence of an amine and at a low temperature, it is reacted with a third metal dimethylaminoformate to obtain a BOC-protected amino group 87731 -29- 200410970 alcohol L.2. The chain is then cleaved under acidic conditions (such as trifluoroacetic acid or hydrochloric acid), or cyclazinone is cyclized under experimental conditions (such as sodium hydride), followed by alkaline hydrolysis to obtain a compound of formula L.3. When R5 is hydroxymethyl, 2-hydroxyethyl, or __hydroxyethyl, the hydroxy group is protected by conventional protective groups (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 1999). Deprotection is performed as described in A before or after coupling.

圖L R4 O^R5 R4〇Y〇i-Bu 〕如 n、ch3 P、ch3 · L_2 L.3 如圖Μ中所示，式r4r5c(〇H)CH2NH(R3)之特定胺亦可由甲基胺基乙醛或甲基胺基-乙醛（例如（甲基（三氟甲烷磺醯基）胺基）乙酸）(Μ·1)之經保護形式製備。在低溫下以金屬化雜芳基試劑處理Μ.1，獲得式Μ.2之醇。氮保護基去保護後 (例如若為三氟甲烷磺醯基，則在醚溶液中以無機酸處理），獲得式Ι·5之胺。熟習本技藝者應了解在某些情況下，“中 _ 存在之路易斯鹼或酸官能性可能需經過度性保護，以協助金屬試劑之形成及圖L中所述後續添加，其程序已完全建立 ⑸eene，Τ· W_; Wilts，R G· Μ·有機合成中之保護基 (Protective Groups in Organic Synthesis), 1999) 〇 87731 OHC R3 V-N: CPh, M.1 R4 OHV3 CPh3 M.2 1.5 R3 -30- 200410970 當胺R4R5C(OH)CH2NH(R3)之之r5取代基為甲基或乙基時，胺可如圖N中所述般製備。晞烴Ν· 1係在醚溶劑中，使用催化量之硫酸，與N-溴丁二醯亞胺反應，獲得溴代醇 Ν·2。所得溴代醇再以一級胺（例如甲基胺或乙胺）處理，獲得式Ν.3之胺。Figure L R4 O ^ R5 R4〇Y〇i-Bu] such as n, ch3 P, ch3 · L_2 L.3 As shown in Figure M, a specific amine of formula r4r5c (〇H) CH2NH (R3) can also Aminoacetaldehyde or methylamino-acetaldehyde (eg, (methyl (trifluoromethanesulfonyl) amino) acetic acid) (M · 1) is prepared in a protected form. Treatment of M.1 with a metallized heteroaryl reagent at low temperature yields an alcohol of formula M.2. After the nitrogen protecting group is deprotected (for example, if it is a trifluoromethanesulfonyl group, it is treated with an inorganic acid in an ether solution) to obtain an amine of formula 1.5. Those skilled in the art should understand that in some cases, "the presence of Lewis base or acid functionality in medium may need to be protected to assist in the formation of metal reagents and subsequent additions as described in Figure L. The procedure has been fully established ⑸eene, T · W_; Wilts, RG · M · Protective Groups in Organic Synthesis, 1999 〇87731 OHC R3 VN: CPh, M.1 R4 OHV3 CPh3 M.2 1.5 R3 -30- 200410970 When the r5 substituent of the amine R4R5C (OH) CH2NH (R3) is methyl or ethyl, the amine can be prepared as described in Figure N. The hydrocarbon N · 1 is in an ether solvent and a catalytic amount of Sulfuric acid is reacted with N-bromosuccinimide to obtain a bromohydrin N · 2. The obtained bromohydrin is then treated with a primary amine (such as methylamine or ethylamine) to obtain an amine of formula N.3.

式R4CH(OH)CH2NH(CH3)之特定胺亦可依據圖〇中所述方法，自R4CH(OH)CH2NH2之一級胺製備。式0.1之胺基醇係以碳酸二甲酯或亦以第三丁氧化鉀處理，獲得式0.2之嘮唑啉啶酮。所得呤唑啉啶酮再於鹼水溶液（例如氫氧化鉀）存在下水解，獲得式〇·3之胺基醇。Specific amines of the formula R4CH (OH) CH2NH (CH3) can also be prepared from the primary amines of R4CH (OH) CH2NH2 according to the method described in Figure 0. The amino alcohol of formula 0.1 is treated with dimethyl carbonate or also with tertiary potassium butoxide to obtain oxazolinidone of formula 0.2. The obtained oxazolinidone is further hydrolyzed in the presence of an aqueous alkaline solution (such as potassium hydroxide) to obtain an amino alcohol of the formula 0.3.

製備圖B中所用R4R5C(〇h)CH2NH2—級胺之方法為熟習有機合成之技藝者所習知（Bergmeier，S. C. Tetrahedron 2000, 56，2561-2576)。除本文中所述外，代表性合成實例包含2_ 胺基-1_碟吩-2_基乙醇出1^131161：，（：.？.；01&331，？.八.；8。11〇12，€· R· J· Org· Chem· 1953，18, 21) ; 2-胺基-1-(1H-嘀哚-3-基）乙醇（DeGraw，J· I· ; Kennedy，J. G. ; Skinner，W· A· J·雜環化學 87731 -31 - 200410970 期刊（J. Hetercyclic Chem.)，1966，3，9); 2_胺基-1-吱喃并 [2,3-b]吡啶-2-基乙醇，2-胺基-1-呋喃并[2,3-c]吡啶-2-基乙醇，2-胺基-1-呋喃并[3,2-c]吡啶-2-基乙醇，及2-胺基-1-呋喃并[3,2-b]吡啶-2-基乙醇（Shiotani，S.J.雜環化學期刊（J· Hetercyclic Chem·)，1993，30，1035) 〇式（I)之化合物可製備成單一對映體或製備成包含消旋混合物之單獨對映體之混合物。由單獨對映體之混合物或消旋混合物優先獲得單一對映體之方法為熟習有機化學技藝者所習知。該方法包含（但不限）使非立體鹽（例如酒石酸鹽或樟腦磺酸鹽）優先結晶，以對掌性非消旋試劑共價衍生化，接著以慣用方法（例如結晶、層析分離或蒸餾）分離所得非立體異構物，且化學反轉成化合物，模擬移動床技術，或使用對掌性靜態相之高/中-壓液態層析（Eliel，E· L.有機化合物之立體化學（Stereochemistry of Organic Compounds)， 1994; Subramanian, G. Chiral 分離技術（Separation Techniques): A Practical Approach，2001)。此等技術亦可用於是（I)之最終化合物上，或用於帶有立體中心之化合物（I) 之任何中間物上。而且，為以上述任一方法協助分離，式 (I)之化合物或帶有立體中心之式⑴化合物之任何中間物均可與非對掌性試劑短暫的反應、分離，再藉由標準合成技術反轉成標示化合物。熟習本技藝者應了解所述之合成程序本質上僅為代表例，且另外之合成方法均為熟習有機化學技藝者所習知。本發明之化合物及其醫藥可接受性鹽可用作抗病毒劑。 87731 -32- 200410970 因此，此等化合物可用於對抗動物之病毒感染。尤其此等化合物具有抗皰疹病毒、細胞巨大型病毒（CMV)之抗病毒活性。此等化合物亦具有抗其他皰疹病毒之活性，如水痘帶狀皰參病毒、EB病毒（Epstein-Barr virus)、單純皰療病毒及人類皰疹病毒8型（HHV-8)。本發明之化合物亦可用於處理許多心血管疾病，如動脈硬化症及再狹窄。此等疾病與管狀動血管壁之發炎有關，造成皰療病毒之感染或再度活動。本發明之化合物亦可用於治療動物之皰疹病毒感染，例 β 如因牛皰疹病毒1-5(BHV)、綿羊皰疹病毒1及2、犬皰疹病毒1、馬皰疹病毒1-8(EHV)、貓科皰疹病毒l(FHV)及擬狂犬病毒（PRV)造成之疾病。醫藥鹽式I之化合物可依其天然形式使用或以其鹽使用。當需要形成安定之無毒鹽時，化合物較好以其醫藥可接受性鹽投藥。醫藥可接受性鹽之實例為與形成生理上可接受之陰離修子之酸形成之有機酸加成鹽（例如甲苯磺酸鹽、甲烷磺酸鹽、乙酸鹽、檸檬酸鹽、丙二酸鹽、酒石酸鹽、丁二酸鹽、苯甲酸鹽、抗壞血酸鹽、氧代戊二酸鹽及甘油基磷酸鹽）。亦可形成適用之無機酸鹽，包含鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、碳酸氫鹽及碳酸鹽。醫藥可接受性鹽可使用技藝中習知之標準程序製備，例如藉由使本發明之化合物與適用之酸反應，獲得生理上可接受之陰離子。 87731 -33 - ZUU410970The method for preparing R4R5C (OH) CH2NH2-grade amine used in Figure B is well known to those skilled in organic synthesis (Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576). In addition to those described herein, representative synthetic examples include 2-amino-1_diephen-2-ylethanol 1 ^ 131161 :, (:.?.; 01 & 331,? .Eight .; 8.11. 12, € · J · Org · Chem · 1953, 18, 21); 2-amino-1- (1H-fluorin-3-yl) ethanol (DeGraw, J. I .; Kennedy, JG; Skinner , W · A · J · Heterocyclic Chemistry 87731 -31-200410970 Journal (J. Hetercyclic Chem.), 1966, 3, 9); 2-Amino-1-Crano [2,3-b] pyridine- 2-ylethanol, 2-amino-1-furo [2,3-c] pyridin-2-ylethanol, 2-amino-1-furo [3,2-c] pyridin-2-ylethanol And 2-amino-1-furo [3,2-b] pyridin-2-ylethanol (Shiotani, SJ Hetercyclic Chem., 1993, 30, 1035). Formula (I The compounds of) can be prepared as a single enantiomer or as a mixture of individual enantiomers containing a racemic mixture. Methods for obtaining single enantiomers preferentially from mixtures of individual enantiomers or racemic mixtures are well known to those skilled in the art of organic chemistry. The method includes, but is not limited to, preferentially crystallizing a non-stereomeric salt (such as tartrate or camphor sulfonate) to covalently derivatize a palm non-racemic reagent, followed by conventional methods (such as crystallization, chromatographic separation, or Distillation) to separate non-stereoisomers and chemically reverse them to compounds, simulated moving bed technology, or use high / medium-pressure liquid chromatography (Eliel, E.L. (Stereochemistry of Organic Compounds), 1994; Subramanian, G. Chiral Separation Techniques: A Practical Approach, 2001). These techniques can also be applied to the final compound of (I) or to any intermediate of compound (I) with a stereocenter. Moreover, in order to assist the separation by any of the methods described above, the compound of formula (I) or any intermediate of the compound of formula ⑴ with stereocenters can be reacted and separated briefly with non-palladium reagents, and then by standard synthesis techniques Invert to labeled compound. Those skilled in the art should understand that the synthetic procedures described are only representative examples in nature, and the other synthetic methods are known to those skilled in organic chemistry. The compounds of the present invention and their pharmaceutically acceptable salts are useful as antiviral agents. 87731 -32- 200410970 These compounds are therefore useful for combating viral infections in animals. In particular, these compounds have antiviral activity against herpes virus and cytomegalovirus (CMV). These compounds also have activity against other herpesviruses, such as Varicella zoster virus, Epstein-Barr virus, herpes simplex virus, and human herpesvirus 8 (HHV-8). The compounds of the present invention are also useful in treating many cardiovascular diseases such as arteriosclerosis and restenosis. These diseases are related to inflammation of the walls of the tubular arteries and blood vessels, causing infection or reactivation of the herpes virus. The compounds of the present invention can also be used to treat herpes virus infections in animals, such as β such as bovine herpes virus 1-5 (BHV), sheep herpes virus 1 and 2, canine herpes virus 1, horse herpes virus 1- 8 (EHV), feline herpesvirus 1 (FHV) and rabies-like virus (PRV). Pharmaceutical salts The compounds of formula I can be used in their natural form or as their salts. When the formation of stable non-toxic salts is desired, the compounds are preferably administered as their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts (e.g., tosylate, methanesulfonate, acetate, citrate, malonate) with acids that form physiologically acceptable cations , Tartrate, succinate, benzoate, ascorbate, oxoglutarate, and glyceryl phosphate). Suitable inorganic acid salts can also be formed, including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate and carbonate. Pharmaceutically acceptable salts can be prepared using standard procedures known in the art, for example, by reacting a compound of the invention with a suitable acid to obtain a physiologically acceptable anion. 87731 -33-ZUU410970

治療或對抗哺乳動物（亦即人類及動物）病毒感染之治療用中|發明《化合物、其醫藥組合物及其他抗病毒劑 " 服非氬腸θ、局邵、直腸、經黏膜或經腸内投藥。 '、=，經腸胃投藥包含非直接注射產生全身作用或直接注射 '、病之區域。非經腸胃投藥之實例為經皮下、經靜脈内、 =肉内、經皮、腦脊髓膜内、眼内、、經鼻、肌肉内注射或灌入技術。〜局部投g包含可輕易以局部應用處理之感染區域或器_ 例如眼晴、耳朵（包含外耳或中耳感染）、陰莖、外傷、皮膚包含表皮及下層真皮結構，或其他較低之腸道。其亦包含經皮輸送產生全身性作用。直腸投藥包含栓劑形式。經黏膜投藥包含鼻内氣溶膠或吸人性應用。較佳之投藥路徑為口服及非經腸胃。In the treatment or combat of mammalian (ie human and animal) viral infections in the therapeutic use | Invention of "Compounds, their pharmaceutical compositions and other antiviral agents" Dosing. ', =, Parenteral administration includes non-direct injection for systemic effect or direct injection', the diseased area. Examples of parenteral administration are subcutaneous, intravenous, intramuscular, transdermal, cerebrospinal membrane, intraocular, intranasal, intramuscular injection or infusion techniques. ~ Topical injections include infected areas or devices that can be easily treated with topical application_ such as clear eyes, ears (including external or middle ear infections), penis, trauma, skin including epidermis and lower dermal structure, or other lower intestinal . It also includes percutaneous delivery for systemic effects. Rectal administration is in the form of suppositories. Transmucosal administration includes intranasal aerosol or inhalation applications. The preferred route of administration is oral and parenteral.

Ua及調配物本發明之醫藥組合物可以技藝中習知之方法，例如以慣· 用义μ合物、落解、造粒、製造糖粉、磨細、乳化、包封、包裝、凍乾法或喷霧乾燥製造。夕依據本發明應用之醫藥組合物可依一般方式，使用一或夕種生理上可接受之載劑（包括佐藥及助劑，其可協助活性化合物加工成醫藥上可用製劑)調配。適用之調配物係依選用之投藥路徑而定。針對口服投樂，化合物可藉由結合活性化合物及技藝中 87731 -34- 200410970 習知之醫藥可接受性載劑調配。該載劑可使本發明化合物凋配成錠劑、藥丸、藥錠、包衣錠、膠囊、液態溶液、乳液、凝膠、糖漿、漿料、懸浮液等，供病患口服攝取。載劑可為至少一種亦可作為稀釋劑、加味劑、溶解劑、潤滑劑、懸浮劑、結合劑、錠劑崩解劑及包封劑功能之物質。該載劑或佐藥之實例包含（但不限）碳酸鎂、硬脂酸鎂、滑石、蔗糖、乳糖、果膠、糊精、甘露糖醇、山梨糖醇、澱 :分、明膠、纖維素物質、低溶點蠟、可可亞奶油或粉末、聚合物如聚乙二醇及其他醫藥可接受性物質。包衣錠蕊係以適當之塗覆提供。針對該目的，可使用濃縮之糖溶液，其可視情況含有***膠、滑石、聚乙締基吡咯哫酮、卡伯醇（carbopol)凝膠、聚乙二醇、及/或二氧化歛、亮光溶液及適用之有機溶劑或溶劑混合物。錠劑或包衣錠中亦可添加染料或顏料，以辨識或使活性化合物劑量之不同結合特性化。可口服使用之醫藥、組合物包含由明膠以及由明膠可塑劑如甘油或山梨糖醇製成之軟質密封膠囊製成之推入式膠囊β推入式膠囊可含與填料如乳糖、結合劑如殿粉、及/ 或潤滑劑％滑石或硬脂酸鎂，1選用之安定劑預混合之活性：分。軟質明膠中，活性化合物可溶解或懸浮於適用之液月瓦中如脂肪油、液態鍵燒、液態聚乙二醇、克雷莫芙 (cremophor)、肯普莫㈣則”、巾等或長鏈單·、二·或三甘油醚。该凋配物中亦可添加安定劑。 ’夜悲組合物包含溶液、懸浮液及乳液。例如，此等溶液 87731 200410970 可為將本發明化合物溶於水及水-丙二醇及水-聚乙二酵系統中，且視情況含有適當慣用之調色劑、加味劑、安定劑及增稠劑獲得。該化合物亦可針對非經腸胃投藥調配，例如經由注射點滴注射或連續注射。非經腸胃投藥之調配物可以單位％型存在，例如安瓶或多劑容器，且添加防腐劑。組合物可以油狀或水性載劑之懸浮液、溶液或乳液形式服用，可含調配物質如懸浮劑、安定劑及/或分散劑。針對注射用，本發明之化合物可於水性溶液中調配，# 好於生理上可相容之緩衝液或生理食鹽水緩衝液中。適用之緩衝劑包含正磷酸三鈉、碳酸氫鈉、檸檬酸鈉、N•甲基葡胺、L(+)-絲胺酸及L(+)-精胺酸。非經腸胃投藥液包含水溶性形式之水溶液，如（但不限）活性化合物之鹽。或者，可於親脂性載劑中製備活性化合物之懸浮液。適用之親脂性載劑包含脂肪油如芝麻油、合成脂肪酸酯如油酸乙酯及三縮水甘油醚，或如脂質之物質。水性注射懸浮液可含增加懸浮液黏度之物質，如叛基甲基纖維素鈉、山梨糖醇或糊精。視情況，懸浮液亦可含適用之安疋劑及/或增加化合物之溶解度以製備高濃度溶液之藥劑。或者，活性成分可為在使用前與適當載劑（例如消毒水、不含熱精之水併用之粉末形式。針對栓劑投藥，化合物亦可藉由使藥劑與在室溫下為固體但在直腸溫度下為液體，且因此在直腸中融化釋出藥物之適用無刺激性佐藥混合調 87731 -36- 200410970 配。該物質包含可可亞奶油、蜜螺及其他縮水甘油酸。針對吸入投藥’本發明之化合物一般可以溶液、乾粉或懸浮液形式，經氣溶膠噴霧輸送。氣溶膠可使用加壓包或贺霧裔及適用之推進劑。當使用加壓之氣溶膠時，可藉由裝置-閥以輸送計量量控制。吸人器中所用明膠膠囊或匿可、I调配成含有粉末基質如乳糖或澱粉之調配物。 ’十·子局PiC用可將醫樂組合物調配成含有懸浮或溶於 -種或多種載劑中之活性成份之適用軟膏。本發明化合物之局部投藥用載劑包含（但不限）礦物油、液態礦脂、白色礦脂、丙二醇、聚環氧乙㉟、聚環氧丙烷化合物、乳化之臘、欠或纟i木組合物可調配成適用之乳液，如含懸浮或冷於#或夕種醫樂可接受性載劑中之活性成份之懸浮 t 目°週用之載劑包含（但不限）礦物油、山梨糖醇單更月曰酸酉曰一 polysorbate6〇、十四烷基酯臘、十六基醇、 2-辛基十二烷醇、苄基醇及水。針對眼睛及耳炎之瘅用，π #糾 θ、 μ用可將醫藥組合物調配成在等滲壓、pH調整之無菌食躏k由 |欠中 < 械米化懸浮液，或較好調配成溶於等滲壓、pH調整 <播囷食鹽水中之溶液，可含或不含防腐劑如苄基烷基氣。式 I 或者針對眼科之應用，可將醫藥 '、、且合物調配於軟膏如礦脂中。除先前所述調配物外，仆人^、化合物亦可調配成植入製劑。該長時間作用之調配物可A括〜、為植入 < 形式。本發明之化合物可針對投藥路徑與適當之聚八、 . 口物、疏水性物質調配，或調配成較不溶之衍生物，如（伸 U-不限）較不溶之鹽。 87731 -37. 200410970 或者，化合物可使用持續釋出之系統輪送。各種持續釋出之物貝均已建乂，且為熟習本技藝者所習知。持續釋出之膠囊依其化學性質可持續釋出化合物24小時或達數天之久0 通用於本發明之醫藥組合物包含其中所含活性成份之量足以達到預期目的（亦即治療或預防感染疾病）之組合物。尤其，治療有效量意指可有效預防、減輕或改善疾病之症狀，或延長欲治療標的物存活時間之化合物量。醫藥組合物及其單位劑型中之活性化合物（亦即本發明化合物可依投藥方式、特殊化合物之效力及期望濃度廣之的改變或調整。治療有效量之決定為熟習本技藝者所習知。通常，活性成份之量在組合物之〇 5%至9〇%(〜〇間。通常’活性成份之抗病毒有效劑量為約〇·1至約400毫克/ 公斤體重/天，更好為約1·〇至約50毫克/公斤體重/天。應了解劑量可依欲治療之病毒感染之各標的物及嚴重性而變。所需劑量一般可依單一劑量或於適當之時間内投藥之分開劑量存在’例如每天二、2、四或更多之次劑量。次劑 Τ本身可再分成例如許多不連續之鬆散分離投藥；如自吸入器多次吸入或加許多滴於眼睛中。而且應了解投藥之起初劑量可增加超過上述之上限，以快速達到所需之血漿濃度。另一方面，起初劑量可小於最週之量’且每曰劑量可隨著治療過程中逐漸增加，依特殊狀況而疋。若需要，每日劑量亦可分成多次劑量投藥，例 87731 200410970 如每天二至四次。針對局部投藥或選擇性攝取，醫藥之有效局部濃度可與血漿濃度無關，且可使用技藝中已知之程序決定所需之劑量。生物數據雖然本發明之許多化合物已經顯示抗CMV聚合物酶之活性，但此等化合物可能因該等或其他作用機構而具有抗細胞巨大型病毒之活性。因此，以下敘述之此等化合物抗CMV 聚合物酶之活性並非將本發明限制在特定之作用機構中。本發明之化合物在一或多種以下所述分析中已顯示活性。所有此等分析均顯示化合物之活性且因此可用作抗病毒劑。 HCMV聚合物酶分析係使用許多參考例（如N.D_ Cook，等人，醫藥製造國際（Pharmaceutical Manufacturing International),第 49-53 頁（1992) ; K. Takeuchi，Laboratory Practice, September issue (1992); US Patent No. 4,568,649 (1986)，均在此提出供參考）中所示之閃燦靠近分析（SPA)進行。反應在96洞版中進行。分析係在100微升體積中與5.4 mM HEPES (pH 7.5)、11.7 mM KC卜 4.5 mM MgCl2、0.36 毫克/毫升BSA及90nM3H-dTTP進行。分析係在配合或不含 CHAPS，最終濃度為2mM之（3·[(3-氣醯胺基丙基）二甲基氨基]-1-丙烷-磺酸酯）下進行。HCMV聚合物酶係於含50%甘油、250 mM NaCU、10 mM HEPES (pH 7.5)、100微克/毫升 BSA及0.01%疊氮化鈉之酶稀釋緩衝液中稀釋。HCMV聚合 87731 -39- 200410970 物酶（其係在重組桿狀病毒-感染之SF-9細胞中表現，且一文獻之程序純化）係在10%(或10微升）最終反應體積，亦即10 微升下添加。化合物係於50%DMSO中稀釋，且於各洞中添加10微升。對照用洞含有相等濃度之DMSO。除非另有說明，否則反應係經由添加6nM生物趨活聚（dA)-寡（dT)型版/ 處理劑起始含有酵素、基材及所需化合物之反應混合物。版係在25°C或37°CH20浴中培養，且經由每洞添加40微升 /0.5 M EDTA(pH 8)之反應終止。反應係在時間架構中終止，期間基材之加入為線性，且隨著所用酵素及條件而變， @ 亦即對HCMV聚合物酶為30分鐘。添加十（10)微升 Streptavidin -SPA珠粒（PBS中20毫克/毫升/10%甘油），接著使反應終止。使版在37t下培養10分鐘，接著均衡至室溫，且在Packard Topcount上計算。進行線性回歸，且使用電腦軟體計算IC50。如上述般執行上述HCMV聚合物酶分析之未改良版，但改變如下：化合物於100%DMSO中稀釋，直到稀釋成分析 φ 用緩衝液為止。依先前分析，化合物於50%DMSO中稀釋。將4.5 mM二硫塞醇（DTT)添加於聚合物酶緩衝液中。而且，使用不同批之CMV聚合物酶，其活性更強因此使聚合物酶反應更快。本發明化合物於該分析中之試驗結果列於下表1中。所有結果均以聚合物酶之Ι〇50(μΜ)值列出。表1中，nn.d.n 一詞係指未測定之數據。 87731 -40- 200410970Ua and formulations The pharmaceutical composition of the present invention can be used in a method known in the art, for example, by using a conventional compound, dehydration, granulation, manufacturing sugar powder, grinding, emulsification, encapsulation, packaging, and lyophilization. Or spray-dried. The pharmaceutical composition applied according to the present invention can be formulated in a general manner using one or more physiologically acceptable carriers (including adjuvants and adjuvants, which can assist the processing of active compounds into pharmaceutically acceptable preparations). The applicable formulation depends on the chosen route of administration. For oral administration, the compounds can be formulated by combining the active compound and a pharmaceutically acceptable carrier known in the art from 87731 -34- 200410970. The carrier enables the compound of the present invention to be formulated into lozenges, pills, tablets, coated tablets, capsules, liquid solutions, emulsions, gels, syrups, slurries, suspensions, etc. for oral ingestion by patients. The carrier may be at least one substance which also functions as a diluent, flavoring agent, dissolving agent, lubricant, suspending agent, binding agent, disintegrating tablet, and encapsulating agent. Examples of such carriers or adjuvants include (but are not limited to) magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, mannitol, sorbitol, yodo: cellulose, gelatin, cellulose Substances, low melting point waxes, cocoa butter or powder, polymers such as polyethylene glycol and other pharmaceutically acceptable substances. Coated tablets are provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may contain acacia gum, talc, polyethylene vinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or dioxin, as appropriate. Solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may also be added to the tablets or coated tablets to identify or characterize different combinations of active compound dosages. Medicines and compositions that can be used orally include push-in capsules made of gelatin and soft sealed capsules made of gelatin plasticizers such as glycerin or sorbitol β push-in capsules can contain fillers such as lactose, binding agents such as Dian powder, and / or lubricant% talc or magnesium stearate, 1 Stabilizer pre-mixed activity: cent. In soft gelatin, the active compound can be dissolved or suspended in suitable liquid tiles such as fatty oil, liquid bond, liquid polyethylene glycol, cremophor, Kemper's rule, towels, etc. Chain mono-, di-, or triglyceryl ether. Stabilizers can also be added to this wither. 'Ye Bei composition contains solutions, suspensions, and emulsions. For example, these solutions 87731 200410970 can be used to dissolve the compounds of the present invention Water and water-propylene glycol and water-polyethylene glycol systems, and optionally containing conventionally used toners, flavoring agents, stabilizers and thickeners. The compounds can also be formulated for parenteral administration, such as via Injection by drip or continuous injection. Formulations for parenteral administration can be in unit% form, such as ampoules or multi-dose containers, with preservatives added. The composition can be in the form of an oily or aqueous carrier suspension, solution or emulsion For administration, it may contain formulating substances such as suspending agents, stabilizers and / or dispersing agents. For injection, the compounds of the present invention can be formulated in aqueous solutions, # better than physiologically compatible buffers or physiological In saline buffer. Suitable buffers include trisodium orthophosphate, sodium bicarbonate, sodium citrate, N • methylglucamine, L (+)-serine and L (+)-spermine. Gastrointestinal solutions include water-soluble forms of aqueous solutions, such as (but not limited to) salts of the active compounds. Alternatively, suspensions of the active compounds can be prepared in lipophilic vehicles. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic Fatty acid esters such as ethyl oleate and triglycidyl ether, or substances such as lipids. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium methylcellulose sodium, sorbitol or dextrin. In some cases, the suspension may also contain suitable elixirs and / or agents that increase the solubility of the compounds to prepare high-concentration solutions. Alternatively, the active ingredient may be an appropriate carrier (eg, sterile water, pyrogen-free) before use. Water is used in powder form. For suppository administration, the compound can also be adjusted by mixing the agent with a suitable non-irritating adjuvant that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. 877 31 -36- 200410970. This substance contains cocoa butter, honey snails and other glycidic acid. For inhalation, the compounds of the present invention can generally be delivered in the form of solutions, dry powders or suspensions by aerosol spray. Aerosols can be used Pressurized bag or He mister and suitable propellant. When using pressurized aerosol, it can be controlled by the device-valve to measure the amount of delivery. Gelatin capsules used in the inhaler, or can be formulated to contain powder Formulations of bases such as lactose or starch. 'Ten · Secret PiC can be used to formulate medicinal compositions into suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Topical administration of the compounds of the present invention Carriers include (but are not limited to) mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide compounds, emulsified wax, oligo, or cypress wood composition can be formulated into a suitable emulsion For example, if the suspension contains active ingredients in suspension or colder than # or Xiyue Medical Music acceptable carrier, the weekly carrier contains (but not limited to) mineral oil, sorbitol monomenoric acid Polyso rbate60, tetradecyl ester wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ocular and otitis, π #correction θ, μ can be used to formulate the pharmaceutical composition into sterile food with isotonic pressure and pH adjustment. From 欠中 < mechanical rice suspension, or better adjustment Formulated as a solution dissolved in isotonic pressure, pH adjustment < sowing salt water, with or without preservatives such as benzyl alkyl gas. Formula I or for ophthalmic applications, medicines can be formulated in ointments such as petrolatum. In addition to the formulations previously described, servants, compounds can also be formulated into implant preparations. The long-acting formulation may be in the form of implantation <. The compound of the present invention can be formulated with appropriate poly-, mastic, hydrophobic substances for the route of administration, or formulated into less soluble derivatives, such as (extended U-unlimited) less soluble salts. 87731 -37. 200410970 Alternatively, compounds can be rotated using a continuous release system. Various continuously released shellfish have been built and are known to those skilled in the art. Sustained-release capsules can continuously release compounds for 24 hours or up to several days depending on their chemical properties. The pharmaceutical composition commonly used in the present invention contains an active ingredient in an amount sufficient to achieve the intended purpose (that is, to treat or prevent infection Disease). In particular, a therapeutically effective amount means an amount of a compound that is effective in preventing, reducing, or ameliorating the symptoms of a disease, or prolonging the survival time of a subject to be treated. The active compound in the pharmaceutical composition and its unit dosage form (that is, the compound of the present invention can be changed or adjusted according to the mode of administration, the potency of the special compound, and the desired concentration. The determination of a therapeutically effective amount is known to those skilled in the art. Generally, the amount of active ingredient is between 05% and 90% (~ 0%) of the composition. Generally, the effective antiviral dose of the active ingredient is from about 0.1 to about 400 mg / kg body weight / day, more preferably about 1.0 to about 50 mg / kg body weight / day. It should be understood that the dose may vary depending on the target substance and severity of the viral infection to be treated. The required dose may generally be divided according to a single dose or administered at an appropriate time. The dose is present, for example, two, two, four or more daily doses. The secondary dose T itself can be subdivided into, for example, many discrete loosely divided administrations; such as multiple inhalations from an inhaler or many drops added to the eye. Understand that the initial dose of the drug can be increased above the upper limit to quickly reach the required plasma concentration. On the other hand, the initial dose can be less than the most weekly amount, and each dose can be changed as the treatment progresses. Increasing gradually, depending on special conditions. If necessary, the daily dose can also be divided into multiple doses, such as 87731 200410970, such as two to four times a day. For local administration or selective ingestion, the effective local concentration of medicine can be compared with the plasma concentration. Irrelevant, and the required dosage can be determined using procedures known in the art. Biological data Although many compounds of the invention have shown anti-CMV polymerase activity, these compounds may have anti-cell activity due to these or other mechanisms of action The activity of megaviruses. Therefore, the anti-CMV polymerase activity of these compounds described below does not limit the invention to specific mechanisms of action. The compounds of the invention have shown activity in one or more of the assays described below. All of these analyses show compound activity and are therefore useful as antiviral agents. HCMV polymerase analysis uses many reference examples (eg, N.D. Cook, et al., Pharmaceutical Manufacturing International, pp. 49- 53 pages (1992); K. Takeuchi, Laboratory Practice, September issue (1992); US Patent No. 4, 568,649 (1986), all of which are hereby incorporated by reference) are performed in close proximity analysis (SPA). The reaction was performed in a 96-hole version. The analysis was performed in a 100 microliter volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KC, 4.5 mM MgCl2, 0.36 mg / ml BSA, and 90nM3H-dTTP. The analysis was performed with or without CHAPS, and the final concentration was 2 mM (3 · [(3-Arylamidopropyl) dimethyl) Amino] -1-propane-sulfonate). HCMV polymerase was diluted in enzyme dilution buffer containing 50% glycerin, 250 mM NaCU, 10 mM HEPES (pH 7.5), 100 μg / ml BSA, and 0.01% sodium azide. HCMV polymer 87731 -39- 200410970 enzymes (which are expressed in recombinant baculovirus-infected SF-9 cells and purified by a documented procedure) are at a final reaction volume of 10% (or 10 microliters), that is, Add at 10 μl. Compounds were diluted in 50% DMSO and 10 microliters were added to each hole. The control holes contained equal concentrations of DMSO. Unless otherwise stated, the reaction is initiated by the addition of 6nM bioactive poly (dA) -oligo (dT) type plate / treatment agent to the reaction mixture containing the enzyme, substrate and desired compound. The plates were cultured in a 25 ° C or 37 ° CH20 bath, and the reaction was terminated by adding 40 μl / 0.5 M EDTA (pH 8) per well. The reaction is terminated in the time frame, during which the addition of the substrate is linear and varies with the enzymes and conditions used, @ for HCMV polymerase is 30 minutes. Ten (10) microliters of Streptavidin-SPA beads (20 mg / ml / 10% glycerol in PBS) were added and the reaction was stopped. The plate was incubated at 37 t for 10 minutes, then equilibrated to room temperature, and calculated on a Packard Topcount. Linear regression was performed and IC50 was calculated using computer software. An unmodified version of the HCMV polymerase analysis described above was performed as described above, but with the following changes: The compound was diluted in 100% DMSO until it was diluted to analysis buffer φ. Based on previous analysis, compounds were diluted in 50% DMSO. 4.5 mM dithiotitol (DTT) was added to the polymerase buffer. Moreover, the use of different batches of CMV polymerase has greater activity and therefore makes the polymerase reaction faster. The test results of the compounds of the invention in this analysis are shown in Table 1 below. All results are listed as 10050 (μM) values of the polymerase. In Table 1, the term nn.d.n refers to unmeasured data. 87731 -40- 200410970

表1 實例聚合物酶Κ：5〇(μΜ) HCMV HSV VZV 1 0.08 0.22 0.06 2 0.04 0.09 0.03 3 0.07 0.26 0.13 4 0.25 0.84 0.39 5 0.01 0.03 0.01 6 0.17 0.47 0.15 7 0.30 0.98 0.33 8 0.26 0.85 0.32 9 1.06 未測定未測定 10 0.45 1.97 0.44 11 0.09 0.20 0.09 12 0.28 未測定未測定 13 0.17 1.92 0.44 14 0.10 0.53 0.12 15 0.24 未測定未測定 16 0.20 0.45 0.19 17 0.12 0.39 0.11 18 0.35 0.91 0.37 19 0.21 0.78 0.29 20 0.22 0.46 0.20 21 0.35 未測定未測定 87731 -41 - 200410970 實例聚合物酶Κ：5〇(μΜ) HCMV HSV VZV 22 0.09 0.17 0.08 23 0.26 未測定未測定 24 0.31 未測定未測定 25 1.80 未測定未測定 26 0.15 0.54 0.33 27 0.36 0.59 0.28 28 0.30 未測定未測定 29 0.60 未測定未測定 30 0.14 0.62 0.20 31 0.07 0.12 0.06 32 0.18 0.74 0.22 33 0.02 0.08 未測定 34 0.24 1.08 0.34 35 0.56 未測定未測定 36 0.83 未測定未測定實例製備例1. N-(4-氣+基）-2-(氣甲基）-7-甲基_4_氧代-4,7-二氫ρ塞吩并 [2,3-b]吡啶-5-羧醯胺程序A·將N-(4-氯卞基）-2-(我基甲基）-7-甲基-4_氧代-4,7_ 二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（3.00克，如美國專利第 6,239，142號中所述般製備）溶於DMF(150毫升）中。添加 87731 -42- 200410970 DMAP(0.150 克）、2,4,6-可力啶（c〇llidine)(2.73 毫升）及甲烷磺醯氯（1·60毫升），且使反應混合物在室溫下攪拌18小時。將反應混合物倒入水（3〇〇毫升）中。所得淡黃色固體經過濾且分散於乙腈中，獲得2.75克標題化合物。物理特徵·· Μ·ρ· 250-256°C (分解）；巾 NMR (400 MHz，DMSO-d6)S 10.48, 8.74, 7.58, 7.41- 7.33, 5.16, 4.55, 3.97; 13C NMR (DMSO-d6)5 172.5, 164.5, 151.8, 146.4, 138.9, 135.7, 131.7, 130.5, 129.5, 128.7, 124.0, 115.0, 43.4, 41.8, 41.1； MS (El) m/z 380 (M+); HRMS (FAB) m/z 381.0255 (M+H)+。分析實測值：C，53.34; H，3.70; N，7.30; Cl，17.91; S，8.51。程序B.於25毫升圓底瓶中以注射加入N-(4-氯爷基）-7-甲基-2-(嗎啉-4-基甲基）-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶 -5-叛醯胺（1_00克，如美國專利第6,239,142號中所述般製備）及氣仿（10毫升）。在氮氣及攪拌下，以注射添加氯甲酸乙酯 (0.55毫升）。使漿料加熱至回流隔夜。將無水***（1〇毫升）於氮氣及攪拌下添加於漿料中。固體經過濾且以***（3 X 10 毫升）洗滌。產物於40°C真空烘箱中乾燥，獲得〇.93克無色結晶標題化合物。物理特徵：4 NMR (400 MHz，TFA-d)5 9.09, 7.69, 7.22, 4.81，4.62, 4.27; 13C NMR (100 MHz，TFA-d) δ 167.6, 166.6, 156.3, 145.2, 143.6, 134.9, 133.3, 129.1，129.0, 127.4, 119·6, 109·9, 45.2, 44.0, 38.0。分析實測值：C，53·44; H， 3·66; Ν，7·35; C1，18·29。製備例2. Ν-(4-氯苄基）-7-((2,2-二甲基-ΐ，3-二嘮茂烷_4_基）甲 87731 -43- 200410970 基）-2-(羥基-甲基l·4-氧代-4,7-二氫嘍吩并[2,3-b]吡啶-5-羧醯胺將碳酸铯（3 ·91克）添加於含N-(4-氯苄基）_4_羥基-2-(羥基甲基）嘧吩并[2,3-b]吡啶-5-羧醯胺（3.49克，如美國專利第 6,239，142號中所述般製備）及4-(溴甲基）_2,2_二甲基-1，3-二口亏茂坑（1 ·95克）之DMF(20毫升）溶液中。使反應混合物於1 〇〇 °C下攪拌17小時。蒸發溶劑且將殘留物溶於10%ch3OH/ CH2C12中。混合物以水洗滌，有機層經脫水(MgS04)、過濾且濃縮。粗產物自EtOAc結晶，獲得2.7克白色固態標題化籲合物。物理特徵：4 NMR (400 MHz，DMSO-d6)S 10.53, 8.70， 7.40, 7.34, 7.28, 5.79, 4.69, 4·53, 4.50, 4.30, 4·14, 3.77, 1.34， 1.23; MS (El) m/z 462 (M+); HRMS (FAB) m/z 463.1087 (M+ H)+。分析實測值：C，57.07; H，5·01; N，6.05。製備例3. 2-(氯甲基）-N-((4-氯苯基）甲基）-7-[(2,2-二甲基-1，3-二哼茂燒-4-基）甲基]-4,7-二氫-4-氧代違吩并[2,3-b]p比淀-5-叛醯馨胺將2,4,6-可力啶（1.78毫升）及少許4-N，N-二甲基胺基吡啶結晶添加於含N-(4-氯芊基）-7-((2,2-二甲基·1，3-二噚茂烷 -4-基）甲基）-2-(經基甲基）-4-氧代-4,7-二氫碟吩并[2,3-b]外匕啶-5-羧醯胺（製備例2，2.33克）之DMF(15毫升）溶液中。滴加甲烷磺醯氯（0.93毫升），且使反應在室溫下攪拌4小時。蒸發溶劑且將殘留物溶於10%MeOH/CH2Cl2中。混合物以水洗滌，經脫水（MgSCU)、過濾且濃縮。殘留物以管柱層析 87731 -44- 200410970 (CH^Cl2/甲醇，95/5)純化。粗產物自Et〇Ac結晶，經過濾且以***洗務’獲得1.73克白色結晶標題化合物。物理特徵： H NMR (400 MHz，DMSO-d6)3 10.42, 8.73, 7·55, 7.39, 7.34， 5.15，4.54，4.51，4.30，4.14，3·77，1.34，1.23; HRMS (FAB) m/z 481.075 8 (Μ+Η)+。分析實測值：c，55·18; Η，4 76; ν， 5.66。製備例4. Ν·(4-氯芊基）-2-(羥基甲基）_4_氧代-7_(3气四氫-211-吡喃-2· 基氧基）丙基）-4,7-二氫嘧吩并[2,3_b]吡啶羧醯胺將碳酸铯（5.54克）添加於含>^(4-氯苄基）-4-羥基-2_(羥基甲基）嘧吩并[2,3-b]吡啶-5-羧醯胺（5.23克，如美國專利第 6,239，142號中所述般製備）及2_(3-碘丙氧基）四氫吡喃 (4.32克，藉由混合等莫耳量之2_碘丙醇及3,4_二氫_2Η_吡喃製備）之DMF(20毫升）溶液中。混合物於6〇t加熱4小時。蒸發溶劑且將殘留物溶於10%Me〇H/CH2Cl2中。混合物以水洗滌，有機層經脫水（MgSCU)、過濾且濃縮。粗產物以管柱層籲析（CH2C12/甲醇，95/5)純化，接著自Et〇Ac再結晶，獲得4·82 克白色結晶標題化合物。物理特徵：iH Nmr (4〇〇 ΜΗζ， DMS〇.d6)6 l〇.55? 8.71? 7.39, 7.33, 7.29, 5.79, 4.705 4.53, 4.49’ 4.38, 3.68, 3.37, 2·11，ΐ·63, 1.53, 1.40; MS (El) m/z 490 (]^);分析實測值{，58.74;11，5.66;队561。製備例5. N-(4-氯苄基）-2-(氯甲基）_4_氧代_7-(3_(四氫·2H_吡喃·2-基氧基）丙基）-4,7-二氫嘍吩并[2,3-b]吡啶-5-羧醯胺 87731 -45 - 200410970 將2,4,6-可力啶（2_51毫升）及少許4-N，N-二甲基胺基p比淀結晶添加於含N-(4 -氯爷基）-2-(經基甲基）_4_氧代-7-(3-(四氫-2H-峨喃-2-基氧基）丙基）-4,7-二氫u塞吩并[2,3-b]!?比淀- 5· 羧醯胺（製備例4，4.0克）之DMF(20毫升）溶液中。滴加甲燒磺醯氯（1.38毫升），且使反應在60°C下攪拌5小時。蒸發溶劑且將殘留物溶於10%MeOH/CH2Cl2中。混合物以水洗〉條，有機層經脫水（MgSCU)、過濾且濃縮。殘留物以管柱層析 (CHWl2/甲醇，95/5)純化。粗產物自EtOAc結晶，經過減且以乙酸洗務，獲仔2 _ 3 5克白色結晶標題化合物。物理特徵：〖H NMR (400 MHz，DMSO_d6)5 10.43, 8·74, 7·56, 7.39, 7.34, 5.15，4.54，4.38，3.70，3.38，2.11，1.61，1.51，1·38; MS (El) m/z 508 (M+); HRMS (FAB) m/z 509.1064 (Μ+Η)+。分析實測值：C，56.00; Η，5.11; Ν，5.56。製備例6. Ν-(4-氯芊基）-2-(羥基甲基）_4·氧代_7_(2兴四氫_2Η•吡喃_2_ 基氧基）乙基）-4,7- 一風違吩并[2,3-1)]峨淀-5-幾酿胺將奴绝（3.91克）添加於含ν-(4-氯苄基）-4-幾基_2-(幾基甲基）噻吩并[2,3-b]吡啶-5_羧醯胺（3·49克，如美國專利第 6,239，142號中所述般製備）及2_(2_碘乙氧基）四氫_2Η_吡喃 (2.56克，藉由混合等莫耳量之2_碘乙醇及3,4_二氫_2]^_吡喃製備）之DMF(20*升）溶液中。反應混合物於1〇〇艽下攪拌小時。瘵發落劑且將殘留物溶於1〇%CH3〇H/CH2C12中。混合物以水洗滌，有機層經脫水（MgS〇4)、過濾且濃縮。粗產物自EtOAc結晶，獲得3.8克白色固態標題化合物。物理特 87731 -46 - 200410970 徵：4 NMR (400 MHz，DMSO-d6)S 10.59, 8.71，7.39, 7.38， 7.29, 5.79, 4.69, 4.58, 4.54, 4.48, 3.96, 3.78, 3.30, 1.54, 1.39， 1.29; MS (El) m/z 476 (M+); HRMS (FAB) m/z 477.1245 (M+ H)+ 〇製備例7. N-(4-氯苄基）-2-(氯甲基）·4-氧代-7-(2-(四氫-2Η·ρ比喃-2-基氧基）乙基）-4,7-二氫嘍吩并[2,3-b]吡啶-5-羧醯胺將2,4,6-可力啶（2.9毫升）及少許4-N，N-二甲基胺基吡啶結晶添加於含N-(4-氯苄基）-2-(羥基甲基）-4-氧代-7-(2-(四 ® 氫-2H-吡喃-2-基氧基）乙基）-4,7-二氫噻吩并[2,3-b]吡啶-5-幾醯胺（製備例6，3.5克）之DMF(20毫升）溶液中。滴加甲烷磺酿氯（1.7毫升），且使反應在室溫下攪拌72小時。將反應混合物倒入水（1 〇〇毫升）中且過濾。濾液以丨0〇/QMeOH/CH2Cl2 萃取。有機層經脫水（MgS04)、過濾且濃縮，獲得2.8克白色固態標題化合物。物理特徵：4 NMR (400 MHz， DMSO-d6)8 10.43，8_75，7.55，7_38，7.33，5·14，4.59，4.53， φ 4.49, 3.96, 3.79, 3.29, 1.52, 1.38, 1.28; MS (El) m/z 494 (M+); HRMS (FAB) m/z 495·〇9〇4 (m+H)+。製備例8. N-(4-氯；基）_2_(氯甲基）_7-(2_羥基乙基）_‘氧代4,7_二氫嘧吩并[2,3-b]吡啶-5-羧醯胺將2,4,6-可力啶（2·9毫升）及少許4_n，N-二甲基胺基吡啶結晶添加於含N-(4-氯苄基）-2-(羥基甲基）-4-氧代_7_(2-(四氫-2H—比喃_2_基氧基）乙基）-4,7_二氫嘧吩并[2,3_b]吨啶_5- 87731 -47- 200410970 羧醯胺（製備例6，3.5克）之DMF(20毫升）溶液中。滴加甲烷磺醯氯（1·7毫升），且使反應在室溫下攪拌72小時。將反應混合物倒入水（100毫升）中且過濾。固體自乙腈再結晶，獲得1.27克白色固態標題化合物。物理特徵·· 1h NMR (400 MHz，DMSO-d6)5 10.47，8·67，7.55，7.40，7.34，5.15，5.14， 4.54，3.34，2.51; MS (El) m/z 410 (M+); HRMS (FAB) m/z 411.0332 (M+H)+。分析實測值：c，52.27; H，4·05; N，6.93。製備例9. N-(4-氯苄基）-7-乙基-2-(羥基甲基）_4_氧代_4,7_二氫嘧吩并 · [2,3-b]#b途-5-叛酸胺將敌fei鉀（0.87克）及？典乙燒（〇·5毫升）添加於含N-(4-氯；基）-4-輕基-2-(羥基甲基）嘧吩并[2,3_b]吡啶羧醯胺（2 〇克’如美國專利第6,239，142號中所述般製備）之無水DMF(60 愛升）溶液中。反應混合物於室溫攪拌18小時。混合物以水 (150毫升）稀釋且過濾。所得白色粉末以水（15毫升）洗滌，接著以***（15毫升）洗滌且於真空烘箱中乾燥，獲得L64克籲白色固態標題化合物。物理特徵：Μ.ρ· 169-172°C ; 4 NMR (300 MHz，DMSO-d6)5 10.65，8.74，7.37，7.29，5.81，4.70， 4.54, 4·32, 1.44; HRMS (FAB) m/z 377.0720 (M+H)+。分析實測值：C，56·87; H，4·77; N，7.38; Cl，9.35; S，8.44。製備例10. N-(4-氯苄基）_2_(氯甲基乙基_4•氧代-4,7_二氫嘧吩并 [2,3-b]吡啶_5_羧醯胺 4_N，N-二甲基胺基吡啶（80毫克）、2,4,6·可力啶（1.41毫升） 87731 -48- 200410970 及甲烷磺醯氯（0.83毫升）添加於含N-(4-氯苄基）_7_乙基 -2-(¾基曱基）-4-氧代-4,7-二氫π塞吩并[2,3-b]e比淀_5_叛酿胺（製備例9, 1.61克）之無水DMF(80毫升）溶液中，反應混合物於室溫下擾摔24小時。混合物以水（150毫升）稀釋且過濾。所得白色粉末自乙腈再結晶且於真空烘箱中乾燥，獲得1.4克白色固態標題化合物。物理特徵：Μ·ρ· 199-200。(：； 4 NMR (300 MHz，DMSO-d6)5 10.45，8.77，7.57，7.38，5.15, 4.54, 4.32, 1.44。分析實測值：c，54·53; H，3.94; Ν，7·03; Cl， ^.574 8.09° 製備例11. N-(4-氯苄基）-7-丙基(羥基甲基）_4_氧代_4J_二氫嘧吩并 [2,3-b]吡啶-5-叛醯胺將碳酸鉀（0.91克）及丨_碘丙烷（0·64毫升）添加於含1^_(扣氯苄基Μ·羥基-2-(羥基曱基）嘧吩并U，3-b]吡啶-5-羧醯胺 (2.0克，如美國專利第6,239，142號中所述般製備）之無水 DMF(60毫升）溶液中。反應混合物於室溫下搅拌*小時。混合物以水（150毫升）稀釋且過遽。所得白色粉末以水（15毫升）洗條接著以***（15毫升）洗務，且在真空烘箱中乾燥，獲得 173克白色固態標題化合物。物理特徵：M.p. 乃乞；a NMR (3〇〇 MHz，DMS〇_d6)s 1〇呤 8 ' 7 % 7 ”，$ 8〇, ，4.55, 4.27, 1.87, G.89;分析實測值：c，58 2(); H，4 96; N 7.^0^8.985 8,8.16 0 製備例12. N-(‘氯苄基）_2-(氯甲基）_7•丙基 •‘氧代-4,7-二氫噻吩并 87731 -49- 200410970 [2,3-b]吡啶-5-羧醯胺 4-N，N - 一甲基胺基117比淀（80¾克）、2,4,6-可力淀（ι·39毫升）及甲氣（〇·81毫升）添加於含Ν-(4-氯节基丙基 2_(#至基甲基）-4•氧代-4,7 -一氲T?塞吩并[2,3-b]P比淀·5-幾酸胺（製備例11，1.63克）之無水DMF(80毫升）溶液中，反應混合物於室溫下攪拌24小時。混合物以水（150毫升）稀釋且過攄。所得淡黃色粉末自乙腈再結晶且於真空烘箱中乾燥，獲得1.4克淡黃色固態標題化合物。物理特徵：Μ ρ· 186.5_ 188〇C ; lU NMR (300 MHz, DMSO-d6)5 10.45, 8.75, 7.56, 7.39 · 5· 15, 4.54, 4.27，1.85, 0.9卜分析實測值：c，55.76; H，4·59; N， 6.95; Cl，16.88; S，7.80。製備例13. N-(4-氯苄基）-2-(羥基甲基）-7-(2-甲氧基乙基）-4_氧代_4,7_ 一氧p塞吩并[2,3-b] ρ比淀-5-幾驢胺將碳酸鉀（5·〇克）及溴乙基甲基醚（5〇克）添加於含小(4_ 氯苄基）-4-羥基-2-(羥基甲基）嘧吩并[2,3_b]吡啶-5_羧醯胺 · (Π·4克，如美國專利第6,239，142號中所述般製備）之無水 DMF(350毫升）溶液中。反應混合物於室溫下攪拌18小時。混合物以水（600毫升）稀釋且過濾。所得白色粉末在真空烘相中乾燥’獲传8.44克白色固態標題化合物。物理特徵·· M.p. 193〇C ; lH NMR (300 MHz, DMSO-d6)6 10.58, 8.65, 7.375 7.29，5.82，4.70，4.54，4.47，3.76，3.24; HRMS (FAB) m/z 407.0836 (M+H)+。分析實測值：c，55 81; h，4.71; N，6.90; Cl， 8.58; S，7.81。 87731 -50- 200410970 製備例14. N_(4-氯苄基）-2-(氯甲基）-7-(2-甲氧基乙基）_‘氧代_4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺將4-N，N-二甲基胺基吡啶（360毫克）、2,4,6-可力啶（6.5毫升）及甲烷磺醯氯（3.8毫升）添加於含^^(4_氯芊基）_2-(羥基甲基）-7_(2·甲氧基乙基）-4_氧代-4,7-二氫嘧吩并[2,3-b]毗啶-5-羧醯胺（製備例13，8.0克）之無水DMF(360毫升）溶液中，反應混合物於室溫下攪拌18小時。混合物以水（6〇〇毫籲升）稀釋且過濾。所得固體於真空烘箱中乾燥，獲得7 〇3克灰白色固態標題化合物。物理特徵：Μ·ρ· 192-193 °C ; 4 NMR (300 MHz, DMSO-d6)5 10.48, 8.67, 7.55, 7.37, 5.14, 4.53，4.46，3.74，3.24; HRMS (FAB) m/z 425.0480 (M+H)+。分析貫測值：C，53.38; H，4.37; N，6.66; Cl，15.77; S，7.69。製備例15. 2-呋喃甲醯溴在(内溫）下，於1小時内將溴（6.5毫升）滴加於含2_乙醯 _ 基吱喃（11.0克）之二噚烷/Ε^Ο( 1/2，60毫升）溶液中。在使反應混合物升溫至室溫，且攪拌2小時。添加飽和氯化胺溶液 (7〇毫升）。移除有機層且以***（2X50毫升）萃取水層。合併之有機層經脫水（MgSCU)、過濾且真空濃縮。所得棕色固體以管柱層析（己烷/CHzCl2，70/30)純化，獲得7.996克黃色油狀標題化合物。物理特徵：iH NMR (400 MHz，DMSO-d6)S 8*〇9, 7·66-7·64, 6·79-6·77, 4·65。製備例16. 87731 -51 - 200410970 消旋-1-(2-呋喃基）-2-(甲基胺基）乙醇在0°C (内溫）下，將含2-呋喃甲醯溴（製備例15，7 5〇克） 4甲醇（40毫升）溶液滴加於含2 〇 M甲基胺之甲醇溶液（198 笔升）中。反應混合物在〇°C下攪拌3〇分鐘。接著滴加含硼氫化納（2.25克）之水（40毫升）溶液。反應混合物在下攪拌 30分鐘，接著以2 NHC1溶液（pH為3-4)終止反應。真空濃縮反應混合物，移除甲醇，接著倒入冰冷Et〇Ac(2〇〇毫升）/2 N NaOH(100毫升）中。移除有機層。水層以2 n NaOH溶液調整至pH為12，且以EtOAc(3 X 200毫升）萃取。合併之有機層經脫水（MgS〇4)、過濾且真空濃縮。所得棕色油狀物以管柱層析（(：11€：13/甲醇，95/5;(：11(：13/甲醇/!^4〇11，90/10/1)純化，獲得2.06克棕色油狀標題化合物。物理特徵：NMR (400 MHz5 DMSO-d6)8 7.56, 6.39-6.37, 6.26-6.25, 5.15, 4.62-4.58, 2.77-2.66, 2.33; MS (ESI+) m/z 142 (M+H)+ 〇製備例17. (1R)_ 1-(2-呋喃基）-2-(甲基胺基）乙醇裝置上頭攪拌器、回流冷凝器、溫度計及添加漏斗之250 毫升圓底瓶中加入（R)-2-胺基-1_(2-咬喃基）乙醇（1〇克）及第三丁氧化鉀（10.6克）。在使溫度維持在50°C以下之速率下加入無水DMF。反應加熱至80°C (内溫），於添加漏斗中加入碳酸二甲酯（50毫升），且將液體滴加於反應中。當碳酸二甲酯滴加完成後，將溫度上升至回流（約100°C )且維持約12小時。反應混合物冷卻至60°C以下，倒入水（100毫升）中，且以乙酸異丙酯（1〇〇毫升）萃取。使層分離，且以額外之乙酸 87731 -52- 200410970 異丙酯（2 X 100毫升）萃取。合併之有基層以水（100毫升）洗滌，且以硫酸鈉及鎂溶膠（magnesol)脫水1〇分鐘。經真空過滤移除固體’且有機層於真空中濃縮。所得油狀物自MTBE (2毫升/克）結晶，獲得10.25克（SR)-5-(2-呋喃基）·3-甲基_1，3_ 呤唑啉啶-2-酮。物理特徵：iH NMR (CDC13, 400 ΜΗζ) δ 7.46, 6.49, 6.39, 5.47, 3.78, 2.97。裝置上頭攪拌器、回流冷凝器及氮氣輸入口之圓底瓶中加入（5R)_5-(2-呋喃基>3·甲基」，3-哼唑啉啶-2-酮（471 克）。添加1 Μ KOH溶液（987毫升），且使所得溶液於5〇°C下加熱。完全後於瓶中注入NaCl(310克）及MTBE(470毫升）。分離水層且以MTBE(470毫升）及CH2C12(23毫升）溶液進一步萃取二次。合併之有機層經脫水（MgS〇4)、過爐且濃縮，獲得38.0克標題化合物。物理特徵：iH NMR (DMSO，400Table 1 Example polymerase K: 50 (μM) HCMV HSV VZV 1 0.08 0.22 0.06 2 0.04 0.09 0.03 3 0.07 0.26 0.13 4 0.25 0.84 0.39 5 0.01 0.03 0.01 6 0.17 0.47 0.15 7 0.30 0.98 0.33 8 0.26 0.85 0.32 9 1.06 Not determined Not determined 10 0.45 1.97 0.44 11 0.09 0.20 0.09 12 0.28 Not determined Not determined 13 0.17 1.92 0.44 14 0.10 0.53 0.12 15 0.24 Not determined Not determined 16 0.20 0.45 0.19 17 0.12 0.39 0.11 18 0.35 0.91 0.37 19 0.21 0.78 0.29 20 0.22 0.46 0.20 21 0.35 Not determined Not determined 87731 -41-200410970 Example polymerase K: 50 (μM) HCMV HSV VZV 22 0.09 0.17 0.08 23 0.26 Not determined Not determined 24 1.31 Not determined Not determined 25 1.80 Not determined Not determined 26 0.15 0.54 0.33 27 0.36 0.59 0.28 28 0.30 Not determined Not determined 29 0.60 Not determined Not determined 30 0.14 0.62 0.20 31 0.07 0.12 0.06 32 0.18 0.74 0.22 33 0.02 0.08 Not determined 34 0.24 1.08 0.34 35 0.56 Not determined Not determined 36 0.83 Not determined Non-determined examples Preparation Example 1. N- (4-Ga + yl) -2- (Gamethyl) -7-methyl_4_oxo-4,7-dihydroρ Sepheno [2,3-b] pyridine-5-carboxamidine Procedure A · N- (4-chlorofluorenyl) -2- (mylmethyl) -7-methyl-4_oxo- 4,7_ Dihydropyrido [2,3-b] pyridine-5-carboxamide (3.00 g, prepared as described in U.S. Patent No. 6,239,142) was dissolved in DMF (150 ml). 87731 -42- 200410970 DMAP (0.150 g), 2,4,6-collidine (2.73 ml) and methanesulfonyl chloride (1.60 ml) were added and the reaction mixture was allowed to stand at room temperature Stir for 18 hours. The reaction mixture was poured into water (300 ml). The obtained pale yellow solid was filtered and dispersed in acetonitrile to obtain 2.75 g of the title compound. Physical characteristics ·· M · ρ · 250-256 ° C (decomposition); NMR (400 MHz, DMSO-d6) S 10.48, 8.74, 7.58, 7.41- 7.33, 5.16, 4.55, 3.97; 13C NMR (DMSO-d6 ) 5 172.5, 164.5, 151.8, 146.4, 138.9, 135.7, 131.7, 130.5, 129.5, 128.7, 124.0, 115.0, 43.4, 41.8, 41.1; MS (El) m / z 380 (M +); HRMS (FAB) m / z 381.0255 (M + H) +. Anal. Found: C, 53.34; H, 3.70; N, 7.30; Cl, 17.91; S, 8.51. Procedure B. Add N- (4-chloroethenyl) -7-methyl-2- (morpholin-4-ylmethyl) -4-oxo-4,7- Dihydropyrido [2,3-b] pyridine-5-benzidineamine (1-00 g, prepared as described in US Patent No. 6,239,142) and aerosol (10 ml). Under nitrogen with stirring, ethyl chloroformate (0.55 ml) was added by injection. The slurry was heated to reflux overnight. Anhydrous diethyl ether (10 ml) was added to the slurry under nitrogen with stirring. The solid was filtered and washed with ether (3 X 10 mL). The product was dried in a vacuum oven at 40 ° C to obtain 0.93 g of the title compound as colorless crystals. Physical characteristics: 4 NMR (400 MHz, TFA-d) 5 9.09, 7.69, 7.22, 4.81, 4.62, 4.27; 13C NMR (100 MHz, TFA-d) δ 167.6, 166.6, 156.3, 145.2, 143.6, 134.9, 133.3 , 129.1, 129.0, 127.4, 119.6, 109.9, 45.2, 44.0, 38.0. Analytical measured values: C, 53 · 44; H, 3.66; N, 7.35; C1, 18 · 29. Production Example 2. Ν- (4-chlorobenzyl) -7-((2,2-dimethyl-fluorene, 3-difluorenyl-4_yl) methyl 87731 -43- 200410970 group) -2- (Hydroxy-methyll-4-oxo-4,7-dihydrofluoreno [2,3-b] pyridine-5-carboxamidine) Cesium carbonate (3.91 g) was added to N- ( 4-chlorobenzyl) _4-hydroxy-2- (hydroxymethyl) pyreno [2,3-b] pyridin-5-carboxamidine (3.49 g, as described in US Patent No. 6,239,142 (Preparation) and 4- (bromomethyl) _2,2-dimethyl-1,3-diisopropanol (1.95 g) in DMF (20 ml). The reaction mixture was allowed to stand at 100 ° Stir for 17 hours at C. Solvent was evaporated and the residue was dissolved in 10% ch3OH / CH2C12. The mixture was washed with water, the organic layer was dehydrated (MgS04), filtered and concentrated. The crude product was crystallized from EtOAc to give 2.7 g of the title as a white solid Chemical compound. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) S 10.53, 8.70, 7.40, 7.34, 7.28, 5.79, 4.69, 4.53, 4.50, 4.30, 4.14, 3.77, 1.34, 1.23 MS (El) m / z 462 (M +); HRMS (FAB) m / z 463.1087 (M + H) +. Analytical measured values: C, 57.07; H, 5.01; N, 6.05. Preparation Example 3.2 -(Chloromethyl) -N-((4-chloro Methyl) -7-[(2,2-dimethyl-1,3-dihumocen-4-yl) methyl] -4,7-dihydro-4-oxobenzo [ 2,3-b] p biyodo-5-benzidineamine added 2,4,6-collidine (1.78 ml) and a little 4-N, N-dimethylaminopyridine to N-containing (4-chlorofluorenyl) -7-((2,2-dimethyl · 1,3-difluorenyl-4-yl) methyl) -2- (transmethyl) -4-oxo -4,7-dihydrodipheno [2,3-b] exordin-5-carboxamide (Preparation Example 2, 2.33 g) in a solution of DMF (15 ml). Methanesulfonyl chloride ( 0.93 mL), and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was dissolved in 10% MeOH / CH2Cl2. The mixture was washed with water, dehydrated (MgSCU), filtered and concentrated. The residue was columned Chromatography 87731 -44- 200410970 (CH ^ Cl2 / methanol, 95/5). The crude product was crystallized from EtoAc, filtered and washed with ether to obtain 1.73 g of the title compound as white crystals. Physical characteristics: H NMR ( 400 MHz, DMSO-d6) 3 10.42, 8.73, 7.55, 7.39, 7.34, 5.15, 4.54, 4.51, 4.30, 4.14, 3.77, 1.34, 1.23; HRMS (FAB) m / z 481.075 8 (Μ + Η) +. Analytical measured values: c, 55 · 18; 4, 4 76; ν, 5.66. Preparation Example 4. Ν · (4-chlorofluorenyl) -2- (hydroxymethyl) _4_oxo-7_ (3-gastetrahydro-211-pyran-2-yloxy) propyl) -4, 7-Dihydropyrimido [2,3_b] pyridinecarboxamide Add cesium carbonate (5.54 g) to a compound containing> ^ (4-chlorobenzyl) -4-hydroxy-2_ (hydroxymethyl) pyrimido [2,3-b] pyridine-5-carboxamide (5.23 g, prepared as described in US Patent No. 6,239,142) and 2- (3-iodopropoxy) tetrahydropyran (4.32 g, Prepared by mixing equimolar amounts of 2-iodopropanol and 3,4_dihydro_2Η_pyran) in DMF (20 ml). The mixture was heated at 60 t for 4 hours. The solvent was evaporated and the residue was dissolved in 10% MeOH / CH2Cl2. The mixture was washed with water, and the organic layer was dehydrated (MgSCU), filtered, and concentrated. The crude product was purified by column chromatography (CH2C12 / methanol, 95/5) and then recrystallized from EtoAc to obtain 4.82 g of the title compound as white crystals. Physical characteristics: iH Nmr (4〇ΜΗζ, DMS〇.d6) 6 l0.55? 8.71? 7.39, 7.33, 7.29, 5.79, 4.705 4.53, 4.49 '4.38, 3.68, 3.37, 2.11, ΐ63 , 1.53, 1.40; MS (El) m / z 490 (] ^); Analytical measured values {, 58.74; 11, 5.66; team 561. Production Example 5. N- (4-chlorobenzyl) -2- (chloromethyl) _4_oxo_7- (3_ (tetrahydro · 2H_pyran · 2-yloxy) propyl) -4 , 7-Dihydropyreno [2,3-b] pyridine-5-carboxamidine 87731 -45-200410970 2,4,6-collidine (2_51 ml) and a little 4-N, N-di Methylamino group p ratio crystal added to N- (4-chloromethyl) -2- (transmethyl group) _4-oxo-7- (3- (tetrahydro-2H-anan-2- Alkoxy) propyl) -4,7-dihydrouthiopheno [2,3-b] !? Pyodo-5 · Carboxamide (Preparation Example 4, 4.0 g) in DMF (20 ml) in. Toluenesulfonyl chloride (1.38 ml) was added dropwise, and the reaction was stirred at 60 ° C for 5 hours. The solvent was evaporated and the residue was dissolved in 10% MeOH / CH2Cl2. The mixture was washed with water, and the organic layer was dehydrated (MgSCU), filtered, and concentrated. The residue was purified by column chromatography (CHWl2 / methanol, 95/5). The crude product was crystallized from EtOAc, and washed with acetic acid to obtain 2 to 3 5 g of the title compound as white crystals. Physical characteristics: 〖H NMR (400 MHz, DMSO_d6) 5 10.43, 8.74, 7.56, 7.39, 7.34, 5.15, 4.54, 4.38, 3.70, 3.38, 2.11, 1.61, 1.51, 1.38; MS (El ) m / z 508 (M +); HRMS (FAB) m / z 509.1064 (Μ + Η) +. Analytical measured values: C, 56.00; H, 5.11; N, 5.56. Production Example 6. Ν- (4-chlorofluorenyl) -2- (hydroxymethyl) _4 · oxo_7_ (2xtetrahydro_2Η • pyran_2_yloxy) ethyl) -4,7 -Yifeng violates pheno [2,3-1)] Edian-5-chimonamine to add pungent (3.91 g) to the compound containing ν- (4-chlorobenzyl) -4-guiline_2- ( Isopropylmethyl) thieno [2,3-b] pyridine-5-carboxamide (3.49 g, prepared as described in US Patent No. 6,239,142) and 2- (2-iodoethoxy) ) Tetrahydro_2Η_pyran (2.56 g, prepared by mixing equal molar amounts of 2-iodoethanol and 3,4_dihydro_2] ^ _ pyran) in DMF (20 * L) solution. The reaction mixture was stirred at 100 ° C for hours. The agent was quenched and the residue was dissolved in 10% CH3OH / CH2C12. The mixture was washed with water, and the organic layer was dehydrated (MgS04), filtered, and concentrated. The crude product was crystallized from EtOAc to give 3.8 g of the title compound as a white solid. Physical characteristics 87731 -46-200410970 Signs: 4 NMR (400 MHz, DMSO-d6) S 10.59, 8.71, 7.39, 7.38, 7.29, 5.79, 4.69, 4.58, 4.54, 4.48, 3.96, 3.78, 3.30, 1.54, 1.39, 1.29; MS (El) m / z 476 (M +); HRMS (FAB) m / z 477.1245 (M + H) + 〇 Preparation Example 7. N- (4-chlorobenzyl) -2- (chloromethyl) · 4-oxo-7- (2- (tetrahydro-2Η · ρbiran-2-yloxy) ethyl) -4,7-dihydrofluoreno [2,3-b] pyridine-5- Carboxamide. 2,4,6-collidine (2.9 ml) and a few crystals of 4-N, N-dimethylaminopyridine were added to N- (4-chlorobenzyl) -2- (hydroxymethyl) ) -4-oxo-7- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4,7-dihydrothieno [2,3-b] pyridine- 5-Chloramine (Preparation Example 6, 3.5 g) in DMF (20 ml). Methanesulfonyl chloride (1.7 ml) was added dropwise, and the reaction was stirred at room temperature for 72 hours. The reaction mixture was poured into water (100 mL) and filtered. The filtrate was extracted with 0 / QMeOH / CH2Cl2. The organic layer was dehydrated (MgS04), filtered and concentrated to obtain 2.8 g of the title compound as a white solid. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 8 10.43, 8_75, 7.55, 7_38, 7.33, 5.14, 4.59, 4.53, φ 4.49, 3.96, 3.79, 3.29, 1.52, 1.38, 1.28; MS (El ) m / z 494 (M +); HRMS (FAB) m / z 4950.090 (m + H) +. Production Example 8. N- (4-chloro; yl) _2_ (chloromethyl) _7- (2_hydroxyethyl) _ 'oxo 4,7_dihydropyrido [2,3-b] pyridine- 5-Carboxamidine Added 2,4,6-collidine (2.9 ml) and a little 4_n, N-dimethylaminopyridine to N- (4-chlorobenzyl) -2- ( Hydroxymethyl) -4-oxo_7_ (2- (tetrahydro-2H-biran_2_yloxy) ethyl) -4,7_dihydropyrido [2,3_b] xantidine_ 5- 87731 -47- 200410970 in a solution of Carboxamide (Preparation Example 6, 3.5 g) in DMF (20 ml). Methanesulfonyl chloride (1.7 ml) was added dropwise, and the reaction was stirred at room temperature for 72 hours. The reaction mixture was poured into water (100 ml) and filtered. The solid was recrystallized from acetonitrile to obtain 1.27 g of the title compound as a white solid. Physical characteristics · 1h NMR (400 MHz, DMSO-d6) 5 10.47, 8.67, 7.55, 7.40, 7.34, 5.15, 5.14, 4.54, 3.34, 2.51; MS (El) m / z 410 (M +); HRMS (FAB) m / z 411.0332 (M + H) +. Analytical measured values: c, 52.27; H, 4.05; N, 6.93. Preparation Example 9. N- (4-chlorobenzyl) -7-ethyl-2- (hydroxymethyl) _4_oxo_4,7_dihydropyrimido · [2,3-b] #b Tu-5-metamidine will be enemy potassium (0.87 g) and? Ethane (0.5 ml) was added to N- (4-chloro; yl) -4-lightyl-2- (hydroxymethyl) pyreno [2,3_b] pyridinecarboxamide (2.0 g) 'In anhydrous DMF (60 liters) solution prepared as described in U.S. Patent No. 6,239,142. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (150 mL) and filtered. The resulting white powder was washed with water (15 ml), then with diethyl ether (15 ml) and dried in a vacuum oven to obtain L64 g of the title compound as a white solid. Physical characteristics: M.ρ · 169-172 ° C; 4 NMR (300 MHz, DMSO-d6) 5 10.65, 8.74, 7.37, 7.29, 5.81, 4.70, 4.54, 4.32, 1.44; HRMS (FAB) m / z 377.0720 (M + H) +. Anal. Found: C, 56 · 87; H, 4.77; N, 7.38; Cl, 9.35; S, 8.44. Production Example 10. N- (4-chlorobenzyl) _2_ (chloromethylethyl_4 • oxo-4,7_dihydropyridino [2,3-b] pyridine_5_carboxyamidamine 4_N , N-dimethylaminopyridine (80 mg), 2,4,6 · colidine (1.41 ml) 87731 -48- 200410970 and methanesulfonyl chloride (0.83 ml) were added to N- (4-chloro Benzyl) _7_ethyl-2- (¾ylfluorenyl) -4-oxo-4,7-dihydroπ thiopheno [2,3-b] ebiyodo_5_Beramine (Preparation Example 9, 1.61 g) of anhydrous DMF (80 ml) solution, the reaction mixture was shaken at room temperature for 24 hours. The mixture was diluted with water (150 ml) and filtered. The white powder obtained was recrystallized from acetonitrile and placed in a vacuum oven. Dry to obtain 1.4 g of the title compound as a white solid. Physical characteristics: M · ρ · 199-200. (:; 4 NMR (300 MHz, DMSO-d6) 5 10.45, 8.77, 7.57, 7.38, 5.15, 4.54, 4.32, 1.44 Analytical measured values: c, 54 · 53; H, 3.94; N, 7.03; Cl, ^ .574 8.09 ° Preparation Example 11. N- (4-chlorobenzyl) -7-propyl (hydroxymethyl) ) _4_oxo_4J_Dihydropyrido [2,3-b] pyridine-5-benzidineamine Potassium carbonate (0.91 g) and 丨 _iodopropane (0.64 ml) were added to a mixture containing 1 ^ _ ( Anhydrous chlorobenzyl M · hydroxy-2- (hydroxyfluorenyl) pyridino U, 3-b] pyridine-5-carboxamide (2.0 g, prepared as described in US Patent No. 6,239,142) DMF (60 ml) solution. The reaction mixture was stirred at room temperature for * hours. The mixture was diluted with water (150 ml) and washed. The resulting white powder was washed with water (15 ml) and washed with ether (15 ml). , And dried in a vacuum oven to obtain 173 g of the title compound as a white solid. Physical characteristics: Mp Naiqi; a NMR (300 MHz, DMS〇_d6) s 10 sulfonate 8 '7% 7 ", $ 80. ,, 4.55, 4.27, 1.87, G.89; Analytical measured values: c, 58 2 (); H, 4 96; N 7. ^ 0 ^ 8.985 8,8.16 0 Preparation Example 12. N-('chlorobenzyl ) _2- (chloromethyl) _7 • propyl • 'oxo-4,7-dihydrothieno 87731 -49- 200410970 [2,3-b] pyridine-5-carboxamide 4-N, N- Monomethylamino group 117 (80¾ g), 2,4,6-colloid (ι · 39 ml) and methyl chloride (0.81 ml) were added to N- (4-chlorobenzylpropyl) 2 _ (# to phenylmethyl) -4 • oxo-4,7-monofluorene T? Thiopheno [2,3-b] P ratio yodo-5-amine (Preparation Example 11, 1.63 g Solution, the reaction mixture was stirred in dry DMF (80 ml) at room temperature for 24 hours. The mixture was diluted with water (150 ml) and filtered. The resulting pale yellow powder was recrystallized from acetonitrile and dried in a vacuum oven to obtain 1.4 g of the title compound as a pale yellow solid. Physical characteristics: M ρ · 186.5_ 188 ° C; 1U NMR (300 MHz, DMSO-d6) 5 10.45, 8.75, 7.56, 7.39 · 5. · 15, 4.54, 4.27, 1.85, 0.9. Analytical measured values: c, 55.76 H, 4.59; N, 6.95; Cl, 16.88; S, 7.80. Production Example 13. N- (4-chlorobenzyl) -2- (hydroxymethyl) -7- (2-methoxyethyl) -4_oxo_4,7_ monooxyp-pheno [2 , 3-b] ρ Biyodo-5-chitanylamine Potassium carbonate (5.0 g) and bromoethyl methyl ether (50 g) were added to a solution containing small (4-chlorobenzyl) -4-hydroxy- 2- (Hydroxymethyl) pyrimido [2,3_b] pyridine-5_carboxamidine (4 g, prepared as described in US Patent No. 6,239,142), anhydrous DMF (350 ml) In solution. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (600 mL) and filtered. The white powder obtained was dried in a vacuum baking phase to obtain 8.44 g of the title compound as a white solid. Physical characteristicsMp 193 ° C; lH NMR (300 MHz, DMSO-d6) 6 10.58, 8.65, 7.375 7.29, 5.82, 4.70, 4.54, 4.47, 3.76, 3.24; HRMS (FAB) m / z 407.0836 (M + H) +. Anal. Found: c, 55 81; h, 4.71; N, 6.90; Cl, 8.58; S, 7.81. 87731 -50- 200410970 Preparation Example 14. N_ (4-chlorobenzyl) -2- (chloromethyl) -7- (2-methoxyethyl) _ 'oxo_4,7-dihydropyrimidine Benzo [2,3-b] pyridine-5-carboxamidinate 4-N, N-dimethylaminopyridine (360 mg), 2,4,6-collidine (6.5 ml) and methanesulfonium Chlorine (3.8 ml) was added to the compound containing ^^ (4-chlorofluorenyl) _2- (hydroxymethyl) -7_ (2 · methoxyethyl) -4_oxo-4,7-dihydropyridino In a solution of [2,3-b] pyrimidin-5-carboxamide (Preparation Example 13, 8.0 g) in anhydrous DMF (360 ml), the reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (600 mL) and filtered. The obtained solid was dried in a vacuum oven to obtain 703 g of the title compound as an off-white solid. Physical characteristics: M · ρ · 192-193 ° C; 4 NMR (300 MHz, DMSO-d6) 5 10.48, 8.67, 7.55, 7.37, 5.14, 4.53, 4.46, 3.74, 3.24; HRMS (FAB) m / z 425.0480 (M + H) +. Analytical measured values: C, 53.38; H, 4.37; N, 6.66; Cl, 15.77; S, 7.69. Preparation Example 15. 2-Furanmethylpyrrolium bromide (6.5 ml) was added dropwise to dioxane / E ^ containing 2-ethylacetic acid sulfan (11.0 g) over 1 hour at (internal temperature) 0 (1/2, 60 ml) solution. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. A saturated amine chloride solution (70 ml) was added. The organic layer was removed and the aqueous layer was extracted with ether (2 × 50 mL). The combined organic layers were dehydrated (MgSCU), filtered and concentrated in vacuo. The obtained brown solid was purified by column chromatography (hexane / CHzCl2, 70/30) to obtain 7.996 g of the title compound as a yellow oil. Physical characteristics: iH NMR (400 MHz, DMSO-d6) S 8 * 〇9, 7.66-7 · 64, 6.79-6 · 77, 4.65. Preparation Example 16. 87731 -51-200410970 Racemic-1- (2-furyl) -2- (methylamino) ethanol at 0 ° C (internal temperature) Example 15, 750 g) 4 methanol (40 ml) solution was added dropwise to a methanol solution (198 liters) containing 200 M methylamine. The reaction mixture was stirred at 0 ° C for 30 minutes. A solution of sodium borohydride (2.25 g) in water (40 ml) was then added dropwise. The reaction mixture was stirred for 30 minutes, and then the reaction was terminated with a 2 NHC1 solution (pH 3-4). The reaction mixture was concentrated in vacuo, the methanol was removed, and then poured into ice-cold EtoAc (200 mL) / 2 N NaOH (100 mL). Remove the organic layer. The aqueous layer was adjusted to pH 12 with 2 n NaOH solution and extracted with EtOAc (3 x 200 mL). The combined organic layers were dehydrated (MgSO4), filtered and concentrated in vacuo. The obtained brown oil was purified by column chromatography ((: 11 €: 13 / methanol, 95/5; (: 11 (: 13 / methanol /! ^ 4〇11, 90/10/1) to obtain 2.06 g The title compound is a brown oil. Physical characteristics: NMR (400 MHz5 DMSO-d6) 8 7.56, 6.39-6.37, 6.26-6.25, 5.15, 4.62-4.58, 2.77-2.66, 2.33; MS (ESI +) m / z 142 (M + H) + 〇 Preparation Example 17. (1R) _ 1- (2-furanyl) -2- (methylamino) ethanol device with 250 ml round bottom stirrer, reflux condenser, thermometer and addition funnel Add (R) -2-amino-1- (2-benzyl) ethanol (10 g) and tertiary potassium butoxide (10.6 g) to the bottle. Add at a rate that keeps the temperature below 50 ° C Anhydrous DMF. The reaction was heated to 80 ° C (internal temperature), dimethyl carbonate (50 ml) was added to the addition funnel, and the liquid was added dropwise to the reaction. After the dropwise addition of dimethyl carbonate was completed, the temperature was increased. To reflux (about 100 ° C) and maintained for about 12 hours. The reaction mixture was cooled to below 60 ° C, poured into water (100 ml), and extracted with isopropyl acetate (100 ml). The layers were separated, With additional acetic acid 87731 -52- 200410970 Isopropyl ester (2 x 100 ml) extraction. The combined base layers were washed with water (100 ml) and dehydrated with sodium sulfate and magnesol for 10 minutes. The solids were removed by vacuum filtration and the organic layer was under vacuum The obtained oily substance was crystallized from MTBE (2 ml / g) to obtain 10.25 g of (SR) -5- (2-furyl) · 3-methyl_1,3-pyrazolinolin-2-one. Physical characteristics: iH NMR (CDC13, 400 ΜΗζ) δ 7.46, 6.49, 6.39, 5.47, 3.78, 2.97. Add the (5R) _5- (2) to the round bottom bottle of the stirrer, reflux condenser and nitrogen inlet on the device. -Furyl> 3.methyl ", 3-humazolin-2-one (471 g). 1 M KOH solution (987 ml) was added, and the resulting solution was heated at 50 ° C. After completion Fill the bottle with NaCl (310 g) and MTBE (470 ml). Separate the aqueous layer and extract twice with MTBE (470 ml) and CH2C12 (23 ml) solution. The combined organic layers are dehydrated (MgS04), Oven and concentrated to obtain 38.0 g of the title compound. Physical characteristics: iH NMR (DMSO, 400

ΜΗζ)δ 7.52, 6.36, 6.24, 4.60, 2.71，2.28; 13C NMR (DMSO, 100 ΜΗζ)δ 157.0, 141.6, 110.1，1〇5·6, 65.2, 56.2, 35·9; [a]22D =+34°(EtOH5 c=1.0) 〇製備例18. 2 -溴-1·(5 -甲基-2-吱喃基）乙酮在o°c(内溫）下，於1小時内將溴（5.丨毫升）滴加於含2_乙醯基-5-甲基呋喃（11.0克）之二噚烷/扮2〇(1/2，6〇毫升）溶液中。使反應混合物在0°C下攪拌30分鐘，再使其升溫至室溫’且稅摔18小時。使反應物冷卻至〇。厂「而、、n 皿），且滴加額外之溴（1·53毫升）。使反應混合物升溫 π '皿土至溫且攪拌1小時。添加飽和氯化胺溶液（100毫升）。移除有機層且以玢2〇(2 87731 -53- 200410970 xioo^：升）卒取水層。合併之有機層經脫水（MgS〇4)、過濾且真空濃縮。所得棕色固體以管柱層析（己烷/CH2C12，70/30) 純化’獲仔育色固體，其自Et0AC/己燒再結晶，獲得8·571 克標題化合物。物理特徵：M p 6〇_63t ; lfi NMr _ ΜΗζ， DMSO-d6)5 7·60，6.44，4.58，2.41。製備例19. 2-(甲基胺基）-1-(5-甲基_2_呋喃基）乙醇在〇°C (内溫）下將含2-溴-:^(5-甲基-2_呋喃基）乙酮（製備例18,8·00克）之甲醇（100毫升）溶液滴加於含2〇M甲基胺之籲甲醇溶液（197毫升）。反應混合物在〇χ：攪拌3〇分鐘。接著添加含硼氫化鈉（2.23克）之水（40毫升）溶液。反應混合物在〇 °C下攪拌1·5小時，接著以2 NHC1溶液（pH為3-4)終止反應。真空k縮反應混合物，移除甲醇，接著倒入冰冷Et〇Ac(2〇〇耄升）/2 N NaOH(100毫升）中。移除有機層。水層以2ΜΗζ) δ 7.52, 6.36, 6.24, 4.60, 2.71, 2.28; 13C NMR (DMSO, 100 ΜΗζ) δ 157.0, 141.6, 110.1, 10.5 · 6, 65.2, 56.2, 35 · 9; [a] 22D = + 34 ° (EtOH5 c = 1.0) 〇 Preparation Example 18. 2-Bromo-1 · (5-methyl-2-creanyl) ethanone at 0 ° C (internal temperature), bromine ( 5. ml) was added dropwise to a solution containing 2-acetamyl-5-methylfuran (11.0 g) in dioxane / 20 (1/2, 60 ml). The reaction mixture was allowed to stir at 0 ° C for 30 minutes, then allowed to warm to room temperature 'and the temperature was dropped for 18 hours. The reaction was allowed to cool to zero. And ", and n dishes), and additional bromine (1.53 ml) was added dropwise. The reaction mixture was warmed to a warm temperature and stirred for 1 hour. A saturated amine chloride solution (100 ml) was added. Remove The organic layer was extracted with 玢 20 (2 87731 -53- 200410970 xioo ^: liter). The combined organic layers were dehydrated (MgS04), filtered, and concentrated in vacuo. The resulting brown solid was subjected to column chromatography (hexane Alkane / CH2C12, 70/30) purified 'to obtain color solids, which were recrystallized from Et0AC / hexane, to obtain 8.571 g of the title compound. Physical characteristics: M p 6〇_63t; lfi NMr_MΗζ, DMSO- d6) 5 7 · 60, 6.44, 4.58, 2.41. Preparation Example 19. 2- (methylamino) -1- (5-methyl_2_furanyl) ethanol was added at 0 ° C (internal temperature). A solution of 2-bromo-: ^ (5-methyl-2_furanyl) ethanone (Preparation Example 18, 8.00 g) in methanol (100 ml) was added dropwise to methanol containing 20 M methylamine Solution (197 ml). The reaction mixture was stirred at 0x: 30 minutes. Then a solution of sodium borohydride (2.23 g) in water (40 ml) was added. The reaction mixture was stirred at 0 ° C for 1.5 hours, followed by 2 NHC1 solution The reaction was stopped (pH 3-4). The reaction mixture was kneaded in vacuo, the methanol was removed, and then poured into ice-cold EtOAc (200 liters) / 2 N NaOH (100 ml). The organic layer was removed. Water Layer with 2

N NaOH 溶液調整至pH為12，且以EtOAc(3 X 200毫升）萃取。合併之有機層經脫水（MgSCU)、過濾且真空濃縮。所得黃色油狀物馨以管柱層析（CHCh/甲醇，95/5，90/10 ; CHC13/甲醇/NH4OH， 90/10/1)純化’獲得1.88克黃色固態標題化合物。物理特徵： M.p. 40-45〇C ； lH NMR (400 MHz, DMSO-d6)5 6.11, 5.97-5.96, 5.05, 4.54-4.51, 2.72-2.65, 2.29, 2.22; MS (ESI+) m/z 156 (M+H)、製備例20. 1-(3-呋喃基）-2·(甲基胺基）乙醇將三甲基統破（20.4克）及3-糠酸（8.65毫升）添加於含氫氧 87731 -54- 200410970 化鉀（11·2克）及水（0.45毫升）之乙腈（150毫升）中。反應混合物加熱至60°C 2.5小時。使反應混合物冷卻至室溫。過濾沉澱物，且真空濃縮濾液。所得粗環氧化物（10.747克）溶於甲醇（50毫升）中，且添加含2.0 Μ甲基胺之甲醇溶液（1〇〇毫升）。反應混合物在室溫下攪拌3天，再加熱至回流3 〇分鐘。使反應混合物冷卻至室溫且真空濃縮。所得棕色油狀物以管柱層析（CHC13/甲醇，95/5，90/10 ; CHC13/甲醇/ΝΗ4ΟΗ， 90/10/1)純化，獲得2.703克黃色油狀標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6)S 7.56-7.55, 7.51，6.44, 5·07， _ 4.58-4.55, 2.62-2.56, 2.30; MS (ESI+) m/z 142 (M+H)+。製備例21. 1-(1-苯并呋喃-2-基）-2-(甲基胺基）乙醇將氫氧化钾（9.2克）及水（3.7毫升）添加於乙腈（125毫升）中。將苯并吱喃-2-甲酸（12·0克）溶於乙腈混合物中。添加三甲基锍碘（16.7克），且使混合物在60°C下攪拌3小時。反應混合物冷卻至室溫且過濾。滤液以***洗條且過滤。重複該程序直到不再有KI沉澱出為止。真空濃縮所得粗環氧化物，且溶於含2·0 Μ甲基胺之甲醇溶液（410毫升）中。使混合物在室溫下攪拌18小時，接著真空濃縮成棕色油。該油狀物以管柱層析（CHC13/甲醇，95/5，90/10 ; CHC13/甲醇 /NH4OH，89/10/1，79/20/1)純化，獲得3·0克灰白色固態標題化合物。物理特徵：4 NMR (300 MHz，DMSO_d60 7.59， 7.53, 7.24, 6.47, 5.62, 4.77, 2.83, 2·32。製備例22. 87731 -55- 200410970 2_(甲基胺基）-1-魂吩-2-基乙醇將噻吩-2-羧醛（8.5克）溶於乙腈（115毫升）中。添加三甲基锍碘（15.5克）、氫氧化鉀（8·5克）及水（3.4毫升），且使混合物在60 C下攪拌3小時。反應混合物冷卻至室溫且過濾。重複該製程直到不再沉澱ΚΙ為止。所得粗環氧化物以真空濃縮且使用Kugelrohr条飾裝置蒸顧（0.8 Torr，洪箱溫度5〇°c )。將粗環氧化物溶於含2_0 Μ甲基胺之甲醇溶液（152毫升）中。混合物室溫下攪拌18小時，在真空濃縮成黃色油狀物。油狀物以管柱層析（CHC13/甲醇，95/5，90/10 ; CHC13/甲醇 _ /NAOH，89/10/1)純化，獲得靜置後固化之黃色油狀標題化合物。1H NMR (300 MHz，DMSO-d6) δ 7.38, 6·95, 5·62， 4.86, 3.34, 2·67,2·31。製備例23. 2-(甲基胺基）_ 1-( 1Η-吡咯-2-基）乙醇將 2-氯小（1H-吡咯-2-基）乙醇（Croce，P· D·; Ferraccioli，R.; Ritieni，Α·合成（Synthesis)，1990, 212-213) (2.04克）溶於甲籲醇（60¾升）中，且在〇°c下滴加含2·〇 Μ甲基胺之甲醇溶液 (71毫升）。反應混合物在〇°c下攪拌1小時，接著使之升溫至室溫。反應混合物在室溫下攪拌18小時，再冷卻至。滴加含棚氫化鈉（0.806克）之水（40毫升）。反應混合物在〇。〇下攪拌1小時，再使之升溫至室溫。反應混合物在室溫下攪拌 4小時，且真空濃縮移除甲醇。加水（50毫升）且以乙酸乙酯 (4 X 100毫升）萃取水層。合併之有機層經脫水（MgS04)，過濾且真空濃縮。所得棕色油狀物以管柱層析（CHC13/甲醇， 87731 -56- 200410970 95/5, 90/10; CHC13/甲醇/NH4〇H，90/10/1)純化，獲得 1.458 克黃色油狀標題化合物。物理特徵：iH NMR (400 MHz， DMSO-d6)5 10.61, 6.61-6.59, 5.91-5.86, 5.01, 4.60-4.57, 2.73-2.68，2.64-2.60，2·30 〇製備例24. 2-(甲基胺基）小（1-甲基-1Η-吡咯_2_基）乙醇將2_氯-1_(1-甲基·1Η-吡咯！基）乙醇（Cr〇ce，P. D·;The N NaOH solution was adjusted to pH 12 and extracted with EtOAc (3 X 200 mL). The combined organic layers were dehydrated (MgSCU), filtered and concentrated in vacuo. The obtained yellow oily substance was purified by column chromatography (CHCh / methanol, 95/5, 90/10; CHC13 / methanol / NH4OH, 90/10/1) 'to obtain 1.88 g of the title compound as a yellow solid. Physical characteristics: Mp 40-45 ° C; lH NMR (400 MHz, DMSO-d6) 5 6.11, 5.97-5.96, 5.05, 4.54-4.51, 2.72-2.65, 2.29, 2.22; MS (ESI +) m / z 156 ( M + H), Preparation Example 20. 1- (3-furyl) -2 · (methylamino) ethanol Trimethyl system (20.4 g) and 3-furoic acid (8.65 ml) were added to hydrogen Oxygen 87731 -54- 200410970 potassium chloride (11.2 g) and water (0.45 ml) in acetonitrile (150 ml). The reaction mixture was heated to 60 ° C for 2.5 hours. The reaction mixture was allowed to cool to room temperature. The precipitate was filtered and the filtrate was concentrated in vacuo. The obtained crude epoxide (10.747 g) was dissolved in methanol (50 ml), and a methanol solution (100 ml) containing 2.0 M methylamine was added. The reaction mixture was stirred at room temperature for 3 days and then heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting brown oil was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; CHC13 / methanol / NΗ40Η, 90/10/1) to obtain 2.703 g of the title compound as a yellow oil. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) S 7.56-7.55, 7.51, 6.44, 5.07, _ 4.58-4.55, 2.62-2.56, 2.30; MS (ESI +) m / z 142 (M + H) +. Production Example 21. 1- (1-Benzfuran-2-yl) -2- (methylamino) ethanol Potassium hydroxide (9.2 g) and water (3.7 ml) were added to acetonitrile (125 ml). Benzofuran-2-carboxylic acid (12.0 g) was dissolved in an acetonitrile mixture. Trimethylphosphonium iodide (16.7 g) was added, and the mixture was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with diethyl ether and filtered. Repeat this procedure until no more KI precipitates. The resulting crude epoxide was concentrated in vacuo and dissolved in a methanol solution (410 ml) containing 2.0 M methylamine. The mixture was allowed to stir at room temperature for 18 hours and then concentrated in vacuo to a brown oil. The oil was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; CHC13 / methanol / NH4OH, 89/10/1, 79/20/1) to obtain 3.0 g of an off-white solid title. Compounds. Physical characteristics: 4 NMR (300 MHz, DMSO_d60 7.59, 7.53, 7.24, 6.47, 5.62, 4.77, 2.83, 2.32. Preparation Example 22. 87731 -55- 200410970 2_ (methylamino) -1-epiphen- 2-Base ethanol dissolves thiophene-2-carboxaldehyde (8.5g) in acetonitrile (115ml). Add trimethylphosphonium iodide (15.5g), potassium hydroxide (8.5g) and water (3.4ml) And the mixture was stirred at 60 C for 3 hours. The reaction mixture was cooled to room temperature and filtered. The process was repeated until K1 no longer precipitated. The crude epoxide obtained was concentrated in vacuo and steamed using a Kugelrohr stripe device (0.8 Torr The temperature of the flood box was 50 ° C.) The crude epoxide was dissolved in a methanol solution (152 ml) containing 2_0 M methylamine. The mixture was stirred at room temperature for 18 hours and concentrated in vacuo to a yellow oil. Oil The material was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; CHC13 / methanol // NAOH, 89/10/1) to obtain the title compound as a yellow oil that solidified after standing. 1H NMR ( 300 MHz, DMSO-d6) δ 7.38, 6.95, 5.62, 4.86, 3.34, 2.67, 2.31. Preparation Example 23. 2- (methylamino) _ 1- (1Η-pyrrole- 2-based) The alcohol dissolves 2-chloro small (1H-pyrrole-2-yl) ethanol (Croce, P.D .; Ferraccioli, R .; Ritieni, A. Synthesis, 1990, 212-213) (2.04 g) Methanol (60¾ liters) and a methanol solution (71 ml) containing 2.0 M methylamine was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, and then allowed to warm to room temperature. Warm. The reaction mixture was stirred at room temperature for 18 hours, and then cooled to. Water (40 ml) containing sodium hydride (0.806 g) was added dropwise. The reaction mixture was stirred at 0.0 for 1 hour and then allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 4 hours, and the methanol was concentrated in vacuo to remove water. Water (50 mL) was added and the aqueous layer was extracted with ethyl acetate (4 X 100 mL). The combined organic layers were dehydrated (MgS04) and filtered. And concentrated in vacuo. The resulting brown oil was purified by column chromatography (CHC13 / methanol, 87731 -56- 200410970 95/5, 90/10; CHC13 / methanol / NH4OH, 90/10/1) to obtain 1.458 G of the title compound as a yellow oil. Physical characteristics: iH NMR (400 MHz, DMSO-d6) 5 10.61, 6.61-6.59, 5.91-5.86, 5.01, 4.60-4.57, 2.73-2 .68, 2.64-2.60, 2.30 〇 Preparation Example 24. 2- (methylamino) small (1-methyl-1Η-pyrrole_2_yl) ethanol will be 2-chloro-1_ (1-methyl · 1Η-pyrrole! Based) ethanol (CrOce, P. D ·;

Ferraccioli，R·; Ritieni，Α·合成（Synthesis)，1990，212-213) · (2·05克）溶於甲醇（40毫升）中，且在〇°c下滴加含2·〇 M甲基胺之甲醇溶液（65毫升）。反應混合物在〇它下攪拌1小時，接著使之升溫至室溫。反應混合物在室溫下攪拌丨8小時，再冷卻至0°C。滴加含硼氫化鈉（0.738克）之水（40毫升）。反應混合物在0°C下攪拌30分鐘，再使之升溫至室溫。反應混合物在室溫下攪拌18小時，且添加額外0.738克（19.5毫莫耳）之硼氫化鈉，且使反應混合物在室溫下攪拌18小時。反應以1 N HC1溶液終止反應，再真空濃縮移除甲醇。水層以2 N _ NaOH溶液調整至PH為12，且以CH2C12(4X100毫升）萃取。合併之有機層經脫水（MgSCU)，過濾且真空濃縮。所得黃色油狀物自乙酸乙酯結晶，獲得0.772克白色固態標題化合物。物理特徵：Μ·ρ· 64-66°C ; 4 NMR (400 MHz，DMSO_d6)5 6·63-6·62, 5·90- 5·86, 5.00, 4.62-4.59, 3.59, 2.81-2.68, 2.32; MS (ESI+) m/z 155 (Μ+Η)+ 0 製備例25. 2_(甲基胺基）-1-(1-甲基-111-咪唑_4-基）乙醇 87731 -57- 200410970 將氫氧化鉀（5.83克）及水（0_23毫升）添加於乙腈（125毫升）中。再添加三甲基硫碘（10.6克）及4(5)-咪唑羧醛（5.00克）。反應混合物加熱至60°C 3小時。使反應混合物冷卻至室溫且過滤。將濾液添加於函2.0 Μ甲基胺之甲醇（250毫升）溶液。反應混合物在室溫下攪拌18小時。真空濃縮反應混合物。所得棕色油狀物以管柱層析（CHC13/甲醇，95/5，90/10 ; (：11(：13/甲醇/：^114〇11，90/10/1)純化，獲得0.145克黃色油狀標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6)3 7·44， ^ 6·91，4.54-4.49，3.60，2.72-2.58，2.30; MS (ESI+) m/z 156 (M+H)+。製備例26. 2-(甲基胺基）-1-(1-三苯基甲基-1H-咪唑-4-基）乙醇合併氫化鈉（1.18克，60%油分散液）及DMSO(20毫升），且在70°C下加熱1 ·5小時。反應混合物冷卻至室溫且添加THF (20毫升）。使反應混合物冷卻至〇°c且添加含三甲基锍碘 (6.04克）之DMSO(25毫升）。使反應混合物升溫至室溫且添 _ 加4-(N-三苯基甲基）咪口坐叛酸（Bernabe，M.; Burger，A. J.Ferraccioli, R ·; Ritieni, Α · Synthesis, 1990, 212-213) · (2.05 g) was dissolved in methanol (40 ml), and 2.0 mg of methyl formaldehyde was added dropwise at 0 ° C. Methanol solution (65 ml). The reaction mixture was stirred at 0 ° C for 1 hour, and then allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 8 hours and then cooled to 0 ° C. Water (40 ml) containing sodium borohydride (0.738 g) was added dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes, and then allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 18 hours, and an additional 0.738 g (19.5 mmol) of sodium borohydride was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was terminated with a 1 N HC1 solution and concentrated in vacuo to remove methanol. The aqueous layer was adjusted to a pH of 12 with a 2 N —NaOH solution, and extracted with CH 2 C 12 (4 × 100 ml). The combined organic layers were dried (MgSCU), filtered and concentrated in vacuo. The resulting yellow oil was crystallized from ethyl acetate to obtain 0.772 g of the title compound as a white solid. Physical characteristics: M · ρ · 64-66 ° C; 4 NMR (400 MHz, DMSO_d6) 5 6 · 63-6 · 62, 5 · 90- 5 · 86, 5.00, 4.62-4.59, 3.59, 2.81-2.68, 2.32; MS (ESI +) m / z 155 (Μ + Η) + 0 Preparation Example 25.2 (methylamino) -1- (1-methyl-111-imidazole_4-yl) ethanol 87731 -57- 200410970 Add potassium hydroxide (5.83 g) and water (0-23 ml) to acetonitrile (125 ml). Add trimethylthioiodide (10.6 g) and 4 (5) -imidazolecarboxaldehyde (5.00 g). The reaction mixture was heated to 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was added to a 2.0 M solution of methylamine in methanol (250 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The obtained brown oil was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; (: 11 (: 13 / methanol /: ^ 114〇11, 90/10/1) to obtain 0.145 g of yellow Oily title compound. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 3 7.44, ^ 6.91, 4.54-4.49, 3.60, 2.72-2.58, 2.30; MS (ESI +) m / z 156 (M + H) + Preparation Example 26. 2- (methylamino) -1- (1-triphenylmethyl-1H-imidazol-4-yl) ethanol combined with sodium hydride (1.18 g, 60% oil dispersion ) And DMSO (20 mL) and heated at 70 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature and THF (20 mL) was added. The reaction mixture was cooled to 0 ° C. and trimethylphosphonium iodide was added. (6.04 g) of DMSO (25 ml). The reaction mixture was allowed to warm to room temperature and 4- (N-triphenylmethyl) imidazole (Bernabe, M .; Burger, AJ) was added.

Med· Chem·，1971，14, 883-885)。反應混合物在室溫下攪拌1 小時，再到入冷水（200毫升）/Et20(100毫升）中。過濾所得淡黃色固體，且添加於含2·0 Μ甲基胺之甲醇溶液（150毫升）中。反應混合物在室溫下攪拌1 8小時，再真空濃縮。所得黃色油狀物以管柱層析（CHC13/甲醇，95/5，90/10 ; CHC13/ 甲醇/NH4〇H，90/10/1)純化。所得固體分散於乙酸乙酯中，Med. Chem., 1971, 14, 883-885). The reaction mixture was stirred at room temperature for 1 hour, and then poured into cold water (200 ml) / Et20 (100 ml). The resulting pale yellow solid was filtered and added to a methanol solution (150 ml) containing 2.0 M methylamine. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The resulting yellow oil was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; CHC13 / methanol / NH4OH, 90/10/1). The resulting solid was dispersed in ethyl acetate,

獲得0.288克白色固態標題化合物。Μ·ρ· 169-171°C ; iHNMR 87731 -58- 200410970 (400 MHz，DMSO-d6)S 7.43-7.38, 7.27, 7.09-7.07, 6.70, 4.98, 4.54-4.51, 2.75-2.71, 2.61-2.56, 2.29; MS (ESI+) m/z 384 (M+H)+ 〇製備例27. 1-(3&，7&_二氫-111-4丨哚-3-基）-2-(甲基胺基）乙醇在〇°C 下，將 2-溴 _1-(ih-W 哚-3-基）乙酮（Guella，G·; Mancini，I·; N’Diaye，I·; Pietra，F· Helv. Chim. Acta” 1994, 77, 1999-2006)(3.50克）添加於含2·0 M甲基胺之甲醇溶液（55毫升）中。反應混合物在0°C下攪拌30分鐘，且使之升溫至室溫。使反應混合物再室溫下攪拌1小時。使反應混合物冷卻至〇°C且添加硼氫化鈉（0.461克）。反應混合物在〇°c下揽拌 30分鐘，接著在室溫下攪拌18小時。添加額外50毫升之甲醇，且使反應混合物加熱至45°C 1小時。1小時後，添加額外之硼氫化鈉（0.461克）且在45°C下持續加熱1小時。使反應混合物冷卻至室溫且加水。真空濃縮混合物移除甲醇。水層以CH2C12(4 X 10毫升）萃取。真空濃縮合併之有機層。所得橘色固體以管柱層析（CHCU/甲醇，95/5)純化，獲得L002 克褐色固態1-(1H-吲哚-3-基）-2-(甲基胺基）乙酮。物理特徵：巾 NMR (400 MHz，DMSO-d6)5 11.96 (br，1H)，8.38 (s， 1H)，8.20-8.18 (m，1H)，7.49-7.46 (m，1H)，7.23-7.17 (m，2H)， 3.83 (s，2H)，2_34 (s，3H); MS (ESI+) m/z 189 (M+H)+。將1-(1H-吲哚-3-基）-2-(甲基胺基）乙酮（ΐ·〇〇克）溶於乙醇 (120毫升）及Η2〇(30毫升）中，且於冰浴中冷卻。添加硼氫化鈉（0.402克）且使反應混合物升溫至室溫。反應混合物在室 87731 -59- 200410970 溫下攪拌4小時。再使反應混合物於冰浴中冷卻，且添加額外0.402克硼氫化鈉。使反應混合物升溫至室溫且攪拌18小時。使反應混合物在冰浴中冷卻且添加丙酮（7毫升）。真空濃縮反應混合物，且於殘留物中添加H2〇(50毫升）。水層以 2 N NaOH溶液調整至pH 12，再以CH2Cl2(4Xl〇〇毫升）萃取。合併之有機層經脫水（MgS04)、過濾且真空濃縮。將所得淡黃色固體分散於乙酸乙酯中，獲得0.415克淡黃色固態標題化合物。物理特徵：Μ·ρ· 117-120T：; iHNMRGOOMHz， DMSO-d6)8 10.88, 7.63-7.61, 7.35-7.33, 7.21-7.20, 7.07-7.03, 6.97-6.94, 4.93-4.90, 2·86-2·72, 2.36; MS (ESI+) m/z 191 (M+ H)+。製備例28. 2-溴-1·(2,5·二甲基-3-呋喃基）乙酮將3-乙醯基-2,5-二甲基呋喃（13.3毫升）溶於1/2二呤燒 /Et2〇(600毫升）中，且冷卻至〇°C。於丨小時内滴加溴（16 〇克）。反應混合物在0°C攪拌1小時，再使其冷卻至室溫。反應混合物在室溫下擅;掉18小時。反應混合物冷卻至〇 t，且添加額外1 _0毫升之溴。使反應混合物升溫至室溫，且揽拌2 小時。反應混合物以飽和氯化銨溶液（1〇〇毫升）終止反應。移除有機層且以Et：20(2 X 100¾升）萃取水層。合併之有機層經脫水（MgS〇4)、過濾且真空濃縮。所得棕色油狀固體以管柱層析（己烷/CHAl2，70/30)純化，獲得14.23克不純之黃色油狀固體，其自己烷再結晶，獲得7.52克白色固態標題化合物。物理特徵：Μ·ρ· 56-58X： ; 4 NMR (400 MHz，DMSO-d6)3 87731 -60- 200410970 6.49, 4.54, 2.50, 2.08; C NMR (100 MHz，CDC“)3 187 2 159.3, 150.5, 118.9, 105.6, 33.2, 14.4? 13.2; 製備例29. l-(2,5-二甲基-3-吱喃基）-2-(甲基胺基）乙醇將2-溴-1-(2,5-二甲基-3-呋喃基）乙酮（7.3〇克）溶於甲醇 (80毫升）中，且在〇°C下滴加於含2_〇 Μ甲基胺之甲醇溶液 (168毫升）中。反應混合物在〇°c下攪拌3〇分鐘，再滴加含硼氫化鈉（1.91克）之水（40毫升）。反應混合物在下攪拌ι·5 小時，再使之升溫至室溫。反應混合物在室溫下攪拌丨8小時。添加額外0.636克硼氫化鈉，且持續攪拌3小時。反應以 1 N HC1溶液終止反應，且真空濃縮移除甲醇。殘留物倒入冷卻2 N NaOH(100毫升）/乙酸乙酯（2〇〇毫升）中。移除有機層且以乙酸乙醋（3 X 200毫升）萃取水層。合併之有機層經脫水（MgSCU)、過濾且真空濃縮。所得黃色油狀物以管柱層析 (CHC13/甲醇，95/5，90/10 ; CHC13/甲醇/NH4OH，90/10/1) 純化。所得淡黃色固體自乙酸乙酯再結晶，獲得2.406克白色固態標題化合物。物理特徵：M.p. 76-77°C ; NMR (400 MHz，DMSO-d60 5.93, 4·82, 4.47-4.43, 2.64-2.54, 2.46-2.42, 2·32, 2·16; MS (ESI+) m/z 170 (M+H)+。製備例30. l-(3a，7a-二氫-1-苯并嘧吩-3-基）-2-(甲基胺基）乙醇將氫氧化鉀（3.11克）及水（0.12毫升）添加於乙腈（50毫升）中。再添加三甲基锍碘（5.65克）及噻嗯-3-羧醛（4·50克）。反應混合物加熱至60°C 4小時。使反應混合物冷卻至室溫且以 87731 -61 - 2004109700.288 g of the title compound was obtained as a white solid. M · ρ · 169-171 ° C; iHNMR 87731 -58- 200410970 (400 MHz, DMSO-d6) S 7.43-7.38, 7.27, 7.09-7.07, 6.70, 4.98, 4.54-4.51, 2.75-2.71, 2.61-2.56 , 2.29; MS (ESI +) m / z 384 (M + H) + 〇 Preparation Example 27. 1- (3 &, 7 & _dihydro-111-4 丨 indol-3-yl) -2- (methyl Amine) ethanol at 0 ° C, 2-bromo_1- (ih-W indol-3-yl) ethyl ketone (Guella, G ·; Mancini, I ·; N'Diaye, I ·; Pietra, F · Helv. Chim. Acta ”1994, 77, 1999-2006) (3.50 g) was added to a methanol solution (55 ml) containing 2.0 M methylamine. The reaction mixture was stirred at 0 ° C for 30 minutes, and The reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for another hour at room temperature. The reaction mixture was cooled to 0 ° C. and sodium borohydride (0.461 g) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes, then at Stir at room temperature for 18 hours. Add an additional 50 ml of methanol and heat the reaction mixture to 45 ° C for 1 hour. After 1 hour, add additional sodium borohydride (0.461 g) and continue heating at 45 ° C for 1 hour The reaction mixture was cooled to room temperature and water was added. The mixture was concentrated in vacuo The methanol was removed. The aqueous layer was extracted with CH2C12 (4 X 10 mL). The combined organic layers were concentrated in vacuo. The resulting orange solid was purified by column chromatography (CHCU / methanol, 95/5) to obtain L002 g of a brown solid 1- ( 1H-indole-3-yl) -2- (methylamino) ethanone. Physical characteristics: NMR (400 MHz, DMSO-d6) 5 11.96 (br, 1H), 8.38 (s, 1H), 8.20 -8.18 (m, 1H), 7.49-7.46 (m, 1H), 7.23-7.17 (m, 2H), 3.83 (s, 2H), 2_34 (s, 3H); MS (ESI +) m / z 189 (M + H) +. 1- (1H-Indol-3-yl) -2- (methylamino) ethanone (ΐ.00 g) was dissolved in ethanol (120 ml) and Η20 (30 ml). And cooled in an ice bath. Sodium borohydride (0.402 g) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature 87731 -59- 200410970 for 4 hours. The reaction mixture was then cooled in an ice bath. An additional 0.402 g of sodium borohydride was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was cooled in an ice bath and acetone (7 mL) was added. The reaction mixture was concentrated in vacuo and H2O (50 mL) was added to the residue. The aqueous layer was adjusted to pH 12 with a 2 N NaOH solution, and extracted with CH2Cl2 (4 × 100 ml). The combined organic layers were dehydrated (MgSO4), filtered, and concentrated in vacuo. The obtained pale yellow solid was dispersed in ethyl acetate to obtain 0.415 g of the title compound as a pale yellow solid. Physical characteristics: M · ρ · 117-120T :; iHNMRGOOMHz, DMSO-d6) 8 10.88, 7.63-7.61, 7.35-7.33, 7.21-7.20, 7.07-7.03, 6.97-6.94, 4.93-4.90, 2.86-2 72, 2.36; MS (ESI +) m / z 191 (M + H) +. Preparation Example 28. 2-Bromo-1 · (2,5 · dimethyl-3-furanyl) ethanone 3-Ethylfluorenyl-2,5-dimethylfuran (13.3 ml) was dissolved in 1/2 Dixanthine / Et20 (600 ml) and cooled to 0 ° C. Bromine (160 g) was added dropwise over an hour. The reaction mixture was stirred at 0 ° C for 1 hour and then allowed to cool to room temperature. The reaction mixture was allowed to stand at room temperature; it was left for 18 hours. The reaction mixture was cooled to 0 t, and an additional 1-0 ml of bromine was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with a saturated ammonium chloride solution (100 ml). The organic layer was removed and the aqueous layer was extracted with Et: 20 (2 X 100 ¾ liters). The combined organic layers were dehydrated (MgSO4), filtered and concentrated in vacuo. The obtained brown oily solid was purified by column chromatography (hexane / CHAl2, 70/30) to obtain 14.23 g of an impure yellow oily solid which was recrystallized from hexane to obtain 7.52 g of the title compound as a white solid. Physical characteristics: M · ρ · 56-58X:; 4 NMR (400 MHz, DMSO-d6) 3 87731 -60- 200410970 6.49, 4.54, 2.50, 2.08; C NMR (100 MHz, CDC ") 3 187 2 159.3, 150.5, 118.9, 105.6, 33.2, 14.4? 13.2; Preparation Example 29. l- (2,5-dimethyl-3-creanyl) -2- (methylamino) ethanol (2,5-Dimethyl-3-furanyl) ethanone (7.30 g) was dissolved in methanol (80 ml) and added dropwise to a methanol solution containing 2.0 mM methylamine at 0 ° C. (168 ml). The reaction mixture was stirred at 0 ° C for 30 minutes, and then water (40 ml) containing sodium borohydride (1.91 g) was added dropwise. The reaction mixture was stirred for 5 hours and then allowed to warm to Room temperature. The reaction mixture was stirred at room temperature for 8 hours. An additional 0.636 g of sodium borohydride was added and the stirring was continued for 3 hours. The reaction was terminated with a 1 N HC1 solution and concentrated in vacuo to remove the methanol. The residue was poured into cooling 2 N NaOH (100 mL) / ethyl acetate (200 mL). The organic layer was removed and the aqueous layer was extracted with ethyl acetate (3 X 200 mL). The combined organic layers were dehydrated (MgSCU), filtered and vacuumed. Concentrated. The resulting yellow The color oil was purified by column chromatography (CHC13 / methanol, 95/5, 90/10; CHC13 / methanol / NH4OH, 90/10/1). The obtained pale yellow solid was recrystallized from ethyl acetate to obtain 2.406 g The title compound is a white solid. Physical characteristics: Mp 76-77 ° C; NMR (400 MHz, DMSO-d60 5.93, 4.82, 4.47-4.43, 2.64-2.54, 2.46-2.42, 2.32, 2.16; MS (ESI +) m / z 170 (M + H) +. Preparation Example 30. l- (3a, 7a-dihydro-1-benzopyrim-3-yl) -2- (methylamino) ethanol Potassium hydroxide (3.11 g) and water (0.12 ml) were added to acetonitrile (50 ml). Trimethylphosphonium iodide (5.65 g) and thien-3-carboxaldehyde (4.50 g) were added. Reaction mixture Heated to 60 ° C for 4 hours. The reaction mixture was cooled to room temperature and the temperature was 87731 -61-200410970.

Et2〇(25毫升）稀釋。過濾沉澱物且真空濃縮濾液。將所得粗環氧化物（6.20克）溶於甲醇（40毫升）中，且添加於含2.〇 M甲基胺之甲醇溶液（100毫升）中。反應混合物在室溫下攪拌3 天。真空濃縮反應混合物。所得棕色油以管柱層析（CHCl3/ 甲醇，95/5，90/10 ; CHC13/甲醇/NH4OH，90/10/1)純化，獲得1.753克黃色固態標題化合物。物理特徵：Μ·ρ· 98-1〇2。(：； ln NMR (400 MHz, DMSO-d6)5 7.98-7.90, 7.51, 7.60, 7.40- 7.33, 5.43, 5.04, 2.80, 2.34; MS (ESI+) m/z 208 (M+H)+。製備例3 1 · 修 2_(甲基胺基）-1-(1-甲基-m-吲哚-2-基）乙醇將氫氧化鉀（3.18克）及水（0.13毫升）添加於乙腈（5〇毫升）中。再添加三甲基锍碘（5.78克）及1-甲基吲哚_2_羧醛（4.50 克）。反應混合物加熱至60°C 3小時。使反應混合物冷卻至室溫且以Et2〇(25毫升）稀釋。過滤沉澱物且真空濃縮濾液。將所得粗環氧化物（5·5〇克）溶於甲醇（30毫升）中，且添加於含2·0 Μ甲基胺之甲醇溶液（1〇〇毫升）中。反應混合物在室溫 _ 下揽拌3天’且加熱至回流2小時。使反應混合物冷卻至室溫且真2濃縮。所得棕色油以管柱層析（CHCl3/甲醇，95/5， 90/10，CHC13/甲醇/NH4OH，90/10/1)純化，獲得 0.100 克黃色固悲不純標題化合物。物理特徵：iH NMR (400 MHz， DMSO-d6)3 7.49，7.41，7.12-7.09，7.00-6.97，6.35，5.36， 4.89-4.85, 3.76, 2·93-2·84, 2·36; MS (ESI+) m/z 205 (M+H)+。製備例32. 5-(2-溴-1-羥基乙基）嘍吩_2_腈 87731 -62- 200410970Et20 (25 mL) was diluted. The precipitate was filtered and the filtrate was concentrated in vacuo. The obtained crude epoxide (6.20 g) was dissolved in methanol (40 ml) and added to a methanol solution (2.0 ml) containing 2.0 M methylamine. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo. The resulting brown oil was purified by column chromatography (CHCl3 / methanol, 95/5, 90/10; CHC13 / methanol / NH4OH, 90/10/1) to obtain 1.753 g of the title compound as a yellow solid. Physical characteristics: M · ρ · 98-102. (: Ln NMR (400 MHz, DMSO-d6) 5 7.98-7.90, 7.51, 7.60, 7.40- 7.33, 5.43, 5.04, 2.80, 2.34; MS (ESI +) m / z 208 (M + H) +. Preparation Example 3 1 · 2- (methylamino) -1- (1-methyl-m-indol-2-yl) ethanol Potassium hydroxide (3.18 g) and water (0.13 ml) were added to acetonitrile (5 0 ml). Trimethylphosphonium iodide (5.78 g) and 1-methylindole-2-carboxaldehyde (4.50 g) were added. The reaction mixture was heated to 60 ° C for 3 hours. The reaction mixture was cooled to room temperature. And diluted with Et20 (25 mL). The precipitate was filtered and the filtrate was concentrated in vacuo. The resulting crude epoxide (5.00 g) was dissolved in methanol (30 mL) and added to a 2.0 M methyl group Amine in methanol solution (100 mL). The reaction mixture was stirred at room temperature for 3 days and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting brown oil was columned. (CHCl3 / methanol, 95/5, 90/10, CHC13 / methanol / NH4OH, 90/10/1) to obtain 0.100 g of the title compound as a yellow solid impurity. Physical characteristics: iH NMR (400 MHz, DMSO-d6 ) 3 7.49, 7.41, 7.12-7.09 7.00-6.97, 6.35, 5.36, 4.89-4.85, 3.76, 2.93-2 · 84, 2.36; MS (ESI +) m / z 205 (M + H) +. Preparation Example 32. 5- (2- Bromo-1-hydroxyethyl) fluorene_2_nitrile 87731 -62- 200410970

於含2-乙醯基-5-氰基嘧吩（1 ·5克）之20毫升對_二噚烷/乙醚（1 ·· 2，v/v)加入溴（0·5毫升）。2小時後，添加冰水（30毫升）。以過濾收集固態沉澱物且以水洗滌，獲得1 ·4克白色固月豆。使滤液靜置隔夜’獲得第二群〇 · 8 6克白色產物，全部產 1為2.26克5_(溴乙酸基）ρ塞吩-2-腈。物理特徵：4 NMR (DMSO-d6)5 8.16, 8.11，4.94; MS (ESI·) m/z 230 (M-Η)·。將NaBH4(5毫升水中含〇·46克）添加於冷卻至· 1 〇。〇之含 5-(溴乙驗基）·噻吩-2-腈（1.85克）之甲醛（50毫升）懸浮液中。10分鐘後，添加48%HBr水溶液將pH調整為3。反應混合物濃縮至約25毫升，再添加水（3〇毫升）。混合物以二氯甲烷（3X40毫升）萃取。合併有機相，以食鹽水洗滌且以MgS〇4 脫水。移除溶劑獲得1·6克橘色油狀標題化合物。物理特徵：To 20 ml of p-dioxane / ethyl ether (1, 2.5, v / v) containing 2-ethylfluorenyl-5-cyanopyrimidine (1.5 g) was added bromine (0.5 ml). After 2 hours, add ice water (30 mL). The solid precipitate was collected by filtration and washed with water to obtain 1.4 g of white solid moon beans. The filtrate was allowed to stand overnight 'to obtain a second group of 0.86 g of a white product, all of which yielded 2.26 g of 5- (bromoacetyl) ρcephen-2-carbonitrile. Physical characteristics: 4 NMR (DMSO-d6) 5 8.16, 8.11, 4.94; MS (ESI ·) m / z 230 (M-Η) ·. NaBH4 (0.46 g in 5 ml of water) was added and cooled to .10. 〇 in a suspension of 5- (bromoethoxy) · thiophene-2-carbonitrile (1.85 g) in formaldehyde (50 ml). After 10 minutes, a 48% HBr aqueous solution was added to adjust the pH to 3. The reaction mixture was concentrated to about 25 ml, and water (30 ml) was added. The mixture was extracted with dichloromethane (3 × 40 ml). The organic phases were combined, washed with brine and dried over MgS04. The solvent was removed to obtain 1.6 g of the title compound as an orange oil. Physical characteristics:

5.17, 3.81, 3.68; MS H NMR (DMSO-d6)5 7.86, 7.23, 6.67, (ESI-) m/z 232 。製備例33. 5-(1-羥基-2-(甲基胺基）乙基）,塞吩-2_腈5.17, 3.81, 3.68; MS H NMR (DMSO-d6) 5 7.86, 7.23, 6.67, (ESI-) m / z 232. Preparation Example 33. 5- (1-Hydroxy-2- (methylamino) ethyl), phenphen-2_nitrile

MeOH/89%CH2Cl2)純化，獲得〇·80克白色固態標題化合物。 87731 -63- 200410970 物理特徵：iHNMR(DMSO-d60 7.81，7.13,6.13,4.93,2.72, 2·33; MS (ESI+) m/z 183 (M+H)+; HRMS (FAB) m/z 183.0600 (M+H)+ 〇製備例34. 2-氯-1-(1，3-p塞峻_2-基）乙艱] 將2-(三甲基矽烷基卜塞唑（4 83克）溶於CH2Cl2(4〇毫升）中’且冷卻至0°C。劇烈攪拌下以注射滴加氯乙醯基氯（5.1 愛升）。4小時後，添加飽和NaHC〇s水溶液，直到溶液為中性pH，且以CH2C12萃取所得混合物。合併之有機層經脫水 (MgSOO、過濾且濃縮，獲得4·27克淡黃色固態標題化合物。物理特徵：4 NMR (400 MHz，CDC13)S 7·90_7·88, 7·65_ 7·64,4·83〇製備例3 5. 2-(甲基胺基）-1-(1，3_ρ墓峻-2-基）乙醇將2-氯_1·(ΐ，3-嘧唑-2-基）乙酮（製備例34, 〇.6克）溶於甲醇 (4¾升）中，且冷卻至〇艺。使含硼氫化鈉（〇·3克）之甲醇笔升）攪摔1小時，再滴加於酮中。反應混合物於下攪拌 30分鐘，再於室溫下攪拌L5小時。添加HC1(1 Ν)直到ρΗ*4 為止，接著添加飽和NaHC〇3水溶液，直到中性ρΗ為止。所得混合物以CHAh萃取。合併之有機層經脫水（MgS〇4)、過濾且濃縮，獲得無色油狀物。將所得油狀物、曱基胺（甲醇中2·0 M，30.0¾升）及Nal(45毫克）置於密封管中，且在6〇 °C下加熱16小時。溶液經濃縮且以色譜儀（2毫米矽膠，99/ι 至90/10 CHAh/MeOH)純化，獲得0.223克灰白色固態標題 87731 -64- 200410970 化合物。物理特徵：NMR (400 MHz，DMSO-d6)S 7.81- 7·80， 7·74_7·73, 6.95, 5·15·5·11，3.33, 3·14-3·09, 2.58; MS (ESI+) m/z 159 (Μ+Η)+。製備例36. 1-(1，3-苯并ρ塞峻_2_基）-2-溴乙嗣將2兴三甲基矽烷基）苯并嘍唑（2.0克，如Bull. Chem. Soc.MeOH / 89% CH2Cl2) to obtain 0.80 g of the title compound as a white solid. 87731 -63- 200410970 Physical characteristics: iHNMR (DMSO-d60 7.81, 7.13, 6.13, 4.93, 2.72, 2.33; MS (ESI +) m / z 183 (M + H) +; HRMS (FAB) m / z 183.0600 (M + H) + 〇 Preparation Example 34. 2-Chloro-1- (1,3-p-sechon_2-yl) ethane] 2- (trimethylsilyl bustazole (4 83 g) Dissolved in CH2Cl2 (40 ml) and cooled to 0 ° C. Chloroacetylammonium chloride (5.1 liters) was added dropwise by injection with vigorous stirring. After 4 hours, a saturated NaHC0s aqueous solution was added until the solution was in the medium. The resulting mixture was extracted with CH2C12. The combined organic layers were dried (MgSOO, filtered, and concentrated to obtain 4.27 g of the title compound as a pale yellow solid. Physical characteristics: 4 NMR (400 MHz, CDC13) S 7.90_7. 88, 7 · 65_ 7,64,4 · 83〇 Preparation Example 3 5. 2- (methylamino) -1- (1,3_ρ Tomb-2-yl) ethanol will be 2-chloro_1 · (ΐ 3,3-pyrazol-2-yl) ethanone (Preparation Example 34, 0.6 g) was dissolved in methanol (4¾ liters), and cooled to 0 ° C. Sodium borohydride (0.3 g) in methanol Stir for 1 hour, and then add dropwise to the ketone. The reaction mixture is stirred for 30 minutes, and then stirred at room temperature for 5 hours. HC1 is added (1 Ν) until ρΗ * 4, followed by the addition of saturated aqueous NaHC03 solution until neutral ρΗ. The resulting mixture was extracted with CHAh. The combined organic layers were dehydrated (MgS04), filtered and concentrated to give a colorless oil. The resulting oil, fluorenylamine (2.0 M in methanol, 30.0¾ liters) and Nal (45 mg) were placed in a sealed tube and heated at 60 ° C for 16 hours. The solution was concentrated and Purified with a chromatograph (2 mm silicone, 99 / ι to 90/10 CHAh / MeOH) to obtain 0.223 g of the title compound 87731 -64- 200410970 as an off-white solid. Physical characteristics: NMR (400 MHz, DMSO-d6) S 7.81-7 · 80, 7.74_7 · 73, 6.95, 5.15 · 5 · 11, 3.33, 3.14-3 · 09, 2.58; MS (ESI +) m / z 159 (Μ + Η) +. Preparation Example 36. 1- (1,3-Benzobenzocyclo-2-yl) -2-bromoacetamidine will be 2 x trimethylsilyl) benzoxazole (2.0 g, such as Bull. Chem. Soc.

Jpn· 1988, 61，3637-3648 中所述）溶於CH2C12(31 毫升）中。滴加含溴乙醯溴化物（1·7毫升）之CH2C12(17毫升），且攪拌3小時。混合物再以飽和NaHC〇3水溶液中和且以CH2C12萃取。鲁合併之有機層經脫水（MgS〇4)、過濾且濃縮，獲得標題化合物。物理特徵：1HNMR(400 MHZ，CDCl3)δ8·23-8·21，8·03- 8.01，7.64-7.57, 4.86。製備例37 1-(1，3-苯并嘧唑-2-基）-2-(甲基胺基）乙醇將1-(1，3-苯并噻唑_2_基）-2_溴乙酮（製備例36, 2 〇克）溶於甲醇（ίο毫升）中，且冷卻至ot:。將硼氫化鈉（0 55克）添加於 _ 甲醇（10耄升）中，攪拌3 〇分鐘，在滴加於酮溶液中。3 〇分鐘後，以1 N HC1終止反應，乙飽*NaHC〇3水溶液中和且以萃取。合併之有機層經脫水（MgS〇4)、過濾且濃縮。殘留物溶於甲醇（5毫升）中，冷卻至且滴加含甲基胺（甲醇中2.0 Μ，49毫升）。混合物在室溫下攪拌2小時再濃縮。所得油狀物以管柱層析（CH/i2至9〇/1〇 CKCIV甲醇）純化，獲得0.289克糊狀固態標題化合物。物理特徵：1hnmr (400 MHz，DMSO-d6)8 8.16-8.14，8.00-7.98，7 56-7 54 87731 -65- 200410970 7·49_7·45，5.35-5.31，3.52-3.49，3·33_3·27，2.54; MS (ESI+) m/z 209 (Μ+Η)+。製備例38. (甲基（三苯甲基）胺基）乙醛將三乙胺（9·3毫升）添加於含2-甲基胺基乙醇（5.〇克）及三苯基甲基氯（18.6克）之CH2Ch(150毫升）中，且使溶液在室溫下攪拌2小時。真空移除溶劑且將殘留物溶於Et〇Ac(2〇〇毫升）中。溶液以水（100毫升）及食鹽水（50毫升）洗滌，經過滤且丨辰縮。殘留物在石夕膠上以20%EtOAc/庚垸層析，獲得18.7 克白色固態2-[甲基（三苯甲基）胺基]乙醇。物理特徵： NMR (400 MHz，DMSO-d6) δ 7.45-7.14, 4.56, 3.65, 2.12, 1.99。將含DMSO(1.47毫升）之CH2C12(60毫升）溶液冷卻至_78 C ’且於10分鐘内滴加草酸氯。滴加含2_三笨甲基甲基胺基乙醇（3.0克）之CH2C12(10毫升）溶液，且使所得混合物攪拌 15分鐘。添加三乙胺（6.6毫升），且使混合物升溫至室溫。加水使反應混合物終止反應，且在以CH2Cl2(l〇〇毫升）稀釋。有機相以水及食鹽水洗滌，經脫水（Na2S04)、過濾、且濃縮。殘留物分散於***中，獲得定量產量之白色固態標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6)3 7.44-7.15, 4.55, 3.66-3.62, 2.11， 1.99 。製備例39. 2-(甲基胺基）-1_(1Η-吡唑-5-基）乙醇二鹽酸鹽將氫化鈉（5.38克，礦物油中60%分散液）於3〇分鐘内添加 87731 -66 - 200410970 於含吡唑（6.10克）之無水DMF(50毫升）冷卻（5°C)溶液中。所得懸浮液再攪拌30分鐘，且於10分鐘内滴加2-(三甲基矽燒基）乙氧基-甲基氯（19毫升）。所得混合物於室溫下攪；拌3小時。加水使反應混合物終止反應再以EtOAc(200毫升）萃取。有機層以水（3X100毫升）及食鹽水（1〇〇毫升）洗滌，經脫水（MgS〇4)、過濾且濃縮，獲得透明油狀ι_((2_(三甲基碎垸基）乙氧基）甲基）-1Η-吡唑。物理特徵：4 NMR (400 MHz， CDC13) δ 7.63-7.55, 6.32, 5.43, 3·54, 0.88, -〇·〇5。將n-BuLi(2.5 Μ溶液，1 ·8毫升）滴加於含1-((2-(三甲基石夕鲁烷基）乙氧基）甲基）-1Η-吡唑（0.80克）之THF/***（50毫升， 3/2)冷卻（-78C)溶液中。30分鐘後，添加含（甲基（三苯甲基）胺基）乙醛（製備例38，1.27克）之THF/***（5毫升，3/2)溶液。反應混合物在-78°C下攪拌1小時，再使之升溫至室溫。添加飽和NEUC1水溶液及滴加水終止反應。所得懸浮液以 £1〇八(：(2\100毫升）萃取。合併之有機層以水（1〇〇毫升）及食鹽水（50¾升）洗務’經脫水（NadO4)、過遽且濃縮。殘留物在矽膠上，以2〇%EtOAc/正庚烷層析純化，獲得〇·7克白色固態2-(甲基（三苯甲基）胺基三甲基矽烷基）乙氧基）甲基）-1H-吡唑-5-基）乙醇。物理特徵：iH NMR (4〇〇 MHz， DMSO-d6)5 7.58-7.49, 7.45-7.43, 7.36-7.32, 7.24-7.21，6·21， 5.76, 5.56-5.46, 5.22-5.20, 3.50-3.45, 2.90-2.80, 2.15, 2.09-1_98, 0.74-0.70, 0.00 ° 將含4 Ν HC1之二噚烷（20毫升）溶液添加於含(甲基（三苯甲基）胺基(三甲基石夕烷基）乙氧基^甲基）_ih^ 87731 -67- 200410970 吐-5-基）乙醇（0·7克）iMeOH(2〇毫升）溶液中，且使混合物回流隔夜。冷卻至室溫後，真空蒸發移除溶劑，且將殘留物懸浮於EtOAc中。以過滤收集所得固體，以熱EtOAc洗滌且真空乾燥，獲得〇·23克白色固態標題化合物。物理特徵： 4 NMR (400 MHz，DMSO-d6)3 9.26，8.83, 7.77, 6.36, 5.04, 3.25-3.09, 2.58。實例1. 消旋-N-(4-氯苄基）-2-(((2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）甲基）_7-甲基-4-氧代_4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺Jpn. 1988, 61, 3637-3648) was dissolved in CH2C12 (31 ml). CH2C12 (17 ml) containing bromoacetamidine bromide (1.7 ml) was added dropwise and stirred for 3 hours. The mixture was neutralized with saturated aqueous NaHC0 solution and extracted with CH2C12. The combined organic layers were dehydrated (MgS04), filtered, and concentrated to give the title compound. Physical characteristics: 1HNMR (400 MHZ, CDCl3) δ 8.23-8.21, 8.03-8.01, 7.64-7.57, 4.86. Preparation Example 37 1- (1,3-benzopyrazol-2-yl) -2- (methylamino) ethanol 1- (1,3-benzothiazol_2_yl) -2-bromoethyl The ketone (Preparation Example 36, 20 g) was dissolved in methanol (1 ml) and cooled to ot :. Sodium borohydride (0.055 g) was added to methanol (10 liters), stirred for 30 minutes, and added dropwise to the ketone solution. After 30 minutes, the reaction was terminated with 1 N HC1, and the solution was neutralized with ethyl acetate and NaHC0 and extracted with water. The combined organic layers were dehydrated (MgSO4), filtered and concentrated. The residue was dissolved in methanol (5 ml), cooled to and added dropwise with methylamine (2.0 M in methanol, 49 ml). The mixture was stirred at room temperature for 2 hours and then concentrated. The resulting oil was purified by column chromatography (CH / i2 to 90/10 CKCIV methanol) to obtain 0.289 g of the title compound as a paste-like solid. Physical characteristics: 1hnmr (400 MHz, DMSO-d6) 8 8.16-8.14, 8.00-7.98, 7 56-7 54 87731 -65- 200410970 7.49_7 · 45, 5.35-5.31, 3.52-3.49, 3.33_3 · 27 2.54; MS (ESI +) m / z 209 (M + H) +. Preparation Example 38. (Methyl (trityl) amino) acetaldehyde Triethylamine (9.3 ml) was added to 2-methylaminoethanol (5.0 g) and triphenylmethyl Chlorine (18.6 g) in CH2Ch (150 ml), and the solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in EtoAc (200 mL). The solution was washed with water (100 ml) and brine (50 ml), filtered and filtered. The residue was chromatographed on stone gum with 20% EtOAc / heptane to obtain 18.7 g of 2- [methyl (trityl) amino] ethanol as a white solid. Physical characteristics: NMR (400 MHz, DMSO-d6) δ 7.45-7.14, 4.56, 3.65, 2.12, 1.99. A solution of CH2C12 (60 ml) containing DMSO (1.47 ml) was cooled to -78 C 'and chlorine oxalate was added dropwise over 10 minutes. A solution of 2-trimethylolaminoethanol (3.0 g) in CH2C12 (10 ml) was added dropwise, and the resulting mixture was stirred for 15 minutes. Triethylamine (6.6 mL) was added and the mixture was allowed to warm to room temperature. The reaction mixture was quenched by the addition of water and diluted with CH2Cl2 (100 ml). The organic phase was washed with water and brine, dried (Na2S04), filtered, and concentrated. The residue was dispersed in diethyl ether to obtain the title compound as a white solid in quantitative yield. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 3 7.44-7.15, 4.55, 3.66-3.62, 2.11, 1.99. Preparation Example 39. 2- (methylamino) -1_ (1Η-pyrazol-5-yl) ethanol dihydrochloride Sodium hydride (5.38 g, 60% dispersion in mineral oil) was added in 30 minutes 87731 -66-200410970 In a cold (5 ° C) solution of pyrazole (6.10 g) in anhydrous DMF. The resulting suspension was stirred for an additional 30 minutes, and 2- (trimethylsilyl) ethoxy-methyl chloride (19 ml) was added dropwise over 10 minutes. The resulting mixture was stirred at room temperature; stirred for 3 hours. The reaction mixture was quenched by addition of water and extracted with EtOAc (200 mL). The organic layer was washed with water (3 × 100 mL) and brine (100 mL), dehydrated (MgS04), filtered, and concentrated to obtain a transparent oily ((2_ (trimethylsulfanyl) ethoxy) ) Methyl) -1H-pyrazole. Physical characteristics: 4 NMR (400 MHz, CDC13) δ 7.63-7.55, 6.32, 5.43, 3.54, 0.88, -0.05. N-BuLi (2.5 M solution, 1.8 ml) was added dropwise to THF containing 1-((2- (trimethylasyl) ethoxy) methyl) -1'-pyrazole (0.80 g) / Ether (50 ml, 3/2) in a cooled (-78C) solution. After 30 minutes, a solution of (methyl (trityl) amino) acetaldehyde (Preparation Example 38, 1.27 g) in THF / ether (5 ml, 3/2) was added. The reaction mixture was stirred at -78 ° C for 1 hour, and then allowed to warm to room temperature. A saturated NEUC1 aqueous solution was added and water was added dropwise to terminate the reaction. The resulting suspension was extracted with £ 108 (: (2 \ 100 ml). The combined organic layers were washed with water (100 ml) and brine (50¾ liters), dehydrated (NadO4), filtered, and concentrated. The residue was purified on silica gel with 20% EtOAc / n-heptane chromatography to obtain 0.7 g of 2- (methyl (trityl) aminotrimethylsilyl) ethoxy) as a white solid) Methyl) -1H-pyrazol-5-yl) ethanol. Physical characteristics: iH NMR (400MHz, DMSO-d6) 5 7.58-7.49, 7.45-7.43, 7.36-7.32, 7.24-7.21, 6.21, 5.76, 5.56-5.46, 5.22-5.20, 3.50-3.45, 2.90-2.80, 2.15, 2.09-1_98, 0.74-0.70, 0.00 ° Add a solution containing 4 N HC1 in dioxane (20 ml) to a solution containing (methyl (trityl) amino) ) Ethoxy ^ methyl) _ih ^ 87731 -67- 200410970 spit-5-yl) ethanol (0.7 g) in iMeOH (20 ml) and the mixture was refluxed overnight. After cooling to room temperature, the solvent was removed by evaporation in vacuo, and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with hot EtOAc and dried in vacuo to give 0.23 g of the title compound as a white solid. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 3 9.26, 8.83, 7.77, 6.36, 5.04, 3.25-3.09, 2.58. Example 1. Racemic-N- (4-chlorobenzyl) -2-((((2- (2-furanyl) -2-hydroxyethyl) (methyl) amino) methyl) _7-methyl -4-oxo_4,7-dihydropyridino [2,3-b] pyridine-5-carboxamide

將N-(4-氣卞基）-2-(氣甲基）-7 -甲基-4-氧代-4,7 -二氯ρ塞吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·250克）懸浮於DMF(14 毫升）中，且添加N，N-二異丙基乙胺（0.23毫升）及1-(2-呋喃基）-2-(甲基胺基）乙醇（製備例17，0.231克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（5〇毫升）中。過濾所得灰白色固體，且以管柱層析（CH2C12/曱醇， 99/1)純化，獲得〇·ΐ73克淡白色固體標題化合物。物理特徵：M.p. 161-166°C ; NMR (400 MHz，DMSO-d6)8 10.61， 8.70, 7·41-7·31，6.40-6.39, 6.29-6.28, 5.30, 4.75, 4.55, 3·93, 3.83，2.81-2.71，2·27; 13C NMR (100 ΜΗζ，CDC13)5 173.0, 164.9, 153,8, 150.6, 144.7, 142.4, 137.3, 132.8, 131.5, 128.9, 87731 -68- 200410970 128.7, 122.0, 115.8, 110.3, 107.2, 63.8, 60.9, 57.2, 43.2, 42.6, 41 ·9; MS (ESI+) m/z 486 (M+H)+。分析實測值：c，59.00; H， 5.04; N，8·58; Cl，7.28; S，6.57。實例2. (+)-N-(4-氯爷基）-2-((((R)-2-(2-吱喃基）-2-幾基乙基）（甲基）胺基）-甲基）-7 -甲基-4 -氧代-4,7 -二氫ρ塞吩并[2,3-b] p比淀- 5· 叛醯胺N- (4-Arylidene) -2- (aeromethyl) -7-methyl-4-oxo-4,7-dichloroρcepheno [2,3-b] pyridine-5- Carboxamide (Preparation Example 1, 0.250 g) was suspended in DMF (14 ml), and N, N-diisopropylethylamine (0.23 ml) and 1- (2-furyl) -2- (Methylamino) ethanol (Preparation Example 17, 0.231 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting off-white solid was filtered and purified by column chromatography (CH2C12 / methanol, 99/1) to obtain 0.73 g of the title compound as a pale white solid. Physical characteristics: Mp 161-166 ° C; NMR (400 MHz, DMSO-d6) 8 10.61, 8.70, 7.41-7 · 31, 6.40-6.39, 6.29-6.28, 5.30, 4.75, 4.55, 3.93, 3.83, 2.81-2.71, 2.27; 13C NMR (100 MHz, CDC13) 5 173.0, 164.9, 153,8, 150.6, 144.7, 142.4, 137.3, 132.8, 131.5, 128.9, 87731 -68- 200410970 128.7, 122.0, 115.8, 110.3, 107.2, 63.8, 60.9, 57.2, 43.2, 42.6, 41 · 9; MS (ESI +) m / z 486 (M + H) +. Anal. Found: c, 59.00; H, 5.04; N, 8.58; Cl, 7.28; S, 6.57. Example 2. (+)-N- (4-chloroethenyl) -2-(((((R) -2- (2-creanyl) -2-quinylethyl) (methyl) amino)) -Methyl) -7-methyl-4 -oxo-4,7-dihydroρ-sedeno [2,3-b] p-Hydro-5-tetamine

將消旋-N-(4-氯爷基）-2-(((2-(2-吱喃基）-2-經基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫魂吩并[2，3-b] ρ比咬 -5 - &酿胺（貫例1)於3 0 C之管柱溫度下製備性的溶於5 X 5 〇公分之ChiralcelOD-H 管柱（Chiral Technologies)上。移動相為50%兴丙Sf»/50%庚燒（v/v)’流速為70¾升/分鐘。高夸係以250 nm UV偵測。將487毫克樣品注入1〇毫升ιρΑ/ 50%CHC13(v/v)中。分離出更慢溶離之對映體，接著以管柱層析（Cf^Ch/甲醇，99/1)進一步純化。所得淡黃色固體自甲醇再結晶，獲得0.124克淡黃色固態標題化合物。物理特徵： M.p. 159-162°C ； lU NMR (400 MHz, DMS〇.d6)5 10.61, 8.70 7.56，7·41_7.31，6.40-6.39，6.30-6.29，5.30，4.76-4 72 455 3·93，3·83，2.81-2.72，2.27; MS (ESI+) m/z 486 (m+h)+; HRMS (FAB) m/z 486.1266 (M+H)+; [a]25D==+16 (c 〇 74, methylene chloride)。分析實測值：C，57·74; H，5.25; N，8 47· 87731 -69· 200410970The racemic-N- (4-chloroethenyl) -2-((((2- (2-creanyl) -2-merylethyl) (methyl) amino) methyl) -7-form Methyl-4-oxo-4,7-dihydroquinobenzo [2,3-b] ρ ratio bite -5-& stuffed amine (Constant Example 1) at a column temperature of 3 0 C Dissolved on a Chiralcel OD-H column (Chiral Technologies) of 5 x 50 cm. The mobile phase was 50% Xingpro Sf »/ 50% heptane (v / v) 'and the flow rate was 70¾ liters / minute. High exaggeration is detected with 250 nm UV. A 487 mg sample was injected into 10 ml ΙρΑ / 50% CHC13 (v / v). The more slowly eluting enantiomer was separated and further purified by column chromatography (Cf ^ Ch / methanol, 99/1). The resulting pale yellow solid was recrystallized from methanol to obtain 0.124 g of the title compound as a pale yellow solid. Physical characteristics: Mp 159-162 ° C; lU NMR (400 MHz, DMS〇.d6) 5 10.61, 8.70 7.56, 7.41_7.31, 6.40-6.39, 6.30-6.29, 5.30, 4.76-4 72 455 3 · 93, 3.83, 2.81-2.72, 2.27; MS (ESI +) m / z 486 (m + h) +; HRMS (FAB) m / z 486.1266 (M + H) +; [a] 25D == + 16 (c 〇74, methylene chloride). Analytical measured values: C, 57 · 74; H, 5.25; N, 8 47 · 87731 -69 · 200410970

Cl，7.03; S，6.36。實例3. 消旋-N-(4-氯苄基）-2-(((2-經基-2-(5-甲基-2-咬喃基）乙基）（甲基）胺基）甲基）-7·甲基_4_氧代-4,7_二氫p塞吩并[2,3-b] 吡啶-5-羧醯胺 CH, 〇 CH3 將N-(4-氯芊基）-2-(氯甲基）-7-甲基_4_氧代-4,7-二氫遠吩并[2,3-b]p比淀-5-複酿胺（製備例1，〇·5〇〇克）懸浮於dmF(30 毫升）中，且添加N，N-二異丙基乙胺（〇·46毫升）及2-(甲基胺基）-1-(5 -甲基-2-吱喃基）乙醇（製備例19，〇·4〇7克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水 (100毫升）中。過濾所得淡黃色固體，且以管柱層析（ch2ci2/ 甲醇，99/1)純化，獲得0.561克淡黃色固體，自乙腈再結晶，獲得0.527克白色固態標題化合物。物理特徵·· M.p. 137-140 φ °C； lH NMR (400 MHz5 DMSO-d6)5 10.61, 8.70, 7.41-7.31, 6.14-6.13，5.99-5.98，5.20, 4.68-4.63，4.55，3.93，3.86， 2.79-2.68, 2.27, 2.17； 13C NMR (100 MHz, CDC13)5 173.0, 165.0, 152.2, 151.9, 150.6, 148.4, 144.7, 138.1，137.3, 132.7， 131.5，128.9，128.6，121.7，115.7，108.2，106.1，63.8, 61.0， 57.2，43.1，42.5，41.8，13.6; MS (ESI+) m/z 500 (M+H)+; HRMS (FAB) m/z 500.1422 (M+H)+。分析實測值：C，59.28; H， 5.44; N，8_69; Cl，6.89; S，6.21。 87731 -70- 200410970 實例4. 消旋-N-(4-氯苄基）-2-(((2-(3-咬喃基）-2-輕基乙基）（甲基）胺基）甲基）-7 -甲基-4-氧代-4,7·二氫p塞吩并[2,3-b]p比淀-5-叛酸胺Cl, 7.03; S, 6.36. Example 3. Racemic-N- (4-chlorobenzyl) -2-((((2-Cycloyl-2- (5-methyl-2-pyranyl) ethyl) (methyl) amino)) (Methyl) -7.methyl_4_oxo-4,7_dihydrop-cepheno [2,3-b] pyridine-5-carboxamidine CH, 〇CH3 N- (4-chlorohydrazone ) -2- (chloromethyl) -7-methyl_4_oxo-4,7-dihydrotepheno [2,3-b] p biyodo-5-rejuvenated amine (Preparation Example 1 0.5 mg) was suspended in dmF (30 ml), and N, N-diisopropylethylamine (0.46 ml) and 2- (methylamino) -1- (5-- Methyl-2-elanyl) ethanol (Preparation Example 19, 4.07 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 ml). The obtained pale yellow solid was filtered and purified by column chromatography (ch2ci2 / methanol, 99/1) to obtain 0.561 g of a pale yellow solid, which was recrystallized from acetonitrile to obtain 0.527 g of the title compound as a white solid. Physical characteristics ·· Mp 137-140 φ ° C; lH NMR (400 MHz5 DMSO-d6) 5 10.61, 8.70, 7.41-7.31, 6.14-6.13, 5.99-5.98, 5.20, 4.68-4.63, 4.55, 3.93, 3.86, 2.79-2.68, 2.27, 2.17; 13C NMR (100 MHz, CDC13) 5 173.0, 165.0, 152.2, 151.9, 150.6, 148.4, 144.7, 138.1, 137.3, 132.7, 131.5, 128.9, 128.6, 121.7, 115.7, 108.2, 106.1 , 63.8, 61.0, 57.2, 43.1, 42.5, 41.8, 13.6; MS (ESI +) m / z 500 (M + H) +; HRMS (FAB) m / z 500.1422 (M + H) +. Analytical measured values: C, 59.28; H, 5.44; N, 8-69; Cl, 6.89; S, 6.21. 87731 -70- 200410970 Example 4. Racemic-N- (4-chlorobenzyl) -2-((((2- (3-Branyl) -2-lightylethyl) (methyl) amino) Methyl) -7-methyl-4-oxo-4,7 · dihydrop-pheneno [2,3-b] p

將1-(3·呋喃基）-2-(甲基胺基）乙醇（製備例20，0.370克）溶 | # 於DMF(30毫升）中，且添加N，N_二異丙基乙胺（〇·46毫升）及 Ν-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫噻吩并 [2,3-b]吡啶-5-羧醯胺（製備例1，0.500克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（1〇〇毫升）中。過濾所得灰白色固體，且以管柱層析（CH2C12/甲醇， 99/1，98/2)純化，獲得0.457克淡黃色固體，其自乙酸乙酯再結晶，獲得0.400克淡黃色固態標題化合物。物理特徵： Μ·ρ· 151-153〇C ; 4 NMR (400 MHz，DMSO_d6)S 10·61，8·70， φ 7.58-7.55, 7.41-7.32, 6.45, 5.03, 4.74-4.70, 4.55, 3.94, 3.86， 2.70-2.59, 2.29; 13C NMR (100 MHz, CDC13)6 173.05 164.9, 150.5, 144.7, 143.4, 139.4, 137.9, 137.3, 132.8, 131.5, 128.9, 128.6, 125.9, 121.7, 115.8, 108.4, 63.6, 62.9, 57.3, 43.2, 42.6, 41.9; MS (ESI+) m/z 486 (M+H)+; HRMS (FAB) m/z 486.1257 (M+H)+。分析實測值：C，59·23; H，4.99; N，8.59; Cl，7.19; S， 6.46。實例5. 87731 -71 - 200410970 消旋-2-(((2-(1-苯并呋喃_2·基）-2-羥基乙基）（甲基）胺基）甲基）-N-(4-氯苄基）-7_甲基_4_氧代二氫噻吩并[2,34]吡淀-5-叛醯胺1- (3 · furanyl) -2- (methylamino) ethanol (Preparation Example 20, 0.370 g) was dissolved in # # DMF (30 ml), and N, N_diisopropylethylamine was added (0.46 ml) and N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] Pyridine-5-carboxamide (Preparation Example 1, 0.500 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). The off-white solid obtained was filtered and purified by column chromatography (CH2C12 / methanol, 99/1, 98/2) to obtain 0.457 g of a pale yellow solid which was recrystallized from ethyl acetate to obtain 0.400 g of the title compound as a pale yellow solid. Physical characteristics: M · ρ · 151-153 ° C; 4 NMR (400 MHz, DMSO_d6) S 10.61, 8.70, φ 7.58-7.55, 7.41-7.32, 6.45, 5.03, 4.74-4.70, 4.55, 3.94 , 3.86, 2.70-2.59, 2.29; 13C NMR (100 MHz, CDC13) 6 173.05 164.9, 150.5, 144.7, 143.4, 133.4, 139.4, 137.9, 137.3, 132.8, 131.5, 128.9, 128.6, 125.9, 121.7, 115.8, 108.4, 63.6 , 62.9, 57.3, 43.2, 42.6, 41.9; MS (ESI +) m / z 486 (M + H) +; HRMS (FAB) m / z 486.1257 (M + H) +. Anal. Found: C, 59 · 23; H, 4.99; N, 8.59; Cl, 7.19; S, 6.46. Example 5. 87731 -71-200410970 racemic-2-((((2- (1-benzofuran_2 · yl) -2-hydroxyethyl) (methyl) amino) methyl) -N- ( 4-chlorobenzyl) -7_methyl_4_oxodihydrothieno [2,34] pyridine-5-benzidine

將N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5_羧醯胺（製備例卜〇·5克）、1_(^苯并呋喃-2-基）-2-(甲基胺基）乙醇（製備例21，〇.5克）及n，N-二異丙基乙 β 胺（0·91毫升）添加於二甲基甲醯胺（28毫升）中。使混合物在 90 C下攪拌2小時。使反應混合物冷卻至室溫且倒入水（丨〇〇耄升）中。开J成灰白色沉殿物且過滤。使沉殿物吸收於石夕膠上，且以管柱層析（Me〇H/CH2Cl2，1%)純化，獲得白色固體。粗物質自乙醇再結晶，獲得〇.36克白色固態所需產物。物理特徵：Μ·ρ. 212-214T： ; 4 NMR (300 MHz，DMSO-d60 10.62, 8.65, 7.59, 7·41，7.38, 7.35, 6.77, 5.60, 4.53, 3·81，3·68，· 2·94, 2·76, 2.33; HRMS (FAB) m/z 536.1406 (Μ+Η)+。分析實測值：C，62.57; Η，4.88; Ν，7.80; Cl，6·62; S5 5.95。實例6. 消旋_N-(4-氯芊基）_2-(((2-羥基-2-嘧吩-2-基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代_4,7_二氫嘧吩并[2,3-b]吡啶-5-羧醯胺N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5_carboxy Ammonium (Preparation Example 0.5 g), 1-(^ benzofuran-2-yl) -2- (methylamino) ethanol (Preparation Example 21, 0.5 g), and n, N-Diiso Propylethyl betaamine (0.91 ml) was added to dimethylformamide (28 ml). The mixture was stirred at 90 C for 2 hours. The reaction mixture was allowed to cool to room temperature and poured into water (1000 mL). Open J into a gray-white sink and filter. The Shen Dianwu was absorbed on Shi Xijiao and purified by column chromatography (MeOH / CH2Cl2, 1%) to obtain a white solid. The crude material was recrystallized from ethanol to obtain 0.36 g of the desired product as a white solid. Physical characteristics: M · ρ. 212-214T:; 4 NMR (300 MHz, DMSO-d60 10.62, 8.65, 7.59, 7.41, 7.38, 7.35, 6.77, 5.60, 4.53, 3.81, 3.68, · 2.94, 2.76, 2.33; HRMS (FAB) m / z 536.1406 (M + Η) +. Anal. Found: C, 62.57; H, 4.88; N, 7.80; Cl, 6.62; S5 5.95. Example 6. Racemic_N- (4-chlorofluorenyl) _2-(((2-hydroxy-2-pyrimin-2-ylethyl) (methyl) amino) methyl) -7-methyl -4-oxo_4,7_dihydropyridino [2,3-b] pyridine-5-carboxamide

87731 -72- 200410970 將N-(4-氯苄基）-2-(氯甲基）-7-甲基-4_氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·5克）、2-(甲基胺基）-卜嘧吩-2-基乙醇（製備例22，0.41克）及N，N-二異丙基乙胺 (0.91毫升）添加於二甲基甲醯胺（28毫升）中。使混合物在90 °C下攪拌2小時。使反應混合物冷卻至室溫且倒入水（100毫升）中。形成灰白色沉澱物且過濾。使沉澱物吸收於矽膠上，且以管柱層析（MeOH/CH2Cl2，3%)純化，獲得〇·51克黃色發泡體標題化合物。物理特徵：1HNMR(300 MHz，DMSO- ά6)δ 10.60, 8.70, 7.39, 7.35, 7.32, 6·97, 5.60, 4.54, 3.93, 3·87, 2.70, 2·31; MS (ESI+) m/z 502 (Μ+Η)+。分析實測值：c，57.20; H，4.97; Ν，8·30; Cl，7.01; S，12.54。實例7. 消旋-N-(4_氯苄基）-2-(((2-羥基-2-(lH-吡咯-2-基）乙基）（甲基）胺基）甲基）-7-甲基氧代-4,7-二氫p塞吩并[2,3-b]p比淀 -5 -羧酿胺87731 -72- 200410970 N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4_oxo-4,7-dihydropyrido [2,3-b] Pyridine-5-carboxamide (Preparation Example 1,5 g), 2- (methylamino) -pyrimidin-2-ylethanol (Preparation Example 22, 0.41 g), and N, N-diiso Propylethylamine (0.91 ml) was added to dimethylformamide (28 ml). The mixture was stirred at 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL). An off-white precipitate formed and was filtered. The precipitate was absorbed on silica gel and purified by column chromatography (MeOH / CH2Cl2, 3%) to obtain 0.51 g of the title compound as a yellow foam. Physical characteristics: 1HNMR (300 MHz, DMSO-ά6) δ 10.60, 8.70, 7.39, 7.35, 7.32, 6.97, 5.60, 4.54, 3.93, 3.87, 2.70, 2.31; MS (ESI +) m / z 502 (M + VII) +. Anal. Found: c, 57.20; H, 4.97; N, 8.30; Cl, 7.01; S, 12.54. Example 7. Racemic-N- (4-chlorobenzyl) -2-((((2-hydroxy-2- (lH-pyrrole-2-yl) ethyl) (methyl) amino) methyl)- 7-methyloxo-4,7-dihydrop-pheneno [2,3-b] p

將2-(甲基胺基）-1-( 1H-吡咯-2-基）乙醇（製備例23，0.541 克）溶於DMF(30毫升）中，且添加n，N_二異丙基乙胺（〇·46毫升）及Ν-(4-氣苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·500克反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（〖〇〇 87731 -73- 200410970 毫升）中。所得褐色固體經過濾且以管柱層析（CH2Cl2/甲醇；99/1 ’ 98/2)純化。所得灰白色固體自乙腈再結晶，獲得0.297克灰白色固態標題化合物。物理特徵；Μ·ρ. 169-172 C (分解）；4 NMR (400 MHz，DMSO-d6)5 10.63-10.60，8.70, 7.41-7.31，6.63-6.61，5.92-5.90，4.94，4.76-4.71，4.55，3.97， 3.84, 2.78-2.64, 2.08; 13C NMR (l〇〇 MHz, CDC13)6 172.9, 164.9，150.4，144.6，137.8，137.3，132.8，131.6，131·4，128.9, 128.7，121.8，117.4，115.8，108.4，104.6, 64.2, 63·1，58.7, 57·3, 43.1，42.6，42.1; MS (ESI+) m/z 485 (M+H)+; HRMS (FAB) m/z 485.1427 (M+H)+。分析實測值：C，59·2〇; H，5 26; N， 11.48; Cl，7.21; S，6.48。實例8. 消旋-N_(4-氯苄基）_2-(((2_羥基-2-(1-甲基-1H-吡咯-2-基）乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b] p比淀-5 -叛酸胺Dissolve 2- (methylamino) -1- (1H-pyrrole-2-yl) ethanol (Preparation Example 23, 0.541 g) in DMF (30 ml) and add n, N-diisopropylethyl Amine (0.46 ml) and N- (4-airbenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3- b] Pyridine-5-carboxamide (Preparation Example 1, 500 g of reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (〖〇87731-73- 200410970 ml) The obtained brown solid was filtered and purified by column chromatography (CH2Cl2 / methanol; 99/1 '98/2). The obtained off-white solid was recrystallized from acetonitrile to obtain 0.297 g of the title compound as an off-white solid. Physical characteristics; M · ρ 169-172 C (decomposition); 4 NMR (400 MHz, DMSO-d6) 5 10.63-10.60, 8.70, 7.41-7.31, 6.63-6.61, 5.92-5.90, 4.94, 4.76-4.71, 4.55, 3.97, 3.84, 2.78-2.64, 2.08; 13C NMR (100MHz, CDC13) 6 172.9, 164.9, 150.4, 144.6, 137.8, 137.3, 132.8, 131.6, 131.4, 128.9, 128.7, 121.8, 117.4, 115.8, 108.4, 104.6 , 64.2, 63 · 1, 58.7, 57 · 3, 43.1, 42.6, 42.1; MS (ESI +) m / z 485 (M + H) +; HRMS (FAB) m / z 485.1427 (M + H) +. Analysis found: C, 59 · 20; H, 5 26; N, 11.48; Cl, 7.21; S , 6.48. Example 8. Racemic-N_ (4-chlorobenzyl) _2-(((2-hydroxy-2- (1-methyl-1H-pyrrole-2-yl) ethyl) (methyl) amine Methyl) -7-methyl-4-oxo-4,7-dihydropyridino [2,3-b] p

ch3 將N-(4-氣苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]p比淀-5-叛酿胺（製備例1，0.500克）懸浮於DMF(30 毫升）中，且添加Ν，Ν·二異丙基乙胺（0·46毫升）及2-(甲基胺基）_1-(1-甲基-1Η-吡咯-2-基）乙醇（製備例24，0.404克）。反應混合物加熱至90°C 1小時。使反應混合物冷卻至室溫且倒入水（100毫升）中。所得褐色固體經過濾且以管柱層析 87731 -74- 200410970 (CHAh/甲醇；99/1)純化，獲得〇·443克淡黃色固體，其自甲醇再結晶，接著自乙酸乙酯再結晶，獲得〇322克灰白色固體標題化合物。物理特徵；Μ·ρ· :^0-1451: 4 NMR (400 MHz，DMSO-d6)5 10.61，8.70, 7.41-7.33, 6.63-6.62, 5.91-5.90, 4.55，3.94，3·90_3·82，3.58，2.83-2.73，2.30; 13C NMR (100 ΜΗζ，CDC13)6 173.0, 164.9, 150.5, 148.4, 144.7, 138.1，137.3, 132.8，131.5，131.4，128.9，128.6，123.4，121.7，115.8, 106.8, 106.0, 62·0, 61.2, 57.4, 43.1，42.5, 42·0, 34·1; MS (ESI+) m/z 499 (Μ+Η)+; HRMS (FAB) m/z 499.1584 (Μ+Η)+。分析實測值：C，59·94; Η，5·56; Ν，10.94; C1，6.94; S，6.25。實例9. 消旋-Ν-(4-氯苄基）-2-(((2_羥基-2-(1-甲基-1Η-咪唑-4-基）乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫遠吩并[2，3-b] 吡啶-5-羧醯胺ch3 converts N- (4-airbenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydropyridino [2,3-b] p 5-Betamin (Preparation Example 1, 0.500 g) was suspended in DMF (30 ml), and Ν, Ν · diisopropylethylamine (0.46 ml) and 2- (methylamino) _1 were added -(1-methyl-1fluorene-pyrrole-2-yl) ethanol (Preparation Example 24, 0.404 g). The reaction mixture was heated to 90 ° C for 1 hour. The reaction mixture was cooled to room temperature and poured into water (100 ml). The resulting brown solid was filtered and purified by column chromatography 87731 -74- 200410970 (CHAh / methanol; 99/1) to obtain 0.443 g of a pale yellow solid which was recrystallized from methanol and then recrystallized from ethyl acetate. Obtained 322 g of the title compound as an off-white solid. Physical characteristics: M · ρ ·: ^ 0-1451: 4 NMR (400 MHz, DMSO-d6) 5 10.61, 8.70, 7.41-7.33, 6.63-6.62, 5.91-5.90, 4.55, 3.94, 3.90_3 · 82, 3.58, 2.83-2.73, 2.30; 13C NMR (100 MHz, CDC13) 6 173.0, 164.9, 150.5, 148.4, 144.7, 138.1, 137.3, 132.8, 131.5, 131.4, 128.9, 128.6, 123.4, 121.7, 115.8, 106.8, 106.0 , 62.0, 61.2, 57.4, 43.1, 42.5, 42.0, 34.1; MS (ESI +) m / z 499 (Μ + Η) +; HRMS (FAB) m / z 499.1584 (Μ + Η) + . Analyzed and measured values: C, 59.94; Η, 5.56; N, 10.94; C1, 6.94; S, 6.25. Example 9. Racemic-N- (4-chlorobenzyl) -2-((((2-hydroxy-2- (1-methyl-1Η-imidazol-4-yl) ethyl) (methyl) amino ) Methyl) -7-methyl-4-oxo-4,7-dihydrotelebenzo [2,3-b] pyridine-5-carboxamide

ch3 將2·(甲基胺基）-1-(1-甲基-1H-味吐-4 -基）乙醇（製備例 25，0.145克）溶於DMF( 12毫升）中，且添加Ν，Ν-二異丙基乙胺（0·18毫升）及Ν-(4-氯芊基）-2-(氯甲基）-7-甲基-4-氧代 -4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·2〇〇克）。反應混合物加熱至90°C 1小時。使反應混合物冷卻至室溫且倒入水（40毫升）中並在冷涞櫃中貯存1小時。所得灰白色固體經過濾且以管柱層析（CHiCh/甲醇；98/2)純化，獲得0.091 87731 -75- 200410970 克黃色膠體狀固體，其自乙酸乙酯再結晶，接著自乙腈再結晶，獲得0.044克淡黃色固體標題化合物。物理特徵；M.p. 124-130。。；巾 NMR (400 MHz，DMSO-d6)5 10.62, 8.70, 7.45, 7.41-7.31， 6.93， 4.79， 4.68-4.64， 4·55， 3.95， 3.86， 3.60, 2.77-2.64，2·30; MS (ESI+) m/z 500 (Μ+Η)+。分析實測值.c 56·05; Η，5·40; N，13.59; Cl, 6.92; S，6.22。製備例40 消旋-N-(4 -氣卞基）-2_(((2-藉基-2-(1-三苯基甲基咪口坐 -4-基）乙基）（甲基）胺基）甲基）_7_甲基-4-氧代-4,7-二氳p塞吩并[2,3-b]吡啶-5-羧醯胺ch3 Dissolve 2 · (methylamino) -1- (1-methyl-1H-weito-4-yl) ethanol (Preparation Example 25, 0.145 g) in DMF (12 ml), and add Ν, N-diisopropylethylamine (0.18 ml) and N- (4-chlorofluorenyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydropyrimidine Benzo [2,3-b] pyridine-5-carboxamide (Preparation Example 1.200 g). The reaction mixture was heated to 90 ° C for 1 hour. The reaction mixture was cooled to room temperature and poured into water (40 mL) and stored in a cold heading cabinet for 1 hour. The obtained off-white solid was filtered and purified by column chromatography (CHiCh / methanol; 98/2) to obtain 0.091 87731 -75- 200410970 g of a yellow colloidal solid which was recrystallized from ethyl acetate and then recrystallized from acetonitrile to obtain 0.044 g of the title compound as a pale yellow solid. Physical characteristics; M.p. 124-130. . NMR (400 MHz, DMSO-d6) 5 10.62, 8.70, 7.45, 7.41-7.31, 6.93, 4.79, 4.68-4.64, 4.55, 3.95, 3.86, 3.60, 2.77-2.64, 2.30; MS ( ESI +) m / z 500 (Μ + Η) +. Analyze measured values. C 56 · 05; Η, 5.40; N, 13.59; Cl, 6.92; S, 6.22. Preparation Example 40 Racemic-N- (4-Arylidene) -2 _ (((2-boryl-2- (1-triphenylmethylimidino-4-yl) ethyl) (methyl) Amine) methyl) _7_methyl-4-oxo-4,7-difluorenylp-pheneno [2,3-b] pyridine-5-carboxamide

將N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]p比淀-5-叛醯胺（製備例1，〇·2〇〇克）懸浮於dmF(11 毫升）中，且添加N，N-二異丙基乙胺（o.u毫升）及2-(甲基胺基）-1-(1-三苯基甲基_1H_咪唑_4-基）乙醇（製備例26，〇·242 克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至 1：溫且倒入水（30毫升）中。所得灰白色固體經過濾且以管柱層析（CHAl2/甲醇；98/2，96/4)純化，獲得0.268克淡黃色固體標越化合物。物理特徵；M.p. 105-112°C ;丨11 NMR (400 MHz，DMSO-d6)S 10.62, 8.69, 7.41-7.28, 7.08-7.06, 6.76, 4.90, 4·69-4·65，4.55，3.87，3.82-3.78，2.84-2.80，2.69-2.64，2.27; 13C NMR (100 MHz, CDC13)5 173.0, 165.0, 150.5, 144.5, 87731 76- 200410970N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] p -Betamine (Preparation Example 1, 0.2 g) was suspended in dmF (11 ml), and N, N-diisopropylethylamine (ou ml) and 2- (methylamino) were added 1- (1-triphenylmethyl_1H_imidazole_4-yl) ethanol (Preparation Example 26, 0.242 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to 1: warm and poured into water (30 mL). The obtained off-white solid was filtered and purified by column chromatography (CHAl2 / methanol; 98/2, 96/4) to obtain 0.268 g of the standard compound as a pale yellow solid. Physical characteristics; Mp 105-112 ° C; 11 NMR (400 MHz, DMSO-d6) S 10.62, 8.69, 7.41-7.28, 7.08-7.06, 6.76, 4.90, 4.69-4 · 65, 4.55, 3.87, 3.82-3.78, 2.84-2.80, 2.69-2.64, 2.27; 13C NMR (100 MHz, CDC13) 5 173.0, 165.0, 150.5, 144.5, 87731 76- 200410970

142.3, 138.6, 137.3, 132.7, 131.6，129.8，128.9，128.6，128.0, 121.4，118.5，115.7，65.1，62.8，57.3，43.1，42.5，42.0; MS (ESI+) m/z 728 (M+H)+。分析實測值：c，68 61; H，5 3七 n， 9.45。實例10· 消旋-Ν·(4-氯芊基）-2-(((2•羥基_2_(1H-咪唑-4_基）乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7_二氫嘧吩并[2,3_b]吡啶142.3, 138.6, 137.3, 132.7, 131.6, 129.8, 128.9, 128.6, 128.0, 121.4, 118.5, 115.7, 65.1, 62.8, 57.3, 43.1, 42.5, 42.0; MS (ESI +) m / z 728 (M + H) + . Analytical measured values: c, 68 61; H, 5 37, n, 9.45. Example 10 Racemic-N · (4-chlorofluorenyl) -2-((((2 • hydroxy_2_ (1H-imidazol-4-yl) ethyl) (methyl) amino) methyl) -7 -Methyl-4-oxo-4,7_dihydropyridino [2,3_b] pyridine

將消旋-N-(4-氯苄基）-2-(((2-羥基-2-(1-三苯基甲基-1H_ 咪唑-4-基）乙基）（甲基）胺基）甲基）_7_甲基_4_氧代·-二氫嘧吩并[2,3-b]吡啶_5_羧醯胺（製備例4〇，〇·243克）溶於 THF(10毫升）中，且滴加含ι·〇 M HC1之EhO溶液（0·37毫升）。反應/m合物在皇溫下擾掉2 0分鐘。添加甲醇（2毫升），接肴添加含1.0MHC1之Et2〇落液（〇·37毫升）。在室溫下持續攪拌1小時，且添加甲醇之鹽酸（1毫升）。反應混合物在室溫下攪拌1小時，再加熱至50°c 6小時。使反應混合物冷卻至 A溫。過滤沉殿之淡黃色固體，且溶於水中，且以2 n NaOH 浴液將〉谷液之pH #1整為8。所得黃色經過濾、，且自乙腈再結晶，獲得〇· 101克淡黃色固態標題化合物。物理特徵：M p. 164-169°C ； !H NMR (400 MHz, DMSO-d6)5 11.87? 10.62, 8.70 7.52，7.41-7.31，6.88，4.89，4·75，4.55，3.94，3.85，2.80-2.68 87731 -77- 200410970 2.29; MS (ESI+) m/z 486 (M+H)+。分析實測值：c，56 46; η 5·02; N，14.24; Cl，7·36; S，6.55。實例11 · 消旋-N-(4-氯苄基）-2-(((2-¾基-2-(1 H-吲嗓-3_基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3讣]吡啶 -5 -叛酿胺The racemic-N- (4-chlorobenzyl) -2-((((2-hydroxy-2- (1-triphenylmethyl-1H_imidazol-4-yl) ethyl) (methyl) amino ) Methyl) _7_methyl_4_oxo · -dihydropyridino [2,3-b] pyridine-5_carboxamidine (Preparation Example 4.0, 243 g) was dissolved in THF (10 Ml), and an EhO solution (0.37 ml) containing 1 · M HC1 was added dropwise. The reaction / m complex was disturbed for 20 minutes at a high temperature. Methanol (2 ml) was added, and then Et20 (1.07 ml) containing 1.0 MHC1 was added. Stirring was continued at room temperature for 1 hour, and methanolic hydrochloric acid (1 ml) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated to 50 ° C for 6 hours. The reaction mixture was allowed to cool to A temperature. Filter the pale yellow solid of Shen Dian, and dissolve it in water, and adjust the pH # 1 of the> valley solution to 8 with 2 n NaOH bath. The resulting yellow was filtered and recrystallized from acetonitrile to obtain 0.101 g of the title compound as a pale yellow solid. Physical characteristics: M p. 164-169 ° C;! H NMR (400 MHz, DMSO-d6) 5 11.87? 10.62, 8.70 7.52, 7.41-7.31, 6.88, 4.89, 4.75, 4.55, 3.94, 3.85, 2.80 -2.68 87731 -77- 200410970 2.29; MS (ESI +) m / z 486 (M + H) +. Analytical measured values: c, 56 46; η 5.02; N, 14.24; Cl, 7.36; S, 6.55. Example 11 Racemic-N- (4-chlorobenzyl) -2-((((2-¾yl-2- (1 H-indol-3-yl) ethyl) (methyl) amino)- (Methyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3 讣] pyridine-5 -fermentamine

將N-(4-氯苄基）-2-(氯甲基）-7-甲基-4_氧代-4,7-二氫嘍吩并[2,3-b]p比淀-5-羧酸胺（製備例1，0.500克）懸浮於dmf(30 毫升）中，且添加N，N-二異丙基乙胺（〇·34毫升）二氫_1Η· Η卜朵-3 -基）-2-(甲基胺基）乙醇（製備例27，0.375 克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（60毫升）中。所得棕白色固體經過濾且以管柱層析（Cl^Ch/甲醇；99/1，98/2)純化。所得黃色膠體狀固體 _ 自乙酸乙酯再結晶，獲得0.245克淡黃色固體標題化合物。物理特徵；Μ·ρ· 120-123°C ; 4 NMR (400 MHz，DMSO-d6)5 10.86, 10.62, 8.69, 7.53-7.51，7.41-7.31，7.22-7·21，7.03-6.99， 6.88-6.85，5.07-5.03, 4.85, 4.55, 3.90, 3.88, 2.85-2.81，2.36; 13C NMR (100 MHz，CDC13)S 173·0，171.2，165.0，150.6， 144.6, 137.3, 136.5, 132.8, 131·5, 128.9, 128.7, 125·7, 122.3， 121.6, 119.7, 119.3, 116.5, 115.7, 111.3, 64.4, 63.4, 60.4, 57.3， 43.1，42.6, 42·1，21.1，14·2; MS (ESI+) m/z 535 (Μ+Η)+。分 87731 -78- 200410970 析實測值：C，61.85; H，5.41; N，9.61; Cl，6.12; S，5.53。實例12· 消旋-Ν-(4-氣苄基）-2-(((2-(2,5-二甲基_3_呋喃基）_2_羥基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代_4,7_二氫噻吩并[2,3、b] p比淀-5-叛Si胺N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4_oxo-4,7-dihydrofluoreno [2,3-b] p ratio lake-5 -Carboxylic acid amine (Preparation Example 1, 0.500 g) was suspended in dmf (30 ml), and N, N-diisopropylethylamine (0.34 ml) was added dihydro-1Η · Η 卜朵 -3- Methyl) -2- (methylamino) ethanol (Preparation Example 27, 0.375 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (60 mL). The obtained brownish white solid was filtered and purified by column chromatography (ClCh / methanol; 99/1, 98/2). The resulting yellow colloidal solid was recrystallized from ethyl acetate to obtain 0.245 g of the title compound as a pale yellow solid. Physical characteristics; M · ρ · 120-123 ° C; 4 NMR (400 MHz, DMSO-d6) 5 10.86, 10.62, 8.69, 7.53-7.51, 7.41-7.31, 7.22-7 · 21, 7.03-6.99, 6.88- 6.85, 5.07-5.03, 4.85, 4.55, 3.90, 3.88, 2.85-2.81, 2.36; 13C NMR (100 MHz, CDC13) S 173 · 0, 171.2, 165.0, 150.6, 144.6, 137.3, 136.5, 132.8, 131.5 , 128.9, 128.7, 125 · 7, 122.3, 121.6, 119.7, 119.3, 116.5, 115.7, 111.3, 64.4, 63.4, 60.4, 57.3, 43.1, 42.6, 42 · 1, 21.1, 14.2; MS (ESI +) m / z 535 (Μ + Η) +. Analysis 87731 -78- 200410970 Found: C, 61.85; H, 5.41; N, 9.61; Cl, 6.12; S, 5.53. Example 12 · Racemic-N- (4-airbenzyl) -2-((((2- (2,5-dimethyl-3_furanyl) _2_hydroxyethyl) (methyl) amino)) (Methyl) -7-methyl-4-oxo_4,7_dihydrothieno [2,3, b] p

ch3 將1-(2,5_二甲基-3-呋喃基）-2-(甲基胺基）乙醇（製備例 _ 29，0.333克）溶於於DMF(30毫升）中，且添加N，N二異丙基乙胺（0.34毫升）及N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代 -4,7-二氫嘍吩并[2,3-13]吡啶-5-羧醯胺（製備例1，〇：5〇〇克）。反應混合物加熱至90°C 1小時。使反應混合物冷卻至室溫且倒入水（100毫办）中。過渡所得灰白色固體，且自乙腈再結晶’獲得〇·550克综色固體，其自甲醇再結晶，獲得〇·337淡黃色固態標題化合物。物理特徵：Μ·ρ· 167-172°C ; 4 NMR φ (400 MHz，DMSO-d6)5 10.61，8.70，7.41-7.31，5.91，4.75， 4.61-4.57, 4.55, 3.97, 3.83, 2.67-2.62, 2.54-2.46, 2.27, 2.17， 2·15; 13C NMR (100 ΜΗζ，CDC13)5 173.0, 164.9, 150.6, 150.1, 146.9，144.7，137.3，132.8，131.5，128.9，128.7，121.8, 119.6， 115.8，104.4，63.3，62.5，57·2，43.2，42.6，41.8，13.4，11·8; MS (ESI+) m/z 515 (Μ+Η)+。分析實測值：c，6〇·35; Η，5·47; Ν， 8·14 〇實例13. 87731 79- 200410970 消旋-2-(((2-(1-苯并4吩-3-基）-2-羥基乙基）（甲基）胺基）甲基）-N-(4_氯苄基）-7-甲基-4-氧代_4,7_二氫噻吩并[2,3_b]吡ch3 1- (2,5_dimethyl-3-furyl) -2- (methylamino) ethanol (Preparation Example_ 29, 0.333 g) was dissolved in DMF (30 ml), and N was added , N-Diisopropylethylamine (0.34 ml) and N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrofluorene [2,3-13] pyridine-5-carboxamide (Preparation Example 1, 0: 500 g). The reaction mixture was heated to 90 ° C for 1 hour. The reaction mixture was cooled to room temperature and poured into water (100 mmol). The resulting off-white solid was transitioned and recrystallized from acetonitrile to obtain 0.550 g of a solid colored solid which was recrystallized from methanol to obtain the title compound as a pale yellow solid of 0.337. Physical characteristics: M · ρ · 167-172 ° C; 4 NMR φ (400 MHz, DMSO-d6) 5 10.61, 8.70, 7.41-7.31, 5.91, 4.75, 4.61-4.57, 4.55, 3.97, 3.83, 2.67-2.62 , 2.54-2.46, 2.27, 2.17, 2.15; 13C NMR (100 MHz, CDC13) 5 173.0, 164.9, 150.6, 150.1, 146.9, 144.7, 137.3, 132.8, 131.5, 128.9, 128.7, 121.8, 119.6, 115.8, 104.4, 63.3, 62.5, 57.2, 43.2, 42.6, 41.8, 13.4, 11.8; MS (ESI +) m / z 515 (M + Η) +. Analyzed and measured values: c, 60.35; Hf, 5.47; N, 8.14. Example 13. 87731 79- 200410970 Racem-2-(((2- (1-benzo4phen-3- Group) -2-hydroxyethyl) (methyl) amino) methyl) -N- (4-chlorobenzyl) -7-methyl-4-oxo_4,7_dihydrothieno [2 , 3_b] pyridine

將l-(3a，7a-二氫小苯并噻唑-3_基）_2-(甲基胺基）乙醇（製備例30，0.408克）溶於於DMF(30毫升）中，且添加n，n_二異丙基乙胺（0.34毫升）及N_(4-氯宇基）_2-(氯甲基）_7_甲基·4_ _ 氧代-4,7-二氫雇吩并[2,3-b]p比啶-5-羧酸胺（製備例1，〇·5〇〇克）。反應混合物加熱至90 C 1小時。使反應混合物冷卻至室溫且倒入水（60毫升）中。過濾所得褐色固體，且自 DMF/H2〇再結晶，獲得0.468克白色固態標題化合物。物理特徵：Μ·ρ· 213-219°C (分解）；bNMR (400 MHz，DMSO-d6)5 10.61，8.67, 7·95-7·93, 7·81，7.57, 7.41-7.33, 7.28-7.21，5.39， 5.17-5.13, 4.55, 3.87, 3.84, 2.89-2.73, 2.39; MS (ESI+) m/z 552 (M+H)+。分析實測值：c，60.75; H，4.75; N，7.60; Cl，6·46; S， 11·62 。實例14. 消旋-N-(4-氯芊基）·2-(((2-羥基-2-(1-甲基吲哚-2-基）乙基）（甲基）胺基）甲基)-7-甲基-4-氧代-4,7-二氫p塞吩并[2,3-b] 吡啶-5-羧醯胺L- (3a, 7a-dihydro small benzothiazol-3-yl) _2- (methylamino) ethanol (Preparation Example 30, 0.408 g) was dissolved in DMF (30 ml), and n was added, n_diisopropylethylamine (0.34 ml) and N_ (4-chloroumyl) _2- (chloromethyl) _7_methyl · 4_ _oxo-4,7-dihydrothiopheno [2, 3-b] p-pyridine-5-carboxylic acid amine (Preparation Example 1.500 g). The reaction mixture was heated to 90 C for 1 hour. The reaction mixture was cooled to room temperature and poured into water (60 mL). The resulting brown solid was filtered and recrystallized from DMF / H20 to obtain 0.468 g of the title compound as a white solid. Physical characteristics: M · ρ · 213-219 ° C (decomposition); bNMR (400 MHz, DMSO-d6) 5 10.61, 8.67, 7.95-7 · 93, 7.81, 7.57, 7.41-7.33, 7.28- 7.21, 5.39, 5.17-5.13, 4.55, 3.87, 3.84, 2.89-2.73, 2.39; MS (ESI +) m / z 552 (M + H) +. Analytical measured values: c, 60.75; H, 4.75; N, 7.60; Cl, 6.46; S, 11.62. Example 14. Racemic-N- (4-chlorofluorenyl) · 2-(((2-hydroxy-2- (1-methylindol-2-yl) ethyl) (methyl) amino) formaldehyde ) -7-methyl-4-oxo-4,7-dihydrop-pheneno [2,3-b] pyridine-5-carboxamide

87731 -80 - 200410970 將2-(甲基胺基）-1-(1-甲基-1H-蚓哚-2-基）乙醇（製備例 31，0.100克）溶於於DMF(10毫升）中，且添加n，N-二異丙基乙胺（0.085毫升）及N-(4-氯苄基）-2-(氣甲基）-7-甲基-4-氧代 -4,7-二氫嘧吩并[2,3吨]吡啶-5-羧醯胺（製備例1，〇.156克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（25毫升）中。過濾所得褐色固體，且以管柱層析 (CH^Ch/甲醇，99/1)純化，獲得0.086克淡黃色固態標題化合物。物理特徵：Μ·ρ· 128-132°C (分解）；iHNMRGOOMHz， DMSO-d6)5 10.60, 8.65, 7.47-7.45, 7.41-7.33, 7.12-7.08, 7.00-6.97, 6.35, 5.35, 5·03·4·99, 4.55, 3.91-3.83, 3.72, 3.71， 2.95-2.83, 2.37; 13C NMR (100 MHz, CDC13)6 173.0, 164.9, 150.5, 144.6, 138.9, 137.9, 137.3, 132_8, 131.5, 128.9, 128.7, 127.2, 121·8, 120.7, 119.6, 115.8, 109.0, 99.3, 63·1，61.3, 57.4, 43·0, 42.6, 42.3, 30.0; MS (ESI+) m/z 549 (M+H)+; HRMS (FAB) m/z 549.1710 (M+H)+。分析實測值·· C，62·79; H，5·49; N，9·96; Cl，6.38; S，5.84。製備例15. 消旋-Ν-(4·氯苄基）-2_(((2-(5-氰基嘧吩-2-基）-2-羥基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫噻吩并[2,3-b] 吡啶-5-羧醯胺87731 -80-200410970 Dissolve 2- (methylamino) -1- (1-methyl-1H-earm-2-yl) ethanol (Preparation Example 31, 0.100 g) in DMF (10 ml) And add n, N-diisopropylethylamine (0.085 ml) and N- (4-chlorobenzyl) -2- (gasmethyl) -7-methyl-4-oxo-4,7- Dihydropyrido [2,3 tons] pyridine-5-carboxamide (Preparation Example 1, 0.156 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (25 ml). The resulting brown solid was filtered and purified by column chromatography (CH / Ch / methanol, 99/1) to obtain 0.086 g of the title compound as a pale yellow solid. Physical characteristics: M · ρ · 128-132 ° C (decomposition); iHNMRGOOMHz, DMSO-d6) 5 10.60, 8.65, 7.47-7.45, 7.41-7.33, 7.12-7.08, 7.00-6.97, 6.35, 5.35, 5.03 4.99, 4.55, 3.91-3.83, 3.72, 3.71, 2.95-2.83, 2.37; 13C NMR (100 MHz, CDC13) 6 173.0, 164.9, 150.5, 144.6, 138.9, 137.9, 137.3, 132_8, 131.5, 128.9, 128.7, 127.2, 121 · 8, 120.7, 119.6, 115.8, 109.0, 99.3, 63 · 1, 61.3, 57.4, 43 · 0, 42.6, 42.3, 30.0; MS (ESI +) m / z 549 (M + H) + HRMS (FAB) m / z 549.1710 (M + H) +. Analytical measured values · C, 62 · 79; H, 5.49; N, 9.96; Cl, 6.38; S, 5.84. Production Example 15. Racemic-N- (4-chlorobenzyl) -2 _ (((2- (5-cyanopyrimin-2-yl) -2-hydroxyethyl) (methyl) amino) formaldehyde ) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide

將5-(1-羥基-2-(甲基胺基）乙基>塞吩_2_腈（製備例33， 87731 -81 - 200410970 0」82克）溶於於DMF(15毫升）中，且添加N，N_二異丙基乙胺 (0.17¾升）及N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·25〇克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（30毫升）中，且以CH2C12(4X25毫升）萃取。合併之有機層經脫水（MgSCU)、過濾且真空濃縮。所得橘色油狀物以管柱層析（CH2C12/甲醇’ 99/1)純化。所得淡黃色固體自乙酸乙酯再結晶，獲得0.117克白色固態標題化合物。物理特徵·· Μρ· 155-160。(：（分解）；4 NMR (400 MHz，DMSO-d6)5 10.60, 8.71， 7.85, 7.41-7.33, 7.15, 6·13, 5.07, 4.55, 3.94, 3.89, 2.72-2.70, 2.32; 13C NMR (100 ΜΗζ，CDC13)5 173.0, 164.8, 154.1，150.5, 144.8, 137.4, 137·3, 136.8, 132.8, 131.5, 128.9, 128.7, 123·3, 122.3，115.9，114.3，108.6, 66.4, 64.4, 57.3, 43.2, 42.6, 41·9; MS (ESI+) m/z 527 (Μ+Η)+。分析實測值：C，56·73; Η，4.44; Ν， 10.54; C1，6·75; S，12·03。實例16· 消旋-Ν-(4_氯苄基）-2_(((2-羥基-2_(1，3-嘧唑-2-基）乙基）（甲基）胺基）-甲基）_7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶 -5-羧醯胺5- (1-Hydroxy-2- (methylamino) ethyl > thiophene 2-nitrile (Preparation Example 33, 87731 -81-200410970 0 "82 g) was dissolved in DMF (15 ml) And add N, N-diisopropylethylamine (0.17¾ liters) and N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7 -Dihydrothieno [2,3-b] pyridine-5-carboxamide (Preparation Example 1, 0.250 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured Into water (30 ml) and extracted with CH2C12 (4X25 ml). The combined organic layers were dehydrated (MgSCU), filtered and concentrated in vacuo. The resulting orange oil was subjected to column chromatography (CH2C12 / methanol '99 / 1) Purification. The obtained pale yellow solid was recrystallized from ethyl acetate to obtain 0.117 g of the title compound as a white solid. Physical characteristics. Mp. 155-160. 10.60, 8.71, 7.85, 7.41-7.33, 7.15, 6.13, 5.07, 4.55, 3.94, 3.89, 2.72-2.70, 2.32; 13C NMR (100 MHz, CDC13) 5 173.0, 164.8, 154.1, 150.5, 144.8, 137.4 , 137.3, 136.8, 132.8, 131.5, 128.9, 128.7, 123.3, 122.3, 115.9, 114.3 108.6, 66.4, 64.4, 57.3, 43.2, 42.6, 41 · 9; MS (ESI +) m / z 527 (Μ + Η) +. Analytical measured values: C, 56.73; Η, 4.44; Ν, 10.54; C1 , 6.75; S, 12.03. Example 16. Racemic-N- (4-chlorobenzyl) -2 _ (((2-hydroxy-2_ (1,3-pyrazol-2-yl) ethyl ) (Methyl) amino) -methyl) _7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxamide

使N-(4-氯爷基）-2-(氯甲基）-7 -甲基-4-氧代-4，7-二氫隹吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇.〇8克）、DMF(2毫升）及 87731 -82 - 200410970 N，N-二異丙基乙胺（〇·11毫升）與4埃分子篩（0.100克）攪拌1 小時，接著添加2-(甲基胺基）-1-(1，3-喳唑-2-基）乙醇（製備例 35, 0.050克）。使混合物在85°C下攪拌3小時。添加飽和NH4C1 水溶液。混合物以CHeu萃取。合併之有機層經脫水 (MgS04)、過濾且濃縮。粗產物自乙腈再結晶，獲得0.059 克灰白色固態標題化合物。物理特徵：M.p. 129-133°C ; 4 NMR (400 MHz，DMSO-d6)3 10.61，8.70, 7.73-7.72, 7.64-7.63, 7.41-7.39, 7.35-7.33, 7.33-7.31, 6.21-6.19, 5.12-5.02, 4.55- 4·53, 3.93, 3.89, 2.94-2.90, 2.79-2.75, 2·34; MS (ESI+) m/z 503 (Μ+Η)+; HRMS (FAB) m/z 503.0983 (Μ+Η)+ 〇實例17 消旋-2-(((2-(1,3-苯并噻唑-2-基）-2-羥基乙基）（甲基）胺基）_ 甲基）-N-(4-氯苄基）-7-甲基_4_氧代-4,7-二氫碟吩并[2,3-b] 吡啶-5-羧醯胺N- (4-chloroethenyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrofluoreno [2,3-b] pyridine-5-carboxy Amidine (Preparation Example 1.08 g), DMF (2 ml) and 87731 -82-200410970 N, N-diisopropylethylamine (0.11 ml) were stirred with 4 angstrom molecular sieve (0.100 g) After 1 hour, 2- (methylamino) -1- (1,3-oxazol-2-yl) ethanol was added (Preparation Example 35, 0.050 g). The mixture was stirred at 85 ° C for 3 hours. A saturated aqueous NH4C1 solution was added. The mixture was extracted with CHeu. The combined organic layers were dried (MgS04), filtered and concentrated. The crude product was recrystallized from acetonitrile to obtain 0.059 g of the title compound as an off-white solid. Physical characteristics: Mp 129-133 ° C; 4 NMR (400 MHz, DMSO-d6) 3 10.61, 8.70, 7.73-7.72, 7.64-7.63, 7.41-7.39, 7.35-7.33, 7.33-7.31, 6.21-6.19, 5.12 -5.02, 4.55- 4.53, 3.93, 3.89, 2.94-2.90, 2.79-2.75, 2.34; MS (ESI +) m / z 503 (Μ + Η) +; HRMS (FAB) m / z 503.0983 (Μ + Η) + 〇 Example 17 Racem-2-(((2- (1,3-benzothiazol-2-yl) -2-hydroxyethyl) (methyl) amino) -methyl) -N -(4-chlorobenzyl) -7-methyl-4_oxo-4,7-dihydrodipheno [2,3-b] pyridine-5-carboxamide

使N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫遠吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·2〇克）、DMF(5毫升）及 N，N-二異丙基乙胺（0.24毫升）與4埃分子篩(0.200克）擾拌i 小時，接著添加1-(1，3-苯并嘧唑-2-基）-2-(甲基胺基）乙醇（製備例37，0.12克）。使混合物在80°C下攪拌3小時。加水且以 CHAh萃取。合併有機層，經脫水（MgSCU)、過濾且濃縮。粗產物以色谱儀純化’獲得0.053克灰白色固態標題化合 87731 -83- 200410970 物。物理特徵：NMR (400 MHz，DMSO-d6)5 10.60, 8.66, 8.09-8.07，7.93-7.91，7.46-7.31，6.45-6.44，5.16，4.55-4.53, 3.895 3.73, 3.02-2.98, 2.92-2.87, 2.38; 13C NMR (CDC13)5 174.5，173.4，165.3, 53.5，150.9, 145.1，137.7，137.6，135.0, 133.2, 13 1.9, 129.3, 129.0, 126.5, 125.4, 123.2, 122.5, 122.2, 116.2, 69.2, 62.8, 57.7, 43.5, 43.0, 42.5; MS (ESI+) m/z 553 (M+H)+; HRMS (FAB) m/z 553.1141 (M+H)+ 〇實例18. 消旋-N_(4-氯爷基）-2-(((2-經基-2-(1 H-p比吨-5_基）乙基）（甲基）胺基甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡淀 -5-羧醯胺Make N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrotepheno [2,3-b] pyridine-5-carboxy Amidine (Preparation Example 1, 0.20 g), DMF (5 ml) and N, N-diisopropylethylamine (0.24 ml) were stirred with 4 angstrom molecular sieve (0.200 g) for 1 hour, followed by adding 1 -(1,3-benzopyrazol-2-yl) -2- (methylamino) ethanol (Preparation Example 37, 0.12 g). The mixture was stirred at 80 ° C for 3 hours. Add water and extract with CHAh. The organic layers were combined, dehydrated (MgSCU), filtered and concentrated. The crude product was purified by chromatography 'to obtain 0.053 g of the title compound 87731-83-200410970 as an off-white solid. Physical characteristics: NMR (400 MHz, DMSO-d6) 5 10.60, 8.66, 8.09-8.07, 7.93-7.91, 7.46-7.31, 6.45-6.44, 5.16, 4.55-4.53, 3.895 3.73, 3.02-2.98, 2.92-2.87, 2.38; 13C NMR (CDC13) 5 174.5, 173.4, 165.3, 53.5, 150.9, 145.1, 137.7, 137.6, 135.0, 133.2, 13 1.9, 129.3, 129.0, 126.5, 125.4, 123.2, 122.5, 122.2, 116.2, 69.2, 62.8 , 57.7, 43.5, 43.0, 42.5; MS (ESI +) m / z 553 (M + H) +; HRMS (FAB) m / z 553.1141 (M + H) + 〇 Example 18. Racemic-N_ (4-chloro Ethyl) -2-(((2-Ethyl-2- (1 Hp than ton-5-yl) ethyl) (methyl) aminomethyl) -7-methyl-4-oxo-4 , 7-dihydropyridino [2,3-b] pyridine-5-carboxamide

使含2-(甲基胺基）-1-(1Η-ρ比峻-5-基）乙醇二鹽酸鹽（製備例39，0.12克）、ΚΙ(0·02克）、三乙胺（〇·ΐ6毫升）及3埃分子篩之播水DMF(15愛升）混合物攪拌2小時。添加n_(4-氯爷基）-2-(氯甲基）-7-曱基-4-氧代-4,7-二氫噻吩并[2,3_b]吡咬 -5 - &酸胺（製備例1，0 · 19克）。所得混合物在室溫下攪拌隔夜。以過濾移除分子篩，且以EtOAc(l〇〇毫升）稀釋濾液。溶液以水（3X50毫升）及食鹽水（50毫升）洗滌，經脫水 (NadOO且濃縮。粗產物以色譜儀（1〇〇〇微轉，以cH2Cw CH3OH/NH3水溶液，90/9/1)純化，接著自Et〇Ac再結晶，獲得0.07克白色固態標題化合物。物理特徵·· Μρ· 177 5_178 6 87731 -84- 200410970 °C ； ln NMR (400 MHz, DMSO-d6)6 12.53, 10.62, 8.70, 7.41-7.71， 6.16, 4.82, 4.54， 3.94, 3.89-3.73, 2.72， 2.30; 13C NMR (DMSO-d6)5 174.2，166.7，152.8，147.4，142.1，140·9, 133.7，132.9，131.4，130.7，122.3，116.6，104.3，65·3，58·6, 45.1，44.5, 43.7, 42.8, 42.8, 42.6; MS (ESI+) m/z 486 (M+H)+; 分析實測值：C，56.60; H，5.03; N，14.33。實例19. N-(4_氯芊基）_2-((((2R)-2-羥基-2-(1Η·吡唑_5_基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫碟吩并[2,3-b]峨淀 -5-羧醯胺2- (methylamino) -1- (1Η-ρbijun-5-yl) ethanol dihydrochloride (Preparation Example 39, 0.12 g), KI (0.02 g), and triethylamine ( 6 ml) and 3 Å molecular sieve in water-seeded DMF (15 liters) were stirred for 2 hours. Add n_ (4-chloroethenyl) -2- (chloromethyl) -7-fluorenyl-4-oxo-4,7-dihydrothieno [2,3_b] pyridine-5-& acid amine (Preparation Example 1.09 g). The resulting mixture was stirred at room temperature overnight. The molecular sieves were removed by filtration, and the filtrate was diluted with EtOAc (100 mL). The solution was washed with water (3 × 50 ml) and brine (50 ml), dehydrated (NadOO and concentrated. The crude product was purified by chromatography (1000 micro-rotation, cH2Cw CH3OH / NH3 aqueous solution, 90/9/1) Then, it was recrystallized from EtoAc to obtain 0.07 g of the title compound as a white solid. Physical characteristics ·· Mρ · 177 5_178 6 87731 -84- 200410970 ° C; ln NMR (400 MHz, DMSO-d6) 6 12.53, 10.62, 8.70 , 7.41-7.71, 6.16, 4.82, 4.54, 3.94, 3.89-3.73, 2.72, 2.30; 13C NMR (DMSO-d6) 5 174.2, 166.7, 152.8, 147.4, 142.1, 140 · 9, 133.7, 132.9, 131.4, 130.7 , 122.3, 116.6, 104.3, 65 · 3, 58.6, 45.1, 44.5, 43.7, 42.8, 42.8, 42.6; MS (ESI +) m / z 486 (M + H) +; Analysis found: C, 56.60; H, 5.03; N, 14.33. Example 19. N- (4-chlorofluorenyl) _2-(((((2R) -2-hydroxy-2- (1 (· pyrazol_5_yl) ethyl) (methyl (Amino) -amino) -methyl) -7-methyl-4-oxo-4,7-dihydrodipheno [2,3-b] eodo-5-carboxamide

消旋_Ν_(4·氯苄基）_2_(((2-羥基_2·(1Η-吡唑-5-基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b] 吡啶-5-羧醯胺（實例18，0.15克）以製備用HPLC(5X25公分 _ Chiralpak AD管柱，90毫升/分鐘，〇 2〇/〇DEA/乙醇，λ =230 nM) 分離’且合併含較慢溶離異構物之餚份且濃縮。粗產物自甲醇/EtOAc再結晶，獲得65毫克白色固態標題化合物。物理特徵：Μ·ρ· 177·3-178·8°(：; iHNMRGOOMHz’DMSO-dW 12.53, 10.62, 8.70, 7.41-7·71，6·16, 4.82, 4.54, 3.94, 3·89-3·73， 2·72, 2·30; 13C NMR (DMSO-d6)S 174.2, 166.7, 152.8，147.4， 142.1，140.9, 133.7, 132.9, 131.4, 130.7, 122.3, 116·6, 104.3， 65.3, 58.6，45.1，44.5，43.7，42.8，42.8，42·6。 87731 -85 - 200410970 實例20. N_(4_氯芊基）_7_乙基-2-((((2R)-2-(2_呋喃基）-2_幾基乙基）（甲基）胺基）-甲基）-4-氧代-4,7-二氫嘧吩并[2,3-b]外1：咬 -5 -複S盛胺Meso_N_ (4 · chlorobenzyl) _2 _ ((((2-hydroxy_2 · (1Η-pyrazol-5-yl) ethyl) (methyl) amino) -methyl) -7-methyl 4-oxo-4,7-dihydropyridino [2,3-b] pyridine-5-carboxamide (Example 18, 0.15 g) for preparative HPLC (5X25 cm_ Chiralpak AD column, 90 Ml / min, 〇0 / 〇DEA / ethanol, λ = 230 nM), separated and combined with slower isomers and concentrated. The crude product was recrystallized from methanol / EtOAc to obtain 65 mg of the title compound as a white solid. Physical characteristics: M · ρ · 177 · 3-178 · 8 ° (:; iHNMRGOOMHz'DMSO-dW 12.53, 10.62, 8.70, 7.41-7 · 71, 6.16, 4.82, 4.54, 3.94, 3.89-3 · 73, 2 · 72, 2 · 30; 13C NMR (DMSO-d6) S 174.2, 166.7, 152.8, 147.4, 142.1, 140.9, 133.7, 132.9, 131.4, 130.7, 122.3, 116 · 6, 104.3, 65.3, 58.6 , 45.1, 44.5, 43.7, 42.8, 42.8, 42.6. 87731 -85-200410970 Example 20. N_ (4_chlorofluorenyl) _7_ethyl-2-((((2R) -2- (2_ Furyl) -2_Ethylethyl) (Methyl) amino) -Methyl) -4-oxo-4,7-dihydropyrimido [2,3-b] Ex 1: bit-5 -Compound S Sheng Amine

將N，N-二異丙基乙胺（0.22毫升）添加於含N-(4-氯节基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]咐淀 -5-羧醯胺（製備例1，250毫克）及（1R)-1_(2_呋喃基）_2_(甲基胺基）乙醇（製備例17，178毫克）之DMF(14毫升）溶液中。使混合物在90°C下攪拌1小時，接著使之冷卻至室溫。真空濃縮混合物且使所得固體自甲醇再結晶，獲得14〇毫克白色固態標題化合物。物理特徵·· Μ·ρ· 123-127°C;NMR (300 MHz，DMSO-d6)S 10.62，8.72，7.56，7.37，7.30，6.39，6·28 5.30，4.75，4.54，4.28，3·83，2·76，2.27，1·43; HRMS (FAB) m/z 500.1396 (Μ+Η)+。實例21. Ν-(4-氣苄基）-2-((((2R)-2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-7-(2-甲氧基乙基）-4-氧代_4,7_二氫遠吩并[2,3-b] 吡啶-5-羧醯胺Add N, N-diisopropylethylamine (0.22 ml) to N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7- Dihydropyridino [2,3-b] Yodo-5-carboxamide (Preparation Example 1,250 mg) and (1R) -1_ (2_furanyl) _2_ (methylamino) ethanol (Preparation Example 17, 178 mg) of DMF (14 ml). The mixture was stirred at 90 ° C for 1 hour, and then allowed to cool to room temperature. The mixture was concentrated in vacuo and the resulting solid was recrystallized from methanol to obtain 14 mg of the title compound as a white solid. Physical characteristics ····· 123-127 ° C; NMR (300 MHz, DMSO-d6) S 10.62, 8.72, 7.56, 7.37, 7.30, 6.39, 6.28 5.30, 4.75, 4.54, 4.28, 3.83 , 2.76, 2.27, 1.43; HRMS (FAB) m / z 500.1396 (M + Η) +. Example 21. N- (4-Gas benzyl) -2-(((((2R) -2- (2-furanyl) -2-hydroxyethyl) (methyl) amino) -methyl) -7 -(2-methoxyethyl) -4-oxo_4,7_dihydrotelepheno [2,3-b] pyridine-5-carboxamide

87731 -86 - 200410970 將N，N-二異丙基乙胺（0.203毫升）添加於含N-(4-氯苄基）-2-(氯甲基）-7-(2-甲氧基乙基）-4-氧代-4,7-二氫嘍吩并 [2,3-b]吡啶-5_羧醯胺（製備例1，25〇毫克）及（lR)-l-(2-呋喃基）-2-(甲基胺基）乙醇（製備例17，165毫克）之DMF(14毫升）溶液中。使混合物在90°C下攪拌1小時，接著使之冷卻至室溫。真空濃縮混合物，且粗產物以層析（以l%MeOH/CHCl3 溶離）純化，獲得142毫克白色固態標題化合物。物理特徵： M.p. 121«122〇C ； 'H NMR (300 MHz, DMSO-d6)8 10.58, 8.63, 7.56, 7.36, 7.29, 6.39, 6.29, 5.29, 4.75, 4.54, 4·43, 3.82, 3.73, 3.25, 2.76, 2.27 〇實例22· 消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲基）胺基）_甲基）-N-(4-氣苄基）-7•乙基_4_氧代-4,7_二氫違吩并[2,3_b]p比啶-5-羧醯胺87731 -86-200410970 Add N, N-diisopropylethylamine (0.203 ml) to N- (4-chlorobenzyl) -2- (chloromethyl) -7- (2-methoxyethyl) Phenyl) -4-oxo-4,7-dihydrofluoreno [2,3-b] pyridine-5-carboxamide (Preparation Example 1,250 mg) and (lR) -l- (2- Furyl) -2- (methylamino) ethanol (Preparation Example 17, 165 mg) in a solution of DMF (14 ml). The mixture was stirred at 90 ° C for 1 hour, and then allowed to cool to room temperature. The mixture was concentrated in vacuo and the crude product was purified by chromatography (isolated with 1% MeOH / CHCl3) to give 142 mg of the title compound as a white solid. Physical characteristics: Mp 121 «122〇C; 'H NMR (300 MHz, DMSO-d6) 8 10.58, 8.63, 7.56, 7.36, 7.29, 6.39, 6.29, 5.29, 4.75, 4.54, 4.43, 3.82, 3.73, 3.25, 2.76, 2.27 〇 Example 22 Racemic-2-(((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) -methyl) -N -(4-Gas benzyl) -7 • ethyl_4_oxo-4,7_dihydrobenzopheno [2,3_b] pbipyridine-5-carboxamide

將N，N- 一異丙基乙胺（0.22毫升）添加於含N-(4_氯窄基）-2-(氣甲基）-7-甲基_4_氧代_4,7_二氫嘧吩并[2,3-b]吡啶 -5-羧醯胺（製備例1，250毫克）及1-(1-苯并呋喃_2_基）_2_(甲基胺基）乙醇（製備例21，240毫克）之DMF(14毫升）溶液中。使此合物在90 C下攪掉1小時，接著使之冷卻至室溫。真空濃縮混合物且使粗產物自甲醇再結晶，獲得272毫克白色固態標題化合物。物理特徵：Μ·ρ· 142_145χ：; lH NMr 0⑻ 87731 -87- 200410970 MHz, DMSO-d6)5 10.60, 8.675 7.61, 7.54, 7.36, 7.29, 7.23, 6.77’ 5.60’ 4.90’ 4.54’ 4.02’ 3.87, 2.83, 2.32, 1.30。分析實測值：C, 62·96; H，5·08; N，7.66; Cl，6.53; s 5 78。實例23. 消旋-2-(((2-(1-苯并呋喃-2-基）_2_羥基乙基）（甲基）胺基）_甲基）-Ν-(4·氯芊基）-7·丙基-4-氧代-4,7_二氫嘧吩并卩……吡淀-5 -叛醯胺Add N, N-monoisopropylethylamine (0.22 ml) to N- (4_chloronyl) -2- (gasmethyl) -7-methyl_4_oxo_4,7_ Dihydropyrido [2,3-b] pyridine-5-carboxamide (Preparation Example 1,250 mg) and 1- (1-benzofuran_2_yl) _2_ (methylamino) ethanol ( Preparation Example 21, 240 mg) in DMF (14 ml). The mixture was allowed to stir at 90 C for 1 hour and then allowed to cool to room temperature. The mixture was concentrated in vacuo and the crude product was recrystallized from methanol to give 272 mg of the title compound as a white solid. Physical characteristics: M · ρ · 142_145χ :; lH NMr 0⑻ 87731 -87- 200410970 MHz, DMSO-d6) 5 10.60, 8.675 7.61, 7.54, 7.36, 7.29, 7.23, 6.77 '5.60' 4.90 '4.54' 4.02 '3.87, 2.83, 2.32, 1.30. Analytical measured values: C, 62 · 96; H, 5.08; N, 7.66; Cl, 6.53; s 5 78. Example 23. Racemic-2-((((2- (1-benzofuran-2-yl) _2_hydroxyethyl) (methyl) amino) _methyl) -N- (4 · chlorofluorenyl ) -7 · propyl-4-oxo-4,7_dihydropyridinopyrene ... pyridine-5 -benzidine

將Ν，Ν_二異丙基乙胺（0.213毫升）添加於含Ν气‘氯苄基）-2-(氯甲基）-7-甲基-4-氧代·4,7-二氫嘧吩并[2,3-b]吡啶 -5-羧醯胺（製備例1，250毫克）及1_(1_苯并呋喃_2_基）-2_(甲基胺基）乙醇（製備例21 ’ 230毫克）之DMF(14毫升）溶液中。使混合物在90 C下攪拌1小時，接著使之冷卻至室溫。真空濃縮混合物且使粗產物自甲醇再結晶，獲得226毫克白色固態標題化合物。物理特徵：M.p· 132-133°C; !H NMR (300 MHz，DMSO-d6)5 10.60，8.66，7.58，7.45，7.36，7.29，7·23, 6.77, 5.61，4.95, 4.54, 4.05, 3.81，2.93, 2.32, 1·70, 〇·81。分析實測值：C，62.96; Η，5·08; Ν，7.66; Cl，6.53; S，5.78。實例24. 消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲基）胺基）_甲基）_N-(4-氯苄基）-7-(2_甲氧基乙基）-4-氧代-4,7·二氫噻吩并[2,3-b]^：淀-5-幾驢胺 87731 -88- 200410970N, N-diisopropylethylamine (0.213 ml) was added to N-containing 'chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo · 4,7-dihydro Pyrido [2,3-b] pyridine-5-carboxamide (Preparation Example 1,250 mg) and 1_ (1_benzofuran_2_yl) -2_ (methylamino) ethanol (Preparation Example 21 '230 mg) in DMF (14 ml). The mixture was stirred at 90 C for 1 hour, and then allowed to cool to room temperature. The mixture was concentrated in vacuo and the crude product was recrystallized from methanol to give 226 mg of the title compound as a white solid. Physical characteristics: Mp. 132-133 ° C;! H NMR (300 MHz, DMSO-d6) 5 10.60, 8.66, 7.58, 7.45, 7.36, 7.29, 7.23, 6.77, 5.61, 4.95, 4.54, 4.05, 3.81 , 2.93, 2.32, 1.70, 0.81. Analysis Measured values: C, 62.96; H, 5.08; N, 7.66; Cl, 6.53; S, 5.78. Example 24. Racemic-2-((((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) _methyl) _N- (4-chlorobenzyl ) -7- (2-methoxyethyl) -4-oxo-4,7 · dihydrothieno [2,3-b] ^: Yodo-5-chitylamine 87731 -88- 200410970

將N，N-二異丙基乙胺（0.203毫升）添加於含N-(4-氯爷基）-2-(氯甲基）-7-(2-甲氧基乙基）·4-氧代-4,7 -二氫π塞吩并 [2,3-b]吡啶-5-羧醯胺（製備例1，250毫克）及1_(1-苯并呋喃 -2-基）-2-(甲基胺基）_乙醇（製備例21，220毫克）之DMF( 14毫升）溶液中。使混合物在90 °C下攪拌2小時，接著使之冷卻至室溫。真空濃縮混合物且以乙酸乙酯分散，獲得206毫克灰白色固態標題化合物。物理特徵：Μ.ρ· 133-140°C ; NMR (300 MHz，DMSO-d6)3 10.60，8·59，7·58，7·46，7.36, 7.29, 7·23, 6.77, 5.61，4.95, 4.54, 4.25, 3.82, 3.61，3·20, 2.89, 2.32; HRMS (FAB) m/z 580.1678 (Μ+Η)+。分析實測值：C， 61.74; Η，5·13; Ν，7·13; Cl，6.05; S，5·42。製備例41. 消旋-2-(((2-(1-苯并咳喃基）-2-龜基乙基）（甲基）胺基）_甲基）-Ν-(4·氯苄基）-7-((2,2-二甲基- l，3 -二$茂燒-4-基）甲基）_4_氧代-4,7-二氫遠吩并[2,3_b]峨啶-5-羧醯胺將碳酸铯（260毫克）及3埃分子篩（1〇〇毫克）添加於含2-(氯甲基）·Ν-((4-氯苄基）甲基）-7-((2,2_二甲基-L3-二呤茂烷_4_ 基）甲基）-4,7-一氲-4-乳代p塞吩并[2,3-b]p比淀-5-幾醢胺（製備例3，336¾克）及1-(1·苯并吱喃·2-基）_2_(甲基胺基）乙醇 (製備例21，133毫克）之DMF(3.0毫升）溶液中。將反應混合物置於6(TC之搖晃段上17小時。蒸發溶劑，殘留物在矽膠 87731 -89 - 200410970 上以5%MeOH/CH2Cl2層析純化。粗產物自EtOAc再結晶，獲得192¾克白色固態標題化合物。物理特徵：nmR (400 MHz，DMSO-d6)5 10.58，8.64，7.59，7.47，7.39，7.35，7.29, 7.22, 6·77, 5.59, 4.90, 4.53, 4.41，4.13, 4.05, 3·84, 3·68, 2.93, 2·79，2·33，1.29，1·21;分析實測值：c，62.13; Η，5·60; Ν， 6·40 〇實例25· 消旋-2-(((2-(1-苯并呋喃_2_基）-2-羥基乙基）（甲基）胺基）-甲基）-义(4-氯芊基）-7-(2,3-二經基丙基）-4-氧代_4,7-二氫遠吩并[2,3比淀-5-羧醯胺N, N-Diisopropylethylamine (0.203 ml) was added to N- (4-chloromethyl) -2- (chloromethyl) -7- (2-methoxyethyl) · 4- Oxo-4,7-dihydroπ thiopheno [2,3-b] pyridine-5-carboxamide (Preparation Example 1,250 mg) and 1_ (1-benzofuran-2-yl) -2 -(Methylamino) _ethanol (Preparation Example 21, 220 mg) in a solution of DMF (14 ml). The mixture was stirred at 90 ° C for 2 hours, and then allowed to cool to room temperature. The mixture was concentrated in vacuo and dispersed in ethyl acetate to give 206 mg of the title compound as an off-white solid. Physical characteristics: M.ρ · 133-140 ° C; NMR (300 MHz, DMSO-d6) 3 10.60, 8.59, 7.58, 7.46, 7.36, 7.29, 7.23, 6.77, 5.61, 4.95 , 4.54, 4.25, 3.82, 3.61, 3.20, 2.89, 2.32; HRMS (FAB) m / z 580.1678 (Μ + Η) +. Analytical measured values: C, 61.74; H, 5.13; N, 7.13; Cl, 6.05; S, 5.42. Production Example 41. Racemic-2-((((2- (1-benzocarbanyl) -2-guidylethyl) (methyl) amino) _methyl) -N- (4 · chlorobenzyl ) -7-((2,2-dimethyl-l, 3-di $ cene-4-yl) methyl) _4_oxo-4,7-dihydrotelebenzo [2,3_b] Eridine-5-carboxamide Adds cesium carbonate (260 mg) and 3 angstrom molecular sieve (100 mg) to a solution containing 2- (chloromethyl) · N-((4-chlorobenzyl) methyl)- 7-((2,2-Dimethyl-L3-dipyridocene-4-yl) methyl) -4,7-monofluorene-4-lacto-p-pheneno [2,3-b] p ratio DMF of 5-Yodo-5-Chloramine (Preparation Example 3, 336¾ g) and 1- (1.benzobenzo-2-yl) _2_ (methylamino) ethanol (Preparation Example 21, 133 mg) (3.0 Ml) solution. The reaction mixture was placed on a 6 ° C shaking section for 17 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel 87731 -89-200410970 with 5% MeOH / CH2Cl2. The crude product was recrystallized from EtOAc to obtain 192¾ g of a white solid Title compound. Physical characteristics: nmR (400 MHz, DMSO-d6) 5 10.58, 8.64, 7.59, 7.47, 7.39, 7.35, 7.29, 7.22, 6.77, 5.59, 4.90, 4.53, 4.41, 4.13, 4.05, 3. · 84, 3.68, 2.93, 2.79, 2.33, 1.29, 1.21; Analytical measured values: c, 62.13; Η, 5.60; Ν, 6.40 〇Example 25 racemic-2- (((2- (1-benzofuran_2_yl) -2-hydroxyethyl) (methyl) amino) -methyl) -sense (4-chlorofluorenyl) -7- (2,3 -Dioxopropyl) -4-oxo_4,7-dihydrotelebenzo [2,3biyodo-5-carboxamidine

將消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲基）胺基）甲基）-Ν-(4·氯苄基）-7-((2,2-二甲基-1，3-二噚茂烷-4-基）籲甲基）-4-氧代-4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例 41，127毫克）溶於THF(3毫升）中，且添加65%過氯酸（0.2毫升）。反應混合物在50°C下攪拌1小時，接著倒入飽和NaHC03 溶液中。混合物以EtOAc( 100毫升）萃取，有機層經脫水 (MgS04)、過濾且濃縮。殘留物在矽膠上以5%MeOH/CH2Cl2 層析純化。粗產物分散於EtOAc上，獲得74毫克白色固態標題化合物。物理特徵：b NMR (400 MHz，DMSO-d6)3 10.55， 8.57, 7.58, 7.47, 7.39, 7.34, 7.31，7.23, 6.76, 5.60, 5·28, 4.92， 87731 -90- 200410970 4.53, 4.01，3.83，3·43, 3.32, 2·91, 2·79, 2.32; HRMS (FAB) m/z 596.1625 (Μ+Η)+ 〇製備例42. Ν-(4-氯芊基）-7-((2,2-二甲基_；ι，3_二噚茂烷_4_基）甲基）-2_((((2R)-2-(2-呋喃基羥基乙基χ甲基）胺基>甲基）_ 氧代-4,7-二氫噻吩并[2,3_b]吡啶羧醯胺將碳酸铯（230毫克）及3埃分子篩（1〇〇毫克）添加於含2气氯甲基）-Ν_((4·氯苄基）甲基）_7-((2,2-二甲基4,3-二呤茂烷_4_ 基）甲基）-4,7-二氫-4-氧代嘧吩并[2,3-b]吡啶-5-幾醯胺（製備例3，200毫克）及（iR)_le(2-呋喃基）-2-(甲基胺基）乙醇（製備例17，100毫克）之DMF(3.0毫升）溶液中。將反應混合物置於60 C之搖晃段上17小時。蒸發溶劑，殘留物在珍膠上以5%MeOH/CH2Cl2層析純化，獲得145毫克白色固態標題化合物。物理特徵：4 NMR (400 MHz, DMSO-d6)3 10.58, 8.68, 7·55, 7.39, 7.34, 7.28, 6·38, 6.28, 5.26, 4.73, 4.53, 4.44, 4·27 4·13, 3·81，3·76, 2·77, 2·68, 1·33, 1·09;分析實測值：c，59·31; Η，5_59; Ν，7_11 〇實例26. Ν-(4-氯；基）_7_(2,3·二羥基丙基）_2_((((2R)_2_(2- ρ失喃基）-2-羥基乙基）（甲基）胺基）甲基）_4_氧代_4,7_二氫嘍吩并 [2,3-b]吡啶-5-羧醯胺The racemic-2-(((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) methyl) -N- (4 · chlorobenzyl)- 7-((2,2-Dimethyl-1,3-difluorenyl-4-yl) methyl) -4-oxo-4,7-dihydrothieno [2,3-b] Pyridine-5-carboxamide (Preparation Example 41, 127 mg) was dissolved in THF (3 ml), and 65% perchloric acid (0.2 ml) was added. The reaction mixture was stirred at 50 ° C. for 1 hour and then poured into a saturated NaHC03 solution. The mixture was extracted with EtOAc (100 mL), and the organic layer was dried (MgSO.sub.4), filtered, and concentrated. The residue was purified by chromatography on silica gel with 5% MeOH / CH2Cl2. The crude product was dispersed in EtOAc to obtain 74 mg of the title compound as a white solid. Physical characteristics: b NMR (400 MHz, DMSO-d6) 3 10.55, 8.57, 7.58, 7.47, 7.39, 7.34, 7.31, 7.23, 6.76, 5.60, 5.28, 4.92, 87731 -90- 200410970 4.53, 4.01, 3.83 , 3.43, 3.32, 2.91, 2.79, 2.32; HRMS (FAB) m / z 596.1625 (M + Η) + 〇 Preparation Example 42 Ν- (4-chlorofluorenyl) -7-(( 2,2-dimethyl_; ι, 3_difluorenyl-4-yl) methyl) -2 _ (((((2R) -2- (2-furylhydroxyethylxmethyl) amino) > Methyl) _oxo-4,7-dihydrothieno [2,3_b] pyridinecarboxamide Add cesium carbonate (230 mg) and 3 angstrom molecular sieve (100 mg) to 2-chlorochloroform ) -N _ ((4 · chlorobenzyl) methyl) _7-((2,2-dimethyl4,3-dipyridinocenyl-4-yl) methyl) -4,7-dihydro-4 -Oxopyrimido [2,3-b] pyridine-5-chiamine (Preparation Example 3, 200 mg) and (iR) _le (2-furyl) -2- (methylamino) ethanol ( Preparation Example 17, 100 mg) in DMF (3.0 ml) solution. The reaction mixture was placed on a shaking section at 60 C for 17 hours. The solvent was evaporated, and the residue was purified by chromatography on 5% MeOH / CH2Cl2 to obtain 145 mg of the title compound as a white solid. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 3 10.58, 8.68, 7.55, 7.39, 7.34, 7.28, 6.38, 6.28, 5.26, 4.73, 4.53, 4.44, 4.27 4.13, 3.81, 3. · 76, 2.77, 2.68, 1.33, 1.09; Analytical measured values: c, 59 · 31; Η, 5_59; Ν, 7_11 〇 Example 26. Ν- (4-chloro; yl) _7_ ( 2,3 · dihydroxypropyl) _2 _ (((((2R) _2_ (2-ρ thiol) -2-hydroxyethyl) (methyl) amino) methyl) _4_oxo_4,7 _Dihydrofluoreno [2,3-b] pyridine-5-carboxamide

87731 -91 - 200410970 將N-(4-氯苄基）-7-((2,2-二甲基- Μ—二嘮茂烷_4_基）甲基）-2-((((2R)-2_(2-呋喃基）-2-羥基乙基甲基）胺基甲基）_ -4-氧代-4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例42， 100¾克）落於THF(10毫升）中，且添加65%過氯酸（0.2毫升）。反應混合物在室溫下攪拌6小時，接著倒入飽和 NaHC〇3溶液中。混合物以Et〇Ac(1〇〇毫升）萃取，有機層經脫水（MgSCU)、過濾且濃縮。殘留物在矽膠上以5%Me〇H/ CHAl2層析純化，獲得56毫克白色固態標題化合物。物理特徵：巾 NMR (400 MHz，DMSO-d6)S 10.5 1，8.60, 7.55, 7.39, 7.33, 7.29, 6.38, 6.28, 5.31，5.29, 4.98, 4.74, 4.53, 4.31，4.12, 3·86, 3.80, 3.49, 3·38, 2.77, 2·66; HRMS (FAB) m/z 546.1463 (M+H)+。製備例43. N-(4-氣苄基）-2-((((2R)-2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-4-氧代-7-(3-(四氫-2H-吡喃-2-基氧基）丙基）-4,7- 一氫違吩并[2,3-b]p比淀-5_幾酸胺將碳酸铯（225毫克）及3埃分子篩（100毫克）添加於含n-(4_ 氯卞基）-2-(氯甲基）-4_氧代·7-(3_(四氫_2H_吡喃-2_基氧基）丙基）-4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例5，200 笔克）及（lR)-l-(2-呋喃基）-2-(甲基胺基）乙醇（製備例17，克）之DMF(2.0毫升）溶液中。將反應混合物置於6〇〇c 之搖晃段上17小時。蒸發溶劑，殘留物在矽膠上以5Q/()Me〇H/ CHWl2層析純化，獲得177毫克白色固態標題化合物。物理特徵·· 4 NMR (400 MHz，DMSO-dW 10.57, 8.68, 7.55, 7.39, 87731 -92- 200410970 7·33, 7.29, 6.38, 6.28, 5.27, 4.73, 4.53, 4.48, 4.34, 3.82, 3·68, 3.38，2.77，2.27，2.10，1.62，1.55，1.17; HRMS (FAB) m/z 614.2105 (Μ+Η)+ 〇實例27. Ν-(4-氯苄基）-2_((()2R)_2-(呋喃基）_2•羥基乙基）（甲基）胺基）-甲基）-7-(3-羥基丙基）-4-氧代_4,7_二氫噻吩并[2,3-b]吡啶-5-羧醯胺87731 -91-200410970 N- (4-chlorobenzyl) -7-((2,2-dimethyl-M-dioxocene_4-yl) methyl) -2-(((((2R ) -2_ (2-furyl) -2-hydroxyethylmethyl) aminomethyl) _- 4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxy Amidine (Preparation Example 42, 100¾ g) was placed in THF (10 ml), and 65% perchloric acid (0.2 ml) was added. The reaction mixture was stirred at room temperature for 6 hours, and then poured into a saturated NaHC03 solution. The mixture was extracted with EtoAc (100 mL), and the organic layer was dehydrated (MgSCU), filtered and concentrated. The residue was purified on silica gel by 5% MeOH / CHAl2 chromatography to obtain 56 mg of the title compound as a white solid Physical characteristics: NMR (400 MHz, DMSO-d6) S 10.5 1, 8.60, 7.55, 7.39, 7.33, 7.29, 6.38, 6.28, 5.31, 5.29, 4.98, 4.74, 4.53, 4.31, 4.12, 3.86, 3.80, 3.49, 3.38, 2.77, 2.66; HRMS (FAB) m / z 546.1463 (M + H) +. Preparation Example 43. N- (4-Gabenzyl) -2-((((2R ) -2- (2-furanyl) -2-hydroxyethyl) (methyl) amino) -methyl) -4-oxo-7- (3- (tetrahydro-2H-pyran-2- Alkoxy) propyl) -4,7-monohydrobenzo [2,3-b] p Yodo-5_ citric acid added cesium carbonate (225 mg) and 3 angstrom molecular sieve (100 mg) to n- (4_chlorofluorenyl) -2- (chloromethyl) -4_oxo · 7- ( 3_ (tetrahydro_2H_pyran-2_yloxy) propyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (Preparation Example 5,200 pen grams) ) And (lR) -l- (2-furyl) -2- (methylamino) ethanol (Preparation Example 17, g) in DMF (2.0 ml). The reaction mixture was placed in 600C Shake for 17 hours. Evaporate the solvent and purify the residue on silica gel with 5Q / () OH / CHWl2 chromatography to obtain 177 mg of the title compound as a white solid. Physical characteristics · 4 NMR (400 MHz, DMSO-dW 10.57 , 8.68, 7.55, 7.39, 87731 -92- 200410970 7.33, 7.29, 6.38, 6.28, 5.27, 4.73, 4.53, 4.48, 4.34, 3.82, 3.68, 3.38, 2.77, 2.27, 2.10, 1.62, 1.55, 1.17; HRMS (FAB) m / z 614.2105 (M + Η) + 〇 Example 27. N- (4-chlorobenzyl) -2 _ ((() 2R) _2- (furanyl) _2 • hydroxyethyl) ( Methyl) amino) -methyl) -7- (3-hydroxypropyl) -4-oxo_4,7_dihydrothieno [2,3-b] pyridine-5-carboxamide

將N-(4-氣苄基）-2-((((2R)_2-(2-呋喃基）-2•羥基乙基）（甲基）胺基）-甲基）-4-氧代-7-(3-(四氫-2H-吡喃-2-基氧基）丙基）-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例43，112毫克）溶於THF(10毫升）中，且添加含65%過氯酸（〇·2毫升）之水 (0·2毫升）。反應混合物在22°C下攪拌7小時，接著倒入飽和 _ NaHC〇3溶液中。混合物以EtOAc(150毫升）萃取，有機層經脫水（MgSCU)、過濾且濃縮。殘留物在矽膠上以5%Me〇H/ CHaCh層析純化，所得粗產物自EtOAc/***再結晶，獲得 57毫克標題化合物。物理特徵··1HNMR(400 MHz，DMSO-(16)δ 10.57, 8.68, 7.55, 7.39, 7.34, 7.29, 6.38, 6.28, 5.29, 4.76， 4.54，4.30，3·81，3.45，2.75，2·27，1·97; HRMS (FAB) m/z 530.1533 (M+H)+。製備例44. 87731 -93- 200410970 消旋-2-(((2-(1-苯并呋喃_2_基）_2_羥基乙基）（甲基）胺基）_甲基）-N-(4-氯苄基）-4·氧代_7_(3_(四氫_2H>吡喃_2-基氧基）丙基）-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺將碳酸絶（245毫克）及3埃分子篩〇〇〇毫克）添加於含^^_(4-氯芊基）-2·(氯甲基>4-氧代-7_(3-(四氫吡喃-2_基氧基）丙基）-4,7-二氫遂吩并[2,3_b]吡啶羧醯胺（製備例$，315 毫克）及1-(1-苯并呋喃-2_基）_2-(甲基胺基）乙醇（製備例 20 ’ 143愛克）之DMF(2.0毫升）溶液中。將反應混合物置於 60 °C之搖晃段上8小時。蒸發溶劑，殘留物在矽膠上以 5%MeOH/CH2Cl2層析純化，獲得156毫克白色固態標題化合物。物理特徵：1h NMR (400 MHz，DMSO-d6)5 10.55, 8.65, 7·58, 7·45, 7.39, 7.33, 7.29, 7.22, 6.77, 5.60, 4.89, 4.53, 4.44, 4.18, 4.05, 3.83, 3.63, 3.33, 2.93, 2.80, 2.32, 1.97, 1.51，1.35; HRMS m/z 664.2278 (Μ+Η)+。分析實測值：c，63.06; Η，5.79; Ν，6.26。實例28. 消旋_2-(((2-(1-苯并呋喃-2-基）·2-羥基乙基）（甲基）胺基）甲基）(4 -鼠卞基）-7-(3-¾基丙基）-4 -氧代_4,7_二氫ρ塞吩并 [2,3-b]p比淀_5_竣醒胺N- (4-Azobenzyl) -2-(((((2R) _2- (2-furanyl) -2 • hydroxyethyl) (methyl) amino) -methyl) -4-oxo -7- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) -4,7-dihydropyrimido [2,3-b] pyridine-5-carboxamide (Preparation Example 43, 112 mg) was dissolved in THF (10 ml) and water (0.2 ml) containing 65% perchloric acid (0.2 ml) was added. The reaction mixture was stirred at 22 ° C for 7 hours, and then poured into a saturated NaHC03 solution. The mixture was extracted with EtOAc (150 mL), and the organic layer was dried (MgSCU), filtered, and concentrated. The residue was purified by chromatography on silica gel with 5% MeOH / CHaCh, and the resulting crude product was recrystallized from EtOAc / ether to obtain 57 mg of the title compound. Physical characteristics · 1HNMR (400 MHz, DMSO- (16) δ 10.57, 8.68, 7.55, 7.39, 7.34, 7.29, 6.38, 6.28, 5.29, 4.76, 4.54, 4.30, 3.81, 3.45, 2.75, 2.27 1.97; HRMS (FAB) m / z 530.1533 (M + H) +. Preparation Example 44. 87731 -93- 200410970 Racem-2-(((2- (1-benzofuran_2_yl) _2_hydroxyethyl) (methyl) amino) _methyl) -N- (4-chlorobenzyl) -4 · oxo_7_ (3_ (tetrahydro_2H > pyran_2-yloxy) ) Propyl) -4,7-dihydropyrido [2,3-b] pyridine-5-carboxamidinium carbonate (245 mg) and 3 angstrom molecular sieves (000 mg) were added to ^^ _ (4-chlorofluorenyl) -2 · (chloromethyl)> 4-oxo-7- (3- (tetrahydropyran-2-yloxy) propyl) -4,7-dihydropheno [2,3_b] Pyridinecarboxamide (Preparation Example $, 315 mg) and 1- (1-benzofuran-2_yl) _2- (methylamino) ethanol (Preparation Example 20 '143 Aike) DMF (2.0 ml) solution. The reaction mixture was placed on a shaking section at 60 ° C for 8 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel with 5% MeOH / CH2Cl2 to obtain 156 mg of the title compound as a white solid. Physics Features: 1h NMR (400 MHz, DMSO-d6) 5 10.55, 8.65, 7.58, 7.45, 7.39, 7.33, 7.29, 7.22, 6.77, 5.60, 4.89, 4.53, 4.44, 4.18, 4.05, 3.83, 3.63, 3.33, 2.93, 2.80, 2.32, 1.97, 1.51, 1.35; HRMS m / z 664.2278 (M + Η) +. Anal. Found: c, 63.06; Hf, 5.79; N, 6.26. Example 28. Racem_2-(((2- (1-benzofuran- 2-yl) · 2-hydroxyethyl) (methyl) amino) methyl) (4-muridine) -7- (3-¾ylpropyl) -4 -oxo_4,7_di Hydrogen-p-pheno [2,3-b] p ratio_5_

將消旋-2-(((2-(1-苯并吱喃-2-基）-2-¾基乙基）（甲基）胺 -94- 87731 200410970 基）甲基）-N-(4_氯苄基）-4•氧代-7-(3-(四氫-2H-吡喃-2-基氧基）丙基）-4,7-二氫碟吩并[2,3-b>比啶-5-羧醯胺（製備例44， 1〇〇毫克）溶於THF(5毫升）中，且添加含65%過氯酸（0.2毫升）之水（0.2毫升）。反應混合物在50。(：下攪拌1小時，接著倒入飽和NaHC〇3溶液中。混合物以EtOAc(150毫升）萃取，有機層經脫水（MgSCU)、過濾且濃縮。殘留物在矽膠上以5% MeOH/CHAl2層析純化，粗產物自EtOAc/***再結晶，獲得87毫克白色結晶標題化合物。物理特徵：NMR (400 MHz，DMSO-d6)3 10.53，8.63，7.59，7·46，7.39，7.34，7.29, 7·22, 6.77, 5.60, 4·89, 4.72, 4.53, 4.14, 4·03, 3·83, 3.39, 2·92, 2.81，2.32, 1·86; HRMS (FAB) m/z 580.1669 (Μ+Η)+。分析實測值：C，61·74; Η，4·85; Ν，7·02。實例29. 消旋-2-(((2-(1-苯并吱喃-2-基）_2-經基乙基）（甲基）胺基）_甲基）-Ν·(4-氯苄基）_7-(2·羥基乙基）-4氧代-4,7-二氫嘧吩并 [2,3-b]峨淀-5-幾醯胺The racemic-2-(((2- (1-benzocrean-2-yl) -2-¾ylethyl) (methyl) amine-94- 87731 200410970 group) methyl) -N- ( 4-chlorobenzyl) -4 • oxo-7- (3- (tetrahydro-2H-pyran-2-yloxy) propyl) -4,7-dihydrodipheno [2,3- b > Bipyridin-5-carboxamide (Preparation Example 44, 100 mg) was dissolved in THF (5 ml), and water (0.2 ml) containing 65% perchloric acid (0.2 ml) was added. The reaction mixture was at 50 ° C. (: Stirred for 1 hour, then poured into saturated NaHC03 solution. The mixture was extracted with EtOAc (150 ml), the organic layer was dehydrated (MgSCU), filtered and concentrated. The residue was layered on silica gel with 5% MeOH / CHAl2. Analytical purification, the crude product was recrystallized from EtOAc / ether to obtain 87 mg of the title compound as white crystals. Physical characteristics: NMR (400 MHz, DMSO-d6) 3 10.53, 8.63, 7.59, 7.46, 7.39, 7.34, 7.29, 7 22, 6.77, 5.60, 4.89, 4.72, 4.53, 4.14, 4.03, 3.83, 3.39, 2.92, 2.81, 2.32, 1.86; HRMS (FAB) m / z 580.1669 (Μ + Η) +. Analytical measured values: C, 61 · 74; Η, 4.85; N, 7.02. Example 29. Racemic-2-((((2- (1-benzofuran-2-yl ) _2-Ethylethyl) (methyl) amino) _methyl) -N · (4-chlorobenzyl) _7- (2 · hydroxyethyl) -4oxo-4,7-dihydropyrimidine Benzo [2,3-b] Edian-5-chiamine

將碳酸铯（2 60¾克）及3埃分子篩（1〇〇毫克）添加於含n-(4-氯苄基）-2-(氯甲基）-7-(2-羥基乙基）-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例8，315毫克）及1-(1-苯并吱喃-2_基）_2_(甲基胺基）乙醇（製備例20，133毫克）之DMF(3.0 毫升）溶液中。將反應混合物置於6(TC之搖晃段上17小時。 87731 -95- 200410970 蒸發溶劑’殘留物在矽膠上以5%MeOH/CH2Cl2層析純化，獲得158毫克白色固態標題化合物。物理特徵：NMR (400 MHz，DMSO-d6)3 10.55, 8·58, 7.59, 7.47, 7.39, 7.33, 7.29, 6.77, 5.59, 5.09, 4.90, 4.54, 4.10, 4.00, 3.83, 3.66, 2.91，2.81， 2.31, 1.09 ； HRMS m/z 566.1514 (Μ+Η)+。製備例45. 消旋-5-(4,5-二甲基-2-吱喃）_3_甲基-1，3-崎唑淋啶-2-酮將含二甲基胺基甲酸第三丁酯（7·6克）及四甲基乙二胺 (13.4毫升）之THF(200毫升）溶液冷卻至_70°C，且添加第二丁基鋰（環己烷中1.3 Μ，49.6毫升），且使溫度維持在-65°C 以下。使混合物在-70°C下攪拌1.25小時。添加含4,5-二甲基味喃基甲醛（5.0克）之THF(20毫升）溶液，且使溫度維持在 -65°C以下且持續攪拌2小時。使混合物升溫至，以冰浴冷卻且以NH4C1( 100毫升）終止反應。混合物以***（3 〇〇毫升）稀釋。分離水層且***（2X 1〇〇毫升）萃取。合併之有機層以飽和ΝΗβΙ水溶液（2X50毫升）洗滌，接著以食鹽水（50毫升）洗滌，經脫水（MgSCU)且濃縮。殘留物溶於THF(100毫升）中，且添加氫化鈉（礦物油中60%分散液，3.23克）。使混合物在室溫下攪拌18小時，以冰浴冷卻且以飽和nH4C1水溶液 (100毫升）終止反應。混合物以***（2〇〇毫升）萃取。有機層以飽和NHUC1水溶液（100毫升）洗滌，接著以食鹽水（丨〇〇毫升）洗滌，經脫水（MgSOO且濃縮。粗產物以管柱層析（庚烷 /EtOAc ’ 4/1 ; 1/1)純化’獲得3.46克標色油狀標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6)3 6.44, 5.46, 3.78, 87731 -96- 200410970 3.64, 2.80, 2·19, 1·90; 13C NMR (100 MHz，DMS〇-d6)3 157.4， 148.8, 147.6，115.1，113.8, 67.4, 49.6, 30.9，11.5, 9·8。分析實測值：C，61·29; Η，6·87; Ν，7.35。製備例46. 消旋-1-(4，5-二甲基-2-吱喃基）-2-(甲基胺基）乙醇使含消旋-5-(4,5-二甲基-2-呋喃）-3-甲基-1，3-嘮唑啉啶-2-酮（製備例45，3.23克）、乙醇（10毫升）及1 μ氫氧化鉀水溶液 (5 8毫升）之混合物加熱至60°C 7小時。使混合物冷卻至室溫，以NaCl飽和且以***（4X100毫升）萃取。將合併之有機修層濃縮至100毫升，且以飽和ΝΗβΙ水溶液（6X50毫升）萃取。合併之有機層以固態氫氧化鈉調整至pH為10。且以乙醚（5X 100毫升）萃取。合併之有機層經脫水（K2C03/Na2S04) 且濃縮。殘留物溶於***中，經矽藻土過濾且濃縮。粗產物於-10°C下自己烷/EtOAc(10/l)結晶，獲得ΐ·〇4克黃色固態標題化合物。物理特徵：Μ·ρ· 59.5-60°C ; 4 NMR (400 MHz， DMSO-d6)5 6.00，5·16, 4.47, 2.69, 2·64, 2.28, 2.14，1·86; 13C ❿ NMR (100 ΜΗζ，CDC13)S 151.8，143.2，111.7，106.7，62.9， 54.1，33.8, 9.0, 7·5; MS (ESI+) m/z 170 (Μ+Η)+。分析實測值：C，63·63; Η，8.78; Ν，8.01 〇實例30. 消旋-Ν-(4-氯苄基）-2-(((2-(4,5-二甲基-2-呋喃基）-2-羥基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b] 吡啶-5-羧醯胺 87731 -97- 200410970Add cesium carbonate (260-60 g) and 3 angstrom molecular sieve (100 mg) to n- (4-chlorobenzyl) -2- (chloromethyl) -7- (2-hydroxyethyl) -4 -Oxo-4,7-dihydropyridino [2,3-b] pyridine-5-carboxamide (Preparation Example 8,315 mg) and 1- (1-benzocrean-2-yl) A solution of _2_ (methylamino) ethanol (Preparation Example 20, 133 mg) in DMF (3.0 ml). The reaction mixture was placed on a shaking section of TC for 17 hours. 87731 -95- 200410970 The residue of the evaporated solvent was purified by chromatography on silica gel with 5% MeOH / CH2Cl2 to obtain 158 mg of the title compound as a white solid. Physical characteristics: NMR (400 MHz, DMSO-d6) 3 10.55, 8.58, 7.59, 7.47, 7.39, 7.33, 7.29, 6.77, 5.59, 5.09, 4.90, 4.54, 4.10, 4.00, 3.83, 3.66, 2.91, 2.81, 2.31, 1.09 HRMS m / z 566.1514 (M + Η) +. Preparation Example 45. Racemic-5- (4,5-dimethyl-2-sweeping) _3_methyl-1,3-oxazolidine- 2-keto cool a THF (200 ml) solution containing dimethylamino carboxylic acid third butyl ester (7.6 g) and tetramethylethylenediamine (13.4 ml) to _70 ° C, and add a second Butyllithium (1.3 M in cyclohexane, 49.6 ml), and the temperature was maintained below -65 ° C. The mixture was stirred at -70 ° C for 1.25 hours. 4,5-Dimethylsulfanyl group was added A solution of formaldehyde (5.0 g) in THF (20 ml) and the temperature was maintained below -65 ° C with continuous stirring for 2 hours. The mixture was warmed to, cooled in an ice bath and terminated with NH4C1 (100 ml). The mixture was treated with Diethyl ether (300 ml) Dilute. Separate the aqueous layer and extract with diethyl ether (2 × 100 mL). The combined organic layers are washed with saturated aqueous ΝβΙΙ solution (2 × 50 mL), then with brine (50 mL), dehydrated (MgSCU) and concentrated. The residue It was dissolved in THF (100 ml) and sodium hydride (60% dispersion in mineral oil, 3.23 g) was added. The mixture was stirred at room temperature for 18 hours, cooled in an ice bath and terminated with saturated nH4C1 aqueous solution (100 ml). The reaction. The mixture was extracted with diethyl ether (200 mL). The organic layer was washed with saturated aqueous NHUC1 solution (100 mL), then with brine (1000 mL), dried (MgSOO and concentrated). The crude product was separated by column Analytical (heptane / EtOAc '4/1; 1/1) purification' gave 3.46 g of the title compound as a standard oil. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) 3 6.44, 5.46, 3.78, 87731 -96 -200410970 3.64, 2.80, 2.19, 1.90; 13C NMR (100 MHz, DMS0-d6) 3 157.4, 148.8, 147.6, 115.1, 113.8, 67.4, 49.6, 30.9, 11.5, 9.8. Analysis found: C, 61 · 29; ·, 6.87; Ν, 7.35. Production Example 46. Racemic-1- (4,5-dimethyl-2-creanyl) -2- (methylamino) ethanol makes racemic-5- (4,5-dimethyl- A mixture of 2-furan) -3-methyl-1,3-oxazolindin-2-one (Preparation Example 45, 3.23 g), ethanol (10 ml), and 1 μ potassium hydroxide aqueous solution (58 ml) Heat to 60 ° C for 7 hours. The mixture was cooled to room temperature, saturated with NaCl and extracted with diethyl ether (4 × 100 mL). The combined organic layers were concentrated to 100 mL and extracted with a saturated aqueous solution of ΝββΙ (6 × 50 mL). The combined organic layers were adjusted to pH 10 with solid sodium hydroxide. And extracted with ether (5X 100 ml). The combined organic layers were dried (K2C03 / Na2S04) and concentrated. The residue was dissolved in ether, filtered through celite and concentrated. The crude product was crystallized from hexane / EtOAc (10 / l) at -10 ° C to obtain ΐ.04 g of the title compound as a yellow solid. Physical characteristics: M · ρ · 59.5-60 ° C; 4 NMR (400 MHz, DMSO-d6) 5 6.00, 5.16, 4.47, 2.69, 2.64, 2.28, 2.14, 1.86; 13C ❿ NMR ( 100 ΜΗζ, CDC13) S 151.8, 143.2, 111.7, 106.7, 62.9, 54.1, 33.8, 9.0, 7.5; MS (ESI +) m / z 170 (Μ + Η) +. Anal. Found: C, 63 · 63; H, 8.78; N, 8.01. Example 30. Racemic-N- (4-chlorobenzyl) -2-(((2- (4,5-dimethyl- 2-furyl) -2-hydroxyethyl) (methyl) amino) methyl) -7-methyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine -5-carboxamidine 87731 -97- 200410970

h3c h3c 將消旋-l-(4,5-二曱基-2-呋喃基）-2-(甲基胺基）乙醇（製備例46，0.169克）溶於〇乂？（15毫升）中，且添加队;^_二異丙基乙胺（〇·17毫升）及N-(4-氯苄基）-2-(氯甲基）-7-甲基_4_氧代 -4,7-二氫嘧吩并[2,3-b]吡啶-5-叛醯胺（製備例1，0.191克）。反應混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且倒入水（50毫升）中，且以EtOAc(3 X 100毫升）萃取。合併之鲁有機層經脫水（NasSCU)且真空濃縮。粗產物以管柱層析 (CH2C12/甲醇，50/1 ; 33/1)純化，獲得0.201克白色固態標題化合物。物理特徵；Μ·ρ· 166-167°C ; 4 NMR (400 MHz， DMSO-d6)3 10·62, 8.70, 7·41-7·33, 7·31，6·03, 5.13, 4.61，4.55， 3.94，3.84，3.78，2.74，2.68，2.27，2·11，1.87; 13C NMR (100 MHz, CDC13)5 172.3, 164.8, 154.0, 150.8, 145.7, 145.5, 140.1, 139.0, 131.7, 130.9, 129.5, 128.7, 120.4, 114.6, 114.2, 109.6， φ 64.8, 61.5, 56.6, 43.1，42.6, 41.7, 11.5, 10·0; MS (ESI+) m/z 514 (Μ+Η)+。分析實測值：C，60.76; Η，5·58; Ν，8.22; Cl，6.85; S，6·23 ° 製備例47. 消旋-3-甲基- 5-(5-苯基-2-吱喃基）-1，3-吟吐淋淀-2-酮將含二甲基胺基甲酸第三丁酯（5.47克）及四甲基乙二胺 (9.6毫升）之THF(160毫升）溶液冷卻至-70°C，且添加第二丁基鋰（環己烷中1·3 Μ，35.7毫升），且使溫度維持在-65°C以 87731 -98- 200410970 下。使混合物在-70 C下攪拌1.25小時。添加含5-苯基吱喃基甲酸（5.0克）之THF(20毫升）溶液，且使溫度維持在_65χ：以下且持續攪拌2小時。使混合物升溫至〇它，以冰浴冷卻且以NH4C1( 100晕升）終止反應。混合物以乙随毫升）稀釋。分離水層且***（2X100毫升）萃取。合併之有機層以飽和NH4C1水溶液（2X50毫升）洗滌，接著以食鹽水（5〇毫升）洗滌’經脫水（MgS〇4)且濃縮。殘留物溶於thf(1〇〇毫升）中，且添加氫化鈉（礦物油中60%分散液，2·32克）。使混合物在室溫下攪拌18小時，以冰浴冷卻且以飽*NH4C1水溶液（1〇〇 _ 毫升）終止反應。混合物以***（2〇〇毫升）萃取。有機層以飽和NH4C1水溶液（100毫升）洗滌，接著以食鹽水（1〇〇毫升）洗滌，經脫水（MgS〇4)且濃縮。粗產物以管柱層析（庚烷 /EtOAc ’ 4/1，1/1)純化’獲得3·48克褐色固態標題化合物。物理特徵·· Μ·ρ· 97-99 C ; 4 NMR (400 MHz，DMSO-d6)S 7.73， 7·45，7.33，7_00，6.81，5·65, 3.88，3_82，2.86; 13C NMR (100 MHz，DMSO-d6)3 158.1，155.6，149.4，13〇·5，129.1，128.4 ❿ 124.4，112.6，106·2，68.2，50.9，31.5; MS (Cl) m/z 244 (M+H)+。分析實測值：C，69.04; H，5.49; N，5.74。製備例48. 消旋-2-(甲基胺基）-1-(5-苯基-2-吱喃基）乙醇使含消旋-3-甲基-5-(5-苯基-2-呋喃基）_i，3_呤唑淋啶_2_ 酮（製備例47, 2.43克）、乙醇（20毫升）及1 μ氫氧化鉀水溶液 (3 5毫升）之混合物加熱至50 °C 7小時。使混合物冷卻至室溫，以NaCl飽和且以***（4 XI 〇〇毫升）萃取。將合併之有機 87731 -99- 200410970 層濃縮至100毫升，且以飽和NH4C1水溶液（6X50毫升）萃取。合併之有機層以固態氫氧化鈉調整至pH為1〇。且以乙醚（5X100毫升）萃取。合併之有機層經脫水（K2C〇3/Na2S〇4) 且濃縮。粗產物自***再結晶，獲得156克白色固態標題化合物。物理特徵：]V[·p.75-76。C;1HNMR(400 MHz，DMSO- (16)δ 7.67, 7.41，7.27, 6.86, 6·38, 5.42, 4.66, 2.84-2.76, 2.32; 13C NMR (100 MHz，CDC13)S 155.4，153.8，131.1，129.0, 127.7，124.1，108.9，106.0, 65.8, 55.9, 36.3; MS (ESI+) m/z 218 (M+H)+。分析實測值：c，71 54; H，6 96; N，6 4〇。實例3 1 · 消旋-N-(4-氯苄基）-2-(((2-(5-苯基-2-呋喃基）-2-羥基乙基）（甲基）胺基）甲基）-7-甲基-4-氧代-4,7-二氫噻吩并R，3-b] 外匕淀-5 -叛酿胺h3c h3c Dissolve racemic-l- (4,5-diamidino-2-furanyl) -2- (methylamino) ethanol (Preparation Example 46, 0.169 g) in 0 乂? (15 ml), and added ^ _diisopropylethylamine (0.17 ml) and N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4_ Oxo-4,7-dihydropyrido [2,3-b] pyridine-5-benzidine (Preparation Example 1, 0.191 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dehydrated (NasSCU) and concentrated in vacuo. The crude product was purified by column chromatography (CH2C12 / methanol, 50/1; 33/1) to obtain 0.201 g of the title compound as a white solid. Physical characteristics; M · ρ · 166-167 ° C; 4 NMR (400 MHz, DMSO-d6) 3 10 · 62, 8.70, 7.41-7 · 33, 7 · 31, 6.03, 5.13, 4.61, 4.55, 3.94, 3.84, 3.78, 2.74, 2.68, 2.27, 2.11, 1.87; 13C NMR (100 MHz, CDC13) 5 172.3, 164.8, 154.0, 150.8, 145.7, 145.5, 140.1, 139.0, 131.7, 130.9, 129.5 , 128.7, 120.4, 114.6, 114.2, 109.6, φ 64.8, 61.5, 56.6, 43.1, 42.6, 41.7, 11.5, 10.0; MS (ESI +) m / z 514 (Μ + Η) +. Analytical and measured values: C, 60.76; Rhenium, 5.58; N, 8.22; Cl, 6.85; S, 6.23 ° Preparation Example 47. Racemic-3-methyl-5- (5-phenyl-2- Cranyl) -1,3-indoline-2-one. THF (160 ml) containing tert-butyl dimethylaminoformate (5.47 g) and tetramethylethylenediamine (9.6 ml) The solution was cooled to -70 ° C, and a second butyl lithium (1.3 M in cyclohexane, 35.7 ml) was added, and the temperature was maintained at -65 ° C at 87731 -98- 200410970. The mixture was stirred at -70 C for 1.25 hours. Add a solution of 5-phenylsuccinic acid (5.0 g) in THF (20 mL) and maintain the temperature at -65x: below and continue stirring for 2 hours. The mixture was allowed to warm to zero, cooled in an ice bath and quenched with NH4C1 (100 liters). The mixture was diluted in B with ml). The aqueous layer was separated and extracted with ether (2 × 100 mL). The combined organic layers were washed with saturated aqueous NH4C1 (2 × 50 ml), then washed with brine (50 ml), dehydrated (MgS04) and concentrated. The residue was dissolved in thf (100 ml) and sodium hydride (60% dispersion in mineral oil, 2.32 g) was added. The mixture was allowed to stir at room temperature for 18 hours, cooled in an ice bath and quenched with saturated aqueous NH4C1 (100 mL). The mixture was extracted with diethyl ether (200 ml). The organic layer was washed with a saturated aqueous NH4C1 solution (100 ml), then washed with brine (100 ml), dried (MgS04) and concentrated. The crude product was purified by column chromatography (heptane / EtOAc '4/1, 1/1)' to obtain 3.48 g of the title compound as a brown solid. Physical characteristics ····· 97-99 C; 4 NMR (400 MHz, DMSO-d6) S 7.73, 7.45, 7.33, 7_00, 6.81, 5.65, 3.88, 3_82, 2.86; 13C NMR (100 MHz, DMSO-d6) 3 158.1, 155.6, 149.4, 130.5, 129.1, 128.4 ❿ 124.4, 112.6, 106.2, 68.2, 50.9, 31.5; MS (Cl) m / z 244 (M + H) + . Analytical measured values: C, 69.04; H, 5.49; N, 5.74. Production Example 48. Racemic-2- (methylamino) -1- (5-phenyl-2-creanyl) ethanol contains racemic-3-methyl-5- (5-phenyl-2 -Furyl) _i, 3_pyrazolidine_2_one (Preparation Example 47, 2.43 g), ethanol (20 ml) and 1 μ potassium hydroxide aqueous solution (35 ml) were heated to 50 ° C for 7 hours . The mixture was allowed to cool to room temperature, saturated with NaCl and extracted with diethyl ether (4 X 100 mL). The combined organic 87731-99-200410970 layers were concentrated to 100 ml and extracted with saturated aqueous NH4C1 solution (6 × 50 ml). The combined organic layers were adjusted to pH 10 with solid sodium hydroxide. And extracted with ether (5 × 100 ml). The combined organic layers were dehydrated (K2CO3 / Na2SO4) and concentrated. The crude product was recrystallized from diethyl ether to obtain 156 g of the title compound as a white solid. Physical characteristics:] V [· p.75-76. C; 1HNMR (400 MHz, DMSO- (16) δ 7.67, 7.41, 7.27, 6.86, 6.38, 5.42, 4.66, 2.84-2.76, 2.32; 13C NMR (100 MHz, CDC13) S 155.4, 153.8, 131.1, 129.0, 127.7, 124.1, 108.9, 106.0, 65.8, 55.9, 36.3; MS (ESI +) m / z 218 (M + H) +. Analysis found: c, 71 54; H, 6 96; N, 6 4〇 Example 3 1 · Racemic-N- (4-chlorobenzyl) -2-((((2- (5-phenyl-2-furanyl) -2-hydroxyethyl) (methyl) amino) (Methyl) -7-methyl-4-oxo-4,7-dihydrothieno R, 3-b] exodium-5 -fermentamine

將消旋-2-(甲基胺基）—^(5-苯基-2-呋喃基）乙醇（製備例 48，0.217克）溶於DMF(15毫升）中，且添加N，N-二異丙基乙胺（0.17毫升）及N-(4-氯苄基）-2-(氯甲基）-7-甲基-4-氧代 _4,7-二氫嘧吩并[2,3_13]说啶-5-羧醯胺（製備例1，〇.191克）。反應混合物加熱至9 0 °C 2小時。使反應混合物冷卻至室溫且倒入水（50毫升）中，且以EtOAc(3XlOO毫升）萃取。合併之有機層經脫水（Na2S04)且真空濃縮。粗產物以管柱層析 (CH2C12/甲醇，100/1 ; 50/1)純化，且自 EtOAc/CH2Cl2/*** 87731 -100- 200410970 再結晶，獲得0.217克白色固態標題化合物。物理特徵；Μ·ρ· 177-178〇C ； lH NMR (400 MHz, DMSO-d6)6 10.61, 8.51, 7.53, 7.42-7.28, 7.17, 6.88, 6.41，5.40, 4.75, 4.55, 3.85, 3.77, 3.68, 2.94, 2.70, 2.34; 13C NMR (100 MHz, CDC13)8 170.9, 163.4, 155.6, 150.6, 149.4, 143.9, 138.9, 137.7, 130.4, 129.4, 128.1， 127.7，127.4，126.0，121.9，119.0，113.3，107.8，105.3, 63.7, 60.0, 55.5, 41.8, 41.4, 40·4; MS (ESI+) m/z 562 (M+H)+。分析實測值：C，63.93; H，5.13; N，7_47; Cl, 6.29; S，5.66。實例32. N-(4-氯苄基）-2-((((2R)-2-(2-呋喃基）_2-羥基乙基）（甲基）胺基）甲基）-4-氧代-7-丙基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶 -5-叛醯胺Dissolve racemic 2- (methylamino)-(5-phenyl-2-furanyl) ethanol (Preparation Example 48, 0.217 g) in DMF (15 ml), and add N, N-di Isopropylethylamine (0.17 ml) and N- (4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo_4,7-dihydropyridino [2, 3-13] Said pyridin-5-carboxamide (Preparation Example 1, 0.191 g). The reaction mixture was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (CH2C12 / methanol, 100/1; 50/1) and recrystallized from EtOAc / CH2Cl2 / ether 87731 -100- 200410970 to obtain 0.217 g of the title compound as a white solid. Physical characteristics; M · ρ · 177-178 ° C; lH NMR (400 MHz, DMSO-d6) 6 10.61, 8.51, 7.53, 7.42-7.28, 7.17, 6.88, 6.41, 5.40, 4.75, 4.55, 3.85, 3.77, 3.68, 2.94, 2.70, 2.34; 13C NMR (100 MHz, CDC13) 8 170.9, 163.4, 155.6, 150.6, 149.4, 143.9, 138.9, 137.7, 130.4, 129.4, 128.1, 127.7, 127.4, 126.0, 121.9, 119.0, 113.3 , 107.8, 105.3, 63.7, 60.0, 55.5, 41.8, 41.4, 40.4; MS (ESI +) m / z 562 (M + H) +. Analysis found: C, 63.93; H, 5.13; N, 7_47; Cl, 6.29; S, 5.66. Example 32. N- (4-chlorobenzyl) -2-(((((2R) -2- (2-furanyl) _2-hydroxyethyl) (methyl) amino) methyl) -4-oxo 7-propyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-benzylamine

使N-(4-氯苄基）-2-(氯甲基）-7-丙基-4-氧代-4,7-二氩嘧吩 · 并[2,3-b]外(：咬叛醯胺（製備例12，0.25克）、（1R)小(2-吱喃基）-2-(甲基胺基）乙醇（製備例17，〇17克）及n，N-二異丙基乙胺（0·21毫升）之DMF(14毫升）混合物在9(rc下加熱bj、時。使反應混合物冷卻至室溫且真空濃縮。粗產物以管柱層析（CHzCl2/甲醇，97/3)純化，且分散於***中，獲得〇.24 克灰白色粉末狀標題化合物。物理特徵：iH NMR (300 MHz， DMSO-d6)5 10.60, 8.69, 7.56, 7·43_7·26, 6·39, 6.29, 5.70, 4.73， 4·55，4·22，3.81，2.74，2.29，1·85，0.89; HRMS (ESI) m/z 87731 -101 - 200410970 514·1588 (M+H)+。製備例4 9. 5-(5•氯_2-呋喃基）_3_甲基-L3号唑啉啶_2_酮使含二甲基胺基甲酸第三丁酯（72克）及N，N，N，，N，_四甲基乙二胺（12.7毫升）之THF(210毫升）混合物冷卻至-70°C。滴加第二丁基鋰（環己烷中14 μ，43.7毫升），且使反應溫度維持在-65 °C以下。使反應在-70°C下攪拌1.5小時。滴加含5-氯-2-糠酸（5.0克）之THF(20毫升）溶液，且使反應溫度維持在-65°C以下。使混合物在_7(TC攪拌丨小時。使混合物升_ 溫至0°C，再以飽和ΝΗβΙ溶液（125毫升）終止反應，同時以冰洛冷卻。混合物以***（3〇〇毫升）稀釋。水層以***（2 X 1〇〇毫升）萃取。合併之有機層以飽*NH4C1水溶液（2χ5〇毫升）洗滌，接著以食鹽水（50毫升）洗滌，經脫水（MgS〇4)且濃縮。所得油狀物溶於THF(115毫升）中，且添加氫化鈉（礦物油中60%分散液，3 · 1克）。使混合物在室溫下攪拌丨8小時，以冰浴冷卻且以飽和NHUC1水溶液（100毫升）終止反應混合 _ 物之反應。混合物以***（200毫升）稀釋。有機層以飽和 NHjCl水落液（100毫升）洗滌，接著以食鹽水（1〇〇毫升）洗滌，經脫水（MgS〇4)且真空濃縮。粗產物以管柱層析（Et〇Ae/ 庚烷，1/1)純化，獲得1.9克琥珀色油狀標題化合物。物理特徵 NMR (400 MHz，DMSO.d6)S 6.8〇, 6 55, 5 %，3 81， 3.69, 2.81 。製備例50. 1-(5 -氯-2-咬喃基）-2-(〒基胺基）乙醇 87731 -102- 200410970 將5-(5-鼠-2-吱喃基）-3•甲基- l，3_p号咬p林淀-2_酉同（製備例 49，2·0克）溶於乙醇（20毫升）中，且添加1 μ KOH水溶液（35 毫升）。混合物加熱至回流4小時。使反應冷卻至室溫，添加NaCl ’且以***萃取反應混合物。真空濃縮有機層至體積100¾升’且以飽和NH/l水溶液（6X50毫升）萃取。合併之有機層以固態NaOH調整至pH為10，接著以***（5 X 1〇〇毫升）萃取。合併之有機層經脫水（1^&28〇4)且濃縮，獲得棕色結晶固態標題化合物。物理特徵：4 NMR (300 MHz， DMSO-d6)S 6.35, 4.54, 2.69, 2.28。實例33. N-(4-氯苄基）-2-(((2-(5-氯_2_呋喃基）-2·羥基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘍吩并[2,3-b]吡啶-5-羧醯胺Make N- (4-chlorobenzyl) -2- (chloromethyl) -7-propyl-4-oxo-4,7-diargyrimidine and [2,3-b] external (: bite Betamine (Preparation Example 12, 0.25 g), (1R) small (2-creanyl) -2- (methylamino) ethanol (Preparation Example 17, 017 g) and n, N-diisopropyl A mixture of DMF (14 ml) of ethylethylamine (0.21 ml) was heated at 9 ° C for bj, h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was subjected to column chromatography (CHzCl2 / methanol, 97 / 3) Purified and dispersed in ether to obtain 0.24 g of the title compound as an off-white powder. Physical characteristics: iH NMR (300 MHz, DMSO-d6) 5 10.60, 8.69, 7.56, 7.43_7 · 26, 6 · 39, 6.29, 5.70, 4.73, 4.55, 4.22, 3.81, 2.74, 2.29, 1.85, 0.89; HRMS (ESI) m / z 87731 -101-200410970 514 · 1588 (M + H) +. Preparation Example 4 9. 5- (5 • Chloro_2-furanyl) _3_methyl-L3 oxazoline_2_one contains dimethylaminoformic acid third butyl ester (72 g) and N, A mixture of N, N ,, N, -tetramethylethylenediamine (12.7 ml) in THF (210 ml) was cooled to -70 ° C. A second butyl lithium (14 μ in cyclohexane, 43.7 ml) was added dropwise. And make The reaction temperature was maintained below -65 ° C. The reaction was stirred at -70 ° C for 1.5 hours. A solution of 5-chloro-2-furic acid (5.0 g) in THF (20 ml) was added dropwise, and the reaction temperature was maintained Below -65 ° C. The mixture was stirred at -7 ° C for 1 hour. The mixture was warmed to 0 ° C, and the reaction was terminated with a saturated ΝβΙΙ solution (125 ml) while cooling with ice cream. The mixture was cooled with ether ( Diluted with 300 mL). The aqueous layer was extracted with ether (2 × 100 mL). The combined organic layers were washed with saturated aqueous NH4C1 (2 × 50 mL), then washed with brine (50 mL), and dehydrated ( MgS04) and concentrated. The resulting oil was dissolved in THF (115 ml), and sodium hydride (60% dispersion in mineral oil, 3.1 g) was added. The mixture was stirred at room temperature for 8 hours, The reaction mixture was quenched with ice bath and saturated with NHUC1 aqueous solution (100 mL). The mixture was diluted with ether (200 mL). The organic layer was washed with saturated aqueous NHjCl solution (100 mL), and then with brine (1〇 0 ml), washed with water (MgS04) and concentrated in vacuo. Crude The product was purified by column chromatography (EtoAe / heptane, 1/1) to obtain 1.9 g of the title compound as an amber oil. Physical characteristics NMR (400 MHz, DMSO.d6) S 6.80, 6 55, 5% , 3 81, 3.69, 2.81. Preparation Example 50. 1- (5-Chloro-2-octanoyl) -2- (fluorenylamino) ethanol 87731 -102- 200410970 5- (5-Mor-2-ylanyl) -3 • methyl The base-1,3_p bit p Lindian-2_ (the same as Preparation Example 49, 2.0 g) was dissolved in ethanol (20 ml), and 1 μ KOH aqueous solution (35 ml) was added. The mixture was heated to reflux for 4 hours. The reaction was allowed to cool to room temperature, NaCl 'was added and the reaction mixture was extracted with diethyl ether. The organic layer was concentrated in vacuo to a volume of 100 ¾ liter 'and extracted with a saturated aqueous NH / 1 solution (6 x 50 ml). The combined organic layers were adjusted to pH 10 with solid NaOH, and then extracted with ether (5 x 100 mL). The combined organic layers were dehydrated (1 & 2804) and concentrated to give the title compound as a brown crystalline solid. Physical characteristics: 4 NMR (300 MHz, DMSO-d6) S 6.35, 4.54, 2.69, 2.28. Example 33. N- (4-chlorobenzyl) -2-((((2- (5-chloro_2_furanyl) -2 · hydroxyethyl) (methyl) amino) -methyl) -7 -Methyl-4-oxo-4,7-dihydrofluoreno [2,3-b] pyridine-5-carboxamide

使义(4_氯苄基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫嘍吩并[2,3-b]吡啶-5-羧醯胺（製備例1，〇·ΐ6克）、1-(5-氯-2-呋喃基）-2-(甲基胺基）乙醇（製備例5〇，〇15克）及n，N-二異丙基乙胺（〇·15毫升）之DMF(12毫升）混合物加熱至90°C 2小時。使反應混合物冷卻至室溫且以水（2〇毫升）稀釋。懸浮液經過濾且所得固體自甲醇再結晶，獲得0.11克灰白色粉末狀標題化合物。物理特徵·· iHNMRpOOMHz’DMSO-dJS 10.62, 8.70, 7.45-7.27，6.41，5.44，4.68，4.53，4.11，3·92，3·81，3.18, 87731 -103- 200410970 2.85-2.60, 2.27。分析實測值：c，5519; Η，4·53; Ν，8 〇1; α， 13.33; S，6·1〇〇製備例5 1 · N-(4-氯卞基）-2-((((2R)-2_(2-呋喃基）_2_羥基乙基甲基）胺基）甲基）-4_氧代_7·(2_(四氫_21^比喃_2•基氧基）乙基）_4,7_ 二氫嘧吩并[2,3_b]吡啶_5_羧醯胺將碳酸絶（260毫克）及3埃分子篩（1〇〇毫克）添加於含沁(4· 氯下基）-2•(氯甲基）_4_氧代_7_(2_(四氫_2H_吡喃_2·基氧基）乙基）-4,7-二氫嘧吩并[2,3_b]吡啶_5_羧醯胺（製備例7，315 耄克）及（lR)-l-(2-呋喃基）_2_(甲基胺基）乙醇（製備例17， 133¾克）之DMF(3.〇毫升）溶液中。將反應混合物(4-chlorobenzyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrofluoreno [2,3-b] pyridine-5-carboxyfluorene Amine (Preparation Example 1, 6 g), 1- (5-chloro-2-furyl) -2- (methylamino) ethanol (Preparation Example 5,0 15 g), and n, N-di A mixture of isopropylethylamine (0.15 ml) in DMF (12 ml) was heated to 90 ° C for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The suspension was filtered and the resulting solid was recrystallized from methanol to obtain 0.11 g of the title compound as an off-white powder. Physical characteristics · iHNMRpOOMHz 'DMSO-dJS 10.62, 8.70, 7.45-7.27, 6.41, 5.44, 4.68, 4.53, 4.11, 3.92, 3.81, 3.18, 87731 -103- 200410970 2.85-2.60, 2.27. Analytical and measured values: c, 5519; hydrazone, 4.53; N, 801; α, 13.33; S, 6.100 Preparation Example 5 1 · N- (4-chlorofluorenyl) -2-(( ((2R) -2_ (2-furanyl) _2_hydroxyethylmethyl) amino) methyl) -4_oxo_7 · (2_ (tetrahydro_21 ^ biran_2 • yloxy ) Ethyl) _4,7_ dihydropyrido [2,3_b] pyridine_5_carboxamidinium carbonate (260 mg) and 3 angstrom molecular sieve (100 mg) were added to ) -2 • (chloromethyl) _4_oxo_7_ (2_ (tetrahydro_2H_pyran_2 · yloxy) ethyl) -4,7-dihydropyrido [2,3_b ] DMF of pyridine_5_carboxamidine (Preparation Example 7,315 g) and (lR) -1- (2-furyl) _2_ (methylamino) ethanol (Preparation Example 17, 133¾ g) 〇mL) solution. Reaction mixture

置於60°C 之搖晃#又上17小時。瘵發溶劑，殘留物在矽膠上以⑷出之管柱層析純化，獲得標題化合物。物理特徵：咕丽R (400 MHz，DMSO_d6)5 1〇 56, 8 71，7 圮 7 抓7 29, 6 % 6.28, 5.28, 4.74, 4.58, 4.45, 3.96, 3.78, 3.34, 3.30, 2.76, 2-50, 2.26, 1.53, 1.38’ 1.27。分析實測值：c，59 76; η，5·8〇; Ν， 6.95。實例34. Ν-(4Κ基）_2-((((2R)-2-(2'呋喃基）-2-獲基乙基）（甲基）胺基）甲基）-7-(2-羥基乙基）_4_惫抑 & 、土 ^ —虱代-4,7-一虱噻吩并[2,3_b]吡咬-5 -幾酿胺Leave at 60 ° C 的摇摇 # for another 17 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography on a silica gel to obtain the title compound. Physical characteristics: Guli R (400 MHz, DMSO_d6) 5 1〇56, 8 71, 7 圮 7 Grab 7 29, 6% 6.28, 5.28, 4.74, 4.58, 4.45, 3.96, 3.78, 3.34, 3.30, 2.76, 2 -50, 2.26, 1.53, 1.38 '1.27. Analysis found: c, 59 76; η, 5.80; Ν, 6.95. Example 34. Ν- (4Κ 基) _2-(((((2R) -2- (2'furanyl) -2-acylethyl) (methyl) amino) methyl) -7- (2- (Hydroxyethyl) _4_ exhaustion & soil 虱 — lice-4,7-one lice thieno [2,3_b] pyridin-5 -jimonamine

87731 -104- 200410970 將62%過氯酸溶液（100微升）添加於含n-(4-氯苄基）-2-((((2R)-2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）甲基）-4-氧代-7-(2-(四氫-2H-吡喃-2-基氧基）乙基）-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺（製備例51，120毫克）之THF(5毫升）溶液中。反應混合物在22 °C下攪拌1小時。混合物以 EtOAc( 150毫升）稀釋，且以飽和碳酸氫鈉水溶液洗滌。有機層經脫水（MgS04)、過濾且濃縮，獲得79毫克標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d60 10.6, 8.62, 7.56, 7.40, 7.38, 7.29, 6.39, 6.28, 5.28, 5.15, 4.74, 4·55, 4.28, 3.86-3.76, 3·33, 2.76, 2.27; MS (Cl) m/z 516 (M+H)+; HRMS (ESI) m/z 516.1368 (M+H)+。製備例52. N-(4-氣苄基）-2-(羥基甲基）_4_氧代_7-(2_(2-(四氫·2Η-吡喃 -2-基氧基）乙氧基）乙基）_4,7_二氫嘧吩并[2,3-b]吡啶-5-羧醯胺將碳酸铯（3 ·25克）添加於含n-(4-氯苄基）_4_羥基-2-(羥基甲基）嘧吩并[2,3_b]吡啶-5-羧醯胺（3.5克，如美國專利第 6,239，142號中所述般製備）及2_(2_(2-氯乙氧基）乙氧基）四氫_2H”比喃（2.1克）之〇娜（12毫升）溶液中。混合物在1〇(Γ(：87731 -104- 200410970 Add 62% perchloric acid solution (100 microliters) to n- (4-chlorobenzyl) -2-(((((2R) -2- (2-furanyl) -2- Hydroxyethyl) (methyl) amino) methyl) -4-oxo-7- (2- (tetrahydro-2H-pyran-2-yloxy) ethyl) -4,7-dihydro A solution of pyrimido [2,3-b] pyridine-5-carboxamide (Preparation Example 51, 120 mg) in THF (5 ml). The reaction mixture was stirred at 22 ° C for 1 hour. The mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous sodium bicarbonate. The organic layer was dehydrated (MgS04), filtered and concentrated to obtain 79 mg of the title compound. Physical characteristics: 4 NMR (400 MHz, DMSO-d60 10.6, 8.62, 7.56, 7.40, 7.38, 7.29, 6.39, 6.28, 5.28, 5.15, 4.74, 4.55, 4.28, 3.86-3.76, 3.33, 2.76, 2.27; MS (Cl) m / z 516 (M + H) +; HRMS (ESI) m / z 516.1368 (M + H) +. Preparation Example 52. N- (4-Gabenzyl) -2- (hydroxy (Methyl) _4_oxo_7- (2_ (2- (tetrahydro · 2Η-pyran-2-yloxy) ethoxy) ethyl) _4,7_dihydropyrido [2,3 -b] pyridine-5-carboxamidine Added cesium carbonate (3.25 g) to n- (4-chlorobenzyl) _4-hydroxy-2- (hydroxymethyl) pyridino [2,3_b] Pyridine-5-carboxamide (3.5 g, prepared as described in US Patent No. 6,239,142) and 2_ (2_ (2-chloroethoxy) ethoxy) tetrahydro_2H ”biran (2.1 G) in Na solution (12 ml). The mixture was in 10 (Γ (:

200410970 5·61; N，5_36。製備例53. N-(4-氯苄基）-2_(氯甲基p‘氧代_7气2_(2_(四氫_2H_吡喃_2_ 基氧基）乙氧基）乙基）·4,7_二氫噻吩并[2,3-b]吡啶-5-羧醯胺將2,4，卜可力啶（1.6毫升）及4-N，N-二甲基胺基吡啶（20毫克）添加於含N-(4-氯苄基）-2-(羥基甲基）·4·氧代_7_(2_(2_(四氫-2Η-吡喃_2_基氧基）乙氧基）乙基）_4,7_二氫噻吩并[2,3吨] 吡哫羧醯胺（製備例52，2.62克）之THF(15毫升）懸浮液中。添加甲燒磺醯氯（〇·78毫升），且使反應在5〇^下加熱1 小時。条發溶劑且經殘留物溶於氯仿中。有機層以水洗滌，經脫水（MgS〇4)且濃縮。粗產物以管柱層析（CH2Cl2/甲醇， 95/5)純化，接著自Et〇Ac結晶，獲得18克褐色固態標題化合物。物理特徵：4 NMR (400 MHz，DMSO_d6)3 10.54, 8.70, 7·55, 7.40-7.33, 5.14, 4.53, 4.47, 4.39, 3.86, 3.61-3.46, 3.37, 3·33, 3·22, 1.49-1.3 卜分析實測值：C，55·65; Η，519; Ν，511。製備例54. Ν-(4-氯爷基咬喃基）-2_經基乙基）（甲基）胺基）甲基）_4_氧代_7_(2-(2_(四氫_2H-p比喃_2_基氧基）乙氧基）乙基）-4,7·二氫違吩并[2,3-b]吡咬-5-羧醯胺將二異丙基乙胺（192微升）及3埃分子篩（1〇〇毫克）添加於含N_(4-氯苄基）-2-(氯甲基）-4•氧代-7-(2-(2-(四氫-2H-吡喃 -2-基氧基）乙氧基）乙基）-4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例53，270毫克）及（1R)小(2-呋喃基）_2-(甲基胺基）乙醇（製備例17，141毫克）之DMF(2.5毫升）溶液中。將反應 87731 -106- 200410970 混合物在室溫下置於搖晃段上17小時。蒸發溶劑，殘留物在矽膠上管柱層析（CH^Ch/甲醇，95/5)純化，獲得標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6)S 10.54, 8.64, 7.95, 7.56, 7.39, 7.33, 7.29, 6·39, 6.28, 5·28, 4.73, 4.53, 4.41， 3.83, 3·61，3.54, 3·51，3.39, 3.25, 2.89, 2.77, 2.73, 2.27, 1.30; MS (Cl) m/z 644 (Μ+Η)+ο HRMS (ESI) m/z 644.2198 (Μ+Η)+〇實例35. Ν-(4-氯苄基）-2-((((2R)-2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）甲基）-7-(2-(2-經基乙氧基）乙基）-4-氧代-4,7-二氫p塞吩并[2,3-b]吡啶-5-幾醯胺200410970 5.61; N, 5_36. Preparation Example 53. N- (4-chlorobenzyl) -2_ (chloromethyl p'oxo_7gas 2_ (2_ (tetrahydro_2H_pyran_2_yloxy) ethoxy) ethyl) · 4,7_Dihydrothieno [2,3-b] pyridine-5-carboxamidine will be 2,4, cobolidine (1.6 ml) and 4-N, N-dimethylaminopyridine ( 20 mg) added to N- (4-chlorobenzyl) -2- (hydroxymethyl) · 4 · oxo_7_ (2_ (2_ (tetrahydro-2Η-pyran_2_yloxy) ethyl) (Oxy) ethyl) -4,7-dihydrothieno [2,3 tons] pyridocarboxamide (Preparation Example 52, 2.62 g) in a THF (15 ml) suspension. Toluenesulfonyl chloride (0.78 mL) was added and the reaction was heated at 50 ° C for 1 hour. The solvent was applied and the residue was dissolved in chloroform. The organic layer was washed with water, dried (MgS04) and concentrated. The crude product was purified by column chromatography (CH2Cl2 / methanol, 95/5) and then crystallized from EtoAc to obtain 18 g of the title compound as a brown solid. Physical characteristics: 4 NMR (400 MHz, DMSO_d6) 3 10.54, 8.70, 7.55, 7.40-7.33, 5.14, 4.53, 4.47, 4.39, 3.86, 3.61-3.46, 3.37, 3.33, 3.22, 1.49- 1.3 Calculated measured values: C, 55 · 65; Η, 519; Ν, 511. Preparation Example 54. Ν- (4-chloroethenylthio) -2-merylethyl) (methyl) amino) methyl) _4_oxo_7_ (2- (2_ (tetrahydro_2H -pbiran_2_yloxy) ethoxy) ethyl) -4,7 · dihydrobenzopheno [2,3-b] pyridine-5-carboxamidine diisopropylethylamine (192 μl) and 3 angstrom molecular sieves (100 mg) were added to N_ (4-chlorobenzyl) -2- (chloromethyl) -4 • oxo-7- (2- (2- (tetra Hydrogen-2H-pyran-2-yloxy) ethoxy) ethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (Preparation Example 53,270 mg ) And (1R) small (2-furyl) _2- (methylamino) ethanol (Preparation Example 17, 141 mg) in DMF (2.5 ml). The reaction 87731 -106- 200410970 mixture was placed on a shaking section at room temperature for 17 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography (CH ^ Ch / methanol, 95/5) to obtain the title compound. Physical characteristics: 4 NMR (400 MHz, DMSO-d6) S 10.54, 8.64, 7.95, 7.56, 7.39, 7.33, 7.29, 6.39, 6.28, 5.28, 4.73, 4.53, 4.41, 3.83, 3.61, 3.54, 3.51, 3.39, 3.25, 2.89, 2.77, 2.73, 2.27, 1.30; MS (Cl) m / z 644 (Μ + Η) + ο HRMS (ESI) m / z 644.2198 (Μ + Η) + 〇 Example 35. Ν- (4-chlorobenzyl) -2-(((((2R) -2- (2-furanyl) -2-hydroxyethyl) (methyl) amino) methyl) -7- (2- (2-Ethylethoxy) ethyl) -4-oxo-4,7-dihydrop-pheneno [2,3-b] pyridine-5-chiamine

將62%過氯酸溶液（1〇〇微升）添加於含n-(4-氯节基）-2_((((2R)-2_(2·呋喃基）-2-羥基乙基）（甲基）胺基）甲基> 4-氧代_7-(2-(2-(四氫-2H-吡喃-2-基氧基）乙氧基）乙基）_4,7· 二氫噻吩并[2,3-b]吡啶-5-羧醯胺（製備例54，200毫克）之 THF(5毫升）溶液中。反應混合物在22°C下攪拌2小時。混合物以EtOAc(150毫升）稀釋，且以飽和碳酸氫鈉水溶液洗滌。有機層經脫水（MgSCU)、過濾且濃縮。粗產物以管柱層析（氯仿/甲醇，95/5)純化，獲得11 8毫克標題化合物。物理特徵：4 NMR (400 MHz，DMSO-d6W 10·6, 8.66, 7.56, 7.39, 7.34, 7·29, 6·38, 6,29, 5,29, 4·73, 4·59, 4.53, 4·41，3·84, 3·80, 87731 -107- 200410970 3·43，3.33，2.75, 2·27; MS (CI) m/z 560 (M+H)+。分析實測值：C，57.52; Η，5·65; Ν，7·19。製備例55. 2-(甲基（二苯甲基）胺基）-1-(1•三苯甲基·ιη_咪吨-2-基）乙醇將含1-三苯甲基咪唑（1·67克）之60毫升THF溶液冷卻至 -78°C，且在氮氣下以n-BuLi溶液（己烷中2.5 Μ，2.15毫升）逐滴處理。所得混合物攪拌30分鐘，再添加含2-Ν-三苯甲基乙胺乙醛（1.0克）之THF(10毫升）溶液。反應混合物在_79 C下攪拌1小時，且使其升溫至室溫。混合物藉由滴加飽和 NH4C1水溶液及水終止反應。所得懸浮液以Et〇Ac(2xi〇0毫升）萃取。合併之有機層以水（100毫升）洗滌，接著以食鹽水 (50¾升）洗滌，經脫水（NadO4)、過滤且真空濃縮。殘留物以管柱層析（CHWU/EtOAc ; 9/1)純化，獲得0.93克白色固態知:題化合物。物理特徵：11_^1^111(400 %1^，匚〇(313)§7.38- 6.99, 6.61，4.28-4.24, 3.51，3.30-3.24, 1.33。製備例56. 1-(1H-咪唑基）-2_(甲基胺基）乙醇二鹽酸鹽含2-(甲基（三苯甲基）胺基）三苯甲基-丨仏咪唑_2•基）乙醇（製備例55，3.4克）之丙酮（70毫升）溶液以含4 N HC1< 二噚烷溶液（5毫升）處理，且在室溫下攪拌4小時。減壓蒸發移除落劑，且將殘留物懸浮在Et〇Ac中。以過濾收集所得固體，且以熱Et0Ac洗滌，獲得〇·92克白色固態標題化合物。物理特欲·M·p.l76·4-177·3。C;1HNMR(400 MHz，D^lSO- d6)3 7.65, 7.40, 5.42, 3.64-3.39, 2.61，13C NMR (DMSO-d6)8 87731 -108- 200410970 146.2, 119.9, 61.4, 51·3, 33.2。製備例36. 消旋-Ν·(4-氯苄基）-2-(((2-羥基_2-(m•咪唑_2_基）乙基χ甲基）胺基）甲基）-7-甲基-4-氧代_4,7-二氫嘍吩并[2,3_b]吡啶 -5-羧醯胺 ch3 將含消旋-2-(2-甲胺基-1-羥基乙基）咪唑二鹽酸鹽（製備鲁例56, 0.17克）、ΚΙ(0·02克）、三乙胺（〇·27毫升）及3埃分子篩之供水DMF( 1 5毫升）混合物擾掉2小時，且以n_(4-氯爷基）-2-(氯甲基）-7-甲基-4-氧代-4,7-二氫噻吩并[2,3_b]吡啶 -5-羧醯胺（製備例1，0.3克）處理。所得混合物在周圍溫度下攪拌隔夜。以過濾移除分子篩，濾液以Et〇Ac(l〇〇毫升）稀釋。混合物以水（3 X 50耄升）洗丨條，接著以食鹽水（5〇毫升）洗滌，經脫水（NadO4)且真空濃縮。粗產物以放射層析再鲁 1000 μ轉子上，以CH2Ch/甲醇/NH3水溶液（90/9/1)溶離純化，接著自甲醇/EtOAc再結晶，獲得〇· 12克白色固態標題化合物。物理特徵：Μ·ρ· 177.9-179.5°C; 4 NMR (400 MHz， DMSO-d6)8 11.93，10.62，8.70，7.41-7.30，6.90，5.44，4.79， 4.54, 3.94, 3.89-3.78, 2.87-2.72, 2.50, 2.29; 13C NMR (DMSO-d6)S 170.5，163·0，149.1，148.1，143.7，138.3，137.2，129.9， 129.2, 127.7, 126.9, 118.6, 112·9, 64.4, 60.4, 54.9, 41.4, 40.8， 39·9; MS (ESI+) m/z 486 (M+H)+ 〇 87731 -109-62% perchloric acid solution (100 microliters) was added to n- (4-chlorobenzyl) -2 _ ((((2R) -2_ (2.furanyl) -2-hydroxyethyl)) Methyl) amino) methyl> 4-oxo_7- (2- (2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) ethyl) _4,7 · di Hydrothieno [2,3-b] pyridine-5-carboxamide (Preparation Example 54, 200 mg) in THF (5 ml). The reaction mixture was stirred at 22 ° C for 2 hours. The mixture was stirred with EtOAc (150 Ml), and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dehydrated (MgSCU), filtered, and concentrated. The crude product was purified by column chromatography (chloroform / methanol, 95/5) to obtain 118 mg of the title compound. Physical characteristics: 4 NMR (400 MHz, DMSO-d6W 10.6, 8.66, 7.56, 7.39, 7.34, 7.29, 6.38, 6,29, 5,29, 4.73, 4.59, 4.53, 4.41, 3.84, 3.80, 87731 -107- 200410970 3.43, 3.33, 2.75, 2.27; MS (CI) m / z 560 (M + H) +. Analysis found: C, 57.52; hydrazone, 5.65; N, 7.19. Preparation Example 55. 2- (methyl (diphenylmethyl) amino) -1- (1 · trityl · ιη_imiton-2- Based) ethanol will contain 1-tritylimidazole (1.67 g) 60 ml of the THF solution was cooled to -78 ° C, and treated dropwise with an n-BuLi solution (2.5 M in hexane, 2.15 ml) under nitrogen. The resulting mixture was stirred for 30 minutes, and then 2-N-tribenzene was added. A solution of methyl ethylamine acetaldehyde (1.0 g) in THF (10 ml). The reaction mixture was stirred at -79 C for 1 hour and allowed to warm to room temperature. The mixture was quenched by the dropwise addition of saturated aqueous NH4C1 solution and water. The resulting suspension was extracted with EtoAc (2x100 mL). The combined organic layers were washed with water (100 mL), then with brine (50¾ liters), dried (NadO4), filtered and concentrated in vacuo. The residue Purified by column chromatography (CHWU / EtOAc; 9/1) to obtain 0.93 g of the title compound as a white solid. Physical characteristics: 11_ ^ 1 ^ 111 (400% 1 ^, 匚〇 (313) §7.38- 6.99, 6.61, 4.28-4.24, 3.51, 3.30-3.24, 1.33. Preparation Example 56.1 1- (1H-imidazolyl) -2_ (methylamino) ethanol dihydrochloride contains 2- (methyl (trityl) ) Amino) Trityl--imidazole_2 • yl) A solution of ethanol (Preparation Example 55, 3.4 g) in acetone (70 ml) containing 4 N HC1 < dioxane solution (5 ml ), And stirred at room temperature for 4 hours. The evaporation agent was removed under reduced pressure, and the residue was suspended in EtoAc. The resulting solid was collected by filtration and washed with hot Et0Ac to obtain 0.92 g of the title compound as a white solid. Physical Desire · M · p.l76 · 4-177 · 3. C; 1HNMR (400 MHz, D ^ lSO-d6) 3 7.65, 7.40, 5.42, 3.64-3.39, 2.61, 13C NMR (DMSO-d6) 8 87731 -108- 200410970 146.2, 119.9, 61.4, 51.3, 33.2 . Production Example 36. Racemic-N · (4-chlorobenzyl) -2-(((2-hydroxy_2- (m • imidazole_2_yl) ethylχmethyl) amino) methyl)- 7-methyl-4-oxo_4,7-dihydrofluoreno [2,3_b] pyridine-5-carboxamidine ch3 will contain racemic-2- (2-methylamino-1-hydroxyethyl Base) imidazole dihydrochloride (Preparation Example 56, 0.17 g), KI (0.02 g), triethylamine (0.27 ml) and a mixture of water supplied DMF (15 ml) with 3 angstrom molecular sieves disturbed 2 Hours and n_ (4-chloroethenyl) -2- (chloromethyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3_b] pyridine-5-carboxyfluorene Treatment with amine (Preparation Example 1, 0.3 g). The resulting mixture was stirred at ambient temperature overnight. The molecular sieves were removed by filtration, and the filtrate was diluted with EtoAc (100 ml). The mixture was washed with water (3 x 50 mL), then with brine (50 mL), dried (NadO4) and concentrated in vacuo. The crude product was purified by radiochromatography on a 1000 μ rotor, and purified by dissolution with CH2Ch / methanol / NH3 aqueous solution (90/9/1), and then recrystallized from methanol / EtOAc to obtain 0.12 g of the title compound as a white solid. Physical characteristics: M · ρ · 177.9-179.5 ° C; 4 NMR (400 MHz, DMSO-d6) 8 11.93, 10.62, 8.70, 7.41-7.30, 6.90, 5.44, 4.79, 4.54, 3.94, 3.89-3.78, 2.87- 2.72, 2.50, 2.29; 13C NMR (DMSO-d6) S 170.5, 163.0, 149.1, 148.1, 143.7, 138.3, 137.2, 129.9, 129.2, 127.7, 126.9, 118.6, 112 · 9, 64.4, 60.4, 54.9, 41.4, 40.8, 39.9; MS (ESI +) m / z 486 (M + H) + 〇87731 -109-

Claims

200410970 拾、申請專利範園： 1 · 一種式I之化合物，具對映體、非立體異構物或互變體異構物，或其醫藥接受性鹽，200410970 Patent and application patent garden: 1 · A compound of formula I, with enantiomers, non-stereoisomers or tautomers, or its pharmaceutically acceptable salts

其中 R1為 · (a) C卜 (b) Br， (c) F ，或 (d) CN ； R2為 (a) 視情況以一或多個〇H或Ci-4烷氧基取代之C!.4烷基，或 _ (b) (CH2)mOCH2CH2OH ； R3為Cw烷基； R4為經由碳員子鍵結之具有1、2或3個選自Ο、S(0)m及N-W 組成之群組之雜原子之五_(5)員雜芳基，其中R4係視情況融合於苯環或吡啶環上，且視情沉以一或多個R6取代；其中W為不存在、；《或<：1-4烷基； R5為 (a) Η，或 87731 200410970 (b)視情況以〇H取代之Cl_2燒基； R6為 (a) 自基， (b) OCF3， (c) 氣基， (d) 硝基， (e) CONR7R8， (f) NR7R8， (g) Ci·7烷基，其係視情況部分不飽和，且視情況以一或多個R9取代， (h) 0(CH2CH20)nR10， (i) OR10， (j) C02R10，或 (k) 視情況以鹵基、Cw烷基或Cw烷氧基取代之苯基； R7及R8獨立為 ⑷Η， (b) 視情況以鹵基'Cw烷基或Cw烷氧基取代之苯基， (c) 視情況以一或多個〇R1G、苯基或自基取代基取代之C 1 · 7燒基， (句（：3_8環烷基， (e) (C=0)Rn，或 (f) R7及R8與其所附接之氮一起形成het，其中het為具有1、2、3個選自由氧、硫或氮組成之雜原子之五-(5)或六_(6)員雜環，其中het係視情況以Cw烷基取代； 87731 -2 - 200410970 R9為 (a) 氧代， (b) 視情況以鹵基、Cw烷基或Cl.7烷氧基取代之苯基， (c) OR10， ⑷ o(ch2ch2)or10， (e) SR10， (f) NR7R8， (g) 1¾ 基， (h) C02R10， (i) C〇NR10R10，或 (j) 視情況以OR1G取代之c38環烷基； R10為 ⑷Η， (b) C!.7烷基， (c) (33.8環垸基，或 (d) 視情況以鹵基、Cl-7烷基或CN7烷氧基取代之苯基； R11為 (a) 基， (b) C3.8環烷基，或 (Ο視情況以鹵基、Cl-7烷基或Cw烷氧基取代之苯基， η為 1、2、3、4或 5 ;且 m為1或2。 2·如申請專利範圍第1項之化合物，其為式认之化合物 87731Where R1 is (a) C, (b) Br, (c) F, or (d) CN; R2 is (a) C, optionally substituted with one or more 0H or Ci-4 alkoxy! .4 alkyl group, or (b) (CH2) mOCH2CH2OH; R3 is Cw alkyl group; R4 is a carbon member bond having 1, 2 or 3 selected from 0, S (0) m and NW The five-membered heteroaryl group of the group (5) member heteroaryl, in which R4 is optionally fused to a benzene ring or a pyridine ring, and optionally substituted with one or more R6; where W is absent; Or <: 1-4 alkyl; R5 is (a) hydrazone, or 87731 200410970 (b) Cl_2 alkyl group optionally substituted with 0H; R6 is (a) self-radical, (b) OCF3, (c) Gas group, (d) nitro, (e) CONR7R8, (f) NR7R8, (g) Ci · 7 alkyl, which is partially unsaturated as appropriate, and optionally substituted with one or more R9, (h) 0 (CH2CH20) nR10, (i) OR10, (j) C02R10, or (k) phenyl substituted with halo, Cw alkyl, or Cw alkoxy, as appropriate; R7 and R8 are independently fluorene, (b) depending on In the case of phenyl substituted with halo'Cw alkyl or Cw alkoxy, (c) optionally with one or more OR1G, phenyl or free radicals Substituted C 1 · 7 alkyl groups, (sentence (: 3-8 cycloalkyl, (e) (C = 0) Rn, or (f) R7 and R8 together with the nitrogen to which they are attached form het, where het is 1, 2, 3 selected from five- (5) or six- (6) -membered heteroatoms consisting of oxygen, sulfur or nitrogen, wherein het is optionally substituted with Cw alkyl; 87731 -2-200410970 R9 Is (a) oxo, (b) optionally substituted phenyl with halo, Cw alkyl or Cl.7 alkoxy, (c) OR10, ⑷ o (ch2ch2) or10, (e) SR10, (f ) NR7R8, (g) 1¾ group, (h) C02R10, (i) CONR10R10, or (j) c38 cycloalkyl substituted with OR1G as appropriate; R10 is fluorene, (b) C! .7 alkyl, (c) (33.8 cyclofluorenyl, or (d) phenyl optionally substituted with halo, Cl-7 alkyl, or CN7 alkoxy; R11 is (a), and (b) C3.8 cycloalkyl Or (0 optionally a phenyl substituted with halo, Cl-7 alkyl or Cw alkoxy, η is 1, 2, 3, 4 or 5; and m is 1 or 2. 2. If the compound in the scope of application for item 1 is a compound recognized by the formula 87731

ΙΑ. •如申請專利範圍第1或2項之化合物，其中R1為氯。 4.如申請專利範圍第【或之項之化合物，其中R2為Cl_3烷基。 5·如申請專利範圍第1或2項之化合物，其中R2為甲基。 •如申請專利範圍第i或2項之化合物，其中R2為以一或二個幾基取代之Cl.3烷基。籲 7·如申睛專利範圍第1或2項之化合物，其中r2為以c14、j^氧基取代之Cw烷基。 8·如申请專利範圍第1或2項之化合物，其中r2為 CH2CH20CH2CH20H。 9·如申請專利範圍第1或2項之化合物，其中R3為甲基。 1〇·如申請專利範圍第1或2項之化合物，其中R3為乙基。 11·如申請專利範圍第1或2項之化合物，其中R4為經碳原子键結之具有一（1)或二（2)個由〇、S及N-W組成之族群之雜原馨子之五_(5)員雜芳基。 12·如申請專利範圍第11項之化合物，其中R4係以R6取代。 13·如申請專利範圍第u項之化合物，其中R4為2_咬喃基、3-呋喃基、噻吩-2—基、1H-吡唑-2-基、丨_甲基]吡唑-2_ 基、1-甲基-1H-咪唑-4·基、1H_咪唑-4_基、i，3-嘧唑-2-基、或1H-峨嗤-5-基。 14. 如申請專利範圍第13項之化合物，其中R4為2_呋喃基。 15. 如申請專利範圍第12項之化合物，其中R4為5甲基-2-呋喃 87731 -4- 200410970 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 基2’5 - —甲基-3-咬喃基、5 -苯基-2·咬喃基、5 -氯-2 -咬喃基 4,5 - 一甲基-2-咬喃基、或5 -夜基ρ塞吩-2-基。如申請專利範圍第1或2項之化合物，其中R4為經碳原子鍵結之具有一（1)或二（2)個由Ο、S及N-W組成之群組之雜原子之五_(5)員雜芳基，其中R4與苯或吡啶環稠合。如申請專利範圍第16項之化合物，其中R4為以R6取代。如申請專利範圍第16項之化合物，其中r4為苯并呋喃基、苯并噻吩_3·基、1H-W哚-3_基、1-甲基-1H-W哚-2-基或1，3-苯并噻唑基。如申請專利範圍第18項之化合物，其中R4為苯并呋喃基。如申請專利範圍第1或2項之化合物，其中r5為氫。如申請專利範圍第12項之化合物，其中R6為〇H、鹵基、 Cw烷基、c1-4烷氧基、氰基、硝基、〇Cf3、nr7r8、苯基或 CONR7R8。如申請專利範圍第17項之化合物，其中R6為0H、_基、 Cb4烷基、CN4烷氧基、氰基、硝基、〇Cf3、NR7R8、苯基或 CONR7R8 〇如申請專利範圍第21項之化合物，其中R6為甲基。如申請專利範圍第22項之化合物，其中R6為甲基。如申請專利範圍第21項之化合物，其中r7&r8與其所附接之氮一起形成het，其中het為嗎啉、哌啶、哌畊、或吡咯如申请專利範圍第22項之化合物，其中以7及以8與其所附接 87731 200410970 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. <氮一起形成het，其中het為嗎啉、哌啶、哌畊、或吡咯一種包括如申請專利範圍第丨項之化合物及醫藥可接受性載劑之醫藥組合物。一種治療受皰疹病毒感染之方法，包括對哺乳動物依其需求投予如申請專利範圍第1或2項之化合物。如申請專利範圍第28項之方法，其中該皰疹病毒為單純皰疹病毒1型、單純皰疹病毒2型、帶狀皰疹病毒、人類、’、田胞巨大型病母、Eg病毒（EpStein_Barr virus)、及人類皰_ 療病毒6、人類皰疹病毒7或人類皰疹病毒8。如申請專利範圍第28項之方法，其中該皰♦病毒為人類細胞巨大型病毒。如申請專利範圍第28項之方法，其中該皰疹病毒為帶狀皰疹病毒或 EB病毒（Epstein-Barr Virus)。如申請專利範圍第28項之方法，其中該皰疹病毒為單純皰療病毒1型或單純皰療病毒2型。如申請專利範圍第28項之方法，其中如中請專利範園第丨寒項之化合物係經口、非經腸胃或局部投藥。如申請專利範圍第28項之方法，其中如申請專利範圍第i 項化合物之量為約〇」至約300毫克/公斤體重。如申請專利範圍第28項之方法，其中如申請專利範圍第工項化合物之量為約i至約30毫克/公斤體重。如申請專利範圍第28項之方法，其中該哺乳動物為人類。如申請專利範圍第28項之方法，其中該哺乳動物為動物。 87731 200410970 38. 39. 40. 41. =治療動脈硬化及再狹窄之方法，包括對哺乳動物依八而求投予如申請專利範圍第丨或2項之化合物。 —種抑制祕病毒DNA聚合物酶之方法，包括使聚合物酶與有效抑制量之如中請專利範圍第i項之化合物接觸。 -種用於製造供治療或預防哺乳動物祕病毒感染之藥物之式I化合物或其醫藥可接受性鹽。如申請專利範圍第1項之化合物，其為 (1) 消旋-N-(4-氯芊基）-2-(((2-(2-呋喃基）_2_羥基乙基）（甲基）胺基）-甲基）-7_甲基_4_氧代_4,7_二氫噻吩并籲 [2,3-b]吡啶-5·瘦醯胺， (2) (+)-N-(4-氯爷基）-2-((((R)-2-(2·吱喃基）-2-幾基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7-二氫嘧吩并 [2,3-b]峨淀-5-叛醯胺， (3) 消旋_N-(4-氣苄基）-2_(((2•羥基-2-(5-甲基-2-呋喃基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3-b]p比淀-5-瘦g盛胺， | (4) 消旋-N-(4-氯芊基）-2-(((2-(3-呋喃基）_2_羥基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7-二氫嘍吩并 [2,3-b]p比淀-5-叛醯胺， (5) 消旋-2-(((2-(1-苯并呋喃-2-基）羥基乙基）（甲基）胺基）-甲基）-N-(4-氣爷基）-7·甲基氧代-4,7-二氫違吩并[2,3-b]吡啶-5-羧醯胺， (6) 消旋-N-(4-氯苄基）-2-(((2-羥基_2_魂吩-2_基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7_二氫違吩并 87731 -7- [2,3-b]p比淀-5-叛酿胺， (7) 消旋-N-(4-氯苄基）_2·(((2-羥基-2-(1H-p比p各·2基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氣嚷吩并 [2,3-b]p比淀-5-叛酿胺， (8) 消旋-N-(4-氯爷基）-2-(((2-輕基-2-(1-甲基a 洛-2-基）乙基）（曱基）胺基）-甲基）-7-甲基-4-氧代* ，* ，·_» 氫p塞吩并[2,3-b]^：淀-5-叛酸胺， (9) 消旋_Ν_(4·氯苄基）-2-(((2-經基-2-(1-甲基朱唑-4-基）乙基）（甲基）胺基）-甲基）-7_甲基_4_氧代_4 7 — 氫p塞吩并[2,3-b]p比咬-5-叛酿胺， (10) 消旋-N_(4-氯苄基）-2-(((2_羥基_2-(1Η-咪唉_4爲）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氣喧吩^ [2,3-b]p比途-5-叛驢胺， (11) 消旋·Ν_(4-氯苄基）_2-(((2_ 羥基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氣屢吩^ [2,3-b]p比淀-5-叛酸胺’ (12) 消旋 _N-(4-氯芊基）-2-(((2-(2,5-二甲基 _3_咬喃基）_2_羥基乙基）（甲基）胺基）-甲基）-7-甲基_4_氧代_4 7 二氫嘧吩并[2,3-b]口比啶-5-叛醯胺， (13) 消旋-2-(((2-(2-苯并嘧吩-2-基）_2_羥基乙基）（y 基）胺基）-甲基）-N-(4-氯苄基）-7-甲基-4-氧代_47 _ — ，~氧屢吩并[2,3-b]p比淀-5-叛酿胺9 (14) 消旋-N-(4-氯芊基）-2-(((2-羥基-2-(1-甲基^丨味-2-基）乙基）（甲基）胺基）-甲基）-7 -甲基-4_氧代y 7 200410970 氯p塞吩并[2,3-b]p比淀_5_叛酿胺， (15) 消旋-N-(4-氯爷基）-2-(((2-(5-氰基p塞吩-2-基）_2_ 羥基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7_二氮魂吩并[2,3-b]p比淀-5-叛酸胺， (16) 消旋-N-(4-氯苄基）-2-(((2•羥基-2_(1，3_,塞吐-2· 基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7-二氯，塞吩并[2,3-b]吡啶-5-羧醯胺， (17) 消旋-2-(((2-(1，3_苯并p塞唆-2_基）-2-罗曼基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-甲基-4-氧代_4,7_ ^ 二氣塞吩并[2,3-b]峨淀-5-幾酿胺， (18) 消旋-Ν·(4_氯苄基）-2-(((2羥基-2-(1Η-吡唑_5_基）乙基）（甲基）胺基）-甲基）_7_甲基-4-氧代-4,7-二氫遗吩并 [2,3-b]吡啶-5-羧醯胺， (19) N-(4-氣节基）_2_((((2R)-2-經基-2_(1Η_ρ比唆-5_基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4，7-二氫p塞吩并 [2,3-b]p比淀-5-叛驢胺， | (20) N_(4-氯芊基）-7-乙基-2-((((2R)_2_(2-嗅喃基）-2- 羥基乙基）（甲基）胺基）-甲基）-4-氧代-4,7-二氫碟吩并 [2,3-b]吡啶-5-羧醯胺， (21) N-(4-氯苄基）-2-((((2R)-2_(2-吱喃基）_2_輕基乙基）（甲基）胺基）-甲基）-7-(2-甲氧基乙基）_4 -氧代_4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (22) 消旋-2-(((2-(1-苯并嗅喃-2-基）-2-輕基乙基）（甲基”安基兴甲基分义^-氯苄基卜了-乙基-‘氧代-七了-二氫違 87731 -9- 200410970 吩并[2,3-b]吡啶-5-羧醯胺， (23) 消旋-2-(((2-(1-苯并咬喃-2 -基）-2-經基乙基）（甲基）胺基）-甲基）-Ν-(4-氯苄基）-7_丙基-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (24) 消旋-2-(((2-(1-苯并呋喃-2-基）-2-羥基乙基）（甲 _ 基）胺基）-甲基）-N-(4-氯芊基）-7-(2-甲氧基乙基）-4-氧代 -4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (25) 消旋-2_(((2-(l -苯并咬喃-2 -基）-2-¾基乙基）（甲基）胺基）-甲基）-N-(4-氯芊基）-7-(2,3-二羥基丙基）-4-氧代·4,7-二氫噻吩并[2,3-b]吡啶-5-羧醯胺， (26) N-(4_ 氯苄基）-7-(2,3_ 二羥基丙基）-2-((((2R)-2-(2-呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-4-氧代-4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (27) N-(4-氯苄基）-2-((()2R)-2-(呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-7-(3-羥基丙基）-4•氧代_4,7_二氫口塞吩并[2,3-b] 口比淀-5-叛縫胺， (28) 消旋·2_(((2_( 1 -苯并呋喃-2·基）-2·羥基乙基）（甲基）胺基）-甲基）-Ν-(4-氯苄基）-7-(3-羥基丙基）-4-氧代 -4,7-二氫嘧吩并[2,3-b]吡啶-5-羧醯胺， (29) 消旋-2-(((2-(1•苯并咬喃-2 -基）-2-幾基乙基）（甲基）胺基）-甲基）-N-(4-氯苄基）-7-(2-#呈基乙基）_4_氧代 -4,7-二氫0塞吩并[2,3-13]0比淀-5-幾酸胺， (3 0)消旋-N-(4-氯苄基）-2-(((2-(4,5-二甲基-2-呋喃基）-2-羥基乙基）（甲基）胺基）-甲基）-7-甲基_4_氧代-4,7- 87731 -10- 200410970 二氣p塞吩并[2，3 - b ] ρ比淀-5 -幾酿胺’ (3 1)消旋-Ν-(4-氯苄基）-2-(((2-(5-苯基-2_呋喃基）_2_ 羥基乙基）（甲基）胺基）-甲基）-7-甲基-4_氧代_4,7-二氣嗔吩并[2,3-b]吡啶-5-羧醯胺， (32) N-(4-氯芊基）-2-((((2R)_2-(2-呋喃基）_2_幾基乙基）（甲基）胺基）-甲基）-4-氧代_7_丙基-4-氧代_4,7_二氣嗜吩并[2,3-b]吡啶-5-叛醯胺， (33) N-(4-氟苄基）-2-(((2-(5 -氯_2_吱喃基）_2_幾基乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代-4,7-二氫遠吩并\ [2,3-b]#b 淀-5-叛酸胺， (34) N-(4-氯芊基）-2-((((2R)-2-(2-呋喃基）_2·經基乙基）（甲基）胺基）-甲基）_7_(2-#垔基乙基氧代_4,7·二气 p塞吩并[2,3-b]^：淀-5-羧醯胺， (3 5) N-(4-氯苄基）-2_((((2R)-2-(2-呋喃基）_2_經基乙基）（甲基）胺基）-甲基）-7-(2-(2-羥基乙氧基）乙基）_4_氧代 -4,7-二氫魂吩并[2,3-b]峨淀-5-羧醢胺， (3 6)消旋-N_(4-氯苄基）-2-(((2-幾基-2-(1 H_咪唑-2-基）乙基）（甲基）胺基）-甲基）-7-甲基-4-氧代_4,7_二氫噻吩并 [2,3-b]吡啶-5-羧醯胺，及其醫藥可接受性鹽。 42. 如申請專利範圍第1項之化合物，其為（+)-N_(4•氯爷基）-2-((((2R)-2-羥基-2-(1Η-咪唑-2-基）乙基）（甲基）胺基）一甲基）-7-甲基-4-氧代-4,7-二氫嘧吩并[2,3讣]吡啶乃-羧醯胺，及其醫藥可接受性鹽。 87731 -11- 200410970 柒、指定代表圖： (一) 本案指定代表圖為：第（）圖。 (二) 本代表圖之元件代表符號簡單說明·· 捌、本案若有化學式時，請揭示最能顯示發明特徵的化學式：IA. • A compound as claimed in item 1 or 2 in which R1 is chlorine. 4. The compound according to item [or of the scope of application for patent, wherein R 2 is Cl 3 alkyl. 5. The compound according to item 1 or 2 of the scope of patent application, wherein R2 is methyl. • For a compound in the scope of application for item i or 2, wherein R2 is a Cl.3 alkyl group substituted with one or two groups. Call 7. The compound of item 1 or 2 of the patent application scope, wherein r2 is a Cw alkyl group substituted with a C14, j ^ oxy group. 8. The compound according to item 1 or 2 of the patent application scope, wherein r2 is CH2CH20CH2CH20H. 9. A compound as claimed in item 1 or 2 in which R3 is methyl. 10. The compound according to item 1 or 2 of the scope of patent application, wherein R3 is ethyl. 11. If the compound in the scope of patent application item 1 or 2, R4 is five of heterozygous sweets with one (1) or two (2) groups consisting of 0, S and NW bonded by carbon atoms. (5) Member heteroaryl. 12. The compound according to item 11 of the application, wherein R4 is substituted with R6. 13. The compound according to item u in the scope of patent application, wherein R4 is 2_anyl, 3-furanyl, thiophen-2-yl, 1H-pyrazol-2-yl, 丨 methyl] pyrazole-2 Group, 1-methyl-1H-imidazol-4.yl, 1H_imidazol-4-yl, i, 3-pyrazol-2-yl, or 1H-erim-5-yl. 14. The compound according to item 13 of the patent application, wherein R4 is 2-furyl. 15. For example, the compound in the scope of patent application No. 12, wherein R4 is 5methyl-2-furan 87731 -4- 200410970 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. group 2'5--methyl-3-pyranyl, 5-phenyl-2.pyranyl, 5-chloro-2 -pyranyl 4,5-monomethyl-2-pyranyl, or 5 -Night-based p-sphen-2-enyl. For example, the compound in the scope of patent application No. 1 or 2, in which R4 is five of heteroatoms having one (1) or two (2) groups consisting of 0, S and NW bonded by carbon atoms. ) Member heteroaryl, wherein R4 is fused with a benzene or pyridine ring. For example, the compound in the 16th scope of the patent application, wherein R4 is substituted with R6. For example, the compound in the 16th scope of the application for patent, wherein r4 is benzofuranyl, benzothiophene-3 · yl, 1H-Windol-3-yl, 1-methyl-1H-Wdol-2-yl, or 1 , 3-benzothiazolyl. For example, the compound in the scope of application for item 18, wherein R4 is benzofuranyl. For example, for the compounds in the scope of claims 1 or 2, r5 is hydrogen. For example, the compound in the scope of application for patent No. 12 wherein R6 is 0H, halo, Cw alkyl, c1-4 alkoxy, cyano, nitro, 0Cf3, nr7r8, phenyl or CONR7R8. For example, the compound in the 17th scope of the patent application, in which R6 is 0H, _ group, Cb4 alkyl, CN4 alkoxy, cyano, nitro, oCf3, NR7R8, phenyl or CONR7R8. Compound, wherein R6 is methyl. For example, the compound in the scope of application for item 22, wherein R6 is methyl. For example, the compound in the scope of patent application No. 21, wherein r7 & r8 together with the nitrogen to which it is attached form a het, where het is morpholine, piperidine, piperon, or pyrrole. 7 and 8 and its attached 87731 200410970 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. < Nitrogen together to form het, where het is morpholine, piperidine, piperidine Or a pyrrole, a pharmaceutical composition comprising the compound as claimed in the scope of the patent application and a pharmaceutically acceptable carrier. A method for treating a herpes virus infection, comprising administering a compound such as item 1 or 2 of a patent application to a mammal according to his needs. For example, the method of claim 28 of the patent scope, wherein the herpes virus is herpes simplex virus type 1, herpes simplex virus type 2, shingles virus, human, ', cell giant disease mother, Eg virus ( EpStein_Barr virus), and human herpesvirus 6, human herpes virus 7 or human herpes virus 8. For example, the method of claim 28, wherein the herpesvirus is a human cell megalovirus. For example, the method of claim 28, wherein the herpes virus is shingles virus or Epstein-Barr Virus. The method of claim 28, wherein the herpes virus is herpes simplex virus type 1 or herpes simplex virus type 2. For example, the method of applying for the scope of patent No. 28, among which the compound of No. 丨 cold of the patent application park is administered orally, parenterally or locally. For example, the method of the scope of patent application No. 28, wherein the amount of the compound of the scope of patent application No. i is about 0 "to about 300 mg / kg body weight. The method according to claim 28, wherein the amount of the compound according to claim 28 is about i to about 30 mg / kg body weight. The method of claim 28, wherein the mammal is a human. The method of claim 28, wherein the mammal is an animal. 87731 200410970 38. 39. 40. 41. = A method for treating arteriosclerosis and restenosis, which involves administering a compound such as item 丨 or 2 of the scope of patent application to a mammal in eighth order. A method for inhibiting a polymerase of a secretory virus DNA, comprising contacting the polymerase with an effective inhibitory amount of a compound such as the item i in the patentable range. -A compound of formula I or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment or prevention of a mammalian viral infection. For example, the compound in the scope of patent application No. 1 is (1) racemic-N- (4-chlorofluorenyl) -2-(((2- (2-furanyl) _2_hydroxyethyl) (methyl ) Amine) -methyl) -7_methyl_4_oxo_4,7_dihydrothieno [2,3-b] pyridine-5 · lepinamine, (2) (+)- N- (4-chloroethenyl) -2-(((((R) -2- (2 · creanyl) -2-quinylethyl) (methyl) amino) -methyl) -7- Methyl-4-oxo_4,7-dihydropyridino [2,3-b] edian-5-benzylamine, (3) racemic_N- (4-airbenzyl) -2_ (((2 • hydroxy-2- (5-methyl-2-furanyl) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-di Hydropyrimido [2,3-b] p than amine-5-leanylamine, | (4) racemic-N- (4-chlorofluorenyl) -2-(((2- (3-furan Group) _2_hydroxyethyl) (methyl) amino) -methyl) -7-methyl-4-oxo_4,7-dihydrofluoreno [2,3-b] p 5-Betamine, (5) racemic-2-(((2- (1-benzofuran-2-yl) hydroxyethyl) (methyl) amino) -methyl) -N- (4 -Phenyl) -7 · methyloxo-4,7-dihydrobenzopheno [2,3-b] pyridine-5-carboxamide, (6) racemic-N- (4-chlorobenzyl ) -2-((((2-hydroxy_2_oxaphene-2_ylethyl) ( Methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydropheno 87731 -7- [2,3-b] p (7) Racemic-N- (4-chlorobenzyl) _2 · (((2-hydroxy-2- (1H-p than p each · 2 groups) ethyl) (methyl) amino) -formaldehyde ) -7-methyl-4-oxo-4,7-digasobenzo [2,3-b] p biyodo-5-fermentamine, (8) racemic-N- (4- Chloroyl) -2-(((2-lightyl-2- (1-methyla-2-oxo) ethyl) (fluorenyl) amino) -methyl) -7-methyl-4 -Oxo *, *, · _ »hydrogen p-cepheno [2,3-b] ^: Yodo-5-metanoic acid amine, (9) racemic_N_ (4 · chlorobenzyl) -2- ( ((2-Ethyl-2- (1-methylzhuazol-4-yl) ethyl) (methyl) amino) -methyl) -7_methyl_4_oxo_4 7 — hydrogen p-Cypheno [2,3-b] p-bita-5-fermentamine, (10) racemic-N_ (4-chlorobenzyl) -2-((((2_hydroxy_2- (1Η- Imidamine_4 is) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-digasoline ^ [2,3-b] p -5-Betamine, (11) racemic · N_ (4-chlorobenzyl) _2-((((2_hydroxyethyl) (methyl) amino) -methyl) -7-methyl-4- Oxo-4,7-digas repeated phen ^^ [2,3-b] pbiyodo-5-metaamine '(12) _N- (4-chlorofluorenyl) -2-((((2- (2,5-dimethyl_3_octanoyl) _2_hydroxyethyl) (methyl) amino) -methyl)- 7-methyl_4_oxo_4 7 dihydropyrimido [2,3-b] opipidine-5-betamine, (13) racem-2-(((2- (2- Benzopyrimin-2-yl) _2_hydroxyethyl) (y group) amino) -methyl) -N- (4-chlorobenzyl) -7-methyl-4-oxo_47 _ — , ~ Oxo-pheno [2,3-b] p ratio Yodo-5-fermentamine 9 (14) racemic-N- (4-chlorofluorenyl) -2-(((2-hydroxy-2- (1-methyl ^ -2-yl) ethyl) (methyl) amino) -methyl) -7-methyl-4_oxo 7 200410970 Chlorophenidio [2,3- b] p 比 ido_5_Beramine, (15) racemic-N- (4-chloroethenyl) -2-(((2- (5-cyanop-phenen-2-yl) _2_ hydroxyl Ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7_diazinopheno [2,3-b] p , (16) Racemic-N- (4-chlorobenzyl) -2-((((2 • hydroxy-2_ (1,3_, septol-2 · yl) ethyl) (methyl) amino)- (Methyl) -7-methyl-4-oxo-4,7-dichloro, cepheno [2,3-b] pyridine-5-carboxamide, (17) racemic 2-(((( 2- (1,3_benzop-pyridin-2-yl) -2-romanylethyl) ( Methyl) amino) -methyl) -N- (4-chlorobenzyl) -7-methyl-4-oxo_4,7_ ^ digasphypheno [2,3-b] ETAO- 5-Chinomine, (18) racemic-N · (4-chlorobenzyl) -2-((((2hydroxy-2- (1Η-pyrazol-5-yl) ethyl) (methyl) amine ) -Methyl) _7_methyl-4-oxo-4,7-dihydroanilo [2,3-b] pyridine-5-carboxamidine, (19) N- (4-Anode Group) _2 _ (((((2R) -2-Cycloyl-2_ (1Η_ρ 比唆 -5_yl) ethyl) (methyl) amino) -methyl) -7-methyl-4-oxo- 4,7-dihydro p-pheneno [2,3-b] p biyodo-5-metamidine, | (20) N_ (4-chlorofluorenyl) -7-ethyl-2-((( (2R) _2_ (2-olyl) -2-hydroxyethyl) (methyl) amino) -methyl) -4-oxo-4,7-dihydrodipheno [2,3-b ] Pyridine-5-carboxamide, (21) N- (4-chlorobenzyl) -2-(((((2R) -2_ (2-creanyl) _2_lightylethyl) (methyl) Amine) -methyl) -7- (2-methoxyethyl) _4-oxo_4,7-dihydropyrido [2,3-b] pyridine-5-carboxamide, (22 ) Racemic 2-(((2- (1-benzo-oxan-2-yl) -2-lightylethyl) (methyl "anhydryl methyl is ^ -chlorobenzyl)- Ethyl-'oxo-hepta-dihydrogen 87731 -9- 2004109 70 Benzo [2,3-b] pyridine-5-carboxamidine, (23) Racem-2-(((2- (1-benzoxan-2-yl) -2-merylethyl ) (Methyl) amino) -methyl) -N- (4-chlorobenzyl) -7-propyl-4-oxo-4,7-dihydropyrido [2,3-b] pyridine -5-carboxamidine, (24) racemic-2-(((2- (1-benzofuran-2-yl) -2-hydroxyethyl) (methyl) amino) -methyl) -N- (4-chlorofluorenyl) -7- (2-methoxyethyl) -4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxyfluorene Amine, (25) racemic-2 _ (((2- (l -benzo-2-anyl) -2-¾ethylethyl) (methyl) amino) -methyl) -N- (4 -Chlorofluorenyl) -7- (2,3-dihydroxypropyl) -4-oxo · 4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide, (26) N- (4-chlorobenzyl) -7- (2,3-dihydroxypropyl) -2-(((((2R) -2- (2-furyl) -2-hydroxyethyl) (methyl) amine ) -Methyl) -4-oxo-4,7-dihydropyridino [2,3-b] pyridine-5-carboxamidine, (27) N- (4-chlorobenzyl) -2 -((() 2R) -2- (furyl) -2-hydroxyethyl) (methyl) amino) -methyl) -7- (3-hydroxypropyl) -4 • oxo_4, 7_Dihydroorthopheno [2,3-b] orbital-5-desolamine, (28) Racemic · 2 _ (((2_ (1 -benzofuran-2 · yl) -2 · hydroxyethyl) (methyl) amino) -methyl) -N- (4-chlorobenzyl) -7- (3-Hydroxypropyl) -4-oxo-4,7-dihydropyrido [2,3-b] pyridine-5-carboxamide, (29) racem-2-(((2- (1 • benzo-2-anyl) -2-quinylethyl) (methyl) amino) -methyl) -N- (4-chlorobenzyl) -7- (2- # (Ethyl) _4_oxo-4,7-dihydro-0 thiopheno [2,3-13] 0 Biyodo-5-chimonic acid amine, (3 0) racemic-N- (4-chlorobenzyl ) -2-(((2- (4,5-dimethyl-2-furanyl) -2-hydroxyethyl) (methyl) amino) -methyl) -7-methyl_4_oxy Dai-4,7- 87731 -10- 200410970 Digas p-cepheno [2,3-b] ρ Biyodo-5 -chivinamine '(3 1) racemic-N- (4-chlorobenzyl) -2-(((2- (5-phenyl-2_furanyl) _2_hydroxyethyl) (methyl) amino) -methyl) -7-methyl-4_oxo_4,7- Digasopheno [2,3-b] pyridine-5-carboxamide, (32) N- (4-chlorofluorenyl) -2-(((((2R) _2- (2-furanyl) _2 _Ethylethyl) (methyl) amino) -methyl) -4-oxo_7_propyl-4-oxo_4,7_Digas pheno [2,3-b] pyridine -5-Betamine, (33) N- (4-fluorobenzyl) -2-(((2 -(5 -Chloro_2_creanyl) _2_Ethylethyl) (methyl) amino) -methyl) -7-methyl-4-oxo-4,7-dihydrotepheno \ [2,3-b] #b Yodo-5-metanoic acid amine, (34) N- (4-chlorofluorenyl) -2-(((((2R) -2- (2-furanyl) _2 · Ethylethyl) (methyl) amino) -methyl) _7_ (2- # fluorenylethyloxo_4,7 · digas p-pheno [2,3-b] ^: lake-5 -Carboxamide, (3 5) N- (4-chlorobenzyl) -2 _ (((((2R) -2- (2-furanyl) _2_ylethyl) (methyl) amino))- (Methyl) -7- (2- (2-hydroxyethoxy) ethyl) _4_oxo-4,7-dihydroanhydropheno [2,3-b] edian-5-carboxamide, (3 6) racemic-N_ (4-chlorobenzyl) -2-(((2-quinyl-2- (1 H_imidazol-2-yl) ethyl) (methyl) amino) -formaldehyde ) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide, and its pharmaceutically acceptable salts. 42. For example, the compound in the scope of patent application No. 1 is (+)-N_ (4 • chloromethyl) -2-(((((2R) -2-hydroxy-2- (1Η-imidazole-2-yl ) Ethyl) (methyl) amino) monomethyl) -7-methyl-4-oxo-4,7-dihydropyridino [2,3 讣] pyridinyl-carboxamide, and Pharmaceutically acceptable salt. 87731 -11- 200410970 (1) Designated representative map: (1) The designated representative map in this case is: (). (II) Brief description of the element representative symbols in this representative diagram ... 捌, if there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention:

R2 I 87731R2 I 87731