TWI310036B - Novel thieno 2,3-d pyrimidinediones, processes for their preparation,and pharmaceutical compositions containing them - Google Patents
Novel thieno 2,3-d pyrimidinediones, processes for their preparation,and pharmaceutical compositions containing them Download PDFInfo
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- TWI310036B TWI310036B TW91116735A TW91116735A TWI310036B TW I310036 B TWI310036 B TW I310036B TW 91116735 A TW91116735 A TW 91116735A TW 91116735 A TW91116735 A TW 91116735A TW I310036 B TWI310036 B TW I310036B
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13100361310036
.ΪΓ::有Γ墓吩並[2,3.二網、其製法、含其之 病。 用去特疋以用於調控自體免疫疾 τ中細反應上扮演重要角色,然而在自體免疫疾 Γ:中’丁·細胞會針對特定組織不當地活化與增纟,例如: 關節炎有關之發炎。抑制τ·細胞增生將有利 疾=化=疫疾病。本發明係有關有㈣調控自體免疫 已知WO 2_/125 14與w〇 2〇〇1/〇38489之化合物適用於調 控免疫反應。此等巾請案包括在4吩㈣切系之%位置 上具有酿胺系-C-N_之化合物。此等化合物出現交互轉換速 ?緩慢之幾何異構物’因為其係繞著醯胺系c_N鏈結之緩 ?旋轉與繞著由醯胺系羰基至嘍吩並嘧啶核心之鍵結緩慢 旋轉所,且成’基於此等叉互轉換速度而可利用HpLC分離異 構物。此等受遮避之旋轉卻使得醫藥化合物之發展產生顯 著問題:平衡時間長,以致若改變合成法·之-做終步驟條件 時,可能產生不同之初始幾何異構混合物,造成分析純度 及粗製固態藥物再現性問題。此外’壽命相當於生物半衰 期 < 幾何異構物應可經不同方式之代謝過程處理,可產生 結構不相似之代謝物,而必須完全研究及紀錄其生物活性 興安全性。吾等現已發現一種在ρ塞吩並嘧啶環系之5_位置 上具有酿胺系-C-N-基之化合物,其具有有利之效力,且不會 出現化合物在室内條件下呈分開之幾何異構物之問題。 根據本發明,係提供一種式(1)化合物: 本紙張尺度適用中國國家標準(cns)A4規格 1310036.ΪΓ:: There are Γ 吩 吩 [ [2,3. 二网, its method of production, including its disease. It plays an important role in the regulation of autoimmune diseases in τ, but in autoimmune diseases: 'Ding cells will be inappropriately activated and enhanced for specific tissues, such as: arthritis Inflammation. Inhibition of τ·cell proliferation will be beneficial to disease = disease = disease. The present invention relates to (four) regulation of autoimmunity. Known compounds of WO 2_/125 14 and w〇 2〇〇1/〇38489 are suitable for use in modulating immune responses. These claims include compounds having a serotonin-C-N_ at the % position of the 4 (4) cut. These compounds exhibit an interactive conversion rate, a slow geometric isomer' because it rotates around the amide-based c_N chain and rotates slowly around the bond from the guanamine-based carbonyl to the phenanthro-pyrimidine core. And by using HpLC to separate isomers based on these cross-switching speeds. These evasive rotations cause significant problems in the development of pharmaceutical compounds: the equilibrium time is so long that, if the synthesis method is changed - the final geometrical mixture may be produced, resulting in analytical purity and crudeness. Solid drug reproducibility issues. In addition, life expectancy is equivalent to biological half-life < geometric isomers should be treated by different metabolic processes, resulting in metabolites with dissimilar structures, and must be fully studied and documented for biosafety. We have now found a compound having a stilbene-CN- group at the 5 position of the ρ-phenantrimidine ring system, which has advantageous potency and does not exhibit a separate geometrical difference in the indoor conditions. The problem of the structure. According to the present invention, a compound of the formula (1) is provided: The paper scale is applicable to the Chinese National Standard (cns) A4 specification 1310036
發明説明(Description of the invention
R (1) 其中 烷美 M獨乂代表Cl·6烷基、C3_6烯基、ς;3·5環烷基C卜3 疋。〔環境基;其各可視需要經ι_3個1^原子取代; 為兴-可唑哫·2·基羰基或四氫異哼畊-2-基羰基,其中各 %可視需要經—個羥基取代; ΟΛ co或-c(r4)(r5)_(其中r4為氫原子或基,且r5 為虱原子或羥基); ' 猶=·至1〇_員芳香環系,其中至多4個環原子可為分別 二夕7列《雜原子:氮、氧與硫’該環系可視需要經 ::個分別獨立選自下列之取代基取代:c"烷基(其 :視T1、2或3個經基取幻、C “垸氧基、函素、⑽ ;、c I基、三函燒基、Cl·4燒氧基C-燒基、Cl成硫 :其匕為羰基、C2.4_、氧代基、硫代基、確基、 二亞=與-(CH2)PN(R8)R9、幾基、C“垸確臨基、 I卜d元亞% fe;基、胺甲样其、Γ .μ* i π、 妝Τ I暴C|-4k基胺曱醯基、二… 坑基)胺甲醯基、羧基 '或含有至多4個分別獨立選^R (1) wherein alkylene M alone represents Cl.6 alkyl, C3_6 alkenyl, anthracene; 3·5 cycloalkyl C Bu 3 疋. [Environmental basis; each of which may be substituted by ι_3 1 atom; a oxo-oxazolyl-2 carbonyl or a tetrahydroisoindole-2-ylcarbonyl, wherein each % may be substituted with a hydroxy group; ΟΛ co or -c(r4)(r5)_ (wherein r4 is a hydrogen atom or a group, and r5 is a halogen atom or a hydroxyl group); 'June=· to 1〇_member aromatic ring system, wherein up to 4 ring atoms can be For the 7th day of the seventh day, "heteroatoms: nitrogen, oxygen and sulfur", the ring system can be replaced by: a substituent independently selected from the following: c " alkyl (which: depending on T1, 2 or 3 Base phantom, C "decyloxy, cyclin, (10);, c I base, tridecyl, Cl · 4 alkoxy C-alkyl, Cl to sulfur: its oxime is carbonyl, C2.4_, oxygen Substituent, thio, decyl, di-subordinate = and -(CH2)PN(R8)R9, a few groups, C"垸定临基, I卜d元亚% fe; base, amine-like, Γ .μ* i π, makeup Τ I violent C|-4k amide group, two... pit base) amine mercapto group, carboxyl group or containing up to 4 separate independent selection ^
<雜原子<5或6員芳香環:氮、氧與硫; lJ p為1至4 ; R6與R7分別獨立代表氫原子、Ci爾基或C“垸基,或 本紙張尺度適用中國國参搮準(CNS) A4規格(2ΐ〇χ 297公爱) 1310036 五、發明説明( 與其8所附接之氮原子共同形成5至7員飽和雜環; R a R刀别獨工代表氫原子、Cw烷醯基或ci 4烷基,或 入^、所附接之氮原子共同形成5-至7-員飽和雜環; 或其醫藥上可接受之鹽或前藥。 〜士叙明另-方面係有關如上述定義之式⑴化合物,或其 醫藥上可接受之鹽。 田咸了i,本發明範圍内之式U)化合物或其鹽可出現互變 兴構化現象,且本說明書所示之化學式僅代表其中一種互 又/、構型’且咸了解本說明書涵括任何互變異構型,且不 僅限於本文所出示之任一楂互變異構型^本說明書所畫出 足化學式僅代表其中一種可能之互變異構型,且咸了解本 說明書涵括本文所示化合物但未畫出之所有可能互變異構 型0 - 本發明係有關如上述定義之式(1)化合物,及其鹽。醫藥 組合物所使用之鹽為醫藥上可接受之鹽,但其他鹽類可能 適用於製造式(1)化合物與其醫藥上可接受.之鹽類。本發明 之醫樂上可接受之鹽可包括例如:其鹼性足以形成鹽之如 上述定義之式(1)化合物之酸加成鹽。此等酸加成鹽包括例 如·與可提供醫藥上可接受之陰離子之無機酸或有機酸形 成之鹽類,如:與氫1¾化物(尤指鹽酸與氫溴酸,以鹽酸特 別佳)或與硫酸或磷酸’或與三氟乙酸、檸檬酸或馬來駿米 成之鹽。合適鹽類包括鹽酸鹽、氫溴酸鹽、ί粦酸鹽、喊於 鹽、硬酸氫鹽、坑基績酸鹽、芳基績酸鹽、乙酸鹽、笨甲 酸鹽、檸檬酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、乳酸 本紙張尺度適用中國國家標準(CNSIA4規格(210X297公釐) 1310036 A7 B7 五、發明説明( 鹽、與酒石酸鹽。此外, 外,若式(1)化合物具有足夠酸性<heteroatom<5 or 6 member aromatic ring: nitrogen, oxygen and sulfur; lJ p is 1 to 4; R6 and R7 independently represent a hydrogen atom, a Ci group or a C thiol group, or the paper size is applicable to China. National Standards (CNS) A4 specifications (2ΐ〇χ 297 public) 1310036 V. Description of the invention (combined with the nitrogen atom attached to the 8 to form a 5 to 7-membered saturated heterocyclic ring; R a R knife alone represents hydrogen An atom, a Cw alkanoyl group or a ci 4 alkyl group, or a nitrogen atom attached thereto, together form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. Further, the present invention relates to a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt thereof. The salt of the compound of the formula U) or a salt thereof within the scope of the present invention may exhibit a tautomerization phenomenon, and The chemical formulas shown in the specification represent only one of the mutual and/or configuration' and it is understood that the specification encompasses any tautomeric form, and is not limited to any one of the tautomeric forms shown herein. The chemical formula represents only one of the possible tautomeric forms, and it is understood that this specification encompasses the compounds shown herein. Illustrative of all possible tautomeric forms 0 - The present invention relates to a compound of the formula (1) as defined above, and a salt thereof. The salt used in the pharmaceutical composition is a pharmaceutically acceptable salt, but other salts may be suitable. To produce a compound of the formula (1) and a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the present invention may include, for example, an acid addition of a compound of the formula (1) as defined above, which is basic enough to form a salt. Salts. These acid addition salts include, for example, salts with inorganic or organic acids which provide pharmaceutically acceptable anions, such as: with hydrogen 13⁄4 (especially hydrochloric acid and hydrobromic acid, especially with hydrochloric acid). Good) or with sulfuric acid or phosphoric acid' or with trifluoroacetic acid, citric acid or malay salt. Suitable salts include hydrochloride, hydrobromide, sulphate, salt, hard acid hydrogen, Pit base acid salt, aryl acid salt, acetate, benzoate, citrate, maleate, fumarate, succinate, lactic acid This paper scale applies to Chinese national standards (CNSIA4 specifications ( 210X297 mm) 1310036 A7 B7 V. Description of invention (salt And tartrate. In addition, an outer, if the formula (1) compounds having a sufficiently acidic
包括例如:鹼金屬鹽,如:鈉或鉀鹽, 機鹼或有機鹼形成 有機鹼形成之鹽類 驗土金屬鹽如:鈣 或鎂鹽’或銨鹽或例如:與甲胺、二甲胺、三甲胺、嗓咬 、嗎啉或參-(2-羥乙基)胺形成之鹽。 較佳鹽類包括酸加成鹽如:鹽酸鹽、氫溴酸鹽、鱗酸鹽 、乙酸鹽、富馬酸鹽、馬來酸鹽、酒石酸鹽、檸檬酸鹽、 草酸鹽、甲磺酸鹽或對甲苯磺酸鹽’,或鹼金屬鹽如:鈉 鹽或钟鹽。 多種不同形式之前藥係相關技藝已知者。例如:此等前 藥衍生物可參見: a) Η· Bundgaard編輯之"Design of Prodrugs" (Elsevier,1985) 及 K· Widder等人編輯之"Methods in Enzymology1', Vol. 42, p. 309-396 (Academic Press,1985); b) Krogsgaard-Larsen與 H. Bundgaard編輯之 MA Textbook of Drug Design and Development”,第 5 章,H. Bundgaard 著之 "Design and Application of Prodrugs " p. 113-191 (1991); c) H. Bundgaard之 Advanced Drug Delivery Reviews. 8., 1-3 8 (1992); d) H. Bundgaard 等人之 Journal of Pharmaceutical Sciences., ZL 285 ( 1 988);與 e) N.Kakeya 等人之 Chem. Pharm. Bull., 692 (1984)。 可使用之此等前藥實例為式(1)化合物之活體内可裂解之 _- 8 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1310036 五、發明説明( 酸。含羥基之式(1)化合物之活體内可裂解之酯為例如:醫 μ上可接受之酯’其可於人體或動物體内水解成醇母體。 4名詞包括無機酯’如:磷酸酯與α _醯氧烷基醚及可於活 體内水解酯形成羥基母體之相關化合物。α _醯氧烷基醚實 例包括乙醯氧甲氧基與2,2-二甲基丙醯氧基甲氧基。可用 於羥基之活體内可水解之酯形成基團包括烷醯基、苯甲醯 基、苯基乙臨基與經取代之苯甲醯基與苯乙醯基,烷氧羰基 (形成烷基碳酸酯)、二烷基胺甲醯基與Κ二烷基胺乙基)_ 燒基胺甲醯基(形成胺甲酸酯)、二烷基胺乙醯基與幾乙 醯基。 亦咸了解,某些式(1)化合物可呈溶劑化型及未溶劑化型 ,例如:水合型。亦咸了解,本發明涵括所有適用於療法 之溶劑化型,特定言之用於下文所述之醫療目的。 本說明書中,除非另有說明,否則烷基、烯基或炔基或 取代基中之烷基、烯基或炔基部份基團可為直鏈或分支。Including, for example, an alkali metal salt such as a sodium or potassium salt, a caustic or organic base to form an organic base to form a salt of a soil test metal salt such as calcium or magnesium salt or an ammonium salt or, for example, with methylamine or dimethylamine a salt formed by trimethylamine, biting, morpholine or cis-(2-hydroxyethyl)amine. Preferred salts include acid addition salts such as: hydrochloride, hydrobromide, sulphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methane An acid salt or p-toluenesulfonate, or an alkali metal salt such as a sodium salt or a clock salt. A variety of different forms of prior art are known to those skilled in the art. For example, such prodrug derivatives can be found in: a) Η· Bundgaard, edited by "Design of Prodrugs" (Elsevier, 1985) and edited by K. Widder et al. "Methods in Enzymology1', Vol. 42, p. 309-396 (Academic Press, 1985); b) MA Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, H. Bundgaard "Design and Application of Prodrugs " p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews. 8., 1-3 8 (1992); d) H. Bundgaard et al. Journal of Pharmaceutical Sciences., ZL 285 (1 988); And e) N.Kakeya et al., Chem. Pharm. Bull., 692 (1984). Examples of such prodrugs that can be used are in vivo cleavable compounds of formula (1) - 8 - This paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) A7 B7 1310036 V. Description of the Invention (Acid. The in vivo cleavable ester of the compound of formula (1) containing a hydroxyl group is, for example, a commercially acceptable ester. It can be hydrolyzed into an alcohol precursor in the human or animal body. 4 Nouns include inorganic esters such as Phosphate esters with α-醯 oxyalkyl ethers and related compounds which can hydrolyze esters in vivo to form hydroxy precursors. Examples of α _ 醯 oxyalkyl ethers include ethoxylated methoxy and 2,2-dimethylpropane oxy Methoxy group. Hydrolyzable ester-forming groups which can be used for hydroxyl groups include alkanoyl, benzamyl, phenylethyl and substituted benzamidine and phenethyl, alkoxycarbonyl (Formation of alkyl carbonate), dialkylamine methyl sulfonyl and decyl dialkylamine ethyl) ketone amine carbaryl (formation of urethane), dialkylamine acetamyl and acetophenone It is also known that certain compounds of formula (1) may be solvated and unsolvated, for example, hydrated. It is also understood that the present invention encompasses all solvated forms suitable for therapy, in particular. For medical purposes as described below. In the present specification, the alkyl, alkenyl or alkynyl group or the alkyl, alkenyl or alkynyl moiety in the substituent may be straight-chain or branched, unless otherwise stated.
Ar可利用環碳或環氮鍵結_c〇_或·基,但其限 制條件為不可造成四級化。 咸了解,-C(R4)(R5)Ar基中,僅當Ar利用碳原子而非雜原 子鍵結/(RW)基時,R5才可代表羥基。此外’應了解 ’ -C(0)Ar中,Ar係利用碳原子而非雜原子與部份基團_c(〇) 鍵結。㈣基可包含-個以上㈣,但以―㈣基較佳。 為了避免懷疑,當紅經氧代基或硫代基取代時,^應包 括芳香環系之二氫型。例如:其包括。塞唑基與&二氫嘧 吐基(當後者經-氧代基或硫代基取代時)。同樣地,^包Ar may be bonded to the _c〇_ or group using a ring carbon or a ring nitrogen, but the limitation is that the quaternization cannot be caused. It is understood that, in the -C(R4)(R5)Ar group, R5 can represent a hydroxyl group only when Ar utilizes a carbon atom instead of a hetero atom to bond a /(RW) group. Further, 'it should be understood that' -C(0)Ar, the Ar system is bonded to a part of the group _c(〇) by a carbon atom instead of a hetero atom. (4) The base may contain more than one (four), but the "(iv) base is preferred. For the avoidance of doubt, when red is substituted with an oxo or thio group, the dihydrogen type of the aromatic ring system should be included. For example: it includes. Retazolyl and & dihydropyrimidin (when the latter is substituted with an oxo or thio group). Similarly, ^ package
1310036 A7 B7 五、發明説明(6 ) 括例如· 2,3-二氫苯並哼唑基、2,3-二氫笨並噻唑基、2,3_ 二氫吡啡基與2,3-二氫苯並咪唑基(當此等基團經一個氧代 基或硫代基取代時)。1310036 A7 B7 V. INSTRUCTIONS (6) include, for example, 2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzothiazolyl, 2,3-dihydropyridinyl and 2,3-di Hydrobenzimidazolyl (when such groups are substituted with an oxo or thio group).
Ar為5-至10-員芳香環系,其中至多4個環原子可為分別 獨立選自下列之雜原子:氮、氧與硫,該環系可視需要經i 、2、3或4個分別獨立選自下列之取代基取代:ci 4烷基(其 可視需i經1、2或3個經基取代)(例如:甲基、乙基、正_丙 基、正_丁基、羥甲基、2-羥乙基、1-羥乙基或3-羥丙基), Cm燒氧基(例如:甲氧基、乙氧基、正-丙氧基或正-丁氧 基),鹵# (例如:氟、氯、溴或碘),鹵烷基(例如:氟甲基 、氣甲基、溴曱基、2-氟乙基、2-氟丙基或3-氟丙基)、二 由垸基(例如:二氟甲基、二氣甲基、氣氟甲基、二溴甲基 、2,2-一氟乙基、2,2-二氟丙基或2,3-二氟丙基),三鹵燒基 (例如:三氟甲基、三氯甲基、2,2,2_三氟乙基、2,2,2_三氟 丙基或2,2,3-三氟丙基),Cw烷氧基CU4烷基(例如:甲氧甲 基、乙氧甲基、2-甲氧乙基、2-甲氧丙基或3-甲氧丙基), C丨烷硫基(例如:甲硫基、乙硫基、正-丙硫基或正-丁硫 基)’ C,_4烷氧羰基(例如:甲氧羰基、乙氧羰基、正·丙氧 羰基、異丙氧羰基或正-丁氧羰基),Cw烷醯基(例如:乙 醯基或丙醯基),氧代基、硫代基、硝基、氰基、_n(r6)r7 (例如:胺基、甲胺基、及-乙胺基、二-N,N-甲胺基或N_ 乙基-ϋ-甲胺基),-(CH2)i)N(R8)R9 [例如:-CH2N(R8)R9、 -ch2ch2n(r8)r9或-CH2CH2CH2N(R8)R9],羥基、c“4烷磺驢 基(例如:甲磺醯基、乙磺醯基或丙磺醯基),cU4烷亞續酶 .__- 10 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) !31〇〇36 Α7Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be i, 2, 3 or 4, respectively, as desired. Substituted independently of the following substituents: ci 4 alkyl (which may optionally be substituted by 1, 2 or 3 trans) (eg methyl, ethyl, n-propyl, n-butyl, hydroxymethyl) Base, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl), Cm alkoxy (eg methoxy, ethoxy, n-propoxy or n-butoxy), halogen # (eg: fluorine, chlorine, bromine or iodine), haloalkyl (eg fluoromethyl, methoxymethyl, bromomethyl, 2-fluoroethyl, 2-fluoropropyl or 3-fluoropropyl), Dimethyl group (for example: difluoromethyl, di-methyl, fluoromethyl, dibromomethyl, 2,2-fluoroethyl, 2,2-difluoropropyl or 2,3-di Fluoropropyl), trihaloalkyl (eg trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoropropyl or 2,2,3- Trifluoropropyl), Cw alkoxy CU4 alkyl (eg methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-methoxypropyl or 3-methoxypropyl), C丨alkyl Base (for example: methylthio, ethylthio, n-propylthio or n-butylthio) 'C, _4 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropyl Oxycarbonyl or n-butoxycarbonyl), Cw alkanoyl (eg, ethyl or propyl), oxo, thio, nitro, cyano, _n(r6)r7 (eg amino group) , methylamino, and -ethylamino, di-N,N-methylamino or N-ethyl-fluorenyl-methylamino), -(CH2)i)N(R8)R9 [eg: -CH2N (R8) R9, -ch2ch2n(r8)r9 or -CH2CH2CH2N(R8)R9], hydroxy, c"4 alkanesulfonyl (for example: methylsulfonyl, ethylsulfonyl or propylsulfonyl), cU4 alkane Enzyme.__- 10 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) !31〇〇36 Α7
發明説明 基(甲亞磺醯基、乙亞磺醯基或丙亞磺醯基),胺甲醯基、 cμ烷基胺曱醯基(例如:甲基胺甲醯基、乙基胺甲醯基與 丙基胺甲醯基)、二_Cl_4烷基胺曱醯基(例如:二氺,氺甲基 胺甲酿基、N-乙基-N-甲基胺甲醯基或二-N,N-乙基胺甲醯 基)、幾基與含有至多4個分別獨立選自下列之雜原子之5或 6員芳香環:氮、氧與硫(例如:苯基、嘧啶基、嘍吩基與 呋喃基)。 芳香環系可為單環或多環狀(例如:雙環狀),其實例包 括笨基、萘基、喳啉基、吡唑基、p塞吩基、呤唑基、咪唑 基、吡啶基、吡哈並[2,3-b]吡啶基、苯並咪唑基、啕唑基 、苯並嘧唑基、2,3-二氫苯並嘍唑基、苯並呤唑基 '嘧唑 基、2,3-二氫嘧唑基、2,3_二氫苯並咪唑基、2,3_二氫苯並 15号吐基、嘧唑並[5,4-b]吡啶基與苯並三唑基。 ^又取代基之進一步定義如下。若適當時,下文或上文所界 疋 < 申請專利範圍或具體實施例中可採用任何此等定義。 在一方面’ Ar為5或6員單環。 另一方面,Ar為8、9或1〇員雙環。 另一方面,Ar為9或1〇員雙環。 广-方面係有關式丨化合物,其中Ar為含有至多4個 選自:氮、氧與硫中之雜原予之5_至1〇_ ^條件為其中含有至少-個環氮,該環可如上述定^ 取代。已發現此等化合物為有利之化合物。 义我·.,二 另一方面.,DESCRIPTION OF THE INVENTION Base (methylsulfinyl, ethanesulfinyl or propylsulfinyl), amine methyl sulfhydryl, cμ alkylamine sulfhydryl (eg methylamine methyl sulfonyl, ethylamine methyl hydrazide) And propylamine-methyl hydrazino), bis-Cl_4 alkylamine fluorenyl (for example: diterpene, hydrazine methylamine, N-ethyl-N-methylaminemethanyl or di-N , N-ethylamine-methyl fluorenyl), a group and a 5- or 6-membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur (eg phenyl, pyrimidinyl, porphin) Base and furanyl). The aromatic ring system may be monocyclic or polycyclic (for example, bicyclic), and examples thereof include a strepto group, a naphthyl group, a porphyrin group, a pyrazolyl group, a p-senyl group, a carbazolyl group, an imidazolyl group, and a pyridyl group. , pyrha[2,3-b]pyridyl, benzimidazolyl, oxazolyl, benzopyrazole, 2,3-dihydrobenzoxazolyl, benzoxazolyl-pyrazolyl , 2,3-Dihydropyrazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo-15, oxazolo[5,4-b]pyridyl and benzo Triazolyl. ^ Further definitions of the substituents are as follows. Any such definition may be employed, where appropriate, in the context of the < patent application or particular embodiments. On the one hand, 'Ar is a single ring of 5 or 6 members. On the other hand, Ar is a double ring of 8, 9 or 1 employee. On the other hand, Ar is a 9 or 1 employee double ring. The broad-side aspect is a compound of the formula: wherein Ar is a compound containing up to 4 selected from the group consisting of nitrogen, oxygen and sulfur, and 5 to 1 〇 ^ ^ is a condition in which at least one ring nitrogen is contained therein. Replace as above. These compounds have been found to be advantageous compounds. Righteousness, I., second, on the other hand.
Ar為含有1或2個環氬及 可视需要含有 —個環 1310036 A7 B7 五、發明説明(8 ) 石瓦或氧原予或含3個環氮原子之5 _至1 〇 _員芳香環系,該環 可視需要如上述定義經取代。 另一方面’ Ar為含有i或2個環氮及可視需要含有一個環 较原子之5-至10-員芳香環系,該環可視需要如上述定義經 取代。 另一方面,Ar為含有2個環氮之5-至10-員芳香環系’該 環可視需要如上述定義經取代。 另一方面’ Ar選自:咪唑基、吹吹基、ρ比洛基、異吟唑 基、苯基、喳啉基、啕哚基、苯並咪唑基、啕唑基、苯並 三吐基、2,3-二氫嚙唑基、2,3-二氫笨並噚唑基、吡咯並 [2,3-b]吡啶基、咪唑並[丨,〗^]吡啶基、咪唑並[4,5-b]吡啶基 、2,3-二氫4唑並[5,4_b^t啶基、2,3_二氫吡畊基、2,3-二 氫苯·並嘧唑基與2,3-二氫苯並咪唑基。 另一方面’ Ar選自:咪》坐基、p比〇坐基、ρ比洛基、異》号峻 基、喳啉基、吲哚基、苯並咪唑基、叫丨唑基、苯並三唑基 、2,3-二氫嘍唑基、2,3-二氫苯並呤唑基、吡咯並[2,3-b]吡 咬基、咪唑並[l,2-a]吡啶基、咪唑並[4,5-b]吡啶基、2,3-二 氫嘧唑並[5,4-b]吡啶基、2,3-二氫吡畊基、2,3-二氫苯並嘧 吐基興2,3 -二瘋1苯並味σ坐基。 另一方面’ Ar選自:味吐基、ρ比哇基、笨並味β全基、ρ弓丨 嗤基、苯並三唑基、2,3-二氫笨並呤唑基、吡咯並[2,3-b] 吹啶基、咪唑並[l,2-a]峨啶基、咪唑並[4,54^比啶基、2,3-二氫嘍唑並[5,4-b]吡啶基、2,3-二氫吡畊基與2,3-二氫苯並 咪峻基。 _ 12 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1310036 A7 _____B7 五、發明説明(9 ) 更特定f之’ Ar選自:咪唆基、峻》林基、^丨嗓基、苯並 咪唑基、啕唑基、吡唑基、苯並三唑基、2,3-二氫π塞唑基 、2,3-二氫苯並吟嗅基、ρ比ρ各並[2,3-b]<»比咬基、<»塞唆並[5,4-b]吡啶基、2,3-二氫苯並嘧唑基與2,3-二氫苯並咪唑基。 另一方面’ Ar選自:咪。坐基、p比σ坐基、u比略基、異p号吐 基、苯基與2,3-二氫吡畊基。 另一方面,Ar選自:喹啉基、吲哚基、苯並咪唑基、蚓 唑基、苯並三唑基、2,3-二氫噻唑基、2,3-二氫苯並哼唑基 、口比嘻並[2,3-b]·7比咬基、咪唆並[i,2-a]p比唉基、咪„坐並 [4,5-b]吡啶基、2,3-二氫苯並嘧唑並[5,4-b]吡啶基、2,3-二 氫苯並噹唑基與2,3 -二氫苯並咪唑基。 另一方面,當Ar上之取代基為5或6員芳香環時,Ar上之 此取代基含有至多2個分別獨立選自:氮、氧與硫中之雜原 子。一方面,其係選自呋喃基、嘍吩基、笨基與嘧啶基。另 一方面’其係選自嘧啶基與苯基。另一方面,其係苯基。 由R6與R7及其所附接之氮原子共同形成之環實例包^吡 洛峻並基、峻咬並基、嗎淋並基、峰啡並基、吖啐並基、 M-呤咩並基與丨,4-二吖啐並基。另一方面,該環選自吡咯 p定並基、喊咬並基或嗎淋並基。 由R8與R9及其所附接之氮原子共同形成之環實例包括吡 嘻咬並基、喊咬並基、嗎啦並基、喊畊並基、π丫畔並基' Μ-号°半並基與1,4-二吖4並基。另一方面’該環選自吡咯 a定並基、味淀並基或嗎琳並基。 R1與R2分別獨立代表Cm烷基,如:Cl 5烷基(例如:甲基 ----- 13 - 本纸張尺度適用中圉國家標準(CNS) A4規格(21〇X 297公釐) 1310036 五 發明說明 10 A7 B7Ar is 1 or 2 ring argon and may optionally contain a ring 1310036 A7 B7 5. Inventive Note (8) Stone or oxygen or 5 ring nitrogen atoms 5 _ to 1 〇 _ aromatic ring The ring may be replaced as desired by the above definition. On the other hand, 'Ar is a 5- to 10-membered aromatic ring system containing i or 2 ring nitrogens and optionally containing a ring of atoms, which ring may be substituted as defined above. On the other hand, Ar is a 5- to 10-membered aromatic ring system containing 2 ring nitrogens. The ring may be substituted as defined above. On the other hand 'Ar is selected from the group consisting of: imidazolyl, blowing group, ρ, carbyl, isoxazolyl, phenyl, porphyrinyl, fluorenyl, benzimidazolyl, oxazolyl, benzotriazole , 2,3-Dihydroalrazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[丨,]^]pyridyl, imidazo[4 ,5-b]pyridyl, 2,3-dihydrotetrazolo[5,4_b^t-pyridyl, 2,3-dihydropyrrolidinyl, 2,3-dihydrobenzene-pyrimidazolyl and 2 , 3-dihydrobenzimidazolyl. On the other hand, 'Ar is selected from the group consisting of: Mi", the base of p, the base of p, the ratio of ρ, 洛基, 》, 喳 喳, 喳 、, benzoimidazolyl, carbazolyl, benzo Triazolyl, 2,3-dihydrocarbazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[l,2-a]pyridyl , imidazo[4,5-b]pyridyl, 2,3-dihydropyrazolo[5,4-b]pyridyl, 2,3-dihydropyrrino, 2,3-dihydrobenzo Pyridoxine 2,3 - 2 mad 1 benzo-flavor σ sitting. On the other hand, 'Ar is selected from the group consisting of: taste base, ρ-wow group, stupid taste β-based, ρ 丨嗤 、, benzotriazolyl, 2,3-dihydro benzoxazolyl, pyrrole [2,3-b] oxaridinyl, imidazo[l,2-a]acridinyl, imidazo[4,54^pyridyl, 2,3-dihydrocarbazo[5,4-b Pyridyl, 2,3-dihydropyrrino and 2,3-dihydrobenzimid. _ 12 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 _____B7 V. Description of invention (9) More specific 'f' from: Mickey, Jun, Lin, ^丨Mercapto, benzimidazolyl, oxazolyl, pyrazolyl, benzotriazolyl, 2,3-dihydropyrrazolyl, 2,3-dihydrobenzindole olynyl, ρ ratio ρ [2,3-b]<» than bite base, <» sedative [5,4-b]pyridyl, 2,3-dihydrobenzopyrazole and 2,3-dihydrobenzo Imidazolyl. On the other hand, 'Ar is selected from: Mi. Sitting group, p ratio σ sitting group, u ratio base, iso-p- oxime, phenyl and 2,3-dihydropyrrole. Ar, on the other hand, is selected from the group consisting of quinolyl, fluorenyl, benzimidazolyl, oxazolyl, benzotriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazole The base and the mouth are more than [2,3-b]·7 than the bite group, the oxime and [i,2-a]p are more than the thiol group, the mers are [4,5-b]pyridyl, 2, 3-Dihydrobenzopyrazolo[5,4-b]pyridyl, 2,3-dihydrobenzoxazolyl and 2,3-dihydrobenzimidazolyl. On the other hand, when on Ar When the substituent is a 5- or 6-membered aromatic ring, the substituent on Ar contains up to two heteroatoms independently selected from nitrogen, oxygen and sulfur. On the one hand, it is selected from furyl, porphinyl, Stupid and pyrimidinyl. On the other hand, it is selected from pyrimidinyl and phenyl. On the other hand, it is a phenyl group. An example of a ring formed by R6 and R7 and the nitrogen atom to which they are attached并 基 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , P is a thiol group, and a ring is formed by a combination of R8 and R9 and the nitrogen atom to which they are attached. , shouting and merging, merging, yelling, and 、 并 并 基 基 号 号 号 号 号 号 号 号 号 号 号 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Dicylene, succinyl or morphine. R1 and R2 independently represent Cm alkyl, such as: Cl 5 alkyl (for example: methyl----- 13 - This paper size is suitable for China Standard (CNS) A4 size (21〇X 297 mm) 1310036 Five invention instructions 10 A7 B7
2,2_二正·丙基、卜甲基乙基、正-丁基、2-甲基丙基、 掄其"^甲基丙基、正-戊基或正-己基)、晞基,如:C3 ~基(例如·, . ^3'4 c -产^ κ丙烯基、丨-丁晞基、1-戊埽基或1-己烯基), 基二 '基C|」垸基(環丙基曱基、環丁基甲基、環戊基甲 ^ -(¾¾基)乙基、2-(環丁基)乙基或2•(環戊基)乙基)或 己3·〇基’如:C“環烷基(環丙基、環丁基、環戍基或環 、土其各可視需要經丨·3個鹵原子取代(例如:三氟甲基 另,—三氟乙基、2-氯乙基、2-氣丙基或3,3,3_三氟丙基)。 芙,二万面,R^R2分別獨立代表Cm烷基或環烷基甲 土 ’ ”各可视需要經1-3個鹵原子取代。 另—方面,R1為乙基、正-丙基、1-甲基乙基、2_甲基丙 基、2,2_二甲基丙基、環丙基甲基、三氟甲基、2,2,2_三氟 乙基.、2-氣乙基、2_氯丙基或3,3,3·三氟丙基。 另 方面,r1為乙基、正-丙基、異丙基或2_甲基丙基。 另—方面,Ri為2-甲基丙基。 另—方面’ R2為甲基或三氟甲基。 -_ 另—方面,R2為甲基》 另一方面’ R3為羥基異》号唑啶_2_基羰基、四氫異σ号畊_2_ 基或羥基四氫異崎畊-2-基羰基。 另一方面,R3為羥基異呤唑啶-2-基羰基或超基四氫異噚 畊-2-基羰基。 另一方面,R3為羥基異崎唑啶-2-基羰基。 另一方面,R3為4-經基異σ号唆定-2-基。 另一方面,R3為4S-羥基異哼唑啶-2-基。 -14 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) !3100362,2_di-n-propyl, propylmethylethyl, n-butyl, 2-methylpropyl, 抡["^methylpropyl, n-pentyl or n-hexyl), fluorenyl, :C3 ~ group (for example, . ^3'4 c - yielding κ acryl, 丨-butyl fluorenyl, 1-pentenyl or 1-hexenyl), bis 2 'yl C|" fluorenyl (cyclopropyl) A fluorenyl group, a cyclobutylmethyl group, a cyclopentylmethyl-(3⁄43⁄4yl)ethyl group, a 2-(cyclobutyl)ethyl group or a 2/(cyclopentyl)ethyl) group or a hexyl group. C"cycloalkyl (cyclopropyl, cyclobutyl, cyclodecyl or ring, each of which may optionally be substituted with 3 halogen atoms (for example: trifluoromethyl, -trifluoroethyl, 2- Chloroethyl, 2-apropyl or 3,3,3-trifluoropropyl). Fu, 20,000 Å, R^R2 independently represent Cm alkyl or cycloalkyl sulphate. 1-3 halogen atoms are substituted. In another aspect, R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropyl a group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 2-gas ethyl group, a 2-chloropropyl group or a 3,3,3·trifluoropropyl group. In addition, r1 is an ethyl group. N-propyl, isopropyl or 2_ Further, Ri is 2-methylpropyl. In another aspect, 'R2 is methyl or trifluoromethyl. -_ Further, R2 is methyl. On the other hand, 'R3 is a hydroxyl group. 》 唑 啶 _2 _ _ _ _ 羰 羰 四 四 或 或 或 或 或 或 或 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 另一方面 。 。 。 。 。 另一方面 。 另一方面 。 。 。 Tetrahydroisoindole-2-ylcarbonyl. On the other hand, R3 is hydroxyisoazazin-2-ylcarbonyl. On the other hand, R3 is 4-iso-iso- sigma-2-yl. On the one hand, R3 is 4S-hydroxyisoxazolidine-2-yl. -14 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210X 297 mm) !310036
另方面R與R分別獨立為氫或甲基。 另一方面,Q為-CO -或_ch2·。 在一方面,Q為-CO-。 另一方面’ Q為-CH2-。 另一方面,Ar為未取代或經i、2或3個取代基取代。 另一方面’ Ar為未取代或經1或2個取代基取代。 另一方面’ Ar之取代基包括c14烷基(其可視需要經 個羥基取代),Cm烷氧基、鹵素、三_烷基、c14烷硫基 、CM烷酿基、氧代基、硫代基、氰基其 中p為1或2)、羥基.、Cm烷磺醯基、胺甲醯基、Cm烷基胺 甲醯基、一 -(C!—4烷基)胺曱醯基、幾基,或為含有至多4個 選自:氮、氧與硫中之雜原子之5或6員芳香環系。 在·特定方面,Ar之取代基選自:.Cl_4烷基、_素、c2_4烷 酿基、三氟甲基、氧代基、硫代基、羥基c14烷基、胺基 、Cm烷胺基與(:|.4烷硫基。 另一方面,Ar之取代基包括甲基、乙基、正-丙基、異丙 基、第二丁基、1-甲基乙基、三氟甲基、氣、氟、溴、經 甲基、乙醯基、曱硫基、胺基、甲胺基、呋喃基、違吩基 、p密淀基、苯基、氰基、硫代基與氧代基。 另一方面,Ar之取代基包括甲基、丙基、異丙基、第= 丁基、1 -甲‘基乙基、三氟甲基、氯、氣 '漠、甲硫基、胺 基、甲胺基、苯基、嘧啶基、氰基、硫代基與氧代基。 另一方面,Ar之特定取代基選自甲基、乙基、丙基、第 三丁基、1-甲基乙基、氣、氟、溴、羥甲基、乙醯基、甲 -15 -In another aspect, R and R are each independently hydrogen or methyl. On the other hand, Q is -CO - or _ch2·. In one aspect, Q is -CO-. On the other hand, 'Q is -CH2-. In another aspect, Ar is unsubstituted or substituted with i, 2 or 3 substituents. On the other hand, 'Ar is unsubstituted or substituted with 1 or 2 substituents. On the other hand, the substituent of Ar includes a c14 alkyl group (which may optionally be substituted by a hydroxyl group), a Cm alkoxy group, a halogen, a tris-alkyl group, a c14 alkylthio group, a CM alkyl alcohol group, an oxo group, a thio group. a cyano group, wherein p is 1 or 2), a hydroxy group, a Cm alkanesulfonyl group, an amine carbaryl group, a Cm alkylamine carbhydryl group, a mono-(C!-4 alkyl)amine fluorenyl group, a few Or a 5 or 6 membered aromatic ring system containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In a specific aspect, the substituent of Ar is selected from: .Cl_4 alkyl, _, c2_4 alkyl, trifluoromethyl, oxo, thio, hydroxy c14 alkyl, amine, Cm alkylamino And (:|.4 alkylthio group. On the other hand, the substituent of Ar includes methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-methylethyl, trifluoromethyl , gas, fluorine, bromine, methyl, ethyl sulfonyl, sulfonylthio, amine, methylamino, furyl, thiophene, p-density, phenyl, cyano, thio and oxo On the other hand, the substituent of Ar includes methyl, propyl, isopropyl, 1,4-butyl, 1-methyl'ethyl, trifluoromethyl, chlorine, gas, desert, methylthio, amine. a group, a methylamino group, a phenyl group, a pyrimidinyl group, a cyano group, a thio group and an oxo group. On the other hand, the specific substituent of Ar is selected from the group consisting of methyl, ethyl, propyl, tert-butyl, 1- Methyl ethyl, gas, fluorine, bromine, hydroxymethyl, ethyl ketone, methyl-15
本纸張尺度適用中國國家標準(CNS) A4规格(210x 297公茇) 1310036 A7 B7 五、發明説明(12 ) 硫基、胺基、甲胺基、硫代基與氧代基。 另一方面’ Ar之特定取代基選自甲基、乙基、丙基、第 三丁基、氟、氯、氧代基、硫代基、羥甲基、胺基、甲胺 基與甲硫基。 另一方面,Ar之特定取代基選自甲基、丙基、第三丁基 、丨-甲基乙基、氣、氟、甲硫基、胺基、甲胺基、硫代基 與氧代i。This paper scale applies to China National Standard (CNS) A4 specification (210x 297 metric tons) 1310036 A7 B7 V. Description of invention (12) Sulfur, amine, methylamino, thio and oxo groups. On the other hand, the specific substituent of 'Ar is selected from the group consisting of methyl, ethyl, propyl, tert-butyl, fluorine, chlorine, oxo, thio, hydroxymethyl, amine, methylamine and methyl sulfide base. In another aspect, the specific substituent of Ar is selected from the group consisting of methyl, propyl, tert-butyl, fluorenyl-methylethyl, gas, fluorine, methylthio, amine, methylamino, thio and oxo. i.
Ar之特别走義包括4,5 - 一氣-2-甲基味峻基、45 -二氯_ 2-羥甲基咪唑-1-基、2,4,5-三氣-2-甲基咪唑_丨_基、4,5•二氣 咪唑-2-基、2-溴-4,5-二氣咪唑-2-基、2-甲硫-咪唑_丨·基、 3,5 - —甲基峨哇-4-基、1,3,5-三甲基p比吐-4-基、3 5-二甲基 叶匕哇-4·基、3-第三丁基-5-甲基吡唑-4-基、3,5-二甲基?比唑_ 1-基、5-甲基-3-苯基吡唑-4-基、5-甲基-3-(三氟甲基)吡唑_ 4-基、5-甲基-3-(丙-2-基)吡唑-4-基、3,5-甲基-i_基、苯基 吡唑-4-基,5-二氣-2,3-二氫-2-氧代嘧唑-3-基、4-氯-2,3-二 氫-2-氧代p塞吐-3-基、3,5-二甲基異吟吐-4-基、2,4-二甲基_ 1-(丙-2-基)ρ比洛-3-基、2-三氟苯基、2,3-二氫-6-曱基-3-氧 代ρ比ρ井基、峻n林-4 -基、Β查11林-5 -基、6 -氣奎a林· 4 -基、8 _敗ρ套 啉-4-基、2-甲基哇啉-4-基、2-甲基吲哚-3-基、7-甲基< 哚-3-基、5-氰基峭哚-1-基、2-甲基苯並咪唑-丨_基、2_乙基 苯並咪唑-1 -基、2-丙基苯並咪唑-1 -基、2-甲基硫苯並咪 唑-1-基、2-羥甲基苯並咪唑-1-基、2-甲胺基苯並咪唑_丨·基 、2 -胺基苯並味吐-1-基、u比p各並[2,3-b]!7比咬-3 -基、2 -甲基 吡咯並[2,3-b]吡啶-1-基、2-甲基吡咯並[2,3-b]吡啶-3-基、 -16 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7Special meanings for Ar include 4,5-mono-2-methyl-zemonyl, 45-dichloro-2-hydroxymethylimidazol-1-yl, 2,4,5-tris-2-methylimidazole _丨_yl, 4,5•diazol-2-yl, 2-bromo-4,5-diimidazol-2-yl, 2-methylthio-imidazole 丨····, 3,5--峨wow-4-yl, 1,3,5-trimethyl p-t-but-4-yl, 3 5-dimethyl-yttrium-4-yl, 3-tert-butyl-5-methyl Pyrazol-4-yl, 3,5-dimethyl? Bisazo-1-yl, 5-methyl-3-phenylpyrazol-4-yl, 5-methyl-3-(trifluoromethyl)pyrazole-4-yl, 5-methyl-3- (prop-2-yl)pyrazol-4-yl, 3,5-methyl-i-yl, phenylpyrazol-4-yl, 5-dioxa-2,3-dihydro-2-oxo Pyrazol-3-yl, 4-chloro-2,3-dihydro-2-oxo psec-3-yl, 3,5-dimethylisoindole-4-yl, 2,4-di Methyl-1-(propan-2-yl)ρbilo-3-yl, 2-trifluorophenyl, 2,3-dihydro-6-mercapto-3-oxo-p-r n林-4 -基,Β查11林-5-yl, 6-qikui alin·4 -yl, 8 _ ρ ρ trocarto-4-yl, 2-methyl morpholin-4-yl, 2 -methylindol-3-yl, 7-methyl<indol-3-yl, 5-cyanothion-1-yl, 2-methylbenzimidazole-indoleyl, 2-ethylbenzene Imidazolyl-1 -yl, 2-propylbenzimidazole-1-yl, 2-methylthiobenzimidazol-1-yl, 2-hydroxymethylbenzimidazol-1-yl, 2-methylamino Benzimidazole 丨 丨 基, 2-amino benzo benzophenone-1-yl, u ratio p and [2,3-b]! 7 ratio bite 3-yl, 2-methylpyrrolo[2 ,3-b]pyridin-1-yl, 2-methylpyrrolo[2,3-b]pyridin-3-yl, -16 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 PCT) A7 B7
1310036 五、發明説明 咪吐並[l,2-a]吡啶-3_基、2·(甲硫基)咪唑並[4,5_b]吨、 基、2-(甲硫基)咪唑並[4,5_b]吡啶_3-基、、笨疋'1-唑-卜基、2·氧代-2,3-二氫笨並嘧唑-3-基、2-硫代3教三 笨並"塞°坐-3_基、2-氧代-2,3-二氫苯並》号唑-1-基、1〜氣 2,3-二氫苯並咪唑-3_基、2_氧代·2,3·二氫苯並咪 代_ 产 1 ·· 5,6-二氟_2'氧代-2,3-二氫苯並咪唑-1-基與2-氧代_2 3 :二 苯並嘧唑並[5,4-b]吡啶-3-基。 〜风1310036 V. Description of the invention: [i,2-[a]pyridin-3-yl, 2,(methylthio)imidazo[4,5-b] ton, yl, 2-(methylthio)imidazo[4 , 5_b]pyridine-3-yl, alum, '1-oxazol-bry, 2,oxo-2,3-dihydrobenzopyrazol-3-yl, 2-thio-3, teach three stupid and " ; stopper °-3_ base, 2-oxo-2,3-dihydrobenzoxazole-1-yl, 1~ gas 2,3-dihydrobenzimidazole-3-yl, 2_oxygen代·2,3·Dihydrobenzimido _ 1 · 5,6-difluoro 2′ oxo-2,3-dihydrobenzimidazol-1-yl and 2-oxo_2 3 : Dibenzothiazolo[5,4-b]pyridin-3-yl. ~wind
Ar之其他特別定義包括4,5-二氯-2-甲基咪唑-丨_基、2,4,5_ 二氣-2-甲基咪唑-1-基、4,5-二氣咪唑-2-基、3,5-二甲基吡 i 4-基、1,3,5_三甲基p比峻-4-基、3,5-二甲基p比。坐_4-基、3-第二丁基-5·甲基吡唑-4-基、5-二氯-2,3-二氫-2-氧代嘧唑-3-基、4-氯-2,3-二氫-2-氧代坐-3-基、峻琳-4-基、+4-5-基、.6-氟喳啉-4-基、8-氟〃查啉-4-基、2-曱基喹啉-4-基、2-甲基吲哚-3-基、7_甲基β哚-3-基、5-氰基啕哚_丨_基、2-甲 基苯並咪唑'1-基、2-乙基苯並咪唑-1-基、2-丙基苯I咪 唑-1-基、2-甲硫基苯並咪唑-1-基、2-羥甲基笨並咪唑-1-基 ' 2 -甲胺基苯並咪吐·丨_基、2 -胺基苯並咪嗤-丨_基、p比咯並 [2,3-b]峨啶-3-基、2-甲基吡咯並[2,3-b]吡啶_1_基、2-甲基 17比略並[2,3-b]吨啶-3-基、1H-1,2,3-苯並三唑-1_基、2-氧代-2,3-二氫苯並4唑-3_基、2-硫代-2,3-二氫苯並嘍唑-3-基、 2-氧代-2,3-二氫笨並吟α坐-1-基、6-甲基-3-氧代-2,3-二氫3比 ρ井-2-基與2-氧代_ι,3·噻唑龙[5,4-b]吡啶-3-基。 在一方面’ R6與R7分別獨立代表氫原子、CU4烷醯基(例 如·甲醞基、乙酿基或丙醯基)或C ! .4燒基(例如:甲基、乙Other specific definitions of Ar include 4,5-dichloro-2-methylimidazolium-indenyl, 2,4,5-di-2-methylimidazol-1-yl, 4,5-diimidazole-2 a ratio of -3,5-dimethylpyridin-4-yl, 1,3,5-trimethyl p to quaternary-4-yl, 3,5-dimethyl p. _4-yl, 3-t-butyl-5-methylpyrazol-4-yl, 5-dichloro-2,3-dihydro-2-oxopyrazole-3-yl, 4-chloro -2,3-dihydro-2-oxo-3-yl, phenyl-4-yl, +4-5-yl, .6-fluoroporphyrin-4-yl, 8-fluoroindole- 4-yl, 2-mercaptoquinolin-4-yl, 2-methylindol-3-yl, 7-methylβ哚-3-yl, 5-cyanoindole_yl-yl, 2- Methyl benzimidazole '1-yl, 2-ethylbenzimidazol-1-yl, 2-propylbenzene I imidazol-1-yl, 2-methylthiobenzimidazol-1-yl, 2-hydroxyl Methyl benzimidazol-1-yl '2-methylaminobenzimidium oxime, 2-aminobenzimidazole-indole-based, p-pyrolo[2,3-b]acridine 3-yl, 2-methylpyrrolo[2,3-b]pyridine_1-yl, 2-methyl-17, succinyl[2,3-b]oxa-3-yl, 1H-1, 2,3-benzotriazol-1_yl, 2-oxo-2,3-dihydrobenzotetrazole-3-yl, 2-thio-2,3-dihydrobenzoxazole-3 -yl, 2-oxo-2,3-dihydroindole 吟α-l-yl, 6-methyl-3-oxo-2,3-dihydro-3 ratio ρ well-2-yl and 2 -oxo_ι,3·thiazolon [5,4-b]pyridin-3-yl. In one aspect, R6 and R7 independently represent a hydrogen atom, a CU4 alkanoyl group (e.g., a methylidene group, an ethyl thiol group or a propyl group) or a C. .4 alkyl group (for example, methyl group, B group).
________- 17 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1310036 A7 B7 五、發明説明(14 ) 基、正-丙基或正-丁基),或與其所附接之氮原子共同形成 5-至7-員飽和雜環。 另一方面’ R6與R7分別獨立代表氫原子或烷基。 在一方面,R8與R9分別獨立代表氫原子、Cm烷醯基(例 如:甲醯基、乙醯基或丙醯基)或ci 4烷基(例如:甲基、乙 基、正-丙基或正-丁基),或與其所附接之氮原子共同形成 5 -至7 -員飽和雜環。 另一方面,R8與R9分別獨立代表氫原子或C14烷基。 —種特定化合物為式(1)化合物,其中: 虎基或C;5-6環烷基甲基; R2為C 1 _5燒基; R3為異今吐咬-2-基羰基或四氫異呤畊-2-基羰基,其中 各環可視需要經一個輕基取代; Q為-CO-或-CH2·(其中R4為氫原子或c14烷基’且尺5為氫 原子或羥基);________- 17 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (14) Base, n-propyl or n-butyl), or attached thereto The nitrogen atoms together form a 5- to 7-membered saturated heterocyclic ring. On the other hand, 'R6 and R7 each independently represent a hydrogen atom or an alkyl group. In one aspect, R8 and R9 each independently represent a hydrogen atom, a Cm alkano group (eg, a decyl group, an ethyl fluorenyl group or a propyl group) or a ci 4 alkyl group (eg, a methyl group, an ethyl group, a n-propyl group). Or n-butyl), or a nitrogen atom attached thereto, to form a 5- to 7-membered saturated heterocyclic ring. On the other hand, R8 and R9 each independently represent a hydrogen atom or a C14 alkyl group. - A specific compound is a compound of the formula (1), wherein: a tiger group or a C; 5-6 cycloalkylmethyl group; R 2 is a C 1 _5 alkyl group; and R 3 is a heterotopic thiophene-2-ylcarbonyl group or a tetrahydroiso a quinone-2-ylcarbonyl group, wherein each ring may be optionally substituted with a light group; Q is -CO- or -CH2. (wherein R4 is a hydrogen atom or a c14 alkyl group and the rule 5 is a hydrogen atom or a hydroxyl group);
Ar為5-至10-員芳香環系,其中至多4個-環原子可為分 別獨立選自下列之雜原子:氮、氧與硫,該環系可視需 要經1、2或3個分別獨立選自下列之取代基取代:Ci 4烷 基(其可視需要經丨' 2或3個羥基取代)、Cw烷氧基、卣 素、!S垃基、二鹵烷基、三鹵烷基、Cl-4烷氧基c14烷基 、C,·4烷硫基、C|.4烷氧羰基、C24烷醯基、氧代基、硝 基、氰基、-N(R6)r7 與 _ch2nr8r9 ; R6與R7分別獨立代表氫原子或C|_4烷基,或與其所附 接之氮原子共同形成5_至7_員飽和雜環; -18 - 本紙張尺度適用中國a家標準(CNS) A4規格(21GX 297公爱) 1310036Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, respectively, which may be independently 1, 2 or 3, respectively. Substituted by a substituent selected from the group consisting of Ci 4 alkyl (which may optionally be substituted with 2' or 3 hydroxyl groups), Cw alkoxy, halogen, ! S,,,,,,,,,,,,,,,,,,,,,, a group, a cyano group, a -N(R6)r7 and a _ch2nr8r9; R6 and R7 each independently represent a hydrogen atom or a C?_4 alkyl group, or a nitrogen atom attached thereto to form a 5- to 7-membered saturated heterocyclic ring; -18 - This paper size applies to China National Standard (CNS) A4 specification (21GX 297 public) 1310036
R興R分別獨立代表氫原子或烷基 接之氮原子共同形成5-至7項飽和雜環;〜’、其所附 或其醫藥上可接受之鹽或前藥。 另一種化合物為式(1)化合物,其中: R為C!-5纪基或c3_6環烷基甲基; R2為Cm烷基; R3為羥基異噚_ _2-基羰基、 基四氫異σ号畊-2 -基鎪基; Q為-CO-或-CH2-: Ar為5-至10-員芳香環系, 立選自下列之環雜原子:氮 異十井-2-基幾基 其/包含至多4個可分別獨 、氧與硫,但其限制條件盖 ,、中S有至少一個環氮’該環可視需要經—個或多個分 別獨互選自下列之取代基取代:C 刀 U 又Ll·4烷基(其可視需要經1 或3個搜基取代)、Cu4燒氧基、_素、_貌基、二画 坑基、三函燒基、c丨成氧紅丨·歲基、Ci成硫基、c" 烷乳碳基、cw充醯基、氧代基、硫代基.、硝基、氛基、 -N(R6)R7與-(CH2)pN(r8)r9、縣、Ci成料基、c^完 亞磺醞基、胺甲醯基、Ci_4烷基胺甲醯基、二烷基) 胺甲醯基、羧基、與含有至多4個分別獨立選自二土之 雒原子之5或6員芳香環:氮、氧與硫: R6與R7分別獨立代表氫原子或Ci 4烷基,或與其所附 接之氮原子共同形成5-至7-員飽和雜環; R8與R9分㈣立代4氫原子或c“4烷&,或與其所附 接之氮原子共同形成5-至7-員飽和雜環; -19 -R R independently represents a hydrogen atom or an alkyl group to form a 5- to 7-member saturated heterocyclic ring; 〜', attached thereto or a pharmaceutically acceptable salt or prodrug thereof. Another compound is a compound of formula (1) wherein: R is C!-5-based or c3_6 cycloalkylmethyl; R2 is Cm alkyl; R3 is hydroxyisoindole__2-ylcarbonyl, thiol iso-iso-sigma No. 2 - fluorenyl; Q is -CO- or -CH2-: Ar is a 5- to 10-membered aromatic ring system, which is selected from the following ring heteroatoms: Nitrogen-Iso-2-yl-based It/comprising up to 4 can be individually, oxygen and sulfur, but the limiting conditions cover, and S has at least one ring nitrogen'. The ring may be replaced by one or more substituents each selected from the following: C Knife U and Ll·4 alkyl (which may be replaced by 1 or 3 searches), Cu4 alkoxy, _ _, _ phenyl, geminary, trifunctional, c 丨 oxy red · Aged, Ci-thio, c" alkanocarbyl, cw-filled, oxo, thio, nitro, aryl, -N(R6)R7 and -(CH2)pN(r8 )r9, county, Ci material base, c ^ sulfinyl group, amine methyl sulfonyl group, Ci_4 alkyl amine methyl sulfonyl group, dialkyl) amine methyl sulfonyl group, carboxyl group, and containing up to 4 separately selected 5 or 6 member aromatic rings from the atom of the earth: nitrogen, oxygen and sulfur: R6 and R7 stand independently An atom or a Ci 4 alkyl group, or a nitrogen atom to which it is attached, together form a 5- to 7-membered saturated heterocyclic ring; R8 and R9 are divided into (four) an alternating 4 hydrogen atom or c "4 alkane"; or attached thereto The nitrogen atoms together form a 5- to 7-membered saturated heterocyclic ring; -19 -
A7 B7 1310036 五、發明説明(16 ) 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物’其中: R1為乙基、正-丙基、1-甲基乙基、2 -甲基丙基、2,2-·— 甲基丙基、環丙基甲基、三氟甲基、2,2,2-三氟乙基、2-氣乙基、2-氯丙基或3,3,3-三氟丙基; R2為甲基; R3為羥基四氩異哼啩-2-基羰基、四氫異呤啩-2-基羰基 或經基四氫異β号畊-2 -基羰基; Q為-CO-或-CH2-;A7 B7 1310036 V. Description of the invention (16) or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-methyl-propyl, cyclopropyl Methyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-oxoethyl, 2-chloropropyl or 3,3,3-trifluoropropyl; R2 is methyl; R3 is hydroxy Tetrahydroisoindol-2-ylcarbonyl, tetrahydroisoindol-2-ylcarbonyl or transtetrahydroisophthalene-2-ylcarbonyl; Q is -CO- or -CH2-;
Ar為5 -至1 0-員芳香環系,其中包含至多4個可分別獨立 選自下列之雜環原子:氮、氧與硫,但其限制條件為其 中含有至少一個環氮,該環可視需要經一個或多個分別 獨立選自下列之取代基取代:Cm烷基(其可視需要經1、 2或3個羥基取代)、Cl4烷氧基、_素、鹵烷基、二鹵烷 基、三鹵烷基、C丨-4烷氧基Cl-4烷基、Cw烷硫基、C卜4烷 氧羰基、C2-4烷醯基、氧代基、硫代基…硝基、氰基、 -N(R6)R7 與-(CH2)PN(R8)R9、羥基、CU4烷磺醯基、Ci-4 烷亞磺醯基、胺甲醯基、Cl_4烷基胺甲醯基、二-(C,-4烷 基)胺甲醯基、羧基、與含有至多4個分別獨立選自下列 之雜原子之5或6員芳香環:氮、氧與硫; R6與R7分別獨立代表氫原子或Cl_4烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; R與R9分別獨立代表氫原子或C! 4淀基,或與其所附接 (氮原子共同形成5 -至7-員飽和雜環; 本纸張尺度適财國國家標準_ A7 B7 1310036 五、發明説明(17 ) 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物,其中: R1為乙基、正-丙基、1-甲基乙基、2-甲基丙基、2,2-二 甲基丙基或環丙基甲基; R2為甲基; R3為羥基四氫異哼唑啶-2-基羰基、四氫異噚畊-2-基羰 基或羥基四氫異呤畊-2-基羰基; Q為-CH2-;Ar is a 5- to 10-membered aromatic ring system comprising up to four heterocyclic atoms which may be independently selected from the group consisting of nitrogen, oxygen and sulfur, but with the proviso that at least one ring nitrogen is present therein, the ring being visible It is desired to be substituted by one or more substituents each independently selected from the group consisting of Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxyl groups), Cl4 alkoxy, _, haloalkyl, dihaloalkyl , trihaloalkyl, C丨-4 alkoxy Cl-4 alkyl, Cw alkylthio, C 4 alkoxycarbonyl, C2-4 alkanoyl, oxo, thio...nitro, cyanide , -N(R6)R7 and -(CH2)PN(R8)R9, hydroxy, CU4 alkanesulfonyl, Ci-4 alkylsulfinyl, amine methyl sulfhydryl, Cl 4 alkylamine fluorenyl, -(C,-4 alkyl)aminecarbamyl, carboxyl, and 5 or 6 membered aromatic rings containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; R6 and R7 each independently represent hydrogen An atom or a Cl 4 alkyl group, or a nitrogen atom to which it is attached, forms a 5- to 7-membered saturated heterocyclic ring; R and R 9 each independently represent a hydrogen atom or a C! 4 aryl group, or are attached thereto (a nitrogen atom Forming a 5- to 7-membered saturated heterocyclic ring; National Standard for Paper Scales _ A7 B7 1310036 V. Description of Invention (17) or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl; R2 is methyl; R3 is hydroxytetrahydroisoxazolidine-2-ylcarbonyl, Tetrahydroisoindole-2-ylcarbonyl or hydroxytetrahydroisoindole-2-ylcarbonyl; Q is -CH2-;
Ar為5-至10-員芳香環系,其中包含至多4個可分別獨立 選自下列之環雜原子:氮、氧與硫,但其限制條件為其 中含有至少一個環氮,該環可視需要經1或2個分別獨立 選自下列之取代基取代:CU4烷基(其可視需要經1、2或3 値羥基取代)、C^4烷氧基、卣素、三_烷基、Cw烷硫基、 C2_4烷醯基、氧代基、硫代基、氰基及-(CH2)pN(R8)R9 (其 中p為1或2)、羥基、Cw烷磺醯基、胺甲醯基、Cm烷基 胺甲醯基、二-(C,^烷基)胺甲醯基、羧基、與含有至多4 ' 個分別獨立選自下列之雜原子之5或6員芳香環:氮、氧 與硫: 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物,其中: R1為乙基、正-丙基、1-甲基乙基、2-甲基丙基、2,2-二 曱基丙基或環丙基甲基; R2為甲基; R3為4-羥基四氫異哼畊-2-基羰基或四氫異哼畊-2-基羰 _- 21 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 131〇〇36 A7Ar is a 5- to 10-membered aromatic ring system comprising up to 4 ring heteroatoms independently separable from nitrogen, oxygen and sulfur, but with the proviso that at least one ring nitrogen is present therein, which may optionally Substituted by 1 or 2 substituents each independently selected from the group consisting of CU4 alkyl (which may optionally be substituted with 1, 2 or 3 hydrazine hydroxy), C^4 alkoxy, halogen, tris-alkyl, Cw alkane Thio group, C2_4 alkyl fluorenyl group, oxo group, thio group, cyano group and -(CH2)pN(R8)R9 (wherein p is 1 or 2), hydroxyl group, Cw alkanesulfonyl group, amine carbenyl group, Cm alkylamine methyl sulfonyl, bis-(C, alkyl) amine methyl sulfonyl, carboxyl, and 5 or 6 member aromatic rings containing up to 4' each independently selected from the following heteroatoms: nitrogen, oxygen and Sulfur: or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimercaptopropyl or cyclopropyl R2 is methyl; R3 is 4-hydroxytetrahydroisoindole-2-ylcarbonyl or tetrahydroisoindole-2-ylcarbonyl_- 21 - This paper scale applies to China National Standard (CNS) A4 specification ( 210X 297 mm) 131〇〇36 A7
B7 基; Q為-ch2-;B7 base; Q is -ch2-;
Ar選自:咪唑基、吡唑基、吡咯基、異哼唑基、苯基、 °查°林基、4哚基、苯並咪唑基、吲唑基、苯並三唑基、 2’3-二氫4唑基、2,3-二氫苯並哼唑基、吡咯並[2,3-b]吡 定基―朱吨並[l,2-a]p比淀基、咪β坐並[4,5-b]p比淀基、2,3-—氫嘍唑並[5,4-b]吡啶基、2,3-二氫吡畊基、2,3-二氫苯 並"塞唆基與2,3-二氫苯並咪唑基,該環系可視需要經1或 2個分別獨立選自下列之取代基取代:甲基、乙基、正· 丙基、異丙基、第三丁基、丨_甲基乙基、三氟甲基、氯 、氟、溴、羥甲基、乙醯基、甲硫基、胺基、甲胺基、 夫南基、°塞吩基、嘧啶基、苯基、氰基、硫代基與氧代 基; 或其醫藥上可接受之鹽。 另—方面’本發明係有關通式(1)化合物Ar is selected from the group consisting of: imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, ° lin, 4-mercapto, benzimidazolyl, oxazolyl, benzotriazolyl, 2'3 -dihydrotetrazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl-Zhuteng [l,2-a]p is more than a decyl group [4,5-b]p ratio decyl, 2,3-hydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrryl, 2,3-dihydrobenzo " ; thiol and 2,3-dihydrobenzimidazolyl, the ring may be substituted by 1 or 2 substituents each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl , tert-butyl, hydrazine-methylethyl, trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, ethyl thiol, methylthio, amine, methylamino, flunan, ° a pyrimidyl group, a phenyl group, a cyano group, a thio group and an oxo group; or a pharmaceutically acceptable salt thereof. Another aspect - the present invention relates to a compound of the formula (1)
其中: R1與R2分別獨立代表Cl_6烷基、C3·6缔基、CM環烷基Cu 燒基或C3.6環烷基;其各可視需要經1至3個鹵原子取代; R3為異咩唑啶-2-基羰基或四氫異吟畊-2-基羰基,其中各 _____- 22 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公楚) 1310036 A7 B7 五、發明説明(19 ) 環可視需要經一個羥基取代; Q為-CO-或-C(R4)(R5)-(其中R4為氫原子或Ci_4烷基,且R5 為氫原子或經基);Wherein: R1 and R2 independently represent a Cl_6 alkyl group, a C3.6 alkyl group, a CM cycloalkyl Cu group or a C3.6 cycloalkyl group; each of which may be substituted with 1 to 3 halogen atoms; R3 is an isoindole Azolidin-2-ylcarbonyl or tetrahydroisoindole-2-ylcarbonyl, wherein each _____- 22 - this paper scale is applicable to China National Standard (CNS) A4 specification (210X297 public Chu) 1310036 A7 B7 V. Description of invention (19) The ring may be optionally substituted with a hydroxyl group; Q is -CO- or -C(R4)(R5)- (wherein R4 is a hydrogen atom or a Ci_4 alkyl group, and R5 is a hydrogen atom or a via group);
Ar為5-至10-員芳香環系,其中至多4個環原子可為分別 獨三選自下列之雜原子:氮、氧與硫,該環系可可視需要經 一個或多個分別獨立選自下列之取代基取代:Cm烷基(其 可視需要經1、2或3個羥基取代)、Cm烷氧基、鹵素、鹵烷 基、二_烷基、三_烷基、Ci 4烷氧基ci 4烷基、d.4烷硫 基、Cm烷氧羰基、Cm烷醯基、氧代基、硫代基、硝基、 氰基、-n(r6)r7與_(CH2)pN(r8)r9、羥基、Ci j磺醯基、 Cm烷亞磺醯基、胺甲醯基、Ci·4烷基胺曱醯基、二 fe基)胺甲醯基、幾基; P為1至4 ;Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be independently selected from the following heteroatoms: nitrogen, oxygen and sulfur, and the ring system may be independently selected by one or more separately as needed. Substituted from the following substituents: Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cm alkoxy, halogen, haloalkyl, di-alkyl, tri-alkyl, Ci 4 alkoxy Alkyl 4 alkyl, d. 4 alkylthio, Cm alkoxycarbonyl, Cm alkanoyl, oxo, thio, nitro, cyano, -n(r6)r7 and _(CH2)pN ( R8) r9, hydroxy, Ci j sulfonyl, Cm alkyl sulfinyl, amine carbaryl, Ci. 4 alkyl fluorenyl, bis-methionylamino group, several groups; P is 1 to 4 ;
Ci-4^g|基或cN4烧基,或 i 7-員飽和雜環; C1 块*酶基或C卜4燒基,或 R6與R7分別獨立代表氫原子、Cu 與其所附接之氮原子共同形成5-至7 R8與R9分別獨立代表氫原子、C,_ 與其所附接之氮原子共同形成5_至7_員飽和雜環; 或其醫藥上可接受之鹽或前藥。 一種特定化合物為式(丨)化合物,其中: R1為Cm烷基或c3_6環烷基甲基; R ‘為C | . 5坑基; R3為異哼唑啶-2·基羰基或四氫異气畊基羰基,其中 各環可視需要經一個羥基取代;Ci-4^g| group or cN4 alkyl group, or i 7-membered saturated heterocyclic ring; C1 block * enzyme group or C 4 alkyl group, or R6 and R7 independently represent a hydrogen atom, Cu and its attached nitrogen The atoms together form 5 to 7 R8 and R9 each independently represent a hydrogen atom, and C, together with the nitrogen atom to which they are attached, form a 5-7 to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. A specific compound is a compound of the formula (丨) wherein: R1 is Cm alkyl or c3-6 cycloalkylmethyl; R ' is C | . 5 pit; R3 is isoxazolidine-2-ylcarbonyl or tetrahydroiso a gas carbonyl-based group in which each ring may be substituted with a hydroxyl group as needed;
1310036 A7 _______ B7 一___ 五、發明説明(2〇 ) 選自下列之雜原子:氮、氧與硫,該環系可視需要經1 、2或3個分別獨立選自下列之取代基取代· C! -4燒基(其 可視需要經1、2或3個經基取代)、C1 -4坡氧基、鹵素、 鹵烷基、二鹵烷基、三鹵烷基、CN4烷氧基Cl·4烷基、 C,_4烷硫基、cU4烷氧羰基、c2-4烷醯基、氧代基、硝基 、氰基 ' -N(R6)R7 與 _CH2NR8R9 ; R0與R7分別獨立代表氫原子或Cl_4烷基,或與其所附接 之氮原子共同形成5-至7_員飽和雜環; R8與R9分別獨立代表氫原子或C μ烷基,或與其所附接 之氮原子共同形成5-至7·員飽和雜環; 或其醫藥上可接受之鹽或前藥。 另一種化合物為式(1)化合物,其中:1310036 A7 _______ B7 a ___ V. Description of the invention (2〇) A hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, which may be substituted by 1, 2 or 3 substituents independently selected from the following: C! -4 alkyl (which may be substituted by 1, 2 or 3 radicals), C1 - 4 -oxy, halo, haloalkyl, dihaloalkyl, trihaloalkyl, CN4 alkoxy · 4 alkyl, C, _4 alkylthio, cU4 alkoxycarbonyl, c2-4 alkanoyl, oxo, nitro, cyano '-N(R6)R7 and _CH2NR8R9; R0 and R7 independently represent A hydrogen atom or a Cl 4 alkyl group, or a nitrogen atom attached thereto, forms a 5- to 7-membered saturated heterocyclic ring; R 8 and R 9 each independently represent a hydrogen atom or a C μ alkyl group, or a nitrogen atom attached thereto Forming a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. Another compound is a compound of formula (1) wherein:
WgCus烷基或c3-6環烷基甲基; R為C 1 .5坑基; R3為羥基四氫異咩畊-2-基羰基或羥基四氫異11号"井-2-基 致基; Q為-CO-或-CH2-;WgCus alkyl or c3-6 cycloalkylmethyl; R is C 1.5 pit; R3 is hydroxytetrahydroisoindole-2-ylcarbonyl or hydroxytetrahydroiso 11 " well-2-yl Base; Q is -CO- or -CH2-;
Ar為5-至10-員芳香環系,其中至多4個環原子可為分別 獨立選自下列之雜原子:氮、氧與硫,該環系可視需要 經1、2或3個分別獨立選自下列之取代基取代:Cl·4烷基 (其可視需要經1、2或3個羥基取代)、Cm烷氧基、_素 、鹵烷基、二_烷基、三鹵烷基、Cw烷氧基Cl·4燒基、 Cufe硫基、CU4垸氧羰基、C2-4烷醯基、氧代基、$肖基 、氰基、N(R6)R7與-CH2NR8R9 ; ____ - 24 - 本紙張尺度適用中國國家標準(CNS) A*規格(21〇χ297公釐) 1310036Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be independently selected by 1, 2 or 3, respectively. Substituted from the following substituents: Cl. 4 alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cm alkoxy, _ s, haloalkyl, di-alkyl, trihaloalkyl, Cw Alkoxy Cl·4 alkyl, Cufe thio, CU4 垸 oxycarbonyl, C2-4 alkyl fluorenyl, oxo, $ 肖基, cyano, N(R6)R7 and -CH2NR8R9 ; ____ - 24 - Ben The paper scale applies to the Chinese National Standard (CNS) A* specification (21〇χ297 mm) 1310036
R與R分別獨立代表氫原子或Cw烷基,或與其所附接 之氮原子共同形成5·至7_員飽和雜環; ’ R與R分別獨立代表氫原子或C|·4烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物,其中: R1為Ci-5燒基或c3-6環燒基甲基; R2為甲基; R3為羥基異哼唑啶-2-基羰基或羥基四氫異崎喵_2_基羰 基: _ Q為-CO-或-CH2-;R and R each independently represent a hydrogen atom or a Cw alkyl group, or a nitrogen atom bonded thereto to form a 5·7-7-membered saturated heterocyclic ring; 'R and R each independently represent a hydrogen atom or a C|·4 alkyl group, Or together with the nitrogen atom to which it is attached, form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is Ci-5 alkyl or c3-6 cycloalkylmethyl; R2 is methyl; R3 is hydroxyisoxazolidin-2-ylcarbonyl or hydroxytetrahydro Isobarosin_2_ylcarbonyl: _Q is -CO- or -CH2-;
Ar為5-至10-員芳香環系,其中至多4個環原子可為分別 獨立選自下列之雜原子:氮、氧與硫,該環系可視需要 經1、2或3個分別獨立選自下列之取代基取代:Cm烷基( 其可視需要經1、2或3個羥基取代)、Cl_4烷氧基、鹵素 、鹵烷基、二鹵烷基、三鹵烷基、Cl.4烷氧基Cw烷基、 Cw烷硫基、Cm烷氧羰基、c2_4烷醯基、氧代基、硝基 、氰基、-N(R6)R7與-CH2NR8R9; R6與R7分別獨立代表氫原子或Cw烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; …與R9分別獨立代表氫原子或Cw烷基,或與其所附接 之氮原子共同形成5 -至7 -員飽和雜環; 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物,其中: -25 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be independently selected by 1, 2 or 3, respectively. Substituted from the following substituents: Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cl 4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, Cl.4 alkane Oxy Cw alkyl, Cw alkylthio, Cm alkoxycarbonyl, c2_4 alkylthio, oxo, nitro, cyano, -N(R6)R7 and -CH2NR8R9; R6 and R7 each independently represent a hydrogen atom or a Cw alkyl group, or a nitrogen atom to which it is attached, together form a 5- to 7-membered saturated heterocyclic ring; and R9 independently represent a hydrogen atom or a Cw alkyl group, respectively, or a nitrogen atom attached thereto to form a 5- to a 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1), where: -25 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)
.装 訂Binding
13100361310036
R為乙基、正-丙基、丨,甲基乙基、2·甲基丙基、2,2•二 甲基丙基或環丙基甲基; R2為甲基; Α R為踁基異呤唑啶-2-基羰基或羥基四氣異崎畊-2-基羰 基; ' Q為-CO-或 _〇η2-;R is ethyl, n-propyl, hydrazine, methylethyl, 2-methylpropyl, 2,2 dimethylpropyl or cyclopropylmethyl; R2 is methyl; Α R is fluorenyl Isoxazolidin-2-ylcarbonyl or hydroxytetraisoxan-2-ylcarbonyl; 'Q is -CO- or _〇η2-;
Ar為5-至丨〇_員芳香環系,其中至多4個環原子可為分別 獨互選自下列之雜原子:氮、氧與硫,該環系可視需要 經1、2或3個分別獨立選自下列之取代基取代:C,-4烷基 (其可視需要經丨、2或3個羥基取代)、Ci_4烷氧基、鹵素 、商坑基、二南烷基、三鹵烷基、C14烷氧基Cm烷基、 C|'4坑硫基、ci-4烷氧羰基、C2.4烷醯基、氧代基、硝基 、氰基、n(r6)r7與-CH2NR8R9 ; R與R7分別獨立代表氫原子或C | 4烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; R8與R9分別獨立代表氫原子或Cl 4烷基,或與其所附接 之氮原子共同形成5_至7_員飽和雜環; 或其醫藥上可接受之鹽。 另一種特定化合物為式(i)化合物,其中: R1為乙基、正-丙基、丨_甲基乙基、2_甲基丙基、2,2-二 甲基丙基或環丙基甲基; R2為甲基; R3為羥基異》号唑啶-2-基羰基; Q為-CO-或-CH2-; _ - 26 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公爱) 1310036 發明説明 23 A7 B7Ar is a 5- to 丨〇-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, respectively, which may be independently 1, 2 or 3, respectively. Substituted by a substituent selected from C, -4 alkyl (which may optionally be substituted with hydrazine, 2 or 3 hydroxy groups), Ci-4 alkoxy, halogen, ketyl, dialkyl, trihaloalkyl, C14 alkoxy Cm alkyl, C|'4 pit thio, ci-4 alkoxycarbonyl, C2.4 alkyl fluorenyl, oxo, nitro, cyano, n(r6)r7 and -CH2NR8R9; R7 and R9 independently represent a hydrogen atom or a C4 alkyl group, respectively The attached nitrogen atoms together form a 5-7 to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another specific compound is a compound of formula (i) wherein: R1 is ethyl, n-propyl, hydrazine-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropyl Methyl; R2 is methyl; R3 is hydroxyisodinyl-2-ylcarbonyl; Q is -CO- or -CH2-; _ - 26 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X) 297 public) 1310036 invention description 23 A7 B7
Ar為5-至i〇_ g分上 υ貝不香環系,其中至多4個環原子可為分別 獨立選自下、 _ 之雜原子:氮、氧與硫,該環系可視需要 經1、2每2伽八 & j 1U刀別獨立選自下列之取代基取代:Cl_4烷基 (其可視需I奴 '‘二1、2或3個經基取代)、C1,4燒氧基、鹵素 商^基、二_烷基、三鹵烷基、Ci.4烷氧基C卜4烷基、 Cufk硫基、Ci_4烷氧羰基、c2_4烷醯基、氧代基、硝基 、6氛基、'N(R6)R7與-CH2NR8R9 ; 77爿】獨工代表氫原子或C_t-4燒基,或與其所附接 之8氮原子共同形成5-至7-員飽和雜環; R與R9分別獨立代表氫原子或C| 4烷基,或與其所附接 之氮原子共同形成5-至7·員飽和雜環; 或其醫藥上可接受之鹽。 另—種化合物為式(1)化合物,其中: R1為乙基、正-丙基、b甲基乙基、2•曱基丙基、2,2-二 曱基丙基或環丙基甲基; R2為甲基; R3為羥基異吟唑啶-2-基羰基; Q為-CO-或-CH2-:Ar is 5- to i〇_g divided into mussel non-fragrance ring system, wherein at most 4 ring atoms may be independently selected from the following, _ heteroatoms: nitrogen, oxygen and sulfur, the ring system may be subjected to 1 2, every 2 gamma 8 & j 1U knife is independently selected from the following substituents: Cl_4 alkyl (which can be replaced by I's two, two or three radicals), C1,4 alkoxy , halogen ketone, di-alkyl, trihaloalkyl, Ci.4 alkoxy C 4 alkyl, Cufk thio, Ci-4 alkoxycarbonyl, c 2 4 alkyl thiol, oxo, nitro, 6 Aromatic group, 'N(R6)R7 and -CH2NR8R9; 77爿] the sole work represents a hydrogen atom or a C_t-4 alkyl group, or a nitrogen atom bonded thereto to form a 5- to 7-membered saturated heterocyclic ring; And R9 independently represent a hydrogen atom or a C 4 alkyl group, or a nitrogen atom to which it is attached, to form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, b methylethyl, 2 mercaptopropyl, 2,2-dimercaptopropyl or cyclopropyl R2 is methyl; R3 is hydroxyisoxazolidin-2-ylcarbonyl; Q is -CO- or -CH2-:
Ar選自:咪唑基、吡唑基、2,3_二氫喳唑基、喳啉基、 ⑼嗓基、苯並咪唑基、4唑基、吡咯並[2,3_b0t啶基、 1H-1,2,3 -笨並三吐基、2,3·二氫苯並u塞峡基、2 3-二氣苯 並咪哇基、2,3-二氫笨並$吐基與1,3-噻唑並[5,4_b]p比淀 基,該環系可視需要經卜2或3個分別獨立選自下列之取 代基取代:Cm燒基(其可視需要經1、2或3個羥基取代) -27 - 本紙張尺度適用中a國家標準(CNS) A4规格(210 X 297公 1310036Ar is selected from the group consisting of: imidazolyl, pyrazolyl, 2,3-dihydrocarbazolyl, porphyrinyl, (9) mercapto, benzimidazolyl, tetrazolyl, pyrrolo[2,3_b0tidine, 1H-1 , 2,3 - stupid and succinyl, 2,3, dihydrobenzo oxothyl, 2 3-dibenzophenidyl, 2,3-dihydro cumin $ thiol and 1,3 - Thiazolo[5,4_b]p is a aryl group which may be substituted by 2 or 3 substituents each independently selected from the group consisting of Cm alkyl (which may be substituted by 1, 2 or 3 hydroxyl groups as desired) ) -27 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public 1310036)
五、 發明説明(24 ) 、完氧基、鹵素、鹵烷基、二鹵烷基、三鹵烷基、 Ci-4烷氧基Ci-4烷基、Cw烷硫基、Ci.4烷氧羰基、C2_4烷 k基、氧代基、硝基、氰基、N(R6)R7與_CH2NR8R9 ; R與R7分別獨立代表氫原子或C|_4烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; R與V分別獨立代表氫原子或C U4烷基,或與其所附接 之氮原子共同形成5-至7-員飽和雜環; 或其醫藥上可接受之鹽。 另一種化合物為式(1)化合物,其中: R1為正-丙基、1-甲基乙基或2-甲基丙基; R2為甲基; R3為4-羥基異呤唑啶-2-基羰基; Q為-co-或-ch2-;V. Description of the invention (24), oxy group, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, Ci-4 alkoxy Ci-4 alkyl, Cw alkylthio, Ci.4 alkoxy Carbonyl group, C2_4 alkyl group, oxo group, nitro group, cyano group, N(R6)R7 and _CH2NR8R9; R and R7 each independently represent a hydrogen atom or a C|_4 alkyl group, or a nitrogen atom attached thereto Forming a 5- to 7-membered saturated heterocyclic ring; R and V each independently represent a hydrogen atom or a C U4 alkyl group, or a nitrogen atom attached thereto to form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable Accept the salt. Another compound is a compound of formula (1) wherein: R1 is n-propyl, 1-methylethyl or 2-methylpropyl; R2 is methyl; R3 is 4-hydroxyisoxazolidine-2- Carbocarbonyl; Q is -co- or -ch2-;
Ar選自:咪唑基、吡唑基、2,3-二氫嘍唑基、喹啉基、 吲哚基、苯並唑基、吡咯並[2,3-b]吡啶基、1H-1,2,3-苯 並二σ坐基、2,3 -二鼠苯並p塞σ坐.基、2,3 - 一武%並1圭基與 1,3-4唑並[5,4-b]吡啶基,該環系可視需要經1、2或3個 分別獨立選自下列之取代基取代:甲基、乙基、丙基、 第三丁基、氯、氟、硫代基、羥甲基、甲硫基、胺基、 甲胺基與氧代基; 或其醫藥上可接受之鹽。 本發明之特定化合物包括: (S)-5-[4-超基異11号吐咬-2 -基羰_基]-3 -甲基-1-(2-甲基丙基)-6-(4-4 啉基甲基)《塞吩並[2,3-d]嘧啶-2,4(1Η,3Η)-:_; -28 - 1310036 A7 B7 五、發明説明(25 ) (艮)5-[4-羥基異噚唑啶_2_基羰基]_3_甲基_1_(2_甲基丙基)_6_ (4-。奎啉基甲基)嚷吩並[2,3_d]嘧啶_2,4(1h,3h)-二酮; (S) 6-[4,5-二氯-2-甲基-1H-咪唑-1-基甲基]-5-[4-羥基-2-異 哼唑啶基羰基]-3-甲基-1-(2-甲基丙基)嘧吩並[2,3_d]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異哼唑啶_2_基羰基]_3_曱基_丨_(2_甲基丙基)_6_ (4-4 啉基羰基)噻吩並[2,3-ci]嘧啶-2,4(1Η,3Η)-:_; (S) 5-[4-羥基異噚唑啶_2_基羰基]_3·甲基_6_[(2•甲基·1Η-啕 哚-3-基)甲基]-1-(2-曱基丙基)嘧吩並[2,3_d]嘧啶·2,4(1Η,3Η)_ 二酮; (S) 5-[4-羥基異呤唑啶_2_基羰基]_3_曱基-^^-甲基丙基)_6_ [(1 Η _ ρ比洛並[2,3 - b ] ρ比症-3 _基)甲基]ρ塞吩並[2,3 , d ] α密峻 -2,4(1Η,3Η)-二酮; (S) 5-[4-起基共巧吐淀_2_基羰基]·3·甲基_6-[(2 -甲基- ΐΗ-β 哚-3-基)羰基]-1-(2-甲基丙基)噻吩並[2,3-d]嘧啶_2,4(丨Η,3Η)- 二酮; (S) 5-[4-羥基異呤唑啶·2_基羰基]_3_曱基_;u(1•甲基乙基)_6_ (1 Η - ϊ比β各並[2,3 - b ] ρ比咬_ 3 -基甲基)p塞吩並[2,3 _ d ] »密淀 -2,4(1H,3H)-二酮; (S) 5 -[4-喪基異4吐啶·2-基羰基]_3 -甲基_ι_丙基_6_(出_叶匕 p各並[2,3-b]p比咬-3-基甲基)t>塞吩並[2,3-d]。密咬_2,4(lH,3H)-二 酮; (S) 6-[4,5- 一氯-2-氧代-3 (2H)-p塞峻基甲基]_5_[4_經基異υ号 唆咬-2-基叛基]-3 -甲基-1-(2-甲基丙基)塞吩並[2,3_d] η密淀 -29 - 本纸張尺度適用中國圏家標準(CNS) Α4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(26 ) 〜 -2,4(1H,3H)-二酮; (S) 6-[(3,5-二甲基-1H-吡唑-4-基)甲基]·5_{4-羥基異哼唑啶-2-基羰基}-1-異丁基-3 -甲基4吩並[2,3-d]嘧啶-2,4(1 Η,3Η)- 二酮; (S) 5-{4-起基異号。坐症-2-基羰基丨_ι_異丁基_3_甲基_6_ [1,3,5 -三甲基-1 Η -吡唑-4 -基甲基]嘍吩並[2,3 - d ]嘧啶 -2,4(1H,3H)-二酮: (R) 6-[(4,5-二氣-2 -甲基-1H-咪唑基)甲基]_5·[4-經基-異 哼唑啶-2-基羰基]-3-甲基-1-(2-甲基丙基)P塞吩並[2,3-d]嘧 啶-2,4(1H,3H)-二酮; (S) 5-[4-經基異气唑啶-2-基羰基]-3-甲基-6-[(2-甲基-111-苯 並咪哇-1-基)甲基]-1-(2-甲基丙基)p塞吩並[2,3-d] p密咬 -2,4(1H,3H)-二酮; (S) 6-[(2-乙基-1H-苯並咪唑-1-基)甲基]·5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-1-(2-甲基丙基)Ρ塞吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基羰基]-3 -曱基-1-(2 -甲基丙基)-6-[(2 -丙基-1H -苯並咪唑-1-基)甲基]嘧吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-經基異》号吐症-2-基羰基]-3 -甲基-1-(2-甲基丙基)-6- [2 -(甲基硫基)-1 -苯並咪唑-1 -基甲基]嘍吩並[2,3 - d ]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基羰基]-6-[2-(羥基甲基)-1Η-苯並 咪吐-1-基甲基]-3-甲基-1-(2-甲基丙基)吩並[2,3-d]p密淀 -30 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐) A7 B7 1310036 五、發明説明(27 ) -2,4(1H,3H)-二酮; (S) 5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-6-[2-(甲基胺基)-1H-苯並咪唑-1-基甲基]-1-(2-甲基丙基)嘧吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基羰基]-3-甲基-6-[2·胺基-1H·苯 並咪唑-1-基甲基]-1-(2-甲基丙基)嘧吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (S)-5-[4-羥基-2-異哼唑啶基羰基]-3-甲基-1-(2-甲基丙基)-6-[(2,4,5 -二氯-1H-味吐-1-基甲基]ρ塞吩並[2,3-d]11密咬 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-1-(2-曱基丙基)-6-[2-硫代基-3 (2H)-苯並α塞唑基T基]4吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基狻基]-3-甲基-1-(2-甲基丙基)-6-[4-氯-2-氧代-3(2^1)-1>塞》坐基曱基]11塞吩並[2,3-<1]'1密咬 -2,4(1H,3H)-二酮; - (S) 5-丨4-羥基異吟唑啶-2·基羰基}-3 -甲基-1-(2-甲基丙基)-6-[2-氧代-1,3-苯並噚唑-3(2只)-基甲基]噻吩並[2,3-(1]嘧啶 -2,4(1H,3H)-二酮: (S) 5-{4-羥基異哼唑啶-2-基羰基}-3-甲基-1-(2-甲基丙基:l· 6-[(2 -氧代[丨,3]嘧唑並[5,4-b]吡啶-1-(2H)-基)甲基]P塞吩並 [2,3-(1]嘧啶-2,4(1只,31^)-二酮: (S) 5-[4-經基異》号吐虎-2-基羰基]-3 -曱基-1-(2-甲基丙基)-6-(1H-1,2,3 -苯並三吨-1-基甲基)σ塞吩並[2,3-d]。密症 -31 - 本纸張尺度適用中@國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(28 ) -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶_2-基羰基]-3-甲基-1-(2-甲基丙基)_6_ (1 Η -吡咯並[2,3 - b ]吡啶-1 -基甲基)P塞吩並[2,3 - d ]嘧啶 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基羰基]-3-甲基-l-(2-f基丙基)-6_ [2-曱基-1H-吡咯並[2,3-b]吡啶-1-基甲基塞吩並[2,3-d]鳴 啶-2,4(1H,3H)-二酮; (S) 1-[1,2,3,4-四氫-5-[4-羥基異呤唑啶_2-基羰基]-3-甲基-1- (2-甲基丙基)-2,4 -一氧代1»墓吩並[2,3-(1]1^密咬-6-基甲基)-111- 叫1嗓-5-腈; (S) 5-{4-羥基異噚唑啶-2-基羰基卜3-甲基-1-(2-甲基丙基)-6-[2-氧代-1,3-苯並喳唑-3 (2H)-基甲基]P塞吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; (R) 5-[4-羥基異噚唑啶-2-基羰基]-3- f基-6-[2-甲基-1H-吲 哚-3-基甲基]-1-(2-甲基丙基)嘧吩並[2,3-d]嘧啶-2,4(1H,3H)- 二酮; - (R) 5-[4-羥基異吟唑啶-2-基羰基]-3-甲基-6-[2-甲基-1H-4 哚-3-基甲基]-1-(2-甲基丙基)嘍吩並[2,3-d]嘧啶-2,4(1H,3H)- 二酮; (S) 5-[4-羥基異哼唑啶-2-基羰基]·3-甲基-6-[2-(曱基胺基)-3Η-咪唑並[4,5-b]吡啶-3-基甲基]·ι_丙基塞吩並[2,3-d]嘧 啶-2,4(1H,3H)-二酮; (S) 6-[4,5-二氣-2-甲基-1H-咪唑-1-基甲基]_5-[4-羥基-2·異 崎吨淀基羰基]-3 -甲基-1-丙基-p基吩並[2,3-d]*1密症 -32 - 本紙張尺度適用中國画家標準(CNS) A4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(29 ) -2,4(1H,3H)-二酮; (3)5-[4-羥基異噚唑啶-2-基羰基]-3-甲基-6-[2-(甲基胺基)_ 1H-苯並咪唑-1-基甲基]-1-(1-甲基乙基)噻吩並[2,3 喃咬 -2,4(1Η,3Η)-二酮; (S) 6-[4,5-二氣-2 -甲基-1Η-咪峻-1-基甲基]-5-[4-超基·2_異 吟唑啶基羰基]-3-甲基-1-(1-甲基乙基)噻吩並[2,3-d]嘧啶-5- 羧醯胺; (S) 6·[3,5-二乙基-1 Η-ρ比吐-4-基甲基]-5-{4-經基異g嗅咬· 2- 基羰基}-3-甲基-1-(2-甲基丙基塞吩並[2,3-d]n密淀 -2,4(1H,3H)-二酮; (3)6-[3-(1,1-二甲基乙基)-5-甲基-1^1-吡唑-4-基曱基]-5-{4-羥基異呤唑啶-2-基羰基-3-甲基-1-(2-甲基丙基)嘧吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; (S) 5-[4-羥基異噚唑啶-2-基羰基]-3-甲基-1-(2-甲基丙基)-6-[2-甲基-4-喳啉基曱基]噻吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; (S) 6-[6-氟-4-喹啉基甲基]-5-{4-羥基異呤唑啶-2-基羰基}- 3- 甲基-1-(2-甲基丙基>塞吩並[2,3-d]嘧啶-2,4(1 H,3H)-二酮; (S) 6-[8 -乳-4-t7查1#•基曱基]-5-{4-經基異崎11坐咬-2-基談基}- 3- 甲基-1-(2-甲基丙基)嘧吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; (S) 5-丨4-羥基異哼唑啶-2-基羰基}-3-甲基-1-(2-甲基丙基)-6-(5-4 啉基甲基)4 吩並[2,3-d]嘧啶-2,4(1 H,3H)-二酮; (S) 5-{4-羥基異哼唑啶-2-基羰基卜3 -甲基-1-丙基-6-(喳啉- 4- 基甲基)4 吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; (S) 5-{4-羥基異哼唑啶-2-基羰基}-3-甲基-1-(1-甲基乙基)- -33 - 本纸張尺度適用中固國家標準(CMS) A4规格(210X 297公釐)Ar is selected from the group consisting of imidazolyl, pyrazolyl, 2,3-dihydrocarbazolyl, quinolyl, decyl, benzoxazolyl, pyrrolo[2,3-b]pyridinyl, 1H-1, 2,3-benzodiazepine, 2,3-di-substrate benzo-p-sigma. base, 2,3 - one y1 and 1 guanyl and 1,3-4 oxazolo[5,4- b] pyridyl group, which may be substituted by 1, 2 or 3 substituents each independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, chloro, fluoro, thio, hydroxy Methyl, methylthio, amine, methylamino and oxo; or a pharmaceutically acceptable salt thereof. Specific compounds of the present invention include: (S)-5-[4-superyliso 11 spit-2-ylcarbonyl-yl]-3-methyl-1-(2-methylpropyl)-6- (4-4 phenylmethyl) "deseno[2,3-d]pyrimidine-2,4(1Η,3Η)-:_; -28 - 1310036 A7 B7 V. Description of invention (25) (艮) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]_3_methyl_1_(2-methylpropyl)_6_(4-. quinolinylmethyl) benzophenan [2,3_d]pyrimidine _2,4(1h,3h)-dione; (S) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2 -isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)sulfono[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5 -[4-hydroxyisoxazolidine-2-ylcarbonyl]_3_indolyl_丨_(2-methylpropyl)_6_(4-4 phenylcarbonyl)thieno[2,3-ci]pyrimidine- 2,4(1Η,3Η)-:_; (S) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]_3·methyl_6_[(2•methyl·1Η-啕哚-3 -yl)methyl]-1-(2-mercaptopropyl)sulfono[2,3_d]pyrimidine·2,4(1Η,3Η)_dione; (S) 5-[4-hydroxyisoindole Azolidinyl-2-ylcarbonyl]_3_indolyl-^^-methylpropyl)_6_ [(1 Η _ ρ 毕洛和[2,3 - b ] ρ比症-3 _基)methyl]ρ Sepheno[2,3 , d ] α -2,4(1Η,3Η)-dione; (S) 5-[4-starting co-dissolving _2-ylcarbonyl]·3·methyl_6-[(2-methyl- ΐΗ-哚 哚-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine_2,4(丨Η,3Η)-dione; (S) 5-[ 4-hydroxyisoxazolidinyl-2-ylcarbonyl]_3_mercapto_; u(1•methylethyl)_6_ (1 Η - ϊ ratio β and [2,3 - b ] ρ ratio bite _ 3 -ylmethyl)p-senteno[2,3 _d]»dense-2,4(1H,3H)-dione; (S) 5 -[4-mouryliso-4-pyridin-2-yl Carbonyl]_3 -methyl_ι_propyl_6_(exit_yellow p and [2,3-b]p is more than -3-ylmethyl)t>seno[2,3-d] . Bite 2,4(lH,3H)-dione; (S) 6-[4,5-monochloro-2-oxo-3 (2H)-p succinylmethyl]_5_[4_ υ υ 唆 -2- -2- 基 ] ] ] ] ] ] ] ] ] ] -3 -3 -3 -3 -3 -3 -3 -3 -3 - - - - - - - - - - - - - - - - - Household Standard (CNS) Α4 Specification (210X 297 mm) 1310036 A7 B7 V. Description of Invention (26) ~ -2,4(1H,3H)-Dione; (S) 6-[(3,5-dimethyl -1H-pyrazol-4-yl)methyl]·5_{4-hydroxyisoxazolidine-2-ylcarbonyl}-1-isobutyl-3-methyl-4-pheno[2,3-d Pyrimidine-2,4(1 Η,3Η)-dione; (S) 5-{4-initial. Sedative-2-ylcarbonyl 丨_ι_isobutyl _3_methyl _6_ [1,3,5-trimethyl-1 Η-pyrazole-4-ylmethyl] 喽 并 [2, 3 - d ] pyrimidine-2,4(1H,3H)-dione: (R) 6-[(4,5-di-gas-2-methyl-1H-imidazolyl)methyl]_5·[4- Benzyl-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)P-seceno[2,3-d]pyrimidine-2,4(1H,3H) -dione; (S) 5-[4-carbazyloxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-111-benzimid-1-yl) Methyl]-1-(2-methylpropyl)p-seceno[2,3-d] p-biti-2,4(1H,3H)-dione; (S) 6-[(2- Ethyl-1H-benzimidazol-1-yl)methyl]·5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)indole Sepheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-indolyl-1 -(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]sulfono[2,3-d]pyrimidine-2,4(1H, 3H)-dione; (S) 5-[4-carbazyl- thiophene-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6- [2- ( Methylthio)-1 -benzimidazol-1-ylmethyl]indeno[2,3 - d ]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4- hydroxyl Isooxazolidine-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1Η-benzid-1-ylmethyl]-3-methyl-1-(2-methylpropane) Benzo[2,3-d]p-dense-30 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1310036 V. Invention description (27) -2,4 ( 1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazole -1-ylmethyl]-1-(2-methylpropyl)sulfono[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4- Hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-6-[2·amino-1H·benzimidazol-1-ylmethyl]-1-(2-methylpropyl)sulfonate And [2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1- (2-methylpropyl)-6-[(2,4,5-dichloro-1H-sodium-1-ylmethyl)-p-indeno[2,3-d]11-bite-2, 4(1H,3H)-dione; (S) 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(2-mercaptopropyl)-6-[2 -thio-3(2H)-benzo-alphazolyl T-yl]4-[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4 -hydroxyisoxazolidine-2-ylindenyl]-3-methyl-1-(2-methylpropyl)-6-[4- -2-oxo-3(2^1)-1> plug" sityl sulfhydryl] 11 phenophene [2,3-<1]'1 bite-2,4(1H,3H)- Ketone; - (S) 5-indole 4-hydroxyisoxazolin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3 -benzoxazole-3(2)-ylmethyl]thieno[2,3-(1]pyrimidine-2,4(1H,3H)-dione: (S) 5-{4-hydroxyiso Oxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl: l·6-[(2-oxo[丨,3]pyrazolo[5,4-b]] Pyridin-1-(2H)-yl)methyl]P-seceno[2,3-(1]pyrimidine-2,4(1,31^)-dione: (S) 5-[4-异异》号吐虎-2-ylcarbonyl]-3 -mercapto-1-(2-methylpropyl)-6-(1H-1,2,3-benzotris-1-ylmethyl σ 塞 并 [2,3-d].密-31 - This paper size is applicable @国标准(CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (28) -2,4(1H,3H)-dione; S) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)_6_ (1 Η-pyrrolo[2,3 - b]pyridine- 1-methyl-)P-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolin-2-ylcarbonyl] -3-methyl-l-(2-f-propyl)-6-[2-indolyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl-seceno[2,3- d] oxaridin-2,4(1H,3H)-dione; (S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidine-2-ylcarbonyl] -3-methyl-1-(2-methylpropyl)-2,4-oxo- 1» tomb-[2,3-(1]1^-Bite-6-ylmethyl)-111 - 1嗓-5-nitrile; (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-(2-methylpropyl)-6-[2-oxo --1,3-benzoxazole-3 (2H)-ylmethyl]P-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5- [4-Hydroxyisoxazin-2-ylcarbonyl]-3-fyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl) Pyrimido[2,3-d]pyrimidine-2,4(1H,3H)-dione; - (R) 5-[4-hydroxyl Oxazolidine-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-4indol-3-ylmethyl]-1-(2-methylpropyl)indole[2] , 3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]·3-methyl-6-[2-( Mercaptoamino)-3Η-imidazo[4,5-b]pyridin-3-ylmethyl]·ι_propyl-seceno[2,3-d]pyrimidine-2,4(1H,3H) - diketone; (S) 6-[4,5-dioxa-2-methyl-1H-imidazol-1-ylmethyl]_5-[4-hydroxy-2·isosalitonyl carbonyl]-3 -Methyl-1-propyl-p-amino-[2,3-d]*1---- This paper scale applies to Chinese Painter Standard (CNS) A4 size (210 X 297 mm) 1310036 A7 B7 , invention description (29) -2,4(1H,3H)-dione; (3) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-( Methylamino)) 1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl) thieno[2,3 gnache-2,4(1Η,3Η)-dione; (S) 6-[4,5-di-gas-2-methyl-1 fluorene-imiton-1-ylmethyl]-5-[4-superyl·2-isoxazolidinylcarbonyl]-3- Methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide; (S) 6·[3,5-diethyl-1 Η-ρ ratio spit -4-ylmethyl]-5-{4-pyro-g-snose · 2-ylcarbonyl}-3-A 1-(2-methylpropyl-deseno[2,3-d]n-dense-2,4(1H,3H)-dione; (3)6-[3-(1,1- Dimethylethyl)-5-methyl-1^1-pyrazol-4-ylindenyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-( 2-methylpropyl)sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolin-2-ylcarbonyl] -3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-indolyl fluorenyl]thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione; (S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl}- 3-methyl-1-( 2-methylpropyl>deseno[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S) 6-[8-emulsion-4-t7cha 1#•曱基基]-5-{4-基基基崎11坐坐-2-基谈基}- 3-methyl-1-(2-methylpropyl) sulfonio[2,3-d] Pyrimidine-2,4(1H,3H)-dione; (S) 5-indole 4-hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)- 6-(5-4 phenylmethyl) 4 benzo[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S) 5-{4-hydroxyisoxazole pyridine- 2-ylcarbonyl-3-ethyl-1-propyl-6-(porphyrin-4-ylmethyl)4 benzo[2,3-d]pyrimidine-2,4(1H,3H)-dione (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl } -3-methyl-1- (1-methylethyl) ---33-- scale applies the solid sheet according to the present national standards (CMS) A4 size (210X 297 mm)
裝 訂Binding
A7 B7 !310036 五、發明説明(30 ) 6-(4-〇奎啉基甲基)嘧吩並[2,3-d]嘧啶-2,4(1 H,3H)-二酮; (S) 5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-1-(2-甲基丙基)-6-[(2-甲基-1H-吡咯並[2,3-b]吡啶-3-基)甲基]嘧吩並[2,3-d]嘧 啶-2,4(1H,3H)-二酮; (R) 5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-1-(2-甲基丙基)-6-[(2-甲基-1H·吡咯並[2,3-b]吡啶-3-基)甲基],塞吩並[2,3-d]嘧 啶-2,4(1H,3H)-二酮; (S) -5-[4-羥基異呤唑啶-2-基羰基]-3-甲基-1-(異丁基)-6-[2,3-二氫-6-甲基-3-氧代-吡畊-2-基甲基]-噻吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮;. (S) 5-[4-羥基異呤唑啶_2_基羰基]-3-甲基_6-[(2-甲基)-1Η-吡 咯並[2,3-b]吡啶-3-基)甲基]-1-丙基塞吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮; 5-[(4S)-4-羥基異呤唑啶-2-基羰基]-6-[2-(羥基甲基)-1Η-苯 並咪唑-1 -基甲基]-3 -甲基-1 -丙基·嘧吩並[2,3 - d ]嘧啶 -2,4(1ϋ,3Γί)-二酮; 5-[(4S)-4-羥基異崎唑啶-2-基羰基]-3 -甲基-1-丙基-6-[2-胺 基-1Η-苯並咪唑-1-基甲基]塞吩並[2,3-d]嘧啶-2,4(1Η,3Η)-二酮; (S)-5-[4-羥基異呤唑啶-2-基羰基]-6-[2-(羥基曱基)-1Η-苯並 咪唑-〖-基甲基]-3 -甲基-1 -(異丙基),墓吩並[2,3 - d ]嘧啶 ,2,4(1H,3H)-二酮; (S)-5-[4-羥基異哼唑啶-2-基羰基]-3-甲基-1-(異丙基)_6_[2_ 胺基-1^1-笨並咪吐-1-基甲基]0塞吩並[2,3-(1]喊淀 -34 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 Δ7 Α7 _Β7 五、發明説明(31 ) -2,4(1H,3H)-二酮; 兴丙基)-6-[2-吩並[2,3-d]嘧啶 1 -(異丙基)-6 - [ 2-吩並[2,3-d]嘧啶 (S)-5-[4-經基異°号吐淀-2-基羰基]-3-甲基. 曱基-1 Η - ρ比11各並[2,3 · b ]»比啶-1 -基甲基]嘴 -2,4(1H,3H)-二酮; (S) 5-[4-羥基異呤唑啶-2-基羰基]-3-甲基 甲基· 1 Η -吡咯並[2,3 - b ]吡啶-3 -基甲基]嚷 -2,4(1H,3H)-二酮; (S)-6-[4,5-二氯-2-m基甲基)-lH-咪吐小基甲基幾基 異十全咬-2-基談基]-3-甲基小(異丁基)”塞吩並[2,3_d]^ -2,4(1H,3H)-二酮; ⑸-6-[3,5-二甲基-m-峨峻-丨-基曱基]_5_[4嘈基異崎喷淀_2 基談基]-3-甲基-1-(異丁基)魂吩並[2,3_d]嘧啶 (S)-6-[2,3-二氫-2-氧代-1H-苯並咪唆小基甲基]-5·[4省基異 十坐咬-2-基談基]-3-甲基-1-(異丁基)”塞吩並[2,3_小密啶 -2,4(1H,3H)-二酮; (S) 6-[3,5-二甲基-1H-吡唑-4-基甲基]_5_[4_羥基異呤唑啶_2_ 基羰基]-3-曱基-1-丙基,塞吩並[2,3-d]嘧啶_2,4(1H 3H)_二酮; (s) 6-[3,5-二甲基-m-吡唑-4-基甲基]·5_[4_羥基異吟唑啶_2_ 基談基]-1-異丙基-3-甲基P塞吩並[2,3_d]嘧啶·2,4(1H,3H)^ 酉同; (S)-6-[3,5-二甲基異巧吐-4-基甲基]-5_[4•經基里哼唑啶_2· 基後基]小(異丁基)-3-甲基,塞吩並[2,3_d]嘧啶_2,4(1H,3H)_ -35 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) A7 B7 1310036 五、發明説明(32 ) 6-[4,5-二氣-2-甲基-111-咪吐-1-基曱基]-1-乙基_5_[(43)-4-輕 基-2-異3号吐咬基羰基]-3-甲基-邊吩並[2,3-d]〇密唉-2,4(lH,3H)-二酮; 1 -乙基- 5-[(4S)-4·經基-2-異17号吃喊基羰基]_3·甲基_6-(1Η-ρ比 ρ各並[2,3-d]p比咬-3-基甲基)-¾ 吩並[2,3-d]"·密淀-2,4(lH,3H)- 二酮; 1-乙基-5-[(4S)-4-經基-2-異·^号哇淀基羰基]_3·甲基_6·[2_丙 基-1 Η-苯並咪唆-1-基甲基]-Β塞吩並.[2,3-d]。密咬_2,4( 1Η,3Η)-二酮; ^ * 1-乙基-5-[(4S)-4-經基-2-異11号吐淀基羰基]_3-甲基·6-[2-氧 代-3(2Η) -苯並〇塞嗤基甲基]-Β塞吩並[2,3-d]«►密咬-2,4(1Η,3Η)- 二酮; 1-乙基- 5-[(4S)-4-||基-2-異号吐喊基鼓基]_3 -甲基- 6-[2 -甲 基-1 Η - ρ比咯並[2,3 - b ]吡啶-3 -基甲基]4吩並[2,3 - d ]嘧啶 -2,4(1H,3H)-二酮; 1-乙基-5-[(4S)-4-羥基-2-異噚唑啶基羰基]_3·甲基-6-[5-氰 基-1H-MI哚-U基甲基]-嘧吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; 5-[(4S)-4-羥基異呤唑啶-2-基羰基]-1-(異丁基)-6-[1-異丙基-3,5-二甲基-1 H-吡唑-4-基甲基]-3 -甲基嘧吩並[2,3-d]嘧啶 -2,4(iH,3H)-二酮; 5-[(4S)-4-羥基異呤唑啶-2-基羰基]-1-(異丁基)-3-甲基-6-[5-甲基-3 -苯基-1 Η -吡唑-4 -基甲基]嘍吩並[2,3 - d ]嘧啶 -2,4(1H,3H)-二酮; 5-[(4S)-4-羥基異呤唑啶-2-基羰基]-I-異丁基-3-甲基-6-[5- -36 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)A7 B7 !310036 V. Description of the invention (30) 6-(4-〇 quinolinylmethyl)sulfono[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2, 3-b]pyridin-3-yl)methyl]sulfeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5-[4-hydroxyisoxazole -2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)- ,]]-[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-3- Methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrrol-2-ylmethyl]-thieno[2,3-d] Pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl_6-[(2-methyl)- 1Η-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propylseceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5 -[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1Η-benzimidazole-1-ylmethyl]-3-methyl-1 -propyl·Mimipheno[2,3 - d ]pyrimidine-2,4(1ϋ,3Γί)-dione; 5-[(4S)-4-hydroxyisoazolidine-2-ylcarbonyl ]-3-Methyl-1-propyl-6-[2-amino-1Η-benzoimidazol-1-ylmethyl]cepheno[2,3-d]pyrimidine-2,4(1Η, 3Η)-dione; (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxyindenyl)-1Η-benzimidazole-[-ylmethyl] -3 -Methyl-1 -(isopropyl), tomb-[2,3-d]pyrimidine, 2,4(1H,3H)-dione; (S)-5-[4-hydroxyisoindole Azolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)_6_[2_amino-1^1- benzopyr-1-ylmethyl]0 pheno[2,3 - (1) shouting -34 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 Δ7 Α7 _Β7 V. Invention description (31) -2,4(1H,3H)- Ketone; propyl)-6-[2-pheno[2,3-d]pyrimidine-1-(isopropyl)-6-[2-pheno[2,3-d]pyrimidine(S)-5 -[4-基基°°号吐苯-2-ylcarbonyl]-3-methyl. Mercapto-1 Η - ρ ratio 11 and [2,3 · b ]»pyridin-1 -ylmethyl Mouth-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methylmethyl· 1 Η-pyrrolo[2, 3-B]pyridin-3-ylmethyl]indole-2,4(1H,3H)-dione; (S)-6-[4,5-dichloro-2-mylmethyl)-lH- Mimi oxime methyl group -基基基]-3-methyl small (isobutyl)"cepheno[2,3_d]^-2,4(1H,3H)-dione; (5)-6-[3,5-dimethyl --m-峨峻-丨-基曱基]_5_[4嘈基异崎喷盐_2 基基基]-3-Methyl-1-(isobutyl) Sophora[2,3_d]pyrimidine (S)-6-[2,3-dihydro-2-oxo-1H-benzopyrimidinylmethyl]-5·[4 provinces -methyl-1-(isobutyl)"cepheno[2,3-small pyridine-2,4(1H,3H)-dione; (S) 6-[3,5-dimethyl- 1H-pyrazol-4-ylmethyl]_5_[4-hydroxyisoxazolidine-2-ylcarbonyl]-3-mercapto-1-propyl, pheno[2,3-d]pyrimidine_2, 4(1H 3H)-dione; (s) 6-[3,5-dimethyl-m-pyrazol-4-ylmethyl]·5_[4-hydroxyisoxazole pyridine-2-phenyl] 1-isopropyl-3-methyl P-seceno[2,3_d]pyrimidine·2,4(1H,3H)^ 酉; (S)-6-[3,5-dimethyllocene吐-4-ylmethyl]-5_[4• via 里 里 oxazolidinyl-2-yl post-group] small (isobutyl)-3-methyl, pheno[2,3_d]pyrimidine_2, 4(1H,3H)_ -35 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Invention description (32) 6-[4,5- 二气-2-甲--111-imidol-1-ylindenyl]-1-ethyl_5_[(43)- 4-Lightyl-2-iso-3 thiolcarbonyl]-3-methyl-p-benzo[2,3-d]indole-2,4(lH,3H)-dione; 1-B Base - 5-[(4S)-4. thiophene-2-iso-17 squid carbonyl]_3·methyl _6-(1Η-ρ ratio ρ and [2,3-d]p ratio bite- 3-ylmethyl)-3⁄4 benzo[2,3-d]"·dense-2,4(lH,3H)-dione; 1-ethyl-5-[(4S)-4- -2--2-iso·^# 瓦 淀 carbonyl]_3·methyl_6·[2_propyl-1 Η-benzopyrimidin-1-ylmethyl]-Β 吩 并. [2,3 -d]. Bite 2,4(1Η,3Η)-dione; ^ * 1-ethyl-5-[(4S)-4-alkyl-2-iso-11-dipylcarbonyl]_3-methyl·6 -[2-oxo-3(2Η)-benzo-hydrazinomethyl]-oxime-[2,3-d]«►-biti-2,4(1Η,3Η)-dione; 1-ethyl-5-[(4S)-4-||yl-2-isophonic stimulating base]_3-methyl-6-[2-methyl-1 Η-ρ ratio [2 ,3-b]pyridin-3-ylmethyl]4-pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 1-ethyl-5-[(4S)-4 -hydroxy-2-isoxazolidinylcarbonyl]_3.methyl-6-[5-cyano-1H-MI哚-U-methyl]-pyrimido[2,3-d]pyrimidine-2, 4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3, 5-dimethyl-1 H-pyrazol-4-ylmethyl]-3-methylsulfonio[2,3-d]pyrimidine-2,4(iH,3H)-dione; 5-[ (4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1-indole-pyrazole- 4-ylmethyl] benzopheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl] -I-isobutyl-3-methyl-6-[5- -36 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)
裝 訂Binding
A7 B7 1310036 五、發明説明(33 ) 甲基-3-(三氟甲基)-1Η-ρ比唑-4-基甲基]魂吩並[2,3_d]n密淀 -2,4(1H,3H)-二酮; 5- [(4S)-4-經基異咬-2 -基談基]-1-異丁基- 6- [3-異丙其^ 5 -甲基- lH-p比嗅-4-基甲基]-3 -甲基p塞吩並 -2,4(iH,3H)-二酮: 6- [3,5-二甲基-1-苯基-1H-吡唑-4-基甲基]-5-[(4S)-4-幾基里 气唑啶-2-基羰基]-1-異丁基-3-甲基嘧吩並[2,3_d]n密淀 -2,4(1H,3H)-二酮; 6-[3,5-二甲基-1-苯基-1H-吡唑-4-基甲基]-5-[(4S)-4-超基異 喝唑啶-2 -基羰基]-3 -甲基-卜丙基嘧吩並[2,3 - d ] π密淀 -2,4(1Η,3Η)-二酮; 6-(1^1-1,2,3-苯並三唆-1-基甲基)-5-[(45)-4-獲基異11号咬咬基 羰基]-3-甲基-1-(異丙基)-,塞吩並[2,3-d]嘧啶-2,4(1Η,3Η>二 酮; 5- [(4S)-4-羥基異呤唑啶基羰基]-3-甲基-1-(異丙基)_6_[(2•氧 代噻唑並[5,4-b]吡啶-1(2H)-基)甲基]嘧吩-並[2,3_d]ij密这 -2,4(IH,3H)-二酮; 6- [2,3-二氫-2-氧代-1士苯並咪唑-1-基甲基]-5-[(43)-4-經基 并11号咬这基凝基]-3 -甲基-1-(異丙基)-p墓吩並[2,3-d] 〇·密咬 -2,4(1H,3H)-二酮; 6-[5,6 - 一氣-2,3-二氣-2-乳代-111-苯並味11坐-1_基甲基]_5· [(4S)-4-羥基-2-異呤唑啶基羰基]-3-甲基-1-(異丁基)_,塞吩並 [2,3-d]嘧啶-2,4(1H,3H)-二酮; 5-[(4S)-4-經基異11号定-2-基羰基]-6-(咪味並[i,2_a]p比淀_3_ _ - 37 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) A7 B7 1310036 五、發明説明(34 ) 基甲基)-1-異丁基-3 -甲基噻吩並[2,3-d]嘧啶-2,4(1H,3H)-二 酉同; 3-甲基-6-[2-甲基印哚-3-基甲基]-1-(異丁基)-5-(四氫異呤 畊-2-基羰基)-嘧吩並[2,3-d]嘧啶-2,4(1Η,3Η)-:_; 6-[2->臭-4,5-二氯-1H -味峻-1-基甲基]-5-[(4S)-4-輕基異11号σ坐 啶基羰基]-3-甲基-1-(異丁基)<»塞吩並[2,3-d]嘧啶-2,4(1Η,3Η)-二酮; 5-[(4S)-4-羥基異哼唑啶-2-基羰基]-3-甲基-1-(異丁基)·6_(;2-(甲基硫基)-1 Η-咪吐並[4,5-b]ρ比读· 1 -基甲基]-ρ塞吩並[2,3-d] 嘧啶-2,4(1H,3H)-二酮; 5- [(4S)-4-經基異号吐咬基羰基]-3 -甲基-1-(異丁基)_6_[2-(甲 基硫基)-3H-咪吐並[4,5-b]峨唉-3-基甲基]吩並[2,3-d]»密 啶-2,4(1H,3H)-二酮; 6- [3,5-士甲基-1H-峨哇-4-基甲基]-3 -乙基-5-[(S)-4-經基-2-異 σ号吐咬基羰基]_i-(異丙基)·ρ塞吩並[2,3_d]n密咬·2,4(ιη,3Η)· 二酮; - 5-[(4S)-4-^基-2-異号吐淀基羰基]-3 -甲基- ΐ-(異丁基)_6_[2_ (三氟甲基)苯基甲基]-嘧吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮; 5-[(43)-4-羥基-2-異哼唑啶基羰基]-3-甲基-1-(異丁基)_6_[2_( 甲基硫基)-1H-咪σ坐-1-基甲基]-II塞吩並[2,3-d]n密咬_2 4(ih 3H)· 二酮:及 (S)-5-[4-羥基異吟唑啶基-2-基羰基]-3-曱基小(異丁基)_6_ [2,3-二氫-6-甲基-3-氧代-吡畊-2-基甲基]-嘍吩並[2,3_d]嘧 啶-2,4(1H,3H)-二酮; -38 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1310036 A7A7 B7 1310036 V. INSTRUCTIONS (33) Methyl-3-(trifluoromethyl)-1Η-ρ-pyrazol-4-ylmethyl] Sophora[2,3_d]n-dense-2,4 ( 1H,3H)-dione; 5-[(4S)-4-carbazide-2-carbyl]-1-isobutyl-6-[3-isopropyl^^-methyl-lH -p than ol-4-ylmethyl]-3-methyl p-seceno-2,4(iH,3H)-dione: 6-[3,5-dimethyl-1-phenyl-1H -pyrazol-4-ylmethyl]-5-[(4S)-4-methylidyloxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylsulfono[2,3_d N-dense-2,4(1H,3H)-dione; 6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S -4-superylisoxazolidine-2-ylcarbonyl]-3-methyl-dipropyl sulfonyl[2,3-d] π-dense-2,4(1Η,3Η)-dione; 6 -(1^1-1,2,3-benzotriazin-1-ylmethyl)-5-[(45)-4-exiyl 11th biting carbonyl]-3-methyl-1 -(isopropyl)-, pheno[2,3-d]pyrimidine-2,4(1Η,3Η>dione; 5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3 -methyl-1-(isopropyl)_6_[(2•oxothiazolo[5,4-b]pyridine-1(2H)-yl)methyl]sulfonyl-[2,3_d]ij This-2,4(IH,3H)-dione; 6-[2,3-dihydro-2-oxo-1-benzimidazol-1-ylmethyl ]-5-[(43)-4-Phase and 11-biting this group] 3-methyl-1-(isopropyl)-p-tomb-[2,3-d] 〇·密Bite-2,4(1H,3H)-dione; 6-[5,6-one gas-2,3-digas-2-milo-111-benzo-flavor 11-l-yl-methyl]_5 · [(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-, pheno[2,3-d]pyrimidine-2,4 ( 1H,3H)-dione; 5-[(4S)-4-ylidyl 11-denyl-2-ylcarbonyl]-6-(imixo[i,2_a]p ratio _3_ _ - 37 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Description of invention (34) Methyl)-1-isobutyl-3-methylthieno[2,3-d Pyrimidine-2,4(1H,3H)-dioxime; 3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(four Hydrogen isoindole-2-ylcarbonyl)-pyrimido[2,3-d]pyrimidine-2,4(1Η,3Η)-:_; 6-[2->odor-4,5-dichloro -1H-Sensyl-1-ylmethyl]-5-[(4S)-4-Lightyliso 11 σ-s-ylcarbonyl]-3-methyl-1-(isobutyl)<» Benzo[2,3-d]pyrimidine-2,4(1Η,3Η)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1 -(isobutyl)·6_(;2-(methylthio)-1 Η-miproxil[4,5-b]ρ Reading · 1 -ylmethyl]-ρ-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-radioisoindyl Carbonyl]-3-methyl-1-(isobutyl)_6_[2-(methylthio)-3H-imipo[4,5-b]indol-3-ylmethyl] benzo[ 2,3-d]»Midine-2,4(1H,3H)-dione; 6-[3,5-S-methyl-1H-indol-4-ylmethyl]-3-ethyl- 5-[(S)-4-Imino-2-iso-sigma carbonyl]]i-(isopropyl)·ρ-seno[2,3_d]n bite ·2,4(ιη,3Η ) · diketone; - 5-[(4S)-4-^yl-2-isomeric decylcarbonyl]-3-methyl-ΐ-(isobutyl)_6_[2_(trifluoromethyl)benzene Methyl]-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(43)-4-hydroxy-2-isoxazolidinylcarbonyl]- 3-methyl-1-(isobutyl)_6_[2_(methylthio)-1H-miso-s-yl-1-ylmethyl]-II-senteno[2,3-d]n-bit 2 4(ih 3H)·dione: and (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-indenyl small (isobutyl)_6_ [2,3-di Hydrogen-6-methyl-3-oxo-pyroxy-2-ylmethyl]-indeno[2,3_d]pyrimidine-2,4(1H,3H)-dione; -38 - paper scale Applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1310036 A7
裝 •線Packing
訂Order
1310036 五、發明説明(36 氫化反應。或者’三烷矽烷基或芳基二烷矽烷基(如: 弟* 丁基〒石夕^基或一甲基苯石夕燒基之脫除法可利用例如 :使用合週酸(如:鹽酸、硫酸、鱗酸或三氣乙旬處理, 或使用驗金屬或按氟化物(如:以以或特定言之四丁基錢 化幻處理。或者,燒基之脫除法可利用例如:验金屬⑴ 4C)'反基硫化物(如:硫代乙醇鈉)處理,或使用驗金屬二芳 基崎化物(如:二苯基鱗化經)處理,或例如:使用删或銘 二由化物(如:三;臭化硼)處理。或者,(1_4〇燒氧甲基或四 虱吡喃基之脫除法可利用例如:使用合適酸(如:鹽酸或三 氟乙酸)處理。 或者,經基之合適保護基為例如:酿基,例如:(2_4c)燒 醒基(尤指乙酿基)或芳醯基(尤指苯甲酿基)。脫除上述保 護基之條件必定隨所選用之保護基變化。因此,例如:酿 基(如:燒Si基或芳酿基之脫除法可利用例如:使用合適驗 如:鹼金屬氫氧化物例如:氫氧化鈉或化鋰水解)。 胺基、亞胺基或烷胺基之合適保護基為例如:醯基,例 如:(2-4C)坑酉盛基(尤指乙醯基)、(1_4〇淀氧基羰基(尤指甲 $羰基、乙氧羰基或第三丁氧羰基)、芳基甲氧羰基(尤指 尽甲氧羰基)或芳醯基((尤指苯甲醯基)。脫除上述保護基 之條件必定隨所選用之保護基變化。目此,例如:酿基又(二 •烷SS基、烷氧羰基或芳醯基之脫除法可利用例如·使用 合適鹼如:鹼金屬氫氧化物例如:氫氧化鈉或化鋰水解)。 或者,醯基(如:第三丁氧羰基)之脫除法可利用例如胖:使 用合適酸(如:鹽酸、硫酸、磷酸或三氟乙酸)處理,芳基 -40 - 本紙張尺度適财g g家料(CNS) A4規格(2削297公爱) 裝 訂 線 1310036 A7 B7 五、發明説明(37 甲氧致基(如·苯甲氧羰基)脫除法可利用例如:觸媒(如·· Pd/C)進行氫化反應。 官能基之保護法與脫除保護法完全說明於L W F. Mc〇mie 編輯之’Protective Groups in有機相 chemistry' Plenum出版 ( 1973)及 T.W. Greene 與 P.G,M· Wuts著之第 2版叩如似_ Groups in有機相 Synthesis,,Wiley_Interscience (i99l)。 式(1)化合物或式(1)中至少—個官能基受保護之化合物可 採用下列方法之一製備: a)由式(〖0)化合物: co2h η1310036 V. Description of the invention (36 hydrogenation reaction. Or 'trialkyl decyl or aryl dialkyl decyl group (such as: * * butyl 〒 夕 或 base or monomethyl phenyl sulphate removal method available For example: use peripheric acid (such as: hydrochloric acid, sulfuric acid, squaric acid or trioxane, or use metal or fluoride (such as: with or specifically tetrabutyl morphine treatment. Or, burn) The base removal method can be treated, for example, by examining metal (1) 4C) 'reverse sulfide (such as sodium thioacetate) or by using a metal diaryl sulphide (such as diphenyl squamization). Or for example: using a deletion or a second treatment by a compound (such as: three; boron odor). Alternatively, (1_4 〇 oxymethyl or tetrapyranyl group can be removed by using, for example, using a suitable acid (such as: Treatment with hydrochloric acid or trifluoroacetic acid. Alternatively, a suitable protecting group via a base is, for example, a stabilizing group, for example: (2_4c) a flammable base (especially an ethyl aryl group) or an aryl fluorenyl group (especially a benzoyl group). The conditions for removal of the above protecting groups must vary with the protecting group selected. Therefore, for example, a brewing group (eg: burning Si-based or The removal of the brewing base can be carried out, for example, by using a suitable test such as: alkali metal hydroxide such as sodium hydroxide or lithium hydrolysis. Suitable protecting groups for the amine, imine or alkylamine group are, for example, mercapto groups. For example: (2-4C) pit base (especially ethyl ketone), (1_4 oxime oxycarbonyl (many nail $ carbonyl, ethoxycarbonyl or tert-butoxycarbonyl), aryl methoxycarbonyl ( In particular, methoxycarbonyl or aryl sulfhydryl (especially benzylidene). The conditions for removal of the above protecting groups must vary with the protecting group chosen. For this reason, for example: The removal method of a group, an alkoxycarbonyl group or an aryl fluorenyl group can be carried out, for example, using a suitable base such as an alkali metal hydroxide such as sodium hydroxide or lithium.) Alternatively, a mercapto group (e.g., a third butoxycarbonyl group) The removal method can be used, for example, fat: treated with a suitable acid (such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid), aryl-40 - paper size gg gg (CNS) A4 specification (2 cut 297 Gong love) Gutter 1310036 A7 B7 V. Description of invention (37 methoxy group (such as benzoyloxycarbonyl) removal method The hydrogenation reaction is carried out using, for example, a catalyst (e.g., Pd/C). The functional group protection and removal protection methods are fully described in LW F. Mc〇mie's 'Protective Groups in Organic Chemistry' published by Plenum (1973) And TW Greene and PG, M. Wuts, the second edition is like _ Groups in Organic Phase, Wiley_Interscience (i99l). At least one of the compounds of formula (1) or formula (1) is protected. The compound can be prepared by one of the following methods: a) From the compound of formula (0): co2h η
R1 Q-Ar (10) 與異吟吨唉或四氫異4 „井(其各可視需要經經基取代)反應 b)當Q為亞甲基時,由式(π)化合物 〇 R3R1 Q-Ar (10) reacts with isoindole or tetrahydroiso(4), each of which may be substituted by a trans group. b) When Q is a methylene group, a compound of formula (π) 〇 R3
CH7L R1 (11) 與式Ar化合物反應; -41 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1310036 五、發明説明(38 c)當Q為亞甲基時,還原式(12)化合物· R3CH7L R1 (11) reacts with compound of formula Ar; -41 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (38 c) when Q is methylene When reducing the compound of formula (12) · R3
R1 (12) CH(〇H)-Ar d)由式(11)或(13)進行一級環合成反應’形成Ar 一 R3R1 (12) CH(〇H)-Ar d) is subjected to primary ring synthesis reaction by formula (11) or (13) to form Ar-R3
R1 CH, (13) e)由式(14)化合物與Ri-L2反應: Λ R3R1 CH, (13) e) Reaction of a compound of formula (14) with Ri-L2: Λ R3
,Q' 'Ar Η (14) 其中L與L2為脫離基,且R1、R2、R3、Q# Ar如上述定義, 且可視需要繼a)、b)、c)或d)之後’轉化式(1)化合物形成其 他式(1)化合物與/或形成其醫藥上可接受之鹽或溶合物。 -42 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(39, Q' 'Ar Η (14) where L and L2 are debonded, and R1, R2, R3, Q# Ar are as defined above, and may be followed by a), b), c) or d) (1) The compound forms a further compound of the formula (1) and/or forms a pharmaceutically acceptable salt or solvate thereof. -42 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (39
式(10)化合物與異哼唑啶或四氫異哼畊(其可視需要經幾 基取代)之間之反應宜在醯胺鍵形成反應條件下反應。例如 :於偶合劑之存在下進行,如:二環己基碳化二亞胺或i _ 乙基-3-(3-二甲胺基丙基)乙基碳化二亞胺。可视需要使用 驗’特定言之有機鹼如:三乙胺。合適溶劑通常為非質子 性溶劑’例如:二甲基甲醯胺或氯化溶劑,例如:二氯甲 ^或二氯甲故。此外,亦可使用可催化這種醯胺鍵形成反 應之化合物,如:丨_羥基苯並三唑。其溫度通常在約_3 至約60°C之範圍内,特定言之在周溫或接近周溫下。 式(丨丨)化合物與Ar之間之反應通常在強鹼(如:氫化鈉)之 存在下進行。合適脫離基包括··_基,特定言之溴。該反 應$在惰性溶劑中(如:四氫呋喃),特定言之在周溫或接 近周溫下進行。有時候,例如:當^含有不需要脫除質子 之環氮原子時,可使用較溫和之鹼,如:碳酸氫鈉。此反 應係料製備其巾Αι·制—環氮原子鏈結之化合物。然而 ,可採用此方法來製備其中Ar利用一環碳原子鏈結之化合 物此反應可使用強鹼與鋅鹽(如:氯化鋅)及可視需要使 用碘化鈉作為觸媒進行。 式(12)化合物可採用相關技藝上已知用於羥基之標準 原條件還原成相應之亞甲基化合物。例如:其可經酸 三氟乙酸)質子化,以三烷基矽烷還原。或者,羥基可轉 成較強之脫離基,如:甲磺酸根與甲苯磺酸根,所得之化. 物於非超基性溶劑中,特定言之四氫吱喃中,使用觸媒(: •Pd/C)’於之溫度範圍内,特定言之於周溫- 7纸張尺ίϊ用中國国家標準格— 43 - ’297公釐)The reaction between the compound of the formula (10) and isoxazolidine or tetrahydroisoindole (which may optionally be substituted with a few groups) is preferably carried out under the conditions of the indole bond formation reaction. For example, it is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide or i-ethyl-3-(3-dimethylaminopropyl)ethylcarbodiimide. The specific organic base such as triethylamine can be used as needed. A suitable solvent is usually an aprotic solvent such as dimethylformamide or a chlorinated solvent such as dichloromethane or dichloromethane. Further, a compound which catalyzes the formation of such a guanamine bond, such as hydrazine-hydroxybenzotriazole, can also be used. The temperature is usually in the range of from about _3 to about 60 ° C, specifically at or near ambient temperature. The reaction between the compound of the formula (丨丨) and Ar is usually carried out in the presence of a strong base such as sodium hydride. Suitable exfoliation groups include ··· groups, specifically bromine. The reaction is carried out in an inert solvent (e.g., tetrahydrofuran), specifically at ambient temperature or near ambient temperature. Sometimes, for example, when a ring nitrogen atom which does not require removal of a proton is contained, a milder base such as sodium hydrogencarbonate can be used. This reaction is a compound prepared by the preparation of a ring-to-ring nitrogen atom chain. However, this method can be used to prepare a compound in which Ar is bonded by a ring carbon atom. This reaction can be carried out using a strong base and a zinc salt (e.g., zinc chloride) and optionally using sodium iodide as a catalyst. The compound of formula (12) can be reduced to the corresponding methylene compound using standard conditions known in the art for hydroxyl groups. For example, it can be protonated by acid trifluoroacetic acid and reduced with trialkylnonane. Alternatively, the hydroxy group can be converted to a stronger cleavage group, such as mesylate and tosylate, and the resulting material is used in a non-hyperradical solvent, specifically tetrahydrofuran, using a catalyst (: • Pd/C)' Within the temperature range, specifically for the weekly temperature - 7 paper size ίϊ with the Chinese national standard grid - 43 - '297 mm)
裝 訂Binding
1310036 A7 B7 五、發明説明(40 ) ,及1-5巴壓力下氫化。 式(1 I)或(1 3)化合物上之-Q-Ar基團宜利用一級環合成法 形成。此反應可參見文獻中之概要:E.C_ Taylor與A. Weissberger之1The Chemistry of Heterocyclic化合物 s’(John Wiley and Sons 出版)及 A.R Katritzky 與 C. W Rees 之 'Comprehensive Heterocyclic Chemistry' (Pergamon Press (Elsevier)出版)。例如:製備式(1)中Ar為3,5-二甲基吡唑-4-基或I,3,5-三甲基吡唑-4_基之化合物時,可參見明確實例 中之實例11與12。 式(14)化合物可與式rLl2化合物,於溫和驗之存在下(如 :碳酸鉀)’於非質子性雙極性溶劑中(如:DMF),於周溫 至170°C之範圍内反應。 式(1)化合物之製法可由另一種式(1)化合物進行化學修飾 法製得。例如:式(1)中Q為亞甲基之化合物可氧化成式(1) 中Q為羰基之化合物。較佳氧化劑為含於有機溶劑中(如: 四氫呋喃)之2,3-二氣-5’6-二氰基-1,4-苯並醌pDQp有時候 ’可由亞甲基化合物曝露到空氣中進行氧化。 式(1〇)中間物可由式(15)化合物形成: C〇2R201310036 A7 B7 V. Inventive Note (40), and hydrogenation at 1-5 bar pressure. The -Q-Ar group on the compound of the formula (1I) or (13) is preferably formed by a primary ring synthesis method. This reaction can be found in the literature: E.C_ Taylor and A. Weissberger 1 The Chemistry of Heterocyclic Compound s' (published by John Wiley and Sons) and AR Katritzky and C. W Rees' 'Comprehensive Heterocyclic Chemistry' (Pergamon Press (Pergamon Press ( Elsevier))). For example, when preparing a compound of the formula (1) wherein Ar is a 3,5-dimethylpyrazol-4-yl group or an I,3,5-trimethylpyrazole-4-yl group, refer to the examples in the clear examples. 11 and 12. The compound of the formula (14) can be reacted with a compound of the formula rL12 in the presence of a mild test (e.g., potassium carbonate) in an aprotic bipolar solvent (e.g., DMF) at a temperature ranging from about 30 °C. The preparation of the compound of the formula (1) can be carried out by another chemical modification of the compound of the formula (1). For example, a compound of the formula (1) wherein Q is a methylene group can be oxidized to a compound of the formula (1) wherein Q is a carbonyl group. Preferably, the oxidizing agent is 2,3-dioxa-5'6-dicyano-1,4-benzoxanthene pDQp contained in an organic solvent (e.g., tetrahydrofuran), sometimes exposed to air by a methylene compound. Oxidation is carried out. The intermediate of formula (1〇) can be formed from the compound of formula (15): C〇2R20
A7 B7 1310036 五、發明説明(41 其中R為Cu烷基,例如:甲基或乙基,且rZ1為(其 中L如上述定義)或-CH(〇H)Ar。 式(15)中R21為-cha之化合物可與^於類似上述方法b)之 條件下反應。 *Ar利用環碳原子鏈結時,式(15)中r2!為_CH(〇H)Ar_^ 化合物可採用類似上述方法c)之條件還原。 式(12)或(15)中,為_ch(0H)Ai^化合物之製法為由式 (16)化合物:A7 B7 1310036 V. Description of the invention (41 wherein R is a Cu alkyl group, for example: methyl or ethyl, and rZ1 is (wherein L is as defined above) or -CH(〇H)Ar. In the formula (15), R21 is The compound of -cha can be reacted with a condition similar to the above method b). * When Ar is bonded by a ring carbon atom, the compound of formula (15) wherein r2! is _CH(〇H)Ar_^ can be reduced by a condition similar to the above method c). In the formula (12) or (15), the compound of the formula _ch(0H)Ai^ is prepared from the compound of the formula (16):
(”中R-2適當時為R3或·〇〇2κ20)與式Ar-CHO,於強驗之存 在下(如.二燒基.胺化經,例如.:二異丙基胺化鋰)’於惰 性有機溶劑中(如:四氫呋喃)反應,先於低溫下(如:_78°C ) 進行,然後使之回升周溫。 中間物一般由式(1 7)化合物製備:("R-2 in the case of R3 or 〇〇2κ20 when appropriate") and the formula Ar-CHO, in the presence of a strong test (eg, dialkyl. amination, for example: lithium diisopropylamide) 'Reaction in an inert organic solvent (eg tetrahydrofuran), preceded by low temperature (eg _78 ° C), and then brought back to the ambient temperature. Intermediates are generally prepared from compounds of formula (17):
R1 07) -45 - 本紙張尺度適用中a國家標準(CNS) A4規格(210X 297公釐)R1 07) -45 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)
1310036 A7B7 五、發明説明(42 ) 其中R23為氫或甲基。 當R21為-CH(OH)Ar時,R23為氫,且式(16)化合物可如上 述式(15)之反應’與Ar-CHO反應。 當^為-CH2L時’ P為甲基,其可經例如··画化反應轉 化成-CH2L。當L為、;臭時,甲基可使用標準澳化劑(如:N-溪 琥珀醯亞胺),於標準條件下進行溴化反應。 式(17)中,R23為氫之化合物製法可先由式(18)化合物:1310036 A7B7 V. Description of the invention (42) wherein R23 is hydrogen or methyl. When R21 is -CH(OH)Ar, R23 is hydrogen, and the compound of the formula (16) can be reacted with Ar-CHO by the reaction of the above formula (15). When ^ is -CH2L, 'P is a methyl group, which can be converted to -CH2L by, for example, a painting reaction. When L is, when odorous, the methyl group can be subjected to a bromination reaction under standard conditions using a standard alkalizing agent (e.g., N-brook amber imine). In the formula (17), the compound wherein R23 is hydrogen may be prepared from the compound of the formula (18):
與溴丙酮酸烷基酯(如:溴丙酮酸乙酯),於溫和鹼之存在 下(如:驗金屬碳酸鹽’例如:碳酸卸),於極性溶劑 如:聽),於代至赃之溫度間反應,然後使所得加人 物經路易士酸(特定言之四氣化鈥),於惰性溶劑中(例如: 二虱甲烷),於-20t至50t之溫度間(特定言之〇Q(:With alkyl bromopyruvate (such as: ethyl bromopyruvate), in the presence of a mild base (such as: test metal carbonate 'for example: carbonic acid unloading), in polar solvents such as: listen), on behalf of the 赃The temperature is reacted, and then the resulting person is subjected to Lewis acid (specifically, the gasification enthalpy) in an inert solvent (for example: dimethane) at a temperature between -20 t and 50 t (specifically, Q ( :
之間)處理。 L ,乂Π)中’ R、甲基之化合物製法可先由式⑽化合物 m2-乳代丁酸烷基醋(如:3_澳上氧代丁酸 Γ和驗之存在下(如:驗金屬叛酸鹽1如:乙酸鈉),於 極性溶劑中(例如:DMF,或特定言之水),於至50力; 溫度間反應,然後使所得加合物經路易士酸(特定言之四: -46 -Between) processing. L, 乂Π) in the 'R, methyl compound can be prepared by the formula (10) compound m2-milobutyric acid alkyl vinegar (such as: 3_O-oxobutanoic acid hydrazine and the presence of the test (such as: test Metal tetrate 1 (such as sodium acetate), in a polar solvent (for example: DMF, or specifically water), to 50 forces; reaction between temperatures, and then the resulting adduct via Lewis acid (specifically Four: -46 -
1310036 A7 B71310036 A7 B7
五、發明説明(43 ) 化鈦),於惰性溶劑中(例如:二氯甲烷),於_2〇t至5(rc之 溫度間(特定言之〇°C至25°C之間)處理。 式(1 7)化合物製法可由式(19)化合物:5. Description of the invention (43) Titanium), treated in an inert solvent (eg dichloromethane) between _2 〇 t and 5 (between rc (specifically 〇 ° C to 25 ° C) The compound of the formula (17) can be produced from the compound of the formula (19):
(19) (其中R24為C|_4:t完基,例如:乙基) 與乙醯基氰酸酯,於惰性溶劑中(例如:甲苯),於至5〇。〇 之Μ度間反應,然後以金屬燒醇鹽之燒醇溶液(例如:甲醇 麵之甲醇溶液)’於〇°C至30°C之溫度間,於式r2_li化合物 之存在下(其中L為脫離基’例.如:碑離子)反應.。式(19)化 合物之製法為由式(20)化合物r1-n=s與威特化合物(wittig 化合物),例如:式(21)化合物反應: ··(19) (wherein R24 is C|_4: t-based, for example: ethyl) and ethoxylated, in an inert solvent (for example: toluene), up to 5 Torr. The reaction between the oxime and the oxime solution is then carried out in the presence of a compound of the formula r2_li (where L is in the range of 〇 ° C to 30 ° C) Deviation from the base 'example. Such as: monument ion) reaction. The compound of the formula (19) is produced by reacting a compound of the formula (20), r1-n=s, with a Witt compound (wittig compound), for example, a compound of the formula (21):
(其中R'為苯基或經取代之苯基,如:〒苯基) 其係於惰性溶劑中’例如:THF,於20。(:至80°C之溫度間 進行’所得之加合物再於原位與式(22)化合物,於-78°C至 60°C之溫度下反應: 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(44 )(wherein R' is phenyl or substituted phenyl, such as fluorenylphenyl) which is in an inert solvent such as THF at 20. (: to the temperature of 80 ° C, 'the obtained adduct is then reacted in situ with the compound of formula (22) at a temperature of -78 ° C to 60 ° C: This paper scale applies to the Chinese national standard (CNS) A4 size (210 X 297 mm) 1310036 A7 B7 V. Description of invention (44)
/R20 式(18)化合物之製法為由式(23)化合物: 〇/R20 The compound of the formula (18) is produced by the compound of the formula (23): 〇
R1 (23)R1 (23)
裝 與驗金屬疏醇(如:硫醇納),於極性溶劑中(如:醇,例如 :乙醇)’.於10至50°C之溫度範圍内反應。 式(23)化合物之製法可由式(24)化合物:It is charged with a metal (for example, a mercaptan) and reacted in a polar solvent (e.g., an alcohol such as ethanol) at a temperature of 10 to 50 °C. The compound of formula (23) can be prepared from a compound of formula (24):
Η (24) 與式R1 -L2化合物,於上述e)方法所述條件下反應。 上述式(1)化合物可轉化成其醫藥上可接受之鹽或溶合物。 有些式(1)化合物可呈立體異構型。咸了解本發明涵括式 (1)化合物之所有幾何與光學異構物及其混合物,包括消旋 -48 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 訂Η (24) is reacted with a compound of the formula R1 - L2 under the conditions described in the above method e). The compound of the above formula (1) can be converted into a pharmaceutically acceptable salt or solvate thereof. Some of the compounds of formula (1) may be stereoisomeric. It is understood that all geometric and optical isomers of the compound of the formula (1) and mixtures thereof, including racemic -48 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)
‘線 1310036 五 、發明説明( 45 物。此等化合物亦形成本發明之 異構物可利用 万面。 段結晶S。對映田# #解折或分離’例如:層析法或分 化合物之其他混Γ物而知技術分離消旋化合物或 (HPLC))。或者,所+、^ ( j Ρ •對掌性高效液相層析法 學活性起始物,於不=學異,物之製法可由適當之光 ••使用高碳對掌性酸二1:"疋化《條件τ反應、,或例如 對映異構性衍生物:;=c,=習广分離非 非對掌性起始物及對掌性試劑製備。所有 括在本發明範圍内。 W有一異構物均包 Π明化合物可使用習知技術自其反應混合物中單離出。 性,.因此可以利類動物體内具有醫療活 口此了以利用。其可作為醫藥,用於 體免疫、.發炎、增生及過度增生性疾病,及:自 之疾病,包括移植器官或組織之排斥反應與:天二= 乏症候群(AIDS)。 八丨王充反缺 此等病症實例為: (1)(呼吸道)呼吸运疾病,包括慢性阻塞性肺病⑴〇 … 喘’如:支一氣管、過敏性、内因性、外因性與粉塵性: %,特疋s足忮性或頑固性氣喘(例如:晚發性 呼吸道過度反應);支氣管炎;急性、慢性、萎縮3 炎與慢性鼻炎’包括乾酷狀鼻炎、肥厚性鼻炎 性鼻炎、乾性鼻炎與藥物性鼻炎;膜性鼻炎包括格二 性鼻炎、纖維性與假膜性鼻炎及腺病性鼻Λ · IW布 ,竽卽性鼻 49 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1310036五、發明説明(46 ) A7 B7'Line 1310036 V. DESCRIPTION OF THE INVENTION (45. These compounds also form the isomer of the present invention, which can be used in various forms. Segmental Crystal S. Pairs of Yingtian ##Unfolding or Separating' For example: chromatography or sub-compounds Other compounds are known to separate racemic compounds or (HPLC). Or, +, ^ ( j Ρ • for palm-shaped high-performance liquid chromatography active starting materials, not = learning, the method of production can be by appropriate light • • use high carbon to palm acid 2:" The conditions of the τ reaction, or, for example, enantiomeric derivatives:; = c, = Xiguang separation non-preferential starting materials and preparation of the palmitic reagents are all included in the scope of the present invention. W has an isomer, and the compound can be isolated from the reaction mixture by conventional techniques. Sexuality, so that it can be used as a medical activity in the body of the animal. Immunity, inflammation, hyperplasia and hyperproliferative diseases, and: from diseases, including transplant organs or tissue rejection and: Tianji = AIDS syndrome. (Respiratory) respiratory diseases, including chronic obstructive pulmonary disease (1) 〇... Asthma: such as: a trachea, allergic, endogenous, exogenous and dusty: %, especially s full or intractable asthma (eg : late onset respiratory tract hyperactivity); bronchitis; acute, slow , atrophy 3 inflammation and chronic rhinitis 'including dry rhinitis, hypertrophic rhinitis rhinitis, dry rhinitis and drug rhinitis; membranous rhinitis including secondary rhinitis, fibrotic and pseudomembranous rhinitis and adenoma sinus IW cloth, sputum nose 49 - This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 V. Invention description (46) A7 B7
炎包括神给性鼻炎(花粉熱)與血管運動神經性鼻炎:結 郎病、農夫肺及相關疾病’肺纖維樣變性 質性肺炎; ^ 間 (2) (骨體與關節)類風濕關節炎、血清陰性脊椎關節病變(包 括黏連性脊椎炎、乾癖性關節炎與菜特氏症(RAMS disease)、貝希特氏症(Behcet, s仏⑽)、索忍氏症候群 (Sjogren's syndrome)與全身性硬化; (3) (皮膚)乾癖、異位性皮膚炎、接觸皮膚炎與其他濕療性 皮膚炎 '皮脂漏性皮膚炎、扁平苔蘚、天疱瘡、大泡 性夭疱瘡、大泡性表皮鬆解、蓴麻疹、乾皮病、脈管 炎、皮膚紅斑、皮膚性嗜伊紅細胞增多症、葡* 、簇狀亮髮與春季結膜炎; … (4) (胃腸道)結腸疾病、直腸炎、嗜伊紅細胞胃腸炎、肥大 細胞增夕症、克隆氏症(Crohn’s disease)、潰瘍性钟腸 炎、由賸部引起之與食物有關之過敏反應,例如:偏頭 痛、_鼻1與濕疹; — 、 (5) (其他组織與全身性疾病)多發性硬化、動脈硬化、後天 性免疫缺乏症候群(AIDS)、紅斑性狼瘡、全身性狼瘡、 紅斑、橋本甲狀腺炎、重症肌無力、I型糖尿病、腎病 症候群、嗜伊紅細胞筋膜炎、過高IgE症候群、麻風結 節性麻風、塞澤里症候群(sezary syndrome)與原發性血 小板減少症紫斑; (6) (同種移植排斥)繼移植例如:腎、心、肝、骨髓、皮声 與角膜後出現之急性與慢性排斥;及慢性移植物對抗宿 ___- 50 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Inflammation includes sacral rhinitis (hay fever) and vasomotor neuropathic rhinitis: lang disease, farmer's lung and related diseases 'pulmonary fibrosis pneumonia; ^ (2) (bone and joint) rheumatoid arthritis Serum-negative spondyloarthropathy (including adhesional spondylitis, dry arthritis and RAMS disease, Behcet (s) (10), Sjogren's syndrome and Systemic sclerosis; (3) (skin) dryness, atopic dermatitis, contact with dermatitis and other moist dermatitis' sebum dermatitis, lichen planus, pemphigus, bullous blisters, big bubbles Sexual epidermis, urticaria, dry skin disease, vasculitis, skin erythema, cutaneous eosinophilia, Portuguese*, clustered hair and spring conjunctivitis; (4) (gastrointestinal) colon disease, straight Enteritis, eosinophilic gastroenteritis, mast cell germination, Crohn's disease, ulcerative enteritis, food-related allergic reactions caused by leftovers, such as migraine, _ nose 1 and eczema ; —, (5) (Other organizations And systemic diseases) multiple sclerosis, arteriosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, renal syndrome, eosinophils Membrane inflammation, excessive IgE syndrome, leprosy nodular leprosy, sezary syndrome and idiopathic thrombocytopenic purpura; (6) (allograft rejection) following transplantation such as: kidney, heart, liver, bone marrow, Acute and chronic rejection after skin and cornea; and chronic graft versus ___- 50 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)
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線 1310036Line 1310036
主之疾病;及 (7)癌症。 „因此本电明提出一種如上述定義之式(1)化合物或其醫 樂上可接党之鹽用於醫療。 ^万® ’本發明提出—種如上述定義之式(1)化合物或 其酱:上可接受之鹽用於抑制T細胞增生。 ,另1:Φ *發明提出—種以如上述定義之式⑴化合物 或其醫藥上可接$之鹽於製造醫藥,供抑制τ細胞增生上 之用途。 本谠月曰中,醫療法” 一詞亦包括”預防法",除非另有 說月因此’醫療"與”醫療性"等名詞應加以解說。 預防法應與過去曾罹患該特定疾病或罹患該特定病症之 危險性提高之個體之處理法特別有關。有發展出該特定疾 病或祕危險之個體通常包括彼等有家族病史者,及彼等 已經過基因:測試或篩選證實特別容易發展出該疾病或病症 本發明進一步提出一種塵抑免疫性之方法(例如:用於心 療:種移植排斥)’其包括對該患者投與醫療有效量之如: 述足義之式(1)化合物或其醫藥上可接受之鹽。 發明亦提出一種對已罹患或可能罹患;吸道 .氣喘或COPD)之患者治療或降低該疾病危險性之方 其包括對該患者投與醫療有效量之如上述定義之式', 物或其醫藥上可接受之鹽。 ^ 化合 上述醫療用法之投藥劑量當然將依所使用之化合物 、投 -51 - l3l〇〇36 A7 B7 五、 發明説明(48 ) 藥方式、所需之處理法及所適合之病症而定。然而,有效 抑制免疫性之式(1)化合物每曰劑量通常為〇1 mg/kg,特定 言之0.3 mg/kg,更特定言之〇·5 mg/kg,及又更特定言之^ mg/kg,至冋達且包括3〇 mg/kg。用於治療呼吸道疾病時, 式(1)化合物每日劑量通常為0.001 mg/kg至3〇 mg/kg。 式(1)化合物與其醫藥上可接受之鹽可呈其本身形式使用 ’但通常呈醫藥組合物之形式投與’纟中使式⑴化合物/ =/溶合物(活性成份)與醫藥上可接受之佐藥、稀釋劑或載 植組合。依投藥模式而定,特定言之醫藥組合物將包含 〇.〇5至"重量%之活性成份,更特定言之80重量%以下: 例如曰1()至7()重量%,甚至更特定言之為5()重量%以下, 所有重量百分比均以組合物總量為基準計。 M因此’本發明亦提出-種醫藥組合物,Λ包含如上述定:《式⑴化合物或其醫藥上可接受之鹽與醫藥上可接受之 佐樂、稀釋劑或載體組合。 本發’亦提出一種製備本發明醫藥组合物之方法 =如上述定義之式⑴化合物或其醫藥上可接受之鹽與 醫柒上可接受之佐藥、稀釋劑或載體。 及:::Γ樂組合物可呈溶液、懸浮液、七氟燒氣霧劑 ,首二:“《形式局邵投與(例如:投至肺部與/或呼吸 ==膚);或呈藥鍵、膠囊、糖漿、粉末或粒劑形式全身 非:腸·經口投樂’或呈溶液或懸浮液之形式進行 或經穿皮式投藥。 次…11形式經直腸投藥, -52 本纸張尺歧財國國家操準(CNg) A4规格(2l0X297i^7 裝 訂 .線 1310036 A7 B7 發明説明(49 該化合物抑制PMA/離子黴素所刺激之周邊 增生作用之能力可採用例如:下文說明之方早核-胞 對Ρ Μ A./離子黴素所刺溆夕g]彳彳/ PMA/離子黴素所刺激PBM〇f生作用之分析法可於 平:微滴定板上進行。取化合物於二甲亞颯 、 保存液。於麵中製成50倍稀釋液,再由此溶液製Μ 列稀釋液。取Η) μ1观稀釋保存液或其卿液加至孔中*,、 使分析法之起始濃度為9·5 μΜ ’然後逐步遞減。在各孔中 添加含1^__(由單——位捐血者之人體周邊血液 製備)(RPMI 1640培養基,其中補充⑽人類血清、2福 麵《與青徽素/鏈徵素。在含此等細胞之已補充之謂 培養基(如i述)中添力口大戟二帖肖肉豆藍酸醋乙酸醋(pMA) (終濃度0.5 ng/ml)及離子黴素(終濃度5⑼ng/mi),使最終分 析體積為0..2 m卜細胞於37t之潮濕蒙氣中,於5%二氧化 碳下培-養I小時。最後6小時培養期則添加%胸答(〇 5㈣ 。測定細胞中所吸收之放射活性,作為増生作用之測定值。 在上述試驗中發現,實例化合物之iAs。值為丄X ι〇-6 M。 下列明顯實例中實例丨在上述試驗之lA5〇值為ΐ7 χ ι〇·ιο M ’實例20 之 IA50值為 5 x l〇-9Kl。 下列實例將說明本發明’除非另有說明: ⑴蒸發法係採用真空旋轉蒸發器進行,且在過濾排除殘 餘固體(如:脫水劑)後,才進行操作: … (ii)於周溫下,亦即丨8_25ΐ之範園内及惰性氣體之蒙 裝 訂 線 -53 - 1310036 A7 B7 五、發明説明(50 ) 氣下’如:氬氣或氮氣下進行操作; (iii)收量僅供說明用’並不一定為最大值; (IV)式(1)終產物之結構式係由核(通常為質子)磁共振 (NMR)及質1晋技術確I忍;質磁共振化學遷移值以δ尺度表示 ’多峰性則以下列代號表示:s,單峰;d,雙φ ; t,參峰 ;m,多峰;br,寬;q,四峰;qUin,五峰。 (v)中間物未完全判別,其純度係採用薄層層析法(丁lC) 、高效液相層析法(HPLC)、質譜儀(MS)、紅外線(IR)或 NMR分析法分析: 縮寫The disease of the Lord; and (7) cancer. „Therefore, the present invention proposes a compound of the formula (1) as defined above or a therapeutic salt of the medicinal compound for use in medicine. ^ Wan® 'The present invention proposes a compound of the formula (1) as defined above or Sauce: an acceptable salt for inhibiting T cell proliferation. Another 1: Φ * The invention proposes a compound of formula (1) as defined above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting tau cell proliferation The use of the above. In this month, the term "medical law" also includes "prevention law", unless otherwise stated, so the terms 'medical" and "medicality" should be explained. The precautionary approach should be particularly relevant to the treatment of individuals who have suffered from this particular disease or who are at increased risk of developing this particular condition. Individuals who develop this particular disease or secret risk usually include those with a family history, and they have passed the gene: testing or screening to demonstrate that it is particularly easy to develop the disease or condition. The present invention further provides a method for suppressing immunity. (eg, for cardiac therapy: species transplant rejection) 'which includes administering to the patient a medically effective amount, such as: a compound of formula (1) or a pharmaceutically acceptable salt thereof. The invention also provides a method of treating or reducing the risk of the disease in a patient suffering from or likely to suffer; aspiration, asthma or COPD, which comprises administering to the patient a medically effective amount of a formula as defined above, or A pharmaceutically acceptable salt. ^ Compounding The dosage of the above medical uses will of course depend on the compound used, the method of administration, the method of treatment, and the condition to be treated. However, the effective dose of the compound of formula (1) is usually 〇1 mg/kg, specifically 0.3 mg/kg, more specifically 55 mg/kg, and more specifically ^ mg /kg, up to 冋 and including 3〇mg/kg. For the treatment of respiratory diseases, the daily dose of the compound of formula (1) is usually from 0.001 mg/kg to 3 mg/kg. The compound of the formula (1) and its pharmaceutically acceptable salt can be used in its own form, but it is usually administered in the form of a pharmaceutical composition. The compound of the formula (1) / = / compound (active ingredient) is pharmaceutically acceptable. Accepted adjuvant, diluent or carrier combination. Depending on the mode of administration, the particular pharmaceutical composition will comprise from 〇5 to "% by weight of active ingredient, more specifically below 80% by weight: for example 曰1() to 7()% by weight, or even more Specifically, it is 5 (% by weight or less), and all weight percentages are based on the total amount of the composition. M Thus, the present invention also provides a pharmaceutical composition comprising, as defined above, a compound of formula (1) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable cola, diluent or carrier. The present invention also provides a method of preparing a pharmaceutical composition of the present invention = a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. And :::: Γ乐 composition can be a solution, suspension, sevoflurane aerosol, the first two: "" form of Shao Shao and (for example: cast to the lungs and / or breathing = = skin); or In the form of a drug bond, capsule, syrup, powder or granules, the whole body is not: intestines, orally administered or in the form of a solution or suspension or by transdermal administration. Sub-11 form of rectal administration, -52 paper Zhang Jiqi Caiguoguo National Standard (CNg) A4 Specification (2l0X297i^7 Binding. Line 1310036 A7 B7 Description of the Invention (49) The ability of this compound to inhibit the peripheral proliferation induced by PMA/ionomycin can be used, for example, as explained below. The method of analyzing the PBM〇f activity stimulated by A./Ionomycin-like g Μ . A./Ionomycin can be carried out on the flat: microtiter plate. In the dimethyl hydrazine, the preservation solution. Make a 50-fold dilution in the surface, and then prepare the dilution solution from the solution. Take the Η) μ1 observation dilution solution or its solution into the hole*, and analyze The initial concentration of the method is 9·5 μΜ 'and then gradually decreasing. Add 1^__ in each well (from the human body of a single blood donor) Blood preparation) (RPMI 1640 medium, supplemented with (10) human serum, 2 Fushou" and Qingxu/streptavidin. In the medium containing such cells (such as i), add force to the mouth肖肖豆豆蓝酸醋acetic acid vinegar (pMA) (final concentration 0.5 ng / ml) and ionomycin (final concentration 5 (9) ng / mi), so that the final analysis volume is 0.. 2 m cells in 37t of moisture In the last 6 hours of culture, the % chest answer was added (〇5 (4). The radioactivity absorbed in the cells was measured as the measured value of the twin effect. In the above experiment, the example was found. The iAs of the compound has a value of 丄X ι〇-6 M. In the following obvious example, the 丨50 value of l7 〇 ι〇·ιο M 'Example 20 in the above test is 57 〇 ι〇·ιο M 'Example 20 The IA50 value of Example 20 is 5 xl 〇-9Kl. The invention will be described 'unless otherwise stated: (1) The evaporation process is carried out using a vacuum rotary evaporator and the operation is carried out after filtration to remove residual solids (eg dehydrating agent): (ii) at ambient temperature, ie丨8_25ΐ之园 and inert gas binding line -53 - 1310036 A7 B7 5. Description of the invention (50) Under the gas, such as: operation under argon or nitrogen; (iii) The amount of the product is only for the description 'not necessarily the maximum value; (IV) the structural formula of the final product of formula (1) The nuclear (usually proton) magnetic resonance (NMR) and mass-induced techniques are forbearance; the mass spectral chemical migration values are expressed in δ scales. 'Multimodality is represented by the following codes: s, singlet; d, double φ ; t, ginseng; m, multimodal; br, broad; q, four peaks; qUin, five peaks. (v) intermediates are not fully discriminated, the purity is by thin layer chromatography (butyl lC), high performance liquid phase Analysis by Chromatography (HPLC), Mass Spectrometry (MS), Infrared (IR) or NMR Analysis: Abbreviation
2,3-·—乱-5,6 -二吼基-1,4 -苯並自昆 DDQ2,3-·- disorder-5,6-dimercapto-1,4-benzoin from Kunming DDQ
二甲基甲醯胺 DMFDimethylformamide DMF
間-氣過氧苯甲酸 mCPBAM-benzoic acid mCPBA
四氫呋喃. , THF 實例1 基異崎唑啶-2-某鞠基1-3甲基-1-(異-丁某)-6-(4-4 — 啉基甲基)遗吩並「2.3-dl嘧啶-2.4ΠΗ.3Η)-二酮Tetrahydrofuran. , THF Example 1 Isoazolidine-2-anthracepin 1-3 methyl-1-(iso-butyl)-6-(4-4-morpholinylmethyl) remnant and "2.3- Dl-pyrimidine-2.4ΠΗ.3Η)-dione
OHOH
a) (S)2-「4-羥基異噚唑啶-2-某1羰基苯甲酸甲酯 添加三乙胺(0.28 ml)至氮氣下,含N-羥基酞醯亞胺(5.00 -54 - 本纸張尺度適用中國國家標準(CMS) A4規格(210X 297公釐)a) (S)2-"4-Hydroxyisoxazolidine-2-one methyl benzobenzoate added with triethylamine (0.28 ml) to nitrogen, containing N-hydroxy quinone imine (5.00 -54 - This paper scale applies to the Chinese National Standard (CMS) A4 specification (210X 297 mm)
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.線 1310036 A7 B7 五、發明説明(51 ) g)與(R)-( + )-表氯醇(2.40 ml)之無水二呤烷(10叫)溶液中。 混合物於50°C下攪拌48小時,再添加(R)-( + )_表氣醇(〇 24 ml)與三乙胺(0.28 ml),續於50°C下攪拌24小時。添加甲醇 (10 ml)與三乙胺(4.27 ml) ’續於50°C下攪拌2小時。混合物 減壓蒸發,殘質溶於飽和碳酸氫鈉溶液(100 ml)中,以乙 酸乙酯萃取(6 X 100 ml)。合併之有機萃液經無水硫酸鋼脫 水’過濾,減壓蒸發。殘質自乙酸乙酯中再結晶,產生小 標題化合物(3.4 g)。MS (ESI) 252 [M+H]+。δ ,,, nCDci3 -3.66 (1H, d,br),3.79 (1H, d,br),3.89-3.99 (IH, m),3 99 4 1〇 (1H, m), 4.74-4.81 (1H, m), 7.46 (1H, d), 7.49 (lH t) 7 62 (1H,t),7_99 (1H,d)。 b) (S)-4-異g等吐峻醇鹽酸鹽 添加鹽酸(4M,15 ml)至步驟a)產物(1.87 g)中,落液回流 加熱3小時。混合物冷卻至室溫,過濾及減壓蒸發。殘質 自丙-2-醇中再結晶,產生小標題化合物之白色針狀物(〇 78 g) ° δ 'Hdmso 3.35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd), 4.07 (1H,d),4.78-4.81 (1H,m)。 ¢) 1,2,3,4-四氣-3-甲某-1-i異丁基)-2.4-二 It 代 4 略並「2.3_dl 嘧啶-5-斿酸乙酯 取6-氫硫基-3·甲基-1-(異丁基)-嘧啶-2,4(1H,3H)-二酮 (49.5 g)溶於無水DMF (900 ml)中,添加溴丙酮酸乙酯(30 ml) ,然後攪拌添加無水碳酸鉀(1 5.95 g)。混合物於室溫下攪 拌5小時後,倒至水(5L)中。水溶液經稀鹽酸酸化後,以乙 酸乙酯徹底萃取。有機萃液脫水(MgS04),於高度真空下Line 1310036 A7 B7 V. INSTRUCTIONS (51) g) In a solution of (R)-(+)-epichlorohydrin (2.40 ml) in anhydrous dioxane (10 Å). The mixture was stirred at 50 ° C for 48 hours, and (R)-(+)-epidol (〇 24 ml) and triethylamine (0.28 ml) were added, and the mixture was stirred at 50 ° C for 24 hours. Methanol (10 ml) and triethylamine (4.27 ml) were added and the mixture was stirred at 50 ° C for 2 hours. The mixture was evaporated under reduced pressure. EtOAc (EtOAc m. The combined organic extracts were dehydrated with anhydrous sulfuric acid steel and filtered. Residue was recrystallized from ethyl acetate to give the subtitle compound (3.4 g). MS (ESI) 252 [M+H]+. δ , , , nCDci3 -3.66 (1H, d, br), 3.79 (1H, d, br), 3.89-3.99 (IH, m), 3 99 4 1〇(1H, m), 4.74-4.81 (1H, m), 7.46 (1H, d), 7.49 (lH t) 7 62 (1H, t), 7_99 (1H, d). b) (S)-4-isog and other succinyl alcohol hydrochloride Hydrochloric acid (4M, 15 ml) was added to the product of step a) (1.87 g), and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature, filtered and evaporated under reduced pressure. The residue was recrystallized from propan-2-ol to give a white powder of the subtitle compound (〇78 g) ° δ 'Hdmso 3.35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd) , 4.07 (1H, d), 4.78-4.81 (1H, m). ¢) 1,2,3,4-tetraqi-3-methyl-1-i-isobutyl)-2.4-di It generation 4 slightly and "2.3_dl pyrimidine-5-decanoic acid ethyl ester to take 6-hydrogen sulfur Base-3·methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (49.5 g) was dissolved in anhydrous DMF (900 ml), and ethyl bromopyruvate was added (30) Anhydrous potassium carbonate (1.95 g) was added with stirring. The mixture was stirred at room temperature for 5 hours and then poured into water (5 L). The aqueous solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. Dehydration (MgS04) under high vacuum
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__ - 55 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明說明(S2 ) j 热發’留下半固體物質。取一部份此咩固體物質(24 g)溶 於二氯甲烷(5〇〇 ml)中,於氮蒙氣下,在冰浴中冷卻。在 充分攪拌下’緩緩添加四氯化鈦(13.5 ml)。反應混合物於 冰浴中攪拌I小時後,於室溫下攪拌3小時。反應混合物在 激烈攪掉下緩緩倒至冰水(1.5L)中’所得懸浮液以二氣甲 燒萃取。脫水後’真空排除有機溶劑,殘質層析(Si〇2n : 1 乙酸乙醋-異己烷),產生小標題化合物之淺黃色固體15 g ° δ lHcDci3 1.0 (6H, d),1.4 (3H,t),2.31-2.45 (1H, m),3·4 (3H’ s),3·8 (2H,d),4 4 (2H,q),7 28 (1H,s)。 幻四氫_-6-[~與基(4-4·»林基、甲基1-3-甲某:丁某L 分並「2_3-dl嘧啶-5-游酸乙酯 在1小時内添加含二異丙基胺化經(5.52 g)之無水THF (80 ml)溶液至-78。(3與氮氣下,含步驟c)產物(8.02 g)與4-»奎p林 叛基搭(8..12 g)之無水THF (80 ml)溶液中。混合物於-78°C 下撥拌1小日争後’添加冰醋酸(丨〇 ml)中止反應,然後使之 回升室·溫―.以飽和碳酸氫鈉溶液(1〇〇 ml)稀釋,以乙酸乙 醋(2 X 1〇〇 mi)萃取。合併之萃液經硫酸鎂脫水,過濾,真 空濃縮。殘質經管柱層析法純化,以3 : 2乙酸乙酯/異己烷 溶離’產生小標題化合物之白色固體(7.35 g)。MS (ESI) 468 [M+H]+。δ 巾⑺⑶ 0.85 (3H,d),0.88 (3H,d),1.43 (3H, t), 2.10-2.16 (1H, m),3.38 (3H, s), 3.49 (1H, dd), 3.61 (1H, s, br), 3.71 (1H, dd), 4.48 (2H, quartet), 6.78 (1H, s), 7.52 (1H, t), 7.72 (1H, t), 7.83 (1H, d), 7.90 (1H, d), 8.17 (1H, d), 9.02 (1H,d)。 -56 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱:) 1310036 A7 B7 五、發明説明(53 ^1^~2^^^1^基-1-(異丁基)-2.4-二笥伙-6-(4-崦呲其 密啶-5-斿酸乙酯 添加二氣乙酸奸(3.33 ml)至室溫與氮氣下,含步驟d)產 物(7.34 g)與二乙胺(6.56 ml)之無水THF (150 ml)溶液中, 混合物攪拌1 5分鐘,添加1 〇% pd/c (5〇〇爪幻,混合物於} 巴下氯化20小時。經寅氏鹽過濾’依序以飽和碳酸氫鈉溶 液(150 ml)及乙酸乙酯(3〇〇爪丨)洗滌。有機物以乙酸乙酯 U 50 ml)萃取,合併之萃液經硫酸鎂脫水,過濾及減壓濃 縮]殘貝經官柱層析法純化,以1 : 1 : 1乙酸乙酯/異己烷 ,令離,產生小標題化合物之固體(5·9〇幻。MS (ESi) 452 [Μ + Η]+ 〇 δ 'Hcdcs 0.90 (6H, d), 1.37 (3H, t), 2.10-2.16 (1H, m), 3.39 (3H, s), 3.64 (2H, d), 4.45 (2H, q), 4.61 (2H, s), 7.29 (1H, d), 7.60 (1H, t), 7.75 (1H, t), 8.11 (1H, d), 8.16 (1H, d), 8.89 (lH,d)。 ’ 四氫-?二^_1:(吳 丁卷)-2,4二^代_6_(4_ _甲基吩~並「2,3-dl嘧咗-5-斿酸麵 - 取含步驟e)產物(5.89 g)之THF (15〇 ml)與甲醇(23 ml)溶 液,於氬氡下經過重復抽氣及氮氣沖刷處理而脫氣。添加 1M氫氧化鈉(18 ml)’混合物攪拌18小時。過濾收集所得沉 澱固體,以THF洗滌,真空乾燥,產生小標題化合物之固 體(5.06 g)。MS (ESI) 424 [Μ + ΗΓ。S 丨%5〇 0.81 (6H, d) 2.10-2.15 (1H, m), 3.20 (3H, s), 3.56 (2H, d), 4.56 (2H, s)[ 7.52 (1H, dd), 7.57 (1H, td), 7.74 (1H, td), 8.〇〇 (iH, dd),8.83 (1H,d)。 , ,· __ - 57 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐)__ - 55 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (S2) j Hot hair leaves a semi-solid substance. A portion of this hydrazine solid (24 g) was dissolved in dichloromethane (5 mL) and cooled in an ice bath under nitrogen. Titanium tetrachloride (13.5 ml) was slowly added with sufficient stirring. The reaction mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 3 hr. The reaction mixture was slowly poured into ice water (1.5 L) under vigorous agitation. The resulting suspension was extracted with a second gas. After dehydration, the organic solvent was removed in vacuo, and residue chromatography (Si </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; t), 2.31-2.45 (1H, m), 3·4 (3H' s), 3·8 (2H, d), 4 4 (2H, q), 7 28 (1H, s). Magic tetrahydro -6-[~ with base (4-4·» 林基, methyl 1-3-甲某: 丁某L分和"2_3-dl-pyrimidine-5-acid ethyl ester in 1 hour Add a solution of diisopropyl amination (5.52 g) in anhydrous THF (80 ml) to -78. (3 with nitrogen, containing step c) product (8.02 g) and 4-»奎普林叛基(8..12 g) in anhydrous THF (80 ml). Mix the mixture at -78 °C for 1 day, then add glacial acetic acid (丨〇ml) to stop the reaction, then bring it back to the room. - diluted with saturated sodium bicarbonate solution (1 mL), extracted with ethyl acetate (2 X 1 〇〇mi). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purified by <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; (3H,d), 1.43 (3H, t), 2.10-2.16 (1H, m), 3.38 (3H, s), 3.49 (1H, dd), 3.61 (1H, s, br), 3.71 (1H, dd ), 4.48 (2H, quartet), 6.78 (1H, s), 7.52 (1H, t), 7.72 (1H, t), 7.83 (1H, d), 7.90 (1H, d), 8.17 (1H, d) , 9.02 (1H,d). -56 - This paper Applicable to China National Standard (CNS) A4 specification (210 x 297 public love:) 1310036 A7 B7 V. Invention description (53 ^1^~2^^^1^ base-1-(isobutyl)-2.4-two笥 -6-6-(4-崦呲其密pyridine-5-decanoic acid ethyl ester was added with dioxoacetic acid (3.33 ml) to room temperature under nitrogen with step d) product (7.34 g) and diethylamine ( 6.56 ml) in anhydrous THF (150 ml), stir the mixture for 15 minutes, add 1 〇% pd/c (5 〇〇 claw magic, the mixture is chlorinated under the bar for 20 hours. Filtered by 寅 salt) The organic layer was extracted with ethyl acetate (50 ml), and the combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 1:1:1 ethyl acetate/isohexane to give the title compound as a solid (5·9 illusion. MS (ESi) 452 [Μ + Η]+ 〇δ 'Hcdcs 0.90 (6H, d), 1.37 (3H, t), 2.10-2.16 (1H, m), 3.39 (3H, s), 3.64 (2H, d), 4.45 (2H, q), 4.61 ( 2H, s), 7.29 (1H, d), 7.60 (1H, t), 7.75 (1H, t), 8.11 (1H, d), 8.16 (1H, d), 8.89 (lH, d). 'tetrahydro-?2^_1: (Wu Ding)-2,4二^代_6_(4_ _Methylphene~ and "2,3-dl-pyrimidin-5-decanoic acid - take step e The product (5.89 g) in THF (15 ml) and methanol (23 ml) was degassed under repeated argon and nitrogen flushing under argon. Add 1 M sodium hydroxide (18 ml). The resulting precipitated solid was collected by EtOAc (EtOAc m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (1H, m), 3.20 (3H, s), 3.56 (2H, d), 4.56 (2H, s)[ 7.52 (1H, dd), 7.57 (1H, td), 7.74 (1H, td), 8. 〇〇(iH, dd),8.83 (1H,d). , ,· __ - 57 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)
裝 訂Binding
:線 1— __ !31〇〇36 A7 B7 五、發明説明(54 羥基異呤唑啶-2-某羰某1-3甲基-14異丁基)-6-(4-邊A基甲基V寒吩並「2.3-cH嘧啶-2.4ΠΗ.3Η)-二酮.:Line 1— __ !31〇〇36 A7 B7 V. Description of the invention (54 hydroxyisoxazolidine-2-carbonylation 1-3 methyl-14 isobutyl)-6-(4-side A-based The base V is cold and "2.3-cH pyrimidine-2.4ΠΗ.3Η)-dione.
裝 在含步驟f)產物(157 mg)之二氯甲烷(5 ml)懸浮液中添加 1 -羥基笨並三唑水合物(1 08 mg),混合物攪拌1 5分鐘。添 加1-乙基-3- (3'-二甲胺基丙基)碳化二亞胺鹽酸鹽(135 mg), 續攪拌1小時。添加(S)-4-異呤唑啶醇鹽酸鹽(實例1,b項)) (69 mg)與三乙胺(147 μΐ)反應混合物攪拌18小時後,減壓 濃縮。殘質經管柱層析法純化,以異己烷/乙酸乙酯溶離(梯 度10-100%),產生標題化合物之固體(丨36 mg)。MS (APCI) 495 [M + H]+。δ 士⑽如 0.80-0.90 (6H,m),2.03-2.17 (1H,m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3.55-3.68 (3H, m), 3.70-4.13 (3H, m), 4.52-4.68 (2.4H, m), 4.78-4.81 (0.6H, m), 5.50 (0.4H, d),5.54 (0.6H, d), 7.42 (0.4H, d), 7.46 (0.6H, d), 7.63 (1H, t), 7-.78 (1H, t), 8.05 (1H, d), 8.24 (0.4H, d), 8.28 (0.6H, d), 8.86 (1H, d)= 實例2 -,一 -〆To a suspension of the product of step f) (157 mg) in dichloromethane (5 ml) was added <RTI ID=0.0>> 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) was added and stirring was continued for 1 hour. The reaction mixture of (S)-4-isoxazolidine hydrochloride (Example 1, item b)) (69 mg) and triethylamine (147 μM) was stirred for 18 hr. The residue was purified by column chromatography eluting with EtOAc EtOAc (EtOAc: MS (APCI) 495 [M + H]+. δ 士(10) such as 0.80-0.90 (6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3.55-3.68 (3H, m), 3.70-4.13 (3H, m), 4.52-4.68 (2.4H, m), 4.78-4.81 (0.6H, m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d), 7.46 (0.6H, d), 7.63 (1H, t), 7-.78 (1H, t), 8.05 (1H, d), 8.24 (0.4H, d), 8.28 (0.6H, d), 8.86 ( 1H, d) = instance 2 -, one - 〆
LR) 5-「4-羥基異噚唑啶-2-基藕某1-3-甲基-1-(異丁某V6-(4- 邊啉甲基V塞吩並「2.3-dl嘧啶-2.4(lH.3m-二酮.LR) 5-"4-Hydroxyisoxazin-2-ylindole 1-3-methyl-1-(isobutyl V6-(4-porphyrin methyl V-secret and 2.3-dl pyrimidine- 2.4 (lH.3m-dione.
OHOH
g)..(R)2-丨4-羥基異崎唑啶-2-基羱某1茉甲_甲酯 -58 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1310036g)..(R)2-丨4-Hydroxyisoxazolidine-2-ylindole-1 Molybdenum-methyl-58 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 1310036
依實例i a)項之製法’由紐酿亞胺與⑻(+)·表氯 醇製備。MS (ESI) 252 [Μ+ΗΓ。s lHc_ 3 66 (iH,d,㈣ 3- 79 (1H, d, br), 3.89-3.99 (1H, m), 3.99-4.10 〇Η, m), 4.74- 4.81 (1H, m), 7.46 (1H, d), 7.49 (1H, t), , 7.62 (1H, 〇, 7.99 (1 H, d)。 kLLR)·4-異噚唑咗醉鹽g祭矂 依實例1 b)項之製法,由步驟a)產物製備。δ IHdms〇3 35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd), 4.07 (1H, d), 4.78-4.81 (1H, m) ° 嗅咬-2-某1基ι·3·甲基_^邕 丁 I、A 基 V塞吩並 l~2.3-dl嘧啶-2 4r〗H.3fn-二舾 在含實例1 f項)產物(200 mg)之二氯甲烷攪拌懸浮液(8 ml)中依序添加羥基苯並三唑(9〇爪幻及丨_乙基·3_(3,_二甲胺 基丙基)碳化二亞胺鹽酸鹽(128 mg)。15分鐘後,添加(R)_ 4- 異$嗤啶踔鹽酸鹽(84 mg)與三乙胺(0.093 ml),續攪拌18 小時。所胥混合物經矽石管柱層析法純化,.以.乙酸乙酯/甲 醉(19 : 1)溶離,產物與醚研磨,產生標題化合物之白色粉 末(92 mg)。MS (APCI) 495 [Μ+Η]+。δ 咕咖〇 〇 8〇 〇 9〇 (6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3- 55-3.68 (3H, m), 3.70-4.13 (3H, m),4.52-4.68 (2.4H, m), 4- 78-4.81 (0.6H. m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d), 7.46 (0.6H, d), 7.63 (1H, t), 7.78 (1H, t), 8.05 (1H, d),8.24 (0.4H, d), 8.28 (0.6H,d), 8.86 (1H, d)。 實例3 -59 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7B7 五、發明説明(56 ) (S)6-丨4,5-二氣-2二甲基lH-咪唑-1-某甲某l-5_「4-羥基-2-吳°号°ϋ..基羰基.1二3 某-1 -(異丁某塞吩並f 2,3 - d 1嘧啶 -2.4( 1H.3H)-二酮According to the method of the example i a), it was prepared from neoprene and (8) (+) epichlorohydrin. MS (ESI) 252 [Μ+ΗΓ. s lHc_ 3 66 (iH,d,(iv) 3- 79 (1H, d, br), 3.89-3.99 (1H, m), 3.99-4.10 〇Η, m), 4.74- 4.81 (1H, m), 7.46 ( 1H, d), 7.49 (1H, t), , 7.62 (1H, 〇, 7.99 (1 H, d). kLLR)· 4-isoxazole 咗 drunk salt g sacrifice according to the method of Example 1 b), Prepared from the product of step a). δ IHdms〇3 35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd), 4.07 (1H, d), 4.78-4.81 (1H, m) ° Sniff bite -2-1 1 ·3·Methyl _ 邕 I I, A base V phenophene and l~2.3-dl pyrimidine-2 4r〗 H.3fn-dioxin stirred in dichloromethane containing the product of Example 1 f) (200 mg) Hydroxybenzotriazole (9〇Claw and 丨_ethyl·3_(3,-dimethylaminopropyl) carbodiimide hydrochloride (128 mg) was added sequentially to the suspension (8 ml). After 15 minutes, (R)_4-iso-(anthracene hydrochloride) (84 mg) and triethylamine (0.093 ml) were added and stirred for 18 hours. The mixture was purified by silica gel column chromatography. The product was dissolved in ether to give the title compound as a white powder (92 mg). MS (APCI) 495 [Μ+Η]+. δ 咕 〇〇 〇〇 8 〇〇9〇(6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3- 55-3.68 (3H, m), 3.70-4.13 ( 3H, m), 4.52-4.68 (2.4H, m), 4- 78-4.81 (0.6H.m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d) , 7.46 (0.6H, d), 7.63 (1H, t), 7.78 (1H, t), 8.05 (1H, d), 8.24 (0.4H, d), 8.28 (0.6H, d), 8.86 ( 1H, d) Example 3 -59 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7B7 V. Invention description (56) (S) 6-丨4,5-two gas -2 dimethyl lH-imidazole-1-one a certain l-5_"4-hydroxy-2-吴°°°ϋ..ylcarbonyl.1二3 某-1 -(isobutylene phenanthrene and f 2 ,3 - d 1 pyrimidine-2.4( 1H.3H)-dione
装 5·)__1,2,3,4-四風-3}互^甲某_ι_(異丁基)-2,4-二氣代-碟吩並 『2,3-(11-嘧啶-5-羧酸甲^Packed with 5·)__1,2,3,4-four winds-3} mutual ^A _ι_(isobutyl)-2,4-digaso-disc and 2,3-(11-pyrimidine- 5-carboxylic acid methyl ^
取6-氫硫基-3-甲基-1-(異丁基)_嘧啶_2,4( 1H,3H)-二酮(50 g) 溶於含乙酸鈉(95.6 g)之水(1.5L)溶液中,攪拌滴加3-溴-2-氧代-丁酸甲酯(44.6 g)。於室溫下攪拌1小時後,以乙酸乙 酯萃取混合物。有機溶液以鹽水洗滌,脫水(MgS04),蒸 發,留下庙狀物。此油狀物(75.1 g)溶於二氯呷烷(800 ml) 中,於冰浴中’在氮蒙氣下冷卻。在充分攪拌緩緩滴加四 氯化鈦(43.3 ml)。反應混合物於冰浴中攪拌1小時後,於室 溫下攪拌3小時。反應混合物在激烈攪拌下緩緩倒至冰·水 (2L)中’所得懸浮液以二氣曱烷萃取。脫水後,真空排除 有機溶劑,殘質層析(Si02/1 : 1乙酸乙酯-異己烷),產生小 標題化合物之淺黃色固體42 g。與異己烷研磨,產生白色 粉末。δ 'Hcdcu 0.98 (6H, d),2.23-2.41 (1H,m),2.46 (3H, s),3.4 (3H,s),3.75 (2H,d),3.96 (3H,s)。 -60 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(57 ) r b) 6-(溴甲基)-1,2,3,4^四新_3-甲基-14異丁基)-2.4-二氩代-p塞吩並|"2,3-dl-p密α定-5-翱醢y酿 取含步驟a)產物(1〇 §)與N_溴琥珀醯亞胺(5.74 g)之氯仿 (350 ml)溶液於鎢絲燈照射下回流4小時。溶液經水、飽和 碳酸氫納溶液、及鹽水依序洗滌。有機層經硫酸鎂脫水,Take 6-hydrothio-3-methyl-1-(isobutyl)-pyrimidine_2,4( 1H,3H)-dione (50 g) dissolved in water containing sodium acetate (95.6 g) (1.5 In the solution of L), methyl 3-bromo-2-oxo-butyrate (44.6 g) was added dropwise with stirring. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate. The organic solution was washed with brine, dehydrated (MgS04), and evaporated to leave a mixture. This oil (75.1 g) was dissolved in dichloromethane (800 ml) and was cooled in a cold bath. Titanium tetrachloride (43.3 ml) was slowly added dropwise with thorough stirring. The reaction mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 3 hr. The reaction mixture was slowly poured into ice water (2 L) with vigorous stirring. The resulting suspension was extracted with dioxane. After dehydration, the organic solvent was evaporated in vacuo to give crystals eluted eluted elut elut elut elut elut elut It was ground with isohexane to give a white powder. δ 'Hcdcu 0.98 (6H, d), 2.23 - 2.41 (1H, m), 2.46 (3H, s), 3.4 (3H, s), 3.75 (2H, d), 3.96 (3H, s). -60 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (57) rb) 6-(Bromomethyl)-1,2,3,4^ Tetramethyl _3-methyl-14 isobutyl)-2.4-di-argon-p-phene-pyrene|"2,3-dl-p-[alpha]--5-翱醢y brewing product containing step a) (1〇§) and N_bromosuccinimide (5.74 g) in chloroform (350 ml) were refluxed for 4 hours under a tungsten lamp. The solution was washed sequentially with water, saturated sodium bicarbonate solution, and brine. The organic layer is dehydrated by magnesium sulfate.
過濾與真空濃縮。殘質經矽石層析法純化,以異己烷:醚 (1 : 1)溶離,產生小標題化合物之白色粉末(8.29 g)。MS (APCI) 390/39 1 [M + H]+。δ 'HcDcnl.OO (6H,d), 2.31 (1H, septet),3.39 (3H,s),3.76 (2H,dd),3.99 (3H,s),4·66 (2H,s)。 c) 6-「4,5-二氯-2 -甲基-1H-呔唑基甲摹1-1.2.3.4-四氣-3-甲 基-1-(異丁一基)-2,4-二氣代4吩並|~2.3-dl-嘧啶-5-翔酸甲酯 滴加4,5-二氣-2-甲基咪唑(1.3 g)之無水四氫呋喃(20 ml) 溶液至室溫與氮氣下,含氫化鈉(0.34 g,60%)之無水四氫 呋喃(20 ml)溶液中。15分鐘後’滴加含步驟b)產物(3.35 g) 之無水四氫呋喃(20 ml)溶液,反應於室溫下攪拌3小時。: 溶液倒—至…水中’以乙酸乙酯萃取。合併之萃液經硫酸鎂脫 一 水’過濾’真空濃縮。殘質經急驟矽石層析法純化,以梯 度5 0-1 00%乙酸乙酯之異己烷溶液溶離,產生小標題化合 物之白色固體(2.28 g)。MS (APCI) 459/460 [M + H]+。δ 'Hcdcij 0.97 (6Η, d), 2.26 (1H, septet), 2.38 (3H, s), 3.39 (3H, s), 3.73 (2H, d),3.99 (3H,s), 5.26 (2H,s)。 d) 64(4,5-二氯-2-甲基-1H-咪唑-1-基)甲某 M.2.3.4·四 i. -3-甲基-1-(異丁基)-2.4-二氧代嘍吩並「2.3-dl-嘧啶-5-羧酸 . 依序添加氫氧化鈉(7.3 ml 1 Μ水溶液)及甲醇(4 ml)至含步 -61 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐) 1310036 A7 B7 五、發明説明(58 ) r 驟C)產物(2.2 8 g)之四氫呋喃(50 ml)溶液中,於室溫下攪拌 3小時。溶液減壓濃縮。殘質加水稀釋,以乙酸乙g旨萃取 。合併之萃液經较酸鎂脫水,過濾,真空濃縮。殘質經急 驟矽石層析法純化,以梯度2-5%乙醇之二氣甲烷溶液溶離 ,產生小標題化合物之白色固體(1.68 g)。MS (APCI) 445/447 [M + H]+。δ hcDc" 0.96 (6H,d),2.22 (1H, septet), 2.37 (3H, s), 3.51 (3H, s), 3.78 (2H, d), 5.78 (2H, s), 15.51 (1 H, br_s) 0 e) 64(4,5-二氯-2-甲基-1H-咪唑-1-基)甲某 l-5-「4-(SV衮某-2-異哼唑啶某羰基1 - 3 -甲基-1 - ί異丁基V裳吩並「2.3 - d 1嘧啶 -2,4ΠΗ,3Η)-二酮 依實例1 g)項之製法,製備標題化合物。MS (APCI) 516/518 [M + H]+。δ 'Hcdch 0.98 (6H, dd); 2.29 (1H, septet); 2.39 (3H, s); 3.38 (3H, s); 3.54 (1H, dd); 3.66-3.70 (1H, m); 3.80-3.87 ( 1H, m); 4.04-4.10 (2H, m); 4.56 (1H, d); 4.70-4.75 : (1H, m); 4:92 (1H,d); 5.13-5.30 (2H,m)。 — 實例4 (S) 5-「4-羥基異哼唑啶-2-基羰基1-3-甲基-1-(異丁基)-6-(4-崦啉基羰基V塞吩並[2,3-dl嘧啶-2,4(1H,3H)-二酮Filter and vacuum to concentrate. The residue was purified by EtOAc (EtOAc) elute MS (APCI) 390/39 1 [M + H]+. δ 'HcDcnl.OO (6H,d), 2.31 (1H, septet), 3.39 (3H, s), 3.76 (2H, dd), 3.99 (3H, s), 4.66 (2H, s). c) 6-"4,5-Dichloro-2-methyl-1H-carbazolylhydrazide 1-1.2.4.3-tetraki-3-methyl-1-(isobutyl-yl)-2,4 - Dihydrogen 4 pheno-[~2.3-dl-pyrimidine-5-cyanate methyl ester dropwise addition of 4,5-di-2-methylimidazole (1.3 g) in anhydrous tetrahydrofuran (20 ml) solution to room temperature Under a nitrogen atmosphere, a solution of sodium hydride (0.34 g, 60%) in anhydrous tetrahydrofuran (20 ml). After 15 minutes, a solution of the product of step b) (3.35 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise. Stir at room temperature for 3 hours.: The solution is poured into -water. The mixture is extracted with ethyl acetate. The combined extracts are taken from <RTI ID=0.0> 5 0-1 00% ethyl acetate in hexanes to give the title compound as a white solid (2.28 g). MS (APCI) 459/460 [M + H] + δ 'Hcdcij 0.97 (6Η, d) , 2.26 (1H, septet), 2.38 (3H, s), 3.39 (3H, s), 3.73 (2H, d), 3.99 (3H, s), 5.26 (2H, s) d) 64 (4, 5 -dichloro-2-methyl-1H-imidazol-1-yl)methyl M.2.3.4. tetra-i--3-methyl-1-(isobutyl)-2.4-dioxoindole "2.3-dl-pyrimidine-5-carboxylic acid. Add sodium hydroxide (7.3 ml 1 Μ aqueous solution) and methanol (4 ml) to step-61 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Invention description (58 r) The product (2.28 g) in tetrahydrofuran (50 ml) was stirred at room temperature for 3 hr. The solution was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. Desiccated with magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting eluting elut elut ) 445/447 [M + H]+.δ hcDc" 0.96 (6H,d), 2.22 (1H, septet), 2.37 (3H, s), 3.51 (3H, s), 3.78 (2H, d), 5.78 (2H, s), 15.51 (1 H, br_s) 0 e) 64(4,5-Dichloro-2-methyl-1H-imidazol-1-yl) A certain l-5-"4-(SV衮a certain 2-isoxazole carbonyl group 1 - 3 -methyl-1 - isopropyl isobutyl V is exemplified by "2.3 - d 1 pyrimidine-2, 4 ΠΗ, 3 Η)-dione according to the example 1 g) The title compound was prepared by the method. MS (APCI) 516/518 [M + H]+. δ 'Hcdch 0.98 (6H, dd); 2.29 (1H, septet); 2.39 (3H, s); 3.38 (3H, s); 3.54 (1H, dd); 3.66-3.70 (1H, m); 3.80-3.87 (1H, m); 4.04-4.10 (2H, m); 4.56 (1H, d); 4.70-4.75: (1H, m); 4:92 (1H, d); 5.13-5.30 (2H, m). - Example 4 (S) 5-"4-Hydroxyisoxazin-2-ylcarbonyl1-3-methyl-1-(isobutyl)-6-(4-purinylcarbonylcarbonyl V-pheno[ 2,3-dl pyrimidine-2,4(1H,3H)-dione
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(59 ) : 依Λ例1 g)項之製法,由實例1 b)項產物(115 mg)與實例1 〇項產物(342 mg)製備’然後使產物曝露在空氣中18小時。 粗產物經逆相製備性HpLC純化,以乙酸銨/乙腈水溶液梯 度落離後,與醚研磨,產生標題化合物之白色粉末(22 mg) ° MS (APC1) 509 [Μ + Η]+。*δ 1_(130。〇) 0.97 (6H,d), 2.23-2.33 ( 1 H, m), 2.68-2.95 (2H, m), 3.23 (3H, s), 3.60 (1H, dd), 3.65-3.75 (1H, m); 3.81 (2H, d), 4.50 (1H, s, br), 7.56 (1H, d), 7.61 (1H, d), 7,73-7.82 (2H, m), 8.10 (1H, d), 8.97 (1 H, d) ° (*N.B物質呈幾何異構物之混合物,因此室溫下 測得之NMR複雜,但在加溫下簡化)。 實例5 (S) 5-[4-幾基異基羰某μ3-甲某_6_「(2-甲某_m•⑷哚- 3-基)甲基1-1-(異嘧吩拔「2,3_di嘧凃_2 4Πη,3Η)-二酮This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (59): According to the method of Example 1 g), the product of Example 1 b) (115 mg And the product of Example 1 (342 mg) was prepared and then the product was exposed to air for 18 hours. The crude product was purified by reverse-phase preparative HpLC eluting with EtOAc EtOAc (EtOAc: EtOAc) *δ 1_(130.〇) 0.97 (6H,d), 2.23-2.33 ( 1 H, m), 2.68-2.95 (2H, m), 3.23 (3H, s), 3.60 (1H, dd), 3.65- 3.75 (1H, m); 3.81 (2H, d), 4.50 (1H, s, br), 7.56 (1H, d), 7.61 (1H, d), 7,73-7.82 (2H, m), 8.10 ( 1H, d), 8.97 (1 H, d) ° (*NB material is a mixture of geometric isomers, so the NMR measured at room temperature is complex, but simplified under heating). Example 5 (S) 5-[4-Alkylisoylcarbonyl]μ3-甲某_6_"(2-甲某_m•(4)哚-3-yl)methyl1-1-(isopyrimidine) 2,3_di-pyrimidine_2 4Πη,3Η)-dione
a) 1,2,3,4-四氫-3-甲某_-6-「(2-甲某-1H-W 唤-3-某)甲某 1-1-(異 丁基)-2,4-二氧代嘍吩並「2.3-dl-嘧啶-5-翔醢甲酯 取含實例3 a)項產物(7 g)與N-溴琥珀醯亞胺(4.42 g)之氣 仿(140 ml)溶液於鎢絲燈照射下回流2小時。溶液冷卻至室 溫’添加飽和碳酸氫鈉水溶液(14〇 ml)與2-甲基4丨哚(5.92 g) ’混合物迅速攪拌48小時。分層,水相以二氯甲烷(1 〇〇 ml) 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(6〇 午取。合併之有機萃液經無水硫酸鎂脫水,過濾與減壓蒸 發°殘貝經5夕石管柱層析法純化,以乙酸乙酯/異己烷(1 :3) 洛離’產生小標題化合物之淺褐色固體(6 68 g)。MS (ESI) 440 [Μ + Η] ° δ lHcD⑶ 0.87 (6H,d), 2.11-2.21 (1H,m),2.42 (3H, s), 3.38 (3H, s), 3.61 (2H, d), 3.99 (3H, s), 4.22 (2H, s), 7.08 (1H, t), 7.15 (1H, t), 7.31 (1H, d), 7.46 (1H, d), 7.91 (1H,s,br)。 m374’一^^基-6-「(2-甲某-1H-叫丨哚-V某)甲某l-1-f異 工.基)-2,4-二_至_^嘧吩並「23_€11_嘧咗-<;_鉑鹼 添加氫氧化鈉溶液(1M,13 6 ml)與甲醇(25 m丨)至含步驟 a)產物(4 g)之四氫呋喃(H)〇⑺丨)攪拌溶液中。28小時後,溶 液減壓濃縮至體積20 ml,加水(2〇〇 ml)稀釋,以醚(2 χ 1〇〇 ml)卒取/4“加濃鹽§文化水相至pH 2,以乙酸乙醋/甲醇 (19 . 1 ’ 2 X 200 mi)萃取。有機萃液經無水硫酸鎂脫水,過濾 減C β 1產生小標題化合物之白色固體(4幻。ms (esi) 426 [Μ+ΗΓ ° δ 'Hdmso 0.80 (6H, d), 1.99-2.09 tlH, m), 2.37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H,t),7_26 (1H,d), 10.96 (1H,s),14.05 〇H,s, br)。 基-6-U2-甲某-1H- 企皇土基)甲^密咬 _2.4n Η·3Η、_ 二銅 依實例1 g)項之製法,由b)項產物與(s)_4_異呤唑啶醇鹽 I策[貝例1 b)員]I備’產生標題化合物之固體。(Ap⑶ 497 [M + H]+。δ G.8(M).83 (6H,m),丨 98_2 G8 (ih,叫 -64 -a) 1,2,3,4-tetrahydro-3-methyl _-6-"(2-methyl-1H-W -3-) 1-1 1-1-(isobutyl)-2 , 4-dioxoindole "2.3-dl-pyrimidine-5-cyanium methyl ester was obtained by gas-like imitation of the product of Example 3 a) (7 g) and N-bromosuccinimide (4.42 g) 140 ml) The solution was refluxed for 2 hours under irradiation with a tungsten lamp. The solution was cooled to room temperature. A mixture of saturated aqueous sodium hydrogencarbonate (14 mL) and 2-methyl 4-indole (5.92 g) was stirred rapidly for 48 hours. Layered, the aqueous phase is methylene chloride (1 〇〇ml). This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (6 〇 取. Combined The organic extract was dehydrated with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/isohexane (1:3). Solid (6 68 g). MS (ESI) 440 [Μ + Η] ° δ lHcD (3) 0.87 (6H,d), 2.11-2.21 (1H,m), 2.42 (3H, s), 3.38 (3H, s), 3.61 (2H, d), 3.99 (3H, s), 4.22 (2H, s), 7.08 (1H, t), 7.15 (1H, t), 7.31 (1H, d), 7.46 (1H, d), 7.91 (1H, s, br) M374'一^^基-6-"(2-甲一-1H-叫丨哚-V) A certain l-1-f isoform. base)-2,4-di_ to _^ "23_€11_pyrimidine-<;_platinum base added sodium hydroxide solution (1M, 13 6 ml) and methanol (25 m 丨) to the product containing step a) (4 g) of tetrahydrofuran (H) 〇 (7)丨) Stir the solution. After 28 hours, concentrate the solution under reduced pressure to a volume of 20 ml, dilute with water (2 〇〇ml), and draw with ether (2 χ 1 〇〇ml) / 4" enriched salt § cultural water phase To pH 2, extracted with ethyl acetate / methanol (19.1 '2 X 200 mi). The organic extract was dehydrated with anhydrous magnesium sulfate, and filtered to give a white solid (4 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> m), 2.37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H, t), 7_26 (1H, d ), 10.96 (1H, s), 14.05 〇 H, s, br).基-6-U2-甲一-1H- 企皇土基)甲^密咬_2.4n Η·3Η, _ 二铜 according to the method of formula 1 g), from item b) and (s)_4_ Isoxazole alkoxide I. [Bee Example 1 b) member] I prepared a solid which gave the title compound. (Ap(3) 497 [M + H]+.δ G.8(M).83 (6H,m),丨 98_2 G8 (ih, called -64 -
1310036 A7 B71310036 A7 B7
2.37 (1H, s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.5〇 (0.5H, d, br), 5.54 (0.5H, d), 6.90 (IH, t), 6.98 (1H, t), 7.25 UH, d), 7·39 (0.5H, d), 7.43 (0.5H,d),10.91 (1H,s)。 實例6 羥基吳_咩唑啶-2·某羰某1-3 -甲基-1 -(墓丁其 LliiL-j 洛座啶-3-某、甲基 1嘧吩並 Γ2 $ -2,4ΠΗ.31·η-二酮2.37 (1H, s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.5〇(0.5H, d, br), 5.54 (0.5H, d), 6.90 (IH, t), 6.98 (1H, t), 7.25 UH, d), 7· 39 (0.5H, d), 7.43 (0.5H, d), 10.91 (1H, s). Example 6 Hydroxy Wu-oxazolidine-2·A certain carbonyl group 1-3-Methyl-1 - (Tomb, LliiL-j, carbazide-3-, methyl 1 sulfenoindole 2 $ -2,4ΠΗ .31·η-diketone
ajj,2,3,4-^_l-i-甲棊-1 (異丁基)-2,4-二氣代-6_『ηΗ j j jj2,3-bn遂-_η)甲基]嘧吩並T2,3-dl嘧咗-5_衮醢甲船 方;10C與氣氣下,在含7 -氬雜Μ丨嗓(〇.78g)之無水THF(3〇 ml) i液中滴加2.5M正丁基组(2_6 ml),所得混合物揽拌! 5 分鐘。添加1 _0M氯化鋅之醚溶液(6·61 ^1),使混合物回升 i溫,撥拌2小時。減壓排除溶劑。以無水甲苯(2〇 mi)稀 釋殘質。依序添加含實例3 b)項產物(3.14 g)之無水甲苯(1〇 ml)溶液與觸媒量之碘化鈉’混合物於氮氣下攪拌72小時。 傾析溶劑,固體殘質分佈在2N鹽酸與乙酸乙酯之間;有機 相經碳酸氫鈉鹼化’以乙酸乙酯(2 X 1〇〇 mi)萃取β合併之 本紙法尺度逋用中國属家搮準(CNS) Α4規格(210X 297公爱) 1310036 A7 ______B7 五、發明説明(62 ) r 萃液經硫酸鎂脫水’過濾與真空濃縮。殘質經管柱層析法 純化’以異己烷/乙酸乙酯(20_75〇/〇梯度)溶離。產生小標題 化合物之黃色固體(1.37 g)。MS (APCI) 427 [M+H]+。δ Hdmso 0.83 (6H, d),2.09 (1H, heptet), 3.20 (3H, s), 3.61 (2H, d), 3.86 (3H, S), 4.22 (2H, s), 7.02-7.05 (1H, m), 7.43 (1H, m),7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s,br)。 皇-3-甲基-1 (異丁基)-2.4-二氣代-6-「(丨+毗坟 基)甲基1嘍吩並「2.3-dl嘧啶-5-跆齡 依實例3步驟d)之製法’由步驟a)產物製備小標題化合物 。MS(ESI) 413 [M + H] + (S) 基異崎唑啶·2·某某ι_3_甲某j畧丁甚卜 唉-3-基)甲某略祐p 忒々 -2,4ΠΗ·3Η、-二獅 依實例1步驟g)之製法,由步驟b)產物Π50 mg),與(s)_4_ 羥基兴°号咮啶製備標題化合物(55 mg)。MS (Apci) 484 _ [M + H] 。S ^omso 0.82-0.85 (6H,m),2,03-2.13 (1H, m), 一 3-20-3.21 (3H, m), 3.53-3.68 (3H, m), 3.75-3.90 (2H, m), 4.00-4.18 (3H, m), 4.60-4.80 (1H, m), 5.50-5.55 (1H, m), 6.99-7.02 (1H, m), 7.41-7.44 (1H, m), 7.90-7.97 (1H, m), 8.18-8.20 (1H, m), 11.53 (1H, s,br) 〇 實例7 111_^11-經基異p等啥咬-2-幕甲某甲某- ΐΗ-β . !^1^1羰基1-1-(異丁基)4吩_^1^3-(11嘧咗-?|心1^1^-二獅. -66 - 本纸張尺度適用中國國家標準(CNS> A4規格(21〇x 297公釐) 1310036 A7 B7 五、發明説明(63 )Ajj,2,3,4-^_l-i- formazan-1 (isobutyl)-2,4-dioxo-6_『ηΗ jj jj2,3-bn遂-_η)methyl]sulfenophene T2,3-dl-pyrimidine-5_衮醢甲船方; 10C and gas, in a solution containing 7-argon (〇.78g) in anhydrous THF (3〇ml) i drip 2.5 M-butyl group (2_6 ml), the mixture was mixed! 5 minutes. Add 1 _0M zinc chloride ether solution (6·61 ^1), bring the mixture back to i temperature, and mix for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with anhydrous toluene (2 〇 mi). A solution containing the product of Example 3 b) (3.14 g) in anhydrous toluene (1 mL) and a mixture of sodium iodide in a solvent amount was added sequentially under stirring for 72 hours under nitrogen. The solvent was decanted, the solid residue was distributed between 2N hydrochloric acid and ethyl acetate; the organic phase was alkalized with sodium bicarbonate, extracted with ethyl acetate (2×1〇〇mi), and the combined paper size of the Chinese genus was used. Home 搮 (CNS) Α 4 specifications (210X 297 public) 1310036 A7 ______B7 V. Description of invention (62) r The extract is dehydrated by magnesium sulfate 'filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with isohexane/ethyl acetate (20-75 〇 / 〇 gradient). The subtitle compound was obtained as a yellow solid (1.37 g). MS (APCI) 427 [M+H]+. δ Hdmso 0.83 (6H, d), 2.09 (1H, heptet), 3.20 (3H, s), 3.61 (2H, d), 3.86 (3H, S), 4.22 (2H, s), 7.02-7.05 (1H, m), 7.43 (1H, m), 7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s, br). Emperor-3-methyl-1 (isobutyl)-2.4-dioxane-6-"(丨+彼墓基)methyl 1 喽 并 "2.3-dl pyrimidine-5-跆 依 according to the example 3 steps d) Method for the preparation of the subtitle compound from the product of step a) MS (ESI) 413 [M + H] + (S) oxazolidine · 2 · ι _ _ _ _ _ _ _ _ _ _ _ _ 3-base) A certain slightly p 忒々-2,4 ΠΗ·3 Η, - two lion according to the method of step 1) g), from step b) product Π 50 mg), and (s) _4_ hydroxy ° ° acridine The title compound (55 mg) was obtained. MS (Apci) 484 _ [M + H]. S^omso 0.82-0.85 (6H,m), 2,03-2.13 (1H, m), a 3-20-3.21 ( 3H, m), 3.53-3.68 (3H, m), 3.75-3.90 (2H, m), 4.00-4.18 (3H, m), 4.60-4.80 (1H, m), 5.50-5.55 (1H, m), 6.99-7.02 (1H, m), 7.41-7.44 (1H, m), 7.90-7.97 (1H, m), 8.18-8.20 (1H, m), 11.53 (1H, s, br) 〇 Example 7 111_^11 - 啥 p -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- β β β β β β β β β β β β β β β β β |心1^1^-二狮. -66 - This paper scale applies to Chinese national standards (CNS> A4 specification (21〇x 297 mm) 1310036 A7 B7 V. Invention description (63)
OHOH
添加2,3-二氯-5,6-二氰基-1,4-苯並醌(48 mg)至含實例5 c) 項產物(48 mg)之四氫呋喃/水(9 : 1,1 ml)攪拌溶液中。1小 時後,減壓蒸發溶液,殘質經逆相製備性HPLC純化,以乙 酸銨/乙腈梯度溶離後,自醚中再結晶,產生標題化合物之 固體(20 mg)。MS (APCI) 511 [M + H]+。δ 0.90 (6H, d), 2.13-2.23 (1H, m), 2.46 (3H, s), 3.23 (0.4H, s), 3.24 (0.6H, s), 3.18-3.25 (0.6H, m), 3.63.-3.93 (5H, m), 4.05-4.12 (0.4H, m), 4.56-4.62 (0.6H, m),4.70-4.76 (0.4H, m), 5.46 (1H, s, br), 7.07 (1H, t), 7.15 (IH, t), 7.39 (1H, d), 7.46-7.53 (1H, m), 12.01 (1H, s)。 實例 8 ' '一 (5)5-『4-羥基異哼唑啶-2-某耧基1-3-甲某-1-(1-甲某乙某)-6-f ( 1 Η - 口比咯並「2,3 - b 1吡啶-3 -某甲某1嘧吩並「2.3 - dl嘧啶 -2,4ΠΗ·3Η)-二酮 a) 2-甲基-5-(Ν,Ν-甲基乙胺某歧吩-3.4-二羧甲酯乙酯 取乙氣幾_.基亞甲基三苯基磷烷(33.8 g)之無水THF (200 ml)溶液’於65°C與氮氣下,經異硫氰酸異丙酯(10.1 g)處 理16小時。混合物冷卻至-78°C,添加3-溴-2-氧代-丁酸甲 酯。使反應緩緩回升室溫。於室溫下24小時後,再添如3_ -67 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(04 ) 溴-2-氧代丁酸甲酯(2.8 g),使混合物加溫至60°C 16小時。 冷卻之反應倒至水(1.5L)中,以醚萃取。脫水與蒸發後,產 生之油狀物經層析(SiO2/10 : 1異己烷-乙酸乙酯,然後5 : 1 異己烷·乙酸乙酯),產生小標題化合物(23.5 g)。δ 1HCDC13 ^23-1.35 (9H, m),2.26 (3H, s), 3.46 (1H, m), 3.82 (3H, s), 4.2 (2H,q), 7.42 (1H,br.s)。 四iu-二甲某-Ml-甲基乙基)-2.4-二氳代-嗓1 嘧啶-5-崧S§甲酯 取氰酸銀(13.5 g)懸浮於無水甲苯(90 ml)中,於氮氣下滴 加乙St氣(5.34 ml)處理,激烈揽拌30分鐘。添加含步驟a) 產物(23 g)之無水甲苯(丨5 ml)溶液,混合物攪拌72小時。添 加酿(3 60 ml),濾出不溶物,以少量醚洗務。合併之有機 溶液以飽和碳酸氫鈉溶液洗滌,脫水與蒸發。殘質經甲醇 鈉之甲醇溶液(25重量%,64 ml)於室溫下處理72小時》反 應於冰中冷卻,以三甲矽烷基氣(50.8 ml)處理,於室溫下 攪拌一 '夜·。一真空排除所有揮發物,殘質分佈在水與乙酸乙 酯之間。有機溶液脫水與蒸發後,殘質經層析(si〇2/2 : i 異己烷-乙酸乙酯,然後3 : 2異己烷-乙酸乙酯),單離出主 要成分(12.2 g)。此物質與碳酸鉀(6.95 g)及甲基碘(7.1 g)_ 起溶於無水DMF (1 50 ml)中’於室溫下72小時。混合物倒 至水(2L)中酸化,以醚萃取。以鹽水洗滌,脫水與蒸發 ’產生之固體於含乙酸乙酯(3 ml)之異己烷(2〇〇 ml)中煮滩 。冷卻時’收集淺黃色固體’乾燥’產生標題化合物(1 〇.5 g)Add 2,3-dichloro-5,6-dicyano-1,4-benzoxanthene (48 mg) to tetrahydrofuran/water (9:1,1 ml) containing the product of Example 5 c) (48 mg) ) Stir the solution. After 1 hour, the solution was evaporated under reduced pressure. EtOAc m. MS (APCI) 511 [M + H]+. δ 0.90 (6H, d), 2.13-2.23 (1H, m), 2.46 (3H, s), 3.23 (0.4H, s), 3.24 (0.6H, s), 3.18-3.25 (0.6H, m), 3.63.-3.93 (5H, m), 4.05-4.12 (0.4H, m), 4.56-4.62 (0.6H, m), 4.70-4.76 (0.4H, m), 5.46 (1H, s, br), 7.07 (1H, t), 7.15 (IH, t), 7.39 (1H, d), 7.46-7.53 (1H, m), 12.01 (1H, s). Example 8 ''-(5)5-"4-Hydroxyisoxazolidine-2-one sulfhydryl 1-3-A certain-1-(1-A certain ethyl)-6-f (1 Η - mouth倍比和"2,3 - b 1pyridine-3 - a certain methyl sulfonate "2.3 - dl pyrimidine - 2,4 ΠΗ · 3 Η)-dione a) 2-methyl-5- (Ν, Ν- Methylethylamine, a phenanthrene-3.4-dicarboxymethyl ester ethyl ester, was taken as a solution of ethane, methylenetriphenylphosphorane (33.8 g) in anhydrous THF (200 ml) at 65 ° C with nitrogen. After treatment with isopropyl isothiocyanate (10.1 g) for 16 hours, the mixture was cooled to -78 ° C, and methyl 3-bromo-2-oxo-butyrate was added. The reaction was allowed to slowly rise to room temperature. After 24 hours at room temperature, add 3_ -67 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (04) Bromo-2-oxobutyl Methyl ester (2.8 g), the mixture was warmed to 60 ° C for 16 hours. The reaction was cooled to water (1.5 L) and extracted with ether. After dehydration and evaporation, the oil was purified by chromatography (SiO2) /10: 1 isohexane-ethyl acetate, then 5:1 isohexane ethyl acetate) to give the subtitle compound (23.5 g). δ 1HCDC13^23-1.35 (9H, m), 2.26 (3H, s), 3.46 (1H, m), 3.82 (3H, s), 4.2 (2H,q), 7.42 (1H,br.s). Four iu-dimethyl-Ml-methylethyl)-2.4- Diterpene-嗓1 pyrimidine-5-嵩S§ methyl ester was obtained by suspending silver cyanide (13.5 g) in anhydrous toluene (90 ml), and adding B-St gas (5.34 ml) under nitrogen to stir vigorously. 30 minutes. Add a solution of the product of step a) (23 g) in anhydrous toluene (5 ml), and the mixture was stirred for 72 hours. Add the mixture (3 60 ml), filter out insolubles, wash with a small amount of ether. The solution was washed with saturated sodium bicarbonate solution, dehydrated and evaporated. The residue was treated with methanolic sodium methoxide (25% by weight, 64 ml) at room temperature for 72 hours. The reaction was cooled in ice to trimethylsulfonyl (50.8). Ml) treatment, stirring at room temperature for one night. A vacuum is used to remove all volatiles, and the residue is distributed between water and ethyl acetate. After dehydration and evaporation of the organic solution, the residue is chromatographed (si〇2/ 2 : i isohexane-ethyl acetate, then 3: 2 isohexane-ethyl acetate), separated from the main component (12.2 g). This material was combined with potassium carbonate (6.95 g) and methyl iodide (7.1 g). Dissolved in anhydrous DMF ( 1 50 ml) was carried out at room temperature for 72 hours. The mixture was poured into water (2 L) and acidified and extracted with ether. Wash with brine, dehydrate and evaporate the resulting solid in a solution of ethyl acetate (3 ml) in isohexane (2 mL). 'Collecting a pale yellow solid' upon drying to give the title compound (1 〇.5 g)
。δ 士⑶⑶ 1.6 (6H,d), 2.44 (3H, s),3.37 (3H,s),3.95 (3H -68 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐). δ士士(3)(3) 1.6 (6H,d), 2.44 (3H, s),3.37 (3H,s),3.95 (3H -68 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)
裝 訂Binding
.線 1310036 A7 B7 五、發明説明(65 s),4.66 (1H, br)。MS (APCI) (M++ H) 297 gLό-(溴甲基」-丨,2,3.4-四氣-3-甲基-l-(l-甲基ζ^l·2.4-二氣 代吩並「2,3-dl嘧啶-5-羧酸甲酯 依實例3 b)項之製法,由b)項產物製備,產生小標題化 合物。δ 士⑶叫 1.62-1.64 (6H,m),3.37 (3H,s), 3 99 (3H,s), 4.60-4.70 (3H,m) ,’ 3丄.丨,2,3,4-四_氫-3-甲某-1-(1-甲基乙某)-2.4-二1_^11_& 喝:並[2,3-bl^-l羞甲基),塞吩並「2,3-cn嘧啶τ品 依實例6 a)項之製法,由c)項產物製備,產生小標題化合 物。MS (ESI) 413 [M+H] + g)-..m4-四复甲基基·m^tdi-6-πΗ-吡 比咬-3-基甲基)p塞吩並『2.3_h1p密喊祿龄 依實例3 d)項之製法,由d)項產物製備,產生小標題化 合物。MS (ESI) 399 [M+H] + filg)5-[[4-後產吳哼兔啶碁1羰基某乙某 2_,3二bi.吡立:3 -基· : -2,4ΠΗ·3Η、-二獅 依實例3幻項之製法,由e)項產物製備,,產生標題化人 物。MS (APCI) 470 [Μ + ΗΓ。δ、⑽丄⑹ 42 (6h :) 3.17-3.19 (3H,m),3·32-3·42 (7H,m),4Kb (〇5h 叫 4.78-4.82 (0_·5Η,m),5.50-5·55 (1H,m),7 〇〇_7 〇3 (m m)’ 7.43-7.44 UH,m),7_95-7.99 ( 1 H,m),8 l9_82i (iH,蚧. 11.54 (1 H, s, br) 實例9 -69 -Line 1310036 A7 B7 V. Description of invention (65 s), 4.66 (1H, br). MS (APCI) (M++ H) 297 gL-(bromomethyl)-oxime, 2,3.4-tetraki-3-methyl-l-(l-methylζ^l·2.4-diode) Methyl 2,3-dlpyrimidine-5-carboxylate was prepared according to the procedure of Example 3 b), starting from the product of b) to give the subtitle compound. δ 士(3) is called 1.62-1.64 (6H, m), 3.37 (3H ,s), 3 99 (3H,s), 4.60-4.70 (3H,m) ,' 3丄.丨,2,3,4-tetrahydro-3-methyl-1-(1-methyl a)-2.4-two 1_^11_& drink: and [2,3-bl^-l shy methyl), sputum and "2,3-cn pyrimidine τ products according to the method of example 6 a), by c The product was prepared to give the subtitle compound. MS (ESI) 413 [M+H] + g)-..m4-tetramethylmethyl·m^tdi-6-πΗ-pyridyl-3-yl The base of the p-Pentene and the "2.3_h1p" is used in the preparation of the product of the item d) to produce the subtitle compound. MS (ESI) 399 [M+H] + filg)5-[ [4- post-production Wusong rabbit pyridine 碁 1 carbonyl a certain B 2_, 3 two bi. Pi Li: 3- base ·: -2,4 ΠΗ · 3 Η, - two lions according to the example 3 magic method, by e) The product is prepared to produce a titled character. MS (APCI) 470 [Μ + ΗΓ.δ, (10)丄(6) 42 (6h :) 3.17-3.19 (3H,m),3·32-3· 42 (7H,m),4Kb (〇5h is 4.78-4.82 (0_·5Η,m), 5.50-5.55 (1H,m),7 〇〇_7 〇3 (mm)' 7.43-7.44 UH, m),7_95-7.99 ( 1 H,m),8 l9_82i (iH,蚧. 11.54 (1 H, s, br) Example 9 -69 -
裝 訂Binding
本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1310036 A7 B7 五、發明説明(66 ) / (S) 544-羥某I噚唑啶-2-&锘其1-V甲某-丨-丙某-6-ΠΗ-吡咯-並 f2,3-b~|g比啶-3-基甲基)>裳吟 # 密啶-2.4Π H,3H)-二酮_ a) 6-乳硫基-3-甲基-1-丙某-P密症-2.4ilH.3H)-二嗣 取含6-氯-3 -甲基-1-丙基-嘧啶-2,4(1H,3H)-二酮(3.76 g)、 氫硫化鈉水合物(6 g)與乙醇(1 〇〇 ml)之混合物於室溫下攪 拌48小時後,真空濃縮。殘質溶於水(500 ml)中,以乙酸 乙酯(2 X 1 〇〇 ml)洗滌。水相經稀鹽酸酸化後,以乙酸乙酯 (3 X 100 ml)萃取。合併之有機相脫水(MgS04),蒸發,留 下之淺黃色固體直接用於下一個步驟。 1))1,2,3_14-四氣-3.6-二甲基-2.4-二氣代-1-丙基4吩並『2.3-(11 嘧啶-5-# S#甲酯 依實例3 a)項之製法,由a)項產物製備。δ 1.00 (3H, t), 1.81 (2H, sextet), 2.46 (3H, s), 3.39 (3H, s), 3.87- 3.90 (2H,m), 3.96 (3H,s)。 c) 6-(连甲羞>1,2,3,4-四ϋ.-3-甲某·2.4·二氧代-K丙某嘧吩 : 並「2,3-dH啶-5-羧醢甲酯 - 依實例3 b)項之製法,由b)項產物製備,產生小標題化 合物。δ 1 HeDC:l;i 1.02 (3H, t), 1.82 (2H, sextet), 3.39 (3H, s), 3.91 (2H, t),4.00 (3H, s), 4.68 (2H, s) d) 儿氫-3-甲基-2,4-二氧代比咯並 [2,3-b]说啶-3-基甲基吩並「2.3-cll嘧啶_5_淼鹼^酉旨 依實例6 a)項之製法’由c)項產物製備,產生、標題化合. 物。MS (ESI) 413 [M + H] + e) 1,2,3,4-四1二3-甲基-2,4-一氧_代二^丙某·6·Πη_吡咯並 _ - 70 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 裝 訂This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Description of invention (66) / (S) 544-Hydroxyl Ioxazolidine-2-& V-A-丨-Bing-6-ΠΗ-pyrrole-and f2,3-b~|g-pyridin-3-ylmethyl)>Sports #Midine-2.4Π H,3H)-dione _ a) 6-lactosyl-3-methyl-1-propanyl-P---2.4 ilH.3H)-diterpenoid containing 6-chloro-3-methyl-1-propyl-pyrimidine-2 A mixture of 4(1H,3H)-dione (3.76 g), sodium sulphate hydrate (6 g) and ethanol (1 mL) was stirred at room temperature for 48 hr. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×1 〇〇 ml). The aqueous phase was acidified with dilute aqueous EtOAc (EtOAc)EtOAc. The combined organic phases were dehydrated (MgS04), evaporated, and the pale yellow solid was taken directly to the next step. 1)) 1,2,3_14-tetraqi-3.6-dimethyl-2.4-di- gas-1-propyl 4-pheno-"2.3-(11 pyrimidine-5-# S# methyl ester according to Example 3 a) The preparation method of the item is prepared from the product of item a). δ 1.00 (3H, t), 1.81 (2H, sextet), 2.46 (3H, s), 3.39 (3H, s), 3.87- 3.90 (2H, m), 3.96 (3H, s). c) 6-(Lianjia Shame>1,2,3,4-Tetraquinone.-3-A.2.4.2-Dioxo-K-propyl thiophene: and "2,3-dH-pyridine-5- Carboxymethyl methacrylate - prepared according to the procedure of Example 3 b), starting from product b), yielding the subtitle compound. δ 1 HeDC: l; i 1.02 (3H, t), 1.82 (2H, sextet), 3.39 (3H , s), 3.91 (2H, t), 4.00 (3H, s), 4.68 (2H, s) d) Hydrogen-3-methyl-2,4-dioxopyrano[2,3-b Said pyridine-3-ylmethyl benzo-"2.3-cll-pyrimidine _5_ 淼 酉 酉 酉 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 ' ' ' ' ' ' ' ' ' ' ' MS MS MS MS MS MS MS ) 413 [M + H] + e) 1,2,3,4-tetra-di-2-methyl-2,4-oxo-substituted 2-propanyl·6·Πη_pyrrolo-- 70 - Ben Paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) Binding
A7 B7 1310036 五、發明説明(67 ) 「2,3-131吡啶-3-基甲基)嘧吩並[2,3-€11嘧啶-5-羧酸 依實例3 d)項之製法,由d)項產物製備,產生小標題化 合物。MS (ESI) 399 [M + H] + Π (S)5-「「4-羥基異哼唑啶-2-某1羰基1-3-甲某-1-丙基-6-ΠΗ-吡咯並「2,3-bl<啶-3-某甲基V裳吩並「2,3-dl嘧啶-2.4ilH.3HV 二二固同 依實例3 e)項之製法,由e)項產物製備,產生標題化合物 ° MS (APCI) 470 [Μ+Η]+ ° δ 'Hcocn 0.81-0.85 (3H, m), I. 55- 1.63 (2H, m), 3.20-3.21 (3H, m), 3.54-4.23 (8H, m), 4.60-4.70 (0.42H, m), 4.77-4.83 (0.58H, m),6.99-7.03 (1H, m), 7.41.7.44 (ih, m), 7.93-7.97 (1H, m), 8.19-8.20 (1H, m), II. 53 (1H, s, br) 實例10 (S) 6-「4,5-二氣-2-氣代-(2H)-嘧唑-3-某甲基l-5-「4-羥某異呤 唑啶-2-基羰基1-3 -甲基-1-(異丁某V塞吩並「2.3-dl嘧啶 -2.4ΠΗ:3Η>-二酮A7 B7 1310036 V. Description of the invention (67) "2, 3-31 pyridin-3-ylmethyl) sulfeno[2,3-€11 pyrimidine-5-carboxylic acid according to the method of Example 3 d), Preparation of the product of d), the title compound is obtained. MS (ESI) 399 [M + H] + Π (S) 5 - "" 4-hydroxyisoxazole pyridine-2-one carbonyl 1-3-A- 1-propyl-6-indole-pyrrolo and "2,3-bl< pyridine-3-methyl-4- oxo" 2,3-dl pyrimidine-2.4 ilH.3 HV di-solids example 3 e) Prepared by the product of item e) to give the title compound: MS (APCI) 470 [Μ+Η]+ ° δ 'Hcocn 0.81-0.85 (3H, m), I. 55- 1.63 (2H, m), 3.20-3.21 (3H, m), 3.54-4.23 (8H, m), 4.60-4.70 (0.42H, m), 4.77-4.83 (0.58H, m), 6.99-7.03 (1H, m), 7.41.7.44 (ih, m), 7.93-7.97 (1H, m), 8.19-8.20 (1H, m), II. 53 (1H, s, br) Example 10 (S) 6-"4,5-two gas-2 - gaso-(2H)-pyrazol-3-methyl-1-5-"4-hydroxyl isoxazolidine-2-ylcarbonyl-3-methyl-1-(isobutyl) And "2.3-dl pyrimidine-2.4ΠΗ: 3Η>-dione
a) 1.2,3.4-四氫-3,6-二甲某-1-〔異丁某V2,4-二氣代嘧吩並 l~2,3-d"l 口密淀-5.-游酸 __- 71 - 本紙張尺度適用中國國家標竿(CNS) A4規格(210 X 297公釐) 1310036 A7 ___ _ B7 五、發明説明(68 ) 依實例3步驟d)之製法,由實例3步驟a)產物製備小標題 化合物。MS (ESI) 297 [M+H]+。δ ^dmso 0.93 (6H,d),2.21 (1H,non),2.53 (3H,s),3.27 (3H,s),3.75 (2H,d),14.04 (ih, s) ° tLXg_)5-「4-羥基異哼唑啶-2-基羰某1-3.6-二甲某丁其、 口塞吩並「2.3-H1 嘧忒-2.4HH.3HV二酮 依實例1步驟g)之製法,由步驟a)產物製備小標題化合物 。MS (APCI) 368 [Μ+Η]+。δ WcDcn 1.00 (6H,m),2.25-2.37 (1H, m), 2.46 (3H, s), 3.39 (3H, s), 3.53-4.09 (5H, m), 4.61 (1H, d), 4.71 (1H, dt),5.05 (1H,d)。 c) 二甲某乙基)二甲矽烷氣某1異呤吔忒早 羰基1-3.6-二甲某-1-(異丁基)嘧吩並「2.3-(11嘧啶-2.4(11_3卩、. 二酮. 在含步驟b)產物(1.2 g)與咪唑(0.24 g)之二氣甲烷(20 ml) 溶液中添加第三丁基二甲矽烷基氯(0.54 g) »於周溫下攪拌 16小時後,以水洗滌混合物,有機相倒至biotage管柱上》 以0至5%甲醇之二氯甲烷溶液梯度溶離,產生小標題化合 物之無色固體(1.55 g)。δ iHcocn 0.09 (3H,s), 0.11 (3H,s), 0.90 (9H, s),0.99 (6H, d),2.30 (1H, non), 2.44 (3H, s), 3.36 (3H, s), 3.54 (1H, dd), 3.64 (1H, dd),3.75 (1H, d),3.84 (1H, dd), 3.98 (1H, dd), 4.47 (1H,dd), 4.89 (1H,dd)。 d) (S)6-(溴甲基)-5-「44(1,1-二甲某乙某)二甲矽烷氧基1異崎 唑啶-2-基羰基1-3·甲某-1-(冀丁某)-4吩並[2,3-糾嘧啶 -2,4ΠΗ,3Η)-二酮 -72 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 裝 訂a) 1.2, 3.4-tetrahydro-3,6-dimethyl-1-(isobutyl) V2,4-di-pyrimidine-l~2,3-d"l-density-5.-tour Acid __- 71 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 ___ _ B7 V. Description of invention (68) According to the method of step 3) of Example 3, by example 3 Step a) Product Preparation of the subtitle compound. MS (ESI) 297 [M+H]+. δ ^dmso 0.93 (6H,d), 2.21 (1H,non),2.53 (3H,s), 3.27 (3H,s),3.75 (2H,d),14.04 (ih, s) ° tLXg_)5-" 4-hydroxyisoxazin-2-ylcarbonyl a 1-3.6-dimethyl butyl sulfonate, and a "2.3-H1 pyridinium-2.4HH.3 HV diketone according to Example 1 step g) Step a) Product Preparation of the subtitle compound MS (APCI) 368 [Μ+Η]+. δ WcDcn 1.00 (6H, m), 2.25-2.37 (1H, m), 2.46 (3H, s), 3.39 (3H, s), 3.53-4.09 (5H, m), 4.61 (1H, d), 4.71 (1H, dt), 5.05 (1H, d) c) Dimethyl) dimethyl dimethyl sulfonate忒 Early carbonyl 1-3.6-dimethyl-1-(isobutyl)sulfono-[2.3-(11-pyrimidine-2.4 (11_3卩,. dione. In step b) product (1.2 g) with imidazole ( 0.24 g) of di-methane (20 ml) was added with tributyldimethyl dimethyl chloride (0.54 g). After stirring at ambient temperature for 16 hours, the mixture was washed with water and the organic phase was poured onto a biotage column. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 0.99 (6H, d), 2.3 0 (1H, non), 2.44 (3H, s), 3.36 (3H, s), 3.54 (1H, dd), 3.64 (1H, dd), 3.75 (1H, d), 3.84 (1H, dd), 3.98 (1H, dd), 4.47 (1H, dd), 4.89 (1H, dd) d) (S)6-(bromomethyl)-5-"44 (1,1-dimethylh-ethyl) dimethyl矽 alkoxy 1 Isoxazolidine-2-ylcarbonyl 1-3·甲一-1-(冀丁某)-4 pheno[2,3-arseny-2,4ΠΗ,3Η)-dione-72 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) Binding
*線 1310036 A7 |______ B7 五、發明説明(69 T ' 依實例3步驟b)之製法,由步驟c)產物製備小標題化合物 。5 lHcDCI3 〇·09 (3H,s),0.12 (3H,s),0.98 (9H,s),1.00 (6H, d),2.3l (1H, non), 3.36 (3H, s),3.63 (1H, dd), 3.68 (1H, dd), 3.81 (1H’ d),3·87 (lH,dd), 4_00 (1H, dd), 4.37 (1H, dd),4.64 (1H,d),4.69 (1H,d),4,87_4 92 (1H,m)。 KS)6-【(4,5-二氣^_氧代-3 唑某、甲某 1-5_「4_「n」_ 基乙基)二氧某]異崎唑啶某蒺某甲基·w異 碁)-pi 吩並二虹P密啶4(1Η·3Η)-二酮 依實例3步驟c)之製法,由步驟d)產物與4,5-二氯-2-氧 代-3(2H)-魂峻酮製備小標題化合物。δ iHcdci3 〇11 (3H,s), 0.12 (3H, s), 0.91 (9H, s), 0.98 (6H, d), 2.28 (1H, non), 3.36 (3H, s), 3.57 (1H, dd), 3.66 (1H, dd), 3.79 (1H, d),3.85 (1H, dd), '3.99 (IH, dd), 4.40 (1H, dd), 4.88 (1H, dd), 5.11 (1H, d), 5.20 (1H,d)。 fl—(S)6-『(4,5-二氣-2-菊,代_3 f2H)-嘧唑某)甲某l-5-「4-羥某畧 g号峻咬:2-茱羰某1-3-甲某_(異丁某、,¾吩並-「2.3-dl嘧嘧 -2,4HH.3HV 二酮 於氮蒙氣下,在含步驟e)產物(180 mg)之THF (5 ml)溶液 中依序添加冰醋酸(〇.1〇 ml)與1N四丁基銨化氟之THF溶液 (0.5 ml)。於周溫下16小時後,以飽和碳酸氫鈉溶液中和混 合物,以乙乙酯萃取。有機相以水洗滌,經硫酸鎂脫水 。真空濃縮,產生之白色固體經逆相HPLC純化’產生標題 化合物之白色固體(100 mg)。δ 'Hdmso 0.92 (6H,d),2.18 (1H, non), 3.20 (3H, s), 3.43-4.11 (6H, m), 4.60-4.76 (1H, m), -73 - ft 1Λ A 'Λ id -1« rn rxn ei> 1Λ -Ut / y^a τ τ\. * λ Xh ί ζ\Λ C\ ^ 007^>S· Jm ) 1310036 A7 B7 五、發明説明(7〇 ) 5.04-5.11 (2H,m),5.51 (1H,s)。 f例丨丨 @1~^11(3,&二_^_^-11^1:.喳‘4-基)甲基1-5-丨4-诲某異崎唑啶-基 ί·-卜Ιχ基-3二T羞-P塞吩並 |~2,3-dl 嘧啶-2.4ΠΗ.3Η)-*Line 1310036 A7 |______ B7 V. Inventive Description (69 T ' According to the procedure of Example 3, step b), the subtitle compound was prepared from the product of step c). 5 lHcDCI3 〇·09 (3H, s), 0.12 (3H, s), 0.98 (9H, s), 1.00 (6H, d), 2.3l (1H, non), 3.36 (3H, s), 3.63 (1H , dd), 3.68 (1H, dd), 3.81 (1H' d), 3·87 (lH, dd), 4_00 (1H, dd), 4.37 (1H, dd), 4.64 (1H, d), 4.69 ( 1H, d), 4, 87_4 92 (1H, m). KS)6-[(4,5-digas^_oxo-3 oxazole, A certain 1-5_"4_"n"_ylethyl)dioxy]isoxazolidinyl w isoindole)-pi phenanthroline P-pyridine 4 (1Η·3Η)-dione according to the procedure of Example 3, step c), from step d) product and 4,5-dichloro-2-oxo-3 (2H) - Sorbone Preparation of the subtitle compound. δ iHcdci3 〇11 (3H, s), 0.12 (3H, s), 0.91 (9H, s), 0.98 (6H, d), 2.28 (1H, non), 3.36 (3H, s), 3.57 (1H, dd ), 3.66 (1H, dd), 3.79 (1H, d), 3.85 (1H, dd), '3.99 (IH, dd), 4.40 (1H, dd), 4.88 (1H, dd), 5.11 (1H, d ), 5.20 (1H, d). Fl—(S)6-“(4,5-diqi-2-Chrysanthemum, generation _3 f2H)-pyrazole)) A certain l-5-"4-hydroxym 畧g No.: bite: 2-茱Carbonyl 1-3-A _ (isobutyl, 3⁄4 pheno-"2.3-dl ulanium-2,4HH.3HV diketone under nitrogen atmosphere, in step e) product (180 mg) Add glacial acetic acid (〇.1〇ml) and 1N tetrabutylammonium fluoride in THF (0.5 ml) in THF (5 ml). After 16 hours at weekly temperature, in saturated sodium bicarbonate solution. And the mixture was extracted with ethyl acetate. EtOAc EtOAc (EtOAc). , d), 2.18 (1H, non), 3.20 (3H, s), 3.43-4.11 (6H, m), 4.60-4.76 (1H, m), -73 - ft 1Λ A 'Λ id -1« rn rxn Ei> 1Λ -Ut / y^a τ τ\. * λ Xh ί ζ\Λ C\ ^ 007^>S· Jm ) 1310036 A7 B7 V. Description of invention (7〇) 5.04-5.11 (2H, m) , 5.51 (1H, s). f Example 丨丨 @1~^11(3,&two _^_^-11^1:.喳'4-base) methyl 1-5-丨4-诲Isoxazolidine-yl ί--diphenyl-3 T-sh-P-Pentenopyrene|~2,3-dl Pyrimidine-2 .4ΠΗ.3Η)-
二 味-4_基)甲某[_〗_里丁某 _3_ 甲基_24· 氫·»塞吩並「2 3-dl嘧啶-s_逄給 添加碳酸鉀(3.55 g)與二氣雙(三笨基膦)钴(„)(〇」g)至氮 豕氣下’含實例3 a)項產物(1 g)與2,4-戍二酮(2.64 ml)之二 氯甲烷(30 ml)攪拌溶液中。48小時後,添加肼水溶液(35% ’ 2.33 ml) ’混合物激烈攪拌卜]、時,加水(3〇 ml)稀釋,以-乙酸乙醋(2 X 60 ml)萃取。有機萃液經無水硫酸鎂脫水, 過濾’減壓蒸發。殘質經矽石管柱層析法純化,以乙酸乙 點溶離。產物溶於四氫呋喃(2〇 ^1)與甲醇(3 ml)中後,以 氫氧化鈉溶液(1 Μ,2.57 ml)處理。3天後,混合物減壓蒸發 至約5 m丨’加水(25 ml)稀釋,以乙酸乙酯(25 ml)萃取。水 相經鹽酸酸化’以乙酸乙酯(3 X 25 ml)萃取。有機萃液經. 無水硫酸鎂脫水,過濾與減壓蒸發,產生小標題化合物之 固體(0.23 g)。MS (ES【)391 [M+H]+。δ lHDMS0 0.85 (6H,d), 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐) A7 B7二味-4_基)甲某[_〗_里丁某_3_ _ _24· Hydrogen·»塞苯和"2 3-dl-pyrimidine-s_逄 to add potassium carbonate (3.55 g) and two gas Bis(trisylphosphine)cobalt („)(〇)g) to a nitrogen-containing gas containing the product of Example 3 a) (1 g) and 2,4-nonanedione (2.64 ml) of dichloromethane ( 30 ml) Stir the solution. After 48 hours, an aqueous solution of hydrazine (35% ' 2.33 ml) was added, and the mixture was vigorously stirred. The mixture was diluted with water (3 ml) and extracted with ethyl acetate (2×60 ml). The organic extract was dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by vermiculite column chromatography and dissolved in acetic acid. The product was dissolved in tetrahydrofuran (2??) and methanol (3 ml). After 3 days, the mixture was evaporated to dryness EtOAc (EtOAc) The aqueous phase was acidified with EtOAc (EtOAc) (3.times. The organic extract was dried over anhydrous MgSO.sub. MS (ES [) 391 [M+H]+. δ lHDMS0 0.85 (6H,d), this paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7
1310036 五、發明説明(71 ) 2.05-2.18 (1H,m),2.08 (6H,s),3.17 (3H, s),3.62 (2H d) 3.71 (2H,s)。 ’ ’ b) (S) 6.-.[(3,5-1 曱基-lHw比唑-4-某、甲某 口定· 2 -基1羰基—1 - 1 -異丁基-3 -甲某-g盡吩並「? · ϋ叫令|卜— -2·4Π Η.3Η)-二酮 依實例1 g)項之製法,由a)項產物(225 11^)與(s)_4_#5其 異哼唑啶鹽酸鹽{實例1 b)項}製備,產生標題化合物之^ 體(98 mg)。MS (ESI) 462 [M+H]+。δ 巾謂50 0.87 ⑽,幻 2.05-2.20 ( 1 H,m),3.19 (2H,s), 3.21 (1H,s),3.48 (0.67H d)’ 3.47-3.85 (6H,m),3.90-4.05 (0.67H, m), 4·1〇·(〇 v^.o/hi, dd), 4.57-4.78 (1H, m), 5.51 (1H,d), 12.08 (1H, s, br)。 實例1 2 裝 (S) 5- M-羥基異g号唑啶-2-某羰某ΚΙ n 「1,3,5-三甲基-11~1-11比吐-4-某甲華:1達吩:^ -2.4ΠΗ.3Η)-二酮1310036 V. INSTRUCTIONS (71) 2.05-2.18 (1H, m), 2.08 (6H, s), 3.17 (3H, s), 3.62 (2H d) 3.71 (2H, s). ' ' b) (S) 6.-.[(3,5-1 曱-lHw azole-4-, a certain thiophene-2-yl 1 carbonyl- 1 - 1 -isobutyl-3 - A-g is exemplified and "? · ϋ 令 | _ _ _ _ _ Π Η Η Η Η - - - 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例_4_#5 Its isoxazolidine hydrochloride {Example 1 b)} Preparation, the title compound (98 mg) was obtained. MS (ESI) 462 [M+H]+. δ towel 50 0.87 (10), Magic 2.05-2.20 ( 1 H,m), 3.19 (2H,s), 3.21 (1H,s), 3.48 (0.67H d)' 3.47-3.85 (6H,m),3.90-4.05 (0.67H, m) , 4·1〇·(〇v^.o/hi, dd), 4.57-4.78 (1H, m), 5.51 (1H,d), 12.08 (1H, s, br). Example 1 2 Pack (S) 5-M-hydroxyiso-g-oxazolidine-2-one carbonyl ΚΙ n "1,3,5-trimethyl-11~1-11 than 吐-4- a huahua: 1 daring: ^ -2.4 ΠΗ.3Η)-dione
OHOH
訂Order
总 a) (S) 6-(溴甲基)-5-彳4-羥某異呤唑啶-2-其^ (異 丁某)碟吩並「2.3-dl嘧啶-2·4ΠΗ.3Ην二^ 依實例3 b)項之製法,由實例10 b)項產物製備。Total a) (S) 6-(bromomethyl)-5-indole 4-hydroxyl isoxazolidine-2-y^(isobutyl) dish 吩"2.3-dl pyrimidine-2·4ΠΗ.3Ην二^ Prepared from the product of Example 10 b) according to the method of Example 3 b).
Hcdci3 -75 -Hcdci3 -75 -
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(72 1.01 (6H, d), 2.27-2.36 (1H, m), 3.39 (3H, s), 3.58 (1H, dd)„ 3.69-3.76 (2H, m),3.88 (1H, dd), 4.01 (iH, d), 4.13 (1H, dd), 4.59 (1H, d), 4.60 (IH,d),4.72 (1H, d),4·89 (1H, d)。 6) (S) 5-丨土^基異哼唑咗-2-某淼I 甲基異丁某V6_ 〔(1,3 : 5 - 基-1 Η -毗唑-4 -某、甲芊1邊吩並f 2.3 - d 1嘧啶 -2,4( 1 H,3H)-二明 添加第三丁醇鉀溶液(1Μ四氫呋喃溶液,2.99 ml)至室溫 與氮氣下’含a)項產物(100 g)與2,4_戊二酮(0.31 ml)之四氫 吱喃(20 ml)攪拌溶液中。1 8小時後,取8 ml此溶液,以甲 基肼(64 μ 1)處理,再過24小時後,混合物減壓蒸發。殘質 經逆相製備性HPLC純化,以乙酸銨水溶液/乙腈梯度溶離 後,經矽石管柱層析法,以乙酸乙酯/甲醇(24 : 1)溶離,產生 標題-化合物之固體(24 mg)。MS (ESI) 476 [Μ+Η]+。δ旧⑽呂。 0.88 (6H, d), 2.02 (3H, s), 2.08-2.18 (4H, m), 3.19 (2H, s), 3.21 (1H, s), 3.47 (0.67H, d), 3.62 (3H, s), 3.55-4.03 (6.67H, m)’ 4.10 (〇;67H,dd),4.58-4.78 (1H, m),5.52 (1H,d)。 實例13Π (_R) 6-K4,5-二f -2-甲某-1H-咪唑-1-矣)甲莘卜—5-[4-淼某著ιΑ 啶-2 -基羰某1 - 3 ·甲某_ 1 -(異丁甚吩並f 2 1 _ d 1 p密1^· -2,4(1Η·3Η、-二獅 依實例1 g)項之製法,由實例3 d)項產物與實例2 b)項產 物製備標題化合物。MS (APCI) 516/518 [M+H]+。δ 1HCdci3 0.98 (6H, dd) ; 2.29 (1H, septet) ; 2.39 (3H, s) ; 3.38 (3H, s) ; 3.54(1H, dd); 3.66-3.70 (IH, m) ; 3.80-3.87 (1 H, m); -76 - 本紙張尺度適用中鷗國家標準(CNS) A4规格(210x 297公釐〉This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (72 1.01 (6H, d), 2.27-2.36 (1H, m), 3.39 (3H, s) , 3.58 (1H, dd) „ 3.69-3.76 (2H, m), 3.88 (1H, dd), 4.01 (iH, d), 4.13 (1H, dd), 4.59 (1H, d), 4.60 (IH,d ), 4.72 (1H, d), 4·89 (1H, d). 6) (S) 5-Alumina ^isoxazole oxime-2-some 淼I methyl isobutylene V6_ [(1,3 : 5 - yl-1 Η - pyrazole-4 - one, formazan 1 side, and f 2.3 - d 1 pyrimidine-2,4( 1 H,3H)-diming, potassium tert-butoxide solution (1 Μ tetrahydrofuran) Solution, 2.99 ml) to a stirred solution of the product containing a) (100 g) and 2,4-pentanedione (0.31 ml) in tetrahydrofuran (20 ml) at room temperature under nitrogen. 8 ml of this solution was taken and treated with methyl hydrazine (64 μl). After 24 hours, the mixture was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC, eluted with aqueous ammonium acetate / acetonitrile gradient. Column chromatography on silica gel, eluting with ethyl acetate/methanol (24:1) to give the title compound as a solid (24 mg). MS (ESI) 476 [Μ+Η]+.δ旧(10)吕. 0.88 (6H, d) , 2.02 (3H, s), 2.08-2.18 (4H, m), 3.19 (2H, s), 3.21 (1H, s), 3.47 (0.67H, d), 3.62 (3H, s), 3.55-4.03 ( 6.67H, m)' 4.10 (〇; 67H, dd), 4.58-4.78 (1H, m), 5.52 (1H, d). Example 13Π (_R) 6-K4,5-dif-2-A- 1H-imidazole-1-oxime)-methylpyrazine-5-[4-淼 some ιΑ pyridine-2-ylcarbonyl one 1 -3 · A certain _ 1 - (isodin phenanthrene f 2 1 _ d 1 p The title compound was prepared from the product of Example 3 d) and the product of Example 2 b). MS (APCI) 516/518. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [M+H]+.δ 1HCdci3 0.98 (6H, dd) ; 2.29 (1H, septet) ; 2.39 (3H, s) ; 3.38 (3H, s) ; 3.54(1H, dd); 3.66-3.70 (IH, m) ; 3.80-3.87 (1 H, m); -76 - This paper size applies to the Chinese Gull National Standard (CNS) A4 specification (210x 297 mm)
装Loading
1310036 A7 B7 五、發明説明(73 ) 4.04-4.10 (2H, m) ; 4.56 (1H, d) ; 4.70-4.75 (1H, m) ; 4.92 (1H, d) ; 5.13-5.30 (2H,m)。 實例13ii) _(S) 5-『4-羥某呉崎唑啶-2-基羰某1-3 -甲基-6-ΙΎ2-甲某-1H-笨 龙咪^_L·基)甲某1-1-(異丁基Vi 吩 # f2.3-dl嘧啶-2.4ΠΗ.3Η)- 士酉同一1310036 A7 B7 V. INSTRUCTIONS (73) 4.04-4.10 (2H, m) ; 4.56 (1H, d) ; 4.70-4.75 (1H, m) ; 4.92 (1H, d) ; 5.13-5.30 (2H, m) . Example 13ii) _(S) 5-"4-Hydroxyl-oxazolidine-2-ylcarbonyl 1-3-methyl-6-oxime 2-A-1H-Bao Longmi ^_L·基) A certain 1 -1-(isobutyl Vi phen # f2.3-dl pyrimidine-2.4ΠΗ.3Η)- gentry
依貫例3 c)項之製法,由實例3 b)項產物與2-甲基苯並咪 a)J,2t3,4-四氡-3-甲基-6-f(2 -甲基- ih_笨並故〇坐小某)甲某卜 1 -(異丁基)2,4·二氧代嚜吩基「2,3_-d~l·奈咗-5-務醢甲崎 HCdci3 0.9 (6H, d), 2.09-s), 3.62 (2H, d), 4.01According to the method of Example 3 c), the product of Example 3 b) and 2-methylbenzimid a)J, 2t3,4-tetradec-3-methyl-6-f (2-methyl- Ih_Stupid and squatting on Xiaomou) A certain 1 - (isobutyl) 2,4 · dioxoindolyl "2,3_-d~l·Nym-5- 醢 醢 HC HC HCdci3 0.9 ( 6H, d), 2.09-s), 3.62 (2H, d), 4.01
唑製備。MS (API) 440 [M+H]+。δ !ί· 2.12 (1Η, rh), 2.63 (3H, s), 3.39 (3H (3H’ s)’ 5.49 (2H,S),7.23-7.35 (3H,m),7·7·7 75 (1H,叫Preparation of azole. MS (API) 440 [M+H]+. δ !ί· 2.12 (1Η, rh), 2.63 (3H, s), 3.39 (3H (3H' s)' 5.49 (2H,S), 7.23-7.35 (3H,m),7·7·7 75 ( 1H, called
c) (S) 5-174-羥基異噚唑啶-2-某 1 H -至_並咪唑-1 -基)甲基1 -1 -(異 -2.4(lH.3m-二酮 c)⑶ 5- J~A-6-!72·甲其- -77 - A7 B7 1310036 五、發明説明(74 ) 依實例3 e)項之製法,由b)項產物製備’產生標題化合物 。MS (APC1) 498 [M + H]+。δ 'Hcdcu 〇.87_〇 93 (6H, m),2 〇2_ 2.17 (1H, m), 2.66 (3H, s), 3.24 (3H, s), 3.38 (3H, s), 3.52-3.58 (2H, m), 3.71-3.δ (1H,m), 4.01-4.07 (2h,m),4 59 (1H, d), 4.71-4.75 (1H m), 4.94 (1H, d), 5.3-5.54 (2H, m), 7.22- 7.28 (2H, m), 7.39-7.42 (1H,m),7.69-7.71 (1H, m)。 實例13ΠΠ (S) 6-『(2-乙某-1H-笨並咪°坐-1-_盖)甲一基羥某異噚吔啶_ 2-某截某 1-3 -甲基-1 _(異丁基吩並峻-2.4ΠΗ.3Η、- 二酮c) (S) 5-174-Hydroxyisoxazolidine-2- 1 H- to _-imidazolyl-1 -yl)methyl 1-1 -(iso-2.4(lH.3m-diketone c)(3) 5-J~A-6-!72·Kaki--77-A7 B7 1310036 V. INSTRUCTIONS (74) According to the preparation method of Example 3 e), the title compound is prepared from the product of item b). MS (APC1) 498 [M + H]+. δ 'Hcdcu 〇.87_〇93 (6H, m), 2 〇2_ 2.17 (1H, m), 2.66 (3H, s), 3.24 (3H, s), 3.38 (3H, s), 3.52-3.58 ( 2H, m), 3.71-3.δ (1H,m), 4.01-4.07 (2h,m),4 59 (1H, d), 4.71-4.75 (1H m), 4.94 (1H, d), 5.3- 5.54 (2H, m), 7.22- 7.28 (2H, m), 7.39-7.42 (1H, m), 7.69-7.71 (1H, m). Example 13ΠΠ(S) 6-『(2-乙一-1H-笨和米°坐-1-_盖)甲一基羟 Someisoindole _ 2- Some 1-3-methyl-1 _(isobutyl phenanthrene-2.4ΠΗ.3Η,-dione
a) 6-ΙΎ2-乙.某-1 H-笨並咪0坐二卜基)甲基1-1 j i'4-四g.-3-甲基-— Μ異丁基二氧代啳吩!「2,3-dl嘧啶-s-跆醢甲酿 依實例3 c)項之製法’由實例3 b)項產物與2-乙基苯並咪 唑製備,經急驟矽石層析法純化,以30%至70%乙酸乙酯 之異己規溶液溶離後’產生小標題化合物。MS (ESI) 455 [M + H] + 0 δ !Hcdci3 0.86-0.88 (6Η,d),1.44-1.50 (3Η, t),2-2.1 (1H, m), 2.89-3 (2H, q), 3.39 (3H, s), 3.59-3.62 ( 2H, d), 4 (3H, s), 5.50 (2H, s), 7.2-7.34 (3H, m), 7.60-7.78 (1H, m) 0 b) 6-「(2-乙某-1H-笨基甲某1-丨.2^ 4肩氣-3-甲某. -78 - 本纸張尺度逋用中國國家搮準(CNS) A4规格(210X297公釐)a) 6-ΙΎ2-B. A-1 H-stupid and 0-diyl)methyl 1-1 j i'4-tetra g.-3-methyl--isobutyl dioxolan Quote! The preparation of 2,3-dl-pyrimidine-s-indole according to Example 3 c) was prepared from the product of Example 3 b) and 2-ethylbenzimidazole, and purified by flash verach chromatography. After dissolving from 30% to 70% of ethyl acetate in the isotactic solution, the title compound is produced. MS (ESI) 455 [M + H] + 0 δ !Hcdci3 0.86-0.88 (6Η, d), 1.44-1.50 (3Η, t),2-2.1 (1H, m), 2.89-3 (2H, q), 3.39 (3H, s), 3.59-3.62 ( 2H, d), 4 (3H, s), 5.50 (2H, s) , 7.2-7.34 (3H, m), 7.60-7.78 (1H, m) 0 b) 6-"(2-B--1H- Stupid A certain 1-丨.2^ 4 shoulder gas-3-A -78 - This paper is available in China National Standard (CNS) A4 size (210X297 mm)
裝 訂Binding
A7 B7 1310036 五、發明説明(75 ) Μ異丁某12.4-二氣代嘍吩並「2,3-dl嘧咗 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物。]^(£31)441[\1 + 1"1]+。8 4謂5〇0.79-0.81(6^1,(1),1.30- 1.35 (3H, t), 2 -2.1 (1H, m), 2.88-2.95 (2H, q), 3.25 (3H, s), 3.58-3.61 ( 2H, d), 5.80 (2H, s),7.2-7.23 (2H, m), 7.57-7.63 (2H, m)。 c) (S) 6-「(2 -乙基-1H-苯並咪吐-1-某)甲某U_「4_與某異崎吐 °定-2-基錄某1-3-甲基-1-(異丁基>塞吩並「2.3-(11啼哈-?.,4(111,311)-二酮 依實例3 e)項之製法,由b)項產物製備,產生標題化合物 ’經急驟矽石層析法純化,以5%甲醇之乙酸乙酯溶液溶離 後’自乙酸乙酯/異己烷中再結晶。MS (APCI) 512 [M+H]+。 δ 'Hdmso 0.80-0.83 (6H, m), 1.29 -1.34 (3H, t), 2 -2.1 (1H, m), 2.88-2.96 (2H, q), 3.20 (3H, s), 3.55-3.71 ( 3H, m),3.81-3.91 (2H, m), 4-4.1 (1H, m), 4.55-4.81 (1H, 2m), 5.51-5.57 (3H, m)', 7:15-7.20 (2H, m), 7.55-7.58 (1H, m), 7.62-7.65 (1H, ~ m)。 實例13iv) (S) 5-「4-與基異哼唑啶-2-基羰某1-3 -甲某-1-Γ異丁某)-6-ΙΪ2-丙基-1Η-苽並咪唑-1-基)甲某1-4吩並r2.3-dl嘧啶-2.4ΠΗ.3Η)- I同 &)1,2,3,4-四氫-3-甲基-1-(異丁某)-2.4-二氣代-6-「(2-丙某-. 1 H-笨並咪吐-卜基)甲基裳吩jj「2.3-dl嘧啶-5-#酸甲酯 依實例3 c)項之製法,由實例3 b)項產物與2-正丙基苯並 _____- 79 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) A7 B7 1310036 五、發明説明(76 ) 咪唑製備,經急驟矽石層析法純化,以異己烷:乙酸乙酯 (1 : 1)溶離後’產生小標題化合物。MS (APCI) 469 [M + H] 。δ Womso 0.81-0.83 (6H, d),0.94-0.99 (3H,t),1.72-1.82 (2H, sextet), 2.01-2.08 (1H, m), 2.80-2.85 (2H, t), 3.19 (3H, s) , 3.59-3.61 (2H, d), 3.78 (3H, s), 5.65 (2H, s),7.15-7.23 (2H, m), 7.53-7.59 (2H, m) 匕、丨-2.3.4-四氫-3-甲基-1-(異丁基)-2.4-二氳代-6-[~(2-丙基- 1H-装技味嗅-1-基)甲基V塞吩並『2,3-dl痛冷_ 依實例1 〇項之製法’由a)項產物製備小標題化合物。 MS (APCI) 455 [M + H]。δ …⑽如 0.78-0.85 (6H,d),0.94-1 (3H,t),1.74-1.86 (2H,sextet), 2-2.07 (1H,rn), 2.87-2.92 (2H, t) , 3.25 (3H, s), 3.58-3.6 (2H, d), 5.82 (2H, s),7.21-7.27 (2H, m), 7.58-7.65 (2H, m)。 ι·(2·丙棊-mji咪峻-i-棊)甲並「2 3_dl嘧啶 -2.4nHT3m-二酮 依貫例3 e)項之製法,由b)項產物與(s)_4_輕基異„号吐淀 鹽酸鹽[實例1 b)項]製備’產生標題化合物二ms (Apci) 526.2 [Μ + Η]+ ° δ 0.80-0.84 (6H,m),〇 954 (3H,t), 1.76-1.83 (2H, sextet), 2-2.1 (1H, m), 2.86-2 90 (2H m) 3 2 (風 S),3.5:61 (3H,m),3_7_3.92(2_5H,m),·… m), 4.5-4.6 (0.4H, m), 4.8 (0.6H, m), 5.52-5.57 (3H, m), 7.16-7.19 (2H,m), 7.55-7.65 (2H, 2m)。 實例13v) -80 -A7 B7 1310036 V. INSTRUCTIONS (75) The preparation method of the 12.4-di-gas oxime and the 2,3-dl-pyrimidine example 3 d) is prepared from the product of item a) to produce the subtitle compound. .]^(£31)441[\1 + 1"1]+.8 4 means 5〇0.79-0.81(6^1,(1),1.30- 1.35 (3H, t), 2 -2.1 (1H, m), 2.88-2.95 (2H, q), 3.25 (3H, s), 3.58-3.61 ( 2H, d), 5.80 (2H, s), 7.2-7.23 (2H, m), 7.57-7.63 (2H, m). c) (S) 6-"(2-Ethyl-1H-benzopyrazine-1-) A certain U_"4_ with a certain squid ° °定定-2-基录一1-3 -Methyl-1-(isobutyl)<""""2.3-(11啼11-?,4(111,311)-dione according to Example 3 e), prepared from product b) The title compound was purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc 'Hdmso 0.80-0.83 (6H, m), 1.29 -1.34 (3H, t), 2 -2.1 (1H, m), 2.88-2.96 (2H, q), 3.20 (3H, s), 3.55-3.71 ( 3H , m),3.81-3.91 (2H, m), 4-4.1 (1H, m), 4.55-4.81 (1H, 2m), 5.51-5.57 (3H, m)', 7:15-7.20 (2H, m ), 7.55-7.58 (1H, m), 7.62-7.6 5 (1H, ~ m). Example 13iv) (S) 5-"4-Isoisoxazole-2-ylcarbonyl 1-3 - A certain -1- Γ 丁)-6-ΙΪ2- Propyl-1Η-indolozolidine-1-yl)methyl 1-4 aryl r2.3-dl pyrimidine-2.4ΠΗ.3Η)-I with &) 1,2,3,4-tetrahydro-3 -Methyl-1-(isobutyl)-2.4-dioxane-6-"(2-propanyl-. 1 H-stupidimidol-bu-ki)methyl-supplemental jj "2.3-dl pyrimidine- 5-# acid methyl ester according to the method of Example 3 c), from the product of example 3 b) and 2-n-propyl benzo _____- 79 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. INSTRUCTION DESCRIPTION (76) Imidazole preparation, which was purified by flash chromatography, eluted with isohexane:ethyl acetate (1:1) to give the subtitle compound. MS (APCI) 469 [M + H]. δ Womso 0.81-0.83 (6H, d), 0.94-0.99 (3H, t), 1.72-1.82 (2H, sextet), 2.01-2.08 (1H, m), 2.80-2.85 (2H, t), 3.19 (3H , s) , 3.59-3.61 (2H, d), 3.78 (3H, s), 5.65 (2H, s), 7.15-7.23 (2H, m), 7.53-7.59 (2H, m) 匕, 丨-2.3. 4-tetrahydro-3-methyl-1-(isobutyl)-2.4-di-deutero-6-[~(2-propyl- 1H-package odor-1-yl)methyl V phenan And "2,3-dl pain-cooling _ according to the method of the preparation of the example 1" from the product of item a) preparation of the subtitle compound. MS (APCI) 455 [M + H]. δ (10) such as 0.78-0.85 (6H, d), 0.94-1 (3H, t), 1.74-1.86 (2H, sextet), 2-2.07 (1H, rn), 2.87-2.92 (2H, t), 3.25 (3H, s), 3.58-3.6 (2H, d), 5.82 (2H, s), 7.21-7.27 (2H, m), 7.58-7.65 (2H, m). ι·(2·丙棊-mji咪峻-i-棊) A method for the preparation of a 2,3 dl-pyrimidine-2.4nHT3m-dione according to Example 3 e), which is lightly produced by b) and (s)_4_ Preparation of the title compound II ms (Apci) 526.2 [Μ + Η]+ ° δ 0.80-0.84 (6H, m), 〇954 (3H, t ), 1.76-1.83 (2H, sextet), 2-2.1 (1H, m), 2.86-2 90 (2H m) 3 2 (wind S), 3.5:61 (3H,m), 3_7_3.92 (2_5H, m),·... m), 4.5-4.6 (0.4H, m), 4.8 (0.6H, m), 5.52-5.57 (3H, m), 7.16-7.19 (2H,m), 7.55-7.65 (2H, 2m). Example 13v) -80 -
1310036 A7 _____B7 五、發明説明(77 ) 以)5-『4-拜某異呤唑咬二2-基羰基1-3-甲臬-丨彳異丁某χ_「2“甲 盈.基)-1Η-苯並咪唑-1-基甲基1魂吩並「2丄十_啶_2.4(1Η 3Η)_ 二酮 4!_,2,3,4-四氡-3-甲基丄-jj· 丁基)·6_[2_(甲結其、_1Η_笨並咮 ’-1-基甲基I-2,4· 一乳代,»襄吩並「2,3-dlp杂g^-5-藉酸甲酉旨 依貫例3 c)項之製法,由實例3 b)項產物與2 -甲硫基苯並 味咬製備’產生小標題化合物。MS(APCI) 474 [M+H]+。 LL 1,2,3,4·四基二 1-(異丁基)_6-Γ2-ί甲硫某、η-苯並呋 啤-1-基甲某1-2Α·Ά.氧代4吩並「2.3-dl嘧啶-5-跆醢 依實例1 f)項之製法,由a)項產物製備,產生小標題化合 物之白色固體。MS (APCI) 459 [M+H]+。 U3) 5-[4-羥基異崎唑啶-2-某蕤某1-3-甲幕_ι_(異丁某 L2 - ( ·甲硫某)-1 Η -笨並咪唑-1 -基甲某1 - 4吩拍『2.3 - d 1嘧啶 -2,4ΠΗ.3Η、-二酮 依實例3 e)項之製法,由b)項產物與(S)-4-異哼唑啶醇鹽 酸鹽製備.,.產生標題化合物。MS (APCI + ) 530 [M + H]+。-δ 'Hcdcij 0.Β7 (3Η, s), 0.81 (3H, s), 1.98-2.19 (2H, m), 2.8 (3H, s), 3.21 (3H, m), 3.58-4.17 (6H, m), 4.6-4.8 (1H, m), 5.43-5.58 (2H,m),7.15-7.19 (2H, m), 7.54-7.6 (2H, m)。 實例13 v Π -羥拳異p号唑啶-2-基粦某l-6-「2-(與甲基V1H-苯並呋 唑-1-基甲某1-3-甲基-1-(異丁某)嘧吩並丨2.3-dl嘧啶-2.4ΠΗ.3Η)-' 二酮 _ - 81 - 本紙乐尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(78 )1310036 A7 _____B7 V. Inventive Note (77) to 5-"4-Bay oxazolidine bis 2 - carbonyl 1-3 - formazan - 丨彳 丁 χ χ _ "2 "甲盈. 基) - 1Η-Benzimidazol-1-ylmethyl 1 soul is exemplified by "2丄10_啶_2.4(1Η 3Η)_dione 4!_,2,3,4-tetraindole-3-methylindole-jj · Butyl)·6_[2_(甲结其,_1Η_笨咮咮1-1-ylmethyl I-2,4·一乳代,»襄” and 2,3-dlp hetero-g^-5 - Preparation of the subtitle compound by the method of the example 3 b) and the 2-methylthiobenzoate bite by the method of the acid methyl hydrazide. MS (APCI) 474 [M+H] +. LL 1,2,3,4·tetrakilyl 1-(isobutyl)_6-Γ2-ί methylthio, η-benzofur beer-1-ylmethyl 1-2Α·Ά.oxo 4 </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; ) 5-[4-hydroxyisoxazosin-2-one 1-31-3-A curtain_ι_(Iso-L2-(·methylthio)-1 Η-stupid imidazole-1-yl-methyl 1 - 4 orders "2.3 - d 1 pyrimidine - 2, 4 ΠΗ. 3 Η, - diketone according to the example 3 e), from the b) product and (S)-4-isoxazol Hydrochloric acid salt preparation, the title compound was obtained. MS (APCI + ) 530 [M + H]+. -δ 'Hcdcij 0.Β7 (3Η, s), 0.81 (3H, s), 1.98-2.19 (2H, m), 2.8 (3H, s), 3.21 (3H, m), 3.58-4.17 (6H, m), 4.6-4.8 (1H, m), 5.43-5.58 (2H, m), 7.15-7.19 (2H, m), 7.54-7.6 (2H, m). Example 13 v Π - hydroxy tongs p poxazin-2-yl hydrazine l-6-"2-(with methyl V1H-benzofurazol-1- 1-3-Methyl-1-(isobutyl)-pyrimidopurine 2.3-dl-pyrimidine-2.4ΠΗ.3Η)-'dione _ - 81 - The paper scale applies to China National Standard (CNS) A4 Specifications (210X 297 mm) 1310036 A7 B7 V. Description of invention (78)
a) 1,2.3.4-四j. -642-(羥甲某)-1Η-笨並吹唾-1-某甲某1-3 -甲 基-1-(異丁基)-2,4-二氧代碟吩並「2.3-dl嘧啶-5-# S#甲西肖a) 1,2.3.4-four j. -642-(hydroxymethyl)-1Η-stupid and squirting-1-a certain 1-3-methyl-1-(isobutyl)-2,4 -dioxosole benzophene "2.3-dl pyrimidine-5-# S#甲西肖
取實例3 b)項產物(0.6 g)溶於DMF (5 ml)中。添加2-羥甲 基-笨並咪》i (0.28 g)與無水碳酸鉀(0.6 g)至溶液中,授拌16 小時。反應混合物過濾與蒸發後,產生小標題化合物之白 裝 色固體(0·18 g)。MS (APCI) 457 [M + H]+。S lHCDCi3 0.87 (3H, s), 0.9 (3H, s), 2.1-2.2 (m, 1H), 3.38 (s, 3H), 3.57-3.64 (m, 3H), 3.96 (s, 3H),4.97 (s, 2H), 5.64 (s, 2H), 7.26-7.38 (m, 2H), 7.22-7.3 (m, 1H)與 7.74-7.8 (m, 1H)。 訂The product of Example 3 b) (0.6 g) was dissolved in DMF (5 mL). 2-Hydroxymethyl- phenylidene i (0.28 g) and anhydrous potassium carbonate (0.6 g) were added to the solution and mixed for 16 hours. The reaction mixture was filtered and evaporated to give white crystals (j. MS (APCI) 457 [M + H]+. S lHCDCi3 0.87 (3H, s), 0.9 (3H, s), 2.1-2.2 (m, 1H), 3.38 (s, 3H), 3.57-3.64 (m, 3H), 3.96 (s, 3H), 4.97 ( s, 2H), 5.64 (s, 2H), 7.26-7.38 (m, 2H), 7.22-7.3 (m, 1H) and 7.74-7.8 (m, 1H). Order
b) 1,2,3.4-四 ϋ, -6-「2-(#f 甲基 Ί-1Η-笨並咪咬- i-l 甲某 i-3_ 甲 基-1-(異丁某)-2,4 -二氧代p塞吩並f2.3-d~| 口,淀-5-藉酸 依實例3 d)項之製法’由a)項產物製備,產生小標題化合 物。MS (APCI) 443 [M + H]+。 c) (S) 5-「4-羥基異°号唑啶-2-某羰某淼甲某丨Η-笨並 咪峻-1-基甲基1-3 -甲基-1-(異丁某宸吩.並「2.3-dlp密喊 -2.4(lH.3m-二酮 依實例3 e)項之製法,由b)項產物製備標題化合物。MS (APCI) 474/475 [M + H]+ 〇 δ 'Hdms〇 0.83 (3Η, s), 0.85 (3H, s), 2.06-2.18 (1H, m), 3.22 (3H, s), 3.42-3.98 (6H, m), 4.7-4.8 -82 - 本纸張尺度適用中國國家橾準(CNS) A4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(79 (1H, _’4.82(2H,s),5.25(1h,s),5 49 (1h,s),5 62 (2h, s), 7.16-7.19 (2H, m)與 7.57-7.6 (2H, m)。 實例13 vii) LW-「4-經基異 ⑽ m 丕一並咪唑-1-某甲茱吩並i2,3-dl^2,4⑽仙· 二酮b) 1,2,3.4-four, -6-"2-(#f methyl Ί-1Η-stupid and imi- il A-i-3_ methyl-1-(isobutyl)-2, 4-(2-oxo-p-phenothi-f2.3-d~| s, y-5-by acid, according to the method of Example 3 d), prepared from the product of item a), yielding the subtitle compound. MS (APCI) 443 [M + H]+. c) (S) 5-"4-Hydroxyisophthylpyridin-2-one carbonyl some 淼A 丨Η- Stupid and imi- -1-ylmethyl 1-3 - A The title compound is prepared from the product of item b). The title compound is prepared from the product of item b). (MS-APCI) 474 /475 [M + H]+ 〇δ 'Hdms〇0.83 (3Η, s), 0.85 (3H, s), 2.06-2.18 (1H, m), 3.22 (3H, s), 3.42-3.98 (6H, m ), 4.7-4.8 -82 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (79 (1H, _'4.82(2H, s), 5.25 (1h, s), 5 49 (1h, s), 5 62 (2h, s), 7.16-7.19 (2H, m) and 7.57-7.6 (2H, m). Example 13 vii) LW-"4- Substituted (10) m 丕 imidazole imidazole-1-methylpyrazine i2,3-dl^2,4(10) sindione
CTCT
丄11^4二四氫-3-甲基-6-「2-(甲胺某L V1H-茇逆 1^1二(異丁基)-2,4-二氧代嘧哈dj「2.3-dl嘧啶 分批添加氫化鈉(0.24 g , 60%礦物油中)至〇°c與气氣 含2-(甲胺基)苯並咪唑(0.93 g)之DMF (50 ml)攪拌溶液中 於室溫下30分鐘後,滴加含實例3 b)項產物(2.16 §)之Dmf (10 ml)溶液’反應於室溫下攪拌16小時。溶液倒至水中 以乙酸乙酯萃取。合併之萃液經硫酸鎂脫水,過擴與真、 濃縮。殘質自乙酸乙酯中再結晶,產生小標題化合物之二 色固體 ’ 1.5 g。MS (ESI) 456 [Μ+Η]+。δ 咕_〇 〇 83^8白 (6Η, d), 2.05 (1H, m), 2.94-2.95 (3H, d), 3.19 〇Η Λ §5丄11^4 Ditetrahydro-3-methyl-6-"2-(methylamine L V1H-茇反1^1二(isobutyl)-2,4-dioxo-pyridyl dj"2.3- The dl-pyrimidine was added in portions to a solution of sodium hydride (0.24 g, 60% in mineral oil) to a stirred solution of 2-(methylamino)benzimidazole (0.93 g) in DMF (50 ml). After 30 minutes of warming, Dmf (10 ml) solution containing the product of Example 3 b) (2.16 §) was added dropwise. The reaction was stirred at room temperature for 16 hours. The solution was poured into water and extracted with ethyl acetate. Dehydration over magnesium sulfate, over-expansion and concentration, and re-crystallized from ethyl acetate to give the title compound as a dichrome solid ' 1.5 g. MS (ESI) 456 [Μ+Η]+.δ 咕_〇 〇83^8 white (6Η, d), 2.05 (1H, m), 2.94-2.95 (3H, d), 3.19 〇Η Λ §5
3.63 (2H, d), 3.84 (3H, s), 5.39 (2H, s), 6.83-6.87 r〇tT in) 6.90-6,99 (1H,t),7.08-7.11 (1H,d), 7-20-7.22 (1H,d)。 _1,2,3,4-四氡-3-甲基-6-「2-(甲胺基 V1H-茇# 呻 H. , ^ 83 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公着) 1310036 A7 ___ B7 五、發明説明(80 ) 基1.-.!-(異.:!二基)-2·4·二氩代嘧吩並r2.3-dl嘧啶-5-#酩 依貫例3 d)項之製法,由a)項產物製備’產生小標題化合 物。MS (APCI) 442 [M + H]+。 c) C_§_L 5 -「4 - 棊異p号峻症-2 -基凝基1 - 3 -甲某-ή -丨2 -(甲脖其卜 1Η-笨並咮唑-1-基甲基ι_ι_(異丁某)魂吩;^ -2,4( 1H,3H) -二銅 添加(S),4-#f_基異〃号嗤淀鹽酸鹽(實例1,b項))(0.08 g)與 三乙胺(0.09 ml)至含b)項產物(0.13 g)之二氯甲烷(5 ml)溶液 中。添加1-羥基苯並三唑(0.09 g)及1-乙基-3-(3,-二甲胺基 丙基)-碳化二亞胺鹽酸鹽(0.12 g)。反應混合物於室溫下撥 拌1 2小時。溶液減壓濃縮。殘質經急驟矽石層析法純化, 以0 - 3 %甲醇之乙酸乙醋溶液梯度溶離。所得產物自乙酸乙 酯/異己烷/甲醇中再結晶,產生標題化合物之白色固體 (0.07 g)。MS (APCI) 513.2 [M+H]+。δ 'Hdwo 〇.82_〇 86 (6Ή, m), 2-2.1 (1H, m), 2.9 (3H, m), 3.2 (3H, s), 3.6-3.68 (3H, m), 3.78-3.84 (1H, m), 3.9-3.94 (1H, m), 4-4.12 (1H, m), 4.6-4.8 (1H, 2m), 5.2-5.61 (3H,m),6.86-6.99 (3H, m), 7.19-7.27 (2H, m)。 實例1 3 v i i Π LU 5-f4-羥基異啐唑啶-2-基羰基1-3-甲某某-1H-苽 盖座唑-1-基T基Η-(異丁基)嘍吩並丨2,3-迎^ 2_4ΠΗ 3Η)_ 二1 I同3.63 (2H, d), 3.84 (3H, s), 5.39 (2H, s), 6.83-6.87 r〇tT in) 6.90-6,99 (1H,t),7.08-7.11 (1H,d), 7 -20-7.22 (1H, d). _1,2,3,4-tetradec-3-methyl-6-"2-(methylamino V1H-茇# 呻H. , ^ 83 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) 1310036 A7 ___ B7 V. Description of invention (80) Base 1.-.!-(Different::! Diyl)-2·4·Di-arsonopyrenoyl r2.3-dl-pyrimidine-5 -# 酩 例 Example 3 d) The preparation method of the product of item a) produces the subtitle compound. MS (APCI) 442 [M + H]+. c) C_§_L 5 - "4 - pp峻峻症-2 -基凝基1 - 3 -甲某-ή -丨2 -(甲领其布1Η-笨笨和咮azole-1-ylmethylι_ι_(异丁某) soul phenophene; ^ -2 , 4( 1H,3H)-di-copper addition (S), 4-#f_yl-iso-salt ylide hydrochloride (example 1, item b)) (0.08 g) and triethylamine (0.09 ml) to In a solution of the product of b) (0.13 g) in dichloromethane (5 ml), 1-hydroxybenzotriazole (0.09 g) and 1-ethyl-3-(3,-dimethylaminopropyl) - carbodiimide hydrochloride (0.12 g). The reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc Ethyl acetate solution was dissolved in a gradient. The obtained product was obtained from acetic acid B. Recrystallization from /hexane/methanol to give the title compound as a white solid (0.07 g). MS (APCI) 513.2 [M+H]+ δ 'Hdwo 〇.82_〇86 (6Ή, m), 2-2.1 (1H, m), 2.9 (3H, m), 3.2 (3H, s), 3.6-3.68 (3H, m), 3.78-3.84 (1H, m), 3.9-3.94 (1H, m), 4-4.12 (1H, m), 4.6-4.8 (1H, 2m), 5.2-5.61 (3H, m), 6.86-6.99 (3H, m), 7.19-7.27 (2H, m). Example 1 3 vii Π LU 5- F4-hydroxyisoxazolidin-2-ylcarbonyl-3-1-3-methyl-1H-indenyloxazolyl-1-yl T-indole-(isobutyl) porphin oxime 2,3-ying^ 2_4ΠΗ 3Η)_2 1 I with
OHOH
本紙張尺度適用中國國家標準(CMS) A4規格(210X297公釐) 1310036 A7 B7 五、發明説明(81 红6 並咮唑小基)甲某卜1 2 3 4-四氢其_ 1 -(豈 丁 其、〇 /1 氢代嘧吩並『2,3-dl嘧啶-5-翔酸甲酯 依貝例13VU 3)項之製法,由實例3 b)項產物(0.4 g)與2-胺 基苯並咪唑(0·1 6 g)製備,產生小標題化合物。MS (ESI) 442 [M + H]+。 咪唑-_ι_-—基)甲基 M-2-34-m 寄 _1甲 f 代碟吩並r2,3-dl嘧啶-5-跆給 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物。MS (ESI) 428 [M+H]+。 哼唑皇幾胺甚」H_ 莖-差咪唑小某.HD-(異丁基)啳吩一並i2,3-dl喳啶·2·4ί1τ^Η、_ 二酮 依實例13vii 〇)項之製法,由b)項產物製備標題化合物。 MS (ESI) 499 [M+H] + δ 'Hcocn 0.93 (6Η, d), 2.16-2.28 (1Η, m), 3.3^34 (5H m) 3.62-4,37 (6H’ m)’ 4.59 (1H,d),4.78與4 9 (1H,t,幾何異構物’ 2.25 (2H,AB q)與 7.16-7.4 (4H,m)。 實例13 ix) (3.) 5-『4-輕基哼唑啶基幾^異丁某 Ud.,5··^·氣-1H-味二基 f 基1嘧,也羞夂 二酮This paper scale applies to Chinese National Standard (CMS) A4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (81 red 6 and carbazole small base) A certain 1 2 3 4-tetrahydro _ 1 - (岂Dingqi, 〇/1 Hydrogenimidophene 2,3-dl pyrimidine-5-comonate methyl carbamide 13VU 3), by example 3 b) product (0.4 g) and 2-amine The benzimidazole (0.16 g) was prepared to give the subtitle compound. MS (ESI) 442 [M + H]+. Imidazole-_ι_--yl)methyl M-2-34-m is a product of the preparation of Example 3 d), and the product of a) Prepared to give the subtitle compound. MS (ESI) 428 [M+H]+.哼 皇 皇 」 」 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H The title compound is prepared from the product of item b). MS (ESI) 499 [M+H] + δ 'Hcocn 0.93 (6Η, d), 2.16-2.28 (1Η, m), 3.3^34 (5H m) 3.62-4,37 (6H' m)' 4.59 ( 1H, d), 4.78 and 4 9 (1H, t, geometric isomers ' 2.25 (2H, AB q) and 7.16-7.4 (4H, m). Example 13 ix) (3.) 5-『4-light哼 哼 啶 基 ^ ^ U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U
本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公董) 1310036 A7B7 五、發明説明(82 ) &)1.2.3,4-四窗.-3-甲基-1-(異丁某)-2.4-二氣代-6-『2,4,5-三 f -1H-咪唑-1-某甲某吩並「2.3-dl嘧啶-5-羧酸甲酯 依實例3 c)項之製法,由2,4,5-三氯-咪唑與實例3 b)項產 物製備小標題化合物,以層析法純化(SiO2/20% -50%乙酸 乙酯-異己烷)。MS (APCI) 479/481/483 [M+H]+。δ WcDcn 0.97 (6H, d), 2.25 (1H, septet), 3.39 (3H, s), 3.74 (2H, d), 3·99 (3H,s),5.37 (2H, s)。 13)1,2,3,生-_四氫-3-甲基-1-(異丁基)-2.4-二氩代-6-|~2,4.5-三 氣-1 H-咪二生-1 -基甲基1嘧吩並「2.3-d~|嘧啶-5-4¾齡 取a)項產物(I 70 mg)經含氫氧化鋰單水合物(3 1 mg)之水 (0.75 ml)、甲醇(0_75 ml)與 THF (2.25 ml)溶液,於室溫下 處理4小時。反應經冰醋酸酸化,蒸發至乾。殘質溶於水 中’以二氯甲烷萃取。脫水與蒸發,產生小標題化合物 (U0 mg)。MS (APCI) 465/467/469 [M+H]+。 基-2-異哼唑淀基羰某卜τ ^ 6 氯-1·Η-咪唑-1-基甲棊1 唓吩 二酉同 依實例1步驟g)之製法’由步驟b)產物製備標題化合物。 MS (APCI) 536/538/540 [Μ + Η1+ 〇 δ 'η c〇ci3 0.98 (6Η, dd); 2.26 (1H, septet); 3.40 (3H<, s); 3.47 (1H ήή\ ,dd); 3.66-3.70 ( 1H, m); 3.80-3.87 (1H, m); 4.04-4.20 (2H m)· 4 }, 4 55 (1H, d); 4.70- 4.75 (IH,m); 4.90 (1H,d); 5_25 (1H,d); 5.40 (lH d 實例 13x) ,d)。 (S) 5-「4-羥某異噚唑啶-2-基裁某l_3_甲 -86 - 本紙張尺度適用中画國家標準(CNS> A4规格(210X 297公釐)_ 1310036 A7 B7 五、發明説明(83 ) 硫代-3(2H)-笨# 4 CT小其田_贫η .公…、#、 , -吩j [U、cH嘧啶·2,4ΠΗ.3ΗΙ 二酉同This paper scale applies to China National Standard (CNS) A4 specification (210X 297 dongdong) 1310036 A7B7 V. Invention description (82) &) 1.2.3,4-four windows.-3-methyl-1-(different Ding Mou)-2.4-digas-6-"2,4,5-trif-1H-imidazole-1-one a certain pheno-"2.3-dl pyrimidine-5-carboxylic acid methyl ester according to Example 3 c) The title compound was prepared from 2,4,5-trichloro-imidazole and the product of Example 3 b) and purified by chromatography (SiO 2 / 20% - 50% ethyl acetate - isohexane). APCI) 479/481/483 [M+H]+.δ WcDcn 0.97 (6H, d), 2.25 (1H, septet), 3.39 (3H, s), 3.74 (2H, d), 3·99 (3H, s), 5.37 (2H, s). 13) 1,2,3, raw-_tetrahydro-3-methyl-1-(isobutyl)-2.4-di-argon-6-|~2,4.5 -Three gas-1 H-imidate-1 -ylmethyl 1 sulfonyl "2.3-d~|pyrimidine-5-43⁄4 age a) product (I 70 mg) containing lithium hydroxide monohydrate (3 1 mg) of water (0.75 ml), methanol (0_75 ml) and THF (2.25 ml) were treated at room temperature for 4 hours. The reaction was acidified with glacial acetic acid and evaporated to dryness. Extraction with dichloromethane, dehydration and evaporation to give the subtitle compound (U0 mg). MS (APCI) 465/ 467/469 [M+H]+. Benzyl-2-isoxazole decyl carbonyl 某^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Preparation of the title compound from the product of step b) MS (APCI) 536/538/540 [Μ + Η1+ 〇δ 'η c〇ci3 0.98 (6Η, dd); 2.26 (1H, septet); 3.40 (3H< , s); 3.47 (1H ήή\ , dd); 3.66-3.70 ( 1H, m); 3.80-3.87 (1H, m); 4.04-4.20 (2H m)· 4 }, 4 55 (1H, d); 4.70- 4.75 (IH,m); 4.90 (1H,d); 5_25 (1H,d); 5.40 (lH d Example 13x), d). (S) 5-"4-Hydroxyisoxazole pyridine-2 -Based on a l_3_甲-86 - This paper scale applies to the Chinese standard of Chinese painting (CNS> A4 specification (210X 297 mm) _ 1310036 A7 B7 V. Invention description (83) Thio-3 (2H)-Stup # 4 CT Xiaoqitian _ poor η. Gong..., #, , - 指 j [U, cH pyrimidine·2,4ΠΗ.3ΗΙ 二酉同
OHOH
二氩代·⑶ -l(2jj)-i並4峻棊甲啶_5_淼龄甲酿 取含實例3步驟b)產物(300 mg)與2砰硫基苯並w塞吐(3〇〇 mg)之二乙二醇二甲醚(3 ml)溶液經微波照射(6〇〇 w)加熱至 ⑽t。⑽鐘後’真空蒸館排除溶劍,㈣經梯度層析 純化·,以二氯甲燒至5%甲醇之二氣甲燒溶液溶離,產生小 標題化合物之白色固體⑽叫卜〜啊㈣⑽… 2.22 (1H,_),3.38 (3H,s),3.71(2H,d),4 〇〇(3H,s) 4 8〇 (2H,S),7_33(lH,dt),7.45(1H,dt),7.77(iH,dd),7 d) ° -丄(2_Η)-苯並嘧唆基)甲某1嘍吩並 心,3,四氫-3-甲某·ΐ·(異丁某代·“… .羧酸 依實例3 d)項之製法,由a)項產物製供 k備小標題化合物。 MS (APCI) 461 [M + H]+。lHDMS0 0.86 (6H 心 * ㈣,d),2.1G (1H,_), 3.25 (3H, s), 3.70 (2H, d), 5.00 (2H ^ , ,”,7.39 (1H t) 7 52 (1H, t),7.93 (iH, d), 8.02 (1H,d)。 ’ ’ c) (S) 544-羥基異哼唑啶-2-基羰某田计 1-(異丁某)-6- -87 - 本紙張尺度適用中國國家搮準(CNS) Α4規格(210x 297公釐) 1310036 A7 _____ B7 五、發明説明(84 ) 代-3(2H)-t基嘍唑棊並「23_di 嘧啶 -2,4(lH.3m-二酮 依實例3 e)項之製法’由b)項產物製備標題化合物。ms (APCI) 533 [M + H]+。δ 丨HDMS。0.81-0.88 (6H,m), 21〇 (1H, non), 3.19 (3H, s), 4.14-4.45 (6H, m), 4.65 ΠΗ 4 77 Γ2Η 一5.晴 m),7.40(iH,㈣ 8.04 (1H, d)。 實例1 3 x i) (S) ·5-丨4-羥基異哼基幾棊卜3二^^·丨異丁農6_r4_ 代-3..(2Η)-4·1ϋ_基吩並^嘧啶 _2 4MH 3m- 二酮Di-argon·(3) -l(2jj)-i and 4 棊 棊 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The solution of 〇mg) diethylene glycol dimethyl ether (3 ml) was heated to (10) t by microwave irradiation (6 〇〇w). (10) After the clock, 'vacuum steaming hall to eliminate the dissolution of the sword, (4) purified by gradient chromatography, dissolved in dichloromethane to 5% methanol in a gas-burning solution, resulting in a white solid of the subtitle compound (10) called bu ~ ah (four) (10)... 2.22 (1H, _), 3.38 (3H, s), 3.71 (2H, d), 4 〇〇 (3H, s) 4 8 〇 (2H, S), 7_33 (lH, dt), 7.45 (1H, dt ), 7.77 (iH, dd), 7 d) ° -丄(2_Η)-benzopyrimidinyl) A certain 1 喽 并, 3, tetrahydro-3-methyl ΐ · (Iso · ".... Carboxylic acid according to the method of Example 3 d), from the product of a), for the preparation of the sub-title compound MS (APCI) 461 [M + H] +. lHDMS0 0.86 (6H heart * (four), d) , 2.1G (1H, _), 3.25 (3H, s), 3.70 (2H, d), 5.00 (2H ^ , , ,, 7.39 (1H t) 7 52 (1H, t), 7.93 (iH, d) , 8.02 (1H,d). ' ' c) (S) 544-hydroxyisoxazolidine-2-ylcarbonyl a certain field 1- (isobutyl)-6- -87 - This paper scale applies to Chinese countries搮Quasi-(CNS) Α4 size (210x 297 mm) 1310036 A7 _____ B7 V. Inventive Note (84) Generation-3(2H)-t-based carbazole oxime and "23_di pyrimidine-2,4 (lH.3m-dione According to the method of the method of item 3 e), the product is prepared from the product of item b) Compounds.ms (APCI) 533 [M + H]+.δ 丨HDMS.0.81-0.88 (6H,m), 21〇(1H, non), 3.19 (3H, s), 4.14-4.45 (6H, m ), 4.65 ΠΗ 4 77 Γ2Η a 5. Clear m), 7.40 (iH, (4) 8.04 (1H, d). Example 1 3 xi) (S) · 5-丨 4-hydroxyisoindolyl 棊 3 3 2 ^ ^·丨异丁农6_r4_代-3..(2Η)-4·1ϋ_ylpheno-pyrimidine_2 4MH 3m-dione
a) 4-氣-2-氣嘧唑酮 取含2,4-二H坐(5 §)與氟化鮮(5 g)之四亞甲基即〇 _ 懸浮液於130t下加熱6小時。再加氟化却(5 g),混合物於 下加熱16小日争。反應混合物真空蒸餾產生小標題 化合物之無色油狀物(l.7g)。δ UH,d)。 b) 4-t.-2(3H)-°塞唑酮 , 取含步驟a)產物(1.7 g)與氫氧化钾(122 g)之水(25响與 -88 - 本紙張尺度適用中囲國家標準(CNS) A4規格(210x 297公釐) 1310036 A7 B7 五、發明説明(85 ) 乙腈(5 m丨)混合物於周溫下攪拌丨6小時。混合物分佈在水 與二氯甲烷之間,收集水層,以冰醋酸酸化,以二氣甲烷 萃取。經硫酸鎂脫水後,有機相過濾,濃縮至乾,產生小 標題化合物之無色油狀物(0·35 g)。δ 1Hcd⑶5 97 (1H,s), 9.47 (1H, s). MS (ESI) 135/137 [M + H] + 氣-2-氧代-3(2Η)-4_^^ 曱基1-1.2.3.4-四氤-3-甲華-卜丄苦丁棊,)-2,4-二氧代ρ塞吩並「Ί(1Ί喊忒甲酯 依貫例3 c)項之製法’由b)項產物製備,產生小標題化合 物。δ 'Hcocn 0.97 (6H,d),2.29 (1H, non), 3.39 (3H,S),3.76 (2H,d),3.99 (3H,s), 5.17 (2H,s),6.08 (1H,s)。 d) 6-(~4-氣-2-氧代- 3(2Η)-"ΐ咬基甲某卜1-2·3 -4_四箭·3_甲華_ 1二(.異丁基)-2,4-二氣代遗吩並f2,3-d~|p奈峻-5-#龄 依實例3 d)項之製法,由c)項產物製備,產生小標題化合 物。 MS (ESI) 430/432 [M+H]+。δ 0.90 (6H,d) , 2.15 (1H, non),3.25 (3H, s) ’ 3.73 (2H,d),5.25 (2H, s), 6.79 (1H, s)。 e) (S) 6-「4-氣-2-氣代-3(2H)-口宸唆某甲某~|-5-「4-轉某異》号P坐 ρ定-2-基羰基1-3·甲某-1-(異丁基寒吩並『2,3-d Ip密咬 -2,4ΠΗ·3Η)-二酮 依實例3 e)項之製法,由d)項產物製備,產生標題化合物 。MS (APC1) 501/503 [M + H]+。'Hdms。0.82-0.92 (6H,m), 2.15-2.20 (1H, m), 3.20 (3H, s), 3.40-3.60 (6H, m), 4.60-4.80 (1H, m), 5.04 (2H, s),5.50 (1H’ s),6.72 (1H, s)。 -89 - 本紙張尺度適用t國國家標準(CNS) A4规格(210 x 297公釐) 1310036 A7 B7a) 4-Gas-2-oxazolone The tetramethylene-containing 2_ suspension containing 2,4-diH(5 §) and fluorinated fresh (5 g) was heated at 130 t for 6 hours. Add fluorination (5 g) and heat the mixture for 16 days. The reaction mixture was evaporated in vacuo to give a crystallite. δ UH, d). b) 4-t.-2(3H)-°serazolidone, taking water containing step a) (1.7 g) and potassium hydroxide (122 g) (25 volts and -88 - this paper size is suitable for 囲National Standard (CNS) A4 Specification (210x 297 mm) 1310036 A7 B7 V. INSTRUCTIONS (85) The acetonitrile (5 m丨) mixture is stirred at ambient temperature for 6 hours. The mixture is distributed between water and dichloromethane. The aqueous layer was collected, dried with EtOAc EtOAc (EtOAc) (EtOAc) ,s), 9.47 (1H, s). MS (ESI) 135/137 [M + H] + gas-2-oxo-3(2Η)-4_^^ 曱 1-1.2.3.4-tetrazine- 3-methyl- 丄 丄 丄 棊 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -2 -2 -2 -2 -2 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Subtitle compound. δ 'Hcocn 0.97 (6H, d), 2.29 (1H, non), 3.39 (3H, S), 3.76 (2H, d), 3.99 (3H, s), 5.17 (2H, s), 6.08 (1H, s) d) 6-(~4-Gas-2-oxo-3(2Η)-"Bite base A certain 1-2·3 -4_Four arrows·3_甲华_ 1 bis (.isobutyl)-2,4-digas The preparation of the sub-detailed f2,3-d~|p Naijun-5-# aging according to the method of Example 3 d) was prepared from the product of item c) to give the subtitle compound MS (ESI) 430/432 [M+ H]+.δ 0.90 (6H,d) , 2.15 (1H, non), 3.25 (3H, s) ' 3.73 (2H,d), 5.25 (2H, s), 6.79 (1H, s). e) ( S) 6-"4-Gas-2-Gas-3(2H)- 口宸唆一甲~|-5-"4-转某异》号 P Sitting ρ定-2-基carbonyl 1-3 · A certain -1- (isobutyl thiophene 2,3-d Ip cleavage-2,4 ΠΗ·3 Η)-dione according to the preparation method of item 3 e), prepared from the product of item d), producing the title Compound. MS (APC1) 501/503 [M + H]+. 'Hdms. 0.82-0.92 (6H, m), 2.15-2.20 (1H, m), 3.20 (3H, s), 3.40-3.60 (6H, m), 4.60-4.80 (1H, m), 5.04 (2H, s), 5.50 (1H's), 6.72 (1H, s). -89 - This paper size applies to National Standard (CNS) A4 (210 x 297 mm) 1310036 A7 B7
異丁某1-6-『?.-ί 2.3 - d 1 ^ ^ 實例13 xihIso Ding 1-6-『? .-ί 2.3 - d 1 ^ ^ Example 13 xih
(SHH-羥某糞崎吔啶·2-基羰某 氧代-1,3 -苽# 〇菩唑-3 ( 2 Η )-某 -2,4( 1 HJHU二 SH aiJ—U/二^_氫·3-甲基·1-(異丁某)_2 4_ - - ^ ~~~~::::^~1戈-6-ΙΎ2- U.- (2Η)-基)甲-基游龄甲酿 依實例3 c)項之製法’由實例3匕)項產物與以-苯並噚唑, 2(3H)-酮製備,產生小標題化合物。δ ιΗ nc〇ci3 0.95 (6H, d), 2.25 (出,septet), 3.39 (3H,d),3·73 (2H,句,4 〇4 (3h, s), 5_18 (2H,s),7.18 (4H,m)。 I f 基-..丨丄異--丁基上1^^代-6-r2-氪夜, 1^^^3(2Η)-基.甲Hi吩^^唉^勒齡叙 依實例3 d)項之製法,由實例3 a)項產物製備’產生小標 題化合物。MS (ESI) 430.1 (M++H) c) (S) 5-Μ-羥基異噚唑啶-2-基羱某Ki 1 ^ 苯並哼唑-3(..2Η).-基 f—^^並 F^3_dl 嘧忒 -2,4ΠΗ·3Η、-二酮 依實例3 e)項之製法,由b)項產物製備,產生小標題化合 物。δ lHCDCI3 0.89 (6H,d),2.15 (1H,m),3·20 (3H,d),3二 (6H, m), 4.68 (1H, m), 5.13 (2H, m), 5.50 (1H, m), 7.18 (2H dd),7.38 (2H, m)。MS (APCI) 50 1 · 1 (M++H)。(SHH-hydroxymethane sputum alkaloids 2-yl carbonyl oxo-1,3 -苽# 〇 oxazolium-3 ( 2 Η )- a certain 2,4 ( 1 HJHU 2 SH aiJ-U / 2 _H3·Methyl·1-(Isobutyl)_2 4_ - - ^ ~~~~::::^~1戈-6-ΙΎ2- U.- (2Η)-基)甲-基游Ageing A is prepared according to the procedure of Example 3 c), from the product of Example 3, and the product of benzoxazole, 2(3H)-one to give the subtitle compound. δ ιΗ nc〇ci3 0.95 (6H, d), 2.25 (out, septet), 3.39 (3H, d), 3·73 (2H, sentence, 4 〇 4 (3h, s), 5_18 (2H, s), 7.18 (4H,m). I f base-..丨丄--butyl on 1^^代-6-r2-氪夜, 1^^^3(2Η)-基.甲Hi指^^唉^ The method for the preparation of the article 3 d) of the method of the preparation of the product of the example 3 a) produces the subtitle compound. MS (ESI) 430.1 (M++H) c) (S) 5-indole-hydroxyisoxazolidine-2-ylindole Ki 1 ^ benzoxazole-3 (..2Η).-based f- ^^ and F^3_dl pyridinium-2,4ΠΗ·3Η,-dione is prepared according to the method of item 3 e), which is prepared from the product of item b) to give the subtitle compound. δ lHCDCI3 0.89 (6H,d), 2.15 (1H,m),3·20 (3H,d),3 2 (6H, m), 4.68 (1H, m), 5.13 (2H, m), 5.50 (1H , m), 7.18 (2H dd), 7.38 (2H, m). MS (APCI) 50 1 · 1 (M++H).
實例 13 xiiiV (S) 5-M-羥基異崎唑啶-2-基羰基卜3-甲早g、丁其n「p 代ί丨,3卜塞峻並『5,4-bl吡啶-1(2H)-基)甲甚~|g塞吩拍p,3_di喊 啶-2,4ΠΗ.3Η)-二酮 -90 - 本纸張尺度適用中國S家標準(CNS) Α4規格(21〇x 297公I)Example 13 xiiiV (S) 5-M-hydroxyisoxazolidine-2-ylcarbonylbu 3-methylas-g, butyl s-n "p-generation 丨, 3 卜塞峻和"5,4-blpyridine-1 (2H)-基)甲甚~|g stoppered p,3_di shouting pyridine-2,4ΠΗ.3Η)-dione-90 - This paper scale applies to China S standard (CNS) Α4 specification (21〇x 297 public I)
裝 訂Binding
1310036 A7 B7 五、發明説明(87 )1310036 A7 B7 V. Description of invention (87)
a) 3 -硝基ρ比咬· 2 -硫酉?· 在含3-硝基-2-氯吡啶(9.07 g)之乙醇(12〇 ml)溶液中添加 NaSΗ (6.41 g),使混合物攪拌30分鐘,然後真空濃縮。加 水至殘質中’以稀HC1酸化’以乙酸乙酯(x 5)萃取。有機 相以水洗條’脫水’真空濃縮’產生小標題化合物之燈色a) 3 -nitro ρ than bite · 2 - thiopurine? - NaS(R) (6.41 g) was added to a solution of 3-nitro-2-chloropyridine (9.07 g) in ethanol (12 mL), and the mixture was stirred for 30 min then concentrated in vacuo. Water was added to the residue 'acidified with dilute HC1' with ethyl acetate (x5). The organic phase is washed with water, 'dehydrated' and vacuum concentrated to produce a light color of the subtitle compound.
固體(9.08 g)。δ 'HcDcn 7.19 (dd,J=2.7,4.2 Hz, 1H); 8.44 (m,2H)。MS(ESI) 154.9 b) 3-胺某吡啶-2-硫酵 在於水浴中冷卻之含a)項產物(0.50 g)之冰醋酸(5 ml)溶 液中添加還原之鐵粉(0.50 g),於室溫下授拌45分鐘。再添 加乙酸(5 ml),續攪拌20分鐘。滴加反應混合物至竣酸氫 鈉溶液中,以乙酸乙酯萃取(X 3)。有機相脫水,真空濃縮 ,產生小標題化合物之深綠色油狀物(0.29 g)。δ tHcDcn 4.95 (s, 2H); 6.68 (t, J=6.8 Hz, 1H); 6.80 (d, J=7.7 Hz, 1H); 7.14 (dj= 5.6 Hz, 1H); 12.75 (s,1H)。 £)「1,314 唑並「5.4-bl吡啶-2ΠΗ)-酮 在含b)項產物(280 mg)之甲苯(300 ml)溶液中添加丨+数 基二咪峻(3 9 2 m g ),加熱至回流1 6小時。反應混合物真工 -91 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 裝Solid (9.08 g). δ 'HcDcn 7.19 (dd, J=2.7, 4.2 Hz, 1H); 8.44 (m, 2H). MS (ESI) 154.9 b) 3-amine pyridine-2-thiol was added to a solution of the product a) (0.50 g) in glacial acetic acid (5 ml), which was cooled in a water bath, and reduced iron powder (0.50 g). Mix for 45 minutes at room temperature. Additional acetic acid (5 ml) was added and stirring was continued for 20 minutes. The reaction mixture was added dropwise to a sodium hydrogen hydride solution and extracted with ethyl acetate (EtOAc). The organic phase was dried <RTI ID=0.0> δ tHcDcn 4.95 (s, 2H); 6.68 (t, J=6.8 Hz, 1H); 6.80 (d, J=7.7 Hz, 1H); 7.14 (dj= 5.6 Hz, 1H); 12.75 (s, 1H). £) "1,314 oxazo"5.4-bl pyridine-2ΠΗ)-one is added to a solution of the product b) (280 mg) in toluene (300 ml) with hydrazine + number base dimi (3 9 2 mg) , heated to reflux for 16 hours. The reaction mixture is true -91 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm)
.線 A7 B7 1310036 五、發明説明(。, 濃縮’殘質缝正相層析法純化,以異己烷··乙酸乙酷(3 : 2)混合物溶離。合併之有機相部份真空濃縮,產生小標題 化合物《灰白色固體(214 mg)。δ iHcocu 7.23 (dd, J=7.9 ’ 7·3δ (dd, J= 8.1, 1.4 Hz, 1H); 8.31 (dd, J=4.9 h5 HZ,1H); 9.5〇 (s, 1H)。MS (ESI) 150.9 [M + H] + 4) 甲某 異丁基)_2 4_二氣代 £1^1嗔 吡啶-1(2^1)-某)甲基 1嘧吩並 r2.3_d]p 5-務酸甲酯 ^ 依貫例3 C)^之製法,由實例3 b)項產物與c)項產物製備 。δ Hcdci3 0.95 (dj j=6.5 Hz, 6H); 2.25 (septet, J=6.9 Hz, 1H); 3.38 (s,3H); 3.73 (d; J=7.9 Hz, 2H); 4.04 (s, 3H), 5.30 (dd, J=0.3, 2.6 Hz, 2H); 7.26 (t, J- 8.8 Hz, 1H); 7.74 (dd, 卜8.4’ L2 Hz,1H); 8.31 (dd, J=5.0, 1.3 Hz,ΪΗ)。MS (ESI) 460.9 [M + H] + g·) 1,2,3.,4-Eg^ 甲基-w 異丁基二氪代 ,代 並丄^_4-blp比啶-U2出-基甲基μι吩並「2夂…,々」. 羧酸 依實例3 d)項之製法,由d)項產物製備。δ icDm 0.96 (q, J=3.3 Hz, 6H); 2.26 (septet, J= 7.7 Hz, 1H); 3.51 (s, 3H); 3.81 (d, J=2l.i Hz, 2H); 6.06 (s, 2H); 7.25 (m, 1H); 7.62 (dd, J=8.1, 1.3 Hz, 1H); 8.32 (m, 1H) » MS (ESI) 447 [M + H] + Π (S) 5_:14-羥某異吟唑啶-2-基蒺基丨-3-甲甚$ 丁 p_6_ [2-氧代ί 1,3~|ρ窠也並『5.4-blg比淀-1(2HV基甲基1峰略並丨2.3-dl 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐〉 裝 訂 .線 1310036 A7 B7 五、發明説明(89 ) 嘧啶-2.4ΠΗ.3Η)-二酮 依實例3 e)項之製法,由e)項產物製備,產生標題化合物 。δ 1 H D M S 0 〇. 89 (q, J=6.5 Hz, 6H); 2.15 (septet, J=7.8 Hz, 1H); 3.20 (d, J=4.0 Hz, 3H); 3.76 (m, 6H); 4.68 (m, 1H); 5.26 (m, 1H); 7.41 (dd, J=8.2, 4.9 Hz, 1H); 7.80 (d, J= 8.3 Hz, 1H),8.31 (d, J=4_8Hz, 1H)。MS (APCI) 518.0 實例13 xiv) (S) 5-「4-羥基異啐唑啶-2-某羰某1-3-甲某-M異丁某)-6-ΠΗ-l,2,3-笨並三唑-l-基甲基)-嘧吩並「2,3-dl嘧啶-2,4(lH,3H)-二 i同 a) 6-Π Η-1.2,3-笨並三唑-1-某甲基)-1,2,3,4-四氣-3-甲基-1-〔異 丁基)-2,4-二氣代吩並「2.3-dl嘧啶-5-羧酸甲酯 依實例3 c)項之製法,由實例3 b)項產物與苯並三唑製備 ,產生小標題化合物。MS [ESI] 3〇9 [M-苯並三唑]+ δ 'Hcocn 0.9 (3H, s), 0.98 (3H, s), 2.18-2.24 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d),4.11 (3H, s), 6.03 (2H, s), 7.41 (1H, t), 7.49 (1H, t),7.71 (1H,d),與 8.09 (1H,d)。 13)6-(1日-1,2,3-笨並三唑-1-基甲基)-1,2,3,4-四氣-3-甲基-1-(異 丁基)-2,4-二氣代4吩並「2.3-dl嘧啶-5-羧酸 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物。MS (ESJ) 414 [M + H]+。δ iHowso 0.87 (3H, s),0.91 (3H, s), 2.01-2.19 (1H, m), 3.2 (3H, s), 3.7 (2H, d), 6.3 (2H, s), 7.46 (1 H, t), 7.6 (1H, t)。 c) (S) 5-「4-羥基異噚唑啶-2-基羰基1-3-甲基-1-(異丁基)-6- -93 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1310036 五、發明説明(90 )Line A7 B7 1310036 V. Inventive Note (., Concentrated 'Residual Slots Normal Phase Chromatography Purification, Dissolve in a mixture of isohexane·ethyl acetate (3:2). The combined organic phases are partially concentrated in vacuo to produce Subtitle compound "off-white solid (214 mg). δ iHcocu 7.23 (dd, J = 7.9 ' 7. 3 δ (dd, J = 8.1, 1.4 Hz, 1H); 8.31 (dd, J = 4.9 h5 HZ, 1H); 9.5〇(s, 1H).MS (ESI) 150.9 [M + H] + 4) A-isobutyl)_2 4_二代代£1^1嗔pyridine-1(2^1)-)) Base 1 sulfono-r2.3_d]p 5-hydroxy acid methyl ester ^ According to the procedure of Example 3 C), the product of Example 3 b) and the product of item c) were prepared. δ Hcdci3 0.95 (dj j=6.5 Hz, 6H); 2.25 (septet, J=6.9 Hz, 1H); 3.38 (s,3H); 3.73 (d; J=7.9 Hz, 2H); 4.04 (s, 3H) , 5.30 (dd, J=0.3, 2.6 Hz, 2H); 7.26 (t, J- 8.8 Hz, 1H); 7.74 (dd, 8.4' L2 Hz, 1H); 8.31 (dd, J=5.0, 1.3 Hz , ΪΗ). MS (ESI) 460.9 [M + H] + g·) 1,2,3.,4-Eg^ methyl-w isobutyl diindole, substituted 丄^_4-blp than pyridine-U2-based Methyl MU is exemplified by "2 夂..., 々". The carboxylic acid is prepared from the product of item d) according to the method of Example 3 d). δ icDm 0.96 (q, J=3.3 Hz, 6H); 2.26 (septet, J= 7.7 Hz, 1H); 3.51 (s, 3H); 3.81 (d, J=2l.i Hz, 2H); 6.06 (s , 2H); 7.25 (m, 1H); 7.62 (dd, J=8.1, 1.3 Hz, 1H); 8.32 (m, 1H) » MS (ESI) 447 [M + H] + Π (S) 5_:14 - hydroxy-isoxazolidine-2-ylindolyl-3-methyl even $-butyl p_6_ [2-oxo ί 1,3~|ρ窠 also 5.4-blg than lake-1 (2HV methyl group 1 Peak and 丨2.3-dl This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Binding. Line 1310036 A7 B7 V. Invention description (89) Pyrimidine-2.4ΠΗ.3Η)- The ketone is prepared from the product of item e) according to the procedure of Example 3 e) to give the title compound. δ 1 HDMS 0 〇. 89 (q, J=6.5 Hz, 6H); 2.15 (septet, J=7.8 Hz, 1H); 3.20 (d, J=4.0 Hz, 3H); 3.76 (m, 6H); 4.68 (m, 1H); 5.26 (m, 1H); 7.41 (dd, J=8.2, 4.9 Hz, 1H); 7.80 (d, J= 8.3 Hz, 1H), 8.31 (d, J=4_8Hz, 1H). MS (APCI) 518.0 Example 13 xiv) (S) 5-"4-Hydroxyisoxazole pyridine-2-one carbonyl some 1-3-A-M-di-butyl"-6-ΠΗ-l,2,3 - stupid and triazole-l-ylmethyl)-pyrimido "2,3-dl pyrimidine-2,4(lH,3H)-dii with a) 6-Π Η-1.2,3-stupid three Imidazole-1-methyl)-1,2,3,4-tetramethyl-3-methyl-1-[isobutyl)-2,4-dioxo-"2.3-dl-pyrimidine-5- The methyl carboxylate was prepared according to the procedure of Example 3 c) from the product of Example 3 b) and benzotriazole to give the subtitle compound. MS [ESI] 3 〇 9 [M-benzotriazole] + δ ' Hcocn 0.9 (3H, s), 0.98 (3H, s), 2.18-2.24 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 4.11 (3H, s ), 6.03 (2H, s), 7.41 (1H, t), 7.49 (1H, t), 7.71 (1H, d), and 8.09 (1H, d). 13) 6-(1st-1, 2, 3-Strepto-triazol-1-ylmethyl)-1,2,3,4-tetrazol-3-methyl-1-(isobutyl)-2,4-difluoro 4"2.3" The dl-pyrimidine-5-carboxylic acid is prepared according to the procedure of Example 3 d), which is obtained from the product of item a) to give the subtitle compound. MS (ESJ) 414 [M + H] + δ iHowso 0.87 (3H, s), 0.91 (3H, s), 2.01-2.19 (1H, m), 3.2 (3H, s), 3.7 (2H, d), 6.3 (2H, s), 7.46 (1 H, t), 7. 6 (1H, t). c) (S) 5-"4-Hydroxyisoxazin-2-ylcarbonyl1-3-methyl-1-(isobutyl)-6--93 - Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (90)
依實例1 g)項之製法’由b)項產物製備,產生小標題化 合物。MS (ESI) 486 [M + H]。δ H〇ms〇 0.87 (3H, s) ' 0.89 (3H, s) > 2.01-2.19 (1H, m),3-08-3.22 (3H, m),3.62-4.17 (6H, m),4.6 2 - 4.8 2 (1 H,m),5 · 6 - 5 · 8 (1H,m),6 · 〇 7 - 6 · 12 (2 H m) 7 4 2 (1H,t),7.6 (1H,q),7.93 (1H,m)與 8.04 (1H,d)。 實例1 3 xv) (S)-5-f4-羥基異呤唑啶-2-基羰基1-3-甲凫異丁某 17比p各並「2,3-b~|p比这-1-基甲基V塞吩並「2,3-c^]Ip密峻_2·4(lH.3H~)- 二酉同Prepared by the product of item b) according to the procedure of Example 1 g) to give the subtitle compound. MS (ESI) 486 [M + H]. δ H〇ms〇0.87 (3H, s) ' 0.89 (3H, s) > 2.01-2.19 (1H, m), 3-08-3.22 (3H, m), 3.62-4.17 (6H, m), 4.6 2 - 4.8 2 (1 H,m),5 · 6 - 5 · 8 (1H,m),6 · 〇7 - 6 · 12 (2 H m) 7 4 2 (1H,t),7.6 (1H, q), 7.93 (1H, m) and 8.04 (1H, d). Example 1 3 xv) (S)-5-f4-hydroxyisoxazolidin-2-ylcarbonyl 1-3-methylpyridinium 17 each than p and "2,3-b~|p ratio-1 -ylmethyl V thiophene and "2,3-c^]Ip dense _2·4(lH.3H~)-
a) 1,2,3,4 -四 n. -3 -甲基-1-(異 丁基)-2,4-二氣代- 6- (1Η-口比吃# [2,3-1)10比峻-1-基甲基V菜吩並於酸甲酉旨 依實例3 c)項之製法,由實例3 b)項產物與7-氮雜吲哚製 備,產生小標題化合物。MS (APCI) 427 [M+H]+。δ 'Hcdch 0.85 (3H, s)., 0.92 (3H, s), 2.15-2.25 (1H, m), 3.38 (3H, s), 3.66 (3H, d), 4.03 (3H, s), 4.97 (s,2H), 5.61 (2H, s), 6.49-6.91 (1H, d), 7.06-7.14 (1H, m), 7·38 (1H, d), 7.91-7.95 (1H,m)與 8.3 1-8.37 (l H, m)。 本纸張尺度適用中國菌家標準(CNS). A4规格(21〇x 297公釐) A7 B7 1310036 五、發明説明(91 ) b) 1,2,3,4-四氣-3-甲基-1-(異丁基)-2,4-二氣代-6-ΠΗ-吡咯並 f2.3-bl吡啶-I-基甲基)碟吩並[2.3-dl嘧啶-5-羧酸 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物。MS (APCI) 412 [M + H] + c) (S)-5-「4-羥基異哼唑啶-2-基羰基1-3-曱某-1-(異丁某V6-(1 Η -吡咯並f 2,3 - b 1吡啶-1 -基甲基V塞吩並「2,3 - d 1嘧啶 -2,4( 1 H,3H)-二酮 依實例3 e)項之製法,由b)項產物製備,產生小標題化合 物。MS (ESI) 484 [M + H]+。δ 'Hdmso 1.82- 1.93 (6H,m), 1.16-1.22 (1H, m), 2.02-2.09 (1H, m), 3.20 (3H, s), 3.42-3.98 (4H, m), 4.03-4.18 (1H, m), 4.9-4.81 (1H, m), 5.39-5.61 (3H, m), 6.52 (1H, d), 7.06-7.18 (1H, m), 7.43-7.57 (1H, m), 7.99 (lH,d)與 8.28-8.33 (1H, m)。 實例13 χνΠ (S)-5-「4-羥基異呤唑啶-2-某羰基1-3-甲基-1-(異丁某V6-「2-甲基-1H-吡咯並l~2,3-bl吡啶-1-基甲基1嘧吩並「2.3-dl嘧啶 -2,4( 1H.3H)-二酮a) 1,2,3,4 -four n. -3 -Methyl-1-(isobutyl)-2,4-digastone - 6- (1Η-口比吃# [2,3-1 The 10 prince-1-ylmethyl V dish is exemplified by the method of Example 3 c), and the product of Example 3 b) is prepared with 7-azaindole to give the subtitle compound. MS (APCI) 427 [M+H]+. δ 'Hcdch 0.85 (3H, s)., 0.92 (3H, s), 2.15-2.25 (1H, m), 3.38 (3H, s), 3.66 (3H, d), 4.03 (3H, s), 4.97 ( s,2H), 5.61 (2H, s), 6.49-6.91 (1H, d), 7.06-7.14 (1H, m), 7·38 (1H, d), 7.91-7.95 (1H, m) and 8.3 1 -8.37 (l H, m). This paper scale applies to Chinese Standards (CNS). A4 size (21〇x 297 mm) A7 B7 1310036 V. Description of invention (91) b) 1,2,3,4-tetrazole-3-methyl -1-(isobutyl)-2,4-dioxo-6-indole-pyrrolof2.3-blpyridine-I-ylmethyl)-disc[2.3-dl-pyrimidine-5-carboxylic acid The preparation of Example 3, d), was prepared from the product of item a) to give the subtitle compound. MS (APCI) 412 [M + H] + c) (S)-5-"4-Hydroxyisoxazolidine-2-ylcarbonyl 1-3-曱一-1-(isobutyl V6-(1 Η -pyrrolof 2,3 - b 1 pyridin-1-ylmethyl V-secret and "2,3 - d 1 pyrimidine-2,4( 1 H,3H)-dione according to Example 3 e) Prepared from product b) to give the subtitle compound. MS (ESI) 484 [M + H] + δ 'Hdmso 1.82- 1.93 (6H, m), 1.16-1.22 (1H, m), 2.02-2.09 ( 1H, m), 3.20 (3H, s), 3.42-3.98 (4H, m), 4.03-4.18 (1H, m), 4.9-4.81 (1H, m), 5.39-5.61 (3H, m), 6.52 ( 1H, d), 7.06-7.18 (1H, m), 7.43-7.57 (1H, m), 7.99 (lH, d) and 8.28-8.33 (1H, m). Example 13 χνΠ (S)-5-"4 -hydroxyisoxazolidine-2-carbonyl 1-3-methyl-1-(isobutyl V6-"2-methyl-1H-pyrrolo-l-2,3-blpyridin-1-ylmethyl 1 thiophene "2.3-dl pyrimidine-2,4( 1H.3H)-dione
-95 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 A7 ______B7 五、發明説明(92 ) — ~" 基甲基1-2,4-二氧代4吩並[2,3-dl嘧啶-5-羟酸 甲g旨 依實例3 c)項之製法,由實例3 b)項產物與2-甲基-7-氮雜 4嗓製備,產生小標題化合物。Ms (ESI) 441 [m+h]+。δ 'HCdci3 0.87 (3H, s), 0.90 (3H, s), 2.04-2.21 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 3.9 (s,3H), 4.21 (2H, s), 7.01- 7.06 (1H,m), 7.76 (1H,d),8.22 (1H,d),與 8.8 (1H,(br) s) ° 基-M 異丁甲某-1H-毗咯並 甲基 1-2,4-1 氧代「2 3_dl嘧咗 _s_斿酸 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物。MS (ESI) 427 [M + H] + 哼唑€ 棊龜基墓丁某)_6- 各並『2,3-_<lgt 吩並『2 3-dl„密 啶-2,4ΠΗ.3ΡΠ-二酮 依實例3 e)項之製法,由b)項產物製備小標題化合物。 MS 剛 498 [M+H]H⑴ 0.88(3h,s),〇 9i(3h,s), 1.2- 1.4 (3H,m),2.13-2.22 (1H,m),3.3δ ㈤ 卜359 (2H’m)’3H8(1H’m),4.28_4.4(4H,m),4 62-4 8 (2H, m),5.〇7-5,18(1H,m),6.91-7.04(1H,m) 7 84 (iH d) 822 (1 H,m)與 9.今 1 (1 H,m)。 實例 13xvii) 幽-[4-幾基異今啥後暴小(異丁心-6_[5- -96 - 本纸張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐)-95 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 ______B7 V. Invention description (92) — ~" methyl 1-2,4-dioxo 4 phenanthrene [2,3-dl-pyrimidine-5-hydroxy acid methyl g was prepared according to the procedure of Example 3 c) from the product of Example 3 b) and 2-methyl-7-aza. Ms (ESI) 441 [m+h]+. δ 'HCdci3 0.87 (3H, s), 0.90 (3H, s), 2.04-2.21 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 3.9 (s ,3H), 4.21 (2H, s), 7.01- 7.06 (1H,m), 7.76 (1H,d),8.22 (1H,d), and 8.8 (1H,(br) s) ° base-M A-1H-pyrrolomethyl 1-2,4-1 oxo "2 3_dl pyridinium ss- decanoic acid according to the method of Example 3 d), prepared from the product of item a), to give the subtitle compound. MS (ESI) 427 [M + H] + carbazole € 棊 turtle base tomb _6- each and "2,3-_<lgt" and "2 3-dl „ pyridine-2,4ΠΗ.3ΡΠ- Diketone The subtitle compound was prepared from the product of item b) according to the procedure of Example 3 e). MS 498 [M+H]H(1) 0.88(3h,s),〇9i(3h,s), 1.2- 1.4 (3H,m),2.13-2.22 (1H,m),3.3δ (5) 359 (2H' m) '3H8(1H'm), 4.28_4.4(4H,m), 4 62-4 8 (2H, m), 5.〇7-5,18(1H,m),6.91-7.04(1H , m) 7 84 (iH d) 822 (1 H, m) and 9. present 1 (1 H, m). Example 13xvii) 幽-[4-基基异异啥后暴小(isoxinxin-6_[5- -96 - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm)
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1310036 五、發明説明( A7 B7 93 ) ^ 01310036 V. Description of invention (A7 B7 93 ) ^ 0
基甲基 1-1,2.3.4-四 i.G-甲甚-丨-r 畧 -塞吩並「2-3-dl嘧啶-5-斿峻甲酯 依貫例3 c)項之製法,由實例3 b)項產物與5_氰基峭哚製 備,產生小標題化合物,經急驟矽石層析法純化,.以4〇% 丨乙魬乙酯之異己烷溶液溶離。MS (ESI) 451 [M+H]+。δ HDMSO 0.84-0.86 (6Η,d),2-2.1 (1Η,m),3.2 (3Η,s), 3.6-3.63 (2H, d), 4.85 (3H, s), 5.68 (2H, s), 6.67-6.68 (1H, d), 7.53-7.56 (1H, dd), 7.62-7.63 (1H, d), 7-7l-7.74 (1H, d), 8.12 (1H, s) 朵-i-棊甲羞四箭m小e .工基)-2,4-二i代嘧吩並「2.3_di嘧 依實md)項之製法,由a)項產物製備’產生小標題化合 物。MS(ESl) 437 [_r4iHDMsc)() 8i_〇 83(6H,d),2. 2」UH,m),3.19(3H,s),3.57_3.59(2H,d) 5 52 (2H,s), 5.59-5.6 7.42-7.45 (lH,d),7.8l.7 82 (iH)58(iH)S); 8.15-8.18 (1_H, d) ϋ-f4-經棊呉今吨症-2-卷^^甲基小^ 丁基^ 減基棊 f 基H吩'嘧啶_2 4nH1HV 二酮 -97 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) A7 B7The method for preparing methyl 1-1,2.3.4-tetra-iG-methyl- 丨-r 畧-cephene and "2-3-dl pyrimidine-5-fluorenylmethyl ester according to Example 3 c) Example 3 b) The product was prepared with 5-cyanohydrazide to give the subtitle compound, which was purified by flash chromatography, eluted with 4% EtOAc EtOAc (EtOAc) [M+H]+.δ HDMSO 0.84-0.86 (6Η,d),2-2.1 (1Η,m),3.2 (3Η,s), 3.6-3.63 (2H, d), 4.85 (3H, s), 5.68 (2H, s), 6.67-6.68 (1H, d), 7.53-7.56 (1H, dd), 7.62-7.63 (1H, d), 7-7l-7.74 (1H, d), 8.12 (1H, s ) -i-棊甲羞羞四箭m小e.工基)-2,4-di-i-imido-"2.3_di-pyrene-md-md) method, prepared from product a) produces a subtitle Compound. MS(ESl) 437 [_r4iHDMsc)() 8i_〇83(6H,d),2.2"UH,m),3.19(3H,s),3.57_3.59(2H,d) 5 52 ( 2H, s), 5.59-5.6 7.42-7.45 (lH, d), 7.8l.7 82 (iH) 58(iH)S); 8.15-8.18 (1_H, d) ϋ-f4- 棊呉 吨 症-2-Volume^^Methyl small^ Butyl^ Substituted 棊f-based H-pheno-pyrimidine_2 4nH1HV diketone-97 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7
1310036 五、發明説明(94 ) 依實例3 e)項之製法,由b)項產物制γ I備,經急驟矽石層 法純化’以0-2%甲醇之乙酸乙酯溶液、 % 奋離後,產生標題化 合物。MS (APCI) 508 [M + H]+。δ H^ms〇 0.82-0.86 (6H, m) 2-2.1 (1H, m), 3.2 (3H,s),3.58-3.7 (3h , m), 3.8-3.9 (2H, m) 4-4.1 (1H, m),4.6-4.8 (lH,2m),5.5-5 6 、 •0 (3H,m), 6.66-6.67 (1H,d),7.49-7.53 ( 1 H,m),7.62-7.65 (lH m、7 。1310036 V. INSTRUCTIONS (94) According to the method of Example 3 e), the product of b) is prepared by γ I, and purified by a flash vermiculite method, with 0-2% methanol in ethyl acetate solution, % Fen After that, the title compound is produced. MS (APCI) 508 [M + H]+. δ H^ms〇0.82-0.86 (6H, m) 2-2.1 (1H, m), 3.2 (3H, s), 3.58-3.7 (3h , m), 3.8-3.9 (2H, m) 4-4.1 ( 1H, m), 4.6-4.8 (lH, 2m), 5.5-5 6 , • 0 (3H, m), 6.66-6.67 (1H, d), 7.49-7.53 (1 H, m), 7.62-7.65 ( lH m, 7 .
m),7.81-7,84 (1H d), 8.il (1H, s) ’ 實例13xvii 2,4(lH.3m-二酮 (s··) 5-H-羥基異哼咮喧-2-棊幾幕上^甲篡」_r g 丁某 礼i戈-1,3- + JL-gi 唑-3(2H)-基 吩 #「厶3_di 忒々 _m), 7.81-7,84 (1H d), 8.il (1H, s) ' Example 13xvii 2,4 (lH.3m-dione (s··) 5-H-hydroxyisoindole-2 - 棊 棊 ^ ^ 篡 篡 篡 _ 丁 丁 i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i
a) 1,2,3,4-四氫-3-甲基-1-(異丁某)-2.4-二氣代-6-「2-氣代-3(2H) -本並g基吐基甲基~|g篆吩並「2,3-dl°·密淀-5-錄.酸甲醋 依實例3 c)項之製法,由實例3 b)項產物與苯並嘍唑酮製 備,產生小標題化合物。MS (APCI) 460 [M + H] + 0 δ 1Hd6-dmso 0.88 (6H, d)_, 2.13 (1H, non), 3.19 (3H, s), 3.67 (2H, d), 3.84 (3H, s), 5.32 (2H, s), 7.23-7.70 (4H,m)。 b) 1,2.3.4-四 H -3 -甲基-1-(異丁某)-2.4-二氧代-642-氣代-3(2H)-苯·1έ破唑基甲基1嘧吩並「2.3-dl嘧啶-5-翔酸 -98 - 本紙張尺度適用中國國家樣準(CNS) A4規格(210X 297公釐)a) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2.4-diox-6-"2-gas-3(2H)-iso-g-based The preparation of the product of the example 3 b) and the preparation of the benzoxazolone by the method of the method of the example 3 b) according to the method of the example 3 c) , produces the subtitle compound. MS (APCI) 460 [M + H] + 0 δ 1Hd6-dmso 0.88 (6H, d)_, 2.13 (1H, non), 3.19 (3H, s), 3.67 (2H, d) , 3.84 (3H, s), 5.32 (2H, s), 7.23-7.70 (4H, m). b) 1,2.3.4-tetra-H-3-methyl-1-(isobutyl)-2.4- Dioxo-642-gas-3(2H)-benzene·1έ oxazolylmethyl 1 sulfonyl “2.3-dl pyrimidine-5-cyanic acid-98 - This paper scale applies to China National Standard (CNS) A4 size (210X 297 mm)
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1310036 A7 B7 五、發明説明(Q5 ) 依貫例3 d)项之製法,由a)項產物製備,產生小標題化合 物。MS (APCI) 468 [M+H]+。δ 巾06_隱0 0.86 (6H,d), 2.13 (1H, non), 3.19 (3H, s), 3.64 (2H, d), 5.20 (2H, s), 7.18 (1H, dt),7.28 (1H, dt), 7.63 (1H, dt), 8.18 (1H, d)。 P—I(S) 5-[4二異哼唑啶_2_某羰基μ3_甲茱裒丁某 U_-氧代-並嘍唑dam-基甲某吩並「2 々 -2,4(1Η,3Η) -二西同1310036 A7 B7 V. INSTRUCTIONS INSTRUCTION (Q5) Depending on the method of preparation of item 3 d), the product of item a) is prepared to produce a subtitle compound. MS (APCI) 468 [M+H]+. δ 巾 06_隐0 0.86 (6H,d), 2.13 (1H, non), 3.19 (3H, s), 3.64 (2H, d), 5.20 (2H, s), 7.18 (1H, dt), 7.28 ( 1H, dt), 7.63 (1H, dt), 8.18 (1H, d). P-I(S) 5-[4 diisoxazole pyridine_2_a carbonyl group μ3_methodamine U_-oxo-xacarbazole dam-yl group a pheno-"2 々-2,4 ( 1Η, 3Η) - 二西同
•線 依實例丨g)項之製法,由b)項產物製備標題化合物。ms (ES ) 517 [M+H]+。δ iHc^-DMso (90〇C) 0.88 (6H,d),2.11 (1H, non), 3.20 (3H, s), 3.70 (5H, m), 4.09 (iH) dt), 4.58-4.82 (1H, m), 5.21 (2H, m), 5.54 (1H, dd), 7.22 (iH, m), 7.40 (2H, m), 7·69 (1 H, d) 〇 實例-1 3 x i x (_S) 5-|~4_#至基異g号吐唉-2_基凝基i_3_甲某二】二(異丁某 二氧-6 -甲..基-3-礼.代_ g比p井_ 2 -基甲某1 〜吩砣「2.3 _ d 1 p密咬 -2,4ΠΗ.3Η)-二西同• Line The title compound was prepared from product b) according to the procedure of Example 丨g). Ms (ES ) 517 [M+H]+. δ iHc^-DMso (90〇C) 0.88 (6H,d),2.11 (1H, non), 3.20 (3H, s), 3.70 (5H, m), 4.09 (iH) dt), 4.58-4.82 (1H , m), 5.21 (2H, m), 5.54 (1H, dd), 7.22 (iH, m), 7.40 (2H, m), 7·69 (1 H, d) 〇Example-1 3 xix (_S) 5-|~4_#至基异g号吐唉-2_基凝基i_3_甲某二]二(isobutyl dioxin-6-甲..基-3-礼.代_g ratio p well _ 2 - 基甲一1 ~ Commanded "2.3 _ d 1 p dense bite-2,4ΠΗ.3Η)-二西同
N Η §丄1’2,,3,4-四風-6-|~2,3-二氫-6-甲基-3-免.代_;:|?1;卜1口并_2_某甲基1_ 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1310036 A7 B7 五、發明説明(96 ) 3-甲基-1-(異丁基)-2,4-二氧代》裳吩並『2.3-dl,啶-5-跆酸甲酯 依實例3 c)項之製法’由實例3 b)項產物與2,3-二氫-6-甲 基-3 -氧代-p比p井製備小標題化合物。粗產物經層析法純化 (Si02/Et0Ac)。MS (APCI) 419 [M+H]+。δ 土⑶⑶ 0.97 (6H, d), 2.23-2.33 (1 H, m), 2.29 (3H, s), 3.38 (3H, s), 3.75 (2H, d), 4.03 (3H, s), 5_39 (2H,s),6.85 (1H, d),7.07 (1H, d)。 b) 1,2,3,4-四氤-6-「2,3-二氫-6-甲基-3-氫代-叶莘甲某1-3 -曱基-1-(異丁基)-2,4 -二乳代p菜吩並[2,3-dlp密p^· -5-藉酸 依實例1 f)項之製法’由步驟a)產物製備。粗產物經真空 乾燥,未再鑑定即直接用於下一個步驟。 c) (S)-5-[4-羥基異哼唑啶-2-基羰基]-3-甲基-1-(異丁基)-6-[2,3-二氩-6-甲基-3-氧代-吡畊-2-基甲基]-嘧吩並[2,3-d]嘧啶 -2,4(1H,3H)-二酮 依實例1 g)項之製法,由步驟b)粗產物與(S)-4-#t基異$ σ坐啶鹽酸鹽反應,產生標題化合物。粗產物經逆相HPLC純 化,使用梯度溶離(75%乙酸銨水溶液/25%乙腈至100〇/〇乙 月青)。MS (APCI) 476 [Μ + Η]+。δ咕⑶⑶(因出現幾何異構物 而使質譜複雜化)1.0 (6H,d),2.3 (3H,s),2.5 (1H,m),3 4N Η §丄1'2,,3,4-Four-6-|~2,3-Dihydro-6-methyl-3-free. Generation_;:|?1; Bu 1 and _2 _Methyl 1_ This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (96) 3-methyl-1-(isobutyl)-2,4-di Oxygen exemplified by "2.3-dl, pyridine-5-decanoic acid methyl ester according to the method of Example 3 c) 'from the product of Example 3 b) and 2,3-dihydro-6-methyl-3 The oxo-p ratio p well was used to prepare the subtitle compound. The crude product was purified by chromatography (Si02/EtOAc). MS (APCI) 419 [M+H]+. δ soil (3)(3) 0.97 (6H, d), 2.23-2.33 (1 H, m), 2.29 (3H, s), 3.38 (3H, s), 3.75 (2H, d), 4.03 (3H, s), 5_39 ( 2H, s), 6.85 (1H, d), 7.07 (1H, d). b) 1,2,3,4-tetrahydro-6-"2,3-dihydro-6-methyl-3-hydrogen-leafyl 1-3-mercapto-1-(isobutyl) - 2,4 - di-milo-p-pheno[2,3-dlp-dense p^.-5-borrowing acid according to the method of Example 1 f) was prepared from the product of step a). The crude product was dried in vacuo. It was used directly in the next step without further identification. c) (S)-5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[ 2,3-Di-argon-6-methyl-3-oxo-pyroxy-2-ylmethyl]-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione The crude product from step b) was reacted with (S)-4-#t-iso-s-s-s-s------------ (75% aqueous ammonium acetate / 25% acetonitrile to 100 〇 / 〇 月). MS (APCI) 476 [Μ + Η] + δ 咕 (3) (3) (complex mass spectrometry due to geometric isomers) 1.0 ( 6H,d),2.3 (3H,s),2.5 (1H,m),3 4
(3H,s),3.5-3.7 (〜2H,m),3.8-4.0 (〜2H, m),4.0-4.2 (〜2H πί),4_ 6-5.0 (~ 2Η,m),5 ·3-5 ·6 (〜2H, dd), 6·9 (1 H, m) 7 1 (I Η, m)。 _ X Μ 14 i)(3H, s), 3.5-3.7 (~2H, m), 3.8-4.0 (~2H, m), 4.0-4.2 (~2H πί), 4_ 6-5.0 (~ 2Η, m), 5 · 3- 5 ·6 (~2H, dd), 6·9 (1 H, m) 7 1 (I Η, m). _ X Μ 14 i)
LgJ 5-『4-羥某異崎唑啶-2-基羰基1-3-甲基-6-JJ-甲某, 基甲基1-U(異丁基V裳吩並『2.3-dl嘧啶-2,4(111.:^^;^^ -100 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(97 ) a) l,2,3」i二四氫-3-甲基-6-Γ7-甲基-1K哚-3-某甲某1-1-(異 丁基)-2,4-二氣代4吩並[~2.3-dl嘧啶-5-崧_甲酯 依實例5 a)項之製法,由實例3 b)項產物與7-甲基蚓哚製 備小標題化合物。MS (APCI) 440 [M+H]+。δ lHCDC丨3 0.85-0.89 (6H, d), 2.1-2.2 (1H, m), 2.5 (3H, s), 3.39 (3H, s), 3.62-3.65 (2H, d), 3.98 (3H, s), 4.28 (2H, s), 7.01-7.07 (2H, m), 7.13-7.14 (1H, d), 7.41-7.43 (1H, d), 8 (1H, (br)s) 1))1,2,3,4-四1.-3-甲基-6-「7-甲基-111-啕哚-3-甚甲基1-1-(異 丁基)-2,4-二氧代p菜吩並「2.3-dlp_峻-5-勒齡 依實例1 c)項之製法’由a)項產物製備,產生小標題化合 *〇MS(APCI) 426 [M + H]+«51Hdmso〇.8〇_0.83(6h,(1),2- 2.1 (1H, m), 2.44 (3H, s), 3.25 (3H, s), 3.6-3.62 (2H, d), 4.37 (2H, s), 6.84-6.89 (2H, m), 7.27-7.31 (2H, m), 11 (lH,bs), 14 (1H,(bs),s)。 c) (S) 羥基異哼唑啶-;2-基1羰基l-i-甲華-β-「7_甲幕H- P^1 % -3-基甲基 1-1-(異丁基 V塞吩並『2,3-d~[p_ 读 j/fiHJH)- 二酮 依實例1 g)項之製法,由步驟b)產物與(s)-4-經基異崎。坐 啶鹽酸鹽[實例1 b項]反應’經急驟矽石層析法純化,以〇· 3%甲醇之乙酸乙酯溶液溶離’及自乙酸乙酯:異己垸(9 : i) 中再結晶後_,產生標題化合物。MS (APCI) 497.1 [M + H]。 δ 'Hdms〇 0.81-0.84 (6H, m), 2-2.1 (1H, m), 2.44 (3H s) 3 2 (3H, s), 3.5-3.9 (6H, 3m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, 2m), 5.5 (1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H, m)> 10.95 (1H, -101 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1310036 A7 B7LgJ 5-"4-Hydroxylisoazolidine-2-ylcarbonyl1-3-methyl-6-JJ-A, methyl-l-U (isobutyl V) and 2.3-dl pyrimidine -2,4(111.:^^;^^ -100 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (97) a) l, 2 , 3"i ditetrahydro-3-methyl-6-indole 7-methyl-1K哚-3-, a certain 1-1-1 (isobutyl)-2,4-difluoro 4-[ 2.3-dl Pyrimidine-5-oxime-methyl ester The subtitle compound was prepared from the product of Example 3 b) and 7-methylindole according to the procedure of Example 5 a). MS (APCI) 440 [M+H]+. δ lHCDC丨3 0.85-0.89 (6H, d), 2.1-2.2 (1H, m), 2.5 (3H, s), 3.39 (3H, s), 3.62-3.65 (2H, d), 3.98 (3H, s ), 4.28 (2H, s), 7.01-7.07 (2H, m), 7.13-7.14 (1H, d), 7.41-7.43 (1H, d), 8 (1H, (br)s) 1))1, 2,3,4-tetra-1.-3-methyl-6-"7-methyl-111-indole-3-m-methyl-1-(isobutyl)-2,4-dioxo The preparation of the p dish "2.3-dlp_Jun-5-Lyin according to Example 1 c) is prepared from the product of item a) to produce a subtitle compound *〇MS(APCI) 426 [M + H]+«51Hdmso 〇.8〇_0.83(6h,(1),2-2.1 (1H, m), 2.44 (3H, s), 3.25 (3H, s), 3.6-3.62 (2H, d), 4.37 (2H, s ), 6.84-6.89 (2H, m), 7.27-7.31 (2H, m), 11 (lH, bs), 14 (1H, (bs), s) c) (S) hydroxyisoxazole pyridine-; 2-yl 1 carbonyl li-methyl-β-"7_甲幕H- P^1 % -3-ylmethyl1-1-(isobutyl V-pheno- and 2,3-d~[p_ Reading j/fiHJH)-dione according to the method of the example 1 g), the product of step b) is reacted with (s)-4-pyridylisosyl. pyridine hydrochloride [example 1 b] Purified by stone chromatography, dissolved in ethyl acetate solution of 3% methanol, and recrystallized from ethyl acetate: isohexyl (9: i) _, produces the title compound. MS (APCI) 497.1 [M + H]. δ 'Hdms〇0.81-0.84 (6H, m), 2-2.1 (1H, m), 2.44 (3H s) 3 2 (3H, s ), 3.5-3.9 (6H, 3m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, 2m), 5.5 (1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H , m)> 10.95 (1H, -101 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7
bs)。 實例14ii) (R) 棊J·呤唑啶-2-^ 3朵-3-·基H 異丁某)4哈更 a) 1,2,3,4-四 1二3-甲某-6-「2-甲 -甲基-ή-ρ -甲某- lH-gH ^-^12^-cn嘧啶-2 4(Ί H.3H)-二 ϋ 巧1哚-3-某甲某1-1-(異_ 啶-5-跆龄甲酿 依貫例5 a)員之製法,由貫例3 a)項產物與2_甲基个朵製Bs). Example 14ii) (R) 棊J· oxazolidine-2-^ 3 -3-·yl H isobutyl) 4 ha a) 1,2,3,4-tetra 1 2 3-A-6 - "2-methyl-methyl-ή-ρ-甲一- lH-gH ^-^12^-cn pyrimidine-2 4(Ί H.3H)-二ϋ Qiao 1哚-3-一甲一1- 1-(iso- pyridine-5-跆 甲 甲 依 依 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 员 员 员 员 员 员 员 员 员 员 员 员
d), 7.91 (1H, s, br) 〇d), 7.91 (1H, s, br) 〇
JL基H4.-二氧塞吩並『23川卜念冲g产咕 依貝例3 d)項之製法,由a)項產物製備。MS (£§1) 426 [M + H卜 δ HDMS〇 0.80 (6H,d),! 99 2 〇9 (1H,⑷,2 37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H,t), 7.26 (1H,d), 10.96 (1H, s),M.05 (1H,s,br)。 21..(民)· 淀基羰某 甲某 _ή_「?_ 甲其」h_ _jl.农.-3-.基„〒基丄丄異丁某皋吟並口密峻 依貫例3 _d)項之製法,由步驟a)產物與(R)_4_異噚唑啶醇 鹽鉍鹽[貫例2 b項]製備。MS (APCI) 497 [M+H]+。δ丨知抑。 0.80-0.83 (6H, m), i.98-2.08 ( 1H, m), 2.37 (1H, s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, _____- 102 - 本紙張尺度適用中國國豕標準(CNS) A·4规格(210 X 297公董) 1310036 A7 B7 五、發明説明(99 ) m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.50 (0.5H, d, br), 5.54 (0.5H, d), 6.90 (1H, t), 6.98 (1H, t), 7.25 (1H, d), 7.39 (0.5H, d),7.43 (0_5H,d),10.91 (1H, s)。 實例14 i i i) (S) 5-「4-羥基異哼唑啶-2-某羰基1-3-甲基-6-ΙΎ2-甲某)-lH-吡 咯並「2.3 - b 1吡啶-3 -基甲某1 - 1 -丙基4吩並「2,3 - d 1嘧啶 -2,4ΠΗ,3Η)-二酮JL-based H4.-dioxetane is produced by the product of item a). MS (£§1) 426 [M + Hb δ HDMS〇 0.80 (6H, d),! 99 2 〇9 (1H, (4), 2 37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H, t ), 7.26 (1H, d), 10.96 (1H, s), M.05 (1H, s, br). 21. (Min) · 盐基炭甲甲____?_甲甲"h_ _jl .N. _. 农 〒 〒 丄丄 丄丄 丄丄 皋吟 皋吟 皋吟 皋吟 皋吟 皋吟 皋吟 口 例 例 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Preparation of salt [Case 2 b]. MS (APCI) 497 [M+H]+. δ丨知抑. 0.80-0.83 (6H, m), i.98-2.08 ( 1H, m), 2.37 (1H , s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, _____- 102 - This paper scale applies to China National Standard (CNS) A.4 specification (210 X 297 dongdong) 1310036 A7 B7 V. Description of invention (99) m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.50 (0.5H, d, br ), 5.54 (0.5H, d), 6.90 (1H, t), 6.98 (1H, t), 7.25 (1H, d), 7.39 (0.5H, d), 7.43 (0_5H, d), 10.91 (1H, s). Example 14 iii) (S) 5-"4-Hydroxyisoxazolidine-2-carbonyl 1-3-methyl-6-oxime-2-methyl)-lH-pyrrolo-"2.3-b 1 pyridine -3 - A certain 1 - 1 -propyl 4 of the base A and "2,3 - d 1 Piperidine -2,4ΠΗ, 3Η) - dione
£〇 3-甲基-64(2-甲基-1Η-吡咯並[2,3-bl吡啶-3-基)甲基1-2.4-二氧代-1-丙基-1.2.3,4-四氤嘧吩並「2.3-dl嘧啶-5-羧酸甲酯 依實例6 b)項之製法,由實例9 c項產物與2-甲基-1H-吡 咯並[2,3-b]吡啶製備小標題化合物。 MS (ESI) 427 [M + H] + δ 1 Hd^-dmso 0.82 (6Η, t), 1.59 (2H, sextet), 2.38 (3H, s), 3.19 (3H, s), 3.72 (2H, t), 3.83 (3H, s), 4.17 (2H, s), 6.98 (1H, dd), 7.75 (1H, d),8.10 (1H, dd), 11.48 (1H, s)。 b) 3-甲基-6-「(2-甲基-1H-吡咯並i2.3-bl吡啶-3-基)甲基1-2.4-二氣代-1-丙基-1.2.3.4-四氤嘧吩並「2,3-dl嘧啶-5-斿酸鈉 -103 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 依實例1 f)項之製法,由a項產物劁供,』 田a .、座物1備小標題化合物。 MS (ESI) 413 [M + H] + δ 'Hd2〇0.77 (3Η, t), 1.55 ΠΗ sextet^ ί λ·^ (in, sextet), 2.43 〇H, s), 3.34 (3Η, s), 3.63 (2H,t), 4.16 (2Η, s),7.08(lH, dd), 7.89 (1 Η, d), 8.06 (1Η, d)。 O. (s) 5-μ-經基 盖藏基 ·6_γγ2_ 甲某)_ih_ -2,4(1H,3H)-二酮 依實例1 g)項之製法,由步驟b)產物與⑻冬昱噚唑啶醇 鹽酸鹽[實例1 b)項]製備,產生標題化合物之固體。 MS (APCI) 484 [M+H]+ 且 δ 'HD6.DMS〇 0.84 (3H, d), 1.64 (2H, d), 2.38 (3H, s), 3.22 (3H, s), 3.41 (1H, d), 3.75 (3H, m),3.93 (2H, S), 4.10 (2H, m), 4.70 (1H, s), 5.00 (1H, s), 6.91 (1H, s), 7.76 (1H, d), 8.06 (1H, s) 10.92 (1H, s)。 ’ ’ 實例15i) (SL·卜「4-羥基異羰基>3-甲基·6_「f2_甲」^ 圭並[4i5_b1吨基 l-i-丙 -2.4ΠΗ.3Η)-二酮 红1,213,4-四氣-1^_^6_丨(21胺基)_3士咪唑^11^^ 喂基甲基卜氧代-1-丙茱-碟吩並「2.3-dl峰 甲酯 ' 依實例13xii a)項之製法,由實例9 c)項產物製備小標, 化合物。 " MS (ESI) 456 [M + H] + ____- 104 -£〇3-methyl-64(2-methyl-1Η-pyrrolo[2,3-blpyridin-3-yl)methyl1-2.4-dioxo-1-propyl-1.2.3,4 - a method for the preparation of tetramethylpyrimidine "2.3-dl pyrimidine-5-carboxylate according to Example 6 b), from the product of Example 9c and 2-methyl-1H-pyrrolo[2,3-b] The title compound was prepared by pyridine. MS (ESI) 427 [M + H] + δ 1 Hd^-dmso 0.82 (6 Η, t), 1.59 (2H, sextet), 2.38 (3H, s), 3.19 (3H, s) , 3.72 (2H, t), 3.83 (3H, s), 4.17 (2H, s), 6.98 (1H, dd), 7.75 (1H, d), 8.10 (1H, dd), 11.48 (1H, s). b) 3-methyl-6-"(2-methyl-1H-pyrrolo-i2.3-blpyridin-3-yl)methyl-1-2.4-di- gaso-1-propyl-1.2.3.4- Tetramethyl thiophene "2,3-dl pyrimidine-5-decanoate-103 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 According to Example 1 f) The method of preparation, from the product of a product, 』田a., 座1, subtitle compound. MS (ESI) 413 [M + H] + δ 'Hd2〇0.77 (3Η, t), 1.55 ΠΗ sextet^ ί λ ·^ (in, sextet), 2.43 〇H, s), 3.34 (3Η, s), 3.63 (2H,t), 4.16 (2Η, s),7.08(lH, dd), 7.89 (1 Η, d) , 8.06 (1Η, d). O. (s) 5 -μ- via base cover ·6_γγ2_甲) _ih_ -2,4(1H,3H)-dione according to the method of the example 1 g), from the product of step b) and (8) oxazolidine hydrochloride The salt [Example 1 b) was prepared to give the title compound as a solid. MS (APCI) 484 [M+H]+ and δ 'HD6.DMS 〇 0.84 (3H, d), 1.64 (2H, d), 2.38 ( 3H, s), 3.22 (3H, s), 3.41 (1H, d), 3.75 (3H, m), 3.93 (2H, S), 4.10 (2H, m), 4.70 (1H, s), 5.00 (1H , s), 6.91 (1H, s), 7.76 (1H, d), 8.06 (1H, s) 10.92 (1H, s). ' 'Example 15i) (SL·Bu 4-hydroxyisocarbonyl>3-methyl·6_“f2_甲”^ 圭和[4i5_b1 ton li-propyl-2.4ΠΗ.3Η)-dione red 1,213, 4-四气-1^_^6_丨(21-amino)_3simidazole^11^^ Feeding methyl-oxo-oxo-propionium-disc and "2.3-dl peak methyl ester" by example 13xii a) Method for the preparation of small standards, compounds from the product of Example 9 c). " MS (ESI) 456 [M + H] + ____- 104 -
本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱) 1310036 A7 B7 五、發明説明(101 ) δ 1 H〇mso 0.83 (3H, s),0.85 (3H,s),2.04-2.11 (1H, m) 2 94 (2H, d), 3.19 (3H, s), 3.6 (2H, d),3.85 (3H, s), 5.4 (2H s) 6.83-6.9 (2H, m), 6.97 (1H, t),7.22 (1H, d)。 b) 1,2,3,4-四氫-3 -甲基-6〇(甲胺基咮吨 # p 5_bK 噱-3-暴甲基卜2,4二^·氧代-1二两基吩並「2 嘧吟二5-教酸 依實例3 d)項之製法,由a)項產物製備,產生小標題化合 物0 MS (APCI) 428 [M + H] + m)· 5-[4-羥暴異噚唑嗑胺基) 处咪 < 並Κ5·卟比密读 -2,4( 1H.3H)-二酮 依實例3 e)項之製法,由b)項產物製備 衣1苛,產生小標題化名 物。 MS (APCI) 499 [M + H]、 δ lHDMS0 0.81 (3H,m),0.86 (2H,mu 58」6l (3H s) 2 ㈤’ S)’ 3.2 (3H,s),3·6“·2 (6H,叫,5 ΐδ_5 62 ⑽,γ 6.88-6.99 (3H,m),7.2-7.3 (2H,m)。 ; 實例15 mThis paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public) 1310036 A7 B7 V. Invention description (101) δ 1 H〇mso 0.83 (3H, s), 0.85 (3H, s), 2.04- 2.11 (1H, m) 2 94 (2H, d), 3.19 (3H, s), 3.6 (2H, d), 3.85 (3H, s), 5.4 (2H s) 6.83-6.9 (2H, m), 6.97 (1H, t), 7.22 (1H, d). b) 1,2,3,4-tetrahydro-3-methyl-6〇(methylaminoxanthene# p 5_bK 噱-3-violet methyl b 2,4 di^-oxo-1 diamyl The preparation method of "2 pyridinium-5-teaching acid according to the example 3 d) is prepared from the product of item a) to produce the subtitle compound 0 MS (APCI) 428 [M + H] + m)· 5-[4 - hydroxy acesulfame oxime oxime) Mimi < Κ 5 · 卟 密 密 - 2, 4 ( 1H. 3H) - dione according to the method of Example 3 e), from the product of b) preparation of clothing 1 Severe, resulting in a subtitle. MS (APCI) 499 [M + H], δ lHDMS0 0.81 (3H, m), 0.86 (2H, mu 58"6l (3H s) 2 (5) 'S)' 3.2 (3H, s),3·6"·2 (6H, ,, 5 ΐδ_5 62 (10), γ 6.88-6.99 (3H, m), 7.2-7.3 (2H, m); Example 15 m
裝 玎装
ΜΜ
LS_)-5-f4-斿基-2-異噚唑啶基藕某丄T,立1 二 丙某-6-f4.5-. 蓋-2 ·甲基-1 Η -味g生-1-基甲基~|g菜吩拍r 2 -> ,,. 1 = 嘧啶-2 4n h._3H 二酉同 _LS_)-5-f4-mercapto-2-isoxazole pyridine 藕 丄 T, 立 1 二丙-6-f4.5-. 盖-2 · methyl-1 Η -味 g生-1 -ylmethyl~|g dish ordered r 2 -> ,,. 1 = pyrimidine-2 4n h._3H dimorphic _
1310036 A7 B7 五、發明説明(102 ) a) β-[4,5-二氣-2-甲基-1H-咪唑甲基 四 基-2,4-二氧代-_1-丙.基-嘍吩並「2,3-(11嘧啶-^^^^7@ 依實例3 c)項之製法’由實例9 c)項產物製備,產1生小標 題化合物。 MS (APCI) 445/447 [M + H] + δ 'HCdcl3 〇·99 (3H, t), 1.76 (2H, sextet), 2.38 (3H s) 3 39 (3H, s), 3.85 (2H, td),3.99 (3H, s), 5.26 (2H, s)。1310036 A7 B7 V. INSTRUCTIONS (102) a) β-[4,5-Dimethyl-2-methyl-1H-imidazolylmethyltetrayl-2,4-dioxo-_1-propyl-yl-indole The preparation of the product 2,3-(11-pyrimidine-^^^^7@ according to Example 3 c) was prepared from the product of Example 9 c), yielding a subtitle compound. MS (APCI) 445/447 [ M + H] + δ 'HCdcl3 〇·99 (3H, t), 1.76 (2H, sextet), 2.38 (3H s) 3 39 (3H, s), 3.85 (2H, td), 3.99 (3H, s) , 5.26 (2H, s).
Mpt. 155-1 56〇C b) 6-『4,5-二乱-2-甲基-1!1-咪吃-1-基甲基1-117>3.4_四氣_3_甲 基- 2,4-二乳代-1-丙基->塞吩並『2,3-dlp密喊-5-勒齡麵鹽 依實例3 d)項之製法’由實例a)項產物製備,產生小標題 化合物。 MS (APCI) 43 1/433 [M+H] + δ 1ΗDMso-D6 〇·87 (3Η, t), 1.67 (2Η, sextet), 2.38 (3Η, s), 3.19 (3H, s),3.78 (2H, t), 5.23 (2H, s)。 c) (S)-5-『4-羥基-2-異哼唑啶某羰某1-3-甲基-1-丙某-ή-μ s. 一氣-2-甲基-1H -味°坐-1-基甲基1-1¾吩抗「2,3-dlp密峻 -2,4( 1H.3H)-二酮 依實例3 e)項之製法,由實例b)項產物製備,產生小標題 化合物。 MS (APCI) 502/504 [M + H] + δ 丨 HcdCI3 Γ.01 (3H, t), 1.79 (2H, sextet), 2.39 (3H, s), 3.35 + 3.38 (3H,2xs 比例 1 : 4),3.47-3.57 (1H, m), 3.81-3.96 (2H, m), 4.01-4.10 (2H, m), 4.57 (1H, d), 4.58-4.75 (1H, m), 4.93 (1H, d), 5.19-5.27 (2H, m)。 -106 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1310036 A7 B7 五、發明説明(103 ) 實例15iii 5-「(4S)-4-羥基異呤唑啶-2-基羰基1-6-「2-(羥甲基)-1Η-笨並 咪唑-1-基甲基1-3-甲基-1-丙基-違吩並嘧啶-2,4ΠΗ,3Η)- 二酉同Mpt. 155-1 56〇C b) 6-『4,5-disorder-2-methyl-1! 1-imi-1-ylmethyl-1-17>3.4_tetraqi_3_methyl - 2,4-di-lactyl-1-propyl-> thiophene and 2,3-dlp screaming -5 - ergon salt according to the method of Example 3 d) 'Preparation of product of example a) , producing a subtitle compound. MS (APCI) 43 1/433 [M+H] + δ 1ΗDMso-D6 〇·87 (3Η, t), 1.67 (2Η, sextet), 2.38 (3Η, s), 3.19 (3H, s), 3.78 ( 2H, t), 5.23 (2H, s). c) (S)-5-"4-Hydroxy-2-isoxazole pyridine a carbonyl 1-3-methyl-1-propanol- ή-μ s. one gas-2-methyl-1H - taste ° The preparation of -1-ylmethyl 1-13⁄4 phenanthrene is resistant to "2,3-dlp mil-2,4(1H.3H)-dione according to Example 3 e), and is prepared from the product of example b). Subtitle compound MS (APCI) 502/504 [M + H] + δ 丨HcdCI3 Γ.01 (3H, t), 1.79 (2H, sextet), 2.39 (3H, s), 3.35 + 3.38 (3H, 2xs Proportion 1: 4), 3.47-3.57 (1H, m), 3.81-3.96 (2H, m), 4.01-4.10 (2H, m), 4.57 (1H, d), 4.58-4.75 (1H, m), 4.93 (1H, d), 5.19-5.27 (2H, m) -106 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Invention description (103) Example 15iii 5-" (4S)-4-hydroxyisoxazolidine-2-ylcarbonyl1-6-"2-(hydroxymethyl)-1Η-stupidimidazol-1-ylmethyl1-3-methyl-1-propane Base-violent pyrimidine-2,4ΠΗ,3Η)-
a) 1,2,3,4-四氣羥甲基)-1Η-苯並咪唑-1-基甲某1-3-甲 基-2,4-二氣代-1-丙基吩並|~2,3-dl嘧啶-5-莪酸甲酯 添加氫化納(6 0 m g,6 0 %懸浮液)至0 °C與氮氣下,含2 -苯 並咪唑甲醇(2 1 0 mg)之無水DMF溶液中。1 0分鐘後,滴加 含實例9c產物(500 mg)之DMF溶液,反應混合物於室溫下 攪拌3小時。加水,過濾所形成之沉澱,以乙酸乙酯與醚 依序洗滌,產生標題化合物之黃色固體(230 mg)。濾液經 二氣曱烷萃取2次。有機相經硫酸鎂脫水,真空濃縮,產 生之褐色固體與先前得到之產物合併,產生標題化合物之 淺褐色固體(4 8 0 m g)。 MS (ES) 443 [M + H] + *δ !Hdmso 0.79-0.84 (3H, t), 1.52-1.62 (2H, q), 3.19 (3H, s), 3.69-3.74 (2H, t), 3.85 (3H, s),4.77-4.79 (2H, d), 5.71 (2H, s), 5.84-5.88 ( 1 H, t), 7.17-7.26 (2H, m), 7.51-7.54 (1H, d), 7.61- -107 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)a) 1,2,3,4-tetramethylolmethyl)-1Η-benzimidazol-1-ylmethyl 1-3-methyl-2,4-dihydro-1-propylphene ~2,3-dl-pyrimidine-5-decanoic acid methyl ester was added with sodium hydride (60 mg, 60% suspension) to 0 ° C under nitrogen with 2-benzimidazole methanol (2 10 mg) In anhydrous DMF solution. After 10 minutes, a solution of the product of Example 9c (500 mg) was applied dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added and the resulting residue was purified eluting elut elut elut elut elut elut elut elut elut The filtrate was extracted twice with dioxane. The organic phase was dried with EtOAc (EtOAc)EtOAc. MS (ES) 443 [M + H] + *δ !Hdmso 0.79-0.84 (3H, t), 1.52-1.62 (2H, q), 3.19 (3H, s), 3.69-3.74 (2H, t), 3.85 (3H, s), 4.77-4.79 (2H, d), 5.71 (2H, s), 5.84-5.88 ( 1 H, t), 7.17-7.26 (2H, m), 7.51-7.54 (1H, d), 7.61- -107 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)
-線 1310036 A7 B7 五、發明説明(104 ) 7.63 (1H,d)。 W_l,2,3,4-四氫羥甲某苽並咪唑-N基甲某 基-2,4-二氧代-1二丙基^盡吩技「2 3-d·!嘧啶_5_淼酸鈉 依實例1 f)項之製法,由實例15iii a)項產物(420 mg)製備 ’產生標題化合物之白色固體(26〇 mg)。 MS (ES) 429 [M + H] +- Line 1310036 A7 B7 V. INSTRUCTIONS (104) 7.63 (1H, d). W_l,2,3,4-tetrahydroxymethyl-indoloimidazole-N-methyl-methyl-2,4-dioxo-1dipropyl^"2 3-d·!pyrimidine_5_ Sodium decanoate was prepared according to the procedure of Example 1f) from EtOAc (m.
依實例13vii c)項之製法,由實例15iii b)項產物製備。粗 產物經逆相製備性HPLC純化,以25%至95%乙腈之〇· ι〇/〇乙 酸銨水溶液溶離,產生標題化合物(75 mg)。 MS (ES) 500.1 583 [M + H] + 5 'HDMs〇 0.79-0.84 (3H, t), 1.54-1.59 (2H, m), 3.2 (3H, s), 3.6-4.2 (6H,m之範圍),4.6-4.8 (3H, 2m),5.4-5.9 (4H, m), 7.18-7.20 (2H, m), 7.6-7.66 (2H, m)。 實例15iv g..:「(4S)-4-.輕基異呤唑啶-2-基羰某i_3_甲基丙甚_6_Γ2_脖 基-1Η-苯並咪吐-1-基甲某1-4吩並rndl嘧啶-2 4r] hh)- 二酮Prepared from the product of Example 15iii b) according to the procedure of Example 13vii c). The crude product was purified by EtOAc EtOAc EtOAc. MS (ES) 500.1 583 [M + H] + 5 'HDMs〇0.79-0.84 (3H, t), 1.54-1.59 (2H, m), 3.2 (3H, s), 3.6-4.2 (6H, m range ), 4.6-4.8 (3H, 2m), 5.4-5.9 (4H, m), 7.18-7.20 (2H, m), 7.6-7.66 (2H, m). Example 15iv g..: "(4S)-4-. Light-based isoxazolidine-2-ylcarbonyl carbonyl i_3_methylpropan _6_Γ2_ neck base-1 Η-benzopyr-1-yl group A 1-4 NB rndl pyrimidine-2 4r] hh)-dione
OHOH
本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1310036 A7 __B7 五、發明説明(105 ) a) 6-f2-胺基-1H -苯並味唆-1-臬甲某ι_ι·2.3,4 -四氣-3-甲莘_ 2.4- 二氧代-1 -丙基->塞吩並「2.3-d~|p密峻-5-斿酸甲酯 添加氫化鈉(60 mg ’ 60%懸浮液)至氮氣下,含2-胺基苯 並咪唑(200 mg)之無水DMF溶液中。1〇分鐘後,滴加含實 例9c產物(500 mg)之無水DMF溶液,反應混合物於室溫下 攪拌3小時。加水’過濾所形成之沉澱,以乙酸乙酯與醚 依序洗滌’產生標題化合物之橙褐色晶體(220 mg)。 MS (ES) 428 [M + H] + δ 'Hdms〇 0.81-0.86 (3H, t), 1.54-1.66 (2H, q), 3.19 (3H, s), 3.72-3.76 (2H, t), 3.88 (3H, s), 5.4 (2H, s), 6.6 (2H, s), 6.84-6.89 (1H, t), 6.93-6.98 (1H, t), 7-7.15 (2H, m) ° b) 6-丨2-胺基-1H-苯並咪唑-i-某甲某·μ i 2 3 4•四氯_3_甲某_ 2.4- 二氧代-1-丙基-魂吩技P. ,3-dl嘧啶-5-務醢 依實例1 f)項之製法’由實例15iv a)項產物(22〇 mg)製備 ,產生4化合物之淺黃色固體(190 mg)。 MS (ES) 414 [M + H] + 丨4 (S)-羥基異呤啥.啶-2-某粦某1-3-甲某-1-丙某-6-l~2-胺 羞苯並咪°坐-1-幕甲某1-4吩抱f2,3-dl嘧咗-2.4ΠΗ.3Η)-二酮 依實例13vii c)項之製法,由實例i5iv b)項產物(190 mg) 製備。粗產_物經逆相製備性HPLC純化,以5%至95%乙腈 之0.1 %乙酸按水溶液溶離,然後與甲醇研磨及過濾,產 生標題化合物之白色固體(19 mg)。 MS (ES) 485.1 63 1 [M + H] + -- -109 - 本紙張尺度適用中國國家標準(CNS) A4规格_(21〇 X 297公爱) 1310036 A7 B7 五、發明説明(106 ) δ 'Hdmso 0.82-0.86 (3H, t), 1.57-1.62 (2H, q), 3.19 (3H, s), 3.65-4.15 (6H, m之範圍),4.65-4.80 (1H, m),5.26-5.60 (3H, m), 6.63-6.69 (2H, bm), 6.84-6.87 (1H, t), 6.93-6.97 (1H, t), 7.12-7.14 (1H,d),7.20-7.27 (1H,2d)。 實例16 i) (3) 5-f4-羥基異哼唑啶-2-某羰基1-3-甲某-6-f2-(甲胺基)-1Η-This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 __B7 V. Description of invention (105) a) 6-f2-Amino-1H-Benzo-indole 臬-1-臬甲Ig_ι·2.3,4 -tetraki-3-carboindole_2.4-dioxo-1 -propyl->ceramone"2.3-d~|p dimethyl-5-decanoate methyl ester added sodium hydride ( 60 mg '60% suspension) to a solution of 2-aminobenzimidazole (200 mg) in anhydrous DMF under nitrogen. After 1 min, an anhydrous DMF solution containing the product of Example 9c (500 mg) was added dropwise. The reaction mixture was stirred at room temperature for 3 hr. EtOAc (EtOAc) EtOAc. + δ 'Hdms〇0.81-0.86 (3H, t), 1.54-1.66 (2H, q), 3.19 (3H, s), 3.72-3.76 (2H, t), 3.88 (3H, s), 5.4 (2H, s), 6.6 (2H, s), 6.84-6.89 (1H, t), 6.93-6.98 (1H, t), 7-7.15 (2H, m) ° b) 6-丨2-amino-1H-benzene And imidazole-i-a certain 甲·μ i 2 3 4•tetrachloro_3_甲某_ 2.4- dioxo-1-propyl-soul tactics P., 3-dl pyrimidine-5- Example 1 Method f) is produced by example 15iv a) Preparation (22 mg), yielding 4 compound as a pale yellow solid (190 mg). MS (ES) 414 [M + H] + 丨4 (S)-hydroxyisoindole. -3-A certain-1-propan-6-l~2-amine benzo benzopyrene ° sitting 1- -1- A 1-4 commanded f2,3-dl pyridinium-2.4ΠΗ.3Η)-two The ketone was prepared according to the procedure of Example 13vii c), which was obtained from the product i iv b) (190 mg). The crude product was purified by reverse phase preparative HPLC eluting with 5% to 95% acetonitrile in 0.1% acetic acid. It is then triturated with methanol and filtered to give the title compound as a white solid (19 mg). MS (ES) 485.1 63 1 [M + H] + -- -109 - The paper size applies to the Chinese National Standard (CNS) A4 specification _( 21〇X 297 公)) 1310036 A7 B7 V. INSTRUCTIONS (106) δ 'Hdmso 0.82-0.86 (3H, t), 1.57-1.62 (2H, q), 3.19 (3H, s), 3.65-4.15 (6H , range of m), 4.65-4.80 (1H, m), 5.26-5.60 (3H, m), 6.63-6.69 (2H, bm), 6.84-6.87 (1H, t), 6.93-6.97 (1H, t) , 7.12-7.14 (1H, d), 7.20-7.27 (1H, 2d). Example 16 i) (3) 5-f4-hydroxyisoxazole pyridine-2-carbonyl 1-3-methyl-6-f2-(methylamino)-1Η-
1^(異丙基)-2,4-二氣代3裳吩並「2,3-dl嘧遠-5-卷酸甲酯 依實例13vii) a)項之製法’由實例8 c)項產物與2-甲胺道 苯並咪唑製備,經與乙酸乙酯研磨及過濾後,產生小標竭 化合物。 MS (ESI) 442[M + H] + δ 'Hdmsq 1.40-1.42 (6Η, d), 2.94-2.96 (3H, d), 3.16 (3H, s) 3.85 (3H, s), 4.3 (lH, bs),5.39 (2H, s), 6.84-6.99 (3H, m) 7. 1 1-7.14 (1Ή, d), 7.20-7.22 (1H,d)。 」,3,4-四氫3-1^6-『(2_甲胺基^]^苽並呋1^1-基_kl-(異丙棊)-代4吩並嘧啶_%鉑給 依貫例3 d)項之製法,由a)項產物製備,產生小標題化1^(isopropyl)-2,4-digastrix 3 exemplified "2,3-dl-pyrim-5-volum acid methyl ester according to Example 13vii) Method a) [Example 8 c) The product was prepared with 2-methylamine benzimidazole, which was triturated with ethyl acetate and filtered to give a small fraction of compound. MS (ESI) 442 [M + H] + δ 'Hdmsq 1.40-1.42 (6Η, d) , 2.94-2.96 (3H, d), 3.16 (3H, s) 3.85 (3H, s), 4.3 (lH, bs), 5.39 (2H, s), 6.84-6.99 (3H, m) 7. 1 1- 7.14 (1Ή, d), 7.20-7.22 (1H,d). ",3,4-tetrahydro-1^6-"(2_methylamino)^苽^furfuryl 1^1-yl_kl -(isopropylidene)-substituted 4-phenothi-pyrimidine_% platinum is prepared according to the method of item 3 d), which is prepared from the product of item a) to produce a subtitle
1310036 A7 B7 五、發明説明(107 ) 物。 MS (ESI) 428[M + H] + C) (sm.4-羥基異啐唑咗-2-某羰基1-3-甲某甲胺某)-1 Η -苯並咪唑-1_-基甲基1 - 1 -(異丙基)gf吩並「2.3 - d 1嘧咗 -2.4ΠΗ.3Η)-二酮 經急驟矽石 然後與趟 依實例1 3vii c)項之製法,由b)項產物製備, 層析法純化’以0-3% f醇之二氯甲烷溶液溶離 研磨,產生小標題化合物。 MS (APCI) 499 [M + H] + δ 'Hdmso 1.41-1.42 (6H, m), 2.94-2.95 (3H, d), 3 1? 3.55-3.66 (1H, 2d), 3.81-3.84 (1H, m), 3.89-4 riR 、 ’ S)’ ’ m), 】 (1H, m), 4.1-4.2 (1H, m),4.6-4.75 (1H, 2m), 5.i7 · •26 (1¾ m), 5.37-5.44 ( 1H, 2m), 5.52-5.61 (1H, 2m),6.89.6 99 ’ m)' 7.19-7.30 (2H, m)。 (3’H,1310036 A7 B7 V. Description of invention (107). MS (ESI) 428 [M + H] + C) (sm. 4-hydroxyisoxazole-2-one carbonyl 1-3-methylamine)-1 Η-benzimidazole-1_-yl Base 1 - 1 -(isopropyl)gf is exemplified by "2.3 - d 1 pyridin-2.4ΠΗ.3Η)-dione via flash meteorite followed by the method of example 1 3vii c), by item b) Preparation of the product, purification by chromatography <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; , 2.94-2.95 (3H, d), 3 1? 3.55-3.66 (1H, 2d), 3.81-3.84 (1H, m), 3.89-4 riR , ' S)' ' m), 】 (1H, m) , 4.1-4.2 (1H, m), 4.6-4.75 (1H, 2m), 5.i7 · •26 (13⁄4 m), 5.37-5.44 (1H, 2m), 5.52-5.61 (1H, 2m), 6.89. 6 99 ' m)' 7.19-7.30 (2H, m). (3'H,
實例16 ii) (S)-5-f4-羥某-2-異啐唑啶某羰基l-6-f4,5-二氯 口圭d -基甲基-3-甲基-1-(異丙基吩-並「2,3_-d]雙Example 16 ii) (S)-5-f4-hydroxyl-2-isoxazole pyridine a carbonyl group l-6-f4,5-dichloromethylid d-ylmethyl-3-methyl-1-(iso Propyl pheno- and "2,3_-d] double
二氮-2-甲某-1H-咪唑-卜基甲基」-3 d --1—ϊ*-^—-- 3 _曱基-1-(異丙某 _ _ - 111 -Diazol-2-methyl-1H-imidazole-buylmethyl"-3 d -1 -ϊ*-^--- 3 _mercapto-1-(isopropyl _ _ - 111 -
本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(108 ) -- 依實例3 c)項之製法,由實例8 c)項產物製備,產生小標 題化合物。 。 MS (APCI) 445/446 [M + H] + δ ’HcDcn 1.56-1.61 (6H, m),2.37-2.38 (3H,m),3.37 (3H,S), 3.98 (3H,s),4.40-4.50 (1H,br.s),5.25 (2H, s)。 ϋ-『4,5·:·二氣-2-甲棊-1_H-咪唑-1-基甲某木四蔚甲 棊-1-(異弓_基)-2,4-二氧代4吩並[2.3-(11嘧味_5-勒酷 依實例3 d)項之製法’由a)項產物製備,產生小標題化合 物。 MS (APCI) 43 1/433 [M + H] + δ 1.53 (6H,d),2.39 (3H,S),3.31 (3H,s,),3.54-3.69 (IH,m),5.32 (2H,s)。 gl (§..)-5-「.4-喪基-2-異p号吐咬基羧基1·6-Γ4,5-二着.-2-甲基-1H-迷__a坐二L-基Jf基-3-甲基-1-(異丙基νϊ吩並f2.3-dl嘧啶-5-#醯胺 依實例3 e)項之製法,由b)項產物製備,產生標題化合物。 MS (APCI) 502/504 [M + H] δ 'Hcocn 1.55-1.61 (6Η, m), 2.39 (3H, s), 3.33 (3H, s), 3.51 (1H, dd), 4.01-4.09 (2H, m), 4.40-4.55 (lH,br.s), 4.57 (1H, d); 4.68-4.75 (1H, m); 4.95 (1H,d); 5.15-5.28 (2H, m)。 實例1 6 i i i (S)-5-「4-羥綦異崎唑啶-2-基羰基1-6-丨?-(拜甲某)-1 H-笨並咪 唑-卜基曱基1-3-甲基-1-(異丙基V塞吩並「2.3-dl嘧啶-2.4UH.3H)-二酮 -112 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1310036 A7 B7 五、發明説明(109 )This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1310036 A7 B7 V. Inventive Note (108) -- According to the method of Example 3 c), it is prepared from the product of Example 8 c), resulting in small Title compound. . MS (APCI) 445/446 [M + H] + δ 'HcDcn 1.56-1.61 (6H, m), 2.37-2.38 (3H, m), 3.37 (3H, S), 3.98 (3H, s), 4.40- 4.50 (1H, br.s), 5.25 (2H, s). Ϋ-『4,5·:· 二气-2-甲棊-1_H-imidazol-1-yl-methyl -4-mu-methyl hydrazine-1-(iso-bone-based)-2,4-dioxo-4 And [2.3-(11-Sulphate_5-Lecool) Example 3 d) process was prepared from the product of item a) to give the subtitle compound. MS (APCI) 43 1/433 [M + H] + δ 1.53 (6H,d), 2.39 (3H,S),3.31 (3H,s,),3.54-3.69 (IH,m),5.32 (2H, s). Gl (§..)-5-".4-丧基-2-iso-p 吐 carboxy group 1·6-Γ4,5-two.-2-methyl-1H- fans__a sit two L a method for the preparation of a compound of the formula (b), which is prepared from the product of item b) to give the title compound MS (APCI) 502/504 [M + H] δ 'Hcocn 1.55-1.61 (6Η, m), 2.39 (3H, s), 3.33 (3H, s), 3.51 (1H, dd), 4.01-4.09 ( 2H, m), 4.40-4.55 (lH, br.s), 4.57 (1H, d); 4.68-4.75 (1H, m); 4.95 (1H, d); 5.15-5.28 (2H, m). 6 iii (S)-5-"4-Hydroxyindisoxazin-2-ylcarbonyl1-6-丨?-(Baijia)-1 H-Bumimidazole-Bulkyl 1-3- Methyl-1-(isopropyl V-seceno[2.3-dl-pyrimidine-2.4UH.3H)-dione-112 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1310036 A7 B7 V. Description of invention (109)
OHOH
^~1,2’3’4 -四 空甲某)-1Η -笼· # 咪口坐-1-某甲基 1-3 -甲 基-1-(呉巧一基)-2,4-二氧代碟吩並T2.3-dl嘧啶-5-翔酸甲酯 添加氫化鈉(79 mg,60%懸浮液)至〇。(:與氮氣下,含2-苯 並咪唑甲醇(280 mg)之無水DMF溶液中。10分鐘後,滴加 含實例8b產物(660 mg)之DMF溶液,反應混合物於室溫下 搜拌3小時。加水’過濾所形成之沉澱,以乙酸乙酯與醚 依序洗滌,產生標題化合物之灰白色固體(350 mg)。 MS (ES) 443 [M + H] + δ 'Hdmso 1.39-1.41 (6H, d), 3.18 (3H, s), 3.85 (3H, s), 4 32 (1H, bs), 4.78-4.80 (2H,s), 5.71 (2H, s), 5.86 (1H, bs), 7.23 (2H,m),7.55-7.57 ( 1 H,d),7.61-7.64 (1H, d)。 b) 1,2,3,4-四氫-6-「2-(羥甲基)-1 H-苯並咮唑-1-某甲某]^^ 基-1 異丙...基)-2,4-二氧代魂吩並【2,3-dl^唉-5-幾酸麵.. 依實例1 f)項之製法,由實例16Hi a)項產物(35〇 mg)製備 ’產生標題化合物之白色固體(340 mg)。 MS (ES) 429 [M+H] +^~1,2'3'4 -四空甲甲)-1Η -Cage · # 咪口坐-1-Methyl 1-3 -Methyl-1-(呉巧一基)-2,4- Dioxophenophene T2.3-dl pyrimidine-5-comonate methyl ester was added sodium hydride (79 mg, 60% suspension) to hydrazine. (: with a solution of 2-benzimidazole in methanol (280 mg) in anhydrous DMF under nitrogen. After 10 min, a solution containing the product of Example 8b (660 mg) was added dropwise and the mixture was stirred at room temperature. The resulting precipitate was filtered with EtOAc (EtOAc) elute elute elute elute elut elut elut elut elut , d), 3.18 (3H, s), 3.85 (3H, s), 4 32 (1H, bs), 4.78-4.80 (2H, s), 5.71 (2H, s), 5.86 (1H, bs), 7.23 (2H,m), 7.55-7.57 ( 1 H,d), 7.61-7.64 (1H, d) b) 1,2,3,4-tetrahydro-6-"2-(hydroxymethyl)-1 H-benzoxazole-1-somemethyl]^^yl-1 isopropyl...yl)-2,4-dioxosindol [2,3-dl^唉-5-acid surface Preparation of the title compound as a white solid (340 mg) from EtOAc (EtOAc)
c) (S) _5-[4-羥基異吟唑啶-2-某羰基l-6-『2-f羥甲某 咪唑二1-基甲基1-3-甲基-1-(異丙基)嘧哈祐μ = -2·4(1Η.3Η)-二酮c) (S) _5-[4-hydroxyisoxazolidine-2-carbonyl-1-6-"2-f-hydroxymethyl-imidazoledi-l-ylmethyl-1-methyl-1-(isopropyl) Base) pyrimine μ = -2·4(1Η.3Η)-dione
-113 - 本泜張尺度適用中®理家標準(CNS) Α4規格(210Χ 297公釐) 1310036 A7 B7 五、發明説明(110 ) 依霄例丨3vu c)項之製法,由實例16iii b)項產物製備。粗 產物經逆相製備性HPLC純化,以25%至95%乙腈之〇· 1。/。乙 酸銨水溶液溶離,產生標題化合物(11〇 mg)。 MS (ES) 500.1610 [m+H] + δ【Ho’ 1.37-1.40 (6H,m),3.18 (3H,s),3.5-4.4 (5H, m之範 圍),4.6-4.8 (3H, 2m), 5.5-6.9 (4H,m), 7.17-7.21 (2H, m), 7.59-7.68 (2H,m)。 ’ ’ 實例16iv (s)-5-Li-_.羥基吴甲某 異丙甚ή_「?_ 胺基-丨ίίϋ咪^二1-基Τ某卜唓2分並「2.3-dl嘧啶-2.4ΠΗ.Ή·Π- 二酉同 ΟΗ-113 - This sheet is applicable to the Standard® (CNS) Α4 specification (210Χ 297 mm) 1310036 A7 B7 5. Inventive Note (110) According to the example 丨3vu c), by example 16iii b) Preparation of the product. The crude product was purified by reverse phase preparative HPLC with 25% to 95% acetonitrile. /. The aqueous solution of ammonium acetate was dissolved to give the title compound (11 mg). MS (ES) 500.1610 [m+H] + δ [Ho' 1.37-1.40 (6H, m), 3.18 (3H, s), 3.5-4.4 (5H, range of m), 4.6-4.8 (3H, 2m) , 5.5-6.9 (4H, m), 7.17-7.21 (2H, m), 7.59-7.68 (2H, m). ' ' Example 16iv (s)-5-Li-_. Hydroxy Wu A certain isopropyl ή _ "?_ Amino- 丨ίίϋ M ^ 2 - Τ Τ 唓 唓 2 points and "2.3-dl pyrimidine-2.4 ΠΗ.Ή·Π- 二酉同ΟΗ
a) 6-[2-版基-1Η·遂·_並咪吨_丨_基甲華ρ 2 3 4•四氦_3-甲某」' (異丙A)- 2土.—代〇家吩被f2,3-dl嘧忒-5-勒酸甲酯a) 6-[2-基基-1Η·遂·_和米吨_丨_基甲华ρ 2 3 4•四氦_3-甲某”' (isopropyl A)- 2 soil.—代〇 Methyl b2,3-dl-pyrimidin-5-l-acid
依實例13vii a)項之製法,由實例8 b)項產物(66〇 mg)與I 月*基苯並咪唑(250 mg)製備。粗產物經急驟矽石層析法純 化,以50%_乙酸乙酯之異己烷溶液’然後以含〇· 1%三乙胺 之4%甲醇I二氣甲烷溶液溶離,產生標題化合物之黃色泡 沫狀物(360 mg)。 MS (ES) 428 [M + H] + _____- 114 - 本紙張又度逋用中㈣轉準(CNS) A4規格(21QX 297公董) ----- 1310036 A7Prepared from the product of Example 8 b) (66 〇 mg) and I.*-benzimidazole (250 mg) according to the procedure of Example 13vii a). The crude product was purified by flash chromatography eluting with 50% ethyl acetate in hexanes</RTI> and then eluted with EtOAc EtOAc EtOAc (360 mg). MS (ES) 428 [M + H] + _____- 114 - This paper is used again. (4) Alignment (CNS) A4 specification (21QX 297 DON) ----- 1310036 A7
dmso 1.40-1.42 (6Η, d), 3.17 (3H, s), 3.88 (3H, Η (lH,bs), 5.42 (2H, S), 6.62 (2H, s), 6.87-6.90 (1H, t) 6g 3 6.98 (1H,t), 7.U-7.丨 5 (2H,m)。 ’ ’ 3~ m2-胺基-1H二^某甲基M 2飞4_四-I 卜(开丙基吩並f2.3-dl嘧啶-5-淼酩鈉 依貫例1 f)項炙製法,由實例16iv a)項產物(36〇 製 ,產生標題化合物之白色固體(丨9〇 mg)。 MS (ES) 414 [M + H] + £l(s) 基羰基 Ί_夂甲某異而^^ U二胺基基甲基 1-p塞吩 #「2 λ_Ηϋ^ -2,4(ΊΗ·3ΗΠ-二酮 ~ 依s例13νπ c)項之製法,由實例i6iv㈨項產物(ι9〇 製備。粗產物經逆相製備性HPLC純化,以25%至95%乙腈 之〇· 1%乙酸銨水溶液溶離,然後與甲醇研磨及過濾,產生 標題化合物之白色固體(2〇 mg)。 MS (ES) 485.1623 [M+H] + δ ^圓。1.35-1,42 (6H,m),3.18 (3H,m),3.6_4.4 (5H,m之範 圍),4.6-4.8 (1H,m),5·2-5.6 (3H,m),6 7_6 8 (2H,㈣,6 86_ 6.90 (1H, t), 6.95-6.98 (1H, t), 7.13-7.15 (1H, d), 7.2-7.3 (lH,2d)。 實例1 6 v) _ 羥基異咩唑啶-2-某粦某1-3-甲甚_丨4昱兩華v6_「2_ t基-1 Η”比哈並[2,3-blp比峻-卜某甲甚p芊吟祐「?υι 口密咬 -2,4( 1 H.3H、-二酮 ____ 115 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Dmso 1.40-1.42 (6Η, d), 3.17 (3H, s), 3.88 (3H, Η (lH, bs), 5.42 (2H, S), 6.62 (2H, s), 6.87-6.90 (1H, t) 6g 3 6.98 (1H,t), 7.U-7.丨5 (2H,m). ' '3~ m2-Amino-1H2^Methyl M 2 fly 4_四-I Bu (opening C The phenanthroline f2.3-dl-pyrimidine-5-indole was subjected to the title compound (m. MS (ES) 414 [M + H] + £l(s) carbonyl hydrazine 夂 夂 某 ^ ^^ U diaminomethyl 1-p thiophene # "2 λ_Ηϋ^ -2,4 (ΊΗ · 3ΗΠ-dione ~ according to the method of s Example 13νπ c), prepared by the product of i6iv (9) (i.9). The crude product was purified by reverse phase preparative HPLC with 25% to 95% acetonitrile and 1% ammonium acetate. The aqueous solution was dissolved in EtOAc (3 mL, EtOAc, m. 3H,m), 3.6_4.4 (5H, range of m), 4.6-4.8 (1H, m), 5·2-5.6 (3H, m), 6 7_6 8 (2H, (4), 6 86_ 6.90 (1H , t), 6.95-6.98 (1H, t), 7.13-7.15 (1H, d), 7.2-7.3 (lH, 2d). Example 1 6 v) _ hydroxyisoxazole pyridine-2- 粦 1-3-A 甚 丨 昱 昱 昱 昱 v v v v v v v v 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2卜 甲 甲 芊吟 芊吟 「 υ υ υ 口 口 口 -2 -2 -2 -2 -2 -2 , -2 -2 , -2 -2 , -2 , , , -2 -2 -2 -2 -2 -2 -2 -2 -2 , -2 , , , , , , , , , 本 本 本
裝 訂Binding
1310036 A7 B7 112 五、發明説明(1310036 A7 B7 112 V. INSTRUCTIONS (
OHOH
幻一i^li·^ 氫 '3- T 基-1-(異 甲甚-1H-A 皮:¾ 基王基kL4-士氧」1^、並「2.3-dl嘧啶-5_跆醢 於氮氣與周溫下,在含60%氫化鈉(0.15 g)之THF (5 ml) 攪拌懸浮液中滴加含2-甲基氮雜吲哚(〇 25 g)之THF (5 ml) 溶液。攪拌5分鐘後’冷卻至〇t,添加含實例22幻項產物 (0.60 g)之THF (10 ml)溶液,混合物回升室溫,揽拌5小時 。加水中止反應’以2.5M HC1酸化,以二氯甲烷萃取,有 機萃液經無水硫酸鎂脫水’過濾與減壓蒸發。殘質經碎石 管柱層析法純化’以乙酸乙酯/異己烷(丨:丨)及乙酸乙醋/甲 §手(9 : 1)依序溶離,產生小標題化合物之固體(〇 〇6 。 MS (ESI) 413 [M + H] + δ 'Hdmso 1.36 (6Η, d), 3.17 (3H, s), 4.20 (1H, s, br), 5.73 (2H, s), 6.32 (1H, s), 7.09-7.12 (1H, s), 7.88-7.90 (iH, m), 8.20-8.2 1 (1 H, m)幻一 i^li·^ Hydrogen '3- T-based-1-(iso-methyl-1H-A skin: 3⁄4 basal kL4-sulphur) 1^, and "2.3-dl pyrimidine-5_跆醢A solution of 2-methylazepine (25 g) in THF (5 ml) was added dropwise to a stirred mixture of THF (5 mL). After stirring for 5 minutes, the mixture was cooled to EtOAc. Extracted with dichloromethane, the organic extract was dehydrated with anhydrous magnesium sulfate. 'Filtered and evaporated under reduced pressure. Residue was purified by column chromatography. Ethyl acetate/isohexane (hexane: oxime) and ethyl acetate/acetic acid § Hand (9:1) is dissolved in sequence to give the title compound as a solid (〇〇6. MS (ESI) 413 [M + H] + δ 'Hdmso 1.36 (6Η, d), 3.17 (3H, s), 4.20 (1H, s, br), 5.73 (2H, s), 6.32 (1H, s), 7.09-7.12 (1H, s), 7.88-7.90 (iH, m), 8.20-8.2 1 (1 H, m )
二[4-羥某異噚唑啶-2-基羰某1-3-甲某-1-Γ異而I 吡咯並「2.3-bl吡啶-1-某甲基吩# 吟 立-2,4(lH.3m-二酮 依s例1 g)項之製法’由a)項產物與(S) - 4 -異11号也咬醇鹽 ______- 116 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公釐). 1310036 A7 B7 五、發明説明( 酸鹽[實例1 b項]製備,產生標題化合物之固體。 MS (APCI) 484 [M + H]十 δ 1 Hdmso 1 8- 1.40 (6Η, m), 2.41 (3H, m), 3.16-3.19 (3H, m), 3.54-4.25 (5H, m), 4.60-4.73 (1H, m), 5.42-5.58 (3H, m), 6.29 (1H, s), 7.09-7.13 (1H, m), 7.88 (1H, dd), 8.22-8.26 (1H, m) 實例17i) (S)-5 44-羥某異啐唑啶-2-某耩某1-3-甲某-1-(昙JI.基)-6-f3,5-二乙基-1H-吡唑-4-某甲某1-4吩並「2.3-dl嘧啶-2,4(1H,3H)-[[4-hydroxylisoxazolidine-2-ylcarbonyl 1-3-methyl-1-pyranyl iso-I pyrrole and "2.3-bl-pyridine-1-methylphenan #吟立-2,4 (1H.3m-dione according to s1g) The method of 'products' and (S) - 4 - is 11 also bite alkoxide ______- 116 - This paper scale applies to Chinese national standards (CNS A4 size (210X297 mm). 1310036 A7 B7 V. Description of the invention (acid salt [Example 1 b] prepared to give the title compound as a solid. MS (APCI) 484 [M + H] dec δ 1 Hdmso 1 8- 1.40 (6Η, m), 2.41 (3H, m), 3.16-3.19 (3H, m), 3.54-4.25 (5H, m), 4.60-4.73 (1H, m), 5.42-5.58 (3H, m), 6.29 (1H, s), 7.09-7.13 (1H, m), 7.88 (1H, dd), 8.22-8.26 (1H, m) Example 17i) (S)-5 44-Hydroxyisoxazole pyridine-2-耩一1-3-甲一-1-(昙JI.基)-6-f3,5-diethyl-1H-pyrazole-4-A certain 1-4 phenanthrene "2.3-dl pyrimidine- 2,4(1H,3H)-
裝 訂Binding
a) 643,5-二乙某-1H-吡唑-4-某甲某 1-3-甲-1-(異丁某)-2.4-二 氣代-1,2,3、4-四氤嘧吩並丨2,3-(11嘧啶-5-#酸 依實例12 a)項之製法,由實例3 c)項產物(1 g)與3,5-庚二 酮製備,產生小標題化合物之固體(0.37 g)。 MS (ESI) 419 [M+H] + δ 'Hdmsq 0.86 (6Η, d), 1.10 (6H, t), 2.05-2.15 (1H, m), 2.49 (4H, q), 3.26 (3H, s), 3.66 (2H, d), 4.06 (2H, s)。a) 643,5-diethyl-1H-pyrazole-4-a certain 1-3-methyl-1-(isobutyl)-2.4-dioxane-1,2,3,4-tetraindole Preparation of the pyrimidopurine 2,3-(11-pyrimidin-5-# acid according to Example 12 a) from the product of Example 3 c) (1 g) and 3,5-heptanedione to give the subtitle compound Solid (0.37 g). MS (ESI) 419 [M+H] + δ 'Hdmsq 0.86 (6Η, d), 1.10 (6H, t), 2.05-2.15 (1H, m), 2.49 (4H, q), 3.26 (3H, s) , 3.66 (2H, d), 4.06 (2H, s).
b) (S) 5-「4-羥基異咩唑啶-2-某錄某1-3-甲某-1-(異丁其彳-ή-「3,5-二乙基-1 Η-ρ比唑·4·基甲某1-嘧吩並[2,3-dl嘧啶-2.4(1 H 二酮 117 - 本故張尺度適用中國8家標準(CNS) Α4規格(210X297公釐) 1310036 A7 B7 五、發明説明(114 ) 依實例3 e)項之製法,由a)項產物與(S)-4-羥基異哼唑啶 鹽酸鹽[實例lb項]製備,產生標題化合物之固體(145mg)。 MS (ESI) 490 [M + H] + 5 'Hdmso 〇·86 (6Η, d), 1.09 (6Η, t), 2.03-2.19 (ΊΗ, m), 2.49-2.52 (4Η, m), 3.19 (2H, s), 3.21 (1H, s), 3.50 (0.67H, d), 3.35-3.63 (1H, m), 3.70 (1H, dd), 3.75-3.80 (3H, m), 3.84 (0.67H, dd), 3.90-4.05 ( 1H, m), 4.09 (0.67H, dd), 4.58-4.80 (1H, m), 5.51 (1H, d),12.18 (1H,s,br)。 實例17ii) (S) 5-「4-羥基異哼唑啶-2-某羰基1-3-甲基-1-(異丁某)-6-「3-Π.1-二甲基乙基)-5-甲基-1H-吡唑-4-基甲基1-嘧吩並「2,3-dl 嘧啶-2.4ΠΗ.3Η)-二酮b) (S) 5-"4-Hydroxyisoxazole pyridine-2-someone 1-3-甲一-1-(isobutyl oxime-ή-"3,5-diethyl-1 Η- ρ-Bistazole·4·Ketyl-1-pyrimido[2,3-dl-pyrimidine-2.4 (1 H diketone 117 - The original Zhang scale applies to China's 8 standards (CNS) Α4 specification (210X297 mm) 1310036 A7 B7 V. Description of the invention (114) Prepared according to the procedure of Example 3 e), starting from product a) and (S)-4-hydroxyisoxazolidinium hydrochloride [Example lb], yielding the title compound as a solid (145mg) MS (ESI) 490 [M + H] + 5 'Hdmso 〇·86 (6Η, d), 1.09 (6Η, t), 2.03-2.19 (ΊΗ, m), 2.49-2.52 (4Η, m ), 3.19 (2H, s), 3.21 (1H, s), 3.50 (0.67H, d), 3.35-3.63 (1H, m), 3.70 (1H, dd), 3.75-3.80 (3H, m), 3.84 (0.67H, dd), 3.90-4.05 (1H, m), 4.09 (0.67H, dd), 4.58-4.80 (1H, m), 5.51 (1H, d), 12.18 (1H, s, br). 17ii) (S) 5-"4-Hydroxyisoxazole-2-one carbonyl 1-3-methyl-1-(isobutyl)-6-"3-Π.1-dimethylethyl) -5-Methyl-1H-pyrazol-4-ylmethyl 1-sulfono-[2,3-dl pyrimidine-2.4ΠΗ.3Η)-dione
依實例12 b)項之製法,由實例12 a)項產物、5,5-二甲基 己烷-2,4-二酮與35%肼水合物製備,產生標題化合物之固 體。 MS (ESI) 50_4 [M + H] + δ 'HdmsoO.85 (6H, d), 1.23 (9H, s), 1.99-2.06 (4H, m), 3.19 (2.25H, s), 3.2 1 (0.7525H, s),3.50-3.60 (2H, m), 3.64-3.72 (1H, m) 3.79 (1H, m), 3.83-3.96 (3H, m), 3.98-4.05 (0.25H, 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Prepared from the product of Example 12 a), 5,5-dimethylhexane-2,4-dione, and 35% hydrazide to give the title compound as a solid. MS (ESI) 50_4 [M + H] + δ 'HdmsoO.85 (6H, d), 1.23 (9H, s), 1.99-2.06 (4H, m), 3.19 (2.25H, s), 3.2 1 (0.7525 H, s), 3.50-3.60 (2H, m), 3.64-3.72 (1H, m) 3.79 (1H, m), 3.83-3.96 (3H, m), 3.98-4.05 (0.25H, this paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm)
M * 1310036 A7 B7 五、發明説明(115) m), 4.07 (0.75H, dd), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.08 (1 H, s, br)。 實例18i) G). 5-『4·羥幕異哼堂S_-2·基羰某l-V甲某-1-(異丁某)-642-翌基-4-喳啉基甲基1嘧吩並「2,3-dl喊θ-2.4ΠΗ,3Η)-二酮M * 1310036 A7 B7 V. INSTRUCTIONS (115) m), 4.07 (0.75H, dd), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.08 (1 H, s, br). Example 18i) G). 5-"4. hydroxy-screen 哼 哼 S S S S S S S l -1- -1- -1- -1- -1- -1- 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 And "2,3-dl shouts θ-2.4ΠΗ, 3Η)-dione
a) Ν-甲氧基-Ν,2-二甲基-4-ρ套株勒疏种1 在含2-甲基-4-喳啉羧酸(8.2 g)之含dmF (1滴)之二氣甲烷 (10 0 m 1)浴液中添加早驢風^4.5 ml)。混合物回流加熱1小時 。真空濃縮至乾後’殘質再溶於二氣甲烷(5〇 ml)中,依序 添加三乙胺(17 ml)與Ν,Ο-二甲基羥胺(8.2 g),反應於周溫 下攪拌16小時。以水(2 X 100 ml)洗滌反應混合物,有機溶 液蒸發,殘質經層析法純化,以乙酸乙酯溶離,產生小標 題化合物之褐色油狀物(10 g)。 MS (ESI) 231 [M + H] + δ 'Hcdcij 2.77 (3Η, s), 3.24/3.40 (3H, s), 3.47/3.74 (3H, s),7.26 (IHa s),7.52 (1H, t),7.71 (1H, t),7.8〇 (IH, d), 8.06 (1H, d)。 b) 2-曱基-4-峰啉藉某醛 添加2.5N二異丁基鋁氫化物之甲苯溶液(5.6 mi)至_78 本紙張尺度適用中國國家標準(CNS) Α4规格(210 297公釐)a) Ν-methoxy-oxime, 2-dimethyl-4-ρ set of Leopard 1 in dmF (1 drop) containing 2-methyl-4-porphyrincarboxylic acid (8.2 g) Add early hurricane ^4.5 ml) to the di-methane (10 0 m 1) bath. The mixture was heated under reflux for 1 hour. After concentrating in vacuo to dryness, the residue was redissolved in di-methane (5 mL), and then triethylamine (17 ml) and hydrazine, dimethyl-hydroxylamine (8.2 g) were added to the reaction at ambient temperature. Stir for 16 hours. The reaction mixture was washed with water (2×100 ml) and evaporated. MS (ESI) 231 [M + H] + δ 'Hcdcij 2.77 (3Η, s), 3.24/3.40 (3H, s), 3.47/3.74 (3H, s), 7.26 (IHa s), 7.52 (1H, t ), 7.71 (1H, t), 7.8 〇 (IH, d), 8.06 (1H, d). b) 2-Mercapto-4-Phenanthroline added 2.5N diisobutylaluminum hydride in toluene solution (5.6 mi) to _78 This paper scale applies to China National Standard (CNS) Α4 specification (210 297 gong) PCT)
Μ 1310036 A7 B7 五、發明説明(116 ) 下’含步驟a)產物(1.6 g)之無水甲苯(4〇 ml)溶液中。2小時 後’添加酒石酸鉀鈉(5 g)之水(25 ml)溶液中止反應,使之 回升室溫。收集有機相,以水洗滌,經硫酸鎂脫水,真空 濃縮至乾。殘質經層析法純化,以30%乙酸乙酯之異己烷 溶液溶離,產生小標題化合物(〇 82 g)。 3 HCDcn 2. 87 (3H, s), 7.26 (1H, s), 7.67 (1H, ddd), 7.69 (1H, s), 7.78 (1H, ddd),8_12 (1H, d),8.96 (1H, d),10.49 (1H, s)。 -3-_甲基-1-(異丁某、·2·4_二氧代吩祐「2.3-咬-5-羧酸1,1 ·二甲某l酯 在含貫例1 c)項產物(2.0 g)之含DMF (1滴)之二氯甲坑(12 ml)溶液中添加草醯氯(1 ·〇 ^1)。混合物於室溫下攪拌丨小時 °真2濃縮至乾後,殘質再溶於二氯甲烷(8 ml)中,依序 添加二乙胺(4 ml)與2-甲基丙-2-醇(8.0 ml) ’反應於周溫下 攪拌4小時。以水(2 X 1〇〇 mi)洗滌反應混合物,有機相脫 水與蒸發’殘質經層析法純化,以異己烷/乙酸乙醋(5 :、) 落離’產生小標題化合物之橙色油狀物(丨6g)。 δ ^00013〇-99 (6Η, d), 1.61 (9H, s), 2.31 (ΙΗ,ηοη), 3.42 (3Η s), 3.80 (2Η, d),7.26 (1Η, s)。 ’ L2,3,4-四氫-6-[幾_基-(2-甲基^喹啉基w取丨 工基)-2,4-二氢代-噚吩並[~2,嘧啶-5-務酸1·] 甲某Λ酷 依實例1步驟d)之製法,由步驟幻與b)產物製備小標題化 合物。 ’ MS(ESI) 510 [M + H] +Μ 1310036 A7 B7 V. Inventive Note (116) The product containing the product of step a) (1.6 g) in anhydrous toluene (4 〇 ml). After 2 hours, a solution of sodium potassium tartrate (5 g) in water (25 ml) was added to quench the reaction and allowed to warm to room temperature. The organic phase was collected, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc (EtOAc) elute 3 HCDcn 2. 87 (3H, s), 7.26 (1H, s), 7.67 (1H, ddd), 7.69 (1H, s), 7.78 (1H, ddd), 8_12 (1H, d), 8.96 (1H, d), 10.49 (1H, s). -3-_Methyl-1-(isobutyl, ·2·4_dioxophene) "2.3-Bite-5-carboxylic acid 1,1 ·Dimethyl l ester in the case of Example 1 c) To the solution of product (2.0 g) containing DMF (1 drop) in dichloromethane (12 ml), add chlorophyll chloride (1 · 〇^1). Mix the mixture at room temperature for 丨 hours. The residue was redissolved in dichloromethane (8 ml), and then diethylamine (4 ml) and 2-methylpropan-2-ol (8.0 ml) were added to the mixture, and the mixture was stirred at ambient temperature for 4 hours. Washing the reaction mixture with water (2 X 1 〇〇mi), dehydration and evaporation of the organic phase. The residue was purified by chromatography eluting with hexane/ethyl acetate (5:,) to give the title compound as an orange oil. (丨6g) δ ^00013〇-99 (6Η, d), 1.61 (9H, s), 2.31 (ΙΗ,ηοη), 3.42 (3Η s), 3.80 (2Η, d), 7.26 (1Η, s ''L2,3,4-tetrahydro-6-[mono-yl-(2-methyl^quinolinyl w))-2,4-dihydro-deutero[~2, Pyrimidine-5-oxyl 1·] Amethyst was prepared according to the procedure of Example 1, step d), subtitle compound was prepared from the product of step and b). MS (ESI) 510 [M + H] +
δ 'HCDC|3 0.85 (6H, d), 1.66 (9H, s), 2.11 (1H, m), 2.82 (3H __- 120 -δ 'HCDC|3 0.85 (6H, d), 1.66 (9H, s), 2.11 (1H, m), 2.82 (3H __- 120 -
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(117 ) s), 3.39 (3H, s), 3.48 (1H, dd), 3.53 (1H, d),3-71 (1H, dd), 6.72 (1H, d), 7.44 (1H, t), 7.67 (1H, t), 7.72 (1H, s), 7.82 (1H,d), 8.07 (1H, d)。 e) 1.2,3.4-四氣-3 -甲基-M異丁基)-64(2-甲基-4-口套啉基)甲 基1-2,4-二氣代-峰吩並[2,3-dl嘧啶-5-羧酸1.1-二甲某乙酯 添加甲磺醯氣(0.46 ml)至室溫與氮氣下,含步驟d)產物 (1.42 g)與三乙胺(1.54 ml)之無水THF (30 ml)溶液中,混合 物攪拌40分鐘。添加10% Pd/C (320 mg),混合物於5巴下 氫化2小時。懸浮液經寅式鹽過濾,以甲醇(1 00 ml)洗滌。 有機物減壓濃縮,殘質經管柱層析法純化,以1 : 3乙酸乙 酯/異己烷溶離,產生小標題化合物之固體(1.0 g)。 MS (ESI) 495[M + H] + δ 'Hcdcu 0-91 (6Η, d), 1.61 (9H, t), 2.18 (1H, non), 2.74 (3H, s), 3.40 (3H, s), 3.64 (2H, d), 4.55 (2H, s), 7.18 (1H, s), 7.52 (1H,t), 7.71 (1H,t), 8.05-8.07 (2H, m)。 Π 1,2,3,4-四i, -3-甲基-M異丁基)-6-f2-甲基-4-唓啉基甲基 1-2,4-二氣代-違吩並|~2.3-(11嘧啶-5-羧酸 於氮氣下,在含步驟e)產物(0.82 g)之二氯曱烷(15 ml)溶 液中添加三氟乙酸(3 ml),混合物攪拌卜】、時。添加飽和碳 酸氫鈉溶液(1 00 ml),以二氯甲烷萃取混合物;有機相以水 (200 ml)洗滌,以硫酸鎂脫水,過濾與濃縮至乾,產生小 標題化合物之紅色固體(0.72 g)。 δ 'HdmsoO.87 (6H, d), 2.13 (ΙΗ,ηοη), 2.76 (3H, s), 3.51 (3H, s), 3.65 (2H, d), 5.21 (2H, s), 7.21 (1H, s), 7.48 (1H, t), 7.70 -121 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(118 ) (1H,t),7.89 (1H, d),8.06 (1H, d)。 g) (S) 5-「4-羥棊異..°号吐t-2-基蓀某1-3-甲某-1-f異丁某)-6-「2-甲基-4-啤啉基f基14吩並f2.3-dl嘧啶-2.4( 1H.3HV二商同 依實例丨步驟g)之製法,由f)項及實例1 b)項產物製備) 標題化合物。 MS (APCI) 509 [M+H] + δ 'HdmsoO.85 (6H, m), 2.00-2.12 (1H, m), 2.62 (3H, S) 3 (3H, s), 3.55-4.12 (6H, m), 4.47-4.63 (2H, m), 4.79 (lu ,This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Inventions (117) s), 3.39 (3H, s), 3.48 (1H, dd), 3.53 (1H, d), 3-71 (1H, dd), 6.72 (1H, d), 7.44 (1H, t), 7.67 (1H, t), 7.72 (1H, s), 7.82 (1H,d), 8.07 (1H , d). e) 1.2, 3.4-tetraqi-3 -methyl-M isobutyl)-64 (2-methyl-4-hydroxylinyl)methyl 1-2,4-di-generation-peak benzo[ 2,3-dl-pyrimidine-5-carboxylic acid 1.1-dimethyl ester was added with methanesulfonate (0.46 ml) to room temperature under nitrogen, containing step d) product (1.42 g) and triethylamine (1.54 ml) The mixture was stirred for 40 minutes in anhydrous THF (30 mL). 10% Pd/C (320 mg) was added and the mixture was hydrogenated at 5 bar for 2 hours. The suspension was filtered through EtOAc (EtOAc) (EtOAc). The organics were concentrated under reduced pressure. EtOAc (EtOAc) MS (ESI) 495 [M + H] + δ 'Hcdcu 0-91 (6Η, d), 1.61 (9H, t), 2.18 (1H, non), 2.74 (3H, s), 3.40 (3H, s) , 3.64 (2H, d), 4.55 (2H, s), 7.18 (1H, s), 7.52 (1H, t), 7.71 (1H, t), 8.05-8.07 (2H, m). Π 1,2,3,4-tetrazine,-3-methyl-M isobutyl)-6-f2-methyl-4-carbolinylmethyl 1-2,4-digas-violet And a solution of the product (0.82 g) in dichloromethane (15 ml) was added with trifluoroacetic acid (3 ml). 】,Time. Add a saturated solution of sodium bicarbonate (1 00 ml), EtOAc (EtOAc)EtOAc. ). δ 'HdmsoO.87 (6H, d), 2.13 (ΙΗ, ηοη), 2.76 (3H, s), 3.51 (3H, s), 3.65 (2H, d), 5.21 (2H, s), 7.21 (1H, s), 7.48 (1H, t), 7.70 -121 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (118) (1H, t), 7.89 (1H, d), 8.06 (1H, d). g) (S) 5-"4-Hydroxypyrene..°#吐t-2-基荪一1-3-甲一-1-f Iso-)-6-"2-Methyl-4- Process for the preparation of the morpholinylf-group 14-pheno-f2.3-dl-pyrimidine-2.4 (1H.3HV dimerization example, step g), starting from product f) and the product of example 1 b)) APCI) 509 [M+H] + δ 'HdmsoO.85 (6H, m), 2.00-2.12 (1H, m), 2.62 (3H, S) 3 (3H, s), 3.55-4.12 (6H, m) , 4.47-4.63 (2H, m), 4.79 (lu ,
s»br)j 5.54 (1H, s,br), 7.31/7.36 (1H, s), 7.54-7.56 (1H , ’ ”,7,71 (IH, t), 7.93 (IH, d), 8.16-8.23 (1H, m) » 實例18 ii) 裝 (S)646-氣-4-4:啉基甲某1·5-丨4-荈某異哼唑啶-2-^ 甲基-1-(異丁基V塞吩並『2.3-dl嘧啶-2,4(1H,3H)-二西^s»br)j 5.54 (1H, s,br), 7.31/7.36 (1H, s), 7.54-7.56 (1H , ' ”, 7,71 (IH, t), 7.93 (IH, d), 8.16- 8.23 (1H, m) » Example 18 ii) Packing (S) 646-Gas-4-4: phenyl-methyl-1·5-丨4-荈~isoxazole pyridine-2-(methyl-1-() Isobutyl V stopper and "2.3-dl pyrimidine-2,4(1H,3H)-二西^
OHOH
a) 6-Γ6-氣-4-崦啉基(羥某)甲某1-3-甲基-1-(異丁 氣代-丨,2,3,4-四氫4吩並「2,3-dl嘧啶-5-羧醢乙酯a) 6-Γ6-gas-4-carbolinyl (hydroxyl)methyl 1-3-methyl-1-(isobutyl oxo-oxime, 2,3,4-tetrahydro 4 pheno-"2, 3-dl pyrimidine-5-carboxymethyl ester
訂Order
奎琳幾 依實例1 _d)項之製法,由實例lc)項產物及6-氟-4~n 基醛製備,產生小標題化合物。 MS(ESI)486[M + H] + δ 'Hcocn 0.87 (3H, d), 0.90 (3H, d), 1.42 (3H, t), 2.〇7_2 a · z I -122 -The product of the example lc) and the 6-fluoro-4~n aldehyde are prepared according to the procedure of Example 1 -d) to give the subtitle compound. MS (ESI) 486 [M + H] + δ 'Hcocn 0.87 (3H, d), 0.90 (3H, d), 1.42 (3H, t), 2.〇7_2 a · z I -122 -
本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(119 ) (1H, m), 3.38 (3H, s), 3.51 (1H, dd), 3.63 (1H, d), 3.75 (1H, dd), 4.49 (2H, q), 6.65 (1H, d), 7.48 (1H, td), 7.57 (1H, dd), 7.84 (1H, d), 8.17 (1H,dd), 8.98 (1H, d)。 b) 6-「6-氟-4-峰啉基甲基1-3-甲某-1-(異丁基)-2,4-二氣代- 1.2.3.4- 四i,嘧吩並f2,3-dl嘧啶-5-斿酸乙酯 依實例丨e)項之製法,由a)項產物製備,產生小標題化合 物。 MS (ESI) 470 [M + H]十 δ 'Hcdcli 0* 91 (6Η, d), 1.38 (3Η, t), 2.13-2.26 (1H, m), 3.40 (3H, s), 3.65 (2H, d), 4.46 (2H,q), 4.53 (2H, s), 7.31 (1H, d), 7.51 (1H, td), 7.75 (1H, dd), 8.16 (1H, dd), 8.85 (1H, d)。 c) 6-「6-氣-4-崦啉基甲基1-3-甲某-M異丁基)-2.4-二氣代- 1.2.3.4- 四氣。塞吩並「2.3-dl嘧啶-5-翔酸鈉鹽 依實例1 f)項之製法,由b)項產物製備,產生小標題化合 物。 MS (ES)+ 442 [M + 2H-Na] + δ 'HDMs〇 0.81 (6Η, d), 2.02-2.16 (1H, m), 3.20 (3H, s), 3.56 (2H, d), 4.51 (2H, s),7.59 (1H, d), 7.63 (1H, td), 8.06 (1H, dd), 8.6 1 (1 H, dd), 8_82 (1 H, d)。 d) (S)646-氟啉基甲某1-5-Γ4-羥基異崎唑啶-2-基羰基1-3-甲某-[-(異丁某吩並「2,3-dl嘧啶-2.4ΠΗ.3Η)-二酮 依實例lg)項之製法,由c)項產物與(S)-4-羥基異哼唑啶 鹽酸鹽{實例113)項}製備,產生小標題化合物。 MS(ESI) 5 13 [M + H] + -123 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 B7 V. Invention description (119) (1H, m), 3.38 (3H, s), 3.51 (1H, dd), 3.63 ( (1H, d) , dd), 8.98 (1H, d). b) 6-"6-Fluoro-4-peakolinylmethyl 1-3-methyl-1-(isobutyl)-2,4-dioxane - 1.2.3.4- tetrai, imipenem f2 , 3-dl pyrimidine-5-decanoic acid ethyl ester was prepared according to the procedure of Example 丨e), which was obtained from the product of item a) to give the subtitle compound MS (ESI) 470 [M + H] δδ 'Hcdcli 0* 91 (6Η, d), 1.38 (3Η, t), 2.13-2.26 (1H, m), 3.40 (3H, s), 3.65 (2H, d), 4.46 (2H, q), 4.53 (2H, s), 7.31 (1H, d), 7.51 (1H, td), 7.75 (1H, dd), 8.16 (1H, dd), 8.85 (1H, d). c) 6-"6-Gas-4-Porphyrinyl 1-3-A-M-butyl-)-2.4-dioxane-1.2.3.4-Four gas. Method for preparing "2.3-dl pyrimidine-5-cyanate salt according to Example 1 f) Prepared from product b) to give the subtitle compound MS (ES) + 442 [M + 2H-Na] + δ 'HDMs 〇 0.81 (6Η, d), 2.02-2.16 (1H, m), 3.20 (3H , s), 3.56 (2H, d), 4.51 (2H, s), 7.59 (1H, d), 7.63 (1H, td), 8.06 (1H, dd), 8.6 1 (1 H, dd), 8_82 ( 1 H, d) d) (S) 646-Fluoroline-methyl 1-5-Γ 4-hydroxyisoxazolidine-2-ylcarbonyl 1-3-A-[-(- 2,3-dl-pyrimidine-2.4ΠΗ.3Η)-dione according to the method of the example lg), from the product of item c) and (S)- Preparation of 4-hydroxyisoxazolidine hydrochloride {Example 113)}, subtitle compound. MS (ESI) 5 13 [M + H] + -123 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)
裝 訂Binding
1310036 A7 B7 五、發明説明(12〇1310036 A7 B7 V. Description of invention (12〇
δ* 'HDMS0 0.82-0.85 (6H, m), 2.04-2.17 (IH, m), 3 ' ^ ι (2 H 3·22 (IH, s), 3.55-3.68 (3H, m), 3.75-4.13 (3H, ^ ’ S), (2^3H, m), 4.78-4.81 (0.67H, m), 5.50-5.56 (\u : 1 - ,rn),7 4 7.53 (1H,m),7.69 (1H,td),8.02-8.16 (2H, m), 8.(lH 2' (*n_b.幾何異構物之混合物,其中不包括次要幾何d) ° 之波峰’此質譜在較高溫下則簡化)。 構物 -實例 1 8 jjjl 氟-4-ϋ基甲某1-5-R-轉某異哼唑啶-2^^ 異丁基>塞吩並「2.3-dl嘧啶-2.4ΠΗ,3Η)-二δ* 'HDMS0 0.82-0.85 (6H, m), 2.04-2.17 (IH, m), 3 ' ^ ι (2 H 3·22 (IH, s), 3.55-3.68 (3H, m), 3.75-4.13 (3H, ^ ' S), (2^3H, m), 4.78-4.81 (0.67H, m), 5.50-5.56 (\u : 1 - , rn), 7 4 7.53 (1H, m), 7.69 ( 1H, td), 8.02-8.16 (2H, m), 8. (lH 2' (*n_b. mixture of geometric isomers, excluding minor geometry d) ° peaks 'this mass spectrum is at higher temperatures Simplified. Structure - Example 1 8 jjjl Fluoro-4-indenyl 1-5-R-trans-isoxazole azole-2^^ isobutyl > thiophene and "2.3-dl pyrimidine-2.4" , 3Η)-two
OHOH
tLliIg-氣-4-崦啉某(蕤某)甲某Μ-甲農 1^^1,2,3.4-四氫嚓吩並[2.3-(11嘧咗-5-教 ij^JL ^ 依實例1 d)項之製法,由實例lc)項產物及氟_4_崎林^ 基酸製備,產生小標題化合物。 MS (ESI) 486 [M + H]+ ^ δ 'Hcocn 0-85 (3H, d), 0.88 (3H, d), 1.43 (3H, t), 2.〇5 3 74 (1 H, (1H, m), 3.3.8 (3H, s), 3.47 (1H, dd), 3.65 (1H, τ 、7 69 (1H, dd), 4.49 (2H, q), 6.74 (1H, d), 7.38-7.50 (2H, d),7.91 (1H, dd), 9.07 (1H, d)。 ^ b) 648-1 -4-峰啉基曱基 1-3-甲某-卜(異:tLliIg-gas-4-porphyrin (蕤) A Μ-A farmer 1^^1,2,3.4-tetrahydro porphin [2.3-(11 pyridin-5-tea ij^JL ^ by example The preparation of the item 1 d), which is prepared from the product of the example lc) and the fluorine _4_Salina acid, yields the subtitle compound. MS (ESI) 486 [M + H]+ ^ δ 'Hcocn 0-85 (3H, d), 0.88 (3H, d), 1.43 (3H, t), 2.〇5 3 74 (1 H, (1H , m), 3.3.8 (3H, s), 3.47 (1H, dd), 3.65 (1H, τ, 7 69 (1H, dd), 4.49 (2H, q), 6.74 (1H, d), 7.38- 7.50 (2H, d), 7.91 (1H, dd), 9.07 (1H, d). ^ b) 648-1 -4-Phosolinyl thiol 1-3-A-B (Different:
本纸張尺度適用中國國家標準(CNS) Α4规格(210X 297公釐)This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm)
装 訂Binding
.線 A7 B7 1310036 五、發明説明(121 ) I J -四氱峰吩並l~2.3-dlp密症-5-费酸r, 依實例1 e)項之製法’由a)項產物製備’產生小標題化合 物0 MS(ESI) 470 [M + H] + δ 'Hcdcl·! 〇·9 丨(6H,d),丨.37 (3H,t),2.13-2.23 (1H,m), 3.39 (3H, s), 3.65 (2H, d), 4.45 (2H,q), 4.60 (2H, s), 7.31 (1H, d), 7.73 (1H, d), 7.44 (1H, td), 7.51-7.57 (1H, m), 7.91 (1H, d), 與 8.94 (1H, d) ° d 6-「S -氣-4-喳啉基甲基卜3 -甲基-1-(異丁莘肚二氫代-1 7 : 4-四i.嘧吩並「2.3-dl嘧啶-g-#酸鈿fi 依實例1 f)項之製法,由b)項產物製備,產生小標題化合 物。 MS(ESI)+ 442 [M + 2H-Na] + δ 'Hdmso 0.81 (6H, d), 2.03-2.13 (1H, m), 3.20 (3H, s), 3.57 (2H, d), 4.55 (2H, s), 7.53-7.58 (2H, m), 7.63 (1H, d), 8.45-8.50 (1H, m), 8.88 (1H, d)。 d) (S)6-「8 -默-4 - g林某〒基l-5-「4 -與(基異〇号。全^·2 -基藏基1· 3 -甲基-1 -(異丁基)碟吟祓r2.3-dlp密啶-2.4Π Η.3Η)-二酮 依實例le)項之製法,由c)項產物與(s)-4-羥基異哼唑啶 鹽酸鹽{實例1 0)項}製備,產生標題化合物。 MS (ESI) 5 L3 [M + H] + *δ 'HDMS〇 0.83-0.85 (6Η, m), 2.04-2.15 (1H, m), 3.21 (2H, s), 3.22 (1H, s), 3.52-3.72 (3H, m), 3.76-4.12 (3H, m), 4.55-4.70 (2.33H, m), 4.78-4.81 (0.67H, m), 5.50-5.57 (1H, m), 7.52 _ - 125 - 本纸張尺度適用中國國家操準(CNS) A4規格(210 X 297公釐)Line A7 B7 1310036 V. Inventive Note (121) IJ - Four Peaks Aligned l~2.3-dlp Secret Disease-5-Finic Acid r, according to the method of Example 1 e) [Preparation of product a) Subtitle Compound 0 MS (ESI) 470 [M + H] + δ 'Hcdcl·! 〇·9 丨(6H,d),丨.37 (3H,t),2.13-2.23 (1H,m), 3.39 ( 3H, s), 3.65 (2H, d), 4.45 (2H, q), 4.60 (2H, s), 7.31 (1H, d), 7.73 (1H, d), 7.44 (1H, td), 7.51-7.57 (1H, m), 7.91 (1H, d), and 8.94 (1H, d) ° d 6-"S-gas-4-carbolinylmethyl b 3-methyl-1-(isobutyl guanine) Hydrogen-1 - 7 : 4-tetra- i. sulfonim "2.3-dl-pyrimidine-g-# acid 钿fi according to the procedure of Example 1 f), which was prepared from the product of b) to give the subtitle compound. ) + 442 [M + 2H-Na] + δ 'Hdmso 0.81 (6H, d), 2.03-2.13 (1H, m), 3.20 (3H, s), 3.57 (2H, d), 4.55 (2H, s) , 7.53-7.58 (2H, m), 7.63 (1H, d), 8.45-8.50 (1H, m), 8.88 (1H, d) d) (S)6-"8 - silent-4 - g Lin 〒基l-5-"4 - with (基异〇号. 全^·2 - basophilic 1·3 -methyl-1 -(isobutyl) dish 吟祓r2.3-dlp-melidine-2.4 Π Η.3Η)-dione according to the method of the formula le), from the product of item c) s) 4-Hydroxyisoxazolidine hydrochloride {Example 10) Preparations to give the title compound MS (ESI) 5 L3 [M + H] + * δ 'HDMS 〇 0.83-0.85 (6 Η, m ), 2.04-2.15 (1H, m), 3.21 (2H, s), 3.22 (1H, s), 3.52-3.72 (3H, m), 3.76-4.12 (3H, m), 4.55-4.70 (2.33H, m), 4.78-4.81 (0.67H, m), 5.50-5.57 (1H, m), 7.52 _ - 125 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)
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1310036 A7 _____ B7 五、發明説明(1221 (0.33H, d), 7.56 (0.67H, d), 7.58-7.63 (2H, m), 8.05-8.13 (1H, m), 8.92 ( 1 H, d)。 (* N ·B _幾何異構物之2 : 1混合物)。 實例18 iv 基異啐砷Θ-2-篡耩某1-3-甲基-1-(異丁某 林基甲基吩# VH1嘧咗-2,4(1Η,3Η)-二酮 ΟΗ1310036 A7 _____ B7 V. Description of invention (1221 (0.33H, d), 7.56 (0.67H, d), 7.58-7.63 (2H, m), 8.05-8.13 (1H, m), 8.92 ( 1 H, d) (* N · B _ geometric isomer 2 : 1 mixture). Example 18 iv iso-iso-arsenic arsenic -2- 篡耩 1-1-3-methyl-1-(isobutyl linyl methyl phene # VH1 pyrimidin-2,4(1Η,3Η)-dione oxime
a) 6-丨羥某(5-4·啉篡)甲I 1-3 -甲基-1-(異丁基)-2.4-二y代-1,2,3,4-四氤4吩#「2.3-€11嘧啶-5-翔酸乙酯 依實例1 d)項之製法,由實例1 c)項產物與5-喳啉羧基醛 製備’產生小標題化合物。 MS (ESI) 468 [M + H] + δ丨HCDC丨3 0.87 (3H, d), 0.89 (3H, d), 1.33 (3H, t), 2.10-2.22 (1H, m), 3.38 (3H, s), 3.52 (1H, s, br), 3.55 (1H, dd), 3.71 (1H, dd), 4.33-4.41 (2H, m), 6.75 (1H, s), 7.39 (1H, dd), 7.77 (1H, t), 7.90 (1H, d), 8.14 (1H,d), 8.39 (lH,d),8.91 (1H, d)。 b) 3-甲基-1>(異丁某)-2.4-二氣代-6-(5-4 啉某甲某)-L2.3.4-四氫嘧吩並「2,3-dl嘧咗-5-崧醢乙酯 依實例丨e)項之製法,由a)項產物製備,產生小標題化合 物。 -126 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) A7 B7 1310036 五、發明説明(123 ) MS (ESI) 452 [M + H] + δ HCdci3 0.87 (6Η, d), 1.42 (3H, t), 2.09-2.19 (1H, m), 3.38 (3H, s),3.60 (2H, d),4.49 (2H,q), 4.59 (2H, s), 7.43 (1H, dd), 7.50 (1H, dd), 7.70 (1H, t),8.1l (ih, d), 8.49 (1H, d), 8.93 (1H, dd)。 甲.基-1-(異丁基_)- 2,4-^^代_6_(5-!?务啉某甲基)_1,2,3,4- 四氫¾吩並「2,3-dlp密咬-5-勒酸叙睡 依貫例1 f)項之製法,由b)項產物製備,產生小標題化合 物。 MS (ESI) 424 [M + 2H-Na] + δ 'Η dms〇 0.79 (6Η, d), 2.00-2.10 (1Η, m), 3.19 (3H, s), 3.53 (2H, d),4.52 (2H, s), 7.46 (1H,dd), 7.64 (1H, d), 7.71 (ih, t),7.93 (1H, d),8.85 (1H,dd), 9.14 (iH,d)。 4) (S)5-「4_羥基異崎唑啶-2;^基羰某甲基異丁華 °奎g林基甲基}口塞吩並「2,3 -d 1 ρ奈咬_2 ·4(Ί Η,3 Η)-二酮._ 依實例1 g)項之製法’由c)項產物與實例1 b)項產物製備 ,產生標題化合物。 MS (ESI) 495 [M + H] + δ 'Η DMS〇 0.80-0.83 (6Η, m), 1.99-2.06 (1Η, m), 3.2〇 (2H s) 3.21 (1H,s), 3.50-3.63 (3H, m),3.77-4.14 (3H, m),4·548. 4.70 (2.33H,m),4.79-4.82 (0.67H, m), 5.50 (0.33H,d), 5 56 (0.67H, d), 7.54 (1H, dd), 7.59 (0.33H, d), 7.63 (0.67H, d) 7.75 (1H, t), 7.98 (1H, d), 8.60 (0.33H, d), 8.64 (0.67H, d) 8.91 (1H,d)。 ’ -127 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 訂a) 6-oxime hydroxy (5-4 oxalinium)methyl I 1-3 -methyl-1-(isobutyl)-2.4-di-y-1,2,3,4-tetradecene #"2.3-€11 pyrimidine-5-hydantoic acid ethyl ester according to the method of Example 1 d), from the product of Example 1 c) and 5-porphyrincarboxyaldehyde to produce the subtitle compound. MS (ESI) 468 [ M + H] + δ丨HCDC丨3 0.87 (3H, d), 0.89 (3H, d), 1.33 (3H, t), 2.10-2.22 (1H, m), 3.38 (3H, s), 3.52 (1H , s, br), 3.55 (1H, dd), 3.71 (1H, dd), 4.33-4.41 (2H, m), 6.75 (1H, s), 7.39 (1H, dd), 7.77 (1H, t), 7.90 (1H, d), 8.14 (1H,d), 8.39 (lH,d),8.91 (1H, d) b) 3-methyl-1>(isobutyl)-2.4-diode-6 -(5-4 porphyrin) - L2.3.4-tetrahydrofuranium "2,3-dl-pyrimidin-5- oxime ethyl ester according to the method of item 丨e), prepared from product a) , produces a subtitle compound. -126 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (123) MS (ESI) 452 [M + H] + δ HCdci3 0.87 (6Η, d), 1.42 (3H, t), 2.09-2.19 (1H, m), 3.38 (3H, s), 3.60 (2H, d), 4.49 (2H,q), 4.59 (2H, s ), 7.43 (1H, dd), 7.50 (1H , dd), 7.70 (1H, t), 8.1l (ih, d), 8.49 (1H, d), 8.93 (1H, dd). A.-1-(isobutyl)- 2,4- ^^代_6_(5-!?), a certain methyl group, 1,2,3,4-tetrahydro 3⁄4 and "2,3-dlp close bite-5-leic acid sleeps according to example 1 f) Prepared by the product of item b) to give the subtitle compound MS (ESI) 424 [M + 2H-Na] + δ 'Η dms〇0.79 (6Η, d), 2.00-2.10 (1Η, m), 3.19 (3H, s), 3.53 (2H, d), 4.52 (2H, s), 7.46 (1H, dd), 7.64 (1H, d), 7.71 (ih, t), 7.93 (1H, d), 8.85 (1H, dd), 9.14 (iH, d). 4) (S)5-"4_Hydroxyisoxazolidine-2; ^-carbonyl carbonyl methyl iso-butyl keine g-methyl-methyl methyl} mouth pheno- and "2,3 -d 1 ρ 奈 _ 2 · 4(Ί Η, 3 Η)-dione._ Prepared according to the procedure of Example 1 g) 'Products from item c) and the product of Example 1 b) gave the title compound MS (ESI) 495 [M + H] + δ 'Η DMS〇0.80-0.83 (6Η, m), 1.99-2.06 (1Η, m), 3.2〇(2H s) 3.21 (1H, s), 3.50-3.63 (3H, m), 3.77- 4.14 (3H, m), 4·548. 4.70 (2.33H, m), 4.79-4.82 (0.67H, m), 5.50 (0.33H, d), 5 56 (0.67H, d), 7.54 (1H, Dd), 7.59 (0.33H, d), 7.63 (0.67H, d) 7.75 (1H, t), 7.98 (1H, d), 8.60 (0.33H, d), 8.64 (0.67H, d) 8.91 (1H , d). ' -127 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding
1310036 A7 B7 五、發明説明(124) 實例1 9 (呈)5-[4-羥基異哼唑啶-2-基蒺基1-3-甲某-1-丙基-6-(崦A -4-基甲基>塞吩並『2,3-d~l·密啶-? 4ΠΗ.3Η)-二酉同 a) 6-氣-3-甲某-1-丙基嘧啶-2 4μη.3Η)-二酮 取含6-氯-3-甲基尿》密咬(1〇 g)與碳酸鉀(10.34 g)之dmF (70 ml)溶液,於氮氣下經正-丙基碘(25 4 g)處理,回流加 熱8小時。反應冷卻後,倒至水(7〇〇 ml)中,以乙酸乙酯萃 取。合併之有機相脫水,真空蒸發,產生小標題化合物橙 色油狀物,17.52 g。 δ 'Hcdch 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1 H, s)。 1?」3 -甲基-l-丙某-6-氫硫某喊峻_2-4(11~1.3]~[)-二酮 取含步驟a)產物(11.43 g)之乙醇(4〇〇 mi)溶液,於氮氣下 經NaSH (6.3 1 g)處理《於室溫下攪拌48小時後,真空蒸發 溶劑,加水稀釋殘質。水相以乙酸乙酯洗滌後,以2M HC1 fe化。然後以乙酸乙酯萃取,合併之有機相脫水,真空蒸 發’產生小標題化合物之橙色油狀物,7 g。 δ 'Hcdcb 0.97 (3H,t),1.72 (2H,m),3.31 (3H,s),4.29 (2H,s)。 cl__3- T基-2,4-二氧代-丨二^_基氣嘧吩並「23_dl嘧 啶-5-藉酸乙酯 在含#驟上)產物(6.95 g)之無水二甲基甲醯胺(1〇〇 ml)溶 液中添加碳酸鉀(2.4 g),攪拌丨〇分鐘。添加溴丙酮酸乙酯 ^ ml),於氬氣與室溫下攪拌2小時。反應倒至水(iL)中, 酞化(2M HCI) ’以乙酸乙酯萃取。有機萃液以鹽水(丨〇〇 _ ______- 128 - 本紙張尺度適用中國國豕標準(CNS) Α4規格(2ι〇X297公爱) 裝 訂1310036 A7 B7 V. INSTRUCTIONS (124) EXAMPLE 1 9 (present) 5-[4-hydroxyisoxazolidine-2-ylindenyl 1-3-methyl-1-propyl-6-(崦A- 4-ylmethyl><2>>2,3-d~l·Midine-? 4ΠΗ.3Η)-二酉同 a) 6-Ga-3-methyl-1-propylpyrimidine-2 4μη .3Η)-dione is a solution of 6-chloro-3-methylurea (1〇g) and potassium carbonate (10.34 g) in dmF (70 ml), and n-propyl iodide under nitrogen ( 25 4 g) Treatment, heating under reflux for 8 hours. After the reaction was cooled, poured into water (7 mL) andEtOAc. The combined organics were dried <RTI ID=0.0> δ 'Hcdch 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1 H, s). 1?"3-Methyl-l-propanyl-6-hydrogen sulphide _2-4(11~1.3]~[)-dione is taken from the ethanol containing step a) (11.43 g) (4〇 〇mi) solution, treated with NaSH (6.3 1 g) under nitrogen. After stirring at room temperature for 48 hours, the solvent was evaporated in vacuo and residue was diluted with water. The aqueous phase was washed with ethyl acetate and then was taken with 2M HCl. After extraction with ethyl acetate, the combined organic phases were dried and evaporatedjjjjjjjjj δ 'Hcdcb 0.97 (3H, t), 1.72 (2H, m), 3.31 (3H, s), 4.29 (2H, s). Cl__3-T-based-2,4-dioxo-indenyl-yl-sulfonyl-[23-dl-pyrimidine-5-acidic acid ethyl ester in the product containing the product (6.95 g) of anhydrous dimethylformamidine Add potassium carbonate (2.4 g) to the amine (1 ml) solution, stir for 丨〇min. Add ethyl bromopyruvate^ ml), stir with argon at room temperature for 2 hours. The reaction is poured into water (iL) Medium, bismuth (2M HCI) 'extracted with ethyl acetate. Organic extract with brine (丨〇〇_ ______- 128 - this paper size applies to China National Standard (CNS) Α 4 specifications (2ι〇X297 public) binding
1310036 A7 B7 五、發明説明(125 ) 洗條。脫水與蒸發,產生油狀物。此油狀物溶於二氯曱燒 (1 00 ml)中,於冰中冷卻,同時攪拌。添加四氯化鈦(7.58 m丨),續於氮氣下攪拌2小時。反應倒至水(1 L)中,以二氣 甲烷萃取。有機相脫水,真空蒸發。殘質經層析純化 (Si02/乙酸乙酯-二氣甲烷0-8%),產生小標題化合物之橙 色油狀物,4.64 g。 δ 'Hcdch 1.02 (3H, t), 1.83 (2H, sextet), 3.42 (3H, s), 3.95 (2H, t), 4.41 (2H, q), 7.30 (1H, s)。 MS (APCI) 297.1 (M++H) d) 6-「羥基卜套啉-4-基)甲基1-3-甲基-2,4-二氣代-1-丙基-1,2,3,4-四氫碟吩並「2,3-(11嘧啶-:5-羧酸乙酯 依實例1 d)項之製法,由c)項產物製備小標題化合物。 δ 1 H c D C I 3 0.89 (3Η, t), 1.41 (3H, t), 1.65 (2H, sextet), 3.38 (3H, s), 3.75 (1H, d), 3.64 (1H, m), 3.80 (1H, m), 4.48 (2H, q), 6.78 (1H, d), 7.52 (1H, m), 7.72 (1H, m) 7.84 (1H, m), 7.90 (1H, d), 8.16 (1H, m),9.02 (1H, d)。 e) 3 -甲基-2,4-二氣代-1-丙基-6-h杳啉-4-基甲基)-1,2,3,4-四 氤遠吩並「2,3-dl嘧啶-5-斿酸乙酯 依實例1 e)項之製法,由d)項產物製備小標題化合物。 MS (ESI) 437.9 (M + + H) t) 3 -甲基- 2T4-一氧代-1-丙基-6-(口套淋-4-基甲基)-1,2,3,4-四 氫g塞吩並『2,3 _ d 1 ρ密唉_ 5 _幾.酉交鈉 依實例1 f)項之製法,由e)項產物製備小標題化合物。 δ 'H dmso 0.80 (3H, t), 1.57 (2H, sextet), 3.68 (2H, t), 4.55 -129 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1310036 A7 B7 五、發明説明(126) (2H, s), 3.19 (3H, s), 7.53 (2H, d),7.57 (1H, m) 7.74 (1H, m), 8.01 (1H, d), 8.61 (1H, d), 8.83 (1H, d) ° g) 哼唑啶-2-某魏某Ί-3-甲基-丨_丙某_6•卜杏呲- 4-基平—基)_嗔 ^JJ2,3-dl嘧啶-2,Π H,3HV二酮 依實例1 g)項之製法’由f)項產物與(s)_異吟唑啶_4_醇鹽 酸鹽製備。 δ 'H DMS0 0.84 (3H,td), 1,60 (2H, septet),3.21 (3H, d), 3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d), 3.90 (1H, m), 4.61 (2H, dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m)’ 7.79 (lH’ m),8.05 (1H,d), 8·27 (1H, dd), 8.87 (1H, d)。 MS (APCI) 1481.1 (M++H) 實例20 (U. 5」4-羥棊号唑啶-2-基錄某}_3_甲基_卜(異丙某V6-(4-4啉基曱基V裳吩並(2,3-(11嘧啶-2.4ΠΗ,3Η)-二酮1310036 A7 B7 V. INSTRUCTIONS (125) Washing strips. Dehydration and evaporation produce an oil. This oil was dissolved in dichlorohydrazine (100 ml) and cooled in ice while stirring. Titanium tetrachloride (7.58 m Torr) was added and the mixture was stirred under nitrogen for 2 hours. The reaction was poured into water (1 L) and extracted with dioxane. The organic phase is dehydrated and evaporated in vacuo. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: δ 'Hcdch 1.02 (3H, t), 1.83 (2H, sextet), 3.42 (3H, s), 3.95 (2H, t), 4.41 (2H, q), 7.30 (1H, s). MS (APCI) 297.1 (M++H) d) 6-"Hydroxypyridin-4-yl)methyl 1-3-methyl-2,4-di-a-1-1-propyl-1,2 , 3,4-tetrahydrodisc, a method for the preparation of 2,3-(11-pyrimidine-:5-carboxylic acid ethyl ester according to Example 1 d), the title compound is prepared from the product of item c) δ 1 H c DCI 3 0.89 (3Η, t), 1.41 (3H, t), 1.65 (2H, sextet), 3.38 (3H, s), 3.75 (1H, d), 3.64 (1H, m), 3.80 (1H, m), 4.48 (2H, q), 6.78 (1H, d), 7.52 (1H, m), 7.72 (1H, m) 7.84 (1H, m), 7.90 (1H, d), 8.16 (1H, m), 9.02 ( 1H, d) e) 3-methyl-2,4-dioxa-1-propyl-6-h porphyrin-4-ylmethyl)-1,2,3,4-tetrazole And 2,3-dl-pyrimidine-5-decanoic acid ethyl ester was prepared according to the procedure of Example 1 e), and the subtitle compound was obtained from the product of item d) MS (ESI) 437.9 (M + + H) t) 3 - A -2T4-monooxo-1-propyl-6-(mouth -4-methyl)-1,2,3,4-tetrahydro-g-phene and "2,3 _d 1 ρ dense唉 _ 5 _ _ _ 酉 酉 钠 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ t), 4.55 -129 - This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) 1310036 A7 B7 V. INSTRUCTIONS (126) (2H, s), 3.19 (3H, s), 7.53 (2H, d), 7.57 (1H, m) 7.74 (1H, m), 8.01 (1H , d), 8.61 (1H, d), 8.83 (1H, d) ° g) oxazolidine-2-some Wei Ί-3-methyl-丨_丙某_6•卜杏呲- 4-based Ping-based) _嗔^JJ2,3-dl-pyrimidine-2, ΠH, 3HV-dione according to the method of Example 1 g) 'Products from item f) and (s)-isoxazolidine-4-alkoxide Preparation of acid salt. δ 'H DMS0 0.84 (3H, td), 1,60 (2H, septet), 3.21 (3H, d), 3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d ), 3.90 (1H, m), 4.61 (2H, dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m)' 7.79 (lH' m) , 8.05 (1H, d), 8·27 (1H, dd), 8.87 (1H, d). MS (APCI) 1481.1 (M++H) Example 20 (U. 5" 4-hydroxyindolozolidine-2-ylyl}}_3_methyl_b (isopropyl V6-(4-4 phenyl) Mercapto V-expressed (2,3-(11-pyrimidine-2.4ΠΗ,3Η)-dione
a). 2-((異丙基)胺某)4吩-3,4-二截酸二乙酯 取含乙氧-羰基亞甲基三苯基磷烷(33.8 g)之無水THF (200 ml)溶液’於65°C與氮氣下,經異硫氰酸異丙酯(1〇.丨g)處 理1 6小時。混合物冷卻至-781,添加溴丙酮酸乙酯(1 9.5 g) 。使反應緩緩回升室溫。於室溫下24小時後,再加溴丙酮 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)a) 2-((isopropyl)amine) 4 phene-3,4-dipic acid diethyl ester containing anhydrous THF containing ethoxy-carbonylmethylenetriphenylphosphorane (33.8 g) (200 The ml solution was treated with isopropyl isothiocyanate (1 〇.丨g) for 16 hours at 65 ° C under nitrogen. The mixture was cooled to -781 and ethyl bromopyruvate (19.5 g) was added. The reaction was allowed to slowly rise to room temperature. After 24 hours at room temperature, add bromoacetone. This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm).
*線 1310036 A7*Line 1310036 A7
斿酸乙酯 二酯(3.1 7 g) ’混合物於室溫下攪拌16小時。反應倒至水 iS:nL)中,以料取。脫水與蒸發,產生油狀物,經層析法 2/5:1異己、淀-乙酸乙酿)’產生小標題化合物(21_2g” UHbrd) 1 23"L43 〇2H,^ 3'46 〇H,^ 4'2"4,35 (4H,m),6'5° 〇H' S)J·52 ^U.2,34- M酸銀(4.5 g)懸浮於無水甲苯(3〇叫中’於氮氣下滴 口乙醯氯(1_78 ml)處理,激烈攪拌3〇分鐘。添加含步驟約 尺物(7.12 g)之無水甲苯(5 ml)溶液,混合物攪掉24小時。 斗加醚(120 ml),濾出不溶物,以少量醚洗滌。合併之有 機'公硬以飽和碳酸氫鈉溶液洗滌’脫水與蒸發。殘質經乙 S于鈉〈乙醇溶液(由丨.95 g鈉與35 ml甲醇製備)於室溫下處 理24小時。反應於冰中冷卻,以三甲矽烷基氣(2〇 m丨)處理 ,於室溫下攪拌一夜。真空排除所有揮發物,殘質分佈在 水與乙酸乙酯之間。有機溶液脫水與蒸發後’殘質與碳酸 鉀(6.W g)及甲基碘(8·5 g) 一起溶於室溫之無admf (5〇 mi) 中24小時。混合物倒至水(1 L)中,酸化,以醚萃取。以鹽 水洗滌,脫水與蒸發後,產生油狀物。經層析(si〇2/3 :夏異 己坑-乙酸乙酯)’產生小標題化合物(3.丨g)。 δ 'HCDC3 1.^9 (3Η, t), 1.6 (6H, d), 3.39 (3H, s), 4.4 (2H, q), 7.25 (1 H, s)。 MS (APCl) (M + + H) 297 經基(4-崦啉甚、甲甚卜j-曱基-1-(異aA)_2,4_二氣代 ___ - 131 - 本紙張尺度通用中國國家標準(CMS) Α4規格(210 X 297公釐) 装 訂The ethyl decanoate diester (3.17 g)' mixture was stirred at room temperature for 16 hours. The reaction was poured into water iS:nL) and taken. Dehydration and evaporation, producing an oily substance, by chromatography 2/5:1 hexahydrate, decyl-acetic acid ethyl) 'produces subtitle compound (21_2g" UHbrd) 1 23"L43 〇2H,^ 3'46 〇H, ^ 4'2"4,35 (4H,m),6'5° 〇H' S)J·52 ^U.2,34- M acid silver (4.5 g) suspended in anhydrous toluene (3 〇 中 ' The mixture was treated with a drop of ethyl acetate (1 - 78 ml) under nitrogen, and stirred vigorously for 3 minutes. A solution of the residue (7.12 g) in anhydrous toluene (5 ml) was added and the mixture was stirred for 24 hours. Ml), insoluble material was filtered off, washed with a small amount of ether. The combined organic 'public hard was washed with saturated sodium bicarbonate solution' dehydration and evaporation. Residues were treated with sodium sate in sodium <ethanol solution (from 95.95 g sodium and 35 Methanol preparation) was treated at room temperature for 24 hours. The reaction was cooled in ice, treated with trimethylsulfanyl (2 〇m) and stirred at room temperature overnight. All volatiles were removed in vacuo. Between ethyl acetate. After dehydration and evaporation of the organic solution, the residue was dissolved in room temperature-free admf (5〇mi) with potassium carbonate (6.W g) and methyl iodide (8·5 g) for 24 hours. Mix the mixture In water (1 L), acidified, extracted with ether, washed with brine, dried and evaporated to give an oil, which was obtained by chromatography (si〇2/3: s. (3.丨g) δ 'HCDC3 1.^9 (3Η, t), 1.6 (6H, d), 3.39 (3H, s), 4.4 (2H, q), 7.25 (1 H, s). MS (APCl) (M + + H) 297 Meridian (4-Porphyrin, Azor, J-Mercapto-1-(iso-aA)_2, 4_Digas ___ - 131 - This paper scale is used in China National Standard (CMS) Α4 Specifications (210 X 297 mm) Binding
-線 1310036 A7 B7 五、發明説明(128 ) 1.2,3,4-四新.p裳吩並「2.3-dl嘴淀-5-幾酸乙醋 依實例1 d)項之製法,由b)項產物與4-喹啉羧基醛製備’ 產生小標題化合物。 MS(ESI) 454 [M + H] + δ 'HCdci31-41 (3H, t),1.43 (3H, d), 1.46 (3H, d), 3.35 (3H, s), 3.66 (1H, d), 4.25-4.45 (1H, m), 4.45-4.51 (2H, m), 6.78 (1H, d), 7.53 (1H, td), 7.72 (IH, td), 7.83 (1H, d), 7.92 (1H, d),8.17 (1H,dd), 9.02 (iH,d)。 cH 3-甲某-卜(異丙基)-2.4-二氧代-6-M-峰啉某甲某)-1.2.3.4-四氳4吩並r2.3-dl嘧啶-5-斿酸乙酯 依實例1 c)項之製法’由c)項產物製備,產生小標題化合 物。 MS (ESI) 438 [M + H] + δ 'Hcdch 1.37 (3Η,t),1.49 (6Η,d), 3.36 (3Η,s), 4.44 (2Η, q), 4.60 (2H,s),4.30-4.60 (1H,m),了七(1H,d), 7.61 (ih, td),7.76 (1H,td),8.13 (1H, dd),8.16 (ih,dd), 8.81 (1H,d)。 6)3-甲棊.-1-(異丙基)-2,4-二乳代-立:^-峰11林某甲疾)_1.2.3,4- 四箭,遠g分並f 2,3 -d 1 p密咬-5 -残酸納鹽_ 依實例1 f)項4製法’由d)項產物製備,產生小標題化合 物。 MS (ESI) 4 W) [M + 2H-Na] + δ Hdmso 1.36 (6H,d),3·16 (3H,s), 4 IQ-4 35 (iH m) 4 52 (2H, s), 7.53 (1H, d), 7.58 (1H, t), 7.74 (ih, t), 8.00 (1H, d), 8.62 (1H,d), 8.82 (1H, d)。 -132 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(129 £L(S) 5-|4二超基異噚吨啶-2·基羰某卜3-甲某- l-(昱丙某、j 14_-^117林..棊更基)啶吩並「2.3-(11嘧啶_-2、4(1幵.3只)-二西同 依實例1 g)項之製法,由 MS (ESI) 481 [M + H] + e)項產物製備,產生標題化合物 0 HDMS〇 1.40-1.44 3.18 (2H!s)53 i9(iH s) ^ 313.98 (〇.33H,m),3·99.4·05 (〇 33h,咕 4 ’ ), dd),4.22-4.4〇(1H,m),4.50-4.68 (2.33H,m) 4 79 (〇67H 二, 5.5〇(0.33H,d),5.54 (0.67H,d),7.44(〇33Hd),7 48 (^」, d), 7.64(1H, t), 7.78 (1H, t), 8.05 (lH d)58 26 (〇 33H ^ 8_30 (0.67H,d), 8.87 (1H,d)。 ’ d), 不包栝次要幾何異 (* N.B.主要幾何異構物之2 : 1混合物 構物之波導) 實例21Π 坐啶-2-基羰基丁 卟比咬-3-基^-Line 1310036 A7 B7 V. Description of invention (128) 1.2,3,4-Four new.p The procedure for the production of "2.3-dl mouth lake-5-several acid vinegar according to example 1 d", by b) Preparation of the product with 4-quinolinecarboxyl aldehyde to give the subtitle compound. MS (ESI) 454 [M + H] + δ 'HCdci31-41 (3H, t), 1.43 (3H, d), 1.46 (3H, d ), 3.35 (3H, s), 3.66 (1H, d), 4.25-4.45 (1H, m), 4.45-4.51 (2H, m), 6.78 (1H, d), 7.53 (1H, td), 7.72 ( IH, td), 7.83 (1H, d), 7.92 (1H, d), 8.17 (1H, dd), 9.02 (iH, d). cH 3-A-Bu (isopropyl)-2.4-diox -6-M-Phospholine a certain methyl group)-1.2.3.4-tetradecene 4 phenanthrene and r2.3-dl pyrimidine-5-decanoic acid ethyl ester according to the preparation method of the formula 1 c) , produces the subtitle compound MS (ESI) 438 [M + H] + δ 'Hcdch 1.37 (3Η, t), 1.49 (6Η, d), 3.36 (3Η, s), 4.44 (2Η, q), 4.60 ( 2H, s), 4.30-4.60 (1H, m), seven (1H, d), 7.61 (ih, td), 7.76 (1H, td), 8.13 (1H, dd), 8.16 (ih, dd), 8.81 (1H, d) 6) 3-methyl 棊.-1-(isopropyl)-2,4-di-dairy-立:^-峰11林某甲病)_1.2.3,4- four arrows , far g points and f 2,3 -d 1 p close bite-5 - Residual acid salt _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ,3·16 (3H,s), 4 IQ-4 35 (iH m) 4 52 (2H, s), 7.53 (1H, d), 7.58 (1H, t), 7.74 (ih, t), 8.00 ( 1H, d), 8.62 (1H, d), 8.82 (1H, d) -132 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention ( 129 £L(S) 5-|4 di-based isoindole oxidine-2·yl carbonyl 卜3-甲某- l-(昱丙某, j 14_-^117林..棊更基) pyridine And the preparation method of "2.3-(11-pyrimidine_-2, 4 (1幵.3)-二西同依例1g), prepared by MS (ESI) 481 [M + H] + e), Produced the title compound 0 HDMS〇1.40-1.44 3.18 (2H!s)53 i9(iH s) ^ 313.98 (〇.33H,m),3·99.4·05 (〇33h,咕4'), dd),4.22- 4.4 〇 (1H, m), 4.50-4.68 (2.33H, m) 4 79 (〇67H 2, 5.5〇 (0.33H, d), 5.54 (0.67H, d), 7.44 (〇33Hd), 7 48 ( ^", d), 7.64(1H, t), 7.78 (1H, t), 8.05 (lH d)58 26 (〇33H^8_30 (0.67H,d), 8.87 (1H,d). ‘d), does not include minor geometrical differences (* N.B. 2:1 mixture of main geometric isomers). Example 21Π Sodium-2-ylcarbonyl butyl 卟 咬 咬 -3- base ^
-2,4HH,3HV 二獅 ^L-2,4HH,3HV two lions ^L
OHOH
基-1-(異丁基 『2,3_bl吡啶基)嘍吩並 _ - 133 - 本紙張尺度適用中圃國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 B7 依實例6 a)項之製法,由實例3 b)項產物與2-甲基氮雜叫丨 哚製備。 MS (APCI) 427 [M + H] + δ 1 H DMSO 0.83 (6Η,d),2.09 (1Η, heptet), 3.20 (3Η, s) 3 6l (2H, d), 3.86 (3H, s), 4.22 (2H, s),7.02-7.〇5 (1H, m), 743 (1H, m), 7.88 (1H,d),8.20 (1H, d),11.56 (1H,s,br)。 丨二3,4-四.i-3-甲基-1-(異 T 基)-並「2,3-bl吡啶-3-基甲某V塞吩並f2,3-dl嘧忒#Λ 依實例3 d)項之製法’由a)項產物製備小標題化Η合物 (1.22 g)。 °Base-1-(isobutyl 2,3_bl pyridyl) porphin _ - 133 - This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 by example 6 a) The preparation method of the item was prepared from the product of Example 3 b) and 2-methylazetium. </ RTI> <RTIgt; 4.22 (2H, s), 7.02-7. 〇5 (1H, m), 743 (1H, m), 7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s, br).丨2,3,4-tetra.i-3-methyl-1-(iso-T-yl)- and "2,3-blpyrid-3-yl-methyl-V-phene-f2,3-dl-pyrimidine#Λ The subtitled chelate (1.22 g) was prepared according to the procedure of Example 3 d) 'Products from item a).
MS (ESI) 413[M + H] + c) fS) 5-「f4-羥某異噚唑啶-2-某1蕤甚 K2-甲基-1H-吡咯並[2,3-bl吡啶-3-某 啶-2,4ΠΗ,3Η)-二酮 依實例1 g)項之製法’由b)項產物製備標題化合物。 MS (APCI) 498 [M + H] + δ 1 Hqiviso 0-87-0.90 (6Η, m), 2.09-2.15 (ih m\ 〇 Λ(· m), 2.46 (3H, 叫, (1H,m) 7.00-7.03 ( 1H,m),7.84-7.89 (1H,m),8 14_815 ⑽), 3.25-3.27 (3H, m), 3.58-3.72 (3H, m), 3.81.393 (2H 4.03-4.22 (3H, m),4.72-4.86 (1H,m),5 57_5 82 ’ Η . 5 1 (1 Η,幻。 實例21ii) (R) 5-「4-衮基異崎唑啶-2-某羰某j T其 曱基-1 Η - g比咯並[2,3 - b.M 啶二/ 134 本紙張尺度適用中國画家標準(CNS) A4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(131 -2,4ΠΗ,3Η)-二酮MS (ESI) 413 [M + H] + c) fS) 5- "f4-hydroxylisoxazole pyridine-2-one quinone K2-methyl-1H-pyrrolo[2,3-blpyridine- 3-The pyridine-2,4ΠΗ,3Η)-dione The title compound was prepared according to the procedure of Example 1 g). MS (APCI) 498 [M + H] + δ 1 Hqiviso 0-87- 0.90 (6Η, m), 2.09-2.15 (ih m\ 〇Λ(· m), 2.46 (3H, 叫, (1H,m) 7.00-7.03 ( 1H,m),7.84-7.89 (1H,m), 8 14_815 (10)), 3.25-3.27 (3H, m), 3.58-3.72 (3H, m), 3.81.393 (2H 4.03-4.22 (3H, m), 4.72-4.86 (1H, m), 5 57_5 82 ' Η . 5 1 (1 Η, 幻. Example 21ii) (R) 5-"4-indolylisoxazolidin-2-one carbonyl some j T its thiol-1 Η - g ratio 咯[2,3 - bM pyridine 2 / 134 This paper size applies to Chinese Painter Standard (CNS) A4 size (210X 297 mm) 1310036 A7 B7 V. Description of invention (131 -2,4ΠΗ,3Η)-dione
依實例i g)項之製法,由實例2Π)步驟b)產物使用(R)-4-羥基異呤唑啶(實例2 b)項)製備,產生標題化合物。 MS (APCI) 498[M + H] + δ 丨 HDMso 0, 81-0.84 (6Η, m), 2.03-2.09 (1Η, m), 2.39 (3H, s), 3.16-3.19 (3H, m), 3.52-3.66 (3H, m), 3.75-3.89 (2H, m), 3.97-4.16 (3H, m), 4.63-4.80 (1H, m), 5.53-5.55 (1H, m), 6.94-6.98 (1H, m), 7.76-7.83 (1H, m), 8.08-8.09 (1H, m), 11.45 (1H, s)。 實例22 (S) 544-羥基異呤唑啶-2-某羰某1-3-甲某-1-(異丙某)-6-「2-甲基-1 Η-峨咯並「2.3-bl吡啶-3-基甲基1歧吩並f2.3-dl嘧啶 -2,4(ΊΗ,3Η)_ 二酮Prepared according to the procedure of Example i g), the product from step (2), step b), using (R)-4-hydroxyisoxazole pyridine (Example 2 b), yielded the title compound. MS (APCI) 498[M + H] + δ 丨HDMso 0, 81-0.84 (6Η, m), 2.03-2.09 (1Η, m), 2.39 (3H, s), 3.16-3.19 (3H, m), 3.52-3.66 (3H, m), 3.75-3.89 (2H, m), 3.97-4.16 (3H, m), 4.63-4.80 (1H, m), 5.53-5.55 (1H, m), 6.94-6.98 (1H , m), 7.76-7.83 (1H, m), 8.08-8.09 (1H, m), 11.45 (1H, s). Example 22 (S) 544-Hydroxyisoxazole pyridine-2-carbonylation 1-3-methyl-1-(isopropyl)-6-"2-methyl-1 Η-峨" and 2.3- Bl pyridin-3-ylmethyl 1 phenanthrene f2.3-dl pyrimidine-2,4(ΊΗ,3Η)_dione
本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of the invention (
132 幻一6-(溴甲某四氯-3-甲其-M異丙某 噬吩# 嘧啶-5-翔_甲巧 取含實例8 b)項產物(1.6 g)、N-溴玻珀醯亞胺(1 g)與偶氮 異丁腈(1 0 mg)之乙酸乙酯(25 ml)溶液回流1小時。溶液冷 卻至室溫’依序以稀氫氧化鈉溶液及水洗滌’有機萃液經 無水硫酸鎂脫水’過濾,減壓蒸發。殘質經矽石管柱層析 法純化,以乙醚/異己烷(1 : 1)溶離,產生小標題化合物之 固體,(1.5 g)。 δ H c D c I 3 1 . 62 (6H, d), 3.37 (3H, s), 3.99 (3H, s), 3.60-3.70 (3H, m) ° b) 1,2,3,4-四氮,-3 -曱基- 丙基甲某- ΙΗ-g 比吃# £1,3-13~|〇比峻-3-基甲基1-2.4-二氧代-12寒吩並「2,3-(11被哈-5-途 酸甲醋 於氬氣與周溫下’在含60%氫化鈉(0.23 g)之THF (1〇 mi) 攪拌懸浮液中滴加含2-甲基氮雜叫丨哚(0.37 g)之THF (10 ml) 溶液。攪拌5分鐘後,添加1M氯化鋅之醚溶液(5.6 ml)。攪 拌5分鐘後,添加含a)項產物(0.88 g)之THF (10 ml)溶液, 混合物攪拌3小時。加水中止反應,以乙酸乙酯萃取,合 併之有機萃液經無水硫酸鎂脫水,過濾與減壓蒸發。殘質 經矽石管柱層析法純化,以乙酸乙酯/異己烷(1 : 1)溶離, 產生小標題Η匕合物之固體(〇.4 g)。 MS (ESI) 427 [M + H] + δ 1.48 (6H, d),2.49 (3H, s), 3.36 (3H,s),4.11 (2H, s), 4.20 (ΊΗ, s, br), 7.03-7.06 (1H, m), 7.79 (1H, d), 8.23 (1H, 136 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)132 幻一6-(Bromomethyl 4-tetrachloro-3-methyl-M-isopropyl phage # pyrimidine-5-翔_甲巧取例例8 b) Item (1.6 g), N-Bromopor A solution of hydrazine (1 g) and azoisobutyronitrile (10 mg) in ethyl acetate (25 ml) was refluxed for one hour. The solution was cooled to room temperature ' washed sequentially with dilute sodium hydroxide solution and water. The residue was purified by EtOAc EtOAc (EtOAc) δ H c D c I 3 1 . 62 (6H, d), 3.37 (3H, s), 3.99 (3H, s), 3.60-3.70 (3H, m) ° b) 1,2,3,4-four Nitrogen, -3 -mercapto-propyl-methyl- ΙΗ-g than eat # £1,3-13~|〇比峻-3-ylmethyl1-2.4-dioxo-12-cold "2 , 3-(11 by Ha-5-trans-methane vinegar under argon and ambient temperature' in a stirred suspension of 60% sodium hydride (0.23 g) in THF (1 〇mi) was added dropwise with 2-methyl Azepine (0.37 g) in THF (10 ml). After stirring for 5 min, 1 M zinc chloride ether solution (5.6 ml) was added. After stirring for 5 minutes, product a) (0.88 g) was added. The THF (10 ml) was stirred and the mixture was stirred for 3 hr. The mixture was stirred and evaporated with ethyl acetate. Purification, elution with ethyl acetate / hexanes (1 : 1) to give the title compound ( s. 4 g). MS (ESI) 427 [M + H] + δ 1.48 (6H, d) , 2.49 (3H, s), 3.36 (3H, s), 4.11 (2H, s), 4.20 (ΊΗ, s, br), 7.03-7.06 (1H, m), 7.79 (1H, d), 8.23 (1H , 136 - This paper scale applies to Chinese national standards (CNS ) A4 size (210X297 mm)
裝 訂Binding
‘線 ·· 1310036 A7 B7‘Line ·· 1310036 A7 B7
由b)項產物製備,Prepared from product b),
五、發明説明(133 )V. Description of invention (133)
二^^ ,... d), 9.10 (1H,s)。 c) 1,2,3,4-四新-3-甲 「2,3-bl峨淀-3-某甲某卜/ 二 依實例1 f)項之製法,由 物之固體。 MS (ESI) 413 [M + H] +Two ^^ ,... d), 9.10 (1H, s). c) 1,2,3,4-tetraxin-3-methyl "2,3-bl峨--3- 甲甲 /二依例1 f), the solids of the substance. MS (ESI ) 413 [M + H] +
-2,4(限3出-二_ - 依實例1 g)項之製法,由幻項產物與(s)_4_異噚唑啶醇鹽 酸鹽[實例lb項]製備’產生標題化合物之固體。 篇 MS (APCI) 484 [M+H] + δ Hdms〇 1.37-1.40 (6H, m), 2.40 (3H, s), 3.17-3.18 (3H, m) 3.52-4.28 (7H, m), 4.66-4.79 (1H, m), 5.50-5.55 (1H, m)^ 6-95-6.99 (1H, m), 7.80-7.86 (1H, m), 8.08-8.10 (1H, m)^ 1 1_45 (1H, s)。 ’ ’ 實例23 i_S)-6-[4,5-士二氯-2-(持某甲基)-1Η-咪唑-i_華甲某-5_「4-碑早 县口可唑哫-2i羧基卜3 -曱某-1-(昇丁塞吩並砷斤 二2,4 ( 1 Η,3 Η 二西同-2,4 (Limited to 3 out - 2 - according to Example 1 g), prepared from the phantom product and (s)_4_isoxazolidine hydrochloride [Example lb] to produce the title compound solid. MS (APCI) 484 [M+H] + δ Hdms〇1.37-1.40 (6H, m), 2.40 (3H, s), 3.17-3.18 (3H, m) 3.52-4.28 (7H, m), 4.66- 4.79 (1H, m), 5.50-5.55 (1H, m)^ 6-95-6.99 (1H, m), 7.80-7.86 (1H, m), 8.08-8.10 (1H, m)^ 1 1_45 (1H, s). ' ' Example 23 i_S)-6-[4,5-Shibodichloro-2-(holding methyl)-1Η-imidazole-i_华甲某-5_"4-碑早县口可唑哫-2i Carboxyl group 3 - 曱一-1- (literate butyl phenanthrene arsenic 2,4 (1 Η, 3 Η two xitong
1310036 A7 B7 五、發明説明(134 ) a) 4,5 -二氣-1H -咪g坐-2-甲醇 添加氫氧化钾(〇 12 g,2.14 mmol)之水(4 ml)溶液至4,5-一氯甲坑中,懸浮液攪拌35分鐘。分批添加多聚甲磁 (0· 1 1 g ’ 3.66 mmol) ’反應混合物揽拌一夜,添加稀HC1酸 化至pH 1後,真空濃縮,產生白色固體,〇 6 g (98%)。 δ ' HCdci3 4.36 (2H, s) ^-—菊,-2-(轉基甲基)-1Η-味g全-1-某甲基ι_ι,2·3·4 -四 氫-3-f基-1-〔異丁基)_2,4·二氧代-噢吩並「2.3-dl嘧啶-5-勒酸 甲酯 添加碳酸鉀(〇_ 14 g,3.1 mmol)與 a)項產物(〇.5 ig,3.09 mmol)至含實例3…項產物之DMF溶液中,反應混合物攪拌 1 6小時。濾出所形成之沉澱固體’濾液真空濃縮,產生橙 色固體0.6 g,其中含有DMF。 δ 'HCDCI3 0.99 (6Η, m), 2.19-2.31 (1H, m), 3.4 (3H, s), 3.72 (2H,d), 4.0 (3H, s), 4.68 (2H,s),5.45 (2H,S)。 ^~ϋ.4’5 - 一 1(,-2-(¾ 基甲基)-1Η -味〇小_1-其〒某~[_ι.2.3·4 -四 氫-3-甲基-1 -(昇工.,基)·2,4-二氧代吟光「2.3_dl碎被-5-勒酸 甲酯 依實例3 d)項之製法,由b)項產物製備。 MS (ESI) 484 [M + H]+。 4) 6-f4,5-二1」2-(羥基甲基)-1Η·咪斗二丨_芊甲芊卜s_p4Sy4- U:·異。号吐鳴羰棊1-3-甲.基-丄^異丁葚w食吩並 °密 p定-2,4(1H.3H)-二酮 依實例3 e)項之製法’由c)項產物製備。產物經逆相製備 -138 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)1310036 A7 B7 V. INSTRUCTIONS (134) a) 4,5-diox-1H-m-m-methyl-potassium hydroxide (potassium 12 g, 2.14 mmol) in water (4 ml) was added to 4, In a 5-chloropiper pit, the suspension was stirred for 35 minutes. The polymethylmagnesium (0·11 g ' 3.66 mmol) was added portionwise. The reaction mixture was stirred overnight and then diluted with EtOAc EtOAc EtOAc EtOAc δ ' HCdci3 4.36 (2H, s) ^--Chrysanthemum, 2-(transmethylmethyl)-1Η-味g all-1-methylmethyl ι_ι,2·3·4 -tetrahydro-3-fyl -1-[Isobutyl)_2,4·dioxo-indenyl-"2.3-dl-pyrimidine-5-le-methyl ester added potassium carbonate (〇_ 14 g, 3.1 mmol) and a) product (〇 .5 ig, 3.09 mmol) to a DMF solution containing the product of Example 3, the reaction mixture was stirred for 16 h. The precipitated solid formed was filtered and concentrated in vacuo to give an orange solid, 0.6 g, containing DMF. δ 'HCDCI3 0.99 (6Η, m), 2.19-2.31 (1H, m), 3.4 (3H, s), 3.72 (2H,d), 4.0 (3H, s), 4.68 (2H, s), 5.45 (2H, S) ^~ϋ.4'5 - a 1(,-2-(3⁄4 ylmethyl)-1Η - miso _1 - its 〒~[_ι.2.3·4 -tetrahydro-3-methyl- 1 - (Shanggong., base) · 2,4-dioxophosphonium "2.3_dl broken by 5-methyl acid methyl ester according to Example 3 d), prepared from product b). MS (ESI) ) 484 [M + H]+. 4) 6-f4,5-di 1"2-(hydroxymethyl)-1Η·miole 2 丨 芊 芊 s s_p4Sy4- U:· No. 吐 棊 棊 棊 - - - 棊 棊 棊 棊 食 食 食 食 食 食 食 食 食 食 食 -2 -2 , , , , , , , , , , , , , , , , , , , , , , , , , Preparation of the product. Preparation of the product by reverse phase -138 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)
•線 鳟 1310036 A7 B7•Line 鳟 1310036 A7 B7
性H P LC純化,以乙酸按:r賠γ7。· 1 敗奴己如(70 · 30)溶離,產生標題化 合物之白色固體。 δ 土⑶cl3〇_89(6H,m),2.06_2.21(1H,m),3 2i(3H,s),3 62_ 4]8 (6H,m),4·44-4.78 (2H,m),5.41 (2H,叫 5 53 (ih,叫與 5.72-5.75 (IH,m)。 實例24Purification of H P LC with acetic acid at rr. · 1 The slain has been dissolved (70 · 30) to give the title compound as a white solid. δ soil (3) cl3〇_89(6H,m), 2.06_2.21(1H,m),3 2i(3H,s),3 62_ 4]8 (6H,m),4·44-4.78 (2H,m ), 5.41 (2H, called 5 53 (ih, called with 5.72-5.75 (IH, m). Example 24
裝 二t基-iH-四氣_3_甲某小 (異丁基)-2,4-二氧代 酯 取實例3 b)項產物(0,4g,_〇1)、2,4_二甲基峨嗅 (0.2g ’ 2.06 mmol)與二甲基乙酿胺(約〇 5 ml)於微波爐中, 在100°C下加熱5分鐘。反應混合物真空濃縮後,研磨, 0.34 g (84% )。 MS (ESI) 40-5 [M + H] + (異丁基)-2,4-二氧代-嘧吩並|~2,3-〇11喩&_5_教,酸 依實例3 d)項之製法,由a)項產物製備。 -139 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 訂Packed with two t-based-iH-tetraqi_3_A small (isobutyl)-2,4-dioxoester as Example 3 b) products (0,4g, _〇1), 2,4_ Dimethyl oxime (0.2 g '2.06 mmol) and dimethyl ethanoamine (about 5 ml) were heated in a microwave oven at 100 ° C for 5 minutes. The reaction mixture was concentrated in vacuo and triturated, 0.34 g (84%). MS (ESI) 40-5 [M + H] + (isobutyl)-2,4-dioxo-sulfonome|~2,3-〇11喩&_5_Teach, acid according to Example 3 d The preparation method of the item is prepared from the product of item a). -139 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)
線 1310036 A7 B7 ' 五、發明説明(136 ) MS (ESI) 391 [M + H] + c) 6-「3,5-二甲基-1H-吡唑-1-某甲某-5-『(4S)-4·羥某異崎唑 口足-2-基幾基1-3 -甲基-1-(異丁基)-口基吩並「2,3-dl 口密咬 _2.4ΠΗ,3Η)_ 二酮 依實例3 e)項之製法,由b)項產物製備。產物經逆相製備 性HPLC純化,以乙酸銨:乙腈(70 : 30)溶離,產生標題化 合物之白色固體。 MS (ESI) 462 [M + H] + δ 'Hcocn 〇·9 (6Η, m), 2.09-2.19 (1H, m), 2.2 (3H, s), 3.2 (3H, s), 3.52-4.1 (6H, m), 4.81-4.77 (1H, m), 5.16-5.23 (2H, m), 5.49-5.57 ( 1 H, m)與 5.82 (1H, s)。 實例25 (S)-6-「2,3-二氳-2-氣代-1H-笨並咪唑-1-基甲基l-5-「4-羥基異 噚唑啶-2-基羰基1-3 -甲基-1-(異丁基)-嘧吩並「2,3-dl嘧啶 -2,4ΠΗ,3Η)-二酮Line 1310036 A7 B7 ' V. Description of the invention (136) MS (ESI) 391 [M + H] + c) 6-"3,5-Dimethyl-1H-pyrazole-1-one A-5-" (4S)-4·Hydroxylisoxazole oxazolidine-2-ylaminol 1-3-methyl-1-(isobutyl)-mouth phenanthrene "2,3-dl mouth bite _2.4" </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI) 462 [M + H] + δ 'Hcocn 〇·9 (6Η, m), 2.09-2.19 (1H, m), 2.2 (3H, s), 3.2 (3H, s), 3.52-4.1 ( 6H, m), 4.81-4.77 (1H, m), 5.16-5.23 (2H, m), 5.49-5.57 ( 1 H, m) and 5.82 (1H, s). Example 25 (S)-6-"2 ,3-dioxin-2-oxo-1H-benzimidazol-1-ylmethyll-5-"4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-(iso) Butyl)-pyrimido "2,3-dl pyrimidine-2,4ΠΗ,3Η)-dione
3-甲基-1-(異丁基)-2,4-二氣代-違吩並「2,3-dl嘧啶-5-#酸甲酯 取實例3 b)項產物(0 · 5 g,1.2 8 m m ο 1)、2 -氣苯並咪峻 (0.21g,1.37 mmol)、石炭酸钾(0.36g,2.6 mmol)與 DMF (10 -140 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 裝 訂3-methyl-1-(isobutyl)-2,4-dihydro--"2,3-dl-pyrimidine-5-# acid methyl ester takes the product of example 3 b) (0 · 5 g , 1.2 8 mm ο 1), 2 - benzophenone (0.21 g, 1.37 mmol), potassium carbate (0.36 g, 2.6 mmol) and DMF (10 -140 - this paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) Binding
1310036 A7 B7 五、發明説明(137 ) ml)攪拌1.5小時。添加乙酸乙酯與水至反應混合物中。勿 離兩相。有機層脫水(MgS〇4)後,真空濃縮^殘貞經 biotage純化,以二氯甲烷溶離,產生小標題化合物之淺只 色固體 ’ 0.36 g (61%)。 δ 4^^0 0.83 與 0.91 (6H, d), 2.1-2.22 (1H, m),3.38 (3H, s),3.67 (2H,d),4_1 (3H,s), 5.58 (2H, s),7.26-7.38 (2H,m), 7.41-7.48 (1H,m)與 7.7-7.8 (1H, m)。 b) 6 -『2,3 - 一 a - 2 -氧代-1 h -笨並吹 -1 -某甲某 i i 3-甲基-1-(異丁基)-2.4-二氧代哈並「2.3-dl嘧啶 添加步驟 a)產物(〇.36g,0.65 mmol)至含 THF (1〇 ml)、水 (1 ml)與三乙胺(〇.〇5 ml)之密封試管中,於180。(:下加熱3天 。反應混合物真空濃縮,產生小標題化合物(收量0.3 g粗產 物)。 MS (ESI) 440 [M+H] + c) β-丨2,3二士氫-2-氧代-1H-苯並咮唑-1-某甲 基異哼唑啶-2-基羰基1-3-甲基-1-(異丁基吩祐 -2·4(1Η,3Η)-二酮 依實例3 e)項之製法,由b)項產物製備。產物經逆相製備 性HPLC純化,以乙酸銨:乙腈(80 : 20)溶離,與乙醚研磨 後,產生標題化合物之淺黃色泡沫狀物。 δ 1 Hd6-dmso'〇-93 (6H, m), 2.1-2.24 (1H, m), 3. (2H, s), 3 26 (3H, s), 3.52-4.18 (5H, m), 4.62-4.82 (1H, s), 5.02-5.2 (2H s), 6.96-7.03 (2H,m), 7.17-7.19 (1H,m)。 實例26 -141 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) 13100361310036 A7 B7 V. INSTRUCTIONS (137) ml) Stir for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. Do not leave the two phases. After the organic layer was dried (MgSO4), EtOAc (EtOAc) δ 4^^0 0.83 and 0.91 (6H, d), 2.1-2.22 (1H, m), 3.38 (3H, s), 3.67 (2H, d), 4_1 (3H, s), 5.58 (2H, s) , 7.26-7.38 (2H, m), 7.41-7.48 (1H, m) and 7.7-7.8 (1H, m). b) 6 - "2,3 - a a - 2 -oxo-1 h - stupid and blow -1 - a certain ii 3-methyl-1-(isobutyl)-2.4-dioxoha "2.3-dl pyrimidine addition step a) product (〇.36g, 0.65 mmol) to a sealed tube containing THF (1 〇ml), water (1 ml) and triethylamine (〇.〇5 ml) at 180 (: heating under 3 days. The reaction mixture was concentrated in vacuo to give title compound (yield: 0.3 g, crude). MS (ESI) 440 [M+H] + c) β-丨2,3 -oxo-1H-benzoxazole-1-methylisoxazolidine-2-ylcarbonyl1-3-methyl-1-(isobutylphenanthene-2·4(1Η,3Η)- The diketone was prepared according to the procedure of Example 3 e), which was obtained from the product of b). The product was purified by reverse phase preparative HPLC, eluted with ammonium acetate: acetonitrile (80: 20), and triturated with diethyl ether to give a pale yellow title compound. δ 1 Hd6-dmso'〇-93 (6H, m), 2.1-2.24 (1H, m), 3. (2H, s), 3 26 (3H, s), 3.52-4.18 (5H, m), 4.62-4.82 (1H, s), 5.02-5.2 (2H s), 6.96-7.03 (2H, m), 7.17-7.19 (1H, m). Example 26 -141 - This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 public) 1310036
^^ !~^-=rr ^ 基-1 Η -叶[•口也-4 - it γρ 1 i* r . ~~棊異呤唑啶 _2.^^ !~^-=rr ^ base-1 Η-leaf [•口也-4 - it γρ 1 i* r . ~~棊 oxazolidine _2.
-2,4_m (0.56 w = 酸)辞(〇.405 g)至含實例9 Ο項產才 • 〈氣仿(1 5 πι 1)溶液中,所爲科、、全、士 、 冷卻 ,< T所传懸〜便回流15分鐘後: 搜拌5分^ =加飽和/人酸氣納溶液〇〇ml),混合物激'? 笨..里、濾,以一虱甲烷(2 x 25 ml)萃取。合併之有书 ::设,.崎溶液(35% ’0.26_處理,攪拌16小時… 脫水’過濾、’減壓蒸發。殘質溶於四氫咬喃(15 ml =甲知(3.1 m丨)中後’以氫氧化鈉溶液(iM,2 μ邮處理 混合物攪拌18小時。過濾收集所得沉澱,以四氫呋喃洗龙 ’真空乾燥’產生小標題化合物(〇 42 MS (ESI) 377 [M + 2H-Na] + δ 'Hdmso 0.^5 (3H, t), 1.63 (2H, sextet), 2.08 (6H, s), 3.1 (3H,s), 3.74 (4H, m)。 b)_Cg.)-6-「L5-二甲基峻-4-某甲摹 荈某異啐吨 啶-2-基援基1-3:·..甲基-1-丙某-g塞吩並|~2.3-d~U_啶_2.4ΠΗ,3Η)- -142 - f紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)-2,4_m (0.56 w = acid) (〇.405 g) to the example 9 Ο 产 • • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 T is suspended ~ then reflowed for 15 minutes: 5 minutes of mixing + = saturated / human acid gas solution 〇〇 ml), the mixture is excited '? Stupid.. Li, filtered, with a methane (2 x 25 Ml) extraction. There are books in the merger:: Set, Saki solution (35% '0.26_ treatment, stirring for 16 hours... Dehydration' filtration, 'decompression under reduced pressure. Residue dissolved in tetrahydroanthene (15 ml = Azhi (3.1 m丨) After the middle and the next 'sodium hydroxide solution (iM, 2 μg of the mixture was stirred for 18 hours. The resulting precipitate was collected by filtration, washed with THF (vacuum drying) to give the subtitle compound (〇42 MS (ESI) 377 [M + 2H -Na] + δ 'Hdmso 0.^5 (3H, t), 1.63 (2H, sextet), 2.08 (6H, s), 3.1 (3H, s), 3.74 (4H, m). b)_Cg.) -6-"L5-Dimethyl quaternary-4-a hyperthyroidism 摹荈 啐 -2- -2- 基 基 基 基 1-3 1-3 1-3 1-3 1-3 1-3 1-3 | | | | | | ~ ~ ~ ~ ~ ~ ~ ~ -d~U_pyridine_2.4ΠΗ,3Η)- -142 - f paper scale applicable to Chinese National Standard (CNS) Α4 specification (210 X 297 mm)
裝 訂Binding
'ψ 1310036 A7 B7 五、發明説明(139 ) 酮'ψ 1310036 A7 B7 V. INSTRUCTIONS (139) Ketone
依貫例I g)項之製法,由a)項產物與(3)_4_異σ号唑啶醇鹽 酸鹽[實例lb項]製備,產生標題化合物之固體。MS (APCI) 440 [M + H] +δ 'HDMs〇 (90°C*) 0.88 (3H, t), 1.68 (1H, sex), 2.08 (6H, s), 3.21 (3H, s), 3.46 (1H, d), 3.67-4.14 (7H, m), 4.63-4.77 (1H,m),5.23 (1H,s, br),11.86 (1H,s,br)。 (* N.B.物質呈幾何異構物之混合物,因此室溫下測得之 NMR複雜’但在加溫下簡化)。 實例26Π Ο 6-[3’5-二甲基-ΙΗ-pth»坐-4-&甲某與某異号吨症-2-羞基-3-甲某 g塞吩並「2.3-dl嘧咗-2.4ΠΗ.3Η)-二酮OH ΛPrepared according to the procedure of Example I g), which was obtained from the product of item a) and (3)____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ MS (APCI) 440 [M + H] +δ 'HDMs〇(90°C*) 0.88 (3H, t), 1.68 (1H, sex), 2.08 (6H, s), 3.21 (3H, s), 3.46 (1H, d), 3.67-4.14 (7H, m), 4.63-4.77 (1H, m), 5.23 (1H, s, br), 11.86 (1H, s, br). (* N.B. The material is a mixture of geometric isomers, so the NMR complex measured at room temperature is 'simplified by heating'). Example 26Π Ο 6-[3'5-dimethyl-ΙΗ-pth»Sitting -4-&A and a certain ton ton-2-shiji-3-a certain g-sent and "2.3-dl Pyrimidine-2.4ΠΗ.3Η)-dione OH Λ
裝 訂Binding
.線 g) 6-丨3,5-二甲基-1Η-吡唑-4-基甲某]-1-異丙基-3 -甲某-2.4-二乳代-1,2,3,4-四氫峰吩並f2,3-dlp乘喊-5-教酸鈉鹽. 依實例26 a)項之製法’由實例8 b)項產物製備,產生小 標題化合物之固體。 MS (ESI) 377 [M + 2H-Na] + δ 1 Η D Μ s Ο 1.44 (6Η, d), 2.10 (6Η, s), 3.17 (3Η, s), 3.74 (2H, s), -143 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1310036 A7 B7 五、發明説明(14〇 ) -- 4·34 (1H,s,br),12.01 (1H,s,br)。 KLLS) 6-R5-二甲吡唑_4_碁T羞上^基異咩砷咗_ 足:.基羰基卜1-異邑_盖-3-甲棊嚐吩並J^3-dl嘧忒以以ιΗ) i同 依實例1 g)項之製法,由a)項產物與(s)_4_異呤唑啶醇鹽 酸鹽[實例lb項]製備,產生標題化合物之固體。 MS (APCI) 448 [M+H] + δ 'Hdms〇 1.43- 1.46 (6H, m), 2.09 (6H, s, br), (1.87H, s), 3.18 (1.13H, s), 3.47 (0.62H, d), 3.58 (0.38H, d), 3.70-3.79 (3H m), 3.80-3.86 (IH, m), 3.88-4.04 (0.38H, m), 4.10 (0.62H, dd), 4.37 (1H, s, br), 4.58-4.78 (1H, s,br), 5.50 (1H, d), 12.11 (1H,s)。 實例27 (S)-6-|~3,5-二甲基異今咬-4-某甲某l-5-「4-與某異崎吐读-2-基羰基1-1-(異丁基)-3 -甲基·»墓吩並「2.3-dl 口密啶-2,4( 1H.3H)-二酮Line g) 6-丨3,5-dimethyl-1Η-pyrazole-4-ylmethyl]-1-isopropyl-3-methyl-2.4-di-daily-1,2,3, The 4-tetrahydrogen peak is exemplified by f2,3-dlp by y--5-sodium salt. The product of Example 26 a) is prepared from the product of Example 8 b) to give the subtitle compound as a solid. MS (ESI) 377 [M + 2H-Na] + δ 1 Η D Μ s Ο 1.44 (6Η, d), 2.10 (6Η, s), 3.17 (3Η, s), 3.74 (2H, s), -143 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Invention description (14〇) -- 4·34 (1H, s, br), 12.01 (1H, s, Br). KLLS) 6-R5-Dimethylpyrazole _4_碁T 上上基基咩 咩 咗 咗 咗 : : : : : : : : : : : : : : : : : : : : : : : : : : : : J J J J J Prepared by the procedure of Example 1 g), starting from the product of item (1) and (s) _4_isoxazolidinol hydrochloride [Example lb], gave the title compound as a solid. MS (APCI) 448 [M+H] + δ 'Hdms〇1.43- 1.46 (6H, m), 2.09 (6H, s, br), (1.87H, s), 3.18 (1.13H, s), 3.47 ( 0.62H, d), 3.58 (0.38H, d), 3.70-3.79 (3H m), 3.80-3.86 (IH, m), 3.88-4.04 (0.38H, m), 4.10 (0.62H, dd), 4.37 (1H, s, br), 4.58-4.78 (1H, s, br), 5.50 (1H, d), 12.11 (1H, s). Example 27 (S)-6-|~3,5-Dimethyl epoxide bit -4- a certain l-5-"4- with a certain succinyl read -2-ylcarbonyl 1-1- (different Butyl)-3-methyl·»Tomb""2.3-dl mouth pyridine-2,4(1H.3H)-dione
OHOH
a) 6-丨3,5-二甲基異哼唑-4-基甲某1-1-(異丁基)_3_甲某-2.4-二氣代-U2,3,4-四氤塞吩並[2,3-dl嘧畦-5-淼醢甲酯 -144 - 本紙張尺度適用中國國家標準(CNS) A4规格(21〇x 297公釐)a) 6-丨3,5-dimethylisoxazol-4-yl-methyl 1-1-(isobutyl)_3_methyl-2.4-diox-U2,3,4-tetrazed [2,3-dl-pyrimidin-5-methyl ester-144 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm)
裝 訂Binding
.線 1310036.线1310036
添加雙(乙酿基醋銅酸)鋅(〇 724幻至含實例3 b)項產物 之氣仿(20 ml)落液中,所得懸浮液於回流下揽拌3〇 刀在里後卻至主溫。添加飽和碳酸氫鈉溶液(20 ml),混 合物激烈攪拌5分鐘’過濾,以二氯甲烷(2 X 2〇邮萃取。 有機萃液經無水硫酸錢脫水’過遽,減壓蒸發。殘質溶於 乙醉(1 〇 ml)中’添加羥胺鹽酸鹽(〇·54 g)與吡啶(〇.62叫, 混合物攪拌16小時。添加鹽酸(2M,5如)續攪拌24小時。 混合物蒸發至少量體積後’加至飽和碳酸氫納溶液(25 _ 中’以乙酸乙醋(2 x 25 ml)萃取。有機萃液經無水硫酸鎂 脫水’㈣與減壓蒸發H經⑦石管柱層析法純化,以 乙酸乙醋/異己烷(2: Ό溶離’產物與醚研磨,產生小標題 化合物(0.55 g)。 MS (ESI) 406 [M + H] + δ HCDC13 0.95 (6Η, d), 2.18 (3H, s), 2.18-2.30 (1H, m), 3.39 (3H’ s),3.70 (2H,d),3.85 (2H,s), 3.95 (3H,s)。 ’ ’ T 基異 $ 嗤-4-某 甲某·2·4_ SAi^d,2,3,4-四i嘧吩並[2,3-(11喊」定_5-勒龄 依實例3d)之製法,由a)項產物製備,產生小標題化合物 之固體。 MS (ESI) 392 [M+H] + δ 'Hdmso 0.89 (6Η, d), 2.09 (3H, s), 2.09-2.20 (1H, m), 2.34 (3H, s),3.22 (3H, s),3.70 (2H,d),4.04 (2H,s)。 ’ 二甲基異Θ嗅-4-基甲基上^(4S V4-鞀其a _ 2-基-幾基1-..1.:.(異丁基)-3-甲基嶁免差_D,3-cn嘧咗〇 -145 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 x 297公釐) 1310036 A7 B7 五、發明説明(142) 二酮 依實例1 g)項之製法,由b)項產物與(S)-4-異咩唑唉醇鹽 酸鹽[實例lb項]製備,產生標題化合物之泡沫狀物。 MS (APCI) 463 [M + H] + δ 丨 HDMS0 0. 89 (6H, d), 2.10 (3H, s), 2.13-2.24 (1H, m), 2.30 (3H, s), 3.22 (3H, s), 3.44 (1H, d,br), 3.65-3.78 (3H, m), 3.82 (2H,s), 3.85-4.10 (2H,m), 4.70 (1H, s, br), 5.18 (1H,d)。 實例28 6-「4,5-二氣-2-甲某-11^-味峻-1-基甲基1-1-乙某-5-「(~4!;^-4-海 基-2-異吟嗤淀基幾某1-3-甲基g塞吩並[2,3-dlp密唉-2.4ΠΗ.3Η、. 二酮Adding a mixture of bis(ethyl acetate) zinc (〇 〇 幻 含 to example 3 b) to the product (20 ml), the resulting suspension was stirred under reflux for 3 knives. Main temperature. Saturated sodium bicarbonate solution (20 ml) was added, and the mixture was stirred vigorously for 5 min. 'filtered, extracted with dichloromethane (2×2 。. The organic extract was dehydrated with anhydrous sulphuric acid) and evaporated under reduced pressure. Add hydroxyamine hydrochloride (〇·54 g) and pyridine (〇.62), and stir the mixture for 16 hours. Add hydrochloric acid (2M, 5) and stir for 24 hours. Evaporate the mixture at least. After volumetric addition, add to saturated sodium bicarbonate solution (25 _ medium 'extracted with ethyl acetate (2 x 25 ml). The organic extract is dehydrated with anhydrous magnesium sulfate' (4) and evaporated under reduced pressure. Purified by EtOAc/EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) 2.18 (3H, s), 2.18-2.30 (1H, m), 3.39 (3H' s), 3.70 (2H, d), 3.85 (2H, s), 3.95 (3H, s). ' ' T嗤-4-A certain ^2·4_ SAi^d, 2,3,4-tetra-i-imido[2,3-(11 shouting _5-Lering according to Example 3d), by a The product was prepared to give the title compound as a solid. MS (ESI) 392 [M+H] + δ 'Hdmso 0.89 (6Η, d), 2.09 (3H, s), 2.09-2.20 (1H, m), 2.34 (3H, s), 3.22 (3H, s), 3.70 (2H, d), 4.04 ( 2H, s). 'Dimethylisoindole ol-4-ylmethyl group ^(4S V4-鼗 a _ 2-yl-monoyl 1-..1.:.(isobutyl)-3- Methyl hydrazine _D,3-cn pyrimidine-145 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Description of invention (142) Diketone example The preparation of 1 g) is prepared from the product of b) and (S)-4-isoxazolidine hydrochloride [Example lb] to give the title compound as a foam. MS (APCI) 463 [M + H] + δ 丨HDMS0 0. 89 (6H, d), 2.10 (3H, s), 2.13-2.24 (1H, m), 2.30 (3H, s), 3.22 (3H, s), 3.44 (1H, d , br), 3.65-3.78 (3H, m), 3.82 (2H, s), 3.85-4.10 (2H, m), 4.70 (1H, s, br), 5.18 (1H, d). Example 28 6-"4,5-diqi-2-methyl-11--weijun-1-ylmethyl-1-1-1--5-"(~4!;^-4-海基- 2-isoindole-based group 1-3-methyl-g-phene-[2,3-dlp 唉-2.4ΠΗ.3Η,. diketone
a) 1-乙基-3,6-二甲某-2.4ΠΗ.3Η)嘧啶二酮 於室溫下’在含3,6-二甲基-2,4(1仏3印嘧啶二酮(2.0§)之 DMF (1 5 ml)懸浮液中添加碳酸鉀(2· 1 g)。混合物攪拌5分 鐘後,添加乙基碘(丨.2 ml),混合物攪拌3天。反應混合物 分佈在水(5Ό0 ml)與乙酸乙酯(3 X 100 ml)之間。’合併之有 機相脫水(MgS04)及蒸發,產生小標題化合物之無色油狀 物(2.0 g)(由NMR判斷含有約30莫耳% DMF)。 δ 'Hcd⑴ 1.32 (3H,t),3.33 (3H,s),4.15 (2H, q),5.92 (1H,s)。 -146 - 本纸張尺度適用中國國家標準(CNS) A4规格(210X297公釐)a) 1-ethyl-3,6-dimethyl-2.4ΠΗ.3Η)pyrimidinedione at room temperature 'in the presence of 3,6-dimethyl-2,4 (1仏3-pyrimidinedione) Potassium carbonate (2.1 g) was added to the DMF (1 5 ml) suspension of 2.0 §). After stirring the mixture for 5 minutes, ethyl iodine (丨. 2 ml) was added and the mixture was stirred for 3 days. The reaction mixture was distributed in water. (5 Ό 0 ml) and ethyl acetate (3 X 100 ml). The combined organic phase was dried (MgSO4) and evaporated to give the title compound as a colorless oil (2.0 g). Ear % DMF) δ 'Hcd(1) 1.32 (3H, t), 3.33 (3H, s), 4.15 (2H, q), 5.92 (1H, s) -146 - This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm)
1310036 A7 B7 五、發明説明(143 ) -- b)J..-乙基-6-氫硫基-3-U^,4 nH.3m 依實例5步驟a)之製法,由步驟a)產物製備。 δ 1.28 (3H, t),3,32 (3H,s),4.14 (2H,s),4 48 (2H )。 必.仙,4-四^^^代」二v dl嘧啶-5-翔酸甲酯 依貫例3步驟a)之製法’由步驟b)產物製備。 MS (ESI) 283 [M + H] + d) 6-(溴甲碁)-1-乙某-丄^_4_四氣甲革二2,4_二氳代 並f2,3-dl嘧啶-5-羧酸甲酿 依實例22步驟a)之製法’由步驟c)產物製備。 4一6-「4,5-二氣-2-甲棊-1^·咪唑·丨-基甲其乙某-123 4_师 乱..:3-甲基-2,4-_二氧代-嘩吩並『2.3-di嘧啶崧醢甲酯 取含步驟d)產物(0.25 g)、碳酸氫鈉(〇·29 g)與4,5-二氯-2- 甲基-1H-咪唑(〇.115幻之乙腈(1〇 ml)混合物回流加熱18小 時。冷卻之混合物分佈在水(5〇 ml)與二氯甲烷(3 χ 5〇 ml) 之間。合併之有機相脫水(Mgs04)及蒸發,產生小標題化 合物之油狀物’直接用於下一個步驟。 MS (ESI) 429/431/433 [M-H] + 二氯-2-甲某-l Η-咪唑-1-某甲某1-ΐ·匕美-1,2.3〆-^ .氫甲基- 2,4·一乳代-ρ菜吩'被『2,3-dl°密咬-5-勒酸納鹽 依貫例1步驟f)之製法,由步驟e)產物製備。 MS (ESI) 417/419/421 [M + H]+。1310036 A7 B7 V. INSTRUCTIONS (143) -- b) J..-Ethyl-6-hydroxythio-3-U^, 4 nH.3m According to the procedure of Example 5, step a), the product from step a) preparation. δ 1.28 (3H, t), 3, 32 (3H, s), 4.14 (2H, s), 4 48 (2H).必.仙, 4-四^^^代"Div dl pyrimidine-5-cyanate methyl ester. According to the procedure of Example 3, step a), the product was prepared from the product of step b). MS (ESI) 283 [M + H] + d) 6-(Bromoformin)-1-By-丄^_4_Four gas leather 2,4_diodes and f2,3-dl pyrimidine- The 5-carboxylic acid was prepared according to the procedure of Example 22, step a), from the product of step c). 4-6-"4,5-digas-2-carboindole-1^.imidazole·丨-基甲其乙某-123 4_师乱..:3-methyl-2,4-_diox产物-哗 并 "2.3-dipyrimidine methyl ester containing step d) product (0.25 g), sodium bicarbonate (〇·29 g) and 4,5-dichloro-2-methyl-1H-imidazole (〇. 115 phantom acetonitrile (1 〇 ml) mixture was heated under reflux for 18 hours. The cooled mixture was distributed between water (5 〇ml) and dichloromethane (3 χ 5 〇ml). The combined organic phase was dehydrated (Mgs04 And evaporating to give the oil of the subtitle compound' directly to the next step. MS (ESI) 429/431/433 [MH] + dichloro-2-methyl-l-indole-imidazole-1-one Ϊ́1-ΐ·匕美-1,2.3〆-^ .Hydromethyl- 2,4·----------------------------------------------------------------------- Preparation of the product of step 1) of Example 1 was carried out from the product of step e) MS (ESI) 417 / 419 / 421 [M + H]+.
S) 6-|~4,5-二氣-2-甲某-1H-咪唑-1-某甲某 1-1-〔某-5-IY4SH __- 147 - 本紙張尺度it用中國國家橾準(CNS) A4規格(210X 297公釐) _ 1310036 A7 B7 五、發明説明(144) 兹基-2 -異二f—吐啶基羰基卜3 - J基,裳吩亦r 2,3 - cM嘧啶 -2,4(1Η,3Η)-二酮 依實例1步驟g)之製法’由步驟f)產物與實例1步驟b)之 胺製備。 MS (ESI) 488/490/492 [M + H] + δ 'Hdms〇 (90°C *)1.25 (3H, ΐ), 2.33 (3Η, s), 3.22 (3Η, s), 2.99 (1H, s), 3.34-3.55 ( 1 H, m),3.70-4.14 (5H, m), 4.63-4.87 (1H, m), 5.27 (2H, m)。 (* N _ B ·物質呈幾何異構物之混合物,因此室溫下測得之 N M R複雜,但在加溫下簡化)。 實例28Π 1-乙基-5-『(4S)-4-羥基-2-異g号唑啶甚淼某1-3-甲基-6-ΠΗ-吡咯 JJ2,3-bl吡啶-3-基甲基V塞吩並『2.3-dl嘧啶-2,4ΠΗ,3Η)-二酮 r\S) 6-|~4,5-diqi-2-methyl-1H-imidazole-1-a certain 1-1-[a-5-IY4SH __- 147 - this paper scale is used in China (CNS) A4 size (210X 297 mm) _ 1310036 A7 B7 V. Description of invention (144) Zilkyz-2 -iso-di-f-pyridylcarbonyl bromide 3 - J-based, 吩 亦 r r 2,3 - cM Pyrimidine-2,4(1Η,3Η)-dione was prepared according to the procedure of Example 1, step g), from the product of step f) and the amine of step b) of Example 1. MS (ESI) 488/490/492 [M + H] + δ 'Hdms〇(90°C *)1.25 (3H, ΐ), 2.33 (3Η, s), 3.22 (3Η, s), 2.99 (1H, s), 3.34-3.55 ( 1 H, m), 3.70-4.14 (5H, m), 4.63-4.87 (1H, m), 5.27 (2H, m). (* N _ B · The substance is a mixture of geometric isomers, so the N M R measured at room temperature is complex, but simplified under heating). Example 28Π 1-Ethyl-5-"(4S)-4-hydroxy-2-isog-oxazolidinyl 1-3-methyl-6-indole-pyrrole JJ2,3-blpyrid-3-yl Methyl V stopper and "2.3-dl pyrimidine-2,4ΠΗ,3Η)-dione r\
Η gj 1-乙基-1,2,3,4-四氛-3-甲某-2.4-二氣代 f2,3-b~|p比喊-3-基甲基V篆吟並[~2,3-dlp密症-5-势 依實例22 b)項之製法,由實例28 d)項產物製備 φ 小標題仆 合物。 〜儿 s),Η gj 1-ethyl-1,2,3,4-tetrazol-3-methyl-2.4-diode f2,3-b~|p is more than -3-methylmethyl V篆吟[~ 2,3-dlp secret disease-5-, according to the method of Example 22 b), the φ subtitle servate was prepared from the product of Example 28 d). ~ children s),
Hcdcu 1_26 (3Η,t),3.49 (3Η, s), 3.87 (2H,q),4 (3 -148 - 本纸喿尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(145) 4.28 (2H,s),7.058 (lH,t),7.93 (lH, d),8.32 (1H,d),與 8.89 (1H,s)〇 乙基二1,2,3,4-四氫-3-甲甚_?.4_二g代_6-(出-被咯並_ 「2,.3^1|1比-^1-..基甲基)嘧吩#[2 3-(11嘧啶-5-#酸 依實例3 d)項之製法製備小標題化合物。 MS (ESI) 386 [M + H] + U -乙基二U;(4S)-4-幾基-2-異崎唑咗莘粦某卜3-甲疾-6-ΠΗ~ 啶-3-基甲某、忒咖:¾ [2·3-ηι崎 &備。產物經逆相製備 ‘ 3 〇)溶離,產生標題化 依實例3 e)項之製法’由b)項產物製備 性HPLC純化,以乙酸銨:乙腈(7〇 : 3〇) 合物之灰白"色固體。 -4.22 (6H, m), 4.62-^7.03 (1H, m), 7.45 4.75 (1H, s), 4.8 (1H, s),: (1H, m), 7.95-8 (1H, m), 8. 實例28iiHcdcu 1_26 (3Η,t), 3.49 (3Η, s), 3.87 (2H,q),4 (3 -148 - Paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1310036 A7 B7 V. INSTRUCTIONS (145) 4.28 (2H, s), 7.085 (lH, t), 7.93 (lH, d), 8.32 (1H, d), and 8.89 (1H, s) 〇 ethyl 2, 2, 3,4-tetrahydro-3-methyl- _..4_di-g- _6-(-------[2,.3^1|1 ratio-^1-..ylmethyl)pyrimidine The title compound was prepared by the procedure of the title compound [[2-(1-(4-pyrimidine-5-# acid))). MS (ESI) 386 [M + H] + U-ethyl-di-U; (4S)-4 - 奇基-2-isoxazole 咗莘粦 卜3-甲病-6-ΠΗ~ 啶-3-基甲, 忒 :: 3⁄4 [2·3-ηι崎 & preparation. Product reverse phase Preparation of '3 〇) </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; -4.22 (6H, m), 4.62-^7.03 (1H, m), 7.45 4.75 (1H, s), 4.8 (1H, s),: (1H, m), 7.95-8 (1H, m), 8 Example 28ii
δ Hdmso 1.12 (3H, m), 3.31 (3H, s),3·58_4 22 (6H 4.75 (1H, s), 4.8 (1H, s), 5.5 (1H, s), 6.9.7 〇3 〇H (1H,m),7.95-8 (1H,m),8.19 (1H,d),U 53 (1H s)δ Hdmso 1.12 (3H, m), 3.31 (3H, s), 3·58_4 22 (6H 4.75 (1H, s), 4.8 (1H, s), 5.5 (1H, s), 6.9.7 〇3 〇H (1H,m), 7.95-8 (1H,m), 8.19 (1H,d),U 53 (1H s)
本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(146 ) a) 1-乙基-1,2,3,4-四氫-3-甲基-2,4-二氣代-6-「2-而早」H节 並咪唑-1 -基甲基 >塞吩並『2.3-dl嘧啶-5-羧酸甲酯 依實例13iv步驟a)之製法,由實例28步驟d)產物製備。 MS (ESI) 441 [M + H]+。 b) 1-乙基-1,2,3,4-四氫-3-甲基-2.4-二氣代-6-f2 -丙華- iH_y 並咪唑-1-基甲基塞吩並「2.3-dl嘧啶-5-斿g#铷睡 依實例1步驟f)之製法,由步驟a)產物製備。 MS (ESI) 427 [M + H]+ (游離酸) c) 1-乙基-5-「(4S)-4-輕農-2 -異17亏峻这某幾某1-3 -甲某 丙基-1H -苯並咪攻-l-基甲某塞p分#f2,3-d~[p·奈g定- 2,4ΠΗ,3Η)- 二酮 MS (ESI) 498 [M + H] + δ 'Hdmso 0.99 (3Η, t), 1.12 (3H, t), 1.80 (2H, sextet), 2.88 (2H, t), 3.20與 3.21 (3H, s), 3.58 (1H, d),3.70-4.15 (5H, m), 4.63 與 4_81 (1H, t), 5.46-5.70 (3H, m),7.15-7.22 (2H,m), 7.54-7.69 (2H,m)。 實例28iii 乙基·5-[(45)-ϋ基-2-異g号唑啶某羰某甲基-6-「2_氣 代-3 (2H) -表並p基峻基甲基塞吩並f2.3-dl痛哈-2,4(1H,3H)· 二酮This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (146) a) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl Benzyl-2,4-dioxo-6-"2-early early" H-membered imidazolium-1-ylmethyl> phenanthrene and 2.3-dl pyrimidine-5-carboxylic acid methyl ester according to Example 13iv step a The process was prepared from the product of Example 28, step d). MS (ESI) 441 [M + H]+. b) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2.4-dialdehyde-6-f2-propyl-iH_y-imidazol-1-ylmethylthiophene "2.3 -dl-pyrimidine-5-斿g# 铷 依 依 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS "(4S)-4-Light Farming-2 - Different 17 Loss Jun This is a certain number of 1-3 - A propyl -1H - Benzene Mi attack -l-基甲一塞p分#f2,3-d ~[p·奈克定- 2,4ΠΗ,3Η)-diketone MS (ESI) 498 [M + H] + δ 'Hdmso 0.99 (3Η, t), 1.12 (3H, t), 1.80 (2H, sextet ), 2.88 (2H, t), 3.20 and 3.21 (3H, s), 3.58 (1H, d), 3.70-4.15 (5H, m), 4.63 and 4_81 (1H, t), 5.46-5.70 (3H, m ), 7.15-7.22 (2H, m), 7.54-7.69 (2H, m). Example 28iii Ethyl 5-[(45)-fluorenyl-2-isog-oxazolidine carbonyl-methyl-6- "2_气代-3 (2H) - exemplified p-based thiomethylthiophene and f2.3-dl Pain-2,4(1H,3H)·dione
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 _B7 五、發明説明(M7 ) 冱)1-^-1,2,3,4-四氫-3-甲基-2^4-二|;伏.6_「2-&代-3(2出-笨並4唑基甲基1嘍吩並[2,3-dl嘧咬乃-教、酸甲醋 依實例13xviii步驟a)之製法,由實例28步驟d)產物製備。 MS (ESI) 432 [M+H] + b) 1-乙基-1乂3,4:四氫-3-甲幕二爱代-6-「2-免代·3Γ2Η、_ 苯並全基甲基V塞吩並「2,3-dl°条冷-5 -藉酸#j鹽 依實例1步驟f)之製法’由步驟a)產物製備。 MS (ESI) 418 [M + H]+ (游離酸) c) 1-乙基-5-「(4S)-4-輕基-2-異°号吐咬基羰基甲基_6-「2-氣 代-3(2H) -笨並嗔咬基甲基1遠吩並f2,3-d~|喊冷_9,,4(~1H,3H)- =酉同 依實例1步驟g)之製法,由步驟b)產物使用實例1步驟b) 之m製備。 MS (ESI) 489 [M+H] + 3丨1^〇|^〇1_19(31'1,〇,3.19與3.20(311,5),3.52-4.00 (6^1,111), 4.56-4.82 (1H, m), 5.09-5.40 (3H, m), 7.19.7,25 (1H, m), 7.33-7.48 (2H,m),7.67-7.72 (1H, m) 0 實例28iv 1-乙基-5-『(4S)-4-羥某-2-異哼吔啶基1基1-3·甲某_6_『2_甲 基-1 Η -吡略並「2,3 - b 比啶-3 -基甲基吃〜並「2 · 3 - d h密峻 -2,4(1Η,3Η)-二酮This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 _B7 V. Invention description (M7) 冱) 1-^-1,2,3,4-tetrahydro-3-methyl -2^4-二|;伏.6_"2-& generation-3 (2 out-stupid and 4-oxazolylmethyl 1 喽 [ [2,3-dl acetylpyrazine-teaching, acid vinegar vinegar Example 13xviii, step a), was prepared from the product of step 28, step d) MS (ESI) 432 [M+H] + b) 1-ethyl-1 乂3,4:tetrahydro-3-methyl Generation-6-"2-free generation · 3Γ2Η, _ benzo-andylmethyl V phenanthrene and "2,3-dl ° strip cold -5 - acid #j salt according to the method of step 1 of step 1) Step a) Preparation of the product MS (ESI) 418 [M + H] + (free acid) c) 1-ethyl-5-"(4S)-4-carbyl-2-iso- oxone carbonyl group Base_6-"2-gaso-3(2H)-stupid and biting methyl 1 far and f2,3-d~| shout cold _9,,4(~1H,3H)- = The product from step b) was prepared according to the procedure of Example 1 step g) using m of Example 1 Step b) MS (ESI) 489 [M+H] + 3丨1^〇|^〇1_19(31'1,〇 , 3.19 and 3.20 (311, 5), 3.52-4.00 (6^1, 111), 4.56-4.82 (1H, m), 5.09-5.40 (3H, m), 7.19.7, 25 (1H, m), 7.33- 7.48 (2H,m), 7.67-7.72 (1H, m) 0 Example 28iv 1-Ethyl-5-"(4S)-4-hydroxy-2-isoindolyl 1 1-3. A _6_"2_methyl-1 Η - pyridine And "2,3 - b eats ~ and -2 - 3 - dh dense -2,4 (1Η,3Η)-dione
本紙張尺度適用中國國家標準(CNS) Α4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(148 ) 阻)1-乙某-1.2,3,4-四氫-3.甲某-6-[2-甲某-11^-1#,吹並[~2.3-卜1 p比p定-3-某甲某1-2,4-二氧代4吩並丨2.3-dlp密喊-5-勒酸甲酯 依實例14iii a)項之製法,由實例28 d)項產物製備。 MS (ESI) 399 [M + H] + b) 1-乙某-1,2,3,4 -四 Jl-3 -甲基-6-[~2 -甲基- lH-g 比 p各拍[2U~| 吡啶-3-某甲基1-2,4-二氣代嘧吩並丨2,3-dl嘧啶-5-# 铷鹽 依實例1 f)項之製法,由a)項產物製備。直接用於下一個 步驟。 c) 1-乙某-5-「(4S)-4-羥基-2-異呤唑啶基羰基1-3-甲其-6-Γ2-甲某-1H-吡咯並「2,3-bl吡啶-3-某甲基~l·塞吩並「2.3-dl嘧啶二 2,4(1Η·3Η)-二酮 依實例1步驟g)之製法,由步驟b)產物使用實例1步驟b) 之胺製備。 MS (ESI) 470 [M+H] + δ 'Hdmso 1.10-1.16 (3H,m),2.40 (3H,s),3.19-3.20 (3H, m), 3.50-4.83 (l〇H, m), 6.94-6.99 (1H, m), 7.78-7.86 (1H, m), 8.09 UH,dd),1 1.46 (1H,s)。 實例28v) 1-乙某-5-「(4S)-4-游某-2-異崎唑啶基羰某1-3-甲某 基-ΙΗ-β 哚-1-基甲某1嘧吩並「2.3-dl 嘧啶-2.4ΠΗ,3Η)-:_Ι1This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (148) Resistance) 1-B-1.2,3,4-tetrahydro-3. A- 6-[2-甲某-11^-1#, Blowing and [~2.3-Bu 1 p is more than p-3-1, a certain 1-2, 4-dioxo 4 丨 丨 2.3-dlp shouting Methyl 5-5-lacate was prepared from the product of Example 28 d) according to the procedure of Example 14 iii a). MS (ESI) 399 [M + H] + b) 1-By-1,2,3,4 -tetra Jl-3 -methyl-6-[~2 -methyl- lH-g ratio p [2U~| Pyridine-3-methyl 1-2,4-difluoropyrimidopurine 2,3-dl pyrimidine-5-# 铷 salt according to the method of Example 1 f), from product a) preparation. Used directly in the next step. c) 1-By-5-"(4S)-4-hydroxy-2-isoxazolidinylcarbonyl1-3-methyl--6-indole-2-methyl-1H-pyrrolo"2,3-bl Pyridine-3-methyl~l·cephene and 2.3-dl-pyrimidine 2,4(1Η·3Η)-dione according to the method of step 1) of Example 1, using step b) product using example 1 step b) Preparation of the amine. MS (ESI) 470 [M+H] + δ 'Hdmso 1.10-1.16 (3H, m), 2.40 (3H, s), 3.19-3.20 (3H, m), 3.50-4.83 (l〇H , m), 6.94-6.99 (1H, m), 7.78-7.86 (1H, m), 8.09 UH, dd), 1 1.46 (1H, s). Example 28v) 1-B-5-"(4S) -4-You -2-isoxazolidinylcarbonyl 1-3-methyl-yl-ΙΗ-β 哚-1-yl-methyl 1 sulfonium "2.3-dl pyrimidine-2.4 ΠΗ, 3 Η)-: _Ι1
本紙張尺度適用中困國家標準(CNS) Α4规格(210 X 297公釐) 1310036 A7 B7 五、發明説明(149) a) 氰棊-1-甚甲某 μι_ 乙基-1,2,3,全^齑甲 基-2,4·二氧代嗥吩並『2.1Η卜奈咗-5-翔酸甲酯 依實例1 3xvii a)項之製法,由實例28 d)項產物製備。 MS (ESI) 42 1 [M + H] ^~卜丄丨-乙基-1,2,3,4 -四氣_5-(~(4S)-4-超基咬某縣基 1-3 -甲基-2,4-二氧代4略# [2-3_d~|嘧啶-6-基甲某1-1 Η·叫呻一 5-腈 依實例13xvii b)與c)項之製法,由a)項產物製備,產生標 題化合物。 δ 'Hdmso 1.10-1.23 (3H, m), 3.2 (3H, s), 3.8-4.12 (6H, m), 4.62-4.81 (1H, m), 5.5-5.64 (3H, m),6.68 (1H, d), 7.5-7.9 (1H, m)’ 7.6-7.65 (1H,m),7.77-7.84 (1H, m)與 8.1 (1H, s)。 實例29i 5-f(4S)-4-羥基異呤唑啶某蒺某·μ1-(異丁某)_6-F1_異丙基· 2,5-二甲基-1H-吡唑-4-某甲某1-3-甲基g窠吩並[~2_3-dl嘧啶-2,4ΠΗ·3Η、-二 a间This paper size applies to the National Standard for Sleepy (CNS) Α4 Specification (210 X 297 mm) 1310036 A7 B7 V. Description of Invention (149) a) Cyanide-1-Vemethym μι_ Ethyl-1,2,3, The product was prepared from the product of Example 28 d) by the method of the procedure of Example 1 3xvii a). MS (ESI) 42 1 [M + H] ^~卜丄丨-ethyl-1,2,3,4 -tetraqi_5-(~(4S)-4-superbase bite a county base 1-3 -Methyl-2,4-dioxo 4## [2-3_d~|pyrimidine-6-yl-methyl 1-1 Η·呻呻5-nitrile according to the example 13xvii b) and c) Prepared from product a) to give the title compound. δ 'Hdmso 1.10-1.23 (3H, m), 3.2 (3H, s), 3.8-4.12 (6H, m), 4.62-4.81 (1H, m), 5.5-5.64 (3H, m), 6.68 (1H, d), 7.5-7.9 (1H, m)' 7.6-7.65 (1H, m), 7.77-7.84 (1H, m) and 8.1 (1H, s). Example 29i 5-f(4S)-4-hydroxyisoxazolidine 蒺一·μ1-(isobutyl)_6-F1_isopropyl·2,5-dimethyl-1H-pyrazole-4- A certain 1-3-methyl g 窠 并 [~2_3-dl pyrimidine-2, 4 ΠΗ · 3 Η, - two a
OH 添加2-碘丙烷(0.1 ml)與碳酸鉀(1〇〇 mg)至含6_[(3,5_二曱 基-丨H-吹吐-4-基)甲基]-5-[(4S)-4-羥基異噚唑啶-2-基羰基]- ___- 153 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐) 裝 訂OH is added 2-iodopropane (0.1 ml) and potassium carbonate (1 〇〇mg) to 6-[(3,5-dimercapto-oxime H-purpur-4-yl)methyl]-5-[( 4S)-4-Hydroxyisoxazole-2-ylcarbonyl]- ___- 153 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) Binding
線 A7 B7 1310036 五、發明説明(150)Line A7 B7 1310036 V. Description of invention (150)
線 1 -(異丁基)-3 -甲基嘧吩並[2,3-d]嘧啶-2,4(1H,3H)-二酮(實例 1 1 ’ 100 mg)之二甲基甲醯胺(1 ml)溶液中,混合物於i〇〇°c 下攪拌。2小時後’再添加2-ί典丙烷(〇·2 ml)與碳酸鉀(200 mg)。再過16小時,混合物冷卻至室溫,加水(2〇 ml)稀釋 ’以乙酸乙酯(2 X 20 ml)萃取。合併有機萃液經吡咯啶(〇. i ml)處理,1小時後,經無水硫酸鎂脫水,過濾,減壓蒸發 。殘質經逆相ΗPLC純化,以0· 1 %乙酸銨水溶液/乙腈梯度 溶離,產生標題化合物(58 mg)之泡沐狀物。 MS (APCI) 504 [M+H] + δ 'Hdmso 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 (8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m)。 實何29ii 5-「(4S)-4-蕤某異啐唑啶-2-某端某1-1-(異丁某)-3-甲甚 甲基-3 笨基-1 Η -吡唑-4 -某甲废1 塞吩並F 2.3 - d 1痛忒 -2,4(1H,3H)-二酮Line 1 -(isobutyl)-3-methylsulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 1 1 '100 mg) of dimethylformamidine In a solution of the amine (1 ml), the mixture was stirred at i 〇〇 °c. After 2 hours, additional 2-propane propane (〇·2 ml) and potassium carbonate (200 mg) were added. After a further 16 hours, the mixture was cooled to room temperature and diluted with water (2 mL). The combined organic extracts were treated with pyrrolidine (1 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc) elut elut MS (APCI) 504 [M+H] + δ 'Hdmso 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 ( 8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m).实何29ii 5-"(4S)-4-蕤A certain isoxazolidine-2-one end 1-1-(isobutyl)-3-methyl-methyl-3 stupyl-1 Η-pyrazole -4 - A waste A 1 phenotype F 2.3 - d 1 忒-2,4(1H,3H)-dione
a) 1-異丁基-3-甲某-6-「5 -甲某-3-苽基-1H-吡唑-4-某甲其卜 2,4-二氧代-1,2,3,4-四j,-歧吩並「2.3-dl嘧啶-5-斿酸甲酯 -154 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 _____B7 五、發明説明(151 ) 添加乙酸鋅(11)(88 mg)至含6-(溴甲基)_丨·異丁基_3_f基- 2.4- 一氧代-1,2,3,4-四氫-嘧吩並[2,3-d]嘧啶-5-羧酸曱酯(185 mg)與1-笨甲醯基丙酮(丨54 mg)之氣仿(1〇如)攪掉溶液中, 混合物回流加熱1小時後,冷卻至室溫。添加飽和碳酸氫 納溶液(20 ml),混合物攪拌30分鐘後,過濾,分層。水相 經二氯曱烷(10 ml)萃取。合併之有機萃液經肼水合物 (0.046 ml)與甲醇處理。20小時後,溶液經無水硫酸鎂脫水 ’過濾與減壓蒸發,產生小標題化合物(3〇〇 mg),其中含 有5-甲基-3-苯基-1H-吡唑雜質。 MS (ESI) 467 [M + H] + δ 'HCDci3 0.90 (6Η, d), 2.17 (1H, non), 2.27 (3H, s), 3.38 (3H, s), 3.65 (2H, d), 3.94 (3H, s),4.10 (2H, s), 7.35 (1H, t), 7.40 (2H,t),7·46 (2H, d)。 b) 1-異丁某-3-甲基-6-f5-甲某-3-苽某-1H-吡唑-4-某甲基1- 2.4- 二氧代-1.2,3,4-四ϋ.-嘧吩雒「2.3-dl嘧啶-5-羧酸 添加氫氧化鈉溶液(1M,0.58 ml)至含步驟a)產物(300 mg) 之四氫呋喃(1 0 ml)與甲醇(1 ml)攪拌溶液中。48小時後, 加水(20 ml)稀釋,以醚(20 ml)萃取混合物。添加濃鹽酸 (2M)酸化水相至pH 5,以乙酸乙酯(2 X 20 ml)萃取。有機 萃液經無水硫酸鎂脫水,過濾,減壓蒸發,產生小標題化 合物之固體(205 mg)。 MS (ESI) 453 [M + H] + δ 0.81 (6H,d), 2.03 (IH,non),2.20 (3H,s),3.25 (3H, s),3.62 (2H, d),4.23 (2H, s),7.32 (1H,t),7.39 (2H,t), 7.49 __- 155 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公I) A7 B7 1310036 五、發明説明(152 ) (2H,d) 〇 c) 5-「(4S)-4-羥基異噚唑啶-2-甚羰基1-1-(昱丁某)-645-甲基-3-苯基-1H-吡唑-4-基甲基1·»塞吩;ϋ|~2,3-dl嘧啶-2,4ΠΗ,3Η)-二酮 添加氯磷酸二乙酯(0.076 ml)至含b)項產物(200 mg)、1-羥基苯並三唑水合物(81 mg)與三乙胺(0.215 ml)之乙腈(2 ml)攪拌溶液中。1 5分鐘後,添加(S)-4-異呤唑啶醇鹽酸鹽[實 例1,b項)’ 61 mg]。再過24小時後,以飽和碳酸氫鈉水溶 液(10 ml)稀釋混合物,以乙酸乙酯(2 X 20 ml)萃取。有機 萃液經無水硫酸鎂脫水,過濾與減壓蒸發。殘質經矽膠管 柱層析法純化,以乙酸乙酯/甲醇(25 : 1)溶離後,自乙酸乙 酿/異己垸中再結晶,產生標題化合物(13 8 mg)。 MS (APCI) 524 [M+H] + δ 'Hqmso 0.82 (6H, d), 2.04 (1H, non), 2.20 (3H, s, br), 3.3q (3H, s), 3.45-4.15 (8H, m), 4.57-4.80 (1H, m), 5.35-5.55 (iH? m), 7.33 (1H, s, br), 7.40 (2H, s, br), 7.54 (2H, s, br), U.73 (0.5H, s, br) 12.86 (0.5H,s,br)。 實例29iii 5-丨(4S)-4-羥某異呤唑啶-2-某揣某M-異丁基-3 -甲基 甲基-3-(三f.甲基)-1Η-吡唑-4-某甲某1魂吩並「2,3-dln^^ _2,4(1H.3HV二產同a) 1-isobutyl-3-methyl-6-"5-methyl-3-methyl-1H-pyrazole-4-methylpyr 2,4-dioxo-1,2,3 , 4-four j,-discriminate "2.3-dl pyrimidine-5-decanoate methyl ester-154 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 _____B7 V. Invention Description (151) Adding zinc acetate (11) (88 mg) to a mixture containing 6-(bromomethyl)-indole isobutyl-3-f-yl-2.4-oxo-1,2,3,4-tetrahydro- The pyrimido[2,3-d]pyrimidine-5-carboxylic acid oxime ester (185 mg) was stirred with a 1-p-methylpyrrolidone (丨54 mg) in a solution (1), and the mixture was refluxed. After heating for 1 hour, it was cooled to room temperature. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added, and the mixture was stirred for 30 min, then filtered, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 ml). The hydrazine hydrate (0.046 ml) was treated with methanol. After 20 hours, the solution was dried over anhydrous magnesium sulfate. Base-1H-pyrazole impurity MS (ESI) 467 [M + H] + δ 'HCDci3 0.90 (6Η, d), 2.17 (1H, non), 2.27 (3H, s), 3.38 (3H, s), 3.65 (2H, d), 3.94 (3H, s), 4.10 (2H, s), 7.35 (1H, t), 7.40 (2H, t), 7·46 (2H, d) b) 1-isotin -3-methyl-6-f5-methyl-3-pyrene-1H-pyrazole-4-methyl-1-2.4-dioxo-1.2,3,4-tetradecyl-pyridinium 2.3-dl pyrimidine-5-carboxylic acid was added to a stirred solution of tetrahydrofuran (10 ml) and methanol (1 ml) containing the product of step a) (300 mg). Diluted with water (20 ml), EtOAc (2 mL)EtOAc. , filtered, and evaporated under reduced pressure to give titled compound ( s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 3.25 (3H, s), 3.62 (2H, d), 4.23 (2H, s), 7.32 (1H, t), 7.39 (2H, t), 7.49 __- 155 - This paper scale applies to Chinese national standards ( CNS) A4 specification (210 X 297 public I) A7 B7 1310036 V. Description of invention (152 ) (2H,d) 〇c) 5-"(4S)-4-hydroxyisoxazolin-2-ylcarbonyl 1- 1-(昱丁)-645-methyl-3-phenyl-1H-pyrazol-4-yl Methyl 1·»cephene; ϋ|~2,3-dl-pyrimidine-2,4ΠΗ,3Η)-dione added diethyl chlorophosphate (0.076 ml) to product containing b) (200 mg), 1- Hydroxybenzotriazole hydrate (81 mg) was stirred with triethylamine (0.215 ml) in acetonitrile (2 ml). After 1 minute, (S)-4-isoxazolidine hydrochloride [Example 1, item b) '61 mg] was added. After a further 24 hours, the mixture was diluted with EtOAc EtOAc. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS (APCI) 524 [M+H] + δ 'Hqmso 0.82 (6H, d), 2.04 (1H, non), 2.20 (3H, s, br), 3.3q (3H, s), 3.45-4.15 (8H , m), 4.57-4.80 (1H, m), 5.35-5.55 (iH? m), 7.33 (1H, s, br), 7.40 (2H, s, br), 7.54 (2H, s, br), U .73 (0.5H, s, br) 12.86 (0.5H, s, br). Example 29iii 5-丨(4S)-4-hydroxylisoxazosin-2-one M-isobutyl-3-methylmethyl-3-(trif.methyl)-1Η-pyrazole -4-A certain 1 soul is ordered and "2,3-dln^^ _2,4 (1H.3HV two production
OHOH
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公ϋ 1310036 A7 B7 五、發明説明(153) -Ml:_甲基H-吡唑_4-某甲 1^^1^1,2,3;4_:四.氫-嚐吩並丄1^^^^酸甲酉旨 依實例29 (ii)a)項之製法,由6·(漠甲基)_丨·異丁基_3_甲 基_2,4-二氧代-丨’^心印氫-p塞吩並密喊^•羧酸曱酯 (3〇〇 mg)與1,1,丨-三氟乙醯基醋酮酸酯製備。粗產物經矽石 管柱層析法純化,以乙酸乙酯/異己烷(2: 3)溶離,產生小 標題化合物(130 mg)。 MS (ESI) 459 [M+H] + δ 'Hdmso 0.94 (6Η, d), 2.22 (1H, non), 2.26 (3H, s), 3.39 (3H s), 3.69 (2H, d), 3.96 (3H, s),4.08 (2H, s), 1〇.29〇H s br) 〇 ? 基-Η5.甲基小(三其 芝基..1-2,4-二氧代-1,2,3,4-翌吩 啶-5-崧齡 依實例29ii b)項之製法,由a)項產物製備,產生小標題化 合物之固體。 $ MS (ESI) 445 [M+H] + δ 'Hdms〇 〇·86 (6Η, d), 2.09 (1Η, non), 2 21 、 •丄1 (3H,s), 3.26 (3H, s),3.67 (2H, ¢1),4.20 (2H, s),13.43 (1H, s), U 9n Mu , α.ζυ (1H, s, br)。 c) 5-[(4S)-4-羥基異哼唑啶-2-某蕤某丄-i 丁计 ^ -ή- 『5-甲基-3-(三氟甲某)-1Η-吡唑-4-某王某]*、 ϋ Γ2.3-dlp·% 啶-2,4ΠΗ,3Η)-二酮 依實例29ii c)項之製法,由b)項產物制供 知備’產生標題化 合物之固體。 MS (APCI) 5 16 [M + H] + δ 'HdmsoO.87 (6H, d), 2.11 (IH, non), 2.18 nu λ Λ δ V3H, S), 3.20 (3H, 157 本紙張尺度適用中菌國家標準(CNS> A4规格(210 X 297公釐) A7 B7 1310036 五、發明説明(154 ) S), 3.50-4.10 (8H,m),4.55-4.78 (1H,m)。 實例29iv 「( 4 S) - 4 -瘫華異°寄吹症-2 -基羰_J· 1 -1 -县二^某_ 6 _显兩早This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 ϋ 1310036 A7 B7 5. Inventions (153) - Ml: _methyl H-pyrazole _ 4- A 1 ^ ^ 1 ^ 1, 2,3;4_:4. Hydrogen-taste 丄1^^^^ acid 甲 酉 according to the method of Example 29 (ii) a), from 6 · (Methyl) 丨 异 isobutyl _ 3_Methyl-2,4-dioxo-丨'^xin-printed hydrogen-p-phene and screams ^•carboxylic acid oxime ester (3〇〇mg) and 1,1,丨-trifluoroethenyl Preparation of acetonic acid esters. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut MS (ESI) 459 [M+H] + δ 'Hdmso 0.94 (6Η, d), 2.22 (1H, non), 2.26 (3H, s), 3.39 (3H s), 3.69 (2H, d), 3.96 ( 3H, s), 4.08 (2H, s), 1〇.29〇H s br) 〇? 基-Η5.Methyl small (Sanqi Zhiji..1-2,4-dioxo-1,2 , 3,4-Propylidine-5-anthracene according to the procedure of Example 29ii b), which was prepared from the product of item a) to give the title compound as a solid. $ MS (ESI) 445 [M+H] + δ 'Hdms〇〇·86 (6Η, d), 2.09 (1Η, non), 2 21 , •丄1 (3H,s), 3.26 (3H, s) , 3.67 (2H, ¢1), 4.20 (2H, s), 13.43 (1H, s), U 9n Mu , α.ζυ (1H, s, br). c) 5-[(4S)-4-hydroxyisoxazolidine-2-one 蕤-丄 计 ^ ^ -ή- 『5-methyl-3-(trifluoromethyl)-1Η-pyrazole -4-A certain Wang]*, ϋ Γ2.3-dlp·% pyridine-2,4ΠΗ,3Η)-dione according to the method of Example 29ii c), from the product of b) for the preparation of the title compound Solid. MS (APCI) 5 16 [M + H] + δ 'HdmsoO.87 (6H, d), 2.11 (IH, non), 2.18 nu λ Λ δ V3H, S), 3.20 (3H, 157) National Standard for Bacteria (CNS> A4 Specification (210 X 297 mm) A7 B7 1310036 V. Description of Invention (154) S), 3.50-4.10 (8H, m), 4.55-4.78 (1H, m). Example 29iv "( 4 S) - 4 - 瘫 异 异 寄 -2 -2 - 2 - carbonyl _J · 1 -1 - County II ^ _ 6 _ Xian two early
i_2,4(1H.3HV二 _I_2, 4 (1H.3HV two _
__1-兴~丁基-6-『3-異丙某-5-甲基-1^1-?比碎-4-基甲基1_3-甲 基- 2,4-二氣代-1,2,3,4-四 -»裳吩並 f2,3-d~|P由 θ - 5-勒醢 依實例29 (iii) a)項之製法,由6-(溴甲基)_ι_異丁基_3-甲 基- 2,4-二氧代-1,2,3,4-四氫塞吩並[2,3-d] °密淀-5-羧酸曱酯 (450 mg)與5-甲基己烷-2,4-二酮製備後,依實例29 (ii) b)項 之製法水解酯,產生小標題化合物(285 mg)之固體。 MS (ESI) 419 [M + H] + δ 'Hdmsq 0.85 (6Η, d), 1.13 (6H, d), 2.07 (3H, s), 2.09 (1H, non.), 2.88 (1H, sept.), 3.26 (3H, s), 3.66 (2H, d), 4.04 (2H, s)。 1^5-[(4 5)-4-羥某異啐唑啶-2-基璣基卜1-異丁基-6-『3-異丙 某-5-甲某-1H-吡唑-4-基甲基1-3 -甲某魂吩並丨2,3-dl嘧啶 -2.4(1H,3H)-二酮 -158 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公董) 1310036 A7 B7 五、發明説明(155 依實例2911 C)項之製法,由a)項產物(281 mg)製備。粗產 物經逆相HPLC純化,以〇·丨%乙酸銨水溶液/乙腈梯度溶離 後’興酿研磨’產生標題化合物(丨7〇 mg)之固體。 (APCI) 490 [M + H] + δ 'Hdmso 0.86 (6H, d), 1.08-1.18 (6H, m), 2.02-2.17 (4H) m), 2.80-2.98 ( 1 H, m), 3.19-3.21 (3H, m), 3.48-4.12 (8H, m), 4.58-4.78 (1H, m), 5.51 (1H,d), 12.15 (1H, s, br)。 實例29 (v) U3,5-二甲基吡唑-4-某甲某 某昱 定-2-基笔基甲基4吩密在 -2,4ΠΗ·3Ι~η-二醐 ΟΗ__1-兴~butyl-6-"3-isopropyl-5-methyl-1^1-?pyridyl-4-ylmethyl 1_3-methyl- 2,4-diox-1,2 , 3,4-tetra-» 吩 并 and f2,3-d~|P from θ - 5- 醢 实例 according to the method of Example 29 (iii) a), from 6-(bromomethyl)_ι_ isobutyl _3-methyl-2,4-dioxo-1,2,3,4-tetrahydroseceno[2,3-d] lyl-5-carboxylate (450 mg) After the preparation of 5-methylhexane-2,4-dione, the ester was hydrolyzed according to the procedure of Example 29 (ii) b) to give the subtitle compound (285 mg) as a solid. MS (ESI) 419 [M + H] + δ 'Hdmsq 0.85 (6Η, d), 1.13 (6H, d), 2.07 (3H, s), 2.09 (1H, non.), 2.88 (1H, sept.) , 3.26 (3H, s), 3.66 (2H, d), 4.04 (2H, s). 1^5-[(4 5)-4-hydroxylisoxazolidine-2-ylindoleyl 1-isobutyl-6-"3-isopropyl-5-methyl-1H-pyrazole- 4-ylmethyl1-3-A, a certain singular, 2,3-dl-pyrimidine-2.4(1H,3H)-dione-158 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) Dong) 1310036 A7 B7 V. Description of the invention (155 according to Example 2911 C), prepared from product a) (281 mg). The crude product was purified by reverse-phase HPLC eluting with EtOAc EtOAc EtOAc (EtOAc) (APCI) 490 [M + H] + δ 'Hdmso 0.86 (6H, d), 1.08-1.18 (6H, m), 2.02-2.17 (4H) m), 2.80-2.98 ( 1 H, m), 3.19- 3.21 (3H, m), 3.48-4.12 (8H, m), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.15 (1H, s, br). Example 29 (v) U3,5-dimethylpyrazole-4-one A certain 昱 -2--2-yl penylmethyl 4 is densely attached at -2,4ΠΗ·3Ι~η-二醐 ΟΗ
al 6-『3,5-_—甲基-1-蹇_盖二j_H-吡唑_4_某甲某1 +異丁某_3_甲 基^1^_二_氧代酸甲酯 依實例26 a)項之製法,由6_(溴甲基)_丨_異丁基·3_甲二_ 2,4·二氧代-1,2,3,4·四氫-4吩並[2,3-dH啶·5_羧酸〒酯(5〇〇 mg) '乙醯基醋酮酸鋅水合物與笨基胼製備。粗產物經矽 石管柱層析法純化,以乙酸乙酯/異己烷(2 : 3)溶離,=生 L___- 159 -__ 本紙張尺度咖t S ® ?料(CNS) A4»(21G X 297公釐) ----- A7 B7Al 6-『3,5-_-methyl-1-蹇_盖二j_H-pyrazole_4_一甲一一+丁丁某_3_methyl^1^_二_ Oxo acid methyl ester According to the method of Example 26 a), 6_(bromomethyl)-丨-isobutyl·3_methylbis-2,4·dioxo-1,2,3,4·tetrahydro-4 is exemplified. [2,3-dH pyridine·5-carboxylic acid oxime ester (5 〇〇 mg) 'Acetyl acetophenone zinc hydrate hydrate and stupid base. The crude product was purified by vermiculite column chromatography and eluted with ethyl acetate/isohexane (2:3). ======================================================================================= 297 mm) ----- A7 B7
1310036 小標題化合物(555 mg)之固體。 MS (ESI) 481 [M + H] + δ 'Η dmso 〇·95 (6Η, d), 2.24 (3Η, s') 〇1310036 Subtitle compound (555 mg) as a solid. MS (ESI) 481 [M + H] + δ 'Η dmso 〇·95 (6Η, d), 2.24 (3Η, s') 〇
八 2.27 (3Η, s),2.2〇_2 3〇 (1Η,m),3.39 (3Η,s),3.71 (2Η,d),3 Qw,u … U .95 (3H,s),3.96 (2H y 7.36-7.50 (5H,m)。 、’ ”, b) 6-f3,5-二曱基-1-本基- lH-p 比— 依實例1 f)項之製法,由a)項產物製備了 一^ 之固體。 MS (ESI) 467 [M + H-Na] + 某-2,4」二氳代-1,2,3,4-四爵.-- —^ m 小標題化合物 Η 0.87 (6H,d),2.17 (3H,s),2_i〇_2 22 (1H,m), 2 17 (3H, s),3.20 (3H,s),3.65 (2H,d),3 84 oh 、 · δ4 (2H, S), 7.34-7.39 (lH,m), 7.46-7.51 (4H, m)。 O 6-D,5-二甲基-1—-笨基其 -2,4ΠΗ,3Η)-二酮8.27 (3Η, s), 2.2〇_2 3〇(1Η,m), 3.39 (3Η,s),3.71 (2Η,d),3 Qw,u ... U .95 (3H,s),3.96 ( 2H y 7.36-7.50 (5H,m)., ' ”, b) 6-f3,5-dimercapto-1-yl-lH-p ratio - according to the method of item 1 f), by item a) The product was prepared as a solid. MS (ESI) 467 [M + H-Na] + -2,4"diodes-1,2,3,4-fourths.---^ m subtitle compound Η 0.87 (6H, d), 2.17 (3H, s), 2_i〇_2 22 (1H, m), 2 17 (3H, s), 3.20 (3H, s), 3.65 (2H, d), 3 84 Oh , · δ4 (2H, S), 7.34-7.39 (lH, m), 7.46-7.51 (4H, m). O 6-D,5-dimethyl-1--stupyl--2,4ΠΗ,3Η)-dione
DMSO 依實例29(ii) c)項之製法’由b)項產物製備,產生標題化 合物之固體。 τ MS (APCI) 538 [M + H] + δ 'HdmsoO.89 (6H, d), 0.21-0.22 (4H, m), 2.25 (3H s) 3 2〇 3.22 (3H, m), 3.45-4.15 (8H, m), 4.55-4.80 (]u 、’r ’ υ m), 5.35-5.55 (1H, m), 7.37-7.40 (1 H, m), 7.44-7.54 (4H,m)。 實例29 (vi) 643 4-二甲基-i-黎一基-1Η-,比唆-4-棊〒^鞀甚呈 -160 - 本紙張尺度逋用中國國家標準(CNS) A4規格(210X 297公釐) 1310036 A7 __B7 五、發明説明(157 ) " °号°坐咬-2 -基歲盖1 - 3 -甲棊-1 —丙某攻g分报「2,3 _ d 1嘧啶 -2-4(1Η,3Η)-二酮DMSO was prepared according to the procedure of Example 29(ii), c), from the product of item b), to give the title compound as a solid. τ MS (APCI) 538 [M + H] + δ 'HdmsoO.89 (6H, d), 0.21-0.22 (4H, m), 2.25 (3H s) 3 2〇3.22 (3H, m), 3.45-4.15 (8H, m), 4.55-4.80 (]u , 'r ' υ m), 5.35-5.55 (1H, m), 7.37-7.40 (1 H, m), 7.44-7.54 (4H, m). Example 29 (vi) 643 4-Dimethyl-i-Li Yiji-1Η-, 唆-4-棊〒^鼗 Very -160 - This paper scale uses Chinese National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 __B7 V. Invention Description (157) "°#°Sit-2 - Base Year Cover 1 - 3 - Hyperthyroidism-1 - Bingyi g-g report "2,3 _ d 1 pyrimidine -2-4(1Η,3Η)-dione
OHOH
取含6-(溴甲基)-3 -甲基-1-丙基_2,4-二氧代_1,2,3,4-四氫-4吩並[2,3-d]喃淀-5-羧酸(500 mg)與乙醯基醋酮酸鋅水合 物(389 mg)之氯仿(10 ml)溶液於回流下攪拌丨小時後,冷卻 至室·溫。添加水(10 ml)與苯基肼(0·27 ml),混合物攪拌3天 ,分層。以二氯甲烷(2 X 1〇 ml)萃取水相。有機萃液經無 水硫酸鎂脫水,過濾與減壓蒸發。殘質溶於乙腊(5 ml)中 ’以1-羥基苯並三唑(173 mg)、三乙胺(〇.63以)與氯磷酸二 乙酯(0.22 ml)處理。混合物攪拌1小時後,添加(s)_4_異$ 唑啶醇鹽酸鹽[實例1 ’ b項),173 mg]。再過24小時後,混 合物減壓蒸發。殘質經逆相HPLC純化,以0.1 %乙酸銨水 溶液/乙腈梯度溶離。產物再經矽石管柱層析法純化,以乙 酸乙酯/甲醇(49 : 1)溶離,產生標題化合物(i 50 mg)之泡沫 狀物。 MS (APCI) 524 [M + H]十 δ 'Η dmso 〇·89 (3Η, t), 1.67 (2Η, sex), 2.16 (3Η, s), 2.26 (3H, ___- 161 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇X 297公釐) 1310036 A7 B7 五、發明説明(158 ) s), 3.20 -3.22 (3H, m), 3.45-3.60 (1H, m), 3.71-4.15 (7H, m), 4.57-4.80 (1H, m), 5.46-5.57 (1H, m), 7.37-7.40 (1H, m),7.44-7.54 (4H, m)。 實例30 ^_-(1.11,2,3-苯三唑-丨·基甲基)-5_「(4sv扣羥基異吟唑啶某 羰基1-3-甲基-1-(異丙某吩並f2,3-dl嘧啶-2,4(1 Η,3Η)-二酮Take 6-(bromomethyl)-3-methyl-1-propyl-2,4-dioxo-1,2,3,4-tetrahydro-4 benzo[2,3-d] A solution of 5-carboxylic acid (500 mg) and zinc acetoxyacetate hydrate (389 mg) in chloroform (10 ml) was stirred under reflux for a few hours and then cooled to room temperature. Water (10 ml) and phenylhydrazine (0·27 ml) were added, and the mixture was stirred for 3 days and layered. The aqueous phase was extracted with dichloromethane (2×1 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was dissolved in EtOAc (5 mL). <RTI ID=0.0>>>> After the mixture was stirred for 1 hour, (s)_4_isoxoxazolidine hydrochloride [Example 1 'b), 173 mg] was added. After a further 24 hours, the mixture was evaporated under reduced pressure. The residue was purified by reverse phase HPLC eluting with 0.1% aqueous ammonium acetate / EtOAc. The product was purified by EtOAc EtOAc EtOAc (EtOAc) MS (APCI) 524 [M + H] 十δ 'Η dmso 〇·89 (3Η, t), 1.67 (2Η, sex), 2.16 (3Η, s), 2.26 (3H, ___- 161 - This paper size applies China National Standard (CNS) A4 Specification (21〇X 297 mm) 1310036 A7 B7 V. Description of Invention (158) s), 3.20 -3.22 (3H, m), 3.45-3.60 (1H, m), 3.71-4.15 (7H, m), 4.57-4.80 (1H, m), 5.46-5.57 (1H, m), 7.37-7.40 (1H, m), 7.44-7.54 (4H, m). Example 30 ^_-(1.11,2,3-Benzatriazole-fluorenylmethyl)-5_"(4sv-decahydroisoxazole carbonyl-3-ylene-1-(isopropyl) F2,3-dl pyrimidine-2,4(1 Η,3Η)-dione
§1.6-(111,213-苯」|三唑_1-基甲基)-1丄34_四|[_3_甲某_1彳昱 否基)-2,4-二氣代嘧吩#「2.3_dl嘧啶-5-跆鹼甲酯 添加氫化鈉(〇·〇6 g ’ 60°/。懸浮液)至氮氣下含笨並三„坐 (〇.19 g)之無水四氫呋喃溶液中。10分鐘後,滴加含實例8 c)項產物(0.6 g)之無水四氫呋喃溶液。反應混合物於室溫 下擾拌一夜。添加水,以乙酸乙酯萃取反應混合物。有機 相以鹽水洗滌,經硫酸鎂脫水後,真空濃縮。殘質經矽石 管柱層析法純化,依序以3〇%及4〇%異己烷之乙酸乙酯溶 液溶離’產生標題化合物之白色泡沫狀物(0.32g)。 ^ H CDCI3 1-50-1.52 (6Η, d), 3.35 (3H, s), 4.05 (3H, s), 4.6 (1H, bs), 6.01 (2H, s),7.4 (1H, m),7.51 (1H, m), 7.75 (1H, m), 8.07 (I H, m)。 包]6-(1?{-1,2,3-笨#::1^_1_某甲早)-112,3,4-四氫-3-甲莘-1-(气 ._- ΙΟ乙· 本紙張尺度適财8 B家標準(CNS) Α4·(21〇x297公董) 1310036§1.6-(111,213-Benzene)|Triazol-1-ylmethyl)-1丄34_tetra|[_3_甲某_1彳昱基基)-2,4-dioxothiophene# "2.3_dl pyrimidine-5-indole base methyl ester was added with sodium hydride (〇·〇6 g '60°/. suspension) to a solution of stupid and tris(s.19 g) in anhydrous tetrahydrofuran under nitrogen. After 10 minutes, a solution of the product of Example 8 c) (0.6 g) in anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred overnight at room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc (EtOAc) eluting eluting ^ H CDCI3 1-50-1.52 (6Η, d), 3.35 (3H, s), 4.05 (3H, s), 4.6 (1H, bs), 6.01 (2H, s), 7.4 (1H, m), 7.51 (1H, m), 7.75 (1H, m), 8.07 (IH, m). Package]6-(1?{-1,2,3-stup#::1^_1_a some early)-112,3,4-tetrahydro-3-methylindole-1-(qi._- ΙΟ B · This paper scale is suitable for 8 B standard (CNS) Α 4 · (21〇x297 DON) 1310036
AT _____B7 _ 五、發明説明(159 ) 丙棊氧代碟j並「2.3-dl嘧啶-5-教酸 添加氫氧化鈉溶液(丨.5 ml,1M)至氮氣下,含實例30 a) 產物之四氫呋喃溶液中。然後添加約1 ml甲醇,使反應混 合物溶解。反應混合物於室溫下攪拌5小時。添加鹽酸(〇 7 nil ’ 2M),反應混合物真空濃縮至乾,產生標題化合物。 。)6-(111-丄2,3-苯並三唑-1_某甲某、_5_|743)-4-羥某異峄岫咗 基幾基.U -甲基-1-(異丙某U盡吩#.「2.3-dl嘧啶-2.4(1Η.3Η)-二酉同 添加羥基苯並三唑(0.23 g)、(4S)-4-羥基異哼唑啶鹽酸鹽 (說明於實例1 b)項)(0.16 g)與三乙胺(0.22 ml)至氮氣下,含 實例30 b)產物之二氣甲烷溶液中。1〇分鐘後,添加EDCI (0.29 g)。反應混合物於室溫下攪拌一夜《加水,以二氯甲 烷萃取混合物。有機相以鹽水洗滌,經硫酸鎂脫水,真空 濃縮。殘質先經矽石層析法純化,以乙酸乙酯溶離後,經 逆相HPLC處理,產生標題化合物之白色泡沫狀物。 MS (APCI)(M++H) 471.1450 δ 1 HDMS〇 1,4 1 -1 · 45 (6H,m), 3.17 (3H,s),3.36-4.13 (4H,m之 範圍),4.4 (lH,bs),4.8 (1H,2m),5.5 (1H,m),6.02-6.15 (2H, m),7.4-7.44 (1H, m), 7.54-7.59 (1H, m),. 7.91-7.95 (1H, m),8.05-8.07 (1 H,d)。 實例3 1 5-「(4SV4-與某異啐唑啶某羰基1-3-甲某:-1-Γ冀丙某)-6-f(2-氧 代嘧唑並「5,4-1?1吡啶-1(21~〇-基)甲某14吩#『2.3-£11嘧啶 -2,4ΠΗ.3Η)-二酮 -163 - 本紙張尺度適用中鼷國家標準(CNS) Α4规格(210 X 297公釐) 1310036AT _____B7 _ 5, invention description (159) propylene oxo dish j and "2.3-dl pyrimidine-5-teaching acid added sodium hydroxide solution (丨. 5 ml, 1M) to nitrogen, containing example 30 a) product To a solution of tetrahydrofuran. A solution of the title compound was obtained. The title compound was obtained from EtOAc (EtOAc). 6-(111-丄2,3-benzotriazole-1_a certain methyl, _5_|743)-4-hydroxylisoindolyl.U-methyl-1-(isopropyl U尽##""2.3-dl-pyrimidine-2.4(1Η.3Η)-dioxin-added hydroxybenzotriazole (0.23 g), (4S)-4-hydroxyisoxazolinidine hydrochloride (described in Example 1) b)) (0.16 g) and triethylamine (0.22 ml) under nitrogen, containing the product of Example 30 b) in dioxane methane. After 1 min, add EDCI (0.29 g). The mixture was stirred overnight. Water was added and the mixture was extracted with methylene chloride. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. Work up to give the title compound as a white foam. MS (APCI) (M++H) 471.1450 δ 1 HDMS 〇1,4 1 -1 · 45 (6H,m), 3.17 (3H,s), 3.36-4.13 (4H, range of m), 4.4 (lH, bs), 4.8 (1H, 2m), 5.5 (1H, m), 6.02-6.15 (2H, m), 7.4-7.44 (1H, m), 7.54-7.59 (1H, m), 7.91-7.95 (1H, m), 8.05-8.07 (1 H, d). Example 3 1 5- "(4SV4- and some isoxazole a carbonyl 1-3-A: -1-Γ冀丙)-6-f (2-oxo-pyrazole and 5,4-1?1 pyridine-1 (21~〇-yl) A 14 phenanthene #『2.3-£11 pyrimidine- 2,4ΠΗ.3Η)-Dione-163 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036
異丙^]^^代冬丨 味並[5,4-b风皮基)f基^分並念n勒酸 甲酯 依實例30 a)項之製法,由[丨,3]嘍唑並[5,4_b]吡啶_2(ih)_ 酮(0.24 g)[說明於實例13xiii c)項中]與實例8 c)項產物(〇6 g)製備。殘質與醚研磨後,過濾,產生小標題化合物。 δ 'H CDCI3 1.57-1.59 (6Η, d), 3.36 (3H, s), 4 (3H, s), 4.5 (1H, bs), 5.3 (2H, s), 7.24-7.28 (1H, m), 7.73-7.76 (1H, d), 8.30-8.32 (1H,d)。 ^1丄2,3,4:四氬-3-丄-(吴丙果)-2,4-二g.代-6-「2-氣代口塞 °坐並「5,4-b~Kfc咬-1(2H)-基甲基裳吩#「2,3-d~l·密歧-5-教酸 添加氫氧化鈉溶液(0.78 ml,1M)至氮氣下,含實例3 1 a) 產物之四氫呋喃溶液中。然後添加1 ml甲醇,使混合物溶 解。反應混合物於室溫下撥拌48小時。過濾所形成之沉澱 ,依序以四氫呋喃及醚洗滌,產生標題化合物(〇. 18 g)。 MS (ES) (M++H) 433 c) 5-『(4S)-4-海某異崎唑啶基羰某1-3-甲某-1-(異丙某 氧代碟唑並f5.4-bl吡啶-1(2H)-基曱基14吩並「2.3-dl嘧免 2,4(1Η·3Η)-二酮 -164 - 本紙張尺度適用中國國家標準(CNS) Α4规格(210 X 297公#) A7 B7 1310036 五、發明説明(161 ) 添加經基苯並三唑(〇· 12 g)至氮氣下,含實例3 1 b)產物之 四氫呋喃懸浮液中。1 〇分鐘後,添加EDCI (0.1 5 g),再過 40分鐘後,添加(4S)-4-羥基異崎唑啶鹽酸鹽(〇 〇6 g)與三乙 胺(0.07 ml)。反應混合物於室溫下攪拌一夜。加水,以二 氣甲烷萃取混合物。有機相以鹽水洗滌,經硫酸鎂脫水, 真2濃縮。殘質經石夕石層析法純化,以5 %甲醇之二氣甲燒 溶液溶離,產生標題化合物之白色泡沫狀物。 MS (APCI) (M + + H) 504.0914 δ H D6DMSO 1.45-1.48 (6Η, m), 3.16 (3Η, s), 3.52-4.1 (4H, m 之範圍),4_4 (1H, bs),4.6-4.8 (1H,m之範圍),5.^-5,57 (3H, m),7.4-7.47 (1H,m),7.79-7.81 (1H,d),8.30-8.31 (1H,d)。 實例32 4_·「2:3-二氫_2-氣代-1H-笨並味咬-1-基甲某錄车 等唑啶基羰基1-3 -甲基-1-(異丙基唂矻[2,3_dl嘧咗 二2,4ΠΗ.3Η)-二酮Isopropyl]]^^========================================================================================== [5,4_b]pyridine-2(ih)-ketone (0.24 g) [depicted in Example 13xiii c)] and Example 8 c) product (〇6 g). The residue is triturated with ether and filtered to give the subtitle compound. δ 'H CDCI3 1.57-1.59 (6Η, d), 3.36 (3H, s), 4 (3H, s), 4.5 (1H, bs), 5.3 (2H, s), 7.24-7.28 (1H, m), 7.73-7.76 (1H, d), 8.30-8.32 (1H, d). ^1丄2,3,4: Tetra Argon-3-丄-(Wu Bingguo)-2,4-二g.代-6-"2-Pneumatic mouth plugs sit and "5,4-b~Kfc bite -1(2H)-ylmethylanthene# "2,3-d~l·Mimi-5-teaching acid added sodium hydroxide solution (0.78 ml, 1 M) to nitrogen, containing example 3 1 a) product The title compound (〇18 g) was obtained by the addition of 1 ml of methanol, and then the mixture was dissolved. The mixture was stirred at room temperature for 48 hr. MS (ES) (M++H) 433 c) 5-『(4S)-4-海某异崎佐 pyridine carboxycarbonyl 1-3-甲一-1-(isopropyl oxo-oxazolyl and f5 .4-blpyridine-1(2H)-ylindenyl 14-"2.3-dl-pyrene 2,4(1Η·3Η)-dione-164 - This paper scale applies to Chinese National Standard (CNS) Α4 specification ( 210 X 297 gong #) A7 B7 1310036 V. Inventive Note (161) Addition of benzotriazole (〇· 12 g) to a suspension of tetrahydrofuran containing the product of Example 3 1 b) under nitrogen. 1 min Add EDCI (0.1 5 g), and after 40 minutes, add (4S)-4-hydroxyisoxazolidine hydrochloride (〇〇6 g) and triethylamine (0.07 ml). Stir at room temperature overnight. Add water and extract the mixture with di-methane. The organic phase is washed with brine, dehydrated with magnesium sulfate, and concentrated. The residue is purified by Shi Xishi chromatography and 5% carbonitrile. The solution was dissolved to give the title compound as a white foam. MS (APCI) (M + + H) 504.0914 δ H D6 DMSO 1.45-1.48 (6 Η, m), 3.16 (3 Η, s), 3.52-4.1 (4H, m Range), 4_4 (1H, bs), 4.6-4.8 (1H, range of m), 5.^-5,57 (3H, m), 7.4-7.47 (1H, m), 7.79-7.81 (1H, d ), 8.30-8.31 (1H, d). Example 32 4_·"2:3-Dihydro-2-gaso-1H-stupid bite-1-yl-A certain car, etc., oxazolidinylcarbonyl 1-3 -Methyl-1-(isopropyl hydrazine [2,3_dl-pyridinium 2,4ΠΗ.3Η)-dione
CL_L_2,3,4-四氣-3-甲某-1-(異丙基)-6-「2-(甲笨抱味 ~-1-基甲基1-2、4-二乳代-1»菜吩並|~2,3-(11;>密喊-5-勒|专甲醋 依實例3 c)項之製法’由實例8 c)項產物與2-甲基氫硫基 笨並咪唑製備,經矽石層析法純化,以異己烷/乙酸乙酿(1 ______- 165 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A7 B7 1310036 五、發明説明(162 ) :〖)溶離後’產生標題化合物之淺黃色固體。 MS (ES) (M + + H) 459 δ 1 H D6DMSO 1.40-1.42 (6Η, d), 2.73 (3Η, s), 3.16 (3H, s), 3.80 (3H, s), 4.3 (1H, bs), 5.56 (2H, s), 7.15-7.23 (2H.m), 7.54-7_58 (2H,m)。 13)1.2.3.4-四氫-3-甲基-1-(異丙篡)-6-「2-(甲碏||某)-1只-笨 並咪唑-1-基甲基1-2,4-二氡代-g盡吩並「2.3-cil嘧啶-5-教酸甲酯 添加mCPBA (1.2 g)至含實例3 1 a)項產物(0.64 g)之二氯 甲烷溶液中。反應混合物於室溫下攪拌2小時。以1 0%偏亞 硫酸氫納落液(40 ml)、碳酸氫鈉及鹽水依序洗條反應混合 物。有機相經硫酸鎂脫水後’真空濃縮,產生小標題化合 物。 MS (ES)(M + + H) 490.8 c) 6-[2,3-二氫-2-氧代-ΙΗ-笨#咪唑-1-某甲某u ?丄4-四雹_ 3-甲基-1-(異丙基)-2,4_二氧代,-嘧吩並丨2·3-η~|嘧啶-5_淼醢 添加碳酸氫鈉(0.55 g)至含實例32 b)項產物(0.54 g)之水 懸浮液中。反應混合物回流加熱17小時。以乙酸乙酯洗滌 反應混合物’取水層冷凍乾燥,產生小標題化合物(〇.7 g)。 MS (ES)(M++H) 415 d) 皂-「^J-士.氫苯並咪唑-1-某甲其 1-5_「r4S)_4_羥 碁異5唑哫基甲杲-丨_(異丙基)p裳吩拍[2 3_di嘧啶 -2,4( 1 H,3HV: 依r例3 I c)員之製法,由實例32 c)項產物製備,經碎石 看析法純化,依序以0%及1%甲醇之乙酸乙g旨溶液溶離後 本紙張尺度適用中a a家標準((:¾ A4规格(21Q χ 2971二)------——- A7 B7 1310036 五、發明説明(163 ) ,經逆相HPLC法純化,以〇· 1 %乙酸銨水溶液:乙腈(95 : 5 至5 : 95)溶離,產生標題化合物。 MS (APCI)(M + + H) (486.1469) 5 1 H D 6 D Μ S Ο 300 Mhz 1.44-1.45 (6H, m), 3.16 (3H, s), 3.5-4.5 (5H, m之範圍),4.6-5.2 (3H, m之範圍),5.5-5.57 (1H, 2m), 6·99 (3H,s),7.2 (1H,m)。 實例33 「(4S)-4-羥基-2-異呤唑啶某羰某1-3-甲某-丨彳異丙基V塞吩並 「2.3-dl^^-2.4nH,3H)-:_CL_L_2,3,4-tetraqi-3-methyl-1-(isopropyl)-6-"2-(A stupid ~-1-ylmethyl 1-2, 4-dilac-1 »菜吩和|~2,3-(11;> 密叫-5-勒|甲甲醋 according to Example 3 c) The method of 'Example 8 c) and 2-methylhydrosulfanyl Prepared by imidazole, purified by vermiculite chromatography, and coated with isohexane/acetic acid (1 ______- 165 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Invention Description (162): 〖After dissolving, the title compound is obtained as a pale yellow solid. MS (ES) (M + + H) 459 δ 1 H D6 DMSO 1.40-1.42 (6Η, d), 2.73 (3Η, s), 3.16 (3H, s), 3.80 (3H, s), 4.3 (1H, bs), 5.56 (2H, s), 7.15-7.23 (2H.m), 7.54-7_58 (2H, m). 13) 1.2.3.4 -tetrahydro-3-methyl-1-(isopropyl hydrazide)-6-"2-(methyl hydrazine||)-1 - stupid imidazol-1-ylmethyl 1-2,4-di Generation-g is exemplified by the addition of mCPBA (1.2 g) to the product of Example 3 1 a) (0.64 g) in dichloromethane. The reaction mixture is at room temperature. Stir for 2 hours. With 10% sodium metabisulfite (40 ml), sodium bicarbonate and brine The reaction mixture was washed with EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - stupid #imidazole-1-some a certain u?丄4-tetrazole_3-methyl-1-(isopropyl)-2,4_dioxo,-sulfimenoxadol 2·3-η~ Pyrimidine-5_淼醢 Add sodium bicarbonate (0.55 g) to an aqueous suspension containing the product of Example 32 b) (0.54 g). The reaction mixture was heated under reflux for 17 hours. The reaction mixture was washed with ethyl acetate. Freeze-drying to give the subtitle compound (〇.7 g) MS (ES) (M++H) 415 d) Soap - "^J-士. Hydrobenzimidazole-1- Some A 1-5_"r4S )_4_ hydroxy oxime 5-oxazolidinyl hydrazine-丨_(isopropyl) p 吩 吩 拍 [2 3_di pyrimidine-2,4 ( 1 H, 3HV: according to r 3 I c) member of the method, by Example 32 Preparation of product c), purified by gravel analysis, sequentially dissolved in 0% and 1% methanol acetic acid solution. The paper size is applicable to the aa standard ((: 3⁄4 A4 specification (21Q χ 2971 2)------——- A7 B7 1310036 V. Inventive Note (163), purified by reverse phase HPLC, with 〇·1% aqueous ammonium acetate: acetonitrile (95: 5 to 5: 95) Dissolution to give the title compound. MS (APCI)(M + + H) (486.1469) 5 1 HD 6 D Μ S Ο 300 Mhz 1.44-1.45 (6H, m), 3.16 (3H, s), 3.5-4.5 (5H, range of m), 4.6-5.2 (3H, range of m), 5.5-5.57 (1H, 2m), 6·99 (3H, s), 7.2 (1H, m). Example 33 "(4S)-4-Hydroxy-2-isoxazole pyridine a carbonyl 1-3-methyl- isopropyl isopropyl thiophene and "2.3-dl^^-2.4nH,3H)-: _
a) 5,6 -二漱.-2 -氣石虎基笨祐味口Φ 取含3,4-二氟-6-硝基苯胺(2 g)與5% Pd/C (100 mg)之乙醇 (3 0 ml)攪拌懸浮液於5巴下攪拌24小時。混合物經寅氏鹽 過濾’真空濃縮’產生之固體溶於DMF (20 ml)中,以二硫 化碳(i0 ml)處理。溶液於周溫下攪拌5小時《溶液倒至水 中’所得混合物以乙酸乙酯(x3)萃取。合併之有機萃液脫 水(MgS04),真空濃縮,產生深紅色固體(2.45g)。 δ 1 H D6DMSO 7.6-7.62 (2Η,m),8.3 (1H, s, br),13 (s,1Η)。 b) 5,6 -二漱_-2-(甲硫某)幕亦.味吨 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)a) 5,6 -二漱.-2 - gas stone tiger base 笨 味 味 Φ Take 3,4-difluoro-6-nitroaniline (2 g) and 5% Pd/C (100 mg) The stirred suspension of ethanol (30 ml) was stirred at 5 bar for 24 hours. The mixture was filtered over EtOAc (EtOAc). The solution was stirred at ambient temperature for 5 hours. The solution was poured into water. The mixture was extracted with ethyl acetate (x3). The combined organic extracts were dehydrated (MgSO.sub.4). δ 1 H D6 DMSO 7.6-7.62 (2Η, m), 8.3 (1H, s, br), 13 (s, 1Η). b) 5,6 - 2漱_-2-(methylthio) curtain also. Wei ton This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)
線 A7 B7 164 1310036 五、發明説明( 取含5,6-二氟-2-氫硫基苯並咪唑(2.4 g)與碳酸鉀(1.78 g) 之丙酮攪拌懸液浮,經甲基碘(0.8 ml)處理,攪拌2小時° 反應蒸發至乾,殘質懸浮於水(300 ml)中。以乙酸乙醋(χ3) 萃取混合物。合併之有機萃液脫水(MgS04),及蒸發。殘 質經層析(Si02/2 : 8乙酸乙酯-異己烷),產生小標題化合物 (1.95 g)。 MS (APCI) 215 [M+H] + c) 6-C5,6-二氣-2-氩代-2,3-二氤-1H-苯並呋吔-1-某甲基上ill 「(4S)-4-羥基異哼唑啶-2-基羰某1-M異丙某)-3-甲某吩i 『2,3-dl嘧啶-2,4( 1H.3H)-二酮 添加mCPB A至二氣甲烷中,反應混合物攪拌1小時。反 應混合物倒至丨0%偏亞硫酸氫納溶液(160 ml)上《分層,有 機相以碳酸氫鈉及鹽水依序洗滌,經硫酸鎂脫水後,真空 濃縮,產生黃色泡沫狀物《以水(5 ml)、THF (5 ml)與碳酸 氫鈉(0.37 g)處理此泡沫狀物。反應混合物回流攪拌48小時 。過濾所形成之沉澱,以水洗滌,產生白色固體。此固體 經 THF (7 ml)、HOBT (0.2g)及 EDCI (0.28 g)處理。反應混 合物回流攪拌35分鐘後,添加三乙胺(0.24 ml)與(S)-羥基異 噚唑啶.HC1 (0_ 1 8 g)。反應混合物回流攪拌2天。殘質經層 析(Si〇2/98 ·· 2乙酸乙醋-甲醇),產生黃色固體。自甲醇中 再結晶’產生標題化合物之白色晶體(0.1 8 g)。 δ 'Η d6dmso 0.84 (6Η, m), 2.02-2.19 (1H, m), 3.19 (1H, s), 3.74-4.17 (5H, m), 4.6-4.81 (1H, m),4.97-5.18 (2H, m), 5.7-5.61 (1H, m),7.02-7.17 (m,lH)與 7.35-7.41 (m’lH)。 -16B ~ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Line A7 B7 164 1310036 V. Description of the invention (According to a stirred suspension of 5,6-difluoro-2-hydrothiobenzimidazole (2.4 g) and potassium carbonate (1.78 g), via methyl iodide ( Treatment with 0.8 ml), stirring for 2 hours. The reaction was evaporated to dryness and the residue was suspended in water (300 ml). The mixture was extracted with ethyl acetate (?3). The combined organic extracts were dehydrated (MgS04) and evaporated. Chromatography (SiO 2 / EtOAc: EtOAc (EtOAc): EtOAc (EtOAc) Argon-2,3-dioxin-1H-benzofurazan-1-methyl ill "(4S)-4-hydroxyisoxazolidine-2-ylcarbonyl 1-Misopropanol)- 3-methyl propyl i 2,3-dl pyrimidine-2,4( 1H.3H)-dione was added to mCPB A to di-methane, and the reaction mixture was stirred for 1 hour. The reaction mixture was poured to 丨0% meta-sulfuric acid. The mixture was washed with a solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow foam, water (5 ml), THF (5 ml) The foam was treated with sodium bicarbonate (0.37 g). The reaction mixture was stirred at reflux for 48 hours. The precipitate formed was filtered and washed with water to give a white solid. EtOAc (EtOAc) (EtOAc) (ml) with (S)-hydroxyisoxazole pyridine.HC1 (0_18 g). The reaction mixture was stirred under reflux for 2 days. The residue was chromatographed (Si 〇 2/98 · · 2 ethyl acetate-methanol). Yellow solid. Recrystallized from methanol to give the title compound as white crystals (0.18 g). δ 'Η d6dmso 0.84 (6Η, m), 2.02-2.19 (1H, m), 3.19 (1H, s), 3.74- 4.17 (5H, m), 4.6-4.81 (1H, m), 4.97-5.18 (2H, m), 5.7-5.61 (1H, m), 7.02-7.17 (m, lH) and 7.35-7.41 (m'lH -16B ~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)
装 訂Binding
線 1310036 A7 B7 五、發明説明(165 ) 實例34 5-f(4S)-4-羥基盘,土这:-2-革卜^^米唑#「^毗咗J· 棊甲基)-1-并X."基二3」f棊噚吩並『2,3-(〇^啶_2 4ΠΗ 3Η)-二酮 ΟΗLine 1310036 A7 B7 V. Inventive Note (165) Example 34 5-f(4S)-4-hydroxy disk, soil this: -2-grab ^^mazole #"^咗咗J· 棊methyl)-1 - and X."基二3"f棊噚"2,3-(〇^啶_2 4ΠΗ 3Η)-dione oxime
a) 6-(咪唑並『l,2-al吡啶-3-某甲某VI-里丁某_3_甲某_2 4_二 氧代-1,2,3,4-四氫峰吩並「2.3-dl°密遗- 5-#醢甲酿 取實例3 b)項產物(1 g)、咪唑並[i,2_a]吡啶(〇 4 ml) '碳 酸鉀(0.3 5 g)與THF (20 ml)於氮氣下攪拌1小時。加水至反 應中’以乙酸乙酯(X 2)萃取。合併之有機萃液脫水 (MgS〇4) ’真空濃縮。殘質經層析(Si〇2/9 : 1乙酸乙酯-己烷 ,及乙酸乙酯),產生小標題化合物之無色油狀物。 LCMS (ESI) 4275 [M + H] + b) 6-(咪唑並f 1,2-al吡啶-3-某甲某)-1-異丁某-3 -甲基-2,4-二 氧代-1,2,3,4-四氫p塞吩並「2.3-dl嘧啶-5-勒醢 取a)項產物’以氫氧化鈉(0.75 ml)、THF (5 ml)及甲醇 (0.05 ml)處理’所得溶液於氮氣下攪拌2小時。反應混合物以 乙酸乙酯洗滌。水相真空濃縮,產生小標題化合物(0.1 3 g)。 c) 5-「(4S)-4-羥基異哼唑啶-2-某羰基1-6-(咮唑並Π .2-a〗吡啶-3-基甲基)-1-異丁某-3-甲基嘧吩並f2,3-dl嘧啶-2,4ΠΗ,3Η)-二酮 __- 169 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1310036 A7 B7 五、發明説明(166 ) 取步驟b)產物(0.13 g)溶於THF (3 ml)中。依序添加H〇BT (0.09 g)與EDCI (0.12 g)。攪拌1〇分鐘後,添加三乙胺(0.05 ml)與(S)-羥基異呤唑啶鹽酸鹽(〇.〇8 g),反應混合物攪拌16 小時。加水(10 ml)與乙酸乙酯(1〇 mi)。分層,水層再以乙 酸乙酯萃取。合併之有機萃液脫水(MgS〇4),真空濃縮。 化合物經RPHPLC純化’以乙酸銨:乙腈(8〇 : 20)溶離,產 生標題化合物之白色固體。 LCMS (APCI) 485 [M + H] + 實例3 5 3 -甲基-642-甲某吲哚-3-某甲某1-1彳異丁某)-5-(四氤異呤a) 6-(imidazolium "l,2-alpyridine-3-one A certain VI-Riding _3_甲某_2 4_dioxo-1,2,3,4-tetrahydro phenanthrene And "2.3-dl ° secrets - 5-# armor brewing example 3 b) product (1 g), imidazo[i,2_a]pyridine (〇4 ml) 'potassium carbonate (0.3 5 g) and THF (20 ml) was stirred under nitrogen for 1 hour. Water was added until the reaction was extracted with ethyl acetate (X 2 ). The combined organic extracts were dehydrated (MgS 〇 4) and concentrated in vacuo. /9:1 ethyl acetate-hexanes, and ethyl acetate) to give the title compound as a colorless oil. LCMS (ESI) 4275 [M + H] + b) 6 Al pyridine-3-methyl meth)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-p-pyrene and 2.3-dl pyrimidine-5 - The product of item a) was treated with sodium hydroxide (0.75 ml), THF (5 ml) and methanol (0.05 ml). The resulting solution was stirred under nitrogen for 2 hours. The reaction mixture was washed with ethyl acetate. Concentration in vacuo gave the subtitle compound (0.13 g). </RTI> </RTI> 5-((4S)-4-hydroxyisoxazole pyridine-2- carbonyl 1-6-(oxazoloindole. 2-a pyridine) 3-methylmethyl)-1-isobutyl-3-methylpyrimidine And f2,3-dl pyrimidine-2,4ΠΗ,3Η)-dione__- 169 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1310036 A7 B7 V. Invention Description (166 The product of step b) (0.13 g) was dissolved in THF (3 ml). H〇BT (0.09 g) and EDCI (0.12 g) were added sequentially. After stirring for 1 min, triethylamine (0.05 ml) was added. (S)-Hydroxyisoxazole pyridine hydrochloride (〇. 〇 8 g), the reaction mixture was stirred for 16 hours. Water (10 ml) and ethyl acetate (1 〇mi) were added. The ethyl ester was extracted and the combined organic extracts were dried (EtOAc mjjjjjjjjjjjjjj M + H] + Example 3 5 3 -Methyl-642-A 吲哚-3-A A certain 1-1 彳 丁 ))-5-(四氤异呤
基-6-「2-甲基吲哚-3-某甲基1-1-(異丁甚vs-(四氤異崎 口井-2-基羰基)->塞吩並「2.3-dl嘧啶-2.4(1 二 sisi 依實例1 g)項之製法’由實例5 b)項產物與四氫-1,2-呤畊 鹽酸鹽製備,產生標題化合物。 MS (APCI) 495 [M + H] + δ 'Η dmso. 130-c 0.82 (6Η, d); 1.72 (4H,br s); 2.11 (1H, septet); 2.35 (3H, s); 3.25 (3H, s); 3.6 (2H,br d); 3.70 (2H,br s); 3.85 __- 170 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A7 B7 1310036 五、發明説明(167 ) (2H,br s); 4.1 (2H, s); 6.9 (1H, t); 6.95 (1H, t); 7.25 (1H, d); 7 · 3 5 (1 H,d); 10 · 4 (1 H,b r s)。 實例36 二氣-1H-味吨-1-基甲其與某異g等岐 立基1-3-甲基-1-(1 丁基μ塞哈祐p vdl嘧啶-2,4ΠΗ,3Η)- 二酉同Base-6-"2-methylindole-3-methyl-1-(isobutyl Vs-(tetramium succinyl-2-ylcarbonyl)-> sputum" 2.3-dl Preparation of the pyrimidine-2.4 (1 disisi according to Example 1 g) product from the product of Example 5 b) and tetrahydro-1,2-indole hydrochloride gave the title compound. MS (APCI) 495 [M + H] + δ 'Η dmso. 130-c 0.82 (6Η, d); 1.72 (4H, s s); 2.11 (1H, septet); 2.35 (3H, s); 3.25 (3H, s); 3.6 (2H , br d); 3.70 (2H, br s); 3.85 __- 170 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Invention description (167) (2H, br s ); 4.1 (2H, s); 6.9 (1H, t); 6.95 (1H, t); 7.25 (1H, d); 7 · 3 5 (1 H, d); 10 · 4 (1 H, brs) Example 36 Dioxane-1H-taste-1-yl-methyl and its iso-g-isodinyl 1-3-methyl-1-(1 butyl-pyrazine p vdl-pyrimidine-2,4ΠΗ,3Η )- 二酉同
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a) 6:f2-溴-4,5-二 f -1Η-呋吨-1-某甲某 1-1.2,3,4-四 1 -3-甲 基-1-(異丁基)-2,4-二氫代-嘧吩並[2.3-…嘧啶_5-羧酸甲酯 添加實例3 b)產物(丨g)至含2-溴-4,5-二氯咪唑(0.73 g)與 碳酸鉀(1 g)之無水二甲基甲醯胺溶液中。反應於室溫下攪 拌2天後,加水稀釋,以乙酸乙酯萃取(2次)。有機相經硫 酸鎂脫水’減壓濃縮^殘質經急驟矽石層析法純化,以2〇0/〇 乙酸乙酯之異己烷溶液溶離’產生小標題化合物(〇.84 g)。 MS (APCI) 524.9 [M + H] δ 'Hcdcu 0.96-0.98 (6H,d),2.2-2.3 (1H, m)’ 3 39 (3H, s), 3.73-3.75 (2H, d), 4 (3H, s), 5.36 (2H, s) kl..6-[2-溴-4,5-二氣-1H-咪唑-1·基甲基1^,3,4_ 四 g 基-1-(異丁基)-2,4 -二氣代-p菜吩並『2,3-41_ -171 本紙張尺度適用中國國家標準(CNS) Α4規格(210Χ 297公釐) 1310036 A7 B7 五、發明説明(168 ) 依序添加氫氧化鈉(2 ml 1M水溶液)及甲醇(〇.5 mi)至含步 驟a)產物(0.85 g)之四氯吱喃(7 ml)溶液中,於室溫下搜^ 小時。過;慮所形成之沉殿’以四氫吱喃徹底洗條,產生小 標題化合物之白色固體(0.81 g)。 MS (APCI) 510.8 [M + H] c)—6—-丄?漠咪吐-l-i甲某卜淼其显碟 吐座基:羰棊Η二異丁基)喧吩並「2,3_dl嘧啶辽4ί1Η 3Ην 二酮 依貫例丨g)項之製法,由實例10 b)項產物與(4S)-4-經基 異巧峻淀鹽酸鹽(實例lb產物)製備,經急驟矽石層析法純 化,以2%甲醇之二氯甲烷溶液溶離後,產生小標題化合物。 MS (APCI) 581.8 [M+H] δ ^dmso 0.89-0.91 (6Η, d), 2.1-2.2 (1H, m), 3.2 (3H, s), 3.6-4 (5H, m), 4-4.1 (1H, m), 4.6-4.8 (1H, 2m), 5.34 (2H, s), 5.51-5.53 (1H, d) 實例37 5-『(4S)-4-羥基異噚唑啶-2-基羰某1-3-甲基-1-(裘丁 I (甲硫基)-川-咪唑並「4,5-!?1吡啶-1-某甲基1硪哈並「2.3-(11嘧 啶-2,4(1Η,3Η)-二酮a) 6: f2-bromo-4,5-dif-1Η-furox-1-one a certain 1-1.2,3,4-tetra-1-3-methyl-1-(isobutyl)-2 , 4-dihydro-sulfono[2.3-...pyrimidine-5-carboxylic acid methyl ester addition example 3 b) product (丨g) to 2-bromo-4,5-dichloroimidazole (0.73 g) and Potassium carbonate (1 g) in anhydrous dimethylformamide solution. After the reaction was stirred at room temperature for 2 days, it was diluted with water and extracted with ethyl acetate (2 times). The organic phase is dehydrated with magnesium sulfate. The residue is purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) MS (APCI) 524.9 [M + H] δ 'Hcdcu 0.96-0.98 (6H,d),2.2-2.3 (1H, m)' 3 39 (3H, s), 3.73-3.75 (2H, d), 4 ( 3H, s), 5.36 (2H, s) kl..6-[2-bromo-4,5-diox-1H-imidazole-1·ylmethyl 1^,3,4_tetrag-yl-1-( Isobutyl)-2,4 -digaso-p dish"2,3-41_ -171 This paper scale applies to Chinese National Standard (CNS) Α4 specification (210Χ 297 mm) 1310036 A7 B7 V. Invention Description (168) Add sodium hydroxide (2 ml 1M aqueous solution) and methanol (〇.5 mi) to a solution containing the product of step a) (0.85 g) in tetrachloropyran (7 ml) at room temperature. ^ hours. After careful treatment, the sinking was formed by washing with a tetrahydrofuran to give a white solid (0.81 g) of the subtitle compound. MS (APCI) 510.8 [M + H] c)—6—-丄?漠咪吐-li A 淼 淼 显 显 显 显 显 显 显 显 : : : : : : : : : : : : 棊Η 棊Η 「 「 「 「 「 「 「 2 2 2 Liao 4ί1Η 3Ην diketone according to the method of g), prepared by the product of example 10 b) and (4S)-4-pyryl sulphate hydrochloride (example lb product), through the emergency vermiculite layer Purification by chromatography, eluting with 2% methanol in dichloromethane to give the subtitle compound. MS (APCI) 581.8 [M+H] δ ^dmso 0.89-0.91 (6Η, d), 2.1-2.2 (1H, m ), 3.2 (3H, s), 3.6-4 (5H, m), 4-4.1 (1H, m), 4.6-4.8 (1H, 2m), 5.34 (2H, s), 5.51-5.53 (1H, d Example 37 5-"(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl 1-3-methyl-1-(anthracene I (methylthio)-chuan-imidazole" 4,5 -!?1 pyridine-1-methyl 1 hip hop and "2.3-(11 pyrimidine-2,4(1Η,3Η)-dione
-172 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1310036 A7 B7 五、發明説明(169 ) a) 2-(曱硫某)-1 H-咪唑並a 添加乙基黃原酸鉀(4_51 g)至含2,3-二胺基吡啶(2.51 g)之 乙醇(25 ml)與水(5 ml)溶液中。反應混合物回流24小時後 ’冷卻。過濾所形成之沉澱,以乙醇及醚依序洗滌,產生 淺粉紅色固體(3.16 g)。添加氫氧化鉀(23 ml,1M)至此固體 中’ 5分鐘後,添加碘甲烷(丨·3 ml)。反應混合物於室溫下 一夜後,以乙酸乙酯萃取。水層真空濃縮。殘質與甲醇研 磨,過濾不溶物固體。濾液真空濃縮後,殘質與二氯甲烷 研磨,過濾,產生標題化合物之米色固體(440 mg)。 MS (ES) 166 [M + H] + δ 'Hdmso 2.56 (3H, s), 6.68-6.73 (1H, m), 7.44-7.47 (1H, d), 7.84- 7.86 (1H, d)。 b) I,2U-四氫-3-甲基-1-(異丁某V6-「2-(甲硫基)-1Η-呋岫光_ l~4,5-bl..峨咬-1 -基甲基 1-2,4-二 ϋ,代-遠吩祓「2.3-dl蜂峻 酸甲酯 依實例13vii a)項之製法,由實例3 b)項產物(815 mg)與 2-(甲硫基)-1Η-咪唑並[4,5-b]吡啶(實例37 a)項)(342 mg)製 備。粗產物經急驟矽石層析法純化,依序以50%乙酸乙酿 之異己烷溶液及3%甲醇之二氯甲烷溶液溶離,產生標題化 合物(190 mg)及實例22i a)項產物(40 mg)。 MS (ES) 474 [M + H] + δ 'HCdci3 0.89-0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 4 (3H, s), 3.6 (2H,d), 4.1 (3H, s),5.82 (2H, s),6.95-7 (1H, t) 7.85- 7.91 (2H,m)。 _- 173 -_ 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公袭^ ' "~~~ -----172 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (169) a) 2-(曱 某)-1 H-imidazolium a Add B Potassium xanthate (4_51 g) to a solution of 2,3-diaminopyridine (2.51 g) in ethanol (25 ml) and water (5 ml). The reaction mixture was refluxed for 24 hours and then cooled. The precipitate formed was filtered and washed with ethanol and ether to give a pale pink solid (3.16 g). Potassium hydroxide (23 ml, 1 M) was added to the solid for 5 minutes, then iodomethane (3 ml) was added. The reaction mixture was taken at room temperature overnight and extracted with ethyl acetate. The aqueous layer was concentrated in vacuo. The residue was ground with methanol and the insoluble solids were filtered. The filtrate was concentrated in vacuo and EtOAc EtOAc m. MS (ES) 166 [M + H] + δ 'Hdmso 2.56 (3H, s), 6.68-6.73 (1H, m), 7.44-7.47 (1H, d), 7.84- 7.86 (1H, d). b) I, 2U-tetrahydro-3-methyl-1-(isobutyl V6-"2-(methylthio)-1Η-furazan _ l~4,5-bl.. bite-1 -Based methyl 1-2,4-diindole, substituted- far-directed "2.3-dl berylic acid methyl ester according to Example 13vii a), by example 3 b) product (815 mg) and 2- (Methylthio)-1 oxime-imidazo[4,5-b]pyridine (Example 37 a)) (342 mg). The crude product was purified by flash chromatography eluting with 50% acetic acid. The title compound (190 mg) and the product of Example 22i a) (40 mg) were obtained eluted from hexanes of hexanes of hexanes of hexanes (MS) s[M+H] + δ 'HCdci3 0.89- 0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 4 (3H, s), 3.6 (2H, d), 4.1 (3H, s), 5.82 (2H, s ), 6.95-7 (1H, t) 7.85- 7.91 (2H, m). _- 173 -_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public attack ^ ' "~~~ ----
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線 1310036 A7 B7 五、發明説明(170 )Line 1310036 A7 B7 V. Description of invention (170)
Qi—H3,4-四氮.-3-甲篡-1-(異工基)-6-「2,(甲硫甚、H_g^…卜甘 [~4,5-131吡啶-1-某甲某卜214-41^代-|71吩並[2.3-(11褚蛉—<产 S交鈉 添加氫氧化鈉(0.8 ml ’ 1M)至氮氣下,含實例37 b)項產 物(1 90 mg)之四氫呋喃溶液中。添加甲醇,使溶液溶解。 反應混合物於室溫下攪拌3小時。添加HC1 (0.4 ml,2M)中 和溶液,混合物真空濃縮,產生標題化合物。 MS (ES) 460 [M+H] +d) 5-f(4SV4-骑某:基·〇哥吐咬-2-基幾某1-3 -甲某- i_(暮丁苹 「2-(甲硫基)-lH-吹唑並丨4,5-bl吡啶-3-某甲其哈沛ρ ιΗ·| 嘧啶-2,4ΠΗ,3ΡΠ-二酮 依實例1 g)項之製法,由實例37 c)項產物製備。粗產物 經逆·相製備性HPLC純化,以含25%至95%乙腈之〇.1 %乙酸按 水溶液梯度溶離,產生標題化合物之無色油狀物(47 mgp MS (ES) 53 1.1494 [M+H] + δ 'Hdmso 0.88-0.90 (6H, m), 2.1-2.2 (1H, m), 2.70 (3H, s), 3.18 (3H, s), 3.6-3.9 (5H, 3m), 4-4.1 (1H, m), 4.6-4.8 (1H, 3m), 5.5-5.9 (3H, m),7.1 (1H,m), 7.9 (2H, m)。 實例37i 5-『(4S)-4-與.基異哼唑啶某羰某1-3-甲某-1-(異丁甚甲 硫基)-3H-咪唑並「4,5-bl吡啶-3-某甲基塞吩並l~2.3-dl嘧晗-2,4(1Η·3Η、-二酮 174 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Qi-H3,4-tetrazo.-3-methylindole-1-(isomeric)-6-"2, (methylthio, H_g^...Bugan [~4,5-131pyridine-1-) A certain 214-41^---71-[2.3-(11褚蛉-<S sodium-added sodium hydroxide (0.8 ml '1M) to nitrogen, containing the product of example 37 b) (1 To a solution of 90 mg) in THF, EtOAc (m.). [M+H] +d) 5-f(4SV4-ride: base·〇哥吐咬-2-基几一1-3 -甲某-i_(暮丁苹"2-(methylthio)- lH-thiazolidine 丨4,5-blpyridine-3- 甲其其哈哈佩ρ ιΗ·| Pyrimidine-2,4ΠΗ,3ΡΠ-dione according to the method of Example 1 g), from the product of Example 37 c) The crude product was purified by reverse-phase preparative EtOAc (EtOAc/EtOAc) M+H] + δ 'Hdmso 0.88-0.90 (6H, m), 2.1-2.2 (1H, m), 2.70 (3H, s), 3.18 (3H, s), 3.6-3.9 (5H, 3m), 4 -4.1 (1H, m), 4.6-4.8 (1H, 3m ), 5.5-5.9 (3H, m), 7.1 (1H, m), 7.9 (2H, m). Example 37i 5-"(4S)-4- and .isoxazole pyridine a carbonyl 1-3- A certain -1-(isobutyl methionyl)-3H-imidazolium "4,5-bl pyridine-3-methyl thiophene and l~2.3-dl pyridinium-2,4 (1 Η · 3 Η, -Dione 174 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)
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線 ► A7 B7Line ► A7 B7
1310036 a) 1,2,3,4-四氬-3-甲基-1-(異 甲硫某 LL.5-bp比咬-.3-基甲基l-2,4-二羞分並r2 3-dl痛冷;: 酸甲酯 ^ 依實例37b)項產物製得。 MS (ES) 474 [M + H] + δ 'HCdci3〇.88-0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 3g (3H,s),3.66-3.68 (2H, d),4 (3H, s), 5.6 (2H, s),7.19.7 23 (1H,m),7.90-7.93 ( 1H,d),8.28-8.29 (1H, d)。 W 1,2,3,4-四氫-3-甲基-1-(異丁幕甲硫甚 f4,5-bl·»比淀-3-基甲基 1·2;4·二氧代-4 吩並 依實例22 c)項之製法,由實例37i a)項產物(4〇 mg)製: ,產生標題化合物。 MS (ES) 460 [M + H] + g) 5-「(4S)-4-羥基異哼唑啶某满某1-3-甲早 甲硫基)-3H -味吐並基甲等 啶·2.4ΠΗ.3Η)-二酮 依實例1 g)項之製法’由實例37i b)項產物製備。粗產物 經急驟矽石層析法純化,以3%甲醇之二氯甲燒溶液溶離後 175 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)1310036 a) 1,2,3,4-tetra-argon-3-methyl-1-(isomethyl sulfide LL.5-bp ratio bite-.3-ylmethyl l-2,4-di shy R2 3-dl pain cold;: acid methyl ester ^ obtained according to the product of example 37b). MS (ES) 474 [M + H] + δ 'HCdci3〇.88-0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 3g (3H, s), 3.66 -3.68 (2H, d), 4 (3H, s), 5.6 (2H, s), 7.19.7 23 (1H, m), 7.90-7.93 (1H, d), 8.28-8.29 (1H, d). W 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl methylthiol f4,5-bl·»pyram-3-ylmethyl1·2;4·dioxo The title compound was obtained from the product of Example 37 i a) (4 mg). MS (ES) 460 [M + H] + g) 5-"(4S)-4-hydroxyisoxazole pyridine, a certain 1-3-methyl-methylthio group)-3H - benzopyrene · 2.4ΠΗ.3Η)-dione according to the preparation of the method of Example 1 g) 'Prepared from the product of Example 37i b). The crude product was purified by flash quenching chromatography and dissolved in 3% methanol in dichloromethane. 175 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm)
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Μ 1310036 A7 B7 五、發明説明(172 ) ’與異己烷研磨’產生標題化合物之淺黃色固體(丨〇 mg)。 MS (ES) 53 1.1 583 [M+H] + δ 1Hcdci3 0.91-0.93 (6H, d), 2.17-2.26 (1H, m), 2.78-2.8 (3H, d), 3.36 (3H, s), 3.5-4.2 (6H,3m), 4.6-5 (2H, 3d), 5.43-5.74 (2H, m), 7.19-7.26 (1H, m), 7.9-7.93 (1H, d), 8.26-8.28 (1H, d) ° 實例3 8 二甲基-1H-吡唑 ~4-某甲某 l-w. A -%「(4S)-4-羥某-2-異g号唆咬基羰基μ!.(異丙基)邊岭並「^丄…喊遗-2,4ΠΗ,3Η)-Μ 1310036 A7 B7 V. Inventive Note (172) 'Polishing with isohexane' yields the title compound as a pale yellow solid ( 丨〇 mg). MS (ES) 53 1.1 583 [M+H] + δ 1Hcdci3 0.91-0.93 (6H, d), 2.17-2.26 (1H, m), 2.78-2.8 (3H, d), 3.36 (3H, s), 3.5 -4.2 (6H, 3m), 4.6-5 (2H, 3d), 5.43-5.74 (2H, m), 7.19-7.26 (1H, m), 7.9-7.93 (1H, d), 8.26-8.28 (1H, d) ° Example 3 8 Dimethyl-1H-pyrazole ~ 4- A certain lw. A -% "(4S)-4-hydroxyl-2-iso-g 唆 carbonyl thio group μ!. (isopropyl Base) Bianling and "^丄... shouting legacy-2, 4ΠΗ, 3Η)-
1,2,3,4-四氫-6 -甲某.卜(異丙基)·2ί4- $代-ρ实吩並「2,3- dl嘧啶-5-羧酸甲酿 取氰酸銀(丨3.5 g)懸浮於無水甲苯(9〇 ml)中,於氬氣下滴 加乙酿氯(5.34 ml)處理,激烈攪拌3〇分鐘。添加含實例8步 驟a)產物(23 g)之無水曱苯(15 ^1)溶液,混合物攪拌72小時 。添加謎(3 60 ml),濾出不溶物,以少量醚洗滌。合併之 有機溶液以飽和碳酸氫鈉溶液洗滌,脫水與蒸發。殘質經 曱醇鈉之曱醇溶液(25重量%,64 ml),於室溫下處理72小 _____- 176 - 本紙伕尺度適用中國國家標準(CNS) A4規格(21〇χ297公釐) 1310036 A7 B71,2,3,4-Tetrahydro-6-A. Bu (isopropyl)·2ί4-$-----"2,3- dl-pyrimidine-5-carboxylic acid (丨3.5 g) was suspended in anhydrous toluene (9 mL) and treated with hexanes (5.34 ml) dropwise under argon and stirred vigorously for 3 min.. Anhydrous benzene (15 ^1) solution was stirred and the mixture was stirred for 72 hours. The mystery (3 60 ml) was added, and the insoluble material was filtered and washed with a small amount of ether. The combined organic solution was washed with saturated sodium hydrogen carbonate solution, dehydrated and evaporated. Sodium sterol sodium sterol solution (25% by weight, 64 ml), treated at room temperature for 72 _____- 176 - Paper size is applicable to China National Standard (CNS) A4 specification (21〇χ297 mm) 1310036 A7 B7
時。反應於冰中冷卻,以三甲矽烷基氯(50 8 ml)處理,於 室溫下攪拌一夜。真空排除所有揮發物,殘質分佈在水與 乙酸乙酯之間。有機溶液脫水與蒸發後,殘質經層析 (Si〇2/2: 1異己燒-乙酸乙酉旨,然後3:2異己烷_乙酸乙酿 單離出小標題化合物(12.2 g)。 MS (ES) 283 [M+H] + 乱aj-甲基-1-CJi_aA)_2,4_二望抑办 並「2,3-dl嘧啶-5-淼甲酯 取a)項產物(0.5 g)、碳酸鉀(0.34 g)、乙基碘(〇n ml)、 DMF (5 m丨)與丙酮(5 ml)於50t下加熱16小時。反應混合物 加水(5 ml)中止反應後,以乙酸乙酯萃取。有機萃液脫水 (MgS〇4) ’真空濃縮。殘質經層析(SicV8 :丨:1異己燒-乙 酸乙醋_二氯甲燒)’產生小標題化合物之淺黃色油狀物。 5'HCDC131.23(3H,t), 1.59(6H,m),2.4 (3H, s), 3.95 (3H, t), 4.01-4.06 (2H,q), 4.6-4.8 (1H, m)。 基-1,2,3,4-四氫基)-2.4-二望代-嚯吩並「2,3-dl嘧啶-5-斿酸甲酯 依實例22 a)項之製法,由b)項產物製備小標題化合物。 MS (ES) 327 [M + OH-Br] + d) β-「3,5-二甲某-1H-吡唑-4-某甲某,, π | -1,2 3 4_四 H 4 L晷丙基)-2,4·^氧代-4吩並[2,3-dl遑^甲酯Time. The reaction was cooled with ice, EtOAc (EtOAc)EtOAc All volatiles were removed by vacuum and the residue was partitioned between water and ethyl acetate. After dehydration and evaporation of the organic solution, the residue was chromatographed (Si 〇 2/2: 1 iso-hexane-acetic acid ethyl acetate, then 3:2 isohexane-acetic acid ethyl acetate to give the subtitle compound (12.2 g). ES) 283 [M+H] + chaos aj-methyl-1-CJi_aA)_2,4_2 hope and "2,3-dl pyrimidine-5-fluorenylmethyl ester a) product (0.5 g) Potassium carbonate (0.34 g), ethyl iodide (〇n ml), DMF (5 m丨) and acetone (5 ml) were heated at 50 t for 16 hours. The reaction mixture was added with water (5 ml) to terminate the reaction. Ester extraction. Dehydration of organic extracts (MgS 〇 4) 'Concentration in vacuo. Residues were chromatographed (SicV8: 丨:1 hexanes-ethyl acetate-dichloromethane). 5'HCDC131.23(3H,t), 1.59(6H,m),2.4 (3H, s), 3.95 (3H, t), 4.01-4.06 (2H,q), 4.6-4.8 (1H, m) Base-1,2,3,4-tetrahydro)-2.4-dioxin- phenanthrene "2,3-dl pyrimidin-5-decanoate methyl ester according to the method of Example 22 a), by b Preparation of the subtitle compound. MS (ES) 327 [M + OH-Br] + d) β- "3,5-dimethyl-1H-pyrazole-4-one A, π | -1 , 2 3 4_tetra H 4 L晷propyl)-2,4·^oxo-4 Benzo[2,3-dl遑^ methyl ester
依實例26 a)項之製法,由c)項產物製 H 〃知備小標題化合物。 MS (ES) 334 [M + H] + e) 6-[3,5-二甲某-1H-吡唑-4-基甲某In,讨c「 -177 - 本紙張尺度適用中國國家標準(CNS) A4规格(21〇X 297公釐) 1310036 A7 B7 五、發明説明(174 ) 2-異呤唑啶基羰某M-f昱雨基嘧啶-2,4(l^L3Hk 二i同 取d)項產物(0.6 mmol)、氯鱗酸二乙酯(0.09 ml)、1-經基 笨並三唑(0.08 g)、三乙胺(0·1 ml)與乙腈(6 ml)攪拌30分鐘 。添加實例1,b)項產物,混合物攪拌16小時。添加碳酸鉀 中止反應。反應混合物經Si〇2層析法,以THF :甲醇(98 : 2)溶離,產生黃色泡沫狀物,再經逆相HPLC純化,產生小 標題化合物之白色固體(30 mg)。 δ 1H〇mso 1.06-1.18 (3H, m), 1.41-1.53 (6H, m), 2.1 (6H, s), 3.42-4.18 (7H, m),4.3-4.47 (1H, s),4.63-4.8 (1H,m)與 5.5 (1 H,m)。 實例39 5-「(4S)-4-與某異呤唑啶某羰基1-3-甲基-1-(異丁某)-6-Γ2-( -氟甲某)苽甲某吩#『2.3-dl嘧啶-2,4ΠΗ,3Η)-二酮According to the method of Example 26 a), the sub-title compound is prepared from the product of item c). MS (ES) 334 [M + H] + e) 6-[3,5-dimethyl-1H-pyrazole-4-yl-methyl-In, discuss c"-177 - This paper scale applies to Chinese national standards ( CNS) A4 size (21〇X 297 mm) 1310036 A7 B7 V. Description of invention (174) 2-Isooxazolidinylcarbonyl A Mf hydrazinyl-2,4 (l^L3Hk II i taken d) The product (0.6 mmol), diethyl chlorophosphate (0.09 ml), 1-pyridyltriazole (0.08 g), triethylamine (0.11 ml) and acetonitrile (6 ml) were stirred for 30 min. The product of Example 1, b) was added, and the mixture was stirred for 16 hours. The reaction was quenched by the addition of potassium carbonate. The reaction mixture was subjected to EtOAc (MeOH:MeOH) eluting with EtOAc:MeOH (98:2). Purification by phase HPLC to give the title compound as a white solid (30 mg). δ 1H 〇mso 1.06-1.18 (3H, m), 1.41-1.53 (6H, m), 2.1 (6H, s), 3.42-4.18 (7H , m), 4.3-4.47 (1H, s), 4.63-4.8 (1H, m) and 5.5 (1 H, m). Example 39 5-((4S)-4- with certain isoxazole carbonyl 1 -3-methyl-1-(isobutyl)-6-Γ2-(-fluoromethyl) 苽甲某”#2.3-dl-pyrimidine-2,4ΠΗ,3Η)-dione
幻1,2,3,4-四ϋ. -3-甲某-1-(異丁基)-2,4-二氳代-6-「2-(三氟甲 基)笨甲某h窠吩並f2,3-dl嘧啶-5-羧酸 在含5-溴-3-甲基-1-(異丁基)-6-[2-(三氟曱基)苯甲基]嘍吩 並[2,3-d]嘧啶-2,4(1H,3H)-二酮(WO 01 83489)之 THF (60 ml) __- 178 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1310036 A7 ___B7 ΐ、發明説明(175 ) 溶液中’於ot與氮氣下滴加異丙基鎂化氯(2M THF溶液’ j . 3 5 m丨)。5分鐘彳反,以一氧化碳氣流處理混合物I 〇分鐘。加 水中止反應混合物之反應’以2N HC1酸化,以乙酸乙酯(x3) 萃取。合併之有機萃液以稀HC1與鹽水洗滌,脫水(MgS04) 及真2濃縮’產生小標題化合物之黃色固體(2.48 g)。 MS (ES) 441 [M + H] + b) 5-f(4S)-4-|j基異4吐啶基羰某I·%〒某異丁某 二齓甲基)笨曱基1峰吩並「2,3-d]p密p含-2,4ΠΗ,3Η) -二酉同 依實例1 g)項之製法,由a)項產物製備。 MS (APCI) 512 [M + H] + δ 'Hdmso 0.8 (6H,m),2.1 (lH,pentet),3.2 (3H, m),3.5-3.8 (4H, m), 4.2 (2H, m), 4.6-4.7 (1H, m),5.5 (1H, m),7.5 (2H, m),7.6 (1H, t)與 7.8 (1H, d)。 實例40 5-「(45)-4-經基-2-異°号吨症基幾基1-3-甲等-1-(異丁基)-6-「2-[_甲硫基)-1Η-咪唑-1-基甲基1-4吩並嘧啶-2,4ΠΗ,3Η)-Magic 1,2,3,4-four. -3-A certain-1-(isobutyl)-2,4-diindole-6-"2-(trifluoromethyl) The phenantho-f2,3-dl-pyrimidine-5-carboxylic acid is contained in 5-bromo-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)benzyl] phenanthrene [2,3-d]pyrimidine-2,4(1H,3H)-dione (WO 01 83489) in THF (60 ml) __- 178 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 ___B7 ΐ, invention description (175) In solution, add isopropylmagnesium chloride (2M THF solution 'j. 3 5 m丨) under ot and nitrogen. 5 minutes 彳, with carbon monoxide The mixture was treated with a stream of air for 1 minute. The reaction of adding the water to the reaction mixture was acidified with 2N HCl and extracted with ethyl acetate (x3). The combined organic extracts were washed with dilute HC1 and brine, dehydrated (MgS04) and concentrated. Subtitle compound of yellow solid (2.48 g) MS (ES) 441 [M + H] + b) 5-f(4S)-4-|j-iso- 4-pyridyl carbonyl some I·%〒一丁丁A diterpene methyl group) awkward base 1 peak is arbitrarily "2,3-d]p dense p contains -2,4 ΠΗ,3 Η) - bismuth is prepared according to the method of item 1 g), which is prepared from product a) MS (APCI) 512 [M + H] + δ 'Hdmso 0.8 (6H, m), 2.1 (lH, pentent), 3.2 (3H, m), 3.5-3.8 (4H, m), 4.2 (2H, m), 4.6-4.7 (1H, m), 5.5 (1H, m), 7.5 (2H, m), 7.6 (1H, t) and 7.8 (1H, d). Example 40 5-((45)-4-Iperyl-2-iso-ton 1-1-3-methyl-1-(isobutyl)-6-"2-[-methylthio)-1Η-imidazol-1-ylmethyl1-41-4-phenanthrimidine-2,4ΠΗ,3Η) -
这)1,2,3,4 -四氫-3 -甲某-1-(異丁基)-6-「2-f甲硫基)-lH -咪吐- ___- 179 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1310036 A7 B7This) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-"2-f-methylthio"-lH-mpy- ___- 179 - This paper size applies China National Standard (CNS) Α4 Specifications (210 X 297 mm) 1310036 A7 B7
1 -棊甲棊:L2,4-_^氧代蒸吩並「2,3^1嘧啶_s_跆醢甲酿 依實例13vi a)項之製法,由實例3…項產物與2_甲硫基咪 唑製備,產生小標題化合物。 MS (ESI) 423 [M + H] +1 - 棊甲棊: L2,4-_^ oxo-deuterated "2,3^1 pyrimidine _s_ 跆醢 酿 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例Preparation of the thioimidazole to give the subtitle compound MS (ESI) 423 [M + H] +
丨-碁甲棊丄氧代-喧吩並「2,3-41遗_咬-5-勒ΒΦ 依實例3 d)項之製法,由a)項產物製備。 MS(ESI) 409 [M + H] + c) 5-K4Sk4-幾U-異吟唑立基幾玉上}甲基小⑦丨-碁甲棊丄 代-喧 并 "2,3-41 _ _ _ _ _ Β Φ Φ according to the method of Example 3 d), prepared from the product of item a) MS (ESI) 409 [M + H] + c) 5-K4Sk4-Several U-isoxazole 立基几上上}Methyl small 7
依實例3 e)項之製法,由b)項產物製備。 MS (APCI) 480 δ 屮⑽so 0.89-0.91 (6H,m),2.11-2.18 (1H,m),2.49·2 52 (3H m), 3.2-3.21 (3Η,m),3_52-4·1 (6Η,m), 4.62-4 78 (1Η 5.23-5.25 (2H, m), 5.5-5.58 (1H, m), 6.97 (1H,d)與7 21-7 23 (1H, m) ° ’ -180 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) ' 一--------Prepared from product b) according to the method of Example 3 e). MS (APCI) 480 δ 屮(10)so 0.89-0.91 (6H,m),2.11-2.18 (1H,m),2.49·2 52 (3H m), 3.2-3.21 (3Η,m),3_52-4·1 ( 6Η,m), 4.62-4 78 (1Η 5.23-5.25 (2H, m), 5.5-5.58 (1H, m), 6.97 (1H,d) and 7 21-7 23 (1H, m) ° ' -180 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) '一--------
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