TWI378923B - Pyrimidine derivatives - Google Patents
Pyrimidine derivatives Download PDFInfo
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- TWI378923B TWI378923B TW093124290A TW93124290A TWI378923B TW I378923 B TWI378923 B TW I378923B TW 093124290 A TW093124290 A TW 093124290A TW 93124290 A TW93124290 A TW 93124290A TW I378923 B TWI378923 B TW I378923B
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- 150000003230 pyrimidines Chemical class 0.000 title description 2
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 165
- -1 trans group Chemical group 0.000 claims description 162
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- 150000001412 amines Chemical class 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 239000007789 gas Substances 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 35
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000005842 heteroatom Chemical group 0.000 claims description 28
- 150000002431 hydrogen Chemical group 0.000 claims description 28
- 125000003277 amino group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 17
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
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Description
丄《378923 九、發明說明: 【發明所屬之技術領域】 本發明係關於新穎嘧啶衍生物、彼等之製備方法、彼等 作為藥劑之用途及含有彼等之醫藥組合物。 【先前技術】 以下文獻曾討論FAK抑制劑。W0 03/018021-本發明包 括2,4-二取代嘧啶基衍生物及其醫藥上可接受鹽,醫藥組 β物’用途及預防與治療癌症之方法❶w〇 〇〇/391〇1敘述 作為抗癌劑之經取代嘧啶。w〇 97/19〇65敘述作為激酶抑 制劑之2-1苯胺基嘧啶。
Ghosh等人作為抗黴菌之"2,4•雙(芳胺基)_5•甲基嘧啶"; J· Med. chem.,1967, ν〇1· 1〇, ν〇· 5, pp. 974-975。 【發明内容】 更特定言之,在本發明的第一個觀點中提供式丨化合物
其中 每一個RQ、R R2及R3係獨立為氫、CrC8烷基、(:2-〇8烯 基、c2-c8炔基、(:3-(:8環烷基、C:3_C8環烷基 基、C5-C1G芳基Ci-Cs院基、經基Ci_c8烧基、Ci_c8烷氧 基(^-(:8烷基、胺基CtC:8烷基、鹵基烷基、未經取 代或經取代之C5-C1()芳基 '未經麥代或經取代之含有J、 95245.doc 1378923 2或3個選自N、0及S之雜原子的5或6員雜環基、羥基、 CrCs烷氧基、羥基Cl_Cs烷氧基、CiC8烷氧基。—^烷 氧基、鹵基G-C8烷氧基、未經取代或經取代之c5_Ci〇芳 基(^-(:8烷氧基、未經取代或經取代之雜環氧基、或未 經取代或經取代之雜環基Ci_Cs院氧基、未經取代或經 取代之胺基、Ci-C8烷硫基' Ci_C8烷基亞硫醯基' Ci_Cs 烷基磺醯基、C5_ClG芳基磺醯基、鹵素、羧基、Ci_C8烷
氧幾基、未經取代或經取代之胺甲酿基、未經取代或經 取代之胺磺醯基'氰基或硝基; 或R0及R1,!^1及R2,及^ 久/ :¾ R及R和與彼等附著之碳原子 一起形成含有〇、1、田,强& 2次3個選自N、〇及S之雜原子的5 或6員碳環系或雜環系環; R4係氫或Ct-Cs烧基; 每一個係獨立為$ 烷基、邊^基、Ci_C8烷氧基 CVCs烷氧基CVCs ^意、竣基、C「Cs
烧氧幾基、未經取代或經取代之胺甲醯了、氰基或硝基; 每一個R7、R8、R、R1°係獨立為(V⑽、C2-C8烯基、 C2 炔基' C3_C8環炫基、我基Ci_c成基、c” 10芳土 Cl C8燒基、經基Cl'C8貌基、CVCs貌氧基Cj-Cs 、-土胺基C! c8貌基、齒基Ci_c8院基、未經取代或經 取代之5 C1〇芳基、未經取代或經取代之含有1、2或. ^ ^ 及S之雜原子的5或6員雜環基、羥基、c丨·c8 炫氧基、經基C丨-η I h烷乳基、cvc8烷氧基cvq烷氧基、 鹵基 C|-C8^ 氣其、, 土 未!取代或經取代之c5-c10芳基C丨- 95245.doc 1378923 c8烷氧基、未經取代或經取代之雜環氧基、或未經取代 或經取代之雜環基CA统氧基、未經取代或經取代之 土 1 Cs烷石爪基、C丨-Cs烷基亞硫醯基、C丨-c8烷基磺 酿基、c5-Cl0芳基續酿基.、㈣、.敌基、Ci C8燒氧幾 基、未經取代或經取代之胺甲醯基、未經取代或 之胺賴基、氰基或德,其中r7、r8&r9彼此也可以 獨立係氫;
或R7及R8, R8及R'及/dRl。和與彼等附著之碳原子 一起形成含有0、i、2或3個選自N、〇及3之雜原子的5 或6員碳環系或雜環系環; % C或N,以C最佳; 及其鹽類。 在上下文所使用的通用術語以具有以下在本揭示内容範 圍内的意義較佳’除非有其它另外的指示: 在使用複數形式的化合物、鹽及類似物時,也代表單一 化合物、鹽或類似物。 任何不對稱碳原子可以(R)_、(s)_或(R,S)組態存在,以 (R)-或(S)-組態較佳。化合物於是可以異構物之混合物或 純異構物存在,以對映異構物-純非對映異構物較佳。 本發明也關於式I化合物可能的互變體。
Ci-Cs烧基代表具有從1至多達8個碳原子之烷基,尤其 係多達4個碳原子,在討論中的基係或直鏈或以一或多個 支鏈支化,Ci-Cs烧基係以丁基(如正丁基、第二丁基、異 丁基、特丁基)、丙基(如正丙基或異丙基)、乙基或甲基較 95245.doc 1378923 佳’尤其係曱基、丙基或特丁基。 C2_cs烯基代表具有從2至多達8個碳原 係多達5個碳原子,在討論中的基係或直:基,尤其 支鏈支化,㈣烯基係以戊婦基(如 或多個 …稀基丁稀基或2· 丁缔.2·二 丙烯基或烯丙基)或乙烯基較佳。 土 以块基代表具有從2至多達8個碳原子之块 宜 係多達5個碳原子,在討論中的基係或直鏈或支鏈c ^ 块基係以丙絲(如卜丙块基或炔丙10或乙炔基M / S C3-CS環烷基代表具有從3至多達8個碳原子之環产基 如?丙基、環丁基、環戊基、環己基、環庚基或環::, 以核丙基、環戊基或環己基較佳。 /i-c8烷氧基尤其係甲氧基 '乙氧基、異丙氧基或特丁 氧基。 羥基c,-c8烧基尤其係經甲基、2_經乙基或2•經基_2_丙基。 經基CrCs烷氧基尤其係2_羥乙氧基或3_羥丙氧基。 C!-C8烷氧基Cl_Cs烷氧基尤其係2甲氧基乙氧基。
Ci-C8烷氧基Cl_Cs烷基尤其係甲氧基甲基、2_甲氧基乙 基或2-乙氧基乙基。 鹵素係以氟、氣、漠或蛾較佳,尤其係氣、氣或漠。 鹵基CrC8烷基係以氯基Ci-Cs烷基或氟基Ci_c8烷基較 佳’尤其係三氟f基或五氟乙基。 ώ基C丨-cs烷氧基係以氣基〇1_〇8烷氧基或氟基Ci_C8烷氧 •基較佳’尤其係三氟尹氧基。 95245.doc 1378923 C^-Cs烷氧羰基尤其係特丁氧羰基、異丙氧羰基、甲氧 羰基或乙氧羰基。 未經取代或經取代之胺甲醯基係以一或兩個選自氫、 CVCs 炫基、c2-c8 稀基、c2_c8 炔基、c3_c8 環炫^ 基、c3_c8 環烷基CVCs烷基、C5-C1()芳基Ci-Cs烷基、羥基(^-(^烷 基' CnC:8烧氧基CVC8烷基、鹵基Ci-C8炫:基、未經取代或 經取代之C5_C1()芳基或胺基CkCs院基的取代基取代之胺甲 醯基,或係其中取代基或胺甲醯基的氮原子代表進一步包 含0、1或2個選自N、〇及s之雜原子的5或6員雜環基之胺 甲醯基;並以胺甲醯基、甲基胺甲醯基、二曱基胺曱醯 基、丙基胺曱醯基、羥乙基甲基胺甲醯基 '二(羥乙基)胺 甲醯基、二曱基胺基乙基胺甲醯基、或吡咯烷羰基、六氫 吡啶羰基、N-曱基六氫吡啩羰基或嗎啉代羰基較佳,尤其 係胺曱醯基或二曱基胺甲醯基。 未經取代或經取代之胺績8¾基係以一或兩個選自氩、 Ci-Cs院基、C2-Cg稀基、C2-C8炔基、C3-Cs環炫基、C3-C8 環烷基Ci-C8烷基、C5-C1()芳基(VC8烷基、羥基(^_(:8烷 基、Ci-Cs烧氧基Ci-Cg烧基、鹵基Ci-Cs烧基、未經取代或 經取代之C5-Ci〇芳基或胺基C「CS烷基的取代基取代之胺磺 醯基,或係其中取代基或胺績醢基的氮原子代表進一步包 含0、1或2個選自N、〇及s之雜原子的5或6員雜環基之胺 磺醯基;並以胺磺醯基、甲基胺磺醯基、丙基胺磺醯基、 環丙基甲基胺石黃酿基、2,2,2·二乳乙基胺石夤酿基、二曱基 胺基乙基胺磺醯基、二甲基胺磺醯基 '羥乙基甲基胺磺醯 95245.doc 10 1378923 基、二(羥乙基)胺磺醯基、或吡咯烷磺醯基、六氫吨咬 橫醯基、N-甲基六氫°比畊續酿基或嗎淋代續醯基較佳’尤 v 其係胺磺醯基或甲基胺磺醯基。 r 未經取代或經取代之胺基係以一或兩個選自氫、CrCs 烧基、C2-C8缔基、C2-C8炔基、C3-C8環烧基' C3-C8環炫 基Ct-Cg烧基、C5-C10芳基Ci-Cg烧基、經基Ci-Cs烧基、Ci_ C8烷氧基Ci-Cs烷基、鹵基Ci-Cs烷基、未經取代或經取代 I 之C5-C10芳基、胺基CrCs烷基、醯基(例如,甲醯基)、Ci-c8烷羰基、C5-C1()芳羰基、C^-Cs烷基磺醯基或c5-c1()芳基 磺醯基之取代基取代之胺基;並以胺基、甲基胺基、二曱 基胺基、丙基胺基、苄基胺基、羥乙基甲基胺基、二(羥 乙基)胺基、二甲基胺基乙基胺基、乙醯基胺基、乙醯基 曱基胺基、苯醯基胺基、甲基磺醯基胺基或苯基磺醯基胺 基較佳,尤其係胺基或二甲基胺基。 胺基Ci-Cs烧基尤其係胺基乙基、甲基胺基乙基、二甲 Φ 基胺基乙基或二甲基胺基丙基。 未經取代或經取代之Cs-Cw芳基係例如苯基、茚基、茚 滿基、萘基或1,2,3,4-四氫萘基,視需要以c丨_c8烷基、C「 C8烧氧基CVCs烷基、鹵基Ct-Cs烷基、羥基、ct-C8烷氧 基、曱二氧基、胺基、經取代之胺基 '函素、羧基、Cl· Cs烷氧羰基、胺甲醯基、胺磺醯基、氰基或硝基取代,以 ,苯基、甲笨基、三氟甲基笨基、甲氧基苯基、二曱氧基苯 ,基、甲一氧基笨基、氣笨基或溴笨基較佳,因此取代基可 在鄰饵、間位或對位,以間位或對位較佳。 95245.doc 1378923 C5-C1G芳氧基尤其係苯氧基或甲氧基苯氧基,例如,對_ 甲氧基苯氧基° % C5_C10芳基Ci-Cs烷基尤其係苄基或2_苯基乙基。 、 Cs-Cio芳基Cl-Cs烷氧基尤其係苄氧基或2-苯基乙氧基。 未經取代或經取代之含有1、2或3個選自N、Ο及S之雜 原子的5或6員雜環基可以係不飽和、部份不飽和或飽和, 進一步濃縮成本并基或5或6貝雜環基,並可經由雜原子或 I 碳原子結合’並係例如吡咯基、吲哚基、吡咯烷基、味唾 基、苯并咪唾基、吡唑基、三唑基、苯并三唑基、四嗤 基、吡啶基、喹啉基、異喹啉基、12,3,4•四氩喹啉基、 六氫吼咬基、嘧啶基、吼畊基、六氫吡畊基、嘌呤基、四 11井基、°惡°坐基、異°惡基、嗎琳基、U塞唾基、苯并嚷。坐基、 噁二唑基及苯并噁二唑基。考慮的取代基係Ci_C8烷基、 經基CVCs烧基、CrCs烧氧基CVCs烷基、c^-Cs烷氧基C「C8 炫•氧基、鹵基eves烧基、經基、胺基、經取代之胺基、Ci· • Cs烷氧基、齒素、羧基、Ci-Cs烷羰基、匕/8烷氧羰基、胺 曱醯基、Ci-C8烷基胺甲醯基、氰基、氧基或在該段落定 義之未經取代或經取代之5或6員雜環基。5或6員雜環基係 以包含1或2個選自N、〇及S之雜原子較佳,並尤其係吲哚 基、吡咯烷基、吡咯烷酮基、咪唑基、N_曱基咪唑基、笨 并咪唑基、S,s-二氧基異噻唑烷基、六氫吡啶基、4_乙醯 " 基胺基六氩咄啶基、4_甲基胺曱醯基六氫吡啶基、4_六氫 吡啶并六氫吡啶基、4_氰基六氫吡啶基、六氫吡畊基、N_ 曱基六氩吡喷基、N-(2-羥乙基)六氫吡畊基、嗎啉基、u 95245.doc -12- 1378923 氮雜-2,2-二氧基_2_硫雜環己基或硫哮基㈣。㈣)。
在未經取代或經取代之雜環氧基I雜環基具有如以上 定義之意義,並尤其係N-甲基·4·六氫。比啶氧基。在未唾 取代或經取代之雜環基CVW氧基中,雜環基具有如以 上定義之意義,並尤其係2_吡咯烷基乙氧基、2·嗎啉代乙 氧基、3·嗎琳代丙氧基、h甲基六氫吼心基甲氧基、% (N-甲基六氫Μ基)丙氧基或2_〇_蜂嗤基)乙氧基。 在含有〇、1、2或3個選自Ν、〇及3之雜原子及以兩個鄰 接的取代基與苯環一起形成的5或6員碳環系或雜環系環 中,可將環進一步取代,例如,以Ci_Cs烷基' c〖_c8烷氧 基、鹵基CrCs烷基、羥基、胺基、經取代之胺基、Ci_c8 烷氧基、鹵素、羧基、CrC8烷氧羰基、胺甲醯基、氰基 或氧基。形成這種環的兩個鄰接的取代基係以丙撐、丁 撐、1-氮雜-2·丙又、3-氮雜-1-丙叉、丨,2_二氮雜_2_丙又、 2,3-二氮雜-1-丙叉、1-氧雜丙撐、丨·氧雜丙叉、甲二氧 基、二氟基曱二氧基、2-氮雜_1_氧丙撐、2·氮雜_2_甲基^ 1-氧丙撐、1-氮雜-2-氧基丙撐、2-氮雜-ΐ,ι·二氧基_ι_硫雜 丙撐或形成6員環之對應的丁撐衍生物。 鹽類尤其係式I化合物在醫藥上可接受之鹽類。 以具有驗性氮原子之式I化合物形成這些鹽類,例如, 成為較佳係具有機或無機酸之酸加成鹽,尤其係成為在醫 藥上可接受之鹽類。適合的無機酸係例如鹵素酸(如氫氯 酸)、硫酸或磷酸。適合的有機酸係例如羧酸、膦酸、磺 或胺基續酸’例如,醋酸、丙酸、辛酸、癸酸、十二烧 95245.d〇, -13- 1378923 酸、乙醇酸、乳酸、富馬酸、號ίό酸、己二酸、庚二酸、 辛二酸、壬二酸 '蘋果酸、酒石酸、檸檬酸、胺基酸(如 谷胺酸或天冬胺酸)、馬來酸、羥基馬來酸'甲基馬來 * s 酸、環己烧羧酸、金鋼烧缓酸、苯甲酸、水揚酸、4-胺基 水楊酸、駄酸、本基醋酸、扁桃酸、肉桂酸、甲烧_或乙 院-績酸、2 -超基乙烧績酸、乙烧-1,2 -二續酸、苯續酸、2_ 萘磺酸、1,5-萘二磺酸、2-、3-或4·甲基笨磺酸、甲基硫 φ 酸、乙基硫酸、十二烷基硫酸、N-環己基胺基磺酸、n-甲 基-、N-乙基-或N-丙基-胺基績酸或其它有機質子酸(如抗 壞血酸)。 以分離及純化為目的,也有可能使用在醫學上不可接受 之鹽類,例如,苦味酸鹽或高氣酸鹽。以治療應用而言, 八使用在醫藥上可接受之鹽類或自由化合物(在適用醫藥 製劑形式時),因此以這些最理想。 有鑑於自由形式的新穎化合物與那些具有彼等鹽類形式 • 的化合物(包括在例如純化或確認新穎化合物時可用作中 門物的那些化合物)之間緊密的關係,故在適當及得宜 時,當然也可將在上下文任何述及的自由化合物稱為對廡 的鹽類。 ~ 式1化合物具有價值的藥理特性,如上下文所述。 在式I中,以下單獨、集體或在任何組合或副組合 義最理相 — ^ 心。在每一個以下的意義中,A係C或n,以c較佳: ()每—個R0或R2係獨立為氫、Ci_Cs烷基(例如,甲基、 基或異丙基)、羥基C! -Cs烧基(例如,經乙基或輕丁 95245.doc -14- 1378923
基)、產基cvC8炫基(例如,三氟甲基)、未經取代或經 取代之c5-cl0芳基(例如,苯基或甲氧基笨基)、未經取 代或經取代之含有“戈2個選自N、〇及3之雜原子的5或 6員雜環基(例%,嗎啉代、六氫吡啶基、六氫吡畊基 或N-f基六氫心井基)、以8烧氧基(例如,甲氧基、 乙氧基或異丙氧基)、南基C丨-c8烷氧基(例如,三氟甲 氧基)、C5-C10芳氧基(例如,笨氧基)、未經取代或經
取代之雜環氧基(例如,丨_甲基·4·六氫吡啶氧基未 經取代或經取代之雜環基Ci_Cs烷氧基(例如,2_(1•咪 »坐基)乙氧基、3-嗎琳代丙氧基或2_嗎琳代乙氧基)、未 經取代隸取代之絲(例如,f基絲、:甲基胺基 或乙酿基胺基)、Cl_C8院基續酿基(例如,曱基續醒 基)、鹵素(例如,a基或氣基)、未經取代或經取代之胺 甲酿基(例如’環己基胺甲酿基、六氫。比錢基、六氫 心井幾基、ν·甲基六氫%料基或嗎似録)、未經 取代或經取代之胺磺醯基(例如, §藍基或二f基胺磺醯基);以氫、 胺績醯基、.甲基胺績 六氫吡啩基、N-.甲基
六氫吡畊基或1-曱基-4-六 (b) R1係氩、Κ8烷基(例如 氫°比啶氧基較佳,特別係氫; 曱基、乙基或異丙基)、經 基CVC8烧基(例如,羥乙基或羥丁基)、齒基Ci_c成基 (例如’三氟甲基)、未經取代或經取代之c5_c〗。芳其 (例如,苯基或甲氧基苯基)、未經取代或經取代之含 如’嗎琳代、六氫口比咬基、‘鸟 ^ 、虱0比畊基或N-甲基 95245.doc -15- 1378923 二井基)、Cl_c8烧氧基(例如,甲氧基、乙氧基或異丙 .· ^基)、卣基011-08烷氧基(例如,三氟甲氧基)、c5_Clc • 芳氧基(例如,苯氧基)、未經取代或經取代之雜環氧 • 基(例如,甲基_4_六1°比咬氧基)、未經取代或經取 代之雜裱基01,8烷氧基(例如,2-(1-咪唑基)乙氧基、 '馬琳代丙氧基或2_嗎琳代乙氧基)、未經取代或經取 代之胺基(例如,曱基胺基、二甲基胺基或乙酿基胺 • 基)、Cl-Cs烷基磺醯基(例如,甲基磺醯基)、鹵素(例 如,氟基或氣基)、未經取代或經取代之胺甲醯基(例 如環己基胺甲醯基、六氫。比啶羰基、六氫。比啩羰 基、N-甲基六氫吼啩羰基或嗎啉代羰基)、未經取代或 經取代之胺磺醯基(例如,胺磺醯基、甲基胺磺醯基或 二甲基胺磺醯基);以氫、六氫。比畊基、N_曱基六氫〇比 畊基、1-曱基-4-六氫吡啶氧基、3_嗎啉代丙氧基或2_ 嗎琳代乙氡基較佳,特別係氫; • (C) R3係氫、Ci-Cs烷基(例如,甲基或乙基)、羥基(^(^烷 基(例如,羥乙基或羥丁基)、鹵基Ci_c8烷基(例如,三 氣甲基)、未經取代或經取代之含有1或2個選自N、〇 及S之雜原子的5或6員雜環基(例如,2-β比η各院嗣基或 S,S-二氧基異噻唑烷基)、Cl-C8烷氧基(例如,甲氧 基)、經取代之胺基(例如,乙醯基胺基、乙醯基-甲基_ 胺基、苯醯基胺基、甲基磺醯基胺基或苯基磺醯基_胺 .基)、Ci-Cs烷基磺醯基(例如,甲基磺醯基)、c5_Ci〇芳 基磺醯基(例如’苯基磺醯基)、鹵素(例如,氟基或氣 95245.doc -16. 1378923 基)、羧基、經取代或未經取代之胺曱醯基(例如,胺 甲醯基、曱基胺甲醯基或二甲基胺甲醯基)、未經取代 或經取代之胺磺醯基(例如,胺磺醯基、甲基胺磺醯 基' 丙基胺磺醯基、異丙基胺磺醯基、異丁基胺磺醯 基、環丙基甲基胺磺醯基、2,2,2-三氟乙基胺磺醯基、 二甲基胺磺醯基或嗎啉代磺醯基);以胺磺醯基、甲基 胺續酿基或丙基胺續酿基較佳; (d) 每一鄰接的取代基配對及Rl,或Rl及R2,或R2及R3 係-0112->111-0:0-、-(:112-(:112->111-(:0-、-(:112-(:0-丽-' -CH2-CH2-CO-NH- ' -CH2-NH-SO2- ' -CH2-CH2-NH- S〇2- ' -CH2-SO2-NH- ^ -CH2-CH2-S〇2-NH- ' -CH2-CH2- S〇2- ' -CH2-CH2-CH2-S02- ' -〇-CH2-0-或-0-CF2-0-及 其中將在NH中的氫以CrCs烧基置換的這些配對;鄰 接的取代基配對RQ及R1,或R1及R2係以_0,ch2_0·較 佳’及鄰接的取代基配對R2及R3係·CjjyNH-co•或_ CH2-NH-S〇2 -幸交佳; (e) R係虱或C丨-Cs燒基(例如,甲基);以氫較佳; (f) R5係氫、C「C8烷基(例如,曱基或乙基)、鹵素(例如, 氣基或溴基)、鹵基CrC8烷基(例如,三氟甲基)、氰基 或硝基;以氫、甲基、乙基、氯基、溴基、三氟甲基 或硝基較佳;特別係氣基或溴基; (g) R6係氫; (h) 每一個R7及R9係獨立為氫、Ci_C8烷基(例如,曱基、 乙基或異丙基)、羥基Ci_Cs烷基(例如,羥乙基或羥丁 95245.doc -17- 基)、MCVC成基(例如,三氟f基)、未經取代或經取 代之C5-Cf。芳基(例如,笨基或?氧基笨基)、未經取代 S!經取代之含有1或2個選自N、〇及S之雜原子的5或6 貝雜環基(例如,嗎啉代、六氫吡啶基、六氫》"基或 N-甲基六氫吡令基)、Cl_Cs烷氧基(例如,甲氧基、乙氧 基或異丙氧基)、^Cl.C成氧基(例如,三氣甲氧基)、 ^ ClG方氧基(例如’苯氧基)、未經取代或經取代之雜環 虱基(例如,1_甲基·4-六氫吡啶氧基)、未經取代或經取 代之雜環基(VC8烧氧基(例如,2_(卜米嗤基)乙氧基、3_ 嗎琳代丙氧基或2•嗎琳代乙氧基)' 未經取代或經取代 之胺基(例如,甲基胺基、二f基胺基或乙醯基胺 基)、G-C8烷基磺醯基(例如,甲基磺醯基)、函素(例 如,氟基或氣基)、未經取代或經取代之胺甲醯基(例 如,環己基胺甲酿基、六氫。比。定艘基、六氣π比喷幾 基、N-甲基六氫。比。井幾基或嗎淋代幾基)、未經取代或 經取代之胺磺醯基(例如,胺磺醯基、甲基胺磺醯基或 二曱基胺磺醯基);以氫、甲基、異丙基、三氟曱基' 苯基、甲氧基苯基、六氫D比啶基、六氫。比畊基、N—甲 基六氫吼畊基、嗎啉代、甲氧基、乙氧基、異丙氧 基、苯氧基、3-嗎啉代丙氧基、2,嗎啉代乙氧基、2_(1_ 咪唑基)乙氧基、二甲基胺基、氟基、嗎啉代羰基 '六氫 吡啶羰基、六氫吡啩羰基或環己基胺曱醯基較佳; R8係氫、CkCs烷基(例如,曱基、乙基或異丙基)、羥 基CrCs烷基(例如,羥乙基或羥丁基)' 鹵基Cl。烷基 •18· 1378923 (例如,三款甲基)、C5_Ci。芳基(例如,苯基或甲氧基 苯基)、未經取代或經取代之含有1或2個選自 之雜原,的5或6員雜環基(例如,嗎琳代、六氯η比啶 基、六氫吼啡基或Ν-甲基六氫❸井基)、Ci_Cs院氧基 (例如f氧基、乙氧基或異丙氧基)、齒基院氧 基(例如,三氟甲氧基)、c5-Cl0芳氧基(例如,苯氧 基)、未經取代或經取代之雜環..氧基(例如,卜甲基_4_ 氫比疋氧基)、未經取代或經取代之雜環基C 1 <8烷 氧基(例如,2-(1_咪唑基)乙氧基、3_嗎啉代丙氧基或2- · 嗎啦代乙氧基)、未經取代或經取代之胺基(例如,甲 基胺基或二甲基胺基)、Ci_C8烷基磺醯基(例如,曱基 續酿基)、i素(例如,氟基或氣基)、未經取代或經二 代之胺曱醯基(例如,環己基胺甲醯基、六氫吡啶羰 基、六氫吡啡羰基、N-曱基六氫吡啡羰基或嗎啉代羰 基)、未經取代或經取代之胺磺醯基(例如,胺磺醯 基、甲基胺磺醯基或二甲基胺磺醯基)、氰基或硝基; · 以氫、甲基、六氫σ比咬基、六氫。比„井基' 甲基六氫 吡畊基、嗎啉代、甲氧基、乙氧基、三氟曱氧基、苯 氧基、1-甲基-4-六氫吡啶氧基、3·嗎啉代丙氧基、2_ 嗎啉代乙氧基、3-(N-甲基六氫。比畊基)_丙氧基、甲基 胺基、氟基、氯基、胺磺醯基或硝基較佳; (j) R10係烷基(例如,甲基、乙基或丁基)、羥基Ci_C8 烷基(例如,羥乙基或羥丁基)、鹵基Cl_C8烷基(例如, 二氟曱基)、Ci-C8烷氧基(例如,甲氧基或乙氧基)、未經 95245.doc -19- 1378923 取代或經取代之雜環基(^-(:8烷氧基(例如,2_(1_咪唑 基)乙氧基)、未經取代或經取代之胺基(例如,甲 基胺基或二甲基胺基)、鹵基(例如,氟基或氯 • 基)、羧基、胺甲醯基或未經取代或經取代之胺磺醯基 (例如’胺崎酿基、甲基胺績酿基或二甲基胺磺醯 基);以曱基、丁基、甲氧基、乙氧基、2(1咪唑基)乙 氧基、甲基胺基、二甲基胺基或氟基較佳;及 φ (k)每一個鄰接的取代基配對R7及R8,或R8&R9,或R9及 R S-NH-CH = CH-、-CH = CH-NH-'-NH-N = CH_ 、-CH=N-NH·、-CH2-CH2-CH2-、-CH2_CH2-CH2-CH2-、-ch2-ch2-o-、-ch=ch-o-、-〇-Ch2_〇_4_〇_CF2_〇· :鄰接的取代基配對r7及r8,或…及尺9係以_0CH20_ 較佳’或鄰接的取代基配對尺9及rio係以_nh_ch=ch· 、-CH=N-NH-、-Ch2-CH2-CH2-、-Ch2-Ch2-CH2-CH2- 或-〇-CF2-〇-較佳。 ® 以下單獨、集體或在任何組合或副組合中的意義更佳: (a’)每一個R〇或r2係獨立為氫、Ci_C8烷基(例如,甲基、 乙基或異丙基)、鹵基貌基(例如,三款甲基)、未 經取代或經取代之含有丨或2個選自N、〇及s之雜原子 的5或6員雜環基(例如,嗎淋代、六氫。比咬基或n甲基 六氫°比畊基)、C^Cs烷氧基(例如,甲氧基、乙氧基或 異丙氧基)、未經取代或經取代之雜環氧基(例如,丨_甲 基4-,、氫吡啶氧基)、未經取代或經取代之雜環基匸1 _ C8烷氧基(例如,2_(1_咪唑基)乙氧基、3_嗎啉代丙氧 95245.doc -20· 1378923 基或2 -嗎琳·代乙氣甚^、土 ^ &)未經取代或經取代之胺基(例 如甲基胺基一甲基胺基或乙酿基胺基)、齒素(例 如,氟基或氣基);以氫、六氫^井基、N-f基六氫吹 味基或i-f基-4-六氫㈣氧基較佳,特別係氣; (b,)Rl係氮、㈣貌基(例如,甲基、乙基或異丙基)、齒 基q C8烧基(例如’二氟f基)、未經取代或經取代之 含有1或2個選自N、〇W之雜原子的5或6員雜環基(例 如,馬琳代、六風°比咬基、六氫°比呼基或N-甲基六氫 〇比絲ΜΑ燒氧基(例如,甲氧基、乙氧基或異丙 氧基)' 未經取代或經取代之雜環氧基(例如…甲基-4·六氣㈣氧基)、未經取代或經取代之雜環基Cl-C8烧 氧基(例如,2-(1-咪唾基)乙氧基、3_嗎琳代丙氧基或2_ 嗎琳代乙氧基)、未經取代或經取代之胺基(例如,甲 基胺基 '二甲基胺基或乙醯基胺基)、_ 基或氣基);以氣、六氯_基、N-甲基六氣t井基、 rm甲基r六氫^氧基、3·嗎琳代丙氧基或 馬啉代乙氧基較佳,特別係氫; ⑻=、㈣院基(例如,甲基或乙基)、一院 = 基)、未經取代或經取代之含㈣2 、 S之雜原子的5或6員雜環基(例如,2“比 略烧嗣基或S,S -二氧某里读也— Η氧基)、.二之、=)、^氧基(例 (例如’乙酿基胺基、乙 Α二醯A〆胺基、苯酿基胺基、甲基石黃酿基胺基或苯 “ ▲胺基)、CVCs燒基續酿基(例%,〒基石黃醯 95245.doc -21 < 1378923 基)、C5-C1()芳基磺醯基(例如’笨基磺醯基)、鹵素(例 如,氟基或氣基)、羧基、經取代或未經取代之胺甲醯 基(例如,胺甲醯基、甲基胺甲醯基或二甲基胺甲醯 • 基)、未經取代或經取代之胺磺醯基(例如,胺磧醯 基、甲基胺磺酿基、丙基胺續醒基、異丙基胺續酿 基、異丁基胺磺醯基、環丙基甲基胺磺醯基、2,2,2-三 氟乙基胺磺醯基、二甲基胺磺醯基或嗎啉代磺醯基); 以胺磺醯基、甲基胺磺醯基或丙基胺磺醯基較佳; (d’)每一個鄰接的取代基配對RG及R1,或R1及R2,或尺2及 R3係-CH2-NH-CO-、-CH2-NH-S〇2- ' -ch2-ch2-so2-、_ O-CHrO-或-O-CFrO-及其中將在NH中的氫以C丨-C8^ 基置換的這些配對;鄰接的取代基配對RG及R1,或R1 及R2係以-〇-CH2_0-較佳,以及鄰接的取代基配對R2及 R3係-CH2-NH-CO-或-CH2-NH-S02-較佳; (e·) R4係氫; Φ (f’)r5係氫、卤素(例如,氣基或溴基)、鹵基eves烷基(例 如,三氟甲基)或硝基;以氫、氣基、溴基、三氟曱基 或硝基較佳;特別係氣基或溴基; (g')R6係氫; (h’)每一個R7及R9係獨立為氫、Cl-Cs烷基(例如,曱基、 乙基或異丙基)、鹵基C1-Cs烷基(例如,三氟甲基)、未 π 經取代或經取代之Cs-C1()芳基(例如,苯基或甲氧基笨 - 基)、未經取代或經取代之含有1或2個選自N、〇及S之 雜原子的5或6員雜環基(例如’嗎琳代、六氫。比咬基、 95245.doc -22- 1378923 六氫。比畊基或N-甲基六氫》比畊基)、C「C8烷氧基(例 如’曱氧基、乙氧基或異丙氧基)、未經取代或經取代 1- T丞-4-六氫
之雜環氧基(例如 代或經取代之雜環基CrCs烷氧基(例如,2-(1-咪唑基) 乙氧基、3-嗎啉代丙氧基或2-嗎啉代乙氧基)、未經取 代或經取代之胺基(例如,甲基胺基、二甲基胺基或乙 醯基胺基)、函素(例如,氟基或氣基)、未經取代或經 取代之胺甲醯基(例如,環己基胺甲醯基、六氫吡啶羰 基、六氫。比畊羰基、N-甲基六氫》比畊羰基或嗎啉代羰 基)、未經取代或經取代之胺磺醯基(例如,胺磺醯 基 '甲基胺磺醯基或二甲基胺磺醯基);以氫、甲基、 異丙基、三氟甲基、苯基、鄰-、間-或對-甲氧基苯 基、六氫'•比啶基、六氫。比畊基、N_甲基六氫吡畊基、 嗎琳代、甲氧基、乙氧基、異丙氧基、苯氧基、3_嗎 啉代丙氧基、2-嗎琳代乙氧基、2_〇•咪唾基)乙氧基、
二甲基胺基、氟基、嗎琳代㈣、六氫㈣幾基、六 氫°比,井羰基或環己基胺甲醯基較佳; ⑺R8係氫、C&院基(例如,甲基、乙基或異丙基广齒 基cvc8烧基(例如,三敗甲基)、C5_Ci。芳基(例如,苯 f或甲氧基苯基)、未經取代或經取代之含有⑷個選 」、〇及S之雜原子的5或6員雜環基(例如,嗎琳代、 六氫吡啶基、六氳吡畊基或
^ ^ 岙次1"1甲基六氧吡畊基)、CV 8烷氧基(例如,甲氧基、惫 C Γ ^ 乙虱基或異丙氧基)、i基 iC8烷虱基(例如,三氟 f乳基)、C5-Ci〇芳氧基(例 95245.doc -23- 1378923 如’苯氧基)、未經取代或經取代之雜環氧基(例如,j _ 甲基-4-六氫吡啶氧基)、未經取代或經取代之雜環基 Ci-Cs烷氧基(例如,2-(1-咪唑基)乙氧基、3_嗎啉代丙 氧基或2-嗎啉代乙氧基)、未經取代或經取代之胺基(例 如,甲基胺基或二,基胺基)、函素(氟基或氯基)、未 經取代或經取代之胺績酿基(例如,胺績酿基、甲基胺 續酿基或二甲基胺磺醯基)或硝基;以氫、甲基、六氫 吡啶基、六氫吡畊基、N-甲基六氫吡畊基、嗎啉代、 甲氧基、乙氧基、三氟甲氧基、苯氧基、甲基_4_六 虱比咬氧基、3-嗎琳代丙氧基、2-嗎琳代乙氧基、% (N-甲基六氫。比嘈基丙氧基、曱基胺基、氟基、氣 基、胺磺醯基或硝基較佳; (j ) R 0係CVCs烷基(例如,甲基、乙基或丁基)、鹵基 烷基(例如,三氟甲基)、Cl_Cs烷氧基(例如,甲氧基 或乙氧基)、未經取代或經取代之雜環基Ci_c8烷氧基 (例如,2-(1-咪唑基)乙氧基)、未經取代或經取代之胺 基(例如,甲基胺基或二甲基胺基)、自素(例如,氟基 或氣基);以甲基、丁基、甲氧基、乙氧基、2_(1_咪唑 基)乙氧基、f基胺基、二甲基胺基或氟基較佳;及 00每一個鄰捿的取代基配對尺7及尺8,或尺8及R9,或…及 R10 CH=N-NH- . -CH2-CH2-CH2- . .CH2-CH2-CH2-CH2- ^ -O-CH^O·或-o-civo·;鄰接的取代基配對…及…,或 R8及R9係以-O-CHz-O-較佳,或鄰接的取代基配對"及 95245.doc •24- 1378923 R10 係以-nh-chsch-、·〇:Η=Ν_ΝΗ_ ' 、-CH2-CH2-CH2-CH2-或-O-CFrO-較佳 最佳的式I化合物係那些其中取代基具有 -ch2-ch2-ch2- 的意義。 在實例中提供 本發明也提供製造式!化合物之方法,其包含將式π化合物
其中R〇、R1、R2、R3、R4、R5及尺6係如以上 之定義,以及 Υ係離棄基,以鹵素較佳,如溴、碘,或特別係氣; 與式III化合物
其中R7、R8、R9及R10係如以上之定義; 反應及:¾必要時將其中取代基具有如以上定義之意義的' I化合物轉化成如定義之另一個式I化合物; 並回收自由形式或成為鹽之所得式Ϊ化合物,並在必要時 將以自由形式所獲得的式I化合物轉化成希望的鹽,或將 所獲得的鹽轉化成自由形式。 可以本身已知的方式進行反應,反應條件尤其係依據離 棄基Y的反應性及在式III苯胺中的胺基反應性而定,經常 95245.doc -25- 1378923 係在適合的溶劑或稀釋劑或其混合物的存在下,以及若必 要時在酸或鹼的存在下,以冷卻或較佳地係以加熱,例 如,在從約-30°C至約+150°C之溫度範圍下,尤其係從〇°C 至+100°C ’以從室溫(約+20。〇至+8(TC較佳,在開放或密 閉的反應容器中及/或在惰性氣體中,例如,在氮氣中。 如果一或多個在式II或III化合物中的其它官能基(例如, 羧基、羥基或胺基)受到或必須受到保護時,因為彼等不 應該參與反應,則這些係經常在肽化合物、頭孢菌素及青 霉素之合成作用中使用的基。 保護基可能已存在於前驅體中,並應該保護有關對抗不 希望的一級反應(如取代反應或溶劑分解作用)的官能基。 保護基具有使彼等合乎輕易移除的特徵,即沒有不希望的 一級反應,典型係例如,在類似於身體條件的條件下以溶 4刀解、還原、光解或也以酵素活性移除,並且彼等不會 存在於最終產物中。專家已知或可輕易建立適合於上述反 應的保護基。 可以本身已知的方式製備具有鹽形成基之式〗化合物的 ^ ^以I或以適合的陰離子交換劑處理,可因此獲得式 1化合物之酸加成鹽類。 經常可將鹽類轉化成自由形式之化合物,例如,以適合 的驗性試劑處理,例如,以驗金屬碳酸鹽、驗金層碳酸氫 鹽或驗金屬氫氧化物’典型係以碳㈣或氫氧化納。 、可將立體異構物混合物(例如,非對映異構物之混合物) 、身已头適口的方離法方式分離成彼等對應的異構物。 95245.doc -26· 1378923 可將非對映異構物例如分離成彼等個別的非對映異構物, 以分餾結晶、色層分離法、溶劑分布及類似的步驟方式。 該分離作用可以發生在或原料化合物階段或式合物本 身。可將對快異構物經由非對映異構物鹽的形成作用分 離,例如,以對映異構物純對掌性酸的鹽形成作用或以使 用具有對掌性配體的色層分離基質的色層分離法方式,例 如,以HPLC »
應強調類似於本章節所述之轉化作用的反應也可以發生 在適當的中間物階段^ 也可以獲得水合物形式的式〗化合物(包括彼等鹽類),或 者彼等晶體可以包括例如用於結晶作用的溶劑(以溶劑化 物存在)。 以式IV化合物
R6
與式V化合物反應,可以獲得作為原料使用的式〗〗化合物 R0
(V) 其中R、R、R ' R4、R5及R6係如以上之定義,以及γ丨及 Y係相同或不相同的離棄基,如以上定義之Y。這些條件 係那些以上所述用於式Π化合物與式m化合物反應的條 95245.doc -27- 1378923 件。 ·. 式1v&v化合物係已知或可根據已知的步驟製造。 . 體外的無細胞激酶檢定法或在細胞檢定法中測試 τ則式1化合物及彼等在醫藥上可接受之鹽類展現有價 .值的藥理特性,並因此用作藥劑。特定言之,本發明的化 合物係點著斑激酶抑制劑,並用作治療與黏著斑激酶有關 連的^號鏈功能障礙所引起的症狀之藥劑,特別係以下所 ^ 述之腫瘤。 黏著斑激酶(FAK)係在以整合素介入之由外而内的信號 鏈中的關鍵酵素(D.雪雷夫(schlaepfer)等人之Pr〇g Bi〇phys
Mol Biol 1999,71,435-478)。在細胞與細胞外基質(ECM) 蛋白之間的交互作用係經由細胞表面受體(整合素)轉導, 成為對生長、存活及移行重要的細胞内信號。FAK在這些 以整合素介入之由外而内的信號鏈中扮演基本角色。在信 號轉導鏈中的觸發物係γ397的自體磷酸化作用。磷酸化之 φ Υ397係Src家族酪胺酸激酶的SH2入籍位置。以束缚的c_
Src激酶使FAK中的其它酪胺酸殘基磷酸化。在其中,磷酸 化之Y925成為Grb2小接附蛋白的SH2位置之結合位置。 Grb2與FAK的該直接結合係其中一個使下游標的(如Ras_ ERK2/MAP激酶鏈)激活的關鍵步驟。 内源性FAK信號抑制作用引起運動減低,並在一些情況 中誘發細胞死亡。另一方面,以外源表現增強FAK信號會 增加細胞運動及傳導來自ECM之細胞存活信號。此外, FAK過度表現在侵入及轉移的上皮細胞、間葉組織、甲狀 95245.doc -28· 1378923 腺及攝護腺鹽。因此,FAk抑制劑有可能係抗腫瘤生長及 轉移藥物。本發明的化合物因此具有例如預防及/或治療 以腫瘤疾病影響的脊椎動物及及更特別係哺乳類的象徵, 特別係乳房腫瘤、腸癌(結腸和直腸)、胃癌、卵巢和攝護 腺癌、非小細胞肺癌、小細胞肺癌、肝癌、黑色素瘤、膀 脱腫瘤及頭和頸癌。
在例如G.A.凡舍維特(van seventer)等人之Eur. j Immunol. 2001,31’ 1417-1427中說明在FAK抑制作用與竟 疫系統之間的關係。因此,本發明的化合物例如有用於洛 療及/或預防以免疫系統異常、以T淋巴細胞、b淋巴細 胞、巨細胞及/或嗜曙紅細胞介入之疾病或異常影響的脊 椎動物及更特別係哺乳類,例如,急性或慢性器官或組織 同種或異種移植排斥、動脈粥樣硬化症、由於血管損傷的 血管阻塞(如企管成形術、再狹窄症、高血壓、心臟衰 竭、慢性阻塞性肺病)、CNS疾病(如阿兹海默氏病或肌萎 縮性脊趙側索硬化症)、癌症、感染性疾病(如Ams、敗血 性休克或成人呼吸壓迫徵候群)、缺血/在灌人損傷(例如, 〜肌梗塞、中風、腸缺血、腎衰竭或出血性休克或創傷休 克)。本發明的試劑也有用於治療及/或預防急性或慢性發 炎疾病或異常或自身免疫性疾病,例如,類風濕性關節 人月關bp火、全身紅斑性狼瘡、橋本氏⑽也m〇t〇,s)甲 狀腺炎、多發性硬化症 '重肌症無力、糖尿_型和剛 和與其有關連的異常、呼吸性疾病(如氣喘病)或發炎性肝 損傷、發炎性腎小球損傷、以免疫介入之異常或疾病的皮 95245.doc -29- 1378923 膚表徵、發炎和高增殖性皮膚疾病(如牛皮癖、異位性皮 膚炎、過敏性接觸皮膚炎'刺激物接觸皮膚炎和更多的濕 • 疹性皮膚炎、脂溢性皮膚炎)、發炎性眼部疾病(例如,修 • · 格連氏(Sj〇egren,s)徵候群、角膜結膜炎或溃瘍)、發炎性 胃部疾病、克隆式(Crohn's)症或潰瘍性結腸炎。 本發明的化合物在如實例中所述之FAK檢定系統中具有 活性及展示在1 nM至100 nM之範圍内的抑制IC5〇。以下所 • 述實例第3-12及3-17號化合物特別具有活性,展示在1至 5 nM之範圍内的IC50值。 本發明的一些化合物也展現2/^_70(與δ鏈有關聯的 70 kD蛋白)蛋白酪胺酸激酶抑制活性。以在水溶液中的人 類ZAP-70蛋白酪胺酸激酶預防例如LAT-11 (T細胞激活的連 接子)磷酸化的能力’可以證明本發明試劑與ZAp_7〇蛋白 路胺酸激酶的交互作用,如實例所述。本發明的化合物因 此也具有預防或治療其中ZAP-70抑制作用扮演一角色之異 φ 常或疾病的象徵。 本發明的的化合物在如實例中所述之ZAP-70檢定系統中 具有活性及展示在1 yM至10 之範圍内的抑制ic50,例 如’如以下所述之實例第2及3-2號化合物。 本發明的化合物也係好的IGF-IR(似生長因子受體1之姨 島素)抑制劑’並因此有用於治療以IGF-IR介入之疾病, " 例如’這些疾病包括增殖性疾病,如腫瘤,如例如乳房、 .· 腎、攝s蒦腺 '結腸、曱狀腺、印巢、胰臟、神經元、肺、 子宮頸和胃腸道腫瘤與骨肉瘤和黑色素瘤。可以使用細胞 95245.doc •30· 1378923 "捕捉ELISA"證明作為IGF-IV酪胺酸激酶活性抑制劑之本 發明化合物的藥效》在該檢定法中,測定對抗誘發IGF-IR 自體磷酸化作用的似胰島素生長因子I(IGF-I)之本發明化 合物的活性。
本發明的化合物也展現有力的退化性淋巴瘤激酶(ALK) 及NPM-ALK之融合蛋白的酪胺酸激酶活性抑制作用。該 蛋白酪胺酸激酶起因於核仁磷酸蛋白(NPM)及退化性淋巴 瘤激酶(ALK)之基因融合,表現非ALK配體依賴性的蛋白 酪胺酸激酶活性。NPM-ALK在許多引起血液及腫瘤疾病 的造血及其它人類細胞中的信號傳導中扮演關鍵角色,例 如,在退化性大細胞淋巴瘤(ALCL)及非何杰金氏 (Hodgkin's)淋巴瘤(NHL)中,尤其係在ALK+NHL或 Alkomas,在發炎性肌纖維母細胞腫瘤(IMT)及神經母細胞 瘤中(達斯特(Duyster)J.等人之 2001 Oncogene 20, 5623-5637)。除了 NPM-ALK之外,已在人類金液及腫瘤疾病中 證實其它的基因融合,主要係TPM3-ALK(非肌肉的旋轉肌 凝素與ALK之融合)。 可以使用已知的方法證明ALK酪胺酸激酶活性抑制作 用,例如,使用類似於在J.烏德(Wood)等人之Cancer Res. 60,2178-2189(2000)所述之VEGF-R激酶檢定法的ALK之重 組體激酶區域。在使用GST-ALK蛋白酪胺酸激酶的活體外 酵素檢定法中,在96井平盤中進行在20 mM Tris-HCl, pH=7.5、3 mM Mg.Ch、10 mM MnCh、1 mM DTT、0.1 /iCi/ 檢定(=30微升)〇33P]-ATP、2 μΜ ATP、3微克/毫升之 95245.doc 1378923 poly(4:l 之 Glu, Tyr)Poly-EY(西加瑪(Sigma)P-0275)、1% DMSO、25毫微克ALK酵素中的過濾結合檢定法》檢定法 係在週遭溫度下培育10分鐘。加入50微升之125 mM EDTA 終止反應,並將反應混合物轉移至事先以甲醇弄濕的 MAIP多篩選(Multiscreen)平盤上(美國麻州貝德福(Bedford) 的密利波(Millipore)),並以H20經5分鐘再水合。在清洗之 後(0.5% H3P04),將平盤在液體閃爍計數器中計數。以抑 制百分比的線性回歸分析計算IC5〇值。與沒有抑制劑的控 制品比較,式I化合物抑制50%之酵素活性(IC5〇),例如, 從0.001至0.5 μΜ之濃度,尤其係從0.01至0.1 μΜ。 式I化合物有效抑制以人類NPM-ALK過度表現的小鼠
BaF3 細胞(德國布倫斯威(Braunschweig)之 DSMZ Deutsche Sammlung von Mikroorganismen imd Zellkulturen GmbH)生 長。以編碼NPM-ALK及接著選擇抗G418細胞的表現載體 pClneo™(美國威斯康辛州麥迪遜(Madison)的Promega公 司)轉染BaF3細胞,達到NPM-ALK表現。未轉染之BaF3細 胞依據細胞存活的IL-3而定。相對之下,以NPM-ALK表現
BaF3細胞(以下稱為BaF3-NPM-ALK)可在沒有IL-3的存在 下增殖,因為彼等經由NPM-ALK激酶獲得增殖信號》假 定的NPM-ALK激酶抑制劑因此廢除生長信號及得到抗增 殖活性。但是,加入經由NPM-ALK獨立機制提供生長信 號的IL-3可以克服假定的NPM-ALK激酶抑制劑的抗增殖活 性。[關於類似於使用FLT3激酶的細胞系統,參考E威士伯 (Weisberg)等人之 Cancer Cell; 1,433-443(2002)]。簡言 95245.doc -32- 1378923 之,如以下測定式I化合物的抑制活性:將BaF3-NPM-ALK 細胞(15,000/微滴平盤井)轉移至96-井微滴平盤中。加入一 系列濃度的試驗化合物[溶解在二甲基亞颯(DMSO)中]’以 這樣的方式使DMSO的最终濃度不超過1%(體積/體積)。在 加完之後,將平盤培育2天,在此期間’沒有試驗化合物 的控制培育物能夠進行兩次細胞分裂週期。以Y〇Pr〇™染 色方式測量BaF3-NPM-ALK細胞的生長[T依達薩瑞克 (Idziorek)等人之 J. Immunol. Methods; 185:249-258 (1995)]:將由 20 mM檸檬酸鈉,pH 4.0、26.8 mM 氣化 鈉、0.4% NP40、20 mM EDTA及20 mM所組成的25微升溶 胞緩衝液加入每一個井中。在室溫下在60分鐘之内完成細 胞溶胞作用,並使用以下設定的Cytofluor II 96-井讀取機 (PerSeptive Biosystems)測量:激發(毫微米)485/20 及放射 (毫微米)530/25,以測定與DNA束缚之Yopro總量。 以電腦辅助系統,使用以下公式測定IC50值: IC50=[(ABStest-ABSstart)/(ABSc<)ntr。丨-ABS_)]xlOO.(ABS=吸收值) 以討論中的試驗化合物引起細胞數比使用沒有抑制劑之 控制品所獲得的細胞數少50%之濃度表示在那些實驗中的 IC50值。式I化合物展現從約0.01至1 μΜ之範圍内的IC50之 抑制活性。
使用與上述BaF3-NPM-ALK細胞株相同的方法,也在 人類KARPAS-299淋巴瘤細胞株中(德國布倫斯威之 DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH)測定式I化合物的抗增殖作用[在WG 95245.doc -33- 1378923 德克斯(Dirks)等人之 Int. J. Cancer 100,49-56(2002)中說 明]。式I化合物展現從約0.01至1 μΜ之範圍内的IC5〇之抑 ’ · 制活性。 •- 以免疫點墨法方式在人類KARPAS-299淋巴瘤細胞株中 測定式I化合物對ALK之自體鱗酸化的作用,如WG德克等 人之Int. J. Cancer 100, 49-56(2002)的說明。在該試驗中, 式I化合物展現從約0.001至1 μΜ之rC5〇。 | 在式I化合物之中,2-[5-氣基-2-(2-甲氧基-4-嗎啉-4-基 笨基胺基)-嘧啶-4-基胺基]-N-甲基-苯醯胺係尤其有效的 ALK抑制劑,其中該化合物以97 nlV[之IC50抑制BaF3-NPM-ALK細胞的生長。用於抑制退化性淋巴瘤激酶(alk)之路 胺酸激酶活性的化合物係以下分別以實例7A及7B與7-2、 7-15、7-36 ' 7-39、7-44及7-52所述之化合物尤其更佳, 所有化合物具有在從<0_5至200 nM之範圍内的ic5〇。 在治療腫瘤疾病及免疫系統異常的以上用途所需要的劑 φ 量當然將依據投藥模式、欲治療的特殊症狀及希望的效應 而定。以從約〇· 1至約1 〇〇毫克/公斤計體重之曰劑量會使身 體獲得需要治療的滿意結果。較大的哺乳類(例如,人類) 需要的曰劑量係在從約〇_5毫克至約2000毫克之範圍内, 方便以每天多達4次的分次劑量或以延緩劑型投藥。 可將本發明的化合物以任何慣用的途徑投藥,特別以非 - 經腸(例如,以注射溶液或懸浮液形式)' 經腸(以口服較 - 佳’例如,以藥片或膠囊形式)、局部(例如,以乳液、、疑 膠、軟膏或乳膏形式)或以鼻内或栓劑形式。以與在醫藥 95245.doc -34- 1378923 可接又之載體或稀釋劑混合的慣用方式可以製造含有本 x月化σ物和與其締結之至少-種在醫藥上可接受之載體 或稀釋劑之醫藥組合物。用於口服投藥的單位劑型包括例 如從約(Μ毫克至約5GG毫克活性物質。局部投藥係例如投 予皮膚。另-種局部投藥形式係投予眼睛。 '身已知的方式製備本發明的醫藥組合物,例如,以 慣用的混合、成粒、塗佈、溶解或冷凍法。 偏好使用活性成份之溶液,並也偏好使用懸浮液或分散 液’尤其係滲透性水溶液、分散液或 懸浮液,例如,在含 有單或與載體(例如’甘露醇)一起的活性成份的冷康型 〇物的If況中’可在使用之前組合。可將醫藥組合物消 毋及/或可以包含賦形劑(例如,保存劑、安定劑、濕潤劑 及/或礼化劑、溶解劑、調節滲透壓之鹽類及/或緩衝劑), 並乂本身已知的方式製備,例如,以慣用的溶解及冷凍 法該/合液或懸浮液可以包含黏度增加劑(典型係羧甲基 ,瘋維素、缓曱基纖維素、右旋糖、聚乙稀基環。比咬酮或白 φ 明膠)或也包含安定劑(例如,Tween 80® (聚氧乙烯(20)花 椒聚糖單油酸醋))。 在油中的懸洋液包含作為以注射為目的慣用的油組份之 植n合成或半合成油。可以液體脂肪酸製成關於這些 特別提及的m括作為酸組份之具有從8至22個碳原 子(尤其係彳< 12至22個碳原子)之長鏈脂肪酸,例如,月桂 酉文十二烷酸、肉丑蔻酸 '十五烷酸、棕櫊酸、珠脂酸、 硬脂酸、花生酸、以酸或對應的不飽和酸(例如,油 95245.doc -35- 酸、反油酸、:工 介于酸、巴西烯酸或亞麻油酸)。若必 k ’則加入抗氢几#丨
冶,例如,維它命E、心胡蘿蔔素或 3’:)-二特丁基 _4· 投基曱本。這些脂肪酸酯的醇組份具有最 夕6個碳原子及單 oo 卞'丨貝:¾夕1貝,例如,單_、二_或三價醇, 例如,f醇、 一 θ 每、丙醇、丁醇或戊醇或其異構物,但 疋尤其係乙二酸j, 哔夂甘油。因此,以下說明作為脂肪酸的 油酸乙酯、肉5 #田
J且寇異丙酯、棕櫊酸異丙酯、"Labrafil M
375 (4乙氧基甘油)、"Labrafil Μ 1944 CS"(以杏子仁 的醇刀解作用所製備及由甘油酯與聚乙二醇酯所組成的 不飽和雙7 —醇化甘油醋)、"Labrasol"(以TCM醇分解作 用所製備及由甘油酯與聚乙二醇酯所組成的飽和聚乙二 醇化甘油醋;全部係取自法國Gattefoss6)及/或"Miglyol 812 (主鍵C8至C12之飽和脂肪酸的三酸甘油酯,取自 德國Hills AG),但是尤其係植物油,如棉籽油、杏仁
油、撤欖油、蓖麻油、芝麻油、大豆油,更尤其係花生 油0 .在例如填充至安瓶或小瓶中及密封容器時,經常在無菌 條件下進行注射製劑的製造。 以例如活性成份與一或多種載體結合,可以獲得用於口 服投藥之醫藥組合物,若必要時,則將所得混合物成粒及 將混合物或顆粒加工,若必要或要求時,則以包含附加的 賦形劑形成藥片或藥片核心。
適合的載體尤其係填充劑(如糖(例如,乳糠、蔗糖 '甘 露醇或山梨醇)、纖維素製劑及/或磷酸鈣(例如,磷酸三鈣 95245.doc • 36· 或碟酸氫鈣)),並也係結合劑(如澱粉(例如,玉米、小 麥 '米或馬铃薯)、甲基纖維素、羥丙基甲基纖維素、羧 曱基纖維素鈉及/或聚乙烯基環吡啶酮)及/或若必要時的崩 散劑(如上述的澱粉、也係羧甲基澱粉、交聯之聚乙烯基 後。比咬_、藤酸或其鹽,如_酸納)。附加的職形劑尤其 係流動調節劑及潤滑劑,例如,矽酸、滑石粉、硬脂酸或 其鹽(如硬脂酸鎂或鈣)及/或聚乙二醇或其衍生物。 藥片核心可具備適合的視需要之腸衣塗層,其係經由使 用例如可以包含阿拉伯膠、滑石粉、聚乙烯基環吡啶酮、 聚乙二醇及/或二氧化鈦之例如濃縮的糖溶液,或在適合 的有機溶劑或溶劑混合物中的塗層溶液,或為了製備腸衣 塗層的適合的纖維素製劑溶液,如乙醯基纖維素酞酸酯或 羥丙基甲基纖維素酞酸酯。可將染料或顏料加入藥片或藥 片塗層中,例如,為了辨認目的或標示不同的活性成份劑 量。 用於口服投藥之醫藥組合物也包括由白明膠所組成的硬 膠囊及也包括由白明膠及增塑劑(如甘油或山梨醇)所組成 的密封型軟膠囊。硬膠囊可以包括顆粒形式的活性成份, 例如’與填充劑(如玉米澱粉)、結合劑及/或助滑劑(如滑 石粉或硬脂酸鎂)及視需要之安定劑之摻合物。在軟膠囊 中’較佳地係將活性成份溶解或懸浮在適合的賦形劑中, 如脂肪油、石蠟油或液體聚乙二醇、或乙二醇或丙二醇之 脂肪酸酯’也可以加入安定劑及清潔劑,例如,聚氧乙稀 花椒聚糖脂肪酸酯型式。 95245.doc -37- 1378923 適合於結腸投樂之醫藥組合物係例如由活性成份與拴劑
、山梨醇及/或右旋糖 基底之結合物所組成的栓劑。適合的栓劑基底係例如天然 或合成的三酸甘油酯、鏈炫拖、取r _ μ上—...^ 及若必要時的安定劑)之水性注射懸浮液尤其適合於非經 腸投藥。視需要與賦形劑一起的活性成份也可以具有冷凍 φ 形式,並在非經腸投藥之前,以加入適合的溶劑可以製成 溶液。 也可以使用例如用於非經腸投藥之溶液作為注射液。 較佳的保存劑係例如抗氧化劑(如抗壞血酸)或殺菌劑(如 山梨酸或苯甲酸)。 可將本發明的化合物作為單獨的活性成份或與其它有用 於對抗腫瘤疾病或有用於免疫調節攝取法的藥物一起投 藥。例如’可以使用根據本發明的本發明試劑與對上述各 • 種疾病有效的醫藥組合物組合,例如,與環磷醯胺、5·氟 尿喷咬、氟達拉賓(fludarabine)、吉西它賓(gemcitabine)、 順氣胺始(cisplatinum)、卡銘(carboplatin)、長春新驗、長 春花驗、依托波塞德(et0p0Side)、依瑞諾它肯 (mnotecan)、太平洋紫杉醇、多希紫杉醇(d〇cetaxel)、瑞 土杉(rituxan)、阿霉素(doxonibicine)、吉非替尼(gefitinib) •或依馬替尼(imatinib);或也與環抱靈、雷帕霉素 .- (rapamycin)、子囊霉素(ascomycin)或彼等的免疫抑治類似 物,例如,環孢靈A ;環孢靈G.、FK-506、西羅莫司 95245.doc -38- 1378923 (sirolimus)或艾維羅莫司(everolimus)、皮質類固醇,例 如,脫氫可的松、環璃醯胺、氮雜硫普瑞(azathioprene)、 ‘ 胺甲蝶吟、金鹽類、硫氮續胺咬(sulfasalazine)、抗瘧劑、 • v 布奎納(brequinar)、來敦諾麥德(leflunomide)、密柔瑞賓 (mizoribine)、霉菌紛酸、霉菌酴酸鹽、莫非替爾 (mofetil)、15-脫氧史波固林(deoxyspergualine)、免疫抑制 單株抗體,例如,白細胞受體之單株抗體(例如,MHC、 CD2、CD3、CD4、CD7、CD25、CD28、CD40、CD45、 CD58、CD80、CD86、CD152、CD137、CD154、ICOS、 LFA-1、VLA-4或彼等配體)或其它的免疫調節化合物(例 如,CTLA41g)。 根據以上所述,本發明也提供: (1) 作為藥劑使用的本發明化合物; (2) 作為FAK抑制劑、ALK抑制劑及/或ZAP-70抑制劑使用 的本發明化合物,例如,用於任何上述特殊的病徵; ^ (3) —種醫藥組合物,例如,用於本文任何上述的病徵,其 包含作為活性成份的本發明化合物與一或多種在醫藥上可 接受之稀釋劑或載體; (4) 治療在需要其之病患中的任何上述特殊的病徵之方法, 其包含投予有效量之本發明化合物或含彼等之醫藥組合 物; (5) 本發明化合物製造藥劑之用途,該藥劑係治療或預防其 .. 中FAK、ALK及/或ZAP-70活化作用扮演一角色或與彼等 有牽連之疾病或症.狀; 95245.doc -39- 1378923 (6)如以上(4)定義之方法,兑包 ” G 3例如以同時或連續共同 投予治療有效量之本發明化合物及 G物及一或多種更多的藥物,
該更多的藥物有用於任何上述特殊的病徵; (7) —種結合物, 多種更多的藥物 徵; 其包含治療有效量之本發明化合物及一或 ’該更多㈣物有用於任何上述特殊的病 (8) 本發明化合物製造藥劑之用;全 # 罘釗之用途,該樂劑係治療或預防回 • 應退化性淋巴瘤激酶抑制作用的疾病; (9) 根據(8)之用途,其中欲治療之疾病係選自退化性大細 胞淋巴瘤、非何杰金氏淋巴瘤、發炎性肌纖維母細胞腫瘤 及神經母細胞瘤; (10) 根據(8)或⑼之用途’其中化合物係2_[5氣基_2-(2_甲 氧基-4-嗎琳-4-基-苯基胺基)κ4_基胺基卜义甲基·苯醯 胺或其在醫藥上可接受之鹽,或在以下實例所述之化合物 或任何其中一種化合物在醫藥上可接受之鹽; • (1 ”一種治療回應退化性淋巴瘤激酶抑制作用的疾病之方 法,尤其係選自退化性大細胞淋巴瘤、非何杰金氏淋巴 瘤發炎性肌纖維母細胞腫瘤及神經母細胞瘤之疾病,該 方法包含投予有效量之本發明化合物(尤其係2[5_氯基_2· (2甲氧基-4-嗎啉-4-基-苯基胺基)_嘧啶_4_基胺基]_Ν_甲基_ . 苯酿胺)或其在醫藥上可接受之鹽。 • 如本文上述根據本發明有用的另外較佳的化合物係尤其 以實例所述之化合物。 根據本發明或用作FAK抑制劑' ALK抑制劑或具有兩種 95245.doc 1378923 抑制作用及基本上根據以上所述之方法可製備的另外尤其 較佳的化合物係如下: 2-[5-氯基-2-(2-甲氧基_4_嗎啉_4_基笨基胺基)·嘧啶_4基胺 基]-N-甲基苯酿胺, 2 Ν -(4·[1,4’]聯六氫啶-•甲氧基苯基)5氣基·ν4_[2_ (丙烧·1-續醯基)-笨基]_嘧啶_2,4_二胺,
2-{5-氣基-2·[2-甲氧基_4·(4-甲基六氫。比畊-1-基)-苯基胺 基]-嘴啶-4-基胺基}_N-異丙基笨磺醯胺, 2-[5-溴基-2-(2-甲氧基-5-嗎啉-4-基苯基胺基)·嘧啶-4-基胺 基]-N-甲基苯續酿胺, 2_{2-[5-(1-乙醯基六氫〇比啶-4-氧基)-2-甲氧基苯基胺基]-5-溴基嘧啶-4-基胺基}-N-甲基苯磺醯胺, 2·[5-溴基-2-(2,5-二甲氧基笨基胺基)-嘧啶-4-基]-N-(4-嗎 啉·‘基苯基)-甲烷磺醯胺,
5-溴基-N-4-(4-氟苯基)-Ν*2*-(2·甲氧基-4-嗎啉·4·基笨基)-喷°定-2,4-二胺, 2-[5-氯基-2-(2-曱氧基-4-六氫吡啩-1-基苯基胺基)-嘧啶-4-基胺基]-N-甲基苯磺醯胺, 2-[5-溴基-2-(5-氟基-2-甲氧基苯基胺基)-嘧啶-4-基胺基]-N-曱基笨磺醯胺, 2_[5-氯基-2-(5-氟基-2-甲氧基笨基胺基)-嘧啶-4-基胺基]-N-異丁基笨磺醯胺,及 2-{5-氯基·2-[2-甲氧基-5-(4-甲基六氩吼畊-1-基甲基)苯基 胺基]-喷咬-4-基胺基}-N-甲基笨績gi胺。 95245.doc -41 . 1378923 本發明也提供式2-{5-氯基-2-[4-(3-曱基胺基-吡咯烷-1-基)-苯基胺基]-°¾淀-4-基胺基} -N-異丙基-苯績酿胺之化合物。
以下的實例當作例證本發明,不是將本發明限制在該範 圍内。 【實施方式】 實例 缩寫
AcOH =醋酸,ALK=退化性淋巴瘤激酶,ATP =腺苷5'-三 鱗酸鹽,brine=氣化鈉飽和溶液,BSA=牛金清白蛋白, DIAD =偶氮二羧酸二異丙酯,DIPCDI=N,N'-二異丙基碳化 二醯亞胺,DMAP=4-二甲基胺基吡啶,DMF=N,N-二甲基 甲醯胺,DTT=1,4-二硫-D,L-蘇糖醇,EDTA=乙撐二胺四 醋酸,Et=乙基,EtOAc=醋酸乙醋,EtOH=乙醇,Eu-PT66=LANCETM以銪- W1024標記之抗填酸酪胺酸抗體(鉑 金艾莫(Perkin Elmer)),FAK=黏著斑激酶,FRET=勞光共 振能量轉移,HEPES=N-2-羥乙基-六氫吡畊-N’-2-乙烷磺 酸,HOAt=l-羥基-7-氮雜苯并三唑,Me=曱基,RT-PCR= 反轉錄聚合酶鏈反應,SA-(SL)APC=與SuperLight™別藻 藍素共輛·之鏈酶親和素(始金艾莫),subst. =經取代, TBTU=0-(苯并三唑-1-基)-N,N,N,,N,-四甲基四氟硼酸銨, THF=四氫吱喃。 實例1:2-[2-(2,5-二甲氧基-苯基胺基)-5-硝基-嘧啶-4-基胺 基】-N_甲基-苯峰醯胺 95245.doc -42- 9;1378923
O'^Y^N,ΟΗΙ^Ν 人Cl 將2,5-二曱氧基苯胺(49毫克’ 0.32毫莫耳)在室溫下加入 在EtOH(3毫升)中的2-(2-氯基-5-硝基-嘧啶-4-基胺基)-N-甲 基-苯磺醯胺(1〇〇毫克,0.29毫莫耳)之溶液中。將混合物 在78 °C下加熱5小時。將溶劑蒸發’並將混合物以反相 HPLC純化,得到標題產物〇 Rf=0.47(正己統:醋酸乙酯=1:1)。W-NMR (400 MHz, CDC13), δ (ppm):2.36 (d,3H), 3.57(s, 3H), 3.73 (s, 3H), 6.72 (d, 1H), 6.99 (d, 1H), 7.17 (s, 1H), 7.35 (t, 1H), 7.4-7.6 (m, 1H), 7.63 (d,lH), 7.81 (d, 1H), 8.0-8.2 (m, 1H), 9.13 (s,1H),9.41 (br.s, 1H),11.0 (s,1H)。 2-(2_氣基-5-硝基-痛咬-4-基胺基)-N-申基-苯續酿胺之製備 作用: 將2,4-二氯基-5-硝基-嘧啶(1.94公克,1〇毫莫耳)及2-胺 基-N-甲基-笨磺醯胺(1·86公克,1〇毫莫耳)溶解在 CHC13(30毫升)中。將反應混合物在61。〇下加熱2小時。將 溶劑蒸發及將殘餘物以醚清洗,得到標題產物。Rf=0.5(正己烷:醋酸乙酯=1:1)。iH_NMIl(4〇〇MHz,CDC13),δ (ppm):2.67(d, 3Η),4.6-4.7 (m,2Η),7·41 (dd,1Η),7.7 (dd, 1H), 8.04 (d3 1H), 8.15 (d, 1H), 9.21 (s5 1H), 11.2 (s, 1H) 〇 實例2 : 2-[5-溴基-2-(2,4-二甲氧基-苯基胺基)-嘧啶_4_基胺
95245.doc • 43- 1378923 基】·Ν-甲基-苯磺醯胺
將1當量氫氣酸(0.03毫升)加入在乙醇(3毫升)中的2-(5-邊基-2-氣基-嘧啶·4-基胺基)_N-甲墓-苯磺醯胺(3〇〇毫克, 0.79毫莫耳)及2,4-二甲氧基苯胺(181 5毫克,丨18毫莫耳) 之容液中’並在回流條件下攪拌5小時,將反應混合物冷 卻至至溫’倒入水中及以醋酸乙酯萃取兩次。將有機層以 水及食鹽水連續清洗’經硫酸鎂乾燥及在真空中蒸發。將 殘餘物以矽膠管柱色層分離法(正己院:醋酸乙酯=5:丨至丨:i) 純化,供應標題化合物。 *Η- NMR (CDC13), δ (ppm):8.95 (s, 1H), 8.44 (d, 1H), 8.20 (s, 1H), 7.98 (dd, 1H), 7.58 (ddd, lH)}7.22-7.32 (m, 1H), 6.51 (d, 1H), 6.40 (d, 1H),4.56-4.48 (m, 1H), 3.86 (s, 3H), 3.81(s, 3H), 2.64 (d,3H)。Rf (正己烷:醋酸乙酯=1:1 ):0.31。 2-(5-溴基·2-氣基-喷啶_4-胺基)-N-甲基-苯磺醯胺之製備作用: 將在包括碳酸鉀(830毫克,6.0毫莫耳)之N,N-二甲基甲 酿胺(10毫升)中的5-溴基-2,4-二氣基嘧啶(684毫克,3.0毫 莫耳)及2-胺基-N-甲基-苯磺醯胺(559毫克,3.0毫莫耳)之 洛液在至溫下搜摔2 3小時。加入飽和水性氣化敍,並將混 合物倒入水中及以醋酸乙酯萃取兩次。將有機層以食鹽水 清洗’經硫酸鈉乾燥及在真空中蒸發《將殘餘物以矽膠管 95245.doc -44· 1378923 柱色層分離法(正己烷-醋酸乙酯梯度)純化,供應成為淺黃 色固體之標題化合物。 !H-NMR (CDCI3), δ (ppm):2.67 (d,3H), 4.79 (q, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd, 1H), 8.37 (s, 1H), 8.48 (d,1H),9.52 (s, 1H)。Rf (正己烷:醋酸乙酯=10:3):0.33。 實例3 : 依照實例2之步驟,自2-(5-溴基-2-氣基-嘧啶-4-基胺基)-
N-甲基-苯磺醯胺及對應的苯胺製備以下的2-[5-溴基-2-(經 取代之苯基胺基)-嘧啶-4-基胺基]-N-甲基-苯磺醢胺:
實例編號 Rx Rf (溶劑). 或MS 'H-NMR (400MHz), δ (ppm) 3-1 ό>: 0.48 (正己炫: AcOEt=1:1) CDCI3: 2.64(d, 3H), 4.48-4.40(m, 1H), 6.78(d,1H), 6.87(bs, 1H), 6.99(dd, 1H), 6.82(s, 1H),7.54(ddd, 1H), 7.79(d, 1H), 7.97(dd, 1H), 8.28(s, 1H), 8.32(dd, 1H), 9.07(s, 1H) 3-2 Me 0.58 (正己炫ν'ί AcOEt=1:1) CDCI3: 2.25(s, 3H), 2.33(s, 3H), 2.63(d, 3H), 4.53-4.45(m, 1H), 6.61 (bs, 1H), 6.99(dd, 1H), 7.04(s, 1H), 7.18(ddd, 1H), 7.43(ddd, 1H), 7.56(d, 1H), 7.92(dd, 1H), 8.19(s, 1H), 8.41(dd, 1H), 9.08(s, 1H) 3-3 0.36 1(正己烷: AcOEt=1:1) CDCI3: 2.23(s, 3H), 2.62(d, 3H), 3.69(s, 3H), 4.53-4.44(m, 1H), 6.62(dd, 1H), 6.69(bs, 1H), 7.1〇(d, 1H), 7.19(dd, 1H), 7.48(d, 1H), 7.51(dd, 1H), 7.93(dd, 1H), 8.22(s, 1H), 8.44(dd, 1H), 9.09(s1, 1H) 3-4 φτ Me 0.41 (正己院: AcOEt=1:1) CDCI3: 2.32(s, 3H), 2.63(d, 3H), 4.45-4.44(m, 1H), 6.85(d, 1H), 6.91 (d, 1H), 7.00(bs, 1H), 7.28-7.24(m, 1H), 7.57(dd, 1H), 7.99(dd, 1H), 8.25 (s, 1H), 8.39(d, 1H), 9.00(bs, 1H) 1 丨丨"丨 1 丨 J 95245.doc - 45 - 1378923 3-5
OMe 0.39 (正己烷: AcOEt=1:1) CDCI3: 2.33(s, 3H), 2.63(d, 3H), 3.87(s, 3H), 4.46-4.44(m, 1H), 6.66(d, 1H), 6.71 (s, 1H), 7.48(bs, 1H), 7.63-7.59(m, 1H), 7.97(dd, 1H), 8.05(d, 1H), 8.23 (s, 1H), 8.44(d, 1H), 8.92(bs, 1H) 3-6 0.27 (正己统: AcOEt=3:1) CDCI3: 2.63(d, 3H), 3.90(s, 3H), 4.45-4.40(m, 1H), 6.90-6.86(m, 2H), 7.00-6.96(m, 1H), 7.23-7.17 (m, 3H), 7.45(dd, 1H), 7.50-7.60(m, 2H), 7.97(dd, 1H), 8.22(d, 1H), 8.26 (s, 1H), 8.43(d, 1H), 8.94(bs, 1H) 3-7 0.34 (正己院: AcOEt=3:1) CDCI3: 2.30(s, 3H), 2.63(d, 3H), 4.44-4.43(m, 1H), 6.68 (bs, 1H), 7.00-6.68(m, 1H), 7.23-7.17(m, 2H), 7.46-7.43(m, 1H), 7.76(d, 1H), 7.93(dd, 1H), 8.22 (s, 1H), 8.40(d, 1H), 9.01 (bs, 1H) 3-8
0.12 (正己烷: AcOEt=3:1) CDCI3: 2.62(d, 3H), 2.81 (s, 3H), 4.07-3.98(m, 1H), 4.52-4.45(m, 1H), 6.37(bs, 1H), 6.77-6.73 (m, 2H), 7.12(dd, 1H), 7.24-7.20(m, 1H), 7.30-7.27(m, 1H), 7.35(dd, 1H), 7.88(dd, 1H), 8.18 (s, 1H), 8.41(d, 1H), 9.19(bs, 1H) 3-9
OMe 0.28 (正己烷: AcOEt=3:1) CDCI3: 2.62(d, 3H), 3.94(s, 3H), 4.49-4.43(m, 1H), 6.99-6.90 (m, 3H), 7.18-7.23(m, 1H), 7.31-7.24(m, 3H), 7.63(bs, 1H), 7.93-7.86(m, 1H), 8.28-8.23(m, 1H), 8.28 (s, 1H), 8.45(bs, 1H), 8.89(bs, 1H) 3-10 0.23 (正己炫:: AcOEt=3:1) CDCI3: 0.91 (t, 3H), 1.37 (dd, 2H), 1.64-1.55 (m, 2H), 2.64-2.60 (m, 2H), 4.45-4.40 (m, 1H), 6.69 (bs, 1H), 7.23-7.10(m, 1H), 7.46-7.38 (m, 1H), 7.73 (d 1H), 7.92 (d, 1H), 8.21 (s, 1H), 8.38-8.46 (m, 1H), 9.09 (bs, 1H) 3-11
0.12 (正己烷: AcOEt=3:1) CDCI3: 2.63 (d, 3H), 4.15-4.10 (m, 1H), 6.58 (bs, 1H), 7.31-7.10(m, 4H), 7.53-7.49 (m, 1H), 7.71(d 1H), 7.95 (d, 1H), 8.30-8.23 (m, 1H), 8.26 (s, 1H), 8.45 (d, 1H), 9.03 (bs, 1H) 95245.doc • 46 - 1378923 3-12
0.4 (正己故: AcOEt=3:1) CDCI3: 2.09 (dd, 2H), 2.63 (d, 3H), 2.85(t, 2H), 2.96 (t, 2H), 4.46-4.43 (m, 2H), 6.73 (bs, 1H), 6.99 (d, 1H), 7.09 (dd, 1H), 7.25-7.20(m, 1H), 7.52 (dd, 1H), 7.74 (d 1H), 7.92 (dd, 1H), 8.22 (s, 1H), 8.42 (d, 1H), 9.02 (bs, 1H) 3-13
0.33 (AcOEt) CDCI3: 2.63 (d, 3H), 4.63-4.64 (m, 1H), 7.11(d, 2H), 7.18(dd, 1H), 7.42-7.34(m, 1H), 7.58-7.55(m, 1H), 7.96(d, 1H), 8.07(s, 1H), 8.19-8.10(m, 1H), 8.24(s, 1H), 9.15(s, 1H), 11.6-11.4(m, 1H) 3-14 0.28 (正己烷 AcOEt=3:1) CDCI3: 2.63(d, 3H), 3.88(s, 3H), 3.89(s, 3H), 4.47-4.41(m, 1H), 6.60(d,1H), 6.92 (dd,1H), 7.64 (dd, 1H),7.66-7.61(m,1H), 7.89(d, 1H), 7.98(dd, 1H), 8.26(s, 1H), 8.43(d, 1H), 8.95(s, 1H) 3-15 AJ MeO, 0.30 (正己烷.: AcOEt=3:1) CDCI3: 2.63(d, 3H), 3.66(s, 3H), 3.85(s, 3H), 4.45-4.44(m, 1H), 6.48(dd,1H), 6.79(d,1H), 7.64(dd, 1H), 7.97(dd, 2H), 8.26(s, 1H), 8.44(d, 1H), 8.96(s, 1H) 3-16
Me Me 0.22 (正己烷:I AcOEt=3:1) CDCI3: 2.17(s, 3H), 2.22(s, 3H), 2.64(s, 3H), 2.63(d, 3H), 4.46-4.44(m, 1H), 6.57(bs, 1H), 7.00(s,1H), 7.17(dd,1H), 7.44-7.40(m,1H), 7.44(s, 1H), 7.93(dd, 1H), 8.19(s, 1H), 8.43(d, 1H), 9.06(s, 1H) 3-17
0.46 (AcOEt) CDCI3: 2.22(s,3H), 2.63(d, 3H), 3.68(s, 3H), 3.89(s, 3H), 4.52-4.47(m, 1H), 6.51 (s,1H), 6.74(s,1H), 7.12(s,1H), 7.16-7.12(m,1H), 7.40(dd, 1H), 7.91(dd, 1H), 8.19(s, 1H), 8.42(d, 1H), 9.12(s, 1H) 3-18
0.35 (正己烷: AcOEt=3:1) CDCI3: 1-16(d, 6H), 2.25 (s, 3H), 2.62(d, 3H), 2.77(t, 1H), 4.49-4.48(m, 1H), 7.00(s,1H), 7.15(d,1H), 7.41-7.37(m,1H), 7.49(d,2H), 7.54(dd, 1H), 7.92(dd, 1H), 8.21 (s, 1H), 8.32(d, 1H), 9.02(s, 1H) 95245.doc -47- 1378923 3-19 V 〔:〕 0.23 ι(正己炫:< AcOEt=1:1) CDCI3: 2.63(d, 3H), 3.13-3.10 (m, 4H), 3.87(s, 3H), 3.89-3.86(m, 4H), 4.97-4.93(m, 1H), 6.41(dd,1H), 6.52(d,1H), 7.24-7.22(m,1H), 7.32(s,1H), 7.57(dd,1H), 7.96(dd, 1H), 8.01 (d, 1H), 8.14(s, 1H), 8.44(d, 1H), 8.98 (s, 1H) 3-20 〇方 0.36 (正己炫: AcOEt=1:1) CDCb: 2.22(s, 3H), 2.64(d, 3H), 3.00-3.2.97 (m, 4H), 3.76-3.74(m, 4H), 4.54-4.50(m, 1H), 6.64(d,1H), 6.66(dd, 1H), 7.11(d,1H), 7.18(dd,1H), 7.37(d, 1H), 7.46(dd, 1H), 7.93(dd, 1H), 8.22(s, 1H), 8.42(d, 1H), 9.09 (s, 1H) I 3-22 0 0.27 (AcOEt) CDCI3: 2.33(s, 3H), 2.65(d, 3H), 3.60-3.45(m, 8H), 4.53-4.49(m, 1H), 6.74(s, 1H), 7.11(d, 1H), 7.22-7.18(m, 1H), 7.58-7.54(m 1H), 7.94(dd, 1H), 8.00(d, 1H), 8.22(s, 1H), 8.37(d, 1H), 9.13(s, 1H) 3-23 ί σΝΗ 0.38 (AcOEt) CDCI3: 1.24-1.08(m, 2H), 1.46-1.32(m, 2H),1.76-1.67(m, 2H), 1.98-1.90(m, 2H), 2.33(s, 3H), 2.64(d, 3H), 3.95-3.90(m, 1H), 4.49-4.47(m, 1H), 5.89-5.80(m, 1H), 6.66(s, 1H), 7.15(dd, 1H), 7.48-7.31(m, 2H), 7.91(dd, 1H), 8.12(s, 1H), 8.23(s, 1H), 8.41(d, 1H), 9.18(S, 1H) | 3-24 ύ 0.11 (AcOEt) CDCb: 2.35(s, 3H), 2.71 (s, 3H), 3.07-2.73(m, 2H), 3.86-3.31(m, 6H), 6.85(s, 1H), 7.10(d, 1H), 7.24-7.19(m, 1H), 7.52-7.48(m, 1H), 7.66-7.59(m, 2H), 7.93(d, 1H), 8.06(s, 1H), 8.27-8.21 (m, 1H), 8.23(s, 1H), 9.11(s, 1H) 3-25 9 Me。/ 0.5 (正己烷: AcOEt=1:1) CDCI3: 2.52(d, 3H), 2.62(s, 3H), 4.36-4.32(m, 1H), 6.74(s, 1H), 6.87(d, 2H), 7.00-6.91 (m, 2H), 7.00-6.97(m, 2H), 7.38(dd, 2H), 7.86(dd, 1H), 7.98(s, 1H), 8.23(s, 1H), 8.28(d, 1H), 9.04(s, 1H) 95245.doc -48· 1378923 3-26 0.45 (正己烷: AcOEt=1:1) CDCI3: 1.62-1.34(m, 6H), 2.13(s, 3H), 2.56(d, 3H), 3.01-2.87(m, 4H), 4.54-4.38(m, 1H), 6.59(s, 1H), 6.69-6.59(m, 1H), 7.02(d, 1H), 7.10-7.07(m, 1H), 7.37(dd, 1H), 7.84(dd, 1H), 8.15(s, 1H), 8.34(d, 1H), 9.01 (s, 1H) 3-27 OMe 0.45 (正己燒: AcOEt=1:1) CDCI3: 2.32(s, 3H), 2.58(d, 3H), 3.75(s, 3H), 4.37-4.44(m, 1H), 6.77-6.73(m, 1H), 6.89-6.82(m 1H), 6.97-6.91 (m, 2H), 6.96(d, 1H), 7.20(dd, 1H), 7.25-7.24(m, 1H), 7.33-7.29(m, 1H) li 3-28 OMe 0.35 (正己烷 AcOEt=1:1) CDCI3: 2.34(s, 3H), 2.64(d, 3H), 3.81 (s, 3H), 4.57- j 4.50(m, 1H), 6.76(bs, 1H), 6.91-6.84(m, 41H), 7.04(d, 1H), 7.83(dd, 1H), 8.06(d, 1H), 8.19(dd, 1H), 8.23(s, 1H), 9.00(s, 1H) 3-29 0.45 (正己烷: AcOEt=1:1) CDCb: 1.50(t, 3H), 2.62 (d, 3H), 4.17(dd, 2H), 4.51-4.44(m, 1H), 6.95-6.89 (m, 2H), 6.94(d, 1H), 7.16 (dd, 1H), 7.31-7.23(m, 5H), 7.67(s, 1H), 7.11(dd, 1H), 7.23(d, 2H), 7.65(s, 1H), 7.88(dd, 1H), 8.28-8.23(m, 1H), 8.28(s, 1H), 8.43(s, 1H), 8.89(s, 1H) 3-30 II 0.45 (正己烷^ AcOEt=1:1) CDCI3: 1.49(t, 3H), 2.63(d, 3H), 3.85(s, 3H), 4.16(dd, 2H), 4.55-4.48(m, 1H), 6.81 (dd, 1H), 6.95-6.91 (m, 3H), 7.11(dd, 1H), 7.23(d, 2H), 7.65(s, 1H), 7.90-7.88(m, 1H), 8.28-8.26(m, 1H), 8.27(s, 1H), 8.39(s, 1H), 8.90(s, 1H) 3-31 0.29 (正己烷: AcOEt=1:1) 'H-NMR : (CDCb) 1.83-1.72 (4H, m), 2.63 (3H, d), 2.66-2.62 (2H, m), 2.80 (2H, t), 4.41-4.44 (1H, m), 6.64 (1H, br.s), 6.92 (1H, d), 7.09 (1H, dd), 7.18 (1H, dd). 7.45 (1H, dd), 7.59 (1H, dd), 7.92 (1H, d), 8.20 (1H, s), 8.42 (1H, d), 9.08 (1H, br.s). '.3-32 rV〆 0.3 (正己烷: AcOEt=1:1) DMSO-de: 2.43(s, 3H), 2.80-2.82(m, 4H), 3.61-3.64 (m, 4H), 3.75(s,3H), 6.62(dd, 1H), 6.93(d, 1H), 7.46(d, 1H), 7.54(dd, 1H), 7.77(dd, 2H), 8.14(bs, 1H), 8.32(s, 1H), 8.38-8.30(m, 1H), 9.14(bs, 1H) 95245.doc -49- 1378923 3-33 φτ。、 °Ό. 0.61 (MeOH: CH2CI2=1: 1) DMSO-d6: 1.59-1.68(m, 2H). 1.88-1.98(mt 2H), 2.13-2.25(m,2H), 2.19(s, 3H), 2.43(s, 3H), 2.60-2.70(m, 2H), 3.75(s, 3H), 4.32-4.40(m, 1H), 6.51 (dd, 1H), 6.64(d, 1H), 7.20(dd, 1H), 7.39(d, 1H), 7.75(dd, 1H), 7.70-7.78(s, 1H), 8.22(s, 1H), 8.26(s, 1H), 8.38-8.41 (m, 1H), 9.22(s, 1H) 丨’ 3-34 cA, 0.17 (AcOEt) CDCIj: 2.11(s, 3H), 2.68(d, 3H), 2.76-2.83(m, 2H), 2.89-2.97(m, 2H), 3.47-3.55(m, 2H), 3.58-3.66(m, | 2H), 3.86(s, 3H), 4.70-4.78(m, 1H), 6.53(dd, 1H), 6.81(d, 1H), 7.23(dd, 1H), 7.54-7.62(m, 2H), 7.97(dd, 1H), 8.02-8.03(m, 1H), 8.29(s, 1H), 8.40(d, 1H), 8.99(bs, 1H) 3-35 Λ。、 s 0 0.22 (AcOEt only) DMSO-d6: 2.40-2.48(m, 7H), 2.63(t, 2H), 3.50-3.58(m, 4H), 3.77(s, 3H), 3.91 (t, 2H), 6.60(dd, 1H), 6.93(d, 1H), 7.28(dd, 1H), 7.56(d, 1H), 7.60(dd, 1H), 7.75-7.80(m, 1H), 7.80(dd, 1H), 8.10(s, 1H), 8.35(s, 1H), 8.40(d, 1H), 9.21(s, 1H) 3-36 > φτρ 0.4 ’(正己院: AcOEt=1:1) DMSO-d6: 2.43(s, 3H), 7.03-7.08(m, 1H), 7.21-7.23(m, 1H), 7.25-7.36(m, 1H), 7.47-7.57(m, 2H)i 7.74-7.77(m, 2H), 8.28(s, 1H), 8.35(d, 1H), 9.09(s, ( 1H), 9.24(s, 1H) 3-37 ^c, F 0.4 (正己烷.· AcOEt=1:1) CDCI3: 2.64(d, 3H), 4.53-4.54(m, 1H), 6.88-6.93(rri, 1H), 7.14-7.28(m, 3H), 7.54-7.58(m, 1H), 7.95-7.98(m, 1H), 8.16-8.21(m, 1H), 8.24(s, 1H), 8.33-8.36(m, 1H), 9.05(s, 1H) 3-38 0.42 (正己坑: AcOEt=1:1) CDCI3: 2.64(d, 3H), 4.46-4.47(m, 1H), 6.63-6.68(m, 1H), 7.30-7.32(m, 2H), 7.55(s, 1H), 7.64-7.68(m, 1H), 7.97-7.99(m, 1H), 8.20-8.39(m, 3H), 9.03(s, 1H) 95245.doc -50- 1378923 3-39 • 铲、 0 I 562, 564 [M+1]+ CDCI3: 2.37(s, 3H), 2.58-2.64(m, 7H), 3.15-3.18(m,4H), 3.87(s, 3H), 4.60-4.65(m,1H), 6.43(dd,1H), 6.44-6.54(m, 1H), 7.22(d, 1H), 7.30(s, 1H), 7.57(dd, 1H), 7.94-7.99(m, 2H), 8.18(s, 1H), 8.45(d, 1H), 8.95(s, 1H) 3-40 <r 0 II N 572, 574 [M+1]+ DMSO-d6: 1.79-1.88(m,2H), 1.98-2.02(m, 2H), 2.43(s, 3H), 3.02-3.08(m, 3H), 3.28-3.39(m, 2H), 3.76(s, 3H), 6.47(dd, 1H), 6.65(d, 1H), 7.22(dd, 1H), 7.39(d, 1H), 7.45-7.50(m, 1H), 7.74-7.77(m, 2H), 8.18(s, 1H), 8.22(s, 1H), 8.41-8.44(m, 1H), 9.21(bs, 1H) i 3-41 <r 0 565, 567 [M+1]+ DMSO-d6: 2.44(d, 3H), 2.69-2.71 (m, 4H), 3.49-3.52(m, 4H), 3.76(s, 3H), 6.45(dd, 1H), 6.62(d, 1H), 7.23(ddd, 1H), 7.38(d, 1H), 7.46-7.50(m, 1H), 7.72-7.77(m, 2H), 8.19(s, 1H), 8.22(s, 1H), 8.42-8.45(m, 1H), 9.22(s, 1H) 3-42 η 八 595, 597 [M+1]+ DMSO-d6: 2.44(s, 3H), 3.31 (s, 6H), 3.48-3.53(m, 8H), 3.72(s, 3H), 6.24(dd, 1H), 6.37(d, 1H), 7.18-7.21 (m, 2H), 7.40-7.55(m, 1H), 7.72-7.76(m, 2H), 8.17- | 8.19(m, 2H), 8.40-8.50(m, 1H), 9.23(s, 1H) 3-43 <r $ h2n '0 590,592 [M+1]+ DMSO-d6: 1.64-1.71 (m, 2H), 1.75-1,82(m, 2H), 2.21-2.28(m,1H), 2.43(d, 3H), 2.62-2.67(m,2H), 3.68-3.74(m, 2H), 3.76(s, 3H), 6.45(dd,1H), 6.63(d, 1H), 6.75-6.81 (m, 1H), 7.20(ddd, 1H), 7.25-7.30(m, 1H), 7.35(d, 1H), 7.45-7.52(m, 1H), 7.70-7.77(m, 2H), 8.18(s, 1H). 8.21(s, 1H), 8.40-8.47(m, 1H), 9.22(s, 1H) 95245.doc -51 - 1378923 3-44 Φ rN、 k 八 597, 599 [Μ+1】+ DMSO-d6: 2.44(s, 3Η), 3.12-3.17(m, 4H), 3.68-3.85(m, 4H), 3.79(s, 3H), 6.55(dd, 1H), 6.71 (d, 1H), 7.19-7.25(m, 1H), 7.43(d, 1H), 7.46-7.53(m, 1H), 7.73-7.78(m, 2H), 8.19-8.22(m, 1H), 8.22(s, 1H), 8.38-8.45(m, 1H), 9.20(bs, 1H) 3-45 l· ό〇 0 600, 602 [Μ+1]+ DMSO-d6: 1.85-1.95(m, 2H), 2.19(t, 2H), 2.25-2.35(m, 4H), 2.43(s, 3H), 3.52-3.64(m, 4H), 4.19(t, 2H), 6.65(d, 1H)t 7.05(dd, 1H), 7.20(d, 1H), 7.23(ddd, 1H), 7.27(d, 1H), 7.40-7.46(m, 1H), 7.42(d, 1H), 7.70-1 7.75(m, 1H), 7.76(dd, 1H), 8.32(s, 1H), 8.45(d, 1H), 9.22(s, 1H), 9.23(s, 1H) 3-46 0 人 590, 592 [Μ+1]+ DMSO-d6: 2.05(s, 3H), 2.44(s, 3H), 3.08-3.17(m, 4H), 3.55-3.63(m, 4H), 3.77(s, 3H), 6.48(dd,1H), 6.67(d, 1H), 7.23(dd, 1H), 7.41(d, 1H), 7.45-7.52(m, 1H), 7.76(dd, 1H), 7.72-7.78(m, 1H), 8.19(s, 1H), 8.22(s, 1H), 8.40-8.47(m, 1H), 9.22(bs, 1H) & 3-47 0 Η 548, 550 [Μ+1]+ DMSO-d6: 2.43(s, 3H), 2.82-2.87(m, 4H), 2.99-3.15(m, 4H), 3.76(s, 3H), 6.43(dd,1H), 6.61(d, 1H), | 7.22(dd, 1H), 7.36(d, 1H), 7.43-7.51 (m, 1H), 7.75(dd, 1H), 8.17(s, 1H), 8.21(s, 1H), 8.38-8.45(m, 1H), 9.12-9.28(m, 1H) 3-48 Λ Τ 0 〆 MS 530, 532 CDCI3: 2.65 (d, 3H), 3.96 (s, 3H), 4.40-4.48 (m, 1H), 6.85-6.88 (m, 2H), 7.22 (d, 1H), 7.25-7.31 (m, 1H), 7.56-7.65 (m, 3H), 7.79 (s, 1H), 8.00 (dd, 1H), 8.29 (s, 1H), 8.39 (dd, 1H), 9.00 (s, 1H). 95245.doc -52- 1378923.
Rf (AcOEt: MeOH=9:1) 0.20 Rf 0.4 (己院:Ac’ OEt=1/1) MS 535, 537 CDCI3: 2.18-2.50 (m, 4H), 2.28 (s, 3H), 2.65 (d. 3H), 3.10-3.75 (m, 4H), 3.93 (s, 3H), 4.50-4.61 (m, 1H), 6.89 (d, 1H), 7.06 (dd, 1H), 7.59-7.67 (m, 2H), 7.93-7.97 (m, 1H), 8.26 (s, 1H), 8.37-8.43 (m, 2H), 9.02 (s, 1H). CDCI3: 2.63 (d, 3H), 3.90 (s, 3H), 4.00 (s, 3H), 4.39-4.47 (m, 1H), 6.23 (d, 1H), 7.00 (s, 1H), 7.22-7.25 (m, 1H), 7.57 (dd, 1H), 7.96 (dd, 1H), 8.22 (s, 1H), 8.25 (d, 1H), 8.37 (d, 1H), 8.96 (s, 1H) CDCI3: 1.17 (t, 3H), 1.71-1.79 (m, 1H), 2.28 (s, 3H), 2.62 (d, 3H), 3.41 (q, 2H), 3.46 (t, 2H), 3.79 (q, 2H), 4.41-4.48 (m, 1H), 6.43 (s, 1H), 6.10-6.18 (m, 2H), 7.15 (dd, 1H), 7.33 (d, 1H), 7.35-7.42 (m, 1H), 7.90 (dd, 1H), 8.16 (s, 1H), 8.45 (d, 1H), 9.07 (s, 1H).
Rf CDCI3: 2.66 (d, 3H), 3.91 (s, 3H), 4.41-4.47 (m, 1H), 6.80 (d, 1H), 6.92 (dd, 1H), 7.26-7.35 (m, 1H), 7.54 (s, 1H), 7.76 (dd, 1H), 8.00 (dd, 1H), 8.27-8.32 (m, 2H), 8.38 (dd, 1H), 8.97 (s, 1H). MS CDCI3: 2.26 (s, 3H), 2.62 (d, 3H), 2.68 (s, 6H), 4.72 491,493 (q, 1H), 6.78 (s, 1H), 6.89 (d, 1H), 7.12 (d, 1H), 7.15 (d, 1H), 7.40-7.47 (m, 2H), 7.91 (dd, 1H), 8.40 (s, 1H), 8.41 (dd, 1H), 9.11 (s, 1H). MS CDCI3: 2.04 (s, 3H), 2.65 (d, 3H), 4.42-4.48 (m, 1H), 525, 527 6.79 (s, 1H), 6.96-7.00 (m, 2H), 7.28-7.34 (m, 4H), 7.87-7.91 (m, 1H), 8.18 (s, 1H), 8.23-8.26 (m, 2H), 8.53 (d, 2H), 9.07 (s, 1H). 95245.doc -53- -37-
1378923Case 4-3291OA 3-55 Rf (己烷: AcOEt=3:1) 0.19 CDCI3: 1.34 (t, 3H), 1.44 (t, 3H), 2.63 (d, 3H), 3.81 (q, 2H), 4.06 (q, 2H), 4.46 (q, 1H), 6.43 (dd, 1H), 6.76 (d, 1H), 7.63-7.69 (m, 2H), 7.94 (d. 1H), 7.98 (dd, 1H), 8.42 (d, 1H), 8.93 (s. 1H). 3-56 0 / MS 570, 572 CDCI3: 2.63 (d. 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.52 (q, 1H), 6.78-6.83 (m, 2H), 6.93 (d, 2H), 6390-7.02 (m, 1H), 7.11-7.15 (m, 1H), 7.21-7.27 (m, 1H), 7.61 (s. 1H), 7.87-7.92 (m, 1H), 8.26 (s, 1H), 8.20-8.30 (m, 1H), 8.38-8.41 (m, 1H), 8.92 (s, 1H). I* 3-57 o Rf (己坑:Ac OEt=3:1) 0.16 CDCI3: 1-44 (t, 3H), 2.65 (d, 3H),2.79-2.89 (m, 4H), 3.65-3.74 (m, 4H), 4.07 (q, 2H), 4.52 (q, 4H), 6.48 4 (dd, 1H), 6.80 (d, 1H), 7.20-7.25 (m, 1H), 7.55-7.67 (m, 2H), 7.92-7.98 (m, 2H), 8.29 (s, 1H), 8.43 (d, 1H), 8.95 (s, 1H). 3-58 O Rf 0.17 (己炫:Ac OEt=1/1) CDCI3: 1.46 (t, 3H), 2.63 (d, 3H), 3.08-3.13 (m, 4H), 3.83-3.90 (m, 4H). 4.09 (q, 2H), 4.46 (q, 1H), 6.39 (dd, 1H), 6.51 (d, 1H), 7.21-7.28 (m, 1H), 7.37 (s, 1H), 7.58 (dd, 1H), 7.97 (dd, 1H), 8.03 (d, 1H), 8.21 (s, 1H), 8.46 (d,1H), 8.94 (s, 1H). 3-59 ) 0 / MS 538, 540 CDCI3: 2.63 (d, 3H), 3.44 (s, 3H), 3.65 (s, 3H), 3.69-3.73 (m, 2H), 4.10-4.15 (m, 2H), 4.40 (q, 1H), 6.45 (dd, 1H), 6.85 (d, 1H), 7.19-7.25 (m, 1H), 7.61 (dd, | 1H), 7.88 (s, 1H), 7.93-7.97 (m, 2H), 8.27 (s, 1H), 8.46 (d, 1H), 8.95 (s, 1H). 3-60 O / Rf (AcOEt) 0.54 CDCI3: 2.63 (d, 3H), 3.67 (s, 3H), 4.18 (t, 2H), 4.38-4.49 (m, 3H), 6.46 (dd, 1H), 6.81 (d, 1H), 7.60-7.69 (m, 2H), 7.92-7.99 (m, 2H), 8.27 (s, 1H), 8.49 (d, 1H), 9.00 (s, 1H). 3-61 0 / Rf (己烷: AcOEt=2:1) 0.46 CDCI3: 1.44 (t, 3H), 2.63 (d, 3H), 3.64 (s, 3H), 4.07 (q, 2H), 4.47 (q, 1H), 6.45 (dd, 1H), 6.78 (d, 1H), 7.21-7.28 (m, 1H), 7.40-7.48 (m, 2H), 7.93-7.99 (m, 2H), 8.26 (s, 1H), 8.44 (d, 1H), 8.96 (s, 1H). 95245.doc •54· 1378923 3-62 0 / Rf (己炫:Ac 0Et=3:1) 0.31 CDCI3: 1.36 (d, 6H), 2.63 (d. 3H), 3.63 (s, 3H), 4.41-4.52 (m, 2H), 6.45 (dd, 1H), 6.81 (d, 1H), 7.21-7.26 (m, 1H), 7.59-7.68 (m, 2H), 7.91-7.98 (m, 2H), 8.26 (s, 1H), 8.45 (d, 1H), 8.96 (s, 1H). 3-63 A。" / RU己烷: AcOEt=3:1) 0.40 CDCI3: 1.07 (t, 3H), 1.84 (m, 2H), 6.63 (d, 3H), 3.64 (s, 3H), 3.96 (t, 2H), 4.40-4.49 (m, 1H), 6.46 (dd, 1H), 6.79 (d, 1H), 7.20-7.27 (m, 1H), 7.58-7.66 (m, 2H), 7.94-7.97 (m, 2H), 8.26 (s. 1H), 8.45 (d, 1H), 8.97 (s, 1H). ’3-64 Μ Rf (己烷:Ac OEt=3:1) 0.19 CDCI3: 2.62 (d, 3H), 6.68 (s, 6H), 3.84 (s, 3H), 4.41-4.48 (m, 1H), 6.36 (dd, 1H), 6.80 (d, 1H), 7.17-7.24 " (m, 1H), 7.51-7.62 (m, 2H), 7.83 (s, 1H), 7.95 (dd, 1H), 8.27 (s, 1H), 8.3*9-8.45 (m, 1H), 8.91 (s, 1H). 3-65 Rf (己烧:Ac OEt=1:1) 0.12 CDCb: 2.66 (d, 3H), 3.97 (s, 3H), 4.47-4.55 (m, 1H), 6.96-7.10 (m, 3H), 7.21-7.24 (m, 1H), 7.66 (s, 1H), 7.93 (dd, 1H), 8.25 (d, 1H), 8.31 (s, 1H), 8.47 (d, 2H), 8.59 (s, 1H), 8.96 (s, 1H). 3-66 \i MS 541, 543 CDCb: 2.65 (d, 3H), 3.96 (s, 3H), 4.61-4.71 (m, 1H), 6.89-7.05 (m, 3H), 7.16 (dd, 1H), 7.15-7.23 (m, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 7.89 (d, 1H), 8.21 (d, 1H), 8.28 (d, 1H), 8.51 (br. s, 2H), 8.57 (s, 1H), 8.93 (s, 1H). I 3-67 MS 541, 543 CDCb: 2.65 (d, 3H), 3.96 (s, 3H), 4.51 (q, 1H), 6.90-7.06 (m, 3H), 7.11-7.16 (m, 1H), 7.38 (d, 1H), 7.50-7.61 (m, 2H), 7.62-7.67 (m, 1H), 7.89 (dd, 1H), 8.29 (s, 1H). 8.34 (d, 1H), 8.53 (d, 1H), 8.79 (br.s, 1H), 8.94 (s, 1H). 3-68 φτ。、 cV 0 LC*MS 590 CDCI3: 1.45-1.59 (m, 2H), 1.70-1.78 (m, 1H), 1.82-1.90 (m, 1H), 2.38-2.50 (m, 1H), 2.43 (s, 3H), 2.62-2.77 (m, 2H), 3.56-3.70 (m, 2H), 3.76 (s, 3H), 6.46 (dd, 1H), 6.63 (d, 1H), 6.82-6.88 (br, 1H), 7.22 (dd, 1H), 7.31-7.40 (m, 2H), 7.43-7.51 (m, 1H), 7.50-7.80 (m, 2H), 8.14-8.20 (br, 1H), 8.21 (s, 1H), 8.39-8.48 95245.doc -55- 1378923 (m, 1H), 9.16-9.26 (br, 1H) 3-69 ΓΝΛ。、 0.34 (CH2CI2:M eOH=9:1) CDCI3: 1.58-1.82 (br, 7H), 1.88-2.03 (br, 3H), 2.44-2.45 (m,5H), 3.42-3.52 (m, 3H), 3.75 (s, 3H), 6.66 (dd, 1H), 6.92 (d, 1H), 7.28 (dd, 1H), 7.44 (br, 1H), 7.51 (dd, 1H), 7.79-7.81 (m, 2H), 8.18 (s, 1H), 8.32 (s, 1H), 8.35-8.37 (m, 1H), 9.17 (s, 1H) 3-70 l· φτ。、 λ 0 Ms:607, 609 DMSO-d6: 1.84-1.92(m, 2H), 2.34-2.41 (m, 4H), 2.41-2.45(m, 3H), 2.44(t, 2H), 3.58(t, 4H), 3.75(s, 3H), 4.02(t, 2H), 6.48(dd, 1H), 6.63(d, 1H), 7.21(dd, 1H), 7.41 (d, 1H), 7.46(dd, 1H), 7.72-7.78(m, 1H), 7.76(dd, ^ 1H), 8.22(s, 1H), 8.25(s, 1H), 8.40(d, 1H), 9.22(s, 1H) 3-71 φτ λ 0 Ms:591, 593 DMSO-d6: 1.84-1.92(m, 2H), 2.14(s, 3H), 2.35-2.4 (m, 4H), 2.43(t, 2H), 2.44(d, 3H), 3.58(t, 4H), 4.01 (t, 2H), 6.77(dd, 1H), 6.82(d, 1H), 7.17(dd, 1H), 7.20(d, 1H), 7.3-7.39(m, 1H, 7.71-7.77(m, 2H), 8.2(s, 1H), 8.35-8.44(m, 1H), 8.71(s, 1H), 9.27(s, 1H) L 3-72 φτ。、 λ 0 I Ms:620, 622 DMSO-d6: 1.82-1.9 (m, 2H), 2.13-2.17 (m, 3H), 2.25-2.47(m, 13H), 3.75 (s, 3H), 4.01 (t, 2H), 6.47 (dd, I 1H), 6.63(d, 1H), 7.19-7.24 (m, 1H), 7.41 (d, 1H), 7.43-7.5(m, 1H), 7.70-7.79(m, 2H), 8.22(s, 1H), 8.25(brs, 1H), 8.37-8.44(m, 1H), 9.22(s, 1H) 3-73 Λ。、 Ms:607, 609 DMSO-d6: 1.78 (t, 2H), 2.32-2.36 (m, 4H9, 2.35-2.38 (m, 3H), 3.54-3.59 (m, 4H), 3.74 (t, 3H), 3.78 (s, 3H), 6.38-6.42 (m, 1H), 6.85 (d, 1H), 6.86-6.95 (m, 1H), 7.33-7.43(m, 2H), 7.63-7.68 (m, 1H), 7.85-8.15 (m, 3H), 8.64-8.8 (m, 1H). 95245.doc -56- 1378923 3-74 b • • φ"、 ί Ms:605, 607 DMSO-d6: 1.47-1.67(m. 2H), 1.84-2.01 (m, 2H), 2.03 (s, 3H), 2.41-2.46 (m, 3H), 3.23-3.39 (m, 2H), 3.65-3.73 (m, 1H), 3.81 (s, 3H), 3.8-3.88 (m, 1H), 4.58-4.65 (m, 1H), 6.55 (dd, 1H), 6.68 (d, 1H), 7.2-7.26(m, 1H), 7.43(d, 1H), 7.42-7.51 (m, 1H), 7.7-7.8(m, 2H), 8.23 (s, 1H), 8.26 (brs, 1H), 8.37-8.44(m, 1H), 9.22(brs, 1H) Λ。、 έ Ms:605, 607 DMSO-d6: 1.38-1.6(m, 2H), 1.74-1.9(m, 2H), 2.0 (s, 3H), 2.42-2.47 (m, 3H), 3.12-3.3 (m, 2H), 3.55-3.65 (m, 1H), 3.7-3.8 (m, 1H), 3.78 (s, 3H), 4.27-4.34 (m, 1H), 6.65 (dd, 1H), 6.94 (d, 1H), 7.24-7.3 (m, 1H), < 7.53-7.63(m, 2H), 7.74-7.83 (m, 2H), 8.09 (brs, 1H), 8.35 (s, 1H), 8.38(d, 1H), 9.19(brs, 1H) 3-75 It 3-76 卢。、 ό I Ms:577, 579 DMSO-do: 1.51-1.61 (m, 2H)t 1.79-1.87 (m, 2H), 2.03-2.11 (m, 2H), 2.14 (s, 3H), 2.42-2.47 (m, 3H), 2.52-2.6 (m, 2H), 3.77 (s, 3H), 4.02-4.09 (m, 1H), 6.6 (dd, 1H), 6.92 (d, 1H), 7.24-7.3 (m, 1H), 7.52-7.6(m, 2H), 7.74-7.82 (m, 2H), 8.08 (brs, 1H), 8.34 (s, 1H), 8.4 (d, 1H), 9.2 (brs, 1H) 3-77 II Λρ Rf: 0.4 (正己烷: AcOEt=7:3) DMSO-d6: 2.41-2.45 (m, 3H), 6.89-6.96 (m, 1H), 6.69(bs, 1H), 7.24-7.33 (m, 2H), 7.51-7.57 (m, 1H), 7.63-7.7 (m, 1H), 7.73-7.78 (m, 1H), 7.79 (dd, 1H), 8.37(s, 1H), 8.41 (d, 1H), 9.21 (brs, 1H), 9.24 (brs, 1H) 3-78 6 Η Ms:563, 565 DMSO-d6: 1.33-1.43 (m, 2H), 1.79-1.86 (m, 2H), 2.43-2.46 (m, 3H), 2.46-2.53 (m, 2H), 2.87-2.94 (m, 2H), 3.77 (s, 3H), 4.07-4.14 (m, 1H). 6.59 (dd, 1H), 6.91 (d, 1H), 7.23-7.28 (m, 1H), 7.53-7.59 (m, 2H), 7.79 (dd. 1H), 8.03 (brs, 1H), 8.32 (s, 1H), 8.38 (d, 1H), 8.7-9.5 (brs, 1H) 95245.doc 57 · 1378923 3-79 (V" ό Η Ms:563, 565 DMSO-d6: 1.41-1.51 (m, 2H), 1.88-1.95 (m, 2H), 2.41-2.45 (m, 3H), 2.54-2.63 (m, 2H), 2.92-3.0 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.50 (dd, 1H), 6.63 (d, 1H), 7.18-7.23 (m, 1H), 7.40 (d, 1H), 7.42-7.48 (m, 1H), 7.75 (dd, 1H), 8.21 (s, 1H)r 8.22-8.25 (m, 1H), 8.37-8.42 (m, 1H), 8.9-9.5 (brs, 1H) 3-80 1丨 φτ" F Ms:482, 484 DMSO-d6: 2.4-2.46 (m, 3H), 3.79 (s, 3H), 6.72 (ddd, 1H), 6.99 (dd, 1H), 7.21-7.26 (m, 1H), 7.47-7.53 (m, 1H), 7.59-7.64 (m, 1H), 7.76 (dd, 1H), 8.25 (s, 1H)t 8.29-8.37 (m, 2H), 8.8-9.6 (m, 1H) 3-81 Λ。、 Ms:482, 484 DMSO-d6: 2.41-2.49 (mt 3H), 3.82 (s, 3H). 6.80 (ddd, 1 1H), 7.01 (dd, 1H), 7.3-7.35 (m, 1H), 7.56-7.63 (m, 1H), 7.7-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H), 8.16 (s, 1H), 8.35 (dd, 1H), 9.18 (brs, 1H) 3-82 ά \ Ms:563, 565 DMSO-d6: 1.73-1.82 (m, 1H), 2.23-2.34 (m, 4H), 2.34-2.42(m, 3H), 2.42-2.46 (m, 3H), 2.59 (dd, 1H), 2.62-2.68 (m, 1H), 2.80 (dd, 1H), 3.75 (s, 1H), 4.85-4.91 (m. 1H), 6.42 (dd, 1H), 6.57(d, 1H), 7.19-7.24(m, 1H), 7.41 (d, 1H), 7.43-7.51 (m, 1H), 7.68-7.79 (m, 2H), 8.22(s, 1H), 8.23(s, 1H), 8.37-8.43 (m, 1H), 9.21 (brs, 1H). 爹 3-83 φτ, MS 544, 546 2.36 (s, 3H), 2.65 (d, 3H), 3.93 (s, 3H), 4.46-4.51 (m,( 1H), 6.75-6.80 (m, 2H), 6.97-7.04 (m, 2h), 7.25-7.30 (m, 1H), 7.56-7.66 (m, 2H), 7.98 (dd, 1H), 8.29 (s, 1H), 8.36-8.44 (m, 2H), 9.01 (s, 1H). 3-84 〇Α’ MS 562, 564 CDCI3: 2.32 (s, 3H), 2.39-2.47 (m, 4H), 2.64 (d, 3H), 2.89-2.97 (m. 4H), 3.85 (s, 3H), 4.54-4.52 (m, 1H), 6.52 (dd, 1H), 6.79 (d, 1H), 7.22 (m, 1H), 7.52-7.64 (m, 2H), 7.94-7.99 (m, 2H), 8.28 (s, 1H), 8.42 (d, 1H), 8.93 (s, 1H). 95245.doc ·58· 1378923 實例4 : 2-【5-溴基-2-(經取代之苯基胺基)-嘧啶_4_基胺基】_ N-丙基··苯磺醯胺 以類似於實例2製備這些化合物,其係使用2_(5•填基_2_ 氣基-嘧啶-4-基胺基)-N-丙基-苯磺醯胺及對應的苯胺,得 到具有以實例3的第3-1至3-31號化合物所列之取代基^的 第4-1至4-31號化合物。 2-(5-溴基-2-氣基-嘧啶-4-基胺基)-N-丙基-苯磺醢胺之製備 作用 將在0河30(1.0毫升)中的氫化鈉(54.2毫克,〇.56毫莫耳)® 加入5-溴基-2,4-二氣基嘧啶(9〇微升,0.70毫莫耳)及2_胺 基-N-丙基-苯磺醯胺(1〇〇毫克,〇47毫莫耳)之溶液中,並 將所得溶液在80°C下攪拌3.0小時》將混合物倒入水中及 以醋酸乙醋萃取三次。將有機層以水及接著以食鹽水清 洗’經硫酸鋼乾燥及在真空中蒸發^將殘餘物以矽膠管柱 色層分離法(正己烷:醋酸乙酯=5:1)純化,供應成為淺黃色 固體之標題化合物。 Ή-NMR (δ, ppm): o 89 (t> 3H), 1.41 (q, 2H), 3.56 (t, 2H), ^ 4.92 (br.s,2H),6.71 (dd,1H), 6.77 (dd,1H),7.33 (dd,1H), 7·54 ⑽,1H)’ 8.79(s,1H)。Rf (己烷:醋酸乙酯=l:i):0.64。 實例5.2-[5-二氟甲基_2 (經取代之苯基胺基)嘧啶_4基胺 基】-N-甲基苯磺醖胺 、通似於實例2製備這些化合物’其係使用2-(2-氣基-5_ 一氟甲基-嘧啶-4-基胺基)-N-甲基-苯磺醯胺及對應的苯 胺付到具有以實例3的第3-1至3-31號化合物所列之取代 95245.doc -59- 1378923 基1的第5-1至5-31號化合物。 2-(2-氣基-5-三氟甲基-嘧啶-4·基胺基)_N_甲基·苯磺醯胺之 製備作用 將2 -胺基-N-甲基-苯續酿胺(3 33毫克,1.79毫莫耳)及 1,8-二氮雜[5.4.0]-雙環-7-十一碳烯(280微升,1.88毫莫耳) 在室溫下連續加入在乙腈(10毫升)中的2,4_二氣基_5二氟 甲基-嘧啶(386毫克’ 1.79毫莫耳)之溶液中。在室溫下攪拌 15小時之後,將二氣曱烷(30毫升)加入混合物中,並將溶液 以飽和水性碳酸氳鈉及飽和水性氣化鈉清洗,經硫酸鎮乾 燥及在真空中祭發。將所得固體以閃蒸色層分離法純化。 H-NMR (CDCI3) 5:3.73 (s, 3H), 6.67-6.69 (m, 1H), 6.72-6.73 (m, 1H), 7.27-7.31 (m, 1H),7.78 (dd, 1H), 8.60 (s, 1H)。Rf (己烷:醋酸乙酯=1:1): 0.28。 實例6 : 2-[5-溴基-2-(2,3-[二氟基甲二氧基】苯基胺基)_嘧 咬-4-基胺基】-苯續酿胺
在以2-(5-漠基-2-氣基嘧啶_4._基胺基)_N_甲基-苯磺醯胺 與2,3-(二氟基甲二氧基)笨胺依照實例2的步驟反應時,獲 得以N-脫曱基化作用所形成之副產物的該化合物。以2·(5_ 溴基-2·•氯基嘧啶-4-基胺基)苯磺醯胺與2,3_(二氟基甲二氧 基)苯胺的反應也可以製備該化合物。 95245.doc •60· 1378923
Rf(正己烷:醋酸乙酯=1:1):0.46。 'H-NMR: (CDC13) 4.83 (bs, 2H), 6.77 (dd, 1H), 6.86 (s,
1H), 6.97 (dd, 1H), 7.31-7.24 (m, 1H) ,7.57 (dd,lH), 7.81 (d, 1H), 8.02 (dd, 1H), 8.28 (d, 1H), 8.29 (s, 1H),8.88 (s, 1H)。 2-(5-溴基-2-氣基嘧啶-4-基胺基)苯磺醯胺之製備作用:
將濃縮氫氣酸(0.06毫升)加入在2_丙醇(3毫升)中的5_溴 基-2’4-二氣基嘧啶(300毫克,丨32毫莫耳)及2胺基·苯磺 醯胺(340毫克,ι·97毫莫耳)之溶液中,並將混合物在9〇。〇 下攪拌4.5小%。將混合物倒入水性碳酸氫鈉中及以醋酸 乙萃取二次。將有機層以水清洗,經硫酸鈉乾燥及在真 空中蒸發。將殘餘物以管柱色層分離法(己烧:醋酸乙醋 = 2:1)純化’供應標題化合物。
Rf(己烧:醋酸乙醋=1:1):0.55。lH_NMR (4〇〇MHz,CDd) δ . 4.78 (br.s, 2H),7.22 (dd, 1H),7.61 (ddd, 1H), 7.95 (dd,
1H),8.32 (s,1H), 8.35 (d, 1H),9.18 (s,1H)。 實例7A · 2-丨s-氣基-2-(2-甲氧基_4_嗎淋_4_基-苯基胺基 喊咬-4-基胺基】_N_甲基-苯醯胺
0 將2-甲氧基-4·嗎啉代苯胺二鹽酸鹽(4 56公克,162毫莫 耳)及17.0毫升之1當量氯化氫乙醇系溶液(17.0毫莫耳)加入 95245.doc 1378923 在90毫升2-甲氧基乙醇中的2·(2,5·二氣基-嘧啶_4·基-胺 基)-Ν-甲基-笨醯胺(5.05公克,17.0毫莫耳)之懸浮液中。
在將反應混合物在11(TC下攪拌4小時及冷卻至室溫之後, 將混合物以1當量NaOH水溶液中和及以EtOAc(i〇〇毫升x3)
萃取。將有機層以食鹽水清洗’經Na2S04乾燥及在減壓下 濃縮。將所得黑色固體以EtOH(90毫升)清洗,接著以矽膠 管柱色層分離法(CH2C12至CH2Cl2:AcOEt=l:2)純化,得到 成為淡黃色固體之2-[5-氣基-2-(2-甲氧基-4-嗎啉-4-基-苯 基胺基)-嘧啶-4-基胺基]-N-甲基-苯醯胺。 ® *H-NMR (400MHz,DMSO-d6,δ): 2.80 (d,3H,J=4.52Hz), 3.10-3.20 (m, 4H), 3.78 (s, 3H), 3.70-3.80 (m, 4H), 6.49 (dd, 1H, J=8.56, 2.52Hz), 6.66 (d, 1H, J=2.52Hz), 7.08 (dd, 1H, J=8.04, 8.04Hz), 7.44(d, 1H, J=8.56Hz), 7.71(dd, 1H, J=8.04, 1.48Hz), 8.10 (s, 1H), 8.13 (s, 1H), 8.59 (d, 1H, J=8.04Hz), 8.68-8.75(m,1H),11.59(s,1H)。MS m/z 469, 471(M+1)+。 依照實例7A之步驟,自2-(2,5-二氣基-嘧啶-4-基胺基)-N-甲基-苯醯胺及對應的苯胺製備以下的2-[5-氯基-2-(經取 代之苯基胺基)-嘧啶-4-基胺基]-N-甲基-苯醯胺。
95245.doc •62· 1378923- 實例 編號
Rx
Rf (溶劑) 或MS NMR (400MHz), δ (ppm) 7-1
MS: m/z 550, 552 (M+1) DMSO-d6: 1.44-1.33 (m, 2H)t 1.64-1.45 (m, 6H), 1.73-1.89 (m, 2H), 2.34-2.44 (m, 1H), 2.43-2.55 (m, 4H), 2.65 (t, 2H), 2.80 (d, 3H), 3.75 (s, 3H), 3.72-3.75 (m, 2H), 6.48 (dd, 1H), 6.62 (d, 1H), 7.06 (dd, 1H), 7.32 (dd, 1H), 7.39 (d, 1H). 7.71 (dd, 1H), 8.09(s, 1H), 8.60 (d, 1H), 8.70 (d, 1H), 11.58 (s, 1H) 7-2
0.3 (MeOH: AcOEt =5:95) CDCI3: 1.70-1.97(m, 4H) ,2.62-2.79(m, 1H), 3.04(d, 3H), 3.02-3.18(m, 2H), 3.23-3.33( m, 2H), 3.88 (s, 3H), 5.39-5.47(m, 1H), 6.15-6.24(m, 1H), 6.55-6.62(m, 2H), 6.74-6.82(m, 1H), 7.09 (dd, 1H),7.23-7.32 (m, 1H), 7.46-7.52(m, 2H), 8.09(s, 1H), 8.15(d, 1H), 8.68(d, 1H) 11.0(bs, 1H) 7-3
MS (ESI) m/z 482, 484 (M+1)* DMSO-d6: 2.24 (s, 3H), 2.45-2.55 (m, 4H), 2.80 (d, 3H, J = 4.52 Hz), 3.12-3.17 (m, 4H), 3.76 (s, 3H), 6.48 (dd, 1H, J = 8.56, 2.52 Hz), 6.63 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.27-7.35 (m, 1H), 7.40 (d, 1H, J = 8.56 Hz), 7.69-7.72 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.65 (m, 1H), 8.67-8.75 (m, 1H), 11.59 (s, 1H) 7-4
o 0.46 (MeOH: CH2CI2=1:4) DMSO-d6: 2.48-2.55(m, 4H), 2.71 (t, 2H), 2.80(d, 3H), 3.58-3.61 (m, 4H), 3.76(s, 3H), 4.11(t, 2H), 6.52(dd, 1H), 6.66(d, 1H), 7.06(dd, 1H), 7.32(dd, 1H), 7.46(d, 1H), 7.71(dd, 1H), 8.11(s, 1H), 8.19 (s, 1H), 8.54-8.60(m, 1H), 8.60-8.75(m, 1H), 11.6(s, 1H) 7-5
m/z 497, 499 (M+1)* DMSO-d6: 1.60-1.70 (m, 2H), 1.90-1.98 (m, 2H), 2.13-2.25 (m, 2H), 2.19 (s, 3H), 2.60-2.67 (m, 2H), 2.80 (d, 3H, J = 4.52 Hz), 3.75 (s, 3H), 4.30-4.40 (m, 1H), 6.54 (dd, 1H, J = 8.56, 2.0 Hz), 6.65 (d, 1H, J = 2.0 Hz), 7.04-7.09 (m, 1H), 7.25-7.35 (m, 1H), 7.43 (d, 1H, J = 8.56 Hz), 7.68-7.73 (m, 1H), 8.10 (s, 1H), 8.18 (s, 1H) 8.52-8.59 (m, 1H), 8.68-8.75 (m, 1H), 11.57 (s, 1H) 95245.doc -63 - 1378923 7-6 Ο ά。、 0.25 (正己烷: AcOEt=1:2) CDCI3 : 2.95 (m, 4H), 3.03 (d, 3H), 3.75 (m, 4H), 3.86 (s, 3H), 6.21-6.19 (br, 1H), 6.49 (dd, 1H), 6.80 (d, 1H), 7.09-7.05 (m, 1H), 7.50 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.68 (d, 1H), 11.07 (s, 1H) 7-7
MS m/z 510, 512 (M+1) DMSO-d6: 2.06 (s, 3H), 2.80 (d, 3H), 3.11 (t, 2H), 3.16 (t, 2H), 3.60 (dd, 4H), 3.77 (s, 3H), 6.51 (dd, 1H), 6.68 (d, 1H), 7.08 (dd, 1H), 7.33 (dd, 1H), 7.46 (d, 1H), 7.71 (d, 1H), 8.10(s, 1H), 8.12(s, 1H), 8.59-8.61 (m, 1H), 8.70-8.71 (m, 1H), 11.59 (s, 1H) 7-8
0.48 (MeOH: AcOEt =5:95) CDCI3: 1.46(d, 1H), 1.68-1.82(m, 2H), 2.02-2.09(m, 2H), 2.83-2.96 (m, 2H), 3.03(d, 3H),3.44*3.53(m, 2H), 3.82-3.92(m, 1H),3.87(s, 3H), 6.15-6.23(m, 1H), 6.51 (d, 1H), 6.56(bs, 1H), 7.07(dd, 1H), 7.48(d, 2H), 8.08(s, 1H), 8.08-8.10(m, 1H), 8.69(d, 1H), 11.0(bs, 1H) 7-9
0.4 (正己炫: AcOEt=1:1) CDCI3: 1.22 (t, 3H), 1.73-1.85 (m, 2H), 2.00-2.09 (m, 2H), 2.81-2.90 (m, 2H), 3.03 (d, 3H), 3.41-3.56 (m, 3H), 3.56 (dd, 2H), 3.58-3.62 (m, 2H), 3.64-3.68 (m, 2H), 3.86 (s, 3H)t 6.15-6.24 (m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07(dd, 1H), 7.24-7.30 (m, 1H), 7.45-7.52(m, 2H), 8.08(s, 1H), 8.06-8.08 (m, 1H), 8.69 (d, 1H), 11.0 (bs, 1H) 7-10
0.4 (正己院: AcOEt=1:1) CDCI3: 1.73-1.85(m, 2H), 2.01-2.10(m, 2H), 2.82-2.90(m, 2H), 3.03(d, 3H), 3.41 (s, 3H), 3.45-3.51 (m, 2H), 3.56-3.58(m, 2H), 3.65-3.68(m, 2H), 3.86(s, 3H), 6.14-6.22(m, 1H), 6.50 (dd, 1H), 6.56 (d, 1H), 7.07(dd, 1H), 7.23-7.30(m, 1H), 7.44-7.52(m, 2H), 8.08(s, 1H), 8.06-8.08(m, 1H), 8.69(d, 1H), 11.0(bs, 1H) 95245.doc 64- 1378923 7-11
N— 0.54 (MeOH: CH2C 丨 2=1:4) DMSO-d6: 1.78-1.89(m, 1H), 2.13-2.22(m, 1H), 2.22(s, 6H), 2.77-2.87(m, 1H), 2.79(d, 3H), 3.04-3.10(m, 1H), 3.23-3.50(m, 3H), 3.75(s, 3H), 6.11(dd, 1H), 6.22(d, 1H), 7.05(dd1H), 7.21-7.32(m, 1H), 7.26(d, 1H), 7.70(d, 1H), 8.06(s, 1H), 8.08(s, 1H), 8.57-8.66(m, 1H), 8.66-8.73 (m, 1H), 11.6(s, 1H) 7-12 Φ
0.27 (MeOH: CH2CI2=1:1) DMSO-d6: 1.77-1.87(m, 1H), 2.09-2.18(m, 1H), 2.35(s, 3H), 2.79(d, 1H), 3.02-3.07(rn, 1H), 3.23-3.50(m, 4H), 3.74(s, 3H), 6.09(dd, 1H), 6.20(d, 1H), 7.04(dd, H), 7.22-7.32(m, 1H), 7.26(d, 1H), 7.70(d, 1H), 8.05(s, 1H), 8.08(s, 1H), 8.57-8.67(m, 1H), 8.67-8.73 (m, 1H), 11.6(s, 1H) 7-13
HjN \〇 0.23 (MeOH: AcOEt =5:95) CDCI3: 1.62-1.74(m, 3H), 1.76-1.85(m, 2H), 2.00-2.09(m, 2H), 2.20-2.31 (m, 1H), 2.64-2.69 (m, 2H), 2.79 (d, 3H), 3.56-4.04(m, 2H), 4.04(s, 3H), 6.49(dd, 1H), 6.63(d, 1H), 6.78(bs, 1H), 7.07 (dd, 1H), 7.28-7.38 (m, 1H), 7.39(d, 1H), 7.71 (d, 1H), 8.09-8.11(m, 2H), 8.09(s, 1H), 8.60(d, 1H), 8.71(d, 1H),11.6(bs, 1H) 7-14 0.30 (MeOH: CH2CI2=4:1) DMSO-d6: 1.61-1.46(m, 2H), 1.92-1.82 (m, 2H), 2.14 (s, 3H), 2.41-2.23 (m, 5H, 2.60-2.45 (m, 4H), 2.67 (t, 2H), 2.79 (d, 3H), 3.75 (s, 3H), 3.71-3.75 (m, 2H), 6.48 (dd, 1H), 6.63 (d, 1H), 7.10-7.03 (m, 1H), 7.34-7.27 (m, 1H), 7.43-7.35 (m, 1H), 7.71 (dd, 1H), 8.09 (s, 1H), 8.11 (bs, 1H), 8.65-8.56 (m, 1H), 8.75-8.67 (m, 1H), 11.6 (s, 1H) 95245.doc 65- 1378923 7-15
MS (ESI) m/z 524, 526 (M+1)+ DMS0-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 (m, 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H) 7-16
MS (ESI) m/z 524, 526 (M+1)+ DMSO-d6: 2.19-2.37 (m, 4H), 2.65-2.85 (m, 3H), 2.80 (d, 3H, J = 4.5 Hz), 3.15-3.21 (m, 1H), 3.48-3.59 (m,( 2H), 3.61-3.67 (m, 1H), 3.72-3.81 (m, 1H), 3.76 (s, 3H), 6.47 (dd, 1H, J = 8.6, 2.5 Hz), 6.65 (d, 1H, J = 2.5 Hz), 7.04-7.10 (m, 1H), 7.28-7.35 (m, 1H), 7.42 (d, 1H, J = 8.6 Hz), 7.69-7.74 (m, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.55-8.63 (m, 1H), 8.68-8.73 (m, 1H), 11.60 (s, 1H) 7-17
MS 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63(m, 1H), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.76(s,3H), 6.50 (dd, 1H), 6.64 (d, 1H), 6.86(bs, 1H), 7.07(dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09(s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58(m, 1H), 8.77-8.70(m, 1H), 11.6(s, 1H) 7-18
MS 510 DMSO-d6: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63(m, 1H), 2.80 (d, 3H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.76(s,3H), 6.50 (dd, 1H), 6.64 (d, 1H), 6.86(bs, 1H), 7.07(dd, 1H), 7.46-7.19 (m, 3H), 7.71 (d, 1H), 8.09(s, 1H), 8.15-8.10 (m, 1H), 8.66-8.58(m, 1H), 8.77-8.70(m, 1H), 11.6(s, 1H) 95245.doc -66- 1378923 7-19 • ρΛ。、 0.16 (CH2CI2:M eOH=9:1) 1.40-1.53 (m, 2H), 1.72-1.80 (m, 2H), 2.18 (s, 3H), 2.19-2.44 (m, 5H), 2.80 (d, 3H), 3.46 (m, 2H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.91 (d, 1H), 7.07-7.10 (m, 1H), 7.36-7.40 (m, 1H), 7.45-7.49 (m, 1H), 7.73 (dd, 1H), 8.12 (s, 1H), 8.18 (s, 1H), 8.61 (d, 1H), 8.72-8.77 (m, 1H), 11.68 (s, 1H) 7-20 l· φτ" Vx Ms : 511 1.25-1.37 (m, 2H), 1.62-1.79 (m, 3H), 1.81-1.9 (m, 2H), 2.16 (s, 3H), 2.75-2.85 (m, 5H), 3.76 (s, 3H), 3.8-3.88 (m, 2H), 6.45-6.55 (m, 1H), 6.6-6.67 (m, 1H), 7.02-7.12 (m, 1H), 7.25-7.35 (m, 1H), 7.4-7.5 (m, 1H), 7.67-7.78 (m, 1H), 8.1 (s, 1H), 8.19 (brs, 1H) 8.5-8.62 4 (m, 1H), 8.66-8.8 (m, 1H), 11.6 (s, 1H) 7-21 ο. Ms :526 2.17 (s, 3H), 2.29-2.39 (m, 3H), 2.45-2.56 (m, 4H), 2.7 (t, 2H), 3.76 (s, 3H), 4.09 (t, 2H), 6.52 (dd, 1H), 6.66 (d, 1H), 7.06 (dd, 1H), 7.31 (dd, 1H), 7.45 (d, 1H), 7.71 (dd, 1H), 8.1 (s, 1H), 8.19 (s, 1H), 8.5-8.6 (m, 1H), 8.67-8.75 (m, 1H), 11.6 (s, 1H) 7-22 Ms :482 2.24 (s, 3H), 2.42-2.5 (m, 4H), 2.8 (d, 3H), 2.94-3.0 (m, 4H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.93 (d, 1H), 7.07-7.14 (m, 1H), 7.34-7.4 (m, 1H), 7.45 (d, 1H), . 7.73 (dd, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.61 (dd, 1H), 8.7-8.77 (m, 1H), 11.7 (s, 1H) 7-23 ΗΝ I Ms :482 1.67-1.76 (m, 1H), 2.0-2.1 (m, 1H), 2.25-2.31 (m, 3H), 2.8 (d, 3H), 2.85-2.91 (m, 1H), 3.04-3.12 (m, 1H), 3.14-3.3 (m, 3H), 3.7 (s, 3H), 6.26 (dd, 1H), 6.91 (d, 1H), 7.01-7.04 (m, 1H), 7.07 (dd, 1H), 7.32 (dd, 1H), 7.72 (d, 1H), 8.14 (s, _1H), 8.17 (s, 1H), 8.63 (d, 1H), 8.7-8.78 (m, 1H), 11.6 (s, 1H) 95245.doc ·67· 1378923 7-24 Ο
Ms : 550 1.35-1.57 (m, 8H), 1.7-1.78 (m, 2H), 2.81 (d, 3H), 3.46-3.52 (m, 2H), 3.74 (s, 3H), 6.65 (dd, 1H), 6.91 (d, 1H), 7.05-7.12 (m, 1H), 7.34-7.42 (m, 1H), 7.46 (d, 1H), 7.73 (dd, 1H), 8.11 (s, 1H), 8.18 (s, 1H), 8.62 (dd, 1H),8.71-8.78 (m, 1H), 11.7 (s, 1H) 7-25
536 [M+1]h DMSO-d6: 1.48-1.58(m, 2H), 1.65-1.72(m, 4H), 1.90-1.97(m, 2H), 2.07-2.14(m, 1H), 2.49-2.55(m, 4H), 2.70-2.77(m, 2H), 2.79(d, 3H), 3.60-3.65(m, 2H), 3.75(s, 3H), 6.48(dd, 1H), 6.63(d, 1H), 7.03-7.09(m, 1H), 7.28-7.34(m, 1H), 7.39(d, 1H), 7.71 (dd, 1H), 8.09(s, 1H), 8.11(s, 1H), 8.55-8.65(m, 1H), 8.69-8.73(m, 1H), 11.59(s, 1H) 7-26
468 [M+1]+ DMSO-d6: 2.80(d, 3H), 2.84-2.89(m, 4H), 3.04-3.08(m, 4H), 3.76(s, 3H), 6.47(dd,1H), 6.62(dd, 1H), 7.04-7.10(m, 1H), 7.28-7.35(m, 1H), 7.40(d, 1H), 7.69 -7.73(m, 1H), 8.09(s, 1H), 8.12(s, 1H), 8.55-8.63(m, 1H), 8.68-8.73(m, 1H), 11.59(s, 1H) (an aliphatic NH is hidden) 7-27
393 [M+1]+ DMSO-d6: 2.80(d, 3H), 6.64-6.67(m, 1H), 7.01-7.08(m, 2H), 7.15(d, 1H), 7.24-7.29(m, 2H), 7.44(d, 1H), 7.69-7.73(m, 1H), 8.20(s, 1H), 8.65-8.73(m, 2H), 9.15(s, 1H), 11.06(s, 1H), 11.63(s, 1H) 7-28
407 [M+1]h DMSO-d6: 2.81 (d, 3H), 3.79(s, 3H), 6.67(d, 1H), 7.05-7.10(m, 1H), 7.12(d, 1H), 7.17(d, 1H), 7.23(d, 1H), 7.25-7.30(m, 1H), 7.50(d, 1H), 7.70-7.73(m, 1H), 8.20(s, 1H), 8.67(d, 1H), 8.70-8.75(m, 1H), 9.17(s, 1H), 11.64(s, 1H) 95245.doc 68- 1378923
7-29 广 492 [M+1J+ DMSO-d6: 2.80(d, 3H), 2.91-2.99(m, 4H), 3.65-3.81(m, 2H), 3.82-3.95(m, 2H), 4.12(s, 3H), 6.58(d, 1H), 6.90(d, 1H), 7.05-7.09(m, 1H), 7.14(d, 1H), 7.22-7.28(m, 1H), 7.30(d, 1H), 7.70(dd, 1H), 8.16(s, 1H), 8.63-8.67(m, 1H), 8.68-8.72(m, 1H), 9.06(s, 1H), 11.64(s, 1H) .* 7-30 & MS DMSO-d6: 2.02 (s, 3H), 2.80 (d, 3H), 2.82-2.92 (m, 2H), 2.92-3.01 (m, 2H), 3.44-3.53 (m, 4H), 3.76 (s, 丫 J 0 m/z 510 3H), 6.68 (dd, 1H), 6.95 (d, 1H), 7.09 (dd, 1H), 7.35-7.40 (m, 1H), 7.50 (brs, 1H), 7.73 (d, 1H), 8.15 (s,塵 1H), 8.19 (s, 1H), 8.59 (d, 1H), 8.69-8.76 (m, 1H), 11.66 (s, 1H). 依照實例7A之步驟,自2-(5-溴基-2-氯基-嘧啶-4-基胺 基)-N-乙基-笨醯胺及對應的苯胺製備以下的2_[5_溴基_2-(經取代之苯基胺基)_嘧啶基胺基]-N•乙基-苯醯胺。
實例 編號 Rx Rf (溶劑) 或MS NM~R 8-1 Λ。、 ο 0.27 (正己烧: AcOEt=1:2) DMSO-d6: 2.80(d, 3H), 2.88(t, 4H), 3.65 (m, 4H), 3.75 (s, 3H), 6.64 (dd, 1H), 6.94 (d, 1H), 7.11-7.08 (m, 1H). 7.38-7.34 (m, 1H), 7.47-7.46 (m, 1H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.26 (s, 1H), 8.51-8.49 (m, 1H), 8.72-8.71 (m, 1H), 11.41 (s, 1H) 95245.doc -69· 1378923 8-2 0 m/z 513, 515 (M+1) DMSO-d6: 2.79 (d, 3H, J = 4.04 Hz), 3.10-3.20 (m, 4H), 3.77 (s, 3H), 3.70-3.80 (m, 4H), 6.45-6.55 (m, 1H), 6.63-6.69 (m, 1H), 7.05-7.10 (m, 1H), 7.28-7.34 (m, 1H), 7.40-7.45 (m, 1H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.16 (s, 1H), 8.50-8.56 (m, 1H) 8.65-8.72 (m, 1H), 11.40 (s, 1H) 8-3 0.48 DMSO-d6: 2.80(d, 3H), 3.83(s, 3H), 4.11(t, 2H), 6.82(ddd, 1H), 7.03(dd, 1H), 7.15(dd, 1H), 7.44(dd, (正己烷: 1H), 7.73(d, 1H), 7.93(dd, 1H), 8.13(s, 1H), 8.33 (s, AcOEt=4:1) 1H), 8.50(d, 1H), 8.70-8.77(m, 1H), 11.3(s, 1H). 8-4 rV。、 MS 2.79 (d, 3H), 3.79 (s, 3H), 6.75 (ddd, 1H), 7.0 (c^ 1H), 7.05-7.12 (m, 1H), 7.3-7.36 (m, 1H), 7.62 (W v 446, 448 1H), 7.69 (dd, 1H), 8.2 (s, 1H), 8.29 (s, 1H), 8.45 (d, T 1H), 8.66-8.73 (m, 1H), 11.4 (brs, 1H). 依照實例7A之步驟,自2-(2,5-二氯基-嘧啶-4-基胺基)-N-乙基-苯醯胺及對應的苯胺製備以下的2-[5-氣基-2-(經取 代之苯基胺基)-嘧啶-4-基胺基]-N-乙基-苯醯胺。
實例 編號 Rx Rf (溶劑)’ 或MS NMR (400MHz), δ (ppm) I / CDCI3: 1.27 (t, 3H), 3.10-3.15 (m, 4H), 3.47-3.58 (m, 9-1 rV 0.35 2H), 3.85-3.93 (m, 4H), 3.89 (s, 3H), 6.08-6.17 (m, v (正己烷: 1H), 6.48 (dd, 1H), 6.53 (d, 1H), 7.05-7.11 (m, 1H), AcOEt=1:2) 7.42-7.53 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.67 (d, Q 1H), 10.94 (brs, 1H). 95245.doc •70· 1378923 9-2 k • 0 1 MS (ESI) m/z 497, 499 (Μ+1Γ CDCI3: 1.26 (t, 3H, J = 7.56Hz), 2.37 (s, 3H), 2.57-2.62 (m, 4H), 3.15-3.20 (m, 4H), 3.49 (dq, 2H, J = 7.56, 1.52 Hz), 3.87 (s, 3H), 6.11-6.16 (m, 1H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz), 7.05-7.10 (m, 1H), 7.23 (s. 1H), 7.41-7.50 (m, 2H), 8.07 (s, 1H), 8.08 (d, 1H, J = 8.56Hz), 8.65-8.69 (m, 1H), 10.93 (s, 1H) 9-3 l· 0 m/z 564, 566 (M+1)+ DMSO-d6: 1.26 (t, 3H, J = 7.56Hz), 1.40-1.50 (m, 2H), 1.56-1.64 (m, 4H), 1.67-1.82 (m, 2H), 1.88-1.97 (m, 2H), 2.33-2.44 (m, 1H), 2.52-2.57 (m, 4H), 2.63-2.73 (m, 2H), 3.51 (dq, 2H, J = 7.56, 1.52 Hz), 3.62* έ 3.69 (m, 2H), 3.86 (s, 3H), 6.10-6.15 (m, 1H), 6.49 (dd, 1H, J = 8.56, 2.52 Hz), 6.55 (d, 1H, J = 2.52 Hz), 7.05- 7.10 (m, 1H), 7.23 (s, 1H), 7.43-7.50 (m, 2H) 8.05- 8.11 (m, 1H), 8.07 (s, 1H), 8.65-8.69 (m, 1H), 10.91 (s, 1H) 9-4 II 〇 0.39 (MeOH: CH2CI2=1:4) DMSO-d6: 1.19 (t, 3H), 1.52-1.68 (m, 2H), 1.71-1.79 (m, 4H), 1.92-2.05 (m, 2H), 2.12-2.23 (m, 1H), 2.76-2.85 (m, 2H), 3.65-3.73 (m, 2H), 3.82 (s, 3H), 6.54 (dd, 1H), 6.69 (d, 1H), 7.13 (m, 1H), 7.45 (d, 1H), 7.79 (dd, 1H), 8.15 (s, 1H), 8.15-8.18 (m, 1H), 8.60-8.68 (m, 1H), 8.74-8.83 (m, 1H). i 9-5 +Φ" 0 Rf (己炫: AcOEt = 1:2): 0.30 CDCI3: 1.27 (t, 3H), 3.08-3.14 (m, 4H), 3.52 (q,2H), 3.71-3.90 (m, 7H), 6.05-6.18 (m, 1H), 6.47 (dd, 1H), 6.53 (dd, 1H), 7.08 (dd, 1H), 7.41-7.53 (m, 2H), 8.08 (s, 1H), 8.12 (d, 1H), 8.67 (d, 1H), 10.94 (s, 1H). 95245.doc -71 - 1378923
Rf DMSO: 1.11 (t, 3H), 1.60-1.69 (m, 1H), 1.88-1.96 (m, 9-6 (AcOEt:Me 2H), 2.19 (s, 3H), 2.55-2.68 (m, 2H), 3.30-3.45 (m, 0H= 4:1) 2H), 3.75 (s, 3H), 4.33-4.43 (m, 1H), 6.54 (dd, 1H), V Λ 1 0.050 6.65 (d, 1H), 7.07 (dd, 1H), 7.30 (dd, 1H), 7.43 (d, 1H), 7.71 (dd, 1H), 8.11 (s, 1H), 8.20 (s, 1H), 8.54 (br.d, 1H), 8.75 (dd, 1H), 11.49 (s, 1H). Λ ——一- - cV、 CDCI3: 1.34 (t, 3H), 1.62-1.68 (m, 2H), 1.93-2.18 (m,, 9-7 0.44 8H), 2.37-2.40 (br, 2H), 2.74-2.86 (br, 3H), 3.20-3.23 (CH2CI2.M (m, 2H), 3.34 (br, 2H), 3.53 (q, 2H), 3.85 (s, 3H), 6.47 ------ — 国 eOH=8:2) (dd, 1H), 6.76 (d, 1H), 7.04-7.08 (m, 1H), 7.30 (dd, 1H), 7.53 (s, 1H), 8.00 (d. 1H), 8.13-8.17 (m, 1H), 8.22 (d, 1H), 8.42-8.53 (br, 1H), 10.91 (s, 1H), 11.59-11.75 (br, 1H) 依照實例7A之步驟’自2-(2,5-二氣基-嘴交-4-基胺基)-6,κτ-二甲基-笨醯胺及對應的苯胺製備以下的2-[5-氣基-2- (經取代之苯基胺基)-嘧啶-4-基胺基]-6,Ν-二甲基-苯醯 胺。
Rx 95245.doc •72- 1378923 實例 编號 10-1
Rx φτ。、。〇、 檢定
NMR (400MHz, DMSO-d6, δ): 1.58-1.68(m, 2Η), 1.87-1.96(m, 2H), 2.13-2.22(m, 2H), 2.18(s, 3H), 2.18(s, 3H), 2.29(s, 3H), 2.57-2.65(m, 2H), 2.76(d, 3H), 3.75(s, 3H), 4.29-4.37(m, 1H), 6.45(dd, 1H), 6.61(d, 1H), 6.98Cd, 1H), 7.18(dd, 1H), 7.47(d, 1H), 7.89(d, 1H), 8.02(s, 1H), 8.07 (s, 1H), 8.37-8.43(m, 1H), 8.49(s, 1H). Rf: 0.39 (MeOH: CH2CI2=1:4). A
10-2 10-3 NMR (400MHz, DMSO-d6, δ): 1.35-1.42 (m, 2H), 1.45-1.60 (m, 6H), 1.75-1.85 (m, 2H), 2.29 (s, 3H), 2.30-2.35 (m, 1H), 2.43-2.50 (m, 4H), 2.57-2.66 (m, 2H), 2.76 (d, 3H, J = 5.0Hz), 3.65-3.74 (m, 2H), 3.76 (s, 3H), 6.40 (dd, 1H, J = 9.0, 2.0 Hz), 6.59 (d, 1H, J = 2.0 Hz), 6.98 (d, 1H, J = 7.6 Hz), 7.20 (dd, 1H, J = 7.6, 7.6 Hz), 7.43 (d, 1H, J = 9.0 Hz), 7.91-7.94 (m, 1H), 7.93 (s, 1H), 8.06 (s, 1H), 8.36-8.42 (m, 1H) 8.47 (s, 1H). MS (ESI) m/z 564, 566 (M+1)+ DMSO-d6: 2.29(s, 3H), 2.77(d, 3H), 3.07-3.11(m, 4H), 3.73-3.76(m, 4H), 3.77(s, 3H), 6.41 (dd, 1H), 6.63(d, 1H), 7.00 (d, 1H), 7.21 (dd, 1H), 7.49(d, 1H), 7.93(d, 1H), 7.96(s, 1H), 8.07(s, 1H), 8.37-8.42(m, 1H), 8.49(s, 1H). MS m/z 483 [M+1]+ 依照實例7A之步驟,自2-(2,5-二氣基-嘴咬-4-基胺基)-5-氟基-N-甲基-苯醯胺及對應的苯胺製備以下的2-[5_氣基_ 2-(經取代之笨基胺基)_嘧啶-4-基胺基]-5_氟基-N_甲基-苯 醯胺。 95245.doc -73· 1378923
實例 編號
Rx 檢定. 11-1
NMR (400MHz, DMSO-d6, δ): 2.79(d, 3Η), 3.10-3.15(m, 4H), 3.74-3.78(m, 7H), 6.50(dd, 1H), 6.66(d, 1H), 7.13-7.20 (m, 1H), 7.41(d, 1H), 7.57(dd, 1H), 8.09(s, 1H), 8.14(s, 1H), 8.55-8.65(m, 1H), 8.75-8.82(m, 1H), 11.39(s, 1H). MS (ESI): m/z 487, 489 (M+1). 11-2
NMR (400MHz, DMSO-d6, δ): 1.68-1.33 (m, 8H), 1.93-1.73 (m, 2H), 2.35-2.60 (m, 1H), 2.62-2.74 (m, 2H), 2.67 (t, 2H), 2.74 (d, 3H), 3.25-3.38 (m, 4H), 3.76 (s, 3H), 3.83-3.71 (m, 2H), 6.48 (dd, 1H), 6.49 (dd, 1H), 6.63 (d, 1H), 7.15 (dd, 1H), 7.36 (d, 1H), 7.57 (dd, 1H), 8.09(s, 1H), 8.12(s, 1H), 8.65-8.55 (m, 1H), 8.78(d, 1H), 11.39 (s, 1H) MS (ESI): m/z 568, 570 (M+1) 11-3
DMSO-d6: 2.80(d, 3H), 3.79(s, 3H), 6.64(d,1H), 7.05-7.20(m, 3H), 7.23(d, 1H), 7.42-7.49(d, 1H), 7.57(dd, 1H), 8.20(s, 1H), 8.62-8.69(m, 1H), 8.75-8.82(m, 1H), 9.17(s, 1H), 11.43(s, 1H). MS m/z 425 [M+1 】+ 11-4
DMSO-d6: 2.06(s, 3H), 2.79(d, 3H), 3.10-3.14(m, 2H), 3.15-3.19(m, 2H), 3.55-3.62(m, 4H), 3.77(s, 3H), 6.52(dd, 1H), 6.69(d, 1H), 7.15-7.23(m, 1H), 7.43(d, 1H), 7.58(dd, 1H), 8.10(s, 1H), 8.14(s, 1H), 8.56-8.65(m, 1H), 8.75-8.81(m, 1H), 11.39(s, 1H). MS m/z 528 [M+1 Γ 95245.doc -74- 1378923 12-1 7-[S-氣基-2-(2-甲氧基_4_嗎啉_4_基·苯基胺基卜嘧啶_ 4_基胺基]-2-甲基-2,夂二氫_異吲哚酮之製備作用 7-(2,5-二氣基-嘧啶_4_基胺基)_2_甲基_2,3_二氫-異吲哚小 酮之合成步驟 N-f基-7-靖基-2,3-二氫異吲哚·丨_酮 將在THF(13毫升)中的2_溴甲基_6_硝基笨甲酸甲酯(丨26 公克’ 4.63毫莫耳)之溶液在室溫卞以在thf申的2 Μ曱基 胺溶液(14毫升)處理’攪拌5小時,以Et〇Ac(1〇〇毫升)稀 釋,以NaHC〇3飽和水溶液(15毫升)及食鹽水(15毫升)清 洗,乾燥(MgS〇4)及蒸發。以閃蒸色層分離法(3〇公克矽 膠,1:1之(:112(:12瓜0入(〇得到630/〇之^甲基-7-硝基-2,3-二 氫異吲°朵-1-酮(0.561公克,2.92毫莫耳)。黃色固體。
RfXniiCH/h/EtOAiOCMeoh-NMRGOOMHz’CDCh) 3.21 (s),4.44 (s),7.63-7.69 (m,2H),7.70-7.75 (m,1H)。 7-胺基-N-甲基-2,3-二氩異吲哚-1-酮 將在EtOAc(8.4毫升)中的N-甲基-7-硝基-2,3-二氫異吲 哚-1-酮(561,0毫克’ 2.92毫莫耳)之溶液在室溫下以 311(:12*2112〇(2.68公克)處理,在80。(:之回流下攪拌5小 時,並在0°C下以3〇毫升之5當量NaOH處理。在將兩層分 開之後,將水層以Et〇Ac(2x8毫升)萃取’將合併的萃取物 以食鹽水(5毫升)清洗,乾燥(MgS04)及蒸發,得到96%之 7-胺基-1^-甲基-2,3-二氫異吲哚-1-酮(455.9公克’2.81毫莫 耳)。黃色固體。(1:12CH2C12/Et〇Ac) 0.53。NMR (400MHz, CDC13) 3.12 (s), 4.28 (s), 5.20 (br.s), 6.56 (d, 95245.doc -75- 1378923 :Γ=8·0),6.68 (d,J=8.〇),7.21 (dd,J=8.0, 8.0)。 7-(4-胺基-2,5-二氯基嘧啶基)胺基_N_甲基_2,3·二氫異吲 0朵· 1 ·嗣
.將在DMF(2.0毫升)中的7_胺基_Ν•甲基·2,3·二氫異吲哚_
1-酮(232.6毫克,1.43毫莫耳)之溶液在(TC下以6〇% NaH
(89.8公克)處理’在相同的溫度下攪拌1 5小時,以在 DMF(3.5毫升)中的2,4,5-三氣嘧啶(0.557公克)處理,攪拌1 小時及溫熱至室溫。在再攪拌丨3小時之後,將混合物以飽 和水性ΝΗπΐ (6毫升)處理,並以過濾收集所得棕色沉澱 物’接著以H2〇、己烷及CH3CN清洗,得到26%之7-(4-胺 基-2,5-二氣基嘴啶-‘基)胺基曱基_2,3-二氫異吲哚-1-酿I (130.2公克,〇·4ΐ6毫莫耳)。棕色固體。灯(1:1之 CH2Cl2/EtOAc) 〇.5〇。iH_ nMR (400MHz,CDC13): 3.22 (s),
4.43 (s), 7.15 (d, J=8.0), 7.59 (dd, J=8.0, 8.0), 8.24 (s), 8.71 (d,J=8.0), ll.〇5 (br s)。
依照實例7A之步騍,自7-(2,5-二氯基-嘧啶-4-基胺基)-2-甲基-2,3·二氫·異吲哚-丨·酮及對應的苯胺製備以下的7_ 95245.doc • 76- 1378923 [5 -氣基-2-(經取代之苯基胺基)-°¾咬-4-基胺基]-2-甲基-2,3-二氫-異吲哚-1-酮。 7-[5 -氣基-2-(2 -甲氧基-4 -嗎淋-4 -基-苯基胺基)-峨咬-4 -基 胺基】-2 -甲基-2,3 -二氣·異°弓丨嘴-l -嗣
!H-NMR (400MHz, DMSO-d6, δ): 3.07 (s, 3Η), 3.13-3.17 (m, 4H), 3.75 (s, 3H), 3.34-3.78 (m, 4H), 4.46 (s, 2H), 6.54 (dd, 1H, J=8.6, 2.5Hz), 6.67 (d, 1H, J=2.5Hz), 7.15 (d, 1H, J=7.6Hz), 7.25-7.34 (m, 1H), 7.36 (d, 1H, J=8.6Hz), 8.13 (s,1H),8.36 (s,1H), 8.37-8.50 (m,1H),10.57 (s,1H)。MS (ESI) m/z 481.483 (M+l)+。 依照實例2之步驟,自7-(2,5-二氯基-嘧啶-4-基胺基)-2-甲基-2,3-二氫-異吲哚-1-酮及對應的苯胺製備以下的7-(5-氣基-2-(經取代之苯基胺基)-嘧啶-4-基胺基)-2-甲基-2,3-二 氫-異吲哚-1-酮:
95245.doc -77- 1378923 f 實例編號
Rx NMR (400MHz) δ (ppm) 12-2
494 [M+lf DMSO-d6: 2.24(s, 3H), 2.45-2.50(m,4H), 3.07(s, 3H), 3.15-3.19(m, 4H), 3.74(s, 3H), 4.46(s, 2H), 6.52(dd, 1H), 6.66(d, 1H), 7.15 (d, 1H), 7.25-7.36(m, 2H), 8.12(s, 1H), 8.35(s, 1H), 8.35-8.45(m, 1H), 10.57(s, 1H) 12-3
495 [M+1]4 DMSO-d6: 1.48-1.57(m, 2H), 1.83-1.88(m, 2H), 2.83-2.90(m, 2H), 3.07(s, 3H), 3.51-3.60(m, 2H), 3.61-3.70(m, 2H), 3.73(s, 3H), 4.46(s, 2H), 4.69(d, 1H), 6.52(dd, 1H), 6.64(d, 1H), 7.14 (d, 1H), 7.25-7.35(m, 2H), 8.12(s, 1H), 8.33(s, 1H), 8.35-8.45(m, 1H), 10.57(s, 1H) 12-4
577 [M+1]+ DMSO-d6: 1.48-1.59(m, 2H), 1.83-1.88(m, 2H), 2.14(s, 3H), 2.25-2.39(m, 4H), 2.42-2.60(m, 5H), 2.66-2.73(m, 2H),3.07(s, 3H), 3.73-3.77(m, 2H), 3.74(s, 3H), 4.46(s, 2H), 6.52(dd, 1H), 6.64(d, 1H), 7.14 (d, 1H), 7.25-7.34(m, 2H), 8.12(s, 1H), 8.34(s, 1H), 8.35-8.45(m, 1H), 10.57(s, 1H) 12-5 Ο
562 [M+1]+ DMSOd6:1_35-1.65(m,8H),1_73-1.85(m,2H),2.40-2.59(m, 7H), 3.08(s, 3H), 3.52-3.61 (m,2H), 3.73(s, 3H), 4.47(s, 2H), 6.72(dd, 1H), 6.94(d, 1H), 7.17(d, 1H), 7.34-7.39(m, 2H), 8.21 (s, 1H), 8.37(s, 1H), 8.45-8.53(m, 1H), 10.64(s, 1H) 95245.doc -78- 1378923 12-6 Ar。、 MS DMSO-de: 2.19-2.42 (m, 4H), 2.65-2.89 (m, 3H), 3.07 * (s, 3H), 3.11-3.30 (m, 1H), 3.48-3.61 (m, 2H), 3.62- Ψ 命 X m/z 3.71 (m, 1H), 3.75 (s, 3H), 3.75-3.83 (m, 2H), 4.47 (s, 骓 〔0 ~~——一..— 536 2H), 6.48-6.52 (m, 1H), 6.66 (d, 1H), 7.15 (d, 1H), 7.26-7.37 (m, 2H), 8.13 (s, 1H), 8.35 (s, 1H), 8.42 (brs, 1H), 10.57 (s, 1H). 依照實例2之步驟,自7-(2,5-二氣基-0¾°¾-4-基胺基)-2-乙基-2,3-二氫-異吲哚-丨_酮及對應的苯胺製備以下的7-(5-氣基_2_(經取代之苯基胺基)-喊。定-4-基胺基)-2 -乙基- 2,3 - — 氮異°引。朵· 1 -酮:
實例 編號 Rx 質量丨(m/z) NMR (400MHz) δ (ppm) 13-1 ί 508 DMSO-d6:1.19(t, 3H), 2.24(s, 3H), 2.47-2.51 (m, 4H), 3.15-3.21 (m, 4H), 3.54(q, 2H), 3.74(s, 3H), 4.48(s, y [M+1]+ 2H), 6.54(dd, 1H), 6.65(d, 1H), 7.15 (d, 1H), 7.26- ΓΊ 7.36(m, 2H), 8.12(s, 1H), 8.34(s, 1H), 8.37-8.48(m, I 1H), 1〇.58(s, 1H) 實例7B:2-[5-氣基_2_(2_甲氧基·4-嗎啉-4-基-苯基胺基)-嘧 啶-4-胺基】-Ν·甲基-苯醢胺(實例7Α之替換合成法) 將Et〗N(2.06毫升,14.8毫莫耳)及氣基甲酸異丁酯(1.7毫 升’ 12·8毫莫耳)在_5°C下加入在100毫升THF中的2-[5-氣 基-2-(2-甲氧基_4_嗎啉_4_基_苯基胺基)_嘧啶_4_基胺基笨甲 95245.doc -79- 1378923 酸(5.5公克,12」毫莫耳)之懸浮液t。在相同的溫度下授 拌3 0分鐘之後’將反應混合物在室溫下再搜拌1小時,並 接著將Ηθ加入反應混合物中。以過濾收集所得沉澱物, 以Η2〇清洗及在減壓下乾燥,得到成為黃色固體之中間物 (4.80 公克)(10.96 毫莫耳,91%)。
NMR (400MHz, DMSO-d6, δ): 3.1〇.3.2〇 (m> 4 ⑽ 4H),3.93 (s,3H),6.53 (dd,1H,w风 2)GHz),6 7〇 (d, 1H, J=2.0Hz), 7.49-7.54 (m, lH), 7.67 (d, 1H, J=8.56Hz), 7.89 (s, lH), 7.85-7.95 (m, 1H), 8.23 (d, 1H, J=9.08Hz), 8.26 (d, 1H, J=8.56Hz), 12.06 (s, 1H) 〇 將82毫克所獲得的中間物(〇 187毫莫耳)及接著將在 中的1 M NaHMDS溶液(560微升,0.56毫莫耳)逐滴加入在 THF中的1 M甲基胺溶液(56〇微升,〇 %毫莫耳)中。在將 反應混合物攪拌10分鐘之後,加入5毫升H20,並以Ac0Et 進行萃取。將有機層以食鹽水清洗,經Na2S04乾燥,在減 壓下濃縮及以石夕膠管柱色層分離法(己烷:Ac〇Et=i:i至
AcOEt)純化’得到成為淡黃色固體之標題化合物。提供在 實例7A中的數據。 使用適S的原料及條件重複上述的步驟,獲得如以下證 貫的以下化合物。
Cl、 A 95245.doc
〇· 1378923 實例 編號 Ry Rf (溶劑) 或MS NMR (400MHz), δ (ppm) 14-1 m m 0.10 (正己烷y AcOEt=1:1) CDCI3: 3.02-3.19 (m, 10H), 3.83-3.91 (m, 4H), 3.87 (s, 3H), 6.45 (dd, 1H), 6.52 (d. 1H), 7.09-7.14 (m, 1H), 7.29 (m, 1H), 7.31 (dd, 1H), 7.38-7.45 (m, 1H), 8.06 (s, 1H), 8.14 (d, 1H), 8.39 (d, 1H), 8.97 (s, 1H). _ 14-2 0.36 (正己烧: AcOEt=1:2) CDCI3: 1.27 (d, 6H), 3.09-3.16 (m, 4H), 3.81-3.92 (m, 4H), 3.89 (s, 3H), 4.26-4.37 (m, 1H), 5.93-5.98 (m, 1H), 6.48 (dd, 1H), 6.53 (d, 1H), 7.05-7.11 (m, 1H), 7.42-7.49 (m, 2H), 8.08 (s, 1H)r 8.12 (d, 1H), 8.65 (d, 1H), 10.88 (br.s, 1H). …— 14-3 II F 505 [M+1]+ DMSO-d6: 2.79(d, 3H), 3.09-3.14(m, 4H), 3.74-3.77(m, 4H), 3.75(s, 3H), 6.49(dd, 1H), 6.65(d, 1H), 7.30 (d, 1H), 7.84(dd, 1H), 8.12(s, 1H)t 8.40(s, 1H), 8.65-8.79(m, 2H), 11.39(s, 1H) 14-4 466 [M+1J+ DMSO-d6: 2.70-2.75(m, 2H), 3.04-3.09(m, 2H), 3.12-3.18(m, 4H), 3.74-3.80(m, 4H), 3.75(s, 3H), 6.54(dd, 1H), 6.67(d, 1H), 7.14 (d, 1H), 7.34(d, 1H), 7.37-7.44(m, 1H), 8.17(s, 1H), 8.35-8.50(m, 1H), 8.44(s, 1H), 10.59(s, 1H) 14-5 II Φ F Rf (己院: AcOEt=1:2) :0.31 DMSO: 1.18 (t, 3H), 3.11-3.21 (4, 4H), 3.30-3.60 (m, 2H), 3.71-3.85 (m, 7H), 6.50-6.58 (m, 1H), 6.71 (d, 1H), 7.17-7.26 (m, 1H), 7.46 (d, 1H), 7.64 (dd, 1H), 8.14 (s, 1H), 8.19 (s, 1H), 8.57-8.68 (m, 1H), 8.80-8.87 (m,1H), 11.36 (s, 1H). 14-6 οΛ 6 Rf (己院: AcOEt=1:1) :0.051 DMSO: 1.71-1.92 (m, 2H), 1.92-2.06 (m, 2H), 3.08-3.14 (m, 4H), 3.48-3.57 (m, 2H), 3.63-3.75 (m, 2H), 3.84-3.90 (m, 7H), 6.47 (dd, 1H), 6.53 (d, 1H), 7.09 (ddd, 1H), 7.25-7.29 (m, 1H), 7.38-7.44 (m, 1H), 8.06 (s, 1H), 8.15 (d, 1H), 8.45 (dd, 1H), 9.60 (s, 1H). 14-7 〇 Λ 0 ^-NMR (400MHz, δ ppm, CDCI3): 3.04-3.10 (m, 4H), 3.10-3.16 (m, 4H), 3.63-3.68 (m, 4H), 3.85-3.90 (m, 7H), 6.46 (dd, 1H), 6.53 (d, 1H), 7.20-7.25 (m, 1H), 7.33 (brs, 1H)t 7.56-7.62 (m, 1H), 7.85 (dd, 1H), 8.03 (d, 1H), 8.12 (s, 1H), 8.57-8.61 (m, 1H), 9.30 (s, 1H). 95245.doc -81 -
I37892T 依照實例2之步驟,自2-(5-氣基-2-曱基-嘧啶-4-基胺基)_ N-甲基-5-吡咯烷-1-基-苯醯胺及對應的苯胺製備以下的2_ *: (5_氣基-2-(經取代之苯基胺基)·嘧啶-4-基胺基)-N_曱基_5_ : 。比洛炫-1 -基-笨醯胺:
實例 編號 Rx 質量(m/z) NMR (400MHz) δ (ppm) 15-1 In DMSO-d6: 1.94-1.99(m, 4H), 2.23(s, 3H), 2.43- Cf 551 2.48(m, 4H), 2.78(d, 3H), 3.11-3.17(m, 4H), 3.22- V [M+1]+ 3.29(m, 4H), 3.76(s, 3H), 6.46(dd, 1H), 6.48-6.53(m, 0 I 1H), 6.63(d, 1H), 6.79(d, 1H), 7.44(d, 1H), 7.89(s, 1H), 7.99(s, 1H), 8.24(d, 1H), 8.60(d, 1H), 10.88(s, 1H) 15-2 f^T〇\ 566 DMSO-d6: 1.60-1.70(m, 2H), 1.90-2.00(m, 6H), 2.12-2.20(m, 2H), 2.18(s, 3H), 2.60-2.65(m, 2H), 2.78(d, [M+1]+ 3H), 3.22-3.28(m, 4H), 3.75(s, 3H), 4.25-4.37(m, 1H), 6.49-6.55(m, 2H), 6.62(d, 1H), 6.80(d, 1H), 7.53(d, 1H), 7.90(s, 1H), 8.00(s, 1H), 8.24(d, 1H), 8.58-8.63(m, 1H), 10.88(s, 1H) 95245.doc -82- 1378923 15-3 538 [M+1]+ DMS0-d6:1.94-1.99(m, 4H), 2.78(d, 3H), 3.09-3.15(m, 4H), 3.22-3.27(m, 4H), 3.73-3.77(m, 4H), 3.76(s, 3H), 6.47(dd, 1H), 6.47-6.53(m, 1H), 6.65(d, 1H), 6.79(d, 1H), 7.47(d, 1H), 7.90(s, 1H), 7.99(s, 1H), 8.24(d, 1H), 8.60(d, 1H), 10.88(s, 1H) 依照實例2之步驟’自對應的苯胺製備以下的2-[5-氯基-2-(4-氟基-2- f氧基-苯基胺基)-嘧啶-4-基胺基]-5-經取代 之N-甲基-苯醯胺:
實例 編號 Ry 質量‘(m/z) NMR (400MHz) δ (ppm) 16-1 I DMSO-d6: 2.79(d, 3H), 3.11-3.15(m, 4H), 3.74- a • ο 487 3.81(m, 4H), 3.81(s, 3H), 6.76(ddd, 1H), 6.95-7.05(m, 1 [M+1]+ 2H), 7.21 (d, 1H), 7.72(dd, 1H), 8.08(s, 1H), 8.09(s, 1H), 8.33(d, 1H), 8.63-8.73(m, 1H), 11.17(s, 1H) 镰 16-2 I DMSO-d6: 2.24(s, 3H), 2.45-2.52(m, 4H),2.79(d, 3H), 〇 500 3.13-3.18(m, 4H), 3.81 (s, 3H), 6.75(ddd, 1H), 6.94- * I [M+1]+ 7.02(m, 2H), 7.20(d, 1H), 7.73(dd, 1H), 8.03-8.11(m, 2H), 8.30(d, 1H), 8.60-8.70(m, 1H), 11.14(s, 1H) 16-3 I DMSO-d6: 2.79(d, 3H), 3.80-3.81 (m, 6H), 6.75(ddd, I 〇 432 1H), 6.90-7.02(m, 2H), 7.27(d, 1H), 7.67(dd, 1H), 雖 · I [M+1]+ 8.10(s, 1H), 8.16(s, 1H), 8.39(d, 1H), 8.70-8.76(m, 1H), 11.20(s, 1H) 95245.doc -83- 1378923
16-4 8 568 [M+1]+ DMSO-d6: 1.35-1.62(m, 8H), 1.78-1.85(m, 2H), 2.30-2.40(m, 1H), 2.41-2.52(m, 4H), 2.60-2.70(m, 2H), 2.78(d, 3H), 3.70-3.80(m, 2H), 3.81 (s, 3H), 6.75(ddd, 1H), 6.95-7.02(m, 2H), 7.20(d, 1H), 7.72(dd, 1H), 8.05-8.08(m, 2H), 8.28(d, 1H), 8.63-8.69(m, 1H), 11.12(s, 1H)
實例16B CDC13:3.01-3.10 (m,4H),3.63-3.68 (m,4H),3.89 (s,3H), 6.59 (ddd,1H), 6.66 (dd,1H), 7.20-7.26 (m,1H),7.36 (s, 1H), 7.57-7.63 (m, 1H), 7.84 (dd, 1H), 8.09-8.14 (m, 1H), 8.14 (s,1H),8.53 (d,1H),9.30 (s,1H)。
實例16C
CDCl3:3.56-3.65 (m, 2H), 3.88 (s, 3H), 5.11-5.19 (m, 1H), 6.50-6.56 (m, 1H), 6.61-6.66 (m, 1H), 7.25-7.29 (m, 1H), 7.38 (brs, 1H), 7.58-7.62 (m, 1H), 7.97 (dd, 1H), 8.02-8.10 (m,1H),8.15 (s,1H), 8.41 (dd, 1H),8.81 (s,1H)。 依照實例2之步驟,自2-(2,5-二氯基-嘧啶-4-基胺基)-5- 95245.doc -84* 1378923 氟基-N-甲基-苯醯胺及對應的苯胺製備以下的2-(5 -氯基-2-(經取代之苯基胺基)_嘧啶_4_基胺基)-5 -氟基-N-曱基-苯醯 胺:
實例 編號 Rx 質量(m/z) NMR (400MHz) δ (ppm) 18-1 丄。 DMSO-d6: 2.06 (s, 3H), 2.78 (d, 3H), 3.05-3.18 (m, 595 8H), 3.53-3.64 (m, 4H), 3.68-3.77 (m, 4H), 3.77 (s, T [M+1]+ 3H), 6.51 (dd, 1H), 6.69 (d, 1H), 6.88 (br.d, 1H), 7.20 ς〕 (d, 1H), 7.43 (d, 1H), 7.99-8.03 (m, 2H), 8.34 (br.d, 〇人 1H), 8.63-8.71 (m, 1H), 11.15 (s. 1H). 依照實例7A之步驟’自2-(5-氣基-2-氯基-嘧啶_4_基胺 基)-N-異丙基-苯續醢胺及對應的笨胺製備以下的2·[5-氣 基-2-(經取代之苯基胺基)-°¾咬-4-基胺基]_ν_異丙基_苯石黃 酿胺。
95245.doc - 85 - 實例编號
Rx
Rf (溶劑) 或MS _ NMR (400MHz), δ (ppm) 19-1
K- 0.39 (MeOH: CH2CI2=1:4) DMSO-d6: 0.94(d, 6H), 1.75-1.84(m, 1H), 2.07-2.16(m, 1H), 2.33(s, 3H), 2.98-3.04(m, 1H), 3.22-3.36(m, 5H), 3.42-3.47(m, 1H), 3.74(s, 3H), 6.05(dd, 1H), 6.18(d, 1H), 7.18(dd, 1H), 7.25(d, 1H), 7.35-7.45(m, 1H), 7.77-7.82(m, 1H), 7.70-8.10(m, 1H), 8.09-8.17 (m, 2H), 8.45-8.63(m, 1H), 9.34(s, 1H) 19-2 a
0.40 (正己烷 AcOEt=1:1) CDCI3: 1.00(d, 6H), 1.13(t, 3H), 1.83-1.92(m, 1H), 2.23-2.30(m,1H), 2.70-2.78(m, 2H), 3.08-3.13(m, 1H), 3.27-3.54 (m, 5H), 3.85(s, 3H), 4.33(d, 1H), 6.05(d, 1H), 6.13(s, 1H), 7.13(bs, 1H), 7.18-7.22(m, 1H), 7.52-7.56(m, 1H), 7.83-7.86(m, 1H), 7.95-7.98(m, 1H), 8.09(s, 1H), 8.47-8.49(m, 1H), 8.89(s, 1H) 19-3
0.30 (n-正己烧: AcOEt=1:1) CDCI3: 0.93 (d, 6H), 1.05-1.09(m, 1H), 1.48-1.99(m, 6H), 2.16(s,3H), 2.61-2.67(m, 1H), 2.80-2.83(m, 1H), 3.75(5, 3H), 3.80-3.89(m, 2H), 6.44-6.47(m, 1H), 6.62-6.63(m, 1H), 7.18-7.22(m, 1H), 7.42-7.46(m, 1H), 7.80-7.89(m, 2H), 8.17(s, 1H), 8.23(s, 1H), 8.42-8.44(m, 1H), 8.89(s, 1H) 19-4
0.69 (MeOH: CH2CI2=1:3) DMSO-d6 : 0.94(d, 6H), 1.45-1.57(m, 2H), 1.80-1.88(m, 2H), 2.14(s, 3H), 2.25-2.35(m, 4H), 2.45-2.55(m, 4H), 2.62-2.70(m, 2H), 3.28-3.37(m, 1H), 3.68-3.74(m, 2H), 3.75(s, 3H), 6.44(dd, 1H, J=8.82, 2.0Hz), 6.61 (d, 1H, J=2.0Hz), 7.21 (dd, 1H), 7.37(d, 1H), 7.45(dd, 1H), 7.81(dd, 1H, J=1.82, 1.52Hz), 7.84-7.92(m, 1H), 8.12-8.20(m, 1H), 8.16(s, 1H), 8.43-8.51(m, 1H), 9.31(s, 1H) 19-5 0.35 (正己烧: AcOEt=1:1) CDCI3: 0.93(d, 6H), 2.23(s, 3H), 2.45-2.48(m, 4H), 3.12-3.15(m,4H), 3.75(s, 3H), 6.42-6.45(m, 1H), 6.63 (s, 1H), 7.19-7.23(m, 1H), 7.38-7.47(m, 2H), 7.80-7.89(m, 2H), 8.16(s, 1H), 8.46-8.48(m, 1H), 9.34(s, 1H) 95245.doc -86 - 1378923— 19-6 Ρ V » φτ。、 F 0.45 (正己烷: AcOEt=1:1) CDCI3: 〇.99(d, 6H), 3.40-3.49(m, 1H), 3.88(s, 3H), 4.29-4.31 (d, 1H), 6.51-6.56(m, 1H), 6.62-6.65 (m, 1H), 7.24-7.28(m, 1H), 7.37(s, 1H), 7.56-7.60(m, 1H), 7.98-8.15(m, 3H), 8.34-8.37(m, 1H), 8.89(s, 1H) 19-7 XX 0.28 (正己烷:’ AcOEt=1:1) DMSO-d6 : 0.93(d, 6H), 1.59-1.67(m, 2H), 1.90-1.93(m, 2H), 2.10-2.24(m, 5H), 2.60-2.67(m, 2H), 3.74(s, 3H), 4.33-4.37(m, 1H), 6.47-6.50(m, 1H), 6.63(d, 1H), 7.18-7.22(m, 1H), 7.41-7.45(m, 2H), 7.79-7.87(m, 2H), 8.16(s, 1H), 8.21(s, 1H), 8.41 -8.43(m, 1H), 9.29(s, 1H) || 19-8 φτ。、 0 0.25 (正己烷: AcOEt=1:1) DMSO-d6 : 0.93(d, 6H), 3.09-3.12(m, 4H), 3.74- i 3.76(m, 7H), 6.43-6.46(m, 1H), 6.64(s, 1H), 7.19-7.23(m, 1H), 7.41-7.48(m, 2H), 7.80(d, 1H), 7.82(d, 1H), 8.17(s, 1H), 8.46-8.48(m, 1H), 9.31(s, 1H) 19-9 Q Ν 一 / 0.56 (MeOH: CH2CI2=1:4) DMSO-d6 : 0.93(d, 6H), 1.89-1.90(m, 1H), 2.30(bs, 6H), 3.13-3.50(m, 6H), 3.74(s, 3H), 6.10(d, 1H), 6.22(s, 1H), 7.16-7.20(m, 1H), 7.25-7.27(m, 1H), 7.40(bs, 1H), 7.79-7.81(m, 1H), 7.86-7.88(m, 1H), 8.12(s, 1H)t 8.15(s, 1H), 8.51(s, 1H), 9.34(s, 1H) 19-10 ΗΝ 0.45 (MeOH: CH2CI2=1:4) CDCI3: 0.99(d, 12H), 2.27(s, 2H)( 2.31(s, 6H), 2.96(s, 2H), 3.39-3.48(m, 1H), 3.83(s, 3H), 4.30(d, 1H), 6.09- | 6.12(m, 1H), 6.19(d, 1H), 7.11(s, 1H), 7.19-7.23(mr 1H), 7.51-7.57(m, 1H), 7.76-7.79(m, 1H), 7.95(d, 1H), 8.09(s, 1H), 8.46-8.49(m, 1H), 8.88(s, 1H) 19-11 φο 0 0.30 (正己烷: AcOEt=1:1) DMSO-d6 : 0.93(d, 6H), 2.96-2.99(m, 4H), 3.74-3.76(m, 7H), 6.67-6.72(m, 1H), 7.21-7.25(m, 1H), 7.31-7.34(m, 1H), 7.44-7.48(m, 1H), 7.80-7.83(m, 1H), 7.88(d, 1H), 8.21(s, 1H), 8.42(d, 1H), 8.58(s, 1H), 9.30 (s, 1H) 95245.doc -87- 1378923 19-12 • • Q B 一 0.42 (MeOH: CH2CI2=1:4) DMSO-d6: 0.94(d, 6H), 1.68-1.76(m, 1H), 1.99-2.07(m, 1H), 2.29(s, 3H), 3.05-3.49(m, 6H), 3.75(s, 3H), 6.36-6.40(m, 1H), 7.10-7.37(m, 3H), 7.70* 7.80(m, 1H), 8.08-8.39(m, 3H), 9.24(s, 1H) 19-13 l· φτ。、 0.50 (MeOH: CH2CI2=1:4) CDCI3: 1.01(d, 6H), 1.94-1.96(m, 1H), 2.01 (s, 3H), 2.29-2.37(m, 1H), 3.19-3.58(m, 5H), 3.86(s, 3H), 4.42(d, 1H), 4.59-4.63(m, 1H), 5.70(d, 1H), 6.05-6.08(m, 1H), 6.15-6.16(m, 1H), 7.17-7.24(m, 2H), 7.53-7.57(m, 1H), 7.90(d, 1H), 7.91-7.98(m, 1H), 8.09(s, 1H), 8.47(d, 1H), 8.91 (s, 1H) * 19-14 φτ。、 0.53 (MeOH: CH2CI2=1:4) CDCI3: 1.00(d, 6H), 2.04(s, 3H), 2.05-2.29(m, 2H), 2.96(s, 3H), 3.19-3.54(m, 5H), 3.86(s, 3H), 4.57-4.63(m, 1H), 5.39-5.46(m, 1H), 6.07-6.09(m, 1H), 6.16(d, 1H), 7.18-7.26(m, 2H), 7.53-7.57(m, 1H), 7.89-7.98(m, 2H), 8.08(s, 1H), 8.47(d, 1H), 8.94(d, 1H) 19-15 I» φτ。、 Ρ 0.56 (MeOH: CH2CI2=1:4) DMSO-d6 : 0.93(d, 6H), 1.48-1.56(m, 2H), 1.65-1.75(m, 4H), 1.90-1.93(m, 2H), 2.05-2.15(m, 1H), 2.45-2.55(m, 5H), 2.69-2.75(m, 2H), 3.61 (d, 2H), 3.74(s, 1H), 6.42-6.51(m, 1H), 6.61(d, 1H), 7.18-7.22(m, 1H), 7.37(d, 1H), 7.43-7.47(m, 1H), 7.80(d, 1H), 7.81-7.89(m, 1H), 8.16(d, 1H), 8.46-8.48(m, 1H), 9.31(s, 1H) 19-16 φτ。、 0.56 (MeOH: CH2CI2=1:4) DMSO-d6 : 0.92(d, 6H), 1.65-1.75(m, 4H), 1.88-2,00(m, 4H), 2.39-2.43(m, 2H), 2.60-2.65(m, 2H), 3.03-3.07(m, 1H), 3.03-3.40(m, 2H), 3.70(s, 3H), 3.77-3.78(m, 1H), 6.09(d, 1H), 6.23(s, 1H), 7.13-7.17(m, 1H), 7.23-7.25(m, 1H), 7.30-7.42(m, 1H), 7.78(d, 1H), 7.86(d, 1H), 8.10(s, 1H), 8.13(s, 1H), 8.40-8.50(m, 1H), 9.31(s, 1H) 95245.doc -88-
1378923Case 4'3291〇A 19-17 0.23 (正己炫: AcOEt=1:1) DMS0-d6 : 0.93(d, 6H), 1.24-1.57(m, 4H), 1.69-1.78(m, 2H), 1.98-2.04(m, 1H), 2.15-2.33(m, 5H), 2.70-2.80(m, 1H), 3.74(s, 3H), 3.91-3.94(m, 1H), 4.05-4.09(m, 1H), 6.46-6.49(m, 1H), 6.63(d, 1H), 7.18-7.22(m, 1H), 7.42-7,46(m, 2H), 7.80(d, 1H), 7.89(d, 1H), 8.17(s, 1H), 8.25(s, 1H), 8.42 -8.44(m, 1H), 9.31(s, 1H) 19-18 I φτ。、 C\c 0 0.48 (正己烷: AcOEt=1:1) DMS0-d6 : 0.93(d, 6H), 1.03(t, 3H), 1.13(t, 3H), 1.42-1.81(m, 4H), 2.57-2.83(m, 4H), 3.17-3.41 (m, 4H), 3.65-3.75(m, 1H), 3.80(s, 3H), 4.21 (bs, 1H), 6.42-6.47(m, 2H), 6.51(d, 1H), 6.63(d, 1H), 7.18-7.22(m, J 1H), 7.38-7.47(m, 2H), 7.80-7.82(m, 1H), 7.89(d, 1H), 8.16(s, 1H), 8.47 -8.49(m, 1H), 9.31(s, 1H) 19-19 φτ。、 ϋγΝΗ2 ο 0.44 (CH2C!2:M eOH=9:1) CDCI3: 1.45-1.62 (m, 2H), 1.72-1.78 (m, 1H), 1.82-1.90 (m, 1H), 2.40-2.46 (m, 1H), 2.61-2.75 (m, 2H), 3.75-3.70 (m, 2H), 3.76 (s, 3H), 6.45 (dd, 1H), 6.62 (d, 1H), 6.85 (s, 1H), 7.19-7.23 (m, 1H), 7.36-7.48 (m, 3H), 7.80-7.82 (m, 1H), 7.85-7.93 (br, 1H), 8.16 (s, 2H), 8.43-8.52 (m, 1H), 9.31 (s, 1H) 19-20 φτ。、 ό \ Ms : 547 DMS0-d6 : 0.94 (d, 6H), 1.73-1.82 (m, 1H), 2.23-2.33 (m, 4H), 2.34-2.41 (m, 1H), 2.54-2.62 (m, 1H), 2.62-2.69 (m, 1H), 2.77-2.82 (m, 1H), 3.25-3.35 (m, 1H), 3.74 (s, 3H), 4.85-4.92 (m, 1H), 6.4 (dd, 1H), 6.57 (d, j 1H), 7.16-7.24 (m, 1H), 7.38-7.51 (m, 1H), 7.81 (d, 1H), 7.82-7.94 (m, 1H), 8.16 (s, 1H), 8.22 (brs, 1H), 8.38-8.48 (m, 1H), 9.3 (brs, 1H) 19-21 扛、 ό I Ms : 579 DMS0-d6 : 0.92 (d, 6H), 1.61-1.71 (m, 2H), 1.86-1.96 (m, 2H), 2.12-2.22 (m, 5H), 2.57-2.64 (m, 2H), 3.2-3.4 (m, 1H), 3.77 (s, 3H), 4.27-4.35(m, 1H), 6.86 (dd, 1H), 7.19-7.27 (m, 1H), 7.39-7.46 (m, 1H), 7.81 (del, 1H), 7.84-7.92 (m, 1H), 8.21 (s, 1H), 8.36-8.42 (m, 1H), 8.62 (s, 1H), 9.28 (s, 1H) 95245.doc -89- 1378923 19-22 i 秦 η φτ。、 m oh V Ms : 549 DMSO-d6 : 0.90 (s, 6H), 0.94 (d, 6H)t 2.9 (d, 2H), 3.24 (d, 2H), 3.25-3.35(m, 1H), 3.27-3.36 (m, 1H), 3.68 (s, 3H), 4.58 (t, 1H), 5.3 (t, 1H), 6.16 (dd, 1H), 6.39 (d, 1H), 7.13 (d, 1H), 7.15-7.21 (m, 1H), 7.35-7.45 (m, 1H), 7.8 (dd, 1H), 7.83-7.92 (m, 1H), 8.09 (s, 1H), 8.11 (s, 1H), 8.45-8.57 (m, 1H), 9.33 (s, 1H) 19-23 φτ。、 NH /、-0H Rf : 0.51 (正己烷:: AcOEt=1:1) DMSO-d6 : 0.94 (d, 6H), 1.22 (s, 6H), 3.25-3.35 (m, 1H), 3.36 (d, 2H), 3.68 (s, 3H), 4.73-4.79 (brs, 1H), 4.81 (t, 1H), 6.29 (dd, 1H), 6.44 (d, 1H), 7.14-7.22 (m, 2H), 7.38-7.46 (m, 1H), 7.8 (dd, 1H), 7.85-7.9 (m, 1H), 8.1 (s, 1H), 8.13 (s, 1H), 8.45-8.55 (m, 1H), 9.32 (s, i 1H) 19-24 φτ。、 V?/ Ms : 577 DMSO-d6 : 0.93 (d, 6H), 0.96 (s, 6H), 2.22 (s, 6H), 3.25-3.35 (m, 1H), 3.7 (s, 3H), 3.75 (s, 3H), 6.46 (dd, 1H), 6.62 (d, 1H), 7.16-7.23 (m, 1H), 7.38-7.47 (m, 1H), 7.81 (dd, 1H), 7.85-7.9 (m, 1H), 8.17 (s, 1H), 8.23 (s, 1H), 8.38-8.48 (m, 1H), 9.31 (s, 1H) 19-25 0 Ms : 521 DMSO-d6 : 0.94 (d, 6H), 3.12 (t, 4H), 3.25-3.35 (m, 1H), 3.75 (t, 4H), 6.73 (dd, 1H), 6.85 (dd, 1H), 7.16-7.24 (m, 1H), 7.25-7.32 (m, 1H), 7.38-7.47 (m, 1H), 7.8 (dd, 1H), 7.88 (d, 1H), 8.18 (s, 1H), 8.42-8.52 (m, 1H), 8.86 (s, 1H), 9.36 (s, 1H) 19-26 x〇 Ms : 565 DMSO-d6 : 0.93 (d, 6H), 2.4-2.56 (m, 4H), 2.69 (t, 2H), 3.25-3.38 (m, 1H), 3.59 (t, 4H), 4.11 (t, 1H), 6.75 (dd, 1H), 6.93 (dd, 1H), 7.16-7.23 (m, 1H), 7.3-7.4 (m, 1H), 7.4-7.38 (m, 1H), 7.8 (dd, 1H), 7.88 (d, 1H), 8.19 (s, 1H), 8.36-8.5 (m, 1H), 8.92 (s, 1H), 9.34 (s, 1H) 95245.doc 90-
-72-1378923CaSe 4-32910A 19-27 秦 m
Ms : 614 DMS0-d6 : 0.93 (d, 6H), 1.3-1.62 (m, 8H), 1.75-1.85 (m, sH), 2.26-2.4 (m, 1H), 2.4-2.58 (m, 4H), 3.28-3.38 (m, 1H), 3.68-3.78 (m, 5H), 6.42 (dd, 1H), 6.64 (d, 1H), 7.18-7.24 (m, 1H), 7.42-7.5 (m, 2H), 7.77 (d, 1H), 7.82 (dd, 1H), 8.13 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.36 (s, 1H) 19-28
Rf: 0.5 (MeOH: CH2CI2=3: 7) DMSO-d6 : 0.93 (d, 6H), 1.6-1.7 (m, 2H), 1.88-1.98 (m, 2H), 2.17-2.35 (m, 5H), 2.6-2.73 (m, 2H), 3.25-3.4 (m, 1H), 4.34-4.44 (m, 1H), 6.75 (dd, 1H), 6.93 (dd, j 1H), 7.16-7.23 (m, 1H), 7.29-7.36 (m, 1H), 7.37-7.47 (m, 1H), 7.8 (dd, 1H), 7.89 (d, 1H), 8.19 (s, 1H), 8.36-8.46 (m, 1H), 8.92 (s, 1H), 9.31 (s, 1H) 19-29
o
Ms : 577 DMSO-d6 : 0.93 (d, 6H), 2.45-2.55 (m, 4H), 2.7 (t, 2H), 3.25-3.35 (m, 1H), 3.59 (t, 3H), 3.76 (s, 3H), 4.1 (t, 1H), 6.48 (dd, 1H), 6.65 (d, 1H), 7.18-7.24 (m, 1H), 7.4-7.5 (m, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.4-8.48 (m, 1H), 9.31 (s, 1H) 19-30
Cl
Ms : 590 DMSO-d6 : 0.93 (d, 6H), 2.15 (s, 3H), 2.2-2.4 (m, 4H), 2.4-2-6 (m, 4H), 2.69 (t, 2H), 3.25-3.35 (m, 1H), 3.75 (s, 3H), 4.08 (t, 2H), 6.47 (dd, 1H), 6.64 (d, 1H), 7.18-7.24 (m, 1H), 7.41-7.49 (m, 2H), 7.81 (dd, 1H), 7.86-7.91 (m, 1H), 8.17 (s, 1H), 8.24 (s, 1H), 8.39-8.46 (m, 1H), 9.31 (s, 1H) 95245.doc -91 - 1378923 19-31 * φτ。、 0, Ms : 588 DMSO*d6 : 0.94 (d, 6H), 2.19-2.36 (m, 4H), 2.66-2.85 (m, 3H), 3.15-3.21 (m, 1H), 3.73-3.8 (m, 5H), 6.43 (dd, 1H), 6.63 (d, 1H), 7.18-7.25 (m, 1H), 7.4 (d, 1H), 7.43-7.5 (m, 1H), 7.81 (dd, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.17 (s, 1H), 8.42-8.52 (m, 1H), 9.32 (s, 1H) I CDCI3 : 1.01(s, 6H), 1.45-1.56 (m, 2H), 2.03-2.11 (m, 19-32 φτ。、 Ms : 560 2H), 2.11-2.2 (m, 2H), 2.31 (s, 3H), 2.78-2.87 (m, 2H), 3.22-3.31 (m, 1H), 3.39-3.5 (m, 1H), 3.82 (s, 3H), 4.5-4.6 (m, 1H), 6.13 (dd, 1H), 6.21 (d, 1H), 7.16 (s, 1H), « Χλ 7.18-7.24 (m, 1H), 7.5-7.57 (m, 1H), 7.82 (d, 1H), 7.97 (dd, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 8.46 (d, 1H), 8.92 (s, 1H) 依照實例A之步驟,自2-(5-氣基-2-氣基-嘧啶-4-基胺 基)-N-曱基-苯磺醯胺及對應的苯胺製備以下的2-[5-氣基-2-(經取代之苯基胺基)-^。定-4 -基胺基]-N-甲基-苯續酿 胺。
實例編號 Rx Rf.(溶劑)' 或MS NMR (400MHz), δ (ppm) 20-1 φτ, 0 0.50 (AcOEt) CDCI3: 2.63(d, 3H), 3.14(t, 4H), 3.87-3.90(m,7H), 4.64(m,1H), 6.45(dd, 1H), 6.55(d, 1H), 7.23-7.26(m, 1H), 7.51-7.55(m, 1H), 7.91(d, 1H), 7.95(dd, 1H), 8.06(s, 1H), 8.47(d, 1H), 9.26(s, 1H) 95245.doc -92- 1378923 20-2 φτ, 0 1 Ac m/z 546, 548 (M+1) DMSO-d6: 2.06 (s, 3H), 2.43 (s, 3H), 3.10 (m, 2H), 3.16 (m, 2H), 3.59-3.62 (m, 4H), 3.77 (s, 3H), 6.49 (dd, 1H), 6.68 (d, 1H), 7.21-7.25 (m, 1H), 7.42 (d, 1H), 7.49 (dd, 1H), 7.75-7.77 (m, 1H), 7.78(s, 1H), 8.16(s, 1H), 8.21 (s, 1H), 8.50(d, 1H), 9.35 (s, 1H) 20-3 0.27 (正己烧: AcOEt=3:1) CDCI3: 2.65(d, 3H), 4.45-4.49(m, 1H), 6.99-7.04(m, 1H), 7.17-7.28(m, 4H), 7.56-7.60(m, 1H), 7.96-7.98(m, 1H), 8.18(s, 1H), 8.31-8.34(m, 1H), 8.41-8.44(m, 1H), 9.14(s, 1H) (20-4 0r 丫 0.27 (正己烷: AcOEt=3:1) CDCI3: 2.65(d, 3H), 4.54-4.58(m, 1H), 6.53(dd, 1H)^ 6.98-7.02(m, 1H), 7.11-7.15(m, 2H), 7.24-7.28(m, 1H), 7.35(bs, 1H), 7.57-7.61 (m, 1H), 7.95-7.98(m, 1H), 8.16(s, 1H), 8.29-8.32(m, 1H), 8.42-8.46(m, 1H), 9.14(s, 1H) 20-5 φτ。、 0.46 (MeOH: CH2CI2=1:4) CDCI3: 1.95-2.00(m, 5H), 2.29-2.37(m, 1H), 2.62(d, 3H), 3.20-3.78(m, 4H), 3.86(s, 3H), 4.60-4.64(m, 2H), 5.68-5.69(m, 1H), 6.09-6.16(m, 2H), 7.15(bs, 1H), 7.19-7.23(m, 1H), 7.54-7.58(m, 1H), 7.88-7.95(m, 2H), 8.06(s, 1H), 8.55-8.57(m, 1H), 9.08(s, 1H) 20-6 > φ"、 0 I 518 [M+1]+ DMSO-d6: 2.23(s, 3H), 2.43(s, 3H), 2.45-2.50(m, 4H), 3.12-3.17(m, 4H), 3.76(s, 3H), 6.45(dd,1H), 6.63(d, | 1H), 7.22(dd, 1H), 7.37(d, 1H), 7.45-7.50(m, 1H), 7.74-7.78(m, 1H), 7.76(d, 1H), 8.15(s, 1H), 8.19(s, 1H), 8.46-8.53(m, 1H), 9.35(bs, 1H) 20-7 <r 〔:〕 504 [M+1]+ DMSO-d6: 2.43(s, 3H), 2.80-2.89(m, 4H), 2.99-3.07(m, 4H), 3.76(s, 3H), 6.44(dd,1H), 6.61(d, 1H), 7.18-7.24(m, 1H), 7.37(d, 1H), 7.44-7.50(m, 1H), 7.76(dd, 1H), 8.15(s, 1H), 8.18(s, 1H), 8.45-8.55(m, 1H), 9.20-9.45(m, 1H) 95245.doc -93- 1378923 20-8 φ m • φτ、 0 586 [Μ+1]+ DMSO-d6: 1.35-1.43(m, 2H), 1.45-1.61 (m, 6H), 1.75-1.85(m,2H), 2.30-2.40(m, 1H), 2.43(d, 3H), 2.42-2.55(m, 4H), 2.60-2.70(m, 2H), 3.68-3.77(m, 2H), 3.75(s, 3H), 6.45(dd,1H), 6.62(d, 1H), 7.21(dd, 1H), 7.36(d, 1H), 7.43-7.51(m, 1H), 7.73-7.81(m, 1H), 7.75(dd, 1H), 8.15(s, 1H), 8.17(s, 1H), 8.45-8.52(m, 1H), 9.34(bs, 1H) 20-9 l· \ 0 I 569 [Μ+1]+ DMSO-d6: 1.85-1.95(m, 2H), 2.15(s, 3H), 2.18(t, 2H), 2.22-2.40(m, 8H), 2.43(s, 3H), 4.17(t, 2H), 6.65(d, 1H), 7.06(dd, 1H), 7.20(d, 1H), 7.22(ddd, 1H), 7.25(d, 1H), 7.39-7.47(m, 2H), 7.72-7.82(m, 1H), 7.77(dd,! 1H), 8.26(s, 1H), 8.52(d, 1H), 9.22(s, 1H), 9.36(s, 1H) 20-10 00 \ 0 556 [Μ+1]+ DMSO-d6: 1.85-1.95(m, 2H), 2.19(t, 2H), 2.25-2.35(m, 4H), 2.43(s, 3H), 3.55-3.60(m, 4H), 4.19(t, 2H), 6.66(d, 1H), 7.06(dd, 1H), 7.17-7.24(m, 1H), 7.21(d, 1H), 7.27(d, 1H), 7.39-7.45(m, 1H), 7.44(d, 1H), 7.70-7.80(m, 1H), 7.76(dd, 1H), 8.26(s, 1H), 8.52(d, 1H), 9.21(s, 1H), 9.36(s, 1H) I» 20-11 ¥ 〇ο^ Rf (己炫: AcOEt=1:1) 0.29 DMSO-d6: 2.64 (d, 3H), 2.87-2.96 (m, 4H), 3.65-3.74 (m, 4H), 3.86 (s, 3H), 4.41-4.51 (m, 1H), 6.50 (dd, 1H), 6.81 (d, 1H), 7.55-7.64 (m, 2H), 7.96 (d, 1H), 8.01 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 9.07 (s, 1H). 20-12 方 0 MS 535 DMSO-d6: 2.64 (d, 3H), 3.05 (bs, 4H), 3.59 (bs, 3H), 3.87(bs, 3H), 3.89 (bs, 4H), 4.52-4.48 (m, 1H), 6.57(bs, 1H), 7.25-7.20(m, 1H), 7.44-7.32 (m, 1H), 7.63-7.52 (m, 1H), 7.94(bs, 1H), 8.06 (d, 1H),8.25(s, 1H), 8.48(d, 1H), 9.06(bs, 1H) 95245.doc -94- 1378923 20-13
〇、 MS 548 DMS0-d6: 2.17 (bs, 3H), 2.63 (d, 3H), 2.68 (bs, 4H), 3.10(bs, 4H), 3.57 (s, 3H), 4.54-4.46 (m, 1H), 6.59(bs, 1H), 7.27-7.18(m, 1H), 7.37 (bs, 1H), 7.62-7.55 (m, 1H), 7.94(bs, 1H), 7.95 (d, 1H), 8.16(s, 1H), 8.48(d, 1H), 9.04(bs, 1H) 20-14 #
MS 546 DMSO-d6: 1.06 (t, 3H), 1.86 (dd, 2H), 2.37 (s, 3H), 2.62- 2.59 (m, 4H), 2.64(d, 3H), 4.00-3.97 (m, 4H), 4.62- 4.54 (m, 1H), 6.44 (dd, 1H), 6.54(d, 1H), 7.27-7.22(m, 1H), 7.34(bs, 1H), 7.58-7.54(m, 1H), 7.95(dd, 1H), 8.02(d, 1H), 8.11(s, 1H), 8.53(d, 1H), ^(bs,' 1H) 20-15
LC-MS 545 DMSO-d6: 1.46-1.62 (m, 2H), 1.72-1.79 (m, 1H), 1.82-1.90 (m, 1H), 2.38-2.46 (m, 1H), 2.43 (s, 3H), 2.62-2.76 (m, 2H), 3.59-3.69 (m, 2H), 3.43 (s, 3H), 6.47 (dd, 1H), 6.63 (d, 1H), 6.82-6.89 (br, 1H), 7.21 (dd, 1H), 7.32-7.41 (m, 2H), 7.44-7.52 (m, 1H), 7.71-7.82 (m, 2H), 8.15 (s, 1H), 8.15-8.20 (br, 1H), 8.44-8.53 (m, 1H), 9.28-9.38 (m, 1H) 20-16
0.24 (CH2CI2:M eOH=8:2) DMSO-d6: 1.47-1.55 (m, 2H), 1.80-1.91 (m, 2H), 2.16 (s, 3H), 2.25-2.41 (m, 5H), 2.42-2.48 (m, 3H), 2.61-2.73 (m, 2H), 3.68-3.79 (m, 5H), 6.45 (dd, 1H)t 6.62 (d, 1H), 7.21 (dd, 1H), 7.34 (d, 1H), 7.45-7.49 (m, 1H), 7.73-7.80 (m, 2H), 8.15 (s, 1H), 8.20 (s, 1H), 8.45-8.54 (m, 1H), 9.34 (s, 1H) 20-17
LC-MS 518 DMSO-d6: 1.76-1.84 (m, 1H), 2.08-2.16 (m, 1H), 2.33 (s, 3H), 2.42 (s, 3H), 3.00-3.03 (m, 1H), 3.23-3.27 (m, 3H), 3.42-3.46 (m, 1H), 3.74 (s, 3H), 6.06 (dd, 1H), 6.18- 6.20 (m, 1H), 7.17-7.23 (m, 1H), 7.38-7.48 (br, 1H), 7.72-7.77 (m, 1H), 8.12 (s, 1H), 8.17-8.21 (br, 1H), 8.46-8.58 (br, 1H), 9.30-9.40 (br, 1H) 95245.doc -95- 1378923 20-18 1 • ΓΝΑ。、 LC-MS 601 DMSO-d6: 1.36-1.49 (m, 2H), 1.69-1.76 (m, 2H), 2.13 (s, 3H), 2.15-2.23 (m, 1H), 2.24-2.36 (br, 4H), 2.39-2.48 (m, 5H), 2.43 (s, 3H), 3.27-3.40 (m, 2H), 3.74 (s, 3H), 6.62 (dd, 1H), 6.90 (d, 1H), 7.22-7.26 (m, 1H), 7.41-7.46 (m, 1H), 7.49-7.53 (m, 1H), 7.55-7.86 (br, 1H), 7.77 (dd, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.42 (d, 1H), 9.28 (s,1H) 20-19 l· ώ。、 LC-MS 519 DMSO-d6: 1.37-1.46 (m, 2H), 1.69-1.75 (m, 2H), 2.43 (s, 3H), 2.53-2.61 (m, 2H), 3.18-3.26 (m, 2H), 3.40-3.74 (m, 2H), 4.62 (d, 1H), 6.62 (dd, 1H), 6.90 (d, 1H), 7.22-7.26 (m, 1H), 7.42-7.46 (br, 1H), 7.48-7.55 (m,i 1H), 7.77-7.80 (m, 2H), 8.13-8.18 (br, 1H), 8.25 (s, 1H), 8.40-8.45 (m, 1H), 9.25-9.30 (m, 1H) 20-20 ΓΝΛ。、 一 f LC-MS 532 DMSO-d6: 1.66-1.76 (m, 1H), 2.00-2.07 (m, 1H), 2.14 (s, 6H), 2.43 (s, 3H), 2.68-2.76 (m, 1H), 2.87-2.91 (m, 1H), 2.99-3.10 (m, 2H), 3.24-3.28 (m, 1H), 3.71 (s, 3H), 6.25 (dd, 1H), 6.90 (d, 1H), 7.00-7.03 (m, 1H), 7.21-7.24 (m, 1H), 7.40-7.45 (m, 1H), 7.78-7.83 (m, 2H), 8.19 (s, 1H), 8.24 (s, 1H), 8.46 (d, 1H), 9.27-9.36 (br, 1H) 20-21 II Λ、 s 0 Ms : 549 DMSO-d6: 2.37-2.47 (m, 4H), 2.48-2.53 (m, 3H), 2.64 (t, 2H), 3.57 (t, 3H), 3.77 (s, 3H), 3.92 (t, 2H), 6.61 (dd, 1H), 6.93 (d, 1H), 7.28 (dd, 1H), 7.56-7.63 (m, 2H), 7.75-7.85 (m, 2H), 7.74-7.84 (m, 2H), 8.14 (s, 1H), 8.29 (s, 1H) 8.46 (d, 1H), 9.33(s, 1H) 20-22 >。、 s 0 N I Ms:562 DMSO-d6: 2.20 (s, 3H), 2.3-2.5 (m, 11H), 2.64 (t, 2H), 3.77 (s, 3H), 3.91 (t, 2H), 6.61(dd, 1H), 6.94 (d, 1H), 7.25-7.31(m, 1H), 7.57 (d, 1H), 7.58-7.64 (m, 1H), 7.74-7.84 (m, 2H), 8.12 (brs, 1H), 8.28 (s, 1H) 8.46 (d, 1H), 9.33(brs, 1H) 95245.doc -96- 1378923 20-23
Ms:438 DMSO-d6: 2.42-2.45 (m, 3H), 3.83 (s, 2H), 6.8 (ddd, 1H), 7.02 (dd, 1H), 7.3-7.36 (m, 1H), 7.58-7.64 (m, 1H), 7.74-7.8 (m, 1H), 7.82 (dd, 1H), 7.85 (dd, 1H), 8.18 (brs, 1H), 8.31 (s, 1H), 8.41 (d, 1H), 9.3 (brs, 1H) 20-24
Ms:438 DMSO-d6: 2.41-2.45 (m, 3H), 3.79 (s, 2H), 6.74 (ddd, 1H), 7.0 (dd, 1H), 7.22-7.28 (m, 1H), 7.49-7.55 (m, 1H), 7.6 (dd, 1H), 7.75-7.8 (m, 2H), 8.21 (s, 1H), 8.37 (brs, 1H), 8.39-8.45 (m, 1H), 9.34 (brs, 1H) 20-25
Ms:547 DMSO-d6: 1.24-1.38 (m, 2H), 1.64-1.8 (m, 3H), 1.83-1.92 (m, 2H), 2.16 (s, 3H), 2.41-2.45(m, 3H), 2.76-2.83 (m, 2H), 3.75 (s, 3H), 3.84 (d, 2H), 6.48 (dd, 1H)^ 6.64 (d, 1H), 7.2-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.5 (m, 1H), 7.74-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H) 8.44-8.5 (m, 1H), 9.34 (brs, 1H) 20-26
Ms:547 DMSO-d6: 1.18-1.3 (m, 2H), 1.56-1.7 (m, 3H), 1.8-1.88 (m, 2H), 2.15 (s, 3H), 2.41-2.45(m, 3H), 2.73-2.8 (m, 2H), 3.75 (s, 3H), 3.65 (d, 2H), 3.77 (s, 3H), 6.57 (dd, 1H), 6.93 (d, 1H), 7.25 (dd, 1H), 7.51-7.6 (m, 2H), 7.7-7.9 (m, 2H), 8.09 (brs, 1H), 8.28 (s, 1H), 8.45 (d, 1H), 9.31 (brs, 1H) 20-27
Ms:533 DMSO-d6: 1.62-1.72 (m, 2H), 1.9-1.99 (m, 2H), 2.3-2.35 (m, 5H), 2.41-2.45(m, 3H), 2.64-2.74 (m, 2H), 3.75 (s, 3H), 4.35-4.43 (m, 1H), 6.52 (dd, 1H), 6.65 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.43-7.49 (m, 1H), 7.74-7.8 (m, 2H), 8.16 (s, 1H), 8.27 (brs, 1H), 8.42-8.5 (m, 1H), 9.34 (brs, 1H) 20-28
Ms:547 DMSO-d6: 0.96-1.2 (m, 2H), 1.75-1.9 (m, 1H), 2.2-2.3 (m, 1H), 2.35-2.45 (m, 1H), 2.41-2.45(m, 2H), 2.43(d, 3H), 2.6-3.0 (m, 3H), 3.76 (s, 3H), 4.85*5.0 (m, 1H), 6.43-6.49 (m, 1H), 6.57-6.64 (m, 1H), 7.18-7.25 (m, 1H), 7.39-7.52 (m, 2H), 7.73-7.83 (m, 2H), 8.17 (s, 1H), 8.27 (brs, 1H), 8.44-8.51 (m, 1H), 9.35 (brs, 1H) 95245.doc -97- -79-
1378923 Case 4-32910A 20-29 夂、 0 \ Ms:519 DMS0-d6: 1.74-1.83 (m, 1H), 2.23-2.31 (m, 1H), 2.28 (s, 3H), 2.35-2.4 (m, 1H), 2.41-2.45(m, 3H), 2.58-2.63 (m, 1H), 2.63-2.7 (m, 1H), 2.78-2.83 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.43 (dd, 1H), 6.58 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H), 7.44-7.51 (m, 1H), 7.73-7.83 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.43-8.52 (m, 1H), 9.34 (brs, 1H) 20-30 I φτ。、 ά \_ Ms : 533 DMS0-d6: 1.04 (t, 3H), 1.74-1.82 (m, 1H), 2.23-2.33 (m, 1H), 2.47-2.5(m, 6H), 2.62-2.72 (m, 2H), 2.8-2.87 (m, 1H), 3.75 (s, 3H), 4.86-4.92 (m, 1H), 6.44 (dd, 1H), 6.59 (d, 1H), 7.19-7.25 (m, 1H), 7.41 (d, 1H)i 7.44-7.51 (m, 1H), 7.73-7.8 (m, 2H), 8.16 (s, 1H), 8.26 (brs, 1H), 8.44-8.51 (m, 1H), 9.34 (brs, 1H) 20-31 Λ。、 Ms : 518 DMS0-d6: 2.23(s, 3H), 2.38-2.47 (m, 7H), 2.87-2.93 (m, 4H), 3.75 (s, 3H)( 6.63 (dd, 1H), 6.93 (d, 1H), 7.22-7.28 (m, 1H), 7.42 (d, 1H), 7.48-7.54 (m, 1H), 7.76-7.84 (m, 1H), 8.2 (s, 1H), 8.25(s, 1H), 8.43 (dd, 1H)9.29 (s, 1H) 20.32 σ° Ms : 586 DMS0-d6: 1.35-1.55 (m, 8H), 1.66-1.75 (m, 2H), 2.23(s, 3H), 2.41-2.45 (m, 3H), 3.74 (s, 3H), 6.63 (dd, 1H), 6.91 (d, 1H)( 7.21-7.28 (m, 1H), 7.44 (d, 1H), 7.48-7.54 (m, 1H), 7.76-7.87 (m, 1H), 8.16 (s, 1H), 8.25 (s, 1H), 8.43 (dd, 1H) 9.29 (s, 1H) w 20-33 ν〇々 Ms : 518 DMS0-d6: 1.62-1.71 (m, 1H), 1.95-2.04 (m, 1H), 2.23-2.27 (m, 3H), 2.39-2.43 (m, 3H), 2.93-3.1 (m, 2H), 3.13-3.26 (m, 2H), 3.71 (s, 3H), 6.19 (dd, 1H), 6.88 (d, 1H), 7.07-7.13 (m, 1H), 7.13-7.2 (m, 1H), 7.4-7.48 (m, 1H), 7.75 (dd, 1H), 8.06 (brs, 1H), 8.18 (s, 1H), 8.4 (d, 1H) 20-34 0 Ms : 546 DMS0-d6: 2.02 (m, 1H), 2.42-2.46 (m, 3H), 2.71-2.91 (m, 4H), 3.44-3.51 (m, 4H), 3.76 (s, 3H), 6.66 (dd, 1H), 6.94 (d, 1H), 7.21-7.27 (m, 1H), 7.75-7.85 (m, 2H), 8.19 (s, 1H), 8.26 (s, 1H), 8.41 (d, 1H), 9.28 (brs, 1H). 95245.doc • 98- 1378923
依照實例7A之步驟,自2-(5-氯基-2-氣基-嘧啶-4-基胺 基)-N-第二丁基-苯磺醯胺及對應的苯胺製備以下的2-[5-氯 基-2-(經取代之笨基胺基)-0¾淀-4 -基胺基]-N -弟二丁基-苯 續酿胺。
實例編號 Rx Rf (溶劑)· 或MS NMR (400MHz),δ (ppm) II 丄〇/ CDCI3: 〇.62(t, 3H), 0.88(d, 3H), 1.22-1.29(m, 2H), 21-1 rV 0.35 2.23(s,3H), 2.45-2.47(m, 4H), 3.05-3.14(m, 5H), 3.75 V (正己烷: (s, 3H), 6.40-6.43(m, 1H), 6.62(s, 1H), 7.18-7.22(m, AcOEt=1:1) 1H), 7.39-7.47(m, 2H), 7.80-7.82(m, 1H), 8.15- I 8.16(m, 2H), 8.44-8.46(m, 1H), 9.32(s, 1H) 21-2 丄〇 0.30 DMSO-d6 : 0.62(t, 3H), 0.87(d, 3H), 1.17-1.26(m, 2H), rV (正己说: 3.03-3.10(m, 1H), 3.79(s, 3H), 6.66-6.71 (m, 1H), V AcOEt=3:1) 6.96-7.00(m, 1H), 7.21-7.25(m, 1H), 7.47-7.51(m, F 1H), 7.60-7.64(m, 1H), 7.79-7.83(m, 2H), 8.21(s, 1H), - 8.31 (s, 1H), 8.35-8.37(m, 1H), 9.29(s, 1H)
95245.doc -99- 1378923 21-3 0.30 (正己烷: AcOEt=1:1) DMSO-d6 : 0.61(t, 3H), 0.87(d, 3H), 1.21-1.29(m, 2H), 1.58-1.67(m,2H), 1.86-1.93(m, 2H), 2.14-2.20(m, 5H), 2.59-2.67(m, 2H), 3.06-3.08(m, 1H), 3.74(s, 3H), 4.32-4.36(m, 1H), 6.46-6.48(m, 1H), 6.63(d, 1H), 7.17-7.21(m, 1H), 7.40-7.50(m, 2H), 7.79-7.81(m, 2H), 8.16(s, 1H), 8.21 (bs, 1H), 8.35-8.42(m, 1H), 9.29(s, 1H) 21-4 〔。 Ό 0.30 (正己烷: AcOEt=1:1) DMSO-d6 : 0.61 (t, 3H), 0.87(d, 3H), 1.22-1.29(m, 2H), 2.43-2.47(m, 2H), 2.61-2.63(m, 1H), 2.68-2.70(m, 2H), 3.04-3.11(m, 1H), 3.56-3.60(m, 5H), 3.75{s, 3H), 3.93-3.96(m, 1H), 4.08-4.11(m, 2H), 6.45-6.47(m,着 1H), 6.64(d, 1H), 7.18-7.22(m( 1H), 7.43-7.46(m, 2H), 7.80-7.82(m, 2H), 8.17(s, 1H), 8.21(s, 1H), 8.42-8.44(m, 1H), 9.31 (s, 1H) 依照實例7A之步驟,自2-(5-氣基-2-氯基-嘧啶-4-基胺 基)-N-異丁基-苯磺醯胺及對應的苯胺製備以下的2-[5-氣 基- 2- (經取代之苯基胺基)-°¾咬-4-基胺基]-N-異丁基-苯續 醯胺。
• 實例編號 Rx Rf (溶劑) 或MS NMR (400MHz), δ (ppm) 22-1 I 0.30 DMSO-d6 : 0.69(d, 6H), 1.52-1.59(m, 1H), 2.57- rV、 (正己炫: 2.58(m, 2H), 3.82(s, 3H), 6.75-6.80(m, 1H), 6.99- AcOEt=3:1) 7.02(m, 1H), 7.29-7.33(m, 1H), 7.56-7.60(m, 1H), 7.82-7.93(m, 3H), 8.14(bs, 1H), 8.31 (s, 1H), 8.33(s, 1H), 9.23(s, 1H) 95245.doc -100- 1378923
• A 22-2 φτ。、 F 0.30 (正己烷: AcOEt=3:1) CDCI3: 〇.74(d, 6H), 1.57-1.64(m, 1H), 2.72-2.76(m,2H), 3.88(s, 3H), 4.55-4.56(m, 1H), 6.52-6.57 (m, 1H), 6.62-6.65(m, 1H), 7.24-7.28(m, 2H), 7.36(bs, 1H), 7.56-7.60(m, 1H), 7.95-8.08(m, 1H), 8.10-8.14(m, 2H), 8.36-8.39(m, 1H), 8.98(bs, 1H) 22-3 rV、 0.54 DMS0-d6 : 0.73(d, 6H), 1.55-1.62(m, 1H), 2.56-2.59(m, 2H), 3.10-3.12(m, 4H), 3.74-3.76(m, 7H), V (AcOEt) 6.43-6.46(m, 1H), 6.65(d, 1H), 7.20-7.24(m, 1H), 0 7.40-7.48(m, 2H), 7.76-7.78(m, 1H), 7.90-7.95(m, 1H), 8.16(s, 1H), 8.17(s, 1H), 8.43-8.45(m, 1H), 9.32(s, 1H) 依照實例7A之步驟,自2-(5-氣基-2-氯基-嘧啶-4-基胺 基)-N-(l-乙丙基)苯績醯胺及對應的苯胺製備以下的2-[5-氣基-2-(經取代之笨基胺基)-嘧啶-4-基胺基]-N-(卜乙丙 基)-苯磺醯胺。
• 實例 編號 Rx Rf (溶劑) 或MS NMR (400MHz), δ (ppm) 23-1 丄η DMS0-d6: 0.58(t, 6H), 1.14-1.34(m, 4H), 1.58- rV、 0.46 1.68(m, 2H), 1.87-1.96(m, 2H), 2.12-2.22(m, 2H), y (MeOH: 2.18(s, 3H), 2.57-2.65(m, 2H), 2.86-2.96(m, 1H), °r^i CH2CI2=3:7) 3.75(s, 3H), 4.30-4.39(m, 1H), 6.46(dd, 1H), 6.63(d, 為~ 1H), 7.19(dd, 1H), 7.39-7.48(m, 2H), 7.75-7.84(m, - 2H), 8.18(s, 1H), 8.20 (s, 1H), 8.39(m, 1H), 9.33(bs, fc ·· 1H) 95245.doc -101 - 1378923 23-2 1 • 0 N 1 0.35 (正己院: AcOEt=1:1) CDCI3: 〇.59(t, 6H), 1.14-1.34(m, 4H), 2.23(s,3H), 2.45-2.47(m, 4H), 2.90-2.95(m, 1H), 3.11-3.14(m, 4H), 3.76 (s, 3H), 6.39-6.42(m, 1H), 6.62(s, 1H), 7.18-7.22(m, 1H), 7.41-7.46(m, 2H), 7.76-7.82(m, 2H), 8.12(s, 1H), 8.16(s, 1H), 8.43-8.44(m, 1H), 9.35(s, 1H) 23-3 1 φτ。、 Q N^ 0.41 (MeOH: CH2CI2=1:4) DMSO-d6: 0.59(t, 6H), 1.16-1.35(m, 4H), 1.75-1.89(m, 1H), 2.08-2.15(m, 1H), 2.32(s, 3H), 2.90-3.02(m, 2H), 3.21-3.45(m, 4H), 3.73(s, 3H), 6.02(dd, 1H), 6.18(d, 1H), 7.16(dd, 1H), 7.27(d, 1H), 7.35-7.45(m, 1H), 7.77-7.82(m, 2H), 8.10 (s, 1H) 8.12 (s, 1H), 8.45-8.55(m, 1H), 9.38(s, 1H) " 23-4 N一1 0.41 (MeOH: CH2CI2=1:4) DMSO-d6: 0.60(t, 6H), 1.04(t, 3H), 1.17-1.35(m, 4H), 1.76-1.83(m, 1H), 2.10-2.15(m, 1H), 2.56-2.64(m, 2H), 2.91-3.01(m, 2H), 3.21-3.47(m, 4H), 3.74(s, 3H), 6.02(dd, 1H), 6.18(d, 1H), 7.14-7.17(m, 1H), 7.28(d, 1H), 7.35-7,45(m, 1H), 7.77-7.82(m, 2H), 8.11 (s, 1H) 8.12 (s, 1H), 8.45-8.55(m, 1H), 9.38(s, 1H) 23-5 φτ。、 0.25 (正己烷: AcOEt=1:1) DMSO-d6 : 0.58(t, 6H), 1.06-2.16(m, 11H), 2.16(s, 3H), 2.62-2.67(m, 1H), 2.81-2.94(m, 2H), 3.75(s, 3H), 3.80-3.89(m, 2H), 6.41-6.44(m, 1H), 6.62(d, 1H), 7.17-7.21 (m, 1H), 7.42-7.47(m, 2H), 7.77-7.82(m, 2H), 8.18(s, 1H), 8.19(s, 1H), 8.35-8.42(m, 1H), { 9.35(s, 1H) 23-6 0 Ms : 561 DMSO-d6 : 0.59 (t, 6H), 1.14-1.38 (m, 4H), 2.87-2.98 (m, 1H), 3.1 (t, 4H), 3.72-3.79 (m, 7H), 6.42 (dd, 1H), 6.64 (d, 1H), 7.18-7.24 (m, 1H), 7.42-7.5 (m, 2H), 7.77 (d, 1H), 7.81 (dd, 1H), 8.13 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.36 (s, 1H) 95245.doc 102- 1378923 23-7 » • ψ。、 A Ms : 575 DMSO-d6 : 0.58 (t, 6H), 1.13-1.37 (m, 4H), 1.72-1.82 (m, 1H), 2.21-2.31 (m, 4H), 2.32-2.4 (m, 1H), 2.54-2.61 (m, 1H), 2.62-2.68 (m, 1H), 2.75-2.82 (m, 1H), 2.87-2.97 (m, 1H), 3.75 (s, 3H), 4.84-4.91 (m, 1H), 6.37 (dd, 1H), 6.56 (d, 1H), 7.14-7.24 (m, 1H), 7.38-7.52 (m, 2H), 7.72-7.86 (m, 1H), 8.12-8.25 (m, 2H), 8.34-8.45 (m, 1H), 9.33 (brs, 1H) 23-8 Λτο、 Ms : 605 DMSO-d6 : 0.58 (t, 6H), 1.14-1.36 (m, 4H), 2.43-2.53 (m, 4H), 2.69 (t, 2H), 2.89-2.95 (m, 1H), 3.59 (t, 4H), 1 V Χ0 3.76 (s, 3H), 4.09 (t, 1H), 6.45 (dd, 1H), 6.64 (d, 1H), 7.17-7.23 (m, 1H), 7.41-7.52 (m, 2H), 7.78 (d, 1H), 7.81 (dd, 1H), 8.18 (s, 1H), 8.19 (s, 1H), 8.36-8.46 (m, 1H), 9.35 (s, 1H) ^ 23-9 Λτο、 Ms : 618 DMSO-d6 : 0.58 (t, 6H), 1.14-1.37 (m, 4H), 2.15 (s, 1H), 2.25-2.4 (m, 4H), 2.45-2.55 (m, 4H), 2.68 (t, 2H), V V 2.88-2.97 (m, 1H), 3.76 (s, 3H), 4.07 (t, 1H), 6.44 (dd, 1H), 6.64 (d, 1H), 7.15-7.23 (m, 1H), 7.41-7.51 (m, 2H), 7.7-7.84 (m, 2H), 8.12-8.22 (m, 1H), 8.34-8.44 (m, 1H), 9.34 (s, 1H) 依照實例7A之步驟’自2-(5-氯基-2-氣基-嘴咬-4-基胺 基)-N-環丁基-苯磺醯胺及對應的苯胺製備以下的2-[5-氣 基-2-(經取代之苯基胺基)-嘧啶-4-基胺基]-N·異丁基-苯磺 醯胺。
95245.doc 103 1378923
實例编號 Rx Rf (溶劑) 或MS NMR (400MHz), δ (ppm) 24-1 φτ。、 0 0.35 (正己烷.-AcOEt=1:1) DMSO-d6 : 1.37-1.48(m, 2H), 1.69-1.91 (m, 4H), 3.09-3.12(m, 4H), 3.63-3.74(m, 1H), 3.76(s, 3H), 6.43-6.45(m, 1H), 6.63(d, 1H), 7.18-7.22(m, 1H), 7.41-7.47(m, 2H), 7.76-7.78(m, 1H), 8.17-8.24(m, 3H), 8.46(d, 1H), 9.33(s, 1H) 24-2 φτ。、 0.46 (MeOH: CH2CI2=3:7) DMSO-d6: 1.37-1,93(m, 10H), 2.18(s, 3H), 2.59-2.62(m, 1H), 3.60-3.74(m, 1H), 3.77(s, 3H), 4.32-4.36(m, 1H), 6.46-6.49(m, 1H), 6.62(d, 1H), 7.16-7.20(m, 1H), 7.41-7.44(m, 2H), 7.75-7.77(m, 1H), 8.16(s, 1H), 8.22 (bs, 1H), 8.40-8.42(m, 1H), 9.30(bs, 1 1H) 24-3 0.46 (MeOH: CH2CI2=1:4) CDCI3: 1.45-1,75(m, 5H), 1.94-2.06(m, 6H), 2.29-2.37(m, 1H), 3.21-3.56(m, 4H), 3.72-3.81(m, 1H), 3.86(s, 3H), 4.55-4.65(m, 1H), 4.90(d, 1H), 5.72(d, 1H), 6.07(bs, 1H), 6.15(bs, 1H), 7.18-7.22(m, 2H), 7.52-7.56(m, 1H), 7.89-7.94(m, 2H), 8.08(s, 1H), 8.50(d, 1H), 9.00(s, 1H) 實例 編號 Rx Ms NMR (400MHz), δ (ppm) I DMSO-d6 : 1.2-1.38 (m, 4H), 1.4-1.65 (m, 4H), 3.11 25-1 rV。、 Ms :559 (t, 4H), 3.42-3.5 (m, 1H), 3.7-3.8 (m, 7H), 6.44 (dd, V 1H), 6.64 (d, 1H), 7.18-7.26 (m, 1H), 7.38-7.5 (m, 2H), ΓΝΊ 7.81 (d, 1H), 7.88-7.96 (m, 1H), 8.16 (s, 1H), 8.17 (s, 1H), 8.4-8.5 (m, 1H), 9.34 (s, 1H) 95245.doc -104- 1378923 I DMSO-d6 : 1.2-1.38 (m, 4H), 1.42-1.6 (m, 6H), 1.88- 25-2 rV。、 Ms : 587 1.98 (m, 2H), 2.1-2.25 (m, 5H), 2.55-2.65 (m, 2H), y 3.4-3.5 (m, 1H), 3.74 (s, 3H), 4.3-4.4 (m, 1H), 6.48 Λ 1 (dd, 1H), 6.63 (d, 1H), 7.18-7.24 (m, 1H), 7.38-7.47 * 〇 (m, 1H), 7.77-7.82 (m, 1H), 7.88-7.96 (m, 1H), 8.17 (s, 1 1H), 8.22 (s, 1H), 8.36-8.46 (m, 1H), 9.31 (s, 1H) 依照實例7A之步驟,自(2,5-二氯基-嘧啶-4·基)·[2-(丙 烷-1-磺醯基)-苯基]-胺及對應的笨胺製備以下的5_氣基_ Ν2-(經取代之苯基)-Ν4-[2-(丙烷-1-磺醯基)-苯基]-嘧啶-2,4-二胺。
實例 Rx Rf (溶劑) NMR (400MHz), δ (ppm) 編號 ,MS 或 Mp 丄〆 CDCI3: 0.97(t,3H), 1.72-1.82(m, 2H), 3.08-3.14(m, 26-1 rV 0.58 6H), 3.87-3.89(m, 7H), 6.46(dd, 1H), 6.53(d,1H), 7.24- y (AcOEt) 7.28(m,1H), 7.30(s, 1H), 7.60-7.64(m, 1H), 7.94(dd, ® 0 1H), 8.05{ό, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.40(s, 1H) I 〆 CDCI3: 0.98(t, 3H), 1.85-1.68(m, 2H), 2.15(s, 3H), 26-2 ry 0.57 3.16-3.07(m, 6H), 3.67-3.62(m, 2H), 3.81-3.78(m, V (MeOH: 2H), 3.89(s, 3H), 6.47(d, 1H), 6.55(d, 1H), 7.36- AcOEt=1:4) 7.33(m, 1H), 7.62 (dd, 1H), 7.95(dd, 1H), 8.08(d, 1H), V Ac 8.15(s, 1H),8.58(d, 1H), 9.41(s, 1H) 95245.doc -105- 1378923 26-3
0.13 (MeOH: AcOEt=1:4) CDCI3: 0.97(t, 3H), 1.43-1.52(m, 2H), 1.52-1.67 (m, 4H), 1.69-1.72(m, 4H), 1.90-1.98(m, 2H), 2.34-2.46(m, 1H), 2.51-2.59(m, 4H), 2.64-2.74(m, 2H), 3.11(dd, 2H), 3.64-3.73(m, 2H), 3.87(s, 3H), 6.47(dd, 1H), 6.56 (d, 1H), 7.24-7.33(m, 1H), 7.62(dd, 1H), 7.94(dd, 1H), 8_00(d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.39(bs, 1H). 26-4
0.22 (AcOEt) CDCI3: 0.97(t, 3H), 1.45(d, 1H), 1.68-1.82(m, 4H), 2.0-2.1(m, 2H), 2.91(ddd, 2H),3.10(ddd, 2H), 3.46-3.51 (m, 2H), 3.84-3.92(m, 1H), 3.88 (s, 1H), 6.48(dd, 1H), 6.57(d, 1H), 7.23-7.32 (m, 1H), 7.62(dd, 1H), 7.94(dd,1H), 8.02 (dd, 1H), 8.14(s, 1H), 8.59(d, 1H), i 9.39(bs, 1H) 26-5
〇/ 、NHj 0.1 (AcOEt) CDCI3: 0.97(t, 3H) ,1.71-1.82(m, 2H), 1.86-1.98(m, 2H), 2.01-2.08(m, 2H), 2.25-2.37(m, 1H), 2.75 (ddd, 2H), 3.10(ddd, 2H), 3.63-3.66(m, 2H), 3.88(s, 3H), 5.25-5.40(m, 1H), 5.40-5.58 (m, 1H), 6.48(dd, 1H), 6.57(d, 1H), 7.22-7.34 (m, 1H), 7.62(ddd, 1H), 7.93 (d, 1H), 7.94 (dd, 1H), 8.02 (d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(m, 1H) 26-6
MS 587 CDCI3: 0.97 (t, 3H), 1.77 (ddd, 2H), 2.00-1.85 (m, 4H), 2.27-2.18(m, 1H), 2.72(ddd, 2H) 3.12-3.08 (m, 2H), 3.69-3.61 (m, 2H), 3.58-3.46(m, 1H), 3.64 (t, 2H), 3.80(t, 2H), 3.88(s,3H), 5.56-5.46 (m, 1H), 6.47(dd, ^ 1H), 6.55(d, 1H), 7.32-7.23 (m, 1H), 7.30(bs, 1H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 8.02(d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(s, 1H) 26-7
MS 587 CDCI3: 0.98 (t, 3H), 1.46(bs, 6H) 1.82-1.73 (m, 2H), 2.17(s, 3H), 3.58-3.46(m, 1H), 2.95-2.84 (m, 2H), 3.12-3.08 (m, 2H), 3.90(s,3H), 6.48(dd, 1H), 6.52(d, 1H), 7.30-7.22 (m, 1H), 7.31 (bs, 1H), 7.66-7.60(m, 1H), 7.95(ddt 1H), 8.06(d, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.43(s, 1H) 95245.doc -106- 1378923 26-8
MS 573 CDCI3: 0.97 (t, 3H), 1.19(t, 3H), 1.77 (ddd, 2H), 2.41 (m, 2H), 3.18-3.09(m, 6H), 3.68-3.64 (m, 2H), 3.85-3.78 (m, 2H), 3.89(s,3H), 6.47(dd, 1H), 6.55(d, 1H), 7.29-7.25 (m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.07(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41 (s, 1H) 26-9
MS 587 CDCI3: 0.97 (t, 3H), 1.17(d, 3H) 1.76 (ddd, 2H), 2.88-2.81 (m, 2H), 3.18-3.05(m, 6H), 3.74-3.67 (m, 2H), 3.86-3.78 (m, 2H), 3.89(s,3H), 6.47(dd, 1H), 6.55(d, 1H), 7.29-7.20(m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.07(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41 (s, 1H) 26-10
MS 517 CDCI3: 0.97 (t, 3H), 1.76 (ddd, 2H), 2.86(d, 3H), 3.14-3.08(m, 2H), 3.13(t, 4H), 3.55 (t, 4H), 3.89(s,3H), 4.48-4.39 (m, 1H), 6.46(dd, 1H), 6.55(d, 1H), 7.29-7.21 (m, 1H), 7.34(bs, 1H), 7.64-7.60(m, 1H), 7.95(dd, 1H), 8.06(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H) 26-11
MS 587 CDCI3: 0.98 (t, 3H), 1.51 (s, 6H), 1.82-1.72 (m, 1H), 2.13 (s, 3H), 3.12-3.08 (m, 2H), 3.26(s, 2H), 3.44 (t, 2H), 3.74(t, 2H), 3.88(s,3H), 5.56-5.46 (m, 1H), 6.45(dd, 1H), 6.51 (d, 1H), 7.00(bs, 1H), 7.62-7.58 (m, 1H), 7.64-7.60(m, 1H), 7.93(d, 1H), 7.96(dd, 1H), 8.13(s, 1H), 8.62(d, 1H), 9.42(s, 1H) 95245.doc 107- 1378923 26-12
MS 559 CDCI3: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63(m, 1H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.89(s,3H), 5.45-5.38 (m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.71-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.35(bs, 1H), 7.65-7.61 (m, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H) 26-13
MS 559 CDCI3: 0.98 (t, 3H), 1.81-1.71 (m, 3H), 1.95-1.84 (m, 3H), 2.68-2.63(m, 1H), 3.12-3.08 (m, 4H), 3.28(d, 2H), 3.89(s,3H), 5.45-5.38 (m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.71-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.35(bs, 1H), 7.65-7.61 (m, 1H), 7.95(dd, 1H), 8.08(d, 1H). 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H) 26-14
MS 559 CDCI3: 0.98 (t, 3H), 1.85-1.74 (m, 3H), 2.00-1.86 (m, 3H), 2.70-2.51 (m, 1H), 3.13-3.08 (m, 4H), 3.29-3.27 (m, 2H), 3.89(s,3H), 5.46-5.37 (m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.69-6.56 (m, 1H), 7.29-7.19 (m, 1H), 7.34(bs, 1H), 7.65-7.61 (m, 1H), 7.95(dd, 1H), 8.08(d, 1H), 8.15(s, 1H), 8.58(d, 1H), 9.41(s, 1H) 26-15
MS 559 CDCI3: 〇.99(t, 3H), 1.79-1.72 (m, 2H), 2.92 (t, 2H), 2.98(t, 2H), 3.16-3.12 (m, 2H), 3.53(t, 2H), 3.67(t, 2H), 3.87(s,3H), 6.54(dd, 1H), 6.82 (d, 1H), 7.29-7.19 (m, 1H), 7.56(bs, 1H), 7.67-7.62(m, 1H), 7.96(dd, 1H), 8.07(d, 1H), 8.21 (s, 1H), 8.59(dd, 1H), 9.46(s, 1H) 26-16 MS 561 CDCI3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 3.12-3.08(m, 2H), 3.18 (t, 2H), 3.74(t, 4H), 3.86(s,3H), 6.53(dd, 1H), 6.20(dd, 1H), 6.26 (d, 1H), 7.13(bs, 1H), 7.25-7.21 (m, 1H), 7.62-7.57(m, 1H), 7.87(dd, 1H), 7.93(dd, 1H), 8.12(s, 1H), 8.62(d, 1H), 9.40(s, 1H) 95245.doc -108- 1378923 26-17 〇0
CDCI3: 0.98 (t, 3H), 1.78-1.73 (m, 2H), 2.49 (t, 4H), MS 2.66 (t, 2H), 2.94-2.92 (m, 4H), 3.15-3.11(m, 2H), 518 3.76-3.73(m, 4H), 3.88(s,3H), 6.52(dd, 1H), 6.82(d, 1H), 7.28-7.24 (m, 1H), 7.57(bs, 1H), 7.25-7.21 (m, 1H), 7.68-7.63(m, 1H), 7.95(dd, 1H), 8.02(d, 1H), 8.20(s, 1H), 8.56(d, 1H), 9.41 (s, 1H) 26-18
MS 559 CDCI3: 0.97 (t, 3H), 1.81-1.72 (m, 2H), 2.08-2.00 (m, 2H), 2.49 (t, 4H), 2.66 (t, 2H), 2.40 (t, 2H), 3.59 (t, 2H), 3.69(t, 2H), 3.87(s,3H), 6.41 (dd, 1H), 6.51 (d, 1H), 7.29-7.25 (m, 2H), 7.65-7.60(m, 1H), 7.95(dd, 1H), 8.05(d, 1H), 8.15(s, 1H), 8.56(d, 1H), 9.41(s, 1H) 26-19
MS 587 CDCI3: 0.98 (t, 3H), 1.82-1.73 (m, 2H), 2.14 (s, 3H), 3.12-3.08 (m, 2H), 3.55-3.45(m, 2H), 3.66-3.56 (m, 4H), 3.79-3.68 (m, 2H), 3.95(s,3H), 6.95(dd, 1H), 7.03 (d, 1H), 7.32-7.28(m, 1H), 7.69-7.64 (m, 1H), 7.71 (s, 1H), 7.97(dd, 1H), 8.22 (s, 1H), 8.39(d, 1H), 8.52(d, 1H), 9.46(s, 1H) 26-20
MS 546 CDCI3: 0.97 (t, 3H), 1.82-1.73 (m, 2H), 3.12-3.08 (m, 2H), 3.80-3.58(m, 8H), 3.94(s,3H), 6.94(dd, 1H), 7.02 (d, 1H), 7.32-7.28(m, 1H), 7.69-7.64 (m, 1H), 7.32-7.28(m, 1H), 7.97(dd, 1H)r 8.21 (s, 1H), 8.34(d, 1H), 8.52(d, 1H), 9.45(s, 1H) 26-21 MS 615 CDCI3: 0.97 (t, 3H), 1.82-1.72 (m, 2H), 2.71 (t, 3H), 3.05 (s, 2H), 3.10 (m, 2H), 3.18 (t, 4H), 3.88(s,3H), 4.17-4.08 (m, 1H), 6.47 (dd, 1H), 6.54 (d, 1H), 6.99-6.89(m, 1H), 7.28-7.24 (m, 1H), 7.31 (bs, 1H), 7.65-7.60 (m, 1H), 7.32-7.28(m, 1H), 7.95(dd, 1H), 8.05 (d, 1H), 8.15(s, 1H), 8.59(d, 1H), 9.41(s, 1H) 95245.doc -109- 1378923 26-22 〔λ MS 530 CDCI3: 0.98 (t, 3H), 1.80-1.74 (m, 2H), 3.12-3.08 (m, 2H), 3.45-3.42 (m, 2H), 3.55-3.53 (m, 2H), 3.87 (s, 2H), 3.89(s,3H), 5.98-5.89 (m, 1H), 6.44 (dd, 1H), 6.50(d, 1H), 7.35-7.19 (m, 2H), 7.62-7.58(m, 1H), 7.95(dd, 1H), 8.09 (d, 1H), 8.15(s, 1H), 8.57(d, 1H), 9.43(s, 1H) 1 / CDCI3: 0.97 (t, 3H), 1.10 (s, 3H), 1.12 (s, 3H), 1.80- 26-23 MS 1.74(m, 2H), 2.80-2.63 (m, 5H), 3.12-3.08 (m, 2H), V 558 3.19-3.17 (m, 4H), 3.87(s,3H), 6.48 (dd, 1H), 6.56(d, 1H), 7.30-7.23 (m, 2H), 7.62-7.58(m, 1H), 7.94(dd, 1 〇 1H), 8.00 (d, 1H), 8.14(s, 1H), 8.59(d, 1H), 9.40(s, λ 人 #< 1H) 貢 I / CDCI3: 0.98 (t, 3H), 1.81-1.72 (m, 2H), 2.03-1.91 (m, 26-24 MS 1H), 2.28-2.19 (m, 1H), 2.33 (s, 6H), 2.92-2.84 (m, V 544 1H), 3.12-3.08 (m, 2H), 3.17(t, 1H), 3.35(ddd, 1H), X 3.51-3.42 (m, 2H), 3.87 (s, 3H), 6.11 (dd, 1H), 6.14 Q (d,1H), 7.09 (s, 1H)( 7.26-7.20(m, 1H), 7.60-7.56 (m, γ 1H), 7.85(d, 1H), 7.92(dd, 1H), 8.11(s, 1H), 8.38(d, 1H), 9.41(s, 1H) I / CDCI3: 0.98 (t, 3H), 1.82-1.71 (m, 2H), 1.96-1.86 (m, 26-25 iV MS 1H), 2.33-2.20 (m, 1H), 2.51 (s, 1H), 3.17-3.08 (m, 1 V 530 3H), 3.35-3.30 (m, 1H), 3.54-3.30 (m, 3H), 3.87 (s, | I 3H), 6.12 (dd, 1H), 6.16 (d,1H), 7.09 (s, 1H), 7.32- Q 7.21(m, 1H), 7.58 (dd, 1H), 7.85(d, 1H), 7.92(dd, 1H), NH / 8.11(s, 1H), 8.64(d, 1H), 9.40(s, 1H) 1 CDCI3: 0.98 (t, 3H), 1.83-1.71 (m, 2H), 1.98-1.81 (m, 26-26 ry MS 2H), 2.16-2.02(m, 2H), 2.53-2.28 (m, 5H), 2.87-2.72 V 546 (m, 2H), 3.12-3.08 (m, 2H), 3.88 (s, 3H), 4.32 (bs, i 3H), 6.44 (dd, 1H), 6.53(d, 1H), 7.32-7.25 (m, 2H), 0 7.63-7.59 (m, 2H), 7.94(dd, 1H), 8.04 (d, 1H), 8.15(s, 1 1H), 8.57(d, 1H), 9.42(s, 1H) 95245-doc -110· 1378923 26-27
OH MS 545 CDCI3: 0.97 (t, 3H), 1.38-1.30 (m, 1H), 1.49-1.40 (m, 2H), 1.70-1.62 (m, 1H), 1.83-1.72 (m, 2H), 1.89 (d, 2H), 2.74-2.10 (m, 2H), 3.12-3.08 (m, 2H), 3.57 (d, 2H), 3.63 (d, 2H), 3.90 (s,3H), 6.50 (d, 1H), 6.58 (s, 1H), 7.34-7.24 (m, 2H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 8.02 (d, 1H), 8.14(s, 1H), 8.60(dd, 1H), 9.40(s, 1H) 26-28
OH MS 517 CDCIj: 0.97 (t, 3H), 1.88-1.65 (m, 3H), 2.05-1.97 (m, 2H), 2.21-2.08 (m, 1H), 2.67-2.55 (m, 4H), 2.78-2.71 (m, 2H), 3.12-3.08 (m, 2H), 3.61 (d, 2H), 3.87 (s,3H), 6.47 (dd, 1H), 6.56 (d, 1H), 7.28-7.23 (m, 2H),! 7.64-7.60(m, 1H), 7.94(dd, 1H), 7.99 (d, 1H), 8.13(s, 1H), 8.60(dd, 1H), 9.39(s, 1H) 26-29 MS 585 CDCI3: 0.97 (t, 3H), 1.89-1.65 (m, 8H), 2.03 (d, 2H), 2.20-2.10 (m, 1H), 2.68-2.58 (m, 4H), 2.78-2.72 (m, 2H), 3.12-3.08 (m, 2H), 3.61(d, 2H), 3.87(s,3H), 6.47 (dd, 1H), 6.56(d, 1H), 7.30-7.23 (m, 2H), 7.64-7.60(m, 1H), 7.94(dd, 1H), 7.99 (dd, 1H), 8.13(s, 1H), 8.60(dd, 1H), 9.39 (s, 1H)
95245.doc MS 451,453 MS 647, 649 0.97 (t, 3H), 1.71-1.82 (m, 2H), 3.06-3.14 (m, 2H), 3.89 (s, 1H), 6.60 (ddd, 1H), 6.66 (dd, 1H), 7.25-7.30 (m, 1H), 7.35 (br.s, 1H), 7.63 (dd, 1H), 7.95 (dd, 1H), 8.09-8.18 (m, 1H), 8.17 (s, 1H), 8.52 (dd, 1H), 9.42 (s, 1H). 0.98 (t. 3H), 1.71-1.83 (m, 2H), 2.18 (s, 3H), 2.47-2.64 (m, 4H), 2.72-2.84 (m, 2H), 3.08-3.15 (m, 2H), 3.42-3.54 (m, 2H), 3.58-3.69 (m, 2H), 3.84 (s, 3H), 3.94-4.03 (m, 2H), 6.45-6.51 (m, 1H), 6.78 (d, 1H), 7.22-7.27 (m, 1H), 7.60 (s, 1H), 7.67-7.74 (m, 1H), 7.93-7.97 (m, 1H), 7.73 (d, 1H), 8.02 (s, 1H), 8.54 (d, 1H), 9.33 (s, 1H). -Ill -
1378923 26-32 ΓΛ。、 /Ο” 熔點 139,4 400MHz, CDCI3, δ (ppm): 0.98 (t; 3H), 1.55-1.90 (m; 6H), 2.38 (s; 3H), 2.45-2.80 (m; 6H), 3.13 (m; 2H), 3.47 (m; 2H), 3.84 (s; 3H), 6.54 (dd; 1H), 6.79 (d; 1H), 7.23 (dd; 1H); 7.51 (s; 1H), 7.64 (dd: 1H), 7.92 (d; 1H), 8.00 (s; 1H), 8.19 (s; 1H), 8.57 (d; 1H), 9.41 (s; 1H). 26-33 1丨 熔點 163,4 400MHz, CDCI3, δ (ppm): 0.98 (t; 3H), 1.50-1.90 (m; 6H), 2.24 (bs; 1H), 2.45-2.65 (m; 6H), 3.12 (m; 2H), 3.45 (m; 2H), 3.77 (m; 4H9, 3.85 (s; 3H), 6.55 (dd; 1H); 6.79 (d; 1H), 7.24 (dd; 1H). 7.52 (s; 1H), 7.64 (dd; 1H), 7.93 (d; 1H), 8.01 (s; 1H), 8.20 (s; 1H9, 9.42 i (s; 1H). 26-34 xy、 熔點 232,9 400MHz, CDCI3, δ (ppm): 1.00 (s; 3H), 1.78 (m; 2H), 2.83 (s; 3H), 3.03 (m; 2H), 3.12 (m; 2H), 3.38-3.60 (m; 8H), 3.88 (s; 3H), 6.56 (m; 1H), 6.82 (d; 1H), 7.29 (m; 1H), 7.60 (s; 1H), 7.64 (m; 1H), 7.95 (d; 1H), 8.12 (s; 1H), 8.20 (s; 1H), 8.59 (d; 1H), 9.50 (s; 1H). 26-35 熔點 197,3 400MHz, CDCI3, δ (ppm): 0.99 (t; 3H), 1.43 (m; 1H), 1.63 (m; 2H), 1.77 (m; 2H), 1.90 (m; 2H), 2.70 (m; 2H), 3.13 (m; 2H), 3.28 (m; 2H), 3.75 (s; 1H), 3.84 (s; 3H), 6.55 (m; 1H), 6.80 (d; 1H), 7.24 (m; 1H), 7.53 (s; 1H), 7.64 (s; 1H), 7.93 (d; 1H), 8.02 (s; 1H), 8.20 (s; 1H), 8.58 (d; 1H), 9.41 (s; 1H). 26-36 ΓΛ。、 οΌ 溶點. 147,6 400MHz, CDCI3, δ (ppm): 1.00 (t; 3H), 1.78 (m; 2H), 3.12 (m; 2H), 3.56 (m; 1H), 3.87 (s; 3H), 6.53 (dd; 1H), 6.80 (d; 1H), 7.30 (dd; 1H), 7.52 (s; 1H), 7.64 (m; 1H), 7.95 (dd; 1H), 8.08 (s; 1H), 8.20 (s; 1H), 8.60 (d; 1H), 9.48 (s; 1H). 26-37 ΗΝ \ 熔點 143.2 500MHz, CDCI3, δ (ppm): 0.96 (t; 3H), 1.70 (m; 2H), 2.11 (m; 1H), 2.39 (m; 1H), 2.75 (s; 3H), 3.02 (m; 1H), 3.22 (m; 2H), 3.43 (d; 2H), 3.82 (s; 3H), 3.86 (m; 1H), 6.40 (dd; 1H), 6.94 (d; 1H), 7.34 (ddd; 1H), 7.47 (s; 1H), 7.63 (ddd; 1H), 7.93 (dd; 1H), 8.18 (s; 1H), 8.51 95245.doc •112· 1378923 (d; 1H). 26-38 iV -N \ 熔點 133.5 400MHz, CDCI3, δ (ppm): 1.00 (t; 3H), 1.70-1.95 (m; 6H), 2.63 (s; 1H), 2,92 (s; 1H), 3.00-3.25 (m; 5H), 3.89 (s; 3H), 5.42 (s; 1H), 6.70 (s; 1H), 6.83 (m; 2H), 7.25 (m; 1H), 7.55 (s; 1H), 7.63 (m; 1H9, 8.95 (m; 1H), 8.15 (S; 1H), 8.23 (s; 1H), 8.54 (d; 1H), 9.45 (s; 1H). 26-39 熔點 188.8 400MHz, CDCI3, δ (ppm): 0.99 (t; 3H), 1.70-1.90 (m; 3H), 2.08 (m; 1H), 2.28 (s; 6H9, 2.83 (s; 1H), 3.00-3.23 (m; 4H9, 3.37 (m; 1H), 3.83 (s; 3H), 6.19 (dd; Λ 1H), 6.83 (d; 1H), 7.23 (dd; 1H), 7.50 (s; 1H), 7.59 (m; 2H), 7.93 (d; 1H), 8.19 (s; 1H), 8.60 (d; 1H), 9.42 (s; 1H). 依照實例7A之步驟’自(2,5-二氣基-°¾°定-4-基)-[2-乙院 磺醯基-苯基]-胺及對應的苯胺製備以下的5-氣基_n2_(經取 代之苯基)-N4-[2-乙烷磺醯基-苯基]-°t咬_2,4·二胺。
實例 編號 Rx Rf (溶劑) 或MS NMR (400MHz), δ (ppm)或 逗留時間分鐘(HPLC) 丄〇/ CDCI3: 1.28(t,3H), 3.12-3.19(m, 6H), 3.87-3.89(m, 27-1 (Ύ 0.53 7H), 6.45(dd, 1H), 6.53(d,1H), 7.24-7.28(m,1H), T (AcOEt) 7.31 (s, 1H), 7.60-7.64(m, 1H), 7.95(dd, 1H), 8.04(d, 0 1H), 8.14(s, 1H), 8.58(d, 1H), 9.39(s, 1H) 95245.doc -113- 1378923 27-2 φτ。、 0 585 (Μ+Η) 2.38 27-3 > φτ、 486 (Μ+Η) 3.07 < 27-4 0 587 (Μ+Η) 2.29 27-5 ► φτ。、 0 人 545 (Μ+Η) 2.59 27-6 φτ。、 〇ν〇 μη2 545 (Μ+Η) 2.45 95245.doc •114- 1378923
管柱.YMC CombiScreen 0DS-A(5 微米,12 毫微米)’ 50x 4.6毫米内徑β HPLC條件 流速:2.0毫升/分鐘 洗提液:A)TFA/水(0.1/100),b)TFA/乙腈(〇1/1〇〇) 梯度:5-100% B(0-5分鐘)
偵測:在215毫微米之UV 依照實例7A之步驟,自(2,5·二氣基·嘧啶·‘基H2_(丙 烷-2-磺醯基)-苯基]•胺及對應的笨胺製備以下的5_氯基_ N2-(經取代之苯基)-N4-[2-(丙烷磺醯基)·苯基;]-嘧啶_2,4_ 二胺。 95245.doc -115- 1378923
實例 編號 Rx 溶劑) 或MS NMR (400iVIHz), δ (ppm)或 逗留時間分鐘(HPLC) 28-1 II όν νη2 0.2 (AcOEt) CDCI3: 1.31 (d, 6H), 1.85-1.73 (m, 1H), 1.86-1.98 (m, 3H), 2.62-2.70 (m, 1H), 3.11-3.13 (m, 2H), 3.21-8.28 (m, 1H), 3.28 (m, 2H), 3.88 8s, 3H), 5.41 (brs, 1H), 6.53 (d, 1H), 6.59 (d, 1H), 6.64 (brs, 1H), 7.28-7.34 (m, 1H), 7.34 (s, 1H), 7.60-7.67 (m, 1H), 7.91 (dd, 1H), 8.08 (d, 1H), 8.13 (s, 1H), 8.60 (d, 1H), 9.55 (s, 1H). 28-2 φτ, 0 Ν ΟΗ MS m/z 561, 563 (M+1). CDCI3: 1.31(d, 6H), 2.64 (t, 2H), 2.68-2.77 (m, 4H), 3.19(t, 4H), 3.17-3.28(m, 1H), 3.68(t, 2H), 3.88(s, 3H), 6.48(dd, 1H), 6.55 (d, 1H), 7.23-7.32(m, 1H), 7.62(ddd, 1H), 7.91(dd, 1H), 8.04(dd, 1H), 8.12(s, 1H), 8.60(d, 1H), 9.54(bs, 1H) 28-3 0 0.55 (AcOEt) CDCb: 1.31(d, 6H), 3.12-3.14(m, 4H), 3.21-3.27(m, 1H), 3.87-3.89(m, 7H), 6.46(dd, 1H), 6.53(d,1H), 7.23-7.27(m, 1H), 7.30(s, 1H), 7.59-7.64(m, 1H), 7.91(dd, 1H), 8.05(d, 1H), 8.14(s, 1H), 8.60(d, 1H), 9.55(s, 1H) 28-4 0 0.37 (AcOEt) CDCI3: 1.32(d, 6H), 3.21-3.27(m, 1H), 4.00(s, 1H), 7.11(dd, 1H), 7.26-7.27(m, 1H), 7.29-7.33(m, 1H), 7.64(s, 1H), 7.66-7.71(m, 1H), 7.95(dd, 1H), 8.10(s, 1H), 8.21(s, 1H), 8.46(d, 1H), 8.50(s, 1H), 8.54(d, 1H), 9.59(s, 1H) 95245.doc -116- 1378923 28-5 t • 0 N 1 0.03 (AcOEt) CDCI3: 1.31(d, 6H), 1.67-1.77(m, 2H), 1.95-2.05 (m, 2H), 2.39-2.48 (m, 1H), 2.48-2.61 (m, 2H), 2.63-2.78(m, 8H), 3.24 (sept, 1H), 3.71-3.63 (m, 2H), 3.87(s, 3H), 6.47(dd, 1H), 6.55 (d, 1H), 7.21-7.28(m, 1H), 7.61 (ddd, 1H), 7.91 (dd, 1H), 8.00(dd, 1H), 8.12(s, 1H), 8.60(d, 1H), 9.53(bs, 1H) 丄 502 (M+H) 2.84 28-6 v 1 0 1 n 478 (M+H) 4.53 28-7 (T^ 。二。 I / CDCI3: 1.31(d, 6H),1.51-1.42(m, 2H), 1.67-1.53(m, 28-8 Λτ° MS 4H), 1.81-1.68(m, 2H), 1.96-1.89(m, 2H), 2.47- V 599 2.36(m, 1H), 2.57-2.54(m, 4H), 2.69(dd, 2H)3.24(sept, 1H), 3.67(d,1H), 3.87( s , 1H), 6.48 (dd, 1H), 6.56 (d, O 1H), 7.31-7.21(m, 1H), 7.63-7.59 (m, 1H), 8.00(d, 1H), T 0 8.12(s, 1H), 8.60(d, 1H), 9.55(s, 1H) ' 28-9 1 / CDCI3: 1.26 (t, 3H), 1.31(d, 6H),1.74-1.68(m, 2H), rV MS 1.85-1.76(m, 4H), 2.08-1,98(m, 2H), 2.19-2.10(m, V 585 2H), 2.67-2.58(m, 4H), 2.79-2.72(m, 2H), 3.24(sept, 1H) 3.61 (d, 2H), 3.87(s,3H), 6.48(dd, 1H), 6.56 (d, 0 1H), 7.29-7.22 (m, 1H), 7.62(dd, 1H), 7.90(dd, 1H), - V 7.99(d, 1H), 8.12(s, 1H), 8.60(d, 1H), 9.53(s, 1H) -117- 95245.doc 1378923 28-10 • • 4 MS 559 CDCI3: 1.31(d, 6H),1.59-1.37(m, 2H), 1.81-1.69(m, 1H), 1.87(d, 2H), 2.73-2.67(m, 2H), 3.28-3.21 (m, 1H), 3.37(s, 3H),3.61(d, 1H),3.87(s, 3H),6.49(dd, 1H),6.57(s, 1H), 7.31-7.21(m, 1H),7.64-7.60 (m, 1H), 7.91(dd, 1H), 8.00(d, 1H), 8.60(d, 1H) 9.53(s, 1H) 28-11 l· 0 ίο MS 558 CDCI3: 1.31((1, 6H), 2.15(s, 3H), 3.12(ddd, 4H), 3.24(sept, 1H), 3.64 (t, 2H), 3.80(t, 2H), 3.89(s, 3H),6.47(dd, 1H),6.55(d, 1H),7.29-7.24(m, 1H),7.33(bs, 1H), 7.62(m, 1H),7.92(dd, 1H), 8.08(d, i 1H), 8.14(s, 1H), 8.60(d, 1H) 9.55(s, 1H) 28-12 φτ, 0 、Ν ; MS 544 CDCI3: 1.16, (t, 3H), 1.31(d, 6H), 2.56-2.44(b, 2H), 2.71-2.60 (m, 4H), 3.28-3.17(m, 5H), 3.88(s, 3H), 6.48(dd, 1H),6.58(d, 1H),7.30-7.22(m, 1H), 7.63-7.58(m, 1H),7.90(dd, 1H), 8.01(d, 1H), 8.12(s, 1H), 8.60(d, 1H)9.54(s, 1H) I / CDCI3: 1.31(d, 6H, J=6.55),1.75-1.63(m, 2H),2.00- ^8-13 iV MS 1.91(m, 2H),2.37-2.27(m, 1H),2.60 (t, 4H, J=4.79), ν 601 2.74-2.59(m, 2H), 3.24(sept, 1H), 3.66 (d, 2H, J=12.1), 3.75(t, 4H, J=4.53), 3.88(s, 3H), 6.48(dd, 1H, 0 J=2.52, 8.56),6.56(d, 1H, J=2.52),7.33-7.22(m, 1H), V 7.64-7.59 (m, 1H),7.91(dd, 1H, J=8.05,1.51), 8.01(d, λ 1H, J=8.56), 8.12(s, 1H), 8.61(d, 1H, J=7.55) 9.54(s, 1H) 118- 95245.doc 28-14 MS 559 CDCI3: 1.11 (d, 6H. J=6.55), 1.31(d, 6H, J=7.05), 2.82-2.68(m, 5H), 3.20-3.17(m, 4H), 3.28-3.17(m, 1H), 3.87(s, 3H), 6.48(dd, 1H, J=2.52, 8.56),6.56(d, 1H, J=2.52),7.33-7.24(m, 1H), 7.62-7.58(m, 1H),7.90(dd, 1H, J=), 8.01 (d, 1H, J=8.56), 8.12(s, 1H), 8.60(d, 1H, J=8.56) 9.54(s, 1H) 28-15
H2N \〇 MS 559 CDCIs: 1.31 (d, 6H, J=7.05), 1.97-1.85(m, 2H), 2.17-1.98(m, 2H), 2.35-2.25(m, 1H), 2.75(m, 2H), 3.24(sept, 1H), 3.65(d, 2H), 3.88(s, 3H), 5.30 (bs, 1H), 5.48(bs, 1H), 6.48(dd, 1H, J=2.51, 8.56), 6.56(d,, 1H, J=2.52), 7.33-7.21 (m, 1H), 7.62 (m, 1H), 7.91 (dd, 1H, J=1.51,8.06), 8.03(dd, 1H, J=3.02, 8.56), 8.13(s, 1H), 8.60(d, 1H, J=8.57), 9.54(s, 1H) 28-16
MS 532 CDCI3: 1.31 (d, 6H, J=7.06), 1.46-1.43(m, 1H), 1.79-1.68(m, 2H), 2.08-1.99(m, 2H),2.99-2.88(m, 2H), 3.24(sept, 1H), 3.51-3.45(m, 2H), 3.91-3.80(m, 1H), 3.88(s, 3H), 6.49(dd, 1H, J=2.52, 8.56),6.57(d, 1H, J=2.52),7.34-7.23(m, 1H), 7.64-7.60(m, 1H),7.91(dd, 1H, J=1.51, 8.06), 8.02(dd, 1H, J=3.02, 9.06), 8.13(s, 1H), 8.60(d, 1H, J=8.06) 9.53 (s, 1H) 28-17
MS 532 CDCI3: 1.31 (d, 6H, J=6.96), 2.18*2.12(m, 2H), 3.24(sept, 1H),3.37-3.32(m, 2H), 3.39(s, 3H), 3.43(d, 1H, J=8.56), 3.51(dd, 1H, J=5.04, 10.6), 3.87(s, 3H), 4.17-4.09 (m,1H) 6.13 (dd, 1H, J=2.51, 8.56),6.16(d, 1H, J=2.52),7.09(bs, 1H),7.31-7.21(m, 1H), 7.60-7.56 (m, 1H),7.85(d, 1H, J=8.56), 7.89(dd, 1H, J=1.51,8.06), 8.10(s, 1H), 8.65(d, 1H, J=9.06) 9.54 (s, 1H) 95245.doc -119· 1378923 I / CDCI3: 1.31 (d, 6H, J=7.05), 1.82-1.7〇(m, 2H), 2.08- 28-18 rV MS 1.99(m, 2H),2.96-2.87(m, 2H), 3.24(sept, 1H), 3.41- t Φ V P /° 546 3.33(m, 1H), 3.40(s, 3H),3.51-3.42(m, 2H), 3.87(s, 3H), 6.49(dd, 1H, J=2.52, 9.07),6.57(d, 1H, J=2.52),7.32-7.22(m, 1H), 7.64-7.60 (m, 1H),7.91(dd, 1H,), 8.00(dd, 1H, J=3.02, 9.06), 8.12(s, 1H), 8.60(d, 1H, J=8.56)9.53 (s, 1H) I · / 0.33 CDCI3: 1.31 (d, 6H, J=7.05), 1.82-1.70(m, 2H), 2.08- 28-19 rV (AcOEt) 1.99(m, 2H),2.96-2.87(m, 2H), 3.24(sept, 1H), 3.41- V 3.33(m, 1H), 3.40(s, 3H),3.51-3.42(m, 2H), 3.87(s, 1 I 6 3H), 6.49(dd, 1H, J=2.52, 9.07),6.57(d, 1H, J J=2.52),7.32-7.22(m, 1H), 7.62(m, 1H),7.91(dd, 1H,), 8.00(dd, 1H, J=3.02, 9.06), 8.12(s, 1H), 8.60(d, 1H, I J=8.56) 9.53 (s, 1H) I / CDCI3: 1.31 (d, 6H), 1.66-1.53(m, 2H), 2.10-2.01 (m, 28-20 MS 2H),2.51 (s, 3H), 2.70-2.13(m, 1H),2.83-2.74(m, 2H), v 544 3.24(Sept, 1H), 3.63-3.55(m, 2H), 3.87(s, 3H), 4.34- 0 4.25(m, 1H), 6.48(dd, 1H),6.56(d, 1H),7.34-7.24(m, 1H), 7.64-7.60(m, 1H),7.9〇(dd, 1H), 8.00(d, 1H), V /NH 8.12(s, 1H), 8.60(dd, 1H), 9.53(s, 1H) I ^ CDCb: 1.30 (s, 3H),1.32 (s, 3H), 2.33-2.22(m, 1H), l_ 28-21 MS 2.54(s, 3H), 3.37-3.20(m, 3H),3.57-3.44(m, 3H), V 531 3.86(s, 3H), 6.12(dd, 1H),6.16(d, 1H),7.14-7.08(m, 1H), 7.30-7.20(m, 1H),7.65-7.58(m, 1H), 7.93-7.87(m, Q NH / 1H,), 8.10(s, 1H), 8.64(d, 1H) 9.54 (s, 1H) 95245.doc 120- 1378923 28*22
MS 545 CDCI3: 1.30 (s, 3H), 1.32 (s, 3H), 2.03-1.89(m, 1H),2.30-2.18(m, 1H), 2.34(s, 6H),2.96-2.83(m, 1H), 3.29-3.16(m, 2H), 3.40-3.34(m, 1H),3.53-3.43(m, 2H), 3.87(s, 3H), 6.11(dd, 1H,)6.13(dd, 1H),7.〇8(bs, 1H),7.31-7.21 (m, 1H), 7.60-7.56(m, 1H),7.85(d, 1H), 7.89(dd, 1H), 8.10(s, 1H), 8.66(d, 1H)9.54(s, 1H) 28-23
MS 545 CDCI3: 1.31 (s, 3H), 1.32 (s, 3H),3.05(s, 3H), 3.24(sept, 1H), 3.50-3.43(m, 4H),3.85(s, 2H), 3.89(s, 3H), 6.11(dd, 1H,)6.43(dd, 1H),6.50(d, 1H),7.31-7.28(m, 1H), 7.64-7.60(m, 1H),7.92(dd, 1H), 8.09(d, 1H), 8.13(s, 1H), 8.58(d, 1H) 9.55(s, 1H) 28-24
0.05 (AcOEt/Me OH=4/1) CDCI3: 1.30 (s, 3H), 1.32 (s, 3H), 1.92-1.83(m, 1H),2.17-1.95(m, 1H), 2.43-2.27(m, 2H),2.79-2.71(m, 4H), 3.15-2.97(m, 4H), 3.23-3.16(m, 4H),3.24(sept, 1H), 3.87(s, 3H), 6.11(dd, 1H,)6.47(dd, 1H),6.55(d, 1H),7.33-7.23(m, 1H), 7.63-7.59(m, 1H),7.95(dd, 1H), 8.01(dd, 1H), 8.12(s, 1H), 8.60(d, 1H) 9.54(s, 1H) 28-25
MS 600 CDCI3: 1.30 (s, 3H), 1.32 (s, 3H), 1.80-1.70(m, 2H),2.01-1.93(m, 2H), 2.49-2.28(m, 12H),2.76-2.62(m, 4H), 3.04-2.96(m, 4H), 3.16-3.05(m, 2H),3.24(sept, 1H), 3.72-3.63(m, 2H), 3.87(s, 3H),6.48(dd, 1H),6.55(d, 1H),7.31-7.23(m, 1H), 7.66-7.589(m, 1H),7.91(dd, 1H), 8.01(d, 1H), 8.12(s, 1H), 8.60(d, 1H) 9.53(s, 1H) 95245.doc -121 - 1378923' 28-26 • • >φ V 0 MS 573 CDCI3: 1.30 (s, 3H), 1.32 (s, 3H), 2.59-2.43 (m, 4H),2.78-2.73(m, 1H), 3.00-2.86(m, 2H),3.38-3.20(m, 3H), 3.54-2.45(m, 1H), 3.73(dd, 1H),3.84-3.77(m, 1H), 3.94-3.87(m, 1H), 3.88(s, 3H),6.46(dd, 1H),6.53(d, 1H),7.32-7.23(m, 1H), 7.31 (bs, 1H), 7.63-7.52(m, 1H),7.91(dd, 1H), 8.04(d, 1H), 8.13(s, 1H), 8.60(d, 1H) 9.54(s, 1H) 1 丨 28-27 (y Or。 nh2 MS 559 CDCI3: 1.30(s, 3H), 1.32 (s. 3H), 1.82-1.73 (m, 1H), 1.97-1.84(m, 3H), 2.73-2.51 (m, 1H), 3.12(t, 2H), .1 3.31-3.20 (m, 3H), 3.90(s,3H), 5.46-5.37(m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.68-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.33(bs, 1H), 7.65-7.61(m, 1H), 7.92(dd, 1H), 8.08(d, 1H), 8.14(s, 1H), 8.60(d, 1H), 9.55(s, 1H) 28-28 φτ, Q 丫。 nh2 MS 559 CDCI3: 1.30(s, 3H), 1.32 (s, 3H), 1.82-1.73 (m, 1H), 1.97-1.84(m, 3H), 2.73-2.51 (m, 1H), 3.12(t, 2H), 3.31-3.20 (m, 3H), 3.90(s,3H), 5.46-5.37(m, 1H), 6.53(dd, 1H), 6.59(d, 1H), 6.68-6.62 (m, 1H), 7.28-7.21 (m, 1H), 7.33(bs, 1H), 7.65-7.61 (m, 1H), 7.92(dd, 1H), 8.08(d, 1H), 8.14(s, 1H), 8.60(d, 1H), 9.55(s, 1H) ( l· 28-29 MS 413 CDCI3: 1.31 (s, 3H), 1.33(s, 3H),2.92(t, 4H), 3.28(sept, 1H) 3.73(t, 4H), 3.87(s,3H), 6.51(dd, 1H), 6.82(d, 1H), 7.32-7.23 (m, 1H), 7.57(bs, 1H), 7.70-7.64(m, 1H), 7.92(dd, 1H), 8.01(bs, 1H), 8.12(s, 1H), 8.60(d, 1H), 9.53(s, 1H) 28-30 方/ 0 1 MS 493 CDCI3: 1.30 (s, 3H), 1.33(s, 3H), 3.25(sept, 1H) 3.60 (bs,3H), 3.89(s, 3H), 6.59(s, 1H), 7.27-7.18 (m, 1H),7.61(dd, 1H), 7.83(bs, 1H), 7.90(dd, 1H), 8.15 < s , 1H), 8.55(d, 1H), 9.55(s, 1H) 95245.doc -122- 1378923 I CDCI3: 1.31(d, 6H),1.59-1.37(m, 2H), 1.8l-1.69(m, 28-31 fV°\ MS 1H), 1.87(d, 2H), 2.73-2.67(m, 2H), 3.28-3.21 (m, 1H), 445 3.37(s, 3H),3.61(d, 1H),3.87(s, 3H),6.49(dd, 1H),7.025(bs, 1H), 7.28-7.23(m, 1H),7.64-7.59(m, 1H), 7.93-7.89(m, 2H), 8.15(s, 1H), 8.57(dd, 1H) 9.56(s, 1H)
實例 編號 Rx HPLC 逗留時間 (分鐘) 質量(ESI) m/z 29-1 0 3.30 546 (M+H) ^29-2 0 2.82 627 (M+H) 29-3 φτ。、 0 人 3.07 587 (M+H) 95245.doc -123 - 1378923 Λ c'Y^n0 ΝΗ I Rx 實例 I編號
Rx HPLC 逗留時間 (分鐘) 質量(ESI) m/z 30-1
2.82 516 (Μ+Η) 30-2 ❹ 30-3 30-4 95245.doc
ΝΗ,
Ο 2.65 2.50 3.10 557 (Μ+Η) 557 (Μ+Η) 498 (Μ+Η) -124- 1378923 30-5 2.30 543 (M+H) 30-6 φτ。、 0丫。 nh2 2.52 557 (M+H) i 30-7 P 0 、H 1 2.23 612 (M+H)
C,\^N HN N, //° m
I
Rx 0 實例 編號 Rx HPLC 逗留時間 (分鐘) 質量(ESI) m/z 31-1 F 3.15 423 (M+H) 95245.doc -125- 1378923
貪例 編號 Rx MS NMR (400MHz) in CDCI3, δ (ppm) 32-1 0 ic 585.3 1.03 (s, 3H), 1.04(s, 3H),2.15(s, 3H), 2.32(sept, 1H) 3.00(d, 2H) 3.10(t, 2H), 3.13(t, 2H), 3.64(t, 2H),3.79(t, 2H), 3.89(s,3H), 6.45(dd, 1H), 6.55(d, 1H), 7.34-7.26 (m, 1H), 7.52(bs, 1H), 7.64-7.60(m, 1H), 7.97(dd, 1H), 8.07(d, 1H), 8.15(s, 1H), 8.54(d, 1H), 9.32(s, 1H) ) I 3.17 32-2 (fV、 532 (M+H) V 0 95245.doc 126- 1378923
實例 編號 Rx MS NMR (400MHz) in CDCI3, δ (ppm) 33-1 0 ic 585.3 1.66-1.52 (m, 2H), 1.92-1.73 (m, 4H), 2.12-2.03 (m, 2H), 2.15(s, 3H), 3.00(d, 2H) 3.11(t, 2H), 3.14(t, 2H), 3.58-3.46(m, 1H), 3.64 (t, 2H),3.80(t, 2H), 3.89(s,3H), J 6.48(dd, 1H), 6.55(d, 1H), 7.30-7.24 (m, 1H), 7.52(bs, 1H), 7.63-7.58(m, 1H), 7.94(dd, 1H), 8.08(d, 1H), 8.14(s, 1H), 8.60(d, 1H), 9.54(s, 1H) 丄η 544 (M+H) 3.15 33-2 V 0
實例 編號 Rx HPLC 逗留時間 (分鐘) 質量(ESI) m/z //0 丄 3.15 532 (M+H) 34-1 95245.doc -127- 1378923 34-2 • % ·* CX/M 〇//Ό 3.34 558 (Μ+Η) 34-3 3.35 546 (Μ+Η) 34-4 1 3.32 546 (Μ+Η) 崎 34-5 3.09 566 (Μ+Η) 34-6 〇//Ό 2.87 552 (Μ+Η) 實例 編號 ^ — MS NMR (400MHz), CDCI3, δ ppm f 34-7 Χι 〇 ΜΝ^ Ν ΝΗ A F MS 435, 436 1.05 (t, 3H), 1.69-1.78 (m, 2H), 2.86-2.95 (m, 1H), 3.16-3.25 (m, 1H), 6.57-6.68 (m, 2H), 7.17 (dd, 1H), 7.35-7.39 (m, 1H), 7.50 (dd, 1H), 8.13 (s, 1H), 8.16-8.21 (m, 1H), 8.48 (d, 1H), 10.14 (s, 1H) 34-8 ο丸 0 f 1 MS 549, 551 0.94 (t, 3H), 1.69-1.80 (m, 2H), 2.38 (s, 3H), 2.55-2.64 (m, 4H), 3.02-3.08 (m, 2H), 3.22-3.29 (m, 4H), 3.88 (s, 3H), 6.55 (ddd, 1H), 6.60-6.66 (m, 1H), 7.13-7.18 (m, 1H), 7.34 (br.s, 1H), 7.44 (d, 1H), 8.10 (s, 1H), 8.10-8.23 (m, 2H), 8.88 (s, 1H). 95245.doc -128· 1378923
NH Rx 35-1 ί 0 567 [Μ+1]+ DMSO-d6: 2.24 (s, 3H), 2.45-2.50 (m, 4H), 2.78 (d, 3H), 3.10.-3.17 (m, 8H), 3.74-3.79 (m, 7H), 6.49 (dd, 1H), 6.66 (d, 1H), 6.85-6.89 (m, 1H), 7.18 (d, 1H), 7.40 (d, 1H), 7.98-8.02 (m, 2H), 8.29 (br.d, 1H), 8.60-8.66 (m, 1H), 11.17 (s, 1H). 35-2 0c> 505 DMSO-d6: 2.24(s, 3H), 2.46-2.50(m, 4H), 2.79(d, 3H), 3.13-3.17(m, 4H), 3.78(s, 3H), 6.69(d, 1H), 6.87(dd, \ [Μ+1Γ 1H), 7.07-7.17(m, 2H), 7.19-7.23(m, 2H), 7.54(d, 1H), 8.13(s, 1H), 8.45(s, 1H), 8.65-8.75(m, 1H), 9.04(s, 1H), 11.19(st 1H)
實例36(左苯胺之中間物)36-1 2_胺基·N^基-苯醯胺之製備作用 Η
MeNli
HjO-THF 92%
將100毫升之2當量甲基胺·四氫呋喃溶液(200毫莫耳)在 室溫下分批加入在Γ00毫升HjO中的16.3公克(100毫莫耳)靛 紅酸酐之懸浮液中。將反應混合物攪拌1小時及接著以 95245.doc -129- 1378923
AcOEt萃取。將有機層以Ηβ及食鹽水清洗,經仙23〇4乾 燥及在減壓下濃縮,得到成為無色固體之13.79公克預期 產物2-胺基-N-曱基-苯醯胺(92毫莫耳,92%)。 NMR (400MHz,CDC13,6 ): 2.97 (d,3H,J=4.52Hz), 5.49 (bs, 1H), 6.07 (bs, 1H), 6·64 (ddd, ih, J=8.04, 7.56, 1.0Hz), 6.68 (dd, 1H, J=8.32, 1.0Hz), 7.20 (ddd, 1H, J=8.32, 7.56,1.52 Hz), 7.29 (ddd, 1H,J=8.04, 1.52Hz)。 36-2 2-(2,5-二氣基-嘧啶-4-基胺基)-N-甲基-笨醖胺
將2,4,5-三氣嘧咬(23.8公克’ 130毫莫耳)及破酸鉀(17.9 公克’ 130毫莫耳)加入在DMF(300毫升)中的15 〇公克(99 8 毫莫耳)2-胺基-N-曱基·苯醯胺之溶液中。將反應混合物在 75°C下攪拌5小時’冷卻至室溫及接著倒入h2〇(600毫升) 中。以過濾收集所得沉澱物,接著以5〇%水性CH3CN(200 毫升)清洗及在減壓下乾燥(4〇。(:,1〇小時),得到成為象牙 白固體之預期的2-(2,5-二氣基-嘧啶-4-基-胺基)-N-甲基-苯 醯胺(26.4公克,88.9毫莫耳,89%)。 NMR (400MHz,DMSO-d6,δ ): 2.81 (d, 3H, J=4.52Hz), 95245.doc • 130- 1378923 7.22 (dd, 1H, J=8.56, 8.04Hz), 7.60 (ddd, 1H, J=8.56, 8.56, 1.0Hz), 7.81 (dd, 1H, J=8.04, 1.0Hz), 8.48 (s, 1H), 8.52 (d, 1H,J = 8_56Hz), 8.80-8.90 (m, 1H), 12.18 (s,1H)。 根據上述的方式製備以下的化合物。 36-3 2-(5-溴基-2-氣基-嘧啶-4-基胺基)-N_甲基-苯醯胺
1.52Hz),7.79 (dd,1H,J=7.8, 1.52Hz), 8.47 (dd, 1H, NMR (400MHz,DMSO-d6, 1H, J=7.54, 7.54, 1.0Hz), J=8.06, 1.0H), 8.55 (s, 1H), δ ): 2.81 (d, 3H), 7.23 (ddd, 7.59 (ddd, 1H, J=7.93, 8.06, 8.81-8.87 (m, 1H), 12.0 (brs,
1H)。Rf:0.46 (正己烷:AcOEt=7:3)。
36-4 2-(2,5-二氣基-嘧啶-4-基胺基)-N-乙基-苯酿胺
NMR (400MHz, CDC13, δ ): 1.28 (t, d=7.04, 3H), 3.48-3.57 (m, 2H), 6.22 (br.s, 1H), 7.11-7.17 (m, 1H), 7.51 (dd, 95245.doc -131 - 1378923 J=l.〇, 8.04, 1H), 7.53-7.61 (m, 1H), 8.22 (s, 1H), 8.69-8.74 (m,1H), 11.66 (br.s, 1H)。Rf:0.60 (己燒:AcOEt=l:l)。 36-5 2_(S-溴基-2-氣基-嘧啶-4-基胺基)-N-甲基-苯磺醯胺之製備 作用
將在包括碳酸舒(830毫克,6.0毫莫耳)之n,N-二甲基甲 酿胺(10毫升)中的5-溴基-2,4-二氣嘧啶(684毫克,3.0毫莫 耳)及2-胺基-N-甲基-苯磺醯胺(559毫克,3.0毫莫耳)之懸 浮液在室溫下攪拌23小時。加入飽和水性氯化銨,並將混 合物倒入水中及以醋酸乙酯萃取兩次。將有機層以食鹽水 清洗,經硫酸鈉乾燥及在真空中蒸發。將殘餘物以矽膠/ 柱色層分離法(正己烷-醋酸乙酯梯度)純化,供應成 色固體之標題化合物。
1H), 1H), :醋酸 H-NMR (CDC13), δ (ppm): 2.67 (d, 3H), 4.79 (q 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd 8.37 (s, 1H),8.48 (d,1H),9.52 (s,1H)。Rf (正己烷, 乙醋=10:3):0.33。 - 根據上述的方式製備以下的化合物。 36-6 95245.doc -132- 1378923 2-(2,5-二氣基-嘧啶-4-基胺基)-N-甲基·苯磺醯胺
NMR (400MHz, CDC13, δ): 2.67 (d, 3Η), 4.97-5.04 (m, 1H), 7.29 (ddd, 1H, J=7.54, 7.54, 1.0Hz), 7.66 (ddd, 1H, J=7.93, 8.08, 1.48Hz), 7.94 (dd, 1H5 J=8.04, 1.52Hz), 8.24 (s,1H),8.51 (dd,1H,J=8.06,1.0Hz),9.64 (brs,1H)。 Rf:0.45 (正己烧:AcOEt=4:l)。 之-口^-二氣基-嘧啶-^基胺基卜&異丙基-苯磺醢胺
將氫化納(6.6公克,165.3毫莫耳)在〇°C下分批加入 DMI(150毫升)中的2_胺基-N-異丙基-苯磺醯胺(16.1公克, 75.1毫莫耳)之溶液中。在將混合物在室溫下攪拌1小時之 後在〇 C下加入2,4,5·三氣嘧啶(2〇 7公克,112刀毫莫 耳)〇在至溫下属'捣士4·* c、
丹稅拌5小時之後,加入水及將混合物以
AcOEt萃取三次。將右她& $有機層以食鹽水清洗,經硫酸鈉乾燥 及在減壓下蒸發。 將殘餘物以矽膠管枉色層分離法(己烷 95245.doc -133. 1378923 供應成為淡棕色固體之標題化 至己烧:AcOEt=4:1)純化 合物(10.2公克,38%)。
lH-NMR (400MHz, CDC1, λν ι 心 δ)· 1.06 (d, 6Η), 3.43-3.53 (m, 1H), 4.38 (d, 1H), 7.29 (dd im -, {ύά, 1H), 7>66 (dd} 1H)j 7 98 (d) 1H ),8 · 2 9 (s,1H) 8 · 5 1 (d 1 w、ο c i
}, 1H)> 9-5l (brs, 1H) 〇 Rf:0.45 (iL 己烧:AcOEt=4:1)。
根據上述相同的方式製備以下的彳匕合物。
實例 編號 Rz Rf (溶劑). 或MS NMR (400ΜΗζ),δ (ppm) 36-8 0.45 (正己烷: AcOEt=4:1) DMSO-d6; 0.63(t, 6H), 0.86(d, 3H), 1.21-1.31 (m, 2H), 3.02-3.12(m, 1H), 7.37(dd,1H), 7.71(dd, 1H), 7.85(d, 1H), 7.89(d, 1H), 8.20(d, 1H), 8.56(s, 1H), 9.51 (brs, 1H) 36-9 0.46 (正己烷:: AcOEt=7:3) CDCI3; 〇.7〇(t, 6H),1.23-1.45(m, 4H), 3.03-3.13(m, 1H), 4.27(d,1H), 7.27(dd, 1H), 7.65(dd, 1H), 7.98(d, 1H), 8.29(s, 1H), 8.52(d, 1H), 9.59(brs, 1H) 36-10 2-(2-氣基-5-硝基-嘧啶_4_基胺基)-N-甲基-苯磺醢胺之製備 作用:
95245.doc •134- Ϊ378923 將2,4-二氯基-5-頌基-0¾咬(1.94公克,ι〇毫莫耳)及2_胺 基-N-甲基-苯續gg胺(1.86公克,1〇毫莫耳)溶解在 CHC13(30毫升)中》將反應混合物在61°C下搜拌2小時。將 溶劑蒸發及將殘餘物以醚清洗,得到標題產物。
Rf:0.50(正己烷:醋酸乙酯=1:1)。iH-NMR (4〇()MHz, CDC13),δ (ppm): 2.67 (d.3H),4.6-4.7 (m,2H),7.41 (t,1H), 7.7 (t, 1H), 8.04 (d, 1H), 8.15 (d, 1H), 9.21 (s, 1H), 11.2 (s, 1H)。 36-11 # (2,S-二氣基-嘧啶_4_基卜丨2_(丙烷磺醯基苯基】胺之製 備作用
將氯化納(1.48公克’ 37毫莫耳)在〇。(:下分批加入在Ν,Ν-—曱基甲醯胺(40毫升)中的2-(丙烷·1-磺醯基)-苯基胺(3.69 公克,18·5毫莫耳)之溶液中。在攪拌之後,加入2,4,5•三 氣嘴咬(2.1毫升’ 18.5毫莫耳)。將混合物在〇。(:下攪拌30 分鐘及在室温下再攪拌7小時。在加入飽和水性氣化銨之 後,將混合物倒入水中及以醋酸乙酯萃取兩次。將有機層 以食鹽水清洗’經硫酸鈉乾燥及在真空中蒸發。將殘餘物 以矽膠官柱色層分離法(正己烷·醋酸乙酯梯度)純化’供應 成為無色固體之標題化合物。 95245.doc •135- 1378923 ^-NMR (CDC13) δ (ppm): 0.99 (t, 3H), 1.77 (d, 2H), 3.07-3.11 (m, 2H), 7.26 (s, 1H), 7.32 (ddd, 1H), 7.73 (ddd, 1H), 7.95 (dd, 1H),8.31 (s,1H),8.61 (dd,1H),9.94 (bs, 1H)。 Rf (正己烷:醋酸乙酯=3:1):0.63。 根據上述的方式製備以下的化合物。
實例 編號 Rx '檢定 36-12 X' \ 1H-NMR (CDCI3), δ (ppm): 1.35(d, 6H), 3.18-3.24(m, 1H), 7.30-7.34(m, 1H), 7.70-7.75(m, 1H), 7.92(dd, 1H), 8.30(s, 1H), 8.63(d, 1H), 10.06(s, 1H). Rf 0.70: (AcOEt) 36-13 NMR (400MHz) in CDCI3, δ (ppm): 1.29(t, 3H), 3.15(q, 1H), 7.31-7.35(m, 1H), 7.71-7.75(m, 1H), 7.96(dd, 1H), 8.31 (s, 1H), 8.60(d, 1H), 9.92(s, 1H). Rf: 0.67~ (AcOEt). 36-14 1.01-1.06(m, 2H), 1.32-1.37(m, 2H), 2.49-2.55(m,1H), 7.29-7.33(m, 1H), 7.69-7.73(m, 1H), 7.91 (dd, 1H), 8.31 (s, 1H), 8.58(d, 1H), 9.90(s, 1H). Rf 0.69 (AcOEt) 36-15 \ 0.99(t, 6H), 1.72-1.90(m, 4H), 2.76-2.82(m, 1H), 7.26-7.34(m, 1H), 7.69-7.74(m, 1H), 7.92(dd, 1H), 8.30(s, 1H), 8.62(d, 1H), 10.02(s, 1H). Rf: 0.73 (AcOEt)
95245.doc -136· 1378923 實例36-16 .· 非市售可取得的經取代之胺的合成作用: “ 3-胺基-4’-尹氧基-4-f基聯苯之製備作用 : 將碳酸鉀(9H)毫克,6.58毫莫耳)、肆(三苯麟)銘⑽」 毫克’ 0.099毫莫耳)及4·漠基·基·2•硝基苯(川毫克, 3.29毫莫耳)加入在甲苯(5.2毫升)及乙醇(13毫升)中的4· 甲氧基苯基蝴酸(500毫克,3_29毫、莫耳)之溶液中,並在 • 1〇〇°C下攪拌7小時。將混合物倒入水中及以醋酸乙酯萃取 兩次。將有機層以水及接著以食鹽水清洗,經硫酸鎮乾燥 及在真空中蒸發。將殘餘物以矽膠管柱色層分離法(正己 烷:醋酸乙酯=5:1)純化,供應成為黃色固體之4,_甲氧基 曱基-3-硝基聯苯. !Η-ΝΜΚ (δ, ppm): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H), 7.54 (dd, 2H), 7.68 (dd, 1H), 8.18 (d 1H)。Rf (己烷:醋酸乙酯=3:1):〇 4〇〇 .將在甲醇(6毫升)中的4·_甲氧基_4_甲基_3_胡基聯苯(63〇 毫克2.95毫莫耳)及1〇%叙_木炭(63毫克,0.059毫莫耳) 之懸浮液在氫氣下攪拌〖2小時。以過濾移除鈀觸媒,並將 所得溶液在真空中蒸發,供應標題化合物。 ^-NMR (δ, ppm): 2.20 (s, 3H), 3.84 (s, 3H), 6.87 (d, 1H)S 6.89 (dd, 1H), 6.95 (d, 2H), 7.09 (d, 1H), 7.48 (d, 2H) 〇 Rf • (正己烷:醋酸乙酯=1 :1):0.50。 4-(3-胺基-4-甲基苯酿基)_六氫吼味叛酸特丁醋之製備 作用 95245.doc •137- 1378923 將三乙胺(300微升,3.59毫莫耳)、TBTU(800毫克,2.49 • 毫莫耳)及HOAt(270_5毫克,1.99毫莫耳)加入在DMF(3.0 -; 毫升)中的4-甲基-3-硝基-苯甲酸(300毫克,2.76毫莫耳)、 —: N-丁氧基羰基-六氫吡p井(340毫克,丨.83毫莫耳)之溶液 中,並在室溫下授拌24小時。將混合物倒入水中及以醋酸 乙酯萃取兩次》將有機層以水及接著以食鹽水清洗,經硫 酸鎮乾燥及在真空中蒸發。將殘餘物以石夕膠管柱色層分離 • 法(正己烷:醋酸乙酯=5:1)純化,供應成為無色固體之4-(4-曱基-3 -頌基笨醯基)-六氫π比p井-1-缓酸特丁 g旨。 •H-NMR (δ, ppm): 1.47 (s, 9H), 2.64 (s, 3H), 3.28-3.88 (m, 8H),7.42 (d,1H),7.56 (dd,1H),8·03 (d, 1H)。Rf (己烷:醋 酸乙酯=10:1): 0.13。 以在曱醇溶液中的1 〇%鈀-木炭上的氫之還原作用獲得標 題化合物。 4-(3-胺基_4_甲基苯基嗎啉之製備作用 • 將二醋酸鈀(31·2毫克,0.139毫莫耳)及2_(二特丁膦基) 聯苯(125毫克,0.403毫莫耳)加入在甲苯中的4_溴基_丨_甲 基-2-硝基苯(225毫克,丨‘⑽毫莫耳)、嗎啉(125微升,125 毫莫耳)及碳酸鉋(474.4毫克,1.46毫莫耳)之溶液中,並在 ‘ 100 C下攪拌5小時。在冷卻之後,將混合物過濾,移除不 _溶物質。將過濾物倒入水中及以醋酸乙醋萃取兩次。將有 :· 機層以水及接著以食鹽水清洗,經硫酸錤乾燥及在真空中 :.· ?矣發。將殘餘物以矽膠管柱色層分離法(正己烷:醋酸乙 酉曰5.1)純化’供應成為黃色固體之⑷甲基_3_硝笨基)· 95245.doc •138- 1378923 嗎咐。 *H-NMR (δ, ppm): 2.50 (s, 3H), 3.17-3.19 (m, 4H), 3.86-3.88(m, 4H),7,04 (dd,1H),7.21 (d,1H),7.47 (d,1H)。Rf (己烷:醋酸乙酯=5:1): 0.20。 以在甲醇溶液中的10%鈀-木炭上的氫之還原作用獲得標 題化合物。 實例37:非市售可取得的經取代之胺的合成作用 37-1 1-(3-甲氧基-4-硝基-苯基)_六氫吼啶_4-醇之製備作用 %r。-
將4-氟基-2-曱氧基-卜硝基-苯(4.0公克,23毫莫耳)加入 在N,N-二甲基曱醯胺(40毫升)中的六氫,比咬-4-醇(2.79公 克’ 28毫莫耳)及碳酸鉀(3.88公克,28毫莫耳)之懸浮液 中,並在室溫下授拌24小時。將混合物倒入水中及以過渡 收集沉澱物》將所得固體在50 °C之真空中乾燥,供應成為 黃色固體之89%產量之1-(3-曱氧基-4-硝基-苯基)-六氫。此 啶-4-醇(5.23公克)》
'H-NMR (400MHz, CDC13, δ, ppm): 1.54 (d, 1H), 1.62-1.7J 95245.doc •139- 1378923 (m, 2H), 1.98-2.04 (m, 2H), 3.22 (ddd, 4H), 3.73-3.80 (m, 2H), 3.95 (s, 3H), 3.98-4.02 (m, 1H), 6.33 (d, 1H), 6.43 (dd, 1H),8.00 (d,1H)。 使用適當的原料及條件重複上述的步驟,獲得以下的化 合物。 實例 編號 Rx 檢走 37-2 φτ、 0 Ή-NMR (400MHz, CDCI3i δ, ppm) :1.53-1.72(m, 2H), 1.80-1.83(m, 4H), 1.99-2.04(m, 2H), 2.24-2.31 (m, 1H), 2.54-2.67(m, 4H), 3.03(dt, 2H), 3.84-3.89 (m, 2H), 3.95(s, 3H), 6.31(d, 1H), 6.42(dd, 1H), 8.01 (d, 1H). Rf 0.54 (AcOEt) 37-3 φτ。、 όν Ή-NMR (400MHz, CDCI3, δ, ppm): 1.81-1.91 (m, 2H), 1.99-2.04(m, 2H), 2.38-2.48(m, 1H), 3.03(ddd, 2H), 3.91-3.96(m, 2H), 3.95(s, 3H), 5.22-5.41 (m, 1H), 5.40-5.53(m, 1H), 6.36(d, 1H), 6.43(dd, 1H), 8.00(d, 1H). Rf 0.15 (AcOEt) 95245.doc 140- 1378923 37-4 • • * φτ。、 Ν\ Η \ 乙基-Π-(3-甲氧基-4-硝 笨基)吡咯烷-3-基]胺 W-NMR (400MHz,CDCI3, δ, ppm): 1.15(t, 3Η), 1.88-1.96(m, 1H), 2.22-2.30(m,1H), 2.68-2.77(m, 2H),3.15-3.18(m, 1H), 3.38-3.44(m, 1H), 3.52-3.62(m, 2H), 3.93(s, 3H), 5.92(d, 1H), 6.07-6.10(m, 1H), 8.00-8.02(m, 1H). Rf 0.65 (n-hexane: AcOEt=1:1). 37-5 ^-NMR (400MHz, CDCI3, δ, ppm): 2.36(s, 3H), 2.52-2.57(m, I ϊ 4H), 3.40-3.43(m, 4H), 3.95(s, 3H), 6.32(d, 1H, J=2.52Hz), , 6.43(dd, 1H, ^=9.56, 2.52Hz), 7.99(d, 1H, J=9.08Hz). Rf 0.60 V 0 Ν 1 1-(3-曱氧基-4-硝苯基) -4-甲基六氫°比啩 (MeOH : CH2CI2=4:1). 37-6 %r〇- I ^-NMR (400MHz, CDCI3, δ, ppm): 1.10-1.19(m, 1H), 1.59- 2.18(m, 6H), 2.28(s,3H), 2.71-2.74(m, 1H), 2.88-2.91(m, 1H), At。、 3.86-3.95 (m, 5H), 6.47-6.52(m, 2H), 7.97-8.00(m, 1H). Rf V 0.65 (π-hexane: AcOEt=1:1) 1丨 ό. 3-(3-曱氧基-4-硝笨氧基 甲基)-1-曱基六氫吡啶 37-7 ^-NMR (400MHz, CDCI3, δ, ppm): 4.08(s,3H), 7.30(dd,1H), 7.58(d, 1H), 8.05(d, 1H), 8.15(s, 1H), 8.67(s, 1H). Rf: 0.42 6r。、 (AcOEt) • Y 0 95245.doc -141 - 1378923 -m • 37-8 0 ^-NMR (400MHz, CDCI3, δ, ppm): 1.40-1.50 (m, 2H), 1.55-1.69 (m, 6H), 1.90-1.96 (m, 2H), 2.45 - 2.53 (m, 5H), 2.90 -2.99 (m, 2H), 3.90 - 4.00 (m, 2H), 3.94 (s, 3H), 6.30 (d, 1H, J =,2.5 Hz ), 6.41 (dd, 1H, J = 9.0, 2.5 Hz), 7.99 (d, 1H, J = 9.0 Hz) • 37-9 > Sr0· φτ。、 Q r ^-NMR (400MHz, DMSO-d6, δ, ppm) : 1.95-1.82(m, 2H), 2.15-2.06 (m, 1H), 2.30 (s, 3H), 3.17 (dd, 1H), 3.32-3.23 (m, 1H), 3.56-3.34 (m, 3H), 3.96 (s, 1H), 6.09 (d, 1H), 6.21 (dd, 1H), 7.91 (d, 1H) 37-10 〔δ 'H-NMR (400MHz, CDCI3, δ, ppm): 2.30 - 2.48 (m, 3H), 2.59 -2.66 (m, 1H), 2.70 - 2.76 (m, 1H), 2.85 - 2.92 (m, 1H), 3.09 -3.17 (m, 1H), 3.30 - 3.34 (m, 1H), 3.52 - 3.58 (m, 1H), 3.68 -3.84 (m, 3H), 3.87 - 3.91 (m, 1H), 3.96 (s, 3H), 6.32 (d, 1H, J =2.5 Hz ), 6.42 (dd, 1H, J = 9.6, 2.5 Hz ), 8.00 (d, 1H, J = 9.6 Hz) 4 4» 37-11 > Q Ν一 / l-NMR (400MHz, DMSO-d6, CDCI3, δ, ppm) : 1.90-1.79(m, 1H), 2.25-2.15 (m, 1H), 2.21 (s, 3H), 2.87-2.77 (m, 1H), 3.16 (dd, 1H), 3.42-3.32 (m, 1H), 3.59-3.52 (m, 1H), 3.67-3.61 (m, 1H), 3.91 (s, 3H), 6.13 (d, 1H), 6.24 (dd, 1H)), 7.91 (dd, 1H) 95245.doc 142· 1378923 參 • w % 37-12 Ή-NMR (400MHz, CDCI3): 1.43-1.00(m, 2H), 1.95-1.81 (m, 2H),2.94-2.17(m, 2H),2.96(s, 3H),3.27 (d, 2H), 3.35(s, 3H),3.97-3.90 (m, 2H), 3.95(s, 3H), 6.30(d, 1H), 6.42(dd, 1H) 8.00(d, 1H). Rf: 0.25 (AcOEt) • 37-13 0 ; Ή-NMR (400MHz, CDCI3): 1.14(t, 3H),2.48(dd, 2H), 2.59(t, 4H),3.42 (t, 4H), 3.95(s,3H), 6.32(d, 1H), 6.43(dd, 1H) 8.01(d, 1H). Rf 0.15 (AcOEt) • 37-14 令。/ 0 'H-NMR (400MHz, CDCI3): 1.02-0.89 (m, 2H), 2.01-1.94 (m, 2H), 2.52-2.38 (m, 1H), 2.65-2.53 (m, 4H),3.04-2.94(m, 2H), 3.79-3.69(m, 4H),3.97-3.88 (m, 2H), 3.95(s,3H), 6.32(d, 1H), 6.42(dd, 1H)8.00(d, 1H).. Rf0.10 (AcOEt) 37-15 %r〇-| / Ή-NMR (400MHz, CDCI3): 1.08 (s, 3H),1.09(s, 3H), 2.66(t, 4H),2.74 (sept, 1H), 3.41 (t, 4H), 3.95(s,3H), 6.32(d, 1H), • * • _ 令。‘ 0 人 6.42(dd, 1H) 8.00(d, 1H). Rf 0.15 (AcOEt)
95245.doc -143- 1378923 37-16
h2n 、o Ή-NMR (400MHz, CDCI3): 1.91-1.81 (m, 2H), 2.06-1,97(m, 2H),2.48-2.40(m, 1H), 3.07-2.98(m, 2H),3.97-3.93(m, 2H), 3.93(s,3H), 5.37-5.30(m, 1H),5.55-5.43 (m, 1H), 6.33(d, 1H), 6.43(dd, 1H) 8.00(d, 1H). Rf 0.10 (AcOEt) 37-17
Ή-NMR (400MHz, CDCI3): 2.18-2.07 (m, 1H), 2.30-2.22 (m, 1H), 3.38(s, 3H), 3.56-3.44(m, 4H),3.95 (s, 3H), 4.13 (ddd,1H), 5.96(d, 1H), 6.12(dd, 1H) 8.03(d, 1H). Rf 0.30 (AcOEt) 37-18
boc 'H-NMR (400MHz, CDCI3): 1.46(s, 9H),1.81-1.68(m, 4H), 2.73(bs, 3H),3.07-2.97(m, 2H), 3.95(s,3H), 4.03-3.94 (m, 2H), 6.32(d, 1H), 6.43(dd, 1H) 8.00(d, 1H). Rf 0.55 (Hexane:AcOEt) 37-19
'H-NMR (400MHz, CDCI3): 3.60-3.57(m, 2H),3.68-3.65(m, 2H), 3.97(s, 3H),4.07(s, 2H), 6.17(bs, 1H), 6.26(d, 1H), 6.39(dd, 1H) 8.04(d, 1H). Rf 0.85 (AcOEt) 95245.doc 144- 1378923
37-20 α〇 ^-NMR (400MHz, CDCI3): 3.08(s, 3H), 3.54(dd, 2H),3.67(dd, 2H), 3.96 (s, 3H), 4.05(s, 2H), 6.25(d, 1H), 6.38(dd, 1H) 8.03(d, 1H). Rf0.30 (AcOEt) 37-21 。- P 0 . N io ^-NMR (400MHz, CDCI3): 1.73-1.55 (m, 2H), 1.99-1.91 (m, 2H), 2.09(s, 3H),2.61-2.49 (m, 5H), 3.47(t, 2H),3.63(t, 2H), 3.99-3.89 (m, 3H), 3.95 (s, 3H), 6.32(d, 1H), 6.42(dd, 1H) 8.01(d, 1H). Rf 0.10 (AcOEt:MeOH=4:1) 37-22 iV 1H-NMR (400MHz, CDCI3): 3.90(s, 3H), 3.98(s, 3H), 3.98 (s, 3H), 6.56(s, 1H), 7.59(s, 1H). Rf 0.605 (AcOEt) 0 I 37-23 V fV 'H-NMR (400MHz, CDCI3): 3.25-3.22 (m, 4H), 3.90-3.87 (m, 4H), 3.95(s, 3H), 6.48(s, 1H), 7.57(s, 1H). Rf 0.060 (Hexane:AcOEt=5:1) -V 0 95245.doc 145- 1378923 4 37-24 0y0 0 N 1 Ή-NMR (400MHz, CDCI3): 2.37 (s, 3H), 2.61 (bs, 4H),3.27 (bs, 4H), 3.88 (s, 3H), 3.95(s, 3H), 6.48(s, 1H), 7.56(s, 1H). Rf 0.10 (AcOEt:MeOH=5:1) • 37-25 丨 ύ Μ, 1 Ή-NMR (400MHz, CDCI3): 1.09(t, 3H), 1.89(dd, 2H), 2.36(s, 3H), 2.55(t, 4H), 3.39(t, 4H), 4.03(t, 2H), 6.32(d, 1H), 6.42(dd, 1H), 7.98(d, 1H). Rf 0.12 (AcOEt:MeOH=9:1) 37-26 ν φτ XX ic 'H-NMR (400MHz, CDCI3): 1.36(s, 3H), 1.38 (s, 3H), 2.10 (s, 2H), 2.17(s, 3H), 3.27-2.96 (m, 2H), 3.71 (d, 2H), 3.96 (s, 3H), 6.33(d, 1H), 6.43(dd, 1H), 8.02(d, 1H). Rf 0.10 (AcOEt) • 37-27 ί ον0· XX Η 'H-NMR (400MHz, CDCI3): 1.16(s, 3H), 1.18 (s, 3H), 2.50(dd, 2H), 3.02-2.47 (m, 2H), 3.69 (dd, 2H), 3.96 (s, 3H), 6.31 (d, 1H), 6.43(dd, 1H), 8.00(d, 1H). Rf 0.070(AcOEt) • 37-28 V rV〆 ^-NMR (400MHz, CDCI3): 1.16(d, 3H), 2.57(dd, 1H), 3.00-2.89 (m, 4H), 3.18-3.11 (m, 1H), 3.75-3.68 (m, 2H),3.96 (s, 3H), 6.31 (d, 1H), 6.43(dd, 1H), 8.01 (d, 1H). Rf 0.070 (AcOEt) • · • - V 乂〕 Η 95245.doc • 146· 1378923 <· • -V •· 37-29 0 > °1 ^-NMR (400MHz, CDCI3): 1.18(t, 3H), 2.40(dd, 2H), 3.47-3.38(m, 4H), 3.71-3.63(m, 2H), 3.85-3.79(m, 2H), 3.96(s, 3H), 6.32(d, 1H), 6.42(dd, 1H), 8.01 (d, 1H). Rf 0.20 (AcOEt) • 37-30 %r〇- ρ 卞 Ή-NMR (400MHz, CDCI3): 1.16(s, 3H), 1.18(s, 3H), 2.82(sept, 1H), 3.50-3.37(m, 4H), 3.77-3.65(m, 2H), 3.86-3.78(m, 2H), 3.96(s, 3H), 6.33(d, 1H), 6.43(dd, 1H), 8.01 (d, 1H) . Rf 0.48 (AcOEt) « 37-31 0 ΝΗ / ^-NMR (400MHz, CDCI3): 2.86(d, 3H), 3.48-3.45(m, 4H), 3.61-3.58(m, 4H), 3.96(s, 3H), 4.48-4.37 (m, 1H), 6.29(d, 1H), 6.40(dd, 1H), 8.01 (d, 1H) · Rf 0.20 (AcOEt) 37-32 丫- ^-NMR (400MHz, CDCI3): 1.72-1,60(m, 2H), 2.06-1,97(m, 2H), 3.25-3.17 (d, 3H), 3.78-3.70(m, 2H), 3.95(s, 3H), 4.04- * φτ。 〇 3.99(m, 1H), 6.33(d, 1H), 6.43(dd, 1H), 8.00(d, 1H). Rf 0.20 (AcOEt) 〇r ΝΗ / 95245.doc -147- 1378923
95245.doc -148· 1378923
❿ 95245.doc \49- 1378923
95245.doc -150- 1378923 37-46 峰 • •· Ο ^-NMR (400MHz, CDCI3) :1.44 (t, 3H), 3.10 (t, 4H), 3.86 (t, 4H), 4.13 (q, 2H), 7.01(dd, 1H), 7.08 (dd, 1H), 7.35 (d, 1H). Rf: 0.25 (£i^:AcOEt=3:l) 37-47 1 〇ν.Ο V ^-NMR (400MHz, CDCI3) :1.26 (t, 3H), 3.32 (t, 4H), 3.85 (t, 4H), 4.15 (q, 2H), 6.34(d, 1H), 6.42 (dd, 1H), 7.98 (d, 1H). Rf: 0_45 (己烧:AcOEt=5:l) 37-48 ί〆 0 / ^-NMR (400MHz, CDCI3) :3.45 (s, 3H), 3.77 (dd, 2H), 3.81 (s, 3H), 4.06 (t, 2H), 7.08-7.08(m, 2H), 7.37 (t, 1H). ^f: 0.45 (&;^:AcOEt=3:l) 37-49 ϊ 'H-NMR (400MHz, CDCI3) :2.44 (t, 1H), 3.83 (s, 3H), 3.96 (ddd, 2H), 4.20 (t, 2H), 7.06 (d, 1H), 7.12(dd, l· & ο / 1H), 7.40 (d,1H). Rf: 0.10(己院:AcOEt=3:l) 37-50 ο、ν.ο 办。 ο / ^-NMR (400MHz, CDCI3) :1.45 (t, 3H), 3.81 (s, 3H), 4.13 (q, 2H), 7.01 (d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H). Rf: 0.20 (己烷:Ac〇Et=3:1) 37-51 V0' L ^-NMR (400MHz, CDCI3) :1.35 (s, 3H), 1.36(s, 3H), 3.81 (s, 3H), 4.52 (sept, 1H), 7.08-7.01 (m, 2H), 7.31 - 办。 0 / (d, 1H). Rf: 0.30 (己烷:AcOEt=3:l)
95245.doc -151 - 1378923 .ft 37-52 ο
Ή-NMR (400MHz, CDCI3) :1.05 (t, 3H), 1.83 (ddd, 2H), 3.81(5, 3H), 4.01 (t, 2H), 7.01 (d, 1H), 7.08 (dd, 1H), 7.36 (d, 1H). Rf: 0.35 (己烷:AcOEt=3:1) 37-53 _ 37-54 37-55 Φ 37-56 ,〇
95245.doc 'H-NMR (400MHz, CDCI3) :3.86 (s, 6H), 3.79 (s, 3H), 6.91 (dd, 1H), 7.00 (d, 1H), 7.18 (d, 1H). Rf: 0.5 (己烷:AcOEt=9:l) ^-NMR (400MHz, CDCI3) :4.04(s, 3H), 7.22 (d, 1H), 7.48(dd, 2H), 7.83 (dd, 1H), 8.16 (d, 1H), 8.69 (dd, 2H). Rf: 0.12 (己烷:AcOEt=l:1) ^-NMR (400MHz, CDCI3) :4.02 (s, 3H),7.22 (d, 1H), 7.39 (ddd, 1H), 7.77(dd, 1H), 7.85(ddd, 1H), 8.08 (d, 1H), 8.63(dd, 1H), 8.83 (d, 1H). Rf: 0.55 (己烧:AcOEt=2:1) ^-NMR (400MHz, CDCI3) :4.03 (s, 3H), 7.19 (d, 1H), 7.28-7.24 (m, 1H), 7.72(dd, 1H), 7.80-7.76(m, 1H), 8.25 (dd, 1H), 8.52 (d, 1H), 8.69 (ddd, 1H). Rf: 0.55 (己院:AcOEt=2:l) -152- 1378923 37-57 %.,。· mp 90.7 °C; Ή-NMR (400MHz, CDCI3) δ (ppm): 1.68 « 9 (m; 2H), 2.00 (m; 2H), 2.36 (s; 1H), 2.62 (bs; 4H), 2.72 (m; 2H), 3.62 (m; 2H), 3.78 (bs; 4H), 3.90 (s; 0° ——— 1 3H), 6.99 (d; 1H); 7.13 (dd; 1H), 7.26 (s; 1H); 7.40 (s; ---- 1H). 38
1-[4·(4-曱氧基_3·硝基-苯基)_六氫吡啩-1-基】-乙酮之製備 作用
將1-乙醯基六氫吡畊(400毫克,3.12毫莫耳)、碳酸铯 Π.0公克’ 3.07毫莫耳)、二醋酸鈀(29.0毫克,0.129毫莫 耳)及2_(二特丁膦基)聯苯(77毫克,0_258毫莫耳)加入在二 °惡燒中的5-溴基-1-甲氧基_2_硝基苯(300毫克,1.29毫莫 耳)之溶液中,並在l〇〇°C下攪拌8小時。在冷卻之後,將 混合物過遽’移除不溶物質。將過濾物倒入水中及以醋酸 乙醋萃取兩次。將有機層以水及接著以食鹽水清洗,經硫 酸鎂乾燥及在真空中蒸發。將殘餘物以矽膠管柱色層分離 法(正己烷:醋酸乙酯梯度)純化,供應成為黃色固體之1- [4_(4_甲氧基·3·硝基-苯基)-六氫°比畊-1-基]-乙酮(319毫 克,44%)。 95245.doc -153· 1378923 ^-NMR (400MHz, CDC13, B, ppm): 2.14 (s, 3H), 3.63 (ddd, 4H), 3.63 (t, 2H), 3.78 (t, 2H), 3.92 (s, 3H), 7.03 (d, 1H), 7.12((1,111),7.41((1,111)。1^(醋酸乙酯):0.18。 39 1-(3-甲氧基-4-硝基·苯基)-六氫吡啶-4-酮之製備作用
將‘氟基-2-曱氧基-1-硝基-苯(1〇.〇公克,0.058莫耳)及 碳酸卸(20_2公克)加入在DMF(80毫升)中的4-六氫《•比咬綱鹽 酸單水合物(1〇.〇公克,0 065莫耳)之溶液中,並將混合物 在70°C下攪拌20小時。在過濾之後,將過濾物倒入ho(約 300毫升)中,並以過濾收集所得沉澱物,接著以h2〇清洗 φ 數次,得到61%產量之標題化合物(8.98公克)。橘色固 體。咕卞1^(40〇]^2,〇)(:13,3):2.65-2.62 (411,111),3.81- 3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, d), 6.45 (1H, dd), 8.05 • (1H,d)。 . 40 l-[l-(3·甲氧基_4_确’基_笨基)_六氫^比咬4基】4甲基·六氫 .’ "比畊之製備作用 95245.doc •154- 1378923
將^甲基六氫吡畊(2.7毫升,0.024莫耳)在〇^:下加入在 二氣乙烷(50毫升)中的1·(3-甲氧基_4_硝基-苯基)·六氫〇比 • 啶酮(4.96公克,〇.020莫耳)之溶液中,並將混合物在室 溫下攪拌。在4小時之後,加入三乙醯氧基硼氫化鈉(5 〇4 公克,0.024莫耳)’並將混合物在室溫下再攪拌24小 時。在0°C下加入1當量氫氧化鈉之後,將混合物倒入水中 及以二氯甲烷萃取三次。將有機層合併及以1當量氯化氫 萃取三次。將水層以2當量氫氧化鈉鹼化及以二氣曱烷萃 取二次。將有機層以食鹽水清洗,經硫酸鈉乾燥及在真空 中蒸發’得到成為黃色固體之91 〇/〇產量之標題化合物(6.〇4 鲁 公克)。 'H-NMR (400MHz, CDC13, δ): 1.70-1.57 (2Η, m), 2.03-1.93 • (2H, m), 2.29 (3H, s), 2.55-2.38 (5H, m), 2.70-2.56 (4H, m), 2.97 (2H, ddd), 3.97-3.92 (2H, m), 3.95 (3H, s), 6.3l (1H,d),6.42 (1H,dd),8.00 (ih,d) e 41 :· 4·-甲氧基-4-甲基硝基_聯苯之製備作用 95245.doc -155- 1378923
將碳酸卸(910毫克’ 6.58毫莫耳)、肆(三苯膦)把(2 28.1 毫克,0.099毫莫耳)及4-溴基-1-甲基_2-硕基苯(711毫克, 3.29毫莫耳)加入在甲苯(5.2毫升)及乙醇(丨3毫升)中的4_甲 氧基苯基-硼酸(500毫克,3.29毫莫耳)之溶液中,並在1〇〇 °C下擾拌7小時。將混合物倒入水中及以醋酸乙酯萃取兩 次。將有機層以水及接著以食鹽水清洗,經硫酸鎂乾燥及 在真空中蒸發。將殘餘物以矽膠管柱色層分離法(正己烷: 醋酸乙酯=5:1)純化,供應成為黃色固體之4’_甲氧基_心甲 基-3-确基-聯苯(630毫克,79%)。 ^-NMR (400MHz, CDC13, δ, ppm): 2.62 (s, 3H), 3.86 (s, 3H), 7.02-6.98 (m, 2H), 7.37 (d, 1H), 7.54 (dd, 2H), 7.68 (dd,1H),8.18 (d,1H)。Rf (己院:醋酸乙酯=3: !):〇 4〇。 42 4-(2-乙氧基-乙氧基甲氧基_4_硝基-苯基卜六氫e比啶 之製備作用 將氫化鈉(1.52公克,3.8毫莫耳)加入在Ν,Ν-二甲基甲醯 胺(3,0毫升)中的丨-(3-罗氧基-4-硝基-苯基)-六氫。比啶-4-醇(300 毫克,1.2毫莫耳)之溶液中。在攪拌之後,加入2_溴乙基 95245.doc •156· 1378923 甲醚(150微升,1.6毫莫耳),並將混合物在70°C下再攪拌 1 5小時。在加入飽和水性氯化録之後,將混合物倒入水申 及以醋酸乙酯萃取兩次。將有機層以食鹽水清洗,經硫酸 鈉乾燥及在真空中蒸發。將殘餘物以矽膠管柱色層分離法 (正己烷-醋酸乙酯梯度)純化,供應成為黃色油之4-(2-甲氧基-乙氧基)-1-(3-甲氧基-4-硝基-苯基)六氫。比啶(111毫克,29%)。 1H-NMR (400MHz, CDC13, δ, ppm): 1.52 (t, 3H), 1.95-2.00 (m, 2H), 1.70-1.79 (m, 2H), 3.23 (ddd, 2H), 3.58-3.64 (m, 2H), 3.65-3.68 (m, 2H), 3.64-3.72 (m, 2H), 3.95 (s, 3H), 6.31 (d, 1H), 6.42 (dd,1H),8_00 (d,1H)。Rf 0·53 (正己烷:AcOEt=l:l)。 根據上述的步驟,使用適當的烷基齒製備以下的化合物。 實例 編號 Rx 檢定 42-1 0 ^-NMR (400MHz, CDCI3l δ, ppm): 2.04-2.21 (m, 1H), 2.63(t, 2H), 2.68(t, 2H), 3.42(t, 4H), 3.87(t, 4H), 3.96(s, 3H), 6.33(d, 1H), 6.44(dd, 1H), 8.02(d, 1H). Rf 0.09 (AcOEt). 42-2 φτ。、 Ρ 0 \ 0 / ^-NMR (400MHz, CDCI3, δ, ppm): 1.71-1.79(m, 2H), 1.95-2.02(m, 2H), 3.22(ddd, 2H), 3.40(s, 3H), 3.55-3.57(m, 2H), 3.59-3.73(m, 3H), 3.65-3.67(m, 2H), 3.95(s, 3H), 6.31 (d, 1H)( 6.42(dd, 1H), 8.00(d, 1H). Rf 0.35 (π-hexane: AcOEt=1:1) 95245.doc •157- 1378923 實例:43 2-甲氧基-4-(1-甲基-六氫咬-4-基氧基)-苯基胺心(3-甲氧 基-4-硝基-苯氧基)-1-甲基六氫咕啶
將4-羥基-1-甲基六氫吡啶(13.8公克,120毫莫耳)及四· 正丁基溴化銨(3.87公克,12毫莫耳)在室溫下加入在曱笨 (50毫升)及25%水性KOH(50毫升)中的4-氟基-2-曱氧基-1-硝基-苯(10.3公克,60毫莫耳)之溶液中。將混合物在6〇«c 下加熱1天。將反應混合物冷卻至室溫,倒入冰水令及以 醋酸乙酯萃取兩次。將有機層以稀釋的HC1及食鹽水連續 清洗’經硫酸鈉乾燥及在真空中蒸發,供應定量產量之粗 化合物(13.4公克)°
Rf=0.22 (甲醇:二氣曱烷= 1··4)。^-NMR (400MHz,CDC13, δ,ppm):l.84-1.92 (m,2H),2.0-2.1 (m,2H),2.3-2.4 (m, 2H), 2.33 (s, 3H), 2.65-2.75 (m, 2H), 3.94 (s, 3H), 4.39-4.46 (m, 1H), 6.49 (dd, 1H), 6.99 (d, 1H), 6.54 (d, 1H), 7.99 (d,1H)。 實例:44 2- 甲氧基-4-(2-嗎啉-4-基-乙氧基)_苯基胺 3- 甲氧基-4-硝基-酚 95245.doc •158· 1378923
將在甲醇_的30% KOMe(49毫升,210毫莫耳)在〇。〇下 加入在THF(3〇〇毫升)中的3_氟基_4-硝基-酚(15_7公克,1〇〇 毫莫耳)之溶液中。將混合物加熱至緩慢回流18小時。 4-[2-(3-甲氧基-4-硝基-苯氧基)·乙基】-嗎啉 ·
將4-(2-氣乙基)嗎啉鹽酸(2 〇5公克,η毫莫耳)、K2C〇3 (1.52公克’ 11毫莫耳)、KI(332毫克,2毫莫耳)在室溫下 加入在DMF(25毫升)中的3_甲氧基_4_硝基_酚(1 69公克, 10毫莫耳)之溶液中。將混合物加熱至緩慢回流4小時。將 反應混合物冷卻至室溫及以水中止。將所得混合物以醋酸 乙酯萃取兩次’並接著將有機層以水及食鹽水連續清洗, 經硫酸鈉乾燥’過濾及在真空中蒸發’供應9〇〇/。產量之粗 化合物(2.55公克)。
Rf=0.11 (只以 AcOEt)。^-NMR (400MHz, CDC13),δ (ppm):2.56-2.61 (m,4Η),2.83 (t, 將反應混合物冷卻至室溫及在〇£>c下以丨當量水性HC1緩 慢中止。將所得混合物以醋酸乙酯萃取兩次,並接著將有 95245.doc -159· 1378923 機層以食鹽水連續清洗,經硫酸鈉乾燥,過濾及在真空中 蒸發,供應94%產量之粗化合物(15.9公克)》
Rf=0.22 (甲醇:二氯曱烷=1:4)。h-NMR (400MHz,CDC13), δ (ppm): 3.95 (s, 3H), 5.49 (s, 1H), 6.44 (dd, 1H, J=8.8, 2.52Hz), 6.54 (d, 1H, J=2.52Hz), 7.96 (d, 1H, J=8.6Hz), 3.72-3.76 (m, 4H), 3.94 (s, 3H), 4.18 (t, 2H), 6.54 (dd, 1H,
J=9.08,2.52Hz), 6.56 (d, 1H,J=2.48Hz),8.00 (d, 1H, J=9.08Hz)。 實例:45 2-甲氧基-4-(2-嗎啉_4-基·乙氧基)-苯基胺 醋酸4-甲氧基-3-硝基-苯酯
將Ac2O(50毫升)在室溫下加入在AcOH(50毫升)中的4-甲 氧基酚(12.4公克,1〇〇毫莫耳)之溶液中。將混合物加熱至 缓慢回流1.5小時。將反應混合物冷卻至室溫,並在〇°c下 緩慢加入濃縮HN03(d=1.38,10毫升)。將混合物加熱至55°C 經1.5小時。將反應混合物冷卻至室溫及在〇艺下以水中 止。將所得固體在布曲納(Buchner)漏斗過濾,供應76%產 率之粗化合物(16.0公克)。
Rf=〇.59 (AcOEt:正己烷=3:7)。h-NMR (400MHz,CDC13), δ (ppm): 2.31 (s, 3H), 3.96 (s, 3H), 7.08 (d, 1H, J=9.04Hz), 7.31 (dd,1H, J=9.04, 3.04Hz),7.96 (d, 1H,J=3.04Hz)。 95245.doc •160· 1378923 4-甲氧基-3-頌基-紛
將1當量水性NaOH(5.5毫升)在〇。0下加入在EtOH(20毫 升)中的醋酸4-甲氧基-3-硝基·笨酯(丨.〇6公克,5毫莫耳)之 溶液中。將混合物在室溫下攪拌2小時。將反應混合物以 AcOH中止及以醋酸乙酯萃取兩次。將有機層以水及食鹽 水連續清洗,經硫酸鈉乾燥,過濾及在真空中蒸發,供應 定量產率之粗化合物(840毫克)。
Rf=0.59 (AcOEt:正己烷=3:7)。iH-NMR (400MHz,CDC13), δ (ppm): 3.91 (s, 3H), 6.99 (d, 1H, J=9.04Hz), 7.17 (dd, 1H, J=9.04, 3.00Hz), 7.38 (d, 1H, J=3.04Hz)。 4-[2-(4-甲氣基-3-頌基-苯氧基)-乙基]-嗎琳
將4-(2-氣乙基)嗎啉鹽酸(1.34公克,7.2毫莫耳)、 反2(303 (2.49公克,18毫莫耳)、〇(2.99公克,18毫莫耳)在 室溫下加入在DMF(15毫升)中的4-甲氧基-3-硝基-酚(1.01 公克,6毫莫耳)之溶液中。將混合物加熱至80 °C經4小 時。將反應混合物冷卻至室溫及以在水中的NH4C1飽和溶 95245.doc -161 - 1378923 液中止。將所得混合物以醋酸乙酯萃取兩次,並接著將有 機層以水及食鹽水連續清洗,經硫酸鈉乾燥,過濾及在真 空中蒸發’供應定量產量之粗化合物(17〇公克Rf=〇 14
UaAcOEthh-NMRGOOMHz’DMSOhSbpnOUe- 2-51 (m, 4H), 2.67 (t, J=5.5, 2H), 3.52-3.60 (m, 4H), 3.86 (s, 3H), 4.11 (t> j=6.〇} 2H), 7.25-7.29 (m, 2H), 7.46-7.49 (m, 1H) 〇 2-曱氧基-4-(1-甲基_六氫吡啶_心基氧基)_苯基胺之製備作 用: #
將5%鈀-木炭(3〇〇毫克)在氮氣下加入在乙醇(50毫升)中 的4 (3-曱氧基_4-石肖基-笨氧基)·ι·甲基-六氫0比咬(3 〇公 克,Π.3毫莫耳)之溶液中。反應容器配備氣球接受器,並 裝入氫及排出三次,直到反應係在氫氣下為止人允許反應 搜摔隔夜。將反應混合物經由C鹽墊過濾及以甲醇清洗。 將過據物在真空中濃縮’供應定量產率之2_曱氧基_ 曱基-六氫"比啶-4-基氧基)-苯基胺(2.7公克)。
Rf 0.41(甲醇:二氣曱烧= i:1)。1r_nmr (400MHz,CDC13), δ (PPm):1.75-1.86 (m, 2H), 1.92-2.05 (m, 2H), 2.2-2.32 (m, 2H), 2.30 (s, 3H), 3.4-3.7 (brs, 2H), 3.82 (s, 3H), 4.1-4.2 95245.doc •162- 1378923 使用適當的原料及條件重複上述的步驟’獲得以下的化 合物。
實例 編號 Rx 檢定 46-1 NH, 々。、 〇 Ή-NMR (400MHz, CDCI3, δ, ppm): 3.92(s,3H), 3.97(br,2H), 6.75(d,1H), 7.00(dd, 1H), 7.12(d, 1H), 8.06(s, 1H), 8.41(s, 1H). Rf 0.32 (AcOEt) 46-2 NH, [1-(4-胺基-3-甲氧基笨 基)°比咯烷基]乙基胺 ^-NMR (400MHz, CDCI3> δ, ppm): 1.13(t, 3H), 1.77-1.86(m, 1H), 2.19-2.27(m,1H), 2.67-2.75(m, 2H), 3.01-3.06(m, 1H), 3.20-3.26(m, 1H), 3.33-3.38(m, 1H), 3.42-3.49(m, 2H), 3.84(s, 3H), 6.04-6.07(m, 1H), 6.14-6.15(m, 1H), 6.64-6.66(m, 1H). Rf 〇·2 (只以AcOEt) 46-3 ΝΗ. 0 1 2-甲氧基-4-(4-甲基六氫. 吡啩-1-基)笨基胺 Ή-NMR (400MHz, CDCI3, δ, ppm): 2.44(s, 3H), 2.70-2.73(m, 4H), 3.13-3.17(m, 4H), 3.48(brs, 2H), 3.84(s, 3H), 6.41(dd, 1H, J=8.5, 2.52Hz). 6.51 (d, 1H, J=2.52Hz), 6.64(d, 1H, ^=8.5Hz). Rf0·2 (只以 AcOEt) 46-4 NH, 2-甲氧基-4-(1-甲基六氫 η比啶-3-基甲氧基)苯基胺 Ή-NMR (400MHz, CDCI3, δ, ppm): 1.01-1.12(m, 1H), 1.57-2.13(m, 6H), 2.26(s,3H), 2.74-2.77(m, 1H), 2.93-2.96(m, 1H), 3.47 (bs, 2H), 3.70-3.80(m, 2H), 3.82(s, 3H), 6.31-6.34(m. 1H), 6.44-6_45(m, 1H), 6.60-6.62(m, 1H). Rf 0.2 (只以 AcOEt) 95245.doc -163· 1378923 46-5 cN〕 N 1 1H-NMR (400 MHz, CDCI3) 1.80-1.67 (2H, m), 1.99-1.90 (2H, m), 2.42-2.27 (1H, m), 2.56-2.43 (4H, m), 2.68-2.58 (2H, m), 2.76-2.58 (4H, m), 3.57-3.48 (2H, m), 3.83 (3H. s), 6.41 (1H, cW), 6.52 (1H, c〇, 6.63 (1H, c〇. 己院/丙酮 1:1) 0.44. 46-6 NH, 0^〇 nh2 'H-NMR (400MHz, CDCI3, δ, ppm): 1.83-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.20-2.31 (m, 1H), 2.60-2.72 (m, 2H), 3.46-3.53 (m, 2H), 3.84 (s, 3H), 5.42-5.60 (m, 1H), 6.43 (dd, 1H), 6.53 (d, 1H), 6.64 (d, 1H). 46-7 NHa Ή-NMR (400MHz, CDCI3, δ, ppm): 2-13 (s, 3H), 3.01-3.05 (m, 4H), 3.59 (t, 2H), 3.75 (t, 2H), 3.81 (s, 3H), 6.30 (dd, 1H), 6.39 (bs, 1H), 6.71 (d, 1H). 46-8 NH, ^-NMR (400MHz, CDCI3, δ, ppm): 1.84-Ϊ.97 (m, 2H), 1.98-2.07 (m, 2H), 2.20-2.32 (m, 1H), 2.61-2.72 (m, 2H), 3.47-3.55 (m, 2H), 3.95 (s, 3H), 5.20-5.38 (m, 1H), 5.40-5.56 (m, 2H), 6.43 (d, 1H), 6.53 (bs, 1H), 6.64 (d, 1H). 46-9 NH, 0 Ή-NMR (400MHz, CDCI3i δ, ppm): 2.59-2.67 (m, 2H), 2.77-2.68 (m, 4H), 3.08-3.15 (m, 4H), 3.49-3.56 (m, 1H), 3.67-3.77 (m, 2H), 3.98 (s, 3H), 6.41-6.43 (m, 1H), 6.52 (bs, 1H), 6.65 (d, 1H). 95245.doc -164- 1378923 46-10 NH, <r、 ^-NMR (400MHz, CDCI3, δ, ppm): 1.72-1.96 (m, 2H), 1.98-2.10 (m, 2H), 2.63 (s, 3H), 2.73-2.84 (m, 2H), 3.40 (s, 3H), 3.34-3.42 (m, 2H), 3.44-3.49 (m, 1H), 3.55-3.57 (m, 2H), 3.64-3.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (bs, 1H), P 0 0 ( 6.63 (d, 1H). 46-11 NH, I ^-NMR (400MHz, CDCI3, δ, ppm): 1.22(t, 3H), 1.72-1.84 (m, σ。、 2H), 2.00-2.10 (m, 2H), 2.72-2.82 (m, 2H), 3.33-3.38 (m, 2H), 3.43-3.49 (m, 1H), 3.55 (q, 2H), 3.58-3.61 (m, 2H), 3.64-3.66 (m, 2H), 3.83 (s, 3H), 6.41-6.43 (m, 1H), 6.53 (bs, 1H), 6.63 O \ 0 / (d, 1H). 46-12 NH, ^-NMR (400MHz, CDCI3, δ, ppm): 2.20 (s, 3H), 3.84 (s, 3H), A/ 6.87 (d, 1H), 6.89 (dd, 1H), 6.95 (d, 2H), 7.09 (d, 1H), 7.48 (d, 2H).Rf (正己烷:醋酸乙酯=1:1):0.50 46-13 Ή- NMR (400MHz, CDCI3, δ, ppm): 1.49 - 1.59 (m, 3H), 1.70 -1.95 (m, 6H), 2.00 - 2.20 (m, 2H), 2.60 - 2.90 (m, 7H), 3.50 V -3.60 (m, 3H), 3.83 (s, 3H), 3.85 - 3.91 (m, 1H), 6.41 (dd, 1H, J = 8.0, 2.5 Hz ), 6.50 (d, 1H, J = 2.5 Hz ), 6.63 (d, 1H, J = 8.0 P 0 Hz) 95245.doc 165- 1378923 46-14 • Φ 户 NH, Q H 一 ^-NMR (400MHz, DMSO-d6, δ, ppm) : 1.87-1.79(m, 1H), 2.22 (ddd, 1H), 2.48 (s, 3H), 3.05 (dd, 1H), 3.28-3.21 (m, 1H), 3.40-3.32 (m, 2H), 3.45 (dd, 1H), 3.84 (s, 3H), 6.06 (dd, 1H), 6.15 (d, 1H)), 6.66 (d, 1H) 46-15 > 令。、 Ή-NMR (400MHz, CDCI3i δ, ppm): 2.35 - 2.73 (m, 4H), 2.68 -2.75 (m, 1H), 2.82-2.93 (m, 2H), 3.14-3.19 (m, 1H), 3.29-3.40 (m, 2H), 3.50 - 3.60 (bs, 2H), 3.69 - 3.78 (m, 2H), 3.84 (s, 3H), 3.85 - 3.91 (m, 1H), 6.40 (dd, 1H, J = 8.0, 2.5 Hz), 6.50 (d, 1H, J = 2.5 Hz ), 6.64 (d, 1H, J = 8.0 Hz ) 46-16 NH, Q N— / W-NMR (400MHz, DMSO-d6, δ, ppm) : 1.95-1.85(m, 1H), 2.22-2.14 (m, 1H), 2.31 (s, 3H), 2.89-2.79 (m, 1H), 3.10 (t, 1H), 3.39-3.25 (m, 3H), 3.42 (t, 1H), 3.85 (s, 3H), 6.05 (dd, 1H), 6.14 (d, 1H), 6.67 (d, 1H) 46-17 I OH ^-NMR (400MHz, CDCI3, δ, ppm) : 1.68-1.81 (m, 2H), 1.97-2.09 (m, 2H), 2.74-2.87 (m, 2H), 3.31-3.41 (m, 2H), 3.77-3.88 (m, 1H), 3.84 (s, 3H), 6.40-6.48 (m, 1H), 6.65 (bs, 1H), 6.64 (d, 1H). 46-18 nh2 0 'H-NMR (400 MHz, CDCI3), δ (ppm): 2.55-2.61 (m, 4H), 2.80(t, 2H), 3.72-3.77(m, 4H), 3.81(s, 3H), 4.05(t, 2H), 6.24 (dd, 1H, J=8.56, 2.52Hz), 6.34 (d, 1H, J=2.52Hz), 6.68 (d, 1H J=8.56Hz).Rf = 0.31 (甲醇:二氣曱烷=1:9) 95245.doc 166- 1378923 46-19 Γ 'H-NMR (400 MHz, CDCI3), δ (ppm): 2.55-2.61 (m, 4H), 2.78(t, At。、 2H), 3.72-3.77(m, 4H), 3.82(s, 3H), 4.05(t, 2H), 6.35 (dd, 1H, • ί I J=8.56, 2.52Hz), 6.47 (d, 1H, J=2.52Hz), 6.63 (d, 1H X J=8.56Hz).Rf = 0.61 (曱醇:二氯甲炫=i:4) Λ λ0 46-20 NH? ^-NMR (DMSO), δ (ppm): 3.84 (s, 3H), 6.95-7.00 (m, 1H), 力。、 7.08-7.12 (m, 2H). 46-21 'H-NMR (400MHz, CDCI3): 1.47-1.34(m, 2H), 1.75-1.63 (m, I fV0 1H), 1.86-1.79(m, 2H), 2.64-2.58 (m, 2H), 3.28(d, 2H),3.61(d, 3H),3.87(s, 3H), 3.36(s, 1H),3.49-3.45 (m, 2H), 3.84(s,3H), V Π 6.43(dd, 1H), 6.53(d, 1H) 6.64(d, 1H) 46-22 Γ2 / 'H-NMR (400MHz, CDCI3): 1.13(t, 3H),2.49(dd, 2H), 2.68-2.59 (m, 4H),3.10 (t, 4H), 3.84(s,3H), 6.43(dd, 1H), 6.53(d, 1H) 6.65(d, 1H) I V 0 Ν ; 46-23 Γ2 / Ή-NMR (400MHz, CDCI3): 1.78-1.68 (m, 2H), 1.99-1.89 (m, 2H), 2.36-2.20(m, 1H),2.67-2.50(m, 6H), 3.56-3.48(m, ||f 2H),3.79-3.69(m, 4H), 3.84(s,3H), 6.42(dd, 1H), 6.52(d, 1H) V Ρ 0 6.64(d, 1Ή) 95245.doc 167- 1378923 46-24 % η φ ΝΗ, 0 人 Ή-NMR (400MHz, CDCI3): 1.08 (s, 3H),1.10 (s, 3H), 2.69(t, 4H),2.72-2.68 (m, 1H), 3.08 (t, 4H), 3.83(s,3H), 6.42(dd, 1H), 6.53(d, 1H)6.64(d, 1H) 46-25 \ ΝΗ, 0 ^-NMR (400MHz, CDCI3): 1.96-1.84 (m, 2H), 2.07-1.99 (m, 2H), 2.32-2.28(m, 1H), 2.70-2.60(m, 2H), 3.54-3.47(m, 2H), 3.84(s, 3H), 5.35-5.24(m,1H), 5.50-5.45 (m, 1H), 6.42(dd, 1H), 6.52(d, 1H)6.64(d, 1H) X η2ν 、〇 46-26 ΝΗ, Q 0 \ Ή-NMR (400MHz, CDCI3): 2.18-2.03 (m, 2H), 3.28-3.19 (m, 2H), 3.39-3.31 (m, 1H), 3.36(s, 3H), 3.49-3.42 (m, 1H), 3.85 (s,3H), 6.07(dd, 1H), 6.16(d, 1H), 6.66(d, 1H) 46-27 ι> ΝΗ, Λ ^-NMR (400MHz, CDCI3): 1.48(s, 9H), 1.88-1.71 (m, 2H), 1.97-1.82 (m, 2H), 2.78 (s, 3H), 2.84-2.64(m, 2H)t 3.55-3.48(m, 2H), 3.95(s,3H), 3.84 (s, 3H), 6.43(d, 1H), 6.52(bs, 1H), 6.64(d, 1H) V /n、c 46-28 ΝΗ, Λ ^-NMR (400MHz, CDCI3): 3.02(s, 3H), 3.33(dd, 2H), 3.44(t, 2H), 3.74 (s, 2H), 3.83(s, 3H), 6.38(dd, 1H), 6.47(d 1H), 6.66(d, 1H) 95245.doc -168 - 1378923
46-29 nh2 P 、N ic 'H-NMR (400MHz, CDCI3): 1.78-1.38 (m, 2H), 1.96-1.89 (m, 2H), 2.30(s, 3H),2.39-2.31(m, 1H), 2.55-2.42(m, 4H),2.71-2.56(m, 6H), 3.35-3.49 (m,2H), 3.83 (s, 3H), 6.41 (dd, 1H), 6.52(d, 1H)6.63(d, 1H) 46-30 nh2 方 0 I Ή-NMR (400MHz, CDCI3): 3.80(s, 3H), 3.82(s, 3H), 3.82 (s, 3H), 6.40(s, 1H), 6.54(s, 1H) 46-31 NH: 〇> Ή-NMR (400MHz, CDCI3): 3.20(t, 2H), 4.57(t, 2H), 6.55(dd, 1H), 6.70-6.65(m, 1H), 6.68 (d, 1H). Rf 040 (AcOEt) 46-32 nh2 方 0 ^-NMR (400MHz, CDCI3): 2.98 (t, 4H), 3.62 (bs, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 3.87(t, 4H), 6.36(s, 1H), 6.53(s, 1H) 46-33 /水 0 N I ^-NMR (400MHz, CDCI3): 2.37 (s, 3H), 2.61 (t, 4H), 3.27 (t, 4H), 3.88 (s, 3H), 3.95(s, 3H), 6.48(s, 1H), 7.56(s, 1H)
95245.doc 169- 1378923 46-34 nh2 ύ Ν 1 1H-NMR (400MHz, CDCI3): 1.05(t, 3H), 1.83 (ddd, 2H), 2.35(s, 3H), 2.58(t, 4H), 3.07(t, 4H), 3.94(t, 2H), 6.41 (dd, 1H), 6.51 (d, 1H),6.65(d, 1H) 46-35 ^-NMR (400MHz, CDCI3): 1.28(s, 3H), 1.30 (s, 3H), 2.04 (s, 2H), 2.17(s, 3H), 2.84-2.72 (m, 2H), 3.20 (d, 2H), 3.86 (s, 3H), V 6.41 (d, 1H), 6.46(dd, 1H), 6.66(d, 1H), XX ίο 46-36 'H-NMR (400MHz, CDCI3): 1.18(t, 3H), 2.39(dd, 2H), 3.07- 2.98(m, 4H), 3.61 (t, 2H), 3.78(t, 2H), 3.88(s, 3H), 6.41 (dd, ΓΥ 1H), 6.51 (d, 1H), 6.65(d, 1H) V 0 °1 46-37 Γ2 / 'H-NMR (400MHz, CDCI3): 1.15(s, 3H), 1.16(s, 3H), 2.83(sept, 1H)( 3.07-2.98(m, 4H), 3.73-3.64(m, 2H), 3.83-3.76(m, 2H), (1 Υ 3.84(s, 3H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65(d, 1H) V ύ _jn 卞 95245.doc 170- 1378923 46-38 m ΝΗ, 0 0=< /ΝΗ 'H-NMR (400MHz, CDCI3): 2.84(d, 3H), 3.02(t, 4H), 3.51 (t, 4H), 3.84(s, 3H), 4.48-4.38(m, 1H), 6.41 (dd, 1H), 6.51 (d, 1H), 6.65(d, 1H) 46-39 ί νη2 〇ρ ΝΗ / W-NMR (400MHz, CDCI3): 1.99-1.81 (m, 2H), 2.23-2.12(m, 2H), 2.69-2.58(m, 2H), 2.84 (d, 3H), 3.54-3.45(m, 2H), 3.84(s, 3H), 5.55-5.45(m, 1H), 6.42(dd, 1H), 6.52(d, 1H), 6.64(d, 1H) 46-40 νη2 彳;〕 Ac M-NMR (400MHz, CDCI3): 1.53 (s, 6H), 2.11 (s, 3H), 3.05(s, 2H), 3.28(t, 2H), 3.64(t, 2H), 3.86 (s, 3H), 6.26 (dd, 1H), 6.33(d, 1H), 6.67(d, 1H) 46-41 'H-NMR (400MHz, CDCI3): 2.55-2.41 (m, 4H), 2.63 (t, 2H), I φτ。/ ΝΗ 0 3.13(t, 2H), 3.77-3.68(m, 4H), 3.83(s, 3H), 6.15(dd, 1H), 6.25 (d,1H), 6.62(d,1H)
95245.doc 171 - 1378923
95245.doc 172- 1378923 46-47 η ύ- ΝΗ, 〔λ Ή-NMR (400MHz, CDCI3): 3.35-3.28 (m, 2H), 3.53-3.46(m, 2H), , 3.76 (s, 2H), 3.84(s, 3H), 5.92-5.83 (m, 1H), 6.40(dd, 1H), 6.48(d, 1H), 6.67 (d,1H) 46-48 \ ΝΗ, 9 ΟΗ Ή-NMR (400MHz, CDCI3): 2.09-2.00 (m, 2H), 2.25-2.15 (m, 2H), 3.29-3.20 (m, 2H), 3.51-3.40(m, 4H), 3.85(s, 3H), 4.62-4.55(m, 1H), 6.08(d, 1H), 6.18(d, 1H), 6.67(d, 1H) 46-49 ΝΗ, Q ΟΗ ^-NMR (400MHz, CDCI3): 1.52-1.40 (m, 2H), 1.90-1.84 (m, 2H), 2.68-2.59 (m, 2H), 3.51*3.45(m, 2H), 3.84(s, 3H), 6.44(dd, 1H), 6.54(d, 1H), 6.64(d, 1H) 46-50 ΝΗ, Λ 0 / \ nH-NMR (400MHz, CDCI3) : 2.14 (s, 3H), 2.66 (s, 6H), 6.44 (d, 1H), 6.54 (d, 1H), 6.98 (t, 1H). 46-51 Jy 1H-NMR (400MHz, CDCI3) :2.63 (s, 3H), 7.49-7.45 (m, 1H), 7.74-7.62 (m, 2H), 7.76 (dd, 1H). 8.24(d, 1H), 8.77-8.64 (m, 2H). 46-52 ΝΗ, 0 / ^-NMR (400MHz, CDCI3) :3.84 (s, 3H), 3.88 (s, 3H), 6.78(d, 1H), 6.83 (d, 1H), 7.00-6.89 (m, 3H), 7.45 (d, 1H). 95245.doc * 173- 1378923
95245.doc • 174- 1378923 46-59 η Γ 0 / Ή-NMR (400MHz, CDCI3) :1.04 (t, 3H), 1.80 (ddd, 2H), 3.72 (s, 3H), 3.85-3.75 (m, 2H), 3.90 (t, 2H), 6.22 (dd, 1H), 6.33 (d, 1H), 6.69 (d, 1H). 46-60 'H-NMR (400MHz, CDCI3) :2.94 (s, 6H), 3.89 (s, 3H), 6.16 (dd, 1H), 6.25 (d, 1H), 6.72 (d, 1H). 46-61 ) Λ。— 'H-NMR (400MHz, CDCI3) :3.91 (s, 3H), 6.87 (d, 1H), 7.02 (dd, 1H), 7.05 (d, 1H), 7.44 (dd, 2H), 8.59 (dd, 2H). 46-62 ΝΗ. (A 〜Ν Ή-NMR (400MHz, CDCI3) :3.91 (s, 3H), 6.88 (d, 1H), 6.96-6.93(m, 1H), 7.31 (ddd, 1H), 7.83-7.80 (m, 1H), 8.51 (dd, 1H), 8.78(dd, 1H). I 46-63 ΝΗ, ☆。一 ^-NMR (400MHz, CDCI3) :3.91 (s, 3H), 6.87 (dd, 1H), 7.16(ddd, 1H), 7.34(dd, 1H), 7.43 (d, 1H), 7.72-7.64 (m, 2H), 8.63-8.61 (m, 1H). 46-64 νη2 0° mp 148.6°C; 1H-NMR (500MHz, CDCI3) δ (ppm): 1.63 (m; 2H), 1.99 (m; 2H), 2.27 (m; 1H), 2.60 (m; 6H), 3.52 (m; 2H), 3.71 (m; 4H), 3.78 (s; 3H), 6.36 (dd; 1H); 6.52 (d; 1H), 6.73 (d; 1H). 95245.doc -175- 47 471378923 4-(3-胺基-4-甲基苯醢基)-六氫0Λ唯-1-敌酸特丁輯之製備 作用
將三乙胺(300微升,3.59毫莫耳)、丁81'1;(800毫克,2.49 毫莫耳)及HOAt(270_5毫克,1.99毫莫耳)加入在dMF(3〇 毫升)中的4-曱基-3-硝基-苯曱酸(300毫克,2.76毫莫耳)及 N-丁氧基羰基六氫。比畊(340毫克,1.83毫莫耳)之溶液中, 並在室溫下攪拌2 4小時。將混合物倒入水中及以醋酸乙酉旨 萃取兩次。將有機層以水及接著以食鹽水清洗,經硫酸鎮 乾燥及在真空中蒸發。將殘餘物以矽膠管柱色層分離法 (正己烷:醋酸乙酯=5:1)純化’供應成為無色固體之4-(4-甲基-3-硝基苯酿基)-六氫α比u井-1_竣酸特丁酯。 ^-NMR (δ, ppm): 1.47 (s, 9H), 2.64 (s, 3H), 3.88-3.28 (m, 8H),7.42 (d,1H),7.56 (dd,1H), 8.03 (d, 1H)。Rf (己烷:醋 酸乙酯=10:1): 〇. 1 3。 以在甲醇溶液中的1〇〇/0鈀-木炭上的氫之還原作用獲得標 題化合物。 48 M3-胺基-4-甲基苯基)-嗎啉之製備作用 95245.doc • 176· 1378923
將二醋酸鈀(31.2毫克,0.139毫莫耳)及2_(二特丁膦基) 聯本(125宅克,0.403¾莫耳)加入在甲苯中的心演基·ι甲 基-2-硝基笨(225毫克,1.04毫莫耳)、嗎琳(125微升,i 25 毫莫耳)及碳酸鉋(474.4毫克,1.46毫莫耳)之懸浮液中,並 在100 C下攪拌5小時。在冷卻之後,將混合物過濾,移除
不溶物質。將過濾物倒入水中及以醋酸乙酯萃取兩次。將 _ 有機層以水及接著以食鹽水清洗,經硫酸鎂乾燥及在真空 中蒸發。將殘餘物以石夕膠管柱色層分離法(正己貌:醋酸乙 知-5.1)純化,供應成為黃色固體之4_(4_甲基-3_硝苯基)_ 嗎琳。 Ή- NMR (δ, ppm): 2 5〇 (Sj 3h)5 3.19-3.17 (m, 4H), 3.88-3·86 (m,4H),7*04 (dd,1H), 7.21 (d, 1H),7.47 (d,1H)。Rf (己烧:醋酸乙酯=5:丨y 〇 2〇 e
以在甲醇溶液中的丨〇%纪-木炭上的氫之還原作用獲得標 籲 題化合物。 49 2-[5-氣基-2-(2-甲氧基_4嗎啉_4基苯基胺基)嘧啶_4基 胺基]苯甲酸之製備作用 95245.doc •177· 1378923
將2-甲氧基-4-嗎啉代苯胺二鹽酸鹽(丨.9公克,6.73毫莫 耳)及6·〇毫升之1當量氣化氫乙醇系溶液(6.0毫莫耳)加入在 15毫升醋酸中的1.0公克(3.37毫莫耳)2-(2,5-二氣基-嘧啶-4-基胺基)-Ν-曱基-苯醯胺之溶液中。在將反應混合物在12〇 °C下攪拌16小時及冷卻至室溫之後,加入NaHC03水溶 液,將酸性調整至介於pH 5至pH 6之間。以過濾收集所得 沉澱物及在減壓下乾燥,得到成為象牙白固體之2-[5-氣 基-2-(2-甲氧基-4-嗎啉-4-基-苯基-胺基)-嘧啶-4-基胺基]-苯甲酸(970毫克,2.12毫莫耳,63%)。 NMR (400MHz,DMSO-d6, δ): 3.10-3.20 (m,4H),3.78 (s, 3H),3.70-3.80 (m,4H),6.52 (dd, 1H,J=8.56, 2.52Hz),6.67 (d, 1H, J=2.52Hz), 7.08 (dd, 1H, J=8.04, 8.04Hz), 7.39 (d, 1H, J=8.56Hz), 7.35-7.45 (m, 1H), 7.99 (dd, 1H, J=8.04, 1.52Hz), 8_14 (s,1H), 8.28 (s,1H), 8.70-8.80 (m,1H)。 實例50 :如以下製備磺醯胺部份: 2-胺基-4-氣基-5-甲基苯磺醢氯之製備作用 將氯化硫(4.4毫升,3.83毫莫耳)加入在二氣乙烧(1〇毫 升)中的2-胺基-5-氣基-4-甲基-苯磺酸(3·0公克,丨·35毫莫 耳)之溶液中,並在6〇t下攪拌。在1小時之後,加入亞硫 95245.doc • 178· 1378923 醯氣(1.3毫升),並將混合物在l〇(TC下再攪拌7 〇小時。將 昆合物倒入冰水中及以謎萃取三次。將有機層以水及接著 以食鹽水清洗,經硫酸鈉乾燥及在真空中蒸發。 H- NMR (5, ppm). 2.35 (s, 3H), 6.68 (s, 1H) 115 (s 1H)。 將該取代之續醯氯與適合的胺反應。在例如與甲基按反 應時,形成2-胺基-5-氣基-4,N-二甲基笨續酿胺。 實例51 2-[5-溴基氧基-4-嗎啉-4-基-笨基胺基)_嘧啶_4_基 ® 胺基】-N,N-二曱基-苯磺酿胺之製備作用
將碳酸鉀(300毫克,2.17毫莫耳)及碘基甲烷(U6微升, 1.86毫莫耳)加入在DMF(l〇毫升)中的2_[5_溴基_2-(2-曱氧 基-4-嗎啉-4-基-笨基胺基)-嘧啶_4_基胺基]_N甲基_苯磺醯 胺(貫例3-19)( 1.0公克,1.82毫莫耳)之溶液中。將所得懸 净液在50 C下攪拌1小時。將水加入反應混合物中及以醋 酸乙酯萃取二次。將有機層以水清洗,經硫酸鈉乾燥及在 真空中》辰縮》將殘餘物以氧化鋁管柱色層分離法(Ac〇Et) 純化,供應標題化合物(728毫克,71%產率)。 NMR (400MHz, CDC13, δ): 2.74 (s, 6H), 3.05-3.18 (m, 4H), 95245.doc -179- 1378923 3.84-3.93 (m, 4H), 3.88 (s, 3H), 6.43 (dd, 1H), 6.53 (d, 1H), 7.24 (m, 1H), 7.31 (s, 1H), 7.56 (m, 1H), 7.87 (dd, 1H), 8.05 (d, 1H), 8.21 (s, 1H), 8.49 (d, 1H), 8.49 (d, 1H), 9.27 (s, 1H)。Rf:0.23 (AcOEt:己烷= 1:1)。 實例52 2-[5-溴基-2-(2-甲氧基-4-嗎啉-4-基-苯基胺基)-嘧啶-4-基 胺基]-5-氟基-N-甲基-苯磺醯胺之製備作用
7-氟基-1,1-二氧基-1,4-二氫-2Η-1λ6-苯并[1,2,4】噻二畊-3-酮之製備作用 將4-氟基苯胺(1.〇公克,8.97毫莫耳)在〇。(:下逐滴加入在 硝基乙烷(10毫升)中的氣基磺醯基異氰酸酯(1.2毫升,13.5 毫莫耳)之溶液中,並將反應混合物攪拌30分鐘。將氣化 銨(1.3公克,9.87毫莫耳)在〇。(:下加入溶液中,並將混合 物在100°C下攪拌1小時。在冷卻至室溫之後,加入水及將 混合物以醋酸乙酯萃取兩次。將有機層以食鹽水清洗,經 硫酸鈉乾燥及在減壓下濃縮。以過濾收集所得固體及以醚 清洗,得到淺灰色固體(803.9毫克,41%)。 NMR (400MHz, DMSO-d6, δ): 7.22-7.28 (m, 1H), 7.45-7.57 (m, 1H),7.60 (m, 1H), 11.15-11.30 (m,1H)。Rf:0.43 95245.doc -180- 1378923 (MeOH:AcOEt =1:5)。 7-氟基-2-甲基-1,1-二氧基-1,4-二氫_2Η-1λ6-苯并【1,2,4]噻 二啩-3-酮之製備作用 將氫化鈉(1.04公克,26.0毫莫耳)及碘基甲烷(1.5毫升, 24.0毫莫耳)連續加入在DMF(50毫升)中的7-氟基-1,1-二氧 基 _1,4_ 二氫-2Η-1-λ6-苯并[1,2,4]嘆二啡-3-酮(5.19公克, 24.0毫莫耳)之溶液中,並將混合物在7〇下攪拌1小時。 在冷卻至室溫之後,將混合物倒入水中及以過濾收集沉澱 物,並以水及己烷連續清洗,得到淺灰色固體(5.38公克, 94%) ° NMR (400MHz, DMSO-d6, δ): 3.32 (s, 3H), 7.44 (dd, 1H), 7.75 (ddd, 1H),7.94 (dd, 1H) » Rf (MeOH: AcOEt=:5): 0.21。Rf.*0.39 (己烷:AcOEt=l:l)。 2-胺基-5-氟基-N-甲基-苯績酿胺之製備作用 將6.79公克7-氟基-2-甲基-ΐ,ι·二氧基-μ-二氫-2Η-1λ6-苯并[1,2,4]噻二畊-3-酮(29.5毫莫耳)溶解在20°/。水性氫氧 化鈉中,並將所得溶液在1 〇〇下攪拌13.5小時,將混合 物冷卻至室溫及倒入水中。加入78毫升之5 Μ水性HC1,並 以過濾收集沉澱物及以水清洗,供應淺紫色固體(3.96公 克,65%)。 NMR (400MHz, CDC13, δ): 2.60 (d, 3H), 4.55-4.82 (m, 3H), 6.74 (dd,1H),7.05-7.12 (m,1H), 7.45 (dd, 1H)。Rf:0.41 (己烷:AcOEt=l:l)。 2-(5-溴基-2-氣基-嘧啶-4·基胺基)·5_氟基甲基·苯磺醯胺 95245.doc -181 - 1378923 以實例B所述的相同方式進行嘧啶與2_胺基·5•氟基_N_甲 基-苯磺醯胺之反應。 NMR (400MHz, CDC13, 6):2.67 (d, 3H), 4.56 (m, 1H), 7.36- 7.45 (m, 1H), 7.68 (dd, 1H), 8.39 (s, 1H), 8.42 (dd, 1H)} 9.26 (s,1H)。Rf 0.59 (己烷:Ac〇Et=1:1)。 2-15-溴基-2-(2-甲氧基-4-嗎啉_4_基_苯基胺基)_嘧啶-4_基 胺基】-5-氟基-N-甲基-苯續酿按 根據實例A所述的方式進行經取代之苯胺的引入作用。 NMR (400MHz, CDC13, δ): 2.65 (d, 3H), 3.09-3.16 (m, 4H), 3.87 (s, 3H), 4.50 (q, 1H), 6.41 (dd, 1H), 6.52 (d, 1H), 7.25-7.33 (m, 2H), 7.69 (dd, 1H), 7.95 (d, 1H), 8.20 (s, 1H),8·37 (dd,1H),8.70 (s,1H)。Rf 0.30 (己烷:AcOEt= 1:1)。 實例53 : FAK檢定法 所有的步驟係在黑色的96井微滴平盤中進行。將以純化 之重組體六組胺酸標籤之人類FAK激酶區域以稀釋緩衝液 (在水中的 50 mM HEPES, pH 7.5、0.01%BSA、0,05〇/〇 Tween-20)稀释成94毫微克/毫升(2.5 nM)濃度。將10微升 5x激酶缓衝液(在水中的250 mM HEPES, ρΗ7·5、50 μΜ Na3V04、5 mM DTT、10 mM MgCl2、50 mM MnCl2、 0·05% BSA、0.25% Tween-20) ' 20微升水、5微升在水溶 液中的4 μΜ主物素化肽基質(Biot_Y397)、在DMSO中的5 微升試驗化合物及5微升重組體酵素溶液混合’製備反應 混合物’並在室溫下培育3〇分鐘。加入5微升在水中的5 μΜ 95245.doc -182- ATP開始酵素反應,並將混合物在37°C下培育3小時。加入 200微升偵測混合物(在稀釋缓衝液中的1 nM EU-PT66、2.5 微克/毫升之SA-(SL)APC、6.25 mM EDTA)終止反應’並 在室溫下培育30分鐘之後,以ARVOsx+L(鉑金艾莫)測量 來自銪至別藻藍素之FRET信號。使用665毫微米對61 5毫 微米之螢光強度比作為數據分析的FRET信號,以便於取 消試驗化合物的驟冷效應。將結果以酵素活性抑制百分比 表示。分別使用DMSO及0.5 M EDTA作為0%及100%抑制 作用的控制品。使用OriginPro 6.1程式(OriginLab)的非線 性曲線近似分析測定1(25〇值。 將Biot-Y397肽(生物素-SETDDYAEIID銨鹽)設計成具有 與來自人類S392至D402之區域相同的胺基酸序列(基因銀 行登錄編號(GenBank Accession Number L13616),並以標 準法製備。 由以下的方式獲得以純化之重組體六組胺酸標籤之人類 FAK基酶區域:以PCR放大作用分離具有5TCR引子 (ATGGCAGCTGCTTACCTTGAC)及 3'PCR 弓 | 子 (TCAGTGTGGTCTCGTCTGCCC)之人類胎盤素 Marathon-ReadyTM cDAN(Clontech,編號 7411-1)的人類全長 FAK cDNA,並次選殖至pGEM-T載體中(Promega,編號 A3600)。在以AccIII分解之後,將純化之DNA片段以 Klenow片段處理。將cDNA片段以BamHI分解及選殖至事 先以 BamHI和 Stu I 切割的 pFastBacHTb 質體中(Invitrogen Japan K.K·,Tokyo)。將所得質體hFAK KD(M384-G706) 95245.doc •183· 1378923 /pFastBacHTb定序,確認其結構。以所得DNA編碼364胺 基酸蛋白,其包括六組胺酸標籤、間隔區域及在N-末端之 rTEV蛋白酶裂解位置和從位置29至351之FAK的激酶區域 (Met384-Gly706)。
將供予質體使用MaxEfficacy DH10Bac大腸桿菌細胞轉 換成桿狀病秦基因組。以Bac-to-Bac®桿狀病毒表現系統 (Invitrogen)所述之簡單的驗溶胞樣本製備Bacmid DNA。 以賣方(CellFECTIN®,Invitrogen)提供的樣本為基準轉染 Sf9昆蟲細胞。以SDS-PAGE及以抗人類FAK單株抗體(來自 Transduction Laboratories 之 Clone #77)之西方轉潰法分析 在每一個溶胞液中的FAK表現。
將顯示最大表現之病毒無性繁殖系進一步以Sf9細胞的 感染作用放大。ExpressSF+®細胞(美國康州子午城 (Meriden)之Protein Sciences Corp.)的表現提供具有低降解 作用的高蛋白值。將細胞溶胞液裝載在以硫酸鎳裝填及以 50 mM HEPES pH7.5、0.5 M NaCl及 10 mM咪唑平衡之 HiTrap™ chelating Sepharose HP 管柱上(Amersham Biosciences)。將捕捉之蛋白質以在HEPES緩衝液/NaCl中 增加的咪唑量洗提,並進一步以在50 mM HEPES pH7.5、 10%甘油及1 mM DTT中的透析作用純化。 實例54:無細胞ZAP-70激酶檢定法 ZAP-70激酶檢定法係以時差式螢光共振能量轉移 (FRET)為基準。將80 nM ZAP-70在室溫下在矽化聚丙烯試 管中以80 nM Lck(淋巴T-細胞酪胺酸激酶)及在ZAP-70激酶 95245.doc •184- 1378923 緩衝液(20 mM Tris ρΗ7·5、10 μΜ Na3V04、1 mM DTT、1 mM MnCl2、0.01% BSA、0.05% Tween-20)中的 4 /zM ATP 培育1小時。接著加入選擇性Lck抑制劑PP2(1-特丁基-3-(4-氯-苯基)-1Η-吡唑并[3,4-d]嘧啶-4-基胺,Alexis Biochemicals)(最終濃度為1.2 μΜ)及再培育10备鐘。將10 微升該溶液與作為基質之10微升生物素化肽LAT-11(1 μΜ) 及20微升的一系列抑制劑稀釋液鹿合,並在室溫下培育4 小時。將激酶反應以10微升在偵測緩衝液(20 mM Tris pH 7.5、0.01% BSA、0.05%Tween-20)中的 10 mM EDTA溶液 終止。加入50微升以銪標示之抗磷酸酪胺酸抗體(Eu-PT66,最終濃度為0.125 nM)及50微升在偵測緩衝液中的 鏈酶親和素別藻藍素(SA-APC,最終濃度為40 nM)。在室 溫下培育1小時之後,在Victor2 Multilabel計數器(Wallac) 上以665毫微米測量螢光。在沒有試驗化合物及ATP的存在 下獲得背景值,並自所有的值扣除。將沒有試驗化合物存 在下所獲得的信號以100%表示(高控制品)。將在試驗化合 物存在下所獲得的抑制作用計算成高控制品之抑制百分 比。自劑量回應曲線測定得到50%抑制作用之試驗化合物 濃度(IC5〇)。在該檢定法中,本發明的試劑具有在10 nM至 2 /xM之範圍内的IC50值,以從10 nM至100 nM較佳。 如以下獲得重組體ZAP-70激酶:將來自Jurkat cDNA庫的 以核酸編碼之人類全長ZAP-70(基因銀行#L05148)以RT-PCR放大及選殖至pBluescript KS載體中(美國力σ州之 Stratagene)。以完全的序列分析評價ZAP-70 cDAN插入物 95245.doc -185 - 1378923 之真確性。接著使用該供予質體建構以另外的Ν·末端六組 胺酸標臧為特點的質體pVL 1392(美國加州之Pharmingen) 為基準之重組體桿狀病毒轉移載體。在以AcNPV病毒DNA 共轉染之後’經由血小板純化作用得到1〇個單獨的病毒分 離體’以小規模放大及接著使用市售的抗—ZAP-70抗體 (Clone 2F3.1,美國紐約州寧靜湖(Lake Placid)之 Upstate Biotechnology)的西方轉潰法分析童組體ZAP-70表現。在 將一正性重組體灰小板進一步故大時,製備及使用滴定的 病毒貯液在限定的適宜條件下感染在無血清之SF900 II培 養基中(瑞士巴塞爾(Basel)之Life Technologies)生長的Sf9 細胞》WNi-NTA管柱(瑞士巴塞爾之Qiagen)之親和性色層 分離法分離感染的Sf9細胞之溶胞液的ZAP-70蛋白質。 以重組體His-標籤之ZAP-70也取自美國威斯康辛州麥迪 遜之 PanVera LLC。 LAT-11 (T細胞激活的連接子):以類似於肽合成的已知方 法製備在ZAP-70激酶檢定法中作為基質使用的生物素化肽 LAT-ll(Biotin-EEGAPDYENLQELN)。使用在 DMF 中的 20%六氫"比咬裂解含有約0.5毫莫耳/公克之Asn的Fmoc-Asn(Trt)-氧曱基-4-苯氧基甲基-共(聚苯乙烯-1%-二乙烯 苯)之Ν-α-Fmoc基》使用在DMF中的DIPCDI及HOBt偶合4 當量在彼等的側鏈中[Asp(OtBu)、Glu(OtBu)、Asn(Trt)、 Gln(Trt)及Tyr(tBu)]受到保護的Fmoc-胺基酸的每一個胺 基。在完成肽鏈組合之後,與先前一樣,以在DMF中的六 氫吡啶移除末端Fmoc保護基。接著將L(+)-生物素基胺基 95245.doc -186- 1378923
己酸使用在DMF中的DIPCDI及HOBt及使用4當量試劑與末 端胺基在RT下經4天偶合。自樹脂載體裂解肽,並在室溫 下使用由在TFA中的5%十二烷基二甲基與5%水所組成的 試劑經2小時同時移除所有側鏈保護基。將樹脂粒子過 遽,以TFA清洗,並加入10至20體積之二乙鍵,使產物自 合併的過渡物沉澱,以醚清洗及乾燥。將產物在使用在 2%水性磷酸中乙腈梯度之C-18寬扎二氧化矽管柱上的色 層分離法純化。收集包括純化合物的餾份,經由陰離子交 換樹脂(Biorad,AG4-X4醋酸鹽形式)過濾及冷凍,得到標 題化合物。MSiBSS.iHM-H)·1。 實例55 : FAK的磷酸化值
以夹心法ELISA定量在Tyr397之FAK的磷酸化值。將鼷 鼠乳腺癌4T1細胞(lxl05)覆蓋在96井培育平盤的井中及以 或不以在包括0.5% BSA之以杜貝寇氏(Dulbecco's)改良之 依格爾氏(Eagle)培養基中的各種抑制劑濃度培育1小時。 將培養基移除及將細胞在包括1% NP-40、0.25%脫氧膽酸 納、150 mM NaCl、1 mM EDTA、1 mM PMSF、1 mM Na3V04、1 mM NaF、1微克/毫升抑肽素、1微克/毫升之亮 肽素及1微克/毫升之胃蛋白酶抑制劑的200微升之50 mM 1^5-11(:1(?117.4)中溶胞。在離心之後,將上層清液進行夾 心法ELISA,定量磷酸化FAK及總FAK。將細胞溶胞液塗 覆在平底的96井ELISA平盤上,已將該平盤在4°C下以在 包括 150 mM NaCl之 50 mM Tris-HCl(pH 9_5)中的 4微克/毫 升之 IS 鼠單株抗-FAK 抗體(clone 77,Becton Dickinson 95245.doc -187 - 1378923
Transduction Laboratories)以 100微升/井經 18小時預塗佈, 並在室溫下以H20經1:4稀釋之300微升BlockAce (Dainippon Pharmacuticals公司)經2小時封阻。在以 TBSN(包括 300 mM NaCl、0.1 %SDS 及 0.05% NP-40 之 20 mM Tris-HCl,pH8.3)清洗之後,以100微升之1微克/毫升 之抗-FAK多株體抗體(#65-6140,Upstate Biology Inc.)偵 測總FAK,並以在經H20以1:10稀釋之BlockAce中的100微 升之0.25微克/微升之抗磷酸化FAK(Y397)抗體(Affinity BioReagents,#OPA1-03071)偵測磷酸化FAK。在室溫下培 育1小時之後,將平盤以TBSN清洗,並將經H20以1:10稀 釋之BlockAce以1:2000稀釋之100微升生物素化抗兔 IgG(#65-6140,Zymed Laboratories Inc.)在室溫下培育 1小 時。在以TBSN清洗之後,以ABTS溶液基質套組(#00-2011,Zymed Laboratories Inc.)用於色彩顯像。在室溫下培 育20分鐘之後,測量在405毫微米下的吸收值《測定引起 FAK之磷酸化值減低50%之化合物濃度。 實例56 :錨定非依賴性腫瘤細胞生長檢定法 將鼷鼠乳腺癌4T1細胞(5xl03)覆蓋在包括10% FBS之100 微升以杜貝寇氏改良之依格爾氏培養基中的96井超低附著 平盤中(#3474,Corning Inc.)。將細胞培育2小時,並加入 在最終濃度為〇· 1% DMS0中的各種濃度之抑制劑。在48小 時之後,以使用水溶性四唑鑌鹽WST8之細胞計數套組· 8(Wako Pure Chemical)檢定細胞生長。將20微升試劑加入 每一個井中,並將細胞進一步培育2小時。在450毫微米下 95245.doc -188 * 測量光學密度。測定引起50%之生長抑制作用的化合物濃 度。 實例57 :在活體外的T細胞移行檢定法 由以下的活體外研究法確定FAK抑制劑對免疫細胞運動 的抑制活性。換言之,將Jurkat T細胞白血病細胞株以1 X 105個細胞放入具有8微米孔之Fluoroblok的上室中(英國 Beckton Dickinson),並在 37°C 下及在 95% 空氣-5% C02 中 栽培4小時,允許細胞株移行,其係依據牛血清白蛋白 (10% FBS)的濃度梯度而定。經由移行至以鈣黃綠素-AM(荷蘭之Molecular Probes)標記之下室中的細胞數評定 細胞運動。為了評估FAK抑制劑,故以各種FAK抑制劑濃 度(0.03-1 /xM)加入上及下室中。與以Ascent(激發:485毫微 米,放射:538毫微米)測量以媒劑處理之組群比較,以遞減 的那些螢光強度計算IC50值。 實例58 :使用細胞"捕捉ELISA”試驗測試對抗以IGF-I誘發 之IGF-IR自體磷酸化作用的活性 如以下進行檢定法: 以如加藤(Kato)等人之 J· Biol. Chem. 268,2655-61,1993 所述製備以人類IGF-IR cDNA(完整的IGF-IR cDNA:基因銀 行登錄第NM_00875號)轉染之NIH-3T3鼷鼠成纖維細胞用 於檢定法。將過度表現人類IGF-IR之細胞在包括10%胎牛 血清(FCS)之杜貝寇氏最低基本(DMEM)培養基中培育。在 第一天時,將用於檢定的5,000個細胞/井覆蓋在一般生長 培養基中的96-井平盤上(Costar #35 95)及在標準的C02細 95245.doc -189- 1378923
胞培育器中以37 °C培育2天。在第3天的細胞密度不超過 70-80%。在第3天時,將培養基棄置及將細胞在最低培養 基中(DMEM,包括0.5% FCS)培育24小時。加入式I化合物 [從10 mM二甲基亞砜(DMSO)貯存溶液],得到〇.〇1、 0.03、0.1、0.3、1、3及10 μΜ之最終濃度,以測定IC50 值。將細胞在I化合物的存在下培育90分鐘。然後將細胞 以50微升IGF-I(在井中的IGF-I最終濃度=10毫微克/毫升, IGF-I係獲自西加瑪,產品碼:I 3769)刺激及在37。(:下培 育10分鐘。將培養基棄置,並將細胞以PBS/0(=以磷酸鹽 緩衝之食鹽水,無CaCl2)清洗兩次及在冰上以50微升/井之 RIPA-緩衝液[50 mM Tris-HCl,ρΗ=7·2、120 mM Naa、1 mM EDTA、6 mM EGTA、1%NP_40、20 mM NaF、1 mM 苄脒、15 mM焦磷酸鈉、1 mM笨基曱基磺醯氯(PMSF)及 0.5 mM Na3V04]經15分鐘溶胞,並使用96井平盤搖動器榣 動10分鐘。 將黑色的Packard HTRF-96平盤在4°C下以濃度為5微克/ 毫升之50微升IGF-IR單株抗體(mAB)(Santa Cruz;目錄編 號:SC-462)經隔夜塗佈。將平盤以在以磷酸鹽緩衝之食 鹽水(PBS)中的0.05%(體積/體積)Tween-20清洗一次及以奈 米純H20清洗一次。在室溫下以在TBS-T緩衝液中(20 mM Tris-HCl,pH=7.6、137 mM NaCl、0.05%Tween-20)的 3% 牛血清白蛋白(BS A)進行2小時封阻。在封阻之後,將平盤 以奈米純H2〇清洗一次。 將細胞萃取物(40微升/井)與40微升與鹼性磷酸酶(AP)共 95245.doc -190- 1378923 軛之抗磷駿酪胺酸鼷鼠mAB ΡΥ-20(在RIPA緩衝液中以 1:1000稀釋;抗體係獲自Transduction Labs,目錄編號: ?11120)吸滴在預塗佈之Packard平盤中。 將萃取物及第二種抗體在4°C下培育2小時之後,將萃取 物棄置,將平盤以在PBS中的0.05%(體積/體積)Tween-20 清洗兩次及以奈米純水清洗一次。
接著加入90微升/井之AP基質(C£)P-Star,獲自Tropix, 目錄編號:MS100RY)及將平盤在室溫下的暗室中培育45 分鐘’接著在Packard Top Count Microplate閃爍計數器中 測量AP活性。經由使用GraphPad Instat程式(美國之 GraphPad軟體)之線性回歸分析計酸式I化合物之ic5〇值。 發現IC5〇值係在5 nM至1 μΜ之範圍内,尤其係在5 nM至 300 nM之範圍内。 實例59 :在裸鼷鼠異種移植模式中的活體内活性: 將BALB/c公或母裸鼷鼠(5-8週齡,日本橫濱之Charles River Japan Inc.)維持在自由供水及食物之無菌條件下。將 腫瘤細胞(人類上皮細胞株MIA PaCa-2 ;英國薩爾斯堡 (Salisbury)之歐洲細胞培養庫(European Collection of Cell Cultures)(ECACC),目錄編號 85062806,來自 65 歲 Caucasian白種男性的未分化之人類姨臟癌細胞株)以皮下 注射至以 Forene® 麻醉(Abbott Japan Co., Ltd. Tokyo, Japan)之鼷鼠左或右肋腹,誘發腫瘤。當平均腫瘤體積達 到約100立方毫米時,則開始以試驗化合物治療。以每週 兩次及在最後治療之後以測定兩個垂直轴長度的方式測量 95245.doc -191 - 1378923 腫瘤的生長》根據發表的方法(參考艾維斯(Evans)等人之 Bnt. J_ Cancer 45, 466-8, 1982)計算腫瘤體積。以未治療
之動物(控制品)平均增加的腫瘤體積除以治療之動物平均 增加的腫瘤體積’測定抗腫瘤藥效,並在乘以1 〇〇之後以 5T/C[%]表示。以開始治療時的平均腫瘤體積除以治療之 動物平均的腫瘤體積變化,提出腫瘤退化的報告,並在乘 以100之後以退化[%]表示。將試驗化合物每天以口服投 藥’具有或不具有藥物空窗期》 也可以相同的方式使用替換細胞株MIA PaCa-2的其它細 胞株,例如: -以BALB/c母鼷鼠的4T1乳癌細胞株(ATCC編號CRL-2539,也參考 Cancer. 88(12 Supple),2979-2988,2000)(注 射至乳腺脂肪墊)。 以這些研究為基準,根據本發明的式I化合物展示治療藥 效’尤其係對抗回應酷·胺酸激酶抑制作用的增殖性疾病。 實例60 :藥片 以慣用的方式製備含有50毫克活性成份(例如,實例1至 13 1所述的式I化合物其中之一)及具有以下組合物之藥片: 組合物: 活性成份 50毫克 小麥;殿粉 150毫克 乳糖 125毫克 膠態矽酸 12.5毫克 滑石粉 22.5毫克 95245.doc -192- 1378923 硬脂酸鎂 2.5毫克 總計: 362.5毫克 製備作用:將活性成份與部份小麥澱粉、與乳糖及膠態矽 酸混合,並迫使混合物通過網篩。將另一部份小麥澱粉在 水浴上以5倍的水量製成糊狀物,並將粉末混合物與糊狀 物捏和,直到獲得輕微的塑料體為止。 將塑料體壓過約3毫米網目尺寸的網篩及乾燥,並再迫 使所得無水顆粒通過篩網。接著將剩餘的小麥澱粉、滑石 粉與硬脂酸鎂混合,並將混合物壓縮,形成重達145毫克 及具有切痕之藥片。 實例61 :軟膠囊 以慣用的方式製備分別含有50毫克活性成份(例如,實 例1至13 1所述的式I化合物其中之一)的5000個軟明膠囊: 組合物: 250公克 2公升 活性成份 Lauroglykol 製備作用:將粉碎的活性成份懸浮在Lauroglykol®中(丙 二醇月桂酸酯,來自法國裡昂(Saint Priest)之Gattefoss《 S.A.)及在濕式粉碎機_研磨成約1至3微米之粒子尺寸。接 著將0.419公克的部份混合物使用膠囊填充機配置在軟明 膠中。 95245.doc • 193- 1378923
生物鲦果: 實例 FAK IC50 (nM) Phos IC50 _ 生長IC50 (μΜ) Τ細胞 移行IC50 _ IGF-1RIC50 (μΜ) 1.00 140 0.7 >10 2.00 13 1.2 3.01 44 0.34 >10 3.02 36 0.85 4 3.03 9.1 0.14 0.8 3.04 32 0.53 2 3.05 21 0.17 2 >10 3.06 13 0.11 2 3.07 16 0.45 2 3.08 74 0.3 6 3.09 48 0.5 0.7 3.10 52 0.95 >10 3.11 9 0.04 0.3 0.2 3.12 5.4 0.01 1 3.13 58 1.7 0.6 0.74 3.14 54 0.4 5 3.15 7 0.02 0.8 0.94 3.16 48 1.1 3 3.17 2.8 0.03 0.2 <0.08 3.18 130 1.5 9 3.19 6.8 0.35 0.8 0.1 3.20 16 0.22 0.3 3.22 120 0.9 2 3.23 38 0.39 0.5 3.24 64 3.5 5 3.25 22 0.3 0.3 0.81 3.26 50 0.79 2 3.28 43 0.71 0.7 3.29 89 0.6 >10 3.30 69 0.6 3 3.31 13 1.1 5 3.32 14 0.18 0.49 0.28 0.12 3.33 2.9 0.03 0.05 0.09 0.13 3.34 7 0.1 0.24 0.13 <0.08 3.35 13 0.02 0.17 0.8 3.55 3.36 43 1.8 2.8 3.37 39 1.1 2.6 3.38 64 1.7 3.8 3.39 2 0.02 0.03 1 0.09 3.40 9 >10 0.9 3.41 22 >10 0.43 3.42 29 0.35 0.3 3.43 5.6 0.2 0.11 0.27 3.44 11 0.05 0.09 0.09 3.45 0.9 0.02 0.02 3.46 4 0.1 0.18 0.3 3.47 1 0.1 0.06 3.48 7 0.07 0.3 0.21 3.49 39 10 0.39 95245.doc -194- 1378923
3.50 13 0.12 1 1.19 3.51 29 0.2 0.4 0.41 3.52 29 0.42 2 3.53 6 0.07 0.21 3.54 0.9 0.01 0.07 <0.08 3.55 34 >10 3 3.56 28 0.53 0.15 3.57 28 0.61 3 3.58 21 0.08 0.3 0.14 3.59 95 1.2 >10 3.60 90 0.93 2 3.61 12 10 >10 3.62 63 >10 >10 3.63 27 >10 >10 3.64 5 0.13 0.7 0.21 3.65 8 0.08 0.1 0.15 3.66 1 0.08 0.07 0.25 3.67 6 0.38 0.39 3.68 5.5 0.2 0.63 1 3.69 4 0.2 0.11 0.58 3.70 3.5 0.02 0.13 3.71 11 0.05 0.08 3.72 2.1 0.11 0.06 3.73 11 0.03 0.29 1.63 3.74 15 0.1 0.15 3.75 72 0.5 1.3 3.76 15 0.29 1.3 0.7 3.77 65 >10 3 3.78 10 >10 0.22 3.79 5 1.3 0.12 3.80 12 0.22 0.45 5 3.81 21 0.52 0.98 >10 3.82 4.8 0.2 0.07 3.83 20 0.08 0.32 0.68 3.84 10 1 0.08 6.00 110 0.35 5 7.00 5.3 0.21 0.47 0.04 0.19 7.01 4.7 0.6 0.54 0.19 7.02 7.5 0.1 0.36 0.77 7.03 2.9 0.3 0.39 0.27 7.04 5:2 1 0.29 7.05 6.2 0.3 0.2 0.25 7.06 17 0.8 1.09 0.25 7.07 4.1 0.9 0.18 7.08 8.7 0,8 1 7.09 8.2 1 0.85 7.10 6.6 1 0.98 7.11 2.5 0.6 1.2 0.77 7.12 1.9 0.9 1 0.31 0.62 7.13 5.5 0.8 1.22 7.14 7.6 0.3 0.36 0.33. 7.15 4.5 0.06 0.19 0.26 7.16 6.4 0.2 0.42 7.17 4.3 07 0.69 7.18 6.2 0.5 0.7 95245.doc -195- 1378923
7.19 13 0.33 7.20 2.5 >10 0.11 7.21 3.3 >10 0.46 7.22 25 0.48 7.23 1.4 0.25 7.24 5.1 0.09 7.25 13 0.2 0.73 7,25 2 >10 0,57 7.26 4.1 0.15 7.27 21 0.5 0.22 7.28 34 « 1 0.15 7.29 57 2 0.48 7.30 2.1 0.3 1 8.01 6.6 0.6 0.33 8.02 2.4 0.5 0.99 8.03 13 0.22 1 >10 8.04 8 >10 1.1 9.01 22 0.36 1 0.6 9.02 15 0.5 0.81 9.03 18 0.1 0.37 9.04 13 0.2 0.73 9.05 22 0.36 1.6 0.6 9.06 23 3 0.4 0.3 9.07 17 >10 0.26 10.01 39 1 0.44 10.02 26 0.9 1.06 10.03 23 0.9 2.4 11.01 9 0.7 0.85 11.02 4.1 0.8 0.69 11.03 26 0.41 0.1 11.04 4.3 >10 3.2 12.01 2.5 0.09 0.4 0.22 12.02 1.6 0.05 12.03 2.3 0.25 12.04 1.1 0.14 12.06 2.6 13.01 65 0.81 14.01 19 0.2 1.47 0.28 14.02 190 2 1.1 1 14.03 30 10 1.01 14.04 18 0.54 14.05 37 >10 1 14.06 63 10 1.11 14.07 7.5 0.2 1.4 15.01 15. 10 0.47 15.02 21 >10 0.66 15.03 44 2 1.67 16.01 44 >10 4 16.02 6 >10 0.6 16.03 21 3 >10 16.04 9.5 >10 0.92 16B 11 3 7 16.C 28 0.9 >10 18.01 19 >10 1.29 19.01 <1 0.2 0.3 0.29 1.41 95245.doc -196 - 1378923
19.02 1.6 0.13 0.38 0.91 19.03 <1 0.3 0.09 0.64 19.04 1.6 0.2 0.34 0.14 19.05 1.8 0.2 0.67 0.07 0.47 19.06 5 1 0.7 19.07 2.1 0.3 0.11 19.08 3.2 0.03 0.4 0.29 0.13 19.09 1.3 0.17 0.39 0.3 0.48 19.10 1.3 0.06 0.56 1.02 19.11 38 >10 2 19.12 9 >10 0.7 0.63 19.13 2.5 0.3 1.1 19.14 2.6 0.4 1.13 0.44 19.15 3.1 0.5 0.36 19.16 2.3 0.7 1.1 19.17 1 >10 0.17 19.18 7 0.13 0.87 19.19 5.7 0.4 19.20 1.6 0.03 0.07 0.23 19.21 84 >10 1.71 19.22 3.4 0.12 0.51 19.23 6.4 0.7 0.71 19.24 1.8 0.05 0.12 19.25 7.2 1 0.49 0.24 19.26 6.1 0.1 0.3 19.27 1.5 0.3 0.4 19.28 4.8 0.1 0.12 0.3 0.46 19.29 1.9 19.30 <1 0.06 0.1 19.31 1.8 0.4 0.38 19.32 1.4 0.2 0.31 20.01 10 0.3 0.18 0.25 0.7 20.02 9 0.12 0.17 0.75 0.52 20.03 42 0.4 2.5 2.78 20.04 23 0.58 1.9 20.05 6.8 0.87 1.46 20.06 5 0.36 0.14 49 20.07 3 0.1 0.05 0.38 20.08 6.8 0.17 0.05 0.29 20.09 2 0.3 0.01 20.10 2 0.1 0.02 20.11 26 2 0.4 20.12 9.5 20.13 6.3 0.04 20.14 33 0.32 20.15 14 0.4 0.97 0.3 20.16 7.5 0.06 20.17 2 0.14 20.18 15 0.81 20.19 28 0.21 20.20 3.12 0.1 20.21 26 3 0.68 20.22 8 >10 0.19 20.23 30 0.49 3 20.24 19 0.48 2
95245.doc •197- 1378923
20.25 6.2 0.21 0.06 20.26 5.3 0.76 0.27 20.27 12 0.85 0.05 0.29 20.28 9.2 0.17 0.08 0.42 20.29 6.1 0.2 0.05 0.31 20.30 7.6 0.3 0.08 0.67 20.31 39 0,5 20.32 13 0.11 20.33 2.5 0.38 20.34 13 1 0.12 20.35 8.7 0.09 0.09 0.15 21.01 .1 0.07 0.19 0.47 21.02 8.5 0.33 >10 21.03 1.7 0.3 0.3 21.04 1.8 0.05 0.3 22.01 43 >10 >10 22.02 26 1 3 22.03 6.6 0.09 0.15 0.26 23.01 3.4 0.6 0.2 0.63 0.53 23.02 1.5 0.2 0.4 0.8 23.03 1.7 1 1.12 0.82 23.04 1.2 0.9 1.07 0.6 23.05 1.9 >10 0.59 23.06 16 1 0.57 23.07 2.1 3 0.84 23.08 6.7 0.3 0.49 23.09 2.1 0.2 0.28 24.01 3.6 0.11 0.44 0.05 24.02 2.1 0.5 0.11 0.39 24.03 1 0.3 1.08 25.01 8.5 3 1 25.02 3 0.4 0.13 0.64 26.01 4,4 0.05 0.35 0.29 26.02 1,9 0.03 0.12 0.09 0.39 26,03 1.4 0.1 0.13 0.23 26.04 4.9 0.05 0,43 0.29 1.16 26.05 2.1 0.09 0.23 1.5 26.06 4.4 0.1 0.35 26.07 11 0.5 0.95 26.08 2.9 0.01 0.18 26.09 2.3 0.04 0.22 26.10 2 0.01 0.14 26.11 4.4 0.4 0.78 0.5 26.12 3.7 0.2 0.19 26,13 1.6 0.2 0.44 26.14 5 0.19 26.15 6.9 1.2 0.08 0.07 26.16 9 0.32 2 26.17 17 0.3 0.1 0.26 26.18 1.3 6 1.17 26.19 9.2 0.43 . 0,79 26.20 10 0.14 0.22 0.6 0.49 26.21 1.1 0.1 0.49 26.22 <1 0.1 0.28 26.23 1.4 0.3 0.09 0.3 0.18 95245.doc -198- 1378923
26.24 1 0.5 0.48 0.9 26.25 <1 0.6 0.73 0.3 26.26 1.9 0.2 0.07 0.34 26.27 4.8 0.6 1.49 26.28 2.1 0.5 1.52 26.29 <1 0.31 0.26 26.30 4.4 1 0.76 26.31 2 0.3 0.16 26.32 1.6 0.05 0.6 26.33 4 0.06 0.23 26.34 7 0.1 0.25 26.35 4.5 0.05 0.3 26.36 1.9 0.07 0.09 26.37 <1 26.38 <1 26.39 3.1 27.01 14 0.06 0.47 27.02 5.1 0.5 1.1 27.03 6.3 >10 0.56 27.04 11 0.1 0.27 27.05 8.2 0.04 0.3 27.06 1 0.08 0.31 27.07 5,5 2 0.57 27.08 9.3 0.6 0.75 27.09 4.2 0.5 0.36 28.01 12 0.3 0.46 0.3 28.02 1.9 0.08 0.44 3.71 28.03 7.4 0.07 0.29 28.04 7.5 0.3 0.3 28.05 6.7 0.1 0.12 1.39 28.06 17 0.6 0.56 28.07 47 3 >10 28.08 4.6 0.4 0.37 28.09 3,1 0.5 0.36 28.10 20 3 1.85 28.11 4.2 0.5 0.63 28.12 3.2 0.3 0.43 0.1 28.13 7.8 0.1 0.55 0.29 28.14 3 0.1 1.44 28.15 10 0.5 0.69 28.16 11 0.11 1 0.6 28.17 15 0.16 1.9 28.18 9.1 >10 2.03 28.19 3.7 0.5 0.14 28.20 4.4 2 0.4 28.21 1.3 0.1 0.23 28.22 1.3 0.1 0.3 28.23 5.9 0.5 0.28 28.24 2.9 0.2 0.09 2.57 28.25 3.9 0.04 0.13 28.26 6.6 0.2 0.57 28.27 2.4 0.3 0.42 0.5 28.28 5.2 0.4 0.52 1 28.29 11 0.4 0.36 28.30 2.3 0.9 0.11 95245.doc -199- 1378923
28.31 7.4 0.06 1.06 29.01 13 0.7 2.2 0.09 29.02 3.3 0.7 1.1 29.03 5.6 0.1 0.99 30.01 22 0.2 0.89 30.02 12 0,2 0.47 30.03 19 0.5 0.68 30.04 25 0.3 0.99 30.05 8.5 2 0.29 30.06 15 1 1.03 30.07 8.8 0.6 0.47 31.01 30 >10 1.6 31.02 31 0.28 0.29 0.42 32.01 4.1 0.1 0.29 32.02 5,9 0.05 0.37 0.12 33.01 2.5 0.08 0.25 33.02 5.2 0.06 0.25 0.1 34.01 8 0.1 0.37 0.28 34.02 11 0.08 1.17 34.03 33 0.19 2.25 34.04 13 >10 1.22 34.05 51 0.36 5.1 34.06 14 >10 3 34.07 27 >10 2.7 34.08 8.7 >10 1.9 35.01 6.8 >10 1.43 35.02 6.1 0.7 0.23 51.00 8.1 0.013 0.19 0.2 52.00 13 0.2 0.41 <0.08 •200- 95245.doc
Claims (1)
1378923 公
申請專利範圍: 1· 一種式(IK匕合物彡 〜,9r24f0號專利申請案 中f申請專利範圍替換本(101年10月) 101.
(I) 其中
每一個RG或R2係獨立為氫、Ci_C8烷基、未經取代或經取 代之含有1或2個選自N、〇及8之雜原子的5或6員雜環 基、C^-Cs烷氧基、未經取代或經取代之雜環氧基、未 經取代或經取代之雜環基Ci_Cs烷氧基、未經取代或經 取代之胺基或鹵素; ”
R丨係氫、Cl-C8烷基、齒基c丨_C8烷基、未經取代或經取 代之含有1或2個選自N、〇及8之雜原子的5或6員雜環 基、G-C8烷氧基、未經取代或經取代之雜環氧基、= 經取代或經取代之雜環基Ci_Cs烧氧基、未經取^ 取代之胺基或自素; R .CrC8烷基亞硫醯基、C|_Cs烷基磺醯基、q-Cio芳 磺醯基或未經取代或經取代之胺甲酿基; 10方基 R4係氫; R5係氣基或漠基; R6係氫; Cl-C8烷基、鹵基Ci_c 烷 每一個R7及R9係獨立為氫 95245-1011017.doc 基、未經取代或經取代之c5.c1Q芳基、未經取代或經 T代之含有1或2個選自N' 0及8之雜原子的5或6員雜 %基' C^C:8烷氧基、未經取代或經取代之雜環氧基' 未經取代或經取代之雜環基Ci_C8烷氧基、未經取代或 經取代之胺基、齒素、未經取代或經取代之胺甲醯基 或未經取代或經取代之胺磺醯基; R8係C5-C1Q芳基、未經取代或經取代之含有個選自 N、0及S之雜原子的5或6員雜環基、CyCiQ芳氧基' 未經取代或經取代之雜環氧基或未經取代或經取代之 雜環基Ci-C8院氧基;且 R10係CVC8烷基、鹵基C丨_Cs烷基、Ci_c8烷氧基、未經取 代或經取代之雜環基Cl_C8烷氧基、未經取代或經取代 之,胺基或鹵素;且 A係C ; 其中未經取代或經取代之胺甲醯基係以一或兩個選自以 下之取代基取代之胺曱醯基:氫、Cl-C8烷基、C”C8 環烧基,及其中取代基及胺甲醯基的氮原子代表進一 步包含0、1或2個選自N、0及s之雜原子的5或6員雜環 基之胺甲醯基; 未經取代或經取代之胺磺醯基係以一或兩個選自以下之 取代基取代之胺磺醯基:氫、CrCs烷基、C3-C8環烷 基、自基Ct-Cs烷基’及其中取代基及胺磺醯基的氮原 子代表進一步包含0、1或2個選自N、0及S之雜原子的 5或6員雜環基之胺磺醯基; 95245-I011017.doc -2- 未經取代或經取代之胺基係以一或兩個選自氫、 基、羥基CVC8烷基、Ci-Cs烷氧基烷基、胺基(V C:8烷基及CrC8烷羰基之取代基取代之胺基; 經取代之C6_C1Q芳基係WCi-C:8烷基及(^-〇8烷氧基取代之 芳基’取代基可在鄰位、間位或對位; 經取代之5或6員雜環基為經以下取代之雜環基:CrCs炫 基、經基CVC8烧基、C,-C8烧氧基Cl-C8烧基、〇,-0:8烷 氧基C^-C8烧氧基、經基、胺基、經取代之胺基、 统幾基、胺甲醯基、CrC8烷基胺甲醯基、氰基、氧基 或未經取代或經取代之5或6員雜環基,其中該經取代 之5或6員雜環基經c〗-C8烷基取代; 其中雜環基為包含1、2或3個選自N、〇及S之雜原子的5 或6員不飽和、部份不飽和或飽和環,其中該環可進 步濃縮成苯并基或5或6員雜環基,並可經由雜原子 或碳原子結合; 雜裒氧基及雜環匚广匚8烧氧基為5或6員環,其中雜環具有 前述定義; 或其鹽類。 2.如明求項}之化合物,其中每一個R〇、Ri或R2係氫。 3·如凊求項!之化合物,其中…係Ci_C8烷基磺醯基、 5 Cl〇芳基續醯基或未經取代或經取代之胺甲酿基。 .如咕求項1之化合物,其中R3係Cl 烷基磺醯基。 如β求項1之化合物,其中R3係C5_C1Q芳基磺酿基。 6·如凊求項丨之化合物,其中R3係未經取代或經取代之胺 95245-1011017.doc 1378923 甲醯基》 7. 如請求項i之化合物,1 八γ 你y、風吡啶基、六氫吡畊 :、N'甲基六氫吡啫基、嗎啉代、苯氧基、!·甲基·4•六 虱口比=氧基、3·嗎琳代丙氧基、2·嗎琳代乙氧基、3-(Ν-甲基六氫0比畊基)·丙氧基。 8. :請求们之化合物’其係未經取代或經取代之包 含1或2個選自N、0AS之雜原子的5或6員雜環基。 烧基續醜基;且R«係未經取代或經取代之包含_個選 自N、〇及S之雜原子的5或6員雜環基。 10. 如請求項9之化合物’其中…係六氫吡啶基、六氫吡畊 基、N-甲基六氫吡畊基或嗎啉代。 11. 如請求項1之化合物,其中該化合物係選自具下列名稱 或式之化合物群: 2-[5-氣基冬(2_甲氡基_4_嗎咐_4_基_笨基胺基卜嘴啶{義 胺基]-N-曱基-苯醯胺; 土
具下式之化合物 義之一:
,其中Rx具下表所示定 95245-10I1017.doc 1378923
化合物編號 Rx 7-1 7-2 φτ。/ Ογο νη2 7-3 (V〆 ν 0 1 7-4 6。、 X ο 7-5 95245-10110l7.doc 1378923
95245-l011017.doc 7-7 7-8 7-9 7-10 7-11
OH
1378923
7-12 7-13 7-14 7-17 7-18
ο κ-
νη2 95245-1011017.doc 1378923
具下式之化合物 義之一:
其中Rx具下表所示定 95245-1011017.doc 1378923
化合物 Rx 1 〇/ 8-2 rY V γνί
具下式之化合物 v ,其中Rx具下表所示
95245-I011017.doc 1378923
具下式之化合物 義之一:
其中Rx具下表所示定 95245-1011017.doc •10- 1378923
義之一:
其中Rx具下表所示定 95245-1011017.doc 1378923
化合物 Rx 11-1 0 11-2 P . 0 11-4 φτ、 0 〇人 具下式之化合物
其中Ry具下表所示定義之
95245-1011017.doc -12- 1378923
0 具下式之化合物 U ,其中RX具下表所示 定義之一: 化合物 Rx 15-1 φτ。、 0 1 95245-1011017.doc -13 - 1378923
具下式之化合物 定義之一:
NH Rx 其中Rx具下表所示
化合物 Rx 18-1 φτ。、 0 Ν 〇人 具下式之化合物 定義之一:
其中Rx具下表所示 95245-1011017.doc -14- 1378923 化合物 Rx 26-1
26-4
95245-1011017.doc -15- 1378923 26-6
26-9
26-10
Ο
95245-1011017.doc -16- 1378923
95245-1011017.doc -17- 1378923 26-21
26-22
Ο 26-23
26-24
ο 26-25
95245-1011017.doc -18 - 1378923
具下式之化合物 定義之一:
NH L 其中Rx具下表所示 95245-1011017.doc -19· 1378923
95245-1011017.doc 化合物 Rx 27-1 0 27-2 φτ。、 Ρ 0 27-3 φτ。、 27-4 φτ。、 0 27-5 φτ。、 0 人 -20-
1378923
具下式之化合物 義之一:
NH L 其中Rx具下表所示定
95245-1011017.doc -21 - 1378923
95245-1011017.doc
28-4 Ο
-22- 1378923
28-8 φτ" 0 28-9 28-10 28-11 0 ic 28-12 φτ, 0 ; 95245-1011017.doc -23- 1378923
28-13 φτ" 0 28-14 0 人 28-15 $ Η2Ν \〇 28-16 φτ〆 Ρ ΟΗ 28-17 φτ, 0 \ 95245-1011017.doc ·24· 1378923 28-18
28-19
28-20
28-21
28-22
95245-1011017.doc -25- 1378923
95245-J011017.doc •26- 1378923
其中Rx具下表 所示定義之
95245-101l017.doc -27 1378923 具下式之化合物 定義之一:
NH L ,其 中Rx具下表所示
化合物 Rx 31-2 φτ。、 0 CI 具下式之化合物 所示定義之一:
〇 HN
NHix ,其中Rx具下表 化合物 Rx 32-1 φτ, 0 ic 95245-1011017.doc -28- ⑧ 1,378923
化合物 Ry 34-1 ,34-3 34-4 34-6 9
95245-1011017.doc -29- 1378923
12.如請求項丨之化合物,其中該化合物為2[5氣基_2_(孓曱 氧基-4-嗎啉-4-基-苯基胺基)·嘧啶斗基胺基]_Ν_曱基笨 甲醜胺或ν2-(4-[ι,4,]聯六氫吡啶-广基曱氧基_苯1'基) 5_氯基-Ν4-[2_ (丙烷-U磺醢基)_苯基卜嘧啶_2,4•二胺,戋 其醫藥上可接受鹽類。 13. 如請求項丨之化合物,其中該未經取代或經取代之雜環氧 基為甲基-4-六氫。比咬氧基。 14. 如請求項丨之化合物,其中該未經取代或經取代之雜環基 C!-C8烷氧基為2_吡咯烷基乙氧基、2_嗎啉代乙氧基、 嗎啉代丙氧基、卜甲基·六氫吡啶_3_基甲氧基、3·⑺甲 基〃、虱°比》井基)丙氧基或2-(1_咪唾基)乙氧基。 15. —種製造如請求項!之式⑴化合物之方法,其包含將式 95245-1011017.doc L378923 (ΙΙΜ匕合物 R° 〇6
(其中 R〇、Ri、R2、r3、r4、 (II)
義,以及Y係離棄基) 與式(III)化合物 R及R6係如請求項1之定
(/、中 、 一▲、久κ ,丨'丁'別項·水項1之定義)
反應,及視需要時將其中取代基具有如請求項i定義4 思義的式(I)化合物轉化成另一個如諳书话】—¥ 月A唄i疋義之式〔 化合物; 並回收自由形式或成為鹽之所得式⑴化合物,並視 時將以自㈣式所獲得的式⑴化合物轉化成希望的睹要 或將所獲得的鹽轉化成自由形式。 ^ 16.-種醫藥組合物,其包含作為活性成份之如請求項丄之 化口物與-或多種在醫藥上可接受之稀釋劑或載體。 17· 一種組合,其包含有效治療量之如請求们之化合物及 95245-1011017.doc 31 1378923 一或多種已知的藥物,該額外藥物有用於治療腫瘤疾病 及免疫系統異常。 18. —種如請求項1之化合物或包含其之醫藥組合物之用 途,其係用以製備用於治療有需要之個體之乳房腫瘤之 藥物。 19. 如請求項18之用途,其中該化合物為2-[5-氯基-2-(2-曱 氧基-4-嗎淋-4-基-苯基-胺基)-哺咬-4-基胺基]-N -甲基-苯 甲酿胺或N2-(4-[l,4」聯六氮D比。定- I1-基-2 -曱氧基-苯基)_ 5-氯基_1^4-[2-(丙烧-1-績酿基)-苯基]-嘴咬-2,4-二胺或其 醫藥上可接受鹽類。
95245-1011017.doc -32-
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