TW202146406A - 新型吡嗪化合物 - Google Patents

新型吡嗪化合物 Download PDF

Info

Publication number
TW202146406A
TW202146406A TW110119810A TW110119810A TW202146406A TW 202146406 A TW202146406 A TW 202146406A TW 110119810 A TW110119810 A TW 110119810A TW 110119810 A TW110119810 A TW 110119810A TW 202146406 A TW202146406 A TW 202146406A
Authority
TW
Taiwan
Prior art keywords
heterocycloalkyl
compound
pharmaceutically acceptable
membered
general formula
Prior art date
Application number
TW110119810A
Other languages
English (en)
Inventor
謝雨禮
吳應鳴
樊后興
錢立暉
Original Assignee
大陸商微境生物醫藥科技(上海)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大陸商微境生物醫藥科技(上海)有限公司 filed Critical 大陸商微境生物醫藥科技(上海)有限公司
Publication of TW202146406A publication Critical patent/TW202146406A/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Liquid Crystal Substances (AREA)

Abstract

一種通式(1)所示的化合物及其製備方法，及通式(1)化合物及其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物作為EGFR抑制劑在抗腫瘤等EGFR相關疾病的藥物製備中的用途。通式(1)中各取代基的定義是如說明書及申請專利範圍所載。

Description

新型吡嗪化合物
本申請要求申請日為 2020 年 6 月 1 日的中國申請 CN202010486394.1、申請日為 2020年 9 月 10 日的中國申請 CN202010947590.4 和申請日為 2021 年 5 月 27 日的中國專利申請 CN202110587528.3 的優先權。本申請引用上述中國申請的全文。
本發明是關於藥物化學領域，特別是指一種吡嗪化合物，及其製備方法和該吡嗪化合物作為 EGFR 抑制劑在製備抗腫瘤藥物中的用途。
肺癌是常見的惡性腫瘤之一，每年全球新發肺癌病例數約在 160 萬，因肺癌導致的死亡患者每年約在 140 萬。而其中，非小細胞肺癌（non-small cell lung cancer, NSCLC）約占肺癌總數的 80%至85%左右（Nature, 2018, 553, 446–454）。
EGFR  蛋白家族是一類蛋白激酶，負責傳導促有絲分裂信號，在生長發育中發揮了重要的作用。大量的體外腫瘤細胞，動物模型以及人類腫瘤樣本的分析和研究表明 EGFR蛋白家族的突變導致人類腫瘤發展，是多種癌症發生和發展的重要誘因之一。因此靶向和抑制 EGFR 突變蛋白的活性是治療相關腫瘤的重要手段。
研究顯示 EGFR 基因突變在大約 12 %到 47%的非小細胞肺癌中能夠被發現。在非小細胞肺癌中，兩類最常見的 EGFR 基因突變為外顯子 19 缺失（Del19）和在外顯子 21 中的L858R 錯譯（L858 missense mutation）突變。這兩類突變會導致 EGFR 蛋白不依賴配體而持續啟動。雖然具有 EGFR 蛋白 Del19或 L858R 突變的 NSCLC 患者對於 EGFR 蛋白激酶抑制劑（EGFR TKI）例如 erlotinib、gefitinib、afatinib 或 osimertinib 的靶向治療更為敏感，能夠在臨床上獲得較高的（60-85%左右）的客觀緩解率（objective response rate, ORR），但是這種回應通常不會持續太久，大多數使用第一代或第二代 EGFR TKIs 的患者會在約11 個月時發生疾病進展。耐藥分析顯示在大約 50%至70%耐藥患者中，耐藥分子機制是 EGFR基因獲得第二種突變，稱為 T790M 突變（T790M+）（Cancer Discov. 2012, 2, 872-5）。這種二次突變使第一代和第二代 EGFR TKIs 對於突變腫瘤細胞失去抑制活性。
Osimertinib 作為第三代共價 EGFR TKI，被開發用來治療具有 EGFR Del19 和 L858R突變並伴隨或不伴隨 T790M 突變的腫瘤。雖然 osimertinib 針對 T790M 突變導致的耐藥具有較高的回應率，然而，大約 70%的患者最終也會發生耐藥，疾病會在大約 10 個月後再次進展（Lung Cancer. 2017, 108, 228-231）。對第三代 EGFR TKI 耐藥的分子機制研究顯示，在大約 20%至40%經歷 osimertinib 治療並復發的病人中，一個主要的耐藥機制是 EGFR基因獲得第三重突變，即 C797S 突變。而且，在經過第三代 EGFR TKI 治療後，具有 EGFR Del19/L858R/T790M/C797S 突變體的患者已不能再對第一代、第二代或第三代 EGFR TKIs回應。2015 年 Thress 等人首次報導了基於 15 例患者對於 osimertinib 的耐藥分析，發現其中約有 40%的耐藥由 C797S 突變而來（Nature Medicine, 2015, 21, 560-562）。2017 年ASCO，Piotrowska和周彩存各報導了 23 例和 99 例患者耐藥分析，兩者的分析結果都顯示大約有 22%左右的耐藥由 C797S 突變引起。所以靶向抑制 EGFR Del19/L858R/T790M/C797S 突變能夠克服 osimertinib 耐藥，但目前還未有上市的 EGFR TKI 能夠抑制 EGFR Del19/L858R/T790M/C797S 突變體，所以研究和發現第四代 EGFR TKI 來滿足這一尚未被滿足的臨床需求非常迫切。
EGFR Del19/L858R/T790M/C797S 突變體作為經第三代 EGFR TKI 治療後新浮現的EGFR 突變體，目前的研究還不是很多。目前只有少數第四代 EGFR TKI 被報導能夠抑制EGFR Del19/L858R/T790M/C797S 突變體。比如 Boehringer Ingelheim 報導了一類大環化合物 BI-4020 具有抗 EGFR Del19/L858R/T790M/C797S 突變體活性以及體內抗腫瘤活性（J Med Chem. 2019, 62, 10272-10293）。而專利 WO2019/015655 中，報導了一類芳基磷氧化合物具有抗 EGFR Del19/L858R/T790M/C797S 突變體活性以及體內抗腫瘤活性。其通式 A 及代表化合物 B(專利中實施例 41)結構如下(式中各符號的定義請參照該專利)：
Figure 02_image004
目前，研究和發現具有針對EGFR Del19/L858R/ T790M/C797S突變活性好的化合物存在迫切的需求。
本發明旨在提供一種通式(1)所示的化合物或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物：
Figure 02_image001
通式(1)中， Y為 (3-11元)雜環烷基、(C6-C14)芳基或(5-10元)雜芳基，其中所述雜環烷基、芳基和雜芳基可任選被1個或多個下列基團取代：-H、鹵素、-R4 、-OR4 、-(CH2 )n OR4 、-(CH2 )n NR4 R5 、-NR4 R5 、-CN、-C(O)NR4 R5 、-NR5 C(O)R4 、-NR5 S(O)2 R4 、-S(O)p R4 、-S(O)2 NR4 R5 和-O-CH2 -O-； L1 為-O-或-NH-； X 為(C6-C14)伸芳基或(5-11元)伸雜芳基，其中所述伸芳基和伸雜芳基可任選被1個或多個下列基團取代：-H、鹵素、(C1-C6)烷基、(C3-C6)環烷基、(C1-C6)烷氧基和(C1-C6)鹵代烷氧基； R1 為-H、鹵素、-(CH2 )n NR6 R7 、-NR6 R7 、-O(CH2 )m NR6 R7 、-N(R5 )(CH2 )m NR6 R7 、(C1-C6)烷氧基、-CH2 -(3-15元)雜環烷基或(3-15元)雜環烷基，其中所述烷氧基和雜環烷基可任選被1個或多個下列基團取代：-H、-R4 、-(CH2 )n NR6 R7 、-NR6 R7 、-O(CH2 )m NR6 R7 、-N(R5 )(CH2 )m NR6 R7 和-R3 ； L2 為-O-、-NH-或者化學鍵； R2 為(C1-C6)烷基、(C3-C14)環烷基、(C6-C14)芳基、(3-4元)雜環烷基、
Figure 02_image007
、
Figure 02_image009
、
Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
、
Figure 02_image017
、
Figure 02_image019
或(6-11元)雜環烷基；其中所述烷基、環烷基、芳基、雜環烷基、
Figure 02_image007
、
Figure 02_image009
、
Figure 02_image011
、
Figure 02_image013
、
Figure 02_image015
、
Figure 02_image017
和
Figure 02_image019
可任選被1個或多個下列基團取代：-H、鹵素、-R4 、-(CH2 )n OR4 -、-(CH2 )n NR4 R5 -、-OR4 、-NR4 R5 、-CN、-C(O)NR4 R5 、-NR5 C(O)R4 、-NR5 S(O)2 R4 、-S(O)p R4 和-S(O)2 NR4 R5 ； R3 為(3-11元)雜環烷基，其中所述雜環烷基可任選被1個或多個下列基團取代：-H、-CD3 、-R4 、-OR4 和-NR4 R5 ； R4 和R5 各自獨立地為-H、(C1-C6)烷基或(C3-C14)環烷基； R6 和R7 各自獨立地為-H、(C1-C6)烷基或(C3-C14)環烷基，或R6 和R7 與其連接的N原子能夠共同組成一個(3-11元)雜環烷基，此雜環烷基可任選被1個或多個下列基團取代：-H、-CD3 、鹵素、-R4 和-OR4 ； R0 為(C1-C6)烷基或(C3-C14)環烷基；和 p為0、1或2的整數，n為0、1、2或3的整數，m為1、2或3的整數。
在另一優選例中，其中所述通式(1)中，Y為(5-6元)雜環烷基、苯基或(5-9元)雜芳基，其中所述雜環烷基、苯基和雜芳基可任選被1個或多個下列基團取代：-H、-F、-Cl、-Br、-CN、-OH、-OCH3 、-NH2 、-N(CH3 )2 、-NHCOCH3 、-NHSO2 CH3 、-CH3 、-CONH2 、-CH2 OH和-O-CH2 -O-。
在另一優選例中，其中所述通式(1)中，Y為：
Figure 02_image023
、
Figure 02_image025
、
Figure 02_image027
、
Figure 02_image029
、
Figure 02_image031
、
Figure 02_image033
、
Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image061
、
Figure 02_image063
、
Figure 02_image065
、
Figure 02_image067
、
Figure 02_image069
、
Figure 02_image071
、
Figure 02_image073
、
Figure 02_image075
、
Figure 02_image077
、
Figure 02_image079
、
Figure 02_image081
、
Figure 02_image083
、
Figure 02_image085
、
Figure 02_image087
、
Figure 02_image089
、
Figure 02_image091
、
Figure 02_image093
、
Figure 02_image095
、
Figure 02_image097
、
Figure 02_image099
、
Figure 02_image101
、
Figure 02_image103
、
Figure 02_image105
、
Figure 02_image107
、
Figure 02_image109
、
Figure 02_image111
、
Figure 02_image113
、
Figure 02_image115
、
Figure 02_image117
、
Figure 02_image119
、
Figure 02_image121
、
Figure 02_image123
、
Figure 02_image125
、
Figure 02_image127
、
Figure 02_image129
、
Figure 02_image131
、
Figure 02_image133
、
Figure 02_image135
、
Figure 02_image137
、
Figure 02_image139
、
Figure 02_image141
、
Figure 02_image143
、
Figure 02_image145
、
Figure 02_image147
、
Figure 02_image149
、
Figure 02_image151
、
Figure 02_image153
、
Figure 02_image155
、
Figure 02_image157
、
Figure 02_image159
、
Figure 02_image161
、
Figure 02_image163
、
Figure 02_image165
、
Figure 02_image167
、
Figure 02_image169
、
Figure 02_image171
、
Figure 02_image173
、
Figure 02_image175
、
Figure 02_image177
、
Figure 02_image179
、
Figure 02_image181
、
Figure 02_image183
、
Figure 02_image185
、
Figure 02_image187
、
Figure 02_image189
、
Figure 02_image191
、
Figure 02_image193
、
Figure 02_image195
、
Figure 02_image197
、
Figure 02_image199
、
Figure 02_image201
、
Figure 02_image203
、
Figure 02_image205
、
Figure 02_image207
、
Figure 02_image209
、
Figure 02_image211
、
Figure 02_image213
、
Figure 02_image215
、
Figure 02_image217
、
Figure 02_image219
、
Figure 02_image221
、
Figure 02_image223
、
Figure 02_image225
、
Figure 02_image227
、
Figure 02_image229
、
Figure 02_image231
、
Figure 02_image233
、
Figure 02_image235
、
Figure 02_image237
、
Figure 02_image239
、
Figure 02_image241
、
Figure 02_image243
、
Figure 02_image245
、
Figure 02_image247
、
Figure 02_image249
、
Figure 02_image251
、
Figure 02_image253
、
Figure 02_image255
、
Figure 02_image257
、
Figure 02_image259
、
Figure 02_image261
、
Figure 02_image263
或
Figure 02_image265
。
在另一優選例中，其中所述通式(1)中，X 為伸苯基或6元伸雜芳基，其中所述伸苯基和伸雜芳基可任選被1個或多個下列基團取代：-H、-F、-CH3 、-CH2 CH3 、-CH(CH3 )2 、
Figure 02_image267
、-OCH3 、-OCF2 H和-OCF3 。
在另一優選例中，其中所述通式(1)中，X為：
Figure 02_image269
、
Figure 02_image271
、
Figure 02_image273
、
Figure 02_image275
、
Figure 02_image277
、
Figure 02_image279
、
Figure 02_image281
、
Figure 02_image283
、
Figure 02_image285
、
Figure 02_image287
、
Figure 02_image289
、
Figure 02_image291
、
Figure 02_image293
、
Figure 02_image295
、
Figure 02_image297
、
Figure 02_image299
、
Figure 02_image301
、
Figure 02_image303
或
Figure 02_image305
。
在另一優選例中，其中所述通式(1)中，R1 為：-H、-N(CH3 )2 、-CH2 -(6-11元)雜環烷基或(6-11元)雜環烷基，其中所述雜環烷基為：
Figure 02_image307
、
Figure 02_image309
、
Figure 02_image311
、
Figure 02_image313
、
Figure 02_image315
、
Figure 02_image317
、
Figure 02_image319
、
Figure 02_image321
、
Figure 02_image323
、
Figure 02_image325
、
Figure 02_image327
、
Figure 02_image329
、
Figure 02_image331
；所述雜環烷基可任選被1個或多個下列基團取代：-H、-CH3 、
Figure 02_image267
、-N(CH3 )2 、
Figure 02_image313
、
Figure 02_image333
、
Figure 02_image335
、
Figure 02_image337
、
Figure 02_image339
、
Figure 02_image341
、
Figure 02_image323
、
Figure 02_image325
、
Figure 02_image343
和-CD3 。
在另一優選例中，其中所述通式(1)中，R1 為：-H、-N(CH3 )2 、
Figure 02_image345
、
Figure 02_image347
、
Figure 02_image349
、
Figure 02_image351
、
Figure 02_image353
、
Figure 02_image355
、
Figure 02_image357
、
Figure 02_image359
、
Figure 02_image361
、
Figure 02_image363
、
Figure 02_image365
、
Figure 02_image367
或
Figure 02_image369
。
在另一優選例中，其中所述通式(1)中，當L2 為-NH-時，R2 為：
Figure 02_image371
、
Figure 02_image373
、
Figure 02_image375
、
Figure 02_image377
、
Figure 02_image379
、
Figure 02_image381
、
Figure 02_image383
、
Figure 02_image385
、
Figure 02_image387
、
Figure 02_image389
、
Figure 02_image391
、
Figure 02_image393
、
Figure 02_image395
、
Figure 02_image397
、
Figure 02_image399
、
Figure 02_image401
、
Figure 02_image403
、
Figure 02_image405
、
Figure 02_image407
、
Figure 02_image409
、
Figure 02_image411
、
Figure 02_image413
、
Figure 02_image415
、
Figure 02_image417
、
Figure 02_image419
、
Figure 02_image421
、
Figure 02_image423
、
Figure 02_image425
、
Figure 02_image427
、
Figure 02_image429
、
Figure 02_image431
、
Figure 02_image433
、
Figure 02_image435
、
Figure 02_image437
、
Figure 02_image439
、
Figure 02_image441
、
Figure 02_image443
、
Figure 02_image445
、
Figure 02_image447
、
Figure 02_image449
、
Figure 02_image451
、
Figure 02_image453
、
Figure 02_image455
、
Figure 02_image457
、
Figure 02_image459
、
Figure 02_image461
、
Figure 02_image463
、
Figure 02_image465
、
Figure 02_image467
、
Figure 02_image469
、
Figure 02_image471
或
Figure 02_image473
。
在另一優選例中，其中所述通式(1)中，當L2 為-O-時，R2 為：
Figure 02_image475
、
Figure 02_image477
、
Figure 02_image479
、
Figure 02_image481
、
Figure 02_image483
、
Figure 02_image485
、
Figure 02_image487
、
Figure 02_image489
、
Figure 02_image491
、
Figure 02_image493
或
Figure 02_image495
。
在另一優選例中，其中所述通式(1)中，當L2 為化學鍵時，R2 為：
Figure 02_image497
、
Figure 02_image499
、
Figure 02_image467
、
Figure 02_image469
、
Figure 02_image503
、
Figure 02_image505
或
Figure 02_image507
。
在各種不同實施方式中，本發明代表性化合物具有以下結構之一：
Figure 02_image509
Figure 02_image511
Figure 02_image513
Figure 02_image515
Figure 02_image517
Figure 02_image519
Figure 02_image521
Figure 02_image523
Figure 02_image525
Figure 02_image527
Figure 02_image529
Figure 02_image531
Figure 02_image533
Figure 02_image535
Figure 02_image537
Figure 02_image539
Figure 02_image541
Figure 02_image543
。
本發明的另一個目的是提供了一種藥物組合物，其含有藥學上可接受的賦形劑或載體，以及本發明通式(1)化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物作為活性成分。
本發明的再一個目的提供了本發明的上述化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物或上述藥物組合物用於製備治療EGFR突變相關疾病藥物中的應用。
本發明的再一個目的還提供治療、調節和/或預防與EGFR突變蛋白相關疾病的方法，包括對受試者給與治療有效量上述化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物或上述藥物組合物。通過合成和仔細研究了多類涉及具有EGFR抑制作用的新化合物，發明人發現在通式(1)化合物中，當 Y為雜環烷基、芳香雜環、芳基時，化合物意外地具有很強的EGFRDel19/T790M/C797S 和EGFRL858R/T790M/C797S 抑制活性，並且對於野生型EGFR WT有較高的選擇性。
應理解，本發明的前述一般性描述和以下詳細描述都是示例性和說明性的，旨在提供對所要求保護的本發明的進一步說明。
化 合物的合成
下面具體地描述本發明通式(1)化合物的製備方法，但這些具體方法不對本發明構成任何限制。
以上說明的通式(1)化合物可使用標準的合成技術或公知的技術與文中結合的方法來合成。此外，在此提到的溶劑，溫度和其他反應條件可以改變。用於化合物的合成的起始物料可以由合成或從商業來源上獲得。本文所述的化合物和其他具有不同取代基的有關化合物可使用公知的技術和原料來合成，包括發現於March，Advanced Organic Chemistry 4th Ed.，(Wiley 1992)； Carey和Sundberg，Advanced Organic Chemistry 4th Ed.，Vols. A和B (Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed.，(Wiley 1999)中的方法。化合物製備的一般方法可通過使用適當的試劑和在此提供的分子式中引入不同基團的條件來改變。
一方面，本文所述的化合物根據工藝中公知的方法。然而方法的條件，例如反應物、溶劑、鹼、所用化合物的量、反應溫度、反應所需時間等不限於下面的解釋。本發明化合物還可以任選將在本說明書中描述的或本領域已知的各種合成方法組合起來而方便的製得，這樣的組合可由本發明所屬領域的技術人員容易的進行。一方面，本發明還提供了一種所述的通式(1)所示化合物的製備方法，其採用下列一般反應流程1或一般反應流程2製備：
一般反應流程 1
Figure 02_image545
通式(1)化合物的實施方式可根據一般反應流程1製備，其中R1 、R2 、X、Y、L1 和L2 如上文中所定義，H表示氫，B表示硼酸、硼酸酯或三氟硼酸鹽。如一般反應流程1所示，化合物1-1和甲醯胺反應生成化合物1-2，化合物1-2和R1 -X-L1 -H在鹼性條件下反應生成化合物1-3，化合物1-3和Y-B進行偶聯反應生成化合物1-4，化合物1-4和R2 - L2 -H在鹼性條件下反應生成目標化合物1-5。
一般反應流程 2
Figure 02_image547
通式(1)化合物的實施方式可根據一般反應流程2製備，其中R1 、R2 、X、Y、L1 和L2 如上文中所定義，H表示氫。如一般反應流程2所示, 化合物2-1和甲醯胺反應生成化合物2-2，化合物2-2和R1 -X-L1 -H在鹼性條件下反應生成化合物2-3，化合物2-3和R2 - L2 -H在鹼性條件下反應生成2-4，化合物2-4和Y-H在鹼性條件下反應生成化合物目標化合物2-5。
化合物的進一步形式
“藥學上可接受”這裡指一種物質，如載體或稀釋液，不會使化合物的生物活性或性質消失，且相對無毒，如，給予個體某物質，不會引起不想要的生物影響或以有害的方式與任何其含有的組分相互作用。
術語“藥學上可接受的鹽”指一種化合物的存在形式，該形式不會引起對給藥有機體的重要的刺激，且不會使化合物的生物活性和性質消失。在某些具體方面，藥學上可接受的鹽是通過式(1)化合物與酸反應獲得，如鹽酸、氫溴酸、氫氟酸、硫酸、磷酸、硝酸、磷酸等無機酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、苦味酸、甲磺酸、苯磺酸、對甲苯磺酸等有機酸以及天冬氨酸、谷氨酸等酸性氨基酸。
應理解藥學上可接受的鹽的參考包括溶劑添加形式或結晶形式，尤其是溶劑化物或多晶型。溶劑化物含有化學計量或非化學計量的溶劑，且是在與藥學上可接受溶劑如水，乙醇等，結晶化過程中選擇性形成的。當溶劑是水時形成水合物，或當溶劑是乙醇時形成醇化物。通式(1)化合物的溶劑化物按照本文所述的方法，很方便的製得或形成。舉例說明，通式(1)化合物的水合物從水/有機溶劑的混合溶劑中重結晶而方便的製得，使用的有機溶劑包括但不限於，四氫呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能夠以非溶劑化和溶劑化形式存在。總之，對於在此提供的化合物和方法為目的，溶劑化形式被認為相當於非溶劑化形式。
在其他具體實施例中，通式(1)化合物被製備成不同的形式，包括但不限於，無定形，粉碎形和毫微-細微性形式。此外，通式(1)化合物包括結晶型，也可以作為多晶型。多晶型包括化合物的相同元素組成的不同晶格排列。多晶型通常有不同的X-射線衍射圖、紅外光譜、熔點、密度、硬度、晶型、光和電的性質、穩定性和溶解性。不同的因素如重結晶溶劑，結晶速率和貯存溫度可能引起單一晶型為主導。
在另一個方面，通式(1)化合物可能存在手性中心和/或軸手性，並因此以消旋體、外消旋混合物、單一對映體、非對映異構體化合物和單一非對映體的形式、和順反異構體的形式出現。每個手性中心或軸手性將獨立地產生兩個旋光異構體，並且所有可能的旋光異構體和非對映體混合物以及純或部分純的化合物包括在本發明的範圍之內。本發明意味著包括這些化合物的所有這種異構形式。
本發明的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素標記化合物，比如氚(3 H) 、碘-125(125 I)和C-14(14 C)。又例如，可用重氫取代氫原子形成氘代化合物，氘與碳構成的鍵比普通氫和碳構成的鍵更堅固，相比於未氘代藥物，通常氘代藥物具有降低毒副作用、增加藥物穩定性、增強療效、延長藥物體內半衰期等優勢。本發明的化合物的所有同位素組成的變換，無論放射性與否，都包含在本發明的範圍之內。
術語
如果無另外說明，用於本發明申請，包括說明書和申請專利範圍中的術語，定義如下。必須注意，在說明書和所附的申請專利範圍中，如果文中無另外清楚指示，單數形式“一個”包括複數意義。如果無另外說明，使用質譜、核磁共振、HPLC、蛋白化學、生物化學、重組DNA技術和藥理的常規方法。在本申請中，如果無另外說明，使用“或”或“和”指“和/或”。
除非另有規定，“烷基”指飽和的脂肪烴基團，包括1至14個碳原子的直鏈和支鏈基團。優選含有1至4個碳原子的低級烷基，例如甲基、乙基、丙基、2-丙基、正丁基、異丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一個或多個鹵素所取代的烷基。優選的烷基選自CH3 、CH3 CH2 、CF3 、CHF2 、CF3 CH2 、CF3 (CH3 )CH、i Pr、n Pr、i Bu、n Bu或t Bu。
除非另有規定，“烯基”指含有碳-碳雙鍵的不飽和脂肪烴基團，包括1至14個碳原子的直鏈或支鏈基團。優選含有1至4個碳原子的低級烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。
除非另有規定，“炔基”指含有碳-碳三鍵的不飽和脂肪烴基團，包括1至14個碳原子的直鏈和支鏈基團。優選含有1至4個碳原子的低級烯基，例如乙炔基、1-丙炔基或1-丁炔基。
除非另有規定，“環烷基”指3至14元全碳單環脂肪烴基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。例如，環丙基、環丁基、環戊基、環己烷、環己二烯等。
除非另有規定，“烷氧基”指通過醚氧原子鍵合到分子其餘部分的烷基。代表性的烷氧基為具有1-6個碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一個或多個鹵素所取代的烷氧基。優選的烷氧基選自OCH3 、OCF3 、CHF2 O、CF3 CH2 O、i- PrO、n- PrO、i- BuO、n- BuO或t- BuO。
除非另有規定，“芳基”指碳氫芳香基團，芳基是單環或多環的，例如單環芳基環與一個或多個碳環芳香基團稠和。芳基的例子包括但不限於，苯基、萘基和菲基。
除非另有規定，“伸芳基”指二價的如上所定義的芳基。伸芳基的例子包括但不限於，伸苯基、伸萘基和伸菲基。
除非另有規定，“雜芳基”指含有一個或多個雜原子(O、S或N)的芳香基團，雜芳基是單環或多環的，例如單環雜芳基環與一個或多個碳環芳香基團或其它單環雜環基基團稠和。雜芳基的例子包括但不限於，吡啶基、噠嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、異喹啉基、呋喃基、噻吩基、異噁唑基、噻唑基、噁唑基、異噻唑基、吡咯基、吲哚基、苯並咪唑基、苯並呋喃基、苯並噻唑基、苯並噻吩基、苯並噁唑基、苯並吡啶基和吡咯並嘧啶基。
除非另有規定，“伸雜芳基”指二價的如上所定義的雜芳基。
除非另有規定，“雜環烷基”指含有一個或多個雜原子(O、S或N)的飽和或部分不飽和環體系基團，其中氮和硫原子任選地被氧化，氮原子任選地被季銨化，作為環原子。除非另有說明，“雜環烷基”的環體系可以是單環、雙環、螺環或多環的環體系。“雜環烷基”可以通過一個以上環碳或雜原子連接於分子的其餘部分。“雜環烷基”的例子包括但不限於吡咯烷、呱啶、N-甲基呱啶、四氫咪唑、吡唑烷、丁內醯胺、戊內醯胺、咪唑啉酮、乙內醯脲、二氧戊環、鄰苯二甲醯伸胺、呱啶、嘧啶-2,4(1H ,3H )-二酮、1,4-二氧六環、嗎啉、硫代嗎啉、硫代嗎啉-S-氧化物、硫代嗎啉-S,S-氧化物、呱嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氫呋喃、四氫噻吩、奎寧環、2-氮雜螺[3.3]庚烷等。
除非另有規定，“鹵素”(或鹵代基)是指氟、氯、溴或碘。在基團名前面出現的術語“鹵代”(或“鹵素取代”)表示該基團是部分或全部鹵代，也就是說，以任意組合的方式被F、Cl、Br或I取代，優選被F或Cl取代。
“任選”或“任選地”指的是隨後描述的事件或狀況可能但不是必需出現，並且該描述包括其中所述事件或狀況發生的情況以及所述事件或狀況不發生的情況。
取代基“-O-CH2 -O-”指該取代基中二個氧原子和雜環烷基、芳基或雜芳基二個相鄰的碳原子連接，比如：
Figure 02_image549
。
當一個連接基團的數量為0時，比如-(CH2 )0 -，表示該連接基團為單鍵。
當其中一個變數選自化學鍵時，表示其連接的兩個基團直接相連，比如X-L-Y中L代表化學鍵時表示該結構實際上是X-Y。
特定藥學及醫學術語
術語“可接受的”，如本文所用，指一個處方組分或活性成分對一般治療目標的健康沒有過分的有害影響。
術語“治療”、“治療過程”或“療法”如本文所用，包括緩和、抑制或改善疾病的症狀或狀況；抑制併發症的產生；改善或預防潛在代謝綜合症；抑制疾病或症狀的產生，如控制疾病或情況的發展；減輕疾病或症狀；使疾病或症狀減退；減輕由疾病或症狀引起的併發症，或預防或治療由疾病或症狀引起的徵兆。如本文所用，某一化合物或藥物組合物，給藥後，可以使某一疾病、症狀或情況得到改善，尤指其嚴重度得到改善，延遲發病，減緩病情進展，或減少病情持續時間。無論固定給藥或臨時給藥、持續給藥或間歇給藥，可以歸因於或與給藥有關的情況。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的藥學上可接受的無機或有機鹽。本發明的化合物可以含有一個或多個不對稱中心(手性中心或軸手性)，並因此以消旋體、外消旋混合物、單一對映體、非對映異構體化合物和單一非對映體的形式出現。可以存在的不對稱中心，取決於分子上各種取代基的性質。每個這種不對稱中心將獨立地產生兩個旋光異構體，並且所有可能的旋光異構體和非對映體混合物以及純或部分純的化合物包括在本發明的範圍之內。本發明意味著包括這些化合物的所有這種異構形式。
“化合物(compound)”、“組合物(composition)”、“藥劑(agent)”或“醫藥品(medicine or medicament)”等詞在此可交替使用，且都是指當施用於個體(人類或動物)時，能夠透過局部和/或全身性作用而誘發所亟求的藥學和/或生理反應的一種化合物或組合物。
“施用(administered、administering或、administration)”一詞在此是指直接施用所述的化合物或組合物，或施用活性化合物的前驅藥(prodrug)、衍生物(derivative)、或類似物(analog)等。
雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值，此處已盡可能精確地呈現具體實施例中的相關數值。然而，任何數值本質上不可避免地含有因個別測試方法所致的標準差。在此處，“約”通常是指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是，“約”一詞代表實際數值落在平均值的可接受標準誤差之內，視本發明所屬技術領域中具有通常知識者的考慮而定。除了實驗例之外，或除非另有明確的說明，當可理解此處所用的所有範圍、數量、數值與百分比（例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其它相似者）均經過“約”的修飾。因此，除非另有相反的說明，本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值，且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與採用一般進位法所得到的數值。
除非本說明書另有定義，此處所用的科學與技術詞彙的含義與本發明所屬技術領域中具有通常知識者所理解的慣用的意義相同。此外，在不和上下文衝突的情形下，本說明書所用的單數名詞涵蓋該名詞的複數型；而所用的複數名詞時亦涵蓋該名詞的單數型。
治療用途
本發明提供了使用本發明化合物或藥物組合物治療疾病的方法，包括但不限於涉及EGFR突變的病況(例如癌症)。
在一些實施方案中，提供了用於癌症治療的方法，該方法包括給予有需要的個體有效量的任何前述的保護結構式(1)化合物的藥物組合物。在一些實施方案中，癌症由EGFR突變介導。在其它實施方案中，該癌症是肺癌、胰腺癌、結腸癌、膀胱癌、腦癌、乳腺癌、尿路上皮癌、前列腺癌、卵巢癌、頭頸癌、胃癌、間皮瘤或所有癌症轉移。
給藥途徑
本發明的化合物及其藥學上可接受的鹽可製成各種製劑，其中包含安全、有效量範圍內的本發明化合物或其藥學上可接受的鹽及藥理上可以接受的賦形劑或載體。其中“安全、有效量”指的是：化合物的量足以明顯改善病情，而不至於產生嚴重的副作用。化合物的安全、有效量根據治療物件的年齡、病情、療程等具體情況來確定。
“藥學上可以接受的賦形劑或載體”指的是：一種或多種相容性固體或液體填料或凝膠物質，它們適合於人使用，而且必須有足夠的純度和足夠低的毒性。“相容性”在此指的是組合物中各組份能與本發明的化合物以及它們之間相互摻和，而不明顯降低化合物的藥效。藥理上可以接受的賦形劑或載體部分例子有纖維素及其衍生物(如羧甲基纖維素鈉、乙基纖維素鈉、纖維素乙酸酯等)、明膠、滑石、固體潤滑劑(如硬脂酸、硬脂酸鎂)、硫酸鈣、植物油(如豆油、芝麻油、花生油、橄欖油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化劑(如吐溫®)、潤濕劑(如十二烷基硫酸鈉)、著色劑、調味劑、穩定劑、抗氧化劑、防腐劑、無熱原水等。
施用本發明化合物時，可以口服、直腸、腸胃外(靜脈內、肌肉內或皮下)、局部給藥。
用於口服給藥的固體劑型包括膠囊劑、片劑、丸劑、散劑和顆粒劑。在這些固體劑型中，活性化合物與至少一種常規惰性賦形劑(或載體)混合，如檸檬酸鈉或磷酸二鈣，或與下述成分混合：(a)填料或增容劑，例如，澱粉、乳糖、蔗糖、葡萄糖、甘露醇和矽酸；(b)黏合劑，例如，羥甲基纖維素、藻酸鹽、明膠、聚乙烯基吡咯烷酮、蔗糖和阿拉伯膠；(c)保濕劑，例如，甘油；(d)崩解劑，例如，瓊脂、碳酸鈣、馬鈴薯澱粉或木薯澱粉、藻酸、某些複合矽酸鹽、和碳酸鈉；(e)緩溶劑，例如石蠟；(f)吸收加速劑，例如，季胺化合物；(g)潤濕劑，例如鯨蠟醇和單硬脂酸甘油酯；(h)吸附劑，例如，高嶺土；和(i)潤滑劑，例如，滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉，或其混合物。膠囊劑、片劑和丸劑中，劑型也可包含緩衝劑。
固體劑型如片劑、糖丸、膠囊劑、丸劑和顆粒劑可採用包衣和殼材製備，如腸衣和其它本領域公知的材料。它們可包含不透明劑，並且，這種組合物中活性化合物或化合物的釋放可以延遲的方式在消化道內的某一部分中釋放。可採用的包埋組分的實例是聚合物質和蠟類物質。必要時，活性化合物也可與上述賦形劑中的一種或多種形成微膠囊形式。
用於口服給藥的液體劑型包括藥學上可接受的乳液、溶液、懸浮液、糖漿或酊劑。除了活性化合物外，液體劑型可包含本領域中常規採用的惰性稀釋劑，如水或其它溶劑，增溶劑和乳化劑，例知，乙醇、異丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲醯胺以及油，特別是棉籽油、花生油、玉米胚油、橄欖油、蓖麻油和芝麻油或這些物質的混合物等。
除了這些惰性稀釋劑外，組合物也可包含助劑，如潤濕劑、乳化劑和懸浮劑、甜味劑、矯味劑和香料。
除了活性化合物外，懸浮液可包含懸浮劑，例如，乙氧基化異十八烷醇、聚氧乙烯山梨醇和脫水山梨醇酯、微晶纖維素、甲醇鋁和瓊脂或這些物質的混合物等。
用於腸胃外注射的組合物可包含生理上可接受的無菌含水或無水溶液、分散液、懸浮液或乳液，和用於重新溶解成無菌的可注射溶液或分散液的無菌粉末。適宜的含水和非水載體、稀釋劑、溶劑或賦形劑包括水、乙醇、多元醇及其適宜的混合物。
用於局部給藥的本發明化合物的劑型包括軟膏劑、散劑、貼劑、噴射劑和吸入劑。活性成分在無菌條件下與生理上可接受的載體及任何防腐劑、緩衝劑，或必要時可能需要的推進劑一起混合。
本發明化合物可以單獨給藥，或者與其他藥學上可接受的化合物聯合給藥。
使用藥物組合物時，是將安全有效量的本發明化合物適用於需要治療的哺乳動物(如人)，其中施用時劑量為藥學上認為的有效給藥劑量，對於60kg體重的人而言，日給藥劑量通常為1～2000 mg，優選50 mg至1000 mg。當然，具體劑量還應考慮給藥途徑、病人健康狀況等因素，這些都是熟練醫師技能範圍之內的。
本發明提到的上述特徵，或實施例提到的特徵可以任意組合。本案說明書所揭示的所有特徵可與任何組合物形式並用，說明書中所揭示的各個特徵，可以任何可提供相同、均等或相似目的的替代性特徵取代。因此除有特別說明，所揭示的特徵僅為均等或相似特徵的一般性例子。
具體實施方式
在下面的說明中將會詳細闡述上述化合物、方法、藥物組合物的各個具體方面、特性和優勢，使本發明的內容變得十分明瞭。在此應理解，下述的詳細說明及實例描述了具體的實施例，僅用於參考。在閱讀了本發明的說明內容後，本領域的技術人員可對本發明作各種改動或修改，這些等價形勢同樣落於本申請所限定的範圍。
所有實施例中，1 H-NMR用Varian Mercury 400核磁共振儀記錄，化學位移以δ (ppm)表示；分離用矽膠未說明均為200目至-300目，沖提液的配比均為體積比。
本發明採用下述縮略詞：CDCl3 代表氘代氯仿；CD3 OD代表氘代甲醇；DMSO-d6代表氘代二甲伸碸；EtOAc代表乙酸乙酯；Hexane代表正己烷；MeCN代表乙腈；DCM代表二氯甲烷；DIPEA代表二異丙基乙基胺；NMP代表1-甲基吡咯烷-2-酮；Dioxane代表 1,4-二氧六環；DMF代表N,N-二甲基甲醯胺；DMSO代表二甲伸碸；h代表小時；K3 PO4 代表磷酸鉀；min代表分鐘；MS代表質譜；NaH代表氫化鈉；NMR代表核磁共振；Pd2 (dba)3 代表三(二伸苄基丙酮)二鈀；Pd(dppf)Cl2 代表1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀；TFA (CF3 COOH)代表三氟乙酸；TLC代表薄層色譜；THF代表四氫呋喃；Xantphos代表4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽。
合成方法 A:
使用合成方法 A 進行具體化合物 135 （ 5-((3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺）及其各光學異構體（化合物 136 、 137 、 138 及 139 ）的合成
Figure 02_image551
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL), 水(300 mL)，攪拌、分液，水相再用EtOAc(150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc：Hexane=0：1 至 1：5 至 1：2)得產物(1.82 g, 產率：10.5%)，回收原料(10.3 g, 產率：68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol)，混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99-6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 5- 氯 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 int_4 ）的合成：
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (167 mg, 0.30 mmol)，無水磷酸鉀 (160 mg, 0.75 mmol)，苯硼酸 (40.23 mg, 0.33 mmol)，Dioxane/H2 O (10 mL/2 mL)，Pd(dppf)2 Cl2 (22 mg)，混合液氬氣置換後快速升溫至105℃反應30 min。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(115mg, 產率: 75.6%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.74 (s, 1H), 7.70 (d,J = 6.5 Hz, 3H), 7.56 (d,J = 8.5 Hz, 2H), 7.44 (p,J = 6.8 Hz, 3H), 6.94 (d,J = 8.6 Hz, 2H), 5.67 (s, 1H), 3.70 (d,J = 11.9 Hz, 2H), 2.83-2.55 (m, 7H), 2.47 (s, 3H), 2.40-2.32 (m, 1H), 2.28 (s, 3H), 1.93 (d,J = 12.4 Hz, 2H), 1.67 (tt,J = 12.5, 6.8 Hz, 2H); LC-MS: 506 [M+H]+ .
步驟 4 ：化合物 5-((3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 135 ）的合成 :
50 mL單口瓶中加入5-氯-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)-6-苯基吡嗪-2-羧醯胺 (133.6 mg, 0.27 mmol)，無水碳酸鉀 (186 mg, 1.35 mmol)，無水氟化鉀 (31 mg, 0.54 mmol)，DMSO (5 mL)，4 Å分子篩(200 mg粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入3-氨基環戊醇鹽酸鹽 (45 mg, 0.32 mmol)，混合液氬氣置換後攪拌升溫至120 ℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(92 mg, 產率: 59.7%)。
MS (ESI): 571 [M+H]+ .
採用手性分離技術，可以得到四個光學純手性異構體：
Figure 02_image553
。
5-(((1R,3S)-3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 136 ）：
1 H NMR (400 MHz, CDCl3 ) δ: 10.71 (s, 1H), 7.65-7.53 (m, 4H), 7.53-7.41 (m, 3H), 7.41-7.31 (m, 1H), 6.98-6.80 (m, 2H), 5.21 (d,J = 6.5 Hz, 1H), 5.13 (s, 1H), 4.56 (h,J = 7.1 Hz, 1H), 4.39 (tt,J = 5.8, 2.9 Hz, 1H), 3.69 (d,J = 12.0 Hz, 2H), 2.80-2.58 (m, 5H), 2.50 (s, 3H), 2.35 (d,J = 9.8 Hz, 1H), 2.30 (s, 3H), 2.29-2.22 (m, 1H), 2.18 (dd,J = 13.8, 7.2 Hz, 1H), 2.06-1.96 (m, 1H), 1.92 (d,J = 12.4 Hz, 2H), 1.71-1.54 (m, 6H), 1.43 (ddd,J = 13.0, 9.1, 6.6 Hz, 1H); MS (ESI): 571 [M+H]+ .
5-(((1R,3R)-3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 137 ） :
1 H NMR (400 MHz, CDCl3 ) δ: 10.78 (s, 1H), 7.60 (dd,J = 8.6, 6.7 Hz, 4H), 7.44 (t,J = 7.5 Hz, 3H), 7.36 (t,J = 7.3 Hz, 1H), 6.91 (d,J = 8.9 Hz, 2H), 6.04 (d,J = 7.4 Hz, 1H), 5.10 (s, 1H), 4.54 (d, J = 7.8 Hz, 1H), 4.44 (s, 1H), 3.68 (d,J = 11.9 Hz, 2H), 2.77-2.57 (m, 5H), 2.48 (s, 3H), 2.36 (s, 1H), 2.29 (s, 3H), 2.17-1.99 (m, 3H), 1.99-1.63 (m, 9H); MS (ESI): 571 [M+H]+ .
5-(((1S,3S)-3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 138 ）：
1 H NMR (400 MHz, CDCl3 ) δ: 10.71 (s, 1H), 7.65-7.53 (m, 4H), 7.53-7.41 (m, 3H), 7.41-7.31 (m, 1H), 6.98-6.80 (m, 2H), 5.21 (d,J = 6.5 Hz, 1H), 5.13 (s, 1H), 4.56 (h,J = 7.1 Hz, 1H), 4.39 (tt,J = 5.8, 2.9 Hz, 1H), 3.69 (d,J = 12.0 Hz, 2H), 2.80-2.58 (m, 5H), 2.50 (s, 3H), 2.35 (d,J = 9.8 Hz, 1H), 2.30 (s, 3H), 2.29-2.22 (m, 1H), 2.18 (dd,J = 13.8, 7.2 Hz, 1H), 2.06-1.96 (m, 1H), 1.92 (d,J = 12.4 Hz, 2H), 1.71-1.54 (m, 6H), 1.43 (ddd,J = 13.0, 9.1, 6.6 Hz, 1H); MS (ESI): 571 [M+H]+ .
5-(((1S,3R)-3- 羥基環戊基 ) 氨基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 139 ） :
1 H NMR (400 MHz, CDCl3 ) δ: 10.78 (s, 1H), 7.60 (dd,J = 8.6, 6.7 Hz, 4H), 7.44 (t,J = 7.5 Hz, 3H), 7.36 (t,J = 7.3 Hz, 1H), 6.91 (d,J = 8.9 Hz, 2H), 6.04 (d,J = 7.4 Hz, 1H), 5.10 (s, 1H), 4.54 (d,J = 7.8 Hz, 1H), 4.44 (s, 1H), 3.68 (d,J = 11.9 Hz, 2H), 2.77-2.57 (m, 5H), 2.48 (s, 3H), 2.36 (s, 1H), 2.29 (s, 3H), 2.17-1.99 (m, 3H), 1.99-1.63 (m, 9H); MS (ESI): 571 [M+H]+ .
使用合成方法 A 進行具體化合物 39 （ 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-( 吡啶 -4- 基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺）的合成
Figure 02_image555
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90 ℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL), 水(300 mL)，攪拌、分液，水相再用EtOAc (150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc: Hexane= 0:1 至 1: 5 至 1: 2)得產物(1.82 g, 產率:10.5%)，回收原料(10.3 g, 產率: 68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol), 混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99- 6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 5- 氯 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-( 吡啶 -4- 基 ) 吡嗪 -2- 羧醯胺（化合物 int_6 ）的合成 :
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺(166.76 mg, 0.30 mmol)，無水磷酸鉀(160 mg, 0.75 mmol)，(吡啶-4-基)硼酸 (40.56 mg, 0.33 mmol)，Dioxane/H2 O(10 mL/ 2 mL)，Pd(dppf)2 Cl2 (22 mg)，混合液氬氣置換後快速升溫至105 ℃反應60 min。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(126 mg, 產率: 82.8%)。
MS (ESI): 507 [M+H]+ .
步驟 4 ：化合物 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-( 吡啶 -4- 基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 39 ）的合成
50 mL單口瓶中加入5-氯-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)-6-(吡啶-4-基)吡嗪-2-羧醯胺(152.1 mg, 0.3 mmol)，無水碳酸鉀(186 mg, 1.35 mmol)，無水氟化鉀 (35 mg, 0.6 mmol)，DMSO (5 mL)，4 Å分子篩(200 mg粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入3-四氫-2H -吡喃-4-胺 (33.4 mg, 0.33 mmol)，混合液氬氣置換後攪拌升溫至120 ℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(130 mg, 產率: 75.8%)。
1 H NMR (400 MHz, CDCl3 ) δ 10.86 (s, 1H), 8.71 (d,J = 5.1 Hz, 2H), 7.55 (t,J = 6.8 Hz, 4H), 7.42 (s, 1H), 6.91 (d,J = 8.8 Hz, 2H), 5.22 (s, 1H), 5.14 (d,J = 7.0 Hz, 1H), 4.17 (m, 1H), 4.01 (d,J = 11.7 Hz, 2H), 3.69 (d,J = 9.2 Hz, 2H), 3.52 (t,J = 11.6 Hz, 2H), 2.69 (m, 11H), 2.38 (s, 3H), 2.09-1.96 (m, 4H), 1.76-1.64 (m, 4H); MS (ESI): 572 [M+H]+ .
使用合成方法 A 進行具體化合物 55 （ 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-(1H - 吡唑 -3- 基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺）的合成
Figure 02_image557
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90 ℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL)及水(300 mL)，攪拌、分液，水相再用EtOAc (150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc: Hexane= 0:1 至 1: 5 至 1: 2)得產物(1.82 g, 產率:10.5%)，回收原料(10.3 g, 產率: 68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol), 混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99- 6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 5- 氯 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-(1H - 吡唑 -3- 基 ) 吡嗪 -2- 羧醯胺（化合物 int_7 ）的合成 :
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (166.76 mg, 0.30 mmol)，無水磷酸鉀 (160 mg, 0.75 mmol)，(1H -吡唑-3-基)硼酸 (37 mg, 0.33 mmol)，Dioxane/ H2 O (10 mL/ 2 mL)，Pd(dppf)2 Cl2 (22 mg)，混合液氬氣置換後快速升溫至105 ℃反應60 min。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(119 mg, 產率: 80%)。
MS (ESI): 496 [M+H]+ .
步驟 4 ：化合物 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-(1H - 吡唑 -3- 基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 55 ）的合成
50 mL單口瓶中加入5-氯-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)-6-(1H -吡唑-3-基)吡嗪-2-羧醯胺 (148.8 mg, 0.3 mmol)，無水碳酸鉀 (186 mg, 1.35 mmol)，無水氟化鉀 (35 mg, 0.6 mmol)，DMSO (5 mL)，4 Å分子篩(200 mg粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入3-四氫-2H -吡喃-4-胺 (33.4 mg, 0.33 mmol)，混合液氬氣置換後攪拌升溫至120 ℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(115 mg, 產率: 68.3%)。
化合物55富馬酸鹽：1 H NMR (400 MHz, DMSO-d 6 ) δ 13.05 (s, 1H), 11.21 (s, 1H), 8.90 (s, 1H), 8.00-7.92 (m, 1H), 7.81 (d,J = 2.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.31 (d,J = 2.8 Hz, 1H), 7.21 (d,J = 2.4 Hz, 1H), 6.89 (d,J = 8.9 Hz, 2H), 6.54 (s, 4H), 4.11 (m,J = 6.2 Hz, 1H), 3.89 (dt,J = 11.5, 3.7 Hz, 2H), 3.62 (d,J = 11.8 Hz, 2H), 3.49 (td,J = 11.5, 2.4 Hz, 2H), 2.88-2.52 (m, 9H), 2.42 (s, 3H), 2.10-1.99 (m, 2H), 1.84 (d,J = 11.1 Hz, 2H), 1.61-1.40 (m, 4H); MS (ESI): 561 [M+H]+ .
使用合成方法 A 進行具體化合物 511 （ 6-(1H - 吲哚 -4- 基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺）的合成
Figure 02_image559
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90 ℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL)，水(300 mL)，攪拌、分液，水相再用EtOAc (150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc: Hexane= 0:1 至 1: 5 至 1: 2)得產物(1.82 g, 產率:10.5%)，回收原料(10.3 g, 產率: 68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol), 混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99- 6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 5- 氯 -6-(1H - 吲哚 -4- 基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_8 ）的合成 :
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (166.76 mg, 0.30 mmol)，無水磷酸鉀 (160 mg, 0.75 mmol)，(1H -吲哚-4-基)硼酸 (53.12 mg, 0.33 mmol)，Dioxane/ H2 O (10 mL/ 2 mL)，Pd(dppf)2 Cl2 (22 mg)，混合液氬氣置換後快速升溫至105 ℃反應60 min。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(131 mg, 產率: 80%)。
MS (ESI): 545 [M+H]+ .
步驟 4 ：化合物 6-(1H - 吲哚 -4- 基 )-3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 511 ）的合成
50 mL單口瓶中加入5-氯-6-(1H -吲哚-4-基)-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (164 mg, 0.3 mmol)，無水碳酸鉀 (186 mg, 1.35 mmol)，無水氟化鉀 (35 mg, 0.6 mmol)，DMSO (5 mL)，4 Å分子篩(200 mg粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入3-四氫-2H -吡喃-4-胺 (33.4 mg, 0.33 mmol)，混合液氬氣置換後攪拌升溫至120℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(127 mg, 產率: 69.4%)。
1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 8.39 (s, 1H), 7.62 (d,J = 8.9 Hz, 2H), 7.55-7.45 (m, 2H), 7.30 (td,J = 6.3, 5.7, 4.0 Hz, 3H), 6.92 (d,J = 8.9 Hz, 2H), 6.54 (d,J = 2.8 Hz, 1H), 5.25 (d,J = 7.2 Hz, 1H), 5.13 (s, 1H), 4.23-4.14 (m, 1H), 3.96 (d,J = 11.7 Hz, 2H), 3.69 (d,J = 11.9 Hz, 2H), 3.56-3.47 (m, 2H), 2.77-2.37 (m, 11H), 2.32 (s, 3H), 2.00 (dd,J = 26.0, 11.4 Hz, 4H), 1.72 (dd,J = 11.8, 3.8 Hz, 2H), 1.49-1.42 (m, 2H); MS (ESI): 610 [M+H]+ .
合成方法 B:
使用合成方法 B 進行具體化合物 19 （ 5- 甲氧基 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺）的合成：
Figure 02_image561
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90 ℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90 ℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL), 水(300 mL)，攪拌、分液，水相再用EtOAc (150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc: Hexane= 0:1 至 1: 5 至 1: 2)得產物(1.82 g, 產率:10.5%)，回收原料(10.3 g, 產率: 68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol), 混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99-6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 5- 氯 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 int_4 ）的合成：
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (167 mg, 0.30 mmol)，無水磷酸鉀 (160 mg, 0.75 mmol)，苯硼酸 (40.23 mg, 0.33 mmol)，Dioxane/ H2 O (10 mL/ 2 mL)，Pd(dppf)2 Cl2 (22 mg)，混合液氬氣置換後快速升溫至105℃反應30 min。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(115 mg, 產率: 75.6%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.74 (s, 1H), 7.70 (d,J = 6.5 Hz, 3H), 7.56 (d,J = 8.5 Hz, 2H), 7.44 (p,J = 6.8 Hz, 3H), 6.94 (d,J = 8.6 Hz, 2H), 5.67 (s, 1H), 3.70 (d,J = 11.9 Hz, 2H), 2.83-2.55 (m, 7H), 2.47 (s, 3H), 2.40-2.32 (m, 1H), 2.28 (s, 3H), 1.93 (d,J = 12.4 Hz, 2H), 1.67 (tt,J = 12.5, 6.8 Hz, 2H); LC-MS: 506 [M+H]+ .
步驟 4 ：化合物 5- 甲氧基 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基吡嗪 -2- 羧醯胺（化合物 19 ）的合成 :
50 mL單口瓶中加入5-氯-3-（（4-（4-（4-甲基呱嗪-1-基）呱啶-1-基）苯基）氨基）-6-苯基吡嗪-2-羧醯胺 (50 mg, 0.10 mmol)，DMF (5 mL)，4 Å分子篩(200 mg,粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入甲醇鈉 (16 mg, 0.3 mmol)，混合液氬氣置換後攪拌升溫至80℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(21 mg, 產率: 42%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.81 (s, 1H), 7.99-7.87 (m, 2H), 7.65 (d,J = 4.4 Hz, 1H), 7.61-7.55 (m, 2H), 7.41 (d,J = 7.8 Hz, 2H), 6.94 (dd,J = 9.0, 3.6 Hz, 2H), 5.42-5.33 (m, 1H), 4.05 (s, 3H), 3.70 (d,J = 12.0 Hz, 2H), 2.78-2.41 (m, 11H), 2.41-2.32 (m, 1H), 2.30 (s, 3H), 1.94 (d,J = 12.4 Hz, 2H), 1.69 (qd,J = 11.8, 3.7 Hz, 2H); MS (ESI): 502 [M+H]+ .
合成方法 C:
使用合成方法 C 進行具體化合物 116 （ 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6- 苯基 -5-(( 四氫 -2H - 吡喃 -4- 基 ) 氧代 ) 吡嗪 -2- 甲醯胺）的合成
Figure 02_image563
步驟 1 ：化合物 3,5- 二氯 -6- 碘吡嗪 -2- 羧醯胺（化合物 int_2 ）的合成 :
500 mL單口瓶中加入3,5-二氯-2-碘吡嗪 (15 g, 54.57 mmol)，甲醯胺 (300 mL)，混合液攪拌升溫至90℃，後分批加入(NH4 )2 S2 O8 (25 g, 109.1 mmol)固體，混合液保溫在90℃攪拌2 h，後再次分批補加K2 S2 O8 (30 g, 109.1 mmol)固體，混合液保溫在90℃攪拌20 h。LC-MS監測反應有產物，剩餘部分原料。混合液中加入EtOAc (150 mL), 水(300 mL)，攪拌、分液，水相再用EtOAc (150 mL)萃取，合併有機相用飽和氯化鈉溶液(150 mL)洗滌、濃縮，殘留物柱層析純化(EtOAc: Hexane= 0:1 至 1: 5 至 1: 2)得產物(1.82 g, 產率:10.5%)，回收原料(10.3 g, 產率: 68.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 7.28 (s, 1H), 5.78 (s, 1H); MS (ESI): 317 [M+H]+ .
步驟 2 ：化合物 5- 氯 -6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_3 ）的合成 :
50 mL單口瓶中加入3,5-二氯-6-碘吡嗪-2-羧醯胺 (280 mg, 0.883 mmol)，4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯胺 (267 mg, 0.971 mmol)，Dioxane (20 mL)和DIPEA (228 mg, 1.766 mmol), 混合液氬氣置換後攪拌升溫至回流反應2 h。LC-MS監測反應完成後，混合液濃縮，殘留物柱層析純化得產物(368 mg, 產率: 75%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.69 (s, 1H), 7.53 (d,J = 3.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.99- 6.88 (m, 2H), 5.67 (d,J = 3.9 Hz, 1H), 3.80-3.63 (m, 2H), 2.84-2.42 (m, 10H), 2.39 (ddt,J = 11.4, 7.3, 3.7 Hz, 1H), 1.96 (dt,J = 12.2, 3.0 Hz, 2H), 1.70 (qd,J = 12.1, 4.0 Hz, 2H); MS (ESI): 556 [M+H]+ .
步驟 3 ：化合物 6- 碘 -3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 int_5 ）的合成 :
50 mL單口瓶中加入5-氯-6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)吡嗪-2-羧醯胺 (150 mg, 0.27 mmol)，無水碳酸鉀 (186 mg, 1.35 mmol)，無水氟化鉀 (31 mg, 0.54 mmol)，DMSO (5 mL)，4 Å分子篩(200 mg, 粉末狀)，混合液氬氣置換後室溫攪拌15 min，後加入3-四氫-2H -吡喃-4-胺 (32 mg, 0.32 mmol)，混合液氬氣置換後攪拌升溫至120℃反應2 h。LC-MS監測反應完成，混合液降溫後柱層析純化得產物(110mg, 產率: 65.7%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.64 (s, 1H), 7.62-7.39 (m, 2H), 7.21 (s, 1H), 6.96-6.76 (m, 2H), 5.41-5.12 (m, 2H), 4.03 (dq,J = 11.4, 3.7 Hz, 3H), 3.67 (d,J = 12.0 Hz, 2H), 3.51 (td,J = 11.6, 2.2 Hz, 2H), 2.84-2.50 (m, 10H), 2.44 (d,J = 11.4 Hz, 1H), 2.37 (s, 3H), 2.11-1.89 (m, 4H), 1.78-1.51 (m, 4H); MS (ESI): 621 [M+H]+ .
步驟 4 ：化合物 3-((4-(4-(4- 甲基呱嗪 -1- 基 ) 呱啶 -1- 基 ) 苯基 ) 氨基 )-6-( 呱啶 -1- 基 )-5-(( 四氫 -2H - 吡喃 -4- 基 ) 氨基 ) 吡嗪 -2- 羧醯胺（化合物 116 ）的合成 :
10ml 微波反應器中加入6-碘-3-((4-(4-(4-甲基呱嗪-1-基)呱啶-1-基)苯基)氨基)-5-((四氫-2H-吡喃-4-基)氨基)吡嗪-2-羧醯胺 (57 mg, 0.10 mmol)，呱啶 (34 mg, 0.40 mmol)，無水氟化銫 (45 mg, 0.30 mmol)，NMP (5 ml)，微波反應器中加熱至180℃攪拌反應8 h。LC-MS監測反應完成後，混合液降溫，柱層析純化得產物(32 mg, 產率: 57.4%)。
1 H NMR (400 MHz, CDCl3 ) δ: 10.57 (s, 1H), 7.55-7.48 (m, 2H), 6.90-6.82 (m, 2H), 5.51 (d,J = 7.3 Hz, 1H), 5.06 (s, 1H), 4.13-4.04 (m, 1H), 4.02-3.96 (m, 2H), 3.64 (d,J = 11.7 Hz, 2H), 3.55 (td,J = 11.5, 2.3 Hz, 2H), 2.87 (t,J = 5.3 Hz, 4H), 2.71-2.58 (m, 5H), 2.48 (s, 3H), 2.36 (t,J = 11.4 Hz, 1H), 2.29 (s, 3H), 2.06 (d,J = 13.1 Hz, 2H), 1.93 (d,J = 12.3 Hz, 2H), 1.73-1.52 (m, 12H); MS (ESI): 578 [M+H]+ .
實施例 1 化合物 1-645 的合成
使用合成方法A、合成方法B或合成方法C，採用不同原料，可以得到表2中目標化合物1-18、化合物20-115、化合物117-135和化合物140-645。
LC-MS分析方法如下： 儀器：Agilent 6125B 色譜柱：Core-shell 2.7 um 4.3×50 mm 柱溫：30 ℃ 波長：254 nm/214 nm 流動相A：H2 O (0.1 %甲酸) 流動相B：乙腈 (0.1 %甲酸) 梯度：
表1
時間(min) 流速(mL/min) 流動相B% 流動相A%
0 2 5 95
0.1 2 5 95
2.2 2 95 5
2.7 2 95 5
2.71 2 5 95
3.2 2 5 95
表2
化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 ) 化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 )
1
Figure 02_image565
 A 571 1.409 2
Figure 02_image567
 B 571 1.278
3
Figure 02_image569
 B 556 1.597 4
Figure 02_image571
 B 585 1.198
5
Figure 02_image573
 A 563 1.507 6
Figure 02_image575
 B 564 1.649
7
Figure 02_image577
 A 584 1.186 8
Figure 02_image579
 A 585 1.434
9
Figure 02_image581
 A 555 1.464 10
Figure 02_image583
 A 515 1.463
11
Figure 02_image585
 A 529 1.489 12
Figure 02_image587
 B 572 1.461
13
Figure 02_image589
 A 501 1.350 14
Figure 02_image591
 B 530 1.521
15
Figure 02_image593
 A 555 1.560 16
Figure 02_image595
 B 558 1.430
17
Figure 02_image597
 A 541 1.542 18
Figure 02_image599
 B 558 1.450
          20
Figure 02_image601
 B 571 1.310
21
Figure 02_image603
 A 559 1.350 22
Figure 02_image605
 A 573 1.337
23
Figure 02_image607
 A 585 1.356 24
Figure 02_image609
 A 585 1.338
25
Figure 02_image611
 B 570 1.551 26
Figure 02_image613
 A 531 --
27
Figure 02_image615
 A 607 1.325 28
Figure 02_image617
 A 558 1.147
29
Figure 02_image619
 A 557 1.289 30
Figure 02_image621
 A 541 1.491
31
Figure 02_image623
 A 557 1.325 32
Figure 02_image625
 A 557 1.310
33
Figure 02_image627
 A 527 1.389 34
Figure 02_image629
 A 571 1.358
35
Figure 02_image631
 A 585 1.425 36
Figure 02_image633
 A 531 1.332
37
Figure 02_image635
 A 572 1.122 38
Figure 02_image637
 A 572 1.475
39
Figure 02_image639
 A 572 1.104 40
Figure 02_image641
 A 575 1.244
41
Figure 02_image643
 A 586 -- 42
Figure 02_image645
 A 601 1.457
43
Figure 02_image647
 A 587 1.378 44
Figure 02_image649
 A 649 1.396
45
Figure 02_image651
 A 601 1.479 46
Figure 02_image653
 A 649 1.402
47
Figure 02_image655
 A 596 1.401 48
Figure 02_image657
 A 619 1.342
49
Figure 02_image659
 A 575 1.294 50
Figure 02_image661
 A 575 1.268
51
Figure 02_image663
 A 601 1.407 52
Figure 02_image665
 A 596 --
53
Figure 02_image667
 A 596 1.368 54
Figure 02_image669
 A 593 1.272
55
Figure 02_image671
 A 561 1.254 56
Figure 02_image673
 A 586 1.094
57
Figure 02_image675
 A 561 1.199 58
Figure 02_image677
 A 602 --
59
Figure 02_image679
 A 516 1.523 60
Figure 02_image681
 A 589 --
61
Figure 02_image683
 A 605 -- 62
Figure 02_image685
 A 589 1.400
63
Figure 02_image687
 A 605 1.423 64
Figure 02_image689
 A 589 1.438
65
Figure 02_image691
 A 605 1.532 66
Figure 02_image693
 A 557 --
67
Figure 02_image695
 A 602 -- 68
Figure 02_image697
 A 562 1.047
69
Figure 02_image699
 A 561 1.331 70
Figure 02_image701
 A 557 1.350
71
Figure 02_image703
 A 601 1.260 72
Figure 02_image705
 A 573 1.236
73
Figure 02_image707
 A 602 1.137 74
Figure 02_image709
 A 586 --
75
Figure 02_image711
 A 626 -- 76
Figure 02_image713
 A 626 --
77
Figure 02_image715
 A 626 -- 78
Figure 02_image717
 A 614 --
79
Figure 02_image719
 A 614 -- 80
Figure 02_image721
 A 614 --
81
Figure 02_image723
 A 614 -- 82
Figure 02_image725
 A 621 1.370
83
Figure 02_image727
 A 602 1.058 84
Figure 02_image729
 A 601 1.241
85
Figure 02_image731
 A 614 1.235 86
Figure 02_image733
 A 614 1.268
87
Figure 02_image735
 A 614 1.292 88
Figure 02_image737
 A 578 1.272
89
Figure 02_image739
 A 615 1.396 90
Figure 02_image741
 A 664 1.312
91
Figure 02_image743
 A 561 1.332 92
Figure 02_image745
 A 586 1.204
93
Figure 02_image747
 A 577 1.350 94
Figure 02_image749
 A 577 1.399
95
Figure 02_image751
 A 586 1.220 96
Figure 02_image753
 A 587 1.225
97
Figure 02_image755
 A 574 1.313 98
Figure 02_image757
 A 586 1.295
99
Figure 02_image759
 A 587 1.336 100
Figure 02_image761
 A 628 1.314
101
Figure 02_image763
 A 621 1.446 102
Figure 02_image765
 A 590 1.058
103
Figure 02_image767
 A 590 1.270 104
Figure 02_image769
 A 615 1.398
105
Figure 02_image771
 A 621 1.393 106
Figure 02_image773
 A 602 1.194
107
Figure 02_image775
 A 664 1.296 108
Figure 02_image777
 A 586 1.109
109
Figure 02_image779
 A 576 1.084 110
Figure 02_image781
 A 575 1.159
111
Figure 02_image783
 A 575 1.308 112
Figure 02_image785
 A 601 1.363
113
Figure 02_image787
 A 601 1.456 114
Figure 02_image789
 A 586 1.226
115
Figure 02_image791
 A 599 1.491          
117
Figure 02_image793
 A 572 1.107 118
Figure 02_image795
 A 489 1.201
119
Figure 02_image797
 A 391 1.499 120
Figure 02_image799
 A 503 1.156
121
Figure 02_image801
 A 488 1.219 122
Figure 02_image803
 A 590 1.222
123
Figure 02_image805
 A 490 1.114 124
Figure 02_image807
 A 434 1.232
125
Figure 02_image809
 A 571 1.387 126
Figure 02_image811
 A 591 1.344
127
Figure 02_image813
 A 543 0.982 128
Figure 02_image815
 A 557 1.192
129
Figure 02_image817
 A 529 -- 130
Figure 02_image819
 A 529 --
131
Figure 02_image821
 B 601 1.138 132
Figure 02_image823
 B 601 1.140
133
Figure 02_image825
 A 571 1.371 134
Figure 02_image827
 A 571 --
135
Figure 02_image829
 A 571 1.397 140
Figure 02_image831
 A 585 1.443
141
Figure 02_image833
 A 585 1.401 142
Figure 02_image835
 A 585 1.443
143
Figure 02_image837
 A 585 1.436 144
Figure 02_image839
 A 585 1.389
145
Figure 02_image841
 A 589 -- 146
Figure 02_image843
 A 612 --
147
Figure 02_image845
 A 504 -- 148
Figure 02_image847
 A 503 1.204
149
Figure 02_image849
 A 626 -- 150
Figure 02_image851
 A 626 --
151
Figure 02_image853
 A 503 -- 152
Figure 02_image855
 A 504 --
153
Figure 02_image857
 A 603 -- 154
Figure 02_image859
 A 600 --
155
Figure 02_image861
 A 626 -- 156
Figure 02_image863
 A 518 --
157
Figure 02_image865
 A 517 -- 158
Figure 02_image867
 A 640 --
159
Figure 02_image869
 A 640 -- 160
Figure 02_image871
 A 603 --
161
Figure 02_image873
 A 600 1.181 162
Figure 02_image875
 A 626 --
163
Figure 02_image877
 A 518 -- 164
Figure 02_image879
 A 517 --
165
Figure 02_image881
 A 640 -- 166
Figure 02_image883
 A 640 --
167
Figure 02_image885
 A 617 -- 168
Figure 02_image887
 A 614 --
169
Figure 02_image889
 A 640 -- 170
Figure 02_image891
 A 532 --
171
Figure 02_image893
 A 531 -- 172
Figure 02_image895
 A 654 --
173
Figure 02_image897
 A 654 -- 174
Figure 02_image899
 A 478 1.436
175
Figure 02_image901
 A 479 -- 176
Figure 02_image903
 A 578 --
177
Figure 02_image905
 A 575 1.439 178
Figure 02_image907
 A 601 --
179
Figure 02_image909
 A 493 -- 180
Figure 02_image911
 A 492 --
181
Figure 02_image913
 A 615 -- 182
Figure 02_image915
 A 615 --
183
Figure 02_image917
 A 592 -- 184
Figure 02_image919
 A 589 1.398
185
Figure 02_image921
 A 615 -- 186
Figure 02_image923
 A 507 --
187
Figure 02_image925
 A 506 -- 188
Figure 02_image927
 A 629 --
189
Figure 02_image929
 A 629 -- 190
Figure 02_image931
 A 492 --
191
Figure 02_image933
 A 493 -- 192
Figure 02_image935
 A 592 --
193
Figure 02_image937
 A 589 -- 194
Figure 02_image939
 A 615 --
195
Figure 02_image941
 A 507 -- 196
Figure 02_image943
 A 506 --
197
Figure 02_image945
 A 629 -- 198
Figure 02_image947
 A 629 --
199
Figure 02_image949
 A 606 -- 200
Figure 02_image951
 A 603 --
201
Figure 02_image953
 A 629 -- 202
Figure 02_image955
 A 521 --
203
Figure 02_image957
 A 520 -- 204
Figure 02_image959
 A 643 --
205
Figure 02_image961
 A 643 -- 206
Figure 02_image963
 A 575 --
207
Figure 02_image965
 A 598 -- 208
Figure 02_image967
 A 490 --
209
Figure 02_image969
 A 489 -- 210
Figure 02_image971
 A 612 --
211
Figure 02_image973
 A 612 -- 212
Figure 02_image975
 A 589 --
213
Figure 02_image977
 A 586 1.580 214
Figure 02_image979
 A 612 --
215
Figure 02_image981
 A 504 -- 216
Figure 02_image983
 A 503 --
217
Figure 02_image985
 A 626 -- 218
Figure 02_image987
 A 626 --
219
Figure 02_image989
 A 603 -- 220
Figure 02_image991
 A 600 --
221
Figure 02_image993
 A 626 -- 222
Figure 02_image995
 A 518 --
223
Figure 02_image997
 A 517 -- 224
Figure 02_image999
 A 640 --
225
Figure 02_image1001
 A 640 -- 226
Figure 02_image1003
 A 605 --
227
Figure 02_image1005
 A 602 -- 228
Figure 02_image1007
 A 628 --
229
Figure 02_image1009
 A 520 -- 230
Figure 02_image1011
 A 519 --
231
Figure 02_image1013
 A 642 -- 232
Figure 02_image1015
 A 642 --
233
Figure 02_image1017
 A 619 -- 234
Figure 02_image1019
 A 616 --
235
Figure 02_image1021
 A 642 -- 236
Figure 02_image1023
 A 534 --
237
Figure 02_image1025
 A 533 -- 238
Figure 02_image1027
 A 656 --
239
Figure 02_image1029
 A 656 -- 240
Figure 02_image1031
 A 633 --
241
Figure 02_image1033
 A 630 -- 242
Figure 02_image1035
 A 656 --
243
Figure 02_image1037
 A 548 -- 244
Figure 02_image1039
 A 547 --
245
Figure 02_image1041
 A 670 -- 246
Figure 02_image1043
 A 670 --
247
Figure 02_image1045
 A 598 -- 248
Figure 02_image1047
 A 624 --
249
Figure 02_image1049
 A 612 -- 250
Figure 02_image1051
 A 626 --
251
Figure 02_image1053
 A 516 -- 252
Figure 02_image1055
 A 515 --
253
Figure 02_image1057
 A 638 -- 254
Figure 02_image1059
 A 638 --
255
Figure 02_image1061
 A 598 -- 256
Figure 02_image1063
 A 624 --
257
Figure 02_image1065
 A 612 -- 258
Figure 02_image1067
 A 626 --
259
Figure 02_image1069
 A 516 -- 260
Figure 02_image1071
 A 515 --
261
Figure 02_image1073
 A 638 -- 262
Figure 02_image1075
 A 638 --
263
Figure 02_image1077
 A 598 -- 264
Figure 02_image1079
 A 624 --
265
Figure 02_image1081
 A 612 -- 266
Figure 02_image1083
 A 626 --
267
Figure 02_image1085
 A 516 -- 268
Figure 02_image1087
 A 515 --
269
Figure 02_image1089
 A 638 -- 270
Figure 02_image1091
 A 638 --
271
Figure 02_image1093
 A 612 -- 272
Figure 02_image1095
 A 638 --
273
Figure 02_image1097
 A 626 -- 274
Figure 02_image1099
 A 640 --
275
Figure 02_image1101
 A 530 -- 276
Figure 02_image1103
 A 529 --
277
Figure 02_image1105
 A 652 -- 278
Figure 02_image1107
 A 652 --
279
Figure 02_image1109
 A 612 -- 280
Figure 02_image1111
 A 638 --
281
Figure 02_image1113
 A 626 -- 282
Figure 02_image1115
 A 640 --
283
Figure 02_image1117
 A 530 -- 284
Figure 02_image1119
 A 529 --
285
Figure 02_image1121
 A 652 -- 286
Figure 02_image1123
 A 652 --
287
Figure 02_image1125
 A 628 -- 288
Figure 02_image1127
 A 654 --
289
Figure 02_image1129
 A 642 -- 290
Figure 02_image1131
 A 656 --
291
Figure 02_image1133
 A 546 -- 292
Figure 02_image1135
 A 545 --
293
Figure 02_image1137
 A 668 -- 294
Figure 02_image1139
 A 668 --
295
Figure 02_image1141
 A 628 -- 296
Figure 02_image1143
 A 654 --
297
Figure 02_image1145
 A 642 -- 298
Figure 02_image1147
 A 656 --
299
Figure 02_image1149
 A 546 -- 300
Figure 02_image1151
 A 545 --
301
Figure 02_image1153
 A 668 -- 302
Figure 02_image1155
 A 668 --
303
Figure 02_image1157
 A 628 -- 304
Figure 02_image1159
 A 654 --
305
Figure 02_image1161
 A 642 -- 306
Figure 02_image1163
 A 656 --
307
Figure 02_image1165
 A 546 -- 308
Figure 02_image1167
 A 545 --
309
Figure 02_image1169
 A 668 -- 310
Figure 02_image1171
 A 668 --
311
Figure 02_image1173
 A 642 -- 312
Figure 02_image1175
 A 668 --
313
Figure 02_image1177
 A 656 -- 314
Figure 02_image1179
 A 670 --
315
Figure 02_image1181
 A 560 -- 316
Figure 02_image1183
 A 559 --
317
Figure 02_image1185
 A 682 -- 318
Figure 02_image1187
 A 682 --
319
Figure 02_image1189
 A 642 -- 320
Figure 02_image1191
 A 668 --
321
Figure 02_image1193
 A 656 -- 322
Figure 02_image1195
 A 670 --
323
Figure 02_image1197
 A 560 -- 324
Figure 02_image1199
 A 559 --
325
Figure 02_image1201
 A 682 -- 326
Figure 02_image1203
 A 682 --
327
Figure 02_image1205
 A 601 -- 328
Figure 02_image1207
 A 615 --
329
Figure 02_image1209
 A 505 -- 330
Figure 02_image1211
 A 504 --
331
Figure 02_image1213
 A 601 -- 332
Figure 02_image1215
 A 615 --
333
Figure 02_image1217
 A 505 -- 334
Figure 02_image1219
 A 504 --
335
Figure 02_image1221
 A 601 -- 336
Figure 02_image1223
 A 615 --
337
Figure 02_image1225
 A 505 -- 338
Figure 02_image1227
 A 504 --
339
Figure 02_image1229
 A 615 -- 340
Figure 02_image1231
 A 629 --
341
Figure 02_image1233
 A 519 -- 342
Figure 02_image1235
 A 518 --
343
Figure 02_image1237
 A 615 -- 344
Figure 02_image1239
 A 629 --
345
Figure 02_image1241
 A 519 -- 346
Figure 02_image1243
 A 518 --
347
Figure 02_image1245
 A 615 -- 348
Figure 02_image1247
 A 629 --
349
Figure 02_image1249
 A 519 -- 350
Figure 02_image1251
 A 518 --
351
Figure 02_image1253
 A 615 -- 352
Figure 02_image1255
 A 629 --
353
Figure 02_image1257
 A 519 -- 354
Figure 02_image1259
 A 518 --
355
Figure 02_image1261
 A 615 -- 356
Figure 02_image1263
 A 629 --
357
Figure 02_image1265
 A 519 -- 358
Figure 02_image1267
 A 518 --
359
Figure 02_image1269
 A 629 -- 360
Figure 02_image1271
 A 643 --
361
Figure 02_image1273
 A 533 -- 362
Figure 02_image1275
 A 532 --
363
Figure 02_image1277
 A 629 -- 364
Figure 02_image1279
 A 643 --
365
Figure 02_image1281
 A 533 -- 366
Figure 02_image1283
 A 532 --
367
Figure 02_image1285
 A 612 -- 368
Figure 02_image1287
 A 626 --
369
Figure 02_image1289
 A 516 -- 370
Figure 02_image1291
 A 515 --
371
Figure 02_image1293
 A 612 -- 372
Figure 02_image1295
 A 626 --
373
Figure 02_image1297
 A 516 -- 374
Figure 02_image1299
 A 515 --
375
Figure 02_image1301
 A 612 -- 376
Figure 02_image1303
 A 626 --
377
Figure 02_image1305
 A 516 -- 378
Figure 02_image1307
 A 515 --
379
Figure 02_image1309
 A 626 -- 380
Figure 02_image1311
 A 640 --
381
Figure 02_image1313
 A 530 -- 382
Figure 02_image1315
 A 529 --
383
Figure 02_image1317
 A 626 -- 384
Figure 02_image1319
 A 640 --
385
Figure 02_image1321
 A 530 -- 386
Figure 02_image1323
 A 529 --
387
Figure 02_image1325
 A 626 -- 388
Figure 02_image1327
 A 640 --
389
Figure 02_image1329
 A 530 -- 390
Figure 02_image1331
 A 529 --
391
Figure 02_image1333
 A 626 -- 392
Figure 02_image1335
 A 640 --
393
Figure 02_image1337
 A 530 -- 394
Figure 02_image1339
 A 529 --
395
Figure 02_image1341
 A 626 -- 396
Figure 02_image1343
 A 640 --
397
Figure 02_image1345
 A 530 -- 398
Figure 02_image1347
 A 529 --
399
Figure 02_image1349
 A 640 -- 400
Figure 02_image1351
 A 654 --
401
Figure 02_image1353
 A 544 -- 402
Figure 02_image1355
 A 543 --
403
Figure 02_image1357
 A 640 -- 404
Figure 02_image1359
 A 654 --
405
Figure 02_image1361
 A 544 -- 406
Figure 02_image1363
 A 543 --
407
Figure 02_image1365
 A 573 -- 408
Figure 02_image1367
 A 573 --
409
Figure 02_image1369
 A 586 -- 410
Figure 02_image1371
 A 602 1.534
411
Figure 02_image1373
 A 606 -- 412
Figure 02_image1375
 A 590 --
413
Figure 02_image1377
 A 586 -- 414
Figure 02_image1379
 A 586 --
415
Figure 02_image1381
 A 606 -- 416
Figure 02_image1383
 A 590 --
417
Figure 02_image1385
 A 591 1.347 418
Figure 02_image1387
 A 627 --
419
Figure 02_image1389
 A 645 1.608 420
Figure 02_image1391
 A 603 1.516
421
Figure 02_image1393
 A 601 1.491 422
Figure 02_image1395
 A 605 --
423
Figure 02_image1397
 A 641 -- 424
Figure 02_image1399
 A 659 --
425
Figure 02_image1401
 A 617 -- 426
Figure 02_image1403
 A 615 --
427
Figure 02_image1405
 A 617 -- 428
Figure 02_image1407
 A 653 --
429
Figure 02_image1409
 A 671 -- 430
Figure 02_image1411
 A 629 --
431
Figure 02_image1413
 A 627 -- 432
Figure 02_image1415
 A 631 --
433
Figure 02_image1417
 A 667 -- 434
Figure 02_image1419
 A 685 --
435
Figure 02_image1421
 A 643 -- 436
Figure 02_image1423
 A 641 --
437
Figure 02_image1425
 A 617 -- 438
Figure 02_image1427
 A 653 --
439
Figure 02_image1429
 A 671 -- 440
Figure 02_image1431
 A 629 --
441
Figure 02_image1433
 A 627 -- 442
Figure 02_image1435
 A 631 --
443
Figure 02_image1437
 A 667 -- 444
Figure 02_image1439
 A 685 --
445
Figure 02_image1441
 A 643 -- 446
Figure 02_image1443
 A 641 --
447
Figure 02_image1445
 A 594 -- 448
Figure 02_image1447
 A 608 --
449
Figure 02_image1449
 A 592 -- 450
Figure 02_image1451
 A 592 --
451
Figure 02_image1453
 A 606 -- 452
Figure 02_image1455
 A 606 --
453
Figure 02_image1457
 A 608 -- 454
Figure 02_image1459
 A 608 --
455
Figure 02_image1461
 A 606 -- 456
Figure 02_image1463
 A 606 --
457
Figure 02_image1465
 A 620 -- 458
Figure 02_image1467
 A 620 --
459
Figure 02_image1469
 A 622 -- 460
Figure 02_image1471
 A 622 --
461
Figure 02_image1473
 A 592 -- 462
Figure 02_image1475
 A 592 --
463
Figure 02_image1477
 A 606 -- 464
Figure 02_image1479
 A 606 --
465
Figure 02_image1481
 A 608 -- 466
Figure 02_image1483
 A 608 --
467
Figure 02_image1485
 A 606 -- 468
Figure 02_image1487
 A 606 --
469
Figure 02_image1489
 A 620 -- 470
Figure 02_image1491
 A 620 --
471
Figure 02_image1493
 A 622 -- 472
Figure 02_image1495
 A 622 --
473
Figure 02_image1497
 A 576 -- 474
Figure 02_image1499
 A 576 --
475
Figure 02_image1501
 A 590 -- 476
Figure 02_image1503
 A 590 --
477
Figure 02_image1505
 A 592 -- 478
Figure 02_image1507
 A 592 --
479
Figure 02_image1509
 A 590 -- 480
Figure 02_image1511
 A 590 --
481
Figure 02_image1513
 A 604 -- 482
Figure 02_image1515
 A 604 --
483
Figure 02_image1517
 A 606 -- 484
Figure 02_image1519
 A 606 --
485
Figure 02_image1521
 A 576 -- 486
Figure 02_image1523
 A 576 --
487
Figure 02_image1525
 A 590 -- 488
Figure 02_image1527
 A 590 --
489
Figure 02_image1529
 A 592 -- 490
Figure 02_image1531
 A 592 --
491
Figure 02_image1533
 A 590 -- 492
Figure 02_image1535
 A 590 --
493
Figure 02_image1537
 A 604 -- 494
Figure 02_image1539
 A 604 --
495
Figure 02_image1541
 A 606 -- 496
Figure 02_image1543
 A 606 --
497
Figure 02_image1545
 A 575 -- 498
Figure 02_image1547
 A 589 --
499
Figure 02_image1549
 A 589 -- 500
Figure 02_image1551
 A 603 --
501
Figure 02_image1553
 A 591 -- 502
Figure 02_image1555
 A 605 --
503
Figure 02_image1557
 A 601 1.384 504
Figure 02_image1559
 A 603 1.320
505
Figure 02_image1561
 A 615 -- 506
Figure 02_image1563
 A 617 --
507
Figure 02_image1565
 A 639 -- 508
Figure 02_image1567
 A 657 --
509
Figure 02_image1569
 A 653 -- 510
Figure 02_image1571
 A 671 --
511
Figure 02_image1573
 A 610 1.357 512
Figure 02_image1575
 A 611 1.235
513
Figure 02_image1577
 A 624 1.459 514
Figure 02_image1579
 A 625 1.337
515
Figure 02_image1581
 A 638 1.465 516
Figure 02_image1583
 A 639 1.325
517
Figure 02_image1585
 A 640 -- 518
Figure 02_image1587
 A 641 --
519
Figure 02_image1589
 A 628 1.505 520
Figure 02_image1591
 A 629 --
521
Figure 02_image1593
 A 568 1.439 522
Figure 02_image1595
 A 566 1.473
523
Figure 02_image1597
 A 580 -- 524
Figure 02_image1599
 A 594 --
525
Figure 02_image1601
 A 596 1.288 526
Figure 02_image1603
 A 624 1.356
527
Figure 02_image1605
 A 622 1.437 528
Figure 02_image1607
 A 598 1.372
529
Figure 02_image1609
 A 610 1.469 530
Figure 02_image1611
 A 586 --
531
Figure 02_image1613
 A 584 -- 532
Figure 02_image1615
 A 598 --
533
Figure 02_image1617
 A 612 --- 534
Figure 02_image1619
 A 614 --
535
Figure 02_image1621
 A 642 -- 536
Figure 02_image1623
 A 640 --
537
Figure 02_image1625
 A 616 -- 538
Figure 02_image1627
 A 611 1.168
539
Figure 02_image1629
 A 611 -- 540
Figure 02_image1631
 A 611 1.232
541
Figure 02_image1633
 A 612 -- 542
Figure 02_image1635
 A 612 --
543
Figure 02_image1637
 A 612 -- 544
Figure 02_image1639
 A 629 --
545
Figure 02_image1641
 A 629 -- 546
Figure 02_image1643
 A 629 --
547
Figure 02_image1645
 A 630 -- 548
Figure 02_image1647
 A 630 --
549
Figure 02_image1649
 A 630 -- 550
Figure 02_image1651
 A 569 --
551
Figure 02_image1653
 A 569 -- 552
Figure 02_image1655
 A 569 --
553
Figure 02_image1657
 A 570 -- 554
Figure 02_image1659
 A 570 --
555
Figure 02_image1661
 A 570 -- 556
Figure 02_image1663
 A 567 --
557
Figure 02_image1665
 A 567 -- 558
Figure 02_image1667
 A 567 --
559
Figure 02_image1669
 A 568 -- 560
Figure 02_image1671
 A 568 --
561
Figure 02_image1673
 A 568 -- 562
Figure 02_image1675
 A 625 --
563
Figure 02_image1677
 A 625 -- 564
Figure 02_image1679
 A 625 --
565
Figure 02_image1681
 A 626 -- 566
Figure 02_image1683
 A 626 --
567
Figure 02_image1685
 A 626 -- 568
Figure 02_image1687
 A 597 --
569
Figure 02_image1689
 A 597 -- 570
Figure 02_image1691
 A 597 --
571
Figure 02_image1693
 A 598 -- 572
Figure 02_image1695
 A 598 --
573
Figure 02_image1697
 A 598 -- 574
Figure 02_image1699
 A 623 --
575
Figure 02_image1701
 A 623 -- 576
Figure 02_image1703
 A 623 --
577
Figure 02_image1705
 A 624 -- 578
Figure 02_image1707
 A 624 --
579
Figure 02_image1709
 A 624 -- 580
Figure 02_image1711
 A 628 --
581
Figure 02_image1713
 A 628 -- 582
Figure 02_image1715
 A 628 --
583
Figure 02_image1717
 A 628 -- 584
Figure 02_image1719
 A 628 --
585
Figure 02_image1721
 A 640 -- 586
Figure 02_image1723
 A 640 --
587
Figure 02_image1725
 A 640 -- 588
Figure 02_image1727
 A 640 --
589
Figure 02_image1729
 A 640 -- 590
Figure 02_image1731
 A 612 --
591
Figure 02_image1733
 A 570 -- 592
Figure 02_image1735
 A 568 --
593
Figure 02_image1737
 A 624 -- 594
Figure 02_image1739
 A 582 1.325
595
Figure 02_image1741
 A 600 -- 596
Figure 02_image1743
 A 583 --
597
Figure 02_image1745
 A 583 -- 598
Figure 02_image1747
 A 583 --
599
Figure 02_image1749
 A 583 -- 600
Figure 02_image1751
 A 584 --
601
Figure 02_image1753
 A 584 -- 602
Figure 02_image1755
 A 584 --
603
Figure 02_image1757
 A 600 -- 604
Figure 02_image1759
 A 600 --
605
Figure 02_image1761
 A 600 -- 606
Figure 02_image1763
 A 600 --
607
Figure 02_image1765
 A 600 -- 608
Figure 02_image1767
 A 584 --
609
Figure 02_image1769
 A 569 -- 610
Figure 02_image1771
 A 567 --
611
Figure 02_image1773
 A 530 1.105 612
Figure 02_image1775
 A 587 1.181
613
Figure 02_image1777
 A 587 1.347 614
Figure 02_image1779
 A 547 1.294
615
Figure 02_image1781
 A 547 1.292 616
Figure 02_image1783
 A 519 1.340
617
Figure 02_image1785
 A 561 1.337 618
Figure 02_image1787
 A 561 1.297
619
Figure 02_image1789
 A 579 -- 620
Figure 02_image1791
 A 565 --
621
Figure 02_image1793
 A 565 -- 622
Figure 02_image1795
 A 537 --
623
Figure 02_image1797
 A 579 -- 624
Figure 02_image1799
 A 579 --
625
Figure 02_image1801
 A 517 -- 626
Figure 02_image1803
 A 535 --
627
Figure 02_image1805
 A 573 1.455 628
Figure 02_image1807
 A 591 --
629
Figure 02_image1809
 A 623 -- 630
Figure 02_image1811
 A 641 --
631
Figure 02_image1813
 A 528 -- 632
Figure 02_image1815
 A 546 --
633
Figure 02_image1817
 A 584 -- 634
Figure 02_image1819
 A 602 --
635
Figure 02_image1821
 A 548 -- 636
Figure 02_image1823
 A 544 --
637
Figure 02_image1825
 A 562 -- 638
Figure 02_image1827
 A 542 --
639
Figure 02_image1829
 A 560 -- 640
Figure 02_image1831
 A 556 --
641
Figure 02_image1833
 A 574 -- 642
Figure 02_image1835
 A 558 --
643
Figure 02_image1837
 A 576 -- 644
Figure 02_image1839
 A 558 --
645
Figure 02_image1841
 A 576 --          
表 1
時間(min) 流速(mL/min) 流動相B% 流動相A%
0 2 5 95
0.1 2 5 95
2.2 2 95 5
2.7 2 95 5
2.71 2 5 95
3.2 2 5 95
表 2
化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 ) 化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 )
1
Figure 02_image565
 A 571 1.409 2
Figure 02_image567
 B 571 1.278
3
Figure 02_image569
 B 556 1.597 4
Figure 02_image571
 B 585 1.198
5
Figure 02_image573
 A 563 1.507 6
Figure 02_image575
 B 564 1.649
7
Figure 02_image577
 A 584 1.186 8
Figure 02_image579
 A 585 1.434
9
Figure 02_image581
 A 555 1.464 10
Figure 02_image583
 A 515 1.463
11
Figure 02_image585
 A 529 1.489 12
Figure 02_image587
 B 572 1.461
13
Figure 02_image589
 A 501 1.350 14
Figure 02_image591
 B 530 1.521
15
Figure 02_image593
 A 555 1.560 16
Figure 02_image595
 B 558 1.430
17
Figure 02_image597
 A 541 1.542 18
Figure 02_image599
 B 558 1.450
          20
Figure 02_image601
 B 571 1.310
21
Figure 02_image603
 A 559 1.350 22
Figure 02_image605
 A 573 1.337
23
Figure 02_image607
 A 585 1.356 24
Figure 02_image609
 A 585 1.338
25
Figure 02_image611
 B 570 1.551 26
Figure 02_image613
 A 531 --
27
Figure 02_image615
 A 607 1.325 28
Figure 02_image617
 A 558 1.147
29
Figure 02_image619
 A 557 1.289 30
Figure 02_image621
 A 541 1.491
31
Figure 02_image623
 A 557 1.325 32
Figure 02_image625
 A 557 1.310
33
Figure 02_image627
 A 527 1.389 34
Figure 02_image629
 A 571 1.358
35
Figure 02_image631
 A 585 1.425 36
Figure 02_image633
 A 531 1.332
37
Figure 02_image635
 A 572 1.122 38
Figure 02_image637
 A 572 1.475
39
Figure 02_image639
 A 572 1.104 40
Figure 02_image641
 A 575 1.244
41
Figure 02_image643
 A 586 -- 42
Figure 02_image645
 A 601 1.457
43
Figure 02_image647
 A 587 1.378 44
Figure 02_image649
 A 649 1.396
45
Figure 02_image651
 A 601 1.479 46
Figure 02_image653
 A 649 1.402
47
Figure 02_image655
 A 596 1.401 48
Figure 02_image657
 A 619 1.342
49
Figure 02_image659
 A 575 1.294 50
Figure 02_image661
 A 575 1.268
51
Figure 02_image663
 A 601 1.407 52
Figure 02_image665
 A 596 --
53
Figure 02_image667
 A 596 1.368 54
Figure 02_image669
 A 593 1.272
55
Figure 02_image671
 A 561 1.254 56
Figure 02_image673
 A 586 1.094
57
Figure 02_image675
 A 561 1.199 58
Figure 02_image677
 A 602 --
59
Figure 02_image679
 A 516 1.523 60
Figure 02_image681
 A 589 --
61
Figure 02_image683
 A 605 -- 62
Figure 02_image685
 A 589 1.400
63
Figure 02_image687
 A 605 1.423 64
Figure 02_image689
 A 589 1.438
65
Figure 02_image691
 A 605 1.532 66
Figure 02_image693
 A 557 --
67
Figure 02_image695
 A 602 -- 68
Figure 02_image697
 A 562 1.047
69
Figure 02_image699
 A 561 1.331 70
Figure 02_image701
 A 557 1.350
71
Figure 02_image703
 A 601 1.260 72
Figure 02_image705
 A 573 1.236
73
Figure 02_image707
 A 602 1.137 74
Figure 02_image709
 A 586 --
75
Figure 02_image711
 A 626 -- 76
Figure 02_image713
 A 626 --
77
Figure 02_image715
 A 626 -- 78
Figure 02_image717
 A 614 --
79
Figure 02_image719
 A 614 -- 80
Figure 02_image721
 A 614 --
81
Figure 02_image723
 A 614 -- 82
Figure 02_image725
 A 621 1.370
83
Figure 02_image727
 A 602 1.058 84
Figure 02_image729
 A 601 1.241
85
Figure 02_image731
 A 614 1.235 86
Figure 02_image733
 A 614 1.268
87
Figure 02_image735
 A 614 1.292 88
Figure 02_image737
 A 578 1.272
89
Figure 02_image739
 A 615 1.396 90
Figure 02_image741
 A 664 1.312
91
Figure 02_image743
 A 561 1.332 92
Figure 02_image745
 A 586 1.204
93
Figure 02_image747
 A 577 1.350 94
Figure 02_image749
 A 577 1.399
95
Figure 02_image751
 A 586 1.220 96
Figure 02_image753
 A 587 1.225
97
Figure 02_image755
 A 574 1.313 98
Figure 02_image757
 A 586 1.295
99
Figure 02_image759
 A 587 1.336 100
Figure 02_image761
 A 628 1.314
101
Figure 02_image763
 A 621 1.446 102
Figure 02_image765
 A 590 1.058
103
Figure 02_image767
 A 590 1.270 104
Figure 02_image769
 A 615 1.398
105
Figure 02_image771
 A 621 1.393 106
Figure 02_image773
 A 602 1.194
107
Figure 02_image775
 A 664 1.296 108
Figure 02_image777
 A 586 1.109
109
Figure 02_image779
 A 576 1.084 110
Figure 02_image781
 A 575 1.159
111
Figure 02_image783
 A 575 1.308 112
Figure 02_image1918
 A 601 1.363
113
Figure 02_image787
 A 601 1.456 114
Figure 02_image789
 A 586 1.226
115
Figure 02_image791
 A 599 1.491          
117
Figure 02_image793
 A 572 1.107 118
Figure 02_image795
 A 489 1.201
119
Figure 02_image797
 A 391 1.499 120
Figure 02_image799
 A 503 1.156
121
Figure 02_image801
 A 488 1.219 122
Figure 02_image803
 A 590 1.222
123
Figure 02_image805
 A 490 1.114 124
Figure 02_image807
 A 434 1.232
125
Figure 02_image809
 A 571 1.387 126
Figure 02_image811
 A 591 1.344
127
Figure 02_image813
 A 543 0.982 128
Figure 02_image815
 A 557 1.192
129
Figure 02_image817
 A 529 -- 130
Figure 02_image819
 A 529 --
131
Figure 02_image821
 B 601 1.138 132
Figure 02_image823
 B 601 1.140
133
Figure 02_image825
 A 571 1.371 134
Figure 02_image827
 A 571 --
135
Figure 02_image829
 A 571 1.397 140
Figure 02_image831
 A 585 1.443
141
Figure 02_image833
 A 585 1.401 142
Figure 02_image835
 A 585 1.443
143
Figure 02_image837
 A 585 1.436 144
Figure 02_image839
 A 585 1.389
145
Figure 02_image841
 A 589 -- 146
Figure 02_image843
 A 612 --
147
Figure 02_image845
 A 504 -- 148
Figure 02_image847
 A 503 1.204
149
Figure 02_image849
 A 626 -- 150
Figure 02_image851
 A 626 --
151
Figure 02_image853
 A 503 -- 152
Figure 02_image855
 A 504 --
153
Figure 02_image857
 A 603 -- 154
Figure 02_image859
 A 600 --
155
Figure 02_image861
 A 626 -- 156
Figure 02_image863
 A 518 --
157
Figure 02_image865
 A 517 -- 158
Figure 02_image867
 A 640 --
159
Figure 02_image869
 A 640 -- 160
Figure 02_image871
 A 603 --
161
Figure 02_image873
 A 600 1.181 162
Figure 02_image875
 A 626 --
163
Figure 02_image877
 A 518 -- 164
Figure 02_image879
 A 517 --
165
Figure 02_image881
 A 640 -- 166
Figure 02_image883
 A 640 --
167
Figure 02_image885
 A 617 -- 168
Figure 02_image887
 A 614 --
169
Figure 02_image889
 A 640 -- 170
Figure 02_image891
 A 532 --
171
Figure 02_image893
 A 531 -- 172
Figure 02_image895
 A 654 --
173
Figure 02_image897
 A 654 -- 174
Figure 02_image899
 A 478 1.436
175
Figure 02_image901
 A 479 -- 176
Figure 02_image903
 A 578 --
177
Figure 02_image905
 A 575 1.439 178
Figure 02_image907
 A 601 --
179
Figure 02_image909
 A 493 -- 180
Figure 02_image911
 A 492 --
181
Figure 02_image913
 A 615 -- 182
Figure 02_image915
 A 615 --
183
Figure 02_image917
 A 592 -- 184
Figure 02_image919
 A 589 1.398
185
Figure 02_image921
 A 615 -- 186
Figure 02_image923
 A 507 --
187
Figure 02_image925
 A 506 -- 188
Figure 02_image927
 A 629 --
189
Figure 02_image929
 A 629 -- 190
Figure 02_image931
 A 492 --
191
Figure 02_image933
 A 493 -- 192
Figure 02_image935
 A 592 --
193
Figure 02_image937
 A 589 -- 194
Figure 02_image939
 A 615 --
195
Figure 02_image941
 A 507 -- 196
Figure 02_image943
 A 506 --
197
Figure 02_image945
 A 629 -- 198
Figure 02_image947
 A 629 --
199
Figure 02_image949
 A 606 -- 200
Figure 02_image951
 A 603 --
201
Figure 02_image953
 A 629 -- 202
Figure 02_image955
 A 521 --
203
Figure 02_image957
 A 520 -- 204
Figure 02_image959
 A 643 --
205
Figure 02_image961
 A 643 -- 206
Figure 02_image963
 A 575 --
207
Figure 02_image965
 A 598 -- 208
Figure 02_image967
 A 490 --
209
Figure 02_image969
 A 489 -- 210
Figure 02_image971
 A 612 --
211
Figure 02_image973
 A 612 -- 212
Figure 02_image975
 A 589 --
213
Figure 02_image977
 A 586 1.580 214
Figure 02_image979
 A 612 --
215
Figure 02_image981
 A 504 -- 216
Figure 02_image983
 A 503 --
217
Figure 02_image985
 A 626 -- 218
Figure 02_image987
 A 626 --
219
Figure 02_image989
 A 603 -- 220
Figure 02_image991
 A 600 --
221
Figure 02_image993
 A 626 -- 222
Figure 02_image995
 A 518 --
223
Figure 02_image997
 A 517 -- 224
Figure 02_image999
 A 640 --
225
Figure 02_image1001
 A 640 -- 226
Figure 02_image1003
 A 605 --
227
Figure 02_image1005
 A 602 -- 228
Figure 02_image1007
 A 628 --
229
Figure 02_image1009
 A 520 -- 230
Figure 02_image1011
 A 519 --
231
Figure 02_image1013
 A 642 -- 232
Figure 02_image1015
 A 642 --
233
Figure 02_image1017
 A 619 -- 234
Figure 02_image1019
 A 616 --
235
Figure 02_image1021
 A 642 -- 236
Figure 02_image1023
 A 534 --
237
Figure 02_image1025
 A 533 -- 238
Figure 02_image1027
 A 656 --
239
Figure 02_image1029
 A 656 -- 240
Figure 02_image1031
 A 633 --
241
Figure 02_image1033
 A 630 -- 242
Figure 02_image1035
 A 656 --
243
Figure 02_image1037
 A 548 -- 244
Figure 02_image1039
 A 547 --
245
Figure 02_image1041
 A 670 -- 246
Figure 02_image1043
 A 670 --
247
Figure 02_image1045
 A 598 -- 248
Figure 02_image1047
 A 624 --
249
Figure 02_image1049
 A 612 -- 250
Figure 02_image1051
 A 626 --
251
Figure 02_image1053
 A 516 -- 252
Figure 02_image1055
 A 515 --
253
Figure 02_image1057
 A 638 -- 254
Figure 02_image1059
 A 638 --
255
Figure 02_image1061
 A 598 -- 256
Figure 02_image1063
 A 624 --
257
Figure 02_image1065
 A 612 -- 258
Figure 02_image1067
 A 626 --
259
Figure 02_image1069
 A 516 -- 260
Figure 02_image1071
 A 515 --
261
Figure 02_image1073
 A 638 -- 262
Figure 02_image1075
 A 638 --
263
Figure 02_image1077
 A 598 -- 264
Figure 02_image1079
 A 624 --
265
Figure 02_image1081
 A 612 -- 266
Figure 02_image1083
 A 626 --
267
Figure 02_image1085
 A 516 -- 268
Figure 02_image1087
 A 515 --
269
Figure 02_image1089
 A 638 -- 270
Figure 02_image1091
 A 638 --
271
Figure 02_image1093
 A 612 -- 272
Figure 02_image1095
 A 638 --
273
Figure 02_image1097
 A 626 -- 274
Figure 02_image1099
 A 640 --
275
Figure 02_image1101
 A 530 -- 276
Figure 02_image1103
 A 529 --
277
Figure 02_image1105
 A 652 -- 278
Figure 02_image1107
 A 652 --
279
Figure 02_image1109
 A 612 -- 280
Figure 02_image1111
 A 638 --
281
Figure 02_image1113
 A 626 -- 282
Figure 02_image1115
 A 640 --
283
Figure 02_image1117
 A 530 -- 284
Figure 02_image1119
 A 529 --
285
Figure 02_image1121
 A 652 -- 286
Figure 02_image1123
 A 652 --
287
Figure 02_image1125
 A 628 -- 288
Figure 02_image1127
 A 654 --
289
Figure 02_image1129
 A 642 -- 290
Figure 02_image1131
 A 656 --
291
Figure 02_image1133
 A 546 -- 292
Figure 02_image1135
 A 545 --
293
Figure 02_image1137
 A 668 -- 294
Figure 02_image1139
 A 668 --
295
Figure 02_image1141
 A 628 -- 296
Figure 02_image1143
 A 654 --
297
Figure 02_image1145
 A 642 -- 298
Figure 02_image1147
 A 656 --
299
Figure 02_image1149
 A 546 -- 300
Figure 02_image1151
 A 545 --
301
Figure 02_image1153
 A 668 -- 302
Figure 02_image1155
 A 668 --
303
Figure 02_image1157
 A 628 -- 304
Figure 02_image1159
 A 654 --
305
Figure 02_image1161
 A 642 -- 306
Figure 02_image1163
 A 656 --
307
Figure 02_image1165
 A 546 -- 308
Figure 02_image1167
 A 545 --
309
Figure 02_image1169
 A 668 -- 310
Figure 02_image1171
 A 668 --
311
Figure 02_image1173
 A 642 -- 312
Figure 02_image1175
 A 668 --
313
Figure 02_image1177
 A 656 -- 314
Figure 02_image1179
 A 670 --
315
Figure 02_image1181
 A 560 -- 316
Figure 02_image1183
 A 559 --
317
Figure 02_image1185
 A 682 -- 318
Figure 02_image1187
 A 682 --
319
Figure 02_image1189
 A 642 -- 320
Figure 02_image1191
 A 668 --
321
Figure 02_image1193
 A 656 -- 322
Figure 02_image1195
 A 670 --
323
Figure 02_image1197
 A 560 -- 324
Figure 02_image1199
 A 559 --
325
Figure 02_image1201
 A 682 -- 326
Figure 02_image1203
 A 682 --
327
Figure 02_image1205
 A 601 -- 328
Figure 02_image1207
 A 615 --
329
Figure 02_image1209
 A 505 -- 330
Figure 02_image1211
 A 504 --
331
Figure 02_image1213
 A 601 -- 332
Figure 02_image1215
 A 615 --
333
Figure 02_image1217
 A 505 -- 334
Figure 02_image1219
 A 504 --
335
Figure 02_image1221
 A 601 -- 336
Figure 02_image1223
 A 615 --
337
Figure 02_image1225
 A 505 -- 338
Figure 02_image1227
 A 504 --
339
Figure 02_image1229
 A 615 -- 340
Figure 02_image1231
 A 629 --
341
Figure 02_image1233
 A 519 -- 342
Figure 02_image1235
 A 518 --
343
Figure 02_image1237
 A 615 -- 344
Figure 02_image1239
 A 629 --
345
Figure 02_image1241
 A 519 -- 346
Figure 02_image1243
 A 518 --
347
Figure 02_image1245
 A 615 -- 348
Figure 02_image1247
 A 629 --
349
Figure 02_image1249
 A 519 -- 350
Figure 02_image1251
 A 518 --
351
Figure 02_image1253
 A 615 -- 352
Figure 02_image1255
 A 629 --
353
Figure 02_image1257
 A 519 -- 354
Figure 02_image1259
 A 518 --
355
Figure 02_image1261
 A 615 -- 356
Figure 02_image1263
 A 629 --
357
Figure 02_image1265
 A 519 -- 358
Figure 02_image1267
 A 518 --
359
Figure 02_image1269
 A 629 -- 360
Figure 02_image1271
 A 643 --
361
Figure 02_image1273
 A 533 -- 362
Figure 02_image1275
 A 532 --
363
Figure 02_image1277
 A 629 -- 364
Figure 02_image1279
 A 643 --
365
Figure 02_image1281
 A 533 -- 366
Figure 02_image1283
 A 532 --
367
Figure 02_image1285
 A 612 -- 368
Figure 02_image1287
 A 626 --
369
Figure 02_image1289
 A 516 -- 370
Figure 02_image1291
 A 515 --
371
Figure 02_image1293
 A 612 -- 372
Figure 02_image1295
 A 626 --
373
Figure 02_image1297
 A 516 -- 374
Figure 02_image1299
 A 515 --
375
Figure 02_image1301
 A 612 -- 376
Figure 02_image1303
 A 626 --
377
Figure 02_image1305
 A 516 -- 378
Figure 02_image1307
 A 515 --
379
Figure 02_image1309
 A 626 -- 380
Figure 02_image1311
 A 640 --
381
Figure 02_image1313
 A 530 -- 382
Figure 02_image1315
 A 529 --
383
Figure 02_image1317
 A 626 -- 384
Figure 02_image1319
 A 640 --
385
Figure 02_image1321
 A 530 -- 386
Figure 02_image1323
 A 529 --
387
Figure 02_image1325
 A 626 -- 388
Figure 02_image1327
 A 640 --
389
Figure 02_image1329
 A 530 -- 390
Figure 02_image1331
 A 529 --
391
Figure 02_image1333
 A 626 -- 392
Figure 02_image1335
 A 640 --
393
Figure 02_image1337
 A 530 -- 394
Figure 02_image1339
 A 529 --
395
Figure 02_image1341
 A 626 -- 396
Figure 02_image1343
 A 640 --
397
Figure 02_image1345
 A 530 -- 398
Figure 02_image1347
 A 529 --
399
Figure 02_image1349
 A 640 -- 400
Figure 02_image1351
 A 654 --
401
Figure 02_image1353
 A 544 -- 402
Figure 02_image1355
 A 543 --
403
Figure 02_image1357
 A 640 -- 404
Figure 02_image1359
 A 654 --
405
Figure 02_image1361
 A 544 -- 406
Figure 02_image1363
 A 543 --
407
Figure 02_image1365
 A 573 -- 408
Figure 02_image1367
 A 573 --
409
Figure 02_image1369
 A 586 -- 410
Figure 02_image1371
 A 602 1.534
411
Figure 02_image1373
 A 606 -- 412
Figure 02_image1375
 A 590 --
413
Figure 02_image1377
 A 586 -- 414
Figure 02_image1379
 A 586 --
415
Figure 02_image1381
 A 606 -- 416
Figure 02_image1383
 A 590 --
417
Figure 02_image1385
 A 591 1.347 418
Figure 02_image1387
 A 627 --
419
Figure 02_image1389
 A 645 1.608 420
Figure 02_image1391
 A 603 1.516
421
Figure 02_image1393
 A 601 1.491 422
Figure 02_image1395
 A 605 --
423
Figure 02_image1397
 A 641 -- 424
Figure 02_image1399
 A 659 --
425
Figure 02_image1401
 A 617 -- 426
Figure 02_image1403
 A 615 --
427
Figure 02_image1405
 A 617 -- 428
Figure 02_image1407
 A 653 --
429
Figure 02_image1409
 A 671 -- 430
Figure 02_image1411
 A 629 --
431
Figure 02_image1413
 A 627 -- 432
Figure 02_image1415
 A 631 --
433
Figure 02_image1417
 A 667 -- 434
Figure 02_image1419
 A 685 --
435
Figure 02_image1421
 A 643 -- 436
Figure 02_image1423
 A 641 --
437
Figure 02_image1425
 A 617 -- 438
Figure 02_image1427
 A 653 --
439
Figure 02_image1429
 A 671 -- 440
Figure 02_image1431
 A 629 --
441
Figure 02_image1433
 A 627 -- 442
Figure 02_image1435
 A 631 --
443
Figure 02_image1437
 A 667 -- 444
Figure 02_image1439
 A 685 --
445
Figure 02_image1441
 A 643 -- 446
Figure 02_image1443
 A 641 --
447
Figure 02_image1445
 A 594 -- 448
Figure 02_image1447
 A 608 --
449
Figure 02_image1449
 A 592 -- 450
Figure 02_image1451
 A 592 --
451
Figure 02_image1453
 A 606 -- 452
Figure 02_image1455
 A 606 --
453
Figure 02_image1457
 A 608 -- 454
Figure 02_image1459
 A 608 --
455
Figure 02_image1461
 A 606 -- 456
Figure 02_image1463
 A 606 --
457
Figure 02_image1465
 A 620 -- 458
Figure 02_image1467
 A 620 --
459
Figure 02_image1469
 A 622 -- 460
Figure 02_image1471
 A 622 --
461
Figure 02_image1473
 A 592 -- 462
Figure 02_image1475
 A 592 --
463
Figure 02_image1477
 A 606 -- 464
Figure 02_image1479
 A 606 --
465
Figure 02_image1481
 A 608 -- 466
Figure 02_image1483
 A 608 --
467
Figure 02_image1485
 A 606 -- 468
Figure 02_image1487
 A 606 --
469
Figure 02_image1489
 A 620 -- 470
Figure 02_image1491
 A 620 --
471
Figure 02_image1493
 A 622 -- 472
Figure 02_image1495
 A 622 --
473
Figure 02_image1497
 A 576 -- 474
Figure 02_image1499
 A 576 --
475
Figure 02_image1501
 A 590 -- 476
Figure 02_image1503
 A 590 --
477
Figure 02_image1505
 A 592 -- 478
Figure 02_image1507
 A 592 --
479
Figure 02_image1509
 A 590 -- 480
Figure 02_image1511
 A 590 --
481
Figure 02_image1513
 A 604 -- 482
Figure 02_image1515
 A 604 --
483
Figure 02_image1517
 A 606 -- 484
Figure 02_image1519
 A 606 --
485
Figure 02_image1521
 A 576 -- 486
Figure 02_image1523
 A 576 --
487
Figure 02_image1525
 A 590 -- 488
Figure 02_image1527
 A 590 --
489
Figure 02_image1529
 A 592 -- 490
Figure 02_image1531
 A 592 --
491
Figure 02_image1533
 A 590 -- 492
Figure 02_image1535
 A 590 --
493
Figure 02_image1537
 A 604 -- 494
Figure 02_image1539
 A 604 --
495
Figure 02_image1541
 A 606 -- 496
Figure 02_image1543
 A 606 --
497
Figure 02_image1545
 A 575 -- 498
Figure 02_image1547
 A 589 --
499
Figure 02_image1549
 A 589 -- 500
Figure 02_image1551
 A 603 --
501
Figure 02_image1553
 A 591 -- 502
Figure 02_image1555
 A 605 --
503
Figure 02_image1557
 A 601 1.384 504
Figure 02_image1559
 A 603 1.320
505
Figure 02_image1561
 A 615 -- 506
Figure 02_image1563
 A 617 --
507
Figure 02_image1565
 A 639 -- 508
Figure 02_image1567
 A 657 --
509
Figure 02_image1569
 A 653 -- 510
Figure 02_image1571
 A 671 --
511
Figure 02_image1573
 A 610 1.357 512
Figure 02_image1575
 A 611 1.235
513
Figure 02_image1577
 A 624 1.459 514
Figure 02_image1579
 A 625 1.337
515
Figure 02_image1581
 A 638 1.465 516
Figure 02_image1583
 A 639 1.325
517
Figure 02_image1585
 A 640 -- 518
Figure 02_image1587
 A 641 --
519
Figure 02_image1589
 A 628 1.505 520
Figure 02_image1591
 A 629 --
521
Figure 02_image1593
 A 568 1.439 522
Figure 02_image1595
 A 566 1.473
523
Figure 02_image1597
 A 580 -- 524
Figure 02_image1599
 A 594 --
525
Figure 02_image1601
 A 596 1.288 526
Figure 02_image1603
 A 624 1.356
527
Figure 02_image1605
 A 622 1.437 528
Figure 02_image1607
 A 598 1.372
529
Figure 02_image1609
 A 610 1.469 530
Figure 02_image1611
 A 586 --
531
Figure 02_image1613
 A 584 -- 532
Figure 02_image1615
 A 598 --
533
Figure 02_image1617
 A 612 --- 534
Figure 02_image1619
 A 614 --
535
Figure 02_image1621
 A 642 -- 536
Figure 02_image1623
 A 640 --
537
Figure 02_image1625
 A 616 -- 538
Figure 02_image1627
 A 611 1.168
539
Figure 02_image1629
 A 611 -- 540
Figure 02_image1631
 A 611 1.232
541
Figure 02_image1633
 A 612 -- 542
Figure 02_image1635
 A 612 --
543
Figure 02_image1637
 A 612 -- 544
Figure 02_image1639
 A 629 --
545
Figure 02_image1641
 A 629 -- 546
Figure 02_image1643
 A 629 --
547
Figure 02_image1645
 A 630 -- 548
Figure 02_image1647
 A 630 --
549
Figure 02_image1649
 A 630 -- 550
Figure 02_image1651
 A 569 --
551
Figure 02_image1653
 A 569 -- 552
Figure 02_image1655
 A 569 --
553
Figure 02_image1657
 A 570 -- 554
Figure 02_image1659
 A 570 --
555
Figure 02_image1661
 A 570 -- 556
Figure 02_image1663
 A 567 --
557
Figure 02_image1665
 A 567 -- 558
Figure 02_image1667
 A 567 --
559
Figure 02_image1669
 A 568 -- 560
Figure 02_image1671
 A 568 --
561
Figure 02_image1673
 A 568 -- 562
Figure 02_image1675
 A 625 --
563
Figure 02_image1677
 A 625 -- 564
Figure 02_image1679
 A 625 --
565
Figure 02_image1681
 A 626 -- 566
Figure 02_image1683
 A 626 --
567
Figure 02_image1685
 A 626 -- 568
Figure 02_image1687
 A 597 --
569
Figure 02_image1689
 A 597 -- 570
Figure 02_image1691
 A 597 --
571
Figure 02_image1693
 A 598 -- 572
Figure 02_image1695
 A 598 --
573
Figure 02_image1697
 A 598 -- 574
Figure 02_image1699
 A 623 --
575
Figure 02_image1701
 A 623 -- 576
Figure 02_image1703
 A 623 --
577
Figure 02_image1705
 A 624 -- 578
Figure 02_image1707
 A 624 --
579
Figure 02_image1709
 A 624 -- 580
Figure 02_image1711
 A 628 --
581
Figure 02_image1713
 A 628 -- 582
Figure 02_image1715
 A 628 --
583
Figure 02_image1717
 A 628 -- 584
Figure 02_image1719
 A 628 --
585
Figure 02_image1721
 A 640 -- 586
Figure 02_image1723
 A 640 --
587
Figure 02_image1725
 A 640 -- 588
Figure 02_image1727
 A 640 --
589
Figure 02_image1729
 A 640 -- 590
Figure 02_image1731
 A 612 --
591
Figure 02_image1733
 A 570 -- 592
Figure 02_image1735
 A 568 --
593
Figure 02_image1737
 A 624 -- 594
Figure 02_image1739
 A 582 1.325
595
Figure 02_image1741
 A 600 -- 596
Figure 02_image1743
 A 583 --
597
Figure 02_image1745
 A 583 -- 598
Figure 02_image1747
 A 583 --
599
Figure 02_image1749
 A 583 -- 600
Figure 02_image1751
 A 584 --
601
Figure 02_image1753
 A 584 -- 602
Figure 02_image1755
 A 584 --
603
Figure 02_image1757
 A 600 -- 604
Figure 02_image1759
 A 600 --
605
Figure 02_image1761
 A 600 -- 606
Figure 02_image1763
 A 600 --
607
Figure 02_image1765
 A 600 -- 608
Figure 02_image1767
 A 584 --
609
Figure 02_image1769
 A 569 -- 610
Figure 02_image1771
 A 567 --
611
Figure 02_image1773
 A 530 1.105 612
Figure 02_image1775
 A 587 1.181
613
Figure 02_image1777
 A 587 1.347 614
Figure 02_image1779
 A 547 1.294
615
Figure 02_image1781
 A 547 1.292 616
Figure 02_image1783
 A 519 1.340
617
Figure 02_image1785
 A 561 1.337 618
Figure 02_image1787
 A 561 1.297
619
Figure 02_image1789
 A 579 -- 620
Figure 02_image1791
 A 565 --
621
Figure 02_image1793
 A 565 -- 622
Figure 02_image1795
 A 537 --
623
Figure 02_image1797
 A 579 -- 624
Figure 02_image1799
 A 579 --
625
Figure 02_image1801
 A 517 -- 626
Figure 02_image1803
 A 535 --
627
Figure 02_image1805
 A 573 1.455 628
Figure 02_image1807
 A 591 --
629
Figure 02_image1809
 A 623 -- 630
Figure 02_image1811
 A 641 --
631
Figure 02_image1813
 A 528 -- 632
Figure 02_image1815
 A 546 --
633
Figure 02_image1817
 A 584 -- 634
Figure 02_image1819
 A 602 --
635
Figure 02_image1821
 A 548 -- 636
Figure 02_image1823
 A 544 --
637
Figure 02_image1825
 A 562 -- 638
Figure 02_image1827
 A 542 --
639
Figure 02_image1829
 A 560 -- 640
Figure 02_image1831
 A 556 --
641
Figure 02_image1833
 A 574 -- 642
Figure 02_image1835
 A 558 --
643
Figure 02_image1837
 A 576 -- 644
Figure 02_image1839
 A 558 --
645
Figure 02_image1841
 A 576 --          
表 1
時間(min) 流速(mL/min) 流動相B% 流動相A%
0 2 5 95
0.1 2 5 95
2.2 2 95 5
2.7 2 95 5
2.71 2 5 95
3.2 2 5 95
表 2
化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 ) 化合物 化合物結構 合成方法 MS (M+H)+ LC-MS 保留時間 ( 分鐘 )
1
Figure 02_image565
 A 571 1.409 2
Figure 02_image567
 B 571 1.278
3
Figure 02_image569
 B 556 1.597 4
Figure 02_image571
 B 585 1.198
5
Figure 02_image573
 A 563 1.507 6
Figure 02_image575
 B 564 1.649
7
Figure 02_image577
 A 584 1.186 8
Figure 02_image579
 A 585 1.434
9
Figure 02_image581
 A 555 1.464 10
Figure 02_image583
 A 515 1.463
11
Figure 02_image585
 A 529 1.489 12
Figure 02_image587
 B 572 1.461
13
Figure 02_image589
 A 501 1.350 14
Figure 02_image591
 B 530 1.521
15
Figure 02_image593
 A 555 1.560 16
Figure 02_image595
 B 558 1.430
17
Figure 02_image597
 A 541 1.542 18
Figure 02_image599
 B 558 1.450
          20
Figure 02_image601
 B 571 1.310
21
Figure 02_image603
 A 559 1.350 22
Figure 02_image605
 A 573 1.337
23
Figure 02_image607
 A 585 1.356 24
Figure 02_image609
 A 585 1.338
25
Figure 02_image611
 B 570 1.551 26
Figure 02_image613
 A 531 --
27
Figure 02_image615
 A 607 1.325 28
Figure 02_image617
 A 558 1.147
29
Figure 02_image619
 A 557 1.289 30
Figure 02_image621
 A 541 1.491
31
Figure 02_image623
 A 557 1.325 32
Figure 02_image625
 A 557 1.310
33
Figure 02_image627
 A 527 1.389 34
Figure 02_image629
 A 571 1.358
35
Figure 02_image631
 A 585 1.425 36
Figure 02_image633
 A 531 1.332
37
Figure 02_image635
 A 572 1.122 38
Figure 02_image637
 A 572 1.475
39
Figure 02_image639
 A 572 1.104 40
Figure 02_image641
 A 575 1.244
41
Figure 02_image643
 A 586 -- 42
Figure 02_image645
 A 601 1.457
43
Figure 02_image647
 A 587 1.378 44
Figure 02_image649
 A 649 1.396
45
Figure 02_image651
 A 601 1.479 46
Figure 02_image653
 A 649 1.402
47
Figure 02_image655
 A 596 1.401 48
Figure 02_image657
 A 619 1.342
49
Figure 02_image659
 A 575 1.294 50
Figure 02_image661
 A 575 1.268
51
Figure 02_image663
 A 601 1.407 52
Figure 02_image665
 A 596 --
53
Figure 02_image667
 A 596 1.368 54
Figure 02_image669
 A 593 1.272
55
Figure 02_image671
 A 561 1.254 56
Figure 02_image673
 A 586 1.094
57
Figure 02_image675
 A 561 1.199 58
Figure 02_image677
 A 602 --
59
Figure 02_image679
 A 516 1.523 60
Figure 02_image681
 A 589 --
61
Figure 02_image683
 A 605 -- 62
Figure 02_image685
 A 589 1.400
63
Figure 02_image687
 A 605 1.423 64
Figure 02_image689
 A 589 1.438
65
Figure 02_image691
 A 605 1.532 66
Figure 02_image693
 A 557 --
67
Figure 02_image695
 A 602 -- 68
Figure 02_image697
 A 562 1.047
69
Figure 02_image699
 A 561 1.331 70
Figure 02_image701
 A 557 1.350
71
Figure 02_image703
 A 601 1.260 72
Figure 02_image705
 A 573 1.236
73
Figure 02_image707
 A 602 1.137 74
Figure 02_image709
 A 586 --
75
Figure 02_image711
 A 626 -- 76
Figure 02_image713
 A 626 --
77
Figure 02_image715
 A 626 -- 78
Figure 02_image717
 A 614 --
79
Figure 02_image719
 A 614 -- 80
Figure 02_image721
 A 614 --
81
Figure 02_image723
 A 614 -- 82
Figure 02_image725
 A 621 1.370
83
Figure 02_image727
 A 602 1.058 84
Figure 02_image729
 A 601 1.241
85
Figure 02_image731
 A 614 1.235 86
Figure 02_image733
 A 614 1.268
87
Figure 02_image735
 A 614 1.292 88
Figure 02_image737
 A 578 1.272
89
Figure 02_image739
 A 615 1.396 90
Figure 02_image741
 A 664 1.312
91
Figure 02_image743
 A 561 1.332 92
Figure 02_image745
 A 586 1.204
93
Figure 02_image747
 A 577 1.350 94
Figure 02_image749
 A 577 1.399
95
Figure 02_image751
 A 586 1.220 96
Figure 02_image753
 A 587 1.225
97
Figure 02_image755
 A 574 1.313 98
Figure 02_image757
 A 586 1.295
99
Figure 02_image759
 A 587 1.336 100
Figure 02_image761
 A 628 1.314
101
Figure 02_image763
 A 621 1.446 102
Figure 02_image765
 A 590 1.058
103
Figure 02_image767
 A 590 1.270 104
Figure 02_image769
 A 615 1.398
105
Figure 02_image771
 A 621 1.393 106
Figure 02_image773
 A 602 1.194
107
Figure 02_image775
 A 664 1.296 108
Figure 02_image777
 A 586 1.109
109
Figure 02_image779
 A 576 1.084 110
Figure 02_image781
 A 575 1.159
111
Figure 02_image783
 A 575 1.308 112
Figure 02_image1918
 A 601 1.363
113
Figure 02_image787
 A 601 1.456 114
Figure 02_image789
 A 586 1.226
115
Figure 02_image791
 A 599 1.491          
117
Figure 02_image793
 A 572 1.107 118
Figure 02_image795
 A 489 1.201
119
Figure 02_image797
 A 391 1.499 120
Figure 02_image799
 A 503 1.156
121
Figure 02_image801
 A 488 1.219 122
Figure 02_image803
 A 590 1.222
123
Figure 02_image805
 A 490 1.114 124
Figure 02_image807
 A 434 1.232
125
Figure 02_image809
 A 571 1.387 126
Figure 02_image811
 A 591 1.344
127
Figure 02_image813
 A 543 0.982 128
Figure 02_image815
 A 557 1.192
129
Figure 02_image817
 A 529 -- 130
Figure 02_image819
 A 529 --
131
Figure 02_image821
 B 601 1.138 132
Figure 02_image823
 B 601 1.140
133
Figure 02_image825
 A 571 1.371 134
Figure 02_image827
 A 571 --
135
Figure 02_image829
 A 571 1.397 140
Figure 02_image831
 A 585 1.443
141
Figure 02_image833
 A 585 1.401 142
Figure 02_image835
 A 585 1.443
143
Figure 02_image837
 A 585 1.436 144
Figure 02_image839
 A 585 1.389
145
Figure 02_image841
 A 589 -- 146
Figure 02_image843
 A 612 --
147
Figure 02_image845
 A 504 -- 148
Figure 02_image847
 A 503 1.204
149
Figure 02_image849
 A 626 -- 150
Figure 02_image851
 A 626 --
151
Figure 02_image853
 A 503 -- 152
Figure 02_image855
 A 504 --
153
Figure 02_image857
 A 603 -- 154
Figure 02_image859
 A 600 --
155
Figure 02_image861
 A 626 -- 156
Figure 02_image863
 A 518 --
157
Figure 02_image865
 A 517 -- 158
Figure 02_image867
 A 640 --
159
Figure 02_image869
 A 640 -- 160
Figure 02_image871
 A 603 --
161
Figure 02_image873
 A 600 1.181 162
Figure 02_image875
 A 626 --
163
Figure 02_image877
 A 518 -- 164
Figure 02_image879
 A 517 --
165
Figure 02_image881
 A 640 -- 166
Figure 02_image883
 A 640 --
167
Figure 02_image885
 A 617 -- 168
Figure 02_image887
 A 614 --
169
Figure 02_image889
 A 640 -- 170
Figure 02_image891
 A 532 --
171
Figure 02_image893
 A 531 -- 172
Figure 02_image895
 A 654 --
173
Figure 02_image897
 A 654 -- 174
Figure 02_image899
 A 478 1.436
175
Figure 02_image901
 A 479 -- 176
Figure 02_image903
 A 578 --
177
Figure 02_image905
 A 575 1.439 178
Figure 02_image907
 A 601 --
179
Figure 02_image909
 A 493 -- 180
Figure 02_image911
 A 492 --
181
Figure 02_image913
 A 615 -- 182
Figure 02_image915
 A 615 --
183
Figure 02_image917
 A 592 -- 184
Figure 02_image919
 A 589 1.398
185
Figure 02_image921
 A 615 -- 186
Figure 02_image923
 A 507 --
187
Figure 02_image925
 A 506 -- 188
Figure 02_image927
 A 629 --
189
Figure 02_image929
 A 629 -- 190
Figure 02_image931
 A 492 --
191
Figure 02_image933
 A 493 -- 192
Figure 02_image935
 A 592 --
193
Figure 02_image937
 A 589 -- 194
Figure 02_image939
 A 615 --
195
Figure 02_image941
 A 507 -- 196
Figure 02_image943
 A 506 --
197
Figure 02_image945
 A 629 -- 198
Figure 02_image947
 A 629 --
199
Figure 02_image949
 A 606 -- 200
Figure 02_image951
 A 603 --
201
Figure 02_image953
 A 629 -- 202
Figure 02_image955
 A 521 --
203
Figure 02_image957
 A 520 -- 204
Figure 02_image959
 A 643 --
205
Figure 02_image961
 A 643 -- 206
Figure 02_image963
 A 575 --
207
Figure 02_image965
 A 598 -- 208
Figure 02_image967
 A 490 --
209
Figure 02_image969
 A 489 -- 210
Figure 02_image971
 A 612 --
211
Figure 02_image973
 A 612 -- 212
Figure 02_image975
 A 589 --
213
Figure 02_image977
 A 586 1.580 214
Figure 02_image979
 A 612 --
215
Figure 02_image981
 A 504 -- 216
Figure 02_image983
 A 503 --
217
Figure 02_image985
 A 626 -- 218
Figure 02_image987
 A 626 --
219
Figure 02_image989
 A 603 -- 220
Figure 02_image991
 A 600 --
221
Figure 02_image993
 A 626 -- 222
Figure 02_image995
 A 518 --
223
Figure 02_image997
 A 517 -- 224
Figure 02_image999
 A 640 --
225
Figure 02_image1001
 A 640 -- 226
Figure 02_image1003
 A 605 --
227
Figure 02_image1005
 A 602 -- 228
Figure 02_image1007
 A 628 --
229
Figure 02_image1009
 A 520 -- 230
Figure 02_image1011
 A 519 --
231
Figure 02_image1013
 A 642 -- 232
Figure 02_image1015
 A 642 --
233
Figure 02_image1017
 A 619 -- 234
Figure 02_image1019
 A 616 --
235
Figure 02_image1021
 A 642 -- 236
Figure 02_image1023
 A 534 --
237
Figure 02_image1025
 A 533 -- 238
Figure 02_image1027
 A 656 --
239
Figure 02_image1029
 A 656 -- 240
Figure 02_image1031
 A 633 --
241
Figure 02_image1033
 A 630 -- 242
Figure 02_image1035
 A 656 --
243
Figure 02_image1037
 A 548 -- 244
Figure 02_image1039
 A 547 --
245
Figure 02_image1041
 A 670 -- 246
Figure 02_image1043
 A 670 --
247
Figure 02_image1045
 A 598 -- 248
Figure 02_image1047
 A 624 --
249
Figure 02_image1049
 A 612 -- 250
Figure 02_image1051
 A 626 --
251
Figure 02_image1053
 A 516 -- 252
Figure 02_image1055
 A 515 --
253
Figure 02_image1057
 A 638 -- 254
Figure 02_image1059
 A 638 --
255
Figure 02_image1061
 A 598 -- 256
Figure 02_image1063
 A 624 --
257
Figure 02_image1065
 A 612 -- 258
Figure 02_image1067
 A 626 --
259
Figure 02_image1069
 A 516 -- 260
Figure 02_image1071
 A 515 --
261
Figure 02_image1073
 A 638 -- 262
Figure 02_image1075
 A 638 --
263
Figure 02_image1077
 A 598 -- 264
Figure 02_image1079
 A 624 --
265
Figure 02_image1081
 A 612 -- 266
Figure 02_image1083
 A 626 --
267
Figure 02_image1085
 A 516 -- 268
Figure 02_image1087
 A 515 --
269
Figure 02_image1089
 A 638 -- 270
Figure 02_image1091
 A 638 --
271
Figure 02_image1093
 A 612 -- 272
Figure 02_image1095
 A 638 --
273
Figure 02_image1097
 A 626 -- 274
Figure 02_image1099
 A 640 --
275
Figure 02_image1101
 A 530 -- 276
Figure 02_image1103
 A 529 --
277
Figure 02_image1105
 A 652 -- 278
Figure 02_image1107
 A 652 --
279
Figure 02_image1109
 A 612 -- 280
Figure 02_image1111
 A 638 --
281
Figure 02_image1113
 A 626 -- 282
Figure 02_image1115
 A 640 --
283
Figure 02_image1117
 A 530 -- 284
Figure 02_image1119
 A 529 --
285
Figure 02_image1121
 A 652 -- 286
Figure 02_image1123
 A 652 --
287
Figure 02_image1125
 A 628 -- 288
Figure 02_image1127
 A 654 --
289
Figure 02_image1129
 A 642 -- 290
Figure 02_image1131
 A 656 --
291
Figure 02_image1133
 A 546 -- 292
Figure 02_image1135
 A 545 --
293
Figure 02_image1137
 A 668 -- 294
Figure 02_image1139
 A 668 --
295
Figure 02_image1141
 A 628 -- 296
Figure 02_image1143
 A 654 --
297
Figure 02_image1145
 A 642 -- 298
Figure 02_image1147
 A 656 --
299
Figure 02_image1149
 A 546 -- 300
Figure 02_image1151
 A 545 --
301
Figure 02_image1153
 A 668 -- 302
Figure 02_image1155
 A 668 --
303
Figure 02_image1157
 A 628 -- 304
Figure 02_image1159
 A 654 --
305
Figure 02_image1161
 A 642 -- 306
Figure 02_image1163
 A 656 --
307
Figure 02_image1165
 A 546 -- 308
Figure 02_image1167
 A 545 --
309
Figure 02_image1169
 A 668 -- 310
Figure 02_image1171
 A 668 --
311
Figure 02_image1173
 A 642 -- 312
Figure 02_image1175
 A 668 --
313
Figure 02_image1177
 A 656 -- 314
Figure 02_image1179
 A 670 --
315
Figure 02_image1181
 A 560 -- 316
Figure 02_image1183
 A 559 --
317
Figure 02_image1185
 A 682 -- 318
Figure 02_image1187
 A 682 --
319
Figure 02_image1189
 A 642 -- 320
Figure 02_image1191
 A 668 --
321
Figure 02_image1193
 A 656 -- 322
Figure 02_image1195
 A 670 --
323
Figure 02_image1197
 A 560 -- 324
Figure 02_image1199
 A 559 --
325
Figure 02_image1201
 A 682 -- 326
Figure 02_image1203
 A 682 --
327
Figure 02_image1205
 A 601 -- 328
Figure 02_image1207
 A 615 --
329
Figure 02_image1209
 A 505 -- 330
Figure 02_image1211
 A 504 --
331
Figure 02_image1213
 A 601 -- 332
Figure 02_image1215
 A 615 --
333
Figure 02_image1217
 A 505 -- 334
Figure 02_image1219
 A 504 --
335
Figure 02_image1221
 A 601 -- 336
Figure 02_image1223
 A 615 --
337
Figure 02_image1225
 A 505 -- 338
Figure 02_image1227
 A 504 --
339
Figure 02_image1229
 A 615 -- 340
Figure 02_image1231
 A 629 --
341
Figure 02_image1233
 A 519 -- 342
Figure 02_image1235
 A 518 --
343
Figure 02_image1237
 A 615 -- 344
Figure 02_image1239
 A 629 --
345
Figure 02_image1241
 A 519 -- 346
Figure 02_image1243
 A 518 --
347
Figure 02_image1245
 A 615 -- 348
Figure 02_image1247
 A 629 --
349
Figure 02_image1249
 A 519 -- 350
Figure 02_image1251
 A 518 --
351
Figure 02_image1253
 A 615 -- 352
Figure 02_image1255
 A 629 --
353
Figure 02_image1257
 A 519 -- 354
Figure 02_image1259
 A 518 --
355
Figure 02_image1261
 A 615 -- 356
Figure 02_image1263
 A 629 --
357
Figure 02_image1265
 A 519 -- 358
Figure 02_image1267
 A 518 --
359
Figure 02_image1269
 A 629 -- 360
Figure 02_image1271
 A 643 --
361
Figure 02_image1273
 A 533 -- 362
Figure 02_image1275
 A 532 --
363
Figure 02_image1277
 A 629 -- 364
Figure 02_image1279
 A 643 --
365
Figure 02_image1281
 A 533 -- 366
Figure 02_image1283
 A 532 --
367
Figure 02_image1285
 A 612 -- 368
Figure 02_image1287
 A 626 --
369
Figure 02_image1289
 A 516 -- 370
Figure 02_image1291
 A 515 --
371
Figure 02_image1293
 A 612 -- 372
Figure 02_image1295
 A 626 --
373
Figure 02_image1297
 A 516 -- 374
Figure 02_image1299
 A 515 --
375
Figure 02_image1301
 A 612 -- 376
Figure 02_image1303
 A 626 --
377
Figure 02_image1305
 A 516 -- 378
Figure 02_image1307
 A 515 --
379
Figure 02_image1309
 A 626 -- 380
Figure 02_image1311
 A 640 --
381
Figure 02_image1313
 A 530 -- 382
Figure 02_image1315
 A 529 --
383
Figure 02_image1317
 A 626 -- 384
Figure 02_image1319
 A 640 --
385
Figure 02_image1321
 A 530 -- 386
Figure 02_image1323
 A 529 --
387
Figure 02_image1325
 A 626 -- 388
Figure 02_image1327
 A 640 --
389
Figure 02_image1329
 A 530 -- 390
Figure 02_image1331
 A 529 --
391
Figure 02_image1333
 A 626 -- 392
Figure 02_image1335
 A 640 --
393
Figure 02_image1337
 A 530 -- 394
Figure 02_image1339
 A 529 --
395
Figure 02_image1341
 A 626 -- 396
Figure 02_image1343
 A 640 --
397
Figure 02_image1345
 A 530 -- 398
Figure 02_image1347
 A 529 --
399
Figure 02_image1349
 A 640 -- 400
Figure 02_image1351
 A 654 --
401
Figure 02_image1353
 A 544 -- 402
Figure 02_image1355
 A 543 --
403
Figure 02_image1357
 A 640 -- 404
Figure 02_image1359
 A 654 --
405
Figure 02_image1361
 A 544 -- 406
Figure 02_image1363
 A 543 --
407
Figure 02_image1365
 A 573 -- 408
Figure 02_image1367
 A 573 --
409
Figure 02_image1369
 A 586 -- 410
Figure 02_image1371
 A 602 1.534
411
Figure 02_image1373
 A 606 -- 412
Figure 02_image1375
 A 590 --
413
Figure 02_image1377
 A 586 -- 414
Figure 02_image1379
 A 586 --
415
Figure 02_image1381
 A 606 -- 416
Figure 02_image1383
 A 590 --
417
Figure 02_image1385
 A 591 1.347 418
Figure 02_image1387
 A 627 --
419
Figure 02_image1389
 A 645 1.608 420
Figure 02_image1391
 A 603 1.516
421
Figure 02_image1393
 A 601 1.491 422
Figure 02_image1395
 A 605 --
423
Figure 02_image1397
 A 641 -- 424
Figure 02_image1399
 A 659 --
425
Figure 02_image1401
 A 617 -- 426
Figure 02_image1403
 A 615 --
427
Figure 02_image1405
 A 617 -- 428
Figure 02_image1407
 A 653 --
429
Figure 02_image1409
 A 671 -- 430
Figure 02_image1411
 A 629 --
431
Figure 02_image1413
 A 627 -- 432
Figure 02_image1415
 A 631 --
433
Figure 02_image1417
 A 667 -- 434
Figure 02_image1419
 A 685 --
435
Figure 02_image1421
 A 643 -- 436
Figure 02_image1423
 A 641 --
437
Figure 02_image1425
 A 617 -- 438
Figure 02_image1427
 A 653 --
439
Figure 02_image1429
 A 671 -- 440
Figure 02_image1431
 A 629 --
441
Figure 02_image1433
 A 627 -- 442
Figure 02_image1435
 A 631 --
443
Figure 02_image1437
 A 667 -- 444
Figure 02_image1439
 A 685 --
445
Figure 02_image1441
 A 643 -- 446
Figure 02_image1443
 A 641 --
447
Figure 02_image1445
 A 594 -- 448
Figure 02_image1447
 A 608 --
449
Figure 02_image1449
 A 592 -- 450
Figure 02_image1451
 A 592 --
451
Figure 02_image1453
 A 606 -- 452
Figure 02_image1455
 A 606 --
453
Figure 02_image1457
 A 608 -- 454
Figure 02_image1459
 A 608 --
455
Figure 02_image1461
 A 606 -- 456
Figure 02_image1463
 A 606 --
457
Figure 02_image1465
 A 620 -- 458
Figure 02_image1467
 A 620 --
459
Figure 02_image1469
 A 622 -- 460
Figure 02_image1471
 A 622 --
461
Figure 02_image1473
 A 592 -- 462
Figure 02_image1475
 A 592 --
463
Figure 02_image1477
 A 606 -- 464
Figure 02_image1479
 A 606 --
465
Figure 02_image1481
 A 608 -- 466
Figure 02_image1483
 A 608 --
467
Figure 02_image1485
 A 606 -- 468
Figure 02_image1487
 A 606 --
469
Figure 02_image1489
 A 620 -- 470
Figure 02_image1491
 A 620 --
471
Figure 02_image1493
 A 622 -- 472
Figure 02_image1495
 A 622 --
473
Figure 02_image1497
 A 576 -- 474
Figure 02_image1499
 A 576 --
475
Figure 02_image1501
 A 590 -- 476
Figure 02_image1503
 A 590 --
477
Figure 02_image1505
 A 592 -- 478
Figure 02_image1507
 A 592 --
479
Figure 02_image1509
 A 590 -- 480
Figure 02_image1511
 A 590 --
481
Figure 02_image1513
 A 604 -- 482
Figure 02_image1515
 A 604 --
483
Figure 02_image1517
 A 606 -- 484
Figure 02_image1519
 A 606 --
485
Figure 02_image1521
 A 576 -- 486
Figure 02_image1523
 A 576 --
487
Figure 02_image1525
 A 590 -- 488
Figure 02_image1527
 A 590 --
489
Figure 02_image1529
 A 592 -- 490
Figure 02_image1531
 A 592 --
491
Figure 02_image1533
 A 590 -- 492
Figure 02_image1535
 A 590 --
493
Figure 02_image1537
 A 604 -- 494
Figure 02_image1539
 A 604 --
495
Figure 02_image1541
 A 606 -- 496
Figure 02_image1543
 A 606 --
497
Figure 02_image1545
 A 575 -- 498
Figure 02_image1547
 A 589 --
499
Figure 02_image1549
 A 589 -- 500
Figure 02_image1551
 A 603 --
501
Figure 02_image1553
 A 591 -- 502
Figure 02_image1555
 A 605 --
503
Figure 02_image1557
 A 601 1.384 504
Figure 02_image1559
 A 603 1.320
505
Figure 02_image1561
 A 615 -- 506
Figure 02_image1563
 A 617 --
507
Figure 02_image1565
 A 639 -- 508
Figure 02_image1567
 A 657 --
509
Figure 02_image1569
 A 653 -- 510
Figure 02_image1571
 A 671 --
511
Figure 02_image1573
 A 610 1.357 512
Figure 02_image1575
 A 611 1.235
513
Figure 02_image1577
 A 624 1.459 514
Figure 02_image1579
 A 625 1.337
515
Figure 02_image1581
 A 638 1.465 516
Figure 02_image1583
 A 639 1.325
517
Figure 02_image1585
 A 640 -- 518
Figure 02_image1587
 A 641 --
519
Figure 02_image1589
 A 628 1.505 520
Figure 02_image1591
 A 629 --
521
Figure 02_image1593
 A 568 1.439 522
Figure 02_image1595
 A 566 1.473
523
Figure 02_image1597
 A 580 -- 524
Figure 02_image1599
 A 594 --
525
Figure 02_image1601
 A 596 1.288 526
Figure 02_image1603
 A 624 1.356
527
Figure 02_image1605
 A 622 1.437 528
Figure 02_image1607
 A 598 1.372
529
Figure 02_image1609
 A 610 1.469 530
Figure 02_image1611
 A 586 --
531
Figure 02_image1613
 A 584 -- 532
Figure 02_image1615
 A 598 --
533
Figure 02_image1617
 A 612 --- 534
Figure 02_image1619
 A 614 --
535
Figure 02_image1621
 A 642 -- 536
Figure 02_image1623
 A 640 --
537
Figure 02_image1625
 A 616 -- 538
Figure 02_image1627
 A 611 1.168
539
Figure 02_image1629
 A 611 -- 540
Figure 02_image1631
 A 611 1.232
541
Figure 02_image1633
 A 612 -- 542
Figure 02_image1635
 A 612 --
543
Figure 02_image1637
 A 612 -- 544
Figure 02_image1639
 A 629 --
545
Figure 02_image1641
 A 629 -- 546
Figure 02_image1643
 A 629 --
547
Figure 02_image1645
 A 630 -- 548
Figure 02_image1647
 A 630 --
549
Figure 02_image1649
 A 630 -- 550
Figure 02_image1651
 A 569 --
551
Figure 02_image1653
 A 569 -- 552
Figure 02_image1655
 A 569 --
553
Figure 02_image1657
 A 570 -- 554
Figure 02_image1659
 A 570 --
555
Figure 02_image1661
 A 570 -- 556
Figure 02_image1663
 A 567 --
557
Figure 02_image1665
 A 567 -- 558
Figure 02_image1667
 A 567 --
559
Figure 02_image1669
 A 568 -- 560
Figure 02_image1671
 A 568 --
561
Figure 02_image1673
 A 568 -- 562
Figure 02_image1675
 A 625 --
563
Figure 02_image1677
 A 625 -- 564
Figure 02_image1679
 A 625 --
565
Figure 02_image1681
 A 626 -- 566
Figure 02_image1683
 A 626 --
567
Figure 02_image1685
 A 626 -- 568
Figure 02_image1687
 A 597 --
569
Figure 02_image1689
 A 597 -- 570
Figure 02_image1691
 A 597 --
571
Figure 02_image1693
 A 598 -- 572
Figure 02_image1695
 A 598 --
573
Figure 02_image1697
 A 598 -- 574
Figure 02_image1699
 A 623 --
575
Figure 02_image1701
 A 623 -- 576
Figure 02_image1703
 A 623 --
577
Figure 02_image1705
 A 624 -- 578
Figure 02_image1707
 A 624 --
579
Figure 02_image1709
 A 624 -- 580
Figure 02_image1711
 A 628 --
581
Figure 02_image1713
 A 628 -- 582
Figure 02_image1715
 A 628 --
583
Figure 02_image1717
 A 628 -- 584
Figure 02_image1719
 A 628 --
585
Figure 02_image1721
 A 640 -- 586
Figure 02_image1723
 A 640 --
587
Figure 02_image1725
 A 640 -- 588
Figure 02_image1727
 A 640 --
589
Figure 02_image1729
 A 640 -- 590
Figure 02_image1731
 A 612 --
591
Figure 02_image1733
 A 570 -- 592
Figure 02_image1735
 A 568 --
593
Figure 02_image1737
 A 624 -- 594
Figure 02_image1739
 A 582 1.325
595
Figure 02_image1741
 A 600 -- 596
Figure 02_image1743
 A 583 --
597
Figure 02_image1745
 A 583 -- 598
Figure 02_image1747
 A 583 --
599
Figure 02_image1749
 A 583 -- 600
Figure 02_image1751
 A 584 --
601
Figure 02_image1753
 A 584 -- 602
Figure 02_image1755
 A 584 --
603
Figure 02_image1757
 A 600 -- 604
Figure 02_image1759
 A 600 --
605
Figure 02_image1761
 A 600 -- 606
Figure 02_image1763
 A 600 --
607
Figure 02_image1765
 A 600 -- 608
Figure 02_image1767
 A 584 --
609
Figure 02_image1769
 A 569 -- 610
Figure 02_image1771
 A 567 --
611
Figure 02_image1773
 A 530 1.105 612
Figure 02_image1775
 A 587 1.181
613
Figure 02_image1777
 A 587 1.347 614
Figure 02_image1779
 A 547 1.294
615
Figure 02_image1781
 A 547 1.292 616
Figure 02_image1783
 A 519 1.340
617
Figure 02_image1785
 A 561 1.337 618
Figure 02_image1787
 A 561 1.297
619
Figure 02_image1789
 A 579 -- 620
Figure 02_image1791
 A 565 --
621
Figure 02_image1793
 A 565 -- 622
Figure 02_image1795
 A 537 --
623
Figure 02_image1797
 A 579 -- 624
Figure 02_image1799
 A 579 --
625
Figure 02_image1801
 A 517 -- 626
Figure 02_image1803
 A 535 --
627
Figure 02_image1805
 A 573 1.455 628
Figure 02_image1807
 A 591 --
629
Figure 02_image1809
 A 623 -- 630
Figure 02_image1811
 A 641 --
631
Figure 02_image1813
 A 528 -- 632
Figure 02_image1815
 A 546 --
633
Figure 02_image1817
 A 584 -- 634
Figure 02_image1819
 A 602 --
635
Figure 02_image1821
 A 548 -- 636
Figure 02_image1823
 A 544 --
637
Figure 02_image1825
 A 562 -- 638
Figure 02_image1827
 A 542 --
639
Figure 02_image1829
 A 560 -- 640
Figure 02_image1831
 A 556 --
641
Figure 02_image1833
 A 574 -- 642
Figure 02_image1835
 A 558 --
643
Figure 02_image1837
 A 576 -- 644
Figure 02_image1839
 A 558 --
645
Figure 02_image1841
 A 576 --          
表 3. 表 2 中部分化合物的核磁共振數據
化合物 核磁共振
1 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 7.73-7.67 (m, 2H), 7.60 (s, 1H), 7.51-7.46 (m, 2H), 7.46-7.40 (m, 2H), 7.37-7.31 (m, 1H), 7.27 (d,J = 2.9 Hz, 1H), 6.92-6.85 (m, 2H), 6.62 (d,J = 7.4 Hz, 1H), 4.11-4.01 (m, 1H), 3.90-3.82 (m, 2H), 3.61 (d,J = 11.9 Hz, 2H), 3.43-3.34 (m, 2H), 2.62-2.55 (m, 2H), 2.48 (m, 4H), 2.38-2.19 (m, 5H), 2.12 (s, 3H), 1.82 (t,J = 11.7 Hz, 4H), 1.61-1.44 (m, 4H).
6 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 8.10 (d,J = 7.6 Hz, 2H), 7.70 (s, 1H), 7.48 (t,J = 7.6 Hz, 3H), 7.42-7.32 (m, 2H), 7.22 (d,J = 7.9 Hz, 2H), 7.11 (d,J = 8.8 Hz, 2H), 6.83 (d,J = 8.0 Hz, 1H), 6.60 (d,J = 8.7 Hz, 2H), 5.41 (s, 1H), 3.58 (d,J = 12.0 Hz, 2H), 2.77-2.36 (m, 11H), 2.33 (s, 3H), 1.94 (m, 2H), 1.69 (m, 2H).
8 1 H NMR (400 MHz, CDCl3 ) δ 10.59 (s, 1H), 7.60-7.55 (m, 2H), 7.49 (t,J = 7.5 Hz, 2H), 7.42 (d,J = 7.5 Hz, 1H), 7.39 (d,J = 8.8 Hz, 2H), 6.94 (d,J = 8.8 Hz, 2H), 5.19 (d,J = 6.7 Hz, 1H), 5.15 (s, 1H), 4.26-4.18 (m, 1H), 3.71 (d,J = 12.0 Hz, 2H), 3.15 (s, 1H), 2.78-2.59 (m, 6H), 2.52 (s, 3H), 2.40 (s, 2H), 2.32 (s, 3H), 2.24-2.13 (m, 1H), 1.93 (d,J = 12.4 Hz, 2H), 1.82-1.65 (m, 7H), 1.08 (s, 3H).
10 1 H NMR (400 MHz, CDCl3 ) δ 10.66 (s, 1H), 7.64-7.56 (m, 4H), 7.50 (s, 1H), 7.43-7.38 (m, 2H), 7.34-7.28 (m, 1H), 6.96-6.91 (m, 2H), 5.19 (s, 1H), 3.69 (d,J = 11.9 Hz, 2H), 2.88 (s, 6H), 2.74-2.36 (m, 11H), 2.32 (s, 3H), 1.95 (d,J = 12.4 Hz, 2H), 1.74 (m, 2H).
11 1 H NMR (400 MHz, CDCl3 ) δ 10.82 (s, 1H), 7.65-7.55 (m, 4H), 7.51-7.36 (m, 4H), 6.96-6.89 (m, 2H), 5.13 (d,J = 7.1 Hz, 2H), 4.26 (dt,J = 13.2, 6.6 Hz, 1H), 3.69 (d,J = 11.9 Hz, 2H), 2.75-2.33 (m, 11H), 2.31 (s, 3H), 1.95 (d,J = 11.8 Hz, 2H), 1.74 (m, 2H).
16 1 H NMR (400 MHz, CDCl3 ) δ 10.79 (s, 1H), 7.60-7.53 (m, 4H), 7.51-7.44 (m, 3H), 7.43-7.37 (m, 1H), 6.95-6.90 (m, 2H), 5.37 (d,J = 6.4 Hz, 1H), 5.19 (s, 1H), 4.63 (d,J = 9.9 Hz, 1H), 3.97-3.87 (m, 2H), 3.81 (td,J = 8.5, 5.8 Hz, 1H), 3.75-3.66 (m, 3H), 2.76-2.32 (m, 11H), 2.30 (s, 3H), 1.95 (d,J = 12.3 Hz, 2H), 1.83 m, 1H), 1.71 (m, 3H).
24 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 7.60 (dd,J = 8.8, 6.7 Hz, 4H), 7.48 (t,J = 7.6 Hz, 3H), 7.40 (t,J = 7.3 Hz, 1H), 6.90 (d,J = 8.9 Hz, 2H), 5.30 (d,J = 7.1 Hz, 1H), 5.14 (s, 1H), 4.00 (d,J = 17.1 Hz, 2H), 3.67 (d,J = 12.0 Hz, 2H), 2.69 (t,J = 11.5 Hz, 6H), 2.53 (s, 4H), 2.44-2.36 (m, 1H), 2.32 (s, 3H), 1.95 (d,J = 12.4 Hz, 2H), 1.84 (d,J = 10.1 Hz, 2H), 1.77-1.68 (m, 8H).
28 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 7.64-7.57 (m, 4H), 7.47 (t,J = 7.5 Hz, 3H), 7.41-7.35 (m, 1H), 6.98-6.89 (m, 2H), 6.02 (t,J = 4.6 Hz, 1H), 5.15 (s, 1H), 3.68 (d,J = 11.9 Hz, 2H), 3.53 (q,J = 5.8 Hz, 2H), 2.75-2.60 (m, 6H), 2.51 (t,J = 6.1 Hz, 6H), 2.42-2.33 (m, 1H), 2.31 (s, 3H), 2.21 (s, 6H), 1.94 (d,J = 11.8 Hz, 2H), 1.67 (d,J = 9.1 Hz, 2H).
30 1 H NMR (400 MHz, CDCl3 ) δ 10.80 (s, 1H), 7.65-7.57 (m, 4H), 7.52-7.44 (m, 3H), 7.43-7.38 (m, 1H), 6.97-6.91 (m, 2H), 5.42 (d,J = 6.8 Hz, 1H), 5.14 (s, 1H), 4.49 (p,J = 7.6 Hz, 1H), 3.70 (d,J = 11.8 Hz, 2H), 2.77-2.63 (m, 6H), 2.52 (s, 4H), 2.47-2.36 (m, 3H), 2.32 (s, 3H), 1.96 (d,J = 12.5 Hz, 2H), 1.90-1.74 (m, 6H).
32 1 H NMR (400 MHz, CDCl3 ) δ 10.70 (s, 1H), 7.62-7.54 (m, 4H), 7.49 (dd,J = 8.4, 6.8 Hz, 3H), 7.41 (t,J = 7.4 Hz, 1H), 6.93 (d,J = 8.9 Hz, 2H), 5.38 (d,J = 5.1 Hz, 1H), 5.17 (s, 1H), 4.50 (q,J = 6.2, 5.2 Hz, 2H), 3.72 (d,J = 12.4 Hz, 2H), 2.72 (dd,J = 24.4, 12.2 Hz, 6H), 2.57 (d,J = 33.4 Hz, 4H), 2.45-2.33 (m, 4H), 2.32 (s, 3H), 2.25 (dt,J = 13.3, 6.6 Hz, 3H), 1.94 (d,J = 12.2 Hz, 2H).
37 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 8.85 (d,J = 2.2 Hz, 1H), 8.62 (dd,J = 4.9, 1.7 Hz, 1H), 7.89 (dt,J = 8.0, 2.0 Hz, 1H), 7.54 (d,J = 8.9 Hz, 2H), 7.40 (dd,J = 7.9, 4.7 Hz, 2H), 6.89 (d,J = 8.9 Hz, 2H), 5.23 (s, 1H), 5.00 (d,J = 7.1 Hz, 1H), 4.14 (q,J = 8.1, 6.2 Hz, 1H), 4.03-3.92 (m, 2H), 3.67 (d,J = 11.8 Hz, 2H), 3.50 (td,J = 11.6, 2.1 Hz, 2H), 2.78-2.42 (m, 10H), 2.41-2.33 (m, 1H), 2.30 (s, 3H), 2.03 (d,J = 12.7 Hz, 2H), 1.94 (d,J = 12.4 Hz, 2H), 1.70 (tt,J = 13.2, 6.6 Hz, 2H), 1.49 (qd,J = 12.1, 4.3 Hz, 2H).
39 1 H NMR (400 MHz, CDCl3 ) δ 10.86 (s, 1H), 8.71 (d,J = 5.1 Hz, 2H), 7.55 (t,J = 6.8 Hz, 4H), 7.42 (s, 1H), 6.91 (d,J = 8.8 Hz, 2H), 5.22 (s, 1H), 5.14 (d,J = 7.0 Hz, 1H), 4.17 (m, 1H), 4.01 (d,J = 11.7 Hz, 2H), 3.69 (d,J = 9.2 Hz, 2H), 3.52 (t,J = 11.6 Hz, 2H), 2.69 (m, 11H), 2.38 (s, 3H), 2.09-1.96 (m, 4H), 1.76 – 1.64 (m, 4H).
40 1 H NMR (400 MHz, CDCl3 ) δ 10.74 (s, 1H), 7.75 (s, 1H), 7.65 (s, 1H), 7.55 (d,J = 8.8 Hz, 2H), 7.42 (s, 1H), 6.90 (d,J = 8.9 Hz, 2H), 5.17 (s, 1H), 5.11 (d,J = 7.0 Hz, 1H), 4.19-4.08 (m, 1H), 3.99 (m, 5H), 3.67 (d,J = 11.9 Hz, 2H), 3.54 (dd,J = 12.4, 10.3 Hz, 2H), 2.78-2.35 (m, 11H), 2.33 (s, 3H), 2.06 (t,J = 11.3 Hz, 2H), 1.96 (d,J = 12.3 Hz, 2H), 1.72 (m, 2H), 1.53 (m, 2H).
43 1 H NMR (400 MHz, CDCl3 ) δ 10.75 (s, 1H), 7.55 (d,J = 8.7 Hz, 2H), 7.47 (s, 1H), 7.34 (t,J = 7.9 Hz, 1H), 7.14-7.10 (m, 1H), 7.05 (s, 1H), 6.88 (t,J = 9.0 Hz, 3H), 5.27 (d,J = 7.1 Hz, 1H), 5.18 (s, 1H), 4.13 (dd,J = 10.2, 3.8 Hz, 1H), 3.98 (d,J = 11.8 Hz, 2H), 3.67 (d,J = 11.9 Hz, 2H), 3.51 (t,J = 11.4 Hz, 2H), 2.73-2.35 (m, 11H), 2.31 (s, 3H), 2.04 (d,J = 8.3 Hz, 2H), 1.95 (d,J = 12.4 Hz, 2H), 1.72 (m, 2H), 1.52-1.48 (m, 2H).
44 1 H NMR (400 MHz, CDCl3 ) δ 10.85 (s, 1H), 8.21 (d,J = 2.1 Hz, 1H), 7.96 (d,J = 7.8 Hz, 1H), 7.90 (d,J = 7.7 Hz, 1H), 7.69 (t,J = 7.8 Hz, 1H), 7.56 (d,J = 8.8 Hz, 2H), 7.40 (s, 1H), 6.91 (d,J = 8.8 Hz, 2H), 5.22 (s, 1H), 5.03 (d,J = 6.9 Hz, 1H), 4.19-4.12 (m, 1H), 3.99 (d,J = 11.7 Hz, 2H), 3.69 (d,J = 11.8 Hz, 2H), 3.52 (t,J = 11.4 Hz, 2H), 3.11 (s, 3H), 2.76-2.38 (m, 11H), 2.35 (s, 3H), 2.01 (m, 4H), 1.74 (m, 2H), 1.50 (m, 2H).
49 1 H NMR (400 MHz, CDCl3 ) δ 10.82 (s, 1H), 8.76 (d,J = 7.1 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.44 (m, 1H), 7.37 (d,J = 2.3 Hz, 1H), 6.94-6.86 (m, 2H), 6.81 (d,J = 2.3 Hz, 1H), 5.24 (s, 1H), 4.27 (ddt,J = 14.3, 10.1, 5.2 Hz, 1H), 4.04 (dt,J = 11.9, 4.0 Hz, 2H), 3.94 (s, 3H), 3.71-3.56 (m, 4H), 2.76-2.34 (m, 11H), 2.32 (s, 3H), 2.14 (dd,J = 13.1, 3.2 Hz, 2H), 1.95 (m, 2H), 1.71 (m, 4H).
53 1 H NMR (400 MHz, CDCl3 ) δ 10.87 (s, 1H), 7.79-7.69 (m, 4H), 7.59-7.53 (m, 2H), 7.40 (s, 1H), 6.90 (d,J = 8.8 Hz, 2H), 5.23 (s, 1H), 5.08-5.01 (m, 1H), 4.23-4.09 (m, 1H), 4.00 (d,J = 11.6 Hz, 2H), 3.69 (d,J = 12.1 Hz, 2H), 3.58-3.46 (m, 3H), 2.95 (s, 8H), 2.72 (t,J = 12.0 Hz, 3H), 2.56 (s, 3H), 2.05 (d,J = 14.1 Hz, 4H), 1.52 (td,J = 11.5, 7.3 Hz, 4H).
55 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.05 (s, 1H), 11.21 (s, 1H), 8.90 (s, 1H), 8.00-7.92 (m, 1H), 7.81 (d,J = 2.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.31 (d,J = 2.8 Hz, 1H), 7.21 (d,J = 2.4 Hz, 1H), 6.89 (d,J = 8.9 Hz, 2H), 6.54 (s, 4H), 4.11 (m,J = 6.2 Hz, 1H), 3.89 (dt,J = 11.5, 3.7 Hz, 2H), 3.62 (d,J = 11.8 Hz, 2H), 3.49 (td,J = 11.5, 2.4 Hz, 2H), 2.88-2.52 (m, 9H), 2.42 (s, 3H), 2.10-1.99 (m, 2H), 1.84 (d,J = 11.1 Hz, 2H), 1.61-1.40 (m, 4H).
59 1 H NMR (400 MHz, CDCl3 ) δ 10.79 (s, 1H), 7.61-7.55 (m, 4H), 7.49 (t,J = 7.6 Hz, 3H), 7.41 (t,J = 7.3 Hz, 1H), 6.91 (d,J = 8.9 Hz, 2H), 5.22-5.12 (m, 2H), 4.19-4.11 (m, 1H), 3.99 (d,J = 11.8 Hz, 2H), 3.68 (d,J = 11.9 Hz, 2H), 3.58-3.47 (m, 2H), 2.71 (t,J = 12.0 Hz, 2H), 2.39 (s, 7H), 2.08-1.97 (m, 4H), 1.76-1.70 (m, 2H), 1.51 (m, 2H).
64 1 H NMR (400 MHz, CDCl3 ) δ 10.77 (s, 1H), 7.55 (dd,J = 8.7, 5.4 Hz, 4H), 7.42 (s, 1H), 7.18 (t,J = 8.6 Hz, 2H), 6.94-6.87 (m, 2H), 5.16 (s, 1H), 5.04 (d,J = 7.1 Hz, 1H), 4.21-4.09 (m, 1H), 3.99 (d,J = 11.5 Hz, 2H), 3.68 (d,J = 12.0 Hz, 2H), 3.57-3.48 (m, 2H), 2.77-2.63 (m, 6H), 2.52 (s, 4H), 2.38 (d,J = 11.7 Hz, 1H), 2.32 (s, 3H), 2.05 (d,J = 12.5 Hz, 3H), 1.96 (d,J = 12.4 Hz, 2H), 1.78-1.70 (m, 2H), 1.52-1.44 (m, 2H).
65 1 H NMR (400 MHz, CDCl3 ) δ 10.78 (s, 1H), 7.59-7.50 (m, 4H), 7.48-7.43 (m, 2H), 7.42 (s, 1H), 6.90 (d,J = 8.9 Hz, 2H), 5.19 (s, 1H), 5.05 (d,J = 7.1 Hz, 1H), 4.19-4.07 (m, 1H), 4.04-3.95 (m, 2H), 3.68 (d,J = 11.8 Hz, 2H), 3.52 (td,J = 11.6, 2.2 Hz, 2H), 2.76-2.59 (m, 6H), 2.50 (s, 4H), 2.38 (t,J = 11.5 Hz, 1H), 2.30 (s, 3H), 2.08-2.01 (m, 2H), 1.96 (d,J = 12.4 Hz, 2H), 1.77-1.69 (m, 2H), 1.56-1.45 (m, 2H).
67 1 H NMR (400 MHz, CDCl3 ) δ 10.82 (s, 1H), 8.42 (s, 1H), 8.39 (d,J = 4.8 Hz, 1H), 7.61-7.53 (m, 2H), 7.38 (d,J = 4.8 Hz, 2H), 6.94-6.87 (m, 2H), 5.20 (s, 1H), 4.92 (d,J = 7.3 Hz, 1H), 4.23-4.12 (m, 1H), 4.04-3.97 (m, 2H), 3.96 (s, 3H), 3.69 (d,J = 11.9 Hz, 2H), 3.53 (td,J = 11.6, 2.2 Hz, 2H), 2.75-2.36 (m, 11H), 2.32 (s, 3H), 2.04 (d,J = 12.8 Hz, 2H), 1.96 (d,J = 12.5 Hz, 2H), 1.72-1.67 (m, 2H), 1.49 (qd,J = 11.7, 4.3 Hz, 2H).
69 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.51 (s, 1H), 7.96 (s, 1H), 7.78 (d,J = 1.8 Hz, 1H), 7.73 (d,J = 8.8 Hz, 2H), 7.48 (s, 3H), 7.26 (d,J = 3.5 Hz, 1H), 7.00 (d,J = 7.2 Hz, 1H), 6.66 (dd,J = 3.5, 1.8 Hz, 1H), 4.17-4.09 (m, 1H), 3.98-3.89 (m, 2H), 3.74 -3.70（m, 2H） 3.57-3.43 (m, 11H), 3.28 (m, 2H), 2.83 (s, 3H), 2.27 (d,J = 36.8 Hz, 4H), 1.98 (d,J = 12.6 Hz, 2H), 1.67 (qd,J = 12.2, 4.5 Hz, 2H).
87 1 H NMR (400 MHz, CDCl3 ) δ 10.72 (s, 1H), 7.60-7.54 (m, 2H), 7.49 (s, 1H), 7.45 (d,J = 8.5 Hz, 2H), 6.92-6.86 (m, 2H), 6.80 (d,J = 8.5 Hz, 2H), 5.26 (d,J = 7.2 Hz, 1H), 5.19 (s, 1H), 4.20-4.08 (m, 1H), 3.98 (dt,J = 11.7, 3.6 Hz, 2H), 3.67 (d,J = 11.9 Hz, 2H), 3.53 (td,J = 11.5, 2.2 Hz, 2H), 3.02 (s, 6H), 2.79-2.61 (m, 6H), 2.51 (s, 4H), 2.39 (td,J = 11.6, 11.2, 5.6 Hz, 1H), 2.31 (s, 3H), 2.05 (d,J = 13.0 Hz, 2H), 1.95 (d,J = 12.6 Hz, 2H), 1.71 (qd,J = 12.0, 3.7 Hz, 2H), 1.57-1.43 (m, 2H).
91 1 H NMR (400 MHz, CDCl3 ) δ 10.76 (s, 1H), 7.74 (t,J = 1.2 Hz, 1H), 7.58-7.52 (m, 3H), 7.44 (s, 1H), 6.93-6.87 (m, 2H), 6.74 (dd,J = 1.8, 0.9 Hz, 1H), 5.20 (s, 1H), 5.12 (d,J = 7.0 Hz, 1H), 4.18-4.10 (m, 1H), 4.05-3.97 (m, 2H), 3.68 (d,J = 12.0 Hz, 2H), 3.54 (td,J = 11.5, 2.1 Hz, 2H), 2.78-2.37 (m, 11H), 2.34 (s, 3H), 2.08 (d,J = 12.9 Hz, 2H), 1.96 (d,J = 12.4 Hz, 2H), 1.70 (m, 2H), 1.57-1.51 (m, 2H).
93 1 H NMR (400 MHz, CDCl3 ) δ 10.79 (s, 1H), 7.59-7.53 (m, 2H), 7.51 (dd,J = 2.9, 1.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.38 (dd,J = 5.0, 1.4 Hz, 1H), 6.92-6.87 (m, 2H), 5.30 (d,J = 7.1 Hz, 1H), 5.20 (s, 1H), 4.15 (ddd,J = 10.9, 8.8, 5.1 Hz, 1H), 4.00 (dt,J = 11.7, 3.5 Hz, 2H), 3.68 (d,J = 12.1 Hz, 2H), 3.54 (td,J = 11.6, 2.2 Hz, 2H), 2.86-2.46 (m, 11H), 2.42 (s, 3H), 2.07 (d,J = 12.9 Hz, 2H), 1.98 (d,J = 11.7 Hz, 2H), 1.78-1.67 (m, 2H), 1.60-1.49 (m,2H).
94 1 H NMR (400 MHz, CDCl3 ) δ 10.79 (s, 1H), 7.58-7.53 (m, 2H), 7.44 (s, 1H), 7.37 (dd,J = 5.1, 1.1 Hz, 1H), 7.27 (dd,J = 3.5, 1.0 Hz, 1H), 7.12 (dd,J = 5.1, 3.6 Hz, 1H), 6.93-6.87 (m, 2H), 5.51 (d,J = 7.0 Hz, 1H), 5.24 (s, 1H), 4.22-4.14 (m, 1H), 4.06-3.98 (m, 2H), 3.68 (d,J = 11.9 Hz, 2H), 3.55 (td,J = 11.5, 2.2 Hz, 2H), 2.78-2.36 (m, 11H), 2.34 (s, 3H), 2.09 (d,J = 12.8 Hz, 2H), 1.96 (d,J = 12.4 Hz, 2H), 1.72 (m, 2H), 1.61-1.54 (m, 2H).
101 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 7.69 (d,J = 8.1 Hz, 2H), 7.63 (d,J = 8.1 Hz, 2H), 7.59-7.53 (m, 2H), 7.43 (s, 1H), 6.94-6.88 (m, 2H), 6.71 (t,J = 56.4 Hz, 1H), 5.22 (s, 1H), 5.10 (d,J = 7.1 Hz, 1H), 4.15 (dd,J = 11.0, 4.0 Hz, 1H), 3.99 (dt,J = 12.4, 3.7 Hz, 2H), 3.69 (d,J = 11.9 Hz, 2H), 3.52 (td,J = 11.6, 2.1 Hz, 2H), 2.92-2.57 (m, 11H), 2.45 (d,J = 12.1 Hz, 1H), 2.40 (s, 3H), 2.08-2.00 (m, 4H), 1.73 (dd,J = 12.1, 3.9 Hz, 2H), 1.55-1.46 (m, 2H).
108 1 H NMR (400 MHz, CDCl3 ) δ 10.85 (s, 1H), 8.59 (d,J = 5.1 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.38 (s, 1H), 7.32 (dd,J = 5.2, 1.7 Hz, 1H), 6.94-6.88 (m, 2H), 5.25 (s, 1H), 5.13 (d,J = 7.0 Hz, 1H), 4.21-4.10 (m, 1H), 4.01 (dd,J = 11.8, 4.2 Hz, 2H), 3.69 (d,J = 11.9 Hz, 2H), 3.52 (td,J = 11.6, 2.1 Hz, 2H), 2.75-2.64 (m, 6H), 2.63 (s, 3H), 2.51 (s, 4H), 2.39 (t,J = 11.4 Hz, 1H), 2.31 (s, 3H), 2.10-2.02 (m, 2H), 1.96 (d,J = 12.1 Hz, 2H), 1.75-1.65 (m, 2H), 1.52 (tt,J = 11.5, 5.7 Hz, 2H).
112 1 H NMR (400 MHz, CDCl3 ) δ 10.90 (s, 1H), 7.61-7.56 (m, 2H), 7.53-7.45 (m, 4H), 7.45-7.40 (m, 1H), 6.96 (d,J = 2.3 Hz, 1H), 6.86 (d,J = 8.6 Hz, 1H), 5.22 (d,J = 7.3 Hz, 1H), 5.18 (s, 1H), 4.19 (dd,J = 10.9, 4.0 Hz, 1H), 3.96 (d,J = 11.7 Hz, 2H), 3.89 (s, 3H), 3.51 (t,J = 11.4 Hz, 4H), 2.94-2.49 (m, 11H), 2.43 (s, 3H), 2.08-1.95 (m, 4H), 1.84 (m, 2H), 1.53-1.47 (m, 2H).
113 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 8.25 (d,J = 8.9 Hz, 1H), 7.75-7.68 (m, 2H), 7.55 (s, 1H), 7.44 (t,J = 7.7 Hz, 2H), 7.38-7.32 (m, 1H), 7.14 (s, 1H), 6.64-6.56 (m, 2H), 6.47 (dd,J = 8.9, 2.5 Hz, 1H), 4.14-3.99 (m, 2H), 3.93-3.79 (m, 5H), 3.65 (d,J = 12.1 Hz, 2H), 3.44-3.35 (m, 4H), 2.60 (t,J = 11.6 Hz, 2H), 2.27 (q,J = 11.0, 10.3 Hz, 5H), 2.12 (s, 3H), 1.84 (t,J = 12.8 Hz, 4H), 1.56 (dtd,J = 36.4, 12.0, 4.1 Hz, 5H).
114 1 H NMR (400 MHz, CDCl3 ) δ 10.94 (s, 1H), 8.73-8.70 (m, 2H), 7.54 (d,J = 5.3 Hz, 2H), 7.51-7.41 (m, 3H), 6.96 (d,J = 8.5 Hz, 1H), 5.23 (s, 1H), 5.14 (d,J = 7.1 Hz, 1H), 4.20 (s, 1H), 4.00 (d,J = 11.6 Hz, 2H), 3.53 (t,J = 11.5 Hz, 2H), 3.16 (d,J = 11.7 Hz, 2H), 2.85-2.57 (m, 11H), 2.39 (s, 3H), 2.31 (s, 3H), 2.07 (d,J = 13.1 Hz, 2H), 1.98 (d,J = 14.9 Hz, 2H), 1.73 (m, 2H), 1.46 (m, 2H).
118 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.54 (s, 1H), 8.76 (d,J = 6.8 Hz, 2H), 8.45 (d,J = 6.2 Hz, 2H), 8.13 (s, 1H), 7.60 (t,J = 9.0 Hz, 4H), 7.02 (d,J = 9.0 Hz, 2H),4.10 (m，1H) 3.92 (d,J = 11.3 Hz, 2H), 3.79 (d,J = 13.0 Hz, 2H), 3.15 (d,J = 11.2 Hz, 3H), 3.01 (t,J = 12.4 Hz, 3H), 2.82 (d,J = 4.3 Hz, 3H), 1.92 (d,J = 12.6 Hz, 2H), 1.64-1.56 (m, 2H).
124 1 H NMR (400 MHz, CDCl3 ) δ 10.76 (s, 1H), 8.71 (s, 2H), 7.59-7.48 (m, 4H), 7.42 (s, 1H), 6.77-6.69 (m, 2H), 5.28 (s, 1H), 5.13 (d,J = 7.0 Hz, 1H), 4.20-4.11 (m, 1H), 4.00 (dt,J = 11.7, 3.8 Hz, 2H), 3.52 (td,J = 11.6, 2.1 Hz, 2H), 2.95 (s, 6H), 2.10-2.01 (m, 2H), 1.52 (qd,J = 11.4, 4.4 Hz, 2H).
125 1 H NMR (400 MHz, CDCl3 ) δ 10.83 (s, 1H), 7.65-7.57 (m, 4H), 7.50 (t,J = 7.6 Hz, 3H), 7.41 (t,J = 7.2 Hz, 1H), 6.96-6.89 (m, 2H), 5.41 (d,J = 5.3 Hz, 1H), 5.17 (s, 1H), 4.52-4.45 (m, 1H), 4.05 (p,J = 6.1 Hz, 1H), 3.69 (d,J = 11.8 Hz, 2H), 3.26 (s, 3H), 2.96-2.61 (m, 12H), 2.46 (d,J = 9.2 Hz, 4H), 2.18 (dt,J = 12.5, 6.0 Hz, 2H), 2.01 (d,J = 16.2 Hz, 4H).
126 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.24 (s, 1H), 7.76 (d,J = 7.1 Hz, 3H), 7.54 (dd,J = 16.3, 6.7 Hz, 3H), 7.50-7.37 (m, 4H), 7.26 (s, 2H), 4.64-4.56 (m, 1H), 4.38 (qd,J = 13.3, 7.3 Hz, 4H), 3.81-3.44 (m, 10H), 2.99 (s, 2H), 2.83 (s, 3H), 2.22 (s, 2H), 1.99 (t,J = 7.6 Hz, 3H).
131 1 H NMR (400 MHz, CDCl3 ) δ 10.74 (s, 1H), 7.96-7.91 (m, 2H), 7.64 (s, 1H), 7.49 (d,J = 8.9 Hz, 2H), 7.42 (t,J = 7.5 Hz, 2H), 7.34 (t,J = 7.3 Hz, 1H), 6.94 (d,J = 9.0 Hz, 2H), 5.47 (t,J = 6.9 Hz, 1H), 5.37 (s, 1H), 3.71 (d,J = 12.1 Hz, 2H), 3.62 (t,J = 5.4 Hz, 2H), 3.10 (dd,J = 11.0, 6.1 Hz, 1H), 2.87-2.78 (m, 2H), 2.76-2.65 (m, 10H), 2.58 (s, 4H), 2.47-2.30 (m, 6H), 2.06 (d,J = 14.1 Hz, 2H), 1.96 (d,J = 12.7 Hz, 2H), 1.42-1.33 (m, 2H).
132 鹽酸鹽 1 H NMR (400 MHz, CDCl3 ) δ 10.74 (s, 1H), 7.96-7.91 (m, 2H), 7.64 (s, 1H), 7.49 (d,J = 8.9 Hz, 2H), 7.42 (t,J = 7.5 Hz, 2H), 7.34 (t,J = 7.3 Hz, 1H), 6.94 (d,J = 9.0 Hz, 2H), 5.47 (t,J = 6.9 Hz, 1H), 5.37 (s, 1H), 3.71 (d,J = 12.1 Hz, 2H), 3.62 (t,J = 5.4 Hz, 2H), 3.10 (dd,J = 11.0, 6.1 Hz, 1H), 2.87-2.78 (m, 2H), 2.76-2.65 (m, 10H), 2.58 (s, 4H), 2.47-2.30 (m, 6H), 2.06 (d,J = 14.1 Hz, 2H), 1.96 (d,J = 12.7 Hz, 2H), 1.42-1.33 (m, 2H).
133 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 11.11 (s, 1H), 7.58-7.52 (m, 2H), 7.45 (dt,J = 7.6, 1.2 Hz, 1H), 7.39 (t,J = 2.8 Hz, 2H), 7.25 (d,J = 3.2 Hz, 1H), 7.23-7.16 (m, 2H), 6.93-6.87 (m, 2H), 6.54 (s, 2H), 6.39 (ddd,J = 3.0, 2.0, 1.0 Hz, 1H), 6.20 (d,J = 6.4 Hz, 1H), 4.07-3.99 (m, 3H), 3.62 (d,J = 12.0 Hz, 3H), 2.65-2.49 (m, 8H), 2.33 (t,J = 11.3 Hz, 1H), 2.25 (s, 3H), 2.07 (dd,J = 12.2, 5.6 Hz, 1H), 1.84 (d,J = 12.9 Hz, 3H), 1.74-1.67 (m, 1H), 1.58-1.42 (m, 5H).
148 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.63 (s, 1H), 10.88 (s, 1H), 8.81-8.75 (m, 2H), 8.53-8.46 (m, 2H), 8.16 (s, 1H), 7.64 (d,J = 7.2 Hz, 1H), 7.58 (d,J = 2.5 Hz, 1H), 7.49 (dd,J = 8.5, 2.6 Hz, 1H), 7.05 (d,J = 8.7 Hz, 1H), 4.17 (dd,J = 11.2, 6.7 Hz, 1H), 3.95-3.88 (m, 2H), 3.43 (td,J = 12.2, 11.7, 8.1 Hz, 4H), 3.13 (tt,J = 24.3, 11.8 Hz, 6H), 2.81 (d,J = 4.5 Hz, 3H), 2.30 (s, 3H), 1.92 (d,J = 12.7 Hz, 2H), 1.62 (qd,J = 11.7, 4.3 Hz, 2H).
174 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 10.63 (s, 1H), 8.93 (d,J = 6.6 Hz, 1H), 7.83 (d,J = 2.4 Hz, 1H), 7.64-7.56 (m, 2H), 7.23 (d,J = 2.4 Hz, 1H), 7.03-6.94 (m, 2H), 4.14 (s, 1H), 3.92 (dt,J = 11.7, 3.7 Hz, 2H), 3.75 (m, 2H), 3.55-3.45 (m, 4H), 3.20-3.08 (m, 2H), 3.08-2.98 (m, 2H), 2.81 (d,J = 4.3 Hz, 3H), 2.10-2.01 (m, 2H), 1.60-1.48 (m, 2H).
177 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 11.32 (s, 1H), 8.97 (s, 1H), 7.97 (s, 1H), 7.82 (d,J = 2.5 Hz, 1H), 7.52 (d,J = 2.6 Hz, 1H), 7.38 (dd,J = 8.6, 2.6 Hz, 1H), 7.33 (d,J = 2.8 Hz, 1H), 7.22 (d,J = 2.2 Hz, 1H), 6.95 (d,J = 8.7 Hz, 1H), 6.53 (s, 2H), 4.16 (q,J = 4.5 Hz, 1H), 3.94-3.87 (m, 2H), 3.48-3.46 (m, 4H), 3.02 (d,J = 11.2 Hz, 2H), 2.63-2.48 (m, 8H), 2.32 (d,J = 11.4 Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 2.05 (d,J = 12.7 Hz, 2H), 1.83 (d,J = 12.0 Hz, 2H), 1.54 (q,J = 11.3 Hz, 4H).
213 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.62 (s, 1H), 10.59 (s, 1H), 8.72 (d,J = 8.3 Hz, 1H), 8.62-8.54 (m, 1H), 8.14 (d,J = 12.3 Hz, 1H), 7.95-7.86 (m, 1H), 7.60 (d,J = 2.5 Hz, 1H), 7.54 (d,J = 8.9 Hz, 2H), 7.35 (dd,J = 7.3, 5.2 Hz, 1H), 7.17 (s, 1H), 4.20 (m, 1H), 3.92 (dt,J = 11.6, 4.0 Hz, 4H), 3.81-3.67 (m, 4H), 3.60-3.47 (m, 6H), 3.31 (m, 2H), 2.90 （m，1H）2.84 (s, 3H), 2.36 (s, 3H), 2.25 (d,J = 11.2 Hz, 2H), 2.05 (d,J = 12.0 Hz, 4H), 1.62 (ddd,J = 13.9, 10.1, 5.1 Hz, 2H).
417 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.06 (s, 1H), 11.33 (s, 1H), 9.03 (s, 1H), 7.98 (s, 1H), 7.82 (d,J = 2.5 Hz, 1H), 7.34 (d,J = 9.1 Hz, 1H), 7.28 (d,J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.83 (d,J = 8.6 Hz, 1H), 6.57 (s, 2H), 4.19 (m, 1H), 3.91-3.83 (m, 2H),3.80 (s, 3H), 3.48-3.36 (m, 6H), 2.66 (d,J = 115.6 Hz, 8H), 2.46（s, 3H), 2.02 (d,J = 12.7 Hz, 2H), 1.85 (d,J = 11.6 Hz, 2H), 1.63-1.43 (m, 4H).
419 三氟乙酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.09 (s, 1H), 11.56 (s, 1H), 9.10 (s, 1H), 8.05 (s, 1H), 7.85 (d,J = 2.4 Hz, 1H), 7.59 (dd,J = 8.9, 2.5 Hz, 1H), 7.41 (s, 1H), 7.28 (d,J = 2.4 Hz, 1H), 7.23 (dd,J = 8.9, 1.4 Hz, 1H), 7.13 (d,J = 2.5 Hz, 1H), 4.21 (d,J = 7.9 Hz, 1H), 3.88 (m, 2H), 3.56-3.42 (m, 6H), 3.36-3.28 (m, 1H), 3.05 (m, 2H), 2.80 (s, 3H), 2.72 (t,J = 11.7 Hz, 2H), 2.06 (m, 4H), 1.75-1.45 (m, 6H), 1.23 (m, 2H).
421 1 H NMR (400 MHz, CDCl3 ) δ 10.84 (s, 1H), 10.31 (s, 1H), 8.74 (d,J = 7.3 Hz, 1H), 7.65 (dd,J = 8.6, 2.5 Hz, 1H), 7.60 (d,J = 2.5 Hz, 1H), 7.50 (s, 1H), 6.93 (d,J = 8.7 Hz, 1H), 6.90 (d,J = 2.5 Hz, 1H), 6.83 (d,J = 2.5 Hz, 1H), 5.20 (s, 1H), 4.30 (ddt,J = 14.1, 9.8, 5.2 Hz, 1H), 4.00 (dt,J = 11.8, 3.9 Hz, 2H), 3.76-3.69 (m, 1H), 3.60 (ddd,J = 12.0, 10.4, 2.5 Hz, 2H), 3.33 (d,J = 11.5 Hz, 2H), 2.77-2.40 (m, 9H), 2.34 (dt,J = 10.7, 3.2 Hz, 1H), 2.29 (s, 3H), 2.10 (d,J = 13.0 Hz, 2H), 1.94 (d,J = 12.1 Hz, 2H), 1.86-1.81 (m, 1H), 1.77-1.65 (m, 4H), 1.00-0.94 (m, 2H), 0.73-0.68 (m, 2H).
503 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 11.33 (s, 1H), 9.04 (s, 1H), 7.98 (s, 1H), 7.80 (d,J = 2.4 Hz, 1H), 7.62 (d,J = 2.6 Hz, 1H), 7.33 (dd,J = 8.6, 2.7 Hz, 1H), 7.31 (s, 1H), 7.18 (d,J = 2.4 Hz, 1H), 7.02 (d,J = 8.7 Hz, 1H), 6.48 (s, 2H), 4.65 (s, 2H), 4.51 (s, 2H), 4.27 (m, 1H), 2.95 (d,J = 11.1 Hz, 2H), 2.74 (ddd,J = 10.2, 7.5, 2.9 Hz, 2H), 2.61 (dt,J = 21.1, 9.7 Hz, 11H), 2.33 (d,J = 2.6 Hz, 3H), 2.15 (td,J = 8.7, 3.0 Hz, 2H), 1.84 (d,J = 11.6 Hz, 2H), 1.54 (td,J = 12.7, 11.9, 8.9 Hz, 2H), 1.18 (t,J = 7.5 Hz, 3H).
504 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (s, 1H), 11.39 (s, 1H), 9.08 (s, 1H), 7.99 (s, 1H), 7.83 (d,J = 2.4 Hz, 1H), 7.34 (d,J = 2.3 Hz, 2H), 7.22 (s, 1H), 7.13 (dd,J = 8.5, 2.3 Hz, 1H), 6.85 (d,J = 8.6 Hz, 1H), 6.55 (s, 2H), 4.65 (s, 2H), 4.52 (s, 2H), 4.38 (q,J = 7.5 Hz, 1H), 3.81 (s, 3H), 3.34 (m, 2H), 2.79-2.72 (m, 2H), 2.56 (d,J = 20.6 Hz, 8H), 2.33 (m, 1H), 2.24 (s, 3H), 2.15 (dd,J = 14.5, 6.2 Hz, 2H), 1.82 (m, 2H), 1.55 (m, 2H).
511 1 H NMR (400 MHz, CDCl3 ) δ 10.81 (s, 1H), 8.39 (s, 1H), 7.62 (d,J = 8.9 Hz, 2H), 7.55-7.45 (m, 2H), 7.30 (td,J = 6.3, 5.7, 4.0 Hz, 3H), 6.92 (d,J = 8.9 Hz, 2H), 6.54 (d,J = 2.8 Hz, 1H), 5.25 (d,J = 7.2 Hz, 1H), 5.13 (s, 1H), 4.23-4.14 (m, 1H), 3.96 (d,J = 11.7 Hz, 2H), 3.69 (d,J = 11.9 Hz, 2H), 3.56-3.47 (m, 2H), 2.77-2.37 (m, 11H), 2.32 (s, 3H), 2.00 (dd,J = 26.0, 11.4 Hz, 4H), 1.72 (dd,J = 11.8, 3.8 Hz, 2H), 1.49-1.42 (m, 2H).
512 1H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 11.10 (s, 1H), 8.25 (d,J = 4.9 Hz, 1H), 7.57-7.40 (m, 4H), 7.39-7.24 (m, 2H), 6.90 (d,J = 9.1 Hz, 2H), 6.49 (d,J = 7.3 Hz, 1H), 6.40 (dd,J = 3.5, 1.9 Hz, 1H), 4.16-4.02 (m, 1H), 3.84 (d,J = 10.8 Hz, 2H), 3.62 (d,J = 11.8 Hz, 2H), 3.37 (dd,J = 12.7, 10.7 Hz, 2H), 2.58 (t,J = 11.8 Hz, 2H), 2.38-2.16 (m, 4H), 2.10 (s, 3H), 1.82 (t,J = 12.6 Hz, 4H), 1.47 (qd,J = 11.9, 4.1 Hz, 4H).
513 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 11.24 (s, 1H), 7.58 (d,J = 2.5 Hz, 1H), 7.50-7.44 (m, 2H), 7.41 (t,J = 2.8 Hz, 1H), 7.25-7.17 (m, 3H), 7.04 (s, 1H), 6.37-6.34 (m, 1H), 6.06 (d,J = 7.4 Hz, 1H), 4.14-4.08 (m, 1H)，3.85 (d,J = 11.3 Hz, 2H), 3.70 (m, 4H), 3.37 (m, 6H), 3.19 (s, 2H), 2.84 (s, 3H), 2.71 (m, 3H), 2.30 (s, 3H), 2.18 (m, 2H), 1.88 (d,J = 12.8 Hz, 4H), 1.47 (d,J = 13.7 Hz, 2H).
515 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.28 (s, 1H), 7.56 (d,J = 8.8 Hz, 1H), 7.50 (d,J = 2.6 Hz, 1H), 7.49-7.44 (m, 1H), 7.41 (t,J = 2.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.11 (s, 1H), 6.38-6.33 (m, 1H), 6.07 (d,J = 7.5 Hz, 1H), 4.17 (s, 1H), 3.89-3.64 (m, 7H), 3.42-3.29 (m, 5H), 3.11 (s, 2H), 2.84 (s, 3H), 2.71 (m, 5H), 2.18 (m, 2H), 1.87 (m, 4H), 1.54-1.42 (m, 2H), 1.27-1.20 (m,3H).
519 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 11.26 (s, 1H), 7.92 (d,J = 15.6 Hz, 1H), 7.45 (d,J = 7.1 Hz, 2H), 7.38 (d,J = 2.9 Hz, 1H), 7.34 (s, 1H), 7.24-7.15 (m, 2H), 7.06 (d,J = 9.7 Hz, 1H), 6.97 (t,J = 9.3 Hz, 1H), 6.53 (s, 2H), 6.33 (s, 1H), 6.13 (d,J = 7.4 Hz, 1H), 4.11-4.08 (m, 1H), 3.84 (d,J = 11.6 Hz, 2H), 3.38 (t,J = 11.5 Hz, 2H), 3.30 (d,J = 11.3 Hz, 2H), 2.60 (t,J = 10.7 Hz, 10H), 2.37 (d,J = 11.2 Hz, 1H), 2.30 (s, 3H), 1.85 (t,J = 12.8 Hz, 4H), 1.58-1.40 (m, 4H).
521 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.26 (s, 1H), 11.11 (s, 1H), 7.53 (d,J = 8.6 Hz, 2H), 7.43 (dd,J = 6.1, 3.0 Hz, 1H), 7.38 (d,J = 2.9 Hz, 2H), 7.24 (s, 1H), 7.17 (d,J = 6.1 Hz, 2H), 6.89 (d,J = 8.6 Hz, 2H), 6.52 (s, 2H), 6.32 (d,J = 2.8 Hz, 1H), 5.79 (d,J = 7.6 Hz, 1H), 4.20 (q,J = 6.7 Hz, 1H), 3.61 (d,J = 11.9 Hz, 2H), 2.63-2.46 (m, 10H), 2.35-2.28 (m, 1H), 2.24 (s, 3H), 1.82 (d,J = 12.2 Hz, 2H), 1.49 (p,J = 10.5, 9.9 Hz, 2H), 1.13 (d,J = 6.4 Hz, 6H).
522 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 11.13 (s, 1H), 7.73 (d,J = 8.6 Hz, 2H), 7.41 (dt,J = 6.3, 3.3 Hz, 2H), 7.36 (d,J = 3.0 Hz, 1H), 7.27 (s, 1H), 7.15 (d,J = 3.6 Hz, 2H), 6.89 (d,J = 8.6 Hz, 2H), 6.52 (s, 2H), 6.42 (d,J = 2.6 Hz, 1H), 6.27 (d,J = 3.1 Hz, 1H), 3.61 (d,J = 12.1 Hz, 2H), 2.74 (dq,J = 6.8, 3.5 Hz, 1H), 2.65-2.47 (m, 10H), 2.36-2.28 (m, 1H), 2.24 (s, 3H), 1.82 (d,J = 12.1 Hz, 2H), 1.55-1.41 (m, 2H), 0.79-0.70 (m, 2H), 0.51 (p,J = 4.6 Hz, 2H).
525 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.24 (s, 1H), 11.05 (s, 1H), 7.55 (d,J = 8.6 Hz, 2H), 7.46-7.36 (m, 3H), 7.24-7.14 (m, 3H), 6.90 (d,J = 8.7 Hz, 2H), 6.49 (s, 3H), 6.30 (d,J = 2.6 Hz, 1H), 6.26 (d,J = 5.6 Hz, 1H), 4.35 (q,J = 6.3 Hz, 1H), 4.21 (p,J = 6.0 Hz, 1H), 3.64 (d,J = 9.2 Hz, 2H), 2.73-2.53 (m, 10H), 2.44-2.36 (m, 1H), 2.33 (s, 3H), 2.23-2.11 (m, 4H), 1.84 (d,J = 12.0 Hz, 2H), 1.51 (dt,J = 12.0, 6.6 Hz, 2H).
526 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.24 (s, 1H), 11.05 (s, 1H), 7.54 (d,J = 8.6 Hz, 2H), 7.45-7.41 (m, 1H), 7.38 (dt,J = 5.8, 2.9 Hz, 2H), 7.21 (d,J = 3.1 Hz, 1H), 7.16 (d,J = 4.5 Hz, 2H), 6.88 (d,J = 8.7 Hz, 2H), 6.49 (s, 2H), 6.29 (d,J = 3.1 Hz, 1H), 5.76 (d,J = 7.3 Hz, 1H), 5.69 (s, 1H), 3.86-3.74 (m, 2H), 3.63-3.56 (m, 2H), 2.56 (q,J = 18.3, 15.2 Hz, 10H), 2.34 (t,J = 11.3 Hz, 1H), 2.26 (s, 3H), 1.91 (d,J = 10.8 Hz, 2H), 1.81 (t,J = 14.7 Hz, 4H), 1.50 (qd,J = 12.4, 3.9 Hz, 2H), 1.21 (q,J = 13.1, 12.5 Hz, 4H).
527 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (d,J = 2.4 Hz, 1H), 10.99 (s, 1H), 7.53-7.48 (m, 2H), 7.42 (dd,J = 6.1, 3.0 Hz, 1H), 7.36 (t,J = 2.8 Hz, 2H), 7.23 (d,J = 3.3 Hz, 1H), 7.15 (q,J = 3.7, 3.2 Hz, 2H), 6.93-6.87 (m, 2H), 6.53 (s, 3H), 6.38 (d,J = 6.4 Hz, 1H), 6.28 (t,J = 2.5 Hz, 1H), 4.59 (s, 2H), 4.39 (s, 2H), 4.18 (h,J = 7.8 Hz, 1H), 2.68-2.49 (m, 12H), 2.38 (dd,J = 12.9, 9.1 Hz, 1H), 2.32 (s, 3H), 2.12-2.03 (m, 2H), 1.83 (d,J = 12.1 Hz, 2H), 1.74-1.68 (m, 1H), 1.50 (qd,J = 12.1, 3.8 Hz, 2H), 1.31 (s, 1H)
528 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.27 (s, 1H), 11.09 (s, 1H), 7.55-7.49 (m, 2H), 7.44 (dd,J = 6.7, 2.4 Hz, 1H), 7.38 (q,J = 2.9, 2.3 Hz, 2H), 7.24 (d,J = 3.1 Hz, 1H), 7.21-7.15 (m, 2H), 6.89 (d,J = 8.5 Hz, 2H), 6.50 (s, 1H), 6.35 (t,J = 2.5 Hz, 1H), 5.99 (t,J = 5.6 Hz, 1H), 3.61 (d,J = 11.9 Hz, 2H), 3.35 (d,J = 5.6 Hz, 2H), 2.62-2.43 (m, 10H), 2.29 (t,J = 11.2 Hz, 1H), 2.21 (d,J = 2.4 Hz, 3H), 1.81 (d,J = 12.2 Hz, 2H), 1.54-1.42 (m, 2H), 1.06 (d,J = 1.4 Hz, 6H).
538 三氟乙酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.03 (d,J = 2.8 Hz, 1H), 11.33 (s, 1H), 9.19 (s, 1H), 8.52 (s, 1H), 8.30 (t,J = 2.9 Hz, 1H), 7.64 (d,J = 8.5 Hz, 3H), 7.41 (s, 1H), 7.11 (d,J = 8.5 Hz, 2H), 6.85 (d,J = 7.2 Hz, 1H), 6.80 (dt,J = 2.6, 1.5 Hz, 1H), 4.12 (dt,J = 11.1, 5.5 Hz, 1H), 3.91-3.83 (m, 2H), 3.77 (d,J = 12.2 Hz, 2H), 3.64-3.00 (m, 11H), 2.82 (m+s, 5H), 2.09 (d,J = 12.0 Hz, 2H), 1.92-1.83 (m, 2H), 1.74 (q,J = 11.4, 10.5 Hz, 2H), 1.44 (qd,J = 12.5, 4.3 Hz, 2H).
540 1 H NMR (400 MHz, CDCl3 ) δ 10.75 (s, 1H), 8.45 (s, 1H), 7.55-7.49 (m, 3H), 7.49-7.45 (m, 1H), 7.32-7.28 (m, 3H), 6.97-6.92 (m, 2H), 6.54 (ddd,J = 3.1, 2.0, 0.9 Hz, 1H), 5.67 (d,J = 5.8 Hz, 1H), 5.17 (s, 1H), 5.09 (q,J = 6.6 Hz, 1H), 4.91 (t,J = 6.9 Hz, 2H), 4.44 (t,J = 6.4 Hz, 2H), 3.70 (d,J = 11.8 Hz, 2H), 2.75-2.41 (m, 10H), 2.37 (ddt,J = 11.3, 7.7, 3.8 Hz, 1H), 2.28 (s, 3H), 1.95 (d,J = 13.0 Hz, 2H), 1.71 (td,J = 12.0, 3.8 Hz, 2H).
611 1 H NMR (400 MHz, CDCl3 ) δ 10.90 (s, 1H), 8.74-8.68 (m, 2H), 7.63-7.56 (m, 2H), 7.56-7.51 (m, 2H), 7.41 (s, 1H), 6.93 (d,J = 8.9 Hz, 2H), 5.20 (s, 1H), 5.09 (d,J = 7.4 Hz, 1H), 4.29 (h,J = 6.6 Hz, 1H), 3.70 (d,J = 12.0 Hz, 2H), 2.77-2.62 (m, 6H), 2.53 (s, 4H), 2.38 (d,J = 12.3 Hz, 1H), 2.32 (s, 3H), 1.96 (d,J = 12.5 Hz, 2H), 1.77-1.71 (m, 2H), 1.25 (d,J = 1.8 Hz, 6H).
612 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.91 (d,J = 5.3 Hz, 1H), 7.57 (s, 1H), 7.47 (d,J = 8.5 Hz, 2H), 7.34 (s, 1H), 6.89 (d,J = 8.6 Hz, 2H), 6.83 (d,J = 5.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d,J = 7.2 Hz, 1H), 6.54 (s, 4H), 6.03 (s, 2H), 4.03 (s, 1H), 3.88 (s, 2H), 3.63 (d,J = 11.7 Hz, 2H), 3.36 (d,J = 11.4 Hz, 2H), 2.60 (d,J = 14.1 Hz, 10H), 2.40 (d,J = 11.5 Hz, 1H), 2.32 (s, 3H), 1.83 (d,J = 12.1 Hz, 4H), 1.54 (ddd,J = 31.1, 12.9, 7.9 Hz, 4H).
615 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 11.70 (s, 1H), 9.15 (s, 1H), 8.06 (s, 1H), 7.94-7.81 (m, 3H), 7.67 (d,J = 8.6 Hz, 2H), 7.41 (d,J = 30.4 Hz, 1H), 7.27 (d,J = 2.4 Hz, 1H), 4.42 (q,J = 6.6 Hz, 2H), 3.75 (s, 8H), 3.55 (d,J = 2.3 Hz, 6H), 2.84 (s, 3H), 2.45-2.34 (m, 4H), 2.28 (ddd,J = 12.6, 6.8, 3.8 Hz, 2H).
616 鹽酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 11.68 (s, 1H), 8.93 (d,J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.82 (q,J = 3.2 Hz, 3H), 7.67 (s, 2H), 7.40 (d,J = 11.6 Hz, 1H), 7.25 (d,J = 2.4 Hz, 1H), 4.24 (q,J = 6.5 Hz, 1H), 3.75-3.59 (m, 12H), 2.82 (s, 3H), 2.37 (s, 4H), 1.32 (d,J = 6.4 Hz, 6H).
627 富馬酸鹽 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (s, 1H), 11.20 (s, 1H), 8.96 (s, 1H), 7.95 (s, 1H), 7.82 (d,J = 2.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.31 (s, 1H), 7.20 (d,J = 2.4 Hz, 1H), 6.95-6.88 (m, 2H), 6.55 (s, 2H), 4.68 (s, 2H), 4.52 (s, 2H), 4.27-4.23 (m, 1H), 3.65 (d,J = 11.8 Hz, 2H), 2.75 (ddd,J = 10.1, 7.4, 2.8 Hz, 2H), 2.68-2.51 (m, 10H), 2.40-2.33 (m, 1H), 2.29 (s, 3H), 2.20-2.09 (m, 2H), 1.85 (d,J = 12.2 Hz, 2H), 1.58-1.45 (m, 2H).
實施例 2 本發明化合物對 EGFR(Del19/T790M/C797S) 、 EGFR(L858R/T790M/C797S) 或 EGFR(WT) 酶的抑制活性的檢測
運用HTRF方法測定化合物對EGFR (Del19/T790M/C797S)、EGFR (L858R/T790M/C797S)或EGFR(WT)酶活的抑制作用。具體如下。
將WT或者突變型EGFR蛋白與梯度稀釋的化合物在28 ℃孵育10分鐘後加入biotin-標記的通用酪氨酸激酶底物 (TK) 和ATP，在室溫反應40分鐘。終止反應後加入針對 TK的Eu3+-Cryptate 標記抗體和streptavidin-XL665，在室溫孵育60分鐘。通過檢測615nm 和665nm 的發光，計算665/615的比值，定量TK底物磷酸化的水準。與對照組相比，計算化合物抑制百分比和IC50 。 結果見下列表4。
表 4. 本發明化合物對 EGFR (Del19/T790M/C797S) 、 EGFR (L858R/T790M/C797S) 或 EGFR (WT) 的抑制活性
化合物 EGFR(Del19/T790M/C797S) 抑制率 (%) （ 0.3 nM 化合物） EGFR (WT) IC50 (nM) EGFR(L858R/T790M/C797S) 抑制率 (%) （ 0.3 nM 化合物）
1 + ＞300 +
2 + ＞100 N.D
4 + ＞100 +
5 + ＞100 +
6 + N.D N.D
7 + N.D N.D
8 + N.D N.D
9 + N.D N.D
10 ++ ＞300 N.D
11 ++ ＞300 N.D
12 + N.D N.D
13 + ＞300 N.D
14 + ＞300 N.D
15 + N.D N.D
16 + N.D N.D
17 + N.D N.D
18 + N.D N.D
19 + N.D N.D
21 ++ ＞300 N.D
22 + N.D N.D
23 ++ N.D +
24 ++ N.D N.D
25 + N.D N.D
27 + N.D N.D
28 + N.D N.D
29 ++ N.D N.D
30 ++ N.D N.D
31 +++ N.D N.D
32 +++ N.D N.D
33 +++ N.D N.D
35 ++ N.D +
36 + N.D N.D
37 + N.D N.D
38 ++ N.D ++
39 +++ ＞300 +++
40 + N.D N.D
42 + N.D N.D
43 + N.D N.D
44 + N.D N.D
45 + N.D N.D
46 + N.D N.D
47 + N.D N.D
49 + N.D N.D
50 + N.D N.D
51 + N.D N.D
52 +++ ＞300 N.D
53 + N.D N.D
54 + N.D N.D
55 +++ ＞300 +
56 + N.D N.D
57 ++ ＞300 ++
59 + ＞300 N.D
60 ++ N.D +
61 ++ N.D N.D
62 + N.D N.D
63 + N.D N.D
64 + N.D N.D
65 ++ N.D N.D
66 + N.D N.D
67 + N.D N.D
68 + N.D N.D
69 + N.D +
70 + N.D N.D
71 + N.D N.D
72 + N.D N.D
82 + N.D N.D
83 ++ N.D ++
88   N.D N.D
90 + N.D N.D
91 ++ N.D N.D
92 ++ N.D N.D
93 ++ N.D N.D
94 ++ N.D +
95 ++ N.D N.D
96 ++ N.D N.D
98 + N.D N.D
99 + N.D N.D
100 + N.D N.D
101 + N.D N.D
102 + N.D N.D
103 ++ N.D N.D
105 + N.D N.D
106 + N.D N.D
107 + N.D N.D
108 +++ N.D N.D
109 + N.D N.D
110 + N.D N.D
111 + N.D N.D
112 + N.D N.D
113 + N.D N.D
114 ++ N.D +++
116 + N.D N.D
117 + N.D N.D
118 ++ N.D N.D
119 + N.D N.D
120 + N.D N.D
121 +++ N.D +++
122 +++ N.D N.D
123 ++ N.D N.D
124 + N.D N.D
125 ++ N.D ++
126 + N.D +
133 ++ N.D N.D
134 ++ N.D N.D
136 ++ N.D N.D
137 ++ N.D ++
138 ++ N.D N.D
139 ++ N.D N.D
146 ++ N.D N.D
154 ++ N.D N.D
177 ++ N.D N.D
206 ++ N.D N.D
207 ++ N.D N.D
255 ++ N.D N.D
263 ++ N.D N.D
264 ++ N.D N.D
271 ++ N.D N.D
379 ++ N.D N.D
383 ++ N.D N.D
503 +++ 10.16 +
511 +++ 2.82 +++
512 +++ N.D N.D
519 +++ N.D +++
520 +++ N.D N.D
521 +++ 0.27 +++
522 +++ 0.22 +++
523 +++ N.D +++
524 +++ N.D +++
525 +++ N.D N.D
526 +++ 0.33 +++
527 +++ 1.7 +++
528 +++ N.D N.D
529 +++ N.D N.D
530 +++ N.D N.D
531 +++ N.D N.D
532 +++ N.D +++
533 +++ N.D N.D
534 +++ N.D N.D
535 +++ N.D +++
536 +++ N.D +++
537 +++ N.D N.D
594 +++ N.D +++
595 +++ N.D N.D
596 +++ N.D N.D
609 +++ N.D N.D
610 +++ N.D N.D
611 +++ N.D N.D
614 +++ N.D N.D
615 +++ N.D N.D
616 +++ N.D N.D
617 ++ N.D N.D
618 ++ N.D N.D
619 ++ N.D N.D
620 ++ N.D N.D
621 +++ N.D N.D
622 +++ N.D N.D
623 +++ N.D N.D
624 ++ N.D N.D
625 +++ N.D N.D
626 +++ N.D N.D
627 ++ N.D N.D
628 ++ N.D N.D
629 +++ N.D N.D
630 +++ N.D N.D
631 +++ N.D N.D
632 +++ N.D N.D
633 +++ N.D N.D
634 +++ N.D N.D
635 +++ N.D N.D
638 +++ N.D N.D
639 +++ N.D N.D
640 +++ N.D N.D
641 +++ N.D N.D
642 +++ N.D N.D
643 +++ N.D N.D
644 +++ N.D N.D
645 +++ N.D N.D
Gilteritinib + N.D +
+表示抑制率小於或等於20% ++表示抑制率為20%至50% +++表示抑制率大於50%。 N.D表示活性未測
從表4數據可知，本發明化合物對EGFR (Del19/T790M/C797S)和EGFR (L858R/T790M/C797S)的酶活性有較好的抑制活性，且對EGFR (WT)有較好的選擇性。
實施例 3 本發明化合物對 Ba/F3(EGFRDel19/T790M/C797S) 三突變細胞和 A431 (EGFR WT) 細胞的抗增殖活性
3000個攜帶EGFR(Del19/T790M/C797S)的Ba/F3 細胞， 或者2000個A431細胞種植於384孔板中，生長一天後，加入梯度稀釋的化合物（Ba/F3細胞最高500 nM，A431細胞最高10 uM）。加入化合物三天後，加入Cell Titer Glow評價細胞生長，計算化合物抑制細胞生長的百分率和IC50 值，結果見下列表5。
表 5. 本發明化合物對 Ba/F3 (EGFRDel19/T790M/C797S) 三突變細胞和 A431 野生型 (EGFR WT) 細胞的抗增殖活性
化合物 細胞抗增殖活性 BaF3(EGFRDel19/T790M/C797S) IC50 (nM) 細胞抗增殖活性 A431 野生型 (WT) IC50 (μM)
1 236 2.5
4 295 1.7
11 107 0.54
13 197 1.3
14 113 0.95
21 48 0.52
23 36 0.95
31 65 0.54
32 26 0.19
33 63 0.22
35 54 0.48
37 48 ＞2
38 48 1.8
39 29 0.34
54 ＞100 3.5
55 16 0.07
57 79 0.32
59 72 1.4
74 ＞100 2.1
83 233 0.75
85 357 1.5
86 21 1.7
88 52 0.28
96 ＞100 1.6
108 23 0.19
110 ＞100 0.46
111 105 0.12
114 27 0.97
115 214 2.0
118 82 4.1
119 ＞100 ＞10
120 119 0.68
121 70 0.59
122 40 0.38
123 140 ＞10
124 ＞100 ＞10
125 99 0.65
126 248 2.6
131 ＞100 ＞10
135 40 0.34
141 27 0.23
148 68 1.7
161 54 1.2
174 51 1.0
177 19 0.69
184 18 0.98
213 226 ＞10
417 57 0.19
420 32 3.7
421 36 0.53
503 61 0.66
504 98 0.33
511 9 0.06
512 6 0.02
513 57 0.56
514 48 0.25
515 42 0.52
516 42 0.35
521 4 0.05
522 2 0.03
525 25 0.06
526 5 0.1
527 4 0.1
528 13 0.07
529 18 0.05
538 35 0.29
540 48 1.2
594 13 0.07
611 21 0.36
616 32 0.36
Gilteritinib ＞500  
從表5數據可知，本發明絕大多數化合物對Ba/F3 (EGFRDel19/T790M/C797S)三突變細胞的抗增殖活性都小於100 nM，而Gilteritinib對於Ba/F3 (EGFRDel19/T790M/C797S)三突變細胞的抗增殖活性大於500 nM，可見Y為芳基、雜芳基或者雜環烷基時，化合物都具有很強的Ba/F3 (EGFRDel19/T790M/C797S)三突變細胞的抗增殖活性。
實施例 4 體內藥效研究 – 小鼠 H1975 皮下移植瘤模型
BALB/c裸小鼠左側背部皮下接種5×106 攜帶EGFR T790M突變的H1975細胞，待腫瘤生長到100至150 mm3 ，隨機分組後，分別灌胃給藥，組1：溶媒對照組；組2：化合物511 (給藥劑量60 mg/kg)，給藥方式口服，給藥頻率每天一次；組3：化合物511 (給藥劑量80 mg/kg)，給藥方式口服，給藥頻率每天一次。每週兩次以及給藥終點測量腫瘤體積。按照腫瘤生長率抑制率（TGI）=1－（給藥組第28天腫瘤體積－給藥組第一天腫瘤體積）/（溶媒對照組第28天腫瘤體積－給藥組第一天腫瘤體積），計算化合物腫瘤生長抑制率。結果見圖1和表6。
表 6. 小鼠 H1975 皮下移植瘤生長抑制率
化合物 劑量 TGI
溶媒對照組 不適用 不適用
化合物511 60 mg/kg 99%
化合物511 80 mg/kg 104%
由圖1和表6可見，化合物511在60 mg/kg和80 mg/kg劑量下，在攜帶EGFR T790M突變的H1975小鼠皮下移植瘤模型中能夠抑制腫瘤生長。
實施例 5 體內藥效研究 – 小鼠 PC9(EGFR Del19/T790M/C797S) 皮下移植瘤模型
BALB/c裸小鼠左側背部皮下接種5×106 攜帶過表達EGFR Del19/T790M/C797S的PC9細胞，待腫瘤生長到100至150 mm3 ，隨機分組後，分別灌胃給藥，組1：溶媒對照組，給藥方式口服，給藥頻率每天一次；組2：化合物511 (給藥劑量60 mg/kg) ，給藥方式口服，給藥頻率每天一次；組3：化合物511 (給藥劑量80 mg/kg)，給藥方式口服，給藥頻率每天一次，每天一次。每週兩次以及給藥終點測量腫瘤體積。按照腫瘤生長率抑制率（TGI）=1－（給藥組第28天腫瘤體積－給藥組第一天腫瘤體積）/（溶媒對照組第28天腫瘤體積－給藥組第一天腫瘤體積），計算化合物腫瘤生長抑制率。結果見圖2。
表 7. 小鼠 PC9(EGFR Del19/T790M/C797S) 皮下移植瘤生長抑制率
化合物 劑量 TGI
溶媒對照組 不適用 不適用
化合物511 60 mg/kg 87.41%
化合物511 80 mg/kg 93.17%
由圖2和表7可見，化合物511在60 mg/kg和80 mg/kg劑量下，在攜帶過表達EGFR Del19/T790M/C797S突變的PC9小鼠皮下移植瘤模型中能夠抑制腫瘤生長。
惟以上所述者，僅為本發明的實施例而已，當不能以此限定本發明實施的範圍，凡是依本發明申請專利範圍及專利說明書內容所作的簡單的等效變化與修飾，皆仍屬本發明專利涵蓋的範圍內。
本發明的其他的特徵及功效，將於參照圖式的實施方式中清楚地呈現，其中： 圖1是本發明實施例4的小鼠體內藥效研究的腫瘤生長抑制率結果； 圖2是本發明實施例5的小鼠體內藥效研究的腫瘤生長抑制率結果。
Figure 110119810-A0101-11-0001-2

Claims (14)

  1. 一種結構如通式(1)所示的化合物或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物：
    Figure 03_image001
    通式(1)中， Y為(3-11元)雜環烷基、(C6-C14)芳基或(5-10元)雜芳基，其中所述雜環烷基、芳基和雜芳基可任選被1個或多個下列基團取代：-H、鹵素、-R4 、-OR4 、-(CH2 )n OR4 、-(CH2 )n NR4 R5 、-NR4 R5 、-CN、-C(O)NR4 R5 、-NR5 C(O)R4 、-NR5 S(O)2 R4 、-S(O)p R4 、-S(O)2 NR4 R5 和-O-CH2 -O-； L1 為-O-或-NH-； X 為(C6-C14)伸芳基或(5-11元)伸雜芳基，其中所述伸芳基和伸雜芳基可任選被1個或多個下列基團取代：-H、鹵素、(C1-C6)烷基、(C3-C6)環烷基、(C1-C6)烷氧基和(C1-C6)鹵代烷氧基； R1 為-H、鹵素、-(CH2 )n NR6 R7 、-NR6 R7 、-O(CH2 )m NR6 R7 、-N(R5 )(CH2 )m NR6 R7 、(C1-C6)烷氧基、-CH2 -(3-15元)雜環烷基或(3-15元)雜環烷基，其中所述烷氧基和雜環烷基可任選被1個或多個下列基團取代：-H、-R4 、-(CH2 )n NR6 R7 、-NR6 R7 、-O(CH2 )m NR6 R7 、-N(R5 )(CH2 )m NR6 R7 和-R3 ； L2 為-O-、-NH-或者化學鍵； R2 為(C1-C6)烷基、(C3-C14)環烷基、(C6-C14)芳基、(3-4元)雜環烷基、
    Figure 03_image007
    、
    Figure 03_image009
    、
    Figure 03_image011
    、
    Figure 03_image013
    、
    Figure 03_image015
    、
    Figure 03_image017
    、
    Figure 03_image019
    或(6-11元)雜環烷基；其中所述烷基、環烷基、芳基、雜環烷基、
    Figure 03_image007
    、
    Figure 03_image009
    、
    Figure 03_image011
    、
    Figure 03_image013
    、
    Figure 03_image015
    、
    Figure 03_image017
    和
    Figure 03_image019
    可任選被1個或多個下列基團取代：-H、鹵素、-R4 、-(CH2 )n OR4 -、-(CH2 )n NR4 R5 -、-OR4 、-NR4 R5 、-CN、-C(O)NR4 R5 、-NR5 C(O)R4 、-NR5 S(O)2 R4 、-S(O)p R4 和-S(O)2 NR4 R5 ； R3 為(3-11元)雜環烷基，其中所述雜環烷基可任選被1個或多個下列基團取代：-H、-CD3 、-R4 、-OR4 和-NR4 R5 ； R4 和R5 各自獨立地為-H、(C1-C6)烷基或(C3-C14)環烷基； R6 和R7 各自獨立地為-H、(C1-C6)烷基或(C3-C14)環烷基，或R6 和R7 與其連接的N原子能夠共同組成一個(3-11元)雜環烷基，所述雜環烷基可任選被1個或多個下列基團取代：-H、-CD3 、鹵素、-R4 和-OR4 ； R0 為(C1-C6)烷基或(C3-C14)環烷基；和 p為0、1或2的整數，n為0、1、2或3的整數，m為1、2或3的整數。
  2. 如請求項1所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，Y為(5-6元)雜環烷基、苯基或(5-9元)雜芳基，其中所述雜環烷基、苯基和雜芳基可任選被1個或多個下列基團取代：-H、-F、-Cl、-Br、-CN、-OH、-OCH3 、-NH2 、-N(CH3 )2 、-NHCOCH3 、-NHSO2 CH3 、-CH3 、-CONH2 、-CH2 OH和-O-CH2 -O-。
  3. 如請求項2所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，Y為：
    Figure 03_image023
    、
    Figure 03_image025
    、
    Figure 03_image027
    、
    Figure 03_image029
    、
    Figure 03_image031
    、
    Figure 03_image033
    、
    Figure 03_image035
    、
    Figure 03_image037
    、
    Figure 03_image039
    、
    Figure 03_image041
    、
    Figure 03_image043
    、
    Figure 03_image045
    、
    Figure 03_image047
    、
    Figure 03_image049
    、
    Figure 03_image051
    、
    Figure 03_image053
    、
    Figure 03_image055
    、
    Figure 03_image057
    、
    Figure 03_image059
    、
    Figure 03_image061
    、
    Figure 03_image063
    、
    Figure 03_image065
    、
    Figure 03_image067
    、
    Figure 03_image069
    、
    Figure 03_image071
    、
    Figure 03_image073
    、
    Figure 03_image075
    、
    Figure 03_image077
    、
    Figure 03_image079
    、
    Figure 03_image081
    、
    Figure 03_image083
    、
    Figure 03_image085
    、
    Figure 03_image087
    、
    Figure 03_image089
    、
    Figure 03_image091
    、
    Figure 03_image093
    、
    Figure 03_image095
    、
    Figure 03_image097
    、
    Figure 03_image099
    、
    Figure 03_image101
    、
    Figure 03_image103
    、
    Figure 03_image105
    、
    Figure 03_image107
    、
    Figure 03_image109
    、
    Figure 03_image111
    、
    Figure 03_image113
    、
    Figure 03_image115
    、
    Figure 03_image117
    、
    Figure 03_image119
    、
    Figure 03_image121
    、
    Figure 03_image123
    、
    Figure 03_image125
    、
    Figure 03_image127
    、
    Figure 03_image129
    、
    Figure 03_image131
    、
    Figure 03_image133
    、
    Figure 03_image135
    、
    Figure 03_image137
    、
    Figure 03_image139
    、
    Figure 03_image141
    、
    Figure 03_image143
    、
    Figure 03_image145
    、
    Figure 03_image147
    、
    Figure 03_image149
    、
    Figure 03_image151
    、
    Figure 03_image153
    、
    Figure 03_image155
    、
    Figure 03_image157
    、
    Figure 03_image159
    、
    Figure 03_image161
    、
    Figure 03_image163
    、
    Figure 03_image165
    、
    Figure 03_image167
    、
    Figure 03_image169
    、
    Figure 03_image171
    、
    Figure 03_image173
    、
    Figure 03_image175
    、
    Figure 03_image177
    、
    Figure 03_image179
    、
    Figure 03_image181
    、
    Figure 03_image183
    、
    Figure 03_image185
    、
    Figure 03_image187
    、
    Figure 03_image189
    、
    Figure 03_image191
    、
    Figure 03_image193
    、
    Figure 03_image195
    、
    Figure 03_image197
    、
    Figure 03_image199
    、
    Figure 03_image201
    、
    Figure 03_image203
    、
    Figure 03_image205
    、
    Figure 03_image207
    、
    Figure 03_image209
    、
    Figure 03_image211
    、
    Figure 03_image213
    、
    Figure 03_image215
    、
    Figure 03_image217
    、
    Figure 03_image219
    、
    Figure 03_image221
    、
    Figure 03_image223
    、
    Figure 03_image225
    、
    Figure 03_image227
    、
    Figure 03_image229
    、
    Figure 03_image231
    、
    Figure 03_image233
    、
    Figure 03_image235
    、
    Figure 03_image237
    、
    Figure 03_image239
    、
    Figure 03_image241
    、
    Figure 03_image243
    、
    Figure 03_image245
    、
    Figure 03_image247
    、
    Figure 03_image249
    、
    Figure 03_image251
    、
    Figure 03_image253
    、
    Figure 03_image255
    、
    Figure 03_image257
    、
    Figure 03_image259
    、
    Figure 03_image261
    、
    Figure 03_image263
    或
    Figure 03_image265
    。
  4. 如請求項1至3中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，X 為伸苯基或6元伸雜芳基，其中所述伸苯基和伸雜芳基可任選被1個或多個下列基團取代：-H、-F、-CH3 、-CH2 CH3 、-CH(CH3 )2 、
    Figure 03_image267
    、-OCH3 、-OCF2 H和-OCF3 。
  5. 如請求項4所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，X為：
    Figure 03_image269
    、
    Figure 03_image271
    、
    Figure 03_image273
    、
    Figure 03_image275
    、
    Figure 03_image277
    、
    Figure 03_image279
    、
    Figure 03_image281
    、
    Figure 03_image283
    、
    Figure 03_image285
    、
    Figure 03_image287
    、
    Figure 03_image289
    、
    Figure 03_image291
    、
    Figure 03_image293
    、
    Figure 03_image295
    、
    Figure 03_image297
    、
    Figure 03_image299
    、
    Figure 03_image301
    、
    Figure 03_image303
    或
    Figure 03_image305
    。
  6. 如請求項1至5中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，R1 為：-H、-N(CH3 )2 、-CH2 -(6-11元)雜環烷基或(6-11元)雜環烷基，其中所述雜環烷基為：
    Figure 03_image307
    、
    Figure 03_image309
    、
    Figure 03_image311
    、
    Figure 03_image313
    、
    Figure 03_image315
    、
    Figure 03_image317
    、
    Figure 03_image319
    、
    Figure 03_image321
    、
    Figure 03_image323
    、
    Figure 03_image325
    、
    Figure 03_image327
    、
    Figure 03_image329
    、
    Figure 03_image331
    ，所述雜環烷基可任選被1個或多個下列基團取代：-H、-CH3 、
    Figure 03_image267
    、-N(CH3 )2 、
    Figure 03_image313
    、
    Figure 03_image333
    、
    Figure 03_image335
    、
    Figure 03_image337
    、
    Figure 03_image339
    、
    Figure 03_image341
    、
    Figure 03_image323
    、
    Figure 03_image325
    、
    Figure 03_image343
    和-CD3 。
  7. 如請求項6所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，R1 為： -H、-N(CH3 )2 、
    Figure 03_image345
    、
    Figure 03_image347
    、
    Figure 03_image349
    、
    Figure 03_image351
    、
    Figure 03_image353
    、
    Figure 03_image355
    、
    Figure 03_image357
    、
    Figure 03_image359
    、
    Figure 03_image2536
    、
    Figure 03_image2538
    、
    Figure 03_image361
    、
    Figure 03_image363
    、
    Figure 03_image365
    、
    Figure 03_image367
    或
    Figure 03_image369
    。
  8. 如請求項1至7中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，當L2 為-NH-時，R2 為：
    Figure 03_image371
    、
    Figure 03_image373
    、
    Figure 03_image375
    、
    Figure 03_image377
    、
    Figure 03_image379
    、
    Figure 03_image381
    、
    Figure 03_image383
    、
    Figure 03_image385
    、
    Figure 03_image387
    、
    Figure 03_image389
    、
    Figure 03_image391
    、
    Figure 03_image393
    、
    Figure 03_image395
    、
    Figure 03_image397
    、
    Figure 03_image399
    、
    Figure 03_image401
    、
    Figure 03_image403
    、
    Figure 03_image405
    、
    Figure 03_image407
    、
    Figure 03_image409
    、
    Figure 03_image411
    、
    Figure 03_image413
    、
    Figure 03_image415
    、
    Figure 03_image417
    、
    Figure 03_image419
    、
    Figure 03_image421
    、
    Figure 03_image423
    、
    Figure 03_image425
    、
    Figure 03_image427
    、
    Figure 03_image429
    、
    Figure 03_image431
    、
    Figure 03_image433
    、
    Figure 03_image435
    、
    Figure 03_image437
    、
    Figure 03_image439
    、
    Figure 03_image441
    、
    Figure 03_image443
    、
    Figure 03_image445
    、
    Figure 03_image447
    、
    Figure 03_image449
    、
    Figure 03_image451
    、
    Figure 03_image453
    、
    Figure 03_image455
    、
    Figure 03_image457
    、
    Figure 03_image459
    、
    Figure 03_image461
    、
    Figure 03_image463
    、
    Figure 03_image465
    、
    Figure 03_image467
    、
    Figure 03_image469
    、
    Figure 03_image471
    或
    Figure 03_image473
    。
  9. 如請求項1至7中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，當L2 為-O-時，R2 為：
    Figure 03_image475
    、
    Figure 03_image477
    、
    Figure 03_image479
    、
    Figure 03_image481
    、
    Figure 03_image483
    、
    Figure 03_image485
    、
    Figure 03_image487
    、
    Figure 03_image489
    、
    Figure 03_image491
    、
    Figure 03_image493
    或
    Figure 03_image495
    。
  10. 如請求項1至7中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述通式(1)中，當L2 為化學鍵時，R2 為：
    Figure 03_image497
    、
    Figure 03_image499
    、
    Figure 03_image467
    、
    Figure 03_image469
    、
    Figure 03_image503
    、
    Figure 03_image505
    或
    Figure 03_image507
    。
  11. 如請求項1所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，其中，所述化合物具有以下結構之一：
    Figure 03_image509
    Figure 03_image2604
    Figure 03_image513
    Figure 03_image515
    Figure 03_image517
    Figure 03_image519
    Figure 03_image521
    Figure 03_image523
    Figure 03_image525
    Figure 03_image527
    Figure 03_image529
    Figure 03_image531
    Figure 03_image533
    Figure 03_image2617
    Figure 03_image537
    Figure 03_image539
    Figure 03_image2621
    Figure 03_image2623
    。
  12. 一種藥物組合物，其含有藥學上可接受的賦形劑或載體，以及如請求項1至11中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物作為活性成分。
  13. 一種如請求項1至11中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物或如請求項12所述的藥物組合物在製備治療EGFR突變相關疾病藥物中的應用。
  14. 一種用於治療、調節和/或預防與EGFR突變蛋白相關的疾病的方法，包括對受試者給與治療有效量的如請求項1至11中任一項所述的化合物、或其各異構體、各晶型、藥學上可接受的鹽、水合物或溶劑合物，或如請求項12所述的藥物組合物。
TW110119810A 2020-06-01 2021-06-01 新型吡嗪化合物 TW202146406A (zh)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202010486394.1 2020-06-01
CN202010486394 2020-06-01
CN202010947590.4 2020-09-10
CN202010947590 2020-09-10
CN202110587528 2021-05-27
CN202110587528.3 2021-05-27

Publications (1)

Publication Number Publication Date
TW202146406A true TW202146406A (zh) 2021-12-16

Family

ID=78830119

Family Applications (1)

Application Number Title Priority Date Filing Date
TW110119810A TW202146406A (zh) 2020-06-01 2021-06-01 新型吡嗪化合物

Country Status (11)

Country Link
US (1) US20230167099A1 (zh)
EP (1) EP4159731A1 (zh)
JP (1) JP2023528859A (zh)
KR (1) KR20230019444A (zh)
CN (1) CN115698000A (zh)
AU (1) AU2021284676A1 (zh)
BR (1) BR112022022220A2 (zh)
CA (1) CA3179395A1 (zh)
MX (1) MX2022013397A (zh)
TW (1) TW202146406A (zh)
WO (1) WO2021244505A1 (zh)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2011011875A (es) * 2009-05-08 2011-12-08 Astellas Pharma Inc Compuesto de carboxamida heterociclica diamino.
US9085540B2 (en) * 2012-01-17 2015-07-21 Astellas Pharma Inc. Pyrazinecarboxamide compound
CN107207468A (zh) * 2015-01-28 2017-09-26 安斯泰来制药株式会社 吡嗪甲酰胺化合物的制造方法及其合成中间体
CA2987054A1 (en) * 2015-06-02 2016-12-08 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
CN108419436B (zh) * 2016-12-09 2021-05-04 深圳市塔吉瑞生物医药有限公司 一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途
CN110944989B (zh) 2017-07-19 2021-06-25 正大天晴药业集团股份有限公司 作为egfr激酶抑制剂的芳基磷氧化合物

Also Published As

Publication number Publication date
CA3179395A1 (en) 2021-12-09
CN115698000A (zh) 2023-02-03
BR112022022220A2 (pt) 2022-12-13
AU2021284676A1 (en) 2023-02-02
KR20230019444A (ko) 2023-02-08
JP2023528859A (ja) 2023-07-06
WO2021244505A1 (zh) 2021-12-09
MX2022013397A (es) 2022-12-13
EP4159731A1 (en) 2023-04-05
US20230167099A1 (en) 2023-06-01

Similar Documents

Publication Publication Date Title
CN115335379B (zh) 含螺环的喹唑啉化合物
CN113767103B (zh) 新型螺环类K-Ras G12C抑制剂
WO2021129824A1 (zh) 新型K-Ras G12C抑制剂
JP2023508482A (ja) スピロ環含有キナゾリン化合物
CN115315427B (zh) Hpk1抑制剂及其制备方法和用途
WO2022063297A1 (zh) 喹唑啉衍生物及其制备方法和用途
WO2021254384A1 (zh) 新型吡啶并[2，3-d]嘧啶-7(8H)-酮衍生物
CN113045570A (zh) 含螺环的喹唑啉化合物
TWI823255B (zh) 作為Wee-1抑制劑的稠環化合物
CN113880804A (zh) 新型苯并咪唑化合物
WO2022171088A1 (zh) 吡唑并[3,4-d]嘧啶-3-酮衍生物
EP4159731A1 (en) New pyrazine compound
CN113754659A (zh) 含螺环的喹唑啉化合物
WO2022012593A1 (zh) 5，6-二氢吡嗪并[2，3-c]异喹啉化合物
WO2023143344A1 (zh) 新型egfr抑制剂
WO2022228511A1 (zh) 作为Wee-1抑制剂的稠环化合物及其制备方法和用途
WO2022262857A1 (zh) 芳基氧膦类化合物
WO2022171126A1 (zh) 作为Wee-1抑制剂的稠环化合物
WO2022228512A1 (zh) 作为Wee-1抑制剂的吡咯并嘧啶衍生物
WO2023051717A1 (zh) 作为shp2抑制剂的稠环化合物
CN118119622A (zh) 作为shp2抑制剂的稠环化合物
TW202306955A (zh) 作為atr抑制劑的萘啶衍生物及其製備方法
WO2023116527A1 (zh) 作为fak抑制剂的化合物及其用途
WO2023083373A1 (zh) 作为Src抑制剂的化合物
WO2023160614A1 (zh) 作为fak抑制剂的化合物及其用途