TW201305118A - 雜環化合物及其用途 - Google Patents
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- TW201305118A TW201305118A TW100139631A TW100139631A TW201305118A TW 201305118 A TW201305118 A TW 201305118A TW 100139631 A TW100139631 A TW 100139631A TW 100139631 A TW100139631 A TW 100139631A TW 201305118 A TW201305118 A TW 201305118A
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- VTZVEVBBXGRODA-UHFFFAOYSA-N tert-butyl 4-[3-methoxy-4-[[4-[3-(prop-2-enoylamino)phenoxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]piperazine-1-carboxylate Chemical compound COC1=CC(N2CCN(CC2)C(=O)OC(C)(C)C)=CC=C1NC(N=1)=NC=C(C(F)(F)F)C=1OC1=CC=CC(NC(=O)C=C)=C1 VTZVEVBBXGRODA-UHFFFAOYSA-N 0.000 description 1
- FHDQQJPNVWQLDP-UHFFFAOYSA-N tert-butyl 4-[4-[[5-chloro-4-[3-(prop-2-enoylamino)phenoxy]pyrimidin-2-yl]amino]-3-methoxyphenyl]-1,4-diazepane-1-carboxylate Chemical compound COC1=CC(N2CCN(CCC2)C(=O)OC(C)(C)C)=CC=C1NC(N=1)=NC=C(Cl)C=1OC1=CC=CC(NC(=O)C=C)=C1 FHDQQJPNVWQLDP-UHFFFAOYSA-N 0.000 description 1
- IEUIEMIRUXSXCL-UHFFFAOYSA-N tert-butyl n-(3-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(N)=C1 IEUIEMIRUXSXCL-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
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- 238000002054 transplantation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 239000010455 vermiculite Substances 0.000 description 1
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- 235000019354 vermiculite Nutrition 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
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Abstract
本發明提供一種化合物、其醫藥上可接受的組合物、及其使用方法。
Description
本發明係關於適用作突變選擇性表皮生長因子受體(EGFR)激酶抑制劑之化合物。本發明亦提供包含本發明化合物之醫藥上可接受的組合物及使用該等組合物以治療多種疾病之方法。
本發明主張2010年11月1日申請之美國臨時申請案第61/409,080號、2010年11月9日申請之第61/411,829號、2010年11月10日申請之第61/412,330號、及2011年9月13日申請之第61/534,323號之優先權,其等各以全文引用的方式併入本文中。
蛋白酪胺酸激酶係一類催化磷酸酯基自ATP或GTP轉移至位於蛋白質基質上之酪胺酸殘基之酶。受體酪胺酸激酶係用於藉由經由磷酸化事件激活二級訊息效應物,將信號自細胞外部傳導至內部。此等信號促進多種細胞過程,其包括增殖、碳水化合物利用、蛋白質合成、血管生成、細胞生長及細胞存活。
存在EGFR參與人類癌症之強有力先例,因為所有實體腫瘤中超過60%過度表現此等蛋白質或其配體中之至少一者。EGFR之過度表現係常見於乳腺、肺、頭及頸部、膀胱腫瘤中。
已在患有非小細胞肺癌之患者中識別EGFR之酪胺酸激酶域中之激活突變(Lin N. U.、Winer E. P.,Breast Cancer Res 6: 204-210,2004)。可逆抑制劑它賽瓦(Tarceva)(埃羅替尼(erlotinib))及易瑞沙(Iressa)(吉非替尼(gefitinib))係目前用於具有激活突變之非小細胞肺癌患者之一線療法。最常見的激活突變係L858R及delE746-A750。
此外,在大多數復發患者中,在至少一半此等臨床抗性患者中已檢測到獲得耐藥性(如藉由守門殘基T790M之突變)。此外,T790M亦可係預先存在,對於T790M突變而言,可能存在獨立的致瘤作用。例如,存在從未接受吉非替尼治療之具有L858R/T790M突變之患者。此外,生殖細胞系EGFR T790M突變係與某些家族肺癌相關。
目前開發中之藥物(包括二代共價抑制劑,如BIBW2992、HKI-272及PF-0299804)係有效抗T790M抗性突變,但是由於同時抑制WT EGFR而顯示劑量限制性毒性。因此,仍需要尋找適用作治療劑之突變選擇性EGFR激酶抑制劑。
現已發現本發明化合物及其醫藥上可接受的組合物作為突變選擇性EGFR激酶抑制劑係有效。該等化合物具有通式I:
或其醫藥上可接受的鹽,其中n、m、W、G、R1、R2、及R5各係如本文所定義及描述。
本發明化合物及其醫藥上可接受的組合物係適用於治療與一或多種EGFR突變相關之癌症。此等疾病、病症、或症狀包括彼等本文所述者。
本發明所提供之化合物亦適用於生物學及病理學現象中之激酶研究;由此等激酶所介導之細胞內信號傳導途徑之研究;及新穎激酶抑制劑之比較評估。
在某些實施例中,本發明提供一種式I化合物或其醫藥上可接受的鹽:
其中:n係0、1、或2;m係0、1、或2,其中m及n不同時為0;W係-O-或-NH-;R1係-OR;各R獨立地為C1-4烷基或C1-4氟烷基;R2係-CF3、Cl、或Br;G係-O-、-NR3-、-S(O)2-、或-CH(OR4)-;R3係-C(O)-R、-C(O)OR、-C(O)NHR、-SO2-R、-SO2NH2、-C(O)-C1-4伸烷基-OH或-SO2-C1-4伸烷基-OH;R4係氫、C1-4烷基、或C1-4氟烷基;且R5係氫或-C(O)OR。
在某些實施例中,本發明提供一種式I化合物或其醫藥上可接受的鹽:
其中:n係0、1、或2;m係0、1、或2,其中m及n不同時為0;W係-O-或-NH-;R1係-OR;各R獨立地為C1-4烷基或C1-4氟烷基;R2係-CF3、Cl、或Br;G係-O-、-NR3-、或-CH(OR4)-;R3係-C(O)-R、-C(O)OR、-C(O)NHR、-SO2-R、-SO2NH2、-C(O)-C1-4伸烷基-OH或-SO2-C1-4伸烷基-OH;及R4係氫、C1-4烷基、或C1-4氟烷基。
如本文所使用,術語「C1-4伸烷基」係指含有1至4個碳原子之二價直鏈或分支鏈飽和烴鏈。
在某些實施例中,n係0且G係-CH(OR4)-。
在某些實施例中,m係0且G係-CH(OR4)-。
在某些實施例中,本發明提供一種式I或I-a化合物,其中W係-NH-。
在某些實施例中,本發明提供一種式I或I-a化合物,其中W係-NH-且R2係-CF3。
在某些實施例中,本發明提供一種式I或I-a化合物,其中W係-O-及R2係-Cl。
在某些實施例中,本發明提供一種其中G係-O-之式I-a化合物,藉此形成式II化合物或其醫藥上可接受的鹽:
其中W及R2係如上針對式I及I-a所定義。
在某些實施例中,本發明提供一種式II化合物,其中W係-NH-。
在某些實施例中,本發明提供一種式II化合物,其中W係-NH-且R2係-CF3。
在某些實施例中,本發明提供一種式I、I-a、或II化合物,其中以下特徵中之至少一者或兩者係適用:
(a) W係-O-或-NH-;及
(b) R2係-CF3或Cl。
在某些實施例中,本發明提供一種式I、I-a、或II化合物,其中以下特徵中之至少一者或兩者係適用:
(a) W係-O-;及
(b) R2係-CF3或Cl。
在某些實施例中,本發明提供一種式I、I-a、或II化合物,其中以下特徵中之至少一者或兩者係適用:
(a) W係-NH-;及
(b) R2係-CF3或Cl。
在某些實施例中,本發明提供一種其中G係-NR3-之式I化合物,藉此形成式III化合物或其醫藥上可接受的鹽:
其中W、R2、及R3係如上針對式I所定義。
在某些實施例中,本發明提供一種其中G係-NR3-之式I-a化合物,藉此形成式III-a化合物或其醫藥上可接受的鹽:
其中W、R2、及R3係如上針對式I所定義。
如上所定義,該式III或III-a之R3基團係-C(O)-C1-4烷基、-SO2-C1-4烷基、-C(O)-C1-4伸烷基-OH或-SO2-C1-4伸烷基-OH。一般技藝者將瞭解,在該哌嗪氮上之R3取代基使得氮係「非鹼性」。應瞭解,相比於(例如)相應的二級胺或其經烷基取代之衍生物,此非鹼性氮基團不易作為質子受體。
在某些實施例中,本發明提供一種式III或III-a化合物,其中W係-NH-。
在某些實施例中,本發明提供一種式III或III-a化合物,其中W係-NH-且R2係-CF3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中W係-O-且R2係-Cl。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-O-或-NH-;
(b) R2係-CF3或Cl;及
(c) R3係-C(O)CH3或-SO2CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-NH-;
(b) R2係-CF3或Cl;及
(c) R3係-C(O)CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-NH-;
(b) R2係-CF3或Cl;及
(c) R3係-SO2CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-O-;
(b) R2係-CF3或Cl;及
(c) R3係-C(O)CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-O-;
(b) R2係Cl;及
(c) R3係-C(O)CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-O-;
(b) R2係-CF3或Cl;及
(c) R3係-SO2CH3。
在某些實施例中,本發明提供一種式III或III-a化合物,其中以下特徵中之至少一者、至少兩者、或全部三者皆適用:
(a) W係-O-;
(b) R2係Cl;及
(c) R3係-SO2CH3。
示例性式I化合物係如下表1所示。
表1. 示例性化合物
在某些實施例中,本發明提供一種表1中所示之化合物或其醫藥上可接受的鹽。
在某些實施例中,所提供之化合物不具有結構
如本文所使用,術語「醫藥上可接受的鹽」係指彼等在合理的醫療判斷範圍內,適用於與人類及低等動物之組織接觸,而無過度毒性、刺激、過敏反應及類似者且與合理的效益/風險比相稱的鹽。醫藥上可接受的鹽係相關技術所熟知。例如,S. M. Berge等人在J. Pharmaceutical Sciences,1977,66,1-19(其以引用的方式併入本文中)中詳細描述醫藥上可接受的鹽。本發明化合物之醫藥上可接受的鹽包括彼等衍生自適宜的無機及有機酸及鹼者。醫藥上可接受的無毒酸加成鹽之實例係胺基與諸如鹽酸、氫溴酸、磷酸、硫酸及高氯酸之無機酸或與諸如乙酸、草酸、馬來酸、酒石酸、檸檬酸、琥珀酸、或丙二酸之有機酸所形成之鹽,或藉由使用相關技術中所用之其他方法(如離子交換)所形成之鹽。其他醫藥上可接受的鹽包括己二酸鹽、海藻酸鹽、抗壞血酸鹽、天門冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、雙葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、富馬酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘酸鹽、2-羥基乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酯酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、特戊酸鹽、丙酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及類似物。
衍生自適當的鹼之鹽包括鹼金屬鹽、鹼土金屬鹽、銨鹽及N+(C1-4烷基)4鹽。代表性鹼金屬或鹼土金屬鹽包括鈉、鋰、鉀、鈣、鎂、及類似物。其他醫藥上可接受的鹽在適當時包括使用諸如鹵離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳數烷基磺酸根及芳基磺酸根之抗衡離子所形成之無毒銨、四級銨、及胺陽離子。
如下文中所詳細描述,所提供之化合物係至少一種EGFR突變之選擇性抑制劑。已驚人地發現,所提供之化合物係相比於野生型(「WT」)EGFR之至少一種EGFR突變之選擇性抑制劑。在某些實施例中,至少一種EGFR突變係T790M。在某些實施例中,該至少一種EGFR突變係缺失突變。在某些實施例中,該至少一種EGFR突變係激活突變。在某些實施例中,所提供之化合物相比於WT EGFR選擇性抑制至少一種抗性突變及至少一種激活突變。在某些實施例中,所提供之化合物選擇性抑制至少一種缺失突變及/或至少一種點突變,且有餘力用於WT EGFR抑制。
EGFR突變可選自T790M(抗性或致瘤)、L858R(激活)、delE746-A750(激活)、G719S(激活)、或其組合。
如本文所使用,相比於WT EGFR抑制所使用之術語「選擇性抑制」意指在本文所述之至少一種試驗(例如,生物學或細胞試驗)中,所提供之化合物抑制至少一種EGFR突變(即,至少一種缺失突變、至少一種激活突變、至少一種抗性突變、或至少一種缺失突變與至少一種點突變之組合)。在某些實施例中,相比於WT EGFR抑制所使用之術語「選擇性抑制」意指所提供之化合物作為如本文所定義及所述之至少一種EGFR突變之抑制劑,比抑制WT EGFR有效至少50倍、至少45倍、至少40倍、至少35倍、至少30倍、至少25倍、或至少20倍。
如本文所使用,術語「有餘力用於WT EGFR」(sparing as to WT EGFR)意指如以上及本文所定義及描述之至少一種EGFR突變之選擇性抑制劑在如本文所述之至少一種試驗(例如,詳述於實例56至58中之生物化學或細胞試驗)之檢測上限抑制EGFR。在某些實施例中,該術語「有餘力用於WT EGFR」意指所提供之化合物抑制WT EGFR,且具有至少10 μM、至少9 μM、至少8 μM、至少7 μM、至少6 μM、至少5 μM、至少3 μM、至少2 μM、或至少1 μM之IC50。
在某些實施例中,所提供之化合物選擇性抑制(a)至少一種激活突變;及(b) T790M,且(c)有餘力用於WT。在某些實施例中,至少一種激活突變係缺失突變。在某些實施例中,至少一種激活突變係點突變。在某些實施例中,激活突變係delE746-A750。在某些實施例中,激活突變係L858R。在某些實施例中,激活突變係G719S。
在某些實施例中,該至少一種EGFR突變係L858R及/或T790M。
雖然不希望受限於任何特定理論,但咸信將所提供之化合物投與給具有至少一種激活突變之患者可預先防止形成T790M抗性突變。因此,在某些實施例中,本發明提供一種抑制患者之激活突變之方法,其包括將如本文所述之所提供之化合物或其組合物投與給該患者。
一般技藝者將瞭解,某些患者具有T790M突變之致瘤形式,即,該T790M突變係在對該患者投與任何EGFR抑制劑之前存在且因此係致瘤性。因此,在某些實施例中,本發明提供一種抑制患者之致瘤性T790M之方法,其包括將如本文所述之所提供之化合物或其組合物投與給該患者。
它賽瓦(Tarceva)(埃羅替尼(erlotinib))及易瑞沙(Iressa)(吉非替尼(gefitinib))係用於具有激活突變之患者之一線療法,但是其由於WT EGFR之同時抑制而顯示劑量限制性毒性。此外,目前開發中之藥物(包括二代共價抑制劑,如BIBW2992、HKI-272及PF-0299804)係有效抗T790M抗性突變,但是由於WT EGFR之同時抑制而顯示劑量限制性毒性。
已驚人地發現,所提供之化合物選擇性抑制各EGFR激活及缺失突變。此外,所提供之化合物係有餘力用於WT EGFR及相關之劑量限制性毒性。
此係與僅稍微有效抗突變型但是保留抗WT EGFR活性且因此受限於與WT EGFR抑制相關之毒性的其他已知EGFR抑制劑(例如,BIBW2992及HKI-272)不同。下表2顯示它賽瓦、BIBW2992及HKI-272相比於所提供之化合物I-2及I-4(其中化合物編號對應於上表1中之化合物編號)之GI50值。表2中所示之數據對應於詳述於實例58中之細胞增殖試驗中所獲得之GI50值,其中A431細胞表現WT EGFR,HCC827表現具有缺失突變delE746-A750之EGFR,且H1975細胞表現具有雙突變L858R/T790M之EGFR。
表2. 對照GI
50
值(nM)
在某些實施例中,如由詳述於以下實例56中之生物化學試驗所測定,所提供之化合物對至少一種EGFR突變之效力比對WT EGFR高至少50、至少45、至少40、至少35、至少30、至少25、或至少20倍。在某些實施例中,如由詳述於以下實例58中之細胞試驗所測定,所提供之化合物對至少一種EGFR突變之效力比對WT EGFR高至少20、至少15、或至少10倍。
在某些實施例中,如由詳述於以下實例56中之生物化學試驗所測定,所提供之化合物對至少一種EGFR缺失突變之效力比對WT EGFR高至少50、至少45、至少40、至少35、至少30、至少25、或至少20倍。在某些實施例中,如由詳述於以下實例58中之細胞試驗所測定,所提供之化合物對至少一種EGFR缺失突變之效力比對WT EGFR高至少20、至少15、或至少10倍。
在某些實施例中,如由詳述於以下實例56中之生物化學試驗所測定,所提供之化合物對EGFR之L858R及/或T790M突變之效力比對WT EGFR高至少50、至少45、至少40、至少35、至少30、至少25、或至少20倍。在某些實施例中,如由詳述於以下實例58中之細胞試驗所測定,所提供之化合物對EGFR之L858R及/或T790M突變之效力比對WT EGFR高至少20、至少15、或至少10倍。
在某些實施例中,如由詳述於以下實例57中之信號傳導試驗所測定,所提供之化合物對H1975細胞中之雙突變型之效力比對WT EGFR高至少20、至少15、或至少10倍。
在某些實施例中,所提供之化合物相比於WT EGFR及其他蛋白激酶(例如,ErbB2、ErbB4(TEC激酶)、及/或JAK3)選擇性抑制至少一種EGFR突變。應瞭解,式I中所述之丙烯醯胺基係相比於WT EGFR及其他蛋白激酶選擇性共價結合至至少一種EGFR突變之結合域中之關鍵半胱胺酸殘基之彈頭基。在結合域中具有半胱胺酸殘基之蛋白激酶係一般技藝者已知。此等在結合域中具有半胱胺酸殘基之蛋白激酶包括蛋白激酶之TEC家族(其包括TEC、BTK、ITK、BMX、JAK3、及RLK)。在某些實施例中,半胱胺酸殘基係保留在蛋白激酶子族(如ErbB1(通常被稱為EGFR)、ErbB2、及ErbB4)中。
雖然不希望受限於任何特定理論,但咸信所提供之化合物相比於WT EGFR及其他蛋白激酶不可逆地選擇性抑制(即,共價修飾)至少一種EGFR突變。在某些實施例中,所提供之化合物相比於選自ErbB1、ErbB2、ErbB4、TEC、BTK、ITK、BMX、JAK3、或RLK之至少一種蛋白激酶不可逆地選擇性抑制至少一種EGFR突變。
然而,在某些實施例中,所提供之化合物不顯著(可逆或不可逆地)抑制其他蛋白激酶。在某些實施例中,所提供之化合物相比於脫靶蛋白激酶選擇性抑制至少一種EGFR突變型,藉此避免與其抑制相關之作用及毒性。
在某些實施例中,利用一或多種以下步驟及中間體,合成所提供之化合物:
其中R2及W係如本文分類及子類中所定義及所述。
在步驟1中,使經R2取代之2,4-二氯嘧啶與(例如)經Boc保護之3-胺基苯酚反應,以形成中間體S1。在某些實施例中,於鹼性條件下進行步驟1。在某些實施例中,於三級胺之存在下進行步驟1。在某些實施例中,於休尼格(Hunig)鹼之存在下進行步驟1。在某些實施例中,於質子溶劑中進行步驟1。在某些實施例中,於醇溶劑中進行步驟1。在某些實施例中,於正丁醇中進行步驟1。
在步驟2中,使中間體S1去保護,以形成中間體S2。在某些實施例中,使用酸使中間體S1去保護。在某些實施例中,於三氟乙酸之存在下,使中間體S1去保護。
在步驟3中,用丙烯醯基使中間體S2醯化,以形成中間體S3。在某些實施例中,丙烯醯氯係該醯化劑。在某些實施例中,於鹵化溶劑中進行步驟3。在某些實施例中,於二氯甲烷中進行步驟3。
中間體S3可與各種苯胺反應,以形成如本文所述之化合物。
根據另一實施例,本發明提供一種包含本發明化合物或其醫藥上可接受的鹽、及醫藥上可接受的載劑、佐劑或媒劑之組合物。本發明組合物中之化合物之含量係使得其有效顯著抑制生物樣品或患者之蛋白激酶,特定言之,相比於WT EGFR選擇性抑制至少一種EGFR突變型。在某些實施例中,至少一種EGFR突變型係T790M。在某些實施例中,該至少一種EGFR突變型係EGFR缺失突變。在某些實施例中,該至少一種EGFR突變係L858R及/或T790M。
在某些實施例中,所提供之組合物中之化合物含量係使得其相比於WT EGFR有效顯著地選擇性抑制至少一種EGFR突變。
在某些實施例中,所提供之組合物中之化合物含量係使得其相比於WT EGFR及其他蛋白激酶(例如,ErbB2、ErbB4(TEC激酶)、及/或JAK3)有效顯著地選擇性抑制至少一種EGFR突變。
在某些實施例中,所提供之組合物中之化合物含量係使得其相比於WT EGFR有效顯著地選擇性抑制生物樣品或患者的至少一種EGFR突變型。在某些實施例中,調配本發明組合物以投與給需要該組合物之患者。在某些實施例中,調配本發明組合物以經口投與給患者。
在某些實施例中,所提供之組合物中之化合物含量係使得其相比於WT EGFR有效顯著地選擇性抑制生物樣品或患者的至少一種EGFR突變型。在某些實施例中,調配本發明組合物以投與給需要該組合物之患者。在某些實施例中,調配本發明組合物以經口投與給患者。
在某些實施例中,所提供之組合物中之化合物含量係使得其相比於WT EGFR及其他蛋白激酶(例如,ErbB2、ErbB4(TEC激酶)、及/或JAK3)有效顯著地選擇性抑制生物樣品或患者的至少一種EGFR突變型。在某些實施例中,調配本發明組合物以投與給需要該組合物之患者。在某些實施例中,調配本發明組合物以經口投與給患者。
如本文所使用,術語「患者」意指動物,較佳係哺乳動物,且最佳係人類。
術語「醫藥上可接受的載劑、佐劑或媒劑」係指不破壞經其調配之化合物之藥理活性之無毒載劑、佐劑或媒劑。可用於本發明組合物中之醫藥上可接受的載劑、佐劑或媒劑包括(但不限於)離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(如人血清白蛋白)、緩衝物質(如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸之偏甘油酯混合物、水、鹽或電解質(如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽)、膠體矽石、三矽酸鎂、聚乙烯吡咯啶酮、基於纖維素之物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇及羊毛脂。
可經口、非經腸、藉由吸入噴劑、局部、經直腸、經鼻、經口頰、經陰道或經由植入式貯存器,投與本發明組合物。如本文所使用,術語「非經腸」包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、損害內及顱內注射或輸注技術。較佳地,經口、腹膜內或靜脈內投與該等組合物。本發明組合物之無菌可注射形式可係水性或油性懸浮液。可根據相關技術中已知之技術,使用適宜的分散劑或潤濕劑及懸浮劑調配此等懸浮液。該無菌可注射製劑亦可係含於非經腸可接受的無毒稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如含於1,3-丁二醇中之溶液。在可接受的媒劑及溶劑中,尤其可使用水、林格氏(Ringer)溶液及等滲氯化鈉溶液。此外,通常使用無菌不揮發油作為溶劑或懸浮介質。
就此目的而言,可使用任何無刺激性不揮發油,其包括合成型單-或二甘油酯。脂肪酸(如油酸及其甘油酯衍生物)可用於製備注射劑,同樣可使用醫藥上可接受的天然油,如橄欖油或蓖麻油,尤其係其聚氧乙基化形式。此等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑或通常用於調配醫藥上可接受的劑型(包括乳液及懸浮液)之類似分散劑。亦可使用其他常用界面活性劑,如Tweens、Spans及通常用於製造醫藥上可接受的固體、液體或其他劑型之其他乳化劑或生物利用度增強劑來進行調配。
可以任何口服上可接受的劑型(包括(但不限於)膠囊、錠劑、水性懸浮液或溶液)經口投與本發明醫藥上可接受的組合物。在供口服使用之錠劑中,常用載劑包括乳糖及玉米澱粉。通常亦添加潤滑劑,如硬脂酸鎂。對於呈膠囊形式之經口投藥而言,可用的稀釋劑包括乳糖及乾燥玉米澱粉。當需要口服水性懸浮液時,將活性成分與乳化劑及懸浮劑組合。如果需要,亦可添加某些甜味劑、調味劑或著色劑。
或者,可以供直腸投藥之栓劑形式投與本發明醫藥上可接受的組合物。可藉由將藥劑與適宜的非刺激性賦形劑(其在室溫下係固體,但在直腸溫度下係液體,且因此將在直腸中融化以釋放該藥物)混合,製備此等栓劑。此等材料包括可可油、蜂蠟及聚乙二醇。
亦可局部投與本發明醫藥上可接受的組合物,尤其係當治療目標包括可容易藉由局部施用接觸之區域或器官時,該治療目標包括眼睛、皮膚、或下部腸道疾病。對於此等區域或器官中之各者而言,容易製備適宜的局部用調配物。
可以直腸栓劑調配物(見上文)或適宜的灌腸劑調配物實現用於下部腸道之局部施用。亦可使用局部經皮貼片。
對於局部施用而言,可將所提供之醫藥上可接受的組合物調配成含有懸浮於或溶解於一或多種載劑中之活性組分之適宜軟膏。用於局部投與本發明化合物之載劑包括(但不限於)礦物油、液體礦脂、白礦脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蠟及水。或者,可將所提供之醫藥上可接受的組合物調配成含有懸浮於或溶解於一或多種醫藥上可接受的載劑中之活性組分之適宜洗劑或乳霜。適宜的載劑包括(但不限於)礦物油、山梨糖醇酐單硬脂酸酯、聚山梨醇酯60、鯨蠟酯蠟、鯨蠟硬脂醇、2-辛基十二烷醇、苯甲醇及水。
對於眼科用途而言,可將所提供之醫藥上可接受的組合物調配成含於等滲及pH經調整之無菌鹽水中之超微懸浮液,或較佳調配成含於等滲及pH經調整之無菌鹽水中之溶液(含有或不含有防腐劑(如氯苄烷銨))。或者,對於眼科用途而言,可將該等醫藥上可接受的組合物調配成軟膏,如礦脂。
亦可藉由鼻用氣溶膠或吸入劑投與本發明醫藥上可接受的組合物。此等組合物係根據醫藥調配技術中熟知之技術製得且可製備成鹽水溶液,其利用苯甲醇或其他適宜的防腐劑、增強生物利用度之吸收促進劑、氟碳化合物及/或其他習知增溶劑或分散劑。
在某些實施例中,本發明醫藥上可接受的組合物係調配成供口服使用。
可與載劑材料組合以製備單一劑型組合物之本發明化合物之含量將根據治療主體及特定投藥模式而變化。較佳地,應調配所提供之組合物以使得可將0.01至100 mg/kg體重/天之抑制劑劑量投與給接受此等組合物之患者。
亦應瞭解,用於任何特定患者之具體劑量及治療方案將取決於多種因素,其包括所使用之具體化合物之活性、年齡、體重、一般健康狀況、性別、飲食、投藥時間、排泄率、藥物組合、及主治醫師之判斷及所治療之特定疾病之嚴重度。該組合物中之本發明化合物之含量亦將取決於該組合物中之特定化合物。
本文所述之化合物及組合物一般適用於相比於WT EGFR選擇性抑制至少一種EGFR突變型。在某些實施例中,至少一種EGFR突變型係T790M。在某些實施例中,該至少一種EGFR突變型係EGFR之缺失突變、EGFR之激活突變、或其組合。在某些實施例中,該至少一種EGFR突變係L858R及/或T790M。
在某些實施例中,所提供之化合物選擇性抑制(a)至少一種激活突變、及(b) T790M,且(c)有餘力用於WT。在某些實施例中,至少一種激活突變係缺失突變。在某些實施例中,至少一種激活突變係點突變。在某些實施例中,激活突變係delE746-A750。在某些實施例中,激活突變係L858R。在某些實施例中,激活突變係G719S。
在某些實施例中,該至少一種EGFR突變係L858R及/或T790M。
可在活體外、活體內或在細胞系中分析本發明所利用之化合物作為相比於WT EGFR之至少一種EGFR突變型之選擇性抑制劑之活性。活體外分析包括測定對活化EGFR(WT或突變型)之磷酸化活性及/或隨後之功能性結果或ATP酶活性之抑制之分析。替代活體外分析對該抑制劑結合至EGFR(WT或突變型)之能力進行定量。可藉由在結合之前放射性標記該抑制劑,單離該抑制劑/EGFR(WT或突變型)複合物,及測定所結合之放射性標記之含量,測量抑制劑結合。或者,可藉由進行競爭實驗(其中利用結合至已知放射性配體之EGFR(WT或突變型)培養新抑制劑)測定抑制劑結合。分析作為EGFR(WT或突變型)抑制劑之本發明化合物之詳細條件係闡述於以下實例中。
蛋白酪胺酸激酶係一類催化磷酸酯基自ATP或GTP轉移至位於蛋白質基質上之酪胺酸殘基之酶。受體酪胺酸激酶係用於藉由經由磷酸化事件激活二級訊息效應物,將信號自細胞外部傳導至內部。此等信號促進多種細胞過程,其包括增殖、碳水化合物利用、蛋白質合成、血管生成、細胞生長及細胞存活。
如本文所使用,術語「療法」及「治療」係指逆轉、減輕如本文所述之疾病或病症或其一或多種症狀、延遲其發作或抑制其進展。在某些實施例中,可在已出現一或多種症狀之後投與療法。在其他實施例中,可在不存在症狀之情況下投與療法。例如,可在症狀發作之前(例如,根據症狀史及/或根據遺傳或其他易感因素),將療法投與給易感個體。亦可在症狀消失後繼續投與療法,以(例如)預防或延遲其復發。
所提供之化合物係至少一種EGFR突變型之抑制劑且因此可用於治療與一或多種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)之活性相關之一或多種疾病。因此,在某些實施例中,本發明提供一種治療由突變型EGFR介導之疾病之方法,其包括將本發明化合物或其醫藥上可接受的組合物投與給有需要之患者之步驟。
如本文所使用,術語「由突變型EGFR介導」之疾病或病症意指其中已知至少一種EGFR突變型發揮作用之任何疾病或其他有害病症。在某些實施例中,至少一種EGFR突變型係T790M。在某些實施例中,該至少一種EGFR突變型係缺失突變。在某些實施例中,該至少一種EGFR突變型係激活突變。在某些實施例中,該至少一種EGFR突變型係L858R及/或T790M。在某些實施例中,所提供之化合物選擇性抑制(a)至少一種激活突變、(b) T790M,且(c)有餘力用於WT。在某些實施例中,至少一種激活突變係缺失突變。在某些實施例中,至少一種激活突變係點突變。在某些實施例中,激活突變係delE746-A750。在某些實施例中,激活突變係L858R。在某些實施例中,激活突變係G719S。
因此,本發明之另一實施例係關於治療其中已知至少一種EGFR突變型發揮作用之一或多種疾病或減輕其嚴重度。具體言之,本發明係關於一種治療選自增生性疾病之疾病或病症或減輕其嚴重度之方法,其中該方法包括將根據本發明之化合物或組合物投與給有需要之患者。
在某些實施例中,本發明提供一種治療一或多種選自癌症之疾病或減輕其嚴重度之方法。在某些實施例中,該癌症係與實體腫瘤相關。在某些實施例中,該癌症係乳腺癌、膠質母細胞瘤、肺癌、頭部及頸部癌症、直腸癌、膀胱癌、或非小細胞肺癌。在某些實施例中,本發明提供一種治療一或多種選自鱗狀細胞癌、唾液腺癌、卵巢癌、或胰腺癌之疾病或減輕其嚴重度之方法。
在某些實施例中,本發明提供一種治療I型神經纖維瘤病(NF1)、II型神經纖維瘤病(NF2)、雪旺氏(Schwann)細胞瘤(例如,MPNST)、或神經鞘瘤(Schwannomas)或減輕其嚴重度之方法。
根據本發明方法,可使用有效治療癌症或減輕其嚴重度之任何含量及任何投藥途徑,投與該等化合物及組合物。所需之精確含量將隨不同個體而變化,其係取決於該個體之物種、年齡及一般健康情況、感染嚴重度、特定藥劑、其投藥模式、及類似者。較佳將本發明化合物調配成單位劑型以便於投藥及劑量之一致性。如本文所使用,表述「單位劑型」係指適用於待治療之患者之藥劑之物理離散單位。然而,應瞭解,本發明化合物及組合物之每日總用量將由主治醫師在合理的醫療判斷範圍內決定。用於任何特定患者或有機體之具體有效劑量水平將取決於多種因素,其包括所治療之疾病及該疾病之嚴重度;所使用之具體化合物之活性;所使用之具體組合物;該患者之年齡、體重、一般健康狀況、性別及飲食;投藥時間、投藥途徑、及所使用之具體化合物之排泄率;治療持續時間、與所使用之具體化合物組合或同時使用之藥物;及醫療技術中熟知之類似因素。如本文所使用,術語「患者」意指動物,較佳係哺乳動物,且最佳係人類。
可根據所治療之感染之嚴重度,將本發明醫藥上可接受的組合物經口、直腸、非經腸、腦池內、陰道內、腹膜內、局部(如藉由粉劑、軟膏或滴劑)、口頰、作為口用或鼻用噴劑、或以類似途徑投與給人類及其他動物。在某些實施例中,可以約0.01 mg/kg至約50 mg/kg或約1 mg/kg至約25 mg/kg個體體重/天之劑量水平,每天經口或非經腸投與本發明化合物一或多次,以獲得所需之治療效果。
用於口服之液體劑型包括(但不限於)醫藥上可接受的乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物以外,該等液體劑型可含有相關技術中常用之惰性稀釋劑,如(例如)水或其他溶劑、增溶劑及乳化劑(如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(尤其係棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油、及芝麻油)、甘油,四氫呋喃甲醇、聚乙二醇及山梨糖醇酐脂肪酸酯、及其混合物)。除惰性稀釋劑以外,該等口服組合物亦可包含佐劑,如潤濕劑、乳化及懸浮劑、甜味劑、調味劑及芳香劑。
可根據已知技術,使用適宜的分散劑或潤濕劑及懸浮劑調配可注射製劑,例如無菌可注射水性或油性懸浮液。該無菌可注射製劑亦可係含於非經腸可接受的無毒稀釋劑或溶劑中之無菌可注射溶液、懸浮液或乳液,例如,含於1,3-丁二醇中之溶液。在可接受的媒劑及溶劑中,尤其可使用水、林格氏溶液、U.S.P.及等滲氯化鈉溶液。此外,通常使用無菌不揮發油作為溶劑或懸浮介質。就此目的而言,可使用任何無刺激性不揮發油,其包括合成型單-或二甘油酯。此外,使用脂肪酸(如油酸)製備注射劑。
可藉由(例如)經由細菌保留過濾器之過濾、終端(熱)滅菌、或經由離子化輻射或藉由併入呈無菌固體組合物形式之滅菌劑(可在使用之前將其溶解或分散於無菌水或其他無菌可注射介質中)之滅菌方法,使可注射調配物滅菌。
為延長本發明化合物之作用,經常需要使來自皮下或肌肉內注射之該化合物的吸收變慢。此可藉由使用具有較差水溶性之結晶或非晶形材料之液體懸浮液來實現。然後,該化合物之吸收速率取決於其溶解速率,其繼而可取決於晶體尺寸及結晶形式。或者,藉由將該化合物溶解或懸浮於油性媒劑中,實現非經腸投與之化合物形式之延遲吸收。藉由在生物可降解聚合物(如聚乳酸交酯-聚乙交酯)中形成該化合物之微膠囊基質,製造可注射貯存形式。可根據化合物對聚合物之比例及所使用之特定聚合物之性質,控制化合物釋放速率。其他生物可降解聚合物之實例包括聚(原酸酯)及聚(酐)。亦可藉由使該化合物包含於可與身體組織相容之脂質體或微乳液中,製備貯存式可注射調配物。
供直腸或陰道投與之組合物較佳係栓劑,其可藉由將本發明化合物與適宜的非刺激性賦形劑或載劑(如可可油、聚乙二醇或栓劑蠟)混合而製得,該等賦形劑或載劑在環境溫度下係固體,但是在身體溫度係係液體,且因此在直腸或陰道腔內融化並釋放該活性化合物。
供口服之固體劑型包括膠囊、錠劑、丸劑、粉劑及粒劑。在此等固體劑型中,將該活性化合物與至少一種醫藥上可接受的惰性賦形劑或載劑(如檸檬酸鈉或磷酸二鈣)及/或以下物質混合:a)填充劑或增量劑,如澱粉、乳糖、蔗糖、葡萄糖、甘露醇、及矽酸;b)黏合劑,如(例如)羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖、及阿拉伯膠;c)保濕劑,如甘油;d)崩解劑;如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽、及碳酸鈉;e)溶液阻滯劑,如石蠟;f)吸收促進劑,如四級銨化合物;g)潤濕劑,如(例如),鯨蠟醇及單硬脂酸甘油酯;h)吸收劑,如高嶺土、膨潤土;及i)潤滑劑,如滑石粉、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉、及其混合物。在膠囊、錠劑及丸劑之情況下,該劑型亦可包含緩衝劑。
亦可使用類似類型之固體組合物作為軟及硬填充明膠膠囊中之填充劑,該等膠囊使用諸如乳糖或奶糖及高分子量聚乙二醇及類似物之賦形劑。可利用包衣及外殼(如腸溶性包衣及醫藥調配技術中熟知之其他包衣)製備錠劑、糖衣丸劑、膠囊、丸劑及粒劑之固體劑型。其等可視情況含有乳濁劑且亦可係使得其等視情況以延遲方式僅在或優先在腸道之特定部位釋放該(等)活性成分之組合物。可使用之包埋組合物之實例包括聚合物質及蠟。亦可使用類似類型之固體組合物作為軟及硬填充明膠膠囊中之填充劑,該等膠囊使用諸如乳糖或奶糖及高分子量聚乙二醇及類似物之賦形劑。在某些實施例中,固體組合物係液體填充型硬明膠膠囊或固體分散液。
該等活性化合物亦可呈具有一或多種上述賦形劑之微封裝形式。可用包衣及外殼(如腸溶性包衣、釋放控制型包衣及醫藥調配技術中熟知之其他包衣),製備錠劑、糖衣丸劑、膠囊、丸劑及粒劑之固體劑型。在此等固體劑型中,可將該活性化合物與至少一種惰性稀釋劑(如蔗糖、乳糖或澱粉)混合。如通常所實踐般,此等劑型亦可包含除惰性稀釋劑以外之其他物質,例如,製錠潤滑劑及其他製錠助劑,如硬脂酸鎂及微晶纖維素。在膠囊、錠劑及丸劑之情況中,該等劑型亦可包含緩衝劑。其等可視情況含有乳濁劑且亦可係使得其等視情況以延遲方式僅在或優先在腸道之特定部位釋放該(等)活性成分之組合物。可使用之包埋組合物之實例包括聚合物質及蠟。
供本發明化合物之局部或經皮投與之劑型包括軟膏、糊劑、乳霜、洗劑、凝膠、粉劑、溶液、噴劑、吸入劑或貼片。在無菌條件下,將該活性組分與醫藥上可接受的載劑及視需要之任何所需之防腐劑或緩衝劑混合。亦預期眼藥調配物、耳用滴劑、及眼用滴劑係在本發明範圍內。此外,本發明包括經皮貼片之用途,該等經皮貼片具有將化合物控制遞送至身體之額外優點。此等劑型可藉由將該化合物溶解或分散於適當介質中製成。亦可使用吸收增強劑來增加該化合物穿過皮膚之通量。可藉由提供速率控制膜或藉由將該化合物分散於聚合物基質或凝膠中來控制速率。
根據另一實施例,本發明係關於一種抑制生物樣品中之至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)活性之方法,其包括使該生物樣品與本發明化合物或包含該化合物之組合物接觸之步驟。在某些實施例中,本發明係關於一種不可逆地抑制生物樣品中之至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)活性之方法,其包括使該生物樣品與本發明化合物或包含該化合物之組合物接觸之步驟。
在某些實施例中,所提供之化合物選擇性抑制生物樣品中之(a)至少一種激活突變、(b) T790M,且(c)有餘力用於WT。在某些實施例中,至少一種激活突變係缺失突變。在某些實施例中,至少一種激活突變係點突變。在某些實施例中,激活突變係delE746-A750。在某些實施例中,激活突變係L858R。在某些實施例中,激活突變係G719S。
如本文所使用,術語「生物樣品」包括(但不限於)細胞培養物或其萃取物、自哺乳動物獲得之活檢材料或其萃取物、及血液、唾液、尿液、糞便、精液、眼淚或其他體液或其萃取物。
生物樣品中之至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)活性之抑制適用於熟習此項技術者已知之各種用途。此等用途之實例包括(但不限於)輸血、器官移植、生物標本儲存、及生物檢測。
本發明之另一實施例係關於一種抑制患者中之至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)活性之方法,其包括將本發明化合物或包含該化合物之組合物投與給該患者之步驟。在某些實施例中,本發明提供一種抑制患者中之(a)至少一種激活突變及(b) T790M且(c)有餘力用於WT之方法,其中該方法包括將所提供之化合物或其組合物投與給該患者。在某些實施例中,至少一種激活突變係缺失突變。在某些實施例中,至少一種激活突變係點突變。在某些實施例中,本發明提供一種抑制患者中之至少一種EGFR突變型之方法,其中激活突變係delE746-A750。在某些實施例中,本發明提供一種抑制患者中之至少一種EGFR突變型之方法,其中激活突變係L858R。在某些實施例中,本發明提供一種抑制患者中之至少一種EGFR突變型之方法,其中激活突變係G719S。
根據另一實施例,本發明係關於一種抑制患者中之至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)活性之方法,其包括將本發明化合物或包含該化合物之組合物投與給該患者之步驟。根據某些實施例,本發明係關於一種不可逆地抑制患者中之至少一種EGFR突變型活性(例如,缺失突變、激活突變、抗性突變、或其組合)之方法,其包括將本發明化合物或包含該化合物之組合物投與給該患者之步驟。在某些實施例中,本發明提供一種不可逆地抑制患者中之(a)至少一種激活突變、及(b) T790M,且(c)有餘力用於WT之方法,其中該方法包含將所提供之化合物或其組合物投與給該患者。在某些實施例中,經不可逆抑制之至少一種激活突變係缺失突變。在某些實施例中,經不可逆抑制之至少一種激活突變係點突變。在某些實施例中,本發明提供一種不可逆地抑制患者中之至少一種EGFR突變型之方法,其中激活突變係delE746-A750。在某些實施例中,本發明提供一種不可逆地抑制患者中之至少一種EGFR突變型之方法,其中激活突變係L858R。在某些實施例中,本發明提供一種不可逆地抑制患者中之至少一種EGFR突變型之方法,其中激活突變係G719S。
在其他實施例中,本發明提供一種在有需要之患者中治療由至少一種EGFR突變型(例如,缺失突變、激活突變、抗性突變、或其組合)中之一或多者介導之疾病之方法,其包括將根據本發明之化合物或其醫藥上可接受的組合物投與給該患者之步驟。此等疾病係詳述於本文中。
根據待治療之特定病症或疾病,本發明組合物中亦可存在用於治療該病症所通常投與之其他治療劑。如本文所使用,用於治療特定疾病或病症所通常投與之其他治療劑被認為係「適用於所治療之疾病或病症」。
例如,本發明化合物或其醫藥上可接受的組合物係與治療增生性疾病及癌症之化療劑組合投與。已知化療劑之實例尤其包括(但不限於)阿黴素(Adriamycin)、地塞米松(dexamethasone)、長春新鹼(vincristine)、環磷醯胺、氟尿嘧啶、托泊替康(topotecan)、紫杉醇、干擾素、鉑衍生物、紫杉烷(例如,太平洋紫杉醇)、長春花生物鹼類(例如,長春花鹼)、蒽環類(例如,多柔比星(doxorubicin))、表鬼臼毒素(例如,依托泊苷(etoposide)),順鉑(、mTOR抑制劑)(例如,雷帕黴素(rapamycin))、甲胺蝶呤(methotrexate)、放線菌素D、多拉司他汀(dolastatin)10、秋水仙鹼、吐根鹼、曲美沙特(trimetrexate)、氯苯胺啶(metoprine)、環孢素、道諾黴素、替尼泊苷(teniposide)、兩性黴素、烷化劑(例如,氮芥苯丁酸(chlorambucil))、5-氟尿嘧啶、喜樹鹼(campthothecin)、順鉑、硝基甲嘧唑乙醇、及GleevecTM。在其他實施例中,本發明化合物係與生物劑(如阿伐斯丁(Avastin)或VECTIBIX)組合投與。
在某些實施例中,將本發明化合物或其醫藥上可接受的組合物與選自以下之任何一或多者之抗增殖劑或化療劑組合投與:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿侖單抗(alemtuzumab)、阿曲諾英(alitretinoin)、別嘌呤醇、六甲蜜胺(altretamine)、胺磷汀(amifostine)、阿那曲唑(anastrozole)、三氧化二砷、天門冬醯胺酶、阿扎胞苷(azacitidine)、卡介苗(BCG)活菌、貝伐組單抗(bevacuzimab)、氟尿嘧啶、貝瑟羅汀(bexarotene)、博萊黴素(bleomycin)、波替單抗(bortezomib)、白消安(busulfan)、卡魯睾酮(calusterone)、卡培他濱(capecitabine)、喜樹鹼(camptothecin)、卡鉑(carboplatin)、卡莫司汀(carmustine)、塞來昔布(celecoxib)、西妥昔單抗(cetuximab)、氮芥苯丁酸(chlorambucil)、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、環磷醯胺、阿糖胞苷(cytarabine)、放線菌素(dactinomycin)、促紅細胞生成素(darbepoetin)α、柔紅黴素(daunorubicin)、德尼白介素(denileukin)、右雷佐生(dexrazoxane)、多西紫杉醇(docetaxel)、多柔比星(doxorubicin)(中性)、鹽酸多柔比星、丙酸屈他雄酮(dromostanolone)、表阿黴素(epirubicin)、α-依泊汀(epoetin)、埃羅替尼(erlotinib)、雌氮芥(estramustine)、磷酸依托泊苷(etoposide)、依托泊苷、依西美坦(exemestane)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟維司群(fulvestrant)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥單抗(gemtuzumab)、醋酸戈舍瑞林(goserelin)、醋酸組胺瑞林(histrelin)、羥基脲、替坦異貝莫單抗(ibritumomab),去甲氧柔紅黴素(idarubicin)、異環磷醯胺、甲磺酸伊馬替尼(imatinib)、干擾素α-2a、干擾素α-2b、伊立替康(irinotecan)、來那度胺(lenalidomide)、來曲唑(letrozole)、甲醯四氫葉酸(leucovorin)、醋酸亮丙瑞林(leuprolide)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、醋酸甲地孕酮(megestrol)、美法侖(melphalan)、巰基嘌呤、6-MP、美司那(mesna)、甲胺喋呤,甲氧沙林(methoxsalen)、絲裂黴素(mitomycin)C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、諾龍(nandrolone)、奈拉濱(nelarabine)、諾非單抗(nofetumomab)、奧普瑞白介素(oprelvekin)、奧沙利鉑(oxaliplatin),太平洋紫杉醇(paclitaxel)、帕利非明(palifermin)、帕米膦酸鹽(pamidronate)、甲氧聚乙二醇琥珀醯胺腺甙脫胺酶(pegademase)、培加帕酶(pegaspargase)、培非格司亭(pegfilgrastim)、培美曲塞(pemetrexed)二鈉、噴托他丁(pentostatin)、呱泊溴烷(pipobroman)、普卡黴素(plicamycin)、卟吩姆(porfimer)鈉、丙卡巴肼(procarbazine)、奎納克林(quinacrine)、拉布立酶(rasburicase)、利妥昔單抗(rituximab)、沙格司亭(sargramostim)、索拉非尼(sorafenib)、鏈脲黴素(streptozoin)、馬來酸舒尼替尼(sunitinib)、滑石、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、VM-26、睾內酯(testolactone)、硫鳥嘌呤、6-TG、塞替派(thiotepa),托泊替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥組單抗(trastuzumab)、維甲酸(tretinoin)、全反式維甲酸(ATRA)、尿嘧啶芥菜、伐蘆比星(valrubicin)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、唑來膦酸鹽(zoledronate)、或唑來膦酸(zoledronic acid)。
亦可與本發明抑制劑組合之藥劑之其他實例包括(但不限於):用於阿茲海默氏(Alzheimer's)症之療法,如鹽酸多奈哌齊(donepezil)()及雷斯替明(rivastigmine)();用於帕金森氏(Parkinson's)病之療法,如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、羅匹尼羅(ropinrole)、普拉克索(pramipexole)、溴隱亭(bromoriptine)、培高利特(pergolide)、三己芬迪(trihexephendyl)、及金剛烷胺;用於治療多發性硬化症(MS)之藥劑,如β干擾素(例如,及)、醋酸格拉雷姆(glatiramer)()、及米托蒽醌(mitoxantrone);用於哮喘之療法,如沙丁胺醇(albuterol)及孟魯司特(montelukast)();用於治療精神分裂症之藥劑,如再普樂(zyprexa)、利培酮(risperdal)、思瑞康(seroquel)、及氟呱啶醇(haloperidol);消炎藥,如糖皮質激素、TNF阻斷劑、IL-1 RA、硫唑嘌呤、環磷醯胺、及柳氮磺胺吡啶;免疫調節及免疫抑制劑,如環孢素(cyclosporin)、他克莫司(tacrolimus)、雷帕黴素(rapamycin)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、干擾素、糖皮質激素、環磷醯胺、硫唑嘌呤及柳氮磺胺吡啶;神經營養因子,如乙醯基膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗驚厥劑、離子通道阻斷劑、利魯唑(riluzole)、及抗帕金森病劑;用於治療心血管疾病之藥劑,如β-阻斷劑、ACE抑制劑、利尿劑、硝酸酯、鈣通道阻斷劑、及他汀類藥物;用於治療肝臟疾病之藥劑,如糖皮質激素、消膽胺、干擾素及抗病毒劑;用於治療血液疾病之藥劑,如糖皮質激素、抗白血病藥及生長因子;及用於治療免疫缺陷疾病之藥劑,如γ球蛋白。
在某些實施例中,將本發明化合物或其醫藥上可接受的組合物係與單株抗體或siRNA治療劑組合投與。
彼等其他藥劑可作為多劑量方案之部份與含有本發明化合物之組合物分開投與。或者,彼等藥劑可係單劑型之部份,並與本發明化合物混合一起成單一組合物。如果該兩種活性劑係作為多劑量方案之部份投與,則可同時、依序或彼此相隔一段時間(通常係彼此相隔5小時)遞送該兩種活性劑。
如本文所使用,術語「組合」、「組合之」及相關術語係指同時或依序投與根據本發明之治療劑。例如,本發明化合物可與另一治療劑以不同的單位劑型同時或依序投與或以單一單位劑型一起投與。因此,本發明提供一種包含所提供之化合物、其他治療劑、及醫藥上可接受的載劑、佐劑或媒劑之單一單位劑型。
可與載劑材料組合以製備單一劑型之本發明化合物及其他治療劑(在彼等包含如上所述之其他治療劑之組合物中)之含量將根據治療主體及特定的投藥模式而變化。較佳地,應將本發明組合物調配成使得可投與0.01至100 mg/kg體重/天之本發明化合物之劑量。
在彼等包含其他治療劑之組合物中,該其他治療劑及本發明化合物可協同作用。因此,此等組合物中之其他治療劑之含量將低於僅利用該治療劑之單療法中所需之含量。在此等組合物中,可投與0.01至1,000 μg/kg體重/天之其他治療劑之劑量。
本發明組合物中所存在之其他治療劑之含量將不超過通常以包含該治療劑作為唯一活性劑之組合物形式投與之含量。較佳地,本發明組合物中之其他治療劑之含量將係包含該藥劑作為唯一治療活性劑之組合物中通常所存在之含量的約50%至100%。
亦可將本發明化合物或其醫藥組合物併入用於塗覆植入式醫療裝置(如假肢、人工瓣膜、血管移植物、支架及導管)之組合物中。例如,已使用血管支架以克服再狹窄(血管壁在損傷後之再變窄)。然而,使用支架或其他植入式裝置之患者具有凝塊形成或血小板活化之風險。可藉由使用包含激酶抑制劑之醫藥上可接受的組合物預塗覆該裝置,防止或減輕此等非所欲的作用。經本發明化合物塗覆之植入式裝置係本發明之另一實施例。
如以下實例中所述,在某些示例性實施例中,根據以下一般步驟製備化合物。應瞭解,雖然該等一般方法描述某些本發明化合物之合成法,但是以下一般方法及一般技藝者已知之其他方法可適用於本文所述之所有化合物及此等化合物中各者之子類及種類。
以下實例中所用之化合物編號對應於上表1中所述之化合物編號。
根據一般技藝者已知之方法製備所提供之化合物,且包括詳細描述於2010年2月4日公開之US 20100029610(其全文以引用的方式併入本文中)中之方法。
在事先配備有磁力攪拌器、熱袋及CaCl2保護管之25 mL 3頸RBF中,注入N-Boc-1,3-二胺基苯(0.96 g)及正丁醇(9.00 mL)。將反應混合物冷卻至0℃。在0℃下,將2,4-二氯-5-三氟甲基嘧啶(1.0 g)滴加至上述反應混合物中。在0℃下,將DIPEA(0.96 mL)滴加至上述反應混合物中,並在0℃至5℃下攪拌該反應混合物1小時。最後,使該反應混合物升溫至室溫。在室溫下,再攪拌該反應混合物4小時。藉由使用己烷:乙酸乙酯(7:3)之TLC,監測反應之完成。將沉澱析出之固體過濾,並用1-丁醇(2 mL)清洗。在減壓及40℃下乾燥固體1小時。1H-NMR(DMSO-d6,400 MHz) δ 1.48(S,9 H),7.02(m,1 H),7.26(m,2 H),7.58(S,1 H),8.57(S,1 H),9.48(S,1 H),9.55(S,1 H)。
在0℃下,將TFA(12.4 mL)緩慢添加至含於DCM(25 mL)中之上述粗製物(3.1 g)中。使該反應混合物升溫至室溫。在室溫下,再攪拌反應混合物10 min。在減壓下,濃縮該粗製物。
將濃縮粗製物溶於DIPEA(2.0 mL)及DCM(25 mL)中,且隨後冷卻至-30℃。在-30℃下,將丙烯醯氯(0.76 g)緩慢添加至該反應混合物中。使該反應物料升溫至室溫,並在室溫下攪拌1小時。在使用己烷:乙酸乙酯(7:3)作為流動相之TLC上監測該反應。1小時之後反應完全。1H-NMR(DMSO-d6,400 MHz) δ 5.76(dd,J=2.0,10.0 Hz,1 H),6.24(dd,J=2.0,17.2 Hz,1 H),6.48(m,1 H),7.14(d,J=8.8 Hz,1 H),7.37(t,J=8.0 Hz,1 H),7.94(S,1 H),8.59(S,1 H),9.60(S,1 H),10.26(S,1 H)。
為獲得該標題化合物I-2,在50℃下,將含於二噁烷(1.0 mL)中之實例1之中間體1(16 mg)及2-甲氧基-4-嗎啉基苯胺之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物,並使用HPLC(TFA改性劑)純化,以獲得標題化合物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.4(S,1 H),9.72(br,1 H),9.18(br,1 H),8.49(br,1 H),7.83(S,1 H),7.59(d,J=8.4 Hz,1 H),7.31-7.48(m,2 H),7.41(t,J=15.2 Hz,1 H),7.12(br,1 H),6.67(S,1 H),6.49(dd,J=10.0,16.8 Hz,1 H),6.25(dd,J=2.0,16.8 Hz,1 H),5.77(dd,J=2.0,10.0 Hz,1 H),3.7-3.9(m,7 H),3.1(br,4 H);C25H25F3N6O3理論質量:514.2,實測值:515.5(M+H+)。
使用2-甲氧基-4-(4-乙醯基哌嗪基)苯胺及實例1之中間體1,如實例2中所述製備該標題化合物I-4。1H-NMR(DMSO-d6,400 MHz) δ 10.2(S,1 H),8.2(br,1 H),8.30(S,1 H),7.73(br,1 H),7.52(d,J=7.8 Hz,1 H),7.45(d,J=7.8 Hz,1 H),7.26(J=8.2 Hz,1 H),7.14(be,1 H),6.60(S,1 H),6.42(dd,J=11.4,16.9 Hz,1 H),6.24(d,J=16.9 Hz,1 H),5.75(d,J=11.4 Hz,1 H),3.76(S,3 H),3.04(br,4 H),2.04(S,3 H);C27H28F3N7O3理論質量:555.2,實測值:556.2(M+H+)。
根據實例1之流程圖1中之步驟1,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 1.48(S,9 H),7.16(d,1 H),7.25(m,2 H),7.70(S,1 H),8.37(S,1 H),9.47(S,1 H),9.55(S,1 H)。
根據實例1之流程圖1中之步驟2,進行標題步驟。
根據實例1之流程圖1中之步驟3,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 5.76(dd,J=1.6,10.8,Hz 1 H),6.25(dd,J=1.6,16.8 Hz,1 H),6.46(m,1 H),7.30(m,2 H),7.46(d,J=8.0 Hz,1 H),7.91(S,1 H),8.38(S,1 H),9.60(S,1 H),10.23(S,1 H)。
根據實例1之流程圖1中之步驟1,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 1.47(S,9 H),6.89(d,J=7.6 Hz,1 H),7.35(m,2 H),7.45(S,1 H),8.89(S,1 H),9.64(S,1H)。
根據實例1之流程圖1中之步驟2,進行標題步驟。
根據實例1之流程圖1中之步驟3,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 5.77(d,J=10.0 Hz,1 H),6.25(d,J=17.2 Hz,1 H),6.45(m,1 H). 7.01(d,J=7.2 Hz,1 H),7.53(m,2 H),7.73(S,1 H),8.98(S,1 H),10.40(S,1 H)。
根據實例1之流程圖1中之步驟1,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 1.50(S,9 H),7.10(d,J=6.0 Hz,1 H),7.25(m,2 H),8.44(S,1 H),9.32(S,1 H),9.47(S,1 H)。
根據實例1之流程圖1中之步驟2,進行標題步驟。
根據實例1之流程圖1中之步驟3,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 5.76(dd,J=1.6,10.0 Hz,1 H),6.25(dd,J=1.6,16.8 Hz,1 H),6.43(m,1 H),7.23(d,J=8.0 Hz,1 H),7.35(t,J=8.0Hz,1 H),7.48(d,J=8.0 Hz,1 H),7.80(S,1 H),8.38(S,1 H),9.36(S,1 H),10.23(S,1 H)。
流程圖5
根據實例1之流程圖1中之步驟1,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 1.47(S,9 H),6.90(d,J=6.0 Hz,1 H),7.35(m,2 H),7.50(S,1 H),9.05(S,1 H),9.65(S,1 H)。
根據實例1之流程圖1中之步驟2,進行標題步驟。
根據實例1之流程圖1中之步驟3,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 5.76(d,J=10.0 Hz,1 H),6.25(dd,J=1.6,16.8 Hz,1 H),6.46(m,2 H),7.01(d,J=8.0 Hz,1 H),7.08(t,J=8.4 Hz,1 H)7.25(S,1 H),9.44(S,1 H),10.02(S,1 H)。
根據實例1之流程圖1中之步驟1,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 1.47(S,9 H),6.60(S,1 H),6.86(d,J=8.4 Hz,1 H),7.13(t,J=7.6 Hz,1 H),7.36(m,1 H),7.50(S,1 H),8.40(S,1 H)。
根據實例1之流程圖1中之步驟2,進行標題步驟。
根據實例1之流程圖1中之步驟3,進行標題步驟。1H-NMR(DMSO-d6,400 MHz) δ 5.78(dd,J=2.0,10.0 Hz,1 H),6.25(dd,J=2.0,17.2 Hz,1 H),6.40(m,1 H),7.02(d,1 H),7.50(m,2 H),7.71(S,1 H),8.40(S,1 H),10.35(S,1 H)。
為獲得該標題化合物,在150℃下,將含於正丁醇中之實例8之中間體6及2-甲氧基-4-嗎啉基苯胺之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並純化,以獲得該標題化合物。1H-NMR(氯仿-d,400 MHz) δ 8.23(S,1 H),7.6-7.8(br,2 H),7.4-7.5(m,3 H),7.00(dd,J=1.4,8.2 Hz,1 H),6.41(m,2 H),6.23(m,2 H),5.77(dd,J=1.4,10.1 Hz,1 H),3.84(m,4 H),3.81(S,3 H),3.04(m,4 H);C24H24ClN5O4理論質量:481.2,實測值:482.2(M+H+)。
使用2-甲氧基-4-(4-(2-羥乙醯基)哌嗪基)苯胺及實例1之中間體1,如實例2中所述製備該標題化合物I-6。1H-NMR(CDCl3,400 MHz) δ 8.33(S,1 H),8.08(br,1 H),7.86(br,1 H),7.60(br,1 H),7.39(m,1 H),6.89(S,1 H),6.22-6.55(m,3 H),5.80(d,J=10.0 Hz),4.24(S,2 H),3.90(S,2 H),3.85(S,2 H),3.64(S,1 H),3.45(S,2 H),3.13(S,3 H);C27H28F3N7O4理論質量:571.2,實測值:572.4(M+H+)。
使用1-(4-(4-胺基-3-甲氧基苯基)-1,4-二氮雜環庚烷-1-基)乙酮及實例1之中間體1,如實例2中所述製備該標題化合物I-7。1H-NMR(DMSO-d6,400 MHz) δ 10.2(S,1 H),9.2(br,1 H),8.7(br,1 H),8.4(br,1 H),7.76(br,1 H),7.49(d,J=8.2 Hz,1 H),7.27(br,2 H),7.1(br,1 H),6.42(dd,J=11.0,16.5 Hz,1 H),6.30(br,1 H),6.24(d,J=16.5 Hz,1 H),5.9(br,1 H),5.74(d,J=11.0 Hz,1 H),3.3-3.7(m,4 H),1.7-1.95(m,5 H);C28H30F3N7O3理論質量:569.2,實測值:570.2(M+H+)。
為獲得該標題化合物,在50℃下,將實例7之中間體5及1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)乙酮(1.0 mL)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得標題化合物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.32(S,1 H),8.92(S,1 H),8.60(S,1 H),7.72(t,J=2.3 Hz,1 H),7.58(d,J=8.7 Hz,1 H),7.43(m,2 H),6.98(m,1 H),6.61(d,J=2.3,1 H),6.42(m,2 H),6.25(dd,J=1.8,16.9 Hz,1 H),5.77(d,J=1.8,10.1 Hz,1 H),3.7-4.0(m,4 H),3.77(S,3 H),3.1(m,4 H),1.99(S,3 H);C27H27F3N6O4理論質量:556.2,實測值:557.1(M+H+)。
使用1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)乙酮及實例8之中間體6,如實例9中所述製備該標題化合物。1H-NMR(氯仿-d,400 MHz) δ 8.26(S,1 H),8.08(br,1 H),7.93(br,1 H),7.68(S,1 H),7.57(m,1 H),7.45(m,2 H),6.96(d,J=7.8 Hz,1 H),6.69(S,1 H),6.60(d,J=7.4 Hz,1 H),6.41(d,J=1.4,17.0 Hz,1 H),6.30(dd,J=10.1,16.5 Hz,1 H),5.75(d,J=1.4,10.1 Hz,1 H),3.97(m,2 H),3.85(S,3 H),3.82(m,2 H),3.29(m,2 H),3.24(m,2 H),2.19(S,3 H);C26H27ClN6O4理論質量:522.2,實測值:523.2(M+H+)。
使用1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)-2-羥基乙酮及實例8之中間體6,如實例9中所述製備該標題化合物。1H-NMR(氯仿-d,400 MHz) δ 8.24(S,1 H),7.71(br,1 H),7.63(m,1 H),7.49(m,1 H),7.44(t,J=8.2 Hz,1 H),7.39(d,J=6.9 Hz,2 H),7.00(dd,J=1.8,7.8 Hz,1 H),6.45(d,J=2.8 Hz,1 H),6.44(dd,J=1.4,16.9 Hz,1 H),6.23(dd,J=10.1,16.9 Hz,1 H),5.79(dd,J=1.4,10.1 Hz,1 H),4.22(S,2 H),3.82(S,3 H),3.80(S,2 H),3.42(m,2 H),3.06(m,4 H);C26H27ClN6O5理論質量:538.2,實測值:539.1(M+H+)。
為獲得該標題化合物,在150℃下,將含於正丁醇中之實例4之中間體2及1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)乙酮之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並純化,以獲得該標題化合物。1H-NMR(DMSO-d6,400 MHz) δ 10.2(S,1 H),8.86(S,1 H),8.07(S,1 H),7.94(br,1 H),7.70(S,1 H),7.68(S,1 H),7.46(d,J=7.6 Hz,1 H),7.27(m,2 H),6.63(d,J=2.4 Hz,1 H),6.46(dd,J=10.0,16.8 Hz,1 H),6.31(br,1 H),6.29(dd,J=2.0,16.8 Hz,1 H),5.76(dd,J=2.0,10.0 Hz,1 H),3.79(S,3 H),3.56(m,4 H),3.0-3.2(m,4 H),2.04(S,3 H);C26H28ClN7O3理論質量:521.2,實測值:522.4(M+H+)。
使用1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)-2-羥基乙酮及實例4之中間體2,如實例15中所述製備該標題化合物。1H-NMR(DMSO-d6,400 MHz) δ 10.2(S,1 H),8.86(S,1 H),8.07(S,1 H),7.94(br,1 H),7.70(m,2 H),7.46(d,J=7.6 Hz,1 H),7.27(m,2 H),6.63(d,J=2.4 Hz,1 H),6.46(dd,J=10.0,16.8 Hz,1 H),6.31(br,1 H),6.29(dd,J=2.0,16.8 Hz,1 H),5.76(dd,J=2.0,10.0 Hz,1 H),4.66(t,J=5.6 Hz,1 H),4.14(t,J=5.6 Hz,2 H),3.79(S,3 H),3.61(br,2 H),3.48(br,2 H),3.05(m,4 H),2.04(S,3 H);C26H28ClN7O4理論質量:537.2,實測值:538.4(M+H+)。
使用1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)-2-羥基乙酮及實例7之中間體5,如實例12中所述製備該標題化合物。1H-NMR(DMSO-d6,400 MHz) δ 10.34(S,1 H),8.84(S,1 H),8.56(br,1 H),7.63(S,1 H),7.53(d,J=8.0 Hz,1 H),7.41(m,1 H),7.16(m,1 H),6.96(br,1 H),6.57(br,1 H),6.45(br,1 H),6.44(dd,J=10.0,16.8 Hz,1 H),6.29(dd,J=1.6,16.8 Hz,1 H),5.79(dd,J=1.6,10.0 Hz,1 H),4.66(t,J=5.6 Hz,1 H),4.14(d,J=5.6 Hz,2 H),3.73(S,3 H),3.60(br,2 H),3.47(br,2 H),3.08(br,4 H);C27H27F3N6O5理論質量:572.2,實測值:573.6(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(20 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。將N-甲基嗎啉(20 uL)、二噁烷(0.5 mL)、及磺醯胺(50 mg)添加至該殘留物中。在90℃下,將該反應混合物微波加熱30分鐘。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.30(s,1 H),8.81(s,1 H),8.54(br,1 H),7.62(s,1 H),7.52(d,J=8.2 Hz,1 H),7.39(t,J=8.2 Hz,1 H),7.16(d,J=8.7 Hz,1 H),6.95(m,1 H),6.85(s,2 H),6.58(m,1 H),6.43(dd,J=11.4,17.0 Hz,1 H),6.26(d,J=17.0 Hz,1 H),5.78(d,J=11.4 Hz,1 H),3.72(S,3 H),3.19(m,4 H),3.06(m,4 H);C25H26F3N7O5S理論質量:593.2,實測值:594.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及胺基甲酸N-甲基-N-羥基琥珀醯酯(50 mg)添加至該殘留物中。在室溫下,攪拌該反應混合物過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C27H29F3N8O3理論質量:570.2,實測值:571.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及氯甲酸甲酯(20 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C27H28F3N7O4理論質量:571.2,實測值:572.2(M+H+)。
實例21
化合物I-17(N-(3-(2-(2-甲氧基-4-(4-(甲基磺醯基)哌嗪-1-基)苯基胺基)-5-(三氟甲基)嘧啶-4-基胺基)苯基)丙烯醯胺)
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及甲磺醯氯(20 μL)添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.22(s,1 H),9.28(br,1 H),8.72(br,1 H),8.37(br,1 H),7.77(s,1 H),7.52(d,J=8.0 Hz,1 H),7.41(d,J=8.0 Hz,1 H),7.30(t,J=8.0 Hz,1 H),7.12(br,1 H),6.62(s,1 H),6.43(dd,J=10.0,16.8 Hz,1 H),6.24(d,J=16.8 Hz,1 H),6.22(br,1 H),5.76(d,J=10.0 Hz,1 H),3.77(s,3 H),3.21(m,4 H),3.18(m,4 H),2.92(s,3 H);C26H28F3N7O4S理論質量:591.2,實測值:592.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)-1,4-二氮雜環庚烷-1-羧酸第三丁酯(21 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及三氟乙酸酐(10 μL)添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.2(s,1 H),9.1(br,1 H),8.6(br,1 H),8.3(br,1 H),7.75(br,1 H),7.50(d,J=8.7 Hz,1 H),7.26(m,2 H),7.11(m,1 H),6.42(dd,J=10.1,17.0 Hz,1 H),6.34(m,1 H),6.23(d,J=17.0 Hz,1 H),5.74(dd,J=1.8,10.1 Hz,1 H),3.3-3.8(m,8 H),1.88(m,2 H);C28H27F6N7O3理論質量:623.2,實測值:624.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(20 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及氯甲酸甲酯(20 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.30(s,1 H),8.80(s,1 H),8.53(br,1 H),7.60(s,1 H),7.51(d,J=8.2 Hz,1 H),7.40(t,J=8.2 Hz,1 H),7.14(d,J=9.6 Hz,1 H),6.93(m,1 H),6.55(m,1 H),6.40(dd,J=10.0,16.8 Hz,1 H),6.24(dd,J=1.8,16.8 Hz,1 H),5.76(dd,J=1.8,10.0 Hz,1 H),3.70(s,3 H),3.58(s,3 H),3.49(m,4 H),3.05(m,4 H);C27H27F3N6O5理論質量:572.2,實測值:573.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(18 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及胺基甲酸N-甲基-N-羥基琥珀醯酯(50 mg)添加至該殘留物中。在室溫下,攪拌該反應混合物過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C27H28F3N7O4理論質量:571.2,實測值:572.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及甲磺醯氯(10 μL)添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C26H27F3N6O5S理論質量:592.2,實測值:593.2(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體6(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及3,3-二甲基丁醯氯添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.33(s,1 H),8.35(s,1 H),8.15(s,1 H),7.60(s,1 H),7.55(d,J=8.2 Hz,1 H),7.40(t,J=8.2 Hz,1 H),7.24(d,J=8.7 Hz,1 H),6.95(d,J=7.8 Hz,1 H),6.57(s,1 H),6.42(dd,J=10.0,16.8 Hz,1 H),6.25(d,J=16.8 Hz,1 H),6.18(m,1 H),6.77(d,J=10.0 Hz,1 H),3.93(s,3 H),3.68(m,4 H),2.99(m,4 H),2.26(s,2 H),0.99(s,9 H);C30H35ClN6O4理論質量:578.2,實測值:579.2(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體6(20 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及三氟乙酸酐(10 μL)添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.32(s,1 H),8.35(s,1 H),8.16(s,1 H),7.59(s,1 H),7.55(d,J=8.2 Hz,1 H),7.40(t,J=8.2 Hz,1 H),7.24(d,J=8.7 Hz,1 H),6.96(d,J=7.8 Hz,1 H),6.57(d,J=2.8 Hz,1 H),6.41(dd,J=10.0,16.8 Hz,1 H),6.24(dd,J=1.8,16.8 Hz,1 H),6.19(m,1 H),5.76(dd,J=1.8,10.0 Hz,1 H),3.72(s,3 H),3.68(m,4 H),3.13(m,4 H);C26H24ClF3N6O4理論質量:576.2,實測值:577.0(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體6(20 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及異氰酸第三丁酯添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.35(s,1 H),8.37(s,1 H),8.19(s,1 H),7.62(s,1 H),7.56(d,J=8.2 Hz,1 H),7.41(t,J=8.2 Hz,1 H),7.28(d,J=8.2 Hz,1 H),6.96(d,J=8.2 Hz,1 H),6.65(s,1 H),6.43(dd,J=10.0,16.8 Hz,1 H),6.29(s,1 H),6.26(d,J=16.8 Hz,1 H),5.92(s,1 H),5.77(d,J=10.0 Hz,1 H),3.74(s,3 H),3.41(s,4 H),3.04(s,4 H),1.26(s,9 H);C29H34ClN7O4理論質量:579.2,實測值:580.2(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體6(20 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及甲磺醯氯添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C25H27ClN6O5S理論質量:558.2,實測值:559.2(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體6(16 mg)及4-(4-胺基-3-乙氧基苯基)哌嗪-1-羧酸第三丁酯(21 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C30H35ClN6O5理論質量:594.2,實測值:595.5(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-三氟甲氧基苯基)哌嗪-1-羧酸第三丁酯(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、N,N-二甲基甲醯胺(1.0 mL)、HATU、及乙醇酸添加至該殘留物中。在室溫下,攪拌該反應混合物30 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.14(s,1 H),8.99(s,1 H),8.61(s,1 H),8.29(s,1 H),7.71(s,1 H),7.44(s,1 H),7.42(s,1 H),7.18(m,2 H),6.85(s,1 H),6.75(m,1 H),6.45(dd,J=10.0,16.8 Hz,1 H),6.26(d,J=16.8 Hz,1 H),5.77(d,J=10.0 Hz,1 H),4.66(t,J=5.6 Hz,1 H),4.14(d,J=5.6 Hz,2 H),3.61(br,2 H),3.49(br,2 H),3.11(br,4 H);C27H25F6N7O4理論質量:625.2,實測值:625.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-二氟甲氧基苯基)哌嗪-1-羧酸第三丁酯(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、N,N-二甲基甲醯胺(1.0 mL)、HATU、及乙醇酸添加至該殘留物中。在室溫下,攪拌該反應混合物30 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C27H26F5N7O4理論質量:607.2,實測值:607.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(16 mg)及2-甲氧基-4-嗎啉基苯胺(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.35(s,1 H),8.83(s,1 H),8.55(br,1 H),7.63(s,1 H),7.53(d,J=8.0 Hz,1 H),7.40(m,1 H),7.16(d,J=8.8 Hz,1 H),6.96(br,1 H),6.54(br,1 H),6.43(m,1 H),6.27(dd,J=1.7,16.8 Hz,1 H),5.77(dd,J=1.7,10.4Hz,1 H),3.72(br,7 H),3.04(br,4 H);C25H24F3N5O4理論質量:515.2,實測值:516.7(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(16 mg)及2-二氟甲氧基-4-嗎啉基苯胺(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.33(s,1 H),9.34(s,1 H),8.55(br,1 H),7.63(s,1 H),7.51(br,1 H),7.40(br,1 H),7.19(d,J=9.2 Hz,1 H),6.96(br,1 H),6.65(br,1 H),6.43(dd,J=10.0,16.8 Hz,1 H),6.27(dd,J=2.0,16.8 Hz,1 H),5.79(dd,J=2.0,10.0 Hz,1 H),3.73(t,J=4.4 Hz,1 H),3.06(m,4 H);C25H22F5N5O4理論質量:551.2,實測值:551.7(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及2-二氟甲氧基-4-嗎啉基苯胺(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.14(s,1 H),8.63(s,1 H),8.28(s,1 H),7.71(s,1 H),7.46(d,J=7.2 Hz,1 H),7.38(s,1 H),7.15(m,2 H),6.91(m,1 H),6.67(m,2 H),6.44(dd,J=10.0,16.8 Hz,1 H),6.25(d,J=16.8 Hz,1 H),5.76(d,J=10.0 Hz,1 H),3.73(t,J=4.4 Hz,1 H),3.05(br,4 H);C25H23F5N6O3理論質量:550.2,實測值:550.9(M+H+)。
在150℃下,將含於正丁醇(1.0 mL)中之中間體2(16 mg)及2-二氟甲氧基-4-嗎啉基苯胺(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ C10.16(s,1 H),8.85(s,1 H),8.07(s,1 H),7.95(br,1 H),7.68(m,2 H),7.45(d,J=7.6 Hz,1 H),7.27(m,2 H),6.60(d,J=2.4 Hz,1 H),6.45(dd,J=10.0,16.8 Hz,1 H),6.26(m,2 H),5.76(dd,J=2.0,10.0 Hz,1 H),3.79(s,3 H),3.73(m,4 H),3.03(m,4 H);C24H25ClN6O3理論質量:480.2,實測值:481.4(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-二氟甲氧基苯基)哌嗪-1-羧酸第三丁酯(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及乙酸酐(50 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.13(s,1 H),8.63(s,2 H),8.29(s,1 H),7.71(s,1 H),7.47(d,J=7.2 Hz,1 H),7.39(m,1 H),7.16(m,2 H),6.91(s,1 H),6.69(s,1 H),9.59(m,1 H),6.44(dd,J=10.0,16.8 Hz,1 H),6.26(d,J=16.8 Hz,1 H),5.77(d,J=10.0 Hz,1 H),3.57(s,4 H),3.10(s,2 H),3.04(s,2 H),2.05(s,3 H);C27H26F5N7O3理論質量:591.2,實測值:591.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-三氟甲氧基苯基)哌嗪-1-羧酸第三丁酯(22 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及乙酸酐(30 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.15(s,1 H),9.00(s,1 H),8.62(s,1 H),8.29(s,1 H),7.71(s,1 H),7.43(s,2 H),7.18(m,2 H),6.84(s,1 H),6.75(br,1 H),6.45(dd,J=10.0,16.8 Hz,1 H),6.26(d,J=16.8 Hz,1 H),5.77(d,J=10.0 Hz,1 H),3.57(br,4 H),3.13(br,2 H),3.06(br,2 H),2.05(s,3 H);C27H25F6N7O3理論質量:609.2,實測值:610.0(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及新戊醯氯(20 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C30H34F3N7O3理論質量:597.3,實測值:598.3(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及丙醯氯(10 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C27H23F3N7O3理論質量:555.2,實測值:556.2(M+H+)。
在150℃下,將含於正丁醇(1.0 mL)中之中間體6(20 mg)及2-二氟甲氧基-4-嗎啉基苯胺(22 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.33(s,1 H),8.71(s,1 H),8.35(s,1 H),7.62(t,J=2.0 Hz,1 H),7.53(d,J=8.0 Hz,1 H),7.40(t,J=8.0 Hz,1 H),7.23(d,J=8.8 Hz,1 H),6.97(dd,J=64.8,66.4 Hz,1 H),6.95(s,1 H),6.64(d,J=2.0 Hz,1 H),6.59(br,1 H),6.44(dd,J=10.0,16.8 Hz,1 H),6.27(dd,J=2.0,16.8 Hz,1 H),5.79(dd,J=2.0,10.0 Hz,1 H),3.72(m,4 H),3.03(m,4 H);C24H22ClF2N5O4理論質量:517.1,實測值:517.7(M+H+)。
在150℃下,將含於正丁醇(1.0 mL)中之中間體6(20 mg)及2-甲氧基-4-(1,4-氧氮雜環庚烷-4-基)苯胺(21 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C25H26ClN5O4理論質量:495.2,實測值:495.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及2-甲氧基-4-(1,4-氧氮雜環庚烷-4-基)苯胺(21 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C26H27F3N6O3理論質量:528.2,實測值:528.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(16 mg)及4-(4-胺基-3-甲氧基苯基)-1,4-二氮雜環庚烷-1-羧酸第三丁酯(21 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C26H27F3N6O3理論質量:528.2,實測值:528.8(M-BoC+H+)。
在150℃下,將含於正丁醇(1 mL)中之中間體4及1-(4-(4-胺基-3-甲氧基苯基)哌嗪-1-基)乙酮(18 mg)之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得該標題化合物。1H-NMR(DMSO-d6,400 MHz) δ 10.15(s,1 H),8.60(br,1 H),8.15(s,1 H),7.89(br,1 H),7.67(m,2 H),7.47(d,J=6.8 Hz,1 H),7.26(m,2 H),6.63(d,J=2.4 Hz,1 H),6.45(dd,J=10.0,16.8 Hz,1 H),6.28(m,1 H),6.26(dd,J=2.0,16.8 Hz,1 H),5.76(dd,J=2.0,10.0 Hz,1 H),3.79(s,3 H),3.56(m,4 H),3.06(m,2 H),3.03(m,2 H),2.05(s,3 H);C26H28BrN7O3理論質量:565.1,實測值:566.3(M+H+)。
在100℃下,將含於正丁醇(1.0 mL)中之中間體2(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。在0℃下,將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及甲磺醯氯(10 μL)添加至該殘留物中。在0℃下,攪拌該反應混合物10 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.16(s,1 H),8.86(s,1 H),8.08(s,1 H),7.95(s,1 H),7.70(m,2 H),7.44(d,J=7.6 Hz,1 H),7.28(m,2 H),6.64(d,J=2.4 Hz,1 H),6.46(dd,J=10.0,16.8 Hz,1 H),6.32(m,1 H),6.26(dd,J=2.0,16.8 Hz,1 H),5.77(dd,J=2.0,10.0 Hz,1 H),3.80(s,3 H),3.30(m,4 H),3.25(m,2 H),3.17(m,2 H),2.93(s,3 H);C25H28ClN7O4S理論質量:557.2,實測值:558.4(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體5(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C30H33F3N6O5理論質量:614.3,實測值:615.2(M+H+)。
在100℃下,將含於正丁醇(1 mL)中之中間體6(16 mg)及4-(4-胺基-3-甲氧基苯基)-1,4-二氮雜環庚烷-1-羧酸第三丁酯(21 mg)之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C30H35ClN6O5理論質量:594.2,實測值:594.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)-1,4-二氮雜環庚烷-1-羧酸第三丁酯(21 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C31H36F3N7O4理論質量:627.3,實測值:628.0(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C30H34F3N7O4理論質量:613.3,實測值:614.1(M+H+)。
在120℃下,將含於正丁醇(1.0 mL)中之中間體6(16 mg)及4-(4-胺基-3-甲氧基苯基)哌嗪-1-羧酸第三丁酯(20 mg)之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C29H33ClN6O5理論質量:580.2,實測值:581.2(M+H+)。
在120℃下,將含於正丁醇(1.0 mL)中之中間體6(16 mg)及4-(4-胺基-3-三氟甲氧基苯基)哌嗪-1-羧酸第三丁酯(22 mg)之混合物與催化性HCl微波加熱20 min。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C29H30ClF3N6O5理論質量:634.2,實測值:635.4(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(16 mg)及(S)-4-(4-胺基-3-甲氧基苯基)哌嗪-1,2-二羧酸1-第三丁酯2-甲酯(23 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化。將該中間體溶於二氯甲烷(1.0 mL)中並用TFA(0.3 mL)處理。10分鐘之後,在減壓下濃縮該混合物。將N,N-二乙基異丙胺(20 μL)、二氯甲烷(1.0 mL)、及乙酸酐(20 μL)添加至該殘留物中。在室溫下,攪拌該反應混合物過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C29H30F3N7O5理論質量:613.2,實測值:614.2(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(18 mg)及2-甲氧基-4-S,S-二側氧基硫嗎啉基苯胺(24 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。1H-NMR(DMSO-d6,400 MHz) δ 10.16(s,1 H),8.66(br,1 H),8.29(s,1 H),8.13(s,1 H),7.77(br,1 H),7.51(s,1 H),7.49(s,1 H),7.26(t,J=8.0 Hz,1 H),7.18(br,1 H),6.64(d,J=2.0 Hz,1 H),6.44(dd,J=10.0,16.8 Hz,1 H),6.31(m,1 H),6.26(dd,J=2.0,16.8 Hz,1 H),5.77(dd,J=2.0,10.0 Hz,1 H),3.79(s,3 H),3.70(m,4 H),3.12(m,4 H);C25H25F3N6OsS理論質量:562.2,實測值:562.8(M+H+)。
在50℃下,將含於二噁烷(1.0 mL)中之中間體1(20 mg)及(S)-4-(4-胺基-3-甲氧基苯基)哌嗪-1,2-二羧酸1-第三丁酯2-甲酯(26 mg)之混合物與催化性三氟乙酸攪拌過夜。在減壓下濃縮該粗製物並使用HPLC(TFA改性劑)純化,以獲得所需物之TFA鹽。C32H36F3N7O6理論質量:671.3,實測值:672.3(M+H+)。
以下描述用於測量所提供之化合物作為相比於WT EGFR(及其他蛋白激酶)之突變型EGFR之選擇性抑制劑之生物活性的試驗。
以下描述使用EGFR-WT及EGFR-T790M/L858R之生物化學試驗。
該試驗平臺之機制最佳係由供應商(Invitrogen,Carlsbad,CA)描述於在其下列URL之網站上:www.invitrogen.com/content.cfm?pageid=11338或www.invitrogen.com/site/us/en/home/Products-and-Services/Applications/Drμg-Discovery/Target-and-Lead-Identification-and-Validation/KinaseBiology/KB-Misc/BioChemical-Assays/Omnia-Kinase-Assays.html。
簡言之,在由20 mM Tris、pH 7.5、5 mM MgCl2、1 mM EGTA、5 mM β-甘油磷酸酯、5%甘油(10X原液,KB002A)及0.2 mM DTT(DS001A)組成之1X激酶反應緩衝劑中,製備EGFR-WT(PV3872)(購自Invitrogen)及EGFR-T790M/L858R(40350)(購自BPS Bioscience,San Diego,CA)、1.13X ATP(AS001A)及適當的Tyr-Sox共軛肽基質(KCZ1001)之10X原液。在25℃下,於Corning(#3574)384孔、白色、非結合性表面微量滴定盤(Corning,NY)中,用0.5 μL體積之50% DMSO及在50% DMSO中製備之連續稀釋化合物,預先培養5 μL之各酶30 min。藉由添加45 μL之ATP/Tyr-Sox肽基質混合物,開始激酶反應,並在Synergy4盤讀取器(購自BioTek(Winooski,VT))中,在λex360/λem485處,每隔71秒監測一次並持續60分鐘。在各試驗結束時,檢查各孔之進展曲線,以獲得線性反應動力學及擬合統計數據(R2、95%置信區間、絕對平方和)。自相對螢光單位與時間(分鐘)之關係曲線之斜率,測定各反應之初始速度(0分鐘至~30分鐘),且隨後將其繪製為與抑制劑濃度之關係曲線,以自log[抑制劑]相對於回應之曲線(來自GraphPad Software(San Diego,CA)之GraphPad Prism中之可變斜率模型)評估IC50。
[EGFR-WT]=5 nM,[ATP]=15 μM,[Y12-Sox]=5 μM(ATP KMapp~12 μM);及[EGFR-T790M/L858R]=2.5 nM,[ATP]=20 μM,[Y12-Sox]=5 μM(ATP KMapp~20 μM)。
表3顯示所選擇之本發明化合物在上述EGFR抑制試驗中之活性。表3顯示相比於WT EGFR之突變型EGFR數據且提供各測試化合物之WT對突變型之選擇性比例。化合物編號對應於表1中之化合物編號。
表3. EGFR(突變型及野生型)生物化學抑制數據
自美國菌種保存中心(American Type CμLture Center)(Manassas,VA)獲得A431人類表皮樣癌細胞、H1975人類NSCLC及HCC827人類NSCLC腺癌細胞。在補充有10%FBS(HyClone,South Logan,UT)及1%青黴素-鏈黴素(P/S,Lonza,Walkersville,MD)之DMEM(Invitrogen,Carlsbad,CA)中,生長A431細胞。在補充有10% FBS及1% P/S之完全RPMI 1640(Invitrogen)中,生長H1975及HCC827細胞。在37℃下及增濕型5% CO2培養箱中,維持所有細胞並以單層培養物形式繁殖。
自Cell Signaling(Danvers,MA)獲得所有初級抗體,且依1:1000使用。依1:10,000使用二級抗體。自LiCor Biosciences(Lincoln,NE)獲得羊抗鼠IgG IRDye 800CW抗體且自Invitrogen獲得羊抗兔IgG Alexa Fluor 680。
使細胞在12孔盤(Corning,Coring,NY)中生長至90%匯合,且隨後在低血清(0.1% FBS)培養基中培養16至18 hr。隨後,在低血清(0.1% FBS)培養基中,用5、1.25、0.31、0.078、0.020或0.005 μM測試化合物處理細胞1 hr。然後,用50 ng/ml EGF(Peprotech,Rocky Hill,NJ)刺激A431細胞15 min。處理後,用冷PBS(Invitrogen)清洗細胞單層,且立即藉由刮削至60 μL補充有完全蛋白酶抑制劑(Roche,Indianapolis,IN)及PhosphoSTOP(Roche)磷酸酶抑制劑之冷細胞萃取緩衝劑中(Invitrogen)使其裂解。
藉由BCA分析(Pierce,Rockford,IL)測定裂解液蛋白質濃度,且藉由4至12%梯度之SDS-PAGE(Invitrogen)分離50 μg之各裂解液,轉移至硝化纖維素膜(Biorad,HercμLes,CA),並用特定抗體探測。使用Odyssey紅外成像法(Li-Cor Biosciences),定量分析磷蛋白質信號。
為評估磷-EGFR信號傳導,用兔抗磷酸化-EGFR(Y1068)及鼠總抗EGFR抗體探測印跡。將各樣品之磷酸化-EGFR信號標準化至總EGFR表現。結果係表示為DMSO對照%。使用具有可變Hill斜率之S形曲線分析程式(Graph Pad Prism,版本5)擬合標準化數據,以測定EC50值。
表4顯示相比於WT EGFR(A431細胞)之H1975(L858R/T790M雙突變)及HCC827(delE746-A750缺失突變)細胞中之突變型EGFR數據。表4中所引用之化合物編號對應於表1中之化合物編號。
表4. EGFR(突變型及野生型)信號傳導(1 hr)
在96孔組織培養盤(Corning)中,將細胞以3,000個細胞/孔之密度接種於補充有5% FBS及1% P/S之生長培養基中。允許細胞沉降4小時,且隨後用5、1.25、0.31、0.078、0.020或0.005 μM測試化合物處理72 hr。藉由CellTiter Glo(Promega,Madison,WI)測定細胞活力,且使用標準曲線將結果轉換為細胞數。藉由Graph Pad Prism測定生長抑制(GI50)值。
此實驗之結果係示於表5中,其中該結果顯示突變選擇性抑制出現在H1975(L858R/T790M雙突變)及HCC827(delE746-A750缺失突變)細胞中,而非WT-EGFR A431細胞中。
表5. EGFR(突變型及野生型)細胞增殖
在12孔組織培養盤中,將細胞以2.0×105個細胞/孔之密度接種於補充有10% FBS及1% P/S之生長培養基中。允許細胞沉降4小時,且隨後保持在低血清(0.1% FBS)培養基中過夜。
第二天早晨,移除培養基,且用含於低血清培養基中之500 nM測試化合物處理該等細胞1 hr。用PBS(Invitrogen)清洗該等細胞2次,以使其不含化合物。如上所示,立即裂解一組細胞以作為0 hr時間點。用完全RPMI-1640生長培養基(10% FBS)培養其餘細胞1、3、6及24 hr。在前1 hr,每30分鐘用PBS清洗細胞2次。在0、3、6及24 hr時間點,收集DMSO(0.5%)對照物。
化合物I-2及I-4顯示化合物移除後延長之作用時間。在移除化合物1 hr之後,pEGFR磷酸化作用被抑制80至100%。在移除化合物之後,pEGFR保持60至90%抑制達至少8小時,但是在第24 h,活性藉由新蛋白質合成恢復至40至60%。
如藉由全蛋白MS分析所證實,化合物I-4單獨且完全修飾EGFR T790M/L858R。以相對於蛋白質過量10倍之化合物I-4,培養完整的EGFR T790M/L858R(BPS,40350)60分鐘。使用15 μL之0.2% TFA稀釋該等樣品之5 μL等分試樣,然後利用微C4 ZipTip吸管尖將其直接轉移至使用芥子酸作為解吸附基質(含於0.1% TFA:乙腈50:50中,10 mg/ml)之MALDI目標物上。A組顯示該完整EGFR T790M/L858R蛋白質之質譜圖(m/z=88,389 Da)。B組顯示經化合物I-4(mw=555.56)培養30分鐘之EGFR T790M/L858R之質譜圖。質心質量(m/z=88,820 Da)顯示431Da(78%)之質量偏移,其表明EGFR T790M/L858R經化合物I-4完全修飾。
類似地測試化合物I-1及I-3且發現其等共價修飾該蛋白質。
將含於50% Matrigel中之1×107個H1975腫瘤細胞皮下植入(0.2 ml注射量)雌性nu/nu小鼠之側腹中。每週記錄腫瘤測量值三次。當腫瘤達到100至150 mg之平均尺寸時,將腫瘤配對。群組大小為10隻小鼠。每天腹膜內投與25 mg/kg測試化合物,持續21天。在第15天(此時對照組達到最大腫瘤體積),測定腫瘤抑制%值。追蹤腫瘤體積,直至腫瘤達到1500 mm3或持續60天。
所提供之化合物之腫瘤抑制值係示於下表6中。
表6.
雖然本文已描述諸多本發明實施例,但顯然可改變基礎實例以提供利用本發明化合物及方法之其他實施例。因此,應瞭解本發明範圍係由隨附申請專利範圍而非已以實例方式呈現之具體實施例所定義。
圖1描繪確定EGFR T790M/L858R經化合物I-4共價修飾之MS分析。
(無元件符號說明)
Claims (62)
- 一種式I化合物或其醫藥上可接受的鹽,
- 一種式I-a化合物或其醫藥上可接受的鹽,
- 如請求項1或2之化合物,其中W係-NH-。
- 如請求項3之化合物,其中R2係-CF3。
- 如請求項1或2之化合物或其醫藥上可接受的鹽,其中該化合物具有式II:
- 如請求項5之化合物,其中W係-NH-。
- 如請求項6之化合物,其中R2係-CF3。
- 如請求項5之化合物,其中定義(a)及(b)中之至少一者係適用:(a) W係-O-或-NH-;及(b) R2係-CF3或Cl。
- 如請求項8之化合物,其中:(a) W係-O-或-NH-;及(b) R2係-CF3或Cl。
- 如請求項5之化合物,其中定義(a)及(b)中之至少一者係適用:(a) W係-O-;及(b) R2係-CF3或Cl。
- 如請求項10之化合物,其中:(a) W係-O-;及(b) R2係-CF3或Cl。
- 如請求項5之化合物,其中定義(a)及(b)中之至少一者係適用:(a) W係-NH-;及(b) R2係-CF3或Cl。
- 如請求項5之化合物,其中:(a) W係-O-;及(b) R2係-CF3或Cl。
- 如請求項1之化合物或其醫藥上可接受的鹽,其中該化合物具有式III:
- 如請求項1之化合物或其醫藥上可接受的鹽,其中該化合物具有式III-a:
- 如請求項14或15之化合物,其中W係-NH-。
- 如請求項14或15之化合物,其中R2係-CF3。
- 如請求項14或15之化合物,其中定義(a)、(b)及(c)中之至少一者係適用:(a) W係-O-或-NH-;(b) R2係-CF3或Cl;及(c) R3係-C(O)CH3或-SO2CH3。
- 如請求項18之化合物,其中定義(a)、(b)及(c)中之至少兩者係適用。
- 如請求項18之化合物,其中定義(a)、(b)及(c)中之全部三者皆適用。
- 如請求項14或15之化合物,其中定義(a)、(b)及(c)中之至少一者係適用:(a) W係-NH-;(b) R2係-CF3或Cl;及(c) R3係-C(O)CH3。
- 如請求項21之化合物,其中定義(a)、(b)及(c)中之至少兩者係適用。
- 如請求項22之化合物,其中定義(a)、(b)及(c)中之全部三者皆適用。
- 如請求項14或15之化合物,其中定義(a)、(b)及(c)中之至少一者係適用:(a) W係-NH-;(b) R5係-CF3或Cl;及(c) R6係-SO2CH3。
- 如請求項24之化合物,其中定義(a)、(b)及(c)中之至少兩者係適用。
- 如請求項25之化合物,其中定義(a)、(b)及(c)中之全部三者皆適用。
- 如請求項14或15之化合物,其中定義(a)、(b)及(c)中之至少一者係適用:(a) W係-O-;(b) R2係-CF3或Cl;及(c) R3係-C(O)CH3。
- 如請求項27之化合物,其中定義(a)、(b)及(c)中之至少兩者係適用。
- 如請求項28之化合物,其中定義(a)、(b)及(c)中之全部三者皆適用。
- 如請求項14或15之化合物,其中定義(a)、(b)及(c)中之至少一者係適用:(a) W係-O-;(b) R2係-CF3或Cl;及(c) R3係-SO2CH3。
- 如請求項30之化合物,其中定義(a)、(b)及(c)中之至少兩者係適用。
- 如請求項31之化合物,其中定義(a)、(b)及(c)中之全部三者皆適用。
- 如請求項1之化合物,其係選自:
- 一種組合物,其包含如請求項1至30中任一項之化合物及醫藥上可接受的載劑、佐劑、或媒劑。
- 如請求項34之組合物,其係與其他治療劑組合。
- 如請求項35之組合物,其中該其他治療劑係化療劑。
- 一種相比於WT EGFR選擇性抑制生物樣品或患者中之至少一種EGFR突變型之方法,其包括使如請求項1至34中任一項之化合物或其組合物與該生物樣品接觸,或將其投與給該患者。
- 如請求項37之方法,其中該方法有餘力(sparing)用於WT EGFR。
- 如請求項37之方法,其中該至少一種突變型係T790M。
- 如請求項38之方法,其中該至少一種突變型係T790M。
- 如請求項37之方法,其中該至少一種EGFR突變型係激活突變型。
- 如請求項39之方法,其中該至少一種EGFR激活突變型係缺失突變型。
- 如請求項41之方法,其中該至少一種EGFR激活突變型係點突變。
- 如請求項42之方法,其中該至少一種激活突變型係delE746-A750。
- 如請求項43之方法,其中該至少一種激活突變型係L858R。
- 如請求項43之方法,其中該至少一種激活突變型係G719S。
- 如請求項37之方法,其中該化合物選擇性抑制至少一種激活突變型及T790M。
- 如請求項47之方法,其中該至少一種EGFR激活突變型係缺失突變型。
- 如請求項47之方法,其中該至少一種EGFR突變型係點突變。
- 如請求項48之方法,其中該至少一種激活突變型係delE746-A750。
- 如請求項49之方法,其中該至少一種激活突變型係L858R。
- 如請求項49之方法,其中該至少一種激活突變型係G719S。
- 如請求項41至52中任一項之方法,其中該化合物有餘力用於WT EGFR。
- 一種治療患者之由突變型EGFR介導之疾病或病症之方法,其包括對該患者投與如請求項34之組合物。
- 如請求項54之方法,其中該疾病或病症係癌症。
- 如請求項55之方法,其中該癌症係非小細胞肺癌。
- 一種化合物,其具有下式:
- 如請求項57之化合物,其中該化合物係選自:
- 一種化合物,其具有下式:
- 如請求項59之化合物,其中該化合物係選自:
- 一種化合物,其具有下式:
- 如請求項61之化合物,其中該化合物係選自:
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US9421208B2 (en) | 2013-08-02 | 2016-08-23 | Pharmacyclics Llc | Methods for the treatment of solid tumors |
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Cited By (2)
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TWI496783B (zh) * | 2012-02-23 | 2015-08-21 | Taiho Pharmaceutical Co Ltd | Quinolylpyrrolopyrimidine condensed cyclic compounds or salts thereof |
US9845329B2 (en) | 2013-02-22 | 2017-12-19 | Taiho Pharmaceutical Co., Ltd. | Method for producing a substituted 6,7,8,9-tetrahydropyrimido[5,4-b]indolizine, substituted 7,8,9,10-tetrahydro-6H-pyrimido[5′,4′:4,5]pyrrolo[1,2-a]azepine and substituted 6,7,8,9,10,11-hexahydropyrimido[5′,4′:4,5]pyrrolo[1,2-a]azocine |
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