TW202302575A - 哺乳動物slc6a19功能之小分子抑制劑 - Google Patents
哺乳動物slc6a19功能之小分子抑制劑 Download PDFInfo
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- TW202302575A TW202302575A TW111108813A TW111108813A TW202302575A TW 202302575 A TW202302575 A TW 202302575A TW 111108813 A TW111108813 A TW 111108813A TW 111108813 A TW111108813 A TW 111108813A TW 202302575 A TW202302575 A TW 202302575A
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- methyl
- compound according
- alkyl
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- 150000003384 small molecules Chemical class 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 title description 2
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- 238000000034 method Methods 0.000 claims abstract description 124
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- 125000000217 alkyl group Chemical group 0.000 claims description 82
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- 125000003342 alkenyl group Chemical group 0.000 claims description 33
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 31
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 21
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 21
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- 125000002469 tricosyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003827 upregulation Effects 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
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000012178 vegetable wax Substances 0.000 description 1
- 229940070384 ventolin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229930195727 α-lactose Natural products 0.000 description 1
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Abstract
本發明揭示可用於藉由調節SLC6A19轉運來治療或預防與胺基酸異常含量相關之疾病或病症的化合物、組合物及方法。
Description
苯丙酮尿症(PKU)係一種由苯丙胺酸羥化酶(PAH,即負責代謝苯丙胺酸之酶)突變引起之先天性代謝錯誤。PKU係其中苯丙胺酸代謝不適當且導致血漿苯丙胺酸含量異常高之體染色體隱性代謝失調。患有PKU之人具有異常高之苯丙胺酸血液含量,若不治療,其可導致不可逆之神經損害,從而導致一系列併發症,例如智力殘疾、癲癇發作、神經發育及行為障礙。由於苯丙胺酸之血液含量與飲食直接相關,故PKU難以治療。患者必須堅持終生嚴格飲食,此影響患者生活之各個態樣。目前護理標準係酶輔因子及酶替代療法,但該等療法並非對所有患者皆有效,且具有不良事件之潛在風險。
負責代謝苯丙胺酸且因此維持苯丙胺酸穩態之酶係苯丙胺酸羥化酶(PAH)。已知染色體12q23.2之PAH基因之功能喪失(LOF)突變引起大多數形式之PKU。該等導致PKU之LOF突變可診斷為經典PKU (最嚴重形式)、以及「輕度PKU」或「高苯丙胺酸血症」(較不嚴重形式)。除了PAH之外,影響苯丙胺酸代謝之其他酶(例如二氫喋啶還原酶(DHPR),該酶負責合成PAH活性所需之輔因子)之突變亦可導致苯丙胺酸含量升高。除了飲食之外,血液胺基酸含量(包括苯丙胺酸含量)亦受SLC6A19調控。SCL6A19位於腎之近端小管且負責胺基酸重吸收回血液。
本發明之一個態樣提供可用於藉由調節SLC6A19轉運來治療或預防與胺基酸之異常含量相關之疾病或病症的化合物、組合物及方法。
因此,本文提供具有式(I)之結構之化合物:
其中:
n為0、1或2;
L
1不存在或選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH
2-;
L
2不存在或為-CH
2-;
L
3不存在或為-C(O)-;
X
1及X
2獨立地選自-H、烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基;條件係X
1及X
2二者不皆為-H;
Y
1選自芳基及雜芳基;
Y
2選自烷基、烯基、炔基、烷氧基、烷氧基烷基、羥基烷基、環烷基、雜環基、芳基、雜芳基、-NH(Y
2')及-N(Y
2'')
2;
Y
2'選自-H、-OH、烷基、烷氧基、烷氧基烷基及環烷基;
每一Y
2''係烷基、或兩個實例與其所鍵結之氮原子一起形成5或6員雜環基;且
Y
3、Y
4、Y
5及Y
6獨立地選自-H、-OH、鹵化物、烷基、鹵代烷基及烷氧基;條件係Y
3及Y
4或Y
5及Y
6二者不皆為-OH;
條件係當L
3係-C(O)-時,則Y
2並非芳基;且該化合物並非選自:
及
;
或其醫藥上可接受之鹽。
本發明之另一態樣係關於治療或預防有需要之個體與苯丙胺酸羥化酶之基因缺陷相關之疾病或病症的方法,其包含向該個體投與有效量之式(I)化合物。
本發明之另一態樣係關於治療或預防有需要之個體之苯丙酮尿症、高苯丙胺酸血症、酪胺酸血症、非酮性高甘胺酸血症、異戊酸血症、甲基丙二酸血症、丙酸血症、楓糖漿尿病、DNAJC12缺乏、尿素循環障礙或高氨血症之方法,其包含向該個體投與有效量之式(I)化合物。
本發明之另一態樣係關於調節有需要之個體之SLC6A19轉運的方法,其包含向該個體投與有效量之式(I)化合物。
除非另有定義,否則本文所用之所有技術及科學術語皆具有與熟習本發明所屬領域技術者通常所理解之含義相同的含義。儘管本發明之實踐或測試中可使用類似或等效於本文所述之方法及材料的方法及材料,但下文闡述適宜方法及材料。本文所提及之所有出版物、專利申請案、專利及其他參考文獻之全部內容皆以引用方式併入本文中。倘若出現衝突,則以本說明書(包括定義)為準。另外,材料、方法及實例僅為闡釋性而並不意欲具有限制性。
自詳細說明及申請專利範圍可明瞭本發明之其他特徵、目標及優勢。
相關申請案本申請案主張於2022年2月10日提交之美國臨時專利申請案系列第63/308,790號、於2021年12月22日提交之第63/292,815號、於2021年8月18日提交之第63/234,487號、於2021年7月28日提交之第63/226,551號及於2021年3月10日提交之第63/159,271號的優先權益。
定義
為了方便起見,在進一步闡述本發明之前,在說明書、實例及所附申請專利範圍中採用之某些術語收集在此。該等定義應根據本揭示內容之其餘部分來閱讀且由熟習此項技術者理解。除非另有定義,否則本文所用之所有技術及科學術語皆具有與熟習此項技術者通常所理解相同之含義。
為了更容易理解本發明,下文及整個說明書中定義某些術語及片語。
冠詞「一(a及an)」在本文中用於指該冠詞之文法受詞之一個或一個以上(亦即係指至少一個)。舉例而言,「要素」意指一個要素或一個以上要素。
如本文在說明書及申請專利範圍中所用片語「及/或」應理解為意指如此結合之要素中之「任一者或兩者」,亦即,在一些情形下以結合方式存在且在其他情形下以分離方式存在之要素。以「及/或」列出之多個要素應視為呈相同型式,亦即,如此結合之要素中之「一或多者」。除由「及/或」從句所特定識別之要素之外的其他要素可視情況存在,無論與所特定識別之彼等要素相關或不相關。因此,作為非限制性實例,當結合諸如「包含」等開放式語言使用時,對「A及/或B」之引用可在一實施例中,係指僅A (視情況包括除B之外之要素);在另一實施例中,係指僅B (視情況包括除A之外之要素);在又一實施例中,係指A及B二者(視情況包括其他要素);等。
如本文中在說明書中和在申請專利範圍中所用,「或」應理解為具有與如上文所定義之「及/或」相同之含義。舉例而言,在分離清單中之物項時,「或」或者「及/或」應闡釋為係包括性的,亦即,包括若干要素或要素清單中之至少一者(但亦包括一者以上)及視情況包括額外未列出物項。術語「僅(only)」明確指示相反情形,諸如「……之僅一者」或「……之恰好一者」或在申請專利範圍中使用時「由……組成」將係指包括若干要素或要素清單中之恰好一個要素。一般而言,本文所用術語「或」在前面有排他性術語(諸如「或者」、「……中之一者」、「……中之僅一者」或「……中之恰好一者」)時應僅將其解釋為指示排他性選擇(亦即,「一者或另一者而非兩者」)。當在申請專利範圍中使用時,「基本上由……組成」應具有如其用於專利法律領域中之普通含義。
如本文在說明書中和在申請專利範圍中所用,關於一或多個要素之清單之片語「至少一」應理解為意指至少一個選自要素清單中之任一或多個要素之要素,但未必包括要素清單內特定列出之各自及每一要素中之至少一者,且不排除要素清單中要素之任何組合。此定義亦容許可視情況存在除片語「至少一」所指之要素清單內特定識別之要素之外之要素,無論與特定識別之彼等要素相關還是不相關。因此,作為非限制性實例,在一個實施例中,「A及B中之至少一者」(或等效地,「A或B中之至少一者」,或等效地,「A及/或B中之至少一者」)可係指至少一個(視情況包括一個以上) A,而不存在B(且視情況包括除B以外之要素);在另一實施例中,係指至少一個(視情況包括一個以上) B,而不存在A (且視情況包括除A以外之要素);在又一實施例中,係指至少一個(視情況包括一個以上) A及至少一個(視情況包括一個以上) B (且視情況包括其他要素);等等。
亦應理解,除非明確指示相反情形,否則在本文所主張之包括一個以上步驟或動作之任何方法中,該方法之步驟或動作之順序不必受限於所列舉之該方法之步驟或動作之順序。
在申請專利範圍以及在上文說明書中,所有過渡性片語(諸如「包含」、「包括」、「攜載」、「具有」、「含有」、「涉及」、「固持」、「由……構成」及諸如此類)應理解為係開放式,亦即,意指包括但不限於。僅過渡性片語「由……組成」及「基本上由……組成」應分別係封閉式或半封閉式過渡性片語,如美國專利局專利審查程序手冊(United States Patent Office Manual of Patent Examining Procedures)第2111.03節中所陳述。
包含在本發明組合物中之某些化合物可以特定幾何或立體異構形式存在。另外,本發明之聚合物亦可係光學活性的。本發明考慮所有該等化合物,包括順式-及反式-異構物、
R-及
S-鏡像異構物、非鏡像異構物、(D)-異構物、(L)-異構物、其外消旋混合物、及其其他混合物,該等化合物皆屬本發明之範圍內。在諸如烷基等取代基中可存在額外不對稱碳原子。所有該等異構物以及其混合物皆意欲包括在本發明中。
「幾何異構物」意指與碳-碳雙鍵、環烷基環或橋接二環系統相關之取代基原子之定向不同之異構物。碳-碳雙鍵之每一側上之原子(除H外)可呈E構形(取代基在碳-碳雙鍵之相對側)或Z構形(取代基在同一側上定向)。「R」、「S」、「S*」、「R*」、「E」、「Z」、「順式」及「反式」指示相對於核心分子之構形。某些揭示之化合物可以「阻轉異構」形式或「阻轉異構物」存在。阻轉異構物係由圍繞單鍵之受阻旋轉產生之立體異構物,其中旋轉之空間應變障壁足夠高以允許分離構形異構物。本發明化合物可藉由異構物特異性合成製備為個別異構物或自異構物之混合物拆分。習用拆分技術包括使用光學活性酸形成異構物對之每一異構物之游離鹼之鹽(之後分段結晶及再生游離鹼)、使用光學活性胺形成異構物對之每一異構物之酸形式之鹽(之後分段結晶及再生游離酸)、使用光學純酸、胺或醇形成異構物對之每一異構物之酯或醯胺(之後層析分離及去除手性助劑)、或使用各種眾所周知之層析方法拆分起始材料或最終產物之異構物混合物。
例如,若期望本發明化合物之特定對映體,可藉由不對稱合成或藉由用手性助劑衍生來製備,其中分離所得非鏡像異構物混合物並裂解輔助基團以提供純的期望鏡像異構物。或者,在分子含有鹼性官能基(例如胺基)或酸性官能基(例如羧基)之情況下,用適當光學活性酸或鹼形成非鏡像異構物鹽,之後藉由業內熟知之分段結晶或層析方式拆分由此形成之非鏡像異構物,且隨後回收純鏡像異構物。
以莫耳分數計之純度百分比係鏡像異構物(或非鏡像異構物)之莫耳數相對於鏡像異構物(或非鏡像異構物)之莫耳數加上其光學異構物之莫耳數之比。當揭示之化合物之立體化學由結構命名或繪示時,命名或繪示之立體異構物相對於其他立體異構物以莫耳分數計純度至少為約60%、約70%、約80%、約90%、約99%或約99.9%。當單一鏡像異構物由結構命名或繪示時,所繪示或命名之鏡像異構物以莫耳分數計純度至少為約60%、約70%、約80%、約90%、約99%或約99.9%。當單一非鏡像異構物由結構命名或繪示時,所繪示或命名之非鏡像異構物以莫耳分數計純度至少為約60%、約70%、約80%、約90%、約99%或約99.9%。
當揭示之化合物由結構命名或繪示而未指示立體化學,且該化合物具有至少一個手性中心時,應理解,該名稱或結構涵蓋不含相應光學異構物之化合物之任一鏡像異構物、化合物之外消旋混合物或相對於其相應光學異構物富含一種鏡像異構物之混合物。當揭示之化合物由結構命名或繪示而未指示立體化學且具有兩個或更多個手性中心時,應理解,該名稱或結構涵蓋不含其他非鏡像異構物之非鏡像異構物、大量不含其他非鏡像異構物對之非鏡像異構物、非鏡像異構物之混合物、非鏡像異構物對之混合物、其中一種非鏡像異構物相對於其他非鏡像異構物富集之非鏡像異構物之混合物、或其中一或多種非鏡像異構物相對於其他非鏡像異構物富集之非鏡像異構物之混合物。本發明涵蓋所有該等形式。
本文繪示之結構亦意指包括僅在一或多個同位素富集之原子存在下不同之化合物。舉例而言,藉由用氘或氚置換氫、或用富含
13C-或
14C之碳置換碳產生之化合物在本發明之範圍內。
如本文所用術語「前藥」涵蓋在生理條件下轉化為治療活性劑之化合物。製備前藥之常見方法係包括在生理條件下水解以顯示期望分子之所選部分。在其他實施例中,前藥由宿主動物之酶活性轉化。
如本文所用片語「醫藥上可接受之賦形劑」或「醫藥上可接受之載劑」意指參與將標的化學品自身體之一個器官或部分攜帶或轉運至身體之另一器官或部分的醫藥上可接受之材料、組合物或媒劑,例如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封材料。在與調配物之其他成分相容、對患者無害且實質上無熱原性之意義上,每一載劑必須係「可接受的」。可用作醫藥上可接受之載劑之材料之一些實例包括:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)澱粉,例如玉米澱粉及馬鈴薯澱粉;(3)纖維素及其衍生物,例如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)粉末狀黃蓍膠;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,例如可可脂及栓劑蠟;(9)油,例如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,例如氫氧化鎂及氫氧化鋁;(15)海藻酸;(16)無熱原水;(17)等滲鹽水;(18)林格氏溶液(Ringer’s solution);(19)乙醇;(20)磷酸鹽緩衝液溶液;及(21)醫藥調配物中所採用之其他無毒相容性物質。在某些實施例中,本發明之醫藥組合物係無熱原性的,即,當投與患者時不會誘發顯著溫度升高。
術語「醫藥上可接受之鹽」係指化合物之相對無毒之無機及有機酸加成鹽。該等鹽可在化合物之最終分離及純化期間原位製備,或藉由將呈游離鹼形式之純化化合物與適宜有機或無機酸單獨反應並分離由此形成之鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、萘酸鹽、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽及月桂基磺酸鹽類及諸如此類。(例如參見Berge等人,(1977) 「Pharmaceutical Salts」,
J. Pharm. Sci. 66:1-19。)
在其他情形下,可用於本發明方法之化合物可含有一或多種酸性官能基且因此能夠與醫藥上可接受之鹼形成醫藥上可接受之鹽。在該等情況下,術語「醫藥上可接受之鹽」係指化合物之相對無毒性之無機及有機鹼加成鹽。同樣,該等鹽可在化合物之最終分離及純化期間原位製備,或藉由使純化合物以其游離酸形式與適宜鹼(例如,醫藥上可接受之金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽)、與氨、或與醫藥上可接受之有機一級、二級或三級胺單獨反應而製備。代表性鹼金屬鹽或鹼土金屬鹽包括鋰、鈉、鉀、鈣、鎂及鋁鹽及諸如此類。可用於形成鹼加成鹽之代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、六氫吡嗪及諸如此類(參見例如Berge等人,同上)。
術語「醫藥上可接受之共晶體」係指不與小分子形成正式離子相互作用之固體共構物。
就用於治療而言,化合物之「治療有效量」(或「有效量」)係指製劑中化合物之量,當作為期望劑量方案之一部分(對哺乳動物,較佳人類)投與時,根據欲治療之病症或病況之臨床上可接受之標準或美容目的,例如以適用於任何醫學治療之合理益處/風險比,該量可減輕症狀、改善病況或減緩疾病病況之發作。
術語「預防性或治療性」治療係業內公認的且包括向宿主投與一或多種標的組合物。若將其在不期望病況(例如宿主動物之疾病或其他不期望狀態)臨床表現前投與,則該治療為預防性的(亦即,其保護宿主免於發生不期望病況),而若將其在不期望病況表現後投與,則該治療為治療性的(亦即,其意欲減少、改善或穩定現存不期望病況或其副作用)。
術語「患者」或「個體」係指需要特定治療之哺乳動物。在某些實施例中,患者係靈長類動物、犬、貓或馬。在某些實施例中,患者係人類。
脂肪族鏈包含下文定義之烷基、烯基及炔基之類別。直鏈脂肪族鏈限於無支鏈之碳鏈部分。如本文所用術語「脂肪族基團」係指直鏈、具支鏈或環狀脂肪族烴基且包括飽和及不飽和脂肪族基團,例如烷基、烯基或炔基。
「烷基」係指具有指定碳原子數或若未指定則具有至多30個碳原子之完全飽和環狀或非環、具支鏈或無支鏈碳鏈部分。舉例而言,1至8個碳原子之烷基係指諸如甲基、乙基、丙基、丁基、戊基、己基、庚基及辛基等部分、以及為該等部分之位置異構物之彼等部分。10至30個碳原子之烷基包括癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基、二十三烷基及二十四烷基。在某些實施例中,直鏈或具支鏈烷基在其主鏈中具有30個或更少之碳原子(例如,直鏈為C
1-C
30,具支鏈為C
3-C
30),且更佳具有20個或更少之碳原子。烷基可經取代或未經取代。
如本文所用術語「雜烷基」係指如上定義之烷基部分,其含有一或多個氧、硫、氮、磷或矽原子來代替碳原子。
如本文所用術語「鹵代烷基」係指經至少一個鹵素取代之如上定義之烷基。
如本文所用術語「羥基烷基」係指經至少一個羥基取代之如上定義之烷基。
如本文所用術語「伸烷基」係指具有指定碳數(例如2至12個碳原子)之烷基,在其最長碳鏈上含有與化合物其餘部分之兩個連接點。伸烷基之非限制性實例包括亞甲基-(CH
2)-、伸乙基-(CH
2CH
2)-、正伸丙基-(CH
2CH
2CH
2)-、異伸丙基-(CH
2CH(CH
3))-及諸如此類。伸烷基可為環狀或非環、具支鏈或無支鏈碳鏈部分,且可視情況經一或多個取代基取代。
「環烷基」意指單環或二環或橋接或螺環、或多環狀飽和碳環,其各自具有3至12個碳原子。較佳環烷基在其環結構中具有3-10個碳原子,且更佳在環結構中具有3-6個碳。環烷基可經取代或未經取代。
如本文所用術語「鹵代環烷基」係指經至少一個鹵素取代之如上定義之環烷基。
「環雜烷基」係指如上定義之環烷基部分,其含有一或多個氧、硫、氮、磷或矽原子來代替碳原子。較佳環雜烷基在其環結構中具有4-8個碳原子及雜原子,且更佳在環結構中具有4-6個碳及雜原子。環雜烷基可經取代或未經取代。
除非碳數另有指示,否則如本文所用之「低碳烷基」係指如上定義之烷基,但在其主鏈結構中具有1至10個碳、更佳1至6個碳原子,例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基。同樣,「低碳烯基」及「低碳炔基」具有類似鏈長度。在整個申請中,較佳烷基係低碳烷基。在某些實施例中,本文中命名為烷基之取代基係低碳烷基。
「烯基」係指任何環狀或非環狀、具支鏈或無支鏈不飽和碳鏈部分,其具有指定碳原子數,或若未指定對碳原子數之限制,則具有至多26個碳原子;且在部分中具有一或多個雙鍵。6至26個碳原子之烯基由己烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一烯基、十二烯基、十三烯基、十四烯基、十五烯基、十六烯基、十七烯基、十八烯基、十九烯基、二十烯基、二十一烯基、二十二烯基、二十三烯基及二十四烯基例示,呈其各種異構形式,其中不飽和鍵可位於該部分之任何位置且可圍繞雙鍵具有(Z)或(E)構形。
「炔基」係指烯基範圍之烴基部分,但在該部分中具有一或多個三鍵。
如本文所用術語「芳基」包括3至12員經取代或未經取代之單環芳香族基團,其中環之每一原子係碳(即,碳環芳基),或其中一或多個原子係雜原子(即,雜芳基)。較佳地,芳基包括5至12員環、更佳6至10員環。術語「芳基」亦包括具有兩個或更多個環之多環系統,其中兩個或更多個碳為兩個相鄰之環所共有,其中至少一個環係芳香族的,例如,其他環可為環烷基、環烯基、環炔基、芳基、雜芳基及/或雜環基。碳環芳基包括苯、萘、菲、酚、苯胺及諸如此類。雜芳基包括經取代或未經取代之芳香族3至12員環結構、更佳5至12員環、更佳5至10員環,其環結構包括1至4個雜原子。雜芳基包括(例如)吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、三唑、吡唑、吡啶、吡嗪、噠嗪及嘧啶及諸如此類。芳基及雜芳基可為單環、二環或多環的。
如本文所用術語「鹵基」、「鹵化物」或「鹵素」意指鹵素且包括(例如但不限於)氟、氯、溴、碘及諸如此類,其呈放射性及非放射性形式。在較佳實施例中,鹵基選自由以下組成之群:氟、氯及溴。
術語「雜環基(heterocyclyl)」或「雜環基(heterocyclic group)」係指3至12員環結構、更佳5至12員環、更佳5至10員環,其環結構包括1至4個雜原子。雜環可為單環、二環、螺環或多環的。雜環基包括(例如)噻吩、噻蒽、呋喃、吡喃、異苯并呋喃、𠳭唏、𠮿、吩噁噻、吡咯、咪唑、吡唑、異噻唑、異噁唑、吡啶、吡嗪、嘧啶、嗒嗪、吲嗪、異吲哚、吲哚、吲唑、嘌呤、喹嗪、異喹啉、喹啉、酞嗪、萘啶、喹喏啉、喹唑啉、㖕啉、喋啶、咔唑、哢啉、菲啶、吖啶、嘧啶、菲咯啉、吩嗪、啡砷𠯤、吩噻嗪、呋呫、吩噁嗪、吡咯啶、氧雜環戊烷、四氫噻吩、噁唑、六氫吡啶、六氫吡嗪、嗎啉、內酯、內醯胺(例如氮雜環丁酮及吡咯啶酮)、磺內醯胺、磺內酯、及諸如此類。雜環可在一或多個位置經上述取代基取代,該等取代基例如鹵素、烷基、芳烷基、烯基、炔基、環烷基、羥基、胺基、硝基、硫氫基、亞胺基、醯胺基、磷酸酯、膦酸酯、次膦酸酯、羰基、羧基、矽基、胺磺醯基、亞磺醯基、醚、烷硫基、磺醯基、酮、醛、酯、雜環基、芳香族或雜芳香族部分、-CF
3、-CN、及諸如此類。
術語「經取代」係指具有置換主鏈之一或多個碳上之氫之取代基的部分。應理解,「取代」或「經……取代」包括隱含前提,亦即此取代應與經取代原子及取代基之允許化合價一致,且該取代會產生穩定化合物,例如,其不會自發發生轉變(例如藉由重排、環化、消去等)。考慮如本文中所用術語「經取代」包括有機化合物之所有允許之取代基。廣義上,該等允許之取代基包括有機化合物之無環狀及環狀、具支鏈及無支鏈、碳環狀及雜環狀、芳香族及非芳香族取代基。對於適當有機化合物而言,該等允許之取代基可為一或多個且可相同或不同。出於本發明之目的,雜原子(例如氮)可具有氫取代基及/或滿足雜原子之化合價之本文所述有機化合物之任何允許之取代基。取代基可包括本文所述之任何取代基,例如鹵素、羥基、羰基(例如羧基、烷氧基羰基、甲醯基或醯基)、硫代羰基(例如硫酯、硫代乙酸酯或硫代甲酸酯)、烷氧基、磷醯基、磷酸酯、膦酸酯、亞膦酸酯、胺基、醯胺基、脒、亞胺、氰基、硝基、疊氮基、巰基、烷硫基、硫酸酯、磺酸酯、胺磺醯基、磺醯胺基、磺醯基、雜環基、芳烷基或芳香族或雜芳香族部分。在較佳實施例中,經取代烷基上之取代基選自C
1-6烷基、C
3-6環烷基、鹵素、羰基、氰基或羥基。在更佳實施例中,經取代烷基上之取代基選自氟、羰基、氰基或羥基。熟習此項技術者應理解,若適當,取代基可自身經取代。除非具體陳述為「未經取代」,否則在本文中所提及之化學部分應理解為包括經取代之變化形式。舉例而言,所提及之「芳基」或部分隱含地包括經取代及未經取代之變化形式二者。
如本文所用,每個表述(例如烷基、m、n等)當在任何結構中出現不止一次時,其定義意欲獨立於其在相同結構中之其他地方之定義。
如本文所用之「小分子」係指分子量低於約3,000道爾頓之小的有機或無機分子。一般而言,可用於本發明之小分子具有小於3,000道爾頓(Da)之分子量。小分子可為(例如)至少約100 Da至約3,000 Da (例如介於約100至約3,000 Da、約100至約2500 Da、約100至約2,000 Da、約100至約1,750 Da、約100至約1,500 Da、約100至約1,250 Da、約100至約1,000 Da、約100至約750 Da、約100至約500 Da、約200至約1500、約500至約1000、約300至約1000 Da,或約100至約250 Da)。
在一些實施例中,「小分子」係指分子量通常小於約1000之有機、無機或有機金屬化合物。在一些實施例中,小分子係大小在1 nm之數量級之有機化合物。在一些實施例中,本發明之小分子藥物涵蓋分子量小於約1000之寡肽及其他生物分子。
「有效量」係足以實現有益或期望結果之量。舉例而言,治療量係達到期望治療效應之量。該量可與預防有效量相同或不同,該預防有效量係預防疾病或疾病症狀發作所必需之量。有效量可以一或多次投與、施加或劑量中投與。組合物之治療有效量取決於所選之組合物。組合物可自每天一或多次至每週一或多次投與;包括每隔一天一次投與。熟習此項技術者將理解,某些因素可影響有效治療個體所需之劑量及時間,包括(但不限於)疾病或病症之嚴重程度、先前治療、個體之總體健康狀況及/或年齡以及存在之其他疾病。此外,用治療有效量之本文所述之組合物治療個體可包括單次治療或一系列治療。
術語「減少」、「降低」(「reduce」、「reduced」、「reduction」)、「減少」及「抑制」在本文中通常皆用於意指相對於參考值減少統計學上顯著之量。然而,為了避免疑問,「降低」(「reduce」、「reduction」)、或「減少」或「抑制」通常意指與參考值相比減少至少10%,且可包括(例如)減少至少約20%、至少約25%、至少約30%、至少約35%、至少約40%、至少約45%、至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約98%、至少約99%,高達且包括(例如)與參考值相比完全不存在給定實體或參數,或與不存在給定治療相比任何減少介於10-99%之間。
術語「增加」(「increased」、「increase」)或「增強」或「活化」在本文中皆用於通常意指增加靜態顯著之量;為了避免任何疑問,術語「增加」(「increased」、「increase」)或「增強」或「活化」意指與參考值相比增加至少10%,例如增加至少約20%、或至少約30%、或至少約40%、或至少約50%、或至少約60%、或至少約70%、或至少約80%、或至少約90%或高達並包括與參考值相比增加100%或任何增加介於10-100%之間,或與參考值相比增加至少約2倍、或至少約3倍、或至少約4倍、或至少約5倍或至少約10倍,或任何增加介於2倍至10倍或更高。
如本文所用術語「調節」包括上調及下調,例如增強或抑制反應。
如本文定義之「放射性醫藥劑」係指含有至少一種放射發射之放射性同位素之醫藥劑。放射性醫藥劑通常用於核醫學中,用於各種疾病之診斷及/或治療。放射標記之醫藥劑(例如放射標記之抗體)含有用作輻射源之放射性同位素(RI)。如本文所考慮,術語「放射性同位素」包括金屬及非金屬放射性同位素。基於放射標記之醫藥劑之醫學應用選擇放射性同位素。當放射性同位素係金屬放射性同位素時,通常採用螯合劑將金屬放射性同位素結合至分子之其餘部分。當放射性同位素係非金屬放射性同位素時,非金屬放射性同位素通常直接或藉由連接體連接至分子之其餘部分。
出於本發明之目的,化學元素根據元素週期表, CAS版, Handbook of Chemistry and Physics, 第67板, 1986-87,封面頁內來鑑別。
本發明化合物 本發明之一個態樣係關於式(I)化合物:
其中:
n為0、1或2;
L
1不存在或選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH
2-;
L
2不存在或為-CH
2-;
L
3不存在或為-C(O)-;
X
1及X
2獨立地選自-H、烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基;條件係X
1及X
2二者不皆為-H;
Y
1選自芳基及雜芳基;
Y
2選自烷基、烯基、炔基、烷氧基、烷氧基烷基、羥基烷基、環烷基、雜環基、芳基、雜芳基、-NH(Y
2')及-N(Y
2'')
2;
Y
2'選自-H、-OH、烷基、烷氧基、烷氧基烷基、羥基烷基及環烷基;
每一Y
2''係烷基、或兩個實例與其所鍵結之氮原子一起形成5或6員雜環基;且
Y
3、Y
4、Y
5及Y
6獨立地選自-H、-OH、鹵化物、烷基、鹵代烷基及烷氧基;條件係Y
3及Y
4或Y
5及Y
6二者不皆為-OH;
條件係當L
3係-C(O)-時,則Y
2並非芳基;且該化合物並非選自:
及
,
或其醫藥上可接受之鹽。
在某些實施例中,Y
2'選自-H、-OH、烷基、烷氧基、烷氧基烷基及環烷基。
在某些實施例中,X
1及X
2中之一者係-H;且X
1及X
2中之另一者選自C
1-C
4烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基。
在某些實施例中,L
1不存在。在其他實施例中,L
1選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH
2-。
在某些實施例中,L
1選自-CH
2-、-C(H)(CH
3)-、-CH
2CH
2-及-C(H)(OH)CH
2-。在其他實施例中,L
1係
。在其他實施例中,L
1選自
及
。在其他實施例中,L
1選自
及
。
在某些實施例中,Y
1係未經取代之芳基,例如未經取代之苯基及未經取代之萘基。
在某些實施例中,Y
1係經取代之芳基。
在某些實施例中,Y
1係
;且
R
1、R
2、R
3、R
4及R
5獨立地選自-H、鹵素、-CN、-CF
3、-CHF
2、-CF
2CH
3、-OCF
3、-OCHF
2、烷基、鹵代烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基及雜芳基;條件係R
1、R
2、R
3、R
4及R
5中之一者不為-H。
在某些實施例中,R
1、R
2、R
3、R
4及R
5獨立地選自-H、-F、-Cl、-Br、-CN、-CH
3、-CH
2CH
3、-CF
3、-CHF
2、-CF
2CH
3、-OCH
3、-OCF
3、-OCHF
2、
、
及
。
在某些實施例中,R
1、R
2、R
3、R
4及R
5中之兩者不為-H。在其他實施例中,R
1、R
2、R
3、R
4及R
5中之三者不為-H。
在某些實施例中,Y
1係經取代之雜芳基。
在某些實施例中,Y
1選自:
及
;且
R
6、R
7、R
8及R
9在每次出現時獨立地選自-H、鹵素、-CN、-OCF
3、-OCHF
2、烷基、鹵代烷基、烯基、炔基、烷氧基、環烷基、芳基及雜芳基;條件係R
6、R
7、R
8及R
9中之至少一者不為-H。
在某些實施例中,L
2不存在。在其他實施例中,L
2係-CH
2-。
在某些實施例中,L
3不存在。在其他實施例中,L
3係-C(O)-。
在某些實施例中,
n係0。在其他實施例中,
n係1。在其他實施例中,
n係2。
在某些實施例中,Y
2係未經取代之雜芳基。
在某些實施例中,Y
2係經取代之雜芳基。
在某些實施例中,Y
2係
;
R
10、R
11及R
12獨立地選自-H、鹵素、-CN、-OH、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、羥基烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14、-CO
2R
15及-C(O)NHSO
2R
15;條件係R
10、R
11及R
12中之至少一者不為-H;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,Y
2係
;
R
10、R
11及R
12獨立地選自-H、鹵素、-CN、-OH、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14、-CO
2R
15及-C(O)NHSO
2R
15;條件係R
10、R
11及R
12中之至少一者不為-H;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,R
10、R
11及R
12獨立地選自-H、-F、-Cl、-Br、-CN、-CH
3、-CH
2CH
3、-CF
3、-CHF
2、-CF
2CH
3、-OCH
3、-OCF
3、-OCHF
2、-OAc、-NH
2、-NHCH
3、-NHAc、-C(O)NH
2、-C(O)NHCH
3、-C(O)NHCH
2CH
3、-C(O)NHSO
2CH
3、-C(O)NHSO
2CH
2CH
3、-CO
2H、苯基、環丙基、環丁基、咪唑基及四唑基。
在某些實施例中,R
10及R
12各自係-H;且R
11選自-CN、-CF
3、-CH
3、-OCH
3、-NH
2、-NHCH
3、-NHAc、-CO
2H、-C(O)NH
2、-C(O)NHCH
3、-C(O)NHCH
2CH
3、
及
。
在某些實施例中,R
11及R
12各自係-H;且R
10選自-CN、-CF
3、-CH
3、-OCH
3、-NH
2、-NHCH
3、-NHAc、-CO
2H、-C(O)NH
2、-C(O)NHCH
3、-C(O)NHCH
2CH
3、
及
。
在某些實施例中,R
10及R
11各自-H;且R
12選自-CN、-CF
3、-CH
3、-OCH
3、-NH
2、-NHCH
3、-NHAc、-CO
2H、-C(O)NH
2、-C(O)NHCH
3、-C(O)NHCH
2CH
3、
及
。
在某些實施例中,Y
2選自
及
;
R
16在每次出現時獨立地選自鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14、-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,Y
2選自
及
;
R
17、R
18、R
19、R
20及R
21在每次出現時獨立地選自-H、鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、羥基烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;條件係R
17、R
18、R
19、R
20及R
21中之至少一者不為-H;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,Y
2選自
及
;
R
17、R
18、R
19、R
20及R
21在每次出現時獨立地選自-H、鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;條件係R
17、R
18、R
19、R
20及R
21中之至少一者不為-H;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,R
17、R
18、R
19、R
20及R
21獨立地選自-H、-CN、-CH
3及-OCH
3。
在某些實施例中,Y
2係未經取代之環烷基或雜環基。
在某些實施例中,Y
2係經取代之環烷基或雜環基。
在某些實施例中,Y
2選自烷基、烯基、炔基、烷氧基、烷氧基烷基及羥基烷基。
在某些實施例中,Y
2選自-CH
3、-CH
2CH(CH
3)
2、-CH
2CH
2C≡CH、-CH
2CH
2OCH
3、-C(H)(CH
3)CH
2OCH
3、-OCH
3、-CH
2OH、-CH
2CH
2OH、-C(CH
3)
2OH及-CH
2OCH
3。
在某些實施例中,Y
2選自-CH
2OH及-CH
2CH
2OH。
在某些實施例中,Y
2係雜芳基。
在某些實施例中,Y
2係
;
R
10、R
11及R
12獨立地選自-H、鹵素、-CN、-OH、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、羥基烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,Y
2係
;
R
10、R
11及R
12獨立地選自-H、鹵素、-CN、-OH、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,R
10、R
11及R
12中之至少一者不為-H。
在某些實施例中,Y
2選自
及
;
R
17、R
18、R
19、R
20及R
21在每次出現時獨立地選自-H、鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、羥基烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,Y
2選自
及
;
R
17、R
18、R
19、R
20及R
21在每次出現時獨立地選自-H、鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中, R
17、R
18、R
19、R
20及R
21中之至少一者不為-H。
在某些實施例中,Y
2選自
及
;
R
22、R
23、R
24及R
25在每次出現時獨立地選自-H、鹵素、-CN、-NH
2、-OCF
3、-OCHF
2、-OAc、-NHAc、烷基、鹵代烷基、烯基、炔基、烷氧基、烷基胺基、環烷基、芳基、雜芳基、-C(O)NR
13R
14及-CO
2R
15;且
R
13、R
14及R
15在每次出現時獨立地選自-H、烷基、芳基及雜芳基。
在某些實施例中,R
22、R
23、R
24及R
25在每次出現時獨立地選自-H、及-CH
3。
在某些實施例中,Y
2係-NH(Y
2')或Y
2係-N (Y
2'')
2。
在某些實施例中,每一Y
2''係-CH
3。在其他實施例中,Y
2''與其所鍵結之氮原子二者一起形成嗎啉基。
在某些實施例中,其中Y
2係-NH(Y
2')。
在某些實施例中,Y
2'選自-H、烷基、烷氧基及羥基烷基。在其他實施例中,Y
2'選自-H、-OCH
3、-CH
3及-CH
2CH
2OH。
在某些實施例中,Y
2'係H。在其他實施例中,Y
2'係-CH
3。在其他實施例中,Y
2'係-CH
2CH
3。在其他實施例中,Y
2'係-OCH
3。在其他實施例中,Y
2'係-CH
2OH。在其他實施例中,Y
2'係-CH
2CH
2OH。
在某些實施例中,Y
3及Y
4二者皆係-H或-F。在其他實施例中,Y
3選自-F、-CF
3、-OH及-OCH
3;且Y
4係-H。在其他實施例中,Y
4選自-F、-CF
3、-OH及-OCH
3;且Y
3係-H。
在某些實施例中,Y
3及Y
4二者皆係-H。在其他實施例中,Y
3及Y
4二者皆係-F。
在某些實施例中,Y
5及Y
6二者皆係-H或-F。在其他實施例中,Y
5選自-F、-CF
3、-OH及-OCH
3;且Y
6係-H。在其他實施例中,Y
6選自-F、-CF
3、-OH及-OCH
3;且Y
5係-H。
在某些實施例中,Y
5及Y
6二者皆係-H。在其他實施例中,Y
5及Y
6二者皆係-F。
在一些實施例中,化合物係阻轉異構物。另外,除非另外陳述,否則本文所繪示之結構亦意欲包括僅在一或多個同位素富集原子存在下不同的化合物。舉例而言,藉由用氘或氚置換氫、或用富含
13C-或
14C之碳置換碳產生之化合物在本發明之範圍內。根據本發明,該等化合物可用作(例如)分析工具、用作生物分析中之探針或用作治療劑。舉例而言,在變量R
1之情形下,(C
1-C
4)烷基或-O-(C
1-C
4)烷基可適宜地經氘化(例如-CD
3、-OCD
3)。
本發明之任何化合物亦可經放射標記用於製備放射性醫藥劑。
治療方法 本發明之一個態樣提供可用於藉由調節SLC6A19轉運來治療或預防與胺基酸之異常含量相關之疾病或病症的化合物、組合物及方法。
本發明之另一態樣係關於調節有需要之個體之SLC6A19轉運的方法,其包含向該個體投與有效量之式(I)化合物。
本發明之另一態樣係關於治療或預防有需要之個體與苯丙胺酸羥化酶之基因缺陷相關之疾病或病症的方法,其包含向該個體投與有效量之式(I)化合物。
在一些實施例中,本發明係關於治療或預防有需要之個體之苯丙酮尿症的方法,其包含向該個體投與有效量之式(I)化合物。
在一些實施例中,本發明係關於治療或預防有需要之個體之高苯丙胺酸血症之方法,其包含向該個體投與有效量之式(I)化合物。
在一些實施例中,該化合物減少個體中之全身性苯丙胺酸含量。
在一些實施例中,本發明係關於治療或預防有需要之個體之酪胺酸血症(I、II或III型)之方法,其包含向該個體投與有效量之式(I)化合物。
在一些實施例中,該化合物降低個體中之全身性甘胺酸含量。
在一些實施例中,本發明係關於治療或預防有需要之個體之異戊酸血症、甲基丙二酸血症、丙酸血症、楓糖漿尿病、DNAJC12缺乏、尿素循環障礙或高氨血症之方法,其包含向該個體投與有效量之式(I)化合物。
在所揭示方法中之任一者之一些實施例中,該化合物調節個體中之SLC6A19。
在所揭示方法中之任一者之一些實施例中,該化合物抑制個體中之SLC6A19。
在所揭示方法中之任一者之一些實施例中,該化合物調節個體中之SLC6A19轉運。
在所揭示方法中之任一者之一些實施例中,該化合物抑制個體中之SLC6A19轉運。
在一些實施例中,該化合物降低個體中之胺基酸之全身含量。
在所揭示方法中之任一者之一些實施例中,其中個體係哺乳動物。在所揭示方法中之任一者之一些實施例中,哺乳動物係人類。
在所揭示方法中之任一者之一些實施例中,式(I)化合物定義為:
(I)
其中:
n為0、1或2;
L
1不存在或選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH
2-;
L
2不存在或為-CH
2-;
L
3不存在或為-C(O)-;
X
1及X
2獨立地選自-H、烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基;條件係X
1及X
2二者不皆為-H;
Y
1選自芳基及雜芳基;
Y
2選自烷基、烯基、炔基、烷氧基、烷氧基烷基、羥基烷基、芳烷基、雜芳烷基、環烷基、雜環基、芳基、雜芳基、-NH(Y
2')及-N(Y
2'')
2;
Y
2'選自-H、-OH、烷基、烷氧基、烷氧基烷基及環烷基;
每一Y
2''係烷基、或兩個實例與其所鍵結之氮原子一起形成5或6員雜環基;
Y
3、Y
4、Y
5及Y
6獨立地選自-H、-OH、鹵化物、烷基、鹵代烷基及烷氧基;條件係Y
3及Y
4或Y
5及Y
6二者不皆為-OH,
或其醫藥上可接受之鹽。
在所揭示方法中之任一者之一些實施例中,該化合物選自表1中所列舉之化合物中之任一者之結構。
在所揭示方法中之任一者之一些實施例中,該化合物選自表2中所列舉之化合物中之任一者之結構。
在所揭示方法中之任一者之一些實施例中,該化合物選自表3中所列舉之化合物中之任一者之結構。
在所揭示方法中之任一者之一些實施例中,該化合物選自表4中所列舉之化合物中之任一者之結構。
在所揭示方法中之任一者之一些實施例中,該化合物選自表5中所列舉之化合物中之任一者之結構。
醫藥組合物、投與途徑及給藥 在某些實施例中,本發明係關於醫藥組合物,其包含本發明化合物及醫藥上可接受之載劑。在某些實施例中,醫藥組合物包含複數種本發明化合物及醫藥上可接受之載劑。
在某些實施例中,本發明之醫藥組合物進一步包含至少一種除本發明化合物外之額外醫藥活性劑。至少一種額外醫藥活性劑可為可用於治療缺血再灌注損傷之藥劑。
本發明之醫藥組合物可藉由組合一或多種本發明化合物與醫藥上可接受之載劑及視情況一或多種額外醫藥活性劑組合來製備。
如上所述,「有效量」係指足以達到期望生物效應之任何量。結合本文提供之教示,藉由在各種活性化合物及權衡因素(例如功效、相對生物利用度、患者體重、不良副作用之嚴重程度及投與方式)中進行選擇,可設計出有效預防性或治療性治療方案,該方案不會引起顯著不期望之毒性,但對治療特定個體有效。任何特定應用之有效量可根據諸如所治療之疾病或病況、所投與之本發明之特定化合物、個體之大小或疾病或病況之嚴重程度等因素而變化。熟習此項技術者可憑經驗確定本發明之特定化合物及/或其他治療劑之有效量,而不需要過多實驗。可使用最大劑量,即根據一些醫學判斷之最高安全劑量。可考慮每天多個劑量以達到化合物之適當全身含量。適當全身含量可藉由(例如)量測患者之藥物之峰值或持續血漿含量來確定。「劑量」(「Dose」)及「劑量」(「dosage」)在本文中可互換使用。
在某些實施例中,化合物之靜脈內投與通常可為0.1 mg/kg/天至20 mg/kg/天。在一個實施例中,化合物之靜脈內投與通常可為0.1 mg/kg/天至2 mg/kg/天。在一個實施例中,化合物之靜脈內投與通常可為0.5 mg/kg/天至5 mg/kg/天。在一個實施例中,化合物之靜脈內投與通常可為1 mg/kg/天至20 mg/kg/天。在一個實施例中,化合物之靜脈內投與通常可為1 mg/kg/天至10 mg/kg/天。
通常,對於人類個體,化合物之每日口服劑量為約0.01毫克/ kg /天至1000毫克/kg /天。預計每天以一或多次投與0.5至50毫克/kg範圍內之口服劑量將產生治療結果。根據投與方式,可適當調整劑量以達到局部或全身之期望藥物含量。舉例而言,預計靜脈內投與將為劑量每天降低一個數量級至若干數量級。若在該等劑量下個體中之反應不足,則可採用甚至更高劑量(或藉由不同、更局部遞送途徑之有效的較高劑量),達個體耐受性允許之程度。考慮每天多個劑量以達到化合物之適當全身含量。
對於本文所述之任何化合物而言,治療有效量最初可自動物模型確定。對於已在人類中測試之化合物及已知展現類似藥理學活性之化合物(例如其他相關活性劑),治療有效劑量亦可自人類數據確定。非經腸投與可需要更高之劑量。可基於所投與化合物之相對生物利用度及功效來調整所施加劑量。基於上述方法及業內眾所周知之其他方法調整劑量以達到最大效能完全在普通熟習此項技術者之能力範圍內。
本發明之調配物可在醫藥上可接受之溶液中投與,該溶液通常可含有醫藥上可接受濃度之鹽、緩衝劑、防腐劑、相容之載劑、佐劑及視情況其他治療成分。
為了用於療法,可藉由將化合物遞送至期望表面之任何方式將有效量之化合物投與個體。投與醫藥組合物可藉由熟習此項技術者已知之任何方式完成。投與途徑包括(但不限於)靜脈內、肌內、腹膜內、膀胱內(膀胱)、經口、皮下、直接注射(例如,注射至腫瘤或膿瘍中)、黏膜(例如,局部注射至眼中)、吸入及局部投與。
對於靜脈內及其他非經腸投與途徑,本發明化合物可調配為凍乾製劑、脂質體嵌入或囊封之活性化合物之凍乾製劑、水性懸浮液中之脂質複合物或鹽複合物。凍乾調配物通常在投與前不久在適宜水溶液中(例如在無菌水或鹽水中)重構。
對於經口投與而言,該等化合物可容易地藉由組合活性化合物與業內熟知之醫藥上可接受之載劑來調配。該等載劑使得能夠將本發明化合物調配為錠劑、丸劑、糖衣錠、膠囊、液體、凝膠、糖漿、漿液、懸浮液及諸如此類,以供欲治療之個體經口攝取。用於經口使用之醫藥製劑可藉由視情況研磨所得混合物並在添加適宜輔助劑(若期望)後處理顆粒混合物以獲得錠劑或糖衣錠核心,以固體賦形劑形式獲得。具體而言,適宜賦形劑係填充劑,例如糖,包括乳糖、蔗糖、甘露醇或山梨醇;纖維素製劑,例如玉米澱粉、小麥澱粉、水稻澱粉、馬鈴薯澱粉、明膠、黃蓍膠、甲基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮(PVP)。若期望,可添加崩解劑,例如交聯聚乙烯吡咯啶酮、瓊脂或海藻酸或其鹽(例如海藻酸鈉)。視情況,經口調配物亦可調配於鹽水或緩衝液(例如EDTA)中用於中和內部酸條件,或可在無任何載劑之情況下投與。
亦特別考慮上述一或多種組分之經口劑型。可對一或多種組分進行化學修飾,從而使衍生物之經口投與有效。通常,考慮之化學修飾係將至少一個部分連接至組分分子本身,其中該部分允許(a)抑制酸水解;及(b)自胃或腸攝取至血流中。亦期望增加一或多種組分之整體穩定性,並增加在體內之循環時間。該等部分之實例包括:聚乙二醇、乙二醇及丙二醇之共聚物、羧甲纖維素、聚葡萄糖、聚乙烯醇、聚乙烯吡咯啶酮及聚脯胺酸。Abuchowski及Davis, 「Soluble Polymer-Enzyme Adducts」, 於以下中:Enzymes as Drugs, Hocenberg及Roberts編輯, Wiley-Interscience, New York, N.Y., 第367-383頁(1981);Newmark等人,
J Appl Biochem4:185-9 (1982)。可使用之其他聚合物係聚-1,3-二氧戊環及聚-1,3,6-三噁環辛烷。如上所指示,對於醫藥用途,聚乙二醇部分係適宜的。
對於組分(或衍生物),釋放之位置可為胃、小腸(十二指腸、空腸或迴腸)或大腸。熟習此項技術者具有可用之調配物,其不會在胃中溶解,但會在十二指腸或腸內其他地方釋放物質。較佳地,藉由保護本發明化合物(或衍生物)或藉由將生物活性物質釋放至胃環境之外(例如在腸中),釋放將避免胃環境之有害效應。
為了確保完全胃抗性,對於至少pH 5.0不滲透之包衣係必要的。用作腸溶包衣之更常見惰性成分之實例係乙酸偏苯三酸纖維素(CAT)、羥丙基甲基纖維素鄰苯二甲酸酯(HPMCP)、HPMCP 50、HPMCP 55、聚乙酸乙烯酯鄰苯二甲酸酯(PVAP)、Eudragit L30D、Aquateric、乙酸纖維素鄰苯二甲酸酯(CAP)、Eudragit L、Eudragit S及蟲膠。該等包衣可用作混合膜。
包衣或包衣之混合物亦可用在錠劑上,其不意欲用於針對胃進行保護。此可包括糖包衣、或使錠劑更容易吞嚥之包衣。膠囊可由用於遞送乾治療劑(例如粉末)之硬殼(例如明膠)組成;對於液體形式,可使用軟明膠殼。扁囊劑之殼材料可為濃澱粉或其他可食用紙。對於丸劑、菱形錠劑、模製錠劑或錠劑研磨劑,可使用濕塊化技術。
治療劑可作為呈粒徑為約1 mm之顆粒或小丸之形式之微細多顆粒包括於調配物中。用於膠囊投與之物質之調配物亦可為粉末、輕度壓縮之栓塞或甚至錠劑。治療劑可藉由壓縮來製備。
著色劑及調味劑皆可包括在內。舉例而言,本發明化合物(或衍生物)可經調配(例如藉由脂質體或微球囊封),且然後進一步包含在可食用產品中,例如含有著色劑及矯味劑之冷凍飲料。
可用惰性材料稀釋或增加治療劑之體積。該等稀釋劑可包括碳水化合物,尤其甘露醇、α-乳糖、無水乳糖、纖維素、蔗糖、經改質聚葡萄糖及澱粉。某些無機鹽亦可用作填充劑,包括三磷酸鈣、碳酸鎂及氯化鈉。一些市售稀釋劑係Fast-Flo、Emdex、STA-Rx 1500、Emcompress及Avicell。
崩解劑可包括於將治療劑製成固體劑型之調配物中。用作崩解劑之材料包括(但不限於)澱粉,包括基於澱粉之商業崩解劑Explotab。澱粉羥乙酸鈉、Amberlite、羧甲基纖維素鈉、超支鏈澱粉、海藻酸鈉、明膠、桔皮、酸性羧甲基纖維素、天然海綿及膨潤土皆可使用。崩解劑之另一種形式係不溶性陽離子交換樹脂。粉末樹膠可用作崩解劑及黏合劑,且該等可包括粉末樹膠,例如瓊脂、刺梧桐樹膠或黃蓍膠。海藻酸及其鈉鹽亦可用作崩解劑。
黏合劑可用於將治療劑保持在一起以形成硬錠劑,且包括來自天然產物之材料,例如阿拉伯樹膠、黃蓍膠、澱粉及明膠。其他包括甲基纖維素(MC)、乙基纖維素(EC)及羧甲基纖維素(CMC)。聚乙烯吡咯啶酮(PVP)及羥丙基甲基纖維素(HPMC)二者皆可在醇溶液中用於將治療劑製粒。
抗摩擦劑可包括於治療劑之調配物中,以防止在調配製程期間黏連。潤滑劑可用作治療劑及模具壁之間之層,且該等可包括(但不限於):硬脂酸(包括其鎂鹽及鈣鹽)、聚四氟乙烯(PTFE)、液體石蠟、植物油及蠟。亦可使用可溶性潤滑劑,例如月桂基硫酸鈉、月桂基硫酸鎂、各種分子量之聚乙二醇、Carbowax 4000及6000。
可添加助流劑,其可改良藥物在調配期間之流動性質並有助於壓縮過程期間之重排。助流劑可包括澱粉、滑石、熱解二氧化矽及水合矽鋁酸鹽。
為了幫助治療劑溶解至水環境中,可添加表面活性劑作為潤濕劑。表面活性劑可包括陰離子清潔劑,例如月桂基硫酸鈉、二辛基磺基琥珀酸鈉及二辛基磺酸鈉。可使用之陽離子清潔劑包括氯化苄烷銨(benzalkonium chloride)及氯化本索寧(benzethonium chloride)。可作為表面活性劑包括於調配物中之潛在非離子清潔劑包括聚桂醇400、聚烴氧40硬脂酸酯、聚氧乙烯氫化蓖麻油10、50及60、單硬脂酸甘油酯、聚山梨醇酯40、60、65及80、蔗糖脂肪酸酯、甲基纖維素及羧甲基纖維素。該等表面活性劑可單獨或以不同比率之混合物存在於本發明化合物或衍生物之調配物中。
可經口使用之醫藥製劑包括由明膠製得之推入配合式(push-fit)膠囊以及由明膠及增塑劑(例如甘油或山梨醇)製得之軟密封膠囊。推入配合式膠囊可含有活性成分與填充劑(例如乳糖)、黏合劑(例如澱粉)及/或潤滑劑(例如滑石粉或硬脂酸鎂)以及視情況穩定劑之混合物。在軟質膠囊中,可將活性化合物溶解或懸浮於適宜液體(例如脂肪油、液體石蠟或液體聚乙二醇)中。此外,可添加穩定劑。亦可使用經調配用於經口投與之微球。該等微球在業內已充分定義。所有經口投與之調配物皆應呈適於該投與之劑量。
對於經頰投與而言,組合物可呈以習用方式調配之錠劑或菱形錠劑形式。
對於局部投與,該化合物可調配為溶液、凝膠、軟膏劑、乳膏、懸浮液等,如業內眾所周知。全身調配物包括設計用於注射(例如皮下、靜脈內、肌內、鞘內或腹膜內注射)投與之彼等,以及設計用於經皮、經黏膜口服或肺投與之彼等。
對於藉由吸入投與,根據本發明使用之化合物可藉由使用適宜推進劑(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他適宜氣體)以氣溶膠噴霧呈遞形式自加壓包裝或霧化器方便地遞送。在加壓氣溶膠之情形中,劑量單位可藉由提供遞送計量量之閥來確定。用於吸入器或吹入器中之明膠之膠囊及藥筒可經調配含有化合物與適宜粉末基質(例如乳糖或澱粉)之粉末混合物。
本文亦考慮本文揭示之化合物(或其鹽)之肺遞送。該化合物在吸入時遞送至哺乳動物之肺,且穿過肺上皮內層進入血流。吸入分子之其他報導包括Adjei等人,
Pharm Res7:565-569 (1990);Adjei等人,
Int J Pharmaceutics63:135-144 (1990) (乙酸柳培林);Braquet等人,
J Cardiovasc Pharmacol13(增刊5):143-146 (1989) (內皮素-1);Hubbard等人,
Annal Int Med3:206-212 (1989) (α1-抗胰蛋白酶);Smith等人,1989,
J Clin Invest84:1145-1146 (a-1-蛋白酶);Oswein等人,1990, 「Aerosolization of Proteins」, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (重組人類生長激素);Debs等人,1988,
J Immunol140:3482-3488 (干擾素-γ及腫瘤壞死因子α)及Platz等人,美國專利第5,284,656號(顆粒球群落刺激因子;以引用方式併入)。用於全身效應之藥物之肺遞送之方法及組合物闡述於1995年9月19日頒予Wong等人之美國專利第5,451,569號(以引用方式併入)中。
考慮在本發明之實踐中使用設計用於肺遞送治療產品之各種機械裝置,包括(但不限於)霧化器、定劑量吸入器及粉末吸入器,所有該等皆係熟習此項技術者所熟悉的。
適於本發明之實踐之市售裝置之一些具體實例係由Mallinckrodt, Inc., St. Louis, Mo.製造之Ultravent霧化器;由Marquest Medical Products, Englewood, Colo.製造之Acorn II霧化器;由Glaxo Inc., Research Triangle Park, North Carolina製造之Ventolin定劑量吸入器;及由Fisons Corp., Bedford, Mass製造之Spinhaler粉末吸入器。
所有該等裝置皆需要使用適於分配本發明化合物之調配物。通常,每一調配物對所採用之裝置類型具有特異性,且除了療法中常用之稀釋劑、佐劑及/或載劑之外,亦可涉及使用適當推進劑材料。此外,考慮使用脂質體、微膠囊或微球、包涵複合物或其他類型之載劑。根據化學修飾之類型或所採用裝置之類型,本發明之化學修飾之化合物亦可以不同調配物製備。
適用於霧化器(噴射或超音波)之調配物通常包含溶解在水中之本發明化合物(或衍生物),濃度為每毫升溶液約0.1至25 mg本發明之生物活性化合物。該調配物亦可包括緩衝劑及簡單糖(例如,用於抑制劑穩定及滲透壓調控)。霧化器調配物亦可含有表面活性劑,以減少或防止在形成氣溶膠時由溶液霧化引起之本發明化合物之表面誘發之聚集。
用於定劑量吸入器裝置之調配物通常包含含有本發明化合物(或衍生物)之細分粉末,該粉末借助於表面活性劑懸浮於推進劑中。推進劑可為用於此目的之任何習用材料,例如氯氟碳、氫氯氟碳、氫氟碳或烴,包括三氯氟甲烷、二氯二氟甲烷、二氯四氟乙醇及1,1,1,2-四氟乙烷、或其組合。適宜表面活性劑包括脫水山梨醇三油酸酯及大豆卵磷脂。油酸亦可用作表面活性劑。
用於自粉末吸入器裝置分配之調配物將包含含有本發明化合物(或衍生物)之細分乾粉末,且亦可包括增積劑,例如乳糖、山梨醇、蔗糖或甘露醇,其量有利於粉末自裝置中分散,例如佔調配物重量之50-90%。本發明化合物(或衍生物)應有利地製備成平均粒徑小於10微米(μm)、最佳0.5μm至5 μm之顆粒形式,用於最有效地遞送至肺深部。
亦考慮本發明之醫藥組合物之經鼻遞送。經鼻遞送允許本發明之醫藥組合物在將治療產品投與至鼻後直接通過血流,而不需要產品在肺中沈積。用於經鼻遞送之調配物包括具有聚葡萄糖或環聚葡萄糖之彼等。
對於經鼻投與,有用之裝置係附接定劑量霧化器之小而硬之瓶子。在一個實施例中,藉由將本發明之醫藥組合物溶液吸入至限定體積之腔室中來遞送定劑量,該腔室具有經定尺寸以當腔室中之液體經壓縮時藉由形成噴霧來氣溶膠化氣溶膠調配物的孔。壓縮腔室以投與本發明之醫藥組合物。在具體實施例中,腔室係活塞佈置。該等裝置有市售。
或者,使用具有孔或開口之塑膠擠壓瓶,該孔或開口經定尺寸以當擠壓時藉由形成噴霧來氣溶膠化氣溶膠調配物。開口通常發現在瓶子之頂部,且頂部通常係錐形的,以部分適合鼻道,用於氣溶膠調配物之有效投與。較佳地,鼻吸入器將提供計量量之氣溶膠調配物,用於投與定劑量之藥物。
當期望全身性遞送化合物時,可藉由注射,例如藉由濃注注射或連續輸注,將化合物調配用於非經腸投與。用於注射之調配物可以單位劑型存在,例如存於安瓿(ampoule)或存於多劑量容器中,同時添加有防腐劑。組合物可採取諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式,且可含有諸如懸浮劑、穩定劑及/或分散劑等調配劑。
用於非經腸投與之醫藥調配物包括呈水溶性形式之活性化合物之水溶液。另外,該等活性化合物之懸浮液可製備成適當油性注射懸浮液。適宜親脂性溶劑或媒劑包括脂肪油(例如芝麻油)或合成脂肪酸酯(例如油酸乙酯或三甘油酸酯)或脂質體。水性注射懸浮液可含有增加該懸浮液之黏度之物質,例如羧甲基纖維素鈉、山梨醇或葡聚糖。視情況,該懸浮液亦可含有適宜穩定劑或增加該等化合物之溶解度之試劑以容許製備高濃度溶液。
或者,活性化合物可呈粉末形式,用於在使用前用適宜媒劑(例如無菌無熱原水)構造。
亦可將該等化合物調配於經直腸或陰道組合物(例如,含有例如習用栓劑基質(例如可可油或其他甘油酯)之栓劑或保留灌腸劑)中。
除上述調配物之外,化合物亦可調配成儲積製劑。該等長效調配物可利用適宜聚合或疏水性材料(例如作為於可接受油中之乳液)或離子交換樹脂來調配,或作為微溶衍生物(例如,作為微溶鹽)來調配。
醫藥組合物亦可包含適宜固相或凝膠相載劑或賦形劑。該等載劑或賦形劑之實例包括(但不限於)碳酸鈣、磷酸鈣、各種糖、澱粉、纖維素衍生物、明膠及聚合物(例如聚乙二醇)。
適宜液體或固體醫藥製劑形式係(例如)用於吸入之水溶液或鹽溶液、微囊化、內嵌、塗覆在微觀金粒子上、包含在脂質體中、霧化、氣溶膠、用於植入皮膚之小丸、或乾燥在尖銳物體上以刮入皮膚。醫藥組合物亦包括顆粒、粉末、錠劑、包衣錠劑、(微)膠囊、栓劑、糖漿劑、乳液、懸浮液、乳霜、滴劑或緩釋活性化合物之製劑,在該等製劑中,通常如上所述使用賦形劑及添加劑及/或助劑,例如崩解劑、黏合劑、包衣劑、溶脹劑、潤滑劑、矯味劑、甜味劑或增溶劑。醫藥組合物適用於多種藥物遞送系統。關於藥物遞送方法之簡要綜述,參見Langer R,
Science249:1527-33 (1990)。
本發明化合物及視情況其他治療劑可本身(純淨)或以醫藥上可接受之鹽或共晶體之形式投與。當用於藥物時,鹽或共晶體應係醫藥上可接受的,但非醫藥上可接受之鹽或共晶體可便捷地用於製備其醫藥上可接受之鹽或共晶體。該等鹽包括(但不限於)由下列酸製備之鹽:鹽酸、氫溴酸、硫酸、硝酸、磷酸、馬來酸、乙酸、柳酸、對甲苯磺酸、酒石酸、檸檬酸、甲磺酸、甲酸、丙二酸、琥珀酸、萘-2-磺酸及苯磺酸。此外,該等鹽可製備成鹼金屬或鹼土金屬鹽,例如羧酸基團之鈉鹽、鉀鹽或鈣鹽。
適宜緩衝劑包括:乙酸及鹽(1-2% w/v);檸檬酸及鹽(1-3% w/v);硼酸及鹽(0.5-2.5% w/v);及磷酸及鹽(0.8-2% w/v)。適宜防腐劑包括氯化苄烷銨(0.003-0.03% w/v);氯丁醇(0.3-0.9% w/v);對羥苯甲酸酯(0.01-0.25% w/v)及硫柳汞(0.004-0.02% w/v)。
本發明之醫藥組合物含有有效量之如本文所述之化合物及視情況包括於醫藥上可接受之載劑中之治療劑。術語「醫藥上可接受之載劑」意指一或多種相容之固體或液體填充劑、稀釋劑或囊封物質,其適於投與人類或其他脊椎動物。術語「載劑」表示天然或合成之有機或無機成分,其與活性成分組合以有利於施加。醫藥組合物之組分亦能夠與本發明化合物混合,且彼此混合,其混合方式使得不存在會實質上損害期望醫藥效率之相互作用。
治療劑(具體包括但不限於本發明化合物)可以粒子之形式提供。如本文所用之粒子意指奈米粒子或微粒(或在某一情況下更大之粒子),其可全部或部分包含本發明化合物或本文所述之其他治療劑。粒子可在由包衣包圍之核中包含治療劑,該包衣包括但不限於腸溶包衣。治療劑亦可分散在整個粒子中。治療劑亦可吸附至粒子中。粒子可具有任何級釋放動力學,包括零級釋放、一級釋放、二級釋放、延遲釋放、持續釋放、立即釋放及其任何組合等。除了治療劑之外,粒子可包括藥學及醫學領域中通常使用之彼等材料中之任一者,包括但不限於可溶蝕、不可溶蝕、可生物降解或不可生物降解之材料或其組合。粒子可為微膠囊,其含有溶液或半固態之本發明化合物。粒子可為實際上任何形狀。
不可生物降解及可生物降解之聚合材料皆可用於製造用於遞送治療劑之粒子。該等聚合物可為天然或合成聚合物。基於期望釋放之時間段選擇聚合物。特別感興趣之生物黏附聚合物包括以下中所述之可生物侵蝕之水凝膠:Sawhney H S等人 (1993)
Macromolecules26:581-7,其教示併入本文中。該等包括聚玻尿酸、酪蛋白、明膠、明膠蛋白、聚酸酐、聚丙烯酸、海藻酸鹽、幾丁聚醣、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸異丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸異癸酯)、聚(甲基丙烯酸月桂基酯)、聚(甲基丙烯酸苯基酯)、聚(丙烯酸甲酯)、聚(丙烯酸異丙酯)、聚(丙烯酸異丁酯)及聚(丙烯酸十八烷基酯)。
治療劑可包含在控制釋放系統中。術語「控制釋放」意欲指任何含有藥物之調配物,其中藥物自調配物中釋放之方式及分佈係受控的。此係指立即釋放及非立即釋放調配物,其中非立即釋放調配物包括(但不限於)持續釋放及延遲釋放調配物。術語「持續釋放」(亦稱為「延長釋放」)以其習用含義使用,指在一段延長之時間內逐漸釋放藥物之藥物調配物,且較佳地,儘管並非必須的,在一段延長之時間內產生實質上恆定之藥物血液含量。術語「延遲釋放」以其習用含義使用,指其中在調配物之投與與藥物自其釋放之間存在時間延遲之藥物調配物。「延遲釋放」可涉及或可不涉及在一段延長之時間內逐漸釋放藥物,且因此可或可不「持續釋放」
使用長期持續釋放植入物可尤其適合於慢性病況之治療。如本文所用,「長期」釋放意指植入物經構築及佈置以遞送治療含量之活性成分達至少7天、較佳30-60天。長期持續釋放植入物為熟習此項技術者所熟知且包括一些上述釋放系統。
熟習此項技術者將理解,鑒於普通熟習此項技術者已知之資訊,對本文所述之組合物及方法之其他適宜修飾及改編自本文包含之本發明之說明中係顯而易見的,且可在不脫離本發明之範圍或其任何實施例之情況下進行。現在已經詳細闡述了本發明,藉由參考以下實例將會更清楚地理解本發明,該等實例僅用於說明之目的且並不意欲限制本發明。
實例在以下實例中進一步闡述本發明,該等實例並不限制申請專利範圍中所述之本發明範圍。
實例 1 : SLC6A19 異白胺酸轉運分析 細胞系產生及維持Flp-In™ T-REx™ 293細胞系購自Thermo Fisher Scientific。該細胞系用於產生可誘導表現具有C-末端V5標籤之人類SLC6A19並穩定表現具有C-末端myc-DDK標籤之人類TMEM27 (亦稱為Collectrin)的穩定細胞系。藉由使用標準方案轉染SLC6A19-及TMEM27編碼質體、之後選擇抗生素,產生穩定細胞系。將穩定細胞維持在補充有Glutamax、10%胎牛血清、100 U/mL青黴素、100 ug/mL鏈黴素、200 ug/mL潮黴素、10 ug/mL殺稻瘟菌素及300 ug/mL新黴素之DMEM/F12 (Thermo Fisher)中。
分析:96孔格式中之異白胺酸轉運分析
在第0天,將穩定細胞系以每孔35,000個細胞之密度接種於聚-D-離胺酸包被之96孔細胞培養物處理之板中。在第1天,藉由使用Tecan D300e數位分配器分配終濃度為1 ug/mL之四環素來誘導SLC6A19之表現。在第2天,運行轉運分析。使用Centrifugal Blue Washer (Blue Cat Bio)之GentleSpin設置自板移除培養基,並使用Blue Washer用175 uL活細胞成像溶液(Thermo Fisher)洗滌細胞。洗滌後,用70 uL DMSO、陽性對照或化合物處理細胞,在室溫下稀釋於Krebs緩衝液(140 mM NaCl,4.7 mM KCl,2.5 mM CaCl
2,1.2 mM MgCl
2,11 mM HEPES,10 mM葡萄糖,pH 7.4)中。20-60分鐘後,添加30 uL 3.3 mM之13C6,15N-L-異白胺酸溶液(Cambridge Isotope Laboratories)。在室溫下與異白胺酸受質一起培育20 min後,使用Blue Washer用175 uL活細胞成像溶液洗滌細胞。然後將細胞溶解在超純水中之150 uL 15 uM D-白胺酸-d10 (CDN同位素)中。將板放在700 rpm之振盪器上最少40分鐘以促進溶解。溶解後,將13C6,15N-L-異白胺酸之標準曲線稀釋液添加至含有未處理細胞之溶解物之孔中。將板放回振盪器中最少2分鐘,以確保標準曲線稀釋液之適當混合。然後將板以4,000 rpm離心5 min以沈澱細胞碎片及沈澱物。將上清液在聚丙烯板中之乙腈+ 0.1%甲酸中以1:10稀釋。
分析:384孔格式中之異白胺酸轉運分析
在第0天,使用Viaflo 384孔吸量管將穩定細胞系以每孔20,000個細胞之密度接種於含有1 ug/mL四環素之培養基中之聚-D-離胺酸包被之384孔細胞培養物處理之板中。次日(第1天)運行轉運分析。使用Centrifugal Blue Washer (Blue Cat Bio)之GentleSpin設置自板移除培養基,並使用Blue Washer用80 uL活細胞成像溶液(Thermo Fisher)洗滌細胞。洗滌後,使用TECAN液體處理器,用稀釋於Krebs緩衝液(140 mM NaCl,4.7 mM KCl,2.5 mM CaCl
2,1.2 mM MgCl
2,11 mM HEPES,10 mM葡萄糖,pH 7.4)中之20 ul DMSO、陽性對照或化合物處理細胞。在室溫下培育20-60分鐘後,添加8.6 uL 3.3 mM之13C6,15N-L-異白胺酸溶液(Cambridge Isotope Laboratories)。在室溫下與異白胺酸受質一起培育20 min後,使用Blue Washer用80 uL活細胞成像溶液洗滌細胞。然後將細胞溶解在超純水中之80 uL 15 uM D-白胺酸-d10 (CDN同位素)中。將板放在700 rpm之振盪器上最少2小時以促進溶解。溶解後,將13C6,15N-L-異白胺酸之標準曲線稀釋液添加至含有未處理細胞之溶解物之孔中。將板放回振盪器中最少5分鐘,以確保標準曲線稀釋液之適當混合。然後將板以4,000 rpm離心10 min以沈澱細胞碎片及沈澱物。將上清液在聚丙烯板中之乙腈+ 0.1%甲酸中以1:10稀釋。
使用RapidFire365-QTOF 6545 (Agilent)實施13C6,15N-L-異白胺酸分析。在質譜儀注射之前,定量樣品分析採用自動化固相萃取(HILIC H6柱)。樣品使用95%乙腈、0.1%甲酸上樣,且用5%乙腈、0.1%甲酸直接自柱溶析用於ESI-MS (電噴霧離子化)分析。使用Agilent Masshunter Quant軟體自高解析度全掃描數據實施分析物之量化。
步驟 1 :化合物 A2 之合成於0℃下在N
2氣氛下向化合物
A1(1 eq.)於甲苯中之溶液中逐滴添加碳酸雙三氯甲酯(BTC) (0.5 eq.)於甲苯中之溶液。將所得混合物於r.t.下攪拌15 min且然後將混合物加熱至130℃且在N
2氣氛下攪拌2小時。冷卻後,將混合物在減壓下濃縮至乾燥,以產生粗製化合物A
2,其不經進一步純化即直接用於下一步驟。
步驟 2 :化合物 A4 之合成於0˚C下在N
2氣氛下向化合物A
3(1 eq.)及TEA (3 eq.)於無水DCM中之混合物中逐滴添加化合物A
2(1 eq.)於無水DCM中之溶液。將所得混合物於0˚C下在N
2氣氛下攪拌1小時。然後將混合物用水稀釋且用EtOAc萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析)純化殘餘物,以產生化合物A
4。
步驟1: M2之合成
向
M1(10 g, 49.93 mmol)及K
2CO
3(20.7 g, 149.8 mmol)於DMF (200 mL)中之混合物中添加3,6-二氯嗒嗪(7.44 g, 49.93 mmol)。將所得混合物於80℃下攪拌16 hr。冷卻後,將所得混合物傾倒至水(800 mL)中。藉由過濾收集沈澱之固體,用水(100 mL)洗滌且然後用EtOAc溶解,將有機層經Na
2SO
4乾燥,分離且在減壓下濃縮,以產生黃色固體狀
M2(12 g, 38.36 mmol, 76.83%產率)。LC/MS (ESI) m/z: 313 (M+H)
+。
步驟2: M3之合成
向
M2(12 g, 38.36 mmol)於MeOH (200 mL)中之溶液添加Pd/C (4.0 g, 10%)。將所得混合物於室溫下在氫氣氣氛下攪拌3 hr。然後過濾混合物,在減壓下濃縮濾液,以產生黃色固體狀
M3(10 g, 35.93 mmol, 93.63%產率)。LC/MS (ESI) m/z: 279 (M+H)
+。
步驟3: M4之合成
向化合物
M3(10 g, 35.93 mmol)於DCM (60 mL)中之溶液中添加TFA (60 mL)。將所得混合物於室溫下攪拌4 hr。將所得混合物在減壓下濃縮至乾燥。用MeOH稀釋殘餘物且添加NaHCO
3。將混合物於r.t.下攪拌40 min以轉換pH=8~9。然後過濾混合物,在減壓下濃縮濾液,以產生黃色油狀
M4(6 g, 33.7 mmol, 93.7%產率)。LC/MS (ESI) m/z: 179 (M+H)
+。
步驟4: M5之合成
向化合物
M4(5.8 g, 32.54 mmol)及2,4-二甲氧基苯甲醛(5.41 g, 32.54 mmol)於DCM (100 mL)中之混合物中添加AcOH (5.86 g, 97.62 mmol)。將混合物於室溫下攪拌1 hr。然後向上述混合物中添加NaBH(OAc)
3(20.7 g, 97.62 mmol)。將所得混合物攪拌3 hr。然後在減壓下濃縮混合物。將殘餘物用EtOAc稀釋且用NaHCO
3水溶液洗滌至pH=8。用鹽水洗滌有機層,經無水Na
2SO
4乾燥並濃縮至乾燥。藉由矽膠上管柱層析(用DCM中之5% MeOH溶析)純化粗產物,以產生黃色固體狀
M5(5 g, 13.7 mmol, 42.10%產率)。LC/MS (ESI) m/z: 329 (M+H)
+。
步驟5: M6之合成
向
M5(800 mg, 2.436 mmol)及(1-乙氧基環丙氧基)三甲基矽烷(1.06 g, 6.09 mmol)於EtOH (10 mL)及THF (20 mL)中之混合物中添加AcOH (2.19 g, 36.54 mmol)及NaBH
3CN (538 mg, 8.526 mmol)。將所得混合物於80℃下攪拌16hr。冷卻後,在減壓下濃縮所得混合物。將殘餘物用EtOAc稀釋並用水及鹽水洗滌。將有機層經無水Na
2SO
4乾燥並濃縮至乾燥。藉由二氧化矽上管柱層析(用DCM中之4% MeOH溶析)純化粗產物,以得到黃色固體狀
M6(560 mg, 1.52 mmol, 62.40%產率)。LC/MS (ESI) m/z: 369 (M+H)
+。
M7之合成
將化合物
M6(560 mg, 1.520 mmol)添加至TFA (18 mL)中且將所得混合物於80℃下攪拌4 hr。冷卻後,在減壓下濃縮混合物,以產生呈TFA鹽形式之粗製
M7(274 mg, 0.825 mmol, 54.26%)。LC/MS (ESI) m/z: 219 (M+H)
+。
3-[(4- 氯 -2- 氟 -5- 甲基苯基 ) 甲基 ]-1- 環丙基 -1-[(3R)-1-( 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ] 尿素向
M7(274 mg, 0.824 mmol)於DCM (10 mL)中之混合物中添加TEA (251 mg, 2.473 mmol)。於r.t.下攪拌30 min後,於0℃下向上述混合物中添加
2(160 mg, 0.824 mmol)於DCM (2 mL)中之溶液。於室溫下將所得混合物攪拌30 min。然後將混合物在減壓下濃縮至乾燥。藉由矽膠上管柱層析(用DCM中之5% MeOH溶析)純化粗產物,以產生淺黃色固體狀
實例 2(103 mg, 0.247 mmol, 30.0%產率)。LC/MS (ESI) m/z: 418 (M+H)
+。
1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.4, 1.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.28 - 7.21 (m, 2H), 6.89 (t, J = 5.8 Hz, 1H), 4.41 - 4.25 (m, 4H), 3.68 - 3.60 (m, 1H), 3.23 - 3.16 (m, 1H), 2.81 - 2.67 (m, 1H), 2.50 - 2.44 (m, 1H), 2.29 (s, 3H), 2.15 - 2.07 (m, 1H), 1.91 - 1.70 (m, 2H), 1.54 - 1.42 (m, 1H), 0.93 - 0.86 (m, 2H), 0.74 - 0.62 (m, 2H)。
19F NMR (400 MHz, DMSO-d6) δ -121.05 (s)。
下表中之化合物係自上述或市售適當起始材料使用上述一般程序A及實例2中之中間體M7來製備。
實例 | 結構及名稱 | 數據 |
3 | 1-環丙基-3-[(3-苯基-1,2-噁唑-5-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 419 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 3.9 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.52 - 7.43 (m, 3H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 6.67 (s, 1H), 4.56 (s, 2H), 4.45 - 4.31 (m, 2H), 3.88 - 3.71(m,1H), 3.34(d,J=12.5Hz,1H), 2.89 (td,J=13.0,2.7Hz,1H), 2.62-2.53(m,1H), 2.27(dd,J=12.6,4.1Hz,1H), 1.98(d,J=11.5Hz,1H), 1.86 (d,J=13.8Hz,1H), 1.63 (d,J=13.2Hz,1H), 1.01-0.93 (m, 2H), 0.84 (dd, J = 8.0, 4.5 Hz, 2H)。 |
4 | 1-環丙基-3-[(2,4-二氟-5-甲基苯基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 402.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J =9.4,1.2Hz,1H), 7.21(t,J=8.5Hz,1H), 6.84 (t,J=9.9Hz,1H), 4.43-4.30(m,4H), 3.77 (tt,J= 11.8, 3.9 Hz, 1H), 3.34 (s, 1H), 2.88 (td, J = 13.0, 2.7 Hz, 1H), 2.60 - 2.49 (m, 1H), 2.31 - 2.23 (m, 1H), 2.22 (s, 3H), 1.96 (d, J = 12.3 Hz, 1H), 1.90 - 1.81 (m, 1H), 1.70 - 1.54 (m, 1H), 0.99 - 0.91 (m, 2H), 0.78 (dd, J = 6.6, 4.1 Hz, 2H)。 |
5 | 3-[(4-氯-2-氟苯基)甲基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 404.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.27 (dd, J = 9.4, 1.2 Hz, 1H), 7.20 - 7.14 (m, 2H), 4.42 (s, 2H), 4.41 - 4.30 (m, 2H), 3.76 (ddd, J = 15.8, 7.8, 3.9 Hz, 1H), 3.28 (s, 1H), 2.88 (td, J = 13.1, 2.7 Hz, 1H), 2.62 - 2.50 (m, 1H), 2.25 (qd, J = 12.5, 4.1 Hz, 1H), 2.03 - 1.78 (m, 2H), 1.71 - 1.54 (m, 1H), 1.00 - 0.91 (m, 2H), 0.83 - 0.76 (m, 2H)。 |
6 | 3-[(4-氯-3-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (d, J = 3.6 Hz, 1H), 7.36 (dd, J = 9.6, 4.4 Hz, 1H),7.28(d,J=8.4Hz,2H),7.22(s,1H),7.11(d,J=8.4Hz,1H),6.93(t,J=5.6 Hz,1H),4.40(d,J=13.6Hz,1H),4.34(d,J=6.0Hz,3H),3.77(tt,J=11.6,4.0 Hz, 1H), 3.35 (s, 1H), 2.88 (td, J = 13.2, 2.8 Hz, 1H), 2.59 - 2.48 (m, 1H), 2.35 (s, 3H), 2.26 (qd, J = 12.4, 4.0 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 1.86 (d, J = 13.2 Hz, 1H), 1.68 - 1.56 (m, 1H), 0.94 (dd, J = 8.4, 5.6 Hz, 2H), 0.83 - 0.75 (m, 2H)。 |
將N-甲基-N-[(3R)-3-六氫吡啶基]胺基甲酸第三丁酯(2.14 g, 10 mmol)、3-溴嗒嗪(2.38 g, 15.00 mmol)、氟化銫(151.90 mg, 1.00 mmol, 36.87 uL)及碳酸鉀(3.46 g, 25.00 mmol, 1.51 mL)溶解於DMSO (100 mL)中且加熱至150℃過夜。然後將反應混合物冷卻至室溫,傾倒至600mL水中,且用乙酸乙酯(3×200 mL)萃取。將合併之有機層用水(1×200mL)及鹽水(1×200ml)洗滌,用無水硫酸鈉乾燥且在減壓下濃縮以提供粗產物,藉由急速管柱層析(乙酸乙酯 :庚烷, 0:100至40:60)對其進行純化,以提供
A2N-甲基-N-[(3R)-1-嗒嗪-3-基-3-六氫吡啶基]胺基甲酸第三丁酯(1.57 g, 5.37 mmol, 53.70%產率)。將
A2(1.57 g, 5.37 mmol)溶解於DCM (4.2 mL)中且添加TFA (6.12 g, 53.70 mmol, 4.14 mL)。將反應混合物攪拌4小時。然後在減壓下藉由旋轉蒸發濃縮反應混合物。將粗製殘餘物溶解於乙酸乙酯中,用1 M NaOH、鹽水洗滌且濃縮,以提供
A3(
R)-N-甲基-1-(嗒嗪-3-基)六氫吡啶-3-胺(450 mg, 2.34 mmol, 43.59%產率),其不經進一步純化即使用。
實例 | 結構及名稱 | 數據 |
7 | 3-[2-(3,4-二甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 380.1 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.46 (s, 1H), 7.37 (s, 1H), 7.30 (dd, J = 9.5, 4.2 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.84 (d, J = 9.0 Hz, 1H), 4.31 (d, J = 33.8 Hz, 2H), 4.07 (s, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.91 (d, J = 13.0 Hz, 1H), 2.85 (s, 3H), 2.72 (dd, J = 7.4, 3.2 Hz, 1H), 2.20 (d, J = 7.7 Hz, 6H), 1.98 (d, J = 3.7 Hz, 1H), 1.87 (s, 3H), 1.68 (s, 1H), 1.11 (dd, J = 16.7, 10.3 Hz, 2H)。 |
8 | 3-{2-[2-(二氟甲氧基)苯基]環丙基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 418.1 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.45 (dd, J = 3.2, 1.2 Hz, 1H), 7.37 (ddd, J = 9.4, 4.4, 0.7 Hz, 1H), 7.28 (ddd, J = 9.4, 2.3, 1.2 Hz, 1H), 7.20 - 7.08 (m, 3H), 7.02 (dd, J = 7.2, 1.9 Hz, 1H), 7.00 - 6.60 (m, 1H), 4.39 (t, J= 15.6 Hz,1H), 4.25 (t,J=15.7Hz,1H), 4.07 (d,J=4.6Hz,1H),3.08 3.00 (m,1H), 2.91 (dt,J=7.6,3.4Hz,2H), 2.86 (s,3H), 2.25 (dtd,J=9.9,6.6,3.5Hz,1H), 1.87(d,J=6.8Hz,3H), 1.67(d,J=11.5Hz, 1H), 1.36 - 1.30 (m, 1H), 1.21 - 1.13 (m, 1H)。 |
9 | 1- 甲基 -1-[(3R)-1-( 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ]-3-{2-[4-( 三氟甲基 ) 苯基 ] 環丙基 } 尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.49 - 8.44 (m, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.38 (ddd, J = 9.3, 4.4, 2.9 Hz, 1H), 7.30 (dd, J = 14.5, 5.4 Hz, 3H), 4.39 - 4.25 (m, 2H), 4.05 (s, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.92 (d, J =14.7Hz,1H), 2.86 (s,3H), 2.83 (dd,J=7.6,4.3Hz,1H), 2.13 (qd,J=6.6,3.5Hz,1H), 1.87(d,J=5.9Hz,3H), 1.67(s,1H), 1.39-1.33 (m,1H), 1.26(d,J=7.5Hz,1H)。 |
10 | 3-[2-(4- 甲氧基苯基 ) 環丙基 ]-1- 甲基 -1-[(3R)-1-( 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ] 尿素 | LC-MS: m/z 382 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 4.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.33 - 7.27 (m, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.37 (d, J = 13.5 Hz, 1H), 4.32 - 4.22 (m, 1H), 4.07 (s, 1H), 3.75 (s, 3H), 3.03 (t, J = 11.9 Hz, 1H), 2.92 (d, J = 12.7 Hz, 1H), 2.86 (s, 3H), 2.72 - 2.65 (m, 1H), 2.04 - 1.96 (m, 1H), 1.88 (dd, J = 11.4, 4.1 Hz, 3H), 1.68 (s, 1H), 1.19 - 1.12 (m, 1H), 1.10 - 1.04 (m, 1H)。 |
11 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-{2-[3-(三氟甲基)苯基]環丙基}尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dt, J = 4.4, 1.4 Hz, 1H), 8.24 (s, 1H), 7.48 (s, 1H), 7.44 (d, J = 5.1 Hz, 2H), 7.42 - 7.36 (m, 2H), 7.33 - 7.28 (m, 1H), 4.40 - 4.25 (m, 2H), 4.05 (s, 1H), 3.08 - 2.97 (m, 1H), 2.96 - 2.88 (m, 1H), 2.86 (s, 3H), 2.83 - 2.77 (m, 1H), 2.18 - 2.11 (m, 1H), 1.92 - 1.83 (m, 3H), 1.68 (s, 1H), 1.37 - 1.30 (m, 1H), 1.28 - 1.20 (m, 1H)。 |
12 | 3-[2-(3- 甲氧基苯基 ) 環丙基 ]-1- 甲基 -1-[(3R)-1-( 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ] 尿素 | LC-MS: m/z 382 (M+H)。 1HNMR (400MHz,MeOD) δ 8.46 (d,J=4.3Hz,1H), 7.38 (ddd,J=9.4,4.4,2.0Hz,1H), 7.30 (ddd,J=9.4,3.9,1.2Hz,1H), 7.13 (t,J=7.9Hz,1H), 6.75- 6.66 (m, 3H), 4.41 - 4.23 (m, 2H), 4.06 (s, 1H), 3.76 (d, J = 0.8 Hz, 3H), 3.07 - 2.97 (m, 1H), 2.95 - 2.81 (m, 4H), 2.76 (dt, J = 7.7, 3.9 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.88 (dd, J = 10.9, 4.5 Hz, 3H), 1.67 (s, 1H), 1.23 - 1.13 (m, 2H) 。 |
13 | 3-[2-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 410 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (d, J = 4.4 Hz, 1H), 7.38 (ddd, J = 9.4, 4.4, 1.9 Hz, 1H), 7.32 - 7.28 (m, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.65 - 6.58 (m, 2H), 4.37 (d, J = 13.0 Hz, 1H), 4.29 - 4.24 (m, 1H), 4.19 (d, J=5.1Hz,4H), 4.06(s,1H),3.02(s,1H), 2.91(d,J=12.8Hz,1H), 2.85(d,J=5.2Hz,3H), 2.67(dd,J=7.5,3.6Hz,1H), 1.97-1.92 (m,1H), 1.87(t,J=8.0Hz,3H), 1.68(s,1H), 1.14-1.09(m,1H), 1.05(d,J = 7.4 Hz, 1H)。 |
14 | 3-[2-(2-甲氧基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 382 (M+H)。 1H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 7.39 (dd, J = 9.3, 4.3 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.93 - 6.87 (m, 2H), 6.86 - 6.80 (m, 1H), 4.39 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 12.6 Hz, 1H), 4.14 - 4.03 (m, 1H), 3.84 (d, J = 2.3 Hz, 3H), 3.08 - 2.98 (m, 1H), 2.94 - 2.87 (m, 2H), 2.86 (s, 3H), 2.34 - 2.25 (m, 1H), 1.88 (t, J = 7.0 Hz, 3H), 1.77 - 1.60 (m, 1H), 1.21 - 1.12 (m, 1H), 1.07 - 1.01 (m, 1H)。 |
15 | 3-[(1R,2S)-2-(2-甲氧基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 382 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (d, J = 4.2 Hz, 1H), 7.38 (dd, J = 9.3, 4.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.15 - 7.09 (m, 1H), 6.93 - 6.88 (m, 2H), 6.86 - 6.81 (m, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 4.1 Hz, 1H), 3.84 (s, 3H), 3.09 - 3.00 (m, 1H), 2.95 - 2.88 (m, 2H), 2.86 (s, 3H), 2.34 - 2.24 (m, 1H), 1.92 - 1.84 (m, 3H), 1.69 (s, 1H), 1.21 - 1.15 (m, 1H), 1.08 - 1.00 (m, 1H)。 |
16 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-[2-(噻吩-3-基)環丙基]尿素 | LC-MS: m/z 358 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.48 - 8.45 (m, 1H), 7.38 (ddd, J = 9.4, 4.4, 1.7 Hz, 1H), 7.32 - 7.26 (m, 2H), 7.00 (d, J = 2.9 Hz, 1H), 6.95 (dt, J = 5.0, 1.1 Hz, 1H), 4.36 (d, J = 13.3 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.06 (s, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.91 (d, J = 13.0 Hz, 1H), 2.85 (s, 3H), 2.73 (td, J = 7.4, 4.1 Hz, 1H), 2.08 (ddt, J = 9.4, 6.3, 3.2 Hz, 1H), 1.90 - 1.82 (m, 3H), 1.68 (s, 1H), 1.20 - 1.14 (m, 1H), 1.10 (dd, J = 13.2, 5.9 Hz, 1H)。 |
17 | 3-[2-(3,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 3.9 Hz, 1H), 7.41 - 7.33 (m, 3H), 7.32 - 7.24 (m, 1H), 7.08 (dd, J = 8.3, 2.0 Hz, 1H), 4.40 - 4.22 (m, 2H), 4.10 - 3.96 (m, 1H), 3.07 - 2.97 (m, 1H), 2.94 - 2.87 (m, 1H), 2.86 (s, 3H), 2.78 - 2.72 (m, 1H), 2.07 - 1.98 (m, 1H), 1.92 - 1.82 (m, 3H), 1.73 - 1.58 (m, 1H), 1.31 - 1.28 (m, 1H), 1.23 - 1.16 (m, 1H)。 |
18 | 3-[(1R,2S)-2-(3,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.50 - 8.45 (m, 1H), 7.41 - 7.34 (m, 3H), 7.31 (dd, J = 9.4, 1.2 Hz, 1H), 7.08 (dd, J = 8.3, 2.1 Hz, 1H), 4.31 (dd, J = 21.5, 8.9 Hz, 2H), 4.09 - 3.98 (m, 1H), 3.07 - 2.99 (m, 1H), 2.95 - 2.87 (m, 1H), 2.86 (s, 3H), 2.78 - 2.73 (m, 1H), 2.06 - 2.00 (m, 1H), 1.92 - 1.84 (m, 3H), 1.74 - 1.60 (m, 1H), 1.35 - 1.28 (m, 1H), 1.23 - 1.16 (m, 1H)。 |
19 | 3-[(1S,2R)-2-(3,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.50 - 8.42 (m, 1H), 7.41 - 7.34 (m, 3H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.08 (dd, J = 8.3, 2.1 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.09 - 3.99 (m, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 2.95 - 2.87 (m, 1H), 2.86 (s, 3H), 2.09 - 2.00 (m, 1H), 1.92 - 1.83 (m, 3H), 1.73 - 1.61 (m, 1H), 1.33 - 1.27 (m, 1H), 1.24 - 1.16 (m, 1H)。 |
20 | 3-[2-(4-氯-3-氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 404 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.50 - 8.44 (m, 1H), 7.39 (ddd, J = 9.4, 4.4, 2.5 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.06 (d, J = 10.7 Hz, 1H), 6.97 (dd, J = 8.3, 1.8 Hz, 1H), 4.31 (dd, J = 22.2, 10.9 Hz, 2H), 4.05 (d, J = 5.4 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.95 - 2.84 (m, 4H), 2.76 (td, J = 7.7, 4.3 Hz, 1H), 2.05 (dq, J = 6.7, 3.6 Hz, 1H), 1.88 (t, J = 7.1 Hz, 3H), 1.66 (d, J = 8.0 Hz, 1H), 1.33 - 1.27 (m, 1H), 1.19 (dd, J = 13.7, 6.1 Hz, 1H)。 |
21 | 3-[(1R,2S)-2-(4-氯-3-氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 404 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 3.8 Hz, 1H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.05 (dd, J = 10.7, 2.0 Hz, 1H), 6.97 (dd, J = 8.3, 1.8 Hz, 1H), 4.35 - 4.27 (m, 2H), 4.04 (d, J = 3.7 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.95 - 2.83 (m, 4H), 2.76 (ddd, J = 7.7, 4.5, 3.3 Hz, 1H), 2.05 (ddd, J = 9.4, 6.2, 3.5 Hz, 1H), 1.93 - 1.83 (m, 3H), 1.72 - 1.59 (m, 1H), 1.33 - 1.28 (m, 1H), 1.19 (dt, J = 7.5, 6.1 Hz, 1H)。 |
22 | LC-MS: m/z 404 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 3.9 Hz, 1H), 7.38 (dd, J = 9.4, 4.3 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.06 (dd, J = 10.7, 2.0 Hz, 1H), 6.97 (dd, J = 8.3, 1.9 Hz, 1H), 4.38 - 4.25 (m, 2H), 4.10 - 3.99 (m, 1H), 3.02 (dd, J = 12.4, 11.4 Hz, 1H), 2.96 - 2.82 (m, 4H), 2.75 (ddd, J = 7.7, 4.5, 3.3 Hz, 1H), 2.05 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.93 - 1.81 (m, 3H), 1.74 - 1.61 (m, 1H), 1.33 - 1.28 (m, 1H), 1.19 (dt, J = 7.5, 6.1 Hz, 1H)。 | |
23 | 3-[(1R,2S)-2-(2,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388 (M+H)。 1HNMR(400MHz,MeOD) δ 8.46 (dd,J=4.4,1.1Hz,1H), 7.38 (dd,J=9.4,4.4Hz,1H), 7.30 (dd,J=9.4,1.2Hz,1H), 7.11 (td,J=8.8,6.4Hz,1H), 6.90- 6.81 (m, 2H), 4.41 - 4.24 (m, 2H), 4.06 (dd, J = 9.6, 5.8 Hz, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 2.91 (ddd, J = 17.6, 9.0, 5.0 Hz, 2H), 2.86 (s, 3H), 2.12 (ddd, J = 9.6, 6.3, 3.4 Hz, 1H), 1.93 - 1.82 (m, 3H), 1.67 (dt, J = 14.1, 9.1 Hz, 1H), 1.31 - 1.27 (m, 1H), 1.14 (dt, J = 7.5, 6.0 Hz, 1H)。 |
24 | 3-[(1S,2R)-2-(2,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388 (M+H)。 1HNMR(400MHz,MeOD) δ 8.46 (dd,J=4.4,1.2Hz,1H), 7.38 (dd,J=9.4,4.4Hz,1H), 7.29( dd,J=9.4,1.2Hz,1H), 7.11 (td,J=8.8,6.4Hz,1H), 6.90-6.81 (m, 2H), 4.41 - 4.23 (m, 2H), 4.13 - 4.01 (m, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 2.96 - 2.87 (m, 2H), 2.86 (s, 3H), 2.14 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.88 (dd, J = 10.9, 4.4 Hz, 3H), 1.68 (dd, J = 11.3, 6.4 Hz, 1H), 1.28 (dd, J = 7.0, 2.6 Hz, 1H), 1.14 (dt, J = 7.5, 6.0 Hz, 1H)。 |
25 | 3-[(1R,2S)-2-(2,5-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.2 Hz, 1H), 7.02 (td, J = 9.3, 4.6 Hz, 1H), 6.92 - 6.77 (m, 2H), 4.39 - 4.32 (m, 1H), 4.28 (dd, J = 12.7, 3.7 Hz, 1H), 4.05 (dt, J = 11.2, 7.7 Hz, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 2.96 - 2.93 (m, 1H), 2.92 - 2.86 (m, 1H), 2.86 (s, 3H), 2.17 (ddd, J = 9.6, 6.2, 3.4 Hz, 1H), 1.92 - 1.84 (m, 3H), 1.73 - 1.60 (m, 1H), 1.39 - 1.32 (m, 1H), 1.18 (dt, J = 7.6, 6.0 Hz, 1H)。 |
26 | 3-{[3-(2-甲氧基苯基)-1,2-噁唑-5-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 423.41 (M+H)。 1H NMR(400 MHz, cdcl3) δ 8.59 - 8.52 (m, 1H), 7.87 - 7.80 (m, 1H), 7.43 - 7.33 (m, 1H), 7.28 - 7.15 (m, 1H), 7.05 - 6.93 (m, 3H), 6.72 (s, 1H), 6.21 (s, 1H), 4.75 - 4.59 (m, 2H), 4.41 - 4.32 (m, 1H), 4.24 (d, J = 13.9 Hz, 1H), 4.01 (t, J = 12.0 Hz, 1H), 3.86 (s, 3H), 3.03 - 2.92 (m, 2H), 2.90 (s, 3H), 2.02 - 1.95 (m, 1H), 1.90 - 1.75 (m, 2H), 1.72 - 1.61 (m, 1H)。 |
27 | 3-{[3-(3-氟苯基)-1,2-噁唑-5-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 411.4 (M+H)。 1H NMR(400 MHz, cdcl3) δ 8.57 (dd, J = 4.4, 1.3 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.52 (ddd, J = 9.7, 2.7, 1.5 Hz, 1H), 7.39 (td, J = 7.9, 5.7 Hz, 1H), 7.22 (dd, J = 9.3, 4.4 Hz, 1H), 7.10 (tdd, J = 8.4, 2.6, 1.1 Hz, 1H), 7.01 (dd, J = 9.3, 1.3 Hz, 1H), 6.75 (s, 1H), 6.60 (s, 1H), , 4.69 (dd, J = 5.7, 2.8 Hz, 2H), 4.50 - 4.41 (m, 2H), 4.10 (d, J = 12.6 Hz, 1H), 3.98 - 3.87 (m, 1H), 3.12 - 2.90 (m, 5H), 2.02 (dd, J = 8.1, 2.6 Hz, 1H), 1.94 - 1.80 (m, 1H), 1.62 (tdd, J = 13.6, 9.1, 4.2 Hz, 1H)。 |
28 | 3-[2-(2,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.30 (ddd, J = 9.4, 2.1, 1.3 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.13 (dd, J = 8.4, 2.1 Hz, 1H), 4.32 (dd, J = 28.6, 13.0 Hz, 2H), 4.07 (d, J = 4.4 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.97 (dt, J = 8.0, 3.6 Hz, 1H), 2.94 - 2.88 (m, 1H), 2.87 (s, 3H), 2.27 (dtd, J = 10.0, 6.7, 3.6 Hz, 1H), 1.88 (d, J = 6.9 Hz, 3H), 1.75 - 1.63 (m, 1H), 1.37 (ddd, J = 9.6, 5.6, 4.5 Hz, 1H), 1.12 - 1.02 (m, 1H)。 |
29 | 3-[(1R,2S)-2-(2,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.29 (d, J = 9.4 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.07 (dd, J = 11.7, 7.5 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.99 - 2.94 (m, 1H), 2.91 (dd, J = 12.8, 2.2 Hz, 1H), 2.87 (s, 3H), 2.28 (ddd, J = 9.8, 6.3, 3.6 Hz, 1H), 1.87 (d, J = 5.7 Hz, 3H), 1.68 (dd, J = 11.5, 6.7 Hz, 1H), 1.37 (dq, J = 5.6, 4.5 Hz, 1H), 1.08 (dt, J = 7.5, 6.0 Hz, 1H)。 |
30 | 3-[(1S,2R)-2-(2,4-二氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.29 (d, J = 9.4 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.07 (dd, J = 11.7, 7.5 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.99 - 2.94 (m, 1H), 2.91 (dd, J = 12.8, 2.2 Hz, 1H), 2.87 (s, 3H), 2.28 (ddd, J = 9.8, 6.3, 3.6 Hz, 1H), 1.87 (d, J = 5.7 Hz, 3H), 1.68 (dd, J = 11.5, 6.7 Hz, 1H), 1.37 (dq, J = 5.6, 4.5 Hz, 1H), 1.08 (dt, J = 7.5, 6.0 Hz, 1H)。 |
31 | 3-[2-(2,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (d, J = 4.4 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.11 (dd, J = 15.2, 8.6 Hz, 1H), 6.89 - 6.83 (m, 2H), 4.32 (dd,J=33.0,12.8Hz,2H), 4.07 (s,1H), 3.03 (t,J=11.9Hz,1H), 2.91 (dd,J=8.3,3.9Hz,2H), 2.86 (s,3H), 2.13(d,J=4.4Hz,1H), 1.87 (d,J=5.5Hz, 3H), 1.68 (s, 1H), 1.29 (s, 1H), 1.14 (dd, J = 13.0, 6.6 Hz, 1H)。 |
32 | 3-[2-(3,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 4.0 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.30 (dd, J = 9.3, 3.8 Hz, 1H), 7.10 (dt, J = 13.7, 7.6 Hz, 2H), 6.96 (dd, J = 6.3, 2.0 Hz, 1H), 4.41 - 4.21 (m, 2H), 4.14 - 3.90 (m, 1H), 3.01 (d, J = 11.8 Hz, 1H), 2.94 - 2.79 (m, 4H), 2.71 (tt, J = 8.6, 4.3 Hz, 1H), 2.04 (qd, J = 6.5, 3.4 Hz, 1H), 1.89 (dd, J = 18.7, 9.2 Hz, 3H), 1.67 (s, 1H), 1.30 - 1.21 (m, 1H), 1.16 (dd, J = 13.3, 6.3 Hz, 1H)。 |
33 | 3-[(1R,2S)-2-(3,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 - 7.04 (m, 2H), 7.00 - 6.93 (m, 1H), 4.40 - 4.24 (m, 2H), 4.04 (dd, J = 9.6, 5.7 Hz, 1H), 3.09 - 2.96 (m, 1H), 2.95 - 2.82 (m, 4H), 2.76 - 2.67 (m, 1H), 2.03 (ddd, J = 9.5, 6.3, 3.2 Hz, 1H), 1.94 - 1.83 (m, 3H), 1.65 (ddd, J = 22.2, 11.9, 5.9 Hz, 1H), 1.29 - 1.21 (m, 1H), 1.16 (dt, J = 7.4, 6.1 Hz, 1H)。 |
34 | 3-[(1S,2R)-2-(3,4-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 4.1 Hz, 1H), 7.38 (dd, J = 9.3, 4.3 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.96 (dd, J = 6.2, 1.8 Hz, 1H), 4.40 - 4.24 (m, 2H), 4.11 - 4.00 (m, 1H), 3.02(t,J=11.9Hz,1H), 2.95-2.83 (m,4H), 2.71 (dq,J=8.7,4.3Hz,1H), 2.04 (ddd, J=9.4,6.3,3.3Hz,1H), 1.88 (t,J=13.8Hz,3H), 1.66(d,J=9.9Hz,1H), 1.29-1.22(m,1H), 1.16(dd, J = 13.5, 6.2 Hz, 1H)。 |
35 | 3-[2-(2,5-二氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dt, J = 4.4, 1.3 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.29 (ddd, J = 9.4, 3.8, 1.2 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.83 (dddd, J = 24.0, 9.2, 6.4, 3.1 Hz, 2H), 4.32 (dd, J = 32.7, 12.2 Hz, 2H), 4.06 (dd, J = 11.5, 7.3 Hz, 1H), 3.07 - 2.99 (m, 1H), 2.94 (dd, J = 7.8, 4.4 Hz, 1H), 2.90 (dd, J = 5.9, 3.2 Hz, 1H), 2.86 (s, 3H), 2.17 (td, J = 9.8, 4.2 Hz, 1H), 1.92 - 1.83 (m, 3H), 1.74 - 1.60 (m, 1H), 1.39 - 1.32 (m, 1H), 1.18 (dt, J = 7.6, 6.0 Hz, 1H)。 |
36 | 1-環丙基-3-[(1S,2R)-2-(4-氟-3-甲基苯基)環丙基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 410.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 8.53 (d, J = 2.9 Hz, 1H), 7.17 (dd, J = 9.1, 4.2 Hz, 1H), 7.03 - 6.92 (m, 3H), 6.91 - 6.85 (m, 1H), 5.69 (s, 1H), 4.45 (d, J = 13.3 Hz, 1H), 4.35 - 4.26 (m, 1H), 3.83 (tt, J = 11.9, 3.9 Hz, 1H), 3.34 - 3.19 (m, 1H), 2.88 (td, J = 13.0, 2.7 Hz, 1H), 2.80 (dt, J = 12.3, 5.1 Hz, 1H), 2.48 - 2.40 (m, 1H), 2.33 - 2.17 (m, 4H), 2.03 - 1.91 (m, 2H), 1.84 (d, J = 12.9 Hz, 1H), 1.69 (s, 1H), 1.19 - 1.07 (m, 2H), 0.96 - 0.85 (m, 2H), 0.84 - 0.72 (m, 2H)。 |
37 | 1-環丙基-3-[(1R,2S)-2-(4-氟-3-甲基苯基)環丙基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 410.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 8.53 (dd, J = 4.4, 1.0 Hz, 1H), 7.18 (dd, J = 9.3, 4.4 Hz, 1H), 7.02 - 6.92 (m, 3H), 6.92 - 6.85 (m, 1H), 5.75 (s, 1H), 4.48 - 4.27 (m, 2H), 3.81 (tt, J = 11.8, 3.9 Hz, 1H), 3.33 - 3.18 (m, 1H), 2.90 (td, J = 13.0, 2.7 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.48 - 2.41 (m, 1H), 2.32 - 2.19 (m, 4H), 2.03 - 1.93 (m, 2H), 1.87 - 1.81 (m, 1H), 1.68 - 1.56 (m, 1H), 1.20 - 1.11 (m, 2H), 0.93 - 0.85 (m, 2H), 0.84 - 0.73 (m, 2H)。 |
38 | 3-[(4-氯-2-甲氧基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 390 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (s, 1H), 7.37 (dd, J = 9.1, 3.9 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.99 - 6.84 (m, 2H), 4.41 - 4.25 (m, 4H), 4.10 (dt, J = 11.2, 7.8 Hz, 1H), 3.83 (s, 3H), 3.07 - 2.99 (m, 1H), 2.90 (s, 3H), 2.86 (dd, J = 13.1, 2.4 Hz, 1H), 1.94 - 1.83 (m, 3H), 1.74 - 1.61 (m, 1H)。 |
39 | 3-{[3-(3-甲氧基苯基)-1,2-噁唑-5-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 423.4 (M+H)。 1H NMR(400 MHz, cdcl3) δ 8.60 - 8.53 (m, 1H), 7.39 - 7.28 (m, 2H), 7.28 - 7.18 (m, 2H), 7.05 - 6.98 (m, 1H), 6.98 - 6.92 (m, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.75 - 4.60 (m, 2H), 4.47 - 4.38 (m, 1H), 4.13 (d, 1H), 3.96 (m, 1H), 3.85 - 3.82 (m, 3H), 3.09 - 2.94 (m, 2H), 2.94 - 2.90 (m, 3H), 2.02 (m, 1H), 1.92 - 1.78 (m, 2H), 1.64 (m, 1H)。 |
40 | 1-{[2-氯-5-(三氟甲基)苯基]甲基}-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 423.4 (M+H)。 1H NMR(400 MHz, cdcl3) δ 8.56 - 8.49 (m, 1H), 7.72 (s, 1H), 7.43 (m, 2H), 7.22 - 7.17 (m, 1H), 7.02 - 6.97 (m, 1H), 6.37 (s, 1H), 4.73 - 4.55 (m, 2H), 4.45 - 4.37 (m, 1H), 4.23 - 4.15 (m, 1H), 4.05 - 3.94 (m, 1H), 3.06 - 2.93 (m, 2H), 2.92 (s, 3H), 2.06 - 1.99 (m, 1H), 1.93 - 1.78 (m, 2H), 1.73 - 1.60 (m, 1H)。 |
41 | 1-[(2,5-二氯苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 394.1 (M+H)。 1H NMR(400 MHz, cdcl3) δ 8.55 (d, 1H), 7.43-7.40 (m, 1H), 7.27-7.18 (m, 2H), 7.16-7.12 (m, 1H), 7.03-6.99 (m, 1H), 6.12 (br, 1H), 4.62-4.46 (m, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 4.08-3.96 (m, 1H), 3.01-2.92 (m, 2H), 2.90 (s, 3H), 2.04-1.95 (m, 1H), 1.90-1.76 (m, 2H), 1.72-1.59 (m, 1H)。 |
42 | 1-[(2,4-二氯苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 394.1 (M+H)。 1H NMR (400 MHz, cdcl3) δ 8.56-8.51 (m, 1H), 7.40 (d, 1H), 7.36-7.33 (m, 1H), 7.22-7.16 (m, 2H), 7.00-6.95 (d, 1H), 6.06 (br, 1H), 4.52 (d, 2H), 4.38 (d, 1H), 4.21 (d, 1H), 4.07-3.95 (m, 1H), 3.01-2.90 (m, 2H), 2.88 (s, 3H), 2.02-1.92 (m, 1H), 1.90-1.75 (m, 2H), 1.73-1.56 (m, 1H)。 |
43 | 1-環丙基-3-[2-(4-氟-3-甲基苯基)環丙基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 410.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (ddd, J = 9.4, 2.6, 1.3 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.99 - 6.93 (m, 1H), 6.92 - 6.85 (m, 1H), 6.67 (s, 1H), 4.37 (dd, J = 26.9, 12.9 Hz, 2H), 3.76 (tt, J = 11.9, 3.9 Hz, 1H), 3.28 - 3.09 (m, 1H), 2.89 (td, J = 13.1, 2.5 Hz, 1H), 2.71 (dt, J = 7.0, 3.6 Hz, 1H), 2.53 - 2.44 (m, 1H), 2.31 - 2.18 (m, 4H), 2.04 - 1.93 (m, 2H), 1.86 (d, J = 13.0 Hz, 1H), 1.62 (dtd, J = 13.0, 9.0, 4.0 Hz, 1H), 1.21 - 1.10 (m, 2H), 0.98 - 0.87 (m, 2H), 0.76 (d, J = 2.5 Hz, 2H)。 |
44 | 3-[(2-甲氧基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 356 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.2 Hz, 1H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.27 (dd, J = 9.4, 1.2 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.95 - 6.85 (m, 2H), 4.38 (d, J = 6.2 Hz, 3H), 4.28 (dd, J = 12.5, 3.9 Hz, 1H), 4.11 (dt, J = 11.1, 7.8 Hz, 1H), 3.83 (s, 3H), 3.10 - 3.01 (m, 1H), 2.92 - 2.84 (m, 4H), 1.93 - 1.84 (m, 3H), 1.76 - 1.62 (m, 1H)。 |
45 | 1-甲基-3-[(5-苯基-1,3-噁唑-2-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.3, 1.1 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.48 - 7.38 (m, 3H), 7.38 - 7.26 (m, 3H), 4.56 (s, 2H), 4.36 (ddd, J = 16.7, 12.9, 2.0 Hz, 2H), 4.11 (ddd, J = 15.6, 11.3, 4.3 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.94 (s, 3H), 2.93 - 2.84 (m, 1H), 1.90 (dd, J = 13.4, 6.0 Hz, 3H), 1.76 - 1.61 (m, 1H)。 |
46 | 1-甲基-3-[(3-苯基-1,2,4-噁二唑-5-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 393.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.3, 1.2 Hz, 1H), 8.10 - 7.99 (m, 2H), 7.56 - 7.47 (m, 3H), 7.33 (ddd, J = 10.6, 9.4, 2.8 Hz, 2H), 4.68 (s, 2H), 4.35 (dd, J = 15.6, 7.4 Hz, 2H), 4.08 (d, J = 4.2 Hz, 1H), 3.08 (dd, J = 12.5, 11.3 Hz, 1H), 2.99 - 2.89 (m, 4H), 1.97 - 1.87 (m, 3H), 1.69 (dd, J = 8.1, 4.3 Hz, 1H)。 |
47 | 1-甲基-3-[(4-苯基-1,3-噁唑-2-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.3, 1.1 Hz, 1H), 8.18 (s, 1H), 7.73 (dd, J = 5.2, 3.3 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.30 (ddd, J = 6.3, 3.6, 1.3 Hz, 2H), 4.54 (s, 2H), 4.42 - 4.29 (m, 2H), 4.11 (d, J = 3.6 Hz, 1H), 3.06 (dd, J = 12.5, 11.3 Hz, 1H), 2.97 - 2.86 (m, 4H), 1.90 (dd, J = 13.8, 5.9 Hz, 3H), 1.68 (dd, J = 10.3, 5.4 Hz, 1H)。 |
48 | 1-{[2-氟-5-(三氟甲基)苯基]甲基}-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 412.4 (M+H)。 |
49 | 1-{[2-氟-4-(三氟甲基)苯基]甲基}-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 412.4 (M+H)。 |
50 | 3-[(2-氟-5-甲氧基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.3 (M+H)。 |
51 | 3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-1-[(2,4,5-三氟苯基)甲基]尿素 | 1H NMR(400 MHz, cdcl3) δ 8.56 (d, 1H), 7.35-7.37 (m, 1H), 7.25-7.20 (m, 1H), 7.04-7.98 (m, 1H), 6.92-6.83 (m, 1H), 6.46 (br, 1H), 4.49 (d, 2H), 4.42 (d, 1H), 4.13 (d, 1H), 10 |
52 | 1-[(2,5-二氟苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 362.36 (M+H)。 |
53 | 1-[(2,4-二氟苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 362.26 (M+H)。 |
54 | 1-甲基-3-[(5-甲基-1-苯并呋喃-2-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 380.3 (M+H)。 |
55 | 3-[2-(3-甲氧基苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 370.4 (M+H)。 |
56 | 1-[2-(3,4-二氟苯基)乙基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.37 (M+H)。 |
57 | 1-[2-(2-氟苯基)乙基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.36 (M+H)。 |
58 | 3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-1-{2-[4-(三氟甲基)苯基]乙基}尿素 | LC-MS: m/z 408.4 (M+H)。 |
59 | 3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-1-{2-[3-(三氟甲基)苯基]乙基}尿素 | LC-MS: m/z 408.4(M+H)。 |
60 | 1-[2-(3,4-二氯苯基)乙基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 408.3(M+H)。 |
61 | 1-[(4-乙炔基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 350.35 (M+H)。 |
62 | 3-[(4-氯-2-氟-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.0 Hz, 1H), 7.18 - 7.12 (m, 2H), 4.40 (s, 2H), 4.38 - 4.25 (m, 2H), 4.09 (dd, J = 9.8, 5.6 Hz, 1H), 3.04 (dd, J = 12.4, 11.5 Hz, 1H), 2.93 - 2.85 (m, 4H), 2.29 (d, J = 2.4 Hz, 3H), 1.92 - 1.84 (m, 3H), 1.74 - 1.61 (m, 1H)。 |
63 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 4.39 - 4.26 (m, 4H), 4.09 (dd, J = 9.6, 5.7 Hz, 1H), 3.04 (dd, J = 12.4, 11.4 Hz, 1H), 2.93 - 2.85 (m, 4H), 2.31 (s, 3H), 1.88 (dt, J = 9.6, 3.9 Hz, 3H), 1.74 - 1.62 (m, 1H)。 |
64 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-{2-[4-(三氟甲氧基)苯基]乙基}尿素 | LC-MS: m/z 424.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 12.7, 4.7 Hz, 3H), 7.16 (d, J = 8.0 Hz, 2H), 4.38 - 4.21 (m, 2H), 4.01 (s, 1H), 3.41 (t, J = 7.3 Hz, 2H), 3.00 (dd, J = 12.4, 11.4 Hz, 1H), 2.93 - 2.81 (m, 6H), 1.92 - 1.80 (m, 3H), 1.65 (dd, J = 14.5, 10.3 Hz, 1H)。 |
65 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-{[4-(三氟甲氧基)苯基]甲基}尿素 | LC-MS: m/z 410 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 3.5 Hz, 1H), 7.44 - 7.34 (m, 3H), 7.28 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 4.40 (s, 2H), 4.38 - 4.26 (m, 2H), 4.10 (dt, J = 11.1, 7.7 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.95 - 2.84 (m, 4H), 1.97 - 1.82 (m, 3H), 1.67 (dt, J = 8.2, 6.1 Hz, 1H)。 |
66 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-{2-[3-(三氟甲氧基)苯基]乙基}尿素 | LC-MS: m/z 410 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.29 - 7.21 (m, 2H), 7.14(s,1H),7.09(d,J=8.2Hz,1H),4.37-4.20(m,2H),4.00(d,J=9.4Hz,1H),3.43(t,J=7.3Hz, 2H), 2.99 (dd, J = 12.4, 11.5 Hz, 1H), 2.91 (d, J = 12.1 Hz, 1H), 2.86 (d, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.91 - 1.81 (m, 3H), 1.70 - 1.58 (m, 1H)。 |
67 | 3-[(4-氯-3-環丙基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.08 (dd, J = 8.1, 2.0 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 4.36 (d, J = 13.1 Hz, 1H), 4.30 (s, 2H), 4.30 - 4.24 (m, 1H), 4.13 - 4.03 (m, 1H), 3.08 - 3.00 (m, 1H), 2.94 - 2.86 (m, 4H), 2.16 (ddd, J = 8.4, 5.2, 3.2 Hz, 1H), 1.94 - 1.82 (m, 3H), 1.68 (dd, J = 10.6, 7.8 Hz, 1H), 1.04 - 0.93 (m, 2H), 0.66 (dt, J = 9.9, 5.1 Hz, 2H)。 |
68 | 3-{[3-(二氟甲基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.2(M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.2 Hz, 1H), 7.50 - 7.36 (m, 5H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 6.74 (t, J = 56.3 Hz, 1H), 4.44 - 4.26 (m, 4H), 4.17 - 4.05 (m, 1H), 3.05 (dd, J = 12.4, 11.4 Hz, 1H), 2.93 - 2.86 (m, 4H), 1.93 - 1.86 (m, 3H), 1.74 - 1.62 (m, 1H)。 |
69 | 3-[(4-環丙基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 366.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.38 (dd, J = 9.4, 4.4Hz,1H),7.28(dd,J=9.4,1.2Hz,1H),7.17(d,J=8.2Hz,2H),7.00(d,J= 8.1 Hz, 2H), 4.42 - 4.23 (m, 4H), 4.17 - 4.05 (m, 1H), 3.03 (dd, J = 12.4, 11.4 Hz, 1H), 2.93 - 2.82 (m, 4H), 1.93 - 1.82 (m, 4H), 1.68 (s, 1H), 0.92 (ddd, J = 8.4, 6.3, 4.3 Hz, 2H), 0.67 - 0.58 (m, 2H)。 |
70 | 3-[(3-環丙基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 366.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 3.5 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.1 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.08 - 6.97 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 4.43 - 4.22 (m, 4H), 4.10 (dt, J = 11.3, 7.6 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.94 - 2.84 (m, 4H), 1.95 - 1.82 (m, 4H), 1.75 - 1.62 (m, 1H), 0.96 - 0.85 (m, 2H), 0.69 - 0.57 (m, 2H)。 |
71 | 3-{[3-(1,1-二氟乙基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 390.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.2 Hz, 1H), 7.47 - 7.33 (m, 5H), 7.24 (dd, J = 9.3, 1.2 Hz, 1H), 7.06 (t, J = 5.8 Hz, 1H), 4.37 - 4.21 (m, 4H), 4.06 - 3.94 (m, 1H), 3.02 - 2.94 (m, 1H), 2.85 - 2.77 (m, 4H), 1.95 (t, J = 18.8 Hz, 3H), 1.83 - 1.70 (m, 3H), 1.62 - 1.50 (m, 1H)。 |
72 | 3-{[4-(二氟甲基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (d, J = 2.5 Hz, 1H), 7.40 (ddd, J = 16.3, 13.6, 6.2 Hz, 5H), 7.27 (dd, J = 9.4, 0.9 Hz, 1H), 6.72 (t, J = 56.4 Hz, 1H), 4.43 (s, 2H), 4.38 - 4.26 (m, 2H), 4.10 (dt, J = 11.1, 7.8 Hz, 1H), 3.03 (dd, J = 12.4, 11.4 Hz, 1H), 2.94 - 2.82 (m, 4H), 1.92 - 1.81 (m, 3H), 1.72 - 1.59 (m, 1H)。 |
73 | 1-甲基-3-[(3-甲基苯基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 340.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 0.9 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 7.10 (ddd, J = 31.1, 19.2, 7.5 Hz, 4H), 4.41 - 4.24 (m, 4H), 4.11 (dd, J = 9.7, 5.5 Hz, 1H), 3.04 (dd, J = 12.5, 11.3 Hz, 1H), 2.95 - 2.84 (m, 4H), 2.31 (s, 3H), 1.93 - 1.83 (m, 3H), 1.74 - 1.61 (m, 1H)。 |
75 | 1-甲基-3-[(4-苯基-1,3-噻唑-2-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 409.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.2 Hz, 1H), 7.88 (dd, J = 5.2, 3.3 Hz, 2H), 7.69 (s, 1H), 7.43 - 7.25 (m, 5H), 4.72 (s, 2H), 4.36 (t, J = 14.0 Hz, 2H), 4.18 - 4.05 (m, 1H), 3.15 - 3.04 (m, 1H), 2.99 - 2.85 (m, 4H), 1.97 - 1.85 (m, 3H), 1.76 - 1.62 (m, 1H)。 |
76 | 3-[(3,4-二氫-2H-1-苯并吡喃-6-基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 382 (M+H)。 |
77 | 3-[(4-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 344.2(M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.0 Hz, 1H), 7.30 (tdd, J = 10.3, 9.3, 2.7 Hz, 4H), 7.13 (t, J = 8.9 Hz, 2H), 7.00 (s, 1H), 4.38 - 4.15 (m, 4H), 3.99 (dd, J = 13.3, 9.4 Hz, 1H), 3.02 - 2.90 (m, 1H), 2.80 (s, 4H), 1.86 - 1.66 (m, 3H), 1.54 (d, J = 12.8 Hz, 1H)。 |
78 | 3-[(4-氯苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 360.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (d, J = 3.5 Hz, 1H), 7.44 - 7.16 (m, 6H), 7.02 (t,J=5.7Hz,1H),4.38-4.17(m,4H),3.99(t,J=11.3Hz,1H),2.96(t,J=11.8 Hz, 1H), 2.86 - 2.74 (m, 4H), 1.76 (dd, J = 22.8, 7.9 Hz, 3H), 1.55 (t, J = 13.1 Hz, 1H)。 |
79 | 3-[(3-氯苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 360.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (s, 1H), 7.38 (dd, J = 9.2, 4.2 Hz, 1H), 7.34-7.16 (m, 5H), 4.41-4.25 (m, 4H), 4.15-4.05 (m, 1H), 3.05 (dd, J = 12.5, 11.3 Hz, 1 H), 2.95-2.85 (m, 4H), 1.94-1.84 (m, 3H), 1.74-1.62 (m, 1H)。 |
80 | 3-[(2-氯苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 360.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (d, J = 3.9 Hz, 1H), 7.42 - 7.18 (m, 6H), 4.48 (s, 2H), 4.41 - 4.28 (m, 2H), 4.12 (dd, J = 9.8, 5.5 Hz, 1H), 3.06 (dd, J = 12.5, 11.3 Hz, 1H), 2.96 - 2.85 (m, 4H), 1.95 - 1.84 (m, 3H), 1.76 - 1.63 (m, 1H)。 |
81 | 3-{[4-甲氧基-3-(三氟甲基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 424.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.0 Hz, 1H), 7.52 (d, J = 7.7 Hz, 2H),7.37(dd,J=9.4,4.4Hz,1H),7.28(dd,J=9.4,1.1Hz,1H),7.11(d,J=8.4 Hz, 1H), 4.41 - 4.23 (m, 4H), 4.14 - 4.03 (m, 1H), 3.87 (s, 3H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.95 - 2.84 (m, 4H), 1.88 (dt, J = 9.5, 4.2 Hz, 3H), 1.67 (dd, J = 11.4, 7.3 Hz, 1H)。 |
82 | 3-[(2-氟-5-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 0.9 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 7.14 (dd, J = 7.3, 1.7 Hz, 1H), 7.06 - 7.00 (m, 1H), 6.90 (dd, J = 10.1, 8.4 Hz, 1H), 4.41 - 4.24 (m, 4H), 4.11 (dt, J = 11.2, 7.8 Hz, 1H), 3.04 (dd, J = 12.5, 11.3 Hz, 1H), 2.92 - 2.84 (m, 4H), 2.29 (s, 3H), 1.93 - 1.84 (m, 3H), 1.69 (ddd, J = 12.6, 8.1, 3.4 Hz, 1H)。 |
83 | 3-[(2-氟-4-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (d, J = 9.3Hz,1H), 7.21 (t,J=7.9Hz,1H), 6.93(d,J=7.8Hz,1H),6.87(d,J=11.4Hz,1H),4.38 (d,J=10.8 Hz, 3H), 4.28 (dd, J = 12.5, 3.9 Hz, 1H), 4.10 (dd, J = 9.6, 5.7 Hz, 1H), 3.09 - 3.00 (m, 1H), 2.92 (m, 4H), 2.31 (s, 3H), 1.93 - 1.83 (m, 3H), 1.68 (dd, J = 12.8, 5.2 Hz, 1H)。 |
84 | 3-[(2,4-二氟-5-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 3.9 Hz, 1H), 7.39 (dd, J = 9.4, 4.4 Hz, 1H),7.30(dd,J=9.4,1.1Hz,1H),7.21(t,J=8.6Hz,1H),6.82(t,J=9.9Hz, 1H), 4.41 - 4.25 (m, 4H), 4.15 - 4.05 (m, 1H), 3.04 (dd, J = 12.5, 11.3 Hz, 1H), 2.93 - 2.84 (m, 4H), 2.21 (s, 3H), 1.93 - 1.82 (m, 3H), 1.75 - 1.61 (m, 1H)。 |
85 | 3-[(4-氯-2-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.1(M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 0.9 Hz, 1H), 7.41 - 7.26 (m, 3H), 7.20 - 7.06 (m, 2H), 4.43 - 4.25 (m, 4H), 4.09 (dt, J = 11.3, 7.6 Hz, 1H), 3.04 (dd, J = 12.4, 11.4 Hz, 1H), 2.94 - 2.84 (m, 4H), 1.93 - 1.82 (m, 3H), 1.74 - 1.61 (m, 1H)。 |
86 | 3-[(2-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 344.2(M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (d, J = 3.4 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.30 - 7.20 (m, 2H), 7.15 - 7.08 (m, 1H), 7.07 - 7.00 (m, 1H), 4.45 (s, 2H), 4.36 (d, J = 13.2 Hz, 1H), 4.28 (dd, J = 12.6, 3.7 Hz, 1H), 4.10 (dd, J = 9.6, 5.5 Hz, 1H), 3.03 (dd, J = 12.3, 11.5 Hz, 1H), 2.92 - 2.84 (m, 4H), 1.87 (dd, J = 10.6, 4.6 Hz, 3H), 1.72 - 1.60 (m, 1H)。 |
87 | 3-[(2,2-二氟-2H-1,3-苯并二氧雜環戊烯-5-基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 406 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (s, 1H), 7.38 (s, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.17 (s, 1H), 7.11 (d, J = 0.8 Hz, 2H), 4.37 (s, 2H), 4.36 - 4.25 (m, 2H), 4.13 - 4.05 (m, 1H), 3.07 - 3.01 (m, 1H), 2.94 - 2.86 (m, 4H), 1.89 (dd, J = 9.9, 4.8 Hz, 3H), 1.72 - 1.62 (m, 1H)。 |
88 | 3-[(5-氯-2-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.1 Hz, 1H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.24 (ddd, J = 8.6, 4.4, 2.7 Hz, 1H), 4.43 - 4.26 (m, 4H), 4.10 (dd, J = 9.6, 5.7 Hz, 1H), 3.07 (dd, J = 12.5, 11.3 Hz, 1H), 2.95 - 2.87 (m, 4H), 1.93 - 1.85 (m, 3H), 1.75 - 1.63 (m, 1H)。 |
89 | 1-甲基-3-[(萘-2-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (d, J = 3.7 Hz, 1H), 7.84 - 7.77 (m, 3H), 7.74 (s, 1H), 7.48 - 7.39 (m, 3H), 7.34 (dd, J = 9.4, 4.4 Hz, 1H), 7.25 (dd, J = 9.4, 1.2 Hz, 1H), 4.55 (s, 2H), 4.39 - 4.26 (m, 2H), 4.18 - 4.09 (m, 1H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.92 (s, 3H), 2.91 - 2.84 (m, 1H), 1.88 (dd, J = 13.6, 5.5 Hz, 3H), 1.73 - 1.62 (m, 1H)。 |
90 | 3-[(3,5-二甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (s, 1H), 7.37 (dd, J = 9.3, 4.1 Hz, 1H), 7.28 (d, J = 9.3 Hz, 1 H), 6.90 (s, 2H), 6.85 (s, 1H), 4.38 (d, J = 13.6 Hz, 1H), 4.30 (s, 2H), 4.26 (d, J = 3.9 Hz, 1H), 4.11 (dd, J = 9.7, 5.4 Hz, 1H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.95 - 2.83 (m, 3H), 2.26 (s, 5H), 1.89 (dd, J = 10.8, 4.4 Hz, 2H), 1.76 - 1.58 (m, 1H)。 |
91 | 3-[2-(1H-吲哚-3-基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 379.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.09 - 7.02 (m, 2H), 7.01 - 6.93 (m, 1H), 4.36 (d, J = 13.8 Hz, 1H), 4.17 (dd, J = 12.7, 3.8 Hz, 1H), 3.98 (s, 1H), 3.54 - 3.44 (m, 2H), 3.02 - 2.93 (m, 3H), 2.85 (dd, J = 18.5, 8.0 Hz, 1H), 2.79 (s, 3H), 1.92 - 1.78 (m, 3H), 1.61 (d, J = 8.6 Hz, 1H)。 |
92 | 3-[(1S,2R)-2-(3-氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 370.2(M+H)。 |
93 | 3-[2-(4-甲氧基苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 370.4(M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.87 - 6.77 (m, 2H), 4.36 (d,J=13.2Hz,1H), 4.22 (dd,J=12.7,3.8Hz,1H), 4.01(d,J=5.5 Hz, 1H), 3.73 (d, J = 3.5 Hz, 3H), 3.40 - 3.33 (m, 2H), 3.00 (dd, J = 12.5, 11.3 Hz, 1H), 2.93 - 2.81 (m, 4H), 2.74 (t, J = 7.4 Hz, 2H), 1.95 - 1.80 (m, 3H), 1.73 - 1.57 (m, 1H)。 |
94 | 3-[(3-氯-2-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (s, 1H), 7.43 - 7.25 (m, 4H), 7.11 (td, J = 7.9, 1.1 Hz, 1H), 4.46 (s, 2H), 4.40 - 4.25 (m, 2H), 4.09 (dt, J = 11.2, 7.6 Hz, 1H), 3.05 (dd, J = 12.5, 11.3 Hz, 1H), 2.94 - 2.86 (m, 4H), 1.89 (tt, J = 9.6, 5.0 Hz, 3H), 1.75 - 1.63 (m, 1H)。 |
95 | 3-[2-(5-氯-1H-吲哚-3-基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.3 (M+H)。 1HNMR(400MHz,MeOD) δ8.45 (d,J=3.9Hz,1H), 7.54(d,J=2.0Hz,1H), 7.37 (dd,J=9.4,4.3Hz,1H), 7.26(d,J=8.6Hz,1H), 7.20(d,J=8.7Hz,1H), 7.12 (s,1H), 7.02 (dd,J=8.6,2.0Hz,1H), 4.36 (d,J=13.8Hz,1H), 4.13 (d,J= 12.3 Hz, 1H), 3.94 (s, 1H), 3.50 - 3.42 (m, 2H), 3.01 - 2.83 (m, 4H), 2.81 (s, 3H), 1.84 (t,J=7.6Hz,3H), 1.60 (d,J=9.1Hz,1H)。 |
96 | 3-[(5-氯-1H-吲哚-3-基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.3 (M+H)。 1H NMR(400 MHz, DMSO) δ 11.04 (s, 1H), 8.57 - 8.47 (m, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.28 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 9.3, 1.0 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 6.77 (t, J = 5.5 Hz, 1H), 4.43 - 4.29 (m, 3H), 4.16 (d, J = 12.5 Hz, 1H), 4.00 (t, J = 11.3 Hz, 1H), 2.98 - 2.91 (m, 1H), 2.76 (s, 4H), 1.81 - 1.67 (m, 3H), 1.55 (t, J = 13.1 Hz, 1H)。 |
97 | 3-{[3-氯-4-(三氟甲基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 428.3 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 9.3, 4.4 Hz, 1H), 7.25 (dd,J=9.3,1.1Hz,1H), 7.14(t,J=5.7Hz,1H),4.40-4.18(m,4H),4.03-3.93 (m, 1H), 3.03 - 2.92 (m, 1H), 2.87 - 2.76 (m, 4H), 1.78 (dt, J = 9.8, 8.7 Hz, 3H), 1.61 - 1.46 (m, 1H)。 |
98 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-[(喹啉-6-基)甲基]尿素 | LC-MS: m/z 377.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.80 (dd, J = 4.3, 1.7 Hz, 1H), 8.44 (d, J =3.3Hz,1H),8.35(d,J=7.5Hz,1H),7.99(d,J=8.7Hz,1H),7.84(s, 1H), 7.77 (dd, J = 8.7, 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 4.3 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 4.59 (s, 2H), 4.35 (t, J = 14.5 Hz, 2H), 4.12 (s, 1H), 3.11 - 3.03 (m, 1H), 2.96 - 2.87 (m, 4H), 1.91 (t, J = 7.6 Hz, 3H), 1.68 (s, 1H)。 |
99 | 3-[(3-氯-4-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.0 Hz, 1H), 7.35 (dd, J = 9.3, 4.4 Hz, 1H), 7.31 - 7.22 (m, 3H), 7.14 (dd, J = 7.7, 1.3 Hz, 1H), 7.00 (t, J = 5.8 Hz, 1H), 4.34 (d, J = 11.7 Hz, 1H), 4.28 - 4.15 (m, 3H), 3.98 (dd, J = 13.3, 9.2 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.85 - 2.76 (m, 4H), 2.29 (s, 3H), 1.85 - 1.66 (m, 3H), 1.60 - 1.47 (m, 1H)。 |
100 | 3-[(4-氯-3-甲氧基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 390.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.1 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 14.0, 4.6 Hz, 2H), 7.03 (d, J = 1.7 Hz, 1H), 6.86 (dd, J = 8.1, 1.9 Hz, 1H), 4.42 - 4.25 (m, 4H), 4.09 (dd, J = 9.6, 5.5 Hz, 1H), 3.86 (s, 3H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.96 - 2.81 (m, 4H), 1.96 - 1.80 (m, 3H), 1.79 - 1.59 (m, 1H)。 |
101 | 3-[(1S,2R)-2-(2-氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 370.2 (M+H)。 |
102 | 1-甲基-3-[(1S,2R)-2-(2-甲基苯基)環丙基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 366.2 (M+H)。 |
103 | 3-[2-(4-氯苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.2 (M+H)。 |
104 | 3-{[4-氯-3-(三氟甲基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.2 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 1.1 Hz, 2H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 4.41 (s, 2H), 4.38 - 4.27 (m, 2H), 4.13 - 4.03 (m, 1H), 3.05 (dd, J = 12.5, 11.3 Hz, 1H), 2.94 - 2.87 (m, 4H), 1.95 - 1.84 (m, 3H), 1.68 (dd, J = 11.2, 8.5 Hz, 1H)。 |
105 | 3-{[3-氟-4-(三氟甲氧基)苯基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 428.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 4.4 Hz, 1H), 7.54 - 7.14 (m, 5H), 4.47 - 4.21 (m, 4H), 4.09 (s, 1H), 3.09 - 2.98 (m, 1H), 2.96 - 2.82 (m, 4H), 1.88 (d, J = 7.8 Hz, 3H), 1.68 (s, 1H)。 |
106 | 1-甲基-3-{[3-(1H-吡唑-1-基)苯基]甲基}-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.32 - 7.25 (m, 2H), 6.57 - 6.44 (m, 1H), 4.47 (d, J = 4.4 Hz, 2H), 4.38 (d, J = 13.2 Hz, 1H), 4.28 (d, J = 12.6 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.10 - 3.00 (m, 1H), 2.92 (s, 3H), 2.91 - 2.81 (m, 1H), 1.90 (dd, J = 13.5, 6.0 Hz, 3H), 1.76 - 1.58 (m, 1H)。 |
107 | 1-甲基-3-[(4-甲基苯基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 340.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.1 Hz, 1H), 7.36 (dd, J = 9.3, 4.4 Hz, 1H), 7.25 (dd, J = 9.3, 1.1 Hz, 1H), 7.13 (dd, J = 21.8, 8.0 Hz, 4H), 6.92 (t,J=5.8Hz,1H), 4.34(d,J=11.2Hz,1H),4.28-4.14 (m,3H), 4.05-3.95(m, 1H), 3.03 - 2.90 (m, 1H), 2.86 - 2.73 (m, 4H), 2.27 (s, 3H), 1.85 - 1.66 (m, 3H), 1.55 (dd, J = 15.2, 11.4 Hz, 1H)。 |
108 | 3-[(2,3-二氫-1-苯并呋喃-2-基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 368.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (s, 1H), 7.43 - 7.36 (m, 1H), 7.29 (dd, J = 8.6,4.6Hz,1H), 7.16-6.97(m,2H), 6.77 (t,J=7.4Hz,1H), 6.69 (d,J=7.8Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.88 (dd, J = 9.5, 5.2 Hz, 1H), 4.39 - 4.21 (m, 2H), 4.03 - 3.87 (m, 1H), 3.56 - 3.41 (m, 2H), 3.28 - 3.21 (m, 1H), 3.04 - 2.85 (m, 3H), 2.80 (s, 3H), 1.90 - 1.76 (m, 3H), 1.62 (s, 1H)。 |
109 | 1-甲基-3-[(1S)-1-(4-甲基苯基)乙基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 354.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (s, 1H), 7.30 (s, 2H), 7.22 (d, J = 8.1 Hz, 3H), 7.10 (d, J = 7.9 Hz, 3H), 4.92 (q, J = 7.0 Hz, 1H), 4.36 (d, J = 13.3 Hz, 1H), 4.24 (d, J = 12.2 Hz, 1H), 4.15 - 4.02 (m, 1H), 3.09 - 2.96 (m, 1H), 2.95 - 2.83 (m, 5H), 2.29 (s, 4H), 1.87 (t, J = 7.7 Hz, 4H), 1.65 (d, J = 9.3 Hz, 1H), 1.47 (d, J = 7.1 Hz, 4H)。 |
110 | 3-[2-(3-氯苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.59 - 8.38 (m, 1H), 7.19 - 7.03 (m, 5H), 6.95 (dd, J = 9.3, 1.0 Hz, 1H), 5.70 (s, 1H), 4.25 (d, J = 12.8 Hz, 1H), 4.11 (d, J = 13.3 Hz, 1H), 3.81 (t, J = 11.2 Hz, 1H), 3.49 (dd, J = 13.2, 6.1 Hz, 2H), 2.97 - 2.80 (m, 5H), 2.77 (s, 3H), 1.90 (d, J = 11.0 Hz, 1H), 1.83 - 1.68 (m, 2H), 1.64 - 1.47 (m, 1H)。 |
111 | 3-[2-(2,4-二氯苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 480.3 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (s, 1H), 7.39 (dd, J = 8.7, 3.0 Hz, 2H), 7.26 (qd, J = 8.2, 2.8 Hz, 3H), 4.35 (d, J = 14.7 Hz, 1H), 4.23 (dd, J = 12.7, 3.9 Hz, 1H), 4.00 (s, 1H), 3.58 - 3.37 (m, 2H), 3.09 - 2.84 (m, 4H), 2.82 (s, 3H), 1.96 - 1.79 (m, 3H), 1.74 - 1.55 (m, 1H)。 |
112 | 3-[2-(4-氟苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (d, J = 3.7 Hz, 1H), 7.39 (dd, J - 9.4, 4.4 Hz, 1H), 7.27 (dd, J = 9.4, 1.1 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.05 - 6.89 (m, 2H), 4.35 (d, J = 13.7 Hz, 1H), 4.24 (dd, J = 12.5, 3.8 Hz, 1H), 4.01 (s, 1H), 3.43 - 3.35 (m, 2H), 3.00 (dd, J = 12.5, 11.4 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.85 - 2.75 (m, 5H), 1.87 (ddd, J = 12.6, 10.3, 5.4 Hz, 3H), 1.74 - 1.58 (m, 1H)。 |
113 | 3-[(2,5-二甲基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 354.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (d, J = 3.8 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.1 Hz, 1H), 7.13 - 6.88 (m, 3H), 4.41 - 4.26 (m, 4H), 4.12 (dt, J = 11.6, 8.0 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.94-2.84(m,4H), 2.28 (d,J=4.9Hz,6H), 1.90 (dd,J=10.9,8.9Hz,3H), 1.68(d,J=9.4Hz,1H)。 |
114 | 3-[(3-氯-4-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 4.1 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.33 - 7.23 (m, 2H), 7.16 (t, J = 8.7 Hz, 1H), 4.42 - 4.26 (m, 4H), 4.15 - 4.01 (m, 1H), 3.10 - 2.98 (m, 1H), 2.95 - 2.84 (m, 4H), 1.98 - 1.82 (m, 3H), 1.76 - 1.58 (m, 1H)。 |
115 | 3-[(4-氯-3-氟苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 378.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.51 (dd, J = 4.4, 1.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 9.3, 4.4 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.14 (dd, J = 8.2, 1.2 Hz, 1H), 7.06 (t, J = 5.8 Hz, 1H), 4.36 - 4.18 (m, 4H), 3.97 (dd, J = 13.3, 9.1 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.86 - 2.74 (m, 4H), 1.86 - 1.67 (m, 3H), 1.59 - 1.46 (m, 1H)。 |
116 | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-{[3-(三氟甲基)苯基]甲基}尿素 | LC-MS: m/z 394.1(M+H)。 |
117 | 3-[(3,4-二氯苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 394.1(M+H)。 |
118 | 1-[(3,4-二氟苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 394.1(M+H)。 1H NMR(400 MHz, MeOD) δ 8.48 (s, 1H), 7.40 (s, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.13 (d, J = 4.3 Hz, 1H), 4.40 - 4.29 (m, 4H), 4.11 (dt, J = 11.2, 7.6 Hz, 1H), 3.06 (dd, J = 12.5, 11.3 Hz, 1H), 2.96 - 2.87 (m, 4H), 1.91 (tt, J = 9.6, 4.9 Hz, 3H), 1.69 (dd, J = 15.6, 6.3 Hz, 1H)。 |
119 | 1-[(2,3-二氟-4-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.1(M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (s, 1H), 7.41 (s, 1H), 7.30 (d, J = 9.1 Hz, 1H), 6.99 (dt, J = 14.6, 7.6 Hz, 2H), 4.42 (s, 2H), 4.37 (d, J = 12.7 Hz, 1H), 4.28 (d, J = 12.6 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.08 - 3.00 (m, 1H), 2.94 - 2.85 (m, 4H), 2.26 (d, J = 2.0 Hz, 3H), 1.93 - 1.83 (m, 3H), 1.67 (d, J = 9.1 Hz, 1H)。 |
120 | 1-{[4-氟-3-(三氟甲基)苯基]甲基}-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 412.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.51 (dd, J = 4.4, 1.1 Hz, 1H), 7.64 (dd, J = 9.2, 6.1 Hz, 2H), 7.45 (dd, J = 10.8, 8.4 Hz, 1H), 7.35 (dd, J = 9.3, 4.4 Hz, 1H), 7.24 (dd,J=9.3,1.1Hz,1H), 7.10 (t,J=5.8Hz,1H),4.38-4.18 (m,4H),3.97 (dd,J = 13.2, 9.2 Hz, 1H), 3.00 - 2.92 (m, 1H), 2.87 - 2.74 (m, 4H), 1.77 (dt, J = 24.0, 11.8 Hz, 3H), 1.62 - 1.47 (m, 1H)。 |
121 | 1-[(3-氟-4-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (s, 1H), 7.29 (d, J = 9.4 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 6.98 (dd, J = 11.9, 9.4 Hz, 2H), 4.44 - 4.23 (m, 5H), 4.10 (s, 1H), 3.10 - 2.98 (m, 1H), 2.95 - 2.83 (m, 5H), 2.22 (d, J = 1.6 Hz, 4H), 1.97 - 1.80 (m, 4H), 1.68 (s, 1H)。 |
122 | 1-[(4-氟-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 358.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (s, 1H), 7.39 (dd, J = 9.2, 4.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.17(d,J=7.5Hz,1H),7.12(ddd,J=7.3,4.9,2.1Hz,1H),6.98-6.91(m,1H),4.38(d,J=13.3Hz, 1H), 4.32 (s, 2H), 4.28 (d, J = 3.9 Hz, 1H), 4.15 - 4.07 (m, 1H), 3.04 (dd, J = 12.5, 11.3 Hz, 1H), 2.93 - 2.87 (m, 4H), 2.24 (d, J = 1.8 Hz, 3H), 1.89 (dt, J = 9.5, 3.9 Hz, 3H), 1.75 - 1.63 (m, 1H)。 |
123 | 3-[2-(3,5-二氯苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 408.3 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.2 Hz, 1H), 7.41 (t, J = 1.9 Hz, 1H), 7.36 (dd, J = 9.3, 4.4 Hz, 1H), 7.29 - 7.16 (m, 3H), 6.47 (t, J = 5.5 Hz, 1H), 4.32 (d, J = 12.7 Hz, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.91 (dd, J = 13.4, 9.2 Hz, 1H), 3.30 - 3.26 (m, 3H), 3.00 - 2.88 (m, 1H), 2.86 - 2.71 (m, 6H), 1.84 - 1.64 (m, 3H), 1.52 (t, J = 13.1 Hz, 1H)。 |
124 | 3-[(4-氰基苯基)甲基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 351.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.51 (dd, J = 4.4, 1.2 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.46(d,J=8.4Hz,2H),7.35(dd,J=9.3,4.4Hz,1H),7.24(dd,J=9.3,1.2Hz, 1H), 7.11 (t, J = 5.8 Hz, 1H), 4.38 - 4.22 (m, 4H), 3.98 (dd, J = 13.4, 9.3 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.85 - 2.75 (m, 4H), 1.77 (dt, J = 8.9, 8.4 Hz, 3H), 1.54 (dd, J = 15.2, 11.2 Hz, 1H)。 |
125 | LC-MS: m/z 354.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.0 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.27 (dd, J = 9.4, 1.2 Hz, 1H), 7.10 - 6.96 (m, 3H), 4.47 - 4.22 (m, 4H), 4.16 - 4.02 (m, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 2.93 - 2.81 (m, 4H), 2.22 (d, J = 6.3 Hz, 6H), 1.88 (dt, J = 9.7, 4.1 Hz, 3H), 1.77 - 1.58 (m, 1H)。 | |
126 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 15.2, 8.3 Hz, 2H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.40 - 4.25 (m, 4H), 4.09 (dd, J = 9.7, 5.7 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.94 - 2.85 (m, 4H), 2.33 (s, 3H), 1.89 (dd, J = 11.2, 4.4 Hz, 3H), 1.74 - 1.61 (m, 1H)。 |
127 | 3-[2-(4-氯-3-甲基苯基)乙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4Hz,1H),7.27(dd,J=9.4,1.2Hz,1H),7.22(d,J=8.1Hz,1H),7.13(d,J= 1.6 Hz, 1H), 7.01 (dd, J = 8.1, 1.9 Hz, 1H), 4.34 (d, J = 11.9 Hz, 1H), 4.23 (dd, J = 12.7, 4.0 Hz, 1H), 3.97 (d, J = 10.2 Hz, 1H), 3.39 (tt, J = 8.4, 4.4 Hz, 2H), 3.00 (dd, J = 12.5, 11.3 Hz, 1H), 2.89 (dd, J = 18.7, 8.0 Hz, 1H), 2.82 (s, 3H), 2.76 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.92 - 1.80 (m, 3H), 1.71 - 1.57 (m, 1H)。 |
實例 128 : 3-(4- 氯 -3- 甲基苄基 )-1- 環丙基 -1-((R)-1-((S)- 四氫呋喃 -2- 羰基 ) 六氫吡啶 -3- 基 ) 尿素之合成 於0℃下向
M2(116 mg, 1.0 mmol)及HATU (474 mg, 1.29 mmol)於DCM (20 mL)中之混合物中逐滴添加TEA (253 mg, 2.5 mmol)。於r.t.下攪拌30 min後,向上述混合物中添加
M1(200 mg, 0.83 mmol)。將所得混合物於r.t.下在N
2氣氛下攪拌2 hr。然後用DCM (20 mL)稀釋混合物,且用水(30 mL)及鹽水(30 mL)洗滌。經無水Na
2SO
4乾燥有機層,過濾,並濃縮至乾燥。經由急速管柱層析(用PE/EtOAc= 100:0至3:1溶析)純化殘餘物,以產生無色油狀
M3(250 mg, 88.8%)。LC/MS (ESI) m/z: 299 (M+H)
+。於0℃下向
M3(250 mg, 0.84 mmol)於DCM (6 mL)中之溶液中逐滴添加TFA (2 mL)。將所得混合物於室溫下攪拌2 hr。然後將反應混合物在減壓下蒸發至乾燥,以產生黃色油狀粗製
M4(160 mg, 96.3%),而不經進一步純化。LC/MS (ESI) m/z: 199 (M+H)
+。於0℃下向
M4(160 mg, 0.81 mmol)及
M5(148 mg, 0.89 mmol)於DCM (10 mL)中之溶液中添加AcOH (145 mg, 2.42 mmol)。將所得混合物於r.t.下攪拌1 hr。然後於0℃下向上述混合物中逐滴添加NaBH(OAc)
3(510 mg, 2.42 mmol)。將所得混合物於r.t.下在N
2氣氛下攪拌過夜。用飽和NaHCO
3溶液(20 mL)淬滅混合物且用EtOAc (30 mL)萃取兩次。將合併之有機層用鹽水(20 mL)洗滌,經無水Na
2SO
4乾燥,過濾。將濾液在減壓下蒸發至乾燥。藉由矽膠上管柱層析(用PE/EtOAc= 100:0至=2:1溶析)純化殘餘物,以產生無色油狀
M6(100 mg, 35.6%)。LC/MS (ESI) m/z: 349 (M+H)
+。向
M6(100 mg, 0.29 mmol)、
M7(125 mg, 0.72 mmol)及AcOH (52 mg, 0.86 mmol)於THF (12 mL)及EtOH (6 mL)中之混合物中添加NaBH
3CN (55 mg, 0.86 mmol)。將所得混合物於80℃下在N
2氣氛下攪拌過夜。冷卻後,將反應物用飽和NaHCO
3水溶液(20 mL)淬滅且用EtOAc (30 mL)萃取兩次。將合併之有機層用鹽水(20 mL)洗滌,經無水Na
2SO
4乾燥,過濾。將濾液在減壓下蒸發至乾燥。藉由急速管柱層析(用PE/EtOAc= 100:0至=2:1溶析)純化殘餘物,以產生無色油狀
M8(50 mg, 44.8%)。LC/MS (ESI) m/z: 389 (M+H)
+。將
M8(50 mg, 0.13 mmol)於TFA (4 mL)中之溶液於80℃下在N
2氣氛下攪拌3 hr。冷卻後,將混合物在減壓下濃縮至乾燥,以產生紫色油狀粗製
M9(30 mg, 97.8%),而不經進一步純化。LC/MS (ESI) m/z: 239 (M+H)
+。
於0˚C下向
M9(30 mg, 0.13 mmol)及TEA (39 mg, 0.39 mmol)於無水DCM (10 mL)中之混合物中逐滴添加
M10(22.9 mg, 0.13 mmol)於無水DCM (2 mL)中之溶液。將所得混合物於0˚C下在N
2氣氛下攪拌1小時。然後用水(20 mL)稀釋反應混合物且用DCM (20 mL)萃取兩次。分離合併之有機層,經無水Na
2SO
4乾燥,過濾且濃縮至乾燥。經由急速管柱層析(用DCM/MeOH = 100:0至20:1溶析)純化殘餘物,以產生粗產物。經由prep-HPLC (Gemini 5μm C18 250*21.2mm, H
2O/MeCN (5-95 %)/0.1% HCOOH)純化粗產物,以產生白色固體狀
實例 128(11 mg, 0.026 mmol, 20.81%產率)。LC/MS (ESI) m/z: 420 (M+H)
+。1H NMR (400 MHz, MeOD) δ 7.28 (dd, J = 8.2, 2.7 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.10 (dd, J = 10.5, 4.1 Hz, 1H), 4.74 - 4.67 (m, 1H), 4.53 - 4.39 (m, 1H), 4.39 - 4.26 (m, 2H), 4.02 - 3.87 (m, 2H), 3.86 - 3.44 (m, 2H), 3.30 - 3.10 (m, 1H), 3.00 - 2.46 (m, 2H), 2.33 (d, J = 9.2 Hz, 3H), 2.32 - 2.13 (m, 2H), 2.05 - 1.79 (m, 5H), 1.66 - 1.39 (m, 1H), 1.02 - 0.87 (m, 2H), 0.85 - 0.66 (m, 2H)。
下表中之化合物係藉由與實例128相同之途徑、以適當市售醯胺M2及其他先前闡述或市售中間體開始來製得。
實例 | 結構及名稱 | 數據 |
129 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[(3S)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 412 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (dd, J = 8.0, 3.5 Hz, 1H), 7.11 (dd, J = 9.7, 6.2 Hz, 1H), 4.52 - 4.29 (m, 3H), 4.12 - 3.98 (m, 1H), 3.95 - 3.74 (m, 5H), 3.48 - 3.39 (m, 1H), 3.17 - 3.09 (m, 1H), 3.05 - 2.96 (m, 1H), 2.85 (d, J = 7.5 Hz, 3H), 2.74 (t, J = 11.9 Hz, 1H), 2.51 (td, J = 13.0, 2.3 Hz, 1H), 2.31 (s, 3H), 2.12 (ddt, J = 17.1, 13.6, 7.6 Hz, 2H), 1.89 - 1.77 (m, 3H), 1.59 - 1.44 (m, 1H)。 |
130 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[(2R)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 412 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 9.7, 6.6 Hz, 1H), 4.70 (dd, J = 14.1, 8.0 Hz, 1H), 4.50 - 4.29 (m, 3H), 4.13 - 3.98 (m, 1H), 3.97 - 3.79 (m, 3H), 3.17 - 3.08 (m, 1H), 2.93 (dd, J = 18.6, 7.7 Hz, 1H), 2.85 (d, J = 4.9 Hz, 3H), 2.74 (t, J = 11.8 Hz, 1H), 2.52 (td, J = 13.0, 2.3 Hz, 1H), 2.31 (s, 3H), 2.28 - 2.12 (m, 1H), 2.03 (ddd, J = 12.9, 10.3, 6.6 Hz, 1H), 1.97 - 1.87 (m, 2H), 1.86 - 1.78 (m, 3H), 1.65 (d, J = 7.3 Hz, 1H), 1.48 (d, J = 9.6 Hz, 1H)。 |
131 | 3-[(4-氯-3-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-[(3S)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.18 (dd, J = 8.2, 2.8 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.04 - 6.97 (m, 1H), 6.81 (dt, J = 26.1, 5.9 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.23 (dd, J = 12.3, 5.8 Hz, 2H), 3.88 (ddd, J = 16.4, 14.3, 8.2 Hz, 2H), 3.79 - 3.65 (m, 3H), 3.45 - 3.29 (m, 2H), 3.07 - 2.83 (m, 1H), 2.49 - 2.36 (m, 2H), 2.25 (s, 3H), 2.17 - 1.91 (m, 3H), 1.90 - 1.68 (m, 2H), 1.51 - 1.28 (m, 1H), 0.92 - 0.78 (m, 2H), 0.74 - 0.54 (m, 2H)。 |
以下實例係根據一般程序A使用市售構建組元來合成:
實例 | 結構及名稱 | 數據 |
132 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 404 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.30 (dd, J = 4.5, 1.1 Hz, 1H), 7.25 (dd, J = 9.2, 4.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 9.8 Hz, 1H), 6.81 (dd, J = 9.2, 1.2 Hz, 1H), 4.48 (dd, J = 9.2, 7.9 Hz, 1H), 4.28 (s, 2H), 3.65 (dd, J = 15.3, 6.8 Hz, 2H), 3.50 (dd, J = 10.2, 8.1 Hz, 1H), 3.34 (dd, J = 17.7, 9.0 Hz, 1H), 2.50 - 2.39 (m, 2H), 2.23 - 2.14 (m, 4H), 0.85 (ddd, J = 6.9, 4.8, 2.8 Hz, 2H), 0.66 (qd, J = 6.4, 3.1 Hz, 2H)。(m, 1H), 2.49 - 2.36 (m, 2H), 2.25 (s, 3H), 2.17 - 1.91 (m, 3H), 1.90 - 1.68 (m, 2H), 1.51 - 1.28 (m, 1H), 0.92 - 0.78 (m, 2H), 0.74 - 0.54 (m, 2H)。 |
133 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-甲基-3-{[1-(嗒嗪-3-基)吡咯啶-2-基]甲基}尿素 | LC-MS: m/z 392 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 4.4 Hz, 1H), 7.35 (dd, J = 9.2, 4.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 4.45 (s, 2H), 4.36 (s, 1H), 3.68 (d, J = 14.5 Hz, 1H), 3.57 (t, J = 8.7 Hz, 1H), 3.31 (s, 1H), 3.18 (d, J = 7.3 Hz, 1H), 3.02 (s, 3H), 2.29 (d, J = 15.1 Hz, 3H), 2.12 (ddd, J = 26.3, 13.1, 5.9 Hz, 4H)。 |
134 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-甲基-3-{[(2S)-1-(嗒嗪-3-基)吡咯啶-2-基]甲基}尿素 | LC-MS: m/z 392 (M+H)。 1HNMR(400MHz,MeOD) δ 8.42 (d,J=4.3Hz,1H), 7.35 (dd,J=9.2,4.4Hz,1H), 7.28(d,J=8.0Hz,1H), 7.09 (d,J=9.7Hz,1H), 7.02 (d,J=9.1Hz,1H), 4.45 (s,2H), 4.36(s,1H), 3.68 (d, J = 14.1 Hz, 1H), 3.57 (t, J = 8.7 Hz, 1H), 3.31 (s, 4H), 3.17 (s, 1H), 3.02 (s, 3H), 2.27 (s, 3H), 2.12 (ddd, J = 26.1, 13.1, 5.8 Hz, 4H)。 |
135 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-乙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 392 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.11 (d, J = 9.8 Hz, 1H), 4.44 - 4.30 (m, 4H), 4.05 - 3.95 (m, 1H), 3.36 (ddd, J = 14.3, 7.2, 3.5 Hz, 2H), 3.09 - 3.01 (m, 1H), 2.92 (td, J = 13.1, 2.4 Hz, 1H), 2.30 (s, 3H), 1.98 - 1.83 (m, 3H), 1.74 - 1.58 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H)。 |
136 | 1-[(4-氯-3-甲基苯基)甲基]-3-環丙基-3-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 386 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.40 (dd, J = 4.4, 1.1 Hz, 1H), 7.36 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 6.97 (t, J = 6.0 Hz, 1H), 6.92 (d,J=9.3Hz,1H),4.65-4.52(m,1H), 4.33 (d,J=4.4Hz,2H), 3.75 (t,J=9.3Hz,2H), 3.61 (dd,J=10.1,8.1Hz,1H), 3.45 (dd,J=17.7,9.0Hz,1H), 2.55 (ddd,J=13.1,8.4,4.7Hz,2H), 2.34 (s, 3H), 2.31 - 2.24 (m, 1H), 0.98 - 0.91 (m, 2H), 0.81 - 0.71 (m, 2H)。 |
137 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-1-(2,2,2-三氟乙基)尿素 | LC-MS: m/z 442(M+H)。 1HNMR(400MHz,MeOD) δ8.50 (d,J=4.0Hz,1H), 7.40(dd,J=9.4,4.4Hz,1H), 7.30(dd,J=9.4,1.1Hz,1H), 7.25(d,J=8.3Hz,2H), 7.14(dd,J=8.2, 1.8Hz,1H), 4.50(d,J=13.0Hz,1H), 4.42(d,J=4.6Hz,2H), 4.38-4.29 (m,1H), 4.20 (d,J=13.7Hz,1H), 3.97(dd,J=16.4,8.7Hz,1H), 3.80 (td,J=11.3, 5.6 Hz, 1H), 3.11 - 3.01 (m, 2H), 2.01 - 1.87 (m, 3H), 1.70 - 1.59 (m, 1H)。 |
138 | 3-[(4-氯-3-甲基苯基)甲基]-1-丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 402 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.51 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.26 - 7.21 (m, 2H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 6.98(d,J=5.6Hz,1H),4.31-4.18(m,4H),3.87(d,J=11.6Hz, 1H), 3.11 (dd, J = 12.7, 6.8 Hz, 2H), 2.97 (t, J = 11.8 Hz, 1H), 2.84 (t, J = 12.2 Hz, 1H), 2.30 (s, 3H), 1.79 (t, J = 15.2 Hz, 3H), 1.50 (dd, J = 14.6, 7.0 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H)。 |
139 | 1-[(4-氯-3-甲基苯基)甲基]-3-乙基-3-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 374.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 4.4 Hz, 1H), 8.21 (s, 1H), 7.40 (dd, J = 9.2, 4.4 Hz, 1H), 7.27 (d,J=8.4Hz,1H),7.21(s,1H), 7.10 (d, J=8.0Hz,1H), 6.98 (dd,J=9.2,1.2Hz,1H), 4.87-4.80(m, 1H), 4.32 (s, 2H), 3.78 - 3.71 (m, 2H), 3.50 - 3.39 (m, 2H), 3.37 - 3.33 (m, 2H), 2.34 (s, 3H), 2.26 (dd, J = 8.4, 6.0 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H)。 |
140 | 3-[(4-氯-3-甲基苯基)甲基]-1-(環丁基甲基)-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 428.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (d, J = 3.5 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 - 7.22 (m, 3H), 7.14 - 7.08 (m, 1H), 4.44 - 4.22 (m, 4H), 3.75 (ddd, J = 15.2, 7.7, 3.9 Hz, 1H), 3.42 (dd, J = 15.1, 7.6 Hz, 1H), 3.26 (dd, J = 15.2, 6.8 Hz, 1H), 3.14 - 3.05 (m, 1H), 2.97 (td, J = 13.2, 2.5 Hz, 1H), 2.59 (dt, J = 15.0, 7.5 Hz, 1H), 2.33 (s, 3H), 2.11 - 1.74 (m, 9H), 1.70 - 1.56 (m, 1H)。 |
141 | 3-[2-(4-氯-3-甲基苯基)乙基]-1-乙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 428.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.39 (dd, J = 9.6, 4.4 Hz, 1H), 7.27 (dd,J=9.6,1.2Hz,1H), 7.20 (d,J=8.0Hz,1H), 7.13(d,J=1.6Hz,1H), 7.01 (dd,J =8.0,2.0Hz,1H), 4.34-4.23(m,2H), 3.87(d,J=4.8Hz,1H), 3.42 (t,J=7.2Hz,2H), 3.37 - 3.32 (m, 1H), 3.25 (dd, J = 15.2, 7.2 Hz, 1H), 3.03 - 2.88 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.29 (s, 3H), 1.94 - 1.83 (m, 3H), 1.71 - 1.52 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H)。 |
142 | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(6-苯基嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 450.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.93 - 7.88 (m, 2H), 7.83 (d, J = 9.6 Hz, 1H), 7.50 - 7.40 (m, 3H), 7.35 (d, J = 9.6 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.12 (dd, J = 8.2, 1.8 Hz, 1H), 4.45 - 4.32 (m, 4H), 4.14 (dt, J = 13.7, 7.0 Hz, 1H), 3.10 (dd, J = 12.4, 11.4 Hz, 1H), 2.97 (dd, J = 12.9, 2.3 Hz, 1H), 2.91 (s, 3H), 2.33 (s, 3H), 1.92 (dd, J = 15.3, 5.2 Hz, 3H), 1.71 (d, J = 12.4 Hz, 1H)。 |
143 | 3-[(4-氯-3-甲基苯基)甲基]-1-(氧雜環丁-3-基)-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 416 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.6, 4.4 Hz, 1H), 7.30 - 7.16 (m, 3H), 7.12 - 7.05 (m, 1H), 4.98 (t, J = 5.6 Hz, 1H), 4.84 - 4.73 (m, 3H), 4.56 - 4.48 (m, 1H), 4.32 (s, 2H), 4.27 (s, 1H), 4.20 (d, J = 13.2 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.30 - 3.21 (m, 1H), 3.00 (td, J = 13.2, 2.8 Hz, 1H), 2.32 (s, 3H), 2.08 - 1.78 (m, 3H), 1.62 (dt, J = 13.2, 4.0 Hz, 1H)。 |
144 | 3-[(1R,2S)-2-(4-氟苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 414.4 (M+H)。 |
145 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 360.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.5, 1.2 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.97 (dd, J = 9.2, 1.2 Hz, 1H), 5.04 (p, J = 7.8 Hz, 1H), 4.32 (s, 2H), 3.80 - 3.64 (m, 2H), 3.46 (ddd, J = 18.1, 13.5, 7.9 Hz, 2H), 2.89 (s, 3H), 2.36 (d, J = 9.7 Hz, 3H), 2.27 - 2.14 (m, 2H)。 |
一般中間體合成,方法 B-G 方法B:K
2CO
3/CsF/DMSO,於90℃下16 hr
方法C:Pd(OAc)
2/DavePhos/t-BuONa/甲苯,於100℃下16 hr
方法D:Pd(OAc)
2/RuPhos/LiHMDS/THF,於70℃下2~8 hr
方法E:XPhos-Pd-G1/XPhos/LiHMDS/THF,於70℃下2~8 hr
方法F:RuPhos-Pd-G2/RuPhos/LiHMDS/THF,於70℃下2~16 hr
方法G:Cul/L-脯胺酸/K
2CO
3/DMSO
一般程序 B : 向化合物
B1(1.0 eq)及芳基鹵化物(1.1 eq)於DMSO (0.1 mol/L)中之混合物中添加K
2CO
3(3.0 eq)及CsF (0.2 eq)。將所得混合物於90℃下攪拌16 hr。然後用H
2O稀釋混合物且用EtOAc萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾,且濃縮至乾燥。藉由矽膠上管柱層析純化殘餘物,以產生化合物
B2 。
一般程序 B 之實例合成: 向化合物
B3(100 mg, 0.47 mmol)及化合物
2(101 mg, 0.47 mmol)於DMSO (8 mL)中之混合物中添加K
2CO
3(194 mg, 1.40 mmol)及CsF (15 mg, 0.09 mmol)。將所得混合物於90℃下攪拌16 hr。然後用H
2O (30 mL)稀釋混合物且用EtOAc (20 mL * 2)萃取。將合併之有機層用鹽水洗滌,經無水Na
2SO
4乾燥且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc= 10: 1至2: 1溶析)純化殘餘物,以產生黃色固體狀化合物
B4(140 mg, 87.5 %產率)。LC/MS (ESI) m/z: 349 (M+H)
+。
一般程序 C : 在N
2氣氛下向化合物
C1(1.2 eq.)及芳基鹵化物(1.0 eq.)於甲苯中之混合物中添加t-BuONa (2.0 eq.)、DavePhos(0.1 eq.)及Pd(OAc)
2(0.1 eq.)。將所得混合物於100℃下在N
2氣氛下攪拌16 hr。然後將混合物用EtOAc稀釋,過濾且濃縮至乾燥。藉由矽膠上管柱層析純化殘餘物以產生化合物
C2。
一般程序 C 之實例合成: 在N
2氣氛下向
C3(0.58 g, 2.72mmol)及
C4(0.3 g, 2.09 mmol)於甲苯(15 mL)中之混合物中添加t-BuONa (410 mg, 4.18 mmol)、DavePhos (83 mg, 0.21 mmol)及Pd(OAc)
2(47 mg, 0.21 mmol)。將所得混合物在120℃下在N
2氣氛下攪拌16 hr。然後將混合物用EtOAc (30 mL)稀釋,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc = 50: 1至20: 1溶析)純化殘餘物,以產生無色油狀化合物
C5(0.58 g, 87%產率)。LC/MS (ESI) m/z: 322 (M+H)
+。
一般程序 D : 在N
2氣氛下向胺
D1(1.1 eq.)及芳基鹵化物(1.0 eq.)於THF中之混合物中添加LiHMDS於THF中之溶液(5.0 eq., 1 M)、RuPhos (0.1 eq.)及Pd(OAc)
2(0.1 eq.)。將所得混合物於80℃下在N
2氣氛下攪拌4hr。然後將混合物用NH
4Cl水溶液淬滅且用EtOAc萃取兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由矽膠上管柱層析純化殘餘物,以產生化合物
D2。
一般程序 D 之實例合成: 在N
2氣氛下向
D2(153 mg, 0.72 mmol)及
D3(100 mg, 0.65 mmol)於THF (12 mL)中之混合物中添加LiHMDS (3.3 mL, 1 M,於THF中)、RuPhos (31 mg, 0.07 mmol)及Pd(OAc)
2(15 mg, 0.07 mmol)。將所得混合物於80℃下在N
2氣氛下攪拌4hr。然後將混合物用 NH
4Cl水溶液(30 mL)淬滅且用EtOAc (20 mL)萃取兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc= 50: 1至5: 1溶析)純化殘餘物,以產生淺黃色固體狀
D4(115 mg, 53%產率)。LC/MS (ESI) m/z: 332 (M+H)
+。
一般程序 E 之實例: 向
E1(100 mg,0.65mmol)及
E2(182 mg, 0.85 mmol)於THF (18mL)中之混合物中添加XPhos-Pd-G1 (25 mg, 0.03mmol)、XPhos (33 mg, 0.07 mmol)及LiHMDS (2.6 mL, 1 M,於THF中)。將所得混合物於80℃下在N
2氣氛下攪拌16hr。然後將混合物用 NH
4Cl水溶液(40 mL)萃取且用EtOAc (25 mL)萃取兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc = 20:1至3: 1溶析)純化殘餘物,以產生淺黃色油狀
E3(130 mg, 60%產率)。LC/MS (ESI) m/z: 332 (M+H)
+。
一般程序 F 之實例: 向
F1(200mg, 1.311mmol)及
F2(280 mg, 1.311mmol)於THF (20mL)中之混合物中添加RuPhos (61mg, 0.131 mmol)及RuPhos-Pd-G2 (101 mg, 0.131mmol)。於0℃下攪拌10 min後,逐滴添加LiHMDS (3.14 mL,1M,於THF中)且將所得混合物於70℃下在N
2氣氛下再攪拌3 hr。冷卻後,將混合物用 NH
4Cl水溶液(30 mL)淬滅且用EtOAc (20 mL)萃取兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由矽膠上管柱層析(用PE:EtOAc=50:1至2: 1溶析)純化殘餘物,以產生黃色油狀
F3(160 mg, 37%產率)。LC/MS (ESI) m/z: 331(M+H)
+。
一般程序 G 之實例: 向
G2(200 mg, 1.235mmol)及
G1(265 mg, 1.235 mmol)於DMSO (10 mL)中之溶液中添加CuI (47 mg, 0.247mmol)、L-脯胺酸(28 mg, 0.247 mmol)及K
2CO
3(512 mg, 3.704 mmol)且將所得混合物於100℃下在N
2氣氛下攪拌16hr。冷卻後,將混合物用 NH
4Cl水溶液(30 mL)萃取且用EtOAc (20 mL)萃取兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由矽膠上管柱層析(用DCM: MeOH = 100: 1至20:1溶析)純化殘餘物,以產生黃色油狀
G3(160 mg, 44%產率)。LC/MS (ESI) m/z: 296 (M+H)
+。
下表中之實例係自先前所述之適當起始材料或市售起始材料使用上述類似方法來製備。
實例 | 方法 | 結構及名稱 | 數據 |
146 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(6-甲基嗒嗪-3-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 416 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.38 (d, J = 0.8 Hz, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.32 (s, 2H), 4.31 - 4.18 (m, 2H), 4.11 (dt, J = 11.2, 7.7 Hz, 1H), 3.07 - 2.99 (m, 1H), 2.94 - 2.85 (m, 4H), 2.49 (s, 3H), 2.33 (s, 3H), 1.92 - 1.83 (m, 3H), 1.74 - 1.61 (m, 1H)。 |
147 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(6-氰基吡啶-2-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 398 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.59 (dd, J = 8.9, 7.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.12 - 7.05 (m, 2H), 7.01 (d, J = 7.0 Hz, 1H), 4.37 - 4.24 (m, 4H), 4.11 - 4.01 (m, 1H), 2.96 (dd, J = 12.5, 11.3 Hz, 1H), 2.89 (s, 3H), 2.81 (td, J = 13.0, 2.4 Hz, 1H), 2.33 (d, J = 5.1 Hz, 3H), 1.89 - 1.81 (m, 3H), 1.69 - 1.57 (m, 1H)。 |
148 | C | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(酞嗪-1-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 424 (M+H)。 1H NMR (400 MHz, MeOD) δ 9.15 (s, 1H), 8.19 (dd, J = 6.0, 3.5 Hz, 1H), 8.05 (dd, J = 6.1, 3.1 Hz, 1H), 7.96 - 7.90 (m, 2H), 7.26 - 7.21 (m, 2H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.53 (s, 1H), 4.35 (s, 2H), 3.89 (dd, J = 27.3, 12.2 Hz, 2H), 3.12 (t, J = 11.6 Hz, 1H), 3.03 (s, 1H), 2.91 (s, 3H), 2.30 (s, 3H), 1.97 (dd, J = 6.4, 3.5 Hz, 3H), 1.92 - 1.84 (m, 1H)。 |
149 | C | (R)-3-(4-氯-3-甲基苄基)-1-(1-(6-甲氧基嘧啶-4-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 404 (M+H)。 |
150 | C | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(5-甲基吡啶-2-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 387 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.18 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.12 (dd, J = 8.2, 1.8 Hz,1H),6.93(t,J=5.7Hz,1H),6.75(d,J=8.7Hz,1H),4.27- 4.16 (m, 2H), 4.15 - 4.05 (m, 2H), 3.93 (d, J = 5.1 Hz, 1H), 2.76 (d, J = 10.3 Hz, 4H), 2.70 - 2.62 (m, 1H), 2.31 (s, 3H), 2.11 (s, 3H), 1.75 - 1.65 (m, 3H), 1.51 (dd, J = 14.0, 9.7 Hz, 1H)。 |
151 | C | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(5-甲基嗒嗪-3-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 388 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.34 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.13 - 7.08 (m, 2H), 4.38 - 4.24 (m, 4H), 4.08 (dd, J = 9.9, 5.4 Hz, 1H), 3.05 - 2.97 (m, 1H), 2.89 (s, 3H), 2.88 - 2.82 (m, 1H), 2.33 (s, 3H), 2.27 (s, 3H), 1.92 - 1.82 (m, 3H), 1.74 - 1.60 (m, 1H)。 |
152 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(嘧啶-4-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 374 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (s, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd,J=8.2,1.7Hz,1H), 6.90(d,J=6.3Hz,1H),4.48(d,J=20.4Hz,2H) ,4.36-4.27(m, 2H), 4.13 - 4.02 (m, 1H), 3.10 (t, J = 12.0 Hz, 1H), 2.94 (dd, J = 9.8, 6.3 Hz, 1H), 2.90 (s, 3H), 2.34 (s, 3H), 1.98 - 1.82 (m, 3H), 1.61 (dt, J = 12.5, 3.5 Hz, 1H)。 |
153 | E | (R)-1-(1-(1H-咪唑并[4,5-b]吡啶-5-基)六氫吡啶-3-基)-3-(4-氯-3-甲基苄基)-1-甲基尿素 | LC-MS: m/z 413 (M+H)。 |
154 | C | (R)-3-(4-氯-3-甲基苄基)-1-(1-(2-甲氧基嘧啶-4-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.90 (d, J = 6.3 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.09 (dd,J=8.0,1.8Hz,1H), 6.42 (d,J=6.3Hz,1H), 4.40(s,1H), 4.31(d,J= 4.7 Hz, 2H), 4.11 - 4.03 (m, 1H), 3.85 (s, 3H), 3.03 (t, J = 11.9 Hz, 1H), 2.87 (d, J = 11.8 Hz, 4H), 2.34 (s, 3H), 1.99 - 1.80 (m, 4H), 1.65 - 1.54 (m, 1H)。 |
155 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(5-(三氟甲基)嗒嗪-3-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 442 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.70 (d, J = 1.3 Hz, 1H), 7.53 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.11 (dd, J = 8.2, 1.6 Hz, 1H), 4.48 (d, J = 12.7 Hz, 1H), 4.39 (dd, J = 12.6, 3.7 Hz, 1H), 4.32 (s, 2H), 4.17 - 4.07 (m, 1H), 3.15 - 3.07 (m, 1H), 3.00 - 2.93 (m, 1H), 2.91 (d, J = 6.2 Hz, 3H), 2.34 (s, 3H), 1.91 (ddd, J = 12.7, 10.2, 5.5 Hz, 3H), 1.75 - 1.61 (m, 1H)。 |
156 | C | (R)-3-(3-氯-2-甲基苄基)-1-(1-(6-甲氧基吡啶甲醯基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 431.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.79 - 7.67 (m, 1H), 7.25 (dd, J = 13.3, 8.3 Hz, 1H), 7.13 (dd, J = 13.9, 6.7 Hz, 2H), 7.04 - 6.79 (m, 2H), 4.65 - 4.51 (m, 1H), 4.36 - 4.11 (m, 3H), 3.94 - 3.77 (m, 4H), 3.20 (t, J = 12.0 Hz, 1H), 3.03 - 2.88 (m, 3H), 2.81 - 2.66 (m, 2H), 2.33 (d, J = 10.4 Hz, 3H), 1.96 - 1.67 (m, 4H)。 |
157 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(嘧啶-2-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 374.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.24 (d, J = 4.8 Hz, 2H), 7.31 - 7.20 (m, 2H),7.11(d,J=8.1Hz,1H),6.91(d,J=5.5Hz,1H),6.54(t,J=4.8Hz, 1H), 4.71 - 4.59 (m, 2H), 4.34 - 4.26 (m, 2H), 3.97 (dd, J = 10.1, 5.2 Hz, 1H), 2.97 (t, J = 11.9 Hz, 1H), 2.89 (s, 3H), 2.85 - 2.76 (m, 1H), 2.34 (s, 3H), 1.91 - 1.79 (m, 3H), 1.66 - 1.53 (m, 1H)。 |
158 | B | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(吡嗪-2-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 374.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.20 (d, J = 1.2 Hz, 1H), 7.99 (dd,J=2.4,1.5Hz,1H), 7.71(d,J=2.7Hz,1H), 7.27(d,J= 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.1, 1.6 Hz, 1H), 4.36 - 4.26 (m, 4H), 4.07 (dd, J = 9.6, 5.5 Hz, 1H), 3.01 - 2.94 (m, 1H), 2.89 (s, 3H), 2.87 - 2.79 (m, 1H), 2.34 (s, 3H), 1.90 - 1.81 (m, 3H), 1.71 - 1.59 (m, 1H)。 |
159 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(6-氰基嗒嗪-3-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 374.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 7.84 (d, J = 9.7 Hz, 1H), 7.34 (dd, J = 9.0, 4.9 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 6.97 (t, J = 5.8 Hz, 1H), 4.44 (dd, J = 31.8, 11.2 Hz, 2H), 4.20 (qd, J = 15.5, 5.8 Hz, 2H), 4.04 - 3.94 (m, 1H), 3.11 (t, J = 12.0 Hz, 1H), 2.99 - 2.89 (m, 1H), 2.80 (s, 3H), 2.31 (s, 3H), 1.87 - 1.65 (m, 3H), 1.58 - 1.45 (m, 1H)。 |
160 | B | (R)-6-(3-(3-(4-氯-3-甲基苄基)-1-甲基脲基)六氫吡啶-1-基)嗒嗪-4-甲酸 | LC-MS: m/z 418.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.84 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.4 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.11 (dd, J = 8.1, 1.8 Hz, 1H), 4.44 - 4.33 (m, 2H), 4.32 (s, 2H), 4.13 (dd, J = 10.2, 5.9 Hz, 1H), 3.16 - 3.09 (m, 1H), 3.02 - 2.94 (m, 1H), 2.90 (s, 3H), 2.34 (s, 3H), 1.97 - 1.87 (m, 3H), 1.72 (dd, J = 14.0, 9.8 Hz, 1H)。 |
161 | C | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(4-甲基嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 388.4 (M+H)。 |
162 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(5-甲基-1,3,4-噻二唑-2-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 394.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.30 (d, J = 2.8 Hz, 2H), 4.20 (ddd, J = 11.2, 10.3, 4.8 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.20 (t, J = 11.8 Hz, 1H), 3.09 - 3.01 (m, 1H), 2.86 (s, 3H), 2.54 (s, 3H), 2.34 (s, 3H), 1.90 - 1.80 (m, 3H), 1.79 - 1.70 (m, 1H)。 |
163 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(5-氰基-1,3,4-噻二唑-2-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 405.1 (M+H)。 1HNMR(400MHz,MeOD) δ 7.27 (d,J=8.2Hz,1H), 7.21 (s,1H), 7.10 (dd,J=8.2,1.7Hz,1H), 4.31 (d,J=4.1Hz,2H), 4.22 (d,J=7.3Hz,1H), 4.00(d,J= 11.3 Hz, 1H), 3.91 (dd, J = 12.4, 4.3 Hz, 1H), 3.43 - 3.35 (m, 1H), 3.23 (td, J = 12.7, 2.9 Hz, 1H), 2.88 (s, 3H), 2.35 (s, 3H), 1.97 - 1.74 (m, 4H)。 |
164 | B | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-[5-(三氟甲基)-1,3,4-噻二唑-2-基]六氫吡啶-3-基]尿素 | LC-MS: m/z 448.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.9 Hz, 1H), 4.31 (d, J = 5.0 Hz, 2H), 4.26 - 4.19 (m, 1H), 3.96 (d, J = 12.8 Hz, 1H), 3.88 (dd, J = 12.4, 4.5 Hz, 1H), 3.36 (d, J = 11.9 Hz, 1H), 3.19 (td, J = 12.7, 2.7 Hz, 1H), 2.88 (s, 3H), 2.33 (d, J = 6.3 Hz, 3H), 1.95 - 1.84 (m, 3H), 1.82 - 1.72 (m, 1H)。 |
165 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(5-環丙基-1,3,4-噻二唑-2-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.36 - 4.26 (m, 2H), 4.18 (td, J = 10.8, 5.5 Hz, 1H), 3.83 - 3.70 (m, 2H), 3.19 (t, J = 11.8 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.86 (s, 3H), 2.34 (s, 3H), 2.20 (tt, J = 8.3, 5.0 Hz, 1H), 1.90 - 1.72 (m, 4H), 1.14 - 1.08 (m, 2H), 0.95 - 0.89 (m, 2H)。 |
166 | B | (R)-5-(3-(3-(4-氯-3-甲基苄基)-1-甲基脲基)六氫吡啶-1-基)-1,3,4-噻二唑-2-甲醯胺 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.30 - 7.24 (m, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.2, 1.7 Hz, 1H), 4.29 (d, J = 6.6 Hz, 2H), 4.22 (dd, J = 7.7, 3.5 Hz, 1H), 3.92 (d, J = 12.5 Hz, 2H), 3.35 - 3.31 (m, 1H), 3.16 (td, J = 12.8, 2.8 Hz, 1H), 2.87 (s, 3H), 2.34 (s, 3H), 1.95 - 1.82 (m, 3H), 1.81 - 1.72 (m, 1H)。 |
167 | E | (R)-3-(4-氯-3-甲基苄基)-1-(1-(5-甲氧基嗒嗪-3-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 404 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.20 (s, 1H), 7.30 - 7.19 (m, 2H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.69 (d, J=2.3Hz,1H), 4.34(d,J=18.1Hz,3H), 4.23 (dd,J=12.7,3.5Hz,1H), 4.10 (dt,J=10.3,7.4Hz,1H), 3.89 (s, 3H), 3.04 (dd, J = 12.4, 11.4 Hz, 1H), 2.96 - 2.85 (m, 4H), 2.33 (s, 3H), 1.94 - 1.82 (m, 3H), 1.77 - 1.59 (m, 1H)。 |
168 | C | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(6-(甲基胺基)嗒嗪-3-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 403.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.50 (s, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 6.97 (d, J = 9.8 Hz, 1H), 4.32 (s, 2H), 4.22 - 4.13 (m, 1H), 4.05 - 3.90 (m, 2H), 2.95 - 2.88 (m, 4H), 2.87 (s, 3H), 2.83 - 2.75 (m, 1H), 2.33 (s, 3H), 1.90 - 1.77 (m, 3H), 1.77 - 1.62 (m, 1H)。 |
169 | F | (R)-1-(1-(7H-吡咯并[2,3-c]嗒嗪-3-基)六氫吡啶-3-基)-3-(4-氯-3-甲基苄基)-1-甲基尿素 | LC-MS: m/z 413.2 (M+H)。 |
170 | E | (R)-1-(1-(6-(1H-咪唑-1-基)嗒嗪-3-基)六氫吡啶-3-基)-3-(4-氯-3-甲基苄基)-1-甲基尿素 | LC-MS: m/z 440.1 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.43 (s, 1H), 7.92 - 7.87 (m, 2H), 7.56 (d,J=9.8Hz,1H),7.34(d,J=8.2Hz,1H),7.23(s,1H),7.14-7.09 (m, 2H), 6.96 (t, J = 5.8 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.28 - 4.17 (m, 3H), 4.00 (d, J = 11.0 Hz, 1H), 3.06 - 2.99 (m, 1H), 2.86 (t, J = 11.9 Hz, 1H), 2.81 (s, 3H), 2.31 (s, 3H), 1.84 - 1.69 (m, 3H), 1.56 (d, J = 12.8 Hz, 1H)。 |
171 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(5-氰基吡嗪-2-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 399.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.31 (d, J = 12.6 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.49 (dd, J = 27.4, 12.4 Hz, 2H), 4.36 - 4.26 (m, 2H), 4.07 (td, J = 11.2, 5.6 Hz, 1H), 3.13 - 3.06 (m, 1H), 2.98 - 2.88 (m, 4H), 2.35 (s, 3H), 1.94 - 1.85 (m, 3H), 1.63 (dt, J = 22.3, 8.6 Hz, 1H)。 |
172 | B | (R)-3-(4-氯-3-甲基苄基)-1-(1-(4-氰基嗒嗪-3-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 399.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.77 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.23 (dd, J = 12.7, 4.8 Hz, 2H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 4.39 (dd, J = 13.4, 2.2 Hz, 1H), 4.35 - 4.28 (m, 3H), 4.25 - 4.13 (m,1H),3.24 (dd,J=12.4,11.3Hz,1H), 3.14-3.05(m,1H), 2.90(d,J=4.9Hz,3H),2.31(d,J=7.9 Hz, 3H), 1.97 - 1.77 (m, 4H)。 |
173 | D | (R)-1-(1-(5-胺基嗒嗪-3-基)六氫吡啶-3-基)-3-(4-氯-3-甲基苄基)-1-甲基尿素 | LC-MS: m/z 389.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.49 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.1, 1.9 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.32 (s, 2H), 4.18 - 4.09 (m, 1H), 4.05 (d,J=13.3Hz,1H), 3.94 (d,J=12.7Hz,1H), 3.12- 3.05 (m, 1H), 2.96 (dd, J = 18.7, 7.8 Hz, 1H), 2.89 (s, 3H), 2.34 (s, 3H), 1.88 (dd, J = 10.1, 4.8 Hz, 3H), 1.74 - 1.62 (m, 1H)。 |
174 | E | (R)-3-(4-氯-3-甲基苄基)-1-(1-(4-甲氧基嘧啶-2-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.92 (d, J = 5.7 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.12 - 7.07 (m, 1H), 5.99 (d, J = 5.7 Hz, 1H), 4.71 - 4.54 (m, 2H), 4.37 - 4.24 (m, 2H), 4.06 - 3.95 (m, 1H), 3.83 (s, 3H), 2.97 (t, J = 11.8 Hz, 1H), 2.88 (s, 3H), 2.81 (dd, J = 19.3, 7.8 Hz, 1H), 2.31 (d, J = 14.5 Hz, 3H), 1.91 - 1.77 (m, 3H), 1.67 - 1.52 (m, 1H)。 |
175 | B | (R)-1-(1-(1,3,4-噻二唑-2-基)六氫吡啶-3-基)-3-(4-氯-3-甲基苄基)-1-甲基尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.79 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.11 (dd, J = 8.1, 1.9 Hz, 1H), 6.97 (t, J = 5.8 Hz, 1H), 4.23 - 4.17 (m, 2H), 4.15 - 4.08 (m, 1H), 3.79 (d, J = 12.0 Hz, 1H), 3.69 (dd, J = 12.0, 4.4 Hz, 1H), 3.18 (d, J = 11.7 Hz, 1H), 3.04 (dt, J = 12.6, 6.2 Hz, 1H), 2.77 (s, 3H), 2.31 (s, 3H), 1.81 - 1.62 (m, 4H)。 |
176 | G | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(1-甲基-1H-1,2,3-三唑-4-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 377.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.31 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 1.4 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 4.31 (s, 2H), 4.25 (dt, J = 8.9, 3.9 Hz, 1H), 3.98 (s, 3H), 3.62 (d, J = 11.1 Hz, 1H), 3.53 (dd, J = 11.4, 4.2 Hz, 1H), 2.86 (s, 3H), 2.77 (t, J = 11.3 Hz, 1H), 2.63 (td, J = 11.8, 2.9 Hz, 1H), 2.34 (s, 3H), 1.87 - 1.67 (m, 4H)。 |
177 | C | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(5-甲氧基嘧啶-2-基)六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.98 (s, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 4.60 - 4.51 (m, 1H), 4.46 (dd, J = 12.5, 4.1 Hz, 1H), 4.38 - 4.28 (m, 2H), 3.98 - 3.87 (m, 1H), 3.76 (s, 3H), 2.94 (dd, J = 12.4, 11.4 Hz, 1H), 2.88 (s, 3H), 2.79 (td, J = 12.9, 2.5 Hz, 1H), 2.34 (s, 3H), 1.83 (ddd, J = 16.9, 11.3, 3.2 Hz, 3H), 1.64 - 1.53 (m, 1H)。 |
178 | D | (R)-3-(4-氯-3-甲基苄基)-1-(1-(3-羥基嗒嗪-4-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 390.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.67 (d, J = 5.0 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 6.59 (d, J = 5.0 Hz, 1H), 4.28 (d, J = 18.3 Hz, 3H), 4.11 (dd, J = 50.5, 11.3 Hz, 2H), 2.95 - 2.88 (m, 1H), 2.87 (s, 3H), 2.72 (t, J = 11.2 Hz, 1H), 2.34 (s, 3H), 1.90 - 1.71 (m, 4H)。 |
179 | B | (R)-2-(3-(3-(4-氯-3-甲基苄基)-1-甲基脲基)六氫吡啶-1-基)噁唑-4-甲酸乙酯 | LC-MS: m/z 435.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.98 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.32 - 4.28 (m, 4H), 4.13 (s, 1H), 3.98 (d, J = 12.6 Hz, 2H), 3.09 (t, J = 11.8 Hz, 1H), 2.93 (d, J = 2.8 Hz, 1H), 2.86 (s, 3H), 2.34 (s, 3H), 1.89 - 1.70 (m, 4H), 1.32 (t, J = 7.1 Hz, 3H)。 |
180 | C | 1-[(3R)-1-(6-胺基嗒嗪-3-基)六氫吡啶-3-基]-3-[(4-氯-3-甲基苯基)甲基]-1-甲基尿素 | LC-MS: m/z 389.2 (M+H)。 |
181 | C | (R)-3-(4-氯-3-甲基苄基)-1-(1-(6-甲氧基嗒嗪-3-基)六氫吡啶-3-基)-1-甲基尿素 | LC-MS: m/z 4031 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.36 (d, J = 9.7 Hz, 1H), 7.29 - 7.21 (m, 2H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 6.98 (d, J = 9.7 Hz, 1H), 4.33 (s, 2H), 4.17 - 4.03 (m, 3H), 3.94 (s, 3H), 2.97 (t, J = 11.6 Hz, 1H), 2.88 (s, 3H), 2.88 - 2.80 (m, 1H), 2.33 (s, 3H), 1.90 - 1.76 (m, 3H), 1.75 - 1.60 (m, 1H)。 |
182 | C | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(5-甲基吡嗪-2-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 388.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.10 (d, J = 1.5 Hz, 1H), 7.80 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.23 (s, 1H), 7.11 (dd, J = 8.1, 1.7 Hz, 1H), 4.32 (s, 2H), 4.27 - 4.17 (m, 2H), 4.07 (dd, J = 11.8, 7.4 Hz, 1H), 2.98 - 2.90 (m, 1H), 2.89 (s, 3H), 2.84 (td, J = 13.2, 2.4 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.85 (t, J = 9.8 Hz, 3H), 1.74 - 1.57 (m, 1H)。 |
183 | B | (R)-3-(4-氯-3-甲基苄基)-1-甲基-1-(1-(吡啶-2-基)六氫吡啶-3-基)尿素 | LC-MS: m/z 388.4 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.93 (dd, J = 5.1, 1.1 Hz, 1H), 7.52 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H), 7.31 - 7.16 (m, 2H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.61 (dd, J = 6.7, 5.4 Hz, 1H), 4.34 (d,J=1.9Hz,2H), 4.23-4.12(m,2H), 4.05(d,J=10.7Hz,1H), 2.97-2.75(m,5H), 2.33 (d,J=10.8 Hz, 3H), 1.85 (td, J = 12.6, 5.9 Hz, 3H), 1.65 (dd, J = 12.3, 3.4 Hz, 1H)。 |
一般程序 H : 作為一般程序,下文實例係根據以下一般方案來合成
向化合物
H1(1 eq.)於甲苯中之溶液中添加TEA (2 eq.)及DPPA (1.2 eq.)。將所得混合物於110℃下在N
2氣氛下攪拌2 hr。冷卻後,將所得混合物在減壓下濃縮至乾燥。粗製化合物未經進一步純化即直接用於下一步驟。於0℃下向化合物
H3(1 eq.)於DCM中之溶液中添加TEA (3eq.)及化合物
H2(1 eq.)。將所得混合物於室溫下在N
2氣氛下攪拌30 min。然後將混合物在減壓下濃縮至乾燥。經由矽膠上管柱層析(用DCM/MeOH溶析)純化粗產物,。以得到化合物
H4。
實例 184 : 3-((1S,2R)-2-(4- 氯 -3- 甲基苯基 ) 環丙基 )-1- 環丙基 -1-((R)-1-( 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ) 尿素之合成 向
M1(200 mg, 0.952 mmol)於甲苯(10 mL)中之溶液中添加TEA (192 mg, 1.904 mmol)及DPPA (314 mg, 1.142 mmol)。將所得混合物於110℃下在N
2氣氛下攪拌2 hr。冷卻後,在減壓下濃縮混合物,以產生粗製
M2(197 mg, 99.9%產率),而不經進一步純化。在0℃下向
M3(207 mg, 0.952 mmol)於無水DCM (10 mL)中之溶液中添加TEA (288 mg, 2.856 mmol)及
M2(197 mg, 0.952 mmol)。將所得混合物於室溫下在N
2氣氛下攪拌30 min。然後將混合物在減壓下濃縮至乾燥。經由矽膠上管柱層析(用DCM中之1% MeOH至DCM中之5% MeOH溶析)純化粗產物,以得到白色固體狀
實例 184(61.1 mg, 15.1 %產率)。LC-MS: m/z 426 (M+H)
+。1H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.2 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 8.2, 2.1 Hz, 1H), 6.69 (s, 1H), 4.43 - 4.31 (m, 2H), 3.80 - 3.69 (m, 1H), 2.91 - 2.81 (m, 1H), 2.78 - 2.71 (m, 1H), 2.51 - 2.45 (m, 1H), 2.32 (s, 3H), 2.30 - 2.20 (m, 1H), 2.03 - 1.94 (m, 2H), 1.90 - 1.83 (m, 1H), 1.66 - 1.57 (m, 1H), 1.24 - 1.14 (m, 2H), 0.95 - 0.89 (m, 2H), 0.79 - 0.72 (m, 2H)。
下表中之化合物係自上述或市售適當起始材料使用如
實例 184中詳述之上述一般程序B來製備。
實例 | 結構及名稱 | 數據 |
185 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.4 Hz, 1H), 7.08 (s, 1H), 6.93 (dd, J = 8.2, 2.1 Hz, 1H), 4.53 - 4.40 (m, 1H), 4.14 - 3.99 (m, 1H), 3.96 - 3.77 (m, 5H), 3.51 - 3.40 (m, 1H), 3.16 - 3.08 (m, 1H), 2.99 (dd, J = 18.7, 7.8 Hz, 1H), 2.80 (d, J = 3.9 Hz, 3H), 2.71 (ddd, J = 10.3, 8.9, 4.4 Hz, 1H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.27 - 2.21 (m, 1H), 2.11 (ddd, J = 20.5, 14.1, 6.7 Hz, 2H), 2.00 - 1.94 (m, 1H), 1.88 - 1.76 (m, 3H), 1.58 - 1.43 (m, 1H), 1.21 - 1.11 (m, 2H)。 |
186 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.0 Hz, 1H), 7.07 (s, 1H), 6.93 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 - 4.39 (m, 1H), 4.14 - 3.98 (m, 1H), 3.96 - 3.74 (m, 5H), 3.45 (t, J = 9.5 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.99 (dd, J = 18.8, 7.8 Hz, 1H), 2.80 (d, J = 4.3 Hz, 3H), 2.76 - 2.67 (m, 2H), 2.51 (dd, J = 13.0, 10.7 Hz, 1H), 2.31 (s, 3H), 2.22 (ddd, J = 12.6, 9.7, 6.1 Hz, 1H), 2.09 (tt, J = 13.9, 7.0 Hz, 2H), 1.95 (ddt, J = 9.2, 6.0, 2.9 Hz, 1H), 1.90 - 1.76 (m, 3H), 1.52 (dd, J = 22.8, 15.9 Hz, 1H), 1.22 - 1.10 (m, 2H)。 |
187 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.10 (dd, J = 8.2, 3.7 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.83 (dd, J = 8.2, 1.9 Hz, 1H), 4.62 (dd, J = 8.5, 4.4 Hz, 1H), 4.42 - 4.25 (m, 1H), 3.94 (dd, J = 37.3, 10.8 Hz, 1H), 3.86 - 3.68 (m,3H),3.05-2.94(m,1H),2.82(dd,J=19.0,8.1Hz,1H),2.71(d,J=9.5Hz,3H),2.62(tt,J=7.5,4.4Hz,2H),2.46-2.36(m,1H),2.23(d,J=11.1Hz,3H),2.20-2.14(m,1H),2.12-2.02(m,1H),1.98- 1.90 (m, 1H), 1.86 (ddd, J = 18.3, 9.8, 5.0 Hz, 3H), 1.76 - 1.65 (m, 3H), 1.59 - 1.46 (m, 1H), 1.38 (dd, J = 10.6, 4.9 Hz, 1H), 1.13 - 0.99 (m, 2H)。 |
188 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.10 (dd, J = 8.2, 3.3 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.83 (dd, J = 8.2, 1.7 Hz, 1H), 4.61 (dd, J = 10.4, 4.9 Hz, 1H), 4.41 - 4.25 (m, 1H), 3.94 (dd, J = 36.8, 10.8 Hz, 1H), 3.77 (ddd, J = 21.1, 14.8, 7.4 Hz, 3H), 3.05 - 2.96 (m, 1H), 2.83 (t, J = 12.2 Hz, 1H), 2.71 (d, J = 9.3 Hz, 3H), 2.66 - 2.57 (m, 2H), 2.45 - 2.37 (m, 1H), 2.22 (s, 3H), 2.20 - 2.13 (m, 1H), 2.07 (dd, J = 12.1, 7.0 Hz, 1H), 1.93 (dd, J = 12.4, 6.6 Hz, 1H), 1.83 (td, J = 13.5, 6.8 Hz, 3H), 1.78 - 1.66 (m, 3H), 1.61 - 1.48 (m, 1H), 1.39 (s, 1H), 1.06 (tdd, J = 13.5, 6.5, 2.6 Hz, 2H)。 |
189 | 3-[2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.0 Hz, 1H), 7.07 (s, 1H), 6.93 (dd, J = 8.2, 1.9 Hz, 1H), 4.46 (dd, J = 31.7, 11.9 Hz, 1H), 4.14 - 3.98 (m, 1H), 3.87 (dddd, J = 30.0, 21.6, 11.4, 5.5 Hz, 5H), 3.45 (dd, J = 17.7, 6.1 Hz, 1H), 3.12 (t, J = 12.1 Hz, 1H), 2.99 (dd, J = 19.0, 7.8 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.71 (ddd, J = 10.8, 10.2, 4.8 Hz, 2H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.28 - 2.19 (m, 1H), 2.11 (ddd, J = 22.0, 10.8, 5.2 Hz, 1H), 2.00 - 1.92 (m, 1H), 1.90 - 1.76 (m, 3H), 1.60 - 1.43 (m, 1H), 1.22 - 1.09 (m, 2H)。 |
190 | 3-[2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.5 Hz, 1H), 7.08 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.72 (dd, J = 11.6, 5.5 Hz, 1H), 4.43 (dd, J = 34.1, 10.5 Hz, 1H), 4.14 - 3.98 (m, 1H), 3.89 (ddd, J = 22.1, 13.8, 6.9 Hz, 3H), 3.10 (t, J = 12.2 Hz, 1H), 2.93 (t, J = 12.3 Hz, 1H), 2.80 (d, J = 5.4 Hz, 3H), 2.75 - 2.66 (m, 2H), 2.52 (t, J = 12.0 Hz, 1H), 2.32 (s, 3H), 2.27 (dd, J = 12.8, 6.8 Hz, 1H), 2.21 - 2.12 (m, 1H), 2.05 (dd, J = 10.9, 6.6 Hz, 1H), 1.95 (dt, J = 12.4, 6.5 Hz, 3H), 1.82 (d, J = 13.0 Hz, 3H), 1.64 (s, 1H), 1.49 (s, 1H), 1.21 - 1.10 (m, 2H)。 |
191 | 1-環丙基-3-[(1R,2S)-2-(4-氟-3-甲基苯基)環丙基]-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 396.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (d, J = 3.8 Hz, 1H), 7.37 (dd, J = 9.2, 4.5 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.99 - 6.92 (m, 2H), 6.91 - 6.84 (m, 1H), 6.71 (s, 1H), 4.58 (dd, J = 9.3, 7.8 Hz, 1H), 3.77 (t, J = 9.2 Hz, 2H), 3.62 (dd, J = 10.2, 8.1 Hz, 1H), 3.50 - 3.42 (m, 1H), 2.70 (dd, J = 7.4, 3.3 Hz, 1H), 2.53 (ddd, J = 10.1, 9.4, 6.1 Hz, 2H), 2.34 - 2.24 (m, 1H), 2.21 (d, J = 1.8 Hz, 3H), 2.00 (ddd, J = 9.5, 6.4, 3.3 Hz, 1H), 1.20 - 1.10 (m, 2H), 0.93 (ddd, J = 9.4, 5.9, 3.2 Hz, 2H), 0.81 - 0.67 (m, 2H)。 |
192 | 6-[(3R)-3-(1-環丙基{[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 396.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.73 (s, 1H), 7.58 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.85 (dd, J = 8.1, 2.0 Hz, 1H), 4.30 (t, J = 14.7 Hz, 2H), 3.64 (t, J = 11.7 Hz, 1H), 3.32 (t, J = 11.8 Hz, 1H), 2.85 (t, J = 12.1 Hz, 1H), 2.67 - 2.60 (m, 1H), 2.41 (dd, J = 6.8, 3.2 Hz, 1H), 2.24 - 2.11 (m, 4H), 1.94 - 1.75 (m, 3H), 1.54 (d, J = 13.1 Hz, 1H), 1.15 - 1.04 (m, 2H), 0.85 - 0.78 (m, 2H), 0.69 (dd, J = 10.4, 6.8 Hz, 2H)。 |
193 | 6-[(3R)-3-(1-環丙基{[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 396.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.83 (s, 1H), 7.69 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 4.40 (t, J = 15.0 Hz, 2H), 3.74 (t, J = 12.0 Hz, 1H), 3.40 (t, J = 12.0 Hz, 1H), 2.95 (t, J = 11.8 Hz, 1H), 2.77 - 2.70 (m, 1H), 2.51 (dd, J = 6.7, 3.5 Hz, 1H), 2.34 - 2.23 (m, 4H), 2.05 - 1.86 (m, 3H), 1.64 (d, J = 12.8 Hz, 1H), 1.19 (ddd, J = 19.3, 11.3, 5.1 Hz, 2H), 0.95 - 0.88 (m, 2H), 0.81 - 0.71 (m, 2H)。 |
194 | 3-[(1S,2R)-2-(4-溴-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 472 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.34 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 9.3 Hz, 1H), 7.00 (s, 1H), 6.77 (dd, J = 8.2, 2.0 Hz, 1H), 4.33 - 4.20 (m, 2H), 3.66 (tt, J = 11.9, 3.8 Hz, 1H), 3.24 (d, J = 7.3 Hz, 1H), 2.79 (td, J = 13.1, 2.5 Hz, 1H), 2.64 (dt, J = 7.5, 3.9 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.22 (d, J = 16.6 Hz, 3H), 2.19 - 2.08 (m, 1H), 1.89 (ddd, J = 23.0, 11.4, 8.3 Hz, 2H), 1.76 (d, J = 13.3 Hz, 1H), 1.52 (dtd, J = 13.0, 9.2, 4.0 Hz, 1H), 1.10 (ddd, J = 19.5, 11.2, 5.2 Hz, 2H), 0.86 - 0.79 (m, 2H), 0.70 - 0.59 (m, 2H)。 |
195 | 3-[(1R,2S)-2-(4-溴-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 472 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.34 (d, J = 3.6 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.22 - 7.15 (m, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 4.35 - 4.19 (m, 2H), 3.66 (tt, J = 11.9, 3.9 Hz, 1H), 3.18 (d, J = 12.2 Hz, 1H), 2.79 (td, J = 13.1, 2.6 Hz, 1H), 2.65 (td, J = 7.5, 4.1 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 15.9 Hz, 3H), 2.14 (td, J = 12.5, 4.0 Hz, 1H), 1.95 - 1.82 (m, 2H), 1.76 (d, J = 13.0 Hz, 1H), 1.58 - 1.47 (m, 1H), 1.10 (ddd, J = 19.5, 11.4, 5.2 Hz, 2H), 0.81 (dt, J = 11.4, 7.3 Hz, 2H), 0.74 - 0.58 (m, 2H)。 |
196 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 412 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.2, 4.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.95 (ddd, J = 5.3, 4.1, 1.6 Hz, 2H), 6.73 (s, 1H), 4.62 - 4.54 (m, 1H), 3.81 - 3.73 (m, 2H), 3.61 (dd, J = 10.2, 8.0 Hz, 1H), 3.46 (dd, J = 17.8, 8.8 Hz, 1H), 2.74 (dd, J = 7.4, 3.4 Hz, 1H), 2.54 (ddd, J = 9.6, 8.6, 6.1 Hz, 2H), 2.31 (s, 3H), 2.29 (dd, J = 8.4, 3.9 Hz, 1H), 2.00 (ddd, J = 9.5, 6.3, 3.2 Hz, 1H), 1.24 - 1.13 (m, 2H), 0.96 - 0.89 (m, 2H), 0.80 - 0.69 (m, 2H)。 |
197 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 412 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (d, J = 3.6 Hz, 1H), 7.37 (dd, J = 9.2, 4.5 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 7.6, 1.6 Hz, 2H), 6.73 (s, 1H), 4.58 (dd, J = 9.3, 7.9 Hz, 1H), 3.76 (t, J = 9.3 Hz, 2H), 3.61 (dd, J = 10.2, 8.1 Hz, 1H), 3.46 (dd, J = 17.7, 9.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.59 - 2.47 (m, 2H), 2.31 (s, 3H), 2.30 - 2.24 (m, 1H), 2.00 (ddd, J = 9.6, 6.3, 3.3 Hz, 1H), 1.25 - 1.15 (m, 2H), 0.93 (ddd, J = 9.0, 4.6, 1.9 Hz, 2H), 0.75 (dt, J = 8.1, 3.9 Hz, 2H)。 |
198 | 3-[(1S,2R)-2-(3-溴-4-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 472 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (d, J = 4.4 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 2H), 7.31 - 7.27 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 - 7.00 (m, 1H), 4.37 (dd, J = 33.8, 13.1 Hz, 2H), 3.76 (t, J = 11.7 Hz, 1H), 3.27 (s, 1H), 2.89 (dd, J = 13.2, 10.4 Hz, 1H), 2.75 - 2.70 (m, 1H), 2.48 (dd, J = 7.1, 3.3 Hz, 1H), 2.32 (s, 3H), 2.25 (dd, J = 12.6, 4.0 Hz, 1H), 2.05 - 1.94 (m, 2H), 1.86 (d, J = 12.8 Hz, 1H), 1.62 (d, J = 13.0 Hz, 1H), 1.24 - 1.14 (m, 2H), 0.94 - 0.90 (m, 2H), 0.77 (d, J = 2.1 Hz, 2H)。 |
199 | 3-[(1R,2S)-2-(3-溴-4-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 472 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.2 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.30 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.8, 1.8 Hz, 1H), 4.37 (dd, J = 27.0, 12.1 Hz, 2H), 3.79 - 3.72 (m, 1H), 3.26 (s, 1H), 2.94 - 2.84 (m, 1H), 2.77 - 2.70 (m, 1H), 2.52 - 2.44 (m, 1H), 2.33 (s, 3H), 2.25 (dd, J = 12.5, 3.9 Hz, 1H), 2.05 - 1.96 (m, 2H), 1.91 - 1.82 (m, 1H), 1.62 (dd, J = 9.0, 4.0 Hz, 1H), 1.25 - 1.15 (m, 2H), 0.92 (dd, J = 7.6, 5.4 Hz, 2H), 0.79 - 0.73 (m, 2H)。 |
200 | 6-[(3R)-3-({[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 444.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.86 (s, 1H), 7.70 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 6.95 (dd, J = 8.2, 2.0 Hz, 1H), 4.42 - 4.32 (m, 2H), 4.05 (s, 1H), 3.15 - 3.05 (m, 1H), 3.03 - 2.93 (m, 1H), 2.87 (s, 3H), 2.78 - 2.70 (m, 1H), 2.32 (s, 3H), 2.05 - 1.98 (m, 1H), 1.97 - 1.85 (m, 3H), 1.70 (s, 1H), 1.27 - 1.21 (m, 1H), 1.18 - 1.10 (m, 1H)。 |
201 | 6-[(3R)-3-({[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 444.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.87 (s, 1H), 7.72 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 7.00 - 6.90 (m, 1H), 4.37 (d, J = 12.5 Hz, 2H), 4.06 (s, 1H), 3.16 - 3.05 (m, 1H), 3.04 - 2.93 (m, 1H), 2.87 (s, 3H), 2.80 - 2.71 (m, 1H), 2.32 (s, 3H), 2.04 - 1.98 (m, 1H), 1.95 - 1.85 (m, 3H), 1.69 (d, J = 11.3 Hz, 1H), 1.27 - 1.21 (m, 1H), 1.19 - 1.10 (m, 1H)。 |
202 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 446.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.14 (dd, J = 8.1, 5.5 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 6.84 (dd, J = 8.2, 2.0 Hz, 1H), 5.51 (d, J = 26.8 Hz, 1H), 4.65 - 4.37 (m, 2H), 4.05 - 3.72 (m, 4H), 3.31 - 2.80 (m, 2H), 2.78 - 2.69 (m, 1H), 2.45 - 2.15 (m, 6H), 2.13 - 1.76 (m, 6H), 1.75 - 1.69 (m, 1H), 1.50 - 1.41 (m, 1H), 1.11 - 1.05 (m, 2H), 0.89 - 0.78 (m, 3H), 0.68 - 0.60 (m, 1H)。 |
203 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 446.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.14 (dd, J = 8.2, 3.6 Hz, 1H), 6.95 (d, J = 5.3 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.50 (d, J = 23.3 Hz, 1H), 4.67 - 4.38 (m, 2H), 4.08 - 3.69 (m, 4H), 3.27 - 2.80 (m, 2H), 2.78 - 2.67 (m, 1H), 2.44 - 2.15 (m, 6H), 2.11 - 1.75 (m, 6H), 1.72 (d, J = 13.1 Hz, 1H), 1.47 - 1.37 (m, 1H), 1.14 - 1.04 (m, 2H), 0.89 - 0.75 (m, 3H), 0.69 - 0.56 (m, 1H)。 |
204 | 3-[(1R,2S)-2-(4-氯-2-氟-5-甲基苯基)環丙基]-1-環丙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 430.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.2, 4.5 Hz, 1H), 7.07 (d, J = 9.9 Hz, 1H), 6.95 (dd, J = 16.7, 8.6 Hz, 2H), 4.58 (p, J = 8.2 Hz, 1H), 3.77 (t, J = 9.3 Hz, 2H), 3.61 (ddd,J=10.3,8.1,4.4Hz,1H), 3.46 (dd,J=17.4,9.1Hz,1H), 2.91 (dt,J=7.5,3.8Hz,1H), 2.65-2.45(m,2H), 2.36-2.23 (m,4H), 2.11 (d,J=8.5Hz,1H), 1.31-1.24 (m,1H), 1.19 (dd,J= 12.7, 6.1 Hz, 1H), 0.97 - 0.88 (m, 2H), 0.83 - 0.69 (m, 2H)。 |
205 | 1-環丙基-3-[2-(4-氟-3-甲基苯基)環丙基]-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 396.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (dd, J = 4.4, 1.1 Hz, 1H), 7.42 (ddd, J = 9.2, 4.4, 2.4 Hz, 1H), 7.06 - 6.97 (m, 2H), 6.95 (dd, J = 6.7, 4.1 Hz, 1H), 6.88 (t, J = 9.0 Hz, 1H), 6.72 (s, 1H), 4.66 - 4.48 (m, 1H), 3.85 - 3.70 (m, 2H), 3.68 - 3.58 (m, 1H), 3.51 - 3.43 (m, 1H), 2.70 (dt, J = 7.4, 3.6 Hz, 1H), 2.62 - 2.45 (m, 2H), 2.36 - 2.25 (m, 1H), 2.21 (s, 3H), 2.00 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.22 - 1.09 (m, 2H), 0.98 - 0.88 (m, 2H), 0.82 - 0.65 (m, 2H)。 |
206 | 6-[(3R)-3-(1-環丙基{[2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 470.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.84 (s, 1H), 7.64 (s, 1H), 7.20 (dd, J = 8.2, 1.5 Hz, 1H), 7.08 (s, 1H), 6.97 - 6.91 (m, 1H), 6.68 (s, 1H), 4.39 (t, J = 12.0 Hz, 2H), 3.74 (dd, J = 15.5, 7.9 Hz, 1H), 3.36 (t, J = 11.7 Hz, 1H), 2.92 (t, J = 12.3 Hz, 1H), 2.80 - 2.69 (m, 1H), 2.56 - 2.43 (m, 1H), 2.31 (s, 3H), 2.29 - 2.19 (m, 1H), 2.04 - 1.84 (m, 3H), 1.64 (dd, J = 14.8, 11.3 Hz, 1H), 1.19 (ddd, J = 18.1, 10.7, 5.2 Hz, 2H), 0.91 (dd, J = 12.2, 9.3 Hz, 2H), 0.82 - 0.71 (m, 2H)。 |
207 | 3-[2-(3-溴-4-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 472 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.1 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.29 (ddd, J = 9.4, 3.1, 1.2 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 4.37 (dd, J = 30.0, 12.7 Hz, 2H), 3.75 (ddd, J = 12.2, 7.5, 4.1 Hz, 1H), 3.26 (d, J = 4.2 Hz, 1H), 2.89 (td, J = 13.1, 2.5 Hz, 1H), 2.73 (td, J = 7.6, 3.2 Hz, 1H), 2.52 - 2.46 (m, 1H), 2.32 (s, 3H), 2.28 - 2.19 (m, 1H), 2.05 - 1.94 (m, 2H), 1.86 (d, J = 12.9 Hz, 1H), 1.68 - 1.58 (m, 1H), 1.25 - 1.14 (m, 2H), 0.96 - 0.89 (m, 2H), 0.81 - 0.71 (m, 2H)。 |
208 | 3-[2-(4-溴-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 470.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.0 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.29 (ddd, J = 9.4, 2.6, 1.3 Hz, 1H), 7.10 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 4.37 (dd, J = 26.7, 12.9 Hz, 2H), 3.75 (ddd, J=15.8,7.8,3.9Hz,1H), 3.26 (d,J=3.7Hz,1H), 2.89 (td,J=13.0,2.5Hz,1H), 2.75 (dt,J=6.9,3.5Hz,1H), 2.53-2.44 (m,1H), 2.34 (d,J=1.4Hz,3H), 2.31-2.18(m,1H), 2.04-1.93 (m,2H), 1.86 (d,J=13.1 Hz, 1H), 1.68 - 1.54 (m, 1H), 1.26 - 1.14 (m, 2H), 0.96 - 0.88 (m, 2H), 0.80 - 0.71 (m, 2H)。 |
209 | 3-[2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 412.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.41 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.2, 4.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.99 - 6.91 (m, 2H), 6.73 (d, J = 2.0 Hz, 1H), 4.63 - 4.52 (m, 1H), 3.77 (dd, J = 10.3, 8.0 Hz, 2H), 3.65 - 3.58 (m, 1H), 3.46 (dd, J = 17.8, 8.9 Hz, 1H), 2.73 (ddd, J = 6.1, 4.4, 3.1 Hz, 1H), 2.61 - 2.47 (m, 2H), 2.31 (s, 3H), 2.28 (dd, J = 8.5, 4.0 Hz, 1H), 2.00 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.25 - 1.13 (m, 2H), 0.95 - 0.89 (m, 2H), 0.81 - 0.67 (m, 2H)。 |
210 | 3-[(1S,2R)-2-(4-溴-3-甲基苯基)環丙基]-1-甲基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 430 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.35 (d, J = 4.4 Hz, 1H), 7.36 (d, J = 4.7 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 4.98 - 4.90 (m, 1H), 3.70 - 3.58 (m, 2H), 3.43 - 3.30 (m, 2H), 2.74 (s, 3H), 2.67 - 2.61 (m, 1H), 2.24 (s, 3H), 2.13 (t, J = 7.7 Hz, 2H), 1.86 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.13 - 1.04 (m, 2H)。 |
211 | 3-[(1R,2S)-2-(4-溴-3-甲基苯基)環丙基]-1-甲基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 431.9 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.2 Hz, 1H), 7.44 (dd, J = 9.3, 4.5 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 9.3, 1.2 Hz, 1H), 6.87 (dd, J = 8.2, 2.2 Hz, 1H), 5.06 - 5.00 (m, 1H), 3.78 - 3.67 (m, 2H), 3.52 - 3.40 (m, 2H), 2.84 (s, 3H), 2.76 - 2.71 (m, 1H), 2.34 (s, 3H), 2.25 - 2.17 (m, 2H), 2.00 - 1.93 (m, 1H), 1.22 - 1.14 (m, 2H)。 |
212 | 6-[(3R)-3-({[2-(4-氯-3-甲基苯基)環丙基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: m/z 444.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.86 (s, 1H), 7.73 (d, J = 3.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), 4.39 - 4.28(m, 2H), 4.07 (s, 1H), 3.16 - 3.06 (m, 1H), 3.02 - 2.92 (m, 1H), 2.87 (s, 3H), 2.77 - 2.71 (m, 1H), 2.31 (s, 3H), 2.02 (d, J = 9.2 Hz, 1H), 1.97 - 1.84 (m, 3H), 1.70 (s, 1H), 1.19 - 1.11 (m, 1H), 0.89 (d, J = 7.6 Hz, 1H)。 |
213 | 3-[(1S,2R)-2-(4-氯-2-氟-5-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 444.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.33 (dd, J = 4.4, 1.1 Hz, 1H), 7.26 (dt, J = 19.6, 9.8 Hz, 1H), 7.19 (d, J = 9.4 Hz, 1H), 6.98 (d, J = 9.9 Hz, 1H), 6.86 (t, J = 12.3 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 4.27 (dd, J = 27.1, 12.8 Hz, 2H), 3.66 (tt, J = 12.0, 3.9 Hz, 1H), 3.19 (d, J = 8.8 Hz, 1H), 2.80 (ddd, J = 16.7, 10.4, 7.6 Hz, 2H), 2.44 - 2.34 (m, 1H), 2.25 - 2.10 (m, 4H), 2.03 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.86 (d, J = 11.8 Hz, 1H), 1.76 (d, J = 13.4 Hz, 1H), 1.53 (ddd, J = 21.6, 12.8, 8.1 Hz, 1H), 1.20 (dd, J = 8.3, 3.8 Hz, 1H), 1.10 (dd, J = 13.5, 6.1 Hz, 1H), 0.85 - 0.79 (m, 2H), 0.72 - 0.62 (m, 2H)。 |
214 | 3-[(1R,2S)-2-(4-氯-2-氟-5-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 444.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.2 Hz, 1H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 7.08 (d, J = 9.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 4.35 (ddd, J = 15.1, 12.6, 7.5 Hz, 2H), 3.76 (tt, J = 11.9, 3.9 Hz, 1H), 3.26 (s, 1H), 2.97 - 2.83 (m, 2H), 2.54 - 2.43 (m, 1H), 2.32 - 2.18 (m, 4H), 2.11 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.96 (d, J = 12.8 Hz, 1H), 1.86 (d, J = 13.3 Hz, 1H), 1.70 - 1.53 (m, 1H), 1.31 (dd, J = 9.8, 5.4 Hz, 1H), 1.19 (dd, J = 13.5, 6.1 Hz, 1H), 0.99 - 0.88 (m, 2H), 0.83 - 0.71 (m, 2H)。 |
215 | 3-[2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 446.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.24 - 7.16 (m, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.58 (dd, J = 23.2, 2.0 Hz, 1H), 4.72 - 4.40 (m, 2H), 4.07 - 3.68 (m, 4H), 3.42 - 2.86 (m, 2H), 2.85 - 2.74 (m, 1H), 2.53 - 2.42 (m, 1H), 2.40 - 2.30 (m, 4H), 2.28 - 1.86 (m, 6H), 1.80 (d, J = 14.5 Hz, 1H), 1.55 - 1.44 (m, 1H), 1.19 - 1.10 (m, 2H), 0.87 (ddd, J = 22.2, 14.4, 7.2 Hz, 3H), 0.77 - 0.66 (m, 1H)。 |
216 | 3-[(1S,2R)-2-(4-氯-2-氟-5-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 418.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.1 Hz, 1H), 7.07 (d, J = 9.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.36 (d, J = 13.4 Hz, 1H), 4.28 (dd, J = 12.6, 3.7 Hz, 1H), 4.06 (dt, J = 11.3, 7.7 Hz, 1H), 3.03 (dd, J = 12.5, 11.4 Hz, 1H), 2.96 - 2.87 (m, 2H), 2.86 (s, 3H), 2.28 (s, 3H), 2.10 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.88 (dt, J = 9.4, 4.3 Hz, 3H), 1.74 - 1.59 (m, 1H), 1.33 - 1.29 (m, 1H), 1.16 (dt, J = 7.5, 6.0 Hz, 1H)。 |
217 | 3-[(1R,2S)-2-(4-氯-2-氟-5-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 418.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.48 - 8.42 (m, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (d, J = 9.4 Hz, 1H), 7.06 (d, J = 9.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.32 - 4.23 (m, 1H), 4.14 - 4.00 (m, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.96 - 2.87 (m, 2H), 2.86 (s, 3H), 2.28 (s, 3H), 2.11 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.87 (t, J = 6.5 Hz, 3H), 1.67 (s, 1H), 1.33 - 1.27 (m, 1H), 1.16 (dd, J = 13.5, 6.0 Hz, 1H)。 |
218 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-乙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, 氯仿-d) δ 8.55 (d, J = 3.9 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.05 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 8.2, 2.2 Hz, 1H), 6.62 (dd, J = 9.1, 1.1 Hz, 1H), 5.08 - 4.94 (m, 1H), 4.85 (s, 1H), 3.88 - 3.71 (m, 2H), 3.54 - 3.42 (m, 1H), 3.37 (dd, J = 10.5, 8.1 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.82 (qd, J = 4.6, 1.8 Hz, 1H), 2.33 (s, 3H), 2.27 (ddd, J = 14.3, 6.2, 2.8 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.99 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.23 - 1.10 (m, 5H)。 |
219 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-乙基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, 氯仿-d) δ 8.56 (d, J = 3.6 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.06 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 8.2, 2.2 Hz, 1H), 6.67 (dd, J = 9.2, 1.2 Hz, 1H), 5.06 - 4.93 (m, 2H), 3.86 - 3.75 (m, 2H), 3.50 (td, J = 9.9, 7.2 Hz, 1H), 3.37 (dd, J = 10.4, 8.2 Hz, 1H), 3.29 - 3.16 (m, 2H), 2.83 (dt, J = 7.2, 3.5 Hz, 1H), 2.34 (s, 3H), 2.29 (ddd, J = 14.2, 6.2, 2.7 Hz, 1H), 2.16 - 2.08 (m, 1H), 2.01 (ddd, J = 9.5, 6.5, 3.3 Hz, 1H), 1.26 - 1.13 (m, 5H)。 |
220 | 3-[(1S,2R)-2-(3-溴-4-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 444.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dd, J = 4.4, 1.2 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.30 (dd, J = 9.4, 1.1 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.9, 1.7 Hz, 1H), 4.32 (dd, J = 28.5, 13.1 Hz, 2H), 4.05 (s, 1H), 3.07 - 2.99 (m, 1H), 2.89 (dd, J = 18.4, 7.7 Hz, 1H), 2.85 (s, 3H), 2.75 - 2.70 (m, 1H), 2.32 (s, 3H), 2.00 (ddd, J = 9.4, 6.2, 3.3 Hz, 1H), 1.92 - 1.83 (m, 3H), 1.67 (s, 1H), 1.22 (dd, J = 9.5, 4.4 Hz, 1H), 1.17 - 1.11 (m, 1H)。 |
221 | 3-[(1R,2S)-2-(3-溴-4-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 446.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dd, J = 4.4, 1.2 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.02 (dd, J = 7.9, 1.8 Hz, 1H), 4.31 (dd, J = 37.5, 13.1 Hz, 2H), 4.05 (s, 1H), 3.07 - 2.98 (m, 1H), 2.94 - 2.87 (m, 1H), 2.85 (s, 3H), 2.75 - 2.69 (m, 1H), 2.32 (s, 3H), 2.01 (ddd, J = 9.4, 6.2, 3.2 Hz, 1H), 1.88 (dd, J = 10.5, 4.7 Hz, 3H), 1.68 (s, 1H), 1.26 - 1.19 (m, 1H), 1.17 - 1.10 (m, 1H)。 |
222 | 3-[(1S,2R)-2-(4-溴-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 446.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dd, J = 4.4, 1.2 Hz, 1H), 7.39 (dd, J = 9.1, 4.4 Hz, 2H), 7.30 (dd, J = 9.4, 1.1 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.87 (dd, J = 8.3, 2.2 Hz, 1H), 4.32 (dd, J = 23.0, 14.8 Hz, 2H), 4.05 (s, 1H), 3.07 - 2.98 (m, 1H), 2.92 (d, J = 13.1 Hz, 1H), 2.85 (s, 3H), 2.77 - 2.72 (m, 1H), 2.34 (s, 3H), 1.99 (ddd, J = 9.4, 6.2, 3.2 Hz, 1H), 1.88 (dd, J = 11.6, 4.6 Hz, 3H), 1.67 (s, 1H), 1.27 - 1.20 (m, 1H), 1.15 (dd, J = 13.5, 6.0 Hz, 1H)。 |
223 | LC-MS: m/z 444.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 8.3, 2.2 Hz, 1H), 4.31 (dd, J = 35.1, 12.7 Hz, 2H), 4.06 (s, 1H), 3.06 - 2.99 (m, 1H), 2.90 (t, J = 11.8 Hz, 1H), 2.85 (s, 3H), 2.76 - 2.71 (m, 1H), 2.34 (s, 3H), 2.00 (ddd, J = 9.4, 6.3, 3.2 Hz, 1H), 1.88 (t, J = 7.7 Hz, 3H), 1.68 (s, 1H), 1.26 - 1.20 (m, 1H), 1.15 (dt, J = 12.0, 6.0 Hz, 1H)。 | |
224 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3S)-1-[(3R)-氧雜環戊烷-3-羰基]吡咯啶-3-基]尿素 | LC-MS: m/z 406.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.92 (d, J = 13.2 Hz, 1H), 4.03 (td, J = 8.2, 4.4 Hz, 1H), 3.96 - 3.81 (m, 3H), 3.79 - 3.60 (m, 2H), 3.53 - 3.32 (m, 1H), 3.31 - 3.22 (m, 1H), 3.18 - 3.04 (m, 1H), 2.82 - 2.70 (m, 4H), 2.33 (s, 3H), 2.25 - 1.94 (m, 5H), 1.22 - 1.08 (m, 2H)。 |
225 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 426.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.33 (dd, J = 4.4, 1.2 Hz, 1H), 7.26 (dd, J = 9.4, 4.4 Hz, 1H), 7.18 (dd, J = 9.4, 1.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H), 4.25 (ddd, J = 15.0, 12.5, 7.6 Hz, 2H), 3.72 - 3.60 (m, 1H), 2.78 (td, J = 13.1, 2.6 Hz, 1H), 2.63 (ddd, J = 7.6, 4.4, 3.4 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.22 (s, 3H), 2.13 (td, J = 12.6, 4.1 Hz, 1H), 1.93 - 1.83 (m, 2H), 1.75 (dd, J = 10.1, 2.8 Hz, 1H), 1.58 - 1.46 (m, 1H), 1.14 - 1.04 (m, 2H), 0.86 - 0.78 (m, 2H), 0.71 - 0.62 (m, 2H)。 |
226 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3S)-1-[(3S)-氧雜環戊烷-3-羰基]吡咯啶-3-基]尿素 | LC-MS: m/z 406.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.21 (dd, J = 8.2, 2.4 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.93 (dd, J = 8.2, 2.1 Hz, 1H), 5.13 - 4.97 (m, 1H), 4.85 (d, J = 13.8 Hz, 1H), 4.01 (q, J = 8.3 Hz, 1H), 3.94 - 3.79 (m, 3H), 3.79 - 3.63 (m, 2H), 3.49 - 3.35 (m, 1H), 3.25 (ddd, J = 18.5, 11.2, 8.5 Hz, 1H), 3.16 - 3.02 (m, 1H), 2.84 - 2.70 (m, 4H), 2.32 (s, 3H), 2.23 - 2.03 (m, 3H), 2.03 - 1.84 (m, 2H), 1.22 - 1.08 (m, 2H)。 |
227 | 3-[(1R,2S)-2-(4-氯苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 386.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.1 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.39 - 4.23 (m, 2H), 4.05 (dd, J = 9.4, 5.6 Hz, 1H), 3.10 - 2.97 (m, 1H), 2.90 (td, J = 13.2, 2.5 Hz, 1H), 2.86 (s, 3H), 2.78 - 2.72 (m, 1H), 2.03 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.88 (t, J = 8.0 Hz, 3H), 1.67 (dd, J = 10.7, 8.3 Hz, 1H), 1.27 - 1.21 (m, 1H), 1.16 (dt, J = 12.1, 6.0 Hz, 1H)。 |
228 | 1-乙基-3-[(1S,2R)-2-(4-氟苯基)環丙基]-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 370.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.5, 1.1 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.18 (dd, J = 8.6, 5.4 Hz, 2H), 7.03 - 6.88 (m, 3H), 4.83 - 4.77 (m, 1H), 3.75 (dt, J = 10.4, 5.8 Hz, 2H), 3.52 - 3.32 (m, 4H), 2.74 - 2.68 (m, 1H), 2.24 (dt, J = 9.1, 6.4 Hz, 2H), 2.02 (ddd, J = 9.5, 6.3, 3.2 Hz, 1H), 1.22 - 1.10 (m, 5H)。 |
229 | 3-[(1R,2S)-2-(4-氟苯基)環丙基]-1-甲基-1-[(3S)-1-(嗒嗪-3-基)吡咯啶-3-基]尿素 | LC-MS: m/z 356.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.5, 1.1 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.02 - 6.92 (m, 3H), 5.02 (p, J = 7.8 Hz, 1H), 3.82 - 3.63 (m, 2H), 3.56 - 3.37 (m, 2H), 2.83 (s, 3H), 2.74 - 2.68 (m, 1H), 2.20 (td, J = 7.6, 4.1 Hz, 2H), 2.01 (ddd, J = 9.5, 6.3, 3.4 Hz, 1H), 1.22 - 1.10 (m, 2H)。 |
230 | 3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (dd, J = 4.4, 1.2 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.0 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 8.2, 2.1 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.12 - 4.00 (m, 1H), 3.06 - 2.99 (m, 1H), 2.94 - 2.87 (m, 1H), 2.85 (s, 3H), 2.74 (ddd, J = 7.6, 4.4, 3.4 Hz, 1H), 2.32 (s, 3H), 2.00 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.91 - 1.83 (m, 3H), 1.65 (dt, J = 13.7, 8.6 Hz, 1H), 1.25 - 1.20 (m, 1H), 1.14 (dt, J = 7.4, 6.0 Hz, 1H)。 |
231 | 3-[(1S,2R)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.49 (dd, J = 4.2, 1.4 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.2, 2.2 Hz, 1H), 4.30 (dd, J = 37.8, 12.3 Hz, 2H), 4.10 (dt, J = 11.2, 6.1 Hz, 1H), 3.12 - 3.04 (m, 1H), 2.95 (dd, J = 18.6, 7.8 Hz, 1H), 2.86 (s, 3H), 2.77 - 2.65 (m, 1H), 2.31 (s, 3H), 2.00 (ddd, J = 9.5, 6.2, 3.2 Hz, 1H), 1.93 - 1.85 (m, 3H), 1.72 - 1.66 (m, 1H), 1.25-1.20 (m, 1H), 1.17-1.12 (m, 1H)。 |
一般程序 I : 作為一般程序,下文實例係根據以下一般方案來合成
向化合物
I1(1 eq.)及DIEA (5 eq.)於DMF中之混合物中添加相應酸
I2(1.2 eq.)、EDCI (1.2 eq.)及HOBt (1.2 eq.)。將所得混合物於r.t.下攪拌16 hr。然後將混合物用水稀釋並用EtOAc萃取兩次。將合併之有機層用飽和NH
4Cl溶液及鹽水洗滌,經無水Na
2SO
4乾燥且過濾,將濾液在真空中濃縮至乾燥。經由prep-HPLC (Xbudge prep C18 250 * 19 mm 5um OBD, H
2O/MeCN (5-95 %)/0.1 % FA)純化殘餘物,以產生化合物
I3。
實例 232 : (
R)-3-(4-
氯 3- 甲基苄基 )-1- 甲基 -1-(1-( 嘧啶 -4- 羰基 ) 六氫吡啶 -3- 基 ) 尿素之合成 向化合物
M1(50 mg, 0.12 mmol)及DIEA (79 mg, 0.61 mmol)於DMF中之混合物中添加嘧啶-4-甲酸
M2(19 mg, 0.14 mmol)、EDCI (28 mg, 0.144 mmol)及HOBt (20 mg, 0.144 mmol)。將所得混合物於r.t.下攪拌16 hr。然後將混合物用水(20 mL)稀釋且用EtOAc (20 mL)萃取兩次。將合併之有機層用飽和NH
4Cl溶液及鹽水洗滌,經無水Na
2SO
4乾燥,過濾且將濾液在真空中濃縮至乾燥。經由prep-HPLC (Xbudge prep C18 250 * 19 mm 5um OBD, H
2O/MeCN (5-95 %)/0.1 % FA)純化殘餘物,以得到白色固體狀
實例 232(9 mg, 18.7 %產率)。LC/MS: m/z 402 (M+H)
+。1H NMR (400 MHz, MeOD) δ 9.21 - 9.12 (m, 1H), 8.94 - 8.90 (m, 1H), 7.66 - 7.63 (m, 1H), 7.28 - 7.23 (m, 1H), 7.14 (s, 1H), 7.12 - 7.00 (m, 1H), 4.64 - 4.49 (m, 1H), 4.38 - 4.11 (m, 3H), 3.70 - 3.54 (m, 1H), 3.28 - 3.18 (m, 1H), 3.08 - 2.42 (m, 5H), 2.36 - 2.29 (m, 3H), 1.98 - 1.76 (m, 3H), 1.76 - 1.62 (m, 1H)。
下表中之化合物係自上述或市售適當起始材料使用上述一般程序I及
實例 232中之中間體
M1來製備。
實例 | 結構及名稱 | 數據 |
233 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-[(2S)-3-甲氧基-2-甲基丙醯基]六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 396.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.58 - 4.46 (m, 1H), 4.40 - 4.27 (m, 2H), 4.02 (dd, J = 41.8, 11.1 Hz, 2H), 3.56 (td, J = 8.7, 6.1 Hz, 1H), 3.31 (d, J = 11.4 Hz, 3H), 3.12 (ddt, J = 51.0, 24.2, 9.1 Hz, 2H), 2.87 (d, J = 7.6 Hz, 3H), 2.79 - 2.46 (m, 1H), 2.36 (s, 3H), 1.84 (t, J = 5.9 Hz, 3H), 1.68 - 1.43 (m, 1H), 1.31 (d, J = 6.5 Hz, 1H), 1.08 (dd, J = 19.5, 6.9 Hz, 3H)。 |
234 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(3-甲氧基丙醯基)六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 382.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.2, 2.0 Hz, 1H), 4.47 - 4.24 (m, 3H), 4.07 (d, J = 6.0 Hz, 1H), 3.56 - 3.39 (m, 1H), 3.28 - 3.07 (m, 1H), 3.03 (t, J = 6.5 Hz, 3H), 2.99 (s, 1H), 2.91 (d, J = 3.6 Hz, 2H), 2.86 (t, J = 6.9 Hz, 3H), 2.72 - 2.62 (m, 1H), 2.34 (s, 3H), 1.95 - 1.81 (m, 3H), 1.70 - 1.52 (m, 1H)。 |
235 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(2-羥基乙醯基)六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 542.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.26 (dd, J = 8.1, 1.8 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.33 - 4.15 (m, 4H), 4.03-3.95 (m, 1H), 3.71 - 3.53 (m, 1H), 3.12 - 2.88 (m, 1H), 2.86 (s , 3H), 2.78 - 2.48 (m, 1H), 2.35 (s , 3H), 1.85-1.79 (m, 3H), 1.63 - 1.46 (m, 1H)。 |
236 | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(1,3-噁唑-2-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 391.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.09 - 8.01 (m, 1H), 7.34 - 7.16 (m, 3H), 7.10 (dd, J = 10.9, 4.7 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.63 - 4.48 (m, 1H), 4.39 - 4.25 (m, 2H), 4.17 - 4.04 (m, 1H), 3.31 - 3.04 (m, 1H), 2.99 - 2.74 (m, 4H), 2.35 (t, J = 7.3 Hz, 3H), 1.99 - 1.81 (m, 3H), 1.77 - 1.59 (m, 1H)。 |
237 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[(3S)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 416.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (dd, J = 8.2, 3.5 Hz, 1H), 7.21 (d, J = 3.7 Hz, 1H), 7.10 (dd, J = 9.7, 3.7 Hz, 1H), 4.54 - 4.41 (m, 1H), 4.37 - 4.25 (m, 2H), 4.09 - 3.89 (m, 3H), 3.89 - 3.74 (m, 3H), 3.51 - 3.40 (m, 1H), 3.20 - 2.95 (m, 1H), 2.85 (d, J = 8.0 Hz, 3H), 2.79 - 2.47 (m, 1H), 2.34 (s, 3H), 2.20 - 2.00 (m, 2H), 1.91 - 1.77 (m, 3H), 1.67 - 1.44 (m, 1H)。 |
238 | (3R)-3-({[(4-氯-3-甲基苯基)甲基]胺甲醯基}(甲基)胺基)六氫吡啶-1-甲酸甲酯 | LC-MS: m/z 354.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 4.31-4.28 (m,2H),4.08-3.95(m,3H),3.67(s,3H),2.88-2.81(m, 4H),2.70-2.64 (m,1H),2.34(s,3H),1.80- 1.68 (m, 3H), 1.60 -1.50 (m, 1H)。 |
239 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(2-甲氧基乙醯基)六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 368.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (dd, J = 8.1, 2.6 Hz, 1H), 7.21 (s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.37 - 4.25 (m, 2H), 4.23 - 4.08 (m, 2H), 4.07 - 3.95 (m, 1H), 3.84 - 3.65 (m, 1H), 3.38 (s, 3H), 3.16 - 2.90 (m, 1H), 2.85 (d, J = 1.7 Hz, 3H), 2.78 - 2.47 (m, 1H), 2.34 (s, 3H), 1.85-1.76 (m, 3H), 1.67 - 1.44 (m, 1H)。 |
240 | 3-[(4-氯-3-甲基苯基)甲基]-1-甲基-1-[(3R)-1-(3-甲基丁醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 380.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.29 - 7.15 (m, 2H), 7.09 (dd, J = 6.4, 3.8 Hz, 1H), 4.59 - 4.42 (m, 1H), 4.39 - 4.22 (m, 2H), 4.15 - 3.77 (m, 2H), 3.15 - 2.93 (m, 1H), 2.84 (d, J = 5.5 Hz, 3H), 2.74 - 2.42 (m, 1H), 2.33 (s , 3H), 2.28 - 220 (m, 2H), 2.12 - 1.99 (m, 1H), 1.88 - 1.71 (m, 3H), 1.62 - 1.42 (m, 1H), 0.98 - 0.88 (m, 6H)。 |
241 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-環丙烷羰基六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 364.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.26 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.09 (d, J = 7.7 Hz, 1H), 4.63 - 4.22 (m, 4H), 4.19 - 3.90 (m, 1H), 3.25 - 2.98 (m, 1H), 2.94 - 2.82 (m, 3H), 2.79 - 2.45 (m, 1H), 2.34 (s, 3H), 2.01 - 1.73 (m, 4H), 1.67 - 1.48 (m, 1H), 0.93 - 0.72 (m, 4H)。 |
242 | 1-[(3R)-1-乙醯基六氫吡啶-3-基]-3-[(4-氯-3-甲基苯基)甲基]-1-甲基尿素 | LC-MS: m/z 338.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28-7.25 (m, 1H), 7.21 (s, 1H), 7.14 - 7.05 (m, 1H), 4.52 - 4.40 (m, 1H), 4.38 - 4.22 (m, 2H), 4.10 - 3.95 (m, 1H), 3.89 - 3.73 (m, 1H), 3.18 - 2.96 (m, 1H), 2.86 (s , 3H), 2.74 - 2.43 (m, 1H), 2.35 (s , 3H), 2.18 - 2.03 (m, 3H), 1.88 - 1.72 (m, 3H), 1.65 - 1.44 (m, 1H)。 |
243 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 394 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (dd, J = 8.2, 3.9 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 5.7, 2.3 Hz, 1H), 4.78 - 4.65 (m, 1H), 4.51 - 4.25 (m, 3H), 4.13 - 3.79 (m, 4H), 3.19 - 2.90 (m, 1H), 2.85 (d, J = 5.7 Hz, 3H), 2.78 - 2.47 (m, 1H), 2.34 (s, 3H), 2.29 - 2.10 (m, 1H), 2.06 - 1.78 (m, 6H), 1.69 - 1.42 (m, 1H)。 |
244 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-{1H-吡咯并[2,3-b]吡啶-6-羰基}六氫吡啶-3-基]尿素 | LC-MS: m/z 440.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.09-8.00(m,1H),7.53-7.41(m,1H),7.33-7.20(m,2H),7.12(d,J = 7.8 Hz, 1H), 7.06 - 6.87 (m, 1H), 6.57 - 6.50 (m, 1H), 4.69 - 4.55 (m, 1H), 4.42 - 4.14 (m, 3H), 3.88-3.82 (m, 1H), 3.26 - 3.00 (m, 1H), 2.99 - 2.71 (m, 4H), 2.38 - 2.19 (m, 3H), 1.99 - 1.65 (m, 4H)。 |
245 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[2-(吡啶-2-基)乙醯基]六氫吡啶-3-基]尿素 | LC-MS: m/z 415.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.64 (s, 1H), 8.25 - 8.13 (m, 1H), 7.73 - 7.60 (m, 2H), 7.30 - 7.16 (m, 2H), 7.11 - 7.05 (m, 1H), 4.56 - 4.41 (m, 1H), 4.37 - 4.26 (m, 2H), 4.14 - 3.86(m, 2H), 3.23 - 3.02 (m, 1H), 2.92 - 2.83 (m, 3H), 2.81 - 2.48 (m, 1H), 2.33 (s, 3H), 1.93 - 1.78 (m, 3H), 1.64 - 1.44( m, 1H)。 |
246 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[2-(嗒嗪-3-基)乙醯基]六氫吡啶-3-基]尿素 | LC-MS: m/z 416.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 9.15 - 9.03 (m, 1H), 7.67 (dd, J = 8.5, 4.7 Hz, 2H), 7.30 - 7.16 (m, 2H), 7.11-7.06 (m, 1H), 4.52 - 3.93 (m, 7H), 3.28 - 3.03 (m, 1H), 2.91 - 2.53 (m, 4H), 2.32 (d, J = 5.6 Hz, 3H), 1.92 - 1.78 (m, 3H), 1.65 - 1.45 (m, 1H)。 |
247 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(噁烷-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 408.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28 - 7.25 (m, 1H), 7.21 (d, J = 6.9 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 4.53 - 4.24 (m, 3H), 4.14 - 3.81 (m, 4H), 3.54 - 3.33 (m, 2H), 3.19 - 2.79 (m, 5H), 2.74 - 2.39 (m, 1H), 2.34 (s, 3H), 2.08 - 1.54 (m, 8H)。 |
248 | 1-[(4-氯-3-甲基苯基)甲基]-3-[(3R)-1-(6-甲氧基嗒嗪-3-羰基)六氫吡啶-3-基]-3-甲基尿素 | LC-MS: m/z 432.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.72 - 7.86 (m, 1H), 7.30 - 7.00 (m, 4H), 4.70 - 4.54 (m, 1H), 4.42 - 4.30 (m, 2H), 4.20 - 3.99 (m, 4H), 3.98 - 3.84 (m, 1H), 3.15 - 2.95 (m, 1H), 2.93 - 2.74 (m, 4H), 2.36 - 2.28 (m, 3H), 2.01 - 1.67 (m, 4H)。 |
249 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[2-(1,3-噻唑-4-基)乙醯基]六氫吡啶-3-基]尿素 | LC-MS: m/z 421.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.95 -8.81 (m, 1H), 7.42 -7.33 (m, 1H), 7.24 (dd, J = 8.2, 3.2 Hz, 1H), 7.18 (d, J = 4.1 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.59 -4.45 (m, 1H), 4.37 - 4.22 (m, 2H), 4.08 - 3.86 (m, 4H), 3.24 - 2.95 (m, 1H), 2.84 (d, J = 9.6 Hz, 3H), 2.80 -2.46 (m, 1H), 2.31 (d, J = 7.5 Hz, 3H), 1.89 -1.73 (m, 3H), 1.55 - 1.39 (m, 1H)。 |
250 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[2-(1H-吡唑-3-基)乙醯基]六氫吡啶-3-基]尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.55-7.51 (m, 1H), 7.25 (dd, J = 8.2, 1.5 Hz, 1H), 7.19 (d, J = 4.3 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.24 - 6.14 (m, 1H), 4.57 - 4.40 (m, 1H), 4.37 - 4.21 (m, 2H), 4.02 - 3.72 (m, 4H), 3.15 - 2.93 (m, 1H), 2.82 (d, J = 1.5 Hz, 3H), 2.81 - 2.45 (m, 1H), 2.32 (d, J = 5.6 Hz, 3H), 1.87 - 1.70 (m, 3H), 1.58 - 1.36 (m, 1H)。 |
251 | 1-[(4-氯-3-甲基苯基)甲基]-3-[(3R)-1-(2,4-二甲基-1,3-噻唑-5-羰基)六氫吡啶-3-基]-3-甲基尿素 | LC-MS: m/z 435.1 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.30 - 7.02 (m, 3H), 4.70 - 3.94 (m, 5H), 3.23 - 2.73 (m, 5H), 2.66 (s, 3H), 2.36 (s, 3H), 2.33 (s, 3H), 1.91 - 1.76 (m, 3H), 1.60 (s, 1H)。 |
252 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1,3-噁唑-5-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 391.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.31 (s, 1H), 7.73 - 7.62 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 7.9 Hz, 1H), 4.61 - 4.13 (m, 5H), 3.21 - 2.68 (m, 5H), 2.34 (s, 3H), 1.94 - 1.85 (m, 3H), 1.65 (s,1H)。 |
253 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(噁烷-4-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 480.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.26 (dd, J = 8.1, 5.3 Hz, 1H), 7.20 (s, 1H), 7.11 - 7.06 (m, 1H), 4.61 - 4.41(m, 1H), 4.36 - 4.23 (m, 2H), 4.14 - 3.84 (m, 4H), 3.55 - 3.41 (m, 2H), 3.16 - 2.89 (m, 2H), 2.84 (d, J = 9.1 Hz, 3H), 2.75 - 2.43 (m, 1H), 2.34 (s , 3H), 1.91- 1.40 (m, 8H)。 |
254 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(噁烷-2-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 480.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.29 - 7.16 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 4.51 - 4.14 (m, 4H), 4.10 - 3.80 (m, 3H), 3.63 - 3.38 (m, 1H), 3.15 - 2.87 (m, 1H), 2.84 (d, J = 6.4 Hz, 3H), 2.76 - 2.44 (m, 1H), 2.33 (s, 3H), 1.95 - 1.76 (m, 4H), 1.75 - 1.39 (m, 6H)。 |
255 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(6-側氧基-1,6-二氫嗒嗪-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 418.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.43 (dd, J = 9.8, 3.8 Hz, 1H), 7.06 (dd, J = 8.2, 3.8 Hz, 1H), 7.04-6.96 (m, 1H), 6.91 - 6.68 (m, 2H), 4.37-4.27 (m, 1H), 4.13 - 3.76 (m, 4H), 3.07 - 2.81 (m, 1H), 2.77 - 2.48 (m, 4H), 2.13 (d, J = 7.2 Hz, 3H), 1.78 - 1.57 (m, 3H), 1.57 - 1.33 (m, 1H)。 |
256 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(6-甲基嗒嗪-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 416.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.82 - 7.66 (m, 2H), 7.29 - 6.96 (m, 3H), 4.72 - 4.54 (m, 1H), 4.39 - 4.26 (m, 2H), 4.24 - 4.01 (m, 1H), 3.80 - 3.72 (m, 1H), 3.11 - 2.96 (m, 1H), 2.95 - 2.74 (m, 4H), 2.74 - 2.66 (m, 3H), 2.35 - 2.28 (m, 3H), 2.01 - 1.62 (m, 4H)。 |
257 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-[2-(1,3-噻唑-5-基)乙醯基]六氫吡啶-3-基]尿素 | LC-MS: m/z 421.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.98 (s, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.14 - 7.05 (m, 1H), 4.53 - 4.41 (m, 1H), 4.35 - 4.27 (m, 2H), 4.16 - 3.87 (m, 4H), 3.24 - 2.98 (m, 1H), 2.90 - 2.83 (m, 3H), 2.81 - 2.52 (m, 1H), 2.34 (s, 3H), 1.92 - 1.77 (m, 3H), 1.62 - 1.45 (m, 1H)。 |
258 | 1-[(4-氯-3-甲基苯基)甲基]-3-[(3R)-1-[2-(1H-咪唑-4-基)乙醯基]六氫吡啶-3-基]-3-甲基尿素 | LC-MS: m/z 404.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.84 (s, 1H), 7.26-7.19 (m, 2H), 7.13 - 6.99 (m, 2H), 4.56 - 4.39 (m, 1H), 4.32 (d, J = 7.3 Hz, 2H), 4.00-3.92 (m, 2H), 3.82-3.71 (m, 2H), 3.20-2.95 (m, 1H), 2.84 (d, J = 10.0 Hz, 3H), 2.77 - 2.48 (m, 1H), 2.31 (d, J = 5.5 Hz, 3H), 1.85-1.74 (m, 3H), 1.055-1.39 (m, 1H)。 |
259 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1,3-噻唑-4-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 407.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.89 - 9.03 (m, 1H), 8.11 - 8.00 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.14-7.03 (m, 1H), 4.63 - 4.54 (m, 1H), 4.35 - 4.24 (m, 2H), 4.13 (d, J = 8.0 Hz, 2H), 3.27 - 2.69 (m, 5H), 2.33 (s , 3H), 1.98 - 1.74 (m, 3H), 1.74 - 1.57 (m, 1H)。 |
260 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(5-甲基-1,2-噁唑-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 405.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.25 (dd, J = 8.2, 4.2 Hz, 1H), 7.19 (d, J = 14.2 Hz, 1H), 7.15- 7.03 (m, 1H), 6.32 (dd, J = 11.6, 0.7 Hz, 1H), 4.65-4.52 (m, 1H), 4.37 - 4.23 (m, 2H), 4.14 - 3.99 (m, 2H), 3.28 - 2.99 (m, 1H), 2.97 - 2.70 (m, 4H), 2.44 (d, J = 16.7 Hz, 3H), 2.33 (d, J = 3.8 Hz, 3H), 1.95 - 1.80 (m, 3H), 1.67 - 1.55(m, 1H)。 |
261 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(4-甲基-1,3-噁唑-5-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 405.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.24 - 8.08 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.19 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 4.51 - 3.98 (m, 5H), 3.15 - 2.67 (m, 5H), 2.33 (s, 3H), 2.31 (s , 3H), 1.94 - 1.80 (m, 3H), 1.71 - 1.57 (m, 1H)。 |
262 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1,2-噁唑-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 391.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.77 (dd, J = 9.2, 1.6 Hz, 1H), 7.26 (dd, J = 8.2, 5.4 Hz, 1H), 7.25-7.22 (m, 1H), 7.14 - 7.04 (m, 1H), 6.70 (dd, J = 12.6, 1.8 Hz, 1H), 4.68 - 4.52 (m, 1H), 4.39 - 4.21 (m, 2H), 4.20 - 4.02 (m, 2H), 3.13 - 2.71 (m, 5H), 2.34 (d, J = 5.2 Hz, 3H), 1.98 - 1.79 (m, 3H), 1.74 - 1.58 (m, 1H)。 |
263 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1-甲基-1H-吡唑-4-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 404.2 (M+H)。 1H NMR(400 MHz, CDCl3) δ 8.03 (s, 1H), 7.75 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.66 - 4.41 (m, 1H), 4.31 (s, 2H), 4.26 - 3.99 (m, 2H), 3.86 (s , 3H), 3.26 - 2.98 (m, 1H), 2.93 - 2.60 (m, 4H), 2.33 (s , 3H), 1.97 - 1.79 (m, 3H), 1.71 - 1.53 (m, 1H)。 |
264 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1H-吡唑-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 390 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.67 (d, J = 6.4 Hz, 1H), 7.30 -6.99 (m, 3H), 6.62 (s, 1H), 4.67 -4.36 (m, 2H), 4.30 (s, 2H), 4.10 (s, 1H), 3.29 -2.98 (m, 1H), 2.96 -2.63 (m, 4H), 2.33 (d, J = 5.8 Hz, 3H), 1.86-1.52 (m, 4H)。 |
265 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(吡嗪-2-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 402.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.82 (dd, J = 5.1, 1.3 Hz, 1H), 8.68-8.50 (m,, 2H), 7.29 - 6.99 (m, 3H), 4.67-4.54 (m, 1H), 4.36-4.10 (m, 3H), 3.83-3.71 (m, 1H), 3.09-2.95 (m, 1H), 2.92-2.71 (m, 4H), 2.33 (s, 3H), 1.95-1.65 (m, 4H)。 |
266 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(吡啶-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 400.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.55 (d, J = 3.9 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.05 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 8.2, 2.2 Hz, 1H), 6.62 (dd, J = 9.1, 1.1 Hz, 1H), 5.08 - 4.94 (m, 1H), 4.85 (s, 1H), 3.88 - 3.71 (m, 2H), 3.54 - 3.42 (m, 1H), 3.37 (dd, J = 10.5, 8.1 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.82 (qd, J = 4.6, 1.8 Hz, 1H), 2.33 (s, 3H), 2.27 (ddd, J = 14.3, 6.2, 2.8 Hz, 1H), 2.16 - 2.07 (m, 1H), 1.99 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.23 - 1.10 (m, 5H)。 |
267 | 3-[(3R)-1-苯甲醯基六氫吡啶-3-基]-1-[(4-氯-3-甲基苯基)甲基]-3-甲基尿素 | LC-MS: m/z 400.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.45-7.40 (m, 5H), 7.29-6.95 (m, 3H), 4.56 (br, 1H), 4.32-4.10 (m, 3H), 3.64 (br, 1H), 3.19-2.67 (m, 5H), 2.32 (s, 3H), 1.94-1.70 (m, 3H), 1.61 (br, 1H)。 |
268 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(3-苯基丙醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 428.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 7.35 -7.13 (m, 7H), 7.08 (t, J = 8.4 Hz, 1H), 6.91 (t, J = 5.7 Hz, 1H), 4.38-4.15 (m,, 3H), 3.95-3.61 (m, 2H), 3.05-2.70 (m, 6H), 2.6 -2.52 (m, 3H), 2.28 (s, 3H), 1.77- .55 (m, 3H), 1.41-1.22 (m, 1H)。 |
269 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(1-甲基-1H-咪唑-4-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 404.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 7.60 (s, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.06 - 6.78 (m, 1H), 5.09 (d, J = 83.9 Hz, 1H), 4.35 (s, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.91 (s, 1H), 3.66 (s, 3H), 3.13 (s, 1H), 2.71 (d, J = 34.3 Hz, 4H), 2.30 (s, 3H), 1.72 (s, 3H), 1.45 (d, J = 12.4 Hz, 1H)。 |
270 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(吡啶-2-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 401.4 (M+H)。 1H NMR(400 MHz, DMSO) δ 8.55 (dd, J = 29.7, 4.5 Hz, 1H), 7.95 - 7.85 (m, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.45 (ddd, J = 11.8, 6.2, 3.0 Hz, 1H), 7.38 - 7.20 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 - 6.92 (m, 1H), 4.41 (dd, J = 48.2, 12.2 Hz, 1H), 4.26 - 3.91 (m, 3H), 3.52 (dd, J = 42.7, 10.9 Hz, 1H), 3.20 - 2.89 (m, 1H), 2.73 (d, J = 50.5 Hz, 3H), 2.29 (d, J = 16.6 Hz, 3H), 1.84 - 1.61 (m, 3H), 1.57 - 1.43 (m, 1H)。 |
271 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(嗒嗪-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 402.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 9.24 (ddd, J = 14.4, 5.0, 1.8 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.30 - 6.99 (m, 3H), 4.70 - 4.57 (m, 1H), 4.34 (t, J = 9.2 Hz, 1H), 4.28 (s, 1H), 4.25 - 4.03 (m, 1H), 3.73 (dd, J = 29.6, 12.1 Hz, 2H), 3.14 - 2.97 (m, 1H), 2.96 - 2.75 (m, 4H), 2.33 (d, J = 15.4 Hz, 3H), 2.01 - 1.65 (m, 4H)。 |
一般程序 J : 實例 272 : (
R)-3-(4-
氯 -3- 甲基苄基 )-1-(1-( 環丙烷羰基 ) 六氫吡啶 -3- 基 )-1- 環丙基尿素之合成 向
J1(67 mg, 0.21 mmol)及DIEA (81 mg, 0.63 mmol)於無水DMF (5 mL)中之混合物中添加環丙烷羧酸
J2(19 mg, 0.22 mmol)及HATU (84 mg, 0.22 mmol)。將所得混合物於r.t.下攪拌1 hr。然後將混合物傾倒至水(10 mL)中且用EtOAc (20 mL)萃取兩次。將合併之有機層用飽和NH
4Cl溶液及鹽水洗滌,經無水Na
2SO
4乾燥,過濾且濃縮至乾燥。經由prep-HPLC純化殘餘物,以得到淺黃色固體狀
實例 272(17 mg, 20.73 %產率)。LC/MS (ESI) m/z: 390 (M+H)
+。1H NMR (400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.13 - 7.05 (m, 1H), 4.54 - 4.39 (m, 1H), 4.37 - 4.21 (m, 3H), 3.57 - 3.34 (m, 1H), 3.22 - 2.91 (m, 1H), 2.65 - 2.43 (m, 2H), 2.34 (s, 3H), 2.28 - 2.12 (m, 1H), 1.99 - 1.76 (m, 3H), 1.62 - 1.36 (m, 1H), 0.97 - 0.68 (m, 8H)。
下表中之化合物係自上述或市售適當起始材料使用上述一般程序J及
實例 272中之中間體
J1來製備。
實例 | 結構及名稱 | 數據 |
273 | 1-[(4-氯-3-甲基苯基)甲基]-3-甲基-3-[(3R)-1-(戊-4-炔醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 376.3 (M+H)。 1H NMR(400 MHz, CDCl 3) δ 7.32 - 7.24 (m, 1H), 7.18 (s, 1H), 7.11 - 7.04 (m, 1H), 4.97 - 4.67 (m, 1H), 4.65 - 4.49 (m, 1H), 4.45 - 4.26 (m, 2H), 4.22 - 4.11 (m, 1H), 3.85 - 3.72 (m, 1H), 2.98 - 2.86 (m, 1H), 2.80 (s, 3H), 2.70 - 2.47 (m, 5H), 2.43 - 2.37 (m, 1H), 2.35 (s, 3H), 1.95 (s, 1H), 1.91 - 1.46 (m, 3H)。 |
一般程序 K : 實例 274 : (
R)-3-(4-
氯 -3- 甲基苄基 )-1- 甲基 -1-(1-(6-( 三氟甲基 ) 嗒嗪 -3- 基 ) 六氫吡啶 -3- 基 ) 尿素之合成 向
K1(59 mg, 0.2 mmol)及K
2CO
3(56 mg, 0.4 mmol)於DMF (6 mL)中之混合物中添加3-氯-6-(三氟甲基)嗒嗪
K2(44 mg, 0.24 mmol)。將所得混合物於80℃下攪拌10 hr。冷卻後,將混合物用飽和NH
4Cl溶液(20 mL)稀釋且用EtOAc (20 mL)萃取兩次。將合併之有機層用飽和NH
4Cl溶液及鹽水洗滌,經無水Na
2SO
4乾燥,過濾且濃縮至乾燥。經由prep-HPLC純化殘餘物,以得到白色固體狀
實例 274(8 mg, 9.1 %產率)。LC/MS (ESI) m/z: 442 (M+H)
+。1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 9.7 Hz, 1H), 7.35 (d, J = 9.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.45 - 4.36 (m, 1H), 4.31 (s, 2H), 4.12 - 4.02 (m, 1H), 3.19 - 3.09 (m, 1H), 3.04 - 2.94 (m, 1H), 2.90 (s, 3H), 2.33 (s, 3H), 1.98 - 1.84 (m, 3H), 1.75 - 1.60 (m, 1H)。
實例 | 結構及名稱 | 數據 |
275 | 3-[(4-氯-3-甲基苯基)甲基]-1-[(3R)-1-(6-氰基吡嗪-2-基)六氫吡啶-3-基]-1-甲基尿素 | LC-MS: m/z 399.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.47 (s, 1H), 8.09 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.46 - 4.29 (m, 4H), 4.10 (dt, J = 10.9, 7.5 Hz, 1H), 3.04 (dd, J = 12.5, 11.5 Hz, 1H), 2.94 - 2.83 (m, 4H), 2.34 (s, 3H), 1.89 (ddd, J = 15.8, 9.8, 3.4 Hz, 3H), 1.73 - 1.58 (m, 1H)。 |
以下實例係藉由
一般程序 A來製備
實例 | 結構 / 名稱 | 數據 |
278 | 3-環丙基-1-{[2-氟-4-(1H-吡唑-1-基)苯基]甲基}-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 435.2 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.46 (dd, J = 16.5, 8.4 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 6.53 (dd, J = 2.5, 1.9 Hz, 1H), 4.53 - 4.44 (m, 2H), 4.43 - 4.31 (m, 2H), 3.78 (tt, J = 11.8, 3.9 Hz, 1H), 3.33 (d, J = 12.4 Hz, 1H), 2.88 (td, J = 13.0, 2.7 Hz, 1H), 2.62 - 2.51 (m, 1H), 2.26 (qd, J = 12.5, 4.0 Hz, 1H), 2.01 - 1.81 (m, 2H), 1.69 - 1.56 (m, 1H), 1.04 - 0.93 (m, 2H), 0.88 - 0.74 (m, 2H)。 |
279 | 3-環丙基-1-{[2-氟-4-(1,3-噻唑-2-基)苯基]甲基}-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 453 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 4.3 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.71 (dd, J = 18.7, 9.5 Hz, 2H), 7.64 - 7.60 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.36 (dd, J = 8.8, 3.8 Hz, 1H), 7.27 (d, J=9.4Hz,1H),6.98(d,J=5.7Hz,1H),4.50(d,J=4.9Hz,2H),4.37(dd,J=23.6,12.7Hz,2H),3.78(t,J=11.8Hz,1H),3.35(s,1H),2.88(t,J=12.9Hz,1H),2.58(s,1H),2.32-2.20(m, 1H), 1.92 (dd, J = 46.2, 12.0 Hz, 2H), 1.62 (q, J = 13.3 Hz, 1H), 0.98 (d, J = 6.7 Hz, 2H), 0.82 (s, 2H)。 |
280 | 3-環丙基-1-{[2-氟-5-(1,3-噻唑-2-基)苯基]甲基}-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 453 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.44 - 8.38 (m, 1H), 7.95 (dd, J = 7.1, 2.2 Hz, 1H), 7.90 - 7.82 (m, 2H),7.58(d,J=3.3Hz,1H),7.34(dd,J=9.4,4.4Hz,1H),7.30-7.16(m,2H),7.07(t,J=6.0Hz, 1H), 4.52 (d, J = 2.5 Hz, 2H), 4.36 (ddd, J = 13.2, 12.6, 7.7 Hz, 2H), 3.78 (tt, J = 12.0, 3.9 Hz, 1H), 3.36 (d, J = 12.3 Hz, 1H), 2.88 (td, J = 13.1, 2.6 Hz, 1H), 2.67 - 2.57 (m, 1H), 2.28 (qd, J = 12.6, 4.1 Hz, 1H), 1.92 (dd, J = 53.6, 12.6 Hz, 2H), 1.63 (ddt, J = 17.1, 13.1, 6.6 Hz, 1H), 1.02 - 0.95 (m, 2H), 0.89 - 0.82 (m, 2H)。 |
281 | 3-環丙基-1-{[2-氟-5-(1H-吡唑-1-基)苯基]甲基}-3-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 436 m/z (M+H)。 1H NMR(400MHz,MeOD) δ 8.41 (dd,J=4.4,1.2Hz,1H), 8.15 (d,J=2.4Hz,1H), 7.74 (dd,J=6.4,2.8Hz,1H), 7.70 (d,J=1.7Hz,1H), 7.61 (ddd,J=8.7, 4.2, 2.9 Hz, 1H), 7.34 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 - 7.18 (m, 2H), 6.52 - 6.49 (m, 1H), 4.56 - 4.47 (m, 2H), 4.35 (ddd, J = 18.6, 12.5, 7.5 Hz, 2H), 3.78 (tt, J = 11.9, 3.9 Hz, 1H), 3.33 (d, J = 12.8 Hz, 1H), 2.87 (td, J = 13.0, 2.7 Hz, 1H), 2.65 - 2.52 (m, 1H), 2.26 (qd, J = 12.6, 4.2 Hz, 1H), 1.97 (d, J = 11.5 Hz, 1H), 1.85 (d, J = 12.8 Hz, 1H), 1.68 - 1.54 (m, 1H), 1.02 - 0.92 (m, 2H), 0.87 - 0.75 (m, 2H)。 |
282 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(1,2,4-三嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 419 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.45 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 4.75 (d, J = 8.6 Hz, 2H), 4.39 (d, J = 5.4 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.42 (t, J = 11.9 Hz, 1H), 2.87 (td, J = 13.1, 2.7 Hz, 1H), 2.60 - 2.55 (m, 1H), 2.32 (s, 3H), 2.31 - 2.23 (m, 1H), 1.90 (dd, J = 27.9, 12.4 Hz, 2H), 1.57 (dt, J = 13.0, 4.0 Hz, 1H), 0.94 (ddd, J = 9.9, 6.9, 3.7 Hz, 2H), 0.83 - 0.73 (m, 2H)。 |
283 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-乙基-3-[(3S)-1-(酞嗪-1-基)吡咯啶-3-基]尿素 | LC-MS: 442 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.88 (s, 1H), 8.42 - 8.38 (m, 1H), 7.94 (tdd, J = 6.9, 5.4, 2.0 Hz, 3H), 7.24 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 9.8 Hz, 1H), 4.80 (d, J = 9.0 Hz, 1H), 4.38 (s, 2H), 4.04 - 3.90 (m, 4H), 3.42 (dd,J=7.1,1.7Hz,2H), 2.29 (d,J=5.8Hz,5H), 1.23(t,J=7.0Hz,3H)。 |
284 | 3-[(4-氯-2,5-二氟苯基)甲基]-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 422 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.3, 1.0 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (ddd, J = 9.3, 3.5, 2.3 Hz, 2H), 7.21 (dd, J = 9.5, 6.5 Hz, 1H), 7.02 (t, J = 5.7 Hz, 1H), 4.42 - 4.30 (m, 4H), 3.76 (tt, J = 11.9, 3.9 Hz, 1H), 3.35 (s, 1H), 2.88 (td, J = 13.1, 2.7 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.25 (qd, J = 12.6, 4.2 Hz, 1H), 1.96 (d, J = 11.5 Hz, 1H), 1.86 (d, J = 13.1 Hz, 1H), 1.68 - 1.54 (m, 1H), 1.02 - 0.92 (m, 2H), 0.81 (dd, J = 6.6, 4.1 Hz, 2H)。 |
285 | 3-{[3-(3-氯苯基)-1,2-噁唑-5-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 427.3 m/z (M+H)。 1H NMR(400 MHz, CDCl3) δ 8.58 (dt, J = 4.4, 1.3 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.69 (dq, J = 6.9, 1.5 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.29 - 7.19 (m, 4H), 7.01 (dd, J = 9.3, 1.3 Hz, 1H), 6.61 (t, J = 0.8 Hz, 1H), 4.77 - 4.62 (m, 2H), 4.47 (d, J = 12.9 Hz, 1H), 4.09 (d, J = 13.8 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.07 (t, J = 12.9 Hz, 1H), 3.02 - 2.91 (m, 5H), 2.03 (s, 0H), 1.89 (td, J = 12.9, 4.5 Hz, 2H), 1.77 - 1.54 (m, 8H), 1.26 (s, 3H)。). |
286 | 1-環丙基-3-{[5-(3-甲氧基苯基)-1,3-噁唑-2-基]甲基}-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 449 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.37 - 7.24 (m, 4H), 7.23 - 7.19 (m, 1H), 6.91 (dd, J = 8.2, 1.7 Hz, 1H), 4.57 (s, 2H), 4.38 (dd, J = 27.6, 13.2 Hz, 2H), 3.84 - 3.78 (m, 4H), 2.95 - 2.82 (m, 1H), 2.65 - 2.57 (m, 1H), 2.27 (tt, J = 13.0, 6.4 Hz, 1H), 1.82 (ddd, J = 94.5, 29.2, 12.5 Hz, 4H), 1.01 - 0.95 (m, 2H), 0.92 - 0.86 (m, 2H)。 |
287 | 1-環丙基-3-[(5-苯基-1,2-噁唑-3-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 419 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (s, 1H), 7.81 (dd, J = 7.8, 1.4 Hz, 2H), 7.51 - 7.41 (m, 3H), 7.35 (d, J = 3.2 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.04 (t, J = 5.8 Hz, 1H), 6.72 (s, 1H), 4.53 - 4.44 (m, 2H), 4.44-4.27(m,2H),3.80(tt,J=11.9,3.9Hz,1H),3.36-3.31(m,1H),2.87(dd,J=18.4,7.6Hz,1H),2.61-2.51(m,1H),2.26(qd,J=12.6,4.0Hz,1H),1.98(d,J=11.6Hz,1H),1.86(d,J=13.3Hz, 1H), 1.62 (dtd, J = 13.0, 9.3, 4.0 Hz, 1H), 1.02 - 0.91 (m, 2H), 0.88 - 0.77 (m, 2H)。 |
288 | 2-[(3R)-3-(1-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)六氫吡啶-1-基]-1,3-噁唑-4-甲酸乙酯 | LC-MS: 479 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 7.99 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.38 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 (dd, J = 12.4, 4.0 Hz, 2H), 3.82 - 3.69 (m, 1H), 3.46 - 3.37 (m, 1H), 2.97 - 2.87 (m, 1H), 2.61 - 2.51 (m, 1H), 2.32 (s, 3H), 2.22 - 2.10 (m, 1H), 1.95 - 1.82 (m, 2H), 1.72 - 1.58 (m, 1H), 1.36 - 1.29 (m, 3H), 0.99 - 0.89 (m, 2H), 0.81 - 0.72 (m, 2H)。 |
289 | 1-環丙基-3-{[3-(3-甲氧基苯基)-1,2-噁唑-5-基]甲基}-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: 449 m/z (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 4.3, 1.0 Hz, 1H), 7.42 - 7.34 (m, 4H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 (t, J = 5.9 Hz, 1H), 7.06 - 6.99 (m, 1H), 6.66 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H), 4.42 - 4.30 (m, 2H), 3.84 (s, 3H), 3.78 (ddd, J = 15.8, 7.9, 4.0 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.89 (td, J = 13.0, 2.7 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.25 (td, J = 12.5, 4.1 Hz, 1H), 1.92 (dd, J = 46.8, 12.7 Hz, 2H), 1.70 - 1.55 (m, 1H), 1.03 - 0.95 (m, 2H), 0.84 (dd, J = 7.9, 4.4 Hz, 2H)。 |
步驟 1於0˚C下在N
2氣氛下向化合物(R)-3-(環丙基胺基)六氫吡啶-1-甲酸(9H-茀-9-基)甲酯(1 eq.)及TEA (3 eq.)於無水DCM中之溶液中逐滴添加化合物
M1(1 eq.)於無水DCM中之溶液。將所得混合物於0˚C下在N
2氣氛下攪拌1小時。然後將混合物用水稀釋且用EtOAc萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用庚烷/乙酸乙酯溶析)純化殘餘物,以產生化合物
M2。
步驟 2將
M2(1 eq)溶解於20%六氫吡啶/DMF (0.1M)中且將反應混合物於r.t.下攪拌1-2小時。然後在真空下濃縮反應混合物且藉由急速管柱層析使用DCM/DCM:7N NH
4MeOH (10:0至0:10)純化粗產物,以得到產物
M3。
步驟 3將
M3(1 eq)、適當羧酸
M4(1.2 eqs)及HATU (1.3 eqs)溶解於DMF (0.1M)中,然後添加DIEA (2 eqs)且於r.t.下攪拌反應物直至完全轉化。添加水並將反應混合物用DCM萃取兩次。經無水Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。藉由prep HPLC純化粗產物,以產生純產物
M5。
1- 環丙基 -1-[(3R)-1-(2- 羥基乙醯基 ) 六氫吡啶 -3- 基 ]-3-[(3- 苯基 -1,2- 噁唑 -5- 基 ) 甲基 ] 尿素 , 實例 290 之合成 於0˚C下在N
2氣氛下向(R)-3-(環丙基胺基)六氫吡啶-1-甲酸(9H-茀-9-基)甲酯(400 mg, 1.10 mmol)及TEA (0.460mL, 3.30mmol.)於無水DCM (11mL)中之溶液中逐滴添加5-(異氰酸基甲基)-3-苯基異噁唑(220mg, 1.10mmol)於無水DCM (5.5mL)中之溶液。將所得混合物於0˚C下在N
2氣氛下攪拌1小時。然後將混合物用水稀釋且用EtOAc萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥並濃縮至乾燥。經由急速管柱層析(用庚烷/乙酸乙酯溶析)純化殘餘物,以產生
X1(280mg, 45%產率)。將
X1(280mg, 0.498mmol)溶解於20%六氫吡啶/DMF (4.98mL)中且將反應混合物於r.t.下攪拌1小時。然後在真空下濃縮反應混合物且藉由急速管柱層析使用DCM/DCM:7N NH
4MeOH (10/0至0/10)純化粗產物,以得到
X2(150mg, 88%產率)。將
X2(20 mg, 0.06mmol)、2-羥基乙酸(5.4mg, 0.072mmol)及HATU (29mg, 0.076mmol)溶解於DMF (0.56mL)中,然後添加DIEA (21uL, 0.12mmol)且將反應物於r.t.下攪拌5分鐘。添加水並將反應混合物用DCM萃取兩次。經無水Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。藉由prep HPLC純化粗產物,以產生白色粉末狀
實例 290(11mg, 47%產率)。LC/MS (ESI) m/z: 399.1 (M+H)
+。
下文實例係藉由
一般程序 M來製備
實例 | 結構 / 名稱 | 數據 |
291 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(2-側氧基吡咯啶-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 451 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28 - 7.20 (m, 1H), 7.13 (dd, J = 9.8, 3.8 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J = 11.8, 5.9 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.45 - 4.31 (m, 2H), 4.12 (dd, J = 25.2, 12.2 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.87 - 3.59 (m, 1H), 3.59 - 3.32 (m, 3H), 3.26 - 2.94 (m, 1H), 2.64 - 2.54 (m, 1H), 2.51 - 2.44 (m, 1H), 2.38 - 2.14 (m, 5H), 1.99 - 1.77 (m, 2H), 1.62 - 1.37 (m, 1H), 1.03 - 0.88 (m, 2H), 0.87 - 0.60 (m, 2H)。 |
292 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(2R)-1,1-二側氧基-1λ⁶-四氫噻吩-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 486 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 - 7.21 (m, 1H), 7.13 (dd, J = 9.8, 2.5 Hz, 1H), 4.54 (dd, J = 39.0, 7.8 Hz, 2H), 4.44 - 4.33 (m, 2H), 4.12 (d, J = 12.9 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.51 - 3.44 (m, 1H), 3.26 (s, 1H), 3.22 - 3.01 (m, 3H), 2.74 - 2.43 (m, 3H), 2.32 (s, 3H), 2.30 - 2.21 (m, 2H), 2.18 - 2.12 (m, 1H), 2.01 (s, 1H), 1.90 - 1.77 (m, 2H), 1.55 - 1.44 (m, 1H), 0.99 - 0.89 (m, 2H), 0.82 - 0.68 (m, 2H)。 |
293 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(5-側氧基吡咯啶-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 451 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.29 - 7.21 (m, 1H), 7.13 (dd, J = 9.8, 4.6 Hz, 1H), 4.49 (t, J = 14.4 Hz, 1H), 4.44 - 4.32 (m, 2H), 3.91 (t, J = 14.0 Hz, 1H), 3.85 - 3.65 (m, 2H), 3.60 - 3.42 (m, 2H), 3.30 - 3.21 (m, 1H), 3.19 - 3.08 (m, 1H), 3.07 - 2.93 (m, 1H), 2.68 - 2.58 (m, 1H), 2.58 - 2.50 (m, 2H), 2.50 - 2.44 (m, 1H), 2.32 (s, 3H), 2.19 (dtd, J = 8.6, 6.8, 4.5 Hz, 1H), 2.03 (s, 1H), 2.02 - 1.79 (m, 2H), 1.57 - 1.43 (m, 1H), 1.03 - 0.87 (m, 2H), 0.86 - 0.64 (m, 2H)。 |
294 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(1-甲基-2-側氧基吡咯啶-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 465 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (t, J = 7.0 Hz, 1H), 7.13 (dd, J = 9.8, 3.2 Hz, 1H), 4.51 (d, J = 12.9 Hz, 1H), 4.41 - 4.31 (m, 2H), 4.15 - 3.92 (m, 2H), 3.78 (d, J = 25.7 Hz, 1H), 3.64 - 3.37 (m, 3H), 3.21 - 2.93 (m, 1H), 2.87 - 2.80 (m, 3H), 2.59 - 2.46 (m, 2H), 2.42 - 2.34 (m, 1H), 2.31 (s, 3H), 2.28 - 2.14 (m, 2H), 1.95 - 1.77 (m, 2H), 1.64 - 1.35 (m, 1H), 0.98 - 0.67 (m, 4H)。 |
295 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(2S)-1,4-二噁烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 454 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.29 - 7.21 (m, 1H), 7.13 (dd, J = 9.8, 3.8 Hz, 1H), 4.48 - 4.33 (m, 4H), 3.98 (dd, J = 44.7, 12.1 Hz, 1H), 3.86 - 3.74 (m, 3H), 3.73 - 3.67 (m, 2H), 3.66 - 3.55 (m, 2H), 3.51 (dd, J = 11.4, 6.5 Hz, 1H), 3.17 - 2.92 (m, 1H), 2.60 - 2.52 (m, 1H), 2.48 (dd, J = 13.0, 2.7 Hz, 1H), 2.32 (s, 3H), 2.30 - 2.17 (m, 1H), 1.94 - 1.77 (m, 2H), 1.60 - 1.37 (m, 1H), 0.99 - 0.87 (m, 2H), 0.83 - 0.68 (m, 2H)。 |
296 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(氧雜環丁烷-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 424 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (t, J = 8.1 Hz, 1H), 7.13 (dd, J = 9.8, 5.5 Hz, 1H), 4.84 - 4.76 (m, 4H), 4.53 - 4.35 (m, 3H), 4.21 - 4.14 (m, 1H), 3.71 - 3.61 (m, 1H), 3.51 (td, J = 11.8, 5.7 Hz, 1H), 3.36 (dd, J = 17.0, 8.4 Hz, 1H), 3.15 (dd, J = 23.8, 12.1 Hz, 1H), 2.90 (td, J = 13.3, 2.7 Hz, 1H), 2.57 - 2.45 (m, 2H), 2.32 (d, J = 3.2 Hz, 3H), 2.14 (ddd, J = 23.0, 13.2, 3.5 Hz, 1H), 1.97 - 1.77 (m, 2H), 1.53 - 1.39 (m, 1H), 0.94 (ddd, J = 16.0, 8.7, 4.3 Hz, 2H), 0.81 - 0.63 (m, 2H)。 |
297 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(2R)-1,4-二噁烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 454 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.21 (dd, J = 17.7, 8.0 Hz, 1H), 7.08 (dd, J = 9.6, 6.9 Hz, 1H), 5.80 - 5.64 (m, 1H), 4.58 - 4.24 (m, 4H), 4.06 - 3.59 (m, 8H), 3.37 - 3.17 (m, 2H), 2.91 (t, J = 11.7 Hz, 1H), 2.56 - 2.33 (m, 2H), 2.31 (d, J = 2.6 Hz, 3H), 1.96 - 1.75 (m, 2H), 1.59 - 1.47 (m, 1H), 0.94 - 0.66 (m, 4H)。 |
298 | 1-[(3R)-1-(3-胺基氧雜環戊烷-3-羰基)六氫吡啶-3-基]-3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基尿素 | LC-MS: m/z 453.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.53 - 4.22 (m, 4H), 4.12 (dd, J = 19.6, 9.3 Hz, 1H), 4.01 - 3.74 (m, 3H), 3.62 (dd, J = 9.2, 4.2 Hz, 2H), 3.16 (dd, J = 24.0, 7.3 Hz, 1H), 2.54 - 2.38 (m, 2H), 2.32 (s, 3H), 2.25 - 2.15 (m, 1H), 2.00 - 1.77 (m, 3H), 1.53 (d, J = 11.4 Hz, 1H), 0.94 (d, J = 5.8 Hz, 2H), 0.75 (s, 2H)。 |
299 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(3-羥基氧雜環戊烷-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 454 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.23 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.42 (d, J = 14.8 Hz, 2H), 4.37 (s, 2H), 4.24 - 4.01 (m, 1H), 4.00 - 3.82 (m, 2H), 3.77 (dd, J = 13.5, 9.6 Hz, 1H), 3.70 - 3.32 (m, 2H), 3.22 - 2.79 (m, 1H), 2.71 - 2.50 (m, 2H), 2.32 (s, 3H), 2.26 - 1.97 (m, 2H), 1.85 (d, J = 48.8 Hz, 2H), 1.49 (s, 1H), 1.01 - 0.88 (m, 2H), 0.83 - 0.68 (m, 2H)。 |
300 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-[(3R)-1-(3-氰基氧雜環戊烷-3-羰基)六氫吡啶-3-基]-1-環丙基尿素 | LC-MS: m/z 463 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.19 (d, J = 8.0 Hz, 1H), 7.12 - 7.05 (m, 1H), 5.76 (d, J = 29.9 Hz, 1H), 4.59 - 4.45 (m, 1H), 4.41 - 4.22 (m, 4H), 3.98 (ddd, J = 27.0, 12.5, 4.7 Hz, 3H), 3.68 (t, J = 11.1 Hz, 2H), 3.49 - 3.28 (m, 1H), 3.10 (d, J = 13.1 Hz, 1H), 2.90 - 2.68 (m, 1H), 2.58 - 2.47 (m, 2H), 2.29 (d, J = 25.8 Hz, 4H), 1.93 - 1.82 (m, 2H), 1.57 - 1.47 (m, 1H), 0.87 (dd, J = 13.1, 6.8 Hz, 3H), 0.76 (d, J = 19.4 Hz, 1H)。 |
301 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-[3-(甲氧基甲基)氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 482 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.20 (dd, J = 8.0, 2.6 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.73 (t, J = 5.6 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.04 - 3.75 (m, 5H), 3.56 (d, J = 8.0 Hz, 1H), 3.49 (q, J = 8.9 Hz, 2H), 3.35 (d, J = 4.6 Hz, 3H), 3.23 (t, J = 11.3 Hz, 1H), 2.46 (s, 1H), 2.31 (s, 3H), 2.29 - 2.14 (m, 2H), 1.99 (dt, J = 13.3, 8.1 Hz, 1H), 1.86 (d, J = 11.6 Hz, 1H), 1.77 (dd, J = 13.6, 2.6 Hz, 1H), 1.62 (s, 3H), 1.53 - 1.42 (m, 1H), 0.88 (d, J = 6.0 Hz, 2H), 0.75 (d, J = 12.6 Hz, 2H)。 |
302 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-{2-氧雜二環[2.1.1]己烷-4-羰基}六氫吡啶-3-基]尿素 | LC-MS: m/z 450.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28 - 7.20 (m, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.54 - 4.30 (m, 4H), 3.86 (dd, J = 33.0, 5.6 Hz, 1H), 3.78 - 3.46 (m, 3H), 3.28 (d, J = 10.9 Hz, 1H), 3.07 (dt, J = 24.5, 12.7 Hz, 1H), 2.56 - 2.47 (m, 1H), 2.31 (s, 3H), 2.24 - 2.07 (m, 3H), 1.97 - 1.76 (m, 4H), 1.48 (qd, J = 13.3, 6.6 Hz, 1H), 1.00 - 0.87 (m, 2H), 0.73 (ddd, J = 25.6, 15.2, 8.2 Hz, 2H)。 |
303 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(3-甲氧基氧雜環戊烷-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 468 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 9.7 Hz, 1H), 6.85 (s, 1H), 4.49 (t, J=13.0Hz,1H),4.38(s,3H),4.06(d,J=9.8Hz,1H),3.97-3.85(m,2H),3.82(dt,J=8.2,4.1Hz, 1H), 3.51 (dd, J = 47.8, 10.0 Hz, 1H), 3.26 - 3.22 (m, 3H), 3.16 - 2.89 (m, 1H), 2.61 - 2.43 (m, 3H), 2.32 (s, 3H), 2.21 (dd, J = 16.7, 11.4 Hz, 2H), 1.94 - 1.81 (m, 2H), 1.58 - 1.44 (m, 1H), 0.98 - 0.90 (m, 2H), 0.75 (s, 2H)。 |
304 | 1-環丙基-3-{[3-(3-甲氧基苯基)-1,2-噁唑-5-基]甲基}-1-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 469 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.38 (dd, J = 4.4, 1.8 Hz, 3H), 7.21 (s, 1H), 7.05 - 7.00 (m, 1H), 6.65 (d, J = 6.9 Hz, 1H), 4.69 - 4.34 (m, 4H), 3.92 (ddd, J = 21.4, 13.8, 6.4 Hz, 3H), 3.84 (d, J = 6.6 Hz, 3H), 3.79 (d,J=6.1Hz,1H),3.56-3.32(m,1H),3.08(t,J=47.9Hz,1H),2.51(dd,J=6.8,2.9Hz,1H),2.32-2.14(m,2H),2.05-1.84(m,5H),1.63-1.43(m,1H),1.06-0.94(m,2H),0.85-0.73(m,2H)。 |
305 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(1-羥基環丙烷羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 424 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 9.7 Hz, 1H), 5.74 (t, J = 5.8 Hz, 1H), 4.48 (t, J = 13.6 Hz, 2H), 4.39 (d, J = 5.9 Hz, 2H), 3.75 (s, 1H), 3.10 (t, J = 11.8 Hz, 1H), 2.61 (s,1H),2.45-2.38(m,1H),2.31(s,3H),2.23-2.12(m,1H),1.97(d,J=11.8Hz,1H),1.81(d,J=13.5Hz,1H),1.58(dt,J=13.2,4.1Hz,1H),1.15(d,J=7.4Hz,1H),1.00-0.86(m,5H),0.75(t,J = 4.3 Hz, 2H)。 |
306 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(2-羥基-2-甲基丙醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 426 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.20 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.74 (t, J = 5.7 Hz, 1H), 4.80 - 4.10 (m, 5H), 3.45 (dd, J = 78.1, 29.3 Hz, 2H), 2.46 (s, 1H), 2.31 (s, 3H), 2.25 (d, J = 11.1 Hz, 1H), 1.93 - 1.78 (m, 3H), 1.53 (s, 3H), 1.48 (s, 3H), 0.89 (t, J = 5.8 Hz, 2H), 0.74 (s, 2H)。 |
307 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(3-氟氧雜環戊烷-3-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 456 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.85 (s, 1H), 4.41 (dd, J = 27.0, 12.4 Hz, 3H), 4.24 - 3.87 (m, 5H), 3.79 - 3.40 (m, 2H), 3.15 (dd, J = 49.8, 38.8 Hz, 1H), 2.76 - 2.43 (m, 3H), 2.32 (s, 3H), 2.23 (d, J = 13.1 Hz, 1H), 1.99 - 1.79 (m, 2H), 1.51 (d, J = 13.4 Hz, 1H), 0.94 (s, 2H), 0.74 (d, J = 10.6 Hz, 2H)。 |
308 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(1,3-噻唑-5-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 451 (M+H)。 1H NMR(400 MHz, MeOD) δ 9.11 (s, 1H), 8.25 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 6.85 (s, 1H), 4.61 - 4.02 (m, 4H), 3.85 - 3.57 (m, 1H), 3.50 - 3.35 (m, 1H), 3.11 - 2.67 (m, 1H), 2.60 - 2.44 (m, 1H), 2.32 - 2.21 (m, 4H), 2.02 - 1.82 (m, 2H), 1.61 (dd, J = 26.3, 13.2 Hz, 1H), 0.94 (d, J = 6.4 Hz, 2H), 0.81 - 0.56 (m, 2H)。 |
309 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(1-甲基環丙烷羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 422 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.36 (t, J = 9.9 Hz, 4H), 3.71 - 3.54 (m, 1H), 3.29 - 3.02 (m, 1H), 2.53 (ddd, J = 10.4, 6.7, 3.9 Hz, 1H), 2.32 (s, 3H), 2.19 (qd, J = 12.6, 4.1 Hz, 1H), 1.87 (dd, J = 28.7, 12.7 Hz, 2H), 1.57 - 1.41 (m, 1H), 1.38 - 1.12 (m, 4H), 0.98 - 0.83 (m, 4H), 0.75 (s, 2H), 0.60 (d, J = 1.4 Hz, 2H)。 |
310 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-[(3R)-1-環丙烷羰基六氫吡啶-3-基]-1-環丙基尿素 | LC-MS: m/z 408 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.32 - 7.19 (m, 1H), 7.13 (d, J = 9.6 Hz, 1H), 4.44 (d, J = 9.3 Hz, 1H), 4.38 (d, J = 8.7 Hz, 2H), 4.32 - 4.22 (m, 1H), 3.75 (d, J = 11.4 Hz, 1H), 3.56 - 3.35 (m, 1H), 3.20 - 2.98 (m, 1H), 2.52 (d, J = 11.0 Hz, 2H), 2.31 (s, 3H), 2.26 - 2.14 (m, 1H), 2.01 - 1.75 (m, 3H), 1.63 - 1.40 (m, 1H), 1.02 - 0.90 (m, 2H), 0.88 - 0.75 (m, 5H), 0.72 (s, 1H)。 |
311 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(3-羥基丙醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 412.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 9.8, 3.7 Hz, 1H), 6.85 (dt, J = 11.7, 5.6 Hz, 1H), 4.51 (t, J = 10.1 Hz, 1H), 4.36 (dd, J = 9.8, 5.9 Hz, 2H), 3.93 (t, J = 11.6 Hz, 1H), 3.79 (dt, J = 16.1, 5.4 Hz, 2H), 3.75 - 3.44 (m, 1H), 3.38 - 3.31 (m, 1H), 3.16 - 2.90 (m, 1H), 2.79 - 2.61 (m, 1H), 2.59 - 2.49 (m, 2H), 2.32 (s, 3H), 2.26 - 2.09 (m, 1H), 1.99 - 1.74 (m, 2H), 1.63 - 1.41 (m, 1H), 0.94 (ddd, J = 16.8, 10.1, 4.6 Hz, 2H), 0.74 (dddd, J = 12.3, 8.4, 5.6, 2.2 Hz, 2H)。 |
312 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(2-羥基乙醯基)六氫吡啶-3-基]尿素 | LC-MS: m/z 398 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.28 - 7.21 (m, 1H), 7.13 (d, J = 9.6 Hz, 1H), 4.59 - 4.33 (m, 3H), 4.31 - 4.13 (m, 2H), 3.73 - 3.48 (m, 2H), 3.26 (d, J = 12.5 Hz, 1H), 3.17 - 2.86 (m, 1H), 2.57 - 2.49 (m, 1H), 2.32 (s, 3H), 2.18 (dd, J = 24.7, 14.2 Hz, 1H), 1.99 - 1.76 (m, 2H), 1.58 - 1.42 (m, 1H), 1.01 - 0.84 (m, 2H), 0.75 (dd, J = 21.6, 8.8 Hz, 2H)。 |
313 | 1-環丙基-3-{[3-(3-甲氧基苯基)-1,2-噁唑-5-基]甲基}-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 469 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.44 - 7.33 (m, 3H), 7.22 - 7.07 (m, 1H), 7.03 (ddd, J = 6.5, 4.2, 2.6 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 4.57 - 4.48 (m, 4H), 4.04 - 3.86 (m, 3H), 3.85 (s, 3H), 3.84 - 3.71 (m, 3H), 3.55 - 3.44 (m, 1H), 3.43 - 3.32 (m, 1H), 3.05 (ddd, J = 24.4, 18.5, 11.6 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.25 - 2.05 (m, 3H), 1.99 - 1.78 (m, 2H), 1.55 - 1.41 (m, 1H), 1.03 - 0.91 (m, 2H), 0.87 - 0.72 (m, 2H)。 |
314 | 1-環丙基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]-3-[(3-苯基-1,2-噁唑-5-基)甲基]尿素 | LC-MS: m/z 439 (M+H)。 1H NMR(400 MHz, CDCl3) δ 7.79 (dd, J = 6.5, 2.9 Hz, 2H), 7.48 - 7.42 (m, 3H), 6.50 (s, 1H), 5.87 (s, 1H), 4.60 (d, J = 4.4 Hz, 2H), 3.97 (d, J = 8.1 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.29 - 3.15 (m, 2H), 2.68 - 2.01 (m, 5H), 1.92 (s, 1H), 1.82 (d, J = 13.2 Hz, 1H), 1.68 (s, 2H), 1.48 (s, 1H), 0.88 (d, J = 56.6 Hz, 4H)。 |
314A | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 438 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (t, J = 8.5 Hz, 1H), 7.13 (dd, J = 9.8, 4.8 Hz, 1H), 6.86 (d, J = 23.0 Hz, 1H), 4.42 (dt, J = 26.8, 12.8 Hz, 3H), 4.04 - 3.72 (m, 6H), 3.45 (dt, J = 14.7, 9.6 Hz, 2H), 3.27 (d,J=12.4Hz,1H),3.12(t,J=11.8Hz,1H),2.99(t,J=12.1Hz,1H),2.59-2.43(m,2H),2.28(d,J=25.5Hz,3H),2.22-2.00(m,3H),1.99-1.78(m,2H),1.55-1.35(m,1H),1.04-0.84(m,2H), 0.82 - 0.60 (m, 2H)。 |
315 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(2S)-氧雜環戊烷-2-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 438.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (t, J = 7.9 Hz, 1H), 7.13 (dd, J = 9.8, 4.4 Hz, 1H), 6.85 (dt, J = 18.8, 5.7 Hz, 1H), 4.70 (dd, J = 9.8, 4.0 Hz, 1H), 4.52 - 4.32 (m, 3H), 4.02 - 3.87 (m, 2H), 3.86 - 3.73 (m, 2H), 3.48 (ddd, J = 15.6, 7.9, 3.9 Hz, 1H), 3.26 (s, 1H), 3.13 (t, J = 11.8 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.61 - 2.45 (m, 2H), 2.32 (s, 3H), 2.28 - 2.11 (m, 2H), 2.05 - 1.79 (m, 5H), 1.62 - 1.40 (m, 1H), 1.00 - 0.86 (m, 2H), 0.84 - 0.64 (m, 2H)。 |
316 | 1-[(4-氯-3-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]尿素 | LC-MS: m/z 420 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.27 (dt, J = 14.1, 7.0 Hz, 1H), 7.21 (d, J = 6.9 Hz, 1H), 7.10 (dd, J = 10.9, 4.5 Hz, 1H), 6.91 (d, J = 29.3 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.40 - 4.27 (m, 2H), 3.86 (dddd, J = 19.0, 17.4, 14.8, 11.4 Hz, 6H), 3.53 - 3.38 (m, 2H), 3.27 (d, J = 12.0 Hz, 1H), 3.13 (t, J = 11.9 Hz, 1H), 2.99 (t, J = 13.1 Hz, 1H), 2.57 - 2.46 (m, 2H), 2.34 (s, 3H), 2.25 - 2.04 (m, 3H), 2.01 - 1.80 (m, 2H), 1.55 - 1.37 (m, 1H), 0.98 - 0.86 (m, 2H), 0.83 - 0.61 (m, 2H)。 |
一般程序 N 於0˚C下在N
2氣氛下向化合物(R)-N-環丙基-1-((2-硝基苯基)磺醯基)六氫吡啶-3-胺(1 eq.)及TEA (3 eq.)於無水DCM中之溶液中逐滴添加化合物
N1(1 eq.)於無水DCM中之溶液。將所得混合物於0˚C下在N
2氣氛下攪拌1小時。然後將混合物用水稀釋且用EtOAc萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥並濃縮至乾燥。經由急速管柱層析(用庚烷/乙酸乙酯溶析)純化殘餘物,以產生化合物
N2。將
N2(1 eq)溶解於DMF (0.1M)中,之後溶解於碳酸鉀(2 eqs)及苯硫酚(1.5 eqs)中且將反應混合物於r.t.下攪拌1-2小時。添加1 M HCl直至pH 2-3且將所得混合物用DCM萃取兩次。然後藉由小心添加NaOH 6N使酸溶液達到pH 10-11。然後用DCM (x3)萃取所得鹼性溶液。經Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。粗製
N3不經任何進一步純化即用於下一步驟。將
N3(1 eq)、適當羧酸
N4(1.2 eqs)及HATU (1.3 eqs)溶解於DMF (0.1M)中,然後添加DIEA (2 eqs)且於r.t.下攪拌反應物直至完全轉化。添加水並將反應混合物用DCM萃取兩次。經無水Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。藉由prep HPLC純化粗產物,以產生純產物
N5 。
一般程序 O : O1係使用程序M或N來合成
O3 之合成將適當胺
O2(2 eqs)及CDI (2 eqs)溶解於DMF (0.1M)中且將反應物於r.t下攪拌2-3小時。然後添加
O1(1 eq)且於50℃下攪拌反應物直至完全轉化(1至4小時)。在真空下濃縮反應混合物且藉由prep HPLC純化粗製物,以產生產物
O3。
(3R)-N- 環丙基 -3-(3- 環丙基 {[(4- 氯 -2- 氟 -5- 甲基苯基 ) 甲基 ] 胺甲醯基 } 胺基 ) 六氫吡啶 -1- 甲醯胺 , ( 實例 317) 之合成 將環丙胺(8.3uL, 0.12mmol)及CDI (19.5mg, 0.12mmol)溶解於DMF中且將反應物於r.t下攪拌2小時。然後添加
X1(20mg, 0.06mmol)且將反應物升溫至50℃並攪拌2小時。然後將反應混合物冷卻至r.t.且在真空下濃縮。藉由prep HPLC純化粗製物,以產生白色粉末狀
X1(10mg, 39%產率)。LC/MS (ESI) m/z: 423.1 (M+H)
+。1H NMR (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 4.37 (t, J = 4.7 Hz, 2H), 3.96 (d, J = 12.8 Hz, 1H), 3.84 (d, J = 12.5 Hz, 1H), 3.61 (ddd, J = 11.8, 7.9, 4.1 Hz, 1H), 3.13 - 3.06 (m, 1H), 2.61 (td, J = 13.0, 2.4 Hz, 1H), 2.55 - 2.47 (m, 2H), 2.32 (s, 3H), 2.07 (td, J = 12.5, 3.8 Hz, 1H), 1.87 (d, J = 11.6 Hz, 1H), 1.74 (d, J = 13.0 Hz, 1H), 1.47 (dt, J = 13.3, 4.2 Hz, 1H), 0.96 - 0.89 (m, 2H), 0.73 (d, J = 3.6 Hz, 2H), 0.66 - 0.60 (m, 2H), 0.47 - 0.40 (m, 2H)。
實例 | 結構 / 名稱 | 數據 |
318 | (3R)-3-(3-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)-N-(2-甲氧基乙基)六氫吡啶-1-甲醯胺 | LC-MS: m/z 441 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.43 - 4.30 (m, 2H), 4.00 - 3.84 (m, 2H), 3.66 - 3.56 (m, 1H), 3.45 - 3.40 (m, 2H), 3.33 (s, 3H), 3.31 - 3.28 (m, 2H), 3.19 - 3.08 (m, 1H), 2.68 - 2.57 (m, 1H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.18 - 2.04 (m, 1H), 1.90 (t, J = 13.4 Hz, 1H), 1.80 - 1.69 (m, 1H), 1.56 - 1.40 (m, 1H), 1.00 - 0.85 (m, 2H), 0.80 - 0.67 (m, 2H)。 |
319 | 1-[(4-氯-2-氟-5-甲基苯基)甲基]-3-環丙基-3-[(3R)-1-(嗎啉-4-羰基)六氫吡啶-3-基]尿素 | LC-MS: m/z 453.1 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.84 (t, J = 5.7 Hz, 1H), 4.44 - 4.29 (m, 2H), 3.82 - 3.73 (m, 1H), 3.67 - 3.56 (m, 6H), 3.27 - 3.16 (m, 4H), 3.07 (t, J = 11.8 Hz, 1H), 2.77 - 2.62 (m, 1H), 2.53 - 2.42 (m, 1H), 2.32 (s, 3H), 2.17 - 2.01 (m, 1H), 1.96 - 1.85 (m, 1H), 1.82 - 1.73 (m, 1H), 1.63 - 1.47 (m, 1H), 0.99 - 0.87 (m, 2H), 0.80 - 0.63 (m, 2H)。 |
320 | (3R)-3-(3-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)-N-甲基六氫吡啶-1-甲醯胺 | LC-MS: m/z 397 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.43 - 4.31 (m, 2H), 3.99 - 3.91 (m, 1H), 3.90 - 3.80 (m, 1H), 3.66 - 3.55 (m, 1H), 3.17 - 3.06 (m, 1H), 2.69 (s, 3H), 2.68 - 2.60 (m, 1H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.18 - 2.04 (m, 1H), 1.88 (d, J = 11.4 Hz, 1H), 1.79 - 1.70 (m, 1H), 1.58 - 1.42 (m, 1H), 1.58 - 1.42 (m, 1H), 0.97 - 0.89 (m, 2H), 0.79 - 0.67 (m, 2H), 0.79 - 0.70 (m, 2H)。 |
321 | (3R)-3-(3-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)六氫吡啶-1-甲醯胺 | LC-MS: m/z 383 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.89 - 6.81 (m, 1H), 4.42 - 4.32 (m, 2H), 4.01 - 3.85 (m, 2H), 3.69 - 3.58 (m, 1H), 3.23 - 3.14 (m, 1H), 2.72 - 2.61 (m, 1H), 2.56 - 2.48 (m, 1H), 2.31 (s, 3H), 2.17 - 2.05 (m, 1H), 1.93 - 1.84 (m, 1H), 1.79 - 1.69 (m, 1H), 1.58 - 1.45 (m, 1H), 0.97 - 0.89 (m, 2H), 0.77 - 0.70 (m, 2H)。 |
322 | (3R)-3-(3-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)-N,N-二甲基六氫吡啶-1-甲醯胺 | LC-MS: m/z 411 (M+H)。 1H NMR(400 MHz, CD3OD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 4.37 (s, 2H), 3.78 (ddd, J = 15.5, 8.0, 3.9 Hz, 1H), 3.61 - 3.53 (m, 2H), 3.08 (t, J = 11.8 Hz, 1H), 2.82 (s, 6H), 2.67 (dt, J = 13.0, 6.6 Hz, 1H), 2.52 - 2.47 (m, 1H), 2.31 (s, 3H), 2.09 (td, J = 12.5, 8.5 Hz, 1H), 1.89 (d, J = 12.3 Hz, 1H), 1.79 - 1.73 (m, 1H), 1.63 - 1.53 (m, 1H), 0.96 - 0.90 (m, 2H), 0.76 - 0.70 (m, 2H)。 |
將N-[(3R)-3-六氫吡啶基]胺基甲酸第三丁酯
P1(25 g, 124.83 mmol)及DIPEA (19.36 g, 149.79 mmol, 26.09 mL)於500mL DCM中之溶液逐滴添加至冰浴中之Fmoc-Cl (44.28 g, 137.31 mmol)於DCM (150 mL)中之溶液,在兩小時內逐滴添加。其後,將反應混合物再攪拌一小時,然後升溫至rt,過濾且濃縮,以提供粗製白色固體狀(3R)-3-(第三丁氧基羰基胺基)六氫吡啶-1-甲酸9H-茀-9-基甲酯
P2(81 g, 191.71 mmol, 153.58%產率),其不經進一步純化即使用。向(3R)-3-(第三丁氧基羰基胺基)六氫吡啶-1-甲酸9H-茀-9-基甲酯
P2(20 g, 47.34 mmol)於THF (200 mL)中之懸浮液中添加二噁烷/HCl (4.0M) (4.0 M, 59.17 mL)且將反應混合物於60˚C下攪拌3小時。然後藉由旋轉蒸發在減壓下濃縮反應混合物且將所得固體用Et2O洗滌2次,以得到白色固體狀(3R)-3-胺基六氫吡啶-1-甲酸9H-茀-9-基甲酯
P3(13.91 g, 38.76 mmol, 81.89%產率, HCl。向(3R)-3-胺基六氫吡啶-1-甲酸9H-茀-9-基甲酯
P3(13.91 g, 38.76 mmol, HCl)於DCM (250 mL)中之懸浮液中添加2,4-二甲氧基苯甲醛(6.12 g, 36.82 mmol)、DIPEA (5.51 g, 42.64 mmol, 7.43 mL)及三乙醯氧基硼氫化鈉(8.22 g, 38.76 mmol)。將反應混合物攪拌過夜,且然後用1 M NaOH、鹽水洗滌,且經無水硫酸鈉乾燥。然後濃縮反應混合物且藉由層析(DCM:MeOH 100:0至95:5)純化,以得到黃色油狀(3R)-3-[(2,4-二甲氧基苯基)甲基胺基]六氫吡啶-1-甲酸9H-茀-9-基甲酯
P4(9.26 g, 19.59 mmol, 50.55%產率)。向(3R)-3-[(2,4-二甲氧基苯基)甲基胺基]六氫吡啶-1-甲酸9H-茀-9-基甲酯(5.75 g, 12.17 mmol)
P4於THF (50 mL)及乙醇(100 mL)中之溶液中添加(1-乙氧基環丙氧基)-三甲基-矽烷(5.30 g, 30.43 mmol, 6.12 mL)、乙酸(10.96 g, 182.55 mmol, 10.44 mL)及氰基硼氫化鈉(2.68 g, 42.60 mmol)。將反應混合物於80˚C下過夜,然後濃縮且將殘餘物溶解於DCM中。將有機層用飽和碳酸鈉水溶液、鹽水洗滌,且經無水硫酸鈉乾燥。濃縮有機層且藉由層析(DCM:MeOH 10:0至9:1)純化,以提供白色發泡體狀(3R)-3-[環丙基-[(2,4-二甲氧基苯基)甲基]胺基]六氫吡啶-1-甲酸9H-茀-9-基甲酯
P5。將(3R)-3-[環丙基-[(2,4-二甲氧基苯基)甲基]胺基]六氫吡啶-1-甲酸9H-茀-9-基甲酯
P5(2.0 g, 3.90 mmol)於TFA (59.20 g, 519.19 mmol, 40 mL)中之溶液加熱至80℃且攪拌6小時。然後將反應混合物冷卻至室溫且濃縮。將殘餘物溶解於DCM中且用飽和Na
2CO
3水溶液洗滌,經無水Na
2SO
4乾燥且濃縮,以提供褐色油狀(3R)-3-(環丙基胺基)六氫吡啶-1-甲酸9H-茀-9-基甲酯
P6(1.35 g, 3.72 mmol, 95.47%產率),將其儲存於-20˚C下且不經進一步純化即使用。
一般程序 Q : 向N-[(3R)-3-六氫吡啶基]胺基甲酸第三丁酯(10 g, 49.93 mmol)
Q1及DIPEA (7.10 g, 54.92 mmol, 9.57 mL)於DCM (500 mL)中之溶液中逐份添加固體狀2-硝基苯磺醯氯(11.62 g, 52.43 mmol)。將反應混合物於環境溫度下攪拌15分鐘且然後緩慢添加TFA (56.93 g, 499.31 mmol, 38.47 mL)。將反應混合物於環境溫度下再攪拌2小時且然後在減壓下藉由旋轉蒸發濃縮。然後將粗製殘餘物重新懸浮於500mL DCM中,且向此溶液中添加DIPEA (11.29 g, 87.38 mmol, 15.22 mL)、2,4-二甲氧基苯甲醛(7.88 g, 47.43 mmol)及三乙醯氧基硼氫化鈉(26.46 g, 124.83 mmol)。將反應混合物於環境溫度下攪拌過夜。然後將反應混合物用1 M NaOH (500 mL)洗滌且然後分離有機層,用無水硫酸鈉乾燥,且在減壓下藉由旋轉蒸發濃縮。藉由驟沸塔層析(DCM:MeOH, 100:0至96:4)純化粗製殘餘物,以提供(3R)-N-[(2,4-二甲氧基苯基)甲基]-1-(2-硝基苯基)磺醯基-六氫吡啶-3-胺(7.94 g, 18.23 mmol, 36.52%產率)
Q2。向(3R)-N-[(2,4-二甲氧基苯基)甲基]-1-(2-硝基苯基)磺醯基-六氫吡啶-3-胺(7.93 g, 18.21 mmol)
Q2於THF (240 mL)及EtOH (120 mL)中之溶液中添加1-乙氧基-1-三甲基矽氧基環丙烷(7.94 g, 45.52 mmol, 9.15 mL)、氰基硼氫化鈉(4.01 g, 63.73 mmol)及乙酸(16.40 g, 273.14 mmol, 15.62 mL)。將反應混合物於80˚C下攪拌過夜,之後將其冷卻至rt,且在減壓下藉由旋轉蒸發濃縮。然後將殘餘物溶解於乙酸乙酯(250 mL)中且用1 M NaOH (250 mL)、鹽水(250 mL)洗滌,用Na
2SO
4乾燥,過濾且在減壓下藉由旋轉蒸發濃縮,以提供(3R)-N-環丙基-N-[(2,4-二甲氧基苯基)甲基]-1-(2-硝基苯基)磺醯基-六氫吡啶-3-胺(8.58 g, 18.04 mmol, 99.08%產率)
Q3,其不經進一步純化即使用。將(3R)-N-環丙基-N-[(2,4-二甲氧基苯基)甲基]-1-(2-硝基苯基)磺醯基-六氫吡啶-3-胺(8.58 g, 18.04 mmol)溶解於TFA (100 mL)
Q3及Et3SiH (10 mL)中且加熱至80℃。4小時後,再添加一份三乙基矽烷(7.28 g, 62.61 mmol, 10 mL)以阻止形成二甲氧基甲苯基陽離子。然後將反應混合物攪拌過夜。然後在減壓下藉由旋轉蒸發濃縮反應混合物且將粗製殘餘物溶解於200 mL乙酸乙酯中。將有機層用3M NaOH (約200 mL)、鹽水(約200mL)洗滌,用Na
2SO
4乾燥,過濾且在減壓下藉由旋轉蒸發濃縮。然後將粗製殘餘物溶解於100 mL二乙醚中且緩慢逐滴添加二乙醚中之氯化氫溶液2.0 M (2.0 M, 9.02 mL)。自溶液過濾產物,以提供褐色固體狀(3R)-N-環丙基-1-(2-硝基苯基)磺醯基-六氫吡啶-3-胺(5.5 g, 15.20 mmol, 84.25%產率, HCl)
Q4。
一般程序 R連接至芳香族環上之雜環之中間體苄胺係藉由以下一般程序來製備:
將適當芳基溴
R1(1 eq)溶解於二噁烷(0.3M)中,然後添加相應稀試劑
R2(1.1 eqs)及鈀(0) 四(三苯基膦) (0.1 eqs)且將反應物於110℃下攪拌過夜。然後將反應混合物冷卻且在真空下濃縮。藉由急速管柱層析使用庚烷/乙酸乙酯純化粗製物,以產生純產物
R3 。將
R3(1 eq)溶解於二噁烷中之HCl 4M (20 eqs)中且於r.t.下攪拌反應物直至完全去保護。添加飽和NaHCO
3溶液且用DCM (x3)萃取反應混合物。經無水Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。粗產物
R4未經進一步純化即用於下一步驟。
經由一般程序 R 之 (2- 氟 -4-( 噁唑 -2- 基 ) 苯基 ) 甲胺 R6 之合成 將
R4(520mg, 1.71mmol)溶解於二噁烷(5.12mL)中,然後添加2-(三丁基錫烷基)噁唑(673mg, 1.88mmol)及鈀(0) 四(三苯基膦) (198mg, 0.17mmol)且將反應物於110℃下攪拌過夜。然後將反應混合物冷卻且在真空下濃縮。藉由急速管柱層析使用庚烷/乙酸乙酯純化粗物質,以產生白色粉末狀純產物
R5(350mg, 70%產率)。將
R5(350mg, 1.20mmol)溶解於二噁烷中之HCl 4M (6mL, 24mmol)中且於r.t.下攪拌反應物直至完全去保護。添加飽和NaHCO
3溶液且用DCM (x3)萃取反應混合物。經無水Na
2SO
4乾燥合併之有機層,過濾並在真空下濃縮。粗產物(2-氟-4-(噁唑-2-基)苯基)甲胺
R6不經進一步純化即用於下一步驟。
實例323-333係自相應芳基或雜芳基-苄基胺及上述一般程序來製備
條目 | 一般程序 | 結構、名稱 | 數據 |
323 | A | 3-{[1-(5-氯-2-氟苯基)-1H-1,2,3-三唑-4-基]甲基}-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 471 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (d, J = 3.8 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 6.4, 2.6 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.49 - 7.41 (m, 1H), 7.37 (dd, J = 9.4, 4.3 Hz, 1H), 7.29 (d, J = 9.1 Hz, 1H), 7.04 (t, J = 5.6 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.37 (dd, J = 28.3, 12.8 Hz, 2H), 3.85 - 3.73 (m, 1H), 3.34 (s, 1H), 2.87 (dt, J = 12.9, 6.6 Hz, 1H), 2.55 (dt, J = 10.1, 3.4 Hz, 1H), 2.25 (qd, J = 12.6, 4.0 Hz, 1H), 1.96 (d, J = 11.6 Hz, 1H), 1.86 (d, J = 13.2 Hz, 1H), 1.69 - 1.54 (m, 1H), 0.95 (dd, J = 8.4, 5.6 Hz, 2H), 0.81 (d, J = 3.3 Hz, 2H)。 |
324 | B | 1-環丙基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]-3-[(5-苯基-1,2-噁唑-3-基)甲基]尿素 | LC-MS: m/z 439.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.81 (d, J = 6.5 Hz, 2H), 7.58 - 7.38 (m, 3H), 7.00 (dd, J = 16.7, 11.5 Hz, 1H), 6.71 (d, J = 5.8 Hz, 1H), 4.57 - 4.41 (m, 3H), 4.06 - 3.74 (m, 6H), 3.59 - 3.38 (m, 2H), 3.26 (s, 1H), 3.13 (t, J = 11.8 Hz, 1H), 3.00 (t, J = 12.2 Hz, 1H), 2.59 - 2.47 (m, 2H), 2.29 - 1.82 (m, 5H), 1.50 (ddd, J = 19.7, 16.9, 8.6 Hz, 1H), 0.95 (ddd, J = 22.2, 12.9, 7.6 Hz, 2H), 0.88 - 0.71 (m, 2H)。 |
325 | B | 1-環丙基-1-[(3R)-1-[(3R)-氧雜環戊烷-3-羰基]六氫吡啶-3-基]-3-[(5-苯基-1,2-噁唑-3-基)甲基]尿素 | LC-MS: m/z 439.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 7.81 (d, J = 6.5 Hz, 2H), 7.58 - 7.38 (m, 3H), 7.00 (dd, J = 16.7, 11.5 Hz, 1H), 6.71 (d, J = 5.8 Hz, 1H), 4.57 - 4.41 (m, 3H), 4.06 - 3.74 (m, 6H), 3.59 - 3.38 (m, 2H), 3.26 (s, 1H), 3.13 (t, J = 11.8 Hz, 1H), 3.00 (t, J = 12.2 Hz, 1H), 2.59 - 2.47 (m, 2H), 2.29 - 1.82 (m, 5H), 1.50 (ddd, J = 19.7, 16.9, 8.6 Hz, 1H), 0.95 (ddd, J = 22.2, 12.9, 7.6 Hz, 2H), 0.88 - 0.71 (m, 2H)。 |
326 | A | 3-{[1-(3-氯苯基)-1H-1,2,3-三唑-4-基]甲基}-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 453.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.42 (dd, J = 3.9, 2.7 Hz, 2H), 7.95 (t, J = 2.0 Hz, 1H), 7.82 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.50 (ddd, J = 8.1, 1.9, 1.0 Hz, 1H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.01 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 4.44 - 4.32 (m, 2H), 3.80 (ddd, J = 15.9, 7.9, 4.0 Hz, 1H), 3.33 (s, 1H), 2.88 (td, J = 13.1, 2.8 Hz, 1H), 2.60 - 2.49 (m, 1H), 2.25 (qd, J = 12.6, 4.2 Hz, 1H), 1.99 (t, J = 9.6 Hz, 1H), 1.86 (d, J = 13.2 Hz, 1H), 1.62 (dtd, J = 13.0, 8.9, 4.1 Hz, 1H), 1.00 - 0.91 (m, 2H), 0.82 (t, J = 4.8 Hz, 2H)。 |
327 | A | 3-{[5-(3-氯苯基)-1,2-噁唑-3-基]甲基}-1-環丙基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 453.2 (M+H)。 1H NMR(400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.1 Hz, 1H), 7.84 (s, 1H), 7.79 - 7.71 (m, 1H), 7.52 - 7.44 (m, 2H), 7.36 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 6.81 (s, 1H), 4.49 (s, 2H), 4.45 - 4.33 (m, 2H), 3.81 (tt, J = 11.9, 3.9 Hz, 1H), 3.33 (d, J = 12.7 Hz, 1H), 2.89 (td, J = 13.0, 2.6 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.27 (qd, J = 12.4, 4.0 Hz, 1H), 1.99 (d, J = 13.2 Hz, 1H), 1.87 (d, J = 13.5 Hz, 1H), 1.63 (tdd, J = 13.0, 9.0, 4.1 Hz, 1H), 1.02 - 0.92 (m, 2H), 0.88 - 0.79 (m, 2H)。 |
328 | A | 1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]-3-({1-[4-(三氟甲基)苯基]-1H-1,2,3-三唑-4-基}甲基)尿素 | LC-MS: m/z 461.35 (M+H)。 |
329 | A | 3-{[1-(2-氯苯基)-1H-1,2,3-三唑-4-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 427.42 (M+H)。 |
330 | A | 3-{[1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 423.32 (M+H)。 |
331 | A | 3-{[1-(3-甲氧基苯基)-1H-1,2,3-三唑-4-基]甲基}-1-甲基-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 423.41 (M+H)。 |
332 | A | 1-甲基-3-[(5-甲基-1-苯基-1H-1,2,3-三唑-4-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 407.3 (M+H)。 |
333 | A | 1-甲基-3-[(1-苯基-1H-1,2,3-三唑-4-基)甲基]-1-[(3R)-1-(嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z 393.3 (M+H)。 |
實例
334-343
實例 | 程序 | 結構、名稱 | 數據 |
334 | R | 3-[(3R)-3-({[(4-氯-3-甲基苯基)甲基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]嗒嗪-4-甲酸 | LC-MS: 418.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.71 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.33 (d,J=1.6Hz,2H),4.18(d,J=3.8Hz,1H),3.95(dd,J=19.1,15.1Hz,2H), 3.22 - 3.14 (m, 1H), 3.04 (dd, J = 17.8, 7.4 Hz, 1H), 2.89 (s, 3H), 2.33 (s, 3H), 1.93 - 1.84 (m, 3H), 1.84 - 1.75 (m, 1H)。 |
335 | R | 6-[(3R)-3-({[(4-氯-3-甲基苯基)甲基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]-N-甲基嗒嗪-4-甲醯胺 | LC-MS: 431.4 (M+H)。 |
336 | R | 6-[(3R)-3-({[(4-氯-3-甲基苯基)甲基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]-N-乙基嗒嗪-4-甲醯胺 | LC-MS: 445.43(M+H)。 |
337 | R | 6-[(3R)-3-(1-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)六氫吡啶-1-基]嗒嗪-4-甲醯胺 | LC-MS: 461(M+H)。 1H NMR (400 MHz, MeOD) δ8.77 (d, J = 1.6 Hz, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.91 (t, J = 5.9 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.42 - 4.36 (m, 3H), 3.78 (ddd, J = 15.7, 7.8, 3.9 Hz, 1H), 3.40 - 3.33 (m, 1H), 2.93 (td, J = 13.1, 2.7 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.32 (s, 3H), 2.30 - 2.21 (m, 1H), 1.97 (d, J = 11.6 Hz, 1H), 1.89 (d, J = 13.3 Hz, 1H), 1.70 - 1.59 (m, 1H), 0.99 - 0.92 (m, 2H), 0.82 - 0.75 (m, 2H)。 |
338 | R | 6-[(3R)-3-(1-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)六氫吡啶-1-基]-N-甲烷磺醯基嗒嗪-4-甲醯胺 | LC-MS: 539 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.82 (s, 1H), 7.97 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.44 - 4.34 (m, 4H), 3.82 - 3.74 (m, 1H), 3.49 (d, J = 11.7 Hz, 1H), 3.21 (s, 3H), 3.03 (dd, J = 13.1, 10.7 Hz, 1H), 2.58 (dt, J = 10.3, 3.5 Hz, 1H), 2.32 (s, 3H), 2.27 (dd, J = 12.4, 8.5 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.67 (q, J = 12.8 Hz, 1H), 0.99 - 0.93 (m, 2H), 0.81 - 0.76 (m, 2H)。 |
339 | R | 6-[(3R)-3-(3-環丙基{[(4-氯-2-氟-5-甲基苯基)甲基]胺甲醯基}胺基)六氫吡啶-1-基]-N-(乙磺醯基)嗒嗪-4-甲醯胺 | LC-MS: 553 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.82 (s, 1H), 7.90 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.7 Hz, 1H), 4.45 - 4.35 (m, 4H), 3.77 (t, J = 11.8 Hz, 1H), 3.51 - 3.38 (m, 3H), 3.01 (t, J = 12.0 Hz, 1H), 2.61 - 2.55 (m, 1H), 2.32 (s, 3H), 2.27 (dd, J = 12.0, 8.1 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.68 (t, J = 13.0 Hz, 1H), 1.34 (t, J = 7.4 Hz, 3H), 0.97 (d, J = 6.2 Hz, 2H), 0.79 (s, 2H)。 |
340 | S | 1-[(3S)-1-(5-胺基嗒嗪-3-基)吡咯啶-3-基]-3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基尿素 | LC-MS: 401 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.95 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 8.3, 2.2 Hz, 1H), 5.92 (d, J = 2.2 Hz, 1H), 4.96 (dd, J = 15.6, 7.7 Hz, 1H), 3.66 - 3.56 (m, 2H), 3.43 - 3.33 (m, 2H), 2.82 (s, 3H), 2.75 - 2.70 (m, 1H), 2.32 (s, 3H), 2.17 (dd, J = 10.7, 6.5 Hz, 2H), 1.97 (td, J = 6.4, 3.1 Hz, 1H), 1.22 - 1.12 (m, 2H)。 |
341 | S | 1-[(3R)-1-(5-胺基嗒嗪-3-基)六氫吡啶-3-基]-3-[(1R,2S)-2-(4-氯-3-甲基苯基)環丙基]-1-甲基尿素 | LC-MS: 415 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.99 (t, J = 2.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 4.12 (dd, J = 27.2, 12.0 Hz, 3H), 2.94 (t, J = 11.7 Hz, 1H), 2.82 (d, J = 17.5 Hz, 4H), 2.77 - 2.70 (m, 1H), 2.32 (s, 3H), 1.98 (d, J = 9.3 Hz, 1H), 1.83 (d, J = 8.8 Hz, 3H), 1.66 (s, 1H), 1.26 - 1.20 (m, 1H), 1.14 (dd, J = 13.5, 6.0 Hz, 1H)。 |
342 | S | N-{6-[(3R)-3-({[(4-氯-3-甲基苯基)甲基]胺甲醯基}(甲基)胺基)六氫吡啶-1-基]嗒嗪-4-基}乙醯胺 | LC-MS: 431 (M+H)。 1H NMR (400 MHz, MeOD)δ 8.53 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.58 (s, 1H), 4.32 (s, 2H), 4.25 (t, J = 12.4 Hz, 2H), 4.08 (d, J = 8.3 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.89 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.88 (dd, J = 9.8, 4.4 Hz, 3H), 1.68 (s, 1H)。 |
343 | R | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-[5-(1H-1,2,3,4-四唑-5-基)嗒嗪-3-基]六氫吡啶-3-基]尿素 | LC-MS: 486 (M+H)。 1H NMR (400 MHz, DMSO) δ 9.05 (d, J = 1.3 Hz, 1H), 7.74 (s, 1H), 7.34 (d, J = 9.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 5.9 Hz, 1H), 4.40 (t, J = 12.8 Hz, 2H), 4.29 (d, J = 5.7 Hz, 2H), 3.68 (d, J = 11.7 Hz,1H), 3.34 (s,1H), 2.89 (d,J=11.6Hz,1H), 2.53 (d,J=3.7Hz,1H), 2.29(s,3H), 2.19-2.10 (m,1H), 1.83 (d,J=12.3Hz,2H), 1.55( d,J=13.4Hz,1H), 0.91 (d,J=6.6Hz,2H), 0.78-0.69(m,2H)。 |
在以下實例中使用一般程序R在最終步驟中製備最終酸、醯胺或磺醯胺且利用先前一般程序:
實例160係藉由一般程序C、之後一般程序R來製備。
實例166、192、193、201、206、212係藉由一般程序B、之後一般程序R來製備。
實例335係藉由一般程序C、之後一般程序R來製備。
實例200係藉由一般程序D、之後一般程序R來製備。
在以下實例中使用一般程序S在最終步驟中製備最終胺或醯胺且利用先前一般程序:
實例180係藉由一般程序C、之後一般程序S來製備。
在實例1中所述之異白胺酸轉運分析中測試選自上文之代表性化合物。結果在圖1中製錶。
步驟 1 : S2 之合成於0℃下在N
2氣氛下向化合物
S1(1eq)及TEA (4eq)於無水THF (0.05M)中之混合物中逐滴添加TMSNCO (1.5 eq),且將所得混合物於室溫下攪拌16小時。然後將混合物傾倒至H
2O中且用EtOAc洗滌兩次。將合併之有機層經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用DCM: MeOH溶析)純化殘餘物,以產生化合物
S2 。
步驟 2 : S3 之合成將
S2(1eq)溶解於DCM/TFA 5:1 (0.1M)中且將所得混合物於室溫下攪拌2小時。然後在減壓下濃縮混合物,以產生粗製化合物
S3,其不經任何進一步純化即用於下一步驟。
步驟 3 : S4 之合成向
S3(1eq)於無水DCM (0.03M)中之添加2,4-二甲氧基苯甲醛(1.2eq)及乙酸(2eq),且將所得混合物於室溫下攪拌1小時。然後向上述混合物中添加NaBH(OAc)
3(2eq)且將所得混合物於45℃下攪拌過夜。然後將混合物傾倒至5% Na
2CO
3溶液中且用DCM (x4)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾並濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析)純化殘餘物,以產生化合物
S4 。
步驟 4 : S5 之合成向
S4(1eq)及乙酸(10eq)於THF/EtOH 1:2 (0.03M)中之混合物中添加(1-乙氧基環丙氧基)三甲基矽烷(1.1eq),之後添加NaBH
3CN (3eq),且將所得混合物於80℃下在N
2氣氛下攪拌16小時。然後將混合物傾倒至5% Na
2CO
3溶液中且用DCM (x3)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾並濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析)純化殘餘物,以產生化合物
S5 。
步驟 5 : S6 之合成將
S5(1eq)添加至TFA (0.1M)中且將所得混合物於80℃下攪拌16小時。然後將混合物在減壓下濃縮至乾燥且經由急速管柱層析(用DCM/MeOH溶析)純化粗產物,以產生化合物
S6 。 步驟 6 : S8 之合成於0℃下在N
2氣氛下向
S6(1eq)於無水DCM (0.03M)中之溶液中添加DIEA (3eq)且將所得混合物於0℃下攪拌15分鐘,之後將其添加至相應異氰酸酯
S7(1eq)於無水DCM (0.08M)中之混合物中。將所得混合物自0℃至室溫攪拌30分鐘。然後將混合物傾倒至飽和NaHCO
3溶液中且用DCM (x3)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾並濃縮至乾燥。經由prep-HPLC純化殘餘物,以產生純
化合物 S8 。
步驟 1 : 346-2 之合成於0℃下在N
2氣氛下向
346-1(150 mg, 0.688 mmol)及TEA (278 mg, 2.752 mmol)於無水THF (10 mL)中之混合物中逐滴添加TMSNCO (119 mg, 1.032 mmol),且將所得混合物於室溫下攪拌16 hr。然後將混合物傾倒至H
2O (50 mL)中且用EtOAc (40 mL)洗滌兩次。經無水Na
2SO
4乾燥合併之有機層,過濾且濃縮至乾燥。經由急速管柱層析(用DCM: MeOH= 100:0至20:1溶析)純化殘餘物,以產生白色固體狀化合物
346-2(150 mg, 83.3 %產率)。LC/MS (ESI) m/z: 162 (M-100+H)
+。
步驟 2 : 346-3 之合成向
346-2(180 mg, 0.575 mmol)於DCM (5 mL)中之溶液添加TFA (1 mL)。在室溫下將所得混合物攪拌2小時。然後在減壓下濃縮混合物,以產生無色油狀粗製化合物
346-3(158 mg, 99.0 %產率),其不經任何進一步純化即用於下一步驟。LC/MS (ESI) m/z: 162.2 (M+H)
+。
步驟 3 : 346-4 之合成向
346-3(158 mg, 0.575 mmol)於無水DCM (15 mL)中之溶液中添加2,4-二甲氧基苯甲醛(115 mg, 0.693 mmol)及乙酸(69 mg, 1.155 mmol)。然後將混合物於室溫下攪拌1小時,之後向上述混合物中添加NaBH(OAc)
3(244 mg, 1.155 mmol)且將所得混合物於45℃下攪拌過夜。然後將混合物傾倒至5% Na
2CO
3溶液(50 mL)中且用DCM (30 mL x 4)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾且濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析= 100:0至12:1)純化殘餘物,以產生無色油狀化合物
346-4(176 mg, 97.8 %產率)。LC/MS (ESI) m/z: 312 (M+H)
+。
步驟 4 : 346-5 之合成向
346-4(176 mg, 0.566 mmol)及乙酸(348 mg, 5.788 mmol)於THF (5 mL)及EtOH(10 mL)中之混合物中添加(1-乙氧基環丙氧基)三甲基矽烷(111 mg, 0.637 mmol),之後添加NaBH
3CN (109 mg, 1.736 mmol)。於80℃下在N
2氣氛下將所得混合物攪拌16小時。然後將混合物傾倒至5% Na
2CO
3溶液(50 mL)中且用DCM (30 mL × 3)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾且濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析= 100:0至20:1)純化殘餘物,以產生無色油狀化合物
346-5(193 mg, 97.5%產率)。LC/MS (ESI) m/z: 352 (M+H)
+。
步驟 5 : 346-6 之合成將
346-5(193 mg, 0.55 mmol)添加至TFA (5 mL)中且將所得混合物於80℃下攪拌16小時。然後將混合物在減壓下濃縮至乾燥。經由急速管柱層析(用DCM/MeOH溶析= 100:0至15:1)純化粗產物,以產生無色油狀化合物
346-6(78 mg, 70.9 %產率)。LC/MS (ESI) m/z: 202 (M+H)
+。
步驟 6 : 346 之合成向
346-6(78 mg, 0.388 mmol)於無水DCM (10 mL)中之溶液中添加DIEA (150 mg, 1.164 mmol)且將所得混合物於0℃下攪拌15分鐘,之後於0℃下在N
2氣氛下將其添加至2-氟-1-(異氰酸基甲基)-4-(三氟甲氧基)苯(92 mg, 0.388 mmol)於無水DCM (5 mL)中之混合物中。將所得混合物自0℃至室溫攪拌30分鐘。然後將混合物傾倒至飽和NaHCO
3溶液(50 mL)中且用DCM (30 mL × 3)萃取。經無水Na
2SO
4乾燥合併之有機層,過濾並濃縮至乾燥。經由prep-HPLC純化殘餘物,以產生白色固體狀
346(27 mg, 16.0 %產率)。LC/MS (ESI) m/z: 437.2 (M+H)
+。
1H NMR (400 MHz, MeOD-d4) δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 7.00 (t, J = 5.7 Hz, 1H), 4.59 - 4.37 (m, 3H), 4.30 (d, J = 12.6 Hz, 1H), 3.84 (d, J = 12.6 Hz, 1H), 3.69 (t, J = 11.9 Hz, 1H), 3.18 (t, J = 12.1 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.59 - 2.53 (m, 1H), 2.37 - 2.24 (m, 2H), 1.01 - 0.92 (m, 2H), 0.83 - 0.73 (m, 2H)。
步驟 1 : T2 之合成於室溫下向相應胺
T1(1eq)於MeCN/DMF 5:1混合物(0.4M)中之混合物中添加CDI (1eq)且將所得混合物攪拌2小時。然後在減壓下濃縮混合物,以產生粗製
T2,其其不經任何進一步純化即用於下一步驟。
步驟 2 : T4 之合成向
T2(0.5eq)及適當
T3(1eq)於MeCN (0.15M)中之混合物中添加TEA (4eq)且將所得混合物於50℃下攪拌16小時。然後將混合物濃縮至乾燥,且將殘餘物溶解於EtOAc中,且用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。經由急速管柱層析(用DCM: MeOH溶析)純化殘餘物,以產生
T4 。
步驟 1 : 347-1 之合成於室溫下向N-甲胺鹽酸鹽(310mg, 4.591 mmol)於MeCN (10 mL)及DMF (2 mL)之混合物中之混合物中添加CDI (744 mg, 4.588 mmol)且將所得混合物於室溫下攪拌2小時。然後在減壓下濃縮混合物,以產生淺黃色油狀粗製
347-1(550 mg, 95.74 %產率),其不經任何進一步純化即用於下一步驟。LC/MS (ESI) m/z: 126 (M+H)
+。
步驟 2 : 347-2 之合成向
347-1(550 mg, 4.395 mmol)及((3
R,5
S)-5-氟六氫吡啶-3-基)胺基甲酸第三丁酯(480 mg, 2.199 mmol)於MeCN (15 mL)中之混合物中添加TEA (888 mg, 8.796 mmol)且將所得混合物於50℃下攪拌16小時。然後將混合物濃縮至乾燥,且將殘餘物溶解於EtOAc (40 mL)中,且用水(50 mL)及鹽水(50 mL)洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。經由急速管柱層析(用DCM: MeOH = 100:0至20:1溶析)純化殘餘物,以產生無色油狀
347-2(302 mg, 49.55 %產率)。LC/MS (ESI) m/z: 176 (M-100+H)
+。
步驟 3 至步驟 7 與一般程序 S' 中之步驟 2 至步驟 6 相同。獲得白色固體狀
實例 347。LC/MS (ESI) m/z: 406.2 (M+H)
+。
1H NMR (400 MHz, MeOD) δ 7.43 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 5.9 Hz, 1H), 4.56 - 4.41 (m, 3H), 4.27 (d, J = 12.4 Hz, 1H), 3.81 (d, J = 12.6 Hz, 1H), 3.66 (t, J = 11.0 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.69 (s, 3H), 2.68 - 2.62 (m, 1H), 2.57 (dt, J = 10.1, 3.4 Hz, 1H), 2.49 (s, 3H), 2.30 (m, 2H), 0.98 - 0.94 (m, 2H), 0.81 - 0.76 (m, 2H)。
步驟 1 : U2 之合成於0℃下在N
2氣氛下向
化合物 U1(11.5 g, 39.59 mmol)及TEA (27.5 mL, 197.95 mmol)於無水THF (200 mL)中之混合物中逐滴添加異氰酸基三甲基矽烷(11.98 g, 83.15 mmol),且將所得混合物於室溫下攪拌16小時。然後將混合物在減壓下濃縮至乾燥。將殘餘物用EtOAc (300 mL)稀釋,且用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用DCM: MeOH= 100:0至95:5溶析)純化粗產物,以得到淺黃色固體狀化合物
U2(10.0 g, 75.7 %產率)。LC/MS (ESI) m/z: 334 (M+H)
+。
步驟 2 : U3 之合成於0℃下在N
2氣氛下將化合物
U2(10 g, 29.99 mmol)逐份添加至TFA (100 mL)中,且然後將所得混合物於80℃下攪拌4小時。然後將反應混合物冷卻至室溫且在減壓下濃縮,以產生紫色油狀粗製化合物
U3(5.48 g, 99.8 %產率),其不經任何進一步純化即用於下一步驟。LC/MS (ESI) m/z: 184 (M+H)
+。
步驟 3 : U5 之合成於0℃下在N
2氣氛下向
U3(1eq)於無水DCM (0.2M)中之溶液中逐滴添加適當異氰酸酯
U4(1eq)及TEA (10eq)於DCM (0.15M)中之混合物。然後在室溫下將所得混合物攪拌1小時,且在減壓下濃縮至乾燥。將殘餘物用EtOAc溶解並用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用DCM: MeOH溶析)純化粗產物,以得到
U5 。
實例 352 之合成 於0℃下在N
2氣氛下向
U3(22.4 mg, 0.095 mmol)於無水DCM (0.4 mL)中之溶液中逐滴添加2-氟-1-(異氰酸基甲基)-4-(三氟甲氧基)苯(17.4 mg, 0.095 mmol)及TEA (0.13 mL, 0.95 mmol)於DCM (0.6 mL)中之混合物。將所得混合物於室溫下攪拌1小時,且然後在減壓下濃縮至乾燥。 將殘餘物溶解於EtOAc (5 mL)中並用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾並濃縮至乾燥。藉由矽膠上管柱層析(用DCM: MeOH= 100:0至95:5溶析)純化粗產物,以得到白色固體狀
352(15 mg, 37.7 %產率)。LC/MS (ESI) m/z: 419.2 (M+H)
+。
1H NMR (400 MHz, MeOD) δ 7.43 (t,
J= 8.6 Hz, 1H), 7.09 (t,
J= 7.9 Hz, 2H), 6.93 (d,
J= 5.4 Hz, 1H), 4.43 (s, 2H), 4.02-3.86 (m, 2H), 3.69 - 3.59 (m, 1H), 3.18 (t,
J= 12.0 Hz, 1H), 2.67 (t,
J= 12.0 Hz, 1H), 2.59 - 2.49 (m, 1H), 2.18 - 2.05 (m, 1H), 1.94-1.84 (m, 1H), 1.80-1.71 (m, 1H), 1.59 - 1.45 (m, 1H), 1.00 - 0.89 (m, 2H), 0.82 - 0.71 (m, 2H)。
V3 係使用程序 M 或 N 來合成 步驟 1 : V2 之合成向適當V
1(1eq)於THF (0.3M)中之溶液中添加TEA (3eq)及CDI (1.2eq),且將所得混合物於室溫下攪拌12小時。然後將混合物在減壓下濃縮至乾燥。將殘餘物溶解於乙酸乙酯中並用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc溶析)純化粗產物,以得到化合物V
2。
步驟 2 : V4 之合成向化合物
V3(1eq)及TEA (3eq)於DCM (0.05M)中之混合物中添加化合物
V2(1.5eq),且將所得混合物於50℃下攪拌16小時。然後將混合物在減壓下濃縮至乾燥,且將殘餘物溶解於EtOAc中且用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc溶析)純化粗產物,以得到化合物
V4 。
步驟 1 : 348-1 之合成向2-((第三丁基二甲基矽基)氧基)乙-1-胺(50 mg, 0.29 mmol)於THF (1 mL)中之溶液中添加TEA (86.5 mg, 0.86 mmol)及CDI (55mg 0.34mmol),且將所得混合物於室溫下攪拌12小時。然後將混合物在減壓下濃縮至乾燥,且將殘餘物溶解於乙酸乙酯(5 mL)中且用水(10 mL)及鹽水(10 mL)洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc = 100:0至4:1溶析)純化粗產物,以得到白色固體狀化合物
348-1(61 mg, 80.26 %產率)。LC/MS (ESI) m/z: 270 (M+H)
+。
步驟 2 : 348-3 之合成向化合物
348-2(15 mg, 0.04)及TEA (12 mg, 0.12)於DCM (0.7 mL)中之混合物中添加化合物
348-1(16 mg, 0.06 mmol),且將所得混合物於50℃下攪拌16小時。然後將混合物在減壓下濃縮至乾燥,且將殘餘物溶解於EtOAc (6 mL)中,且用水及鹽水洗滌。然後經無水Na
2SO
4乾燥有機層,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用PE: EtOAc = 100:0至1:1溶析)純化粗產物,以得到黃色油狀化合物
348-3(19.5 mg, 82.29 %產率)。LC/MS (ESI) m/z: 577 (M+H)
+。
步驟 6 : 348 之合成於0℃下向HCl/二噁烷(0.5 mL, 4 M)中逐份添加化合物
348-3(19.5 mg, 0.034 mmol)且將所得混合物於室溫下攪拌1小時。然後將混合物在減壓下濃縮且將殘餘物用DCM/MeOH (15:1, 1 mL)稀釋。緩慢添加飽和NaHCO
3溶液以使pH至8~9,然後分離有機層,用水及鹽水洗滌,經無水Na
2SO
4乾燥,過濾且濃縮至乾燥。藉由矽膠上管柱層析(用DCM: MeOH =100:0至20:1溶析)純化殘餘物,以產生黃色油狀
348(15 mg, 96.2 %產率)。 LC/MS (ESI) m/z: 463.3 (M+H)
+。
1H NMR (400 MHz, MeOD) δ 7.43 (t,
J= 8.1 Hz, 1H), 7.08 (d,
J= 9.3 Hz, 2H), 4.51 - 4.34 (m, 2H), 3.94 (dd,
J= 30.8, 9.7 Hz, 2H), 3.62 (d,
J= 25.8 Hz, 3H), 3.28 (s, 2H), 3.14 (s, 1H), 2.70 - 2.66 (m, 1H), 2.55 - 2.51 (m, 1H), 2.11 (d,
J= 11.1 Hz, 1H), 1.94 - 1.90 (m, 1H), 1.77 - 1.73 (m, 1H), 1.53 (s, 1H), 0.97 - 0.93 (m, 2H), 0.76 (brs, 2H)。
實例
344-370
實例 | 程序 | 結構、名稱 | 數據 |
344 | T (X=F) | (3 R,5 S)-3-(1-環丙基-3-(2-氟-4-(三氟甲氧基)苄基)脲基)-5-氟- N-甲基六氫吡啶-1-甲醯胺 | LC-MS: 451.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 7.00 (s, 1H), 4.52 - 4.37 (m, 3H), 4.28 (d, J = 12.3 Hz, 1H), 3.81 (d, J = 11.8 Hz, 1H), 3.67 (t, J = 11.7 Hz, 1H), 3.13 (t, J = 12.0 Hz, 1H), 2.69 (s, 3H), 2.65 (s, 1H), 2.56 (dd, J = 6.7, 3.2 Hz, 1H), 2.28 (dd, J = 22.6, 11.2 Hz, 2H), 0.96 (d, J = 6.7 Hz, 2H), 0.77 (s, 2H)。 |
345 | T (X=F) | (3 R,5 S)-3-(3-(4-溴-2-氟苄基)-1-環丙基脲基)-5-氟- N-甲基六氫吡啶-1-甲醯胺 | LC-MS: 445.1 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.31 (t, J = 6.9 Hz, 2H), 7.26 (t, J = 8.1 Hz, 1H), 4.45 (d, J = 50.0 Hz, 3H), 4.28 (d, J = 12.8 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 3.66 (s, 1H), 3.13 (t, J = 12.0 Hz, 1H), 2.69 (s, 3H), 2.64 (dd, J = 16.6, 6.5 Hz, 1H), 2.57 - 2.52 (m, 1H), 2.27 (dd, J = 22.7, 11.3 Hz, 2H), 0.98 - 0.92 (m, 2H), 0.76 (s, 2H)。 |
346 | S' (X=F) | (3 R,5 S)-3-(1-環丙基-3-(2-氟-4-(三氟甲氧基)苄基)脲基)-5-氟六氫吡啶-1-甲醯胺 | LC-MS: 437.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.43 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 7.8 Hz, 2H), 7.00 (t, J = 5.7 Hz, 1H), 4.59 - 4.37 (m, 3H), 4.30 (d, J = 12.6 Hz, 1H), 3.84 (d, J = 12.6 Hz, 1H), 3.69 (t, J = 11.9 Hz, 1H), 3.18 (t, J = 12.1 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.59 - 2.53 (m, 1H), 2.37 - 2.24 (m, 2H), 1.01 - 0.92 (m, 2H), 0.83 - 0.73 (m, 2H)。 |
347 | T (X=F) | (3 R,5 S)-3-(3-(4-氰基-2-氟-5-甲基苄基)-1-環丙基脲基)-5-氟- N-甲基六氫吡啶-1-甲醯胺 | LC-MS: 406.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.43 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 5.9 Hz, 1H), 4.56 - 4.41 (m, 3H), 4.27 (d, J = 12.4 Hz, 1H), 3.81 (d, J = 12.6 Hz, 1H), 3.66 (t, J = 11.0 Hz, 1H), 3.17 - 3.08 (m, 1H), 2.69 (s, 3H), 2.68 - 2.62 (m, 1H), 2.57 (dt, J = 10.1, 3.4 Hz, 1H), 2.49 (s, 3H), 2.30 (m, 2H), 0.98 - 0.94 (m, 2H), 0.81 - 0.76 (m, 2H)。 |
348 | V | ( R)-3-(1-環丙基-3-(2-氟-4-(三氟甲氧基)苄基)脲基)- N-(2-羥基乙基)六氫吡啶-1-甲醯胺 | LC-MS: 463.3 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.43 (t, J= 8.1 Hz, 1H), 7.08 (d, J= 9.3 Hz, 2H), 4.51 - 4.34 (m, 2H), 3.94 (dd, J= 30.8, 9.7 Hz, 2H), 3.62 (d, J= 25.8 Hz, 3H), 3.28 (s, 2H), 3.14 (s, 1H), 2.70 - 2.66 (m, 1H), 2.55 - 2.51 (m, 1H), 2.11 (d, J= 11.1 Hz, 1H), 1.94 - 1.90 (m, 1H), 1.77 - 1.73 (m, 1H), 1.53 (s, 1H), 0.97 - 0.93 (m, 2H), 0.76 (brs, 2H)。 |
349 | O | ( R)-3-(3-(4-氯-5-乙基-2-氟苄基)-1-環丙基脲基)- N-甲氧基六氫吡啶-1-甲醯胺 | LC-MS: 427.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.25 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.89 (t, J = 5.3 Hz, 1H), 4.38 (s, 2H), 3.85 (dd, J = 32.8, 12.9 Hz, 2H), 3.65 - 3.57 (m, 4H), 3.17 (t, J = 12.0 Hz, 1H), 2.72(q,J=7.5Hz,2H),2.65(dd,J=14.4,12.1Hz,1H),2.56-2.50(m,1H),2.11(tt,J=12.5,6.4Hz,1H),1.82(dd,J=47.9,13.0Hz,2H),1.50(q,J=13.2Hz,1H),1.21(t,J=7.5Hz,3H),0.98- 0.91 (m, 2H), 0.74 (d, J = 3.4 Hz, 2H)。 |
350 | N | ( R)-3-(5-氯-2,4-二氟苄基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS: 416.4 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.53 - 7.37 (m, 2H), 6.99 - 6.81 (m, 1H), 4.39 - 4.20 (m, 3H), 3.86 - 3.68 (m, 1H), 3.59 (t, J = 6.6 Hz, 2H), 3.21 - 3.15 (m, 1H), 2.81 (t, J = 11.9 Hz, 1H), 2.46 - 2.40 (m, 2.5H), 2.38 - 2.27 (m, 0.5H), 2.04 - 1.97 m, 1H), 1.86 - 1.61 (m, 2H), 1.42 - 1.21 (m, 1H), 0.89 - 0.84 (m, 2H), 0.73 - 0.53 (m, 2H)。 |
351 | T (X=F) | (3 R,5 S)-3-(1-環丙基-3-(4-環丙基-2-氟苄基)脲基)-5-氟- N-甲基六氫吡啶-1-甲醯胺 | LC-MS: 407.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.18 (t, J = 8.0 Hz, 1H), 6.86 (dd, J = 7.9, 1.3 Hz, 1H), 6.80 (t, J = 5.9 Hz, 1H), 6.76 (d, J = 11.8 Hz, 1H), 4.55 - 4.39 (m, 1H), 4.37 (s, 2H), 4.29 (d, J = 12.3 Hz, 1H), 3.79 (d,J=12.8Hz,1H),3.67(t,J=11.6Hz,1H),3.13(t,J=12.0Hz,1H),2.69(s,3H),2.64(dd,J=16.6,6.4Hz,1H),2.56-2.49(m,1H),2.29(dt,J=22.9,8.5Hz,2H),1.94-1.85(m,1H),0.99-0.90 (m, 4H), 0.68 (ddd, J = 17.9, 9.7, 4.1 Hz, 4H)。 |
352 | S' (X=H) | ( R)-3-(1-環丙基-3-(2-氟-4-(三氟甲氧基)苄基)脲基)六氫吡啶-1-甲醯胺 | LC-MS: 419.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.43 (t, J= 8.6 Hz, 1H), 7.09 (t, J= 7.9 Hz, 2H), 6.93 (d, J= 5.4 Hz, 1H), 4.43 (s, 2H), 4.02-3.86 (m, 2H), 3.69 - 3.59 (m, 1H), 3.18 (t, J= 12.0 Hz, 1H), 2.67 (t, J= 12.0 Hz, 1H), 2.59 - 2.49 (m, 1H), 2.18 - 2.05 (m, 1H), 1.94-1.84 (m, 1H), 1.80-1.71 (m, 1H), 1.59 - 1.45 (m, 1H), 1.00 - 0.89 (m, 2H), 0.82 - 0.71 (m, 2H)。 |
353 | N | ( R)-1-環丙基-3-(2-氟-4-(三氟甲氧基)苄基)-1-(1-(2-羥基乙醯基)六氫吡啶-3-基)尿素 | LC-MS: 434.4 (M+H)。 1 H NMR (400 MHz, dmso)δ 7.41 (t, J= 8.2 Hz, 1H), 7.30 (d, J= 10.7 Hz, 1H), 7.20 (d, J= 8.6 Hz, 1H), 6.90 (s, 1H), 4.44 (t, J= 5.4 Hz, 1H), 4.30 (d, J= 5.8 Hz, 3H), 4.03 (d, J= 5.4 Hz, 2H), 3.63 - 3.41 (m, 2H), 2.94 - 2.74 (m, 1H), 2.43 (s, 2H), 2.01 (d, J= 9.9 Hz, 1H), 1.83 - 1.63 (m, 2H), 1.32 (s, 1H), 0.87 (d, J= 6.6 Hz, 2H), 0.65 (d, J= 10.7 Hz, 2H)。 |
354 | O | ( R)-3-(1-環丙基-3-(2,4,5-三氟苄基)脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:385.4 (M+H)。 1H NMR (400 MHz, dmso)δ 7.52 - 7.41 (m, 1H), 7.35 - 7.24 (m, 1H), 6.88 (t, 1H), 6.32 (m, 1H), 4.26 (d, 2H), 3.89 - 3.78 (m, 2H), 3.50 - 3.40 (m, 1H), 2.95 (t, 1H), 2.54 (d, 3H), 2.48 - 2.42 (m, 2H), 1.93 (ddd, 1H), 1.76 -1.58 (m, 2H), 1.37 - 1.25 (m, 1H), 0.90 - 0.83 (m, 2H), 0.66 - 0.60 (m, 2H)。 |
355 | N | ( R)-3-((3-(3-溴苯基)異噁唑-5-基)甲基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:491.2 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 8.05 (dd, J = 1.8, 1.8 Hz, 1H), 7.88 (dd, J = 7.9, 1.2 Hz, 1H), 7.68 (dd, J = 8.1, 1.2 Hz, 1H), 7.46 (dd, J = 7.9, 7.9 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.87 (d, J = 4.6 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 4.39 - 4.28 (m, 1H), 3.87 - 3.70 (m, 1H), 3..61 - 3.5 (m, 2H), 3.25 - 3.14 (m, 2H), 2.82 (t, J = 12.0 Hz, 1H), 2.46 - 2.42 (m, 2.5H), 2.40 - 2.29 (m, 0.5H), 2.05 - 1.99 (m, 1H), 1.88 - 1.62 (m, 2H), 1.40 - 1.26 (m, 1H), 0.90 - 0.85 (m, 2H), 0.77 - 0.61 (m, 2H)。 |
356 | M | ( R)-3-((3-(3-氯-5-氟苯基)異噁唑-5-基)甲基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:465.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.72 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.33 (dd, J = 8.5, 1.8 Hz, 1H), 7.22 - 7.12 (m, 1H), 6.74 (d, J = 4.4 Hz, 1H), 4.53 (d, J = 5.2 Hz, 2H), 4.50 (s, 1H), 4.33 (s, 1H), 4.03 - 3.90 (m, 1H), 3.81 (t, J = 6.3 Hz, 2H), 3.77 - 3.69 (m, 1H), 3.58 - 3.49 (m, 1H), 3.15 - 2.93 (m, 1H), 2.71 - 2.46 (m, 4H), 2.27 - 2.14 (m, 1H), 2.02 - 1.87 (m, 1H), 1.81 (d, J = 6.9 Hz, 1H), 1.60 - 1.43 (m, 1H), 1.04 - 0.93 (m, 2H), 0.88 - 0.73 (m, 2H)。 |
357 | N | ( R)-1-環丙基-3-(4-乙基-2-氟苄基)-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:392.4 (M+H)。 1 H NMR (400 MHz, dmso)δ 7.21 (q, J= 7.7 Hz, 1H), 7.03 - 6.96 (m, 2H), 6.82 - 6.71 (m, 1H), 4.45 (q, J= 5.6 Hz, 1H), 4.36 (d, J= 13.7 Hz, 1H), 4.27 (d, J= 5.5 Hz, 2H), 3.85 - 3.72 (m, 1H), 3.61 (q, J= 5.9 Hz, 2H), 3.57 - 3.39 (m, 1H), 3.20 (t, J= 12.0 Hz, 1H), 2.83 (t, J= 11.7 Hz, 1H), 2.59 (q, J= 7.6 Hz, 2H), 2.45 (t, J= 6.6 Hz, 3H), 2.10 - 1.95 (m, 1H), 1.84 - 1.66 (m, 2H), 1.45 - 1.23 (m, 1H), 1.16 (t, J= 7.6 Hz, 3H), 0.87 (d, J= 4.8 Hz, 2H), 0.73 - 0.57 (m, 2H)。 |
358 | N | ( R)-1-環丙基-3-(4-環丙基-2-氟苄基)-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:404.4 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.15 (dd, J = 7.7, 7.7 Hz, 1H), 6.90 - 6.79 (m, 2H), 6.76 - 6.69 (m, 1H), 4.38 - 4.17 (m, 3H), 3.84 - 3.66 (m, 1H), 3.64 - 3.48 (m, 2.5H), 3.45 - 3.38 (m, 0.5H), 3.22 - 3.11 (m, 1H), 2.84 - 2.77 (m, 1H), 2.45 - 2.36 (m, 2.5H), 2.35 - 2.29 (m, 0.5H), 2.04 - 1.93 (m, 1H), 1.92 - 1.85 (mz, 1H), 1.83 - 1.60 (m, 2H), 1.43 - 1.16 (m, 1H), 0.95 - 0.78 (m, 4H), 0.71 - 0.52 (m, 4H)。 |
359 | N | ( R)-1-環丙基-3-(2-氟-4-甲基苄基)-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:378.4 (M+H)。 1 H NMR (400 MHz, dmso)δ 7.22 - 7.12 (m, 1H), 6.96 (s, 1H), 6.94 (d, J= 4.7 Hz, 1H), 6.74 (d, J= 15.6 Hz, 1H), 4.42 (t, J= 5.6 Hz, 1H), 4.34 (d, J= 16.7 Hz, 1H), 4.25 (d, J= 5.7 Hz, 2H), 3.84 - 3.70 (m, 1H), 3.59 (q, J= 6.0 Hz, 2H), 3.54 (s, 1H), 3.18 (t, J= 12.0 Hz, 1H), 2.81 (t, J= 11.8 Hz, 1H), 2.43 (t, J= 6.4 Hz, 3H), 2.27 (s, 3H), 2.01 (s, 1H), 1.70 (s, 2H), 1.44 - 1.19 (m, 1H), 0.85 (d, J= 4.6 Hz, 2H), 0.70 - 0.56 (m, 2H)。 |
360 | N | ( R)-1-環丙基-3-(4-環丙基-2-氟苄基)-1-(1-(2-羥基乙醯基)六氫吡啶-3-基)尿素 | LC-MS:390.4 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.19 - 7.10 (m, 1H), 6.90 - 6.78 (m, 2H), 6.76 - 6.71 (m, 1H), 4.31 - 4.19 (m, 3H), 4.08 - 3.99 (m, 2H), 3.17 (t, J = 12.8 Hz, 0.5H), 2.89 (t, J = 11.7 Hz, 0.5H), 2.77 (t, J = 13.6 Hz, 0.5H), 2.46 - 2.39 (m, 1.5H), 2.08 - 1.96 (m, 1H), 1.92 - 1.85 (m, 1H), 1.81 - 1.67 (m, 2H), 1.44 - 1.29 (m, 1H), 0.96 - 0.78 (m, 4H), 0.68 - 0.51 (m, 4H)。 |
361 | O | ( R)-3-(1-環丙基-3-(4-環丙基-2-氟苄基)脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:389.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.14 (dd, J = 8.0, 8.0 Hz, 1H), 6.87 (dd, J = 7.9, 1.8 Hz, 1H), 6.81 (dd, J = 11.8, 1.7 Hz, 1H), 6.72 - 6.69 (m, 1H), 6.32 - 6.29 (m, 1H), 4.24 (d, J = 5.8 Hz, 2H), 3.91 - 3.73 (m, 2H), 3.49 - 3.41 (m, 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.52 (d, J = 4.3 Hz, 3H),2.49 - 2.47 (m, 1H), 2.45 - 3.38 (m, 2H), 1.97 - 1.85 (m, 2H), 1.76 - 1.65 (m, 1H), 1.63 - 1.58 (m, 1H), 1.38 - 1.21 (m, 1H), 0.95 - 0.88 (m, 2H), 0.87 - 0.82 (m, 2H), 0.67 - 0.59 (m, 4H)。 |
362 | N | ( R)-3-((3-(3-氯苯基)異噁唑-5-基)甲基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:447.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.92 (d, J = 2.0 Hz, 1H), 7.84 (dt, J = 6.8, 1.8 Hz, 1H), 7.61 - 7.43 (m, 2H), 7.06 - 6.99 (m, 1H), 6.87 (d, J = 4.9 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 4.39 - 4.27 (m, 1H), 3.82 - 3.74 (m, 1H), 3.61 - 3.51 (m, 2H), 3.18 (t, J = 12.0 Hz, 1H), 2.82 (t, J = 11.9 Hz, 1H), 2.46 - 2.42 (m, 2H), 2.40 - 2.25 (m, 1H), 2.11 - 1.94 (m, 1H), 1.88 - 1.64 (m, 2H), 1.53 - 1.14 (m, 1H), 0.90 - 0.86 (m, 3H), 0.76 - 0.63 (m, 2H)。 |
363 | N | ( R)-3-(4-氯-2-氟苄基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:398.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.37 - 7.27 (m, 2H), 7.26 - 7.23 (m, 1H), 6.89 - 6.83 (m, 1H), 4.45 - 4.41 (m, 1H), 4.38 - 4.24 (m, 3H), 3.76 (dd, J = 28.6, 13.2 Hz, 1H), 3.63 - 3.48 (m, 2.25H), 3.47 - 3.36 (m, 0.25H), 3.18 (t, J = 12.0 Hz, 0.5H), 2.81 (t, J = 12.0 Hz, 1H), 2.46 - 2.39 (m, 2.5H), 2.38 - 2.28 (m, 0.5H), 2.09 - 1.92 (m, 1H), 1.85 - 1.62 (m, 2H), 1.39 - 1.25 (m, 1H), 0.89 - 0.83 (m, 2H), 0.72 - 0.56 (m, 2H)。 |
364 | N | ( R)-3-(4-溴-2-氟苄基)-1-環丙基-1-(1-(3-羥基丙醯基)六氫吡啶-3-基)尿素 | LC-MS:442.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.45 (d, J = 9.9, 1H), 7.40 - 7.35 (m, 1H), 7.28 - 7.22 (m, 1H), 6.89 - 6.83 (m, 1H), 4.47 - 4.38 (m, 1H), 4.37 - 4.21 (m, 3H), 3.85 - 3.68 (m, 1H), 3.64 - 3.48 (m, 2.5H), 3.47 - 3.36 (m, 0.5H), 3.21 - 3.15 (m, 0.5H), 2.81 (dd, J = 13.3, 10.6 Hz, 1H), 2.46 - 2.39 (m, 2H), 2.36 - 2.30 (m, 0.5H), 2.04 - 1.97 (m, 1H), 1.84 - 1.62 (m, 2H), 1.45 - 1.18 (m, 1H), 0.88 - 0.83 (m, 2H), 0.72 - 0.55 (m, 2H)。 |
365 | O | ( R)-3-(3-(4-氰基-2-氟-5-甲基苄基)-1-環丙基脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:388.3 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.42 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 7.1 Hz, 1H), 6.98 (t, J = 5.8 Hz, 1H), 4.44 (d, J = 4.4 Hz, 2H), 3.98 - 3.84 (m, 2H), 3.61 (tt, J = 11.8, 3.9 Hz, 1H), 3.14 (t, J = 12.0 Hz, 1H), 2.70 (s, 3H), 2.64 (td, J = 13.1, 2.5 Hz, 1H), 2.57 - 2.51 (m, 1H), 2.49 (s, 3H), 2.10 (qd, J = 12.5, 4.0 Hz, 1H), 1.88 (d, J = 12.1 Hz, 1H), 1.74 (d, J = 13.3 Hz, 1H), 1.55 - 1.42 (m, 1H), 1.00 - 0.92 (m, 2H), 0.80 - 0.71 (m, 2H)。 |
366 | N | ( R)-3-(4-溴-2-氟苄基)-1-環丙基-1-(1-(2-羥基乙醯基)六氫吡啶-3-基)尿素 | LC-MS:428.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.45 (dd, J = 9.8, 2.0 Hz, 1H), 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.25 (dd, J = 8.2, 8.2 Hz, 1H), 6.89 - 6.84 (m, 1H), 4.25 (d, J = 6.1 Hz, 3H), 4.03 (brs, 2H), 3.60 - 3.42 (m, 2.5H), 3.17 (t, J = 12.9 Hz, 0.5H), 2.89 (t, J = 11.8 Hz, 0.5H), 2.82 - 2.70 (m, 0.5H), 2.46 - 2.40 (m, 1H), 2.11 - 1.93 (m, 1H), 1.82 - 1.67 (m, 2H), 1.44 - 1.29 (m, 1H), 0.88 - 0.82 (m, 2H), 0.70 - 0.54 (m, 2H)。 |
367 | O | ( R)-3-(3-(4-氯-2-氟苄基)-1-環丙基脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:383.3 (M+H)。 1H NMR (400 MHz, DMSO)δ 7.39 - 7.34 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.26 (dd, J = 8.3, 1.9 Hz, 1H), 6.89 (t, J = 5.8 Hz, 1H), 6.35 (d, J = 4.3 Hz, 1H), 4.28 (d, J = 5.8 Hz, 2H), 3.84 (t, J = 15.6 Hz, 2H), 3.52 - 3.39 (m, 2H), 2.95 (t, J = 11.8 Hz, 1H), 2.54 (d, J = 4.3 Hz, 3H), 2.48 - 2.40 (m, 2H), 1.93 (dd, J = 13.0, 4.3 Hz, 1H), 1.67 (dd, J = 40.5, 12.6 Hz, 2H), 1.34 - 1.28 (m, 1H), 0.91 - 0.83 (m, 2H), 0.64 (dd, J = 6.2, 3.6 Hz, 2H)。 |
368 | V | ( R)-3-(3-(4-氯-2-氟苄基)-1-環丙基脲基)- N-(2-羥基乙基)六氫吡啶-1-甲醯胺 | LC-MS:413.3 (M+H)。 1H NMR (400 MHz, DMSO-d6)δ 7.36 - 7.27 (m, 2H), 7.24 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (t, J = 5.9 Hz, 1H), 6.37 (t, J = 5.5 Hz, 1H), 4.26 (d, J = 5.8 Hz, 2H), 3.91 - 3.77 (m, 2H), 3.50 - 3.42 (m, 1H), 3.35 (t, J = 6.3 Hz, 3H), 3.05 (q, J = 6.1 Hz, 2H), 2.94 (t, J = 11.8 Hz, 1H), 2.46 - 2.39 (m, 2H), 1.97 - 1.86 (m, 1H), 1.75 - 1.67 (m, 1H), 1.63 - 1.58 (m, 1H), 1.37 - 1.25 (m, 1H), 0.88 - 0.83 (m, 2H), 0.64 - 0.61 (m, 2H)。 |
369 | O | ( R)-3-(1-環丙基-3-(4-乙基-2-氟苄基)脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:377.3 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.22 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 11.4 Hz, 1H), 6.77 (s, 1H), 4.47 - 4.31 (m, 2H), 4.02 - 3.92 (m, 1H), 3.90 - 3.80 (m, 1H), 3.68 - 3.56 (m, 1H), 3.19 - 3.04 (m, 1H), 2.70 (s, 3H), 2.67 - 2.56 (m, 3H), 2.54 - 2.46 (m, 1H), 2.17 - 2.03 (m, 1H), 1.94 - 1.84 (m, 1H), 1.80 - 1.69 (m, 1H), 1.57 - 1.41 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 0.97 - 0.87 (m, 2H), 0.77 - 0.68 (m, 2H)。 |
370 | O | ( R)-3-(3-(4-溴-2-氟苄基)-1-環丙基脲基)- N-甲基六氫吡啶-1-甲醯胺 | LC-MS:427.2 (M+H)。 1H NMR (400 MHz, MeOD)δ 7.28 (dt, J = 16.3, 7.1 Hz, 3H), 6.90 (t, J = 5.8 Hz, 1H), 4.44 - 4.32 (m, 2H), 3.95 (d, J = 12.0 Hz, 1H), 3.86 (d, J = 12.6 Hz, 1H), 3.61 (tt, J = 11.8, 3.9 Hz, 1H), 3.31 (s, 3H), 3.13 (t, J = 12.0 Hz, 1H), 2.70 (s, 3H), 2.63 (td, J = 13.0, 2.4 Hz, 1H), 2.55 - 2.48 (m, 1H), 2.16 - 2.02 (m, 1H), 1.88 (d, J = 11.6 Hz, 1H), 1.74 (d, J = 13.4 Hz, 1H), 1.48 (qt, J = 13.0, 4.1 Hz, 1H), 0.94 (dt, J = 5.9, 3.1 Hz, 2H), 0.74 (dd, J = 6.6, 3.2 Hz, 2H)。 |
實例 371-377下表中所述之化合物係藉由改變上述實驗一般程序G、R'及S來製備:
實例 | 結構及名稱 | 數據 |
371 | 3-[(4-氯-2-氟苯基)甲基]-1-環丙基-1-[(3R)-1-[5-(羥基甲基)嗒嗪-3-基]六氫吡啶-3-基]尿素 | LC-MS: m/z = 434.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.34 (t, J = 8.3 Hz, 1H), 7.27 - 7.14 (m, 3H), 4.59 (s, 2H), 4.46 - 4.32 (m, 4H), 3.77 (dd, J = 15.8, 7.6 Hz, 1H), 3.34 (d, J = 12.3 Hz, 1H), 2.89 (dd, J = 13.0, 10.7 Hz, 1H), 2.56 (dt, J = 10.6, 3.6 Hz, 1H), 2.25 (tt, J = 12.5, 6.3 Hz, 1H), 1.96 (d, J = 12.8 Hz, 1H), 1.87 (d, J = 13.2 Hz, 1H), 1.62 (dt, J = 16.9, 13.0 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), 0.80 (d, J= 2.8 Hz, 2H)。 |
372 | 3-[(4-氯-2-氟苯基)甲基]-1-環丙基-1-[(3R)-1-[4-(羥基甲基)嘧啶-2-基]六氫吡啶-3-基]尿素 | LC-MS: m/z = 434.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.25 (d, J = 5.0 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.69 (d, J = 5.0 Hz, 1H), 4.71 (t, J = 8.2 Hz, 2H), 4.47 (s, 2H), 4.41 (s, 2H), 3.64 (tt, J = 11.8, 3.9 Hz, 1H), 3.26 (d, J = 11.9 Hz, 1H), 2.75 (td, J = 13.0, 2.4 Hz, 1H), 2.59 - 2.52 (m, 1H), 2.21 (qd, J = 12.6, 4.1 Hz, 1H), 1.84 (dd, J = 41.9, 12.5 Hz, 2H), 1.58 - 1.45 (m, 1H), 0.98 - 0.88 (m, 2H), 0.86 - 0.72 (m, 2H)。 |
373 | 3-[(3R)-1-(2-胺基嘧啶-4-基)六氫吡啶-3-基]-1-[(4-氯-2-氟苯基)甲基]-3-環丙基尿素 | LC-MS: m/z = 419.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.69 (d, J = 6.4 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.24 - 7.09 (m, 2H), 6.11 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 14.8 Hz, 4H), 3.65 (t, J= 11.8 Hz, 1H), 3.21 (t, J = 11.9 Hz, 1H), 2.77 (t, J = 12.0 Hz, 1H), 2.54 (dt, J = 10.0, 3.3 Hz, 1H), 2.20 (tt, J = 12.6, 6.3 Hz, 1H), 1.92 (d, J = 12.9 Hz, 1H), 1.80 (d, J = 12.3 Hz, 1H), 1.52 (d, J = 13.1 Hz, 1H), 0.94 (dd, J = 15.3, 7.4 Hz, 2H), 0.78 (s, 2H)。 |
374 | 3-[(3R)-1-(4-胺基嘧啶-2-基)六氫吡啶-3-基]-1-[(4-氯-2-氟苯基)甲基]-3-環丙基尿素 | LC-MS: m/z = 419.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.63 (d, J = 6.6 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.96 (t, J = 5.8 Hz, 1H), 5.96 (d, J = 6.6 Hz, 1H), 4.48 - 4.38 (m, 4H), 3.71 (ddd, J = 15.4, 8.0, 4.0 Hz, 1H), 3.33 (s, 1H), 2.85 (dd, J = 13.1, 11.1 Hz, 1H), 2.58 - 2.50 (m, 1H), 2.20 (qd, J = 12.5, 4.0 Hz, 1H), 1.89 (dd, J = 38.9, 12.5 Hz, 2H), 1.64 - 1.52 (m, 1H), 0.96 (dd, J = 8.2, 5.6 Hz, 2H), 0.78 (s, 2H)。 |
375 | 3-[(4-氯-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(5-羥基嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z = 434.2 1H NMR:1H NMR (400 MHz, MeOD) δ 7.59 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 9.8 Hz, 1H), 6.04 (s, 1H), 4.38 (q, J = 15.7 Hz, 2H), 3.80 (t, J = 11.6 Hz, 3H), 3.35 (d, J = 13.8 Hz, 1H), 2.94 (t, J = 11.9 Hz, 1H), 2.58 - 2.48 (m, 1H), 2.32 (s, 3H), 2.25 - 2.13 (m, 1H), 1.94 (dd, J = 33.2, 11.8 Hz, 2H), 1.73 - 1.57 (m, 1H), 0.96 (d, J = 6.5 Hz, 2H), 0.75 (dd, J = 32.5, 9.2 Hz, 2H)。 |
376 | 3-[(4-氰基-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(1,2,4-三嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z = 410.3 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.45 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 5.7 Hz, 1H), 4.76 (t, J = 10.5 Hz, 2H), 4.46 (d, J = 5.8 Hz, 2H), 3.67 (dd, J = 15.7, 7.9 Hz, 1H), 3.41 (t, J = 11.9 Hz, 1H), 2.87 (dd, J = 13.0, 10.8 Hz, 1H), 2.63 - 2.56 (m, 1H), 2.50 (s, 3H), 2.29 (dt, J = 12.7, 8.9 Hz, 1H), 1.90 (dd, J = 28.7, 13.1 Hz, 2H), 1.57 (q, J = 13.1 Hz, 1H), 0.96 (dt, J = 9.4, 6.7 Hz, 2H), 0.86 - 0.77 (m, 2H)。 |
377 | 3-[(4-氰基-2-氟-5-甲基苯基)甲基]-1-環丙基-1-[(3R)-1-(5-羥基嗒嗪-3-基)六氫吡啶-3-基]尿素 | LC-MS: m/z = 425.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.58 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.36 (d, J = 7.1 Hz, 1H), 7.05 (t, J = 6.0 Hz, 1H), 6.02 (s, 1H), 4.53 - 4.39 (m, 2H), 3.80 (t, J = 11.8 Hz, 3H), 3.37 (s, 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.60 - 2.53 (m, 1H), 2.49 (s, 3H), 2.19 (dd, J = 12.2, 8.7 Hz, 1H), 1.94 (dd, J = 35.5, 12.7 Hz, 2H), 1.68 (t, J = 13.1 Hz, 1H), 0.98 (d, J = 6.7 Hz, 2H), 0.79 (dd, J = 28.2, 9.6 Hz, 2H)。 |
下表中所述之實例 378-400係藉由改編下表中所述之一般程序W、X或Y來製備:
實例 | 程序 | 結構 | 名稱及數據 |
378 | W | (3R,5S)-3-{1-環丙基[({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}-5-氟六氫吡啶-1-甲醯胺 LC-MS: m/z = 486.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 5.9 Hz, 1H), 6.83 (s, 1H), 4.60 - 4.52 (m, 1H), 4.49 (d, J = 5.8 Hz, 2H), 4.43 (dd, J =10.4,5.3Hz,1H), 4.31(d,J=11.2Hz,1H), 3.87(d,J=12.4Hz,1H),3.73(t,J=11.6Hz,1H),3.24-3.16(m,1H),2.73-2.65 (m,1H), 2.57(ddd,J=10.4,6.8,3.9Hz,1H),2.36(d,J=8.7Hz,1H),2.33-2.26 (m, 1H), 0.97 (dd, J = 6.5, 2.9 Hz, 2H), 0.85 - 0.78 (m, 2H)。 | |
379 | X | 1-環丙基-1-[(3R)-1-(2-羥基乙醯基)六氫吡啶-3-基]-3-({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)尿素 LC-MS: m/z = 483.1 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.84 (s, 1H), 4.52 - 4.41 (m, 3H), 4.25 (q, J = 15.4 Hz, 2H), 3.67 (dd, J = 39.4, 25.9 Hz, 2H), 3.18 (dd, J = 30.3, 18.5 Hz, 1H), 2.96 - 2.48 (m, 2H), 2.20 (dd, J = 12.8, 3.8 Hz, 1H), 2.03 - 1.78 (m, 2H), 1.61 - 1.44 (m, 1H), 0.95 (t, J = 7.2 Hz, 2H), 0.87 - 0.73 (m, 2H)。 | |
380 | Y | 1-[(3R,5S)-1-乙醯基-5-氟六氫吡啶-3-基]-1-環丙基-3-({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)尿素 LC-MS: m/z = 485.1 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 3.7 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.69 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 15.2, 9.7 Hz, 1H), 4.79 - 4.59 (m, 1H), 4.53 (t, J = 5.2 Hz, 2H), 4.49 - 4.33 (m, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 3.60 (s, 1H), 3.26 (s, 1H), 3.17 - 2.92 (m, 1H), 2.59 - 2.50 (m, 2H), 2.45 - 2.26 (m, 2H), 2.12 (d, J = 6.5 Hz, 3H), 0.96 (dd, J = 16.5, 5.2 Hz, 2H), 0.88 - 0.71 (m, 2H)。 | |
381 | X | (3R,5S)-3-{1-環丙基[({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}-5-氟-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 500.3 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 4.53 (dd, J = 10.4, 5.3 Hz, 1H), 4.48 (s, 2H), 4.45 - 4.37 (m, 1H), 4.29 (d, J = 12.4 Hz, 1H), 3.84 (d, J = 12.9 Hz, 1H), 3.71 (t, J = 11.0 Hz, 1H), 3.18 - 3.12 (m, 1H), 2.70 (s, 3H), 2.68 - 2.63 (m, 1H), 2.58 - 2.52 (m, 1H), 2.39 - 2.33 (m, 1H), 2.31 - 2.23 (m, 1H), 0.97 (dd, J = 6.6, 2.3 Hz, 2H), 0.84 - 0.79 (m, 2H)。 | |
382 | X | 1-[(3R)-1-乙醯基六氫吡啶-3-基]-1-環丙基-3-({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)尿素 LC-MS: m/z = 467.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.64 - 7.57 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 3.5 Hz, 1H), 4.52 - 4.45 (m, 3H), 3.86 (d, J = 12.6 Hz, 1H), 3.81 - 3.74 (m, 0.5H), 3.59 - 3.46 (m, 0.5H), 3.35 (s, 0.5H), 3.14 - 2.96 (m, 1H), 2.56 (td, J = 6.6, 3.4 Hz, 0.5H), 2.50 (ddd, J = 16.1, 9.7, 2.9 Hz, 1H), 2.26 - 2.13 (m, 1H), 2.10 (d, J = 6.9 Hz, 3H), 1.94 (dd, J = 28.4, 11.9 Hz, 1H), 1.87 - 1.76 (m, 1H), 1.62 - 1.40 (m, 1H), 0.95 (ddd, J = 17.4, 8.7, 5.5 Hz, 2H), 0.87 - 0.73 (m, 2H)。 | |
383 | Y | 1-環丙基-1-[(3R)-1-(2-羥基乙醯基)六氫吡啶-3-基]-3-({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)尿素 LC-MS: m/z = 483.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 7.94 - 7.74 (m, 2H), 7.68 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1H), 4.53 (s, 2H), 4.46 (d, J = 12.7 Hz, 1H), 4.35 - 4.12 (m, 2H), 3.79 - 3.54 (m, 2H), 3.19 (dd, J = 39.2, 12.0 Hz, 1H), 2.63 (dd, J = 89.0, 78.0 Hz, 2H), 2.17 (dd, J = 12.7, 8.9 Hz, 1H), 2.01 - 1.76 (m, 2H), 1.59 - 1.41 (m, 1H), 0.94 (s, 2H), 0.78 (d, J = 15.8 Hz, 2H)。 | |
384 | X | (3R)-3-{1-環丙基[({5-[3-氟-5-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 500.1 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.65 (dd, J = 8.9, 1.4 Hz, 1H), 7.60 (s, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.02 (t, J = 5.8 Hz, 1H), 6.90 (s, 1H), 4.48 (d, J = 4.8 Hz, 2H), 4.03 - 3.80 (m, 2H), 3.72 - 3.58 (m, 1H),3.14(t,J=12.0Hz,1H),2.74-2.56(m,4H),2.55-2.48(m,1H),2.16-2.00(m,1H),1.91(d,J=12.0Hz,1H),1.75(d,J=13.4Hz,1H),1.58-1.42(m,1H),1.01-0.85(m,2H),0.80(dd,J=5.3, 3.4 Hz, 2H)。 | |
385 | W | 1-環丙基-1-[(3R)-1-(2-羥基乙醯基)六氫吡啶-3-基]-3-({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)尿素 LC-MS: m/z = 483.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.20 - 7.08 (m, 1H), 6.72 (d, J = 3.5 Hz, 1H), 4.50 (dd, J = 33.8, 8.0 Hz, 3H), 4.32 - 4.13 (m, 2H), 3.77 - 3.52 (m, 2H), 3.29 - 3.08 (m, 1H), 2.98 - 2.46 (m, 2H), 2.18 (td, J = 12.6, 4.0 Hz, 1H), 2.02 - 1.76 (m, 2H), 1.60 - 1.42 (m, 1H), 0.96 (dd, J = 13.7, 6.4 Hz, 2H), 0.88 - 0.69 (m, 2H)。 | |
386 | Y | (3R,5S)-3-{1-環丙基[({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)胺甲醯基]胺基}-5-氟-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 500.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.88 (dd, J = 12.0, 3.9 Hz, 2H), 7.69 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H), 4.52 - 4.47 (m, 1H), 4.40 (ddd, J = 15.6, 10.4, 5.0 Hz, 1H), 4.29 (d, J = 12.5 Hz, 1H), 3.82 (d, J = 12.8 Hz, 1H), 3.71 (t, J = 11.1 Hz, 1H), 3.13 (dd, J = 12.6, 11.4 Hz, 1H), 2.69 (s, 3H), 2.68 - 2.62 (m, 1H), 2.57 - 2.51 (m, 1H), 2.38 - 2.31 (m, 1H), 2.30 - 2.19 (m, 1H), 0.99 - 0.91 (m, 2H), 0.83 - 0.76 (m, 2H)。 | |
387 | Y | (3R,5S)-3-{1-環丙基[({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)胺甲醯基]胺基}-5-氟六氫吡啶-1-甲醯胺 LC-MS: m/z = 486.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.91 - 7.82 (m, 2H), 7.69 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 5.6 Hz, 1H), 4.58 - 4.42 (m, 3H), 4.30 (d, J = 11.9 Hz, 1H), 3.86 (d, J = 12.7 Hz, 1H), 3.73 (s, 1H), 3.21 - 3.14 (m, 1H), 2.74 - 2.64 (m, 1H), 2.54 (td, J = 6.7, 3.4 Hz, 1H), 2.29 (dd, J = 22.7, 11.4 Hz, 2H), 0.96 (dd, J = 10.3, 3.9 Hz, 2H), 0.84 - 0.76 (m, 2H)。 | |
388 | W | (3R)-3-{1-環丙基[({3-[3-氟-5-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 500.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.69 - 7.59 (m, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 5.9 Hz, 1H), 6.75 (s, 1H), 4.53 (t, J = 10.9 Hz, 2H), 3.99 - 3.87 (m, 2H), 3.70 - 3.58 (m, 1H), 3.19 - 3.09 (m, 1H), 2.69(d,J=4.9Hz,3H),2.63(dd,J=13.1,2.6Hz,1H),2.53(ddd,J=10.5,6.6,3.7Hz,1H),2.11(qd,J=12.6,4.0Hz,1H),1.90(d,J=12.0Hz,1H),1.75(d,J=13.1Hz,1H),1.57-1.42(m,1H), 1.02 - 0.90 (m, 2H), 0.85 - 0.72 (m, 2H)。 | |
389 | X | (3R)-3-{1-環丙基[({5-[3-氟-5-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}六氫吡啶-1-甲醯胺 LC-MS: m/z = 486.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 8.9 Hz, 1H), 7.60 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 5.8 Hz, 1H), 6.90 (s, 1H), 4.52 - 4.43 (m, 2H), 4.04 - 3.88 (m, 2H), 3.73 - 3.60 (m, 1H), 3.25 - 3.15 (m, 1H), 2.75 - 2.63 (m, 1H), 2.57 - 2.49 (m, 1H), 2.20 - 2.05 (m, 1H), 1.96 - 1.87 (m, 1H), 1.83 - 1.71 (m, 1H), 1.61 - 1.43 (m, 1H), 0.99 - 0.90 (m, 2H), 0.84 - 0.74 (m, 2H)。 | |
390 | W | (3R,5S)-3-{1-環丙基[({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}-5-氟-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 500.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 6.72 (s, 1H), 4.55 (s, 2H), 4.50 (dd, J = 10.4, 5.3 Hz, 1H), 4.40 (td, J = 10.4, 5.1 Hz, 1H), 4.28 (d, J = 10.5 Hz, 1H), 3.83 (d, J = 12.7 Hz, 1H), 3.69 (t, J = 11.1 Hz, 1H), 3.18 - 3.11 (m, 1H), 2.69 (s, 3H), 2.68 - 2.62 (m, 1H), 2.56 (ddd, J = 10.5, 6.8, 3.9 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.32 - 2.21 (m, 1H), 0.97 (t, J=6.0Hz,2H),0.82(d,J=3.5Hz,2H)。 | |
391 | W | (3R)-3-{1-環丙基[({3-[3-氟-5-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}六氫吡啶-1-甲醯胺 LC-MS: m/z = 486.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.68 - 7.60 (m, 2H), 7.25 (d, J = 9.0 Hz, 1H), 7.13 (t, J = 5.8 Hz, 1H), 6.75 (s, 1H), 4.54 (d, J = 5.4 Hz, 2H), 3.95 (t, J = 14.6 Hz, 2H), 3.66 (ddd, J = 11.7, 7.9, 4.1 Hz, 1H), 3.23 - 3.15 (m, 1H), 2.68 (dd, J = 12.8, 10.7 Hz, 1H), 2.58 - 2.51 (m, 1H), 2.12 (qd, J = 12.6, 4.0 Hz, 1H), 1.91 (d, J = 11.7 Hz, 1H), 1.76 (d, J = 13.9 Hz, 1H), 1.59 - 1.45 (m, 1H), 0.96 (dd, J = 8.8, 6.0 Hz, 2H), 0.83 - 0.76 (m, 2H)。 | |
392 | W | (3R,5S)-3-{1-環丙基[({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}-5-氟六氫吡啶-1-甲醯胺 LC-MS: m/z = 486.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 5.8 Hz, 1H), 6.72 (s, 1H), 4.60 - 4.50 (m, 3H), 4.48 - 4.37 (m, 1H), 4.30 (d, J = 12.6 Hz, 1H), 3.86 (d, J = 12.4 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.18 (dd, J = 24.4, 12.6 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.61 - 2.53 (m, 1H), 2.41 - 2.22 (m, 2H), 1.04 - 0.94 (m, 2H), 0.87 - 0.78 (m, 2H)。 | |
393 | W | 1-[(3R)-1-乙醯基六氫吡啶-3-基]-1-環丙基-3-({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)尿素 LC-MS: m/z = 467.1 (M+H) | |
394 | Y | 1-[(3R)-1-乙醯基六氫吡啶-3-基]-1-環丙基-3-({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)尿素 LC-MS: m/z = 467.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 4.5 Hz, 1H), 7.92 - 7.81 (m, 2H), 7.68 (dd, J = 8.7, 7.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4.53 (t, J = 5.7 Hz, 2H), 4.49 (d, J = 12.2 Hz, 1H), 3.89 - 3.82 (m, 1H), 3.77 (dt, J = 12.2, 3.9 Hz, 1H), 3.55 (tt, J = 12.0, 4.0 Hz, 1H), 3.33 (s, 1H), 3.11 - 2.96 (m, 1H), 2.58 - 2.44 (m, 2H), 2.27 - 2.12 (m, 1H), 2.10 (d, J = 6.0 Hz, 3H), 2.01 - 1.78 (m, 2H), 1.60 - 1.40 (m, 1H), 1.01 - 0.89 (m, 2H), 0.86 - 0.71 (m, 2H)。 | |
395 | W | (3R)-3-{1-環丙基[({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 482.1 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 4.48 (s, 2H), 3.93 (dd, J = 24.8, 12.3 Hz, 2H), 3.70 - 3.61 (m, 1H), 3.18 - 3.11 (m, 1H),2.70(d,J=5.5Hz,3H), 2.65 (dd,J=13.2,10.6Hz,1H),2.56-2.50 (m,1H),2.19-2.07(m,1H), 1.91 (d,J=12.1Hz,1H),1.76(d,J=13.3Hz,1H),1.55-1.45(m,1H),0.94 (dt, J=10.0,5.7Hz,2H), 0.85- 0.75 (m, 2H)。 | |
396 | W | (3R)-3-{1-環丙基[({5-[3-(三氟甲氧基)苯基]-1,2-噁唑-3-基}甲基)胺甲醯基]胺基}六氫吡啶-1-甲醯胺 LC-MS: m/z = 468.1 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 5.9 Hz, 1H), 6.83 (s, 1H), 4.48 (d, J = 4.5 Hz, 2H), 4.03 - 3.89 (m, 2H), 3.72 - 3.62 (m, 1H), 3.22 - 3.12 (m, 1H), 2.68 (t, J = 11.8 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.19 - 2.08 (m, 1H), 1.92 (dd, J = 8.4, 4.0 Hz, 1H), 1.79 - 1.73 (m, 1H), 1.54 (m, 1H), 0.95 (m, 2H), 0.81 (d, J = 3.5 Hz, 2H)。 | |
397 | Y | (3R)-3-{1-環丙基[({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)胺甲醯基]胺基}-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 482.0 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.92 - 7.81 (m, 2H), 7.69 (t, J = 8.2 Hz, 1H), 7.45 - 7.38 (m, 1H), 6.98 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 4.3 Hz, 2H), 3.91 (ddd, J = 15.1, 12.6, 6.8 Hz, 2H), 3.66 (tt, J = 11.8, 4.0 Hz, 1H), 3.16 - 3.09 (m, 1H), 2.75 - 2.58 (m, 4H), 2.55 - 2.47 (m, 1H), 2.09 (tt, J = 12.5, 6.3 Hz, 1H), 1.90 (d, J = 12.0 Hz, 1H), 1.75 (d, J = 13.7 Hz, 1H), 1.56 - 1.43 (m, 1H), 0.98 - 0.87 (m, 2H), 0.84 - 0.73 (m, 2H)。 | |
398 | Y | (3R)-3-{1-環丙基[({1-[3-(三氟甲氧基)苯基]-1H-1,2,3-三唑-4-基}甲基)胺甲醯基]胺基}六氫吡啶-1-甲醯胺 LC-MS: m/z = 468.0 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.93 - 7.80 (m, 2H), 7.68 (t, J = 8.2 Hz, 1H), 7.46 - 7.38 (m, 1H), 4.52 (d, J = 4.2 Hz, 2H), 3.94 (dd, J = 24.0, 13.0 Hz, 2H), 3.74 - 3.62 (m, 1H), 3.22 - 3.12 (m, 1H), 2.72 - 2.62 (m, 1H), 2.55 - 2.48 (m, 1H), 2.18 - 2.03 (m, 1H), 1.90 (d, J = 11.9 Hz, 1H), 1.76 (d, J = 13.3 Hz, 1H), 1.58 - 1.44 (m, 1H), 1.00 - 0.89 (m, 2H), 0.82 - 0.71 (m, 2H)。 | |
399 | W | (3R)-3-{1-環丙基[({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}-N-甲基六氫吡啶-1-甲醯胺 LC-MS: m/z = 482.0 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.75 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.43 - 7.35 (m, 1H), 6.72 (s, 1H), 4.60 - 4.45 (m, 2H), 4.00 - 3.84 (m, 2H), 3.71 - 3.56 (m, 1H), 3.13 (t, J = 11.9 Hz, 1H), 2.73 - 2.60 (m, 4H), 2.57 - 2.48 (m, 1H), 2.19 - 2.03 (m, 1H), 1.96 - 1.86 (m, 1H), 1.75 (d, J = 13.4 Hz, 1H), 1.57 - 1.42 (m, 1H), 1.00 - 0.90 (m, 2H), 0.83 - 0.73 (m, 2H)。 | |
400 | W | (3R)-3-{1-環丙基[({3-[3-(三氟甲氧基)苯基]-1,2-噁唑-5-基}甲基)胺甲醯基]胺基}六氫吡啶-1-甲醯胺 LC-MS: m/z = 468.2 (M+H) 1H NMR:1H NMR (400 MHz, MeOD) δ 7.86 - 7.77 (m, 1H), 7.74 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.43 - 7.31 (m, 1H), 6.71 (s, 1H), 4.59 - 4.44 (m, 2H), 4.05 - 3.84 (m, 2H), 3.72 - 3.56 (m, 1H), 3.24 - 3.14 (m, 1H), 2.75 - 2.61 (m, 1H), 2.58 - 2.48 (m, 1H), 2.22 - 2.05 (m, 1H), 1.97 - 1.84 (m, 1H), 1.81 - 1.68 (m, 1H), 1.61 - 1.45 (m, 1H), 1.03 - 0.90 (m, 2H), 0.88 - 0.75 (m, 2H)。 |
步驟 1 : W2 之合成於0℃下在N
2氣氛下向適當醛
W1(1 eq.)及羥胺鹽酸鹽(1.1 eq.)於DCM中之混合物中逐滴添加TEA (1.1 eq.)。在室溫下將所得混合物攪拌45分鐘。然後將混合物用水稀釋並用DCM萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥,以產生粗製化合物
W2,其不經任何進一步純化即用於下一步驟。
步驟 2 : W4 之合成於0℃下在N
2氣氛下向
W2(1 eq.)及
W3(1 eq.)於MeOH/H
2O (4:1, V/V)中之混合物中添加[雙(三氟乙醯氧基)碘]苯(1.3 eq.)。在室溫下將所得混合物攪拌1小時。然後用水稀釋混合物且用EtOAc萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用PE/EtOAc溶析)純化殘餘物,以產生化合物
W4。
步驟 3 : W5 之合成於0℃下將
W4(1 eq.)逐滴添加至TFA/DCM (1:4, V/V)之混合物中且將所得混合物於室溫下攪拌1小時。然後將混合物在減壓下濃縮至乾燥,以產生粗製化合物
W5,其不經任何進一步純化即用於下一步驟。
步驟 4 : W 之合成於-30℃下在N
2氣氛下向W
5(1 eq.)及NaHCO
3(3 eq.)於DCM中之混合物中添加逐滴DCM中之三光氣溶液(0.5 eq.)。將所得混合物於室溫下攪拌30分鐘,然後於0℃下在N
2氣氛下逐滴添加
W6(1 eq.)及TEA (3 eq.)於無水DCM中之混合物。將所得混合物於室溫下攪拌1小時,然後將混合物用水稀釋且用DCM萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由prep-HPLC純化殘餘物,以產生純化合物
W。
步驟 1 : W2 之合成於0℃下在N
2氣氛下向
W1(1.0 g, 5.26 mmol)及羥胺鹽酸鹽(402 mg, 5.79 mmol)於DCM (25 mL)中之溶液中逐滴添加TEA (586 mg, 5.79 mmol),且將所得混合物於室溫下攪拌45分鐘。然後用水(25 mL)稀釋混合物且用DCM (25 mL)萃取兩次。分離合併之有機層,用鹽水(30 mL)洗滌,經無水Na
2SO
4乾燥,過濾且在減壓下濃縮至乾燥,以產生粗製化合物
W2(950 mg, 88.05%產率),其不經任何進一步純化即用於下一步驟。LC/MS (ESI) m/z: 206 (M+H)
+。
步驟 2 : W4 之合成於0℃下在N
2氣氛下向
W2(950 mg, 4.63 mmol)及
W3(719 mg, 4.63 mmol)於MeOH (40 mL)及H
2O (10 mL)中之混合物中添加[雙(三氟乙醯氧基)碘]苯(2.59 g, 6.02 mmol),且將所得混合物於室溫下攪拌1小時。然後將混合物用水(60 mL)稀釋且用EtOAc (50 mL)萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用PE中之10~50% EtOAc溶析)純化殘餘物,以產生白色固體狀純化合物
W4(390 mg, 23.50%產率)。LC/MS (ESI) m/z: 359 (M+H)
+。
步驟 3 : W5 之合成於0℃下在N
2氣氛下向
W4(390 mg, 1.09 mmol)於DCM (4 mL)中之混合物中添加TFA (1 mL),且將所得混合物於室溫下攪拌1小時。然後將混合物在減壓下濃縮至乾燥,以產生粗產物
W5(550 mg),其不經任何進一步純化即用於下一步驟。LC/MS (ESI) m/z: 259 (M+H)
+。
步驟 4 : 400 之合成於-30℃下在N
2氣氛下向粗製
W5(60 mg, 0.232 mmol)及NaHCO
3(59 mg, 0.697 mmol)於DCM (5 mL)中之溶液中逐滴添加三光氣(35 mg, 0.54 mmol)於DCM (2 mL)中之溶液,且將所得混合物於室溫下攪拌30分鐘。然後於0℃下在N
2氣氛下逐滴添加
W6(43 mg, 0.232 mmol)及TEA (71 mg, 0.697 mmol)於無水DCM (5 mL)中之混合物,且將所得混合物於室溫下攪拌1小時。然後用水(10 mL)稀釋混合物並用DCM (10 mL)萃取兩次。 分離合併之有機層,用鹽水(12 mL)洗滌,經無水Na
2SO
4乾燥,過濾,並濃縮至乾燥。經由prep-HPLC純化殘餘物,以得到白色固體狀
400(22 mg, 20.25 %產率)。LC/MS: m/z 468 (M+H)
+。
1H NMR (400 MHz, MeOD) δ 7.86 - 7.77 (m, 1H), 7.74 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.43 - 7.31 (m, 1H), 6.71 (s, 1H), 4.59 - 4.44 (m, 2H), 4.05 - 3.84 (m, 2H), 3.72 - 3.56 (m, 1H), 3.24 - 3.14 (m, 1H), 2.75 - 2.61 (m, 1H), 2.58 - 2.48 (m, 1H), 2.22 - 2.05 (m, 1H), 1.97 - 1.84 (m, 1H), 1.81 - 1.68 (m, 1H), 1.61 - 1.45 (m, 1H), 1.03 - 0.90 (m, 2H), 0.88 - 0.75 (m, 2H)。
步驟 1 : X2 之合成於0℃下在N
2氣氛下向
X1(1 eq.)及草酸二乙酯(1.1 eq.)於無水THF中之溶液中添加NaH (1.1 eq.),且將所得混合物於室溫下攪拌3小時。然後用水淬滅混合物且用DCM萃取兩次。分離合併之有機層,用鹽水洗滌,經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥,以產生粗製化合物
X2,其不經任何進一步純化即用於下一步驟。
步驟 2 : X3 之合成向
X2(1 eq.)於EtOH中之溶液中添加羥胺鹽酸鹽(2.5 eq.),且將所得混合物於80℃下在N
2氣氛下攪拌2小時。冷卻後,將混合物在減壓下濃縮至乾燥且經由急速管柱層析(用PE/EtOAc溶析)純化殘餘物,以產生化合物
X3。
步驟 3 : X4 之合成於0℃下向化合物
X3(1 eq.)於EtOH中之溶液中逐份添加NaBH
4(2.5 eq.),且將所得混合物於室溫下攪拌2小時。然後用水淬滅混合物且用EtOAc萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥。藉由急速管柱層析(用PE/EtOAc溶析)純化殘餘物,以產生化合物
X4。
步驟 4 : X5 之合成向化合物
X4(1 eq.)於甲苯中之溶液中添加TEA (2 eq.)及DPPA (1.2 eq.),且將所得混合物於室溫下在N
2氣氛下攪拌20小時。然後用水稀釋混合物且用EtOAc萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥,以產生粗產物
X5,其不經進一步純化即用於下一步驟。
步驟 5 : X6 之合成向X
5(1 eq.)於THF/H
2O (4:1, V/V)中之混合物中添加PPh
3(2 eq.),且將所得混合物於室溫下在N
2氣氛下攪拌17小時。然後將混合物用2N HCl (aq.)稀釋且用MTBE洗滌。分離水層且用EtOAc萃取兩次,之後用飽和NaHCO
3水溶液將pH調整至8。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並在減壓下濃縮至乾燥,以產生粗產物
X6,其不經進一步純化即用於下一步驟。
步驟 6 : X 之合成於-30℃下在N
2氣氛下向
X6(1 eq.)及NaHCO
3(3 eq.)於無水DCM中之混合物中逐滴添加三光氣(0.5 eq.)於DCM中之溶液,且將所得混合物於室溫下攪拌30分鐘。然後於0℃下在N
2氣氛下逐滴添加
X7(1 eq.)及TEA (3 eq.)於無水DCM中之混合物,且將所得混合物於室溫下攪拌1小時。然後將混合物用水稀釋並用DCM萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由prep-HPLC純化殘餘物,以產生化合物
X。
步驟 1 : Y2 之合成於0℃下在N
2氣氛下向
Y1(1 eq.)於MeCN中之溶液中逐滴添加t-BuONO (1.2 eq.)及TMSN
3(1.2 eq.)。在室溫下將所得混合物攪拌1 hr。TLC指示起始材料完全消耗後,
Y2於MeCN中之溶液不經進一步純化即直接用於下一步驟。
步驟 2 : Y4 之合成於0℃下在N
2氣氛下向
Y3(1.2 eq.)、抗壞血酸鈉(0.2 eq.)及CuSO
4(0.2 eq.)於MeCN中之混合物中逐滴添加
Y2(1 eq.)於MeCN中之溶液。將所得混合物於r.t.下在N
2氣氛下攪拌過夜。然後將混合物用水稀釋且用EtOAc萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由急速管柱層析(用PE/EtOAc溶析)純化殘餘物,以產生
Y4。
步驟 3 : Y5 之合成於0℃下向TFA於DCM (1:3, V/V)中之混合物中逐滴添加
Y4(1 eq.)。於r.t.下將所得混合物攪拌30 min。然後將混合物濃縮至乾燥。將殘餘物溶解於EtOAc中,用NaHCO
3水溶液中和且用EtOAc萃取兩次。將合併之有機層用鹽水洗滌,經無水Na
2SO
4乾燥,過濾且濃縮,以獲得粗製
5,其不經進一步純化即直接用於下一步驟。
步驟 4 : Y7 之合成於-78℃下在N
2氣氛下向
Y5(1.0 eq.)及Y
6(1.0 eq.)於DCM中之混合物中逐滴添加TEA
(3.0 eq.)及BTC (0.5 eq.)於DCM中之溶液。於r.t.下將所得混合物攪拌1 hr。然後用水稀釋混合物並用DCM萃取兩次。用鹽水洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。藉由prep-HPLC純化殘餘物,以產生
Y7 。
步驟 1 : Y2 之合成於0℃下在N
2氣氛下向
Y1(3.0 g, 16.95 mmol)於MeCN (30 mL)中之溶液中逐滴添加t-BuONO (2.10 g, 20.34 mmol)及TMSN
3(2.34 g, 20.34 mmol)。在室溫下將所得混合物攪拌1 hr。在TLC指示起始材料完全消耗後,
Y2於MeCN中之溶液不經進一步純化即直接用於下一步驟。
步驟 2 : Y4 之合成於0℃下向
Y3(3.15 g, 20.34 mmol)、抗壞血酸鈉(810 mg, 4.07 mmol)及CuSO
4(650 mg, 4.07 mmol)於MeCN (20 mL)中之混合物中逐滴添加
Y2於MeCN (30 mL)中之混合物。將所得混合物於r.t.下在N
2氣氛下攪拌過夜。然後將混合物用水稀釋且用EtOAc (40 mL)萃取兩次。用鹽水(40 mL)洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。藉由急速管柱層析(用PE/EtOAc= 100:0至3:2溶析)純化殘餘物,以產生純
Y4(2.3 g, 37.80%產率)。LC/MS (ESI) m/z: 359 (M+H)
+。
步驟 3 : Y5 之合成於0℃下向
Y4(80 mg, 0.223 mmol)於DCM (6 mL)中之溶液中逐滴添加TFA (2 mL)。於r.t.下將所得混合物攪拌30 min。然後將混合物濃縮至乾燥。將殘餘物溶解於EtOAc (4 mL)中,用NaHCO
3水溶液中和至pH=8。將混合物用EtOAc (10 mL)萃取兩次。將合併之有機層用鹽水(20 mL)洗滌,經無水Na
2SO
4乾燥,過濾且濃縮,以獲得粗製
Y5(55 mg, 96.49%產率),其不經進一步純化即直接用於下一步驟。LC/MS (ESI) m/z: 259 (M+H)
+。
步驟 4 : 化合物 386 之合成於-78℃下在N
2氣氛下向
Y5(55 mg, 0.212 mmol)及Y
6(46 mg, 0.212 mmol)於DCM (5 mL)中之混合物中逐滴添加TEA
(64 mg, 0.636 mmol)及BTC (31 mg, 0.106 mmol)於DCM(1 mL)中之溶液。於r.t.下將所得混合物攪拌1 hr。然後,用水(20 mL)稀釋混合物並用DCM (20 mL)萃取兩次。用鹽水(30 mL)洗滌合併之有機層,經無水Na
2SO
4乾燥,過濾並濃縮至乾燥。經由prep-HPLC純化殘餘物,以得到白色固體狀
386(15 mg, 9.74 %產率)。LC/MS (ESI) m/z: 500 (M+H)
+。
1HNMR (400 MHz, MeOD) δ 8.43 (s, 1H), 7.88 (dd, J = 12.0, 3.9 Hz, 2H), 7.69 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 4.52 (s, 2H), 4.52 - 4.47 (m, 1H), 4.44 - 4.36 (m, 1H), 4.29 (d, J = 12.5 Hz, 1H), 3.82 (d, J = 12.8 Hz, 1H), 3.71 (t, J = 11.1 Hz, 1H), 3.18 - 3.08 (m, 1H), 2.69 (s, 3H), 2.68 - 2.62 (m, 1H), 2.57 - 2.51 (m, 1H), 2.38 - 2.31 (m, 1H), 2.30 - 2.19 (m, 1H), 0.99 - 0.91 (m, 2H), 0.83 - 0.76 (m, 2H)。
在實例1中所述之異白胺酸轉運分析中測試選自上文之代表性化合物。結果在圖2及圖3中製表。
以引用方式併入 本文引用之所有美國專利及美國專利申請公開案皆以引用方式併入本文中。
等效形式彼等熟習此項技術者僅使用常規實驗將認識到或能確定本文所述本發明之具體實施例的許多等效形式。此等等效形式意欲涵蓋於以下申請專利範圍中。
圖 1係概述本發明之實例性化合物之異白胺酸轉運數據的表。A = IC
50<500 nM;B = IC
50500 nM - 1500 nM;C = IC
501500 nM - 5000 nM;D
= IC
505000 nM - 10000 nM;E = IC
50>10000 nM。
圖 2係概述本發明之額外實例性化合物之異白胺酸轉運數據的表。A = IC
50<500 nM;B = IC
50500 nM - 1,500 nM;C = IC
501,500 nM - 5,000 nM;D
= IC
505,000 nM - 10,000 nM;及E = IC
50>10,000 nM。
圖 3係概述本發明之額外實例性化合物之異白胺酸轉運數據的表。A = IC
50<500 nM;B = IC
50500 nM - 1,500 nM;C = IC
501,500 nM - 5,000 nM;D
= IC
505,000 nM - 10,000 nM;及E = IC
50>10,000 nM。
Claims (101)
- 一種式(I)之化合物, 或其醫藥上可接受之鹽, 其中: n為0、1或2; L 1不存在或選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH 2-; L 2不存在或為-CH 2-; L 3不存在或為-C(O)-; X 1及X 2獨立地選自-H、烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基;條件係X 1及X 2二者不皆為-H; Y 1選自芳基及雜芳基; Y 2選自烷基、烯基、炔基、烷氧基、烷氧基烷基、羥基烷基、環烷基、雜環基、芳基、雜芳基、-NH(Y 2')及-N(Y 2'') 2; Y 2'選自-H、-OH、烷基、烷氧基、烷氧基烷基、羥基烷基及環烷基; 每一Y 2''獨立地係烷基、或兩個實例與其所鍵結之氮原子一起形成5或6員雜環基;且 Y 3、Y 4、Y 5及Y 6獨立地選自-H、-OH、鹵化物、烷基、鹵代烷基及烷氧基;條件係Y 3及Y 4或Y 5及Y 6二者不皆為-OH; 條件係當L 3係-C(O)-時,則Y 2並非芳基;且該化合物並非選自: 及 。
- 如請求項1之化合物,其中Y 2'選自-H、-OH、烷基、烷氧基、烷氧基烷基及環烷基。
- 如請求項1或2之化合物,其中X 1及X 2中之一者係-H;且X 1及X 2中之另一者選自C 1-C 4烷基、鹵代烷基、環烷基、烷基-環烷基及雜環基。
- 如請求項4之化合物,其中X 1係-H;且X 2係-CH 3。
- 如請求項4之化合物,其中X 2係-H;且X 1係-CH 3。
- 如請求項1至8中任一項之化合物,其中L 1不存在。
- 如請求項1至8中任一項之化合物,其中L 1選自-烷基-、-羥基烷基-、-環烷基-及-雜芳基-CH 2-。
- 如請求項10之化合物,其中L 1選自-CH 2-、-C(H)(CH 3)-、-CH 2CH 2-及-C(H)(OH)CH 2-。
- 如請求項1至15中任一項之化合物,其中Y 1係未經取代之芳基。
- 如請求項16之化合物,其中Y 1選自未經取代之苯基及未經取代之萘基。
- 如請求項1至15中任一項之化合物,其中Y 1係經取代之芳基。
- 如請求項19至21中任一項之化合物,其中R 1、R 2、R 3、R 4及R 5中之兩者不為-H。
- 如請求項19至21中任一項之化合物,其中R 1、R 2、R 3、R 4及R 5中之三者不為-H。
- 如請求項1至15中任一項之化合物,其中Y 1係未經取代之雜芳基。
- 如請求項1至15中任一項之化合物,其中Y 1係經取代之雜芳基。
- 如請求項1至29中任一項之化合物,其中L 2不存在。
- 如請求項1至29中任一項之化合物,其中L 2係-CH 2-。
- 如請求項1至31中任一項之化合物,其中L 3不存在。
- 如請求項1至31中任一項之化合物,其中L 3係-C(O)-。
- 如請求項1至33中任一項之化合物,其中 n為0。
- 如請求項1至33中任一項之化合物,其中 n為1。
- 如請求項1至33中任一項之化合物,其中 n為2。
- 如請求項37至39中任一項之化合物,其中Y 2係未經取代之雜芳基。
- 如請求項37至39中任一項之化合物,其中Y 2係經取代之雜芳基。
- 如請求項44之化合物,其中R 10、R 11及R 12獨立地選自-H、-F、-Cl、-Br、-CN、-CH 3、-CH 2CH 3、-CF 3、-CHF 2、-CF 2CH 3、-OCH 3、-OCF 3、-OCHF 2、-OAc、-NH 2、-NHCH 3、-NHAc、-C(O)NH 2、-C(O)NHCH 3、-C(O)NHCH 2CH 3、-C(O)NHSO 2CH 3、-C(O)NHSO 2CH 2CH 3、-CO 2H、苯基、環丙基、環丁基、咪唑基及四唑基。
- 如請求項51之化合物,其中R 17、R 18、R 19、R 20及R 21獨立地選自-H、-CN、-CH 3及-OCH 3。
- 如請求項54至56中任一項之化合物,其中Y 2係未經取代之環烷基或雜環基。
- 如請求項54至56中任一項之化合物,其中Y 2係經取代之環烷基或雜環基。
- 如請求項54至56中任一項之化合物,其中Y 2選自烷基、烯基、炔基、烷氧基、烷氧基烷基及羥基烷基。
- 如請求項62之化合物,其中Y 2選自-CH 3、-CH 2CH(CH 3) 2、-CH 2CH 2C≡CH、-CH 2CH 2OCH 3、-C(H)(CH 3)CH 2OCH 3、-OCH 3、-CH 2OH、-CH 2CH 2OH、-C(CH 3) 2OH及-CH 2OCH 3。
- 如請求項63之化合物,其中Y 2選自-CH 2OH及-CH 2CH 2OH。
- 如請求項54至56中任一項之化合物,其中Y 2係雜芳基。
- 如請求項67之化合物,其中R 10、R 11及R 12中之至少一者不為-H。
- 如請求項69之化合物,其中R 17、R 18、R 19、R 20及R 21中之至少一者不為-H。
- 如請求項71之化合物,其中R 22、R 23、R 24及R 25在每次出現時獨立地選自-H及-CH 3。
- 如請求項54至56中任一項之化合物,其中Y 2係-NH(Y 2')或Y 2係-N (Y 2'') 2。
- 如請求項73之化合物,其中每一Y 2''係-CH 3。
- 如請求項73之化合物,其中Y 2''與其所鍵結之氮原子二者一起形成嗎啉基。
- 如請求項54至56中任一項之化合物,其中Y 2係-NH(Y 2')。
- 如請求項77之化合物,其中Y 2'選自-H、烷基、烷氧基及羥基烷基。
- 如請求項78之化合物,其中Y 2'選自-H、-OCH 3、-CH 3及-CH 2CH 2OH。
- 如請求項1至79中任一項之化合物,其中Y 3及Y 4二者皆係-H或二者皆係-F。
- 如請求項1至79中任一項之化合物,其中Y 3選自-F、-CF 3、-OH及-OCH 3;且Y 4係-H。
- 如請求項1至79中任一項之化合物,其中Y 4選自-F、-CF 3、-OH及-OCH 3;且Y 3係-H。
- 如請求項1至79中任一項之化合物,其中Y 5及Y 6二者皆係-H或二者皆係-F。
- 如請求項1至79中任一項之化合物,其中Y 5選自-F、-CF 3、-OH及-OCH 3;且Y 6係-H。
- 如請求項1至79中任一項之化合物,其中Y 6選自-F、-CF 3、-OH及-OCH 3;且Y 5係-H。
- 一種醫藥組合物,其包含如請求項1至89中任一項之化合物;及醫藥上可接受之賦形劑。
- 一種治療或預防與苯丙胺酸羥化酶中基因缺陷相關之疾病或病症的方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 一種治療或預防苯丙酮尿症之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 一種治療或預防高苯丙胺酸血症之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 如請求項91至93中任一項之方法,其中該化合物降低該個體之全身性苯丙胺酸含量。
- 一種治療或預防酪胺酸血症(I、II或III型)之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 如請求項95之方法,其中該化合物降低該個體之全身酪胺酸含量。
- 一種治療或預防非酮性高甘胺酸血症之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 如請求項97之方法,其中該化合物降低該個體之全身甘胺酸含量。
- 一種治療或預防異戊酸血症、甲基丙二酸血症、丙酸血症、楓糖漿尿病、DNAJC12缺乏、尿素循環障礙或高氨血症之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 一種治療或預防糖尿病、慢性腎病、非酒精性脂肪肝病、非酒精性脂肪性肝炎、代謝症候群、肥胖症有關之病症或神經發育及泛自閉症障礙之方法,其包含向有需要之個體投與有效量之如請求項1至89中任一項之化合物。
- 如請求項91至100中任一項之方法,其中該化合物抑制該個體中之SLC6A19。
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