JP2013508373A - Toll様受容体の調節因子 - Google Patents
Toll様受容体の調節因子 Download PDFInfo
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- JP2013508373A JP2013508373A JP2012535257A JP2012535257A JP2013508373A JP 2013508373 A JP2013508373 A JP 2013508373A JP 2012535257 A JP2012535257 A JP 2012535257A JP 2012535257 A JP2012535257 A JP 2012535257A JP 2013508373 A JP2013508373 A JP 2013508373A
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- substituted
- heteroalkyl
- alkyl
- compound
- aryl
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Abstract
Description
本出願は、一般的にToll様受容体(TLR−7など)を選択的に調節するビアリールプリンおよび3−デアザプリン誘導体および医薬組成物、およびそうした化合物を製造、使用する方法に関連する。
自然免疫系は、身体に侵入する病原体に対する第一線の防御を提供する。自然免疫反応において、侵入する病原体は、生殖細胞系列を符合化した受容体によって認識され、その活性化によってサイトカイン発現の誘発につながるシグナル伝達カスケードが開始される。自然免疫系の受容体は、異なる病原体間での保存性が高い分子構造が認識される広範な特異性を持つ。これらの受容体の一つのファミリーは、最初に同定され、ショウジョウバエで命名された受容体とのその相同性のためにToll様受容体(TLR)として知られ、またマクロファージ、樹状細胞、および上皮細胞などの細胞内に存在する。
上記に基づき、本発明の一側面において式Iの化合物:
L1は、−NR8−、−O−、−S−、−N(R8)C(O)−、−S(O)2−、−S(O)−、または共有結合であり;
R1は、H、アルキル、置換アルキル、ハロアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであり;
X2は、NまたはC−R5であり;
R5は、H、ハロゲン、アルキル、置換アルキル、ハロアルキル、アルコキシ、置換アルコキシ、ハロアルコキシ、アミノアルキル、置換アミノアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキル、シアノ、アジド、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−S(O)2NR8R9、−C(O)OR8、または−C(O)NR9R10であり;
それぞれの非水素R5はX1に任意に結合して追加的な5〜8員炭素環または複素環を形成しうる;
それぞれの非水素R5はD1に任意に結合して追加的な5〜8員炭素環または複素環を形成しうる;
X1は、アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、アルケニレン、置換アルケニレン、アルキニレン、置換アルキニレン、カルボシクリレン、置換カルボシクリレン、ヘテロシクリレン、置換ヘテロシクリレン、−NR8−、−O−、−C(O)−、−S(O)−、−S(O)2−、または共有結合であり;
D1は、アリールまたはヘテロアリールであり;
D2は、アリールまたはヘテロアリールであり;
各L2は、独立的に アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、または共有結合であり;
各R2は、独立的に−NR6R7であり;
mは、1または2であり;
各R3およびR4は、独立的にアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロゲン、ハロアルキル、ハロアルコキシ、ヘテロアルキル、置換ヘテロアルキル、=O、−OR8、−SR8、−NR9R10、=NR8、=NOR8、=NNR8R9、−CN、−OCN、−SCN、−N=C=O、−NCS、−NO、−NO2、=N2、−N3、−NR8C(=O)R9、−NR8C(=O)OR9、−NR8C(=O)NR9R10、−C(=O)NR9R10、−C(=O)OR8、−OC(=O)NR9R10、−OC(=O)OR8、−C(=O)R8、−S(=O)2OR8、−S(=O)2R8、−OS(=O)2OR8、−S(=O)2NR9R10、−S(=O)R8、−NR8S(=O)2R9、−NR8S(=O)2NR9R10、−NR8S(=O)2OR9、−OS(O)2NR9R10、 −OP(=O)(OR8)2、−P(=O)(OR8)2、−P(O)(OR8)(R9)、−P(O)R9R10、−OP(=O)R9R10、−C(=S)R8、−C(=S)OR8、−C(=O)SR8、−C(=S)SR8、−C(=S)NR9R10、−C(=NR8)NR9R10、または−NR8C(=NR8)NR9R10であり;
各nは、R3およびR4のそれぞれについて十分な付着点が存在するよう、描画した環D1およびD2のサイズに応じて、独立的に0、1、2、3、4または5であり;
R6およびR7は、それぞれ独立的に、H、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキル、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−C(O)OR8、または−C(O)NR9R10、S(O)2NR9R10であるか;または
R6およびR7は、両方が結合する窒素と共に置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうるか;または
R7は、L2と共に、また両方が結合されるNと共に、置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうるか;または
R7は、D2、L2と共に、またR7およびL2の両方が結合されるNと共に、置換または未置換の5〜15員複素環またはヘテロアリールを形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる;
R8は、H、アルキル、置換アルキル、ハロアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであり;ならびに
R9およびR10はそれぞれ独立的に、H、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクリルアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであるか;または
R9およびR10は、両方が結合する原子と共に、置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる。
ここで、発明のある一定の請求項に対する詳細な言及をするが、その例については付随の構造および式に図示している。発明は列挙した請求項と関連付けて説明するが、発明をそれらの請求項に限定する意図はないことが理解される。そうではなく、発明は、請求項によって定義されている本発明の範囲内に含まれうる全ての代替物、修正物、および等価物を網羅することが意図される。
別途記載のない限り、以下の用語および句は本書で使用するとき、以下の意味を持つことを意図する。特定の用語または句が具体的に定義されていない場合、あいまいさや明瞭さの欠如とは関連せず、むしろ本書の用語は、その通常の意味の範囲内の意味で使用されている。本書で商品名が使用されているとき、出願人は、商品名の製品および商品名の製品の医薬品有効成分を独立的に含める意図がある。
本発明の文脈において、保護基には、プロドラッグ部分および化学的保護基が含まれる。
エステル形成基には、(1) ホスホンアミデート・エステル、ホスホロチオ酸 エステル、ホスホン酸エステル、およびホスホン−ビス−アミダートなどのホスホン酸エステル形成基;(2) カルボキシル エステル形成基、および (3) スルホン酸、硫酸塩、およびスルフィン酸塩などの硫黄エステル形成基が含まれる。
また、本書に記載した化合物の生体内での代謝性生成物が本発明の範囲に含まれる。こうした生成物は、投与した化合物の酸化、還元、加水分解、アミド化、エステル化およびこれに類する反応から、主に酵素プロセスにより、生じうる。したがって、発明には、本発明の化合物を哺乳動物に、その代謝性生成物を産生するために十分な時間だけ接触させることを含む、プロセスにより生成される化合物が含まれる。こうした生成物は一般に、放射標識化した(例えば、C14またはH3)本発明の化合物を準備し、それを非経口的に検出可能な用量(例えば、約0.5 mg/kgを超える)で、ラット、マウス、モルモット、サルなどの動物もしくはヒトに投与し、代謝が発生するために十分な時間(一般に約30秒〜30時間)の後に、尿、血液またはその他の生体サンプルからその変換産物を単離することにより、同定される。これらの生成物は、標識化されているため簡単に単離される(その他は、代謝生成物中に存続するエピトープと結合する能力を持つ抗体を使用して単離される)。代謝物の構造は、従来の方法、例えば、MSまたはNMR 分析により決定される、一般に、代謝生成物の分析は、当業者にとって周知の従来の薬物代謝研究と同様の方法で実施される。変換産物は、生体内で別の方法で見つからない限り、それ自体に抗感染活性を持たない場合でも、本発明の化合物の治療投薬のための診断評価法にとって有用である。
本化合物の様々な属および亜属についての定義および置換基が、本書に記載・図示されている。上述の定義および置換基の任意の組み合わせが、実施不可能な種または化合物となるべきではないことが、当業者によって理解されるべきである。「実施不可能な種または化合物」は、関連する科学法則に違反する化合物の構造(例えば、4つを超える共有結合に結合した炭素原子など)、または不安定すぎで、単離や、医薬品として容認できる剤形への製剤化ができない化合物を意味する。
この発明の化合物は、従来の担体および賦形剤を用いて製剤化されるが、これは通常の慣行に従い選択されることになる。錠剤は、賦形剤、滑剤、増量剤、結合剤およびこれに類するものを含む。水溶性の製剤は、無菌形態で調製され、経口投与以外による全身への送達が意図されているとき、等張性である。全ての製剤は、医薬品添加物ハンドブック(Handbook of Pharmaceutical Excipients) (1986)に記載のあるものなどの賦形剤を任意に含み、ここに参照することによりその全体を組み込む。賦形剤には、アスコルビン酸およびその他の酸化防止剤、EDTAなどのキレート剤、デキストリン、ヒドロキシアルキルセルロース、ヒドロキシアルキルメチルセルロース、ステアリン酸およびこれに類するものなどの炭水化物が含まれる。製剤のpHは、約2〜約11の範囲であるが、通常は約7〜10である。
1つ以上の本発明の化合物(本書で有効成分という)は、治療する状態に対して適切な任意の経路により投与される。適切な経路には、経口、直腸、経鼻、局所(頬側および舌下を含む)、膣および非経口(皮下、筋肉内、静脈内、皮内、くも膜下腔内および硬膜外を含む)、およびこれに類するものが含まれる。望ましい経路は、例えば、受け手の状態に応じて変化しうることが理解される。この発明の化合物の利点は、経口で生物学的に利用可能であり、経口投与できることである。
一実施態様において、本発明の化合物は、追加的な有効治療成分または薬剤との組み合わせで使用される。
2) リバビリンおよびその類似体、例えば、リバビリン(レベトール、コペガス)、およびタリバビリン(ビラミジン)、
3) HCV NS3 プロテアーゼ阻害剤、例えば、ボセプレビル(SCH−503034、SCH−7)、テラプレビル(VX−950)、VX−813、TMC−435(TMC435350)、ABT−450、BI−201335、BI−1230、MK−7009、SCH−900518、VBY−376、VX−500、GS−9256、GS−9451、BMS−790052、BMS−605339、PHX−1766、AS−101、YH−5258、YH5530、YH5531、およびITMN−191(R−7227)、
4) α−グルコシダーゼ 1阻害剤、例えば、セルゴシビル(MX−3253)、ミグリトール、およびUT−231B、
5) 肝臓保護剤、例えば、エメリカサン(IDN−6556)、ME−3738、GS−9450(LB−84451)、シリビニン、およびMitoQ、
6) HCV NS5B ポリメラーゼのヌクレオシドまたはヌクレオチド阻害剤、例えば、R1626、R7128(R4048)、IDX184、IDX−102、PSI−7851、BCX−4678、バロピシタビン(NM−283)、およびMK−0608、
7) HCV NS5B ポリメラーゼの非ヌクレオシド阻害剤、例えば、フィリブビル(PF−868554)、ABT−333、ABT−072、BI−207127、VCH−759、VCH−916、JTK−652、MK−3281、VBY−708、VCH−222、A848837、ANA−598、GL60667、GL59728、A−63890、A−48773、A−48547、BC−2329、VCH−796(ネスブビル)、GSK625433、BILN−1941、XTL−2125、およびGS−9190、
8) HCV NS5A阻害剤、例えば、AZD−2836(A−831)、AZD−7295(A−689)、およびBMS−790052、
9) TLR−7作動薬、例えば、イミキモド、852A、GS−9524、ANA−773、ANA−975、AZD−8848(DSP−3025)、PF−04878691、およびSM−360320、
10) シクロフィリン阻害剤、例えば、DEBIO−025、SCY−635、およびNIM811、
11) HCV IRES阻害剤、例えば、MCI−067、
12) 薬物動態学的 エンハンサー、例えば、BAS−100、SPI−452、PF−4194477、TMC−41629、GS−9350、GS−9585、およびロキシスロマイシン、
13) HCVを治療するためのその他の薬物、例えば、チモシン α 1(ザダキシン)、ニタゾキサニド(アリネア、NTZ)、BIVN−401(ビロスタット)、PYN−17(altirex)、KPE02003002、アクティロン(CPG−10101)、GS−9525、KRN−7000、シバシール、GI−5005、XTL−6865、BIT225、PTX−111、ITX2865、TT−033i、ANA 971、NOV−205、tarvacin、EHC−18、VGX−410C、EMZ−702、AVI 4065、BMS−650032、BMS−791325、バビツキシマブ、MDX−1106(ONO−4538)、オグルファニド、FK−788、およびVX−497(メリメポジブ)。
2) 逆転写酵素のHIV非ヌクレオシド阻害剤、例えば、カプラビリン、エミビリン、デラビリジン(レスクリプター)、エファビレンツ(サスティバ)、ネビラピン(ビラミューン)、(+)−カラノリド A、カラノリド B、エトラビリン(インテレンス)、GW5634、DPC−083、DPC−961、DPC−963、MIV−150、MIV−160、MIV−170、ダピビリン(TMC−120)、リルピビリン(TMC−278)、BILR 355 BS、VRX 840773、UK−453061、およびRDEA806、RDEA 427、RDEA 640、IDX 899、ANX−201(Thiovir)、R−1206、LOC−dd、IQP−0410(SJ−3366)、YM−215389、YM−228855、CMX−052、およびCMX−182,
3) 逆転写酵素のHIVヌクレオシド阻害剤、例えば、ジドブジン(レトロビル)、エムトリシタビン(エムトリバ)、ジダノシン(ヴァイデックス)、スタブジン(ゼリット)、ザルシタビン(ハイビッド)、ラミブジン(エピビル)、アバカビル(ザイアジェン)、アムドキソビル、エルブシタビン(ACH 126443)、アロブジン(MIV−310)、MIV−210、ラシビル(ラセミのFTC、PSI−5004)、D−d4FC、ホスファジド、フォジブジン チドキシル、アプリシタビン(AVX754、SPD−754)、GS−7340、KP−1461、AVX756、OBP−601、ジオキソラン チミン、TMC−254072、INK−20、PPI−801、PPI−802、MIV−410、4’−Ed4T、B−108、およびフォサルブジン チドキシル(HDP 99.0003)、
4) 逆転写酵素のHIVヌクレオチド阻害剤、例えば、テノホビル ジソプロキシル フマル酸塩(ビリアード)、およびアデホビル ジピボキシル、
5) HIVインテグラーゼ阻害剤、例えば、クルクミン、クルクミン誘導体、チコリ酸、チコリ酸誘導体、3,5−ジカフェオイルキナ酸、3,5−ジカフェオイルキナ酸誘導体、アウリントリカルボン酸、アウリントリカルボン酸誘導体、コーヒー酸フェネチルエステル、コーヒー酸フェネチルエステル誘導体、チルホスチン、チルホスチン誘導体、ケルセチン、ケルセチン誘導体、S−1360、ジンテビル(AR−177)、L−870812、およびL−870810、ラルテグラビル(Isentress、MK−0518)、エルビテグラビル(GS−9137)、BMS−538158、GSK364735C、BMS−707035、MK−2048、GSK−349572(S−349572)、GSK−265744(S−265744)、GSK−247303(S−247303)、S−1360(GW810871)、1,5−DCQA、INH−001、INT−349、V−165、RIN−25、BFX−1001、BFX−1002、BFX−1003、RSC−1838、BCH−33040、およびBA 011、
6) gp41阻害剤、例えば、エンフビルチド(フューゼオン)、シフビルチド、MPI−451936、FB006M、A−329029、およびトリ−1144、
7) CXCR4阻害剤、例えば、AMD−070、KRH−3955(CS−3955)、AMD−9370、AMD−3451、RPI−MN、MSX−122、およびPOL−2438,
8) 侵入阻害剤、例えば、SP01A、PA−161、SPC3、TNX−355、DES6、SP−10、SP−03、CT−319、およびCT−326,
9) gp120阻害剤、例えば、BMS−488043およびそのプロドラッグ、BlockAide/ CR、KPC−2、およびMNLP62、
10) G6PDおよびNADH−オキシダーゼ阻害剤、例えば、イムニチン、
11) CCR5阻害剤、例えば、アプラビロック、ニフェビロック、ビクリビロック(SCH−417690)、マラビロック(セルセントリ)、PRO−140、PRO−542、INCB15050、INCB9471、PF−232798、SCH−532706、GSK−706769、TAK−652、TAK−220、ESN−196、RO−1752、ZM−688523、AMD−887、YM−370749、NIBR−1282、SCH−350634、ZM−688523、およびCCR5mAb004、
12) CCR8阻害剤、例えば、ZK−756326,
13) RNase H阻害剤、例えば、ODN−93、およびODN−112,
14) 成熟阻害剤、例えば、ベビリマット(PA−457)、PA−040、MPC−9055(vicecon、MPI−49839)、ACH−100703、ACH−100706
15) 薬物動態学的エンハンサー、例えば、BAS−100、SPI−452、PF−4194477、TMC−41629、GS−9350、GS−9585、およびロキシスロマイシン、
16) HIV治療のためのその他の薬物、例えば、REP 9、SP−01A、TNX−355、DES6、ODN−93、ODN−112、VGV−1、アンプリゲン、HRG214、サイトリン、VGX−410、VGX−820、KD−247、AMZ 0026、CYT 99007、A−221 HIV、HPH−116、DEBIO−025、BAY 50−4798、MDX010(イピリムマブ)、PBS 119、BIT−225、UBT−8147、ITI−367、AFX−400、BL−1050、GRN−139951、GRN−140665、AX−38679、RGB−340638、PPI−367、およびALG 889。
パクリタキセルは、米国で難治性卵巣がんの治療(Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991 ; McGuire et al., Ann. Intern, Med., 11 1 :273,1989)および乳癌の治療(Holmes et al., J. Nat. Cancer Inst., 83:1797,1991)での臨床使用が認可されている。これは、皮膚の腫瘍(Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46)および頭部と頚部の悪性腫瘍(Forastire et. al., Sem. Oncol., 20:56, 1990)の治療の潜在的候補である。化合物は、腎多嚢胞病(Woo et. al., Nature, 368:750. 1994)、肺癌およびマラリアの治療に対する可能性も示している。パクリタキセルで患者を治療すると、結果的に骨髄抑制が起こるが(複数細胞系譜、Ignoff, RJ. et. al, Cancer Chemotherapy Pocket GuideA 1998)、これは閾値の濃度(5OnM)を超える投薬の持続時間に関連している(Kearns, CM. et. al., Seminars in Oncology, 3(6) p.16−23, 1995)。
本書で使用するとき、「作動薬」は、その結合パートナー、一般に受容体を刺激する物質である。刺激は、特定の分析の文脈で定義されるか、または当業者によって理解される実質的に類似した状況下で、特定の結合パートナーの「作動薬」または「拮抗薬」として認められた因子または物質と比較する本書の考察の文献から明らかであることがある。刺激は、作動薬または部分作動薬と結合パートナーとの相互作用によって誘発された特定の効果または機能の増加に関して定義することができ、アロステリック効果が含まれうる。
2: 1H−NMR: 300 MHz, (CDCl3) δ: 7.87 (s, 1H), 5.58−5.68 (m, 3H), 4.33 (t, 2H, J = 7 Hz), 4.15 (m, 1H), 3.77 (m, 1H), 1.5−2.1 (m, 10H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C14H22N5O2の計算値: 292.4 (M+H+); 実測値: 292.2 (M+H).
3: 1H−NMR: 300 MHz, (CDCl3) δ: 5.60 (m, 3H), 4.31 (m, 2H), 4.17 (m, 1H), 3.73 (m, 1H), 3.08 (m, 1H), 2.13 (m, 1H), 1.47−1.80 (m, 8H), 0.98 (t, 3H, J = 7 Hz).
LCMS−ESI+: C14H21BrN5O2の計算値: 371.2 (M+H+); 実測値: 370.0 [372.0] (M+H) −臭素同位体.
粗製物をフラッシュカラムクロマトグラフィー(EtOAc/ヘキサン)で精製した。
4: 1H−NMR: 300 MHz, (CDCl3) δ: 5.51 (m, 1H), 5.29 (br s, 2H), 4.29 (t, 2H, J = 7 Hz), 4.12 (m, 4H), 3.71 (m, 1H), 2.79 (m, 1H), 2.10 (m, 1H), 1.47−1.80 (m, 8H), 0.98 (t, 3H, J = 7 Hz).
LCMS−ESI+: C15H24N5O3の計算値: 322.4 (M+H+); 実測値: 322.2 (M+H).
5: 1H−NMR: 300 MHz, (CD3OD) δ: 4.48 (t, 2H, J = 7 Hz), 4.14 (s, 3H), 1.79 (m, 2H), 1.50 (m, 2H), 0.98 (t, 3H, J = 7 Hz).
LCMS−ESI+: C10H16N5O2の計算値: 238.3 (M+H+); 実測値: 238.1 (M+H).
LCMS−ESI+: C17H21IN5O2の計算値: 454.3 (M+H+); 実測値: 454.0 (M+H).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
10: 1H−NMR: 300 MHz, (CDCl3) δ: 7.27−7.61 (m, 8H), 5.31 (br s, 2H), 5.16 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.68 (s, 2H), 2.55 (br s, 4H), 1.71−1.81 (m, 6H), 1.44 (m, 2H), 0.95 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
B: 1H−NMR: 300 MHz, (CD3OD) δ: 7.89 (s, 1H), 7.78 (s, 1H), 7.42−7.67 (m, 6H), 5.11 (s, 2H), 4.50 (m, 4H), 3.52 (br m, 2H), 3.22 (br m, 2H), 2.19 (br m, 2H), 2.04 (br m, 2H), 1.76 (m, 2H), 1.45 (m, 2H), 0.94 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
11: 1H−NMR: 300 MHz, (CDCl3) δ: 7.60 (s, 1H), 7.27−7.51 (m, 7H), 5.30 (br s, 2H), 5.16 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.67 (s, 2H), 2.55 (br s, 4H), 1.72−1.81 (m, 6H), 1.48 (m, 2H), 0.95 (t, 3 H, J = 7 Hz).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
C: 1H−NMR: 300 MHz, (CD3OD) δ: 7.44−7.74 (m, 8H), 5.11 (br s, 2H), 4.52 (br s, 2H), 4.45 (s, 2H), 3.54 (br s, 2H), 3.24 (br s, 2H), 2.21 (br m, 2H), 2.04 (br m, 2H), 1.77 (br m, 2H), 1.45 (br m, 2H), 0.95 (br m, 3H).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
12: 1H−NMR: 300 MHz, (CDCl3) δ: 7.64 (d, 2H, J = 8 Hz), 7.07 (d, 2H, J = 8 Hz), 5.34 (br s, 2H), 5.04 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 4.09 (s, 3H), 1.78 (m, 2H), 1.50 (m, 2 H), 0.97 (t, J = 7 Hz).
LCMS−ESI+: C17H21IN5O2の計算値: 454.3 (M+H+); 実測値: 454.0 (M+H).
13: 1H−NMR: 300 MHz, (CDCl3) δ: 7.56 (d, 1H, J = 8 Hz), 7.19−7.36 (m, 7H), 5.27 (br s, 2H), 5.15 (s, 2H), 4.33 (t, 2H, J = 7 Hz), 4.13 (s, 3H), 3.53 (s, 2H), 2.43 (m, 4H), 1.72−1.81 (m, 6H), 1.49 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
D: 1H−NMR: 300 MHz, (CD3OD) δ: 7.77 (m, 1H), 7.50−7.59 (m, 4H), 7.32−7.7.49 (m, 3H), 5.14 (s, 2H), 4.59 (m, 2H), 4.43 (s, 2H), 3.39 (br m, 2H), 2.85 (br m, 2H), 1.81−1.91 (m, 6H), 1.51 (m, 2H), 1.00 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
14: 1H−NMR: 300 MHz, (CDCl3) δ: 7.26−7.56 (m, 8H), 5.28 (br s, 2H), 5.14 (s, 2H), 4.32 (t, 2H, J = 7 Hz), 4.11 (s, 3H), 3.67 (s, 2H), 2.54 (br s, 4H), 1.74−1.83 (m, 6H), 1.51 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
E: 1H−NMR: 300 MHz, (CD3OD) δ: 7.88 (br s, 1H), 7.70 (br m, 3H), 7.53 (br m, 4H), 5.09 (s, 2H), 4.55 (br m, 2H), 4.46 (s, 2H), 3.53 (br m, 2H), 3.23 (br m, 2H), 2.19 (br m, 2H), 2.04 (br m, 2H), 1.81 (m, 2H), 1.50 (m, 2H), 0.99 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
15: 1H−NMR: 300 MHz, (CDCl3) δ: 7.51 (m, 4H), 7.38 (m, 4H), 5.42 (br s, 2H), 5.13 (s, 2H), 4.32 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.65 (s, 2H), 2.54 (br s, 4H), 1.78 (m, 6H), 1.50 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H35N6O2の計算値: 487.6 (M+H+); 実測値: 487.1 (M+H).
F: 1H−NMR: 300 MHz, (CD3OD) δ: 7.44−7.80 (m, 8H), 5.10 (br s, 2H), 4.55 (br m, 2H), 4.42 (br s, 2H), 3.52 (br m, 2H), 3.23 (br m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H), 1.81 (br m, 2H), 1.50 (br m, 2H), 0.98 (br m, 3H).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.2 (M+H).
16: 1H−NMR: 300 MHz, (CDCl3) δ: 8.44 (d, 1H, J = 2 Hz), 7.58 (dd, 1H, J = 8, 2 Hz), 7.43 (d, 1H, J = 8 Hz), 5.26 (br s, 2H), 5.07 (s, 2H), 4.30 (t, 2H, J = 7 Hz), 4.11 (s, 3H), 1.78 (m, 2H), 1.50 (m, 2H), 0.98 (t, 3H, J = 7 Hz).
LCMS−ESI+: C16H20BrN6O2の計算値: 408.3 (M+H+); 実測値: 407.0 [409.0] (M+H) − 臭素同位体.
17: 1H−NMR: 300 MHz, (CDCl3) δ: 8.72 (s, 1H), 7.65−7.92 (m, 4H), 7.40 (m, 2H), 5.31 (br s, 2H), 5.14 (s, 2H), 4.32 (t, 2H, J = 7 Hz), 4.11 (s, 3H), 3.70 (s, 2H), 2.55 (br s, 4H), 1.78 (m, 6H), 1.51 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
G: 1H−NMR: 300 MHz, (CD3OD) δ: 9.03 (br s, 1H), 8.74 (br s, 1H), 8.53 (br s, 1H), 8.36 (br s, 1H), 8.10 (br s, 1H), 7.92 (br m, 1H), 7.79 (br m, 1H), 5.37 (br s, 2H), 4.59 (br m, 4H), 3.57 (br m, 2H), 3.20 (br m, 2H), 2.22 (br m, 2H), 2.05 (br m, 2H), 1.84 (br m, 2H), 1.53 (br m, 2H), 1.00 (br m, 3H).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
18: 1H−NMR: 300 MHz, (CDCl3) δ: 8.71 (s, 1H), 7.89 (d, 2H, J = 8 Hz), 7.74 (d, 1H, J = 8 Hz), 7.65 (d, 1H, J = 8 Hz), 7.42 (d, 1H, J = 8 Hz), 5.41 (br s, 2H), 5.13 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.68 (s, 2H), 2.55 (br s, 4H), 1.77 (m, 6H), 1.50 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
H: 1H−NMR: 300 MHz, (CD3OD) δ: 8.98 (br s, 1H), 8.61 (br s, 1H), 8.36 (br s, 1H), 8.11 (br s, 2H), 7.88 (br s, 2H), 5.33 (br s, 2H), 4.55 (br m, 4H), 3.56 (br m, 2H), 3.27 (br m, 2H), 2.22 (br m, 2H), 2.05 (br m, 2H), 1.83 (br m, 2H), 1.52 (br m, 2H), 1.00 (br m, 3H).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
19: 1H−NMR: 300 MHz, (CDCl3) δ: 8.31 (d, 1H, J = 5 Hz), 7.38 (s, 1H), 7.13 (d, 1H, J = 5 Hz), 5.39 (br s, 2H), 5.07 (s, 2H), 4.29 (t, 2H, J = 7 Hz), 4.11 (s, 3H), 1.77 (m, 2H), 1.50 (m, 2H), 0.96 (t, 3H, J = 7 Hz).
LCMS−ESI+: C16H20BrN6O2の計算値: 408.3 (M+H+); 実測値: 407.0 [409.0] (M+H) −臭素同位体.
20: 1H−NMR: 300 MHz, (CDCl3) δ: 8.60 (d, 1H, J = 5 Hz), 7.88 (d, 2H, J = 8 Hz), 7.62 (s, 1H), 7.43 (d, 2H, J = 8 Hz), 7.09 (d, 1H, J = 5 Hz), 5.36 (br s, 2H), 5.15 (s, 2H), 4.28 (t, 2H, J = 7 Hz), 4.09 (t, 3H), 3.69 (s, 2H), 2.56 (br s, 4H), 1.74 (m, 6H), 1.49 (m, 2H), 0.94 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
I: 1H−NMR: 300 MHz, (CD3OD) δ: 8.84 (br s, 1H), 8.40 (br s, 1H), 8.09 (br s, 2H), 7.90 (br m, 3H), 5.43 (br s, 2H), 4.56 (br s, 2H), 4.47 (br m, 2H), 3.56 (br m, 2H), 3.27 (br m, 2H), 2.22 (br m, 2H), 2.05 (br m, 2H), 1.76 (br m, 2H), 1.46 (br m, 2H), 0.95 (br m, 3H).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
21: 1H−NMR: 300 MHz, (CDCl3) δ: 8.61 (s, 1H), 7.73 (d, 1H, J = 8 Hz), 6.99 (d, 1H, J = 8 Hz), 5.32 (br s, 2H), 5.21 (s, 2H), 4.25 (t, 2H, J = 7 Hz), 4.08 (s, 3H), 1.71 (m, 2H), 1.46 (m, 2H), 0.94 (t, 3H, J = 7 Hz).
LCMS−ESI+: C16H20BrN6O2の計算値: 408.3 (M+H+); 実測値: 407.0 [409.0] (M+H) −臭素同位体.
22: 1H−NMR: 300 MHz, (CDCl3) δ: 8.77 (s, 1H), 7.79 (d, 1H, J = 8 Hz), 7.48 (m, 4H), 7.12 (d, 1H, J = 8 Hz), 4.26 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.74 (s, 2H), 2.63 (m, 4H), 1.84 (m, 4H), 1.74 (m, 2H), 1.46 (m, 2H), 0.94 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
J: 1H−NMR: 300 MHz, (CD3OD) δ: 9.19 (s, 1H), 8.87 (br s, 1H), 8.12 (br s, 1H), 7.95 (d, 2H, J = 8 Hz), 7.80 (d, 2H, J = 8 Hz), 5.52 (s, 2H), 4.50 (m, 4H), 3.55 (br m, 2H), 3.26 (br m, 2H), 2.21 (br m, 2H), 2.06 (br m, 2H), 1.77 (m, 2H), 1.46 (m, 2H), 0.95 (t, 3H, J = 7 Hz).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
23: 1H−NMR: 300 MHz, (CDCl3) δ: 8.78 (s, 1H), 7.80 (d, 1H, J = 8 Hz), 7.53 (s, 1H), 7.41 (m, 3H), 7.12 (d, 1H, J = 8 Hz), 5.37 (br s, 2H), 5.31 (s, 2H), 4.26 (t, 2H, J = 7 Hz), 4.09 (s, 3H), 3.69 (s, 2H), 2.56 (br m, 4H), 1.74 (m, 6H), 1.47 (m, 2H), 0.93 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
K: 1H−NMR: 300 MHz, (CD3OD) δ: 9.31 (s, 1H), 9.02 (m, 1H), 8.20 (m, 2H), 7.97 (m, 2H), 7.73 (m, 2H), 5.55 (s, 2H), 4.52 (m, 4H), 3.56 (m, 2H), 3.27 (m, 2H), 2.20 (m, 2H), 2.06 (m, 2H), 1.78 (m, 2H), 1.47 (m, 2H), 0.96 (t, 3H, J = 7 Hz).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
24: 1H−NMR: 300 MHz, (CDCl3) δ: 7.58 (s, 1H), 5.26 (s, 2H), 4.33 (t, 2H, J = 7 Hz), 4.14 (s, 3H), 1.80 (m, 2H), 1.53 (m, 2H), 0.99 (t, 3H, J = 7 Hz).
LCMS−ESI+: C14H18BrN6O2Sの計算値: 414.3 (M+H+); 実測値: 413.0 [415.0] (M+H) −臭素同位体.
25: 1H−NMR: 300 MHz, (CDCl3) δ: 7.74−7.82 (m, 3H), 7.33−7.44 (m, 2H), 5.30 (s, 2H), 5.26 (s, 2H), 4.34 (t, 2H, J = 7 Hz), 4.15 (s, 3H), 3.67 (s, 2H), 2.54 (m, 4H), 1.79 (m, 6H), 1.54 (m, 2H), 0.99 (t, 3H, J = 7 Hz).
LCMS−ESI+: C25H32N7O2Sの計算値: 494.6 (M+H+); 実測値: 494.1 (M+H).
L: 1H−NMR: 300 MHz, (CD3OD) δ: 8.22 (br s, 1H), 8.14 (s, 1H), 8.03 (m, 1H), 7.77 (m, 1H), 7.65 (m, 1H), 5.38 (s, 2H), 4.65 (br m, 2H), 4.51 (s, 2H), 3.54 (br m, 2H), 3.25 (br m, 2H), 2.20 (m, 2H), 2.04 (m, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.01 (t, 3H, J = 7 Hz).
LCMS−ESI+: C24H30N7O2Sの計算値: 480.6 (M+H+); 実測値: 480.1 (M+H).
26: 1H−NMR: 300 MHz, (CDCl3) δ: 7.80 (m, 3H), 7.38 (m, 2H), 5.42 (br s, 2H), 5.28 (s, 2H), 4.34 (m, 2H), 4.13 (s, 3H), 3.64 (s, 2H), 2.52 (m, 4H), 1.79 (m, 6H), 1.51 (m, 2H), 0.97 (m, 3H).
LCMS−ESI+: C25H32N7O2Sの計算値: 494.6 (M+H+); 実測値: 494.1 (M+H).
M: 1H−NMR: 300 MHz, (CD3OD) δ: 8.10 (br s, 1H), 8.03 (br m, 2H), 7.75 (br m, 2H), 5.37 (s, 2H), 4.64 (br m, 2H), 4.48 (s, 2H), 3.54 (br m, 2H), 3.23 (br m, 2H), 2.20 (m, 2H), 2.04 (m, 2H), 1.87 (m, 2H), 1.54 (m, 2H), 1.02 (t, 3H, J = 7 Hz).
LCMS−ESI+: C24H30N7O2Sの計算値: 480.6 (M+H+); 実測値: 480.2 (M+H).
27: 1H−NMR: 300 MHz, (CDCl3): δ: 7.74 (d, 2H, J = 8 Hz), 7.30 (d, 2H, J = 8 Hz), 5.28 (br s, 2H), 5.11 (s, 2H), 4.30 (t, 2H, J = 7 Hz), 4.08 (s, 3H), 1.77 (m, 2H), 1.51 (m, 2H), 1.33 (s, 12H), 1.00 (t, 3H, J = 7 Hz).
LCMS−ESI+: C23H33BN5O4の計算値: 454.3 (M+H+); 実測値: 454.1 (M+H).
28: 1H−NMR: 300 MHz, (CDCl3): δ: 8.61 (s, 1H), 7.77 (d, 1H, J = 8 Hz), 7.32 (d, 1H, J = 8 Hz), 3.74 (s, 2H), 2.57 (m, 4H), 1.81 (m, 4H).
LCMS−ESI+: C10H14BrN2の計算値: 242.1 (M+H+); 実測値: 241.1 [243.1] (M+H) −臭素同位体.
29: 1H−NMR: 300 MHz, (CDCl3): δ: 8.75 (s, 1H), 7.81 (d, 1H, J = 8 Hz), 7.42−7.53 (m, 5H), 5.20 (br s, 2H), 5.15 (s, 2H), 4.32 (t, 2H, J = 7 Hz), 4.11 (s, 3H), 3.87 (s, 2H), 2.68 (m, 4H), 1.75−1.85 (m, 6H), 1.51 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.1 (M+H).
N: 1H−NMR: 300 MHz, (CD3OD) δ: 9.14 (s, 1H), 8.59 (d, 1H, J = 8 Hz), 8.08 (d, 1H, J = 8 Hz), 7.81 (d, 2H, J = 8 Hz), 7.62 (d, 2H, J = 8 Hz), 5.15 (s, 2H), 4.81 (s, 2H), 4.56 (t, 2H, J = 7 Hz), 3.73 (br m, 2H), 3.22 (br m, 2H), 2.18 (br m, 4H), 1.82 (m, 2H), 1.50 (m, 2H), 0.98 (t, 3H, J= 7 Hz).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H).
30: 1H−NMR: 300 MHz, (CDCl3): δ: 8.30 (s, 1H), 7.58 (d, 1H, J = 8 Hz), 7.44 (d, 1H, J = 8 Hz), 3.59 (s, 2H), 2.51 (m, 4H), 1.80 (m, 4H).
LCMS−ESI+: C10H14BrN2の計算値: 242.1 (M+H+); 実測値: 241.1 [243.1] (M+H) −臭素同位体.
31: 1H−NMR: 300 MHz, (CDCl3): δ: 8.60 (s, 1H), 7.92 (d, 2H, J = 8 Hz), 7.81 (br d, 1H J = 8 Hz), 7.66 (d, 1H, J = 8 Hz), 7.42 (d, 2H, J = 8 Hz), 5.15 (br s, 4H), 4.32 (t, 2H, J = 7 Hz), 4.09 (s, 3H), 3.71 (s, 2H), 2.61 (m, 4H), 1.73−1.84 (m, 6H), 1.50 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H34N7O2の計算値: 488.6 (M+H+); 実測値: 488.2 (M+H).
O: 1H−NMR: 300 MHz, (CD3OD) δ: 9.20 (s, 1H), 8.94 (d, 1H, J = 8 Hz), 8.50 (d, 1H, J = 8 Hz), 8.04 (d, 2H, J = 8 Hz), 7.74 (d, 2H, J = 8 Hz), 5.21 (s, 2H), 4.81 (s, 2H), 4.55(t, 2H, J = 7 Hz), 3.68 (br m, 2H), 3.31 (br m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H), 1.49 (m, 2H), 0.99 (t, 3H, J= 7 Hz).
LCMS−ESI+: C26H32N7O2の計算値: 474.6 (M+H+); 実測値: 474.1 (M+H).
32: 1H−NMR: 300 MHz, (CDCl3): δ: 7.11 (s, 1H), 3.76 (s, 2H), 2.60 (m, 4H), 1.80 (m, 4H).
LCMS−ESI+: C8H12BrN2Sの計算値: 248.2 (M+H+); 実測値: 247.0 [249.0] (M+H) −臭素同位体.
33: 1H−NMR: 300 MHz, (CDCl3) δ: 7.88 (d, 2H, J = 8 Hz), 7.37 (d, 2H, J = 8 Hz), 7.16 (d, 1H), 5.25 (br s, 2H), 5.12 (s, 2H), 4.30 (t, 2H, J = 7 Hz), 4.08 (s, 3H), 3.86 (s, 2H), 2.67 (m, 4H), 1.75−1.82 (m, 6H), 1.50 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C25H32N7O2Sの計算値: 494.6 (M+H+); 実測値: 494.1 (M+H).
P: 1H−NMR: 300 MHz, (CD3OD) δ: 8.01 (d, 2H, J = 8 Hz), 7.82 (s, 1H), 7.54 (d, 2H, J = 8 Hz), 5.11 (s, 2H), 4.54 (m, 4H), 3.64 (m, 2H), 3.33 (s, 2H), 2.19 (m, 2H), 2.06 (m, 2H), 1.80 (m, 2H), 1.49 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C24H30N7O2Sの計算値: 480.6 (M+H+); 実測値: 480.1 (M+H).
34: 1H−NMR: 300 MHz, (CDCl3): δ: 7.38 (s, 1H), 3.79 (s, 2H), 2.56 (m, 4H), 1.80 (m, 4H).
LCMS−ESI+: C8H12BrN2Sの計算値: 248.2 (M+H+); 実測値: 247.0 [249.0] (M+H) −臭素同位体.
35: 1H−NMR: 300 MHz, (CDCl3) δ: 7.85 (d, 2H, J = 8 Hz), 7.63 (s, 1H), 7.37 (d, 2H, J = 8 Hz), 5.20 (br s, 2H), 5.12 (s, 2H), 4.30 (t, 2H, J = 7 Hz), 4.09 (s, 3H), 3.86 (s, 2H), 2.60 (m, 4H), 1.75−1.81 (m, 6H), 1.50 (m, 2H), 0.96 (t, 3H, J = 7 Hz).
LCMS−ESI+: C25H32N7O2Sの計算値: 494.6 (M+H+); 実測値: 494.1 (M+H).
Q: 1H−NMR: 300 MHz, (CD3OD) δ: 8.15 (br s, 1H), 7.98 (br m, 2H), 7.58 (br m, 2H), 5.12 (br s, 2H), 4.80 (br s, 2H), 4.54 (br m, 2H), 3.64 (m, 2H), 3.29 (m, 2H), 2.22 (m, 2H), 2.07 (m, 2H), 1.80 (m, 2H), 1.48 (m, 2H), 0.98 (br t, 3H, J = 7 Hz).
LCMS−ESI+: C24H30N7O2Sの計算値: 480.6 (M+H+); 実測値: 480.2 (M+H).
36: 1H−NMR: 300 MHz, (CDCl3) δ: 7.47 (d, 1H, J = 8 Hz), 7.37 (d, 1 H, J = 8 Hz), 7.26 (m, 3H), 6.85 (d, 2H, J = 8 Hz), 5.29 (br s, 2H), 5.13 (s, 2H), 4.32 (t, 2H, J = 7 Hz), 4.10 (s, 3H), 3.79 (s, 5H), 3.59 (s, 3H), 2.53 (m, 4H), 1.79 (m, 6H), 1.51 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C29H37N6O3の計算値: 517.6 (M+H+); 実測値: 517.2 (M+H).
R: 1H−NMR: 300 MHz, (CD3OD) δ: 7.49 (m, 5H), 7.00 (d, 2H, J = 8 Hz), 5.09 (s, 2H), 4.57 (m, 2H), 4.37 (s, 2H), 4.13 (s, 3H), 3.47 (m, 2H), 3.19 (m, 2H), 2.17 (m, 2H), 2.02 (m, 2H), 1.83 (m, 2H), 1.50 (m, 2H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H35N6O3の計算値: 503.6 (M+H+); 実測値: 503.1 (M+H).
37: 1H−NMR: 300 MHz, (CDCl3) δ: 7.20−7.51 (m, 7H), 5.30 (s, 2H), 5.14 (s, 2H), 4.31 (t, 2H, J = 7 Hz) 4.10 (s, 3H), 3.72 (s, 2H), 2.59 (m, 4H), 1.78 (m, 6H), 1.50 (m, 2H), 0.97 (t, 2H, J = 7 Hz).
LCMS−ESI+: C28H34FN6O2の計算値: 505.6 (M+H+); 実測値: 505.1 (M+H).
S: 1H−NMR: 300 MHz, (CD3OD) δ: 7.46−7.73 (m, 7H), 5.10 (br s, 2H), 4.52 (br m, 4H), 3.59 (br m, 2H), 3.28 (br m, 2H), 2.21 (br m, 2H), 2.08 (br m, 2H), 1.80 (br m, 2H), 1.50 (br m, 2H), 0.98 (br m, 3H).
LCMS−ESI+: C27H32FN6O2の計算値: 491.6 (M+H+); 実測値: 491.2 (M+H).
38: 1H−NMR: 300 MHz, (CDCl3) δ: 7.88 (s, 1H), 5.62−5.65 (m, 2H), 4.51 (t, J = 4.9 Hz, 2H), 4.14−4.17 (m, 1H), 3.77 (t, J = 4.6 Hz, 2H), 3.44 (s, 3H), 1.66−2.11 (m, 6H).
LCMS−ESI+: C13H19N5O3の計算値: 294.3 (M+H+); 実測値: 294.0 (M+H).
39: 1H−NMR: 300 MHz, (CDCl3) δ: 5.78 (br m, 2H), 4.49 (t, J = 4.9 Hz, 2H), 4.14−4.18 (m, 1H), 3.77 (t, J = 4.6 Hz, 2H), 3.44 (s, 3H), 1.60−1.83 (m, 6H).
LCMS−ESI+: C13H18BrN5O3の計算値: 372.1 (M+H+); 実測値: 371.8 (M+H).
40: 1H−NMR: 300 MHz, (CDCl3) δ: 5.44−5.52 (m, 2H), 4.47 (br m, 2H), 4.10−4.15 (m, 4H), 3.66−3.77 (m, 2H), 3.45 (s, 3H), 1.56−1.76 (m, 6H).
LCMS−ESI+: C14H21N5O4の計算値: 324.1 (M+H+); 実測値: 323.9 (M+H).
41: 1H−NMR: 300 MHz, (CDCl3) δ: 4.66 (br m, 2H), 4.21 (s, 3H), 3.79 (br m, 2H), 3.44 (s, 3H).
LCMS−ESI+: C9H13N5O3の計算値: 240.1 (M+H+); 実測値: 240.0 (M+H).
LCMS−ESI+: C16H24N5O3の計算値: 334.4 (M+H+); 実測値: 334.1 (M+H).
LCMS−ESI+: C16H23BrN5O3の計算値: 413.3 (M+H+); 実測値: 412.1 (M+H).
LCMS−ESI+: C17H26N5O4の計算値: 364.4 (M+H+); 実測値: 346.2 (M+H).
45: 1H−NMR: 300 MHz, (CD3OD) δ: 4.33 (d, 2H, J = 6 Hz), 4.16 (s, 3H), 3.98 (m, 2H), 3.46 (t, 2H, J = 12 Hz), 2.11 (m, 1H), 1.73 (m, 2H), 1.47 (m, 2H).
LCMS−ESI+: C12H18N5O3の計算値: 280.3 (M+H+); 実測値: 280.1 (M+H).
46: 1H−NMR: 300 MHz, (CDCl3) δ:7.03−7.62 (m, 2H), 7.24−7.06 (m, 2H), 5.03 (s, 2H), 4.46 (t, J = 4.9 Hz, 2H), 4.09 (s, 3H), 3.75 (t, J = 4.9 Hz, 2H), 3.43 (s, 3H).
LCMS−ESI+: C16H18N5O3の計算値: 456.0 (M+H+); 実測値: 456.0 (M+H).
47: 1H−NMR: 300 MHz, (CD3OD) δ: 7.77−7.43 (m, 8H), 5.23 (s, 2H), 4.59 (t, J = 4.6 Hz, 2H), 4.44 (s, 2H), 4.18 (s, 3H), 3.76 (t, J = 4.6 Hz, 2H), 3.52 (br m, 2H), 3.40 (s, 3H), 3.24 (br m, 2H), 2.20 (br m, 2H), 2.02 (br m, 2H).
LCMS−ESI+: C27H32N6O3の計算値: 489.6 (M+H+); 実測値: 489.2 (M+H).
T1H−NMR: 300 MHz, (CD3OD) δ: 7.71−7.54 (m, 8H), 5.09 (s, 2H), 4.67 (br m, 2H), 4.46(s, 2H), 3.77 (br m, 2H), 3.53 (br m, 2H), 3.40 (s, 3H), 3.24 (br m, 2H), 2.19 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H30N6O3の計算値: 475.6 (M+H+); 実測値: 475.2 (M+H).
48: 1H−NMR: 300 MHz, (CD3OD) δ: 7.75−7.43 (m, 8H), 5.23 (s, 2H), 4.59 (br m, 2H), 4.42 (s, 2H), 4.18 (s, 3H), 3.76 (br m, 2H), 3.52 (br m, 2H), 3.32 (s, 3H), 3.24 (br m, 2H), 2.20 (br m, 2H), 2.02 (br m, 2H).
LCMS−ESI+: C27H32N6O3の計算値: 489.6 (M+H+); 実測値: 489.2 (M+H).
U: 1H−NMR: 300 MHz, (CD3OD) δ: 7.73−7.51 (m, 8H), 5.10 (s, 2H), 4.64 (t, J = 4.2 Hz, 2H), 4.43 (s, 2H),3.76 (t, J = 4.2 Hz, 2H), 3.53 (br m, 2H), 3.38 (s, 3H), 3.24 (br m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H30N6O3の計算値: 475.6 (M+H+); 実測値: 475.1 (M+H).
49: 1H−NMR: 300 MHz, (CD3OD) δ: 7.73−7.43 (m, 8H), 5.23 (s, 2H), 4.59 (br m, 2H) , 4.41 (br m, 1H), 4.18 (br m, 3H), 3.76 (br m, 4H), 3.40 (s, 3H), 3.09 (br m, 2H), 2.07 (br m, 4H), 1.75 (br m, 3H).
LCMS−ESI+: C28H34N6O3の計算値: 503.6 (M+H+); 実測値: 503.0 (M+H+).
V: 1H−NMR: 300 MHz, (CD3OD) δ: 7.74−7.46 (m, 8H), 5.10 (s, 2H), 4.64 (t, J = 4.2 Hz, 2H) , 4.42 − 4.45 (m, 1H), 3.82−3.74 (m, 4H), 3.38 (s, 3H), 3.02−3.11 (m, 2H), 2.06−2.20 (m, 4H), 1.77 (d, J = 6.9 Hz, 3H).
LCMS−ESI+: C27H32N6O3の計算値: 489.6 (M+H+); 実測値: 489.0 (M+H+).
50: 1H−NMR: 300 MHz, (CD3OD) δ: 7.76−7.46 (m, 8H), 5.23 (s, 2H), 4.60 (br s, 2H) , 4.35 (br s, 2H), 4.19 (br s, 3H), 3.77 (br m, 2H), 3.47 (br m, 2H), 3.40 (s, 3H), 2.98 (br m, 2H), 1.72−1.92 (m, 6H).
LCMS−ESI+: C28H34N6O3の計算値: 503.6 (M+H+); 実測値: 503.2 (M+H+).
W: 1H−NMR: 300 MHz, (CD3OD) δ: 7.85−7.50 (m, 8H), 5.10 (s, 2H), 4.66 (br m, 2H) , 4.37 (s, 2H), 3.76 (br m, 2H), 3.46−3.50 (m, 2H), 3.38 (s, 3H), 2.98−3.02 (m, 2H), 1.79−1.97 (m, 6H).
LCMS−ESI+: C27H32N6O3の計算値: 489.6 (M+H+); 実測値: 489.2 (M+H+).
51: 1H−NMR: 300 MHz, (CD3OD) δ: 7.76−7.44 (m, 8H), 5.23 (s, 2H), 4.62 (br m, 2H) , 4.41 (s, 2H), 4.19 (s, 3H), 4.03 (br m, 2H), 3.77 (br m, 4H), 3.31−3.41 (m, 7H).
LCMS−ESI+: C27H32N6O4の計算値: 505.6 (M+H+); 実測値: 505.2 (M+H+).
X: 1H−NMR: 300 MHz, (CD3OD) δ: 7.76−7.51 (m, 8H), 5.10 (s, 2H), 4.64 (br m, 2H) , 4.42 (s, 2H), 4.08−4.03 (m, 2H), 3.84−3.76 (m, 4H), 3.38 (s, 3H), 3.30−3.21 (m, 4H). LCMS−ESI+: C26H30N6O4の計算値: 491.6 (M+H+); 実測値: 491.1 (M+H+).
52: 1H−NMR: 300 MHz, (CD3OD) δ: 7.78−7.44 (m, 8H), 5.23 (s, 2H), 4.61 (t, J = 4.4 Hz, 2H), 4.43 (s, 2H), 4.19 (s, 3H), 4.03 (br m, 2H), 3.78−3.75 (m, 4H), 3.40 (s, 3H), 3.30−3.21 (br m, 4H).
LCMS−ESI+: C27H32N6O4の計算値: 505.6 (M+H+); 実測値: 505.2 (M+H+).
Y: 1H−NMR: 300 MHz, (CD3OD) δ: 7.87−7.52 (m, 8H), 5.10 (s, 2H), 4.65 (t, J = 4.5 Hz, 2H), 4.45 (s, 2H), 4.06− 4.03 (m, 2H), 3.80−3.75 (m, 4H), 3.38 (s, 3H), 3.30−3.21 (br m, 4H).
LCMS−ESI+: C26H30N6O4の計算値: 491.6 (M+H+); 実測値: 491.2 (M+H+).
53: 1H−NMR: 300 MHz, (CD3OD) δ: 7.64−7.39 (m, 8H), 5.23 (s, 2H), 4.63−4.65 (m, 2H), 4.20 (s, 3H), 3.91 (s, 2H), 3.76 (br m, 2H), 3.31−3.40 (m, 11H), 2.88 (s, 3H).
LCMS−ESI+: C28H35N7O3の計算値: 518.6 (M+H+); 実測値: 518.3 (M+H+).
Z: 1H−NMR: 300 MHz, (CD3OD) δ: 7.74−7.52 (m, 8H), 5.10 (s, 2H), 4.66 (t, J = 4.5 Hz, 2H), 4.53 (s, 2H), 3.78−3.65 (m, 10H), 3.38 (s, 3H), 3.01 (s, 3H).
LCMS−ESI+: C27H33N7O3の計算値: 504.6 (M+H+); 実測値: 504.3 (M+H+).
54: LCMS−ESI+: C16H17ClN5O3の計算値: 490.0 (M+H+); 実測値: 490.0 (M+H+).
55: 1H−NMR: 300 MHz, (CDCl3) δ: 7.75−7.30 (m, 7H), 5.30 (s, 2H), 4.48 (br m, 2H), 4.26 (s, 2H), 4.15 (s, 3H), 3.72−3.66 (m, 4H), 3.36 (s, 3H), 2.87 (br m, 2H), 2.11 (br m, 4H).
LCMS−ESI+: C27H31ClN6O3の計算値: 523.0 (M+H+); 実測値: 523.2 (M+H+).
AA: 1H−NMR: 300 MHz, (CD3OD) δ: 7.74−7.54 (m, 7H), 5.23 (s, 2H), 4.43 (br m, 2H), 3.63−3.51 (m, 6H), 3.34 (s, 3H), 3.20−3.23 (m, 2H), 2.20 (br m, 2H), 2.03 (br m, 2H).
LCMS−ESI+: C26H29ClN6O3の計算値: 509.2 (M+H+); 実測値: 509.1 (M+H+).
56: 1H−NMR: 300 MHz, (CDCl3) δ: 7.51−7.42 (m, 6H), 7.18 (s, 1H), 5.30 (s, 2H), 4.50 (t, J = 4.5 Hz, 2H), 4.25 (s, 2H), 4.16 (s, 3H), 3.69 (br m, 4H), 3.37 (s, 3H), 2.89 (br m, 2H), 2.11 (br m, 4H).
LCMS−ESI+: C27H31ClN6O3の計算値: 523.0 (M+H+); 実測値: 523.2 (M+H+).
AB1H−NMR: 300 MHz, (CD3OD) δ: 7.72−7.53 (m, 7H), 5.25 (s, 2H), 4.45 (br m, 2H), 4.42 (s, 2H), 3.62 (br m, 2H), 3.52 (br m, 2H), 3.32 (s, 3H), 3.20−3.23 (m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H29ClN6O3の計算値: 509.2 (M+H+); 実測値: 509.1 (M+H+).
57: 1H−NMR: 300 MHz, (CDCl3) δ: 7.75 (d, J = 3.6 Hz, 2H), 7.30 (d, J = 3.6 Hz, 2H), 5.10 (s, 2H), 4.47 (t, J = 4.5 Hz, 2H), 4.09 (s, 3H), 3.75 (t, J = 4.5 Hz, 2H), 3.43 (s, 3H), 1.33 (s, 12H).
LCMS−ESI+: C22H30BN5O5の計算値: 456.3 (M+H+); 実測値: 456.2 (M+H+).
58: 1H−NMR: 300 MHz, (CD3OD) δ: 8.76 (s, 1H), 8.05−7.97 (m, 4H),7.49 (d, J = 8.1Hz, 2H), 5.26 (s, 2H), 4.64(t, J = 3.9 Hz, 2H), 4.50 (s, 2H), 4.20 (s, 3H), 3.77 (t, J = 4.3 Hz, 2H), 3.54 (br m, 4H), 3.39 (s, 3H), 2.20 (br m, 2H), 2.06 (br m, 2H).
LCMS−ESI+: C26H31N7O3の計算値: 490.6 (M+H+); 実測値: 490.1 (M+H+).
AC: 1H−NMR: 300 MHz, (CD3OD) δ: 9.11 (s, 1H), 8.76 (d, J = 4.2 Hz, 1H), 8.40 (d, J = 4.2 Hz, 1 H), 8.03 (d, J = 3.9 Hz, 2 H), 7.72 (dd, J = 3.9 Hz, 2 H), 5.20 (s, 2 H), 4.70 (s, 2H), 4.67 (br m, 2H), 3.76 (br m, 2H), 3.66−3.57 (m, 4H), 3.39 (s, 3H), 2.24−2.22 (m, 2H), 2.09 (br m, 2H).
LCMS−ESI+: C25H29N7O3の計算値: 476.5 (M+H+); 実測値: 476.1 (M+H+).
59: 1H−NMR: 300 MHz, (CD3OD) δ: 8.92 (s, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.69 (d, J = 4.0 Hz, 2 H), 7.55−7.48 (m, 2H), 7.21 (d, J = 4.0 Hz, 1H), 5.25 (s, 2 H), 4.65−4.59 (m, 4H), 4.19 (s, 3H), 3.78−3.70 (m, 6H), 3.39 (s, 3H), 2.15 (bm, 4H).
LCMS−ESI+: C26H31N7O3の計算値: 490.6 (M+H+); 実測値: 490.1 (M+H+).
AD: 1H−NMR: 300 MHz, (CD3OD) δ: 9.01 (s, 1H), 8.30 (d, J = 3.9 Hz, 1H), 7.78−7.33 (m, 2 H), 7.65−7.59 (m, 2H), 7.40 (d, J = 3.6 Hz, 1H), 5.14 (s, 2 H), 4.68 (br m, 4H), 3.75−3.58 (m, 6H), 3.38 (s, 3H), 2.16 (bm, 4H).
LCMS−ESI+: C26H31N7O3の計算値: 476.5 (M+H+); 実測値: 476.1 (M+H+).
60: 1H−NMR: 300 MHz, (CD3OD) δ: 8.78 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 3.9 Hz, 2H), 7.48 (d, J = 3.9 Hz, 2H), 5.23 (s, 2 H), 4.56 (bm, 2H), 4.17 (s, 3H), 3.75 (bm, 2 H), 3.54−3.44 (m, 4H), 3.39 (s, 3H), 3.08 (br m, 4H), 1.48 ( t, J = 7.2 Hz, 3 H).
LCMS−ESI+: C26H31N7O3の計算値: 490.6 (M+H+); 実測値: 490.0 (M+H+).
AE: 1H−NMR: 300 MHz, (CD3OD) δ: 8.93 (s, 1H), 8.30 (s, 1H), 7.74 (d, J = 4.0 Hz, 2H), 7.60 (d, J = 3.9 Hz, 2H), 5.13 (s, 2 H), 4.63 (br m, 2H), 3.75 (br m, 2 H), 3.57−3.45 (m, 4H), 3.39 (s, 3H), 3.08 (br m, 4H), 1.48 ( t, J = 7.2 Hz, 3 H).
LCMS−ESI+: C25H29N7O3の計算値: 476.5 (M+H+); 実測値: 476.2 (M+H+).
61: 1H−NMR: 300 MHz, (CDCl3) δ: 8.42 (s, 1H), 7.58−7.41 (m, 2H), 5.17 (br s, 2H, NH2), 5.06 (s, 2H), 4.46 (t, J = 4.8 Hz, 2 H), 4.10 (s, 3H), 3.76 (t, J = 4.9 Hz, 2 H), 3.44 (s, 3H).
LCMS−ESI+: C15H17BrN6O3の計算値: 409.0 (M+H+); 実測値: 409.0 (M+H+).
62: 1H−NMR: 300 MHz, (CD3OD) δ: 8.64 (s, 1H), 7.93 (d, J = 4.2 Hz, 2H), 7.84 (m, 2 Hz, 2H), 7.48 (d, J = 4.2 Hz, 2H), 5.21 (s, 2 H), 4.46 (t, J = 4.6 Hz, 2H), 4.16 (s, 3 H), 3.74−3.72 (m, 4H), 3.40 (s, 3H), 2.63 (bm, 4H), 1.84 (bm, 4H).
LCMS−ESI+: C26H31N7O3の計算値: 490.6 (M+H+); 実測値: 490.1 (M+H+).
AF: 1H−NMR: 300 MHz, (CD3OD) δ: 8.97 (s, 1H), 8.60 (br m, 1H), 8.36 (br m, 1H), 8.02 (br m, 2H), 7.85 (br m, 2H), 5.32 (s, 2 H), 4.69 (br m, 2H), 4.53 (s, 2H), 3.78 (br m, 2H), 3.57 (br m, 4H), 3.40 (s, 3H), 2.22 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C25H29N7O3の計算値: 476.5 (M+H+); 実測値: 476.1 (M+H+).
63: 1H−NMR: 300 MHz, (CD3OD) δ: 8.69 (s, 1H), 7.97−7.44 (m, 6 H), 5.15 (s, 2 H), 4.48 (br m, 2H), 4.13 (s, 3 H), 3.79 (br m, 4H), 3.46 (s, 3H), 2.70 (br m, 4H), 1.87 (br m, 4H).
LCMS−ESI+: C26H31N7O3の計算値: 490.6 (M+H+); 実測値: 490.2 (M+H+).
AG: 1H−NMR: 300 MHz, (CD3OD) δ: 8.99 (s, 1H), 8.64 (br m, 1H), 8.42 (br m, 1H), 8.29 (s, 1H), 8.07 (br m, 1H), 7.87−7.77 (m, 2H), 5.34 (s, 2 H), 4.70 (br m, 2H), 4.55 (s, 2H), 3.79 (br m, 2H), 3.57 (br m, 4H), 3.40 (s, 3H), 2.22 (br m, 2H), 2.07 (br m, 2H).
LCMS−ESI+: C25H29N7O3の計算値: 476.5 (M+H+); 実測値: 476.2 (M+H+).
64: LCMS−ESI+: C16H17ClN5O3の計算値: 490.0 (M+H+); 実測値: 490.0 (M+H+).
65: 1H−NMR: 300 MHz, (CD3OD) δ: 7.67−7.38 (m, 7H), 5.25 (s, 2 H), 4.37 (t, J = 4.8 Hz, 2H), 4.10 (s, 3H), 3.67−3.64 (m, 4H), 3.34 (s, 3H), 2.56 (br m, 4H), 1.81 (br m, 4H).
LCMS−ESI+: C27H31ClN6O3の計算値: 523.0 (M+H+); 実測値: 523.1 (M+H+).
AH: 1H−NMR: 300 MHz, (CD3OD) δ: 7.76−7.44 (m, 7H), 5.23 (s, 2 H), 4.58 (br m, 2H), 4.44 (s, 2H), 3.70 (br m, 2H), 3.56−3.50 (m, 2H), 3.33 (s, 3H), 3.26−3.23 (m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H29ClN6O3の計算値: 509.9 (M+H+); 実測値: 509.1 (M+H+).
66: LCMS−ESI+: C16H17ClN5O3の計算値: 490.0 (M+H+); 実測値: 490.0 (M+H+).
67: 1H−NMR: 300 MHz, (CD3OD) δ: 7.47−7.30 (m, 7H), 5.14 (s, 2 H), 4.54 (t, J = 4.7 Hz, 2H), 4.17 (s, 3H), 3.73(t, J = 4.5 Hz, 2H), 3.69 (s, 2H), 3.39 (s, 3H), 2.60 (br m, 4H), 1.83 (br m, 4H).
LCMS−ESI+: C27H31ClN6O3の計算値: 523.0 (M+H+); 実測値: 523.2 (M+H+).
AI: 1H−NMR: 300 MHz, (CD3OD) δ: 7.67−7.36 (m, 7H), 5.23 (s, 2 H), 4.70 (br m, 2H), 4.46 (s, 2H), 3.78 (br m, 2H), 3.59−3.53 (m, 2H), 3.38 (s, 3H), 3.27−3.23 (m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H29ClN6O3の計算値: 509.9 (M+H+); 実測値: 509.1 (M+H+).
68: LCMS−ESI+: C16H17BrN5O3の計算値: 426.0; (M+H+); 実測値: 426.0 (M+H+).
69: 1H−NMR: 300 MHz, (CD3OD) δ: 7.58 (d, J = 4.2 Hz, 2H), 7.43−7.36 (m, 4H), 7.23 (t, J = 9 Hz, 1H), 5.21 (s, 2 H), 4.42 (t, J = 4.9 Hz, 2H), 4.12 (s, 3H), 3.72−3.68 (m, 4H), 3.37 (s, 3H), 2.62 (br m, 4H), 1.86−1.82 (m, 4H).
LCMS−ESI+: C27H31FN6O3の計算値: 507.2 (M+H+); 実測値: 507.2 (M+H+).
AJ: 1H−NMR: 300 MHz, (CD3OD) δ: 7.67−7.44 (m, 7H), 5.17 (s, 2 H), 4.64 (br m, 2H), 4.44 (s, 2H), 3.74−3.72 (m, 2H), 3.56−3.52 (m, 2H), 3.36 (s, 3H), 3.28−3.23 (m, 2H), 2.22−2.20 (m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H29FN6O3の計算値: 493.5 (M+H+); 実測値: 493.1 (M+H+).
70: LCMS−ESI+: C17H17BrN6O3の計算値: 433.0; (M+H+); 実測値: 433.0 (M+H+).
71: 1H−NMR: 300 MHz, (CD3OD) δ: 8.02−7.38 (m, 7H), 5.36 (s, 2 H), 4.41 (t, J = 4.8 Hz, 2H), 4.14 (s, 3H), 3.70−3.66 (m, 4H), 3.35 (s, 3H), 2.59 (br m, 4H), 1.84−1.82 (m, 4H).
LCMS−ESI+: C28H31N7O3の計算値: 514.6 (M+H+); 実測値: 514.2 (M+H+).
AK: 1H−NMR: 300 MHz, (CD3OD) δ: 8.09−7.69 (m, 7H), 5.32 (s, 2 H), 4.68 (br m, 2H), 4.46 (s, 2H), 3.73 (br m, 2H), 3.59−3.53 (m, 2H), 3.35 (s, 3H), 3.28−3.23 (m, 2H), 2.21 (br m, 2H), 2.06 (br m, 2H).
LCMS−ESI+: C27H29N7O3の計算値: 500.5 (M+H+); 実測値: 500.1 (M+H+).
72: LCMS−ESI+: C22H29BFN5O5の計算値: 474.2; (M+H+); 実測値: 474.2 (M+H+).
73: 1H−NMR: 300 MHz, (CD3OD) δ: 7.57 (d, J = 4.2 Hz, 2H), 7.42−7.36 (m, 4H), 7.23 (t, J = 9 Hz, 1H), 5.21 (s, 2 H), 4.42 (t, J = 4.8 Hz, 2H), 4.12 (s, 3H), 3.72−3.68 (m, 4H), 3.37 (s, 3H), 2.59 (br m, 4H), 1.84−1.81 (m, 4H).
LCMS−ESI+: C27H31FN7O3の計算値: 507.6 (M+H+); 実測値: 507.1 (M+H+).
AL: 1H−NMR: 300 MHz, (CD3OD) δ: 7.75−7.44 (m, 7H), 5.17 (s, 2 H), 4.63 (t, J = 4.0 Hz, 2H), 4.45 (s, 2H), 3.74 (t, J = 3 Hz, 2H), 3.58−3.53 (m, 2H), 3.35 (s, 3H), 3.28−3.23 (m, 2H), 2.20 (br m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C26H29FN6O3の計算値: 493.5 (M+H+); 実測値: 493.1 (M+H+).
74: 1H−NMR: 300 MHz, (CD3OD) δ: 7.82 (s, 1H), 7.76 (s, 1H), 7.63−7.40 (m, 5H), 5.16 (s, 2 H), 4.44 (t, J = 4.6 Hz, 2H), 4.12 (s, 3H), 3.75−3.70 (m, 4H), 3.37 (s, 3H), 2.57 (br m, 4H), 1.83−1.81 (m, 4H).
LCMS−ESI+: C28H31F3N6O3の計算値: 557.6 (M+H+); 実測値: 557.2 (M+H+).
AM: 1H−NMR: 300 MHz, (CD3OD) δ: 8.20−7.57 (m, 7H), 5.13 (s, 2 H), 4.68 (br m, 2H), 4.47 (s, 2H), 3.77 (br m, 2H), 3.59−3.56 (m, 2H), 3.38 (s, 3H), 3.28−3.23 (m, 2H), 2.22 (br m, 2H), 2.06 (br m, 2H).
LCMS−ESI+: C27H29F3N6O3の計算値: 543.5 (M+H+); 実測値: 543.2 (M+H+).
75: 1H−NMR: 300 MHz, (CD3OD) δ: 7.69−7.33 (m, 3H), 5.07 (s, 2 H), 4.44 (br m, 2H), 4.09 (s, 3H), 3.73 (br m, 2H), 3.41(s, 3H).
LCMS−ESI+: C17H17BrF3N5O3の計算値: 476.0 (M+H+); 実測値: 476.0 (M+H+).
76: 1H−NMR: 300 MHz, (CD3OD) δ: 7.79 (s, 1H), 7.56 (d, J = 3.9 Hz, 1H), 7.39−7.24 (m, 5H), 5.23 (s, 2 H), 4.45 (t, J = 4.6 Hz, 2H), 4.15 (s, 3H), 3.74−3.71 (m, 4H), 3.39 (s, 3H), 2.60 (br m, 4H), 1.85−1.82 (m, 4H).
LCMS−ESI+: C28H31F3N6O3の計算値: 557.6 (M+H+); 実測値: 557.2 (M+H+).
AN: 1H−NMR: 300 MHz, (CD3OD) δ: 7.93−7.39 (m, 7H), 5.13 (s, 2 H), 4.69 (br m, 2H), 4.46 (s, 2H), 3.77 (br m, 2H), 3.59−3.54 (m, 2H), 3.39 (s, 3H), 3.28−3.23 (m, 2H), 2.22 (br m, 2H), 2.06 (br m, 2H).
LCMS−ESI+: C27H29F3N6O3の計算値: 543.5 (M+H+); 実測値: 543.1 (M+H+).
77: 1H−NMR: 300 MHz, (CD3OD) δ: 7.79 (s, 1H), 7.56 (d, J = 3.9 Hz, 1H), 7.39−7.24 (m, 5H), 5.23 (s, 2 H), 4.45 (t, J = 4.6 Hz, 2H), 4.15 (s, 3H), 3.72 (t, J = 4.8 Hz, 2H), 3.69(s, 2H), 3.39 (s, 3H), 2.58 (br m, 4H), 1.83−1.81 (m, 4H).
LCMS−ESI+: C28H31F3N6O3の計算値: 557.6 (M+H+); 実測値: 557.2 (M+H+).
AO: 1H−NMR: 300 MHz, (CD3OD) δ: 7.93−7.39 (m, 7H), 5.19 (s, 2 H), 4.69 (br m, 2H), 4.45 (s, 2H), 3.79 (br m, 2H), 3.50 (br m, 2H), 3.39 (s, 3H), 3.28−3.23 (m, 2H), 2.21−2.18 (m, 2H), 2.04 (br m, 2H).
LCMS−ESI+: C27H29F3N6O3の計算値: 543.5 (M+H+); 実測値: 543.2 (M+H+).
78: 1H−NMR: 300 MHz, (CDCl3) δ: 8.57 (d, 1H, J = 2 Hz), 7.70 (dd, 1H, J = 8, 2 Hz), 7.07 (d, 1H, J = 8 Hz), 2.80 (t, 2H, J = 7 Hz), 2.55 (m, 6H), 1.94 (m, 2H), 1.80 (m, 4H).
LCMS−ESI+: C12H18BrN2の計算値: 270.2 (M+H+); 実測値: 269.1 [271.1] (M+H+) −臭素同位体.
79: 1H−NMR: 300 MHz, (CDCl3) δ: 8.71 (s, 1H), 7.75 (d, 1H, J = 8Hz), 7.49 (d, 2H, J = 8 Hz), 7.42 (d, 2H, J = 8 Hz), 7.22 (d, 1H, J = 8 Hz), 5.17 (br s, 2H), 5.14 (s, 2H), 4.78 (t, 2H, J = 7 Hz), 4.12 (s, 3H), 3.76 (d, 2H, J = 7 Hz), 3.43 (s, 3H), 2.87 (t, 2H, J = 7 Hz), 2.54 (m, 6H), 1.99 (m, 2H), 1.79 (m, 4H).
LCMS−ESI+: C28H36N7O3の計算値: 518.3 (M+H+); 実測値: 518.2 (M+H+).
AP: 1H−NMR: 300 MHz, (CD3OD) δ: 9.07 (s, 1H), 8.86 (br m, 1H), 8.15 (br m, 1H), 7.84 (br d, 2H, J = 8 Hz), 7.65 (br d, 2H, J = 8 Hz), 5.16 (s, 2H), 4.67 (br m, 2H), 3.73 (br m, 4H), 3.39 (s, 3H) 3.30 (m, 2H), 3.14 (br m, 4H), 2.06−2.32 (br m, 6H).
LCMS−ESI+: C27H34N7O3の計算値: 504.3 (M+H+); 実測値: 504.1 (M+H+).
80: LCMS−ESI+: C19H22IN5O3の計算値: 496.1; (M+H+); 実測値: 496.0 (M+H+).
81: 1H−NMR: 300 MHz, (CD3OD) δ: 7.60−7.33 (m, 8H), 5.16 (s, 2 H), 4.19−4.17 (m, 2H), 4.13 (s, 3H), 3.97−3.93 (m, 2H), 3.74 (s, 2H), 3.42−3.35 (m, 2H), 2.63 (br m, 4H), 2.01 (br m, 1H), 1.85−1.82 (m, 4H), 1.76−1.72 (m, 2H), 1.43−1.40 (m, 2H).
LCMS−ESI+: C30H36N6O3の計算値: 529.6 (M+H+); 実測値: 529.2 (M+H+).
AQ: 1H−NMR: 300 MHz, (CD3OD) δ: 7.90 (s, 1H), 7.17−7.54 (m, 7H), 5.16 (s, 2 H), 4.46−4.34 (m, 4H), 3.95−3.92 (m, 2H), 3.52 (br m, 2H), 3.44−3.37 (m, 2H), 3.28 (br m, 2H), 2.17−2.04 (m, 5H), 1.72−1.68 (m, 2H), 1.40 (br m, 2H).
LCMS−ESI+: C29H34N6O3の計算値: 515.6 (M+H+); 実測値: 515.3 (M+H+).
82: 1H−NMR: 300 MHz, (CD3OD) δ: 7.59−7.54 (m, 4H), 7.41−7.35 (m, 4H), 5.16 (s, 2 H), 4.19−4.17 (m, 2H), 4.13 (s, 3H), 3.97−3.93 (m, 2H), 3.66 (s, 2H), 3.45−3.38 (m, 2H), 2.57 (br m, 4H), 2.03 (br m, 1H), 1.82 (br m, 4H), 1.77−1.72 (m, 2H), 1.45−1.40 (m, 2H).
LCMS−ESI+: C30H36N6O3の計算値: 529.6 (M+H+); 実測値: 529.1 (M+H+).
AR: 1H−NMR: 300 MHz, (CD3OD) δ: 7.73−7.54 (m, 8H), 5.12 (s, 2 H), 4.43 (br m, 4H), 3.96−3.93 (m, 2H), 3.52 (br m, 2H), 3.44−3.37 (m, 2H), 3.22 (br m, 2H), 2.20−2.03 (m, 5H), 1.72−1.68 (m, 2H), 1.45−1.40 (m, 2H).
LCMS−ESI+: C29H34N6O3の計算値: 515.6 (M+H+); 実測値: 515.1 (M+H+).
83: 1H−NMR: 300 MHz, (CD3OD) δ: 7.74−7.32 (m, 3H), 5.32−5.29 (m, 2H), 5.08 (s, 2 H), 4.14−3.98 (m, 5H), 3.45−3.38 (m, 2H), 2.08 (br m, 1H), 1.80−1.76 (m, 2H), 1.45−1.38 (m, 2H).
LCMS−ESI+: C20H21BrF3N5O3の計算値: 516.1 (M+H+); 実測値: 516.0 (M+H+).
84: 1H−NMR: 300 MHz, (CD3OD) δ: 7.80−7.23 (m, 7H), 5.23 (s, 2 H), 4.19−4.17 (m, 2H), 4.15 (s, 3H), 3.97−3.93 (m, 2H), 3.47 (s, 2H), 3.46−3.38 (m, 2H), 2.58 (br m, 4H), 2.03 (br m, 1H), 1.84−1.80 (m, 4H), 1.77−1.72 (m, 2H), 1.45−1.39 (m, 2H).
LCMS−ESI+: C31H35F3N6O3の計算値: 597.6 (M+H+); 実測値: 597.2 (M+H+).
AS: 1H−NMR: 300 MHz, (CD3OD) δ: 7.93−7.38 (m, 7H), 5.19 (s, 2 H), 4.48−4.42 (m, 4H), 3.96−3.93 (m, 2H), 3.59−3.41 (m, 4H), 3.22 (br m, 2H), 2.21−2.05 (m, 5H), 1.75−1.72 (m, 2H), 1.46−1.39 (m, 2H).
LCMS−ESI+: C30H33F3N6O3の計算値: 583.6 (M+H+); 実測値: 583.2 (M+H+).
85: 1H−NMR: 300 MHz, (CD3OD) δ: 7.80 (s, 1H), 7.57−7.23 (m, 6H), 5.24 (s, 2 H), 4.19−4.17 (m, 2H), 4.16 (s, 3H), 3.98−3.93 (m, 2H), 3.68 (s, 2H), 3.47−3.40 (m, 2H), 2.56 (br m, 4H), 2.03 (br m, 1H), 1.82−1.73 (m, 6H), 1.44−1.34 (m, 2H).
LCMS−ESI+: C31H35F3N6O3の計算値: 597.6 (M+H+); 実測値: 597.2 (M+H+).
AT: 1H−NMR: 300 MHz, (CD3OD) δ: 7.94−7.42 (m, 7H), 5.20 (s, 2 H), 4.44 (br m, 4H), 3.99−3.96 (m, 2H), 3.59−3.44 (m, 4H), 3.22 (br m, 2H), 2.21−2.04 (m, 5H), 1.72 (br m, 2H), 1.43 (m, 2H).
LCMS−ESI+: C30H33F3N6O3の計算値: 583.6 (M+H+); 実測値: 583.2 (M+H+).
86: 1H−NMR: 300 MHz, (CDCl3) δ: 7.74 (d, 2H, J = 8 Hz), 7.28 (d, 2H, J = 8 Hz), 5.36 (br s, 2H), 5.11 (s, 2H), 4.13 (d, 2H, J = 7 Hz), 4.06 (s, 2H), 3.98 (dd, 2H, J = 11, 4 Hz), 3.41 (t, 2H, J = 11 Hz), 2.04 (m, 1H), 1.77 (d, 2H, J = 11 Hz), 1.44 (m, 2H), 1.32 (s, 12H).
LCMS−ESI+: C25H35BN5O5の計算値: 496.3 (M+H+); 実測値: 496.2 (M+H+).
87: 1H−NMR: 300 MHz, (CDCl3) δ: 8.74 (s, 1H), 7.82 (d, 1H, J = 8 Hz), 7.51 (m, 3H), 7.42 (d, 2H, J = 8 Hz), 5.16 (br s, 4H), 4.17 (d, 2H, J = 7 Hz), 4.10 (s, 3H), 4.00 (m, 2H), 3.91 (s, 2H), 3.42 (t, 2H, J = 12 Hz), 2.73 (br s, 4H), 2.10 (br m, 1H), 1.83 (m, 6H), 1.46 (m, 2H).
LCMS−ESI+: C29H36N7O3の計算値: 530.3 (M+H+); 実測値: 530.1 (M+H+).
AU: 1H−NMR: 300 MHz, (CD3OD) δ: 8.99 (s, 1H), 8.27 (d, 2H, J = 6 Hz), 7.73 (m, 3H), 7.59 (d, 2H, J = 8 Hz), 5.14 (s, 2H), 4.67 (s, 2H), 4.42 (d, 2H, J = 6 Hz), 3.94 (dd, 2H, J = 11, 3 Hz), 3.49 (br m, 4H), 3.41 (t, 2H, J = 11 Hz), 2.16 (br m, 4H), 1.70 (d, 2H, J = 11 Hz), 1.44 (m, 2H).
LCMS−ESI+: C28H34N7O3の計算値: 516.3 (M+H+); 実測値: 516.1 (M+H+).
88: 1H−NMR: 300 MHz, (CDCl3) δ: 8.60 (s, 1H), 7.93 (d, 2H, J = 8 Hz), 7.80 (d, 1H, J = 8 Hz), 7.66 (d, 1H, J = 8 Hz), 7.41 (d, 2H, J = 8 Hz), 5.20 (br s, 2H), 5.16 (s, 2H), 4.17 (d, 2H, J = 7 Hz), 4.10 (s, 3H), 4.00 (br d, 2H, J = 7 Hz), 3.71 (s, 2H), 3.42 (m, 2H), 2.60 (br s, 4H), 2.08 (m, 1H), 1.83 (m, 6H), 1.43 (m, 2H).
LCMS−ESI+: C29H36N7O3の計算値: 530.3 (M+H+); 実測値: 530.1 (M+H+).
AV: 1H−NMR: 300 MHz, (CD3OD) δ: 9.11 (s, 1H), 8.75 (d, 1H, J = 8 Hz), 8.40 (d, 1H, J = 8 Hz), 8.04 (d, 2H, J = 8 Hz), 7.71 (d, 2H, J = 8 Hz), 5.20 (s, 2H), 4.70 (s, 2H), 4.41 (d, 2H, J = 7 Hz), 3.94 (m, 2H), 3.66 (br m, 2H), 3.42 (t, 2H, J = 11 Hz), 3.30 (br m, 2H), 2.24 (m, 2H), 2.10 (m, 2H), 1.70 (br d, 2H, J = 11 Hz), 1.45 (m, 2H).
LCMS−ESI+: C28H34N7O3の計算値: 516.3 (M+H+); 実測値: 516.1 (M+H+).
90: 1H−NMR: 300 MHz, (CDCl3) δ: 7.67 (d, 2H, J = 8 Hz), 7.01 (d, 2H, J = 8 Hz), 6.97 (s, 1H), 4.77 (s, 2H), 4.16 (q, 2H, J = 7 Hz), 1.21 (t, 3H, J = 7 Hz).
LCMS−ESI+: C15H13Cl2IN3O4の計算値: 497.1 (M+H+); 実測値: 496.9 (M+H+).
91: 1H−NMR: 300 MHz, (DMSO) δ: 7.67 (d, 2H, J = 8 Hz), 7.12 (d, 2H, J = 8 Hz), 6.66 (s, 1H), 4.85 (s, 2H), 4.04 (m, 2H), 1.08 (t, 3H, J = 7 Hz).
LCMS−ESI+: C15H15ClIN4O4の計算値: 477.7 (M+H+); 実測値: 476.9 (M+H+).
92: 1H−NMR: 300 MHz, (CDCl3) δ: 7.65 (d, 2H, J = 8 Hz), 7.06 (d, 2H, J = 8 Hz), 6.60 (br s, 2H), 5.88 (s, 1H), 5.05 (m, 1H), 4.41 (m, 3H), 4.12 (q, 2H, J = 7 Hz), 3.67 (t, 2H, J = 7 Hz), 3.41 (s, 3H), 1.26 (t, 3H, J = 7 Hz).
LCMS−ESI+: C18H22IN4O6の計算値: 517.3 (M+H+); 実測値: 517.2 (M+H+).
93: 1H−NMR: 300 MHz, (CD3OD) δ: 7.34−7.61 (m, 8H), 5.84 (s, 1H), 5.13 (m, 1H), 4.30−4.51 (m, 3H), 4.11 (m, 2H), 3.78 (br s, 2H), 3.65 (br m, 2H), 3.39 (s, 3H), 2.67 (br s, 4H), 1.85 (br s, 4H), 1.20 (br m, 3H).
LCMS−ESI+: C29H36N5O6の計算値: 550.6 (M+H+); 実測値: 550.1 (M+H+).
AW: 1H−NMR: 300 MHz, (CD3OD) δ: 7.89 (s, 1H), 7.48−7.73 (m, 7H), 6.48 (s, 1H), 5.17 (s, 2H), 4.50 (s, 2H), 4.38 (m, 2H), 3.76 (m, 2H), 3.55 (br m, 2H), 3.37 (s, 3H), 3.29 (br m, 2H), 2.21 (m, 2H), 2.02 (m, 2H).
LCMS−ESI+: C27H32N5O3の計算値: 474.6 (M+H+); 実測値: 474.1 (M+H+).
94: 1H−NMR: 300 MHz, (CD3OD) δ: 7.33−7.71 (m, 8H), 5.83 (s, 1H), 5.13 (m, 1H), 4.30−4.57 (m, 3H), 4.11 (m, 2H), 3.65−3.73 (m, 4H), 3.37 (s, 3H), 2.60 (br s, 4H), 1.83 (br s, 4H), 1.16 (br m, 3H).
LCMS−ESI+: C29H36N5O6の計算値: 550.6 (M+H+); 実測値: 550.1 (M+H+).
AX: 1H−NMR: 300 MHz, (CD3OD) δ: 7.48−7.73 (m, 8H), 6.49 (s, 1H), 5.18 (s, 2H), 4.46 (s, 2H), 4.36 (m, 2H), 3.76 (m, 2H), 3.53 (br m, 2H), 3.37 (s, 3H), 3.29 (br m, 2H), 2.22 (m, 2H), 2.02 (m, 2H).
LCMS−ESI+: C27H32N5O3の計算値: 474.6 (M+H+); 実測値: 474.2 (M+H+).
AY: 1H−NMR: 300 MHz, (CD3OD) δ: 7.70 (d, 2H, J = 8 Hz), 7.62 (d, 4H, J = 8 Hz), 7.34 (d, 2H, J = 8 Hz), 5.46 (s, 2H), 4.49 (m, 2H), 4.43 (s, 2H), 3.75 (m, 2H), 3.52 (br m, 2H), 3.38 (s, 3H), 3.22 (br m, 2H), 2.19 (m, 2H), 2.04 (m, 2H).
LCMS−ESI+: C27H31ClN5O3の計算値: 508.0 (M+H+); 実測値: 508.1 (M+H+).
95: 1H−NMR: 300 MHz, (CDCl3) δ: 7.65 (d, 2H, J = 8 Hz), 7.07 (d, 2H, J = 8 Hz), 6.62 (br s, 2H), 5.77 (s, 1H), 5.10 (m, 1H), 4.42 (m, 1H), 3.98−4.16 (m, 6H), 3.42 (t, 2H, J =11 Hz), 2.00 (m, 1H), 1.65 (m, 2H), 1.42 (m, 2H), 1.28 (t, 3H, J = 7 Hz).
LCMS−ESI+: C21H26IN4O6の計算値: 557.4 (M+H+); 実測値: 557.2 (M+H+).
96: 1H−NMR: 300 MHz, (CDCl3) δ: 7.50−7.57 (m, 4H), 7.33−7.42 (m, 4H), 6.64 (br s, 2H), 5.82 (s, 1H), 5.24 (br m, 1H), 4.47 (br m, 1H), 4.06−4.24 (m, 6H), 3.96 (m, 2H), 3.68 (s, 2H), 3.38 (t, 2H, J = 11 Hz), 2.56 (m, 4H), 1.99 (m, 1H), 1.66 (m, 4H), 1.15−1.42 (m, 7H).
LCMS−ESI+: C32H40N5O6の計算値: 590.7 (M+H+); 実測値: 590.1 (M+H+).
AZ: 1H−NMR: 300 MHz, (CD3OD) δ: 7.73 (d, 2H, J = 8Hz), 7.65 (m, 4H), 7.47 (d, 2H, J = 8 Hz), 6.44 (s, 1H), 5.18 (s, 2H), 4.91 (s, 2H), 4.08 (d, 2H, J = 6 Hz), 3.95 (dd, 2H, J = 11, 4 Hz), 3.53 (m, 2H), 3.40 (t, 2H, J = 11 Hz), 3.22 (m, 2H), 2.02−2.21 (m, 5H), 1.72 (d, 2H, J = 11 Hz), 1.47 (m, 2H).
LCMS−ESI+: C30H36N5O3の計算値: 514.6 (M+H+); 実測値: 514.1 (M+H+).
97: 1H−NMR: 300 MHz, (CDCl3) δ: 8.79 (s, 1H), 7.85 (d, 2H, J = 8 Hz), 7.44−7.57 (m, 4H), 7.33−7.42 (m, 4H), 6.62 (br s, 2H), 5.86 (s, 1H), 5.20 (br m, 1H), 4.56 (br m, 1H), 3.96−4.24 (m, 6H), 3.85 (s, 2H), 3.39 (t, 2H, J = 11 Hz), 2.64 (m, 4H), 1.99 (m, 1H), 1.84 (m, 4H), 1.65 (m, 2H), 1.41 (m, 2H).
LCMS−ESI+: C31H39N6O6の計算値: 591.7 (M+H+); 実測値: 591.1 (M+H+).
BA: LCMS−ESI+: C29H35N6O3の計算値: 515.7 (M+H+); 実測値: 515.2 (M+H+).
LCMS−ESI+: C8H12BrN2Sの計算値: 248.2 (M+H+); 実測値: 246.9 (M+H+).
98: 1H−NMR: 300 MHz, (CDCl3) δ: 7.84 (d, 2H, J = 8 Hz), 7.46 (s, 1H), 7.36 (d, 2H, J = 8 Hz), 6.61 (br s, 2H), 5.80 (s, 1H), 5.20 (br m, 1H), 4.52 (br m, 1H), 3.97−4.22 (m, 8H), 3.39 (t, 2H, J = 11 Hz), 2.78 (m, 4H), 1.99 (m, 1H), 1.89 (m, 4H), 1.62 (m, 2H), 1.40 (m, 2H).
LCMS−ESI+: C29H37N6O6Sの計算値: 597.7 (M+H+); 実測値: 597.2 (M+H+).
LCMS−ESI+: C27H33N6O3Sの計算値: 521.7 (M+H+); 実測値: 521.1 (M+H+).
100: 1H−NMR: 300 MHz, (CDCl3) δ: 7..
LCMS−ESI+: C19H24IN4O5の計算値: 515.3 (M+H+); 実測値: 515.1 (M+H+).
101: 1H−NMR: 300 MHz, (CDCl3) δ: 7.56 (m, 4H), 7.40 (m, 4H), 6.12 (br s, 2H), 5.84 (s, 1H), 4.47 (m, 1H), 4.22 (m, 2H), 4.12 (m, 1H), 3.68 (s, 2H), 2.57 (m, 4H), 1.82 (m, 4H), 1.67 (m, 2H), 1.42 (m, 2H), 1.19 (m, 3H), 0.94 (t, 3H, J = 7 Hz).
LCMS−ESI+: C30H38N5O5の計算値: 548.7 (M+H+); 実測値: 548.1 (M+H+).
BC: 1H−NMR: 300 MHz, (CDCl3) δ: 7.43 (d, 2H, J = 8 Hz), 7.67 (d, 2H, J= 8 Hz), 7.62 (d, 2H, J = 8 Hz), 7.48 (d, 2H, J = 8 Hz), 6.42 (s, 1H), 5.18 (s, 2H), 4.43 (d, 2H), 4.22 (t, 2H, J = 7 Hz), 3.53 (m, 2H), 3.24 (m, 2H), 2.20 (m, 2H), 2.06 (m, 2H), 1.80 (m, 2H), 1.52 (m, 2H), 0.98 (t, 3H, J = 7 Hz).
LCMS−ESI+: C28H34N5O2の計算値: 472.6 (M+H+); 実測値: 472.1 (M+H+).
102: 1H−NMR: 300 MHz, (CDCl3) δ: 8.27 (s, 1H), 7.54 (m, 2H), 7.06 (s, 1H), 4.81 (s, 2H), 4.18 (q, 2H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz).
LCMS−ESI+: C14H12BrCl2N4O4の計算値: 451.1 (M+H+); 実測値: 450.9 (M+H+).
103: 1H−NMR: 300 MHz, (CDCl3) δ: 8.30 (s, 1H), 7.63 (m, 1H), 7.48 (m, 1H), 6.45 (s, 1H), 6.41 (br s, 2H), 4.87 (s, 2H), 4.14 (q, 2H, J = 7 Hz), 1.26 (t, 3H, J = 7 Hz).
LCMS−ESI+: C14H14BrClN5O4の計算値: 431.6 (M+H+); 実測値: 431.9 (M+H+).
104: 1H−NMR: 300 MHz, (CDCl3) δ: 8.25 (s, 1H), 7.70 (m, 1H), 7.48 (d, 1H, J = 8 Hz), 6.67 (br s, 2H), 5.80 (s, 1H), 4.97 (m, 1H), 4.60 (m, 1H), 3.97−4.18 (m, 4H), 3.37−3.50 (m, 4H), 2.02 (m, 1H), 1.72 (m, 2H), 1.35 (m, 2H), 1.15 (t, 3H, J= 7 Hz).
LCMS−ESI+: C20H25BrN5O6の計算値: 511.3 (M+H+); 実測値: 510.1 (M+H+).
105: 1H−NMR: 300 MHz, (CDCl3) δ: 8.55 (s, 1H), 7.17−7.95 (m, 6H), 6.65 (br s, 2H), 5.85 (s, 1H), 5.01 (m, 1H), 4.66 (m, 1H), 3.97−4.21 (m, 6H), 3.37−3.70 (m, 4H), 2.56 (m, 4H), 2.02 (m, 1H), 1.80 (m, 4H), 1.68 (m, 2H), 1.35 (m, 2H), 1.17 (br m, 3H).
LCMS−ESI+: C31H39N6O6の計算値: 591.7 (M+H+); 実測値: 591.2 (M+H+).
BD: 1H−NMR: 300 MHz, (CD3OD) δ: 8.94 (s, 1H), 8.46 (d, 1H, J = 8 Hz), 8.30 (m, 2H), 8.07 (d, 1H, J = 8 Hz), 7.79 (m, 2H), 6.73 (s, 1H), 5.37 (s, 2H), 4.54 (s, 2H), 4.16 (d, 2H, J = 7 Hz), 3.99 (m, 2H), 3.53 (m, 4H), 3.29 (m, 2H), 2.21 (m, 2H), 2.06 (m, 2H), 1.77 (m, 2H), 1.48 (m, 2H).
LCMS−ESI+: C29H35N6O3の計算値: 515.6 (M+H+); 実測値: 515.1 (M+H+).
106: 1H−NMR: 300 MHz, (CDCl3) δ: 8.54 (s, 1H), 7.94 (d, 2H, J = 8 Hz), 7.75 (m, 1H), 7.45 (d, 2H, J = 8 Hz), 7.19 (m, 1H), 6.65 (br s, 2H), 5.85 (s, 1H), 5.11 (m, 1H), 4.66 (m, 1H), 3.97−4.22 (m, 6H), 3.51 (m, 2H), 3.40 (m, 2H), 2.55 (m, 4H), 2.00 (m, 1H), 1.81 (m, 4H), 1.67 (m, 2H), 1.35 (m, 2H), 1.17 (br m, 3H).
LCMS−ESI+: C31H39N6O6の計算値: 591.7 (M+H+); 実測値: 591.1 (M+H+).
BE: 1H−NMR: 300 MHz, (CD3OD) δ: 9.03 (s, 1H), 8.70 (d, 1H, J = 8 Hz), 8.42 (d, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz), 7.90 (d, 2H, J = 8 Hz), 6.82 (s, 1H), 5.44 (s, 2H), 4.55 (s, 2H), 4.18 (d, 2H, J = 7 Hz), 3.99 (m, 2H), 3.54 (m, 2H), 3.44 (m, 2H), 3.27 (m, 2H), 2.22 (m, 2H), 2.06 (m, 2H), 1.78 (m, 2H), 1.49 (m, 2H).
LCMS−ESI+: C29H35N6O3の計算値: 515.6 (M+H+); 実測値: 515.1 (M+H+).
107: 1H−NMR: 300 MHz, (CDCl3) δ: 8.26 (s, 1H), 7.68 (m, 1H), 7.47 (d, 1H, J = 8 Hz), 6.67 (br s, 2H), 5.80 (s, 1H), 4.98 (m, 1H), 4.59 (m, 1H), 4.08−4.28 (m, 4H), 1.72 (m, 2H), 1.42 (m, 2H), 1.15 (m, 3H), 0.97 (t, 3H, J = 7 Hz).
LCMS−ESI+: C18H23BrN5O5の計算値: 469.3 (M+H+); 実測値: 468.1 (M+H+).
108: 1H−NMR: 300 MHz, (CDCl3) δ: 8.56 (s, 1H), 7.19−7.95 (m, 6H), 6.65 (br s, 2H), 5.85 (s, 1H), 5.11 (m, 1H), 4.65 (m, 1H), 4.23 (m, 4H), 3.72 (s, 2H), 2.57 (m, 4H), 1.80 (m, 4H), 1.67 (m, 2H), 1.40 (m, 2H), 1.17 (br m, 3H), 0.95 (t, 3H, J = 7 Hz).
LCMS−ESI+: C29H37N6O5の計算値: 549.6 (M+H+); 実測値: 549.1 (M+H+).
BF: 1H−NMR: 300 MHz, (CD3OD) δ: 8.99 (s, 1H), 8.61 (d, 1H, J = 8 Hz), 8.42 (d, 1H, J = 8 Hz), 8.29 (s, 1H), 8.07 (d, 1H, J = 8 Hz), 7.86 (d, 1H, J = 8 Hz), 7.78 (t, 1H, J = 8 Hz), 6.76 (s, 1H), 5.42 (s, 2H), 4.56 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 3.60 (m, 2H), 3.28 (m, 2H), 2.22 (m, 2H), 2.07 (m, 2H), 1.86 (m, 2H), 1.56 (m, 2H), 1.01 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.1 (M+H+).
109: 1H−NMR: 300 MHz, (CDCl3) δ: 8.55 (s, 1H), 7.18−7.96 (m, 6H), 6.65 (br s, 2H), 5.85 (s, 1H), 5.12 (m, 1H), 4.63 (m, 1H), 4.23 (m, 2H), 4.12 (q, 2H, J = 7 Hz), 3.69 (s, 2H), 2.55 (m, 4H), 1.81 (m, 4H), 1.68 (m, 2H), 1.41 (m, 2H), 1.17 (br m, 3H), 0.95 (t, 3H, J = 7 Hz).
LCMS−ESI+: C29H37N6O5の計算値: 549.6 (M+H+); 実測値: 549.1 (M+H+).
BG: 1H−NMR: 300 MHz, (CD3OD) δ: 8.99 (s, 1H), 8.61 (d, 1H, J = 8 Hz), 8.37 (d, 1H, J = 8 Hz), 8.10 (d, 2H, J = 8 Hz), 7.87 (d, 2H, J = 8 Hz), 6.77 (s, 1H), 5.42 (s, 2H), 4.54 (s, 2H), 4.31 (t, 2H, J = 7 Hz), 3.56 (m, 2H), 3.27 (m, 2H), 2.22 (m, 2H), 2.06 (m, 2H), 1.86 (m, 2H), 1.56 (m, 2H), 1.01 (t, 3H, J = 7 Hz).
LCMS−ESI+: C27H33N6O2の計算値: 473.6 (M+H+); 実測値: 473.1 (M+H+).
生物学的例
PBMC分析実施計画書
本発明の化合物を使用してヒト末梢血単核細胞(PMBC)からの24時間でのサイトカイン刺激を判定するために分析を実施した。分析は、二つ組で、8点の半対数希釈曲線を用いて実施した。本発明の化合物を10 mM DMSO溶液から希釈した。細胞上澄は、IFNαについて直接、およびTNFαについて1:10希釈で評価する。評価法は、Bioorg. Med. Chem. Lett. 16, 4559, (2006)に記載のあるものと類似した方法で実施した。具体的には、凍結保存したPBMCを解凍し、190μL/ウェルの細胞培養液中750,000 細胞/ウェルで96ウェルプレートに播種した。次に、PBMCを37oC、5% CO2中で1時間培養した。次に、本発明の化合物を、10μLの細胞培養液に8ポイントの半対数希釈漸増で加えた。プレートを37oC、5% CO2中で、24時間培養してから、1200rpmで10分間回転させ、この後で上澄を採取し、それを−80°Cで保存した。サイトカイン分泌をLuminexおよびUpstateマルチプレックスキットで、Luminex分析器を使用して分析した。化合物についてのIFN MEC値は、化合物によるIFN−α産生誘導がバックグラウンドの3倍に達した時点での最低濃度で、上記の分析方法を使用して決定した。
Claims (21)
- 式Iの化合物:
L1は、−NR8−、−O−、−S−、−N(R8)C(O)−、−S(O)2−、−S(O)−、または共有結合であり;
R1は、H、アルキル、置換アルキル、ハロアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであり;
X2は、NまたはC−R5であり;
R5は、H、ハロゲン、アルキル、置換アルキル、ハロアルキル、、アルコキシ、置換アルコキシ、ハロアルコキシ、アミノアルキル、置換アミノアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキル、シアノ、アジド、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−S(O)2NR8R9、−C(O)OR8、または−C(O)NR9R10であり;
それぞれの非水素R5はX1に任意に結合して追加的な5〜8員炭素環または複素環を形成しうる;
それぞれの非水素R5はD1に任意に結合して追加的な5〜8員炭素環または複素環を形成しうる;
X1は、アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、アルケニレン、置換アルケニレン、アルキニレン、置換アルキニレン、カルボシクリレン、置換カルボシクリレン、ヘテロシクリレン、置換ヘテロシクリレン、−NR8−、−O−、−C(O)−、−S(O)−、−S(O)2−、または共有結合であり;
D1は、アリールまたはヘテロアリールであり;
D2は、アリールまたはヘテロアリールであり;
各L2は、独立的に アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、または共有結合であり;
各R2は、独立的に −NR6R7であり;
mは、1または2であり;
各R3およびR4は、独立的に アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロゲン、ハロアルキル、ハロアルコキシ、ヘテロアルキル、置換ヘテロアルキル、=O、−OR8、−SR8、−NR9R10、=NR8、=NOR8、=NNR8R9、−CN、−OCN、−SCN、−N=C=O、−NCS、−NO、−NO2、=N2、−N3、−NR8C(=O)R9、−NR8C(=O)OR9、−NR8C(=O)NR9R10、−C(=O)NR9R10、−C(=O)OR8、−OC(=O)NR9R10、−OC(=O)OR8、−C(=O)R8、−S(=O)2OR8、−S(=O)2R8、−OS(=O)2OR8、−S(=O)2NR9R10、−S(=O)R8、−NR8S(=O)2R9、−NR8S(=O)2NR9R10、−NR8S(=O)2OR9、−OS(O)2NR9R10、 −OP(=O)(OR8)2、−P(=O)(OR8)2、−P(O)(OR8)(R9)、−P(O)R9R10、−OP(=O)R9R10、−C(=S)R8、−C(=S)OR8、−C(=O)SR8、−C(=S)SR8、−C(=S)NR9R10、−C(=NR8)NR9R10、または−NR8C(=NR8)NR9R10であり;
各nは、R3およびR4のそれぞれについて十分な付着点が存在するよう、描画した環D1およびD2のサイズに応じて、独立的に0、1、2、3、4または5であり;
R6およびR7はそれぞれ独立的に、H、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル,カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキル、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−C(O)OR8、または−C(O)NR9R10、S(O)2NR9R10であるか;または
R6およびR7、両方が結合する窒素と共に、置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうるか;または
R7は、L2と共に、また両方が結合するNと共に、置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうるか;または
R7は、D2、L2と共に、またR7およびL2の両方が結合するNと共に、置換または未置換の5〜15員複素環またはヘテロアリールを形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる;
R8は、H、アルキル、置換アルキル、ハロアルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであり;ならびに
R9およびR10はそれぞれ独立的に、H、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクリルアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルであるか;または
R9およびR10は、両方が結合する原子と共に、置換または未置換の3〜8員複素環を形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる。 - 請求項1の化合物またはその医薬品として容認できる塩であって、ここで:
L1は、−NH−または−O−であり;
R1は、H、アルキル、置換アルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、ヘテロシクリル、置換ヘテロシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリルアルキル、または置換ヘテロシクリルアルキルであり;
X1は、アルキレン、置換アルキレン、ヘテロアルキレン、または置換ヘテロアルキレンであり;
D1は、アリールまたはヘテロアリールであり;
D2は、アリールまたはヘテロアリールであり;
nは、0、1、または2であり;
各R3およびR4は、独立的にアルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロゲン、ハロアルキル、ハロアルコキシ、ヘテロアルキル、置換ヘテロアルキル、=O、−OR8、−SR8、−NR9R10、=NR8、=NOR8、=NNR8R9、−CN、−OCN、−SCN、−N=C=O、−NCS、−NO、−NO2、=N2、−N3、−NR8C(=O)R9、−NR8C(=O)OR9、−NR8C(=O)NR9R10、−C(=O)NR9R10、−C(=O)OR8、−OC(=O)NR9R10、−OC(=O)OR8、−C(=O)R8、−S(=O)2OR8、−S(=O)2R8、−OS(=O)2OR8、−S(=O)2NR9R10、−S(=O)R8、−NR8S(=O)2R9、−NR8S(=O)2NR9R10、−NR8S(=O)2OR9、−OS(O)2NR9R10、 −OP(=O)(OR8)2、−P(=O)(OR8)2、−P(O)(OR8)(R9)、−P(O)R9R10、−OP(=))R9R10、−C(=S)R8、−C(=S)OR8、−C(=O)SR8、−C(=S)SR8、−C(=S)NR9R10、−C(=NR8)NR9R10、または−NR8C(=NR8)NR9R10であり;
mは、1または2であり;
L2は、アルキレンまたはヘテロアルキレンであり;
X2は、NまたはC−R5であり;
R5は、H、ハロゲン、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シアノ、アジド、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−S(O)2NR8R9、−C(O)OR8、または−C(O)NR9R10であり;
R2は、−NR6R7であり;および
各of R6およびR7 独立的には、H、アルキル、置換アルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、ヘテロシクリル、置換ヘテロシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、または置換へテロアリールアルキルであるか;またはそれらが結合する窒素と共に、置換または未置換の3〜8員環ヘテロシクリルを形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる;および
R8、R9、およびR10はそれぞれ独立的に、H、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルである。 - 請求項1の化合物、またはその医薬品として容認できる塩であって、ここで:
L1は、−NH−または−O−であり;
R1は、H、アルキル、置換アルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、ヘテロシクリル、置換ヘテロシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリルアルキル、または置換ヘテロシクリルアルキルであり;
X1は、アルキレン、置換アルキレン、ヘテロアルキレン、または置換ヘテロアルキレンであり;
D1は、アリールまたはヘテロアリールであり;
D2は、アリールまたはヘテロアリールであり;
nは、0、1、または2であり;
各R3およびR4は、独立的に アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロゲン、ハロアルキル、ハロアルコキシ、ヘテロアルキル、置換ヘテロアルキル、=O、−OR8、−SR8、−NR9R10、=NR8、=NOR8、=NNR8R9、−CN、−OCN、−SCN、−N=C=O、−NCS、−NO、−NO2、=N2、−N3、−NR8C(=O)R9、−NR8C(=O)OR9、−NR8C(=O)NR9R10、−C(=O)NR9R10、−C(=O)OR8、−OC(=O)NR9R10、−OC(=O)OR8、−C(=O)R8、−S(=O)2OR8、−S(=O)2R8、−OS(=O)2OR8、−S(=O)2NR9R10、−S(=O)R8、−NR8S(=O)2R9、−NR8S(=O)2NR9R10、−NR8S(=O)2OR9、−OS(O)2NR9R10、 −OP(=O)(OR8)2、−P(=O)(OR8)2、−P(O)(OR8)(R9)、−P(O)R9R10、−OP(=))R9R10、−C(=S)R8、−C(=S)OR8、−C(=O)SR8、−C(=S)SR8、−C(=S)NR9R10、−C(=NR8)NR9R10、または−NR8C(=NR8)NR9R10であり;
mは、1または2であり;
L2は、アルキレンまたはヘテロアルキレンであり;
X2は、NまたはC−R5であり;
R5は、H、ハロゲン、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シアノ、アジド、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−S(O)2NR8R9、−C(O)OR8、または−C(O)NR9R10であり;
R2は、−NR6R7であり;
R6およびR7は、それらが結合する窒素と共に、置換または未置換の3〜8員ヘテロシクリルを形成するが、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる;ならびに
R8、R9、およびR10はそれぞれ独立的に、H、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクリルアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルである。 - 請求項1の化合物、またはその医薬品として容認できる塩であって、ここで:
L1は、−NH−または−O−であり;
R1は、H、アルキル、置換アルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、ヘテロシクリル、置換ヘテロシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリルアルキル、または置換ヘテロシクリルアルキルであり;
X1は、アルキレン、置換アルキレン、ヘテロアルキレン、または置換ヘテロアルキレンであり;
D1は、アリールまたはヘテロアリールであり;
D2は、アリールまたはヘテロアリールであり;
nは、0、1、または2であり;
各R3およびR4は、独立的に アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、ハロゲン、ハロアルキル、ハロアルコキシ、ヘテロアルキル、置換ヘテロアルキル、=O、−OR8、−SR8、−NR9R10、=NR8、=NOR8、=NNR8R9、−CN、−OCN、−SCN、−N=C=O、−NCS、−NO、−NO2、=N2、−N3、−NR8C(=O)R9、−NR8C(=O)OR9、−NR8C(=O)NR9R10、−C(=O)NR9R10、−C(=O)OR8、−OC(=O)NR9R10、−OC(=O)OR8、−C(=O)R8、−S(=O)2OR8、−S(=O)2R8、−OS(=O)2OR8、−S(=O)2NR9R10、−S(=O)R8、−NR8S(=O)2R9、−NR8S(=O)2NR9R10、−NR8S(=O)2OR9、−OS(O)2NR9R10、 −OP(=O)(OR8)2、−P(=O)(OR8)2、−P(O)(OR8)(R9)、−P(O)R9R10、−OP(=))R9R10、−C(=S)R8、−C(=S)OR8、−C(=O)SR8、−C(=S)SR8、−C(=S)NR9R10、−C(=NR8)NR9R10、または−NR8C(=NR8)NR9R10であり;
mは、1または2であり;
L2は、アルキレンまたはヘテロアルキレンであり;
X2は、NまたはC−R5であり;
R5は、H、ハロゲン、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、シアノ、アジド、−C(O)H、−C(O)R8、−S(O)R8、−S(O)2R8、−S(O)2NR8R9、−C(O)OR8、または−C(O)NR9R10であり;
R2は、−NR6R7であり;ならびに
R6は、H、アルキル、置換アルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、ヘテロシクリル、置換ヘテロシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリルアルキル、置換ヘテロシクリルアルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリール、置換ヘテロアリール、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、または置換へテロアリールアルキルであるか;またはR7およびそれらが結合する窒素と共に、置換または未置換の3〜8員環のヘテロシクリルを形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうるか;または
R7は、D2、L2と共に、またR7およびL2の両方が結合するNと共に置換または未置換の5〜15員複素環またはヘテロアリールを形成し、これがN、O、S、またはPから選択される1個以上の追加的なヘテロ原子を含みうる;ならびに
R8、R9、およびR10はそれぞれ独立的に、H、アルキル、置換アルキル、ハロアルキル、ヘテロアルキル、置換ヘテロアルキル、カルボシクリル、置換カルボシクリル、カルボシクリルアルキル、置換カルボシクリルアルキル、ヘテロシクリル、置換ヘテロシクリル、ヘテロシクリルアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、置換ヘテロシクリルアルキル、アリールアルキル、置換アリールアルキル、ヘテロアリールアルキル、置換へテロアリールアルキル、カルボシクリルアルケニル、置換カルボシクリルアルケニル、カルボシクリルアルキニル、置換カルボシクリルアルキニル、ヘテロシクリルアルケニル、置換ヘテロシクリルアルケニル、ヘテロシクリルアルキニル、置換ヘテロシクリルアルキニル、アリールアルケニル、置換アリールアルケニル、アリールアルキニル、置換アリールアルキニル、ヘテロアリールアルケニル、置換ヘテロアリールアルケニル、ヘテロアリールアルキニル、置換ヘテロアリールアルキニル、カルボシクリルヘテロアルキル、置換カルボシクリルヘテロアルキル、ヘテロシクリルへテロアルキル、置換ヘテロシクリルへテロアルキル、アリールへテロアルキル、置換アリールヘテロアルキル、ヘテロアリールへテロアルキル、または置換ヘテロアリールヘテロアルキルである。 - X2がNである、請求項1〜4のうちいずれかの化合物。
- X2がC−R5である、請求項1〜5のうちいずれかの化合物。
- L1が酸素である、請求項1〜6のうちいずれかの化合物。
- X1がアルキレンである、請求項1〜7のうちいずれかの化合物。
- D1がアリールである、請求項1〜8のうちいずれかの化合物。
- D1がフェニルである、請求項9の化合物。
- D2がアリールである、請求項1〜10のうちいずれかの化合物。
- L2がアルキレンである、請求項1〜11のうちいずれかの化合物。
- 請求項1〜12による化合物および1つ以上の医薬品として容認できる担体または賦形剤を含む医薬組成物。
- さらに1つ以上の追加的な治療薬を含む、請求項13の医薬組成物。
- 請求項1〜12による化合物の投与を含む、ウイルス感染の治療方法。
- 治療の結果がウィルス負荷の低減またはウィルスRNAの排除のうち1つ以上をもたらす、請求項15の方法。
- ウイルス感染治療用の薬物の製造のための、請求項1〜12による化合物の使用。
- ウイルス感染の治療用の、請求項1〜12による化合物。
- 治療の結果がウィルス負荷の低減またはウィルスRNAの排除のうち1つ以上をもたらす、請求項17または18の使用または化合物。
- 請求項1〜12による化合物の投与を含む、黒色腫、非小細胞性肺癌、肝細胞癌、基底細胞癌、腎細胞癌、骨髄腫、アレルギー性鼻炎、喘息、COPD、潰瘍性大腸炎、肝線維症、HBV、HCV、HPV、RSV、SARS、HIV、またはインフルエンザの治療または予防のための方法。
- 黒色腫、非小細胞性肺癌、肝細胞癌、基底細胞癌、腎細胞癌、骨髄腫、アレルギー性鼻炎、喘息、COPD、潰瘍性大腸炎、肝線維症、HBV、HCV、HPV、RSV、SARS、HIV、またはインフルエンザの治療または予防のための薬物の製造での、請求項1〜12による化合物の使用。
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JP7194170B2 (ja) | 2017-08-16 | 2022-12-21 | ブリストル-マイヤーズ スクイブ カンパニー | 三環式基を有するトル様受容体7(tlr7)アゴニスト、そのコンジュゲート、ならびにそれらの方法および使用 |
JP7228571B2 (ja) | 2017-08-16 | 2023-02-24 | ブリストル-マイヤーズ スクイブ カンパニー | 免疫刺激因子トル様受容体7(tlr7)アゴニストとしての6-アミノ―7,9-ジヒドロ-8h-プリン-8-オン誘導体 |
WO2019088159A1 (ja) * | 2017-11-01 | 2019-05-09 | 大日本住友製薬株式会社 | 置換プリン化合物 |
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