JPWO2006109729A1 - ピリジルメチルスルホン誘導体 - Google Patents
ピリジルメチルスルホン誘導体 Download PDFInfo
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- 0 **C(CN=C)c1c(*)cc(C(O)=O)nc1 Chemical compound **C(CN=C)c1c(*)cc(C(O)=O)nc1 0.000 description 7
- LVJJUULKCMABSO-UHFFFAOYSA-N CCOC(Sc(cc1)cc(C)c1F)=S Chemical compound CCOC(Sc(cc1)cc(C)c1F)=S LVJJUULKCMABSO-UHFFFAOYSA-N 0.000 description 1
- ZEPXQLSWMUALFN-UHFFFAOYSA-N CCOC(Sc(cc1)ccc1[O](C)CC)=S Chemical compound CCOC(Sc(cc1)ccc1[O](C)CC)=S ZEPXQLSWMUALFN-UHFFFAOYSA-N 0.000 description 1
- VKSNGTDKHDWQIM-UHFFFAOYSA-N CCOC(Sc(cc1F)ccc1OC)=S Chemical compound CCOC(Sc(cc1F)ccc1OC)=S VKSNGTDKHDWQIM-UHFFFAOYSA-N 0.000 description 1
- NMXQWJMMCNTSKK-NRFANRHFSA-N CCOc(cc1)ccc1S([C@@H](c1cc(F)ccc1F)c1c(C)cc(C(O)=O)nc1)(=O)=O Chemical compound CCOc(cc1)ccc1S([C@@H](c1cc(F)ccc1F)c1c(C)cc(C(O)=O)nc1)(=O)=O NMXQWJMMCNTSKK-NRFANRHFSA-N 0.000 description 1
- YYRQVQHKOQQDSG-UHFFFAOYSA-N Cc(cc1)ccc1SC(c(cc(cc1)F)c1F)c1c(C)cc(C=O)nc1 Chemical compound Cc(cc1)ccc1SC(c(cc(cc1)F)c1F)c1c(C)cc(C=O)nc1 YYRQVQHKOQQDSG-UHFFFAOYSA-N 0.000 description 1
- CEKHQGWUUOKPCN-UHFFFAOYSA-N Cc1c(C(C(C=C(CC2)F)=C2F)S(c2cnc(C(F)(F)F)cc2)=O)cnc(C(N(C)C)=O)c1 Chemical compound Cc1c(C(C(C=C(CC2)F)=C2F)S(c2cnc(C(F)(F)F)cc2)=O)cnc(C(N(C)C)=O)c1 CEKHQGWUUOKPCN-UHFFFAOYSA-N 0.000 description 1
- FYFCFCYLELRYJP-UHFFFAOYSA-N Cc1c(C(c(c(F)ccc2F)c2F)Cl)cnc(Br)c1 Chemical compound Cc1c(C(c(c(F)ccc2F)c2F)Cl)cnc(Br)c1 FYFCFCYLELRYJP-UHFFFAOYSA-N 0.000 description 1
- CPHLILIWIKEALC-UHFFFAOYSA-N Cc1c(C(c(cc(cc2)F)c2F)S(c(cc2)ccc2F)(=O)=O)cnc(C(NCOC(COCc(cc2)ccc2OC)=O)=O)c1 Chemical compound Cc1c(C(c(cc(cc2)F)c2F)S(c(cc2)ccc2F)(=O)=O)cnc(C(NCOC(COCc(cc2)ccc2OC)=O)=O)c1 CPHLILIWIKEALC-UHFFFAOYSA-N 0.000 description 1
- YJXDQJDZFYIPLB-UHFFFAOYSA-N Cc1c(C(c2cc(C3CC3)ccc2F)S(c(cc2)ccc2F)(=O)=O)cnc(C(NCOC(CO)=O)=O)c1 Chemical compound Cc1c(C(c2cc(C3CC3)ccc2F)S(c(cc2)ccc2F)(=O)=O)cnc(C(NCOC(CO)=O)=O)c1 YJXDQJDZFYIPLB-UHFFFAOYSA-N 0.000 description 1
- WVTKYFAIULMONB-UHFFFAOYSA-N Cc1c(C(c2cc(F)ccc2F)S(C2=CC=C(C(F)(F)F)N=CC2)(=O)=O)cnc(C(N(C)C)=O)c1 Chemical compound Cc1c(C(c2cc(F)ccc2F)S(C2=CC=C(C(F)(F)F)N=CC2)(=O)=O)cnc(C(N(C)C)=O)c1 WVTKYFAIULMONB-UHFFFAOYSA-N 0.000 description 1
- PUJYWJMTQHYWQY-UHFFFAOYSA-N Cc1c(C(c2cc(F)ccc2F)S(c(cc2)ccc2F)=O)cnc(C(N(C)C)=O)c1 Chemical compound Cc1c(C(c2cc(F)ccc2F)S(c(cc2)ccc2F)=O)cnc(C(N(C)C)=O)c1 PUJYWJMTQHYWQY-UHFFFAOYSA-N 0.000 description 1
- KAHVURQDIFMYJU-UHFFFAOYSA-N Cc1c(C(c2cc(F)ccc2F)S(c(cc2)ccc2P)(=O)=O)cnc(C(NCCCSC)=O)c1 Chemical compound Cc1c(C(c2cc(F)ccc2F)S(c(cc2)ccc2P)(=O)=O)cnc(C(NCCCSC)=O)c1 KAHVURQDIFMYJU-UHFFFAOYSA-N 0.000 description 1
- ZEFKTTDSFYVKFF-UHFFFAOYSA-N Cc1c(C(c2cc(F)ccc2F)S(c2ncc(C(F)(F)F)cc2)(=O)=O)cnc(C(O)=O)c1 Chemical compound Cc1c(C(c2cc(F)ccc2F)S(c2ncc(C(F)(F)F)cc2)(=O)=O)cnc(C(O)=O)c1 ZEFKTTDSFYVKFF-UHFFFAOYSA-N 0.000 description 1
- WAYBAQQTPDBTDP-UHFFFAOYSA-N Cc1c(C(c2cc(F)ccc2F)Sc2cc(F)cc(F)c2)cnc(Br)c1 Chemical compound Cc1c(C(c2cc(F)ccc2F)Sc2cc(F)cc(F)c2)cnc(Br)c1 WAYBAQQTPDBTDP-UHFFFAOYSA-N 0.000 description 1
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Description
すなわち、本発明は次の一般式(1)
Ar2は置換基を有することもあるフェニル基又は置換基を有することもある複素環基を示し;
Xは−S−、−SO−、又は−SO2−を示し;
Yは水素原子、−NR1R2(式中、R1は水素原子、低級アルキル基、又は水酸基を示し、R2は水素原子、置換基を有することもある低級アルキル基、低級アルカノイル基、置換基を有することもあるアルコキシカルボニル基、置換基を有することもある低級アルコキシ基、置換基を有することもあるアミノ基、ホスホノ基、置換基を有することもあるフェニル基、又は置換基を有することもある芳香族複素環基を示し、あるいは、R1とR2はこれらが結合する窒素原子と一緒になって飽和複素環基を形成し、さらに当該飽和複素環基は置換基を有していてもよいことを示す。)、又は−OR1’(式中、R1’は水素原子又は置換基を有していてもよい低級アルキル基を示す。)を示し;
Zは酸素原子又は硫黄原子を示し;
R3は水素原子、低級アルキル基、又はハロゲン原子を示す。]
で表される化合物、その塩、又はそれらの溶媒和物を提供するものである。
この中でフェニル基、4−メチルフェニル基、4−クロロフェニル基、4−フルオロフェニル基、4−トリクロロメチルフェニル基、4−トリフルオロメチルフェニル基、4−メトキシフェニル基、4−(トリフルオロメトキシ)フェニル基、3,4−ジフルオロフェニル基、3,5−ジフルオロフェニル基、4−クロロ−3−メチルフェニル基、4−フルオロ−3−メチルフェニル基、5−クロロピリジン−2−イル基、5−フルオロピリジン−2−イル基、5−メチルピリジン−2−イル基、5−(フルオロメチル)ピリジン−2−イル基、5−(ジフルオロメチル)ピリジン−2−イル基、5−(トリフルオロメチル)ピリジン−2−イル基、6−クロロピリジン−3−イル基、6−フルオロピリジン−3−イル基、6−メチルピリジン−3−イル基、6−(フルオロメチル)ピリジン−3−イル基、6−(ジフルオロメチル)ピリジン−3−イル基、6−(トリフルオロメチル)ピリジン−3−イル基、2−(トリフルオロメチル)ピリミジン−5−イル基、5−クロロチオフェン−2−イル基、5−フルオロチオフェン−2−イル基、ベンゾフラン−6−イル基、2,3−ジヒドロベンゾフラン−6−イル基等が好ましく、フェニル基、4−メチルフェニル基、4−トリフルオロメチルフェニル基、4−クロロフェニル基、4−フルオロフェニル基、4−メトキシフェニル基、4−(トリフルオロメトキシ)フェニル基、3,4−ジフルオロフェニル基、4−クロロ−3−メチルフェニル基、4−フルオロ−3−メチルフェニル基、3,5−ジフルオロフェニル基、5−(トリフルオロメチル)ピリジン−2−イル基、6−(トリフルオロメチル)ピリジン−3−イル基、及びベンゾフラン−6−イル基であることがさらに好ましい。
トルエン又はジエチルエーテルなどの溶媒中で、2,5−ジブロモピリジン誘導体(2)に当量の有機金属試薬(代表的には、有機リチウム試薬、又はグリニャール試薬)を反応させることによりピリジンの5位を選択的にリチオ化できる。この溶液に求電子試薬としてAr1−CHOで示されるアルデヒドを加えることにより、アルコール誘導体(3)を得ることができる。
別法としては、上記の反応において、求電子試薬としてジメチルホルムアミド又はギ酸エチルを加えることにより、アルデヒド誘導体(4)を得ることができる。これに、テトラヒドロフラン又はジエチルエーテルなどの溶媒中でAr1−Br又はAr1−Hと当量から2等量の有機金属試薬(代表的には有機リチウム試薬)で調整されるAr1−Liを加えることによっても合成できる。
尚、上記の製造工程中で用いたアリールカルバルデヒド(Ar1−CHO)、アリールブロミド(Ar1−Br)、若しくはアリール(Ar1−H)、又は2、5−ジブロモピリジン誘導体(2)は、公知化合物であるか、又はこの分野の当業者に周知な方法を組み合わせることにより製造することができる。
アルコール誘導体(3)を化合物(5)に導いた後、得られた化合物(5)とチオール化合物(Ar2−SH)を塩基存在下に反応させることによりスルフィド化合物(6)を製造することができる。この場合、チオール化合物は、アルカリ金属塩若しくはアルカリ土類金属塩(例えばリチウム、ナトリウム、カリウム)として用いてもよい。
尚、上記の製造工程中で用いたチオール化合物(Ar2−SH)は、公知化合物、又はこの分野の当業者に周知な方法を組み合わせることにより製造することができる。
2−ブロモピリジン誘導体(6)は有機金属試薬を加え攪拌した後に、求電子試薬として二酸化炭素を加えることによりピリジン−2−カルボン酸誘導体(7)を製造することができる。
この反応溶液中に、求電子試薬として気体又は固体の二酸化炭素を加える。反応における温度は通常−100〜50℃、好ましくは−78〜0℃である。反応時間は通常0.1時間〜1日である。
2−ブロモピリジン誘導体(6)は有機金属試薬を加え攪拌した後に、求電子試薬としてジメチルホルムアミド又はギ酸エチルなどのギ酸エステルを加えることによりピリジン−2−カルバルデヒド誘導体(8)を製造することができる。
この反応溶液中に、ジメチルホルムアミド又はギ酸エチルなどのギ酸エステルを加える。
反応における温度は通常−100〜50℃、好ましくは−78〜0℃である。反応時間は通常0.1時間〜3日である。得られたピリジン−2−カルバルデヒド誘導体(8)は、溶媒中で酸化剤により酸化することによりピリジン−2−カルボン酸誘導体(9)を製造することができる。
本発明中のピリジン誘導体に関してピリジン−2−カルボキサミド誘導体(1aN)又は(1cN)は、下記のように、溶媒中でピリジン−2−カルボン酸誘導体(7)又は(9)、1級若しくは2級アミン(HNR1R2)又はその塩、及び縮合剤を加えることにより製造することができる。
反応温度は通常−20〜200℃、好ましくは0〜50℃であり、反応時間は通常0.5時間から3日である。溶媒としては、エーテル系溶媒、ハロゲン系溶媒、芳香族系溶媒、アルコール系溶媒、ニトリル系溶媒、アミド系溶媒、ケトン系溶媒、スルホキシド系溶媒、水を挙げることができ、これらの2種類以上を混合して用いることもできる。これらの中では、テトラヒドロフラン、塩化メチレン、クロロホルム等が好ましい。
別法としてピリジン−2−カルボキサミド誘導体(1aN)又は(1cN)はピリジン−2−カルボン酸誘導体(7)又は(9)を酸クロリドに変換した後に、溶媒中で1級又は2級アミンを加えることによっても製造することができる。
具体的な反応例を挙げるとピリジン−2−カルボン酸誘導体(7)又は(9)に、室温で過剰量の塩化チオニルを加える。極少量のジメチルホルムアミドが共存していた方が好ましく、溶媒を用いた場合には塩化メチレン、クロロホルム等が好ましい。これを濃縮した後に、溶媒で希釈して等量から過剰量のアミンを加えることによりピリジン−2−カルボキサミド誘導体(1aN)又は(1cN)を製造することができる。溶媒にはテトラヒドロフラン、塩化メチレン、クロロホルム、又はジメチルホルムアミド等が好ましく、この時に、塩基として、トリエチルアミン等の3級アミン、又はピリジン等の芳香族アミンが存在していても良い。
尚、上記の製造工程中で用いたアミン(HNR1R2)は、公知化合物、又はこの分野の当業者に周知な方法を組み合わせることにより製造することができる。
本発明中のピリジン誘導体に関してピリジン−2−カルボキシラート誘導体(1aO)又は(1cO)は、下記のように、溶媒中でピリジン−2−カルボン酸誘導体(7)又は(9)、アルコール及び縮合剤を加えることにより製造することができる。
反応温度は通常−20〜200℃、好ましくは0〜50℃であり、反応時間は通常0.5時間から3日である。溶媒としては、エーテル系溶媒、ハロゲン系溶媒、芳香族系溶媒、ニトリル系溶媒、アミド系溶媒、ケトン系溶媒、スルホキシド系溶媒を挙げることができ、これらの2種類以上を混合して用いることもできる。これらの中では、トルエン、テトラヒドロフラン、塩化メチレン等が好ましい。
別法としてピリジン−2−カルボキシラート誘導体(1aO)又は(1cO)はピリジン−2−カルボン酸誘導体(7)又は(9)を酸クロリドに変換した後に、溶媒中で塩基共存下にアルコールを加えることによっても製造することができる。
具体的な反応例を挙げるとピリジン−2−カルボン酸誘導体(7)又は(9)に、室温で過剰量の塩化チオニルを加える。極少量のジメチルホルムアミドが共存していた方が好ましく、溶媒を用いた場合には塩化メチレン、クロロホルム等が好ましい。これを濃縮した後に、溶媒で希釈して等量から過剰量のアルコール及び塩基を加えることによりピリジン−2−カルボキシラート誘導体(1aO)又は(1cO)を製造することができる。溶媒にはテトラヒドロフラン、塩化メチレン、クロロホルム、又はジメチルホルムアミド等が好ましく、この時に、塩基として、トリエチルアミン又はピリジン等の3級アミン又は芳香族アミンが存在していても良い。
尚、上記の製造工程中で用いたアルコールは(HOR1’)は、公知化合物、又はこの分野の当業者に周知な方法を組み合わせることにより製造することができる。
本発明中のピリジン誘導体に関して、スルフィニル化合物(1b)又はスルホニル化合物(1c)は、下記のように、スルフィド化合物(1a)を溶媒中で酸化剤により酸化することにより製造することができる。
反応温度は通常−20〜150℃、好ましくは0〜50℃であり、反応時間は通常0.5時間から3日である。
本発明の化合物(1)においてZが硫黄原子である場合、本発明のピリジン誘導体は以下の方法により製造可能である。
ピリジル−2−カルボキサミド誘導体(1:Y=NR1R2、Z=O)又はピリジル−2−カルボキシラート誘導体(1:Y=OR1’、Z=O)は公知の方法によりピリジル−2−チオアミド誘導体(1:Y=NR1R2、Z=S)、ピリジル−2−チオカルボキシラート誘導体(1:Y=OR1’、Z=S)へ変換することができる。一例を挙げるならば、ピリジル−2−カルボキサミド誘導体(1:Y=NR1R2、Z=O)又はピリジル−2−カルボキシラート誘導体(1:Y=OR1、Z=O)に溶媒中で、1から5等量のLawesson’s試薬(2,4−ビス(4−メトキシフェニル)−1,3−ジチア−2,4−ジホスフェタン−2,4−ジスルフィド)を加えればよい。溶媒としてはトルエン、キシレン、テトラヒドロフラン、ジオキサン、塩化メチレン等が好ましく、反応温度は0℃から200℃、好ましくは室温から130℃であり、反応時間は通常0.5時間から3日間である。
一般式(1)において、Ar1が2,3,6−トリフルオロフェニル基であり、Ar2が4−フルオロフェニル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、下記式(1−3)で表される化合物、
一般式(1)において、Ar1が2,3,6−トリフルオロフェニル基であり、Ar2がフェニル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、下記式(1−4)で表される化合物、
一般式(1)において、Ar1が2,3,6−トリフルオロフェニル基であり、Ar2が6−(トリフルオロメチル)ピリジン−3−イル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、下記式(1−5)で表される化合物、
1H−NMR(400MHz,CDCl3)δ:2.27(3H,s),2.53(1H,d,J=4.2Hz),6.22(1H,d,J=4.2Hz),6.95−7.06(2H,m),7.08−7.14(1H,m),7.29(1H,s),8.36(1H,s).
MSm/z:314,316(M++H).
得られた残渣のN,N−ジメチルホルムアミド(45ml)溶液に窒素雰囲気下、0℃にて4−クロロベンゼンチオール(575mg,3.98mmol)のN,N−ジメチルホルムアミド(5ml)溶液、次いで炭酸カリウム(550mg,3.98mmol)を加え、室温にて30分間攪拌した。反応混合物に0℃にて酢酸エチル及び水を加え、分液操作後、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥、ろ過後、ろ液を減圧濃縮し、得られた残渣をフラッシュシリカゲルクロマトグラフィーに付した。ヘキサン:酢酸エチル=20:1溶出部より得た分画を減圧濃縮し、標記化合物(1.48g,3.36mmol,84%)を白色固体として得た。
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),5.77(1H,s),6.92−7.03(2H,m),7.19−7.25(4H,m),7.28−7.34(1H,m),7.29(1H,s),8.39(1H,s).
MS m/z:440,442(M++H).
1H−NMR(400MHz,CDCl3)δ:2.43(3H,s),5.88(1H,s),6.94−7.05(2H,m),7.20−7.27(4H,m),7.36−7.42(1H,m),7.75(1H,s),8.79(1H,s),10.02(1H,s).
MS m/z:390(M++H).
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),5.98(1H,s),6.93−7.01(1H,m),7.03−7.10(1H,m),7.44−7.48(2H,m),7.61−7.65(2H,m),7.72−7.78(1H,m),8.03(1H,s),9.22(1H,s).
IR(ATR)cm−1:1739,1712,1495,1417,1311,1155,1092,727.
mp:208−209℃.
Anal.Calcd for C20H14ClF2NO4S:C,54.86;H,3.22;Cl,8.10;F,8.68;N,3.20;S,7.32.Found:C,54.55;H,3.15;Cl,8.02;F,8.60;N,3.25;S,7.44.
MS m/z:438(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),3.04(3H,d,J=5.1Hz),5.96(1H,s),6.92−7.08(2H,m),7.43(2H,d,J=8.6Hz),7.61(2H,d,J=8.6Hz),7.74−7.81(1H,m),7.97(1H,s),8.00(1H,br d,J=5.1Hz),9.13(1H,s).
IR(ATR)cm−1:1674,1533,1495,1329,1151.
mp:200−201℃.
Anal.Calcd for C21H17ClF2N2O3S:C,55.94;H,3.80;Cl,7.86;F,8.43;N,6.21;S,7.11.Found:C,55.70;H,3.72;Cl,7.91;F,8.51;N,6.17;S,7.26.
MS m/z:451(M++H).
1H−NMR(400MHz,CDCl3)δ:2.24(3H,s),3.14(6H,s),5.96(1H,s),6.91−6.98(1H,m),7.00−7.07(1H,m),7.44(2H,d,J=8.6Hz),7.47(1H,s),7.65(2H,d,J=8.6Hz),7.72−7.78(1H,m),9.16(1H,s).
IR(ATR)cm−1:1633,1493,1327,1151,1084.
mp:207−208℃.
Anal.Calcd for C22H19ClF2N2O3S:C,56.84;H,4.12;Cl,7.63;F,8.17;N,6.03;S,6.90.Found:C,56.53;H,4.08;Cl,7.53;F,8.25;N,5.93;S,7.00.
MS m/z:465(M++H).
1H−NMR(400MHz,CDCl3)δ:2.46(3H,s),5.88(1H,s),6.95−7.05(2H,m),7.24(4H,s),7.36−7.42(1H,m),8.02(1H,s),8.61(1H,s).
MS m/z:406(M++H).
1H−NMR(400MHz,CDCl3)δ:2.42(3H,s),5.55(1H,br s),5.88(1H,s),6.93−7.04(2H,m),7.22(4H,s),7.35−7.41(1H,m),7.77(1H,br s),8.00(1H,s),8.58(1H,s).
MS m/z:405(M++H).
1H−NMR(400MHz,CDCl3)δ:1.95(2.1H,s),2.15(0.9H,s),5.35(0.3H,s),5.37(0.7H,s),5.51−5.62(1H,m),6.88−7.08(2H,m),7.23−7.55(5H,m),7.80−7.90(1H,m),7.94(0.7H,s),7.99(0.3H,s),8.87(0.7H,m),9.05(0.3H,s).
IR(ATR)cm−1:3126,1695,1595,1493,1421,1053,823.
Anal.Calcd for C20H15ClF2N2O2S:C,57.08;H,3.59;Cl,8.42;F,9.03;N,6.66;S,7.62.Found:C,56.75;H,3.59;Cl,8.35;F,9.06;N,6.65;S,7.71.
MS m/z:421(M++H).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),5.57(1H,br s),5.97(1H,s),6.92−7.00(1H,m),7.01−7.09(1H,m),7.44(2H,d,J=8.5Hz),7.62(2H,d,J=8.5Hz),7.75−7.81(1H,m),7.82(1H,br s),7.99(1H,s),9.16(1H,s).
IR(ATR)cm−1:3442,3288,1701,1493,1315,1153,1088.
mp:241−242℃.
MS m/z:437(M++H).
1H−NMR(400MHz,CDCl3)δ:2.36(3H,s),6.42(1H,s),7.01−7.07(2H,m),7.26−7.32(1H,m),7.33(1H,s),8.31(1H,s).
MS m/z:332,334(M++H).
1H−NMR(400MHz,CDCl3)δ:2.28(3H,s),5.72(1H,s),6.91−6.98(4H,m),7.27−7.34(3H,m),7.28(1H,s),8.43(1H,s).
MS m/z:424,426(M++H).
1H−NMR(400MHz,CDCl3)δ:2.39(3H,s),5.83(1H,s),6.92−7.00(4H,m),7.30−7.36(2H,m),7.37−7.43(1H,m),7.73(1H,s),8.83(1H,s),10.03(1H,s).
MS m/z:374(M++H).
1H−NMR(400MHz,CDCl3)δ:2.30(3H,s),5.97(1H,s),6.91−6.99(1H,m),7.03−7.10(1H,m),7.16(2H,t,J=8.4Hz),7.68−7.78(3H,m),8.02(1H,s),9.23(1H,s).
IR(ATR)cm−1:3361,1763,1593,1493,1402,1288,1236,1149.
Anal.Calcd for C20H14F3NO4S:C,57.01;H,3.35;F,13.53;N,3.32;S,7.61.Found:C,56.87;H,3.23;F,13.54;N,3.39;S,7.86.
MS m/z:422(M++H).
1H−NMR(400MHz,CDCl3)δ:2.20(3H,s),3.04(3H,d,J=5.1Hz),5.95(1H,s),6.92−6.99(1H,m),7.01−7.08(1H,m),7.10−7.17(2H,m),7.66−7.72(2H,m),7.75−7.80(1H,m),7.96(1H,s),8.01(1H,br d,J=5.1Hz),9.14(1H,s).
IR(ATR)cm−1:1672,1591,1533,1493,1327,1294,1236,1146,1082.
mp:201−202℃.
Anal.Calcd for C21H17F3N2O3S: C,58.06;H,3.94;F,13.12;N,6.45;S,7.38.Found:C,58.05;H,3.83;F,13.05;N,6.47;S,7.51.
MS m/z:435(M++H).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),3.14(6H,s),5.95(1H,s),6.90−6.97(1H,m),7.00−7.07(1H,m),7.11−7.18(2H,m),7.47(1H,s),7.70−7.78(3H,m),9.18(1H,s).
IR(ATR)cm−1:1633,1589,1493,1404,1327,1294,1236,1147,1084.
mp:176−177℃.
Anal.Calcd for C22H19F3N2O3S: C,58.92;H,4.27;F,12.71;N,6.25;S,7.15.Found:C,58.74;H,4.18;F,12.68;N,6.32;S,7.26.
MS m/z:449(M++H).
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),5.58(1H,br s),5.96(1H,s),6.91−6.99(1H,m),7.01−7.08(1H,m),7.11−7.18(2H,m),7.67−7.73(2H,m),7.76−7.82(1H,m),7.83(1H,br s),7.98(1H,s),9.17(1H,s).
IR(ATR)cm−1:3429,3168,1691,1589,1491,1421,1313,1234,1146,1080.
Anal. Calcd for C20H15F3N2O3S:C,57.14;H,3.60;F,13.56;N,6.66;S,7.63.Found:C,56.96;H,3.55;F,13.76;N,6.67;S,7.82.
MS m/z:421(M++H).
1H−NMR(400MHz,CDCl3)δ:1.27(3H,t,J=7.4Hz),2.19(3H,s),3.51(2H,dq,J=7.4,6.1Hz),5.95(1H,s),6.92−6.99(1H,m),7.01−7.08(1H,m),7.11−7.17(2H,m),7.66−7.73(2H,m),7.75−7.81(1H,m),7.96(1H,s),8.00(1H,br t,J=6.1Hz),9.14(1H,s).
IR(ATR)cm−1:1672,1591,1520,1493,1292,1240,1149.
mp:191−193℃.
Anal.Calcd for C22H19F3N2O3S:C,58.92;H,4.27;F,12.71;N,6.25;S,7.15.Found:C,58.64;H,4.31;F,12.84;N,6.22;S,7.20.
MS m/z:449(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),2.58(1H,br s),3.63−3.68(2H,m),3.85(2H,t,J=4.9Hz),5.95(1H,s),6.92−6.99(1H,m),7.01−7.08(1H,m),7.11−7.18(2H,m),7.67−7.73(2H,m),7.75−7.80(1H,m),7.96(1H,s),8.40(1H,br t,J=6.1 Hz),9.16(1H,s).
IR(ATR)cm−1:3554,3410,1676,1589,1520,1493,1279,1236,1144.
mp:153−154℃.
Anal.Calcd for C22H19F3N2O4S:C,56.89;H,4.12;F,12.27;N,6.03;S,6.90.Found:C,56.85;H,4.05;F,12.56;N,6.03;S,6.97.
MS m/z:465(M++H).
1H−NMR(400MHz,CDCl3)δ:1.19−1.30(3H,m),2.23(3H,s),3.10(3H,s),3.47(1.2H,q,J=7.4Hz),3.60(0.8H,q,J=7.4Hz),5.95(1H,s),6.89−6.97(1H,m),6.99−7.07(1H,m),7.14(2H,t,J=8.3Hz),7.44(0.6H,s),7.46(0.4H,s),7.69−7.79(3H,m),9.17(0.6H,s),9.18(0.4H,s).
IR (ATR)cm−1:1626,1591,1493,1286,1240,1147,1084.
mp:165−167℃.
Anal.Calcd for C23H21F3N2O3S:C,59.73;H,4.58;F,12.32;N,6.06;S,6.93.Found:C,59.31;H,4.31;F,12.59;N,6.00;S,7.05.
MS m/z:463(M++H).
1H−NMR(400MHz,CDCl3)δ:2.24(0.3H,s),2.29(2.7H,s),3.17(2.7H,s),3.21(0.3H,s),3.47−4.01(4H,m),5.95(1H,s),6.89−6.96(1H,m),7.01−7.08(1H,m),7.15(2H,t,J=8.5Hz),7.52(0.1H,s),7.68(0.9H,s),7.70−7.78(3H,m),9.08(0.9H,s),9.19(0.1H,s).
IR(ATR)cm−1:3228,1626,1591,1495,1236,1149,833.
mp:123−125℃.
Anal.Calcd for C23H21F3N2O4S・0.25H2O:C,57.20;H,4.49;F,11.80;N,5.80;S,6.64.Found:C,57.13;H,4.34;F,11.92;N,5.86;S,6.84.
MS m/z:479(M++H).
1H−NMR(400MHz,CDCl3)δ:2.41(3H,s),5.83(1H,s),6.89−7.03(4H,m),7.27−7.44(3H,m),8.00(1H,s),8.67(1H,s).
MS m/z:390(M++H).
1H−NMR(400MHz,CDCl3)δ:1.94(1.95H,s),2.13(1.05H,s),3.04(1.95H,d,J=5.1Hz),3.05(1.05H,d,J=5.1Hz),5.32(0.35H,s),5.35(0.65H,s),6.87−7.13(4H,m),7.27−7.35(2.35H,m),7.48−7.54(0.65H,m),7.92(0.65H,s),7.97(0.35H,s),8.00(0.35H,br d,J=5.1Hz),8.03(0.65H,br d,J=5.1Hz),8.84(0.65H,s),9.01(0.35H,s).
IR(ATR)cm−1:3359,1664,1591,1529,1491,1228,1086,1051.
Anal.Calcd for C21H17F3N2O2S:C,60.28;H,4.10;F,13.62;N,6.69;S,7.66.Found:C,59.86;H,4.04;F,13.65;N,6.65;S,7.67.
MS m/z:419(M++H).
1H−NMR(400MHz,CDCl3)δ:2.03(2H,s),2.11(1H,s),3.14(4H,s),3.15(2H,s),5.31(0.33H,s),5.37(0.67H,s),6.87−7.13(4H,m),7.30−7.40(3H,m),7.43(0.67H,s),7.46(0.33H,s),8.96(0.67H,s),9.03(0.33H,s).
IR(ATR)cm−1:1631,1587,1493,1408,1217,1049.
Anal.Calcd for C22H19F3N2O2S:C,61.10;H,4.43;F,13.18;N,6.48;S,7.41.Found:C,60.83;H,4.36;F,13.43;N,6.44;S,7.42.
MS m/z:433(M++H).
1H−NMR(400MHz,CDCl3)δ:2.38(3H,s),5.56(1H,br s),5.83(1H,s),6.91−7.01(4H,m),7.28−7.34(2H,m),7.36−7.41(1H,m),7.77(1H,br s),7.99(1H,s),8.61(1H,s).
MS m/z:389(M++H).
1H−NMR(400MHz,CDCl3)δ:1.95(1.9H,s),2.14(1.1H,s),5.33(0.37H,s),5.36(0.63H,s),5.51−5.64(1H,m),6.87−7.14(4H,m),7.27−7.37(2.37H,m),7.49−7.56(0.63H,m),7.80−7.90(1H,m),7.94(0.63H,s),7.98(0.37H,s),8.87(0.63H,s),9.05(0.37H,s).
IR(ATR)cm−1:3458,3377,3155,1697,1491,1421,1348,1227,1082,1043.
Anal.Calcd for C20H15F3N2O2S:C,59.40;H,3.74;F,14.09;N,6.93;S,7.93.Found:C,59.29;H,3.76;F,13.88;N,6.88;S,7.93.
MS m/z:405(M++H).
参考例1で得られた(6−ブロモ−4−メチルピリジン−3−イル)(2,5−ジフルオロフェニル)メタノール(3.14g,10.0mmol)の塩化メチレン(50ml) 溶液に、0℃にて塩化チオニル(7.29ml,100mmol)及びN,N−ジメチルホルムアミド(0.50ml)を加え室温にて2時間攪拌した。反応混合物を減圧濃縮した後、残渣に酢酸エチルを加え、0℃にて水、次いで飽和重曹水を滴下した。分液操作後、有機層を無水硫酸ナトリウムにて乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣のN,N−ジメチルホルムアミド(45ml)溶液に窒素雰囲気下、0℃にて6−(トリフルオロメチル)ピリジン−3−チオールのN,N−ジメチルホルムアミド(5ml)溶液、次いで炭酸カリウム(1.52g,11.0mmol)を加え、室温にて16時間攪拌した。反応混合物に0℃にて酢酸エチル及び水を加え、分液操作後、有機層を飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムにて乾燥、ろ過後、ろ液を減圧濃縮し、得られた残渣をフラッシュシリカゲルクロマトグラフィーに付した。ヘキサン:酢酸エチル=19:1溶出部より得た分画を減圧濃縮し、得られた残渣をジエチルエーテル及びヘキサンの混合溶媒にて洗浄後、ろ取し、標記化合物(3.43g,7.22mmol,72%)を淡黄色固体として得た。
1H−NMR(400MHz,CDCl3)δ:2.36(3H,s),5.93(1H,s),6.97−7.09(2H,m),7.25−7.32(1H,m),7.35(1H,s),7.55(1H,d,J=8.3Hz),7.67(1H,dd,J=8.3,2.2Hz),8.39(1H,s),8.53(1H,d,J=2.2Hz).
MS m/z:475,477(M++H).
1H−NMR(400MHz,CDCl3)δ:2.52(3H,s),6.04(1H,s),7.01−7.11(2H,m),7.33−7.39(1H,m),7.57(1H,d,J=8.3Hz),7.70(1H,dd,J=8.3,2.2Hz),8.08(1H,s),8.55(1H,d,J=2.2Hz),8.62(1H,s).
MS m/z:441(M++H).
1H−NMR(400MHz,CDCl3)δ:2.43(3H,s),3.08(3H,s),3.12(3H,s),6.02(1H,s),6.97−7.08(2H,m),7.31−7.37(1H,m),7.49(1H,s),7.55(1H,d,J=8.1Hz),7.68(1H,dd,J=8.1,2.0Hz),8.54(1H,d,J=2.0Hz),8.57(1H,s).
MS m/z:468(M++H).
化合物A
1H−NMR(400MHz,CDCl3)δ:2.30(3H,s),3.15(6H,s),6.01(1H,s),6.91−6.99(1H,m),7.05−7.12(1H,m),7.52(1H,s),7.65−7.71(1H,m),7.80(1H,d,J=8.1Hz),8.20(1H,dd,J=8.1,2.2Hz),8.99(1H,d,J=2.2Hz),9.22(1H,s).
IR(ATR)cm−1:1630,1493,1333,1155,1105,1076,723,625.
Anal.Calcd for C22H18F5N3O3S:C,52.90;H,3.63;F,19.02;N,8.41;S,6.42.Found:C,52.69;H,3.58;F,19.14;N,8.42;S,6.51.
MS m/z:500(M++H).
化合物B
1H−NMR(400MHz,CDCl3)δ:2.10(2.1H,s),2.17(0.9H,s),3.14(2.1H,s),3.15(2.1H,s),3.16(0.9H,s),3.16(0.9H,s),5.38(0.3H,s),5.51(0.7H,s),6.84−7.11(2H,m),7.19−7.32(1H,m),7.47(0.7H,s),7.52(0.3H,s),7.72(0.3H,dd,J=8.1.0.7Hz),7.77(0.7H,dd,J=8.1.0.7Hz),7.84(0.3H,dd,J=8.1,2.0Hz),8.04(0.7H,dd,J=8.1,2.0Hz),8.50(0.7H,d,J=2.0Hz),8.65(0.3H,d,J=2.0Hz),9.02(0.7H,s),9.15(0.3H,s).
IR(ATR)cm−1:1631,1493,1331,1169,1132,1068.
Anal.Calcd for C22H18F5N3O2S:C,54.66;H,3.75;F,19.65;N,8.69;S,6.63.Found:C,54.38;H,3.66;F,19.94;N,8.70;S,6.68.
MS m/z:484(M++H).
1H−NMR(400MHz,CDCl3)δ:2.46(3H,s),2.52(1H,br s),3.61−3.67(2H,m),3.84(2H,t,J=4.9Hz),6.03(1H,s),6.98−7.09(2H,m),7.29−7.35(1H,m),7.55(1H,d,J=8.3Hz),7.67(1H,dd,J=8.3,2.2Hz),8.04(1H,s),8.33(1H,br t,J=6.1Hz),8.54(1H,d,J=2.2Hz),8.59(1H,s).
MS m/z:484(M++H).
1H−NMR(400MHz,CDCl3)δ:2.30(3H,s),2.49(1H,br s),3.64−3.70(2H,m),3.86(2H,t,J=4.7Hz),6.02(1H,s),6.92−7.00(1H,m),7.05−7.13(1H,m),7.64−7.71(1H,m),7.80(1H,d,J=8.3Hz),8.04(1H,s),8.18(1H,dd,J=8.3,2.0Hz),8.41(1H,br t,J=5.6Hz),8.97(1H,d,J=2.0Hz),9.22(1H,s).
IR(ATR)cm−1:3373,1662,1533,1493,1327,1238,1184,1155,1138,1074,723.
Anal.Calcd for C22H18F5N3O4S:C,51.26;H,3.52;F,18.43;N,8.15;S,6.22.Found:C,51.02;H,3.46;F,18.86;N,8.14;S,6.29.
MS m/z:516(M++H).
1H−NMR(400MHz,CDCl3)δ:2.47(3H,s),5.56(1H,br s),6.04(1H,s),6.98−7.09(2H,m),7.31−7.37(1H,m),7.56(1H,d,J=8.3Hz),7.67(1H,dd,J=8.3,2.2Hz),7.75(1H,br s),8.06(1H,s),8.54(1H,d,J=2.2Hz),8.59(1H,s).
MS m/z:440(M++H).
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),5.59(1H,br s),6.03(1H,s),6.92−7.00(1H,m),7.06−7.13(1H,m),7.66−7.72(1H,m),7.80(1H,d,J=8.3Hz),7.82(1H,br s),8.05(1H,s),8.19(1H,dd,J=8.3,2.0Hz),8.98(1H,d,J=2.0Hz),9.24(1H,s).
IR(ATR)cm−1:3410,1685,1495,1331,1157,1136,1103,1076.
Anal.Calcd for C20H14F5N3O3S:C,50.96;H,2.99;F,20.15;N,8.91;S,6.80.Found:C,51.06;H,2.94;F,20.25;N,8.94;S,6.96.
MS m/z:472(M++H).
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),2.83(1H,br s),6.29(1H,s),6.84−6.92(1H,m),7.11−7.21(1H,m),7.28(1H,s),8.53(1H,s).
MS m/z:332,334(M++H).
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),6.45(1H,s),6.86−6.93(1H,m),7.14−7.23(1H,m),7.29(1H,s),8.80(1H,s).
MS m/z:350,352(M++H).
1H−NMR(400MHz,CDCl3)δ:2.16(3H,s),5.67(1H,s),6.75−6.82(1H,m),6.91−6.99(2H,m),7.01−7.11(1H,m),7.24(1H,s),7.33−7.39(2H,m),8.88(1H,s).
MS m/z:442,444(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),3.47(1H,br s),5.74(1H,s),6.73−6.81(1H,m),6.90−6.98(2H,m),7.00−7.10(1H,m),7.29−7.35(2H,m),7.93(1H,s),9.12(1H,s).
MS m/z:408(M++H).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),3.12(3H,s),3.13(3H,s),5.77(1H,s),6.75−6.83(1H,m),6.91−6.99(2H,m),7.02−7.11(1H,m),7.33−7.39(2H,m),7.42(1H,s),9.07(1H,s).
MS m/z:435(M++H).
化合物A
1H−NMR(400MHz,CDCl3)δ:2.13(3H,s),3.13(3H,s),3.15(3H,s),5.90(1H,s),6.82−6.90(1H,m),7.13−7.24(3H,m),7.47(1H,s),7.75−7.82(2H,m),9.40(1H,s).
IR(ATR)cm−1:1631,1587,1491,1406,1329,1234,1146.
Anal.Calcd for C22H18F4N2O3S:C,56.65;H,3.89;F,16.29;N,6.01;S,6.87.Found:C,56.63;H,3.91;F,16.54;N,6.01;S,7.04.
MS m/z:467(M++H).
化合物B
1H−NMR(400MHz,CDCl3)δ:1.88(0.9H,s),2.36(2.1H,s),3.10(0.9H,s),3.13(0.9H,s),3.14(2.1H,s),3.15(2.1H,s),5.41(0.3H,s),5.44(0.7H,s),6.72−6.80(0.7H,m),6.91−6.98(0.3H,m),7.02−7.23(3H,m),7.36(0.3H,s),7.42−7.47(0.6H,m),7.51(0.7H,s),7.55−7.61(1.4H,m),9.00(0.3H,s),9.12(0.7H,s).
IR(ATR)cm−1:1637,1589,1491,1223,1086,1066.
Anal.Calcd for C22H18F4N2O2S:C,58.66;H,4.03;F,16.87;N,6.22;S,7.12.Found:C,58.51;H,3.98;F,16.84;N,6.15;S,7.22.
MS m/z:451(M++H).
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),5.55(1H,br s),5.78(1H,s),6.75−6.83(1H,m),6.92−6.99(2H,m),7.02−7.12(1H,m),7.32−7.38(2H,m),7.84(1H,br s),7.96(1H,s),9.08(1H,s).
MS m/z:407(M++H).
1H−NMR(400MHz,CDCl3)δ:2.36(3H,s),5.46(1H,s),5.60(1H,br s),6.74−6.82(1H,m),7.04−7.16(3H,m),7.52−7.59(2H,m),7.85(1H,br s),8.05(1H,s),9.12(1H,s).
IR(ATR)cm−1:3446,3209,1689,1587,1495,1412,1342,1230,1043.
Anal.Calcd for C20H14F4N2O2S:C,56.87;H,3.34;F,17.99;N,6.63;S,7.59.Found:C,56.66;H,3.38;F,18.12;N,6.63;S,7.65.
MS m/z:423(M++H).
1H−NMR(400MHz,CDCl3)δ:2.14(3H,s),5.59(1H,br s),5.90(1H,s),6.82−6.90(1H,m),7.14−7.25(3H,m),7.73−7.79(2H,m),7.87(1H,br s),7.98(1H,s),9.43(1H,s).
IR(ATR)cm−1:3396,3167,1687,1587,1496,1419,1296,1234,1144,1078,845,816.
Anal.Calcd for C20H14F4N2O3S:C,54.79;H,3.22;F,17.33;N,6.39;S,7.31.Found:C,54.54;H,3.26;F,17.17;N,6.37;S,7.39.
MS m/z:439(M++H).
1H−NMR(400MHz,CDCl3)δ:2.26(3H,s),3.77(3H,s),5.66(1H,s),6.77(2H,d,J=8.5Hz),6.89−6.98(2H,m),7.25(1H,s),7.29(2H,d,J=8.5Hz),7.31−7.38(1H,m),8.43(1H,s).
MS m/z:436,438(M++H).
1H−NMR(400MHz,CDCl3)δ:2.36(3H,s),3.76(3H,s),5.77(1H,s),6.77(2H,d,J=8.8Hz),6.93−6.98(2H,m),7.29(2H,d,J=8.8Hz),7.42−7.47(1H,m),7.71(1H,s),8.82(1H,s),10.02(1H,s).
MS m/z:386(M++H).
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),3.87(3H,s),5.95(1H,s),6.91(2H,d,J=8.8Hz),6.93−6.99(1H,m),7.01−7.08(1H,m),7.59(2H,d,J=8.8Hz),7.80−7.86(1H,m),7.98(1H,s),9.18(1H,s).
mp:194−195℃.
MS m/z:434(M++H).
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),2.56(1H,br s),3.62−3.68(2H,m),3.82−3.88(2H,m),3.86(3H,s),5.93(1H,s),6.90(2H,d,J=8.8Hz),6.92−7.07(2H,m),7.57(2H,d,J=8.8Hz),7.82−7.88(1H,m),7.93(1H,s),8.40(1H,br t,J=5.6Hz),9.11(1H,s).
IR(ATR)cm−1:3456,3367,1653,1591,1535,1493,1294,1265,1147.
mp:134−135℃.
Anal.Calcd for C23H22F2N2O5S:C,57.97;H,4.65;F,7.97;N,5.88;S,6.73.Found:C,57.93;H,4.39;F,8.18;N,5.91;S,6.79.
MS m/z:477(M++H).
1H−NMR(400MHz,CDCl3)δ:1.33−1.37(3H,m),3.93(3H,s),4.60−4.63(2H,m),6.98−7.00(1H,m),7.23−7.25(2H,m).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),3.85(3H,s),5.69(1H,s),6.79−7.12(5H,m),7.28(1H,s),7.28−7.33(1H,m),8.42(1H,m).
1H−NMR(400MHz,CDCl3)δ:2.40(3H,s),3.85(3H,s),5.80(1H,s),6.79−6.85(1H,m),6.94−7.01(2H,m),7.06−7.13(2H,m),7.36−7.42(1H,m),7.73(1H,s),8.82(1H,m),10.03(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),3.96(3H,s),5.97(1H,s),6.91−7.10(3H,m),7.37−7.45(2H,m),7.72−7.78(1H,m),8.02(1H,s),9.21(1H,s).
mp:196−197℃.
MS m/z:452(M++H).
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),2.55(1H,br s),3.62−3.68(2H,m),3.85(2H,t,J=4.9Hz),3.95(3H,s),5.95(1H,s),6.92−7.08(3H,m),7.37−7.45(2H,m),7.74−7.80(1H,m),7.96(1H,s),8.40(1H,br t,J=5.4Hz),9.14(1H,s).
IR(ATR)cm−1:3460,3371,1651,1599,1535,1493,1281,1219,1134.
mp:137−138℃.
Anal.Calcd for C23H21F3N2O5S:C,55.87;H,4.28;F,11.53;N,5.67;S,6.48.Found:C,55.73;H,4.00;F,11.77;N,5.66;S,6.58.
MS m/z:495(M++H).
1H−NMR(400MHz,CDCl3)δ:1.24−1.43(6H,m),4.03−4.07(2H,m),4.60(2H,q,J=7.1Hz),6.92−6.93(2H,m),7.38−7.40(2H,m).
1H−NMR(400MHz,CDCl3)δ:1.39(3H,t,J=7.1Hz),2.25(3H,s),3.98(2H,q,J=7.1Hz),5.65(1H,s),6.75(2H,d,J=8.8Hz),6.89−6.98(2H,m),7.25(1H,m),7.27(2H,d,J=8.8Hz),7.31−7.37(1H,m),8.43(1H,m).
1H−NMR(400MHz,CDCl3)δ:1.38(3H,t,J=7.1Hz),2.36(3H,s),3.98(2H,q,J=7.1Hz),5.76(1H,s),6.75(2H,d,J=8.6Hz),6.92−6.99(2H,m),7.27(2H,d,J=8.6Hz),7.41−7.48(1H,m),7.71(1H,s),8.82(1H,s),10.02(1H,s).
1H−NMR(400MHz,CDCl3)δ:1.44(3H,t,J=7.1Hz),2.24(3H,s),4.08(2H,q,J=7.1Hz),5.95(1H,s),6.89(2H,d,J=8.8Hz),6.92−6.99(1H,m),7.01−7.08(1H,m),7.57(2H,d,J=8.8Hz),7.80−7.86(1H,m),7.98(1H,s),9.17(1H,s).
MS m/z:448(M++H).
1H−NMR(400MHz,CDCl3)δ:1.44(3H,t,J=7.1Hz),2.15(3H,s),2.57(1H,br t,J=5.1Hz),3.62−3.68(2H,m),3.82−3.88(2H,m),4.07(2H,q,J=7.1Hz),5.93(1H,s),6.87(2H,d,J=8.8Hz),6.92−7.06(2H,m),7.56(2H,d,J=8.8Hz),7.82−7.89(1H,m),7.92(1H,s),8.40(1H,br t,J=5.6Hz),9.11(1H,s).
IR(ATR)cm−1:3381,1668,1593,1527,1493,1321,1269,1140.
Anal.Calcd for C24H24F2N2O5S:C,58.77;H,4.93;F,7.75;N,5.71;S,6.54.Found:C,58.41;H,4.90;F,7.91;N,5.73;S,6.66.
MS m/z:491(M++H).
1H−NMR(400MHz,CDCl3)δ:7.45(1H,dd,J=9.0,2.2Hz),7.59(1H,d,J=9.0Hz),7.81(1H,m).
MS m/z:180(M++H).
1H−NMR(400MHz,CDCl3)δ:2.43(3H,s),6.72(1H,s),6.93−7.07(2H,m),7.19−7.25(1H,m),7.28(1H,d,J=8.3Hz),7.32(1H,s),7.70(1H,dd,J=8.3,2.2Hz),8.35(1H,m),8.58−8.60(1H,m).
MS m/z:475,477(M++H).
1H−NMR(400MHz,CDCl3)δ:2.56(3H,s),6.85(1H,s),6.95−7.09(2H,m),7.23−7.29(1H,m),7.31(1H,d,J=8.5Hz),7.71(1H,dd,J=8.5,2.0Hz),7.79(1H,m),8.58−8.60(1H,m),8.79(1H,s),10.02(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.63(3H,s),6.95(1H,s),6.97−7.07(2H,m),7.67−7.73(1H,m),8.09(1H,s),8.15−8.17(2H,m),8.96(1H,s),9.07(1H,s).
MS m/z:473(M++H).
1H−NMR(400MHz,CDCl3)δ:2.46(1H,br s),2.55(3H,s),3.61−3.66(2H,m),3.83(2H,br t,J=5.1Hz),6.90(1H,s),6.97−7.07(2H,m),7.66−7.72(1H,m),8.02(1H,s),8.12−8.15(2H,m),8.34(1H,br t,J=5.6Hz),8.96(1H,s),9.03(1H,s).
IR(ATR)cm−1:3377,1664,1529,1495,1325,1165,1138,1099,1072.
Anal.Calcd for C22H18F5N3O4S:C,51.26;H,3.52;F,18.43;N,8.15;S,6.22.Found:C,51.39;H,3.61;F,18.36;N,8.04;S,6.31.
MS m/z:516(M++H).
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),5.81(1H,s),6.93−7.00(2H,m),7.22−7.39(7H,m),8.37(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.42(3H,s),5.91(1H,s),6.95−7.01(2H,m),7.23−7.32(5H,m),7.44−7.47(1H,m),7.74(1H,s),8.78(1H,s),10.02(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),5.99(1H,s),6.91−7.08(2H,m),7.46−7.52(2H,m),7.64−7.70(3H,m),7.80−7.84(1H,m),7.98(1H,s),9.20(1H,s).
MS m/z:404(M++H).
1H−NMR(400MHz,CDCl3)δ:2.14(3H,s),2.52−2.56(1H,m),3.62−3.68(2H,m),3.82−3.87(2H,m),5.97(1H,s),6.90−7.07(2H,m),7.43−7.49(2H,m),7.62−7.69(3H,m),7.81−7.87(1H,m),7.93(1H,s),8.39(1H,br s),9.13(1H,s).
IR (ATR)cm−1:3413,2940,1662,1650,1529,1496,1307,1143.
MS m/z:447(M++H).
FAB−MS:447.1194(Calcd for C22H21F2N2O4S:447.1190).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),2.30(3H,s),5.75(1H,s),6.90−6.99(2H,m),7.05(2H,d,J=8.1Hz),7.21(2H,d,J=7.8Hz),7.26(1H,s),7.33−7.39(1H,m),8.38(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),2.41(3H,s),5.85(1H,s),6.96−6.98(2H,m),7.05(2H,d,J=8.1Hz),7.22(2H,d,J=8.1Hz),7.45−7.47(1H,m),7.72(1H,s),8.78(1H,s),10.02(1H,s).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),2.43(3H,s),5.97(1H,s),6.92−7.08(2H,m),7.26(2H,d,J=8.3Hz),7.56(2H,d,J=8.3Hz),7.81−7.86(1H,m),7.98(1H,s),9.17(1H,s).
MS m/z:418(M++H).
1H−NMR(400MHz,CDCl3)δ:2.14(3H,s),2.42(3H,s),2.58(1H,t,J=5.2Hz),3.62−3.67(2H,m),3.85(2H,q,J=5.2Hz),5.95(1H,s),6.92−7.07(2H,m),7.24(2H,d,J=8.3Hz),7.54(2H,d,J=8.3Hz),7.83−7.88(1H,m),7.92(1H,s),8.40(1H,br s),9.11(1H,s).
IR(ATR)cm−1:3388,1664,1594,1527,1492,1145.
MS m/z:461(M++H).
Anal.Calcd for C23H22F2N2O4S:C,59.99;H,4.82;F,8.25;N,6.08,S,6.96.Found:C,59.94;H,4.81;F,8.03;N,5.94;S,6.81.
1H−NMR(400MHz,CDCl3)δ:1.34(3H,t,J=7.1Hz),2.39(3H,s),4.61(2H,q,J=7.1Hz),7.25−7.40(3H,m).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),2.31(3H,s),5.78(1H,s),6.93−7.33(7H,m),8.39(1H,s).
MS m/z:454,456(M++H).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),2.43(3H,s),5.88(1H,s),6.99−7.05(3H,m),7.19−7.21(2H,m),7.38−7.41(1H,m),7.75(1H,s),8.79(1H,s),10.02(1H,s).
MS m/z:404(M++H).
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),2.38(3H,s),5.97(1H,s),6.93−7.09(2H,m),7.41−7.44(2H,m),7.56−7.57(1H,m),7.73−7.77(1H,m),8.03(1H,s),9.22(1H,s).
MS m/z:452(M++H).
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),2.38(3H,s),2.58−2.59(1H,m),3.65−3.66(2H,m),3.84−3.86(2H,m),5.95(1H,s),6.92−7.07(2H,m),7.37−7.43(2H,m),7.55(1H,s),7.74−7.80(1H,m),7.97(1H,s),8.40(1H,br s),9.14(1H,s).
IR(ATR)cm−1:3390,1664,1527,1492,1147,1049.
MS m/z:495(M++H).
Anal.Calcd for C23H21ClF2N2O4S・0.25H2O:C,55.31;H,4.34;Cl,7.10;F,7.61;N,5.61,S,6.42.Found:C,55.29;H,4.24;Cl,7.50;F,7.56;N,5.64;S,6.51.
1H−NMR(400MHz,CDCl3)δ:1.30−1.35(3H,m),2.29(3H,s),4.59−4.63(2H,m),7.05(1H,t,J=8.9Hz),7.26−7.37(2H,m).
1H−NMR(400MHz,CDCl3)δ:2.19(3H,s),2.28(3H,s),5.71(1H,s),6.85−7.33(7H,m),8.43(1H,s).
MS m/z:438,440(M++H).
1H−NMR(400MHz,CDCl3)δ:2.18(3H,s),2.39(3H,s),5.82(1H,s),6.85−6.99(3H,m),7.09−7.19(2H,m),7.37−7.41(1H,m),7.73(1H,s),8.82(1H,s),10.02(1H,s).
MS m/z:388(M++H).
1H−NMR(400MHz,CDCl3)δ:2.28(3H,s),2.30(3H,s),5.96(1H,s),6.93−7.10(3H,m),7.48−7.58(2H,m),7.73−7.77(1H,m),8.02(1H,s),9.23(1H,s).
MS m/z:436(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),2.27(3H,s),2.57(1H,t,J=5.2Hz),3.63−3.67(2H,m),3.85(2H,q,J=5.2Hz),5.94(1H,s),6.92−7.08(3H,m),7.44−7.49(1H,m),7.54−7.57(1H,m),7.74−7.78(1H,m),7.96(1H,s),8.40(1H,br s),9.15(1H,s).
IR(ATR)cm−1:3388,1664,1527,1490,1240,1141.
MS m/z:479(M++H).
Anal.Calcd for C23H21F3N2O4S:C,57.73;H,4.42;F,11.91;N,5.85,S,6.70.Found:C,57.57;H,4.63;F,11.66;N,5.60;S,6.59.
1H−NMR(400MHz,CDCl3)δ:1.90−2.00(2H,m),2.13(3H,s),2.20(3H,s),2.60(2H,t,J=7.2Hz),3.55−3.65(2H,m),5.95(1H,s),6.90−7.20(4H,m),7.66−7.75(2H,m),7.75−7.84(1H,m),7.96(1H,s),8.13−8.20(1H,m),9.14(1H,s).
IR(ATR)cm−1:3421,1679,1589,1525,1494,1295,1278,1234,1143,850,825.
MS m/z:509(M++H).
1H−NMR(400MHz,CDCl3)δ:2.10−2.20(2H,m),2.23(3H,s),2.58−2.61(3H,m),2.76−2.83(2H,m),3.60−3.71(2H,m),5.96(1H,s),6.90−7.09(2H,m),7.11−7.19(2H,m),7.68−7.74(2H,m),7.75−7.82(1H,m),7.96(1H,s),8.21−8.29(1H,m),9.15(1H,s).
IR(ATR)cm−1:3394,1670,1590,1525,1492,1319,1288,1236,1149,1049.
mp:170−173℃
MS m/z:525(M++H).
Anal.calcd for C24H23F3N2O4S2:C,54.95;H,4.42;F,10.87;N,5.34;S,12.23.
Found:C,54.96;H,4.34;F,11.14;N,5.42;S,12.20.
1H−NMR(400MHz,CDCl3)δ:2.17−2.28(2H,m),2.23(3H,s),2.93(3H,s),3.09−3.17(2H,m),3.62−3.70(2H,m),5.96(1H,s),6.90−7.09(2H,m),7.10−7.20(2H,m),7.67−7.82(3H,m),7.95(1H,s),8.18−8.28(1H,m),9.15(1H,s).
IR(ATR)cm−1:3392,1668,1590,1525,1494,1317,1288,1236,1151,1141,1081.
mp:182−185℃
MS m/z:541(M++H).
Anal.calcd for C24H23 F3N2O5S2:C,53.32;H,4.29;F,10.54;N,5.18;S,11.86.
Found:C,53.38;H,4.24;F,10.54;N,5.19;S,12.01.
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),2.46−2.57(2H,m),3.87−4.03(4H,m),4.10−4.19(1H,m),5.96(1H,s),6.90−7.09(2H,m),7.11−7.19(2H,m),7.67−7.74(2H,m),7.75−7.82(1H,m),7.96(1H,s),8.63(1H,br d,J=7.6Hz),9.17(1H,s).
IR(ATR)cm−1:3421,3278,1639,1590,1536,1494,1319,1292,1234,1143,1076,1041.
mp:150−152℃
MS m/z:495(M++H).
Anal.calcd for C23H21F3N2O5S:C,55.87;H,4.28;F,11.53;N,5.67;S,6.48.
Found:C,55.74;H,4.13;F,11.74;N,5.68;S,6.63.
1H−NMR(400MHz,CDCl3)δ:1.60−1.72(2H,m),1.90−2.09(2H,m),2.25(3H,s),3.30−3.50(2H,m),3.82−4.08(2H,m),4.12−4.28(1H,m),5.95(1H,s),6.89−6.98(1H,m),7.00−7.08(1H,m),7.10−7.20(2H,m),7.46(1H,s),7.70−7.80(3H,m),9.17(1H,s).
IR(ATR)cm−1:3463,1606,1589,1492,1444,1326,1282,1238,1147,1081,1027.
mp:171−173℃
MS m/z:505(M++H).
Anal.calcd for C25H23F3N2O4S:C,59.52;H,4.59;F,11.30;N,5.55;S,6.36.
Found:C,59.43;H,4.68;F,11.41;N,5.55;S,6.53.
1H−NMR(400MHz,CDCl3)δ:2.26(3H,s),3.68−3.86(8H,m),5.95(1H,s),6.89−7.08(2H,m),7.10−7.20(2H,m),7.53(1H,s),7.70−7.80(3H,m),9.17(1H,s).
IR(ATR)cm−1:1629,1590,1492,1461,1324,1280,1226,1147,1114,1083.
mp:165−167℃
MS m/z:491(M++H).
Anal.calcd for C24H21F3N2O4S:C,58.77;H,4.32;F,11.62;N,5.71;S,6.54.
Found:C,58.81;H,4.25;F,11.94;N,5.78;S,6.71.
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),3.91(3H,s),5.94(1H,s),6.90−7.10(2H,m),7.11−7.20(2H,m),7.65−7.80(3H,m),7.95(1H,s),9.11(1H,s),10.21(1H,br s).
IR(ATR)cm−1:3343,1689,1587,1475,1295,1238,1207,1172,1141,1112,1079.
mp:231−234℃
MS m/z:451(M++H).
Anal.calcd for C21H17F3N2O4S:C,56.00;H,3.80;F,12.65;N,6.22;S,7.12.
Found:C,56.00;H,3.80;F,12.85;N,6.32;S,7.23.
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),3.42(3H,br s),3.81(3H,s),5.95(1H,s),6.90−7.09(2H,m),7.10−7.19(2H,m),7.48−7.59(1H,m),7.68−7.81(3H,m),9.20(1H,s).
IR(ATR)cm−1:1631,1590,1490,1425,1324,1286,1232,1147,1083,987,904.
mp:156−158℃
MS m/z:465(M++H).
Anal.calcd for C22H19F3N2O4S:C,56.89;H,4.12;F,12.27;N,6.03;S,6.90.
Found:C,56.96;H,4.11;F,12.53;N,6.08;S,7.02.
1H−NMR(400MHz,CDCl3)δ:1.29(3H,t,J=7.1Hz),2.20(3H,s),2.64(2H,t,J=6.1Hz),3.70−3.79(2H,m),4.20(2H,q,J=7.1Hz),5.95(1H,s),6.90−7.09(2H,m),7.14(2H,t,J=8.6Hz),7.65−7.73(2H,m),7.76−7.83(1H,m),7.95(1H,s),8.40−8.50(1H,m),9.14(1H,s).
IR(ATR)cm−1:3396,1727,1671,1589,1521,1492,1326,1292,1236,1186,1147,1081.
MS m/z:520(M+).
1H−NMR(400MHz,CDCl3)δ:2.20(3H,s),2.74(2H,t,J=6.3Hz),3.78(2H,q,J=6.3Hz),5.95(1H,s),6.90−7.09(2H,m),7.14(2H,t,J=8.5Hz),7.65−7.75(2H,m),7.76−7.82(1H,m),7.96(1H,s),8.47(1H,br t,J=6.3Hz),9.17(1H,s).
IR(ATR)cm−1:3062,2969,1716,1654,1589,1531,1490,1326,1230,1182,1145,1085.
mp:223−226℃
MS m/z:493(M++H).
Anal.calcd for C23H19F3N2O5S:C,56.09;H,3.89;F,11.57;N,5.69;S,6.51.
Found:C,56.00;H,3.91;F,11.57;N,5.67;S,6.60.
1H−NMR(400MHz,CDCl3)δ:1.43(9H,s),2.20(3H,s),3.32−3.45(2H,m),3.53−3.65(2H,m),4.87−4.97(1H,m),5.95(1H,s),6.90−7.09(2H,m),7.14(2H,t,J=8.4Hz),7.67−7.82(3H,m),7.95(1H,s),8.25−8.35(1H,m),9.15(1H,s).
IR(ATR)cm−1:3334,1700,1670,1589,1521,1492,1365,1328,1236,1145,1081.
MS m/z:564(M++H).
1H−NMR(400MHz,CDCl3)δ:1.99(3H,s),2.23(3H,s),3.46−3.54(2H,m),3.58−3.59(2H,m),5.96(1H,s),6.18−6.28(1H,m),6.90−7.09(2H,m),7.15(2H,t,J=8.5Hz),7.77−7.92(3H,m),7.96(1H,s),8.33−8.43(1H,m),9.16(1H,s).
IR(ATR)cm−1:3392,3361,1587,1536,1490,1454,1317,1276,1232,1147.
MS m/z:505(M+).
Anal.calcd for C24H22F3N3O4S:C,57.02;H,4.39;F,11.27;N,8.31;S,6.34.
Found:C,56.88;H,4.47;F,11.45;N,8.25;S,6.44.
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),3.40−3.48(2H,m),3.58−3.65(2H,m),3.68(3H,s),5.11−5.22(1H,m),5.96(1H,s),6.90−7.09(2H,m),7.15(2H,t,J=8.5Hz),7.68−7.73(2H,m),7.75−7.82(1H,m),7.95(1H,s),8.28−8.35(1H,m),9.15(1H,s).
IR(ATR)cm−1:3396,3340,1718,1670,1589,1533,1490,1452,1315,1270,1234,1145.
mp:167−169℃
MS m/z:521(M+).
Anal.calcd for C24H22F3N3O5S:C,55.27;H,4.25;F,10.93;N,8.06;S,6.15.
Found:C,55.23;H,4.21;F,11.13;N,7.96;S,6.20.
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),3.06(1H,br),5.01(2H,t,J=6.8Hz),5.96(1H,s),6.92−6.98(1H,m),7.01−7.08(1H,m),7.14(2H,t,J=8.8Hz),7.67−7.73(2H,m),7.75−7.80(1H,m),7.96(1H,s),8.78−8.85(1H,br),9.17(1H,s).
IR(ATR)cm−1:3405,1683,1589,1511,1492,1236,1147,1035,723,593,555,522.
Mp:164−166℃.
MS m/z:451(M++H).
Anal.Calcd for C21H17F3N2O4S:C,56.00;H,3.80;F,12.65;N,6.22;S,7.12.
Found:C,55.97;H,3.80;F,12.83;N,6.12;S,7.18.
1H−NMR(400MHz,CDCl3)δ:2.08(3H,s),2.23(3H,s),5.47(2H,d,J=7.3Hz),5.96(1H,s),6.91−6.97(1H,m),7.01−7.08(1H,m),7.14(2H,t,J=8.8Hz),7.70(2H,dd,J=8.8,5.1Hz),7.74−7.80(1H,m),7.99(1H,s),8.96(1H,t,J=7.3Hz),9.17(1H,s).
IR(ATR)cm−1:3280,1735,1677,1519,1492,1234,1147,1018,715,568,530.
Mp 111−113℃.
MS m/z:493(M++H).
Anal.Calcd for C23H19F3N2O5S:C,56.09;H,3.89;F,11.57;N,5.69;S,6.51.
Found:C,55.91;H,3.77;F,11.68;N,5.66;S,6.67.
1H−NMR(400MHz,CDCl3)δ:1.32−1.60(4H,m),1.98−2.18(4H,m),2.20(3H,s),3.64−3.75(1H,m),3.89−4.00(1H,m),5.95(1H,s),6.90−7.09(2H,m),7.11−719(2H,m),7.68−7.74(2H,m),7.75−7.82(1H,m),7.88(1H,br d,J=8.8Hz),7.96(1H,s),9.13(1H,s).
IR(ATR)cm−1:3380,2933,1664,1589,1521,1492,1326,1292,1236,1145,1081.
MS m/z:518(M+).
Anal.calcd for C26H25F3N2O4S:C,60.22;H,4.86;F,10.99;N,5.40;S,6.18.
Found:C,60.15;H,4.86;F,10.82;N,5.41;S,6.21.
1H−NMR(400MHz,CDCl3)δ:2.08−2.14(1H,m),2.17(1.5H,s),2.19(1.5H,s),4.02−4.12(1H,m),4.42−4.62(2H,m),4.70−4.80(1H,m),4.95−5.07(1H,m),5.94(1H,s),6.90−7.09(2H,m),7.11−7.19(2H,m),7.65−7.72(2H,m),7.75−7.82(1H,m),7.89(0.5H,s),7.91(0.5H,s),9.17(1H,s).
IR(ATR)cm−1:3409,1612,1587,1546,1494,1461,1419,1359,1324,1294,1234,1216,1143.
mp:219−221℃
MS m/z:477(M++H).
Anal.calcd for C23H19F3N2O4S:C,57.98;H,4.02;F,11.96;N,5.88;S,6.73.
Found:C,57.70;H,4.04;F,12.21;N,5.90;S,6.79.
1H−NMR(400MHz,CDCl3)δ:2.22(1.5H,s),2.27(1.5H,s),3.49−3.65(2H,m),3.92−4.15(2H,m),4.40−4.53(2H,m)5.96(1H,s),5.99−6.10(1H,m),6.89−7.10(2H,m),7.11−7.20(2H,m),7.58(0.5H,s),7.65(0.5H,s),7.70−7.83(3H,m),9.16(0.5H,s),9.18(0.5H,s).
IR(ATR)cm−1:1681,1660,1619,1589,1492,1471,1413,1322,1297,1236,1218.
MS m/z:504(M++H).
FAB−MS:504.1189(Calcd for C24H21O4N3F3S:504.1205).
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),3.69−3.90(4H,m),5.96(1H,s),6.90−7.09(2H,m),7.11−7.20(2H,m),7.67−7.74(2H,m),7.77−7.83(1H,m),7.96(1H,s),8.37−8.45(1H,m),9.17(1H,s).
IR(ATR)cm−1:3369,1685,1590,1525,1488,1438,1328,1295,1232,1147,1078.
MS m/z:483(M++H).
1H−NMR(400MHz,CDCl3)δ:1.45(3H,t,J=7.1Hz),2.23(3H,s),4.47(2H,q,J=7.1Hz),5.97(1H,s),6.90−7.09(2H,m),7.10−7.18(2H,m),7.69−7.80(3H,m),7.90(1H,s),9.36(1H,s).
IR(ATR)cm−1:1739,1589,1556,1332,1317,1278,1232,1216,1145,1101,1081.
mp:151−153℃
MS m/z:450(M++H).
FAB−MS:450.1008(Calcd for C22H19O4NF3S:450.0987).
1H−NMR(400MHz,CDCl3)δ:2.26(3H,s),3.24(3H,s),3.60(3H,s),5.94(1H,s),6.88−7.08(2H,m),7.10−7.19(2H,m),7.43(1H,s),7.70−7.80(3H,m),9.09(1H,s).
IR(ATR)cm−1:1585,1527,1492,1407,1315,1292,1230,1139,1081.
mp:161−164℃
MS m/z:465(M++H).
Anal.calcd for C22H19F3N2O2S2:C,56.88;H,4.12;F,12.27;N,6.03;S,13.81.
Found:C,56.60;H,4.10;F,12.27;N,6.06;S,13.64.
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),2.68−2.75(1H,m),3.62−3.68(2H,m),3.82−3.89(2H,m),5.78(1H,s),6.75−6.84(1H,m),6.92−7.00(2H,m),7.02−7.12(1H,m),7.32−7.39(2H,m),7.94(1H,s),8.37−8.45(1H,m),9.07(1H,s).
MS m/z:451(M++H).
1H−NMR(400MHz,CDCl3)δ:2.14(3H,s),2.60(1H,t,J=5.4Hz),3.63−3.69(2H,m),3.83−3.89(2H,m),5.89(1H,s),6.82−6.90(1H,m),7.14−7.25(3H,m),7.73−7.79(2H,m),7.97(1H,s),8.41−8.48(1H,m),9.42(1H,s).
IR(ATR)cm−1:3379,1662,1533,1493,1329,1230,1146,1082,820.
mp:164−165℃.
Anal.Calcd for C22H18F4N2O4S:C,54.77;H,3.76;F,15.75;N,5.81;S,6.65.Found:C,54.76;H,3.69;F,15.76;N,5.84;S,6.75.
MS m/z:483(M++H).
1H−NMR(400MHz,CDCl3)δ:2.37(3H,s),2.57−2.65(1H,m),3.61−3.66(2H,m),3.80−3.87(2H,m),5.82(1H,s),6.91−7.00(4H,m),7.28−7.38(3H,m),8.00(1H,s),8.31−8.37(1H,m),8.61(1H,s).
LC−MS m/z:433(M++H).
1H−NMR(400MHz,CDCl3)δ:1.94(1.5H,s),2.13(1.5H,s),2.51−2.65(1H,m),3.63−3.70(2H,m),3.83−3.90(2H,m),5.33(0.5H,s),5.35(0.5H,s),6.87−7.14(4H,m),7.28−7.37(2.5H,m),7.48−7.54(0.5H,m),7.92(0.5H,s),7.97(0.5H,s),8.36−8.46(1H,m),8.85(0.5H,s),9.03(0.5H,s).
IR(ATR)cm−1:3383,1660,1589,1527,1489,1225,1082,1049.
Anal.Calcd for C22H19F3N2O3S:C,58.92;H,4.27;F,12.71;N,6.25;S,7.15.Found:C,58.53;H,4.30;F,12.91;N,6.16;S,7.08.
MS m/z:449(M++H).
1H−NMR(400MHz,CDCl3)δ:1.36(3H,t,J=7.1Hz),4.63(2H,q,J=7.1Hz),6.87−6.94(1H,m),7.03−7.10(2H,m).
1H−NMR(400MHz,CDCl3)δ:2.37(3H,s),5.86(1H,s),6.62−6.69(1H,m),6.71−6.78(2H,m),6.96−7.07(2H,m),7.27−7.32(1H,m),7.33(1H,s),8.32(1H,m).
MS m/z:442,444(M++H).
1H−NMR(400MHz,CDCl3)δ:2.49(3H,s),5.97(1H,s),6.63−6.70(1H,m),6.73−6.80(2H,m),6.98−7.09(2H,m),7.33−7.39(1H,m),7.79(1H,s),8.74(1H,m),10.03(1H,s).
MS m/z:392(M++H).
1H−NMR(400MHz,CDCl3)δ:2.38(3H,s),6.02(1H,s),6.95−7.02(1H,m),7.06−7.15(2H,m),7.23−7.30(2H,m),7.64−7.70(1H,m),8.07(1H,s),9.24(1H,s).
MS m/z:440(M++H).
1H−NMR(400MHz,CDCl3)δ:2.30(3H,s),2.47−2.53(1H,m),3.63−3.69(2H,m),3.82−3.89(2H,m),6.00(1H,s),6.93−7.13(3H,m),7.22−7.30(2H,m),7.65−7.72(1H,m),8.01(1H,s),8.36−8.44(1H,m),9.17(1H,s).
IR(ATR)cm−1:3388,1660,1604,1529,1493,1444,1333,1298,1146,1078,989.
mp:82−84℃.
Anal.Calcd for C22H18F4N2O4S:C,54.77;H,3.76;F,15.75;N,5.81;S,6.65.Found:C,54.89;H,3.95;F,15.46;N,5.76;S,6.78.
MS m/z:483(M++H).
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),3.04−3.09(1H,m),5.01(2H,t,J=7.2Hz),5.89(1H,s),6.85−6.88(1H,m),7.15−7.23(3H,m),7.74−7.78(2H,m),7.97(1H,s),8.84−8.88(1H,br),9.43(1H,s).
IR(ATR)cm−1:3332,1650,1592,1521,1496,1145,1054,817,582.
MS m/z:469(M++H).
Anal.Calcd for C21H16F4N2O4S 0.5H2O:C,52.83;H,3.59;F,15.92;N,5.87;S,6.72.Found:C,52.65;H,3.56;F,15.87;N,5.81;S,6.65.
1H−NMR(400MHz,CDCl3)δ:2.17(3H,s),5.76(1H,s),6.76−6.82(1H,m),7.02−7.10(1H,m),7.24−7.36(6H,m),8.90(1H,s).
MS m/z:424(M++H).
1H−NMR(400MHz,CDCl3)δ:2.28(3H,s),5.88(1H,s),6.78−6.84(1H,m),7.04−7.12(1H,m),7.24−7.38(5H,m),7.70(1H,s),9.34(1H,s),10.06(1H,s).
MS m/z:374(M++H).
1H−NMR(400MHz,CDCl3)δ:2.16(3H,s),5.91(1H,s),6.82−6.88(1H,m),7.17−7.25(1H,m),7.50−7.54(2H,m),7.68(1H,t,J=7.5Hz),7.72(2H,d,J=7.3Hz),7.99(1H,s),9.53(1H,s).
MS m/z:422(M++H).
1H−NMR(400MHz,CDCl3)δ:2.09(3H,s),5.67(1H,br s),5.92(1H,s),6.82−6.88(1H,m),7.14−7.24(1H,m),7.50(2H,t,J=7.5Hz),7.67(1H,t,J=7.5Hz),7.74(2H,d,J=7.5Hz),7.88(1H,bs),7.96(1H,s),9.45(1H,s).
MS m/z:421(M++H).
1H−NMR(400MHz,CDCl3)δ:2.11(3H,s),3.14−3.18(1H,m),5.01(2H,t,J=7.1Hz),5.91(1H,s),6.80−6.90(1H,m),7.12−7.24(1H,m),7.45−7.53(2H,m),7.61−7.78(3H,m),7.94(1H,s),8.88(1H,br),9.45(1H,s).
IR(ATR)cm−1:3382,3334,1654,1494,1149,1054,987,723,595,555.
MS m/z:451(M++H).
1H−NMR(400MHz,CDCl3)δ:2.29(3H,s),2.60(2H,s),5.96(1H,s),5.97(1H,s),6.92−6.98(1H,m),7.02−7.08(1H,m),7.15(2H,t,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.74−7.79(1H,m),8.03(1H,s),9.20(1H,s),10.38(1H,bs).
IR(ATR)cm−1:1725,1706,1589,1463,1259,1234,1187,1143,1079,970,844,717,671,593,520,487.
mp:182−183℃.
MS m/z:463(M++H).
Anal.Calcd for C22H17F3N2O4S:C,57.14;H,3.71;F,12.32;N,6.06;S,6.93.
Found:C,57.33;H,3.62;F,12.64;N,6.09;S,7.00.
1H−NMR(400MHz,CDCl3)δ:3.82(3H,s),4.11(2H,s),4.58(2H,m),6.89(2H,d,J=8.5Hz),7.29(2H,d,J=8.5Hz),9.50(1H,bs).
1H−NMR(400MHz,CDCl3)δ:2.23(3H,s),3.79(3H,s),4.56(2H,s),5.56(2H,d,J=7.5Hz),5.96(1H,s),6.86(2H,d,J=8.8Hz),6.91−6.98(1H,m),7.01−7.07(1H,m),7.14(2H,t,J=8.8Hz),7.28(2H,d,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.74−7.79(1H,m),7.98(1H,s),9.00(1H,t,J=7.5Hz),9.17(1H,s).
IR(ATR)cm−1:3386,1751,1691,1589,1511,1492,1236,1145,1105,1081,817,723,590,524.
1H−NMR(400MHz,CDCl3)δ:2.24(3H,s),4.19(2H,s),5.60(2H,d,J=7.5Hz),5.96(1H,s),6.91−6.98(1H,m),7.01−7.08(1H,m),7.15(2H,t,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.74−7.78(1H,m),7.99(1H,s),9.02(1H,t,J=7.5Hz),9.18(1H,s).
IR(ATR)cm−1:3386,1747,1687,1589,1515,1492,1236,1145,1081,590,526.
mp:84℃.
MS m/z:509(M++H).
Anal.Calcd for C23H19F3N2O6S:C,54.33;H,3.77;F,11.21;N,5.51;S,6.31.
Found:C,54.61;H,3.93;F,11.32;N,5.59;S,6.33.
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),2.38(6H,s),4.33(2H,d,J=5.6Hz),5.97(1H,s),6.91−6.98(1H,m),7.01−7.08(1H,m),7.15(2H,t,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.75−7.81(1H,m),7.98(1H,s),8.43(1H,t,J=5.6Hz),9.16(1H,s).
IR(ATR)cm−1:3340,1670,1592,1521,1494,1238,1145,1039,838,817,711,657,590,530.
Anal.Calcd for C23H22F3N3O3S.0.75H2O:C,56.26;H,4.82;F,11.61;N,8.56;S,6.53.
Found:C,55.97;H,4.56;F,12.44;N,8.46;S,6.51.
1H−NMR(400MHz,CDCl3)δ:1.04(9H,s),2.21(3H,s),3.65−3.85(4H,m),4.95−5.05(2H,m),5.96(1H,s),6.90−7.08(4H,m),7.30−7.43(6H,m),7.60−7.80(7H,m),7.98(1H,s),8.65−7.02(1H,m),9.14(1H,s).
MS m/z:733(M++H).
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),3.68−3.80(4H,m),4.95−5.05(2H,m),5.96(1H,s),6.90−7.08(2H,m),7.10−7.18(2H,m),7.60−7.80(3H,m),7.99(1H,s),8.75(1H,br t,J=7.0Hz),9.18(1H,s).
IR(ATR)cm−1:3347,1668,1589,1513,1494,1309,1282,1230,1147.
mp:175−177℃
MS m/z:495(M++H).
Anal.calcd for C23H21F3N2O5S:C,55.87;H,4.28;F,11.53;N,5.67;S,6.48.Found:C,55.63;H,4.27;F,11.40;N,5.54;S,6.43.
1H−NMR(400MHz,CDCl3)δ:2.25(3H,s),4.66(2H,s),5.00−5.10(2H,m),5.97(1H,s),6.90−7.08(2H,m),7.10−7.18(2H,m),7.25−7.33(1H,m),7.67−7.80(4H,m),8.01(1H,s),8.50−8.55(1H,m),8.60(1H,br s),8.74(1H,br t,J=7.1Hz),9.18(1H,s).
IR(ATR)cm−1:1675,1590,1523,1492,1309,1295,1236,1147.
mp:121−123℃
MS m/z:541(M+).
Anal.calcd for C27H22F3N3O4S:C,59.88;H,4.09;F,10.52;N,7.79;S,5.92.Found:C,59.80;H,4.07;F,10.73;N,7.70;S,6.13.
1H−NMR(400MHz,CDCl3)δ:2.24(3H,s),5.87(1H,s),6.81−6.90(1H,m),7.08−7.18(1H,m),7.30(1H,s),7.57(1H,d,J=8.3Hz),7.76(1H,dd,J=8.3,2.0Hz),8.60(1H,d,J=2.0Hz),8.85(1H,s).
MS m/z:493,495(M++H).
1H−NMR(400MHz,CDCl3)δ:2.35(3H,s),5.99(1H,s),6.83−6.91(1H,m),7.10−7.20(1H,m),7.58(1H,d,J=8.3Hz),7.76(1H,s),7.79(1H,dd,J=8.3,2.0Hz),8.60(1H,d,J=2.0Hz),9.29(1H,s),10.06(1H,s).
MS m/z:443(M++H).
1H−NMR(400MHz,CDCl3)δ:2.26(3H,s),5.93(1H,s),6.85−6.93(1H,m),7.23−7.33(1H,m),7.86(1H,d,J=8.3Hz),8.07(1H,s),8.26(1H,dd,J=8.3,2.2Hz),8.99(1H,d,J=2.2Hz),9.50(1H,s).
MS m/z:491(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),5.61(1H,br s),5.96(1H,s),6.85−6.93(1H,m),7.21−7.31(1H,m),7.84(1H,d,J=8.3Hz),7.85(1H,br s),8.04(1H,s),8.24(1H,dd,J=8.3,2.2Hz),8.99(1H,d,J=2.2Hz),9.39(1H,s).
IR(ATR)cm−1:3462,3159,1701,1595,1495,1329,1192,1163,1140,1107,1078,1018,989.
mp:237−238℃.
MS m/z:490(M++H).
Anal.Calcd for C20H13F6N3O3S:C,49.08;H,2.68;F,23.29;N,8.59;S,6.55.Found:C,48.99;H,2.70;F,23.14;N,8.60;S,6.70.
1H−NMR(400MHz,CDCl3)δ:2.22(3H,s),3.10(1H,t,J=7.8Hz),5.02(2H,dd,J=7.8,6.4Hz),5.95(1H,s),6.84−6.93(1H,m),7.21−7.31(1H,m),7.84(1H,d,J=8.3Hz),8.02(1H,s),8.24(1H,dd,J=8.3,2.2Hz),8.86(1H,t,J=6.4Hz),8.99(1H,d,J=2.2Hz),9.39(1H,s).
IR(ATR)cm−1:3249,1655,1541,1496,1333,1186,1161,1105,1078,1043.
mp:181−182℃.
MS m/z:520(M++H).
Anal.Calcd for C21H15F6N3O4S:C,48.56;H,2.91;F,21.95;N,8.09;S,6.17.Found:C,48.48;H,2.84;F,21.67;N,8.18;S,6.39.
1H−NMR(400MHz,CDCl3)δ:1.07(9H,s),1.85(3H,s),6.11(1H,s),6.58−6.65(1H,m),6.91−7.01(1H,m),7.12(1H,s),7.20−7.54(10H,m),9.12(1H,s).
MS m/z:570,572(M++H).
1H−NMR(400MHz,CDCl3)δ:1.09(9H,s),1.96(3H,s),5.56(1H,br s),6.23(1H,s),6.58−6.65(1H,m),6.92−7.01(1H,m),7.20−7.54(10H,m),7.85(1H,s),7.88(1H,br s),9.33(1H,s).
MS m/z:535(M++H).
1H−NMR(400MHz,CD3OD)δ:2.22(3H,s),6.35(1H,s),6.93−7.02(1H,m),7.24−7.34(1H,m),7.85(1H,s),8.99(1H,s).
MS m/z:297(M++H).
1H−NMR(400MHz,CDCl3)δ:2.38(3H,s),3.04(3H,s),5.65(1H,br s),6.91−6.98(1H,m),7.16(1H,s),7.21−7.30(1H,m),7.84(1H,br s),8.02(1H,s),8.88(1H,s).
MS m/z:375(M++H).
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),5.62(1H,br s),5.90(1H,s),6.83−6.91(1H,m),7.16−7.26(1H,m),7.45−7.50(2H,m),7.65−7.70(2H,m),7.87(1H,br s),7.99(1H,s),9.42(1H,s).
IR(ATR)cm−1:3396,3168,1687,1496,1419,1311,1238,1146,1082.
MS m/z:455(M++H).
1H−NMR(400MHz,CDCl3)δ:2.16(3H,s),3.06(1H,t,J=7.8Hz),5.01(2H,dd,J=7.8,6.6Hz),5.90(1H,s),6.83−6.91(1H,m),7.16−7.26(1H,m),7.45−7.50(2H,m),7.65−7.70(2H,m),7.97(1H,s),8.88(1H,t,J=6.6Hz),9.42(1H,s).
IR(ATR)cm−1:3251,1657,1537,1493,1335,1232,1149,1088,1047.
mp:177−178℃.
MS m/z:485(M++H).
Anal.Calcd for C21H16ClF3N2O4S:C,52.02;H,3.33;Cl,7.31;F,11.75;N,5.78;S,6.61.Found:C,52.06;H,3.31;Cl,7.23;F,11.46;N,5.78;S,6.69.
1H−NMR(400MHz,CDCl3)δ:2.18(3H,s),5.59(1H,br s),5.90(1H,s),6.84−6.92(1H,m),7.18−7.35(2H,m),7.49−7.56(1H,m),7.58−7.65(1H,m),7.87(1H,br s),8.01(1H,s),9.42(1H,s).
IR(ATR)cm−1:3396,3165,1691,1597,1498,1417,1333,1279,1238,1142.
mp:200−201℃.
MS m/z:457(M++H).
Anal.Calcd for C20H13F5N2O3S:C,52.63;H,2.87;F,20.81;N,6.14;S,7.03.Found:C,52.58;H,2.77;F,20.94;N,6.18;S,7.14.
1H−NMR(400MHz,CDCl3)δ:2.19(3H,s),3.15(1H,t,J=7.6Hz),5.01(2H,dd,J=7.6,6.8Hz),5.90(1H,s),6.84−6.92(1H,m),7.19−7.35(2H,m),7.50−7.56(1H,m),7.58−7.64(1H,m),7.99(1H,s),8.87(1H,t,J=6.8Hz),9.42(1H,s).
IR(ATR)cm−1:3394,3332,1647,1522,1496,1417,1335,1284,1213,1141,1055.
mp:119−120℃.
MS m/z:487(M++H).
Anal.Calcd for C21H15F5N2O4S:C,51.85;H,3.11;F,19.53;N,5.76;S,6.59.Found:C,51.64;H,3.01;F,19.45;N,5.81;S,6.74.
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),5.62(1H,br s),5.90(1H,s),6.83−6.91(1H,m),7.16−7.26(1H,m),7.45−7.50(2H,m),7.66−7.71(2H,m),7.88(1H,br s),7.99(1H,s),9.42(1H,s).
IR(ATR)cm−1:3438,3161,1703,1597,1493,1419,1323,1255,1217,1151.
mp:219−220℃.
MS m/z:505(M++H).
Anal.Calcd for C21H14F6N2O4S:C,50.00;H,2.80;F,22.60;N,5.55;S,6.36.Found:C,49.65;H,2.74;F,22.49;N,5.52;S,6.43.
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),3.09(1H,t,J=7.6Hz),5.01(2H,dd,J=7.6,6.6Hz),5.89(1H,s),6.82−6.90(1H,m),7.16−7.36(3H,m),7.77−7.83(2H,m),7.98(1H,s),8.88(1H,t,J=6.6Hz),9.43(1H,s).
IR(ATR)cm−1:3236,1657,1541,1495,1252,1227,1151,1043.
mp:140−141℃.
MS m/z:535(M++H).
Anal.Calcd for C22H16F6N2O5S:C,49.44;H,3.02;F,21.33;N,5.24;S,6.00.Found:C,49.44;H,2.94;F,21.42;N,5.29;S,6.15.
1H−NMR(400MHz,CDCl3)δ:1.33(3H,t,J=7.1Hz),4.62(2H,q,J=7.1Hz),6.80−6.84(1H,m),7.35−7.40(1H,m),7.64(1H,d,J=8.1Hz),7.68−7.69(1H,m),7.71(1H,d,J=2.2Hz).
MS m/z:239(M++H).
1H−NMR(400MHz,CDCl3)δ:2.26(3H,s),5.48−5.54(1H,m),5.88(1H,s),6.74(1H,m),6.76−6.83(1H,m),7.06(1H,ddd,J=18.1,9.0,4.9Hz),7.26−7.28(1H,m),7.49(1H,d,J=8.0Hz),7.54(1H,s),7.63(1H,d,J=2.2Hz),7.84(1H,s),7.94(1H,s),9.14(1H,s).
MS m/z:429(M++H).
1H−NMR(400MHz,CDCl3)δ:2.08(3H,s),5.55(1H,s),5.98(1H,s),6.80−6.87(1H,m),6.89(1H,dd,J=2.2,1.0Hz),7.19(1H,ddd,J=18.0,9.3,4.9Hz),7.60(1H,dd,J=8.1,1.7Hz),7.69(1H,d,J=8.1Hz),7.85(1H,d,J=2.2Hz),7.86−7.90(1H,br s),7.94(2H,m),9.48(1H,s).
IR(ATR)cm−1:3456,3153,1699,1597,1493,1427,1313,1242,1182,1149,1124,1051,989,887,829,771,727,708,633,586,563,501,420.
mp:237−240℃.
MS m/z:461(M++H).
Anal.calcd for C22H15F3N2O4S:C,57.39;H,3.28;F,12.38;N,6.08;S,6.96.Found:C,57.25;H,3.25;F,12.37;N,5.91;S,6.97.
1H−NMR(400MHz,CDCl3)δ:2.09(3H,s),3.04(1H,t,J=7.3Hz),5.01(2H,t,J=7.3Hz),5.98(1H,s),6.80−6.87(1H,m),6.89(1H,dd,J=2.2,0.7Hz),7.19(1H,ddd,J=17.8,9.0,4.9Hz),7.60(1H,dd,J=8.0,1.7Hz),7.69(1H,d,J=8.0Hz),7.85(1H,d,J=2.2Hz),7.93(2H,m),8.85−8.91(1H,m),9.48(1H,s).
IR(ATR)cm−1:3394,1670,1601,1516,1496,1423,1321,1302,1230,1186,1144,1126,1054,1036,822,729,714,633,586,552,532,496.
mp:185−186℃(dec.).
MS m/z:491(M++H).
Anal.calcd for C23H17F3N2O5S・0.25C3H8O:C,56,43;H,3.79;F,11.28;N,5.54;S,6.34.Found:C,56.38;H,3.76;F,11.51;N,5.49;S,6.43.
1H−NMR(400MHz,CDCl3)δ:2.14(3H,s),5.58(1H,br s),5.93(1H,s),6.83−6.91(1H,m),7.17−7.26(1H,m),7.75−7.81(2H,m),7.84−7.94(3H,m),8.00(1H,s),9.43(1H,s).
MS m/z:489(M++H).
1H−NMR(400MHz,CDCl3)δ:2.15(3H,s),3.03−3.08(1H,m),4.98−5.05(2H,m),5.93(1H,s),6.83−6.91(1H,m),7.18−7.26(1H,m),7.77(2H,d,J=8.5Hz),7.89(2H,d,J=8.5Hz),7.98(1H,s),8.83−8.91(1H,m),9.43(1H,s).
IR(ATR)cm−1:3479,3381,1682,1520,1491,1402,1321,1255,1186,1171,1147,1128,1055,1016.
mp:190−192℃.
Anal.Calcd for C22H16F6N2O4S:C,50.97;H,3.11;F,21.99;N,5.40;S,6.19.Found:C,50.95;H,3.06;F,22.24;N,5.47;S,6.31.
MS m/z:519(M++H).
1H−NMR(400MHz,CDCl3)δ:1.27(3H,t,J=7.2Hz),2.22(3H,s),4.15−4.25(4H,m),5.08(2H,d,J=7.2Hz),5.96(1H,s),6.90−7.20(4H,m),7.67−7.82(3H,m),7.98(1H,s),8.76(1H,br t,J=7.2Hz),9.18(1H,s).
IR(ATR)cm−1:1752,1683,1590,1513,1494,1286,1236,1203,1149,1093.
MS (m/z):537(M++H).
Anal.calcd for C25H23F3N2O6S:C,55.97;H,4.32;F,10.62;N,5.22;S,5.98.Found:C,55.93;H,4.24;F,10.33;N,5.28;S,6.06.
1H−NMR(400MHz,CDCl3)δ:2.24(3H,s),4.24(2H,s),4.98−5.05(2H,m),5.96(1H,s),6.90−7.20(4H,m),7.67−7.80(3H,m),8.00(1H,s),8.85−8.95(1H,m),9.19(1H,s).
IR(ATR)cm−1:1762,1682,1589,1521,1492,1321,1292,1236,1147.
MS (m/z):509(M++H).
Anal.calcd for C23H19F3N2O6S・0.75H2O:C,52.92;H,3.96;F,10.92;N,5.37;S,6.14.
Found:C,53.20;H,3.90;F,10.69;N,5.19;S,6.03
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),2.49(1H,t,J=8.8Hz),4.55−4.65(2H,m),5.95(1H,s),6.90−7.20(4H,m),7.67−7.80(3H,m),7.96(1H,s),8.45−8.55(1H,m),9.16(1H,s).
IR(ATR)cm−1:1673,1589,1508,1492,1315,1286,1238,1211,1147.
mp:190−193℃
EI−MS(m/z):466(M+).
Anal.calcd for C21H17F3N2O3S2:C,54.07;H,3.67;F,12.22;N,6.01;S,13.75.Found:C,54.05;H,3.64;F,12.13;N,6.07;S,13.78.
1H−NMR(400MHz,CDCl3)δ:2.27(3H,s),3.25(3H,s),4.70−4.84(2H,m),5.67(1H,t,J=8.0Hz),5.95(1H,s),6.90−7.19(4H,m),7.69−7.78(4H,m),9.12(1H,s).
IR(ATR)cm−1:1635,1589,1490,1326,1295,1230,1149,1039.
mp:184−186℃
MS m/z:465(M++H).
Anal.Calcd for C22H19F3N2O4S:C,56.89;H,4.12;F,12.27;N,6.03;S,6.90.Found:C,56.83;H,4.03;F,12.18;N,5.90;S,6.90.
1H−NMR(400MHz,CDCl3)δ:6.61(1H,t,J=55.2Hz),7.55(1H,d,J=8.3Hz),7.98(1H,dd,J=8.3,2.2Hz),8.72(1H,d,J=2.2Hz).
MS m/z:208,210(M++H).
1H−NMR(400MHz,CDCl3)δ:1.53(9H,s),6.66(1H,t,J=55.6Hz),6.62(1H,br s),7.58(1H,d,J=8.6Hz),8.09−8.16(1H,m),8.46(1H,d,J=2.5Hz).
MS m/z:245(M++H).
1H−NMR(400MHz,CDCl3)δ:3.91(2H,br s),6.56(1H,t,J=55.9Hz),7.04(1H,dd,J=8.5,2.7Hz),7.41(1H,d,J=8.5Hz),8.07(1H,d,J=2.7Hz).
MS m/z:145(M++H).
1H−NMR(400MHz,CDCl3)δ:1.37(3H,t,J=7.1Hz),4.64(2H,q,J=7.1Hz),6.67(1H,t,J=7.1Hz),7.72(1H,d,J=8.1Hz),7.98(1H,dd,J=8.1,2.2Hz),8.71(1H,d,J=2.2Hz).
参考例14で得た5−[ヒドロキシ(2,3,6−トリフルオロフェニル)メチル]−4−メチルピリジン−2−カルボキサミド(355mg,1.20mmol)のN,N−ジメチルホルムアミド(6ml)溶液に、窒素雰囲気下、室温にて塩化メタンスルホニル(0.186ml,2.40mmol)、次いでトリエチルアミン(0.502ml,3.60mmol)を加え1時間攪拌した。反応混合物に酢酸エチル、水、次いで飽和塩化アンモニウム水溶液を加えて分液操作を行った。得られた有機層を飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣をN,N−ジメチルホルムアミド(12ml)に溶解し、先に得たチオール並びに炭酸カリウム(199mg,1.44mmol)を加え、窒素雰囲気下、室温にて2時間攪拌した。反応混合物に酢酸エチル及び水を加え、有機層を分取した。有機層を飽和塩化アンモニウム水溶液、次いで、飽和食塩水にて洗浄した。得られた有機層を無水硫酸ナトリウムにて乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣をフラッシュシリカゲルクロマトグラフィーに付し、ヘキサン:酢酸エチル=1:1溶出部より得た分画を減圧濃縮し、標記化合物(133mg,0.303mmol,37%)を淡褐色泡状物質として得た。
1H−NMR(400MHz,CDCl3)δ:2.31(3H,s),5.55(1H,br s),5.93(1H,s),6.59(1H,t,J=55.4Hz),6.81−6.88(1H,m),7.07−7.17(1H,m),7.54(1H,d,J=8.3Hz),7.77(1H,dd,J=8.3,2.2Hz),7.81(1H,br s),8.00(1H,s),8.55(1H,d,J=2.2Hz),9.08(1H,s).
MS m/z:440(M++H).
1H−NMR(400MHz,CDCl3)δ:2.20(3H,s),5.56(1H,br s),5.94(1H,s),6.68(1H,t,J=54.9Hz),6.84−6.91(1H,m),7.20−7.27(1H,m),7.79(1H,d,J=8.3Hz),7.85(1H,br s),8.03(1H,s),8.19(1H,dd,J=8.3,2.2Hz),8.93(1H,d,J=2.2Hz),9.40(1H,s).
MS m/z:472(M++H).
1H−NMR(400MHz,CDCl3)δ:2.21(3H,s),3.05(1H,t,J=7.8Hz),4.98−5.05(2H,m),5.94(1H,s),6.68(1H,t,J=54.9Hz),6.84−6.92(1H,m),7.20−7.27(1H,m),7.79(1H,d,J=8.3Hz),8.01(1H,s),8.19(1H,dd,J=8.3,2.2Hz),8.86(1H,t,J=6.9Hz),8.92(1H,d,J=2.2Hz),9.40(1H,s).
IR(ATR)cm−1:3442,3383,1676,1523,1491,1338,1153,1084,1055,1036,1014.
mp:181−183℃.
Anal.Calcd for C21H16F5N3O4S:C,50.30;H,3.22;F,18.94;N,8.38;S,6.39.Found:C,50.07;H,3.35;F,19.03;N,8.40;S,6.50.
MS m/z:502(M++H).
化合物のβアミロイド蛋白生成阻害活性は、ヒトグリオーマ細胞(H4細胞)にヒト野生型βアミロイド蛋白前駆体蛋白遺伝子であるAPP751遺伝子を導入したE35細胞を用いて、培養液中に分泌されるβアミロイド蛋白(Aβ)の量をサンドイッチ型の酵素結合免疫吸着(ELISA)法で定量することにより測定した。
(実験方法)
化合物(1)の一例として、実施例22、実施例85、実施例101、実施例106、実施例118に記載された化合物(それぞれ、上記式(1−1)、(1−2)、(1−3)、(1−4)及び(1−5)で示される化合物。以下、それぞれ化合物(1−1)、(1−2)、(1−3)、(1−4)及び(1−5)と記す。)または対照化合物LYを0.5%メチルセルロース水溶液に懸濁し、雄性SDラット(約5週齢)に単回経口投与した。溶媒対照群には0.5%メチルセルロース水溶液のみを投与した。投与3時間後に脳を摘出し、大脳を採取した。大脳を42%ギ酸水溶液でホモジナイズし、100,000×gで60分間遠心した。得られた上清を1M Trisで中和し、これらサンプル中のAβ濃度を試験例1に記載したサンドイッチELISA法を用いて測定した。また、化合物(1−1)〜(1−5)又は対照化合物LYを7日間経口反復投与した雄性SDラットの病理組織学的及び血清学的な検査を行うことにより、これらの化合物の免疫抑制作用を評価した。
(結果)
化合物(1−1)、(1−2)、(1−3)、(1−4)及び(1−5)について、統計学的に有意な脳内Aβ量の低下を示す用量と免疫抑制作用を示す用量との間に充分な乖離が認められた。一方、対照化合物LYについては、薬効用量と毒性を示す用量との間に充分な差は認められなかった。
Claims (37)
- 一般式(1)
Ar2は置換基を有することもあるフェニル基又は置換基を有することもある複素環基を示し;
Xは−S−、−SO−、又は−SO2−を示し;
Yは水素原子、−NR1R2(式中、R1は水素原子、低級アルキル基、又は水酸基を示し、R2は水素原子、置換基を有することもある低級アルキル基、低級アルカノイル基、置換基を有することもあるアルコキシカルボニル基、置換基を有することもある低級アルコキシ基、置換基を有することもあるアミノ基、ホスホノ基、置換基を有することもあるフェニル基、又は置換基を有することもある芳香族複素環基を示し、あるいは、R1とR2はこれらが結合する窒素原子と一緒になって飽和複素環基を形成し、さらに当該飽和複素環基が置換基を有していてもよいことを示す。)、又は−OR1’(式中、R1’は水素原子又は置換基を有していてもよい低級アルキル基を示す。)を示し;
Zは酸素原子又は硫黄原子を示し;
R3は水素原子、低級アルキル基、又はハロゲン原子を示す。]で表される化合物、その塩又はそれらの溶媒和物。 - Ar1が2,5−ジフルオロフェニル基又は2,3,6−トリフルオロフェニル基である、請求項1に記載の化合物、その塩又はそれらの溶媒和物。
- Ar2が置換基を有することもあるフェニル基である、請求項1又は2に記載の化合物、その塩又はそれらの溶媒和物。
- 置換基を有することもあるフェニル基がフェニル基、4−メチルフェニル基、4−クロロフェニル基、4−フルオロフェニル基、4−メトキシフェニル基、4−(トリフルオロメトキシ)フェニル基、4−トリフルオロメチルフェニル基、4−クロロ−3−メチルフェニル基、4−フルオロ−3−メチルフェニル基、3,4−ジフルオロフェニル基、又は3,5−ジフルオロフェニル基である、請求項3に記載の化合物、その塩、又はそれらの溶媒和物。
- Ar2が置換基を有することもある複素環基である、請求項1又は2に記載の化合物、その塩、又はそれらの溶媒和物。
- 置換基を有することもある複素環基が5−(トリフルオロメチル)ピリジン−2−イル基、6−(トリフルオロメチル)ピリジン−3−イル基、又はベンゾフラン−6−イル基である、請求項5に記載の化合物、その塩、又はそれらの溶媒和物。
- Yが−NR1R2(式中、R1は水素原子、低級アルキル基、又は水酸基を示し、R2は水素原子、置換基を有することもある低級アルキル基、低級アルカノイル基、置換基を有することもあるアルコキシカルボニル基、置換基を有することもある低級アルコキシ基、置換基を有することもあるアミノ基、ホスホノ基、置換基を有することもあるフェニル基、又は置換基を有することもある芳香族複素環基を示し、あるいは、R1とR2はこれらが結合する窒素原子と一緒になって形成され、さらに置換基を有することもある4〜7員の飽和複素環基であることを示す。)である、請求項1〜6のいずれか1項に記載の化合物、その塩又はそれらの溶媒和物。
- R1が水素原子である、請求項7に記載の化合物、その塩、又はそれらの溶媒和物。
- R1がメチル基である、請求項7に記載の化合物、その塩、又はそれらの溶媒和物。
- R2が水素原子、メチル基、エチル基、tert−ブチル基、シクロプロピル基、カルボキシメチル基、2−カルボキシエチル基、2−(エトキシカルボニル)エチル基、ヒドロキシメチル基、2−ヒドロキシエチル基、4−ヒドロキシシクロヘキシル基、2−ヒドロキシ−1−ヒドロキシメチルエチル基、アセトキシメチル基、メチルチオプロピル基、メチルスルフィニルプロピル基、メチルスルホニルプロピル基、メチルカルボニルアミノエチル基、メトキシカルボニルアミノエチル基、tert−ブトキシカルボニルアミノエチル基、2−クロロエチル基、ヒドロキシアセトキシメチル基、ジメチルアミノメチル基、カルボキシメトキシメチル基、エトキシカルボニルメトキシメチル基、メルカプトメチル基、2−ヒドロキシエトキシメチル基、(ピリジン−3−イルメトキシ)メチル基、アセチル基、又はメトキシ基である、請求項7〜9のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物。
- R2が水素原子、メチル基、エチル基、ヒドロキシメチル基、2−ヒドロキシエチル基、ジメチルアミノメチル基、又はメトキシ基である、請求項7〜9のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物。
- R1とR2がこれらが結合する窒素原子と一緒になって形成する飽和複素環であり、当該飽和複素環はさらに置換基を有することもある、請求項7に記載の化合物、その塩、又はそれらの溶媒和物。
- 置換基を有することもある4〜7員の飽和複素環基が4−ヒドロキシピペリジン−1−イル基、3−オキソピペラジン−1−イル基、又はモルホリン−4−イル基である、請求項12に記載の化合物、その塩、又はそれらの溶媒和物。
- Yが−OR1’(式中、R1’は水素原子又は置換基を有していてもよい低級アルキル基を示す。)である、請求項1〜6のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物。
- R1’がメチル基である、請求項14に記載の化合物、その塩、又はそれらの溶媒和物。
- Zが酸素原子である請求項1〜15のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物。
- R3がメチル基である、請求項1〜16のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物。
- Ar1が2,5−ジフルオロフェニル基であり、Ar2が4−フルオロフェニル基であり、Xが−SO−であり、Yがジメチルアミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項1に記載の化合物、その塩、又はそれらの溶媒和物。
- 5−[(2,5−ジフルオロフェニル)[(4−フルオロフェニル)スルフィニル]メチル]−N,N,4−トリメチルピリジン−2−カルボキサミド、その塩、又はそれらの溶媒和物。
- Ar1が2,5−ジフルオロフェニル基又は2,3,6−トリフルオロフェニル基であり、Ar2がフェニル基、4−フルオロフェニル基、又は6−(トリフルオロメチル)ピリジン−3−イル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基またはアミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項1に記載の化合物、その塩、又はそれらの溶媒和物。
- Ar1が2,5−ジフルオロフェニル基であり、Ar2が4−フルオロフェニル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項20に記載の化合物、その塩、又はそれらの溶媒和物。
- 5−[(2,5−ジフルオロフェニル)[(4−フルオロフェニル)スルホニル]メチル]−N−(1−ヒドロキシメチル)−4−メチルピリジン−2−カルボキサミド、その塩、又はそれらの溶媒和物。
- Ar1が2,3,6−トリフルオロフェニル基であり、Ar2が4−フルオロフェニル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項20に記載の化合物、その塩、又はそれらの溶媒和物。
- 5−[[(4−フルオロフェニル)スルホニル](2,3,6−トリフルオロフェニル)メチル]−N−(1−ヒドロキシメチル)−4−メチルピリジン−2−カルボキサミド、その塩、又はそれらの溶媒和物。
- Ar1が2,3,6−トリフルオロフェニル基であり、Ar2がフェニル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項20に記載の化合物、その塩、又はそれらの溶媒和物。
- N−(1−ヒドロキシメチル)−4−メチル−5−[(フェニルスルホニル)(2,3,6−トリフルオロフェニル)メチル]ピリジン−2−カルボキサミド、その塩、又はそれらの溶媒和物。
- Ar1が2,3,6−トリフルオロフェニル基であり、Ar2が6−(トリフルオロメチル)ピリジン−3−イル基であり、Xが−SO2−であり、Yが(ヒドロキシメチル)アミノ基であり、Zが酸素原子であり、R3がメチル基である、請求項20に記載の化合物、その塩、又はそれらの溶媒和物。
- N−(1−ヒドロキシメチル)−4−メチル−5−[[[6−(トリフルオロメチル)ピリジン−3−イル]スルホニル](2,3,6−トリフルオロフェニル)メチル]ピリジン−2−カルボキサミド、その塩、又はそれらの溶媒和物。
- 請求項1〜28のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物を有効成分として含有する医薬。
- βアミロイド蛋白の産生及び/又は分泌異常に起因する疾患の予防又は治療薬である、請求項29に記載の医薬。
- βアミロイド蛋白の産生及び/又は分泌異常に起因する疾患がアルツハイマー病又はダウン症である、請求項30に記載の医薬。
- 請求項1〜28のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物及び製薬学的に許容し得る担体を含有する医薬組成物。
- 請求項1〜28のいずれか1項に記載の化合物、その塩、又はそれらの溶媒和物の、医薬製造のための使用。
- 医薬がβアミロイド蛋白の産生及び/又は分泌異常に起因する疾患の予防又は治療薬である、請求項33に記載の使用。
- βアミロイド蛋白の産生及び/又は分泌異常に起因する疾患がアルツハイマー病又はダウン症である、請求項34に記載の使用。
- 請求項1〜28のいずれか1項記載の化合物、その塩、又はそれらの溶媒和物を有効量投与することを特徴とするβアミロイド蛋白の産生及び/又は分泌異常に起因する疾患の処置方法。
- βアミロイド蛋白の産生及び/又は分泌異常に起因する疾患がアルツハイマー病又はダウン症である、請求項36に記載の処置方法。
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AU2009253812A1 (en) * | 2008-06-04 | 2009-12-10 | Ambrilia Biopharma Inc. | HIV integrase inhibitors from pyridoxine |
EP2593434A1 (en) | 2010-07-16 | 2013-05-22 | Purdue Pharma LP | Pyridine compounds as sodium channel blockers |
WO2013136170A1 (en) | 2012-03-16 | 2013-09-19 | Purdue Pharma L.P. | Substituted pyridines as sodium channel blockers |
WO2014096941A1 (en) | 2012-12-20 | 2014-06-26 | Purdue Pharma L.P. | Cyclic sulfonamides as sodium channel blockers |
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NO20075080L (no) | 2007-11-05 |
EP1867636A4 (en) | 2010-06-02 |
JP5039543B2 (ja) | 2012-10-03 |
HK1115123A1 (en) | 2008-11-21 |
ES2413705T9 (es) | 2013-09-19 |
RU2404968C2 (ru) | 2010-11-27 |
IL186107A0 (en) | 2008-01-20 |
US8114886B2 (en) | 2012-02-14 |
AU2006234441B2 (en) | 2011-07-07 |
BRPI0610532A2 (pt) | 2010-06-29 |
RU2007141412A (ru) | 2009-05-20 |
CA2603320A1 (en) | 2006-10-19 |
WO2006109729A1 (ja) | 2006-10-19 |
EP1867636A1 (en) | 2007-12-19 |
KR20070116865A (ko) | 2007-12-11 |
EP1867636B1 (en) | 2013-06-05 |
AU2006234441A1 (en) | 2006-10-19 |
NZ561961A (en) | 2010-06-25 |
US20090149439A1 (en) | 2009-06-11 |
ES2413705T3 (es) | 2013-07-17 |
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