JP2021530470A - カテプシンc阻害剤 - Google Patents
カテプシンc阻害剤 Download PDFInfo
- Publication number
- JP2021530470A JP2021530470A JP2021500105A JP2021500105A JP2021530470A JP 2021530470 A JP2021530470 A JP 2021530470A JP 2021500105 A JP2021500105 A JP 2021500105A JP 2021500105 A JP2021500105 A JP 2021500105A JP 2021530470 A JP2021530470 A JP 2021530470A
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- Japan
- Prior art keywords
- compound
- phenyl
- substituted
- cathepsin
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 150000001875 compounds Chemical class 0.000 claims abstract description 177
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- 108090000267 Cathepsin C Proteins 0.000 claims abstract description 41
- 102000001301 EGF receptor Human genes 0.000 claims abstract description 9
- 108060006698 EGF receptor Proteins 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- -1 2-oxol Chemical compound 0.000 claims description 152
- 150000003839 salts Chemical class 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000002552 dosage form Substances 0.000 claims description 15
- 239000000651 prodrug Substances 0.000 claims description 15
- 229940002612 prodrug Drugs 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
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- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 6
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
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- 230000002401 inhibitory effect Effects 0.000 claims description 3
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- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 2
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001345 alkine derivatives Chemical class 0.000 claims description 2
- RIYVKHUVXPAOPS-UHFFFAOYSA-N dithiine Chemical compound S1SC=CC=C1 RIYVKHUVXPAOPS-UHFFFAOYSA-N 0.000 claims description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- WUHLVXDDBHWHLQ-UHFFFAOYSA-N pentazole Chemical compound N=1N=NNN=1 WUHLVXDDBHWHLQ-UHFFFAOYSA-N 0.000 claims description 2
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- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- YYMWVZQRBNARFZ-UHFFFAOYSA-M sodium;2-[2,3-bis(sulfanyl)propoxy]ethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCOCC(S)CS YYMWVZQRBNARFZ-UHFFFAOYSA-M 0.000 claims description 2
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
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- 150000003852 triazoles Chemical class 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- 239000007787 solid Substances 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000002360 preparation method Methods 0.000 description 49
- 239000000243 solution Substances 0.000 description 36
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 29
- 230000000694 effects Effects 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
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- 239000012074 organic phase Substances 0.000 description 24
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 23
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 20
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- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
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- 125000002619 bicyclic group Chemical group 0.000 description 15
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 15
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- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 9
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 125000006413 ring segment Chemical group 0.000 description 8
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Images
Classifications
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- C07D213/00—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
- C07D213/02—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
- 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
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- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C07—ORGANIC CHEMISTRY
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Description
下記式:
Xは、O、SまたはNR5であり;
Arは、置換または無置換の5〜6員のアリールまたはヘテロアリールであり;
R1は、置換または無置換のエテニルまたはエチニルであり;
R2およびR3は、それぞれ独立して、置換されていてもよく、ヘテロ原子を含んでいてもよく、環状であってもよいC1〜C18ヒドロカルビル、または置換されていてもよいヘテロ原子であり;
R4およびR5は、それぞれ独立して、H、置換されていてもよく、ヘテロ原子を含んでいてもよく、環状であってもよいC1〜C18ヒドロカルビル、または置換されていてもよいヘテロ原子であり;
n1およびn2は、それぞれ独立して、0、1、2または3である)
で示される化合物、またはその薬学的に許容される塩、水和物もしくは立体異性体
を提供する。
XはOであり;
Arは、置換もしくは無置換の、ピロール、アゾール(たとえば、ピラゾール、イミダゾール、トリアゾール、テトラゾール、ペンタゾール、オキサゾール、イソオキサゾール、チアゾールもしくはイソチアゾール)、フラン、ジオキソール、チオフェン、ジチオールもしくはオキサチオールであるか、好ましくは2位の置換基、たとえば、2−アゾール、2−ピロール、2−アゾール(たとえば、2−ピラゾール、2−イミダゾール、2−オキサゾール、2−イソオキサゾール、2−チアゾールもしくは2−イソチアゾール)、2−フラン、2−チオフェン、2−オキソール、ジオキソールもしくは2−チオールであるか、置換もしくは無置換の、フェニル、ピリジン、ピラン、塩類、ジアジン、オキサジン、チアジン、ジオキシン、ジチインもしくはトリアジンであり;
R1は、それぞれフッ素化されていてもよい、エテニル、エチニル、プロペニル、2−メチルプロペニルもしくはプロピンであり;
R2およびR3は、それぞれ独立して、それぞれフッ素化されていてもよい、ハロゲン(たとえば、F、Cl、Br)、CN、もしくは置換されていてもよいC1〜C4のアルキル、アルケニル、アルキニルもしくはアルキルオキシ(たとえば、メチル、CF3、メトキシ、エチニル、ジメチルアミン、ピロリジニル、モルホリニル、ピペリジニル、フェニル、3−ヒドロキシルピロリジニル、3−ヒドロキシルピペリジニル、4−メチルピペラジニルもしくはフェニル)であり;かつ/または
R4およびR5は、それぞれ独立して、それぞれフッ素化されていてもよい、H、置換されていてもよいC1〜C4のアルキル、アルケニルもしくはアルキニル、もしくはCN(たとえば、メチル、CF3もしくはベンジル)である。
特にArは、
R’、R’’およびR’’’は、それぞれ独立して、水素、無置換の(C1〜C8)アルキルもしくはヘテロアルキル、1〜3個のハロゲンで置換された(C1〜C8)アルキルもしくはヘテロアルキル、無置換のアリール、1〜3個のハロゲンで置換されたアリール、無置換のアルキル基、無置換のアルコキシ基、無置換のチオアルコキシ基、またはアリール−(C1〜C4)アルキル基であり、
好ましい置換基は、ハロゲン、−R’、−OR’、=O、−NR’R’’、−SR’、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’’CO2R’、−NR’−SO2NR’’R’’’、−S(O)R’、−SO2R’、−SO2NR’R’’、−NR’’SO2R、−CN、−NO2、パーフルオロ(C1〜C4)アルコキシおよびパーフルオロ(C1〜C4)アルキル(R’およびR’’は前記で定義したとおりである)から選択される。
該化合物のEGFRに対するIC50は、カテプシンCに対するIC50の少なくとも3倍、10倍、100倍または1000倍である。
6−(3−アミノフェノキシ)−5−クロロ−N−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)ピリジン−2−アミン(63mg、0.14mmol)とトリエチルアミン(30μl、0.21mmol)のジクロロメタン(2mL)溶液に、塩化アクリロイル(14mg、0.16mmol)を0℃で滴下した。反応混合物を0℃で1時間撹拌した。水とジクロロメタンを反応溶液に加え、分離後、水相をジクロロメタンで2回抽出した。合わせた有機相を食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機相をろ過後、減圧下で濃縮した。得られた残渣をジクロロメタン(2mL)とTFA(0.25mL)の混合溶媒に溶解させ、表題化合物のTFA塩を得た。ジクロロメタンと過剰なTFAを減圧下で除去し、残渣をメタノールに溶解させ、0.15‰TFAを含有するアセトニトリルを溶離液として用いた逆相HPLCにより精製した。生成物を含む画分を減圧下で濃縮して溶媒を除き、表題化合物(20mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.71 (bs, 1H), 8.23 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 2.4 Hz, 1H), 7.40-7.35 (m, 2H), 6.86 (dd, J = 8.0, 2.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 6.07 (dd, J = 8.8, 2.8 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.66 (bs, 2H), 3.48 (bs, 2H), 3.13 (bs, 2H), 2.83 (bs, 2H), 2.86 (s, 3H). HRMS C26H28ClN5O3 (M + H)+ calculated mass, 494.1959; found, 494.1972.
N−(3−((3−クロロ−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.71 (bs, 1H), 8.23 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 2.4 Hz, 1H), 7.40-7.35 (m, 2H), 6.86 (dd, J = 8.0, 2.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 6.07 (dd, J = 8.8, 2.8 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.66 (bs, 2H), 3.48 (bs, 2H), 3.13 (bs, 2H), 2.83 (bs, 2H), 2.86 (s, 3H). HRMS C26H28ClN5O3 (M + H)+ calculated mass, 494.1959; found, 494.1972.
N−(3−((3−クロロ−6−((4−モルホリノフェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程bにおいて4−モルホリノアニリンを用いて調製することにより、表題化合物(20mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.09 (s, 1H), 7.67-7.61 (m, 2H), 7.54 (t, J = 2.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.13 (bs, 2H), 6.89 (dd, J = 8.0, 2.4 Hz, 1H), 6.67 (bs, 2H), 6.47 (s, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.73 (bs, 4H), 2.98 (bs, 4H). HRMS C24H24ClN4O3 (M + H)+ calculated mass, 451.1537; found, 451.1521.
N−(3−((3−クロロ−6−(フェニルアミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程bにおいてアニリンを用いて調製した。工程dにいて、粗生成物をシリカゲルクロマトグラフィーで精製することにより、表題化合物(22mg)を灰色固体として得た。1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.4, 0.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.46 (s, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.19-7.13 (m, 4H), 6.98-6.95 (m, 2H), 6.46-6.40 (m, 2H), 6.22 (dd, J = 16.8, 10.0 Hz, 1H), 5.77 (d, J = 10.0 Hz, 1H). HRMS C20H17ClN3O2 (M + H)+ calculated mass, 366.1009; found, 366.1019.
N−(3−((3−クロロ−6−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程bにおいて4−(4−メチルピペラジン−1−イル)アニリンを用いて調製することにより、表題化合物(8mg)を灰色固体として得た。1H NMR (400 MHz, MeOH) δ 7.82 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.91 (dd, J = 8.0, 2.0 Hz, 1H), 6.42-6.38 (m, 3H), 5.78 (dd, J = 9.6, 2.8 Hz, 1H), 3.59 (t, J = 14.0 Hz, 4H), 3.27-3.20 (m, 2H), 2.96 (s, 3H), 2.92-2.87 (m, 2H). HRMS C25H27ClN5O2 (M + H)+ calculated mass, 464.1853; found, 464.1866.
N−(3−((6−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
逆相HPLCにより化合物4を精製した際に、化合物5が同時に得られた。1H NMR (400 MHz, MeOH) δ 7.67 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.40-7.36 (m, 2H), 7.27 (bs, 2H), 6.75 (bs, 2H), 6.89 (dd, J = 8.0, 2.4 Hz, 1H), 6.46-6.33 (m, 3H), 6.24 (s, 1H), 5.77 (dd, J = 9.6, 2.4 Hz, 1H), 6.42-6.38 (m, 3H), 5.78 (dd, J = 9.6, 2.8 Hz, 1H), 3.64-3.56 (m, 4H), 3.27-3.20 (m, 2H), 2.96 (s, 3H), 2.92-2.88 (m, 2H). HRMS C25H28N5O2 (M + H)+ calculated mass, 430.2243; found, 430.2249.
N−(3−((6−((3−(アミノメチル)フェニル)アミノ)−3−クロロピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、(3−アミノベンジル)カルバミン酸tert−ブチルを用いて工程bを実施した後、工程cおよび工程dを実施することにより調製して、(3−((6−(3−アクリルアミドフェノキシ)−5−クロロピリジン−2−イル)アミノ)ベンジル)カルバミン酸tert−ブチル(中間体6d、MS m/z: 495.50 (M+1))を得た。次に、中間体7dをジクロロメタンとTFAの混合溶媒(2:1)に溶解させ、得られた混合物を室温で2時間撹拌した。混合物を蒸発乾固し、メタノールに溶解させ、0.15‰TFAを含有するアセトニトリルを溶離液として用いた逆相HPLCにより精製して、表題化合物(13mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.39 (s, 1H), 8.03 (s,2H), 7.76 (d, J = 8.8 Hz, 1H), 7.58-7.57 (m, 1H), 7.55-7.54 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.97-6.94 (m, 1H), 6.87 (t, J = 8.0 Hz, 1H), 6.60 (t, J = 8.4 Hz, 1H), 6.40 (dd, J = 16.8, 10.0 Hz, 1H), 6.24 (dd, J = 17.2, 2.0 Hz, 1H), 5.76 (dd, J = 10.0, 2.0 Hz, 1H), 3.74 (s, 2H). HRMS C21H20ClN4O2 (M + H)+ calculated mass, 395.1275; found, 395.1284.
N−(3−((3−クロロ−6−((4−(ピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物6の調製(スキーム1)に従い、工程bにおいて4−(4−アミノフェニル)ピペラジン−1−カルボン酸tert−ブチルを用いて調製することにより、表題化合物(10mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.11 (s, 1H), 8.76 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.65-7.63 (m, 1H), 7.49 (t, J = 2.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 9.2 Hz, 2H), 6.91-6.88 (m, 1H), 6.63 (d, J = 9.2 Hz, 2H), 6.47 (d, J = 8.4 Hz, 1H), 6.43 (dd, J = 16.8, 10.0 Hz, 1H),6.26 (dd, J = 16.8, 2.4 Hz, 1H), 5.77 (dd, J = 10.0, 2.4 Hz, 1H), 3.21-3.18 (m, 4H), 3.15-3.12 (m, 4H). HRMS C24H25ClN5O2 (M + H)+ calculated mass, 450.1697; found, 450.1704.
(E)−N−(3−((3−クロロ−6−((4−(ピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)ブタ−2−エナミド
化合物7の調製(スキーム1)に従い、工程dにおいて塩化(E)−ブタ−2−エノイルを用いて調製することにより、表題化合物(9mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.61 (dd, J = 8.0, 2.0 Hz, 1H), 7.48 (t, J = 2.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 9.2 Hz, 2H), 6.79 (dd, J = 15.2, 7.2 Hz, 1H), 6.63 (d, J = 8.8 Hz, 2H), 6.43 (d, J = 8.4 Hz, 1H), 6.11 (dd, J = 15.2, 2.0 Hz, 1H), 5.98-5.88 (m, 1H), 5.19-5.09 (m, 1H), 3.13-3.12 (m, 4H), 3.11-3.10 (m, 4H), 1.86 (dd, J = 6.8, 1.6 Hz, 1H). HRMS C25H27ClN5O2 (M + H)+ calculated mass, 464.1853; found, 464.1852.
(R)−N−(3−((6−((4−(3−アミノピペリジン−1−イル)−2−メトキシフェニル)アミノ)−3−クロロピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物6の調製(スキーム1)に従い、工程bにおいて(R)−(1−(4−アミノ−3−メトキシフェニル)ピペリジン−3−イル)カルバミン酸tert−ブチルを用いて調製することにより、表題化合物(18mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.21 (s, 1H), 7.93 (bs, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.61-7.59 (m, 1H), 7.46 (t, J = 2.0 Hz, 1H), 7.36 (m, 2H), 6.88-6.85 (m, 1H), 5.62 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 17.2, 2.0 Hz, 1H), 6.08 (dd, J = 8.8, 2.8 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.35-3.32 (m, 2H), 3.13-3.09 (m, 1H), 2.90-2.81 (m, 2H), 1.89-1.80 (m, 2H), 1.61-1.52 (m, 2H). HRMS C26H29ClN5O3 (M + H)+ calculated mass, 494.1959; found, 494.1955.
N−(3−((6−((4−(2−アミノエチル)フェニル)アミノ)−3−クロロピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物6の調製(スキーム1)に従い、工程bにおいて(4−アミノフェネチル)カルバミン酸tert−ブチルを用いて調製することにより、表題化合物(11mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.26 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.72 (s, 2H), 7.64-761 (m,1H), 7.51 (s, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.21-7.18 (m, 2H), 6.93-6.90 (m, 1H), 6.86-6.84 (m, 2H), 6.54 (d, J = 8.4 Hz, 1H), 6.41 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 17.2, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 2.92 (bs, 2H), 2.67 (t, J = 8.0 Hz, 2H). HRMS C22H22ClN4O2 (M + H)+ calculated mass, 409.1431; found, 409.1437.
実施例1(スキーム1)に従い、工程bにおいて3−メトキシ−4−(4−メチルピペラジン−1−イル)アニリンを用いて調製することにより、表題化合物(13mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.53 (s, 1H), 9.22 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.59-7.56 (m, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.88-6.85 (m, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.40 (dd, J = 17.2, 10.0 Hz, 1H), 6.25 (dd, J = 17.2, 2.0 Hz, 1H), 5.76 (dd, J = 10.0, 2.4 Hz, 1H), 3.44 (d, J = 12.0 Hz, 2H), 3.40 (s, 3H), 3.30 (d, J = 12.8 Hz, 2H), 3.18-3.10 (m, 2H), 2.84-2.73 (m, 5H). HRMS C26H29ClN5O3 (M + H)+ calculated mass, 494.1959; found, 494.1967.
N−(3−((3−クロロ−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)−3−メチルブタ−2−エナミド
実施例1(スキーム1)に従い、工程dにおいて塩化3−メチルブタ−2−エノイルを用いて調製することにより、表題化合物(16mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53-7.49 (m, 1H), 7.43 (t, J = 2.4 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.79-6.77 (m, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 5.85 (t, J = 1.6 Hz, 1H), 3.78 (s, 3H), 3.03 (bs, 4H), 2.28 (bs, 4H), 2.13 (s, 3H), 1.86-1.84 (m, 3H), 1.74 (s, 3H). HRMS C28H33ClN5O3 (M + H)+ calculated mass, 522.2272; found, 522.2275.
3−(トリメチルシリル)プロピオル酸(1.1当量)を無水ジクロロメタンに溶解させ、塩化オキサリル(1.44当量)を0℃で滴下後、DMFを1滴加えた。反応混合物を室温で2時間撹拌した。過剰な塩化オキサリルを減圧下で除去し、残渣をジクロロメタンに溶解させて次の変換工程に使用した。窒素雰囲気下において、この中間体2c(1当量)とトリエチルアミン(1.5当量)を25mLの三つ口フラスコに順に入れた。このフラスコに、塩化3−(トリメチルシリル)プロピオロイルのジクロロメタン溶液を0℃で滴下した。反応混合物を0℃で1時間撹拌した。反応混合物に飽和炭酸水素ナトリウム溶液を0℃で加え、水相をジクロロメタンで2回抽出した。合わせた有機相を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機相をろ過後、減圧下で濃縮した。LC-MS m/z: 564.73 (M+1)
N−(3−((3−クロロ−6−((4−(4−(シクロプロピルメチル)ピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物7(30mg、0.067mmol)をDMF(2mL)に溶解させ、炭酸カリウム(18mg、0.13mmol)と(ブロモメチル)シクロプロパン(9mg、0.067mmol)を加えた。混合物を70℃で4時間撹拌した。水と酢酸エチルを反応混合物に加え、分離後、水相を酢酸エチルで3回抽出した。合わせた有機相を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。有機相をろ過後、減圧下で濃縮した。得られた残渣をジクロロメタン(2mL)とTFA(0.25mL)の混合溶媒に溶解させ、表題化合物のTFA塩を得た。ジクロロメタンと過剰なTFAを減圧下で除去し、残渣をメタノールに溶解させ、0.15‰TFAを含有するアセトニトリルを溶離液として用いた逆相HPLCにより精製して、表題化合物(5mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.55 (s, 1H), 9.09 (s, 1H), 7.68-7.64 (m, 2H), 7.47 (t, J = 2.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 9.2 Hz, 2H), 6.91-6.88 (m, 1H), 6.65 (d, J = 9.2 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 6.42 (dd, J = 17.2, 10.0 Hz, 1H), 6.26 (dd, J = 17.2, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.60 (d, J = 11.6 Hz, 2H), 3.15-3.06 (m, 4H), 2.86 (t, J = 12.0 Hz, 2H), 1.12-1.06 (m, 1H), 0.70-0.65 (m, 2H), 0.41-0.37 (m, 2H). HRMS C28H31ClN5O2 (M + H)+ calculated mass, 504.2166; found, 504.2181.
N−(3−((3−クロロ−6−((4−(4−(シクロペンチルメチル)ピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物14の調製に従い、最終工程において(ブロモメチル)シクロペンタンを用いて調製することにより、表題化合物(7mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.09 (s, 1H), 7.68-7.64 (m, 2H), 7.47 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.54-7.51 (m, 2H), 6.91-6.88 (m, 1H), 6.64 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 6.43 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.57-3.54 (m, 2H), 3.38-3.28 (m, 2H), 3.17-3.14 (m, 2H), 2.94-2.88 (m, 2H), 1.87-1.81 (m, 2H), 1.65-1.52 (m, 4H), 1.28-1.21 (m, 5H). HRMS C30H35ClN5O2 (M + H)+ calculated mass, 532.2479; found, 532.2522.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(トリフルオロメチル)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程aにおいて2,6−ジクロロ−3−(トリフルオロメチル)ピリジンを用いて調製することにより、表題化合物(20mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.66-7.64 (m, 1H), 7.55 (t, J = 2.4 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.92-6.89 (m, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 8.8 Hz, 1H), 6.41 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 6.00 (dd, J = 8.8, 2.4 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.80 (s, 3H), 3.01 (t, J = 4.8 Hz, 4H), 2.42 (t, J = 4.8 Hz, 4H), 2.21 (s, 3H). HRMS C27H29F3N5O3 (M + H)+ calculated mass, 528.2222; found, 528.2232.
N−(3−((3−シアノ−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程aにおいて2,6−ジクロロニコチノニトリルを用いて調製することにより、表題化合物(19mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.31 (s, 1H), 7.59-7.57 (m, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 2.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.85-6.82 (m, 1H), 6.54 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 6.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.76 (dd, J = 10.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.00 (t, J = 4.8 Hz, 4H), 2.41 (t, J = 4.8 Hz, 4H), 2.21 (s, 3H). HRMS C27H29N6O3 (M + H)+ calculated mass, 485.2301; found, 485.2312.
N−(5−((3−クロロ−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例1(スキーム1)に従い、工程aにおいて4−メチル−3−ニトロフェノールを用いて調製することにより、表題化合物(16mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.18 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 8.0, 2.4 Hz, 1H), 6.60-6.58 (m, 2H), 6.57 (dd, J = 16.8, 10.0 Hz, 1H), 6.23 (dd, J = 17.2, 2.0 Hz, 1H), 6.11 (dd, J = 8.8, 2.8 Hz, 1H), 5.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.71 (bs, 2H), 3.49 (bs, 2H), 3.14 (bs, 2H), 2.86 (bs, 5H), 2.27 (s, 3H). HRMS C27H31ClN5O3 (M + H)+ calculated mass, 508.2115; found, 508.2112.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2(スキーム2)に従い、工程aにおいて3−ニトロフェノールを用い、工程bにおいてピロリジンを用いて調製することにより、表題化合物(14mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.69 (s, 1H), 7.57-7.53 (m, 1H), 7.40-7.35 (m, 2H), 6.89-6.85 (m, 1H), 6.64-6.59 (m, 2H), 6.07-6.00 (m, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H), 3.50 (d, J = 12.0 Hz, 4H), 3.12 (bs, 2H), 2.87-2.77 (m, 5H), 1.99 (bs, 4H). HRMS C30H37N6O3 (M + H)+ calculated mass, 529.2927; found, 529.2923.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
逆相HPLCにより化合物20を精製した際に、化合物21が同時に得られた。1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.00 (s, 1H), 7.57-7.49 (m, 3H), 7.46-7.44 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.84-6.81 (m, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.42 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz, 1H), 6.21 (d, J = 8.0 Hz, 1H), 6.18 (dd, J = 8.8, 2.4 Hz, 1H), 5.76 (dd, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H), 3.70 (d, J = 13.2 Hz, 2H), 3.50 (d, J = 12.0 Hz, 2H), 3.18-3.09 (m, 2H), 2.87-2.82 (m, 5H). HRMS C26H30N5O3 (M + H)+ calculated mass, 460.2349; found, 460.2361.
N−(3−((3−(ジメチルアミノ)−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2(スキーム2)に従い、工程aにおいて3−ニトロフェノールを用い、工程bにおいてジメチルアミンを用いて調製することにより、表題化合物(20mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.57-7.54 (m, 1H), 7.50 (s, 1H), 7.46 (t, J = 2.4 Hz, 1H), 7.37-7.33 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 6.82-6.79 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 16.8, 10.0 Hz, 1H), 6.24 (dd, J = 16.8, 2.0 Hz, 1H), 6.02 (dd, J = 8.8, 2.4 Hz, 1H), 6.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.75 (s, 3H), 2.97 (t, J = 5.2 Hz, 1H), 2.69 (s, 6H), 2.43 (t, J = 5.2 Hz, 1H), 2.22 (s, 3H). HRMS C28H35N6O3 (M + H)+ calculated mass, 503.2771; found, 503.2770.
N−(3−(ベンジル(6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)アミノ)フェニル)アクリルアミド
化合物24の調製に従い、ヨードメタンの代わりに(ブロモメチル)ベンゼンを用いて調製することにより、表題生成物(16mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.53-7.48 (m, 3H), 7.31-7.25 (m, 4H), 7.21-7.17 (m, 2H), 6.98-6.95 (m, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.39 (dd, J = 16.8, 9.6 Hz, 1H), 6.22 (dd, J = 16.8, 2.0 Hz, 1H), 6.17 (d, J = 8.0 Hz, 1H), 6.14 (dd, J = 8.8, 2.4 Hz, 1H), 5.93 (d, J = 8.0 Hz, 1H), 5.73 (dd, J = 10.0, 2.0 Hz, 1H), 5.14 (s, 2H), 3.78 (s, 3H), 3.04 (bs, 4H), 2.48 (bs, 4H), 2.25 (s, 3H). HRMS C33H37N6O2 (M + H)+ calculated mass, 549.2978; found, 549.2986.
N−(3−((6−(ベンジル(4−(ピペラジン−1−イル)フェニル)アミノ)−3−クロロピリジン−2−イル)オキシ)フェニル)アクリルアミド
化合物26の調製に従い、ヨードメタンの代わりに(ブロモメチル)ベンゼンを用いて調製することにより、表題生成物(16mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.70 (bs, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.38-7.35 (m, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.12-7.08 (m, 2H), 7.06-7.03 (m, 2H), 7.00-6.97 (m, 2H), 6.87-6.83 (m, 3H), 6.44 (dd, J = 16.8, 10.0 Hz, 1H), 6.28 (dd, J = 16.8, 2.0 Hz, 1H), 5.94 (d, J = 8.4 Hz, 1H), 5.79 (dd, J = 10.0, 2.0 Hz, 1H), 4.71 (s, 2H), 3.78 (s, 3H), 3.32 (bs, 4H), 3.22 (bs, 4H). LC-MS C31H31ClN5O2 (M + H) + calculated mass, 540.2166; found, 540.61.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.54 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.32-7.28 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.62-6.55 (m, 3H), 6.23 (dd, J = 17.2, 2.0 Hz, 1H), 6.09 (dd, J = 8.8, 2.4 Hz, 1H), 5.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.72 (d, J = 12.8 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.42 (bs, 2H), 3.18-3.10 (m, 2H), 2.87 (s, 3H), 2.91-2.84 (m, 2H), 2.28 (s, 3H), 1.86 (bs, 4H), 1.59 (bs, 2H). HRMS C32H40N6O3 (M + H)+ calculated mass, 557.3240; found, 557.3245.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2(スキーム2)に従い、工程bにおいてピロリジンを用いて調製することにより、表題化合物(25mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.0, 2.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 6.21 (dd, J = 17.2, 2.0 Hz, 1H), 6.05 (dd, J = 8.8, 2.4 Hz, 1H), 5.73 (dd, J = 10.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.17 (t, J = 6.0 Hz, 1H), 3.00 (t, J = 5.2 Hz, 1H), 2.43 (t, J = 5.2 Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.86-1.83 (m, 4H). HRMS C31H39N6O3 (M + H)+ calculated mass, 543.3084; found, 543.3088.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−モルホリノピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2(スキーム2)に従い、工程bにおいてモルホリンを用いて調製することにより、表題化合物(23mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.32-7.23 (m, 3H), 6.83 (dd, J = 8.4, 2.8 Hz, 1H), 6.58 (dd, J = 17.6, 10.8 Hz, 1H), 6.53-6.51 (m, 2H), 6.21 (dd, J = 17.2, 2.0 Hz, 1H), 6.02 (dd, J = 8.8, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.0 Hz, 1H), 3.75 (s, 3H), 3.70 (t, J = 4.8 Hz, 4H), 3.02 (bs, 4H), 2.95 (t, J = 4.8 Hz, 4H), 2.46 (bs, 4H), 2.27 (s, 3H), 2.24 (s, 3H). HRMS C31H38N6O4 (M + H)+ calculated mass, 559.3033; found, 559.3063.
N−(5−((3−(3−ヒドロキシピロリジン−1−イル)−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
N−(5−((3−(3−ヒドロキシピペリジン−1−イル)−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(4−メチルピペラジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2(スキーム2)に従い、工程bにおいて1−メチルピペラジンを用いて調製することにより、表題化合物(18mg)を灰色固体として得た。1H NMR (400 MHz, MeOH) δ 7.51 (s, 1H), 7.39 (s, 1H), 7.31-7.28 (m, 2H), 6.91 (dd, J = 8.0, 2.4 Hz, 1H), 6.64-6.58 (m, 1H), 6.52 (dd, J = 16.8, 10.4 Hz, 1H), 6.53-6.46 (m, 1H), 6.35 (dd, J = 16.8, 2.0 Hz, 1H), 6.25-6.17 (m, 1H), 5.79 (dd, J = 10.4, 2.0 Hz, 1H), 3.84 (s, 3H), 3.56-3.52 (m, 4H), 3.49-3.46 (m, 4H), 3.24-3.19 (m, 4H), 2.97 (s, 3H), 2.94 (s, 3H), 2.33 (s, 3H). HRMS C32H42N7O3 (M + H)+ calculated mass, 572.3349; found, 572.3361.
N−(5−((6−((2−メトキシ−6−(4−メチルピペラジン−1−イル)ピリジン−3−イル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
N−(5−((6−((4−(4−アセチルピペラジン−1−イル)−2−メトキシフェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2に従い、工程cにおいて1−(4−(4−アミノ−3−メトキシフェニル)ピペラジン−1−イル)エタン−1−オンを用いて調製することにより、表題化合物(25mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.26-7.23 (m, 1H), 6.96 (s, 1H), 6.64-6.57 (m, 2H), 6.61 (dd, J = 16.8, 10.0 Hz, 1H), 6.23 (dd, J = 17.2, 2.0 Hz, 1H), 6.06 (d, J = 8.0 Hz, 1H), 5.76 (dd, J = 10.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.57-3.55 (m, 4H), 3.06-3.01 (m, 4H), 2.30 (s, 3H), 2.05 (s, 3H), 1.88 (bs, 4H), 1.53 (bs, 2H). LC-MS C33H41N6O4 (M + H)+ calculated mass, 585.3189; found, 585.44.
N−(5−((6−((4−(4−(ジメチルアミノ)ピペリジン−1−イル)−2−メトキシフェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
N−(2−メチル−5−((6−((4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2に従い、工程cにおいて4−(4−メチルピペラジン−1−イル)アニリンを用いて調製することにより、表題化合物(13mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.58 (s, 1H), 7.49 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 6.58 (dd, J = 16.8, 10.0 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 6.22 (dd, J = 16.8, 2.0 Hz, 1H), 5.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.61 (d, J = 12.8 Hz, 2H), 3.51 (d, J = 12.0 Hz, 2H), 3.18-3.10 (m, 2H), 2.86-2.80 (m, 5H), 2.30 (s, 3H), 1.81 (bs, 4H), 1.57 (bs, 2H). HRMS C31H39N6O2 (M + H)+ calculated mass, 527.3134; found, 527.3146.
N−(2−メトキシ−5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2に従い、工程aにおいて4−メトキシ−3−ニトロフェノールを用い、工程bにおいてピロリジンを用いて調製することにより、表題化合物(8mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.07-8.03 (m, 1H), 7.45-7.40 (m, 1H), 7.12-7.08 (m, 1H), 6.90-6.86 (m, 1H), 6.75 (dd, J = 16.8, 10.0 Hz, 1H), 6.61-6.55 (m, 2H), 6.20 (dd, J = 17.2, 2.0 Hz, 1H), 6.08-6.04 (m, 1H), 5.72 (dd, J = 10.0, 2.0 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.52-3.49 (m, 4H), 3.13-3.08 (m, 4H), 2.87-2.80 (m, 5H), 1.96 (bs, 4H). HRMS C31H39N6O4 (M + H)+ calculated mass, 559.3033; found, 559.3047.
N−(2−メトキシ−5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
逆相HPLCにより化合物39を精製した際に、化合物40が同時に得られた。1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.92 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 8.8, 2.8 Hz, 1H), 6.75 (dd, J = 16.8, 10.0 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.22 (dd, J = 8.8, 2.4 Hz, 1H), 6.20 (dd, J = 16.8, 2.0 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 5.71 (dd, J = 10.0, 2.0 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.73 (d, J = 13.2 Hz, 2H), 3.51 (d, J = 12.8 Hz, 2H), 3.19-3.11 (m, 2H), 2.91-2.84 (m, 5H). HRMS C27H32N5O4 (M + H)+ calculated mass, 490.2454; found, 490.2463.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2に従い、工程aにおいて2−メチル−3−ニトロフェノールを用い、工程bにおいてピロリジンを用いて調製することにより、表題化合物(12mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.28-7.21 (m, 2H), 6.96-6.90 (m, 1H), 6.67-6.54 (m, 2H), 6.61 (dd, J = 17.2, 10.0 Hz, 1H), 6.28 (dd, J = 17.8, 2.0 Hz, 1H), 6.12-6.06 (m, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.52-3.49 (m, 4H), 3.16-3.07 (m, 2H), 2.87-2.80 (m, 5H), 2.06 (s, 3H), 1.98 (bs, 4H). HRMS C31H39N6O3 (M + H)+ calculated mass, 543.3084; found, 543.3085.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)−4−メチルフェニル)アクリルアミド
実施例2に従い、工程aにおいて2−メチル−5−ニトロフェノールを用い、工程bにおいてピロリジンを用いて調製することにより、表題化合物(13mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.64 (s, 1H), 7.58-7.55 (m, 1H), 7.39-7.22 (m, 3H), 6.67-6.54 (m, 2H), 6.39 (dd, J = 16.8, 10.0 Hz, 1H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 6.04-5.94 (m, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.51-3.48 (m, 4H), 3.15-3.07 (m, 2H), 2.86 (d, J = 4.4 Hz, 3H), 2.82-2.79 (m, 2H), 2.09 (s, 3H), 1.95 (bs, 4H). HRMS C31H38N6O3 (M + H)+ calculated mass, 543.3084; found, 543.3091.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
逆相HPLCにより化合物29を精製した際に、化合物43が同時に得られた。1H NMR (400 MHz, MeOH) δ 7.64 (s, 1H), 7.49 (s, 1H), 7.29-7.28 (m, 2H), 6.93 (dd, J = 8.0, 2.4 Hz, 1H), 6.68-6.63 (m, 1H), 6.51 (dd, J = 16.8, 10.0 Hz, 1H), 6.35 (dd, J = 16.8, 2.0 Hz, 1H), 6.24-6.15 (m, 1H), 5.79 (dd, J = 10.0, 2.0 Hz, 1H), 3.91-3.81 (bs, 4H), 3.64-3.57 (bs, 4H), 2.97 (s, 3H), 2.30 (s, 3H). HRMS C27H32N5O3 (M + H)+ calculated mass, 474.2505; found, 474.2515.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピロリジン−1−イル)ピリジン−2−イル)オキシ)−2−(トリフルオロメチル)フェニル)アクリルアミド
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−(トリフルオロメチル)フェニル)アクリルアミド
化合物44の調製に従い、ピロリジンの代わりにピペリジンを用いて調製することにより、表題化合物(30mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.64 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.38-7.30 (m, 2H), 7.22 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.54 (dd, J = 17.2, 10.0 Hz, 1H), 6.23 (dd, J = 17.2, 2.0 Hz, 1H), 6.12 (d, J = 9.2 Hz, 1H), 5.78 (dd, J = 10.4, 2.0 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J = 13.2 Hz, 2H), 3.52 (d, J = 4.8 Hz, 2H), 3.16-3.08 (m, 2H), 2.89-2.82 (m, 5H), 1.67 (bs, 4H), 1.51 (bs, 2H). HRMS C32H38F3N6O3 (M + H)+ calculated mass, 611.2957; found, 611.2964.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)−3−メチルブタ−2−エナミド
実施例2に従い、工程eにおいて塩化3−メチルブタ−2−エノイルを用いて調製することにより、表題化合物(13mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.39 (s, 1H), 7.32-7.25 (m, 3H), 6.91-6.90 (m, 1H), 6.60-6.56 (m, 2H), 6.08 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.71 (d, J = 13.2 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.18-3.12 (m, 2H), 3.09 (s, 3H), 2.87 (s, 3H), 2.86 (s, 3H), 2.25 (s, 3H), 1.83 (bs, 4H), 1.85-1.76 (m, 7H), 1.55 (bs, 2H). LC-MS C34H45N6O3 (M + H)+ calculated mass, 585.3553; found, 585.54.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)ブタ−2−インアミド
6−(3−アミノ−4−メチルフェノキシ)−N−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)−5−(ピペリジン−1−イル)ピリジン−2−アミン(中間体2d、60mg、0.12mmol)とブタ−2−イン酸(11mg、0.13mmol)からなる混合物の無水アセトニトリル(3mL)溶液を室温で10分間撹拌した。混合物にDMTMM(36mg、0.13mmol)を加え、室温で一晩撹拌した。溶媒を除去し、反応溶液に水を室温で加えた後、ジクロロメタンで3回抽出した。合わせた有機相を食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過後、減圧下で濃縮した。得られた残渣をジクロロメタン(2mL)とTFA(0.25mL)の混合溶媒に溶解させ、表題化合物のTFA塩を得た。ジクロロメタンと過剰なTFAを減圧下で除去し、残渣をメタノールに溶解させ、0.15‰TFAを含有するアセトニトリルを溶離液として用いた逆相HPLCにより精製して、表題化合物(22mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.81 (s, 1H), 7.28-7.20 (m, 3H), 6.94 (s, 1H), 6.60-6.56 (m, 2H), 6.09 (d, J = 8.8 Hz, 1H), 3.77 (s, 3H), 3.72 (d, J = 13.2 Hz, 2H), 3.54-3.51 (m, 2H), 3.18-3.10 (m, 2H), 2.90-2.84 (m, 5H), 2.24 (s, 3H), 2.04 (s, 3H), 1.77 (bs, 4H), 1.55 (bs, 2H). LC-MS C33H41N6O3 (M + H)+ calculated mass, 569.3240; found, 569.54.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)プロピオールアミド
2−フルオロ−N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
化合物47の調製に従い、工程eにおいて2−フルオロアクリル酸を用いて調製することにより、表題化合物(21mg)を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 10.05 (s, 1H), 7.76 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.31-7.29 (m, 1H), 7.21 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.61-6.57 (m, 2H), 6.14 (d, J = 8.8 Hz, 1H), 5.68 (dd, J = 48.0, 3.6 Hz, 1H), 5.43 (dd, J = 15.6, 3.6 Hz, 1H), 3.78 (s, 3H), 3.72 (d, J = 12.8 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.17-3.09 (m, 2H), 3.92 (d, J = 12.8 Hz, 2H), 2.85 (s, 3H), 2.24 (s, 3H), 1.86 (bs, 4H), 1.59 (bs, 2H). LC-MS C32H40FN6O3 (M + H)+ calculated mass, 575.3146; found, 575.17.
N−(5−((3−クロロ−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−(トリフルオロメチル)フェニル)アクリルアミド
実施例1(スキーム1)に従い、工程aにおいて3−ニトロ−4−(トリフルオロメチル)フェノールを用いて調製することにより、表題化合物を灰色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.73 (s, 1H), 8.33 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 6.54 (dd, J = 16.8, 10.0 Hz, 1H), 6.24 (dd, J = 16.8, 2.0 Hz, 1H), 6.13 (dd, J = 8.8, 2.4 Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.73-3.69 (m, 2H), 3.53-3.50 (m, 2H), 3.17-3.10 (m, 2H), 2.91-2.88 (m, 2H), 2.86 (s, 3H). HRMS C27H28ClF3N5O3 (M + H)+ calculated mass, 562.1833; found, 562.1862.
N−(5−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)−2−(トリフルオロメチル)フェニル)アクリルアミド
逆相HPLCにより化合物50を精製した際に、化合物51が同時に得られた。1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.79 (s, 1H), 8.10 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.54 (dd, J = 16.8, 10.0 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 6.21 (dd, J = 8.8, 2.4 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.79 (s, 3H), 3.72 (d, J = 13.6 Hz, 2H), 3.52 (d, J = 12.0 Hz, 2H), 3.18-3.10 (m, 2H), 2.91-2.84 (m, 2H), 2.87 (s, 3H). HRMS C27H29F3N5O3 (M + H)+ calculated mass, 528.2222; found, 528.2271.
N−(3−((6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2(スキーム2)に従い、工程aにおいて3−ニトロフェノールを用いて調製することにより、表題化合物を褐色固体として得た。1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.91 (s, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.44 (dd, J = 16.8, 10.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 6.05 (d, J = 8.8 Hz, 1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H), 3.67 (d, J = 13.2 Hz, 2H), 3.51 (d, J = 12.0 Hz, 2H), 3.16-3.09 (m, 2H), 2.86 (s, 3H), 2.84-2.81 (m, 2H), 1.83 (bs, 4H), 1.58 (bs, 2H). HRMS C31H38N6O3 (M + H)+ calculated mass, 543.3084; found, 543.3133.
N−(3−((3−(アゼパン−1−イル)−6−((2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニル)アミノ)ピリジン−2−イル)オキシ)フェニル)アクリルアミド
実施例2(スキーム2)に従い、工程aにおいて3−ニトロフェノールを用い、工程bにおいてアゼパンを用いて調製することにより、表題化合物を褐色固体として得た。工程bの反応条件:t−BuONa、キサントホス、Pd2(dba)3、トルエン、110℃、一晩。工程cの反応条件:Cs2CO3、DavePhos、Pd2(dba)3、1,2−ジメトキシエタン、90℃、一晩。1H NMR (400 MHz, MeOD) δ 7.84 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.60 (bs, 1H), 8.44 (dd, J = 16.8, 9.6 Hz, 1H), 6.37 (dd, J = 16.8, 2.4 Hz, 1H), 6.13 (bs, 1H), 5.80 (dd, J = 9.6, 2.4 Hz, 1H), 3.83 (bs, 4H), 3.59 (d, J = 12.0 Hz, 2H), 3.25-3.19 (m, 2H), 2.97 (s, 3H), 2.13 (bs, 4H), 1.87 (bs, 4H). HRMS C32H41N6O3 (M + H)+ calculated mass, 557.3240; found, 557.3273.
N−(5−((6−((2−メトキシ−4−(ピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
実施例2(スキーム2)に従い、工程cにおいて4−(4−アミノ−3−メトキシフェニル)ピペラジン−1−カルボン酸tert−ブチルを用いて調製することにより、4−(4−((6−(3−アクリルアミド−4−メチルフェノキシ)−5−(ピペリジン−1−イル)ピリジン−2−イル)アミノ)−3−メトキシフェニル)ピペラジン−1−カルボン酸tert−ブチルを得た後、TFAを用いたBOCの脱保護工程を実施して、表題化合物を得た。1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.81 (s, 1H), 7.51 (s, 1H), 7.32-7.28 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.62-6.56 (m, 3H), 6.23 (dd, J = 16.8, 2.0 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz, 1H), 6.07 (d, J = 9.6 Hz, 1H), 5.75 (dd, J = 10.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.45 (bs, 4H), 2.29 (s, 3H), 1.84 (bs, 4H), 1.58 (bs, 2H). HRMS C31H39N6O3 (M + H)+ calculated mass, 543.3084; found, 543.3109.
N−(5−((6−((5−(4−(ジメチルアミノ)ピペリジン−1−イル)ピリジン−2−イル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
N−(5−((6−((2−メトキシ−4−(4−(プロパ−2−イン−1−イル)ピペラジン−1−イル)フェニル)アミノ)−3−(ピペリジン−1−イル)ピリジン−2−イル)オキシ)−2−メチルフェニル)アクリルアミド
化合物14の調製における最終工程に従い、化合物7の代わりに化合物54を使用し、(ブロモメチル)シクロプロパンの代わりに3−ブロモプロパ−1−インを用いて調製することにより、表題化合物を得た。1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.47 (s, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.29-7.23 (m, 2H), 6.83 (dd, J = 8.4, 2.4 Hz, 1H), 6.58 (dd, J = 17.2, 10.0 Hz, 1H), 6.52-6.50 (m, 2H), 6.22 (dd, J = 17.2, 2.0 Hz, 1H), 6.02 (dd, J = 8.8, 2.8 Hz, 1H), 5.73 (dd, J = 10.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.19 (t, J = 2.4 Hz, 1H), 3.03 (t, J = 5.2 Hz, 2H), 2.90 (t, J = 5.2 Hz, 2H), 2.58 (t, J = 5.2 Hz, 2H), 2.27 (s, 3H), 1.64-1.59 (m, 4H), 1.51-1.45 (m, 2H). HRMS C34H45N6O3 (M + H)+ calculated mass, 581.3240; found, 581.3262.
黒色の384ウェルプレートにおいてカテプシンC(CatC)酵素アッセイを行った。まず、活性化バッファー(25mM MES、5mM DTT、pH6.0)中において、rhCatL(300nM)を使用して室温で2時間処理することによりrhCatC(440nM)を活性化させ、アッセイバッファー(25mM MES、50mM NaCl、5mM DTT、0.01%(v/v)Triton X100、pH6.0)を使用して、活性化されたrhCatCを4.4nMに希釈した。各化合物を1μL含む10%DMSO溶液または10%DMSOと活性化されたrhCatC 14μlを室温で3時間インキュベートした後、基質(Gly-Phe-AFC)5μlを最終濃度100μMとなるように加えた。60分間反応させた後、Enspireプレートリーダーにおいて、励起波長(Ex)λ=400nmおよび蛍光波長(Em)λ=505nmとして、反応生成物中のAFCの蛍光を測定した。アストラゼネカ社製の標準的な不可逆的CatC阻害剤10(J. Med. Chem. 2014,57,2357-2367)をアッセイの阻害剤コントロールとして使用した。
C57BL/6マウス(20〜25g)を無作為に4つの群(n=10)に分け、1ケージ当たり5匹を入れて飼育した。化合物31を6.7mg/kg/日、20mg/kg/日または60mg/kg/日の用量で1日2回、6日間にわたり経口投与した。また、条件を一致させた群に、溶媒コントロール(100mMクエン酸バッファー中0.5%Methocel(商標)および0.1%Tween80、pH3)を1日2回、6日間にわたり投与した。マウスの体重を毎日測定し、測定した体重に応じて用量を調節した。また、Sprague Dawleyラット(280〜300g)には、1mg/kg/日、5mg/kg/日または20mg/kg/日の用量で1日2回、8日間にわたり腹腔内注射した。投与の終了後、14時間ごとに眼穿刺法により採血した。その後、マウスを屠殺し、氷冷RPMI1640培地を用いて大腿骨と脛骨から骨髄細胞を直ちに採取した。過去に報告されているプロトコル8の変法により血液細胞と骨髄細胞を溶解させた。簡潔に述べると、50mM Tris(pH7.4)、750mM NaCl、1%(v/v)TritonX-100を含む細胞溶解バッファーを使用して、細胞溶解物を氷上で穏やかに超音波処理した。細胞溶解後、好中球セリンプロテアーゼ(NSP)の活性の分析まで上清を−80℃で保存した。
過去の報告に従って分析を行った。簡潔に述べると、様々なアッセイバッファーを用いて細胞溶解物を各タンパク質濃度に希釈した。カテプシンC(Cat C)活性の分析に使用したアッセイバッファーは、25mM MES、50mM NaCl、5mM DTT、pH6.0で構成されており、好中球エラスターゼ(NE)活性およびプロテアーゼ3(Pr3)活性の分析に使用したアッセイバッファーは、50mM Tris、750mM NaCl、pH7.4で構成されており、カテプシンG(CatG)活性の分析に使用したアッセイバッファーは、50mM Tris、750mM NaCl、5mM EDTA、pH7.4で構成されていた。血球溶解物は、骨髄溶解物よりも5倍高い濃度に希釈した。各溶解物とDMSOコントロールまたは各プロテアーゼ阻害剤(CatC活性の分析にはアストラゼネカ社製の阻害剤10を使用し、NE活性の分析にはavelestatを使用し、Pr3活性の分析にはシベレスタットを使用し、CatG活性の分析にはカテプシンG阻害剤1を使用した)を384ウェルプレートに加えた。各合成ペプチド基質(CatC活性の分析にはGly−Phe−AFC(SM Biochemicals)を使用し、NE活性の分析にはメトキシスクシニル−Ala−Ala−Pro−Val−AMC(シグマ)を使用し、Pr3活性の分析にはアミノベンゾイル−Val−Ala−Asp−Cys−Ala−Asp−Gln−エチレンジアミン2,4−ジニトロフェニル(Peptide Synthetics)を使用し、CatG活性の分析にはN−スクシニル−Ala−Ala−Pro−Phe−pNA(シグマ)を使用した)を加えた後、プレートの蛍光または吸光度を計測した。アッセイ動態は90分までモニターした。GraphPad Prism(GraphPad Software,Inc.、米国カリフォルニア州サンディエゴ)を使用してデータを解析した。
セルレイン(50μg/kg体重)を1時間ごとに8時間まで腹腔内注射することにより急性膵炎を誘導した。36匹のC57BL/6マウス(20〜25g)を無作為に4つの群(n=5)に分けた。化合物28を20mg/kgの用量で1日2回、6日間にわたり経口投与した。また、条件を一致させた群に、溶媒コントロール(100mMクエン酸バッファー中0.5%Methocel(商標)および0.1%Tween80、pH3)を1日2回、6日間にわたり投与した。6日目に、1回目の化合物の投与後にマウスに膵炎を誘導し、最後のセルレイン注射後に2回目の化合物の投与をマウスに行った。偽処置群は、セルレインの代わりに生理食塩水を投与したこと以外は溶媒コントロールと同様に処置した。最後のセルレイン注射の1時間後にマウスを屠殺した。マウスの屠殺の直後に組織を採取した。膵臓試料の一部を液体窒素で凍結し、ホモジネートを調製した。さらに、組織学的検査を行うため、膵臓を4.5%ホルマリンで固定し、パラフィン包埋し、ヘマトキシリン・エオシン染色を行った。また、血清試料を調製し、−20℃で保存した。
Claims (11)
- 下記式:
Xは、O、SまたはNR5であり;
Arは、置換または無置換の5〜6員のアリールまたはヘテロアリールであり;
R1は、置換または無置換のエテニルまたはエチニルであり;
R2およびR3は、それぞれ独立して、置換されていてもよく、ヘテロ原子を含んでいてもよく、環状であってもよいC1〜C18ヒドロカルビル、または置換されていてもよいヘテロ原子であり;
R4およびR5は、それぞれ独立して、H、置換されていてもよく、ヘテロ原子を含んでいてもよく、環状であってもよいC1〜C18ヒドロカルビル、または置換されていてもよいヘテロ原子であり;
n1およびn2は、それぞれ独立して、0、1、2または3である)
で示される化合物、またはその薬学的に許容される塩、水和物もしくは立体異性体。 - XがOであり;
Arが、置換もしくは無置換の、ピロール、アゾール(たとえば、ピラゾール、イミダゾール、トリアゾール、テトラゾール、ペンタゾール、オキサゾール、イソオキサゾール、チアゾールもしくはイソチアゾール)、フラン、ジオキソール、チオフェン、ジチオールもしくはオキサチオールであるか、好ましくは2位の置換基、たとえば、2−アゾール、2−ピロール、2−アゾール(たとえば、2−ピラゾール、2−イミダゾール、2−オキサゾール、2−イソオキサゾール、2−チアゾールもしくは2−イソチアゾール)、2−フラン、2−チオフェン、2−オキソール、ジオキソールもしくは2−チオールであるか、置換もしくは無置換の、フェニル、ピリジン、ピラン、塩類、ジアジン、オキサジン、チアジン、ジオキシン、ジチインもしくはトリアジンであり;
R1が、それぞれフッ素化されていてもよい、エテニル、エチニル、プロペニル、2−メチルプロペニルもしくはプロピンであり;
R2およびR3が、それぞれ独立して、それぞれフッ素化されていてもよい、ハロゲン(たとえば、F、Cl、Br)、CN、もしくは置換されていてもよいC1〜C4のアルキル、アルケニル、アルキニルもしくはアルキルオキシ(たとえば、メチル、CF3、メトキシ、エチニル、ジメチルアミン、ピロリジニル、モルホリニル、ピペリジニル、フェニル、3−ヒドロキシルピロリジニル、3−ヒドロキシルピペリジニル、4−メチルピペラジニルもしくはフェニル)であり;かつ/または
R4およびR5が、それぞれ独立して、それぞれフッ素化されていてもよい、H、置換されていてもよいC1〜C4のアルキル、アルケニルもしくはアルキニル、もしくはCN(たとえば、メチル、CF3もしくはベンジル)である、
請求項1に記載の化合物。 - Arが、カテプシンCと塩橋を形成する置換基、特に環状アミンまたは鎖状アミンで置換されており、該アミンの窒素原子がカテプシンCと塩橋を形成することにより、カテプシンC抑制活性が維持されている、請求項1に記載の化合物。
- 前記置換された基が、ハロゲン、−R’、−OR’、=O、=NR’、=N−OR’、−NR’R’’、−SR’、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’−C(O)NR’’R’’’、−NR’−SO2NR’’’、−NR’’CO2R’、−NH−C(NH2)=NH、−NR’C(NH2)=NH、−NH−C(NH2)=NR’、−S(O)R’、−SO2R’、−SO2NR’R’’、−NR’’SO2R、−CN、−NO2、−N3、−CH(Ph)2、パーフルオロ(C1〜C4)アルコキシおよびパーフルオロ(C1〜C4)アルキルから選択される1〜6個、好ましくは1〜3個の置換基を含み、
R’、R’’およびR’’’が、それぞれ独立して、水素、無置換の(C1〜C8)アルキルもしくはヘテロアルキル、1〜3個のハロゲンで置換された(C1〜C8)アルキルもしくはヘテロアルキル、無置換のアリール、1〜3個のハロゲンで置換されたアリール、無置換のアルキル基、無置換のアルコキシ基、無置換のチオアルコキシ基、またはアリール−(C1〜C4)アルキル基であり、
好ましい置換基が、ハロゲン、−R’、−OR’、=O、−NR’R’’、−SR’、−SiR’R’’R’’’、−OC(O)R’、−C(O)R’、−CO2R’、−CONR’R’’、−OC(O)NR’R’’、−NR’’C(O)R’、−NR’’CO2R’、−NR’−SO2NR’’R’’’、−S(O)R’、−SO2R’、−SO2NR’R’’、−NR’’SO2R、−CN、−NO2、パーフルオロ(C1〜C4)アルコキシおよびパーフルオロ(C1〜C4)アルキル(R’およびR’’は前記で定義したとおりである)から選択される、請求項1、2、3または4に記載の化合物。 - 本明細書に開示されている構造、たとえば表1、表2または表3に記載の構造を有する、請求項1に記載の化合物。
- 前記化合物が、(たとえば、IC50が30μM未満、10μM未満、3μM未満または1μM未満の)カテプシンC阻害剤であり、上皮成長因子受容体(EGFR)阻害剤ではなく、
該化合物のEGFRに対するIC50が、カテプシンCに対するIC50の少なくとも3倍、10倍、100倍または1000倍である、請求項1、2、3、4、5または6に記載の化合物。 - 請求項1、2、3、4、5、6または7に記載の化合物の治療有効量と、1種以上の薬学的に許容される添加剤とを単位剤形に含む医薬組成物。
- 請求項1、2、3、4、5、6、7または8に記載の化合物または組成物を使用して、カテプシンCを抑制する方法であって、カテプシンCの抑制を必要とする細胞またはヒトに、請求項1に記載の化合物またはそのプロドラッグの有効量を投与する工程を含む方法。
- 請求項1、2、3、4、5、6、7または8に記載の化合物または組成物を使用して、炎症を治療する方法であって、炎症の治療を必要とする細胞またはヒトに、請求項1に記載の化合物またはそのプロドラッグの有効量を投与する工程を含む方法。
- 炎症を診断する工程を前記工程の前にさらに含むか、前記工程による炎症の緩和を検出する工程を前記工程の後にさらに含む、請求項10に記載の方法。
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