JP6116554B2 - がんの処置のための置換されたアザ複素環 - Google Patents
がんの処置のための置換されたアザ複素環 Download PDFInfo
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- JP6116554B2 JP6116554B2 JP2014517492A JP2014517492A JP6116554B2 JP 6116554 B2 JP6116554 B2 JP 6116554B2 JP 2014517492 A JP2014517492 A JP 2014517492A JP 2014517492 A JP2014517492 A JP 2014517492A JP 6116554 B2 JP6116554 B2 JP 6116554B2
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- JP
- Japan
- Prior art keywords
- pyridin
- trifluoromethyl
- hal
- pyrimidin
- difluoro
- 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.)
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- 206010028980 Neoplasm Diseases 0.000 title claims description 27
- 201000011510 cancer Diseases 0.000 title claims description 19
- -1 2,1,3-thiadiazolyl Chemical group 0.000 claims description 125
- 150000001875 compounds Chemical class 0.000 claims description 117
- 238000000034 method Methods 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 17
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- 238000002360 preparation method Methods 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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- 125000003118 aryl group Chemical group 0.000 claims description 9
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
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- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
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- VSQKSAVQLJJEDW-UHFFFAOYSA-N 1-[6-[(2,4-difluorophenyl)methylamino]-2-[5-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carbonyl]piperidine-4-carboxamide Chemical compound C1CC(C(=O)N)CCN1C(=O)C1=CC(NCC=2C(=CC(F)=CC=2)F)=NC(C=2C=C(C=NC=2)C(F)(F)F)=N1 VSQKSAVQLJJEDW-UHFFFAOYSA-N 0.000 claims description 2
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- GTJGUNLWJZEFFD-UHFFFAOYSA-N 6-[(2,4-difluorophenyl)methylamino]-n-[(1-methylpyrrolidin-3-yl)methyl]-2-[5-(trifluoromethyl)pyridin-3-yl]pyrimidine-4-carboxamide Chemical compound C1N(C)CCC1CNC(=O)C1=CC(NCC=2C(=CC(F)=CC=2)F)=NC(C=2C=C(C=NC=2)C(F)(F)F)=N1 GTJGUNLWJZEFFD-UHFFFAOYSA-N 0.000 claims description 2
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
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- GRNIVLPUPCYBDK-UHFFFAOYSA-N 2-(2-amino-5-chloropyridin-3-yl)-n-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine Chemical compound NC1=NC=C(Cl)C=C1C1=NC=CC(NCC=2C(=CC(F)=CC=2)C(F)(F)F)=N1 GRNIVLPUPCYBDK-UHFFFAOYSA-N 0.000 claims 1
- PGLBIWGFOGGPMB-UHFFFAOYSA-N 2-(5-chloropyridin-3-yl)-n-[(2,4-difluorophenyl)methyl]pyrimidin-4-amine Chemical compound FC1=CC(F)=CC=C1CNC1=CC=NC(C=2C=C(Cl)C=NC=2)=N1 PGLBIWGFOGGPMB-UHFFFAOYSA-N 0.000 claims 1
- VLEPAEOPIJYCMY-UHFFFAOYSA-N 2-(5-chloropyridin-3-yl)-n-[[4-chloro-2-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC(Cl)=CC=C1CNC1=CC=NC(C=2C=C(Cl)C=NC=2)=N1 VLEPAEOPIJYCMY-UHFFFAOYSA-N 0.000 claims 1
- STHPZBUGZFHUAH-UHFFFAOYSA-N 2-(5-chloropyridin-3-yl)-n-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine Chemical compound FC(F)(F)C1=CC(F)=CC=C1CNC1=CC=NC(C=2C=C(Cl)C=NC=2)=N1 STHPZBUGZFHUAH-UHFFFAOYSA-N 0.000 claims 1
- UEYKQIXIBDETAX-UHFFFAOYSA-N 2-[2-amino-5-(trifluoromethyl)pyridin-3-yl]-n-[[2-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine Chemical compound NC1=NC=C(C(F)(F)F)C=C1C1=NC=CC(NCC=2C(=CC=CC=2)C(F)(F)F)=N1 UEYKQIXIBDETAX-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- 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
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Description
チロシンキナーゼは、細胞増殖、細胞生存、細胞移動を含む、多くの細胞過程の調節において重要な役割を演じる。あるチロシンキナーゼは、突然変異によって活性化されるようになるか、または多くのヒトがんにおいて異常に発現されることが知られている。例えば、上皮成長因子受容体(EGFR)は、乳がん、肺がん、脳がん、扁平上皮細胞がん、および他のヒトがんにおいて、突然変異および/または過剰発現されることが見出されている。EGFRのチロシンキナーゼ活性の選択的インヒビターは、突然変異および/または過剰発現されたEGFRを有するがんの処置において臨床的価値があることが示されている。よって、特定のチロシンキナーゼの選択的インヒビターは、がん等の増殖性疾患の処置において有用である。
FAKの阻害に好適なものとして記載されている化合物は、とりわけWO 08/116139、WO 09/039542およびWO 10/126922に開示されている。
本発明の目的は、過剰増殖性の疾患、特に哺乳動物におけるがん等の前記タンパク質キナーゼの機能亢進に関連するものの処置に有用な新規FAKインヒビターであって、それらの活性とそれらの溶解性、代謝クリアランスおよびバイオアベイラビリティ特性との両方に関する優れた薬理学的特性を有する該インヒビターを提供することである。
当該化合物は式(I)で定義される:
R1’、R1’’が、独立に、H、A、Hal、Cyc、CO(Cyc)であり、
R2が、H、A、Q1−(C(LA)H)n−Q2、Cycであり
R3が、H、A、−LA−Cycであり、
Aが、1個、2個、3個、4個もしくは5個のC原子を有する、非分岐または分岐の直鎖あるいは環状のアルキルであって、1個のCH2基が、O原子もしくはS原子および/または−NH−基、−CO−基、−NHCOO−基、−NHCONH−基、−CONH−基、−NHCO−基、−CH=CH−基、−N=CH−基あるいは−CH=N−基で置換されていてもよく、1〜5個のH原子が、Halで置換されていてもよく、1個のCH基が、Nで置換されていてもよく、1個のCH3基が、CNで置換されていてもよく、
Halが、F、Cl、BrまたはIであり、
Q1が、−NH−、−O−、−COO−、−CONH−、または単結合であり、
Q2が、NH2、NH(LA)、N(LA)2、CONH2、CONH(LA)、CON(LA)2、COOH、COO(LA)、Cyc、CO(Cyc)であり、
nが、0、1、2、3または4であり、
環のN原子において、O原子で置換され、N−オキシド基を形成してもよく、
二環式系の場合、一方の環が芳香族であり、他方の環が非芳香族であってもよく、
Xが、CH2、NH、Oであり、
W、Y、Zが、CHまたはNであり、W、Y、Zの少なくとも2個がCHであり、
mが、0または1であり、ならびに、
LAが、H、あるいは、1個、2個もしくは3個もしくは4個のC原子を有する非分岐または分岐の直鎖アルキルであって、1個、2個または3個のH原子が、Halで置換されていてもよい、
したがって、本発明は、特に、当該残基の少なくとも1個が以下に示される好ましい意味の1つを有する式(I)の化合物に関する。
Halは、フッ素、塩素、臭素またはヨウ素、特にフッ素または塩素を表す。
「A」はさらに、先に定義したようなアルキルを表し、その1個のCH2基は、O原子もしくはS原子および/または−NH−基、−CO−基、−NHCOO−基、−NHCONH−基、−CONH−基、−NHCO−基、−CH=CH−基、−N=CH−基あるいは−CH=N−基で置換されていてもよく、その1〜5個のH原子は、Halで置換されていてもよく、その1個のCH基は、Nで置換されていてもよく、その1個のCH2基は、CNで置換されていてもよく、
例えば、トリフルオロメチル、ペンタフルオロエチル、1,1−ジフルオロメチル、1,1,1−トリフルオロエチル、メトキシ、エトキシ、n−プロポキシ、イソプロポキシ、n−ブトキシ、イソブトキシ、sec−ブトキシもしくはtert−ブトキシ、N,N’−ジメチルアミノアルキル、2−アミノエチル、3−アミノプロピル、4−アミノブチル、5−アミノペンチル、3−アミノメチルシクロブチルまたはシアノアルキルである。
環状のAは、好ましくは、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルを表す。
より好ましくは、1,3−ベンゾジオキソール−2−、4−もしくは−5−イル、チオフェン−2−もしくは3−イル、1,4−ベンゾジオキサン−6−イル、2,1,3−ベンゾチアジアゾール−4−もしくは5−イルまたは2,1,3−ベンズオキサジアゾール−5−イル、フラン−2−もしくは3−イル、2,3−ジヒドロ−ベンゾフラン−2−、3−、4−もしくは5−イル、クロマン−2−、3−、4−、5−、6−、7−もしくは8−イル、イソインドリン−1−オン−2−、3−、4−、5−もしくは6−イル、ピラゾロ[1,5−a]ピリジン−2−、3−、4−、5−、6−もしくは7−イル、2,3−ジヒドロ−ベンゾフラン−3−、4−、5−、6−もしくは7−イル、2,3−ジヒドロ−ベンゾ[1,4]ダイオキシン−2−、3−、5−もしくは6−イルを表し、
それぞれが、非置換であるか、あるいは、例えばカルボニル酸素、F、Cl、Br、メチル、メトキシ、エチル、プロピル、フェニル、ベンジル、−CH2−シクロヘキシル、ヒドロキシル、メトキシ、トリフルオロメチル、トリフルオロメトキシ、N−メチルメタンスルホンアミジル、エトキシ、アミノ、メチルアミノ、ジメチルアミノ、ニトロ、シアノ、カルボキシル、メトキシカルボニル、アミノカルボニル、メチルアミノカルボニル、ジメチルアミノカルボニル、アセトアミノ、ウレイド、メチルスルホニルアミノ、ホルミル、アセチルアミノスルホニルおよび/もしくはメチルスルホニルで一置換、二置換または三置換されていてもよい。
それぞれが、非置換であるか、あるいは、例えばカルボニル酸素、F、Cl、Br、メチル、エチル、プロピル、フェニル、ベンジル、−CH2−シクロヘキシル、ヒドロキシル、メトキシ、エトキシ、アミノ、メチルアミノ、ジメチルアミノ、ニトロ、シアノ、カルボキシル、メトキシカルボニル、アミノカルボニル、メチルアミノカルボニル、ジメチルアミノカルボニル、アセトアミノ、ウレイド、メチルスルホニルアミノ、ホルミル、アセチルアミノスルホニルおよび/もしくはメチルスルホニルで一置換、二置換または三置換されていてもよい。
用語「置換された」は、好ましくは、前記置換基による置換に関し、別段の指示がない限り、異なる置換度を複数とり得る。
下位式1において、
Arが、フェニル、ピリジル、2,1,3−ベンゾチアジアゾリル、1,3−ベンゾジオキソリル、ピラゾロ[1,5−a]ピリジル、ピリミジル、モルホリニル、2,3−ジヒドロ−ベンゾフラニル、ピラゾリルであって、それらの全てが、非置換であっても、Hal、LA、OH、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、CN、OCN、SCN、COOH、COO(LA)、CONH2、CONH(LA)、CON(LA)2、NHCO(LA)、NHCONH(LA)、NHCONH2、NHSO2(LA)、CHO、CO(LA)、SO2NH2、SO2(LA)、SO2Hal、(X)m−Cycで一置換または二置換されていてもよく、
R3が、Hであり、
下位式3において、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
下位式4において、
R2が、Hであり、
下位式5において、
R2が、Q1−(C(LA)H)n−Q2であり、
下位式6において、
Arが、Hal、LA、OH、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、CN、OCN、SCN、COOH、COO(LA)、CONH2、CONH(LA)、CON(LA)2、NHCO(LA)、NHCONH(LA)、NHCONH2、NHSO2(LA)、CHO、CO(LA)、SO2NH2、SO2(LA)、SO2Hal、Cyc、O−Cycで独立に一置換または二置換されているフェニルであり、
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジンであり、
下位式8において、
Arが、F、Cl、メチルまたはCF3で、オルト位および/もしくはパラ位に、独立して一置換または二置換されているフェニルであり、
下位式9において、
R2が、Hであり、
R3が、Hであり、
下位式10において、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Hであり、
R3が、Hであり、
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジルであり、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Hであり、
R3が、Hであり、
下位式12において、
R2が、Q1−(CH2)n−Q2であり、
下位式13において、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Q1−(CH2)n−Q2であり、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Q1−(CH2)n−Q2であり、
R3が、Hであり、
下位式15において、
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジルであり、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Q1−(CH2)n−Q2であり、
R3が、Hであり、
下位式16において、
Arが、Fで、オルト位およびパラ位に二置換されているフェニルであり、
R1’が、CF3であり、
R1’’が、Hであり、
R2が、Q1−(CH2)n−Q2であり、
R3が、Hである、
ならびに、残りの残基は、先の式(I)において示されたような意味を有する。
本発明に従う化合物のラセミ体または立体異性体の薬学的な活性が異なり得るため、鏡像異性体を使用することが望ましいと考えられる。これらの場合、最終生成物または中間体でさえも、当業者に知られている化学的または物理的な手段によって鏡像異性体の化合物に分けることができ、また、合成過程においてそのようなものとして利用することもできる。
必要に応じて、同位体は、当該技術分野に周知の方法により、例えば液体クロマトグラフィにより、分離することができる。同じことが、例えばキラル固定相を使用することによって、鏡像異性体に適用される。加えて、鏡像異性体は、それらをジアステレオマーに変換すること、すなわち、鏡像的に純粋な補助化合物と結合させ、続いて得られたジアステレオマーを分離し、補助残基を切断することによって単離してもよい。代わりに、本発明の化合物のエナンチオマーのいずれも、光学的に純粋な出発材料を使用する立体選択的合成から得られる。
用語「薬学的に許容し得る塩」は、無機塩基または無機酸および有機塩基または有機酸を含む薬学的に許容し得る塩基または酸から調製される塩を指す。本発明の化合物が1個または2個以上の酸性基または塩基性基を含む場合、本発明はまた、それらの対応する薬学的に許容し得る塩も含む。よって、酸性基を含む本発明の化合物は、塩の形態で存在し、本発明に従い、例えば、アルカリ金属塩、アルカリ土類金属塩として、またはアンモニウム塩として使用することができる。かかる塩のより明確な例としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、あるいは、アンモニアまたは例えばエチルアミン、エタノールアミン、トリエタノールアミンもしくはアミノ酸等の有機アミンとの塩が挙げられる。1個または2個以上の塩基性基、すなわち水素化され得る基を含む本発明の化合物は、塩の形態で存在し、本発明に従い、無機酸または有機酸とのそれらの付加塩の形態で使用され得る。
a)本化合物の全ての立体異性体もしくは互変異生体、または、それらの混合物、
b)本化合物、または、これらのプロドラッグの立体異性体もしくは互変異生体のプロドラッグ、
c)本化合物ならびに(a)および(b)の下で言及した事項の薬学的に許容し得る塩、
d)本化合物ならびに(a)、(b)および(c)の下で言及した事項の溶媒和物。
化合物への全ての言及は、これらの事項、とりわけ本化合物の溶媒和物または薬学的に許容し得るそれらの塩の溶媒和物を含むことは理解されるべきである。
医薬組成物は、経口の、直腸への、局所的な、非経口の(皮下、筋肉内および静脈内を含む)、目(眼)への、肺への(鼻または口からの吸入)、または経鼻の投与に好適な組成物を含むが、所定の場合のいずれかの中で最も好適な経路は、処置される条件の性質および重篤性、ならびに活性成分の性質によるだろう。それらは、単位用量の便利な形態で存在してもよく、薬学の技術分野において周知な方法のいずれでも都合よく調製することができる。
本発明はまた、FAKの機能亢進に関する過剰増殖性の疾患、ならびに哺乳動物においてFAKカスケードにより調節される疾患、またはがんおよび炎症等の異常増殖によってもたらされる障害の処置のための医薬の調製のための、本発明に従う化合物の使用にも関する。
a)本発明に従う化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物の有効量、ならびに、
b)さらなる医薬活性成分の有効量
の別個のパックからなるセット(キット)にも関する。
セットは、好適な、箱等の容器、個々の瓶、バッグまたはアンプルを含む。
例として、セットは、別個のアンプルを含んでもよく、それぞれは、溶解されるか、または凍結乾燥された形態で、本発明に従う化合物の有効量と、さらなる医薬活性成分の有効量とを含む。
本願中に登場し得るいくつか略記は以下のとおりである:
略記
さらに、当該技術分野における通常の技術と併せて、本明細書に記載の手順を利用することにより、本明細書にクレームされる本発明の追加の化合物は容易に調製することができる。しかしながら、例において実証された化合物が、本発明と考えられる1つの属しか形成しないとの解釈はなされるものではない。例はさらに、本発明の化合物の調製について詳細に実証する。当業者は、以下の調製手順の条件および過程における知られている変動が、これらの化合物を調製するために使用され得ることは、容易に理解する。
本発明はまた、以下に記載のスキームおよび実施例に従って、式(I)、(II)、(III)、(IV)または(V)ならびに下位式1〜16の化合物を製造するための方法にも関する。
スキーム1
式中、ボロン酸の酸素原子と繋がったRが、H、LA(先に記載したとおり、メチルまたはイソプロピル等)、または1,1,2,2−テトラメチルエチル(ボロン酸ピナコールエステルを生じる)等のアルキル鎖であり、他の全ての置換基は、式(I)で定義したような意味を有する。
DMF/H2Oの1:1混合物中の3当量のNa2CO3、触媒量のテトラキストリフェニルホスフィンと、ボロン酸5(0.5equiv)との、40℃、12hのスズキ反応により、対称的に2つが結合した微量の副生成物と5の異性体しか得られない。5は、クロマトグラフィにより未反応の出発材料からも分離することができる。6〜7と5との反応は、様々な条件下で行うことができ、そのままで、もしくはDMFのような溶媒中、最高120℃まで反応物を単に加熱するか、または、トルエンのような溶媒中でのパラジウム触媒のいずれかで行える。
化合物番号1〜55および148〜273を全て精製し、以下の方法を使用して特徴付けた。
LCMS
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
HPLC
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
カラム:Xterra 2.1×30 3.5um
フロー:400uL/min
温度:室温
溶媒A:水+0.1%TFA
溶媒B:アセトニトリル+0.1%TFA
勾配:3.2分間Bを15〜95%、1.4分間95%で保持
ランタイム:7分間
波長:254nm
質量範囲:100〜900ダルトン
カラム:Xbridge C8、4.6×50mm 5um
移動相A:水+0.1%TFA
移動相B:ACN+0.1%TFA
勾配:8分間Bを2〜100%
フロー:2mL/min
波長:254nm
質量走査:100〜900Da
カラム:Xbridge C18、4.6×50mm 5um
移動相A:水+0.1%TFA
移動相B:ACN+0.1%TFA
勾配:3.5分間Bを5〜95%
フロー:0.8mL/min
波長:254nm
質量走査:100〜900Da
下に示す実施例は、本発明の特定の態様を実証することを目的としており、明細書またはクレームの範囲を限定することを目的としては決してない。
化学合成
このセクションは、式(I)に従う多数の例示化合物およびそれらの合成中間体について実験の詳細を提供するものである。
基本プロトコール:
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.4
LCMS:Mass found (+MS, 286)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.56面積%:99.03(maxで)、99.45(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.58面積%:99.58(maxで)、99.83(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.36 (brs, 1H), 8.25-7.93 (m, 1H), 7.15-7.11 (m, 1H), 7.02-6.97 (m, 1H), 6.50 (d, J = 5.96 Hz, 1H), 4.48-4.41 (m, 2H), 3.84 (s, 3H).
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.3
LCMS:Mass found (+MS, 330)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):4.63面積%:98.73(maxで)、98.10(254nmで)。
HPLC:>98%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):4.55面積%:98.42(maxで)、98.04(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.49-8.35 (m, 1H), 8.05-7.91 (m, 1H), 7.34-7.30 (m, 2H), 7.24-7.18 (m, 2H), 7.06-7.00 (m, 2H), 6.96 (d, J = 8.52 Hz, 2H), 6.49 (d, J = 5.84 Hz, 1H), 4.47-4.45 (m, 2H).
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.4
LCMS:Mass found (+MS, 272)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.93面積%:98.20(maxで)、99.01(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.81面積%:99.30(maxで)、99.25(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.39 (t, J = 5.36 Hz, 1H), 7.94 (d, J = 5.56 Hz, 1H), 7.44 (dd, J = 10.04, 2.04 Hz, 1H), 7.40-7.36 (m, 1H), 7.27 (dd, J = 8.28, 1.88 Hz, 1H), 6.52 (d, J = 5.80 Hz, 1H), 4.50 (d, J = 4.88 Hz, 2H).
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.3
LCMS:Mass found (+MS, 290)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):4.00面積%:98.05(maxで)、99.43(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):4.00面積%:99.61(maxで)、99.63(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.35-8.20 (m, 1H), 8.00-7.90 (m, 1H), 7.08 (d, J = 7.20 Hz, 1H), 7.00 (d, J = 7.40 Hz, 1H), 6.76 (t, J = 7.48 Hz, 1H), 6.52-6.42 (m, 1H), 4.36-4.21 (m, 2H), 3.00 (s, 2H), 1.41 (s, 6H).
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.5
LCMS:Mass found (+MS, 314)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.19面積%:96.86(maxで)、98.78(254nmで)。
HPLC:>96%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.05面積%:96.54(maxで)、98.26(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.53 (d, J = 1.28 Hz, 1H), 8.40-8.39 (m, 1H), 8.37 (d, J = 2.64 Hz, 1H), 8.19-8.18 (m, 1H), 8.00-7.92 (m, 1H), 7.41 (t, J = 7.88 Hz, 1H), 7.20 (d, J = 7.76 Hz, 1H), 7.14 (s, 1H), 7.11-7.09 (m, 1H), 6.51 (d, J = 5.72 Hz, 1H), 4.53-4.52 (m, 2H).
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 305)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):2.15面積%:96.87(maxで)、98.74(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):2.15面積%:99.87(maxで)、99.62(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.42-8.25 (m, 1H), 7.99-7.88 (m, 1H), 7.18 (d, J = 8.56 Hz, 2H), 6.90 (d, J = 8.52 Hz, 2H), 6.47 (d, J = 5.64 Hz, 1H), 4.38-4.30 (m, 2H), 2.71 (t, J = 4.84 Hz, 4H), 3.05 (t, J = 4.76 Hz, 4H).
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.5
LCMS:Mass found (+MS, 286)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.24面積%:99.72(maxで)、99.79(254nmで)。
HPLC:>98%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.14面積%:98.15(maxで)、99.57(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.48-8.44 (m, 2H), 7.94 (d, J = 5.72 Hz, 1H), 7.82 (s, 1H), 7.73-7.71 (m, 2H), 7.45 (t, J = 7.92 Hz, 1H), 7.24 (d, J = 7.56 Hz, 1H), 6.54-6.53 (m, 2H), 4.58-4.46 (m, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.3
LCMS:Mass found (+MS, 278)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.12面積%:97.86(maxで)、98.16(254nmで)。
HPLC:>98%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.04面積%:98.95(maxで)、98.21(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.43-8.27 (m, 1H), 7.95-7.89 (m, 1H), 6.81-6.75 (m, 3H), 6.47 (d, J = 5.84 Hz, 1H), 4.35 (d, J = 5.36 Hz, 2H), 4.20 (s, 4H).
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.4
LCMS:Mass found (+MS, 184.0)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):2.28面積%:99.02(maxで)、99.32(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):2.27面積%:99.33(maxで)、99.07(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.02 (brs, 1H), 7.86 (d, J = 5.76 Hz, 1H), 6.44 (d, J = 5.84 Hz, 1H), 3.14-3.11 (m, 2H), 1.04-0.96 (m, 1H), 0.47-0.43 (m, 2H), 0.23-0.19 (m, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.5
LCMS:Mass found (+MS, 226.2)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.75面積%:99.56(maxで)、99.80(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):2.28面積%:99.13(maxで)、99.06(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 7.87-7.83 (m, 2H), 6.43 (d, J = 5.92 Hz, 1H), 3.11 (t, J = 6.20, 2H), 1.71-1.59 (m, 5H), 1.22-1.15 (m, 4H), 0.92-0.86 (m, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.5
LCMS:Mass found (+MS, 220)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.14面積%:99.75(maxで)、99.50(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.13面積%:99.81(maxで)、99.39(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.37 (s, 1H), 7.92 (d, J = 5.60 Hz, 1H), 7.36-7.24 (m, 5H), 6.51 (d, J = 5.64 Hz, 1H), 4.49 (d, J = 5.16 Hz, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.5
LCMS:Mass found (+MS, 238)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.32面積%:98.65(maxで)、99.10(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.36面積%:99.25(maxで)、99.08(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.37 (brs, 1H), 7.93 (d, J = 5.76 Hz, 1H), 7.39-7.31 (m, 2H), 7.22-7.16 (m, 2H), 6.52 (d, J = 5.64 Hz, 1H), 4.52 (d, J = 5.20 Hz, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.5
LCMS:Mass found (+MS, 238.0)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.30面積%:97.62(maxで)、99.24(254nmで)。
HPLC:>99%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.24面積%:99.00(maxで)、99.40(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.37 (s, 1H), 7.92 (d, J = 5.36 Hz, 1H), 7.37-7.33 (m, 2H), 7.19-7.14 (m, 2H), 6.50 (d, J = 6.16 Hz, 1H), 4.47 (d, J = 5.40 Hz, 2H).
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.5
LCMS:Mass found (+MS, 256.0)
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min。
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.48面積%:97.51(maxで)、98.99(254nmで)。
HPLC:>97%
方法:A−水中0.1%TFA、B−ACN中0.1%TFA;流速:2ml/min
カラム:XBridge C8(50×4.6mm、3.5μ)
Rt(min):3.41面積%:97.89(maxで)、98.48(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.39 (t, J = 5.36 Hz, 1H), 7.95 (d, J = 5.52 Hz, 1H), 7.30-7.24 (m, 1H), 7.20-7.15 (m, 2H), 6.53 (d, J = 5.92 Hz, 1H), 4.51 (d, J = 4.96 Hz, 2H).
基本プロトコール:
スターラーバーを有する10mlのマイクロ波バイアルに、クロロ−ピリジン中間体(1equiv)、それぞれのボロン酸(1.5equiv)、酢酸パラジウム(0.05equiv)、2−ジシクロヘキシルホスフィノ−2’,6’−ジメトキシビフェニル(0.15equiv)および炭酸カリウム(5equiv)を加えた。試薬をジオキサン(3ml)/水(0.5ml)中に懸濁し、マイクロ波反応器中120℃で45分間処理した。反応物を室温まで冷却し、水(30ml)およびEtOAc(50ml)で希釈し、EtOAc(30ml)で抽出した。合わせた有機層を水(50ml)およびブライン溶液で洗浄した後、無水硫酸マグネシウムで乾燥し、蒸発させた。残渣をカラムクロマトグラフィで精製し、最終化合物を得た。いくつかの場合において、分取HPLCを、最終化合物を精製するために使用した。
(2,3−ジフルオロ−4−メトキシ−ベンジル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.4
LCMS:Mass found (+MS, 359)
Rt(min):3.16面積%:98.12(maxで)、97.40(254nmで)。
HPLC:>97%
Rt(min):3.17面積%:97.68(maxで)、97.17(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.03 (d, J=1.6 Hz, 1H), 8.36 (d, J = 2.92 Hz, 1H), 8.25-8.19 (m, 1H), 8.15-8.10 (m, 1H), 8.08-8.07 (m, 1H), 7.19 (t, J = 7.76 Hz, 1H), 7.00-6.95 (m, 1H), 6.52 (d, J = 5.88 Hz, 1H), 4.63 (brs, 2H), 3.89 (s, 3H), 3.82 (s, 3H).
[4−(4−フルオロ−フェノキシ)−ベンジル]−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.3
LCMS:Mass found (+MS, 403.3)
Rt(min):3.98面積%:97.05(maxで)、97.62(254nmで)。
HPLC:>97%
Rt(min):3.99面積%:97.29(maxで)、97.35(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.02 (s, 1H), 8.36 (d, J = 2.84 Hz, 1H), 8.19-8.18 (m, 1H), 8.10 (t, J = 5.84 Hz, 1H), 8.06 (s, 1H), 7.39 (d, J = 8.32 Hz, 2H), 7.19 (t, J = 8.72 Hz, 2H), 7.03-6.99 (m, 2H), 6.95 (d, J = 8.48 Hz, 2H), 6.51 (d, J = 5.00 Hz, 1H), 4.62 (brs, 2H), 3.87 (s, 3H).
[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−[3−(ピラジン−2−イルオキシ)−ベンジル]−アミン
TLC:CHCl3/MeOH(9/1):Rf:0.4
LCMS:Mass found (+MS, 387.3)
Rt(min):2.79面積%:94.44(maxで)、96.00(254nmで)。
HPLC:>94%
Rt(min):2.78面積%:94.89(maxで)、95.35(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.00 (s, 1H), 8.50 (s, 1H), 8.33 (s, 2H), 8.17-8.12 (m, 3H), 8.03 (s, 1H), 7.40 (t, J = 7.84 Hz, 1H), 7.28 (d, J = 7.56 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J = 7.96 Hz, 1H), 6.52 (d, J = 4.68 Hz, 1H), 4.67 (brs, 2H), 3.85 (s, 3H).
[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−モルホリン−4−イル−ベンジル)−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 378)
Rt(min):2.20面積%:97.47(maxで)、95.91(254nmで)。
HPLC:>94%
Rt(min):2.21面積%:97.32(maxで)、94.93(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.03 (s, 1H), 8.36 (d, J = 2.92 Hz, 1H), 8.16 (brs, 1H), 8.08-8.07 (m, 1H), 8.05-7.96 (m, 1H), 7.25 (d, J = 8.40 Hz, 2H), 6.90 (d, J = 8.72 Hz, 2H), 6.48 (d, J = 5.08 Hz, 1H), 4.54 (brs, 2H), 3.88 (s, 3H), 3.70 (t, J = 4.92 Hz, 4H), 3.04 (t, J = 4.80 Hz, 4H).
[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−(3−ピラゾール−1−イル−ベンジル)−アミン
TLC:CHCl3/MeOH(9/1):Rf:0.4
LCMS:Mass found (+MS, 359.3)
Rt(min):2.86面積%:93.69(maxで)、93.01(254nmで)。
HPLC:>92%
Rt(min):2.86面積%:93.29(maxで)、92.91(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.01 (d, J=1.36 Hz, 1H), 8.45 (d, J = 2.40 Hz, 1H), 8.34 (d, J = 2.72 Hz, 1H), 8.22-8.19 (m, 2H), 8.04 (s, 1H), 7.91 (s, 1H), 7.71-7.68 (m, 2H), 7.44 (t, J = 7.88 Hz, 1H), 7.32 (d, J = 7.60 Hz, 1H), 6.55-6.52 (m, 2H), 4.71 (brs, 2H), 3.83 (s, 3H).
(2,3−ジヒドロ−ベンゾ[1,4]ダイオキシン−6−イルメチル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.3
LCMS:Mass found (+MS, 351)
Rt(min):2.80面積%:97.74(maxで)、95.87(254nmで)。
HPLC:>94%
Rt(min):2.83面積%:94.72(maxで)、96.83(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.03 (s, 1H), 8.36 (d, J = 2.84 Hz, 1H), 8.17 (brs, 1H), 8.07-8.02 (m, 2H), 6.88-6.78 (m, 3H), 6.49 (d, J = 4.72 Hz, 1H), 4.51 (brs, 2H), 4.18 (s, 4H), 3.89 (s, 3H).
[4−(4−フルオロ−フェノキシ)−ベンジル]−[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.4
LCMS:Mass found (+MS, 391)
Rt(min):4.11面積%:98.76(maxで)、98.47(254nmで)。
HPLC:>97%
Rt(min):4.12面積%:98.50(maxで)、97.81(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.28 (t, J = 1.56 Hz, 1H), 8.67 (d, J = 2.84 Hz, 1H), 8.32 (dd, J = 10.02, 1.64 Hz, 1H), 8.20-8.13 (m, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.22-7.17 (m, 2H), 7.03-6.99 (m, 2H), 6.98-6.94 (m, 2H), 6.54 (d, J = 5.84 Hz, 1H), 4.64 (brs, 2H).
(2,2−ジメチル2,3−ジヒドロ−ベンゾフラン−7−イルメチル)−[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.3
LCMS:Mass found (+MS, 351.3)
Rt(min):3.71面積%:97.04(maxで)、97.77(254nmで)。
HPLC:>96%
Rt(min):3.70面積%:96.27(maxで)、98.78(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.28 (s, 1H), 8.66 (d, J = 2.80 Hz, 1H), 8.31-8.28 (m, 1H), 8.18 (d, J = 5.12 Hz, 1H), 8.05 (t, J = 6.00 Hz, 1H), 7.05 (d, J = 7.20 Hz, 2H), 6.74 (t, J = 7.44 Hz, 1H), 6.55-6.54 (m, 1H), 4.54 (brs, 2H), 3.00 (s, 2H), 1.44 (s, 6H).
[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−[3−(ピラジン−2−イルオキシ)−ベンジル]−アミン
TLC:CHCl3/MeOH(9/1):Rf:0.5
LCMS:Mass found (+MS, 375)
Rt(min):2.84面積%:92.75(maxで)、96.57(254nmで)。
HPLC:>92%
Rt(min):2.89面積%:92.00(maxで)、96.14(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.26 (t, J = 1.52 Hz, 1H), 8.65 (d, J = 2.68 Hz, 1H), 8.50 (d, J=1.08 Hz, 1H), 8.33-8.28 (m, 2H), 8.21-8.19 (m, 2H), 8.11 (s, 1H), 7.40 (t, J = 7.84 Hz, 1H), 7.28 (d, J = 7.64 Hz, 1H), 7.22 (s, 1H), 7.08 (dd, J = 7.98, 1.68 Hz, 1H), 6.55 (d, J = 5.80 Hz, 1H), 4.68 (brs, 2H).
[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−モルホリン−4−イル−ベンジル)−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 366)
Rt(min):2.26面積%:96.60(maxで)、98.58(254nmで)。
HPLC:>98%
Rt(min):2.26面積%:98.02(maxで)、98.03(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.30 (s, 1H), 8.67 (d, J = 2.88 Hz, 1H), 8.34 (d, J = 9.72 Hz, 1H), 8.18 (d, J = 4.88 Hz, 1H), 8.06 (brs, 1H), 7.25 (d, J = 8.40 Hz, 2H), 6.90 (d, J = 8.72 Hz, 2H), 6.52 (d, J = 5.24 Hz, 1H), 4.56 (brs, 2H), 3.70 (t, J = 4.92 Hz, 4H), 3.04 (t, J = 4.84 Hz, 4H).
[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−(3−ピラゾール−1−イル−ベンジル)−アミン
収率:19.82%
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 347)
Rt(min):2.96面積%:98.88(maxで)、99.53(254nmで)。
HPLC:>98%
Rt(min):2.98面積%:98.67(maxで)、99.63(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.28 (d, J=1.44 Hz, 1H), 8.65 (d, J = 2.56 Hz, 1H), 8.46 (d, J = 2.44 Hz, 1H), 8.35-8.31 (m, 1H), 8.26-8.21 (m, 2H), 7.92 (s, 1H), 7.71-7.69 (m, 2H), 7.45 (t, J = 7.88 Hz, 1H), 7.32 (d, J = 7.60 Hz, 1H), 6.58 (d, J = 5.08 Hz, 1H), 6.53-6.52 (m, 1H), 4.74 (brs, 2H).
(2,3−ジヒドロ−ベンゾ[1,4]ダイオキシン−6−イルメチル)−[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.3
LCMS:Mass found (+MS, 339)
Rt(min):2.90面積%:95.46(maxで)、96.88(254nmで)。
HPLC:>97%
Rt(min):2.94面積%:97.58(maxで)、97.30(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.29 (s, 1H), 8.67 (d, J = 2.84 Hz, 1H), 8.34-8.31 (m, 1H), 8.19 (brs, 1H), 8.07 (brs, 1H), 6.87-6.78 (m, 3H), 6.52 (d, J = 5.16 Hz, 1H), 4.53 (brs, 2H), 4.18 (s, 4H).
(5−{4−[4−(4−フルオロ−フェノキシ)−ベンジルアミノ]−ピリミジン−2−イル}−ピリジン−3−イル)−モルホリン−4−イル−メタノン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 486.3)
Rt(min):3.63面積%:97.12(maxで)、97.24(254nmで)。
HPLC:>95%
Rt(min):3.70面積%:95.92(maxで)、97.14(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.45 (d, J = 2.00 Hz, 1H), 8.69 (d, J = 2.08 Hz, 1H), 8.54-8.53 (m, 1H), 8.20 (d, J = 4.32 Hz, 1H), 8.13 (t, J = 5.84 Hz, 1H), 7.39 (d, J = 8.52 Hz, 2H), 7.22-7.17 (m, 2H), 7.03-7.00 (m, 2H), 6.97-6.94 (m, 2H), 6.53 (d, J = 4.44 Hz, 1H), 4.64 (brs, 2H), 3.65-3.53 (m, 8H).
モルホリン−4−イル−{5−[4−(4−モルホリン−4−イル−ベンジルアミノ)−ピリミジン−2−イル]−ピリジン−3−イル}−メタノン
TLC:CHCl3/MeOH(9/1):Rf:0.4
LCMS:Mass found (+MS, 461.2)
Rt(min):2.02面積%:99.33(maxで)、99.78(254nmで)。
HPLC:>99%
Rt(min):2.00面積%:99.48(maxで)、99.60(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.46 (s, 1H), 8.69 (d, J = 2.12 Hz, 1H), 8.54 (t, J = 2.04 Hz, 1H), 8.18 (brs, 1H), 8.04 (brs, 1H), 7.24 (d, J = 8.52 Hz, 2H), 6.90 (d, J = 8.72 Hz, 2H), 6.50 (brs, 1H), 4.56 (brs, 2H), 3.71-3.66 (m, 8H), 3.56-3.51 (m, 2H), 3.40-3.37 (m, 2H), 3.04 (t, J = 4.80 Hz, 4H).
(5−{4−[(2,3−ジヒドロ−ベンゾ[1,4]ダイオキシン−6−イルメチル)−アミノ]−ピリミジン−2−イル}−ピリジン−3−イル)−モルホリン−4−イル−メタノン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 434)
Rt(min):2.51面積%:97.17(maxで)、97.84(254nmで)。
HPLC:>96%
Rt(min):2.53面積%:96.83(maxで)、97.27(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.46 (s, 1H), 8.69 (d, J = 2.04 Hz, 1H), 8.54 (t, J = 2.04 Hz, 1H), 8.19 (d, J = 4.64 Hz, 1H), 8.06 (t, J = 6.12 Hz, 1H), 6.87-6.78 (m, 3H), 6.51 (d, J = 4.96 Hz, 1H), 4.53 (brs, 2H), 4.18 (s, 4H), 3.66-3.54 (m, 8H).
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.4
LCMS:Mass found (+MS, 345)
Rt(min):3.36面積%:94.97(maxで)、96.56(254nmで)。
HPLC:>96%
Rt(min):3.35面積%:96.86(maxで)、97.08(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 8.99 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.20-8.15 (m, 2H), 8.03 (s, 1H), 7.45-7.41 (m, 2H), 7.25 (dd, J = 8.30, 1.76 Hz, 1H), 6.55 (d, J = 5.48 Hz, 1H), 4.64 (brs, 2H), 3.87 (s, 3H).
(2,2−ジメチル2,3−ジヒドロ−ベンゾフラン−7−イルメチル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.3
LCMS:Mass found (+MS, 363.3)
Rt(min):3.51面積%:98.36(maxで)、98.55(254nmで)。
HPLC:>98%
Rt(min):3.53面積%:98.66(maxで)、98.40(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.02 (d, J=1.28 Hz, 1H), 8.35 (d, J = 2.92 Hz, 1H), 8.16 (brs, 1H), 8.06-8.05 (m, 1H), 7.96 (t, J = 5.76 Hz, 1H), 7.07-7.04 (m, 2H), 6.74 (t, J = 7.48 Hz, 1H), 6.51 (brs, 1H), 4.53 (brs, 2H), 3.87 (s, 3H), 3.00 (s, 2H), 1.43 (s, 6H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(2,2−ジメチル2,3−ジヒドロ−ベンゾフラン−7−イルメチル)−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.3
LCMS:Mass found (+MS, 367)
Rt(min):3.89面積%:98.19(maxで)、98.95(254nmで)。
HPLC:>99%
Rt(min):3.94面積%:99.21(maxで)、99.39(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.33 (d, J=1.64 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.51 (s, 1H), 8.18 (brs, 1H), 8.06 (t, J = 5.60 Hz, 1H), 7.05 (d, J=7.44 Hz, 2H), 6.74 (t, J = 7.44 Hz, 1H), 6.55 (brs, 1H), 4.54 (brs, 2H), 3.00 (s, 2H), 1.44 (s, 6H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−[3−(ピラジン−2−イルオキシ)−ベンジル]−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 391)
Rt(min):3.08面積%:94.75(maxで)、95.16254nmで)。
HPLC:>92%
Rt(min):3.10面積%:92.07(maxで)、92.93(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.31 (d, J=1.72 Hz, 1H), 8.69 (d, J=2.24 Hz, 1H), 8.51-8.50 (m, 2H), 8.32 (d, J=2.4 Hz, 1H),8.22-8.19(m, 2H), 8.10 (brs, 1H), 7.41 (t, J = 7.80 Hz, 1H), 7.27 (d, J= 7.96 Hz, 1H), 7.21 (s, 1H), 7.08 (dd, J =7.80, 1.64 Hz, 1H), 6.55 (brs, 1H), 4.67 (brs, 2H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−モルホリン−4−イル−ベンジル)−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 382)
Rt(min):2.54面積%:98.20(maxで)、98.94(254nmで)。
HPLC:>98%
Rt(min):2.53面積%:98.09(maxで)、98.92(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.34 (s, 1H), 8.71 (d, J = 2.44 Hz, 1H), 8.56-8.55 (m, 1H), 8.17 (brs, 1H), 8.06 (brs, 1H), 7.25 (d, J = 8.40 Hz, 2H), 6.90 (d, J = 8.72 Hz, 2H), 6.52 (brs, 1H), 4.54 (brs, 2H), 3.70 (t, J = 4.72 Hz, 4H), 3.04 (t, J = 4.80 Hz, 4H).
(2,3−ジフルオロ−4−メトキシ−ベンジル)−[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 347)
Rt(min):3.33面積%:99.62(maxで)、99.66(254nmで)。
HPLC:>99%
Rt(min):3.25面積%:99.27(maxで)、99.50(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.27 (s, 1H), 8.73 (d, J = 2.48 Hz, 1H), 8.59 (s, 1H), 8.37-8.35 (m, 1H), 8.23-8.22 (m, 1H), 7.21-7.19 (m, 1H), 7.01-6.97 (m, 1H), 6.62 (d, J=6.2 Hz, 1H), 4.69 (brs, 2H), 3.82 (s, 3H).
{5−[4−(4−クロロ−2−フルオロ−ベンジルアミノ)−ピリミジン−2−イル]−ピリジン−3−イル}−モルホリン−4−イル−メタノン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 428.0)
Rt(min):3.37面積%:95.61(maxで)、95.92(254nmで)。
HPLC:>96%
Rt(min):3.03面積%:97.52(maxで)、96.69(254nmで)。
1H NMR (400 MHz, DMSO-d6): δ 9.43 (d, J = 2.00 Hz, 1H), 8.69 (d, J = 2.00 Hz, 1H), 8.50 (s, 1H), 8.23-8.18 (m, 2H), 7.46-7.41 (m, 2H), 7.26-7.24 (m, 1H), 6.56 (d, J = 5.72 Hz, 1H), 4.66 (brs, 2H), 3.66-3.54 (m, 8H).
モルホリン−4−イル−(5−{4−[3−(ピラジン−2−イルオキシ)−ベンジルアミノ]−ピリミジン−2−イル}−ピリジン−3−イル)−メタノン
TLC:CHCl3/MeOH(9/1):Rf:0.2
LCMS:Mass found (+MS, 470.3)
Rt(min):2.50面積%:97.14(maxで)、99.02(254nmで)。
HPLC:>97%
Rt(min):2.55面積%:97.21(maxで)、98.66(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.43 (d, J = 2.00 Hz, 1H), 8.68 (d, J = 2.00 Hz, 1H), 8.52-8.50 (m, 2H), 8.33 (d, J = 2.40 Hz, 1H), 8.21-8.13 (m, 3H), 7.40 (t, J = 8.00 Hz, 1H), 7.27 (d, J = 7.60 Hz, 1H), 7.20 (s, 1H), 7.08 (dd, J = 7.98, 1.64 Hz, 1H), 6.54 (d, J = 5.84 Hz, 1H), 4.69 (brs, 2H), 3.32-3.65 (m, 6H).
(2,3−ジフルオロ−4−メトキシ−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 397)
Rt(min):3.87面積%:90.42(maxで)、97.36(254nmで)。
HPLC:>94%
Rt(min):3.87面積%:94.12(maxで)、97.58(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.67 (d, J = 1.60 Hz, 1H), 9.07 (d, J = 1.48 Hz, 1H), 8.79 (s, 1H), 8.26-8.22 (m, 2H), 7.20-7.17 (m, 1H), 6.99-6.95 (m, 1H), 6.58 (d, J = 5.96 Hz, 1H), 4.63 (s, 2H), 3.81 (s, 3H) .
[4−(4−フルオロ−フェノキシ)−ベンジル]−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 441.3)
Rt(min):4.62面積%:97.72(maxで)、98.95(254nmで)。
HPLC:>98%
Rt(min):4.62面積%:98.37(maxで)、98.18(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.65 (d, J = 1.72 Hz, 1H), 9.07 (d, J = 1.32 Hz, 1H), 8.77 (s, 1H), 8.26-8.22 (m, 2H), 7.39 (d, J = 8.44 Hz, 2H), 7.21-7.16 (m, 2H), 7.02-6.93 (m, 4H), 6.57 (d, J = 5.48 Hz, 1H), 4.63 (s, 2H).
(2,2−ジメチル2,3−ジヒドロ−ベンゾフラン−7−イルメチル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(4/6):Rf:0.4
LCMS:Mass found (+MS, 401.2)
Rt(min):4.34面積%:98.50(maxで)、99.21(254nmで)。
HPLC:>98%
Rt(min):4.33面積%:98.94(maxで)、99.19(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.66 (d, J = 1.60 Hz, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.21-8.11 (m, 2H), 7.06-7.05 (m, 2H), 6.74 (t, J = 7.36 Hz, 1H), 6.58 (brs, 1H), 4.55 (brs, 2H), 3.00 (s, 2H), 1.43 (s, 6H).
[3−(ピラジン−2−イルオキシ)−ベンジル]−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.3
LCMS:Mass found (+MS, 425.3)
Rt(min):3.49面積%:93.59(maxで)、94.61(254nmで)。
HPLC:>95%
Rt(min):3.45面積%:97.16(maxで)、95.35(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.63 (s, 1H), 9.06 (s, 1H), 8.76 (s, 1H), 8.49 (s, 1H), 8.37-8.31 (m, 2H), 8.24-8.22 (m, 1H), 8.09 (s, 1H), 7.40 (t, J = 7.88 Hz, 1H), 7.28 (d, J = 7.68 Hz, 2H), 7.07 (d, J =7.6 Hz, 1H), 6.59 (d, J = 5.88 Hz 1H), 4.69 (brs, 2H).
(4−モルホリン−4−イル−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 416.0)
Rt(min):2.88面積%:98.06(maxで)、98.51(254nmで)。
HPLC:>99%
Rt(min):2.91面積%:99.21(maxで)、99.52(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.67 (s, 1H), 9.07 (d, J = 1.20 Hz, 1H), 8.80 (s, 1H), 8.20-8.13 (m, 2H), 7.25 (d, J = 8.32 Hz, 2H), 6.90 (d, J = 8.80 Hz, 2H), 6.54(d, J = 5.72 Hz, 1H), 4.54 (brs, 2H), 3.70 (t, J = 4.92 Hz, 4H), 3.04 (t, J = 5.08 Hz, 4H).
(3−ピラゾール−1−イル−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.4
LCMS:Mass found (+MS, 397.0)
Rt(min):3.53面積%:99.29(maxで)、99.56(254nmで)。
HPLC:>99%
Rt(min):3.61面積%:99.69(maxで)、99.44(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.66 (d, J = 1.60 Hz, 1H), 9.05 (s, 1H), 8.76 (s, 1H), 8.45 (d, J = 2.40 Hz, 1H), 8.32-8.23 (m, 2H), 7.91 (s, 1H), 7.71-7.68 (m, 2H), 7.44 (t, J = 7.88 Hz, 1H), 7.32 (d, J = 7.52 Hz, 1H), 6.61 (d, J = 5.2 Hz, 1H), 6.52-6.51 (m, 1H), 4.73 (brs, 2H).
(2,3−ジヒドロ−ベンゾ[1,4]ダイオキシン−6−イルメチル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 389.0)
Rt(min):3.50面積%:98.03(maxで)、98.70 (254nmで)。
HPLC:>99%
Rt(min):3.61面積%:99.46(maxで)、99.60 (254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.67 (s, 1H), 9.07 (d, J = 1.36 Hz, 1H), 8.79 (s, 1H), 8.21-8.14 (m, 2H), 6.87-6.78 (m, 3H), 6.55(d, J = 5.52 Hz, 1H), 4.52 (brs, 2H), 4.18 (s, 4H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−[4−(4−フルオロ−フェノキシ)−ベンジル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.3
LCMS:Mass found (+MS, 407)
Rt(min):4.30面積%:97.51(maxで)、97.49(254nmで)。
HPLC:>97%
Rt(min):4.33面積%:97.19(maxで)、97.23(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.33 (d, J = 1.72 Hz, 1H), 8.71 (d, J = 2.44 Hz, 1H), 8.54-8.53 (m, 1H), 8.20-8.16 (m, 2H), 7.39 (d, J = 8.52 Hz, 2H), 7.22-7.17 (m, 2H), 7.04-6.99 (m, 2H), 6.98-6.94 (m, 2H), 6.54 (d, J = 5.96 Hz, 1H), 4.64 (s, 2H).
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.3
LCMS:Mass found (+MS, 349)
Rt(min):3.74面積%:96.65(maxで)、98.63(254nmで)。
HPLC:>98%
Rt(min):3.76面積%:98.92(maxで)、98.76(254nmで)。
1H NMR (400MHz, CDCl3): δ 9.44 (d, J = 1.76 Hz, 1H), 8.65-8.61 (m, 2H), 8.30 (d, J = 5.88 Hz, 1H), 7.38-7.34 (m, 1H), 7.16-7.12 (m, 2H), 6.35 (d, J = 5.92 Hz, 1H), 5.34 (brs, 1H), 4.72 (brs, 2H).
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−フルオロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 333)
Rt(min):3.52面積%:93.46(maxで)、93.80(254nmで)。
HPLC:>93%
Rt(min):3.49面積%:93.70(maxで)、93.80(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.26-9.26 (m, 1H), 8.67 (d, J = 2.88 Hz, 1H), 8.33-8.29 (m, 1H), 8.22-8.19 (m, 2H), 7.46-7.42 (m, 2H), 7.25 (dd, J = 8.26, 1.80 Hz, 1H), 6.56 (d, J = 5.84 Hz, 1H), 4.67 (s, 2H).
モルホリン−4−イル−{5−[4−(3−ピラゾール−1−イル−ベンジルアミノ)−ピリミジン−2−イル]−ピリジン−3−イル}−メタノン
TLC:CHCl3/MeOH(9/1):Rf:0.3
LCMS:Mass found (+MS, 442)
Rt(min):2.63面積%:99.55(maxで)、99.30(254nmで)。
HPLC:>98%
Rt(min):2.60面積%:98.79(maxで)、99.22(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.45 (d, J = 1.96 Hz, 1H), 8.68 (d, J = 1.60 Hz, 1H), 8.53 (s, 1H), 8.46 (d, J = 2.48 Hz, 1H), 8.25-8.15 (m, 2H), 7.90 (s, 1H), 7.71-7.69 (m, 2H), 7.44 (t, J = 7.88 Hz, 1H), 7.32 (d, J = 7.60 Hz, 1H), 6.58 (d, J = 3.52 Hz, 1H), 6.52-6.51 (m, 1H), 4.74 (s, 2H), 3.64-3.51 (m, 8H).
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 383)
Rt(min):4.11面積%:99.19(maxで)、98.32(254nmで)。
HPLC:>99%
Rt(min):4.10面積%:99.66(maxで)、99.33(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.63 (s, 1H), 9.10 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.25 (d, J = 5.52 Hz, 1H), 7.48-7.41 (m, 2H), 7.25 (d, J = 8.04 Hz, 1H), 6.64 (d, J = 6.04 Hz, 1H), 4.68 (s, 2H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−シクロプロピルメチルアミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 261)
Rt(min):2.88面積%:98.18(maxで)、97.74(254nmで)。
HPLC:>98%
Rt(min):2.90面積%:98.87(maxで)、98.03(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.35 (d, J = 1.20 Hz, 1H), 8.72 (d, J = 2.44 Hz, 1H), 8.57-8.55 (m, 1H), 8.16 (brs, 1H), 7.75 (brs, 1H), 6.50 (d, J = 5.80 Hz, 1H), 1.09-1.07 (m, 1H), 0.50-0.45 (m, 2H), 0.28-0.25 (m, 2H).
1H NMR (400MHz, DMSO-d6,D2O): δ 9.32 (d, J = 1.44 Hz, 1H), 8.69 (d, J = 2.44 Hz, 1H), 8.55-8.54 (m, 1H), 8.13 (brs, 1H), 6.48 (d, J = 5.84 Hz, 1H), 3.28 (s, 2H), 1.06-1.05 (m, 1H), 0.48-0.43 (m, 2H), 0.26-0.22 (m, 2H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−シクロヘキシルメチルアミン
TLC:石油エーテル/酢酸エチル(5/5):Rf:0.4
LCMS:Mass found (+MS, 303)
Rt(min):3.92面積%:99.34(maxで)、99.56(254nmで)。
HPLC:>97%
Rt(min):3.89面積%:97.87(maxで)、99.56(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.34 (s, 1H), 8.72 (d, J = 2.48 Hz, 1H), 8.55-8.54 (m, 1H), 8.12 (d, J = 5.76 Hz, 1H), 7.66-7.65 (m, 1H), 6.48 (d, J = 5.88 Hz, 1H), 3.32-3.28 (m, 2H), 1.77-1.67 (m, 4H), 1.62-1.60 (m, 2H), 1.24-1.12 (m, 3H), 1.02-0.93 (m, 2H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(2−フルオロ−ベンジル)−アミン
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.3
LCMS:Mass found (+MS, 315)
Rt(min):3.34面積%:99.20(maxで)、99.59(254nmで)。
HPLC:>99%
Rt(min):3.32面積%:99.16(maxで)、99.38(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.32 (s, 1H), 8.71 (d, J = 2.08 Hz, 1H), 8.54 (s, 1H), 8.19 (brs, 2H), 7.43 (t, J = 7.48 Hz, 1H), 7.32-7.28 (m, 1H), 7.23-7.14 (m, 2H), 6.57 (d, J = 5.84 Hz, 1H), 4.68 (s, 2H).
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−フルオロ−ベンジル)−アミン
TLC:石油エーテル/酢酸エチル(6/4):Rf:0.3
LCMS:Mass found (+MS, 315)
Rt(min):3.35面積%:97.23(maxで)、98.28(254nmで)。
HPLC:>97%
Rt(min):3.40面積%:97.29(maxで)、98.95(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.32 (d, J = 1.56 Hz, 1H), 8.71 (d, J = 2.24 Hz, 1H), 8.53 (s, 1H), 8.21 (s, 2H), 7.43-7.40 (m, 2H), 7.18-7.13 (m, 2H), 6.55 (d, J = 4.88 Hz, 1H), 4.64 (brs, 2H).
(5−{4−[(2,2−ジメチル2,3−ジヒドロ−ベンゾフラン−7−イルメチル)−アミノ]−ピリミジン−2−イル}−ピリジン−3−イル)−モルホリン−4−イル−メタノン
TLC:CHCl3/MeOH(9.5/0.5):Rf:0.5
LCMS:Mass found (+MS, 446.3)
Rt(min):3.21面積%:97.75(maxで)、97.85(254nmで)。
HPLC:>98%
Rt(min):3.20面積%:98.19(maxで)、97.78(254nmで)。
1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.52-8.51 (m, 1H), 8.22 (d, J = 6.00 Hz, 1H), 7.08 (d, J = 7.16 Hz, 2H), 6.75 (t, J = 8.56 Hz, 1H), 6.66 (d, J = 6.36 Hz, 1H), 4.60 (s, 2H), 3.65-3.54 (m, 6H), 3.00 (s, 2H), 1.42 (s, 6H).
2−クロロ−6−(2,4−ジフルオロ−ベンジルアミノ)−ピリミジン−4−カルボン酸メチルエステル
収率:45.93%
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.4
LCMS:Mass found (+MS, 314.0)
Rt(min):4.16面積%:97.75(maxで)、98.54(254nmで)
HPLC:>99%
Rt(min):4.23面積%:99.27(maxで)、98.66(254nmで)
1H NMR (400MHz, DMSO-d6): δ 8.79-8.76 (m, 1H), 7.47-7.41 (m, 1H), 7.30-7.24 (m, 1H), 7.12 (s, 1H), 7.10-7.05 (m, 1H), 4.71 (d, J = 5.52 Hz, 2H), 3.83 (s, 3H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸メチルエステル
収率:44.31%
TLC:石油エーテル/酢酸エチル(7/3):Rf:0.4
LCMS:Mass found (+MS, 425.0)
Rt(min):5.08面積%:94.29(maxで)、96.71(254nmで)。
HPLC:>98%
Rt(min):5.08面積%:98.15(maxで)、98.80(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.67 (d, J = 1.52 Hz, 1H), 9.10 (d, J = 1.32 Hz, 1H), 8.77 (s, 1H), 8.66 (t, J = 5.72 Hz, 1H), 7.54-7.48 (m, 1H), 7.27-7.20 (m, 2H), 7.07-7.04 (m, 1H), 4.71 (d, J = 5.48 Hz, 2H), 3.89 (s, 3H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸
収率:95.44%
TLC:CHCl3/MeOH(9/1):Rf:0.3
LCMS:Mass found (+MS, 411.0)
Rt(min):4.47面積%:98.02(maxで)、99.15(254nmで)。
HPLC:>98%
Rt(min):4.46面積%:98.29(maxで)、98.61(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.72 (d, J = 1.6 Hz, 1H), 9.08 (d, J = 1.40 Hz, 1H), 8.89 (s, 1H), 8.58 (s, 1H), 7.53-7.47 (m, 1H), 7.27-7.21 (m, 1H), 7.15 (s, 1H), 7.07-7.03 (m, 1H), 4.71 (d, J = 5.00 Hz, 2H).
41
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−カルバモイル−エチル)−アミド
1H NMR (400MHz, DMSO): δ 9.92 (s, 1H), 9.19-9.17 (m, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.62-8.59 (m, 1H), 7.52-7.46 (m, 1H), 7.40 (s, 1H), 7.25-7.20 (m, 1H), 7.17 (s, 1H), 7.06-7.02 (m, 1H), 6.89 (s, 1H), 4.71 (d, J = 5.36 Hz, 2H), 3.52-3.47 (m, 2H), 2.38 (t, J = 7.20 Hz, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−ジエチルカルバモイル−エチル)−アミド
1H NMR (400MHz, DMSO-d6): δ 9.90 (s, 1H), 9.20-9.17 (m, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.63-8.60 (m, 1H), 7.53-7.47 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (s, 1H), 7.06-7.02 (m, 1H), 4.71 (d, J = 5.28 Hz, 2H), 3.53-3.52 (m, 2H), 3.30-3.26 (m, 4H), 2.60 (t, J = 7.16 Hz, 2H), 1.08 (t, J = 7.16 Hz, 3H), 1.00 (t, J = 8.92 Hz, 3H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−モルホリン−4−イル−3−オキソ−プロピル)−アミド
1H NMR (400MHz, DMSO-d6): δ 9.91 (s, 1H), 9.18 (t, J = 6.2 Hz, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.62 (t, J = 5.68 Hz, 1H), 7.52-7.47 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (s, 1H), 7.06-7.02 (m, 1H), 4.71 (d, J = 5.40 Hz, 2H), 3.55-3.50 (m, 6H), 3.45-3.43 (m, 4H), 2.63 (t, J = 7.12 Hz, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−yl)−ピリミジン−4−カルボン酸 [3−(4−メチルピペラジン−1−yl)−3−オキソ−プロピル]−アミド
1H NMR (400MHz, DMSO-d6): δ 9.90 (s, 1H), 9.17 (t, J = 6.08 Hz, 1H), 9.10 (s, 1H), 8.96 (s, 1H), 8.62 (t, J = 5.56 Hz, 1H), 7.52-7.46 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (s, 1H), 7.06-7.02 (m, 1H), 4.71 (d, J = 5.32 Hz, 2H), 3.53-3.49 (m, 2H), 3.46-3.41 (m, 4H), 2.62 (t, J = 7.04 Hz, 2H), 2.26-2.20 (m, 4H), 2.12 (s, 3H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−yl)−ピリミジン−4−カルボン酸 (3−ジメチルアミノ−プロピル)−アミド
1H NMR (400MHz, DMSO-d6): δ 9.94 (s, 1H), 9.20-9.19 (m, 1H), 9.10 (s, 1H), 8.95 (s, 1H), 8.62-8.60 (m, 1H), 7.52-7.46 (m, 1H), 7.26-7.21 (m, 1H), 7.18 (s, 1H), 7.06-7.02 (m, 1H), 4.70 (d, J = 5.32 Hz, 2H), 3.37-3.32 (m, 2H), 2.39 (s, 2H), 2.23 (s, 6H), 1.72-1.69 (m, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−イミダゾール−1−イル−プロピル)−アミド
1H NMR (400MHz, DMSO-d6): δ 9.97 (s, 1H), 9.14 (t, J = 6.08 Hz, 1H), 9.10 (s, 1H), 8.99 (s, 1H), 8.60 (t, J = 5.68 Hz, 1H), 7.66 (s, 1H), 7.52-7.46 (m, 1H), 7.26-7.18 (m, 3H), 7.06-7.02 (m, 1H), 6.88 (s, 1H), 4.71 (d, J = 5.36 Hz, 2H), 4.00 (t, J = 6.84 Hz, 2H), 3.33-3.29 (m, 2H), 2.02-1.95 (m, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸[3−(2−オキソ−ピロリジン−1−イル)−プロピル]−アミド
1H NMR (400MHz, DMSO-d6): δ 9.95 (s, 1H), 9.23 (t, J = 6.08 Hz, 1H), 9.10 (d, J = 5.64 Hz, 2H), 8.60 (t, J = 4.92 Hz, 1H), 7.53-7.47 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (s, 1H), 7.06-7.02 (m, 1H), 4.71 (d, J = 4.96 Hz, 2H), 3.37-3.32 (m, 2H), 3.28-3.24 (m, 4H), 2.32-2.31 (m, 2H), 1.96-1.89 (m, 2H), 1.71-1.68 (m, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−モルホリン−4−イル−プロピル)−アミド
1H NMR (400MHz, CD3OD): δ 9.84 (s, 1H), 9.12 (s, 1H), 8.97 (s, 1H), 7.51-7.46 (m, 1H), 7.19 (s, 1H), 7.00-6.90 (m, 2H), 4.77 (s, 2H), 3.69 (t, J = 4.68 Hz, 4H), 3.50 (t, J = 6.92 Hz, 2H), 2.50-2.46 (m, 6H), 1.91-1.84 (m, 2H).
1−[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボニル]−ピペリジン−4−カルボン酸アミド
1H NMR (400MHz, DMSO-d6): δ 9.64 (d, J = 1.28 Hz, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.50-8.47 (m, 1H), 7.53-7.51 (m, 1H), 7.31 (s, 1H), 7.27-7.21 (m, 1H), 7.08-7.03 (m, 1H), 6.82 (s, 1H), 6.65 (s, 1H), 4.69 (brs, 2H), 4.41 (d, J = 12.92 Hz, 1H), 3.79 (d, J = 12.60 Hz, 1H), 3.09-3.03 (m, 1H), 2.87-2.80 (m, 1H), 2.43-2.36 (m, 1H), 1.81-1.52 (m, 4H).
1−[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボニル]−ピペリジン−3−カルボン酸アミド
1H NMR (400MHz, DMSO-d6): δ 9.64 (s, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.49-8.48 (m, 1H), 7.52-7.51 (m, 1H), 7.42-7.21 (m, 2H), 7.05 (t, J = 8.52 Hz, 1H), 6.92-6.81 (m, 1H), 6.65 (d, J = 10.84 Hz, 1H), 4.70-4.69 (m, 2H), 4.49 - 4.30 (m, 1H), 3.85-3.70 (m, 1H), 3.20-2.97 (m, 1H), 2.82 (t, J = 14.00 Hz, 1H), 2.40-2.31 (m, 1H), 2.01-1.90 (m, 1H), 1.79-1.53 (m, 2H), 1.45-1.42 (m, 1H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(1−メチルピロリジン−3−イルメチル)−アミド
1H NMR (400MHz, DMSO-d6): δ 9.97 (s, 1H), 9.21 (t, J = 5.56 Hz, 1H), 9.10 (s, 1H), 8.96 (s, 1H), 8.63 (t, J = 5.72 Hz, 1H), 7.52-7.46 (m, 1H), 7.26-7.20 (m, 1H), 7.18 (s, 1H), 7.06-7.02 (m, 1H), 4.70 (d, J = 5.36 Hz, 2H), 3.33 (brs, 2H), 2.85-2.81 (m, 2H), 2.67-2.66 (m, 2H), 2.60-2.56 (m, 1H), 2.50-2.47 (m, 3H), 1.99-1.90 (m, 1H), 1.65-1.57 (m, 1H), .
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸[2−(1H−イミダゾール−4−イル)−エチル]−アミド
1H NMR (400MHz, DMSO-d6): δ 11.90 (brs, 1H), 9.97 (s, 1H), 9.37 (s, 1H), 9.10 (s, 1H), 8.99 (s, 1H), 8.60 (t, J = 5.44 Hz, 1H), 7.57 (s, 1H), 7.52-7.47 (m, 1H), 7.26-7.18 (m, 2H), 7.06-7.02 (m, 1H), 6.88 (s, 1H), 4.71 (d, J = 5.20 Hz, 2H), 3.56-3.51 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(4−ジメチルアミノ−ブチル)−アミド
1H NMR (400MHz, DMSO-d6,D2O): δ 9.91 (s, 1H), 9.07 (s, 1H), 8.97 (s, 1H), 7.50-7.44 (m, 1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 4.67 (s, 2H), 3.30 (t, J = 7.00 Hz, 2H), 2.43-2.39 (m, 2H), 2.24 (s, 6H), 1.55-1.45 (m, 4H).
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(1−メチルピペリジン−4−イル)−アミド
1H NMR (400MHz, DMSO-d6): δ 10.02 (s, 1H), 9.11 (s, 1H), 8.92 (s, 1H), 8.73 (d, J = 8.08 Hz, 1H), 8.60 (t, J = 5.12 Hz, 1H), 7.51-7.45 (m, 1H), 7.26-7.18 (m, 2H), 7.06-7.02 (m, 1H), 4.70 (d, J = 5.40 Hz, 2H), 3.80-3.78 (m, 1H), 2.82 (brs, 2H), 2.21 (s, 3H), 2.02 (brs, 2H), 1.80-1.74 (m, 4H).
(2,6−ジクロロピリミジン−4−イル)−(2,4−ジフルオロ−ベンジル)−アミン
収率:37.97%
TLC:石油エーテル/酢酸エチル(8/2):Rf:0.4
LCMS:Mass found (+MS, 290.0)
Rt(min):4.74面積%:97.36(maxで)、99.51(254nmで)
HPLC:>99%
Rt(min):4.81面積%:99.61(maxで)、99.49(254nmで)
1H NMR (400MHz, DMSO-d6): δ 8.65-8.63 (m, 1H), 7.46-7.40 (m, 1H), 7.29-7.24 (m, 1H), 7.10-7.05 (m, 1H), 6.57 (s, 1H), 4.52-4.44 (m, 2H).
収率:21.73%
TLC:石油エーテル/酢酸エチル(8/2):Rf:0.4
LCMS:Mass found (+MS, 401.0)
Rt(min):5.70面積%:98.35(maxで)、95.87(254nmで)
HPLC:>97%
Rt(min):5.79面積%:98.74(maxで)、97.70(254nmで)
1H NMR (400MHz, DMSO-d6): δ 9.61 (s, 1H), 9.12 (s, 1H), 8.75-8.71 (m, 1H), 8.53 (t, J = 4.92 Hz, 1H), 7.53-7.47 (m, 1H), 7.27-7.21 (m, 1H), 7.07-7.03 (m, 1H), 6.63 (s, 1H), 4.69 (d, J = 5.36 Hz, 2H).
55
1−[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−ピペリジン−3−カルボン酸アミド
収率:20.80%
TLC:CHCl3/MeOH(9/1):Rf:0.4
LCMS:Mass found (+MS, 493.0)
Rt(min):4.07面積%:97.80(maxで)、96.94(254nmで)。
HPLC:>96%
Rt(min):4.03面積%:97.81(maxで)、96.66(254nmで)。
1H NMR (400MHz, DMSO-d6): δ 9.63 (d, J = 1.64 Hz, 1H), 9.03 (d, J = 1.40 Hz, 1H), 8.72 (s, 1H), 7.51-7.47 (m, 1H), 7.45-7.41 (m, 1H), 7.38 (s, 1H), 7.22-7.17 (m, 1H), 7.05-7.01 (m, 1H), 6.88 (s, 1H), 5.76 (s, 1H), 4.56 (s, 2H), 4.45-4.20 (m, 2H), 2.96-2.82 (m, 2H), 2.32-2.26 (m, 1H), 1.90-1.87 (m, 1H), 1.73-1.70 (m, 1H), 1.66-1.55 (m, 1H), 1.49-1.36 (m, 1H).
1.FAK活性についての生化学的酵素アッセイ
本明細書に記載のFAKアッセイを、2つのCaliper Life SciencesのシステムであるLC3000およびEZ Reader IIで実施する。これらは、酵素反応の終わりにリン酸化または非リン酸化された蛍光標識基質ペプチドの相対量を測定することによって、酵素活性のデータを提供するものである。ペプチドのこれら異なる状態は、試料のいたる所に電位差を加えることによって分割する。生成物(基質とは対照的に)上の荷電したリン酸基の存在は、2つのペプチド間で異なる移動度の差をもたらす。これを、基質上および生成物であるペプチド上の蛍光標識の励起によって可視化し、分析ソフトウェア内でピークとして表す。
FAKの阻害活性を測定するため、TTP Mosquito液体を取り扱う機器であるCaliper Life Sciences LC3000において、インヒビターを、100%DMSO中の適切な濃度のインヒビター0.25ulを384ウェルプレートの各ウェルの中に入れるために使用する。この反応に、成分を、最終容量が25ulになるように加える:
100uM ATP
1mM DTT
1mM MgCl2
1uM 基質ペプチド(配列FITC−KGWMEDYDYVHLQGKK−(CONH2)
1mM FERMペプチド(配列NH2−GATQSFIIR−COOH)
100mM HEPES pH7.5
0.015% Brij−35
反応は、25℃で90minインキュベートした後、70ulのStop緩衝液(100mM HEPES pH7.5、0.015% Brij−35、10mM EDTA)の添加により停止する。
EZ Reader IIは、基質から生成物への変換パーセンテージを算出するためのLC 3000と同じ原理を利用する。Caliper Life Sciencesは、選択したキナーゼを含む予め製造された急速冷凍の独自の384ウェルプレートを提供する。384プレート中の各カラムは、特定の選択したキナーゼを含む。第2プレート「基質プレート」は、蛍光標識されたペプチド基質およびATPの混合物を含む。これらは、基質プレートから酵素プレートへの移動が、正確な酵素濃度に正確な基質/ATP濃度を提供するように、カラム中に配置される。化合物を、単一濃度で、所望の形式の解凍した酵素プレートに加える。反応は、基質プレートから基質/ATP混合物を移動することによって、始まる。酵素プレートを25℃で90minインキュベートする。反応を、70ulのStop緩衝液(100mM HEPES pH7.5、0.015% Brij−35、10mM EDTA)の添加により停止する。
接着斑キナーゼ(FAK)の細胞活性は、Luminexをベースとしたアッセイを使用して、チロシン397のFAK自己リン酸化の度合いにより決定する。HT29細胞を、100μlの培地(90%DMEM/10%FCS)中、96ウェルプレートのウェル当たり30,000細胞播種する。翌日、試験化合物を段階希釈して、無血清条件下、30min間、加える。その後、細胞を、90μlの溶解緩衝液(20mM Tris/HCl pH8,0、150mM NaCl、1% NP40、10% グリセロール、1% Phosphatase-Inhibitor II、20mM □−グリセロールリン酸、0,1% Protease-Inhibitor Cocktail III、0,01% ベンゾナーゼ(Benzonase))で溶解し、溶解物を、96ウェルフィルタープレート(0.65μm)を介して遠心分離により澄ませた。試料を、抗総FAK抗体に結合したLuminexビーズとともに、緩やかに撹拌しながら、4℃で終夜インキュベートした。リン酸−Y397−FAK検出のため、リン酸特異的な抗体および種特異的なPE標識二次抗体を加える。リン酸−Y397−FAKの量は、60秒以内にウェル当たり100事象を測定するLuminex100機で決定する。
化合物の阻害可能性を査定するために、IC50値を、下表に示すとおり、決定した。
IC50の範囲は、以下のように割り当てた:A:<0.1μM;B:0.100〜1μM;C:1〜10μM;D:>10μM
Claims (11)
- 式(IV)または(V)
R1’、R1’’が、独立に、H、A、Hal、Cyc、CO(Cyc)であり、
R2が、H、Q1−(C(LA)H)n−Q2、Cycであり
R3が、H、A、−LA−Cycであり、
Aが、1個、2個、3個、4個もしくは5個のC原子を有する、非分岐または分岐の直鎖あるいは環状のアルキルであって、1個のCH2基が、O原子もしくはS原子および/または−NH−基、−CO−基、−NHCOO−基、−NHCONH−基、−CONH−基、−NHCO−基、−CH=CH−基、−N=CH−基あるいは−CH=N−基で置換されていてもよく、1〜5個のH原子が、Halで置換されていてもよく、1個のCH基が、Nで置換されていてもよく、1個のCH3基が、CNで置換されていてもよく、
Halが、F、Cl、BrまたはIであり、
Cycが、0個、1個もしくは2個のN原子、O原子および/またはS原子と、4個、5個もしくは6個の骨格原子とを有する、単環の、非芳香族または芳香族の、同素環あるいは複素環であって、該環は、非置換であっても、Hal、LA、OH、カルボニル酸素、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、CN、OCN、SCN、COOH、COO(LA)、CONH2、CONH(LA)、CON(LA)2、NHCO(LA)、NHCONH(LA)、NHCONH2、NHSO2(LA)、CHO、CO(LA)、SO2NH2、SO2(LA)および/またはSO2Halで互いに独立して一置換または二置換されていてもよく、
Q1が、−NH−、−O−、−COO−、−CONH−、または単結合であり、
Q2が、NH2、NH(LA)、N(LA)2、CONH2、CONH(LA)、CON(LA)2、COOH、COO(LA)、Cyc、CO(Cyc)であり、
nが、0、1、2、3または4であり、
Arが、0個、1個、2個、3個もしくは4個のN、O原子および/またはS原子と、5個、6個、7個、8個、9個または10個の骨格原子とを有する、単環もしくは二環の、芳香族の同素環または複素環であって、該環は、非置換であっても、Hal、A、OH、SH、OA、NH2、NHA、NA2、NO2、CN、OCN、SCN、COOH、CONH2、CONHA、CONA2、NHCOA、NHCONHA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A、SO2Halおよび/または(X)m−Cycで互いに独立して一置換、二置換または三置換されていてもよく、
環のN原子において、O原子で置換され、N−オキシド基を形成してもよく、
二環式系の場合、一方の環が芳香族であり、他方の環が非芳香族であってもよく、
Xが、CH2、NH、Oであり、
mが、0または1であり、ならびに、
LAが、H、あるいは、1個、2個もしくは3個もしくは4個のC原子を有する非分岐または分岐の直鎖アルキルであって、1個、2個または3個のH原子が、Halで置換されていてもよい、
前記の化合物(但し、(5−メチル−ピリミジン−2−イルメチル)−(6−フェニル−2−ピリジン−3−イル−ピリミジン−4−イル)−アミン、
4−[(2−ピリジン−3−イル−ピリミジン−4−イルアミノ)−メチル]−安息香酸メチルエステル、および
N−ベンジル−2−(ピリジン−3−イル)ピリミジン−4−アミンを除く)、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物。 - より詳細に指定されない残基は式(IV)または(V)において示された意味を有するが、
Arが、フェニル、ピリジル、2,1,3−ベンゾチアジアゾリル、1,3−ベンゾジオキソリル、ピラゾロ[1,5−a]ピリジル、ピリミジル、モルホリニル、2,3−ジヒドロ−ベンゾフラニル、ピラゾリルであって、それらの全てが、非置換であっても、Hal、LA、OH、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、CN、OCN、SCN、COOH、CONH2、CONH(LA)、CON(LA)2、NHCO(LA)、NHCONH(LA)、NHCONH2、NHSO2(LA)、CHO、CO(LA)、SO2NH2、SO2(LA)、SO2Hal、(X)m−Cycで一置換または二置換されていてもよい、
または
R3が、Hである、
または
下位式3において、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、かつ
R1’’が、H、NH2である、
または
R2が、Hである、
または
R2が、Q1−(C(LA)H)n−Q2である、
または
Arが、Hal、LA、OH、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、CN、OCN、SCN、COOH、CONH2、CONH(LA)、CON(LA)2、NHCO(LA)、NHCONH(LA)、NHCONH2、NHSO2(LA)、CHO、CO(LA)、SO2NH2、SO2(LA)、SO2Hal、Cyc、O−Cycで独立に一置換または二置換されているフェニルである、
または
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジンである、
または
Arが、F、Cl、メチルまたはCF3で、オルト位および/もしくはパラ位に、独立して一置換または二置換されているフェニルである、
または
R2が、Hであり、かつ
R3が、Hである、
または
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Hであり、かつ
R3が、Hである、
または
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジルであり、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Hであり、かつ
R3が、Hである、
または
R2が、Q1−(CH2)n−Q2である、
または
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、かつ
R2が、Q1−(CH2)n−Q2である、
または
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Q1−(CH2)n−Q2であり、かつ
R3が、Hである、
または
Arが、Hal、LA、OH、O(LA)、NH2、NH(LA)、N(LA)2、NHSO2(LA)、CO(LA)、SO2NH2、SO2(LA)、SO2Halで、オルト位および/もしくはパラ位に、独立して一置換または二置換されている、フェニルあるいはピリジルであり、
R1’が、H、Hal、LA、O(LA)、CO(Cyc)であり、
R1’’が、H、NH2であり、
R2が、Q1−(CH2)n−Q2であり、かつ
R3が、Hである、
または
Arが、Fで、オルト位およびパラ位に二置換されているフェニルであり、
R1’が、CF3であり、
R1’’が、Hであり、
R2が、Q1−(CH2)n−Q2であり、かつ
R3が、Hである、
請求項1に記載の式(IV)または(V)に従う化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物。 - 化合物が、以下:
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸カルバモイルメチル−アミド、
[2−(2−アミノ−5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−フルオロ−2−トリフルオロメチル−ベンジル)−アミン、
[2−(2−アミノ−5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−(2−トリフルオロメチル−ベンジル)−アミン、
1−[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボニル]−ピペリジン−3−カルボン酸アミド、
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−フルオロ−2−トリフルオロメチル−ベンジル)−アミン、
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−カルバモイル−エチル)−アミド、
(4−フルオロ−2−トリフルオロメチル−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン、
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(2,4−ジフルオロ−ベンジル)−アミン、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−アセチルアミノ−エチル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−モルホリン−4−イル−3−オキソ−プロピル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−モルホリン−4−イル−プロピル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−ピリジン−3−イル−エチル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(3−ジメチルアミノ−プロピル)−アミド、
[2−(5−クロロ−ピリジン−3−イル)−ピリミジン−4−イル]−(4−クロロ−2−トリフルオロメチル−ベンジル)−アミン、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(1−メチルピロリジン−3−イルメチル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(4−ジメチルアミノ−ブチル)−アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(2−ジメチルアミノ−エチル)−アミド、
(4−クロロ−2−フルオロ−ベンジル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン、
1−[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボニル]−ピペリジン−4−カルボン酸アミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸ジメチルアミド、
6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−カルボン酸(1−カルバモイル−エチル)−アミド、
[6−(2,4−ジフルオロ−ベンジルアミノ)−2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−モルホリン−4−イル−メタノン、
(2,4−ジフルオロ−ベンジル)−[4−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−2−イル]−アミン、
(4−フルオロ−2−トリフルオロメチル−ベンジル)−[4−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−2−イル]−アミン、
(2,4−ジフルオロ−ベンジル)−(5’−トリフルオロメチル−[2,3’]ビピリジニル−6−イル)−アミン、
(2,4−ジフルオロ−ベンジル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン、
(3,5−ジフルオロ−ピリジン−2−イルメチル)−[2−(5−トリフルオロメチル−ピリジン−3−イル)−ピリミジン−4−イル]−アミン、
(4−フルオロ−2−トリフルオロメチル−ベンジル)−[2−(5−メトキシ−ピリジン−3−イル)−ピリミジン−4−イル]−アミン
からなる群から選択される、請求項1に記載の化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物。 - 薬学的に許容し得る担体とともに、請求項1〜3のいずれか一項に記載の化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物を活性成分として含む医薬組成物。
- 請求項1〜3のいずれか一項に記載の化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物を含む、医薬。
- 過剰増殖性の疾患を処置するための、請求項4に記載の医薬組成物。
- 疾患が、がん、炎症、膵炎または腎疾患、疼痛、皮膚の良性過形成、再狭窄、前立腺、脈管形成または血管新生に関連する疾患、腫瘍血管新生、乾癬、湿疹および強皮症から選択される皮膚疾患、糖尿病、糖尿病性網膜症、未熟児網膜症、加齢性黄斑変性症、血管腫、神経膠腫、黒色腫ならびにカポジ肉腫からなる群から選択される、請求項6に記載の医薬組成物。
- 過剰増殖性の疾患の処置のための医薬の調製における、請求項1〜3のいずれか一項に記載の化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物の使用。
- 疾患が、がん、炎症、膵炎または腎疾患、疼痛、皮膚の良性過形成、再狭窄、前立腺、脈管形成または血管新生に関連する疾患、腫瘍血管新生、乾癬、湿疹および強皮症から選択される皮膚疾患、糖尿病、糖尿病性網膜症、未熟児網膜症、加齢性黄斑変性症、血管腫、神経膠腫、黒色腫ならびにカポジ肉腫からなる群から選択される、請求項8に記載の使用。
- a)請求項1〜3のいずれか一項に記載の化合物、または、その立体異性体もしくは互変異性体、または、薬学的に許容し得る前記それぞれの塩、あるいは、あらゆる比でのそれらの混合物の有効量、ならびに、
b)さらなる医薬活性成分の有効量
の別個のパックからなるセット(キット)。 - 請求項1に記載の式(IV)または(V)の化合物を製造するための方法であって、
式(X’)
式中、前記ボロン酸の酸素原子と繋がったRが、H、LAまたはアルキル鎖であり、他の全ての置換基は、請求項1に記載の式(IV)または(V)で定義したような意味を有する、前記製造方法。
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