JP7378488B2 - Fgfr4キナーゼ阻害剤、その製造方法及び用途 - Google Patents
Fgfr4キナーゼ阻害剤、その製造方法及び用途 Download PDFInfo
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- JP7378488B2 JP7378488B2 JP2021553854A JP2021553854A JP7378488B2 JP 7378488 B2 JP7378488 B2 JP 7378488B2 JP 2021553854 A JP2021553854 A JP 2021553854A JP 2021553854 A JP2021553854 A JP 2021553854A JP 7378488 B2 JP7378488 B2 JP 7378488B2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000002476 tumorcidal effect Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- C07—ORGANIC CHEMISTRY
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
XはN又はCHであり、
R0は-O-C1~6アルキル基であり、
R1はH、ハロゲンから選ばれ、
式(I)で2つのR0は同じでもよいし異なってもよく、2つのR1は同じでもよいし異なってもよく、
R2、R3はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R4はH、C1~6アルキル基、-O-C1~6アルキル基から選ばれ、
R14は
R6、R8はそれぞれ独立してH、C1~6アルキル基から選ばれ、又はR6とR8が接続して結合が形成され、
R7はH、C1~6アルキル基、-O-C1~6アルキル基、-NR9R10から選ばれ、ただしR9、R10はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R5はH、ハロゲン、ヒドロキシ基、C1~6アルキル基、-NR11R12、-(CH2)n-R13から選ばれ、
R11、R12はそれぞれ独立してH、C1~6アルキル基、-C1~6アルキレン-NR14R15基から選ばれ、ただしR14、R15はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R13は3~12員のヘテロシクロアルキル基であり、且つR13は任意選択でBoc、-SO2-C1~6アルキル基、-SO2-N-(C1~6アルキル)2基、C1~6アルキル基、ヒドロキシ基、アミノ基、シアノ基、アセチル基、-O-C1~6アルキル基、-(CH2)n-アリール基、-(CH2)n-ヘテロアリール基、-(CH2)n-C3~8シクロアルキル基、又は-C3~8ヘテロシクロアルキル基によって置換されてもよく、ただし前記-C3~8ヘテロシクロアルキル基は任意選択でC1~6アルキル基によって置換されてもよく、
nは独立して0又は1であり、
いくつかの実施形態において、R0はメトキシ基であり、
いくつかの実施形態において、R1はハロゲンであり、
いくつかの実施形態において、R2、R3はHであり、
いくつかの実施形態において、R4は-O-C1~6アルキル基であり、
いくつかの実施形態において、R6、R8はHであり、又はR6とR8が接続して結合が形成され、
いくつかの実施形態において、R7はHであり、
いくつかの実施形態において、R5は3~12員のヘテロシクロアルキル基であり、前記3~12員のヘテロシクロアルキル基は任意選択でBoc、-SO2-C1~6アルキル基、-SO2-N-(C1~6アルキル)2基、C1~6アルキル基、アセチル基、-C3~8シクロアルキル基、又は-C3~8ヘテロシクロアルキル基によって置換されてもよく、ただし前記-C3~8ヘテロシクロアルキル基は任意選択でC1~6アルキル基によって置換されてもよく、
いくつかの実施形態において、本発明化合物は
から選ばれ、又は薬学的に許容されるそれらの塩、溶媒和物、結晶多形もしくは異性体である。
XはN又はCHであり、
R0は-O-C1~6アルキル基であり、
R1はH、ハロゲンから選ばれ、
式(II)で2つのR0は同じでもよいし異なってもよく、2つのR1は同じでもよいし異なってもよく、
R2、R3はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R4はH、C1~6アルキル基、-O-C1~6アルキル基から選ばれ、
R6、R8はそれぞれ独立してH、C1~6アルキル基から選ばれ、又はR6とR8が接続して結合が形成され、
R7はH、C1~6アルキル基、-O-C1~6アルキル基、-NR9R10から選ばれ、ただしR9、R10はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R5はH、ハロゲン、ヒドロキシ基、C1~6アルキル基、-NR11R12、-(CH2)n-R13から選ばれ、
R11、R12はそれぞれ独立してH、C1~6アルキル基、-C1~6アルキレン-NR14R15基から選ばれ、ただしR14、R15はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R13は3~12員のヘテロシクロアルキル基であり、且つR13は任意選択でC1~6アルキル基、ヒドロキシ基、アミノ基、シアノ基、アセチル基、-O-C1~6アルキル基、-(CH2)n-アリール基、-(CH2)n-ヘテロアリール基、-(CH2)n-C3~8シクロアルキル基、-C3~8ヘテロシクロアルキル基によって置換され、ただし前記-C3~8ヘテロシクロアルキル基は任意選択でC1~6アルキル基によって置換されてもよく、
nは0又は1であり、
いくつかの実施形態において、R0はメトキシ基であり、
いくつかの実施形態において、R1はハロゲンであり、いくつかの実施形態において、R2、R3はHであり、
いくつかの実施形態において、R4は-O-C1~6アルキル基であり、
いくつかの実施形態において、R6、R8はHであり、又はR6とR8が接続して結合が形成され、
いくつかの実施形態において、R7はHであり、
いくつかの実施形態において、R5は-NR11R12、-(CH2)n-R13から選ばれ、ただし、
R11、R12はそれぞれ独立してH、C1~6アルキル基、-C1~6アルキレン-NR14R15基から選ばれ、ただしR14、R15はそれぞれ独立してH、C1~6アルキル基から選ばれ、
R13は3~12員のヘテロシクロアルキル基であり、且つR13は任意選択でC1~6アルキル基、ヒドロキシ基、アミノ基、シアノ基、アセチル基、-O-C1~6アルキル基、-(CH2)n-アリール基、-(CH2)n-ヘテロアリール基、-(CH2)n-C3~8シクロアルキル基、-C3~8ヘテロシクロアルキル基によって置換され、ただし前記-C3~8ヘテロシクロアルキル基は任意選択でC1~6アルキル基によって置換されてもよく、
nは独立して0又は1であり、
いくつかの実施形態において、本発明化合物は
用語「任意選択」、「任意選択の」及び「任意選択で」とは続いて記載される事象又は状況が生じるか生じないかの両方の可能性があることで、当該記述は前記事象又は状況が生じる場合、前記事象又は状況が生じない場合を含む。例えば、「任意選択で置換されたアルキル基」とは「非置換のアルキル基」又は「置換されたアルキル基」を表す。任意選択で置換された基は非置換のもの(例えば、-CH2CH3)、完全に置換されたもの(例えば、-CF2CF3)、一置換されたもの(例えば、-CH2CH2F)、又は一置換と完全置換との間の任意の置換(例えば、-CH2CHF2、-CF2CH3、-CFHCHF2など)のいずれでもよい。当業者が理解したように、1つ又は複数の置換基を含む任意の基には、空間的に存在し得ない及び/又は合成し得ない置換又は置換形態を導入することが認められない。
(i)哺乳類、特にすでに特定の疾患又は障害にさらされていたが、当該疾患又は障害とは診断されてない哺乳類にその疾患又は障害が生じることを予防する。
(ii)疾患又は障害を抑制し、即ちその進行をコントロールする。
(iii)疾患又は障害を緩和し、即ち疾患又は障害を軽減又は解消させる。
(iv)疾患又は障害がもたらす症状を緩和させる。
次に記載の実施例は限定するのではなく説明するためのものであり、これにより本発明は限定されなくなる。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-オキサ-8-アザスピロ[4.5]デカン-8-イル)フェニル)アクリルアミド
化合物1(2g)のN-メチルピロリドン(15mL)溶液に化合物2(2.49g)、炭酸カリウム(5.29g)を加えた。反応液を100℃に加熱して一晩反応させた。反応液を室温に冷却して、水に注いだ。濾過し、ケーキを蒸留水で洗浄し乾燥して、化合物3(3.58g)を得た。
-20℃下で、化合物3(3.58g)のTHF(100mL)溶液に塩化スルフリル(2.3mL)を滴加した。引き続き当該温度下で反応液を2時間攪拌した。飽和炭酸水素ナトリウム水溶液で反応をクエンチした。静置して層化させ、有機相を取り分けた。水相を得て酢酸エチルで抽出した。有機相を合わせ、無水硫酸ナトリウムで乾燥して、減圧下で濃縮した。残留物を得てフラッシュカラムクロマトグラフィー(ジクロロメタン:メタノール=100:1)で精製して、化合物4(3.24g)を得た。
化合物4(3.24g)のエタノール(18mL)溶液にクロロアセトアルデヒド(18mL)を加えた。反応液を80℃に加熱して一晩反応させた。反応液を水に注いで濾過した。固体を得て乾燥して、化合物5(3.1g)を得た。
窒素保護下で、化合物5(1.23g)のジオキサン:水(20mL:5mL)溶液にテトラキス(トリフェニルホスフィン)パラジウム(0)(500mg)、化合物6(1.5g)、無水炭酸ナトリウム(1.5g)を加えた。反応液を80℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮し、残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=500:1)による分離で精製して、化合物7(1.12g)を得た。
化合物7(200mg)のDMF(1mL)溶液に無水炭酸セシウム(120mg)、モルホリン(0.1mL)を加え、60℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮した。残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=100:1~50:1)による分離で精製して、化合物8(120mg)を得た。
化合物8(120mg)のテトラヒドロフラン(5mL)溶液にパラジウム炭素(50mg)を加え、窒素で反応系を置換した。室温下で反応系を一晩反応させて、珪藻土で濾過した。濾液を減圧下で濃縮して化合物9(71mg)を得た。
氷浴下で、化合物9(71mg)のジクロロメタン(2mL)溶液にDIEA(5μL)、塩化アクリロイル(11μL)を加えた。氷浴下で反応液を2時間攪拌して、メタノールを加えて反応をクエンチして減圧下で濃縮した。残留物を得て分取薄層クロマトグラフィー(ジクロロメタン:メタノール=30:1)による分離で精製して化合物10(35mg)を得た。
1H NMR(400MHz,CDCl3),9.21(1H,s),9.00(1H,s),8.35(1H,s),8.22(1H,s),8.12(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.81(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.91-3.95(5H,m),3.68(2H,s),2.85-2.99(4H,m),1.87(2H,t,J=7.2Hz),1.78-1.83(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(7-オキサ-2-アザスピロ[3.5]ノナン-2-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.12(1H,s),8.41(1H,s),8.11(1H,s),8.01(1H,s),7.68(1H,s),7.46(1H,s),7.22(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8Hz,10.8Hz),6.09(1H,s),5.78(1H,d,J=10.8Hz),3.97(6H,s),3.94(3H,s),3.77(4H,s),3.60-3.67(4H,m),1.77-1.83(4H,m)。
N-(2-(8-シクロプロピル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.95(1H,s),8.42(1H,s),8.37(1H,s),8.13(1H,s),7.69(1H,s),7.49(1H,s),7.02-7.13(1H,brs),6.70(1H,s),6.45(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.96(6H,s),3.88(3H,s),3.21-3.78(4H,m),2.79(2H,d,J=10.4Hz),2.20-2.38(2H,m),1.97-2.18(3H,m),0.81-0.91(2H,m),0.56-0.70(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(テトラヒドロ-1H-フロ[3,4-c]ピロール-5(3H)-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.87(1H,s),8.37(1H,s),8.15(1H,s),8.12(1H,d,J=1.6Hz),7.68(1H,d,J=1.6Hz),7.49(1H,s),6.79(1H,s),6.70(1H,s),6.43(1H,d,J=17.2Hz),6.30(1H,dd,J=17.2Hz,10.0Hz),5.76(1H,d,J=10.0Hz),3.88-4.01(11H,m),3.76(2H,d,J=10.0Hz),3.17-3.24(2H,m),2.96-3.07(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-オキサ-7-アザスピロ[2.5]オクタン-7-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),9.01(1H,s),8.37(2H,s),8.12(1H,s),7.69(1H,s),7.49(1H,s),6.88(1H,s),6.70(1H,s),6.44(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.8Hz),5.78(1H,d,J=10.8Hz),3.90-4.01(11H,m),3.10(2H,t,J=7.2Hz),2.87(2H,s),0.91-0.99(2H,m),0.58-0.66(2H,m)。
N-(2-(3-オキサ-8-アザビシクロ[3.2.1]オクタン-8-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.19(1H,s),8.85(1H,s),8.38(1H,s),8.12(1H,s),7.84(1H,s),7.68(1H,s),7.49(1H,s),6.70(1H,s),6.61(1H,s),6.43(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.88-3.98(11H,m),3.75(2H,d,J=10.8Hz),3.62-3.65(2H,m),2.01-2.18(4H,m)。
N-(2-(8-アセチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.36(1H,s),8.32(1H,s),8.12(1H,d,J=1.6Hz),7.69(1H,d,J=1.6Hz),7.50(1H,s),6.86(1H,s),6.70(1H,s),6.46(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.0Hz),5.80(1H,d,J=10.0Hz),4.85-4.90(1H,m),4.24-4.28(1H,m),3.97(6H,s),3.90(3H,s),3.21(1H,d,J=9.6Hz),2.93-3.01(2H,m),2.85(1H,d,J=9.6Hz),1.98-2.28(7H,m)。
N-(2-(3-シクロプロピル-3,8-ジアザビシクロ[3.2.1]オクタン-8-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.01(1H,s),8.41(1H,s),8.27(1H,s),8.09(1H,s),7.49(1H,s),7.40(1H,s),6.63(1H,s),6.51(1H,s),6.19-6.33(2H,m),5.67(1H,d,J=10.0Hz),3.97(3H,s),3.86(6H,s),3.57-3.63(2H,m),3.19-3.24(1H,m),2.76(2H,d,J=10.8Hz),2.54(2H,d,J=10.8Hz),1.68-1.83(4H,m),0.29-0.36(2H,m),0.19-0.25(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4,7-ジアザスピロ[2.5]オクタン-7-イル)フェニル)アクリルアミドトリフルオロアセテート
1H NMR(400MHz,DMSO),9.44(2H,s),9.32(1H,s),9.28(1H,s),8.79(1H,s),8.73(1H,s),8.34(1H,s),7.80(1H,s),7.68(1H,s),7.08(1H,s),6.88(1H,s),6.62(1H,dd,J=16.8Hz,10.0Hz),6.23(1H,d,J=16.8Hz),5.75(1H,d,J=10.0Hz),3.99(6H,s),3.96(3H,s),3.39-3.48(2H,m),3.23-3.32(2H,m),3.05(2H,s),1.06-1.12(2H,m),0.83-0.90(2H,m)。
N-(2-(4-シクロプロピル-4,7-ジアザスピロ[2.5]オクタン-7-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.47(1H,s),8.35(1H,s),8.12(1H,s),7.69(1H,s),7.49(1H,s),6.90(1H,s),6.70(1H,s),6.43(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.97(6H,s),3.90(3H,s),3.02-3.21(4H,m),2.63-2.85(2H,m),1.95-2.15(1H,m),1.02-1.16(2H,m),0.40-0.61(6H,m)。
N-(2-(4-アセチル-4,7-ジアザスピロ[2.5]オクタン-7-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.28(1H,s),9.22(1H,s),8.72(1H,d,J=1.2Hz),8.70(1H,s),8.32(1H,s),7.72(1H,s),7.60(1H,d,J=1.2Hz),7.07(1H,s),6.95(1H,s),6.57(1H,dd,J=16.8Hz,10.4Hz),6.23(1H,dd,J=16.8Hz,1.6Hz),5.75(1H,d,J=10.4Hz),3.67-4.05(11H,m),2.65-3.12(4H,m),2.13(2.4H,s),2.03(0.6H,s),0.78-1.06(4H,m)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ビニルスルホンアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.39(1H,s),8.11(2H,s),7.70(1H,s),7.49(1H,s),7.40-7.47(1H,brs),6.93(1H,s),6.70(1H,s),6.66(1H,dd,J=16.4Hz,9.6Hz),6.42(1H,d,J=16.4Hz),6.01(1H,d,J=9.6Hz),3.98(6H,s),3.89(3H,s),3.63-3.69(1H,m),2.84-3.14(4H,m),1.66-1.92(4H,m),0.80-0.90(2H,m),0.56-0.66(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(4-(N,N-ジメチルスルホンアミド)ピペラジン-1-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.36(1H,s),8.12(2H,s),7.69(1H,s),7.50(1H,s),6.84(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.97(6H,s),3.92(3H,s),3.43-3.48(4H,m),3.01-3.06(4H,m),2.90(6H,s)。
N-(2-(7-アセチル-2,7-ジアザスピロ[3.5]ノナン-2-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.07(1H,s),8.39(1H,s),8.10(1H,s),7.95(1H,s),7.70-7.82(1H,brs),7.65(1H,s),7.43(1H,s),6.68(1H,s),6.36-6.44(2H,m),5.99-6.04(1H,m),5.70-5.75(1H,m),3.95(6H,s),3.90(3H,s),3.69-3.81(4H,m),3.48-3.55(2H,m),3.29-3.38(2H,m),2.06(3H,s),1.69-1.80(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(7,7-ジオキソ-7-チオ-2-アザスピロ[3.5]ノナン-2-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.39(1H,s),9.20(1H,s),8.67(1H,s),8.66(1H,s),7.88(1H,s),7.66(1H,s),7.58(1H,s),7.06(1H,s),6.46(1H,dd,J=16.8Hz,10.4Hz),6.20(1H,dd,J=16.8Hz,1.6Hz),6.15(1H,s),5.69(1H,dd,J=10.4Hz,1.6Hz),3.98(6H,s),3.95(3H,s),3.80(4H,s),3.08-3.13(4H,m),2.17-2.23(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(1-オキサ-8-アザスピロ[4.5]デカン-8-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.36(1H,s),8.31(1H,s),8.12(1H,s),7.68(1H,s),7.49(1H,s),6.90(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.4Hz),5.75(1H,d,J=10.4Hz),3.97(6H,s),3.91(2H,t,J=6.8Hz),3.90(3H,s),3.07-3.13(2H,m),2.85-2.92(2H,m),1.99(2H,qui,J=6.8Hz),1.77-1.91(6H,m)。
N-(2-(7-シクロプロピル-2,7-ジアザスピロ[3.5]ノナン-2-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.04(1H,s),9.38(1H,s),8.24(1H,s),8.09(1H,s),7.94(1H,s),7.63(1H,s),7.40(1H,s),6.67(1H,s),6.49(1H,dd,J=16.8Hz,10.0Hz),6.38(1H,d,J=16.8Hz),6.01(1H,s),5.70(1H,d,J=10.0Hz),3.93(6H,s),3.89(3H,s),3.74(4H,s),2.62-2.98(4H,m),1.89-2.06(5H,m),0.79-0.88(2H,m),0.55-0.64(2H,m)。
N-(2-(6-シクロプロピル-2,6-ジアザスピロ[3.4]オクタン-2-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.10(1H,s),8.41(1H,s),8.11(1H,s),7.99(1H,s),7.60-7.75(2H,m),7.44(1H,S),6.69(1H,s),6.38-6.45(2H,m),6.07(1H,s),5.74-5.77(1H,m),3.88-4.09(11H,m),2.92-3.24(4H,m),2.16-2.25(2H,m),1.88-2.06(3H,m),0.80-0.90(2H,m),0.53-0.62(2H,m)。
N-(2-(9-シクロプロピル-3,9-ジアザスピロ[5.5]ウンデカン-3-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.27(1H,s),9.09(1H,s),8.70(1H,s),8.69(1H,s),8.40(1H,s),7.70(1H,s),7.59(1H,s),7.06(1H,s),6.85(1H,s),6.65(1H,dd,J=16.8Hz,10.4Hz),6.22(1H,d,J=16.8Hz),5.71(1H,d,J=10.4Hz),3.98(6H,s),3.94(3H,s),2.88-2.96(4H,m),1.36-2.02(13H,m),0.96-1.12(2H,m),0.66-0.86(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-オキサ-6-アザスピロ[3.4]オクタン-6-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.14(1H,s),8.41(1H,s),8.35(1H,s),8.11(1H,s),7.68(1H,s),7.47(1H,s),7.42(1H,s),6.70(1H,s),6.51(1H,s),6.42(1H,d,J=16.4Hz),6.29(1H,dd,J=16.4Hz,10.0Hz),5.77(1H,d,J=10.0Hz),4.64-4.71(4H,m),3.97(6H,s),3.94(3H,s),3.55(2H,s),3.33(2H,t,J=7.2Hz),2.27(2H,t,J=7.2Hz)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(3-オキサ-9-アザスピロ[5.5]ウンデカン-9-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.20(1H,s),8.99(1H,s),8.36(1H,s),8.21(1H,s),8.12(1H,d,J=1.6Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.86(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.4Hz),5.77(1H,d,J=10.4Hz),3.97(6H,s),3.92(3H,s),3.71-3.75(4H,m),2.90-2.95(4H,m),1.74-1.79(4H,m),1.61-1.66(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(7-メチル-2,7-ジアザスピロ[4.4]ノナン-2-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.08(1H,s),8.42(1H,s),8.11(1H,s),8.09(1H,s),7.66(1H,s),7.44(1H,s),6.67-6.71(2H,m),6.49-6.61(1H,m),6.41(1H,d,J=16.8Hz),6.36(1H,s),5.73(1H,d,J=10.8Hz),3.93-4.01(13H,m),3.37-3.56(4H,m),2.81(3H,s),1.99-2.26(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-メチル-4,7-ジアザスピロ[2.5]オクタン-7-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),9.02(1H,s),8.44(1H,s),8.36(1H,s),8.12(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.50(1H,s),6.90(1H,s),6.70(1H,s),6.44(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.78(1H,d,J=10.0Hz),3.98(6H,s),3.93(3H,s),3.09-3.13(2H,m),3.02-3.08(2H,m),2.67-2.78(2H,m),2.46(3H,s),0.84-0.90(2H,m),0.49-0.52(2H,m)。
N-(2-(5-シクロプロピルヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.25(1H,s),9.05(1H,s),8.70(2H,s),8.17(1H,s),7.69(1H,s),7.59(1H,s),7.06(1H,s),6.61-6.74(2H,m),6.21-6.30(1H,m),5.69-5.78(1H,m),3.94-4.01(9H,m),3.54-3.63(4H,m),3.06-3.14(4H,m),2.90-3.02(3H,m),1.20-1.30(2H,m),0.74-0.84(2H,m)。
N-(2-(8-シクロプロピル-2,8-ジアザスピロ[4.5]デカン-2-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.52(1H,s),9.20(1H,s),8.68(1H,s),8.66(1H,s),7.91(1H,s),7.66(1H,s),7.58(1H,s),7.06(1H,s),6.38-6.51(2H,m),6.19(1H,d,J=16.8Hz),5.70(1H,d,J=10.4Hz),3.99(3H,s),3.98(6H,s),3.38-3.54(4H,m),3.14-3.30(4H,m),2.76-2.94(1H,m),1.69-1.91(4H,m),1.39-1.62(2H,m),0.96-1.12(2H,m),0.69-0.87(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-オキサ-7-アザスピロ[4.4]デカン-7-イル)フェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.15(1H,s),8.40(1H,s),8.15(1H,s),8.11(1H,s),7.68(1H,s),7.62(1H,s),7.46(1H,s),6.70(1H,s),6.42(1H,s),3.89-3.97(11H,m),3.75(1H,d,J=8.4Hz),3.67(1H,d,J=8.4Hz),3.44-3.49(2H,m),3.34(1H,d,J=9.2Hz),3.30(1H,d,J=9.2Hz),1.88-2.03(7H,m)。
N-(2-((1S,4S)-2-オキサ-5-アザビシクロ[2.2.1]ヘプタン-5-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.16(1H,s),8.39(1H,s),8.26(1H,s),8.11(1H,s),7.68(1H,s),7.53(1H,s),7.47(1H,s),6.70(1H,s),6.49(1H,s),4.65(1H,s),4.29(1H,s),4.10(1H,d,J=8.0Hz),3.97(6H,s),3.93(3H,s),3.87(1H,d,J=8.0Hz),3.49(1H,d,J=9.2Hz),3.49(1H,d,J=9.2Hz),1.96-2.06(5H,m)。
N-(2-(3-オキサ-8-アザビシクロ[3.2.1]オクタン-8-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.19(1H,s),8.67(1H,s),8.34(1H,s),8.11(1H,s),7.88(1H,s),7.68(1H,s),7.49(1H,s),6.70(1H,s),6.60(1H,s),3.93-4.01(8H,m),3.89(3H,s),3.76-3.79(2H,m),3.64-3.68(2H,m),2.01-2.17(7H,m)。
1H NMR(400MHz,CDCl3),9.21(1H,s),8.80(1H,s),8.33(1H,s),8.25(1H,s),8.12(1H,s),7.68(1H,s),7.49(1H,s),6.84(1H,s),6.70(1H,s),3.96(6H,s),3.89-3.95(7H,m),2.95-2.98(4H,m),2.03(3H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(1,1-ジオキソチオモルホリン)-4-メトキシフェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.22(1H,s),8.74(1H,s),8.33(1H,s),8.12(1H,s),7.96(1H,s),7.70(1H,s),7.51(1H,s),6.87(1H,s),6.71(1H,s),3.98(6H,s),3.92(3H,s),3.49-3.53(4H,m),3.31-3.35(4H,m),2.05(3H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-モルホリンピペリジン-1-イル)フェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.79(1H,s),8.32(1H,s),8.17(1H,s),8.11(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.49(1H,s),6.82(1H,s),6.70(1H,s),3.97(6H,s),3.79-3.92(7H,m),3.18-3.24(2H,m),2.61-2.84(6H,m),2.13-2.23(1H,m),2.04(3H,s),1.59-1.91(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-メチル-4,7-ジアザスピロ[2.5]オクタン-7-イル)フェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.79(1H,s),8.32(2H,s),8.11(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.49(1H,s),6.86(1H,s),6.70(1H,s),3.98(6H,s),3.92(3H,s),3.02-3.28(4H,m),2.38-2.87(5H,m),2.04(3H,s),0.79-0.96(2H,m),0.61-0.77(2H,m)。
N-(5-(6-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1’,2’:1,6]ピリド[2,3-d]ピリミジン-2-イル)-4-メトキシ-2-(4-(オキセタン-3-イル)ピペラジン-1-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.34(1H,s),9.07(1H,s),8.58(1H,s),8.26(1H,s),7.68(1H,s),7.43(1H,s),6.94(1H,s),6.71(1H,s),6.41(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8Hz,10.4Hz),5.77(1H,d,J=10.4Hz),4.66-4.75(4H,m),3.98(6H,s),3.93(3H,s),3.60-3.66(1H,m),3.02-3.09(4H,m),2.48-2.64(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(5-メチル-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.07(1H,s),8.84(1H,s),8.40(1H,s),8.35(1H,s),8.10(1H,s),7.63(1H,s),7.42(1H,s),6.61-6.75(3H,m),6.39(1H,dd,J=16.8Hz,1.2Hz),5.69(1H,d,J=10.4Hz),4.44-4.50(1H,m),4.10-4.20(2H,m),3.91-3.98(9H,m),3.64-3.81(1H,m),3.43-3.52(1H,m),3.19-3.27(1H,m),2.87(3H,s),2.26-2.38(2H,m)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(6-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1’,2’:1,6]ピリド[2,3-d]ピリミジン-2-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,DMSO),9.55(1H,s),9.17(1H,s),8.51(1H,d,J=1.6Hz),8.33(1H,s),7.75(1H,s),7.64(1H,d,J=1.6Hz),7.09(1H,s),6.87(1H,s),6.63(1H,dd,J=16.8Hz,10.4Hz),6.23(1H,dd,J=16.8Hz,1.6Hz),5.73(1H,dd,J=10.4Hz,1.6Hz),3.99(6H,s),3.89(3H,s),2.92-2.97(4H,m),2.74-2.79(4H,m),1.68-1.74(1H,m),0.42-0.47(2H,m),0.30-0.36(2H,m)。
N-(2-((1S,4S)-2-オキサ-5-アザビシクロ[2.2.1]ヘプタン-5-イル)-5-(6-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1’,2’:1,6]ピリド[2,3-d]ピリミジン-2-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.31(1H,s),8.58(1H,s),8.55(1H,s),7.69(1H,s),7.43(1H,s),7.39(1H,s),6.72(1H,s),6.62(1H,s),6.46(1H,d,J=16.8Hz),6.33(1H,dd,J=16.8Hz,10.0Hz),5.81(1H,d,J=10.0Hz),4.65-4.69(1H,m),4.27-4.31(1H,m),4.12(1H,d,J=8.0Hz),3.99(6H,s),3.97(3H,s),3.88(1H,d,J=8.0Hz),3.42-3.46(2H,m),1.99-2.09(2H,m)。
N-(2-(4-アセチルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.39(1H,s),8.24(1H,s),8.14(1H,s),7.70(1H,s),7.51(1H,s),6.81(1H,s),6.71(1H,s),6.43(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.94(3H,s),3.79-3.87(2H,m),3.64-3.70(2H,m),2.94-2.99(4H,m),2.17(3H,s)。
(S)-N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-メチルモルホリン)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),9.01(1H,s),8.39(1H,s),8.28(1H,s),8.14(1H,d,J=1.2Hz),7.68(1H,d,J=1.2Hz),7.50(1H,s),6.83(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.76(1H,dd,J=10.0Hz,1.2Hz),4.04(1H,d,J=11.6Hz),3.96(6H,s),3.92(3H,s),3.77-3.86(2H,m),2.88-2.95(3H,m),2.63(1H,t,J=10.8Hz),1.24(3H,t,J=6.4Hz)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-(メチルスルホニル)ピペラジン-1-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.19(1H,s),8.96(1H,s),8.37(1H,s),8.11(1H,d,J=1.6Hz),8.10(1H,s),7.68(1H,d,J=1.2Hz),7.49(1H,s),6.83(1H,s),6.69(1H,s),6.42(1H,d,J=16.8Hz),6.27(1H,dd,J=16.8Hz,10.0Hz),5.76(1H,d,J=10.0Hz),3.96(6H,s),3.91(3H,s),3.42-3.46(4H,m),3.05-3.08(4H,m),2.88(3H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(2,2-ジメチルモルホリン)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.22(1H,s),8.99(1H,s),8.39(1H,s),8.22(1H,s),8.13(1H,d,J=1.2Hz),7.70(1H,d,J=1.2Hz),7.51(1H,s),6.84(1H,s),6.71(1H,s),6.46(1H,d,J=16.8Hz),6.26(1H,dd,J=16.8Hz,10.4Hz),5.78(1H,d,J=10.4Hz),3.92-4.02(11H,m),2.97(2H,t,J=4.4Hz),2.71(2H,s),1.41(6H,s)。
(R)-N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-メチルモルホリン)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.99(1H,s),8.39(1H,s),8.27(1H,s),8.14(1H,d,J=1.2Hz),7.69(1H,d,J=1.2Hz),7.51(1H,s),6.84(1H,s),6.70(1H,s),6.41(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),4.04(1H,d,J=11.2Hz),3.96(6H,s),3.92(3H,s),3.78-3.87(2H,m),2.88-2.98(3H,m),2.63(1H,dd,J=11.2Hz,10.0Hz),1.25(3H,d,J=6.4Hz)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)-2-メチルイミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.17(1H,s),8.97(1H,s),8.36(1H,s),8.28(1H,s),7.86(1H,s),7.43(1H,s),6.85(1H,s),6.68(1H,s),6.42(1H,d,J=16.8Hz),6.32(1H,dd,J=16.8Hz,10.0Hz),5.77(1H,d,J=10.0Hz),3.96(6H,s),3.82(3H,s),2.75-3.05(8H,m),2.47(3H,s),1.70-1.81(1H,m),0.46-0.61(4H,m)。
tert-ブチル2-(2-アクリルアミド-4-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-5-メトキシフェニル)-2,7-ジアザスピロ[3.5]ノナン-7-カルボキシレート
1H NMR(400MHz,CDCl3),9.11(1H,s),8.42(1H,s),8.11(1H,s),8.04(1H,s),7.68(1H,s),7.45(1H,s),7.03(1H,s),6.70(1H,s),6.42(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8Hz,10.0Hz),6.12(1H,s),5.78(1H,d,J=10.0Hz),3.97(6H,s),3.95(3H,s),3.76(4H,s),3.35-3.41(4H,m),1.72-1.81(4H,m),1.46(9H,s)。
N-(2-(8-オキサ-3-アザビシクロ[3.2.1]オクタン-3-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3),9.22(1H,s),9.01(1H,s),8.38(1H,s),8.36(1H,s),8.13(1H,d,J=1.2Hz),7.71(1H,d,J=1.2Hz),7.51(1H,s),6.93(1H,s),6.72(1H,s),6.47(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz,10.0Hz),5.81(1H,d,J=10.0Hz),4.52(2H,s),3.99(6H,s),3.92(3H,s),3.19(2H,d,J=11.2Hz),2.78(2H,d,J=11.2Hz),2.09-2.05(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2,7-ジアザスピロ[3.5]ノナン-2-イル)フェニル)アクリルアミド塩酸塩
1H NMR(400MHz,CD3OD),9.49(1H,s),9.04(1H,s),9.01(1H,s),8.22(1H,s),8.02(1H,s),7.91(1H,s),7.08(1H,s),6.51(1H,dd,J=16.8Hz,10.0Hz),6.41(1H,dd,J=16.8Hz,2.0Hz),6.27(1H,s),5.86(1H,dd,J=10.0Hz,2.0Hz),4.07(3H,s),4.04(6H,s),3.95(4H,s),3.21-3.24(4H,m),2.07-2.11(4H,m)。
N-(2-(((4-(クロロメチル)ピペリジン-4-イル)メチル)アミノ)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド塩酸塩
1H NMR(400MHz,CD3OD),9.59(1H,s),9.20(1H,d,J=2.0Hz),9.09(1H,s),8.36(1H,s),8.14(1H,d,J=2.0Hz),7.97(1H,s),7.11(1H,s),6.75(1H,s),6.62(1H,dd,J=16.8Hz,10.4Hz),6.41(1H,dd,J=16.8Hz,1.2Hz),5.85(1H,dd,J=10.4Hz,1.2Hz),4.13(3H,s),4.05(6H,s),3.83(2H,s),3.53(2H,s),3.30-3.36(2H,m),3.19-3.25(2H,m),1.90-2.03(4H,m)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ブト-2-インアミド
1H NMR(400MHz,CDCl3),9.22(1H,s),8.82(1H,s),8.34(1H,s),8.30(1H,s),8.13(1H,s),7.71(1H,s),7.51(1H,s),6.88(1H,s),6.72(1H,s),3.99(6H,S),3.89(3H,s),2.78-3.11(8H,m),2.06(3H,s),1.77-1.84(1H,m),0.44-0.64(4H,m)。
(Z)-N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)-4-メトキシブト-2-エナミン
1H NMR(400MHz,CDCl3),9.21(1H,s),8.89(1H,s),8.44(1H,s),8.33(1H,s),8.11(1H,s),7.68(1H,s),7.49(1H,s),6.85(1H,s),6.70(1H,s),6.25(1H,d,J=6.0Hz),4.66-4.72(1H,m),3.98(6H,s),3.87(3H,s),3.72(3H,s),3.24(2H,d,J=7.6Hz),2.77-3.24(8H,m),1.78-1.87(1H,m),0.47-0.59(4H,m)。
2-クロロ-N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アセトアミド
1H NMR(400MHz,CDCl3),9.48(1H,s),9.22(1H,s),8.96(1H,s),8.37(1H,s),8.12(1H,d,J=1.2Hz),7.70(1H,d,J=1.2Hz),7.50(1H,s),6.92(1H,s),6.71(1H,s),4.27(2H,s),3.98(6H,s),3.84(3H,s),2.85-3.08(8H,m),1.76-1.82(1H,m),0.49-0.63(4H,m)。
2-シアノ-N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アセトアミド
1H NMR(400MHz,CDCl3),9.28(1H,s),9.23(1H,s),8.92(1H,s),8.37(1H,s),8.12(1H,s),7.70(1H,s),7.51(1H,s),6.95(1H,s),6.71(1H,s),3.98(6H,s),3.90(3H,s),3.62(2H,s),2.86-3.17(8H,m),1.76-1.95(1H,m),0.50-0.79(4H,m)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ブト-3-インアミド
1H NMR(400MHz,CDCl3),9.21(1H,s),8.92(1H,s),8.41(1H,s),8.34(1H,s),8.11(1H,d,J=1.6Hz),7.69(1H,d,J=1.2Hz),7.49(1H,s),6.87(1H,s),6.70(1H,s),6.03-6.14(1H,m),5.38-5.43(2H,m),3.98(6H,s),3.87(3H,s),3.25(2H,d,J=7.6Hz),2.77-3.02(8H,m),1.69-1.89(1H,m),0.48-0.61(4H,m)。
(E)-N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)ブト-2-エナミン
1H NMR(400MHz,CDCl3),9.33(1H,s),9.11(1H,s),8.48(1H,s),8.23-8.26(2H,m),7.81(1H,d,J=1.2Hz),7.62(1H,s),7.08-7.17(1H,m),7.00(1H,s),6.83(1H,s),6.12(1H,d,J=16.8Hz),4.10(6H,s),4.01(3H,s),2.90-3.20(8H,m),2.07(3H,d,J=6.8Hz),1.83-1.96(1H,m),0.57-0.80(4H,m)。
N-(2-(4-シクロプロピルピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)プロピオールアミド
1H NMR(400MHz,CDCl3),9.23(1H,s),8.85(1H,s),8.49-8.55(1H,brs),8.35(1H,s),8.13(1H,s),7.71(1H,s),7.51(1H,s),6.90(1H,s),6.72(1H,s),3.99(6H,s),3.91(3H,s),2.85-3.07(9H,m),1.74-1.83(1H,m),0.46-0.61(4H,m)。
1.化合物のインビトロタンパク質活性測定:
均一時間分解蛍光(HTRF)法を用いてFGFR-4キナーゼ活性検出プラットフォームを確立して、化合物活性の測定を行った。100%DMSOを用いて1000μMから化合物の3倍の勾配希釈を11回行い(合計で12の濃度)、各濃度は4μLを取り分けて96μLの反応バッファー(50mMのHEPES、pH7.4、5mMのMnCl2、0.1mMのNaVO3、0.001%Tween-20、0.01%BAS、1mMのDTT)に加えて均一に混合して、4×化合物(最終濃度は0.017nM~1000nM)として待機した。反応バッファーを使用して2×FGFR-4キナーゼ(最終濃度は1nM)を調製し、反応バッファーで4×基質(ATP+TKペプチド)を調製した(TKペプチドはHTRF(登録商標)KinEASE(商標)-TKで、Cisbioより購入した。TKペプチドの最終濃度は1μMで、ATPの最終濃度は25μMであった)。4×化合物から2.5μL取り分けて384ウェルプレート(OptiPlate-384、PerkinElmerより購入)に加え、次に5μLの2×FGFR-4キナーゼを加えて、遠心分離して均一に混合させ、そして2.5μLの4×基質混合物を加えて反応を開始させた(総反応体積は10μL)。384ウェルプレートをインキュベーターに入れて23℃下で60分間攪拌し、次に5μLのEu3+ クリプテート標識抗ホスホチロシン抗体(Eu3+ cryptate-labled anti-phosphotyrosine antibody)(HTRF(登録商標)KinEASE(商標)-TK、Cisbioより購入)、5μLのストレプトアビジン(Streptavidin)-XL-665(HTRF(登録商標)KinEASE(商標)-TK、Cisbioより購入)を加えて反応を停止させた。インキュベーターにおいて1時間インキュベートした後、Envision(PerkinElmerより購入)において蛍光値を読み取った(320nmで励起し、665nm及び620nmでの発光を検出し、二者の比の値は酵素活性である)。各化合物はそれぞれ12の濃度において酵素活性を測定し、ソフトウェアGraphPad prism 5.0を用いてデータから当該化合物のIC50値を算出した。
Promega社のCell Titer-Glo(登録商標)検出試薬を用いて浮遊細胞増殖阻害スクリーニングという方法を確立した。10%ウシ胎児血清(Hyclone(登録商標))を添加したMEM(Gibco(登録商標))培地でヒト肝がん細胞Hep3b(協和細胞研究センター)を培養し、培養条件は37℃、95%空気及び5%CO2であり、25cm2又は75cm2のプラスチック製組織培養フラスコ(Corning(登録商標))において培養し、週に2~3回継代させた。
北京維通利華実験働物技術有限公司が提供する雄SDラットを用い、1群当たり3匹でラットの群分けを実施し、それぞれ1回の強制経口で被験サンプル懸濁液(5mg/kg)を投与した。動物は実験前に一晩絶食させ、絶食時間は投与前10時間から投与後4時間までとした。投与後0.25時間、0.5時間、1時間、2時間、4時間、6時間、8時間、24時間に採血した。小動物用麻酔器を用いてイソフルランで麻酔した後、眼窩静脈叢から0.3mLの全血を採取してヘパリン抗凝固採血管に入れ、サンプルは4℃、4000rpmで5分間遠心分離し、血漿を遠沈管に移して、分析に備えて-80℃において保存した。タンパク質沈殿法で血漿中からサンプルを抽出して、LC/MS/MSで抽出液を分析した。
化合物1(2g)のN-メチルピロリドン(15mL)溶液に化合物2(2.49g)、炭酸カリウム(5.29g)を加えた。100℃下で反応液を一晩加熱した。反応液を室温に冷却して、水に注いだ。濾過し、ケーキを蒸留水で洗浄し乾燥して、化合物3(3.58g)を得た。
-20℃下で、化合物3(3.58g)のTHF(100mL)溶液に塩化スルフリル(2.3mL)を滴加した。引き続き-20℃下で、反応が完了するまで反応液を2時間攪拌した。飽和炭酸水素ナトリウム水溶液で反応をクエンチした。有機相を分離し、水相は酢酸エチルで抽出した。有機相を合わせ、無水硫酸ナトリウムで乾燥して、減圧下で濃縮した。残留物を得てフラッシュカラムクロマトグラフィー(ジクロロメタン:メタノール=100:1)で精製して、化合物4(3.24g)を得た。
化合物4(3.24g)のエタノール(18mL)溶液にクロロアセトアルデヒド(18mL)を加えた。反応液を80℃に加熱して一晩反応させた。反応液を水に注いで濾過した。固体を得て乾燥して、化合物5(3.1g)を得た。
窒素保護下で、化合物5(1.23g)のジオキサン:水(20mL:5mL)溶液にテトラキス(トリフェニルホスフィン)パラジウム(0)(500mg)、化合物6(1.5g)、無水炭酸ナトリウム(1.5g)を加えた。反応液を80℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮し、残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=500:1)による分離で精製して、化合物7(1.12g)を得た。
化合物7(200mg)のDMF(1mL)溶液に無水炭酸セシウム(120mg)、モルホリン(0.1mL)を加え、60℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮した。残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=100:1~50:1)による分離で精製して、化合物8(120mg)を得た。
化合物8(120mg)のテトラヒドロフラン(5mL)溶液にパラジウム炭素(50mg)を加え、窒素で反応系を置換した。室温下で反応系を一晩反応させて、珪藻土で濾過した。濾液を減圧下で濃縮して化合物9(71mg)を得た。
0℃下で、化合物9(71mg)のジクロロメタン(2mL)溶液にDIEA(5μL)、塩化アクリロイル(11μL)を加えた。0℃下で反応液を2時間攪拌して、メタノールを加えてクエンチして減圧下で濃縮した。残留物を得て分取薄層クロマトグラフィー(ジクロロメタン:メタノール=25:1)による分離で精製して、実施例54(35mg)を得た。
1H NMR(400MHz,CDCl3)δ 9.22(1H,s),9.02(1H,s),8.38(1H,s),8.27(1H,s),8.14(1H,s),7.70(1H,s),7.51(1H,s),6.86(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.87-3.95(7H,m),2.95-3.02(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-((4-メチルピペラジン-1-イル)メチル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.62-10.21(1H,brs),9.20(1H,s),8.82(1H,s),8.39(1H,s),8.15(1H,s),7.70(1H,s),7.51(1H,s),6.88(1H,s),6.71(1H,s),6.39(1H,d,J=16.8Hz),6.18-6.29(1H,m),5.75(1H,d,J=11.6Hz),3.98(6H,s),3.92(3H,s),3.78(2H,s),2.75-3.02(8H,m),2.69(3H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(3-ヒドロキシ-8-アザ[3.2.1]オクト-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.19(1H,s),8.87(1H,s),8.38(1H,s),8.12(1H,s),7.75(1H,s),7.69(1H,s),7.49(1H,s),6.71(1H,s),6.66(1H,s),6.45(1H,d,J=16.8Hz),6.29(1H,dd,J=16.8,10.4Hz),5.77(1H,d,J=10.4Hz),4.24-4.29(1H,m),3.98(6H,s),3.91(3H,s),3.75-3.83(2H,m),2.32-2.39(2H,m),2.21-2.31(2H,m),2.04-2.12(2H,m),1.94-2.03(2H,m)。
N-(2-(4-(シクロプロピルメチル)ピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),9.04(1H,s),8.37(1H,s),8.33(1H,s),8.12(1H,s),7.70(1H,s),7.50(1H,s),6.93(1H,s),6.71(1H,s),6.42(1H,d,J=17.2Hz),6.29(1H,dd,J=17.2,10.0Hz),5.77(1H,d,J=10.0Hz),3.98(6H,s),3.91(3H,s),3.01-3.08(4H,m),2.67-2.85(4H,m),2.39(2H,d,J=6.4Hz),0.81-0.94(1H,m),0.55-0.63(2H,m),0.15-0.23(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-モルホリニルピペリジン-1-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),9.01(1H,s),8.36(1H,s),8.19(1H,s),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.85(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.0Hz),5.76(1H,d,J=10.0Hz),3.98(6H,s),3.91(3H,s),3.76-3.83(4H,m),3.20(2H,d,J=10.8Hz),2.79(2H,t,J=11.6Hz),2.61-2.71(4H,m),2.30-2.42(1H,m),2.12(2H,d,J=11.6Hz),1.64-1.78(2H,m)。
N-(2-(4-シクロプロピルピペリジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),9.03(1H,s),8.30-8.38(2H,m),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.89(1H,s),6.71(1H,s),6.43(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8Hz),5.78(1H,d,J=10.0Hz),3.98(6H,s),3.89(3H,s),2.94-3.04(4H,m),2.79-2.93(4H,m),1.72-1.82(1H,m),0.42-0.59(4H,m)。
N-(2-(4-シアノピペラジン-1-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),8.99(1H,s),8.37(1H,s),8.13(1H,s),8.05(1H,s),7.70(1H,s),7.51(1H,s),6.84(1H,s),6.71(1H,s),6.43(1H,d,J=17.2Hz),6.28(1H,dd,J=17.2 ,10.4Hz),5.74(1H,d,J=10.4Hz),3.98(6H,s),3.93(3H,s),3.43-3.53(4H,m),3.03-3.12(4H,m)。
N-(2-((1S,4S)-2-オキサ-5-アザビシクロ[2.2.1]ヘプト-5-イル)-5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.15(1H,s),8.41(1H,s),8.40(1H,s),8.13(1H,s),7.69(1H,s),7.60(1H,s),7.48(1H,s),6.70(1H,s),6.52(1H,s),6.41(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8,10.0Hz),5.75(1H,d,J=10.0Hz),4.62(1H,s),4.24(1H,s),4.08(1H,d,J=7.6Hz),3.97(6H,s),3.92(3H,s),3.83(1H,d,J=7.6Hz),3.42(1H,d,J=9.6Hz),3.37(1H,d,J=9.6Hz),1.94-2.01(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(2-オキサ-7-アザスピロ[4,4]ノン-7-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.14(1H,s),8.42(1H,s),8.28(1H,s),8.12(1H,s),7.68(1H,s),7.63(1H,s),7.47(1H,s),6.70(1H,s),6.46(1H,s),6.37(1H,d,J=16.8Hz),6.31(1H,dd,J=16.8,10.8Hz),5.76(1H,d,J=10.8Hz),3.97(6H,s),3.94(3H,s),3.87-3.93(2H,m),3.72(1H,d,J=8.4Hz),3.65(1H,d,J=8.4Hz),3.37-3.43(2H,m),3.30(1H,d,J=9.2Hz),3.25(1H,d,J=9.2Hz),1.86-2.03(4H,m)。
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),8.86(1H,d,J=9.2Hz),8.37(1H,s),8.14(1H,s),7.71(1H,s),7.51(1H,s),7.46(1H,s),6.87(1H,d,J=12.4Hz),6.71(1H,s),6.46(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.0Hz),5.80(1H,d,J=10.0Hz),3.98(6H,s),3.93(3H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル)フェニル)アクリルアミド
1H NMR(400MHz,DMSO-d6)δ 9.51(1H,s),9.32(1H,s),9.12(1H,s),8.93(1H,s),8.38(1H,s),8.21(1H,s),8.08(1H,s),7.15(1H,s),6.90(1H,s),6.89(1H,dd,J=17.2,10.0Hz),6.25(1H,d,J=17.2Hz),5.75(1H,d,J=10.0Hz),4.01(6H,s),3.97(3H,s),3.68-3.86(4H,m),3.49-3.65(4H,m),3.32-3.48(3H,m),2.75-2.88(5H,m),2.14-2.26(2H,m),1.96-2.12(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(4-(オキセタン-3-イル)ピペラジン-1-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),9.02(1H,s),8.37(1H,s),8.24(1H,s),8.12(1H,s),7.70(1H,s),7.50(1H,s),6.91(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),4.67-4.75(4H,m),3.98(6H,s),3.92(3H,s),3.60-3.68(1H,m),3.01-3.12(4H,m),2.46-2.67(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-((2-(ジメチルアミノ)エチル)(メチル)アミノ)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CD3OD)δ 9.20(1H,s),8.54(1H,s),8.35(1H,s),8.24(1H,s),7.65(1H,s),7.56(1H,s),6.93(1H,s),6.85(1H,s),6.69(1H,dd,J=17.2,10.4Hz),6.43(1H,d,J=17.2Hz),5.83(1H,d,J=10.4Hz),4.02(6H,s),4.01(3H,s),3.43-3.51(2H,m),3.12-3.21(2H,m),2.83(3H,s),2.75(6H,s)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(4-ジメチルアミノ)ピペリジン-1-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.18(1H,s),8.92(1H,s),8.37(1H,s),8.12-8.18(2H,m),7.69(1H,s),7.49(1H,s),6.79(1H,s),6.71(1H,s),6.42-6.45(2H,m),5.77-5.80(1H,m),3.98(6H,s),3.90(3H,s),3.31(2H,d,J=12.0Hz),3.12-3.24(1H,m),2.79-2.89(8H,m),2.35(2H,d,J=11.2Hz),2.07-2.22(2H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-4-メトキシ-2-(8-オキサ-2-アザスピロ[4.5]デカ-2-イル)フェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.13(1H,s),8.40(1H,s),8.29(1H,s),8.12(1H,s),7.78(1H,s),7.68(1H,s),7.47(1H,s),6.70(1H,s),6.44(1H,s),6.42(1H,d,J=16.8Hz),6.34(1H,dd,J=16.8,10.0Hz),5.77(1H,d,J=10.0Hz),3.97(6H,s),3.94(3H,s),3.61-3.71(4H,m),3.36(2H,t,J=6.8Hz),3.14(2H,s),1.81(2H,t,J=6.8Hz),1.52-1.68(4H,m)。
N-(5-(4-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1,2-a][1,6]ナフチリジン-8-イル)-2-(4-エチルピペラジン-1-イル)-4-メトキシフェニル)アクリルアミド
1H NMR(400MHz,CDCl3)δ 9.21(1H,s),9.04(1H,s),8.37(1H,s),8.32(1H,s),8.12(1H,s),7.69(1H,s),7.50(1H,s),6.91(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.30(1H,dd,J=16.8,10.4Hz),5.77(1H,d,J=10.4Hz),3.98(6H,s),3.90(3H,s),3.01-3.05(4H,m),2.58-2.75(4H,m),2.54(2H,q,J=7.2Hz),1.17(3H,t,J=7.2Hz)。
N-(5-(6-(2,6-ジクロロ-3,5-ジメトキシフェニル)イミダゾ[1’,2’:1,6]ピリド[2,3-d]ピリミジン-2-イル)-4-メトキシ-2-(4-(オキセタン-3-イル)ピペラジン-1-イル)フェニル)アクリルアミド
室温下で、化合物2(3.0g)のテトラヒドロフラン(20mL)溶液に水素化ナトリウム(774mg)を加え、室温下で混合物を1.5時間攪拌し、次に混合物に化合物10(2.86g)を加え、室温下で混合物を一晩攪拌した。飽和塩化アンモニウム水溶液で反応をクエンチして、ジクロロメタンで希釈し、有機相を分離し、飽和塩化アンモニウム水溶液で洗浄して、無水硫酸ナトリウムで乾燥し、濾過、濃縮して、残留物はフラッシュシリカゲルカラムクロマトグラフィー(DCM:MeOH=100:1)で精製して、化合物11(5.2g)を得た。
-20℃下で、化合物11(5.2g)のテトラヒドロフラン(100mL)溶液にゆっくりと塩化スルフリル(2.81g)を滴加した。滴加が完了した後、-20℃下で混合物を2時間攪拌した。次に、飽和炭酸水素ナトリウム水溶液で反応をクエンチした。酢酸エチルで混合物を抽出し、抽出液は無水硫酸ナトリウムで乾燥し、濾過して濃縮し、残留物はフラッシュシリカゲルカラムクロマトグラフィー(DCM:MeOH=100:2)で精製して、化合物12(4.7g)を得た。
化合物12(2.0g)のエタノール(20mL)溶液に40%クロロアセトアルデヒド水溶液(8mL)を加え、80℃下で混合物を一晩加熱した。混合物を飽和炭酸水素ナトリウム水溶液に注いで、攪拌して濾過し、ケーキを乾燥して、淡黄色の固体13(2.1g)を得た。当該化合物は精製せずそのまま次のステップの反応に使用した。
化合物13(2.1g)のジクロロメタン:メタノール:水(20mL:20mL:20mL)溶液に過硫酸水素カリウム複塩(18.4g)を加え、混合物を40℃に加熱して一晩攪拌した。水を加えて混合物を希釈して、ジクロロメタンで抽出し、抽出液は無水硫酸ナトリウムで乾燥し、濾過して濃縮した。淡黄色の固体14を得て精製せずそのまま次のステップの反応に使用した。
化合物14(2.5g)のTHF(10mL)溶液に水酸化カリウム(924mg)の水(10mL)溶液を加えた。室温下で反応液を一晩攪拌した。減圧下で濃縮してTHFを除去し、pHが2になるまで濃塩酸を滴加した。濾過して、白い固体を得て無水アセトニトリル(5mL)で洗浄し乾燥して、化合物15(2.1g)を得た。
化合物15(2.1g)のアセトニトリル(20mL)溶液に塩化ホスホリル(20mL)を加え、反応液を80℃に加熱して3時間反応させ、次に室温に冷却した。反応液を減圧下で濃縮して氷水を加えた。濾過し、固体を得て無水アセトニトリルで洗浄し、乾燥して、化合物16(1.9g)を得た。
窒素保護下で、化合物16(1.14g)のジオキサン:水(20mL:5mL)溶液にテトラキス(トリフェニルホスフィン)パラジウム(0)(500mg)、化合物6(1.3g)、無水炭酸ナトリウム(1.2g)を加えた。反応液を80℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮し、残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=500:1)による分離で精製して、化合物17(920mg)を得た。
化合物17(200mg)のDMF(1mL)溶液に無水炭酸セシウム(120mg)、化合物18(120mg)を加え、60℃に加熱して一晩反応させた。反応液を室温に冷却して、減圧下で濃縮した。残留物を得てフラッシュシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=100:1~50:1)による分離で精製して、化合物19(110mg)を得た。
化合物19(110mg)のテトラヒドロフラン(5mL)溶液にパラジウム炭素(50mg)を加え、窒素で反応系を置換した。室温下で反応系を一晩反応させて、珪藻土で濾過した。濾液を減圧下で濃縮して化合物20(63mg)を得た。
氷浴下で、化合物20(63mg)のジクロロメタン(2mL)溶液にDIEA(5μL)、塩化アクリロイル(11μL)を加えた。氷浴下で反応液を2時間攪拌して、メタノールを加えてクエンチして減圧下で濃縮した。残留物を得て分取薄層クロマトグラフィー(ジクロロメタン:メタノール=20:1)による分離で精製して、実施例70(33mg)を得た。
1H NMR(400MHz,CDCl3)δ 9.34(1H,s),9.07(1H,s),8.58(1H,s),8.26(1H,s),7.68(1H,s),7.43(1H,s),6.93(1H,s),6.71(1H,s),6.42(1H,d,J=16.8Hz),6.28(1H,dd,J=16.8,10.4Hz),5.78(1H,d,J=10.4Hz),4.74(2H,t,J=6.4Hz),4.68(2H,t,J=6.4Hz),3.98(6H,s),3.93(3H,s),3.61-3.67(1H,m),3.03-3.09(4H,m),2.51-2.65(4H,m)。
1.化合物のインビトロタンパク質活性測定:
均一時間分解蛍光(HTRF)法を用いてFGFR-4キナーゼ活性検出プラットフォームを確立して、化合物活性の測定を行った。100%DMSOを用いて1000μMから化合物の3倍の勾配希釈を11回行い(合計で12の濃度)、各濃度は4μLを取り分けて96μLの反応バッファー(50mMのHEPES、pH7.4、5mMのMnCl2、0.1mMのNaVO3、0.001%Tween-20、0.01%BAS、1mMのDTT)に加えて均一に混合して、4×化合物(最終濃度は0.017nM~1000nM)として待機した。反応バッファーを使用して2×FGFR-4キナーゼ(最終濃度は1nM)を調製し、反応バッファーで4×基質(ATP+TKペプチド)を調製した(TKペプチドはHTRF(登録商標)KinEASE(商標)-TKで、Cisbioより購入した。TKペプチドの最終濃度は1μMで、ATPの最終濃度は25μMであった)。4×化合物から2.5μL取り分けて384ウェルプレート(OptiPlate-384、PerkinElmerより購入)に加え、次に5μLの2×FGFR-4キナーゼを加えて、遠心分離して均一に混合させ、そして2.5μLの4×基質混合物を加えて反応を開始させた(総反応体積は10μL)。384ウェルプレートをインキュベーターに入れて23℃下で60分間攪拌し、次に5μLのEu3+ クリプテート標識抗ホスホチロシン抗体(Eu3+ cryptate-labled anti-phosphotyrosine antibody)(HTRF(登録商標)KinEASE(商標)-TK、Cisbioより購入)、5μLのストレプトアビジン(Streptavidin)-XL-665(HTRF(登録商標)KinEASE(商標)-TK,Cisbioより購入)を加えて反応を停止させた。インキュベーターにおいて1時間インキュベートした後、Envision(PerkinElmerより購入)において蛍光値を読み取った(320nmで励起し、665nm及び620nmでの発光を検出し、二者の比の値は酵素活性である)。各化合物はそれぞれ12の濃度において酵素活性を測定し、ソフトウェアGraphPad prism 5.0を用いてデータから当該化合物のIC50値を算出した。
Promega社のCell Titer-Glo(登録商標)検出試薬を用いて浮遊細胞増殖阻害スクリーニングという方法を確立した。10%ウシ胎児血清(Hyclone(登録商標))を添加したMEM(Gibco(登録商標))培地でヒト肝がん細胞Hep3b(協和細胞研究センター)を培養し、培養条件は37℃、95%空気及び5%CO2であり、25cm2又は75cm2のプラスチック製組織培養フラスコ(Corning(登録商標))において培養し、週に2~3回継代させた。
北京維通利華実験働物技術有限公司が提供する雄SDラットを用い、1群当たり3匹でラットの群分けを実施し、それぞれ1回の強制経口で被験サンプル懸濁液(5mg/kg)を投与した。動物は実験前に一晩絶食させ、絶食時間は投与前10時間から投与後4時間までとした。投与後0.25時間、0.5時間、1時間、2時間、4時間、6時間、8時間、24時間に採血した。小動物用麻酔器を用いてイソフルランで麻酔した後、眼窩静脈叢から0.3mLの全血を採取してヘパリン抗凝固採血管に入れ、サンプルは4℃、4000rpmで5分間遠心分離し、血漿を遠沈管に移して、分析に備えて-80℃において保存した。タンパク質沈殿法で血漿中からサンプルを抽出して、LC/MS/MSでの抽出液を分析した。
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