JP7461390B2 - メニン-mll相互作用の阻害剤 - Google Patents
メニン-mll相互作用の阻害剤 Download PDFInfo
- Publication number
- JP7461390B2 JP7461390B2 JP2022000946A JP2022000946A JP7461390B2 JP 7461390 B2 JP7461390 B2 JP 7461390B2 JP 2022000946 A JP2022000946 A JP 2022000946A JP 2022000946 A JP2022000946 A JP 2022000946A JP 7461390 B2 JP7461390 B2 JP 7461390B2
- Authority
- JP
- Japan
- Prior art keywords
- diazaspiro
- pyrimidin
- fluoro
- methyl
- mmol
- 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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- 239000003112 inhibitor Substances 0.000 title description 58
- 230000003993 interaction Effects 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims description 142
- -1 N-isopropylbenzamide bis-hydrochloride Chemical compound 0.000 claims description 106
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 85
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 72
- 239000007787 solid Substances 0.000 claims description 69
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 61
- FRVSRBKUQZKTOW-UHFFFAOYSA-N N-ethyl-2-[4-[7-[[4-(ethylsulfonylamino)cyclohexyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl]oxy-5-fluoro-N-propan-2-ylbenzamide Chemical compound CCN(C(C)C)C(=O)C1=C(OC2=C(N=CN=C2)N2CC3(C2)CCN(CC2CCC(CC2)NS(=O)(=O)CC)CC3)C=CC(F)=C1 FRVSRBKUQZKTOW-UHFFFAOYSA-N 0.000 claims description 16
- 230000005855 radiation Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 description 256
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
- 239000000203 mixture Substances 0.000 description 179
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 167
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- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 122
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- 239000012267 brine Substances 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
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- 125000003118 aryl group Chemical group 0.000 description 29
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
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- 239000007832 Na2SO4 Substances 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
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- 125000003545 alkoxy group Chemical group 0.000 description 13
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- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 12
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
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- DDYHEQVMLVMWJA-UHFFFAOYSA-N 2-(4-chloropyrimidin-5-yl)oxy-5-fluoro-N,N-di(propan-2-yl)benzamide Chemical compound ClC1=NC=NC=C1OC1=C(C(=O)N(C(C)C)C(C)C)C=C(C=C1)F DDYHEQVMLVMWJA-UHFFFAOYSA-N 0.000 description 8
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Description
本発明はさらに、式Iの化合物の医薬的に許容し得る塩形態を提供する。
本発明はさらに、式Iの化合物の結晶形態を提供する。
本発明はさらに、治療有効量の式Iの化合物又はその医薬的に許容し得る塩を患者に投与することを含む、患者の癌を治療する方法を提供する。
本発明はさらに、治療有効量の式Iの化合物又はその医薬的に許容し得る塩を患者に投与することを含む、患者のインスリン抵抗性、糖尿病前症、糖尿病、糖尿病リスク、又は高血糖症を治療する方法を提供する。
-C(RA1)(RA2)-C(=O)-、及び-N=C(NH2)-から選択され、ここでA、B、D、及びEの1個以下は、-C(RA1)(RA2)-O-、-C(RA1)(RA2)-NRA3-、 -C(RA1)(RA2)-C(=O)-、-C(=O)-、又は-N=C(NH2)-であり;
mは、0又は1であり;
pは、0、1、2、又は3であり;
qは、0、1、又は2であり;
aは、0又は1であり;そして
bは、0又は1であり、
ここで任意のシクロアルキル又はヘテロシクロアルキル基は、場合により1又は2個のオキソ基でさらに置換される。
いくつかの実施態様において、YはNRY3である。いくつかの実施態様において、YはNHである。
いくつかの実施態様において、UはCRUである。いくつかの実施態様において、UはCHである。
いくつかの実施態様において、WはNである。
いくつかの実施態様において、WはCRWである。いくつかの実施態様において、WはCHである。
いくつかの実施態様において、XはNである。
いくつかの実施態様において、XはCRXである。いくつかの実施態様において、Xは、CH又はCNH2から選択される。
いくつかの実施態様において、A、B、D、及びEは、それぞれ独立して-CH2-、-CH2-CH2-、及び-CH2O-から選択される。
いくつかの実施態様において、A、B、D、及びEは、それぞれ独立して、-CH2-又は-CH2-CH2-から選択される。
いくつかの実施態様において、Lはメチレンである。
いくつかの実施態様において、aは0である。
いくつかの実施態様において、bは1である。
いくつかの実施態様において、bは0である。
いくつかの実施態様において、a及びbはそれぞれ1である。
いくつかの実施態様において、a及びbはそれぞれ0である。
いくつかの実施態様において、aは1であり、bは0である。
いくつかの実施態様において、aは0であり、bは1である。
いくつかの実施態様において、各Cy2は、C6-10アリール、C3-10シクロアルキル、5~10員ヘテロアリール、及び4~10員ヘテロシクロアルキルから独立して選択され、その各々は、RCy2から独立して選択される1、2、3、又は4個の置換基で場合により置換される。
いくつかの実施態様において、nは1である。
いくつかの実施態様において、mは0である。
いくつかの実施態様において、mは1である。
いくつかの実施態様において、pは0である。
いくつかの実施態様において、pは1である。
いくつかの実施態様において、qは0である。
いくつかの実施態様において、qは1である。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「シクロアルキルアルキル」は、シクロアルキル基で置換されたアルキル基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「ヘテロアリールアルキル」は、ヘテロアリール基で置換されたアルキル基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「ヘテロシクロアルキルアルキル」は、ヘテロシクロアルキル基で置換されたアルキル基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「Ci-jアルキルスルフィニル」は、式-S(=O)2-(Ci-jアルキル)の基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「カルボキシ」は、-C(=O)OH基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「Ci-jアルコキシカルボニル」は、式-C(=O)O-(Ci-jアルキル)の基を指す。
本明細書において、単独で又は他の用語と組み合わせて使用される用語「アミノカルボニル」は、式-C(=O)NH2の基を指す。
本発明の化合物(その塩を含む)は、公知の有機合成技術を使用して調製することができ、多数の可能な合成経路のいずれかに従って合成することができる。
本発明の化合物は、メニンとMLL及びMLL融合タンパク質との相互作用の阻害剤である。いくつかの実施態様において、本発明は、メニンとMLL又はMLL融合タンパク質と本発明の化合物とを接触させることによって、メニンとMLL又はMLL融合タンパク質との相互作用を阻害する方法に関する。接触はインビトロ又はインビボで行うことができる。いくつかの実施態様において、本発明の化合物はメニンに結合することができ、それにより、MLLとメニンへの結合を妨げることができる。いくつかの実施態様において本発明は、MLL又はMLL融合タンパク質の存在下でメニンに本発明の化合物を接触させることによって、メニンの活性を阻害する方法を提供する。さらなる実施態様において本発明は、MLL又はMLL融合タンパク質の存在下でメニンに本発明の化合物を接触させることを含む、MLL又はMLL融合タンパク質とメニンとの結合を阻害する方法を提供する。
本発明はさらに、本明細書に記載の疾患又は障害を治療するための併用療法に関する。いくつかの実施態様において併用療法は、少なくとも1つの本発明の化合物を、メニン/MLLによって媒介される癌又は他の障害を治療するための1種以上の他の薬学的に活性な物質と、組み合わせて投与することを含む。いくつかの実施態様において併用療法は、例えば癌の治療のための1種以上の他の薬学的に活性な物質と組み合わせて、本発明の少なくとも1つの化合物を投与することを含む。薬学的に活性な物質は、単一剤形で本発明の化合物と組み合わせることができ、又は治療薬を別々の剤形として同時に又は連続して投与することができる。
医薬品として使用する場合、本発明の化合物は、本発明の化合物又はその医薬的に許容し得る塩と、少なくとも1種の医薬的に許容し得る担体との、組み合わせである医薬組成物の形態で投与することができる。これらの組成物は、医薬分野で公知の方法で調製することができ、局所的又は全身的治療が所望されるかどうか及び治療される領域に応じて、様々な経路で投与することができる。投与は、局所的(例えば鼻腔内、膣、及び直腸送達を含む眼の膜及び粘膜に)、肺投与(例えば、噴霧器;気管内、鼻腔内、表皮、及び経皮を含む、粉末又はエアロゾルの吸入又は吹送による)、眼、又は、非経口投与であり得る。眼内送達のための方法は、局所投与(点眼)、結膜下、眼周囲又は硝子体内への注射、又は結膜嚢に外科的に配置されたバルーンカテーテル又は眼科用インサートによる導入を含み得る。非経口投与には、静脈内、動脈内、皮下、腹腔内、又は筋肉内注射もしくは注入;又は頭蓋内、例えば髄腔内又は脳室内投与が含まれる。非経口投与は、単一ボーラス用量の形態であってもよく、又は例えば、連続灌流ポンプであってもよい。局所投与のための医薬組成物及び製剤には、経皮パッチ剤、軟膏剤、ローション剤、クリーム剤、ゲル剤、滴剤、坐剤、スプレー剤、液体剤、及び散剤が含まれ得る。従来の医薬担体、水性、粉末、又は油性基剤、増粘剤などが、必要又は望ましいことがある。
RP-HPLC(C-18、Boston Green ODS 150×30mm×5μm;溶出液勾配:水+0.1%TFA/アセトニトリル=81:19~51:49)。
移動相A:水+0.1%TFA;移動相B:CH3CN;流速:30mL/分;検出:UV 220nm/254nm;カラム:Boston Green ODS 150×30mm×5μm;カラム温度:30℃。
RP-HPLC(C-18、Phenomenex Synergi C18 250×21.2mm×4μm;溶出液勾配:水+0.1%TFA/アセトニトリル=75:25~45:55)。
移動相A:水+0.1%TFA;移動相B:CH3CN;流速:25mL/分;検出:UV 220nm/254nm;カラム:Phenomenex Synergi C18 250×21.2mm×4μm;カラム温度:30℃。
RP-HPLC(C-18、Phenomenex Synergi C18 250×21.2mm×4μm;溶出液勾配:水+0.05%HCl/アセトニトリル=82:18~52:48)。
移動相A:0.05%HClを含む水;移動相B:CH3CN;流速:30mL/分;検出:UV 220nm/254nm;カラム:Phenomenex Gemini 150×30mm×4μm;カラム温度:30℃。
RP-HPLC(C-18、Phenomenex Gemini 150×25mm×10m;溶出液勾配:水+0.05%アンモニア水/アセトニトリル=30:70~0:100)。
移動相A:0.05%アンモニア水を含む水;移動相B:CH3CN;流速:25mL/分;検出:UV 220nm/254nm;カラム:Phenomenex Gemini 150×25mm×10m;カラム温度:30℃。
移動相A:0.1%TFAを含む水;移動相B:0.1%TFAを含むアセトニトリル;流速:25mL/分;検出:UV 220nm/254nm;カラム:C-18 Synergi Max-RP 150×30mm×4μm;カラム温度:30℃。
移動相A:水
移動相B:CH3CN
流速:120mL/分
検出:UV 220nm/254nm
カラム:Phenomenex Synergi Max-RP 250×50mm×10um
カラム温度:30℃
移動相A:水(10mM NH4HCO3)
移動相B:CH3CN
流速:25mL/分
検出:UV 220nm/254nm
カラム:Xtimate C18 150×25mm×5μm
カラム温度:30℃
LCMS方法A:
HPLCシステム:Waters ACQUITY;カラム:Waters ACQUITY CSH(商標) C18 1.7μM。ガードカラム:Waters Assy. Frit. 0.2μM、2.1mm;カラム温度:40℃。
移動相:A:TFA:水(1:1000、v:v);移動相B:TFA:ACN(1:1000、v:v);流速:0.65mL/分;注入量:2μL;採取時間:約1.5分。
勾配プログラム:
ソース温度:120℃;脱溶媒温度:500℃;脱溶媒ガス流:窒素設定650(L/h)。コーンガス流量:窒素設定50(L/h)。
HPLCシステム:Waters ACQUITY;カラム:Waters ACQUITY CSH(商標) C18 1.7μM。ガードカラム:Waters Assy. Frit. 0.2μM、2.1mm;カラム温度:40℃。
移動相:A:TFA:水(1:1000、v:v)。移動相B:TFA:ACN(1:1000、v:v)。流速:0.65mL/分;注入量:2μL;採取時間:約1.5分。
ソース温度:120℃;脱溶媒温度:500℃;脱溶媒ガス流:窒素設定650(L/h)。コーンガス流量:窒素設定50(L/h)。
HPLCシステム:Waters ACQUITY ;カラム:Waters ACQUITY CSH(商標)C18 1.7μM;
ガードカラム:Waters Assy. Frit. 0.2μM、2.1mm;カラム温度:40℃。
移動相:A:TFA:水(1:1000、v:v);;移動相B:TFA:ACN(1:1000、v:v)。流速:1mL/分;注入量:2μL;採取時間:約115分。
ソース温度:120℃;脱溶媒温度:500℃;脱溶媒ガス流:窒素設定650(L/h)。コーンガス流量:窒素設定50(L/h)。
装置:Thar SFC80;カラム:AD 250mm×30mm、5μm;移動相:A:超臨界CO2、B:IPA(0.05%DEA)、A:B=80:20(60mL/分で)。カラム温度:38℃;ノズル圧力:100バール;ノズル温度:60℃;エバポレーター温度:20℃;トリマー温度:25℃;波長:220nm。
装置:SFCMG2;カラム:OJ 250mm×30mm、5μm;移動相:A:超臨界CO2、B:MeOH(0.05%DEA)、A:B=90:10(70mL/分で)。カラム温度:38℃;ノズル圧力:100バール;ノズル温度:60℃;エバポレーター温度:20℃;トリマー温度:25℃;波長:220nm。
高速D/teX検出器を備えたRigaku MiniFlex 600 X線回折装置を、以下の条件で使用した:40kV、15mA、Cu Kα線(波長=1.54Å)。2θ走査範囲は3~45°であり、走査速度は10°/minであった。
透過配置
XRPDパターンは、PANalytical X'Pert PRO MPD回折計を使用して、Optix社製の長焦点微小焦点線源(long, fine-focus source)を使用して生成したCu放射線の入射ビームを使用して採取した。楕円状に傾斜した多層ミラーを使用して、CuKα X線を試料を通して検出器上に集束させた。分析前に、シリコン試料(NIST SRM 640e)を分析して、Si-111ピークの観測位置がNIST認定位置と一致することを確認した。試料を厚さ3μmのフィルムの間に置き、透過配置で分析した。空気によって発生するバックグラウンドを最小限に抑えるために、ビームストップ、短い乱反射エクステンション、及び飛散防止ナイフエッジを使用した。入射ビーム用のソラースリットと回折ビームを使用して、軸方向の発散からの広がりを最小限に抑えた。回折パターンは、試料から240mmのところに位置する走査位置感知型検出器(X'Celerator)及びData Collectorソフトウェアv.2.2bを使用して採取した。
XRPDパターンは、PANalytical X'Pert PRO MPD回折計を使用して、長焦点微小焦点線源及びニッケルフィルターを使用して生成されたCu Kα線の入射ビームを使用して採取した。回折計は、対称Bragg-Brentano 配置を使用して構成した。分析前に、シリコン試料(NIST SRM 640e)を分析して、Si-111ピークの観測位置がNIST認定位置と一致することを確認した。試料は、シリコンのゼロ-バックグラウンド基板上に中心を置く薄い円形層として準備された。空気によって発生するバックグラウンドを最小限に抑えるために、飛散防止スリット(SS)を使用した。入射ビーム用のソーラスリットと回折ビームを使用して、軸方向発散からの広がりを最小限に抑えた。回折パターンは、試料から240mmのところに位置する走査位置感知型検出器(X'Celerator)及びData Collectorソフトウェアv.2.2bを使用して採取した。
DSC測定は、TA Instruments 2920示差走査熱量計を使用して行った。温度較正は、NIST追跡可能インジウム金属を使用して行った。
水分吸着/脱着データをVTI SGA-100蒸気吸着分析器で採取した。NaCl及びPVPを較正基準として使用した。分析前に試料を乾燥しなかった。吸着及び脱着のデータは、窒素パージ下で、10%RH刻みで5%~95%RHの範囲で採取した。分析に使用した平衡基準は、5分間で0.0100%未満の重量変化であり、最大平衡時間は3時間であった。試料の初期含水量についてデータを補正しなかった。
TG分析は、TA Instruments Q5000 IR熱重量分析器を使用して行った。温度較正は、ニッケル及びALUMEL(商標)を使用して行った。各試料を白金パンに調製し、炉を窒素下で加熱した。
SOCl2(500mL)中の5-(2-ブロモ-4-フルオロフェノキシ)ピリミジン-4-オール(55g)の溶液に、無水DMF(5mL)を加えた。混合液を70℃で4時間加熱した。混合液を濃縮し、DCM(500mL)で溶解し、次に飽和NaHCO3(水溶液)(500mL)に注ぎ、室温で2時間撹拌した。有機層を分離し、Na2SO4で乾燥し、濾過し、濃縮した。次に残留物をシリカゲルのISCOカラム(100%石油エーテルからEtOAc:石油エーテル=9:1)で精製して、5-(2-ブロモ-4-フルオロフェノキシ)-4-クロロピリミジンを淡黄色固体として得た。収量:32g。LCMS方法C:Rt=0.858分、(M+H)+=302.9, 304.9(塩素及び臭素同位体);1H NMR (CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 7.45 (dd, J = 7.6 3.2 Hz, 1H), 7.06-7.12 (m, 2H). 1F NMR (CDCl3): δ -113.64 (s, 1F)。
CH2Cl2(3mL)中の7-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチル(100mg、1.87mmol)の溶液に、TFA(1mL)を加えた。混合液を20~25℃で2時間撹拌した。次に反応混合液をNH3-H2O(pH=8)で中和し、水(80mL)で洗浄し、CH2Cl2(3×50mL)で抽出した。有機層を無水Na2SO4で乾燥し、濾過し、真空中で濃縮して、粗2-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)2,7-ジアザスピロ[4.4]ノナンを黄色固体として得て、これをさらに精製することなく次の工程に使用した。収量:90mg;HPLC方法C:Rt=0.575分;(M+H)+=435.2。
無水DCM(10mL)中の7-(5-(4-フルオロ-2-(イソプロピル(メチル)カルバモイル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチル(1g、1.95mmol)の溶液に、0℃、N2下で、HCl-MeOH(2mL、MeOH中4mol/L)をゆっくり加えた。反応液を17~23℃で16時間撹拌した。混合液をNaOH水溶液(1mol/L)でpH=11~12に調整し、次にEtOAc(50mL×3)で抽出した。合わせた有機層を食塩水(50mL)で洗浄し、Na2SO4で乾燥し、濾過し、減圧下で濃縮して、粗2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピル-N-メチルベンズアミドを褐色固体として得た。収量:0.8g(95%粗生成物)。LCMS方法C:Rt=0.508分、(M+H)+=414.0。
CHCl3(30mL)中のEt3N(7.3g、72.3mmol)の溶液に、0℃でPOCl3(12.5g、81.7mmol)を加えた。次に混合液を、CHCl3(270mL)中の5-(2-(ジイソプロピルカルバモイル)-4-フルオロフェノキシ)ピリミジン-1-オキシド(16.0g、48.0mmol)の溶液に、0℃でゆっくり加えた。混合液を65℃で16時間撹拌した。次に混合液をゆっくり飽和NaHCO3溶液(500mL)に加え、pHを飽和NaHCO3溶液で7~8に調整した。混合液を酢酸エチル(2×300mL)で抽出した。合わせた有機層を無水Na2SO4で乾燥し、濾過し、減圧下で濃縮した。残留物を石油エーテル:酢酸エチル=5:1で溶出するシリカゲルカラムクロマトグラフィーにより精製して、2-((4-クロロピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(6g)を黄色固体として得た。HPLC方法C:Rt=0.735分、(M+H)+=351.9。1H NMR (CDCl3): δ 8.71 (s, 1H), 8.21 (s, 1H), 7.02-7.12 (m, 3H), 3.73-3.80 (m, 1H), 3.46-3.53 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). 19F NMR (CDCl3): δ -114.5。
1-(2-ヒドロキシエチル)-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド及び蟻酸2-(5-ホルミル-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)エチル
MeOH(5mL)中の7-(5-(2-(ベンジルオキシ)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチル(160mg、0.3mmol)の溶液に、パラジウム担持炭素(5%乾燥基準、33mg、30μmol)を加えた。混合液を水素バルーンの雰囲気下で3時間室温で撹拌し、セライトパッドで濾過した。次に濾液を減圧下で濃縮した。粗生成物をさらに精製することなく次工程の反応に直接使用した。LCMS方法B:Rt=1.56分;(M+H)+=431。
HCOOH(3mL)及びH2O(1mL)中のN-(2-(5-シアノ-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)エチル)アセトアミド(20mg、0.082mmol)の溶液に、Ni-Al(35mg、0.41mmol)を加え、次に反応液を90℃で12時間撹拌した。反応液を濾過し、濾液を減圧下で濃縮して、N-(2-(5-ホルミル-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)エチル)アセトアミド(15mg、純度92%、75%)を得た。残留物を、さらに精製することなく、褐色固体として次の工程に使用した。収量:15mg。LCMS方法F:Rt=Rt値:0.773分;(M+H)+=248.1。
DCM中の6-(ヒドロキシメチル)-3-メチル-2-オキソインドリン-3-カルボニトリル(0.597g、2.95mmol)の溶液に、活性MnO2(2.57g、29.56mmol)を加えた。混合液を室温で一晩撹拌し、次にセライトの短いパッドを通して濾過した。濾液を濃縮して溶媒を除去した。残留物をフラッシュクロマトグラフィーにより精製して、6-ホルミル-3-メチル-2-オキソインドリン-3-カルボニトリルを得た。収量0.347g。LCMS方法B:Rt=1.25分、(M+H)+=201.1。
CH2Cl2(160mL)中の(R)-ヒドロキシ((1r、4R)-4-(メチルスルホンアミド)シクロヘキシル)メタンスルホン酸ナトリウム(16.5g、53.4mmol)の混合液に、Na2CO3水溶液(1M、160mL)を加えた。混合液を室温で30分間撹拌した。混合液を分離し、水層をCH2Cl2(3×80mL)で抽出した。合わせた有機層を食塩水(300mL)で洗浄し、無水Na2SO4で乾燥し、濾過し、減圧下で濃縮して、粗N-((1r,4r)-4-ホルミルシクロヘキシル)メタンスルホンアミド(7.5g、69%)を白色固体として得て、これをさらに精製することなく次の工程に使用した。1H NMR (CDCl3): δ 9.66 (s, 0.021H), 9.62 (s, 1H), 4.38 (brs, 1H), 3.30-3.25 (m, 1H), 2.98 (s, 3H), 2.18-2.14 (m, 3H), 2.05-2.01 (m, 2H), 1.42-1.30 (m, 4H)。
SOCl2(5mL)中の粗5-フルオロ-2-((4-ヒドロキシピリミジン-5-イル)オキシ)安息香酸メチル(11g、42mmol)の溶液に、DMF(0.5mL)を加えた。得られた混合液を70℃で2時間加熱した。混合液を濃縮して残留物を得て、これをDCM(100mL)及びH2O(100mL)に溶解した。混合液を飽和NaHCO3(50mL)で中和した。分離した有機層をNa2SO4で乾燥し、濾過し、濃縮し、残留物をクロマトグラフィーカラム(石油エーテル:酢酸エチル=5:1~1:1)により精製して、2-((4-クロロピリミジン-5-イル)オキシ)-5-フルオロ安息香酸メチルを褐色固体として得た(8.3g、57%)。LCMS方法C:Rt=0.74分;(M+H)+=283.5。
工程2の化合物5-フルオロ-2-(ピリミジン-5-イルオキシ)安息香酸メチルを含有するメタノール性溶液を、100Lのジャケット付きガラス反応器に入れ、水(17.00L)で希釈した。その後、50wt%水酸化ナトリウム水溶液(10.11kg、126.36mol)を、バッチ内温度を35~45℃に保ちながら加えた。添加が完了後、温度を35~45℃に調整し、バッチを少なくとも14時間撹拌した。真空蒸留によって反応容量を、87から33リットルに低下させた(27インチHgの真空が達成された;最終的にバッチ温度は32.4℃であった)。次にバッチを水(42.5L)で希釈し、20~30℃に冷却し、Celite(商標)パッドで濾過して触媒を除去した。水層をMTBE(17L)で2回抽出した。内部バッチ温度を10~20℃に保ちながら、6M塩酸(約17L)を使用してバッチをpH=2に調整した。酸の添加が完了したら、バッチを0~10℃に冷却し、フィルター/ドライヤーを使用してポリプロピレン布で濾過した。濾過ケーキを水(17.00L)で洗浄し、KF分析により水分が0.3重量%になるまで数日間40~45℃の窒素気流下で乾燥した。生成物を102%収率(7.57kg)でHPLC純度97.5%(AUC)及びNMR分析により94重量%純度で単離した。
無水DCM(300mL)中の粗N-((1r,4r)-4-(ヒドロキシメチル)シクロヘキシル)エタンスルホンアミド(30g、136mmol)の溶液に、TsCl(25.84g、136mmol)、DMAP(1.66g、13.6mmol)、及びEt3N(41.2g、408mmol)を加えた。混合液をN2下で10℃で6時間撹拌した。次に混合液をH2O(200mL)でクエンチした。分配後、有機層をH2O(2×150mL)及び食塩水(150mL)で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残留物を石油エーテル/酢酸エチル=1/0~2/1で溶出するシリカゲルカラムクロマトグラフィーにより精製して、((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル4-メチルベンゼンスルホネート(37g、73%)を白色固体として得た;1H NMR (CDCl3 400 MHz): δ 7.78 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 4.23 (d, J = 7.6 Hz, 1 H), 3.81 (d, J = 6.4 Hz, 2 H), 3.19-3.14 (m, 1 H), 3.01 (q, J = 7.6 Hz, 2 H), 2.46 (s, 3 H), 2.09-2.03 (m, 2 H), 1.79-1.74 (m, 2 H), 1.66-1.56 (m, 1 H), 1.35 (t, J = 7.6 Hz, 3 H), 1.28-1.18 (m, 2 H), 1.09-1.01 (m, 2 H)。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(ラセミ混合物)
2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(730mg、1.654mmol)、2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、536mg、3.308mmol)、及び4Åモレキュラーシーブ(100mg)の混合物に、無水MeOH(20mL)を加え、次に反応液をN2下で60℃で30分間撹拌した。次に溶液にNaBH3CN(513mg、8.270mmol)を加え、反応混合液を60℃で4時間撹拌した。次に反応混合液を濾過し、減圧下で濃縮した。得られた残留物をMeOH(15mL)で希釈し、混合液を分取RP-HPLC方法C(HCl)により精製して、化合物5-フルオロ-N,N-ジイソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドを白色固体として得た。収量:540mg(55%)。LCMS方法C:Rt=0.931;(M+H)+=588.5。1H NMR (CD3OD): δ 8.30-8.38 (m, 1 H), 7.62-7.84 (m, 1 H), 6.86-7.15 (m, 6 H), 4.22-4.30 (m, 3 H), 3.20-4.03 (m, 9 H), 1.87-2.04 (m, 5 H), 0.81-1.30 (m, 11 H).19F NMR (CD3OD): δ -117.14。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(異性体1及び2)
異性体1(実施例1A):LCMS方法C:Rt=0.931;(M+H)+=588.5. 1H NMR (CD3OD): δ 8.54-8.61 (m, 1 H), 7.86-8.09 (m, 1 H), 7.20-7.31 (m, 5 H), 7.15 (d, J = 36.4 Hz, 1 H), 4.41-4.51 (m, 3 H), 3.40-4.02 (m, 9 H), 2.15-2.25 (m, 4 H), 1.06-1.48 (m, 12 H).19F NMR (CD3OD): δ -117.11. SFC分析方法A:tR=0.569分、ee=100%。
N-エチル-5-フルオロ-N-イソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(ラセミ混合物)
N-エチル-5-フルオロ-N-イソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(異性体1~2)
異性体1(実施例2A):収量:92.5mg。LCMS方法E:Rt=1.132分;(M+H)+ = 574.3. 1H NMR (CD3OD): δ 8.20-8.29 (m, 1 H), 7.72-7.80 (m, 1 H), 6.85-7.16 (m, 6 H), 4.35-4.41 (m, 1 H), 3.45-3.89 (m, 8H), 3.12-3.23 (m, 1H), 2.50-2.71 (m, 4 H), 1.76-1.96 (m, 4 H), 1.05-1.27 (m, 8 H). 19F NMR (CD3OD): δ -120.380. SFC分析方法A:tR=0.722分、ee=100%。
5-フルオロ-2-((4-(7-((1-(2-ヒドロキシエチル)-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4,4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N,N-ジイソプロピルベンズアミド(異性体1~2)
N-エチル-5-フルオロ-2-((4-(7-((1-(2-ヒドロキシエチル)-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N-イソプロピルベンズアミド
N-エチル-5-フルオロ-2-((4-(7-((1-(2-ヒドロキシエチル)-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N-イソプロピルベンズアミド(異性体1~2)
5-フルオロ-N-(2-ヒドロキシエチル)-N-イソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド
無水MeOH(3mL)中の2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-(2-ヒドロキシエチル)-N-イソプロピルベンズアミド(34mg、0.0761mmol)の溶液に、2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、25mg、0.1522mmol)及びNaBH3CN(24mg、0.3805mmol)を加えた。混合液をN2下で60℃で16時間撹拌した。LCMSは反応が完了したことを示した。混合液を減圧下で濃縮し、RP-HPLC方法Dにより直接精製して、5-フルオロ-N-(2-ヒドロキシエチル)-N-イソプロピル-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドを淡黄色固体として得た。収量:10.00mg。LCMS方法C:Rt=0.560分、(M+H)+=590.2. 1H NMR (CDCl3): δ 10.35-10.15 (m, 0.5H), 9.75-9.60 (m, 0.5H), 9.01-8.77 (m, 1H), 8.36 (s, 1H), 7.81-7.70 (m, 1H), 7.35-7.25 (m, 0.5H), 7.18-7.08 (m, 0.5H), 7.05-6.90 (m, 2H), 6.89-6.75 (m, 2H), 6.65-6.50 (m, 1H), 4.05-3.25 (m, 12H), 2.97-2.25 (m, 4H), 2.12-1.85 (m, 4H), 1.30-1.07 (m, 6H). 19F NMR (CDCl3): δ -119.3。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(実施例6A)及び5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1s、4s)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(実施例6B)の代替合成。
5-((7-(5-(2-(アミノ(シクロペンチル)メチル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
上記粗生成物をMeOH(1mL)及び4M HCl/ジオキサン(3mL)に溶解した。溶液を室温で30分間撹拌した後、溶媒を減圧下で除去した。残留物をRP-HPLC方法Aにより精製して、5-((7-(5-(2-(アミノ(シクロペンチル)メチル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オンを得た。LCMS方法A:Rt=0.15分、(M+H)+=558.3. 1H NMR (CD3OD) δ: 8.57 (s, 1H), 7.83 (m, 1H), 7.41 (m, 1H), 7.26-7.17 (m, 4H), 7.09 (d, J = 7.6 Hz, 1H), 4.42 (m, 2H), 4.07 (m, 4H), 3.64-3.34 (m,4H), 2.48 (m, 1H), 2.22-2.03 (m, 5 H), 1.78-1.48 (m, 6H), 1.39 (d, J = 6.4 Hz, 1H)。
5-((7-(5-(2-(シクロペンチル(ジメチルアミノ)メチル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
N-(シクロペンチル(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)メチル)アセトアミド
6-((7-(5-(4-フルオロ-2-(1-ヒドロキシ-2-メチルプロピル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-3,3-ジメチルインドリン-2-オン
工程1からの粗生成物を、TEA(0.1mL)を含有するDCM(1mL)に溶解した。次に溶媒を減圧下で除去した。得られた残留物をDCM(2mL)に溶解した。この溶液に、中間体45(32mg、0.17mmol)及びNaBH(OAc)3(72mg、0.34mmol)を加え、混合液を30分間撹拌した。溶媒を除去し、残留物を分取HPLC方法Aにより精製して、標題化合物をTFA塩として得た。LCMS方法A:Rt=075分、(M+H)+=560.3. 1H NMR (CD3OD) δ: 8.53 (s, 1H), 7.58 (s, 1H), 7.36-7.10 (m, 6H), 4.53-3.78 (m, 11H), 2.22 (m, 4 H), 1.96 (m, 1H), 1.34 (s, 6H), 1.00 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H)。
6-((7-(5-(4-フルオロ-2-イソブチリルフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-3-メチル-2-オキソインドリン-2-イル)3-カルボニトリル
5-フルオロ-2-((4-(6-(3-(4-フルオロフェニル)プロパノイル)-2,6-ジアザスピロ[3.4]オクタン-2-イル)ピリミジン-5-イル)オキシ)-N,N-ジイソプロピルベンズアミド
5-((7-(5-(4-フルオロ-2-(1-イソプロピル-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-3-オキソ-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
無水THF(5mL)中の2-(3,4-ジアミノベンジル)-7-(5-(4-フルオロ-2-(1-イソプロピル-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-3-オン(13mg、0.023mmol)の溶液に、Et3N(10μL)及びビス(トリクロロメチル)カーボネート(7mg、0.023mmol)を加え、得られた混合液を18~26℃で16時間撹拌した。TLC(DCM:MeOH=10:1、Rf=0.7)は新たなスポットを示し、2-(3,4-ジアミノベンジル)-7-(5-(4-フルオロ-2-(1-イソプロピル-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-3-オンは完全には消費されなかった。混合液を水(5mL)に注ぎ、EA(10mL×2)で抽出した。合わせた有機層を食塩水(30mL×2)で洗浄し、Na2SO4で乾燥し、濃縮して、塩基性分取RP-HPLC方法Dにより精製して、5-((7-(5-(4-フルオロ-2-(1-イソプロピル-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-3-オキソ-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンを白色固体として得た。収量:2.9mg(22%)。LCMS方法C:Rt=1.596分、(M+H)+=583.2. 1H NMR (MeOD): δ 8.30 (s, 1H), 7.83 (s, 1H), 7.48 (s, 1H), 7.25-7.35 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.00-7.05 (m, 1H), 6.95-7.00 (m, 3H), 6.16 (s, 1H), 4.35-4.55 (m, 3H), 3.80-3.90 (m, 1H), 3.55-3.70 (m, 2H), 3.45-3.55 (m, 1H), 3.20-3.30 (m, 2H), 1.85-2.20 (m, 4H), 1.35-1.45 (m, 6H).19F NMR (MeOD): δ -120.78。
N-(4-フルオロ-2-(5-イソプロピル-3-メチルイソオキサゾール-4-イル)フェニル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミン(実施例14A)及び4-(5-フルオロ-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-5-イソプロピル-3-メチルイソオキサゾール(実施例14B)
ジクロロエタン(2mL、1%AcOHを含む)中の、粗N-(4-フルオロ-2-(5-イソプロピル-3-メチルイソオキサゾール-4-イル)フェニル)-4-(2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミン及びN-(4-フルオロ-2-(3-イソプロピル-5-メチルイソオキサゾール-4-イル)フェニル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミン(工程7からイソオキサゾール位置異性体の4:1混合物、0.079mmol)、及びテトラヒドロ-2H-ピラン-4-カルバルデヒド(27mg、0.24mmol)の溶液に、室温でNaBH(OAc)3(50mg、0.24mmol)を加えた。反応混合液を30分間撹拌し、LCMS分析によって完了を確認した。溶媒を蒸発後、HPLC方法Aを使用して精製して、N-(4-フルオロ-2-(5-イソプロピル-3-メチルイソオキサゾール-4-イル)フェニル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミンTFA塩及びN-(4-フルオロ-2-(3-イソプロピル-5-メチルイソオキサゾール-4-イル)フェニル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミンTFA塩を、イソオキサゾール位置異性体の4:1混合物(15mg)として得た。LCMS方法B:tR=1.124;[M+H]+=507.70。
:主要イソオキサゾール位置異性体 LCMS方法B:tR=1.013;[M+H]+=507.70 1H NMR (CD3OD). δ 8.55 (bs, 1H), 7.79 (bs, 1H), 7.17-7.12 (m, 1H), 7.00 (dd, J = 3.2, 8.8 Hz, 1H), 6.83 (dd, J = 5.2, 9.2 Hz, 1H), 4.60-4.35 (m, 8H), 3.93 (dd, J = 4.0, 11.6 Hz, 2H), 3.40 (t, J = 11.6 Hz, 2H), 3.11 (d, J = 7.2 Hz, 2H), 3.07-3.00 (m, 1H), 2.17 (s, 3H), 1.93-1.87 (m, 1H), 1.60 (d, J = 11.6 Hz, 2H), 1.37-1.20 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.21-1.16 (1H, m)。
:マイナーイソオキサゾール位置異性体 LCMS方法B tR=1.124;[M+H]+=507.70。
N-(5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-アミン
丸底フラスコに7-(5-((2-(ジイソプロピルカルバモイル)-4-フルオロフェニル)アミノ)ピリミジン-4-イル)-2,7-ジアザスピロ[3.5]ノナン-2-カルボン酸tert-ブチル(300mg)、DCM(5mL)、及びTFA(5mL)を加え、反応混合液を室温で30分間撹拌した。次に揮発性物質を真空下で除去した。粗残留物をDCMで2回共蒸発させて、2-((4-(2,7-ジアザスピロ[3.5]ノナン-7-イル)ピリミジン-5-イル)アミノ)-5-フルオロ-N,N-ジイソプロピルベンズアミドビス-TFA塩を得た。丸底フラスコに、ビス-TFA塩(20mg)、2,2-ジメチルオキシラン(11mg)、トリエチルアミン(21μL)、及びTHF:エタノール(2mL、1:1の比)を加えた。フラスコに蓋をし、混合液を65℃で一晩加熱した。反応が完了したら、揮発性物質を真空下で除去した。粗物質をRP-HPLC方法Aにより精製して、5-フルオロ-2-((4-(2-(2-ヒドロキシ-2-メチルプロピル)-2,7-ジアザスピロ[3.5]ノナン-7-イル)ピリミジン-5-イル)アミノ)-N,N-ジイソプロピルベンズアミド(3.7mg)を得た。LCMS方法G Rt=3.65分;(M+H)+=513.61. 1H NMR (d4-MeOH) 8.52 (s, 1H), 7.87 (s, 1H), 7.07 - 7.15 (m, 2H), 6.93 (m, 1H), 4.23 (d, 2H), 4.04 (d, 2H), 3.82 - 3.89 (m, 6H), 1.93 - 1.99 (m, 4H), 1.26 - 1.34 (m, 18H)。
5-((7-(5-(2-(ジメチルホスホリル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
工程2~3は、実施例1の工程4~5の手順に従って実施した。LCMS方法E:Rt=1.344分;(M+H)+=537.2. 1H NMR (CD3OD): δ 8.34 (s, 1 H), 7.89 (s, 1 H), 7.61 (m, 1 H), 7.22-7.60 (m, 1 H), 6.96-7.00 (m, 3 H), 6.73-6.77 (m, 1 H), 3.59 (s, 6 H), 2.43-2.67 (m, 4 H), 1.90 (d, J = 14 Hz, 8 H), 1.78 (t, J = 6.4 Hz, 2 H). 19F NMR (CD3OD): δ -120.92。
2-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-N-(4-フルオロベンジル)-5-オキサ-2-アザスピロ[3.4]オクタン-7-アミン
MEOH(2mL)中の2-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-5-オキサ-2-アザスピロ[3.4]オクタン-7-オン(14mg、0.03mmol)及び(4-フルオロフェニル)メタンアミン(0.006ml、0.047mmol)の溶液に、NaBH3CN(8mg、0.12mmol)を加え、反応混合液を50℃で6時間撹拌した。溶媒を蒸発させ、ギルソンHPLCを使用して精製して、4.6mgの2-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-N-(4-フルオロベンジル)-5-オキサ-2-アザスピロ[3.4]オクタン-7-アミンTFA塩を得た。LCMS方法A:tR=0.572分;[M+H]+=545.60. 1H NMR (CD3OD): δ 9.10 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.69 (s, 1H), 7.38-7.34 (m, 2H), 7.30-7.22 (m, 2H), 7.10-7.03 (m, 3H), 4.19 (bs, 1H), 4.14-4.03 (m, 3H), 3.91 (dd, J = 6.0, 9.0 Hz, 1H), 3.75 (d, J = 6.4 Hz, 2H), 3.71-3.66 (m, 1H), 3.46-3.41 (m, 1H), 3.08-3.01 (m, 1H), 2.35-2.30 (m, 1H), 2.08-2.02 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H)。
4-(((2-(5-((5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-5-オキサ-2-アザスピロ[3.4]オクタン-7-イル)アミノ)メチル)ベンゾニトリル
7-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-N-(4-フルオロベンジル)-1-オキサ-7-アザスピロ[4.4]ノナン-3-アミン
5-フルオロ-N-イソプロピル-N-メチル-2-((4-(7-(((1r,4r)-4-(メチルカルバモイル)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド
DMF(0.5mL)中の工程2からの粗生成物の溶液に、MeNH2HCl(15mg)及びEt3N(200μL)、続いてHATU(20mg)を加え、得られた溶液を室温で30分間撹拌した。生成物を分取RP-HPLC方法Aにより精製して、5-フルオロ-N-イソプロピル-N-メチル-2-((4-(7-(((1r,4r)-4-(メチルカルバモイル)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドをTFA塩(7mg)として得た;LCMS方法B:Rt=0.60分、(M+H)+=567.6; 1H NMR (MeOH-d4): δ 8.38, 8.37 (s, 1 H), 7.73, 7.61 (br.s, 1 H), 7.24-7.12 (m, 3 H), 4.65 (m, 1 H), 4.52-3.96 (m, 4 H), 3.45 (m, 2 H), 2.88 (m, 4 H), 2.82, 2.68 (two s, 3 H), 2.58 (s, 3 H), 2.16 (m, 2 H), 2.08-1.88 (m, 3 H), 1.74 (m, 5 H), 1.41 (m, 2 H), 1.12-0.92 (m, 8 H)。
2-((4-(7-アミノ-7-(4-シアノベンジル)-2-アザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(異性体1~2)
イソプロパノール(0.5mL)中の工程3からの粗生成物の溶液に、2-((4-クロロピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(中間体41、30mg)及びEt3N(200μL)を加え、得られた溶液をCEMマイクロ波反応器中で110℃で1時間加熱した。反応液を室温に冷却し、分取RP-HPLC方法Aにより精製して、以下を得た:
TFA塩として異性体1(1.22mg);LCMS方法B:Rt=0.83分;(M+H)+=571.4. 1H NMR (MeOH-d4): δ 8.49 (s, 1 H), 7.92 (s, 1 H), 7.70 (m, 2H), 7.47 (d, J =6.8 Hz , 2 H), 7.19 (m, 2 H), 7.07 (br, 1 H), 4.04-3.66 (m, 4 H), 3.61 (m, 2 H), 3.26 (m, 1 H), 3.08 (s, 2 H), 2.28-1.76 (m, 8 H), 1.49 (m, 3 H), 1.40 (m, 3 H), 1.17 (d, J = 7.6 Hz, 3 H), 1.10 (m, 3 H);及び
TFA塩として異性体2(1.36mg);LCMS方法B:Rt=0.89分;(M+H)+=571.4. 1H NMR (MeOH-d4): δ 8.36 (s, 1 H), 7.86 (br, 1 H), 7.57 (d, J = 8 Hz, 2H), 7.32 (d, J =7.6 Hz , 2 H), 7.04 (d, J = 7.6 Hz, 2 H), 6.96 (br, 1 H), 3.80-3.48 (m, 5 H), 3.18 (m, 1 H), 2.94 (s, 2 H), 2.05 (m, 2 H), 1.86-1.58 (m, 4 H), 1.49 (m, 2 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 6. 4 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H)。
5-フルオロ-2-((4-(7-ヒドロキシ-8-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2-アザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N,N-ジイソプロピルベンズアミド(異性体1~3)
イソプロパノール(0.3mL)中の工程3からの粗生成物の溶液に、2-((4-クロロピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(中間体41、20mg)及びEt3N(150μL)を加え、得られた溶液をCEMマイクロ波反応器中で110℃で1時間加熱した。LC-MSは、1:1:5の比で、tR=0.88、0.90、及び0.95分の3つの生成物を示した。生成物を分取RP-HPLC方法Aにより単離して以下を得た:
TFA塩として異性体1(1.4mg)、LCMS方法B:Rt=0.88分;(M+H)+=603.5. 1H NMR (MeOH-d4): δ 8.37 (s, 1 H), 7.68, 7.54 (two br, 1 H), 7.10 (m, 3 H), 6.84-6.72 (m, 3 H), 4.08-3.94 (m, 2 H), 3.94-3.50 (m, 5 H), 3.00-2.74 (m, 1 H), 2.52-2.26 (m, 1 H), 2.14-1.78 (m, 5 H), 1.68-1.30 (m, 6 H), 1.24-1.02 (m, 6 H), 1.02-0.82 (m, 2 H);
TFA塩として異性体2(0.82mg)、LCMS方法B:Rt=0.90分;(M+H)+=603.5. 1H NMR (MeOH-d4): δ 8.33 (s, 1 H), 7.62, 7.50 (two br, 1 H), 7.10 (m, 3 H), 6.84-6.70 (m, 3 H), 3.98-3.54 (m, 6 H), 3.52-3.34 (m, 1 H), 3.02-2.92 (m, 1 H), 2.78, 2.48 (two br, 1 H), 2.28 (m, 1 H), 2.08-1.92 (m, 2 H), 1.90-1.72 (m, 2 H), 1.68-1.46 (m, 2 H), 1.34 (m, 3 H), 1.28-0.84 (m, 7 H);及び
TFA塩として異性体3(5mg)、LCMS方法B:Rt=0.95分;(M+H)+=603.5. 1H NMR (MeOH-d4): δ 8.35 (s, 1 H), 7.68-7.50 (m, 1 H), 7.22-7.04 (m, 3 H), 6.77 (m, 3 H), 4.08-3.90 (m, 2 H), 3.90-3.56 (m, 4 H), 3.56-3.32 (m, 1 H), 2.76 (m, 1 H), 2.45 (m, 1 H), 2.11 (m, 1 H), 1.88-1.58 (m, 4 H), 1.55-1.24 (m, 6 H), 1.22-0.98 (m, 6 H), 0.92 (br, 1 H), 0.84 (br, 1 H)。
2-((4-(7-アミノ-8-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2-アザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(異性体1~2)
MeOH(2mL)中の工程4からの粗生成物に6N HCl(2mL)を加え、得られた溶液を室温で一晩撹拌した。LC-MSは、1:6の比でtr=0.65、0.67分の2つの生成物を示した。生成物を分取RP-HPLC方法Aにより単離し、2つの異性体を得た:
異性体2をTFA塩として(4.24mg)。LCMS方法B:Rt=0.69分、(M+H)+=602.5. 1H NMR (MeOH-d4): δ 8.34 (s, 1 H), 7.80 (br, 1 H), 7.09 (m, 2 H), 6.99 (m, 1 H), 6.82 (m, 1 H), 6.76 (m, 2 H), 3.84-3.62 (m, 3 H), 3.58-3.42 (m, 2 H), 3.36-3.26 (m, 1 H), 3.08-2.98 (m, 1 H), 2.45-2.12 (m, 2 H), 1.88-1.54 (m, 4 H), 1.37 (m, 6 H), 1.22 (m, 1 H), 1.05 (m, 6 H), 0.95 (m, 2 H)。
2-((4-(7-アミノ-8-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2-アザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミド(異性体3)
5-フルオロ-2-((4-(8-(4-フルオロベンジル)-7-(2-ヒドロキシエチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N,N-ジイソプロピルベンズアミド(異性体1~2)
THF(0.5mL)中の粗2-((4-(7-(2-((tert-ブチルジメチルシリル)オキシ)エチル)-8-(4-フルオロベンジル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N,N-ジイソプロピルベンズアミドの溶液に、室温でTHF溶液中のTBAF(1M、0.1mL、0.1μmol)を加えた。反応混合液を室温で2時間撹拌し、減圧下で濃縮した。粗生成物をギルソン-HPLCにより精製して、標題生成物を2つのラセミ化合物の混合物として得た。
異性体2:LCMS方法A:tR=0.92分、[M+H]+=594.3. 1H NMR (CD3OD): δ 8.56 (s, 1H), 8.00 (s, 1H), 7.33 - 7.31 (m, 2H), 7.28 - 7.25 (m, 1H), 7.24 - 7.20 (m, 2H), 7.10 - 7.08 (m, 2H), 3.90 - 3.81 (m, 8H), 3.62 - 3.53 (m, 2H), 3.48 - 3.41 (m, 2H), 3.24 - 3.13 (m, 2H), 2.90 - 2.81 (m, 1H), 2.16 - 2.10 (m, 2H), 1.94 - 1.91 (m, 2H), 1.53 - 1.51 (m, 3H), 1.29 - 1.27 (m, 3H), 1.21 - 1.19 (m, 3H), 1.11 - 1.07 (m, 3H)。
6-((7-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン-2-イル)メチル)-1-メチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン
MeOH(3mL、無水)中の7-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン(30mg、0.07mmol、粗製物)及び1-メチル-2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(12mg、0.07mmol)の溶液に、NaBH3CN(22mg、0.35mmol)を加えた。得られた混合液を10~21℃で約16時間撹拌した。混合液を濃縮し、酸性分取RP-HPLC方法Aにより精製して、6-((7-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン-2-イル)メチル)-1-メチル-1H-ベンゾ[d]イミダゾール-2(3H)-オン(TFA塩)を白色固体として得た。収量:15mg。LCMS方法E:Rt=0.902分;(M+H)+=508.3, 510.3(塩素同位体)。1H NMR (MeOD-d4): δ 8.70-8.85 (m, 1 H), 7.99 (d, J = 5.2 Hz, 1 H), 7.35-7.50 (m, 1 H), 7.10-7.35 (m, 5 H), 4.35-4.50 (m, 2 H), 3.80-3.95 (m, 1 H), 3.35-3.70 (m, 6 H), 3.20-3.30 (m, 1 H), 1.75-2.40 (m, 8 H). 19F NMR (MeOD-d4): δ -77.02, -116.39。
5-((7-(3-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
工程3及び4は、実施例1の工程4~5に記載のように行った.LCMS方法C:Rt=1.190分;(M+H)+=580.3。1H NMR (MeOD-d4): δ 9.12 (s, 1H), 8.67 (s, 1H), 7.91-8.10 (m, 2H), 7.10-7.38 (m, 6H), 6.89 (s, 1H), 4.40-4.48 (m, 2H), 3.37-3.87 (m, 8H), 3.00-3.14 (m, 1H), 1.99-2.25 (m, 4H), 1.11-1.29 (m, 6H). 19F NMR (MeOD-d4): δ -118.50, -76.93。
5-((7-(5-(2-(3-シクロプロピル-1-メチル-6-オキソ-1,6-ジヒドロピリジン-2-イル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン(ラセミ混合物)
標題生成物を、実施例28の工程2~4に記載のように調製した.LC/MS方法G Rt=3.15分。M+H=608.64. 1H NMR (d4-MeOH) 8.21 (s, 1H), 7.75 (s, 1H), 7.30 - 7.34 (m, 2H), 7.15 (m, 1H), 6.97 - 7.06 (m, 4 H), 6.54 (d, 1H), 3.57 - 3.69 (m, 4H), 3.42 - 3.52 (m, 2H), 3.31 (d, 3H), 2.72 (bm, 2H), 2.55 (bm, 2H), 1.89 (m, 2H), 1.79 (m, 2H), 1.28 (m, 1H), 0.75 (m, 1H), 0.66 (m, 1H), 0.55 (m, 1H), 0.48 (m, 1H) ppm。
5-((7-(5-(2-(3-シクロプロピル-1-メチル-6-オキソ-1,6-ジヒドロピリジン-2-イル)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン(異性体1~2)
実施例29A(異性体1):1H NMR (CD3OD ): δ 8.24 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 7.30-7.40 (m, 2H), 7.10-7.20 (m, 1H), 6.95-7.07 (m, 4H), 6.50-6.60 (m, 1H), 3.40-3.70 (m, 6H), 3.30-3.40 (m, 3H), 2.60-2.70 (m, 2H), 2.40-2.50 (m, 2H), 1.75-1.95 (m, 4H), 1.20-1.35 (m, 1H), 0.40-0.85 (m, 4H). 19F NMR: (CD3OD 400 MHz): δ -119.20 ~ -119.12。SFC:tR=17.556分、EE=98.93%。回転:OR°弧=0.389。
実施例29B(異性体2):1H NMR (CD3OD): δ 8.24 (d, J = 5.2 Hz, 1H), 7.77 (s, 1H), 7.30-7.40 (m, 2H), 7.10-7.20 (m, 1H), 7.00-7.07 (m, 4H), 6.50-6.60 (m, 1H), 3.50-3.70 (m, 6H), 3.30-3.40 (m, 3H), 2.60-2.75 (m, 2H), 2.40-2.50 (m, 2H), 1.75-1.95 (m, 4H), 1.20-1.35 (m, 1H), 0.45-0.85 (m, 4H). 19F NMR: (CD3OD): δ -119.21 ~ -119.13。SFC:tR=14.363分、EE=98.46%。
N-(5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)-4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリジン-3-アミン
2-(5-((4',5-ジフルオロ-2'-(2-フルオロプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン
MeOH(2mL、無水)中の2-(5-((4',5-ジフルオロ-2'-(2-フルオロプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン(44mg、0.10mmol、粗製物)及びテトラヒドロ-2H-ピラン-4-カルバルデヒド(15mg、0.13mmol)の溶液に、NaBH3CN(12mg、0.20mmol)を加え、混合液を20~25℃で17時間撹拌した。LCMSは、所望の生成物が約30%の収率で生成し、副生成物も約32%の収率で生成したことを示した。混合液を濃縮し、残留物を塩基性RP-HPLC方法Dにより精製して、2-(5-((4',5-ジフルオロ-2'-(2-フルオロプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタンを無色のゲルとして得た。収量:6.7mg。LCMS方法C:Rt=0.88分;(M+H)+=539.2. 1H NMR (CD3OD): δ 8.15 (s, 1H), 7.61 (s, 1H), 7.25 (dd, J = 10.8, 2.4 Hz, 1H), 7.04-7.20 (m, 4H), 7.00 (dd, J = 9.2, 4.8 Hz, 1H), 4.14-4.22 (m, 4H), 3.93 (dd, J = 11.2, 4.0 Hz, 2H), 3.35-3.45 (m, 6H), 2.38 (d, J = 6.4 Hz, 2H), 1.57-1.66 (m, 8H), 1.19-1.33 (m, 2H). 19F NMR (CD3OD): δ -115.50, -121.33, -132.73。
5-フルオロ-N-イソプロピル-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)ベンゼンスルホンアミド
ジクロロエタン(2mL、1%AcOHを含む)中の粗2-((4-(2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンゼンスルホンアミド及びテトラヒドロ-2H-ピラン-4-イル-カルバルデヒド(14mg、0.12mmol)の溶液に、室温でNaBH(OAc)3(25mg、0.12mmol)を加えた。反応混合液を30分間撹拌し、LCMS分析によって反応が完了したことを確認した。溶媒を蒸発させた後、ギルソンHPLCを使用して精製して、5-フルオロ-N-イソプロピル-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)ベンゼンスルホンアミドTFA塩を得た。LCMS方法B:Rt=1.293分;(M+H)+=506.57。1H NMR (CD3OD): δ 8.55 (d, J = 4.8 Hz, 1H), 7.77-7.75 (m, 2H), 7.53-7.49 (m, 1H), 7.40-7.37 (m, 1H), 4.60-4.40 (m, 8H), 3.96 (d, J = 11.6 Hz, 2H), 3.57-3.54 (m, 1H), 3.44 (t, J = 11.6 Hz, 2H), 3.17 (d, J = 6.8 Hz, 2H), 2.00-1.84 (m, 1H), 1.63 (d, J = 11.6 Hz, 2H), 1.40-1.32 (m, 2H), 1.17 (d, J = 6.0 Hz, 6H)。
5-((7-(5-(4-フルオロ-2-(2-メトキシブタン-2-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
MeOH(3mL)中の粗2-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)ブタン-2-オール及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、7mg、0.04mmol)の溶液に、室温でNaBH3CN(8mg、0.13mmol)を加え、反応混合液を15時間撹拌した。溶媒を蒸発させ、続いてRP-HPLC方法Aにより精製して、5-((7-(5-(4-フルオロ-2-(2-メトキシブタン-2-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オンTFA塩を得た。LCMS方法G:Rt=4.01分;(M+H)+=547.62。1H NMR (CD3OD): δ 8.52 (bs, 1H), 7.65 (m, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.21-7.18 (m, 2H), 7.13-7.10 (m, 3H), 4.43 (s, 2H), 4.20-3.95 (m, 4H), 3.70-3.50 (m, 2H), 3.47-3.36 (m, 2H), 3.15 (s, 3H), 2.34-2.05 (m, 4H), 1.96-1.87 (m, 2H), 1.58 (s, 3H), 0.76 (t, J = 7.6 Hz, 3H)。
5-((7-(5-(4-フルオロ-2-(3-ヒドロキシペンタン-3-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
MeOH(3mL)中の上記からの粗3-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)ペンタン-3-オール及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、20mg、0.12mmol)の溶液に、NaBH3CN(10mg、0.16mmol)を室温で加え、反応混合液を4時間撹拌した。溶媒を蒸発させ、続いてRP-HPLC方法Aにより、5-((7-(5-(4-フルオロ-2-(3-ヒドロキシペンタン-3-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オンを得た。LCMS方法G:Rt=3.197分;(M+H)+=547.61. 1H NMR (CD3OD): δ 8.52 (bs, 1H), 7.60 (m, 1H), 7.45 (dd, J = 2.8, 10.6 Hz, 1H), 7.21-7.18 (m, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.05-6.96 (m, 1H), 4.43 (s, 2H), 4.20-3.90 (m, 4H), 3.70-3.50 (m, 2H), 3.48-3.33 (m, 2H), 2.34-1.90 (m, 6H), 1.89-1.80 (m, 2H), 0.78 (t, J = 7.2 Hz, 6H)。
2-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-N-メチルシクロプロパンカルボキサミド(実施例35)及び5-((7-(5-(4-フルオロ-2-(3-ヒドロキシ-3-メチルブチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(実施例36)
無水MeOH(2mL)中の2-(5-(4-フルオロ-2-(3-フルオロ-3-メチルブチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン(50mg、0.12mmol)の溶液に、2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、22mg、0.14mmol)及びNaBH3CN(23mg、0.37mmol)を加え、溶液を50℃で16時間撹拌した。LCMSは、所望の化合物を示し、2-(5-(4-フルオロ-2-(3-フルオロ-3-メチルブチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナンが消費されたことを示した。混合液を塩基性分取RP-HPLC方法Dにより精製して、5-((7-(5-(4-フルオロ-2-(3-フルオロ-3-メチルブチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン及び5-((7-(5-(4-フルオロ-2-(3-ヒドロキシ-3-メチルブチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンの両方の生成物を白色固体として得た。
2-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)シクロプロパンカルボン酸メチル
MeOH(2mL)中の2-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)シクロプロパンカルボン酸メチル(110mg、0.27mmol)及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、53mg、0.33mmol)の溶液に、NaBH3CN(34mg、0.54mmol)を加えた。混合液を11~16℃で16時間撹拌した。混合液を濃縮し、シリカクロマトグラフィー(DCM:MeOH=10:1)により精製して、2-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)シクロプロパンカルボン酸メチルを白色固体として得た。収量:80mg。LCMS方法E:Rt=0.898分;(M+H)+=599.3. 1H NMR (CDCl3): δ 9.95-10.20 (s, 2H), 8.32-8.39 (m, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 6.0 Hz, 1H), 6.88-6.97 (m, 2H), 6.77-6.86 (m, 1H), 6.58-6.72 (m, 2H), 3.51-3.79 (m, 9H), 2.41-2.81 (m, 5H), 1.75-1.98 (m, 5H), 1.55-1.60 (m, 1H), 1.25-1.38 (m, 1H). 19F NMR (CDCl3): δ -119.00。
2-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-N-メチルシクロプロパンカルボキサミド
2-(6-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン-2-カルボニル)-2,3-ジヒドロ-1H-インデン-5-スルホンアミド
DMF(4mL、無水)中の、5-スルファモイル-2,3-ジヒドロ-1H-インデン-2-カルボン酸(131mg、0.31mmol)及び酸脱保護により中間体20Aから合成した2-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン(100mg、0.31mmol)の溶液に、HATU(177mg、0.47mmol)及びDIEA(120mg、154μL)を加えた。混合液を13~20℃で17時間撹拌し、その時点でLCMSは、所望の生成物が約17%の収率で生成したことを示した。混合液をEtOAc(20mL)で希釈し、H2O(20mL)、食塩水(20mL)で洗浄し、無水Na2SO4で乾燥し、濾過し、濃縮した。残留物を酸性分取RP-HPLC方法Aにより精製して、2-(6-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン-2-カルボニル)-2,3-ジヒドロ-1H-インデン-5-スルホンアミド(TFA塩)を白色固体として得た。収量:9mg。LCMS方法E:Rt=0.843分;(M+H)+=544.2. 1H NMR (CD3OD): δ 8.48 (s, 1H), 7.67-7.76 (m, 2H), 7.59 (s, 1H), 7.50 (dd, J = 8.4, 3.2 Hz, 1H), 7.33-7.43 (m, 2H), 7.21-7.29 (m, 1H), 4.71-4.86 (m, 4H), 4.57 (s, 2H), 4.27 (s, 2H), 3.36-3.45 (m, 1H), 3.17-3.24 (m, 4H). 19F NMR (CD3OD): δ -77.02, -115.29。
5-((7-(5-((5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
MeOH(130mL)中の2-(5-((5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン(6.8g、15.7mmol)、2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、3.05g、18.8mmol)、NaBH3CN(3.9g、62.8mmol)、及びHOAc(3.4mL)の溶液を、70℃で18時間撹拌した。次に混合液を減圧下で濃縮し、残留物を飽和NaHCO3溶液でpH=8に調整し、酢酸エチル(3×150mL)で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥し、濾過し、減圧下で濃縮した。残留物を塩基性分取RP-HPLC方法Dにより精製して、5-((7-(5-((5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンをわずかに黄色の固体として得た。収量:7.2g。LCMS方法C:Rt=0.663分;(M+H)+=579.1. 1H NMR (CD3OD): δ 8.13 (s, 1H), 7.58 (d, J = 6.8 Hz, 1H), 6.95-7.35 (m, 10H), 3.62 (s, 2H), 3.40-3.55 (m, 3H), 2.55-2.85 (m, 4H), 2.30-2.45 (m, 2H), 1.65-1.85 (m, 4H), 1.00-1.10 (m, 6H)。
5-((7-(5-((5-フルオロ-2'-イソプロピル-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(異性体1~2)
2-シクロプロピル-5'-フルオロ-2'-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボニトリル(ラセミ混合物)
2-シクロプロピル-5'-フルオロ-2'-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボニトリル(異性体1~2)
異性体1:LCMS方法D:Rt値:1.435分、(M+H)+=602.2;1H NMR (CD3OD ) : δ 8.15 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 7.10-7.20 (m, 3H), 7.05-7.10 (m, 2H), 7.01 (s, 2H), 3.63 (s, 2H), 3.35-3.60 (m, 4H), 2.60-2.75 (m, 2H), 2.35-2.50 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.75 (m, 3H), 0.87 (s, 2H), 0.66 (s, 2H).19F NMR (CD3OD): δ -120.38。SFC分析方法D:tR=5.306分、ee=99.70%。
異性体2:LCMS方法D:Rt値:1.435分、(M+H)+=602.2;1H NMR (CD3OD 400 MHz): δ 8.15 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.10-7.25 (m, 3H), 6.95-7.10 (m, 4H), 3.60-3.70 (m, 2H), 3.35-3.60 (m, 4H), 2.55-2.75 (m, 2H), 2.35-2.50 (m, 2H), 1.80-1.90 (m, 2H), 1.60-1.75 (m, 3H), 0.87 (s, 2H), 0.65 (s, 2H).19F NMR (CD3OD 400 MHz) : δ -120.383。SFC分析方法D:tR=7.188分、ee=99.32%。
2-シクロプロピル-5'-フルオロ-2'-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボキサミド(実施例43)及び2-シクロプロピル-5'-フルオロ-2'-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボン酸(実施例44)
2-シクロプロピル-5'-フルオロ-N,N-ジメチル-2'-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボキサミド
5-((7-(2-クロロ-5-(4-フルオロ-2-(1-イソプロピル-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
5-((7-(5-(4-フルオロ-2-(2-イソプロピル-1H-イミダゾール-1-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
無水MeOH(2mL)中の2-(5-(4-フルオロ-2-(2-イソプロピル-1H-イミダゾール-1-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン(10mg、0.024mmol)の溶液に、2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、6mg、0.036mmol)を加え、混合液をN2下で5分間撹拌した。次にNaBH3CN(70mg、0.118mmol)を加え、得られた混合液を65℃で16時間撹拌した。次に反応混合液を減圧下で濃縮して残留物を得て、これを分取RP-HPLC方法Gにより精製して、5-((7-(5-(4-フルオロ-2-(2-イソプロピル-1H-イミダゾール-1-イル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンを白色固体として得た。収量:2.7mg(20%)、LCMS方法D:Rt=1.675分、(M+H)+=569.1. 1H NMR (CD3OD): δ 8.27 (s, 1 H), 7.78 (s, 1 H), 7.30-7.40 (m, 2 H), 6.98-7.11 (m, 6 H), 3.41-3.65 (m, 6 H), 2.81-2.96 (m, 1 H), 2.62-2.70 (m, 2H), 2.42-2.55 (m, 2 H), 1.71-1.96 (m, 4 H), 1.22 (d, J = 5.2 Hz, 6 H). 19F NMR (CD3OD): δ -119.023。
5-((7-(5-(2-(シクロプロピルメトキシ)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
DCM(2mL)中の7-(5-(2-(シクロプロピルメトキシ)-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチル(42mg、87μmol)の溶液に、室温でTFA(0.4mL)を加えた。反応混合液を1時間撹拌し、次にNaHCO3水溶液で中和した。混合液をDCM(5×15mL)で抽出した。有機層を合わせ、Na2SO4で乾燥し、濾過し、減圧下で濃縮した。粗生成物をさらに精製することなく使用した。
2-(7-(5-((4'-シアノ-2'-シクロプロピル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)チアゾール-4-カルボン酸エチル
2-(7-(5-((4'-シアノ-2'-シクロプロピル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)チアゾール-4-カルボン酸
2-(7-(5-((4'-シアノ-2'-シクロプロピル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)-N-メチルチアゾール-4-カルボキサミド
2-(7-(5-((4'-シアノ-2'-シクロプロピル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル-2,7-ジアザスピロ[4.4]ノナン-2-イル)-N,N-ジメチルチアゾール-4-カルボキサミド
ジオキサン(2mL)及びH2O(1mL)中の7-ベンジル-2-(5-(2-クロロ-4-フルオロフェノキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン(70mg、0.16mmol)、(4-イソプロピルピリミジン-5-イル)ボロン酸(40mg、0.24mmol)の溶液に、N2下でエスホスパラダサイクル(6mg、0.008mmol)及びK3PO4(85mg、0.4mmol)を加え、得られた混合液をマイクロ波下で115℃で45分間撹拌した。得られた混合液を水(20mL)で希釈し、EtOAc(3×20mL)で抽出した。有機層を食塩水(20mL)で洗浄し、Na2SO4で乾燥し、濾過し、濃縮して残留物を得て、これをRP-HPLC方法Aにより精製して、7-ベンジル-2-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン(TFA塩)を白色固体として得た。収量:45mg。LCMS方法D:Rt=1.135分、(M+H)+=524.4. 1H NMR (CD3OD): δ 9.03-9.20 (m, 1 H), 8.55-8.67 (m, 1 H), 8.48 (s, 1 H), 7.93 (s, 1 H), 7.21-7.40 (m, 5 H), 7.10-7.20 (m, 3 H), 3.35-3.93 (m, 4 H), 2.95-3.12 (m, 1 H), 2.55-2.70 (m, 2 H), 2.20-2.40 (m, 1 H), 1.49-1.96 (m, 6 H), 1.10-1.30 (m, 8 H) 19F NMR (MeOD): δ -77.23, -117.91。
5-((7-(5-((5-フルオロ-2'-(1-ヒドロキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(混合物)
MeOH(10mL、無水)中の1-(2'-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5'-フルオロ-[1,1'-ビフェニル]-2-イル)エタノール(330mg、0.66mmol、粗製物)及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、106mg、0.66mmol)の溶液に、AcOH(0.2mL)を加えた。混合液を17~25℃で約30分間撹拌し、次にNaBH3CN(82mg、1.32mmol)を加え、得られた混合液を17~25℃で約16時間撹拌した。混合液を飽和NaHCO3水溶液(10mL)でクエンチし、CH2Cl2(3×20mL)で抽出した。合わせた有機層を食塩水(20mL)で洗浄し、Na2SO4で乾燥し、濾過し、濃縮して残留物を得て、これをRP-HPLC方法Aにより精製して、5-((7-(5-((5-フルオロ-2'-(1-ヒドロキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(TFA塩)を白色固体として得た。収量:290mg。LCMS方法C:Rt=0.593分、(M+H)+=581.2. 1H NMR (CD3OD): δ 8.00-8.15 (m, 1 H), 7.50-7.70 (m, 2 H), 6.90-7.40 (m, 9 H), 4.67 (s, 1 H), 4.43 (s, 2 H), 3.35-3.95 (m, 8 H), 1.90-2.25 (m, 4 H), 1.20-1.35 (m, 3 H).19F NMR (CD3OD): δ -76.92, -117.29 ~ -118.17。
5-((7-(5-((5-フルオロ-2'-(1-ヒドロキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(異性体1~4)
5-フルオロ-N-イソプロピル-N-メチル-2-((4-(7-(3-(2-オキソオキサゾリジン-3-イル)ベンジル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド
標題化合物を、実施例41の工程4に記載の手順に従って調製した。粗生成物をRP-HPLC方法Dにより精製して、5-フルオロ-N-イソプロピル-N-メチル-2-((4-(7-(3-(2-オキソオキサゾリジン-3-イル)ベンジル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドを白色固体として得た。LCMS方法E:Rt=1.230分、(M+H)+=589.2. 1H NMR (CD3OD): δ 8.20-8.30 (m, 1H), 7.70-7.85 (m, 1H), 7.56 (s, 1H), 7.40-7.50 (m, 1H), 7.25-7.35 (m, 1H), 7.05-7.20 (m, 3H), 6.75 - 6.95 (m, 1H), 4.40-4.55 (m, 2H), 4.00-4.15 (m, 2H), 3.55-3.80 (m, 6H), 2.94 (d, J = 4.0 Hz, 2H), 2.77 (s, 2H), 2.60-2.75 (m, 2H), 2.40-2.60 (m, 2H), 1.85-2.00 (m, 2H), 1.70-1.85 (m, 2H), 1.05-1.25 (m, 6H).19F NMR (MeOD) : δ -120.09 ~ -120.54。
5-フルオロ-N-イソプロピル-N-メチル-2-((4-(7-(4-(2-オキソオキサゾリジン-3-イル)ベンジル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド
5-((7-(5-((5-フルオロ-2'-(2-ヒドロキシプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
THF(5mL、無水)中の5-((7-(5-((2'-アセチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン(100mg、0.17mmol)の溶液に、MeMgBr(0.6mL、1.7mmol、エーテル中3M)を-78℃でN2下で滴加し、得られた混合液を-78℃でN2下で約4時間撹拌した。次に混合液を飽和NH4Cl水溶液(10mL)でクエンチし、EtOAc(3×20mL)で抽出した。合わせた有機層を食塩水(20mL)で洗浄し、Na2SO4で乾燥し、濾過し、濃縮して、残留物を得て、これを塩基性分取RP-HPLC方法Dにより精製して、5-((7-(5-((5-フルオロ-2'-(2-ヒドロキシプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンを白色固体として得た。収量:6mg。LCMS方法C:Rt=0.614分、(M+H)+=595.2. 1H NMR (CD3OD): δ 8.10-8.31 (m, 1 H), 7.58-7.86 (m, 2 H), 7.24-7.40 (m, 1 H), 6.81-7.22 (m, 8 H), 4.04 (s, 2 H), 3.45-3.63 (m, 4 H), 2.69-3.20 (m, 4 H), 1.80-2.03 (m, 4 H), 1.23-1.55 (m, 6 H). 19F NMR (CD3OD): δ -76.92, -121.82。
2-(1,4-ジオキサスピロ[4.5]デカン-8-イルメチル)-6-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン
4-((6-(5-(4-フルオロ-2-(4-イソプロピルピリミジン-5-イル)フェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)メチル)シクロヘキサノール
2-シクロプロピル-5'-フルオロ-2'-((4-(6-((4-ヒドロキシシクロヘキシル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)-[1,1'-ビフェニル]-4-カルボニトリル
2-(5-((5-フルオロ-2'-(1-メトキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン
無水MeOH(10mL)中の2-(5-((5-フルオロ-2'-(1-メトキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3,3]ヘプタン(35mg、0.083mmol、粗製物)、テトラヒドロ-2H-ピラン-4-カルバルデヒド(19mg、0.17mmol)、及びHOAc(20μL)の溶液を、19~25℃で0.5時間撹拌した。次にNaBH3CN(21mg、0.33mmol)を加え、反応混合液を60℃で4時間撹拌し、その時点でLCMSは所望の生成物が生成したことを示した。次に混合液を減圧下で濃縮し、得られた残留物をHPLC方法Aにより精製して、2-(5-((5-フルオロ-2'-(1-メトキシエチル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン(TFA塩)を白色固体として得た。収量:22mg。LCMS方法C:Rt=0.735分、(M+H)+=519.2. 1H NMR (CD3OD): δ 8.38 (d, J = 1.6 Hz, 1H), 7.72 (s, 1H), 7.55-7.60 (m, 1H), 7.40-7.50 (m, 1H), 7.30-7.34 (m, 3H), 7.13-7.28 (m, 2H), 4.4.25-4.60 (m, 9H), 3.94 (d, J = 11.6 Hz, 2H), 3.35-3.45 (m, 2H), 3.05-3.15 (m, 5H), 1.80-1.95 (m, 1H), 1.62 (d, J = 12.4 Hz, 2H), 1.27-1.37 (m, 5H).19F NMR (MeOD): δ -76.83, 117.75。
5-(5-フルオロ-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-2,3-ジヒドロ-1H-インデン-2-アミン
CH2Cl2(3mL)中の(5-(5-フルオロ-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-2,3-ジヒドロ-1H-インデン-2-イル)カルバミン酸tert-ブチル(35mg、0.06mmol)の混合液に、TFA(1mL)を氷冷水下で加え、混合液を室温で2時間撹拌した。混合液を減圧下で濃縮し、残留物をRP-HPLC方法Dにより精製して、5-(5-フルオロ-2-((4-(6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-2,3-ジヒドロ-1H-インデン-2-アミンを白色固体として得た。収量:1.2mg。LCMS方法C:Rt=0.516分、(M+H)+=516.2. 1H NMR (CD3OD): δ 8.10 (s, 1H), 7.30-7.40 (m, 4H), 7.10-7.23 (m, 3H), 4.31 (s 4H), 3.90-4.05 (m, 3H), 3.35-3.40 (m, 8H), 2.85-2.95 (m, 2H), 2.37-2.39 (d, J = 6.0 Hz, 2H), 1.62-1.64 (d, J = 10.0 Hz, 3H), 1.20-1.35 (m, 2H). 19F NMR (CD3OD): δ -76.93, -119.56。
5-((7-(5-((5-フルオロ-2'-(1-ヒドロキシプロパン-2-イル)-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
5-((7-(5-(4-フルオロ-2-(モルホリノメチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オン
無水MeOH(3mL)中の4-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロベンジル)モルホリン(20mg、粗製物、0.05mmol)及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、16mg、0.10mmol)の溶液に、NaBH3CN(17mg、0.25mmol)をN2下で加え、反応混合液を55℃で16時間撹拌した。反応混合液を減圧下で濃縮して残留物を得て、これをRP-HPLC方法Fにより精製して、化合物5-((7-(5-(4-フルオロ-2-(モルホリノメチル)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1H-ベンゾ[d]イミダゾール-2(3H)-オンを白色固体として得た。収量:7.10mg。LCMS方法E:Rt=1.635分、(M+H)+=560.2. 1H NMR (CD3OD): δ 8.23 (s, 1H), 7.57 (s, 1H), 7.27 (dd, J = 9.2, 3.2 Hz, 1H), 7.00-7.05 (dd, J = 8.8, 4.4 Hz, 4H), 3.74-3.81 (m, 3H), 3.57-3.68 (m, 9H), 2.59-2.74 (m, 3H), 2.45-2.51 (m, 5H), 1.93-1.99 (s, 2H), 1.84 (t, J = 6.8 Hz, 2H). 19F NMR (CD3OD): δ -121.05。
1-(7-(5-((2'-エチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)アミノ)ピリミジン-4-イル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)-2-メチルプロパン-2-オール
無水EtOH(3mL)中のN-(2'-エチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)-4-(2-(3,3,3-トリフルオロプロピル)-2,7-ジアザスピロ[3.5]ノナン-7-イル)ピリミジン-5-アミン(20mg、0.05mmol)、2,2-ジメチルオキシラン(5mg、0.07mmol)、及びEt3N(24mg、0.4mL、0.24mmol)の溶液を、60℃で18時間撹拌した。混合液を減圧下で濃縮し、RP-HPLC方法Aにより精製して、1-(7-(5-((2'-エチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)アミノ)ピリミジン-4-イル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)-2-メチルプロパン-2-オール(TFA塩)を無色油状物として得た。収量:15.8mg。LCMS方法C:Rt=0.616分、(M+H)+=490.1. 1H NMR (CD3OD): δ 8.39 (s, 1H), 7.68 (s, 1H), 7.30-7.40 (m, 2H), 7.15-7.25 (m, 1H), 7.05-7.15 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.85-6.95 (m, 1H), 4.15-4.25 (m, 2H), 3.95-4.05 (m, 2H), 3.65-3.85 (m, 4H), 3.25-3.35 (m, 2H), 2.40-2.55 (m, 2H), 1.70-2.00 (m, 4H), 1.27 (s, 1H), 1.08 (t, J = 7.6 Hz, 3H). 19F NMR (CD3OD): δ -76.88, -122.09。
1-((6-(5-(4-フルオロ-2-(1-イソプロピル-3-(トリフルオロメチル)-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)メチル)シクロヘキサン-1-オール
丸底フラスコに、2-(5-(4-フルオロ-2-(1-イソプロピル-3-(トリフルオロメチル)-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタンビス-TFA塩(20mg、1当量)、1-オキサスピロ[2.5]オクタン(16mg、5当量)、トリエチルアミン(21μL、5当量)、及びイソプロパノール(2mL)を加えた。フラスコに蓋をして、混合液を70℃で一晩加熱した。次に揮発性物質を真空下で除去し、得られた粗物質をRP-HPLC方法Aにより精製して、1-((6-(5-(4-フルオロ-2-(1-イソプロピル-3-(トリフルオロメチル)-1H-ピラゾール-5-イル)フェノキシ)ピリミジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタン-2-イル)メチル)シクロヘキサン-1-オール(2.42mg)を無色油状物として得た。LCMS方法G:Rt=5.58分。M+H=575.68. 1H NMR (d4-MeOH) 8.41 (s, 1H), 7.84 (s, 1H), 7.25 - 7.38 (m, 3H), 6.67 (s, 1H), 4.58 (bs, 2H), 4.20 - 4.49 (m, 6H), 3.12 - 3.32 (m, 7H), 1.39 (m , 5H), 1.24 - 1.30 (m, 6H)。
N-(2-アミノ-2-オキソエチル)-N-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)イソブチルアミド
無水MeOH(4mL)中のN-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)-N-(2-アミノ-2-オキソエチル)イソブチルアミド(40mg、粗製物)及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、29mg、0.18mmol)の溶液に、4Åモレキュラーシーブ(50mg)を加え、次に反応液を50℃でN2下で2時間撹拌した。2時間後、溶液にNaBH3CN(28mg、0.45mmol)を加え、反応混合液を50℃で12時間撹拌した。次に反応混合液を濾過し、減圧下で濃縮し、RP-HPLC方法Gにより精製して、N-(2-アミノ-2-オキソエチル)-N-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)イソブチルアミドを白色固体として得た。収量:7.00mg。LCMS方法E:Rt=1.498分、(M+H)+=603.3. 1H NMR (CD3OD): δ 8.30 (s, 1 H), 7.76 (d, J = 2.4 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 6.87-7.03 (m, 4 H), 4.73 (dd, J = 16.4, 3.6 Hz, 1 H), 3.82 (dd, J =16.0, 4.8 Hz, 1 H), 3.56-3.85 (m, 5 H), 2.45-2.69 (m, 5 H), 1.81-1.94 (m, 5 H), 1.05 (dd, J = 36.8, 6.8 Hz, 6 H).19F NMR (CD3OD): δ -119.24。
N-(5-フルオロ-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)プロパン-2-スルホンアミド
4M HCl/ジオキサン(4mL)を含むMeOH(10mL)中の2-(5-(4-フルオロ-2-(1-メチルエチルスルホンアミド)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[3.5]ノナン-7-カルボン酸tert-ブチル(526mg、0.98mmol)の混合液を、室温で30分間撹拌した。反応混合液を減圧下で濃縮して、N-(2-((4-(2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)プロパン-2-スルホンアミドをHCl塩として得た。LCMS方法B:Rt=0.56分、(M+H)+=436.1。
工程3~5は、実施例6Aの工程3~5について記載したように行った。LCMS方法A:Rt=0.68分、(M+H)+=625.1. 1H NMR (CD3OD) δ: 8.50 (s, 1H), 7.62 (brs, 1H), 7.35 (dd, J= 8.8, 1.6 Hz, 1H), 7.24 (dd, J= 8.8, 1.6 Hz, 1H), 7.03 (m, 1H), 4.64 (m, 2H), 4.22 (m, 2H), 3.58 (d, J = 12.4 Hz, 2H), 3.47 (m, 1H), 3.17 (m, 1H), 3.03-2.94 (m, 7H), 2.28 (d, J = 13.6 Hz, 2 H), 2.13 (d, J = 12.8 Hz, 2 H), 2.06 (d, J = 10.8 Hz, 2 H), 1.87 (d, J = 12.8 Hz, 2 H), 1.81 (m, 1H), 1.41 (d, J = 6.8 Hz, 6 H), 1.36 (m, 2H), 1.17 (m, 2H)。
無水THF(10mL)中の7-(5-(4-フルオロ-2-イソブチルアミドフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチル(400mg、0.80mmol)及びCH3I(500mg、3.5mmol)の混合液に、NaH(96mg、4.00mmol)をN2下で加え、反応混合液を12~21℃で2時間撹拌した。溶媒を減圧下で除去して残留物を得て、これをEtOAc(10mL)及びH2O(5mL)で抽出した。有機層を食塩水(20mL)で洗浄し、無水Na2SO4で乾燥し、濾過し、減圧下で濃縮して残留物を得て、これをシリカゲルカラムクロマトグラフィー(DCM:MeOH=1:0~10:1で溶出)により精製して、7-(5-(4-フルオロ-2-(N-メチルイソブチルアミド)フェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチルを白色固体として得た。収量:201mg。LCMS方法D:Rt=0.995分、(M+H)+=514.1. 1H NMR (CD3OD): δ 8.29-8.34 (m, 1 H), 7.78 (s, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17-7.21 (m, 1 H), 6.85-7.05 (m, 1 H), 3.35-3.81 (m, 8 H), 2.57-2.62 (m, 1 H), 1.88-1.97 (m, 5 H), 1.45 (s, 11 H), 1.05 (dd, J = 18.8, 6.8 Hz, 6 H).19F NMR (CD3OD): δ -119.09。
N-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-N-メチルイソブチルアミド
無水MeOH(2mL)及びHOAc(0.1mL)中のN-(2-((4-(2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロフェニル)-N-メチルイソブチルアミド(55mg、0.15mmol)及び2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-5-カルバルデヒド(中間体40、45mg、0.28mmol)の溶液に、NaBH3CN(43.4mg、0.7mmol)をN2下で加え、反応混合液を65℃で2時間撹拌し、その時点でLCMSは、出発物質が消費されたことを示した。反応混合液を濾過し、減圧下で濃縮し、得られた残留物をMeOH(5mL)で希釈し、分取HPLC方法Gにより精製して、N-(5-フルオロ-2-((4-(7-((2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミ:ダゾール-5-イル)メチル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)フェニル)-N-メチルイソブチルアミドを白色固体として得た。収量:7.8mg。LCMS方法E:Rt=0.936分、(M+H)+=560.1. 1H NMR (CD3OD): δ 8.29 (s, 1 H), 7.74 (s, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.14 (brs, 1 H), 6.87-6.91 (m, 4 H), 3.60-3.73 (m, 2 H), 3.61 (d, J = 4.4 Hz, 2 H), 3.21 (s, 3 H), 2.45-2.67 (m, 6 H), 1.79-1.95 (m, 5 H), 1.06 (d, J = 6.8 Hz, 6 H). 19F NMR (CD3OD): δ -119.16。
5-((7-(5-(4-フルオロ-2-イソブチルフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-イル)メチル)-1,3-ジヒドロ-2H-ベンゾ[d]イミダゾール-2-オン
標題化合物を、実施例41の3~4に記載の方法に従って、7-(5-(2-ベンジル-4-フルオロフェノキシ)ピリミジン-4-イル)-2,7-ジアザスピロ[4.4]ノナン-2-カルボン酸tert-ブチルから合成した。LCMS方法G:Rt=4.07分。M+H=551.59。
2-(3-((2'-エチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)メチル)ピリジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタン
2-(3-((2'-エチル-5-フルオロ-[1,1'-ビフェニル]-2-イル)メチル)ピリジン-4-イル)-2,6-ジアザスピロ[3.3]ヘプタンをMeOH(2mL)に溶解し、K2CO3(40mg)を加え、得られた混合液を10分間撹拌し、HPLCマイクロフィルターで濾過した。濾液を濃縮乾固して遊離アミンを得た。アミンの3分の1をDCM(1mL)に溶解し、この溶液に1滴のHOAc及びテトラヒドロ-2H-ピラン-4-カルバルデヒド(1滴)、続いてNaBH(OAc)3(18mg、0.085mmol)を加えた。混合液を室温で30分間撹拌し、濃縮して溶媒を除去した。得られた残留物を分取HPLC方法Aにより精製して、1.93mgの2-(3-((2'-エチル-5-フルオロ-[1,1'-ビフェニル)-2-イル)メチル]ピリジン-4-イル)-6-((テトラヒドロ-2H-ピラン-4-イル)メチル)-2,6-ジアザスピロ[3.3]ヘプタンをTFA塩として得た。LCMS方法B:Rt=0.89分。M+H=496.1. 1H NMR (CD3OD) δ: 7.99 (d, J = 7.2 Hz, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 7.26 (m, 1H), 7.21-7.18 (m, 2H), 6.99 (m, 2H), 6.44 (d, J = 7.2 Hz, 2H), 4.43 (m, 4H), 3.95 (m, 2H), 3.84 (d, J = 16.4 Hz, 2H), ), 3.71 (d, J = 16.4 Hz, 2H),3.41 (m, 2H), 3.12 (d, J = 7.2 Hz, 2H), 2.31 (m, 2H), 1.90 (m, 1H), 1.61 (m, 2H), 1.34 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H)。
2'-((4-(7-アミノ-7-ベンジル-2-アザスピロ[4.4]ノナン-2-イル)ピリミジン-5-イル)オキシ)-2-シクロプロピル-5'-フルオロ-[1,1'-ビフェニル]-4-カルボニトリル(異性体1~2)
MeOH(1mL)中のN-(7-ベンジル-2-(5-((4'-シアノ-2'-シクロプロピル-5-フルオロ-[1,1'-ビフェニル]-2-イル)オキシ)ピリミジン-4-イル)-2-アザスピロ[4.4]ノナン-7-イル)-2-メチルプロパン-2-スルフィンアミドの溶液に、6N塩酸(1mL)を加え、得られた溶液を室温で、出発物質がなくなるまで撹拌した。溶媒を真空下で除去し、残留物を分取RP-HPLC方法Eにより精製して、所望の生成物を2つの異性体として得た。
2-((4-(3-(4-アセトアミドベンジル)-2-アミノ-4-オキソ-1,3,7-トリアザスピロ[4.4]ノン-1-エン-7-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピル-N-メチルベンズアミド
i-PrOH(5mL)中のN-(4-((2-アミノ-4-オキソ-1,3,7-トリアザスピロ[4.4]ノン-1-エン-3-イル)メチル)フェニル)アセトアミド(25mg、0.077mmol)、及び中間体43(30mg、0.1mmol)の溶液に、DIEA(60mg、0.462mmol)を加え、反応混合液を還流下で110℃に18時間加熱還流した。反応混合液を減圧下で濃縮して残留物を得て、これを分取HPLC方法Aにより精製して、標題生成物を白色固体として得た。収量:10.20mg(22%)。LCMS方法D:Rt=0.995分;(M+H)+=589.1. 1H NMR (CD3OD): δ 8.55-8.79 (m, 1H), 7.99 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.25-7.46 (m, 5H), 4.16-4.88 (m, 6H), 3.91 (brs, 1H), 2.72-3.03 (m, 3H), 2.43-2.70 (m, 2H), 2.14 (s, 3H), 1.02-1.30 (m, 6H). 19F NMR (CD3OD): δ -116.87, 117.22。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド
0℃で無水DCM(2mL)中の2-((4-(7-(((1r,4r)-4-アミノシクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N-エチル-5-フルオロ-N-イソプロピルベンズアミド塩酸塩(0.25mmol)及びEt3N(75mg、0.75mmol)の溶液に、塩化エタンスルホニル(33mg、0.26mmol)を滴加し、混合液を0℃で2時間撹拌した。反応混合液をH2O(5mL)でクエンチし、DCM(3×5mL)で抽出し、合わせた有機層を食塩水(5mL)で洗浄し、無水Na2SO4で乾燥し、濾過し、減圧下で濃縮した。残留物を、8~10%MeOH/DCMで溶出するISCOフラッシュカラムにより精製して、N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドを白色固体として得た(41mg、26%)。LCMS方法B:Rt=0.73分;(M+H)+=631.6; 1H NMR (MeOD-d4): δ 8.23, 8.22 (two s, 1 H), 7.74, 7.70 (two s, 1 H), 7.22-7.15 (m, 2 H), 7.03-6.96 (m, 1 H), 4.45, 3.51 (two m, 1 H), 4.08-3.82 (m, 4 H), 3.36 (m, 1 H), 3.24 (m, 1 H), 3.12-2.94 (m, 3 H), 2.32 (m, 4 H), 2.10 (d, J = 6.8 Hz, 2 H), 1.96 (m, 2 H), 1.88-1.76 (m, 6 H), 1.48 (m, 1 H), 1.20-1.04 (m, 14 H), 1.02 (m, 2 H); 19F NMR (MeOD-d4): δ -119.7。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドのスケールアップ合成
N-メチル-2-ピロリドン(400mL)中の工程5からの2-((4-(2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-N-エチル-5-フルオロ-N-イソプロピルベンズアミド(39.0g、91.3mmol)の混合液に、(1r、4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル4-メチルベンゼンスルホネート(中間体50、41g、109.56mmol)、KI(16.9g、95.9mmol)、及びK2CO3(63g、456.5mmol)を加えた。次に反応混合液を70~75℃でN2雰囲気下で6時間撹拌した。反応液を室温に冷却し、追加の((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル4-メチルベンゼンスルホネート(中間体50、4.0g、10.9mmol)を加え、反応混合液を70-75℃でN2雰囲気下でさらに12時間撹拌した。混合液を室温に冷却し、水(500mL)で希釈し、DCM(3×800mL)で抽出した。合わせた有機層を水(3×1.5L)で洗浄し、無水Na2SO4で乾燥し、濾過し、減圧下で濃縮した。残留物を中性分取HPLC方法Aにより精製して、N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド(20.9g、36.8%)を白色固体として得た。LCMS方法A:Rt=1.82分; [M+H]+ = 631.3; 1H NMR (CDCl3 400 MHz): δ ppm 8.36-8.37 (m, 1 H), 7.76 (s, 1 H), 6.99-7.04 (m, 2 H), 6.74-6.80 (m, 1 H), 4.59-4.66 (m, 0.2 H), 4.04-4.06 (m, 1 H), 3.83-3.93 (m, 4 H), 3.48-3.53 (m, 0.8 H), 3.30-3.39 (m, 1 H), 3.17-3.21 (m, 1 H), 3.02-3.06 (m, 2 H), 2.25 (s, 4 H), 2.03-2.05 (s, 4 H), 1.73-1.84 (m, 7 H), 1.12-1.36 (m, 14 H), 0.89-0.98 (m, 2 H); 19F NMR (CDCl3 400 MHz): δ ppm -118.57; SFC方法A:tR=1.357分;HPLC方法A:tR=6.84分。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド遊離アミン結晶化
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド(0.50g)を、EtOAc(6mL)及びヘキサン(9mL)の混合液に溶解して透明な溶液を得て、これに<1mgの5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド遊離アミン結晶(実施例6A)を接種した。得られた溶液を25℃で2日間撹拌し、濾過して白色固体を集め、高真空下で一晩乾燥した(0.39g、76%)。1H NMR (MeOD-d4): δ 8.23, 8.22 (two s, 1 H), 7.74, 7.70 (two s, 1 H), 7.22-7.15 (m, 2 H), 7.03-6.96 (m, 1 H), 4.45, 3.51 (two m, 1 H), 4.08-3.82 (m, 4 H), 3.36 (m, 1 H), 3.24 (m, 1 H), 3.12-2.94 (m, 3 H), 2.32 (m, 4 H), 2.10 (d, J = 6.8 Hz, 2 H), 1.96 (m, 2 H), 1.88-1.76 (m, 6 H), 1.48 (m, 1 H), 1.20-1.04 (m, 14 H), 1.02 (m, 2 H); 19F NMR (MeOD-d4): δ -119.7;融点=156.6~157.6℃。pH=7を達成するため水で濃縮:7.6mg/mL。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドセスキフマル酸塩(セスキフマル酸塩)結晶化
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド遊離アミン(497.2mg、0.79mmol)及びフマル酸(137.2mg、1.5当量)を、EtOH(5mL)に溶解して透明な溶液を得た;EtOHを真空下で除去し、塩を高真空下で一晩乾燥した。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-メタンスルホン酸塩(ビス-メシル酸塩)結晶化
iPrOH(2.5mL)及びEtOAc(3mL)中のN-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド遊離アミン(419.7mg)の透明な溶液に、MeSO3H(>99.5%、Sigma-Aldrich)(0.13g、88.6μL、2.05当量)を滴加した。得られた溶液にさらに3mLのEtOAcを加え、混合液を室温で一晩撹拌した。次に白色固体を濾過して集め、全ての固体を母液とともに2回移し、高真空下で2日間乾燥した(535.1g、97%)。1H-NMR (MeOD-d4): δ 8.53, 8.52 (two s, 1 H), 7.92, 7.82, 7.71 (three s, 1 H), 7.38-7.22 (m, 3 H), 4.69-4.16 (br, m, 4 H), 3.90 (m, 1 H), 3.57 (m, 2 H), 3.45 (m, 1 H), 3.26 (m, 1 H), 3.16 (m, 1 H), 3.03 (q, J = 7.6 Hz, 2 H), 2.98 (m, 4 H), 2.68 (s, 6 H), 2.22-2.02 (m, 6 H), 1.92-1.74 (m, 3 H), 1.44-1.06 (m, 16 H); 19F NMR (MeOD-d4): δ -116.53, -116.79, -117.27;融点=207.6~209.7℃。pH=7を達成するため水で濃縮:261mg/mL。
N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-塩酸塩(ビス-塩酸塩)結晶化
EtOH(3mL)中のN-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミド遊離アミン(0.71g)の透明な溶液に、1N塩酸(2.25mL、2当量)を滴加した。得られた溶液を混合し、高真空下で溶媒を蒸発乾固させた。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド遊離アミン結晶化
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(実施例6A、0.79g)の遊離アミンを、EtOAcとヘキサンの混合液(28mL、約38%容量のEtOAc)に溶解した。すべての材料が溶液に入ったら、透明な溶液は徐々に混濁した。得られた溶液を25℃で一晩撹拌した。次に濾過して白色固体を集め、高真空下で一晩乾燥した(0.58g、73%)。1H NMRは、微量のEtOAcを含む純粋な化合物を示した。融点=177~178℃。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-メタンスルホン酸塩(ビス-メシル酸塩)結晶化
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(実施例6A)遊離アミン(1.02g)をiPrOH(25mL)に溶解し、この溶液にMeSO3H(>99.5%、Sigma-Aldrich)(0.31g、207.5μL、2.05当量)をゆっくり加えた。得られた溶液に5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-メタンスルホン酸塩(実施例264)の単結晶を接種し、室温で一晩撹拌した。濾過して白色固体を集め、高真空下で4日間乾燥した(0.94g、73%)。1H NMRは溶媒ピークのないビス-メシル酸塩を確認した;融点=217.6~219.6℃。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩(セスキフマル酸塩)結晶化
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(実施例6A)遊離アミン(0.34g)をMeCN(2mL)に溶解した。フマル酸(82.3mg、1.3当量)をEtOHに溶解した(1.5mL、溶解するまで温めた)。次にフマル酸溶液をアミン溶液に移し、よく混合し、次に溶媒を真空下で除去して乾燥した。得られた残留物をMeCN(10mL)及びEtOH(0.2mL)の混合液に再溶解して透明な溶液を得た。セスキフマル酸塩(実施例265)の単結晶を接種した後、溶液を30℃で一晩撹拌した。濾過して白色固体を集め、高真空下で24時間乾燥した(0.35g、83%)。融点=176~178℃。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-塩酸塩(ビス-塩酸塩)
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド(約86g、約92%純度)の粗遊離塩基に、室温でEtOH(13容量)を加えた。この溶液にEtOH中の3当量の1~2M HCl溶液を室温で加えた。溶液を約15分間撹拌し、次にジイソプロピルエーテル(iPr2O、7容量)を撹拌EtOH溶液に室温でゆっくり加えた。混合液を室温で撹拌して、約1日かけて白色沈殿物を形成させた。白色沈殿物を濾過し、EtOHとiPr2Oの1:1混合液で洗浄して、HPLC分析によって約96%の純度の67gのビスHCl塩を得た。得られた物質は非晶質形態と結晶形態の混合物であると思われた。残存するEtOH(約4.5重量%)を約8容量の水で凍結乾燥することによって除去した。凍結乾燥後の物質は、約210~215℃の融点を有し、融点分析中にこれらの温度で分解するようであった。
結晶応答分析
デジタルフィルタ法
実施例258~261について、結晶応答パーセントを測定した。X線粉末回折データにおいて、結晶性物質の存在は、鋭く明確に画定された回折ピークの存在によって示される。結晶応答パーセントは、本質的に試料からの全回折信号に対するパーセントとして表される全ての結晶ピークに含まれる全回折信号である。試料からの回折応答を測定するために、測定されたデータを、まず装置のバックグラウンドを除去することによって前処理し、次に共通領域に標準化した。次に前処理されたデータを2つのデジタルフィルタに通した:1つはコンプトン及び熱拡散散乱を除去するため、もう1つはパターンから非結晶試料応答を除去するためである。データをデジタルフィルタに通した後に残っている全標準化強度のパーセントは、試料中の完全な結晶性物質のパーセントを示す。デジタルフィルタを使用して測定された結晶応答値パーセントは表20に要約される。これらの数値は、欠陥のある結晶性物質を含まず、その結果、試料の絶対結晶性値パーセントではない。表20に示されるような結晶性値パーセントは、同じ結晶多形を含む試料間の結晶性パーセントの相対比較を可能にする。
実施例261で観察された本質的に非結晶性の応答を、全ての試料について代表的な非結晶性パターンであると見なすと、観察されたデータによって許容される最大の非結晶性成分を推定するために使用できるベイズモデルの定義が可能になる。ベイズモデルを使用する組み合わせの結晶性パーセント結果を表21に示す。ベイズモデルは、データセット実施例259で観察された拡散X線散乱の良好な近似を与え、71%~75%の結晶値パーセントが妥当であることを示唆した。ベイズモデルは、例258及び260についてはあまり良好な適合度を与えなかった。両方のデータセットは本質的に結晶質であるように見える。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩の結晶形態スクリーニング
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩
固体形態のスクリーニングアッセイに使用されたフマル酸塩は、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド遊離アミン塩基から、以下の手順に従って調製された:
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩の7個の異なる固体形態が観察され、それらは以下に記載される。同定されたセスキフマル酸塩形態についてのX線粉末回折(XRPD)パターン(XRPD方法C)を図9に示す。
形態A:セスキフマル酸一水和物;比率2:3:2の5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド:フマル酸:水。
・DSC/TG:70~130℃のTGでの重量減少と同時に起こる広範な吸熱。図11に示すように、最終吸熱事象は179℃で開始した。図12に示すように、1.7%の重量減少が90℃まで観察された。
・DVS:5から95%RHへ0.92%の重量増加。脱着時に失われた重量を図13に示す。
・可変温度(VT)-XRPD:形態変化は観察されなかった。図14に示すように、ピークシフトは加熱時の熱膨張と一致した。165℃でのXRPDパターンは形態Aと一致した。
・真空乾燥又は加熱時の変化は無かった。
・形態B及び形態Dは、0.22aw以上の水分活性スラリー中で、形態Aに変換された。
・形態Bは、MeOH及びEtOH実験から観察された。XRPDパターン(XRPD方法C)は指数化され、図15に示すように溶媒和物と一致した.2θピークのリストを以下の表23に示す。
・1H-NMRは、分析した試料中で限られた量のMeOHを示した。
・スケールアップ実験中に、2つのサブ試料(スラリー及び湿潤ケーキ)が単離され、B型であることが観察された。図16に示すように45℃の真空オーブン中でバルク物質を乾燥すると、D型に変換された(XRPD方法C)。
・安定性:水分活性スラリー(0.22aw)中で形態Aに変換された。
・XRPD:図16及び23に示すように、より低い結晶性(XRPD方法C)。2θピークのリストを以下の表24に示す。
・1H NMRはセスキフマル酸塩と一致し、有機溶媒は観察されなかった。
・DSC/TG:図18に示すように、157℃で開始される広範な吸熱事象がDSC(図17)で観察され、90℃まで加熱すると0.4%の重量減少があった。
・安定性:水分活性スラリー(0.22aw)中で形態Aに変換された。
・45℃の真空オーブン中で1日後に、XRPDに変化は観察されなかった(XRPD方法C)。
・1H-NMRはTHF溶媒和物を示す。真空乾燥後、0.6モルのTHFが依然として明らかである。
・DSC:65℃付近で最大の広範な低温吸熱が、109℃付近で最大の発熱に至った。図19に示すように、143℃付近で最終吸熱が始まった。
・ACN/水混合液中でスラリー化すると、形態Aへの変換が観察された。
表25は、種々の水性溶媒系及び有機溶媒系での、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩の水分活性分析の結果を示す。
表26は、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩の物理的安定性分析の結果を示す。
単結晶5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-メタンスルホン酸塩(ビス-メシル酸塩)の調製
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-メタンスルホン酸塩の単結晶を、EtOAcからiPrOH溶液へのゆっくりした拡散によって得て、X線構造解析によって確認した。単結晶X線構造解析の概要を以下の表27に示す.50%確率熱振動楕円体を有するビスメタンスルホン酸塩のORTEP表示を図20~21に示す。
単結晶5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩(セスキフマル酸塩)の調製
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩の単結晶を、MeCN溶液中でゆっくり蒸発させることにより得た。単結晶のX線分析は、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドとフマル酸の比率1:1.5を示した。単結晶X線構造解析の概要を以下の表28に示す.50%熱振動楕円体を有する5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドセスキフマル酸塩のORTEP表示を図22に示す。
単結晶5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-塩酸塩の調製
iPrOH(2mL)中の5N塩酸を、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド遊離塩基(140mg)に室温で加えた。室温で30分間撹拌した後、溶媒を除去して、5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドのビス-塩酸塩を得た。この白色非晶質物質の一部(約25mg)を採取し、MeCN(0.5mL)を室温で加えた。得られた懸濁液を、この物質が完全に溶解するまで2分間穏やかに加熱した。次にこの溶液を一晩放置して室温に冷却して、結晶性5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドビス-塩酸塩を得た。融点:約210~215℃。
5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミドの結晶塩スクリーニング
医薬的に許容し得る対イオンを既知のpKa値に基づいて選択し、溶液又は懸濁液にの5-フルオロ-N,N-ジイソプロピル-2-((4-(7-(((1r,4r)-4-(メチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)ベンズアミド遊離塩基(実施例6A)に対する対イオンの約1又は2モル当量を直接添加する一般的手順に従って、塩結晶化実験を行った。十分な量の沈殿が生じたときに固体物質を採取した。冷却、逆溶媒添加、及び/又はスラリー化などの追加の工程を実施して、結晶化を誘導し、又は必要に応じて収率を増加させた。生成物は、偏光顕微鏡法(PLM)及び/又はXRPDによって結晶性について定性的に評価した。真空乾燥を使用して、潜在的な塩の非溶媒和結晶形態を同定した。溶液1H-NMR分光法を使用して、組成及び化学量論(化学分解は起きていないこと)を確認し、存在する溶媒の量を評価した。塩酸塩については、エネルギー分散型X線(EDX)分光法を使用して化学量論を確認した。表29は、塩スクリーニング実験で同定された医薬的に許容し得る塩のリストを示す。「n/a」は、データが入手できないことを意味する(例えば、円が結晶形態で単離できなかった;相対湿度75%で潮解した;円が別の形態に変換した;又は乱れたXRPDパターンが観察された)。
アッセイ1(結合アッセイ)
メニン/MLL結合に対する阻害剤化合物の効力を、ビオチン化した(1)野生型メニン、又は(2)変異型メニン(Huang et al, 2012, Nature, 482, 542-546に記載)、及びそのC末端にFLAGエピトープを有するMLL-AF9融合タンパク質を使用するAlphaLISAアッセイにより評価した。メニンタンパク質を大腸菌で発現させ、EZ-Link(商標)スルホ-NHS-ビオチン(ThermoFisher カタログ番号21217)を製造業者のプロトコールに従って使用して、ビオチンを用いて共有結合的に修飾した。AF91-92及びC末端FLAGペプチドに融合したMLL1-1,396をHEK293細胞で発現させ、21,000×gで10分間清澄化した溶解物として使用した。
細胞増殖に対する阻害化合物の効力を、ATP定量に基づいて、ヒト急性単球性白血病細胞株MV-4-11(ATCC(登録商標)CRL-9591(商標))に対して評価した。MV-4-11細胞又は毒性対照HL-60細胞(ATCC(登録商標)CCL-240(商標))を、96ウェル組織培養プレート(1ウェル当たり10%FBSを含む200μL培養培地中1.67×104細胞)中で、試験化合物有り又は無しで、37℃、5%CO2で72時間インキュベートした。インキュベーション後、各ウェルをピペッティングにより混合し、各ウェルから95μLを96ウェルブラックOptiPlate(登録商標)プレート(PerkinElmer)中のウェルに移した。等量のCellTiter-Glo(登録商標)発光細胞生存率アッセイ試薬(Promega)を各ウェルに加え、続いてオービタルプレートシェーカーで5分間混合した。Wallac EnVision 2104 Multilabel Reader(PerkinElmer)を用いて発光を測定して、ATPを定量」た。少なくとも100xLD50を生じる濃度の強力なメニン阻害剤で処理した細胞に対する阻害されていない細胞増殖(DMSO)に基づいて、試験化合物による細胞増殖の阻害パーセントを計算した。阻害パーセント対化合物濃度の用量応答曲線に基づいてEC50値を計算し、これを以下の表30に示す。
Claims (10)
- Cu Kα線を使用して、2θの点から、約9.7°、約11.6°、約12.6°、約16.6°、約17.5°、約18.8°、約19.2°、約19.8°、約21.0°、及び約25.3°から選択される、少なくとも4個のXRPDピークを有する化合物N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドの固体形態。
- 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドが、以下の図1:
- Cu Kα線を使用して、2θの点から、約5.8°、約8.7°、約13.2°、約16.0°、約17.4°、約17.6°、約19.1°、約20.3°、約21.8°、約23.0°、約23.3°、約24.9°、及び約26.0°から選択される、少なくとも4個のXRPDピークを有するN-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドセスキフマル酸塩の固体形態。
- 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドセスキフマル酸塩が、以下の図2:
- 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドセスキフマル酸塩が、Cu Kα線を使用して、2θの点から、約5.8°、約8.7°、約13.2°、約16.0°、約17.4°、約17.6°、約19.1°、約20.3°、約21.8°、及び約23.0°から選択される、少なくとも4個のXRPDピークを有する、請求項3に記載の固体形態。
- 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドセスキフマル酸塩が、Cu Kα線を使用して、2θの点から、約5.8°、約8.7°、約13.2°、約16.0°、約17.4°、約17.6°、及び約19.1°から選択される、少なくとも4個のXRPDピークを有する、請求項3に記載の固体形態。
- Cu Kα線を使用して、2θの点から、約5.6°、約11.0°、約13.3°、約16.7°、約20.1°、約20.9°、約22.1°、約23.6°、約24.9°、及び約29.6°から選択される、
、N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-メタンスルホン酸塩の固体形態。 - 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-メタンスルホン酸塩が、以下の図3:
- Cu Kα線を使用して、2θの点から、約4.7°、約10.7°、約13.4°、約15.9°、約17.0°、約19.5°、約20.1°、約23.8°、約25.8°、及び約28.1°から選択される、少なくとも4個のXRPDピークを有する、N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-塩酸塩の固体形態。
- 前記N-エチル-2-((4-(7-(((1r,4r)-4-(エチルスルホンアミド)シクロヘキシル)メチル)-2,7-ジアザスピロ[3.5]ノナン-2-イル)ピリミジン-5-イル)オキシ)-5-フルオロ-N-イソプロピルベンズアミドビス-塩酸塩が、以下の図4:
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