JP2022545007A - インターフェロン遺伝子の刺激因子stingの単環式アゴニスト - Google Patents
インターフェロン遺伝子の刺激因子stingの単環式アゴニスト Download PDFInfo
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- JP2022545007A JP2022545007A JP2022511100A JP2022511100A JP2022545007A JP 2022545007 A JP2022545007 A JP 2022545007A JP 2022511100 A JP2022511100 A JP 2022511100A JP 2022511100 A JP2022511100 A JP 2022511100A JP 2022545007 A JP2022545007 A JP 2022545007A
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- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
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- UNEPXPMBVGDXGH-UHFFFAOYSA-N tributyl(pyridin-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=NC=C1 UNEPXPMBVGDXGH-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/5365—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 ortho- or peri-condensed with heterocyclic ring systems
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
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- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
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Abstract
Description
cGAS-STINGシグナル伝達経路は、哺乳動物宿主細胞が多様なDNAおよびRNAウイルスを除去するために開始する自然免疫応答において重要な役割を果たす。STING(Stimulator of Interferon Genes)は、ミトコンドリア関連膜に部分的に局在する小胞体(ER)常在シグナル伝達タンパク質であり、免疫および非免疫細胞型の両方で広く発現される。環状GMP-AMPシンターゼ(cGAS)によりサイトゾルDNAに反応して産生される2'-3'cGAMPを含む、環状ジヌクレオチド(CDN)に反応して、STINGは核周囲領域に移動し、ここでTBK1-/IRF3-依存的様式でI型インターフェロン(IFN)および炎症性サイトカイン産生を急速に誘導する。STINGはサイトゾルDNAと直接結合することも判明しているが、直接的DNAセンシング活性の生理学的関連性はなお十分に特徴づけるべきである。
様々な態様において、本開示はインターフェロン遺伝子の刺激因子(STING)のアゴニストを提供し、これは腫瘍の処置に使用することができる。
からなる組より独立に選択される1、2、もしくは3つの基で置換された、1、2、または3つのN原子を含む5または6員ヘテロアリールであり、ここで波線は結合の位置を示す。
式中、
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)であり;
R1はそれぞれ独立に、H、F、Cl、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;かつ
Rは、H、アルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくは1,2,3,4トリアゾールなどのエステル同配体で置換され得る。
多様な免疫腫瘍学的適用のためのSTING経路アゴニストの開発に多大な関心がある。最も顕著なことに、STING経路アゴニストは、チェックポイント遮断単独に反応しない患者において、免疫チェックポイント標的薬物を含む併用療法の一部として重要な適用の可能性を有する。
などの生物学的に等価な置換物で置き換えられてもよく、ここでRは本明細書に定義するRAと同じ定義を有する。例えば、The Practice of Medicinal Chemistry (Academic Press: New York, 1996), at page 203を参照されたい。
からなる群より独立に選択される1、2、もしくは3つの基で置換された、1、2、または3つのN原子を含む5または6員ヘテロアリールであり、ここで波線は結合の位置を示す。
本開示は、1つの態様において、ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法も提供する。この方法は、有効用量の本明細書に記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む。
本開示は、別の態様において、本明細書に記載の化合物またはその薬学的に許容される塩を薬学的に許容される担体または賦形剤との組み合わせで含む薬学的組成物を提供する。
略語。 以下の略語を用いる:テトラヒドロフラン(THF)、ジクロロメタン(DCM)、N,N-ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、ジメチルスルホキシド(DMSO)、トリフルオロ酢酸(TFA)、トリエチルアミン(TEA)、ジイソプロピルエチルアミン(DIPEA)、(1-シアノ-2-エトキシ-2-オキソエチリデンアミノオキシ)ジメチルアミノ-モルホリノ-カルベニウムヘキサフルオロホスフェート(COMU)、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート、N-[(ジメチルアミノ)-1H-1,2,3-トリアゾロ-[4,5-b]ピリジン-1-イルメチレン]-N-メチルメタンアミニウムヘキサフルオロホスフェートN-オキシド(HATU)。
6-クロロピリダジン-3-カルボン酸エチル(4.0g、21.4mmol)のアルゴンパージした溶液に、1,4-ジオキサン(40mL)中の4-(トリブチルスタニル)ピリジン(8.71g、23.65mmol)を加え、得られた混合物を室温で10分間撹拌した後、Pd(PPh3)4(2.48g、2.15mmol)を加えた。反応混合物を110℃で16時間撹拌した。完了後、反応混合物を飽和NaHCO3水溶液(50mL)で希釈し、EtOAc(30mL×3)で抽出し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣をカラムクロマトグラフィで精製して、6-(ピリジン-4-イル)ピリダジン-3-カルボン酸エチル(2.5g、収率46%)を白色固体で得た。
水(10mL)中の水酸化リチウム一水和物(0.55g、13.1mmol)の水溶液を、THF(10mL)中の6-(ピリジン-4-イル)ピリダジン-3-カルボン酸エチル(2.5g、10.9mmol)の溶液に0℃で加え、得られた混合物を室温で5時間撹拌した。MeOH(10mL)を加え、混合物を60℃で1時間撹拌した。反応の完了後、THFおよびMeOHを減圧下で除去し、水層を2N HClで酸性化した(pH4)。得られた固体をろ過し、水で洗浄し、乾燥した。次いで、アセトニトリルで粉砕し、ろ過し、ろ過ケークを乾燥して、化合物A(1.4g、収率53%)を淡褐色固体で得た。
1,4-ジオキサン(175mL)および水(25mL)中のピラゾール-4-ボロン酸(4.51g、40.31mmol)、Na2CO3(7.1g、67.2mmol)および6-クロロピリダジン-3-カルボン酸エチル(5g、26.88mmol)の溶液にアルゴンガスを10分間パージした後、Pd(PPh3)4(1.55g、1.34mmol)を加えた。反応混合物を90℃で1時間撹拌した。反応の完了後、室温まで冷却し、EtOAc(250mL)で希釈した。次いで、水(100mL)、食塩水(100mL)で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過し、減圧下で濃縮した。残渣をシリカゲルのカラムクロマトグラフィで精製して、3.2gの6-(1H-ピラゾル-4-イル)ピリダジン-3-カルボン酸エチルをオフホワイト固体で得た。LC-MS (ESI+): m/z; 219.0 [M+H]+。
NaH(60重量%)(0.422g、17.6mmol)を、THF(64mL)およびDMF(30mL)中の6-(1H-ピラゾル-4-イル)ピリダジン-3-カルボン酸エチル(3.2g、14.67mmol)の撹拌溶液に0℃で少しずつ加え、10分間撹拌した。これにSEM-Cl(2.93g、17.61mmol)を加え、反応混合物を0℃で30分間撹拌した。次いで、10%クエン酸溶液で反応停止し、こうして得られた固体をろ過し、水(5mL×2)で洗浄し、乾燥した。残渣をシリカゲルのカラムクロマトグラフィ(溶離剤としてジクロロメタン中0~5%メタノールを使用)で精製して、2.65gの6-(1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピラゾル-4-イル)ピリダジン-3-カルボン酸エチルをオフホワイト固体で得た。LC-MS (ESI+): m/z; 349.1 [M-H]+。
水酸化リチウム一水和物(0.382g、9.13mmol、水3mL中)の水溶液を、THF(9mL)中の6-(1-((2-(トリメチルシリル)エトキシ)メチル)-1H-ピラゾル-4-イル)ピリダジン-3-カルボン酸エチル(2.65g、7.61mmol)の溶液に0℃で加え、室温で2時間撹拌した。反応の完了後、反応混合物を水(10mL)で希釈し、EtOAc(30mL×2)で洗浄した。水層を2N HCl溶液を用いて酸性化し(pH4)、こうして得られた固体をろ過し、水(2mL×2)で洗浄し、乾燥して、1.1gのBをオフホワイト固体で得た。
THF(10mL)中の6-クロロピリダジン-3-カルボン酸メチル(1g、5.79mmol)の溶液に、エチニル(トリメチル)シラン(4.0mL、29.0mmol)、Pd(PPh3)2Cl2(407mg、0.58mmol)、CuI(221mg、1.2mmol)およびEt3N(0.807mL、5.79mmol)を加え、得られた混合物を25℃で1時間撹拌した。反応の完了後、混合物をシリカゲルのパッドを通してろ過し、ろ液を減圧下で濃縮した。残渣をカラムクロマトグラフィ(PE/EtOAc)で精製して、6-((トリメチルシリル)エチニル)ピリダジン-3-カルボン酸メチル(500mg、収率37%)を黄色固体で得た。
THF(10mL)中の6-((トリメチルシリル)エチニル)ピリダジン-3-カルボン酸メチル(500mg、2.13mmol)の溶液に、TBAF(1M/THF、4.27mL、4.27mmol)を加え、反応混合物を室温で1時間撹拌した。完了後、反応混合物をH2O(50mL)に加え、DCM(30mL×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、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(PE/EtOAc)で精製して、6-エチニルピリダジン-3-カルボン酸メチル(260mg、収率75%)を褐色固体で得た。
H2O(4mL)およびt-BuOH(16mL)中の6-エチニルピリダジン-3-カルボン酸メチル(500mg、3.1mmol)および1-(アジドメチル)-4-メトキシ-ベンゼン(1.0g、6.2mmol)の溶液に、CuSO4(98.4mg、0.62mmol)およびアスコルビン酸ナトリウム(489mg、2.5mmol)を加えた。反応混合物を窒素でパージし、40℃で2時間撹拌した。反応の完了後、EtOAc(50mL)およびH2O(20mL)で希釈した。沈澱をろ過し、ろ過ケークをDCM/MeOH 10/1(500mL)で洗浄した。ろ液を減圧下で濃縮して、6-(1-(4-メトキシベンジル)-1H-1,2,3-トリアゾル-4-イル)ピリダジン-3-カルボン酸メチル(600mg、収率60%)を灰色固体で得た。LCMS (ESI+): m/z 325.9 [M+H]+。
THF(2.5mL)中の6-(1-(4-メトキシベンジル)-1H-1,2,3-トリアゾル-4-イル)ピリダジン-3-カルボン酸メチル(250mg、0.77mmol)の溶液に、水(2.5mL)中の水酸化リチウム一水和物(96.7mg、2.3mmol)の溶液を0℃で加えた。室温で12時間撹拌した後、沈澱をろ過し、ろ過ケークを減圧下で乾燥した。残渣をアセトニトリルで粉砕し、ろ過して、酸C(70.0mg、収率29%)を灰色固体で得た。LCMS (ESI+): m/z 312 [M+H]+。
すべての化合物を、以下に例示する手順を用いて調製した。
DCE(30mL)中の中間体C(1.4g、7.0mmol)およびDIPEA(6.17mL、34.8mmol)の溶液に、T3P(50%/EtOAc)(13.29mL、20.89mmol)を室温で加え、続いて2-アミノ-5-フルオロ-4-((トリメチルシリル)エチニル)安息香酸メチル(1.8g、7.0mmol)を加えた。反応混合物を80℃で7時間撹拌した。反応の完了後、揮発性物質を減圧下で除去し、飽和NaHCO3水溶液(15mL)を加えた。得られた固体をろ過し、水で洗浄し、乾燥した。残渣をカラムクロマトグラフィ(PE/EtOAc)で精製して、5-フルオロ-2-(6-(ピリジン-4-イル)ピリダジン-3-カルボキサミド)-4-((トリメチルシリル)エチニル)安息香酸メチル(2.2g、収率70%)を淡クリーム色固体で得た。
TBAF(1M/THF)(4.9mL、4.9mmol)を、THF(22mL)中の5-フルオロ-2-(6-(ピリジン-4-イル)ピリダジン-3-カルボキサミド)-4-((トリメチルシリル)エチニル)ベンゾエート(2.2g、4.90mmol)の撹拌溶液に0℃で加え、得られた混合物を室温で30分間撹拌した。反応の完了後、飽和NaHCO3水溶液(20mL)を加えた。固体をろ過し、水で洗浄し、乾燥した。得られた残渣をカラムクロマトグラフィ(DCM/MeOH)で精製して、4-エチニル-5-フルオロ-2-(6-(ピリジン-4-イル)ピリダジン-3-カルボキサミド)安息香酸メチル(1.1g、収率60%)を淡橙色固体で得た。
水(2mL)中の水酸化リチウム一水和物(33.4mg、0.8mmol)の水溶液に、THF(4mL)中の4-エチニル-5-フルオロ-2-(6-(ピリジン-4-イル)ピリダジン-3-カルボキサミド)安息香酸メチル(200mg、0.5mmol)の溶液を0℃で加え、得られた混合物を室温で2時間撹拌した。反応の完了後、得られた固体をろ過し、水で洗浄し、乾燥した。次いで、アセトニトリルで粉砕し、ろ過し、乾燥して、リチウム塩としての化合物1(99mg、収率54%)をオフホワイト固体で得た。
H2O(100mL)中のBoc-グリシン(20.0g、114.2mmol)の懸濁液に、3,6-ジクロロピリダジン(10.0g、67.1mmol)および硝酸銀(1.1g、6.7mmol)を加え、得られた混合物を80℃で加熱した。反応混合物に、H2O(40mL)中の硫酸アンモニウム(27.6g、120.9mmol)の溶液を80℃で30分かけて滴加した。次いで、反応混合物を80℃でさらに30分間撹拌した。次いで、これを室温まで冷却し、濃水酸化アンモニウムで塩基性化し(pH10)、EtOAc(100mL×2)で抽出した。合わせた有機層を食塩水(200mL)で洗浄し、無水Na2SO4で乾燥し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(ヘキサン/EtOAc)で精製して、((3,6-ジクロロピリダジン-4-イル)メチル)カルバミン酸tert-ブチル(15.0g、収率40%)を淡紅色粘稠油状物で得た。
THF(200mL)中のイミダゾール(5.9g、86.2mmol)の溶液に、NaH(鉱油中60%)(3.5g、86.2mmol)を0℃で加え、得られた混合物を15分間撹拌した。((3,6-ジクロロピリダジン-4-イル)メチル)カルバミン酸tert-ブチル(20.0g、72.1mmol)を加え、反応混合物を60℃で2時間撹拌した。完了後、反応混合物を室温まで冷却し、水(200mL)で希釈し、EtOAc(200mL×3)で抽出した。合わせた有機層を食塩水(200mL)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(PE/EtOAc)で精製して、所望の化合物の混合物(8.1g、収率36%)を淡褐色固体で得、これを混合物として次の段階で用いた。LC-MS (ESI+): m/z r.t. = 1.24 min, 310.19 [M+H] +およびr.t. = 1.28 min, 310.15 [M+H]+。
EtOH(97.5mL)中の化合物((6-クロロ-3-(1H-イミダゾル-1-イル)ピリダジン-4-イル)メチル)カルバミン酸tert-ブチルおよび((3-クロロ-6-(1H-イミダゾル-1-イル)ピリダジン-4-イル)メチル)カルバミン酸tert-ブチル(6.5g、21.0mmol)の混合物の溶液に、酢酸ナトリウム(3.4g、41.9mmol)を加え、得られた混合物をアルゴンで10分間パージした。次いで、Pd(dppf)Cl2(0.77g、1.0mmol)を加え、反応混合物をCO圧(100psi)下、90℃で24時間撹拌した。次いで、これを室温まで冷却し、揮発性物質を減圧下で蒸発させた。飽和NaHCO3水溶液(100mL)を加え、EtOAc(100mL×3)で抽出した。合わせた有機層を食塩水(100mL)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(DCM/MeOH)で精製して、5-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボン酸エチルおよび4-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボン酸エチルの混合物(6.5g、収率89%)を褐色固体で得た。LC-MS: m/z r.t. = 1.36 min, 348.4 [M+H]+およびr.t. = 1.29 min, 348.3 [M+H]+。
水(12.5mL)中の水酸化リチウム一水和物(0.32g、7.7mmol)の水溶液を、THF(25mL)中の5-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボン酸エチルおよび4-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボン酸エチル(2.5g、7.2mmol)の溶液に加え、得られた混合物を室温で30分間撹拌した。反応の完了後、THFを減圧下で除去し、水層を3N HClで酸性化した(pH4~5)。揮発性物質を凍結乾燥により除去して、対応するカルボン酸の混合物を得た。混合物をDMF(41mL)に溶解し、4,5-ジフルオロアントラニル酸メチル(3.2g、17.1mmol)およびDIPEA(7.38mL、42.40mmol)を加えた。反応混合物に、HATU(4.9g、12.8mmol)を加え、反応混合物を80℃で7時間撹拌した。完了後、反応混合物を室温まで冷却し、飽和NaHCO3水溶液(220mL)で希釈し、EtOAc(100mL×3)で抽出した。合わせた有機層を食塩水(200mL)で洗浄し、無水Na2SO4で乾燥し、ろ過し、減圧下で濃縮した。残渣をカラムクロマトグラフィ(DCM/MeOH)で精製して、2-(5-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボキサミド)-4,5-ジフルオロ安息香酸メチル(0.75g、収率21%)を黄色固体で、および2-(4-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボキサミド)-4,5-ジフルオロ安息香酸メチル(0.11g、収率3%)を飛散性淡褐色固体で得た。5-置換化合物:
4-置換化合物:
DCM(0.5mL)中の2-(4-(((tert-ブトキシカルボニル)アミノ)メチル)-6-(1H-イミダゾル-1-イル)ピリダジン-3-カルボキサミド)-4,5-ジフルオロベンゾエート(600mg、1.2mmol)の溶液に、4M HCl/ジオキサン(5mL)を加え、反応混合物を室温で3時間撹拌した。反応の完了後、揮発性物質を減圧下で除去し、ジエチルエーテル(10mL)を残渣に加えた。得られた固体をろ過し、乾燥して、化合物2(HCl塩)(34mg、収率7%)をオフホワイト固体で得た。
塩化チオニル0.5mL中の化合物1(36mg、0.1mmol)の懸濁液を2時間加熱還流した。次いで、過剰のチオニルを減圧下で除去した。無水アセトニトリル2mLを固体に加え、無水アセトニトリル2mL中のDIPEA(35μL、0.2mmol)の溶液を室温で加えた。30分間撹拌した後、得られた沈澱を分離し、アセトニトリルで洗浄して、生成物(28mg、収率80%)を得た。
[本発明1001]
式(IA)もしくは式(II)の化合物、またはその薬学的に許容される塩:
式中
Xは、S、-N=C(R 1 )-、または-C(R 1 )=C(R 1 )であり;
各R 1 は独立に、H、F、Cl、C 1 ~C 6 -アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;
R 2 は、-C(O)OR、-C(O)NH(C 1 ~C 6 -アルキル)(ここでアルキルは置換されていてもよい)、置換されていてもよいC 3 ~C 6 -シクロアルケニル、および3~10員ヘテロシクリルからなる群より選択され;
Rは、H、-((C 1 ~C 6 -アルキル)OC(O)OC 1 ~C 6 -アルキル)または3~10員ヘテロシクリルで置換されていてもよいアルキル、およびベンジルからなる群より選択され、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;
環Aは、無置換の、またはNH 2 、NH-ベンジル(ここでベンジルは、無置換であるかまたはメトキシル、シアノ、アルキルニトリル、ハロアルキル、ヒドロキシメチル、アミノメチル、アミノプロピル、カルボキサミド、もしくはアルコキシで置換されている)、
からなる群より独立に選択される1、2、もしくは3つの基で置換された、1、2、または3つのN原子を含む5または6員ヘテロアリールであり、ここで波線は結合の位置を示す。
[本発明1002]
式(IA)の化合物が式(I)のものであり:
式中
Xは、S、-N=C(R 1 )-、または-C(R 1 )=C(R 1 )であり;
各R 1 は独立に、H、F、Cl、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;かつ
Rは、H、アルキル、またはベンジルであり、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得る、
本発明1001の化合物。
[本発明1003]
式(II)のものである、本発明1001の化合物。
[本発明1004]
環Aが、ピリダジニル、トリアゾリル、ピリミジニル、およびピリジニルの任意の1つを含み、そのいずれも無置換であり得、または置換され得る、本発明1001~1003のいずれかの化合物。
[本発明1005]
以下の表:
から選択されるものである、本発明1001の化合物。
[本発明1006]
以下の表:
から選択されるものである、本発明1001の化合物。
[本発明1007]
ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法であって、有効用量の本発明1001~1006のいずれかの化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
[本発明1008]
患者における腫瘍の処置方法であって、有効用量の本発明1001~1006のいずれかの化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
[本発明1009]
投与する段階が、経口もしくは腫瘍内投与、または両方を含む、本発明1007または1008の方法。
[本発明1010]
投与する段階が、前記化合物を、抗体-薬物結合体として、またはリポソーム製剤で患者に投与することを含む、本発明1007または1008の方法。
[本発明1011]
有効用量の免疫チェックポイント標的薬物を投与する段階
をさらに含む、本発明1007または1008の方法。
[本発明1012]
免疫チェックポイント標的薬物が、抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体、または抗4-1BB抗体を含む、本発明1011の方法。
[本発明1013]
電離放射線または抗がん剤を投与する段階
をさらに含む、本発明1007または1008の方法。
[本発明1014]
本発明1001~1006のいずれかの化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを含む、薬学的組成物。
[本発明1015]
ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法において用いるための、本発明1001~1006のいずれかの化合物またはその薬学的に許容される塩。
[本発明1016]
患者における腫瘍の処置方法において用いるための、本発明1001~1006のいずれかの化合物またはその薬学的に許容される塩。
[本発明1017]
経口もしくは腫瘍内投与、または両方により患者に投与する、本発明1015または1016の使用のための化合物。
Claims (17)
- 式(IA)もしくは式(II)の化合物、またはその薬学的に許容される塩:
式中
Xは、S、-N=C(R1)-、または-C(R1)=C(R1)であり;
各R1は独立に、H、F、Cl、C1~C6-アルキル、エテニルもしくはエチニル(そのいずれも置換され得る)、シアノ、アルコキシル、またはハロアルキルであり;
R2は、-C(O)OR、-C(O)NH(C1~C6-アルキル)(ここでアルキルは置換されていてもよい)、置換されていてもよいC3~C6-シクロアルケニル、および3~10員ヘテロシクリルからなる群より選択され;
Rは、H、-((C1~C6-アルキル)OC(O)OC1~C6-アルキル)または3~10員ヘテロシクリルで置換されていてもよいアルキル、およびベンジルからなる群より選択され、ここでベンジルは無置換であり得、あるいはメトキシルで、または酸もしくはエステル同配体で置換され得;
環Aは、無置換の、またはNH2、NH-ベンジル(ここでベンジルは、無置換であるかまたはメトキシル、シアノ、アルキルニトリル、ハロアルキル、ヒドロキシメチル、アミノメチル、アミノプロピル、カルボキサミド、もしくはアルコキシで置換されている)、
からなる群より独立に選択される1、2、もしくは3つの基で置換された、1、2、または3つのN原子を含む5または6員ヘテロアリールであり、ここで波線は結合の位置を示す。 - 式(II)のものである、請求項1記載の化合物。
- 環Aが、ピリダジニル、トリアゾリル、ピリミジニル、およびピリジニルの任意の1つを含み、そのいずれも無置換であり得、または置換され得る、請求項1~3のいずれか一項記載の化合物。
- ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法であって、有効用量の請求項1~6のいずれか一項記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
- 患者における腫瘍の処置方法であって、有効用量の請求項1~6のいずれか一項記載の化合物またはその薬学的に許容される塩を患者に投与する段階を含む、方法。
- 投与する段階が、経口もしくは腫瘍内投与、または両方を含む、請求項7または8記載の方法。
- 投与する段階が、前記化合物を、抗体-薬物結合体として、またはリポソーム製剤で患者に投与することを含む、請求項7または8記載の方法。
- 有効用量の免疫チェックポイント標的薬物を投与する段階
をさらに含む、請求項7または8記載の方法。 - 免疫チェックポイント標的薬物が、抗PD-L1抗体、抗PD-1抗体、抗CTLA-4抗体、または抗4-1BB抗体を含む、請求項11記載の方法。
- 電離放射線または抗がん剤を投与する段階
をさらに含む、請求項7または8記載の方法。 - 請求項1~6のいずれか一項記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを含む、薬学的組成物。
- ヒト患者におけるインターフェロン遺伝子の発現を刺激する方法において用いるための、請求項1~6のいずれか一項記載の化合物またはその薬学的に許容される塩。
- 患者における腫瘍の処置方法において用いるための、請求項1~6のいずれか一項記載の化合物またはその薬学的に許容される塩。
- 経口もしくは腫瘍内投与、または両方により患者に投与する、請求項15または16記載の使用のための化合物。
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MX2022002144A (es) | 2022-05-13 |
WO2021035257A1 (en) | 2021-02-25 |
CN114981256A (zh) | 2022-08-30 |
AU2020332005A1 (en) | 2022-04-07 |
EP4017592A1 (en) | 2022-06-29 |
JP7485399B2 (ja) | 2024-05-16 |
IL290772A (en) | 2022-04-01 |
CA3151846A1 (en) | 2021-02-25 |
US20220288065A1 (en) | 2022-09-15 |
AU2020332005B2 (en) | 2024-05-23 |
KR20220066277A (ko) | 2022-05-24 |
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