JP7265275B2 - Shp2阻害剤およびその使用 - Google Patents
Shp2阻害剤およびその使用 Download PDFInfo
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- JP7265275B2 JP7265275B2 JP2020550667A JP2020550667A JP7265275B2 JP 7265275 B2 JP7265275 B2 JP 7265275B2 JP 2020550667 A JP2020550667 A JP 2020550667A JP 2020550667 A JP2020550667 A JP 2020550667A JP 7265275 B2 JP7265275 B2 JP 7265275B2
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Description
フェニル基、
2,3-ジクロロフェニル基、
ナフタレン-1-イル基、
2-(トリフルオロメチル)フェニル基、
2-(トリフルオロメチル)ピリジン-3-イル基、
5-アミノ-2-クロロフェニル基、
5-アミノ-2-クロロピリジン-3-イル基、
3-アミノ-2-クロロフェニル基、
2-アミノ-3-クロロピリジン-4-イル基、
2-クロロ-3-メトキシフェニル基、
3-クロロ-2-メトキシピリジン-4-イル基、
3-フルオロ-1H-インドール-4-イル基、
3,3-ジフルオロ-2-オキソインドリン-4-イル基、
1-アセチル-3,3-ジフルオロインドリン-4-イル基、
2-クロロ-3-(4-ヒドロキシ-1,5,5-トリメチル-2-オキソ-2,5-ジヒドロ-1H-ピロール-3-カルボキサミド)フェニル基、
2-クロロ-3-(2-ヒドロキシ-4-オキソ-4H-ピリド[1,2-a]ピリミジン-3-カルボキサミド)フェニル基、
2-クロロ-3-(2-ヒドロキシ-4-オキソ-4H-ピラジノ[1,2-a]ピリミジン-3-カルボキサミド)フェニル基、
2-クロロ-3-(7-ヒドロキシ-5-オキソ-5H-チアゾロ[3,2-a]ピリミジン-6-カルボキサミド)フェニル基、
2-クロロ-3-(7-ヒドロキシ-5-オキソ-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-6-カルボキサミド)フェニル基、
2-クロロ-3-(2-ヒドロキシ-4-オキソ-6,7,8,9-テトラヒドロ-4H-ピリド[1,2-a]ピリミジン-3-カルボキサミド)フェニル基、
2,3-ジクロロピリジン-4-イル基、
2,3-ジフルオロフェニル基、
3-クロロ-2-フルオロピリジン-4-イル基、
2,3-ジフルオロピリジン-4-イル基、
2-クロロ-3-メチルフェニル基、
3-クロロ-2-メチルピリジン-4-イル基、
3,3-ジフルオロ-1-メチル-2-オキソインドリン-4-イル基、
3-クロロ-1-メチル-2-オキソ-1,2-ジヒドロピリジン-4-イル基、または
2-クロロ-3-フルオロフェニル基。
5-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(3-(アミノメチル)-3-メチルピロリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(3,6-アザビシクロ[3.2.0]ヘプタン-6-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
6-オキソ-5-(ピペリジン-4-イルアミノ)-1,6-ジヒドロピラジン-2-イル基、
5-(2-アミノスピロ[ビシクロ[3.1.0]ヘキサン-3,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-((1R,3R)-1-アミノ-3-メチル-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)アミノ基、
6-(3-(アミノメチル)-3-メチルピロリジン-1-イル)-4-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-d]ピリミジン-3-イル基、
7-アミノ-2-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-オキソ-3,4-ジヒドロキナゾリン-5-イル基、
2-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-オキソ-3,4-ジヒドロピリド[3,4-d]ピリミジン-5-イル基、
2-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-7-オキソ-7,8-ジヒドロピリド[2,3-d]ピリミジン-5-イル基、
5-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-1H-ピラゾロ[4,3-d]チアゾール-3-イル基、
6-(1-(1-アミノプロパン-2-イル)ピペリジン-4-イル)-7-オキソ-6,7-ジヒドロ-1H-ピラゾロ[4,3-d]ピリミジン-3-イル基、
8-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-6-オキソ-6,7-ジヒドロ-1H-プリン-2-イル基、
6-アミノ-8-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-7H-プリン-2-イル基、
4-アミノ-2-(3-(アミノメチル)-3-メチルピロリジン-1-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
2-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-シアノ-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(3,6-アザビシクロ[3.2.0]ヘプタン-6-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-3-アザビシクロ[3.2.0]ヘプタン-3-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-2-アザスピロ[3.4]オクタン-2-イル)-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-3-アザビシクロ[3.1.0]ヘキサン-3-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-2-アザスピロ[3.4]オクタン-2-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
5-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(2-アミノスピロ[ビシクロ[3.1.0]ヘキサン-3,4'-ピペリジン]-1'-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-((1R,3R)-1-アミノ-3-メチル-8-アザスピロ[4.5]デカン-8-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-d]ピリミジン-3-イル基、
6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-4-メチル-5-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-b]ピラジン-3-イル基、
6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-5-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-b]ピラジン-3-イル基、
6-(3-(アミノメチル)-3-メチルピロリジン-1-イル)-5-メチル-4-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-d]ピリミジン-3-イル基、
6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-5-メチル-4-オキソ-4,5-ジヒドロ-1H-ピラゾロ[3,4-d]ピリミジン-3-イル基、
6-(4-(アミノメチル)-4-メチルピペリジン-1-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル基、
4-アミノ-2-(ヘキサヒドロピロロ[3,4-c]ピロール-2(1H)-イル)-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-3-アザビシクロ[3.1.0]ヘキサン-3-イル)-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
4-アミノ-2-(6-アミノ-3-アザビシクロ[3.2.0]ヘプタン-3-イル)-1-メチル-6-オキソ-1,6-ジヒドロピリミジン-5-イル基、
5-(4-(アミノメチル)-4-フルオロピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(4-(アミノメチル)-4-ヒドロキシピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(R)-5-(6-アミノ-2-アザスピロ[3.4]オクタン-2-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(6-アミノ-2-アザスピロ[3.4]オクタン-2-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
1-(3-アミノシクロヘキシル)-2-オキソ-1,2-ジヒドロピリジン-4-イル基、
(R)-5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(4-アミノ-4-(フルオロメチル)ピペリジン-1-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(R)-5-(1-アミノ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
5-(6-アミノ-3-アザビシクロ[3.1.0]ヘキサン-3-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(R)-5-(3-アミノ-3H-スピロ[ベンゾフラン-2,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
2-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-3-メチル-4-オキソ-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル基、
2-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-4-オキソ-4, 7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル基、
(R)-5-(1-アミノ-3,3-ジフルオロ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1, 6-ジヒドロピラジン-2-イル基、
5-((1R)-1-アミノ-3-フルオロ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(5-アミノ-5,7-ジヒドロスピロ[シクロペンタ[b]ピリジン-6,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(1-アミノ-1,3-ジヒドロスピロ[インデン-2,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(S)-5-(4-アミノ-2-クロロ-4,6-ジヒドロスピロ[シクロペンタ[d]チアゾール-5,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、
(R)-5-(3-アミノスピロ[インドリン-2,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、または
(S)-5-(1-アミノ-4-メトキシ-1,3-ジヒドロスピロ[インデン-2,4'-ピペリジン]-1'-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基。
共通の合成方法:
本発明の化合物またはその薬学的に許容される塩は、以下のスキーム1-6に記載の方法によって合成することができる。なお、すべての提案された、溶媒の選択、反応雰囲気、反応温度、実験の持続時間および後処理の手順を含む反応条件は、いずれも当該反応の標準条件とされているが、これらの条件は当業者に既知のものである。有機合成分野の技術者であれば、最適な反応条件は、使用される特定の反応物または溶媒にもよるが、このような条件は当業者によって通常の最適化の手段によって決定される。さらに、当業者にわかるように、多くの場合、これらの化合物は立体異性体の混合物で、たとえば結晶化、順相クロマトグラフィー、 逆相クロマトグラフィーやキラルクロマトグラフィーを含むが、これらに限定されない、通常の技術によって単一のエナンチオマーを得ることができる。すべての保護および脱保護に関する方法は、Philip J. Kocienski,"Protecting Groups",Georg Thieme Verlag Stuttgart,New York,1994年、およびTheodora W. GreeneとPeter GM Wuts,"Protective Groups in Organic Synthesis", Wiley lnterscience,第3版,1999年を参照する。スキーム1-6は、本発明の化合物の合成に使用できる代表的な方法である。これらは、何らかの形で本発明の範囲を制限することはない。
実験は、通常、特に酸素ガスまたは湿気に敏感な試薬や中間体を使用する場合、不活性の雰囲気(窒素ガスやアルゴンガス)において行われる。市販の溶媒および試薬は、適切な無水溶媒も含め、通常、さらに精製せずに使用することができる。産物は、通常、真空で乾燥した後、さらなる反応または生物学の試験に供する。質量分析のデータは液体クロマトグラフィー-質量分析(LC-MS)装置によるものである。質量分析MS(m/z)はエレクトロスプレーイオン化(ESI)または大気圧化学イオン化(APCI)によって記録された。関連する場合、別途に説明しない限り、提供されるm/zデータは同位元素19F、35Cl、79Brおよび127Iに適する。核磁気共鳴(NMR)のデータの化学シフトは百万分率(ppm、δ)で表示され、そして使用される重水素化溶媒の残留ピークを参照とし、主なピークは通常の略称:s,シングレット;d,ダブレット;t,トリプレット;q,カルテット;m,マルチプレット;br,ブロードで表示される。通常の溶媒は以下の略称が使用される。CDCl3は重水素化クロロホルムを、d6-DMSOは重水素化ジメチルスルホキシドを、CD3ODは重水素化メタノールを表す。
本明細書で公開された一部の化合物の選択的にSHP2活性を抑制する能力を評価した。本明細書に記載の化合物の抑制性質は以下の測定方法におけるテストによって証明することができる。
IC50値は、室温において、384ウェル黒色ポリスチレンプレートで、使用された最終反応体積が15μLで、そして60 mM Hepes(pH = 7.2)、75 mM NaCl、75 mM KCIおよび1 mM EDTA、0.05%P-20、5 mMジチオトレイトール(DTT)という緩衝液条件で測定された。全長のSHP2酵素(反応緩衝液で0.1 nMに希釈された)を1uM IRS-1ペプチドおよび0.01 nM~10μMの本発明の化合物と60分間インキュベートした。代替基質DiFMUP(5 pL,100 mM)を添加し、そして室温で60分間インキュベートした。その後、5μLの40 mMのbpV(Phen)溶液を添加することによって反応をクエンチングした。マイクロプレートリーダー(Envision,Perkin-Elmer)によって、それぞれ360nmと450nmの励起波長と発光波長で蛍光信号をモニタリングした。正規化IC50回帰曲線(対照に基づいた正規化とフィッティングされたもの)を使用し、阻害剤の用量反応曲線を分析した。表2は本発明の化合物の抑制活性の結果を示す。
細胞を384ウェル細胞培養プレートに接種し、そして一晩インキュベートした。被験化合物を細胞プレートに添加し、そして細胞プレートを2-6 hインキュベートした。p-ERKの検出には、AlphaLISA SureFire Ultra p-ERKキットによって細胞プレートを検出し、全ERKの検出には、全ERK HTRFキットによって細胞プレートをモニタリングした。Envision装置によってプレートを読み取った。表3は本発明の化合物の抑制活性の結果を示す。
まず、細胞を384ウェル細胞培養プレートに接種し、そして一晩インキュベートした。被験化合物を細胞プレートに添加し、そして3-5日インキュベートした。その後、CellTiter-Glo試薬によって細胞プレートを検出した。表4は本発明の化合物の抑制活性の結果を示す。
KYSE-520細胞を培養して増幅させ、収穫して6-8週齢の雌BALB/cヌードマウスに皮下注射した(5×106細胞/匹で、腫瘍が進展しやすいようにマトリゲル(1:1)を追加し、各群のn = 9である)。腫瘍の大きさの平均が約150-200 mm3に達した時点から、経口胃管によって化合物の後続の投与を始めた。治療期間(1回/日、4週間持続)で、腫瘍体積をノギスで測定した。一元配置分散分析によって両群間の腫瘍体積の差の統計分析を行った。単独の溶媒は陰性対照である。
Claims (15)
- 下記式で表される化合物:
(ただし、XはSであり、
環Aは任意に置換されてもよいフェニル基、任意に置換されてもよいピリジン-4-イル基、および任意に置換されてもよい2-オキソ-1,2-ジヒドロピリジン-4-イル基、からなる群から選択され、
環Aは無置換のものである、または環AはCl, NH2, -OCH3, F, CH3, OHおよびその組み合わせからなる群から選択された1つまたは複数の置換基で置換され、
環Bは任意に置換されてもよい6-オキソ-5-(2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1,6-ジヒドロピラジン-2-イル基からなる群から選択され、
環Bは無置換のものである、または環Bは-CH3, -CH2NH2, -NH2, -CH2CH2NH2, -F, -Cl, -CH2Fおよびその組み合わせからなる群から選択された1つまたは複数の置換基で置換される)。 - 環Aは任意に置換されてもよいフェニル基、および任意に置換されてもよいピリジン-4-イル基からなる群から選択されることを特徴とする請求項1に記載の化合物。
- 環Aは無置換のものである、または環A はCl、NH2、F、CH3、およびその任意の組み合わせからなる群から選択された1つまたは複数の置換基で置換されることを特徴とする請求項1または2に記載の化合物。
- 環Aは2つのCl置換基を有する、または環AはNH2置換基およびCl置換基を有することを特徴とする請求項1または2に記載の化合物。
- 環Aは、フェニル基、2,3-ジクロロフェニル基、5-アミノ-2-クロロフェニル基、3-アミノ-2-クロロフェニル基、2-アミノ-3-クロロピリジン-4-イル基、2-クロロ-3-メトキシフェニル基、3-クロロ-2-メトキシピリジン-4-イル基、2,3-ジクロロピリジン-4-イル基、2,3-ジフルオロフェニル基、3-クロロ-2-フルオロピリジン-4-イル基、2,3-ジフルオロピリジン-4-イル基、2-クロロ-3-メチルフェニル基、3-クロロ-2-メチルピリジン-4-イル基、3-クロロ-1-メチル-2-オキソ-1,2-ジヒドロピリジン-4-イル基、および2-クロロ-3-フルオロフェニル基のいずれかであることを特徴とする請求項1または2に記載の化合物。
- 環Bは、6-オキソ-5-(2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1,6-ジヒドロピラジン-2-イル基、および5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基からなる群から選択されるであることを特徴とする請求項1乃至5のいずれか一項に記載の化合物。
- 環Bは無置換のもの、または環Bは、-CH3、-NH2、およびこれらの任意の組み合わせからなる群から選択される1つまたは複数の置換基で置換されていることを特徴とする請求項1乃至5のいずれか一項に記載の化合物。
- 環Bは 、(S)-5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1-メチル-6-オキソ-1,6-ジヒドロピラジン-2-イル基、 (R)-5-(4-アミノ-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基、および5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基のいずれかであることを特徴とする請求項1乃至5のいずれか一項に記載の化合物。
- 環Aは、任意に置換されてもよいピリジン-4-イル基であり、
環Bは任意に置換されてもよい6-オキソ-5-(2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-1,6-ジヒドロピラジン-2-イル基、及び任意に置換されてもよい5-((3S,4S)-4-アミノ-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-8-イル)-6-オキソ-1,6-ジヒドロピラジン-2-イル基からなる群から選択されることを特徴とする請求項1に記載の化合物。 - 前記化合物はR-エナンチオマー、またはS-エナンチオマーであることを特徴とする請求項1乃至9のいずれかに記載の化合物。
- 前記化合物は重水素化されたものであることを特徴とする請求項1乃至10のいずれかに記載の化合物。
- 請求項1乃至12のいずれか一項に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賦形剤、希釈剤または担体とを含む薬物組成物。
- SHP2異常活性に関連する疾患、障害または病状の治療のための薬品の製造において請求項1乃至12のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用。
- 前記SHP2異常活性に関連する疾患、障害または病状が癌または自己免疫性疾患である請求項14に記載の使用。
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CA3097709A1 (en) | 2019-09-26 |
RU2020133727A (ru) | 2022-04-21 |
KR20200144102A (ko) | 2020-12-28 |
WO2019182960A1 (en) | 2019-09-26 |
EP3768664A4 (en) | 2021-12-15 |
TW201940167A (zh) | 2019-10-16 |
JP2021518395A (ja) | 2021-08-02 |
EP3768664A1 (en) | 2021-01-27 |
RU2020133727A3 (ja) | 2022-04-21 |
CN112368272B (zh) | 2023-04-21 |
CN112368272A (zh) | 2021-02-12 |
US10561655B2 (en) | 2020-02-18 |
AU2019239658A1 (en) | 2020-11-12 |
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