JP2022538042A - Cdkキナーゼ阻害剤 - Google Patents
Cdkキナーゼ阻害剤 Download PDFInfo
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
Description
Qは、任意に置換された6~18員のアリーレン基または任意に置換された5~18員のヘテロアリーレン基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R1は、任意に置換された3~8員のヘテロシクリル基、任意に置換された6~14員の縮合ヘテロシクリル基または任意に置換された6~12員のスピロヘテロシクリル基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R2は、H、ハロ、任意に置換された3~10員のシクロアルケニル基、任意に置換された3~10員のヘテロシクロアルケニル基、任意に置換された3~10員のシクロアルキル基、任意に置換された3~10員のヘテロシクロアルキル基、任意に置換された6~18員のアリール基または任意に置換された5~18員のヘテロアリール基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキル、C1-6アルコキシ-C1-6アルコキシおよびオキソからなる群から選択され;
R3は、H、CN、-C(=O)-NR4R5、任意に置換された6~18員のアリール基、任意に置換された5~18員のヘテロアリール基または任意に置換された5~8員のラクタム基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R4およびR5はそれぞれ独立してメチルまたはエチルであり;かつ
R3が-C(=O)-NR4R5である場合、R2は、任意に置換された3~10員のシクロアルケニル基、任意に置換された3~10員のヘテロシクロアルケニル基、式(I)におけるR2ではない構造のN原子と接続している任意に置換された3~10員のヘテロシクロアルキル基、または任意に置換された6~18員のアリール基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキル、C1-6アルコキシ-C1-6アルコキシおよびオキソからなる群から選択される。]。
Qは、任意に置換されたフェニレンまたは任意に置換されたピリジニレンであり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R1は、任意に置換された3~8員のヘテロシクリル基、任意に置換された6~14員の縮合ヘテロシクリル基または任意に置換された6~12員のスピロヘテロシクリル基であり、置換されている場合、置換基は、C1-6アルキルから選択され;
R2は、ハロゲン原子、任意に置換されたシクロペンテニル、任意に置換されたシクロヘキセニル、任意に置換されたシクロペンチル、任意に置換されたシクロヘキシル、任意に置換されたオキサシクロヘキセニル、任意に置換されたアザシクロヘキセニル、任意に置換されたオキソラニル、任意に置換されたアザシクロペンチル、任意に置換されたオキサシクロヘキシル、任意に置換されたアザシクロヘキシル、任意に置換されたフェニル、任意に置換されたナフチル、任意に置換されたピリジニル、任意に置換されたチエニル、任意に置換されたピラゾリル、任意に置換されたオキサゾリル、任意に置換されたイソキサゾリルおよび任意に置換されたキノリルからなる群から選択され、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキルおよびオキソからなる群から選択され;
R3は、H、-CN、-C(=O)-NR4R5、任意に置換されたフェニル、ナフチル、ピラゾリル、ピリジニル、チエニル、オキサゾリル、イソキサゾリル、ピリミジニル、イミダゾリル、ピロリル、
R4およびR5はいずれもメチルである。
以下の略語は、後述する合成スキームで使用される:
Boc:t-ブトキシカルボニル;
Et:エチル;
H:時間;
rt/RT:室温;
Me:メチル;
MeOH:メタノール;
DIPEA:N,N-ジイソプロピルエチルアミン;
DCM:ジクロロメタン;
NMP:N-メチルピロリドン;
TEA:トリエチルアミン;
TFA:トリフルオロ酢酸;
THF:テトラヒドロフラン;
HATU:2-(7-ベンゾトリアゾールオキシド)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスフェート;
DMF:ジメチルホルムアミド;
NBS:N-ブロモスクシンイミド;
NIS:N-ヨードスクシンイミド;
DPPF PdCl2:[1,1’-ビス(ジフェニルホスフィノ)フェロセン]二塩化パラジウム;
XantPhos:4,5-ビスジフェニルホスフィノ-9,9-ジメチルキサンテン;
Pd2(dba)3:トリス(ジベンジリデンアセトン)ジパラジウム。
in vitroの無細胞キナーゼ活性アッセイにおいて、CDK6/サイクリンD1(商品名:Carna、製品番号04-114)に対する本発明の化合物の半分の阻害濃度(IC50)を以下の方法により検出した。アッセイも同様の方法で実施できることに留意されたい。この試験例のアッセイ手順は次のとおりである。
以下のステップに従って、いくつかの実施例の化合物を用いてin vitro細胞生存率アッセイを行った。
1.回収後、MCF-7細胞(Shanghai Cell Bank of the Chinese Academy of Sciencesから入手)を37℃、5%CO2、95%湿度で培養した。
2.各実施例の化合物について、異なる濃度の8つの化合物溶液を調製した。各濃度の化合物溶液50μLを96ウェルブラックプレートに入れた。
3.細胞濃度を約30,000細胞/mLに調整した。100μLの細胞懸濁液を96ウェルプレートに添加し、約3,000細胞/ウェルの最終細胞密度になるまで十分に混合した。
4.96ウェルプレートを37℃、5%CO2、95%湿度で168時間、すなわち7日間インキュベートした。
5.細胞生存率は、CellTiter-Glo(登録商標) Luminescent Cell Viability Assay(Promega、カタログ番号G7572)の方法により測定した。蛍光データは、マイクロプレートリーダー(EnVision(商標)、多機能マイクロプレート検出器、PerkinElmer)で読み取った。
6.得られた蛍光データをGraphPad Prismソフトウェアを用いて分析した。各濃度の各実施例の化合物について細胞生存率を計算し、各実施例の化合物のIC50区間を決定した。
Claims (10)
- 式(I)の化合物またはその薬学的に許容可能な塩:
Qは、任意に置換された6~18員のアリーレン基または任意に置換された5~18員のヘテロアリーレン基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R1は、任意に置換された3~8員のヘテロシクリル基、任意に置換された6~14員の縮合ヘテロシクリル基または任意に置換された6~12員のスピロヘテロシクリル基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R2は、H、ハロ、任意に置換された3~10員のシクロアルケニル基、任意に置換された3~10員のヘテロシクロアルケニル基、任意に置換された3~10員のシクロアルキル基、任意に置換された3~10員のヘテロシクロアルキル基、任意に置換された6~18員のアリール基または任意に置換された5~18員のヘテロアリール基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキル、C1-6アルコキシ-C1-6アルコキシおよびオキソからなる群から選択され;
R3は、H、CN、-C(=O)-NR4R5、任意に置換された6~18員のアリール基、任意に置換された5~18員のヘテロアリール基または任意に置換された5~8員のラクタム基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
R4およびR5はそれぞれ独立してメチルまたはエチルであり;かつ
R3が-C(=O)-NR4R5である場合、R2は、任意に置換された3~10員のシクロアルケニル基、任意に置換された3~10員のヘテロシクロアルケニル基、式(I)におけるR2ではない構造のN原子と接続している任意に置換された3~10員のヘテロシクロアルキル基、または任意に置換された6~18員のアリール基であり、置換されている場合、置換基は、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキル、C1-6アルコキシ-C1-6アルコキシおよびオキソからなる群から選択される。]。 - 前記Qが、任意に置換されたフェニレンまたは任意に置換されたピリジニレンであり、置換されている場合、前記置換基が、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシおよびハロ-C1-6アルキルからなる群から選択され;
前記R1が、任意に置換された3~8員のヘテロシクリル基、任意に置換された6~14員の縮合ヘテロシクリル基または任意に置換された6~12員のスピロヘテロシクリル基であり、置換されている場合、前記置換基が、C1-6アルキルから選択され;
前記R2が、ハロゲン原子、任意に置換されたシクロペンテニル、任意に置換されたシクロヘキセニル、任意に置換されたシクロペンチル、任意に置換されたシクロヘキシル、任意に置換されたオキサシクロヘキセニル、任意に置換されたアザシクロヘキセニル、任意に置換されたオキソラニル、任意に置換されたアザシクロペンチル、任意に置換されたオキサシクロヘキシル、任意に置換されたアザシクロヘキシル、任意に置換されたフェニル、任意に置換されたナフチル、任意に置換されたピリジニル、任意に置換されたチエニル、任意に置換されたピラゾリル、任意に置換されたオキサゾリル、任意に置換されたイソキサゾリルおよび任意に置換されたキノリルからなる群から選択され、置換されている場合、前記置換基が、ハロ、ヒドロキシ、C1-6アルキル、C1-6アルコキシ、ハロ-C1-6アルキルおよびオキソからなる群から選択され;
前記R3が、H、-CN、-C(=O)-NR4R5、任意に置換されたフェニル、ナフチル、ピラゾリル、ピリジニル、チエニル、オキサゾリル、イソキサゾリル、ピリミジニル、イミダゾリル、ピロリル、
R4およびR5がいずれもメチルである、
請求項1に記載の化合物またはその薬学的に許容可能な塩。 - 前記C1-6アルキルがメチルまたはエチルである、請求項4に記載の化合物またはその薬学的に許容可能な塩。
- CDK4/6キナーゼの活性を阻害するための、請求項1~7のいずれか一項に記載の化合物。
- 治療有効量の請求項1~8のいずれか一項に記載の化合物、および薬学的に許容可能な担体または賦形剤を含む、医薬組成物。
- CDK4/6キナーゼによって媒介される癌関連疾患の治療および/または予防のための薬剤の製造における、請求項1~8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可能な塩の使用であって、前記癌関連疾患が、脳腫瘍、肺癌、扁平上皮癌、膀胱癌、胃癌、卵巣癌、腹膜癌、膵臓癌、乳癌、頭頸部癌、子宮頸癌、子宮内膜癌、直腸癌、肝臓癌、腎臓癌、食道腺癌、食道扁平上皮癌、前立腺癌、女性生殖管癌、上皮内癌、リンパ腫、神経線維腫、甲状腺癌、骨癌、皮膚癌、脳癌、結腸癌、精巣癌、胃腸間質腫瘍、前立腺腫瘍、マスト細胞腫瘍、多発性骨髄腫、黒色腫、神経膠腫または肉腫である、使用。
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AU2020295509A1 (en) | 2022-02-03 |
AU2020295509B2 (en) | 2023-10-26 |
US20230002393A1 (en) | 2023-01-05 |
EP3988551A1 (en) | 2022-04-27 |
CN112094272A (zh) | 2020-12-18 |
CA3143813A1 (en) | 2020-12-24 |
JP7369798B2 (ja) | 2023-10-26 |
EP3988551A4 (en) | 2023-06-21 |
KR20220020951A (ko) | 2022-02-21 |
WO2020253458A1 (zh) | 2020-12-24 |
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