JP2017512186A - ジヒドロプテリジノン誘導体およびその使用 - Google Patents
ジヒドロプテリジノン誘導体およびその使用 Download PDFInfo
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- JP2017512186A JP2017512186A JP2016549433A JP2016549433A JP2017512186A JP 2017512186 A JP2017512186 A JP 2017512186A JP 2016549433 A JP2016549433 A JP 2016549433A JP 2016549433 A JP2016549433 A JP 2016549433A JP 2017512186 A JP2017512186 A JP 2017512186A
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical class NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 208000028010 vulval Paget disease Diseases 0.000 description 1
- 208000002003 vulvitis Diseases 0.000 description 1
- 208000010484 vulvovaginitis Diseases 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical class [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Abstract
Description
本出願は、35 U.S.C. §119(e)の下で、2014年1月31日に出願された米国仮特許出願U.S.S.N. 61/934,624に基づく優先権を主張するものであり、この仮出願は本明細書中に参考により組み込まれる。
ブロモドメイン含有タンパク質は、転写因子複合体の成分およびエピジェネティックメモリー(epigenetic memory)の決定因子として、大きな生物学的関心を呼んでいる。例えば、ブロモおよび特異的末端(bromo and extra terminal)(BET)タンパク質ファミリー(例えば、ブロモドメイン含有タンパク質2(BRD2)、ブロモドメイン含有タンパク質3(BRD3)、ブロモドメイン含有タンパク質4(BRD4)、およびブロモドメイン精巣特異的タンパク質(BRDT))は、高レベルの配列保存を示す2つのアミノ末端ブロモドメインと、より多岐な(divergent)カルボキシ末端動員(recruitment)ドメインを特徴とする、共通のドメインアーキテクチャを共有する(Filippakopoulos et al., Nature 2010, 468, 1067-1073)。BRD2およびBRD3は、活発に転写される遺伝子に沿ってヒストンと関連することが報告されており、転写伸長の促進に関与し得る(Leroy et al., Mol. Cell. 2008, 30, 51-60)。また、BRD4またはBRD3は、精巣内の核タンパク質(NUT)と融合し、上皮新形成の悪性度の高い形態において、新たな融合がん遺伝子BRD4−NUTまたはBRD3−NUTを形成することが報告されている(French et al., Cancer Res., 2003, 63, 304-307;French et al., J. Clin. Oncol. 2004, 22, 4135-4139)。データは、BRD−NUT融合タンパク質が発癌に寄与することを示唆している(French et al., Oncogene 2008, 27, 2237-2242)。BRDTは、精巣と卵巣において独特に発現する。BETのすべてのファミリーメンバーは、細胞周期の局面(aspects)を制御または実行する際にいくつかの機能を有することが報告されており、細胞分裂中の染色体と複合して残存することが示され、エピジェネティックメモリーの維持における役割が示唆されている。また、いくつかのウイルスは、BETタンパク質を利用して、ウイルス複製のプロセスの一部としてそのゲノムを宿主細胞クロマチンにつなげる(You et al., Cell 2004, 117, 349-360)。BRD4は、pTEF−b複合体の誘導性遺伝子への動員に関与するようであり、RNAポリメラーゼのリン酸化と増加した転写出力がもたらされる(Hargreaves et al., Cell 2009, 138, 129-145)。ヒトにおいて、BRD2、BRD3、BRD4、およびBRDTは、類似した遺伝子配列、ドメイン構成、およびいくつかの機能的特性を示す(Wu et al., J. Biol. Chem. 2007, 282, 13141-13145)。
本発明は、式(I)で表される化合物(例えば、式(I)で表される化合物)を提供する。本明細書に記載の化合物は、ブロモドメイン含有タンパク質(例えば、BETタンパク質)などの転写因子のバインダーであると考えられており、男性避妊および、広範囲の疾患(例えば、ブロモドメインに関連する疾患、ブロモドメインの活性(例えば、異常な活性)に関連する疾患、ブロモドメイン含有タンパク質に関連する疾患、およびブロモドメイン含有タンパク質の活性(例えば、異常な活性)に関連する疾患)を処置および/または予防するのに有用であり得る。本発明の方法により処置および/または予防され得る疾患としては、限定はされないが、増殖性疾患(例えば、がん、良性新生物、血管新生、炎症性疾患、および自己免疫疾患)、心血管疾患、ウイルス感染、線維性疾患、代謝性疾患、内分泌疾患、および放射能中毒が挙げられる。また、本発明において提供されるのは、本明細書に記載の化合物を含むかまたは使用する、医薬組成物、キット、方法、および使用である。
化学的な定義
特定の官能基および化学用語の定義は、以下にさらに詳細に記載される。化学元素は、CAS version, Handbook of Chemistry and Physics, 75th Ed.の表紙内側の元素周期表に従って同定され、特定の官能基は、本明細書に記載されるように一般的に定義される。さらに、有機化学の一般原理、ならびに特定の官能部分および反応性は、以下に記載されている:Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;およびCarruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987。
Raaの各々は、独立して、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択されるか、または2つのRaa基は結び合って、3〜14員ヘテロシクリルまたは5〜14員ヘテロアリール環を形成し、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており;
Rbbの各々は、独立して、水素、−OH、−ORaa、−N(Rcc)2、−CN、−C(=O)Raa、−C(=O)N(Rcc)2、−CO2Raa、−SO2Raa、−C(=NRcc)ORaa、−C(=NRcc)N(Rcc)2、−SO2N(Rcc)2、−SO2Rcc、−SO2ORcc、−SORaa、−C(=S)N(Rcc)2、−C(=O)SRcc、−C(=S)SRcc、−P(=O)2Raa、−P(=O)(Raa)2、−P(=O)2N(Rcc)2、−P(=O)(NRcc)2、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択されるか、または2つのRbb基は結び合って、3〜14員ヘテロシクリルまたは5〜14員ヘテロアリール環を形成し、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており;
Rccの各々は、独立して、水素、C1〜10アルキル、C1〜10ペルハロアルキル、C2〜10アルケニル、C2〜10アルキニル、C3〜10カルボシクリル、3〜14員ヘテロシクリル、C6〜14アリール、および5〜14員ヘテロアリールから選択されるか、または2つのRcc基は結び合って、3〜14員ヘテロシクリルまたは5〜14員ヘテロアリール環を形成し、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRdd基で置換されており;
Rddの各々は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−ORee、−ON(Rff)2、−N(Rff)2、−N(Rff)3 +X-、−N(ORee)Rff、−SH、−SRee、−SSRee、−C(=O)Ree、−CO2H、−CO2Ree、−OC(=O)Ree、−OCO2Ree、−C(=O)N(Rff)2、−OC(=O)N(Rff)2、−NRffC(=O)Ree、−NRffCO2Ree、−NRffC(=O)N(Rff)2、−C(=NRff)ORee、−OC(=NRff)Ree、−OC(=NRff)ORee、−C(=NRff)N(Rff)2、−OC(=NRff)N(Rff)2、−NRffC(=NRff)N(Rff)2、−NRffSO2Ree、−SO2N(Rff)2、−SO2Ree、−SO2ORee、−OSO2Ree、−S(=O)Ree、−Si(Ree)3、−OSi(Ree)3、−C(=S)N(Rff)2、−C(=O)SRee、−C(=S)SRee、−SC(=S)SRee、−P(=O)2Ree、−P(=O)(Ree)2、−OP(=O)(Ree)2、−OP(=O)(ORee)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリール、5〜10員ヘテロアリールから選択され、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されているか、または2つのジェミナルRdd置換基は結び合って、=Oまたは=Sを形成することができ;
Reeの各々は、独立して、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリル、および3〜10員ヘテロアリールから選択され、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されており;
Rffの各々は、独立して、水素、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、3〜10員ヘテロシクリル、C6〜10アリール、および5〜10員ヘテロアリールから選択されるか、または2つのRff基は結び合って、3〜14員ヘテロシクリルまたは5〜14員ヘテロアリール環を形成し、ここで各アルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリール、およびヘテロアリールは、独立して、0、1、2、3、4、または5個のRgg基で置換されており;および
Rggの各々は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−OC1〜6アルキル、−ON(C1〜6アルキル)2、−N(C1〜6アルキル)2、−N(C1〜6アルキル)3 +X−、−NH(C1〜6アルキル)2 +X−、−NH2(C1〜6アルキル)+X−、−NH3 +X−、−N(OC1〜6アルキル)(C1〜6アルキル)、−N(OH)(C1〜6アルキル)、−NH(OH)、−SH、−SC1〜6アルキル、−SS(C1〜6アルキル)、−C(=O)(C1〜6アルキル)、−CO2H、−CO2(C1〜6アルキル)、−OC(=O)(C1〜6アルキル)、−OCO2(C1〜6アルキル)、−C(=O)NH2、−C(=O)N(C1〜6アルキル)2、−OC(=O)NH(C1〜6アルキル)、−NHC(=O)(C1〜6アルキル)、−N(C1〜6アルキル)C(=O)(C1〜6アルキル)、−NHCO2(C1〜6アルキル)、−NHC(=O)N(C1〜6アルキル)2、−NHC(=O)NH(C1〜6アルキル)、−NHC(=O)NH2、−C(=NH)O(C1〜6アルキル)、−OC(=NH)(C1〜6アルキル)、−OC(=NH)OC1〜6アルキル、−C(=NH)N(C1〜6アルキル)2、−C(=NH)NH(C1〜6アルキル)、−C(=NH)NH2、−OC(=NH)N(C1〜6アルキル)2、−OC(NH)NH(C1〜6アルキル)、−OC(NH)NH2、−NHC(NH)N(C1〜6アルキル)2、−NHC(=NH)NH2、−NHSO2(C1〜6アルキル)、−SO2N(C1〜6アルキル)2、−SO2NH(C1〜6アルキル)、−SO2NH2、−SO2C1〜6アルキル、−SO2OC1〜6アルキル、−OSO2C1〜6アルキル、−SOC1〜6アルキル、−Si(C1〜6アルキル)3、−OSi(C1〜6アルキル)3−C(=S)N(C1〜6アルキル)2、C(=S)NH(C1〜6アルキル)、C(=S)NH2、−C(=O)S(C1〜6アルキル)、−C(=S)SC1〜6アルキル、−SC(=S)SC1〜6アルキル、−P(=O)2(C1〜6アルキル)、−P(=O)(C1〜6アルキル)2、−OP(=O)(C1〜6アルキル)2、−OP(=O)(OC1〜6アルキル)2、C1〜6アルキル、C1〜6ペルハロアルキル、C2〜6アルケニル、C2〜6アルキニル、C3〜10カルボシクリル、C6〜10アリール、3〜10員ヘテロシクリル、5〜10員ヘテロアリールであるか;または2つのジェミナルRgg置換基は結び合って、=Oまたは=Sを形成することができ;ここでX−は対イオンである。
以下の定義は、本出願全体を通して使用される、より一般的な用語である。
近年、いくつかの化合物が、ブロモドメイン結合剤であることが報告されている:例えば、WO 2012/075383、WO 2011/054553、WO 2011/054841、WO 2011/054844、WO 2011/054845、WO 2011/054846、WO 2011/054848 WO 2011/143669、およびWO 2011/161031。さらに、日本特許出願公開JP 2008/156311は、BRD2ブロモドメイン結合剤であると言われているベンズイミダゾール誘導体を開示しており、これは、ウイルス感染および/または増殖に対して効用を有する。国際PCT公開WO 2009/084693は、アセチル化ヒストンとブロモドメイン含有タンパク質との結合を阻害すると言われている一連のチエノトリアゾロジアゼピン誘導体を開示しており、これは、抗がん剤として有用であると言われている。国際PCT公開WO 2011/054843は、ブロモドメインとその同族アセチル化タンパク質との結合を阻害する化合物が、自己免疫疾患または状態および炎症性疾患または状態の範囲の処置に、効用を有し得ることを示唆する。しかし、さらなる強力かつ安全なブロモドメインバインダーの必要性が残されている。
本発明は、式(I):
Aは、=N−または=C(RB4)−であり;
A1は、−N(R4)−または−C(R4)2−であり;
R1は、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、または、置換または非置換ヘテロアリールであり;
R2およびR3は、各々独立して、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−C(=O)RD1、−C(=O)ORD1、−C(=O)N(RD1)2、または、窒素保護基であるが、ここでRD1の各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)、であるか、あるいは、2つのRD1基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成するか、または、窒素保護基(窒素原子へ付着されているとき)であり;
R4は、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−C(=O)RD1、−C(=O)ORD1、または、−C(=O)N(RD1)2であるが、ここでRD1の各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRD1基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成するか、または、窒素保護基(窒素原子へ付着されているとき)であり;
RB1の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB1a、−N(RB1a)2、−SRB1a、−CN、−SCN、−C(=NRB1a)RB1a、−C(=NRB1a)ORB1a、−C(=NRB1a)N(RB1a)2、−C(=O)RB1a、−C(=O)ORB1a、−C(=O)N(RB1a)2、−NO2、−NRB1aC(=O)RB1a、−NRB1aC(=O)ORB1a、−NRB1aC(=O)N(RB1a)2、−OC(=O)RB1a、−OC(=O)ORB1a、または、−OC(=O)N(RB1a)2であるが、ここでRB1aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB1a基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB2の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB2a、−N(RB2a)2、−SRB2a、−CN、−SCN、−C(=NRB2a)RB2a、−C(=NRB2a)ORB2a、−C(=NRB2a)N(RB2a)2、−C(=O)RB2a、−C(=O)ORB2a、−C(=O)N(RB2a)2、−NO2、−NRB2aC(=O)RB2a、−NRB2aC(=O)ORB2a、−NRB2aC(=O)N(RB2a)2、−OC(=O)RB2a、−OC(=O)ORB2a、または、−OC(=O)N(RB2a)2であるが、ここでRB2aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB2a基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB3の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB3a、−N(RB3a)2、−SRB3a、−CN、−SCN、−C(=NRB3a)RB3a、−C(=NRB3a)ORB3a、−C(=NRB3a)N(RB3a)2、−C(=O)RB3a、−C(=O)ORB3a、−C(=O)N(RB3a)2、−NO2、−NRB3aC(=O)RB3a、−NRB3aC(=O)ORB3a、−NRB3aC(=O)N(RB3a)2、−OC(=O)RB3a、−OC(=O)ORB3a、または、−OC(=O)N(RB3a)2であるが、ここでRB3aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB3a基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB4の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB4a、−N(RB4a)2、−SRB4a、−CN、−SCN、−C(=NRB4a)RB4a、−C(=NRB4a)ORB4a、−C(=NRB4a)N(RB4a)2、−C(=O)RB4a、−C(=O)ORB4a、−C(=O)N(RB4a)2、−NO2、−NRB4aC(=O)RB4a、−NRB4aC(=O)ORB4a、−NRB4aC(=O)N(RB4a)2、−OC(=O)RB4a、−OC(=O)ORB4a、または、−OC(=O)N(RB4a)2であるが、ここでRB4aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB4a基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
mは、0、または、境界も含めて1と8との間の整数であり;
pは、0、または、境界も含めて1と4との間の整数であり;
L1およびL2の各々は、独立して、単結合、
Ra1の各々は、独立して、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、または、窒素保護基であるか;または、L1が、
Rc1の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORc1a、−N(Rc1a)2、−SRc1a、−CN、−C(=O)Rc1a、−C(=O)ORc1a、−C(=O)N(Rc1a)2、−NRc1aC(=O)Rc1a、−NRc1aC(=O)ORc1a、−NRc1aC(=O)N(Rc1a)2、−OC(=O)Rc1a、または、−OC(=O)N(Rc1a)2であるが、ここでRc1aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)、または、硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRc1a基は結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成する、
で表される化合物またはその薬学的に許容し得る塩を提供する。
vは、0、1、2、3または4であり;
Yは、−O−または−NRa2−であり;および、
Ra2は、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、または、窒素保護基である、
で表される化合物、または、その薬学的に許容し得る塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識の誘導体またはプロドラッグである。
本発明は、本明細書に記載の化合物(例えば、式(I)で表される化合物、またはその薬学的に許容し得る塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識誘導体、もしくはプロドラッグ)、および任意に薬学的に許容し得る賦形剤を含む、医薬組成物を提供する。ある態様において、本明細書に記載の医薬組成物は、式(I)で表される化合物、またはその薬学的に許容し得る塩、および任意に薬学的に許容し得る賦形剤を含む。ある態様において、本明細書に記載の医薬組成物は、式(I)で表される化合物、またはその薬学的に許容し得る塩、および薬学的に許容し得る賦形剤を含む。
本発明は、広範囲の疾患、例えばブロモドメインに関連する疾患、ブロモドメインの活性(例えば、異常な活性)に関連する疾患、ブロモドメイン含有タンパク質に関連する疾患、ブロモドメイン含有タンパク質の活性(例えば、異常な活性)に関連する疾患などの、処置のための方法を提供する。例示の疾患としては、限定はされないが、増殖性疾患、心血管疾患、ウイルス感染、線維性疾患、代謝性疾患、内分泌疾患、および放射能中毒が挙げられる。本発明によってさらに提供されるのは、避妊(例えば、男性避妊)の方法である。さらに本発明は、ブロモドメインまたはブロモドメイン含有タンパク質の活性(例えば、上昇した活性などの異常な活性)を阻害する方法、ブロモドメイン含有タンパク質のブロモドメインの、第2タンパク質(例えば、ヒストン)のアセチルリジン残への結合を阻害する方法、転写伸長を調整する(例えば阻害する)方法、ブロモドメイン含有タンパク質によって調節される遺伝子の発現(例えば、転写)を調整する(例えば、下方制御または阻害する)方法を、提供する。
本明細書に記載の本発明のより完全な理解のために、以下の実施例を記載する。本出願に記載の合成的および生物学的実施例は、本明細書に提供される化合物、医薬組成物、および方法を説明するために提供され、いかなる方法においてもその範囲を限定するものとして解釈されるべきではない。
確立された様々な合成方法を、本明細書に記載の本発明の化合物に到達するために使用してもよい。一態様において、本発明の化合物は、スキーム1に提供される順番を使用して調製することができる。アミンS−1とケトンまたはアルデヒドS−2とを使用する還元的アミノ化によって、中間体S−3(ここでRs1は、水素、または、置換または非置換アルキルである)が提供される。ある態様において、Rs1は、メチルである。ある態様において、R1が付着している炭素は、(S)配置の立体中心である。ある態様において、R1が付着している炭素は、(R)配置の立体中心である。ある態様において、R1が付着している炭素は、(R)および(S)配置の立体中心の混合物である。
例1.(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)オキシ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
例2.(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)(メチル)アミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
(R)−エチル4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)(メチル)アミノ)−3−メトキシベンゾエート
(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)(メチル)アミノ)−3−メトキシ安息香酸
(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)(メチル)アミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド
例3.(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)アミノ)−3−(シクロペンチルオキシ)−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
例4.(R)−4−((8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)アミノ)−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
例5.(R)−4−((8−シクロペンチル−5,7−ジエチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)アミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
例6.(R)−1−(8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミドの調製
(R)−1−(8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)インドリン−5−カルボン酸
(R)−1−(8−シクロペンチル−7−エチル−5−メチル−6−オキソ−5,6,7,8−テトラヒドロプテリジン−2−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミド
例7.(R)−4−((4−シクロペンチル−3−エチル−1−メチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)アミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミドの調製
(R)−2−アミノ−N−(2,6−ジクロロピリジン−3−イル)ブタンアミド ジ−HCl
(R)−2−(シクロペンチルアミノ)−N−(2,6−ジクロロピリジン−3−イル)ブタンアミド
(R)−6−クロロ−4−シクロペンチル−3−エチル−3,4−ジヒドロピリド[2,3−b]ピラジン−2(1H)−オン
(R)−6−クロロ−4−シクロペンチル−3−エチル−1−メチル−3,4−ジヒドロピリド[2,3−b]ピラジン−2(1H)−オン
(R)−4−((4−シクロペンチル−3−エチル−1−メチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)アミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド
例8.(R)−1−(4−シクロペンチル−3−エチル−1−メチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミドの調製
その結果生じた材料を、THF(0.34mL)および水(0.17mL)に溶解した。LiOH(2.4mg)を加え、混合物を室温にて撹拌した。溶解性に乏しいのと、変換が緩慢なことから、追加して2.4mgのLiOH、0.17mLの水および0.17mLのMeOHを加えた。2日後、混合物をMeOHで希釈し、分取HPLCで精製することで、暗褐色油が得られた(16.78mg、0.0399mmol、2ステップ以上により59%)。1H NMR (400 MHz, クロロホルム-d) δ 8.10 (d, J = 8.6 Hz, 1H), 7.83 (dd, J = 8.6, 1.7 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.16 - 7.11 (m, 1H), 6.21 (d, J = 8.4 Hz, 1H), 4.62 - 4.54 (m, 1H), 4.13 - 4.00 (m, 3H), 3.31 - 3.30 (m, 3H), 3.20 (t, J = 8.7 Hz, 2H), 2.14 - 2.04 (m, 2H), 1.80 - 1.54 (m, 8H), 0.86 (td, J = 7.6, 2.8 Hz, 3H)。LCMS 421.51 (M+H)。
(R)−1−(4−シクロペンチル−3−エチル−1−メチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミド
例9.(R)−1−(4−シクロペンチル−1,3−ジメチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミドの調製
(R)−1−(4−シクロペンチル−1,3−ジメチル−2−オキソ−1,2,3,4−テトラヒドロピリド[2,3−b]ピラジン−6−イル)−N−(1−メチルピペリジン−4−イル)インドリン−5−カルボキサミド
アセチル−ヒストン結合アッセイ
アッセイは、製造業者のプロトコル(PerkinElmer, USA)からの軽微な変更を加えて実施した。すべての試薬は、50mMのHEPES、150mMのNaCl、0.1%w/vのBSA、および0.01%w/vのTween 20でpH7.5にて希釈し、プレートに加える前に、室温に平衡化させた。アルファビーズをマスター溶液に添加した後、後続のすべてのステップは、低光条件で行った。80nmのBRD4.1、25μg/mlのニッケルコーティングされたアクセプタービーズ、および80nMのビオチン化H4−テトラアセチルの最終濃度での成分の2倍溶液を、10μLで、384ウェルプレート(AlphaPlate-384、PerkinElmer, USA)に加えた。BRD4.1のためのビオチン化ペプチドは、CEM Liberty 9008005マイクロ波ペプチド合成機で、社内で合成した:H4−テトラアセチル、ビオチン−PEG2−SGRGKacGGKacGLGKacGGAKacRHRK−COOH。ウェルへの添加は、マルチチャンネルピペット(最適化実験用)またはBiotek EL406液体ハンドラーのいずれかを用いて行った。1000rpmで1分間スピンダウンした後、ストックプレートからの本発明の化合物の溶液100nLを、Janus Workstation(PerkinElmer, USA)を使用して、分注ピン(pin transfer)により添加した。ストレプトアビジンでコーティングされたドナービーズ(最終25μg/ml)は、前の溶液と同様に、2倍、10μLの容量で添加した。この添加の後、プレートをホイルで密封して露光を遮断し、蒸発を防いだ。プレートを1000rpmで1分間、再度スピンダウンした。次にプレートを、プレートリーダーと共に室内で1.5時間インキュベートした後(温度平衡のため)、アッセイを読み取った。AlphaScreen測定は、Envision 2104(PerkinElmer, USA)上で製造者のプロトコルを利用して実施した。
本発明の化合物は、BRD4依存性細胞株において、細胞活性についても評価し、細胞IC50値を生成した。
ITCは、GE(商標)(Northampton, MA)からのITC200マイクロ熱量計を用いて実施した。すべての実験は25℃で、1000rpmで攪拌しながら、ITC緩衝液(50mMのHEPES、25℃にてpH7.4、150mMのNaCl)中で行った。マイクロシリンジに、タンパク質試料の溶液(ITC緩衝液中225μM)を充填した。化合物の溶液(ITC緩衝液中22.5μM)を、シリンジを介して、タンパク質溶液中に滴定した。全ての滴定は、0.2μlの最初の注射、続いて5秒の持続時間(注射当たり)での19回同一の2μl注射、および注射の間の90秒の間隔を用いて実施した。希釈熱は、独立した滴定(緩衝液へのタンパク質)により測定し、実験データから差し引いた。収集されたデータは、機器に付属のMicroCal(商標)Originソフトウェアに関連させて、結合のエンタルピー(ΔH)および結合定数(Ka)を生成した。収集されたデータは、Wisemanと共同研究者らによって前に記載されているように、機器に付属のMicroCal(商標)Originソフトウェアに関連させて、結合のエンタルピー(ΔH)および結合定数(KB)を生成した。熱力学のパラメータを算出した(ΔG=ΔH−TΔS=−RTlnKB、式中、ΔG、ΔHおよびΔSはそれぞれ、自由エネルギー、結合のエンタルピーおよびエントロピーにおける変化である)。単一結合部位モデルを使用した。
797、MOLM−13、およびHL60細胞を、T−75フラスコにプレーティングし、10%ウシ胎児血清および1%ペニシリン/ストレプトマイシンを含有するDMEM(797)またはRPMI(MOLM−13およびHL60)で増殖させた。細胞を、1uM(797)または500nM(MOLM−13およびHL60)の化合物、または等価容量のDMSOで、24時間処理した。2×106細胞を、500×g、4℃で数分間スピンし、PBSで洗浄した。ペレットを、1mLの冷PBSに再懸濁し、穏やかにボルテックスしながら、15mLのポリプロピレン遠心管中の9mLの70%エタノールに滴下した。次いで固定した細胞を、−20℃で終夜凍結した。翌日、細胞を500×g、4℃で10分間遠心分離し、3mLの冷PBSで洗浄した。細胞を、500μLのヨウ化プロピジウム染色溶液(PBS中、0.2mg/mLのRNase A、0.2mg/mLのヨウ化プロピジウム、01.%のTriton-X)に再懸濁し、37℃で20分間インキュベートした。次いで、試料を氷に移し、BD FACS Canto IIで分析した。ヒストグラムを生成し、細胞周期分析を、ModFitフローサイトメトリー解析ソフトウェアを用いて行った。
表1に示すのは、2.5μMの化合物濃度での、BRD4.1のin vitroパーセント阻害、BRD4.1での化合物IC50値(M)、BRD4依存性細胞株(798、HL60)における化合物のEC50値(M)、および、ITCにより測定されたBRD4.1での化合物Kd値である。
クレームにおいて、「a」、「an」および「the」などの冠詞は、1または1より多いことを意味してもよいが、それと反する指示がないか、またはそれとは別に、文脈から明らかでない場合に限る。ある群の1以上のメンバー間に「or」を含むクレームまたは記載は、その群のメンバーのうち、1つ、1つより多いか、または、すべてが、所定の生成物またはプロセスに存在するか、それに用いられるか、あるいはそれとは別に、それに関係があるか、を満たすと考えるが、それと反する指示がないか、またはそれとは別に、文脈から明らかでない場合に限る。本発明は、その群のうち、厳密に1つのメンバーが、所定の生成物またはプロセスに存在するか、それに用いられるか、またはそれとは別に、それに関係がある態様を含む。本発明は、その群のメンバーのうち、1つより多いかまたはすべてが、所定の生成物またはプロセスに存在するか、それに用いられるか、またはそれとは別に、それに関係がある態様を含む。
Claims (101)
- 式(I):
Aは、=N−または=C(RB4)−であり;
A1は、−N(R4)−または−C(R4)2−であり;
R1は、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、または、置換または非置換ヘテロアリールであり;
R2およびR3は、各々独立して、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−C(=O)RD1、−C(=O)ORD1、−C(=O)N(RD1)2または窒素保護基であり、ここでの各々RD1は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRD1基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成するか、または、窒素保護基(窒素原子へ付着されているとき)であり;
R4は、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−C(=O)RD1、−C(=O)ORD1または−C(=O)N(RD1)2であり、ここでRD1の各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRD1基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成するか、または、窒素保護基(窒素原子へ付着されているとき)であり;
RB1の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB1a、−N(RB1a)2、−SRB1a、−CN、−SCN、−C(=NRB1a)RB1a、−C(=NRB1a)ORB1a、−C(=NRB1a)N(RB1a)2、−C(=O)RB1a、−C(=O)ORB1a、−C(=O)N(RB1a)2、−NO2、−NRB1aC(=O)RB1a、−NRB1aC(=O)ORB1a、−NRB1aC(=O)N(RB1a)2、−OC(=O)RB1a、−OC(=O)ORB1aまたは−OC(=O)N(RB1a)2であり、ここでRB1aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB1a基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB2の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB2a、−N(RB2a)2、−SRB2a、−CN、−SCN、−C(=NRB2a)RB2a、−C(=NRB2a)ORB2a、−C(=NRB2a)N(RB2a)2、−C(=O)RB2a、−C(=O)ORB2a、−C(=O)N(RB2a)2、−NO2、−NRB2aC(=O)RB2a、−NRB2aC(=O)ORB2a、−NRB2aC(=O)N(RB2a)2、−OC(=O)RB2a、−OC(=O)ORB2aまたは−OC(=O)N(RB2a)2であり、ここでRB2aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB2a基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB3の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB3a、−N(RB3a)2、−SRB3a、−CN、−SCN、−C(=NRB3a)RB3a、−C(=NRB3a)ORB3a、−C(=NRB3a)N(RB3a)2、−C(=O)RB3a、−C(=O)ORB3a、−C(=O)N(RB3a)2、−NO2、−NRB3aC(=O)RB3a、−NRB3aC(=O)ORB3a、−NRB3aC(=O)N(RB3a)2、−OC(=O)RB3a、−OC(=O)ORB3aまたは−OC(=O)N(RB3a)2であり、ここでRB3aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB3a基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
RB4の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORB4a、−N(RB4a)2、−SRB4a、−CN、−SCN、−C(=NRB4a)RB4a、−C(=NRB4a)ORB4a、−C(=NRB4a)N(RB4a)2、−C(=O)RB4a、−C(=O)ORB4a、−C(=O)N(RB4a)2、−NO2、−NRB4aC(=O)RB4a、−NRB4aC(=O)ORB4a、−NRB4aC(=O)N(RB4a)2、−OC(=O)RB4a、−OC(=O)ORB4aまたは−OC(=O)N(RB4a)2であり、ここでRB4aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRB4a基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;
mは、0、または、境界も含めて1と8との間の整数であり;
pは、0、または、境界も含めて1と4との間の整数であり;
L1およびL2の各々は、独立して、単結合、
Ra1の各々は、独立して、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、または、窒素保護基であるか;または、L1が、
そのときL1のRa1およびL1に対してオルトであるRB1の1つは結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成し;および、
Rc1の各々は、独立して、水素、ハロゲン、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、−ORc1a、−N(Rc1a)2、−SRc1a、−CN、−C(=O)Rc1a、−C(=O)ORc1a、−C(=O)N(Rc1a)2、−NRc1aC(=O)Rc1a、−NRc1aC(=O)ORc1a、−NRc1aC(=O)N(Rc1a)2、−OC(=O)Rc1aまたは−OC(=O)N(Rc1a)2であり、ここでRc1aの各々は、独立して、水素、置換または非置換アシル、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、窒素保護基(窒素原子へ付着されているとき)、酸素保護基(酸素原子へ付着されているとき)または硫黄保護基(硫黄原子へ付着されているとき)であるか、あるいは、2つのRc1a基が結び合って、置換または非置換の複素環、または、置換または非置換ヘテロアリール環を形成する、
で表される化合物またはその薬学的に許容し得る塩。 - L1が、
そのときL1のRa1およびL1に対してオルトであるRB1の1つは結び合って、置換または非置換の複素環も、置換または非置換ヘテロアリール環も形成しない、請求項1に記載の化合物。 - 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
vは、0、1、2、3または4であり;
Yは、−O−または−NRa2−であり;および、
Ra2は、水素、置換または非置換アルキル、置換または非置換アルケニル、置換または非置換アルキニル、置換または非置換カルボシクリル、置換または非置換ヘテロシクリル、置換または非置換アリール、置換または非置換ヘテロアリール、または、窒素保護基である、
で表される、請求項1に記載の化合物またはその薬学的に許容し得る塩。 - 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- 化合物が、式:
- R1へ付着されている炭素が、(R)または(S)配置の立体中心であるか、または、それらの混合物である、請求項1〜23のいずれか一項に記載の化合物。
- R1が、置換または非置換シクロアルキル、置換または非置換ヘテロシクリル、置換または非置換アリール、または、置換または非置換ヘテロアリールである、請求項1〜24のいずれか一項に記載の化合物。
- R1が、置換または非置換C1〜6アルキルである、請求項1〜24のいずれか一項に記載の化合物。
- R1が、エチルである、請求項26に記載の化合物。
- R1が、メチルである、請求項26に記載の化合物。
- R2が、置換または非置換C1〜6アルキルである、請求項1〜28のいずれか一項に記載の化合物。
- R2が、置換または非置換シクロアルキルである、請求項1〜28のいずれか一項に記載の化合物。
- R2が、シクロブチル、シクロペンチルまたはシクロヘキシルである、請求項30に記載の化合物。
- R2が、置換または非置換アリール環、または、置換または非置換ヘテロアリール環である、請求項1〜28のいずれか一項に記載の化合物。
- R3が、置換または非置換C1〜6アルキルである、請求項1〜32のいずれか一項に記載の化合物。
- R3が、置換または非置換C2〜6アルキルである、請求項33に記載の化合物。
- R3が、n−プロピル、イソプロピル、n−ブチルまたはt−ブチルである、請求項34に記載の化合物。
- R3が、エチルである、請求項34に記載の化合物。
- R3がメチルである、請求項33に記載の化合物。
- R3が、水素ではない、請求項1〜32のいずれか一項に記載の化合物。
- R3が、メチルではない、請求項1〜32および38のいずれか一項に記載の化合物。
- RB1の少なくとも1つが、−ORB1aである、請求項1〜39のいずれか一項に記載の化合物。
- RB1の少なくとも1つが、−OMeである、請求項40に記載の化合物。
- RB1の少なくとも1つが、−ORB1aであり、ここでRB1aが、置換または非置換の、3〜7員の、単環式カルボシクリルである、請求項40に記載の化合物。
- RB1の少なくとも1つが、−O(シクロペンチル)である、請求項42に記載の化合物。
- RB1の少なくとも1つが、−ORB1aであり、ここでRB1aが、置換または非置換の、3〜7員の、単環式ヘテロシクリルであり、ここで複素環系中の1、2または3つの原子は、独立して、窒素、酸素または硫黄である、請求項40に記載の化合物。
- RB1の少なくとも1つが、
- pが、1ではない、請求項1〜45のいずれか一項に記載の化合物。
- L1が、
- L1が、
- L1が、
- L1が、
- Ra1と、L1に対してオルトであるRB1の1つとが結び合って、置換または非置換の、5〜7員の、単環式複素環を形成し、ここで複素環系中の1、2または3つの原子は、独立して、窒素、酸素または硫黄であり、および、複素環系中の少なくとも1つの原子が、窒素である、請求項50に記載の化合物。
- Ra1と、L1に対してオルトであるRB1の1つとが結び合って、置換または非置換の、5〜6員の、単環式ヘテロアリール環を形成し、ここでヘテロアリール環系中の1、2または3つの原子は、独立して、窒素、酸素または硫黄であり、および、ヘテロアリール環系中の少なくとも1つの原子は、窒素である、請求項50に記載の化合物。
- L2が、
- L2が、
- L1およびL2の少なくとも1つが、
- Ra1の少なくとも1つが、置換または非置換C1〜6アルキルである、請求項1〜16、18、19および21〜55のいずれか一項に記載の化合物。
- Ra1の少なくとも1つが、メチルである、請求項56に記載の化合物。
- 環Bが、
- 環Bが、
- R4の少なくとも1つが、水素である、請求項1〜59のいずれか一項に記載の化合物。
- R4の少なくとも1つが、メチルである、請求項1〜60のいずれか一項に記載の化合物。
- R4の少なくとも1つが、
- A1が、−N(R4)−であり、および、R4が、メチルである、請求項1〜59のいずれか一項に記載の化合物。
- A1が、−CH(R4)−であり、および、R4が、
- Aが、=N−である、請求項1〜5、10および24〜64のいずれか一項に記載の化合物。
- Aが、=C(RB4)−である、請求項1〜5、10および24〜64のいずれか一項に記載の化合物。
- RB3が、メチルである、請求項1〜66のいずれか一項に記載の化合物。
- 式:
- 式:
- 式:
- 請求項1〜70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し得る塩、および、薬学的に許容し得る賦形剤を含む、医薬組成物。
- 容器、請求項1〜70のいずれか一項に記載の化合物の医薬組成物、および、患者における使用のための説明書を含む、キット。
- 追加の薬物または剤をさらに含む、請求項72に記載のキット。
- ブロモドメインの異常な活性に関連する疾患の処置が必要な対象における、前記処置を行う方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与することを含む、前記方法。
- ブロモドメイン含有タンパク質に関連する疾患の予防または前記疾患を有するリスクの低減が必要な対象における、前記予防または低減を行う方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与することを含む、前記方法。
- ブロモドメインの異常な活性に関連する疾患の予防または前記疾患を有するリスクの低減が必要な対象における、前記予防または低減を行う方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与することを含む、前記方法。
- ブロモドメインの異常な活性が、ブロモドメインの上昇した活性である、請求項74または76に記載の方法。
- 避妊が必要な対象における避妊の方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与することを含む、前記方法。
- 対象または細胞における、ブロモドメイン含有タンパク質の活性を阻害する方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与すること、あるいは、細胞をそれと接触させることを含む、前記方法。
- 対象または細胞における、ブロモドメインの活性を阻害する方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与すること、あるいは、細胞をそれと接触させることを含む、前記方法。
- 化合物またはその薬学的に許容し得る塩が、ブロモドメインの活性を、キナーゼの活性と比較して、選択的に阻害する、請求項80に記載の方法。
- 対象または細胞における、ブロモドメイン含有タンパク質のブロモドメインの、ヒストンのアセチル−リシン残基への結合を阻害する方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与すること、あるいは、細胞をそれと接触させることを含む、前記方法。
- 対象または細胞における、ブロモドメイン含有タンパク質によって調節される遺伝子の転写を調整する方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与すること、あるいは、細胞をそれと接触させることを含む、前記方法。
- 対象または細胞における、ブロモドメイン含有タンパク質によって調節される遺伝子の転写を阻害する方法であって、方法は、有効量の、請求項1〜70のいずれか一項に記載の化合物、または、請求項71に記載の医薬組成物を対象へ投与すること、あるいは、細胞をそれと接触させることを含む、前記方法。
- ブロモドメイン含有タンパク質が、ブロモおよび特異的末端(BET)タンパク質である、請求項75、79および82〜84のいずれか一項に記載の方法。
- ブロモドメイン含有タンパク質が、ブロモドメイン含有タンパク質2(BRD2)、ブロモドメイン含有タンパク質3(BRD3)またはブロモドメイン含有タンパク質4(BRD4)である、請求項75、79および82〜84のいずれか一項に記載の方法。
- ブロモドメイン含有タンパク質が、TBP(TATAボックス結合タンパク質)関連因子タンパク質(TAF)である、請求項75、79および82〜84のいずれか一項に記載の方法。
- ブロモドメイン含有タンパク質が、TAF1またはTAF1Lである、請求項75、79および82〜84のいずれか一項に記載の方法。
- ブロモドメイン含有タンパク質が、CREB結合タンパク質(CBP)である、請求項75、79および82〜84のいずれか一項に記載の方法。
- ブロモドメイン含有タンパク質が、E1A結合タンパク質p300(EP300)である、請求項75、79および82〜84のいずれか一項に記載の方法。
- 疾患が、自己免疫疾患、心血管疾患、ウイルス感染、線維性疾患または代謝性疾患である、請求項74〜76および85〜90のいずれか一項に記載の方法。
- 疾患が、リウマチ性関節炎、敗血症、アテローム発生、アテローム性動脈硬化、ヒト免疫不全ウイルス(HIV)感染、後天性免疫不全症候群(AIDS)、ヒトパピローマウイルス(HPV)感染、C型肝炎ウイルス(HCV)感染、単純ヘルペスウイルス(HSV)感染、エボラウイルス感染、重症急性呼吸器症候群(SARS)、インフルエンザ、放射線毒性、強皮症、特発性肺線維症、移植片対宿主病(GVHD)、糖尿病または肥満である、請求項74〜76および85〜90のいずれか一項に記載の方法。
- 疾患が、アテローム発生である、請求項92に記載の方法。
- 疾患が、エボラウイルス感染である、請求項92に記載の方法。
- 疾患が、重症急性呼吸器症候群(SARS)である、請求項92に記載の方法。
- s
疾患が、放射性中毒である、請求項92に記載の方法。 - 疾患が、特発性肺線維症である、請求項92に記載の方法。
- 疾患が、2型糖尿病または妊娠糖尿病である、請求項92に記載の方法。
- 疾患が、肥満である、請求項92に記載の方法。
- 対象が、ヒトである、請求項74〜99のいずれか一項に記載の方法。
- 対象が、ヒト男性である、請求項100に記載の方法。
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JP2021512960A (ja) * | 2018-02-06 | 2021-05-20 | シャンハイ ハイファ ファーマシューティカル カンパニー,リミティッド | Bet阻害活性を有する化合物並びにその製造方法及び使用 |
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CA2936871A1 (en) | 2015-08-06 |
RU2016133196A (ru) | 2018-03-01 |
RU2016133196A3 (ja) | 2018-06-07 |
MX2016009975A (es) | 2016-10-31 |
WO2015117055A1 (en) | 2015-08-06 |
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