JP7436630B2 - アデノシン受容体拮抗薬 - Google Patents
アデノシン受容体拮抗薬 Download PDFInfo
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- JP7436630B2 JP7436630B2 JP2022506061A JP2022506061A JP7436630B2 JP 7436630 B2 JP7436630 B2 JP 7436630B2 JP 2022506061 A JP2022506061 A JP 2022506061A JP 2022506061 A JP2022506061 A JP 2022506061A JP 7436630 B2 JP7436630 B2 JP 7436630B2
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YKEGUYTXACKXKS-IRXDYDNUSA-N tert-butyl (1s,5s)-3-[5-methyl-6-(2-methylpyridin-3-yl)oxypyrimidin-4-yl]oxy-8-azabicyclo[3.2.1]octane-8-carboxylate Chemical compound CC1=NC=CC=C1OC1=NC=NC(OC2C[C@@H]3CC[C@H](N3C(=O)OC(C)(C)C)C2)=C1C YKEGUYTXACKXKS-IRXDYDNUSA-N 0.000 description 1
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 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
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- C07C335/04—Derivatives of thiourea
- C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
- C07C335/28—Y being a hetero atom, e.g. thiobiuret
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- 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
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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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
- C07D487/04—Ortho-condensed systems
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
前記R1、R2は任意選択でそれぞれ独立してR4から選ばれる0、1個、2個、3個、4個又は5個の置換基によって置換され、R4はC1-C6アルキル基、ヒドロキシ(C1-C6アルキル)-基、C2-C6アルケニル基、C2-C6アルキニル基、C3-C6シクロアルキル基、C6-C12アリール基、5-12員のヘテロアリール基、C1-C6ハロアルキル基、ハロゲン、オキソ、ニトロ基、シアノ基、-NRaRb、-ORa、-SRa、-SORa、-SO2Ra、-SO3Ra、-NRaC(O)Ra、-NRaC(O)ORa、-NRaS(O)2Ra、-C(O)ORa、-C(O)NRaRb、-C(O)Ra、-(CRaRb)m-ORa、-(CRaRb)m-NRaRb、-(CRaRb)m-NRa-(CRaRb)n-ORa、-(CRaRb)m-O-(CRaRb)n-NRaRb、-(CRaRb)m-O-(CRaRb)n-ORa、-(CRaRb)m-NRa-(CRaRb)n-NRaRbから選ばれ、又は置換基の数が2で、且つ当該2つの置換基が互いに隣接する場合に、それらが任意選択で環化して飽和又は不飽和の4-7員環になり、且つさらに、当該環には任意選択でO、S、Nから選ばれる0、1つ又は2つのヘテロ原子が含まれ、
R3は水素、C1-C6アルキル基、ヒドロキシ(C1-C6アルキル)-基、C2-C6アルケニル基、C2-C6アルキニル基、C3-C6シクロアルキル基、C6-C12アリール基、5-12員のヘテロアリール基、C1-C6ハロアルキル基、ハロゲン、ニトロ基、シアノ基、-NRaRb、-ORa、-SRa、-SORa、-SO2Ra、-SO3Ra、-NRaC(O)Ra、-NRaC(O)ORa、-NRaS(O)2Ra、-C(O)ORa、-C(O)NRaRb、-C(O)Ra、-(CRaRb)m-ORa、-(CRaRb)m-NRaRb、-(CRaRb)m-NRa-(CRaRb)n-ORa、-(CRaRb)m-O-(CRaRb)n-NRaRb、-(CRaRb)m-O-(CRaRb)n-ORa又は-(CRaRb)m-NRa-(CRaRb)n-NRaRbを表し、Ra、Rbはそれぞれ独立して水素、ハロゲン、C1-C6アルキル基、C3-C6シクロアルキル基又は-(C0-C6アルキレン)-(C6-C12)アリール基を表し、
又は、Ra、Rbが同じ原子に接続されている場合に、それらが任意選択でそれらに接続されている原子と環化して飽和又は不飽和の3-7員環になり、且つ当該環には任意選択でN、O、Sから選ばれる0、1個又は2個のヘテロ原子が含まれ、
n、mはそれぞれ独立して0、1、2、3又は4を表す。)
Rc、Rdはそれぞれ独立して水素、ハロゲン、C1-C6アルキル基又はC3-C6シクロアルキル基を表す。
又は、Rc、Rdが同じ原子に接続されている場合に、それらが任意選択でそれらに接続されている原子と環化して飽和又は不飽和の3-7員環になり、且つ当該環には任意選択でN、O、Sから選ばれる0、1個又は2個のヘテロ原子が含まれる。)
特段の説明がない限り、本出願の明細書及び特許請求の範囲で使用される用語は、次の定義を有する。なお、明細書及び特許請求の範囲において、特段の説明がない限り、数量詞が付いていない名詞には一般にその複数形の意味が含まれる。特段の説明がない限り、質量分析、核磁気共鳴、HPLC、タンパク質化学、生化学、組換えDNA技術、薬理学分野の従来の方法を用いる。
本明細書で使用される用語「許容される」は、配合成分又は有効成分は治療対象の健康には一般的に過度の不利な影響がないことを指す。
適切な投与経路は、経口、静脈注射、経直腸、エアゾール剤、非経口投与、眼内投与、肺内投与、経皮投与、経膣投与、耳道内投与、鼻腔投与、局所投与を含み、ただしそれらに限定されない。また、例示的に、非経口投与は、筋肉内注射、皮下注射、静脈注射、髄内注射、心室注射、腹腔内注射、リンパ内注射、鼻腔内注射を含む。
本発明は、1種又は複数種の薬用担体(添加剤)及び/又は希釈剤と配合された治療有効量の1種又は複数種の本発明の化合物と、任意選択に1種又は複数種の上記のその他治療薬とを含む薬用組成物をさらに提供する。上記の任意の用途で用いるために、任意の適切な方式で、例えば、経口(例えば、錠剤、丸剤、粉末剤、顆粒剤、エリキシル剤、チンキ剤、懸濁液(ナノ懸濁液、マイクロ懸濁液、噴霧乾燥された分散液を含む)、シロップ、乳濁液)、舌下、頬側、非経口(例えば、皮下、静脈内、筋肉内、胸骨内注射又は注入技術(例えば、注射用の無菌水性もしくは非水性溶液もしくは懸濁液))、経鼻(例えば、鼻膜への投与(例えば、吸入スプレー))、局所(例えば、クリーム剤もしくは軟膏剤)、経直腸(例えば、坐剤)により本発明の化合物を投与することができる。また、単独で投与することができるが、一般には所定の投与経路及び標準的な薬学実験に基づいて医薬担体を選んで投与する。
ここで、上記の適応症を治療するために使用されるキット/製品包装を説明する。これらのキットは輸送装置、薬品パック又はコンテナーボックスから構成され、コンテナーボックスはいくつかの部分に分割されて、1種又は複数種の容器(例えば、バイアル、試験管など)を収容することができ、各容器には前記方法に係る1種の成分が含まれる。適切な容器はボトル、バイアル、注射器、試験管などを含む。容器は使用が許容されるガラス又はプラスチックなどの材料から製造される。
次に、特定の実施例と結び付けて、本発明をさらに説明する。なお、これらの実施例は本発明の範囲を限定するものではなくその説明に過ぎない。次の実施例で具体的な条件を示さない実験方法は、通常の条件又はメーカーが推奨する条件で行われる。特段の説明がない限り、パーセンテージ、部数はいずれも重量に基づくものである。
合成手順が示されない中間体は、市販品であってもよい(例えば、シグマーアルドリッチ社やAlfa社の製品)。
市販試薬を使用する場合は精製が不要である。室温は20-27℃を指す。1H NMRスペクトルはブルカー社製の核磁気共鳴装置を用いて500MHzにおいて記録される。化学シフト値、即ちδ値は、百万分率で示す。次の略号はNMR信号の多重度を示す。sは一重線、brsは幅広線、dは二重線、tは三重線、mは多重線である。スピン結合定数はJ値で記載され、単位はHzである。NMR及び質量分析の結果はバックグラウンドに基づいて補正される。クロマトグラフィーとは窒素加圧(フラッシュクロマトグラフィー)において100メッシュのシリカゲルを用いて行われるカラムクロマトグラフィーを指す。反応を監視するために用いるTLCは、特定の移動相及びメルク社製のシリカゲルF254を固定相として行われるTLCを指す。
装置:Thermo U3000、ALLtech ELSD、MSQ、ELSDとMSDを組み合わせたUV検出器(溶出比4:1)。カラム:Waters X-Bridge C-18、3.5μm、4.6×50mm、カラム温度:30℃。勾配[時間(分)/溶媒A中のB(%)]:0.00/5.0、0.70/95、1.40/95、1.41/5、1.50/5。(溶媒A=水中の0.01%トリフルオロ酢酸、溶媒B=アセトニトリル中の0.01%トリフルオロ酢酸)。UV検出:214/254/280/300nm、DAD検出:200-400nm、流量:4mL/min、MS:ESI、100-1500m/z。
化合物INT-1の合成:
1H NMR(500MHz,CHCl3-d)δ 6.44(d,J=3.0Hz,1H),6.05-5.94(m,1H),2.33(s,3H),1.62-1.48(m,6H),1.37-1.29(m,6H),1.12-0.98(m,6H),0.94-0.87(m,9H)。
1H NMR(500MHz,CHCl3-d)δ 9.20(s,1H),8.29(s,1H),7.11(s,1H),4.25(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H)。
1H NMR(500MHz,CHCl3-d)δ 4.19(q,J=7.1Hz,2H),2.50(s,3H),1.33(t,J=7.1Hz,3H)。
MS:179.1[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 7.58(s,1H),5.83(s,1H),2.33(s,3H)。
MS:200.9[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.33(d,J=2.0Hz,1H),8.30(d,J=3.5Hz,1H),6.60(d,J=3.5Hz,1H),6.58(d,J=2.0Hz,1H),2.56(s,3H),2.49(s,3H)。
MS:247.2[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.35(d,J=3.5Hz,1H),8.07(s,1H),6.38(d,J=3.5Hz,1H),2.68(s,3H),2.54(s,3H)。
MS:325.0[M+H]+。
MS:341.1[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.14(s,1H),8.13(d,J=3.5Hz,1H),7.52(s,2H),6.53(d,J=3.5Hz,1H),2.44(s,3H)。
MS:294.0[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.16(d,J=3.5Hz,1H),7.44(s,2H),6.52(d,J=3.5,1H),2.43(s,3H),2.31(s,3H)。
MS:308.1[M+H]+。
MS:284.9[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.18(d,J=3.5Hz,1H),6.73(s,1H),6.60(d,J=3.5Hz,1H),2.55(s,3H),2.49(s,3H)。
MS:281.1[M+H]+。
MS:359.2[M+H]+。
MS:374.5[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.06(d,J=3.5Hz,1H),7.69(brs,2H),6.56(d,J=3.5Hz,1H),3.57(s,3H),2.46(s,3H)。
MS:329.1[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 7.99(d,J=3.5Hz,1H),7.66(brs,2H),6.53(d,J=3.5Hz,1H),3.55(s,3H),2.43(s,3H)。
MS:312.2[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 7.80(d,J=2.2Hz,1H),6.71(d,J=2.2Hz,1H),3.90(s,3H),3.76(s,3H)。
1H NMR(500MHz,DMSO-d6)δ 8.13(s,1H),7.94(d,J=2.3Hz,1H),7.53(d,J=2.3Hz,1H),7.50(s,2H),4.00(s,3H)。
MS:294.0[M+H]+。
実施例1:
MS:205.6[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 11.27(s,1H),7.26-7.23(m,2H),7.10-7.06(m,3H),4.42(s,2H),3.60(s,2H)。
MS:192.6[M+H]+。
MS:323.3[M+H]+。
MS:277.4[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 12.79(s,1H),7.89(s,1H),7.32-7.29(m,2H),7.11-7.08(m,2H),3.87(s,2H),2.55(s,3H)。
MS:291.3[M+H]+。
MS:309.2[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.34(d,J=3.5Hz,1H),7.92(s,1H),6.99-6.95(m,1H),6.35(d,J=3.5Hz,1H),4.05(s,2H),2.63(s,3H),2.53(s,3H)。
MS:355.3[M+H]+。
MS:387.3[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.19(d,J=3.0Hz,1H),7.94(s,1H),7.30-7.23(m,2H),7.20(s,2H),7.12-7.05(m,2H),6.53(d,J=3.0Hz,1H),3.85(s,2H),2.46(s,3H)。
MS:324.4[M+H]+。
MS:161.3[M+H]+。
MS:175.1[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.69(t,J=7.7Hz,1H),7.34(d,J=7.7Hz,1H),7.15(d,J=7.7Hz,1H),4.58(s,2H),3.51(s,3H),3.14(t,J=7.4Hz,2H),2.86(t,J=7.4Hz,2H)。
MS:177.6[M+H]+。
MS:232.6[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 7.69(t,J=7.7Hz,1H),7.20(d,J=7.7Hz,1H),7.13(s,1H),7.11(d,J=7.7Hz,1H),4.46(s,2H),3.72(s,2H),3.35(s,3H)。
MS:219.6[M+H]+。
MS:287.4[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.28(d,J=3.5Hz,1H),7.91(s,1H),7.73(t,J=7.8Hz,1H),7.33(d,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),6.47(d,J=3.5Hz,1H),4.56(s,2H),4.12(s,2H),3.48(s,3H),2.51(s,3H)。
MS:351.5[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.87(d,J=3.9Hz,1H),7.93(d,J=5.0Hz,1H),7.92(s,1H),7.71(t,J=7.7Hz,1H),7.31(d,J=7.7Hz,1H),7.30-7.28(m,1H),7.21(d,J=7.7Hz,1H),4.54(s,2H),4.11(s,2H),3.45(s,3H)。
MS:353.3[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 9.28(d,J=3.0Hz,1H),8.01(s,1H),7.67(t,J=7.7Hz,1H),7.34(s,2H),7.20(d,J=7.7Hz,1H),7.10(d,J=7.7Hz,1H),6.53(d,J=3.0Hz,1H),4.45(s,2H),3.98(s,2H),3.34(s,3H),2.31(s,3H)。
MS:351.4[M+H]+。
化合物5:1H NMR(500MHz,MeOH-d4)δ 8.25(d,J=3.5Hz,1H),7.89(s,1H),7.71(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=3.5Hz,1H),4.68(s,2H),4.09(s,2H),2.48(s,3H)。
MS:337.3[M+H]+。
化合物6:1H NMR(500MHz,MeOH-d4)δ 8.25(d,J=3.5Hz,1H),7.91(s,1H),7.70(t,J=7.8Hz,1H),7.36(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),6.44(d,J=3.5Hz,1H),4.59(s,2H),4.11(s,2H),2.48(s,3H)。
MS:399.1[M+H]+。
MS:355.2[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.28(d,J=3.5Hz,1H),7.92(s,1H),7.73(t,J=7.7Hz,1H),7.39(d,J=7.7Hz,1H),7.22(d,J=7.7Hz,1H),6.47(d,J=3.5Hz,1H),4.66(s,2H),4.12(s,2H),3.76-3.72(m,2H),3.65-3.61(m,2H),3.40(s,3H),2.51(s,3H)。
MS:395.4[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.17(d,J=3.5Hz,1H),7.97(s,1H),7.61(t,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),7.18(s,2H),7.04(d,J=8.0Hz,1H),6.55-6.49(m,1H),3.97(s,2H),3.80(s,2H),3.40(t,J=5.5Hz,2H),3.22(s,3H),2.71(t,J=5.5Hz,2H),2.44(s,3H)。
MS:394.4[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.25(d,J=3.5Hz,1H),7.89(s,1H),7.70(t,J=7.5Hz,1H),7.30(d,J=7.5Hz,1H),7.19(d,J=7.5Hz,1H),6.44(d,J=3.5Hz,1H),4.64(s,2H),4.10(s,2H),3.48-3.43(m,1H),2.48(s,3H),0.65-0.61(m,2H),0.54-0.47(m,2H)。
MS:377.4[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.15(s,1H),7.13-7.09(m,1H),6.82-6.78(m,2H),5.05(s,2H),3.68(s,2H)。
1H NMR(500MHz,CHCl3-d)δ 8.50(d,J=3.6Hz,1H),7.92(s,1H),7.49-7.42(m,1H),6.83-6.76(m,2H),6.45(d,J=3.6Hz,1H),4.02(s,2H),2.56(s,3H)。
MS:342.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.36(d,J=3.5Hz,1H),7.69(s,1H),7.29(s,2H),7.18-7.10(m,1H),6.93-6.88(m,1H),6.87-6.80(m,1H),6.38(d,J=3.5Hz,1H),3.91(s,2H),2.56(s,3H),2.34(s,3H)。
MS:338.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.32(d,J=3.5Hz,1H),7.79(s,1H),6.69-6.61(m,2H),6.34(d,J=3.5Hz,1H),5.26(s,2H),3.95(s,2H),2.52(s,3H)。
MS:360.3[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.25(d,J=3.5Hz,1H),7.84(s,1H),6.44(d,J=3.5Hz,1H),2.48(s,3H),2.46(d,J=7.0Hz,2H),2.21-2.16(m,1H),2.05-2.00(m,1H),1.72-1.70(m,3H),1.66-1.63(m,1H),1.60-1.55(m,1H),1.23-1.18(m,2H),1.02-0.87(m,2H)。
MS:312.5[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.38(d,J=3.5Hz,1H),7.90(s,1H),6.38(d,J=3.5Hz,1H),5.42(s,2H),2.55(s,3H),2.20(m,2H),1.89-1.49(m,9H)。
MS:298.4[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.37(d,J=3.5Hz,1H),7.87(s,1H),6.37(d,J=3.5Hz,1H),5.26(s,2H),2.72(d,J=7.5Hz,2H),2.66(m,1H),2.55(s,3H),2.15-2.07(m,2H),1.91-1.85(m,2H),1.78-1.74(m,2H)。
MS:284.4[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.36(d,J=3.4Hz,1H),8.04(s,1H),7.45(t,J=7.7Hz,1H),6.76(d,J=7.7Hz,1H),6.55(d,J=7.7Hz,1H),6.35(d,J=3.4Hz,1H),5.32(s,2H),4.04(s,2H),3.94(s,3H),2.53(s,3H)。
MS:337.4[M+H]+。
MS:228.6[M+H]+。
MS:208.8[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.64(t,J=7.7Hz,1H),7.31(d,J=7.7Hz,1H),7.26(s,1H),7.09(d,J=7.7Hz,1H),4.66-4.59(m,2H),4.31-4.28(m,1H),4.00-3.93(m,2H),3.89-3.88(m,3H),3.52(s,2H),2.11-2.03(m,2H)。
MS:275.7[M+H]+。
化合物17f:MS:437.3[M+H]+。
化合物17:1H NMR(500MHz,MeOH-d4)δ 8.27(d,J=3.5Hz,1H),8.02(s,1H),7.54(d,J=7.8Hz,1H),7.46(t,J=7.8Hz,1H),7.26(d,J=7.8Hz,1H),6.45(d,J=3.5Hz,1H),4.85(d,J=11.0Hz,1H),4.78(d,J=11.0Hz,2H),4.41-4.40(m,1H),4.22(s,2H),3.96-3.91(m,2H),3.87-3.82(m,2H),2.49(s,3H),2.14-2.10(m,2H)。
MS:423.3[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.28(d,J=3.5Hz,1H),7.92(s,1H),7.73(t,J=7.7Hz,1H),7.36(d,J=7.7Hz,1H),7.22(d,J=7.7Hz,1H),6.47(d,J=3.5Hz,1H),4.66-4.60(m,2H),4.35-4.33(m,1H),4.12(s,2H),3.95-3.90(m,2H),3.86-3.85(m,2H),2.51(s,3H),2.05-2.04(m,2H)。
MS:407.1[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.55(t,J=7.7Hz,1H),7.38-7.34(m,2H),4.07(s,1H),1.54(s,6H)。
MS:216.3[M+H]+。
MS:189.5[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.28(d,J=3.5Hz,1H),7.96(s,1H),7.68(t,J=7.8Hz,1H),7.43(d,J=7.8Hz,1H),7.14(d,J=7.8Hz,1H),6.47(d,J=3.5Hz,1H),4.13(s,2H),2.51(s,3H),1.55(s,6H)。
MS:365.4[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 9.90(s,1H),8.04-7.96(m,3H)。
MS:209.3[M+H]+。
MS:211.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.38-7.35(m,5H),7.31-7.29(m,1H),6.52(d,J=7.2Hz,1H),6.29(d,J=8.2Hz,1H),4.88(s,1H),4.54(d,J=5.8Hz,2H),2.97(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H)。
MS:238.5[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.36(d,J=3.5Hz,1H),7.95(s,1H),7.44-7.40(m,3H),7.37-7.34(m,2H),7.28(t,J=7.3Hz,1H),6.55(d,J=3.5Hz,1H),6.54(d,J=7.3Hz,1H),6.42(d,J=7.3Hz,1H),4.59(s,2H),4.00(s,2H),2.59(s,3H)。
MS:412.4[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.36(d,J=3.5Hz,1H),8.02(s,1H),7.48(t,J=8.0Hz,1H),6.57-6.55(m,2H),6.50(d,J=8.5Hz,1H),4.02(s,2H),3.66(t,J=5.4Hz,2H),3.57(t,J=5.4Hz,2H),3.44(s,3H),2.59(s,3H)。
MS:380.4[M+H]+。
MS:442.5[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.27(d,J=3.5Hz,1H),7.93(s,1H),7.62(t,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),6.60(d,J=8.0Hz,1H),6.45(d,J=3.5Hz,1H),4.00(s,2H),2.48(s,3H)。
MS:322.3[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.35(d,J=3.5Hz,1H),7.98(s,1H),7.97(d,J=1.8Hz,1H),7.66(t,J=8.0Hz,1H),6.81(dd,J=3.5,1.8Hz,1H),6.69(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),4.02(s,2H)。
MS:308.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.45(s,1H),7.28(t,J=7.5Hz,1H),7.22(d,J=7.5Hz,1H),7.04(d,J=7.5Hz,1H),6.49(s,1H),4.67(s,2H),1.52(s,9H)。
1H NMR(500MHz,CHCl3-d)δ 7.51(s,1H),7.27-7.25(m,1H),7.21-7.19(m,1H),7.07-7.05(m,1H),6.48(s,1H),4.46(s,2H),1.52(s,9H)。
MS:421.5[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.47(d,J=3.7Hz,1H),7.97(s,1H),7.49(t,J=7.8Hz,1H),7.43(d,J=7.8Hz,1H),7.32(t,J=1.9Hz,1H),7.25(d,J=7.8Hz,1H),6.58(d,J=3.7Hz,1H),4.10(s,2H),2.52(s,3H)。
MS:321.3[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.48(d,J=3.5Hz,1H),8.10(d,J=1.8Hz,1H),7.98(s,1H),7.51-7.43(m,2H),7.30(s,1H),7.28-7.22(m,1H),6.89(dd,J=3.5,1.8Hz,1H),4.09(s,2H)。
MS:306.9[M+H]+。
化合物26b:1H NMR(500MHz,CHCl3-d)δ 7.38-7.29(m,4H),6.50(s,1H),4.48(s,2H),1.51(s,9H)。
化合物26:1H NMR(500MHz,MeOH-d4)δ 8.48(d,J=3.7Hz,1H),7.95(s,1H),7.49-7.45(m,2H),7.36-7.32(m,2H),6.58(d,J=3.7Hz,1H),4.07(s,2H),2.52(s,3H)。
MS:320.9[M+H]+。
化合物27b:MS:285.9[M+H]+。
MS:321.2[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 8.64(s,1H),6.93-6.90(m,1H),6.60(s,1H),3.91(s,3H),1.53(s,9H)。
1H NMR(500MHz,CHCl3-d)δ 8.13(s,1H),6.85-6.81(m,1H),6.57(s,1H),4.70(s,2H),1.86(s,1H),1.52(s,9H)。
1H NMR(500MHz,CHCl3-d)δ 8.17(s,1H),6.87-6.83(m,1H),6.60(s,1H),4.46(s,2H),1.53(s,9H)。
1H NMR(500MHz,DMSO-d6)δ 8.18(d,J=3.5Hz,1H),7.88(s,1H),7.20(s,2H),6.97-6.91(m,1H),6.52(d,J=3.5Hz,1H),6.50-6.44(m,1H),4.83(s,2H),3.72(s,2H),2.44(s,3H)。
MS:357.2[M+H]+。
化合物29b:1H NMR(500MHz,CHCl3-d)δ 7.84(d,J=7.2Hz,1H),7.24-7.16(m,2H),6.29(s,1H),4.46(s,2H),2.23(s,3H),1.52(s,9H)。
化合物29:1H NMR(500MHz,MeOH-d4)δ 8.50(d,J=3.5Hz,1H),7.96(s,1H),7.34-7.25(m,3H),6.59(d,J=3.5Hz,1H),4.03(s,2H),2.52(s,3H),2.38(s,3H)。
MS:335.3[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.19(d,J=3.6Hz,1H),7.05(s,2H),6.72(s,1H),6.69(d,J=7.9Hz,1H),6.50(d,J=3.6Hz,1H),6.45(d,J=7.9Hz,1H),4.55(s,2H),3.62(s,2H),2.43(s,3H),2.18(s,3H),1.95(s,3H)。
MS:349.5[M+H]+。
化合物31b:1H NMR(500MHz,CHCl3-d)δ 7.71(d,J=7.7Hz,1H),7.16(t,J=7.7Hz,1H),7.09(d,J=7.7Hz,1H),6.27(s,1H),4.52(s,2H),2.27(s,3H),1.52(s,9H)。
化合物31:1H NMR(500MHz,DMSO-d6)δ 8.16(d,J=3.5Hz,1H),7.78(s,1H),7.19-7.03(m,3H),6.51(d,J=3.5Hz,1H),3.85(s,2H),2.44(s,3H),2.24(s,3H)。
MS:335.3[M+H]+。
化合物32b:1H NMR(500MHz,CHCl3-d)δ 8.13-7.98(m,1H),7.15-7.08(m,2H),6.72(s,1H),4.44(s,2H),1.52(s,9H)。
化合物32:1H NMR(500MHz,DMSO-d6)δ 8.16(d,J=3.5Hz,1H),7.88(s,1H),7.18(s,2H),6.84-6.80(m,1H),6.74-6.70(m,1H),6.66-6.60(m,1H),6.51(d,J=3.5Hz,1H),4.87(s,2H),3.68(s,2H),2.43(s,3H)。
MS:339.4[M+H]+。
化合物33b:1H NMR(500MHz,CHCl3-d)δ 7.72(s,1H),7.08-6.99(m,2H),6.52(s,1H),4.44(s,2H),1.53(s,9H)。
化合物33:1H NMR(500MHz,DMSO-d6)δ 8.19(d,J=3.5Hz,1H),8.04(s,1H),7.59-7.53(m,1H),7.17-7.11(m,1H),7.09-7.05(m,1H),6.54(d,J=3.5Hz,1H),4.00(s,2H),2.44(s,3H)。
MS:339.4[M+H]+。
化合物34b:1H NMR(500MHz,CHCl3-d)δ 8.15(d,J=8.6Hz,1H),7.38(s,1H),7.26(d,J=6.5Hz,1H),7.03(s,1H),4.42(s,2H),1.53(s,9H)。
化合物34:1H NMR(500MHz,MeOH-d4)δ 8.43(d,J=3.6Hz,1H),7.96(s,1H),7.47(s,1H),7.32-7.28(m,2H),6.55(d,J=3.6Hz,1H),4.00(s,2H),2.51(s,3H)。
MS:355.2[M+H]+。
化合物35b:1H NMR(500MHz,CHCl3-d)δ 7.44(s,1H),7.16-7.05(m,2H),6.42(s,1H),4.47(s,2H),2.34(s,3H),1.51(s,9H)。
化合物35:1H NMR(500MHz,DMSO-d6)δ 8.18(d,J=3.5Hz,1H),7.76(s,1H),7.16(s,2H),6.76(d,J=7.9Hz,1H),6.52(d,J=3.5Hz,1H),6.28(dd,J=7.9,2.3Hz,1H),6.24(d,J=2.3Hz,1H),4.67(s,2H),3.65(s,2H),2.44(s,3H),2.11(s,3H)。
MS:335.4[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 6.99-6.91(m,2H),6.59(t,J=7.5Hz,1H),4.58(s,2H),2.17(s,3H)。
1H NMR(500MHz,CHCl3-d)δ 7.25(d,J=7.2Hz,1H),7.21-7.14(m,2H),6.38(s,1H),4.57(s,2H),2.28(s,3H),1.51(s,9H)。
化合物36d:1H NMR(500MHz,CHCl3-d)δ 7.25-7.19(m,2H),7.18-7.12(m,1H),6.21(s,1H),4.52(s,2H),2.29(s,3H),1.52(s,9H)。
化合物36:1H NMR(500MHz,DMSO-d6)δ 8.17(d,J=3.5Hz,1H),7.87(s,1H),7.21(s,2H),6.78(d,J=7.5,2H),6.51(d,J=3.5Hz,1H),6.39(t,J=7.5Hz,1H),4.64(s,2H),3.65(s,2H),2.44(s,3H),2.04(s,3H)。
MS:335.2[M+H]+。
MS:177.2[M+H]+。
MS:261.1[M+H]+。
MS:297.1[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 13.01(s,1H),8.19(s,1H),8.15(d,J=3.5Hz,1H),7.92(s,1H),7.35-7.30(m,1H),7.23(s,2H),7.23-7.17(m,1H),6.90-6.87(m,1H),6.50(d,J=3.5Hz,1H),4.13(s,2H),2.43(s,3H)。
MS:346.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 10.11(s,1H),7.91-7.85(m,1H)。
1H NMR(500MHz,CHCl3-d)δ 6.93-6.89(m,1H),4.80(s,2H)。
MS:328.3[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 6.70-6.63(m,1H),4.73(s,2H),3.58(s,2H)。
化合物38e:1H NMR(500MHz,CHCl3-d)δ 6.71-6.64(m,1H),4.49(s,2H),3.59(s,2H)。
化合物38:1H NMR(500MHz,DMSO-d6)δ 8.16(d,J=3.5Hz,1H),7.73(s,1H),7.08-6.94(m,1H),6.53(d,J=3.5Hz,1H),3.80(s,2H),2.45(s,3H)。
MS:375.2[M+H]+。
MS:200.1[M+H]+。
化合物39d:MS:353.7[M+H]+。
化合物39:1H NMR(500MHz,MeOH-d4)δ 8.25(d,J=3.5Hz,1H),7.82(s,1H),7.26(d,J=2.0Hz,1H),7.22-7.17(m,1H),6.76(d,J=8.0Hz,1H),6.45-6.42(m,1H),3.83(s,2H),2.48(s,3H)。
MS:389.3[M+H]+。
化合物40b:1H NMR(500MHz,CHCl3-d)δ 7.49(d,J=7.0Hz,1H),7.23-7.17(m,1H),7.00-6.94(m,1H),6.45(s,1H),4.47(s,2H),1.51(s,9H)。
化合物40:1H NMR(500MHz,DMSO-d6)δ 8.18(d,J=3.5Hz,1H),7.87(s,1H),7.17(s,2H),6.77(dd,J=9.9,8.6Hz,1H),6.52(d,J=3.5Hz,1H),6.38-6.30(m,1H),6.30-6.20(m,1H),4.77(s,2H),3.72(s,2H),2.44(s,3H)。
MS:339.2[M+H]+。
1H NMR(500MHz,CHCl3-d)δ 7.79-7.73(m,2H),6.71(d,J=9.0Hz,1H),5.01(brs,2H),3.91-3.81(m,3H),1.71-1.64(m,1H),0.98-0.91(m,2H),0.69-0.62(m,2H)。
MS:192.2[M+H]+。
MS:263.9[M+H]+。
1H NMR(500MHz,MeOH-d4)δ 8.23(d,J=3.5Hz,1H),7.75(s,1H),6.90-6.82(m,2H),6.67-6.61(m,1H),6.43(d,J=3.5,1H),3.77(s,2H),2.48(s,3H),1.67-1.60(m,1H),0.92-0.81(m,2H),0.56-0.44(m,2H)。
MS:361.3[M+H]+。
化合物42b:1H NMR(500MHz,CHCl3-d)δ 7.03(s,1H),7.01-6.95(m,1H),5.96(s,1H),4.39(s,2H),2.28(s,3H),1.49(s,9H)。
化合物42:1H NMR(500MHz,DMSO-d6)δ 8.16(d,J=3.5Hz,1H),6.74-6.67(m,1H),6.53-6.49(m,1H),4.57(s,2H),3.66(s,2H),2.44(s,3H),2.04(s,3H)。
MS:353.2[M+H]+。
化合物43b:1H NMR(500MHz,CHCl3-d)δ 7.25(s,1H),7.10(s,1H),6.88(s,1H),6.42(s,1H),4.42(s,2H),2.31(s,3H),1.51(s,9H)。
化合物43:1H NMR(500MHz,DMSO-d6)δ 8.17(d,J=3.5Hz,1H),7.86(s,1H),7.14(s,2H),6.51(d,J=3.5Hz,1H),6.20(s,1H),6.17(s,1H),6.15(s,1H),4.81(s,2H),3.64(s,2H),2.44(s,3H),2.07(s,3H)。
MS:335.2[M+H]+。
化合物44b:1H NMR(500MHz,CHCl3-d)δ 7.65(d,J=8.5Hz,1H),7.14(d,J=8.5Hz,1H),7.10(s,1H),6.57(s,1H),4.47(s,2H),2.29(s,3H),1.53(s,9H)。
化合物44:1H NMR(500MHz,MeOH-d4)δ 8.23(d,J=3.6Hz,1H),7.81(s,1H),6.92(s,1H),6.80(d,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),6.43(d,J=3.6Hz,1H),3.77(s,2H),2.48(s,3H),2.18(s,3H)。
MS:335.2[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.20(d,J=3.5Hz,1H),7.05(s,2H),6.89-6.82(m,1H),6.50(d,J=3.5Hz,1H),6.34(d,J=7.6Hz,1H),6.33-6.29(m,2H),4.87(s,2H),3.66(s,2H),2.43(s,3H),2.20(s,3H)。
MS:335.3[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.12(d,J=3.5Hz,1H),7.40(s,2H),6.89(t,J=7.8Hz,1H),6.56(d,J=3.5,1H),6.39(d,J=7.8Hz,1H),6.35(d,J=7.6Hz,2H),4.92(s,2H),3.69(s,2H),2.47(s,3H)。
MS:355.4[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 8.02(d,J=3.5Hz,1H),7.35(s,2H),6.87(t,J=7.8Hz,1H),6.52(d,J=3.5Hz,1H),6.39-6.31(m,3H),4.93(s,2H),3.61(s,2H),2.43(s,3H)。
MS:339.4[M+H]+。
1H NMR(500MHz,DMSO-d6)δ 7.92(d,J=2.5Hz,1H),7.86(s,1H),7.58(d,J=2.5Hz,1H),7.13(s,2H),6.87(t,J=7.7Hz,1H),6.41-6.36(m,2H),6.33(dd,J=7.7,2.2Hz,1H),4.89(s,2H),3.99(s,3H),3.69(s,2H)。
MS:321.4[M+H]+。
MS:198.1[M-H]-。
1H NMR(500MHz,CHCl3-d)δ 8.65(dd,J=5.8,3.0Hz,1H),8.27(dd,J=5.8,3.0Hz,1H),3.98(s,3H),2.43(d,J=2.5Hz,3H)。
1H NMR(500MHz,CHCl3-d)δ 7.01(dd,J=5.8,3.0Hz,1H),6.68(dd,J=5.8,3.0Hz,1H),3.90(s,3H),2.22(d,J=2.5Hz,3H)。
化合物49e:1H NMR(500MHz,CHCl3-d)δ 7.25-7.22(m,1H),7.13(dd,J=5.9,2.8Hz,1H),6.37(s,1H),4.46(d,J=1.3Hz,2H),2.25(d,J=2.3Hz,3H),1.51(s,9H)。
化合物49:1H NMR(500MHz,DMSO-d6)δ 8.18(d,J=3.5Hz,1H),7.85(s,1H),7.17(s,2H),6.52(d,J=3.5Hz,1H),6.25-6.17(m,1H),6.13-6.03(m,1H),3.70(s,2H),2.44(s,3H),2.07(d,J=1.9Hz,3H)。
MS:353.3[M+H]+。
A2A/A2B受容体拮抗機能実験:
A2A細胞株はPerkinElmer(製品番号ES-011-C)から、A2B細胞株はPerkinElmer(製品番号ES-013-C)から提供される。実験ステップはACS Medicinal Chemistry Letters(2011)2,213-218を参照する。実際には北京康龍化成新薬技術有限公司が、次のステップのとおりに実施した。室温下で、10nLの化合物のDMSOストック溶液(10mM)、10μLのA2A又はA2B細胞懸濁液(3万個の細胞/mL)をこの順に384ウェルプレートの試験ウェルに移し、室温下で20分間インキュベートした。EC80活性化濃度に対応する5'-N-エチルカルボキサミドアデノシン(5'-N-ethylcarboxamidoadenosine)の量を各試験ウェルに注入し、37℃と5%CO2と湿度95%の条件下でさらに30分間インキュベートした後、Eu-cAMPトレーサーワーキングソリューション、Ulight-anti-cAMPワーキングソリューションをこの順に5μL/ウェルで細胞培養プレートに加え、Envisionにおいて細胞培養プレートから蛍光値を読み取った(励起波長320nm、発光波長665nmと615nm)。下式から各ウェルに対応する阻害率を得て、非線形回帰モデルで用量-阻害率S字曲線を作成してIC50値を算出した。
Claims (12)
- 式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物。
R2は、5-12員のヘテロアリール基を表し、
ここで、前記R1、R2は任意選択でそれぞれ独立してR4(ここで、R4はC1-C6アルキル基、ヒドロキシ(C1-C6アルキル基)-、C2-C6アルケニル基、C2-C6アルキニル基、C3-C6シクロアルキル基、C6-C12アリール基、5-12員のヘテロアリール基、C1-C6ハロアルキル基、ハロゲン、オキソ、ニトロ基、シアノ基、-NRaRb、-ORa、-SRa、-SORa、-SO2Ra、-SO3Ra、-NRaC(O)Ra、-NRaC(O)ORa、-NRaS(O)2Ra、-C(O)ORa、-C(O)NRaRb、-C(O)Ra、-(CRaRb)m-ORa、-(CRaRb)m-NRaRb、-(CRaRb)m-NRa-(CRaRb)n-ORa、-(CRaRb)m-O-(CRaRb)n-NRaRb、-(CRaRb)m-O-(CRaRb)n-ORa、及び-(CRaRb)m-NRa-(CRaRb)n-NRaRbから選ばれる)から選ばれる0、1個、2個、3個、4個又は5個の置換基によって置換され、又は置換基の数が2で、且つ該2つの置換基が互いに隣接する位置にある場合に、それらが任意選択で環化して飽和又は不飽和の4-7員環になり、且つさらに、該環にはO、S、Nから選ばれる0、1個又は2個のヘテロ原子が任意選択で含まれ、
R3はC1-C6アルキル基、ヒドロキシ(C1-C6アルキル基)-、C3-C6シクロアルキル基、C6-C12アリール基、ハロゲン、-NRaRb、-ORa、-C(O)ORa、又は-(CRaRb)m-ORaを表し、
ここで、Ra、Rbはそれぞれ独立して水素、ハロゲン、C1-C6アルキル基、C3-C6シクロアルキル基、-(C0-C6アルキレン基)-(C6-C12)アリール基を表し、又は、Ra、Rbが同じ原子に連結されている場合に、それらがそれらに相接する原子と一緒に任意選択で環化して飽和又は不飽和の3-7員環になり、且つ該環にはN、O、Sから選ばれる0、1個又は2個のヘテロ原子が任意選択で含まれ、
n、mはそれぞれ独立して0、1、2、3又は4を表す。) - 下記の式(III)の構造を有する請求項1又は2に記載の式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物。
ここで、Rc、Rdはそれぞれ独立して水素、ハロゲン、C1-C6アルキル基又はC3-C6シクロアルキル基を表し、
又は、Rc、Rdが同じ原子に連結されている場合に、それらがそれらに相接する原子と一緒に任意選択で環化して飽和又は不飽和の3-7員環になり、且つ該環にはN、O、Sから選ばれる0、1個又は2個のヘテロ原子が任意選択で含まれる。) - 請求項1~4のいずれか1項に記載の式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物と、任意選択的な薬学的に許容される担体とを含む医薬組成物。
- 他の治療薬及び/又はチェックポイント阻害薬をさらに含み、
前記他の治療薬はクロラムブシル、メルファラン、シクロホスファミド、イホスファミド、ブスルファン、カルムスチン、ロムスチン、ストレプトゾトシン、シスプラチン、カルボプラチン、オキサリプラチン、ダカルバジン、テモゾロミド、プロカルバジン、メトトレキサート、フルオロウラシル、シタラビン、ゲムシタビン、メルカプトプリン、フルダラビン、ビンブラスチン、ビンクリスチン、ビノレルビン、パクリタキセル、ドセタキセル、トポテカン、イリノテカン、エトポシド、トラベクテジン、ダクチノマイシン、ドキソルビシン、エピルビシン、ダウノマイシン、ミトキサントロン、ブレオマイシン、マイトマイシンC、イクサベピロン、タモキシフェン、フルタミド、ゴナドレリン類似体、メゲストロール、プレドニゾン、デキサメタゾン、メチルプレドニゾロン、サリドマイド、インターフェロンα、ロイコボリンカルシウム、シロリムス、テムシロリムス、エベロリムス、アファチニブ、アリサーチブ(alisertib)、アムバチニブ(amuvatinib)、アパチニブ、アキシチニブ、ボルテゾミブ、ボスチニブ、ブリバニブ、カボザンチニブ、セディラニブ、クレノラニブ(crenolanib)、クリゾチニブ、ダブラフェニブ、ダコミチニブ、ダヌセルチブ、ダサチニブ、ドビチニブ、エルロチニブ、フォレチニブ(foretinib)、ガネテスピブ(ganetespib)、ゲフィチニブ、イブルチニブ、イコチニブ、イマチニブ、イニパリブ(iniparib)、ラパチニブ、レンバチニブ(lenvatinib)、リニファニブ(linifanib)、リンシチニブ(linsitinib)、マシチニブ、モメロチニブ(momelotinib)、モテサニブ、ネラチニブ、ニロチニブ、ニラパリブ(niraparib)、オプロゾミブ(oprozomib)、オラパリブ(olaparib)、パゾパニブ、ピクチリシブ(pictilisib)、ポナチニブ、キザルチニブ(quizartinib)、レゴラフェニブ、リゴサチブ(rigosertib)、ルカパリブ(rucaparib)、ルキソリチニブ、サラカチニブ、サリデジブ(saridegib)、ソラフェニブ、スニチニブ、テラチニブ、チバンチニブ(tivantinib)、チボザニブ、トファシチニブ、トラメチニブ、バンデタニブ、ベリパリブ、ベムラフェニブ、ビスモデギブ、ボラセルチブ(volasertib)、アレムツズマブ、ベバシズマブ、ブレンツキシマブ ベドチン、カツマキソマブ、セツキシマブ、デノスマブ、ゲムツズマブ、イピリムマブ、ニモツズマブ、オファツムマブ、パニツムマブ、リツキシマブ、トシツモマブ、トラスツズマブから選ばれ、
前記チェックポイント阻害薬は抗PD-1抗体、抗PD-L1抗体、LAG3抗体、TIM-3抗体、抗CTLA-4抗体から選ばれる請求項5に記載の医薬組成物。 - アデノシン受容体の阻害により腫瘍、がん、ウイルス感染、臓器移植の拒絶反応、神経変性疾患、注意欠陥関連疾患又は自己免疫疾患を予防又は治療に使用するための、請求項1~4のいずれか1項に記載の式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物、あるいは請求項5~6のいずれか1項に記載の医薬組成物。
- 前記アデノシン受容体が、A2A受容体及びA2B受容体から選ばれる、請求項7に記載の使用のための、式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物、あるいは医薬組成物。
- 前記腫瘍又はがんは皮膚がん、膀胱がん、卵巣がん、乳がん、胃がん、膵臓がん、前立腺がん、結腸がん、肺がん、骨がん、脳がん、神経細胞腫、直腸がん、結腸がん、家族性腺腫性ポリポーシス、遺伝性非ポリポーシス結腸直腸がん、食道がん、唇がん、喉頭がん、下咽頭がん、舌がん、唾液腺がん、胃がん、腺がん、甲状腺髄様がん、乳頭状甲状腺がん、腎臓がん、腎実質がん、卵巣がん、子宮頸がん、子宮体がん、子宮内膜がん、絨毛がん、膵臓がん、前立腺がん、精巣がん、泌尿器がん、黒色腫、脳腫瘍(例えば、膠芽腫、星細胞腫、髄膜腫、髄芽腫、末梢性神経外胚葉性腫瘍)、ホジキンリンパ腫、非ホジキンリンパ腫、バーキットリンパ腫、急性リンパ性白血病(ALL)、慢性リンパ性白血病(CLL)、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、成人T細胞白血病リンパ腫、びまん性大細胞型B細胞リンパ腫(DLBCL)、肝細胞がん、胆嚢がん、気管支がん、小細胞肺がん、非小細胞肺がん、多発性骨髄腫、基底細胞がん、奇形腫、網膜芽細胞腫、脈絡膜黒色腫、セミノーマ、横紋筋肉腫、頭蓋咽頭腫、骨肉腫、軟骨肉腫、筋肉腫、脂肪肉腫、線維肉腫、ユーイング肉腫、形質細胞性腫瘍から選ばれる、請求項7又は8に記載の使用のための、式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物、あるいは医薬組成物。
- 腫瘍、がん、ウイルス感染、臓器移植の拒絶反応、神経変性疾患、注意欠陥関連疾患又は自己免疫疾患の予防又は治療に使用するための、請求項1~4のいずれか1項に記載の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物、あるいは請求項5又は6に記載の医薬組成物。
- アデノシン受容体の活性の阻害に使用するための、請求項1~4のいずれか1項に記載の式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物。
- 前記アデノシン受容体が、A2A受容体、A2B受容体から選ばれる、請求項11に記載の使用のための、式(I)の化合物又は薬学的に許容されるその塩、同位体誘導体、もしくはその溶媒和物、あるいは医薬組成物。
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