CN103140484A - 环状胺氮杂杂环甲酰胺 - Google Patents
环状胺氮杂杂环甲酰胺 Download PDFInfo
- Publication number
- CN103140484A CN103140484A CN201180037015XA CN201180037015A CN103140484A CN 103140484 A CN103140484 A CN 103140484A CN 201180037015X A CN201180037015X A CN 201180037015XA CN 201180037015 A CN201180037015 A CN 201180037015A CN 103140484 A CN103140484 A CN 103140484A
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- CN
- China
- Prior art keywords
- amino
- carboxamide
- quinazoline
- pyrrolidin
- fluorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Cyclic amine Chemical class 0.000 title claims abstract description 272
- 150000003857 carboxamides Chemical class 0.000 title claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims abstract description 10
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 258
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 176
- GYBHRTQLUQOYID-UHFFFAOYSA-N quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1 GYBHRTQLUQOYID-UHFFFAOYSA-N 0.000 claims description 164
- 238000000034 method Methods 0.000 claims description 116
- 150000003839 salts Chemical class 0.000 claims description 61
- 239000012453 solvate Substances 0.000 claims description 35
- 239000000651 prodrug Substances 0.000 claims description 29
- 229940002612 prodrug Drugs 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 230000033115 angiogenesis Effects 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- UCCMBYMWGPFBRR-UHFFFAOYSA-N 4-[(4-phenylpiperidin-3-yl)amino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NC1CNCCC1C1=CC=CC=C1 UCCMBYMWGPFBRR-UHFFFAOYSA-N 0.000 claims description 4
- KOMPUKVXGCHUQI-CVEARBPZSA-N 4-[[(3r,4s)-4-(3-chlorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=CC(Cl)=C1 KOMPUKVXGCHUQI-CVEARBPZSA-N 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 claims description 4
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 206010039710 Scleroderma Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 208000017520 skin disease Diseases 0.000 claims description 4
- SYHLKJDNDGXBIB-UHFFFAOYSA-N tert-butyl 3-amino-4-(4-chlorophenyl)piperidine-1-carboxylate Chemical compound NC1CN(C(=O)OC(C)(C)C)CCC1C1=CC=C(Cl)C=C1 SYHLKJDNDGXBIB-UHFFFAOYSA-N 0.000 claims description 4
- 230000005747 tumor angiogenesis Effects 0.000 claims description 4
- 230000004862 vasculogenesis Effects 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- WTFCZPZLONUDQK-HZPDHXFCSA-N 4-[[(3s,4r)-4-(phenylcarbamoyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound O=C([C@@H]1CNC[C@H]1NC1=C2C=CC=C(C2=NC=N1)C(=O)N)NC1=CC=CC=C1 WTFCZPZLONUDQK-HZPDHXFCSA-N 0.000 claims description 3
- SSNXOPPAPGLLMA-UHFFFAOYSA-N 4-[[4-(3-fluorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NC1CNCC1C1=CC=CC(F)=C1 SSNXOPPAPGLLMA-UHFFFAOYSA-N 0.000 claims description 3
- NDBSXBPJIJZEGV-UHFFFAOYSA-N 4-[[4-(4-fluorophenyl)-1-methylpyrrolidin-3-yl]amino]quinoline-8-carboxamide Chemical compound C1N(C)CC(NC=2C3=CC=CC(=C3N=CC=2)C(N)=O)C1C1=CC=C(F)C=C1 NDBSXBPJIJZEGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 3
- BBAUBGGIYPPJEW-UHFFFAOYSA-N 2-ethyl-4-[(4-phenylpiperidin-3-yl)amino]quinazoline-8-carboxamide Chemical compound C=12C=CC=C(C(N)=O)C2=NC(CC)=NC=1NC1CNCCC1C1=CC=CC=C1 BBAUBGGIYPPJEW-UHFFFAOYSA-N 0.000 claims description 2
- AAVCWLSKIGHTCV-SJORKVTESA-N 2-ethyl-4-[[(3r,4s)-4-(3-fluorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC=2N=C(N=C3C(C(N)=O)=CC=CC3=2)CC)=CC=CC(F)=C1 AAVCWLSKIGHTCV-SJORKVTESA-N 0.000 claims description 2
- AAVCWLSKIGHTCV-DLBZAZTESA-N 2-ethyl-4-[[(3s,4r)-4-(3-fluorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@@H]2CNC[C@H]2NC=2N=C(N=C3C(C(N)=O)=CC=CC3=2)CC)=CC=CC(F)=C1 AAVCWLSKIGHTCV-DLBZAZTESA-N 0.000 claims description 2
- LOMBZOOLOXXADC-UHFFFAOYSA-N 2-ethyl-4-[[4-(3-fluorophenyl)piperidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C=12C=CC=C(C(N)=O)C2=NC(CC)=NC=1NC1CNCCC1C1=CC=CC(F)=C1 LOMBZOOLOXXADC-UHFFFAOYSA-N 0.000 claims description 2
- SBEDUCXZVSFTPH-UHFFFAOYSA-N 2-methyl-4-[(4-phenylpiperidin-3-yl)amino]quinazoline-8-carboxamide Chemical compound C=12C=CC=C(C(N)=O)C2=NC(C)=NC=1NC1CNCCC1C1=CC=CC=C1 SBEDUCXZVSFTPH-UHFFFAOYSA-N 0.000 claims description 2
- NFSOEIWHAKBKMG-UHFFFAOYSA-N 2-methyl-4-[(4-phenylpyrrolidin-3-yl)amino]quinazoline-8-carboxamide Chemical compound C=12C=CC=C(C(N)=O)C2=NC(C)=NC=1NC1CNCC1C1=CC=CC=C1 NFSOEIWHAKBKMG-UHFFFAOYSA-N 0.000 claims description 2
- VSXMSYVKRKWKDG-UHFFFAOYSA-N 3-ethyl-1,2-oxazol-5-amine Chemical compound CCC=1C=C(N)ON=1 VSXMSYVKRKWKDG-UHFFFAOYSA-N 0.000 claims description 2
- HNSKXMKIVSLCQE-UHFFFAOYSA-N 4-[(4-phenylpiperidin-3-yl)amino]quinoline-8-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=CC2=C1NC1CNCCC1C1=CC=CC=C1 HNSKXMKIVSLCQE-UHFFFAOYSA-N 0.000 claims description 2
- LIFSGRPIOYAGJC-UHFFFAOYSA-N 4-[(4-phenylpyrrolidin-3-yl)amino]quinazoline-8-carboxamide Chemical compound N1=CN=C2C(C(=O)N)=CC=CC2=C1NC1CNCC1C1=CC=CC=C1 LIFSGRPIOYAGJC-UHFFFAOYSA-N 0.000 claims description 2
- YQWVFVHQQCZNAE-UHFFFAOYSA-N 4-[(4-phenylpyrrolidin-3-yl)amino]quinoline-8-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=CC2=C1NC1CNCC1C1=CC=CC=C1 YQWVFVHQQCZNAE-UHFFFAOYSA-N 0.000 claims description 2
- SWVUIRWDSSXFJM-HOTGVXAUSA-N 4-[[(3r,4r)-4-[3-(trifluoromethoxy)phenyl]pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=CC(OC(F)(F)F)=C1 SWVUIRWDSSXFJM-HOTGVXAUSA-N 0.000 claims description 2
- HONUPUIOQQZSBS-PBHICJAKSA-N 4-[[(3r,4r)-4-[3-(trifluoromethyl)phenyl]piperidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CCNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=CC(C(F)(F)F)=C1 HONUPUIOQQZSBS-PBHICJAKSA-N 0.000 claims description 2
- MZMRLMYVOFQUPZ-PBHICJAKSA-N 4-[[(3r,4r)-4-[4-(trifluoromethyl)phenyl]piperidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CCNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=C(C(F)(F)F)C=C1 MZMRLMYVOFQUPZ-PBHICJAKSA-N 0.000 claims description 2
- IGKXNOCSPNCGBO-HOTGVXAUSA-N 4-[[(3r,4r)-4-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=C(C(F)(F)F)C=C1 IGKXNOCSPNCGBO-HOTGVXAUSA-N 0.000 claims description 2
- GATOZHYZDBDJHL-WBMJQRKESA-N 4-[[(3r,4s)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC(F)=C(F)C=C1F GATOZHYZDBDJHL-WBMJQRKESA-N 0.000 claims description 2
- MDXIDUZFOIUWOE-ZBFHGGJFSA-N 4-[[(3r,4s)-4-(2-chlorophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=CC=C1Cl MDXIDUZFOIUWOE-ZBFHGGJFSA-N 0.000 claims description 2
- JVSFOURDVOJEHM-SJORKVTESA-N 4-[[(3r,4s)-4-(3-cyanophenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC2=C3C=CC=C(C3=NC=N2)C(=O)N)=CC=CC(C#N)=C1 JVSFOURDVOJEHM-SJORKVTESA-N 0.000 claims description 2
- OOLBUEZLEPIOFT-WBVHZDCISA-N 4-[[(3r,4s)-4-(3-fluoro-2-methylphenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound CC1=C(F)C=CC=C1[C@@H]1[C@@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CNC1 OOLBUEZLEPIOFT-WBVHZDCISA-N 0.000 claims description 2
- NKVQBPPXOLUUHX-ZBFHGGJFSA-N 4-[[(3r,4s)-4-(3-fluoro-4-methoxyphenyl)pyrrolidin-3-yl]amino]quinazoline-8-carboxamide Chemical compound C1=C(F)C(OC)=CC=C1[C@@H]1[C@@H](NC=2C3=CC=CC(=C3N=CN=2)C(N)=O)CNC1 NKVQBPPXOLUUHX-ZBFHGGJFSA-N 0.000 claims description 2
- BBMMVJHNHCAYBZ-SJORKVTESA-N 4-[[(3r,4s)-4-(3-fluorophenyl)pyrrolidin-3-yl]amino]-2-methylquinazoline-8-carboxamide Chemical compound C1([C@H]2CNC[C@@H]2NC=2N=C(N=C3C(C(N)=O)=CC=CC3=2)C)=CC=CC(F)=C1 BBMMVJHNHCAYBZ-SJORKVTESA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
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Abstract
本发明提供了式(I)、式(II)和式(III)的新的环状胺氮杂杂环甲酰胺,它们的制备及其用于治疗过度增殖性疾病诸如癌症的用途。
Description
技术领域
本发明涉及一系列可用于治疗哺乳动物的过度增殖性疾病诸如癌症的环状胺氮杂杂环甲酰胺化合物。本发明还包括所述化合物在治疗哺乳动物尤其是人的过度增殖性疾病的用途,以及包含所述化合物的药物组合物。
发明背景
蛋白激酶组成一大族担负细胞内多种信号转导过程控制的结构相关酶(Hardie,G.和Hanks,S.(1995)The Protein Kinase Facts Book.I和II,Academic Press,San Diego,CA)。通过它们磷酸化的底物(例如蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸、脂质等),可将激酶分成多族。已确定了一般对应于这些激酶各族的序列模体(例如,Hanks,S.K.,Hunter,T.,FASEB J.,9:576-596(1995);Knighton,等人,Science,253:407-414(1991);Hiles等人,Cell,70:419-429(1992);Kunz等人,Cell,73:585-596(1993);Garcia-Bustos,等人,EMBO J.,13:2352-2361(1994))。
蛋白激酶可由其调节机制表征。这些机制包括例如自磷酸化作用、由其它激酶转磷酸作用、蛋白质-蛋白质相互作用、蛋白质-脂质相互作用和蛋白质-多核苷酸相互作用。单个蛋白激酶可由多于一种机制调节。
通过将磷酸基团加到靶蛋白,激酶可调节很多不同的细胞过程,包括但不限于增殖、分化、细胞凋亡、运动性、转录、翻译及其他信号传导过程。这些磷酸化事件充当能够调节或调整靶蛋白生物功能的分子通断开关。靶蛋白的磷酸化响应于多种胞外信号(激素、神经递质、生长和分化因子等)、细胞周期事件、环境或营养应激等而发生。适合的蛋白激酶在信号传导通路中起作用以活化或钝化(直接或间接)例如代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道或泵或转录因子。由蛋白磷酸化控制缺陷导致的不受控的信号传导涉及多种疾病,包括例如炎症、癌症、过敏/哮喘、免疫系统疾病和病症、中枢神经系统疾病和病症及血管生成。
蛋白激酶70S6K,即70kDa核糖体蛋白激酶p70S6K(也称为SK6、p70/p85S6激酶、p70/p85核糖体S6激酶和pp70S6K)是蛋白激酶的AGC亚家族的成员。p70S6K是丝氨酸-苏氨酸激酶,其是磷脂酰肌醇3激酶(PI3K)/AKT通路的组成部分。p70S6K为PI3K的下游部分,且通过响应多种有丝分裂原、激素和生长因子在多个位点的磷酸化而被激活。由于雷帕霉素起到抑制p70S6K活性的作用,p70S6K活性也受包含mTOR的复合物(TORC1)的控制。p70S6K通过PI3K下游靶点AKT和PKCζ调节。Akt直接磷酸化并钝化TSC2,由此激活mTOR。此外,对于被渥曼青霉素抑制而不被雷帕霉素抑制的p70S6K的突变体等位基因的研究表明PI3K通路可以不依赖mTOR活性的调节而对p70S6K产生作用。
酶p70S6K通过S6核糖体蛋白的磷酸化而调控蛋白合成。S6磷酸化与翻译装置(translational apparatus)的mRNA编码组件的翻译的增加相关,所述翻译装置包括核糖体蛋白和翻译延伸因子(其表达增加对细胞生长和增殖是必不可少的)。这些mRNA在其5′转录起始端(称为5′TOP)包含寡嘧啶片段,已证明这对于其在翻译水平的调节是必不可少的。
除了参与翻译之外,p70S6K激活还涉及细胞周期控制、神经细胞分化、在肿瘤转移中重要的细胞运动性和细胞响应的调节、免疫应答和组织修复。p70S6K抗体破坏了大鼠成纤维细胞进入S期所驱动的促有丝分裂响应,这就表明了p70S6K功能在细胞周期中从G1期至S期的进程中是必不可少的。此外,已经确定在细胞周期的G1期至S期雷帕霉素对细胞周期增殖的抑制是其抑制生成过度磷酸化的激活形式的p70S6K的结果。
p70S6K肿瘤细胞增殖和保护细胞免于细胞凋亡中的作用受到支持,这是基于其在肿瘤组织中参与生长因子受体信号转导、过表达和激活。例如,RNA印迹分析和蛋白质印迹分析表明,PS6K基因的扩增分别伴有mRNA和蛋白质表达的相应增加(CancerRes.(1999)59:1408-11-PS6K在乳腺癌中定位于染色体区17q23及其扩增的测定(Localization of PS6K to Chromosomal Region17q23and Determination of Its Amplificationin Breast Cancer))。
染色体17q23在以下肿瘤和癌症中扩增:高达20%的原发性乳腺肿瘤、87%含有BRCA2突变的乳腺肿瘤和50%含有BRCA1突变的肿瘤以及其它癌症类型,例如胰腺癌、膀胱癌和成神经细胞瘤(参见M.Barlund,O.Monni,J.Kononen,R.Cornelison,J.Torhorst,G.Sauter,O.-P.Kallioniemi和Kallioniemi A.,Cancer Res.,2000,60:5340-5346)。研究表明,17q23在乳腺癌中的扩增涉及PAT1、RAD51C、PS6K和SIGMA1B基因(CancerRes.(2000):60,第5371-5375页)。
p70S6K基因已被鉴定为这些部位扩增和过表达的靶点,并且观察到扩增和预后不良之间在统计上显著相关。
在用上游激酶mTOR的抑制剂CCI-779(雷帕霉素酯)治疗的肾癌患者中,观察到p70S6K激活的临床抑制。据报道,疾病进程和p70S6K活性抑制之间有显著的线性相关性。
在响应能量应激时肿瘤抑制因子LKB1激活AMPK,AMPK磷酸化TSC1/2复合物,并使得其钝化mTOR/p70S6K通路。LKB1中的突变引起波伊茨-耶格综合征(Peutz-Jeghers syndrome PJS),患有PJS的患者发展为的癌症可能性是一般人群的15倍。此外,1/3的肺腺癌潜伏有未激活的LKB1突变。
p70S6K涉及代谢疾病和障碍。据报道,缺乏p70S6K避免患年龄和饮食诱发的肥胖症并同时提高胰岛素敏感性。基于这些发现,支持了p70S6K在肥胖症、糖尿病、代谢综合征、胰岛素抵抗、高血糖、高氨基酸血症和高脂血症等代谢疾病和障碍中的作用。
在WO 03/064397,WO 04/092154,WO 05/054237,WO 05/056014,WO 05/033086,WO 05/117909,WO 05/039506,WO 06/120573,WO 06/136821,WO 06/071819,WO06/131835,WO 08/140947和PCT/US10/000313中公开了被描述为适于抑制p70S6K的化合物。
发明内容
本发明的目的是提供新的p70S6K抑制剂,其用于治疗过度增殖性疾病,尤其是与以上提及的蛋白激酶的活动过度相关的那些,诸如哺乳动物中的癌症,所述化合物在活性以及溶解度、代谢清除率和生物利用度特性方面具有优良的药理性质。
因此,本发明提供了新的环状胺氮杂杂环甲酰胺化合物及其可药用盐、溶剂化物或前药,它们是激酶抑制剂且可用于治疗以上提及的疾病。
所述化合物为式(I)化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药,
其中:
X是N或C-R3,
Y是N、NH或不存在,
R1是L1–R4–L2–R5-L3-R6、L1–R4–L2–R5或L1–R4,
R2是A、Hal、OH、OA、SH、CN、NH2、NO2、NHA、NH–L1–Ar、NHCOA、NHCO–L1–Ar、NHSO2A、NHSO2–L1–Ar、NHCONHA、NHCONH–L1–Ar、L1–Ar、O-L1–Ar、L1–R4或H,
L1、L3各自相互独立地是单键、亚甲基、或甲基取代的亚甲基,其中亚甲基或甲基取代的亚甲基中的甲基可以是未取代或者被Hal、OH、CN、NH2,NH(LA)、N(LA)2、NO2、COOH、N3、乙烯基或乙炔基单取代或二取代,和/或被R4单取代,且其中一个或两个CH2基团可以被O或S原子替代或被–NH-、-N(LA)-、-CONH-、-N(LA)COO-、-SO2-或-NHCO-基团替代,
R3是H、A、Hal、OH、COOH、SH、NH2、NO2或CN,
R4、R5、R6各自相互独立地是Ar、或环状A,它们可以被Hal或LA单取代或二取代,
L2是-NHCO-、-NHCOO-、–NHCONH–、–NHCONA–、–NHCOA–、–O–、–S–、-NH-、-NHSO2-、-SO2NH–、–CONH–、–CONHCONH–、–NHCONHCO–或–A-,
Ar是具有0、1、2、3或4个N、O和/或S原子和5、6、7、8、9或10个骨架原子的单环或二环的芳族碳环或杂环,其可以未被取代或相互独立地被Hal、A、OH、SH、OA、NH2、NHA、NA2、NO2、CN、OCN、SCN、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、NHCONHA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A和/或SO2Hal单、二或三取代,且其中环N-原子可以被O-原子取代以形成N-氧化物基团,且其中在二环芳族环的情况下两个环之一可以是部分饱和的,
A是具有1、2、3、4、5、6、7或8个C原子的无支链的或有支链的直链或环状烷基,其中一个或两个CH2基团可以被O或S原子所替代和/或被–NH-、-CO-、-NHCOO-、-NHCONH-、-N(LA)-、-CONH-、-NHCO-或–CH=CH–基团所替代,且其中1-3个H原子可以被Hal所替代,且其中一个或两个CH3基团可以被OH、SH、NH2、NH(LA)、N(LA)2、NHCOOH、NHCONH2或CN所替代,
LA是具有1、2、3或4个C原子的无支链的或有支链的直链烷基,且其中1、2或3个H原子可以被Hal所替代,以及
Hal是F、Cl、Br或I。
通常,所有出现超过一次的基团可以是相同或不同的,即,是相互独立的。在上下文中,除非另有明确说明,各基团和参数具有为式(I)所指定的含义。
因此,本发明特别是涉及式(I)化合物,其中所述基团中至少一个具有下文所示的优选的含义。
“Hal”表示氟、氯、溴或碘,特别是氟或氯。
“A”表示例如,甲基,此外表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基。“A”还表示如上文所定义的烷基,其中一个或两个CH2基团可以被O或S原子所替代和/或被NH、N(LA)、CONH、NHCO或-CH=CH-基团所替代,和/或还有1-3个H原子可以被F和/或Cl所替代,例如,三氟甲基、五氟乙基、1,1-二氟甲基、1,1,1-三氟乙基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
在“A”的其它实例中,一个或两个CH3基团被OH,SH,NH2,N(LA)H,N(LA)2或CN替代,例如,N,N’-二甲基氨基烷基、2-氨基乙基、3-氨基丙基、4-氨基丁基、5-氨基戊基、3-氨基甲基环丁基或氰基烷基。环状A优选地表示环丙基、环丁基、环戊基、环己基或环庚基。
“LA”表示具有1、2、3或4个C原子的无支链的或有支链的直链烷基,其中1、2或3个H原子可以被Hal所替代,例如甲基、乙基、三氟甲基、二氟甲基、1,1,1-三氟乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基。
“Ar”表示例如,未被取代的苯基、萘基或联苯基,此外还优选例如,苯基、萘基或联苯基,其各自被A、氟、氯、溴、碘、羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊基氧基、己基氧基、硝基、氰基、甲酰基、乙酰基、丙酰基、三氟甲基、氨基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、苄基氧基、磺酰氨基、甲基磺酰氨基、乙基磺酰氨基、丙基磺酰氨基、丁基磺酰氨基、二甲基磺酰氨基、苯基磺酰氨基、羧基、甲氧基羰基、乙氧基羰基、氨基羰基单、二或三取代。
“Ar”还表示苯基、邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基、邻-、间-或对-丙基苯基、邻-、间-或对-异丙基苯基、邻-、间-或对-叔丁基苯基、邻-、间-或对-羟基苯基、邻-、间-或对-硝基苯基、邻-、间-或对-氨基苯基、邻-、间-或对-(N-甲基氨基)苯基、邻-、间-或对-(N-甲基氨基羰基)苯基、邻-、间-或对-乙酰氨基苯基、邻-、间-或对-甲氧基苯基、邻-、间-或对-乙氧基苯基、邻-、间-或对-乙氧基羰基苯基、邻-、间-或对-(N,N-二甲基氨基)苯基、邻-、间-或对-(N,N-二甲基氨基羰基)苯基、邻-、间-或对-(N-乙基氨基)苯基、邻-、间-或对-(N,N-二乙基氨基)苯基、邻-、间-或对-氟苯基、邻-、间-或对-溴苯基、邻-、间-或对-氯苯基、邻-、间-或对-(甲基磺酰氨基)苯基、邻-、间-或对-(甲磺酰基)苯基,还优选2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基、2,4-或2,5-二硝基苯基、2,5-或3,4-二甲氧基苯基、3-硝基-4-氯苯基、3-氨基-4-氯-、2-氨基-3-氯-、2-氨基-4-氯-、2-氨基-5-氯-或2-氨基-6-氯苯基、2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨基苯基、2,3-二氨基苯基、2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基、2,4,6-三甲氧基苯基、2-羟基-3,5-二氯苯基、对-碘苯基、3,6-二氯-4-氨基苯基、4-氟-3-氯苯基、2-氟-4-溴苯基、2,5-二氟-4-溴苯基、3-溴-6-甲氧基苯基、3-氯-6-甲氧基苯基、3-氯-4-乙酰氨基苯基、3-氟-4-甲氧基苯基、3-氨基-6-甲基苯基、3-氯-4-乙酰氨基苯基或2,5-二甲基-4-氯苯基、(4-甲氧基苯基)甲基、(3-甲氧基苯基)甲基、(4-甲氧基苯基)乙基、(3-甲氧基苯基)乙基。
“Ar”还优选地表示2-、3-或4-苯基、2-、3-或4-苯基甲基、2-、3-或4-苯基乙基、2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-唑基、3-、4-或5-异唑基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、3-或4-吡啶基、2-、3-或4-吡啶基甲基、2-、3-或4-吡啶基乙基、2-、4-、5-或6-嘧啶基、2-、3-、5-或6-吡嗪-1-或4-基,此外还优选地表示1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-二唑-4-或-5-基、1,2,4-二唑-3-或-5-基、1,3,4-二唑-2-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-哒嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-或5-异吲哚基、2-、6-或8-嘌呤基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并唑基、3-、4-、5-、6-或7-苯并异唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并异噻唑基、4-、5-、6-或7-苯并-2,1,3-二唑基、1-、3-、4-、5-、6-、7-或8-异喹啉基、3-、4-、5-、6-、7-或8-喹啉基、2-、4-、5-、6-、7-或8-喹唑啉基、喹喔啉-2-、3-、4-或5-基、4-、5-或6-酞嗪基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-嗪基,还优选1,3-苯并间二氧杂环戊烯-2-、4-或5-基、噻吩-2-或3-基、1,4-苯并二烷-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并二唑-5-基、呋喃-2-或3-基、2,3-二氢-苯并呋喃-2-、3-、4-或5-基,其各自未被取代或可以被例如羰基氧、F、Cl、Br、甲基、乙基、丙基、苯基、苄基、-CH2-环己基、羟基、甲氧基、乙氧基、氨基、甲基氨基、二甲基氨基、硝基、氰基、羧基、甲氧基羰基、氨基羰基、甲基氨基羰基、二甲基氨基羰基、乙酰氨基、脲基、甲磺酰基氨基、甲酰基、乙酰基、氨基磺酰基和/或甲磺酰基单、二或三取代。
在那些其中R1是L1–R4–L2–R5的情况中,基团R4显然具有桥接功能,并且被连结基团L1和L2所取代,而该取代独立于其可能具有的任何另外的取代基。
除非另有说明,术语“被取代的”优选是指被上述取代基取代,其中可能有多种不同程度的取代。
这些化合物的所有的生理学可接受的盐、衍生物、溶剂化物、盐的溶剂化物和立体异构体,包括其所有比例的混合物,也符合本发明。
式(I)化合物可以具有一个或多个手性中心。因此所述化合物可能以多种对映异构形式出现并可能为外消旋形式或旋光体。因此本发明还涉及这些化合物的旋光体(立体异构体)、对映异构体、外消旋物、非对映异构体和水合物及溶剂化物。
因为本发明化合物的外消旋物或立体异构体的药学活性可能存在差异,可能需要使用对映体。在这些情况下,可采用本领域技术人员已知的或甚至在合成上直接采用的化学或物理方法将终产物甚至中间体拆分成为对映异构化合物。
在分子结构中存在外消旋胺的情况下,混合物可与光学活性拆分试剂形成非对映体。合适的拆分试剂实例为具有光学活性的酸类,如R型或S型的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸和乳酸,合适的N-保护氨基酸类(例如N-苯甲酰脯氨酸或N苯磺酰脯氨酸),或各种光学活性的樟脑磺酸。借助于光学活性拆分剂(例如固定在硅胶上的二硝基苯甲酰苯基甘氨酸、三醋酸纤维素或碳水化合物的其他衍生物或手性衍生化甲基丙烯酸聚合物)的对映体的色谱拆分法也具有优势。为此目的所使用的合适洗脱剂为含水或含醇的溶剂混合物,例如乙烷/异丙醇/腈,例如比例为82∶15∶3。
一种拆分包含酯基(例如乙酰基酯)的外消旋物的巧妙的方法是使用酶、特别是酯酶类。
一组优选的式(I)化合物中各变量和取代基具有以下含义:
X是N,
Y是NH,
R1是L1–R4–L2–R5,
R2是LA、Hal、OH、O(LA)、SH、CN、NH2、NO2、NH(LA)、NHCO(LA)、NHSO2(LA)、NHCONH(LA),
L1、L3是甲基取代的亚甲基,其中所述甲基取代的亚甲基中的甲基被NH2或NH(LA)、N(LA)2或环状A单取代,所述取代基可以是被Hal或LA单取代或二取代,
R4、R5是具有0、1或2个N、O和/或S原子和5或6个骨架原子的单环的芳族碳环或杂环,其可以未被取代或相互独立地被Hal、A、OH、SH、OA、NH2、NHA、NA2、NO2、CN、OCN、SCN、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、NHCONHA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A和/或SO2Hal单、二或三取代,
L2是-NHCO-、-NHCOO-、–NHCONH–、–NHCONA–、–NHCOA–、–O–、–S–、-NH-、-NHSO2-、-SO2NH–、–CONH–、–CONHCONH–、–NHCONHCO–或–A-,
A是具有1、2、3、4、5、6、7或8个C原子的无支链的或有支链的直链或环状烷基,其中一个或两个CH2基团可以被O或S原子所替代和/或被–NH-、-CO-、-NHCOO-、-NHCONH-、-N(LA)-、-CONH-、-NHCO-或–CH=CH–基团所替代,且其中1-3个H原子可以被Hal所替代,且其中一个或两个CH3基团可以被OH、SH,NH2、NH(LA)、N(LA)2、NHCOOH、NHCONH2或CN所替代,
LA是具有1、2、3或4个C原子的无支链的或有支链的直链烷基,且其中1、2或3个H原子可以被Hal所替代,以及
Hal是F、Cl、Br或I。
在优选的实施例中,本发明的化合物以式(II)和式(III)及其可药用盐、溶剂化物、盐的溶剂化物或前药表示,其中与式(I)重叠的基团标识符具有与式(I)相同的含义,即X和R2,而其余的标识符,即Y’、Z和Z’描述如下:
其中,
Y’是CH2或NH,使得当Y’是NH时,Z是CH2(或不存在)以及当Y’是CH2时,Z是NH,
Z是CH2、NH或不存在,使得当Z是CH2(或不存在)时,Y是NH以及当Z是NH时,Y是CH2,以及
Z’是Ar、烷基、卤素、OR、NRR、CF3、CN、OCF3、SR或H(被上述任意组合单、二或三取代)。
本发明化合物可为前药化合物形式。“前药化合物”是指于生物体中在生理学条件下可以通过例如氧化反应、还原反应、水解反应等转化为本发明的生物学活性化合物的衍生物,每种反应均可以在有酶或没有酶的参与的情况下下进行。前药的实例为下述情况的化合物:其中本发明化合物中的氨基基团被酰化、烷基化或磷酸化,例如,二十酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基;或其中羟基基团被酰化、烷基化、磷酸化或转化为硼酸酯,例如乙酰基氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基;或其中羧基基团被酯化或酰胺化;或其中硫羟基基团与载体分子(例如肽)形成二硫桥,所述载体分子选择性地将药物递送至靶点和/或至细胞溶胶。这些化合物可根据已知的方法由本发明化合物制得。前药的其它实例为如下的化合物,其中本发明化合物中的羧酸酯例如被转化为烷基-、芳基-、胆碱、氨基、酰氧基甲酯、亚麻酰基(linolenoyl)-酯。
本发明化合物的代谢物也在本发明范围内。
当本发明化合物或其前药的互变异构(例如,酮-烯醇互变异构)现象存在时,既要求保护它们分别的单个形式(例如,酮或烯醇形式),也要求保护其任意比例的混合物。这同样适用于它们的立体异构体,例如,对映异构体、顺/反异构体、构象异构体等。
如有需要,异构体可根据本领域已知的方法(例如液相色谱法)分离。这同样适用于它们的对映异构体,例如,采用手性固定相分离。此外,对映异构体可通过转化为非对映异构体进行分离,即与对映异构纯的辅助化合物偶连,随后分离所得的非对映异构体并裂解辅助残基。或者,本发明化合物的任何对映异构体可用光学纯原料由立体选择性合成获得。
本发明化合物可以是可药用盐或溶剂化物形式。术语“可药用盐”是指由可药用的无毒碱或酸(包括无机碱或酸和有机碱或酸)制得的盐。在本发明化合物含有一个或多个酸性或碱性基团的情况下,本发明同样包括它们相应的药学上或毒物学上可接受的盐,尤其是它们药学上可利用的盐。因此,含有酸性基团的本发明化合物可以盐形式存在,并且根据本发明,可以作为例如碱金属盐、碱土金属盐或铵盐使用。更多此类盐的精确实例包括:钠盐、钾盐、钙盐、镁盐或含有氨或有机胺(例如,乙基胺、乙醇胺、三乙醇胺或氨基酸)的盐。含有一个或多个碱性基团(即,可被质子化的基团)的本发明化合物可以盐形式存在,并且根据本发明,可以与无机或有机酸形成的加成盐形式存在。适当的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和其它本领知的酸。如果本发明化合物在分子中同时包含酸性和碱性基团,那么除了所述盐形式外,本发明同样包含内盐或内铵盐(两性离子)。所述各盐可通过本领域技术人员已知的常规方法制得,例如使它们在溶剂或分散剂中与有机或无机酸或碱接触,或者使阴离子或阳离子与其它的盐交换。本发明同样包含如下所有本发明化合物的盐,其因低生理学兼容性不适宜在药物中直接使用,但可作为例如化学反应中间体或在可药用盐的制备中使用。
“溶剂化物”是指含有化学计量或非化学计量溶剂的溶剂加成物形式。许多化合物倾向于捕获固定摩尔量的结晶固态溶剂分子而形成溶剂化物。例如,如果溶剂是水,形成的溶剂化物是水合物,当溶剂是醇,形成的溶剂化物是醇化物,如果溶剂是醚,形成的溶剂化物是乙醚配合物。溶剂化物的具体例子包括一水合物或二水合物、甲醇化物、乙醇化物或二乙醚配合物。
本领域技术人员懂得,在许多情况下,可将药物活性成分或它们的可药用盐的溶剂化物用在药物组合物中,并知道怎样获得这些溶剂化物。
另外,本发明涉及包含作为活性成分的本发明化合物或其前药化合物或其可药用盐或其溶剂化物以及包含可药用载体的药物组合物。
“药物组合物”是指一种或多种活性成分和组成载体的一种或多种惰性组分以及由下列直接或间接获得的任意产物:任意两种或多种组分组合、复合、聚集,或者一种或多种组分解离,或者一种或多种组分的其它类型的反应或相互作用。
因此,本发明药物组合物包括通过本发明化合物和可药用载体混合而制得的任意组合物。
本发明药物组合物可另外含有一种或多种作为活性成分的其它化合物,例如一种或多种另外的本发明化合物、前药化合物或其它p70S6K抑制剂。
药物组合物包括经口、直肠、局部、肠胃外(包括皮下、肌肉内和静脉内)、眼球(眼)、肺(鼻或颊吸入)或鼻给药的适宜组合物,在任何已知的情况中最适宜的途径取决于治疗的病症的性质和严重性以及活性组分的性质。它们可方便地以单位剂量形式存在并采用药物领域已知的任意方法制备。
在一个实施方案中,所述化合物和药物组合物用于治疗以下疾病:癌症,例如脑癌、肺癌、结肠癌、表皮样癌、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头癌、颈癌、肾癌、肾的癌、肝癌、卵巢癌、前列腺癌、结直肠癌、子宫癌、直肠癌、食管癌、睾丸癌、妇科癌、甲状腺癌、黑素瘤、恶性血液病,诸如急性髓性白血病、多发性骨髓瘤、慢性髓性白血病、骨髓细胞白血病、神经胶质瘤、卡波西肉瘤,或其它任何类型的实体或液体肿瘤。优选地,治疗的癌症选自乳腺癌、结直肠癌、肺癌、前列腺癌或胰腺癌或成胶质细胞瘤。
本发明还涉及本发明化合物在制备药物中的用途,所述药物用于治疗哺乳动物中与p70S6K活动过度有关的过度增殖性疾病以及由p70S6K级联所调节的疾病,或用于治疗异常增殖介导的病症,例如癌症和炎症。
本发明还涉及用于治疗哺乳动物中与血管发生或血管生成有关的疾病的化合物或药物组合物,其包含治疗有效量的本发明化合物或其可药用盐、前药或水合物以及可药用的载体。
在一个实施方案中,所述化合物或药物组合物可以用于治疗下列疾病:肿瘤血管生成、慢性炎症(例如类风湿性关节炎、炎性肠疾病)、动脉粥样硬化、皮肤病(例如银屑病、湿疹和硬皮病)、糖尿病、糖尿病性视网膜病、早产儿视网膜病和年龄相关性黄斑变性。
本发明还涉及用于抑制哺乳动物中异常细胞生长的化合物或药物组合物,其包含一定量的本发明化合物或其可药用盐或溶剂化物或前药以及一定量的另外的抗癌治疗药物,其中所述化合物、盐、溶剂化物或前药的量与化学治疗剂的量一起对抑制异常细胞生长是有效的。许多抗癌治疗药物目前在本领域内中是已知的。在一个实施方案中,所述抗癌治疗药物是选自以下的化学治疗剂:有丝分裂抑制剂、烷化剂、抗代谢药、嵌入抗生素(intercalating antibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物学应答调节剂、抗激素、血管生成抑制剂和抗雄激素。在另一个实施方案中,所述抗癌治疗药物是选自以下的抗体:贝伐单抗、CD40-特异性抗体、chTNT-1/B、地舒单抗、扎木单抗、IGF1R-特异性抗体、林妥珠单抗、依决洛单抗、WX G250、利妥昔单抗、替西木单抗、曲妥单抗和西妥昔单抗。在另一个实施方案中,所述抗癌治疗药物是另一种蛋白激酶的抑制剂,所述蛋白激酶诸如Akt、Axl、Aurora A、Aurora B、dyrk2、epha2、fgfr3、igf1r、IKK2、JNK3、Vegfr1、Vegfr2、Vegfr3(也称为Flt-4)、KDR、MEK、MET、Plk1、RSK1、Src、TrkA、Zap70、cKit、bRaf、EGFR、Jak2、PI3K、NPM-Alk、c-Abl、BTK、FAK、PDGFR、TAK1、LimK、Flt-3、PDK1和Erk。
本发明还涉及抑制哺乳动物中异常细胞生长或治疗过度增殖性疾病的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐或溶剂化物或前药,与放射治疗联合使用,其中所述化合物、盐、溶剂化物或前药的量联合放射治疗对抑制哺乳动物中的异常细胞生长或治疗过度增殖性疾病是有效的。施用放射治疗的技术在本领域中是已知的,并且这些技术可用于本文中所述的联合治疗中。在该联合治疗中,本发明化合物的施用可如本文所述确定。一般认为,本发明化合物可以使得异常细胞对放射治疗更为敏感,从而可以杀死和/或抑制此类细胞生长。
因此,本发明还涉及使哺乳动物中的异常细胞对放射治疗敏感化的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐、溶剂化物或前药,所述量可以有效地使得异常细胞对放射治疗敏感化。本方法中化合物、盐或溶剂化物的量可根据本文所述的确定所述化合物的有效量的方法进行测定。本发明还涉及抑制哺乳动物中异常细胞生长的方法,其包括一定量的本发明化合物或其可药用盐、溶剂化物、前药或同位素标记的衍生物以及一定量的一种或多种选自抗血管生成剂、信号传导抑制剂和抗增殖性药物。
在实际应用中,根据常规药物配制技术,本发明化合物作为活性成分可以与药用载体结合为紧密混合物。所述载体可根据施用(例如,经口或胃肠外(包括静脉内的))所需的制剂形式而采用多种形式。在制备口服剂型组合物时,可使用任何常规药用介质,例如,水、乙二醇、油类、醇类、矫味剂、防腐剂、着色剂等。在口服液体制剂的情况中,可使用任何常规药用介质,例如,混悬剂、酏剂和溶液剂;或载体例如淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。在口服固体制剂情况下,组合物可作为例如粉剂、硬和软胶囊以及片剂形式存在,相对液体剂型来说,优选固体口服剂型。
因为片剂和胶囊容易给药,所以片剂和胶囊代表最有益的口服单位剂型,在此情况下,明显可以采用固体药物载体。如有需要,片剂可通过标准含水或不含水技术包衣。所述组合物和制剂应包含至少0.1%的活性化合物。当然,活性化合物在这些组合物中的百分比可变化,可以有益地在约2%到约60%的单位重量范围内。在所述治疗有用的组合物中的活性化合物的量为能够获得有效剂量的量。活性化合物同样可经鼻内给药,例如,液体滴剂或喷雾剂。
片剂、丸剂、胶囊等可同样包含:粘合剂,例如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、土豆淀粉、海藻酸;润滑剂,例如硬脂酸镁;和甜味剂,例如蔗糖、乳糖或糖精。单位剂型为胶囊时,可包含除上述类型材料之外的液体载体,例如脂肪油。
各种不同的其它物质可以作为包衣材料存在,或用于改变单位剂量的物理形式。例如,片剂可用虫胶、糖衣或两者一起包衣。除了活性组分外,糖浆剂或酏剂还可包含:作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、着色剂和矫味剂(例如樱桃或橙子口味)。
本发明化合物也可以经肠胃外给药。这些活性化合物的溶液或悬浮液可通过在水中与表面活性剂(例如羟基-丙基纤维素)适当地混合来制备。分散液可由甘油、液态聚乙二醇以及其在油中的混合物制备。在储存和使用的常规条件下,这些制剂可以包含防腐剂以防止微生物的生长。
适宜于注射使用的药物形式包括用于即时制备无菌注射溶液或分散体的无菌注射水溶液或分散体和无菌粉末。在所有情况中,该形式必须为无菌的并必须具有足够的流动性使它们易于注射。在制备和储存的情况下,所述形式必须稳定并且必须能够对抗微生物(例如细菌和真菌)的污染。载体可包括溶剂或分散介质,例如水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇)、其适宜的混合物和植物油。
任何适宜的给药途径可以提供哺乳动物(尤其是人类)有效剂量的本发明化合物。例如,可经口、直肠、局部、肠胃外、眼、肺、鼻等给药。剂型包括片剂、口含片剂、分散剂、混悬剂、溶液剂、胶囊剂、霜剂、软膏剂、气雾剂等。优选本发明化合物经口给药。
施用的活性组分的有效量可取决于该施用的具体化合物、施用模式、待治疗的病症以及待治疗病症的严重性。所述剂量可很容易被本领域技术人员确定。
治疗或预防作为本发明化合物的适应症的癌症、炎症或其它增殖性疾病时,在给予日剂量为约0.01mg到约100mg/kg动物体重时即可以获得大致满意的结果,优选给予单一日剂量。对于大型哺乳动物而言,总的日剂量为约0.1mg到约1000mg,优选为约0.2mg到约50mg。在70kg的成年人情况中,总的日剂量大致为约0.2mg到200mg。所述剂量方案可以调整从而能提供最佳治疗响应。
本发明还涉及药盒(套盒),该药盒包含下列独立包装:
a)有效量的本发明化合物或其生理学可接受的盐、溶剂化物或前药;以及
b)有效量的另外的药物活性成分。
所述药盒包含适当的容器,例如盒子、独立瓶子、袋子或安瓿。药盒可包括例如独立安瓿,每一个含有有效量的本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物)以及溶解形式或冻干形式的有效量的另外的药物活性成分。
具体实施方式
实验部分
在本申请中可能出现的某些缩写如下:
缩写
名称 | |
ACN | 乙腈 |
ATP | 三磷酸腺苷 |
b | 宽峰 |
d | 双峰 |
DMSO | 二甲基亚砜 |
DIEA | N,N-二异丙基乙胺 |
DTT | 二硫苏糖醇 |
EDTA | 乙二胺四乙酸 |
equiv. | 当量 |
Et | 乙基 |
h | 小时 |
HEPES | 4-(2-羟基乙基)-1-哌嗪乙磺酸 |
HPLC | 高压液相色谱法 |
LC/MS | 液相色谱法-质谱法 |
m | 多重峰 |
M | 分子离子 |
m/z | 质荷比 |
Me | 甲基 |
min | 分钟 |
MS | 质谱法 |
N | 当量(浓度单位) |
NMO | 4-甲基吗啉N-氧化物 |
NMR | 核磁共振 |
PG | 保护基团 |
psi | 磅/平方英寸 |
q | 四重峰 |
Rf | 保留因子 |
RT | 室温 |
Rt. | 保留时间 |
s | 单峰 |
Tert | 叔 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THAB | 四己基溴化铵 |
THF | 四氢呋喃 |
UV | 紫外 |
VIS | 可见 |
本发明化合物可以根据下文流程和实施例中的方法采用适当的物质制备,在下面的具体的实施例中进一步举例说明。
此外,通过使用本文所述方法,结合本领域的常规技术,可容易地制备本文所要求的其它化合物。然而,不能将实施例中说明的化合物理解为是作为本发明的唯一类型。实施例还说明了本发明化合物的制备的详细描述。本领域技术人员容易理解,下列制备方法的条件和过程的已知变通方法能用于制备这些化合物。
本发明化合物通常以其可药用盐形式分离,诸如如上所述的那些。相应于分离的盐的作为游离胺的碱可以用适宜的碱中和制得,所述碱诸如碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾水溶液,将释放的作为游离胺的碱用有机溶剂萃取,然后蒸发。通过所述方式分离的作为游离胺的可通过将其溶解于有机溶剂中,然后加入适当的酸,最终蒸发、沉淀或结晶而进一步转化为其它可药用的盐。
通过以下流程和实施例中所述的具体实施方案阐述但不限制本发明。除非在流程中另外说明,否则任何变量具有如上所述的同样意义。
除非另外说明,所有的原料来自商业供应商,且未经进一步纯化地使用。除非另外说明,所有的温度以℃表示,且所有的反应在室温进行。化合物通过二氧化硅色谱或制备型HPLC纯化。
本发明还涉及根据下文所述流程和操作实施例制备式(I)、(II)和(III)的化合物的方法。
具体而言,本发明涉及式(I)化合物的制备方法,其中X是N且Y是NH,且所有其它的取代基具有如对权利要求1中的式(I)所定义的含义,其中将式(IV)的甲酸酯
与式(V)的化合物反应,
得到式(VI)的化合物,
最后,将式(VI)的化合物转化为式(I)的甲酰胺
通用合成方法
流程1
在碱性条件下,芳醛1a与硝基甲烷反应,生成羟基衍生物1b,在乙酸酐促进的去除条件下将羟基衍生物1b转化为烯烃1c。烯烃1c与N-苄基-1-甲氧基-N-((三甲基硅烷基)甲基)甲胺进行环化反应,生成吡咯烷衍生物1d。以拉尼镍为催化剂还原吡咯烷衍生物1d的硝基,然后用N-[2-(三甲基硅烷基)乙氧基羰基氧基]琥珀酰亚胺Teoc保护得到的氨基,生成化合物1f。在加氢条件下去除化合物1f的N-苄基,并用二碳酸二叔丁酯保护,生成化合物1h。化合物1h中的Teoc保护的伯胺经四丁基氟化铵处理后被释放出来,生成化合物1i。
流程2
化合物2a与N-苄基-1-甲氧基-N-((三甲基硅烷基)甲基)甲胺在三氟乙酸存在下偶合,生成吡咯烷衍生物2b。用ACE-Cl除去吡咯烷衍生物2b中的苄基保护基,生成游离的仲胺2c。用二碳酸二叔丁酯处理仲胺2c,再用铟促进还原硝基,得到化合物2e。
流程3
化合物3a与3-氨基-4-芳基吡咯烷偶合,生成化合物3b。化合物3b与氨在甲醇中反应,将化合物3b中的甲酯转化为酰胺3c。用二噁烷中的盐酸处理酰胺3c,去除Boc保护基,得到化合物3d。
流程4
吡咯烷衍生物4a用甲醛和甲酸处理,生成N-甲基吡咯烷4b。用四丁基氟化铵处理后,N-甲基吡咯烷4b中的Teoc保护的伯胺被释放出来,生成化合物4c。
流程5
3-氨基-4-芳基吡咯烷与4-氯喹啉-8-腈5a在碱性条件下反应,生成化合物5b,该化合物水解后得到酰胺5c。接着去除保护基,得到化合物5d。
流程6
化合物6a被保护为氨基甲酸苄酯,得到化合物6b。随后进行酯水解和酰胺偶合,生成化合物6d。氢化反应除去Cbz并与甲基4-氯喹唑啉-8-甲酸酯反应,得到化合物6e。将酯转化为酰胺并去除保护基,得到化合物6h。
流程7
1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯(7a)与碳酸钾进行中和反应,生成化合物7b,它与芳基溴化镁反应后生成化合物7c,是顺式和反式异构体的混合物。用甲醇钠促进差向异构化反应,唯一形成热力学更稳定的反式异构体7d。用ACE-Cl除去甲基,再用甲醇在回流条件下处理,得到化合物7e。用二碳酸二叔丁酯保护胺,再水解酯,生成酸7g。用叠氮磷酸二苯酯(DPPA)对化合物7g进行Curtius重整,再用水淬灭反应,得到化合物7i。
流程8
化合物8a与3-氨基-4-芳基哌啶偶合,生成化合物8b。甲酯与氨在甲醇中进行氨解,再脱保护胺,得到化合物8d。
流程9
将格利雅试剂(grignar reagent)9b加入到1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯中,生成化合物9c,是顺式和反式异构体的混合物。用甲醇钠促进差向异构化反应,唯一形成热力学更稳定的反式异构体9d。用ACE-Cl除去甲基,再用甲醇在回流条件下处理,得到化合物9e。仲胺被保护为氨基甲酸苄酯,再水解酯,生成化合物9h。用叠氮磷酸二苯酯(DPPA)对化合物9h进行Curtius重整,再用叔丁醇淬灭反应,得到Boc保护的哌啶9j。在酸性条件下除去Boc,得到化合物9k,它与4-氯喹唑啉-8-甲酸甲酯偶合,得到化合物9l。甲酯与氨在甲醇中进行氨解反应,再除去Cbz,得到所希望的化合物9n。
流程10
化合物10a用甲醛和甲酸处理,生成N-甲基化合物10b。
流程11
与流程5一样,化合物5a与3-氨基-4-芳基哌啶衍生物偶合,生成化合物11b。水解腈并去除Boc,得到化合物11d。
流程12
以乙酸钾为催化剂,2-双环己基磷-2',6'-二甲氧基联苯(s-phos)为配体,在碱性条件下化合物12a与芳基硼酸偶合,生成化合物12b,除去Boc,得到化合物12c。
分析方法
使用以下三个方法进行分析性LC/MS:
方法A:使用Discovery C18,5μm,3x30mm柱,流速400μL/分钟,进样环5μL,流动相(A)含0.1%甲酸的水,流动相(B)含0.1%甲酸的甲醇;保留时间以分钟计。方法详述:(I)使用Quaternary Pump G1311A(Agilent),备有UV/VIS二极管阵列检测器G1315B(Agilent)和Finnigan LCQ Duo MS检测器(ESI+模式),UV-检测在254和280nm,梯度:15-95%(B)3.2分钟线性梯度,(II)在95%(B)保持1.4分钟,(III)从95-15%(B)0.1分钟线性梯度,(IV)在15%(B)保持2.3分钟。
方法B:使用Waters Symmetry C18,3.5μm,4.6x75mm柱,流速1mL/分钟,进样环10μL,流动相(A)为含0.05%TFA的水,流动相(B)为含0.05%TFA的ACN;保留时间以分钟计。方法详述:(I)使用Binary Pump G1312A(Agilent),备有UV/Vis二极管阵列检测器G1315B(Agilent)和Agilent G1956B(SL)MS检测器(ESI+模式),UV-检测在254和280nm,梯度:20-85%(B)10分钟线性梯度,(II)在85%(B)保持1分钟,(III)从85-20%(B)0.2分钟线性梯度,(IV)在20%(B)保持3.8分钟。
方法C:梯度:4.2分钟/流速:2ml/分钟99∶01-0∶100水+0.1%(体积)TFA;乙腈+0.1%(体积)TFA;0.0至0.2分钟:99∶01;0.2至3.8分钟:99∶01→0∶100;3.8至4.2分钟:0∶100;柱:Chromolith Performance RP18e;长度100mm,直径3mm;波长:220nm。
分析型手性HPLC
使用来自Daicel Chemical Industries,Ltd.的ChiralPak AD-H柱(250X4.6mm)在Agilent1100系列系统进行分析型手性HPLC。该方法使用5.0μL进样体积,流速1mL/分钟,使用100%甲醇在25℃运行15分钟,且UV-检测在254和280nm。
制备型HPLC
使用Waters Atlantis dC18OBD TM10μM(30X250mm)柱或Waters Sunfire Prep C18OBD10μM(30X250mm)柱进行制备型HPLC。所述柱在装备有进样环(10mL)和ISCOUA-6UV/Vis检测器的Waters Prep LC4000System以60mL/分钟的流速使用。流动相从含有(A)水和(B)HPLC-级乙腈的两个溶剂瓶中吸入。通常的制备使用线性梯度(例如,0-60%溶剂B经历60分钟)。
实施例
以下操作实施例旨在阐明本发明的具体实施方案,并不意欲以任何方式限制说明书或权利要求的范围。
化学合成
本节为许多式(I)的实施例化合物及其合成中间体提供实验详细描述。
合成中间体
3-氨基-4-(3-氟苯基)吡咯烷-1-甲酸叔丁酯(1)
1-(3-氟-苯基)-2-硝基-乙醇:
3-氟苯甲醛(21.37ml;201.43mmol;1.00eq.)和硝基甲烷(13.06ml;241.71mmol;1.20eq.)在甲醇(40ml)中的溶液冷却至-10°C。在10分钟内加入NaOH(8.46g;211.50mmol;1.05eq.)在水(20ml)中的溶液,保持温度低于-5°C。反应混合物于-5°C搅拌15min,在此期间反应溶液凝固为白色固体。加热反应混合物至0°C,用水(150ml)稀释。待全部固体溶解后,加入HCl(4M,100ml)。反应混合物用DCM(300ml x2)萃取。合并萃取液,用盐水洗涤,浓缩,得到所希望的中间体(34.8g,得率为93%)。
1-氟-3-((E)-2-硝基-乙烯基)-苯:
0°C下将N,N-二甲基吡啶-4-胺(2.30g;18.80mmol)加入至1-(3-氟苯基)-2-硝基乙醇(34.80g;187.95mmol)在乙酸酐(35.53ml;375.90mmol)中的溶液中,室温搅拌72h。倒入强烈搅拌的饱和NaHCO3溶液(400mL)中,将反应混合物淬火。用乙酸乙酯(3x100mL)萃取所希望的中间体。有机萃取液用饱和NaHCO3溶液、盐水洗涤,硫酸镁干燥,过滤,浓缩,得到所希望的中间体(26.0g,得率为83%)。
反式1-苄基-3-(3-氟-苯基)-4-硝基-吡咯烷:
将N-苄基-1-甲氧基-N-[(三甲基硅烷基)甲基]甲胺加入至1-氟-3-[(E)-2-硝基乙烯基]苯(6.00g;35.90mmol)在DCM(50ml)中的溶液中。冷却反应溶液至0°C,滴加入TFA(0.30ml;3.95mmol),室温搅拌过夜。反应溶液用水和盐水洗涤,硫酸镁干燥,过滤,浓缩。粗物料经Biotage(340g柱)纯化,洗脱液为乙酸乙酯的己烷溶液,得到所希望的产物5.5g,得率为51%)。
反式1-苄基-4-(3-氟-苯基)-吡咯烷-3-基胺:
将反式1-苄基-3-(3-氟苯基)-4-硝基吡咯烷(5.50g;18.31mmol)溶解在甲醇(300mL)中。加入NH3(30ml,2.0M的甲醇溶液),溶液通过H cube柱(流速:1.5min/min,全氢,50°C)。反应溶液浓缩后得到所希望的中间体(4.6g,得率为92%)。LC-MS(M+H=271,obsd=271)。
[反式1-苄基-4-(3-氟-苯基)-吡咯烷-3-基]-氨基甲酸丙酯:
0°C下将1-({[2-(三甲基硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮(4.5g;17.37mmol)加入至反式1-苄基-4-(3-氟苯基)吡咯烷-3-胺(4.5g;16.87mmol)和DIEA(4.5ml;25.30mmol)在DCM(50ml)中的溶液中,加热至室温,室温搅拌1小时。反应溶液用盐水洗涤,硫酸镁干燥,过滤和浓缩。粗物料经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液30至60%梯度,得到所希望的中间体(6.0g,得率为99%)。LC-MS(M+H=415,obsd=415)。
[反式4-(3-氟-苯基)-吡咯烷-3-基]-氨基甲酸丙酯:
将AcOH(2mL)加入至2-(三甲基硅烷基)乙基[反式苄基-4-(3-氟苯基)吡咯烷-3-基]氨基甲酸酯(2.50g;6.03mmol)在乙醇(150ml)中的溶液中。加入Pd/C(1.25g,潮湿,10%Pd),将反应混合物放在Parr振动器(60Psi)中,反应2h。过滤反应混合物,滤液浓缩,得到所希望的产物(1.96g,定量得率)。LC-MS(M+H=325,obsd=325)。
反式3-(3-氟-苯基)-4-丙氧基羰基氨基-吡咯烷-1-甲酸叔丁酯:
将二碳酸二叔丁酯(1.27g;5.82mmol)加入至2-(三甲基硅烷基)乙基[反式4-(3-氟苯基)吡咯烷-3-基]氨基甲酸酯(1.80g;5.55mmol)和DIEA(2.2ml;12.26mmol)在DCM(100ml)中的溶液中,室温搅拌过夜。反应混合物浓缩,粗产物经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液20至60%,得到所希望的中间体(2.0g,得率为85%)。LC-MS(M+H=425,obsd=425)。
1-苄基-4-(3-氟苯基)吡咯烷-3-胺:
反式3-(3-氟苯基)-4-({[2-(三甲基硅烷基)乙氧基]羰基}氨基)-吡咯烷-1-甲酸叔丁酯(2.4g;5.76mmol)和N,N,N-三丁基丁烷-1-氟化铵(20.00ml;1.00M;20.00mmol)溶解在甲醇中,室温搅拌过夜。粗产物经Biotage纯化,洗脱液为甲醇在DCM中的溶液5至10%,得到所希望的产物1(1.61g,得率79%)。LC-MS(M+H=281,obsd=281)。1HNMR(DMSO-d6)δ1.39(s,9H),1.55(s,1H),2.90-2.99(m,2H),3.24-3.26(m,1H),3.33-3.37(m,1H),3.55-3.57(m,1H),3.60-3.68(m,1H),3.70-3.72(m,1H),7.05-7.06(m,1H),7.13-7.15(m,2H),7.35-7.36(m,1H)。
反式外消旋物4-((4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(2)
IC50p70S6K[uM]:0.003
4-((1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酸甲酯:
4-氯喹唑啉-8-甲酸甲酯(80.00mg;0.36mmol)、DIEA(0.13ml;0.72mmol)和外消旋物反式3-氨基-4-(3-氟苯基)吡咯烷-1-甲酸叔丁酯(109mg;0.37mmol)溶解在CH3CN中,室温搅拌过夜。反应混合物浓缩,重溶于甲醇中的NH3(1.50ml;7.00M;10.50mmol)中,室温搅拌72h。反应混合物浓缩,得到所希望的中间体。LC-MS(M+H=452,obsd=452)。
4-((4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺
将在二噁烷中的HCl(1.5ml;4.00M;6.00mmol)加入至3-{[8-(氨基羰基)喹唑啉-4-基]氨基}-4-(3-氟苯基)-吡咯烷-1-甲酸叔丁酯(162mg;0.36mmol)在甲醇(1.5ml)中的溶液中,室温搅拌过夜。得到的沉淀物过滤,用甲醇和醚洗涤,真空干燥,得到产物2(67mg,44%得率),为一种盐酸盐。LC-MS(M+H=352,obsd=352)。1HNMR(DMSO-d6)δ2.86-2.88(m,2H),3.39-3.42(m,2H),4.09-4.11(d,1H),4.81-4.84(m,1H),7.05(t,1H),7.17(t,1H),7.32(q1H),7.62(t,1H),7.81(d,1H),8.52-8.65(m,4H),10.33(d,1H)。
反式外消旋物4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(3)
IC50p70S6K[uM]:0.0049
采用反式外消旋物3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=334,obsd=334)。1HNMR(DMSO-d6)δ3.42-3.45(m,2H),3.78-3.86(m,2H),4.04-4.08(m,1H),5.23(t,1H),7.26-7.32(m,1H),7.32-7.34(m,2H),7.48-7.05(m,2H),7.84(t,1H),8.15(s,1H),8.54(d,1H),8.77(s,1H),8.98(s,1H),9.80(s,2H)。
4-((4-(2-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(4)
IC50p70S6K[uM]:0.0035
采用反式外消旋物3-氨基-4-(2-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=352,obsd=352)。
4-((4-(4-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(5)
IC50p70S6K[uM]:0.0026
采用3-氨基-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=352,obsd=352)。
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(6)
IC50p70S6K[uM]:0.002
采用3-氨基-4-(4-甲氧基苯基)-吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=364,obsd=364)。
4-((4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(7)
IC50p70S6K[uM]:0.0026
采用3-氨基-4-(3-甲氧基苯基)-吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=364,obsd=364)。
4-((4-(2-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(8)
IC50p70S6K[uM]:0.018
采用3-氨基-4-(2-甲氧基苯基)-吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=364,obsd=364)。
反式外消旋物4-((4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(9)
IC50p70S6K[uM]:0.0013
采用反式外消旋物3-氨基-4-(3-氯-苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=368,obsd=368/370)。
反式外消旋物4-((4-(2-氯-6-氟苯基)吡咯烷-3-基)氨基)-喹唑啉-8-甲酰胺(10)
IC50p70S6K[uM]:0.007
采用反式外消旋物3-氨基-4-(2-氯-6-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=386,obsd=386/388)。
反式外消旋物4-((4-(3-溴苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(11)
外消旋物1-苄基-3-(3-溴苯基)-4-硝基吡咯烷
将N-苄基-1-甲氧基-N-[(三甲基硅烷基)甲基]甲胺(5.05g;20.00mmol)加入至1-溴-3-[(E)-2-硝基乙烯基]苯(3.80g;16.66mmol)在DCM(50ml)中的溶液中,冷却至0°C。加入TFA(0.14ml;1.83mmol),室温搅拌反应混合物过夜。反应混合物用水和盐水洗涤,硫酸镁干燥,过滤,浓缩。粗产物经Biotage(100g柱)纯化,洗脱液为5%乙酸乙酯的己烷溶液,得到所希望的中间体。LC-MS(M+H=362,obsd=360/362)。
3-(3-溴苯基)-4-硝基吡咯烷-1-甲酸叔丁酯
将Cs2CO3(0.47g;1.45mmol)和1-氯乙基氯碳酸酯(2.00ml;18.33mmol)加入至(3R,4S)-1-苄基-3-(3-溴苯基)-4-硝基吡咯烷(2.62g;7.25mmol)在DCE(100ml)中的溶液中,80°C搅拌2h。过滤反应混合物,浓缩滤液,残留物重溶于甲醇(100ml)中。反应溶液在60°C搅拌2h,浓缩,得到黄色油。
将上述中间体、DIEA(3.91ml;21.76mmol)和二碳酸二叔丁酯(1.90g;8.70mmol)溶解于DCM(100ml)中,室温搅拌过夜。反应溶液用盐水洗涤,硫酸镁干燥,过滤,浓缩。粗产物经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液10%至20%,得到所希望的中间体(1.11g,得率为41%)。LC-MS(M+H=272,obsd=270/272)。
3-氨基-4-(3-溴苯基)吡咯烷-1-甲酸叔丁酯
3-(3-溴苯基)-4-硝基吡咯烷-1-甲酸叔丁酯(1.10g;2.96mmol)、铟(3.40g;29.63mmol)和氯化铵(1.59g;29.63mmol)溶解于水(70ml)和乙醇(70ml)中,回流4小时。过滤反应混合物,浓缩滤液。得到的残留物用DCM稀释,盐水洗涤,硫酸镁干燥,过滤,并浓缩。LC-MS(M+H=342,obsd=340/342)。
采用上述中间体、反式外消旋物3-氨基-4-(3-溴苯基)吡咯烷-1-叔丁酸酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=413,obsd=413)。
反式外消旋物4-((4-(3-氟苯基)-1-甲基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(12)
IC50p70S6K[uM]:0.023
(4-(3-氟苯基)-1-甲基吡咯烷-3-基)氨基甲酸2-(三甲基硅烷基)乙酯
[4-(3-氟苯基)吡咯烷-3-基]氨基甲酸2-(三甲基硅烷基)乙酯(300.00mg;0.92mmol)、甲酸(0.10ml;2.31mmol)和甲醛(0.09ml;1.11mmol)溶解于乙醇中,80°C搅拌3小时。反应溶液浓缩,得到所希望的中间体。LC-MS(M+H=339,obsd=339)。
4-(3-氟苯基)-1-甲基吡咯烷-3-胺
[4-(3-氟苯基)-1-甲基吡咯烷-3-基]氨基甲酸2-(三甲基硅烷基)乙酯(300.00mg;0.89mmol)和N,N,N-三丁基丁烷-1-氟化铵(5.00ml;1.00M;5.00mmol;5.64eq.)溶解于甲醇中,室温搅拌3h。粗产物经制备型HPLC纯化,得到所希望的中间体(150mg,得率为55%)。LC-MS(M+H=195,obsd=195)。
采用上述中间体、反式外消旋物4-(3-氟苯基)-1-甲基吡咯烷-3-胺和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=366,obsd=366)。
反式外消旋物4-((-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(13)
采用反式外消旋物3-氨基-4-(萘-2-基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=384,obsd=384)。
反式外消旋物4-((4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(14)
采用反式外消旋物3-氨基-4-(萘-1-基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=384,obsd=384)。
6-甲基-4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(15)
IC50p70S6K[nM]:349
采用反式外消旋物3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯和4-氯-6-甲基喹唑啉-8-甲酰胺,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=348,obsd=348)。
2-甲基-4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(16)
IC50p70S6K[uM]:0.006
采用反式外消旋物3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酰胺,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=348,obsd=348)。
4-((4-(4-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(17)
IC50p70S6K[uM]:0.0024
采用3-氨基-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酰胺,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=366,obsd=366)。
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(18)
IC50p70S6K[uM]:0.0018
采用3-氨基-4-(4-甲氧基苯基)吡咯烷-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酰胺,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=378,obsd=378)。
4-((4-(4-氟苯基)-1-甲基吡咯烷-3-基)氨基)喹啉-8-甲酰胺(19)
IC50p70S6K[uM]:0.5
3-(8-氰基-喹啉-4-基氨基)-4-(4-氟-苯基)-吡咯烷-1-甲酸叔丁酯
4-氯喹啉-8-腈(200mg;1.06mmol)、3-氨基-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯(386mg;1.38mmol)和K2CO3(732mg;5.30mmol)溶解在DMF(7mL)中,80-100°C搅拌7天。反应材料经HPLC直接纯化,得到所希望的中间体(50mgs)。LC-MS(M+H=433,obsd=433)。1H NMR(400MHz,DMSO-D6):3.3890(m,2H),3.8405(m,2H),4.1107(m,1H),4.9560(m,1H),6.7967(m,1H),7.1788(t,2H),7.5442(m,2H),7.8425(m,1H),8.2160(s,1H),8.5086(m,2H),8.7933(m,1H),9.1442(d,1H),9.8576(m,1H),9.9730(m,1H),10.0985(m,1H)。
3-((8-氰基喹啉-4-基)氨基)-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯
3-[(8-氰基喹啉-4-基)氨基]-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯(20mg;0.05mmol)和K2CO3(51mg;0.37mmol)溶解在DMSO(5mL)中。滴加入H2O2(179mg;1.85mmol),反应混合物在50°C搅拌过夜。粗产物经制备型HPLC纯化,得到所希望的中间体(35mg)。LC-MS(M+H=451,obsd=451)。
4-((4-(4-氟苯基)-1-甲基吡咯烷-3-基)氨基)喹啉-8-甲酰胺
3-{[8-(氨基羰基)喹啉-4-基]氨基}-4-(4-氟苯基)吡咯烷-1-甲酸叔丁酯(25mg;0.02mmol)溶解在HCl的二噁烷溶液(0.06ml;4.00M;0.22mmol),搅拌30分钟。得到的沉淀物过滤,用醚洗涤,真空干燥,得到化合物14(21mg)。LC-MS(M+H=351,obsd=351)。1H NMR(400MHz,DMSO-D6):3.3890(m,2H),3.8405(m,2H),4.1107(m,1H),4.9560(m,1H),6.7967(m,1H),7.1788(t,2H),7.5442(m,2H),7.8425(m,1H),8.2160(s,1H),8.5086(m,2H),8.7933(m,1H),9.1442(d,1H),9.8576(m,1H),9.9730(m,1H),10.0985(m,1H)。
4-((4-苯基吡咯烷-3-基)氨基)喹啉-8-甲酰胺(20)
采用3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-甲腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=333,obsd=333)。
4-((4-(3-氟苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺(21)
IC50p70S6K[uM]:0.013
采用3-氨基-4-(3-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=351,obsd=351)。
4-((4-(2-氟苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺(22)
IC50p70S6K[uM]:0.0094
采用3-氨基-4-(2-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=351,obsd=351)。
4-((4-(2-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺(23)
IC50p70S6K[uM]:0.046
采用3-氨基-4-(2-甲氧基苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-甲腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=363,obsd=363)。
4-((4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺(24)
采用3-氨基-4-(3-甲氧基苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=363,obsd=363)。
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺(25)
采用3-氨基-4-(4-甲氧基苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹啉-8-腈,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=363,obsd=363)。
反式4-(4-苯基氨甲酰基-吡咯烷-3-基氨基)-喹唑啉-8-甲酸酰胺(26)
IC50p70S6K[uM]:0.022F
(反式)-4-苄基氧基羰基氨基-吡咯烷-1,3-二甲酸1-叔丁酯3-乙酯
(反式)-4-氨基吡咯烷-1,3-二甲酸1-叔丁酯3-乙酯盐酸盐(500mg;1.70mmol)和DIEA(886μl;5.09mmol)溶解在DMF(17ml)中。溶液冷却至0°C,通过注射器滴加氯甲酸苄酯(358;2.54mmol),反应混合物室温搅拌过夜。反应混合物用水稀释,乙酯乙酯(3x10mL)萃取。有机萃取液干燥,二氧化硅浓缩,Biotage(10g柱)纯化,洗脱液为1%甲醇在DCM中的溶液,得到所希望的中间体(600mg,得率为43%)。LC-MS:(M-Boc)+H=293,obsd.=293)。
(反式)-4-苄基氧羰基氨基-吡咯烷-1,3-二甲酸1-叔丁酯
(反式)-4-苄基氧基羰基氨基-吡咯烷-1,3-二甲酸1-叔丁酯3-乙酯(284mg;0.72mmol)溶解在THF(5ml)中,用LiOH(0.72ml;3.00M;2.17mmol)处理。反应混合物室温搅拌2小时。反应混合物用水稀释,用乙酸乙酯洗涤。水层用固体KHSO4酸化并用乙酸乙酯萃取(3x)。有机萃取液用水和盐洗涤,硫酸钠干燥,过滤,浓缩,得到所希望的中间体(定量得率),为白色固体。1H NMR(DMSO):1.39(s,9H),2.93(m,1H),3.07(m,1H),3.51-3.55(m,3H),4.23(m,1H),5.03(s,2H),7.32-7.38(m,5H),7.70(m,1H),12.5(s,1H)。LC-MS:(M–Boc)+H=265,obsd.=265。
(反式)-3-苄基氧基羰基氨基-4-苯基氨甲酰基-吡咯烷-1-甲酸叔丁酯
(反式)-4-苄基氧基羰基氨基-吡咯烷-1,3-二碳酸1-叔丁酯(270mg;0.74mmol)和1-羟基苯并三唑(105mg,0.78mmol)溶解在DMF(5mL)中,搅拌5分钟直至固体完全溶解。加入苯胺(81μl;0.89mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(193mg,1.01mmol),黄色溶液在50°C搅拌90分钟。用水(40mL)和甲醇(5mL)淬灭反应。过滤得到的沉淀物(293mg,得率为90%)。LC-MS:(M–Boc)+H=340,obsd.=340。
1HNMR(DMSO):1.39(s,9H),3.10(m,2H),3.35(m,1H),3.63-3.67(m,2H),4.27(m,1H),5.01-5.04(m,2H),7.04-7.07(t,1H),7.22-7.32(m,7H),7.56-7.58(d,2H),7.72(d,1H),10.03(s,1H)。
4-((反式)-1-叔丁氧基羰基-4-苯基氨甲酰基-吡咯烷-3-基氨基)-喹唑啉-8-甲酸甲酯
(反式)-3-苄基氧基羰基氨基-4-苯基氨甲酰基-吡咯烷-1-甲酸叔丁酯(286mg;0.65mmol)溶解在甲醇(15ml)中。加入10%Pd-C(143mg),反应混合物室温和氢气气氛(气球)下搅拌过夜。经硅藻土过滤反应混合物,浓缩。
将上面获得的粗原料、4-氯喹唑啉-8-甲酸甲酯(138mg;0.65mmol)和DIEA(325;1.87mmol)溶解在THF(5ml)中,60°C搅拌4天。反应混合物浓缩,经制备型HPLC纯化,得到所希望的中间体(300mg,两步的得率为80%),为白色固体。LC-MS:M+H=492,obsd.=492。1HNMR(in DMSO):1.43(s,9H),3.43-3.51(m,3H),3.87-3.91(m,2H),5.17(d,1H),7.03-7,06(t,1H),7.28-7.30(t,2H),7,53-7.55(d,2H),7.83(t,1H),8.08(s,1H),8.55-8.57(d,1H),8.69(d,1H),8.76(s,1H),9.00-9.90(s,2H),10.1(s,1H)。
4-((反式)-4-苯基氨甲酰基-吡咯烷-3-基氨基)-喹唑啉-8-甲酰胺
4-((反式)-1-叔丁氧基羰基-4-苯基氨甲酰基-吡咯烷-3-基氨基)-喹唑啉-8-甲酸甲酯(290mg;0.48mmol)溶解在iPrOH(2ml)、DMSO(4ml)和氢氧化铵(4ml)中,70°C搅拌过夜。部分浓缩反应混合物,用水稀释,乙酸乙酯(3x)萃取。有机萃取液用1N NaOH和盐水洗涤,硫酸钠干燥,过滤,浓缩。粗物料经制备型HPLC纯化。
将上述纯化的物料(153mg;0.26mmol)溶解在二噁烷(3mL)和4.0M HCl的二噁烷溶液(3mL),室温搅拌90min。反应混合物浓缩,用甲醇(2x)洗涤,得到化合物26(114mg,得率为98%),为白色固体。LC-MS:M+H=377,obsd.=377。1HNMR(in DMSO):3.39-3.87(m,5H),5.21(t,1H),7.05-7.08(t,1H),7.29-7.32(t,2H),7.58-7.63(d,2H),7.84(t,1H),8.10(s,1H),8.58(d,1H),8.77(s,1H),9.07(s,1H),9.54(s,1H),9.66(s,1H),10.6(s,1H)。
反式外消旋物4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(27)
IC50p70S6K[uM]:0.0063
3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-苯基哌啶-1-甲酸叔丁酯
4-氯喹唑啉-8-甲酸甲酯(750mg;3.37mmol)、DIEA(1.21ml;6.74mmol)和反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯(959.00mg;3.47mmol)溶解在CH3CN(5mL)中,45°C搅拌72h。反应混合物浓缩。
将上面获得的粗残留物溶解在甲醇中的氨(4.8ml;7.00M;33.69mmol)中,60°C搅拌过夜。反应混合物浓缩,重溶于HCl的甲醇溶液(5.00ml;4.00M;20.00mmol)中,室温搅拌过夜。过滤反应混合物,沉淀物用甲醇和醚洗涤,得到化合物27(1000mg,得率为81%)。LC-MS(M+H=421,obsd=348)。1HNMR(DMSC-d6)δ1.69-1.70(m,1H),1.79(d,1H),2.50-2.51(m,1H),3.00-3.03(m,2H),3.18(d,1H),4.62-4.66(m,1H)。7.05(t,1H),7.16(t,2H),7.299t,2H),7.54(t,1H),7.78(d,1H),8.15(d,1H),8.30(d,1H),8.47-8.499d,2H)。
反式外消旋物4-((4-(3-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(28)
IC50p70S6K[uM]:0.0018
采用反式3-氨基-4-(3-氟苯基)哌啶-1-甲酸甲酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=366,obsd=366)。
顺式外消旋物4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(29)
采用顺式外消旋物3-氨基-4-苯基哌啶-1-甲酸甲酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=348,obsd=348)。1HNMR(DMSC-d6)δ1.98-2.20(d,1H),2.60-2.70(m,1H),3.50-3.56(m,4H),5.34(d,1H),6.91(t,1H),7.14-7.21(m,3H),7.76(t,1H),7.98(s,1H),8.52-8.55(m,3H),8.72(d,1H),9.169d,1H)。
反式外消旋物4-((4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(30)
IC50p70S6K[uM]:0.0021
采用反式外消旋物3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=416,obsd=416)。
反式外消旋物4-((4-(间甲苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(31)
IC50p70S6K[uM]:0.0031
采用反式外消旋物3-氨基-4-(间甲苯基)哌啶-1-甲酸甲酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=362,obsd=362)。
反式外消旋物4-((4-(4-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(32)
IC50p70S6K[uM]:0.0032
采用反式外消旋物3-氨基-4-(4-氟苯基)哌啶-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=366,obsd=366)。
反式外消旋物3-氨基-4-(4-氯苯基)哌啶-1-甲酸叔丁酯(33)
1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯.
K2CO3(50g;361.78mmol)溶解在1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯氢溴酸盐(50g;211.77mmol)在水(50ml)和DCM(250ml)中的溶液中,室温搅拌30分钟。分离出有机层,用盐水洗涤,硫酸镁干燥,过滤,浓缩,得到所希望的中间体(34g,定量得率)。
4-(4-氯苯基)-1-甲基哌啶-3-甲酸甲酯.
-10°C下于45分钟内将溴(4-氯苯基)镁(47ml;1.00M;47.27mmol)加入至1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯(5.24g;33.76mmol)在醚(150ml)中的溶液中。反应混合物搅拌20min,用饱和NH4Cl溶液淬灭反应。有机层用盐水洗涤,硫酸镁干燥,过滤,浓缩。粗产物经Biotage纯化,洗涤液为含4%TEA的乙酸乙酯的己烷溶液20至60%梯度,得到所希望的中间体,为顺式和反式异构体的混合物(2.8g)。
反式外消旋物4-(4-氯苯基)-1-甲基哌啶-3-甲酸甲酯
将甲醇钠(4.3g;19.83mmol)加入至4-(4-氯苯基)-1-甲基哌啶-3-甲酸甲酯(5.3g;19.83mmol)在甲醇(100ml)中的溶液中,60°C搅拌6h。反应混合物浓缩,残留物用乙酸乙酯(100ml)稀释,饱和NH4Cl溶液和盐水洗涤,硫酸镁干燥,过滤,浓缩,得到所希望的反式中间体(4.9g,得率为92%)。1HNMR(DMSO-d6)δ1.91(m,1H),2.20-2.22(m,1H),2.78(s,3H)2.99-3.01(m,1H0,3.06-3.25(m,2H),3.31-3.52(m,2H),3.36(s,1H),7.22(d,2H),7.43(d,2H)。
反式外消旋物3-甲基4-(4-氯苯基)哌啶-1,3-二甲酸酯1-叔丁酯
将Cs2CO3(1.19g;3.65mmol)加入至反式外消旋物4-(4-氯苯基)-1-甲基哌啶-3-甲酸甲酯(4.89g;18.26mmol)在DCE(100ml)中的溶液中。滴加入1-氯乙基氯碳酸酯(2.99ml;27.39mmol),反应混合物在80°C搅拌1h。浓缩反应混合物,残留物重溶于甲醇(100ml)中,60°C搅拌2h。反应混合物浓缩,残留物重溶于DCM(100ml)中。加入DIEA(9.84ml;54.79mmol)和二碳酸二叔丁酯(4.78g;21.92mmol),反应混合物室温搅拌过夜。反应溶液用盐水洗涤,硫酸钠干燥,过滤,浓缩。粗物料经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液10至25%梯度,得到所希望的中间体(4.8g,得率为74%)。LC-MS(M+H=354,obsd=354)。
反式外消旋物1-(叔丁氧基羰基)-4-(4-氯苯基)哌啶-3-甲酸
3-甲基4-(4-氯苯基)哌啶-1,3-二甲酸酯1-叔丁酯(4.80g;13.57mmol)和LiOH(0.97g;40.70mmol)溶解在THF(20ml)和水(20ml)中,40°C搅拌过夜。加入乙酸调pH至5。产物用DCM萃取,盐水洗涤,硫酸镁干燥,过滤,浓缩,得到所希望的中间体(3.66g,得率为79%)。MS[240,断片,M+1minus C(O)-O-t-Bu]。
反式外消旋物3-氨基-4-(4-氯苯基)哌啶-1-甲酸叔丁酯
1-(叔丁氧基羰基)-4-(4-氯苯基)哌啶-3-甲酸(1.4g;4.12mmol)、叠氮磷酸二苯酯(1.10ml;4.94mmol)和TEA(1.74ml;12.36mmol)溶解在DCE(5ml)中,室温搅拌3h。反应混合物用甲苯稀释,盐水洗涤,硫酸镁干燥,过滤,浓缩。残留物重溶于甲苯(10ml)中,回流加热5h。反应混合物冷却至室温,加入水(445mg;24.72mmol),反应混合物再次回流加热12h。反应混合物浓缩,粗物料经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液20至60%梯度,得到化合物33(577mg)。LC-MS(M+H=311,obsd=255和小311)。
反式外消旋物3-氨基-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯(34)
4-(3-氟-4-甲基苯基)-1-甲基哌啶-3-甲酸甲酯
20分钟内将4-溴-2-氟-1-甲基苯(3.70g;20mmol)在醚(25mL)中的溶液滴加入至Mg(0.49g;20.75mmol)在醚(20ml)中的悬液中,保持轻轻的回流,反应混合物室温搅拌2h。将反应混合物冷却至-10°C,15分钟内滴加入1-甲基-1,2,5,6-四氢吡啶-3-甲酸甲酯(1.90g;10mmol)在醚(20ml)中的溶液中,反应混合物搅拌1h。用饱和NH4Cl水溶液(35ml)淬灭反应混合物并用乙酸乙酯(50mL)稀释。分离出有机层,用NH4Cl和盐水洗涤,硫酸钠干燥,浓缩。粗物料经Biotage纯化,洗脱液为含4%TEA的乙酸乙酯的己烷溶液30至50%梯度,得到所希望的产物(2.0g,得率为62%),为顺式和反式异构体的混合物。LC-MS(M+H=311,obsd=266)。
反式外消旋物4-(3-氟-4-甲基苯基)-1-甲基哌啶-3-甲酸甲酯
将甲醇钠(1.6g;7.54mmol)加入至4-(3-氟-4-甲基苯基)-1-甲基哌啶-3-甲酸甲酯(2.0g;7.54mmol)在甲醇(30ml)中的溶液中,60°C搅拌4小时。反应混合物浓缩,得到所希望的中间体(1.64g,得率为82%)。
反式外消旋物1-苄基3-甲基4-(3-氟-4-甲基苯基)哌啶-1,3-二甲酸1-苄酯
将Cs2CO3(0.40g;1.23mmol)加入至反式外消旋物4-(3-氟-4-甲基苯基)-1-甲基哌啶-3-甲酸甲酯(1.64g,6.17mmol)在DCE(100ml)中的溶液中。滴加入1-氯乙基氯碳酸酯(0.71ml;6.48mmol),反应混合物80°C搅拌1h。反应混合物浓缩,重溶于甲醇(100ml)中,60°C搅拌过夜。反应混合物浓缩,残留物溶解在DCM(100ml)中,加入DIEA(2.22ml;12.34mmol)和1-{[(苄基氧基)羰基]氧基}吡咯烷-2,5-二酮(1.61g;6.48mmol),反应混合物室温搅拌3h。反应混合物用盐水洗涤,硫酸钠干燥,过滤,浓缩。粗物料经Biotage纯化,洗脱液为20%乙酸乙酯的己烷溶液,得到所希望的中间体(1.2g,两步的得率为50%)。LC-MS(M+H=386,obsd=386)。
反式外消旋物1-((苄基氧基)羰基)-4-(3-氟-4-甲基苯基)哌啶-3-甲酸
3-甲基4-(3-氟-4-甲基苯基)哌啶-1,3-二甲酸1-苄酯(1.20g;3.11mmol)和LiOH(0.22g;9.34mmol)溶解在水(5ml)和THF(5ml)中,40°C搅拌过夜。加入乙酸调pH至5。产物用DCM(50ml x2)萃取。合并的有机萃取液经硫酸钠干燥,过滤,浓缩。粗物料经Biotage纯化,洗脱液为乙酸乙酯的己烷溶液20至50%梯度,得到所希望的中间体(0.8g,得率为70%)。LC-MS(M+H=372,obsd=372)。
反式外消旋物3-氨基-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯
1-[(苄基氧基)羰基]-4-(3-氟-4-甲基苯基)哌啶-3-甲酸(457.00mg;1.23mmol)和TEA(0.52ml;3.69mmol)溶解在DCE(5ml)中。加入叠氮磷酸二苯酯((0.33ml;1.48mmol),反应混合物室温搅拌3h。反应溶液用甲苯稀释,NaHCO3和盐水洗涤,硫酸镁干燥,过滤,浓缩。残留物重溶于甲苯(5ml)中,110°C搅拌4h。加入2-甲基丙-2-醇(0.33ml;3.69mmol),溶液搅拌过夜。反应混合物浓缩,残留物重溶于甲醇(3ml)中,加入HCl的二噁烷溶液(3.00ml;4.00M;12.00mmol),反应混合物室温搅拌2h。反应混合物浓缩,醚中研磨,过滤,得到化合物34(240mg,得率为47%)。LC-MS(M+H=415,obsd=343)。1HNMR(DMSC-d6)δ1.68-1.73(m,1H),2.21(s,1H),2.84-2.88(m,3H),3.35-3.39(m,1H0<3.56(3.63(m,2H),4.07(d,1H),4.48(d,1H),5.11(s,2H),7.09(d,1H),7.18-7.26(m,2H)7.39-7.41(m,5H),7.98(s,2H)。
反式外消旋物苄基3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-(3-氟-4-甲基苯基)哌啶-1-甲 酸酯(35)
IC50p70S6K[nM]:1000
4-氯喹唑啉-8-甲酸甲酯(120mg;0.54mmol)、DIEA(0.39ml;2.16mmol)和反式外消旋物3-氨基-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯二盐酸盐(230mg;0.56mmol)溶解在CH3CN中,40°C搅拌72h。反应混合物浓缩,重溶于甲醇中的氨(0.77ml;7.00M;5.39mmol),45°C搅拌过夜。反应混合物浓缩,粗产物经制备型HPLC纯化,得到化合物35(150mg,得率为54%)。LC-MS(M+H=514,obsd=514)。
反式外消旋物4-((4-(3-氟-4-甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(36)
3-{[8-(氨基羰基)喹唑啉-4-基]氨基}-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯(23mg;0.04mmol)溶解在乙醇(1.5ml)中,加入氨处理过的蚁酸(28mg;0.45mmol)和Pd(OH)2(30mg;0.02mmol;50%湿度),反应混合物60°C搅拌20min。粗产物用制备型HPLC直接纯化,得到化合物36。LC-MS(M+H=380,obsd=380)。1HNMR(DMSO-d6)δ2.09(s,3H),2.21(m,1H),3.13-3.24(m,2H),3.52-3.59(d,1H),3.72-2.77(d,1H),4.86-4.90(m,2H),5.20-5.25(m,1H),7.01-7.07(m,3H),7.68(t,1H),8.26-8.29(d,1H),8.54-8.56(d,1H),8.65(s,1H)。
反式外消旋物4-((4-(3-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(37)
IC50p70S6K[nM]:2.5
采用反式外消旋物3-氨基-4-(3-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酰胺,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=380,obsd=380)。
反式外消旋物2-乙基-4-((4-(3-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(38)
IC50p70S6K[uM]:0.0017
采用反式外消旋物3-氨基-4-(3-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酰胺,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=394,obsd=394)。
反式外消旋物2-乙基-4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(39)
IC50p70S6K[uM]:0.0048
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酰胺,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=376,obsd=376)。
反式外消旋物2-甲基-4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(40)
IC50p70S6K[uM]:0.0064
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酰胺,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=362,obsd=362)。
反式外消旋物4-((4-苯基哌啶-3-基)氨基)喹啉-8-甲酰胺(41)
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-8-氰基喹啉-3-甲酸乙酯,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=347,obsd=347)。
反式外消旋物8-氨甲酰基-4-(4-苯基哌啶-3-基)氨基)喹啉-3-甲酸乙酯(42)
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-8-氰基喹啉-3-乙酯,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=419,obsd=419)。
反式外消旋物8-氨甲酰基-4-((4-苯基哌啶-3-基)氨基)喹啉-3-甲酸(43)
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-8-氰基喹啉-3-甲酸,依据实施例化合物19的方法合成标题化合物。LC-MS(M+H=391,obsd=391)。
反式外消旋物4-(3-氟-4-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(44)
采用3-氨基-4-(3-氟-4-甲基苯基)吡咯烷-1-甲酸叔丁酯(外消旋物反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=365,obsd=365)。
反式外消旋物4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(45)
IC50p70S6K[nM]:1.9
采用3-氨基-4-(3-氟-5-(三氟甲基)苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=419,obsd=419)。
4-(((3S,4R)-4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(46)
IC50p70S6K[nM]:2.6
通过手性色谱法从4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=419,obsd=419)。
4-(((3R,4S)-4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(47)
IC50p70S6K[nM]:160
通过手性色谱法从4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=419,obsd=419)。
反式外消旋物4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(48)
IC50p70S6K[nM]:1.7
采用3-氨基-4-(3-(三氟甲基)苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=402,obsd=402)。
4-(((3S,4R)-4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(49)
IC50p70S6K[nM]:60
通过手性色谱法从4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=402,obsd=402)。
4-(((3R,4S)-4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(50)
IC50p70S6K[nM]:3
通过手性色谱法从4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=402,obsd=402)。
顺式外消旋物4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(51)
采用3-氨基-4-(3-(三氟甲基)苯基)吡咯烷-1-甲酸叔丁酯(顺式_外消旋物)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=402,obsd=402)。
反式外消旋物4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(52)
IC50p70S6K[nM]:6.5
采用3-氨基-4-(4-(三氟甲基)苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=402,obsd=402)。
4-(((3R,4S)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(53)
IC50p70S6K[nM]:66
通过手性色谱法从4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=402,obsd=402)。
4-(((3R,4R)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(54)
IC50p70S6K[nM]:1.3
通过手性色谱法从4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=402,obsd=402)。
顺式外消旋物4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(55)
IC50p70S6K[nM]:9.0
采用3-氨基-4-(3-(三氟甲氧基)苯基)吡咯烷-1-甲酸叔丁酯(顺式-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=418,obsd=418)。
反式外消旋物4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(56)
IC50p70S6K[nM]:2.4
采用3-氨基-4-(3-(三氟甲氧基)苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=418,obsd=418)。
4-(((3R,4S)-4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺)(57)
IC50p70S6K[nM]:2.1
通过手性色谱法从4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=418,obsd=418)。
4-(((3R,4R)-4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(58)
IC50p70S6K[nM]:0.98
通过手性色谱法从4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=418,obsd=418)。
反式外消旋物4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(59)
IC50p70S6K[nM]:1.7
采用3-氨基-4-(4-(三氟甲氧基)苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=418,obsd=418)。
4-(((3R,4S)-4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(60)
IC50p70S6K[nM]:120
通过手性色谱法从4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=418,obsd=418)
4-(((3S,4R)-4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(61)
IC50p70S6K[nM]:1.5
通过手性色谱法从4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=418,obsd=418)。
4-(((3S,4R)-4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(62)
IC50p70S6K[nM]:1.5
通过手性色谱法从4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=382,obsd=382)。
4-(((3R,4S)-4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(63)
IC50p70S6K[nM]:810
通过手性色谱法从4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=382,obsd=382)。
4-(((3R,4S)-4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(64)
通过手性色谱法从4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=367,obsd=367)。
4-(((3R,4S)-4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(65)
IC50p70S6K[nM]:340
通过手性色谱法从4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=367,obsd=367)。
4-(((3S,4R)-4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(66)
IC50p70S6K[nM]:1.4
通过手性色谱法从4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=367,obsd=367)。
4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(67)
IC50p70S6K[nM]:1.54
通过手性色谱法从4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=352,obsd=352)。
4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(68)
IC50p70S6K[nM]:48
通过手性色谱法从4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=352,obsd=352)。
反式外消旋物4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(69)
IC50p70S6K[nM]:3.2
采用3-氨基-4-(喹啉-6-基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=385,obsd=385)。
4-(((3R,4S)-4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(70)
IC50p70S6K[nM]:3.3
通过手性色谱法从4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(反式_外消旋物)分离出标题化合物。LC-MS(M+1=385,obsd=385)。
4-(((3S,4R)-4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(71)
IC50p70S6K[nM]:62
通过手性色谱法从4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=385,obsd=385)。
4-(((3R,4S)-4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(72)
IC50p70S6K[nM]:360
通过手性色谱法从反式外消旋物4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=364,obsd=364)。
4-(((3S,4R)-4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(73)
IC50p70S6K[nM]:6.4
通过手性色谱法从反式外消旋物4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=364,obsd=364)。
反式外消旋物4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(74)
IC50p70S6K[nM]:8.8
采用3-氨基-4-(4-氟-3-甲基苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3R,4S)-4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(75)
IC50p70S6K[nM]:64
通过手性色谱法从反式外消旋物4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3S,4R)-4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(76)
IC50p70S6K[nM]:3.4
通过手性色谱法从反式外消旋物4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
反式外消旋物4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(77)
采用3-氨基-4-(萘-1-基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=384,obsd=384)。
4-(((3R,4S)-4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(78)
通过手性色谱法从反式外消旋物4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=384,obsd=384)。
4-(((3S,4R)-4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(79)
IC50p70S6K[nM]:1.2
通过手性色谱法从反式外消旋物4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=384,obsd=384)。
4-(((3R,4S)-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(80)
IC50p70S6K[nM]:24
通过手性色谱法从反式外消旋物4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=384,obsd=384)。
4-(((3S,4R)-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(81)
通过手性色谱法从反式外消旋物4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=384,obsd=384)。
反式外消旋物4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(82)
采用3-氨基-4-(3-氟苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(83)
IC50p70S6K[nM]:160
通过手性色谱法从反式外消旋物4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(84)
IC50p70S6K[nM]:1.7
通过手性色谱法从反式外消旋物4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
反式外消旋物4-(3-溴苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(85)
IC50p70S6K[nM]:1.8
采用3-氨基-4-(3-溴苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=411/413,obsd=411/413)。
顺式外消旋物4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(86)
IC50p70S6K[nM]:14
采用3-氨基-4-(3-氰基苯基)吡咯烷-1-甲酸叔丁酯(顺式_外消旋物)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=359,obsd=359)。
4-(((3R,4S)-4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(87)
IC50p70S6K[nM]:81
通过手性色谱法从反式外消旋物4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=359,obsd=359)。
4-(((3S,4R)-4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(88)
IC50p70S6K[nM]:2.4
通过手性色谱法从反式外消旋物4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=359,obsd=359)。
反式外消旋物4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(89)
IC50p70S6K[nM]:3.2
采用3-氨基-4-(2,3-二氢苯并呋喃-5-基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=376,obsd=376)。
4-(((3R,4S)-4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(90)
IC50p70S6K[nM]:4
通过手性色谱法从反式外消旋物4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=376,obsd=376)。
4-(((3S,4R)-4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(91)
IC50p70S6K[nM]:53
通过手性色谱法从反式外消旋物4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=376,obsd=376)。
反式外消旋物4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(92)
IC50p70S6K[nM]:2
采用3-氨基-4-(3-氟-2-甲基苯基)吡咯烷-1-甲酸叔丁酯(外消旋物-反式)和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3R,4S)-4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(93)
IC50p70S6K[nM]:1.2
通过手性色谱法从反式外消旋物4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3S,4R)-4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(94)
IC50p70S6K[nM]:52
通过手性色谱法从反式外消旋物4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=366,obsd=366)。
4-(((3R,4S)-4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(95)
IC50p70S6K[nM]:48
通过手性色谱法从反式外消旋物4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=367,obsd=367)。
4-(((3S,4R)-4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(96)
IC50p70S6K[nM]:4.1
通过手性色谱法从反式外消旋物4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=364,obsd=364)。
4-(((3R,4S)-4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(97)
IC50p70S6K[nM]:81
通过手性色谱法从反式外消旋物4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=364,obsd=364)。
反式外消旋物2-氯苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(98)
IC50p70S6K[nM]:2.7
采用3-氨基-4-(2-氯苯基)吡咯烷-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=381,obsd=381)。
反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(99)
IC50p70S6K[nM]:.088
采用3-氨基-4-(4-氯-3-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=314,obsd=314)。
反式外消旋物4-(3-氯-4-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(100)
IC50p70S6K[nM]:1.4
采用3-氨基-4-(3-氯-4-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=314,obsd=314)。
4-(((3S,4R)-4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(101)
IC50p70S6K[nM]:1.1
通过手性色谱法从反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=314,obsd=314)。
反式外消旋物4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(102)
IC50p70S6K[nM]:2.9
采用3-氨基-4-(3-氟-4-甲氧基苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=311,obsd=311)。
反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(103)
IC50p70S6K[nM]:1.8
采用3-氨基-4-(4-氯-3-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=401,obsd=401)。
反式外消旋物2-乙基-4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(104)
通过手性色谱法从反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)-2-乙基喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=380,obsd=380)。
反式外消旋物4-(((3R,4S)-4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(105)
IC50p70S6K[nM]:420
通过手性色谱法从反式外消旋物4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=388,obsd=388)。
4-(((3S,4R)-4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(106)
IC50p70S6K[nM]:2.8
通过手性色谱法从反式外消旋物4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=388,obsd=388)。
反式外消旋物2-乙基-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(107)
IC50p70S6K[nM]:5.5
采用3-氨基-4-(3-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=380,obsd=380)。
2-乙基-4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(108)
通过手性色谱法从反式外消旋物2-乙基-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=380,obsd=380)。
反式外消旋物4-(3-氯-2-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(109)
IC50p70S6K[nM]:2.1
采用3-氨基-4-(3-氯-2-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=385,obsd=385)。
反式外消旋物4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(110)
IC50p70S6K[nM]:1.54
采用3-氨基-4-(萘-2-基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=384,obsd=384)。
反式外消旋物4-(4-(甲基磺酰基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(111)
IC50p70S6K[nM]:7.5
采用3-氨基-4-(4-(甲基磺酰基)苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=412,obsd=412)。
4-(((3R,4S)-4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(112)
IC50p70S6K[nM]:330
通过手性色谱法从反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=385,obsd=385)。
反式外消旋物4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)-2-乙基喹唑啉-8-甲酰胺(113)
采用3-氨基-4-(4-氯-3-氟苯基)吡咯烷-1-甲酸丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=413,obsd=413)。
反式外消旋物4-(3-氯-5-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(114)
IC50p70S6K[nM]:1.5
采用3-氨基-4-(3-氯-5-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=385,obsd=385)。
反式外消旋物6-氟-4-(((3R,4S)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲 酰胺(115)
采用3-氨基-4-(3-氯-5-氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯-6-氟喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=420,obsd=420)。
反式外消旋物4-(2,3-二氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(116)
IC50p70S6K[nM]:4.1
采用3-氨基-4-(2,3-二氟苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=370,obsd=370)。
反式外消旋物4-(((3R,4S)-4-(3-(吡咯烷-1-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰 胺(117)
IC50p70S6K[nM]:5.9
采用3-氨基-4-(3-(吡咯烷-1-基)苯基)吡咯烷-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+1=403,obsd=403)。
反式外消旋物4-([1,1'-联苯基]-3-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(118)
将3-[8-(氨基羰基)喹唑啉-4-基]氨基-4-(3-溴苯基)吡咯烷-1-甲酸酯(反式外消旋物)(15.00mg;0.03mmol;1.00eq.)、苯基硼酸(10.71mg;0.09mmol;3.00eq.)、二乙酸钯(2+)(3.94mg;0.02mmol;0.60eq.)、二环己基(2',6'-二甲氧基联苯基-2-基)膦(12.02mg;0.03mmol;1.00eq.)和碳酸氢钾(12.14mg;0.09mmol;3.00eq.)在二噁烷1ml和水0.1ml中的反应混合物放在5ml微波管内,在120°C下接受微波加热20min。
LC-MS显示转化反应完成。
过滤以移除溶剂中的滤渣,将残留物加入甲醇1ml,再加入氯化氢(1.00ml;4.00M;4.00mmol;136.64eq.)1ml,搅拌2h。
lc-MS显示所希望的产物。经HPLC纯化后,收集所希望的产物。LC-MS(M+1=411,obsd=411)。
反式外消旋物4-(4-氟-3-(吡啶-3-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(119)
IC50p70S6K[nM]:15
采用3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-(3-氯-4-氟苯基)吡咯烷-1-甲酸叔丁酯(反式_外消旋物)与吡啶-3-基硼酸偶合,再去除boc基团,依据实施例化合物118的方法合成标题化合物。LC-MS(M+1=429,obsd=429)。
反式外消旋物4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(120)
IC50p70S6K[nM]:1.4
采用3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-(4-氯-3-氟苯基)吡咯烷-1-甲酸叔丁酯(反式_外消旋物)与苯基硼酸偶合,再去除boc基团,依据实施例化合物118的方法合成标题化合物。LC-MS(M+1=428,obsd=428)。
反式外消旋物4-(3-氟-4-(吡啶-3-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(121)
IC50p70S6K[nM]:6.0
采用3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-(4-氯-3-氟苯基)吡咯烷-1-甲酸叔丁酯(反式_外消旋物)与吡啶-3-基硼酸偶合,再去除boc基团,依据实施例化合物118的方法合成标题化合物。LC-MS(M+1=429,obsd=429)。
反式外消旋物2-乙基-4-((4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(122)
采用反式外消旋物3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=444,obsd=444)。
反式外消旋物4-(3,5-二氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(123)
IC50p70S6K[nM]:2.3
采用反式外消旋物3-氨基-4-(3,5-二氟苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=444,obsd=444)。
反式外消旋物1-甲基-4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(124)
IC50p70S6K[nM]:22
4-[苯基哌啶-3-基]氨基喹唑啉-8-甲酰胺三氟乙酸酯(反式_外消旋物)(21.00mg;0.05mmol;1.00eq.)、甲酸(0.01ml;0.11mmol;2.50eq.)和甲醛(0.00ml;0.05mmol;1.20eq.)在乙醇中的混合物于80°C搅拌3hr。LC-MS显示干净的所希望的产物。
冻干后收集所希望的产物。LC-MS(M+H=408,obsd=408)。
反式外消旋物2-乙基-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(125)
IC50p70S6K[nM]:3.9
采用反式_外消旋物3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=444,obsd=444)。
反式外消旋物4-(3-甲氧基苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(126)
IC50p70S6K[nM]:4.5
采用反式外消旋物3-氨基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=392,obsd=392)。
反式外消旋物4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(127)
IC50p70S6K[nM]:2.0
采用反式外消旋物3-氨基-4-(4-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=416,obsd=416)。
4-(((3S,4S)-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺)(128)
IC50p70S6K[nM]:230
通过手性色谱法从反式外消旋物4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+H=416,obsd=416)。
4-(((3R,4R)-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(129)
IC50p70S6K[nM]:1.2
通过手性色谱法从反式外消旋物4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+H=416,obsd=416)。
4-(((3R,4R)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(130)
IC50p70S6K[nM]:1.2
通过手性色谱法从反式外消旋物4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+H=416,obsd=416)。
4-(((3S,4S)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(131)
IC50p70S6K[nM]:160
通过手性色谱法从反式外消旋物4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+H=416,obsd=416)。
反式外消旋物4-(4-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(132)
IC50p70S6K[nM]:5.4
采用反式外消旋物3-氨基-4-(4-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=380,obsd=380)。
反式外消旋物2-乙基-4-(4-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(133)
IC50p70S6K[nM]:3.6
采用反式外消旋物3-氨基-4-(4-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=394,obsd=394)。
反式外消旋物4-(4-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(134)
IC50p70S6K[nM]:4.2
采用反式外消旋物3-氨基-4-(4-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2甲基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=380,obsd=380)。
反式外消旋物4-(3-甲氧基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(135)
IC50p70S6K[nM]:4.3
采用反式外消旋物3-氨基-4-(3-甲氧基苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=378,obsd=378)。
反式外消旋物4-(2-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺(136)
IC50p70S6K[nM]:210
采用反式外消旋物3-氨基-4-(2-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=380,obsd=380)。
反式外消旋物4-(3-氟-4-甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(137)
采用反式外消旋物3-氨基-4-(3-氟-4-甲基苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=380,obsd=380)。
反式外消旋物2-甲基-4-(((3R,4R)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲 酰胺(138)
IC50p70S6K[nM]:2.7
采用反式外消旋物3-氨基-4-(3-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=430,obsd=431)。
反式外消旋物4-(3,4-二甲氧基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(139)
IC50p70S6K[nM]:18
采用反式外消旋物3-氨基-4-(3,4-二甲氧基苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=408,obsd=408)。
反式外消旋物4-(3-氟-5-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(140)
IC50p70S6K[nM]:3.1
采用反式外消旋物3-氨基-4-(3-氟-5-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=434,obsd=434)。
反式外消旋物2-甲基-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(141)
IC50p70S6K[nM]:2.9
采用反式外消旋物3-氨基-4-(4-(三氟甲基)苯基)哌啶-1-甲酸叔丁酯和4-氯-2-甲基喹唑啉-8-甲酸甲酯,依据实施例化合物2的方法合成标题化合物。LC-MS(M+H=430,obsd=430)。
反式外消旋物2-乙基-4-(2-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺
(142)IC50p70S6K[nM]:450
采用反式外消旋物3-氨基-4-(2-氟苯基)哌啶-1-甲酸叔丁酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=394,obsd=394)。
反式外消旋物4-(4-氯苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(143)
采用反式外消旋物3-氨基-4-(4-氯苯基)哌啶-1-甲酸叔丁酯和4-氯-喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=381,obsd=381)。
反式外消旋物2-乙基-4-(间甲苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(144)
IC50p70S6K[nM]:5.0
采用反式外消旋物3-氨基-4-(间甲苯基)哌啶-1-甲酸甲酯和4-氯-2-乙基喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=390,obsd=390)。
反式外消旋物4-((4-(3,5-二甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺(145)
IC50p70S6K[nM]:10
采用反式外消旋物3-氨基-4-(3,5-二甲基苯基)哌啶-1-甲酸叔丁酯和4-氯喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=376,obsd=376)。
反式外消旋物6-氟-4-(((3R,4R)-4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺(146)
IC50p70S6K[nM]:7.1
采用反式外消旋物3-氨基-4-苯基哌啶-1-甲酸叔丁酯和4-氯-6-氟喹唑啉-8-甲酸甲酯,依据实施例化合物27的方法合成标题化合物。LC-MS(M+H=366,obsd=366)。
4-(((3R,4S)-4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(147)
通过手性色谱法从反式外消旋物4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=428,obsd=428)。
4-(((3S,4R)-4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺(148)
通过手性色谱法从反式外消旋物4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺分离出标题化合物。LC-MS(M+1=428,obsd=428)。
生物活性
P70S6K激酶试验
将P70S6K抑制剂化合物稀释,并铺于96孔板中。将包含以下组分的反应混合液加入该化合物板中以开始酶反应;将P70S6K(3nM,T412E突变体,Millipore)与24μM ATP在试验缓冲液中混合,所述缓冲液包含100mM Hepes(pH7.5)、5mM MgCl2、1mM DTT、0.015%Brij和1μM底物肽FITC-AHA-AKRRRLSSLRA-OH(源自S6核糖体蛋白质序列,FITC=异硫氰酸荧光素,AHA=6-氨基己酸)。将该反应物在25℃孵育90分钟,之后加入10mM EDTA以停止该反应。在Caliper Life Sciences Lab Chip3000分析底物和产物(磷酸化的)肽的比例,压力为-1.4psi,下游电压和下游电压分别为-3000和-700。在获得色谱图上,解析出产物峰在底物峰之前。
为评价所述化合物的抑制潜力测定了IC50-值,如上文化学合成部分中所示。
通过以上对本发明及非限制实施例的描述充分阐明了本发明,但本发明的精神和范围由所附权利要求书限定。
Claims (15)
1.式(I)化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药:
其中:
X是N或C-R3,
Y是N、NH或不存在,
R1是L1–R4–L2–R5-L3-R6、L1–R4–L2–R5或L1–R4,
R2是A、Hal、OH、OA、SH、CN、NH2、NO2、NHA、NH–L1–Ar、NHCOA、NHCO–L1–Ar、NHSO2A、NHSO2–L1–Ar、NHCONHA、NHCONH–L1–Ar、L1–Ar、O-L1–Ar、L1–R4或H,
L1、L3各自相互独立地是单键、亚甲基、或甲基取代的亚甲基,其中亚甲基或甲基取代的亚甲基中的甲基可以是未取代或者被Hal、OH、CN、NH2,NH(LA)、N(LA)2、NO2、COOH、N3、乙烯基或乙炔基单取代或二取代,和/或被R4单取代,且其中一个或两个CH2基团可以被O或S原子替代或被–NH-、-N(LA)-、-CONH-、-N(LA)COO-、-SO2-或-NHCO-基团替代,
R3是H、A、Hal、OH、COOH、SH、NH2、NO2或CN,
R4、R5、R6各自相互独立地是Ar、或环状A,它们可以被Hal或LA单取代或二取代,
L2是-NHCO-、-NHCOO-、–NHCONH–、–NHCONA–、–NHCOA–、–O–、–S–、-NH-、-NHSO2-、-SO2NH–、–CONH–、–CONHCONH–、–NHCONHCO–或–A-,
Ar是具有0、1、2、3或4个N、O和/或S原子和5、6、7、8、9或10个骨架原子的单环或二环的芳族碳环或杂环,其可以未被取代或相互独立地被Hal、A、OH、SH、OA、NH2、NHA、NA2、NO2、CN、OCN、SCN、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、NHCONHA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A和/或SO2Hal单、二或三取代,且其中环N-原子可以被O-原子取代以形成N-氧化物基团,且其中在二环芳族环的情况下两个环之一可以是部分饱和的,
A是具有1、2、3、4、5、6、7或8个C原子的无支链的或有支链的直链或环状烷基,其中一个或两个CH2基团可以被O或S原子所替代和/或被–NH-、-CO-、-NHCOO-、-NHCONH-、-N(LA)-、-CONH-、-NHCO-或–CH=CH–基团所替代,且其中1-3个H原子可以被Hal所替代,且其中一个或两个CH3基团可以被OH、SH、NH2、NH(LA)、N(LA)2、NHCOOH、NHCONH2或CN所替代,
LA是具有1、2、3或4个C原子的无支链的或有支链的直链烷基,且其中1、2或3个H原子可以被Hal所替代,以及
Hal是F、Cl、Br或I。
2.如权利要求1所述的化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药,其中:
X是N,
Y是NH,
R1是L1–R4–L2–R5,
R2是LA、Hal、OH、O(LA)、SH、CN、NH2、NO2、NH(LA)、NHCO(LA)、NHSO2(LA)、NHCONH(LA),
L1是甲基取代的亚甲基,其中所述甲基取代的亚甲基中的甲基被NH2或NH(LA)、N(LA)2或环状A单取代,所述取代基可以是被Hal或LA单取代或二取代,
R4、R5是具有0、1或2个N、O和/或S原子和5或6个骨架原子的单环的芳族碳环或杂环,其可以未被取代或相互独立地被Hal、A、OH、SH、OA、NH2、NHA、NA2、NO2、CN、OCN、SCN、COOH、COOA、CONH2、CONHA、CONA2、NHCOA、NHCONHA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A和/或SO2Hal单、二或三取代,
A是具有1、2、3、4、5、6、7或8个C原子的无支链的或有支链的直链或环状烷基,其中一个或两个CH2基团可以被O或S原子所替代和/或被–NH-、-CO-、-NHCOO-、-NHCONH-、-N(LA)-、-CONH-、-NHCO-或–CH=CH–基团所替代,且其中1-3个H原子可以被Hal所替代,且其中一个或两个CH3基团可以被OH、SH,NH2、NH(LA)、N(LA)2、NHCOOH、NHCONH2或CN所替代,
L2是-NHCO-、-NHCOO-、–NHCONH–、–NHCONA–、–NHCOA–、–O–、–S–、-NH-、-NHSO2-、-SO2NH–、–CONH–、–CONHCONH–、–NHCONHCO–或–A-,
LA是具有1、2、3或4个C原子的无支链的或有支链的直链烷基,且其中1、2或3个H原子可以被Hal所替代,以及
Hal是F、Cl、Br或I。
3.式(II)化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药:
其中:
X是N或C-R3,
R2是A、Hal、OH、OA、SH、CN、NH2、NO2、NHA、NH–L1–Ar、NHCOA、NHCO–L1–Ar、NHSO2A、NHSO2–L1–Ar、NHCONHA、NHCONH–L1–Ar、L1–Ar、O-L1–Ar、L1–R4,
R3是H、A、Hal、OH、COOH、SH、NH2、NO2或CN,
Y’是CH2或NH,使得当Y’是NH时,Z是CH2(或不存在)以及当Y’是CH2时,Z是NH,
Z是CH2、NH或不存在,使得当Z是CH2(或不存在)时,Y是NH以及当Z是NH时,Y是CH2,以及
Z’是Ar、烷基、卤素、OR、NRR、CF3、CN、OCF3、SR或H(被上述任意组合单、二或三取代)。
4.式(III)化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药:
其中:
X是N或C-R3,
R2是A、Hal、OH、OA、SH、CN、NH2、NO2、NHA、NH–L1–Ar、NHCOA、NHCO–L1–Ar、NHSO2A、NHSO2–L1–Ar、NHCONHA、NHCONH–L1–Ar、L1–Ar、O-L1–Ar、L1–R4,
R3是H、A、Hal、OH、COOH、SH、NH2、NO2或CN,
Y’是CH2或NH,使得当Y’是NH时,Z是CH2(或不存在)以及当Y’是CH2时,Z是NH,
Z是CH2、NH或不存在,使得当Z是CH2(或不存在)时,Y是NH以及当Z是NH时,Y是CH2,以及
Z’是Ar、烷基、鹵素、OR、NRR、CF3、CN、OCF3、SR或H(被上述任意组合单、二或三取代)。
5.如权利要求1的化合物及其可药用盐、溶剂化物或前药,其中所述化合物选自:
反式外消旋物4-((4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(2-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(4-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺,
4-((4-(2-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(2-氯-6-氟苯基)吡咯烷-3-基)氨基)-喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(3-溴苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(3-氟苯基)-1-甲基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
6-甲基-4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺,
2-甲基-4-((4-苯基吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(4-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-((4-(4-氟苯基)-1-甲基吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-苯基吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-(3-氟苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-(2-氟苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-(2-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
4-((4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹啉-8-甲酰胺;
反式4-(4-苯基氨甲酰基-吡咯烷-3-基氨基)-喹唑啉-8-甲酸酰胺;
反式外消旋物4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
外消旋物反式4-((4-(3-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
顺式外消旋物4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(间甲苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(4-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物3-氨基-4-(4-氯苯基)哌啶-1-甲酸叔丁酯;
外消旋物反式3-氨基-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯;
反式外消旋物3-((8-氨甲酰基喹唑啉-4-基)氨基)-4-(3-氟-4-甲基苯基)哌啶-1-甲酸苄酯;
外消旋物反式4-((4-(3-氟-4-甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-(3-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
反式外消旋物2-乙基-4-((4-(3-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物2-乙基-4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物2-甲基-4-((4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
反式外消旋物4-((4-苯基哌啶-3-基)氨基)喹啉-8-甲酰胺;
反式外消旋物8-氨甲酰基-4-(4-苯基哌啶-3-基)氨基)喹啉-3-甲酸乙酯;
反式外消旋物8-氨甲酰基-4-((4-苯基哌啶-3-基)氨基)喹啉-3-甲酸;
4-(3-氟-4-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氟-5-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4R)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4R)-4-(3-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(4-(三氟甲氧基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(2-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(喹啉-6-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(4-氟-3-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(萘-1-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(3-溴苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氰基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(2,3-二氢苯并呋喃-5-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(3-氟-2-甲基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-氯苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
2-氯苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氯-4-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟-4-甲氧基苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
2-乙基-4-(((3S,4R)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(2,4,5-三氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-(((3R,4S)-4-(3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氯-2-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(萘-2-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-(甲基磺酰基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氯-3-氟苯基)吡咯烷-3-基)氨基)-2-乙基喹唑啉-8-甲酰胺;
4-(3-氯-5-氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
6-氟-4-(((3R,4S)-4-(4-(三氟甲基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(2,3-二氟苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(3-(吡咯烷-1-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-([1,1'-联苯基]-3-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氟-3-(吡啶-3-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟-4-(吡啶-3-基)苯基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-((4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3,5-二氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
1-甲基-4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-甲氧基苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4S)-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4R)-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4R)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4S)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
2-乙基-4-(4-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(3-甲氧基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(2-氟苯基)哌啶-3-基)氨基)-2-甲基喹唑啉-8-甲酰胺;
4-(3-氟-4-甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
2-甲基-4-(((3R,4R)-4-(3-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3,4-二甲氧基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(3-氟-5-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
2-甲基-4-(4-(三氟甲基)苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-(2-氟苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(4-氯苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
2-乙基-4-(间甲苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-((4-(3,5-二甲基苯基)哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
6-氟-4-(((3R,4R)-4-苯基哌啶-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3R,4S)-4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺;
4-(((3S,4R)-4-(2-氟-[1,1'-联苯基]-4-基)吡咯烷-3-基)氨基)喹唑啉-8-甲酰胺。
6.包含作为活性成分的如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药以及可药用载体的药物组合物。
7.用作药物的如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药。
8.用于治疗过度增殖性疾病的如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药。
9.如权利要求8的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药,其中所述疾病选自:癌症、炎症、胰腺炎或肾脏疾病、疼痛、皮肤的良性增生、再狭窄、前列腺疾病、与血管发生或血管生成相关的疾病、肿瘤血管生成、选自银屑病、湿疹和硬皮病的皮肤病、糖尿病、糖尿病性视网膜病、早产儿视网膜病、年龄相关性黄斑变性、血管瘤、神经胶质瘤、黑素瘤和卡波西肉瘤。
10.如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药在制备用于治疗过度增殖性疾病的药物中的用途。
11.如权利要求10的用途,其中所述疾病选自:癌症、炎症、胰腺炎或肾脏疾病、疼痛、皮肤的良性增生、再狭窄、前列腺疾病、与血管发生或血管生成相关的疾病、肿瘤血管生成、选自银屑病、湿疹和硬皮病的皮肤病、糖尿病、糖尿病性视网膜病、早产儿视网膜病、年龄相关性黄斑变性、血管瘤、神经胶质瘤、黑素瘤和卡波西肉瘤。
12.一种用于治疗过度增殖性疾病的方法,所述方法包括向个体施用如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药。
13.如权利要求12所述的方法,其中所述疾病选自:癌症、炎症、胰腺炎或肾脏疾病、疼痛、皮肤的良性增生、再狭窄、前列腺疾病、与血管发生或血管生成相关的疾病、肿瘤血管生成、选自银屑病、湿疹和硬皮病的皮肤病、糖尿病、糖尿病性视网膜病、早产儿视网膜病、年龄相关性黄斑变性、血管瘤、神经胶质瘤、黑素瘤和卡波西肉瘤。
14.一种药盒(套盒),该药盒包含下列独立包装:
a)有效量的如权利要求1至5中任何一项所述的化合物或其可药用盐、溶剂化物、盐的溶剂化物或前药,以及
b)有效量的另外的药物活性成分。
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RS55582B1 (sr) | 2011-05-13 | 2017-06-30 | Array Biopharma Inc | Jedinjenja pirolidinil uree, pirolidinil tiouree i pirolidinil guanidina kao inhibitori trka kinaze |
MX347241B (es) | 2011-09-12 | 2017-04-20 | Merck Patent Gmbh | Derivados de aminopirimidina para usarse como moduladores de la actividad de cinasa. |
WO2013040059A1 (en) | 2011-09-12 | 2013-03-21 | Merck Patent Gmbh | Novel imidazole amines as modulators of kinase activity |
AR093512A1 (es) | 2012-11-16 | 2015-06-10 | Merck Patent Gmbh | Derivados heterociclicos como moduladores de la actividad de cinasas |
CN105102435A (zh) | 2012-11-16 | 2015-11-25 | 默克专利有限公司 | 用作激酶活性调节剂的新颖的咪唑-哌啶基衍生物 |
UA115154C2 (uk) * | 2012-11-29 | 2017-09-25 | Мерк Патент Гмбх | Похідні азахіназолінкарбоксаміду |
SG10201900954SA (en) | 2013-03-11 | 2019-02-27 | Merck Patent Gmbh | Heterocycles as Modulators of Kinase Activity |
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JP6616390B2 (ja) | 2019-12-04 |
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US20130217709A1 (en) | 2013-08-22 |
EA201201670A1 (ru) | 2013-07-30 |
BR112013002212A2 (pt) | 2017-09-26 |
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US9586938B2 (en) | 2017-03-07 |
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AU2011282684B2 (en) | 2015-05-21 |
JP2013535473A (ja) | 2013-09-12 |
US10087166B2 (en) | 2018-10-02 |
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