CN110637018A - 2-氨基-喹啉衍生物 - Google Patents
2-氨基-喹啉衍生物 Download PDFInfo
- Publication number
- CN110637018A CN110637018A CN201880014574.0A CN201880014574A CN110637018A CN 110637018 A CN110637018 A CN 110637018A CN 201880014574 A CN201880014574 A CN 201880014574A CN 110637018 A CN110637018 A CN 110637018A
- Authority
- CN
- China
- Prior art keywords
- quinolin
- optionally substituted
- salt
- ethoxymethyl
- imidazo
- 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.)
- Pending
Links
- 150000005013 2-aminoquinolines Chemical class 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 238000000034 method Methods 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 208000026935 allergic disease Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 143
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 59
- -1 (4- ((4-amino-2- (ethoxymethyl) -1-methyl-1H-imidazo [4,5-c ] quinolin-9-yl) oxy) butyl) -stearamide Chemical compound 0.000 claims description 40
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 229910003827 NRaRb Inorganic materials 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- 125000000962 organic group Chemical group 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 12
- HSEMFIZWXHQJAE-UHFFFAOYSA-N hexadecanamide Chemical compound CCCCCCCCCCCCCCCC(N)=O HSEMFIZWXHQJAE-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052705 radium Inorganic materials 0.000 claims description 10
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- OVYWMEWYEJLIER-UHFFFAOYSA-N quinolin-6-ol Chemical compound N1=CC=CC2=CC(O)=CC=C21 OVYWMEWYEJLIER-UHFFFAOYSA-N 0.000 claims description 7
- QOYVKJKPMJGWOA-UHFFFAOYSA-N 1-[4-amino-2-(ethoxymethyl)-9-methoxyimidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2CC(C)(O)C)COCC)OC QOYVKJKPMJGWOA-UHFFFAOYSA-N 0.000 claims description 6
- YGDTZZRKAQEXFO-UHFFFAOYSA-N 2-(ethoxymethyl)-9-(3-methylbutoxy)-3H-imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1NC2=C(C(=NC=3C=CC=C(C2=3)OCCC(C)C)N)N=1 YGDTZZRKAQEXFO-UHFFFAOYSA-N 0.000 claims description 6
- PLKWRVIXFITHLR-UHFFFAOYSA-N 2-(ethoxymethyl)-9-methoxy-1-(2-methylpropyl)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC)N)N=1)CC(C)C PLKWRVIXFITHLR-UHFFFAOYSA-N 0.000 claims description 6
- FLKJVZNZWBSCNA-UHFFFAOYSA-N 4-[4-amino-2-(ethoxymethyl)-1-(2-methylpropyl)imidazo[4,5-c]quinolin-9-yl]oxy-2-methylbutan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2CC(C)C)COCC)OCCC(C)(O)C FLKJVZNZWBSCNA-UHFFFAOYSA-N 0.000 claims description 6
- 229910017711 NHRa Inorganic materials 0.000 claims description 6
- 208000036142 Viral infection Diseases 0.000 claims description 6
- 230000009385 viral infection Effects 0.000 claims description 6
- BLYHFWNPCIGTHH-UHFFFAOYSA-N 1-[[4-amino-2-(ethoxymethyl)-3H-imidazo[4,5-c]quinolin-9-yl]oxy]propan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2)COCC)OCC(C)O BLYHFWNPCIGTHH-UHFFFAOYSA-N 0.000 claims description 5
- VOZORYRGGNVPJW-UHFFFAOYSA-N 10-oxa-4,14-diazatricyclo[7.5.1.05,15]pentadeca-1(15),2,4,6,8,11,13-heptaen-12-ol Chemical compound N1=CC=C2C=3C(=CC=CC1=3)OC=C(C=N2)O VOZORYRGGNVPJW-UHFFFAOYSA-N 0.000 claims description 5
- QCKBYROORIRUPN-UHFFFAOYSA-N 4-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxy-2-methylbutan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2C)COCC)OCCC(C)(O)C QCKBYROORIRUPN-UHFFFAOYSA-N 0.000 claims description 5
- ITPHJKRCXVELDB-UHFFFAOYSA-N 4-[[4-amino-2-(2-methoxyethyl)-3H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methylbutan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2)CCOC)OCCC(C)(O)C ITPHJKRCXVELDB-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HRWIFFDHQMFGNN-UHFFFAOYSA-N 2-(ethoxymethyl)-9-(2-propan-2-yloxyethoxy)-3H-imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1NC2=C(C(=NC=3C=CC=C(C2=3)OCCOC(C)C)N)N=1 HRWIFFDHQMFGNN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- GKFPOIUULJGQPN-UHFFFAOYSA-N 1-[4-amino-2-(2-hydroxyethyl)-9-methoxyimidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2CC(C)(O)C)CCO)OC GKFPOIUULJGQPN-UHFFFAOYSA-N 0.000 claims description 3
- WZRGIGQHNDGFIG-UHFFFAOYSA-N 1-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxy-2-methylpropan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2C)COCC)OCC(C)(O)C WZRGIGQHNDGFIG-UHFFFAOYSA-N 0.000 claims description 3
- YHYFYUKNKQMNOK-UHFFFAOYSA-N 1-[4-amino-9-methoxy-2-(2-methoxyethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2CC(C)(O)C)CCOC)OC YHYFYUKNKQMNOK-UHFFFAOYSA-N 0.000 claims description 3
- UEFOMEYNTZNHQB-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-(2-methylpropoxy)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OCC(C)C)N)N=1)C UEFOMEYNTZNHQB-UHFFFAOYSA-N 0.000 claims description 3
- XDTSMYJPPAAGLU-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-(2-propan-2-yloxyethoxy)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OCCOC(C)C)N)N=1)C XDTSMYJPPAAGLU-UHFFFAOYSA-N 0.000 claims description 3
- JMPLICVAWWJXQP-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-(3-methylbutoxy)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OCCC(C)C)N)N=1)C JMPLICVAWWJXQP-UHFFFAOYSA-N 0.000 claims description 3
- AZTFHSKKWCHQKW-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-(oxolan-3-yloxy)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC2COCC2)N)N=1)C AZTFHSKKWCHQKW-UHFFFAOYSA-N 0.000 claims description 3
- IXJQFWNIWIELNR-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-piperidin-4-yloxyimidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC2CCNCC2)N)N=1)C IXJQFWNIWIELNR-UHFFFAOYSA-N 0.000 claims description 3
- UIVUUEFCKIJLNB-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-propan-2-yloxyimidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC(C)C)N)N=1)C UIVUUEFCKIJLNB-UHFFFAOYSA-N 0.000 claims description 3
- WAFQYUYNGVIVNG-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-pyrrolidin-3-yloxyimidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC2CNCC2)N)N=1)C WAFQYUYNGVIVNG-UHFFFAOYSA-N 0.000 claims description 3
- XKMXEEZJOCABSN-UHFFFAOYSA-N 2-(ethoxymethyl)-9-(2-methylpropoxy)-3H-imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1NC2=C(C(=NC=3C=CC=C(C2=3)OCC(C)C)N)N=1 XKMXEEZJOCABSN-UHFFFAOYSA-N 0.000 claims description 3
- VUJGOQDZTMOKFV-UHFFFAOYSA-N 2-(ethoxymethyl)-9-methoxy-1-(2-propan-2-yloxyethyl)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OC)N)N=1)CCOC(C)C VUJGOQDZTMOKFV-UHFFFAOYSA-N 0.000 claims description 3
- KEXGXOJEMYADSG-UHFFFAOYSA-N 2-butyl-9-(3-methylbutoxy)pyrazolo[3,4-c]quinolin-4-amine Chemical class C(CCC)N1N=C2C(=NC=3C=CC=C(C=3C2=C1)OCCC(C)C)N KEXGXOJEMYADSG-UHFFFAOYSA-N 0.000 claims description 3
- OCIADYZDROIKDL-UHFFFAOYSA-N 4-[4-amino-2-(ethoxymethyl)-9-methoxyimidazo[4,5-c]quinolin-1-yl]-2-methylbutan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2CCC(C)(O)C)COCC)OC OCIADYZDROIKDL-UHFFFAOYSA-N 0.000 claims description 3
- REWHSGXVPGPMCX-UHFFFAOYSA-N 4-[[4-amino-2-(ethoxymethyl)-3H-imidazo[4,5-c]quinolin-9-yl]oxy]-2-methylbutan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2)COCC)OCCC(C)(O)C REWHSGXVPGPMCX-UHFFFAOYSA-N 0.000 claims description 3
- JWARRFKQCPVLSR-UHFFFAOYSA-N 4-[[4-amino-2-(ethoxymethyl)-3H-imidazo[4,5-c]quinolin-9-yl]oxy]butan-2-ol Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2)COCC)OCCC(C)O JWARRFKQCPVLSR-UHFFFAOYSA-N 0.000 claims description 3
- AMPBTPQXPBRJCY-UHFFFAOYSA-N 4-amino-2-(3-methylbutyl)pyrazolo[3,4-c]quinolin-9-ol Chemical class NC1=NC=2C=CC=C(C=2C=2C1=NN(C=2)CCC(C)C)O AMPBTPQXPBRJCY-UHFFFAOYSA-N 0.000 claims description 3
- PCQZTOCRIVZHOB-UHFFFAOYSA-N 4-amino-3H-pyrazolo[3,4-c]quinolin-9-ol Chemical class NC1=NC=2C=CC=C(C=2C=2C1=NNC=2)O PCQZTOCRIVZHOB-UHFFFAOYSA-N 0.000 claims description 3
- DDNHKOMVKLDTQY-UHFFFAOYSA-N 7H-quinolin-6-one Chemical compound N1=CC=CC2=CC(CC=C12)=O DDNHKOMVKLDTQY-UHFFFAOYSA-N 0.000 claims description 3
- FUZYNMASMKHRIW-UHFFFAOYSA-N 9-(3-aminopropoxy)-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-4-amine Chemical class NCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC FUZYNMASMKHRIW-UHFFFAOYSA-N 0.000 claims description 3
- FSIDHUJJSWXKCQ-UHFFFAOYSA-N 9-(3-methylbutoxy)-2-(3-methylbutyl)pyrazolo[3,4-c]quinolin-4-amine Chemical class C(CC(C)C)N1N=C2C(=NC=3C=CC=C(C=3C2=C1)OCCC(C)C)N FSIDHUJJSWXKCQ-UHFFFAOYSA-N 0.000 claims description 3
- HTLWKFKYFYPSCH-UHFFFAOYSA-N 9-methoxy-3H-imidazo[4,5-c]quinolin-4-amine Chemical class COC=1C=2C3=C(C(=NC=2C=CC=1)N)N=CN3 HTLWKFKYFYPSCH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- BQICROVULNIKFQ-UHFFFAOYSA-N N-[2-[2-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxyethoxy]ethyl]methanesulfonamide Chemical class NC1=NC=2C=CC=C(C=2C2=C1N=C(N2C)COCC)OCCOCCNS(=O)(=O)C BQICROVULNIKFQ-UHFFFAOYSA-N 0.000 claims description 3
- IXGVMYREGNTOBW-UHFFFAOYSA-N N-[3-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxypropyl]acetamide Chemical class C(C)(=O)NCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC IXGVMYREGNTOBW-UHFFFAOYSA-N 0.000 claims description 3
- FQDKRRYLMFABOK-UHFFFAOYSA-N N-[3-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxypropyl]methanesulfonamide Chemical class CS(=O)(=O)NCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC FQDKRRYLMFABOK-UHFFFAOYSA-N 0.000 claims description 3
- KPRPJCGNUMXCGE-UHFFFAOYSA-N N-[3-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxypropyl]octadecanamide Chemical class C(CCCCCCCCCCCCCCCCC)(=O)NCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC KPRPJCGNUMXCGE-UHFFFAOYSA-N 0.000 claims description 3
- DUCMVTIPWNWNEK-UHFFFAOYSA-N N-[4-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxybutyl]acetamide Chemical class C(C)(=O)NCCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC DUCMVTIPWNWNEK-UHFFFAOYSA-N 0.000 claims description 3
- XSTUUKIVJMZMLY-UHFFFAOYSA-N N-[4-[4-amino-2-(ethoxymethyl)-1-methylimidazo[4,5-c]quinolin-9-yl]oxybutyl]methanesulfonamide Chemical class CS(=O)(=O)NCCCCOC=1C=2C3=C(C(=NC=2C=CC=1)N)N=C(N3C)COCC XSTUUKIVJMZMLY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- HJNCPVOAGHSHPK-UHFFFAOYSA-N 2-(ethoxymethyl)-1-methyl-9-(2-morpholin-4-ylethoxy)imidazo[4,5-c]quinolin-4-amine Chemical class C(C)OCC=1N(C2=C(C(=NC=3C=CC=C(C2=3)OCCN2CCOCC2)N)N=1)C HJNCPVOAGHSHPK-UHFFFAOYSA-N 0.000 claims description 2
- ICOJRQWKSUISLK-UHFFFAOYSA-N 9-methoxy-3H-pyrazolo[3,4-c]quinolin-4-amine Chemical class COc1cccc2nc(N)c3n[nH]cc3c12 ICOJRQWKSUISLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 63
- 102100039390 Toll-like receptor 7 Human genes 0.000 abstract description 18
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 abstract description 15
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 239000000556 agonist Substances 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 5
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- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
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- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
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- 229940124613 TLR 7/8 agonist Drugs 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
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- WCZBVBVBEZJZNO-UHFFFAOYSA-N 4-chloro-5-methoxy-3-nitroquinoline Chemical compound COc1cccc2ncc(c(Cl)c12)[N+]([O-])=O WCZBVBVBEZJZNO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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Abstract
本文描述了作为toll样受体7和toll样受体8(TLR7和TRL8)的激动剂2‑氨基‑喹啉衍生物,药物组合物以及使用所述化合物和组合物治疗各种疾病(例如病毒疾病、癌症及过敏性疾病)的方法,所述方法包括根据需要给药治疗有效量的2‑氨基‑喹啉衍生物。
Description
相关申请的交叉引用
本申请要求2017年4月27日提交的中国申请CN201710287322.2的权益和优先权,该中国申请的全部内容通过引用并入本文。
技术领域
本发明涉及2-氨基-喹啉衍生物,例如作为toll样受体7和toll样受体8(TLR7和TRL8)的激动剂的咪唑并喹啉类似物及吡唑并喹啉类似物,以及包含所述2-氨基-喹啉衍生物的药物组合物。本发明还涉及所述化合物和所述组合物的用途以及在治疗多种疾病中激活TLR7和TRL8的方法。
背景技术
TLR家族在病原体识别及激活先天性免疫方面起到根本作用。TLR7和TLR8分别为toll样受体7和toll样受体8,且它们在人类X染色体上彼此靠近。TLR7和TLR8两者都识别病毒(例如,HIV病毒及HCV病毒)的单链RNA。TLR7已显示出在自身免疫性疾病(例如,全身性红斑狼疮(SLE))的发病机制及抗病毒免疫调节方面发挥重要作用。最近,TLR8的遗传变异体已经与肺结核易感性相关联。TLR7在人体内及小鼠体内均起作用,而TLR8仅在人体内起作用,但是TLR8看起来会抵消TLR7的活性。作为免疫反应增强剂的TLR7/8激动剂的主要优势在于它们同时刺激多种细胞类型。TLR7和TLR8主要在诸如抗原呈递细胞之类的免疫细胞(包括浆细胞样树突细胞(pDC)和髓样树突细胞(mDC))和自然杀伤细胞以及巨噬细胞上表达。pDC和mDC上TLR7/8的活化导致I型干扰素(IFN)、肿瘤坏死因子α(TNFα)和白介素12(IL-12)的诱导和释放,这是启动先天性免疫和获得性免疫以杀伤癌细胞的重要步骤。鉴于这些原因,TLR7和TLR8已成为抗病毒治疗和癌症治疗中值得关注的靶点。本领域也越来越多地关注于toll样受体的靶定,例如,用于治疗过敏性疾病的TLR7/8。
由于TLR7和TLR8具有很强的抗病毒及抗肿瘤活性,因此,在抗病毒研究和癌症研究中对TLR7和TLR8的小分子激动剂产生了浓厚的兴趣。咪唑并喹啉家族的先导化合物咪喹莫特对许多原发性皮肤肿瘤和皮肤转移肿瘤有效,并且咪喹莫特作为局部用制剂在市场上销售。来自于相同的咪唑并喹啉家族的瑞喹莫德(R-848)是一种低分子量的合成分子,其通过TLR7/TLR8 MyD88依赖性信号转导通路激活免疫细胞。瑞喹莫德(R-848)起免疫反应调节剂的作用,并具有抗病毒及抗肿瘤活性。瑞喹莫德(R-848)具有多种作用机制,其可以作为toll样受体7和8的激动剂及阿片生长因子受体的上调剂。R-848用作治疗皮肤病变的局部用凝胶,所述皮肤病变例如由单纯疱疹病毒和皮肤T细胞淋巴瘤引起的皮肤病变,R-848用作提高疫苗的有效性的佐剂,并且用作过敏性鼻炎(AR)患者的免疫治疗佐剂。因此,TLR7/8激动剂除了作为独立的免疫治疗剂之外,还有望成为癌症疫苗的佐剂或T细胞过继转移操作中的佐剂。如上所述,对已知的合成的TLR7/8激动剂家族的拓展为TLR7/8激动剂的研究和发现铺平了道路,TLR7/8激动剂具有良好耐受性,对有效抗肿瘤和抗病毒活性具有更高的选择性,具有广泛适用性并且可作为更有效的佐剂。
发明内容
本文描述了2-氨基-喹啉衍生物、其药学上可接受的盐、溶剂化物,前药及活性代谢物,它们是toll样受体7和8(TLR7/8)的激动剂。这些化合物可通过给药治疗有效量的2-氨基-喹啉衍生物用于治疗有此需求的受治者的病毒(例如,HCV)感染、癌症及过敏性疾病。
一些实施方式包括式1表示的化合物:
其中,虚线表示存在化学键或不存在化学键;A1为CR1,NR1A或者N;A2为CR2,NR2A,O,或者S;B1为CR5或者N;B2为CR6或者N;B3为CR7或者N;R1和R2独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra;X为化学键,O,NRa,-CO-,-SO-,或者-SO2-,-CONRa,烃基,并且R3为H或者C1-30有机基团;或者X-R3为F或者Cl;R1A,R2A,R4,Ra及Rb独立地为H或者C1-30有机基团;R5,R6及R7独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,-SO2Ra,-SO2NHRa,或者-X1-(CmH2mO0-1)-Z-(CnH2n+1),-(CmH2mO0-1)-Z-(CnH2n+1),其中,R5和R6或者R6和R7可被任选地连接形成环;其中,X1为化学键,O,NRa,-CO-,-SO-,或者-SO2-;Z为化学键,O,NHSO2,或者NHCO;m为0,1,2,3,4,5,6,7,8,9,或者10;以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
一些实施方式包括包含上述化合物的药物剂型。上述化合物或者组合物可用于激活TLR7/8。上述化合物或组合物除了用作独立的免疫治疗剂(例如,抗病毒和抗癌剂)之外,还可用作癌症疫苗的佐剂或T细胞过继转移操作中的佐剂。
一些实施方式包括治疗与TLR7/8激动剂相关的疾病或者失调的方法,所述方法包括将有效量的上述化合物给药于在需要这种治疗的哺乳动物。
一些实施方式包括上述化合物在制造用于治疗与TLR7/8激动剂相关的疾病或者失调的药物中的应用。
具体实施方式
除非另有说明,当化合物或者化学结构特征(例如,烷基,烯基,炔基,芳基,杂芳基等)被称为“任选地取代的”时,它包括没有取代基的特征(即,未取代)或者被取代的特征(是指所述特征具有一个或者多个取代基)。术语“取代基”具有本领域的普通技术人员已知的最广泛的含义,其包括如下基团:该基团占据通常由连接到母体化合物或者母体结构特征的一个或者多个氢原子所占据的位置。在一些实施方式中,取代基可以是本领域已知的普通的有机基团,所述有机基团可具有如下分子量(例如,所述取代基的原子的原子质量的总和):15-50g/mol,15-100g/mol,15-150g/mol,15-200g/mol,15-300g/mol,或者15-500g/mol。在一些实施方式中,取代基包括或者由如下原子组成:0-30个,0-20个,0-10个或者0-5个碳原子;以及0-30个,0-20个,0-10个或者0-5个杂原子,其中,每个杂原子可独立地为:N,O,S,Si,F,Cl,Br,或者I;条件是所述取代基包括一个C,N,O,S,Si,F,Cl,Br,或者I原子。取代基的实例包括但不限于:烷基,烯基,炔基,杂烷基,芳基,杂芳基,羟基,烷氧基,芳氧基,酰基,酰氧基,烷基羧酸酯,巯基,烷硫基,氰基,卤代,硫代羰基,O-氨基甲酰基,N-氨基甲酰基,O-硫代氨基甲酰基,N-硫代氨基甲酰基,C-酰胺基,N-酰胺基,S-磺酰胺基,N-磺酰胺基,异氰酸酯,硫氰酸酯,异硫氰酸酯,硝基,甲硅烷基,硫基,亚磺酰基,磺酰基,卤代烷基,卤代烷氧基,三卤代甲磺酰基,三卤代甲磺酰胺基,氨基等。
即使分子的某个基团或分子的一部分可能不是完整的分子,但是为了方便,将术语“分子量”用于所述分子的某个基团或分子的一部分以表示在所述分子的某个基团或分子的一部分中的原子的原子质量的总和。
本文使用的术语“烷基”具有本领域通常理解的最广泛的含义,其可包括由不含有双键或者三键的碳和氢组成的基团。烷基可以是直链烷基,支链烷基,环烷基,或者它们的组合;在一些实施方式中,烷基可包含1-35个碳原子。在一些实施方式中,烷基可包含C1-10直链烷基,例如,甲基(-CH3),亚甲基(-CH2-),乙基(-CH2CH3),亚乙基(-C2H4-),亚丙基(-C3CH6-),正-丁基(-CH2CH2CH2CH3),正-戊基(-CH2CH2CH2CH2CH3),正-己基(-CH2CH2CH2CH2CH2CH3)等;C3-10支链烷基,例如C3H7(例如,异丙基),C4H9(例如,支链丁基异构体),C5H11(例如,支链戊基异构体),C6H13(例如,支链己基异构体),C7H15(例如,庚基异构体)等;C3-10环烷基,例如C3H5(例如,环丙基),C4H7(例如,环丁基异构体,例如环丁基,甲基环丙基等),C5H9(例如,环戊基异构体,例如环戊基,甲基环丁基,二甲基环丙基等),C6H11(例如,环己基异构体),C7H13(例如,环庚基异构体)等。
本文使用的术语“芳基”包括可通过从单环芳烃和多环芳烃的环碳原子上去掉一个氢原子而衍生得到的基团。所述“芳基”可包括芳香族环或者芳香族环系统,例如苯基、萘基等。
术语“杂芳基”具有本领域普通技术人员理解的最广泛的含义,其包括在环或者环系统中具有一个或者多个杂原子的“芳基”,例如,吡啶基,呋喃基,噻吩基,恶唑基,噻唑基,咪唑基,三唑基,恶二唑基,异恶唑基,吲哚基,喹啉基,苯并呋喃基,苯并噻吩基,苯并恶唑基,苯并噻唑基,苯并咪唑基等。
除非另有说明,通过结构、名称或者任何其他方式提到的本文的化合物包括:药学上可接受的盐(例如盐酸盐,溴酸盐,碘酸盐,硫酸盐,醋酸盐,柠檬酸盐,磷酸盐,钠盐,钾盐及铵盐);前药(例如酯类前药);可选的固体剂型(例如,多晶型物,溶剂化物,水合物等);互变异构体;或者在本文所描述的使用化合物的条件下可迅速转化成本文所描述的化合物的任何其它化学物质。
如果没有指明立体化学,那么名称或结构示意图包括任何立体异构体或者立体异构体的任意混合物。
为了实现本文所公开的目的,“治疗(treat,treating或treatment)”包括在诊断、治愈、减轻、治疗或者预防疾病或者其它不期望的病症中使用化合物,组合物,治疗活性剂或者药物。
关于任何相关的结构示意图,例如式1,虚线表示存在化学键或不存在化学键。例如,式1A和1B表示的化合物被包括在本文中。
关于任何相关的结构示意图,例如,式1,式1A或者式1B,A1为CR1,NR1A,或者N。在一些实施方式中,A1为CR1。在一些实施方式中,A1为NR1A。在一些实施方式中,A1为N。
关于任何相关的结构示意图,例如,式1,式1A或者式1B,A2为CR2,NR2A,O或者S。在一些实施方式中,A2为CR2。在一些实施方式中,A2为NR2A。在一些实施方式中,A2为O。在一些实施方式中,A2为S。
关于任何相关的结构示意图,例如,式1,式1A或者式1B,X为化学键,O,NRa,-C(=O)-,-S(=O)-,-S(=O)2-,-CONRa,烃基;R3为H或者C1-30有机基团;或者X-R3为F或者Cl。在一些实施方式中,X为化学键。在一些实施方式中,X为O。在一些实施方式中,X为NRa。在一些实施方式中,X为-C(=O)-。在一些实施方式中,X为-S(=O)-。在一些实施方式中,X为-S(=O)2-。在一些实施方式中,X-R3为F。在一些实施方式中,X-R3为Cl。
关于任何相关的结构示意图,例如式1,1A或者1B中的Ra,NRa,-ORa,-OCORa,或者-SO2Ra,-NRaRb,Ra或者Rb独立地为H或者有机基团,例如C1-30有机基团,其包括在碳原子处具有自由价的任何有机取代基团(无论是不是功能型),例如:任选地取代的烷基,例如,任选地取代的C1-30烷基,C1-12烷基,C1-6烷基,或者C1-3烷基,其包括甲基,乙基,C3烷基,C4烷基,C5烷基,C6烷基,C7烷基,C8烷基,C9烷基,C10烷基,C11烷基,C12烷基,C13烷基,C14烷基,C15烷基,C16烷基,C17烷基,C18烷基,C19烷基,C20烷基,C21烷基,C22烷基,C23烷基,C24烷基,C25烷基,C26烷基,C27烷基,C28烷基,C29烷基,C30烷基,C3环烷基,C4环烷基,C5环烷基,C6环烷基,C7环烷基,C8环烷基,C9环烷基,C10环烷基,C11环烷基,C12环烷基等;任选地取代的烯基,例如,任选地取代的C2-12或者C2-6烯基,其包括乙烯基,C3烯基,C4烯基,C5烯基,C6烯基,C7烯基,C8烯基,C9烯基,C10烯基,C11烯基,C12烯基,C4环烯基,C5环烯基,C6环烯基,C7环烯基,C8环烯基,C9环烯基,C10环烯基,C11环烯基,C12环烯基等;任选地取代的炔基,例如,任选地取代的C2-12或者C2-6炔基,其包括乙炔基,C3炔基,C4炔基,C5炔基,C6炔基,C7炔基,C8炔基,C9炔基,C10炔基,C11炔基,C12炔基,C5环炔基,C6环炔基,C7环炔基,C8环炔基,C9环炔基,C10环炔基,C11环炔基,C12环炔基等;任选地取代的芳基,例如,任选地取代的苯基,任选地取代的萘基等;任选地取代的杂环,任选地取代的杂芳基等;有机基团还包括CN,-C(O)Ra,-C(O)ORa,-C(O)NHRa,-C(O)NRaRb,-C(O)-Z-有机基团,其中,Z为化学键,O,S,或者NRaRb,-C(RaRb)-ORa,-C(RaRb)-NRaRb。在一些实施方式中,Ra或Rb独立地为H或者C1-30烃基,例如,烷基,烯基,炔基,或者苯基。在一些实施方式中,C1-30有机基团可被卤素,羟基,胺类,烷氧基,芳基,杂芳基,砜,磺酰胺,羧酸,酰胺,逆向酰胺,酯,环烷基,杂环烷基,羰基,烷基,烯基,炔基,膦酰胺酸,次膦酰胺或者氧化膦取代。
一些实施方式包括式2或者式2A的化合物。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,或者式2A,B1为CR5或者N。在一些实施方式中,B1为CR5。在一些实施方式中,B1为N。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,或者式2A,B2为CR6或者N。在一些实施方式中,B2为CR6。在一些实施方式中,B2为N。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,或者式2A,B3为CR7或者N。在一些实施方式中,B3为CR7。在一些实施方式中,B3为N。
一些实施方式包括式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12或者式13的化合物。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12或者式13,R1或者R1A独立地为H或者任何取代基,例如,F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra。在一些实施方式中,R1或者R1A为CrH2r+1O,其中,r为1,2,3,4,5,6,7,8,9,或10,包括:C2H5O(例如,-(CH2)2OH);C3H7O(例如-CH2OCH2CH3,-(CH2)2OCH3等);R1或者R1A为C1-12烷基,例如-(CH2)3CH3,-CH2CH2CH(CH3)2等。
在一些实施方式中,R1或者R1A为-(CH2)2OH。在一些实施方式中,R1或者R1A为-CH2OCH2CH3。在一些实施方式中,R1或者R1A为-(CH2)2OCH3。在一些实施方式中,R1或者R1A为-(CH2)3CH3。在一些实施方式中,R1或者R1A为-CH2CH2CH(CH3)2。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式4,式5,式6,式7,式8,式9,或者式10,R2或者R2A独立地为H或者任何取代基,例如,-CH3,-CH2CH(CH3)2,-CH2C(CH3)2R8,-CH2CH2C(CH3)2R8,-C4H9O,-CH2CH2OCH(CH3)2。
在一些实施方式中,R2或者R2A为H。在一些实施方式中,R2或者R2A为CH3。在一些实施方式中,R2或者R2A为-CH2CH(CH3)2。在一些实施方式中,R2或者R2A为-CH2C(CH3)2R8。在一些实施方式中,R2或者R2A为-CH2C(CH3)2OH。在一些实施方式中,R2或者R2A为-CH2CH2C(CH3)2OH。在一些实施方式中,R2或者R2A为-CH2CH2OCH(CH3)2。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式4,式5,式6,式7,式8,式9,或者式10,R3为任何取代基,例如:C1-30任选地取代的烷基;-CwH2w+1O或其酯(其中,w为0,1,2,3,4,5,6,7,8,9,或10);-(CuH2uO0-1)-Z-(CvH2v+1)(其中,Z为化学键,O,NHSO2,或者NHCO,u为0,1,2,3,4,5,6,7,8,9,或10以及v为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,或者24);或者-(CtH2tO0-1)-Ht(其中,t为0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,或者20,并且Ht为任选地取代的C3-10杂环基)。
在一些实施方式中,R3为H。在一些实施方式中,R3为CH3。在一些实施方式中,R3为-CH2CH(CH3)2。在一些实施方式中,R3为-(CH2)2CH(CH3)2。在一些实施方式中,R3为-CH2CH(OH)CH3。在一些实施方式中,R3为-(CH2)2CH(OH)CH3。在一些实施方式中,R3为-(CH2)2C(CH3)2OH。在一些实施方式中,R3为(CH2)2OCH(CH3)2,-(CH2)3NHSO2CH3,-(CH2)4NHSO2CH3,-(CH2)2O(CH2)2NHSO2CH3,-(CH2)3NHCOC17H35,-(CH2)3NHCOCH3,-(CH2)4NHCOCH3,-(CH2)4NHCOC17H35,-(CH2)3NH2,
或者
关于任何相关的结构示意图,例如,式3E,R3为由1-6个相同或者不同的R8A任选地取代的C1-3烷基,其中,R8A为OH,氧化物,C1-6有机基团,或者-O-(C1-6有机基团)。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12,或者式13,R4为H或者任何取代基,例如,烃基。
在一些实施方式中,R4为H。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12,或者式13,R5为H或者任何取代基,例如,F,Cl,Ra,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra,其中,Ra或者Rb独立地为H或者C1-30有机基团。在一些实施方式中,R5为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,-NHSO2,或者-NHCO,m为0,1,2,3,4,5,6,7,8,9,或10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,或者24。在一些实施方式中,R5为H。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12,或者式13,R6为H或者任何取代基,例如,F,Cl,Ra,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra,其中,Ra或者Rb独立地为H或者C1-30有机基团。在一些实施方式中,R6为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,-NHSO2,或者-NHCO,m为0,1,2,3,4,5,6,7,8,9,或10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,或者24。在一些实施方式中,R6为H。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式3E,式4,式5,式6,式7,式8,式9,式10,式11,式12,或者式13,R7为H或者任何取代基,例如,F,Cl,Ra,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra,其中,Ra或者Rb独立地为H或者C1-30有机基团。在一些实施方式中,R7为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,-NHSO2,或者-NHCO,m为0,1,2,3,4,5,6,7,8,9,或10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,或者24。在一些实施方式中,R7为H。
关于任何相关的结构示意图,例如,式4,式5,式6,式7,式8,式9,或者式10,R8为H,OH,或者C1-6烷基。在一些实施方式中,R8为H。在一些实施方式中,R8为OH。在一些实施方式中,R8为CH3。
关于任何相关的结构示意图,例如,式3E,R8A为OH,氧化物,C1-6有机基团,或者-O-(C1-6有机基团)。1-6个相同或者不同的R8A可连接至任何环C原子。在一些实施方式中,R8A为OH。在一些实施方式中,R8A为CH3。在一些实施方式中,两个不同的R8A(例如,CH3和OH)连接至同一环C原子。在一些实施方式中,R8A为-C(CH3)2OH。
关于任何相关的结构示意图,例如,式1,式1A,式1B,式2,式2A,式3A,式3B,式3C,式3D,式4,式5,式6,式7,式8,式9,或者式10,在一些实施方式中,R3和R4独立地为H或者C1-12有机基团;R1,R2,R5,R6,及R7独立地为F,Cl,Br,I,NO2,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra;R1A及R2A为Ra;Ra及Rb独立地为H或者C1-12有机基团;以及R8为H或者OH。在一些实施方式中,R5和R6或者R6和R7可任选地被连接以形成饱和的或者不饱和的环。
一些实施方式包括任选地取代的9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐。
一些实施方式包括:任选地取代的1-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;任选地取代的2-(乙氧基甲基)-1-异丁基-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的1-(4-氨基-9-甲氧基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;任选地取代的1-(4-氨基-2-(2-羟乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丁醇或其盐;任选地取代的1-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丙醇或其盐;任选地取代的4-((4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;或任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-异丁基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;任选地取代的2-(乙氧基甲基)-1-(2-异丙氧基乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的4-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丁醇或其盐;任选地取代的2-(乙氧基甲基)-9-异丁氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-9-异丁氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)甲磺酰胺或其盐;任选地取代的N-(2-(2-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)乙氧基)乙基)-甲磺酰胺或其盐;任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)乙酰胺或其盐;任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)甲磺酰胺或其盐;任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)硬脂酰胺或其盐;任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)乙酰胺或其盐;任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)-硬脂酰胺或其盐;任选地取代的2-(乙氧基甲基)-1-甲基-9-(2-吗啉乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-1-甲基-9-((四氢呋喃-3-基)氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-1-甲基-9-(吡咯烷-3-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-1-甲基-9-(哌啶-4-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)棕榈酰胺或其盐;任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)棕榈酰胺或其盐;任选地取代的9-(3-氨基丙氧基)-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的2-(乙氧基甲基)-9-异丙氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;任选地取代的1-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丙醇或其盐;任选地取代的2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-10-胺或其盐;任选地取代的(R)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;任选地取代的(S)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥(azenometheno))[1,5]氧杂吖辛因并(oxazocino)[4,3,2-de]喹啉-6-醇或其盐;任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并-[4,3,2-de]喹啉-6-醇或其盐;任选地取代的2-氨基-12-(乙氧基甲基)-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6(7H)-酮或其盐;或者任选地取代的叔丁基4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)哌啶-1-羧酸酯或其盐。
表3
一些实施方式包括:任选地取代的4-氨基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;或者任选地取代的4-氨基-2-异戊基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;任选地取代的2-异戊基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐;或者任选地取代的2-丁基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐。
表4
本文特别考虑下述实施方式。
实施方式1:下式表示的化合物或其盐:
其中,虚线表示存在化学键或不存在化学键;
A1为CR1,NR1A或者N;
A2为CR2,NR2A,O,或者S;
B1为CR5或者N;
B2为CR6或者N;
B3为CR7或者N;
R1和R2独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra;
X为化学键,O,NRa,-CO-,-SO-,或者-SO2-,-CONRa,烃基,并且R3为H或者C1-30有机基团;或者X-R3为F或者Cl;
R1A,R2A,R4,Ra及Rb独立地为H或者C1-30有机基团;
R5,R6及R7独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,-SO2Ra,或者-X1-(CmH2mO0-1)-Z-(CnH2n+1),-(CmH2mO0-1)-Z-(CnH2n+1),其中,R5和R6或者R6和R7可被任选地连接形成环;
其中,X1为化学键,O,NRa,-CO-,-SO-,或者-SO2-;
Z为化学键,O,NHSO2,或者NHCO;
m为0,1,2,3,4,5,6,7,8,9,或者10;以及
n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
实施方式2:如实施方式1所述的化合物,其进一步为由下式表示的化合物或其盐:
或者
其中,R3为C1-30有机基团。在一些实施方式中,R3为由1-6个R8A基团任选地取代的C1-3烷基,其中,R8A基团独立地为-OH,氧化物,C1-6有机基团,或者-O-(C1-6有机基团)。
实施方式3:如实施方式1所述的化合物,其进一步为由下式表示的化合物或其盐:
其中,R4为氢,C1-30非芳香族有机基团或者包含未直接连接至N原子的芳香族基团的C1-30芳香族有机基团。
实施方式4:如实施方式1,2或者3的化合物,其中,R1或者R1A为C1-12任选地取代的烷基。
实施方式5:如实施方式4的化合物,其中,R1或者R1A为-CrH2r+1O或其酯,其中,r为1,2,3,4,5,6,7,8,9,或10。
实施方式6:如实施方式5的化合物,其中,R1或者R1A为-C3H7O。
实施方式7:如实施方式6的化合物,其中,R1或者R1A为-CH2OCH2CH3。
实施方式8:如实施方式1,2,3,4,5,6,或者7的化合物,其中,R2或者R2A为H或者C1-12任选地取代的烷基。
实施方式9:如实施方式8的化合物,其中,R2或者R2A为C1-6烷基,或者-CyH2y+1O或其酯,其中,y为1,2,3,4,5,6,7,8,9,或10。
实施方式10:如实施方式9的化合物,其中,R2或者R2A为-C4H9O。
实施方式11:如实施方式10的化合物,其中,R2或者R2A为-CH2-CH(CH3)2-OH。
实施方式12:如实施方式8的化合物,其中,R2或者R2A为H。
实施方式13:如实施方式1,2,3,4,5,6,7,8,9,10,11,或者12的化合物,其中,R3为C1-30任选地取代的烷基。
实施方式14:如实施方式13的化合物,其中,R3为C1-10烷基,或者-CwH2w+1O或其酯,其中,w为1,2,3,4,5,6,7,8,9,或10。
实施方式15:如实施方式1,2,3,4,5,6,7,8,9,10,11,12或者13的化合物,其中,R3为-(CtH2tO0-1)-Ht,其中,t为0,1,2,3,4,5,6,7,8,9,或者10,以及Ht为任选地取代的C3-6杂环基。
实施方式16:如实施方式1,2,3,4,5,6,7,8,9,10,11,12或者13的化合物,其中,R3为-(CuH2uO0-1)-Z-(CvH2v+1),其中,Z为化学键,O,NHSO2,或者NHCO,u为0,1,2,3,4,5,或者6,以及v为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
实施方式17:如实施方式1,2,3,4,5,6,7,8,9,10,11,12或者13的化合物,其中,R3为-(CuH2uO0-1)-NRaRb,以及u为1,2,3,4,5,或者6,其中,Ra及Rb独立地为H或者C1-6烷基。
实施方式18:如实施方式14的化合物,其中,R3为C5H11O。
实施方式19:如实施方式18的化合物,其中,R3为-CH2-CH2-CH(CH3)2OH。
实施方式20:如实施方式17的化合物,其中,R3为-CH2-CH2-CH2-NH2。
实施方式21:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,或20的化合物,其中,R4为H或者C1-6烷基。
实施方式22:如实施方式21的化合物,其中,R4为H。
实施方式23:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,或22的化合物,其中,R5为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,其中,Ra和Rb独立地为H或者C1-6烷基。
实施方式24:如实施方式23的化合物,其中,R5为H。
实施方式25:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,或22的化合物,其中,R5为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,或者25。
实施方式26:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,或25的化合物,其中,R6为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,其中,Ra或者Rb独立地为H或者C1-6烷基。
实施方式27:如实施方式26的化合物,其中,R6为H。
实施方式28:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,或25的化合物,其中,R6为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10;以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
实施方式29:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,或28的化合物,其中,R7为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,其中,Ra或者Rb独立地为H或者C1-6烷基。
实施方式30:如实施方式29的化合物,其中,R7为H。
实施方式31:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,或28的化合物,其中,R7为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
实施方式32:如实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,或者31的化合物,R8为H,OH或者CH3。
实施方式33:如实施方式32的化合物,其中,R8为OH。
实施方式34:如实施方式32的化合物,其中,R8为H。
实施方式35:下列化合物或者这些化合物的盐,或者具有-OH基团的这些化合物的酯:
或者实施方式36:化合物为任选地取代的9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺。实施方式37:化合物为任选地取代的9-甲氧基-2H-吡唑并[3,4-c]喹啉-4-胺。实施方式38:实施方式36的化合物为:
任选地取代的1-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的2-(乙氧基甲基)-1-异丁基-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的1-(4-氨基-9-甲氧基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的1-(4-氨基-2-(2-羟乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丁醇或其盐;
任选地取代的1-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丙醇或其盐;
任选地取代的4-((4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-异丁基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-1-(2-异丙氧基乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-异丁氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-异丁氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)甲磺酰胺或其盐;
任选地取代的N-(2-(2-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)乙氧基)乙基)-甲磺酰胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)乙酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)甲磺酰胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)硬脂酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)乙酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)-硬脂酰胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(2-吗啉乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9((四氢呋喃-3-基)氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(吡咯烷-3-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(哌啶-4-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)棕榈酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)棕榈酰胺或其盐;
任选地取代的9-(3-氨基丙氧基)-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-异丙氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的1-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丙醇或其盐;
任选地取代的2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-10-胺或其盐;
任选地取代的(R)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;
任选地取代的(S)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;
任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并-[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的2-氨基-12-(乙氧基甲基)-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6(7H)-酮或其盐;
任选地取代的叔丁基4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)哌啶-1-羧酸酯或其盐。
实施方式39:实施方式37的化合物为:
任选地取代的4-氨基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;
任选地取代的4-氨基-2-异戊基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;
任选地取代的2-异戊基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐;
任选地取代的2-丁基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐。
实施方式40:治疗病毒感染,癌症或者过敏性疾病的方法,所述方法包括将实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,或者39的化合物给药于需要这种治疗的哺乳动物。
实施方式41:实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,或者39的化合物在制造用于治疗病毒感染,癌症或者过敏性疾病的药物中的应用。
实施方式42:实施方式40的方法或者实施方式41的应用,其中,所述病毒感染包括HCV感染。
实施方式43:适于给药于哺乳动物的剂型,其包括实施方式1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,或者39的化合物。
实施例:
在下文描述的合成方案中,除非另有说明,所有的温度均为摄氏度,所有的部分及百分比均为按重量计。试剂和溶剂购自例如Aldrich化学公司的供应商,除非另有说明,所述试剂和溶剂无需进一步提纯就可使用。从商业来源购买的四氢呋喃(THF)及N,N-二甲基甲酰胺(DMF)储存在密封瓶中,并且收到后就被使用。
下面列出的反应通常在环境温度下(除非另有说明),在无水溶剂中,氩气或氮气的正压力下进行。对玻璃器皿进行烘箱干燥和/或热干燥。采用TLC和/或LC-MS分析所述反应,通过起始物料的消耗判断所述反应的终止。分析型薄层层析(TLC)在预涂有0.25毫米硅胶60F254板(EM科学)的玻璃板上进行,并以紫外光(254nm)和/或以商售乙醇磷钼酸加热进行显像。制备型薄层层析(TLC)在预涂有0.5毫米硅胶60F254板(20x 20cm,来自商业来源)的玻璃板上进行,并以紫外光(254nm)进行显像。
通常通过使用反应溶剂或者萃取溶剂使反应体积加倍来进行反应,然后,除非另有说明,采用指明的水溶液(萃取体积的25体积%)进行洗涤操作。在无水Na2SO4和/或MgSO4上干燥产品溶液,之后进行过滤,在旋转蒸发器上,在减压条件下蒸发溶剂,并且需要注意的是,在真空条件下除去溶剂。使用230-400目的硅胶,在正压力条件下完成柱层析。
1H-NMR和13C-NMR光谱记录在在400MHZ条件下操作的Varian Mercury-VX400仪器上。NMR光谱使用CDCl3溶液(氯仿作为参比标准(7.27ppm表示质子,77.00ppm表示C));CD3OD(3.4ppm及4.8ppm表示质子,49.3ppm表示C),DMSO-d6(2.49ppm表示质子)获得,或者在适当的时候使用四甲基硅烷作为内参(0.00ppm)。根据需要可使用其他的NMR溶剂。
实施例1:
合成1-[4-氨基-2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇
方案1
步骤1:合成1-[(5-甲氧基-3-硝基-4-喹啉基)氨基]-2-甲基-2-丙醇
将4-氯-5-甲氧基-3-硝基-喹啉(1.00g,4.19mmol,1.0当量)加至1-氨基-2-甲基-2-丙醇(747.10mg,8.38mmol,2.0当量)和三乙胺(Et3N)(2.12g,20.95mmol,2.90mL,5.0当量)的DCM(50.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。采用水(30mL)和盐水(30mL)通过萃取来洗涤反应混合物。在无水Na2SO4上干燥有机相,过滤,在真空条件下浓缩。采用柱层析法(DCM:DCM/MeOH=20/1)纯化残留物。获得所需要的产品:1-[(5-甲氧基-3-硝基-4-喹啉基)氨基]-2-甲基-2-丙醇(1.00g,3.43mmol,产率81.86%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.51(s,1H),9.03(s,1H),7.63(t,J=8.0Hz,1H),7.58(d,J=8.4Hz,1H),6.94(d,J=7.2Hz,1H),4.10(s,3H),2.95(d,J=4.8Hz,2H),1.29(s,6H);ES-LCMS m/z 292.3[M+H]+。
步骤2:合成1-[(3-氨基-5-甲氧基-4-喹啉基)氨基]-2-甲基-2-丙醇
在N2条件下,将雷尼Ni(Raney-Ni)(626.42mg,7.31mmol,2.1当量)加至1-[(5-甲氧基-3-硝基-4-喹啉基)氨基]-2-甲基-2-丙醇(1.00g,3.43mmol,1.0当量)的MeOH(100.00mL)的溶液中。悬浮液在真空条件下脱气并用H2净化几次。在H2(15psi)条件下,在25℃下搅拌得到的混合物持续3h。将反应混合物过滤。滤液在真空条件下浓缩。获得所需要的产品:1-[(3-氨基-5-甲氧基-4-喹啉基)氨基]-2-甲基-2-丙醇)(870.00mg,3.33mmol,产率97.08%),黄色固体。1H NMR(400MHz,CD3OD)δppm:8.26(s,1H),7.38(d,J=8.0Hz,1H),7.31(t,J=8.0Hz,1H),6.88(d,J=7.6Hz,1H),4.02(s,3H),3.22(s,2H),1.29(s,6H);ES-LCMSm/z 262.3[M+H]+。
步骤3:合成1-[2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇
在120℃,微波条件下,搅拌1-[(3-氨基-5-甲氧基-4-喹啉基)氨基]-2-甲基-2-丙醇(400.00mg,1.53mmol,1.0当量)和MS(200mg)的2-乙氧乙酸(3.30g,31.7mmol,3mL,20.7当量)溶液持续4h。之后过滤反应混合物。将滤液溶解在DCM(80mL)中,并用2M NaOH调节至pH=8。将有机层分离,并在无水Na2SO4上干燥,过滤并在真空条件下浓缩。采用柱层析法(DCM:DCM/MeOH=10/1)纯化混合物。获得所需要的产品:1-[2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇(230.00mg,698.26μmol,产率45.62%),黄色固体。1H NMR(400MHz,CD3OD)δppm:9.09(s,1H),7.79(d,J=8.0Hz,1H),7.67(t,J=8.2Hz,1H),7.25(d,J=7.2Hz,1H),5.68(s,1H),5.39(s,1H),4.63(m,2H),4.14(s,3H),3.62(m,2H),1.32-1.26(m,3H),1.25-1.23(m,3H),0.76(m,3H);ES-LCMS m/z:330.3[M+H]+。
步骤4:合成1-[2-(乙氧基甲基)-9-甲氧基-5-氧化-咪唑并[4,5-c]喹啉-5-基-1-基]-2-甲基-2-丙醇
将m-CPBA(212.64mg,1.05mmol,纯度85%,1.5当量)加至1-[2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇(230.00mg,698.26μmol,1.0当量)的DCM(30.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续1h。使用K2CO3水溶液将反应混合物调节至pH=8,并在DCM(50mL)和水(20mL)之间分配所述反应混合物。分离有机层,用盐水(20mL)洗涤,在无水Na2SO4上干燥并过滤。过滤后,将滤液在真空条件下浓缩。采用制备型TCL(DCM/MeOH=8/1,Rf=0.3)纯化残留物。获得所需要的产品:1-[2-(乙氧基甲基)-9-甲氧基-5-氧化-咪唑并[4,5-c]喹啉-5-基-1-基]-2-甲基-2-丙醇)(150.00mg,434.29μmol,产率62.20%),黄色固体。1H NMR(400MHz,CD3OD)δppm:9.10(s,1H),8.52(d,J=8.8Hz,1H),7.85(t,J=8.6Hz,1H),7.45(d,J=7.6Hz,1H),5.54(s,1H),5.31(s,1H),4.58(s,2H),4.19(s,3H),3.62(m,2H),1.28-1.23(m,6H),0.84(m,3H);ES-LCMS m/z:346.3[M+H]+。
步骤5:合成1-[4-氨基-2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇
将TsCl(99.36mg,521.15μmol,1.2当量)加至1-[2-(乙氧基甲基)-9-甲氧基-5-氧化-咪唑并[4,5-c]喹啉-5-基-1-基]-2-甲基-2-丙醇(150.00mg,434.29μmol,1.0当量)及NH3·H2O(543.64mg,4.34mmol,597.41μL,纯度28%,10.0当量)的CHCl3(20.00mL)溶液中。在20℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:1-[4-氨基-2-(乙氧基甲基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇(50.00mg,131.28μmol,产率30.23%,纯度100%,为盐酸盐),白色固体。1H NMR(400MHz,CD3OD)δppm:7.63(t,J=8.2Hz,1H),7.30(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),5.50(s,1H),5.21(s,1H),4.76(s,1H),4.55(s,1H),4.09(s,3H),3.59(m,2H),1.23-1.20(m,6H),0.82(m,3H);ES-LCMS m/z:345.3[M+H]+。
实施例2:
合成2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉-4-胺
方案2
步骤1:合成2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉
将2-乙氧基乙酰氯(99.91mg,815.26μmol,2.0当量)加至N4-异丁基-5-甲氧基-喹啉-3,4-二胺(100.00mg,407.63μmol,1.0当量)及吡啶(322.44mg,4.08mmol,329.02μL,10.0当量)的DCM(4.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续1h。在真空条件下除去溶剂。将残留物溶解在NaOH(2M,4.95mL,24.3当量)中,并在100℃条件下持续搅拌5h。将混合物溶解在水(10mL)中并用DCM(50mL x 2)萃取。用盐水(20mL)洗涤合并的有机相,在无水Na2SO4上干燥,过滤并在真空条件下浓缩。采用制备型TCL(DCM/MeOH=15/1)纯化残留物。获得所需要的产品:2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉(80.00mg,255.27μmol,产率62.62%),棕色固体。1HNMR(400MHz,CDCl3)δppm:9.27(s,1H),7.70(d,J=8.4Hz,1H),7.60(t,J=8.2Hz,1H),7.04(d,J=8.0Hz,1H),4.89(s,2H),4.62(br,s.2H),4.08(s,3H),3.65-3.59(m,2H),2.11-2.02(m,1H),1.26(t,J=7.0Hz,3H),0.75-0.72(m,6H);ES-LCMS m/z:314.3[M+H]+。
步骤2:合成2-(乙氧基甲基)-1-异丁基-9-甲氧基-5-氧化-咪唑并[4,5-c]喹啉-5-基
将m-CPBA(48.59mg,239.33μmol,纯度85%,1.5当量)加至2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉(50.00mg,159.55μmol,1.0当量)的DCM(5.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。向所述混合中加入DCM(40mL)和水(10mL),并通过加入NaOH的水溶液将pH调至8。然后分离有机层,用盐水(10mL)洗涤,在无水Na2SO4上干燥并过滤。在真空条件下浓缩滤液。获得所需要的产品:2-(乙氧基甲基)-1-异丁基-9-甲氧基-5-氧化-咪唑并[4,5-c]喹啉-5-基(50.00mg,151.80μmol,产率95.14%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.05(s,1H),8.71(d,J=8.8Hz,1H),7.70(t,J=8.2Hz,1H),7.17(d,J=7.2Hz,1H),4.56(s,2H),4.44(br,s.2H),4.11(s,3H),3.65-3.59(m,2H),2.06-1.99(m,1H),1.27(t,J=7.0Hz,3H),0.76-0.72(m,6H);ES-LCMS m/z:330.2[M+H]+。
步骤3:合成2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉-4-胺
将TsCl(34.73mg,182.16μmol,1.2当量)加至2-(乙氧基甲基)-1-异丁基-9-甲氧基-5-氧化-咪唑并[4,5-c]-喹啉-5-基(50.00mg,151.80μmol,1.0当量)和NH3·H2O(190.27mg,1.52mmol,209.09μL,纯度28%,10.0当量)的CHCl3(10.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:2-(乙氧基甲基)-1-异丁基-9-甲氧基-咪唑并[4,5-c]喹啉-4-胺(30.00mg,78.31μmol,51.59%的产率,纯度95.24%,为盐酸盐),白色固体。1H NMR(400MHz,CD3OD)δppm:7.69(t,J=8.2Hz,1H),7.36(d,J=8.0Hz,1H),7.18(d,J=8.4Hz,1H),4.87(s,2H),4.62(br,s.2H),4.13(s,3H),3.69-3.64(m,2H),2.05-1.95(m,1H),1.27(t,J=7.0Hz,3H),0.80-0.75(m,6H);ES-LCMS m/z:329.4[M+H]+。
采用与实施例1或2的相同的方法,使用相应的试剂制备下述化合物。
获得1-[4-氨基-9-甲氧基-2-(2-甲氧基乙基)咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇的盐酸盐,白色固体,产率为9.18%,纯度为98.5%。1H NMR(400MHz,CD3OD)δppm:7.67(t,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),5.60(m,1H),4.48(m,1H),4.14(s,3H),3.97(m,2H),3.47-3.44(m,2H),3.42(s,3H),1.26(s,3H),0.89(s,3H);ES-LCMS m/z:345.3[M+H]+。
获得1-[4-氨基-2-(2-羟乙基)-9-甲氧基-咪唑并[4,5-c]喹啉-1-基]-2-甲基-2-丙醇的盐酸盐,白色固体,产率为3.47%,纯度为100%。1H NMR(400MHz,CD3OD)δppm:7.61(t,J=8.4Hz,1H),7.28(d,J=8.0Hz,1H),7.12(d,J=7.6Hz,1H),5.54(m,1H),4.41(m,1H),4.08(s,3H),4.07-4.05(m,2H),3.27(m,2H),1.20(s,3H),0.85(s,3H);ES-LCMS m/z:331.2[M+H]+。
获得4-[[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇的盐酸盐,白色固体,产率为40.57%。1H NMR(400MHz,CD3OD)δppm:7.68(t,J=8.4Hz,1H),7.34(d,J=8.4Hz,1H),7.15(d,J=8.4Hz,1H),4.84(s,2H),4.50(t,J=6.0Hz,2H),3.76-3.70(m,2H),2.19(t,J=5.8Hz,2H),1.43(s,6H),1.31(t,J=7.0Hz,3H);ES-LCMS m/z:345.3[M+H]+。
实施例3:
合成2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉-4-胺
方案3
步骤1:合成5-异戊氧基-3-硝基-喹啉-4-胺
将异戊基-4-甲基苯磺酸酯(1.06g,4.38mmol,3.0当量)的DCM(4.00mL)溶液加至4-氨基-3-硝基-喹啉-5-醇(300.00mg,1.46mmol,1.0当量),TBAB(470.66mg,1.46mmol,1.0当量)和KI(242.36mg,1.46mmol,1.0当量)的NaOH(1M,4.38mL,3.0当量)溶液中。在20℃条件下,搅拌得到的混合物持续40h。用水(10mL)稀释反应混合物并用DCM(30mL x 2)萃取。用盐水(10mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤并在减压条件下浓缩以提供残留物。采用柱层析法(PE:PE/EA=1/2)纯化所述残留物。获得所需要的产品:5-异戊氧基-3-硝基-喹啉-4-胺(140.00mg,508.54μmol,产率34.83%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.33(s,1H),9.25(s,1H),9.10(s,1H),7.66(t,J=8.2Hz,1H),7.57(d,J=8.4Hz,1H),6.94(d,J=7.6Hz,1H),4.28(t,J=6.2Hz,2H),1.88(m,3H),1.05(d,J=6.0Hz,6H);ES-LCMS m/z:276.3[M+H]+。
步骤2:合成5-异戊氧基喹啉-3,4-二胺
在N2条件下,将Raney-Ni(100.00mg,1.17mmol,2.3当量)加至5-异戊氧基-3-硝基-喹啉-4-胺(140.00mg,508.54μmol,1.0当量)的MeOH(50.00mL)溶液中。悬浮液在真空条件下脱气并用H2净化3次。在H2(15psi)条件下,在20℃下搅拌得到的混合物持续2h。将反应混合物过滤。滤液在真空条件下浓缩。获得所需要的产品:5-异戊氧基喹啉-3,4-二胺(120.00mg,489.16μmol,产率96.19%),绿色固体。1H NMR(400MHz,CD3OD)δppm:8.01(s,1H),7.53(t,J=8.2Hz,1H),7.27(d,J=8.8Hz,1H),6.96(d,J=8.0Hz,1H),4.30(t,J=6.2Hz,2H),1.89-1.87(m,3H),1.04(d,J=6.4Hz,6H);ES-LCMS m/z:246.3[M+H]+。
步骤3:合成2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉
将5-异戊氧基喹啉-3,4-二胺(110.00mg,448.39μmol,1.0当量),2-乙氧乙酸(1.21g,11.62mmol,1.10mL,25.9当量)和MS(150.00mg)置于微波管中。在微波,130℃条件下加热密封管持续1h。将固体过滤掉。用DCM(50mL)和水(20mL)稀释滤液。用NaOH(1M)的水溶液将混合物的pH调至7。分离各层。用盐水(20mL)洗涤有机相,在无水Na2SO4上干燥,过滤并在真空条件下浓缩。采用制备型TLC(DCM/MeOH=20/1)纯化残留物。获得所需要的产品:2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉(130.00mg,414.82μmol,产率92.51%),黄色固体。1H NMR(400MHz,CD3OD)δppm:9.10(s,1H),7.73(d,J=8.8Hz,1H),7.66(t,J=8.4Hz,1H),7.20(d,J=7.6Hz,1H),4.80(s,2H),4.48(t,J=6.6Hz,2H),3.73-3.68(m,2H),1.95-1.88(m,3H),1.29(t,J=7.0Hz,3H),1.05(d,J=6.0Hz,6H);ES-LCMS m/z:314.3[M+H]+。
步骤4:合成2-(乙氧基甲基)-9-异戊氧基-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基
将m-CPBA(126.33mg,622.23μmol,纯度85%,1.5当量)加至2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉(130.00mg,414.82μmol,1.0当量)的DCM(30.00mL)溶液中。在20℃条件下搅拌得到的混合物持续0.5h。用DCM(20mL)稀释反应混合物,并用饱和的K2CO3(10mL)通过萃取洗涤所述反应混合物。用盐水(15mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤并在减压条件下浓缩。获得所需要的产品:2-(乙氧基甲基)-9-异戊氧基-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基(130.00mg,394.67μmol,产率95.14%),棕色固体。1H NMR(400MHz,CD3OD)δppm:9.11(s,1H),8.31(d,J=8.4Hz,1H),7.82(t,J=8.8Hz,1H),7.41-7.38(m,1H),4.88(s,2H),4.54(t,J=6.6Hz,2H),3.73-3.67(m,2H),1.94-1.86(m,3H),1.29(t,J=7.0Hz,3H),1.04(d,J=6.0Hz,6H);ES-LCMS m/z:330.3[M+H]+。
步骤5:合成2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉-4-胺
将TsCl(112.87mg,592.00μmol,1.5当量)加至2-(乙氧基甲基)-9-异戊氧基-5-氧化-1H-咪唑并[4,5-c]-喹啉-5-基(130.00mg,394.67μmol,1.0当量)及NH3·H2O(494.04mg,3.95mmol,542.90μL,纯度28%,10.0当量)的CHCl3(6.00mL)溶液中。在25℃条件下搅拌得到的混合物持续0.5h。然后,在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:2-(乙氧基甲基)-9-异戊氧基-1H-咪唑并[4,5-c]喹啉-4-胺(75.00mg,196.61μmol,产率49.82%,纯度95.65%,盐酸盐固体),白色固体。1H NMR(400MHz,CD3OD)δppm:7.68(t,J=8.2Hz,1H),7.33(d,J=8.4Hz,1H),7.17(d,J=8.4Hz,1H),4.86(s,2H),4.51(t,J=6.8Hz,2H),3.75-3.70(m,2H),1.94-1.86(m,3H),1.31(t,J=7.0Hz,3H),1.05(d,J=6.4Hz,6H);ES-LCMS m/z:329.3[M+H]+。
采用与实施例3描述的方法相同的方法,使用相应的试剂制备下述化合物。
获得4-[[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]2-丁醇的盐酸盐为白色固体,产率为20.06%,纯度为100%。1H NMR(400MHz,CD3OD)δppm:7.65(t,J=8.4Hz,1H),7.31(d,J=8.0Hz,1H),7.13(d,J=8.4Hz,1H),4.79(s,2H),4.54-4.53(m,1H),4.42-4.40(m,1H),4.25-4.16(m,1H),3.72-3.66(m,2H),2.15-2.09(m,2H),1.35(d,J=6.4Hz,3H),1.27(t,J=7.0Hz,3H);ES-LCMS m/z:330.9[M+H]+。
实施例4:
合成1-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丙醇方案4
步骤1:合成1-[(4-氨基-3-硝基-5-喹啉基)氧]丙-2-酮
在25℃条件下,将乙酰甲基-4-甲基苯磺酸酯(3.33g,14.61mmo,3.0当量)的DCM(8.00mL)溶液加至4-氨基-3-硝基-喹啉-5-醇(1.00g,4.87mmol,1.0当量),TBAB(1.57g,4.87mmol,1.0当量),KI(809.09mg,4.87mmol,1.0当量)的NaOH(2M,7.31mL,3.0当量)溶液中。在25℃条件下,搅拌混合物持续48h。用水(20mL)稀释反应混合物,并用DCM(50mL x 2)萃取。用盐水(20mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤并在减压条件下浓缩以提供残留物。采用柱层析法(DCM:DCM/MeOH=20/1)纯化残留物。获得所需要的产品:1-[(4-氨基-3-硝基-5-喹啉基)氧]丙-2-酮(220.00mg,842.17μmol,产率17.29%),黄色固体。1HNMR(400MHz,CDCl3)δppm:9.84(br s,1H),9.41(br s,1H),9.35(s,1H),7.66-7.60(m,2H),6.80-6.77(m,1H),4.92(s,2H),2.37(s,3H);ES-LCMS m/z:262.2[M+H]+。
步骤2:合成1-[(3,4-二氨基-5-喹啉基)氧]-2-丙醇
在N2条件下,将Raney-Ni(100.29mg,1.17mmol,1.39当量)加至1-[(4-氨基-3-硝基-5-喹啉基)氧]丙-2-酮(220.00mg,842.17μmol,1.0当量)的MeOH(100.00mL)溶液中。悬浮液在真空条件下脱气并用H2净化几次。在H2(15psi)条件下,在25℃条件下搅拌混合物持续1h。将固体过滤掉。滤液在真空条件下浓缩。获得所需要的产品:1-[(3,4-二氨基-5-喹啉基)氧]-2-丙醇(160.00mg,685.90μmol,产率81.44%),绿色固体。1H NMR(400MHz,CD3OD)δppm:7.95(s,1H),7.64-7.60(m,1H),7.28-7.26(m,1H),7.02-6.90(m,1H),4.32-4.29(m,2H),4.07-4.04(m,1H),1.33(d,J=6.4Hz,3H);ES-LCMS m/z:234.1[M+H]+。
步骤3:合成1-[[2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]2-丙醇
将1-[(3,4-二氨基-5-喹啉基)氧]2-丙醇(150.00mg,643.03μmol,1.0当量),2-乙氧乙酸(1.10g,10.57mmol,1.00mL,16.4当量)和MS(50.00mg)置于微波管中。在微波,120℃条件下加热密封管持续0.5h。将3M NaOH(10mL)的水溶液和THF(3mL)加至反应混合物中。在50℃条件下,搅拌得到的混合物持续2h。用乙酸乙酯(50mL x 3)萃取混合物。将合并的有机层用饱和的盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤并在减压条件下浓缩以提供残留物。采用制备型TLC(DCM/MeOH=15/1)纯化所述残留物。获得所需要的产品:1-[[2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]2-丙醇(23.00mg,76.33μmol,产率11.87%),黄色固体。1H NMR(400MHz,CDCl3)δppm:11.52(s,1H),9.20(s,1H),7.81(d,J=8.4Hz,1H),7.50(t,J=8.0Hz,1H),6.97(d,J=7.6Hz,1H),4.83(s,2H),4.42(m,1H),4.32-4.28(m,1H),4.02(t,J=8.2Hz,1H),3.64-3.61(m,2H),1.40(m,3H),1.25(m,3H);ES-LCMS m/z:302.2[M+H]+。
步骤4:合成1-[[2-(乙氧基甲基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-丙醇
在25℃的条件下,将m-CPBA(30.99mg,152.65μmol,纯度85%,2.0当量)一次性加至1-[[2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]2-丙醇(23.00mg,76.33μmol,1.0当量)的DCM(8.00mL)的混合物中。在25℃条件下,搅拌混合物持续1h。在真空条件下除去溶剂。无需进一步纯化,将粗产品用于下一步骤中。获得粗产品:1-[[2-(乙氧基甲基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-丙醇(20.00mg,63.02μmol,产率82.57%),棕色固体。1H NMR(400MHz,CDCl3)δppm:9.17(s,1H),8.39(d,J=8.8Hz,1H),7.47-7.45(m,1H),7.05-7.01(m,1H),4.86(s,2H),4.48(m,1H),4.37(m,1H),4.06(d,J=8.4Hz,1H),3.74-3.71(m,2H),1.47(br d,J=6.4Hz,3H),1.35(t,J=7.2Hz,3H);ES-LCMSm/z:=318.2[M+H]+。
步骤5:合成1-[[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-丙醇
在25℃条件下,将TsCl(24.03mg,126.05μmol,2.0当量)加至1-[[2-(乙氧基甲基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-丙醇(20.00mg,63.02μmol,1.0当量)和NH3·H2O(78.89mg,630.24μmol,86.69μL,纯度28%,10.0当量)的CHCl3(6.00mL)的混合物中。在25℃条件下,搅拌混合物持续3h。在减压条件下浓缩反应混合物以除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:1-[[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-丙醇(4.68mg,13.26μmol,产率21.04%,盐酸盐),白色固体。1H NMR(400MHz,CD3OD)δppm:7.66(t,J=8.4Hz,1H),7.35(d,J=8.4Hz,1H),7.20(d,J=8.4Hz,1H),4.83(s,2H),4.42-4.39(m,1H),4.36(m,1H),4.18-4.16(m,1H),3.71-3.68(m,2H),1.36(d,J=6.4Hz,3H),1.29(t,J=7.2Hz,3H);ES-LCMS m/z:317.2[M+H]+。
实施例5:
合成4-[[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇
方案5
步骤1:合成4-[[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇
将3-甲氧基丙酰氯(80.66mg,658.20μmol,2.0当量)加至4-[(3,4-二氨基-5-喹啉基)氧]-2-甲基-2-丁醇(179.17mg,329.10μmol,1.0当量)和吡啶(260.32mg,3.29mmol,265.63μL,10.0当量)的DCM(2.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续16h。在真空条件下除去溶剂。将残留物溶解在NaOH(2M,4.00mL,24.3当量)中,并在100℃条件下持续搅拌1h。用水(10mL)稀释混合物,并用DCM(50mL x 2)萃取。用盐水(30mL)洗涤合并的有机相,在无水Na2SO4上干燥,过滤并在真空条件下浓缩。采用制备型TLC(DCM/MeOH=15/1)纯化残留物。获得所需要的产品:4-[[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇(90.00mg,273.23μmol,产率83.02%),棕色固体。1H NMR(400MHz,CD3OD)δppm:9.08(s,1H),7.73(d,J=8.4Hz,1H),7.65(t,J=8.0Hz,1H),7.18(d,J=7.2Hz,1H),4.51(t,J=6.0Hz,2H),3.93(t,J=6.4Hz,2H),3.42(s,3H),3.33-3.28(m,2H),2.23(t,J=6.0Hz,2H),1.44(s,6H);ES-LCMS m/z:330.3[M+H]+。
步骤2:合成4-[[2-(2-甲氧基乙基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-甲基-2-丁醇
将m-CPBA(83.21mg,409.85μmol,纯度85%,1.5当量)加至4-[[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇(90.00mg,273.23μmol,1.0当量)的DCM(10.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型TLC(DCM/MeOH=15/1)纯化残留物。获得所需要的产品:4-[[2-(2-甲氧基乙基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-甲基-2-丁醇(60.00mg,173.72μmol,产率63.58%),黄色固体。1H NMR(400MHz,CDCl3)δppm:8.97(s,1H),8.36(d,J=8.8Hz,1H),7.54(t,J=8.4Hz,1H),6.94(d,J=8.0Hz,1H),4.38(t,J=5.6Hz,2H),3.81(t,J=6.2Hz,2H),3.40(s,3H),3.17(t,J=6.0Hz,2H),2.24(t,J=5.6Hz,2H),1.48(s,6H);ES-LCMS m/z:345.9[M+H]+。
步骤3:合成4-[[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇
将TsCl(66.24mg,347.44μmol,2.0当量)加至4-[[2-(2-甲氧基乙基)-5-氧化-1H-咪唑并[4,5-c]喹啉-5-基-9-基]氧]-2-甲基-2-丁醇(60.00mg,173.72μmol,1.0当量)和NH3·H2O(217.81mg,1.74mmol,239.35μL,纯度28%,10.0当量)的CHCl3(6.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:4-[[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基]氧]-2-甲基-2-丁醇(24.95mg,63.20μmol,产率36.38%,纯度96.48%,盐酸盐固体),白色固体。1H NMR(400MHz,CD3OD)δppm:7.66(t,J=8.2Hz,1H),7.32(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),4.49(t,J=6.0Hz,2H),3.93(t,J=6.6Hz,2H),3.42(s,3H),3.26(t,J=6.2Hz,2H),2.19(t,J=5.8Hz,2H),1.43(s,6H);ES-LCMS m/z:345.3[M+H]+。
实施例6:
合成4-[4-氨基-2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
方案6
步骤1:合成4-(甲基氨基)-3-硝基-喹啉-5-醇
在-78℃条件下,将BBr3(1.62g,6.45mmol,621.48μL,5.0当量)滴加至5-甲氧基-N-甲基-3-硝基-喹啉-4-胺(300.00mg,1.29mmol,1.0当量)的DCM(15.00mL)溶液中。在60℃条件下,搅拌得到的混合物持续2h。在-30℃条件下,将所述混合物滴加至MeOH(100mL)中。在真空条件下除去溶剂。获得所需要的产品:4-(甲基氨基)-3-硝基-喹啉-5-醇(300.00mg,粗产品),棕色固体。1H NMR(400MHz,CD3OD)δppm:9.22(s,1H),7.79(m,1H),7.33(m,1H),7.15-7.13(m,1H),3.08(s,3H);ES-LCMS m/z:220.2[M+H]+。
步骤2:合成2-甲基-4-[[4-(甲基氨基)-3-硝基-5-喹啉基]氧]2-丁醇
将(3-羟基-3-甲基-丁基)4-甲基苯磺酸酯(883.49mg,3.42mmol,3.0当量)的DCM(3.00mL)溶液加至4-(甲基氨基)-3-硝基-喹啉-5-醇(250.00mg,1.14mmol,1.0当量),TBAB(367.67mg,1.14mmol,1.0当量)和KI(189.32mg,1.14mmol,1.0当量)的NaOH(2M,1.71mL,3.0当量)溶液中。在25℃条件下,搅拌得到的混合物持续64h。用水(10mL)稀释反应混合物,并用DCM(30mL x 2)萃取。用盐水(10mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤并在减压条件下浓缩以提供残留物。采用柱层析法(DCM/MeOH=20/1)纯化所述残留物。获得所需要的产品:2-甲基-4-[[4-(甲基氨基)-3-硝基-5-喹啉基]氧]2-丁醇)(100.00mg,327.51μmol,产率28.73%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.36(s,1H),9.02(s,1H),7.61-7.55(m,2H),6.91(d,J=6.8Hz,1H),4.36(t,J=5.8Hz,2H),2.84(d,J=5.2Hz,3H),2.13(t,J=5.8Hz,2H),1.41(s,6H);ES-LCMS m/z:306.0[M+H]+。
步骤3:合成4-[[3-氨基-4-(甲基氨基)-5-喹啉基]氧]-2-甲基-2-丁醇
在N2条件下,将Raney-Ni(100.00mg,1.17mmol,3.6当量)加至2-甲基-4-[[4-(甲基氨基)-3-硝基-5-喹啉基]氧]2-丁醇(100.00mg,327.51μmol,1.0当量)的MeOH(50.00mL)溶液中。所得的悬浮液在真空条件下脱气并用H2净化几次。在H2(15psi)条件下,在25℃下搅拌得到的混合物持续1h。将混合物过滤。滤液在真空条件下浓缩。获得所需要的产品:4-[[3-氨基-4-(甲基氨基)-5-喹啉基]氧]-2-甲基-2-丁醇(80.00mg,290.54μmol,产率88.71%),绿色固体。1H NMR(400MHz,CD3OD)δppm:8.07(s,1H),7.44(t,J=8.0Hz,1H),7.29(d,J=8.4Hz,1H),6.95(d,J=7.6Hz,1H),4.35(t,J=6.4Hz,2H),3.19(d,J=10.4Hz,3H),2.10(d,J=6.4Hz,2H),1.33(s,6H);ES-LCMS m/z:276.3[M+H]+。
步骤4:合成4-[2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
将4-[[3-氨基-4-(甲基氨基)-5-喹啉基]氧]-2-甲基-2-丁醇(70.00mg,254.22μmol,1.0当量),2-乙氧乙酸(1.65g,15.85mmol,1.50mL,62.4当量)和MS(100.00mg)置于微波管中。在微波,120℃条件下加热密封管持续30分钟。过滤混合物。用DCM(50mL)和水(10mL)稀释滤液,并用NaOH(2M)的水溶液将pH调节至7。分离有机层,用盐水(10mL)洗涤有机层,在无水Na2SO4上干燥,过滤并在真空条件下浓缩。采用制备型TLC(DCM/MeOH=15/1)纯化粗产品。获得所需要的产品:4-[2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(20.00mg,58.24μmol,产率22.91%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.25(s,1H),7.88(d,J=7.6Hz,1H),7.59(t,J=8.2Hz,1H),7.10(d,J=7.2Hz,1H),4.89(s,2H),4.48(t,J=7.6Hz,2H),4.32(s,3H),3.66-3.61(m,2H),2.20(t,J=7.6Hz,2H),1.38(s,6H),1.26(m,3H);ES-LCMS m/z:344.3[M+H]+。
步骤5:合成4-[2-(乙氧基甲基)-1-甲基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇
将m-CPBA(23.65mg,116.48μmol,纯度85%,2.0当量)加至4-[2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(20.00mg,58.24μmol,1.0当量)的DCM(5.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型TLC(DCM/MeOH=10/1)纯化残留物。获得所需要的产品:4-[2-(乙氧基甲基)-1-甲基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇(20.00mg,粗产品),白色固体。1H NMR(400MHz,CDCl3)δppm:9.28(s,1H),8.70(d,J=8.8Hz,1H),7.71(t,J=8.2Hz,1H),7.22(d,J=8.0Hz,1H),4.86(s,2H),4.52-4.48(m,2H),4.28(s,3H),3.67-3.61(m,2H),2.23-2.16(m,2H),1.35(s,6H),1.29-1.27(m,3H);ES-LCMS m/z:360.3[M+H]+。
步骤6:合成4-[4-氨基-2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
将TsCl(15.91mg,83.47μmol,1.5当量)加至4-[2-(乙氧基甲基)-1-甲基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇(20.00mg,55.65μmol,1.0当量)和NH3·H2O(69.66mg,556.45μmol,76.54μL,纯度28%,10.0当量)的CHCl3(2.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:4-[4-氨基-2-(乙氧基甲基)-1-甲基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(6.00mg,15.19μmol,产率27.30%,盐酸盐),白色固体。1H NMR(400MHz,CD3OD)δppm:7.65(t,J=8.2Hz,1H),7.31(d,J=8.4Hz,1H),7.18(d,J=8.0Hz,1H),4.85(s,2H),4.48(t,J=7.8Hz,2H),4.26(s,3H),3.68-3.63(m,2H),2.16(t,J=7.8Hz,2H),1.31(s,6H),1.26(t,J=6.8Hz,3H);ES-LCMS m/z:359.3[M+H]+。
采用与实施例5和6描述的方法类似的方法,使用相应的试剂制备下述化合物。
获得2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺,白色固体盐酸盐,产率为40.79%,纯度为100%。1H NMR(400MHz,CD3OD)δppm:7.63(t,J=8.2Hz,1H),7.30(d,J=8.4Hz,1H),7.18(d,J=8.0Hz,1H),4.79(s,2H),4.54-4.51(m,2H),3.94-3.91(m,2H),3.75-3.69(m,1H),3.66-3.64(m,2H),1.24(t,J=7.0Hz,3H),1.15(d,J=6.0Hz,6H);ES-LCMS m/z:345.3[M+H]+。
实施例7:
合成4-[4-氨基-2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
方案7
步骤1:合成3-氨基-4-(异丁基氨基)喹啉-5-醇
在-78℃条件下,将BBr3(2.30g,9.17mmol,883.73μL,5.0当量)滴加至N4-异丁基-5-甲氧基-喹啉-3,4-二胺(450.00mg,1.83mmol,1.0当量)的DCM(30.00mL)溶液中。在60℃条件下,搅拌得到的混合物持续2h。在-30℃条件下,将所述混合物滴加至MeOH(100mL)中。在真空条件下除去溶剂。获得所需要的产品:3-氨基-4-(异丁基氨基)喹啉-5-醇)(500.00mg,1.64mmol,产率89.81%的,盐酸(2HCl)盐),棕色固体。1H NMR(400MHz,CD3OD)δppm:8.19(s,1H),7.65(t,J=8.2Hz,1H),7.24(d,J=8.4Hz,1H),6.97(d,J=7.2Hz,1H),3.80(d,J=6.4Hz,2H),2.07-2.02(m,1H),1.10(d,J=6.4Hz,6H);ES-LCMS m/z:232.3[M+H]+。
步骤2:合成2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-醇
将2-乙氧基乙酰氯(271.92mg,2.22mmol,1.5当量)加至3-氨基-4-(异丁基氨基)喹啉-5-醇(450.00mg,1.48mmol,1.0当量,盐酸(2HCl)盐)的吡啶(4.90g,61.95mmol,5.0mL,41.9当量)溶液中。在25℃条件下,搅拌得到的混合物持续1h。在真空条件下除去溶剂。将残留物溶解在NaOH(2M,7.40mmol,3.0mL,5.0当量)中,并在100℃的条件下持续搅拌2h。混合物在DCM(40mL)和水(10mL)之间分配。分离有机层,用盐水(10mL)洗涤,在无水Na2SO4上干燥,过滤,并在真空条件下浓缩。采用柱层析法(DCM:DCM/MeOH=10/1)纯化残留物。获得所需要的产品:2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-醇(100.00mg,334.03μmol,产率2.58%),红色固体。1H NMR(400MHz,CD3OD)δppm:9.06(s,1H),7.69-7.67(m,1H),7.56(t,J=8.0Hz,1H),7.11-7.08(m,1H),4.89(s,2H),4.65-4.63(m.2H),3.68-3.62(m,2H),2.24-2.16(m,1H),1.26(t,J=7.0Hz,3H),0.79-0.76(m,6H);ES-LCMS m/z:300.3[M+H]+。
步骤3:合成4-[2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
将(3-羟基-3-甲基-丁基)4-甲基苯磺酸酯(155.32mg,601.26μmol,3.0当量)的DCM(3.00mL)溶液加至2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-醇(60.00mg,200.42μmol,1.0当量),TBAB(64.61mg,200.42μmol,1.0当量)和KI(33.27mg,200.42μmol,1.0当量)的NaOH(2M,300.63μL,3.0当量)溶液中。在25℃条件下,搅拌得到的混合物持续64h。将反应混合物用水(20mL)稀释,并用DCM(50mL x 2)萃取。用盐水(20mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤,并在减压条件下浓缩以提供残留物。采用柱层析法(DCM:DCM/MeOH=10/1)纯化所述残留物。获得所需要的产品:4-[2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(60.00mg,155.64μmol,77.66%的产率),红色固体。1H NMR(400MHz,CDCl3)δppm:9.26(s,1H),7.88(d,J=8.4Hz,1H),7.59(t,J=8.2Hz,1H),7.09(d,J=7.2Hz,1H),4.88(s,2H),4.68(br,s.2H),4.48(t,J=7.4Hz,2H),3.65-3.59(m,2H),2.19(t,J=7.6Hz,2H),2.06-2.02(m,1H),1.34(s,6H),1.28-1.24(m,3H),0.66(d,J=6.0Hz,6H);ES-LCMS m/z:386.4[M+H]+。
步骤4:合成4-[2-(乙氧基甲基)-1-异丁基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇
将m-CPBA(47.40mg,233.46μmol,纯度85%,1.5当量)加至4-[2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(60.00mg,155.64μmol,1.0当量)的DCM(10.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型TLC(DCM/MeOH=10/1)纯化残留物。获得所需要的产品:4-[2-(乙氧基甲基)-1-异丁基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇(50.00mg,124.53μmol,产率80.01%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.07(s,1H),8.68(d,J=8.0Hz,1H),7.68(t,J=8.4Hz,1H),7.22(d,J=8.0Hz,1H),4.84(s,2H),4.61(br,s.2H),4.51(t,J=7.8Hz,2H),3.65-3.59(m,2H),2.19(t,J=7.6Hz,2H),1.99-1.94(m,1H),1.35(s,6H),1.29-1.27(m,3H),0.67(d,J=6.0Hz,6H);ES-LCMS m/z:402.4[M+H]+。
步骤5:合成4-[4-氨基-2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇
将TsCl(28.49mg,149.44μmol,1.2当量)加至4-[2-(乙氧基甲基)-1-异丁基-5-氧化-咪唑并[4,5-c]喹啉-5-基-9-基]氧-2-甲基-2-丁醇(50.00mg,124.53μmol,1.0当量)和NH3·H2O(155.89mg,1.25mmol,171.31μL,纯度28%,10.0当量)的CHCl3(5.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。在真空条件下除去溶剂。采用制备型HPLC(MeCN/H2O为洗脱液,酸性条件)纯化残留物。冻干后,获得所需要的产品:4-[4-氨基-2-(乙氧基甲基)-1-异丁基-咪唑并[4,5-c]喹啉-9-基]氧-2-甲基-2-丁醇(26.50mg,60.38μmol,48.48%的产率,纯度99.56%,盐酸盐),白色固体。1H NMR(400MHz,CD3OD)δppm:7.69(t,J=8.2Hz,1H),7.34(t,J=8.0Hz,1H),7.22(d,J=8.4Hz,1H),4.87(s,2H),4.71(br,s.2H),4.53(t,J=7.6Hz,1H),3.69-3.63(m,2H),2.18(t,J=7.6Hz,2H),2.02-1.97(m,1H),1.29(s,6H),1.26(t,J=7.0Hz,3H),0.74(d,J=4.2Hz,6H);ES-LCMS m/z:401.4[M+H]+。
实施例8
中间体的制备
中间体1:4-氯-5-甲氧基-3-硝基-喹啉
方案8
步骤1:合成2-甲氧基-6-[[(E)-2-硝基乙烯基]氨基]苯甲酸
在0℃条件下,将CH3NO2(23.73g,388.84mmol,21.00mL,1.3当量)加至NaOH(40.20g,1.01mol,3.4当量)的水(100mL)溶液中。将混合物升温至40℃,并在40℃条件下缓慢地加入额外量的CH3NO2(23.73g,388.84mmol,21.00mL,1.3当量)。维持温度为40℃直至所有的固体溶解并获得澄清的红色溶液。通过倒入300g碎冰将所述溶液冷却至30℃,并用浓HCl(100mL)酸化。立即将混合物加至2-氨基-6-甲氧基-苯甲酸(50.00g,299.11mmol,1.0当量)及浓HCl(35mL)的水(1400mL)溶液中。在20℃的条件下搅拌上述溶液持续16h。过滤混合物。用水(300mL x 3)洗涤块状物,并在真空条件下干燥。获得所需要的产品:2-甲氧基-6-[[(E)-2-硝基乙烯基]氨基]苯甲酸)(67.00g,281.28mmol,产率94.04%),黄色固体。1HNMR(400MHz,CD3OD)δppm:7.70(d,J=6.0Hz,1H),7.51(t,J=8.4Hz,1H),7.11(d,J=8.4Hz,1H),6.93(d,J=8.4Hz,1H),6.68(d,J=6.0Hz,1H),3.89(d,J=4.4Hz,3H);ES-LCMSm/z:261.1[M+Na]+。
步骤2:合成5-甲氧基-3-硝基-喹啉-4-醇
在105℃的条件下,加热2-甲氧基-6-[[(E)-2-硝基乙烯基]氨基]苯甲酸(56.00g,235.10mmol,1.0当量)的Ac2O(300.00mL)溶液持续0.5h,并获得澄清的溶液。向所述溶液中加入AcOK(27.69g,282.12mmol,1.2当量)。在105℃的条件下,搅拌得到的混合物持续2h。过滤混合物。用醋酸(30mL x 2)和水(100mL x 3)洗涤块状物。将所述块状物在油泵上干燥。获得所需要的产品:5-甲氧基-3-硝基-喹啉-4-醇(19.00g,86.29mmol,产率36.70%),类白色固体。1H NMR(400MHz,DMSO-d6)δppm:12.59(s,1H),8.96(s,1H),7.62(t,J=8.2Hz,1H),7.16(d,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),3.83(s,3H);ES-LCMS m/z:221.2[M+H]+。
步骤3:合成4-氯-5-甲氧基-3-硝基-喹啉
将DMF(66.39mg,908.35μmol,69.89μL,0.1当量)加至5-甲氧基-3-硝基-喹啉-4-醇(2.00g,9.08mmol,1.0当量)的SOCl2(8.20g,68.92mmol,5.00mL,7.6当量)悬浮液中。在80℃条件下,搅拌得到的混合物持续4h。在真空条件下除去溶剂。获得所需要的产品:4-氯-5-甲氧基-3-硝基-喹啉(2.10g,8.80mmol,产率96.92%),棕色固体。1H NMR(400MHz,CDCl3)δppm:9.12(s,1H),8.08(t,J=8.8Hz,1H),7.96-7.92(m,1H),7.20(d,J=8.4Hz,1H),4.08(s,3H);ES-LCMS m/z:239.2[M+H]+。
中间体2:4-氨基-3-硝基-喹啉-5-醇
方案9
步骤1:合成5-甲氧基-3-硝基-喹啉-4-胺
在0℃条件下,将4-氯-5-甲氧基-3-硝基-喹啉(5.28g,22.13mmol,1.0当量)的THF(50mL)溶液滴加至NH3·H2O(91.00g,726.96mmol,100.00mL,纯度28%,32.9当量)的THF(100mL)中。在25℃的条件下,搅拌混合物持续2h。将反应混合物过滤。用水(50mL x 3)洗涤残留物,并在真空条件下干燥。获得所需要的产品:5-甲氧基-3-硝基-喹啉-4-胺(4.83g,22.03mmol,产率99.55%),黄色固体。1H NMR(400MHz,CD3OD)δppm:9.17(s,1H),7.75(t,J=8.4Hz,1H),7.46(d,J=8.4Hz,1H),7.15(d,J=8.0Hz,1H),4.13(s,3H);ES-LCMS m/z:220.2[M+H]+。
步骤2:合成4-氨基-3-硝基-喹啉-5-醇
在-78℃条件下,将BBr3(22.86g,91.20mmol,8.79mL,10.0当量)滴加至5-甲氧基-3-硝基-喹啉-4-胺(2.00g,9.12mmol,1.0当量)的DCM(100.00mL)溶液中。在60℃条件下,搅拌反应混合物持续16h。在-30℃条件下,将所述反应混合物加至MeOH(200mL)中,然后在减压条件下进行浓缩以提供残留物。将所述残留物悬浮在DCM中,并过滤。在真空条件下干燥块状物。获得所需要的产品:4-氨基-3-硝基-喹啉-5-醇(2.53g,粗产品),绿色固体。1H NMR(400MHz,CD3OD)δppm:9.41(s,1H),7.83(t,J=8.4Hz,1H),7.33(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H);ES-LCMS m/z:206.2[M+H]+。
中间体3:N4-异丁基-5-甲氧基-喹啉-3,4-二胺
方案10
步骤1:合成N-异丁基-5-甲氧基-3-硝基-喹啉-4-胺
将4-氯-5-甲氧基-3-硝基-喹啉(1.00g,4.19mmol,1.0当量)加至2-甲基丙烷-1-胺(612.91mg,8.38mmol,828.26μL,2.0当量)和Et3N(2.12g,20.95mmol,2.90mL,5.0当量)的DCM(50.00mL)溶液中。在25℃条件下,搅拌得到的混合物持续0.5h。用水(30mL)和盐水(30mL)通过萃取洗涤反应混合物。有机相在无水Na2SO4上干燥,过滤,并在真空条件下浓缩。采用柱层析法(PE:PE/EtOAc=1/1)纯化残留物。获得所需要的产品:N-异丁基-5-甲氧基-3-硝基-喹啉-4-胺(1.00g,3.63mmol,产率86.69%),黄色固体。1H NMR(400MHz,CD3OD)δppm:8.85(s,1H),7.70(t,J=8.2Hz,1H),7.47(d,J=7.6Hz,1H),7.16(d,J=8.0Hz,1H),4.14(s,3H),2.85(d,J=6.4Hz,2H),2.04-1.94(m,1H),1.00(d,J=6.8Hz,6H);ES-LCMS m/z:276.2[M+H]+。
步骤2:合成N4-异丁基-5-甲氧基-喹啉-3,4-二胺
在N2条件下,将Raney-Ni(100.00mg,1.17mmol,1.1当量)加至N-异丁基-5-甲氧基-3-硝基-喹啉-4-胺(300.00mg,1.09mmol,1.0当量)的MeOH(50.00mL)溶液中。所得的悬浮液在真空条件下脱气并用H2净化几次。在H2(15psi)条件下,在25℃下搅拌混合物持续1h。过滤反应混合物。滤液在真空条件下进行浓缩。获得所需要的产品:N4-异丁基-5-甲氧基-喹啉-3,4-二胺(250.00mg,1.02mmol,产率93.49%),黄色固体。1H NMR(400MHz,CD3OD)δppm:8.28(s,1H),7.42-7.40(m,1H),7.33(t,J=8.2Hz,1H),6.91(d,J=7.6Hz,1H),4.03(s,3H),3.08(d,J=6.8Hz,2H),1.90-1.80(m,1H),1.02(d,J=6.8Hz,6H);ES-LCMS m/z:246.3[M+H]+。
中间体4:4-[(3,4-二氨基-5-喹啉基)氧]-2-甲基-2-丁醇
方案11
步骤1:合成4-[(4-氨基-3-硝基-5-喹啉基)氧]-2-甲基-2-丁醇
将(3-羟基-3-甲基-丁基)4-甲基苯磺酸酯(5.67g,21.93mmol,3.0当量)的DCM(15.00mL)溶液加至4-氨基-3-硝基-喹啉-5-醇(1.50g,7.31mmol,1.0当量),TBAB(2.36g,7.31mmol,1.0当量)及KI(405.04mg,2.44mmol,1.0当量)的NaOH(2M,3.66mL,3.0当量)溶液中。在25℃的条件下,搅拌得到的混合物持续64h。用水(10mL)稀释反应混合物,并用DCM(50mL x 2)进行萃取。用盐水(10mL)洗涤合并的有机层,在无水Na2SO4上干燥,过滤并在减压条件下浓缩以提供残留物。采用柱层析法(SiO2,DCM/MeOH=100/1至20/1)纯化所述残留物。获得所需要的产品:4-[(4-氨基-3-硝基-5-喹啉基)氧]-2-甲基-2-丁醇(646.00mg,2.22mmol,产率30.34%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.59(br s,1H),9.29(s,1H),9.22(br s,1H),7.63(t,J=8.2Hz,1H),7.54(dd,J=8.4,0.8Hz,1H),6.92(d,J=7.6Hz,1H),4.38(t,J=6.2Hz,2H),2.14(t,J=6.2Hz,2H),1.41(s,6H);ES-LCMS m/z:292.3[M+H]+。
步骤2:合成4-[(3,4-二氨基-5-喹啉基)氧]-2-甲基-2-丁醇
在N2条件下,将Raney-Ni(200.00mg,2.33mmol,1.1当量)加至4-[(4-氨基-3-硝基-5-喹啉基)氧]-2-甲基-2-丁醇)(640.00mg,2.20mmol,1.0当量)的MeOH(150.00mL)溶液中。悬浮液在真空条件下脱气并用H2净化几次。在H2(15psi)条件下,在25℃条件下,搅拌混合物持续1h。过滤反应混合物。滤液在减压条件下浓缩以提供残留物。无需进一步纯化,就可以将产品直接用于下一步中。获得所需要的产品:4-[(3,4-二氨基-5-喹啉基)氧]-2-甲基-2-丁醇(570.00mg,2.18mmol,产率99.15%),黑棕色固体。1H NMR(400MHz,CDCl3)δppm:8.24(s,1H),7.47(d,J=8.4Hz,1H),7.30(t,J=8.0Hz,1H),6.68(d,J=7.6Hz,1H),5.89(br s,2H),4.28(t,J=6.4Hz,2H),2.11(t,J=6.4Hz,2H),1.36(s,6H);ES-LCMS m/z:262.2[M+H]。
中间体5:5-甲氧基-N-甲基-3-硝基-喹啉-4-胺
方案12
将4-氯-5-甲氧基-3-硝基-喹啉(1.00g,4.19mmol,1.0当量)的DCM(30.00mL)溶液加至MeNH2(在THF中的浓度为2M,40.00mL,19.1当量)中。在25℃条件下,搅拌混合物持续2h。浓缩混合物以提供残留物。采用柱层析法((SiO2,DCM/MeOH=50/1至20/1))纯化所述残留物。获得所需要的产品:5-甲氧基-N-甲基-3-硝基-喹啉-4-胺(400.00mg,1.72mmol,产率40.93%),黄色固体。1H NMR(400MHz,CDCl3)δppm:9.03(s,1H),8.79(s,1H),7.62-7.60(m,2H),6.94-6.92(m,1H),4.09(s,3H),2.94(d,J=5.6Hz,3H);ES-LCMS m/z:234.0[M+H]+。
中间体6:2-乙氧基乙酰氯
在0℃条件下,将乙二酰氯(1.83g,14.41mmol,1.26mL,1.5当量)加至2-乙氧基乙酸(1.00g,9.61mmol,909.09μL,1.0当量)及催化量的DMF(10.00mg,136.82μmol,10.53μL,0.01当量)的DCM(30.00mL)溶液中。在25℃条件下,搅拌产生的混合物持续2h。在减压条件下浓缩反应混合物以除去溶剂。获得2-乙氧基乙酰氯(900.00mg,7.34mmol,产率76.42%),黄色油状物。
中间体7:3-甲氧基丙酰氯
采用与制备中间体6的方法相同的方法,使用相应的起始物料3-甲氧基丙酸制备3-甲氧基丙酰氯(黄色油状物,产率为84.9%)。
中间体8:(3-羟基-3-甲基-丁基)4-甲基苯磺酸酯
在0℃条件下,将TsCl(17.39g,91.22mmol,0.95eq)的DCM(100mL)溶液滴加至3-甲基丁烷-1,3-二醇(10.00g,96.02mmol,10.20mL,1.0当量),Et3N(14.57g,144.03mmol,19.96mL,1.5当量)和DMAP(14.08g,115.22mmol,1.2当量)的DCM(200.00mL)溶液中。在0℃条件下,搅拌产生的混合物持续1h。使用柠檬酸将混合物的pH调节至6。分离有机层,并用盐水(100mL)洗涤,在无水Na2SO4上干燥,过滤,并在真空条件下浓缩。获得(3-羟基-3-甲基-丁基)4-甲基苯磺酸酯(19.80g,76.65mmol,产率79.83%),无色油状物。1H NMR(400MHz,CDCl3)δppm:7.80-7.78(m,2H),7.34(d,J=8.0Hz,2H),4.22-4.19(m,2H),2.45(s,3H),1.87-1.84(m,2H),1.21(d,J=1.2Hz,6H);ES-LCMS m/z:276.2[M+H2O]+。
中间体9:异戊基-4-甲基苯磺酸酯
采用与制备中间体8的方法类似的方法,使用相应的起始物料3-甲基正丁醇制备异戊基-4-甲基苯磺酸酯,并采用硅胶层析法(PE/EA=20/1至10/1)进行纯化,以获得异戊基-4-甲基苯磺酸酯(分离的产率72.76%,黄色油状物)。1H NMR(400MHz,CDCl3)δppm:7.81-7.79(m,2H),7.35(d,J=8.0Hz,2H),4.06(t,J=6.6Hz,2H),2.46(s,3H),1.70-1.67(m,1H),1.57-1.51(m,2H),0.88-0.84(m,6H);ES-LCMS m/z:264.9[M+Na]+。
中间体10:2-异丙氧基乙基4-甲基苯磺酸酯
采用与制备中间体8的方法类似的方法,使用相应的起始物料2-异丙氧基乙醇制备2-异丙氧基乙基4-甲基苯磺酸酯,产率81.44%,无色油状物。1H NMR(400MHz,CDCl3)δppm:7.80(d,J=8.0Hz,2H),7.33(d,J=8.4Hz,2H),4.14-4.11(m,2H),3.60-3.58(m,2H),3.55-3.54(m,1H),2.44(s,3H),1.08(d,J=6.0Hz,6H);ES-LCMS m/z:259.3[M+H]+。
中间体11:3-羟丁基4-甲基苯磺酸酯
采用与制备中间体8的方法类似的方法,使用相应的起始物料丁烷-1,3-二醇制备3-羟丁基4-甲基苯磺酸酯,产率59.04%,无色油状物。1H NMR(400MHz,CDCl3)δppm:7.83-7.79(m,2H),7.37-7.34(m,2H),4.26-4.22(m,1H),4.15-4.12(m,1H),3.98-3.93(m,1H),2.46(s,3H),1.85-1.81(m,1H),1.74-1.68(m,1H),1.20(m,3H);ES-LCMS m/z:245.2[M+H]+。
中间体12:乙酰甲基4-甲基苯磺酸酯
采用与制备中间体8的方法类似的方法,使用相应的起始物料1-羟基-2-丙酮制备乙酰甲基4-甲基苯磺酸酯,产率25.31%,无色油状物。1H NMR(400MHz,CDCl3)δppm:7.82(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.48(s,2H),2.46(s,3H),2.22(s,3H);ES-LCMS m/z:229.2[M+H]+。
采用与实施例1-7描述的方法类似的方法制备其它2-氨基-喹啉衍生物,它们在表1中列出。这些化合物被制备成盐酸盐的形式和/或中性胺的形式。本领域技术人员可清楚地理解及知晓,可采用与实施例1-7描述的方法相同或类似的方法制备其它的类似物。这些实施例不会以任何方式来限制采用与本文所述的方法相同或类似的方法制备的类似物。
通过刺激和测定PBMC中细胞因子的生成测试所制备的化合物中的一些的化合物功能。
人PBMC由来自健康自愿供体的血沉棕黄层通过Ficoll离心进行制备并且调节最终细胞浓度至1x106细胞/mL。
对于评估化合物活性而言,将1x105PBMC接种于100μl补充有10%胎牛血清的RPMI1640完全培养基(批号:31800-022,Life Technologies生产的GIBCO,格兰德岛,纽约,美国)中的96孔板中,所测试的化合物首先溶解于DMSO中并进一步在PBS和RPMI 1640培养基中稀释至最终浓度为20μM(对应于6.28μg/mL),随后在96孔圆底板中进行三倍连续稀释。100μl稀释的化合物被加至相同体积的1x105PBMC板中并在37℃,大气湿度为5%CO2的条件下培养20-22小时。收集上清液,根据生产厂商(Mabtech AB,瑞典)的说明通过ELISA检测分析人IFN-α,IL 12(p70)和IL-6。瑞喹莫德用作阳性对照。
下表2列出了对所制备的大多数化合物的细胞因子生成的评估测试结果。
表2*
*注释1:所有化合物在浓度为10μM条件下测试。
*注释2:“+”是指在PBMC上生成IFNa或IL-6,而“-”是指没有检测到PBMC上生成IFNa或IL-6。
Claims (43)
1.由下式表示的化合物或其盐:
其中,虚线表示存在化学键或不存在化学键;
A1为CR1,NR1A或者N;
A2为CR2,NR2A,O,或者S;
B1为CR5或者N;
B2为CR6或者N;
B3为CR7或者N;
R1和R2独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,或者-SO2Ra;
X为化学键,O,NRa,-CO-,-SO-,或者-SO2-,-CONRa,烃基,并且R3为H或者C1-30有机基团;或者X-R3为F或者Cl;
R1A,R2A,R4,Ra及Rb独立地为H或者C1-30有机基团;
R5,R6及R7独立地为F,Cl,Br,I,NO2,CN,Ra,-ORa,-NRaRb,-NHCORa,-NHSO2Ra,-OCORa,-SO2Ra,-SO2NHRa或者-X1-(CmH2mO0-1)-Z-(CnH2n+1),-(CmH2mO0-1)-Z-(CnH2n+1),其中,R5和R6或者R6和R7可被任选地连接形成环;
其中,X1为化学键,O,NRa,-CO-,-SO-,或者-SO2-;
Z为化学键,O,NHSO2,或者NHCO;
m为0,1,2,3,4,5,6,7,8,9,或者10;以及
n为0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
2.如权利要求1所述的化合物,其进一步为由下式表示的化合物或其盐:
其中,R3为C1-30有机基团。
3.如权利要求1所述的化合物,其进一步为由下式表示的化合物或其盐:
其中,R4为氢,C1-30非芳香族有机基团或者包含未直接连接至N原子的芳香族基团的C1-30芳香族有机基团。
4.如权利要求1,2或3所述的化合物,其中,R1或者R1A为C1-12任选地取代的烷基。
5.如权利要求4所述的化合物,其中,R1或者R1A为-CrH2r+1O或其酯,其中,r为1,2,3,4,5,6,7,8,9,或10。
6.如权利要求5所述的化合物,其中,R1或者R1A为-C3H7O。
7.如权利要求6所述的化合物,其中,R1或者R1A为-CH2OCH2CH3。
8.如权利要求1,2,3,4,5,6,或7所述的化合物,其中,R2或者R2A为H或者C1-12任选地取代的烷基。
9.如权利要求8所述的化合物,其中,R2或者R2A为C1-6烷基,或者-CyH2y+1O或其酯,其中,y为1,2,3,4,5,6,7,8,9,或10。
10.如权利要求9所述的化合物,其中,R2或者R2A为CH3。
11.如权利要求8所述的化合物,其中,R2或者R2A为H。
12.如权利要求8所述的化合物,其中,R2或者R2A为C4H9。
13.如权利要求1至12中任一项所述的化合物,其中,R3为C1-30任选地取代的烷基。
14.如权利要求13的化合物,其中,R3为C1-10烷基,或者-CwH2w+1O或其酯,其中,w为1,2,3,4,5,6,7,8,9,或10。
15.如权利要求1至13中任一项所述的化合物,其中,R3为-(CtH2tO0-1)-Ht,其中,t为0,1,2,3,4,5,6,7,8,9,或者10,以及Ht为任选地取代的C3-6杂环基。
16.如权利要求1至13中任一项所述的化合物,其中,R3为-(CuH2uO0-1)-Z-(CvH2v+1),其中,Z为化学键,O,NHSO2,或者NHCO,u为0,1,2,3,4,5,或者6,以及v为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
17.如权利要求1至13中任一项所述的化合物,其中,R3为-(CuH2uO0-1)-NRaRb,以及u为1,2,3,4,5,或者6,其中,Ra及Rb独立地为H或者C1-6烷基。
18.如权利要求14所述的化合物,其中,R3为C5H11O。
19.如权利要求18所述的化合物,其中,R3为-CH2-CH2-CH(CH3)2OH。
20.如权利要求17所述的化合物,其中,R3为-CH2-CH2-CH2-NH2。
21.如权利要求1至20中任一项所述的化合物,其中,R4为H或者C1-6烷基。
22.如权利要求21所述的化合物,其中,R4为H。
23.如权利要求1至22中任一项所述的化合物,其中,R5为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,-SO2NHRa,其中,Ra和Rb独立地为H或者C1-6烷基。
24.如权利要求23所述的化合物,其中,R5为H。
25.如权利要求1至20中任一项所述的化合物,其中,R5为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,或者25。
26.如权利要求1至25中任一项所述的化合物,其中,R6为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,-SO2NHRa,其中,Ra或者Rb独立地为H或者C1-6烷基。
27.如权利要求26所述的化合物,其中,R6为H。
28.如权利要求1至25中任一项所述的化合物,其中,R6为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10;以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
29.如权利要求1至28中任一项所述的化合物,其中,R7为Ra,F,Cl,-CO2Ra,-CONRaRb,CN,-ORa,-NRaRb,-OCORa,或者-SO2Ra,-SO2NHRa,其中,Ra或者Rb独立地为H或者C1-6烷基。
30.如权利要求29所述的化合物,其中,R7为H。
31.如权利要求1至28中任一项所述的化合物,其中,R7为-(CmH2mO0-1)-Z-(CnH2n+1),其中,Z为化学键,O,NHSO2,或者NHCO,m为0,1,2,3,4,5,6,7,8,9,或者10,以及n为1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,或者23。
32.如权利要求1至31中任一项所述的化合物,R8为H,OH或者CH3。
33.如权利要求32所述的化合物,其中,R8为OH。
34.如权利要求32所述的化合物,其中,R8为H。
35.下列化合物或者这些化合物的盐,或者具有-OH基团的这些化合物的酯:
36.一种化合物,其为任选地取代的9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺。
37.一种化合物,其为任选地取代的9-甲氧基-2H-吡唑并[3,4-c]喹啉-4-胺。
38.如权利要求36所述的化合物,其为:
任选地取代的1-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的2-(乙氧基甲基)-1-异丁基-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的1-(4-氨基-9-甲氧基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的1-(4-氨基-2-(2-羟乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丙醇或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丁醇或其盐;
任选地取代的1-((4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-丙醇或其盐;
任选地取代的4-((4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基2-丁醇或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-((4-氨基-2-(乙氧基甲基)-1-异丁基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-1-(2-异丙氧基乙基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的4-(4-氨基-2-(乙氧基甲基)-9-甲氧基-1H-咪唑并[4,5-c]喹啉-1-基)-2-甲基-2-丁醇或其盐;
任选地取代的2-(乙氧基甲基)-9-异丁氧基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-(2-异丙氧基乙氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-(异戊氧基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-异丁氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)甲磺酰胺或其盐;
任选地取代的N-(2-(2-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)乙氧基)乙基)-甲磺酰胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)乙酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)甲磺酰胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)硬脂酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)乙酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)-硬脂酰胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(2-吗啉乙氧基)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-((四氢呋喃-3-基)氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(吡咯烷-3-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-1-甲基-9-(哌啶-4-基氧)-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的N-(3-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丙基)棕榈酰胺或其盐;
任选地取代的N-(4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)丁基)棕榈酰胺或其盐;
任选地取代的9-(3-氨基丙氧基)-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的2-(乙氧基甲基)-9-异丙氧基-1-甲基-1H-咪唑并[4,5-c]喹啉-4-胺或其盐;
任选地取代的1-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)-2-甲基-2-丙醇或其盐;
任选地取代的2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-10-胺或其盐;
任选地取代的(R)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;
任选地取代的(S)-2-(10-氨基-2-(乙氧基甲基)-3,4-二氢-5-氧杂-1,2a,9-三氮杂萘[2,1,8-cde]薁-3-基)-2-丙醇或其盐;
任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6-甲基-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(R)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的(S)-2-氨基-12-(乙氧基甲基)-6,7-二氢-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并-[4,3,2-de]喹啉-6-醇或其盐;
任选地取代的2-氨基-12-(乙氧基甲基)-5H-3,4-(次氮基次甲基桥)[1,5]氧杂吖辛因并[4,3,2-de]喹啉-6(7H)-酮或其盐;
任选地取代的叔丁基4-((4-氨基-2-(乙氧基甲基)-1-甲基-1H-咪唑并[4,5-c]喹啉-9-基)氧)哌啶-1-羧酸酯或其盐。
39.如权利要求37所述的化合物,其为:
任选地取代的4-氨基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;
任选地取代的4-氨基-2-异戊基-2H-吡唑并[3,4-c]喹啉-9-醇或其盐;
任选地取代的2-异戊基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐;
任选地取代的2-丁基-9-(异戊氧基)-2H-吡唑并[3,4-c]喹啉-4-胺或其盐。
40.一种治疗病毒感染,癌症或者过敏性疾病的方法,所述方法包括将权利要求1至39中任一项所述的化合物给药于需要这种治疗的哺乳动物。
41.权利要求1至39中任一项所述的化合物在制造用于治疗病毒感染,癌症或者过敏性疾病的药物中的应用。
42.如权利要求40所述的方法或如权利要求41所述的应用,其中,所述病毒感染包括HCV感染。
43.适于给药于哺乳动物的剂型,其包括权利要求1至39中任一项所述的化合物。
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RU2019138177A3 (zh) | 2021-05-27 |
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JP7179357B2 (ja) | 2022-11-29 |
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US11834448B2 (en) | 2023-12-05 |
EP3615539B1 (en) | 2023-08-09 |
WO2018196823A1 (en) | 2018-11-01 |
EP3615539A4 (en) | 2020-08-19 |
BR112019022246A2 (pt) | 2020-08-11 |
AU2018259831B2 (en) | 2022-06-16 |
US20210261548A1 (en) | 2021-08-26 |
IL270219B (en) | 2022-09-01 |
MX2019012676A (es) | 2020-02-05 |
RU2019138177A (ru) | 2021-05-27 |
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