CN114591339A - 一类Toll样受体抑制剂及其制备和应用 - Google Patents
一类Toll样受体抑制剂及其制备和应用 Download PDFInfo
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- CN114591339A CN114591339A CN202210500160.7A CN202210500160A CN114591339A CN 114591339 A CN114591339 A CN 114591339A CN 202210500160 A CN202210500160 A CN 202210500160A CN 114591339 A CN114591339 A CN 114591339A
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- alkyl
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- cycloalkyl
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- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 208000037976 chronic inflammation Diseases 0.000 claims abstract description 4
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims abstract description 4
- -1 hydroxy, amino Chemical group 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
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- 239000011541 reaction mixture Substances 0.000 description 25
- 239000012043 crude product Substances 0.000 description 18
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- 239000012074 organic phase Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
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- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
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- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
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- 239000006143 cell culture medium Substances 0.000 description 3
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- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
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- 229910052731 fluorine Inorganic materials 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
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- FHJATBIERQTCTN-UHFFFAOYSA-N 1-[4-amino-2-(ethylaminomethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol Chemical compound C1=CC=CC2=C(N(C(CNCC)=N3)CC(C)(C)O)C3=C(N)N=C21 FHJATBIERQTCTN-UHFFFAOYSA-N 0.000 description 1
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
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- USMPPCLBZYKBPT-UHFFFAOYSA-N 5-bromo-2-methyl-2,7-naphthyridin-1-one Chemical compound CN(C=CC(C1=CN=C2)=C2Br)C1=O USMPPCLBZYKBPT-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供了一类Toll样受体抑制剂及其制备和应用,具体地,本发明提供了一种式I所示的化合物,及其制备方法和作为TLR7和/或TLR8抑制剂的用途。所述的化合物可以用于制备治疗或预防自身免疫性疾病或慢性炎性疾病的药物组合物。
Description
技术领域
本发明涉及小分子药物化合物领域,具体地,本发明提供了一类Toll样受体抑制剂及其制备和应用。
背景技术
自身免疫疾病是一系列慢性全身性炎症性疾病,其特征是免疫系统失调,最终导致对自身抗原的耐受性下降。尽管这些疾病的确切病因和发病机制仍不清楚,但先天和适应性免疫系统的异常过程已证明参与这些疾病的发生。多个研究表明Toll样受体 (Toll-like receptors, TLRs)在各种自身免疫性疾病中起着重要作用,包括干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎,系统性硬化症和牛皮癣。
TLRs是一类结构保守的蛋白质,在先天免疫反应中形成第一道屏障。通过识别各种保守的病原体相关分子模式 (pathogen-associated molecular patterns, PAMP),TLRs可以识别侵入性微生物和组织损伤或非生理性细胞死亡后释放的内源性分子,并激活信号级联反应,从而产生促炎性细胞因子。人TLRs家族有10个已知成员,它们是I型跨膜蛋白,其特征是具有富含亮氨酸的胞外结构域和包含保守的Toll / 白介素-1受体 (Toll/interleukin (IL)-1 receptor, TIR)结构域的胞质尾巴。在该家族中,TLR3、TLR7、TLR8和TLR9位于内涵体隔室。内涵体TLRs识别病毒和内源的双链RNA (dsRNA;TLR3),单链RNA(ssRNA;TLR7/8)或未甲基化的CpG序列 (TLR9)。
TLR7和8与某些针对自身RNA和DNA/蛋白质复合物的自身免疫疾病的病因有关,这些RNA和DNA/蛋白质最有可能在正常细胞死亡和清除期间释放。现在,大量的科学证据将TLR7/8途径的不适当的持续内源性激活与自身免疫疾病中对自身抗原的持续反应联系起来。已经证明TLR7在系统性红斑狼疮的发病机理中起作用。此外,TLR8多态性与类风湿关节炎有关。由于多数自身免疫性疾病可能会受益于涉及调节细胞因子,干扰素 (interferon,IFN) 的产生和B细胞活性的治疗,因此调节TLR7和/或TLR8活性的化合物以及使用这些化合物的方法可为多种自身免疫性患者提供实质的治疗益处。
综上所述,本领域迫切需要提供一种可以用于调节TLR7和/或TLR8活性的化合物。
发明内容
本发明的目的是提供一种可以用于调节TLR7和/或TLR8活性的化合物。
本发明的第一方面,提供了一种如下式I所示的化合物,或其可药用的盐:
所述的R1选自下组:
R2、R3、R4和R5选自下组:H、卤素、CF3、CN、C1-6烷基或C1-6烷氧基;
R6选自下组:H、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或C3-7环烷基;
L选自下组:键、-C(=O)-或C1-3亚烷基;
R7选自下组:H、C1-6烷基、卤代C1-6烷基或C3-7环烷基;
R8选自下组:H、-C(=O)NH2、羧酸、C3-9环烷基或3-9元杂环烷基,其中C3-9环烷基、3-9元杂环烷基可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;
Ra选自下组:H、卤素、羟基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2、-(CH2)m-C(=O)OH;其中m为0、1、2或3,Ra-1和Ra-2选自下组:氢、C1-6烷基;
X选自N或CR9,R9选自下组:H、卤素、C1-6烷基、CF3、CN、C1-6烷氧基,或所述的R9被-L-R8取代基取代。
在另一优选例中,所述的X为CR9。
在另一优选例中,R8选自下组:C3-9环烷基或3-9元杂环烷基,且所述的R8可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;
Ra选自下组:H、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2;其中m为0、1、2或3,Ra-1和Ra-2选自下组:氢、C1-6烷基。
在另一优选例中,R8选自下组:C5-6环烷基或5-6元杂环烷基,且所述的R8可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;Ra选自下组:H、-(CH2)m-C(=O)NRa-1Ra-2;其中m为0或1,Ra-1和Ra-2选自下组:氢、C1-6烷基。
在另一优选例中,L选自下组:键、-C(=O)-。
在另一优选例中,R2、R3、R4和R5为H;且R6选自下组:H、C1-6烷基、卤代C1-6烷基。
在另一优选例中,所述的R6选自下组:H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
在另一优选例中,R7为C1-6烷基或卤代C1-6烷基。
在另一优选例中,所述的R7选自下组:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
在另一优选例中,所述的化合物具有如下式II所示的结构:
其中,Y为N或CH,其余各基团的定义如上文中所述。
在另一优选例中,所述的R9被-L-R8取代基取代。
在另一优选例中,所述的化合物为实施例化合物I-1至I-9之一。
本发明的第二方面,提供了一种药物组合物,其特征在于,所述的药物组合物包括:如本发明第一方面所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第三方面,提供了一种如本发明第一方面所述的式I化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其用于制备治疗或预防自身免疫性疾病或者慢性炎性疾病的药物组合物。
在另一优选例中,所述的疾病选自下组:干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎、系统性硬化症、牛皮癣、系统性红斑狼疮、狼疮肾炎。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,发现了一类具有TLR7和/或TLR8抑制活性的小分子化合物,所述的化合物结构新颖,且具有与现有技术中同类化合物相当或更为优异的抑制活性。基于上述发现,发明人完成了本发明。
术语
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义,各个基团在从左往右书写的情况下,意在同样包括从右往左书写,例如,“-CH2-CO-”意在包括-CH2-CO-和-CO-CH2-。
在本发明中,术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等;优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中,术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中,术语“C3-C7环烷基”是指在环上具有3至7个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C5-C6环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基,如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“3-9元碳环基”是指在饱和或不饱和(非芳香性环,包括单环,并环,螺环,桥环等形式)的3-9元环基,其环骨架结构仅包括碳原子,例如环戊基、环己基等。
在本发明中,术语“3-9元杂环基”是指在环上含有1~3个选自氧、硫和氮中的杂原子的饱和或不饱和(非芳香性环,包括单环,并环,螺环,桥环等形式)的3-9元环基,例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基、C1-10磺酰基等。
本发明提供了一类Toll样受体抑制剂及其制备和应用,具体地,本发明提供了一种式I所示的化合物,及其制备方法和作为TLR7和/或TLR8抑制剂的用途。所述的化合物可以用于制备治疗或预防自身免疫性疾病或慢性炎性疾病的药物组合物。
所述的R1选自下组:
R2、R3、R4和R5选自下组:H、卤素、CF3、CN、C1-6烷基或C1-6烷氧基;
R6选自下组:H、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或C3-7环烷基;
L选自下组:键、-C(=O)-或C1-3亚烷基;
R7选自下组:H、C1-6烷基、卤代C1-6烷基或C3-7环烷基;
R8选自下组:H、-C(=O)NH2、羧酸、C3-9环烷基或3-9元杂环烷基,其中C3-9环烷基、3-9元杂环烷基可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;
Ra选自下组:H、卤素、羟基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2、-(CH2)m-C(=O)OH;其中m为0、1、2或3,Ra-1和Ra-2选自下组:氢、C1-6烷基;
X选自N或CR9,R9选自下组:H、卤素、C1-6烷基、CF3、CN、C1-6烷氧基。
式I化合物的制备方法
本发明还提供了上述的如式I所示的化合物的制备方法,其为如下任一方法:
方法1,其包括以下步骤:溶剂中,在催化剂和碱的作用下,如式III所示的化合物和如式IV所示的化合物进行反应,得如式I所示的化合物
其中,Q1和Q2各自独立地为卤素、OTf或硼酸酯基。
方法2,其包括以下步骤:溶剂中,在碱的作用下,如式VIII所示的化合物和如式I-1所示的化合物进行取代反应,得如式I所示的化合物;
Q3为OMs、氟、氯或溴,R8’为“3-9元杂环烷基,可以被一个或多个Ra取代”。
R8-1为“C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2、-(CH2)m-C(=O)OH”。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
以下实施例中,化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
SHIMADZU LC系统(色谱柱:Xselect® CSHTM Prep-C18,19 * 150mm,液体处理机LH-40,泵LC-20AP,检测器SPD-20A,系统控制器CBM-20A,溶剂系统:乙腈和0.05%三氟乙酸水溶液)。
使用LC/MS(Agilent Technologies 1200 Series)获得化合物的LC/MS光谱。LC/MS条件如下(运行时间为10分钟):
酸性条件:A:0.05%三氟乙酸的水溶液;B:0.05%三氟乙酸的乙腈溶液;
碱性条件:A:0.05%NH3•H2O的水溶液;B:乙腈
中性条件:A:10 mM NH4OAC的水溶液;B:乙腈
如无特别说明,以下实施例中,中间体和最终化合物使用硅胶柱色谱法纯化、或使用XselectCSHTM Prep-C18(5μm,OBDTM 19 * 150mm)色谱柱或使用XBridgeTM PrepPhenyl(5μm,OBDTM 30 * 100mm)在反相色谱柱上通过制备性HPLC纯化。
硅胶柱色谱法一般使用烟台黄海硅胶200~300目硅胶为载体。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层色谱法(TLC)硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析检测产品使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(AccelaChemBio Inc)、达瑞化学品等公司。
缩略词:Ac2O:醋酐;AIBN:偶氮二异丁腈;BINAP:1,1'-联萘-2,2'-双二苯膦;Boc2O:碳酸叔丁氧基羰基叔丁酯;Conc.HCl:浓盐酸;Cs2CO3:碳酸铯;DCM:二氯甲烷;DCE:1,2-二氯乙烷;DIAD:偶氮二甲酸二异丙酯;Dioxane:1,4-二氧六环;DIEA:N,N-二异丙基乙胺;DMAP:4-二甲氨基吡啶;DMF:二甲基甲酰胺;DMSO:二甲基亚砜;DMF-DMA:1,1-二甲氧基-N,N-二甲基-甲胺;EtOH:乙醇;Ethyl propiolate:丙酸乙酯;HOAc;醋酸;H2:氢气;I2:碘;K2CO3:碳酸钾;K3PO4:磷酸钾;LiAlH4:氢化铝锂;LiHMDS:双三甲基硅基胺基锂;LiOH:氢氧化锂;mCPBA:间氯过氧苯甲酸;MeOH:甲醇;NaH:氢化钠;NaHCO3:碳酸氢钠;NaHMDS:双(三甲基硅基)氨基钠;PPA:多聚磷酸;PCy3:三环己基膦;Pd(dppf)Cl2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯;Pd(OAc)2:醋酸钯;Pd/C:钯碳;Pd2(dba)3:三(二亚苄基丙酮)二钯;Pd(PPh3)4:四三苯基膦钯;POCl3:三氯氧磷;PPh3:三苯基膦;t-BuOK:叔丁醇钾;t-BuLi:叔丁基锂;KF:氟化钾;TEA:三乙胺;TFA:三氟乙酸;TFAA:三氟乙酸酐;TfOH:三氟甲磺酸;THF:四氢呋喃;TLC:薄层层析;TMP:磷酸三甲酯;XantPhos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽;Zn:锌;ZnCl2:氯化锌;Zn(CN)2:氰化锌。
中间体 A
7-溴-3-甲基吡咯[2,1-f][1,2,4]三嗪-4(3H)-酮
步骤 1: 7-溴吡咯并[2,1-f][1,2,4]三嗪-4-醇的制备(中间体A-1)
在0度搅拌下,将NBS(0.83克, 4.66毫摩尔)加入到吡咯并[2,1-f][1,2,4]三嗪-4-醇(0.700克, 5.18毫摩尔)的DCM (10毫升)和AcOH (5毫升)溶液中,并在0℃时继续搅拌3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体A-1 (540毫克, 49%)。MS: 214.2 & 216.2 (M+H)+。
步骤 2: 7-溴-3-甲基吡咯[2,1-f][1,2,4]三嗪-4(3H)-酮的制备(中间体A)
将中间体A-1 (540毫克, 2.52毫摩尔), 碳酸钾(1.05克, 7.57毫摩尔)和碘甲烷(0.72克, 5.05毫摩尔)的DMF (10毫升)溶液在70℃继续搅拌16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A (360毫克, 63%)。MS:228.2 & 230.2 (M+H)+。
中间体 B
8-溴-6-甲基咪唑[1,2-c]嘧啶-5(6H)-酮
将4-氨基-5-溴嘧啶-2(1H)-酮(1.00克, 5.26毫摩尔)和2-氯乙醛(1.08克, 5.53毫摩尔)的DMF (10毫升)溶液在100℃搅拌反应3小时,反应完毕后,将反应液冷却至室温,未经处理纯化直接用于下一步反应。MS: 214.2 & 216.2 (M+H)+。
将K2CO3(2.17克, 15.69毫摩尔)和碘甲烷(1.49克, 10.46毫摩尔)加入到上述反应液中,并将反应混合物在70℃继续搅拌16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体B (418毫克, 35%)。MS: 228.2 & 230.2 (M+H)+。
中间体 C
步骤1: 5-溴-3-异丙基-lH-吲哚的制备(中间体C-1)
在70度搅拌条件下,将5-溴吲哚(10克, 36.4毫摩尔)和丙酮(2.53克, 43.6毫摩尔)的甲苯(30毫升)溶液缓慢滴加到三乙基硅烷(12.69克, 109毫摩尔)和三氟乙酸(6.22克, 54.6毫摩尔)的甲苯(200毫升)溶液中,滴加完毕后,并将反应混合物在70℃继续搅拌2小时。然后向反应混合物中加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到中间体C-1(6.8克, 79%)。MS: 238.2 (M+H)+。
步骤2: 4-(3-异丙基-1H-吲哚-5-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备(中间体C-2)
在氮气的保护下,将中间体C-1 (6.8克, 28.6毫摩尔), 磷酸钾(6.81克, 86毫摩尔), PdCl2(dppf) (2.09克, 2.86毫摩尔)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(9.71克, 31.4毫摩尔)的二氧六环(200毫升)和水(10毫升)的混合溶液在100℃搅拌反应16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到中间体C-2(8.0克, 82%)。MS: 285.1 (M-56)+。
步骤3:4-(3-异丙基-1H-吲哚-5-基)哌啶-1-羧酸叔丁酯的制备 (中间体C-3)
将中间体C-2 (8克, 23.50毫摩尔)溶于乙酸乙酯(300毫升)中,在搅拌条件下向反应混合物中加入钯碳(800毫克)。反应混合物在20度氢气压力下搅拌反应16小时,然后将混合溶液过滤,浓缩,得到中间体C-3(6.0克, 88%)。MS: 287.1 (M-56)+。
步骤4: 4-(2-溴-3-异丙基-1H-吲哚-5-基)哌啶-1-羧酸叔丁酯的制备(中间体C-4)
在0度搅拌条件下,将NBS (3.76克, 21.15毫摩尔)缓慢滴到中间体C-3 (6.0克,17.62毫摩尔)的二氯甲烷(200毫升)溶液中,然后将反应混合物在0℃继续搅拌3小时。然后向反应混合物中加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到中间体C-4(5.0克, 67.3%)。MS: 365.1 & 367.2 (M+H)+。
步骤5:中间体C的制备
在氮气的保护下,将中间体C-4 (2.2克, 6.07毫摩尔),碳酸钾(2.52克, 18.22毫摩尔),PdCl2(dppf) (0.444克, 0.607毫摩尔)和联硼酸频那醇酯(1.54克, 6.07毫摩尔)的二氧六环(20毫升)混合溶液在100℃搅拌反应16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到中间体C(1.98 克, 70%)。MS: 469.2 (M+H)+。
中间体 D
步骤 1: 中间体D-1的制备
在70度搅拌条件下,将哌啶(30毫升)缓慢滴到6-甲氧基吡啶醛(20克, 146毫摩尔)和丙二酸(30.4克, 292毫摩尔)的吡啶(300毫升)溶液中,然后将反应混合物在70℃继续搅拌13小时。然后向反应混合物中加入冰盐酸水中淬灭反应,析出固体并过滤,用水洗涤,干燥得到白色固体中间体D-1 (20克, 77%)。MS: 180.1 (M+H)+。
步骤 2: 中间体D-2的制备
将中间体D-1 (8.0克, 41.4毫摩尔)溶于甲醇(300毫升)中,在搅拌条件下向反应混合物中加入钯碳(1克)。反应混合物在20度氢气压力下搅拌反应16小时,然后将混合溶液过滤,浓缩,得到中间体D-2 (7.0克, 87%)。MS: 182.1 (M+H)+。
步骤 3: 中间体D-3的制备
将中间体D-2 (7.0克, 36.2毫摩尔)溶于无水四氢呋喃(150毫升)中,在0度搅拌缓慢加入1.0 M铝锂氢的四氢呋喃溶液(10毫摩尔),加完后,将反应混合物在20度继续搅3小时,然后加入冰水和酒石酸钾钠淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体中间体D-3 (5.1克, 84%)。MS: 168.1 (M+H)+。
步骤 4: 中间体D-4的制备
将中间体D-3(5.1克, 30.5毫摩尔)的48%氢溴酸(119克, 1473毫摩尔)溶液在80℃搅拌反应6小时。冷却反应混合液,然后向反应混合物中加入氢氧化钠(27.5克, 0.690摩尔)中和反应液,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物得到棕色固体中间体D-4 (2.8克, 67.9%)。MS: 136.1 (M+H)+。
步骤 5: 中间体D-5的制备
在0度搅拌条件下,将NBS(3.69克, 20.72毫摩尔)缓慢加到中间体D-4(2.8克,20.72毫摩尔)的ACN(30毫升)溶液中,然后将反应混合物在20℃继续搅拌6小时。然后向反应混合物中加入冰水中淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物得到棕色中间体D-5 (2.0克, 45.1%)。MS:214.1 & 216.1 (M+H)+。
步骤 6: 中间体D的制备
在氮气的保护下,将中间体D-5(1.3克, 6.07毫摩尔), 碳酸钾(2.52克, 18.22毫摩尔), PdCl2(dppf)(0.444克, 0.607毫摩尔)和联硼酸频那醇酯(1.54克, 6.07毫摩尔)的二氧六环(20毫升)混合溶液在100℃搅拌反应6小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体D (800毫克, 50.4%)。MS: 261.2 (M+H)+。
中间体 E
中间体 E的合成参考中间体C,通过使用6-溴吲哚代替5-溴吲哚制备得到中间体E。MS: 469.1 (M+H)+。
中间体 F
步骤 1:中间体F-1的制备
将Pd2(dba)3(138毫克, 0.15毫摩尔),碳酸铯(1469毫克, 4.51毫摩尔),二环己基(2',6'-二异丙氧基-[1,1'-联苯]-2-基)膦(70.1毫克, 0.15毫摩尔),哌嗪-1-羧酸叔丁酯(560毫克, 3.01毫摩尔)和中间体C-1(357毫克, 1.50毫摩尔)溶于DMF(20毫升)中。反应混合物在氮气的保护下缓慢升至100℃并搅拌16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到中间体F-1(310毫克, 60%)。MS: 344.1 (M+H)+。
步骤 2:中间体F的制备
中间体F的合成参考中间体C-4,通过使用中间体F-1代替中间体C-3制备得到中间体F。MS: 422.1 & 424.1 (M+H)+。
中间体 G
步骤 1:中间体G-1的制备
中间体G-1的合成参考中间体C-1,通过使用1H-吲哚-5-羧酸甲酯代替5-溴吲哚制备得到中间体 G-1。MS: 218.1 (M+H)+。
步骤 2:中间体G-2的制备
将中间体G-1(500毫克, 2.30毫摩尔)和氢氧化锂(276毫克, 11.51毫摩尔)的甲醇(3毫升),水(2毫升)和四氢呋喃(3毫升)的反应混合物在20度搅拌反应4小时。将反应混合物倒入冰水中,并用1N的盐酸调节Ph值到4,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体G-2(380毫克, 81%)。MS: 204.1 (M+H)+。
步骤 3:中间体G-3的制备
将中间体G-2(150毫克, 0.74毫摩尔),HATU(267毫克, 0.738毫摩尔), DIEA(286毫克, 2.21毫摩尔)和哌嗪-1-羧酸叔丁酯(137毫克, 0.738毫摩尔)的DMF (2毫升)混合溶液在20度搅拌反应6小时。然后将反应混合物倒入冰水中,并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体G-3(130毫克, 47.4%)。MS: 372.2 (M+H)+。
步骤 4:中间体G的制备
中间体G的合成参考中间体C-4,通过使用中间体G-3代替中间体C-3制备得到中间体G。MS: 450.1 & 452.1 (M+H)+。
实施例
化合物I-1: 7-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-3-甲基吡咯[2,1-f][1,2,4]三嗪-4(3H)-酮
步骤1: 4-(3-异丙基-2-(3-甲基-4-氧代-3,4-二氢吡咯[2,1-f][1,2,4]三嗪-7-基)-1H-吲哚-5-基)哌啶-1-羧酸叔丁酯的制备(中间体I-1-1)
将中间体C (0.1克, 0.213毫摩尔),中间体A (0.073克, 0.32毫摩尔),碳酸钾(0.089克, 0.64毫摩尔)和Pd(dppf)Cl2(0.016克, 0.021毫摩尔)的1,4-二氧六环(6毫升)和水(1.5毫升)溶液在90℃搅拌反应16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体I-1-1 (20毫克, 19%)。MS: 490.2 (M+H)+。
步骤2: 7-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-3-甲基吡咯[2,1-f][1,2,4]三嗪-4(3H)-酮的制备(化合物I-1)
将中间体I-1-1(20毫克, 0.041毫摩尔)DCM(6毫升)和三氟乙酸(3毫升)溶液在10度搅拌反应2小时。反应混合物浓缩蒸干,并用乙酸乙酯萃取。有机相用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗产物,粗产物经Prep-HPLC纯化得到黄色固体化合物I-1。MS: 390.2 (M+H)+。1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H),8.51 (s, 1H), 8.30 - 8.16 (m, 1H), 8.13 (s, 1H), 7.53 (s, 1H), 7.34 (d, J =8.4 Hz, 1H), 7.05 (d, J = 4.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.70 (d, J =4.4 Hz, 1H), 3.41 (s, 3H), 3.14 (dd, J = 13.7, 6.7 Hz, 1H), 3.02 (d, J = 12.4Hz, 2H), 2.91 (s, 1H), 1.97 (d, J = 14.0 Hz, 2H), 1.87 (t, J = 13.0 Hz, 2H),1.36 (d, J = 7.0 Hz, 6H)。
实施例
化合物 I-2: 5-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-2-甲基-2,7-萘啶-1(2H)-酮
化合物I-2的合成参考化合物I-1,通过使用5-溴-2-甲基-2,7-萘啶-1(2H)-酮代替中间体A制备得到白色固体化合物I-2。MS: 401.1 (M+H)+。1H NMR (400 MHz, DMSO-d 6 )δ 11.02 (s, 1H), 9.44 (s, 1H), 8.69 (d, J = 5.7 Hz, 1H), 8.58 – 8.49 (m, 1H),8.25 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.14 (d,J = 5.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.61 (s, 3H), 3.07 – 2.97 (m, 2H),2.97 – 2.85 (m, 2H), 2.66 (s, 1H), 2.00 – 1.94 (m, 3H), 1.93 – 1.84 (m, 2H),1.32 (d, J = 7.0 Hz, 6H)。
实施例
化合物 I-3: 8-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-6-甲基咪唑[1,2-c]嘧啶-5(6H)-酮
化合物I-3的合成参考化合物I-1,通过使用中间体B代替中间体A制备得到白色固体化合物I-3。MS: 390.1 (M+H)+。1H NMR (400 MHz, DMSO-d 6 ) δ 10.95 (s, 1H), 8.56(s, 1H), 8.28 (br s, 1H), 7.92 br s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.47(s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 1.6 Hz, 1H), 3.62 (s,3H), 3.39 (d, J = 12.4 Hz, 2H), 3.18 (p, J = 7.0 Hz, 1H), 3.03 (q, J = 12.0Hz, 2H), 2.91 (t, J = 12.0 Hz, 1H), 1.97 (d, J = 12.0 Hz, 2H), 1.93 – 1.78(m, 2H), 1.39 (d, J = 7.2 Hz, 6H)。
实施例
化合物 I-4: 8-(3-异丙基-5-(哌啶-4-基)-1H-吲哚-2-基)-2,3-二氢吲哚嗪-5(1H)-酮
化合物I-4的合成参考化合物I-1,通过使用中间体D-5代替中间体A制备得到白色固体化合物I-4。MS: 376.1 (M+H)+。1H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 8.54(s, 1H), 8.26 (s, 1H), 7.47 (s, 1H), 7.35 (d, J = 9.1 Hz, 1H), 7.24 (d, J =8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.31 (d, J = 9.2 Hz, 1H), 4.06 (t, J =7.2 Hz, 2H), 3.38 (s, 2H), 3.08 – 2.83 (m, 6H), 2.09 (p, J = 7.5 Hz, 2H),2.01 – 1.77 (m, 4H), 1.33 (d, J = 7.0 Hz, 6H).
实施例
化合物 I-5: 2-(4-(3-异丙基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-8-基)-1H-吲哚-5-基)哌啶-1-基)乙酰胺
将化合物I-4(50毫克, 0.133毫摩尔),TEA(40.4毫克, 0.399毫摩尔)和2-溴乙酰胺(18.37毫克, 0.133毫摩尔)的乙腈(10毫升)溶液在20℃搅拌反应1小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经Prep-HPLC纯化得到白色固体化合物化合物 I-5 (24.5毫克, 42.5%)。MS: 433.1 (M+H)+。
实施例
化合物 I-6: 8-(3-异丙基-6-(哌啶-4-基)-1H-吲哚-2-基)-2,3-二氢吲哚嗪-5(1H)-酮
化合物I-6的合成参考化合物I-4,通过使用中间体E代替中间体C制备得到白色固体化合物I-6。MS: 376.1 (M+H)+。
实施例
化合物 I-7: 2-(4-(3-异丙基-2-(5-氧代-1,2,3,5-四氢吲哚嗪-8-基)-1H-吲哚-6-基)哌啶-1-基)乙酰胺
化合物I-7的合成参考化合物I-5,通过使用化合物I-6代替化合物I-4制备得到白色固体化合物I-7。MS: 433.1 (M+H)+。
实施例
化合物 I-8: 8-(3-异丙基-5-(哌嗪-1-基)-1H-吲哚-2-基)-2,3-二氢吲哚嗪-5(1H)-酮
化合物I-8的合成参考化合物I-4,通过使用中间体F代替中间体D-5和中间体D代替中间体C制备得到白色固体化合物I-8。MS: 377.1 (M+H)+ 。
实施例
化合物 I-9: 8-(3-异丙基-5-(哌嗪-1-羰基)-1H-吲哚-2-基)-2,3-二氢吲哚嗪-5(1H)-酮
化合物I-9的合成参考化合物I-8,通过使用中间体G代替中间体F制备得到白色固体化合物I-9。MS: 405.1 (M+H)+。
效果实施例1 细胞水平药效评价
采用稳定表达人源TLR7或者TLR8的HEK-BlueTM 细胞评价本发明化合物对TLR7或者TLR8的抑制活性,使用其对在IFN-β最小启动子融合到5个NF-κB和ap-1结合位点的控制下的SEAP报告基因的诱导能力来检测,具体如下:
将HEK-BlueTM hTLR7 (Invivogen,每孔80000个细胞) 或者 HEK-BlueTM hTLR8(Invivogen,每孔60000个细胞)加入到96孔细胞培养板,随后加入待测化合物,待测化合物在培养基中的最终浓度范围为:0.001~36μM,孵育15分钟。然后加入TLR7配体(Gardiquimod,购自MedChemExpress,在细胞培养基中化合物的最终浓度为:10 μM) 或者TLR8配体 (Resiquimod,购自MedChemExpress,在细胞培养基中化合物的最终浓度为:10 μM),孵育20小时。根据制造商的说明书,用HEK-Blue检测试剂Quanti-blue (Invivogen)来检测细胞培养基中的SEAP水平。利用GraphPad Prism计算药物半数抑制浓度IC50。
表1:本发明化合物在HEK-Blue hTLR7/8/细胞中的活性
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式I所示的化合物,或其可药用的盐:
所述的R1选自下组:
R2、R3、R4和R5选自下组:H、卤素、CF3、CN、C1-6烷基或C1-6烷氧基;
R6选自下组:H、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或C3-7环烷基;
L选自下组:键、-C(=O)-或C1-3亚烷基;
R7选自下组:H、C1-6烷基、卤代C1-6烷基或C3-7环烷基;
R8选自下组:H、-C(=O)NH2、羧酸、C3-9环烷基或3-9元杂环烷基,其中C3-9环烷基、3-9元杂环烷基可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;
Ra选自下组:H、卤素、羟基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2、-(CH2)m-C(=O)OH;其中m为0、1、2或3,Ra-1和Ra-2选自下组:氢、C1-6烷基;
X选自N或CR9,R9选自下组:H、卤素、C1-6烷基、CF3、CN、C1-6烷氧基,或所述的R9被-L-R8取代基取代。
2.如权利要求1所述的式I化合物,或其可药用的盐,其特征在于,R8选自下组:C3-9环烷基或3-9元杂环烷基,且所述的R8可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;
Ra选自下组:H、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-6环烷基、-(CH2)m-C(=O)NRa-1Ra-2;其中m为0、1、2或3,Ra-1和Ra-2选自下组:氢、C1-6烷基。
3.如权利要求1所述的式I化合物,或其可药用的盐,其特征在于,R8选自下组:C5-6环烷基或5-6元杂环烷基,且所述的R8可以被一个或多个Ra取代;所述杂环烷基独立地含有1-3个选自N、O、S的杂原子;Ra选自下组:H、-(CH2)m-C(=O)NRa-1Ra-2;其中m为0或1,Ra-1和Ra-2选自下组:氢、C1-6烷基。
4.如权利要求1所述的式I化合物,或其可药用的盐,其特征在于,L选自下组:键、-C(=O)-。
5.如权利要求1所述的式I化合物,或其可药用的盐,其特征在于,R2、R3、R4和R5为H;且R6选自下组:H、C1-6烷基、卤代C1-6烷基。
6.如权利要求1所述的式I化合物,或其可药用的盐,其特征在于,R7为C1-6烷基或卤代C1-6烷基。
8.一种药物组合物,其特征在于,所述的药物组合物包括:如权利要求1所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
9.如权利要求1所述的式I化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其特征在于,用于制备治疗或预防自身免疫性疾病或者慢性炎性疾病的药物组合物。
10.如权利要求9所述的用途,其特征在于,所述的疾病选自下组:干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎、系统性硬化症、牛皮癣、系统性红斑狼疮、狼疮肾炎。
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Cited By (1)
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---|---|---|---|---|
WO2024027712A1 (zh) * | 2022-08-01 | 2024-02-08 | 索智生物科技(浙江)有限公司 | 含氮杂环类化合物、其制备方法及其应用 |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060235037A1 (en) * | 2005-04-15 | 2006-10-19 | Purandare Ashok V | Heterocyclic inhibitors of protein arginine methyl transferases |
CN110997670A (zh) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | [1,2,4]三唑并[4,3-a]吡啶基取代的吲哚化合物 |
CN110997656A (zh) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | 用作tlr7/8/9抑制剂的取代的吲哚化合物 |
CN111448190A (zh) * | 2017-11-14 | 2020-07-24 | 百时美施贵宝公司 | 取代的吲哚化合物 |
CN111491918A (zh) * | 2017-12-20 | 2020-08-04 | 百时美施贵宝公司 | 芳基和杂芳基取代的吲哚化合物 |
CN111491930A (zh) * | 2017-12-19 | 2020-08-04 | 百时美施贵宝公司 | 可用作tlr抑制剂的经取代的吲哚化合物 |
CN111491929A (zh) * | 2017-12-20 | 2020-08-04 | 百时美施贵宝公司 | 可用作tlr抑制剂的氨基吲哚化合物 |
CN111511744A (zh) * | 2017-12-20 | 2020-08-07 | 百时美施贵宝公司 | 二氮杂吲哚化合物 |
CN111511730A (zh) * | 2017-12-19 | 2020-08-07 | 百时美施贵宝公司 | 可用作tlr抑制剂的被酰胺取代的吲哚化合物 |
CN111699185A (zh) * | 2017-12-19 | 2020-09-22 | 百时美施贵宝公司 | 6-氮杂吲哚化合物 |
CN111819176A (zh) * | 2017-12-18 | 2020-10-23 | 百时美施贵宝公司 | 4-氮杂吲哚化合物 |
CN112955450A (zh) * | 2018-10-24 | 2021-06-11 | 百时美施贵宝公司 | 经取代的吲哚和吲唑化合物 |
-
2022
- 2022-05-10 CN CN202210500160.7A patent/CN114591339B/zh active Active
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060235037A1 (en) * | 2005-04-15 | 2006-10-19 | Purandare Ashok V | Heterocyclic inhibitors of protein arginine methyl transferases |
CN110997670A (zh) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | [1,2,4]三唑并[4,3-a]吡啶基取代的吲哚化合物 |
CN110997656A (zh) * | 2017-08-04 | 2020-04-10 | 百时美施贵宝公司 | 用作tlr7/8/9抑制剂的取代的吲哚化合物 |
CN111448190A (zh) * | 2017-11-14 | 2020-07-24 | 百时美施贵宝公司 | 取代的吲哚化合物 |
CN111819176A (zh) * | 2017-12-18 | 2020-10-23 | 百时美施贵宝公司 | 4-氮杂吲哚化合物 |
CN111491930A (zh) * | 2017-12-19 | 2020-08-04 | 百时美施贵宝公司 | 可用作tlr抑制剂的经取代的吲哚化合物 |
CN111511730A (zh) * | 2017-12-19 | 2020-08-07 | 百时美施贵宝公司 | 可用作tlr抑制剂的被酰胺取代的吲哚化合物 |
CN111699185A (zh) * | 2017-12-19 | 2020-09-22 | 百时美施贵宝公司 | 6-氮杂吲哚化合物 |
CN111491918A (zh) * | 2017-12-20 | 2020-08-04 | 百时美施贵宝公司 | 芳基和杂芳基取代的吲哚化合物 |
CN111491929A (zh) * | 2017-12-20 | 2020-08-04 | 百时美施贵宝公司 | 可用作tlr抑制剂的氨基吲哚化合物 |
CN111511744A (zh) * | 2017-12-20 | 2020-08-07 | 百时美施贵宝公司 | 二氮杂吲哚化合物 |
CN112955450A (zh) * | 2018-10-24 | 2021-06-11 | 百时美施贵宝公司 | 经取代的吲哚和吲唑化合物 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024027712A1 (zh) * | 2022-08-01 | 2024-02-08 | 索智生物科技(浙江)有限公司 | 含氮杂环类化合物、其制备方法及其应用 |
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