CN112110936B - 四氢喹啉类衍生物及其制备方法和应用 - Google Patents
四氢喹啉类衍生物及其制备方法和应用 Download PDFInfo
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- CN112110936B CN112110936B CN201910536807.XA CN201910536807A CN112110936B CN 112110936 B CN112110936 B CN 112110936B CN 201910536807 A CN201910536807 A CN 201910536807A CN 112110936 B CN112110936 B CN 112110936B
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- Prior art keywords
- methyl
- benzyl
- tetrahydroquinolin
- carboxamide
- thieno
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 23
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 54
- -1 nitro, amino Chemical group 0.000 claims description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- ODQCXSNSHAXEJD-UHFFFAOYSA-N 4-methylthieno[3,2-b]pyrrole-5-carboxamide Chemical compound S1C=CC2=C1C=C(C(N)=O)N2C ODQCXSNSHAXEJD-UHFFFAOYSA-N 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 2
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- LYASTVLDAJIXBL-UHFFFAOYSA-N 1,3-benzothiazole-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=NC2=C1 LYASTVLDAJIXBL-UHFFFAOYSA-N 0.000 claims description 2
- FXWOAMWXZDFVTM-UHFFFAOYSA-N 1-(diaminomethylideneamino)-1-hydrazinylguanidine Chemical compound NNN(C(N)=N)NC(N)=N FXWOAMWXZDFVTM-UHFFFAOYSA-N 0.000 claims description 2
- ZRINNFFYRQVHGO-UHFFFAOYSA-N 1-methyl-N-[1-[(4-piperidin-4-yloxyphenyl)methyl]-3,4-dihydro-2H-quinolin-8-yl]indole-2-carboxamide Chemical compound CN1C(=CC2=CC=CC=C12)C(=O)NC=1C=CC=C2CCCN(C=12)CC1=CC=C(C=C1)OC1CCNCC1 ZRINNFFYRQVHGO-UHFFFAOYSA-N 0.000 claims description 2
- PWCFBPOHRCMWLV-UHFFFAOYSA-N 4-methyl-N-[1-[(4-piperidin-4-yloxyphenyl)methyl]-3,4-dihydro-2H-quinolin-5-yl]thieno[3,2-b]pyrrole-5-carboxamide Chemical compound CN1C2=C(C=C1C(=O)NC1=C3CCCN(C3=CC=C1)CC1=CC=C(C=C1)OC1CCNCC1)SC=C2 PWCFBPOHRCMWLV-UHFFFAOYSA-N 0.000 claims description 2
- KQHUDUNXEMXDTN-UHFFFAOYSA-N 4-methyl-N-[1-[[4-[(1-methylpiperidin-4-yl)methoxy]phenyl]methyl]-3,4-dihydro-2H-quinolin-8-yl]thieno[3,2-b]pyrrole-5-carboxamide Chemical compound CN1C2=C(C=C1C(=O)NC=1C=CC=C3CCCN(C=13)CC1=CC=C(C=C1)OCC1CCN(CC1)C)SC=C2 KQHUDUNXEMXDTN-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- XZIAUQDQIWHGAM-UHFFFAOYSA-N N-[1-[(4-piperidin-4-yloxyphenyl)methyl]-3,4-dihydro-2H-quinolin-8-yl]-1-benzofuran-2-carboxamide Chemical compound C1CC2=C(C(=CC=C2)NC(=O)C3=CC4=CC=CC=C4O3)N(C1)CC5=CC=C(C=C5)OC6CCNCC6 XZIAUQDQIWHGAM-UHFFFAOYSA-N 0.000 claims description 2
- XZVRATDGBQXSAG-UHFFFAOYSA-N N-[1-[[4-(3-aminopropyl)phenyl]methyl]-3,4-dihydro-2H-quinolin-8-yl]-4-methylthieno[3,2-b]pyrrole-5-carboxamide Chemical compound CN1C2=C(C=C1C(=O)NC3=CC=CC4=C3N(CCC4)CC5=CC=C(C=C5)CCCN)SC=C2 XZVRATDGBQXSAG-UHFFFAOYSA-N 0.000 claims description 2
- INCFWWZFXGSWFE-UHFFFAOYSA-N N-[1-[[4-[3-(dimethylamino)propoxy]phenyl]methyl]-3,4-dihydro-2H-quinolin-8-yl]-4-methylthieno[3,2-b]pyrrole-5-carboxamide Chemical compound CN(CCCOC1=CC=C(CN2CCCC3=CC=CC(=C23)NC(=O)C2=CC3=C(N2C)C=CS3)C=C1)C INCFWWZFXGSWFE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 3
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- OJWYYSVOSNWCCE-UHFFFAOYSA-N 2-methoxyethyl hypofluorite Chemical group COCCOF OJWYYSVOSNWCCE-UHFFFAOYSA-N 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 abstract description 15
- 239000000651 prodrug Substances 0.000 abstract description 15
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
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- 201000010099 disease Diseases 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
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- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
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- 239000000243 solution Substances 0.000 description 18
- 101001050886 Homo sapiens Lysine-specific histone demethylase 1A Proteins 0.000 description 17
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Abstract
本发明属于药物合成领域,提供了如通式(Ⅰ)所示的四氢喹啉类衍生物及其药学上可接受的盐、其立体异构体或前药,其中,A、Ra、Rb、n、m、R如权利要求和说明书所述。所述通式Ⅰ的四氢喹啉类衍生物及其药学上可接受的盐、其立体异构体或前药可单独或联合用药,作为赖氨酸特异性脱甲基酶‑1(LSD1)抑制剂,用于治疗诸如癌症等疾病。
Description
技术领域
本发明属于化学合成药物技术领域,涉及一类新型四氢喹啉类衍生物,以及所述衍生物的药学可接受的盐或前药,它们的制备方法及其作为治疗剂特别是作为赖氨酸特异性脱甲基酶-1(LSD1)抑制剂的用途。
背景技术
表观遗传学调控不同于基因调控,它是在人体在基因序列完全相同的情况下,调控基因的表达,从而对人体的生理功能进行调节。表观遗传学对基因的调控主要通过对核染色质的修饰来对基因转录进行调控,这是一个动态、可逆的过程。核染色质的修饰包括DNA甲基化、核小体重塑、组蛋白修饰,而组蛋白修饰涉及组蛋白乙酰化、磷酸化、泛素化、甲基化等过程,与核染色质修饰相关蛋白的非正常表达或调控,会导致人体机能紊乱引起包括肿瘤等疾病的产生。通过作用与疾病相关的核染色质修饰蛋白,可以起到缓解或治疗相关疾病的作用。
组蛋白赖氨酸去甲基化酶在开发表观遗传学领域的药物中占据着非常重要的地位,直到2004年,Shi Yang课题组第一次发现了组蛋白赖氨酸特异性去甲基化酶1,揭示了组蛋白甲基化过程是一个可逆、可控的过程(Cell 2004,119,941–953.)。研究发现LSD1在辅因子黄素腺嘌呤二核苷酸(FAD)的辅助下可以特异性地去除组蛋白赖氨酸的单甲基或双甲基,通过作用于不同位置甲基化的赖氨酸可以分别发挥基因转录激活和转录抑制的作用,进而调控下游信号通路,发挥调节作用。通过去除H3K4的双甲基化修饰,LSD1可以与转录共阻遏物诱导抑癌基因的沉默,从而促进肿瘤细胞的生长。因此,LSD1抑制剂的开发有利于抗肿瘤药物的研发,可以单独或者与其他药物组合用于癌症的治疗。
甲基化修饰的赖氨酸在LSD1和FAD的催化下可以发生氧化脱甲基,所以LSD1也属于胺氧化酶家族,与单胺氧化酶A(MAO A)和单胺氧化酶B(MAO B)具有很高同源性。研究初期,研究者发现MAO抑制剂对LSD1具有一定的抑制活性,因此,针对LSD1抑制剂的开发主要集中在胺氧化酶抑制剂的结构改造上。已上市的反苯环丙胺对LSD1显示出中等程度的抑制活性,研究者对反苯环丙胺进行了一系列的研究,发现其可以与辅因子FAD形成共价结合,这是它发挥抑制活性的重要机制。基于反苯环丙胺骨架,研究者发现很多活性、成药性优良的化合物,目前处于临床研究阶段的代表性LSD1抑制剂ORY-1001、ORY-2001、GSK-2879552、IMG-7289均以反苯环丙胺为结构母核。
目前基于反苯环丙胺骨架以外开发的抑制剂多数处于开发初期,开发更多新骨架LSD1抑制剂是目前抗肿瘤领域的研究热门。本发明所述通式Ⅰ化合物作为LSD1抑制剂,在体外酶水平表现出优异的活性。
发明内容
本发明的目的在于提供一种通式I所示的新型四氢喹啉类衍生物,以及所述衍生物的药学可接受的盐,其立体异构体或前药,用于制备LSD1抑制剂,
其中:
A环选自苯基、C5-C10环烷基、C5-C10芳杂基,其中,所述C5-C10芳杂基可含有1-4个选自N、O或S的杂原子,并且A环可任选1-5个相同或不同Ra取代;
Ra选自氢、羟基、巯基、卤素、硝基、氨基、氰基、羧基、酰胺、C1~C5烷基、C2~C5烯基、C2~C5炔基、C1~C5烷氧基、C1~C5烷硫基、C1~C3烷氧基酰基,C1~C3烷基亚磺酰基,C1~C3烷基磺酰基,C3~C6环烷基,且所述C1~C5烷基、C1~C5烷氧基、C3~C6环烷基,可被一个或多个卤素、羟基、羧基、氰基取代;
n为1至5之间的整数;
m为0至3之间的整数;
R选自C1~C7烷基、C1~C7环烷基、C1~C7杂环烷基、苯基、五至六元芳杂环;其中,所述苯基、C1~C7杂环烷基、五至六元芳杂环,可被一个或多个Rb取代,且所述C1~C7杂环烷基、五至六元芳杂环含有1~3个选自N、O或S的杂原子;
Rb选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺、C2-C10碳酸酯基;
A环以酰胺键与四氢喹啉母核的苯环相连,优选连接在8位,次优选连接在5位;
本发明优选涉及通式(I)所示的新型四氢喹啉类衍生物及其药学可接受的盐,其立体异构体或前药,其中,
A环为苯基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、恶唑基、异恶唑基、1,2,3-三氮唑基、1,2,4-三氮唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基、苯并嘧啶基、苯并哒嗪基、苯并吡嗪基、噻吩并吡咯基、噻吩并咪唑基、噻吩并嘧啶基、吡咯并嘧啶基、噻吩并吡啶基、噻唑并吡啶基,并且A环可任选1-5个相同或不同Ra取代;
进一步地,本发明优选涉及通式(I)所示的新型四氢喹啉类衍生物及其药学可接受的盐,其立体异构体或前药,
其中
A环优选苯基、吡啶基、嘧啶基、苯并呋喃基、苯并咪唑基、吲哚基、噻吩并吡咯基,并且A环任选1-5个相同或不同Ra取代;
Ra选自氢、羟基、巯基、卤素、硝基、氨基、氰基、羧基、酰胺、C1~C5烷基、C1~C5烷氧基,且所述C1~C5烷基、C1~C5烷氧基可被一个或多个卤素、羟基、羧基、氰基取代;
A环以酰胺键与四氢喹啉母核的苯环相连,优选连接在8位,次优选连接在5位;
本发明优选涉及通式(I)所示的新型四氢喹啉类衍生物及其药学可接受的盐,其立体异构体或前药,
其中,
A环优选苯基、吡啶基、嘧啶基、苯并呋喃基、苯并咪唑基、吲哚基、噻吩并吡咯基,并且A环任选1-5个相同或不同Ra取代;
Ra优选但不限于甲基、乙基、丙基、异丙基、甲氧基、乙氧基、氟、氯、三氟甲基、二氟甲基、三氟甲氧基,且乙基、丙基、异丙基、乙氧基、可被一个或多个氟、羟基、羧基、氰基取代;
n为1至5之间的整数;
更进一步地,本发明优选涉及通式(I)所示的新型四氢喹啉类衍生物及其药学可接受的盐,其立体异构体或前药,
其中
R优选但不限于
m为0至3之间的整数;
本发明优选涉及通式(I)所示的新型四氢喹啉类衍生物及其药学可接受的盐,其立体异构体或前药,
其中
Rb优选但不限于甲基、乙基、氟、氯、三氟甲基、氨基、氨甲基、肼基、脒基、胍基;
本发明通式I化合物及其药学上可接受的盐优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
4-甲基-N-[1-[4-(哌啶-4-氧)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(1-甲基哌啶-4-基)甲氧基]苄基]-1,2,3,4-四氢喹啉-8-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-(3-氨基丙基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[3-(二甲胺基)丙氧基]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
1,1-二甲基-4-[[4-[[8-(4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺)-3,4-二氢喹啉-1(2H)-基]甲基]苯氧基]-1-哌啶-2-碘鎓
1,1-二甲基-4-[[4-[[8-(4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺)-3,4-二氢喹啉-1(2H)-基]甲基]苯氧基]甲基]-1-哌啶-2-碘鎓
N-[1-[4-[[(1r,4r)-4-二甲胺基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1r,4r)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1s,4s)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(S)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(R)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(四氢-2H-吡喃-4-基)甲氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(吡咯烷-3-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[(4-氨基甲酰苄基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(4-硝苯基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(3-硝苯基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[(4-氨苄基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[(4-氰苄基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[(3-氰苄基)氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[[3-(甲胺)苄基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[3-(二甲氨基)苄基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1r,4r)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-5-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1s,4s)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-5-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(四氢-2H-吡喃-4-基)甲氧基]苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(S)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(R)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(吡咯烷-3-氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-(三氟甲基)苯甲酰胺
2-氟-N-[1-[4-(哌啶-4-氧基)苄基)-1,2,3,4-四氢喹啉-8-基)-4-(三氟甲基)苯甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-6-(三氟甲基)烟酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并[d]噻唑-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并[b]噻吩-2-甲酰胺
N N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并呋喃-2-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]烟酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]喹啉-3-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]喹啉-2-甲酰胺
1-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H–吲哚-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H–苯并[d]咪唑-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H-吲哚-4-甲酰胺。
而且,按照本发明所属领域的一些通常方法,本发明中通式I的化合物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的一些通常方法,本发明中通式I的化合物可以与相关试剂生成药学上可接受的前药。将通式I的化合物通过化学方法制备成相应的酯、酰胺、氨基甲酸酯、亚胺、磷酰胺、Mannich碱、半缩醛、缩醛、半缩酮、缩酮,或在分子中引入偶氮基、糖苷基、肽键与醚键。优选的将通式I化合物分子中胺基片段通过化学方法制备成氨基甲酸甲酯、氨基甲酸乙酯、氨基甲酸丙酯、氨基甲酸异丙酯、氨基甲酸叔丁酯等。
本发明中“卤素”是指氟、氯、溴或碘;“烷基”是指直链或支链的烷基;“环烷基”是指成环的烷基;“芳杂环”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,该环状体系是指具有芳香性的,并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团,如噻唑基,咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基,吲哚基,苯并噻唑基,噁唑基,异噁唑基,萘基,喹啉基,异喹啉基,苯并咪唑基,苯并噁唑基等;杂环烷基是指含有一个或多个选自N、O、S的杂原子的单环的环状体系,如四氢吡咯烷基、吗啉基、哌嗪基、哌啶基、四氢吡唑烷基、四氢咪唑烷基和四氢噻唑啉基等。
本发明可以含有通式I的衍生物,及其药学上可接受的盐或前药作为活性成份,与药学上可接受的载体或赋型剂混合制备成组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他毒副作用作用。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式(I)化合物,可按照路线1的方法或路线2方法制备得来。
路线1
路线2
如路线1所示,其中应用的全部可变因数除R’和X外,如权利要求中的定义。
起始原料I经过还原反应得到中间体II,反应条件a可以为各种钯类催化剂催化下的氢化还原,各种路易斯酸、质子酸等作为催化剂配合硼氢化钠或氢原子被多个取代基置换的硼氢化钠进行的还原,各种路易斯酸、质子酸等作为催化剂配合氢化铝锂的还原;反应溶剂可以是四氢呋喃、甲醇、乙醇、二氯甲烷等,优选四氢呋喃;反应温度优选室温。中间体II经过Boc酸酐、Fmoc-Cl等氨基保护试剂对苯环伯胺进行保护得到中间体III,氨基保护试剂优选Boc酸酐、Fmoc-Cl;反应溶剂可以是四氢呋喃、甲醇、乙醇、乙酸乙酯、二氯甲烷、水等,优选四氢呋喃、二氯甲烷。中间体IV与中间体V发生Mitsunobu反应得到中间体VI,在三苯膦(PPh3)和偶氮二甲酸二乙酯(DEAD)或偶氮二甲酸二异丙酯(DIAD)的催化下发生成醚,反应溶剂可为四氢呋喃、乙醚、二氯甲烷、甲苯、乙酸乙酯、乙腈和N’N-二甲基甲酰胺等,优选四氢呋喃;反应温度为-20℃-25℃。中间体VI经还原反应得中间体VII,还原试剂可以是硼氢化钠、乙酰氧基硼氢化钠、氰基硼氢化钠、氢化铝锂、甲酸等,优选硼氢化钠,也可在各种钯类催化剂氢化还原;反应溶剂可为四氢呋喃、乙醚、二氯甲烷、氯仿、甲苯等,优选四氢呋喃;反应温度为0℃-25℃。中间体VII经卤化或与对甲苯磺酰氯反应得中间体VIII,卤化试剂可以是氯化亚砜、三氯化磷、三溴化磷、碘等,可加适量催化剂,优选卤化试剂是碘;反应溶剂可为四氢呋喃、乙醚、二氯甲烷、氯仿、甲苯、甲醇等,优选四氢呋喃;反应温度25℃-85℃。中间体III与中间体VIII发生亲核取代得到中间体IX,反应体系可为碳酸钾/N’N-二甲基甲酰胺、碳酸钠/N’N-二甲基甲酰胺、三乙胺/二氯甲烷、三乙胺/四氢呋喃等,优选碳酸钾/N’N-二甲基甲酰胺体系,反应温度为室温。中间体IX经脱保护得中间体X,脱保护条件根据氨基保护基的种类选择合适的脱保护条件,优选HCl/MeOH脱除Boc,25%哌啶溶液脱除Fmoc。中间体X与中间体XI经酰化反应得到通式I的终产品,或者再经过1-2步的还原反应或对末端氮原子修饰得通式I的终产品。
如路线2所示,其中应用的全部可变因数除X外,如权利要求中的定义。具体的反应条件和操作与路线1中的相应反应条件和操作一致。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定,质谱用Agilent 1100LC/MSD测定;所用试剂均为分析纯或化学纯。
表1.实施例结构式、化学名、相对分子质量
实施例1:4-甲基-N-[1-[4-(哌啶-4-氧)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺的制备
步骤A-1:8-氨基四氢喹啉的制备(A)
将1.74g 8-硝基喹啉(10mmol)、4.74g六水合二氯化镍(20mmol)置于100mL单口反应瓶中,加入50mL甲醇,冰浴降温、搅拌;将1.9g硼氢化钠(50mmol)分批加入反应瓶,加毕,室温继续搅拌反应2h。停止搅拌,将反应液过滤,滤液通过减压浓缩,得黑色油状物;用二氯甲烷(50mL)溶解黑色油状物,以10mL×3、饱和食盐水10mL×3洗涤有机相后,用无水硫酸钠干燥,减压除去溶剂,硅胶柱层析分离纯化得0.90g白色固体,收率(60.8%)。
步骤A-2:9H-芴-9-甲基-1,2,3,4-四氢喹啉-8-氨基甲酸酯的制备(B)
将0.90g 8-氨基四氢喹啉(6.0mmol)、0.64g碳酸钠(6.0mmol)投入50mL反应瓶中,加入20mL四氢呋喃/水(V:V=1:1),冰浴降温、搅拌;将1.54g芴甲氧羰酰氯溶于5mL四氢呋喃中滴加至反应体系,30min滴加完毕;室温反应1h后,将反应液减压浓缩,用二氯甲烷10mL×3萃取,合并二氯甲烷相,用无水硫酸钠干燥,浓缩得粗品1.52g,无需纯化,可直接用于下一步反应。
步骤A-3:4-(4-醛基苯氧基)哌啶-1-羧酸叔丁酯的制备(C)
将1.22g对羟基苯甲醛(10mmol)、2.0g N-Boc-4-羟基哌啶(10mmol)、2.62g三苯基膦(10mmol)投入50mL反应瓶中,加入30mL四氢呋喃,搅拌降温至-20℃;将1.74g偶氮二甲酸二乙酯溶于4mL四氢呋喃中,滴加至反应体系,1h滴加完毕,将反应体系温度逐渐升至室温,继续反应4h。将反应液浓缩至5mL后加入40mL水,用二氯甲烷10mL×3萃取,合并二氯甲烷相,用无水硫酸钠干燥,浓缩得粗品,硅胶柱层析分离纯化得1.77g白色固体,收率(56.0%)。
步骤A-4:4-(4-羟甲基苯氧基)哌啶-1-羧酸叔丁酯的制备(D)
将1.77g 4-(4-醛基苯氧基)哌啶-1-羧酸叔丁酯(5.6mmol)、20mL甲醇投入50mL反应瓶中,室温搅拌,分批加入0.1g硼氢化钠,加毕,继续反应1h。减压除去溶剂,加入20mL乙酸乙酯,以10mL×3、饱和食盐水10mL×3洗涤有机相后,浓缩得粗品1.40g,无需纯化,可直接用于下一步反应。
步骤A-5:4-(4-碘甲基苯氧基)哌啶-1-羧酸叔丁酯的制备(E)
将1.76g三苯基膦(6.7mmol)、1.70g碘(6.7mmol)加入50mL反应瓶中,室温搅拌1h,将1.77g中间体D加入反应体系,室温反应4h。加入5mL饱和硫代硫酸钠水溶液,剧烈搅拌10min,分液,取二氯甲烷相,以10mL×3、饱和食盐水10mL×3洗涤有机相后,用无水硫酸钠干燥,减压除去溶剂,硅胶柱层析分离纯化得1.40g淡黄色固体,收率(50.2%)。
步骤A-6:4-[4-[[8-氨基-3,4-二氢喹啉-1(2H)]甲基]苯氧基]哌啶-1-羧酸叔丁酯的制备(G)
50mL反应瓶中加入0.76g中间体B(2.0mmol)、0.83g中间体E(2.0mmol)、20mL二氯甲烷,随后加入0.2g三乙胺(2.0mmol),室温搅拌反应1h后向反应体系加入4mL哌啶,继续室温反应2h。以10mL×3、饱和食盐水10mL×3洗涤反应液后,用无水硫酸钠干燥,减压除去溶剂,硅胶柱层析分离纯化得0.57g白色固体,两步总收率为65.4%。
步骤A-7:4-[4-[[8-(4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺)-3,4-二氢喹啉-1(2H)]甲基]苯氧基]哌啶-1-羧酸叔丁酯的制备(I)
将0.44g中间体G(1.0mmol)、0.18g中间体H(1.0mmol)、0.38g 2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.0mmol)加入10mL反应瓶,加入2mL无水DMF和0.26gN,N-二异丙基乙胺,室温反应12h。将反应液倒入20mL水中,用二氯甲烷10mL×3萃取,合并二氯甲烷相,用无水硫酸钠干燥,浓缩得粗品,硅胶柱层析分离纯化得0.33g白色固体,收率(56.1%)。
步骤A-8:4-甲基-N-[1-[4-(哌啶-4-氧)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺盐酸盐的制备(J)
将0.33g中间体I加入2mL 4摩尔每升的氯化氢甲醇溶液中,室温搅拌1h,将溶剂减压除去既得粗品,粗品用乙酸乙酯打浆得纯品,0.15g白色固体,收率50.8%。
步骤A-9:4-甲基-N-[1-[4-(哌啶-4-氧)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺的制备
将中间体J溶于水中,以氢氧化钠水溶液调节PH=10,用乙酸乙酯10mL×3萃取,合并乙酸乙酯相,用无水硫酸钠干燥,浓缩得4-甲基-N-(1-(4-(哌啶-4-氧)苄基)-1,2,3,4-四氢喹啉-8-基)-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺。
实施例2、实施例3的制备采用不同的底物,按照实施例1的操作步骤制备得到。
实施例4、5、6、7以不同的底物制备,在脱去R侧链末端氮原子的Boc保护基后,对氮原子甲基化修饰后得到。
实施例8-14、16、17、19、20以不同的底物,按照实施例1的操作步骤制备得到。
实施例15是通过对实施例19水解得到。
实施例18通过还原实施例16的硝基得到。
实施例21、22通过将实施例17的硝基还原为氨基后,对氨基甲基化修饰后得到。
实施例23-30以5-硝基喹啉为起始原料,参照实施例1的操作得到。
实施例31-42以8-硝基喹啉为起始原料,参照路线1或路线2的合成路线得到。
实施例43是对实施例23分子中哌啶氮原子进行修饰得到。具体实施方法如下:
将0.1g 4-甲基-N-[1-[4-(哌啶-4-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺(0.2mmol)、0.03g三乙胺(0.3mmol)投入10mL反应瓶中,加入3mL二氯甲烷,冰浴降温并搅拌,逐滴加入0.02g氯甲酸乙酯(0.2mmol),继续反应2h。将反应液减压浓缩,硅胶柱层析分离纯化得0.08g白色固体,收率为68.2%。
本发明部分产物的体外药理测试
单甲基或双甲基化修饰的赖氨酸在LSD1和FAD的催化下发生氧化脱甲基,同时产生H2O2。基于辣根过氧化物酶检测方法的LSD1抑制活性检测试剂盒可以捕获赖氨酸发生氧化脱甲基过程产生的H2O2,来实现对LSD1酶活力评估。本发明采购Cayman公司的700120试剂盒对部分化合物的LSD1抑制活性进行检测,检测原理如下:
(1)H3K4双甲基化的肽链底物在FAD的辅助下被LSD1去除甲基,同时FAD被还原为FADH2,FADH2在氧气存在的情况下被氧化为FAD,生成的FAD会继续辅助H3K4的甲基化,完成催化循环。
(2)FADH2在氧气存在的情况下被氧化为FAD的同时会产生一分子H2O2。
(3)荧光性底物10-乙酰基-3,7-二羟基吩噁嗪(ADHP)在辣根过氧化物酶(HRP)的催化下与H2O2反应生成强荧光性物质N-乙基-N-乙氧基乙基-4-氨基苯甲醛;7-羟基-3H-吩恶嗪(试卤灵),试卤灵在530-540nm的激发波长下会发射出585-595nm的荧光。
(4)根据发射出585-595nm的荧光强度分析化合物的LSD1抑制活性。荧光强度越高,抑制活性越弱。
具体操作步骤:
(1)检测设置100%活性孔、背景孔、阳性对照孔和化合物孔。每组设三个复孔。
(2)100%活性孔:依次加入120μL LSD1Buffer溶液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μL LSD1酶、20μL LSD1检测肽。
(3)测试孔和阳性对照孔:依次加入120μL LSD1Buffer溶液、10μL待测化合物溶液、20μL LSD1酶、20μL LSD1检测肽。
(4)背景孔:依次加入140μL LSD1Buffer溶液、10μL溶液(与溶解化合物和阳性药相同成分的溶液)、20μL LSD1酶。
(5)加溶液过程中将96孔板置于冰袋上降温,防止酶促反应的进行。加毕,避光,室温孵育30min。
(6)孵育30min后,依次向每个孔加入20μL辣根过氧化物酶溶液、10μL荧光底物溶液。避光,室温孵育10min。
(7)酶标仪530nM波长下激发,检测590nM的发射荧光的强弱。
抑制率%=(100%活性孔–样品孔)/100%活性孔*100
表2.实施例核磁氢谱、酶抑制活性数据
注:体外酶水平活性测试IC50被指定为在以下范围内:
A:<0.1μΜ
B:>0.1μΜ至<1μΜ
C:>1μΜ至<10μΜ
D:>10μΜ
实施例24、27、28、29、30、32为盐酸盐的形式,即化合物药学上可接受的盐。可将其盐酸盐参考实施例1中的操作步骤去除,得到原型药。
实施例43为实施例23的前药形式,但实施例23的前药形式并不限于实施例43。
本发明中通式I的化合物及其药学上可接受的盐或前药可单独施用,但通常是和药用载体混合物给予,所述药用载体的选择要根据所需用药途径和标准药物实践,下面分别用该类化合物的各种药物剂型,例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法,说明其在制药领域中的新应用。
实施例85:片剂
用含有权利要求1中化合物的化合物(以实施例1化合物为例)10g,按照药剂学一般压片法加辅料20g混匀后,压制成100片,每片重300mg。
实施例86:胶囊剂
用含有权利要求1中化合物的化合物(以实施例2化合物为例)10g,按照药剂学胶囊剂的要求将辅料20g混匀后,装入空心胶囊,每个胶囊重300mg。
实施例87:注射剂
用含有权利要求1中化合物的化合物(以实施例3化合物为例)10g,按照药剂学常规方法,进行活性炭吸附,经0.65μm微孔滤膜过滤后,填入氮气罐制成水针制剂,每只装2mL,共灌装100瓶。
实施例88:气雾剂
用含有权利要求1中化合物的化合物(以实施例5化合物为例)10g,用适量丙二醇溶解后,加入蒸馏水及其他辐料后,制成500mL的澄清溶液即得。
实施例89:栓剂
用含有权利要求1中化合物的化合物(以实施例9化合物为例)10g,将之研细加入甘油适量,研匀后加入已熔化的甘油明胶,研磨均匀,倾入已涂润滑剂的模型中,制得栓剂50颗
实施例90:膜剂
用含有权利要求1中化合物的化合物(以实施例23化合物为例)10g,将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解,80目筛网过滤,再将实施例18化合物加入到滤液中搅拌溶解,涂膜机制膜100片。
实施例91:滴丸剂
用含有权利要求1中化合物的化合物(以实施例30化合物为例)10g,与明胶等基质50g加热熔化混匀后,滴入低温液体石蜡中,共制得滴丸1000丸。
实施例92:外用搽剂
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g,按照常规药剂学方法与乳化剂等辅料2.5g混合研磨,再加蒸馏水至200mL制得。
实施例93:软膏剂
用含有权利要求1中化合物的化合物(以实施例40化合物为例)10g,研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围。
Claims (13)
1.通式(Ⅰ)所示的化合物,及其药学上可接受的盐、立体异构体:
其中:
A环选自苯基、C5-C10芳杂环,其中,所述C5-C10芳杂环含有1-4个选自N、O或S的杂原子,并且A环可任选1-5个相同或不同Ra取代;
Ra选自氢、卤素、硝基、氰基、C1~C5烷基、C2~C5烯基、C2~C5炔基、C1~C5烷氧基、C1~C5烷硫基、C1~C3烷氧基酰基,C1~C3烷基亚磺酰基,C1~C3烷基磺酰基,且所述C1~C5烷基、C1~C5烷氧基可被一个或多个卤素、羟基、羧基、氰基取代;
n为1至5之间的整数;
m为0至3之间的整数;
R选自C1~C7环烷基、C1~C7杂环烷基、五-六元芳杂环;其中,所述C1~C7杂环烷基、五-六元芳杂环,可被一个或多个Rb取代,且所述C1~C7杂环烷基、五-六元芳杂环含有1~3个选自N、O或S的杂原子;
Rb选自C1~C3烷基、羟基、巯基、卤素、硝基、氨基、氰基、羧基、肼基、脒基、胍基、酰胺、C2-C10碳酸酯基;
A环以酰胺键与四氢喹啉母核的苯环相连,连接在8位或5位。
2.权利要求1中所述的通式(Ⅰ)所示的化合物,及其药学上可接受的盐、立体异构体:
其中,
Ra为甲基、乙基、丙基、异丙基、甲氧基、乙氧基、氟、氯、三氟甲基、二氟甲基、三氟甲氧基,且乙基、丙基、异丙基、乙氧基被一个或多个氟、羟基、羧基、氰基取代。
3.权利要求1中所述的通式(Ⅰ)所示的化合物,及其药学上可接受的盐、立体异构体:
其中,
Rb为:甲基、乙基、氟、氯、三氟甲基、氨基、氨甲基、肼基、脒基、胍基。
4.权利要求1中所述的通式(Ⅰ)所示的化合物,及其药学上可接受的盐、立体异构体:
其中,
A环以酰胺键与四氢喹啉母核的苯环相连,连接在5位。
5.权利要求1中所述的通式(Ⅰ)所示的化合物,及其药学上可接受的盐、立体异构体:
其中,
A环为苯基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噻唑基、异噻唑基、恶唑基、异恶唑基、1,2,3-三氮唑基、1,2,4-三氮唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基、苯并嘧啶基、苯并哒嗪基、苯并吡嗪基、噻吩并吡咯基、噻吩并咪唑基、噻吩并嘧啶基、吡咯并嘧啶基、噻吩并吡啶基、噻唑并吡啶基,并且A环可任选1-5个相同或不同Ra取代;
A环以酰胺键与四氢喹啉母核的苯环相连,连接在8位或5位。
6.权利要求1-5中任何一项所述的通式(Ⅰ)的化合物,及其药学上可接受的盐、立体异构体,
其中,
A环为苯基、吡啶基、嘧啶基、苯并呋喃基、苯并咪唑基、吲哚基、噻吩并吡咯基,并且A环任选1-5个相同或不同Ra取代。
8.如下所示的化合物,及其药学上可接受的盐、立体异构体,选自:
4-甲基-N-[1-[4-(哌啶-4-氧)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(1-甲基哌啶-4-基)甲氧基]苄基]-1,2,3,4-四氢喹啉-8-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-(3-氨基丙基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[3-(二甲胺基)丙氧基]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
1,1-二甲基-4-[[4-[[8-(4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺)-3,4-二氢喹啉-1(2H)-基]甲基]苯氧基]-1-哌啶-2-碘鎓
1,1-二甲基-4-[[4-[[8-(4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺)-3,4-二氢喹啉-1(2H)-基]甲基]苯氧基]甲基]-1-哌啶-2-碘鎓
N-[1-[4-[[(1r,4r)-4-二甲胺基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1r,4r)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1s,4s)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(S)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(R)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-[(四氢-2H-吡喃-4-基)甲氧]苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(吡咯烷-3-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1r,4r)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-5-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-[[(1s,4s)-4-氨基环己基]氧]苄基]-1,2,3,4-四氢喹啉-5-基]-4-甲基-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(S)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
(R)-4-甲基-N-[1-[4-(吡咯烷-3-甲氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(吡咯烷-3-氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-5-基]-4H-噻吩并[3,2-b]吡咯-5-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-4-(三氟甲基)苯甲酰胺
2-氟-N-[1-[4-(哌啶-4-氧基)苄基)-1,2,3,4-四氢喹啉-8-基)-4-(三氟甲基)苯甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并[d]噻唑-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并[b]噻吩-2-甲酰胺
N N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]苯并呋喃-2-甲酰胺
4-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]烟酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]喹啉-2-甲酰胺
1-甲基-N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H–吲哚-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H–苯并[d]咪唑-2-甲酰胺
N-[1-[4-(哌啶-4-氧基)苄基]-1,2,3,4-四氢喹啉-8-基]-1H-吲哚-4-甲酰胺。
10.一种药用组合物,包含权利要求1-8中任何一项的化合物及其药学上可接受的盐、立体异构体作为活性成分以及药学上可接受的赋形剂。
11.权利要求1-8中任何一项的化合物及其药学上可接受的盐、立体异构体或权利要求10所述的药物组合物在制备LSD1抑制剂中的应用。
12.权利要求1-8中任何一项的化合物及其药学上可接受的盐、立体异构体或权利要求10所述的药物组合物在制备抗肿瘤药物中的应用。
13.权利要求11或12所述的应用,其中,所述的化合物及其药学上可接受的盐、立体异构体或权利要求10所述的药物组合物单独或与其他药物联合使用。
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