CN113943278B - 一种免疫调节剂 - Google Patents
一种免疫调节剂 Download PDFInfo
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- CN113943278B CN113943278B CN202110805261.0A CN202110805261A CN113943278B CN 113943278 B CN113943278 B CN 113943278B CN 202110805261 A CN202110805261 A CN 202110805261A CN 113943278 B CN113943278 B CN 113943278B
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- alkylene
- alkyl
- hydrogen
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- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 208000013274 squamous cell breast carcinoma Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明公开了一种免疫调节剂,具体涉及一类抑制IL‑17A的化合物及其作为免疫调节剂在制备药物中的用途。本发明公开了式I所示的化合物、或其立体异构体在制备抑制IL‑17A类药物中的用途,为临床上筛选和/或制备与IL‑17A活性相关的疾病的药物提供了一种新的选择。
Description
技术领域
本发明涉及一种免疫调节剂及其在制备药物中的用途。
背景技术
IL-17(白细胞介素-17)是促炎性细胞因子,在诱导其他炎性细胞因子、趋化因子和粘附因子中发挥作用。IL-17家族由参与急性和慢性炎症反应的细胞因子组成,包括IL-17A(CTLA-8)、IL-17B、IL-17C、IL-17D、IL-17E(IL-25)和IL-17F。IL-17A由TH17细胞表达,其参与炎症和自身免疫性疾病的病理发生。人类IL-17A是分子量约为17000道尔顿的糖蛋白。IL-17A通过IL-17受体复合物(IL-17RA和IL-17RC)将信号传送至细胞内(Wright,etal.Journal of immunology,2008,181:2799-2805)。IL-17A的主要功能是通过促炎和嗜中性粒细胞迁移细胞因子和趋化因子(包括IL-6,G-CSF,TNF-α,IL-1,CXCL1,CCL2,CXCL2)的上调来协调局部组织炎症,以及基质金属蛋白酶来允许活化的T细胞穿透细胞外基质。有研究表明IL-17A在严重哮喘和慢性阻塞性肺疾病(COPD)中发挥重要作用,那些患者通常对目前可用的药物无响应或响应不良(Al-Ramli et al.J Allergy Clin Immunol,2009,123:1185-1187)。IL-17A水平上调涉及许多疾病,包括类风湿性关节炎(RA)、骨侵蚀、腹膜内脓肿、炎性肠病、同种异体移植物排斥反应、牛皮癣、动脉粥样硬化、哮喘和多发性硬化症(Gaffen,SL et al.Arthritis Research&Therapy,2004,6:240-247)。
靶向IL-17A与IL-17RA的结合是治疗IL-17A介导的自身免疫性炎性疾病的有效策略。通过IL-17A中和抗体治疗动物在自身免疫性脑脊髓炎中降低疾病发病率和严重性(Komiyama Y et al.J.Immunol.,2006,177:566-573)。已有IL-17A抗体的临床试验在IL-7A介导的炎性疾病(包括哮喘、牛皮癣、类风湿性关节炎、强直性脊柱炎和多发性硬化症)上显示出良好的结果。IL-17A抗体(Novartis的Cosentyx/secukinumab)在2015年1月已被FDA批准用于牛皮癣的治疗。
尽管存在多种IL-17A抗体,但很少有对具有口服生物利用度的IL-17的小分子特异性抑制剂进行研究。鉴于产生抗体的成本考虑和给药途径的限制,开发IL-17A小分子抑制剂药物具有良好的研发前景。
发明内容
本发明提供了一种式I所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,
R1选自-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-C(O)R11、-C0~2亚烷基-C(O)NR11R12、-C0~2亚烷基-C(O)OR11、-C0~2亚烷基-S(O)R11、-C0~2亚烷基-S(O)NR11R12、-C0~2亚烷基-S(O)OR11、-C0~2亚烷基-S(O)2R11、-C0~2亚烷基-S(O)2NR11R12、-C0~2亚烷基-S(O)2OR11、-C0~2亚烷基-P(O)R11R12、-C0~2亚烷基-P(O)(OR11)R12、-C0~2亚烷基-P(O)(OR11)(OR12);其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1a取代;
R11、R12分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1a取代;
每个R1a分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR1b、-C0~2亚烷基-C(O)R1b、-C0~2亚烷基-C(O)NR1bR1c、-C0~2亚烷基-NR1bR1c、-C0~2亚烷基-NR1bC(O)R1c、-C0~4亚烷基-S(O)2R1bR1c、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R1b取代;
R1b、R1c分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
R2选自氢、-C1~6烷基、-C0~2亚烷基-(3~10元环烷基);
A环选自3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个或三个独立的RA1取代;
每个RA1分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
R3、R4分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R31取代;
或者,R3、R4相连形成3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R31取代;
每个R31分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
X1、X2、X3分别独立选自N或CRx;
每个Rx分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
R选自-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)或其中亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的RR取代;
每个RR分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-ORR1、-C0~2亚烷基-OC(O)RR1、-C0~2亚烷基-C(O)RR1、-C0~2亚烷基-C(O)ORR1、-C0~2亚烷基-C(O)NRR1RR2、-C0~2亚烷基-NRR1RR2、-C0~2亚烷基-NRR1C(O)RR2、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的RR3取代;
RR1、RR2分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
每个RR3分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
R5、R6分别独立选自氢、C1~6烷基、-C0~2亚烷基-O(C1~6烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(3~10元环烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(3~10元杂环烷基)、-C0~2亚烷基-O(C0~2亚烷基)-(5~10元芳环)、-C0~2亚烷基-O(C0~2亚烷基)-(5~10元芳杂环)、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R51取代;
或者,R5、R6相连形成3~10元环烷基、3~10元杂环烷基;其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C0~2亚烷基-OR52、-C0~2亚烷基-OC(O)R52、-C0~2亚烷基-C(O)R52、-C0~2亚烷基-C(O)OR52、-C0~2亚烷基-C(O)NR52R53、-C0~2亚烷基-NR52R53、-C0~2亚烷基-NR52C(O)R53、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)或-C0~2亚烷基-R54;
R52、R53分别独自选自氢、-C1~10烷基、卤素取代的-C1~10烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
R54选自
R55、R56分别独自选自氢、-C1~10烷基、-C0~4亚烷基-(3~10元环烷基)、-C0~4亚烷基-(3~10元杂环烷基);
R7、R8分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环)、-C0~2亚烷基-(5~12元螺环)、-C0~2亚烷基-(5~12元螺杂环)、-C0~2亚烷基-(5~12元桥环)、-C0~2亚烷基-(5~12元桥杂环)或-C0~4亚烷基-OR75、-C0~4亚烷基-NR75R76;其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环、螺环、螺杂环、桥环、桥杂环可进一步被一个、两个或三个独立的R71取代;
每个R71分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR72、-C0~2亚烷基-OC(O)R72、-C0~2亚烷基-C(O)R72、-C0~2亚烷基-C(O)OR72、-C0~2亚烷基-C(O)NR72R73、-C0~2亚烷基-NR72R73、-C0~2亚烷基-NR72C(O)R73、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);其中烷基、亚烷基、环烷基、杂环烷基、芳环、芳杂环可进一步被一个、两个或三个独立的R74取代;
R72、R73分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基)、-C0~2亚烷基-(5~10元芳环)、-C0~2亚烷基-(5~10元芳杂环);
每个R74分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基);
R75、R76分别独自选自氢、C1~6烷基、
R77、R78分别独自选自氢、-C1~10烷基、-C0~4亚烷基-(3~10元环烷基)、-C0~4亚烷基-(3~10元杂环烷基)。
进一步地,所述R1选自
进一步地,
A环选自3~6元环烷基;其中环烷基可进一步被一个、两个或三个独立的RA1取代;
每个RA1分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)。
进一步地,
R3、R4分别独立选自氢、3~6元环烷基;其中环烷基可进一步被一个、两个或三个独立的R31取代;
每个R31分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)。
进一步地,
X1、X2、X3分别独立选自N或CRx;每个Rx分别独立选自氢、卤素。
进一步地,R5、R6分别独立选自氢、C1~6烷基、3~6元杂环烷基。
进一步地,
R5、R6相连形成3~6元杂环烷基;其中杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、卤素、氰基、羰基、硝基、-OH、-O(C1~6烷基)、-NH2、-NH(C1~6烷基)、-N(C1~6烷基)(C1~6烷基)、-C(O)(C1~6烷基)、-C(O)O(C1~6烷基)。
进一步地,
R7、R8分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R71取代;
每个R71分别独立选自氢、卤素、氰基、羰基、硝基、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR72、-C0~2亚烷基-OC(O)R72、-C0~2亚烷基-C(O)R72、-C0~2亚烷基-C(O)OR72、-C0~2亚烷基-C(O)NR72R73、-C0~2亚烷基-NR72R73、-C0~2亚烷基-NR72C(O)R73、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);
R72、R73分别独立选自氢、C1~6烷基、-C0~2亚烷基-(3~10元环烷基)。
进一步具体地,式I所述的化合物具体为:
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本发明还提供了前述化合物、或其立体异构体、或其药学上可接受的盐在制备治疗IL-17A介导的疾病的药物中的用途。
进一步地,所述IL-17A介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
本发明还提供了一种药物组合物,它是以前述化合物、或其立体异构体、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗IL-17A介导的疾病的药物中的用途。
本发明所定义的IL-17A介导的疾病是IL-17A在该疾病的病理发生中起重要作用的疾病。IL-17A的主要功能是协调局部组织炎症,从而在各种疾病中起作用。IL-17A介导的疾病包括炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。。
“癌症”或“恶性肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种,受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期,中期或晚期阶段的细胞。癌症包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌和前列腺癌。在一些实施方案中,式I的化合物用于治疗选自结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌的癌症。在一些实施方案中,癌症选自黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌。在一些实施方案中,所治疗的癌症是转移性癌症。
自身免疫性疾病是由身体对体内正常存在的物质和组织的免疫反应引起的。自身免疫疾病的例子包括心肌炎、狼疮性肾炎、原发性胆汁性肝硬化、牛皮癣、1型糖尿病、格雷夫氏病、腹腔疾病、克罗恩病、自身免疫性中性白细胞减少症、幼年型关节炎、类风湿性关节炎、纤维肌痛、吉兰巴利综合征、多发性硬化症和自身免疫性视网膜病变。本发明的一些实施方案涉及治疗自身免疫疾病如牛皮癣或多发性硬化症。
炎症疾病包括以组织病理性炎症为特征的多种病症。炎性疾病的例子包括寻常性痤疮、哮喘、腹腔疾病、慢性前列腺炎、肾小球性肾炎、炎症性肠病、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、血管炎、房尘螨引起的气道炎症和间质性膀胱炎。炎性疾病与自身免疫性疾病之间存在显著重叠。本发明的一些实施方案涉及炎性疾病哮喘的治疗。免疫系统通常涉及炎症性疾病,在过敏反应和一些肌病中都有表现,许多免疫系统疾病导致异常炎症。IL-17A介导的疾病也包括自身免疫性炎症性疾病。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1~4烷基”是指包含1~4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1~6烷基是指具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其他基团为例如C1~C6烷氧基。
“环烷基”、“环烷烃”是指具有碳原子且没有环杂原子且具有单个环或多个环(包括稠合、并和)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时,适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团,诸如环己烯基。环烷基基团的实例包括例如,金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。例如
“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基基团。例如,(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如,(C2-C6)炔基意在包括乙炔基、丙炔基等。
“卤素”为氟、氯、溴或碘。
“卤素烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1~4卤素烷基指氢原子被一个或多个卤素原子取代的包含1~4个碳原子的烷基。
“杂环”、“杂环烷基”、“杂环烷烃”指包含至少一个杂原子的饱和环或非芳香性的不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“芳杂环”指包含至少一个杂原子的芳香性不饱和环;其中杂原子指氮原子、氧原子、硫原子;
“立体异构体”包括对映异构体和非对映异构体;
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
化合物的结构是通过核磁共振(NMR)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 AvanceIII 400和Bruker Avance 300)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)。
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
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,或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明,反应在氮气氛围下进行。实施例中无特殊说明,溶液是指水溶液。实施例中无特殊说明,反应的温度为室温。实施例中无特殊说明,M/N是摩尔每升。
THF:四氢呋喃;DCM:二氯甲烷;
DBU:1,5-二氮杂二环[5.4.0]十一-5-烯;
DIBAL:二异丁基氢化铝;EA:醋酸乙酯;
m-CPBA:间氯过氧苯甲酸;TEA:三乙胺;
HBTU:O-苯并三氮唑-四甲基脲六氟磷酸酯;
LDA:二异丙基胺基锂;TEA:三乙胺;
DIPEA:N,N-二异丙基乙胺;HOBt:1-羟基苯并三唑;
EDCI:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐;
HOAt:1-羟基-7-氮杂苯并三氮唑;DMF:二甲基甲酰胺;
TFA:三氟乙酸;Xantphos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽。
PPTs:吡啶对甲苯磺酸盐;CbzOSU:N-苄氧羰氧基丁二酰亚胺。
中间体Za-1的制备
步骤1,中间体Za-1-a的制备
冰浴氮气保护下,向60%质量分数的氢化钠(10.49mmol)的无水THF(25mL)分散液中滴加三乙基2-膦酰基丙酯(2.04g,10.49mmol),零度下搅拌20min分钟,然后滴加环丁基甲醛(840mg,9.99mmol),滴加完毕,逐渐升至室温并搅拌过夜。反应完后用饱和氯化铵淬灭,乙酸乙酯萃取,合并的有机相旋干,粗品用硅胶柱分离纯化得到中间体Za-1-a(1.6g,9.51mmol,95.24%收率)。
步骤2,中间体Za-1-b的制备
-70℃条件下,向中间体Za-1-a(9.0g,53.50mmol)的DCM(60mL)溶液中滴加DIBAL(15.11g,107.00mmol,18.93mL),滴加完毕后,保温反应2小时,TLC检测反应完全,滴加水淬灭,过滤反应液,滤液分层,有机相旋干得到的粗品,用硅胶柱分离纯化,得到中间体Za-1-b(5.6g,44.38mmol,82.95%收率)。
步骤3,中间体Za-1-c的制备
冰浴下,向中间体Za-1-b(1.5g,12.12mmol)的DCM(60mL)溶液中加入CBr4(4.57g,13.94mmol),然后滴加PPh3(3.33g,127.30mmol)的DCM(5mL)溶液。反应液在0℃下搅拌1小时,然后过滤反应混合液,滤液浓缩后得到的粗品,用硅胶柱纯化(洗脱剂石油醚)得到中间体Za-1-c(2.2g,11.6mmol,95.96%收率)。
步骤4,中间体Za-1-d的制备
室温下,向Za-1-c(1.4g,7.40mmol)和(2Z)-2-[((S)-叔丁基亚磺酰基]亚氨基乙酸乙酯)(507mg,2.47mmol)的THF(15mL)溶液中加入Sat.NaBr.H2O(679.68mg,2.59mmol,30mL),随后加入Indium(铟1.13g,9.87mmol),反应混合液在氮气保护下室温搅拌过夜。混合液过滤,滤液加水稀释,乙酸乙酯萃取,合并的有机相用食盐水洗涤,无水硫酸钠干燥,过滤,然后浓缩得到中间Za-1-d(770mg,2.44mmol)粗品,未经纯化直接用于下一步反应。MSm/z:316.0(M+1)+。
步骤5,中间体Za-1-e的制备
冰浴下,向Za-1-d(150mg,475.48umol)的甲醇溶液(1.6mL)中滴加HCl/EA(4M,0.5mL),反应液室温下搅拌1小时,后浓缩,粗品溶解在THF(2mL)和水(2mL)的混合液,在冰浴下,NaHCO3(79.88mg,950.96umol)和CbzOSU(118.50mg,475.48umol)依次加入反应液中,反应液室温下搅拌30分钟,混合液用水稀释,乙酸乙酯萃取,无水硫酸钠干燥,过滤浓缩后得粗品,用硅胶柱分离纯化得到中间体Za-1-e(20mg,57.90umol,12.18%收率)。MS m/z:346.0(M+1)+。
步骤6,中间体Za-1-f的制备
室温氮气保护下,向Za-1-e(500mg,1.45mmol)的干燥二氯甲烷(10mL)加入CH2ICl(1.1mL),冷却至零下20度到零下25度,缓慢滴加ZnEt2(8.7mL),滴加完毕后,反应液室温搅拌过夜。
反应液用饱和氯化铵淬灭,乙酸乙酯萃取,合并的有机相浓缩得到粗品,粗品中还有约10%的Za-1-e未反应完,将粗品溶于MeOH/THF/H2O(1/1/1,共150mL)溶液中,加入K2OsO4(70mg,0.19mmol),混合液室温搅拌过夜,反应完成后,反应液浓缩,加水稀释,乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,浓缩后得粗品,用硅胶柱分离纯化得到中间体Za-1-f(313mg,收率59%)。MS m/z:360.0(M+1)+。
步骤7,中间体Za-1的制备
向Za-1-f(420mg,1.17mmol)的THF(2mL)/MeOH(2mL)/H2O(2mL)的混合溶液中加入LiOH.H2O(147.22mg,3.51mmol),反应液室温搅拌过夜,反应完成后,反应液减压浓缩,粗品用水稀释,用6N稀盐酸调pH到至4~6,用二氯甲烷萃取,合并的有机相用无水硫酸钠干燥,过滤、浓缩后得到中间体Za-1(340mg,1.03mmol,87.80%收率),MS m/z:332.0(M+1)+。
中间体Zb-1的合成
步骤1中间体Zb-1-a的制备
室温下,向对硝基苯乙酸(300g,1.66mol)的乙醇(1L)溶液中加入催化量的浓H2SO4(1.66mol,2mL),升温至80℃并搅拌16小时,原料消失后,减压浓缩至干,溶于2L的乙酸乙酯,碳酸氢钠水溶液洗涤,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩即可得到中间体Zb-1-a(330g,1.58mol,95.25%产率),MS m/z:210[M+1]+。
步骤2中间体Zb-1-b的制备
氮气保护下,将中间体Zb-1-a对硝基苯乙酸乙酯(29.4g,140.54mmol)溶于干燥的1.2L的N,N-二甲基乙酰胺中,干冰-乙醇浴冷却至內温-40℃,加入碳酸铯(114.54g,351.34mmol),-40℃搅拌15min,2-氯乙基氯甲基醚(19.94g,154.59mmol)缓慢滴加至反应液中,滴毕,允许反应恢复至室温,并搅拌过夜,待原料消失后,加入3L的冰水淬灭反应,乙酸乙酯(2L*2)萃取,有机相经饱和食盐水(2L*2)洗,无水硫酸钠干燥,过滤,减压浓缩至干,粗品经硅胶柱层析分离得到中间体Zb-1-b(6.5g,24.50mmol,17.44%产率),MS m/z:266[M+1]+.步骤3中间体Zb-1-c的制备
将中间体Zb-1-b(15g,56.55mmol)溶于EtOH(100mL)中,氮气置换后,加入10%Pd/C(3g),常压氢气氛下搅拌反应过夜,原料消失后,经硅藻土抽滤,乙醇洗涤,滤液减压浓缩至干,得到中间体Zb-1-c(12.7g,53.98mmol,95.46%产率),MS m/z:236[M+1]+,产物未经纯化直接用于下一步反应。
步骤4中间体Zb-1-d的制备
将中间体Zb-1-c(16g,68.00mmol)溶于醋酐(136mL)中,冷却至0℃,并搅拌15min,缓慢滴加HNO3(9.45g,102.01mmol,68%质量分数),滴毕,反应继续搅拌30min,原料消失,将反应液倾入冰水中,乙酸乙酯(2*300mL)萃取,有机相经饱和碳酸钠洗涤,无水硫酸钠干燥,过滤,减压浓缩至干得到中间体Zb-1-d粗品(21g,65.15mmol,95.81%产率),MS m/z:323[M+1]+,产物未经纯化直接用于下一步反应。
步骤5中间体Zb-1-e的制备
将中间体Zb-1-d(21g,65.15mmol)溶于150ml乙醇中,加入SOCl2(23.25g,195.46mmol,14.18mL),加热至50℃搅拌1小时,LC-MS显示原料消失,反应液减压浓缩至干,加入CH2Cl2(150mL)和H2O(150mL),用饱和NaHCO3调pH值~8,水相再经CH2Cl2(2*150mL)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干,得到中间体Zb-1-e粗品(18g,64.22mmol,98.57%产率),MS m/z:281[M+1]+,产物未经纯化直接用于下一步反应。
步骤6中间体Zb-1的制备
将中间体Zb-1-e(19g,67.79mmol)溶于甲醇中,氮气氛下加入Pd/C(5.7g),随后氢气置换并常压氢化反应过夜,原料消失后,经硅藻土抽滤,滤液减压浓缩至干,MPLC C18反相柱纯化得到消旋体Zb-1-f,经SFC手性柱拆分分离,得单一构型Zb-1(7.5g,44%产率),MSm/z:251[M+1]+.
中间体Zb-2的制备
步骤1,Zb-2-a的合成
零度下,向2-(4-溴苯基)乙酸酯的(20g,0.83mmol)的乙腈(220mL)溶液加入DBU(15g,98.73mmol)和p-ABSA(4-乙酰氨基苯磺酰叠氮19.76g,82.27mmol),反应液升温至25℃并搅拌48h。反应完成后,加入饱和aq.NH4Cl淬灭反应,然后用乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,过滤浓缩后,用正相硅胶柱分离纯化得Zb-2-a(8g,29.63mmol,收率36%)。
步骤2,Zb-2-b的合成
向Zb-2-a(1g,3.72mmol)甲苯(16mL)中加入Rh2(esp)2(14mg,0.018mmol),N-Cbz3-氯丙胺(846mg,3.72mmol),混合液氮气置换后在氮气保护下升温至60℃并搅拌5小时。冷却至室温后,加入四丁基溴化铵(1.2g,3.72mmol)和CsOH.H2O(1.25g,7.43mmol),混合液室温搅拌过夜,反应液过滤,用乙酸乙酯洗涤,浓缩滤液,粗品用正相硅胶柱分离纯化得到Zb-2-b(1.29g,2.97mmol)。MS m/z:432[M+1]+.
步骤3,Zb-2-c的合成
向Zb-2-b(4.8g,11.14mmol)的dioxane(二氧己环70mL)中加入AcNH2(986mmol,55.68mmol),Pd2(dba)3(510mg,0.55mmol),Xantphos(645mg,1.12mmol)和Cs2CO3(10.9g,33.43mmol),反应混合液氮气置换几次,在氮气的保护下80℃搅拌过夜。反应完成后,浓缩反应液,加水和乙酸乙酯萃取,合并的有机相用无水硫酸钠干燥,浓缩后的粗品用正相硅胶柱分离纯化得Zb-2-c(2.7g,6.5mmol,59%收率)。MS m/z:411[M+1]+.
步骤4,Zb-2-d的合成
零度下,向Zb-2-c(3.8g,9.3mmol)的Ac2O(40mL)中加入65%硝酸(1.5mL,18.6mmol),混合液逐渐升至室温,并搅拌过夜,反应完成后,浓缩反应液,粗品加水稀释,乙酸乙酯萃取,合并的有机相旋干后,用正相硅胶柱分离纯化得Zb-2-d(3.2g,7.0mmol,收率75%),MS m/z:456[M+1]+.
步骤5,Zb-2-e的合成
零度下,向Zb-2-e(3.2g,7.0mmol)的乙醇(35mL)溶液中加入SOCl2(1mL),滴加完毕后,缓慢升温至70℃,并在此温度搅拌5小时。反应完成后,旋干溶液,粗品用正相硅胶柱分离纯化得Zb-2-e(1.36g,3.29mmol,收率47%),MS m/z:414[M+1]+.
步骤6,Zb-2的合成
零度下,向Zb-2-e(1.36g,3.29mmol)的甲醇(15mL)溶液中加入氨水(1.5mL),加入保险粉(2.6g,15mmol)的水溶液,反应完成后,滤除混合液中固体,浓缩滤液加水和乙酸乙酯萃取,合并的有机相用水和饱和食盐水洗涤,浓缩,粗品用硅胶柱分离纯化得Zb-2(819mg,2.1mmol,65%收率),MS m/z:384[M+1]+。未经纯化直接用于下一步反应。
中间体Zb-3的制备
步骤1,中间体Zb-3-a的制备
在反应瓶中加入4-溴-3氟-2硝基苯胺(10g,42.55mmol)的二氧六环(200mL)和水(20mL)溶液中,依次加入3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(8.94g,42.55mmol)、Pd(dppf)Cl2(1.55g,2.12mmol)和K2CO3(17.60g,127.54mmol),混合均匀后,抽真空氮气保护,升温到100℃反应3小时,反应完后降温到室温,过滤,滤液加入乙酸乙酯和盐水分层,浓缩干得到粗品Zb-3-a(9.69g,40.68mmol,95.60%收率),MS m/z:239.0(M+1)+
步骤2,中间体Zb-3-b的制备
向Zb-3-a(700mg,2.94mmol)的醋酸(7mL)溶液中加入Ac2O(484mg,4.74mmol),混合液加热到90℃反应2小时,反应完后滴加到35ml水中,过滤浓缩干后得Zb-3-b(618mg,2.21mmol,75.04%收率)。MS m/z:281.0(M+1)+
步骤3,中间体Zb-3-c的制备
向Zb-3-b(200mg,713.65umol)的二氯甲烷溶液中加入m-CPBA(246.31mg,1.43mmol),混合液室温搅拌过夜,原料1/3剩余,反应液升温至40℃继续反应4h后,加碳酸钠水溶液和乙酸乙酯萃取,有机层用亚硫酸钠水溶液洗涤,分离的有机层经浓缩后得到中间体Zb-3-c(205mg,691.98umol,96.96%收率),MS m/z:297.0(M+1)+
步骤4,中间体Zb-3-d的制备
冰浴下,向Zb-3-c(1.9g,6.41mmol)的二氯甲烷(50mL)溶液中加入BF3.OEt(2.74g,19.28mmol),逐步升至室温并搅拌2小时,反应完后用碳酸钠淬灭,乙酸乙酯萃取,旋干有机相后得粗品,用正向硅胶柱分离纯化,(洗脱剂,二氯甲烷/乙酸乙酯=10:1~5:1)得到Zb-3-d(1.37g,4.62mmol,72.11%收率)产品。MS m/z:297.0(M+1)+
步骤5,中间体Zb-3-e的制备
在反应瓶中加入NaClO2(1.31g,12.95mmol)和NaH2PO4(1.59g,10.17mmol),混匀后降温到0℃,滴加Zb-3-d(1.37g,4.62mmol)的叔丁醇(12mL)和水(9mL)的混合溶液,保温搅拌1小时,反应完后调酸到pH=5-6,乙酸乙酯萃取后浓缩有机相得到Zb-3-e(1.38g,4.42mmol,95.57%收率)。MS m/z:297.0(M+1)+
步骤6,中间体Zb-3-f的制备
向Zb-3-e(600mg,1.92mmol)的EtOH(12mL)溶液中滴加SOCl2(685.82mg,5.76mmol,418.18uL),滴加完毕后升温到60℃反应12小时。冷却至室温,反应液倒入碳酸氢钠溶液中,然后用乙酸乙酯萃取,浓缩得到粗品Zb-3-f(434mg,1.46mmol,75.72%收率),MSm/z:299.0(M+1)+
步骤7,中间体Zb-3的制备
向Zb-3-f(434mg,1.61mmol)的乙醇(8mL)溶液中加入钯碳,氢气球置换后在室温下搅拌12小时,反应完后过滤掉钯碳,滤液浓缩,用正向硅胶柱(二氯甲烷/甲醇=50/1,v/v)纯化得到Zb-3(187mg,697.02umol,43.40%收率),MS m/z:269.0(M+1)+,中间体Zc-1的制备
步骤1,中间体Zc-1-a的制备
冰浴下,向Fmoc-D-(1-甲基环丁基)甘氨酸(10g,27.37mmol)的二氯甲烷(137mL)溶液中加入HBTU(8.34g,32.84mmol)和三乙胺(8.31g,82.10mmol),然后加入甲胺盐酸盐(3.67g,54.73mmol)。反应液逐渐升至室温搅拌1小时,加水稀释,以二氯甲烷萃取,合并的有机相用无水硫酸钠干燥,旋干得到的粗品,用硅胶柱分离纯化,得到中间体Zc-1-a(9.3g,24.7mmol,90%的收率),MS m/z:379.0(M+1)+。
步骤2,中间体Zc-1-b的制备
冰浴下,于50mL三口瓶中加入Zc-1-a(500mg,1.32mmol),氮气保护下,依次加入THF(6mL)和BH3THF(2.76mL),氮气保护下加热至65℃,然后搅拌反应5小时。反应体系冷却至室温,加入甲醇(1mL),Boc2O(451mg,2.1mmol)和水(1mL),继续室温搅拌1小时。体系旋干后,加水稀释,用乙酸乙酯萃取,有机相用水、饱和食盐水洗涤,无水硫酸钠干燥,旋干后粗品用正相硅胶柱纯化得到中间体Zc-1-b(167mg,0.36mmol,26%收率),MS m/z:465.0(M+1)+。
步骤3,中间体Zc-1的制备
向Zc-1-b(167mg,0.36mmol)的THF(6mL),H2O(2mL)和MeOH(1mL)的混合溶液中加入LiOHH2O(20mg,0.5mmol),室温下搅拌过夜,反应完后,直接旋干反应液,粗品用石油醚洗涤,得到中间体Zc-1(75mg,0.31mmol,85%收率)。MS m/z:243.0(M+1)+。
中间体Zc-2的制备
参照中间体Zc-1的制备方法,用Fmoc-D-环丁基甘氨酸(10g,27.37mmol)替换Fmoc-D-(1-甲基环丁基)甘氨酸,用氯化铵替换甲胺盐酸盐,其余步骤不变。得Zc-2。MS m/z:215.0(M+1)+。
中间体Zc-3的制备
步骤1Zc-3-a的制备
零度下,向环丁基甲酸(20g,199.77mmol)的THF(200mL)溶液中逐滴加入LDA(53.50g,499.42mmol,188mL),混合液0℃下搅拌30分钟,然后零度下加入逐滴碘甲烷(31.19g,219.75mmol),滴加完毕后,反应液室温搅拌过夜。反应用水淬灭,用6N HCl调节pH至4.0,乙酸乙酯萃取,合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后浓缩得Zc-3-a(21g,183.98mmol,92.10%收率),MS m/z:115(M+1)+。
步骤2Zc-3-b的制备
向Zc-3-a(21g,183.98mmol)的DMF(300mL)溶液中加入Weinreb酰胺(16.83g,276mmol),TEA(2.8mL,20mmol),室温搅拌10分钟后,加入HOBt(1.62g,12mmol),然后加入EDCI(2.3g,12mmol)。反应混合液室温搅拌过夜。浓缩反应液,残余物溶于1N HCl水溶液中,加乙酸乙酯萃取,合并的有机相用饱和NaHCO3(50mL)洗涤,食盐水洗涤,无水MgSO4干燥,浓缩后得Zc-3-b(26.3g,167.4mmol,收率91%)。MS m/z:158(M+1)+。
步骤3Zc-3-c的制备
-10℃下,向Zc-3-b(15g,95.5mmol)的THF(1000mL)溶液中加入分批次加入LiAlH4(4.58g,114.6mmol)。40-50min后,KHSO4(28g)的H2O(1000mL)溶液缓慢加入,然后加入1NHCl(500mL).混合液搅拌1小时后,混合液用乙酸乙酯萃取,合并的有机相依次用饱和NaHCO3、食盐水洗涤,无水MgSO4干燥,浓缩得到Zc-3-c(9.26g,94.5mmol)。
步骤4Zc-3-d的制备
向Zc-3-c(3g,30.6mmol)的DCM(200mL)溶液中,加入叔丁基亚磺酰胺(3.7g,30.6mmol),PPTs(75mg,0.3mmol)和MgSO4(5g)。混合液室温搅拌过夜,反应完成后,过滤,旋干滤液,粗品用正相硅胶柱分离纯化得Zc-3-d(2.0g,10.0mmol,33%收率)。MS m/z:202(M+1)+。
步骤5Zc-3-e的制备
-10℃下,向Zc-3-d(1.0g,5.0mmol)的THF(20mL)溶液中加入甲基格式试剂(7.5mL,7.5mmol,1M的己烷溶液)。混合液缓慢升至室温搅拌1小时。反应完成后,加水淬灭,乙酸乙酯萃取,合并的有机相用水、饱和食盐水洗涤,浓缩后用正相硅胶柱分离纯化得Zc-3-e(781mg,3.6mmol)。MS m/z:218(M+1)+。
步骤6Zc-3的制备
向Zc-3-e(781mg,3.6mmol)的乙酸乙酯(15mL)溶液中加入HCl/EA(4N,1.5mL),室温下搅拌40分钟,反应完成后,旋干溶剂,得Zc-3(406mg,3.6mmol)。MS m/z:114(M+1)+。未经纯化直接用于下一步。
实施例1化合物1的制备
步骤1,1-1的制备
将中间体Zb-1(461.20mg,1.84mmol),EDCI(424.54mg,2.21mmol),DIPEA(1.19g,9.21mmol,1.60mL),HOAt(300.72mg,2.21mmol)及N-Boc环己基-L-丙氨酸盐酸盐(500mg,1.84mmol)依次加入到DCM(10mL)中,室温反应3小时,加水淬灭,减压除去大部分有机溶剂,乙酸乙酯(20ml*3)萃取,合并有机相,再分别饱和氯化铵和饱和食盐水洗,无水硫酸钠干燥,减压旋干,粗品经硅胶柱层析纯化分离(石油醚/乙酸乙酯5:1)即可得到中间体1-1(588mg,1.17mmol,63.36%收率),MS m/z:504(M+1)+。
步骤2,1-2的制备
将1-1(588mg,1.17mmol)溶于AcOH(12mL)中,混合液升温至60℃并搅拌反应过夜。反应完成后,旋干AcOH,用饱和NaHCO3溶液调节pH至弱碱性,DCM(25*2)萃取,有机相用无水Na2SO4干燥,旋干后得1-2(547mg,1.13mmol,96.48%收率),粗品MS m/z:486(M+1)+
步骤3,1-3的制备
向1-2(270mg,556.00umol)的DCM(1.5mL)中加入TFA(1mL),0℃搅拌反应2hr,反应液旋干得1-3(198mg,513.62umol,92.38%产率)。未经纯化直接用于下一步。MS(ESI)m/z=386(M+1)+
步骤4,1-4的制备
向25mL茄型瓶中依次加入1-3(198mg,513.62umol),2-甲基吡唑-3-羧酸(71.25mg,564.98umol),HBTU(169.51mg,667.71umol)、DIPEA(331.90mg,2.57mmol,447.31uL)和DCM(3mL),反应液室温搅拌2小时。反应完成后,旋干反应液,粗品用反相柱分离纯化得1-4(250mg,450.77umol,87.76%收率,89%纯度)。MS(ESI)m/z=494(M+1)+.
步骤5,1-5的制备
向1-4(250mg,450.77umol)的EtOH(2mL)/H2O(0.4mL)混合液中加入NaOH(101.30mg,2.53mmol),反应液升温至85℃搅拌过夜。反应完成后,用6N HCl溶液将体系pH调节至5,用DCM(20*2)萃取体系,有机相用无水Na2SO4干燥后,浓缩得1-5(197mg,380.85umol,75.19%收率,90%纯度)粗品。
步骤6,1的制备
向1-4(40.00mg,85.92umol)的DMF(1mL)溶液中依次加入HBTU(26.18mg,103.11umol),(1-甲基环丁基)甲胺(12.82mg,94.51umol)和DIPEA(33.31mg,257.76umol,44.90uL),反应液室温搅拌过夜,反应完成后,加水淬灭,旋干溶剂,粗品用Prep-HPLC纯化得到实施例1(26mg,0.047mmol,55%收率)。MS(ESI)m/z=547(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.73–7.66(m,2H),7.54–7.48(m,2H),6.97(d,J=2.2Hz,1H),5.56(dd,J=10.0,5.7Hz,1H),4.58(d,J=8.7Hz,1H),4.09(s,3H),4.06(d,J=8.8Hz,1H),4.00–3.95(m,2H),3.13(t,J=6.4Hz,2H),2.96(dt,J=12.7,6.3Hz,1H),2.40(dt,J=12.7,7.9Hz,1H),2.15–2.08(m,1H),2.07–2.00(m,1H),1.91–1.74(m,7H),1.71–1.59(m,2H),1.50(tdt,J=7.9,5.7,3.2Hz,2H),1.40–1.30(m,2H),1.23(dd,J=11.5,8.5Hz,2H),1.14–1.00(m,2H),0.96(s,3H).
实施例2化合物2的制备
向1-5(26mg,55.85umol)的DCM(3mL)溶液中依次加入DIPEA(28.87mg,223.39umol,38.91uL),HBTU(17.01mg,67.02umol)和2,2,2-三氟乙胺(27.66mg,279.24umol),反应液室温搅拌1小时,浓缩反应液,粗品用反相硅胶柱纯化得实施例2(15.35mg,28.08umol,50.29%收率),MS(ESI)m/z=547(M+1)+;1HNMR(400M,MeOD),δ=7.74-7.76(d,j=8.0,1H),7.726-7.729(d,J=1.2,1H),7.53-7.55(m,1H),7.512-7.517(d,J=2.0,1H),6.990-6.995(d,J=2.0,1H),5.56-5.60(m,1H),4.51-4.53(d,J=8.84,1H),4.08(s,3H),4.05-4.07(d,J=8,1H),3.95-3.99(m,2H),3.78-3.92(m,1H),2.89-2.95(m,1H),2.37-2.44(m,1H),2.17-2.21(m,1H),2.12-2.20(m,1H),1.98-2.05(m,1H),1.68-1.89(m,5H),1.44-1.48(m,1H),1.00-1.33(m,5H).
实施例3化合物3的制备
参照实施例1中步骤1到步骤6的合成方法,以(S)-2-(叔丁氧羰基)氨基)-3,3-二环丙基丙酸(参考专利WO2020127685A1制备)替换步骤1中的N-Boc环己基-L-丙氨酸,用中间体Zc-3替代步骤6中的(1-甲基环丁基)甲胺,其余条件不变得到实施例3。MS(ESI)m/z=559(M+1)+。
实施例4到实施例8化合物的制备
参照实施例1中步骤6的方法,以实施例3的中间体3-5替代中间体1-5,用下表中的胺替代(1-甲基环丁基)甲胺,其余方法相同,即可得到下表中对应的实施例4~8。
实施例9化合物9的制备
参照实施例1中步骤1到步骤6的方法,用中间体Zb-2替代步骤1中的中间体Zb-1,在步骤6中用Zc-3替代(1-甲基环丁基)甲胺,其余方法条件不变,得中间体9-6。最后用Pd/C催化加氢的方法脱掉保护基Cbz得实施例9,MS(ESI)m/z=680(M+1)+。
实施例10到实施例14化合物的制备
参照实施例9中步骤1到步骤7的合成方法,用下表中列出的相应Boc保护的氨基酸替代步骤1中N-Boc环己基-L-丙氨酸,用表中相应伯胺替代步骤6中的Zc-3,其余方法不变,得到下列表中相应实施例10~14化合物。
实施例15化合物15的制备
参照实施例1中步骤1到步骤6的合成方法,用中间体Za-1替代步骤1中的N-Boc环己基-L-丙氨酸,用三氟乙胺替代步骤6中的(1-甲基环丁基)甲胺,其余方法不变,可得实施例15。MS(ESI)m/z=573(M+1)+。
实施例16化合物16的制备
参照实施例1步骤6的方法,用中间体15-5代替中间体1-5,其余方法不变,得实施例16。MS(ESI)m/z=573(M+1)+。
实施例17化合物17的制备
参照实施例1中步骤1到步骤6的制备方法,在步骤1中,用Zb-3替代步骤1中的Zb-1;Za-1替代的N-Boc环己基-L-丙氨酸,;用三氟乙胺基替代步骤6中的(1-甲基环丁基)甲胺,其余方法相同,可得实施例17。MS(ESI)m/z=591(M+1)+。
实施例18化合物18的制备
参照实施例1中步骤1到步骤6的合成方法,在步骤1中,用2-(3,4-二氨基苯基)-2-甲基丙酸乙酯(参考专利CN110511213A制备)替代Zb-1,同时用(S)-2-(叔丁氧羰基)氨基)-3,3-二环丙基丙酸代替N-Boc环己基-L-丙氨酸。在步骤6中,用中间体Zc-1替代(1-甲基环丁基)甲胺,其余方法相同,得18-6。最后用TFA/DCM体系脱掉Boc,即得实施例18。MS(ESI)m/z=560(M+1)+。
实施例19化合物19的制备
参照实施例1中步骤6的方法,用中间体19-1替代中间体1-5,同时用中间体Zc-2替代(1-甲基环丁基)甲胺,其余方法相同,缩合得19-2。最后用TFA/DCM体系脱掉Boc,即得实施例19。MS(ESI)m/z=532(M+1)+。
实施例20到实施例24化合物20-24的制备
参照实施例1中的方法,由中间体1-5与下表中的胺替代(1-甲基环丁基)甲胺,其余方法相同,即可得到下表中对应的实施例20~22,其中实施例化合物23-24则需再经三氟乙酸/二氯甲烷体积比1:1在冰浴下搅拌30分钟至1小时脱去叔丁氧羰基保护基后(参考实施例18最后一步方法),经MPLC纯化即可得到。
实施例20核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.69(s,2H),7.49(d,J=2.0Hz,1H),7.45(d,J=9.3Hz,1H),6.87(d,J=7.4Hz,1H),5.62–5.47(m,1H),4.52(d,J=8.9Hz,1H),4.07(d,J=1.1Hz,3H),4.02–3.93(m,2H),3.93–3.76(m,2H),2.92(dt,J=13.0,6.6Hz,2H),2.83–2.68(m,2H),2.48–2.34(m,1H),2.21–2.05(m,2H),2.04–1.82(m,4H),1.73(d,J=7.5Hz,1H),1.69–1.57(m,1H),1.02(d,J=1.7Hz,3H),0.55–0.44(m,1H),0.32–0.23(m,1H),-0.33(s,2H).
实施例21核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.58(d,J=1.7Hz,1H),7.52(d,J=8.5Hz,1H),7.47(d,J=2.1Hz,1H),7.29–7.23(m,1H),6.91(d,J=2.1Hz,1H),5.50–5.40(m,1H),4.67(d,J=8.6Hz,1H),4.16(dd,J=9.6,3.4Hz,1H),4.09(s,3H),4.01(d,J=8.7Hz,1H),3.99–3.93(m,2H),3.52–3.36(m,5H),3.04–2.96(m,1H),2.47–2.38(m,4H),2.35(d,J=4.6Hz,1H),2.27(d,J=7.9Hz,2H),2.09–1.91(m,3H),1.91–1.79(m,5H),1.77–1.61(m,5H),1.45–1.16(m,7H),1.16–0.99(m,3H),0.96(s,3H).
实施例22核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.81(d,J=1.6Hz,1H),7.76(d,J=8.7Hz,1H),7.63(dd,J=8.7,1.7Hz,1H),7.53(d,J=2.1Hz,1H),7.17(d,J=9.3Hz,1H),7.01(d,J=2.2Hz,1H),5.61(dd,J=10.2,5.5Hz,1H),4.63(d,J=8.8Hz,1H),4.10(s,3H),4.02(dd,J=7.8,4.8Hz,3H),3.58(dd,J=11.4,3.8Hz,1H),3.42(dd,J=11.4,8.5Hz,1H),2.95(dt,J=12.8,6.4Hz,1H),2.51(dt,J=12.8,7.8Hz,1H),2.25–2.12(m,1H),2.10–1.66(m,10H),1.65–1.21(m,7H),1.20–1.05(m,2H),1.00(s,3H).
实施例23核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.76(d,J=1.6Hz,1H),7.71(d,J=8.6Hz,1H),7.55–7.49(m,2H),6.98(d,J=2.2Hz,1H),5.60–5.50(m,1H),4.74(d,J=8.8Hz,1H),4.31–4.23(m,1H),4.08(s,3H),4.07–3.96(m,2H),3.93(d,J=8.8Hz,1H),3.00(d,J=6.7Hz,2H),2.96–2.84(m,1H),2.66(s,3H),2.65–2.58(m,1H),2.20–2.07(m,1H),2.07–1.98(m,1H),1.92–1.72(m,8H),1.72–1.63(m,2H),1.63–1.53(m,1H),1.34–1.18(m,5H),1.18–1.00(m,2H),0.93(s,3H).
参照实施例18中的方法,由中间体18-5与下表中的胺替代Zc-1,其余方法相同,即可得到下表中对应的实施例化合物25~26。
实施例25核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.76(d,J=1.6Hz,1H),7.72(dd,J=8.7,1.7Hz,1H),7.60(dd,J=8.8,1.7Hz,1H),7.53(d,J=2.1Hz,1H),7.05(d,J=2.1Hz,1H),6.97(d,J=8.6Hz,1H),5.55(dd,J=7.5,3.6Hz,1H),4.06(s,3H),3.90–3.77(m,1H),3.49–3.41(m,2H),1.64(d,J=3.2Hz,6H),1.62–1.52(m,1H),1.44–1.26(m,2H),1.17–1.06(m,1H),1.03–0.94(m,1H),0.93–0.86(m,1H),0.83(t,J=7.4Hz,3H),0.65–0.50(m,2H),0.50–0.39(m,1H),0.39–0.24(m,3H),0.14–0.05(m,1H).
实施例26核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.80(d,J=1.6Hz,1H),7.73(dd,J=8.7,2.2Hz,1H),7.60(dd,J=8.7,1.8Hz,1H),7.52(d,J=2.2Hz,1H),7.05(d,J=2.2Hz,1H),5.58(d,J=6.9Hz,1H),4.10(dd,J=9.9,3.0Hz,1H),4.06(s,3H),2.99(dd,J=13.0,3.1Hz,1H),2.88(ddd,J=12.9,9.9,2.2Hz,1H),2.69(s,3H),2.42–2.28(m,1H),2.06–1.94(m,1H),1.84–1.68(m,7H),1.62(s,3H),1.59–1.52(m,1H),1.10(td,J=9.2,6.9Hz,1H),1.04–0.94(m,1H),0.94–0.80(m,1H),0.62–0.51(m,2H),0.47–0.39(m,1H),0.38–0.20(m,3H),0.18–0.07(m,1H),-0.03–-0.14(m,1H).
类似地,参照实施例18中的方法,以中间体2-(3,4-二氨基苯基)-2-甲基丙酸乙酯(参考专利CN110511213A制备)和Za-1为起始原料,经由相同的路线方法,即可得到实施例27~28。
实施例27化合物27
实施例27化合物表征数据:MS(ESI)m/z=574(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.80(d,J=1.6Hz,1H),7.72(d,J=8.7Hz,1H),7.57(dd,J=8.8,1.7Hz,1H),7.48(d,J=2.2Hz,1H),6.93(d,J=2.2Hz,1H),5.61(d,J=9.7Hz,1H),4.07(s,4H),2.98(dd,J=13.1,3.0Hz,1H),2.86(dd,J=13.1,10.0Hz,1H),2.75(q,J=9.0,8.5Hz,1H),2.69(s,3H),2.39–2.25(m,1H),2.17–2.05(m,2H),2.05–1.92(m,3H),1.92–1.82(m,1H),1.83–1.64(m,9H),1.62(s,3H),1.60–1.47(m,1H),1.03(s,3H),0.49(dt,J=10.0,5.1Hz,1H),0.27(dt,J=9.8,5.1Hz,1H),-0.31(dt,J=9.6,5.1Hz,1H),-0.37(dt,J=10.0,5.1Hz,1H).
实施例28化合物28
实施例28化合物表征数据:MS(ESI)m/z=535(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.79(d,J=1.7Hz,1H),7.73(d,J=8.8Hz,1H),7.59(dd,J=8.7,1.7Hz,1H),7.50(d,J=2.2Hz,1H),6.92(d,J=2.2Hz,1H),5.60(d,J=9.4Hz,1H),4.08(s,3H),3.87–3.79(m,1H),3.49–3.42(m,2H),2.85–2.70(m,1H),2.20–2.05(m,2H),2.02–1.84(m,3H),1.81–1.68(m,2H),1.65(d,J=3.6Hz,6H),1.61–1.51(m,1H),1.41–1.27(m,1H),1.03(s,3H),0.83(t,J=7.4Hz,3H),0.58–0.48(m,1H),0.37–0.25(m,1H),-0.19–-0.37(m,2H).
实施例29到实施例37化合物29~37的制备
参照实施例9中的合成方法,以相应的氨基酸和芳二胺为起始原料,分别替代实施例9起始原料N-Boc环己基-L-丙氨酸和Zb-2,经由相同的路线方法,即可得到实施例29~37化合物,如下列表中所示。
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实施例29核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.79–7.69(m,2H),7.61–7.54(m,1H),7.53(d,J=2.2Hz,1H),7.04(d,J=2.2Hz,1H),5.59–5.47(m,1H),4.06(s,3H),3.89(d,J=12.1Hz,1H),3.83–3.70(m,2H),3.70–3.52(m,2H),3.41–3.35(m,2H),3.04–2.84(m,1H),2.53–2.41(m,1H),2.14(s,1H),2.05(s,2H),1.64–1.45(m,1H),1.43–1.23(m,2H),1.14–1.02(m,1H),1.02–0.82(m,3H),0.80–0.67(m,3H),0.62–0.50(m,2H),0.50–0.38(m,1H),0.38–0.23(m,3H),0.13–0.05(m,1H).
实施例30核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.75–7.70(m,1H),7.69(d,J=2.8Hz,1H),7.55–7.49(m,1H),7.37–7.31(m,1H),5.65–5.57(m,1H),4.53(d,J=10.6Hz,1H),4.35(d,J=12.2Hz,1H),3.89(d,J=12.1Hz,1H),3.82–3.71(m,1H),3.69–3.53(m,2H),3.41–3.35(m,2H),3.09–2.93(m,1H),2.93–2.84(m,1H),2.52(s,3H),2.50–2.39(m,1H),2.14(s,1H),2.04(s,2H),1.37–1.25(m,3H),1.13–1.02(m,1H),0.97–0.82(m,3H),0.76(t,J=7.4Hz,1H),0.73–0.67(m,1H),0.56(d,J=7.8Hz,2H),0.48–0.39(m,1H),0.39–0.26(m,3H),0.16–0.07(m,2H).
实施例31核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.56(s,2H),7.37–7.22(m,1H),5.59(dd,J=6.4,1.4Hz,1H),4.63(dd,J=47.1,10.0Hz,1H),4.36(dd,J=83.4,12.1Hz,1H),4.02–3.80(m,1H),3.77–3.64(m,2H),3.61–3.33(m,3H),3.00–2.67(m,2H),2.53(s,3H),2.51–2.34(m,1H),1.64–1.46(m,1H),1.34–1.24(m,5H),1.17(dd,J=6.7,2.2Hz,2H),1.11–1.05(m,4H),1.02–0.93(m,1H),0.90–0.79(m,3H),0.74(t,J=7.4Hz,1H),0.65(t,J=7.4Hz,1H),0.61–0.43(m,3H),0.42–0.18(m,4H),0.15–0.05(m,1H),-0.06(q,J=6.5,5.8Hz,1H).
实施例32核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.76–7.68(m,2H),7.67–7.58(m,1H),7.56–7.50(m,1H),5.62(d,J=6.4Hz,1H),4.56(dd,J=10.6,4.4Hz,1H),4.40(dd,J=20.0,12.0Hz,1H),3.85–3.68(m,1H),3.66–3.56(m,2H),3.24(q,J=7.7Hz,1H),2.99–2.84(m,1H),2.52(s,3H),2.50–2.43(m,1H),2.15–2.03(m,3H),1.15–1.04(m,4H),0.97–0.82(m,3H),0.82–0.73(m,1H),0.62–0.53(m,2H),0.48–0.39(m,2H),0.38–0.29(m,3H),0.16–0.05(m,3H).
实施例33核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.78–7.68(m,2H),7.51(dd,J=8.3,2.3Hz,1H),5.62(d,J=6.6Hz,1H),4.58(dd,J=10.7,4.8Hz,1H),4.42(dd,J=12.2,5.0Hz,1H),3.91–3.68(m,3H),3.66–3.58(m,1H),2.99–2.79(m,1H),2.58–2.47(m,4H),2.15–2.01(m,3H),1.14–1.04(m,1H),0.97–0.83(m,2H),0.64–0.52(m,2H),0.48–0.40(m,1H),0.39–0.27(m,3H),0.17–0.06(m,1H).
实施例34核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.81–7.72(m,2H),7.65–7.54(m,1H),5.64(dd,J=6.4,2.7Hz,1H),4.66–4.32(m,1H),3.89–3.79(m,1H),3.75–3.54(m,2H),3.51–3.34(m,1H),3.03–2.83(m,1H),2.51(s,3H),2.50–2.38(m,1H),2.30–2.15(m,1H),2.09(dd,J=37.7,1.6Hz,3H),2.00–1.83(m,1H),1.81–1.36(m,6H),1.17–1.06(m,1H),1.02–0.82(m,5H),0.64–0.53(m,2H),0.48–0.40(m,1H),0.40–0.25(m,3H),0.15–0.06(m,1H),-0.01–-0.09(m,1H).
实施例35核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.81–7.70(m,2H),7.59(ddd,J=8.7,3.6,1.9Hz,1H),5.63(dd,J=6.5,1.7Hz,1H),4.66–4.35(m,1H),3.87–3.67(m,2H),3.63–3.58(m,1H),3.51–3.38(m,1H),3.03–2.84(m,1H),2.52(s,3H),2.50–2.42(m,1H),2.09(dd,J=36.4,1.3Hz,3H),1.49–1.23(m,3H),1.16–1.06(m,1H),1.06–0.85(m,5H),0.81–0.52(m,5H),0.51–0.41(m,1H),0.41–0.26(m,3H).
实施例36核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ7.79–7.63(m,2H),7.57–7.46(m,1H),5.61(dd,J=6.6,1.2Hz,1H),4.67(dd,J=10.6,3.6Hz,1H),4.46–4.35(m,1H),3.88–3.76(m,3H),3.73(dd,J=10.4,3.0Hz,1H),3.70–3.60(m,2H),3.50–3.39(m,1H),3.01–2.92(m,1H),2.88–2.79(m,1H),2.79–2.69(m,1H),2.51(s,4H),1.37–1.27(m,2H),1.17(d,J=6.8Hz,1H),1.12–1.04(m,6H),0.98–0.78(m,3H),0.57(q,J=6.0Hz,2H),0.44(s,1H),0.39–0.25(m,3H),0.12(dd,J=10.0,5.4Hz,1H),-0.04(d,J=2.3Hz,1H).
实施例37核磁氢谱数据:1H NMR(400MHz,Methanol-d4)δ8.28(dt,J=22.0,6.4Hz,1H),7.77–7.66(m,2H),7.50(dd,J=8.6,1.8Hz,1H),5.61(d,J=6.4Hz,1H),4.59(d,J=10.5Hz,1H),4.42(d,J=12.0Hz,1H),3.89–3.69(m,3H),3.67–3.54(m,2H),3.02–2.90(m,3H),2.58–2.45(m,1H),2.08(d,J=33.7Hz,3H),1.30(t,J=7.5Hz,3H),1.14–1.01(m,1H),0.95–0.84(m,2H),0.64–0.52(m,2H),0.44(qd,J=8.8,8.2,3.7Hz,1H),0.39–0.26(m,3H),0.15–0.08(m,1H).
实施例38化合物38的制备
将中间体(S)-2-(((叔丁氧)羰基)氨基)-3,3-二环丙基-丙酸(100mg,230.75umol)溶于2mL二氯甲烷中,室温搅拌下依次加入HOAt 62.77mg,461.51umol),EDCI(62.03mg,323.06umol),DIPEA(119.29mg,923.02umol,160.77uL),之后加入中间体38-1,室温反应3小时,加水淬灭,减压除去大部分有机溶剂,乙酸乙酯(20ml*3)萃取,合并有机相,再分别饱和氯化铵和饱和食盐水洗,无水硫酸钠干燥,减压旋干,粗品经硅胶柱层析纯化分离(石油醚/乙酸乙酯3:1)即可得到中间体38-2(120mg,194.22umol,84.17%yield).MS(ESI)m/z=618(M+1)+.
类似地,参考实施例1步骤2方法,中间体38-2在冰醋酸中60℃反应过夜即可得到关环产物38-3,MS(ESI)m/z=600(M+1)+。
将中间体38-3(100mg,166.7umol)溶于2mL二氯甲烷中,0℃并氮气保护下依次加入TEA(25.30mg,250.07umol,34.88uL)、PdCl2(11.80mg,66.68umol),随后冰浴下加入Et3SiH(193.39mg,1.67mmol,268.59uL),反应允许升至室温反应2小时,过滤,滤液浓缩至干,经反相MPLC纯化分离即可得到中间体38-4(65mg,139.57umol,83.72%产率).MS(ESI)m/z=466(M+1)+。
类似地,参考实施例1步骤4方法,中间体38-4与2-甲基吡唑-3-羧酸缩合即可得到中间体38-5,MS(ESI)m/z=574(M+1)+。
向中间体38-5(37mg,64.48umol)的DCM(0.4mL)中加入TFA(0.4mL),0℃搅拌反应1hr,反应液旋干得粗品,粗品再经反相MPLC柱分离纯化即可得化合物38(25mg,56.20umol,87.15%yield),MS(ESI)m/z=444(M+1)+.1H NMR(400MHz,Methanol-d4)δ7.86(dd,J=8.6,3.0Hz,1H),7.70(d,J=1.6Hz,1H),7.56(dt,J=8.5,1.3Hz,1H),7.53(d,J=2.2Hz,1H),7.08(d,J=2.1Hz,1H),5.60(d,J=6.6Hz,1H),4.08(s,3H),2.34(d,J=2.8Hz,6H),1.21–1.09(m,1H),1.08–0.96(m,1H),0.95–0.86(m,1H),0.66–0.53(m,2H),0.51–0.43(m,1H),0.40–0.26(m,3H),0.21–0.11(m,1H),0.04–0.00(m,1H).
类似地,中间体38-4与不同的吡唑酸或呋咱酸可得到如下实施例化合物39、40、41。
实施例39化合物39
化合物40表征数据:MS(ESI)m/z=458(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.64(d,J=11.0Hz,1H),7.53(d,J=2.1Hz,1H),7.38(s,1H),7.17(dd,J=8.3,1.6Hz,1H),6.96(d,J=2.1Hz,1H),5.58(d,J=6.7Hz,1H),4.59–4.50(m,2H),2.25(s,6H),1.37(t,J=7.2Hz,3H),1.00–0.91(m,1H),0.89–0.75(m,2H),0.55–0.45(m,2H),0.44–0.35(m,1H),0.32–0.22(m,3H),0.19–0.11(m,1H),-0.02–-0.08(m,1H).
实施例40化合物40
化合物40表征数据:MS(ESI)m/z=472(M+1)+,1H NMR(400MHz,Methanol-d4)δ7.63(d,J=8.2Hz,1H),7.55(d,J=2.1Hz,1H),7.42(d,J=32.4Hz,1H),7.17(dd,J=8.3,1.6Hz,1H),6.90(d,J=2.1Hz,1H),5.57(d,J=6.8Hz,1H),5.43(p,J=6.7Hz,1H),2.26(s,6H),1.44(dd,J=14.1,6.6Hz,6H),0.96(td,J=9.2,6.8Hz,1H),0.83(ddt,J=22.1,13.0,4.1Hz,2H),0.51(tdt,J=8.2,6.3,4.0Hz,2H),0.45–0.35(m,1H),0.28(qd,J=9.4,4.8Hz,3H),0.16(dq,J=9.6,5.1Hz,1H),-0.01–-0.10(m,1H).
实施例41
MS(ESI)m/z=460(M+1)+。
为了说明本发明的有益效果,本发明提供以下试验例。
试验例1IL-17A酶联免疫吸附测定(ELISA)实验
通过竞争性ELISA对IL-17A抑制剂对受体-配体结合的抑制情况进行了定量检测。将0.2μg/ml IL-17A(Sino Biological lnc.Cat#12047-H07B)以100μl每孔在96孔板中37度孵育30分钟。用PBST(PBS,0.05%Tween-20)洗板4次,每次200μl每孔,加入200μl 5%脱脂牛奶于25度摇床上孵育30分钟。准备100X浓度待测化合物,浓度从0.003μM到30μM。用PBST(PBS,0.05%Tween-20)洗板4次后加入89μl PBST和1μl 100X浓度待测化合物混匀后于25度预孵育10分钟。加入10μl 16nM IL-17R于25度摇床上孵育30分钟。洗板4次后,加入100μl抗Fc标签HRP偶联抗体于25度摇床上孵育30分钟。洗板4次后,加入100μl TMB底物溶液25度避光孵育。加入20%HCl后,采用酶标仪于450nm波长检测光吸收值。
按照上述方法对实施例制备的化合物进行去IL-17A抑制活性检测。
按照上述方法对实施例制备的化合物进行去IL-17A抑制活性检测,试验结果见表1,其中测定各化合物的IC50按照说明分类,表1中:
“+”表示IC50测定值小于100μM大于1μM;
“++”表示IC50测定值小于1μM大于100nM;
“+++”表示IC50测定值小于100nM;
表1、化合物对IL-17A的抑制活性
实施例 | IC50 | 实施例 | IC50 |
1 | +++ | 33 | +++ |
20 | +++ | 34 | +++ |
21 | +++ | 35 | +++ |
22 | +++ | 36 | +++ |
23 | +++ | 37 | +++ |
24 | +++ | 38 | ++ |
25 | +++ | 39 | ++ |
26 | ++ | 40 | +++ |
27 | +++ | 41 | ++ |
28 | +++ | ||
29 | ++ | ||
30 | +++ | ||
31 | +++ | ||
32 | +++ |
试验表明,本发明实施例的化合物具有良好的IL-17A抑制活性,可以有效用于与IL-17A活性异常疾病的治疗。
综上所述,本发明公开的式I所示的新化合物,表现出了良好的IL-17A抑制活性,为临床治疗与IL-17A活性异常相关的疾病提供了一种新的药用可能。
Claims (10)
1.式I所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,
R1选自-C0~2亚烷基-C(O)R11;
R11选自-C0~2亚烷基-(5~10元芳杂环);其中芳杂环可进一步被一个、两个或三个独立的R1a取代;
每个R1a分别独立选自氢、-C1~6烷基;
R2选自氢;
A环选自3~10元环烷基;其中环烷基可进一步被一个、两个或三个独立的RA1取代;
每个RA1分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基;
R3选自氢、-C1~6烷基;
R4选自-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);其中环烷基、杂环烷基可进一步被一个、两个或三个独立的R31取代;
每个R31分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基;
X1、X2、X3分别独立选自CRx;
每个Rx分别独立选自氢;
R选自
R5、R6相连形成3~10元杂环烷基;其中杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-C(O)R52;
R52选自氢、-C1~10烷基、卤素取代的-C1~10烷基;
R7、R8分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R71取代;
每个R71分别独立选自氢、-C1~6烷基、卤素取代的-C1~6烷基、-C0~2亚烷基-OR72、-C0~2亚烷基-NR72R73、-C0~2亚烷基-(3~10元环烷基)、-C0~2亚烷基-(3~10元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R74取代;
R72、R73分别独立选自氢、-C1~6烷基、-C0~2亚烷基-(3~10元环烷基);
每个R74分别独立选自氢、-C1~6烷基。
2.根据权利要求1所述的化合物,其特征在于:所述R1选自
3.根据权利要求1所述的化合物,其特征在于:
A环选自3~6元环烷基;其中环烷基可进一步被一个、两个或三个独立的RA1取代;
每个RA1分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基。
4.根据权利要求1所述的化合物,其特征在于:
R3选自氢;R4选自3~6元环烷基;其中环烷基可进一步被一个、两个或三个独立的R31取代;
每个R31分别独立选自氢、-C1~6烷基、卤素取代的C1~6烷基。
5.根据权利要求1所述的化合物,其特征在于:
R5、R6相连形成3~6元杂环烷基;其中杂环烷基可进一步被一个、两个或三个独立的R51取代;
每个R51分别独立选自氢、-C(O)(C1~6烷基)。
6.根据权利要求1所述的化合物,其特征在于:
R7、R8分别独立选自氢、C1~6烷基、卤素取代的C1~6烷基、-C0~2亚烷基-(3~6元环烷基)、-C0~2亚烷基-(3~6元杂环烷基);其中烷基、亚烷基、环烷基、杂环烷基可进一步被一个、两个或三个独立的R71取代。
7.根据权利要求1所述的化合物,其特征在于:式I所述的化合物具体为:
8.权利要求1-7任一项所述的化合物、或其立体异构体、或其药学上可接受的盐在制备治疗IL-17A介导的疾病的药物中的用途。
9.权利要求8所述的用途,其特征在于:所述IL-17A介导的疾病是与炎症、自身免疫性疾病、感染性疾病、癌症、癌前期综合征相关的疾病中的一种或几种。
10.一种药物组合物,其特征在于:它是以权利要求1~7任一项所述的化合物、或其立体异构体、或其药学上可接受的盐,加上药学上可接受的辅料制备而成的制剂。
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CN112341440A (zh) * | 2019-08-09 | 2021-02-09 | 成都先导药物开发股份有限公司 | 一种免疫调节剂 |
CN113999234A (zh) * | 2020-07-28 | 2022-02-01 | 成都先导药物开发股份有限公司 | 一种免疫调节剂 |
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