CN107312005B - 具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用 - Google Patents
具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用 Download PDFInfo
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- CN107312005B CN107312005B CN201610273075.6A CN201610273075A CN107312005B CN 107312005 B CN107312005 B CN 107312005B CN 201610273075 A CN201610273075 A CN 201610273075A CN 107312005 B CN107312005 B CN 107312005B
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- imidazo
- isoindol
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- urea
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 129
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- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229940101270 nicotinamide adenine dinucleotide (nad) Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
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- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- RVLHQTNUNYWCIH-UHFFFAOYSA-N pyrrolidin-2-ylidenemethanone Chemical compound O=C=C1CCCN1 RVLHQTNUNYWCIH-UHFFFAOYSA-N 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- JSUZSOMKTOGLKA-UHFFFAOYSA-N tert-butyl 2-(5H-imidazo[5,1-a]isoindol-5-yl)acetate Chemical compound CC(C)(C)OC(=O)CC1c2ccccc2-c2cncn12 JSUZSOMKTOGLKA-UHFFFAOYSA-N 0.000 description 1
- FWLYHQMHIKFOFB-UHFFFAOYSA-N tert-butyl 2-(7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)acetate Chemical compound CC(C)(C)OC(=O)CC1c2cc(F)ccc2-c2cncn12 FWLYHQMHIKFOFB-UHFFFAOYSA-N 0.000 description 1
- KXIBKMGPVUALLB-UHFFFAOYSA-N tert-butyl 2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)acetate Chemical compound CC(C)(C)OC(=O)CC1c2ccc(F)cc2-c2cncn12 KXIBKMGPVUALLB-UHFFFAOYSA-N 0.000 description 1
- IMVHJTISTXFPQC-UHFFFAOYSA-N tert-butyl 2-[6-(trifluoromethyl)-5H-imidazo[5,1-a]isoindol-5-yl]acetate Chemical compound CC(C)(C)OC(=O)CC1c2c(cccc2C(F)(F)F)-c2cncn12 IMVHJTISTXFPQC-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及一种式(I)结构的具有IDO/TDO抑制活性的稠合咪唑衍生物及其制备方法和应用。该系列稠合咪唑衍生物对IDO/TDO具有很高的抑制活性,可广泛应用于治疗或预防癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病,也可用于抑制患者的免疫抑制,有望开发成新一代免疫抑制剂。
Description
技术领域
本发明属于药物开发技术领域,具体涉及一种具有IDO/TDO抑制活性的稠合咪唑衍生物及其制备方法和应用。
背景技术
色氨酸(Trp)是一种人体必需的氨基酸,是人体合成蛋白质、烟酸和神经递质5-羟色胺(血清素)所必需的营养物质。色氨酸在体内有两种代谢途径:5-羟色胺途径和犬尿氨酸途径。少部分色氨酸通过色氨酸羟化酶生成5-羟色胺,约95%的色氨酸在吲哚胺2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)或色氨酸2,3-双加氧酶(tryptophan 2,3-dioxygenase,TDO)的作用下生成犬尿氨酸。犬尿氨酸也有两条代谢通路,大部分在犬尿氨酸羟化酶(kynurenine 3-hydroxylase)的作用下生成3-羟犬尿氨酸(3-hydroxykynurenine),继而由犬尿氨酸酶(kynureninase,KYNU)催化水解生成3-羟邻氨苯甲酸,最后经过多级酶促反应生成喹啉酸、吡啶羧酸类及尼克酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD)等活性分子参与体内各种生理过程;另外一条通路是在犬尿氨酸氨基转移酶(kynurenine aminitric oxide transferase I andⅡ,KAT I/1I)的作用下生成犬尿喹啉酸(kynurenic acid,KYNA)。
吲哚胺2,3-双加氧酶(IDO)是色氨酸/犬尿氨酸途径的限速酶,在哺乳动物IDO广泛存在于除肝脏以外的组织细胞内,包括星形胶质细胞、小胶质细胞、巨噬细胞和血管内皮细胞,作用于比TDO更广泛的含有吲哚胺的底物。TDO几乎都在肝脏中表达,对底物有较高的选择性。
IDO可以被前炎症因子所诱导,其中干扰素γ是最强的诱导剂,在高水平干扰素γ的刺激活化期间,激活IDO,促进了色氨酸的代谢。
对怀孕小鼠模型研究发现,母胎体界面的合胞体滋养层细胞和抗原提呈细胞可以合成IDO,并且IDO表达的动态变化与胚胎形成一致,如果特异性阻断IDO的合成,则可导致小鼠流产,表明IDO可以阻止免疫排斥,是一种免疫调节酶。IDO与肿瘤细胞逃避免疫系统对其监视和攻击的免疫逃逸有关。多种肿瘤细胞高表达IDO抗原,使局部T细胞增殖受到抑制,从而介导肿瘤细胞逃避免疫系统的攻击。IDO参与调节T细胞反应,T细胞对色氨酸耗竭很敏感,当色氨酸浓度降低是,T细胞增殖就会停止在G1期,IDO通过降解色氨酸抑制了T细胞的活化。
IDO活化与多种疾病发病机制密切相关,是肿瘤,阿尔茨海默氏症,帕金森氏症,抑郁症等相关疾病领域的重要靶点,针对IDO/TDO的抑制剂,能够解放机体的防御系统,并帮助T细胞更好地攻击肿瘤,因此具有治疗广泛类型肿瘤的潜力,IDO/TDO抑制剂具有广阔的应用前景,但迄今为止没有IDO/TDO抑制剂上市,因此,寻找和开发新型高效的IDO抑制剂具有重要的理论意义和应用价值。
目前吲哚胺2,3-双加氧酶抑制剂的研发均处于研发早期,包括NewLink公司的Indoximod,NLG-919(IDO/TDO双特异性),Incyte公司的Epacadostat(INCB024360),以及BMS,Flexus,Iomet,Iteos,Curadev等公司的IDO或TDO抑制剂。本发明的实施例化合物在酶学和细胞模型中对吲哚胺2,3-双加氧酶(IDO)具有很高的抑制活性,对色氨酸2,3-双加氧酶(TDO)也具有抑制活性,并且在PK动物模型中具有很好的暴露量。
发明内容
为了解决现有技术存在的缺陷,发明人在研究过程中发现一类具有式(I)结构的的稠合咪唑衍生物,该系列化合物对IDO/TDO具有很高的抑制活性,可以单独或联合用药用于治疗由IDO/TDO介导的色氨酸代谢紊乱的病理学特征的疾病。可广泛应用于治疗或预防癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病,也可用于抑制患者的免疫抑制,有望开发成新一代免疫抑制剂。
本发明一方面提供一种具有如下式(I)的化合物、其立体异构体或其药学上可接受盐:
其中,
R1、R2各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR5、-C0-8-O-R6、-C0-8-C(O)OR6、-C0-8-C(O)R6、-C0-8-O-C(O)R7、-C0-8-NR8R9、-C0-8-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6,
任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-8烷基、任选取代或未取代的C3-8环烷基、任选取代或未取代的3-8元杂环基、任选取代或未取代的C5-10芳基、任选取代或未取代的5-10元杂芳基、-C0-8-S(O)rR5、-C0-8-O-R6、-C0-8-C(O)OR6、-C0-8-C(O)R6、-C0-8-O-C(O)R7、-C0-8-NR8R9、-C0-8-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6的取代基所取代;
R、R3、R4各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-8烷基、任选取代或未取代的C2-8链烯基、任选取代或未取代的C2-8链炔基、任选取代或未取代的C3-8环烷基、任选取代或未取代的3-8元杂环基、任选取代或未取代的C5-10芳基、任选取代或未取代的5-10元杂芳基、-C0-8-S(O)rR5、-C0-8-O-R6、-C0-8-C(O)OR6、-C0-8-C(O)R6、-C0-8-O-C(O)R7、-C0-8-NR8R9、-C0-8-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6;
R5、R6各自独立的选自氢、氘、任选取代或未取代的C1-8烷基、任选取代或未取代的C2-8链烯基、任选取代或未取代的C2-8链炔基、任选取代或未取代的C3-8环烷基、任选取代或未取代的3-8元杂环基、任选取代或未取代的C5-10芳基、任选取代或未取代的5-10元杂芳基、任选取代或未取代的氨基或任选取代或未取代的C1-8烷酰基;
R7选自氢、氘、任选取代或未取代的C1-8烷基、任选取代或未取代的C2-8链烯基、任选取代或未取代的C2-8链炔基、任选取代或未取代的C1-8烷氧基、任选取代或未取代的C3-8环烷基、任选取代或未取代的C3-8环烷氧基、任选取代或未取代的3-8元杂环基、任选取代或未取代的3-8元杂环氧基、任选取代或未取代的C5-10芳基、任选取代或未取代的C5-10芳基氧基、任选取代或未取代的5-10元杂芳基、任选取代或未取代的5-10元杂芳基氧基或任选取代或未取代的氨基;
R8、R9各自独立的选自氢、氘、羟基、任选取代或未取代的C1-8烷基、任选取代或未取代的C2-8链烯基、任选取代或未取代的C2-8链炔基、任选取代或未取代的C3-8环烷基、任选取代或未取代的3-8元杂环基、任选取代或未取代的C5-10芳基、任选取代或未取代的5-10元杂芳基、任选取代或未取代的C1-8烷酰基或任选取代或未取代的氨基;
m为0、1、2、3或4;
n为0、1、2、3、4或5;
r为0、1或2。
作为进一步优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,R1选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6,任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6的取代基所取代;优选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C3-6环烷基、3-6元杂环基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6或-C0-4-NR8R9,任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6的取代基所取代;更优选自氢、氘、卤素、氰基、C1-4烷基、卤取代C1-4烷基、羟基取代C1-4烷基、C3-6环烷基、3-6元杂环基、-C0-4-S(O)rR5、-C0-4-C(O)OR6或-C0-4-NR8R9。
作为更进一步优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,R、R3、R4各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-4烷基、任选取代或未取代的C2-4链烯基、任选取代或未取代的C2-4链炔基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6;R、R3、R4各自独立的优选自氢、氘、卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7或-C0-4-NR8R9;R、R3、R4各自独立的更优选自氢、氘、氟、氯、溴、甲基、乙基、三氟甲基、异丙基、羟甲基、环丙基。
作为更进一步优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,R2选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6,任选进一步被一个或多个选自卤素、氰基、硝基、叠氮基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6、-C0-4-O-C(O)R7、-C0-4-NR8R9、-C0-4-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6的取代基所取代;优选自氢、氘、卤素、氰基、C1-4烷基、C3-6环烷基、3-6元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-O-R6、-C0-4-C(O)OR6或-C0-4-C(O)R6,任选进一步被一个或多个选自卤素、氰基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6或-C0-4-O-C(O)R7的取代基所取代。
作为更进一步优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,所述任选取代的取代基选自氘、卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、C1-8烷基、三氟甲基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基。
作为更进一步优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,选自式(Ⅱ)化合物:
其中,
R选自氢、氘、氟、氯、溴、甲基、乙基、三氟甲基、异丙基、羟甲基、环丙基;
R1选自氢、氘、氟、氯、溴、氰基、硝基、甲基、异丙基、三氟甲基、羟甲基、环丙基、哌嗪基、吗啉基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、羧基或氨基;
R2选自氢、氘、氟、氯、溴、氰基、C1-4烷基、C3-6环烷基、哌嗪基、吗啉基、咪唑基、吡唑基、吡咯基、吡啶基、三氮唑基、异噁唑、-C0-4-O-R6或-C0-4-C(O)OR6,任选进一步被一个或多个选自卤素、氰基、任选取代或未取代的C1-4烷基、任选取代或未取代的C3-6环烷基、任选取代或未取代的3-6元杂环基、任选取代或未取代的C5-8芳基、任选取代或未取代的5-8元杂芳基、-C0-4-S(O)rR5、-C0-4-O-R6、-C0-4-C(O)OR6、-C0-4-C(O)R6或-C0-4-O-C(O)R7的取代基所取代,所述任选取代的取代基选自卤素、羟基、巯基、氰基、乙酰氨基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、C1-4烷基、三氟甲基、C3-6环烷基、3-6元杂环基、C1-4烷氧基、C1-4烷氧羰基、C1-4烷基羰基、C1-4烷基羰基氧基、3-6元杂环基氧基、3-6元杂环基硫基、C5-8芳基、C5-8芳基氧基、C5-8芳基硫基、5-8元杂芳基、5-8元杂芳基氧基、5-8元杂芳基硫基、氨基、单C1-4烷基氨基或二C1-4烷基氨基。
作为最优选的方案,所述式(I)化合物、其立体异构体或其药学上可接受盐,
选自如下化合物:
本发明另一方面提供一种前所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法,包括如下步骤:
本发明另一方面提供一种药物组合物,所述药物组合物包括治疗有效剂量的前述化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明另一方面提供一种前述化合物、其立体异构体或其药学上可接受盐,或前述药物组合物在制备用于治疗由IDO/TDO介导的色氨酸代谢紊乱的病理学特征的疾病的药物中的应用;所述IDO/TDO介导的色氨酸代谢紊乱的病理学特征的疾病优选自癌症或肿瘤、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病。
具体实施方式
详细说明:除非有相反陈述,下列用在说明书和权利要求书中的术语具有下述含义。
“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基,烷基指饱和的脂族烃基团,C0-8是指不含碳原子或者C1-8烷基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,“C3-8环烷基”指包括3至8个碳原子的环烷基,“5-10元环烷基”指包括5至10个碳原子的环烷基,例如:
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基,螺环烷基的非限制性实施例包含:
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,稠环烷基的非限制性实施例包含:
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,桥环烷基的非限制性实施例包含:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。“5-10元杂环基”指包含5至10个环原子的环基,“3-8元杂环基”指包含3至8个环原子的环基。
单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子,其余环原子为碳。这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基。螺环烷基的非限制性实施例包含:
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子,其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基,稠杂环基的非限制性实施例包含:
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子,其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,桥环烷基的非限制性实施例包含:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,非限制性实施例包含:
杂环基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团,“C5-10芳基”指含有5-10个碳的全碳芳基,“5-10元芳基”指含有5-10个碳的全碳芳基,例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
芳基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“杂芳基”指包含1至4个杂原子的杂芳族体系,所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子,5-7元杂芳基指含有5-7个环原子的杂芳族体系,5-10元杂芳基指含有5-10个环原子的杂芳族体系,例如呋喃基、噻吩基、吡啶基、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,非限制性实施例包含:
杂芳基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基,C2-8链烯基指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。
烯基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基,C2-8链炔基指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-,2-或3-丁炔基等。
炔基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“烷氧基”指-O-(烷基),其中烷基的定义如上所述。C1-8烷氧基指含1-8个碳的烷基氧基,非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的,当被取代时,取代基,优选为一个或多个以下基团,独立地选自卤素、羟基、巯基、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-8元杂环基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、-C0-8-S(O)rR4、-C0-8-O-R5、-C0-8-C(O)OR5、-C0-8-C(O)R6、-C0-8-O-C(O)R6、-C0-8-NR7R8、-C0-8-C(O)NR7R8、-N(R7)-C(O)R6或-N(R7)-C(O)OR5的取代基所取代;
“卤取代的C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团,例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“卤取代的C1-8烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“卤素”指氟、氯、溴或碘。
“DMSO”指二甲基亚砜。
“LDA”指二异丙基氨基锂。
“DIAD”指偶氮二甲酸二异丙酯。
“DMF”指N,N-二甲基甲酰胺。
“DPPA”指叠氮磷酸二苯酯。
“Pd(dppf)Cl2”指[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
“THF”指四氢呋喃。
“任选取代”指基团中的一个或多个氢原子,彼此独立地被相应数目的氘、卤素、羟基、巯基、氰基、硝基、叠氮基、C1‐8烷基、C2‐8链烯基、C2‐8链炔基、卤取代C1‐8烷基、C3‐8环烷基、3‐8元杂环基、3‐8元杂环基氧基、3‐8元杂环基硫基、C5‐10芳基、C5‐10芳基氧基、C5‐10芳基硫基、5‐10元杂芳基、5‐10元杂芳基氧基、5‐10元杂芳基硫基、-C0-8-S(O)rR5、-C0-8-O-R6、-C0-8-C(O)OR6、-C0-8-C(O)R7、-C0-8-O-C(O)R7、-C0-8-NR8R9、-C0-8-C(O)NR8R9、-N(R8)-C(O)R7或-N(R8)-C(O)OR6的取代基所取代;优选氘、卤素、羟基、巯基、氰基、硝基、乙酰氨基、叠氮基、磺酰基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、C1-8烷基、三氟甲基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-8元杂环基、C1-8烷氧基、C1-8烷氧羰基、C1-8烷基羰基、C1-8烷基羰基氧基、3-8元杂环基氧基、3-8元杂环基硫基、C5-10芳基、C5-10芳基氧基、C5-10芳基硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、氨基、单C1-8烷基氨基或二C1-8烷基氨基的取代基所取代。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和键(如烯属)的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明,但决非限制本发明,本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代甲醇(CD3OD)和氘代氯仿(CDCl3)内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,TLC采用的规格是0.15mm~0.20mm,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。
本发明实施例中的起始原料是已知的并且可以在市场上买到,或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下,本发明的所有反应均在连续的磁搅拌下,在干燥氮气或氩气氛下进行,溶剂为干燥溶剂。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。氢气氛是指反应瓶连接一个约1L容积的氢气气球。
在无特殊说明的情况下,实施例中的溶液是指水溶液。反应的温度为室温。室温为最适宜的反应温度,为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用色谱(LC-MS)反应所使用的展开剂体系有:二氯甲烷和甲醇体系,正己烷和乙酸乙酯体系,石油醚和乙酸乙酯体系,丙酮,溶剂的体积比可根据化合物的极性不同而进行调节。柱层析的洗脱剂的体系包括:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:二氯甲烷和乙酸乙酯体系,D:乙酸乙酯和甲醇,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的氨水和醋酸等进行调节。
实施例1:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基苯基)脲
第一步:1-(2-溴苯甲基)-1H-咪唑的制备
将邻溴甲苯(20g,117mmol),溴代丁二酰亚胺(22.0g,123mmol),偶氮二异丁腈(1g)溶于干燥四氯化碳(200mL),在氮气保护下加热回流16小时。反应冷至室温后过滤,滤液加入咪唑(15.9g,234mmol)和碳酸钾(33g,234mmol),氮气保护下加热回流5小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(100mL),用水(2X50mL)洗涤。分离有机相,用无水硫酸钠干燥,过滤,浓缩,残留物通过快速硅胶柱纯化得到1-(2-溴苯甲基)-1H-咪唑(20g)。
LC-MS:236.9,239.1,tR=1.541min.
第二步:5H-咪唑并[5,1-a]异吲哚的制备
将1-(2-溴-苯甲基)-1H-咪唑(20g,84.0mmol),醋酸钯(500mg),三苯基膦(500mg),碳酸钾(23g,167mmol)溶于DMSO(200mL),在氮气保护下加热至140℃搅拌2小时。LC-MS显示反应完全,将反应液浓缩干,剩余物溶于乙酸乙酯(200mL),依次用水(2X100mL),饱和食盐水(50mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到5H-咪唑并[5,1-a]异吲哚(10.0g)。
LC-MS:157.1,tR=1.466min.
第三步:(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇的制备
5H-咪唑并[5,1-a]异吲哚(668mg,4.277mmol),多聚甲醛(193mg,6.427mmol)于四氢呋喃(5mL)中搅拌,氮气保护下冷至-78℃,滴加LDA(3.2mL,2M in THF)。缓慢升温至室温,搅拌过夜。加水,二氯甲烷提取,干燥,柱层析纯化得(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇(196mg)。
LC-MS:187.1,tR=1.396min.
第四步:2-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)异二氢吲哚-1,3-二酮的制备
将(5H-咪唑并[5,1-a]异吲哚-5-基)甲醇(180mg,0.967mmol),邻苯二甲酰亚胺(294mg,2.0mmol),三苯基膦(525mg,2.0mmol)溶于甲苯(5mL)中,氮气保护下搅拌,室温下滴加DIAD(404mg,2.0mmol)的甲苯(5mL)溶液,搅拌过夜。过滤,滤液加水,乙酸乙酯提取,干燥,柱层析纯化得2-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)异二氢吲哚-1,3-二酮(93mg)。
LC-MS:316.0,tR=1.866min.
第五步:(5H-咪唑并[5,1-a]异吲哚-5-基)甲胺的制备
2-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)异二氢吲哚-1,3-二酮(93mg,0.295mmol),水合肼(85%,1mL)于乙醇(2mL)中回流4小时,冷却,浓缩,残留物经柱层析纯化得(5H-咪唑并[5,1-a]异吲哚-5-基)甲胺(20mg)。
LC-MS:186.1,tR=0.618min.
第六步:1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基苯基)脲的制备
(5H-咪唑并[5,1-a]异吲哚-5-基)甲胺(20mg,0.108mmol),4-氰基苯异氰酸酯(20mg,0.139mmol),三乙胺(22mg,0.217mmol)于DMF(2mL)中室温搅拌过夜,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基苯基)脲(5mg)。
LC-MS:330.1,tR=1.896min;
1H NMR(400MHz,d6-DMSO)δ9.25(s,1H),8.24(s,1H),7.72-7.57(m,4H),7.56-7.41(m,3H),7.39-7.27(m,2H),6.64(t,J=5.9Hz,1H),5.61-5.46(m,1H),4.07-3.94(m,1H),3.66-3.55(m,1H).
实施例2:
1-(4-氰基苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
第一步:1-(2-氟-6-溴苯甲基)-1H-咪唑的制备
将1-溴-3-氟-2-甲苯(8.0g,42.3mmol),溴代丁二酰亚胺(9.0g,50.8mmol),偶氮二异丁腈(300mg)溶于干燥四氯化碳(100mL),在氮气保护下加热回流16小时。反应冷至室温后过滤,滤液加入咪唑(8.7g,126.9mmol)和碳酸钾(17.5g,126.9mmol),在氮气保护下加热回流5小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,残留物经过快速硅胶柱层析纯化得到1-(2-溴-6-氟苯甲基)-1H-咪唑(6.0g)。
第二步:6-氟-5H-咪唑并[5,1-a]异吲哚的制备
将1-(2-溴-6-氟苯甲基)-1H-咪唑(6.0g,23.5mmol),醋酸钯(200mg),三苯基膦(300mg),碳酸钾(6.5g,47.0mmol)溶于DMSO(50mL)中,反应在氮气保护下加热至140℃搅拌2小时。LC-MS显示反应完全,将反应液浓缩干,剩余物溶于乙酸乙酯(200mL),依次用水(2X100mL),饱和食盐水(50mL)洗涤。有机相干燥过滤,浓缩,残留物通过快速硅胶柱纯化得到6-氟-5H-咪唑并[5,1-a]异吲哚(3.0g)。
第三步:2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸叔丁酯的制备
6-氟-5H-咪唑并[5,1-a]异吲哚(200mg,1.148mmol)溶于干燥的四氢呋喃(2mL),氮气保护下冷至-78℃,滴加LDA(0.86mL,2M in THF)。缓慢升至室温,搅拌3小时,加水,二氯甲烷提取,干燥,柱层析纯化得2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸叔丁酯(245mg)。
LC-MS:289.1,tR=1.989min.
第四步:2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸的制备
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸叔丁酯(245mg,0.850mmol)溶于乙酸乙酯(2mL),加入氯化氢/二氧六环溶液(2mL),室温搅拌过夜,柱层析纯化得2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸(93mg)。
LC-MS:233.1,tR=1.532min.
第五步:1-(4-氰基苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲的
制备
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5基)乙酸(30mg,0.129mmol),4-氰基苯胺(17mg,0.144mmol),DPPA(39mg,0.142mmol),三乙胺(20mg,0.198mmol)于甲苯(4mL)中氮气保护下回流4小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-(4-氰基苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(11mg)。
LC-MS:348.1,tR=1.853min;
1H NMR(400MHz,d6-DMSO)δ9.57(s,1H),9.17(s,1H),7.83(s,1H),7.62(ddd,J=15.6,12.4,7.7Hz,4H),7.49(d,J=8.7Hz,2H),7.33(t,J=9.0Hz,1H),7.16(s,1H),5.99(s,1H),4.21(d,J=15.0Hz,1H),3.69(d,J=8.2Hz,1H).
实施例3:
1-(4-溴苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg,0.86mmol),叠氮磷酸二苯酯(DPPA)(475mg,1.72mmol),三乙胺(180mg,1.72mmol),对溴苯胺(300mg,1.72mmol)溶于无水甲苯(20mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-溴苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(6.0mg)。
LC-MS:401.0,tR=2.118min;
1H NMR(400MHz,MeOD)δ7.96(s,1H),7.56-7.43(m,2H),7.42-7.31(m,2H),7.27-7.18(m,3H),7.15-7.03(m,1H),5.77-5.61(m,1H),4.22(dd,J=14.4,3.9Hz,1H),3.68(dd,J=14.4,5.9Hz,1H).
实施例4:
1-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)
苯基)脲
第一步:4-(1-甲基-1H-吡唑-4-基)苯胺的制备
将对溴苯胺(2.0g,11.5mmol),1-甲基吡唑-4-硼酸频哪醇酯(2.4g,11.5mmol),Pd(dppf)Cl2(100mg),磷酸钾(4.8g,23.0mmol)溶于1,4-二氧六环(20mL)和20mL水中,在氮气保护下加热至100℃搅拌3小时。LC-MS显示反应完全。反应液浓缩,剩余物溶于二氯甲烷(50mL),用水(2X30mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到4-(1-甲基-1H-吡唑-4-基)苯胺(1.5g)。
第二步:1-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡
唑-4-基)苯基)脲的制备
将2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg,0.86mmol),叠氮磷酸二苯酯(DPPA)(475mg,1.72mmol),三乙胺(180mg,1.72mmol),4-(1-甲基-1H-吡唑-4-基)苯胺(300mg,1.72mmol)溶于无水甲苯(20mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)脲(20.8mg)。
LC-MS:403.15,tR=1.831min;
1H NMR(400MHz,MeOD)δ7.97(s,1H),7.86(s,1H),7.74(s,1H),7.53-7.45(m,2H),7.44-7.38(m,2H),7.30-7.25(m,2H),7.22(s,1H),7.09(ddd,J=9.5,6.3,2.9Hz,1H),5.69(dd,J=5.8,4.0Hz,1H),4.22(dd,J=14.4,3.9Hz,1H),3.91(s,3H),3.66.
实施例5:
1-(4-氰基苯基)-3-((6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
第一步:1-(2-溴-6-(三氟甲基)苯甲基)-1H-咪唑的制备
将1-溴-3-(三氟甲基)-2-甲苯(5.0g,20.9mmol),溴代丁二酰亚胺(3.72g,20.9mmol),偶氮二异丁腈(300mg)溶于干燥四氯化碳(100mL),在氮气保护下加热回流16小时。反应冷至室温后过滤,滤液加入咪唑(2.85g,42mmol)和碳酸钾(4.34g,31.37mmol),在氮气保护下加热回流5小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(50mL),用水(2X40mL)洗涤。有机相干燥过滤,浓缩,剩余物通过快速硅胶柱纯化得到1-(2-溴-6-(三氟甲基)苯甲基)-1H-咪唑(5.0g)。
第二步:6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚的制备
将1-(2-溴-6-(三氟甲基)苯甲基)-1H-咪唑(5.0g,16.4mmol),醋酸钯(184mg),三苯基膦(430mg),碳酸钾(4.4g,32.8mmol)溶于DMSO(50mL)中,在氮气保护下加热至140℃搅拌2小时。LC-MS显示反应完全,将反应液浓缩干,剩余物溶于乙酸乙酯(200mL),依次用水(2X100mL),饱和食盐水(50mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚(2.9g)。
第三步:2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯的制备
将6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚(2.9g,12.9mmol)溶于无水THF(100mL)中,在-30℃下缓慢滴加LDA(9.7mL,19.4mmol,2M in THF)。滴毕,在-30℃搅拌15分钟,缓慢滴入溴乙酸叔丁酯(3.8g,19.4mmol)。在-30℃至0℃下搅拌1小时,LC-MS显示反应完全,用饱和NH4Cl(100mL)淬灭。有机相分层干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(2g)。
第四步:2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸的制备
将2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(230mg,0.68mmol)溶于三氟乙酸(2mL),二氯甲烷(2mL)中,在室温下搅拌1小时,反应液浓缩,得到粗品2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg)。
第五步:1-(4-腈基苯基-3-((6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)甲
基)脲的制备
将2-(6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg,0.71mmol),叠氮磷酸二苯酯(DPPA)(487mg,1.77mmol),三乙胺(0.4mL,2.83mmol),4-氨基苯乙腈(0.21mg,1.77mmol)溶于无水甲苯(20mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-腈基苯基-3-((6-(三氟甲基)-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(6.1mg)。
LC-MS:398.0,tR=2.044Min;
1H NMR(400MHz,MeOD)δ7.99(s,1H),7.93(d,J=5.5Hz,1H),7.73-7.64(m,2H),7.57(d,J=8.8Hz,2H),7.46(d,J=8.8Hz,2H),7.27(s,1H),5.88-5.82(m,1H),4.35(dd,J=14.6,2.9Hz,2H),3.57(dd,J=14.6,5.8Hz,2H);
19F NMR(400MHz,MeOD)δ-60.9.
实施例6:
1-((6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基苯基)脲
将2-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(420mg,1.69mmol)溶于15mL甲苯,加入DPPA(511mg,1.859mmol),三乙胺(256mg,2.533mmol)和对氰基苯胺(219mg,1.859mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到1-((6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基苯基)脲(58mg)。
LC-MS:364.0,tR=1.926min;
1H NMR(400MHz,d6-DMSO)δ9.02(s,1H),7.93(s,1H),7.63(dd,J=15.8,8.1Hz,3H),7.53-7.42(m,3H),7.34(dd,J=7.7,4.2Hz,1H),7.21(s,1H),6.44(t,J=6.0Hz,1H),5.61(dd,J=6.1,3.3Hz,1H),4.28(ddd,J=14.1,5.7,3.4Hz,1H),3.65-3.51(m,1H).
实施例7:
1-(3-氟-4-甲氧苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
将2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(80mg,0.35mmol),叠氮磷酸二苯酯(DPPA)(190mg,0.69mmol),三乙胺(100mg,0.9mmol),3-氟-4-甲氧基苯胺(100mg,0.69mmol)溶于无水甲苯(10mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(3-氟-4-甲氧苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(16.0mg)。
LC-MS:371.0,tR=1.970min;
1H NMR(400MHz,MeOD)δ7.96(s,1H),7.54-7.44(m,2H),7.20(dd,J=13.4,2.4Hz,2H),7.09(ddd,J=9.5,6.5,2.6Hz,1H),6.96(t,J=9.0Hz,1H),6.88(ddd,J=8.8,2.4,1.3Hz,1H),5.69(dd,J=5.7,4.1Hz,1H),4.20(dd,J=14.4,3.9Hz,1H),3.82(s,3H),3.66(dd,J=14.4,6.0Hz,1H).
实施例8:
1-(3-溴苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
将2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(80mg,0.35mmol),叠氮磷酸二苯酯(DPPA)(190mg,0.69mmol),三乙胺(100mg,0.9mmol),3-溴苯胺(120mg,0.69mmol)溶于无水甲苯(10mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(3-溴苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(2.1mg)。
LC-MS:401.0,tR=2.11min;
1H NMR(400MHz,MeOD)δ7.97(s,1H),7.63(s,1H),7.48(s,2H),7.15(dd,J=26.1,17.6Hz,4H),5.70(s,1H),4.22(d,J=14.0Hz,1H),3.78-3.54(m,1H).
实施例9:
1-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氟苯基)脲
将2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(80mg,0.35mmol),叠氮磷酸二苯酯(DPPA)(190mg,0.69mmol),三乙胺(100mg,0.9mmol),4-氟苯胺(80mg,0.69mmol)溶于无水甲苯(10mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氟苯基)脲(11.2mg)。
LC-MS:341.0,2.116min;
1H NMR(400MHz MeOD)δ7.98(s,1H),7.92-7.81(m,1H),7.53-7.41(m,2H),7.22(s,1H),7.08(ddd,J=17.2,9.7,5.1Hz,3H),7.00-6.93(m,1H),5.79-5.62(m,1H),4.24(dd,J=14.4,3.8Hz,1H),3.73(dd,J=14.5,5.6Hz,1H).
实施例10:
1-(4-(1-甲基-1H-吡唑-4-基)苯基)-3-((6-(三氟甲基)-5H-咪唑并[5,1-a]异吲
哚-5-基)甲基)脲
制备方法同实施例5。
LC-MS:453.1,tR=1.983min;
1H NMR(400MHz,MeOD)δ7.86(s,1H),7.83-7.77(m,1H),7.74(s,1H),7.61(s,1H),7.59-7.49(m,2H),7.33-7.25(m,2H),7.18-7.09(m,3H),5.71(s,1H),4.21(dd,J=14.5,3.4Hz,1H),3.79(s,3H),3.39(dd,J=14.5,6.1Hz,1H);
19F NMR(400MHz,MeOD)δ-60.9.
实施例11:
1-((6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)
苯基)脲
将2-(6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(245mg,0.984mmol)溶于15mL甲苯,然后加入DPPA(298mg,1.083mmol),三乙胺(149mg,1.478mmol)和4-(1-甲基-1H-吡唑-4-基)苯胺(188mg,1.083mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1)得到1-((6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)脲(50mg)。
LC-MS:419.0,tR=1.920min;
1H NMR(400MHz,d6-DMSO)δ8.48(s,1H),7.96(d,J=23.3Hz,2H),7.74(s,1H),7.61(d,J=7.4Hz,1H),7.45(t,J=7.8Hz,1H),7.45-7.23(m,5H),7.22(s,1H),6.20(t,J=5.9Hz,1H),5.60(dd,J=6.1,3.2Hz,1H),4.29(ddd,J=14.1,5.7,3.5Hz,1H),3.83(s,3H),3.58-3.47(m,1H).
实施例12:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2-氟苯基)脲
第一步:2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯的制备
将5H-咪唑并[5,1-a]异吲哚(1.0g,6.41mmol)溶于无水THF(30mL),在-30℃下缓慢滴加LDA(4.8mL,9.61mmol,2M in THF)。滴毕,反应在-30℃搅拌20分钟,缓慢滴入溴乙酸叔丁酯(1.3g,7.05mmol)。反应在-30℃度至0℃下搅拌2小时,LC-MS显示反应完全,反应用饱和NH4Cl(10mL)淬灭。有机相分层干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(250mg)。
第二步:2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸的制备
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(200mg,0.71mmol)溶于三氟乙酸(2mL),二氯甲烷(2mL)中,在室温下搅拌1小时,反应液浓缩,得到粗品2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(150mg)。
第三步:1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2-氟苯基)脲的制
备
将2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(200mg,0.934mmol),4-溴-2-氟苯胺(213mg,1.121mmol),DPPA(308mg,1.119mmol)和三乙胺(142mg,1.403mmol)溶于甲苯(20mL)中氮气保护下回流4小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2-氟苯基)脲(97mg)。
LC-MS:401.0,403.0,tR=2.052min;
1H NMR(400MHz,MeOD)δ8.02-7.84(m,2H),7.62(dd,J=23.6,7.6Hz,2H),7.45(t,J=7.4Hz,1H),7.40-7.10(m,4H),5.49(t,J=4.8Hz,1H),4.12(dd,J=14.4,4.1Hz,1H),3.66(dd,J=14.4,5.8Hz,1H).
实施例13:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2-氟-4-(1-甲基-1H-吡唑-4-基)
苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2-氟苯基)脲(45mg,0.112mmol),1-甲基-1H-吡唑-4-硼酸频哪醇酯(47mg,0.226mmol),Pd(dppf)Cl2(40mg,0.055mmol)和碳酸钾(31mg,0.224mmol)溶于1,4-二氧六环/水(5mL/1mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加20毫升水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(1.1mg)。
LC-MS:403.1,tR=1.885min;
1H NMR(400MHz,MeOD)δ7.93(dq,J=17.3,8.8Hz,3H),7.78(s,1H),7.63(dd,J=22.7,7.5Hz,2H),7.51-7.24(m,4H),7.19(s,1H),5.55-5.46(m,1H),4.12(dd,J=14.3,4.1Hz,1H),3.92(s,3H),3.64(dd,J=14.3,6.1Hz,1H).
实施例14:
1-(4-氰基苯基)-3-((7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
第一步:1-(2-溴-5-氟)苯甲基)-1H-咪唑的制备
将1-溴-4-氟-2-甲苯(5.0g,26.5mmol),溴代丁二酰亚胺(5.65g,31.7mmol),偶氮二异丁腈(400mg)溶于干燥四氯化碳(100mL),在氮气保护下加热回流16小时。反应冷至室温后过滤,滤液加入咪唑(3.65g,52.3mmol)和碳酸钾(5.42g,39.2mmol),在氮气保护下加热回流5小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(50mL),用水(2X40mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-(2-溴-5-氟)苯甲基)-1H-咪唑(5.0g)。
第二步:7-氟-5H-咪唑并[5,1-a]异吲哚的制备
将1-(2-溴-5-氟)苯甲基)-1H-咪唑(1.5g,5.9mmol),醋酸钯(66mg),三苯基膦(154mg)和碳酸钾(1.6g,11.8mmol)溶于DMSO(30mL)中,在氮气保护下加热至140℃搅拌2小时。LC-MS显示反应完全,将反应液浓缩干,剩余物溶于乙酸乙酯(100mL),依次用水(2X100mL),饱和食盐水(50mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到7-氟-5H-咪唑并[5,1-a]异吲哚(0.8g)。
第三步:2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯的制备
将7-氟-5H-咪唑并[5,1-a]异吲哚(0.8g,4.6mmol)溶于无水THF(50mL),在-30℃下缓慢滴加LDA(3.4mL,6.9mmol,2M in THF)。滴毕,在-30℃搅拌15分钟,缓慢滴入溴乙酸叔丁酯(1.4g,6.9mmol)。在-30℃到0℃下搅拌1小时,LC-MS显示反应完全,反应用饱和NH4Cl(20mL)淬灭。有机相分层干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(0.5g)。
第四步:2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸的制备
将2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(400mg,1.4mmol)溶于三氟乙酸(2mL),二氯甲烷(2mL)中,在室温下搅拌1小时,反应液浓缩,得到粗品2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(300mg)。
第五步:1-(4-腈基苯基-3-((7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲的制
备
将2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(300mg,0.71mmol),叠氮磷酸二苯酯(DPPA)(487mg,1.77mmol),三乙胺(0.4mL,2.83mmol)和4-氨基苯乙腈(0.21mg,1.77mmol)溶于无水甲苯(20mL),在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-腈基苯基-3-((7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(0.10mg)。
LC-MS:348.1,tR=1.93min;
1H NMR(400MHz,MeOD)δ7.95(s,1H),7.64(dd,J=8.4,4.9Hz,1H),7.59(d,J=8.8Hz,2H),7.52(d,J=8.8Hz,2H),7.40(dd,J=8.8,2.0Hz,1H),7.20(td,J=9.0,2.3Hz,1H),7.14(s,1H),5.51(t,J=5.1Hz,1H),4.10(dd,J=14.4,4.2Hz,1H),3.70(dd,J=14.4,5.8Hz,1H);
19F NMR(400MHz,MeOD)δ-116.1.
实施例15:
1-(4-氰基苯基)-3-((8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
第一步:1-(2-溴-4-氟)苯甲基)-1H-咪唑的制备
将2-溴-4-氟-1-甲苯(5.0g,26.5mmol),溴代丁二酰亚胺(5.65g,31.7mmol),偶氮二异丁腈(400mg)溶于干燥四氯化碳(100mL),在氮气保护下加热回流16小时。反应冷至室温后过滤,滤液加入咪唑(3.65g,52.3mmol)和碳酸钾(5.42g,39.2mmol),在氮气保护下加热回流5小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(50mL),用水(2X40mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-(2-溴-4-氟)苯甲基)-1H-咪唑(4.0g)。
第二步:8-氟-5H-咪唑并[5,1-a]异吲哚的制备
将1-(2-溴-4-氟)苯甲基)-1H-咪唑(3g,11.0mmol),醋酸钯(132mg),三苯基膦(308mg)和碳酸钾(3.2g,23.6mmol)溶于DMSO(50mL),在氮气保护下加热至140℃搅拌2小时。LC-MS显示反应完全,将反应液浓缩干,剩余物溶于乙酸乙酯(100mL),依次用水(2X100mL),饱和食盐水(50mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到8-氟-5H-咪唑并[5,1-a]异吲哚(1.6g)。
第三步:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯的制备
将8-氟-5H-咪唑并[5,1-a]异吲哚(1g,5.8mmol)溶于无水THF(50mL),在-30℃下缓慢滴加LDA(4.3mL,8.6mmol,2M in THF)。滴毕,在-30℃搅拌15分钟,缓慢滴入溴乙酸叔丁酯(1.6g,8.6mmol)。在-30℃到0℃下搅拌1小时,LC-MS显示反应完全,反应用饱和NH4Cl(20mL)淬灭。有机相分层干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(0.8g)。
第四步:2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸的制备
将2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸叔丁酯(400mg,1.4mmol)溶于三氟乙酸(2mL),二氯甲烷(2mL)中,在室温下搅拌1小时,反应液浓缩,得到粗品2-(8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(300mg)。
第五步:1-(4-腈基苯基-3-((8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲的制
备
将2-(7-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(300mg,0.71mmol),叠氮磷酸二苯酯(DPPA)(487mg,1.77mmol),三乙胺(0.4mL,2.83mmol),4-氨基苯乙腈(0.21mg,1.77mmol)溶于无水甲苯(20mL),在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-腈基苯基-3-((8-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(0.10mg)。
LC-MS:348.1,tR=1.90min;
1H NMR(400MHz,MeOD)δ7.98(s,1H),7.70-7.55(m,3H),7.55-7.48(m,2H),7.41(dd,J=8.7,2.4Hz,1H),7.22(s,1H),7.15-7.03(m,1H),5.49(t,J=4.8Hz,1H),4.11(dd,J=14.4,4.1Hz,1H),3.66(dd,J=14.4,5.9Hz,1H);19F NMR(400MHz,MeOD)δ-115.0(s,1H).
实施例16:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)
脲
将1-((6-氯-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)脲(40mg,0.095mmol)溶于8mL甲醇,然后加入10mg Pd-C,在氢气下室温反应3天。LC-MS检测反应完全。反应液过滤,旋干滤液得粗产品,粗产品经快速柱层析得到淡黄色固体1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-甲基-1H-吡唑-4-基)苯基)脲(15mg)。
LC-MS:385.1,tR=1.824min;
1H NMR(400MHz,MeOD)δ8.07(s,1H),7.72(d,J=12.9Hz,2H),7.64(d,J=7.3Hz,2H),7.57(d,J=7.6Hz,1H),7.50-7.29(m,6H),7.23(s,1H),5.57-5.48(m,1H),4.10(dd,J=14.4,4.3Hz,1H),3.93(s,3H),3.46(dd,J=14.4,7.1Hz,1H).
实施例17:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-甲氧苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(150mg,0.70mmol),叠氮磷酸二苯酯(DPPA)(400mg,1.42mmol),三乙胺(180mg,1.42mmol)和3-甲氧基-4-溴苯胺(284mg,1.42mmol)溶于无水甲苯(20mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-甲氧苯基)脲(19.0mg)。
LC-MS:413.0,tR=2.052min;
1H NMR(400MHz,MeOD)δ7.95(s,1H),7.62(dd,J=22.4,7.6Hz,2H),7.45(t,J=7.5Hz,1H),7.40-7.31(m,2H),7.28(d,J=2.1Hz,1H),7.18(s,1H),6.70(dd,J=8.5,2.2Hz,1H),5.56-5.43(m,1H),4.10(dd,J=14.3,4.2Hz,1H),3.85(s,3H),3.60(dd,J=14.4,6.3Hz,1H).
实施例18:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-甲氧基-4-(1-甲基-1H-吡唑-
4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-甲氧苯基)脲(30mg,0.07mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(32mg,0.15mmol),Pd(dppf)Cl2(5mg),碳酸钾(40mg,0.28mmol)溶于二氧六环(3mL)和水(1.5mL),在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),用水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-甲氧基-4-(1-甲基-1H-吡唑-4-基)苯基)脲(3.4mg)。
LC-MS:415.1,tR=2.052min;
1H NMR(400MHz,MeOD)δ7.95(s,2H),7.82(s,1H),7.62(dd,J=21.4,6.9Hz,2H),7.50-7.32(m,2H),7.26(s,1H),7.19(s,1H),6.79(d,J=7.7Hz,1H),5.49(s,1H),4.10(d,J=13.8Hz,1H),3.91(s,1H),3.90(s,1H),3.71-3.52(m,1H).
实施例19:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(4-甲基哌嗪-1-基)苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(79mg,0.37mmol)溶于8mL甲苯,然后加入DPPA(112mg,0.407mmol),三乙胺(56mg,0.553mmol)和4-(4-甲基哌嗪-1-基)苯胺(78mg,0.407mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(4-甲基哌嗪-1-基)苯基)脲(15mg)。
LC-MS:403.1,tR=1.448min;
1H NMR(400MHz,MeOD)δ7.93(s,1H),7.63(d,J=7.6Hz,1H),7.56(d,J=7.6Hz,1H),7.44(t,J=7.5Hz,1H),7.34(td,J=7.6,1.0Hz,1H),7.18(dd,J=9.4,2.8Hz,3H),6.97-6.83(m,2H),5.45(dd,J=6.1,4.6Hz,1H),4.04(dd,J=14.3,4.3Hz,1H),3.53(dd,J=14.3,6.6Hz,1H),3.22-3.03(m,4H),2.77-2.61(m,4H),2.39(s,3H).
实施例20:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(4-甲基哌嗪-1-基)苯
基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(79mg,0.37mmol)溶于8mL甲苯,然后加入DPPA(112mg,0.407mmol),三乙胺(56mg,0.553mmol)和3-氟-4-(4-甲基哌嗪-1-基)苯胺(85mg,0.407mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(4-甲基哌嗪-1-基)苯基)脲(20mg)。
LC-MS:421.1,tR=1.564min;
1H NMR(400MHz,MeOD)δ7.93(s,1H),7.64(d,J=7.6Hz,1H),7.58(d,J=7.6Hz,1H),7.44(t,J=7.5Hz,1H),7.35(td,J=7.6,1.0Hz,1H),7.26(dd,J=14.6,2.1Hz,1H),7.17(s,1H),6.97-6.86(m,2H),5.49-5.39(m,1H),4.07(dd,J=14.4,4.3Hz,1H),3.57(dd,J=14.3,6.4Hz,1H),3.33(dt,J=3.3,1.6Hz,2H),3.05(s,4H),2.65(s,4H),2.38(s,3H).
实施例21:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-苯甲基-1H-吡唑-4-基)苯
基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(79.2mg,0.37mmol)溶于8mL甲苯,然后加入DPPA(112mg,0.407mmol),三乙胺(56mg,0.555mmol)和4-(1-苯甲基-1H-吡唑-4-基)苯胺(101mg,0.407mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到白色固体(20mg)。
LC-MS:416.2,tR=2.124min;
1H NMR(400MHz,MeOD)δ7.92-7.12(m,17H),5.45(s,1H),5.33(s,2H),4.14-3.96(m,1H),3.39(dd,J=14.4,6.6Hz,1H).
实施例22:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲
2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(300mg,1.4mmol),4-溴-3-氟苯胺(320mg,1.684mmol),DPPA(465mg,1.690mmol)和三乙胺(215mg,2.125mmol)于甲苯(20mL)中氮气保护下回流4小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲的制备(330mg)。
LC-MS:401.0,tR=2.113min;
1H NMR(400MHz,MeOD)δ7.95(s,1H),7.65(d,J=7.6Hz,1H),7.59(d,J=7.6Hz,1H),7.52-7.32(m,4H),7.18(s,1H),6.93(dd,J=8.4,2.0Hz,1H),5.57-5.44(m,1H),4.11(dd,J=14.4,4.2Hz,1H),3.62(dd,J=14.4,6.2Hz,1H);
19F NMR(400MHz,MeOD)δ-108.8.
实施例23:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-甲基-1H-吡唑-4-基)
苯基)脲
制备方法同实施例18。
LC-MS:403.1,tR=1.920min;
1H NMR(400MHz,MeOD)δ7.99(s,1H),7.95-7.93(m,1H),7.81(s,1H),7.66(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.55-7.42(m,2H),7.41-7.34(m,2H),7.19(s,1H),7.00(dd,J=8.5,2.1Hz,1H),5.57-5.47(m,1H),4.12(dd,J=14.4,4.2Hz,1H),3.94(s,2H),3.62(dd,J=14.4,6.2Hz,1H);
19F NMR(400MHz,MeOD)δ-115.8(s,1H).
实施例24:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基-3-氟苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(79mg,0.37mmol)溶于8mL甲苯,然后加入DPPA(112mg,0.407mmol),三乙胺(56mg,0.553mmol)和4-氨基-2-氟苯甲腈(55mg,0.407mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基-3-氟苯基)脲(10mg)。
LC-MS:348.1,tR=1.979min;
1H NMR(400MHz,MeOD)δ7.98(s,1H),7.72-7.51(m,4H),7.45(t,J=7.4Hz,1H),7.41-7.33(m,1H),7.19(s,1H),7.11(dd,J=8.6,1.9Hz,1H),5.55-5.45(m,1H),4.14(dd,J=14.4,4.1Hz,1H),3.66(dd,J=14.4,5.9Hz,1H).
实施例25:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氯-4-氰基苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(79mg,0.37mmol)溶于8mL甲苯,然后加入DPPA(112mg,0.407mmol),三乙胺(56mg,0.553mmol)和4-氨基-2-氯苯甲腈(62mg,0.407mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氯-4-氰基苯基)脲(10mg)。
LC-MS:364.0,tR=2.008min;
1H NMR(400MHz,MeOD)δ9.16(s,1H),7.80(ddd,J=26.8,8.8,3.3Hz,4H),7.67-7.53(m,3H),7.26(dd,J=8.6,1.9Hz,1H),5.85(s,1H),4.46-4.36(m,1H),3.84-3.74(m,1H).
实施例26:
1-(4-(1H-咪唑-1-基)苯基)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(100mg,0.43mmol),叠氮磷酸二苯酯(DPPA)(250mg,0.92mmol),三乙胺(232mg,2.32mmol),4-(1H-咪唑-1-基)苯胺(150mg,0.92mmol)溶于无水甲苯(10mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-(1H-咪唑-1-基)苯基)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(3.4mg)。
LC-MS:371.0,tR=1.468min;
1H NMR(400MHz,MeOD)δ8.05(s,1H),7.96(s,1H),7.63(dd,J=19.9,7.5Hz,2H),7.48(dt,J=16.7,5.1Hz,6H),7.36(t,J=7.5Hz,1H),7.16(d,J=19.2Hz,2H),5.58-5.45(m,1H),4.12(dd,J=14.4,4.2Hz,1H),3.63(dd,J=14.4,6.3Hz,1H).
实施例27:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3,5-二氟苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg,0.93mmol),叠氮磷酸二苯酯(DPPA)(520mg,1.86mmol),三乙胺(190mg,1.86mmol),4-溴-3,5-二氟苯胺(400mg,1.86mmol)溶于无水甲苯(10mL)中,在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3,5-二氟苯基)脲(3.0mg)。
LC-MS:418.2,tR=2.259min;
1H NMR(400MHz,MeOD)δ7.95(s,1H),7.62(dd,J=21.3,7.5Hz,2H),7.41(dt,J=35.5,7.4Hz,2H),7.24-7.06(m,3H),5.58-5.45(m,1H),4.11(dd,J=14.3,4.1Hz,1H),3.63(dd,J=14.4,6.1Hz,1H).
实施例28:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3,5-二氟-4-(1-甲基-1H-吡唑-
4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3,5-二氟苯基)脲(30mg,0.07mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(32mg,0.15mmol),Pd(dppf)Cl2(5mg),碳酸钾(20mg,0.14mmol)溶于二氧六环(3mL)和水(1.5mL)混合物,在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),用水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(2.0mg)。
LC-MS:421.1,tR=1.970min;
1H NMR(400MHz,MeODδ7.96(d,J=5.4Hz,2H),7.83(s,1H),7.62(dd,J=20.2,7.2Hz,2H),7.41(dt,J=34.6,7.3Hz,2H),7.26-7.01(m,3H),5.50(s,1H),4.11(d,J=11.2Hz,1H),3.95(s,3H),3.62(dd,J=14.3,6.1Hz,1H).
实施例29:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-溴-4-氟苯基)脲
制备同实施例27。
LC-MS:401.0,tR=2.083min;
1H NMR(400MHz,MeOD)δ7.94(s,1H),7.72(dd,J=6.2,2.5Hz,1H),7.64(d,J=7.5Hz,1H),7.58(d,J=7.6Hz,1H),7.45(t,J=7.5Hz,1H),7.36(t,J=7.5Hz,1H),7.23-7.15(m,2H),7.08(t,J=8.7Hz,1H),5.52-5.45(m,1H),4.09(dd,J=14.4,4.2Hz,1H),3.60(dd,J=14.4,6.2Hz,1H);
19F NMR(400MHz,MeOD)δ-118.2.
实施例30:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氯苯基)脲
制备同实施例27。
LC-MS:419.0,tR=2.252min;
1H NMR(400MHz,MeOD)δ7.95(s,1H),7.70(d,J=2.5Hz,1H),7.65(d,J=7.5Hz,1H),7.60(d,J=7.7Hz,1H),7.50(d,J=8.8Hz,1H),7.45(t,J=7.5Hz,1H),7.36(t,J=7.1Hz,1H),7.18(s,1H),7.09(dd,J=8.8,2.5Hz,1H),5.52-5.47(m,1H),4.11(dd,J=14.4,4.2Hz,1H),3.62(dd,J=14.4,6.2Hz,1H).
实施例31:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氯-4-(1-甲基-1H-吡唑-4-基)
苯基)脲
制备操作同实施例28。
LC-MS:419.0,tR=2.416min;
1H NMR(400MHz,MeOD)δ7.84(d,J=9.0Hz,2H),7.64(s,1H),7.53(d,J=7.5Hz,1H),7.51-7.46(m,2H),7.33(t,J=7.4Hz,1H),7.26(dd,J=14.0,8.0Hz,2H),7.10-7.04(m,2H),5.43-5.34(m,1H),3.99(dd,J=14.4,4.1Hz,1H),3.83(s,3H),3.50(dd,J=14.3,6.2Hz,1H).
实施例32:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2-甲氧苯基)脲
制备同实施例27。
LC-MS:414.0,tR=2.140min;
1H NMR(400MHz,MeOD)δ7.94(s,1H),7.89(d,J=8.7Hz,1H),7.65(d,J=7.6Hz,1H),7.59(d,J=7.6Hz,1H),7.45(t,J=7.5Hz,1H),7.36(t,J=7.6Hz,1H),7.17(s,1H),7.08(d,J=2.1Hz,1H),7.01(dd,J=8.6,2.1Hz,1H),5.56-5.42(m,1H),4.09(dd,J=14.4,4.2Hz,1H),3.86(s,3H),3.62(dd,J=14.4,6.1Hz,1H).
实施例33:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2-甲氧基-4-(1-甲基-1H-吡唑-
4-基)苯基)脲
制备方法同实施例28。
LC-MS:415.1,tR=1.888min;
1H NMR(400MHz,d6-DMSO)δ8.06(s,2H),8.00(d,J=8.3Hz,1H),7.89(s,1H),7.80(s,1H),7.62(d,J=7.6Hz,1H),7.56(d,J=7.5Hz,1H),7.41(t,J=7.4Hz,1H),7.30(t,J=7.4Hz,1H),7.17-7.09(m,2H),7.03(dd,J=8.4,1.6Hz,1H),6.98(t,J=5.9Hz,1H),5.43-5.40(m,1H),4.00-3.89(m,1H),3.86(s,3H),3.84(s,3H),3.65-3.47(m,1H).
实施例34:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2-氯-4-氰基苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(150mg,0.7mmol)溶于10mL甲苯,然后加入DPPA(212mg,0.77mmol),三乙胺(106mg,1.05mmol)和4-氨基-3-氯苯甲腈(118mg,0.77mmol)。在氮气保护下加热回流2小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2-氯-4-氰基苯基)脲(10mg)。
LC-MS:364.0,tR=1.981min;
1H NMR(400MHz,MeOD)δ9.23(s,1H),8.27(dd,J=8.7,2.1Hz,1H),7.91-7.85(m,1H),7.76(t,J=5.0Hz,3H),7.66-7.51(m,3H),5.89(t,J=3.8Hz,1H),4.49(dd,J=14.9,3.6Hz,1H),3.88(dd,J=14.9,4.3Hz,1H).
实施例35:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-溴苯基)脲
制备方法同实施例27。
LC-MS:384.0,tR=2.081min;
1H NMR(400MHz,MeOD)δ7.84(s,1H),7.62-7.50(m,2H),7.47(d,J=7.6Hz,1H),7.33(t,J=7.4Hz,1H),7.28-7.18(m,1H),7.12-6.94(m,4H),5.43-5.31(m,1H),3.98(dd,J=14.4,4.2Hz,1H),3.49(dd,J=14.4,6.2Hz,1H).
实施例36:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-(1-甲基-1H-吡唑-4-基)苯基)
脲
制备方法同实施例28。
LC-MS:385.1,tR=1.867min;
1H NMR(400MHz,d6-DMSO)δ8.59(s,1H),8.03(s,1H),7.90(s,1H),7.73(s,1H),7.63(d,J=7.5Hz,1H),7.56(dd,J=6.5,5.1Hz,2H),7.42(t,J=7.5Hz,1H),7.36-7.27(m,1H),7.23-7.13(m,3H),7.12-7.05(m,1H),6.37(t,J=5.9Hz,1H),5.52-5.37(m,1H),3.99-3.87(m,1H),3.86(s,3H),3.59-3.46(m,1H).
实施例37:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基-2-氟苯基)脲
2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(100mg,0.467mmol),4-溴-2-氟苯胺(76mg 0.558mmol),DPPA(154mg,0.560mmol),三乙胺(75mg,0.741mmol)于甲苯(10mL),氮气保护下回流4小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氰基-2-氟苯基)脲(5.6mg)。
LC-MS:348.1,tR=1.943min;
1H NMR(400MHz,MeOD)δ9.21(s,1H),8.25(s,1H),7.68(dd,J=104.4,48.2Hz,7H),5.88(s,1H),4.46(s,2H),3.86(s,1H).
实施例38:
1-(4-(1H-吡唑-1-基)苯基)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲
2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(100mg,0.467mmol),4-(1H-吡唑-1-基)苯胺(90mg0.565mmol),DPPA(155mg,0.563mmol),三乙胺(75mg,0.741mmol)于甲苯(10mL),氮气保护下回流4小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-(4-(1H-吡唑-1-基)苯基)-3-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(21mg)。
LC-MS:371.0,tR=1.902min;
1H NMR(400MHz,MeOD)δ8.13(s,2H),7.51(dd,J=113.4,52.2Hz,10H),6.51(s,1H),5.55(s,1H),4.14(s,1H),3.65(s,1H).
实施例39:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2,5-二氟苯基)脲
将2-(5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(200mg,0.93mmol),叠氮磷酸二苯酯(DPPA)(520mg,1.86mmol),三乙胺(190mg,1.86mmol),4-溴-2,5-二氟苯胺(400mg,1.86mmol)溶于无水甲苯(10mL),在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2,5-二氟苯基)脲(3.0mg)。
LC-MS:421.0,tR=2.221min;
1H NMR(400MHz,MeOD)δ8.04(dd,J=11.1,7.0Hz,1H),7.95(s,1H),7.62(dd,J=21.4,7.6Hz,2H),7.45(t,J=7.4Hz,1H),7.38(dt,J=14.1,7.0Hz,2H),7.17(s,1H),5.50(t,J=4.7Hz,1H),4.15(dd,J=14.4,4.1Hz,1H),3.70(dd,J=14.5,5.6Hz,1H).
实施例40:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡唑-
4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2,5-二氟苯基)脲(30mg,0.07mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(32mg,0.15mmol),Pd(dppf)Cl2(5mg),碳酸钾(20mg,0.14mmol)溶于二氧六环(3mL),水(0.5mL),在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),用水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(2.0mg)。
LC-MS:421.0,tR=1.963min;
1H NMR(400MHz,MeOD)δ7.96(s,2H),7.91(dd,J=13.1,6.9Hz,1H),7.83(s,1H),7.63(dd,J=20.3,7.5Hz,2H),7.45(t,J=7.5Hz,1H),7.38(dd,J=16.0,7.7Hz,2H),7.18(s,1H),5.51(s,1H),4.15(dd,J=14.7,4.0Hz,1H),3.94(s,3H),3.69(dd,J=14.3,5.9Hz,1H).
实施例41和42:
(R)-1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡
唑-4-基)苯基)脲和(S)-1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-
甲基-1H-吡唑-4-基)苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(420mg)经过手性拆分得到(R-1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(176mg)和(S)-1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)脲(202mg)。拆分条件如下:
实施例43:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-(三氟甲基)苯基)脲
制备方法同实施例39。
LC-MS:325.0,tR=2.376min;
1H NMR(400MHz,MeOD)δ8.21(s,1H),7.82(d,J=2.4Hz,1H),7.63(d,J=8.4Hz,2H),7.52(d,J=8.8Hz,1H),7.45(dt,J=14.9,7.2Hz,2H),7.37(dd,J=8.7,2.6Hz,1H),7.26(s,1H),5.59-5.49(m,1H),4.21(dd,J=14.4,4.0Hz,1H),3.64(dd,J=14.5,5.8Hz,1H);
19F NMR(400MHz,MeOD)δ-64.1,-76.9。
实施例44:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-氟-3-(1-甲基-1H-吡唑-4-基)
苯基)脲
制备方法同实施例40。
LC-MS:403.1,tR=2..536min;
1H NMR(400MHz,DMSO)δ8.61(s,1H),8.05(d,J=1.9Hz,1H),7.91(s,1H),7.74(s,1H),7.66-7.60(m,2H),7.56(d,J=7.5Hz,1H),7.42(t,J=7..4Hz,1H),7.31(t,J=7.5Hz,1H),7.23-7.04(m,3H),6.37(t,J=5.8Hz,1H),5.51 5.37(m,1H),3.93-3.84(m,1H),3.86(s,3H),3.59-3.46(m,1H);
19F NMR(400MHz,DMSO)δ-124.1.
实施例45:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-乙基-1H-吡唑-4-基)
苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(100mg,0.249mmol),1-乙基-1H-吡唑-4-硼酸频哪醇酯(110mg,0.495mmol),Pd(dppf)Cl2(91mg,0.124mmol)和碳酸钾(69mg,0.499mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-乙基-1H-吡唑-4-基)苯基)脲(33.4mg)。
LC-MS:417.1,tR=1.998min;
1H NMR(400MHz,MeOD)δ7.96(s,2H),7.81(s,1H),7.61(dd,J=20.9,7.5Hz,2H),7.54-7.30(m,4H),7.17(s,1H),6.99(dd,J=8.5,1.6Hz,1H),5.47(s,1H),4.22(q,J=7.3Hz,2H),4.09(dd,J=14.4,3.8Hz,1H),3.59(dd,J=14.3,6.0Hz,1H),1.48(t,J=7.3Hz,3H).
实施例46:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(100mg,0.249mmol),1H-吡唑-4-硼酸频哪醇酯(97mg,0.5mmol),Pd(dppf)Cl2(91mg,0.124mmol)和碳酸钾(69mg,0.499mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)脲(16.7mg)。
LC-MS:389.2,tR=1.793min;
1H NMR(400MHz,MeOD)δ7.96(d,J=13.4Hz,3H),7.76-7.30(m,6H),7.19(s,1H),7.01(d,J=8.0Hz,1H),5.51(s,1H),4.11(d,J=11.6Hz,1H),3.62(dd,J=14.5,5.7Hz,1H).
实施例47:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-甲氧基乙基)-1H-
吡唑-4-基)苯基)脲
第一步:1-(2-甲氧基乙基)-1H-吡唑-4-硼酸频哪醇酯的制备
1H-吡唑-4-硼酸频哪醇酯(1.0g,5.155mmol),2-溴乙基甲基醚(0.788g,5.669mmol)和碳酸铯(5.04g,15.469mmol)溶于乙腈(20mL),氮气保护下50℃搅拌过夜,过滤,浓缩至干得1-(2-甲氧基乙基)-1H-吡唑-4-硼酸频哪醇酯(1.310g)。
LC-MS:253.1,tR=2.373min.
第二步:1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-甲氧基乙
基)-1H-吡唑-4-基)苯基)脲的制备
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(129mg,0.322mmol),1-(2-甲氧基乙基)-1H-吡唑-4-硼酸频哪醇酯(162mg,0.643mmol),Pd(dppf)Cl2(118mg,0.161mmol)和碳酸钾(89mg,0.644mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)苯基)脲(53.0mg)。
LC-MS:447.1,tR=1.912min;
1H NMR(400MHz,CDCl3)δ9.75(s,1H),8.10(s,1H),7.79(d,J=4.2Hz,2H),7.64-7.31(m,7H),7.21(s,1H),7.09(d,J=8.1Hz,1H),6.68(s,1H),5.60(d,J=7.2Hz,1H),4.30(s,3H),3.78(d,J=5.0Hz,3H),3.32(d,J=14.5Hz,3H).
实施例48:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-异丙基-1H-吡唑-4-
基)苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(120mg,0.299mmol),1-异丙基-1H-吡唑-4-硼酸频哪醇酯(141mg,0.597mmol),Pd(dppf)Cl2(109mg,0.149mmol)和碳酸钾(83mg,0.601mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-异丙基-1H-吡唑-4-基)苯基)脲(14.0mg)。
LC-MS:431.2,tR=2.101min;
1H NMR(400MHz,MeOD)δ9.00(s,1H),7.98(s,1H),7.92-7.07(m,8H),6.95(d,J=7.9Hz,1H),6.40(s,1H),5.80(s,1H),4.57(s,1H),4.36(d,J=15.1Hz,1H),3.77(s,1H),1.31(s,6H).
实施例49:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-异丁基-1H-吡唑-4-
基)苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)脲(12mg,0.031mmol),异丁基溴(8.5mg,0.062mmol)和碳酸铯(30mg,0.092mmol)于2mL乙腈中氮气保护下50℃搅拌过夜,过滤,滤液柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-异丁基-1H-吡唑-4-基)苯基)脲(7.3mg)。
LC-MS:445.1,tR=2.219min;
1H NMR(400MHz,MeOD)δ7.86(s,2H),7.73(s,1H),7.52(dd,J=18.2,7.6Hz,2H),7.45-7.21(m,4H),7.07(s,1H),6.93(dd,J=8.4,2.0Hz,1H),5.47-5.33(m,1H),3.98(dd,J=14.3,4.3Hz,1H),3.89(d,J=7.3Hz,2H),3.50(dd,J=14.3,6.5Hz,1H),2.16-2.07(m,1H),0.83(t,J=5.8Hz,6H).
实施例50:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-异丁基-1H-吡
唑-4-基)苯基)脲
第一步:5-氯-2-氟-4-(1-异丁基-1H-吡唑-4-基)苯胺的制备
4-溴-5-氯-2-氟苯胺(100mg,0.446mmol),1-异丁基-1H-吡唑-4-硼酸频哪醇酯(223mg,0.891mmol),Pd(dppf)Cl2(163mg,0.223mmol)和碳酸钾(123mg,0.890mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得5-氯-2-氟-4-(1-异丁基-1H-吡唑-4-基)苯胺(67.0mg)。
LC-MS:268.1,270.1,tR=2.712min.
第二步:1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-异丁
基-1H-吡唑-4-基)苯基)脲的制备
2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(45mg,0.209mmol),5-氯-2-氟-4-(1-异丁基-1H-吡唑-4-基)苯胺(67mg,0.250mmol),DPPA(69mg,0.251mmol)和三乙胺(32mg,316mol)于甲苯(10mL)保护下回流5小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-异丁基-1H-吡唑-4-基)苯基)脲(9mg)。
LC-MS:479.2.0,481.1,tR=2.310min;
1H NMR(400MHz,MeOD)δ8.11(s,1H),7.91(d,J=29.2Hz,2H),7.73(s,1H),7.53(d,J=19.0Hz,2H),7.27(dd,J=40.6,22.5Hz,3H),7.08(s,1H),5.41(s,1H),4.05(d,J=11.8Hz,1H),3.91(s,2H),3.59(d,J=9.4Hz,1H),2.12(s,1H),0.85(d,J=3.7Hz,6H).
实施例51:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-环丁基甲基-
1H-吡唑-4-基)苯基)脲
第一步:1-环丁基甲基-1H-吡唑-4-硼酸频哪醇酯的制备
1H-吡唑-4-硼酸频哪醇酯(500mg,2.577mmol),环丁基甲基溴(768mg,5.153mmol)和碳酸铯(2.520g,7.734mmol)溶于乙腈(10mL),氮气保护下50℃搅拌过夜,过滤,浓缩至干得1-环丁基甲基-1H-吡唑-4-硼酸频哪醇酯(405mg)。
第二步:5-氯-2-氟-4-(1-环丁基甲基-1H-吡唑-4-基)苯胺的制备
4-溴-5-氯-2-氟苯胺(86mg,0.383mmol),1-环丁基甲基-1H-吡唑-4-硼酸频哪醇酯(200mg,0.763mmol),Pd(dppf)Cl2(140mg,0.191mmol)和碳酸钾(105mg,0.760mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得5-氯-2-氟-4-(1-环丁基甲基-1H-吡唑-4-基)苯胺(47.0mg)。
LC-MS:280.0,282.1,tR=2.787min.
第三步:1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-环丁基
甲基-1H-吡唑-4-基)苯基)脲的制备
2-(5H-咪唑并[5,1-a]异吲哚-5基)乙酸(30mg,0.140mmol),5-氯-2-氟-4-(1-环丁基甲基-1H-吡唑-4-基)苯胺(47mg,0.168mmol),DPPA(46mg,0.167mmol)和三乙胺(21mg,0.208mmol)于甲苯(10mL)中氮气保护下回流5小时,冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-环丁基甲基-1H-吡唑-4-基)苯基)脲(1.6mg)。
LC-MS:491.2,493.1,tR=2.430min;
1H NMR(400MHz,MeOD)δ8.19(d,J=7.6Hz,1H),8.03(s,2H),7.80(s,1H),7.64(dd,J=23.4,7.5Hz,2H),7.43(dt,J=30.5,7.4Hz,2H),7.30(d,J=12.2Hz,2H),5.53(s,1H),4.20(d,J=7.3Hz,2H),3.71(dd,J=14.5,5.6Hz,1H),2.87(dt,J=15.0,7.5Hz,1H),2.24-2.17(m,1H),2.09(dd,J=16.8,8.2Hz,3H),1.89(ddd,J=25.6,14.0,7.8Hz,3H).
实施例52和53:2-(4-(4-(3-(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟
苯基)-1H-吡唑-1-基)乙基乙酸酯和1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-
4-(1-(2-羟乙基)-1H-吡唑-4-基)苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)脲(74mg),2-溴乙基乙酸酯(34mg,0.204mmol)和碳酸铯(167mg,0.513mmol)于乙腈(10mL)中氮气保护下50℃搅拌过夜,过滤,滤液柱层析纯化得到2-(4-(4-(3-(5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟苯基)-1H-吡唑-1-基)乙基乙酸酯(5.2mg)和1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-羟乙基)-1H-吡唑-4-基)苯基)脲(3.1mg)。
实施例52:
LC-MS:475.1,tR=1.936min;
1H NMR(400MHz,CDCl3)δ9.35(s,1H),9.02(s,1H),8.00-7.31(m,8H),7.19(s,1H),5.65(s,1H),5.35(s,1H),4.41(d,J=29.1Hz,3H),3.69(d,J=46.1Hz,4H),2.04(s,3H).
实施例53:
LC-MS:433.1,tR=2.780min;
1H NMR(400MHz,MeOD)δ8.00(s,2H),7.85(s,1H),7.65(d,J=21.0Hz,2H),7.44(d,J=35.4Hz,5H),7.00(s,1H),5.52(s,1H),4.27(s,2H),4.14(d,J=11.6Hz,1H),3.92(s,2H),3.65(s,1H).
实施例54:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-异丁基-1H-吡
唑-4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-2,5-二氟苯基)脲(30mg,0.07mmol),1-异丁基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(32mg,0.15mmol),Pd(dppf)Cl2(5mg)和碳酸钾(20mg,0.14mmol)溶于二氧六环(3mL)和水(0.5mL),在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-异丁基-1H-吡唑-4-基)苯基)脲(2.2mg)。
LC-MS:463.1,tR=2.263min;
1H NMR(400MHz,MeOD)δ8.01-7.73(m,1H),7.54(dd,J=21.2,7.5Hz,1H),7.43-7.24(m,1H),7.11(s,1H),5.41(s,1H),4.06(dd,J=14.3,3.7Hz,1H),3.90(d,J=7.3Hz,1H),3.60(dd,J=14.3,5.6Hz,1H),2.12(dt,J=13.5,6.8Hz,1H),0.83(t,J=8.5Hz,2H).
实施例55:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-(吡咯烷-1-基)乙
基)-1H-吡唑-4-基)苯基)脲
制备操作同实施例48。
LC-MS:486.1,tR=2.153min;
1H NMR(400MHz,MeOD)δ7.96(d,J=1.4Hz,1H),7.88(s,1H),7.81(s,1H),7.56(d,J=7.5Hz,1H),7.51(d,J=7.5Hz,1H),7.42(t,J=8.6Hz,1H),7.36(t,J=7.5Hz,1H),7.32(d,J=2.0Hz,1H),7.31-7.25(m,2H),7.10(s,1H),6.92(dd,J=8.5,2.0Hz,1H),5.46-5.37(m,1H),4.38(t,J=6.3Hz,2H),4.03(dd,J=14.4,4.2Hz,1H),3.53(dd,J=14.4,6.2Hz,1H),3.34-3.24(m,2H),1.90-1.80(m,4H),1.30-1.20(m,4H);
19F NMR(400MHz,MeOD)δ-115.7.
实施例56:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-吗啡啉乙基)-1H-
吡唑-4-基)苯基)脲
制备操作同实施例48。
LC-MS:502.1,tR=2.014min;
1H NMR(400MHz,MeOD)δ9.18(s,1H),8.08(s,1H),7.93(s,1H),7.90-7.82(m,1H),7.75(d,J=8.0Hz,2H),7.60(dd,J=5.5,3.2Hz,2H),7.50(t,J=8.6Hz,1H),7.38(dd,J=13.7,1.5Hz,1H),6.98(d,J=8.4Hz,1H),5.86(t,J=4.0Hz,1H),4.68(t,J=5.8Hz,2H),4.37(dd,J=14.8,3.5Hz,1H),4.20-3.80(m,4H),3.82-3.69(m,3H),3.66-3.31(m,4H);
19F NMR(400MHz,MeOD)δ-115.6.
实施例57:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-(环丙基甲基)-1H-吡唑-4-
基)-3-氟苯基)脲
制备操作同实施例48。
LC-MS:443.1,tR=2.067min;
1H NMR(400MHz,MeOD)δ7.93(d,J=1.4Hz,1H),7.87(s,1H),7.74(s,1H),7.56(d,J=7.5Hz,1H),7.51(d,J=7.6Hz,1H),7.42(t,J=8.6Hz,1H),7.36(t,J=7.5Hz,1H),7.29(dt,J=14.4,5.0Hz,2H),7.09(s,1H),6.91(dd,J=8.5,2.0Hz,1H),5.47-5.38(m,1H),4.02(dd,J=14.4,4.2Hz,1H),3.95(d,J=7.1Hz,2H),3.53(dd,J=14.4,6.2Hz,1H),1.25(ddd,J=12.6,7.6,4.8Hz,1H),0.62-0.49(m,2H),0.35(q,J=4.8Hz,2H);
19F NMR(400MHz,MeOD)δ-115.8.
实施例58和59:
2-(4-(4-(3((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟苯基)-1H-吡唑-
1-基)乙酸乙酯和2-(4-(4-(3((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟苯基)-
1H-吡唑-1-基)乙酸
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(120mg,0.299mmol),1-乙酸乙酯-1H-吡唑-4-硼酸频哪醇酯(191mg),Pd(dppf)Cl2(109mg,0.149mmol)和碳酸钾(83mg,0.601mmol)于1,4-二氧六环/水(10mL/2mL)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得2-(4-(4-(3((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟苯基)-1H-吡唑-1-基)乙酸乙酯(12.3mg)和2-(4-(4-(3((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲基)-2-氟苯基)-1H-吡唑-1-基)乙酸(3.8mg)。
实施例58:
LC-MS:475.1,tR=2.030min;
1H NMR(400MHz,MeOD)δ7.87(d,J=1.5Hz,2H),7.74(s,1H),7.51(d,J=7.5Hz,1H),7.45(d,J=7.5Hz,1H),7.37(t,J=8.6Hz,1H),7.30(dd,J=14.0,6.5Hz,2H),7.25-7.18(m,1H),6.86(d,J=8.3Hz,1H),5.34(s,1H),4.91(s,2H),4.10(q,J=7.1Hz,2H),3.97(d,J=11.5Hz,1H),3.47(dd,J=14.4,6.1Hz,1H),1.14(d,J=7.2Hz,3H);
19F NMR(400MHz,MeOD)δ-115.6.
实施例59:
LC-MS:447.1,tR=1.770min;
1H NMR(400MHz,d6-DMSO)δ8.97(s,1H),8.79(s,1H),8.04(d,J=1.7Hz,1H),7.90-7.75(m,2H),7.70(d,J=9.6Hz,2H),7.52(dt,J=13.9,6.3Hz,3H),7.43(dd,J=14.0,1.7Hz,1H),6.97(dd,J=8.5,1.7Hz,1H),6.44(t,J=6.0Hz,1H),5.74(s,1H),4.99(s,2H),4.21-4.07(m,1H),3.71(dt,J=13.9,5.7Hz,1H);
19F NMR(400MHz,d6-DMSO)δ-114.0.
实施例60:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-(环丁基甲基)-1H-吡唑-4-
基)-3-氟苯基)脲
将化合物1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)(110mg,0.274mmol)溶于10mL 1,4-二氧六环和2mL水,加入1-(环丁基甲基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(86mg,0.329mmol),碳酸钠(87mg,0.823mmol)和Pd(dppf)Cl2(20mg,0.027mmol)。在氮气保护下,104℃反应1小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-(环丁基甲基)-1H-吡唑-4-基)-3-氟苯基)脲(5.7mg)。
LC-MS:457.1,tR=2.237min;
1H NMR(400MHz,MeOD)δ7.95(d,J=6.4Hz,2H),7.81(s,1H),7.62(dd,J=20.2,7.5Hz,2H),7.54-7.29(m,4H),7.18(s,1H),7.01(d,J=8.4Hz,1H),5.53-5.42(m,1H),4.19(d,J=7.3Hz,2H),4.10(dd,J=14.4,4.2Hz,1H),3.60(dd,J=14.3,6.3Hz,1H),2.86(dt,J=15.2,7.6Hz,1H),2.15-2.02(m,2H),2.00-1.67(m,4H).
实施例61:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(四氢-2H-吡喃-4-
基)-1H-吡唑-4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(90mg,0.224mmol)溶于10mL 1,4-二氧六环和2mL水,然后加入1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(75mg,0.269mmol),碳酸钠(71mg,0.673mmol)和Pd(dppf)Cl2(16mg,0.022mmol)。在氮气保护下,104℃反应1小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)苯基)脲(5.8mg)。
LC-MS:473.2,tR=1.943min;
1H NMR(400MHz,MeOD)δ8.05(d,J=12.8Hz,2H),7.85(s,1H),7.73-7.34(m,7H),7.23(s,1H),7.00(dd,J=8.5,2.0Hz,1H),5.61-5.43(m,1H),4.45(ddd,J=15.7,10.9,4.6Hz,1H),4.22-3.98(m,3H),3.61(ddd,J=13.7,11.2,5.0Hz,3H),2.22-1.95(m,4H).
实施例62:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1,3,5-三甲基-1H-
吡唑-4-基)苯基)脲
制备方法同实施例54。
LC-MS:449.2,tR=2.14min;
1H NMR(400MHz,MeOD)δ7.88-7.78(m,2H),7.51(dd,J=19.5,7.5Hz,2H),7.34(t,J=7.5Hz,1H),7.29-7.22(m,1H),7.06(s,1H),6.86(dd,J=11.4,6.7Hz,1H),5.40(t,J=4.8Hz,1H),4.04(dd,J=14.4,4.1Hz,1H),3.65(s,3H),3.58(dd,J=14.4,5.7Hz,1H),2.06(d,J=7.1Hz,3H),1.99(s,3H).
实施例63:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-(2-羰基吡咯烷-
1-基)乙基)-1H-吡唑-4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-3-氟苯基)脲(100mg,0.249mmol)溶于10mL 1,4-二氧六环和2mL水,加入1-(2-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-基)乙基)吡咯烷-2-酮(91mg,0.299mmol),碳酸钠(79mg,0.748mmol)和Pd(dppf)Cl2(18mg,0.025mmol)。在氮气下104℃反应1小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(3-氟-4-(1-(2-(2-羰基吡咯烷-1-基)乙基)-1H-吡唑-4-基)苯基)脲(8.5mg)。
LC-MS:500.2,tR=1.823min;
1H NMR(400MHz,MeOD)δ8.06(s,1H),7.97(d,J=1.6Hz,1H),7.85(s,1H),7.63(dd,J=23.0,7.5Hz,2H),7.47(dt,J=12.1,8.0Hz,2H),7.42-7.34(m,2H),7.22(s,1H),6.99(dd,J=8.5,2.0Hz,1H),5.52(t,J=5.0Hz,1H),4.36(t,J=5.8Hz,2H),4.12(dd,J=14.4,4.1Hz,1H),3.70(t,J=5.8Hz,2H),3.62(dd,J=14.4,6.2Hz,1H),3.21(t,J=7.0Hz,2H),2.31(t,J=8.1Hz,2H),2.01-1.90(m,2H).
实施例64:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1,3,5-三甲基-
1H-吡唑-4-基)苯基)脲
将1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-5-氯-2-氟苯基)脲(70mg,0.161mmol)溶于10mL1,4-二氧六环和2mL水,然后加入1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(57mg,0.241mmol),碳酸钠(51mg,0.482mmol)和Pd(dppf)Cl2(12mg,0.016mmol)。在氮气下104℃反应1小时。LC-MS检测反应完全。反应液浓缩,剩余物用快速硅胶柱层析法纯化(二氯甲烷:甲醇=10:1),得到1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1,3,5-三甲基-1H-吡唑-4-基)苯基)脲(3.5mg)。
LC-MS:465.1,tR=2.007min;
1H NMR(400MHz,MeOD)δ8.24(d,J=7.6Hz,1H),7.97(s,1H),7.63(dd,J=19.5,7.5Hz,2H),7.46(t,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.19(s,1H),7.00(d,J=11.5Hz,1H),5.52(t,J=4.7Hz,1H),4.17(dt,J=14.4,3.7Hz,1H),3.75(d,J=13.0Hz,3H),3.71(dd,J=14.4,5.6Hz,1H),2.09(d,J=24.4Hz,6H).
实施例65:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-异丁基-3,5-二
甲基-1H-吡唑-4-基)苯基)脲
制备方法同实施例64。
LC-MS:507.1,tR=2.35min;
1H NMR(400MHz,MeOD)δ8.24(d,J=7.5Hz,1H),7.98(s,1H),7.63(dd,J=19.7,7.6Hz,2H),7.46(t,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.19(s,1H),7.01(d,J=11.5Hz,1H),5.52(t,J=4.7Hz,1H),4.17(dt,J=14.4,4.0Hz,1H),3.85(dd,J=7.5,1.0Hz,2H),3.71(dd,J=14.4,5.6Hz,1H),2.21(dt,J=13.7,6.9Hz,1H),2.09(d,J=17.2Hz,6H),0.94(t,J=6.6Hz,6H).
实施例66:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-4-(3,5-二甲基-1H-吡唑-
4-基)-2-氟苯基)脲
制备方法同实施例64。
LC-MS:451.1,tR=1.954min;
1H NMR(400MHz,MeOD)δ8.23(d,J=7.6Hz,1H),8.02(s,1H),7.64(dd,J=20.5,7.6Hz,2H),7.47(t,J=7.5Hz,1H),7.42-7.36(m,1H),7.21(s,1H),7.01(d,J=11.5Hz,1H),5.53(t,J=4.7Hz,1H),4.18(dd,J=14.4,4.1Hz,1H),3.71(dd,J=14.4,5.6Hz,1H),2.11(s,6H).
实施例67:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-(环丙基甲基)-3,5-二甲
基-1H-吡唑-4-基)-2,5-二氟苯基)脲
制备方法同实施例54。
LC-MS:489.1,tR=2.21min;
1H NMR(400MHz,MeOD)δ7.86(s,1H),7.82(dd,J=11.9,7.0Hz,1H),7.54(d,J=7.5Hz,1H),7.49(d,J=7.6Hz,1H),7.34(t,J=7.4Hz,1H),7.26(t,J=7.6Hz,1H),7.07(d,J=4.8Hz,1H),6.87(dd,J=11.4,6.7Hz,1H),5.40(t,J=4.7Hz,1H),4.05(dd,J=14.4,4.1Hz,1H),3.84(d,J=6.8Hz,2H),3.59(dd,J=14.5,5.7Hz,1H),2.08(s,3H),2.01(s,3H),1.31-1.07(m,6H),0.47(q,J=5.8Hz,2H),0.29(q,J=4.9Hz,2H);
19F NMR(400MHz,MeOD)δ-119.43,-138.60.
实施例68:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-4-(1-(环丙基甲基)-3,5-
二甲基-1H-吡唑-4-基)-2-氟苯基)脲
制备方法同实施例64。
LC-MS:505.1,tR=2.24min;
1H NMR(400MHz,MeOD)δ8.24(d,J=7.6Hz,1H),7.98(s,1H),7.66(d,J=7.5Hz,1H),7.61(d,J=7.4Hz,1H),7.46(t,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.19(s,1H),7.01(d,J=11.5Hz,1H),5.52(t,J=4.8Hz,1H),4.17(dt,J=14.4,4.2Hz,1H),3.95(dt,J=9.8,4.9Hz,2H),3.71(dd,J=14.4,5.6Hz,2H),2.14(s,3H),2.08(s,3H),0.59(d,J=8.1Hz,2H),0.45-0.35(m,2H);
19F NMR(400MHz,MeOD)δ-134.87.
实施例69:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-异丁基-3,5-二
甲基-1H-吡唑-4-基)苯基)脲
制备方法同实施例54。
LC-MS:491.2,tR=2.301min;
1H NMR(400MHz,MeOD)δ8.01(s,1H),7.94(dd,J=11.9,7.0Hz,1H),7.64(dd,J=20.5,7.6Hz,2H),7.46(t,J=7.5Hz,1H),7.38(t,J=7.6Hz,1H),7.20(s,1H),6.99(dd,J=11.4,6.7Hz,1H),5.53(t,J=4.7Hz,1H),4.18(dd,J=14.4,4.1Hz,1H),3.86(d,J=7.5Hz,2H),3.71(dd,J=14.4,5.7Hz,1H),2.68(s,1H),2.17(s,3H),2.13(s,3H),0.94(d,J=6.7Hz,6H).
实施例70:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-2-氟-4-(1-(2-甲氧基乙
基)-3,5-二甲基-1H-吡唑-4-基)苯基)脲
制备方法同实施例64。
LC-MS:509.2,tR=2.086min;
1H NMR(400MHz,MeOD)δ8.23(d,J=7.6Hz,1H),8.00(s,1H),7.64(dd,J=20.2,7.6Hz,2H),7.46(t,J=7.4Hz,1H),7.38(t,J=7.1Hz,1H),7.20(s,1H),7.00(d,J=11.5Hz,1H),5.53(t,J=4.8Hz,1H),4.28-4.12(m,3H),3.73(qd,J=10.3,5.3Hz,3H),3.31(s,3H),2.10(d,J=23.8Hz,6H).
实施例71:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(2,5-二氟-4-(1-(2-甲氧基乙
基)-3,5-二甲基-1H-吡唑-4-基)苯基)脲
制备方法同实施例54。
LC-MS:493.1,tR=2.010min;
1H NMR(400MHz,MeOD)δ8.05-7.86(m,2H),7.63(dd,J=20.3,7.5Hz,2H),7.49-7.33(m,2H),7.19(s,1H),6.98(dd,J=11.4,6.7Hz,1H),5.52(t,J=4.8Hz,1H),4.30-4.09(m,3H),3.80-3.64(m,3H),3.32(s,3H),2.16(d,J=24.7Hz,6H).
实施例72:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(1-(环丁基甲基)-3,5-二甲
基-1H-吡唑-4-基)-2,5-二氟苯基)脲
制备方法同实施例54。
LC-MS:503.2,tR=2.35min;
1H NMR(400MHz,MeOD)δ7.97(s,1H),7.93(dd,J=11.9,7.0Hz,1H),7.66(d,J=7.6Hz,1H),7.61(d,J=7.7Hz,1H),7.46(t,J=7.5Hz,1H),7.41-7.34(m,1H),7.19(s,1H),6.98(dd,J=11.4,6.7Hz,1H),5.52(t,J=4.8Hz,1H),4.16(dd,J=14.4,4.1Hz,1H),4.07(d,J=7.2Hz,2H),3.70(dd,J=14.4,5.7Hz,1H),2.82(dt,J=14.9,7.5Hz,1H),2.18(s,3H),2.12(s,3H),2.10-2.00(m,2H),1.91(ddt,J=21.7,17.7,7.5Hz,4H);
19F NMR(400MHz,MeOD)δ-119.45,-138.60.
实施例73:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-4-(1-(环丁基甲基)-3,5-
二甲基-1H-吡唑-4-基)-2-氟苯基)脲
制备方法同实施例64。
LC-MS:519.1,tR=2.46min;
1H NMR(400MHz,MeOD)δ8.23(d,J=7.6Hz,1H),7.97(s,1H),7.66(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.46(t,J=7.5Hz,1H),7.38(t,J=7.5Hz,1H),7.19(s,1H),7.00(d,J=11.5Hz,1H),5.52(t,J=4.8Hz,1H),4.17(dt,J=14.4,4.1Hz,1H),4.07(d,J=7.1Hz,2H),3.71(dd,J=14.4,5.7Hz,1H),2.82(dt,J=15.1,7.4Hz,2H),2.12(s,3H),2.10-1.99(m,5H),1.99-1.80(m,4H);
19F NMR(400MHz,MeOD)δ-134.86.
实施例74:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-4-(3,5-二甲基-1-(氧杂环
丁-3-基)-1H-吡唑-4-基)-2-氟苯基)脲
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-溴-5-氯-2-氟苯基)脲(55mg,0.126mmol),3,5-二甲基-1-(氧杂环丁-3-基)-1H-吡唑-4-硼酸频哪醇酯(70mg,0.252mmol),Pd(dppf)Cl2(46mg,0.0629mmol)和碳酸钾(35mg,0.253mmol)于1,4-二氧六环/水(10ml/2ml)中搅拌,氮气保护下升温至110℃微波反应1小时。冷却至室温,加水,二氯甲烷提取,干燥,柱层析纯化得1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(5-氯-4-(3,5-二甲基-1-(氧杂环丁-3-基)-1H-吡唑-4-基)-2-氟苯基)脲(1.4mg)。
LC-MS:507.1,tR=2.08min;
1H NMR(400MHz,MeOD)δ8.24(d,J=7.6Hz,1H),7.99(s,1H),7.63(dd,J=20.5,7.6Hz,2H),7.42(dt,J=33.7,7.4Hz,2H),7.20(s,1H),7.00(d,J=11.4Hz,1H),5.64-5.55(m,1H),5.51(s,1H),5.36(t,J=4.7Hz,1H),5.17(t,J=6.3Hz,1H),5.11(t,J=6.3Hz,1H),5.03(dd,J=14.0,6.6Hz,2H),4.17(d,J=14.3Hz,1H),3.71(dd,J=14.3,5.6Hz,1H),2.13(s,3H),2.08(s,3H).
实施例75:
1-(2,5-二氟-4-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,
1-a]异吲哚-5-基)甲基)脲
第一步:1-(4-溴-2,5-二氟苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲
基)脲的制备
将2-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)乙酸(160mg,0.71mmol),叠氮磷酸二苯酯(DPPA)(390mg,1.4mmol),三乙胺(1mL),4-溴-2,5-二氟苯胺(220mg)溶于无水甲苯(15mL),在氮气保护下加热回流4小时。LC-MS显示反应完全,反应液浓缩,剩余物溶于二氯甲烷(20mL),依次用水(2X10mL),饱和食盐水(10mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化和反向快速柱纯化得到1-(4-溴-2,5-二氟苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(70mg)。
第二步:1-(2,5-二氟-4-(1,3,5-三甲基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪
唑并[5,1-a]异吲哚-5-基)甲基)脲的制备
将1-(4-溴-2,5-二氟苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(36mg,0.07mmol),1,3,5-三甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(42mg,0.15mmol),Pd(dppf)Cl2(5mg),碳酸钾(20mg,0.14mmol)溶于二氧六环(3mL)和水(0.5mL)的混合液,在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),用水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(6.0mg)。
LC-MS:467.0,tR=2.53min;
1H NMR(400MHz,MeOD)δ7.99(s,1H),7.89(dd,J=11.8,6.9Hz,1H),7.49(t,J=5.0Hz,2H),7.23(s,1H),7.15-7.06(m,1H),6.97(dd,J=11.4,6.6Hz,1H),5.73(t,J=4.2Hz,1H),4.27(dd,J=14.5,3.7Hz,1H),3.84-3.78(m,1H),3.76(s,3H),2.17(s,3H),2.11(s,3H).
实施例76:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(3,5-二甲基-1-(氧杂环丁-3-
基)-1H-吡唑-4-基)-2,5-二氟苯基)脲
制备方法同实施例54。
LC-MS:491.2,tR:=2.04min;
1H NMR(400MHz,MeOD)δ7.85(s,1H),7.84-7.79(m,1H),7.53(t,J=6.7Hz,1H),7.49(d,J=7.4Hz,1H),7.34(t,J=7.5Hz,1H),7.25(t,J=7.5Hz,1H),7.06(s,1H),6.86(dd,J=11.4,6.7Hz,1H),5.48(dt,J=14.2,7.0Hz,1H),5.40(t,J=4.7Hz,1H),5.01(t,J=6.4Hz,2H),4.94-4.87(m,2H),4.05(dd,J=14.4,4.1Hz,1H),3.58(dd,J=14.4,5.7Hz,1H),2.06(s,3H),2.02(s,3H);
19F NMR(376MHz,MeOD)δ-119.44,-138.56.
实施例77:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-3,5-二甲基-1H-吡唑-4-基)-
2,5-二氟苯基)脲
LC-MS:435.1,tR=1.92min;
1H NMR(400MHz,MeOD)δ7.98(s,1H),7.93(dd,J=11.9,7.0Hz,1H),7.66(d,J=7.5Hz,1H),7.61(d,J=7.6Hz,1H),7.46(t,J=7.5Hz,1H),7.38(dd,J=10.9,4.2Hz,1H),7.19(s,1H),7.00(dd,J=11.5,6.7Hz,1H),5.52(t,J=4.8Hz,1H),4.16(dd,J=14.4,4.1Hz,1H),3.70(dd,J=14.4,5.7Hz,1H),2.17(s,6H);
19F NMR(376MHz,MeOD)δ-119.51,-138.67.
实施例78:
1-((5H-咪唑并[5,1-a]异吲哚-5-基)甲基)-3-(4-(3,5-二甲基-1-(氧杂环丁-3-
基甲基)-1H-吡唑-4-基)-2,5-二氟苯基)脲
LC-MS:505.1,tR=2.03min;
1H NMR(400MHz,MeOD)δ9.23(s,1H),8.05(m,1H),7.89(m,1H),7.77m,2H),7.64(m,2H),7.17(m,1H),6.74(s,1H),5.89(m,1H),5.36(m,4H),4.61(d,J=9.6Hz,2H),4.40(m,2H),2.21(t,J=7.6Hz,3H),2.06(m,4H).
实施例79:
1-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异
吲哚-5-基)甲基)脲
将1-(4-溴-2,5-二氟苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(36mg,0.07mmol),1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(34mg,0.15mmol),Pd(dppf)Cl2(5mg),碳酸钾(20mg,0.14mmol)溶于二氧六环(3mL)和水(0.5mL)地混合液,在氮气保护下加热回流2小时。LC-MS显示反应完全,反应液过滤,滤液浓缩,剩余物溶于二氯甲烷(10mL),用水(2X5mL)洗涤。有机相干燥过滤,浓缩。剩余物通过快速硅胶柱纯化得到1-(2,5-二氟-4-(1-甲基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(7.0mg)。
LC-MS:439.1,tR=2.03min;
1H NMR(400MHz,MeOD)δ7.96(d,J=15.5Hz,2H),7.85(dd,J=13.1,6.9Hz,1H),7.80(s,1H),7.48(dd,J=13.2,5.2Hz,2H),7.35(dd,J=12.0,6.9Hz,1H),7.21(s,1H),7.15-7.01(m,1H),5.70(t,J=4.3Hz,1H),4.25(dd,J=14.5,3.7Hz,1H),3.92(s,3H),3.76(dd,J=14.5,5.3Hz,1H);
19F NMR(376MHz,MeOD)δ-120.02,-120.23,-138.39.
实施例80:
1-(4-(1-(环丙基甲基)-1H-吡唑-4-基)-2,5-二氟苯基)-3-((6-氟-5H-咪唑并
[5,1-a]异吲哚-5-基)甲基)脲
制备方法同实施例80。
LC-MS:479.2,tR=2.47min;
1H NMR(400MHz,MeOD)δ8.04(d,J=1.3Hz,1H),7.98(s,1H),7.91-7.78(m,2H),7.54-7.43(m,2H),7.38(dd,J=12.0,6.8Hz,1H),7.21(s,1H),7.14-7.02(m,1H),5.70(t,J=4.4Hz,1H),4.25(dd,J=14.5,3.7Hz,1H),4.03(d,J=7.1Hz,2H),3.76(dd,J=14.5,5.4Hz,1H),1.38-1.25(m,1H),0.64(q,J=5.8Hz,2H),0.43(q,J=4.8Hz,2H).
实施例81:
1-(2,5-二氟-4-(1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-
基)甲基)脲
制备方法同实施例80。
LC-MS:425.1,tR=1.94min;
1H NMR(400MHz,MeOD)δ8.05-7.93(m,3H),7.86(dd,J=13.1,6.9Hz,1H),7.55-7.44(m,2H),7.40(dd,J=12.0,6.9Hz,1H),7.22(s,1H),7.10(ddd,J=9.5,6.8,2.3Hz,1H),5.71(t,J=4.5Hz,1H),4.25(dd,J=14.5,3.8Hz,1H),3.77(dd,J=14.5,5.4Hz,1H);
19F NMR(376MHz,MeOD)δ-120.04,-120.36,-138.39.
实施例82:
1-(2,5-二氟-4-(1-(噁丁环-3-基)-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并
[5,1-a]异吲哚-5-基)甲基)脲
1-(2,5-二氟-4-(1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(15mg)和碳酸铯(100mg)溶于DMF(1mL),3-碘噁丁环(30mg),50℃搅拌过夜,反应液冷却至室温,直接经反相柱层析纯化得到1-(2,5-二氟-4-(1-(噁丁环-3-基)-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)甲基)脲(3mg)。
LC-MS:481.0,tR=2.130min;
1H NMR(400MHz,MeOD)δ8.14(s,1H),8.00(dd,J=12.7,6.0Hz,2H),7.56(d,J=7.6Hz,1H),7.42(td,J=16.3,9.4Hz,3H),7.11(t,J=8.9Hz,1H),6.43-6.35(m,1H),5.65-5.58(m,1H),5.07(d,J=6.9Hz,4H),4.61(s,1H),3.43(d,J=2.9Hz,1H),3.38(d,J=5.4Hz,1H).
实施例83:
1-(4-(1-(环丁基甲基)-1H-吡唑-4-基)-2,5-二氟苯基)-3-((6-氟-5H-咪唑并
[5,1-a]异吲哚-5-基)甲基)脲
制备方法同实施例80。
LC-MS:493.1,tR=2.32min;
1H NMR(400MHz,MeOD)δ7.98(d,J=15.3Hz,2H),7.91-7.75(m,2H),7.48(d,J=7.3Hz,2H),7.36(dd,J=11.8,6.8Hz,1H),7.23(s,1H),7.11(d,J=8.7Hz,1H),5.71(s,1H),4.25(dd,J=14.5,3.2Hz,1H),4.18(d,J=7.3Hz,2H),3.77(dd,J=14.4,5.0Hz,1H),2.85(dt,J=14.9,7.5Hz,1H),2.17-1.74(m,6H).
实施例84:
1-(2,5-二氟-4-(1-异丁基-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,1-a]
异吲哚-5-基)甲基)脲
制备方法同实施例80。
LC-MS:481.1,tR=2.393min;
1H NMR(400MHz,MeOD)δ7.88(d,J=14.0Hz,2H),7.80-7.69(m,2H),7.37(t,J=5.1Hz,2H),7.27(dd,J=12.0,6.9Hz,1H),7.12(s,1H),6.99(dd,J=11.3,7.5Hz,1H),5.61(s,1H),4.15(dd,J=14.5,3.7Hz,1H),3.87(d,J=7.3Hz,2H),3.67(dd,J=14.5,5.3Hz,1H),2.10(dt,J=13.4,6.8Hz,1H),0.82(d,J=6.7Hz,6H).
实施例85:
1-(2,5-二氟-4-(2-甲氧基乙基)-1H-吡唑-4-基)苯基)-3-((6-氟-5H-咪唑并[5,
1-a]异吲哚-5-基)甲基)脲
制备方法同实施例81。
LC-MS:483.1,tR=2.08min;
1H NMR(400MHz,MeOD)δ8.05-7.94(m,2H),7.86(dd,J=13.8,6.2Hz,2H),7.55-7.43(m,2H),7.38(dd,J=12.0,6.8Hz,1H),7.22(s,1H),7.16-7.02(m,1H),5.72(t,J=4.5Hz,1H),4.34(t,J=5.2Hz,2H),4.26(dd,J=14.4,3.8Hz,1H),3.87-3.70(m,3H),3.34(s,3H);
19F NMR(400MHz,MeOD)δ-120.07,-120.28,-138.44.
生物学评价
一、IDO活性抑制的酶学测试
人的吲哚胺2,3-双加氧酶(IDO)购自BPS Bioscience Inc。人吲哚胺(idoleamine)2,3-双加氧酶(IDO)酶学反应在96孔板进行,反应体积为20μL,反应条件为:40nM IDO酶,0.2mM L-色氨酸,50mM KPB(pH 6.5)缓冲液,20mM L-抗坏血酸钠,10μM亚甲蓝,0.2mg/mL过氧化氢酶,不同浓度的化合物,<1%二甲基亚砜。在30℃反应60分钟后,每孔加入5μL 30%(W/V)三氯乙酸(50mM KPB缓冲液配制)50℃孵育30分钟使N-甲酰基-犬尿氨酸水解为犬尿氨酸。每孔加入25μL 2%(W/V)p-(二甲基氨基)苯甲醛(p-DMBA)/冰醋酸溶液,用BioTek Synergy H1酶标仪(Molecular Devices)读取490nm吸光值。
待测化合物贮备溶液用二甲基亚砜配制为10mM,实验时用用二甲基亚砜稀释至试验最高浓度,然后进行1:3梯度稀释,一般稀释成8到10个浓度点,每个浓度点设复孔,每次实验均包含1个参照化合物。分析酶标仪读取490nm吸光值原始数据,计算受试化合物不同浓度点对IDO酶活性的抑制,采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。
本发明实施例化合物的活性通过以上试验方法进行测定,酶学IDO抑制活性IC50值结果见下表:
测试数据表明,本发明的实施例化合物具有较强的IDO抑制作用。
二、IDO活性抑制的细胞模型测试
干扰素γ可诱导Hela细胞表达IDO,这一模型被用来测试化合物对吲哚胺2,3-双加氧酶(IDO)活性抑制活性。Hela细胞(ATCC)的培养液为含100μML-色氨酸的不含酚红的RPMI-1640。待测化合物贮备溶液用二甲基亚砜配制为10mM,实验时用二甲基亚砜稀释至试验最高浓度,实验时用培养基进行3倍系列稀释,一般稀释成8到10个浓度点,每个浓度点设复孔。DMSO终浓度为0.5%,每次实验均包含内参化合物。
试验的程序为:在96孔培养板上每孔加入20,000个Hela细胞(ATCC)过夜培养,24小时后将干扰素γ(终浓度为50ng/mL)和不同浓度的待测化合物和内参化合物加到培养的细胞。24时后,将140μL上清液/孔转移至一个新的96孔板中,每孔加入10μL 6.1N的三氯乙酸,50℃孵育30分钟使N-甲酰基-犬尿氨酸水解为犬尿氨酸。反应混合物离心(2500转10分钟)去除沉淀物,将上清液100μL转移至另一个新的96孔板中,每孔加入100μL 2%(W/V)p-(二甲基氨基)苯甲醛(p-DMBA)/冰醋酸溶液,用BioTek Synergy H1酶标仪(MolecularDevices)读取490nm吸光值。
分析酶标仪读取490nm吸光值原始数据,计算受试化合物不同浓度点对IDO酶活性的抑制,采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析得到化合物的半数抑制浓度IC50值。
本发明实施例化合物的活性通过以上试验方法进行测定,细胞学IDO抑制活性IC50值结果见下表:
测试数据表明,本发明的实施例化合物具有较强的细胞活性。
Claims (5)
4.药物组合物,其包括治疗有效剂量的权利要求1所述的式(I)化合物或其药学上可接受盐及可药用的载体。
5.权利要求1所述的式(I)化合物或其药学上可接受盐,或权利要求4所述的药物组合物在制备用于治疗由IDO介导的色氨酸代谢紊乱的病理学特征的疾病的药物中的应用;所述IDO介导的色氨酸代谢紊乱的病理学特征的疾病选自癌症、病毒感染、抑郁症、神经变性病症、创伤、年龄相关的白内障、器官移植排斥或自身免疫疾病。
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