CN111825658A - 新型egfr三突变抑制剂及其应用 - Google Patents
新型egfr三突变抑制剂及其应用 Download PDFInfo
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- CN111825658A CN111825658A CN201910315199.XA CN201910315199A CN111825658A CN 111825658 A CN111825658 A CN 111825658A CN 201910315199 A CN201910315199 A CN 201910315199A CN 111825658 A CN111825658 A CN 111825658A
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- halogen
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- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000004400 serine Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明通式I或II所示化合物。本发明的化合物是结构全新的EGFR抑制性化合物,能够显著抑制EGFR 19del/T790M/C797S,L858R/T790M/C797S三突变,从而能够开发作为新一代的EGFR抑制剂并用于EGFR介导的相关疾病的治疗用途。
Description
技术领域
本发明涉及药物化学领域;具体地说,本发明涉及新型吲哚类和三取代咪唑类化合物作为EGFR三突变抑制剂及其作为EGFR抑制剂在制备肿瘤相关疾病的药物中的应用。
背景技术
表皮生长因子受体(epidermal growth factor receptor,EGFR)是一类存在于人组织细胞膜上的跨膜糖蛋白,分子量为170-kDa,其与ErbB-2(HER2/Neu)、ErbB-3(HER3)、ErbB-4(HER4)同属ErbB受体酪氨酸激酶(receptor tyrosine kinase,RTK)家族。这些受体是由细胞外配体结合结构域组成,然后通过跨膜区与细胞内酪氨酸激酶连接。ErbB受体内的酪氨酸激酶结构域是高度保守的,相反,胞外结构域有明显的差异,这也致使受体在结合配体时显现出不同的特异性。EGFR与ErbB-4带有完整的胞外配体结合域和可激活的激酶结构域,ErbB-2的胞外域则可能不具备配体结合力,ErbB-3虽然能与ATP结合,但无活性酪氨酸激酶受体,它的同源二聚体不具备活性。EGFR的信号传递方式主要是结合特异的配体,引起二聚化,激活其胞内酪氨酸激酶活性,使末端的一些酪氨酸残基自磷酸化,从而激活下游信号通路。
研究发现,表皮生长因子受体在细胞的增殖、代谢等方面扮演着重要的角色。由于它在多种癌细胞中存在过表达现象,因而,以EGFR为药物靶点极具研究意义。目前针对EGFR的肿瘤分子靶向药物,按其性质主要分为两大类:一类是直接作用于细胞外受体区域的单克隆抗体;另一类是干扰细胞内EGFR酪氨酸激酶活性的小分子抑制剂。单克隆抗体药物通过与EGFR的膜外配体结合域作用,使EGF等内源性配体无法与EGFR结合,从而阻止信号传入细胞;小分子药物则通过与胞内酪氨酸激酶催化区结合,抑制其催化活性,从而阻断细胞增殖信号。
EGFR的突变主要集中在18-21号外显子上,这几个外显子负责编码EGFR酪氨酸激酶域。其中19号外显子缺失占据了EGFR酪氨酸激酶敏感性突变的44%。在21号外显子上的点突变-L858R突变,占据了EGFR酪氨酸激酶敏感性突变的41%。719号残基从甘氨酸突变到丝氨酸,丙氨酸或者半胱氨酸占据了总突变的10%,而20号外显子的***或复制突变占据了剩余的5%。其中19号外显子缺失和L858R点突变是最普遍的敏感性突变。这些突变会增强EGFR激酶的活性,从而提高下游信号通路。另外报道发现,由EGFR酪氨酸激酶抑制剂治疗产生的耐药性中,50%的病人发现了20号外显子上的T790M点突变。这种突变被认为是在治疗期间产生的,因为在未治疗病人中并未检测到这种突变。针对这些不同的突变衍生出了一系列的小分子抑制剂。
首先是第一代EGFR小分子抑制剂,例如Gefitinib、Erlotinib。这些抑制剂主要针对的是敏感性突变,但随着T790M抗性突变的发现,患者逐渐产生耐药性。因此衍生出了第二代及第三代EGFR抑制剂,该类抑制剂主要通过分子上的迈克尔受体与蛋白的半胱氨酸797残基发生共价结合来提高抑制活性。
虽然利用第三代EGFR抑制剂治疗携带有T790M突变的非小细胞肺癌病人有希望,但耐药性也逐渐产生。经过研究发现其耐药性的发生主要是由于Cys797残基发生突变形成Ser797残基,破坏了小分子与激酶间的结合力,导致第三代抑制剂基本失去作用。
因此,本领域急需开发新一代的抑制剂来克服EGFR的L858R/T790M/C797S以及EGFR 19del/T790M/C797S三突变。
发明内容
本发明的目的在于提供一种新型的EGFR抑制性化合物,这种化合物能够抑制EGFR19del/T790M/C797S三突变。
本发明的另一目的是提供包含上述化合物的药物组合物。
本发明还有一目的是提供上述化合物在制备治疗EGFR相关疾病或抑制EGFR的药物中的用途。
在第一方面,本发明提供通式I所示的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
式中,
W是CH或N;
X是CH或N;
Y是CH或N或C卤素;
Z是CH或N;
R1的数量为1-5中任意的整数,任选位于1’、2’、5’、6’或7’位,并且独立选自:H、卤素、C1-C6取代或未取代的烷基、
其中,n为0~4的整数;
P为1-2个C1-C3烷基或不存在;
Q为-OH、-SH、-NH2、-NHCH3、-COOH、-CONH2、-NHCONH2、-NHCONHNH2、-SO3H、-SO2NH2;
X为O、S、NH;
R2选自:氢、C1-C5取代或未取代的烷基甲酰胺基、C2-C5取代或未取代的烯基甲酰胺基;
R3选自:氢、卤素、NR7R8、取代的N-C1-C3烷基哌嗪基;
R7和R8独立选自:H、C1-C6取代或未取代的烷基、NR9R10;
R9和R10独立选自:H、C1-C3取代或未取代的烷基。
在具体的实施方式中,
W是CH;
X是CH或N;
Y是CH或N;
Z是CH;
R1的数量为1或2,任选位于1’或5’位,并且独立选自:H、C1-C6取代或未取代的烷基羟基或多羟基、卤素;
R2选自:氢、C1-C3取代或未取代的烷基甲酰胺基、C2-C3取代或未取代的烯基甲酰胺基;
R3选自:卤素、NR7R8;
R7和R8独立选自:H、C1-C3取代或未取代的烷基、NR9R10;
R9和R10独立选自:H、C1-C3取代或未取代的烷基。
在具体的实施方式中,本发明提供以下的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
在第二方面,本发明提供通式II所示的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
式中,
R1选自:
其中,n为0~4的整数;
P为1-2个C1-C3烷基或不存在;
Q为-OH、-SH、-NH2、-NHCH3,、-COOH、-CONH2、-NHCONH2、-NHCONHNH2、-SO3H、-SO2NH2;
X为O、S、NH;
A的数量为0-4的任一整数,并且独立选自:卤素、取代或未取代的C1-C3烷氧基;
V、S、T的数量分别为0-4的任一整数,并且独立选自卤素、取代或未取代的C1-C3烷氧基;
R6选自:H、取代或未取代的C1-C3烷基。
在具体的实施方式中,
A的数量为0-4的任一整数,并且独立选自:卤素、取代或未取代的C1-C3烷氧基;
V的数量为0-4的任一整数,并且独立选自卤素、取代或未取代的C1-C3烷氧基;
R6选自:H。
在具体的实施方式中,本发明提供选自以下的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
在第三方面,本发明提供一种药物组合物,所述药物组合物含有第一或第二方面所述的化合物或其立体异构体或光学异构体或其药学上可接受的盐,以及任选的药学上可接受的载体或赋形剂。
在优选的实施方式中,所述药物组合物是适于口服的剂型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
在第四方面,本发明提供第一或第二方面所述的化合物或其立体异构体或光学异构体或其药学上可接受的盐,或第三方面所述的药物组合物在制备治疗或预防EGFR介导的疾病或抑制EGFR的药物中的用途。
在具体的实施方式中,所述EGFR介导的疾病为癌症。
在具体的实施方式中,所述癌症选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌和实体瘤。
在第五方面,本发明提供治疗或预防EGFR介导的疾病方法,包括将第一或第二方面所述的化合物或第三方面所述的药物组合物给予有此需要的对象。
在优选的实施方式中,所述EGFR介导的疾病为癌症;优选地,所述癌症选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌和实体瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地发现了一系列结构全新的EGFR抑制性化合物,所述化合物能够显著抑制EGFR 19del/T790M/C797S三突变,从而能够开发作为新一代的EGFR抑制剂并且为开发新一代的EGFR抑制剂奠定了全新的物质基础。在此基础上完成了本发明。
术语定义
本文中涉及到的一些基团定义如下:
本文中,“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基,优选的烷基包括长2-8个、1-6个、1-4个、3-8个、1-3个碳原子不等的烷基。烷基的例子包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。烷基可以被1个或多个取代基取代,例如被卤素或卤代烷基取代。例如,烷基可以是被1-4个氟原子取代的烷基,或者烷基可以是被氟代烷基取代的烷基。
本文中,“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基,更优选为长1-4个碳原子的烷氧基。烷氧基的例子包括但不限于:甲氧基、乙氧基、丙氧基等。
本文中,“卤素”指氟、氯、溴和碘。
本文中,“酰氨基”指结构式为“-R’-NH-C(O)-R”的基团,其中,R’可选自氢或烷基,R可选自烷基、链烯基、炔基、被NRcRd取代的烷基、被NRcRd取代的链烯基和NRcRd取代的炔基、被卤素取代的烷基、被氰基取代的链烯基,其中,Rc和Rd可选自烷基和链烯基。
本文中,“取代或未取代的”或“任选取代的”指其所修饰的取代基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本文所用的术语“取代”是指特定基团上的一个或多个氢原子被特定的取代基所替代。特定的取代基可以是前文中相应描述的取代基,也可以是各实施例中出现的具体取代基。因此,在本发明中,通式中的取代基可以各自独立地为实施例中具体化合物中的相应基团;即,本发明包括上述通式中各取代基的组合,也包括通式中所示部分取代基与实施例中出现的其它具体取代基的组合。
本发明的化合物
本发明提供了一系列结构全新的EGFR抑制性化合物,所述化合物能够显著抑制EGFR 19del/T790M/C797S三突变。在具体的实施方式中,本发明提供通式I或II所示的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
式中,各取代基如上所述定义。
在本发明的化合物的基础上,本领域技术人员可以其制成药学上可接受的盐。例如,可以将本发明的化合物与无机酸或有机酸反应形成常规的可药用盐。所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者将本发明的化合物与无机碱形成钠盐、钾盐、钙盐、铝盐或铵盐;或者与有机碱形成甲胺盐、乙胺盐或乙醇胺盐。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明的药物组合物以及施用方法
本发明的化合物能够用于制备治疗EGFR(尤其是EGFR 19del/T790M/C797S三突变)介导的疾病,例如癌症,包括但不限于:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌和实体瘤。
有鉴于此,在本发明的化合物及其药学上可接受的盐的基础上。本发明还提供了包含本发明化合物的药物组合物,所述药物组合物任选包含药学上可接受的赋形剂。
在具体的实施方式中,本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐以及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。
“药学上可以接受的赋形剂或载体”是指:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量。本发明的化合物和药物组合物可通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服,一次性服用或分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的优点:
1.本发明的化合物是结构全新的EGFR抑制性化合物;和
2.本发明的化合物能够显著抑制EGFR 19del/T790M/C797S三突变,从而能够开发作为新一代的EGFR抑制剂并且为开发新一代的EGFR抑制剂奠定了全新的物质基础。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例
材料
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
制备方法
本发明的化合物的制备方法可以是本领域的常规方法,也可以采用本发明的合成路线。
吲哚类化合物合成方案
其中,各个步骤的反应试剂和条件如下所示:
(a)DMSO,KOH,25℃,1h,3-chloropropan-1-ol,8h,36%;
(b)DCE,AlCl3,0℃,2,4-dichloropyrimidine,55℃,1.5h,31%;
(c)TsOH,2-pentanol,4-fluoro-2-methoxy-5-nitroaniline,105℃,2.5h,76%;
(d)Fe,MeOH/DCM,AcOH,55℃,4h;
(e)acryloyl chloride,DCM,DIPEA,0℃,1.5h,35%;
(f)N,N,N-trimethylethane-1,2-diamine,DMF,K2CO3,110℃,3h,60%;
(g)Pd/C,H2,MeOH,25℃,5h.
实施例1:化合物1的合成
3-(1H-吲哚-1-基)丙-1-醇(2b)的合成(步骤a)
称取氢氧化钾(4.48g,80.0mmol)于250mL单口瓶,加入二甲基亚砜100mL,室温搅拌15min,加入2a(4.46g,40.0mmol),室温反应1h,向溶液中逐滴加入3-氯-1-丙醇(5.67g,60.0mmol),室温反应,TLC监测,反应8h,反应结束,加入大量水淬灭,用乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,旋干溶剂,粗品经硅胶柱层析,以石油醚:乙酸乙酯=20:1分离,得到2c黄色液体2.59g,收率36%。
1H NMR(400MHz,Chloroform-d):δ7.55(d,J=7.9Hz,1H),7.29(d,J=8.2Hz,1H),7.16–7.09(m,1H),7.06–6.97(m,2H),6.41(d,J=3.1Hz,1H),4.17(t,J=6.7Hz,2H),3.47(t,J=6.0Hz,2H),1.94(p,J=6.3Hz,2H),1.59(s,1H).LC-MS:m/z:176.2(M+H)+.
3-(3-(2-氯嘧啶-4-基)-1H-吲哚-1-基)丙-1-醇(2c)的合成(步骤b)
将2b(2.59g,14.7mmol)溶于50mL 1,2-二氯乙烷,冰浴至0℃,加入无水三氯化铝(2.81g,21.0mmol),10min后升至室温搅拌15min,加入2,4-二氯嘧啶(1.73g,11.0mmol),升温至55℃并反应1.5h,TLC监测,反应结束,静置冷却至室温,随后冰浴下加入甲醇/水(20mL/10mL),再恢复至室温搅拌30min后,抽滤并收集滤液,并用二氯甲烷萃取,无水硫酸钠干燥,旋干溶剂经硅胶柱层析,以石油醚:乙酸乙酯=20:1分离,得到2c淡黄色固体1.05g,收率31%。
1H NMR(400MHz,Chloroform-d):δ8.30(d,J=5.4Hz,1H),8.26–8.19(m,1H),7.92(s,1H),7.45–7.31(m,2H),7.27–7.19(m,2H),4.27(t,J=6.7Hz,2H),3.54(t,J=5.7Hz,2H),2.02(p,J=6.3Hz,2H).LC-MS:m/z:288.1(M+H)+.
3-(3-(2-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-1-基)丙-1-醇(2e)的合成(步骤c)
将4-甲基苯磺酸水合物(0.75g,4.3mmol)一次性加入到含有2c(1.05g,3.6mmol)和4-氟-2-甲氧基-5-硝基苯胺(0.75g,4.0mmol)的25mL 2-戊醇溶液中。所得混合物在105℃下搅拌2.5h。TLC监测,结束反应,将该混合物冷却至室温。过滤,滤饼用冰的2-戊醇洗涤,收集滤饼并真空干燥,得到2d黄色固体1.225g,收率76%。
1H NMR(400MHz,DMSO-d6):δ10.21(s,1H),8.83(s,1H),8.73(d,J=8.2Hz,1H),8.37(d,J=6.6Hz,1H),8.16(s,1H),7.65(d,J=8.3Hz,1H),7.58–7.48(m,2H),7.30(t,J=7.4Hz,1H),7.11(q,J=7.5,6.8Hz,1H),4.37(t,J=7.0Hz,2H),4.00(s,3H),3.43(t,J=6.0Hz,2H),2.52(p,J=1.9Hz,1H),2.00(p,J=6.5Hz,2H).LC-MS:m/z:438.2(M+H)+.
3-(3-(2-((5-氨基-4-氟-2-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-1-基)丙-1-醇(2f)的合成(步骤d)
将2d(600.00mg,1.4mmol)溶于混合溶剂(二氯甲烷∶甲醇=3:1)40mL中,加入铁粉(2.92g,52.1mmol)和冰醋酸12mL,搅拌,于55℃反应4h。TLC监测,反应结束,过滤,将滤液浓缩至干,向残余物加入饱和碳酸氢钠溶液调节pH至碱性。用乙酸乙酯萃取,收集有机相并用无水硫酸钠干燥,旋干溶剂,直接用于下一步反应。
N-(2-氟-5-((4-(1-(3-羟丙基)-1H-吲哚-3基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(1)的合成(步骤e)
将溶于3.5mL二氯甲烷中的丙烯酰氯(128.00mg,1.4mmol)滴加到溶于16mL二氯甲烷的2e(500.00mg,1.2mmol)和N,N-二异丙基乙胺(0.24mL,1.4mmol)的溶液中,在冰水浴中冷却。将混合物搅拌1.5h,TLC监测,反应结束,使用少量二氯甲烷稀释并用饱和碳酸氢钠水溶液洗涤。收集有机相,同时将含水层用二氯甲烷再次萃取,合并有机相并用无水硫酸钠干燥,旋干溶剂经硅胶柱层析,以二氯甲烷:甲醇=200:1分离,得到化合物1黄色固体200mg,收率35%。
1H NMR(400MHz,DMSO-d6):δ9.88(s,1H),8.61(d,J=8.5Hz,1H),8.47(s,1H),8.32(dd,J=8.7,6.5Hz,2H),8.09(s,1H),7.56(d,J=8.2Hz,1H),7.31–7.18(m,2H),7.18–7.07(m,2H),6.59(dd,J=17.0,10.2Hz,1H),6.26(dd,J=17.1,2.0Hz,1H),5.76(dd,J=10.2,2.0Hz,1H),4.69(s,1H),4.33(t,J=7.0Hz,2H),3.87(s,3H),3.40(t,J=6.2Hz,2H),1.96(p,J=6.6Hz,2H).13C NMR(151MHz,DMSO):δ163.79,162.58,160.30,151.53,149.93,148.22,137.47,133.06,132.01,127.26,125.97,125.04,122.59,122.39,121.39,118.59,117.76,113.01,110.99,107.87,100.23,58.19,56.85,43.56,33.24.HRMS(EI)(m/z):calcd for C25H24FN5O3[M]+461.1863,found461.1862.
实施例2:N-(2-氟-5-((4-(1-(3-羟丙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(2)的合成(步骤e)
化合物2是参照化合物1的合成路线得到。淡黄色固体,收率为23%。
1H NMR(400MHz,DMSO-d6):δ9.54(s,1H),8.49(d,J=8.6Hz,1H),8.46(s,1H),8.35(d,J=8.0Hz,1H),8.31(d,J=5.4Hz,1H),8.00(s,1H),7.57(d,J=8.2Hz,1H),7.27–7.21(m,2H),7.19–7.13(m,1H),7.08(d,J=12.2Hz,1H),4.70(t,J=4.9Hz,1H),4.34(t,J=7.0Hz,2H),3.86(s,3H),3.42(q,J=5.8Hz,2H),2.37(q,J=7.5Hz,2H),1.97(p,J=6.5Hz,2H),1.08(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO-d6):δ172.49,162.45,160.50,157.76,151.61,150.02,147.90,137.45,132.90,126.00,125.07,122.56,121.31,118.90,118.12,113.02,110.97,107.84,100.13,58.20,56.81,43.53,33.25,29.28,10.19.HRMS(EI)(m/z):calcd for C25H24FN5O3[M]+463.2020,found 463.2021.
3-(3-(2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-1-基)丙-1-醇(2i)的合成
将N,N,N'-三甲基乙二胺(35.00mg,0.3mmol)、N,N-二异丙基乙胺(46.00mg,0.3mmol)和2.5mL N,N-二甲基乙酰胺依次装入10mL单口瓶,25℃反应0.5h,之后加入2d(108.00mg,0.6mmol),升温至85℃反应3h,TLC监测,停止反应,静置至室温,加入饱和食盐水和乙酸乙酯萃取,收集有机相并用无水硫酸钠干燥,抽滤,滤液旋干经硅胶柱层析,以二氯甲烷:甲醇=20:1分离,得到2i黄红色固体84mg,收率65%。
1H NMR(400MHz,Chloroform-d):9.50(s,1H),9.00(s,1H),8.30(d,J=5.2Hz,1H),8.03–7.94(m,1H),7.67(s,1H),7.41–7.33(m,1H),7.19(dq,J=8.0,5.3Hz,3H),6.71(s,1H),4.54(t,J=5.8Hz,2H),3.73(s,3H),3.51(t,J=5.2Hz,2H),2.95–2.88(m,2H),2.62(s,3H),2.43(q,J=7.7Hz,2H),2.32(s,6H),2.00(p,J=5.2Hz,2H).
实施例3:N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(1-(3羟丙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(3)的合成
淡橙色固体,收率26%。
1H NMR(400MHz,Chloroform-d):δ9.84(s,1H),9.50(s,1H),9.00(s,1H),8.30(d,J=5.2Hz,1H),8.03–7.94(m,1H),7.67(s,1H),7.41–7.33(m,1H),7.19(dq,J=8.0,5.3Hz,3H),6.67(s,1H),4.44(t,J=5.8Hz,2H),3.79(s,3H),3.48(t,J=5.2Hz,2H),2.95–2.88(m,2H),2.59(s,3H),2.49(q,J=7.7Hz,2H),2.38(s,2H),2.29(s,6H),2.00(p,J=5.2Hz,2H),1.28(t,J=7.6Hz,3H).13C NMR(151MHz,CDCl3-d6)δ173.20,161.94,159.52,158.07,144.35,137.12,134.86,134.36,129.30,127.77,126.26,121.84,121.03,120.37,113.58,110.55,109.76,107.95,104.66,57.49,57.23,56.11,55.79,45.29,44.32,42.54,32.54,31.26,10.90.HRMS(EI)(m/z):calcd forC30H39N7O3[M]+545.3114,found 545.3111.
N1-(3-甲氧基-4-硝基苯基)-N1,N2,N2-三甲基乙烷-1,2-二胺(2g)的合成(步骤f)
将2f(425.00mg,2.5mmol)溶于5mL N,N-二甲基甲酰胺,依次向其中加入N,N,N'-三甲基乙二胺(380.00mg,3.72mmol)和碳酸钾(750.00mg,4.9mmol),于110℃下反应3h,TLC监测,反应结束冷却至室温,加入水,并用乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,抽滤,旋干滤液经硅胶柱层析,以二氯甲烷:甲醇=100:1分离,得到2g黄绿色液体370mg,收率60%。
1H NMR(400MHz,Chloroform-d):δ8.00–7.86(m,1H),6.17(ddd,J=9.5,6.8,2.4Hz,1H),6.11–6.00(m,1H),3.89(dd,J=5.8,1.8Hz,3H),3.48(q,J=6.8Hz,2H),3.09–2.98(m,3H),2.45(dt,J=10.3,6.4Hz,2H),2.24(dd,J=5.6,1.8Hz,6H)。LC-MS:m/z:254.3(M+H)+.
N1-(3-甲氧基-4-胺基苯基)-N1,N2,N2-三甲基乙烷-1,2-二胺(2h)的合成(步骤g)
将2g(250.00mg,1.0mmol)装入50mL三口瓶,加入10mL甲醇,溶解后加入钯碳(50.00mg,20%),氢气置换三次,于25℃反应5h,硅藻土助滤,收集滤液,旋干,直接用于下一步反应。
实施例4:3-(3-(2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-1-基)丙-1-醇(4)的合成
绿色固体,收率14%。
1H NMR(400MHz,Chloroform-d):δ8.30–8.25(m,1H),8.23–8.17(m,2H),7.84(s,1H),7.38–7.31(m,1H),7.25(s,1H),7.22–7.13(m,3H),6.91(d,J=5.3Hz,1H),6.38(dd,J=8.8,2.7Hz,1H),6.32(d,J=2.7Hz,1H),4.27(t,J=6.7Hz,2H),3.80(s,3H),3.54(t,J=5.8Hz,2H),3.47(t,J=7.4Hz,2H),2.87(s,3H),2.63(t,J=7.3Hz,2H),2.39(s,6H),2.01(p,J=6.4Hz,2H).13C NMR(151MHz,DMSO-d6):δ162.59,161.61,157.33,152.88,146.91,146.10,138.16,132.17,126.23,125.98,123.18,122.52,121.02,119.12,113.22,110.77,106.71,104.46,97.44,58.15,55.92,54.72,49.35,44.68,43.46,39.07,33.18,21.26.HRMS(EI)(m/z):calcd for C27H34N6O2[M]+474.2743,found 474.2745.
7-乙烯基-1H-吲哚(2k)的合成
将甲基三苯基碘化(1.30g,3.2mmol)装入100mL三口瓶,氮气置换三次,加入10mL无水四氢呋喃,通过恒压滴液漏斗向三口瓶中逐滴加入双(三甲基硅烷基)氨基钾(3.22mL,3.2mmol)和10mL无水四氢呋喃混合液,25℃反应1h,加入2j(188.00mg,1.3mmol)并于25℃反应2h,TLC监测,停止反应,饱和氯化铵溶液淬灭,加入水与乙酸乙酯萃取,无水硫酸钠干燥,抽滤,旋干滤液经硅胶柱层析,以石油醚:乙酸乙酯=15:1分离,得到中间体淡绿色液体171mg,收率90%。冰浴下,将中间体装入100mL三口瓶,加入10mL无水四氢呋喃混合,氮气置换三次,逐滴加入硼烷四氢呋喃(5mL,5.0mmol),滴加完毕,恢复至室温,反应1h,之后再逐滴缓慢加入氢氧化钠溶液(10mL,1mol/L)以及双氧水(10mL,30%),回流反应1h,TLC监测,反应结束,冷却至室温并加入15mL饱和亚硫酸钠溶液,乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,抽滤,滤液经硅胶柱层析,以石油醚;乙酸乙酯=20:1分离,得到2k淡绿色液体38mg,收率20%。
1H NMR(400MHz,Chloroform-d):δ8.91(s,1H),7.46(d,J=7.8Hz,1H),7.09(t,J=2.8Hz,1H),6.98(t,J=7.5Hz,1H),6.89(d,J=7.0Hz,1H),6.47(dd,J=3.2,2.0Hz,1H),3.87(t,J=5.8Hz,2H),2.98(t,J=5.7Hz,2H).LC-MS:m/z:162.2(M+H)+.
实施例5:2-(3-(2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-7-基)乙醇(10)的合成
化合物10是参照化合物4的合成路线得到。淡黄色固体,收率23%。
1H NMR(400MHz,DMSO-d6):δ11.69(d,J=3.0Hz,1H),8.24(d,J=6.7Hz,1H),8.21(d,J=3.0Hz,1H),8.18(d,J=5.3Hz,1H),7.78(s,1H),7.63(d,J=8.7Hz,1H),7.15(d,J=5.3Hz,1H),6.99(q,J=4.2Hz,2H),6.42(d,J=2.6Hz,1H),6.32(dd,J=8.8,2.6Hz,1H),4.71(t,J=5.1Hz,1H),3.80(s,3H),3.71(td,J=7.0,4.8Hz,2H),3.49(t,J=7.2Hz,2H),3.03(t,J=7.0Hz,2H),2.94(s,3H),2.57(s,2H),2.32(s,6H).13C NMR(151MHz,DMSO-d6):δ167.54,164.71,156.53,153.88,147.54,144.32,139.21,134.32,127.63,126.32,122.78,122.62,120.32,119.54,113.73,110.81,106.82,103.86,97.74,60.25,55.52,54.42,49.43,44.78,43.46,33.32.HRMS(EI)(m/z):calcd for C26H32N6O2[M]+460.2587,found460.2581.
实施例6:N-(2-氟-5-((4-(6-氟-1-(3-羟基丙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(5)的合成
化合物5是参照化合物1的合成路线得到。黄色固体,收率21%。
1H NMR(400MHz,DMSO-d6):δ9.54(s,1H),8.45(s,1H),8.33(dd,J=21.5,6.9Hz,3H),8.17(s,1H),7.46(dd,J=10.2,2.4Hz,1H),7.23(d,J=5.5Hz,1H),7.09(d,J=12.1Hz,1H),6.99(td,J=9.2,2.3Hz,1H),4.30(t,J=6.9Hz,2H),3.85(s,3H),3.41(t,J=6.1Hz,2H),2.35(q,J=7.5Hz,2H),1.96(p,J=6.6Hz,2H),1.07(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO):δ172.50,162.42,160.42,158.85,152.08,150.45,148.58,137.74,133.58,124.70,123.93,122.68,119.81,118.12,113.25,109.64,107.61,100.35,97.58,58.09,56.79,43.67,33.09,29.24,10.13.HRMS(EI)(m/z):calcd for C25H25F2N5O3[M]+481.1925,found 481.1927.
2-(1H-吲哚-1-基)乙醇(2l)的合成
将2-溴乙醇(230.00mg,1.8mmol)装入25mL单口瓶,加入4mL二氯甲烷溶解,随后依次加入叔丁基二甲基氯硅烷(300.00mg,2.0mmol)和咪唑(140.00mg,2.0mmol),于25℃反应3h,抽滤,二氯甲烷洗涤,收集滤液,旋干得到中间体,称取2a(108.00mg,0.9mmol)和氢化钠(72.00mg,1.8mmol)置于50mL两口瓶中,氮气置换3次,冰浴下,缓慢加入无水7mL N,N-二甲基甲酰胺溶液,搅拌15分钟后,加入中间体,升温至100℃反应4h,TLC监测,反应结束冷却至室温,加水淬灭并用二氯甲烷萃取,收集有机相,无水硫酸钠干燥,旋干得到2l黄色液体230mg,收率80%。
1H NMR(400MHz,Chloroform-d):δ7.55(d,J=7.9Hz,1H),7.29(d,J=8.2Hz,1H),7.16–7.09(m,1H),7.06–6.97(m,2H),6.41(d,J=3.1Hz,1H),4.09(t,J=6.7Hz,2H),3.50(t,J=6.0Hz,2H),.LC-MS:m/z:162.2(M+H)+.
实施例7:N-(2-氟-5-((4-(1-(2-羟乙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(6)的合成
化合物6是参照化合物1的合成路线得到。白色固体,收率23%。
1H NMR(400MHz,DMSO-d6):δ9.51(s,1H),8.48(d,J=8.4Hz,1H),8.42(s,1H),8.32(dd,J=13.6,6.7Hz,2H),7.97(s,1H),7.57(d,J=8.1Hz,1H),7.22(t,J=6.2Hz,2H),7.15(t,J=7.5Hz,1H),7.07(d,J=12.0Hz,1H),4.96(t,J=5.1Hz,1H),4.32(t,J=5.5Hz,2H),3.86(s,3H),3.79(q,J=5.4Hz,2H),2.36(q,J=7.5Hz,2H),1.07(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO):δ172.48,172.45,162.52,160.49,157.72,151.66,150.06,147.97,147.90,137.73,133.47,126.04,125.08,122.40,121.25,118.94,118.09,118.00,112.86,111.19,107.80,100.21,100.05,60.44,56.81,49.25,29.25,10.16.HRMS(EI)(m/z):calcdfor C24H24FN5O3[M]+449.1863,found449.1862.
实施例8:N-(2-氟-5-((4-(1-(4-羟基丁基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(7)的合成
化合物7是参照化合物1的合成路线得到。土黄色固体,收率10%。
1H NMR(400MHz,DMSO-d6):δ9.54(s,1H),8.52(s,1H),8.48(d,J=8.6Hz,1H),8.31(t,J=7.3Hz,2H),8.13(s,1H),7.58(d,J=8.2Hz,1H),7.28–7.21(m,2H),7.16(t,J=7.5Hz,1H),7.08(d,J=12.2Hz,1H),4.30(t,J=7.0Hz,2H),3.86(s,3H),3.41(t,J=6.4Hz,2H),2.37(q,J=7.6Hz,2H),1.92–1.79(m,2H),1.51–1.35(m,2H),1.08(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO):δ172.52,137.54,126.01,122.79,122.52,121.61,112.83,111.21,107.61,100.44,100.27,60.71,56.84,46.54,30.14,29.29,26.88,10.18.HRMS(EI)(m/z):calcd for C26H28FN5O3[M]+477.2176,found 477.2179.
1H-吲哚-2-甲醛(2n)的合成
冰浴下,将2m(806.00mg,5.0mmol)装入100mL三口瓶,加入30mL无水四氢呋喃溶解,边搅拌边分批加入四氢铝锂(380.00mg,10.0mmol),加入完毕恢复至室温,反应14h,反应结束,饱和氯化铵溶液淬灭,抽滤,收集滤液并用乙酸乙酯萃取,无水硫酸钠干燥,旋干溶剂得到中间体。将中间体溶解于10mL二甲基亚砜,加入2-碘酰基苯甲酸(1.70g,6.0mmol),于25℃反应10h,TLC监测,结束反应加入大量水并乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液经硅胶柱层析,以石油醚:乙酸乙酯=20:1分离,得到2n白色固体650mg,收率89%。
1H NMR(400MHz,Chloroform-d):δ9.78(s,1H),9.30(s,1H),7.68(d,J=8.0Hz,1H),7.43–7.37(m,1H),7.32(ddd,J=8.2,6.8,1.1Hz,1H),7.23–7.16(m,1H),7.11(ddd,J=8.0,6.9,1.0Hz,1H).LC-MS:m/z:146.1(M+H)+.
3-(1H-吲哚-2-基)丙-1-醇(2o)的合成
冰浴下,将磷酰基乙酸三乙酯(6.67g,29.7mmol)和氢化钠(1.5g,37.5mmol)装入100mL三口瓶,缓慢加入20mL无水四氢呋喃溶解,搅拌1h后,通过恒压滴液漏斗逐滴加入溶于20mL无水四氢呋喃的2n(3.60g,24.8mmol)溶液,于25℃反应10h,TLC监测,结束反应用饱和氯化铵溶液淬灭反应,旋干溶剂,用水与乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液得到中间体。冰浴下,将四氢铝锂(2.00g,52.6mmol)缓慢加入到30mL无水四氢呋喃溶液中,接着向其中缓慢加入溶于30mL无水四氢呋喃的中间体溶液,于20℃反应8h,TLC监测,结束反应,加水淬灭并用乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液经硅胶柱层析,以石油醚:乙酸乙酯=8:1分离得到2o白色固体2.58g,收率60%。
1H NMR(400MHz,Chloroform-d):δ8.15(s,1H),7.44(dd,J=7.2,1.6Hz,1H),7.20–7.13(m,1H),7.00(dtd,J=16.2,7.2,1.3Hz,2H),6.16–6.09(m,1H),3.57(t,J=6.1Hz,2H),2.70(t,J=7.3Hz,2H),1.81(tt,J=7.3,6.1Hz,2H).LC-MS:m/z:176.2(M+H)+.
实施例9:N-(2-氟-5-((4-(2-(3-羟基丙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(8)的合成
化合物8是参照化合物1的合成路线得到。黄褐色固体,收率23%。
1H NMR(400MHz,DMSO-d6):δ11.56(s,1H),9.45(s,1H),8.36(d,J=5.3Hz,1H),8.29(d,J=8.5Hz,1H),8.07–7.94(m,2H),7.36(d,J=7.9Hz,1H),7.14–7.01(m,4H),4.60(d,J=5.2Hz,1H),3.85(s,3H),3.44(q,J=5.6Hz,2H),3.11(t,J=7.8Hz,2H),2.31(q,J=7.5Hz,2H),1.85(p,J=6.7Hz,2H),1.05(t,J=7.5Hz,3H).13CNMR(151MHz,DMSO):δ172.41,163.18,160.64,157.83,143.57,135.84,126.99,125.08,121.73,120.60,119.76,111.56,110.31,109.85,100.17,60.76,56.82,32.64,29.12,24.61,10.17.HRMS(EI)(m/z):calcdfor C25H26FN5O3[M]+463.2020,found463.2023.
实施例10:N-(2-氟-5-((4-(7-(2-羟基乙基)-1H-吲哚-3-基)嘧啶-2-基)氨基)-4-甲氧基苯基)丙酰胺(9)的合成
化合物9是参照化合物1的合成路线得到。浅黄色固体,收率22%。
1H NMR(400MHz,DMSO-d6):δ11.73(d,J=3.0Hz,1H),9.50(s,1H),8.36(d,J=8.6Hz,1H),8.30(d,J=3.0Hz,1H),8.27(d,J=5.4Hz,1H),8.25–8.19(m,1H),7.99(s,1H),7.29(d,J=5.4Hz,1H),7.10–6.97(m,3H),4.71(t,J=5.0Hz,1H),3.85(s,3H),3.72(td,J=7.0,4.7Hz,2H),3.04(t,J=7.0Hz,2H),2.33(q,J=7.6Hz,2H),1.06(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO):δ172.48,172.45,162.52,160.49,157.72,151.66,150.06,147.97,148.91,137.73,133.47,126.04,125.08,122.40,121.25,118.95,118.06,118.00,112.86,112.19,107.80,100.21,99.05,60.44,56.81,49.25,29.25,10.16.HRMS(EI)(m/z):calcd for C24H24FN5O3[M]+449.1863,found449.1862.
实施例11:N-(2-氟-5-((6-(6-氟-1-(3-羟基丙基)-1H-吲哚-3-基)嘧啶-4-基)氨基)-4-甲氧基苯基)丙酰胺(16)的合成
化合物16是参照化合物1的合成路线得到。白色固体,收率30%。
1H NMR(400MHz,DMSO-d6):δ9.53(s,1H),8.72(s,1H),8.54(d,J=1.0Hz,1H),8.31(dd,J=8.9,5.6Hz,1H),8.26(d,J=8.5Hz,1H),8.15(s,1H),7.47(dd,J=10.2,2.4Hz,1H),7.29(s,1H),7.12–6.98(m,2H),4.67(t,J=5.0Hz,1H),4.29(t,J=6.8Hz,2H),3.87(s,3H),2.35(q,J=7.5Hz,2H),1.92(q,J=6.5Hz,2H),1.08(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO):δ172.59,161.36,158.75,158.30,137.65,131.87,124.23,122.90,122.51,120.49,117.99,113.68,109.42,109.27,100.36,97.58,58.04,56.80,43.43,33.03,29.15,10.18.HRMS(EI)(m/z):calcd for C25H25F2N5O3[M]+481.1925,found481.1927.
三取代咪唑类化合物的合成方案
其中,各个步骤的反应试剂和条件如下所示:
(h)SeO2,1,4-dioxane,H2O,100℃,overnight;
(i)HCl,H2O,25℃,5h;
(j)NH4OAc,MeOH,25℃,overnight,6%;
(k)Pd/C,H2,MeOH,25℃,6h,69%;
(l)2-(1-oxoisoindolin-2-yl)-2-phenylacetic acid,HATU,DIPEA,DMF,25℃,6h,5%;
(m)NIS,MeCN,80℃,16h,30%;
(n)1,4-dioxane,K2CO3,H2O,Pd(dppf)Cl2·CH2Cl2,N-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine,90℃,12h,32%.
3-(4-(4-硝基苯基)-1H-咪唑-2-基)丙-1-醇(2t)的合成(步骤j)
将二氧化硒(5.36g,48.7mmol)装入250mL三口瓶,加入60mL 1,4-二氧六环和20mL水于55℃搅拌溶解,待彻底溶解后,加入2p(2.00g,12.1mmol),升温至100℃,反应10h,结束反应冷却至室温,抽滤,并用硅藻土助滤,收集滤液并用乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液经硅胶柱层析,得到2q中间体。冰浴下,称取盐酸(14mL,2mol/L)装入50mL三口瓶中,将2r(1.40g,20.0mmol)逐滴加入,搅拌0.5h,恢复至室温继续反应5h,TLC检测,结束反应用二氯甲烷萃取,收集有机相,旋干溶剂,得到中间2s。将2s和醋酸铵(4.90g,63.6mmol)依次装入250mL单口瓶,加入30mL甲醇溶解,2p溶于60mL甲醇中,并将其逐滴滴加至单口瓶中,25℃反应过夜,TLC检测,结束反应将溶剂浓缩,使用饱和碳酸氢钠调节pH值至7,加入乙酸乙酯萃取,无水硫酸钠干燥,抽滤,滤液经硅胶柱层析,以二氯甲烷:甲醇=150:1分离,得到2t黄色液体260mg,收率6%。
1H NMR(400MHz,DMSO-d6):δ8.25–8.17(m,2H),8.02–7.94(m,2H),7.81(s,1H),3.48(t,J=6.3Hz,2H),2.72(dd,J=8.2,7.1Hz,2H),1.85(dq,J=8.1,6.4Hz,2H)..LC-MS:m/z:248.1(M+H)+.
3-(4-(4-氨基苯基)-1H-咪唑-2-基)丙-1-醇(2u)的合成(步骤k)
将2t(184.00mg,0.8mmol)、钯碳(40.00mg,20%)和12mL甲醇依次装入100ml单口瓶,氢气置换三次,25℃,反应6h,TLC监测,结束反应,硅藻土助滤,滤液经硅胶柱层析,以二氯甲烷:甲醇=40:1分离,得到2u橙黄色液体112mg,收率69%。
1H NMR(400MHz,DMSO-d6):δ7.39–7.31(m,2H),7.09(s,1H),6.60–6.51(m,2H),3.47(t,J=6.3Hz,2H),2.67(t,J=7.6Hz,2H),1.89–1.73(m,2H).LC-MS(m/z):218.1(M+H)+.
2-(1-氧代异吲哚啉-2-基)-2-苯基乙酸(2w)的合成
将邻苯二甲醛(1.00g,7.5mmol)装入250mL单口瓶,用35mL乙腈溶解,加入D,L-苯甘氨酸(1.13g,7.5mmol)和2mL醋酸,氮气置换3次,回流反应3h,TLC监测,反应结束,抽滤,淋洗滤饼并真空干燥得到2w黑色固体1.3g,收率65%。1H NMR(400MHz,DMSO-d6):δ13.39(s,1H),7.75(d,J=7.5Hz,1H),7.60(td,J=7.4,1.2Hz,1H),7.57–7.49(m,2H),7.50–7.37(m,5H),6.00(s,1H),4.64(d,J=17.4Hz,1H),3.92(d,J=17.4Hz,1H).LC-MS:m/z:268.1(M+H)+.
实施例12:N-(3-(2-(3-羟丙基)-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(11)的合成
将2u(176.00mg,0.8mmol)、2w(108.00mg,0.4mmol)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸盐(308.00mg,0.8mmol)装入25mL单口瓶中,加入2.5mL N,N-二甲基甲酰胺溶解,搅拌下加入N,N-二异丙基乙胺(212.00mg,1.6mmol),25℃反应6h,TLC监测,反应结束用水与乙酸乙酯萃取,收集有机相,无水硫酸钠干燥,抽滤,滤液经硅胶柱层析,以二氯甲烷:甲醇=200:1分离,得到11白色固体20mg,收率5%。
1H NMR(400MHz,DMSO-d6):δ10.57(s,1H),8.01(d,J=1.8Hz,1H),7.76(d,J=7.5Hz,1H),7.65–7.35(m,12H),7.29(t,J=7.9Hz,1H),6.24(s,1H),4.85(d,J=17.7Hz,1H),3.97(d,J=17.6Hz,1H),3.45(t,J=6.3Hz,2H),2.70(t,J=7.6Hz,2H),1.82(p,J=6.8Hz,2H).13C NMR(151MHz,DMSO):δ168.63,168.18,149.08,142.88,139.32,135.93,132.16,132.00,129.49,129.08,128.93,128.43,124.12,123.41,120.28,117.77,115.72,60.62,59.02,48.90,31.58,24.94.HRMS(ESI)(m/z):calcd forC39H34N6O3[M+H]+467.2083,found 467.2084.
实施例13:N-(4-(2-(3-羟丙基)-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(12)的合成
化合物12是参照化合物11的合成路线得到。土黄色固体,收率8%。
1H NMR(400MHz,DMSO-d6):δ10.55(s,1H),7.76(d,J=7.5Hz,1H),7.70–7.55(m,6H),7.54–7.37(m,7H),6.24(s,1H),4.85(d,J=17.7Hz,1H),3.98(d,J=17.7Hz,1H),3.46(t,J=6.3Hz,2H),2.70(t,J=7.6Hz,2H),1.83(p,J=6.6Hz,2H).13C NMR(151MHz,DMSO)δ168.74,168.23,150.06,148.90,147.73,142.88,138.65,135.71,133.80,132.21,131.94,129.56,129.05,128.46,127.57,126.69,125.79,124.14,123.41,120.11,114.30,112.01,60.23,59.05,48.89,30.85,23.80.HRMS(ESI)(m/z):calcd for C39H34N6O3[M+H]+467.2083,found 467.2084.
3-氯-N-苯基吡啶-2-胺(2x)的合成
将醋酸钯(13.5mg,0.1mmol)和2,2'-双-(二苯膦基)-1,1'-联萘(37.5mg,0.1mmol)装入50mL单口瓶,氮气置换三次,用10mL甲苯溶解,25℃,搅拌10min,随后将溶液转移至含2,3-二氯吡啶(441.00mg,3.0mmol)、苯胺(329.00uL,3.6mmol)、碳酸钾(8.30g,60.0mmol)和17mL甲苯的溶液中,氮气置换3次,回流4h,TLC监测,反应结束冷却至室温,硅藻土助滤,滤液用二氯甲烷萃取,无水硫酸钠干燥,抽滤,收集滤液,旋干滤液经硅胶柱层析,以石油醚:乙酸乙酯=100:1分离,得到2x淡橙色液体267mg,收率43%。
1H NMR(400MHz,Chloroform-d):δ8.03(dd,J=4.8,1.7Hz,1H),7.57–7.51(m,2H),7.46(dd,J=7.7,1.7Hz,1H),7.29–7.22(m,2H),7.00–6.93(m,1H),6.90(s,1H),6.60(dd,J=7.7,4.8Hz,1H).LC-MS:m/z:205.1(M+H)+.
N-苯基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-胺(2y)的合成
将三(二亚苄基丙酮)二钯(12.00mg,0.013mmol)、联硼酸频那醇酯(1.00g,3.9mmol)、2-二环己基磷-2,4,6-三异丙基联苯(13.00mg,0.026mmol)和醋酸钾(385.00mg,3.9mmol)装入50mL三口瓶,氮气置换三次,称取2x(267.00mg,1.3mmol)溶于8mL无水1,4-二氧六环,并将其加入到三口瓶中,于110℃反应16h,TLC监测,反应结束冷却至室温,抽滤,硅藻土助滤,滤液用乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液经硅胶柱层析,以石油醚:乙酸乙酯=20:1分离,得到2y淡橙色液体直接用于下一步的反应。
N-(3-(2-(3-羟丙基)-5-碘-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(2v)的合成(步骤m)
将11(104.00mg,0.2mmol)装入25mL单口瓶中,加入6mL乙腈溶解,搅拌下分批加入N-碘代丁二酰亚胺(61.00mg,0.3mmol),升温至80℃,反应16h,TLC监测,停止反应,冷却至室温,乙酸乙酯萃取,无水硫酸钠干燥,旋干滤液经硅胶柱层析,以二氯甲烷:甲醇=100:1分离,得到2v淡黄色固体40mg,收率30%。
1H NMR(400MHz,DMSO-d6):δ10.51(s,1H),8.11(d,J=1.8Hz,1H),7.76(d,J=7.5Hz,1H),7.65–7.35(m,11H),7.29(t,J=7.9Hz,1H),6.25(s,1H),4.82(d,J=17.7Hz,1H),3.82(d,J=17.6Hz,1H),3.41(t,J=6.3Hz,2H),2.81(t,J=7.6Hz,2H),1.91(p,J=6.8Hz,2H).LC-MS:m/z:593.1(M+H)+.
实施例14:N-(3-(2-(3-羟基丙基)-5-(2-(苯基氨基)吡啶-3-基)-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基基)-2-苯基乙酰胺(13)的合成
将碳酸钾(24.00mg,0.2mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(6.00mg,0.007mmol)依次装入25mL三口瓶中,氮气置换三次,加入溶于4mL 1,4-二氧六环与1mL水的2v、2y溶液,于90℃反应14h,TLC监测,反应结束冷却至室温,用乙酸乙酯萃取,无水硫酸钠干燥,抽滤,收集有机相,旋干滤液经硅胶柱层析,以二氯甲烷:甲醇=100:1分离,得到13白色固体14mg,收率32%。
1H NMR(400MHz,Chloroform-d):δ9.95(s,1H),8.98(s,1H),8.03(d,J=4.8Hz,1H),7.69(d,J=7.6Hz,1H),7.61–7.32(m,11H),7.24–7.10(m,3H),6.97–6.73(m,3H),6.49(s,1H),6.44(q,J=7.1,6.5Hz,1H),4.86(d,J=17.5Hz,1H),4.00(d,J=17.5Hz,1H),3.56(t,J=5.5Hz,2H),2.83(d,J=7.0Hz,2H),1.91(s,2H).13CNMR(151MHz,DMSO):δ168.54,168.31,154.02,149.33,144.23,143.29,141.73,139.49,135.23,132.71,132.11,131.84,129.37,129.17,129.07,129.01,128.85,128.31,128.10,126.36,124.35,124.11,120.72,120.33,118.34,116.37,114.64,60.24,59.34,48.69,31.70,23.87.HRMS(ESI)(m/z):calcd for C39H34N6O3[M+H]+635.2771,found 635.2772.
实施例15:N-(4-(2-(3-羟基丙基)-5-(2-(苯基氨基)吡啶-3-基)-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基基)-2-苯基乙酰胺(14)的合成
化合物14是参照化合物13的合成路线得到。白色固体,收率25%。
1H NMR(400MHz,DMSO-d6):δ12.41(s,1H),10.72(s,1H),10.66(s,1H),8.05(dd,J=4.8,1.9Hz,1H),7.76(d,J=7.6Hz,1H),7.68(dd,J=15.3,8.2Hz,3H),7.63–7.54(m,2H),7.54–7.40(m,5H),7.36(dd,J=8.4,2.0Hz,3H),7.28(t,J=7.7Hz,2H),6.89(t,J=7.4Hz,1H),6.62(dd,J=7.5,4.9Hz,1H),6.23(s,1H),4.83(d,J=17.7Hz,1H),4.61(t,J=5.1Hz,1H),3.98(d,J=17.7Hz,1H),3.56(q,J=6.0Hz,2H),2.82(t,J=7.6Hz,2H),1.97(p,J=6.9Hz,2H).13C NMR(151MHz,DMSO):δ168.74,168.21,153.08,148.23,145.73,142.89,141.89,138.39,135.73,132.20,132.01,131.94,129.57,129.17,129.08,129.02,128.95,128.46,128.00,126.66,124.16,123.41,120.88,120.00,118.60,115.27,114.34,60.60,59.04,48.89,31.40,24.77.HRMS(ESI)(m/z):calcd for C39H34N6O3[M+H]+635.2771,found 635.2772.
N-苯基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2-胺(2z)的合成
将[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(31.00mg,0.04mmol)、联硼酸频那醇酯(480.00mg,2.0mmol)、4-溴-7-氮杂吲哚(184.00mg,1.0mmol)和醋酸钾(240.00mg,3.0mmol)依次装入25mL三口瓶,氮气置换三次,加入无水1,4-二氧六环,于90℃反应18h,TLC监测,停止反应,冷却至室温,抽滤,硅藻土助滤,用乙酸乙酯萃取,无水硫酸钠干燥,抽滤,滤液旋干,得到2z直接用于下一步的反应。
实施例16:N-(3-(2-(3-羟基丙基)-5-(2-(苯基氨基)吡啶-3-基)-1H-咪唑-4-基)苯基)-2-(1-氧代异吲哚啉-2-基基)-2-苯基乙酰胺(15)的合成
将碳酸钾(59.00mg,0.4mmol)、[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(14.00mg,0.017mmol)依次装入25mL三口瓶中,氮气置换三次,加入溶于5mL 1,4-二氧六环与1.25mL水的2v、2z溶液,于90℃反应12h,TLC监测,反应结束冷却至室温,用乙酸乙酯萃取,无水硫酸钠干燥,抽滤,旋干滤液经硅胶柱层析,以二氯甲烷:甲醇=100:1分离,得到15白色固体10mg,收率10%。
1H NMR(400MHz,Chloroform-d):δ9.95(s,1H),8.98(s,1H),8.03(d,J=4.8Hz,1H),7.69(d,J=7.6Hz,1H),7.61–7.32(m,11H),7.24–7.10(m,3H),6.97–6.73(m,3H),6.49(s,1H),6.44(q,J=7.1,6.5Hz,1H),4.86(d,J=17.5Hz,1H),4.00(d,J=17.5Hz,1H),3.56(t,J=5.5Hz,2H),2.83(d,J=7.0Hz,2H),1.91(s,2H).13CNMR(151MHz,DMSO):δ168.68,168.17,149.57,142.86,139.22,136.37,135.79,132.18,131.93,130.07,129.53,128.97,128.44,126.64,124.37,124.13,123.40,118.83,117.59,115.26,100.73,60.53,58.87,48.84,29.48,22.56,14.43.HRMS(ESI)(m/z):calcd for C39H34N6O3[M+H]+635.2771,found635.2772.
生物评价方法:
酪氨酸激酶:EGFR(WT)
EGFRT790M/L858R(LR/TM)
EGFRT790M/L858R/C797S(LR/TM/CS)
ELISA激酶活性检测
用酶联免疫吸附法(Enzyme-Linked Immunosorbent Assay,ELISA)检测激酶磷酸化底物的能力,计算化合物对激酶活性的抑制作用。激酶采用EGFRL858R/T790M/C797S(购自BPS Bioscience)。
ELISA主要步骤如下:酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS稀释成2.5μg/孔,37℃反应12-16h包被酶标板,备用。每孔加入用反应缓冲液(50mM HEPES pH 7.4,20mM MgCl2,0.1mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP(终浓度5μM)溶液,加入化合物或溶剂对照,然后加入激酶启动反应,37℃摇床反应1h。T-PBS洗板三次,加入抗体PY99(含5mg/mL BSA的T-PBS,1:500稀释)100μL于37℃摇床反应0.5h。T-PBS洗板后,加入辣根过氧化物酶标记的羊抗鼠的IgG(含5mg/mL BSA的T-PBS,1:2000稀释)100μL,37℃摇床反应0.5h。再次洗板后,加入含0.03%H2O2,2mg/mL的OPD(0.1mol/L,pH 5.4柠檬酸盐缓冲液配制)显色液100μL/孔,25℃避光反应1-10min。加入50μL/孔2M H2SO4终止反应,用可调波长式微孔板酶标仪(SpectraMax Plus384,Molecular Devices)读数,波长为490nm。IC50值由抑制曲线得到。
酶活性测试结果如下表:
a激酶活性测试通过使用ELISA基EGFR-TK测试进行。数据是至少两次独立测定的平均值并以平均值±SD(标准偏差)表示。b二突变体(EGFRL858R/T790M).c三突变体(EGFRL858R /T790M/C797S).
a激酶活性测试通过使用ELISA基EGFR-TK测试进行。数据是至少两次独立测定的平均值并以平均值±SD表示。
细胞增殖抑制测试
酪氨酸激酶:EGFRT790M/19DEL/C797S
测试方法:实验选用小鼠原B细胞株BaF3细胞株和EGFR19del/T790M/C797S-BaF3。实验起始选取对数生长期的细胞,96孔板中设立3组表达19del+T790M+C797S突变的细胞,每组细胞的数量为5000,分别使药物最高浓度为10μmol/L,按1:2递减,72小时后,每孔加入CCK810ul,用thermo的酶标仪,在450nm测细胞活性,最后经过拟合曲线得到IC50值。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.通式I所示的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
式中,
W是CH或N;
X是CH或N;
Y是CH或N或C卤素;
Z是CH或N;
R1的数量为1-5中任意的整数,任选位于1’、2’、5’、6’或7’位,并且独立选自:H、卤素、C1-C6取代或未取代的烷基、
其中,n为0~4的整数;
P为1-2个C1-C3烷基或不存在;
Q为-OH、-SH、-NH2、-NHCH3、-COOH、-CONH2、-NHCONH2、-NHCONHNH2、-SO3H、-SO2NH2;
X为O、S、NH;
R2选自:氢、C1-C5取代或未取代的烷基甲酰胺基、C2-C5取代或未取代的烯基甲酰胺基;
R3选自:氢、卤素、NR7R8、取代的N-C1-C3烷基哌嗪基;
R7和R8独立选自:H、C1-C6取代或未取代的烷基、NR9R10;
R9和R10独立选自:H、C1-C3取代或未取代的烷基。
2.如权利要求1所述的化合物或其立体异构体或光学异构体或其药学上可接受的盐,其特征在于,
W是CH;
X是CH或N;
Y是CH或N;
Z是CH;
R1的数量为1或2,任选位于1’或5’位,并且独立选自:H、C1-C6取代或未取代的烷基羟基或多羟基、卤素;
R2选自:氢、C1-C3取代或未取代的烷基甲酰胺基、C2-C3取代或未取代的烯基甲酰胺基;
R3选自:卤素、NR7R8;
R7和R8独立选自:H、C1-C3取代或未取代的烷基、NR9R10;
R9和R10独立选自:H、C1-C3取代或未取代的烷基。
4.通式II所示的化合物或其立体异构体或光学异构体或其药学上可接受的盐:
式中,
R1选自:
其中,n为0~4的整数;
P为1-2个C1-C3烷基或不存在;
Q为-OH、-SH、-NH2、-NHCH3,、-COOH、-CONH2、-NHCONH2、-NHCONHNH2、-SO3H、-SO2NH2;
X为O、S、NH;
A的数量为0-4的任一整数,并且独立选自:卤素、取代或未取代的C1-C3烷氧基;
V、S、T的数量分别为0-4的任一整数,并且独立选自卤素、取代或未取代的C1-C3烷氧基;
R6选自:H、取代或未取代的C1-C3烷基。
7.一种药物组合物,所述药物组合物含有权利要求1-6中任一项所述的化合物或其立体异构体或光学异构体或其药学上可接受的盐,以及任选的药学上可接受的载体或赋形剂。
8.权利要求1-6中任一项所述的化合物或其立体异构体或光学异构体或其药学上可接受的盐,或权利要求7所述的药物组合物在制备治疗或预防EGFR介导的疾病或抑制EGFR的药物中的用途。
9.如权利要求9所述的用途,其特征在于,所述EGFR介导的疾病为癌症。
10.如权利要求9所述的用途,其特征在于,所述癌症选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌和实体瘤。
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CN113292542A (zh) * | 2021-05-26 | 2021-08-24 | 乳源东阳光药业有限公司 | 一种瑞舒伐他汀钙中间体杂质及其制备方法 |
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