WO2015078417A1 - Pyrrolopyrimidine compound and use thereof in preparation of hypoglaecemic drug - Google Patents

Pyrrolopyrimidine compound and use thereof in preparation of hypoglaecemic drug Download PDF

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WO2015078417A1
WO2015078417A1 PCT/CN2014/092580 CN2014092580W WO2015078417A1 WO 2015078417 A1 WO2015078417 A1 WO 2015078417A1 CN 2014092580 W CN2014092580 W CN 2014092580W WO 2015078417 A1 WO2015078417 A1 WO 2015078417A1
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compound
mmol
alkyl
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PCT/CN2014/092580
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French (fr)
Chinese (zh)
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谢永美
魏于全
耿福能
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四川好医生药业集团有限公司
四川大学
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Publication of WO2015078417A1 publication Critical patent/WO2015078417A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • the present invention relates to pyrrolopyrimidine compounds and their use in the preparation of hypoglycemic agents.
  • the number of patients with diabetes in China has reached 92.4 million, ranking first in the world (Yang W, et al. NEngl J Med, 2010, 362 (12): 1090-1101).
  • the cost of diabetes treatment in China is as high as 173.4 billion yuan per year.
  • the direct medical expenses caused by diabetes account for 13% of China's total medical expenditure (Alcorn T, et al. Lancet, 2012, 379 (9833): 2227-2228). It can be seen that diabetes not only seriously jeopardizes the health of the people, but also brings a heavy economic burden to the country. It is imperative to prevent and treat diabetes.
  • diabetes is mainly divided into four types: insulin-dependent (type 1), non-insulin-dependent (type 2), malnutrition-related and secondary diabetes.
  • type 2 diabetes (T2D) patients accounted for more than 90% of the total number of people with diabetes. Therefore, the research of T2D therapeutic drugs is the focus and hot spot.
  • T2D therapeutic drugs commonly used in clinical practice include insulin, biguanide, sulfonylurea, glycosidase inhibitor, thiazolidinedione, glitazone and glinide, but they often have different degrees of side effects, such as Hypoglycemia, weight gain, cardiovascular side effects, etc.
  • R 1 is selected from the group consisting of H, hydrazine, and -YR 20 ;
  • R 2 is selected from the group consisting of H, hydrazine, halogen, amino, -Y-R20;
  • Y is selected from O, S;
  • R 20 is selected from C1-C5 alkyl, deuterated or aryl C1-C4 alkyl;
  • R 3 and R 4 are each independently selected from H or
  • R 7 , R 8 and R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
  • R 3 and R 4 are formed together with the N connected thereto. among them:
  • Z is selected from C, O or N;
  • n 1 or 2;
  • R 10 is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group or
  • R 11 is selected from C 1 -C 4 alkyl or alkoxy, halogen substituted C 1 -C 4 alkyl or alkoxy or R 12 is selected from H or a C1-C4 alkyl group;
  • R 13 is selected from a C1-C4 alkyl group or a halogenated C1-C4 alkyl group
  • W 1 is selected from O or S, and W 2 is selected from C or N;
  • R 14 is selected from H, halogen, C1-C4 alkyl or haloalkyl, 5- or 6-membered cycloalkyl containing O or S, or
  • R 15 and R 16 are each independently selected from H, C1-C4 alkyl or haloalkyl
  • R 17 is selected from H, C1-C4 alkyl or haloalkyl
  • R 18 is selected from H, C1-C4 alkyl or haloalkyl
  • R 19 is selected from H, C1-C6 alkyl or haloalkyl, C5-C10 aryl or heterocyclic aromatic hydrocarbon, or halogenated C5-C10 aryl or heterocyclic aromatic hydrocarbon;
  • R 5 is selected from an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted hetero atom-containing aryl group, and the substituent is selected from a C 1 -C 4 alkyl group, a halogen or a sulfonyl group;
  • R 6 is selected from C 1 -C 4 alkyl, aryl or deuterated C 1 -C 4 alkyl;
  • X is selected from Or not;
  • the halogen is F, Cl or Br.
  • R 1 is selected from H and hydrazine
  • R 2 is selected from H, hydrazine, halogen or -OR 20 , and R 20 is selected from C1 to C5 alkyl;
  • R 3 and R 4 are each independently selected from H or
  • R 7 to R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
  • Z is selected from C, N, O or S
  • n 1 or 2;
  • R 10 is selected from the group consisting of H, C1-C4 alkyl, or
  • R 11 is selected from a C 1 -C 4 alkyl or alkoxy group
  • R 13 is selected from a C1 to C4 alkyl group or a halogenated alkyl group
  • R 5 is a phenyl group
  • R 6 is a C1-C4 alkyl group.
  • R 20 is selected from a methyl group
  • R 3 and R 4 are each independently selected from H, or
  • R 7 to R 9 are each independently selected from H, halogen, methyl or methoxy;
  • R 3 and R 4 are formed together with the N connected thereto.
  • the compound is as shown in formula II:
  • R 6 is selected from a C 1 -C 4 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group;
  • R 13 is selected from a C1-C4 haloalkyl group
  • R 20 is selected from a C1 to C5 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group.
  • R 13 is selected from the group consisting of perhalogenated C1-C4 alkyl groups.
  • R 6 and R 20 are each independently selected from methyl, deuterated methyl, ethyl or deuterated ethyl; R 13 is selected from trifluoromethyl, trichloromethyl, pentafluoroethyl or pentachloroethyl. base.
  • R 13 is selected from the group consisting of trifluoromethyl.
  • the structural formula of the compound is as follows:
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a hypoglycemic agent.
  • the drug is a drug for treating type 2 diabetes.
  • the present invention also provides a pharmaceutical composition for treating diabetes, which comprises the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with a pharmaceutically-acceptable adjuvant or auxiliary ingredient.
  • a pharmaceutical composition for treating diabetes which comprises the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with a pharmaceutically-acceptable adjuvant or auxiliary ingredient.
  • the preparation of the present invention is an injection.
  • the salt of the present invention may be the above compound and hydrochloric acid, phosphoric acid, acetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, p-toluenesulfonic acid,
  • the pharmaceutically acceptable salt formed by methanesulfonic acid or the like is not limited to the kind of the above acid.
  • the invention prepares a novel pyrrolopyrimidine compound, which can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical medication.
  • Et ethyl
  • NaOEt sodium ethoxide
  • EtOH ethanol
  • Formamide formamide
  • DMF N, N-dimethylformamide
  • Malonic acid malonic acid
  • HOBT 1-hydroxybenzotriazole
  • TEA triethanolamine
  • DMSO dimethyl sulfoxide
  • TLC thin layer chromatography
  • EA ethyl acetate
  • 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • BINAP ( ⁇ )-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl
  • Boc tert-butoxy Carbonyl
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • mice Five-week-old C57BL/6J mice, male, were fed with normal and high fat diets for 10 weeks. Male mice with successful modeling were randomly divided into groups of 5, and body weight was recorded. The drug-administered group was given 10 mg/kg of different compounds, and the blank control group and the normal group were given the same volume of physiological saline. The rats were intraperitoneally administered once a day for 5 days, and the fasting basal blood glucose and glucose tolerance of the mice were measured. Data were presented as mean ⁇ standard deviation and significant differences were determined by t test. When P ⁇ 0.05, it was considered to have a significant difference. The test results of some of the compounds of the present invention are shown in Table 2.
  • test results showed that compared with the blank control group, compounds 6, 8, 9, 10, 11, 12, 13, 16, 18, 22, 23, 25, 28, 31, 40 can all have blood glucose levels in diabetic animal models. Different degrees of reduction; in particular, compounds 13, 25 and 40 can significantly reduce blood glucose levels in diabetic animal models.
  • the present invention investigated the acute toxicity of compounds 13, 25 and 40.
  • Compounds 13, 25 and 40 were dispersed in 1% sodium carboxymethylcellulose, ground to a suspension, and formulated into 300 mg/ml.
  • Kunming mice were given 1g/kg by oral gavage alone. During the 14-day observation period, the mice did not die.
  • blood biochemical tests were performed, and no obvious abnormal changes were found in blood biochemical indicators.
  • no abnormal drug-related changes were observed in the main organs of the pathological anatomy of mice.
  • the animals in the drug-administered group showed no abnormalities compared with the vehicle control group and the normal group.
  • the novel pyrrolopyrimidine compound prepared by the invention can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical use.

Abstract

Provided is a compound as represented by formula I, or pharmaceutically acceptable salt, hydrate or solvate thereof. Also provided in the present invention are new uses of the compound or the pharmaceutically acceptable salt, hydrate or solvate thereof. The pyrrolopyrimidine compound prepared in the present invention can significantly reduce fasting blood sugar of mice with diabetes and has high safety, providing clinical medication with a new option.

Description

吡咯并嘧啶化合物及其在制备降血糖药物中的用途Pyrrolopyrimidine compound and use thereof in preparing hypoglycemic drugs 技术领域Technical field
本发明涉及吡咯并嘧啶化合物及其在制备降血糖药物中的用途。The present invention relates to pyrrolopyrimidine compounds and their use in the preparation of hypoglycemic agents.
背景技术Background technique
据统计，目前我国糖尿病的患病人数已经达到了9240万，居全球之首(Yang W,et al.NEngl J Med,2010,362(12):1090-1101)。中国糖尿病治疗费用每年高达1734亿元，糖尿病所致的直接医疗开支已经占到中国医疗总开支的13％(Alcorn T,et al.Lancet,2012,379(9833):2227-2228)。可见，糖尿病不仅严重危害人民的健康，而且为国家带来沉重的经济负担，防治糖尿病刻不容缓。According to statistics, the number of patients with diabetes in China has reached 92.4 million, ranking first in the world (Yang W, et al. NEngl J Med, 2010, 362 (12): 1090-1101). The cost of diabetes treatment in China is as high as 173.4 billion yuan per year. The direct medical expenses caused by diabetes account for 13% of China's total medical expenditure (Alcorn T, et al. Lancet, 2012, 379 (9833): 2227-2228). It can be seen that diabetes not only seriously jeopardizes the health of the people, but also brings a heavy economic burden to the country. It is imperative to prevent and treat diabetes.
根据病因和临床表现不同，糖尿病主要分为4种类型：胰岛素依赖型(1型)、非胰岛素依赖型(2型)、营养不良相关型和继发型糖尿病。其中2型糖尿病(T2D)患者占糖尿病总人数的90％以上。因此，T2D治疗药物的研究是重点和热点。According to the etiology and clinical manifestations, diabetes is mainly divided into four types: insulin-dependent (type 1), non-insulin-dependent (type 2), malnutrition-related and secondary diabetes. Among them, type 2 diabetes (T2D) patients accounted for more than 90% of the total number of people with diabetes. Therefore, the research of T2D therapeutic drugs is the focus and hot spot.
目前，临床常用的T2D治疗药物有胰岛素、双胍类、磺脲类、糖苷酶抑制剂、噻唑烷二酮类、格列酮类和格列奈类等，但它们常具有不同程度的副作用，如低血糖、体重增加、心血管副作用等。At present, T2D therapeutic drugs commonly used in clinical practice include insulin, biguanide, sulfonylurea, glycosidase inhibitor, thiazolidinedione, glitazone and glinide, but they often have different degrees of side effects, such as Hypoglycemia, weight gain, cardiovascular side effects, etc.
因此，开发作用于新靶点、避免传统抗糖尿病药物副作用、对胰岛β细胞具有保护作用的新型抗糖尿病药物成为国内外研究的热点。经过努力，目前有多个具有新作用机制的抗糖尿病药物已经批准上市，如：二肽基肽酶-4(DPP-4)抑制剂和胰高血糖素样多肽-1(GLP-1)受体激动剂，此类药物的缺点是能够引起胰腺炎、鼻咽炎、呼吸道感染、头痛、过敏等副作用。从而，高效低毒的T2D创新药物的研究具有重要意义。Therefore, the development of new anti-diabetic drugs that act on new targets, avoid the side effects of traditional anti-diabetic drugs, and have protective effects on islet β cells have become a hot research topic at home and abroad. After efforts, a number of anti-diabetic drugs with new mechanisms of action have been approved for marketing, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1). Body agonists, such drugs have the disadvantage of causing side effects such as pancreatitis, nasopharyngitis, respiratory infections, headaches, allergies and the like. Therefore, the research of high-efficiency and low-toxic T2D innovative drugs is of great significance.
发明内容Summary of the invention
本发明的目的在于提供一种吡咯并嘧啶化合物。It is an object of the present invention to provide a pyrrolopyrimidine compound.
本发明提供的式I所示的化合物或其药学上可接受的盐、水合物或溶剂合物：A compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, provided by the invention:
Figure PCTCN2014092580-appb-000001
Figure PCTCN2014092580-appb-000001
R1选自H、氘、-Y-R20；R 1 is selected from the group consisting of H, hydrazine, and -YR 20 ;
R2选自H、氘、卤素、氨基、-Y-R20；R 2 is selected from the group consisting of H, hydrazine, halogen, amino, -Y-R20;
Y选自O、S；R20选自C1-C5的烷基、氘代或芳基代C1～C4烷基； Y is selected from O, S; R 20 is selected from C1-C5 alkyl, deuterated or aryl C1-C4 alkyl;
R3、R4分别独立选自H或
Figure PCTCN2014092580-appb-000002
R 3 and R 4 are each independently selected from H or
Figure PCTCN2014092580-appb-000002
R7、R8、R9分别独立选自H、卤素、C1～C4的烷基或烷氧基、或卤代C1～C4的烷基或烷氧基；R 7 , R 8 and R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
或者，R3、R4与其相连的N共同形成
Figure PCTCN2014092580-appb-000003
Figure PCTCN2014092580-appb-000004
其中：Or, R 3 and R 4 are formed together with the N connected thereto.
Figure PCTCN2014092580-appb-000003
Figure PCTCN2014092580-appb-000004
among them:
Z选自C、O或N；Z is selected from C, O or N;
n＝1或2；n=1 or 2;
R10选自H、C1～C4的烷基、卤代C1～C4的烷基或
Figure PCTCN2014092580-appb-000005
R 10 is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group or
Figure PCTCN2014092580-appb-000005
R11选自C1～C4的烷基或烷氧基、卤素取代的C1～C4的烷基或烷氧基或
Figure PCTCN2014092580-appb-000006
R12选自H或C1～C4烷基；R 11 is selected from C 1 -C 4 alkyl or alkoxy, halogen substituted C 1 -C 4 alkyl or alkoxy or
Figure PCTCN2014092580-appb-000006
R 12 is selected from H or a C1-C4 alkyl group;
R13选自C1～C4的烷基、或卤代C1～C4的烷基；R 13 is selected from a C1-C4 alkyl group or a halogenated C1-C4 alkyl group;
W1选自O或S，W2选自C或N；W 1 is selected from O or S, and W 2 is selected from C or N;
R14选自H、卤素、C1～C4的烷基或卤代烷基、含O或S的五元或六元环烷基、或
Figure PCTCN2014092580-appb-000007
R 14 is selected from H, halogen, C1-C4 alkyl or haloalkyl, 5- or 6-membered cycloalkyl containing O or S, or
Figure PCTCN2014092580-appb-000007
R15、R16分别独立选自H、C1～C4烷基或卤代烷基；R 15 and R 16 are each independently selected from H, C1-C4 alkyl or haloalkyl;
R17选自H、C1～C4烷基或卤代烷基；R 17 is selected from H, C1-C4 alkyl or haloalkyl;
R18选自H、C1～C4烷基或卤代烷基；R 18 is selected from H, C1-C4 alkyl or haloalkyl;
R19选自H、C1～C6烷基或卤代烷基、C5～C10的芳基或杂环芳烃基、或卤代C5～C10的芳基或杂环芳烃基； R 19 is selected from H, C1-C6 alkyl or haloalkyl, C5-C10 aryl or heterocyclic aromatic hydrocarbon, or halogenated C5-C10 aryl or heterocyclic aromatic hydrocarbon;
R5选自烷基、取代或未取代的芳基、取代或未取代含杂原子芳基，所述取代基选自C1～C4的烷基、卤素或磺酰基；R 5 is selected from an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted hetero atom-containing aryl group, and the substituent is selected from a C 1 -C 4 alkyl group, a halogen or a sulfonyl group;
R6选自C1～C4烷基、芳基或氘代的C1～C4烷基；R 6 is selected from C 1 -C 4 alkyl, aryl or deuterated C 1 -C 4 alkyl;
X选自
Figure PCTCN2014092580-appb-000008
或无；X is selected from
Figure PCTCN2014092580-appb-000008
Or not;
所述卤素为F、Cl或Br。The halogen is F, Cl or Br.
优选的，Preferably,
R1选自H、氘；R 1 is selected from H and hydrazine;
R2选自H、氘、卤素或-O-R20，R20选自C1～C5的烷基；R 2 is selected from H, hydrazine, halogen or -OR 20 , and R 20 is selected from C1 to C5 alkyl;
R3、R4分别独立选自H或
Figure PCTCN2014092580-appb-000009
R 3 and R 4 are each independently selected from H or
Figure PCTCN2014092580-appb-000009
R7～R9分别独立选自H、卤素、C1～C4的烷基或烷氧基、或卤代C1～C4的烷基或烷氧基；R 7 to R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
或者，R3、R4与其相连的N共同形成
Figure PCTCN2014092580-appb-000010
Figure PCTCN2014092580-appb-000011
其中：Or, R3, R4 and their connected N form together
Figure PCTCN2014092580-appb-000010
Figure PCTCN2014092580-appb-000011
among them:
Z选自C、N、O或S；Z is selected from C, N, O or S;
n＝1或2；n=1 or 2;
R10选自H、C1～C4的烷基、或
Figure PCTCN2014092580-appb-000012
R 10 is selected from the group consisting of H, C1-C4 alkyl, or
Figure PCTCN2014092580-appb-000012
R11选自C1～C4的烷基或烷氧基；R 11 is selected from a C 1 -C 4 alkyl or alkoxy group;
R13选自C1～C4的烷基或卤代烷基；R 13 is selected from a C1 to C4 alkyl group or a halogenated alkyl group;
R5为苯基；R 5 is a phenyl group;
R6为C1～C4的烷基。R 6 is a C1-C4 alkyl group.
优选的，Preferably,
R20选自甲基； R 20 is selected from a methyl group;
R3、R4分别独立选自H、或
Figure PCTCN2014092580-appb-000013
R 3 and R 4 are each independently selected from H, or
Figure PCTCN2014092580-appb-000013
R7～R9分别独立选自H、卤素、甲基或甲氧基；R 7 to R 9 are each independently selected from H, halogen, methyl or methoxy;
或者，R3、R4与其相连的N共同形成
Figure PCTCN2014092580-appb-000014
Figure PCTCN2014092580-appb-000015
Or, R 3 and R 4 are formed together with the N connected thereto.
Figure PCTCN2014092580-appb-000014
Figure PCTCN2014092580-appb-000015
优选的，所述化合物如式II所示：Preferably, the compound is as shown in formula II:
Figure PCTCN2014092580-appb-000016
Figure PCTCN2014092580-appb-000016
R6选自C1～C4的烷基、部分氘代烷基或全氘代烷基；R 6 is selected from a C 1 -C 4 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group;
R13选自C1～C4的卤代烷基；R 13 is selected from a C1-C4 haloalkyl group;
R20选自C1～C5的烷基、部分氘代烷基或全氘代烷基。R 20 is selected from a C1 to C5 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group.
优选的，R13选自全卤代的C1～C4烷基。Preferably, R 13 is selected from the group consisting of perhalogenated C1-C4 alkyl groups.
优选的，R6、R20分别独立选自甲基、氘代甲基、乙基或氘代乙基；R13选自三氟甲基、三氯甲基、五氟乙基或五氯乙基。Preferably, R 6 and R 20 are each independently selected from methyl, deuterated methyl, ethyl or deuterated ethyl; R 13 is selected from trifluoromethyl, trichloromethyl, pentafluoroethyl or pentachloroethyl. base.
优选的，R13选自三氟甲基。Preferably, R 13 is selected from the group consisting of trifluoromethyl.
优选的，所述化合物结构式如下： Preferably, the structural formula of the compound is as follows:
Figure PCTCN2014092580-appb-000017
Figure PCTCN2014092580-appb-000017
本发明还提供了上述化合物或其药学上可接受的盐、水合物或溶剂合物在制备降血糖药物中的用途。The present invention also provides the use of the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the preparation of a hypoglycemic agent.
所述化合物或其药学上可接受的盐、水合物或溶剂合物在制备降血糖药物中的用途。Use of the compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a hypoglycemic agent.
所述药物是治疗2型糖尿病的药物。The drug is a drug for treating type 2 diabetes.
本发明还提供了一种治疗糖尿病的药物组合物，它是由上述化合物或其药学上可接受的盐、水合物或溶剂合物为活性成分，加上药学上常用的辅料或辅助性成分制备而成的制剂。The present invention also provides a pharmaceutical composition for treating diabetes, which comprises the above compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, together with a pharmaceutically-acceptable adjuvant or auxiliary ingredient. The preparation.
本发明所述制剂为注射剂。The preparation of the present invention is an injection.
本发明所述盐，可以是上述化合物与盐酸、磷酸、乙酸、丙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、对甲苯磺酸、甲磺酸等生成的药学上可接受的盐，但不限于上述酸的种类。The salt of the present invention may be the above compound and hydrochloric acid, phosphoric acid, acetic acid, propionic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, p-toluenesulfonic acid, The pharmaceutically acceptable salt formed by methanesulfonic acid or the like is not limited to the kind of the above acid.
本发明制备了一种新的吡咯并嘧啶化合物，可以明显降低糖尿病小鼠的空腹血糖，且安全性较高，为临床用药提供了新的选择。The invention prepares a novel pyrrolopyrimidine compound, which can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical medication.
具体实施方式detailed description
本发明中，缩写或英文代表的中文名称如下所述：In the present invention, the Chinese names of the abbreviations or English representatives are as follows:
Et：乙基；NaOEt：乙醇钠；EtOH：乙醇；Formamide：甲酰胺；DMF：N,N-二甲基甲酰胺；Malonic acid：丙二酸；HOBT：1-羟基苯并***；EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；TEA：三乙醇胺；DMSO：二甲基亚砜；TLC：薄层色谱；EA：乙酸乙酯；Pd2(dba)3：三(二亚苄基丙酮)二钯；BINAP：(±)-2,2'-双-(二苯膦基)-1,1'-联萘；Boc：叔丁氧羰基；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；NIS：N-碘代丁二酰亚胺；Pd(OAc)2：乙酸钯。Et: ethyl; NaOEt: sodium ethoxide; EtOH: ethanol; Formamide: formamide; DMF: N, N-dimethylformamide; Malonic acid: malonic acid; HOBT: 1-hydroxybenzotriazole; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; TEA: triethanolamine; DMSO: dimethyl sulfoxide; TLC: thin layer chromatography; EA: ethyl acetate; 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; BINAP: (±)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; Boc: tert-butoxy Carbonyl; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NIS: N-iodosuccinimide; Pd (OAc) 2 : palladium acetate.
实施例1Example 1
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(1H-1,2,4-三氮唑-1-基)丙-2-烯-1-酮 (E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(1H-1,2, 4-triazol-1-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000018
Figure PCTCN2014092580-appb-000018
化合物1的合成Synthesis of Compound 1
N2保护条件下，0℃将16.6g 3-脒基丙酸乙酯盐酸盐和10.4g NaOEt溶于无水乙醇中，搅拌20分钟后将温度升至60℃，缓慢加入10g 2-溴苯乙酮，反应2小时后减压除去乙醇，然后加水稀释，乙酸乙酯萃取。有机相用饱和盐水洗涤，硫酸钠干燥，浓缩，柱层析得4.5g化合物1，收率39.1％。Under N 2 protection conditions, 16.6 g of ethyl 3-mercaptopropionate hydrochloride and 10.4 g of NaOEt were dissolved in absolute ethanol at 0 ° C. After stirring for 20 minutes, the temperature was raised to 60 ° C, and 10 g of 2-bromo was slowly added. Acetophenone, after reacting for 2 hours, the ethanol was removed under reduced pressure, then diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate and evaporated.
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),7.48(d,J＝7.4Hz,2H),7.29(t,J＝7.0Hz,2H),7.09(t,J＝6.8Hz,1H),6.47(s,1H),5.66(s,2H),4.12(d,J＝6.4Hz,2H),1.25(t,J＝6.4Hz,3H)。 1 H NMR (400MHz, DMSO- d 6) δ10.73 (s, 1H), 7.48 (d, J = 7.4Hz, 2H), 7.29 (t, J = 7.0Hz, 2H), 7.09 (t, J = 6.8 Hz, 1H), 6.47 (s, 1H), 5.66 (s, 2H), 4.12 (d, J = 6.4 Hz, 2H), 1.25 (t, J = 6.4 Hz, 3H).
化合物2的合成Synthesis of Compound 2
取9.5g化合物1，30mL甲酸，200mL甲酰胺，75mL DMF，150℃搅拌24小时。TLC监测，反应完全后，冷却，析出固体，抽滤后真空干燥，得7.1g化合物2，收率81.4％。9.5 g of Compound 1, 30 mL of formic acid, 200 mL of formamide, and 75 mL of DMF were taken and stirred at 150 ° C for 24 hours. After TLC was monitored, the reaction was completed, cooled, and the solid was separated, filtered, and dried in vacuo to give 7.1 g of Compound 2 in a yield of 81.4%.
1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),11.87(s,1H),7.92–7.80(m,3H),7.42(t,J＝7.3Hz,2H),7.28(t,J＝7.2Hz,1H),6.95(s,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 11.87 (s, 1H), 7.92 - 7.80 (m, 3H), 7.42 (t, J = 7.3 Hz, 2H), 7.28 ( t, J = 7.2 Hz, 1H), 6.95 (s, 1H).
化合物3的合成Synthesis of Compound 3
N2保护下，将3mL DMF加入到装有211mg化合物2和48mg NaH的三口瓶中，0℃搅拌10min后，缓慢滴加0.1mL CH3I，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得淡黄色化合物3约190mg，收率79.2％。Under N 2 protection, 3 mL of DMF was added to a three-necked flask containing 211 mg of Compound 2 and 48 mg of NaH, and after stirring at 0 ° C for 10 min, 0.1 mL of CH 3 I was slowly added dropwise, and stirred at room temperature overnight. After TLC monitoring, after the reaction was completed, water was slowly added dropwise to the reaction flask, and then extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. %.
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.59–7.43(m,5H),6.63(s,1H),3.73(s,3H),3.50(s,3H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 7.59 - 7.43 (m, 5H), 6.63 (s, 1H), 3.73 (s, 3H), 3.50 (s, 3H).
化合物4的合成Synthesis of Compound 4
N2保护下，取119mg化合物3溶于2mL DMF中，0℃条件下滴加POCl3，反应3h后加 水，用1mol/L的NaOH溶液调节pH大于14，析出沉淀，抽滤得108mg化合物4，白色固体，收率81.1％。Under N 2 protection, 119 mg of compound 3 was dissolved in 2 mL of DMF, and POCl 3 was added dropwise at 0 ° C. After 3 h of reaction, water was added, and the pH was adjusted to be greater than 14 with 1 mol/L NaOH solution, and the precipitate was precipitated, and 108 mg of compound 4 was obtained by suction filtration. , white solid, yield 81.1%.
1H NMR(400MHz,CDCl3)δ10.35(s,1H),7.99(s,1H),7.61–7.38(m,5H),3.66(s,3H),3.62(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 10.35 (s, 1H), 7.99 (s, 1H), 7.61 - 7.38 (m, 5H), 3.66 (s, 3H), 3.62 (s, 3H).
化合物5的合成Synthesis of Compound 5
取100mg化合物4，104mg丙二酸，0.25mL哌啶溶于4mL吡啶中，回流反应5h。反应完全后，减压除去吡啶，加水稀释后，用1mol/L的HCl溶液调节pH到6，析出沉淀，抽滤得101mg化合物5，淡黄色固体，收率87.3％。100 mg of compound 4, 104 mg of malonic acid, 0.25 ml of piperidine were dissolved in 4 mL of pyridine, and refluxed for 5 h. After completion of the reaction, the pyridine was removed under reduced pressure, diluted with water, and then adjusted to pH 6 with a 1 mol/L HCl solution, and the precipitate was precipitated, and filtered to give 101 mg of Compound 5 as a pale yellow solid, yield: 87.3%.
1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.39(s,1H),7.60–7.48(m,5H),7.35(s,2H),3.53(s,3H),3.52(s,3H)。 1 H NMR (400MHz, DMSO- d 6) δ11.88 (s, 1H), 8.39 (s, 1H), 7.60-7.48 (m, 5H), 7.35 (s, 2H), 3.53 (s, 3H), 3.52 (s, 3H).
化合物6((E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(1H-1,2,4-三氮唑-1-基)丙-2-烯-1-酮)的合成Compound 6 ((E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(1H-1 Synthesis of 2,4-triazol-1-yl)prop-2-en-1-one)
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入8.3mg 1H-1,2,4-三氮唑(0.12mmol,)，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得34.2mg化合物6，白色固体，收率94％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 8.3 mg of 1H-1 was added. 2,4-Triazole (0.12 mmol,), stirred at room temperature overnight. TLC was monitored. After completion of the reaction, water was added and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. .
1H NMR(400MHz,CDCl3)δ9.01(d,J＝16Hz,1H),8.96(s,1H),8.12(s,1H),8.01(s,1H),7.91(d,J＝16Hz,1H),7.59-7.56(m,3H),7.41-7.39(m,2H),3.69(s,3H),3.64(s,3H)。MS:m/z＝361.2[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 16 Hz, 1H), 8.96 (s, 1H), 8.12 (s, 1H), 8.1 (s, 1H), 7.91 (d, J = 16 Hz) , 1H), 7.59-7.56 (m, 3H), 7.41-7.39 (m, 2H), 3.69 (s, 3H), 3.64 (s, 3H). MS: m/z = 361.2 [M + H] + .
实施例2Example 2
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(哌啶-1-基)丙-2-烯-1-酮的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(piperidin-1-yl) Synthesis of prop-2-en-1-one
Figure PCTCN2014092580-appb-000019
Figure PCTCN2014092580-appb-000019
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入10.2mg(0.12mmol)哌啶，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得35.8mg化合物8，白色固体，收率95％。 30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 10.2 mg (0.12 mmol) Piperidine, stirred at room temperature overnight. TLC was monitored. After completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. .
1H NMR(400MHz,CDCl3)δ8.32(d,J＝16Hz,1H),7.94(s,1H),7.54–7.43(m,4H),7.38–7.36(m,2H),3.68-3.63(m,4H),3.61(s,3H),3.57(s,3H),1.63-1.57(m,6H)。MS:m/z＝377.4[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, J = 16 Hz, 1H), 7.94 (s, 1H), 7.54 - 7.43 (m, 4H), 7.38 - 7.36 (m, 2H), 3.68-3.63 (m, 4H), 3.61 (s, 3H), 3.57 (s, 3H), 1.63-1.57 (m, 6H). MS: m/z = 377.4 [M+H] + .
实施例3Example 3
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(4-甲基哌嗪哌啶-1-基)丙-2-烯-1-酮的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(4-methylpiperazine Synthesis of piperidin-1-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000020
Figure PCTCN2014092580-appb-000020
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入12mg(0.12mmol)N-甲基哌嗪，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得37.5mg化合物9，白色固体，收率95.9％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 12 mg (0.12 mmol) N-methylpiperazine was stirred at room temperature overnight. TLC was monitored. After completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. .
1H NMR(400MHz,CDCl3)δ8.35(d,J＝12Hz,1H),7.95(s,1H),7.53(d,J＝16Hz,1H),7.50–7.43(m,3H),7.38–7.35(m,2H),3.80(s,2H),3.72(s,2H),3.62(s,3H),3.59(s,3H),2.48(s,2H),2.41(s,2H),2.32(s,3H)。MS:m/z＝392.5[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J = 12 Hz, 1H), 7.95 (s, 1H), 7.53 (d, J = 16 Hz, 1H), 7.50 - 7.43 (m, 3H), 7.38 –7.35(m,2H), 3.80(s,2H), 3.72(s,2H), 3.62(s,3H),3.59(s,3H),2.48(s,2H),2.41(s,2H), 2.32 (s, 3H). MS: m/z = 392.5 [M + H] + .
实施例4Example 4
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-吗啉丙-2-烯-1-酮的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-morpholineprop-2-ene Synthesis of 1-ketone
Figure PCTCN2014092580-appb-000021
Figure PCTCN2014092580-appb-000021
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入11mg(0.12mmol)吗啉，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得白色固体，44mg化合物10，收率94.4％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 11 mg (0.12 mmol) Morpholine was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to give a white solid.
1H NMR(400MHz,CDCl3)δ8.33(d,J＝16Hz,1H),7.96(s,1H),7.54(d,J＝16Hz,1H),7.50–7.45(m,3H),7.38–7.36(m,2H),3.77–3.70(m,8H),3.61(s,3H),3.59(s,3H)。MS: m/z＝379.4[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ8.33 (d, J = 16Hz, 1H), 7.96 (s, 1H), 7.54 (d, J = 16Hz, 1H), 7.50-7.45 (m, 3H), 7.38 –7.36 (m, 2H), 3.77–3.70 (m, 8H), 3.61 (s, 3H), 3.59 (s, 3H). MS: m/z = 379.4 [M+H] + .
实施例5Example 5
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(4-甲基-[1,4]二氮杂环庚烷-1-基)丙-2-烯-1-酮的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(4-methyl-[ Synthesis of 1,4]diazepan-1-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000022
Figure PCTCN2014092580-appb-000022
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入14mg(0.12mmol)N-甲基高哌嗪，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得白色固体，36.5mg化合物11，收率89.9％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 14 mg (0.12 mmol) N-methylhomopiperazine was stirred at room temperature overnight. TLC was monitored. After completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to give a white solid, 36.5 mg Compound 11. .
1H NMR(400MHz,CDCl3)δ8.33-8.28(m,1H),7.95(s,1H),7.57-7.46(m,4H),7.38-7.36(m,2H),3.85-3.68(m,4H),3.62(s,3H),3.59(s,3H),2.80–2.58(m,4H),2.41(d,J＝4Hz,3H),2.10-1.95(m,2H)。MS:m/z＝406.4[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33-8.28 (m, 1H), 7.95 (s, 1H), 7.57-7.46 (m, 4H), 7.38-7.36 (m, 2H), 3.85-3.68 (m , 4H), 3.62 (s, 3H), 3.59 (s, 3H), 2.80 - 2.58 (m, 4H), 2.41 (d, J = 4 Hz, 3H), 2.10 - 1.95 (m, 2H). MS: m/z = 406.4 [M + H] + .
实施例6Example 6
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-methoxy-7-methyl-6- Phenyl-7H-pyrrole
[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成Synthesis of [2,3-d]pyrimidin-5-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000023
Figure PCTCN2014092580-appb-000023
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入28mg(0.12mmol)6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得46mg化合物12，白色固体，收率94％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 28 mg (0.12 mmol) 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, stirred at room temperature overnight. TLC was monitored. After completion of the reaction, water was added, and EA was applied three times (15 mL each). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ8.38(t,J＝16Hz,1H),7.96(s,1H),7.56(d,J＝12Hz,1H),7.52-7.45(m,3H),7.37(d,J＝8Hz,2H),6.72-6.62(m,2H),4.85(s,1H),4.73(s,1H),3.59 (s,3H),2.80–2.58(m,4H),2.41(d,J＝4Hz,3H),2.10-1.95(m,2H)。MS:m/z＝485.3[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (t, J = 16 Hz, 1H), 7.96 (s, 1H), 7.56 (d, J = 12 Hz, 1H), 7.52-7.45 (m, 3H), 7.37 (d, J=8 Hz, 2H), 6.72-6.62 (m, 2H), 4.85 (s, 1H), 4.73 (s, 1H), 3.59 (s, 3H), 2.80–2.58 (m, 4H), 2.41 (d, J = 4 Hz, 3H), 2.10 - 1.95 (m, 2H). MS: m/z = 485.3 [M + H] + .
实施例7Example 7
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)丙-2-烯-1-酮盐酸盐的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3-(trifluoromethyl) ,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)prop-2-en-1-one hydrochloride synthesis
Figure PCTCN2014092580-appb-000024
Figure PCTCN2014092580-appb-000024
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入28mg(0.12mmol)3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪盐酸盐，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得白色固体产品(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)丙-2-烯-1-酮47.8mg，收率99％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 28 mg (0.12 mmol) 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, stirred at room temperature overnight. After TLC monitoring, after completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate Methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3-(trifluoromethyl)-5,6-dihydro -[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)prop-2-en-1-one 47.8 mg, yield 99%.
1H NMR(400MHz,CDCl3)δ8.47(d,J＝12Hz,1H),7.98(s,1H),7.56(d,J＝12Hz,1H),7.52-7.50(m,3H),7.36(d,J＝4Hz,2H),5.21(s,2H),4.18(s,4H),3.64(s,3H),3.60(s,3H)。MS:m/z＝484.3[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 12 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 12 Hz, 1H), 7.52-7.50 (m, 3H), 7.36 (d, J = 4 Hz, 2H), 5.21 (s, 2H), 4.18 (s, 4H), 3.64 (s, 3H), 3.60 (s, 3H). MS: m/z = 484.3 [M + H] + .
取上述固体40mg，加入5ml二氯甲烷溶解，冰浴下将HCl乙酸乙酯溶液缓慢滴加到上述溶液中，析出白色固体，加入***，0℃搅拌2h，抽滤用***洗涤，真空干燥，得(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)丙-2-烯-1-酮盐酸盐38mg。40 mg of the above solid was taken, dissolved in 5 ml of dichloromethane, and the HCl solution of HCl was slowly added dropwise to the above solution to precipitate a white solid, diethyl ether was added, and the mixture was stirred at 0 ° C for 2 h, filtered with diethyl ether and dried in vacuo. (E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3-(trifluoro) Methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)prop-2-en-1-one hydrochloride 38mg.
1H NMR(400MHz,CDCl3)δ8.47(d,J＝12Hz,1H),7.98(s,1H),7.56(d,J＝12Hz,1H),7.52-7.50(m,3H),7.36(d,J＝4Hz,2H),5.21(s,2H),4.18(s,4H),3.64(s,3H),3.60(s,3H)。MS:m/z＝484.3[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (d, J = 12 Hz, 1H), 7.78 (s, 1H), 7.56 (d, J = 12 Hz, 1H), 7.52-7.50 (m, 3H), 7.36 (d, J = 4 Hz, 2H), 5.21 (s, 2H), 4.18 (s, 4H), 3.64 (s, 3H), 3.60 (s, 3H). MS: m/z = 484.3 [M+H] +
实施例8Example 8
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(4-(3-甲氧苯基)哌嗪-1-基)丙-2-烯-1-酮的合成 (E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(4-(3-A) Synthesis of oxyphenyl)piperazin-1-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000025
Figure PCTCN2014092580-appb-000025
化合物14的合成Synthesis of Compound 14
取309mg(1mmol)化合物5，加575mg(3mmol)EDCI，270mg(2mmol)HOBT，用10mlDMF溶解，再滴加三乙胺0.25ml，室温搅拌30min后，加入224mg(1.2mmol)N-Boc哌嗪，室温搅拌过夜。向反应体系中加入200mlEA，饱和NaCl溶液洗涤两次，无水硫酸钠干燥，浓缩后柱层析，得400mg化合物14，白色粉末，收率83.8％。309 mg (1 mmol) of compound 5, 575 mg (3 mmol) of EDCI, 270 mg (2 mmol) of HOBT, dissolved in 10 ml of DMF, and then added dropwise 0.25 ml of triethylamine. After stirring at room temperature for 30 min, 224 mg (1.2 mmol) of N-Boc piperazine was added. Stir at room temperature overnight. To the reaction system, 200 ml of EA was added, and the mixture was washed twice with a saturated NaCI solution and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ8.33(d,J＝16Hz,1H),7.96(s,1H),7.56-7.36(m,6H),3.76-3.67(m,4H),3.62(s,3H),3.59(s,3H),2.50-3.43(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 16 Hz, 1H), 7.96 (s, 1H), 7.56-7.36 (m, 6H), 3.76-3.67 (m, 4H), 3.62 (s) , 3H), 3.59 (s, 3H), 2.50-3.43 (m, 4H).
化合物15的合成Synthesis of Compound 15
取240mg(0.5mmol)化合物14，装入25ml圆底烧瓶中，先用2ml干燥二氯甲烷溶解，将3ml干燥二氯甲烷和1.25ml三氟乙酸混合后逐滴加入至反应体系中，室温搅拌10h。加饱和NaHCO3溶液中和，用二氯甲烷萃取，饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，浓缩后柱层析，得到130mg化合物15，白色粉末，收率68.9％。240 mg (0.5 mmol) of compound 14 was taken in a 25 ml round bottom flask, dissolved in 2 ml of dry dichloromethane, and 3 ml of dry dichloromethane and 1.25 ml of trifluoroacetic acid were mixed and added dropwise to the reaction system, and stirred at room temperature. 10h. Saturated NaHCO 3 solution and extracted with dichloromethane, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography to give 130mg compound 15 as a white powder, yield 68.9%.
1H NMR(400MHz,CDCl3)δ8.34(d,J＝16Hz,1H),7.95(s,1H),7.55-7.44(m,4H),7.38-7.36(m,2H),3.74-3.67(m,4H,3.62(s,3H),3.59(s,3H),2.92-2.86(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 16 Hz, 1H), 7.95 (s, 1H), 7.55-7.44 (m, 4H), 7.38-7.36 (m, 2H), 3.74-3.67 (m, 4H, 3.62 (s, 3H), 3.59 (s, 3H), 2.92 - 2.86 (m, 4H).
化合物16Compound 16
(E)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(4-(3-甲氧苯基)哌嗪-1-基)丙-2-烯-1-酮)的合成(E)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(4-(3-A) Synthesis of oxyphenyl)piperazin-1-yl)prop-2-en-1-one
取30mg(0.08mmol)化合物15和19mg(0.1mmol)间溴苯甲醚，3mg(0.003mmol)Pd2(dba)3，15mg(0.16mmol)叔丁醇钠，4mg(0.006mmol)1,1'-联萘-2,2'-双二苯膦(BINAP) 置于反应试管中，氮气置换后，加入甲苯1ml，100℃过夜反应。浓缩后柱层析，得30mg化合物16，白色粉末，收率62％。30 mg (0.08 mmol) of compound 15 and 19 mg (0.1 mmol) of m-bromoanisole, 3 mg (0.003 mmol) of Pd 2 (dba) 3 , 15 mg (0.16 mmol) of sodium tert-butoxide, 4 mg (0.006 mmol) 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine (BINAP) was placed in a reaction tube, and after nitrogen substitution, 1 ml of toluene was added, and the reaction was carried out at 100 ° C overnight. After concentration and column chromatography, 30 mg of Compound 16 was obtained as white powder, yield 62%.
1H NMR(400MHz,CDCl3)δd8.40(d,1H),7.96(s,1H),7.57-7.47(m,4H),7.38-7.36(m,2H),7.18(t,J＝8Hz,1H),6.56-6.53(m,1H),6.47-6.43(m,2H),3.92-3.85(m,4H),3.79(s,3H),3.64(s,3H),3.59(s,3H),3.25-3.19(m,4H)。MS:m/z＝484.2[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δd 8.40 (d, 1H), 7.96 (s, 1H), 7.57-7.47 (m, 4H), 7.38-7.36 (m, 2H), 7.18 (t, J = 8 Hz) , 1H), 6.56-6.53 (m, 1H), 6.47-6.43 (m, 2H), 3.92-3.85 (m, 4H), 3.79 (s, 3H), 3.64 (s, 3H), 3.59 (s, 3H) ), 3.25-3.19 (m, 4H). MS: m/z = 484.2 [M + H] + .
实施例9(E)-N-(4-苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 9(E)-N-(4-Phenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5- Synthesis of acrylamide
Figure PCTCN2014092580-appb-000026
Figure PCTCN2014092580-appb-000026
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析,浓缩后柱层析，得36.2mg白色固体化合物17，收率94.2％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of aniline was added. Stir at room temperature overnight. After TLC monitoring, after completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, The yield was 94.2%.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.89(d,J＝15.1Hz,1H),7.57～7.64(m,3H),7.47～7.54(m,4H),7.35～7.41(m,2H),7.27～7.33(m,2H),7.06(t,J＝7.4Hz,1H),3.64(s,3H),3.60(s,3H)。MS:m/z＝385.3[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.89 (d, J = 15.1 Hz, 1H), 7.57 to 7.64 (m, 3H), 7.47 to 7.54 (m, 4H), 7.35 - 7.41 (m, 2H), 7.27 to 7.33 (m, 2H), 7.06 (t, J = 7.4 Hz, 1H), 3.64 (s, 3H), 3.60 (s, 3H). MS: m/z = 385.3 [M + H] + .
实施例10(E)-N-(4-对甲氧苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 10(E)-N-(4-p-methoxyphenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine Synthesis of -5-yl)acrylamide
Figure PCTCN2014092580-appb-000027
Figure PCTCN2014092580-appb-000027
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对甲氧基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)， 有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得37.5mg白色固体化合物18，收率90.5％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of a pair of The anilide was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, water was added, and EA was extracted three times (15 mL each time). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.87(d,J＝15.1Hz,1H),7.58(d,J＝15.1Hz,1H),7.45～7.55(m,5H),7.34～7.42(m,3H),6.84(d,J＝9.0Hz,2H),3.78(s,3H),3.65(s,3H),3.60(s,3H).MS:m/z＝415.2[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.87 (d, J = 15.1 Hz, 1H), 7.58 (d, J = 15.1 Hz, 1H), 7.45 to 7.55 (m, 5H) , 7.34 to 7.42 (m, 3H), 6.84 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.60 (s, 3H). MS: m/z = 415.2 [M+H] +
实施例11(E)-N-(4-氟苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 11(E)-N-(4-Fluorophenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5 -based) synthesis of acrylamide
Figure PCTCN2014092580-appb-000028
Figure PCTCN2014092580-appb-000028
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对氟苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得35.6mg白色固体化合物19，收率88.6％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of fluorine was added. The aniline was stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.88(d,J＝15.1Hz,1H),7.59(d,J＝15.3Hz,2H),7.43～7.57(m,6H),7.38(d,J＝7.4Hz,2H),6.99(t,J＝8.7Hz,2H),3.65(s,3H),3.61(s,3H)。MS:m/z＝403.2[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.88 (d, J = 15.1 Hz, 1H), 7.59 (d, J = 15.3 Hz, 2H), 7.43 to 7.57 (m, 6H) , 7.38 (d, J = 7.4 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 3.65 (s, 3H), 3.61 (s, 3H). MS: m/z = 403.2 [M+H] +
实施例12(E)-N-(4-间氟苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 12(E)-N-(4-m-fluorophenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 5-based acrylamide
Figure PCTCN2014092580-appb-000029
Figure PCTCN2014092580-appb-000029
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的间氟苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)， 有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得34.2mg白色固体化合物20，收率85.1％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 0.12 mmol of m-fluoro The aniline was stirred at room temperature overnight. TLC monitoring, after the reaction was completed, water was added, and EA was extracted three times (15 mL each time). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.89(d,J＝15.0Hz,1H),7.57～7.66(m,2H),7.47～7.56(m,5H),7.34～7.41(m,2H),7.13～7.25(m,2H),6.72～6.79(m,1H),3.65(s,3H),3.61(s,3H)。MS:m/z＝403.2[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.89 (d, J = 15.0 Hz, 1H), 7.57 to 7.66 (m, 2H), 7.47 to 7.56 (m, 5H), 7.34 7.41 (m, 2H), 7.13 to 7.25 (m, 2H), 6.72 to 6.79 (m, 1H), 3.65 (s, 3H), 3.61 (s, 3H). MS: m/z = 403.2 [M+H] +
实施例13(E)-N-(4-间三氟甲基苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 13(E)-N-(4-m-Trifluoromethylphenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000030
Figure PCTCN2014092580-appb-000030
取30.9mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的间三氟甲基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得37.1mg白色固体化合物21，收率82.1％。30.9 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 0.12 mmol of the three Fluoromethylaniline was stirred overnight at room temperature. After the reaction was completed, water was added, and EA was added three times (15 mL each time), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give 37.1 mg of white solid compound 21 in a yield of 82.1%.
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.99(s,1H),7.92(d,J＝15.1Hz,1H),7.68(d,J＝7.8Hz,1H),7.58～7.65(m,2H),7.47～7.57(m,3H),7.35～7.43(m,3H),7.31(d,J＝7.8Hz,1H),3.65(s,3H),3.61(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 15.1 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.58 ~ 7.65 (m, 2H), 7.47 to 7.57 (m, 3H), 7.35 to 7.43 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 3.65 (s, 3H), 3.61 (s, 3H) ).
MS:m/z＝453.2[M+H]+。MS: m/z = 453.2 [M + H] + .
实施例14Example 14
(E)-N-(4-氯苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成(E)-N-(4-chlorophenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Synthesis of acrylamide
Figure PCTCN2014092580-appb-000031
Figure PCTCN2014092580-appb-000031
取31mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入16mg(0.12mmol) 对氯苯胺，室温下搅拌过夜。加入20ml EA后用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤后浓缩，柱层析得到29mg化合物22，黄色粉末，收率69％。31 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 16 mg (0.12 mmol) The p-chloroaniline was stirred at room temperature overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered and concentrated,
1H NMR(400MHz,CDCl3)δ7.96(s,1H),7.85(d,J＝16Hz,1H),7.69(s,1H),7.59-7.49(m,6H),7.37-7.35(m,2H),7.23(d,J＝8Hz,2H),3.61(s,3H),3.58(s,3H)。MS:m/z＝419.4[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ7.96 (s, 1H), 7.85 (d, J = 16Hz, 1H), 7.69 (s, 1H), 7.59-7.49 (m, 6H), 7.37-7.35 (m , 2H), 7.23 (d, J = 8 Hz, 2H), 3.61 (s, 3H), 3.58 (s, 3H). MS: m/z = 419.4 [M+H] + .
实施例15Example 15
(E)-N-(4-甲基苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成(E)-N-(4-methylphenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl ) Synthesis of acrylamide
Figure PCTCN2014092580-appb-000032
Figure PCTCN2014092580-appb-000032
取31mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入13mg(0.12mmol)对甲苯胺，室温下搅拌过夜。加入20ml EA后用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，浓缩后柱层析，得到30mg化合物23，黄色粉末，收率75.2％。Take 31 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolve with 2 mL of DMF, add 0.025 mL of triethylamine, and stir at room temperature for 30 minutes; then add 13 mg (0.12 mmol) of the pair. Toluidine was stirred at room temperature overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered, and evaporated
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.76(d,J＝16Hz,1H),7.57-7.39(m,7H),7.29-7.27(m,2H),7.00(d,J＝8,2H),3.52(s,3H),3.48(s,3H),2.21(s,3H)。MS:m/z＝399.3[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (s, 1H), 7.76 (d, J = 16 Hz, 1H), 7.57-7.39 (m, 7H), 7.29-7.27 (m, 2H), 7.00 (d) , J=8, 2H), 3.52 (s, 3H), 3.48 (s, 3H), 2.21 (s, 3H). MS: m/z = 399.3 [M+H] + .
实施例16Example 16
(E)-N-(3,5-二甲基苯基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成(E)-N-(3,5-Dimethylphenyl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 5-based acrylamide
Figure PCTCN2014092580-appb-000033
Figure PCTCN2014092580-appb-000033
取31mg(0.1mmol)化合物5，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入15mg(0.12mmol) 3,5-二甲基苯胺，室温下搅拌过夜。加入20ml EA后用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤后浓缩，柱层析得到36mg化合物24，黄色粉末，收率87.4％。31 mg (0.1 mmol) of compound 5, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 15 mg (0.12 mmol) 3,5-Dimethylaniline was stirred at room temperature overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 36 mg of Compound 24 as a yellow powder.
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.86-7.82(m,1H),7.66-7.46(m,5H),7.37-7.34(m,2H),7.25(s,2H),6.99(s,1H),3.59(s,3H),3.56(s,3H),2.26(s,6H)。MS:m/z＝413.5[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.86-7.82 (m, 1H), 7.66-7.46 (m, 5H), 7.37-7.34 (m, 2H), 7.25 (s, 2H) ), 6.99 (s, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 2.26 (s, 6H). MS: m/z = 413.5 [M+H] + .
实施例17Example 17
(E)-1-(2-(1H-吡唑-1-基)-4-(三氟甲基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-3-(4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮)的合成(E)-1-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H) -yl)-3-(4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one) Synthesis
Figure PCTCN2014092580-appb-000034
Figure PCTCN2014092580-appb-000034
取25mg(0.08mmol)化合物5，60.83mg(0.16mmol)HATU,用2mL DMF溶解后加入0.02mL三乙胺，室温下搅拌30分钟；然后加入26.9mg2-(1H-吡唑-1-基)-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(0.1mmol,)，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后加入少量甲醇，析出18.1mg化合物25，白色固体，收率40％。Take 25 mg (0.08 mmol) of compound 5, 60.83 mg (0.16 mmol) of HATU, dissolve with 2 mL of DMF, add 0.02 mL of triethylamine, and stir at room temperature for 30 minutes; then add 26.9 mg of 2-(1H-pyrazol-1-yl) 4-(Trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.1 mmol,) was stirred at room temperature overnight. After TLC monitoring, after completion of the reaction, water was added, and EA was extracted three times (15 mL each time), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and then a small amount of methanol was added to precipitate 18.1 mg of compound 25, white solid, yield 40% .
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.45(d,J＝15.1Hz,1H),7.91(s,1H),7.79(s,1H),7.52(d,J＝13.3Hz,1H),7.43(d,J＝6.3Hz,3H),7.29(d,J＝6.7Hz,2H),6.45(s,1H),5.05(d,2H),3.97(d,2H),3.59(s,3H),3.53(s,3H),3.04(d,2H)。MS:m/z＝561.4[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ8.55 (s, 1H), 8.45 (d, J = 15.1Hz, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.52 (d, J = 13.3 Hz, 1H), 7.43 (d, J = 6.3 Hz, 3H), 7.29 (d, J = 6.7 Hz, 2H), 6.45 (s, 1H), 5.05 (d, 2H), 3.97 (d, 2H) , 3.59 (s, 3H), 3.53 (s, 3H), 3.04 (d, 2H). MS: m/z = 561.4 [M + H] + .
实施例18Example 18
N-(4-氯苯基)-4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Synthesis of N-(4-chlorophenyl)-4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
Figure PCTCN2014092580-appb-000035
Figure PCTCN2014092580-appb-000035
化合物26的合成Synthesis of Compound 26
取0.1g(0.42mmol)化合物3置于25ml圆底烧瓶中，氮气置换后加入1mlDMF溶解，0℃下逐滴加入0.5mlDMF溶解的三氟乙酸酐，继续搅拌5h。加入3ml水混合，用EA萃取，浓缩。加入5ml 10％NaOH水溶液和5ml甲醇，100℃搅拌过夜。降至室温后，加水混合，用EA洗。水层用1M HCl酸化，过滤，干燥，得到60mg化合物26，白色粉末，收率50％。0.1 g (0.42 mmol) of compound 3 was placed in a 25 ml round bottom flask, dissolved in nitrogen, dissolved in 1 ml of DMF, and 0.5 ml of DMF dissolved trifluoroacetic anhydride was added dropwise at 0 ° C, and stirring was continued for 5 h. It was mixed with 3 ml of water, extracted with EA, and concentrated. 5 ml of 10% aqueous NaOH solution and 5 ml of methanol were added, and the mixture was stirred at 100 ° C overnight. After cooling to room temperature, add water and wash with EA. The aqueous layer was acidified with 1M EtOAc then filtered and dried
化合物27(N-(4-氯苯基)-4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺)的合成Synthesis of Compound 27 (N-(4-Chlorophenyl)-4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide)
取28mg(0.1mmol)化合物9，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；加入对氯苯胺15mg(0.12mmol)继续搅拌过夜。加入20ml EA后用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤后浓缩，柱层析得到20mg化合物27，白色粉末，收率51％。28 mg (0.1 mmol) of compound 9, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; p-chloroaniline 15 mg (0.12 mmol) ) Continue stirring overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered, and concentrated.
1H NMR(400MHz,CDCl3)δ12.6(s,1H),7.94(s,1H),7.65(d,J＝8Hz,2H),7.45-7.43(m,3H),7.34-7.32(m,2H),7.13(d,J＝8Hz,2H),3.64(s,3H),3.44(s,3H)。MS:m/z＝393.3[M+H]+。 1 H NMR (400MHz, CDCl 3 ) δ12.6 (s, 1H), 7.94 (s, 1H), 7.65 (d, J = 8Hz, 2H), 7.45-7.43 (m, 3H), 7.34-7.32 (m , 2H), 7.13 (d, J = 8 Hz, 2H), 3.64 (s, 3H), 3.44 (s, 3H). MS: m/z = 393.3 [M + H] + .
实施例19Example 19
N-(4-甲基苯基)-4-甲氧基-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Synthesis of N-(4-methylphenyl)-4-methoxy-7-methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
Figure PCTCN2014092580-appb-000036
Figure PCTCN2014092580-appb-000036
取28mg(0.1mmol)化合物9，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；加入对甲基苯胺13mg(0.12mmol)继续搅拌过夜。加入20mlEA后用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤后浓缩，柱层析得到22mg化合物28，白色粉末，收率59％。28 mg (0.1 mmol) of compound 9, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; p-methylaniline 13 mg (0.12) Methyl) Continue stirring overnight. After adding 20 ml of EA, it was washed with a saturated NaCI solution, dried over anhydrous sodium sulfate, filtered and concentrated, and
1H NMR(400MHz,CDCl3)δ12.4(s,1H),7.91(s,1H),7.58(d,J＝8Hz,2H),7.45-7.40(m,3H),7.35-7.32(m,2H),6.98(d,J＝8Hz,2H),3.63(s,3H),3.43(s,3H)。MS:m/z＝373.2[M+H]+。 1 H NMR (400 MHz, CDCl 3 ) δ 12.4 (s, 1H), 7.91 (s, 1H), 7.58 (d, J = 8 Hz, 2H), 7.45-7.40 (m, 3H), 7.35-7.32 (m , 2H), 6.98 (d, J = 8 Hz, 2H), 3.63 (s, 3H), 3.43 (s, 3H). MS: m/z = 373.2 [M + H] + .
实施例20 Example 20
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-氯-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-chloro-7-methyl-6-phenyl Synthesis of -7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000037
Figure PCTCN2014092580-appb-000037
化合物29的合成Synthesis of Compound 29
取化合物2(4.22g)，加入35mL的POCl3，90℃条件下反应5h。反应完全后，减压出去残余的POCl3，然后在冰浴条件下缓慢向反应瓶中滴加水，用1mol/L的NaOH溶液调节pH到12，抽滤，固体用水洗涤，干燥得5.1g化合物29粗产品，直接用于下一步。化合物30的合成Compound 2 (4.22 g) was taken, and 35 mL of POCl 3 was added thereto, and the mixture was reacted at 90 ° C for 5 hours. After the reaction was completed, the residual POCl 3 was removed under reduced pressure, and then water was slowly added dropwise to the reaction flask under ice bath conditions, and the pH was adjusted to 12 with a 1 mol/L NaOH solution, suction filtered, and the solid was washed with water and dried to give 5.1 g of compound. 29 crude product, used directly in the next step. Synthesis of Compound 30
N2保护下，将20mL DMF加入到装有1.15g化合物23和240mg NaH的三口瓶中，0℃搅拌10min后缓慢滴加0.6mL CH3I，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得690mg化合物30，收率56.8％。Under N 2 protection, 20 mL of DMF was added to a three-necked flask containing 1.15 g of compound 23 and 240 mg of NaH. After stirring at 0 ° C for 10 min, 0.6 mL of CH 3 I was slowly added dropwise and stirred at room temperature overnight. After the completion of the reaction, water was slowly added dropwise to the reaction flask, followed by extraction with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate,
化合物31的合成Synthesis of Compound 31
取122mg化合物24用CH2Cl2溶解后，0℃条件下加入169mg NIS，室温下搅拌5h。TLC监测，反应完全后，向反应瓶中加入CH2Cl2，有机相依次用饱和NaHCO3溶液、饱和盐水洗涤，无水硫酸钠干燥，浓缩得化合物31，直接用于下一步。After dissolving 122 mg of Compound 24 in CH 2 Cl 2 , 169 mg of NIS was added at 0 ° C, and stirred at room temperature for 5 h. After the reaction was completed, CH 2 Cl 2 was added to the reaction mixture, and the organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous sodium sulfate
化合物32的合成Synthesis of Compound 32
取230mg 6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐，加入5ml CH2Cl2，0.1mL三乙胺，0℃条件下缓慢滴加0.1mL丙烯酰氯，室温下搅拌4h。TLC监测，反应完全后，浓缩后柱层析，得白色固体170mg化合物32，收率68.8％。Take 230 mg of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, add 5 ml of CH 2 Cl 2 , 0.1 mL of triethylamine, and slowly add 0.1 mL at 0 °C. Acryloyl chloride was stirred at room temperature for 4 h. After TLC was monitored, the reaction was completed, and then concentrated and purified to afford white crystals (yield:
化合物33(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-氯-7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮)的合成Compound 33(E)-1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-chloro-7-methyl-6- Synthesis of Phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
取100mg化合物25，120mg化合物26，50mg Na2CO3，3mg醋酸钯，N2保护下向反应瓶中加入3mLDMF，100℃反应24h。停止反应后，加水，用EA萃取，有机相用饱和 盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得54mg化合物33，收率40.8％。100 mg of compound 25, 120 mg of compound 26, 50 mg of Na 2 CO 3 , 3 mg of palladium acetate, and 3 mL of DMF were added to the reaction flask under N 2 protection, and reacted at 100 ° C for 24 h. After the reaction was stopped, water was added and extracted with EtOAc. EtOAc EtOAc m.
MS:m/z＝489.5[M+H]+。MS: m/z = 489.5 [M+H] + .
实施例21Example 21
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(7-methyl-6-phenyl-7H-pyrrole Synthesis of [2,3-d]pyrimidin-5-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000038
Figure PCTCN2014092580-appb-000038
化合物34的合成Synthesis of Compound 34
取350mg化合物30,用20ml甲醇溶解，加入70mg钯碳(10％)，置换氮气后，通入氢气反应过夜。过滤除掉钯碳，浓缩后得到100mg化合物34，白色固体，收率33.3％。350 mg of the compound 30 was taken, dissolved in 20 ml of methanol, and 70 mg of palladium carbon (10%) was added thereto, and after replacing the nitrogen gas, hydrogen gas was introduced to react overnight. The palladium carbon was removed by filtration and concentrated to give 100 mg of compound 34 as a white solid.
化合物35的合成Synthesis of Compound 35
取100mg化合物34，0℃下加入干燥二氯甲烷2ml，溶解后加入300mg NIS,搅拌1h后移至室温搅拌过夜。反应结束后，加入硫代硫酸钠溶液，用二氯甲烷萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥后浓缩，得到102mg化合物35，淡黄色固体，收率64％。100 mg of compound 34 was added, and 2 ml of dry dichloromethane was added at 0 ° C. After dissolution, 300 mg of NIS was added, and after stirring for 1 hour, it was stirred to room temperature and stirred overnight. After completion of the reaction, a sodium thiosulfate solution was added, and the mixture was extracted with methylene chloride, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to give crystals.
化合物36Compound 36
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(7-甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5- 基)丙-2-烯-1-酮盐酸盐的合成(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(7-methyl-6-phenyl-7H-pyrrole And [2,3-d]pyrimidine-5- Synthesis of propyl-2-en-1-one hydrochloride
取50mg化合物35,25mg化合物32，10mg碳酸钠，3mg醋酸钯，氮气置换后，加入无水DMF1ml，110℃反应。反应结束后，加入饱和氯化钠溶液，EA萃取。无水硫酸钠干燥后浓缩，柱层析，得到20mg化合物36，黄色固体，收率30％。50 mg of compound 35, 25 mg of compound 32, 10 mg of sodium carbonate, 3 mg of palladium acetate, and nitrogen were added, and then 1 ml of anhydrous DMF was added thereto, and the mixture was reacted at 110 °C. After the reaction was completed, a saturated sodium chloride solution was added and EA was extracted. After drying over anhydrous sodium sulfate, the mixture was concentrated and purified mjjjjjjjj
MS:m/z＝455.3[M+H]+。MS: m/z = 455.3 [M + H] + .
实施例22Example 22
(E)-3-(4-三氘代甲氧基-7-氘代甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)丙-2-烯-1-酮的合成(E)-3-(4-trideuteromethoxy-7-deuterated methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)prop-2-en-1- Ketone synthesis
Figure PCTCN2014092580-appb-000039
Figure PCTCN2014092580-appb-000039
化合物37的合成Synthesis of Compound 37
N2保护下，将21mL DMF加入到装有化合物2(1.5g)和NaH 350mg的三口瓶中，0℃搅拌10min后缓慢滴加1mL CD3I，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩过柱，得500mg化合物37，收率31％。Under N 2 protection, 21 mL of DMF was added to a three-necked flask containing Compound 2 (1.5 g) and NaH 350 mg. After stirring at 0 ° C for 10 min, 1 mL of CD 3 I was slowly added dropwise and stirred at room temperature overnight. After the completion of the reaction, water was slowly added dropwise to the reaction flask, followed by extraction with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and
1H NMR(400MHz,CDCl3)δ7.88(d,1H),7.47(m,4H),7.41(d,1H),6.75(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, 1H), 7. 7. (m, 4H), 7.41 (d, 1H), 6.75 (s, 1H).
化合物38的合成Synthesis of Compound 38
N2保护下，取化合物37(500mg)溶于10mL DMF中，0℃条件下滴加POCl3,反应3h后加水，用1mol/L的NaOH溶液调节pH大于14，析出沉淀，抽滤得300mg化合物38，白色固体，收率54％。Under the protection of N 2 , compound 37 (500 mg) was dissolved in 10 mL of DMF, and POCl 3 was added dropwise at 0 ° C. After 3 h of reaction, water was added, and the pH was adjusted to be greater than 14 with 1 mol/L NaOH solution, and the precipitate was precipitated. Compound 38, white solid, yield 54%.
化合物39的合成Synthesis of Compound 39
取化合物38(300mg)，丙二酸312mg，哌啶0.75mL溶于12mL吡啶中，回流反应5h。反应完全后，减压除去吡啶，加水稀释后，用1mol/L的HCl溶液调节pH到6，析出沉淀，抽滤得200mg化合物39，淡黄色固体，收率58％。Compound 38 (300 mg), 312 mg of malonic acid, 0.75 mL of piperidine were dissolved in 12 mL of pyridine, and refluxed for 5 h. After completion of the reaction, the pyridine was removed under reduced pressure, and then diluted with water, and then adjusted to pH 6 with a 1 mol/L HCl solution, and the precipitate was precipitated, and filtered to give 200 mg of Compound 39 as a pale yellow solid, yield 58%.
化合物40的合成 Synthesis of Compound 40
取45mg化合物39，1.5mlDMF溶解后，加入缩合剂HATU 90mg，三乙胺90乙胺，室温搅拌30min后加入3-(三氟甲基)-5,6,7,8-四氢-[1,2，4]***并[4,3-a]吡嗪盐酸盐42mg，搅拌过夜。反应结束后，加入饱和食盐水，EA萃取。合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后过柱，得到无色针状结晶40mg，收率58％。After 45 mg of compound 39 and 1.5 ml of DMF were dissolved, the condensing agent HATU 90 mg, triethylamine 90 ethylamine was added, and stirred at room temperature for 30 min, then 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1 , 2,4] Triazolo[4,3-a]pyrazine hydrochloride 42 mg, stirred overnight. After completion of the reaction, saturated brine was added and EA was extracted. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated.
1H NMR(400MHz,CDCl3)δ8.48(d,J＝12Hz,1H),7.96(s,1H),7.57(d,J＝12Hz,1H),7.53-7.50(m,3H),7.35(d,J＝4Hz,2H),5.22(s,2H),4.19(s,4H)。MS:m/z＝513.3[M+Na]+。 1 H NMR (400MHz, CDCl 3 ) δ8.48 (d, J = 12Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 12Hz, 1H), 7.53-7.50 (m, 3H), 7.35 (d, J = 4 Hz, 2H), 5.22 (s, 2H), 4.19 (s, 4H). MS: m/z = 513.3 [M + Na] + .
取上述固体30mg，加入5ml二氯甲烷溶解，冰浴下将HCl乙酸乙酯溶液缓慢滴加到上述溶液中，析出白色固体，加入***，0℃搅拌2h，抽滤用***洗涤，真空干燥，得26mg化合物40。30 mg of the above solid was taken, dissolved in 5 ml of dichloromethane, and the HCl solution of HCl was slowly added dropwise to the above solution to precipitate a white solid. diethyl ether was added, and the mixture was stirred at 0 ° C for 2 hr, washed with diethyl ether and dried in vacuo. 26 mg of compound 40 were obtained.
1H NMR(400MHz,CDCl3)δ8.48(d,J＝12Hz,1H),7.96(s,1H),7.57(d,J＝12Hz,1H),7.53-7.50(m,3H),7.35(d,J＝4Hz,2H),5.22(s,2H),4.19(s,4H)。MS:m/z＝513.3[M+Na]+。 1 H NMR (400MHz, CDCl 3 ) δ8.48 (d, J = 12Hz, 1H), 7.96 (s, 1H), 7.57 (d, J = 12Hz, 1H), 7.53-7.50 (m, 3H), 7.35 (d, J = 4 Hz, 2H), 5.22 (s, 2H), 4.19 (s, 4H). MS: m/z = 513.3 [M + Na] + .
实施例23Example 23
(E)-3-(4-三氘代甲氧基-7-氘代甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶)丙-2-烯-1-酮的合成(E)-3-(4-trideuteromethoxy-7-deuterated methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl 2-methyl-4-(three Synthesis of fluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-D]pyrimidine)prop-2-en-1-one
Figure PCTCN2014092580-appb-000040
Figure PCTCN2014092580-appb-000040
取30mg化合物39，1mlDMF溶解后，加入缩合剂HATU 90mg，三乙胺90乙胺，室温搅拌30min后加入2-甲基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶盐酸盐50mg，搅拌过夜。反应结束后，加入饱和食盐水，EA萃取。合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后过柱，得到25mg化合物41，白色结晶，收率51％。After taking 30 mg of compound 39 and dissolving 1 ml of DMF, add 90 mM of the condensing agent HATU, triethylamine 90 ethylamine, and stir at room temperature for 30 min, then add 2-methyl-4-(trifluoromethyl)-5,6,7,8-tetra Hydrogen pyrido[3,4-D]pyrimidine hydrochloride 50 mg was stirred overnight. After completion of the reaction, saturated brine was added and EA was extracted. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate.
MS:m/z＝515.5[M+H]+。MS: m/z = 515.5 [M + H] + .
实施例24Example 24
(E)-3-(4-三氘代甲氧基-7-氘代甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并 [3,4-D]嘧啶)丙-2-烯-1-酮的合成(E)-3-(4-trideuteromethoxy-7-deuterated methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl-2-phenyl-4-(III Fluoromethyl)-5,6,7,8-tetrahydropyridine Synthesis of [3,4-D]pyrimidine)prop-2-en-1-one
Figure PCTCN2014092580-appb-000041
Figure PCTCN2014092580-appb-000041
取30mg化合物39，1mlDMF溶解后，加入缩合剂HATU 90mg，三乙胺90乙胺，室温搅拌30min后加入2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶盐酸盐55mg，搅拌过夜。反应结束后，加入饱和食盐水，EA萃取。合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后过柱，得到26mg化合物42，白色结晶，收率47％。After taking 30 mg of compound 39 and dissolving 1 ml of DMF, add 90 mM of the condensing agent HATU, triethylamine 90 ethylamine, and stir at room temperature for 30 min, then add 2-phenyl-4-(trifluoromethyl)-5,6,7,8-tetra Hydrogen pyrido[3,4-D]pyrimidine hydrochloride 55 mg was stirred overnight. After completion of the reaction, saturated brine was added and EA was extracted. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate.
MS:m/z＝599.6[M+Na]+。MS: m/z = 599.6 [M+Na] + .
实施例25Example 25
(E)-3-(4-三氘代甲氧基-7-氘代甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基2-吡唑基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶)丙-2-烯-1-酮的合成(E)-3-(4-trideuteromethoxy-7-deuterated methyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl 2-pyrazolyl-4-( Synthesis of trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-D]pyrimidine)prop-2-en-1-one
Figure PCTCN2014092580-appb-000042
Figure PCTCN2014092580-appb-000042
取30mg化合物39，1mlDMF溶解后，加入缩合剂HATU 90mg，三乙胺90乙胺，室温搅拌30min后加入2-吡唑基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶盐酸盐55mg，搅拌过夜。反应结束后，加入饱和食盐水，EA萃取。合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后过柱，得到31mg化合物43，无色针状结晶，收率58％。After taking 30 mg of compound 39 and dissolving 1 ml of DMF, add 90 mM of condensing agent HATU, triethylamine 90 ethylamine, and stir at room temperature for 30 min, then add 2-pyrazolyl-4-(trifluoromethyl)-5,6,7,8- 55 mg of tetrahydropyrido[3,4-D]pyrimidine hydrochloride was stirred overnight. After completion of the reaction, saturated brine was added and EA was extracted. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated.
MS:m/z＝566.4[M+H]+。 MS: m/z = 566.4 [M+H] + .
实施例26Example 26
22(E)-3-(4-三氘代甲氧基-7-氘代甲基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基2-乙酸乙酯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶)丙-2-烯-1-酮的合成22(E)-3-(4-tridemethoxy--7-deuteromethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-( 3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl 2-ethyl acetate-4 Synthesis of -(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-D]pyrimidine)prop-2-en-1-one
Figure PCTCN2014092580-appb-000043
Figure PCTCN2014092580-appb-000043
取30mg化合物39，1mlDMF溶解后，加入缩合剂HATU 90mg，三乙胺90乙胺，室温搅拌30min后加入乙基-2-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶-2-基)乙酸酯盐酸盐52mg，搅拌过夜。反应结束后，加入饱和食盐水，EA萃取。合并有机层后，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后过柱，得到20mg化合物44，白色结晶，收率36％。After taking 30 mg of compound 39 and dissolving 1 ml of DMF, add 90 mM of condensing agent HATU, triethylamine 90 ethylamine, and stir at room temperature for 30 min, then add ethyl-2--4-(trifluoromethyl)-5,6,7,8-tetra Hydrogen pyrido[3,4-D]pyrimidin-2-yl)acetate hydrochloride 52 mg, stirred overnight. After completion of the reaction, saturated brine was added and EA was extracted. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated.
MS:m/z＝609.6[M+Na]+。MS: m/z = 609.6 [M + Na] + .
实施例27Example 27
(E)-3-(4-甲氧基-7-甲基-6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基)丙-2-烯-1-酮的合成 (E)-3-(4-methoxy-7-methyl-6-(4-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)prop-2-en-1- Ketone synthesis
Figure PCTCN2014092580-appb-000044
Figure PCTCN2014092580-appb-000044
化合物45的合成Synthesis of Compound 45
N2保护条件下，0℃将1.66g 3-脒基丙酸乙酯盐酸盐和1.04g NaOEt溶于无水乙醇中，搅拌20分钟后将温度升至60℃，缓慢加入10g 2-溴苯乙酮，反应2小时后减压除去乙醇，然后加水稀释，乙酸乙酯萃取。有机相用饱和盐水洗涤，硫酸钠干燥，浓缩，柱层析得0.656g化合物45，收率43％。Under N 2 protection conditions, 1.66 g of ethyl 3-mercaptopropionate hydrochloride and 1.04 g of NaOEt were dissolved in absolute ethanol at 0 ° C. After stirring for 20 minutes, the temperature was raised to 60 ° C, and 10 g of 2-bromo was slowly added. Acetophenone, after reacting for 2 hours, the ethanol was removed under reduced pressure, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.52–7.33(m,4H),6.54(s,1H),5.71(s,2H),4.14(q,J＝7.0Hz,2H),1.34–1.19(m,3H)。 1 H NMR (400MHz, DMSO- d 6) δ10.80 (s, 1H), 7.52-7.33 (m, 4H), 6.54 (s, 1H), 5.71 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.34–1.19 (m, 3H).
化合物46的合成Synthesis of Compound 46
取533mg化合物45，1.35mL甲酸，9mL甲酰胺，10mL DMF，150℃搅拌24小时。TLC监测，反应完全后，冷却，部分产物析出，抽滤后真空干燥，同时用EA萃取滤液，浓缩，共得498mg化合物46，收率99％。533 mg of compound 45, 1.35 mL of formic acid, 9 mL of formamide, 10 mL of DMF were taken and stirred at 150 ° C for 24 hours. After TLC monitoring, after the reaction was completed, the mixture was cooled, and some of the product was precipitated. After suction filtration, the mixture was dried in vacuo. The filtrate was extracted with EA and concentrated to give 498 mg of Compound 46.
1H NMR(400MHz,DMSO-d6)δ12.40(d,J＝25.9Hz,1H),11.91(s,1H),7.89(s,1H),7.80(d,J＝8.2Hz,2H),7.60(d,J＝8.2Hz,2H),6.99(s,1H)。 1 H NMR (400MHz, DMSO- d 6) δ12.40 (d, J = 25.9Hz, 1H), 11.91 (s, 1H), 7.89 (s, 1H), 7.80 (d, J = 8.2Hz, 2H) , 7.60 (d, J = 8.2 Hz, 2H), 6.99 (s, 1H).
化合物47的合成Synthesis of Compound 47
N2保护下，将3mL DMF加入到装有145mg化合物46和48mg NaH的三口瓶中，0℃搅拌10min后，缓慢滴加0.1mL CH3I，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得120mg化合物47,淡黄色产品，收率75.4％。Under N 2 protection, 3 mL of DMF was added to a three-necked flask containing 145 mg of compound 46 and 48 mg of NaH, and after stirring at 0 ° C for 10 min, 0.1 mL of CH 3 I was slowly added dropwise, and stirred at room temperature overnight. After TLC monitoring, after completion of the reaction, water was slowly added dropwise to the reaction flask, and then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, 75.4%.
化合物48的合成Synthesis of Compound 48
N2保护下，取110mg化合物47溶于2mL DMF中，0℃条件下滴加0.5mlPOCl3，反应3h后加水，用1mol/L的NaOH溶液调节pH大于7，析出沉淀，抽滤得85mg化合物48，黄色固体，收率71％。 Under the protection of N 2 , 110 mg of compound 47 was dissolved in 2 mL of DMF, and 0.5 ml of POCl 3 was added dropwise at 0 ° C. After 3 h of reaction, water was added, and the pH was adjusted to be greater than 7 with 1 mol/L NaOH solution, and the precipitate was precipitated and filtered to obtain 85 mg of the compound. 48, yellow solid, yield 71%.
化合物49的合成Synthesis of Compound 49
取70mg化合物48，100mg丙二酸，0.2mL哌啶溶于4mL吡啶中，回流反应5h。反应完全后，减压除去吡啶，加水稀释后，析出沉淀，抽滤得52mg化合物49，淡黄色固体，收率66％。70 mg of compound 48, 100 mg of malonic acid, 0.2 mL of piperidine were dissolved in 4 mL of pyridine, and refluxed for 5 h. After completion of the reaction, the pyridine was removed under reduced pressure, and the mixture was diluted with water, and then the precipitate was precipitated, and filtered to give 52 mg of Compound 49 as a pale yellow solid.
化合物50的合成Synthesis of Compound 50
取38.8mg(0.1mmol)化合物49，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入27.4mg3-(三氟甲基)-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪盐酸盐(0.12mmol,)，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得43.7mg化合物50，黄色固体产品，收率78％。38.8 mg (0.1 mmol) of compound 49, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 27.4 mg of 3-(3) Fluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.12 mmol,) was stirred at room temperature overnight. After TLC monitoring, after completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate %.
1H NMR(400MHz,CDCl3)NMR(400MHJ＝14.7Hz,1H),7.93(d,J＝15.4Hz,2H),7.59(d,J＝7.9Hz,2H),7.16(d,J＝8.0Hz,2H),5.13(d,J＝50.8Hz,2H),4.10(s,4H),3.56(s,3H),3.52(s,3H)。 1 H NMR (400MHz, CDCl 3 ) NMR (400MHJ = 14.7Hz, 1H), 7.93 (d, J = 15.4Hz, 2H), 7.59 (d, J = 7.9Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 5.13 (d, J = 50.8 Hz, 2H), 4.10 (s, 4H), 3.56 (s, 3H), 3.52 (s, 3H).
MS:m/z＝562.2[M+Na]+。MS: m/z = 562.2 [M + Na] + .
实施例28Example 28
(E)-3-(4-甲氧基-7-甲基-6-(4-溴苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(3-(三氟甲基)-5,6-二氢-[1,2,4]***并[4,3-a]吡嗪-7(8H)-基2-苯基-4-(三氟甲基)-5,6,7,8-四氢吡啶并[3,4-D]嘧啶)丙-2-烯-1-酮的合成(E)-3-(4-methoxy-7-methyl-6-(4-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(3) -(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl-2-phenyl-4-(III Synthesis of fluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-D]pyrimidine)prop-2-en-1-one
Figure PCTCN2014092580-appb-000045
Figure PCTCN2014092580-appb-000045
取38.8mg(0.1mmol)化合物49，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入37.8mg2-苯基-4-(三氟甲基)-5,,6,7,8-四氢吡啶并[3,4-d]嘧啶盐酸盐(0.12mmol,)，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后加入少量甲醇，析出36.2mg化合物51，白色固体，收率56％。38.8 mg (0.1 mmol) of compound 49, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 37.8 mg of 2-phenyl 4-(Trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride (0.12 mmol,) was stirred at room temperature overnight. After TLC monitoring, after completion of the reaction, water was added, and EA was extracted three times (15 mL each time), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and then a small amount of methanol, 36.2 mg of compound 51, white solid, yield 56% .
1H NMR(400MHz,DMSO-d6)7.59(s,3H),7.46(d,J＝8.0Hz,2H),7.32(d,J＝14.9Hz,1H),4.98(d,J＝45.9Hz,2H),3.94(d,J＝47.1Hz,2H),3.56(d,J＝8.3Hz,6H),3.02(d,J＝47.4Hz,2H)。MS:m/z＝649.3[M+H]+。 1 H NMR (400MHz, DMSO- d 6) 7.59 (s, 3H), 7.46 (d, J = 8.0Hz, 2H), 7.32 (d, J = 14.9Hz, 1H), 4.98 (d, J = 45.9Hz , 2H), 3.94 (d, J = 47.1 Hz, 2H), 3.56 (d, J = 8.3 Hz, 6H), 3.02 (d, J = 47.4 Hz, 2H). MS: m/z = 649.3 [M + H] + .
实施例29Example 29
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-ethoxy-7-ethyl-6- Synthesis of Phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000046
Figure PCTCN2014092580-appb-000046
化合物52的合成Synthesis of Compound 52
N2保护下，将3mL DMF加入到装有211mg化合物2和48mg NaH的三口瓶中，0℃搅拌10min后，缓慢滴加0.15mL CH3CH2I，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得229.6mg化合物52，收率为86％。Under N 2 protection, 3 mL of DMF was added to a three-necked flask containing 211 mg of Compound 2 and 48 mg of NaH. After stirring at 0 ° C for 10 min, 0.15 mL of CH 3 CH 2 I was slowly added dropwise and stirred at room temperature overnight. After the completion of the reaction, water was slowly added dropwise to the reaction flask, and then extracted with EA. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate .
化合物53的合成Synthesis of Compound 53
N2保护下，取134mg化合物52溶于2mL DMF中，0℃条件下滴加POCl3，反应3h后加水，用1mol/L的NaOH溶液调节pH大于14，析出沉淀，抽滤得126.3mg白色固体化合物53，收率85.6％。Under N 2 protection, 134 mg of compound 52 was dissolved in 2 mL of DMF, and POCl 3 was added dropwise at 0 ° C. After 3 h of reaction, water was added, and the pH was adjusted to be greater than 14 with 1 mol/L NaOH solution, and the precipitate was precipitated and filtered to obtain 126.3 mg of white. Solid compound 53, yield 85.6%.
化合物54的合成Synthesis of Compound 54
取100mg化合物53，104mg丙二酸，0.25mL哌啶溶于4mL吡啶中，回流反应5h。反应完全后，减压除去吡啶，加水稀释后，用1mol/L的HCl溶液调节pH到6，析出沉淀，抽滤得92.9mg化合物54，收率81.3％。100 mg of compound 53, 104 mg of malonic acid, 0.25 ml of piperidine were dissolved in 4 mL of pyridine, and refluxed for 5 h. After completion of the reaction, the pyridine was removed under reduced pressure, and the mixture was diluted with water. The mixture was adjusted to pH 6 with a 1 mol/L HCl solution, and the precipitate was precipitated, and filtered to give 92.9 mg of Compound 54 in a yield of 81.3%.
化合物55(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成Compound 55(E)-1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-ethoxy-7-ethyl- Synthesis of 6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入28mg(0.12mmol)6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得43.8mg白色固体化合物55，收率85.6％。 33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 28 mg (0.12 mmol) 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.21(d,J＝15.3Hz,1H),7.55～7.64(m,3H),7.38～7.50(m,2H),7.25(d,J＝15Hz,1H),6.61～6.86(m,2H),4.60(s,1H),4.56(s,1H),3.95～4.18(m,4H),3.60～3.85(m,8H),2.69(s,1H),2.65(s,1H),1.31(t,J＝7.0Hz,3H),1.09(t,J＝7.0Hz,3H).MS:m/z＝513.2[M+H]+ 1 H NMR (400MHz, DMSO- d 6) δ8.42 (s, 1H), 8.21 (d, J = 15.3Hz, 1H), 7.55 ~ 7.64 (m, 3H), 7.38 ~ 7.50 (m, 2H), 7.25 (d, J=15 Hz, 1H), 6.61 to 6.86 (m, 2H), 4.60 (s, 1H), 4.56 (s, 1H), 3.95 to 4.18 (m, 4H), 3.60 to 3.85 (m, 8H) ), 2.69 (s, 1H), 2.65 (s, 1H), 1.31 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H). MS: m/z = 513.2 [M+ H] +
实施例30(E)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-(4-甲基哌嗪哌啶-1-基)丙-2-烯-1-酮的合成Example 30(E)-3-(4-Ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-(4-A Synthesis of Piperazine Piperidin-1-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000047
Figure PCTCN2014092580-appb-000047
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的N-甲基哌嗪，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得28.1mg白色固体化合物56，收率67.1％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of N- Methylpiperazine was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ8.31(d,J＝15.1Hz,1H),7.94(s,1H),7.43～7.52(m,4H),7.33～7.40(m,2H),4.09(dq,J＝14.4,7.2Hz,4H),3.74(d,J＝27.3Hz,4H),2.42(d,J＝26.5Hz,4H),2.30(s,3H),1.44(t,J＝7.2Hz,3H),1.18(t,J＝7.2Hz,3H).MS:m/z＝420.3[M+H]+ 1 H NMR (400MHz, CDCl 3 ) δ8.31 (d, J = 15.1Hz, 1H), 7.94 (s, 1H), 7.43 ~ 7.52 (m, 4H), 7.33 ~ 7.40 (m, 2H), 4.09 ( Dq, J = 14.4, 7.2 Hz, 4H), 3.74 (d, J = 27.3 Hz, 4H), 2.42 (d, J = 26.5 Hz, 4H), 2.30 (s, 3H), 1.44 (t, J = 7.2) Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). MS: m/z = 420.3 [M+H] +
实施例26(E)-N-(4-对甲氧苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成 Example 26(E)-N-(4-p-methoxyphenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine Synthesis of -5-yl)acrylamide
Figure PCTCN2014092580-appb-000048
Figure PCTCN2014092580-appb-000048
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对甲氧基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得39.9mg白色固体化合物57，收率90.4％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of a pair of The anilide was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated.
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.42(s,1H),7.67(d,J＝15.4Hz,1H),7.58～7.64(m,5H),7.44～7.50(m,2H),7.28(d,J＝15.3Hz,1H),6.84(d,J＝9.1Hz,2H),3.96～4.19(m,4H),3.71(s,3H),1.33(t,J＝6.9Hz,3H),1.10(t,J＝7.0Hz,3H).MS:m/z＝443.2[M+H]+ 1 H NMR (400MHz, DMSO- d 6) δ9.96 (s, 1H), 8.42 (s, 1H), 7.67 (d, J = 15.4Hz, 1H), 7.58 ~ 7.64 (m, 5H), 7.44 ~ 7.50 (m, 2H), 7.28 (d, J = 15.3 Hz, 1H), 6.84 (d, J = 9.1 Hz, 2H), 3.96 to 4.19 (m, 4H), 3.71 (s, 3H), 1.33 (t , J=6.9Hz, 3H), 1.10(t, J=7.0Hz, 3H).MS:m/z=443.2[M+H] +
实施例27(E)-3-(7-乙基-4-(乙基)-6-苯基7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2,3-二氢苯并[b][1,4]二恶唑-6-基)丙烯酰胺的合成Example 27(E)-3-(7-ethyl-4-(ethyl)-6-phenyl 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2,3 Synthesis of dihydrobenzo[b][1,4]dioxazol-6-yl)acrylamide
Figure PCTCN2014092580-appb-000049
Figure PCTCN2014092580-appb-000049
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的3,4-亚乙二氧基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得35.4mg白色固体化合物58，收率75.4％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of 3, 4-Ethylenedioxyaniline was stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.42(s,1H),7.65(d,J＝15.3Hz,1H),7.57～7.64(m,3H),7.44～7.50(m,2H),7.36(d,J＝2.2Hz,1H),7.27(d,J＝15.3Hz,1H),7.11 (dd,J＝8.8,2.2Hz,1H),6.73(d,J＝8.8Hz,1H),4.16～4.24(m,4H),3.98～4.14(m,4H),1.33(t,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H).MS:m/z＝471.2[M+H]+ 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.42 (s, 1H), 7.65 (d, J = 15.3 Hz, 1H), 7.57 to 7.64 (m, 3H), 7.44 7.50 (m, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 15.3 Hz, 1H), 7.11 (dd, J = 8.8, 2.2 Hz, 1H), 6.73 (d, J) = 8.8 Hz, 1H), 4.16 to 4.24 (m, 4H), 3.98 to 4.14 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). :m/z=471.2[M+H] +
实施例28(E)-N-(4-对氟苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 28(E)-N-(4-p-fluorophenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 5-based acrylamide
Figure PCTCN2014092580-appb-000050
Figure PCTCN2014092580-appb-000050
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对氟苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得35.8mg白色固体化合物59，收率83.4％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of fluorine was added. The aniline was stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.86(d,J＝15.1Hz,1H),7.72(s,1H),7.46～7.61(m,6H),7.32～7.41(m,2H),6.97(t,J＝8.7Hz,2H),4.11(p,J＝7.0Hz,4H),1.45(t,J＝7.2Hz,3H),1.20(t,J＝7.1Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.86 (d, J = 15.1 Hz, 1H), 7.72 (s, 1H), 7.46 to 7.61 (m, 6H), 7.32 to 7.41 ( m, 2H), 6.97 (t, J = 8.7 Hz, 2H), 4.11 (p, J = 7.0 Hz, 4H), 1.45 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).
MS:m/z＝431.2[M+H]+ MS: m/z = 431.2 [M+H] +
实施例29(E)-N-(4-苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 29(E)-N-(4-Phenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5- Synthesis of acrylamide
Figure PCTCN2014092580-appb-000051
Figure PCTCN2014092580-appb-000051
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得38.3mg白色固体化合物60，收率93.1％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of aniline was added. Stir at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.43(s,1H),7.66～7.76(m,3H),7.55～7.65(m,3H),7.43～7.53(m,2H),7.31(d,J＝15.3Hz,1H),7.26(t,J＝7.8Hz,2H),7.0(t,J＝7.3Hz,1H),3.95～4.15(m,4H),1.33(t,J＝7.0Hz,3H),1.10(t,J＝7.1Hz,3H).MS:m/z＝413.2[M+H]+ 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.43 (s, 1H), 7.66 to 7.76 (m, 3H), 7.55 to 7.65 (m, 3H), 7.43 to 7.53 (m) , 2H), 7.31 (d, J = 15.3 Hz, 1H), 7.26 (t, J = 7.8 Hz, 2H), 7.0 (t, J = 7.3 Hz, 1H), 3.95 to 4.15 (m, 4H), 1.33 (t, J = 7.0 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H). MS: m/z = 413.2 [M+H] +
实施例30(E)-N-(4-对三氟甲基苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 30(E)-N-(4-p-Trifluoromethylphenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000052
Figure PCTCN2014092580-appb-000052
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对三氟甲基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得33.7mg白色固体化合物61，收率70.2％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of p-three Fluoromethylaniline was stirred overnight at room temperature. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.90(d,J＝15.1Hz,1H),7.69～7.78(m,3H),7.56(d,J＝9.4Hz,2H),7.50～7.54(m,4H),7.35～7.40(m,2H),4.04～4.20(m,4H),1.47(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.98 (s, 1H), 7.90 (d, J = 15.1Hz, 1H), 7.69 ~ 7.78 (m, 3H), 7.56 (d, J = 9.4Hz, 2H) , 7.50 to 7.54 (m, 4H), 7.35 to 7.40 (m, 2H), 4.04 to 4.20 (m, 4H), 1.47 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H) ).
MS:m/z＝481.2[M+H]+ MS: m/z = 481.2 [M+H] +
实施例31(E)-N-(4-间氟苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成 Example 31 (E)-N-(4-m-fluorophenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 5-based acrylamide
Figure PCTCN2014092580-appb-000053
Figure PCTCN2014092580-appb-000053
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的间氟苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得35.5mg白色固体化合物62，收率82.6％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 0.12 mmol of m-fluoro The aniline was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.87(d,J＝15.1Hz,1H),7.63(dd,J＝11.2,2.0Hz,1H),7.47～7.59(m,5H),7.34～7.41(m,2H),7.13～7.26(m,2H),6.70～6.79(m,1H),4.12(dq,J＝10.3,7.2Hz,4H),1.47(t,J＝7.2Hz,3H),1.20(t,J＝7.2Hz,3H).MS:m/z＝431.2[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 (s, 1H), 7.87 (d, J = 15.1 Hz, 1H), 7.63 (dd, J = 11.2, 2.0 Hz, 1H), 7.47 to 7.59 (m, 5H), 7.34 to 7.41 (m, 2H), 7.13 to 7.26 (m, 2H), 6.70 to 6.79 (m, 1H), 4.12 (dq, J = 10.3, 7.2 Hz, 4H), 1.47 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). MS: m/z = 431.2 [M+H] +
实施例32(E)-N-(4-间三氟甲基苯基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 32(E)-N-(4-Inter-Trifluoromethylphenyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000054
Figure PCTCN2014092580-appb-000054
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的间三氟甲基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得34.7mg白色固体化合物63， 收率72.3％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 0.12 mmol of the three Fluoromethylaniline was stirred overnight at room temperature. TLC was monitored. After the reaction was completed, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The yield was 72.3%.
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.98(s,1H),7.91(d,J＝15.1Hz,1H),7.73(s,1H),7.69(d,J＝8.1Hz,1H),7.56(d,J＝15.1Hz,1H),7.47～7.54(m,3H),7.34～7.43(m,3H),7.30(d,J＝7.7Hz,1H),4.12(dq,J＝10.9,7.2Hz,4H),1.47(t,J＝7.2Hz,3H),1.21(t,J＝7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.91 (d, J = 15.1 Hz, 1H), 7.73 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 15.1 Hz, 1H), 7.47 to 7.54 (m, 3H), 7.34 to 7.43 (m, 3H), 7.30 (d, J = 7.7 Hz, 1H), 4.12 ( Dq, J = 10.9, 7.2 Hz, 4H), 1.47 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H).
MS:m/z＝481.3[M+H]+ MS: m/z = 481.3 [M+H] +
实施例33(E)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-吗啉丙-2-烯-1-酮的合成Example 33(E)-3-(4-Ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1-morpholinepropene- Synthesis of 2-en-1-one
Figure PCTCN2014092580-appb-000055
Figure PCTCN2014092580-appb-000055
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的吗啉，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得32.7mg白色固体化合物64，收率80.5％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of morpholine was added. Stir at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate,
1H NMR(400MHz,CDCl3)δ8.29(d,J＝15.0Hz,1H),7.94(s,1H),7.44～7.54(m,4H),7.32～7.40(m,2H),4.09(p,J＝7.1Hz,4H),3.69(s,8H),1.44(t,J＝7.1Hz,3H),1.18(t,J＝7.1Hz,3H).MS:m/z＝407.3[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (d, J = 15.0 Hz, 1H), 7.94 (s, 1H), 7.44 to 7.54 (m, 4H), 7.32 to 7.40 (m, 2H), 4.09 ( p, J = 7.1 Hz, 4H), 3.69 (s, 8H), 1.44 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). MS: m/z = 407.3 [M +H] +
实施例34(E)-N-(4-(2-氨基吡啶)基)-3-(4-乙氧基-7-乙基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成 Example 34(E)-N-(4-(2-Aminopyridinyl)-3-(4-ethoxy-7-ethyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000056
Figure PCTCN2014092580-appb-000056
取33.7mg(0.1mmol)化合物54，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的2-氨基吡啶，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得29.4mg白色固体化合物65，收率71.3％。33.7 mg (0.1 mmol) of compound 54, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of 2- Aminopyridine was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.4Hz,1H),8.39(d,J＝8.4Hz,1H),8.03(d,J＝15.6Hz,1H),8.01(s,1H),7.80(d,J＝15.6Hz,1H),7.46～7.56(m,3H),7.33～7.42(m,3H),4.04～4.22(m,4H),1.47(t,J＝7.1Hz,3H),1.24(t,J＝7.2Hz,3H).MS:m/z＝415.3[M+H]+ 1 H NMR (400MHz, CDCl 3 ) δ8.69 (d, J = 4.4Hz, 1H), 8.39 (d, J = 8.4Hz, 1H), 8.03 (d, J = 15.6Hz, 1H), 8.01 (s , 1H), 7.80 (d, J = 15.6 Hz, 1H), 7.46 to 7.56 (m, 3H), 7.33 to 7.42 (m, 3H), 4.04 to 4.22 (m, 4H), 1.47 (t, J = 7.1) Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). MS: m/z = 415.3 [M+H] +
实施例35Example 35
(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-苄基-7-苄基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成(E)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-benzyl-7-benzyl-6-benzene Synthesis of -7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
Figure PCTCN2014092580-appb-000057
Figure PCTCN2014092580-appb-000057
化合物66的合成Synthesis of Compound 66
N2保护下，将3mL DMF加入到装有211mg化合物2和48mg NaH的三口瓶中，0℃搅 拌10min后，缓慢滴加0.2mL PhCH2Br，室温搅拌过夜。TLC监测，反应完成后，向反应瓶中缓慢滴加水，然后用EA萃取，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得324.5mg化合物66，收率为83％。Under N 2 protection, 3 mL of DMF was added to a three-necked flask containing 211 mg of Compound 2 and 48 mg of NaH, and after stirring at 0 ° C for 10 min, 0.2 mL of PhCH 2 Br was slowly added dropwise, and stirred at room temperature overnight. After the completion of the reaction, water was slowly added dropwise to the reaction flask, and then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated .
化合物67的合成Synthesis of Compound 67
N2保护下，取196mg化合物66溶于2mL DMF中，0℃条件下滴加POCl3，反应3h后加水，用1mol/L的NaOH溶液调节pH大于14，析出沉淀，抽滤得170.9mg化合物67，收率81.6％。Under N 2 protection, 196 mg of compound 66 was dissolved in 2 mL of DMF, POCl 3 was added dropwise at 0 ° C, water was added after 3 h of reaction, pH was adjusted to be greater than 14 with 1 mol/L NaOH solution, and precipitate was precipitated, and 170.9 mg of compound was obtained by suction filtration. 67, the yield was 81.6%.
化合物68的合成Synthesis of Compound 68
取120mg化合物67，104mg丙二酸，0.25mL哌啶溶于4mL吡啶中，回流反应5h。反应完全后，减压除去吡啶，加水稀释后，用1mol/L的HCl溶液调节pH到6，析出沉淀，抽滤得108.7mg化合物68，收率82.3％。120 mg of compound 67, 104 mg of malonic acid, 0.25 ml of piperidine were dissolved in 4 mL of pyridine, and refluxed for 5 h. After completion of the reaction, the pyridine was removed under reduced pressure, and the mixture was diluted with water. The mixture was adjusted to pH 6 with a 1 mol/L HCl solution, and the precipitate was precipitated, and filtered to give 108.7 mg of Compound 68 in a yield of 82.3%.
化合物69(E)-1-(6,7-二甲氧基-3,4-二氢异喹啉-2(1H)-基)-3-(4-苄基-7-苄基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙-2-烯-1-酮的合成Compound 69(E)-1-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-benzyl-7-benzyl-6 Synthesis of phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)prop-2-en-1-one
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入28mg(0.12mmol)6,7-二甲氧基-1,2,3,4-四氢异喹啉盐酸盐，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得52.8mg白色固体化合物69，收率83.1％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then added 28 mg (0.12 mmol) 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ8.38(dd,J＝15.1,4.2Hz,1H),7.98(d,J＝3.4Hz,1H),7.50(dd,J＝15.1,7.6Hz,1H),7.30～7.43(m,8H),7.15～7.22(m,5H),6.79～6.88(m,2H),6.65(d,J＝14.4Hz,1H),6.61(s,1H),5.29(d,J＝3.8Hz,2H),5.25(s,2H),4.83(s,1H),4.71(s,1H),3.94(t,J＝5.7Hz,1H),3.85(d,J＝3.5Hz,6H),2.87(t,J＝5.5Hz,1H),2.77(d,J＝5.3Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ8.38 (dd, J = 15.1,4.2Hz, 1H), 7.98 (d, J = 3.4Hz, 1H), 7.50 (dd, J = 15.1,7.6Hz, 1H) , 7.30 to 7.43 (m, 8H), 7.15 to 7.22 (m, 5H), 6.79 to 6.88 (m, 2H), 6.65 (d, J = 14.4 Hz, 1H), 6.61 (s, 1H), 5.29 (d) , J = 3.8 Hz, 2H), 5.25 (s, 2H), 4.83 (s, 1H), 4.71 (s, 1H), 3.94 (t, J = 5.7 Hz, 1H), 3.85 (d, J = 3.5 Hz) , 6H), 2.87 (t, J = 5.5 Hz, 1H), 2.77 (d, J = 5.3 Hz, 1H).
MS:m/z＝637.3[M+H]+ MS: m/z = 637.3 [M+H] +
实施例36(E)-N-(4-(2-氨基吡啶)基)-3-(4-苯氧基-7-苯基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 36(E)-N-(4-(2-Aminopyridinyl)-3-(4-phenoxy-7-phenyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000058
Figure PCTCN2014092580-appb-000058
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的 2-氨基吡啶，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得37.3mg白色固体化合物70，收率69.3％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol 2-Aminopyridine was stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was extracted three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate,
1H NMR(400MHz,CDCl3)δ8.22(d,J＝15.2Hz,1H),7.97(s,1H),7.50(d,J＝15.2Hz,1H),7.34～7.43(m,10H),7.14～7.22(m,7H),6.80～6.86(m,3H),5.25(d,J＝4.5Hz,4H).MS:m/z＝539.3[M+H]+ 1 H NMR (400MHz, CDCl 3 ) δ8.22 (d, J = 15.2Hz, 1H), 7.97 (s, 1H), 7.50 (d, J = 15.2Hz, 1H), 7.34 ~ 7.43 (m, 10H) , 7.14~7.22(m,7H), 6.80~6.86(m,3H), 5.25(d,J=4.5Hz,4H).MS:m/z=539.3[M+H] +
实施例37(E)-N-(4-苯基)-3-(4-苯氧基-7-苯基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 37(E)-N-(4-Phenyl)-3-(4-phenoxy-7-phenyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5- Synthesis of acrylamide
Figure PCTCN2014092580-appb-000059
Figure PCTCN2014092580-appb-000059
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得50.5mg白色固体化合物71，收率94.2％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of aniline was added. Stir at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate,
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.87(d,J＝15.1Hz,1H),7.51～7.64(m,4H),7.31～7.46(m,8H),7.24～7.30(m,2H),7.15～7.23(m,5H),7.04(t,J＝7.4Hz,1H),6.80～6.89(m,2H),5.26(d,J＝3.7Hz,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.87 (d, J = 15.1 Hz, 1H), 7.51 to 7.64 (m, 4H), 7.31 to 7.46 (m, 8H), 7.24 7.30 (m, 2H), 7.15 to 7.23 (m, 5H), 7.04 (t, J = 7.4 Hz, 1H), 6.80 to 6.89 (m, 2H), 5.26 (d, J = 3.7 Hz, 4H).
MS:m/z＝537.3[M+H]+ MS: m/z = 537.3 [M+H] +
实施例38(E)-N-(4-对氟苯基)-3-(4-苯氧基-7-苯基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 38(E)-N-(4-p-fluorophenyl)-3-(4-phenoxy-7-phenyl-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine- Synthesis of 5-based acrylamide
Figure PCTCN2014092580-appb-000060
Figure PCTCN2014092580-appb-000060
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI， 用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对氟苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得49.9mg白色固体化合物72，收率90.1％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, After dissolving with 2 mL of DMF, 0.025 mL of triethylamine was added and stirred at room temperature for 30 minutes; then 0.12 mmol of p-fluoroaniline was added and stirred at room temperature overnight. After the completion of the reaction, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.61(s,1H),7.71(dd,J＝8.8,5.1Hz,2H),7.65(d,J＝15.3Hz,1H),7.47～7.58(m,3H),7.26～7.44(m,8H),7.16～7.24(m,3H),7.09(t,J＝8.9Hz,2H),6.78～6.87(m,2H),5.31(d,J＝5.6Hz,4H).MS:m/z＝555.4[M+H]+ 1 H NMR (400MHz, DMSO- d 6) δ10.16 (s, 1H), 8.61 (s, 1H), 7.71 (dd, J = 8.8,5.1Hz, 2H), 7.65 (d, J = 15.3Hz, 1H), 7.47 to 7.58 (m, 3H), 7.26 to 7.44 (m, 8H), 7.16 to 7.24 (m, 3H), 7.09 (t, J = 8.9 Hz, 2H), 6.78 to 6.87 (m, 2H) , 5.31 (d, J = 5.6 Hz, 4H). MS: m / z = 555.4 [M + H] +
实施例39(E)-N-(4-对三氟甲基苯基)-3-(4-苯氧基-7-苯基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 39(E)-N-(4-p-Trifluoromethylphenyl)-3-(4-phenoxy-7-phenyl-6-phenyl-7H-pyrrolo[2,3-d Synthesis of pyrimidine-5-yl)acrylamide
Figure PCTCN2014092580-appb-000061
Figure PCTCN2014092580-appb-000061
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对三氟甲基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得43mg白色固体化合物73，收率71.2％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of p-three Fluoromethylaniline was stirred overnight at room temperature. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.62(s,1H),7.90(d,J＝8.5Hz,2H),7.70(d,J＝15.3Hz,1H),7.62(d,J＝8.7Hz,2H),7.48～7.58(m,3H),7.27～7.44(m,8H),7.15～7.25(m,3H),6.77～6.89(m,2H),5.31(d,J＝6.2Hz,4H).MS:m/z＝605.3[M+H]+ 1 H NMR (400MHz, DMSO- d 6) δ10.48 (s, 1H), 8.62 (s, 1H), 7.90 (d, J = 8.5Hz, 2H), 7.70 (d, J = 15.3Hz, 1H) , 7.62 (d, J = 8.7 Hz, 2H), 7.48 to 7.58 (m, 3H), 7.27 to 7.44 (m, 8H), 7.15 to 7.25 (m, 3H), 6.77 to 6.89 (m, 2H), 5.31 (d, J = 6.2 Hz, 4H). MS: m/z = 605.3 [M+H] +
实施例40(E)-N-(4-对甲氧基苯基)-3-(4-苯氧基-7-苯基-6-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)丙烯酰胺的合成Example 40(E)-N-(4-p-methoxyphenyl)-3-(4-phenoxy-7-phenyl-6-phenyl-7H-pyrrolo[2,3-d] Synthesis of pyrimidin-5-yl)acrylamide
Figure PCTCN2014092580-appb-000062
Figure PCTCN2014092580-appb-000062
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI， 用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的对三氟甲基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得50.4mg白色固体化合物74，收率89.1％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, After dissolving with 2 mL of DMF, 0.025 mL of triethylamine was added and stirred at room temperature for 30 minutes; then 0.12 mmol of p-trifluoromethylaniline was added and stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.85(d,J＝15.1Hz,1H),7.48～7.58(m,4H),7.29～7.46(m,8H),7.14～7.24(m,5H),6.77～6.88(m,4H),5.27(s,4H),3.77(s,3H).MS:m/z＝567.3[M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.85 (d, J = 15.1 Hz, 1H), 7.48 to 7.58 (m, 4H), 7.29 to 7.46 (m, 8H), 7.14 7.24 (m, 5H), 6.77 to 6.88 (m, 4H), 5.27 (s, 4H), 3.77 (s, 3H). MS: m/z = 567.3 [M+H] +
实施例41(E)-3-(7-苄基-4-(苄氧基)-6-苯基7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2,3-二氢苯并[b][1,4]二恶唑-6-基)丙烯酰胺的合成Example 41(E)-3-(7-Benzyl-4-(benzyloxy)-6-phenyl 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-(2, Synthesis of 3-dihydrobenzo[b][1,4]dioxazol-6-yl)acrylamide
Figure PCTCN2014092580-appb-000063
Figure PCTCN2014092580-appb-000063
取46.1mg(0.1mmol)化合物68，27mg(0.2mmol)HOBT，57.5mg(0.3mmol)EDCI，用2mL DMF溶解后加入0.025mL三乙胺，室温下搅拌30分钟；然后加入0.12mmol的3,4-亚乙二氧基苯胺，室温下搅拌过夜。TLC监测，反应完成后，加水，EA萃取三次(每次15mL)，有机相用饱和盐水洗涤，无水硫酸钠干燥，浓缩后柱层析，得47.6mg白色固体化合物75，收率80.2％。46.1 mg (0.1 mmol) of compound 68, 27 mg (0.2 mmol) of HOBT, 57.5 mg (0.3 mmol) of EDCI, dissolved in 2 mL of DMF, and then added 0.025 mL of triethylamine, stirred at room temperature for 30 minutes; then 0.12 mmol of 3, 4-Ethylenedioxyaniline was stirred at room temperature overnight. After the reaction was completed, water was added, and EA was added three times (15 mL each time). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.82(d,J＝15.1Hz,1H),7.53(d,J＝15.1Hz,1H),7.29～7.47(m,9H),7.14～7.25(m,6H),6.99(d,J＝6.8Hz,1H),6.85(d,J＝3.6Hz,2H),6.76(d,J＝8.7Hz,1H),5.27(s,4H),4.21(s,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.82 (d, J = 15.1 Hz, 1H), 7.53 (d, J = 15.1 Hz, 1H), 7.29 to 7.47 (m, 9H) , 7.14 to 7.25 (m, 6H), 6.99 (d, J = 6.8 Hz, 1H), 6.85 (d, J = 3.6 Hz, 2H), 6.76 (d, J = 8.7 Hz, 1H), 5.27 (s, 4H), 4.21 (s, 4H).
MS:m/z＝595.3[M+H]+ MS: m/z = 595.3 [M+H] +
实施例42Example 42
根据实施例1～41的步骤，更换部分原料，得到表1所示化合物：According to the procedures of Examples 1 to 41, part of the raw materials were replaced to obtain the compounds shown in Table 1:
表1Table 1
Figure PCTCN2014092580-appb-000064
Figure PCTCN2014092580-appb-000064
Figure PCTCN2014092580-appb-000065
Figure PCTCN2014092580-appb-000065
Figure PCTCN2014092580-appb-000066
Figure PCTCN2014092580-appb-000066
Figure PCTCN2014092580-appb-000067
Figure PCTCN2014092580-appb-000067
Figure PCTCN2014092580-appb-000068
Figure PCTCN2014092580-appb-000068
Figure PCTCN2014092580-appb-000069
Figure PCTCN2014092580-appb-000069
Figure PCTCN2014092580-appb-000070
Figure PCTCN2014092580-appb-000070
Figure PCTCN2014092580-appb-000071
Figure PCTCN2014092580-appb-000071
Figure PCTCN2014092580-appb-000072
Figure PCTCN2014092580-appb-000072
Figure PCTCN2014092580-appb-000073
Figure PCTCN2014092580-appb-000073
Figure PCTCN2014092580-appb-000074
Figure PCTCN2014092580-appb-000074
为了说明本发明的有益效果，本发明提供了以下试验例：In order to illustrate the beneficial effects of the present invention, the present invention provides the following test examples:
试验例1化合物降血糖试验Test Example 1 Compound Hypoglycemic Test
采用5周龄C57BL/6J小鼠，雄性，用普通饲料和高脂饲料喂养10周。将造模成功的雄性小鼠随机分组，每组5只，记录体重，给药组给予10mg/kg不同化合物，空白对照组和正常组给予相同体积的生理盐水。每天腹腔注射给药1次，连续给药5天后，检测小鼠空腹基础血糖和葡萄糖耐量。数据均以平均值±标准差的形式加以显示，显著性差异通过t检验加以确定。当P<0.05时，视为具有显著性差异。本发明部分化合物试验结果见表2。Five-week-old C57BL/6J mice, male, were fed with normal and high fat diets for 10 weeks. Male mice with successful modeling were randomly divided into groups of 5, and body weight was recorded. The drug-administered group was given 10 mg/kg of different compounds, and the blank control group and the normal group were given the same volume of physiological saline. The rats were intraperitoneally administered once a day for 5 days, and the fasting basal blood glucose and glucose tolerance of the mice were measured. Data were presented as mean ± standard deviation and significant differences were determined by t test. When P < 0.05, it was considered to have a significant difference. The test results of some of the compounds of the present invention are shown in Table 2.
表2 化合物对空腹血糖的影响Table 2 Effect of compounds on fasting blood glucose
Figure PCTCN2014092580-appb-000075
Figure PCTCN2014092580-appb-000075
Figure PCTCN2014092580-appb-000076
Figure PCTCN2014092580-appb-000076
注：*：±表示与空白对照组相比具有显著性差异(P<0.05)Note: *: ± indicates a significant difference compared with the blank control group (P<0.05)
试验结果表明，与空白对照组相比，化合物6、8、9、10、11、12、13、16、18、22、23、25、28、31、40均能使糖尿病动物模型血糖水平有不同程度的降低；特别是，化合物13、25和40能使糖尿病动物模型血糖水平显著下降。The test results showed that compared with the blank control group, compounds 6, 8, 9, 10, 11, 12, 13, 16, 18, 22, 23, 25, 28, 31, 40 can all have blood glucose levels in diabetic animal models. Different degrees of reduction; in particular, compounds 13, 25 and 40 can significantly reduce blood glucose levels in diabetic animal models.
试验例2急毒实验Test Example 2 Acute Toxicity Test
本发明对化合物13、25和40的急毒进行研究。将化合物13、25和40分散于1％羧甲基纤维素钠，研磨成混悬状，配制成300mg/ml。昆明小鼠单次经口灌胃给予1g/kg，在14天观察期内，小鼠未见死亡；试验第15天进行血生化检查，血生化指标未见明显异常改变。此外，小鼠病理解剖主要脏器未见与药物相关的异常改变，给药组动物与溶剂对照组及正常组动物相比未有异常表现。The present invention investigated the acute toxicity of compounds 13, 25 and 40. Compounds 13, 25 and 40 were dispersed in 1% sodium carboxymethylcellulose, ground to a suspension, and formulated into 300 mg/ml. Kunming mice were given 1g/kg by oral gavage alone. During the 14-day observation period, the mice did not die. On the 15th day of the experiment, blood biochemical tests were performed, and no obvious abnormal changes were found in blood biochemical indicators. In addition, no abnormal drug-related changes were observed in the main organs of the pathological anatomy of mice. The animals in the drug-administered group showed no abnormalities compared with the vehicle control group and the normal group.
综上所述，本发明制备的吡咯并嘧啶新型化合物，可以明显降低糖尿病小鼠的空腹血糖，且安全性较高，为临床用药提供了新的选择。 In summary, the novel pyrrolopyrimidine compound prepared by the invention can significantly reduce the fasting blood glucose of diabetic mice, and has high safety, and provides a new choice for clinical use.

Claims (10)

  1. 式I所示的化合物或其药学上可接受的盐、水合物或溶剂合物：a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof:
    Figure PCTCN2014092580-appb-100001
    Figure PCTCN2014092580-appb-100001
    R1选自H、氘、-Y-R20；R 1 is selected from the group consisting of H, hydrazine, and -YR 20 ;
    R2选自H、氘、卤素、氨基、-Y-R20；R 2 is selected from the group consisting of H, hydrazine, halogen, amino, -Y-R20;
    Y选自O、S；R20选自C1-C5的烷基、氘代或芳基代C1～C4烷基；Y is selected from O, S; R 20 is selected from C1-C5 alkyl, deuterated or aryl C1-C4 alkyl;
    R3、R4分别独立选自H或
    Figure PCTCN2014092580-appb-100002
    R 3 and R 4 are each independently selected from H or
    Figure PCTCN2014092580-appb-100002
    R7、R8、R9分别独立选自H、卤素、C1～C4的烷基或烷氧基、或卤代C1～C4的烷基或烷氧基；R 7 , R 8 and R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
    或者，R3、R4与其相连的N共同形成
    Figure PCTCN2014092580-appb-100003
    Figure PCTCN2014092580-appb-100004
    Figure PCTCN2014092580-appb-100005
    其中：    Or, R 3 and R 4 are formed together with the N connected thereto.
    Figure PCTCN2014092580-appb-100003
    Figure PCTCN2014092580-appb-100004
    Figure PCTCN2014092580-appb-100005
    among them:
    Z选自C、O或N；Z is selected from C, O or N;
    n＝1或2；n=1 or 2;
    R10选自H、C1～C4的烷基、卤代C1～C4的烷基或
    Figure PCTCN2014092580-appb-100006
    R 10 is selected from the group consisting of H, a C1-C4 alkyl group, a halogenated C1-C4 alkyl group or
    Figure PCTCN2014092580-appb-100006
    R11选自C1～C4的烷基或烷氧基、卤素取代的C1～C4的烷基或烷氧基或
    Figure PCTCN2014092580-appb-100007
    R12选自H或C1～C4烷基；    R 11 is selected from C 1 -C 4 alkyl or alkoxy, halogen substituted C 1 -C 4 alkyl or alkoxy or
    Figure PCTCN2014092580-appb-100007
    R 12 is selected from H or a C1-C4 alkyl group;
    R13选自C1～C4的烷基、或卤代C1～C4的烷基；R 13 is selected from a C1-C4 alkyl group or a halogenated C1-C4 alkyl group;
    W1选自O或S，W2选自C或N；W 1 is selected from O or S, and W 2 is selected from C or N;
    R14选自H、卤素、C1～C4的烷基或卤代烷基、含O或S的五元或六元环烷基、或
    Figure PCTCN2014092580-appb-100008
    R 14 is selected from H, halogen, C1-C4 alkyl or haloalkyl, 5- or 6-membered cycloalkyl containing O or S, or
    Figure PCTCN2014092580-appb-100008
    R15、R16分别独立选自H、C1～C4烷基或卤代烷基；R 15 and R 16 are each independently selected from H, C1-C4 alkyl or haloalkyl;
    R17选自H、C1～C4烷基或卤代烷基；R 17 is selected from H, C1-C4 alkyl or haloalkyl;
    R18选自H、C1～C4烷基或卤代烷基；R 18 is selected from H, C1-C4 alkyl or haloalkyl;
    R19选自H、C1～C6烷基或卤代烷基、C5～C10的芳基或杂环芳烃基、或卤代C5～C10的芳基或杂环芳烃基；R 19 is selected from H, C1-C6 alkyl or haloalkyl, C5-C10 aryl or heterocyclic aromatic hydrocarbon, or halogenated C5-C10 aryl or heterocyclic aromatic hydrocarbon;
    R5选自烷基、取代或未取代的芳基、取代或未取代含杂原子芳基，所述取代基选自C1～C4的烷基、卤素或磺酰基；R 5 is selected from an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted hetero atom-containing aryl group, and the substituent is selected from a C 1 -C 4 alkyl group, a halogen or a sulfonyl group;
    R6选自C1～C4烷基、芳基或氘代的C1～C4烷基；R 6 is selected from C 1 -C 4 alkyl, aryl or deuterated C 1 -C 4 alkyl;
    X选自
    Figure PCTCN2014092580-appb-100009
    或无；    X is selected from
    Figure PCTCN2014092580-appb-100009
    Or not;
    所述卤素为F、Cl或Br。The halogen is F, Cl or Br.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized by:
    R1选自H、氘；R 1 is selected from H and hydrazine;
    R2选自H、氘、卤素或-O-R20，R20选自C1～C5的烷基；R 2 is selected from H, hydrazine, halogen or -OR 20 , and R 20 is selected from C1 to C5 alkyl;
    R3、R4分别独立选自H或
    Figure PCTCN2014092580-appb-100010
    R 3 and R 4 are each independently selected from H or
    Figure PCTCN2014092580-appb-100010
    R7～R9分别独立选自H、卤素、C1～C4的烷基或烷氧基、或卤代C1～C4的烷基或烷氧基；R 7 to R 9 are each independently selected from H, halogen, C1-C4 alkyl or alkoxy, or halogenated C1-C4 alkyl or alkoxy;
    或者，R3、R4与其相连的N共同形成
    Figure PCTCN2014092580-appb-100011
    Figure PCTCN2014092580-appb-100012
    其中：    Or, R3, R4 and their connected N form together
    Figure PCTCN2014092580-appb-100011
    Figure PCTCN2014092580-appb-100012
    among them:
    Z选自C、N、O或S；Z is selected from C, N, O or S;
    n＝1或2；n=1 or 2;
    R10选自H、C1～C4的烷基、或
    Figure PCTCN2014092580-appb-100013
    R 10 is selected from the group consisting of H, C1-C4 alkyl, or
    Figure PCTCN2014092580-appb-100013
    R11选自C1～C4的烷基或烷氧基；R 11 is selected from a C 1 -C 4 alkyl or alkoxy group;
    R13选自C1～C4的烷基或卤代烷基；R 13 is selected from a C1 to C4 alkyl group or a halogenated alkyl group;
    R5为苯基；R 5 is a phenyl group;
    R6为C1～C4的烷基。R 6 is a C1-C4 alkyl group.
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, which is characterized in that:
    R20选自甲基；R 20 is selected from a methyl group;
    R3、R4分别独立选自H、或
    Figure PCTCN2014092580-appb-100014
    R 3 and R 4 are each independently selected from H, or
    Figure PCTCN2014092580-appb-100014
    R7～R9分别独立选自H、卤素、甲基或甲氧基；R 7 to R 9 are each independently selected from H, halogen, methyl or methoxy;
    或者，R3、R4与其相连的N共同形成
    Figure PCTCN2014092580-appb-100015
    Figure PCTCN2014092580-appb-100016
    Or, R 3 and R 4 are formed together with the N connected thereto.
    Figure PCTCN2014092580-appb-100015
    Figure PCTCN2014092580-appb-100016
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：所述化合物如式II所示： The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is as shown in formula II:
    Figure PCTCN2014092580-appb-100017
    Figure PCTCN2014092580-appb-100017
    R6选自C1～C4的烷基、部分氘代烷基或全氘代烷基；R 6 is selected from a C 1 -C 4 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group;
    R13选自C1～C4的卤代烷基；R 13 is selected from a C1-C4 haloalkyl group;
    R20选自C1～C5的烷基、部分氘代烷基或全氘代烷基。R 20 is selected from a C1 to C5 alkyl group, a partially halogenated alkyl group or a fully halogenated alkyl group.
  5. 根据权利要求4所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：R13选自全卤代的C1～C4烷基。The compound according to claim 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 13 is selected from the group consisting of a perhalogenated C1-C4 alkyl group.
  6. 根据权利要求4所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：R6、R20分别独立选自甲基、氘代甲基、乙基或氘代乙基；R13选自三氟甲基、三氯甲基、五氟乙基或五氯乙基。The compound according to claim 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 6 and R 20 are each independently selected from methyl, deuterated methyl, ethyl or deuterated. Ethyl; R 13 is selected from the group consisting of trifluoromethyl, trichloromethyl, pentafluoroethyl or pentachloroethyl.
  7. 根据权利要求6所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：R13选自三氟甲基。The compound according to claim 6 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R 13 is selected from the group consisting of trifluoromethyl.
  8. 根据权利要求4所述的化合物或其药学上可接受的盐、水合物或溶剂合物，其特征在于：所述化合物结构式如下：The compound according to claim 4, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has the formula:
    Figure PCTCN2014092580-appb-100018
    Figure PCTCN2014092580-appb-100018
  9. 权利要求1～8任意一项所述化合物或其药学上可接受的盐、水合物或溶剂合物在制备降血糖药物中的用途。Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the manufacture of a hypoglycemic agent.
  10. 根据权利要求9所述的用途，其特征在于：所述药物是治疗2型糖尿病的药物。 The use according to claim 9, wherein the drug is a drug for treating type 2 diabetes.
PCT/CN2014/092580 2013-11-29 2014-11-28 Pyrrolopyrimidine compound and use thereof in preparation of hypoglaecemic drug WO2015078417A1 (en)

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