WO2022247676A1 - Compound with dipyrrolopyridine structure, and preparation method therefor and medical use thereof - Google Patents

Compound with dipyrrolopyridine structure, and preparation method therefor and medical use thereof Download PDF

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WO2022247676A1
WO2022247676A1 PCT/CN2022/093052 CN2022093052W WO2022247676A1 WO 2022247676 A1 WO2022247676 A1 WO 2022247676A1 CN 2022093052 W CN2022093052 W CN 2022093052W WO 2022247676 A1 WO2022247676 A1 WO 2022247676A1
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pyrrolo
pyridin
cyclohexyl
preparation
pyridine
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PCT/CN2022/093052
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French (fr)
Chinese (zh)
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尤启冬
姜正羽
鲍启超
孟凡莹
郭小可
徐晓莉
王磊
孙浩
向齐琦
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南京康屹生物医药中心(有限合伙)
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Definitions

  • the invention belongs to the field of medicinal chemistry and relates to a compound with a dipyrrolopyridine structure, a preparation method and a medical application.
  • JAKs protein kinase family
  • JAKs are hubs for signaling processes in response to multiple cytokine receptors. Therefore, JAKs are important targets for a variety of novel diseases, such as autogenous or acquired immune diseases and blood diseases, which play a crucial role.
  • cytokine When a cytokine binds to the extracellular recognition region of its corresponding receptor, it causes a conformational change in the dimerization or multimerization of the receptor itself. At the same time, the conformation of cytokine receptors bound to JAKs in the cytoplasm changes, enabling specific dimerization of JAKs proteins, forming signaling complexes, triggering a series of phosphorylation reactions, and ultimately promoting signal transduction Phosphorylation process of activator (signal transducers and activators of transcription, STAT), phosphorylated STAT can dimerize. Phosphorylated STAT dimerization complexes can enter the nucleus and specifically bind and regulate corresponding target genes. Thus, it exerts its macroscopic effect on biological functions.
  • JAK plays a vital role in a variety of diseases, such as bone marrow and extramyeloid proliferative diseases, and various immune diseases.
  • JAK small molecule inhibitors can be used to treat rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, etc.
  • the object of the present invention is to provide a compound with dipyrrolopyridine structure, a preparation method and a medical application.
  • a compound with dipyrrolopyridine structure is as follows:
  • n 0, 1, 2;
  • A cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
  • R 2 methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
  • the structural formula of the compound of the dipyrrolopyridine structure is as follows:
  • a method for synthesizing the above-mentioned compound, the synthetic route is as follows:
  • n 0, 1, 2;
  • A cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
  • R 2 methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
  • the above-mentioned compound 5a is synthesized by the following route:
  • the above-mentioned compound 6a is synthesized by the following route:
  • the above-mentioned compound or its pharmaceutically acceptable salt is used for the medical application of preparing JAK inhibitor medicine.
  • JAKs are important targets of various novel diseases, such as autologous or acquired immune diseases, blood diseases, cancers, and central nervous system diseases.
  • the compound provided by the present invention has obvious inhibitory activity on JAK family proteins, and is an effective JAK inhibitor, so it has the prospect of being developed into a drug for inhibiting JAK and then treating diseases, so it can be used for its anti-proliferation and/or pro-apoptotic activity and A method for treating the human or animal body.
  • the present invention also relates to a preparation method of the compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and its use in the preparation of anti-proliferation and/or pro-apoptosis and anti-inflammatory drugs the use of.
  • the compound provided by the present invention or its pharmaceutically acceptable salt can be used for treating autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis and the like.
  • Treatment includes myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depression, allergies, asthma, Sjogren's syndrome, dry eye, transplant rejection, cancer, inflammation venereal enteropathy, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions in mammals (including atopic dermatitis)
  • the compound provided by the invention or the pharmaceutically acceptable salt thereof has value in the treatment of myelodysplasia, myelodysplastic syndrome and cancer.
  • Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndromes and cancer-related processes.
  • myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelocytosis and chronic myelodysplastic syndromes, myelodysplastic syndromes, and neoplastic diseases such as breast, ovarian, lung, colon, prostate, or other tissue cancers, as well as leukemia, myeloma, and lymphoma.
  • myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelocytosis and chronic myelodysplastic syndromes, myelodysplastic syndromes, and neoplastic diseases such as breast, ovarian, lung, colon, prostate,
  • the compound provided by the invention or the pharmaceutically acceptable salt thereof has blood-brain barrier permeability in the test process, and has value in the treatment of central nervous system diseases.
  • Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of CNS inflammatory disease-associated processes.
  • activity against central nervous system inflammation is expected, such as epilepsy, dementia, Parkinson's disease, depression, and the like.
  • Step 1 Preparation of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (intermediate 2a)
  • Step 3 Preparation of 1-cyclohexyl-2-(p-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(4-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(4-methoxyphenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to the mixture.
  • t-BuOK 252.3 mg, 2.25 mmol
  • the reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 3 Preparation of 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)benzonitrile
  • Benzyl bromide (5.8mmol), trimethylethynylsilane (682mg, 6.9mmol), Pd(PPh 3 ) 2 Cl 2 (203mg, 0.29mmol), CuI (110mg, 0.58mmol) and triethylamine 2.5mL were added In 25mL of acetonitrile, heat to reflux at 80°C.
  • Step 4 Preparation of N-cyclohexyl-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 5 Preparation of 2-benzyl-1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 3 Preparation of 4-chloro-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 4 Preparation of N-cyclohexyl-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 5 Preparation of 1-cyclohexyl-2-(4-methylbenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 4-chloro-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 4 Preparation of N-cyclohexyl-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 5 Preparation of 1-cyclohexyl-2-(4-fluorobenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 4-chloro-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 4 N-cyclohexyl-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation
  • Step 5 Preparation of 1-cyclohexyl-2-(4-methoxybenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of N-cyclohexyl-5-(3-phenoxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 4 Preparation of 1-cyclohexyl-2-(phenoxymethyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of 4-chloro-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 3 Preparation of N-cyclohexyl-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 4 Preparation of 1-cyclohexyl-2-((p-tolyloxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of 4-chloro-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 3 Preparation of N-cyclohexyl-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 4 Preparation of 1-cyclohexyl-2-((4-fluorophenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of 4-chloro-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
  • Step 3 N-cyclohexyl-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation of
  • Step 4 1-cyclohexyl-2-((4-methoxyphenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine preparation of
  • Step 3 Preparation of N-cyclohexyl-5-(3-(phenylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 4 Preparation of N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)aniline
  • Step 3 Preparation of N-cyclohexyl-5-(3-(p-tolylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 2 Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-fluoroaniline
  • Step 3 N-cyclohexyl-5-(3-((4-fluorophenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation of
  • Step 4 N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)-4-fluoroaniline preparation of
  • Step 2 Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-methoxyaniline
  • Step 3 N-cyclohexyl-5-(3-((4-methoxyphenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-4 - Preparation of amines
  • Step 2 Preparation of 4-((3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile
  • Step 3 4-((3-(4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile preparation
  • Step 4 4-(((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)amino)benzonitrile preparation of
  • Step 2 Preparation of N-cyclohexyl-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(2-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(m-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of 5-((3-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)aniline
  • Step 3 Preparation of 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)phenol
  • Step 2 Preparation of N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(4-(trifluoromethyl)phenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(4-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 2 Preparation of 5-((4-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)aniline
  • Step 1 Preparation of 4-chloro-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3,5-dimethoxyphenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3,5-difluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(2,4-difluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3,5-dichlorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 3 Preparation of 1-cyclohexyl-2-cyclopropyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-cyclopentyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(thiophen-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(pyridin-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(pyridin-4-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(pyrimidin-5-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 3 Preparation of 1-cyclohexyl-2-(pyrimidin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 2-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile
  • Step 2 Preparation of 2-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile
  • Step 3 Preparation of 1-cyclohexyl-2-(3-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(4-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 1-Cyclohexyl-2-(3-(trifluoromethyl)pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Preparation of pyridine
  • N-cyclohexyl-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(3-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(6-fluoropyridin-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(6-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(5-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(5-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(5-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(6-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(6-nitropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • N-cyclohexyl-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours.
  • Step 1 Preparation of 4-chloro-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(6-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of 4-chloro-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
  • Step 2 Preparation of N-cyclohexyl-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 3 Preparation of 1-cyclohexyl-2-(5-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
  • Step 1 Preparation of N-((2S)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 2 1-((2S)-2-Methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
  • Step 1 Preparation of N-((2R)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
  • Step 2 1-((2R)-2-Methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
  • Step 1 tert-butyl 3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxylate preparation

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Abstract

Disclosed in the present invention are a compound with a dipyrrolopyridine structure, and a preparation method therefor and the medical use thereof. The compound with the dipyrrolopyridine structure provided by the present invention has significant inhibitory activity on JAK family proteins, is an effective JAK inhibitor, and therefore has the prospect of being developed into a drug for inhibiting JAK so as to treat diseases.

Description

一种二吡咯并吡啶结构的化合物、制备方法和医药用途A compound of dipyrrolopyridine structure, preparation method and medical application 技术领域technical field
本发明属于药物化学领域，涉及一种二吡咯并吡啶结构的化合物、制备方法和医药用途。The invention belongs to the field of medicinal chemistry and relates to a compound with a dipyrrolopyridine structure, a preparation method and a medical application.
背景技术Background technique
JAKs(Janus kinases)蛋白激酶家族是存在于细胞内的一类非受体型酪氨酸激酶。JAKs是响应多种细胞因子受体信号进程的枢纽。因此，JAKs是多种新型疾病的重要靶标，如自身性或获得性免疫疾病和血液疾病中体现了至关重要的作用。The JAKs (Janus kinases) protein kinase family is a class of non-receptor tyrosine kinases present in cells. JAKs are hubs for signaling processes in response to multiple cytokine receptors. Therefore, JAKs are important targets for a variety of novel diseases, such as autogenous or acquired immune diseases and blood diseases, which play a crucial role.
当细胞因子与其相应受体的细胞膜外识别区域相结合，引起受体本身二聚化或多聚化的构象变化。于此同时，胞浆内与JAKs相结合的细胞因子受体构象改变，使得JAKs蛋白能够发生特异性的二聚化，形成信号复合物，触发一系列的磷酸化反应，最终促进了信号转导活化因子(signal transducers and activators of transcription，STAT)的磷酸化过程，磷酸化的STAT能够发生二聚化。磷酸化的STAT二聚化复合物能够入核并特异性结合并调控到相应的靶基因。从而，在生物功能上发挥其宏观作用。When a cytokine binds to the extracellular recognition region of its corresponding receptor, it causes a conformational change in the dimerization or multimerization of the receptor itself. At the same time, the conformation of cytokine receptors bound to JAKs in the cytoplasm changes, enabling specific dimerization of JAKs proteins, forming signaling complexes, triggering a series of phosphorylation reactions, and ultimately promoting signal transduction Phosphorylation process of activator (signal transducers and activators of transcription, STAT), phosphorylated STAT can dimerize. Phosphorylated STAT dimerization complexes can enter the nucleus and specifically bind and regulate corresponding target genes. Thus, it exerts its macroscopic effect on biological functions.
JAK在多种疾病起到至关重要的作用，如骨髓及外骨髓增殖疾病，多种免疫疾病等。目前，JAK小分子抑制剂可用于治疗类风湿性关节炎、多发性骨髓瘤、特应性皮炎、系统性红斑狼疮、溃疡性结肠炎等。JAK plays a vital role in a variety of diseases, such as bone marrow and extramyeloid proliferative diseases, and various immune diseases. Currently, JAK small molecule inhibitors can be used to treat rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, etc.
发明内容Contents of the invention
本发明的目的在于提供一种二吡咯并吡啶结构的化合物、制备方法和医药用途。The object of the present invention is to provide a compound with dipyrrolopyridine structure, a preparation method and a medical application.
本发明上述目的通过如下技术方案实现：The above object of the present invention is achieved through the following technical solutions:
一种二吡咯并吡啶结构的化合物，结构式如下：A compound with dipyrrolopyridine structure, the structural formula is as follows:
Figure PCTCN2022093052-appb-000001
Figure PCTCN2022093052-appb-000001
其中：in:
n＝0、1、2；n=0, 1, 2;
m＝4、5、6、7；m=4, 5, 6, 7;
X＝O，N；X = O, N;
Y＝C、N；Y = C, N;
A＝环丙基、环己基、环戊基、环己基、噻吩、呋喃、苯环、吡啶、嘧啶；吡咯并吡啶、噻吩并吡啶、呋喃并吡啶、苯并吡咯、苯并噻吩、苯并呋喃；A = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
R 1＝
Figure PCTCN2022093052-appb-000002
n 1＝1、2、3；n 2＝1、2、3、4； R 1 =
Figure PCTCN2022093052-appb-000002
n 1 =1, 2, 3; n 2 =1, 2, 3, 4;
R 2＝甲基、乙基、甲氧基、氟、氯、硝基、环丙基、氰基、氨基、羟基、三氟甲基；双取代的甲基、氯、氟、甲氧基；三取代的甲基、甲氧基。 R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
优选地，所述二吡咯并吡啶结构的化合物的结构式如下：Preferably, the structural formula of the compound of the dipyrrolopyridine structure is as follows:
Figure PCTCN2022093052-appb-000003
Figure PCTCN2022093052-appb-000003
一种合成上述化合物的方法，合成路线如下：A method for synthesizing the above-mentioned compound, the synthetic route is as follows:
Figure PCTCN2022093052-appb-000004
Figure PCTCN2022093052-appb-000004
其中：in:
n＝0、1、2；n=0, 1, 2;
m＝4、5、6、7；m=4, 5, 6, 7;
X＝O，N；X = O, N;
Y＝C、N；Y = C, N;
A＝环丙基、环己基、环戊基、环己基、噻吩、呋喃、苯环、吡啶、嘧啶；吡咯并吡啶、噻吩并吡啶、呋喃并吡啶、苯并吡咯、苯并噻吩、苯并呋喃；A = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
R 1＝
Figure PCTCN2022093052-appb-000005
n 1＝1、2、3；n 2＝1、2、3、4； R 1 =
Figure PCTCN2022093052-appb-000005
n 1 =1, 2, 3; n 2 =1, 2, 3, 4;
R 2＝甲基、乙基、甲氧基、氟、氯、硝基、环丙基、氰基、氨基、羟基、三氟甲基；双取代的甲基、氯、氟、甲氧基；三取代的甲基、甲氧基。 R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
优选地，上述化合物5a通过如下路线合成：Preferably, the above-mentioned compound 5a is synthesized by the following route:
Figure PCTCN2022093052-appb-000006
Figure PCTCN2022093052-appb-000006
优选地，上述化合物6a通过如下路线合成：Preferably, the above-mentioned compound 6a is synthesized by the following route:
Figure PCTCN2022093052-appb-000007
Figure PCTCN2022093052-appb-000007
上述化合物或其药学上可以接受的盐用于制备JAK抑制剂药物的医药用途。The above-mentioned compound or its pharmaceutically acceptable salt is used for the medical application of preparing JAK inhibitor medicine.
上述化合物或其药学上可以接受的盐在制备抑制JAK进而治疗疾病的药物方面的用途，所述疾病包括类风湿性关节炎、多发性骨髓瘤、特应性皮炎、系统性红斑狼疮、溃疡性结肠炎、斑秃、多发性骨髓瘤、黑色素瘤以及帕金森、癫痫、抑郁症等。Use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting JAK and then treating diseases, said diseases including rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative Colitis, alopecia areata, multiple myeloma, melanoma, Parkinson's, epilepsy, depression, etc.
有益效果：Beneficial effect:
本领域技术人员知道JAKs是多种新型疾病的重要靶标，如自身性或获得性免疫疾病、血液疾病、癌症及中枢神经系统疾病等。Those skilled in the art know that JAKs are important targets of various novel diseases, such as autologous or acquired immune diseases, blood diseases, cancers, and central nervous system diseases.
本发明提供的化合物对JAK家族蛋白具有明显的抑制活性，为有效的JAK抑制剂，因此具备开发成抑制JAK进而治疗疾病的药物的前景，因此可用于其抗增殖和/或促凋亡活性以及用于治疗人或动物体的方法。本发明还涉及所述化合物或其药学上可接受的盐的制备方法，涉及包含该化合物的药物组合物，及其在制备用于产生抗增殖和/或促凋亡作用、抗炎的药物中的用途。The compound provided by the present invention has obvious inhibitory activity on JAK family proteins, and is an effective JAK inhibitor, so it has the prospect of being developed into a drug for inhibiting JAK and then treating diseases, so it can be used for its anti-proliferation and/or pro-apoptotic activity and A method for treating the human or animal body. The present invention also relates to a preparation method of the compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and its use in the preparation of anti-proliferation and/or pro-apoptosis and anti-inflammatory drugs the use of.
本发明提供的化合物或其药学上可接受的盐可以用于治疗自身免疫性类风湿性关节炎、特应性皮炎、系统性红斑狼疮、溃疡性结肠炎等。治疗包括肌炎、血管炎、天疱疮、克罗恩病、狼疮、肾炎、牛皮癣、多发性硬化症、重度抑郁症、过敏、哮喘、干燥综合征、干眼症、移植排斥、癌症、炎性肠病、湿疹、牛皮癣、硬皮病、狼疮、瘙痒，其他瘙痒症、哺乳动物的过敏反应(包括过敏性皮炎)The compound provided by the present invention or its pharmaceutically acceptable salt can be used for treating autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis and the like. Treatment includes myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depression, allergies, asthma, Sjogren's syndrome, dry eye, transplant rejection, cancer, inflammation venereal enteropathy, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions in mammals (including atopic dermatitis)
本发明提供的化合物或其药学上可接受的盐在骨髓增生异常，骨髓增生异常综合症和癌症的治疗中具有价值。治疗方法靶向酪氨酸激酶活性，特别是JAK家族活性，其涉及多种骨髓增生性疾病，骨髓增生异常综合症和癌症相关过程。因此，预期对骨髓增生性疾病具有活性，例如慢性粒细胞白血病、真性红细胞增多症、原发性血小板增多症、伴有骨髓纤维化的骨髓化生、特发性骨髓纤维化、慢性粒细胞增多症和慢性粒细胞增多症、骨髓增生异常综合症和肿瘤疾病，例如乳腺癌、卵巢癌、肺癌、结肠癌、前列腺癌或其他组织癌，以及白血病、骨髓瘤和淋巴瘤。The compound provided by the invention or the pharmaceutically acceptable salt thereof has value in the treatment of myelodysplasia, myelodysplastic syndrome and cancer. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndromes and cancer-related processes. Therefore, activity is expected in myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelocytosis and chronic myelodysplastic syndromes, myelodysplastic syndromes, and neoplastic diseases such as breast, ovarian, lung, colon, prostate, or other tissue cancers, as well as leukemia, myeloma, and lymphoma.
本发明提供的化合物或其药学上可接受的盐在测试过程中具有的血脑屏障透过性，在中枢神经系统疾病的治疗中具有价值。治疗方法靶向酪氨酸激酶活性，特别是JAK家族活性，其涉及多种中枢神经系统炎症疾病相关过程。因此，预期对中枢神经系统炎症具有活性，例如癫痫、痴呆、帕金森疾病、抑郁症等。The compound provided by the invention or the pharmaceutically acceptable salt thereof has blood-brain barrier permeability in the test process, and has value in the treatment of central nervous system diseases. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of CNS inflammatory disease-associated processes. Thus, activity against central nervous system inflammation is expected, such as epilepsy, dementia, Parkinson's disease, depression, and the like.
具体实施方式Detailed ways
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。The substantive content of the present invention will be described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.
实施例1Example 1
步骤1：4-氯-1-(三异丙基硅烷基)-1H-吡咯并[2,3-b]吡啶(中间体2a)的制备Step 1: Preparation of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (intermediate 2a)
Figure PCTCN2022093052-appb-000008
Figure PCTCN2022093052-appb-000008
在0℃下向搅拌的1(16.0g,0.10mol)的THF(300ml)溶液中分批加入NaH(60％在矿物油中,5g,0.14mol)，并在相同温度下搅拌混合物保持20分钟，然后滴加三异丙基甲硅烷基氯(22.3g,0.16mol)，保持温度在0℃。反应完成后，将反应混合物用饱和NH 4Cl溶液(10mL)淬灭，用水稀释并用乙酸乙酯(3×200ml)萃取。通过柱色谱法纯化粗化合物， 得到无色油状液2 30.0g，收率92.6％。 1H NMR(300MHz,DMSO-d 6)δ8.18(d,J＝5.16Hz,1H),7.59(d,J＝3.80Hz,1H),7.23(d,J＝5.16Hz,1H),6.67(d,J＝3.52Hz,1H),1.82-1.90(m,3H),1.05(d,J＝7.52Hz,18H). To a stirred solution of 1 (16.0 g, 0.10 mol) in THF (300 ml) was added NaH (60% in mineral oil, 5 g, 0.14 mol) in portions at 0 °C and the mixture was stirred at the same temperature for 20 min , then triisopropylsilyl chloride (22.3 g, 0.16 mol) was added dropwise, keeping the temperature at 0°C. After completion of the reaction, the reaction mixture was quenched with saturated NH 4 Cl solution (10 mL), diluted with water and extracted with ethyl acetate (3×200 ml). The crude compound was purified by column chromatography to obtain 30.0 g of a colorless oily liquid 2 with a yield of 92.6%. 1 H NMR (300MHz, DMSO-d 6 )δ8.18(d, J=5.16Hz, 1H), 7.59(d, J=3.80Hz, 1H), 7.23(d, J=5.16Hz, 1H), 6.67 (d,J=3.52Hz,1H),1.82-1.90(m,3H),1.05(d,J=7.52Hz,18H).
步骤2：4-氯-5-碘-1-(三异丙基硅烷基)-1H-吡咯并[2,3-b]吡啶(3a)的制备Step 2: Preparation of 4-chloro-5-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3a)
Figure PCTCN2022093052-appb-000009
Figure PCTCN2022093052-appb-000009
在-78℃下向2a(11.0g,35.7mmol)的THF(100mL)溶液中，在30分钟内滴加Sec-BuLi(仲丁基锂)(53mL,78.5mmol)，并且将反应混合物在给定温度下再搅拌1.5小时。然后在相同温度下经30分钟滴加碘(18g,71.1mmol)的THF(50ml)溶液，将所得悬浮液搅拌1小时并缓慢升温至0℃。用饱和NH 4Cl溶液淬灭反应，用EtOAc萃取，用水和盐水洗涤，经Na 2SO 4干燥，并在减压下浓缩，得到粗化合物，通过硅胶色谱法纯化，得到淡黄色油状液体3a 8.25g，收率53.2％。 1H NMR(300MHz,DMSO-d 6)δ8.52(s,1H),7.57(d,J＝3.52Hz,1H),6.67(d,J＝3.48Hz,1H),1.80-1.88(m,3H),1.04(d,J＝7.52Hz,18H). To a solution of 2a (11.0 g, 35.7 mmol) in THF (100 mL) was added dropwise Sec-BuLi (sec-butyllithium) (53 mL, 78.5 mmol) over 30 minutes at -78 °C, and the reaction mixture was Stirring was continued for 1.5 hours at constant temperature. A solution of iodine (18 g, 71.1 mmol) in THF (50 ml) was then added dropwise at the same temperature over 30 minutes, and the resulting suspension was stirred for 1 hour and slowly warmed to 0°C. The reaction was quenched with saturated NH4Cl solution , extracted with EtOAc, washed with water and brine, dried over Na2SO4 , and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography to give 3a8.25 as a light yellow oily liquid g, yield 53.2%. 1 H NMR (300MHz, DMSO-d 6 )δ8.52(s, 1H), 7.57(d, J=3.52Hz, 1H), 6.67(d, J=3.48Hz, 1H), 1.80-1.88(m, 3H), 1.04(d, J=7.52Hz, 18H).
步骤3：4-氯-5-碘-1H-吡咯并[2,3-b]吡啶(4a)的制备Step 3: Preparation of 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (4a)
Figure PCTCN2022093052-appb-000010
Figure PCTCN2022093052-appb-000010
在0℃下向搅拌的3(11.0g,25.3mmol)的无水THF(200ml)溶液中加入TBAF(1MTHF溶液,27mL,27mmol)并搅拌30分钟。反应完成后，蒸发溶剂，用EtOAc稀释，用水和盐水洗涤，并经无水Na 2SO 4干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化，得到淡黄色固体4a 7.0g，收率95.6％。 1H NMR(300MHz,DMSO-d 6)δ12.15(s,1H),8.50(s,1H),7.58(d,J＝3.40Hz,1H),6.49(d,J＝3.44Hz,1H),5.09(s,1H). To a stirred solution of 3 (11.0 g, 25.3 mmol) in anhydrous THF (200 ml) was added TBAF (1 M THF solution, 27 mL, 27 mmol) at 0 °C and stirred for 30 min. After the reaction was complete, the solvent was evaporated, diluted with EtOAc, washed with water and brine , and dried over anhydrous Na2SO4 , and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography to give 4a as a pale yellow solid 7.0 g, Yield 95.6%. 1 H NMR (300MHz,DMSO-d 6 )δ12.15(s,1H),8.50(s,1H),7.58(d,J=3.40Hz,1H),6.49(d,J=3.44Hz,1H) ,5.09(s,1H).
步骤4：4-氯-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 4: Preparation of 4-chloro-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000011
Figure PCTCN2022093052-appb-000011
将中间体4a(1g，3.6mmol)，苯炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶790mg，收率82.5％。 1H NMR(300MHz,CDCl 3)δ8.85(s,1H),7.81(s,1H),7.55(dd,J＝7.5,2.0Hz,2H),7.45–7.37(m,2H),7.34(m,J＝8.2,6.6,2.2Hz,1H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H)。 Intermediate 4a (1 g, 3.6 mmol), phenylene (4.3 mmol), Pd(PPh 3 ) 2 Cl 2 (126 mg, 0.18 mmol), CuI (34 mg, 0.18 mmol) and 1 ml of triethylamine were added to 25 ml of acetonitrile, Heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), the corresponding solid compound 4-chloro-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine 790 mg was obtained, with a yield of 82.5%. 1 H NMR (300MHz, CDCl 3 ) δ8.85(s, 1H), 7.81(s, 1H), 7.55(dd, J=7.5, 2.0Hz, 2H), 7.45–7.37(m, 2H), 7.34( m, J=8.2, 6.6, 2.2Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 6.68 (d, J=7.5Hz, 1H).
步骤5：N-环己基-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 5: Preparation of N-cyclohexyl-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000012
Figure PCTCN2022093052-appb-000012
将化合物4-氯-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，490mg，收率57.3％。 1H NMR(300MHz,CDCl 3)δ8.63(s,1H),7.86(s,1H),7.55(d,J＝7.4Hz,2H),7.41(t,J＝7.4Hz,2H),7.37–7.30(m,1H),7.23(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.92(s,1H),3.34(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.78(dd,J＝13.4,6.3Hz,2H),1.72–1.62(m,3H),1.62–1.57(m,1H),1.35(m,J＝13.0,6.6Hz,2H). The compound 4-chloro-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol ), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) were added to 20ml of dioxane, Heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 490mg , yield 57.3%. 1 H NMR (300MHz, CDCl 3 ) δ8.63(s, 1H), 7.86(s, 1H), 7.55(d, J=7.4Hz, 2H), 7.41(t, J=7.4Hz, 2H), 7.37 –7.30(m,1H),7.23(d,J=7.5Hz,1H),6.83(d,J=7.5Hz,1H),3.92(s,1H),3.34(s,1H),2.04(dd, J=13.0,7.0Hz,2H),1.78(dd,J=13.4,6.3Hz,2H),1.72–1.62(m,3H),1.62–1.57(m,1H),1.35(m,J=13.0, 6.6Hz, 2H).
步骤6：N-环己基-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 6: Preparation of N-cyclohexyl-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000013
Figure PCTCN2022093052-appb-000013
在室温下向N-环己基-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物N-环己基-5-(苯基乙炔基)-1H-吡咯并[2,3-b]吡啶，313.5mg，收率62.7％。m.p.204.5-205.1℃。 1H NMR(300MHz,DMSO-d 6)δ11.46(s,1H),7.86(s,1H),7.18(s,1H),6.84(dd,J＝94.0,7.8Hz,5H),6.46(s,1H),5.96(t,J＝6.5Hz,1H),5.16(d,J＝8.7Hz,1H),4.18(d,J＝6.5Hz,2H),3.86(s,1H),2.21(s,3H),1.91–1.83(m,2H),1.66(s,2H),1.39(d,J＝11.8Hz,2H),1.19(d,J＝8.6Hz,2H),1.01(d,J＝11.9Hz,2H). To a mixture of N-cyclohexyl-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK at room temperature (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound N-cyclohexyl-5-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine, 313.5 mg, yield 62.7%. mp204.5-205.1°C. 1 H NMR (300MHz, DMSO-d 6 ) δ11.46(s, 1H), 7.86(s, 1H), 7.18(s, 1H), 6.84(dd, J=94.0, 7.8Hz, 5H), 6.46( s,1H),5.96(t,J=6.5Hz,1H),5.16(d,J=8.7Hz,1H),4.18(d,J=6.5Hz,2H),3.86(s,1H),2.21( s,3H),1.91–1.83(m,2H),1.66(s,2H),1.39(d,J=11.8Hz,2H),1.19(d,J=8.6Hz,2H),1.01(d,J =11.9Hz,2H).
实施例2Example 2
步骤1：4-氯-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000014
Figure PCTCN2022093052-appb-000014
将中间体4a(1g，3.6mmol，参照实施例1中的制备方法)，对甲基苯乙炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶892mg，收率88.5％。 1H NMR(300MHz,CDCl 3)δ8.85(s,1H),7.81(s,1H),7.52–7.46(m,2H),7.19(d,J＝7.5Hz,1H),7.13–7.07(m,2H),6.68(d,J＝7.5Hz,1H),2.34(d,J＝1.4Hz,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method in Example 1), p-methylphenylacetylene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18 mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain 892 mg of the corresponding solid compound 4-chloro-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine with a yield of 88.5%. 1 H NMR (300MHz, CDCl 3 ) δ8.85(s, 1H), 7.81(s, 1H), 7.52–7.46(m, 2H), 7.19(d, J=7.5Hz, 1H), 7.13–7.07( m,2H),6.68(d,J=7.5Hz,1H),2.34(d,J=1.4Hz,3H).
步骤2：N-环己基-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000015
Figure PCTCN2022093052-appb-000015
将化合物4-氯-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，535mg，收率60.8％。 1H NMR(300MHz,CDCl 3)δ8.57(s,1H),7.87(s,1H),7.47(d,J＝7.5Hz,2H),7.19(d,J＝7.5Hz,1H),7.10(d,J＝7.5Hz,2H),6.79(d,J＝7.5Hz,1H),5.33(s,1H),3.86(s,1H),2.34(s,3H),2.10–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.56(m,4H),1.38(dd,J＝12.8,7.0Hz,2H). Compound 4-chloro-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol ), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) were added to 20ml of dioxane, Heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 535mg , yield 60.8%. 1 H NMR (300MHz, CDCl 3 )δ8.57(s,1H),7.87(s,1H),7.47(d,J=7.5Hz,2H),7.19(d,J=7.5Hz,1H),7.10 (d,J=7.5Hz,2H),6.79(d,J=7.5Hz,1H),5.33(s,1H),3.86(s,1H),2.34(s,3H),2.10–2.01(m, 2H), 1.80(m, J＝13.1, 6.0Hz, 2H), 1.67–1.56(m, 4H), 1.38(dd, J＝12.8, 7.0Hz, 2H).
步骤3：1-环己基-2-(对甲苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(p-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000016
Figure PCTCN2022093052-appb-000016
在室温下向4-氯-5-(对甲苯乙炔基)-1H-吡咯并[2,3-b]吡啶(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(对甲苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，292.5mg，收率58.4％。m.p.203.6-205.0℃。 1H NMR(300MHz,DMSO-d6)δ11.54(s,1H),7.98(s,1H),7.41(dd,J＝23.0,7.4Hz,3H),7.22(d,J＝7.5Hz,2H),6.5(s,1H),4.31(s,1H),2.33(s,3H),2.31–2.23(m,2H),2.04(m,J＝13.2,6.9Hz,2H),1.85–1.69(m,3H),1.53–1.42(m,1H),1.42–1.33(m,2H). To a mixture of 4-chloro-5-(p-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(p-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridine, 292.5 mg, yield 58.4%. mp203.6-205.0°C. 1 H NMR (300MHz, DMSO-d6) δ11.54(s, 1H), 7.98(s, 1H), 7.41(dd, J=23.0, 7.4Hz, 3H), 7.22(d, J=7.5Hz, 2H ),6.5(s,1H),4.31(s,1H),2.33(s,3H),2.31–2.23(m,2H),2.04(m,J＝13.2,6.9Hz,2H),1.85–1.69( m,3H),1.53–1.42(m,1H),1.42–1.33(m,2H).
实施例3Example 3
步骤1：4-氯-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000017
Figure PCTCN2022093052-appb-000017
将中间体4a(1g，3.6mmol，参照实施例1中的制备方法)，4-氟苯炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶790mg，收率82.5％。 1H NMR(300MHz,CDCl 3)δ8.85(s,1H),7.81(s,1H),7.55(dd,J＝7.5,2.0Hz,2H),7.45–7.37(m,2H),7.34(m,J＝8.2,6.6,2.2Hz,1H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H)。 Intermediate 4a (1g, 3.6mmol, refer to the preparation method in Example 1), 4-fluorophenylyne (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18 mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain 790 mg of the corresponding solid compound 4-chloro-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine, Yield 82.5%. 1 H NMR (300MHz, CDCl 3 ) δ8.85(s, 1H), 7.81(s, 1H), 7.55(dd, J=7.5, 2.0Hz, 2H), 7.45–7.37(m, 2H), 7.34( m, J=8.2, 6.6, 2.2Hz, 1H), 7.19 (d, J=7.5Hz, 1H), 6.68 (d, J=7.5Hz, 1H).
步骤2：N-环己基-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000018
Figure PCTCN2022093052-appb-000018
将化合物4-氯-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，502mg，收率55.7％。 1H NMR(300MHz,CDCl 3)δ8.63(s,1H),7.86(s,1H),7.57(d,J＝7.5Hz,2H),7.23(d,J＝7.3Hz,1H),7.06(dd,J＝9.0,7.5Hz,2H),6.82(d,J＝7.5Hz,1H),3.94(s,1H),3.38(s,1H),2.03(dd,J＝13.0,7.0Hz,2H),1.85–1.75(m,2H),1.70–1.57(m,4H),1.37(m,J＝12.9,6.5Hz,2H). Compound 4-chloro-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml di Hexane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine- 4-amine, 502 mg, yield 55.7%. 1 H NMR (300MHz, CDCl 3 )δ8.63(s,1H),7.86(s,1H),7.57(d,J=7.5Hz,2H),7.23(d,J=7.3Hz,1H),7.06 (dd,J=9.0,7.5Hz,2H),6.82(d,J=7.5Hz,1H),3.94(s,1H),3.38(s,1H),2.03(dd,J=13.0,7.0Hz, 2H),1.85–1.75(m,2H),1.70–1.57(m,4H),1.37(m,J＝12.9,6.5Hz,2H).
步骤3：1-环己基-2-(4-氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(4-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000019
Figure PCTCN2022093052-appb-000019
在室温下向N-环己基-5-((4-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(4-氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，284.5mg，收率56.9％。m.p.200.6-202.1℃。 1H NMR(300MHz,DMSO-d 6)δ8.02(s,1H),7.66–7.59(m,2H),7.34–7.27(m,2H),7.22(dd,J＝3.6,2.3Hz,1H),6.58(dd,J＝3.7,1.7Hz,1H),5.69(d,J＝8.6Hz,1H),3.37(s,3H),2.11(s,1H),2.06(s,2H),1.76(s,2H),1.73–1.48(m,2H),1.44(s,2H),1.33(d,J＝46.8Hz,2H). To a mixture of N-cyclohexyl-5-((4-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to t-BuOK. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(4-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d]pyridine, 284.5 mg, yield 56.9%. mp200.6-202.1°C. 1 H NMR (300MHz,DMSO-d 6 )δ8.02(s,1H),7.66–7.59(m,2H),7.34–7.27(m,2H),7.22(dd,J＝3.6,2.3Hz,1H ),6.58(dd,J=3.7,1.7Hz,1H),5.69(d,J=8.6Hz,1H),3.37(s,3H),2.11(s,1H),2.06(s,2H),1.76 (s,2H),1.73–1.48(m,2H),1.44(s,2H),1.33(d,J＝46.8Hz,2H).
实施例4Example 4
步骤1：4-氯-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000020
Figure PCTCN2022093052-appb-000020
将中间体4a(1g，3.6mmol，参照实施例1中的制备方法)，苯炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶861mg，收率80.8％。 1H NMR(300MHz,CDCl 3)δ8.84(s,1H),7.81(s,1H),7.50–7.43(m,2H),7.19(d,J＝7.5Hz,1H),6.97–6.91(m,2H),6.68(d,J＝7.5Hz,1H),3.80(s,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method in Example 1), benzyne (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and Add 1ml of triethylamine into 25ml of acetonitrile and heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine 861 mg, yield 80.8%. 1 H NMR (300MHz, CDCl 3 ) δ8.84(s, 1H), 7.81(s, 1H), 7.50–7.43(m, 2H), 7.19(d, J=7.5Hz, 1H), 6.97–6.91( m,2H),6.68(d,J=7.5Hz,1H),3.80(s,3H).
步骤2：N-环己基-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000021
Figure PCTCN2022093052-appb-000021
将化合物4-氯-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，590mg，收率64.1％。 1H NMR(300MHz,CDCl 3)δ8.63(s,1H),7.86(s,1H),7.44(d,J＝7.5Hz,2H),7.23(d,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,2H),6.82(d,J＝7.5Hz,1H),3.94(s,1H),3.80(s,3H),3.31(s,1H),2.03(dd,J＝13.5,6.3Hz,2H),1.78(m,J＝13.5,6.3Hz,2H),1.70–1.57(m,4H),1.37(m,J＝13.1,6.6Hz,2H). Compound 4-chloro-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t -BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) added 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b] Pyridin-4-amine, 590 mg, yield 64.1%. 1 H NMR (300MHz, CDCl 3 )δ8.63(s,1H),7.86(s,1H),7.44(d,J=7.5Hz,2H),7.23(d,J=7.5Hz,1H),6.94 (d,J=7.5Hz,2H),6.82(d,J=7.5Hz,1H),3.94(s,1H),3.80(s,3H),3.31(s,1H),2.03(dd,J= 13.5,6.3Hz,2H),1.78(m,J=13.5,6.3Hz,2H),1.70–1.57(m,4H),1.37(m,J=13.1,6.6Hz,2H).
步骤3：1-环己基-2-(4-甲氧基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(4-methoxyphenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000022
Figure PCTCN2022093052-appb-000022
在室温下向N-环己基-5-((4-甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(4-甲氧基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，301.5mg，收率60.2％。 1H NMR(300MHz,DMSO-d6)δ11.50(s,1H),8.00(s,1H),7.51(d,J＝8.3Hz,2H),7.21(t,J＝2.9Hz,1H),7.01(d,J＝8.3Hz,2H),6.57(d,J＝3.5Hz,1H),5.63(d,J＝8.6Hz,1H),3.82(s,3H),3.37(s,2H),2.06(s,2H),1.75(s,2H),1.63(d,J＝11.5Hz,1H),1.50–1.39(m,4H),1.26(s,1H). N-cyclohexyl-5-((4-methoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(4-methoxyphenyl)-1,6-dihydrodipyrrolo[2,3-b : 2',3'-d]pyridine, 301.5 mg, yield 60.2%. 1 H NMR (300MHz, DMSO-d6) δ11.50(s, 1H), 8.00(s, 1H), 7.51(d, J=8.3Hz, 2H), 7.21(t, J=2.9Hz, 1H), 7.01(d, J=8.3Hz, 2H), 6.57(d, J=3.5Hz, 1H), 5.63(d, J=8.6Hz, 1H), 3.82(s, 3H), 3.37(s, 2H), 2.06(s,2H),1.75(s,2H),1.63(d,J=11.5Hz,1H),1.50–1.39(m,4H),1.26(s,1H).
实施例5Example 5
步骤1：4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈的制备Step 1: Preparation of 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)benzonitrile
Figure PCTCN2022093052-appb-000023
Figure PCTCN2022093052-appb-000023
将中间体4a(1g，3.6mmol，参照实施例1中的制备方法)，对氰基苯炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈855mg，收率84.5％。 1H NMR(300MHz,CDCl 3)δ8.85(s,1H),7.84–7.75(m,3H),7.66–7.59(m,2H),7.20(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method in Example 1), p-cyanophenylene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18 mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain 855 mg of the corresponding solid compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)benzonitrile, Yield 84.5%. 1 H NMR (300MHz, CDCl 3 ) δ8.85(s, 1H), 7.84–7.75(m, 3H), 7.66–7.59(m, 2H), 7.20(d, J=7.5Hz, 1H), 6.68( d,J=7.5Hz,1H).
步骤2：4-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈的制备Step 2: Preparation of 4-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)benzonitrile
Figure PCTCN2022093052-appb-000024
Figure PCTCN2022093052-appb-000024
将化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物4-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈，531.6mg，收率57.7％。 1H NMR(300MHz,CDCl 3)δ8.57(s,1H),7.87(s,1H),7.77(d,J＝7.3Hz,2H),7.63(d,J＝7.5Hz,2H),7.19(d,J＝7.5Hz,1H),6.79(d,J＝7.5Hz,1H),5.16(s,1H),3.87(s,1H),2.10–2.01(m,2H),1.80(m,J＝13.1,5.9Hz,2H),1.66–1.56(m,4H),1.39(m,J＝12.9,6.9Hz,2H). Compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)benzonitrile (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml di Hexane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) afforded the corresponding solid compound 4-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl) Benzonitrile, 531.6 mg, yield 57.7%. 1 H NMR (300MHz, CDCl 3 )δ8.57(s,1H),7.87(s,1H),7.77(d,J=7.3Hz,2H),7.63(d,J=7.5Hz,2H),7.19 (d,J=7.5Hz,1H),6.79(d,J=7.5Hz,1H),5.16(s,1H),3.87(s,1H),2.10–2.01(m,2H),1.80(m, J=13.1,5.9Hz,2H), 1.66–1.56(m,4H),1.39(m,J=12.9,6.9Hz,2H).
步骤3：4-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苄腈的制备Step 3: Preparation of 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)benzonitrile
Figure PCTCN2022093052-appb-000025
Figure PCTCN2022093052-appb-000025
在室温下向4-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苄腈(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物4-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苄腈，278.6mg，收率55.6％。m.p.209.7-212.0℃。 1H NMR(300MHz,DMSO-d 6)δ7.96(s,1H),7.26(d,J＝8.2Hz,2H),7.21(t,J＝2.5Hz,1H),6.60(d,J＝8.3Hz,2H),6.55(d,J＝3.5Hz,1H),5.91(d,J＝7.9Hz,1H),5.52(d,J＝8.6Hz,1H),3.24(q,J＝9.7Hz,1H),2.06(d,J＝9.6Hz,2H),1.99–1.89(m,2H),1.76–1.72(m,2H),1.63(d,J＝12.5Hz,2H),1.40(d,J＝8.4Hz,3H),1.20(m,J＝9.7,8.0,4.1Hz,3H). To a mixture of 4-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)benzonitrile (1.5 mmol) and THF (10 mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Pyridin-2-yl)benzonitrile, 278.6 mg, yield 55.6%. mp209.7-212.0°C. 1 H NMR (300MHz, DMSO-d 6 )δ7.96(s, 1H), 7.26(d, J=8.2Hz, 2H), 7.21(t, J=2.5Hz, 1H), 6.60(d, J= 8.3Hz, 2H), 6.55(d, J=3.5Hz, 1H), 5.91(d, J=7.9Hz, 1H), 5.52(d, J=8.6Hz, 1H), 3.24(q, J=9.7Hz ,1H),2.06(d,J=9.6Hz,2H),1.99–1.89(m,2H),1.76–1.72(m,2H),1.63(d,J=12.5Hz,2H),1.40(d, J=8.4Hz,3H),1.20(m,J=9.7,8.0,4.1Hz,3H).
实施例6Example 6
步骤1:(3-苯基丙-1-炔-1-基)三甲基硅烷的制备Step 1: Preparation of (3-phenylprop-1-yn-1-yl)trimethylsilane
Figure PCTCN2022093052-appb-000026
Figure PCTCN2022093052-appb-000026
将溴苄(5.8mmol)，三甲基乙炔基硅(682mg,6.9mmol)，Pd(PPh 3) 2Cl 2(203mg,0.29mmol)，CuI(110mg,0.58mmol)和三乙胺2.5mL加入25mL乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100mL)，饱和食盐水(1×100mL)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE:EA＝100:1)，经柱层析分离纯化得到白色油状液体(3-苯基丙-1-炔-1-基)三甲基硅烷，0.91g，收率83.6％。 1H NMR(300MHz,CDCl 3)δ7.29–7.23(m,3H),7.23–7.16(m,2H),3.29(t,J＝1.1Hz,2H),0.08(s,9H). Benzyl bromide (5.8mmol), trimethylethynylsilane (682mg, 6.9mmol), Pd(PPh 3 ) 2 Cl 2 (203mg, 0.29mmol), CuI (110mg, 0.58mmol) and triethylamine 2.5mL were added In 25mL of acetonitrile, heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100mL), saturated brine (1×100mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=100:1), separated and purified by column chromatography to obtain (3-phenylprop-1-yn-1-yl)trimethylsilane as a white oily liquid, 0.91g, yield 83.6 %. 1 H NMR (300MHz, CDCl 3 )δ7.29–7.23(m,3H),7.23–7.16(m,2H),3.29(t,J=1.1Hz,2H),0.08(s,9H).
步骤2：3-苯-1-丙炔的制备Step 2: Preparation of 3-Benzene-1-propyne
Figure PCTCN2022093052-appb-000027
Figure PCTCN2022093052-appb-000027
将化合物(3-苯基丙-1-炔-1-基)三甲基硅烷(4.8mmol)，K 2CO 3(3.3g，24mmol)，加入20ml甲醇中，0℃搅拌。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物3-苯-1-丙炔520mg，收率93.5％。 1H NMR(300MHz,CDCl 3)δ7.29–7.16(m,5H),3.34(d,J＝3.1Hz,2H),2.12(t,J＝2.9Hz,1H). Add the compound (3-phenylprop-1-yn-1-yl)trimethylsilane (4.8mmol), K 2 CO 3 (3.3g, 24mmol) into 20ml of methanol, and stir at 0°C. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography yielded 520 mg of the product 3-benzene-1-propyne with a yield of 93.5%. 1 H NMR (300MHz, CDCl 3 ) δ7.29–7.16 (m, 5H), 3.34 (d, J=3.1Hz, 2H), 2.12 (t, J=2.9Hz, 1H).
步骤3：4-氯-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 3: Preparation of 4-chloro-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000028
Figure PCTCN2022093052-appb-000028
将中间体4(1g，3.6mmol，参照实施例1中的制备方法)，3-苯-1-丙炔(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶790mg，收率82.5％。 1H NMR(300MHz,CDCl 3)δ11.39(s,1H),8.73(s,1H),7.32–7.19(m,5H),7.18(d,J＝7.5Hz,1H),6.67(d,J＝7.5Hz,1H),3.43(s,2H). Intermediate 4 (1g, 3.6mmol, referring to the preparation method in Example 1), 3-benzene-1-propyne (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2 ,3-b]pyridine 790mg, yield 82.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.39(s, 1H), 8.73(s, 1H), 7.32–7.19(m, 5H), 7.18(d, J=7.5Hz, 1H), 6.67(d, J＝7.5Hz,1H),3.43(s,2H).
步骤4：N-环己基-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 4: Preparation of N-cyclohexyl-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000029
Figure PCTCN2022093052-appb-000029
将化合物4-氯-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺490mg，收率57.3％。 1H NMR(300MHz,CDCl 3)δ11.37(s,1H),8.56(s,1H),7.32–7.19(m,5H),7.19(d,J＝7.3Hz,1H),6.77(d,J＝7.5Hz,1H),4.27(s,1H),3.98(s,1H),3.29(s,2H),1.90(dd,J＝13.3,6.0Hz,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.60–1.47(m,4H),0.89–0.77(m,2H). Compound 4-chloro-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol) , t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol ) into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[ 2,3-b]pyridin-4-amine 490 mg, yield 57.3%. 1 H NMR (300MHz, CDCl 3 ) δ11.37(s, 1H), 8.56(s, 1H), 7.32–7.19(m, 5H), 7.19(d, J=7.3Hz, 1H), 6.77(d, J＝7.5Hz, 1H), 4.27(s, 1H), 3.98(s, 1H), 3.29(s, 2H), 1.90(dd, J＝13.3, 6.0Hz, 2H), 1.61(dd, J＝6.5 ,1.6Hz,2H),1.60–1.47(m,4H),0.89–0.77(m,2H).
步骤5：2-苄基-1-环己基-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶的制备Step 5: Preparation of 2-benzyl-1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000030
Figure PCTCN2022093052-appb-000030
在室温下向N-环己基-5-(3-苯基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅 拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，经柱层析分离纯化得到产物2-苄基-1-环己基-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶490mg，收率57.3％。 1H NMR(300MHz,CDCl 3)δ11.37(s,1H),8.56(s,1H),7.32–7.19(m,5H),7.19(d,J＝7.3Hz,1H),6.77(d,J＝7.5Hz,1H),4.27(s,1H),3.98(s,1H),3.29(s,2H),1.90(dd,J＝13.3,6.0Hz,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.60–1.47(m,4H),0.89–0.77(m,2H). N-cyclohexyl-5-(3-phenylprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), separated and purified by column chromatography to obtain the product 2-benzyl-1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2' , 3'-d]pyridine 490mg, yield 57.3%. 1 H NMR (300MHz, CDCl 3 ) δ11.37(s, 1H), 8.56(s, 1H), 7.32–7.19(m, 5H), 7.19(d, J=7.3Hz, 1H), 6.77(d, J＝7.5Hz, 1H), 4.27(s, 1H), 3.98(s, 1H), 3.29(s, 2H), 1.90(dd, J＝13.3, 6.0Hz, 2H), 1.61(dd, J＝6.5 ,1.6Hz,2H),1.60–1.47(m,4H),0.89–0.77(m,2H).
实施例7Example 7
步骤1:(3-(对甲苯基)丙-1-炔-1-基)三甲基硅烷的制备Step 1: Preparation of (3-(p-tolyl)prop-1-yn-1-yl)trimethylsilane
Figure PCTCN2022093052-appb-000031
Figure PCTCN2022093052-appb-000031
将对甲基溴苄(5.8mmol)，三甲基乙炔基硅(682mg,6.9mmol)，Pd(PPh 3) 2Cl 2(203mg,0.29mmol)，CuI(110mg,0.58mmol)和三乙胺2.5mL加入25mL乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100mL)，饱和食盐水(1×100mL)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE:EA＝100:1)，经柱层析分离纯化得到白色油状液体(3-(对甲苯基)丙-1-炔-1-基)三甲基硅烷，1.0g，收率为85.3％。 1H NMR(300MHz,DMSO-d 6)δ7.16–7.07(m,4H),3.35(t,J＝1.0Hz,2H),2.21(s,3H),0.08(s,9H). p-methylbenzyl bromide (5.8mmol), trimethylethynyl silicon (682mg, 6.9mmol), Pd(PPh 3 ) 2 Cl 2 (203mg, 0.29mmol), CuI (110mg, 0.58mmol) and triethylamine Add 2.5mL into 25mL acetonitrile and heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100mL), saturated brine (1×100mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=100:1), separated and purified by column chromatography to obtain white oily liquid (3-(p-tolyl)prop-1-yn-1-yl)trimethylsilane, 1.0g, The yield was 85.3%. 1 H NMR (300MHz, DMSO-d 6 ) δ7.16–7.07 (m, 4H), 3.35 (t, J=1.0Hz, 2H), 2.21 (s, 3H), 0.08 (s, 9H).
步骤2：1-甲基-4-(丙-2-炔-1-基)苯的制备Step 2: Preparation of 1-methyl-4-(prop-2-yn-1-yl)benzene
Figure PCTCN2022093052-appb-000032
Figure PCTCN2022093052-appb-000032
将化合物(3-(对甲苯基)丙-1-炔-1-基)三甲基硅烷(4.8mmol)，K 2CO 3(3.3g，24mmol)，加入20ml甲醇中，0℃搅拌。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-甲基-4-(丙-2-炔-1-基)苯575mg，收率92.3％。 1H NMR(300MHz,CDCl 3)δ7.11(q,J＝7.5Hz,4H),3.33(d,J＝3.0Hz,2H),2.21(s,2H),2.12(t,J＝3.0Hz,1H). Add the compound (3-(p-tolyl)prop-1-yn-1-yl)trimethylsilane (4.8mmol), K 2 CO 3 (3.3g, 24mmol) into 20ml of methanol, and stir at 0°C. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography yielded 575 mg of the product 1-methyl-4-(prop-2-yn-1-yl)benzene with a yield of 92.3%. 1 H NMR (300MHz, CDCl 3 ) δ7.11(q, J=7.5Hz, 4H), 3.33(d, J=3.0Hz, 2H), 2.21(s, 2H), 2.12(t, J=3.0Hz ,1H).
步骤3：4-氯-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 3: Preparation of 4-chloro-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000033
Figure PCTCN2022093052-appb-000033
将中间体4(1g，3.6mmol，参照实施例1中的制备方法)，1-甲基-4-(丙-2-炔-1-基)苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶892mg，收率88.5％。 1H NMR(300MHz,CDCl 3)δ11.28(s,1H),8.73(s,1H),7.21–7.10(m,5H),6.67(d,J＝7.5Hz,1H),3.29(d,J＝1.4Hz,2H),2.21(d,J＝1.2Hz,3H). Intermediate 4 (1g, 3.6mmol, refer to the preparation method in Example 1), 1-methyl-4-(prop-2-yn-1-yl)benzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrole And[2,3-b]pyridine 892mg, yield 88.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.28(s, 1H), 8.73(s, 1H), 7.21–7.10(m, 5H), 6.67(d, J=7.5Hz, 1H), 3.29(d, J＝1.4Hz, 2H), 2.21(d, J＝1.2Hz, 3H).
步骤4：N-环己基-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 4: Preparation of N-cyclohexyl-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000034
Figure PCTCN2022093052-appb-000034
将化合物4-氯-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺535mg，收率60.8％。 1H NMR(300MHz,CDCl 3)δ11.37(s,1H),8.47(s,1H),7.23–7.11(m,5H),6.74(d,J＝7.5Hz,1H),5.26(s,1H),3.79(s,1H),3.29(s,2H),2.21(s,3H),2.02–1.93(m,2H),1.77–1.68(m,2H),1.61(m,J＝6.4,1.7Hz,2H),1.44(m,J＝12.9,6.9Hz,2H),1.30(m,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg , 0.13mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H- Pyrrolo[2,3-b]pyridin-4-amine 535 mg, yield 60.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.37(s, 1H), 8.47(s, 1H), 7.23–7.11(m, 5H), 6.74(d, J=7.5Hz, 1H), 5.26(s, 1H),3.79(s,1H),3.29(s,2H),2.21(s,3H),2.02–1.93(m,2H),1.77–1.68(m,2H),1.61(m,J＝6.4, 1.7Hz, 2H), 1.44(m, J=12.9, 6.9Hz, 2H), 1.30(m, J=12.9, 6.9Hz, 2H).
步骤5：1-环己基-2-(4-甲基苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶的制备Step 5: Preparation of 1-cyclohexyl-2-(4-methylbenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000035
Figure PCTCN2022093052-appb-000035
在室温下向N-环己基-5-(3-(对甲苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，经柱层析分离纯化得到产物1-环己基-2-(4-甲基苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶292.5mg，收率58.4％。m.p.183.1-184.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.49(s,1H),7.98(s,1H),7.43(d,J＝7.8Hz,2H),7.27–7.16(m,3H),6.55(s,1H),5.64(d,J＝8.6Hz,1H),4.09(s,1H),3.72(s,2H),2.34(s,3H),2.04(s,2H),1.73(s,2H),1.41(t,J＝9.2Hz,4H),1.23(s,2H). To N-cyclohexyl-5-(3-(p-tolyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) at room temperature To a mixture with THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), separated and purified by column chromatography to obtain the product 1-cyclohexyl-2-(4-methylbenzyl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine 292.5 mg, yield 58.4%. mp183.1-184.0°C. 1 H NMR (300MHz, DMSO-d 6 ) δ11.49(s, 1H), 7.98(s, 1H), 7.43(d, J=7.8Hz, 2H), 7.27–7.16(m, 3H), 6.55( s,1H),5.64(d,J=8.6Hz,1H),4.09(s,1H),3.72(s,2H),2.34(s,3H),2.04(s,2H),1.73(s,2H ), 1.41(t, J=9.2Hz, 4H), 1.23(s, 2H).
实施例8Example 8
步骤1:(3-(4-氟苯基)丙-1-炔-1-基)三甲基硅烷的制备Step 1: Preparation of (3-(4-fluorophenyl)prop-1-yn-1-yl)trimethylsilane
Figure PCTCN2022093052-appb-000036
Figure PCTCN2022093052-appb-000036
将4-氟溴苄(5.8mmol)，三甲基乙炔基硅(682mg,6.9mmol)，Pd(PPh 3) 2Cl 2(203mg,0.29mmol)，CuI(110mg,0.58mmol)和三乙胺2.5mL加入25mL乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100mL)，饱和食盐水(1×100mL)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE:EA＝100:1)，经柱层析分离纯化得到白色油状液体(3-(4-氟苯基)丙-1-炔-1-基)三甲基硅烷，0.98g，收率为82.1％。 1H NMR(300MHz,CDCl 3)δ7.17(m,J＝5.9,1.1Hz,2H),7.06–6.97(m,2H),3.35(d,J＝1.1Hz,2H),0.08(s,9H). 4-Fluorobenzyl bromide (5.8mmol), trimethylethynyl silicon (682mg, 6.9mmol), Pd(PPh 3 ) 2 Cl 2 (203mg, 0.29mmol), CuI (110mg, 0.58mmol) and triethylamine Add 2.5mL into 25mL acetonitrile and heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100mL), saturated brine (1×100mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=100:1), separated and purified by column chromatography to obtain white oily liquid (3-(4-fluorophenyl)prop-1-yn-1-yl)trimethylsilane, 0.98 g, the yield is 82.1%. 1 H NMR (300MHz, CDCl 3 ) δ7.17(m, J=5.9, 1.1Hz, 2H), 7.06–6.97(m, 2H), 3.35(d, J=1.1Hz, 2H), 0.08(s, 9H).
步骤2：1-氟-4-(丙-2-炔-1-基)苯的制备Step 2: Preparation of 1-fluoro-4-(prop-2-yn-1-yl)benzene
Figure PCTCN2022093052-appb-000037
Figure PCTCN2022093052-appb-000037
将化合物((3-(4-氟苯基)丙-1-炔-1-基)三甲基硅烷(4.8mmol)，K 2CO 3(3.3g，24mmol)，加入20ml甲醇中，0℃搅拌。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-氟-4-(丙-2-炔-1-基)苯616mg，收率93.5％。 1H NMR(300MHz,CDCl 3)δ7.20–7.14(m,2H),7.05–6.97(m,2H),3.33(d,J＝3.2Hz,2H),2.12(t,J＝3.0Hz,1H). Add the compound ((3-(4-fluorophenyl)prop-1-yn-1-yl)trimethylsilane (4.8mmol), K 2 CO 3 (3.3g, 24mmol) into 20ml methanol, 0°C After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound , separated and purified by column chromatography to obtain 616 mg of the product 1-fluoro-4-(prop-2-yn-1-yl)benzene, with a yield of 93.5%. 1 H NMR (300MHz, CDCl 3 )δ7.20–7.14(m ,2H),7.05–6.97(m,2H),3.33(d,J=3.2Hz,2H),2.12(t,J=3.0Hz,1H).
步骤3：4-氯-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 3: Preparation of 4-chloro-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000038
Figure PCTCN2022093052-appb-000038
将中间体4(1g，3.6mmol，参照实施例1中的制备方法)，1-氟-4-(丙-2-炔-1-基)苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶805mg，收率78.8％。 1H NMR(300MHz,CDCl 3)δ11.39(s,1H),8.72(s,1H),7.25–7.15(m,3H),7.08–7.00(m,2H),6.67(d,J＝7.5Hz,1H),3.42(d,J＝1.4Hz,2H). Intermediate 4 (1g, 3.6mmol, refer to the preparation method in Example 1), 1-fluoro-4-(prop-2-yn-1-yl)benzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H - 805mg of pyrrolo[2,3-b]pyridine, yield 78.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.39(s,1H), 8.72(s,1H), 7.25–7.15(m,3H), 7.08–7.00(m,2H), 6.67(d,J=7.5 Hz,1H),3.42(d,J=1.4Hz,2H).
步骤4：N-环己基-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 4: Preparation of N-cyclohexyl-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000039
Figure PCTCN2022093052-appb-000039
将化合物4-氯-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺502mg，收率55.7％。 1H NMR(300MHz,CDCl 3)δ11.37(s,1H),8.48(s,1H),7.24(d,J＝7.5Hz,2H),7.17(d,J＝7.5Hz,1H),7.05(dd,J＝9.0,7.5Hz,2H),6.75(d,J＝7.5Hz,1H),5.14(s,1H),3.81(s,1H),3.29(s,2H),2.05–1.96(m,2H),1.81–1.68(m,2H),1.61(m,J＝6.3,1.6Hz,2H),1.52–1.42(m,2H),1.32(m,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine ( 600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine 502 mg, yield 55.7%. 1 H NMR (300MHz, CDCl 3 ) δ11.37(s, 1H), 8.48(s, 1H), 7.24(d, J=7.5Hz, 2H), 7.17(d, J=7.5Hz, 1H), 7.05 (dd,J=9.0,7.5Hz,2H),6.75(d,J=7.5Hz,1H),5.14(s,1H),3.81(s,1H),3.29(s,2H),2.05–1.96( m,2H),1.81–1.68(m,2H),1.61(m,J＝6.3,1.6Hz,2H),1.52–1.42(m,2H),1.32(m,J＝12.9,6.9Hz,2H) .
步骤5：1-环己基-2-(4-氟苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶的制备Step 5: Preparation of 1-cyclohexyl-2-(4-fluorobenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000040
Figure PCTCN2022093052-appb-000040
在室温下向N-环己基-5-(3-(4-氟苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5 mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，经柱层析分离纯化得到产物1-环己基-2-(4-氟苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶284.5mg，收率56.9％。m.p.181.1–183.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.50(s,1H),7.99(s,1H),7.60(dd,J＝8.5,5.4Hz,2H),7.27(t,J＝8.7Hz,2H),7.19(d,J＝3.8Hz,1H),6.55(d,J＝3.4Hz,1H),5.67(d,J＝8.6Hz,1H),4.07(s,1H),3.73(s,2H),2.01(d,J＝13.2Hz,2H),1.73(s,2H),1.61(d,J＝12.6Hz,1H),1.41(t,J＝9.3Hz,4H),1.22(s,1H). To N-cyclohexyl-5-(3-(4-fluorophenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), separated and purified by column chromatography to obtain the product 1-cyclohexyl-2-(4-fluorobenzyl)-1,6-dihydrodipyrrolo[2,3 -b: 2',3'-d]pyridine 284.5 mg, yield 56.9%. mp 181.1–183.0°C. 1 H NMR (300MHz, DMSO-d 6 )δ11.50(s,1H),7.99(s,1H),7.60(dd,J=8.5,5.4Hz,2H),7.27(t,J=8.7Hz, 2H), 7.19(d, J=3.8Hz, 1H), 6.55(d, J=3.4Hz, 1H), 5.67(d, J=8.6Hz, 1H), 4.07(s, 1H), 3.73(s, 2H), 2.01(d, J=13.2Hz, 2H), 1.73(s, 2H), 1.61(d, J=12.6Hz, 1H), 1.41(t, J=9.3Hz, 4H), 1.22(s, 1H).
实施例9Example 9
步骤1:(3-(4-甲氧基苯基)丙-1-炔-1-基)三甲基硅烷的制备Step 1: Preparation of (3-(4-methoxyphenyl)prop-1-yn-1-yl)trimethylsilane
Figure PCTCN2022093052-appb-000041
Figure PCTCN2022093052-appb-000041
将4-甲氧基溴苄(5.8mmol)，三甲基乙炔基硅(682mg,6.9mmol)，Pd(PPh 3) 2Cl 2(203mg,0.29mmol)，CuI(110mg,0.58mmol)和三乙胺2.5mL加入25mL乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100mL)，饱和食盐水(1×100mL)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE:EA＝100:1)，经柱层析分离纯化得到白色油状液体(3-(4-甲氧基苯基)丙-1-炔-1-基)三甲基硅烷，1.0g，收率为80.3％。 1H NMR(300MHz,CDCl 3)δ7.13(m,J＝7.5,1.1Hz,2H),6.82–6.76(m,2H),3.80(s,3H),3.29(t,J＝1.0Hz,2H),0.08(s,9H). 4-Methoxybenzyl bromide (5.8mmol), trimethylethynyl silicon (682mg, 6.9mmol), Pd(PPh 3 ) 2 Cl 2 (203mg, 0.29mmol), CuI (110mg, 0.58mmol) and tri Add 2.5 mL of ethylamine into 25 mL of acetonitrile, and heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100mL), saturated brine (1×100mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=100:1), separated and purified by column chromatography to obtain white oily liquid (3-(4-methoxyphenyl)prop-1-yn-1-yl)trimethylsilane , 1.0g, the yield was 80.3%. 1 H NMR (300MHz, CDCl 3 )δ7.13(m, J＝7.5, 1.1Hz, 2H), 6.82–6.76(m, 2H), 3.80(s, 3H), 3.29(t, J＝1.0Hz, 2H),0.08(s,9H).
步骤2：1-甲氧基-4-(丙-2-炔-1-基)苯的制备Step 2: Preparation of 1-methoxy-4-(prop-2-yn-1-yl)benzene
Figure PCTCN2022093052-appb-000042
Figure PCTCN2022093052-appb-000042
将化合物(3-(4-甲氧基苯基)丙-1-炔-1-基)三甲基硅烷(4.8mmol)，K 2CO 3(3.3g，24mmol)，加入20ml甲醇中，0℃搅拌。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-甲氧基-4-(丙-2-炔-1-基)苯630mg，收率90.2％。 1H NMR(300MHz,CDCl 3)δ7.13(m,J＝7.6,1.1Hz,2H),6.82–6.75(m,2H),3.80(s,3H),3.32–3.26(m,2H),2.12(t,J＝3.0Hz,1H). The compound (3-(4-methoxyphenyl)prop-1-yn-1-yl)trimethylsilane (4.8mmol), K 2 CO 3 (3.3g, 24mmol), was added to 20ml of methanol, 0 °C and stir. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography yielded 630 mg of the product 1-methoxy-4-(prop-2-yn-1-yl)benzene with a yield of 90.2%. 1 H NMR (300MHz, CDCl 3 ) δ7.13 (m, J=7.6, 1.1Hz, 2H), 6.82–6.75 (m, 2H), 3.80 (s, 3H), 3.32–3.26 (m, 2H), 2.12(t,J=3.0Hz,1H).
步骤3：4-氯-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 3: Preparation of 4-chloro-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000043
Figure PCTCN2022093052-appb-000043
将中间体4(1g，3.6mmol，参照实施例1中的制备方法)，1-甲氧基-4-(丙-2-炔-1-基)苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶861mg，收率80.8％。 1H NMR(300MHz,CDCl 3)δ11.52(s,1H),8.73(s,1H),7.21–7.15(m,3H),6.85–6.78(m,2H),6.67(d,J＝7.5Hz,1H),3.80(s,3H),3.29(d,J＝1.2Hz,2H). Intermediate 4 (1g, 3.6mmol, referring to the preparation method in Example 1), 1-methoxy-4-(prop-2-yn-1-yl)benzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl) -1H-pyrrolo[2,3-b]pyridine 861 mg, yield 80.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.52(s,1H), 8.73(s,1H), 7.21–7.15(m,3H), 6.85–6.78(m,2H), 6.67(d,J=7.5 Hz,1H),3.80(s,3H),3.29(d,J=1.2Hz,2H).
步骤4：N-环己基-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 4: N-cyclohexyl-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation
Figure PCTCN2022093052-appb-000044
Figure PCTCN2022093052-appb-000044
将化合物4-氯-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺590mg，收率64.1％。 1H NMR(300MHz,CDCl 3)δ11.37(s,1H),8.53(s,1H),7.20(dd,J＝7.5,1.7Hz,3H),6.81(dd,J＝14.8,7.5Hz,3H),3.86(s,1H),3.81(d,J＝8.4Hz,4H),3.29(s,2H),1.94–1.85(m,2H),1.65–1.54(m,4H),1.42–1.33(m,2H),1.22–1.14(m,2H). Compound 4-chloro-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexyl Amine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba ) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl )-1H-pyrrolo[2,3-b]pyridin-4-amine 590 mg, yield 64.1%. 1 H NMR (300MHz, CDCl 3 ) δ11.37(s, 1H), 8.53(s, 1H), 7.20(dd, J=7.5, 1.7Hz, 3H), 6.81(dd, J=14.8, 7.5Hz, 3H), 3.86(s, 1H), 3.81(d, J＝8.4Hz, 4H), 3.29(s, 2H), 1.94–1.85(m, 2H), 1.65–1.54(m, 4H), 1.42–1.33 (m,2H),1.22–1.14(m,2H).
步骤5：1-环己基-2-(4-甲氧基苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶的制备Step 5: Preparation of 1-cyclohexyl-2-(4-methoxybenzyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000045
Figure PCTCN2022093052-appb-000045
在室温下向N-环己基-5-(3-(4-甲氧基苯基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，经柱层析分离纯化得到产物1-环己基-2-(4-甲氧基苄基)-1,6-二氢二吡咯并[2，3-b：2'，3'-d]吡啶301.5mg，收率60.2％。m.p.193.6-195.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.51(s,1H),7.99(d,J＝1.8Hz,1H),7.34(t,J＝9.7Hz,3H),7.17(s,2H),6.52(s,1H),5.64(d,J＝8.7Hz,1H),4.10(s,1H),3.89(s,2H),3.79(s,3H)2.34–2.31(m,2H),2.03(s,2H),1.42(t,J＝9.4Hz,4H),1.22(s,2H). N-cyclohexyl-5-(3-(4-methoxyphenyl)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine at room temperature (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), separated and purified by column chromatography to obtain the product 1-cyclohexyl-2-(4-methoxybenzyl)-1,6-dihydrodipyrrolo[2 , 3-b: 2',3'-d]pyridine 301.5 mg, yield 60.2%. mp193.6-195.0°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.51(s,1H),7.99(d,J=1.8Hz,1H),7.34(t,J=9.7Hz,3H),7.17(s,2H) ,6.52(s,1H),5.64(d,J=8.7Hz,1H),4.10(s,1H),3.89(s,2H),3.79(s,3H)2.34–2.31(m,2H),2.03 (s,2H),1.42(t,J=9.4Hz,4H),1.22(s,2H).
实施例10Example 10
步骤1：(丙-2-炔-1-基氧基)苯的制备Step 1: Preparation of (prop-2-yn-1-yloxy)benzene
Figure PCTCN2022093052-appb-000046
Figure PCTCN2022093052-appb-000046
将苯酚(10.6mmol)，3-溴丙炔(1.5g，12.7mmol)，K 2CO 3(5.8g，42.4mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝80:1)，经柱层析分离纯化得到产物(丙-2-炔-1-基氧基)苯1.29g，收率91.8％。 1H NMR(300MHz,CDCl 3)δ7.34–7.26(m,2H),6.91(m,J＝7.5,2.0Hz,1H),6.89–6.82(m,2H),4.68(d,J＝2.9Hz,2H),2.99(t,J＝3.0Hz,1H). Phenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K 2 CO 3 (5.8g, 42.4mmol) were added to 25ml of acetone, and heated to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave crude compound, which was purified by silica gel chromatography (PE:EA=80:1), separated and purified by column chromatography to obtain the product (prop-2-yn-1-yloxy)benzene 1.29g, yield 91.8%. 1 H NMR (300MHz, CDCl 3 ) δ7.34–7.26 (m, 2H), 6.91 (m, J=7.5, 2.0Hz, 1H), 6.89–6.82 (m, 2H), 4.68 (d, J=2.9 Hz,2H),2.99(t,J=3.0Hz,1H).
步骤2：4-氯-5-(3-苯氧基-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 2: Preparation of 4-chloro-5-(3-phenoxy-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000047
Figure PCTCN2022093052-appb-000047
将中间体4(1g，3.6mmol)，(丙-2-炔-1-基氧基)苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-苯氧基-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶810.1mg，收率79.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.81(s,1H),7.34–7.26(m,2H),7.19(d,J＝7.5Hz,1H),6.90(m,J＝15.3,7.6,2.0Hz,3H),6.67(d,J＝7.5Hz,1H),4.68(s,2H). Intermediate 4 (1 g, 3.6 mmol), (prop-2-yn-1-yloxy)benzene (4.3 mmol), Pd(PPh 3 ) 2 Cl 2 (126 mg, 0.18 mmol), CuI (34 mg, 0.18 mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-phenoxy-1-yn-1-yl)-1H-pyrrolo[2 ,3-b]pyridine 810.1 mg, yield 79.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.81(s, 1H), 7.34–7.26(m, 2H), 7.19(d, J=7.5Hz, 1H), 6.90(m, J=15.3,7.6,2.0Hz,3H),6.67(d,J=7.5Hz,1H),4.68(s,2H).
步骤3：N-环己基-5-(3-苯氧基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: Preparation of N-cyclohexyl-5-(3-phenoxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000048
Figure PCTCN2022093052-appb-000048
将化合物4-氯-5-(3-苯氧基-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-苯氧基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺473mg，收率52.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.50(s,1H),7.30(t,J＝7.5Hz,2H),7.18(d,J＝7.5Hz,1H),6.94–6.85(m,3H),6.78(d,J＝7.5Hz,1H),5.41(s,1H),4.68(s,2H),3.85(s,1H),2.10–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.68–1.57(m,4H),1.38(m,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(3-phenoxy-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol) , t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol ) into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-phenoxyprop-1-yn-1-yl)-1H-pyrrolo [2,3-b]pyridin-4-amine 473 mg, yield 52.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.50(s, 1H), 7.30(t, J=7.5Hz, 2H), 7.18(d, J=7.5Hz, 1H), 6.94 –6.85(m,3H),6.78(d,J＝7.5Hz,1H),5.41(s,1H),4.68(s,2H),3.85(s,1H),2.10–2.01(m,2H), 1.80(m, J=13.1,6.0Hz,2H),1.68–1.57(m,4H),1.38(m,J=12.9,6.9Hz,2H).
步骤4：1-环己基-2-(苯氧基甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 4: Preparation of 1-cyclohexyl-2-(phenoxymethyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000049
Figure PCTCN2022093052-appb-000049
在室温下向N-环己基-5-(3-苯氧基丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-环己基-2-(苯氧基甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶262.5mg，收率52.5％。m.p.174.6-176.1℃。 1H NMR(300MHz,DMSO-d 6)δ11.46(s,1H),7.97(s,1H),7.46(s,3H),7.18(s,1H),7.08(s,1H),7.05(s,1H),6.54(s,1H),5.60(d,J＝8.8Hz,1H),5.15(s,2H),4.07(s,1H),2.03(s,2H),1.72(s,2H),1.40(s,4H),1.20(d,J＝16.9Hz,2H). To N-cyclohexyl-5-(3-phenoxyprop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography yielded 262.5 mg of the product 1-cyclohexyl-2-(phenoxymethyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine, Yield 52.5%. mp174.6-176.1°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.46(s,1H),7.97(s,1H),7.46(s,3H),7.18(s,1H),7.08(s,1H),7.05( s,1H),6.54(s,1H),5.60(d,J＝8.8Hz,1H),5.15(s,2H),4.07(s,1H),2.03(s,2H),1.72(s,2H ),1.40(s,4H),1.20(d,J=16.9Hz,2H).
实施例11Example 11
步骤1：1-甲基-4-(丙-2-炔-1-基氧基)苯的制备Step 1: Preparation of 1-methyl-4-(prop-2-yn-1-yloxy)benzene
Figure PCTCN2022093052-appb-000050
Figure PCTCN2022093052-appb-000050
将对甲苯酚(10.6mmol)，3-溴丙炔(1.5g，12.7mmol)，K 2CO 3(5.8g，42.4mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝80:1)，经柱层析分离纯化得到产物1-甲基-4-(丙-2-炔-1-基氧基)苯1.45g，收率93.6％。 1H NMR(300MHz,CDCl 3)δ7.08–7.02(m,2H),6.79–6.72(m,2H),4.68(d,J＝2.9Hz,2H),2.99(t,J＝3.0Hz,1H),2.31(d,J＝1.4Hz,3H). Add p-cresol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K 2 CO 3 (5.8g, 42.4mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave the crude compound, which was purified by silica gel chromatography (PE:EA=80:1), separated and purified by column chromatography to give the product 1-methyl-4-(prop-2-yne- 1-yloxy)benzene 1.45g, yield 93.6%. 1 H NMR (300MHz, CDCl 3 )δ7.08–7.02(m,2H),6.79–6.72(m,2H),4.68(d,J=2.9Hz,2H),2.99(t,J=3.0Hz, 1H), 2.31(d, J=1.4Hz, 3H).
步骤2：4-氯-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 2: Preparation of 4-chloro-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000051
Figure PCTCN2022093052-appb-000051
将中间体4(1g，3.6mmol，参照实施例1中的制备办法)，1-甲基-4-(丙-2-炔-1-基氧基)苯4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶804.5mg，收率75.5％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.81(s,1H),7.19(d,J＝7.5Hz,1H),7.10–7.04(m,2H),6.82–6.75(m,2H),6.67(d,J＝7.5Hz,1H),4.68(s,2H),2.31(d,J＝2.1Hz,1H),2.31(s,2H). Intermediate 4 (1g, 3.6mmol, referring to the preparation method in Example 1), 1-methyl-4-(prop-2-yn-1-yloxy)benzene 4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H - 804.5 mg of pyrrolo[2,3-b]pyridine, yield 75.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.81(s, 1H), 7.19(d, J=7.5Hz, 1H), 7.10-7.04(m, 2H), 6.82-6.75( m,2H),6.67(d,J=7.5Hz,1H),4.68(s,2H),2.31(d,J=2.1Hz,1H),2.31(s,2H).
步骤3：N-环己基-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: Preparation of N-cyclohexyl-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000052
Figure PCTCN2022093052-appb-000052
将化合物4-氯-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺450.8mg，收率48.3％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.53(s,1H),7.20(d,J＝7.5Hz,1H),7.11(d,J＝7.5Hz,2H),6.89(d,J＝7.5Hz,2H),6.79(d,J＝7.5Hz,1H),4.68(s,2H),3.89(s,1H),3.81(s,1H),2.31(s,3H),1.90(m,J＝13.5,6.3Hz,2H),1.68–1.57(m,4H),1.48–1.38(m,2H),1.19(m,J＝13.0,6.7Hz,2H). Compound 4-chloro-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine ( 600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(p-tolyloxy)prop-1-yn-1-yl)- 1H-pyrrolo[2,3-b]pyridin-4-amine 450.8 mg, yield 48.3%. 1 H NMR (300MHz, CDCl 3 )δ11.12(s,1H),8.53(s,1H),7.20(d,J=7.5Hz,1H),7.11(d,J=7.5Hz,2H),6.89 (d,J=7.5Hz,2H),6.79(d,J=7.5Hz,1H),4.68(s,2H),3.89(s,1H),3.81(s,1H),2.31(s,3H) ,1.90(m,J＝13.5,6.3Hz,2H),1.68–1.57(m,4H),1.48–1.38(m,2H),1.19(m,J＝13.0,6.7Hz,2H).
步骤4：1-环己基-2-((对-甲苯基氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 4: Preparation of 1-cyclohexyl-2-((p-tolyloxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000053
Figure PCTCN2022093052-appb-000053
在室温下向N-环己基-5-(3-(对甲苯基氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-环己基-2-((对-甲苯基氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶293.2mg，收率58.6％。m.p.168.6-170.9℃。 1H NMR(300MHz,DMSO-d 6)δ11.47(s,1H),7.99(s,1H),7.43(d,J＝7.8Hz,2H),7.31–7.15(m,3H),6.55(s,1H),5.62(d,J＝8.6Hz,1H),5.17(s,2H),4.11(s,1H),2.34(s,3H),2.03(s,2H),1.73(s,2H),1.41(s,4H),1.23(s,2H). To N-cyclohexyl-5-(3-(p-tolyloxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Purified by column chromatography to obtain the product 1-cyclohexyl-2-((p-tolyloxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d ] Pyridine 293.2mg, yield 58.6%. mp168.6-170.9°C. 1 H NMR (300MHz, DMSO-d 6 ) δ11.47(s, 1H), 7.99(s, 1H), 7.43(d, J=7.8Hz, 2H), 7.31–7.15(m, 3H), 6.55( s,1H),5.62(d,J=8.6Hz,1H),5.17(s,2H),4.11(s,1H),2.34(s,3H),2.03(s,2H),1.73(s,2H ),1.41(s,4H),1.23(s,2H).
实施例12Example 12
步骤1：1-氟-4-(丙-2-炔-1-基氧基)苯的制备Step 1: Preparation of 1-fluoro-4-(prop-2-yn-1-yloxy)benzene
Figure PCTCN2022093052-appb-000054
Figure PCTCN2022093052-appb-000054
将对氟苯酚(10.6mmol)，3-溴丙炔(1.5g，12.7mmol)，K 2CO 3(5.8g，42.4mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝80:1)，经柱层析分离纯化得到产物1-氟-4-(丙-2-炔-1-基氧基)苯1.43g，收率90.5％。 1H NMR(300MHz,CDCl 3)δ7.06–6.98(m,2H),6.84–6.76(m,2H),4.68(d,J＝2.9Hz,2H),3.00(t,J＝3.0Hz,1H). Add p-fluorophenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K 2 CO 3 (5.8g, 42.4mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave crude compound, which was purified by silica gel chromatography (PE:EA=80:1), separated and purified by column chromatography to give the product 1-fluoro-4-(prop-2-yne-1 -yloxy)benzene 1.43g, yield 90.5%. 1 H NMR (300MHz, CDCl 3 )δ7.06–6.98(m,2H),6.84–6.76(m,2H),4.68(d,J=2.9Hz,2H),3.00(t,J=3.0Hz, 1H).
步骤2：4-氯-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 2: Preparation of 4-chloro-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000055
Figure PCTCN2022093052-appb-000055
将中间体4(1g，3.6mmol，参照实施例1中的制备办法)，1-氟-4-(丙-2-炔-1-基氧基)苯4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶785.2mg，收率72.7％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.80(s,1H),7.19(d,J＝7.5Hz,1H),7.08–7.00(m,2H),6.89–6.81(m,2H),6.67(d,J＝7.5Hz,1H),4.68(s,2H). Intermediate 4 (1g, 3.6mmol, refer to the preparation method in Example 1), 1-fluoro-4-(prop-2-yn-1-yloxy)benzene 4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)- 1H-pyrrolo[2,3-b]pyridine 785.2 mg, yield 72.7%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.80(s, 1H), 7.19(d, J=7.5Hz, 1H), 7.08–7.00(m, 2H), 6.89–6.81( m,2H),6.67(d,J=7.5Hz,1H),4.68(s,2H).
步骤3：N-环己基-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: Preparation of N-cyclohexyl-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000056
Figure PCTCN2022093052-appb-000056
将化合物4-氯-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺521.9mg，收率55.3％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.50(s,1H),7.18(d,J＝7.5Hz,1H),7.04(dd,J＝9.0,7.5Hz,2H),6.80(dd,J＝21.4,7.5Hz,3H),5.42(s,1H),4.68(s,2H),3.85(s,1H),2.05(dd,J＝13.5,6.4Hz,2H),1.85–1.76(m,2H),1.67–1.57(m,4H),1.38(m,J＝13.1,6.6Hz,2H). Compound 4-chloro-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl) - 1H-pyrrolo[2,3-b]pyridin-4-amine 521.9 mg, yield 55.3%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.50(s, 1H), 7.18(d, J=7.5Hz, 1H), 7.04(dd, J=9.0, 7.5Hz, 2H) ,6.80(dd,J=21.4,7.5Hz,3H),5.42(s,1H),4.68(s,2H),3.85(s,1H),2.05(dd,J=13.5,6.4Hz,2H), 1.85–1.76(m,2H),1.67–1.57(m,4H),1.38(m,J＝13.1,6.6Hz,2H).
步骤4：1-环己基-2-((4-氟苯氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 4: Preparation of 1-cyclohexyl-2-((4-fluorophenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000057
Figure PCTCN2022093052-appb-000057
在室温下向N-环己基-5-(3-(4-氟苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-环己基-2-((4-氟苯氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶268.5mg，收率53.7％。m.p.164.1-166.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.55(s,1H),8.76(s,1H),8.54(s,1H),7.99(d,J＝19.8Hz,2H),7.45(s,1H),7.20(s,1H),6.57(s,1H),5.80(s,1H),5.23(s,2H),4.07(s,1H),2.03(s,2H),1.74(s,2H),1.43(s,4H),1.21(s,2H). To N-cyclohexyl-5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine at room temperature ( 1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Purified by column chromatography to obtain the product 1-cyclohexyl-2-((4-fluorophenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d ] Pyridine 268.5 mg, yield 53.7%. mp164.1-166.0°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.55(s,1H),8.76(s,1H),8.54(s,1H),7.99(d,J=19.8Hz,2H),7.45(s, 1H),7.20(s,1H),6.57(s,1H),5.80(s,1H),5.23(s,2H),4.07(s,1H),2.03(s,2H),1.74(s,2H ),1.43(s,4H),1.21(s,2H).
实施例13Example 13
步骤1：1-甲氧基-4-(丙-2-炔-1-基氧基)苯的制备Step 1: Preparation of 1-methoxy-4-(prop-2-yn-1-yloxy)benzene
Figure PCTCN2022093052-appb-000058
Figure PCTCN2022093052-appb-000058
将对氟苯酚(10.6mmol)，3-溴丙炔(1.5g，12.7mmol)，K 2CO 3(5.8g，42.4mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝80:1)，经柱层析分离纯化得到产物1-甲氧基-4-(丙-2-炔-1-基氧基)苯1.58g，收率92.1％。 1H NMR(300MHz,CDCl 3)δ6.78(s,4H),4.68(d,J＝2.9Hz,2H),3.80(s,3H),2.99(t,J＝2.9Hz,1H). Add p-fluorophenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K 2 CO 3 (5.8g, 42.4mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave crude compound, which was purified by silica gel chromatography (PE:EA=80:1), separated and purified by column chromatography to obtain the product 1-methoxy-4-(prop-2-yne -1-yloxy)benzene 1.58g, yield 92.1%. 1 H NMR (300MHz, CDCl 3 ) δ6.78(s, 4H), 4.68(d, J=2.9Hz, 2H), 3.80(s, 3H), 2.99(t, J=2.9Hz, 1H).
步骤2：4-氯-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶的制备Step 2: Preparation of 4-chloro-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000059
Figure PCTCN2022093052-appb-000059
将中间体4(1g，3.6mmol，参照实施例1中的制备办法)，1-氟-4-(丙-2-炔-1-基氧基)苯4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，经柱层析分离纯化得到产物4-氯-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶828.9mg，收率73.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.81(s,1H),7.19(d,J＝7.5Hz,1H),6.86–6.77(m,4H),6.67(d,J＝7.5Hz,1H),4.68(s,2H),3.80(s,3H). Intermediate 4 (1g, 3.6mmol, refer to the preparation method in Example 1), 1-fluoro-4-(prop-2-yn-1-yloxy)benzene 4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1), separated and purified by column chromatography to obtain the product 4-chloro-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl )-1H-pyrrolo[2,3-b]pyridine 828.9 mg, yield 73.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.81(s, 1H), 7.19(d, J=7.5Hz, 1H), 6.86–6.77(m, 4H), 6.67(d, J＝7.5Hz,1H),4.68(s,2H),3.80(s,3H).
步骤3：N-环己基-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: N-cyclohexyl-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation of
Figure PCTCN2022093052-appb-000060
Figure PCTCN2022093052-appb-000060
将化合物4-氯-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，经柱层析分离纯化得到产物N-环己基-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺560.2mg，收率57.5％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.49(s,1H),7.18(d,J＝7.5Hz,1H),6.84–6.75(m,5H),5.45(s,1H),4.68(s,2H),3.85(s,1H),3.80(s,3H),2.05(dd,J＝13.0,7.0Hz,2H),1.85–1.76(m,2H),1.68–1.57(m,4H),1.38(m,J＝13.1,6.5Hz,2H). Compound 4-chloro-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), ring Hexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 ( dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1), separated and purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(4-methoxyphenoxy)prop-1-yne-1- Base)-1H-pyrrolo[2,3-b]pyridin-4-amine 560.2 mg, yield 57.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.49(s, 1H), 7.18(d, J=7.5Hz, 1H), 6.84–6.75(m, 5H), 5.45(s, 1H), 4.68(s, 2H), 3.85(s, 1H), 3.80(s, 3H), 2.05(dd, J＝13.0, 7.0Hz, 2H), 1.85–1.76(m, 2H), 1.68–1.57 (m,4H),1.38(m,J=13.1,6.5Hz,2H).
步骤4：1-环己基-2-((4-甲氧基苯氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 4: 1-cyclohexyl-2-((4-methoxyphenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine preparation of
Figure PCTCN2022093052-appb-000061
Figure PCTCN2022093052-appb-000061
在室温下向N-环己基-5-(3-(4-甲氧基苯氧基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物1-环己基-2-((4-甲氧基苯氧基)甲基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶253.5mg，收率50.7％。m.p.180.2-183.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.63(s,1H),8.45(s,1H),8.12(s,1H),7.69–7.57(m,2H),7.48(s,1H),7.10–6.96(m,2H),6.47(s, 1H),5.54(s,2H),4.27(s,1H),3.80(d,J＝3.0Hz,3H),1.71(d,J＝12.1Hz,2H),1.60(s,2H),1.34–1.08(m,4H),1.04(d,J＝11.4Hz,2H). To N-cyclohexyl-5-(3-(4-methoxyphenoxy)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-4- To a mixture of amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Purified by column chromatography to obtain the product 1-cyclohexyl-2-((4-methoxyphenoxy)methyl)-1,6-dihydrodipyrrolo[2,3-b:2',3' -d] Pyridine 253.5 mg, yield 50.7%. mp180.2-183.0°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.63(s,1H),8.45(s,1H),8.12(s,1H),7.69–7.57(m,2H),7.48(s,1H), 7.10–6.96(m,2H),6.47(s,1H),5.54(s,2H),4.27(s,1H),3.80(d,J＝3.0Hz,3H),1.71(d,J＝12.1Hz ,2H),1.60(s,2H),1.34–1.08(m,4H),1.04(d,J＝11.4Hz,2H).
实施例14Example 14
步骤1：N-(丙-2-炔-1-基)苯胺的制备Step 1: Preparation of N-(prop-2-yn-1-yl)aniline
Figure PCTCN2022093052-appb-000062
Figure PCTCN2022093052-appb-000062
将苯胺(10.7mmol)，3-溴丙炔(1.5g，12.8mmol)，K 2CO 3(5.9g，42.8mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝50:1)，经柱层析分离纯化得到产物N-(丙-2-炔-1-基)苯胺1.13g，收率78.8％。 1H NMR(300MHz,CDCl 3)δ7.03(t,J＝7.4Hz,2H),6.71(m,J＝7.5,2.0Hz,1H),6.60–6.53(m,2H),4.24(s,1H),3.80(d,J＝2.9Hz,2H),2.87(t,J＝2.9Hz,1H). Add aniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave the crude compound, which was purified by silica gel chromatography (PE:EA=50:1), separated and purified by column chromatography to give the product N-(prop-2-yn-1-yl)aniline 1.13g, yield 78.8%. 1 H NMR (300MHz, CDCl 3 ) δ7.03(t, J=7.4Hz, 2H), 6.71(m, J=7.5, 2.0Hz, 1H), 6.60–6.53(m, 2H), 4.24(s, 1H), 3.80(d, J=2.9Hz, 2H), 2.87(t, J=2.9Hz, 1H).
步骤2：N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)苯胺的制备Step 2: Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)aniline
Figure PCTCN2022093052-appb-000063
Figure PCTCN2022093052-appb-000063
将中间体4(1g，3.6mmol，参照实施例1的制备)，N-(丙-2-炔-1-基)苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝8:1)，经柱层析分离纯化得到产物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)苯胺735.4mg，收率72.8％。 1H NMR(300MHz,CDCl 3)δ1.12(s,1H),8.79(s,1H),7.19(d,J＝7.5Hz,1H),7.08–7.01(m,2H),6.75–6.64(m,2H),6.63–6.56(m,2H),4.29(s,1H),3.80(s,2H). Intermediate 4 (1g, 3.6mmol, refer to the preparation of Example 1), N-(prop-2-yn-1-yl)aniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol ), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=8:1), separated and purified by column chromatography to obtain the product N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)propane -2-yn-1-yl)aniline 735.4 mg, yield 72.8%. 1 H NMR (300MHz, CDCl 3 ) δ1.12(s, 1H), 8.79(s, 1H), 7.19(d, J=7.5Hz, 1H), 7.08-7.01(m, 2H), 6.75-6.64( m,2H),6.63–6.56(m,2H),4.29(s,1H),3.80(s,2H).
步骤3：N-环己基-5-(3-(苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: Preparation of N-cyclohexyl-5-(3-(phenylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000064
Figure PCTCN2022093052-appb-000064
将化合物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)苯胺(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)。经柱层析分离纯化得到产物N-环己基-5-(3-(苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺499.6mg，收率55.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.60(s,1H),7.25(d,J＝7.5Hz,1H),7.05(t,J＝7.5Hz,2H),6.83(d,J＝7.5Hz,1H),6.71(t,J＝7.5Hz,1H),6.60(d,J＝7.5Hz,2H),4.39(s,1H),4.01(s,1H),3.80(s,2H),2.42(s,1H),2.01(dd,J＝13.5,6.3Hz,2H),1.79–1.57(m,6H),1.39–1.25(m,2H). The compound N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)aniline (2.6mmol), cyclohexylamine (600ul , 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 ( 75mg, 0.13mmol) was added into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by chromatography on silica gel (PE:EA=2:1). Separation and purification by column chromatography to obtain the product N-cyclohexyl-5-(3-(phenylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine 499.6 mg, yield 55.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.60(s, 1H), 7.25(d, J=7.5Hz, 1H), 7.05(t, J=7.5Hz, 2H), 6.83 (d,J=7.5Hz,1H),6.71(t,J=7.5Hz,1H),6.60(d,J=7.5Hz,2H),4.39(s,1H),4.01(s,1H),3.80 (s,2H),2.42(s,1H),2.01(dd,J＝13.5,6.3Hz,2H),1.79–1.57(m,6H),1.39–1.25(m,2H).
步骤4：N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)苯胺的制备Step 4: Preparation of N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)aniline
Figure PCTCN2022093052-appb-000065
Figure PCTCN2022093052-appb-000065
在室温下向N-环己基-5-(3-(苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝1:1)，经柱层析分离纯化得到产物N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)苯胺268.4mg，收率53.6％。m.p.167.6-171.0℃。 1H NMR(300MHz,DMSO-d6)δ11.45(s,1H),7.86(s,1H),7.16(d,J＝7.9Hz,2H),6.77(d,J＝8.0Hz,2H),6.66(t,J＝7.3Hz,1H),6.47(d,J＝3.5Hz,1H),6.17(t,J＝6.4Hz,1H),5.24(d,J＝8.7Hz,1H),4.21(d,J＝6.3Hz,2H),3.88(d,J＝9.8Hz,1H),1.93–1.86(m,2H),1.66(s,2H),1.39(d,J＝12.7Hz,2H),1.22–1.10(m,2H),1.11–1.00(m,2H). To N-cyclohexyl-5-(3-(phenylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) at room temperature To a mixture with THF (10 ml) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=1:1), separated and purified by column chromatography to obtain the product N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridin-2-yl)methyl)aniline 268.4 mg, yield 53.6%. mp167.6-171.0°C. 1 H NMR (300MHz, DMSO-d6) δ11.45(s, 1H), 7.86(s, 1H), 7.16(d, J=7.9Hz, 2H), 6.77(d, J=8.0Hz, 2H), 6.66(t, J=7.3Hz, 1H), 6.47(d, J=3.5Hz, 1H), 6.17(t, J=6.4Hz, 1H), 5.24(d, J=8.7Hz, 1H), 4.21( d,J=6.3Hz,2H),3.88(d,J=9.8Hz,1H),1.93–1.86(m,2H),1.66(s,2H),1.39(d,J=12.7Hz,2H), 1.22–1.10(m,2H),1.11–1.00(m,2H).
实施例15Example 15
步骤1：N-(丙-2-炔-1-基)苯胺的制备Step 1: Preparation of N-(prop-2-yn-1-yl)aniline
Figure PCTCN2022093052-appb-000066
Figure PCTCN2022093052-appb-000066
将对甲基苯胺(10.7mmol)，3-溴丙炔(1.5g，12.8mmol)，K 2CO 3(5.9g，42.8mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝50:1)，经柱层析分离纯化得到产物N-(丙-2-炔-1-基)苯胺1.12g，收率73.7％。 1H NMR(300MHz,CDCl 3)δ6.81–6.75(m,2H),6.56–6.50(m,2H),4.08(s,1H),3.80(d,J＝2.9Hz,2H),2.88(t,J＝3.0Hz,1H),2.33(d,J＝1.2Hz,3H). Add p-methylaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave the crude compound, which was purified by silica gel chromatography (PE:EA=50:1), separated and purified by column chromatography to give the product N-(prop-2-yn-1-yl)aniline 1.12g, yield 73.7%. 1 H NMR (300MHz, CDCl 3 ) δ6.81–6.75 (m, 2H), 6.56–6.50 (m, 2H), 4.08 (s, 1H), 3.80 (d, J=2.9Hz, 2H), 2.88 ( t,J=3.0Hz,1H),2.33(d,J=1.2Hz,3H).
步骤2：N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲基苯胺的制备Step 2: Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-methylaniline
Figure PCTCN2022093052-appb-000067
Figure PCTCN2022093052-appb-000067
将中间体4(1g，3.6mmol，参照实施例1的制备)，N-(丙-2-炔-1-基)苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝8:1)，经柱层析分离纯化得到产物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲基苯胺791.2mg，收率74.5％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.80(s,1H),7.19(d,J＝7.5Hz,1H),6.83–6.77(m,2H),6.67(d,J＝7.5Hz,1H),6.59–6.52(m,2H),4.24(s,1H),3.80(s,2H),2.33(s,2H),2.33(d,J＝2.1Hz,1H) Intermediate 4 (1g, 3.6mmol, refer to the preparation of Example 1), N-(prop-2-yn-1-yl)aniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol ), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=8:1), separated and purified by column chromatography to obtain the product N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)propane -2-Alkyn-1-yl)-4-methylaniline 791.2 mg, yield 74.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.80(s, 1H), 7.19(d, J=7.5Hz, 1H), 6.83–6.77(m, 2H), 6.67(d, J=7.5Hz, 1H), 6.59–6.52(m, 2H), 4.24(s, 1H), 3.80(s, 2H), 2.33(s, 2H), 2.33(d, J=2.1Hz, 1H)
步骤3：N-环己基-5-(3-(对甲苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: Preparation of N-cyclohexyl-5-(3-(p-tolylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000068
Figure PCTCN2022093052-appb-000068
将化合物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲基苯胺(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)。经柱层析分离纯化得到产物N-环己基-5-(3-(对甲苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺497.5mg，收率53.4％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.60(s,1H),7.25(d,J＝7.5Hz,1H),6.82(dd,J＝14.5,7.4Hz,3H),6.57(d,J＝7.5Hz,2H),4.22(s,1H),4.01(s,1H),3.80(s,2H),2.40(s,1H),2.33(s,3H),2.06–1.97(m,2H),1.80–1.62(m,4H),1.61(dd,J＝6.4,1.6Hz,2H),1.32(dd,J＝13.5,6.3Hz,2H). The compound N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-methylaniline (2.6mmol), Cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by chromatography on silica gel (PE:EA=2:1). Purified by column chromatography to obtain the product N-cyclohexyl-5-(3-(p-tolylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-4- Amine 497.5 mg, yield 53.4%. 1 H NMR (300MHz, CDCl 3 )δ11.12(s,1H),8.60(s,1H),7.25(d,J=7.5Hz,1H),6.82(dd,J=14.5,7.4Hz,3H) ,6.57(d,J=7.5Hz,2H),4.22(s,1H),4.01(s,1H),3.80(s,2H),2.40(s,1H),2.33(s,3H),2.06– 1.97(m,2H),1.80–1.62(m,4H),1.61(dd,J=6.4,1.6Hz,2H),1.32(dd,J=13.5,6.3Hz,2H).
步骤4：N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-甲基苯胺的制备Step 4: N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)-4-methyl Preparation of aniline
Figure PCTCN2022093052-appb-000069
Figure PCTCN2022093052-appb-000069
在室温下向N-环己基-5-(3-(对甲苯基氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝1:1)，经柱层析分离纯化得到产物N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-甲基苯胺237.6mg，收率47.6％。m.p.166.6-177.7℃。 1H NMR(300MHz,DMSO-d6)δ11.46(s,2H),7.86(s,2H),7.18(s,2H),6.84(dd,J＝94.0,7.8Hz,10H),6.46(s,2H),5.96(t,J＝6.5Hz,2H),5.16(d,J＝8.7Hz,2H),4.18(d,J＝6.5Hz,4H),3.86(s,2H),2.21(s,6H),1.91–1.83(m,4H),1.66(s,4H),1.39(d,J＝11.8Hz,4H),1.19(d,J＝8.6Hz,4H),1.01(d,J＝11.9Hz,4H),0.88(s,1H). To N-cyclohexyl-5-(3-(p-tolylamino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol ) and THF (10ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=1:1), separated and purified by column chromatography to obtain the product N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridin-2-yl)methyl)-4-methylaniline 237.6 mg, yield 47.6%. mp166.6-177.7°C. 1 H NMR (300MHz, DMSO-d6) δ11.46(s, 2H), 7.86(s, 2H), 7.18(s, 2H), 6.84(dd, J=94.0, 7.8Hz, 10H), 6.46(s ,2H),5.96(t,J=6.5Hz,2H),5.16(d,J=8.7Hz,2H),4.18(d,J=6.5Hz,4H),3.86(s,2H),2.21(s ,6H),1.91–1.83(m,4H),1.66(s,4H),1.39(d,J＝11.8Hz,4H),1.19(d,J＝8.6Hz,4H),1.01(d,J＝ 11.9Hz,4H),0.88(s,1H).
实施例16Example 16
步骤1：4-氟-N-(丙-2-炔-1-基)苯胺的制备Step 1: Preparation of 4-fluoro-N-(prop-2-yn-1-yl)aniline
Figure PCTCN2022093052-appb-000070
Figure PCTCN2022093052-appb-000070
将对氟苯胺(10.7mmol)，3-溴丙炔(1.5g，12.8mmol)，K 2CO 3(5.9g，42.8mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝50:1)，经柱层析分离纯化得到产物4-氟-N-(丙-2-炔-1-基)苯胺1.21g，收率80.5％。 1H NMR(300MHz,CDCl 3)δ6.89–6.81(m,2H),6.59–6.51(m,2H),3.95(s,1H),3.80(d,J＝2.9Hz,2H), 2.87(t,J＝2.9Hz,1H). Add p-fluoroaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave crude compound, which was purified by silica gel chromatography (PE:EA=50:1), separated and purified by column chromatography to give the product 4-fluoro-N-(prop-2-yne-1 -yl) aniline 1.21g, yield 80.5%. 1 H NMR (300MHz, CDCl 3 ) δ6.89–6.81(m,2H),6.59–6.51(m,2H),3.95(s,1H),3.80(d,J=2.9Hz,2H), 2.87( t,J=2.9Hz,1H).
步骤2：N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-氟苯胺的制备Step 2: Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-fluoroaniline
Figure PCTCN2022093052-appb-000071
Figure PCTCN2022093052-appb-000071
将中间体4(1g，3.6mmol，参照实施例1的制备)，4-氟-N-(丙-2-炔-1-基)苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝8:1)，经柱层析分离纯化得到产物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-氟苯胺837.4mg，收率77.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.79(s,1H),7.19(d,J＝7.5Hz,1H),6.91–6.83(m,2H),6.67(d,J＝7.5Hz,1H),6.61–6.53(m,2H),4.10(s,1H),3.80(s,2H). Intermediate 4 (1g, 3.6mmol, referring to the preparation of Example 1), 4-fluoro-N-(prop-2-yn-1-yl)aniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 ( 126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=8:1), separated and purified by column chromatography to obtain the product N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)propane -2-Alkyn-1-yl)-4-fluoroaniline 837.4 mg, yield 77.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.79(s, 1H), 7.19(d, J=7.5Hz, 1H), 6.91–6.83(m, 2H), 6.67(d, J＝7.5Hz,1H),6.61–6.53(m,2H),4.10(s,1H),3.80(s,2H).
步骤3：N-环己基-5-(3-((4-氟苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: N-cyclohexyl-5-(3-((4-fluorophenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine preparation of
Figure PCTCN2022093052-appb-000072
Figure PCTCN2022093052-appb-000072
将化合物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-氟苯胺(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)。经柱层析分离纯化得到产物N-环己基-5-(3-((4-氟苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺468.7mg，收率49.8％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.52(s,1H),7.19(d,J＝7.5Hz,1H),6.87(dd,J＝9.0,7.5Hz,2H),6.78(d,J＝7.5Hz,1H),6.57(d,J＝7.5Hz,2H),5.03(s,1H),4.06(s,1H),3.85(s,1H),3.80(s,2H),2.09–2.00(m,2H),1.80(m,J＝13.1,5.9Hz,2H),1.67–1.56(m,4H),1.38(dd,J＝12.9,7.0Hz,2H). Compound N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-fluoroaniline (2.6mmol), ring Hexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 ( dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by chromatography on silica gel (PE:EA=2:1). Separation and purification by column chromatography to obtain the product N-cyclohexyl-5-(3-((4-fluorophenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b] Pyridin-4-amine 468.7 mg, yield 49.8%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.52(s, 1H), 7.19(d, J=7.5Hz, 1H), 6.87(dd, J=9.0, 7.5Hz, 2H) ,6.78(d,J=7.5Hz,1H),6.57(d,J=7.5Hz,2H),5.03(s,1H),4.06(s,1H),3.85(s,1H),3.80(s, 2H),2.09–2.00(m,2H),1.80(m,J＝13.1,5.9Hz,2H),1.67–1.56(m,4H),1.38(dd,J＝12.9,7.0Hz,2H).
步骤4：N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-氟苯胺的制备Step 4: N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)-4-fluoroaniline preparation of
Figure PCTCN2022093052-appb-000073
Figure PCTCN2022093052-appb-000073
在室温下向N-环己基-5-(3-((4-氟苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物， 通过硅胶色谱法纯化(PE：EA＝1:1)，经柱层析分离纯化得到产物N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-氟苯胺225.6mg，收率49.7％。m.p.180.9-183.3℃。 1H NMR(300MHz,DMSO-d 6)δ11.45(s,1H),7.86(s,1H),7.18(d,J＝2.9Hz,1H),7.06–7.00(m,2H),6.78–6.74(m,2H),6.47(dd,J＝3.7,1.7Hz,1H),6.12(t,J＝6.5Hz,1H),5.17(d,J＝8.8Hz,1H),4.20(d,J＝6.5Hz,2H),3.87(d,J＝9.0Hz,1H),1.89(d,J＝12.5Hz,2H),1.66(s,2H),1.39(d,J＝12.5Hz,2H),1.20(dd,J＝24.3,13.0Hz,2H),1.02(dd,J＝12.7,9.7Hz,2H). N-cyclohexyl-5-(3-((4-fluorophenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-4- To a mixture of amine (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was passed through Purified by silica gel chromatography (PE:EA=1:1), separated and purified by column chromatography to obtain the product N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridin-2-yl)methyl)-4-fluoroaniline 225.6 mg, yield 49.7%. mp180.9-183.3°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.45(s,1H),7.86(s,1H),7.18(d,J=2.9Hz,1H),7.06–7.00(m,2H),6.78– 6.74(m,2H),6.47(dd,J=3.7,1.7Hz,1H),6.12(t,J=6.5Hz,1H),5.17(d,J=8.8Hz,1H),4.20(d,J =6.5Hz,2H),3.87(d,J=9.0Hz,1H),1.89(d,J=12.5Hz,2H),1.66(s,2H),1.39(d,J=12.5Hz,2H), 1.20(dd,J=24.3,13.0Hz,2H),1.02(dd,J=12.7,9.7Hz,2H).
实施例17Example 17
步骤1：4-甲氧基-N-(丙-2-炔-1-基)苯胺的制备Step 1: Preparation of 4-methoxy-N-(prop-2-yn-1-yl)aniline
Figure PCTCN2022093052-appb-000074
Figure PCTCN2022093052-appb-000074
将对甲氧基苯胺(10.7mmol)，3-溴丙炔(1.5g，12.8mmol)，K 2CO 3(5.9g，42.8mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝50:1)，经柱层析分离纯化得到产物4-甲氧基-N-(丙-2-炔-1-基)苯胺1.26g，收率73.4％。 1H NMR(300MHz,CDCl 3)δ6.63–6.57(m,2H),6.54–6.47(m,2H),3.89(s,1H),3.80(d,J＝3.2Hz,2H),3.80(s,3H),2.86(t,J＝3.0Hz,1H). Add p-methoxyaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) into 25ml of acetone, and heat to reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Drying over sodium and concentrating under reduced pressure gave crude compound, which was purified by silica gel chromatography (PE:EA=50:1), separated and purified by column chromatography to obtain the product 4-methoxy-N-(prop-2-yne -1-yl)aniline 1.26g, yield 73.4%. 1 H NMR (300MHz, CDCl 3 ) δ6.63–6.57 (m, 2H), 6.54–6.47 (m, 2H), 3.89 (s, 1H), 3.80 (d, J=3.2Hz, 2H), 3.80 ( s,3H),2.86(t,J=3.0Hz,1H).
步骤2：N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲氧基苯胺的制备Step 2: Preparation of N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-methoxyaniline
Figure PCTCN2022093052-appb-000075
Figure PCTCN2022093052-appb-000075
将中间体4(1g，3.6mmol，参照实施例1的制备)，4-甲氧基-N-(丙-2-炔-1-基)苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝8:1)，经柱层析分离纯化得到产物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲氧基苯胺830.7mg，收率74.2％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.78(s,1H),7.18(d,J＝7.5Hz,1H),6.70–6.59(m,3H),6.58–6.51(m,2H),3.94(s,1H),3.80(s,5H). Intermediate 4 (1g, 3.6mmol, refer to the preparation of Example 1), 4-methoxy-N-(prop-2-yn-1-yl)aniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=8:1), separated and purified by column chromatography to obtain the product N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)propane -2-Alkyn-1-yl)-4-methoxyaniline 830.7 mg, yield 74.2%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.78(s, 1H), 7.18(d, J=7.5Hz, 1H), 6.70–6.59(m, 3H), 6.58–6.51( m,2H),3.94(s,1H),3.80(s,5H).
步骤3：N-环己基-5-(3-((4-甲氧基苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 3: N-cyclohexyl-5-(3-((4-methoxyphenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine-4 - Preparation of amines
Figure PCTCN2022093052-appb-000076
Figure PCTCN2022093052-appb-000076
将化合物N-(3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)-4-甲氧基苯胺(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物， 通过硅胶色谱法纯化(PE：EA＝2:1)。经柱层析分离纯化得到产物N-环己基-5-(3-((4-甲氧基苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺486.2mg，收率50.5％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.52(s,1H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.3Hz,1H),6.62(d,J＝7.5Hz,2H),6.54(d,J＝7.5Hz,2H),4.38(s,1H),4.31(s,1H),4.20(s,1H),3.80(s,5H),2.04–1.94(m,2H),1.80–1.71(m,2H),1.66–1.56(m,4H),1.38(dd,J＝12.8,7.0Hz,2H). Compound N-(3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)-4-methoxyaniline (2.6mmol) , cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was passed through Purified by chromatography on silica gel (PE:EA=2:1). The product N-cyclohexyl-5-(3-((4-methoxyphenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3- b] Pyridin-4-amine 486.2 mg, yield 50.5%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.52(s, 1H), 7.20(d, J=7.5Hz, 1H), 6.80(d, J=7.3Hz, 1H), 6.62 (d,J=7.5Hz,2H),6.54(d,J=7.5Hz,2H),4.38(s,1H),4.31(s,1H),4.20(s,1H),3.80(s,5H) ,2.04–1.94(m,2H),1.80–1.71(m,2H),1.66–1.56(m,4H),1.38(dd,J＝12.8,7.0Hz,2H).
步骤4：N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-甲氧基苯胺的制备Step 4: N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)-4-methoxy Preparation of phenylaniline
Figure PCTCN2022093052-appb-000077
Figure PCTCN2022093052-appb-000077
在室温下向N-环己基-5-(3-((4-甲氧基苯基)氨基)丙-1-炔-1-基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝1:1)，经柱层析分离纯化得到产物N-((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)-4-甲氧基苯胺221.4mg，收率43.2％。m.p.220.3-221.6℃. 1H NMR(300MHz,DMSO-d 6)δ11.54(s,1H),8.04(s,1H),7.77(s,4H),7.20(s,1H),6.58(s,1H),6.18(s,1H),5.82(d,J＝8.6Hz,1H),4.52(s,2H),4.09(s,1H),2.05(s,2H),1.75(s,2H),1.44(s,4H),1.21(d,J＝18.2Hz,2H). 13C NMR(300MHz,DMSO-d6)δ159.73,149.97,149.15,147.92,147.57,143.15,136.54,130.95,126.35,122.57,122.35,111.98,104.65,99.97,71.00,42.74,33.40,25.13,24.21. To N-cyclohexyl-5-(3-((4-methoxyphenyl)amino)prop-1-yn-1-yl)-1H-pyrrolo[2,3-b]pyridine- To a mixture of 4-amine (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=1:1), separated and purified by column chromatography to obtain the product N-((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridin-2-yl)methyl)-4-methoxyaniline 221.4 mg, yield 43.2%. mp220.3-221.6℃. 1 H NMR (300MHz, DMSO-d 6 ) δ11.54(s, 1H), 8.04(s, 1H), 7.77(s, 4H), 7.20(s, 1H), 6.58( s,1H),6.18(s,1H),5.82(d,J＝8.6Hz,1H),4.52(s,2H),4.09(s,1H),2.05(s,2H),1.75(s,2H ),1.44(s,4H),1.21(d,J=18.2Hz,2H). 13 C NMR(300MHz,DMSO-d6)δ159.73,149.97,149.15,147.92,147.57,143.15,136.54,130.95,126.35,122.57 ,122.35,111.98,104.65,99.97,71.00,42.74,33.40,25.13,24.21.
实施例18Example 18
步骤1：4-(丙-2-炔-1-基氨基)苄腈的制备Step 1: Preparation of 4-(prop-2-yn-1-ylamino)benzonitrile
Figure PCTCN2022093052-appb-000078
Figure PCTCN2022093052-appb-000078
将4-氨基苄腈(10.7mmol)，3-溴丙炔(1.5g，12.8mmol)，K 2CO 3(5.9g，42.8mmol)加入25ml丙酮中，50℃加热回流5h。反应完成后，抽滤去除K 2CO 3，并用丙酮多次洗，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝50:1)，经柱层析分离纯化得到产物4-(丙-2-炔-1-基氨基)苄腈1.19g，收率71.7％。 1H NMR(300MHz,CDCl 3)δ7.47–7.40(m,2H),6.76–6.69(m,2H),4.50(s,1H),3.80(d,J＝2.9Hz,2H),2.87(t,J＝3.0Hz,1H). Add 4-aminobenzonitrile (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) into 25ml of acetone, and heat at reflux at 50°C for 5h. After the reaction was completed, K 2 CO 3 was removed by suction filtration, washed with acetone several times, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml) and saturated brine (1×100ml) successively, and washed with anhydrous sulfuric acid Dry over sodium and concentrate under reduced pressure to give the crude compound, which is purified by silica gel chromatography (PE:EA=50:1), separated and purified by column chromatography to give the product 4-(prop-2-yn-1-ylamino) Benzonitrile 1.19g, yield 71.7%. 1 H NMR (300MHz, CDCl 3 ) δ7.47–7.40 (m, 2H), 6.76–6.69 (m, 2H), 4.50 (s, 1H), 3.80 (d, J=2.9Hz, 2H), 2.87 ( t,J=3.0Hz,1H).
步骤2:4-((3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈的制备Step 2: Preparation of 4-((3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile
Figure PCTCN2022093052-appb-000079
Figure PCTCN2022093052-appb-000079
将中间体4(1g，3.6mmol，参照实施例1的制备)，4-(丙-2-炔-1-基氨基)苄腈(4.3mmol)， Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝8:1)，经柱层析分离纯化得到产物4-((3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈767.8mg，收率69.7％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.79(s,1H),7.49–7.42(m,2H),7.19(d,J＝7.5Hz,1H),6.79–6.72(m,2H),6.67(d,J＝7.5Hz,1H),4.59(s,1H),3.80(s,2H). Intermediate 4 (1g, 3.6mmol, refer to the preparation of Example 1), 4-(prop-2-yn-1-ylamino)benzonitrile (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=8:1), separated and purified by column chromatography to obtain the product 4-((3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl) Prop-2-yn-1-yl)amino)benzonitrile 767.8 mg, yield 69.7%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.79(s, 1H), 7.49–7.42(m, 2H), 7.19(d, J=7.5Hz, 1H), 6.79–6.72( m,2H),6.67(d,J=7.5Hz,1H),4.59(s,1H),3.80(s,2H).
步骤3：4-((3-(4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈的制备Step 3: 4-((3-(4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile preparation
Figure PCTCN2022093052-appb-000080
Figure PCTCN2022093052-appb-000080
将化合物4-((3-(4-氯-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)。经柱层析分离纯化得到产物4-((3-(4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈466.3mg，收率48.6％。 1H NMR(300MHz,CDCl 3)δ11.12(s,1H),8.51(s,1H),7.46(d,J＝7.5Hz,2H),7.19(d,J＝7.5Hz,1H),6.77(dd,J＝11.0,7.5Hz,3H),4.88(s,1H),4.60(s,1H),3.85(s,1H),3.80(s,2H),2.09–2.00(m,2H),1.80(m,J＝13.1,5.9Hz,2H),1.67–1.57(m,4H),1.38(dd,J＝12.9,6.9Hz,2H). Compound 4-((3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile (2.6mmol), ring Hexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 ( dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by chromatography on silica gel (PE:EA=2:1). Purified by column chromatography to obtain the product 4-((3-(4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl) Amino)benzonitrile 466.3 mg, yield 48.6%. 1 H NMR (300MHz, CDCl 3 ) δ11.12(s, 1H), 8.51(s, 1H), 7.46(d, J=7.5Hz, 2H), 7.19(d, J=7.5Hz, 1H), 6.77 (dd,J=11.0,7.5Hz,3H),4.88(s,1H),4.60(s,1H),3.85(s,1H),3.80(s,2H),2.09–2.00(m,2H), 1.80(m, J=13.1, 5.9Hz, 2H), 1.67–1.57(m, 4H), 1.38(dd, J=12.9, 6.9Hz, 2H).
步骤4：4-(((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)氨基)苄腈的制备Step 4: 4-(((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)methyl)amino)benzonitrile preparation of
Figure PCTCN2022093052-appb-000081
Figure PCTCN2022093052-appb-000081
在室温下向4-((3-(4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)丙-2-炔-1-基)氨基)苄腈(1.5mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝1:1)，经柱层析分离纯化得到产物4-(((1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)甲基)氨基)苄腈229.3mg，收率45.7％。m.p.203.6-205.0℃。 1H NMR(300MHz,DMSO-d 6)δ7.96(s,1H),7.26(d,J＝8.2Hz,2H),7.21(t,J＝2.5Hz,1H),6.60(d,J＝8.3Hz,2H),6.55(d,J＝3.5Hz,1H),5.91(d,J＝7.9Hz,1H),5.52(d,J＝8.6Hz,1H),3.24(q,J＝9.7Hz,1H),2.06(d,J＝9.6Hz,2H),1.99–1.89(m,2H),1.76–1.72(m,2H),1.63(d,J＝12.5Hz,2H),1.40(d,J＝8.4Hz,3H),1.20(m,J＝9.7,8.0,4.1Hz,3H). 4-((3-(4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)prop-2-yn-1-yl)amino)benzonitrile (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=1:1), separated and purified by column chromatography to obtain the product 4-(((1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2' , 3'-d]pyridin-2-yl)methyl)amino)benzonitrile 229.3mg, yield 45.7%. mp203.6-205.0°C. 1 H NMR (300MHz, DMSO-d 6 )δ7.96(s, 1H), 7.26(d, J=8.2Hz, 2H), 7.21(t, J=2.5Hz, 1H), 6.60(d, J= 8.3Hz, 2H), 6.55(d, J=3.5Hz, 1H), 5.91(d, J=7.9Hz, 1H), 5.52(d, J=8.6Hz, 1H), 3.24(q, J=9.7Hz ,1H),2.06(d,J=9.6Hz,2H),1.99–1.89(m,2H),1.76–1.72(m,2H),1.63(d,J=12.5Hz,2H),1.40(d, J=8.4Hz,3H),1.20(m,J=9.7,8.0,4.1Hz,3H).
实施例19Example 19
步骤1：4-氯-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000082
Figure PCTCN2022093052-appb-000082
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-2-氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，770.8mg，收率73.6％。 1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.85(s,1H),7.56(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J＝7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine, 770.8 mg, yield 73.6%. 1 H NMR (300MHz, Chloroform-d) δ8.57(s, 1H), 7.85(s, 1H), 7.56(d, J=7.5Hz, 1H), 7.36(t, J=7.5Hz, 1H), 7.19(d,J=7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J=7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01 (m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H).
步骤2：N-环己基-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000083
Figure PCTCN2022093052-appb-000083
将化合物4-氯-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，706mg，收率65.4％。 1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.85(s,1H),7.56(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J＝7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H). Compound 4-chloro-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml di Hexane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine- 4-amine, 706 mg, yield 65.4%. 1 H NMR (300MHz, Chloroform-d) δ8.57(s, 1H), 7.85(s, 1H), 7.56(d, J=7.5Hz, 1H), 7.36(t, J=7.5Hz, 1H), 7.19(d,J=7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J=7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01 (m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H).
步骤3：1-环己基-2-(2-氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000084
Figure PCTCN2022093052-appb-000084
在室温下向N-环己基-5-((2-氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(2-氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，85.0mg，收率28.2％。m.p.223.4-225.7℃。1H NMR(300MHz,DMSO-d 6)δ8.02(s,1H),7.24–7.19(m,1H),6.73(d,J＝2.3Hz,2H),6.59(dd,J＝3.7,1.9Hz,1H),6.55(t,J＝2.3Hz,1H),5.73(d,J＝8.7Hz,1H),2.06(s,2H),1.77(s,2H),1.70–1.49(m,2H),1.45(s,2H),1.34(d,J＝47.5Hz,2H). To a mixture of N-cyclohexyl-5-((2-fluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to t-BuOK. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d]pyridine, 85.0 mg, yield 28.2%. mp223.4-225.7°C. 1H NMR (300MHz, DMSO-d 6 ) δ8.02(s, 1H), 7.24–7.19(m, 1H), 6.73(d, J=2.3Hz, 2H), 6.59(dd, J=3.7, 1.9Hz ,1H),6.55(t,J=2.3Hz,1H),5.73(d,J=8.7Hz,1H),2.06(s,2H),1.77(s,2H),1.70–1.49(m,2H) ,1.45(s,2H),1.34(d,J=47.5Hz,2H).
实施例20Example 20
步骤1：4-氯-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000085
Figure PCTCN2022093052-appb-000085
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-硝基-2-氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，749.7mg，收率72.4％。 1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),7.86(t,J＝3.7Hz,2H),7.80(d,J＝7.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.53(t,J＝7.5Hz,1H),7.23(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.91(s,1H),3.51(s,1H),2.11–2.02(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.71–1.62(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.35(dd,J＝13.0,7.0Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-nitro-2-fluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine, 749.7 mg, yield 72.4%. 1 H NMR (300MHz, Chloroform-d) δ8.73(s, 1H), 7.86(t, J=3.7Hz, 2H), 7.80(d, J=7.4Hz, 1H), 7.63(t, J=7.4 Hz, 1H), 7.53(t, J=7.5Hz, 1H), 7.23(d, J=7.5Hz, 1H), 6.83(d, J=7.5Hz, 1H), 3.91(s, 1H), 3.51( s,1H),2.11–2.02(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.71–1.62(m,2H),1.61(dd,J＝6.4,1.7Hz,2H) ,1.35(dd,J=13.0,7.0Hz,2H).
步骤2：N-环己基-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000086
Figure PCTCN2022093052-appb-000086
将化合物4-氯-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，326.2mg，收率37.3％。 1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.88–7.83(m,2H),7.80(d,J＝7.4Hz,1H),7.63(t,J＝7.5Hz,1H),7.53(t,J＝7.4Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.3Hz,1H),3.95(s,1H),2.83(s,1H),2.09–2.00(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H). Compound 4-chloro-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t- BuONa (750 mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110 mg, 0.26 mmol), Pd 2 (dba) 3 (75 mg, 0.13 mmol) was added to 20 ml In dioxane, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine -4-amine, 326.2 mg, yield 37.3%. 1 H NMR (300MHz, Chloroform-d) δ8.76(s, 1H), 7.88–7.83(m, 2H), 7.80(d, J=7.4Hz, 1H), 7.63(t, J=7.5Hz, 1H ),7.53(t,J=7.4Hz,1H),7.24(d,J=7.5Hz,1H),6.84(d,J=7.3Hz,1H),3.95(s,1H),2.83(s,1H ),2.09–2.00(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.36( dd,J=13.0,7.0Hz,2H).
步骤3：1-环己基-2-(2-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(2-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000087
Figure PCTCN2022093052-appb-000087
在室温下向N-环己基-5-((2-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(2-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，59.9mg，收率19.1％。m.p.233.6-236.0℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.06(s,1H),7.80(t,J＝7.1Hz,2H),7.63(t,J＝7.4Hz,1H),7.51(t,J＝7.5Hz,1H),7.35(d,J＝7.3Hz,1H),6.99–6.91(m,2H),4.32(s,1H),2.60–2.50(m,2H), 2.06(m,J＝12.9,6.9Hz,2H),1.88–1.71(m,3H),1.55–1.35(m,3H). To N-cyclohexyl-5-((2-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature To the mixture was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(2-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b: 2',3'-d]pyridine, 59.9 mg, yield 19.1%. mp233.6-236.0°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s, 1H), 8.06(s, 1H), 7.80(t, J=7.1Hz, 2H), 7.63(t, J=7.4Hz, 1H), 7.51(t, J＝7.5Hz, 1H), 7.35(d, J＝7.3Hz, 1H), 6.99–6.91(m, 2H), 4.32(s, 1H), 2.60–2.50(m, 2H), 2.06 (m,J=12.9,6.9Hz,2H),1.88–1.71(m,3H),1.55–1.35(m,3H).
实施例21Example 21
步骤1：4-氯-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000088
Figure PCTCN2022093052-appb-000088
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-3-甲基苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶，738.8mg，收率68.4％。 1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.55(t,J＝7.5Hz,1H),7.47(s,1H),7.25(dd,J＝16.7,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-3-methylbenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain the corresponding solid compound 4-chloro-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine, 738.8 mg, yield 68.4%. 1 H NMR (300MHz, Chloroform-d) δ8.64(s,1H),7.87(s,1H),7.55(t,J=7.5Hz,1H),7.47(s,1H),7.25(dd,J =16.7,7.5Hz,2H),7.13(d,J=7.5Hz,1H),6.83(d,J=7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s ,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
步骤2：N-环己基-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000089
Figure PCTCN2022093052-appb-000089
将化合物-氯-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶，(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，323.3mg，收率29.9％。 1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.55(t,J＝7.5Hz,1H),7.47(s,1H),7.25(dd,J＝16.7,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H). Compound-chloro-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridine, (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane , heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 323.3 mg, yield 29.9%. 1 H NMR (300MHz, Chloroform-d) δ8.64(s,1H),7.87(s,1H),7.55(t,J=7.5Hz,1H),7.47(s,1H),7.25(dd,J =16.7,7.5Hz,2H),7.13(d,J=7.5Hz,1H),6.83(d,J=7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s ,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
步骤3：1-环己基-2-(间甲苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(m-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000090
Figure PCTCN2022093052-appb-000090
在室温下向N-环己基-5-(间甲苯基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(间甲苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，59.9mg，收率19.1％。 1H NMR(300MHz,DMSO-d 6)δ11.53(s,1H),8.02(s,1H),7.45–7.27(m,3H),7.21(q,J＝4.9,3.9Hz,2H),6.58(dd,J＝3.5,1.7Hz,1H),5.67(d,J＝8.6Hz,1H),2.16–1.98(m,2H),1.85–1.69(m,2H),1.44(t,J＝9.3Hz,4H). To a mixture of N-cyclohexyl-5-(m-tolylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t- BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(m-tolyl)-1,6-dihydrodipyrrolo[2,3-b:2', 3'-d]pyridine, 59.9 mg, yield 19.1%. 1 H NMR (300MHz,DMSO-d 6 )δ11.53(s,1H),8.02(s,1H),7.45–7.27(m,3H),7.21(q,J=4.9,3.9Hz,2H), 6.58(dd,J=3.5,1.7Hz,1H),5.67(d,J=8.6Hz,1H),2.16–1.98(m,2H),1.85–1.69(m,2H),1.44(t,J= 9.3Hz, 4H).
实施例22Example 22
步骤1：3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺的制备Step 1: Preparation of 3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline
Figure PCTCN2022093052-appb-000091
Figure PCTCN2022093052-appb-000091
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，3-乙炔基苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺，729.0mg，收率67.6％。 1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),7.85(s,1H),7.20(d,J＝7.5Hz,1H),7.03(t,J＝7.4Hz,1H),6.92(d,J＝7.5Hz,1H),6.83–6.75(m,2H),6.64(d,J＝7.4Hz,1H),4.33(s,1H),4.12(d,J＝2.9Hz,3H),2.08–1.99(m,2H),1.80–1.66(m,2H),1.66–1.56(m,4H),1.28(dd,J＝12.8,7.0Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 3-ethynylaniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline, 729.0mg , yield 67.6%. 1 H NMR (300MHz, Chloroform-d) δ8.60(s, 1H), 7.85(s, 1H), 7.20(d, J=7.5Hz, 1H), 7.03(t, J=7.4Hz, 1H), 6.92(d, J=7.5Hz, 1H), 6.83–6.75(m, 2H), 6.64(d, J=7.4Hz, 1H), 4.33(s, 1H), 4.12(d, J=2.9Hz, 3H ),2.08–1.99(m,2H),1.80–1.66(m,2H),1.66–1.56(m,4H),1.28(dd,J＝12.8,7.0Hz,2H).
步骤2：5-((3-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of 5-((3-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000092
Figure PCTCN2022093052-appb-000092
将化合物-3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺，(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物5-((3-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺，357.8mg，收率33.1％。 1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),7.86(s,1H),7.21(d,J＝7.5Hz,1H),7.03(t,J＝7.5Hz,1H),6.92(d,J＝7.5Hz,1H),6.82–6.75(m,2H),6.63(d,J＝7.5Hz,1H),4.79(s,1H),4.11(s,2H),3.91(s,1H),1.92–1.82(m,2H),1.78–1.69(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.38(m,J＝13.2,6.8Hz,2H),1.24(dd,J＝12.8,6.9Hz,2H). Compound-3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline, (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t- BuONa (750 mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110 mg, 0.26 mmol), Pd 2 (dba) 3 (75 mg, 0.13 mmol) was added to 20 ml In dioxane, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound 5-((3-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine- 4-amine, 357.8 mg, yield 33.1%. 1 H NMR (300MHz, Chloroform-d) δ8.60(s, 1H), 7.86(s, 1H), 7.21(d, J=7.5Hz, 1H), 7.03(t, J=7.5Hz, 1H), 6.92(d, J=7.5Hz, 1H), 6.82–6.75(m, 2H), 6.63(d, J=7.5Hz, 1H), 4.79(s, 1H), 4.11(s, 2H), 3.91(s ,1H),1.92–1.82(m,2H),1.78–1.69(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.38(m,J＝13.2,6.8Hz,2H), 1.24(dd,J=12.8,6.9Hz,2H).
步骤3：3-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯胺的制备Step 3: Preparation of 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)aniline
Figure PCTCN2022093052-appb-000093
Figure PCTCN2022093052-appb-000093
在室温下向5-((3-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物3-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯胺，84.1mg，收率23.6％。m.p.231.8-236.3℃。 1H NMR(300MHz,Chloroform-d)δ8.02(s,1H),7.21(d,J＝17.7Hz,3H),7.02(s,1H),6.59(d,J＝8.0Hz,2H),6.45(s,1H),5.51(d,J＝8.2Hz,1H),3.91(s,1H),3.64(s,1H),2.10(d,J＝11.4Hz,2H),1.74(s,2H), 1.34(s,2H),1.17(s,2H),-0.08(s,3H). To a mixture of 5-((3-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to t-BuOK. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Pyridin-2-yl)aniline, 84.1 mg, yield 23.6%. mp231.8-236.3°C. 1 H NMR (300MHz, Chloroform-d) δ8.02(s, 1H), 7.21(d, J=17.7Hz, 3H), 7.02(s, 1H), 6.59(d, J=8.0Hz, 2H), 6.45(s,1H),5.51(d,J=8.2Hz,1H),3.91(s,1H),3.64(s,1H),2.10(d,J=11.4Hz,2H),1.74(s,2H ), 1.34(s,2H),1.17(s,2H),-0.08(s,3H).
实施例23Example 23
步骤1：3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚的制备Step 1: Preparation of 3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol
Figure PCTCN2022093052-appb-000094
Figure PCTCN2022093052-appb-000094
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，3-乙炔基苯酚(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚，729.8mg，收率67.6％。 1H NMR(300MHz,Chloroform-d)δ8.66(s,1H),7.86(s,1H),7.25(d,J＝7.5Hz,1H),7.19(t,J＝7.5Hz,1H),7.11–7.05(m,2H),6.82(dd,J＝16.7,7.5Hz,2H),6.52(s,1H),3.97(s,1H),2.75(s,1H),2.08–1.98(m,2H),1.84–1.73(m,2H),1.68(dd,J＝13.4,6.2Hz,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.34(dd,J＝12.9,6.9Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 3-ethynylphenol (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol, 729.8mg , yield 67.6%. 1 H NMR (300MHz, Chloroform-d) δ8.66(s, 1H), 7.86(s, 1H), 7.25(d, J=7.5Hz, 1H), 7.19(t, J=7.5Hz, 1H), 7.11–7.05(m,2H),6.82(dd,J＝16.7,7.5Hz,2H),6.52(s,1H),3.97(s,1H),2.75(s,1H),2.08–1.98(m, 2H), 1.84–1.73(m, 2H), 1.68(dd, J＝13.4, 6.2Hz, 2H), 1.61(dd, J＝6.4, 1.6Hz, 2H), 1.34(dd, J＝12.9, 6.9Hz ,2H).
步骤2：3-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚的制备Step 2: Preparation of 3-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol
Figure PCTCN2022093052-appb-000095
Figure PCTCN2022093052-appb-000095
将化合物3-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物3-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚，353.7mg，收率32.7％。 1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.26–7.16(m,2H),7.10–7.05(m,2H),6.81(dd,J＝11.8,7.4Hz,2H),6.51(s,1H),3.95(s,1H),3.31(s,1H),2.09–2.00(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.70–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H). Compound 3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa ( 750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxygen In the six rings, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) afforded the corresponding solid compound 3-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl) Phenol, 353.7mg, yield 32.7%. 1 H NMR (300MHz, Chloroform-d) δ8.64(s,1H),7.87(s,1H),7.26–7.16(m,2H),7.10–7.05(m,2H),6.81(dd,J= 11.8,7.4Hz,2H),6.51(s,1H),3.95(s,1H),3.31(s,1H),2.09–2.00(m,2H),1.79(m,J＝13.1,5.9Hz,2H ),1.70–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
步骤3：3-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯酚的制备Step 3: Preparation of 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)phenol
Figure PCTCN2022093052-appb-000096
Figure PCTCN2022093052-appb-000096
在室温下向3-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物3-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯酚，51.6mg，收率16.6％。m.p.201.0-203.6℃。 1H NMR(300MHz,Chloroform-d)δ7.99(s,1H),7.09(d,J＝3.6Hz,1H),6.51(d,J＝3.6Hz,1H),5.61(d,J＝8.2Hz,1H),3.97(d,J＝10.8Hz,2H),2.17(d,J＝11.9Hz,2H),1.92(s,2H),1.81(s,2H),1.39(s,2H). To a mixture of 3-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 3-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Pyridin-2-yl)phenol, 51.6 mg, yield 16.6%. mp201.0-203.6°C. 1 H NMR (300MHz, Chloroform-d) δ7.99(s, 1H), 7.09(d, J=3.6Hz, 1H), 6.51(d, J=3.6Hz, 1H), 5.61(d, J=8.2 Hz,1H),3.97(d,J=10.8Hz,2H),2.17(d,J=11.9Hz,2H),1.92(s,2H),1.81(s,2H),1.39(s,2H).
实施例24Example 24
步骤1：4-氯-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000097
Figure PCTCN2022093052-appb-000097
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，3-乙炔基硝基苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，777.5mg，收率72.0％。 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.91–7.82(m,2H),7.48(t,J＝7.5Hz,1H),7.23(d,J＝7.3Hz,1H),6.84(d,J＝7.5Hz,1H),3.91(s,1H),3.43(s,1H),2.12–2.03(m,2H),1.88(m,J＝13.1,6.1Hz,2H),1.70(dd,J＝13.5,6.4Hz,2H),1.61(dd,J＝6.4,1.5Hz,2H),1.41–1.32(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 3-ethynylnitrobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine, 777.5 mg, yield 72.0%. 1 H NMR (300MHz, Chloroform-d) δ8.61(s, 1H), 8.41(s, 1H), 8.18(d, J=7.5Hz, 1H), 7.91–7.82(m, 2H), 7.48(t ,J=7.5Hz,1H),7.23(d,J=7.3Hz,1H),6.84(d,J=7.5Hz,1H),3.91(s,1H),3.43(s,1H),2.12–2.03 (m,2H),1.88(m,J=13.1,6.1Hz,2H),1.70(dd,J=13.5,6.4Hz,2H),1.61(dd,J=6.4,1.5Hz,2H),1.41– 1.32(m,2H).
步骤2：N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000098
Figure PCTCN2022093052-appb-000098
将化合物4-氯-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，340.5mg，收率31.5％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.90–7.83(m,2H),7.49(t,J＝7.5Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01(m,2H),1.84(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H). Compound 4-chloro-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t- BuONa (750 mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110 mg, 0.26 mmol), Pd 2 (dba) 3 (75 mg, 0.13 mmol) was added to 20 ml In dioxane, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine -4-amine, 340.5 mg, yield 31.5%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s, 1H), 8.41(s, 1H), 8.18(d, J=7.5Hz, 1H), 7.90–7.83(m, 2H), 7.49(t ,J=7.5Hz,1H),7.24(d,J=7.5Hz,1H),6.84(d,J=7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01 (m,2H),1.84(m,J=13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J=6.4,1.6Hz,2H),1.36(dd,J=13.0 ,7.0Hz,2H).
步骤3：1-环己基-2-(3-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000099
Figure PCTCN2022093052-appb-000099
在室温下向N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，70.4mg，收率20.1％。m.p.>250.0℃。 1H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.37(s,1H),8.13(d,J＝7.3Hz,1H),8.08(s,1H),7.79(d,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.36(d,J＝7.5Hz,1H),7.04(s,1H),6.95(d,J＝7.5Hz,1H),4.21(s,1H),2.32(m,J＝13.0,7.0Hz,2H),2.09(m,J＝13.0,6.9Hz,2H),1.78(m,J＝30.2,12.5, 6.9Hz,3H),1.54–1.44(m,1H),1.44–1.31(m,2H). To N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature To the mixture was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b: 2',3'-d]pyridine, 70.4 mg, yield 20.1%. mp>250.0°C. 1 H NMR (300MHz, Chloroform-d) δ9.32(s,1H),8.37(s,1H),8.13(d,J=7.3Hz,1H),8.08(s,1H),7.79(d,J =7.5Hz,1H),7.56(t,J=7.5Hz,1H),7.36(d,J=7.5Hz,1H),7.04(s,1H),6.95(d,J=7.5Hz,1H), 4.21(s,1H),2.32(m,J=13.0,7.0Hz,2H),2.09(m,J=13.0,6.9Hz,2H),1.78(m,J=30.2,12.5,6.9Hz,3H) ,1.54–1.44(m,1H),1.44–1.31(m,2H).
实施例25Example 25
步骤1：4-氯-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000100
Figure PCTCN2022093052-appb-000100
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-3-(三氟甲基)苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，769.1mg，收率71.2％。 1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.61–7.55(m,2H),7.51(d,J＝7.3Hz,2H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H) Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-3-(trifluoromethyl)benzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18 mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 769.1 mg, yield 71.2%. 1 H NMR (300MHz, Chloroform-d) δ8.85(s, 1H), 7.82(s, 1H), 7.61–7.55(m, 2H), 7.51(d, J=7.3Hz, 2H), 7.19(d ,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H)
步骤2：N-环己基-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000101
Figure PCTCN2022093052-appb-000101
将化合物4-氯-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，365.8mg，收率33.9％。 1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),7.86(s,1H),7.59–7.49(m,4H),7.21(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),4.44(s,1H),3.88(s,1H),2.10–2.01(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.69–1.57(m,4H),1.40–1.31(m,2H). The compound 4-chloro-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 365.8 mg, yield 33.9%. 1 H NMR (300MHz, Chloroform-d) δ8.59(s, 1H), 7.86(s, 1H), 7.59–7.49(m, 4H), 7.21(d, J=7.5Hz, 1H), 6.81(d ,J=7.5Hz,1H),4.44(s,1H),3.88(s,1H),2.10–2.01(m,2H),1.79(m,J=13.1,5.9Hz,2H),1.69–1.57( m,4H),1.40–1.31(m,2H).
步骤3：1-环己基-2-(4-(三氟甲基)苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(4-(trifluoromethyl)phenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000102
Figure PCTCN2022093052-appb-000102
在室温下向N-环己基-5-((4-(三氟甲基)苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(4-(三氟甲基)苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，67.4mg，收率22.1％。m.p.243.0-245.3℃。 1H NMR(300MHz,DMSO-d 6)δ11.57(s,1H),8.08(s,1H),7.80(d,J＝2.0Hz,5H),7.24(dd,J＝ 3.6,2.4Hz,1H),6.61(dd,J＝3.6,1.9Hz,1H),5.84(d,J＝8.6Hz,1H),2.05(d,J＝15.6Hz,3H),1.80(s,3H),1.49(d,J＝7.7Hz,4H). To N-cyclohexyl-5-((4-(trifluoromethyl)phenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(4-(trifluoromethyl)phenyl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine, 67.4 mg, yield 22.1%. mp243.0-245.3°C. 1 H NMR (300MHz, DMSO-d 6 )δ11.57(s, 1H), 8.08(s, 1H), 7.80(d, J=2.0Hz, 5H), 7.24(dd, J=3.6, 2.4Hz, 1H), 6.61(dd, J=3.6, 1.9Hz, 1H), 5.84(d, J=8.6Hz, 1H), 2.05(d, J=15.6Hz, 3H), 1.80(s, 3H), 1.49( d,J=7.7Hz,4H).
实施例26Example 26
步骤1：4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚的制备Step 1: Preparation of 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol
Figure PCTCN2022093052-appb-000103
Figure PCTCN2022093052-appb-000103
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，4-乙炔基苯酚(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚，777.5mg，收率72.0％。 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.91–7.82(m,2H),7.48(t,J＝7.5Hz,1H),7.23(d,J＝7.3Hz,1H),6.84(d,J＝7.5Hz,1H),3.91(s,1H),3.43(s,1H),2.12–2.03(m,2H),1.88(m,J＝13.1,6.1Hz,2H),1.70(dd,J＝13.5,6.4Hz,2H),1.61(dd,J＝6.4,1.5Hz,2H),1.41–1.32(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 4-ethynylphenol (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol, 777.5mg , yield 72.0%. 1 H NMR (300MHz, Chloroform-d) δ8.61(s, 1H), 8.41(s, 1H), 8.18(d, J=7.5Hz, 1H), 7.91–7.82(m, 2H), 7.48(t ,J=7.5Hz,1H),7.23(d,J=7.3Hz,1H),6.84(d,J=7.5Hz,1H),3.91(s,1H),3.43(s,1H),2.12–2.03 (m,2H),1.88(m,J=13.1,6.1Hz,2H),1.70(dd,J=13.5,6.4Hz,2H),1.61(dd,J=6.4,1.5Hz,2H),1.41– 1.32(m,2H).
步骤2：N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000104
Figure PCTCN2022093052-appb-000104
将化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯酚(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，340.5mg，收率31.5％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.90–7.83(m,2H),7.49(t,J＝7.5Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01(m,2H),1.84(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H). Compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)phenol (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa ( 750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxygen In the six rings, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine -4-amine, 340.5 mg, yield 31.5%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s, 1H), 8.41(s, 1H), 8.18(d, J=7.5Hz, 1H), 7.90–7.83(m, 2H), 7.49(t ,J=7.5Hz,1H),7.24(d,J=7.5Hz,1H),6.84(d,J=7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01 (m,2H),1.84(m,J=13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J=6.4,1.6Hz,2H),1.36(dd,J=13.0 ,7.0Hz,2H).
步骤3：1-环己基-2-(3-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000105
Figure PCTCN2022093052-appb-000105
在室温下向N-环己基-5-((3-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3-硝基苯基)-1,6-二氢二吡 咯并[2,3-b：2'，3'-d]吡啶，84.7mg，收率23.9％。m.p.203.6-205.0℃。 1H NMR(300MHz,DMSO-d 6)δ11.48(s,1H),8.00(s,1H),7.52(d,J＝2.0Hz,1H),7.50(d,J＝2.4Hz,2H),7.49–7.46(m,2H),7.44–7.42(m,1H),7.42–7.38(m,1H),7.21(dd,J＝3.6,2.4Hz,1H),7.12–7.07(m,2H),5.62(d,J＝8.7Hz,1H),5.18(s,2H),4.11(s,1H),2.06(s,2H),1.64(d,J＝12.6Hz,1H),1.44(s,4H). To N-cyclohexyl-5-((3-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature To the mixture was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(3-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b: 2',3'-d]pyridine, 84.7 mg, yield 23.9%. mp203.6-205.0°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.48(s,1H),8.00(s,1H),7.52(d,J=2.0Hz,1H),7.50(d,J=2.4Hz,2H) ,7.49–7.46(m,2H),7.44–7.42(m,1H),7.42–7.38(m,1H),7.21(dd,J＝3.6,2.4Hz,1H),7.12–7.07(m,2H) ,5.62(d,J=8.7Hz,1H),5.18(s,2H),4.11(s,1H),2.06(s,2H),1.64(d,J=12.6Hz,1H),1.44(s, 4H).
实施例27Example 27
步骤1：4-氯-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000106
Figure PCTCN2022093052-appb-000106
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，4-乙炔基硝基苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，796.1mg，收率71.2％。 1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),8.28–8.22(m,2H),7.82(dd,J＝5.4,2.1Hz,3H),7.20(d,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 4-ethynylnitrobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine, 796.1 mg, yield 71.2%. 1 H NMR (300MHz, Chloroform-d) δ8.86(s, 1H), 8.28–8.22(m, 2H), 7.82(dd, J=5.4, 2.1Hz, 3H), 7.20(d, J=7.5Hz ,1H),6.69(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000107
Figure PCTCN2022093052-appb-000107
将化合物4-氯-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，316.9mg，收率29.3％。 1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.25(d,J＝7.5Hz,2H),7.88–7.79(m,3H),7.25(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.94(s,1H),2.89(s,1H),2.09–2.00(m,2H),1.79(m,J＝13.0,5.8Hz,2H),1.72–1.63(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.35(dd,J＝12.9,7.0Hz,2H). The compound 4-chloro-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t- BuONa (750 mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110 mg, 0.26 mmol), Pd 2 (dba) 3 (75 mg, 0.13 mmol) was added to 20 ml In dioxane, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine -4-amine, 316.9 mg, yield 29.3%. 1 H NMR (300MHz, Chloroform-d) δ8.65(s, 1H), 8.25(d, J=7.5Hz, 2H), 7.88–7.79(m, 3H), 7.25(d, J=7.5Hz, 1H ),6.84(d,J=7.5Hz,1H),3.94(s,1H),2.89(s,1H),2.09–2.00(m,2H),1.79(m,J=13.0,5.8Hz,2H) ,1.72–1.63(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.35(dd,J＝12.9,7.0Hz,2H).
步骤3：1-环己基-2-(4-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(4-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000108
Figure PCTCN2022093052-appb-000108
在室温下向N-环己基-5-((4-硝基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶 色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(4-硝基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，79.6mg，收率24.5％。m.p.219.9-222.2℃。 1H NMR(300MHz,Chloroform-d)δ9.33(s,1H),8.18(d,J＝7.5Hz,2H),8.08(s,1H),7.66(d,J＝7.5Hz,2H),7.35(d,J＝7.5Hz,1H),7.05(s,1H),6.94(d,J＝7.5Hz,1H),4.21(s,1H),2.28(m,J＝13.0,7.0Hz,2H),2.07(m,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.43(m,1H),1.43–1.31(m,2H). To N-cyclohexyl-5-((4-nitrophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature To the mixture was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(4-nitrophenyl)-1,6-dihydrodipyrrolo[2,3-b: 2',3'-d]pyridine, 79.6 mg, yield 24.5%. mp219.9-222.2°C. 1 H NMR (300MHz, Chloroform-d) δ9.33(s, 1H), 8.18(d, J=7.5Hz, 2H), 8.08(s, 1H), 7.66(d, J=7.5Hz, 2H), 7.35(d, J=7.5Hz, 1H), 7.05(s, 1H), 6.94(d, J=7.5Hz, 1H), 4.21(s, 1H), 2.28(m, J=13.0, 7.0Hz, 2H ),2.07(m,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.43(m,1H),1.43–1.31(m,2H).
实施例28Example 28
步骤1：4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺的制备Step 1: Preparation of 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline
Figure PCTCN2022093052-appb-000109
Figure PCTCN2022093052-appb-000109
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，4-乙炔基苯胺(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺，745.2mg，收率69.0％。 1H NMR(300MHz,Chloroform-d)δ8.83(s,1H),7.80(s,1H),7.46–7.40(m,2H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H),6.63–6.57(m,2H),4.52(s,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 4-ethynylaniline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline, 745.2mg , yield 69.0%. 1 H NMR (300MHz, Chloroform-d) δ8.83(s, 1H), 7.80(s, 1H), 7.46–7.40(m, 2H), 7.19(d, J=7.5Hz, 1H), 6.68(d ,J＝7.5Hz,1H),6.63–6.57(m,2H),4.52(s,2H).
步骤2：5-((4-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of 5-((4-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000110
Figure PCTCN2022093052-appb-000110
将化合物4-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)苯胺(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物5-((4-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺，334.9mg，收率31.0％。 1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),7.84(s,1H),7.40(d,J＝7.3Hz,2H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,2H),4.41(s,2H),4.30(s,1H),4.11(s,1H),2.09–2.00(m,2H),1.72(dd,J＝12.9,6.9Hz,2H),1.66–1.56(m,4H),1.28(m,J＝13.2,6.6Hz,2H). Compound 4-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)aniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa ( 750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxygen In the six rings, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound 5-((4-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridine- 4-amine, 334.9 mg, yield 31.0%. 1 H NMR (300MHz, Chloroform-d) δ8.59(s, 1H), 7.84(s, 1H), 7.40(d, J=7.3Hz, 2H), 7.20(d, J=7.5Hz, 1H), 6.80(d,J=7.5Hz,1H),6.59(d,J=7.5Hz,2H),4.41(s,2H),4.30(s,1H),4.11(s,1H),2.09–2.00(m ,2H),1.72(dd,J=12.9,6.9Hz,2H),1.66–1.56(m,4H),1.28(m,J=13.2,6.6Hz,2H).
步骤3：4-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯胺的制备Step 3: Preparation of 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridin-2-yl)aniline
Figure PCTCN2022093052-appb-000111
Figure PCTCN2022093052-appb-000111
在室温下向5-((4-氨基苯基)乙炔基)-N-环己基-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶 色谱法纯化(PE：EA＝2:1)，得到相应固体化合物4-(1-环己基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶-2-基)苯胺，77.3mg，收率20.6％。m.p.200.9-203.7℃。 1H NMR(300MHz,DMSO-d 6)δ7.95(s,1H),7.23(d,J＝2.0Hz,1H),7.20(q,J＝2.0Hz,2H),6.63–6.56(m,2H),6.55(dd,J＝3.6,1.9Hz,1H),5.50(d,J＝7.0Hz,3H),2.13–1.95(m,2H),1.74(s,2H),1.57(dd,J＝40.4,12.1Hz,2H),1.43(d,J＝9.1Hz,2H),1.31(d,J＝21.4Hz,2H). To a mixture of 5-((4-aminophenyl)ethynyl)-N-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added to t-BuOK. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 4-(1-cyclohexyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Pyridin-2-yl)aniline, 77.3 mg, yield 20.6%. mp200.9-203.7°C. 1 H NMR (300MHz, DMSO-d 6 )δ7.95(s,1H),7.23(d,J=2.0Hz,1H),7.20(q,J=2.0Hz,2H),6.63–6.56(m, 2H), 6.55(dd, J＝3.6, 1.9Hz, 1H), 5.50(d, J＝7.0Hz, 3H), 2.13–1.95(m, 2H), 1.74(s, 2H), 1.57(dd, J =40.4,12.1Hz,2H),1.43(d,J=9.1Hz,2H),1.31(d,J=21.4Hz,2H).
实施例29Example 29
步骤1：4-氯-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000112
Figure PCTCN2022093052-appb-000112
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-3,5-二甲氧基苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，790mg，收率82.5％。 1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),7.82(s,1H),7.19(d,J＝7.5Hz,1H),6.85(d,J＝2.0Hz,2H),6.68(d,J＝7.5Hz,1H),6.38(t,J＝2.0Hz,1H),3.81(s,6H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-3,5-dimethoxybenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18 mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=10:1) to give the corresponding solid compound 4-chloro-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 790 mg, yield 82.5%. 1 H NMR (300MHz, Chloroform-d) δ8.86(s, 1H), 7.82(s, 1H), 7.19(d, J=7.5Hz, 1H), 6.85(d, J=2.0Hz, 2H), 6.68(d, J=7.5Hz, 1H), 6.38(t, J=2.0Hz, 1H), 3.81(s, 6H).
步骤2：N-环己基-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000113
Figure PCTCN2022093052-appb-000113
将化合物4-氯-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，380.6mg，收率35.2％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.86(s,1H),7.40(d,J＝7.5Hz,2H),7.24(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,2H),4.44(s,2H),3.95(s,1H),3.13(s,1H),2.09–2.00(m,2H),1.80(m,J＝13.4,6.3Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝13.6,6.4Hz,2H). The compound 4-chloro-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 380.6 mg, yield 35.2%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s, 1H), 7.86(s, 1H), 7.40(d, J=7.5Hz, 2H), 7.24(d, J=7.5Hz, 1H), 6.83(d,J=7.5Hz,1H),6.59(d,J=7.5Hz,2H),4.44(s,2H),3.95(s,1H),3.13(s,1H),2.09–2.00(m ,2H),1.80(m,J=13.4,6.3Hz,2H),1.71–1.57(m,4H),1.37(dd,J=13.6,6.4Hz,2H).
步骤3：1-环己基-2-(3,5-二甲氧基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3,5-dimethoxyphenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000114
Figure PCTCN2022093052-appb-000114
在室温下向N-环己基-5-((3,5-二甲氧基苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱 和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3,5-二甲氧基苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶61.8mg，收率19.1％。m.p.223.6-226.5℃。 1H NMR(300MHz,DMSO-d 6)δ11.58(s,1H),8.04(s,1H),7.64(m,J＝7.6,1.8Hz,1H),7.48–7.36(m,2H),7.32–7.22(m,2H),6.60(dd,J＝3.7,1.9Hz,1H),5.71(d,J＝8.6Hz,1H),4.13(d,J＝9.4Hz,1H),2.09(d,J＝11.0Hz,2H),1.75(s,2H),1.58(dd,J＝42.5,12.1Hz,2H),1.40(s,2H),1.31(d,J＝29.6Hz,2H). To N-cyclohexyl-5-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(3,5-dimethoxyphenyl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine 61.8 mg, yield 19.1%. mp223.6-226.5°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.58(s,1H),8.04(s,1H),7.64(m,J＝7.6,1.8Hz,1H),7.48–7.36(m,2H), 7.32–7.22(m,2H),6.60(dd,J=3.7,1.9Hz,1H),5.71(d,J=8.6Hz,1H),4.13(d,J=9.4Hz,1H),2.09(d ,J=11.0Hz,2H),1.75(s,2H),1.58(dd,J=42.5,12.1Hz,2H),1.40(s,2H),1.31(d,J=29.6Hz,2H).
实施例30Example 30
步骤1：4-氯-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000115
Figure PCTCN2022093052-appb-000115
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-3.5-二氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，797mg，收率73.8％。 1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.19(d,J＝7.5Hz,1H),7.02(m,J＝9.3,2.2,1.2Hz,2H),6.84(m,J＝9.0,2.0Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-3.5-difluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 797 mg, yield 73.8%. 1 H NMR (300MHz, Chloroform-d) δ8.85(s, 1H), 7.82(s, 1H), 7.19(d, J=7.5Hz, 1H), 7.02(m, J=9.3, 2.2, 1.2Hz ,2H),6.84(m,J=9.0,2.0Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000116
Figure PCTCN2022093052-appb-000116
将化合物4-氯-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，331.2mg，收率30.7％。 1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.24(d,J＝7.5Hz,1H),6.82(d,J＝15.0Hz,3H),6.44(s,1H),3.95(s,1H),3.81(s,6H),3.18(s,1H),2.09–1.99(m,2H),1.83–1.49(m,8H). The compound 4-chloro-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 331.2 mg, yield 30.7%. 1 H NMR (300MHz, Chloroform-d) δ8.64(s, 1H), 7.87(s, 1H), 7.24(d, J=7.5Hz, 1H), 6.82(d, J=15.0Hz, 3H), 6.44(s,1H),3.95(s,1H),3.81(s,6H),3.18(s,1H),2.09–1.99(m,2H),1.83–1.49(m,8H).
步骤3：1-环己基-2-(3,5-二氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3,5-difluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000117
Figure PCTCN2022093052-appb-000117
在室温下向N-环己基-5-((3,5-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅 拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3,5-二氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，79.2mg，收率24.5％。m.p.226.6-229.5℃。 1H NMR(300MHz,DMSO-d 6)δ11.57(s,1H),8.04(s,1H),7.34(m,J＝9.7,7.1,2.3Hz,4H),7.23(dd,J＝3.5,2.3Hz,1H),6.59(dd,J＝3.6,1.8Hz,1H),5.81(d,J＝8.6Hz,1H),2.05(t,J＝10.2Hz,3H),1.86–1.69(m,3H),1.48(m,J＝11.3,10.8Hz,6H). N-cyclohexyl-5-((3,5-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(3,5-difluorophenyl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 79.2 mg, yield 24.5%. mp226.6-229.5°C. 1 H NMR (300MHz, DMSO-d 6 ) δ11.57(s, 1H), 8.04(s, 1H), 7.34(m, J=9.7, 7.1, 2.3Hz, 4H), 7.23(dd, J=3.5 ,2.3Hz,1H),6.59(dd,J＝3.6,1.8Hz,1H),5.81(d,J＝8.6Hz,1H),2.05(t,J＝10.2Hz,3H),1.86–1.69(m ,3H),1.48(m,J=11.3,10.8Hz,6H).
实施例31Example 31
步骤1：4-氯-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000118
Figure PCTCN2022093052-appb-000118
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-2-氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶，701mg，收率64.9％。 1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),7.80(s,1H),7.58(m,J＝7.5,5.7Hz,1H),7.19(d,J＝7.5Hz,1H),6.88–6.78(m,2H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 701 mg, yield 64.9%. 1 H NMR (300MHz, Chloroform-d) δ8.86(s,1H),7.80(s,1H),7.58(m,J=7.5,5.7Hz,1H),7.19(d,J=7.5Hz,1H ),6.88–6.78(m,2H),6.68(d,J＝7.5Hz,1H).
步骤2：N-环己基-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000119
Figure PCTCN2022093052-appb-000119
将化合物4-氯-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，364.2mg，收率33.7％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.87(s,1H),7.23(d,J＝7.5Hz,1H),7.01(d,J＝8.8Hz,2H),6.87–6.79(m,2H),3.94(s,1H),3.47(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.81(dd,J＝13.4,6.3Hz,2H),1.70–1.57(m,4H),1.38(m,J＝13.0,6.5Hz,2H). Compound 4-chloro-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 364.2 mg, yield 33.7%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s, 1H), 7.87(s, 1H), 7.23(d, J=7.5Hz, 1H), 7.01(d, J=8.8Hz, 2H), 6.87–6.79(m,2H),3.94(s,1H),3.47(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.81(dd,J＝13.4,6.3Hz,2H) ,1.70–1.57(m,4H),1.38(m,J＝13.0,6.5Hz,2H).
步骤3：1-环己基-2-(2,4-二氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(2,4-difluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000120
Figure PCTCN2022093052-appb-000120
在室温下向N-环己基-5-((2,4-二氟苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅 拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(2,4-二氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，59.9mg，收率19.7％。m.p.230.6-233.9℃。 1H NMR(300MHz,DMSO-d 6)δ11.57(s,1H),8.03(s,1H),7.72(m,J＝8.6,6.5Hz,1H),7.48(m,J＝9.7,2.6Hz,1H),7.26–7.20(m,2H),6.60(dd,J＝3.7,1.9Hz,1H),5.70(d,J＝8.6Hz,1H),1.77(d,J＝12.6Hz,2H),1.75–1.50(m,2H),1.46(d,J＝12.9Hz,2H),1.41(s,2H),1.38–1.18(m,2H). N-cyclohexyl-5-((2,4-difluorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(2,4-difluorophenyl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 59.9 mg, yield 19.7%. mp230.6-233.9°C. 1 H NMR (300MHz,DMSO-d 6 )δ11.57(s,1H),8.03(s,1H),7.72(m,J=8.6,6.5Hz,1H),7.48(m,J=9.7,2.6 Hz,1H),7.26–7.20(m,2H),6.60(dd,J=3.7,1.9Hz,1H),5.70(d,J=8.6Hz,1H),1.77(d,J=12.6Hz,2H ),1.75–1.50(m,2H),1.46(d,J＝12.9Hz,2H),1.41(s,2H),1.38–1.18(m,2H).
实施例32Example 32
步骤1：4-氯-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000121
Figure PCTCN2022093052-appb-000121
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-2-氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶706mg，收率65.4％。 1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.41(d,J＝2.0Hz,2H),7.33(t,J＝2.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine 706 mg, yield 65.4%. 1 H NMR (300MHz, Chloroform-d) δ8.85(s,1H),7.82(s,1H),7.41(d,J=2.0Hz,2H),7.33(t,J=2.0Hz,1H), 7.19(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000122
Figure PCTCN2022093052-appb-000122
将化合物4-氯-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，329.5mg，收率30.5％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.86(s,1H),7.39(s,2H),7.33(s,1H),7.23(d,J＝7.5Hz,1H),6.82(d,J＝7.5Hz,1H),3.94(s,1H),3.39(s,1H),2.04(dd,J＝13.5,6.4Hz,2H),1.86–1.77(m,2H),1.71–1.57(m,4H),1.39(m,J＝13.1,6.5Hz,2H). The compound 4-chloro-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 329.5 mg, yield 30.5%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s,1H),7.86(s,1H),7.39(s,2H),7.33(s,1H),7.23(d,J＝7.5Hz,1H ),6.82(d,J=7.5Hz,1H),3.94(s,1H),3.39(s,1H),2.04(dd,J=13.5,6.4Hz,2H),1.86–1.77(m,2H) ,1.71–1.57(m,4H),1.39(m,J＝13.1,6.5Hz,2H).
步骤3：1-环己基-2-(3,5-二氯苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3,5-dichlorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000123
Figure PCTCN2022093052-appb-000123
在室温下向N-环己基-5-((3,5-二氯苯基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol) 和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3,5-二氯苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，59.5mg，收率19.7％。 1H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.08(s,1H),7.53(s,2H),7.38–7.30(m,2H),7.04(s,1H),6.94(d,J＝7.5Hz,1H),4.24(s,1H),2.29(m,J＝12.8,6.9Hz,2H),2.06(m,J＝13.2,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.42(m,1H),1.42–1.33(m,2H). N-cyclohexyl-5-((3,5-dichlorophenyl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(3,5-dichlorophenyl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 59.5 mg, yield 19.7%. 1 H NMR (300MHz, Chloroform-d) δ9.32(s,1H),8.08(s,1H),7.53(s,2H),7.38–7.30(m,2H),7.04(s,1H),6.94 (d, J=7.5Hz, 1H), 4.24(s, 1H), 2.29(m, J=12.8, 6.9Hz, 2H), 2.06(m, J=13.2, 6.9Hz, 2H), 1.86–1.69( m,3H),1.53–1.42(m,1H),1.42–1.33(m,2H).
实施例33Example 33
步骤1：4-氯-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000124
Figure PCTCN2022093052-appb-000124
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，乙炔基环丙烷(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶，513.7mg，收率70.5％。 1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.77(s,1H),7.18(d,J＝7.5Hz,1H),6.66(d,J＝7.5Hz,1H),1.40(p,J＝7.0Hz,1H),0.59(m,J＝7.1,4.2Hz,2H),0.42–0.33(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), ethynylcyclopropane (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) Add 1ml of triethylamine into 25ml of acetonitrile, and heat to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain the corresponding solid compound 4-chloro-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridine, 513.7 mg, yield 70.5%. 1 H NMR (300MHz, Chloroform-d) δ8.76(s, 1H), 7.77(s, 1H), 7.18(d, J=7.5Hz, 1H), 6.66(d, J=7.5Hz, 1H), 1.40(p,J=7.0Hz,1H),0.59(m,J=7.1,4.2Hz,2H),0.42–0.33(m,2H).
步骤2：N-环己基-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000125
Figure PCTCN2022093052-appb-000125
将化合物4-氯-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，142.4mg，收率34.7％。 1H NMR(300MHz,Chloroform-d)δ8.56(s,1H),7.81(s,1H),7.23(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.97(s,1H),2.66(s,1H),2.10–2.01(m,2H),1.73(m,J＝30.5,13.9,6.4Hz,4H),1.66–1.57(m,2H),1.43(s,1H),1.37(dd,J＝13.5,6.3Hz,2H),0.58–0.53(m,2H),0.41–0.36(m,2H). The compound 4-chloro-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane , heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 142.4 mg, yield 34.7%. 1 H NMR (300MHz, Chloroform-d) δ8.56(s, 1H), 7.81(s, 1H), 7.23(d, J=7.5Hz, 1H), 6.83(d, J=7.5Hz, 1H), 3.97(s,1H),2.66(s,1H),2.10–2.01(m,2H),1.73(m,J＝30.5,13.9,6.4Hz,4H),1.66–1.57(m,2H),1.43( s,1H),1.37(dd,J＝13.5,6.3Hz,2H),0.58–0.53(m,2H),0.41–0.36(m,2H).
步骤3：1-环己基-2-环丙基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-cyclopropyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000126
Figure PCTCN2022093052-appb-000126
在室温下向N-环己基-5-(环丙基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小 时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-环丙基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，53.0mg，收率29.5％。m.p.219.6-222.3℃。 1H NMR(300MHz,Chloroform-d)δ9.40(s,1H),7.36(d,J＝7.5Hz,1H),6.50(d,J＝7.5Hz,1H),5.79(s,1H),3.64(s,1H),1.79(m,J＝12.7,6.5Hz,2H),1.73–1.67(m,1H),1.67–1.53(m,4H),1.53–1.50(m,1H),1.46(m,J＝11.4,9.2,6.3,3.0Hz,4H),0.82–0.76(m,2H),0.76–0.70(m,2H). To a mixture of N-cyclohexyl-5-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t- BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-cyclopropyl-1,6-dihydrodipyrrolo[2,3-b:2',3' -d] pyridine, 53.0 mg, yield 29.5%. mp219.6-222.3°C. 1 H NMR (300MHz, Chloroform-d) δ9.40(s, 1H), 7.36(d, J=7.5Hz, 1H), 6.50(d, J=7.5Hz, 1H), 5.79(s, 1H), 3.64(s,1H),1.79(m,J＝12.7,6.5Hz,2H),1.73–1.67(m,1H),1.67–1.53(m,4H),1.53–1.50(m,1H),1.46( m,J＝11.4,9.2,6.3,3.0Hz,4H),0.82–0.76(m,2H),0.76–0.70(m,2H).
实施例34Example 34
步骤1：4-氯-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(cyclopentylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000127
Figure PCTCN2022093052-appb-000127
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，乙炔基环戊烷(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶，579.9mg，收率79.6％。 1H NMR(300MHz,Chloroform-d)δ8.74(s,1H),7.85(s,1H),7.28(d,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H),2.85(m,J＝7.0Hz,1H),1.88(m,J＝12.2,6.5,2.7Hz,2H),1.63(m,J＝26.2,12.2,6.0,2.6Hz,4H),1.52(m,J＝10.1,5.2,3.4,1.8Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), ethynylcyclopentane (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain the corresponding solid compound 4-chloro-5-(cyclopentylethynyl)-1H-pyrrolo[2,3-b]pyridine, 579.9 mg, yield 79.6%. 1 H NMR (300MHz, Chloroform-d) δ8.74(s, 1H), 7.85(s, 1H), 7.28(d, J=7.5Hz, 1H), 6.69(d, J=7.5Hz, 1H), 2.85(m, J=7.0Hz, 1H), 1.88(m, J=12.2, 6.5, 2.7Hz, 2H), 1.63(m, J=26.2, 12.2, 6.0, 2.6Hz, 4H), 1.52(m, J＝10.1,5.2,3.4,1.8Hz,2H).
步骤2：N-环己基-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(cyclopentylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000128
Figure PCTCN2022093052-appb-000128
将化合物4-氯-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，136.7mg，收率33.3％。 1H NMR(300MHz,Chloroform-d)δ8.53(s,1H),7.75(s,1H),7.10(d,J＝7.5Hz,1H),6.77(d,J＝7.5Hz,1H),4.07(s,1H),3.84(s,1H),2.90(s,1H),1.98–1.83(m,4H),1.79–1.66(m,4H),1.66–1.53(m,8H),1.28(dd,J＝12.8,7.0Hz,2H). Compound 4-chloro-5-(cyclopentylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane , heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(cyclopentylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 136.7 mg, yield 33.3%. 1 H NMR (300MHz, Chloroform-d) δ8.53(s, 1H), 7.75(s, 1H), 7.10(d, J=7.5Hz, 1H), 6.77(d, J=7.5Hz, 1H), 4.07(s,1H),3.84(s,1H),2.90(s,1H),1.98–1.83(m,4H),1.79–1.66(m,4H),1.66–1.53(m,8H),1.28( dd,J=12.8,7.0Hz,2H).
步骤3：1-环己基-2-环戊基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-cyclopentyl-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000129
Figure PCTCN2022093052-appb-000129
在室温下向N-环己基-5-(环戊基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯 化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-环戊基-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，74.4mg，收率41.5％。m.p.240.3-245.0℃。 1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),7.95(s,1H),7.24(d,J＝7.5Hz,1H),6.87(d,J＝7.5Hz,1H),6.20(s,1H),4.43(s,1H),3.43(d,J＝12.6Hz,1H),2.20(d,J＝12.5Hz,1H),2.16–2.06(m,2H),1.86–1.70(m,6H),1.51–1.38(m,6H),0.85(s,3H). t- BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-cyclopentyl-1,6-dihydrodipyrrolo[2,3-b:2',3' -d] pyridine, 74.4 mg, yield 41.5%. mp240.3-245.0°C. 1 H NMR (300MHz, Chloroform-d) δ9.29(s, 1H), 7.95(s, 1H), 7.24(d, J=7.5Hz, 1H), 6.87(d, J=7.5Hz, 1H), 6.20(s,1H),4.43(s,1H),3.43(d,J=12.6Hz,1H),2.20(d,J=12.5Hz,1H),2.16–2.06(m,2H),1.86–1.70 (m,6H),1.51–1.38(m,6H),0.85(s,3H).
实施例35Example 35
步骤1：4-氯-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000130
Figure PCTCN2022093052-appb-000130
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，乙炔基环己烷(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶，528.9mg，收率72.6％。 1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.78(s,1H),7.18(d,J＝7.5Hz,1H),6.66(d,J＝7.5Hz,1H),2.37(s,1H),2.03(m,J＝13.1,6.6Hz,2H),1.83–1.61(m,5H),1.30–1.18(m,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), ethynylcyclohexane (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=10:1) to obtain the corresponding solid compound 4-chloro-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridine, 528.9 mg, yield 72.6 %. 1 H NMR (300MHz, Chloroform-d) δ8.76(s, 1H), 7.78(s, 1H), 7.18(d, J=7.5Hz, 1H), 6.66(d, J=7.5Hz, 1H), 2.37(s,1H),2.03(m,J＝13.1,6.6Hz,2H),1.83–1.61(m,5H),1.30–1.18(m,3H).
步骤2：N-环己基-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000131
Figure PCTCN2022093052-appb-000131
将化合物4-氯-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，39.6mg，收率34.1％。 1H NMR(300MHz,Chloroform-d)δ8.48(s,1H),7.83(s,1H),7.18(d,J＝7.5Hz,1H),6.77(d,J＝7.5Hz,1H),5.31(s,1H),3.84(s,1H),2.40(s,1H),2.04(m,J＝13.1,8.3,7.0Hz,4H),1.86–1.70(m,5H),1.70–1.55(m,6H),1.37(dd,J＝13.0,6.9Hz,2H),1.31–1.18(m,3H). Compound 4-chloro-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol ), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) were added to 20ml of dioxane, Heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine, 39.6 mg, yield 34.1%. 1 H NMR (300MHz, Chloroform-d) δ8.48(s, 1H), 7.83(s, 1H), 7.18(d, J=7.5Hz, 1H), 6.77(d, J=7.5Hz, 1H), 5.31(s,1H),3.84(s,1H),2.40(s,1H),2.04(m,J＝13.1,8.3,7.0Hz,4H),1.86–1.70(m,5H),1.70–1.55( m,6H), 1.37(dd,J=13.0,6.9Hz,2H),1.31–1.18(m,3H).
步骤3：1-环己基-2-(2-氟苯基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000132
Figure PCTCN2022093052-appb-000132
在室温下向N-环己基-5-(环己基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(2-氟苯基)-1,6-二氢二吡咯并[2,3-b： 2'，3'-d]吡啶，51.4mg，收率28.5％。m.p.213.7-216.9℃。 1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.03(s,1H),7.34(s,1H),6.92(s,1H),6.23(s,1H),4.75(s,1H),2.97(d,J＝12.8Hz,1H),2.50–2.38(m,2H),2.31(d,J＝13.0Hz,2H),1.98(d,J＝13.0Hz,2H),1.87–1.74(m,7H),1.65(d,J＝13.0Hz,2H),1.47(dd,J＝17.8,13.0Hz,3H),1.42–1.34(m,2H). To a mixture of N-cyclohexyl-5-(cyclohexylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK at room temperature (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), the corresponding solid compound 1-cyclohexyl-2-(2-fluorophenyl)-1,6-dihydrodipyrrolo[2,3-b: 2 ', 3'-d]pyridine, 51.4 mg, yield 28.5%. mp213.7-216.9°C. 1 H NMR (300MHz, Chloroform-d) δ9.27(s,1H),8.03(s,1H),7.34(s,1H),6.92(s,1H),6.23(s,1H),4.75(s ,1H),2.97(d,J=12.8Hz,1H),2.50–2.38(m,2H),2.31(d,J=13.0Hz,2H),1.98(d,J=13.0Hz,2H),1.87 –1.74(m,7H),1.65(d,J=13.0Hz,2H),1.47(dd,J=17.8,13.0Hz,3H),1.42–1.34(m,2H).
实施例36Example 36
步骤1：4-氯-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000133
Figure PCTCN2022093052-appb-000133
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，3-乙炔基噻吩(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶，510.0mg，收率70.0％。 1H NMR(300MHz,Chloroform-d)δ8.80(s,1H),7.88(s,1H),7.53–7.44(m,2H),7.30(dd,J＝7.5,5.5Hz,2H),6.71(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 3-ethynylthiophene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 510.0 mg, Yield 70.0%. 1 H NMR (300MHz, Chloroform-d) δ8.80(s,1H),7.88(s,1H),7.53–7.44(m,2H),7.30(dd,J=7.5,5.5Hz,2H),6.71 (d,J=7.5Hz,1H).
步骤2：N-环己基-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000134
Figure PCTCN2022093052-appb-000134
将化合物4-氯-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，147.5mg，收率36.0％。 1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.78(s,1H),7.56–7.47(m,2H),7.32(d,J＝7.5Hz,1H),7.13(d,J＝7.5Hz,1H),6.79(d,J＝7.5Hz,1H),3.93(s,1H),3.15(s,1H),2.04–1.95(m,2H),1.81–1.68(m,2H),1.68–1.57(m,4H),1.32(dd,J＝12.9,7.0Hz,2H). Compound 4-chloro-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 147.5 mg, yield 36.0%. 1 H NMR (300MHz, Chloroform-d) δ8.63(s, 1H), 7.78(s, 1H), 7.56–7.47(m, 2H), 7.32(d, J=7.5Hz, 1H), 7.13(d ,J=7.5Hz,1H),6.79(d,J=7.5Hz,1H),3.93(s,1H),3.15(s,1H),2.04–1.95(m,2H),1.81–1.68(m, 2H), 1.68–1.57(m, 4H), 1.32(dd, J＝12.9, 7.0Hz, 2H).
步骤3：1-环己基-2-(噻吩-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(thiophen-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000135
Figure PCTCN2022093052-appb-000135
在室温下向N-环己基-5-(噻吩-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(噻吩-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，52.5mg，收率29.2％。m.p.193.7-197.2℃。 1H NMR(300MHz,Chloroform-d)δ9.34(s,1H),8.00(s,1H),7.37(s,1H),7.33(d,J＝7.5Hz,1H),7.27(dd,J＝11.2,7.5Hz,2H), 7.09(s,1H),6.92(d,J＝7.5Hz,1H),4.47(s,1H),2.23(m,J＝11.7,6.2Hz,2H),1.89–1.71(m,5H),1.51–1.38(m,3H). To a mixture of N-cyclohexyl-5-(thiophen-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(thiophen-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d] pyridine, 52.5 mg, yield 29.2%. mp193.7-197.2°C. 1 H NMR (300MHz, Chloroform-d) δ9.34(s,1H),8.00(s,1H),7.37(s,1H),7.33(d,J=7.5Hz,1H),7.27(dd,J =11.2,7.5Hz,2H), 7.09(s,1H),6.92(d,J=7.5Hz,1H),4.47(s,1H),2.23(m,J=11.7,6.2Hz,2H),1.89 –1.71(m,5H),1.51–1.38(m,3H).
实施例37Example 37
步骤1：4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000136
Figure PCTCN2022093052-appb-000136
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶，59.9mg，收率76.8％。 1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.39(dd,J＝5.0,1.2Hz,1H),7.82(s,1H),7.56(dd,J＝8.1,1.1Hz,1H),7.47(m,J＝8.0,1.3Hz,1H),7.30–7.23(m,2H),6.68(d,J＝7.3Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynylpyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 59.9 mg, Yield 76.8%. 1 H NMR (300MHz, Chloroform-d) δ8.72(s,1H),8.39(dd,J=5.0,1.2Hz,1H),7.82(s,1H),7.56(dd,J=8.1,1.1Hz ,1H),7.47(m,J=8.0,1.3Hz,1H),7.30–7.23(m,2H),6.68(d,J=7.3Hz,1H).
步骤2：N-环己基-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000137
Figure PCTCN2022093052-appb-000137
将化合物4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，146.7mg，收率35.8％。 1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.48(s,1H),7.86(s,1H),7.63(d,J＝8.0Hz,1H),7.56(t,J＝7.9Hz,1H),7.35(d,J＝7.9Hz,1H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),4.30(s,1H),4.05(s,1H),2.07–1.98(m,2H),1.78–1.66(m,2H),1.66–1.56(m,4H),1.29(dd,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 146.7 mg, yield 35.8%. 1 H NMR (300MHz, Chloroform-d) δ8.60(s,1H),8.48(s,1H),7.86(s,1H),7.63(d,J＝8.0Hz,1H),7.56(t,J =7.9Hz,1H),7.35(d,J=7.9Hz,1H),7.20(d,J=7.5Hz,1H),6.80(d,J=7.5Hz,1H),4.30(s,1H), 4.05(s,1H),2.07–1.98(m,2H),1.78–1.66(m,2H),1.66–1.56(m,4H),1.29(dd,J＝12.9,6.9Hz,2H).
步骤3：1-环己基-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000138
Figure PCTCN2022093052-appb-000138
在室温下向N-环己基-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，50.9mg，收率28.3％。m.p.243.2-246.9℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.70(s,1H),8.07(s,1H),7.91(d,J＝8.0Hz,1H),7.71(t,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,1H),7.29(d,J＝7.9Hz,1H),7.18(s,1H),6.95(d,J＝7.5Hz,1H),4.49(s,1H),2.46(m,J＝13.3,6.9Hz,2H),2.04(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.55–1.36(m,3H). To a mixture of N-cyclohexyl-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d]pyridine, 50.9 mg, yield 28.3%. mp243.2-246.9°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.70(s,1H),8.07(s,1H),7.91(d,J＝8.0Hz,1H),7.71(t,J =8.0Hz,1H),7.35(d,J=7.5Hz,1H),7.29(d,J=7.9Hz,1H),7.18(s,1H),6.95(d,J=7.5Hz,1H), 4.49(s,1H),2.46(m,J=13.3,6.9Hz,2H),2.04(m,J=13.2,6.9Hz,2H),1.86–1.70(m,3H),1.55–1.36(m, 3H).
实施例38Example 38
步骤1：4-氯-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000139
Figure PCTCN2022093052-appb-000139
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，3-乙炔基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶，539.7mg，收率74.1％。 1H NMR(300MHz,Chloroform-d)δ8.71–8.66(m,2H),8.41(dd,J＝5.0,1.2Hz,1H),7.83–7.74(m,2H),7.30–7.20(m,2H),6.68(d,J＝7.5Hz,1H) Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 3-ethynylpyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 539.7 mg, Yield 74.1%. 1 H NMR (300MHz, Chloroform-d) δ8.71–8.66 (m, 2H), 8.41 (dd, J=5.0, 1.2Hz, 1H), 7.83–7.74 (m, 2H), 7.30–7.20 (m, 2H), 6.68(d, J=7.5Hz, 1H)
步骤2：N-环己基-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000140
Figure PCTCN2022093052-appb-000140
将化合物4-氯-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，131.8mg，收率32.1％。 1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),8.54(s,1H),8.50(s,1H),7.88–7.82(m,2H),7.33(d,J＝8.1Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.12(s,1H),3.80(s,1H),2.10–2.01(m,2H),1.80(m,J＝13.1,5.8Hz,2H),1.66–1.56(m,4H),1.38(dd,J＝12.8,7.0Hz,2H). Compound 4-chloro-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 131.8 mg, yield 32.1%. 1 H NMR (300MHz, Chloroform-d) δ8.76(s,1H),8.54(s,1H),8.50(s,1H),7.88–7.82(m,2H),7.33(d,J＝8.1Hz ,1H),7.19(d,J=7.5Hz,1H),6.78(d,J=7.5Hz,1H),5.12(s,1H),3.80(s,1H),2.10–2.01(m,2H) ,1.80(m,J=13.1,5.8Hz,2H),1.66–1.56(m,4H),1.38(dd,J=12.8,7.0Hz,2H).
步骤3：1-环己基-2-(吡啶-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(pyridin-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000141
Figure PCTCN2022093052-appb-000141
在室温下向N-环己基-5-(吡啶-3-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(吡啶-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，65.4mg，收率36.4％。m.p.192.7-193.5℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.91(s,1H),8.64(s,1H),8.13–8.06(m,2H),7.55(d,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),7.05(s,1H),6.94(d,J＝7.5Hz,1H),4.23(s,1H),2.29(m,J＝12.9,7.0Hz,2H),2.06(m,J＝13.2,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.43(m,1H),1.43–1.34(m,2H). To a mixture of N-cyclohexyl-5-(pyridin-3-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(pyridin-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d]pyridine, 65.4 mg, yield 36.4%. mp192.7-193.5°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.91(s,1H),8.64(s,1H),8.13–8.06(m,2H),7.55(d,J=7.9Hz ,1H),7.35(d,J=7.5Hz,1H),7.05(s,1H),6.94(d,J=7.5Hz,1H),4.23(s,1H),2.29(m,J=12.9, 7.0Hz, 2H), 2.06(m, J=13.2, 6.9Hz, 2H), 1.86–1.69(m, 3H), 1.53–1.43(m, 1H), 1.43–1.34(m, 2H).
实施例39Example 39
步骤1：4-氯-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000142
Figure PCTCN2022093052-appb-000142
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，4-乙炔基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶，568.9mg，收率78.0％。 1H NMR(300MHz,Chloroform-d)δ8.69(s,1H),8.35(d,J＝5.1Hz,2H),7.82(s,1H),7.49(d,J＝5.0Hz,2H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 4-ethynylpyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 568.9 mg, Yield 78.0%. 1 H NMR (300MHz, Chloroform-d) δ8.69(s,1H),8.35(d,J=5.1Hz,2H),7.82(s,1H),7.49(d,J=5.0Hz,2H), 7.28(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000143
Figure PCTCN2022093052-appb-000143
将化合物4-氯-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，148.3mg，收率36.2％。 1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),8.45(s,2H),7.86(s,1H),7.57(s,2H),7.21(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),4.19(s,1H),3.82(s,1H),2.09–2.00(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.69–1.57(m,4H),1.35(dd,J＝13.6,6.4Hz,2H). Compound 4-chloro-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 148.3 mg, yield 36.2%. 1 H NMR (300MHz, Chloroform-d) δ8.57(s,1H),8.45(s,2H),7.86(s,1H),7.57(s,2H),7.21(d,J=7.5Hz,1H ),6.81(d,J=7.5Hz,1H),4.19(s,1H),3.82(s,1H),2.09–2.00(m,2H),1.78(m,J=13.1,5.9Hz,2H) ,1.69–1.57(m,4H),1.35(dd,J＝13.6,6.4Hz,2H).
步骤3：1-环己基-2-(吡啶-4-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(pyridin-4-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000144
Figure PCTCN2022093052-appb-000144
在室温下向N-环己基-5-(吡啶-4-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(吡啶-4-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，68.5mg，收率38.0％。m.p.236.2-237.3℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.67(s,2H),8.08(s,1H),7.81(s,2H),7.35(d,J＝7.5Hz,1H),7.07(s,1H),6.94(d,J＝7.5Hz,1H),4.25(s,1H),2.28(m,J＝12.8,6.9Hz,2H),2.06(m,J＝13.2,6.9Hz,2H),1.86–1.69(m,3H),1.54–1.42(m,1H),1.42–1.33(m,2H). To a mixture of N-cyclohexyl-5-(pyridin-4-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(pyridin-4-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d] pyridine, 68.5 mg, yield 38.0%. mp236.2-237.3°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.67(s,2H),8.08(s,1H),7.81(s,2H),7.35(d,J=7.5Hz,1H ),7.07(s,1H),6.94(d,J=7.5Hz,1H),4.25(s,1H),2.28(m,J=12.8,6.9Hz,2H),2.06(m,J=13.2, 6.9Hz, 2H), 1.86–1.69(m, 3H), 1.54–1.42(m, 1H), 1.42–1.33(m, 2H).
实施例19Example 19
步骤1：4-氯-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000145
Figure PCTCN2022093052-appb-000145
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，5-乙炔基嘧啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶，509.7mg，收率69.9％。 1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),9.05(s,2H),8.84(s,1H),7.81(s,1H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 5-ethynylpyrimidine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 509.7 mg, Yield 69.9%. 1 H NMR (300MHz, Chloroform-d) δ9.27(s,1H),9.05(s,2H),8.84(s,1H),7.81(s,1H),7.28(d,J=7.5Hz,1H ),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000146
Figure PCTCN2022093052-appb-000146
将化合物4-氯-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，140.1mg，收率34.2％。 1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),9.03(s,2H),8.80(s,1H),7.85(s,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.84(d,J＝1.3Hz,2H),2.09–1.99(m,2H),1.80(m,J＝13.1,5.8Hz,2H),1.68–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 140.1 mg, yield 34.2%. 1 H NMR (300MHz, Chloroform-d) δ9.27(s,1H),9.03(s,2H),8.80(s,1H),7.85(s,1H),7.22(d,J=7.5Hz,1H ),6.81(d,J=7.5Hz,1H),3.84(d,J=1.3Hz,2H),2.09–1.99(m,2H),1.80(m,J=13.1,5.8Hz,2H),1.68 –1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
步骤3：1-环己基-2-(嘧啶-5-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(pyrimidin-5-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000147
Figure PCTCN2022093052-appb-000147
在室温下向N-环己基-5-(嘧啶-5-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(嘧啶-5-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，73.5mg，收率40.8％。m.p.196.4-197.8℃。 1H NMR(300MHz,Chloroform-d)δ9.45(s,1H),9.17(s,1H),9.05(s,2H),8.08(s,1H),7.35(d,J＝7.5Hz,1H),7.05(s,1H),6.94(d,J＝7.5Hz,1H),4.18(s,1H),2.29(m,J＝13.3,6.9Hz,2H),2.07(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.55–1.43(m,1H),1.46–1.35(m,2H). To a mixture of N-cyclohexyl-5-(pyrimidin-5-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(pyrimidin-5-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d] pyridine, 73.5 mg, yield 40.8%. mp196.4-197.8°C. 1 H NMR(300MHz,Chloroform-d)δ9.45(s,1H),9.17(s,1H),9.05(s,2H),8.08(s,1H),7.35(d,J=7.5Hz,1H ),7.05(s,1H),6.94(d,J=7.5Hz,1H),4.18(s,1H),2.29(m,J=13.3,6.9Hz,2H),2.07(m,J=13.3, 6.9Hz, 2H), 1.87–1.70(m, 3H), 1.55–1.43(m, 1H), 1.46–1.35(m, 2H).
实施例41Example 41
步骤1：4-氯-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000148
Figure PCTCN2022093052-appb-000148
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基嘧啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶，500.7mg，收率68.7％。 1H NMR(300MHz,Chloroform-d)δ8.84(s,1H),8.79(d,J＝4.9Hz,2H),7.80(s,1H),7.39(t,J＝5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.67(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynylpyrimidine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol ) and 1ml of triethylamine were added into 25ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine, 500.7 mg, Yield 68.7%. 1 H NMR (300MHz, Chloroform-d) δ8.84(s, 1H), 8.79(d, J=4.9Hz, 2H), 7.80(s, 1H), 7.39(t, J=5.0Hz, 1H), 7.27(d,J=7.5Hz,1H),6.67(d,J=7.5Hz,1H).
步骤2：N-环己基-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000149
Figure PCTCN2022093052-appb-000149
将化合物4-氯-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，147.1mg，收率35.9％。 1H NMR(300MHz,Chloroform-d)δ8.84(s,1H),8.79(s,2H),7.86(s,1H),7.38(s,1H),7.24(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.91(s,1H),2.85(s,1H),2.12–2.03(m,2H),1.84–1.71(m,2H),1.68(dd,J＝12.8,6.8Hz,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.37(dd,J＝12.9,6.9Hz,2H). Compound 4-chloro-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg , 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml dioxane In the ring, heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine-4- Amine, 147.1 mg, yield 35.9%. 1 H NMR(300MHz,Chloroform-d)δ8.84(s,1H),8.79(s,2H),7.86(s,1H),7.38(s,1H),7.24(d,J=7.5Hz,1H ),6.83(d,J＝7.5Hz,1H),3.91(s,1H),2.85(s,1H),2.12–2.03(m,2H),1.84–1.71(m,2H),1.68(dd, J=12.8,6.8Hz,2H),1.61(dd,J=6.4,1.6Hz,2H),1.37(dd,J=12.9,6.9Hz,2H).
步骤3：1-环己基-2-(嘧啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(pyrimidin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000150
Figure PCTCN2022093052-appb-000150
在室温下向N-环己基-5-(嘧啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(嘧啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，67.7mg，收率37.6％。m.p.188.5-189.4℃。 1H NMR(300MHz,Chloroform-d)δ9.45(s,1H),9.06(s,2H),8.08(s,1H),7.47(s,1H),7.37–7.29(m,2H),6.95(d,J＝7.5Hz,1H),4.51(s,1H),2.45(m,J＝13.3,6.9Hz,2H),2.04(m,J＝13.2,6.9Hz,2H),1.88–1.71(m,3H),1.55–1.37(m,3H). To a mixture of N-cyclohexyl-5-(pyrimidin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5 mmol) and THF (10 mL) was added at room temperature t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(pyrimidin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2 ', 3'-d]pyridine, 67.7 mg, yield 37.6%. mp188.5-189.4°C. 1 H NMR (300MHz, Chloroform-d) δ9.45(s,1H),9.06(s,2H),8.08(s,1H),7.47(s,1H),7.37–7.29(m,2H),6.95 (d, J=7.5Hz, 1H), 4.51(s, 1H), 2.45(m, J=13.3, 6.9Hz, 2H), 2.04(m, J=13.2, 6.9Hz, 2H), 1.88–1.71( m,3H),1.55–1.37(m,3H).
实施例42Example 42
步骤1：2-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈的制备Step 1: Preparation of 2-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile
Figure PCTCN2022093052-appb-000151
Figure PCTCN2022093052-appb-000151
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基烟腈(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物2-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈，586.9mg，收率80.5％。 1H NMR(300MHz,Chloroform-d)δ8.75(dd,J＝5.1,1.2Hz,1H),8.72(s,1H),8.09(dd,J＝8.1,1.3Hz,1H),7.81(s,1H),7.56(dd,J＝8.0,5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynylnicotinonitrile (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18 mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 2-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile, 586.9 mg, yield 80.5%. 1 H NMR (300MHz, Chloroform-d) δ8.75(dd, J=5.1,1.2Hz,1H),8.72(s,1H),8.09(dd,J=8.1,1.3Hz,1H),7.81(s ,1H),7.56(dd,J=8.0,5.0Hz,1H),7.27(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：2-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈的制备Step 2: Preparation of 2-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile
Figure PCTCN2022093052-appb-000152
Figure PCTCN2022093052-appb-000152
将化合物2-((4-氯-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物2-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈，133.5mg，收率32.6％。 1H NMR(300MHz,Chloroform-d)δ8.81(s,1H),8.56(s,1H),8.14(d,J＝8.0Hz,1H),7.86(s,1H),7.62(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),5.36(s,1H),3.77(s,1H),2.08–1.98(m,2H),1.85–1.73(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.27(m,2H). Compound 2-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml di Hexane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) afforded the corresponding solid compound 2-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl) Niacinonitrile, 133.5 mg, yield 32.6%. 1 H NMR (300MHz, Chloroform-d) δ8.81(s,1H),8.56(s,1H),8.14(d,J=8.0Hz,1H),7.86(s,1H),7.62(d,J =7.9Hz,1H),7.19(d,J=7.5Hz,1H),6.80(d,J=7.5Hz,1H),5.36(s,1H),3.77(s,1H),2.08–1.98(m ,2H),1.85–1.73(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.27(m,2H).
步骤3：1-环己基-2-(3-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000153
Figure PCTCN2022093052-appb-000153
在室温下向2-((4-(环己基氨基)-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)烟腈(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，55.9mg，收率31.1％。m.p.205.6-206.4℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.51(s,1H),8.07(s,1H),7.61(t,J＝8.0Hz,1H),7.45(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.13(s,1H),6.95(d,J＝7.5Hz,1H),4.44(s,1H),2.52–2.43(m,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.56–1.36(m,3H). To a mixture of 2-((4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl)nicotinonitrile (1.5 mmol) and THF (10 mL) at room temperature t-BuOK (252.3 mg, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(3-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 55.9 mg, yield 31.1%. mp205.6-206.4°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.51(s,1H),8.07(s,1H),7.61(t,J=8.0Hz,1H),7.45(d,J =8.1Hz,1H),7.35(d,J=7.5Hz,1H),7.13(s,1H),6.95(d,J=7.5Hz,1H),4.44(s,1H),2.52–2.43(m ,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.56–1.36(m,3H).
实施例43Example 43
步骤1：4-氯-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000154
Figure PCTCN2022093052-appb-000154
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，1-乙炔基-2-氟苯(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，770.8mg，收率73.6％。 1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.85(s,1H),7.56(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J＝7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 770.8 mg, yield 73.6%. 1 H NMR (300MHz, Chloroform-d) δ8.57(s, 1H), 7.85(s, 1H), 7.56(d, J=7.5Hz, 1H), 7.36(t, J=7.5Hz, 1H), 7.19(d,J=7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J=7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01 (m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H).
步骤2：N-环己基-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000155
Figure PCTCN2022093052-appb-000155
将化合物4-氯-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，143.0mg，收率34.9％。 1H NMR(300MHz,Chloroform-d)δ8.56(s,1H),7.85(s,1H),7.45(t,J＝7.4Hz,1H),7.40(d,J＝7.4Hz,1H),7.29(dd,J＝8.8,7.3Hz,1H),7.19(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),5.38(s,1H),3.83(s,1H),2.08–1.96(m,2H),1.85–1.74(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.28(m,2H). The compound 4-chloro-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 143.0 mg, yield 34.9%. 1 H NMR (300MHz, Chloroform-d) δ8.56(s, 1H), 7.85(s, 1H), 7.45(t, J=7.4Hz, 1H), 7.40(d, J=7.4Hz, 1H), 7.29(dd, J=8.8,7.3Hz,1H),7.19(d,J=7.5Hz,1H),6.80(d,J=7.5Hz,1H),5.38(s,1H),3.83(s,1H ),2.08–1.96(m,2H),1.85–1.74(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.28(m,2H).
步骤3：1-环己基-2-(4-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(4-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000156
Figure PCTCN2022093052-appb-000156
在室温下向N-环己基-5-((3-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(4-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，66.5mg，收率36.9％。m.p.187.2-189.6℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.66(s,1H),8.08(s,1H),7.53(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.28(d,J＝8.1Hz,1H),7.20(s,1H),6.95(d,J＝7.5Hz,1H),4.44(s,1H),2.46(m,J＝12.8,6.9Hz,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.54–1.35(m,3H). N-cyclohexyl-5-((3-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(4-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 66.5 mg, yield 36.9%. mp187.2-189.6°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.66(s,1H),8.08(s,1H),7.53(d,J＝8.1Hz,1H),7.35(d,J =7.5Hz,1H),7.28(d,J=8.1Hz,1H),7.20(s,1H),6.95(d,J=7.5Hz,1H),4.44(s,1H),2.46(m,J ＝12.8,6.9Hz,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.54–1.35(m,3H).
实施例44Example 44
步骤1：4-氯-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000157
Figure PCTCN2022093052-appb-000157
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-4-氟吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，584.7mg，收率80.2％。 1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.31(t,J＝5.0Hz,1H),7.82(s,1H),7.32–7.25(m,2H),7.06(m,J＝7.9,4.9,0.9Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-4-fluoropyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 584.7 mg, yield 80.2%. 1 H NMR (300MHz, Chloroform-d) δ8.72(s, 1H), 8.31(t, J=5.0Hz, 1H), 7.82(s, 1H), 7.32–7.25(m, 2H), 7.06(m ,J=7.9,4.9,0.9Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000158
Figure PCTCN2022093052-appb-000158
将化合物4-氯-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，135.1mg，收率33.1％。 1H NMR(300MHz,Chloroform-d)δ8.55(s,1H),8.41(s,1H),7.85(s,1H),7.37(d,J＝8.1Hz,1H),7.17(dd,J＝19.9,7.8Hz,2H),6.78(d,J＝7.5Hz,1H),5.02(s,1H),3.79(s,1H),2.10–2.00(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.66–1.56(m,4H),1.38(dd,J＝13.6,6.4Hz,2H). The compound 4-chloro-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 135.1 mg, yield 33.1%. 1 H NMR (300MHz, Chloroform-d)δ8.55(s,1H),8.41(s,1H),7.85(s,1H),7.37(d,J=8.1Hz,1H),7.17(dd,J =19.9,7.8Hz,2H),6.78(d,J=7.5Hz,1H),5.02(s,1H),3.79(s,1H),2.10–2.00(m,2H),1.79(m,J= 13.1,5.9Hz,2H),1.66–1.56(m,4H),1.38(dd,J＝13.6,6.4Hz,2H).
步骤3：1-环己基-2-(3-(三氟甲基)吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: 1-Cyclohexyl-2-(3-(trifluoromethyl)pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d] Preparation of pyridine
Figure PCTCN2022093052-appb-000159
Figure PCTCN2022093052-appb-000159
在室温下向N-环己基-5-((4-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3-(三氟甲基)吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，62.9mg，收率34.6％。m.p.192.5-193.7℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.85(s,1H),8.07(s,1H),7.93(d,J＝8.1Hz,1H),7.62(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.12(s,1H),6.94(d,J＝7.5Hz,1H),4.19(s,1H),2.45(m,J＝13.0,7.0Hz,2H),2.06(m,J＝13.0,6.9Hz,2H),1.85–1.78(m,1H),1.81–1.69(m,2H),1.54–1.44(m,1H),1.46–1.32(m,2H). N-cyclohexyl-5-((4-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-cyclohexyl-2-(3-(trifluoromethyl)pyridin-2-yl)-1,6-dihydrodipyrrolo [2,3-b: 2',3'-d]pyridine, 62.9 mg, yield 34.6%. mp192.5-193.7°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.85(s,1H),8.07(s,1H),7.93(d,J＝8.1Hz,1H),7.62(d,J =8.1Hz,1H),7.35(d,J=7.5Hz,1H),7.12(s,1H),6.94(d,J=7.5Hz,1H),4.19(s,1H),2.45(m,J ＝13.0,7.0Hz,2H),2.06(m,J＝13.0,6.9Hz,2H),1.85–1.78(m,1H),1.81–1.69(m,2H),1.54–1.44(m,1H), 1.46–1.32(m,2H).
实施例45Example 45
步骤1：4-氯-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000160
Figure PCTCN2022093052-appb-000160
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-3-(三氟甲基)吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，770.8mg，收率73.6％。513.5mg，收率70.5％。 1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.49(dd,J＝5.2,1.3Hz,1H),7.81(s,1H),7.66–7.60(m,1H),7.39(dd,J＝8.0,5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-3-(trifluoromethyl)pyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18 mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2 ,3-b]pyridine, 770.8 mg, yield 73.6%. 513.5 mg, yield 70.5%. 1 H NMR (300MHz, Chloroform-d)δ8.72(s,1H),8.49(dd,J＝5.2,1.3Hz,1H),7.81(s,1H),7.66–7.60(m,1H),7.39 (dd, J=8.0,5.0Hz,1H),7.27(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000161
Figure PCTCN2022093052-appb-000161
将化合物4-氯-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，138.5mg，收率33.8％。 1H NMR(300MHz,Chloroform-d)δ8.59(d,J＝12.1Hz,2H),7.86(s,1H),7.72(d,J＝8.1Hz,1H),7.48(d,J＝8.1Hz,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.98(s,1H),3.87(s,1H),2.05(dd,J＝13.5,6.3Hz,2H),1.78(dd,J＝13.4,6.2Hz,2H),1.72–1.63(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.39(m,J＝13.1,6.5Hz,2H). Compound 4-chloro-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul , 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 ( 75mg, 0.13mmol) was added into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[ 2,3-b]pyridin-4-amine, 138.5 mg, yield 33.8%. 1 H NMR (300MHz, Chloroform-d) δ8.59(d, J=12.1Hz, 2H), 7.86(s, 1H), 7.72(d, J=8.1Hz, 1H), 7.48(d, J=8.1 Hz,1H),7.22(d,J=7.5Hz,1H),6.81(d,J=7.5Hz,1H),3.98(s,1H),3.87(s,1H),2.05(dd,J=13.5 ,6.3Hz,2H),1.78(dd,J＝13.4,6.2Hz,2H),1.72–1.63(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.39(m,J＝ 13.1,6.5Hz,2H).
步骤3：1-环己基-2-(3-甲基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(3-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000162
Figure PCTCN2022093052-appb-000162
在室温下向N-环己基-5-((3-(三氟甲基)吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(3-甲基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，51.1mg，收率28.4％。m.p.214.2-215.6℃。 1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),8.66(s,1H),8.07(s,1H),7.65(d,J＝8.1Hz,1H),7.47(d,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),6.99–6.92(m,2H),4.35(s,1H),2.41(d,J＝19.0Hz, 5H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.54–1.34(m,3H). To N-cyclohexyl-5-((3-(trifluoromethyl)pyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol ) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(3-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3 -b: 2',3'-d]pyridine, 51.1 mg, yield 28.4%. mp214.2-215.6°C. 1 H NMR (300MHz, Chloroform-d) δ9.29(s,1H),8.66(s,1H),8.07(s,1H),7.65(d,J＝8.1Hz,1H),7.47(d,J =7.9Hz,1H),7.35(d,J=7.5Hz,1H),6.99–6.92(m,2H),4.35(s,1H),2.41(d,J=19.0Hz,5H),2.04(m ,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.54–1.34(m,3H).
实施例46Example 46
步骤1：4-氯-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000163
Figure PCTCN2022093052-appb-000163
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-3-甲基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，572.7mg，收率78.6％。 1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.30(dd,J＝4.9,1.3Hz,1H),7.81(s,1H),7.36(dd,J＝8.1,1.3Hz,1H),7.30–7.21(m,2H),6.68(d,J＝7.5Hz,1H),2.48(s,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-3-picoline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridine, 572.7 mg, yield 78.6%. 1 H NMR (300MHz, Chloroform-d) δ8.71(s,1H),8.30(dd,J＝4.9,1.3Hz,1H),7.81(s,1H),7.36(dd,J＝8.1,1.3Hz ,1H),7.30–7.21(m,2H),6.68(d,J＝7.5Hz,1H),2.48(s,3H).
步骤2：N-环己基-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000164
Figure PCTCN2022093052-appb-000164
将化合物4-氯-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，136.8mg，收率33.4％。 1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),8.40(s,1H),7.85(s,1H),7.45(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.86(s,1H),3.71(s,1H),2.48(s,3H),2.09–1.99(m,2H),1.82–1.73(m,2H),1.69–1.57(m,4H),1.35(m,J＝13.0,6.6Hz,2H). Compound 4-chloro-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol) , t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol ) into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridin-4-amine, 136.8 mg, yield 33.4%. 1 H NMR (300MHz, Chloroform-d) δ8.59(s,1H),8.40(s,1H),7.85(s,1H),7.45(d,J=7.9Hz,1H),7.33(d,J =8.1Hz,1H),7.22(d,J=7.5Hz,1H),6.81(d,J=7.5Hz,1H),3.86(s,1H),3.71(s,1H),2.48(s,3H ),2.09–1.99(m,2H),1.82–1.73(m,2H),1.69–1.57(m,4H),1.35(m,J＝13.0,6.6Hz,2H).
步骤3：1-环己基-2-(6-氟吡啶-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(6-fluoropyridin-3-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000165
Figure PCTCN2022093052-appb-000165
在室温下向N-环己基-5-((3-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(6-氟吡啶-3-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，52.4mg，收率29.1％。206.2-208.8℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.72(s,1H),8.30(d,J＝8.1Hz,1H),8.08(s,1H),7.35(d,J＝7.5Hz,1H),7.16(t,J＝8.0Hz,1H),7.04(s,1H),6.94(d,J＝7.5Hz,1H),4.17(s,1H),2.29(m,J＝12.9,6.9Hz,2H),2.07(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.33(m,3H). N-cyclohexyl-5-((3-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(6-fluoropyridin-3-yl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 52.4 mg, yield 29.1%. 206.2-208.8°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.72(s,1H),8.30(d,J＝8.1Hz,1H),8.08(s,1H),7.35(d,J =7.5Hz,1H),7.16(t,J=8.0Hz,1H),7.04(s,1H),6.94(d,J=7.5Hz,1H),4.17(s,1H),2.29(m,J ＝12.9,6.9Hz,2H),2.07(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.33(m,3H).
实施例47Example 47
步骤1：4-氯-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000166
Figure PCTCN2022093052-appb-000166
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，5-乙炔基-2-氟吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，528.6mg，收率72.5％。 1H NMR(300MHz,Chloroform-d)δ8.68(s,1H),8.46(d,J＝1.2Hz,1H),8.05(m,J＝8.1,5.0,1.3Hz,1H),7.81(s,1H),7.28(d,J＝7.5Hz,1H),6.88(t,J＝8.0Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 5-ethynyl-2-fluoropyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 528.6 mg, yield 72.5%. 1 H NMR (300MHz, Chloroform-d) δ8.68(s, 1H), 8.46(d, J=1.2Hz, 1H), 8.05(m, J=8.1, 5.0, 1.3Hz, 1H), 7.81(s ,1H),7.28(d,J=7.5Hz,1H),6.88(t,J=8.0Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000167
Figure PCTCN2022093052-appb-000167
将化合物4-氯-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，149.0mg，收率36.3％。 1H NMR(300MHz,Chloroform-d)δ8.54(d,J＝11.2Hz,2H),8.11(d,J＝7.9Hz,1H),7.85(s,1H),7.19(d,J＝7.5Hz,1H),6.96(t,J＝8.1Hz,1H),6.78(d,J＝7.3Hz,1H),4.99(s,1H),3.80(s,1H),2.05(dd,J＝13.5,6.4Hz,2H),1.85–1.76(m,2H),1.66–1.56(m,4H),1.39(m,J＝13.1,6.5Hz,2H). The compound 4-chloro-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 149.0 mg, yield 36.3%. 1 H NMR (300MHz, Chloroform-d) δ8.54(d, J=11.2Hz, 2H), 8.11(d, J=7.9Hz, 1H), 7.85(s, 1H), 7.19(d, J=7.5 Hz,1H),6.96(t,J=8.1Hz,1H),6.78(d,J=7.3Hz,1H),4.99(s,1H),3.80(s,1H),2.05(dd,J=13.5 ,6.4Hz,2H),1.85–1.76(m,2H),1.66–1.56(m,4H),1.39(m,J＝13.1,6.5Hz,2H).
步骤3：1-环己基-2-(6-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(6-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000168
Figure PCTCN2022093052-appb-000168
在室温下向N-环己基-5-((6-氟吡啶-3-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(6-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，71.9mg，收率40.0％。m.p.207.1-208.6℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.07(s,1H),7.90(d,J＝8.0Hz,1H),7.85(t,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),7.21(s,1H),6.96(d,J＝7.5Hz,1H),6.89(t,J＝7.9Hz,1H),4.44(s,1H),2.48 (m,J＝13.4,6.8Hz,2H),2.05(m,J＝13.3,6.8Hz,2H),1.87–1.71(m,3H),1.55–1.37(m,3H). N-cyclohexyl-5-((6-fluoropyridin-3-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(6-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 71.9 mg, yield 40.0%. mp207.1-208.6°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s, 1H), 8.07(s, 1H), 7.90(d, J=8.0Hz, 1H), 7.85(t, J=7.9Hz, 1H), 7.35(d, J=7.5Hz, 1H), 7.21(s, 1H), 6.96(d, J=7.5Hz, 1H), 6.89(t, J=7.9Hz, 1H), 4.44(s, 1H), 2.48 (m, J=13.4,6.8Hz,2H),2.05(m,J=13.3,6.8Hz,2H),1.87–1.71(m,3H),1.55–1.37(m,3H).
实施例48Example 48
步骤1：4-氯-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000169
Figure PCTCN2022093052-appb-000169
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-5-氟吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，517.7mg，收率71.0％。 1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.41(dd,J＝8.1,1.3Hz,1H),7.81(s,1H),7.55(dd,J＝8.1,5.0Hz,1H),7.33(m,J＝8.0,1.3Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-5-fluoropyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI ( 34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b] Pyridine, 517.7 mg, yield 71.0%. 1 H NMR (300MHz, Chloroform-d) δ8.71(s,1H),8.41(dd,J＝8.1,1.3Hz,1H),7.81(s,1H),7.55(dd,J＝8.1,5.0Hz ,1H),7.33(m,J=8.0,1.3Hz,1H),7.27(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000170
Figure PCTCN2022093052-appb-000170
将化合物4-氯-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，137.3mg，收率33.5％。 1H NMR(300MHz,Chloroform-d)δ8.56–8.47(m,2H),7.85(s,1H),7.61(d,J＝8.1Hz,1H),7.41(t,J＝8.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.07(s,1H),3.79(s,1H),2.04(dd,J＝12.9,7.0Hz,2H),1.79(dd,J＝13.4,6.4Hz,2H),1.66–1.56(m,4H),1.38(m,J＝13.1,6.6Hz,2H). Compound 4-chloro-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd2 (dba) 3 (75mg, 0.13mmol) Add 20ml of dioxane and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridin-4-amine, 137.3 mg, yield 33.5%. 1 H NMR (300MHz, Chloroform-d) δ8.56–8.47(m, 2H), 7.85(s, 1H), 7.61(d, J=8.1Hz, 1H), 7.41(t, J=8.0Hz, 1H ), 7.19(d, J=7.5Hz, 1H), 6.78(d, J=7.5Hz, 1H), 5.07(s, 1H), 3.79(s, 1H), 2.04(dd, J=12.9, 7.0Hz ,2H),1.79(dd,J=13.4,6.4Hz,2H),1.66–1.56(m,4H),1.38(m,J=13.1,6.6Hz,2H).
步骤3：1-环己基-2-(5-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(5-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000171
Figure PCTCN2022093052-appb-000171
在室温下向N-环己基-5-((5-氟吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(5-氟吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，71.9mg，收率40.0％。m.p.186.5-187.7℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.75(d,J＝7.9Hz,1H),8.07(s,1H),7.91(d,J＝8.1Hz,1H),7.62(t,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.12(s,1H),6.95(d,J＝7.5Hz,1H),4.44(s,1H),2.45 (m,J＝13.3,6.9Hz,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.56–1.36(m,3H). N-cyclohexyl-5-((5-fluoropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF (10mL ) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(5-fluoropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3- b: 2',3'-d]pyridine, 71.9 mg, yield 40.0%. mp186.5-187.7°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s, 1H), 8.75(d, J=7.9Hz, 1H), 8.07(s, 1H), 7.91(d, J=8.1Hz, 1H), 7.62(t, J=8.1Hz, 1H), 7.35(d, J=7.5Hz, 1H), 7.12(s, 1H), 6.95(d, J=7.5Hz, 1H), 4.44(s, 1H), 2.45 (m, J=13.3,6.9Hz,2H),2.05(m,J=13.3,6.9Hz,2H),1.87–1.70(m,3H),1.56–1.36(m,3H).
实施例49Example 49
步骤1：4-氯-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000172
Figure PCTCN2022093052-appb-000172
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-5-甲基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，494.8mg，收率67.5％。 1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.22(d,J＝1.3Hz,1H),7.81(s,1H),7.48(d,J＝8.0Hz,1H),7.37(dd,J＝8.1,1.3Hz,1H),7.27(d,J＝7.3Hz,1H),6.68(d,J＝7.5Hz,1H),2.32(s,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-5-picoline (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridine, 494.8 mg, yield 67.5%. 1 H NMR (300MHz, Chloroform-d) δ8.71(s, 1H), 8.22(d, J=1.3Hz, 1H), 7.81(s, 1H), 7.48(d, J=8.0Hz, 1H), 7.37(dd, J=8.1,1.3Hz,1H),7.27(d,J=7.3Hz,1H),6.68(d,J=7.5Hz,1H),2.32(s,3H).
步骤2：N-环己基-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000173
Figure PCTCN2022093052-appb-000173
将化合物4-氯-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，223.4mg，收率30.5％。 1H NMR(300MHz,Chloroform-d)δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J＝7.9Hz,1H),7.25(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.24(s,1H),3.80(d,J＝16.3Hz,4H),2.05(dd,J＝13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J＝13.0,6.6Hz,2H). Compound 4-chloro-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol) , t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol ) into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridin-4-amine, 223.4 mg, yield 30.5%. 1 H NMR (300MHz, Chloroform-d) δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J=7.9Hz,1H),7.25(d,J =7.9Hz,1H),7.19(d,J=7.5Hz,1H),6.78(d,J=7.5Hz,1H),5.24(s,1H),3.80(d,J=16.3Hz,4H), 2.05(dd,J=13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J=13.0,6.6Hz,2H).
步骤3：1-环己基-2-(5-甲基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(5-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000174
Figure PCTCN2022093052-appb-000174
在室温下向N-环己基-5-((5-甲基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(5-甲基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，83.5mg，收率33.8％。m.p.196.5-198.2℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(s,1H),6.95(d,J＝7.5Hz,1H),4.48(s,1H),2.50–2.41(m,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37 (m,3H). N-cyclohexyl-5-((5-methylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(5-methylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3 -b: 2',3'-d]pyridine, 83.5 mg, yield 33.8%. mp196.5-198.2°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J =8.1Hz,1H),7.35(d,J=7.5Hz,1H),7.15(s,1H),6.95(d,J=7.5Hz,1H),4.48(s,1H),2.50–2.41(m ,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37 (m,3H).
实施例50Example 50
步骤1：4-氯-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000175
Figure PCTCN2022093052-appb-000175
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-5-甲氧基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，466.6mg，收率68.0％。 1H NMR(300MHz,Chloroform-d)δ8.70(s,1H),8.18(d,J＝1.2Hz,1H),7.81(s,1H),7.58(d,J＝8.0Hz,1H),7.27(d,J＝7.5Hz,1H),7.19(dd,J＝8.1,1.3Hz,1H),6.68(d,J＝7.5Hz,1H),3.80(s,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-5-methoxypyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34 mg, 0.18 mmol) and 1 ml of triethylamine were added to 25 ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=10:1) to give the corresponding solid compound 4-chloro-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 466.6 mg, yield 68.0%. 1 H NMR (300MHz, Chloroform-d) δ8.70(s, 1H), 8.18(d, J=1.2Hz, 1H), 7.81(s, 1H), 7.58(d, J=8.0Hz, 1H), 7.27(d, J=7.5Hz, 1H), 7.19(dd, J=8.1, 1.3Hz, 1H), 6.68(d, J=7.5Hz, 1H), 3.80(s, 3H).
步骤2：N-环己基-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000176
Figure PCTCN2022093052-appb-000176
将化合物4-氯-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，202.6mg，收率29.5％。 1H NMR(300MHz,Chloroform-d)δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J＝7.9Hz,1H),7.25(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.24(s,1H),3.80(d,J＝16.3Hz,4H),2.05(dd,J＝13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J＝13.0,6.6Hz,2H). The compound 4-chloro-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 202.6 mg, yield 29.5%. 1 H NMR (300MHz, Chloroform-d) δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J=7.9Hz,1H),7.25(d,J =7.9Hz,1H),7.19(d,J=7.5Hz,1H),6.78(d,J=7.5Hz,1H),5.24(s,1H),3.80(d,J=16.3Hz,4H), 2.05(dd,J=13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J=13.0,6.6Hz,2H).
步骤3：1-环己基-2-(5-甲氧基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(5-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000177
Figure PCTCN2022093052-appb-000177
在室温下向N-环己基-5-((5-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(5-甲氧基吡啶-2- 基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，60.0mg，收率29.6％。m.p.202.4-204.7℃。 1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),8.59(s,1H),8.07(s,1H),7.95(d,J＝8.1Hz,1H),7.42(d,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),7.11(s,1H),6.96(d,J＝7.5Hz,1H),4.49(s,1H),3.85(s,3H),2.46(m,J＝13.3,6.8Hz,2H),2.04(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H). To N-cyclohexyl-5-((5-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(5-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine, 60.0 mg, yield 29.6%. mp202.4-204.7°C. 1 H NMR (300MHz, Chloroform-d) δ9.29(s,1H),8.59(s,1H),8.07(s,1H),7.95(d,J＝8.1Hz,1H),7.42(d,J =7.9Hz,1H),7.35(d,J=7.5Hz,1H),7.11(s,1H),6.96(d,J=7.5Hz,1H),4.49(s,1H),3.85(s,3H ),2.46(m,J＝13.3,6.8Hz,2H),2.04(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H).
实施例51Example 51
步骤1：4-氯-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000178
Figure PCTCN2022093052-appb-000178
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-6-甲氧基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，483.2mg，收率70.5％。 1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),7.82(s,1H),7.42(t,J＝8.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.90(dd,J＝8.0,1.0Hz,1H),6.73–6.65(m,2H),3.94(s,3H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-6-methoxypyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34 mg, 0.18 mmol) and 1 ml of triethylamine were added to 25 ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=10:1) to give the corresponding solid compound 4-chloro-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 483.2 mg, yield 70.5%. 1 H NMR (300MHz, Chloroform-d) δ8.71(s, 1H), 7.82(s, 1H), 7.42(t, J=8.0Hz, 1H), 7.27(d, J=7.5Hz, 1H), 6.90(dd,J=8.0,1.0Hz,1H),6.73–6.65(m,2H),3.94(s,3H).
步骤2：N-环己基-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000179
Figure PCTCN2022093052-appb-000179
将化合物4-氯-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，243.2mg，收率35.5％。 1H NMR(300MHz,Chloroform-d)δ8.55(s,1H),7.86(s,1H),7.50(t,J＝8.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.96(d,J＝7.9Hz,1H),6.79(dd,J＝7.8,5.6Hz,2H),5.14(s,1H),3.94(s,3H),3.79(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.84–1.75(m,2H),1.66–1.56(m,4H),1.38(m,J＝13.0,6.6Hz,2H). The compound 4-chloro-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 243.2 mg, yield 35.5%. 1 H NMR (300MHz, Chloroform-d) δ8.55(s, 1H), 7.86(s, 1H), 7.50(t, J=8.0Hz, 1H), 7.19(d, J=7.5Hz, 1H), 6.96(d, J=7.9Hz, 1H), 6.79(dd, J=7.8, 5.6Hz, 2H), 5.14(s, 1H), 3.94(s, 3H), 3.79(s, 1H), 2.04(dd ,J=13.0,7.0Hz,2H),1.84–1.75(m,2H),1.66–1.56(m,4H),1.38(m,J=13.0,6.6Hz,2H).
步骤3：1-环己基-2-(6-甲氧基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(6-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000180
Figure PCTCN2022093052-appb-000180
在室温下向N-环己基-5-((6-甲氧基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物， 通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(6-甲氧基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，41.3mg，收率24.5％。m.p.187.3-189.9℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.08(s,1H),7.71(t,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),7.17(s,1H),6.94(dd,J＝12.3,7.7Hz,2H),4.49(s,1H),3.94(s,3H),2.44–2.35(m,2H),2.02(m,J＝13.2,6.9Hz,2H),1.86–1.70(m,3H),1.45(m,J＝32.3,13.6,6.0Hz,3H). To N-cyclohexyl-5-((6-methoxypyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was passed through Purify by silica gel chromatography (PE:EA=2:1) to obtain the corresponding solid compound 1-cyclohexyl-2-(6-methoxypyridin-2-yl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine, 41.3 mg, yield 24.5%. mp187.3-189.9°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s, 1H), 8.08(s, 1H), 7.71(t, J=8.1Hz, 1H), 7.35(d, J=7.5Hz, 1H), 7.24(d,J=8.1Hz,1H),7.17(s,1H),6.94(dd,J=12.3,7.7Hz,2H),4.49(s,1H),3.94(s,3H),2.44–2.35 (m,2H),2.02(m,J=13.2,6.9Hz,2H),1.86–1.70(m,3H),1.45(m,J=32.3,13.6,6.0Hz,3H).
实施例52Example 52
步骤1：4-氯-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000181
Figure PCTCN2022093052-appb-000181
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-乙炔基-6-硝基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，547.9mg，收率79.9％。 1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),8.22(dd,J＝8.0,1.1Hz,1H),8.09(dd,J＝8.1,0.9Hz,1H),7.89–7.80(m,2H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-ethynyl-6-nitropyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=10:1) gave the corresponding solid compound 4-chloro-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b ] Pyridine, 547.9 mg, yield 79.9%. 1 H NMR (300MHz, Chloroform-d) δ8.73 (s, 1H), 8.22 (dd, J＝8.0, 1.1Hz, 1H), 8.09 (dd, J＝8.1, 0.9Hz, 1H), 7.89–7.80 (m,2H),7.28(d,J=7.5Hz,1H),6.68(d,J=7.5Hz,1H).
步骤2：N-环己基-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000182
Figure PCTCN2022093052-appb-000182
将化合物4-氯-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，159.6mg，收率23.3％。 1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),8.31(d,J＝7.9Hz,1H),8.15(d,J＝8.1Hz,1H),7.95(t,J＝8.0Hz,1H),7.86(s,1H),7.27(d,J＝7.5Hz,1H),6.86(d,J＝7.5Hz,1H),4.00(s,1H),2.09(dd,J＝12.9,6.8Hz,2H),2.01–1.92(m,2H),1.90(s,1H),1.76–1.67(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.56–1.44(m,2H). Compound 4-chloro-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol) , t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol ) into 20ml of dioxane, heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to obtain the corresponding solid compound N-cyclohexyl-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridin-4-amine, 159.6 mg, yield 23.3%. 1 H NMR (300MHz, Chloroform-d) δ8.64(s, 1H), 8.31(d, J=7.9Hz, 1H), 8.15(d, J=8.1Hz, 1H), 7.95(t, J=8.0 Hz,1H),7.86(s,1H),7.27(d,J=7.5Hz,1H),6.86(d,J=7.5Hz,1H),4.00(s,1H),2.09(dd,J=12.9 ,6.8Hz,2H),2.01–1.92(m,2H),1.90(s,1H),1.76–1.67(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.56–1.44( m,2H).
步骤3：1-环己基-2-(6-硝基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(6-nitropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000183
Figure PCTCN2022093052-appb-000183
在室温下向N-环己基-5-((6-硝基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱 和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(6-硝基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，47.6mg，收率26.3％。m.p.181.5-183.9℃。 1H NMR(300MHz,Chloroform-d)δ9.31(s,1H),8.43(dd,J＝17.3,7.9Hz,2H),8.15(t,J＝8.0Hz,1H),8.08(s,1H),7.36(d,J＝7.5Hz,1H),7.25(s,1H),6.98(d,J＝7.5Hz,1H),4.16(s,1H),2.27–2.16(m,2H),1.89–1.75(m,4H),1.69–1.54(m,3H),1.53–1.42(m,1H). N-cyclohexyl-5-((6-nitropyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF ( 10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-cyclohexyl-2-(6-nitropyridin-2-yl)-1,6-dihydrodipyrrolo[2,3 -b: 2',3'-d]pyridine, 47.6 mg, yield 26.3%. mp181.5-183.9°C. 1 H NMR (300MHz, Chloroform-d) δ9.31(s, 1H), 8.43(dd, J=17.3, 7.9Hz, 2H), 8.15(t, J=8.0Hz, 1H), 8.08(s, 1H ),7.36(d,J=7.5Hz,1H),7.25(s,1H),6.98(d,J=7.5Hz,1H),4.16(s,1H),2.27–2.16(m,2H),1.89 –1.75(m,4H),1.69–1.54(m,3H),1.53–1.42(m,1H).
实施例53Example 53
步骤1：4-氯-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000184
Figure PCTCN2022093052-appb-000184
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，2-环丙基-6-乙炔基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，536.7mg，收率78.2％。 1H NMR(300MHz,Chloroform-d)δ8.82(s,1H),7.89(s,1H),7.55–7.46(m,2H),7.29(d,J＝7.5Hz,1H),7.07(dd,J＝7.0,2.0Hz,1H),6.71(d,J＝7.5Hz,1H),1.84(p,J＝6.9Hz,1H),0.90(m,J＝7.1,4.1Hz,2H),0.76(m,J＝7.2,4.3Hz,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 2-cyclopropyl-6-ethynylpyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34 mg, 0.18 mmol) and 1 ml of triethylamine were added to 25 ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=10:1) to give the corresponding solid compound 4-chloro-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 536.7 mg, yield 78.2%. 1 H NMR (300MHz, Chloroform-d) δ8.82 (s, 1H), 7.89 (s, 1H), 7.55–7.46 (m, 2H), 7.29 (d, J=7.5Hz, 1H), 7.07 (dd ,J=7.0,2.0Hz,1H),6.71(d,J=7.5Hz,1H),1.84(p,J=6.9Hz,1H),0.90(m,J=7.1,4.1Hz,2H),0.76 (m,J=7.2,4.3Hz,2H).
步骤2：N-环己基-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000185
Figure PCTCN2022093052-appb-000185
将化合物4-氯-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，177.0mg，收率25.8％。 1H NMR(300MHz,Chloroform-d)δ8.52(s,1H),7.85(s,1H),7.54–7.45(m,2H),7.18(d,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.49(s,1H),3.78(s,1H),2.05(dd,J＝13.0,7.0Hz,2H),1.86–1.75(m,3H),1.68–1.57(m,4H),1.37(m,J＝13.1,6.6Hz,2H),0.92–0.87(m,2H),0.78–0.72(m,2H). Compound 4-chloro-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=3:1) to give the corresponding solid compound N-cyclohexyl-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 177.0 mg, yield 25.8%. 1 H NMR (300MHz, Chloroform-d) δ8.52(s, 1H), 7.85(s, 1H), 7.54–7.45(m, 2H), 7.18(d, J=7.5Hz, 1H), 7.07(d ,J=7.5Hz,1H),6.78(d,J=7.5Hz,1H),5.49(s,1H),3.78(s,1H),2.05(dd,J=13.0,7.0Hz,2H),1.86 –1.75(m,3H),1.68–1.57(m,4H),1.37(m,J＝13.1,6.6Hz,2H),0.92–0.87(m,2H),0.78–0.72(m,2H).
步骤3：1-环己基-2-(6-环丙基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(6-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000186
Figure PCTCN2022093052-appb-000186
在室温下向N-环己基-5-((6-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物 在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(6-环丙基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，41.9mg，收率24.7％。m.p.214.2-215.1℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.07(s,1H),7.77(d,J＝8.1Hz,1H),7.70(t,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),7.23–7.15(m,2H),6.96(d,J＝7.5Hz,1H),4.56(s,1H),2.61(m,J＝13.2,6.7Hz,2H),2.02(m,J＝13.2,6.7Hz,2H),1.89(s,1H),1.87–1.71(m,3H),1.48(m,J＝11.9,6.4,4.9Hz,3H),0.96–0.90(m,2H),0.81–0.76(m,2H). To N-cyclohexyl-5-((6-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), the corresponding solid compound 1-cyclohexyl-2-(6-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine, 41.9 mg, yield 24.7%. mp214.2-215.1°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s, 1H), 8.07(s, 1H), 7.77(d, J=8.1Hz, 1H), 7.70(t, J=7.9Hz, 1H), 7.35(d, J=7.5Hz, 1H), 7.23–7.15(m, 2H), 6.96(d, J=7.5Hz, 1H), 4.56(s, 1H), 2.61(m, J=13.2, 6.7Hz ,2H),2.02(m,J＝13.2,6.7Hz,2H),1.89(s,1H),1.87–1.71(m,3H),1.48(m,J＝11.9,6.4,4.9Hz,3H), 0.96–0.90(m,2H),0.81–0.76(m,2H).
实施例54Example 54
步骤1：4-氯-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶的制备Step 1: Preparation of 4-chloro-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2022093052-appb-000187
Figure PCTCN2022093052-appb-000187
将中间体4a(1g，3.6mmol，参照实施例1的制备方法)，5-环丙基-2-乙炔基吡啶(4.3mmol)，Pd(PPh 3) 2Cl 2(126mg，0.18mmol)，CuI(34mg，0.18mmol)和三乙胺1ml加入25ml乙腈中，80℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝10:1)，得到相应固体化合物4-氯-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶，460.6mg，收率67.1％。 1H NMR(300MHz,Chloroform-d)δ8.82(s,1H),8.25(d,J＝1.2Hz,1H),7.88(s,1H),7.59(d,J＝8.1Hz,1H),7.37(dd,J＝8.1,1.3Hz,1H),7.29(d,J＝7.5Hz,1H),6.70(d,J＝7.5Hz,1H),1.68(m,J＝7.0Hz,1H),1.05–0.96(m,2H),0.76–0.67(m,2H). Intermediate 4a (1g, 3.6mmol, refer to the preparation method of Example 1), 5-cyclopropyl-2-ethynylpyridine (4.3mmol), Pd(PPh 3 ) 2 Cl 2 (126mg, 0.18mmol), CuI (34 mg, 0.18 mmol) and 1 ml of triethylamine were added to 25 ml of acetonitrile, and heated to reflux at 80°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purify by silica gel chromatography (PE:EA=10:1) to give the corresponding solid compound 4-chloro-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3- b] Pyridine, 460.6 mg, yield 67.1%. 1 H NMR (300MHz, Chloroform-d) δ8.82(s, 1H), 8.25(d, J=1.2Hz, 1H), 7.88(s, 1H), 7.59(d, J=8.1Hz, 1H), 7.37(dd, J=8.1,1.3Hz,1H),7.29(d,J=7.5Hz,1H),6.70(d,J=7.5Hz,1H),1.68(m,J=7.0Hz,1H), 1.05–0.96(m,2H),0.76–0.67(m,2H).
步骤2：N-环己基-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 2: Preparation of N-cyclohexyl-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000188
Figure PCTCN2022093052-appb-000188
将化合物4-氯-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶(2.6mmol)，环己胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物N-环己基-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺，210.7mg，收率30.7％。 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.32(s,1H),7.86(s,1H),7.55(d,J＝8.1Hz,1H),7.46(d,J＝7.9Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.94(s,1H),2.80(s,1H),2.32(s,3H),2.07(dd,J＝12.9,7.0Hz,2H),1.78(dd,J＝13.5,6.3Hz,2H),1.72–1.57(m,4H),1.40(m,J＝12.9,6.5Hz,2H). Compound 4-chloro-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol ), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13 mmol) was added into 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound N-cyclohexyl-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3 -b] Pyridin-4-amine, 210.7 mg, yield 30.7%. 1 H NMR (300MHz, Chloroform-d) δ8.61(s,1H),8.32(s,1H),7.86(s,1H),7.55(d,J＝8.1Hz,1H),7.46(d,J =7.9Hz,1H),7.24(d,J=7.5Hz,1H),6.84(d,J=7.5Hz,1H),3.94(s,1H),2.80(s,1H),2.32(s,3H ), 2.07(dd, J＝12.9, 7.0Hz, 2H), 1.78(dd, J＝13.5, 6.3Hz, 2H), 1.72–1.57(m, 4H), 1.40(m, J＝12.9, 6.5Hz, 2H).
步骤3：1-环己基-2-(5-环丙基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: Preparation of 1-cyclohexyl-2-(5-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine
Figure PCTCN2022093052-appb-000189
Figure PCTCN2022093052-appb-000189
在室温下向N-环己基-5-((5-环丙基吡啶-2-基)乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-环己基-2-(5-环丙基吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，45.5mg，收率25.8％。m.p.214.2-215.1℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.50(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.58(d,J＝8.0Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(s,1H),6.95(d,J＝7.5Hz,1H),4.47(s,1H),2.45(m,J＝13.3,6.9Hz,2H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,4H),1.54–1.36(m,3H),1.06–1.00(m,2H),0.78–0.73(m,2H). To N-cyclohexyl-5-((5-cyclopropylpyridin-2-yl)ethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol) and THF at room temperature (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purified by silica gel chromatography (PE:EA=2:1), the corresponding solid compound 1-cyclohexyl-2-(5-cyclopropylpyridin-2-yl)-1,6-dihydrodipyrrolo[2, 3-b: 2',3'-d]pyridine, 45.5 mg, yield 25.8%. mp214.2-215.1°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.50(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.58(d,J =8.0Hz,1H),7.35(d,J=7.5Hz,1H),7.15(s,1H),6.95(d,J=7.5Hz,1H),4.47(s,1H),2.45(m,J ＝13.3,6.9Hz,2H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,4H),1.54–1.36(m,3H),1.06–1.00(m,2H), 0.78–0.73(m,2H).
实施例55Example 55
步骤1：N-((2S)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 1: Preparation of N-((2S)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000190
Figure PCTCN2022093052-appb-000190
将中间体4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(1g，3.6mmol，参照实施例37的制备方法)，(2S)2-甲基环己-1-胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物N-((2S)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺205.3mg，收率23.9％。 1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.49(dd,J＝4.9,1.3Hz,1H),7.86(s,1H),7.62(dd,J＝7.9,1.1Hz,1H),7.56(m,J＝7.9,1.2Hz,1H),7.35(m,J＝7.8,4.9,1.1Hz,1H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),4.77(s,1H),3.38(q,J＝7.1Hz,1H),1.75–1.57(m,2H),1.60–1.46(m,5H),1.33–1.20(m,1H),1.03(d,J＝6.5Hz,3H). The intermediate 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (1g, 3.6mmol, refer to the preparation method of Example 37), (2S)2 -Methylcyclohexan-1-amine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography to obtain the product N-((2S)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 205.3 mg, yield 23.9%. 1 H NMR (300MHz, Chloroform-d) δ8.60(s,1H),8.49(dd,J=4.9,1.3Hz,1H),7.86(s,1H),7.62(dd,J=7.9,1.1Hz ,1H),7.56(m,J=7.9,1.2Hz,1H),7.35(m,J=7.8,4.9,1.1Hz,1H),7.20(d,J=7.5Hz,1H),6.80(d, J＝7.5Hz, 1H), 4.77(s, 1H), 3.38(q, J＝7.1Hz, 1H), 1.75–1.57(m, 2H), 1.60–1.46(m, 5H), 1.33–1.20(m ,1H),1.03(d,J=6.5Hz,3H).
步骤2：1-((2S)-2-甲基环己基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 2: 1-((2S)-2-Methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
Figure PCTCN2022093052-appb-000191
Figure PCTCN2022093052-appb-000191
在室温下向N-((2S)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)， 饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-((2S)-2-甲基环己基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，68.9mg，收率39.0％。m.p.189.5-192.9℃。 1H NMR(300MHz,Chloroform-d)δ9.30(d,J＝1.6Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.07(s,1H),7.87(dd,J＝7.9,1.0Hz,1H),7.71(m,J＝8.0,1.3Hz,1H),7.35(d,J＝7.5Hz,1H),7.29(m,J＝8.0,5.0,1.1Hz,1H),7.09(d,J＝1.5Hz,1H),6.93(d,J＝7.5Hz,1H),3.88(m,J＝7.1Hz,1H),2.57(m,J＝6.9Hz,1H),1.96(m,J＝12.9,7.1Hz,1H),1.88–1.77(m,1H),1.75–1.64(m,2H),1.68–1.54(m,1H),1.55(m,J＝4.4,2.4Hz,1H),1.56–1.46(m,1H),1.38(m,J＝12.5,6.9Hz,1H),1.10(d,J＝6.8Hz,3H). To N-((2S)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol ) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-((2S)-2-methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodi Pyrrolo[2,3-b:2',3'-d]pyridine, 68.9 mg, yield 39.0%. mp189.5-192.9°C. 1 H NMR (300MHz, Chloroform-d) δ9.30 (d, J = 1.6Hz, 1H), 8.70 (dd, J = 5.0, 1.2Hz, 1H), 8.07 (s, 1H), 7.87 (dd, J =7.9,1.0Hz,1H),7.71(m,J=8.0,1.3Hz,1H),7.35(d,J=7.5Hz,1H),7.29(m,J=8.0,5.0,1.1Hz,1H) ,7.09(d,J=1.5Hz,1H),6.93(d,J=7.5Hz,1H),3.88(m,J=7.1Hz,1H),2.57(m,J=6.9Hz,1H),1.96 (m,J=12.9,7.1Hz,1H),1.88–1.77(m,1H),1.75–1.64(m,2H),1.68–1.54(m,1H),1.55(m,J=4.4,2.4Hz ,1H),1.56–1.46(m,1H),1.38(m,J=12.5,6.9Hz,1H),1.10(d,J=6.8Hz,3H).
实施例56Example 56
步骤1：N-((2R)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺的制备Step 1: Preparation of N-((2R)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine
Figure PCTCN2022093052-appb-000192
Figure PCTCN2022093052-appb-000192
将中间体4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(1g，3.6mmol，参照实施例37的制备方法)，(2R)2-甲基环己-1-胺(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，经柱层析分离纯化得到产物N-((2S)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺281.5mg，收率41％。 1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.48(dd,J＝5.0,1.2Hz,1H),7.86(s,1H),7.63(dd,J＝8.1,1.1Hz,1H),7.56(m,J＝8.0,1.3Hz,1H),7.35(m,J＝7.8,5.1,1.1Hz,1H),7.24(d,J＝7.5Hz,1H),6.82(d,J＝7.5Hz,1H),3.51(m,J＝7.1Hz,1H),3.19(s,1H),2.10(m,J＝6.9Hz,1H),1.85–1.35(m,8H),1.01(d,J＝6.8Hz,3H). The intermediate 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (1g, 3.6mmol, refer to the preparation method of Example 37), (2R)2 -Methylcyclohexan-1-amine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was washed by Separation and purification by column chromatography to obtain the product N-((2S)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 281.5 mg, yield 41%. 1 H NMR (300MHz, Chloroform-d) δ8.61(s,1H),8.48(dd,J=5.0,1.2Hz,1H),7.86(s,1H),7.63(dd,J=8.1,1.1Hz ,1H),7.56(m,J=8.0,1.3Hz,1H),7.35(m,J=7.8,5.1,1.1Hz,1H),7.24(d,J=7.5Hz,1H),6.82(d, J＝7.5Hz, 1H), 3.51(m, J＝7.1Hz, 1H), 3.19(s, 1H), 2.10(m, J＝6.9Hz, 1H), 1.85–1.35(m, 8H), 1.01( d,J=6.8Hz,3H).
步骤2：1-((2R)-2-甲基环己基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 2: 1-((2R)-2-Methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
Figure PCTCN2022093052-appb-000193
Figure PCTCN2022093052-appb-000193
在室温下向N-((2R)-2-甲基环己基)-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-胺(1.5mmol)和THF(10mL)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-((2R)-2-甲基环己基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶，73.5mg，收率33.8％。m.p.216.5-218.2℃。 1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(s,1H),6.95(d,J＝7.5Hz,1H),4.48(s,1H),2.50–2.41(m,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H). To N-((2R)-2-methylcyclohexyl)-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (1.5mmol ) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 1-((2R)-2-methylcyclohexyl)-2-(pyridin-2-yl)-1,6-dihydrodi Pyrrolo[2,3-b:2',3'-d]pyridine, 73.5 mg, yield 33.8%. mp216.5-218.2°C. 1 H NMR (300MHz, Chloroform-d) δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J =8.1Hz,1H),7.35(d,J=7.5Hz,1H),7.15(s,1H),6.95(d,J=7.5Hz,1H),4.48(s,1H),2.50–2.41(m ,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H).
实施例57Example 57
步骤1：3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧 酸叔丁酯的制备Step 1: tert-butyl 3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxylate preparation
Figure PCTCN2022093052-appb-000194
Figure PCTCN2022093052-appb-000194
将化合物4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(1g，3.6mmol，参照实施例37的制备方法)，3-氨基哌啶-1-羧酸叔丁酯(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯，510mg，收率31.0％。m.p.206.5-207.8℃。 1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.49(dd,J＝5.0,1.2Hz,1H),7.93(s,1H),7.63(dd,J＝7.9,1.1Hz,1H),7.57(m,J＝7.9,1.2Hz,1H),7.36(m,J＝7.9,4.9,1.1Hz,1H),7.29(d,J＝7.5Hz,1H),6.85(d,J＝7.5Hz,1H),4.52(m,J＝12.4,7.1Hz,1H),4.27(dd,J＝12.5,7.0Hz,1H),3.52(dd,J＝12.5,7.1Hz,1H),3.16(p,J＝7.0Hz,1H),3.02(m,J＝12.5,7.1Hz,1H),2.61(s,1H),2.33(m,J＝14.0,7.1Hz,1H),1.84–1.63(m,2H),1.54(m,J＝13.9,7.0Hz,1H),1.47(s,9H). Compound 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (1g, 3.6mmol, referring to the preparation method of Example 37), 3-aminopiperidine - tert-butyl 1-carboxylate (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride (110mg, 0.26 mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound 3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )amino)tert-butyl-1-carboxylate tert-butyl ester, 510 mg, yield 31.0%. mp206.5-207.8°C. 1 H NMR (300MHz, Chloroform-d) δ8.65(s,1H),8.49(dd,J=5.0,1.2Hz,1H),7.93(s,1H),7.63(dd,J=7.9,1.1Hz ,1H),7.57(m,J=7.9,1.2Hz,1H),7.36(m,J=7.9,4.9,1.1Hz,1H),7.29(d,J=7.5Hz,1H),6.85(d, J＝7.5Hz, 1H), 4.52(m, J＝12.4, 7.1Hz, 1H), 4.27(dd, J＝12.5, 7.0Hz, 1H), 3.52(dd, J＝12.5, 7.1Hz, 1H), 3.16(p, J=7.0Hz, 1H), 3.02(m, J=12.5, 7.1Hz, 1H), 2.61(s, 1H), 2.33(m, J=14.0, 7.1Hz, 1H), 1.84–1.63 (m,2H),1.54(m,J=13.9,7.0Hz,1H),1.47(s,9H).
步骤2：3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯的制备Step 2: tert-butyl 3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidine-1-carboxylate Preparation of esters
Figure PCTCN2022093052-appb-000195
Figure PCTCN2022093052-appb-000195
在室温下向3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯(1.2mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯317mg，收率26.1％。 1H NMR(300MHz,Chloroform-d)δ9.32(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.11(s,1H),7.93(dd,J＝8.1,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.36(d,J＝7.5Hz,1H),7.32–7.25(m,2H),6.89(d,J＝7.5Hz,1H),4.56(m,J＝12.5,7.1Hz,1H),4.44(dd,J＝12.5,7.1Hz,1H),4.06(dd,J＝12.5,7.0Hz,1H),3.85(m,J＝7.1Hz,1H),3.13(m,J＝12.5,7.2Hz,1H),2.29(m,J＝13.0,7.0Hz,1H),1.92(m,J＝13.8,7.0Hz,1H),1.75(m,J＝48.5,13.2,7.0Hz,2H),1.47(s,9H). 3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxylic acid tert-butyl ester at room temperature (1.2mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound 3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridine- 1(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester 317 mg, yield 26.1%. 1 H NMR (300MHz, Chloroform-d) δ9.32 (d, J = 1.5Hz, 1H), 8.70 (dd, J = 5.0, 1.2Hz, 1H), 8.11 (s, 1H), 7.93 (dd, J =8.1,1.0Hz,1H),7.71(m,J=8.0,1.2Hz,1H),7.36(d,J=7.5Hz,1H),7.32–7.25(m,2H),6.89(d,J= 7.5Hz, 1H), 4.56(m, J＝12.5, 7.1Hz, 1H), 4.44(dd, J＝12.5, 7.1Hz, 1H), 4.06(dd, J＝12.5, 7.0Hz, 1H), 3.85( m,J=7.1Hz,1H),3.13(m,J=12.5,7.2Hz,1H),2.29(m,J=13.0,7.0Hz,1H),1.92(m,J=13.8,7.0Hz,1H ),1.75(m,J＝48.5,13.2,7.0Hz,2H),1.47(s,9H).
步骤3：1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: 1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine preparation
Figure PCTCN2022093052-appb-000196
Figure PCTCN2022093052-appb-000196
在室温下向3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯(307mg，0.3mmol)和CDCl 2(30ml)的混合物中加入10ml TFA。将反应混合 物在室温下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶80.8mg收率84.9％。 1H NMR(300MHz,Chloroform-d)δ9.30(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.07(s,1H),7.91(dd,J＝8.0,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.35(d,J＝7.5Hz,1H),7.29(m,J＝8.0,5.0,1.1Hz,1H),7.18(d,J＝1.5Hz,1H),6.96(d,J＝7.5Hz,1H),4.26(m,J＝7.0Hz,1H),3.31(dd,J＝12.6,7.1Hz,1H),3.24(m,J＝12.5,7.0Hz,1H),3.15(dd,J＝12.4,6.9Hz,1H),2.87(m,J＝12.4,7.1Hz,1H),2.33(m,J＝13.9,7.0Hz,1H),1.80(m,J＝13.1,7.0Hz,1H),1.69–1.49(m,2H),1.30(s,1H). 3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidine-1-carboxylic acid tert To a mixture of butyl ester (307mg, 0.3mmol) and CDCl2 (30ml) was added 10ml of TFA. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydro The yield of 80.8 mg of dipyrrolo[2,3-b:2',3'-d]pyridine was 84.9%. 1 H NMR (300MHz, Chloroform-d) δ9.30 (d, J = 1.5Hz, 1H), 8.70 (dd, J = 5.0, 1.2Hz, 1H), 8.07 (s, 1H), 7.91 (dd, J =8.0,1.0Hz,1H),7.71(m,J=8.0,1.2Hz,1H),7.35(d,J=7.5Hz,1H),7.29(m,J=8.0,5.0,1.1Hz,1H) ,7.18(d,J=1.5Hz,1H),6.96(d,J=7.5Hz,1H),4.26(m,J=7.0Hz,1H),3.31(dd,J=12.6,7.1Hz,1H) ,3.24(m,J=12.5,7.0Hz,1H),3.15(dd,J=12.4,6.9Hz,1H),2.87(m,J=12.4,7.1Hz,1H),2.33(m,J=13.9 ,7.0Hz,1H),1.80(m,J＝13.1,7.0Hz,1H),1.69–1.49(m,2H),1.30(s,1H).
步骤4：3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈的制备Step 4: 3-oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl) Preparation of piperidin-1-yl)propionitrile
Figure PCTCN2022093052-appb-000197
Figure PCTCN2022093052-appb-000197
在室温下向1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶(71.3，0.2mmol)、氰基乙酸、DCC溶解在40ml CDCl 2，并将混合物在40℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈68.3mg，收率79.5％。m.p.241.5-244.8℃。 1H NMR(300MHz,Chloroform-d)δ9.31(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.08(s,1H),7.92(dd,J＝8.0,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.35(d,J＝7.5Hz,1H),7.32–7.24(m,2H),6.84(d,J＝7.5Hz,1H),4.64(dd,J＝12.4,6.9Hz,1H),4.12(m,J＝12.6,7.1Hz,1H),3.90–3.80(m,2H),3.65(dd,J＝12.5,7.1Hz,1H),3.58(d,J＝12.4Hz,1H),3.14(m,J＝12.5,7.0Hz,1H),2.19–2.08(m,1H),1.97(m,J＝13.8,7.0Hz,1H),1.81(m,J＝13.1,7.0Hz,1H),1.73–1.61(m,1H). To 1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine at room temperature (71.3, 0.2 mmol), cyanoacetic acid, DCC were dissolved in 40 ml CDCl 2 , and the mixture was stirred at 40° C. for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound 3-oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo[2,3 -b: 2',3'-d]pyridin-1(6H)-yl)piperidin-1-yl)propionitrile 68.3 mg, yield 79.5%. mp241.5-244.8°C. 1 H NMR (300MHz, Chloroform-d) δ9.31 (d, J = 1.5Hz, 1H), 8.70 (dd, J = 5.0, 1.2Hz, 1H), 8.08 (s, 1H), 7.92 (dd, J =8.0,1.0Hz,1H),7.71(m,J=8.0,1.2Hz,1H),7.35(d,J=7.5Hz,1H),7.32–7.24(m,2H),6.84(d,J= 7.5Hz, 1H), 4.64(dd, J=12.4, 6.9Hz, 1H), 4.12(m, J=12.6, 7.1Hz, 1H), 3.90–3.80(m, 2H), 3.65(dd, J=12.5 ,7.1Hz,1H),3.58(d,J=12.4Hz,1H),3.14(m,J=12.5,7.0Hz,1H),2.19–2.08(m,1H),1.97(m,J=13.8, 7.0Hz, 1H), 1.81(m, J=13.1, 7.0Hz, 1H), 1.73–1.61(m, 1H).
实施例1～57化合物对JAK家族的抑制活性测试The inhibitory activity test of the compound of embodiment 1～57 to JAK family
一、实验材料1. Experimental materials
Figure PCTCN2022093052-appb-000198
Figure PCTCN2022093052-appb-000198
Figure PCTCN2022093052-appb-000199
Figure PCTCN2022093052-appb-000199
二、实验方法2. Experimental method
1、配制1x激酶反应缓冲液:1. Prepare 1x Kinase Reaction Buffer:
名称name 储液浓度Stock solution concentration 体积volume 终浓度Final concentration
HepesHepes 1M(20X)1M(20X) 12500μL12500μL 50mM50mM
MgCl 2 MgCl 2 1M(100X)1M(100X) 2500μL2500μL 10mM10mM
Brij 35Brij 35 // 25μL25 μL 0.01％0.01%
EGTAEGTA 1M(1000X)1M(1000X) 250μL250μL 1mM1mM
DTTDTT 1M(500X)1M(500X) 500μL500μL 2mM2mM
ddH2OddH2O  the 235000μL235000μL  the
2、激酶反应条件:2. Kinase reaction conditions:
Figure PCTCN2022093052-appb-000200
Figure PCTCN2022093052-appb-000200
3、测试流程：3. Test process:
3.1在稀释板中用DMSO对化合物进行4倍梯度稀释，化合物起始浓度为1.5uM。3.1 The compound was serially diluted 4 times with DMSO in the dilution plate, and the initial concentration of the compound was 1.5 uM.
3.2将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。3.2 Dilute the compound 50 times into 1X kinase reaction buffer and shake it on a shaker for 20 minutes.
3.3用1X的酶反应缓冲液配制准备2X激酶。3.3 Prepare 2X Kinase with 1X Enzyme Reaction Buffer.
3.4向反应板中每孔加入2μl激酶(步骤3中配制)。3.4 Add 2 μl of kinase (prepared in step 3) to each well of the reaction plate.
3.5.向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000g离心30秒，室温放置10分钟。3.5. Add 1 μl of the compound diluted in buffer to each well, seal the plate with a plate sealer, centrifuge at 1000g for 30 seconds, and place at room temperature for 10 minutes.
3.6用1X的酶反应缓冲液配制4xATP/底物混合液，向反应板中加入1μl 4x ATP/底物混合液。3.6 Prepare 4xATP/substrate mixture with 1X enzyme reaction buffer, add 1μl 4x ATP/substrate mixture to the reaction plate.
3.7.用封板膜封住板子1000g离心30秒，室温反应60分钟。3.7. Seal the plate with a sealing film, centrifuge at 1000g for 30 seconds, and react at room temperature for 60 minutes.
3.8转移4μL ADP-Glo到384反应板中1000rpm/min,离心1min，25℃孵育40min。3.8 Transfer 4 μL of ADP-Glo to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min.
3.9转移8μL Detection溶液到384反应板中1000rpm/min,离心1min，25℃孵育40min。3.9 Transfer 8 μL of Detection solution to the 384 reaction plate at 1000 rpm/min, centrifuge for 1 min, and incubate at 25°C for 40 min.
3.10使用Biotek多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。3.10 Read the RLU (Relative luminescence unit) signal with a Biotek multifunctional plate reader. Signal intensity is used to characterize the degree of kinase activity.
4、数据处理：4. Data processing:
化合物抑制率(％inh)＝100％-(化合物-阳性对照)/(阴性对照-阳性对照)*100％Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%
阳性对照：所有阳性对照孔2μM Tofacitinib孔的比值的平均值Positive control: the average value of the ratio of all positive control wells 2μM Tofacitinib wells
阴性对照：所有阴性对照孔0.5％DMSO孔的读值的平均值Negative Control: Average of readings from all negative control wells 0.5% DMSO wells
三、实验结果3. Experimental results
表.本发明化合物对JAK家族蛋白的抑制活性。Table. Inhibitory activity of compounds of the present invention on JAK family proteins.
Figure PCTCN2022093052-appb-000201
Figure PCTCN2022093052-appb-000201
Figure PCTCN2022093052-appb-000202
Figure PCTCN2022093052-appb-000202
Figure PCTCN2022093052-appb-000203
Figure PCTCN2022093052-appb-000203
Figure PCTCN2022093052-appb-000204
Figure PCTCN2022093052-appb-000204
实施例58Example 58
步骤1：(R)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯的制备Step 1: (R)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxylic acid Preparation of tert-butyl ester
Figure PCTCN2022093052-appb-000205
Figure PCTCN2022093052-appb-000205
将化合物4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(1g，3.6mmol，参照实施例37的制备方法)，(R)-3-氨基哌啶-1-羧酸叔丁酯(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物(R)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯，510mg，收率35.0％。 1H NMR(300MHz,Chloroform-d)δ8.67(s,1H),8.47(dd,J＝5.0,1.2Hz,1H),7.90(s,1H),7.69(dd,J＝7.9,1.1Hz,1H),7.59(m,J＝7.9,1.2Hz,1H),7.38(m,J＝7.9,4.9,1.1Hz,1H),7.31(d,J＝7.5Hz,1H),6.86(d,J＝7.5Hz,1H),4.58(m,J＝12.4,7.1Hz,1H),4.30(dd,J＝12.5,7.0Hz,1H),3.51(dd,J＝12.5,7.1Hz,1H),3.15(p,J＝7.0Hz,1H),3.05(m,J＝12.5,7.1Hz,1H),2.65(s,1H),2.32(m,J＝14.0,7.1Hz,1H),1.84–1.61(m,2H),1.52(m,J＝13.9,7.0Hz,1H),1.45(s,9H). Compound 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (1g, 3.6mmol, referring to the preparation method of Example 37), (R)-3 -aminopiperidine-1-carboxylate tert-butyl ester (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (110mg, 0.26mmol), Pd 2 (dba) 3 (75mg, 0.13mmol) were added to 20ml of dioxane, and heated to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound (R)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine -4-yl)amino)tert-butyl-1-carboxylic acid tert-butyl ester, 510 mg, yield 35.0%. 1 H NMR (300MHz, Chloroform-d) δ8.67(s,1H),8.47(dd,J=5.0,1.2Hz,1H),7.90(s,1H),7.69(dd,J=7.9,1.1Hz ,1H),7.59(m,J=7.9,1.2Hz,1H),7.38(m,J=7.9,4.9,1.1Hz,1H),7.31(d,J=7.5Hz,1H),6.86(d, J＝7.5Hz, 1H), 4.58(m, J＝12.4, 7.1Hz, 1H), 4.30(dd, J＝12.5, 7.0Hz, 1H), 3.51(dd, J＝12.5, 7.1Hz, 1H), 3.15(p, J=7.0Hz, 1H), 3.05(m, J=12.5, 7.1Hz, 1H), 2.65(s, 1H), 2.32(m, J=14.0, 7.1Hz, 1H), 1.84–1.61 (m,2H),1.52(m,J=13.9,7.0Hz,1H),1.45(s,9H).
步骤2：(R)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯的制备Step 2: (R)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidin-1 -Preparation of tert-butyl formate
Figure PCTCN2022093052-appb-000206
Figure PCTCN2022093052-appb-000206
在室温下向(R)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯(0.5g，1.2mmol)和THF(10ml)的混合物中加入t-BuOK(252.3mg，2.25mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(589.1mg，5.25mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(R)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯165mg，收率30％。 1H NMR(300MHz,Chloroform-d)δ11.61(s,1H),8.58(d,J＝4.9Hz,1H),8.06(s,1H)7.83(td,J＝7.8,1.8Hz,1H),7.59(d,J＝7.8Hz,1H),7.35(dd,J＝7.6,4.9Hz,1H),7.25(t,J＝3.0Hz,1H),6.65(s,1H),5.81(d,J＝8.5Hz,1H),4.24(s,1H),3.90(d,J＝12.8Hz,1H),3.58(d,J＝12.8Hz,1H)3.12(t,J＝11.1Hz,2H),2.06(s,1H),1.74(s,2H),1.56(s,1H),1.25(s,9H). To (R)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxy To a mixture of tert-butyl acid ester (0.5 g, 1.2 mmol) and THF (10 ml) was added t-BuOK (252.3 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1 mg, 5.25 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound (R)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'- d] tert-butyl pyridin-1(6H)-yl)piperidine-1-carboxylate 165 mg, yield 30%. 1 H NMR (300MHz, Chloroform-d) δ11.61(s,1H),8.58(d,J=4.9Hz,1H),8.06(s,1H)7.83(td,J=7.8,1.8Hz,1H) ,7.59(d,J=7.8Hz,1H),7.35(dd,J=7.6,4.9Hz,1H),7.25(t,J=3.0Hz,1H),6.65(s,1H),5.81(d, J＝8.5Hz, 1H), 4.24(s, 1H), 3.90(d, J＝12.8Hz, 1H), 3.58(d, J＝12.8Hz, 1H), 3.12(t, J＝11.1Hz, 2H), 2.06(s,1H),1.74(s,2H),1.56(s,1H),1.25(s,9H).
步骤3：(R)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: (R)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
Figure PCTCN2022093052-appb-000207
Figure PCTCN2022093052-appb-000207
在室温下向(R)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯(150mg，0.36mmol)和CH 3Cl 2(15ml)的混合物中加入5ml TFA。将反应混合物在室温下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(R)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶88mg收率75％。 1H NMR(300MHz,Chloroform-d)δ11.58(s,1H),8.60(d,J＝4.9Hz,1H),8.06(s,1H),7.85(t,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.45–7.31(m,1H),7.23(s,1H),6.62(s,1H),6.26(d,J＝8.6Hz,1H),4.23(s,1H),3.08(d,J＝11.8Hz,1H),2.80–2.68(m,3H),1.90(d,J＝10.1Hz,1H),1.58(d,J＝60.4Hz,4H). To (R)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidine- To a mixture of tert-butyl 1-carboxylate (150mg, 0.36mmol) and CH3Cl2 ( 15ml ) was added 5ml of TFA. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound (R)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1, 6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine 88 mg yield 75%. 1 H NMR (300MHz, Chloroform-d) δ11.58(s, 1H), 8.60(d, J=4.9Hz, 1H), 8.06(s, 1H), 7.85(t, J=7.8Hz, 1H), 7.70(d, J=7.8Hz, 1H), 7.45–7.31(m, 1H), 7.23(s, 1H), 6.62(s, 1H), 6.26(d, J=8.6Hz, 1H), 4.23(s ,1H),3.08(d,J=11.8Hz,1H),2.80–2.68(m,3H),1.90(d,J=10.1Hz,1H),1.58(d,J=60.4Hz,4H).
步骤4：(R)-3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈的制备Step 4: (R)-3-Oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridine-1(6H )-yl)piperidin-1-yl)propionitrile preparation
Figure PCTCN2022093052-appb-000208
Figure PCTCN2022093052-appb-000208
在室温下向(R)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶(70mg，0.2mmol)、氰基乙酸、DCC溶解在40ml CH 3Cl 2，并将混合物在40℃下搅拌 2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(R)-3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈55mg，收率70％。m.p.232.5-239.7℃。1H NMR(300MHz,DMSO-d6)δ11.62(s,1H),8.59(s,1H),8.07(s,1H),7.83(t,J＝7.8Hz,1H),7.62(t,J＝9.1Hz,1H),7.36(t,J＝6.2Hz,1H),7.25(s,1H),6.69(d,J＝11.2Hz,1H),5.80(d,J＝8.2Hz,1H),4.12(t,J＝32.8Hz,4H),3.5(d,J＝11.8Hz,1H)3.27–3.13(m,2H),2.10(s,1H),1.74(s,3H).HPLC purity:99.37％,t R＝4.380min.
Figure PCTCN2022093052-appb-000209
-33.2°(c＝1.0).ee＝100％. To (R)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3' at room temperature -d] Pyridine (70 mg, 0.2 mmol), cyanoacetic acid, DCC were dissolved in 40 ml CH 3 Cl 2 , and the mixture was stirred at 40° C. for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound (R)-3-oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo [2,3-b: 2',3'-d]pyridin-1(6H)-yl)piperidin-1-yl)propionitrile 55 mg, yield 70%. mp232.5-239.7°C. 1H NMR (300MHz, DMSO-d6) δ11.62(s, 1H), 8.59(s, 1H), 8.07(s, 1H), 7.83(t, J=7.8Hz, 1H), 7.62(t, J= 9.1Hz, 1H), 7.36(t, J=6.2Hz, 1H), 7.25(s, 1H), 6.69(d, J=11.2Hz, 1H), 5.80(d, J=8.2Hz, 1H), 4.12 (t, J=32.8Hz, 4H), 3.5(d, J=11.8Hz, 1H), 3.27–3.13(m, 2H), 2.10(s, 1H), 1.74(s, 3H). HPLC purity: 99.37% ,t R ＝4.380min.
Figure PCTCN2022093052-appb-000209
-33.2°(c=1.0).ee=100%.
实施例59Example 59
步骤1：(S)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯的制备Step 1: (S)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxylic acid Preparation of tert-butyl ester
Figure PCTCN2022093052-appb-000210
Figure PCTCN2022093052-appb-000210
将化合物4-氯-5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶(1.00g，3.6mmol，参照实施例37的制备方法)，(S)-3-氨基哌啶-1-羧酸叔丁酯(600ul，5.2mmol)，t-BuONa(750mg，11.4mmol)，1,3-双(2,6-二异丙基苯基)氯化咪唑鎓(110mg，0.26mmol)，Pd 2(dba) 3(75mg，0.13mmol)加入20ml二氧六环中，130℃加热回流。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝3:1)，得到相应固体化合物(S)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯，0.42g，收率28％。m.p.206.5-207.8℃。 1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.49(dd,J＝5.0,1.2Hz,1H),7.93(s,1H),7.63(dd,J＝7.9,1.1Hz,1H),7.57(m,J＝7.9,1.2Hz,1H),7.36(m,J＝7.9,4.9,1.1Hz,1H),7.29(d,J＝7.5Hz,1H),6.85(d,J＝7.5Hz,1H),4.52(m,J＝12.4,7.1Hz,1H),4.27(dd,J＝12.5,7.0Hz,1H),3.52(dd,J＝12.5,7.1Hz,1H),3.16(p,J＝7.0Hz,1H),3.02(m,J＝12.5,7.1Hz,1H),2.61(s,1H),2.33(m,J＝14.0,7.1Hz,1H),1.84–1.63(m,2H),1.54(m,J＝13.9,7.0Hz,1H),1.47(s,9H). The compound 4-chloro-5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine (1.00g, 3.6mmol, referring to the preparation method of Example 37), (S)- tert-butyl 3-aminopiperidine-1-carboxylate (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1,3-bis(2,6-diisopropylphenyl)imidazole chloride Add onium (110 mg, 0.26 mmol), Pd 2 (dba) 3 (75 mg, 0.13 mmol) into 20 ml of dioxane, and heat to reflux at 130°C. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=3:1) gave the corresponding solid compound (S)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridine -4-yl)amino)tert-butyl-1-carboxylic acid tert-butyl ester, 0.42g, yield 28%. mp206.5-207.8°C. 1 H NMR (300MHz, Chloroform-d) δ8.65(s,1H),8.49(dd,J=5.0,1.2Hz,1H),7.93(s,1H),7.63(dd,J=7.9,1.1Hz ,1H),7.57(m,J=7.9,1.2Hz,1H),7.36(m,J=7.9,4.9,1.1Hz,1H),7.29(d,J=7.5Hz,1H),6.85(d, J＝7.5Hz, 1H), 4.52(m, J＝12.4, 7.1Hz, 1H), 4.27(dd, J＝12.5, 7.0Hz, 1H), 3.52(dd, J＝12.5, 7.1Hz, 1H), 3.16(p, J=7.0Hz, 1H), 3.02(m, J=12.5, 7.1Hz, 1H), 2.61(s, 1H), 2.33(m, J=14.0, 7.1Hz, 1H), 1.84–1.63 (m,2H),1.54(m,J=13.9,7.0Hz,1H),1.47(s,9H).
步骤2：(S)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯的制备Step 2: (S)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidin-1 -Preparation of tert-butyl formate
Figure PCTCN2022093052-appb-000211
Figure PCTCN2022093052-appb-000211
在室温下向(S)-3-((5-(吡啶-2-基乙炔基)-1H-吡咯并[2,3-b]吡啶-4-基)氨基)叔丁基-1-羧酸叔丁酯(0.40g，0.95mmol)和THF(8ml)的混合物中加入t-BuOK(201.8mg，1.8mmol)。将反应混合物在室温下搅拌2小时然后再向该溶液中加入t-BuOK(471.3mg，4.2mmol)并将混合物在50℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用水(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(S)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯158mg，收率40％。 1H NMR(300MHz,Chloroform-d)δ11.62(s,1H),8.60(d,J＝4.9Hz,1H),8.08(s,1H)7.85(td,J＝7.8,1.8Hz,1H),7.61(d,J＝7.8Hz,1H),7.37(dd,J＝7.6,4.9Hz,1H),7.26(t,J＝3.0Hz,1H),6.67 (s,1H),5.82(d,J＝8.5Hz,1H),4.22(s,1H),3.91(d,J＝12.8Hz,1H),3.56(d,J＝12.8Hz,1H)3.11(t,J＝11.1Hz,2H),2.05(s,1H),1.73(s,2H),1.54(s,1H),1.23(s,9H). To (S)-3-((5-(pyridin-2-ylethynyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)tert-butyl-1-carboxy To a mixture of tert-butyl acid ester (0.40 g, 0.95 mmol) and THF (8 ml) was added t-BuOK (201.8 mg, 1.8 mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (471.3 mg, 4.2 mmol) was added to the solution and the mixture was stirred at 50°C for 2 hours. After the reaction was complete, the solvent was evaporated, extracted with EtOAc, the organic layer was washed with water (2×100ml), saturated brine (1×100ml) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound, which was obtained by Purification by silica gel chromatography (PE:EA=2:1) gave the corresponding solid compound (S)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'- d] tert-butyl pyridin-1(6H)-yl)piperidine-1-carboxylate 158 mg, yield 40%. 1 H NMR (300MHz, Chloroform-d) δ11.62(s,1H),8.60(d,J=4.9Hz,1H),8.08(s,1H)7.85(td,J=7.8,1.8Hz,1H) ,7.61(d,J=7.8Hz,1H),7.37(dd,J=7.6,4.9Hz,1H),7.26(t,J=3.0Hz,1H),6.67(s,1H),5.82(d, J＝8.5Hz, 1H), 4.22(s, 1H), 3.91(d, J＝12.8Hz, 1H), 3.56(d, J＝12.8Hz, 1H), 3.11(t, J＝11.1Hz, 2H), 2.05(s,1H),1.73(s,2H),1.54(s,1H),1.23(s,9H).
步骤3：(S)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶的制备Step 3: (S)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'- d] Preparation of pyridine
Figure PCTCN2022093052-appb-000212
Figure PCTCN2022093052-appb-000212
在室温下向(S)-3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-甲酸叔丁酯(150mg，0.36mmol)和CH3Cl 2(15ml)的混合物中加入5ml TFA。将反应混合物在室温下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(S)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶90mg收率78％。 1H NMR(300MHz,Chloroform-d)δ11.58(s,1H),8.60(d,J＝4.9Hz,1H),8.06(s,1H),7.85(t,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.45–7.31(m,1H),7.23(s,1H),6.62(s,1H),6.26(d,J＝8.6Hz,1H),4.23(s,1H),3.08(d,J＝11.8Hz,1H),2.80–2.68(m,3H),1.90(d,J＝10.1Hz,1H),1.58(d,J＝60.4Hz,4H). To (S)-3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridin-1(6H)-yl)piperidine- To a mixture of tert-butyl 1-carboxylate (150 mg, 0.36 mmol) and CH3Cl2 (15 mL) was added 5 mL of TFA. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound (S)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1, 6-Dihydrodipyrrolo[2,3-b:2',3'-d]pyridine 90 mg yield 78%. 1 H NMR (300MHz, Chloroform-d) δ11.58(s, 1H), 8.60(d, J=4.9Hz, 1H), 8.06(s, 1H), 7.85(t, J=7.8Hz, 1H), 7.70(d, J=7.8Hz, 1H), 7.45–7.31(m, 1H), 7.23(s, 1H), 6.62(s, 1H), 6.26(d, J=8.6Hz, 1H), 4.23(s ,1H),3.08(d,J=11.8Hz,1H),2.80–2.68(m,3H),1.90(d,J=10.1Hz,1H),1.58(d,J=60.4Hz,4H).
步骤4：(S)-3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈的制备Step 4: (S)-3-Oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo[2,3-b:2',3'-d]pyridine-1(6H )-yl)piperidin-1-yl)propionitrile preparation
Figure PCTCN2022093052-appb-000213
Figure PCTCN2022093052-appb-000213
在室温下向(S)-1-(哌啶-3-基)-2-(吡啶-2-基)-1,6-二氢二吡咯并[2,3-b：2'，3'-d]吡啶(70mg，0.2mmol)、氰基乙酸、DCC溶解在40ml CH 3Cl 2，并将混合物在40℃下搅拌2小时。反应完成后，蒸发溶剂，加入EtOAc萃取，依次用饱和碳酸氢钠溶液(2×100ml)，饱和食盐水(1×100ml)洗涤有机层，并经无水硫酸钠干燥，并在减压下浓缩得到粗化合物，通过硅胶色谱法纯化(PE：EA＝2:1)，得到相应固体化合物(S)-3-氧代-3-(3-(2-(吡啶-2-基)二吡咯并[2,3-b：2'，3'-d]吡啶-1(6H)-基)哌啶-1-基)丙腈40mg，收率50％。m.p.238.1-243.5℃。1H NMR(300MHz,DMSO-d6)δ11.65(s,1H),8.66–8.56(m,1H),8.09(d,J＝3.7Hz,1H),7.91–7.80(m,1H),7.64(dd,J＝10.8,7.8Hz,1H),7.38(dd,J＝7.5,4.9Hz,1H),7.28(t,J＝3.0Hz,1H),6.71(d,J＝10.2Hz,1H),5.92(dd,J＝46.4,8.7Hz,1H),4.38–3.96(m,4H),3.67(dd,J＝81.7,13.0Hz,1H),3.21(dd,J＝13.2,8.7Hz,2H),2.12(s,1H),1.92–1.51(m,3H).HPLC purity:98.97％,t R＝4.208min.
Figure PCTCN2022093052-appb-000214
+29.70°(c＝1.0).ee＝100％. To (S)-1-(piperidin-3-yl)-2-(pyridin-2-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3' at room temperature -d] Pyridine (70 mg, 0.2 mmol), cyanoacetic acid, DCC were dissolved in 40 ml CH 3 Cl 2 , and the mixture was stirred at 40° C. for 2 hours. After the reaction was completed, the solvent was evaporated, extracted with EtOAc, the organic layer was washed successively with saturated sodium bicarbonate solution (2×100ml), saturated brine (1×100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was obtained, which was purified by silica gel chromatography (PE:EA=2:1) to give the corresponding solid compound (S)-3-oxo-3-(3-(2-(pyridin-2-yl)dipyrrolo [2,3-b: 2',3'-d]pyridin-1(6H)-yl)piperidin-1-yl)propionitrile 40 mg, yield 50%. mp238.1-243.5°C. 1H NMR (300MHz, DMSO-d6) δ11.65(s, 1H), 8.66–8.56(m, 1H), 8.09(d, J=3.7Hz, 1H), 7.91–7.80(m, 1H), 7.64( dd,J=10.8,7.8Hz,1H),7.38(dd,J=7.5,4.9Hz,1H),7.28(t,J=3.0Hz,1H),6.71(d,J=10.2Hz,1H), 5.92(dd, J=46.4, 8.7Hz, 1H), 4.38–3.96(m, 4H), 3.67(dd, J=81.7, 13.0Hz, 1H), 3.21(dd, J=13.2, 8.7Hz, 2H) ,2.12(s,1H),1.92–1.51(m,3H).HPLC purity:98.97%,t R ＝4.208min.
Figure PCTCN2022093052-appb-000214
+29.70°(c=1.0).ee=100%.
实施例58、59制备的化合物58、59对JAK家族的抑制活性测试Inhibitory Activity Test of Compounds 58 and 59 Prepared in Examples 58 and 59 to JAK Family
一、实验材料1. Experimental materials
Figure PCTCN2022093052-appb-000215
Figure PCTCN2022093052-appb-000215
Figure PCTCN2022093052-appb-000216
Figure PCTCN2022093052-appb-000216
二、实验方法2. Experimental method
1、配制1x激酶反应缓冲液:1. Prepare 1x Kinase Reaction Buffer:
名称name 储液浓度Stock solution concentration 体积volume 终浓度Final concentration
HepesHepes 10001000 150150 5050
MgCl2MgCl2 10001000 3030 1000.00％1000.00%
Brij35Brij35 0.30.3 11 0.01％0.01%
DTTDTT 10001000 66 22
H2OH2O N/AN/A 28132813 N/AN/A
EGTAEGTA N/AN/A 158158 N/AN/A
 the  the totaltotal 30003000
2、激酶反应条件:2. Kinase reaction conditions:
Figure PCTCN2022093052-appb-000217
Figure PCTCN2022093052-appb-000217
3、测试流程：3. Test process:
1.在稀释板中用DMSO对化合物进行4倍梯度稀释，化合物起始浓度为10uM。1. The compound was serially diluted 4-fold with DMSO in the dilution plate, and the initial concentration of the compound was 10 uM.
2.将化合物50倍稀释到1X激酶反应缓冲液中，在振荡器上震荡20分钟。2. Dilute the compound 50 times into 1X kinase reaction buffer and shake it on a shaker for 20 minutes.
3.用1X的酶反应缓冲液配制准备2X激酶。3. Prepare 2X Kinase with 1X Enzyme Reaction Buffer.
4.向反应板中每孔加入2μl激酶。4. Add 2 μl of kinase per well to the reaction plate.
5.向每孔加入1μl在缓冲液中稀释好的化合物，用封板膜封住板子1000rpm离心60秒，25℃孵育10分钟。5. Add 1 μl of the compound diluted in buffer to each well, seal the plate with a sealing film, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 10 minutes.
6.用1X的酶反应缓冲液配制4xATP/底物混合液，向反应板中加入1μl 4x ATP/底物混合液。6. Prepare 4xATP/substrate mixture with 1X enzyme reaction buffer, add 1μl 4x ATP/substrate mixture to the reaction plate.
7.用封板膜封住板子1000rpm离心60秒，25℃孵育60分钟。7. Seal the plate with a sealing film, centrifuge at 1000 rpm for 60 seconds, and incubate at 25°C for 60 minutes.
8.转移4μL ADP-Glo到384反应板中1000rpm,离心1min，25℃孵育40min。8. Transfer 4 μL of ADP-Glo to the 384 reaction plate at 1000 rpm, centrifuge for 1 min, and incubate at 25°C for 40 min.
9.转移8μL Detection溶液到384反应板中1000rpm,离心1min，25℃孵育40min。9. Transfer 8 μL Detection solution to the 384 reaction plate at 1000 rpm, centrifuge for 1 min, and incubate at 25°C for 40 min.
10.使用BMG多功能读板机读取RLU(Relative luminescence unit)信号。信号强度用于表征激酶的活性程度。10. Use the BMG multifunctional plate reader to read the RLU (Relative luminescence unit) signal. Signal intensity is used to characterize the degree of activity of the kinase.
4、数据处理：4. Data processing:
化合物抑制率(％inh)＝100％-(化合物-阳性对照)/(阴性对照-阳性对照)*100％Compound inhibition rate (%inh) = 100% - (compound - positive control) / (negative control - positive control) * 100%
阳性对照：所有阳性对照孔2μM Tofacitinib孔的比值的平均值Positive control: the average value of the ratio of all positive control wells 2μM Tofacitinib wells
阴性对照：所有阴性对照孔0.5％DMSO孔的读值的平均值Negative Control: Average of readings from all negative control wells 0.5% DMSO wells
IC50通过抑制率由Prism GraphPad7.0计算。IC50 was calculated by Prism GraphPad7.0 by inhibition rate.
三、实验结果3. Experimental results
表 本发明化合物对JAK家族蛋白的抑制活性Table The inhibitory activity of the compounds of the present invention on JAK family proteins
Figure PCTCN2022093052-appb-000218
Figure PCTCN2022093052-appb-000218
本领域技术人员知道JAKs是多种新型疾病的重要靶标，如自身性或获得性免疫疾病和血液疾病。上述实施例表明，本发明提供的化合物对JAK家族蛋白具有明显的抑制活性，为有效的JAK抑制剂，因此具备开发成抑制JAK进而治疗疾病的药物的前景，疾病包括类风湿性关节炎、多发性骨髓瘤、特应性皮炎、系统性红斑狼疮和溃疡性结肠炎。Those skilled in the art know that JAKs are important targets for a variety of novel diseases, such as auto or acquired immune diseases and blood diseases. The above examples show that the compounds provided by the present invention have obvious inhibitory activity on JAK family proteins, and are effective JAK inhibitors, so they have the prospect of being developed into drugs that inhibit JAK and then treat diseases. Diseases include rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, and ulcerative colitis.
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。The purpose of the above embodiments is to specifically introduce the substantive content of the present invention, but those skilled in the art should know that the protection scope of the present invention should not be limited to the specific embodiments.

Claims (10)

  1. 一种二吡咯并吡啶结构的化合物，其特征在于，结构式如下：A compound with a dipyrrolopyridine structure, characterized in that the structural formula is as follows:
    Figure PCTCN2022093052-appb-100001
    Figure PCTCN2022093052-appb-100001
    其中：in:
    n＝0、1、2；n=0, 1, 2;
    m＝4、5、6、7；m=4, 5, 6, 7;
    X＝O，N；X = O, N;
    Y＝C、N；Y = C, N;
    A＝环丙基、环己基、环戊基、环己基、噻吩、呋喃、苯环、吡啶、嘧啶；吡咯并吡啶、噻吩并吡啶、呋喃并吡啶、苯并吡咯、苯并噻吩、苯并呋喃；A = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
    Figure PCTCN2022093052-appb-100002
    n 1＝1、2、3；n 2＝1、2、3、4；
    Figure PCTCN2022093052-appb-100002
    n 1 =1, 2, 3; n 2 =1, 2, 3, 4;
    R 2＝甲基、乙基、甲氧基、氟、氯、硝基、环丙基、氰基、氨基、羟基、三氟甲基；双取代的甲基、氯、氟、甲氧基；三取代的甲基、甲氧基。 R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
  2. 根据权利要求1所述的化合物，其特征在于，结构式如下：The compound according to claim 1, wherein the structural formula is as follows:
    Figure PCTCN2022093052-appb-100003
    Figure PCTCN2022093052-appb-100003
  3. 一种合成权利要求1所述化合物的方法，其特征在于，合成路线如下：A method for synthesizing the compound described in claim 1, characterized in that the synthetic route is as follows:
    Figure PCTCN2022093052-appb-100004
    Figure PCTCN2022093052-appb-100004
    其中：in:
    n＝0、1、2；n=0, 1, 2;
    m＝4、5、6、7；m=4, 5, 6, 7;
    X＝O，N；X = O, N;
    Y＝C、N；Y = C, N;
    A＝环丙基、环己基、环戊基、环己基、噻吩、呋喃、苯环、吡啶、嘧啶；吡咯并吡啶、噻吩并吡啶、呋喃并吡啶、苯并吡咯、苯并噻吩、苯并呋喃；A = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran ;
    Figure PCTCN2022093052-appb-100005
    n 1＝1、2、3；n 2＝1、2、3、4；
    Figure PCTCN2022093052-appb-100005
    n 1 =1, 2, 3; n 2 =1, 2, 3, 4;
    R 2＝甲基、乙基、甲氧基、氟、氯、硝基、环丙基、氰基、氨基、羟基、三氟甲基；双取代的甲基、氯、氟、甲氧基；三取代的甲基、甲氧基。 R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Trisubstituted methyl, methoxy.
  4. 根据权利要求3所述的方法，其特征在于，化合物5a通过如下路线合成：The method according to claim 3, wherein compound 5a is synthesized by the following route:
    Figure PCTCN2022093052-appb-100006
    Figure PCTCN2022093052-appb-100006
  5. 根据权利要求3所述的方法，其特征在于，化合物6a通过如下路线合成：The method according to claim 3, wherein compound 6a is synthesized by the following route:
    Figure PCTCN2022093052-appb-100007
    Figure PCTCN2022093052-appb-100007
  6. 权利要求1或2所述的化合物或其药学上可以接受的盐用于制备JAK抑制剂药物的医药用途。The medical use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a JAK inhibitor drug.
  7. 权利要求1或2所述的化合物或其药学上可以接受的盐具有JAK激酶抑制活性，因此可用于其抗增殖和/或促凋亡活性以及用于治疗人或动物体的方法。本发明还涉及所述化合物及其光学异构体或其药学上可接受的盐的制备方法，涉及包含该化合物的药物组合物，及 其在制备用于产生抗增殖和/或促凋亡作用、抗炎的药物中的用途。The compound according to claim 1 or 2 or the pharmaceutically acceptable salt thereof has JAK kinase inhibitory activity, so it can be used for its anti-proliferation and/or pro-apoptotic activity and for the method of treating human or animal body. The present invention also relates to the preparation method of the compound and its optical isomer or pharmaceutically acceptable salt thereof, to the pharmaceutical composition containing the compound, and to its preparation for producing antiproliferative and/or proapoptotic effects , use in anti-inflammatory drugs.
  8. 通过抑制酪氨酸激酶，特别是JAK家族。权利要求1或2所述的化合物或其药学上可接受的盐可以用于治疗自身免疫性类风湿性关节炎、特应性皮炎、系统性红斑狼疮、溃疡性结肠炎等。治疗包括肌炎、血管炎、天疱疮、克罗恩病、狼疮、肾炎、牛皮癣、斑秃、多发性硬化症、重度抑郁症、过敏、哮喘、干燥综合征、干眼症、移植排斥、癌症、炎性肠病、湿疹、牛皮癣、硬皮病、狼疮、瘙痒，其他瘙痒症、哺乳动物的过敏反应(包括过敏性皮炎)。By inhibiting tyrosine kinases, especially the JAK family. The compound of claim 1 or 2 or the pharmaceutically acceptable salt thereof can be used for treating autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis and the like. Treatment includes myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, alopecia areata, multiple sclerosis, major depression, allergies, asthma, Sjogren's syndrome, dry eye, transplant rejection, cancer , inflammatory bowel disease, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions (including atopic dermatitis) in mammals.
  9. 通过抑制酪氨酸激酶，特别是JAK家族。权利要求1或2所述的化合物或其药学上可接受的盐在骨髓增生异常，骨髓增生异常综合症和癌症的治疗中具有价值。治疗方法靶向酪氨酸激酶活性，特别是JAK家族活性，其涉及多种骨髓增生性疾病，骨髓增生异常综合症和癌症相关过程。因此，预期对骨髓增生性疾病具有活性，例如慢性粒细胞白血病、真性红细胞增多症、原发性血小板增多症、伴有骨髓纤维化的骨髓化生、特发性骨髓纤维化、慢性粒细胞增多症和慢性粒细胞增多症、骨髓增生异常综合症和肿瘤疾病，例如乳腺癌、卵巢癌、肺癌、结肠癌、前列腺癌或其他组织癌，以及白血病、骨髓瘤和淋巴瘤。By inhibiting tyrosine kinases, especially the JAK family. The compound of claim 1 or 2 or the pharmaceutically acceptable salt thereof has value in the treatment of myelodysplasia, myelodysplastic syndrome and cancer. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndromes and cancer-related processes. Therefore, activity is expected in myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelocytosis and chronic myelodysplastic syndromes, myelodysplastic syndromes, and neoplastic diseases such as breast, ovarian, lung, colon, prostate, or other tissue cancers, as well as leukemia, myeloma, and lymphoma.
  10. 通过抑制酪氨酸激酶，特别是JAK家族。权利要求1或2所述的化合物或其药学上可接受的盐在测试过程中具有的血脑屏障透过性，在中枢神经系统疾病的治疗中具有价值。治疗方法靶向酪氨酸激酶活性，特别是JAK家族活性，其涉及多种中枢神经系统炎症疾病相关过程。因此，预期对中枢神经系统炎症具有活性，例如癫痫、痴呆、帕金森疾病、抑郁症等。By inhibiting tyrosine kinases, especially the JAK family. The compound according to claim 1 or 2 or the pharmaceutically acceptable salt thereof has blood-brain barrier permeability in the test process, and has value in the treatment of central nervous system diseases. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of CNS inflammatory disease-associated processes. Thus, activity against central nervous system inflammation is expected, such as epilepsy, dementia, Parkinson's disease, depression, and the like.
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