CN115385911A - Compound with dipyrrolopyridine structure, preparation method and medical application - Google Patents

Compound with dipyrrolopyridine structure, preparation method and medical application Download PDF

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CN115385911A
CN115385911A CN202210491640.1A CN202210491640A CN115385911A CN 115385911 A CN115385911 A CN 115385911A CN 202210491640 A CN202210491640 A CN 202210491640A CN 115385911 A CN115385911 A CN 115385911A
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pyrrolo
pyridin
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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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Nanjing Kangyi Biomedical Center LP
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Abstract

The invention discloses a compound with a dipyrrolopyridine structure, a preparation method and medical application. The compound with the dipyrrolopyridine structure provided by the invention has obvious inhibitory activity on JAK family proteins, is an effective JAK inhibitor, and therefore has a prospect of being developed into a medicine for inhibiting JAK and further treating diseases.

Description

Compound with dipyrrolopyridine structure, preparation method and medical application
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a compound with a dipyrrolopyridine structure, a preparation method and medical application thereof.
Background
The JAKs (Janus kinases) family of protein kinases is a class of non-receptor tyrosine kinases that exist within cells. The JAKs are pivotal in response to the signaling processes of various cytokine receptors. Thus, JAKs represent important targets for a variety of novel diseases, such as autoimmune or acquired immune diseases and hematological diseases, which represent crucial roles.
When cytokines bind to the extracellular recognition regions of their respective receptors, they cause conformational changes in the dimerization or multimerization of the receptors themselves. Meanwhile, conformation change of cytokine receptors combined with JAKs in cytoplasm enables specific dimerization of JAKs proteins to occur, a signal complex is formed, a series of phosphorylation reactions are triggered, finally, the phosphorylation process of Signal Transducers and Activators (STATs) is promoted, and phosphorylated STATs can be dimerized. Phosphorylated STAT dimerization complexes are capable of nuclear entry and specifically bind to and regulate to the corresponding target genes. Thus, it exerts its macroscopic role in biological function.
JAKs play a vital role in a variety of diseases, such as myeloproliferative and myeloproliferative disorders, a variety of immunological disorders, and the like. Currently, small molecule inhibitors of JAK are useful in the treatment of rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, and the like.
Disclosure of Invention
The invention aims to provide a compound with a dipyrrolopyridine structure, a preparation method and medical application.
The above purpose of the invention is realized by the following technical scheme:
a compound with a dipyrrolopyridine structure, which has the following structural formula:
Figure BDA0003631268110000011
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure BDA0003631268110000012
R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
Preferably, the structural formula of the compound with the dipyrrolopyridine structure is as follows:
Figure BDA0003631268110000021
the synthesis method of the compound comprises the following steps:
Figure BDA0003631268110000022
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure BDA0003631268110000023
R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
Preferably, the above compound 5a is synthesized by the following route:
Figure BDA0003631268110000024
preferably, the above compound 6a is synthesized by the following route:
Figure BDA0003631268110000031
the compound or the pharmaceutically acceptable salt thereof is used for preparing JAK inhibitor medicines.
The use of a compound as described above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of JAK and the treatment of a disease including rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, alopecia areata, multiple myeloma, melanoma, and parkinson's disease, epilepsy, depression and the like.
Has the advantages that:
those skilled in the art are aware that JAKs are important targets for a variety of novel diseases, such as autoimmune and acquired immune diseases, hematological diseases, cancer, and central nervous system diseases.
The compound provided by the invention has obvious inhibition activity on JAK family protein, is an effective JAK inhibitor, has a prospect of being developed into a medicament for inhibiting JAK and further treating diseases, and can be used for antiproliferative and/or proapoptotic activity of the compound and a method for treating a human or animal body. The invention also relates to a preparation method of the compound or the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound in preparing anti-proliferative and/or pro-apoptotic and anti-inflammatory medicines.
The compound or the pharmaceutically acceptable salt thereof provided by the invention can be used for treating autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis and the like. The treatment includes myositis, vasculitis, pemphigus, crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depressive disorder, allergy, asthma, sjogren's syndrome, dry eye, transplant rejection, cancer, inflammatory bowel disease, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions in mammals (including allergic dermatitis)
The compounds provided by the present invention or pharmaceutically acceptable salts thereof are of value in the treatment of myelodysplasia, myelodysplastic syndromes and cancer. Therapeutic methods target tyrosine kinase activity, particularly JAK family activity, which is implicated in a variety of myeloproliferative diseases, myelodysplastic syndromes, and cancer-related processes. Thus, activity against myeloproliferative diseases such as chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelometaplasia with myelofibrosis, idiopathic myelofibrosis, chronic granulocytosis and chronic granulocytosis, myelodysplastic syndromes and neoplastic diseases such as breast cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer or other tissue cancers, as well as leukemia, myeloma and lymphoma are expected.
The compounds or pharmaceutically acceptable salts thereof provided by the invention have blood brain barrier permeability in the testing process, and have 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 central nervous system inflammatory disease-related processes. Thus, activity on central nervous system inflammation is expected, such as epilepsy, dementia, parkinson's disease, depression, and the like.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
Example 1
Step 1: preparation of 4-chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ] pyridine (intermediate 2 a)
Figure BDA0003631268110000032
To a stirred solution of 1 (16.0 g,0.10 mol) in THF (300 ml) at 0 deg.C was added NaH (60% in mineral oil, 5g,0.1 mol) in portions, and the mixture was stirred at the same temperature for 20 minutes, after which triisopropylsilyl chloride (22.3 g,0.16 mol) was added dropwise, maintaining the temperature at 0 deg.C. After the reaction was complete, the reaction mixture was washed with saturated NH 4 The Cl solution (10 mL) was quenched, diluted with water and extracted with ethyl acetate (3X 200 mL). The crude compound was purified by column chromatography to give 230.0g of a colorless oily liquid in 92.6% yield. 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).
Step 2: preparation of 4-chloro-5-iodo-1- (triisopropylsilyl) -1H-pyrrolo [2,3-b ] pyridine (3 a)
Figure BDA0003631268110000041
Sec-BuLi (Sec-butyllithium) (53mL, 78.5 mmol) was added dropwise over 30 minutes to a solution of 2a (11.0g, 35.7mmol) in THF (100 mL) at-78 deg.C, and the reaction mixture was further stirred at the given temperature for 1.5 hours. A solution of iodine (18g, 71.1mmol) 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 ℃. With saturated NH 4 The reaction was quenched with Cl solution, extracted with EtOAc, washed with water and brine, and washed with Na 2 SO 4 Drying and concentration under reduced pressure gave the crude compound which was purified by silica gel chromatography to give 3a as a pale yellow oil 8.25g, 53.2% yield. 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).
And 3, step 3: preparation of 4-chloro-5-iodo-1H-pyrrolo [2,3-b ] pyridine (4 a)
Figure BDA0003631268110000042
To a stirred solution of 3 (11.0 g,25.3 mmol) in dry THF (200 mL) at 0 deg.C was added TBAF (1M solution in THF, 27mL, 27mmol) and stirred for 30 min. After completion of the reaction, the solvent was evaporated, diluted with EtOAc, washed with water and brine, and dried over anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave crude compound, which was purified by silica gel chromatography to give 4a 7.0g as pale yellow solid in 95.6% yield. 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).
And 4, step 4: preparation of 4-chloro-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000043
Intermediate 4a (1g, 3.6 mmol), benzyne (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (phenylethynyl) -1H-pyrrolo [2,3-b]Pyridine 790mg, 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)。
And 5: preparation of N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000051
The compound 4-chloro-5- (phenylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give 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).
Step 6: preparation of N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000052
To N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After the reaction is completed, the reaction solution is added,the solvent was evaporated, etOAc was added for extraction, the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 313.5mg, yield 62.7%. m.p.204.5-205.1 ℃. 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).
Example 2
Step 1: preparation of 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000053
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), p-methylphenylacetylene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b]892mg of pyridine was obtained, yield 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).
And 2, step: preparation of N-cyclohexyl-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000061
The compound 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 535mg, yield 60.8%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2- (p-tolyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000062
To 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (p-tolyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 292.5mg, yield 58.4%. m.p.203.6-205.0 deg.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).
Example 3
Step 1: preparation of 4-chloro-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000071
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 4-fluorobenzeneyne (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine 790mg, yield 82.5%. 1 HNMR(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)。
And 2, step: preparation of N-cyclohexyl-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000072
The compound 4-chloro-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After the reaction is finishedThe solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 502mg, yield 55.7%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (4-fluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000073
To N-cyclohexyl-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (4-fluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 284.5mg, yield 56.9%. m.p.200.6-202.1 deg.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).
Example 4
Step 1: preparation of 4-chloro-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000081
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), phenylalkyne (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine 861mg, yield 80.8%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000082
The compound 4-chloro-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 590mg, 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).
And step 3: 1-cyclohexyl-2- (4-methoxyphenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000083
To N-cyclohexyl-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (4-methoxyphenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 301.5mg, 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).
Example 5
Step 1: preparation of 4- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) benzonitrile
Figure BDA0003631268110000091
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), p-cyanophenylyne (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) benzonitrile 855mg, yield 84.5%. 1 HNMR(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).
And 2, step: preparation of 4- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) benzonitrile
Figure BDA0003631268110000092
A compound of 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) benzonitrile (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound 4- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) benzonitrile, 531.6mg, yield 57.7%. 1 HNMR(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).
And step 3: preparation of 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) benzonitrile
Figure BDA0003631268110000093
To 4- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) benzonitrile (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) benzonitrile, 278.6mg, yield 55.6%. m.p.209.7-212.0 ℃. 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).
Example 6
Step 1 preparation of (3-phenylprop-1-yn-1-yl) trimethylsilane
Figure BDA0003631268110000101
Benzyl bromide (5.8 mmol), trimethylethynylsilicon (682mg, 6.9mmol), pd (PPh) 3 ) 2 Cl 2 (203mg, 0.29mmol), cuI (110mg, 0.58mmol) and 2.5mL of triethylamine were added to 25mL of acetonitrile and heated at 80 ℃ under reflux. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 mL), saturated brine (1 × 100 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 100) and fractionated by column chromatography (PE: EA =100The resulting mixture was subjected to centrifugal purification to give (3-phenylprop-1-yn-1-yl) trimethylsilane as a white oily liquid, 0.91g, in 83.6% yield. 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).
And 2, step: preparation of 3-benzene-1-propyne
Figure BDA0003631268110000102
The compound (3-phenylprop-1-yn-1-yl) trimethylsilane (4.8 mmol), K 2 CO 3 (3.3 g, 24mmol) was added to 20ml of methanol and stirred at 0 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was isolated and purified by column chromatography to give the product 3-benzene-1-propyne 520mg, yield 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).
And step 3: preparation of 4-chloro-5- (3-phenylprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000103
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 3-benzene-1-propyne (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the product 4-chloro-5- (3-phenylprop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine 790mg, yield 82.5%. 1 HNMR(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).
And 4, step 4: preparation of N-cyclohexyl-5- (3-phenylprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000111
The compound 4-chloro-5- (3-phenylpropan-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 3) and isolated by column chromatography to give the product N-cyclohexyl-5- (3-phenylpropan-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridin-4-amine 490mg, yield 57.3%. 1 HNMR(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).
And 5: 2-benzyl-1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000112
To N-cyclohexyl-5- (3-phenylprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added and extracted successively with water (2X 100 ml), saturated withAnd brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which is purified by silica gel chromatography (PE: EA =2 1) to give 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).
Example 7
Step 1 preparation of (3- (p-tolyl) prop-1-yn-1-yl) trimethylsilane
Figure BDA0003631268110000113
P-methylbenzyl bromide (5.8 mmol), trimethylethynylsilicon (682mg, 6.9mmol) and Pd (PPh) 3 ) 2 Cl 2 (203mg, 0.29mmol), cuI (110mg, 0.58mmol) and 2.5mL of triethylamine were added to 25mL of acetonitrile and heated at 80 ℃ under reflux. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 mL), saturated brine (1 × 100 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 100) and by column chromatography to give a white oily liquid (3- (p-tolyl) prop-1-yn-1-yl) trimethylsilane, 1.0g, yield 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).
Step 2: preparation of 1-methyl-4- (prop-2-yn-1-yl) benzene
Figure BDA0003631268110000121
The compound (3- (p-tolyl) prop-1-yn-1-yl) trimethylsilane (4.8 mmol), K 2 CO 3 (3.3 g, 24mmol) was added to 20ml of methanol and stirred at 0 deg.CAnd (4) stirring. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was separated and purified by column chromatography to give 575mg of 1-methyl-4- (prop-2-yn-1-yl) benzene as a product in 92.3% yield. 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).
And step 3: preparation of 4-chloro-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000122
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 1-methyl-4- (prop-2-yn-1-yl) benzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) and by column chromatography to give the product 4-chloro-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]892mg of pyridine was obtained in 88.5% yield. 1 HNMR(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).
And 4, step 4: preparation of N-cyclohexyl-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000123
The compound 4-chloro-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diiso-iso-pyridine)Propylphenyl) imidazolium chloride (110mg, 0.26mmol), pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) and column chromatography to give the product N-cyclohexyl-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]535mg of pyridin-4-amine, yield 60.8%. 1 HNMR(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).
And 5: 1-cyclohexyl-2- (4-methylbenzyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000131
To N-cyclohexyl-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) and isolated by column chromatography to give the product 1-cyclohexyl-2- (4-methylbenzyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 292.5mg, yield 58.4%. m.p.183.1-184.0 deg.C. 1 HNMR(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).
Example 8
Step 1 preparation of (3- (4-fluorophenyl) prop-1-yn-1-yl) trimethylsilane
Figure BDA0003631268110000132
4-fluorobenzyl bromide (5.8 mmol), trimethylethynylsilicon (682mg, 6.9mmol) and Pd (PPh) 3 ) 2 Cl 2 (203mg, 0.29mmol), cuI (110mg, 0.58mmol) and 2.5mL of triethylamine were added to 25mL of acetonitrile and heated at 80 ℃ under reflux. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 mL), saturated brine (1 × 100 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 100) and column chromatography to give a white oily liquid (3- (4-fluorophenyl) prop-1-yn-1-yl) trimethylsilane, 0.98g, yield 82.1%. 1 HNMR(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).
Step 2: preparation of 1-fluoro-4- (prop-2-yn-1-yl) benzene
Figure BDA0003631268110000133
The compound ((3- (4-fluorophenyl) prop-1-yn-1-yl) trimethylsilane (4.8 mmol), K 2 CO 3 (3.3 g, 24mmol) was added to 20ml of methanol and stirred at 0 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was separated and purified by column chromatography to give 616mg of 1-fluoro-4- (prop-2-yn-1-yl) benzene as a product in 93.5% yield. 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).
And 3, step 3: preparation of 4-chloro-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000134
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yl) benzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the product 4-chloro-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]805mg of pyridine was obtained, 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＝7.5Hz,1H),3.42(d,J＝1.4Hz,2H).
And 4, step 4: preparation of N-cyclohexyl-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000141
The compound 4-chloro-5- (3- (4-fluorophenyl) prop-1-yne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the product N-cyclohexyl-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]502mg of pyridin-4-amineThe ratio was 55.7%. 1 HNMR(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).
And 5: 1-cyclohexyl-2- (4-fluorobenzyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000142
To N-cyclohexyl-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) and isolated by column chromatography to give the product 1-cyclohexyl-2- (4-fluorobenzyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]284.5mg of pyridine was obtained, yield 56.9%. m.p.181.1-183.0 deg.C. 1 HNMR(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).
Example 9
Step 1 preparation of (3- (4-methoxyphenyl) prop-1-yn-1-yl) trimethylsilane
Figure BDA0003631268110000151
4-methoxy radicalBenzyl bromide (5.8 mmol), trimethylethynylsilicon (682mg, 6.9mmol), pd (PPh) 3 ) 2 Cl 2 (203mg, 0.29mmol), cuI (110mg, 0.58mmol) and 2.5mL of triethylamine were added to 25mL of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 mL), saturated brine (1 × 100 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 100) and by column chromatography to give a white oily liquid (3- (4-methoxyphenyl) prop-1-yn-1-yl) trimethylsilane, 1.0g, yield 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).
And 2, step: preparation of 1-methoxy-4- (prop-2-yn-1-yl) benzene
Figure BDA0003631268110000152
The compound (3- (4-methoxyphenyl) prop-1-yn-1-yl) trimethylsilane (4.8 mmol), K 2 CO 3 (3.3 g, 24mmol) was added to 20ml of methanol and stirred at 0 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added and extracted, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was isolated and purified by column chromatography to give 630mg of 1-methoxy-4- (prop-2-yn-1-yl) benzene as a product 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).
And step 3: preparation of 4-chloro-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000153
Intermediate 4 (1g, 3.6mmol, see 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, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the product 4-chloro-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]861mg of pyridine was added thereto, and the yield was 80.8%. 1 HNMR(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).
And 4, step 4: preparation of N-cyclohexyl-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000154
The compound 4-chloro-5- (3- (4-methoxyphenyl) prop-1-yne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the product N-cyclohexyl-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]590mg of pyridin-4-amine, 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).
And 5: 1-cyclohexyl-2- (4-methoxybenzyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000161
To N-cyclohexyl-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the product 1-cyclohexyl-2- (4-methoxybenzyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 301.5mg, yield 60.2%. m.p.193.6-195.0 ℃. 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).
Example 10
Step 1: preparation of (prop-2-yn-1-yloxy) benzene
Figure BDA0003631268110000162
Phenol (10.6 mmol), 3-bromopropyne (1.5g, 12.7 mmol), K 2 CO 3 (5.8 g,42.4 mmol) was added to 25ml of acetone and heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, K is removed by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added for extraction, the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =80, 1) over silica gelThe product (prop-2-yne-1-yloxy) benzene is obtained by column chromatography separation and purification in a yield of 91.8 g. 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＝2.9Hz,2H),2.99(t,J＝3.0Hz,1H).
Step 2: preparation of 4-chloro-5- (3-phenoxy-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000163
Intermediate 4 (1g, 3.6 mmol), (prop-2-yn-1-yloxy) benzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the product 4-chloro-5- (3-phenoxy-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine 810.1mg, 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).
And step 3: preparation of N-cyclohexyl-5- (3-phenoxyprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000171
The compound 4-chloro-5- (3-phenoxy-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added and extracted, followed by water (2X 100 ml), saturated with waterAnd brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which is purified by silica gel chromatography (PE: EA = 3) and column chromatography to give the product N-cyclohexyl-5- (3-phenoxyprop-1-yn-1-yl) -1H-pyrrolo [2,3-b]473mg of pyridin-4-amine, 52.8% yield. 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).
And 4, step 4: 1-cyclohexyl-2- (phenoxymethyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000172
To N-cyclohexyl-5- (3-phenoxyprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product 1-cyclohexyl-2- (phenoxymethyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 262.5mg, yield 52.5%. m.p.174.6-176.1 ℃. 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).
Example 11
Step 1: preparation of 1-methyl-4- (prop-2-yn-1-yloxy) benzene
Figure BDA0003631268110000173
P-cresol (10.6 mmol), 3-bromopropyne (1.5g, 12.7 mmol), and K 2 CO 3 (5.8g, 42.4 mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 hours. After the reaction is finished, removing K by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =80: 1) to give the product 1-methyl-4- (prop-2-yn-1-yloxy) benzene 1.45g, yield 93.6% by column chromatography separation and purification. 1 HNMR(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).
And 2, step: preparation of 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000181
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 1-methyl-4- (prop-2-yn-1-yloxy) benzene 4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) and column chromatography to give the product 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine 804.5mg, 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).
And 3, step 3: preparation of N-cyclohexyl-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000182
The compound 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) and column chromatography to give the product N-cyclohexyl-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridin-4-amine 450.8mg, 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).
And 4, step 4: 1-cyclohexyl-2- ((p-tolyloxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000191
To N-cyclohexyl-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After the reaction was complete, the solvent was evaporated, etOAc was added and extracted, followed by water (2 in ethanol)100 ml), the organic layer was washed with saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product 1-cyclohexyl-2- ((p-tolyloxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 293.2mg, yield 58.6%. m.p.168.6-170.9 deg.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).
Example 12
Step 1: preparation of 1-fluoro-4- (prop-2-yn-1-yloxy) benzene
Figure BDA0003631268110000192
P-fluorophenol (10.6 mmol), 3-bromopropyne (1.5g, 12.7 mmol) and K 2 CO 3 (5.8 g,42.4 mmol) was added to 25ml of acetone and heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, removing K by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =80: 1) to give the product 1-fluoro-4- (prop-2-yn-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).
And 2, step: preparation of 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000193
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yloxy) benzene 4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 10) and column chromatography to give the product 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine 785.2mg, 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).
And step 3: preparation of N-cyclohexyl-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000201
The compound 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the product N-cyclohexyl-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridin-4-amine 521.9mg, 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).
And 4, step 4: 1-cyclohexyl-2- ((4-fluorophenoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000202
To N-cyclohexyl-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product 1-cyclohexyl-2- ((4-fluorophenoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 268.5mg, yield 53.7%. m.p.164.1-166.0 ℃. 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).
Example 13
Step 1: preparation of 1-methoxy-4- (prop-2-yn-1-yloxy) benzene
Figure BDA0003631268110000203
P-fluorophenol (10.6 mmol), 3-bromopropyne (1.5g, 12.7 mmol) and K 2 CO 3 (5.8 g,42.4 mmol) was added to 25ml of acetone and heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, K is removed by suction filtration 2 CO 3 And washed multiple times with acetone, the solvent was evaporated, etOAc was added and extracted, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 80) and isolated by column chromatography to give the product 1-methoxy-4- (prop-2-yn-1-yloxy) benzene1.58g, yield 92.1%. 1 HNMR(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).
Step 2: preparation of 4-chloro-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000211
Intermediate 4 (1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yloxy) benzene 4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the product 4-chloro-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine 828.9mg, 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).
And step 3: preparation of N-cyclohexyl-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000212
The compound 4-chloro-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added and extracted successively with water (2X 100 ml) and saturated brineThe organic layer was washed (1 × 100 ml) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA =3]Pyridin-4-amine 560.2mg, 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).
And 4, step 4: 1-cyclohexyl-2- ((4-methoxyphenoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000213
To N-cyclohexyl-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product 1-cyclohexyl-2- ((4-methoxyphenoxy) methyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 253.5mg, yield 50.7%. m.p.180.2-183.0 deg.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).
Example 14
Step 1: preparation of N- (prop-2-yn-1-yl) aniline
Figure BDA0003631268110000221
Aniline (10.7 mmol), 3-bromopropyne (1.5g, 12.8 mmol), K 2 CO 3 (5.9g, 42.8mmol) was added to 25ml of acetone, and the mixture was heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, K is removed by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =50 1) 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).
Step 2: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) aniline
Figure BDA0003631268110000222
Intermediate 4 (1g, 3.6mmol, prepared according to example 1), N- (prop-2-yn-1-yl) aniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 8) to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) prop-2-yn-1-yl) aniline 735.4mg, 72.8% yield. 1 HNMR(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).
And step 3: preparation of N-cyclohexyl-5- (3- (phenylamino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000223
Reacting the compound N- (3- (4-chloro-1H-pyrrolo [2,3-b ]]Pyridin-5-yl) prop-2-yn-1-yl) aniline (2.6 mmol), 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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2. Separating and purifying by column chromatography to obtain product N-cyclohexyl-5- (3- (phenylamino) prop-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]499.6mg of pyridin-4-ylamine, 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).
And 4, step 4: preparation of N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) methyl) aniline
Figure BDA0003631268110000231
To N-cyclohexyl-5- (3- (phenylamino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml) and dried over anhydrous sodium sulfateDrying and concentration under reduced pressure gave the crude compound, which was purified by silica gel chromatography (PE: EA = 1) and column chromatography to afford the product N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d)]Pyridin-2-yl) methyl) aniline 268.4mg, yield 53.6%. m.p.167.6-171.0 ℃. 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).
Example 15
Step 1: preparation of N- (prop-2-yn-1-yl) aniline
Figure BDA0003631268110000232
P-methylaniline (10.7 mmol), 3-bromopropyne (1.5g, 12.8mmol), and K 2 CO 3 (5.9g, 42.8mmol) was added to 25ml of acetone, and the mixture was heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, K is removed by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added and extracted, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 50) and isolated by column chromatography to give the product N- (prop-2-yn-1-yl) aniline 1.12g in 73.7% yield. 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).
And 2, step: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline
Figure BDA0003631268110000233
Intermediate 4 (1g, 3.6mmol, prepared according to example 1), N- (prop-2-yn-1-yl) aniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 8) to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline 791.2mg, 74.5% yield. 1 HNMR(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)
And step 3: preparation of N-cyclohexyl-5- (3- (p-tolylamino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000241
Reacting the compound N- (3- (4-chloro-1H-pyrrolo [2,3-b ]]Pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2. Separating and purifying by column chromatography to obtain product N-cyclohexyl-5- (3- (p-tolylamino) prop-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridin-4-amine 497.5mg, 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).
And 4, step 4: preparation of N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) methyl) -4-methylaniline
Figure BDA0003631268110000242
To N-cyclohexyl-5- (3- (p-tolylamino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 1) and isolated by column chromatography to give the product N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) methyl) -4-methylaniline 237.6mg, yield 47.6%. m.p.166.6-177.7 ℃. 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).
Example 16
Step 1: preparation of 4-fluoro-N- (prop-2-yn-1-yl) aniline
Figure BDA0003631268110000251
Para-fluoroaniline (10.7 mmol), 3-bromopropyne (1.5g, 12.8mmol), K 2 CO 3 (5.9g, 42.8mmol) was added to 25ml of acetone, and the mixture was heated at 50 ℃ under reflux for 5 hours. After the reaction is finished, K is removed by suction filtration 2 CO 3 Washing with acetone for several times, evaporating the solvent, addingThe organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =50 1) and isolated and purified by column chromatography to give the product 4-fluoro-N- (prop-2-yn-1-yl) aniline 1.21g with a yield of 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).
Step 2: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) -4-fluoroaniline
Figure BDA0003631268110000252
Intermediate 4 (1g, 3.6mmol, prepared according to example 1), 4-fluoro-N- (prop-2-yn-1-yl) aniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 8) to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) prop-2-yn-1-yl) -4-fluoroaniline 837.4mg, 77.8% yield. 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).
And 3, step 3: preparation of N-cyclohexyl-5- (3- ((4-fluorophenyl) amino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000253
Reacting the compound N- (3- (4-chloro-1H-pyrrolo [2,3-b ]]Pyridin-5-yl) prop-2-yn-1-yl) -4-fluoroaniline (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2. Separating and purifying by column chromatography to obtain the product N-cyclohexyl-5- (3- ((4-fluorophenyl) amino) prop-1-alkyne-1-radical) -1H-pyrrolo [2, 3-b)]468.7mg of pyridin-4-amine was obtained in 49.8% yield. 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).
And 4, step 4: preparation of N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) methyl) -4-fluoroaniline
Figure BDA0003631268110000261
To N-cyclohexyl-5- (3- ((4-fluorophenyl) amino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 1), and by column chromatography to give the product N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) methyl) -4-fluoroaniline 225.6mg, yield 49.7%. m.p.180.9-183.3 deg.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).
Example 17
Step 1: preparation of 4-methoxy-N- (prop-2-yn-1-yl) aniline
Figure BDA0003631268110000262
P-methoxyaniline (10.7 mmol), 3-bromopropyne (1.5g, 12.8mmol), and K 2 CO 3 (5.9g, 42.8mmol) was added to 25ml of acetone, and the mixture was heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, removing K by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added and extracted, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 50) and isolated by column chromatography to give the product 4-methoxy-N- (prop-2-yn-1-yl) aniline 1.26g, yield 73.4%. 1 HNMR(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).
And 2, step: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline
Figure BDA0003631268110000263
Intermediate 4 (1g, 3.6mmol, prepared according to example 1), 4-methoxy-N- (prop-2-yn-1-yl) aniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added and extraction was carried out, and the organic phase was washed successively with water (2X 100 ml) and saturated brine (1X 100 ml)Layer, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA =8 1) to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline (830.7 mg, yield 74.2%). 1 HNMR(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).
And step 3: preparation of N-cyclohexyl-5- (3- ((4-methoxyphenyl) amino) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000271
The compound N- (3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2. Separating and purifying by column chromatography to obtain product N-cyclohexyl-5- (3- ((4-methoxyphenyl) amino) prop-1-alkyne-1-radical) -1H-pyrrolo [2, 3-b)]486.2mg of pyridin-4-amine was obtained in 50.5% yield. 1 HNMR(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).
And 4, step 4: preparation of N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) methyl) -4-methoxyaniline
Figure BDA0003631268110000272
To N-cyclohexyl-5- (3- ((4-methoxyphenyl) amino) prop-1-yn-1-yl) -1H-pyrrolo [2, 3-b) at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 1), and by column chromatography to give the product N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) methyl) -4-methoxyaniline, 221.4mg, 43.2% yield. m.p.220.3-221.6 ℃. 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.
Example 18
Step 1: preparation of 4- (prop-2-yn-1-ylamino) benzonitrile
Figure BDA0003631268110000281
4-aminobenzonitrile (10.7 mmol), 3-bromopropyne (1.5g, 12.8mmol), and K 2 CO 3 (5.9g, 42.8mmol) was added to 25ml of acetone, and the mixture was heated under reflux at 50 ℃ for 5 hours. After the reaction is finished, removing K by suction filtration 2 CO 3 And washed with acetone several times, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed with water (2 × 100 ml), saturated brine (1 × 100 ml) and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =50The product, 4- (prop-2-yn-1-ylamino) benzonitrile, 1.19g is obtained in 71.7% yield. 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).
Step 2 preparation of 4- ((3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile
Figure BDA0003631268110000282
Intermediate 4 (1g, 3.6mmol, prepared according to example 1), 4- (prop-2-yn-1-ylamino) benzonitrile (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 8) and isolated and purified by column chromatography to give the product 4- ((3- (4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile 767.8mg, yield 69.7%. 1 HNMR(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).
And step 3: preparation of 4- ((3- (4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile
Figure BDA0003631268110000283
Compound 4- ((3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile (2.6 mmol), 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 under reflux at 130 ℃. After the reaction is complete, evaporation is carried outThe solvent, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 2. Separating and purifying by column chromatography to obtain product 4- ((3- (4- (cyclohexylamino) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile 466.3mg, 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).
And 4, step 4: preparation of 4- (((1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) methyl) amino) benzonitrile
Figure BDA0003631268110000291
To 4- ((3- (4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]To a mixture of pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile (1.5 mmol) and THF (10 ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 1), and separated and purified by column chromatography to give 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%. m.p.203.6-205.0 deg.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).
Example 19
Step 1: preparation of 4-chloro-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000292
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10)]Pyridine, 770.8mg, yield 73.6%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000293
The compound 4-chloro-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml) and then dried over anhydrous sodium sulfateSodium sulfate was dried and concentrated under reduced pressure to give the crude compound, which was purified 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]Pyridin-4-amine, 706mg, 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).
And step 3: 1-cyclohexyl-2- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000301
To N-cyclohexyl-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 85.0mg, yield 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).
Example 20
Step 1: preparation of 4-chloro-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000302
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-nitro-2-fluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 749.7mg, 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＝7.4Hz,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).
Step 2: preparation of N-cyclohexyl-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000311
The compound 4-chloro-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3)]Pyridin-4-amine, 326.2mg, yield 37.3%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (2-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000312
To N-cyclohexyl-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (2-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 59.9mg, yield 19.1%. m.p.233.6-236.0 deg.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).
Example 21
Step 1: preparation of 4-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000313
Intermediate 4a (1g, 3.6mmol, preparation of reference example 1)Method), 1-ethynyl-3-methylbenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 738.8mg, 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).
Step 2: preparation of N-cyclohexyl-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000321
The compound-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridine, (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 323.3mg, 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).
And step 3: 1-cyclohexyl-2- (m-tolyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000322
To N-cyclohexyl-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (m-tolyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 59.9mg, 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).
Example 22
Step 1: preparation of 3- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) aniline
Figure BDA0003631268110000323
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylaniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added, and the mixture was extracted, washed successively with water (2X 100 ml) and saturated brine (1X 100 ml)The organic layer was washed and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =10: 1) to give the corresponding solid compound 3- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) aniline, 729.0mg, yield 67.6%. 1 HNMR(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).
Step 2: preparation of 5- ((3-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000331
Compound-3- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) aniline, (2.6 mmol), 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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =3]Pyridin-4-amine, 357.8mg, 33.1% yield. 1 HNMR(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).
And step 3: preparation of 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) aniline
Figure BDA0003631268110000332
To 5- ((3-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) aniline, 84.1mg, yield 23.6%. m.p.231.8-236.3 ℃. 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).
Example 23
Step 1: preparation of 3- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) phenol
Figure BDA0003631268110000341
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 3-ethynylphenol (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 3- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) phenol, 729.8mg, yieldThe rate was 67.6%. 1 HNMR(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).
Step 2: preparation of 3- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) phenol
Figure BDA0003631268110000342
Compound 3- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound 3- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) phenol, 353.7mg, yield 32.7%. 1 HNMR(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).
And step 3: preparation of 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) phenol
Figure BDA0003631268110000343
To 3- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) phenol (1.5 mmol) and THF (10 mL)To the mixture was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) phenol, 51.6mg, yield 16.6%. m.p.201.0-203.6 deg.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＝8.2Hz,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).
Example 24
Step 1: preparation of 4-chloro-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000351
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylnitrobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10)]Pyridine, 777.5mg, yield 72.0%. 1 HNMR(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).
And 2, step: preparation of N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000352
The compound 4-chloro-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 340.5mg, yield 31.5%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000353
To N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After the reaction was complete, the solvent was evaporated, etOAc was added for extraction, and the sequence was repeatedThe organic layer was washed with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 70.4mg, yield 20.1%. m.p.>250.0℃。 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).
Example 25
Step 1: preparation of 4-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000361
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3- (trifluoromethyl) benzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 769.1mg, 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)
And 2, step: preparation of N-cyclohexyl-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000362
The compound 4-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 365.8mg, 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).
And step 3: 1-cyclohexyl-2- (4- (trifluoromethyl) phenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000371
To N-cyclohexyl-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (4- (trifluoromethyl) phenyl) -1, 6-dihydrodipyrrolo [2,3-b:2'，3'-d]pyridine, 67.4mg, yield 22.1%. m.p.243.0-245.3 ℃. 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).
Example 26
Step 1: preparation of 4- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) phenol
Figure BDA0003631268110000372
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylphenol (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =10: 1) to give the corresponding solid compound 4- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) phenol, 777.5mg, yield 72.0%. 1 HNMR(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).
And 2, step: preparation of N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000373
Compound 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol (2.6 mmol), 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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 340.5mg, yield 31.5%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000381
To N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 84.7mg, yield 23.9%. m.p.203.6-205.0 deg.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).
Example 27
Step 1: preparation of 4-chloro-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000382
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 4-ethynylnitrobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10)]Pyridine, 796.1mg, yield 71.2%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000383
The compound 4-chloro-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml) and then dried over anhydrous sodium sulfateDried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA =3]Pyridin-4-amine, 316.9mg, yield 29.3%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (4-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000391
To N-cyclohexyl-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (4-nitrophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 79.6mg, yield 24.5%. m.p.219.9-222.2 ℃. 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).
Example 28
Step 1: preparation of 4- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) aniline
Figure BDA0003631268110000392
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 4-ethynylaniline (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =10: 1) to give the corresponding solid compound 4- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) aniline, 745.2mg, yield 69.0%. 1 HNMR(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).
Step 2: preparation of 5- ((4-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000401
A compound of 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) aniline (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =3]Pyridin-4-amine, 334.9mg, yield 31.0%. 1 HNMR(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).
And step 3: preparation of 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d ] pyridin-2-yl) aniline
Figure BDA0003631268110000402
To 5- ((4-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridin-2-yl) aniline, 77.3mg, yield 20.6%. m.p.200.9-203.7 ℃. 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).
Example 29
Step 1: preparation of 4-chloro-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000403
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3, 5-dimethoxybenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg，0.18mmol)，CuI(34mg，0.18mmol) And triethylamine 1ml were added to 25ml of acetonitrile, and heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 790mg, 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).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000411
The compound 4-chloro-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 380.6mg, yield 35.2%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (3, 5-dimethoxyphenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000412
To N-cyclohexyl-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (3, 5-dimethoxyphenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 61.8mg, yield 19.1%. m.p.223.6-226.5 ℃. 1 HNMR(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).
Example 30
Step 1: preparation of 4-chloro-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000421
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3.5-difluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound which was passed through silica gelPurification by gel chromatography (PE: EA =10 1) gave the corresponding solid compound 4-chloro-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 797mg, yield 73.8%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000422
The compound 4-chloro-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 331.2mg, yield 30.7%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (3, 5-difluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000423
To N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 79.2mg, yield 24.5%. m.p.226.6-229.5 ℃. 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).
Example 31
Step 1: preparation of 4-chloro-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000431
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 701mg, yield 64.9%. 1 HNMR(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).
And 2, step: preparation of N-cyclohexyl-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000432
The compound 4-chloro-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 364.2mg, yield 33.7%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (2, 4-difluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000433
To N-cyclohexyl-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 2)The solid compound 1-cyclohexyl-2- (2, 4-difluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 59.9mg, yield 19.7%. m.p.230.6-233.9 deg.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＝9.7,2.6Hz,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).
Example 32
Step 1: preparation of 4-chloro-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000441
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10)]Pyridine 706mg, yield 65.4%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000442
The compound 4-chloro-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =3: 1) to give the corresponding solid compound N-cyclohexyl-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 329.5mg, yield 30.5%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (3, 5-dichlorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000451
To N-cyclohexyl-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 59.5mg, yield 19.7%. 1 HNMR(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).
Example 33
Step 1: preparation of 4-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000452
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), ethynylcyclopropane (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 513.7mg, 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).
Step 2: preparation of N-cyclohexyl-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000453
The compound 4-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound, N-ringHexyl-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 142.4mg, yield 34.7%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2-cyclopropyl-1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000461
To N-cyclohexyl-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 53.0mg, yield 29.5%. m.p.219.6-222.3 ℃. 1 HNMR(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).
Example 34
Step 1: preparation of 4-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000462
Intermediate 4a (1)g,3.6mmol, see preparation of example 1), ethynylcyclopentane (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 579.9mg, 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).
Step 2: preparation of N-cyclohexyl-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000463
The compound 4-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 136.7mg, yield 33.3%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2-cyclopentyl-1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000471
To N-cyclohexyl-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2-cyclopentyl-1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 74.4mg, yield 41.5%. m.p.240.3-245.0 ℃. 1 HNMR(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).
Example 35
Step 1: preparation of 4-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000472
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), ethynylcyclohexane (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound which was purified by ethanol extraction, methanol extraction, ethanol extraction, etcPurification by silica gel chromatography (PE: EA = 10) gave the corresponding solid compound 4-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 528.9mg, 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).
And 2, step: preparation of N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000473
Reacting the compound 4-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ]]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 39.6mg, 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).
And step 3: 1-cyclohexyl-2- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000481
To N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]Mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL)To the mixture was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 51.4mg, yield 28.5%. m.p.213.7-216.9 ℃. 1 HNMR(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).
Example 36
Step 1: preparation of 4-chloro-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000482
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylthiophene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (thiophen-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 510.0mg, 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).
Step 2: preparation of N-cyclohexyl-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000483
The compound 4-chloro-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 147.5mg, 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).
And step 3: 1-cyclohexyl-2- (thiophen-3-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000491
To N-cyclohexyl-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2)1) to give the corresponding solid compound 1-cyclohexyl-2- (thien-3-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 52.5mg, yield 29.2%. m.p.193.7-197.2 ℃. 1 HNMR(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).
Example 37
Step 1: preparation of 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000492
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 59.9mg, 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).
Step 2: preparation of N-cyclohexyl-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000501
Reacting the compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylbenzene)Yl) imidazolium chloride (110mg, 0.26mmol), pd 2 (dba) 3 (75mg, 0.13mmol) was added to 20ml of dioxane, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 146.7mg, 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).
And step 3: 1-cyclohexyl-2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000502
To N-cyclohexyl-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 50.9mg, yield 28.3%. m.p.243.2-246.9 ℃. 1 HNMR(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).
Example 38
Step 1: preparation of 4-chloro-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000503
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 539.7mg, yield 74.1%. 1 HNMR(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)
Step 2: preparation of N-cyclohexyl-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000511
The compound 4-chloro-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography(PE: EA =3: 1) to give the corresponding solid compound N-cyclohexyl-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 131.8mg, 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).
And step 3: 1-cyclohexyl-2- (pyridin-3-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000512
To N-cyclohexyl-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (pyridin-3-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 65.4mg, yield 36.4%. m.p.192.7-193.5 ℃. 1 HNMR(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).
Example 39
Step 1: preparation of 4-chloro-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000513
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 568.9mg, 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).
And 2, step: preparation of N-cyclohexyl-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000521
The compound 4-chloro-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 148.3mg, 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).
And step 3: 1-cyclohexyl-2- (pyridin-4-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000522
To N-cyclohexyl-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (pyridin-4-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 68.5mg, yield 38.0%. m.p.236.2-237.3 ℃. 1 HNMR(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).
Example 19
Step 1: preparation of 4-chloro-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000523
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 5-ethynylpyrimidine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2X 100 ml), saturated brine (1X 100 ml), anddried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 509.7mg, 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).
Step 2: preparation of N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000531
The compound 4-chloro-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 140.1mg, 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).
And step 3: 1-cyclohexyl-2- (pyrimidin-5-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000532
To N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridin-4-amine (1)5 mmol) and THF (10 mL) was added t-BuOK (252.3 mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (pyrimidin-5-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 73.5mg, yield 40.8%. m.p.196.4-197.8 ℃. 1 HNMR(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).
EXAMPLE 41
Step 1: preparation of 4-chloro-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000541
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynylpyrimidine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine, 500.7mg, 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).
Step 2: preparation of N-cyclohexyl-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000542
The compound 4-chloro-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 147.1mg, 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).
And step 3: 1-cyclohexyl-2- (pyrimidin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000543
To N-cyclohexyl-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound,purification by silica gel chromatography (PE: EA =2 1) gave the corresponding solid compound 1-cyclohexyl-2- (pyrimidin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 67.7mg, yield 37.6%. m.p.188.5-189.4 ℃. 1 HNMR(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).
Example 42
Step 1: preparation of 2- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) nicotinonitrile
Figure BDA0003631268110000551
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynylnicotinonitrile (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =10: 1) to give the corresponding solid compound 2- ((4-chloro-1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) nicotinonitrile, 586.9mg, 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).
And 2, step: preparation of 2- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) nicotinonitrile
Figure BDA0003631268110000552
A compound of 2- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) nicotinonitrile (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound 2- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b]Pyridin-5-yl) ethynyl) nicotinonitrile, 133.5mg, yield 32.6%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2- (3-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000553
To 2- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) nicotinonitrile (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 55.9mg, yield 31.1%. m.p.205.6-206.4 ℃. 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).
Example 43
Step 1: preparation of 4-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000561
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 770.8mg, yield 73.6%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000562
The compound 4-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated and extracted with EtOAcThe organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 143.0mg, yield 34.9%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (4-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000563
To N-cyclohexyl-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 66.5mg, yield 36.9%. m.p.187.2-189.6 ℃. 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).
Example 44
Step 1: preparation of 4-chloro-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000571
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-4-fluoropyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 584.7mg, yield 80.2%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000572
The compound 4-chloro-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 135.1mg, yield 33.1%。 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (3- (trifluoromethyl) pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000581
To N-cyclohexyl-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (3- (trifluoromethyl) pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 62.9mg, yield 34.6%. m.p.192.5-193.7 ℃. 1 HNMR(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).
Example 45
Step 1: preparation of 4-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000582
Will be inIntermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-3- (trifluoromethyl) pyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 770.8mg, yield 73.6%.513.5mg, yield 70.5%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000583
The compound 4-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 138.5mg, 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＝8.1Hz,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).
And 3, step 3: 1-cyclohexyl-2- (3-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000591
To N-cyclohexyl-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 51.1mg, yield 28.4%. m.p.214.2-215.6 ℃. 1 HNMR(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).
Example 46
Step 1: preparation of 4-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000592
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 2-ethynyl-3-methylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg，0.18mmol)，CuI(34mg，0.18mmol) and 1ml of triethylamine are added to 25ml of acetonitrile and heated to reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 572.7mg, yield 78.6%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000593
The compound 4-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 136.8mg, yield 33.4%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (6-fluoropyridin-3-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000601
To N-cyclohexyl-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1-cyclohexyl-2- (6-fluoropyridin-3-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 52.4mg, yield 29.1%.206.2-208.8 ℃. 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).
Example 47
Step 1: preparation of 4-chloro-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000602
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 5-ethynyl-2-fluoropyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =10) To obtain the corresponding solid compound 4-chloro-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 528.6mg, yield 72.5%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000611
The compound 4-chloro-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 149.0mg, yield 36.3%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2- (6-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000612
To N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridine compoundTo a mixture of (E) -4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 71.9mg, yield 40.0%. m.p.207.1-208.6 ℃. 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).
Example 48
Step 1: preparation of 4-chloro-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000613
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 2-ethynyl-5-fluoropyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 517.7mg, yield 71.0%. 1 HNMR(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).
And 2, step: preparation of N-cyclohexyl-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000621
The compound 4-chloro-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 137.3mg, yield 33.5%. 1 HNMR(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).
And 3, step 3: 1-cyclohexyl-2- (5-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000622
To N-cyclohexyl-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After the reaction was complete, the solvent was evaporated, etOAc was added for extraction, and the sequence was repeatedThe organic layer was washed with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =2: 1) to give the corresponding solid compound 1-cyclohexyl-2- (5-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 71.9mg, yield 40.0%. m.p.186.5-187.7 ℃. 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).
Example 49
Step 1: preparation of 4-chloro-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000623
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-5-methylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 494.8mg, yield 67.5%. 1 HNMR(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).
And 2, step: preparation of N-cyclohexyl-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000631
The compound 4-chloro-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 223.4mg, yield 30.5%. 1 HNMR(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).
And step 3: 1-cyclohexyl-2- (5-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000632
To N-cyclohexyl-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1 to give the corresponding solid compound 1-cyclohexyl-2- (5-methylpyridin-2-yl) -1,6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 83.5mg, yield 33.8%. m.p.196.5-198.2 ℃. 1 HNMR(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).
Example 50
Step 1: preparation of 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000641
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 2-ethynyl-5-methoxypyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 466.6mg, 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).
Step 2: preparation of N-cyclohexyl-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000642
The compound 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 202.6mg, 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).
And step 3: 1-cyclohexyl-2- (5-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000643
To N-cyclohexyl-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 60.0mg, yield 29.6%. m.p.202.4-204.7 ℃. 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).
Example 51
Step 1: preparation of 4-chloro-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000651
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-6-methoxypyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 483.2mg, 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).
And 2, step: preparation of N-cyclohexyl-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000652
The compound 4-chloro-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After the reaction was complete, the solvent was evaporated and EtOAc was added for extractionThe organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 243.2mg, 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).
And step 3: 1-cyclohexyl-2- (6-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000653
To N-cyclohexyl-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 41.3mg, yield 24.5%. m.p.187.3-189.9 ℃. 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).
Example 52
Step 1: preparation of 4-chloro-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000661
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-6-nitropyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 547.9mg, yield 79.9%. 1 HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000662
The compound 4-chloro-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((6-nitropyridin-2-yl) Ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 159.6mg, 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＝8.0Hz,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).
And 3, step 3: 1-cyclohexyl-2- (6-nitropyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000671
To N-cyclohexyl-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 47.6mg, yield 26.3%. m.p.181.5-183.9 ℃. 1 HNMR(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).
Example 53
Step 1: preparation of 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000672
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-cyclopropyl-6-ethynylpyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and the mixture was refluxed at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 536.7mg, 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).
And 2, step: preparation of N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000673
The compound 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 177.0mg, 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).
And step 3: 1-cyclohexyl-2- (6-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000681
To N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 41.9mg, yield 24.7%. m.p.214.2-215.1 ℃. 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).
Example 54
Step 1: preparation of 4-chloro-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003631268110000682
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 5-cyclopropyl-2-ethynylPyridine (4.3 mmol), pd (PPh) 3 ) 2 Cl 2 (126mg, 0.18mmol), cuI (34mg, 0.18mmol) and triethylamine (1 ml) were added to 25ml of acetonitrile, and the mixture was heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 10) to give the corresponding solid compound 4-chloro-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 460.6mg, 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).
Step 2: preparation of N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000691
The compound 4-chloro-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6 mmol), 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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-amine, 210.7mg, 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).
And 3, step 3: 1-cyclohexyl-2- (5-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000692
To N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine, 45.5mg, yield 25.8%. m.p.214.2-215.1 ℃. 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).
Example 55
Step 1: preparation of N- ((2S) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000693
Intermediate 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see the preparation method of example 37), (2S) 2-methylcyclohex-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 under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product N- ((2S) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] -a]Pyridin-4-amine 205.3mg, 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).
Step 2:1- ((2S) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000701
To N- ((2S) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 68.9mg, yield 39.0%. m.p.189.5-192.9 ℃. 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).
Example 56
Step 1: preparation of N- ((2R) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003631268110000702
Intermediate 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see preparation method in example 37), (2R) 2-methylcyclohexa-1-amine (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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by column chromatography to give the product N- ((2S) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] -b-pyrrole]281.5mg of pyridin-4-amine, 41% yield. 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).
Step 2:1- ((2R) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000711
To N- ((2R) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5 mmol) and THF (10 mL) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2): 2',3' -d]Pyridine, 73.5mg, yield 33.8%. m.p.216.5-218.2 ℃. 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).
Example 57
Step 1: preparation of tert-butyl 3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) tert-butyl-1-carboxylate
Figure BDA0003631268110000712
Reacting the compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see preparation method of example 37), 3-aminopiperidine-1-carboxylic acid tert-butyl ester (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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give a crude compoundTo the corresponding solid compound 3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2, 3-b)]Pyridin-4-yl) amino) tert-butyl-1-carboxylic acid tert-butyl ester, 510mg, yield 31.0%. m.p.206.5-207.8 ℃. 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).
Step 2: preparation of 3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0003631268110000721
To 3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-4-yl) amino) tert-butyl-1-carboxylate (1.2 mmol) and THF (10 ml) were added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester 317mg, yield 26.1%. 1 HNMR(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).
And step 3:1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000722
To 3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d at room temperature]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester (307mg, 0.3mmol) and CDCl 2 To the mixture (30 ml) was added 10ml TFA. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound 1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 80.8mg yield 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).
And 4, step 4: preparation of 3-oxo-3- (3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidin-1-yl) propionitrile
Figure BDA0003631268110000731
To a solution of 1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine (71.3, 0.2mmol), cyanoacetic acid, DCC were dissolved in 40ml CDCl 2 And the mixture was brought to 40 deg.CStirring was continued for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2-yl) 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 68.3mg, yield 79.5%. m.p.241.5-244.8 ℃. 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).
EXAMPLES 1 to 57 test for inhibitory Activity of Compounds on JAK family
1. Experimental materials
Figure BDA0003631268110000732
2. Experimental method
1. Preparing 1 Xkinase reaction buffer:
Figure BDA0003631268110000733
Figure BDA0003631268110000741
2. kinase reaction conditions:
Figure BDA0003631268110000742
3. and (3) a test flow:
3.1 compounds were diluted in 4-fold gradient in DMSO in dilution plates, starting at a concentration of 1.5uM.
3.2 compounds were diluted 50-fold into 1 Xkinase reaction buffer and shaken on a shaker for 20 minutes.
3.3 preparation of 2X kinase using 1X enzyme reaction buffer.
3.4 Add 2. Mu.l of kinase to each well of the reaction plate (prepared in step 3).
3.5. Mu.l of the diluted compound in buffer was added to each well, and the plate was centrifuged at 1000g for 30 seconds with a sealing plate membrane and left at room temperature for 10 minutes.
3.6 prepare 4 xATP/substrate mixture with 1 Xenzyme reaction buffer, add 1. Mu.l of 4 xATP/substrate mixture to the reaction plate.
3.7. Plates were then centrifuged at 1000g for 30 seconds with a sealing plate membrane and allowed to react at room temperature for 60 minutes.
3.8 transfer 4. Mu. LADP-Glo to 384 reaction plates at 1000rpm/min, centrifuge for 1min and incubate for 40min at 25 ℃.
3.9 transfer 8 u LDelection solution to 384 reaction plates 1000rpm/min, centrifugation 1min,25 ℃ incubation 40min.
3.10 reading RLU (Relative luminescence unit) signals using a Biotek multifunctional plate reader. The signal intensity is used to characterize the degree of kinase activity.
4. Data processing:
compound inhibition (% inh) =100% - (compound-positive control)/(negative control-positive control) × 100%
Positive control: average of ratios of 2. Mu.M Tofacitinib wells for all positive control wells
Negative control: average of readings of 0.5% of all negative control wells in DMSO well
3. Results of the experiment
The inhibitory activity of the compounds of the present invention against JAK family proteins.
Figure BDA0003631268110000743
Figure BDA0003631268110000751
Figure BDA0003631268110000761
Figure BDA0003631268110000771
Example 58
Step 1: preparation of tert-butyl (R) -3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) tert-butyl-1-carboxylate
Figure BDA0003631268110000772
Reacting the compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see preparation method of example 37), (R) -3-aminopiperidine-1-carboxylic acid tert-butyl ester (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, and heated under reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3) to give the corresponding solid compound (R) -3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridin-4-yl) amino) tert-butyl-1-carboxylic acid tert-butyl ester, 510mg, 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).
And 2, step: preparation of tert-butyl (R) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidine-1-carboxylate
Figure BDA0003631268110000781
To (R) -3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-4-yl) amino) tert-butyl-1-carboxylic acid tert-butyl ester (0.5g, 1.2mmol) and THF (10 ml) was added t-BuOK (252.3mg, 2.25mmol). The reaction mixture was stirred at room temperature for 2 hours and then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound (R) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester 165mg, 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).
And step 3: (R) -1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000782
To (R) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d) at room temperature]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester (150mg, 0.36mmol) and CH 3 Cl 2 To the mixture (15 ml) was added 5ml TFA. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) 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 88mg yield 75%. 1 HNMR(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).
And 4, step 4: preparation of (R) -3-oxo-3- (3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidin-1-yl) propionitrile
Figure BDA0003631268110000783
To a solution of (R) -1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine (70mg, 0.2mmol), cyanoacetic acid, DCC were dissolved in 40ml of CH 3 Cl 2 And the mixture was stirred at 40 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) 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 55mg, yield 70%. m.p.232.5-239.7 ℃.1H NMR (300mhz, dmso-d 6) δ 11.62 (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％,
Figure BDA0003631268110000791
Example 59
Step 1: preparation of tert-butyl (S) -3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl) amino) tert-butyl-1-carboxylate
Figure BDA0003631268110000792
The compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1.00g, 3.6mmol, see preparation of example 37), (S) -3-aminopiperidine-1-carboxylic acid tert-butyl ester (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 dioxane, and heated to reflux at 130 ℃. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 3)]Pyridin-4-yl) amino) tert-butyl-1-carboxylic acid tert-butyl ester, 0.42g, yield 28%. m.p.206.5-207.8 ℃. 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).
Step 2: preparation of tert-butyl (S) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidine-1-carboxylate
Figure BDA0003631268110000793
To (S) -3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-4-yl) amino) tert-butyl-1-carboxylate (0.40g, 0.95mmol) and THF (8 ml) were added t-BuOK (201.8mg, 1.8mmol). The reaction mixture was stirred at room temperature for 2 hours then t-BuOK (471.3mg, 4.2mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with water (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) to give the corresponding solid compound (S) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester 158mg, yield 40%. 1 HNMR(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).
And step 3: (S) -1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b: preparation of 2',3' -d ] pyridines
Figure BDA0003631268110000801
To (S) -3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d) at room temperature]Pyridin-1 (6H) -yl) piperidine-1-carboxylic acid tert-butyl ester (150mg, 0.36mmol) and CH3Cl 2 To the mixture (15 ml) was added 5ml TFA. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA =2 1) to give the corresponding solid compoundThe compound (S) -1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine 90mg yield 78%. 1 HNMR(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).
And 4, step 4: preparation of (S) -3-oxo-3- (3- (2- (pyridin-2-yl) dipyrrolo [2,3-b:2',3' -d ] pyridin-1 (6H) -yl) piperidin-1-yl) propionitrile
Figure BDA0003631268110000802
To a solution of (S) -1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2,3-b:2',3' -d]Pyridine (70mg, 0.2mmol), cyanoacetic acid, DCC were dissolved in 40ml of CH 3 Cl 2 And the mixture was stirred at 40 ℃ for 2 hours. After completion of the reaction, the solvent was evaporated, etOAc was added for extraction, and the organic layer was washed successively with saturated sodium bicarbonate solution (2 × 100 ml), saturated brine (1 × 100 ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography (PE: EA = 2) 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 40mg, yield 50%. m.p.238.1-243.5 ℃.1HNMR (300mhz, dmso-d 6) δ 11.65 (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, 8.8.2, 2H), 2.12 (1H), 1.51H, 1H, 51H: 98.97%, t R ＝4.208min.[a]2D0+29.70°(c＝1.0).ee＝100％.
Test of inhibitory Activity of Compounds 58, 59 prepared in examples 58, 59 on the JAK family
1. Experimental materials
Figure BDA0003631268110000811
2. Experimental method
1. Preparing 1x kinase reaction buffer:
name(s) Concentration of stock solution Volume of Final concentration
Hepes 1000 150 50
MgCl2 1000 30 1000.00％
Brij35 0.3 1 0.01％
DTT 1000 6 2
H2O N/A 2813 N/A
EGTA N/A 158 N/A
total 3000
2. Kinase reaction conditions:
Figure BDA0003631268110000821
3. the test flow comprises the following steps:
1. compounds were diluted in a 4-fold gradient with DMSO in dilution plates, starting at 10uM.
2. Compounds were diluted 50-fold into 1X kinase reaction buffer and shaken on a shaker for 20 minutes.
3. 2X kinase was prepared using 1X enzyme reaction buffer.
4. Mu.l of kinase was added to each well of the reaction plate.
5. Mu.l of the diluted compound in buffer was added to each well, plates were sealed with a sealing plate and centrifuged at 1000rpm for 60 seconds, and incubated at 25 ℃ for 10 minutes.
6. A4 xATP/substrate mixture was prepared with 1 Xenzyme reaction buffer, and 1. Mu.l of the 4 xATP/substrate mixture was added to the reaction plate.
7. Plates were centrifuged at 1000rpm for 60 seconds with sealing plate membranes and incubated for 60 minutes at 25 ℃.
8. Transfer 4. Mu.LADP-Glo to 384 reaction plates at 1000rpm, centrifuge for 1min and incubate for 40min at 25 ℃.
9. Transfer 8. Mu.L of the selection solution to 384 reaction plates at 1000rpm, centrifuge for 1min and incubate for 40min at 25 ℃.
10. The RLU (Relative luminescence unit) signal is read using a BMG multifunction board reader. The signal intensity is used to characterize the degree of activity of the kinase.
4. Data processing:
compound inhibition (% inh) =100% - (compound-positive control)/(negative control-positive control) × 100%
Positive control: average of ratios of 2. Mu.M Tofacitinib wells for all positive control wells
Negative control: average of readings of 0.5% of all negative control wells in DMSO well
IC50 was calculated from Prism graphpad7.0 by inhibition.
3. Results of the experiment
TABLE inhibitory Activity of the Compounds of the invention against JAK family proteins
Figure BDA0003631268110000822
The person skilled in the art is aware that JAKs are important targets for a variety of novel diseases, such as autoimmune and acquired immune diseases and hematological diseases. The above examples show that the compounds provided by the present invention have significant inhibitory activity against JAK family proteins and are potent JAK inhibitors, and therefore have the potential to be developed into drugs for inhibiting JAK and further treating diseases including rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus and ulcerative colitis.
The above-described embodiments are intended to illustrate the material nature of the present invention, but those skilled in the art will recognize that the scope of the present invention should not be limited to such embodiments.

Claims (10)

1. A compound with a dipyrrolopyridine structure, which is characterized by the following structural formula:
Figure FDA0003631268100000011
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure FDA0003631268100000012
n 1 ＝1、2、3；n 2 ＝1、2、3、4；
R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
2. The compound of claim 1, of the formula:
Figure FDA0003631268100000013
3. a method for synthesizing the compound of claim 1, wherein the synthetic route is as follows:
Figure FDA0003631268100000021
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure FDA0003631268100000022
n 1 ＝1、2、3；n 2 ＝1、2、3、4；
R 2 = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
4. The method according to claim 3, wherein compound 5a is synthesized by the following route:
Figure FDA0003631268100000023
5. the method according to claim 3, wherein compound 6a is synthesized by the following route:
Figure FDA0003631268100000024
6. the use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for a JAK inhibitor.
7. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having JAK kinase inhibitory activity and therefore useful for its antiproliferative and/or pro-apoptotic activity and in methods of treatment of the human or animal body. The invention also relates to a preparation method of the compound and optical isomers or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compound, and application of the compound in preparing anti-proliferative and/or pro-apoptotic and anti-inflammatory medicines.
8. By inhibiting tyrosine kinases, particularly the JAK family. The compound of claim 1 or 2 or a 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 depressive disorder, allergy, asthma, sjogren's syndrome, dry eye, transplant rejection, cancer, inflammatory bowel disease, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions in mammals including allergic dermatitis.
9. By inhibiting tyrosine kinases, particularly the JAK family. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, of value in the treatment of myelodysplasia, myelodysplastic syndrome and cancer. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is implicated in a variety of myeloproliferative diseases, myelodysplastic syndromes, and cancer-related processes. Thus, activity against myeloproliferative diseases, such as chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, myelometaplasia with myelofibrosis, idiopathic myelofibrosis, chronic granulocytosis and chronic granulocytosis, myelodysplastic syndromes and neoplastic diseases, such as breast, ovarian, lung, colon, prostate or other tissue cancers, as well as leukemias, myelomas, and lymphomas, are contemplated.
10. By inhibiting tyrosine kinases, particularly the JAK family. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, has blood-brain barrier permeability during the test and is of value in the treatment of central nervous system disorders. Therapeutic approaches target tyrosine kinase activity, particularly JAK family activity, which is involved in a variety of central nervous system inflammatory disease-related processes. Thus, activity on central nervous system inflammation is expected, such as epilepsy, dementia, parkinson's disease, depression, and the like.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102712640A (en) * 2010-01-12 2012-10-03 弗·哈夫曼-拉罗切有限公司 Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2013007765A1 (en) * 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
CN110088105A (en) * 2016-12-16 2019-08-02 詹森药业有限公司 The micromolecular inhibitor of JAK family kinase
CN110312719A (en) * 2016-12-16 2019-10-08 詹森药业有限公司 Imidazo pyrrolopyridine as JAK family kinase inhibitors
CN112313233A (en) * 2018-06-15 2021-02-02 詹森药业有限公司 Small molecule inhibitors of JAK family kinases

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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US20120034250A1 (en) * 2009-04-14 2012-02-09 Astellas Pharma Inc. Condensed pyrrolopyridine derivative
CN113292561A (en) * 2021-05-22 2021-08-24 中国药科大学 Compound with dipyrrolopyridine structure, preparation method and medical application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102712640A (en) * 2010-01-12 2012-10-03 弗·哈夫曼-拉罗切有限公司 Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2013007765A1 (en) * 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
CN110088105A (en) * 2016-12-16 2019-08-02 詹森药业有限公司 The micromolecular inhibitor of JAK family kinase
CN110312719A (en) * 2016-12-16 2019-10-08 詹森药业有限公司 Imidazo pyrrolopyridine as JAK family kinase inhibitors
CN112313233A (en) * 2018-06-15 2021-02-02 詹森药业有限公司 Small molecule inhibitors of JAK family kinases

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