CN113292561A - 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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CN113292561A
CN113292561A CN202110561592.4A CN202110561592A CN113292561A CN 113292561 A CN113292561 A CN 113292561A CN 202110561592 A CN202110561592 A CN 202110561592A CN 113292561 A CN113292561 A CN 113292561A
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added
give
pyrrolo
cyclohexyl
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
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Nanjing KANGYI biomedical Center (L.P.)
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中国药科大学
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Priority to CN202210491640.1A priority patent/CN115385911A/en
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Abstract

The invention discloses a compound with a dipyrrolopyridine structure, a preparation method and medical application thereof. 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. 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 bound 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 specific binding and regulation 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 BDA0003079214730000011
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a ═ cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, phenyl rings, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure BDA0003079214730000012
n1＝1、2、3；n2＝1、2、3、4；
R2methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
The synthesis method of the compound comprises the following steps:
Figure BDA0003079214730000021
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a ═ cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, phenyl rings, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
Figure BDA0003079214730000022
n1＝1、2、3；n2＝1、2、3、4；
R2methyl, 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 BDA0003079214730000023
preferably, the above compound 6a is synthesized by the following route:
Figure BDA0003079214730000024
the compound is used for preparing JAK inhibitor medicines.
The use of the above compounds in the manufacture of a medicament for the inhibition of JAK and the treatment of diseases including rheumatoid arthritis, multiple myeloma, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, multiple myeloma, melanoma, and parkinson's disease, epilepsy, depression and the like.
Has the advantages that:
the person skilled in the art is aware that JAKs are important targets for a variety of novel diseases, such as autoimmune or acquired immune diseases, hematological diseases, cancer and diseases of the central nervous system.
The compound provided by the invention has obvious inhibitory activity on JAK family proteins, is an effective JAK inhibitor, has a prospect of being developed into a medicine 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 human or animal bodies. 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 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 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 2a)
Figure BDA0003079214730000031
To a stirred solution of 1(16.0g,0.10mol) in THF (300ml) was added NaH (60% in mineral oil, 5g,0.14mol) in portions at 0 ℃ and the mixture was stirred at the same temperature for 20 minutes, then triisopropylsilyl chloride (22.3g,0.16mol) was added dropwise, keeping the temperature at 0 ℃. After completion of the reaction, the reaction mixture was washed with saturated NH4The Cl solution (10mL) 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.1HNMR(300MHz,DMSO-d6)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 (3a)
Figure BDA0003079214730000041
Sec-BuLi (Sec-butyllithium) (53mL,78.5mmol) was added dropwise over 30 minutes to a solution of 2a (11.0g,35.7mmol) in THF (100mL) at-78 deg.C, and the reaction mixture was stirred at the given temperature for an additional 1.5 hours. A solution of iodine (18g,71.1mmol) in THF (50ml) 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 NH4The reaction was quenched with Cl solution, extracted with EtOAc, washed with water and brine, and washed with Na2SO4Drying and concentration under reduced pressure gave the crude compound which was purified by silica gel chromatography to give 3a 8.25g as a pale yellow oily liquid in 53.2% yield.1HNMR(300MHz,DMSO-d6)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 step 3: preparation of 4-chloro-5-iodo-1H-pyrrolo [2,3-b ] pyridine (4a)
Figure BDA0003079214730000042
TBAF (1MTHF solution, 27mL,27mmol) was added to a stirred solution of 3(11.0g,25.3mmol) in dry THF (200mL) at 0 deg.C 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 Na2SO4Drying and concentration under reduced pressure gave the crude compound, which was purified by silica gel chromatography to give 4a 7.0g as a pale yellow solid in 95.6% yield.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000043
Intermediate 4a (1g, 3.6mmol), phenylalkyne (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine 790mg, yield 82.5%.1HNMR(300MHz,CDCl3)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 BDA0003079214730000044
The compound 4-chloro-5- (phenylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- (phenylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 490mg, yield 57.3%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000051
To N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 N-cyclohexyl-5- (phenylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 313.5mg, yield 62.7%. m.p.204.5-205.1 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000052
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), p-methylphenylacetylene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]892mg of pyridine was obtained, yield 88.5%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of N-cyclohexyl-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000061
The compound 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 535mg, yield 60.8%.1H NMR(300MHz,CDCl3)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 step 3: 1-cyclohexyl-2- (p-tolyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000062
To 4-chloro-5- (p-tolylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (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.1HNMR(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 BDA0003079214730000063
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), 4-fluorobenzeneyne (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((4-fluorophenyl) acetylene1H-pyrrolo [2,3-b ] yl]Pyridine 790mg, yield 82.5%.1H NMR(300MHz,CDCl3)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)。
Step 2: preparation of N-cyclohexyl-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000071
The compound 4-chloro-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 502mg, yield 55.7%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000072
To N-cyclohexyl-5- ((4-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). Mixing the reaction mixtureAfter stirring at room temperature for 2 hours, 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 × 100ml), saturated brine (1 × 100ml), 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- (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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000073
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), phenylalkyne (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine 861mg, yield 80.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000081
The compound 4-chloro-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 590mg, yield 64.1%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000082
To N-cyclohexyl-5- ((4-methoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude compound which was purified by silica gel chromatographyPurification (PE: EA ═ 2:1) afforded the corresponding solid compound 1-cyclohexyl-2- (4-methoxyphenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 301.5mg, yield 60.2%.1H NMR(300MHz,DMSO-d6)δ11.50(s,1H),8.00(s,1H),7.51(d,J＝8.3Hz,2H),7.21(t,J＝2.9Hz,1H),7.01(d,J＝8.3Hz,2H),6.57(d,J＝3.5Hz,1H),5.63(d,J＝8.6Hz,1H),3.82(s,3H),3.37(s,2H),2.06(s,2H),1.75(s,2H),1.63(d,J＝11.5Hz,1H),1.50–1.39(m,4H),1.26(s,1H).
Example 5
Step 1: preparation of 4- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) benzonitrile
Figure BDA0003079214730000091
Intermediate 4a (1g, 3.6mmol, see preparation method in example 1), p-cyanophenylyne (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ] as a compound]Pyridin-5-yl) ethynyl) benzonitrile 855mg, yield 84.5%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of 4- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) benzonitrile
Figure BDA0003079214730000092
Compound 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) benzonitrile (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) chlorideImidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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 4- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-5-yl) ethynyl) benzonitrile, 531.6mg, yield 57.7%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000093
To 4- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) benzonitrile (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 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 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000101
Benzyl bromide (5.8mmol), trimethylethyne silicon (682mg,6.9mmol), Pd (PPh)3)2Cl2(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 × 100mL), saturated brine (1 × 100mL), 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 ═ 100:1), and by column chromatography to give (3-phenylprop-1-yn-1-yl) trimethylsilane as a white oily liquid, 0.91g, yield 83.6%.1H NMR(300MHz,CDCl3)δ7.29–7.23(m,3H),7.23–7.16(m,2H),3.29(t,J＝1.1Hz,2H),0.08(s,9H).
Step 2: preparation of 3-benzene-1-propyne
Figure BDA0003079214730000102
The compound (3-phenylprop-1-yn-1-yl) trimethylsilane (4.8mmol), K2CO3(3.3g, 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 × 100ml), saturated brine (1 × 100ml), 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%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000103
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 3-benzene-1-propyne (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product 4-chloro-5- (3-phenylpropan-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]Pyridine 790mg, yield 82.5%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000104
The compound 4-chloro-5- (3-phenylpropan-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1), and by column chromatography to give the product N-cyclohexyl-5- (3-phenylpropan-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]Pyridin-4-amine 490mg, yield 57.3%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000111
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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), and isolated and purified by column chromatography to give the product 2-benzyl-1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine 490mg, yield 57.3%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000112
P-methylbenzyl bromide (5.8mmol), trimethylacetylene silicon (682mg,6.9mmol), Pd (PPh)3)2Cl2(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 the reaction is finished, steamingThe solvent was extracted with EtOAc, and the organic layer was washed successively with water (2 × 100mL), saturated brine (1 × 100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA ═ 100:1), and by column chromatography to give (3- (p-tolyl) prop-1-yn-1-yl) trimethylsilane as a white oily liquid, 1.0g, in 85.3% yield.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000113
The compound (3- (p-tolyl) prop-1-yn-1-yl) trimethylsilane (4.8mmol), K2CO3(3.3g, 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 × 100ml), saturated brine (1 × 100ml), 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.1HNMR(300MHz,CDCl3)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 BDA0003079214730000121
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 1-methyl-4- (prop-2-yn-1-yl) benzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 (2X 100ml), saturated brine (1X 100ml) 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 ═ 10:1) and column chromatography to give the product 4-chloro-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] p-pyrrolo [2,3-b ] a]892mg of pyridine was obtained, yield 88.5%.1HNMR(300MHz,CDCl3)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 BDA0003079214730000122
The compound 4-chloro-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product N-cyclohexyl-5- (3- (p-tolyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]535mg of pyridin-4-amine, yield 60.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000123
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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), and isolated and purified 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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000131
4-Fluorobromobenzyl (5.8mmol), trimethylethynylsilicon (682mg,6.9mmol), Pd (PPh)3)2Cl2(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 × 100mL), saturated brine (1 × 100mL), 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 ═ 100:1), and by column chromatography to give (3- (4-fluorophenyl) prop-1-yn-1-yl) trimethylsilane as a white oily liquid, 0.98g, in 82.1% yield.1HNMR(300MHz,CDCl3)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 BDA0003079214730000132
The compound ((3- (4-fluorophenyl) prop-1-yn-1-yl) trimethylsilane (4.8mmol), K2CO3(3.3g, 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 × 100ml), saturated brine (1 × 100ml), 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.1H NMR(300MHz,CDCl3)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 step 3: preparation of 4-chloro-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000133
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yl) benzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and column chromatography to give the product 4-chloro-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridine 805mg, yield 78.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000141
The compound 4-chloro-5- (3- (4-fluorophenyl) prop-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product N-cyclohexyl-5- (3- (4-fluorophenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridin-4-amine 502mg, yield 55.7%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000142
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressureThe crude compound was obtained and purified by silica gel chromatography (PE: EA ═ 2:1) and column chromatography to afford 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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000143
4-methoxybenzyl bromide (5.8mmol), trimethylacetylene silicon (682mg,6.9mmol), Pd (PPh)3)2Cl2(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 × 100mL), saturated brine (1 × 100mL), 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 ═ 100:1), and by column chromatography to give (3- (4-methoxyphenyl) prop-1-yn-1-yl) trimethylsilane as a white oily liquid, 1.0g, yield 80.3%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of 1-methoxy-4- (prop-2-yn-1-yl) benzene
Figure BDA0003079214730000151
The compound (3- (4-methoxyphenyl) prop-1-yn-1-yl) trimethylsilane (4.8mmol), K2CO3(3.3g, 24mmol) was added20ml of methanol, stirring 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 × 100ml), saturated brine (1 × 100ml), 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 1-methoxy-4- (prop-2-yn-1-yl) benzene 630mg, yield 90.2%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000152
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)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and column chromatography to give the product 4-chloro-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridine 861mg, yield 80.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000153
The compound 4-chloro-5- (3- (4-methoxyphenyl) prop-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol)Cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) and column chromatography to give the product N-cyclohexyl-5- (3- (4-methoxyphenyl) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -5- (3- (4-methoxyphenyl) propan-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]590mg of pyridin-4-amine, yield 64.1%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000161
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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), and isolated and purified by column chromatography to give the product 1-cyclohexyl-2- (4-methoxybenzyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]301.5mg of pyridine was obtained, yield 60.2%. m.p.193.6-195.0 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000162
Phenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K2CO3(5.8g, 42.4mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product (prop-2-yn-1-yloxy) benzene 1.29g, yield 91.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000163
Intermediate 4(1g, 3.6mmol), (prop-2-yn-1-yloxy) benzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and column chromatography to give the product 4-chloro-5- (3-phenoxy-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]Pyridine 810.1mg, yield 79.8%。1HNMR(300MHz,CDCl3)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 BDA0003079214730000171
The compound 4-chloro-5- (3-phenoxy-1-alkyne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1), and by column chromatography to give the product N-cyclohexyl-5- (3-phenoxyprop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]473mg of pyridin-4-amine, 52.8% yield.1H NMR(300MHz,CDCl3)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 BDA0003079214730000172
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours and then added to the reaction mixturet-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 h. After completion of the reaction, the solvent was evaporated, EtOAc was added for extraction, and the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000173
P-cresol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol), K2CO3(5.8g, 42.4mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product 1-methyl-4- (prop-2-yn-1-yloxy) benzene 1.45g, yield 93.6%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000181
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 1-methyl-4- (prop-2-yn-1-yloxy) benzene 4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] a]Pyridine 804.5mg, yield 75.5%.1H NMR(300MHz,CDCl3)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 step 3: preparation of N-cyclohexyl-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000182
The compound 4-chloro-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product N-cyclohexyl-5- (3- (p-tolyloxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]450.8mg of pyridin-4-amine, yield 48.3%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000183
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000191
P-fluorophenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol) and K2CO3(5.8g, 42.4mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3Washing with acetone, evaporating solvent, extracting with EtOAc, and purifyingThe organic layer was washed with water (2 × 100ml) and saturated brine (1 × 100ml) successively, 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) and isolated and purified by column chromatography to give 1.43g of 1-fluoro-4- (prop-2-yn-1-yloxy) benzene as a product with a yield of 90.5%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000192
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yloxy) benzene 4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and column chromatography to give the product 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridine 785.2mg, yield 72.7%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000193
The compound 4-chloro-5- (3- (4-fluorophenoxy) prop-1-yne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis(2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1), and by column chromatography to give the product N-cyclohexyl-5- (3- (4-fluorophenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]521.9mg of pyridin-4-amine, yield 55.3%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000201
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000202
P-fluorophenol (10.6mmol), 3-bromopropyne (1.5g, 12.7mmol) and K2CO3(5.8g, 42.4mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and by column chromatography to give the product 1.58g of 1-methoxy-4- (prop-2-yn-1-yloxy) benzene in 92.1% yield.1H NMR(300MHz,CDCl3)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 BDA0003079214730000203
Intermediate 4(1g, 3.6mmol, see preparation method in example 1), 1-fluoro-4- (prop-2-yn-1-yloxy) benzene 4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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), and column chromatography to give the product 4-chloro-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridine 828.9mg, yield 73.8%.1HNMR(300MHz,CDCl3)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 BDA0003079214730000211
The compound 4-chloro-5- (3- (4-methoxyphenoxy) prop-1-yne-1-yl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1), and by column chromatography to give the product N-cyclohexyl-5- (3- (4-methoxyphenoxy) prop-1-yn-1-yl) -1H-pyrrolo [2,3-b ] -a]Pyridin-4-amine 560.2mg, yield 57.5%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000212
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 hours and then added to the solutiont-BuOK (589.1mg, 5.25mmol) was added and the mixture was stirred at 50 ℃ for 2 h. After completion of the reaction, the solvent was evaporated, EtOAc was added for extraction, and the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000213
Aniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K2CO3(5.9g, 42.8mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 by column chromatography to give the product N- (prop-2-yn-1-yl) aniline 1.13g, yield 78.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000221
Intermediate 4(1g, 3.6mmol, prepared according to example 1), N- (prop-2-yn-1-yl) aniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ═ 8:1), and isolated and purified by column chromatography to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-5-yl) prop-2-yn-1-yl) aniline, 735.4mg, yield 72.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000222
The compound N- (3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) aniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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). 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-amine, yield 55.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000223
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 (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25 mmol). 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 1:1), and by column chromatography to give the product N- ((1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d)]Pyridin-2-yl) methyl) aniline 268.4mg, yield 53.6%. m.p.167.6-171.0 ℃.1HNMR(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 BDA0003079214730000231
P-methylaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K2CO3(5.9g, 42.8mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3In combination with acetoneMultiple washes were performed, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 50:1), column chromatography to give the product N- (prop-2-yn-1-yl) aniline 1.12g, yield 73.7%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline
Figure BDA0003079214730000232
Intermediate 4(1g, 3.6mmol, prepared according to example 1), N- (prop-2-yn-1-yl) aniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ═ 8:1), and isolated and purified by column chromatography to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline 791.2mg, yield 74.5%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000233
The compound N- (3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) -4-methylaniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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). 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%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000241
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 (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25 mmol). 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 1:1), 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-methylaniline 237.6mg, yield 47.6%. m.p.166.6-177.7 ℃.1H NMR(300MHz,DMSO-d6)δ11.46(s,2H),7.86(s,2H),7.18(s,2H),6.84(dd,J＝94.0,7.8Hz,10H),6.46(s,2H),5.96(t,J＝6.5Hz,2H),5.16(d,J＝8.7Hz,2H),4.18(d,J＝6.5Hz,4H),3.86(s,2H),2.21(s,6H),1.91–1.83(m,4H),1.66(s,4H),1.39(d,J＝11.8Hz,4H),1.19(d,J＝8.6Hz,4H),1.01(d,J＝11.9Hz,4H),0.88(s,1H).
Example 16
Step 1: preparation of 4-fluoro-N- (prop-2-yn-1-yl) aniline
Figure BDA0003079214730000242
Para-fluoroaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K2CO3(5.9g, 42.8mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 by column chromatography to give the product 4-fluoro-N- (prop-2-yn-1-yl) aniline 1.21g, yield 80.5%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000251
Intermediate 4(1g, 3.6mmol, prepared according to example 1), 4-fluoro-N- (prop-2-yn-1-yl) aniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 (2X 100ml), saturated brine (1X 100ml), anddrying over anhydrous sodium sulfate and concentrating under reduced pressure to give crude compound, purifying by silica gel chromatography (PE: EA ═ 8:1), and purifying by column chromatography to give N- (3- (4-chloro-1H-pyrrolo [2, 3-b) product]Pyridin-5-yl) prop-2-yn-1-yl) -4-fluoroaniline 837.4mg, 77.8% yield.1H NMR(300MHz,CDCl3)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 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 BDA0003079214730000252
The compound N- (3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) -4-fluoroaniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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). Separating and purifying by column chromatography to obtain product N-cyclohexyl-5- (3- ((4-fluorophenyl) amino) prop-1-alkyne-1-radical) -1H-pyrrolo [2,3-b]Pyridin-4-amine 468.7mg, yield 49.8%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000253
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 (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25 mmol). 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 1:1), 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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000261
P-methoxyaniline (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K2CO3(5.9g, 42.8mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 50:1) and column chromatography to give the product 4-methoxy-N- (propylphenyl) ethyl acetate-2-yn-1-yl) aniline 1.26g, yield 73.4%.1H NMR(300MHz,CDCl3)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).
Step 2: preparation of N- (3- (4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline
Figure BDA0003079214730000262
Intermediate 4(1g, 3.6mmol, prepared according to example 1), 4-methoxy-N- (prop-2-yn-1-yl) aniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ═ 8:1), and isolated and purified by column chromatography to give the product N- (3- (4-chloro-1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline, 830.7mg, yield 74.2%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000263
The compound N- (3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) -4-methoxyaniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) was added to 20ml dioxane and heated to reflux at 130 ℃. After the reaction was completed, the solvent was evaporated,EtOAc was added for extraction, and the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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). 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, yield 50.5%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000271
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 (1.5mmol) and THF (10ml) was added t-BuOK (252.3mg, 2.25 mmol). 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 1:1), 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, yield 43.2%. m.p.220.3-221.6 ℃.1H NMR(300MHz,DMSO-d6)δ11.54(s,1H),8.04(s,1H),7.77(s,4H),7.20(s,1H),6.58(s,1H),6.18(s,1H),5.82(d,J＝8.6Hz,1H),4.52(s,2H),4.09(s,1H),2.05(s,2H),1.75(s,2H),1.44(s,4H),1.21(d,J＝18.2Hz,2H).13C NMR(300MHz,DMSO-d6)δ159.73,149.97,149.15,147.92,147.57,143.15,136.54,130.95,126.35,122.57,122.35,111.98,104.65,99.97,71.00,42.74,33.40,25.13,24.21.
Example 18
Step 1: preparation of 4- (prop-2-yn-1-ylamino) benzonitrile
Figure BDA0003079214730000272
4-aminobenzonitrile (10.7mmol), 3-bromopropyne (1.5g, 12.8mmol), K2CO3(5.9g, 42.8mmol) was added to 25ml of acetone and heated at 50 ℃ under reflux for 5 h. After the reaction is finished, K is removed by suction filtration2CO3And washed with acetone several times, the solvent was evaporated, EtOAc was added and extracted, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 50:1), and by column chromatography to give the product 4- (prop-2-yn-1-ylamino) benzonitrile 1.19g, yield 71.7%.1HNMR(300MHz,CDCl3)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 BDA0003079214730000281
Intermediate 4(1g, 3.6mmol, prepared according to example 1), 4- (prop-2-yn-1-ylamino) benzonitrile (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ═ 8:1), and column chromatography to give the product 4- ((3- (4-chloro-1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-5-yl) prop-2-yn-1-yl) amino) benzylNitrile 767.8mg, yield 69.7%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000282
Compound 4- ((3- (4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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). 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%.1H NMR(300MHz,CDCl3)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 BDA0003079214730000283
To 4- ((3- (4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Mixture of pyridin-5-yl) prop-2-yn-1-yl) amino) benzonitrile (1.5mmol) and THF (10ml)To this was added t-BuOK (252.3mg, 2.25 mmol). 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, the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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 ═ 1:1), and 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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000291
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 770.8mg, yield 73.6%.1HNMR(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 BDA0003079214730000292
The compound 4-chloro-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 706mg, yield 65.4%.1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.85(s,1H),7.56(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J＝7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H).
And step 3: 1-cyclohexyl-2- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000293
To N-cyclohexyl-5- ((2-fluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 2 h then t-BuOK (589.1mg, 5.25mmol) was added to the solution and the mixture was stirred at 50 ℃ for 2 hThen (c) is performed. After completion of the reaction, the solvent was evaporated, EtOAc was added for extraction, and the organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 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 BDA0003079214730000301
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-nitro-2-fluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 749.7mg, yield 72.4%.1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),7.86(t,J＝3.7Hz,2H),7.80(d,J＝7.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.53(t,J＝7.5Hz,1H),7.23(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.91(s,1H),3.51(s,1H),2.11–2.02(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.71–1.62(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.35(dd,J＝13.0,7.0Hz,2H).
Step 2: preparation of N-cyclohexyl-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000302
The compound 4-chloro-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 326.2mg, yield 37.3%.1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.88–7.83(m,2H),7.80(d,J＝7.4Hz,1H),7.63(t,J＝7.5Hz,1H),7.53(t,J＝7.4Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.3Hz,1H),3.95(s,1H),2.83(s,1H),2.09–2.00(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (2-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000311
To N-cyclohexyl-5- ((2-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude productThe compound was purified by silica gel chromatography (PE: EA ═ 2:1) to give the corresponding solid compound 1-cyclohexyl-2- (2-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 59.9mg, yield 19.1%. m.p.233.6-236.0 deg.C.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.06(s,1H),7.80(t,J＝7.1Hz,2H),7.63(t,J＝7.4Hz,1H),7.51(t,J＝7.5Hz,1H),7.35(d,J＝7.3Hz,1H),6.99–6.91(m,2H),4.32(s,1H),2.60–2.50(m,2H),2.06(m,J＝12.9,6.9Hz,2H),1.88–1.71(m,3H),1.55–1.35(m,3H).
Example 21
Step 1: preparation of 4-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000312
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3-methylbenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ]]Pyridine, 738.8mg, yield 68.4%.1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.55(t,J＝7.5Hz,1H),7.47(s,1H),7.25(dd,J＝16.7,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
Step 2: preparation of N-cyclohexyl-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000313
The compound-chloro-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b]Pyridine, (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 323.3mg, yield 29.9%.1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.55(t,J＝7.5Hz,1H),7.47(s,1H),7.25(dd,J＝16.7,7.5Hz,2H),7.13(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.95(s,1H),3.15(s,1H),2.57(s,3H),2.09–1.99(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
And step 3: 1-cyclohexyl-2- (m-tolyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000321
To N-cyclohexyl-5- (m-tolylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (m-tolyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 59.9mg, yield 19.1%.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000322
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylaniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ] as the compound]Pyridin-5-yl) ethynyl) aniline, 729.0mg, yield 67.6%.1HNMR(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 BDA0003079214730000323
Compound-3- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) aniline, (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) was added20ml of dioxane, and heating and refluxing 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 × 100ml), saturated brine (1 × 100ml), 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 5- ((3-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] of 5]Pyridin-4-amine, 357.8mg, yield 33.1%.1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),7.86(s,1H),7.21(d,J＝7.5Hz,1H),7.03(t,J＝7.5Hz,1H),6.92(d,J＝7.5Hz,1H),6.82–6.75(m,2H),6.63(d,J＝7.5Hz,1H),4.79(s,1H),4.11(s,2H),3.91(s,1H),1.92–1.82(m,2H),1.78–1.69(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.38(m,J＝13.2,6.8Hz,2H),1.24(dd,J＝12.8,6.9Hz,2H).
And step 3: preparation of 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d ] pyridin-2-yl) aniline
Figure BDA0003079214730000331
To 5- ((3-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 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 ℃.1H NMR(300MHz,Chloroform-d)δ8.02(s,1H),7.21(d,J＝17.7Hz,3H),7.02(s,1H),6.59(d,J＝8.0Hz,2H),6.45(s,1H),5.51(d,J＝8.2Hz,1H),3.91(s,1H),3.64(s,1H),2.10(d,J＝11.4Hz,2H),1.74(s,2H),1.34(s,2H),1.17(s,2H),-0.08(s,3H).
Example 23
Step 1: preparation of 3- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) phenol
Figure BDA0003079214730000332
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylphenol (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ] as the compound]Pyridin-5-yl) ethynyl) phenol, 729.8mg, yield 67.6%.1HNMR(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 BDA0003079214730000341
Compound 3- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an extractTo the crude compound, it was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound 3- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol, 353.7mg, yield 32.7%.1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.26–7.16(m,2H),7.10–7.05(m,2H),6.81(dd,J＝11.8,7.4Hz,2H),6.51(s,1H),3.95(s,1H),3.31(s,1H),2.09–2.00(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.70–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
And step 3: preparation of 3- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d ] pyridin-2-yl) phenol
Figure BDA0003079214730000342
To 3- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) phenol (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 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.1H NMR(300MHz,Chloroform-d)δ7.99(s,1H),7.09(d,J＝3.6Hz,1H),6.51(d,J＝3.6Hz,1H),5.61(d,J＝8.2Hz,1H),3.97(d,J＝10.8Hz,2H),2.17(d,J＝11.9Hz,2H),1.92(s,2H),1.81(s,2H),1.39(s,2H).
Example 24
Step 1: preparation of 4-chloro-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000343
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylnitrobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 777.5mg, yield 72.0%.1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.91–7.82(m,2H),7.48(t,J＝7.5Hz,1H),7.23(d,J＝7.3Hz,1H),6.84(d,J＝7.5Hz,1H),3.91(s,1H),3.43(s,1H),2.12–2.03(m,2H),1.88(m,J＝13.1,6.1Hz,2H),1.70(dd,J＝13.5,6.4Hz,2H),1.61(dd,J＝6.4,1.5Hz,2H),1.41–1.32(m,2H).
Step 2: preparation of N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000351
The compound 4-chloro-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 340.5mg, yield 31.5%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.90–7.83(m,2H),7.49(t,J＝7.5Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01(m,2H),1.84(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000352
To N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 70.4mg, yield 20.1%. m.p.>250.0℃。1H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.37(s,1H),8.13(d,J＝7.3Hz,1H),8.08(s,1H),7.79(d,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.36(d,J＝7.5Hz,1H),7.04(s,1H),6.95(d,J＝7.5Hz,1H),4.21(s,1H),2.32(m,J＝13.0,7.0Hz,2H),2.09(m,J＝13.0,6.9Hz,2H),1.78(m,J＝30.2,12.5,6.9Hz,3H),1.54–1.44(m,1H),1.44–1.31(m,2H).
Example 25
Step 1: preparation of 4-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000353
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3- (trifluoromethyl)) Benzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 769.1mg, yield 71.2%.1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.61–7.55(m,2H),7.51(d,J＝7.3Hz,2H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H)
Step 2: preparation of N-cyclohexyl-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000361
The compound 4-chloro-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 365.8mg, yield 33.9%.1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),7.86(s,1H),7.59–7.49(m,4H),7.21(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),4.44(s,1H),3.88(s,1H),2.10–2.01(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.69–1.57(m,4H),1.40–1.31(m,2H).
And step 3: 1-cyclohexyl-2- (4- (trifluoromethyl) phenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000362
To N-cyclohexyl-5- ((4- (trifluoromethyl) phenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (4- (trifluoromethyl) phenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 67.4mg, yield 22.1%. m.p.243.0-245.3 ℃.1HNMR(300MHz,DMSO-d6)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 BDA0003079214730000371
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylphenol (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 a crude compoundTo the corresponding solid compound 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol, 777.5mg, yield 72.0%.1HNMR(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).
Step 2: preparation of N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000372
Compound 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) phenol (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 340.5mg, yield 31.5%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),8.41(s,1H),8.18(d,J＝7.5Hz,1H),7.90–7.83(m,2H),7.49(t,J＝7.5Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.92(s,1H),3.14(s,1H),2.11–2.01(m,2H),1.84(m,J＝13.1,6.0Hz,2H),1.73–1.64(m,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.36(dd,J＝13.0,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (3-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000373
To N-cyclohexyl-5- ((3-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (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.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000381
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylnitrobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 796.1mg, yield 71.2%.1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),8.28–8.22(m,2H),7.82(dd,J＝5.4,2.1Hz,3H),7.20(d,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000382
The compound 4-chloro-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 316.9mg, yield 29.3%.1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.25(d,J＝7.5Hz,2H),7.88–7.79(m,3H),7.25(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.94(s,1H),2.89(s,1H),2.09–2.00(m,2H),1.79(m,J＝13.0,5.8Hz,2H),1.72–1.63(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.35(dd,J＝12.9,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (4-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000383
To N-cyclohexyl-5- ((4-nitrophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 deg.CStirred 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 × 100ml), saturated brine (1 × 100ml), 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- (4-nitrophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 79.6mg, yield 24.5%. m.p.219.9-222.2 ℃.1H NMR(300MHz,Chloroform-d)δ9.33(s,1H),8.18(d,J＝7.5Hz,2H),8.08(s,1H),7.66(d,J＝7.5Hz,2H),7.35(d,J＝7.5Hz,1H),7.05(s,1H),6.94(d,J＝7.5Hz,1H),4.21(s,1H),2.28(m,J＝13.0,7.0Hz,2H),2.07(m,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.43(m,1H),1.43–1.31(m,2H).
Example 28
Step 1: preparation of 4- ((4-chloro-1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) aniline
Figure BDA0003079214730000391
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylaniline (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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 ] as a compound]Pyridin-5-yl) ethynyl) aniline, 745.2mg, yield 69.0%.1HNMR(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 BDA0003079214730000392
Compound 4- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) aniline (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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 5- ((4-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 334.9mg, yield 31.0%.1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),7.84(s,1H),7.40(d,J＝7.3Hz,2H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,2H),4.41(s,2H),4.30(s,1H),4.11(s,1H),2.09–2.00(m,2H),1.72(dd,J＝12.9,6.9Hz,2H),1.66–1.56(m,4H),1.28(m,J＝13.2,6.6Hz,2H).
And step 3: preparation of 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d ] pyridin-2-yl) aniline
Figure BDA0003079214730000401
To 5- ((4-aminophenyl) ethynyl) -N-cyclohexyl-1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 4- (1-cyclohexyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d)]Pyridine-2-yl) aniline, 77.3mg, yield 20.6%. m.p.200.9-203.7 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000402
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3, 5-dimethoxybenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 790mg, yield 82.5%.1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),7.82(s,1H),7.19(d,J＝7.5Hz,1H),6.85(d,J＝2.0Hz,2H),6.68(d,J＝7.5Hz,1H),6.38(t,J＝2.0Hz,1H),3.81(s,6H).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000403
Mixing the compound 4-chloro-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride(110mg，0.26mmol)，Pd2(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 × 100ml), saturated brine (1 × 100ml), 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-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 380.6mg, yield 35.2%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.86(s,1H),7.40(d,J＝7.5Hz,2H),7.24(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),6.59(d,J＝7.5Hz,2H),4.44(s,2H),3.95(s,1H),3.13(s,1H),2.09–2.00(m,2H),1.80(m,J＝13.4,6.3Hz,2H),1.71–1.57(m,4H),1.37(dd,J＝13.6,6.4Hz,2H).
And step 3: 1-cyclohexyl-2- (3, 5-dimethoxyphenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000411
To N-cyclohexyl-5- ((3, 5-dimethoxyphenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (3, 5-dimethoxyphenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine 61.8mg, yield 19.1%. m.p.223.6-226.5 ℃.1H NMR(300MHz,DMSO-d6)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 BDA0003079214730000412
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-3.5-difluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 797mg, yield 73.8%.1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.19(d,J＝7.5Hz,1H),7.02(m,J＝9.3,2.2,1.2Hz,2H),6.84(m,J＝9.0,2.0Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000413
The compound 4-chloro-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate and washed with water and then with water, and the residue was washed with water, saturated brine and dried over anhydrous sodium sulfateConcentration under reduced pressure gave crude compound which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ═ b]Pyridin-4-amine, 331.2mg, yield 30.7%.1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),7.87(s,1H),7.24(d,J＝7.5Hz,1H),6.82(d,J＝15.0Hz,3H),6.44(s,1H),3.95(s,1H),3.81(s,6H),3.18(s,1H),2.09–1.99(m,2H),1.83–1.49(m,8H).
And step 3: 1-cyclohexyl-2- (3, 5-difluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000421
To N-cyclohexyl-5- ((3, 5-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (3, 5-difluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 79.2mg, yield 24.5%. m.p.226.6-229.5 ℃.1HNMR(300MHz,DMSO-d6)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 BDA0003079214730000422
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 701mg, yield 64.9%.1H NMR(300MHz,Chloroform-d)δ8.86(s,1H),7.80(s,1H),7.58(m,J＝7.5,5.7Hz,1H),7.19(d,J＝7.5Hz,1H),6.88–6.78(m,2H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000431
The compound 4-chloro-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 364.2mg, yield 33.7%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.87(s,1H),7.23(d,J＝7.5Hz,1H),7.01(d,J＝8.8Hz,2H),6.87–6.79(m,2H),3.94(s,1H),3.47(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.81(dd,J＝13.4,6.3Hz,2H),1.70–1.57(m,4H),1.38(m,J＝13.0,6.5Hz,2H).
And step 3: 1-cyclohexyl-2- (2, 4-difluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000432
To N-cyclohexyl-5- ((2, 4-difluorophenyl) ethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (2, 4-difluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 59.9mg, yield 19.7%. m.p.230.6-233.9 ℃.1HNMR(300MHz,DMSO-d6)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 BDA0003079214730000433
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, EtOAc was added and extracted successively with water (2X 100ml), saturated withThe organic layer was washed with brine (1 × 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA ═ 10:1) to give the corresponding solid compound 4-chloro-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]706mg of pyridine was added, yield 65.4%.1H NMR(300MHz,Chloroform-d)δ8.85(s,1H),7.82(s,1H),7.41(d,J＝2.0Hz,2H),7.33(t,J＝2.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000441
The compound 4-chloro-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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 ] as a crude compound]Pyridin-4-amine, 329.5mg, yield 30.5%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.86(s,1H),7.39(s,2H),7.33(s,1H),7.23(d,J＝7.5Hz,1H),6.82(d,J＝7.5Hz,1H),3.94(s,1H),3.39(s,1H),2.04(dd,J＝13.5,6.4Hz,2H),1.86–1.77(m,2H),1.71–1.57(m,4H),1.39(m,J＝13.1,6.5Hz,2H).
And step 3: 1-cyclohexyl-2- (3, 5-dichlorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000442
To N-cyclohexyl-5- ((3, 5-dichlorophenyl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (3, 5-dichlorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 59.5mg, yield 19.7%.1H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.08(s,1H),7.53(s,2H),7.38–7.30(m,2H),7.04(s,1H),6.94(d,J＝7.5Hz,1H),4.24(s,1H),2.29(m,J＝12.8,6.9Hz,2H),2.06(m,J＝13.2,6.9Hz,2H),1.86–1.69(m,3H),1.53–1.42(m,1H),1.42–1.33(m,2H).
Example 33
Step 1: preparation of 4-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000443
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), ethynylcyclopropane (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ]]Pyridine, 513.7mg, yield 70.5%.1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.77(s,1H),7.18(d,J＝7.5Hz,1H),6.66(d,J＝7.5Hz,1H),1.40(p,J＝7.0Hz,1H),0.59(m,J＝7.1,4.2Hz,2H),0.42–0.33(m,2H).
Step 2: preparation of N-cyclohexyl-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000451
The compound 4-chloro-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 142.4mg, yield 34.7%.1H NMR(300MHz,Chloroform-d)δ8.56(s,1H),7.81(s,1H),7.23(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.97(s,1H),2.66(s,1H),2.10–2.01(m,2H),1.73(m,J＝30.5,13.9,6.4Hz,4H),1.66–1.57(m,2H),1.43(s,1H),1.37(dd,J＝13.5,6.3Hz,2H),0.58–0.53(m,2H),0.41–0.36(m,2H).
And step 3: 1-cyclohexyl-2-cyclopropyl-1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000452
To N-cyclohexyl-5- (cyclopropylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), anddried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography (PE: EA ═ 2:1) to give the corresponding solid compound 1-cyclohexyl-2-cyclopropyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 53.0mg, yield 29.5%. m.p.219.6-222.3 ℃.1H NMR(300MHz,Chloroform-d)δ9.40(s,1H),7.36(d,J＝7.5Hz,1H),6.50(d,J＝7.5Hz,1H),5.79(s,1H),3.64(s,1H),1.79(m,J＝12.7,6.5Hz,2H),1.73–1.67(m,1H),1.67–1.53(m,4H),1.53–1.50(m,1H),1.46(m,J＝11.4,9.2,6.3,3.0Hz,4H),0.82–0.76(m,2H),0.76–0.70(m,2H).
Example 34
Step 1: preparation of 4-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000461
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), ethynylcyclopentane (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 579.9mg, yield 79.6%.1H NMR(300MHz,Chloroform-d)δ8.74(s,1H),7.85(s,1H),7.28(d,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,1H),2.85(m,J＝7.0Hz,1H),1.88(m,J＝12.2,6.5,2.7Hz,2H),1.63(m,J＝26.2,12.2,6.0,2.6Hz,4H),1.52(m,J＝10.1,5.2,3.4,1.8Hz,2H).
Step 2: preparation of N-cyclohexyl-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000462
The compound 4-chloro-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- (cyclopentylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 136.7mg, yield 33.3%.1H NMR(300MHz,Chloroform-d)δ8.53(s,1H),7.75(s,1H),7.10(d,J＝7.5Hz,1H),6.77(d,J＝7.5Hz,1H),4.07(s,1H),3.84(s,1H),2.90(s,1H),1.98–1.83(m,4H),1.79–1.66(m,4H),1.66–1.53(m,8H),1.28(dd,J＝12.8,7.0Hz,2H).
And step 3: 1-cyclohexyl-2-cyclopentyl-1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000463
To N-cyclohexyl-5- (cyclopentylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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-cyclopentyl-1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 74.4mg, yield 41.5%. m.p.240.3-245.0 ℃.1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),7.95(s,1H),7.24(d,J＝7.5Hz,1H),6.87(d,J＝7.5Hz,1H),6.20(s,1H),4.43(s,1H),3.43(d,J＝12.6Hz,1H),2.20(d,J＝12.5Hz,1H),2.16–2.06(m,2H),1.86–1.70(m,6H),1.51–1.38(m,6H),0.85(s,3H).
Example 35
Step 1: preparation of 4-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000471
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), ethynylcyclohexane (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 528.9mg, yield 72.6%.1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),7.78(s,1H),7.18(d,J＝7.5Hz,1H),6.66(d,J＝7.5Hz,1H),2.37(s,1H),2.03(m,J＝13.1,6.6Hz,2H),1.83–1.61(m,5H),1.30–1.18(m,3H).
Step 2: preparation of N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000472
The compound 4-chloro-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 100ml), saturated brine (1X 100ml) and dried over anhydrous sodium sulfateDrying and concentration under reduced pressure gave the crude compound which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b ═ the corresponding solid compound]Pyridin-4-amine, 39.6mg, yield 34.1%.1H NMR(300MHz,Chloroform-d)δ8.48(s,1H),7.83(s,1H),7.18(d,J＝7.5Hz,1H),6.77(d,J＝7.5Hz,1H),5.31(s,1H),3.84(s,1H),2.40(s,1H),2.04(m,J＝13.1,8.3,7.0Hz,4H),1.86–1.70(m,5H),1.70–1.55(m,6H),1.37(dd,J＝13.0,6.9Hz,2H),1.31–1.18(m,3H).
And step 3: 1-cyclohexyl-2- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000473
To N-cyclohexyl-5- (cyclohexylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (2-fluorophenyl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 51.4mg, yield 28.5%. m.p.213.7-216.9 ℃.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),8.03(s,1H),7.34(s,1H),6.92(s,1H),6.23(s,1H),4.75(s,1H),2.97(d,J＝12.8Hz,1H),2.50–2.38(m,2H),2.31(d,J＝13.0Hz,2H),1.98(d,J＝13.0Hz,2H),1.87–1.74(m,7H),1.65(d,J＝13.0Hz,2H),1.47(dd,J＝17.8,13.0Hz,3H),1.42–1.34(m,2H).
Example 36
Step 1: preparation of 4-chloro-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000481
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylthiophene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 510.0mg, yield 70.0%.1H NMR(300MHz,Chloroform-d)δ8.80(s,1H),7.88(s,1H),7.53–7.44(m,2H),7.30(dd,J＝7.5,5.5Hz,2H),6.71(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000482
The compound 4-chloro-5- (thiophene-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 147.5mg, yield 36.0%.1H NMR(300MHz,Chloroform-d)δ8.63(s,1H),7.78(s,1H),7.56–7.47(m,2H),7.32(d,J＝7.5Hz,1H),7.13(d,J＝7.5Hz,1H),6.79(d,J＝7.5Hz,1H),3.93(s,1H),3.15(s,1H),2.04–1.95(m,2H),1.81–1.68(m,2H),1.68–1.57(m,4H),1.32(dd,J＝12.9,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (thiophen-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000483
To N-cyclohexyl-5- (thien-3-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (thiophen-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 52.5mg, yield 29.2%. m.p.193.7-197.2 ℃.1H NMR(300MHz,Chloroform-d)δ9.34(s,1H),8.00(s,1H),7.37(s,1H),7.33(d,J＝7.5Hz,1H),7.27(dd,J＝11.2,7.5Hz,2H),7.09(s,1H),6.92(d,J＝7.5Hz,1H),4.47(s,1H),2.23(m,J＝11.7,6.2Hz,2H),1.89–1.71(m,5H),1.51–1.38(m,3H).
Example 37
Step 1: preparation of 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000491
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 phase was washed successively with water (2X 100ml) and saturated brine (1X 100ml)Layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 10:1) to give the corresponding solid compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] as the title compound]Pyridine, 59.9mg, yield 76.8%.1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.39(dd,J＝5.0,1.2Hz,1H),7.82(s,1H),7.56(dd,J＝8.1,1.1Hz,1H),7.47(m,J＝8.0,1.3Hz,1H),7.30–7.23(m,2H),6.68(d,J＝7.3Hz,1H).
Step 2: preparation of N-cyclohexyl-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000492
The compound 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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-2-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 146.7mg, yield 35.8%.1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.48(s,1H),7.86(s,1H),7.63(d,J＝8.0Hz,1H),7.56(t,J＝7.9Hz,1H),7.35(d,J＝7.9Hz,1H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),4.30(s,1H),4.05(s,1H),2.07–1.98(m,2H),1.78–1.66(m,2H),1.66–1.56(m,4H),1.29(dd,J＝12.9,6.9Hz,2H).
And step 3: 1-cyclohexyl-2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000493
To N-cyclohexyl-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 50.9mg, yield 28.3%. m.p.243.2-246.9 ℃.1HNMR(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 BDA0003079214730000501
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 3-ethynylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 539.7mg, yield 74.1%.1HNMR(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 BDA0003079214730000502
The compound 4-chloro-5- (pyridine-3-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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 ] as a crude compound]Pyridin-4-amine, 131.8mg, yield 32.1%.1H NMR(300MHz,Chloroform-d)δ8.76(s,1H),8.54(s,1H),8.50(s,1H),7.88–7.82(m,2H),7.33(d,J＝8.1Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.12(s,1H),3.80(s,1H),2.10–2.01(m,2H),1.80(m,J＝13.1,5.8Hz,2H),1.66–1.56(m,4H),1.38(dd,J＝12.8,7.0Hz,2H).
And step 3: 1-cyclohexyl-2- (pyridin-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000511
To N-cyclohexyl-5- (pyridin-3-ylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (pyridin-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 65.4mg, yield 36.4%. m.p.192.7-193.5 ℃.1HNMR(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 BDA0003079214730000512
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 4-ethynylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 568.9mg, yield 78.0%.1H NMR(300MHz,Chloroform-d)δ8.69(s,1H),8.35(d,J＝5.1Hz,2H),7.82(s,1H),7.49(d,J＝5.0Hz,2H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000513
The compound 4-chloro-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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-4-ylethynyl) -1H-pyrrolo [2,3-b ] a]Pyridin-4-amine, 148.3mg, yield 36.2%.1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),8.45(s,2H),7.86(s,1H),7.57(s,2H),7.21(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),4.19(s,1H),3.82(s,1H),2.09–2.00(m,2H),1.78(m,J＝13.1,5.9Hz,2H),1.69–1.57(m,4H),1.35(dd,J＝13.6,6.4Hz,2H).
And step 3: 1-cyclohexyl-2- (pyridin-4-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000521
To N-cyclohexyl-5- (pyridin-4-ylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (pyridin-4-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 68.5mg, yield 38.0%. m.p.236.2-237.3 ℃.1HNMR(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 BDA0003079214730000522
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 5-ethynylpyrimidine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 509.7mg, yield 69.9%.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),9.05(s,2H),8.84(s,1H),7.81(s,1H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000523
The compound 4-chloro-5- (pyrimidine-5-yl ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 mixture was washed with water (2X 100ml) and saturated brine (1X 100ml) in that orderThe organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] the corresponding solid compound]Pyridin-4-amine, 140.1mg, yield 34.2%.1H NMR(300MHz,Chloroform-d)δ9.27(s,1H),9.03(s,2H),8.80(s,1H),7.85(s,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.84(d,J＝1.3Hz,2H),2.09–1.99(m,2H),1.80(m,J＝13.1,5.8Hz,2H),1.68–1.57(m,4H),1.37(dd,J＝12.9,6.9Hz,2H).
And step 3: 1-cyclohexyl-2- (pyrimidin-5-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000531
To N-cyclohexyl-5- (pyrimidin-5-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (pyrimidin-5-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 73.5mg, yield 40.8%. m.p.196.4-197.8 ℃.1HNMR(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 BDA0003079214730000532
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynylpyrimidine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 500.7mg, yield 68.7%.1H NMR(300MHz,Chloroform-d)δ8.84(s,1H),8.79(d,J＝4.9Hz,2H),7.80(s,1H),7.39(t,J＝5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.67(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000533
The compound 4-chloro-5- (pyrimidine-2-yl ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 147.1mg, yield 35.9%.1H NMR(300MHz,Chloroform-d)δ8.84(s,1H),8.79(s,2H),7.86(s,1H),7.38(s,1H),7.24(d,J＝7.5Hz,1H),6.83(d,J＝7.5Hz,1H),3.91(s,1H),2.85(s,1H),2.12–2.03(m,2H),1.84–1.71(m,2H),1.68(dd,J＝12.8,6.8Hz,2H),1.61(dd,J＝6.4,1.6Hz,2H),1.37(dd,J＝12.9,6.9Hz,2H).
And step 3: 1-cyclohexyl-2- (pyrimidin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000541
To N-cyclohexyl-5- (pyrimidin-2-ylethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (pyrimidin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 67.7mg, yield 37.6%. m.p.188.5-189.4 ℃.1HNMR(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 BDA0003079214730000542
Intermediate 4a (1g, 3.6mmol, see preparation of example 1), 2-ethynylnicotinonitrile (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, EtOAc was added and extracted, successively with water (2 × 1)00ml), the organic layer was washed with saturated brine (1 × 100ml), 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%.1H NMR(300MHz,Chloroform-d)δ8.75(dd,J＝5.1,1.2Hz,1H),8.72(s,1H),8.09(dd,J＝8.1,1.3Hz,1H),7.81(s,1H),7.56(dd,J＝8.0,5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of 2- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] pyridin-5-yl) ethynyl) nicotinonitrile
Figure BDA0003079214730000543
Compound 2- ((4-chloro-1H-pyrrolo [2, 3-b)]Pyridin-5-yl) ethynyl) nicotinonitrile (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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 2- ((4- (cyclohexylamino) -1H-pyrrolo [2,3-b ] as a compound]Pyridin-5-yl) ethynyl) nicotinonitrile, 133.5mg, yield 32.6%.1H NMR(300MHz,Chloroform-d)δ8.81(s,1H),8.56(s,1H),8.14(d,J＝8.0Hz,1H),7.86(s,1H),7.62(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),5.36(s,1H),3.77(s,1H),2.08–1.98(m,2H),1.85–1.73(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.27(m,2H).
And step 3: 1-cyclohexyl-2- (3-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000551
To 2- ((4- (cyclohexylamino) -1H-pyrrolo [2, 3-b) at room temperature]Pyridin-5-yl) ethynyl) nicotinonitrile (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (3-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 55.9mg, yield 31.1%. m.p.205.6-206.4 ℃.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.51(s,1H),8.07(s,1H),7.61(t,J＝8.0Hz,1H),7.45(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.13(s,1H),6.95(d,J＝7.5Hz,1H),4.44(s,1H),2.52–2.43(m,2H),2.05(m,J＝13.3,6.9Hz,2H),1.87–1.70(m,3H),1.56–1.36(m,3H).
Example 43
Step 1: preparation of 4-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000552
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 1-ethynyl-2-fluorobenzene (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 770.8mg, yield 73.6%.1H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.85(s,1H),7.56(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.11–7.01(m,2H),6.78(d,J＝7.5Hz,1H),5.13(s,1H),3.86(s,1H),2.11–2.01(m,2H),1.80(m,J＝13.1,6.0Hz,2H),1.67–1.57(m,4H),1.43–1.34(m,2H).
Step 2: preparation of N-cyclohexyl-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000561
The compound 4-chloro-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 143.0mg, yield 34.9%.1H NMR(300MHz,Chloroform-d)δ8.56(s,1H),7.85(s,1H),7.45(t,J＝7.4Hz,1H),7.40(d,J＝7.4Hz,1H),7.29(dd,J＝8.8,7.3Hz,1H),7.19(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),5.38(s,1H),3.83(s,1H),2.08–1.96(m,2H),1.85–1.74(m,4H),1.61(dd,J＝6.5,1.6Hz,2H),1.41–1.28(m,2H).
And step 3: 1-cyclohexyl-2- (4-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000562
To N-cyclohexyl-5- ((3-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg,2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (4-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 66.5mg, yield 36.9%. m.p.187.2-189.6 ℃.1HNMR(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 BDA0003079214730000563
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-4-fluoropyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 584.7mg, yield 80.2%.1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.31(t,J＝5.0Hz,1H),7.82(s,1H),7.32–7.25(m,2H),7.06(m,J＝7.9,4.9,0.9Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000571
The compound 4-chloro-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 135.1mg, yield 33.1%.1H NMR(300MHz,Chloroform-d)δ8.55(s,1H),8.41(s,1H),7.85(s,1H),7.37(d,J＝8.1Hz,1H),7.17(dd,J＝19.9,7.8Hz,2H),6.78(d,J＝7.5Hz,1H),5.02(s,1H),3.79(s,1H),2.10–2.00(m,2H),1.79(m,J＝13.1,5.9Hz,2H),1.66–1.56(m,4H),1.38(dd,J＝13.6,6.4Hz,2H).
And step 3: 1-cyclohexyl-2- (3- (trifluoromethyl) pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000572
To N-cyclohexyl-5- ((4-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressureThe crude compound was obtained and purified by silica gel chromatography (PE: EA ═ 2:1) 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 ℃.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.85(s,1H),8.07(s,1H),7.93(d,J＝8.1Hz,1H),7.62(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.12(s,1H),6.94(d,J＝7.5Hz,1H),4.19(s,1H),2.45(m,J＝13.0,7.0Hz,2H),2.06(m,J＝13.0,6.9Hz,2H),1.85–1.78(m,1H),1.81–1.69(m,2H),1.54–1.44(m,1H),1.46–1.32(m,2H).
Example 45
Step 1: preparation of 4-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000573
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-3- (trifluoromethyl) pyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 770.8mg, yield 73.6%. 513.5mg, yield 70.5%.1H NMR(300MHz,Chloroform-d)δ8.72(s,1H),8.49(dd,J＝5.2,1.3Hz,1H),7.81(s,1H),7.66–7.60(m,1H),7.39(dd,J＝8.0,5.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000581
The compound 4-chloro-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- ((3- (trifluoromethyl) pyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as]Pyridin-4-amine, 138.5mg, yield 33.8%.1H NMR(300MHz,Chloroform-d)δ8.59(d,J＝12.1Hz,2H),7.86(s,1H),7.72(d,J＝8.1Hz,1H),7.48(d,J＝8.1Hz,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.98(s,1H),3.87(s,1H),2.05(dd,J＝13.5,6.3Hz,2H),1.78(dd,J＝13.4,6.2Hz,2H),1.72–1.63(m,2H),1.61(dd,J＝6.5,1.6Hz,2H),1.39(m,J＝13.1,6.5Hz,2H).
And step 3: 1-cyclohexyl-2- (3-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000582
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 (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 (2X 100ml), saturated brine (1X 100ml), 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-(3-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 51.1mg, yield 28.4%. m.p.214.2-215.6 ℃.1H NMR(300MHz,Chloroform-d)δ9.29(s,1H),8.66(s,1H),8.07(s,1H),7.65(d,J＝8.1Hz,1H),7.47(d,J＝7.9Hz,1H),7.35(d,J＝7.5Hz,1H),6.99–6.92(m,2H),4.35(s,1H),2.41(d,J＝19.0Hz,5H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.69(m,3H),1.54–1.34(m,3H).
Example 46
Step 1: preparation of 4-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000591
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-3-methylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 572.7mg, yield 78.6%.1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.30(dd,J＝4.9,1.3Hz,1H),7.81(s,1H),7.36(dd,J＝8.1,1.3Hz,1H),7.30–7.21(m,2H),6.68(d,J＝7.5Hz,1H),2.48(s,3H).
Step 2: preparation of N-cyclohexyl-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000592
The compound 4-chloro-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis(2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 136.8mg, yield 33.4%.1H NMR(300MHz,Chloroform-d)δ8.59(s,1H),8.40(s,1H),7.85(s,1H),7.45(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.22(d,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),3.86(s,1H),3.71(s,1H),2.48(s,3H),2.09–1.99(m,2H),1.82–1.73(m,2H),1.69–1.57(m,4H),1.35(m,J＝13.0,6.6Hz,2H).
And step 3: 1-cyclohexyl-2- (6-fluoropyridin-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000593
To N-cyclohexyl-5- ((3-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (6-fluoropyridin-3-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 52.4mg, yield 29.1%. 206.2-208.8 ℃.1HNMR(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 BDA0003079214730000601
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 5-ethynyl-2-fluoropyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 528.6mg, yield 72.5%.1H NMR(300MHz,Chloroform-d)δ8.68(s,1H),8.46(d,J＝1.2Hz,1H),8.05(m,J＝8.1,5.0,1.3Hz,1H),7.81(s,1H),7.28(d,J＝7.5Hz,1H),6.88(t,J＝8.0Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000602
The compound 4-chloro-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 100ml), saturated brine (1X 100ml) and then with anhydrous sulfurSodium salt was dried and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] as]Pyridin-4-amine, 149.0mg, yield 36.3%.1H NMR(300MHz,Chloroform-d)δ8.54(d,J＝11.2Hz,2H),8.11(d,J＝7.9Hz,1H),7.85(s,1H),7.19(d,J＝7.5Hz,1H),6.96(t,J＝8.1Hz,1H),6.78(d,J＝7.3Hz,1H),4.99(s,1H),3.80(s,1H),2.05(dd,J＝13.5,6.4Hz,2H),1.85–1.76(m,2H),1.66–1.56(m,4H),1.39(m,J＝13.1,6.5Hz,2H).
And step 3: 1-cyclohexyl-2- (6-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000603
To N-cyclohexyl-5- ((6-fluoropyridin-3-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- (6-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 71.9mg, yield 40.0%. m.p.207.1-208.6 ℃.1HNMR(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 BDA0003079214730000611
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-5-fluoropyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 517.7mg, yield 71.0%.1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.41(dd,J＝8.1,1.3Hz,1H),7.81(s,1H),7.55(dd,J＝8.1,5.0Hz,1H),7.33(m,J＝8.0,1.3Hz,1H),7.27(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000612
The compound 4-chloro-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) 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 × 100ml), saturated brine (1 × 100ml), 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- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 137.3mg, yield 33.5%.1H NMR(300MHz,Chloroform-d)δ8.56–8.47(m,2H),7.85(s,1H),7.61(d,J＝8.1Hz,1H),7.41(t,J＝8.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.07(s,1H),3.79(s,1H),2.04(dd,J＝12.9,7.0Hz,2H),1.79(dd,J＝13.4,6.4Hz,2H),1.66–1.56(m,4H),1.38(m,J＝13.1,6.6Hz,2H).
And step 3: 1-cyclohexyl-2- (5-fluoropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000621
To N-cyclohexyl-5- ((5-fluoropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 ℃.1HNMR(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 BDA0003079214730000622
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-5-methylpyridine(4.3mmol)，Pd(PPh3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 494.8mg, yield 67.5%.1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),8.22(d,J＝1.3Hz,1H),7.81(s,1H),7.48(d,J＝8.0Hz,1H),7.37(dd,J＝8.1,1.3Hz,1H),7.27(d,J＝7.3Hz,1H),6.68(d,J＝7.5Hz,1H),2.32(s,3H).
Step 2: preparation of N-cyclohexyl-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000623
The compound 4-chloro-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 223.4mg, yield 30.5%.1H NMR(300MHz,Chloroform-d)δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J＝7.9Hz,1H),7.25(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.24(s,1H),3.80(d,J＝16.3Hz,4H),2.05(dd,J＝13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J＝13.0,6.6Hz,2H).
And step 3: 1-cyclohexyl-2- (5-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000631
To N-cyclohexyl-5- ((5-methylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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-methylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 83.5mg, yield 33.8%. m.p.196.5-198.2 ℃.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(s,1H),6.95(d,J＝7.5Hz,1H),4.48(s,1H),2.50–2.41(m,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H).
Example 50
Step 1: preparation of 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000632
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-5-methoxypyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine were added to 25ml of acetonitrile, and heated under reflux at 80 ℃. After completion of the reaction, the solvent was evaporated, EtOAc was added and extracted, successively with water (2X 100ml) and saturated with foodThe organic layer was washed with brine (1 × 100ml) 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 ═ 10:1) to give the corresponding solid compound 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as]Pyridine, 466.6mg, yield 68.0%.1H NMR(300MHz,Chloroform-d)δ8.70(s,1H),8.18(d,J＝1.2Hz,1H),7.81(s,1H),7.58(d,J＝8.0Hz,1H),7.27(d,J＝7.5Hz,1H),7.19(dd,J＝8.1,1.3Hz,1H),6.68(d,J＝7.5Hz,1H),3.80(s,3H).
Step 2: preparation of N-cyclohexyl-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000633
The compound 4-chloro-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 202.6mg, yield 29.5%.1H NMR(300MHz,Chloroform-d)δ8.54(s,1H),8.29(s,1H),7.85(s,1H),7.65(d,J＝7.9Hz,1H),7.25(d,J＝7.9Hz,1H),7.19(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.24(s,1H),3.80(d,J＝16.3Hz,4H),2.05(dd,J＝13.0,7.0Hz,2H),1.84–1.74(m,2H),1.66–1.56(m,4H),1.37(m,J＝13.0,6.6Hz,2H).
And step 3: 1-cyclohexyl-2- (5-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000641
To N-cyclohexyl-5- ((5-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 60.0mg, yield 29.6%. m.p.202.4-204.7 ℃.1HNMR(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 BDA0003079214730000642
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-6-methoxypyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((6-methoxypyrazine) as a solidPyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine, 483.2mg, yield 70.5%.1H NMR(300MHz,Chloroform-d)δ8.71(s,1H),7.82(s,1H),7.42(t,J＝8.0Hz,1H),7.27(d,J＝7.5Hz,1H),6.90(dd,J＝8.0,1.0Hz,1H),6.73–6.65(m,2H),3.94(s,3H).
Step 2: preparation of N-cyclohexyl-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000651
The compound 4-chloro-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 243.2mg, yield 35.5%.1H NMR(300MHz,Chloroform-d)δ8.55(s,1H),7.86(s,1H),7.50(t,J＝8.0Hz,1H),7.19(d,J＝7.5Hz,1H),6.96(d,J＝7.9Hz,1H),6.79(dd,J＝7.8,5.6Hz,2H),5.14(s,1H),3.94(s,3H),3.79(s,1H),2.04(dd,J＝13.0,7.0Hz,2H),1.84–1.75(m,2H),1.66–1.56(m,4H),1.38(m,J＝13.0,6.6Hz,2H).
And step 3: 1-cyclohexyl-2- (6-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000652
To N-cyclohexyl-5- ((6-methoxypyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]Pyridin-4-amine (1.5mmol) and THF (10mL)t-BuOK (252.3mg, 2.25mmol) was added to the mixture. 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 × 100ml), saturated brine (1 × 100ml), 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- (6-methoxypyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 41.3mg, yield 24.5%. m.p.187.3-189.9 ℃.1HNMR(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 BDA0003079214730000653
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-ethynyl-6-nitropyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), 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-chloro-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 547.9mg, yield 79.9%.1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),8.22(dd,J＝8.0,1.1Hz,1H),8.09(dd,J＝8.1,0.9Hz,1H),7.89–7.80(m,2H),7.28(d,J＝7.5Hz,1H),6.68(d,J＝7.5Hz,1H).
Step 2: preparation of N-cyclohexyl-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000661
The compound 4-chloro-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 159.6mg, yield 23.3%.1H NMR(300MHz,Chloroform-d)δ8.64(s,1H),8.31(d,J＝7.9Hz,1H),8.15(d,J＝8.1Hz,1H),7.95(t,J＝8.0Hz,1H),7.86(s,1H),7.27(d,J＝7.5Hz,1H),6.86(d,J＝7.5Hz,1H),4.00(s,1H),2.09(dd,J＝12.9,6.8Hz,2H),2.01–1.92(m,2H),1.90(s,1H),1.76–1.67(m,2H),1.61(dd,J＝6.4,1.7Hz,2H),1.56–1.44(m,2H).
And step 3: 1-cyclohexyl-2- (6-nitropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000662
To N-cyclohexyl-5- ((6-nitropyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 and EtOAc was added for extractionThe organic layer was washed successively with water (2 × 100ml), saturated brine (1 × 100ml), 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- (6-nitropyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 47.6mg, yield 26.3%. m.p.181.5-183.9 ℃.1H NMR(300MHz,Chloroform-d)δ9.31(s,1H),8.43(dd,J＝17.3,7.9Hz,2H),8.15(t,J＝8.0Hz,1H),8.08(s,1H),7.36(d,J＝7.5Hz,1H),7.25(s,1H),6.98(d,J＝7.5Hz,1H),4.16(s,1H),2.27–2.16(m,2H),1.89–1.75(m,4H),1.69–1.54(m,3H),1.53–1.42(m,1H).
Example 53
Step 1: preparation of 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridine
Figure BDA0003079214730000671
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 2-cyclopropyl-6-ethynylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 10:1) to give the corresponding solid compound 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 536.7mg, yield 78.2%.1H NMR(300MHz,Chloroform-d)δ8.82(s,1H),7.89(s,1H),7.55–7.46(m,2H),7.29(d,J＝7.5Hz,1H),7.07(dd,J＝7.0,2.0Hz,1H),6.71(d,J＝7.5Hz,1H),1.84(p,J＝6.9Hz,1H),0.90(m,J＝7.1,4.1Hz,2H),0.76(m,J＝7.2,4.3Hz,2H).
Step 2: preparation of N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000672
The compound 4-chloro-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 177.0mg, yield 25.8%.1H NMR(300MHz,Chloroform-d)δ8.52(s,1H),7.85(s,1H),7.54–7.45(m,2H),7.18(d,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),6.78(d,J＝7.5Hz,1H),5.49(s,1H),3.78(s,1H),2.05(dd,J＝13.0,7.0Hz,2H),1.86–1.75(m,3H),1.68–1.57(m,4H),1.37(m,J＝13.1,6.6Hz,2H),0.92–0.87(m,2H),0.78–0.72(m,2H).
And step 3: 1-cyclohexyl-2- (6-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000673
To N-cyclohexyl-5- ((6-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 2:1) to give a phaseThe solid compound 1-cyclohexyl-2- (6-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 41.9mg, yield 24.7%. m.p.214.2-215.1 ℃.1HNMR(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 BDA0003079214730000681
Intermediate 4a (1g, 3.6mmol, see preparation method of example 1), 5-cyclopropyl-2-ethynylpyridine (4.3mmol), Pd (PPh)3)2Cl2(126mg, 0.18mmol), CuI (34mg, 0.18mmol) and 1ml of triethylamine 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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 10:1) to give the corresponding solid compound 4-chloro-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridine, 460.6mg, yield 67.1%.1H NMR(300MHz,Chloroform-d)δ8.82(s,1H),8.25(d,J＝1.2Hz,1H),7.88(s,1H),7.59(d,J＝8.1Hz,1H),7.37(dd,J＝8.1,1.3Hz,1H),7.29(d,J＝7.5Hz,1H),6.70(d,J＝7.5Hz,1H),1.68(m,J＝7.0Hz,1H),1.05–0.96(m,2H),0.76–0.67(m,2H).
Step 2: preparation of N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000682
The compound 4-chloro-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b]Pyridine (2.6mmol), cyclohexylamine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound, which was purified by silica gel chromatography (PE: EA ═ 3:1) to give the corresponding solid compound N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-amine, 210.7mg, yield 30.7%.1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.32(s,1H),7.86(s,1H),7.55(d,J＝8.1Hz,1H),7.46(d,J＝7.9Hz,1H),7.24(d,J＝7.5Hz,1H),6.84(d,J＝7.5Hz,1H),3.94(s,1H),2.80(s,1H),2.32(s,3H),2.07(dd,J＝12.9,7.0Hz,2H),1.78(dd,J＝13.5,6.3Hz,2H),1.72–1.57(m,4H),1.40(m,J＝12.9,6.5Hz,2H).
And step 3: 1-cyclohexyl-2- (5-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000691
To N-cyclohexyl-5- ((5-cyclopropylpyridin-2-yl) ethynyl) -1H-pyrrolo [2,3-b ] at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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-cyclopropylpyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 45.5mg, yield 25.8%. m.p.214.2-215.1 ℃.1HNMR(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 BDA0003079214730000692
Intermediate 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see preparation 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), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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%.1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.49(dd,J＝4.9,1.3Hz,1H),7.86(s,1H),7.62(dd,J＝7.9,1.1Hz,1H),7.56(m,J＝7.9,1.2Hz,1H),7.35(m,J＝7.8,4.9,1.1Hz,1H),7.20(d,J＝7.5Hz,1H),6.80(d,J＝7.5Hz,1H),4.77(s,1H),3.38(q,J＝7.1Hz,1H),1.75–1.57(m,2H),1.60–1.46(m,5H),1.33–1.20(m,1H),1.03(d,J＝6.5Hz,3H).
Step 2: 1- ((2S) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000693
To N- ((2S) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- ((2S) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 68.9mg, yield 39.0%. m.p.189.5-192.9 ℃.1H NMR(300MHz,Chloroform-d)δ9.30(d,J＝1.6Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.07(s,1H),7.87(dd,J＝7.9,1.0Hz,1H),7.71(m,J＝8.0,1.3Hz,1H),7.35(d,J＝7.5Hz,1H),7.29(m,J＝8.0,5.0,1.1Hz,1H),7.09(d,J＝1.5Hz,1H),6.93(d,J＝7.5Hz,1H),3.88(m,J＝7.1Hz,1H),2.57(m,J＝6.9Hz,1H),1.96(m,J＝12.9,7.1Hz,1H),1.88–1.77(m,1H),1.75–1.64(m,2H),1.68–1.54(m,1H),1.55(m,J＝4.4,2.4Hz,1H),1.56–1.46(m,1H),1.38(m,J＝12.5,6.9Hz,1H),1.10(d,J＝6.8Hz,3H).
Example 56
Step 1: preparation of N- ((2R) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine
Figure BDA0003079214730000701
Intermediate 4-chloro-5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b]Pyridine (1g, 3.6mmol, see preparation of example 37), (2R) 2-methylcyclohex-1-amine (600ul, 5.2mmol), t-BuONa (750mg, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(dba)3(75mg, 0.13mmol) was added to 20ml dioxane and heated to reflux at 130 ℃. After the reaction is completed, the reaction solution is added,evaporation of the solvent and extraction with EtOAc, washing of the organic layer with water (2X 100ml), in turn saturated brine (1X 100ml), and drying over anhydrous sodium sulfate and concentration under reduced pressure gave the 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 281.5mg, yield 41%.1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.48(dd,J＝5.0,1.2Hz,1H),7.86(s,1H),7.63(dd,J＝8.1,1.1Hz,1H),7.56(m,J＝8.0,1.3Hz,1H),7.35(m,J＝7.8,5.1,1.1Hz,1H),7.24(d,J＝7.5Hz,1H),6.82(d,J＝7.5Hz,1H),3.51(m,J＝7.1Hz,1H),3.19(s,1H),2.10(m,J＝6.9Hz,1H),1.85–1.35(m,8H),1.01(d,J＝6.8Hz,3H).
Step 2: 1- ((2R) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000702
To N- ((2R) -2-methylcyclohexyl) -5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b at room temperature]To a mixture of pyridin-4-amine (1.5mmol) and THF (10mL) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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- ((2R) -2-methylcyclohexyl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine, 73.5mg, yield 33.8%. m.p.216.5-218.2 ℃.1H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.54(s,1H),8.07(s,1H),7.95(d,J＝7.9Hz,1H),7.68(d,J＝8.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.15(s,1H),6.95(d,J＝7.5Hz,1H),4.48(s,1H),2.50–2.41(m,2H),2.33(s,3H),2.04(m,J＝13.3,6.9Hz,2H),1.86–1.70(m,3H),1.54–1.37(m,3H).
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 BDA0003079214730000711
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, 11.4mmol), 1, 3-bis (2, 6-diisopropylphenyl) imidazolium chloride (110mg, 0.26mmol), Pd2(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 × 100ml), saturated brine (1 × 100ml), 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 3- ((5- (pyridin-2-ylethynyl) -1H-pyrrolo [2,3-b ] as a crude compound]Pyridin-4-yl) amino) tert-butyl-1-carboxylic acid tert-butyl ester, 510mg, yield 31.0%. m.p.206.5-207.8 ℃.1HNMR(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 3- (2- (pyridin-2-yl) dipyrrolo [2, 3-b: 2', 3' -d ] pyridin-1 (6H) -yl) piperidine-1-carboxylate
Figure BDA0003079214730000712
To 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 (1.2 mmo)l) and THF (10ml) was added t-BuOK (252.3mg, 2.25 mmol). 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 × 100ml), saturated brine (1 × 100ml), 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 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%.1H NMR(300MHz,Chloroform-d)δ9.32(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.11(s,1H),7.93(dd,J＝8.1,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.36(d,J＝7.5Hz,1H),7.32–7.25(m,2H),6.89(d,J＝7.5Hz,1H),4.56(m,J＝12.5,7.1Hz,1H),4.44(dd,J＝12.5,7.1Hz,1H),4.06(dd,J＝12.5,7.0Hz,1H),3.85(m,J＝7.1Hz,1H),3.13(m,J＝12.5,7.2Hz,1H),2.29(m,J＝13.0,7.0Hz,1H),1.92(m,J＝13.8,7.0Hz,1H),1.75(m,J＝48.5,13.2,7.0Hz,2H),1.47(s,9H).
And step 3: 1- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: preparation of 2', 3' -d ] pyridines
Figure BDA0003079214730000721
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 CDCl2To the mixture (30ml) 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 × 100ml), saturated brine (1 × 100ml), 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- (piperidin-3-yl) -2- (pyridin-2-yl) -1, 6-dihydrodipyrrolo [2, 3-b: 2', 3' -d]Pyridine 80.8mg yield 84.9%.1H NMR(300MHz,Chloroform-d)δ9.30(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.07(s,1H),7.91(dd,J＝8.0,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.35(d,J＝7.5Hz,1H),7.29(m,J＝8.0,5.0,1.1Hz,1H),7.18(d,J＝1.5Hz,1H),6.96(d,J＝7.5Hz,1H),4.26(m,J＝7.0Hz,1H),3.31(dd,J＝12.6,7.1Hz,1H),3.24(m,J＝12.5,7.0Hz,1H),3.15(dd,J＝12.4,6.9Hz,1H),2.87(m,J＝12.4,7.1Hz,1H),2.33(m,J＝13.9,7.0Hz,1H),1.80(m,J＝13.1,7.0Hz,1H),1.69–1.49(m,2H),1.30(s,1H).
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 BDA0003079214730000722
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 CDCl2And 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 × 100ml), saturated brine (1 × 100ml), 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, 3-oxo-3- (3- (2- (pyridin-2-yl) dipyrrolo [2, 3-b: 2', 3' -d ═ 2,3-b]Pyridin-1 (6H) -yl) piperidin-1-yl) propionitrile 68.3mg, yield 79.5%. m.p.241.5-244.8 ℃.1H NMR(300MHz,Chloroform-d)δ9.31(d,J＝1.5Hz,1H),8.70(dd,J＝5.0,1.2Hz,1H),8.08(s,1H),7.92(dd,J＝8.0,1.0Hz,1H),7.71(m,J＝8.0,1.2Hz,1H),7.35(d,J＝7.5Hz,1H),7.32–7.24(m,2H),6.84(d,J＝7.5Hz,1H),4.64(dd,J＝12.4,6.9Hz,1H),4.12(m,J＝12.6,7.1Hz,1H),3.90–3.80(m,2H),3.65(dd,J＝12.5,7.1Hz,1H),3.58(d,J＝12.4Hz,1H),3.14(m,J＝12.5,7.0Hz,1H),2.19–2.08(m,1H),1.97(m,J＝13.8,7.0Hz,1H),1.81(m,J＝13.1,7.0Hz,1H),1.73–1.61(m,1H).
EXAMPLE 58 test for inhibitory Activity of the Compounds of the present invention on the JAK family
First, experimental material
Figure BDA0003079214730000731
Second, Experimental methods
1. Preparing 1x kinase reaction buffer:
name (R) Concentration of stock solution Volume of Final concentration
Hepes 1M(20X) 12500μL 50mM
MgCl2 1M(100X) 2500μL 10mM
Brij 35 / 25μL 0.01％
EGTA 1M(1000X) 250μL 1mM
DTT 1M(500X) 500μL 2mM
ddH2O 235000μL
2. Kinase reaction conditions:
Figure BDA0003079214730000732
3. the test flow comprises the following steps:
3.1 Compounds were diluted in 4-fold gradient in DMSO in dilution plates, starting at a concentration of 1.5 uM.
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 kinase per well to 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.L ADP-Glo to 384 reaction plates at 1000rpm/min, centrifuge for 1min, incubate for 40min at 25 ℃.
3.9 transfer 8. mu.L of Detection solution to 384 reaction plates at 1000rpm/min, centrifuge for 1min, incubate for 40min at 25 ℃.
3.10 reading RLU (relative luminescence unit) signals using a Biotek multifunctional plate 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 from all negative control wells in 0.5% DMSO
Third, experimental results
The inhibitory activity of the compounds of the present invention against JAK family proteins.
Figure BDA0003079214730000741
Figure BDA0003079214730000751
Figure BDA0003079214730000761
The skilled artisan is aware that JAKs are important targets for a variety of novel diseases, such as autoimmune or 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 be illustrative of the nature of the invention, but those skilled in the art will recognize that the scope of the invention is not limited to the specific embodiments.

Claims (9)

1. A compound with a dipyrrolopyridine structure, which is characterized by the following structural formula:
Figure FDA0003079214720000011
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a ═ cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, phenyl rings, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
R1＝
Figure FDA0003079214720000012
n1＝1、2、3；n2＝1、2、3、4；
R2methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
2. A method for synthesizing the compound of claim 1, wherein the synthetic route is as follows:
Figure FDA0003079214720000013
wherein:
n＝0、1、2；
m＝4、5、6、7；
X＝O，N；
Y＝C、N；
a ═ cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, phenyl rings, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furopyridine, benzopyrrole, benzothiophene, benzofuran;
R1＝
Figure FDA0003079214720000021
n1＝1、2、3；n2＝1、2、3、4；
R2methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; trisubstituted methyl, methoxy.
3. The method according to claim 2, wherein compound 5a is synthesized by the following route:
Figure FDA0003079214720000022
4. the method according to claim 2, wherein compound 6a is synthesized by the following route:
Figure FDA0003079214720000023
5. the use of a compound of claim 1 for the preparation of a JAK inhibitor medicament.
6. The compounds of claim 1 have JAK kinase inhibitory activity and are therefore useful for their antiproliferative and/or proapoptotic activity and in methods of treatment of the 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.
7. By inhibiting tyrosine kinases, particularly the JAK family. The compound of claim 1 or a pharmaceutically acceptable salt thereof can be used for the treatment of autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, ulcerative colitis, and the like. Treatment includes myositis, vasculitis, pemphigus, crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major 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.
8. By inhibiting tyrosine kinases, particularly the JAK family. A compound of claim 1 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 cancer, ovarian cancer, lung cancer, colon cancer, prostate cancer or other tissue cancers, as well as leukemia, myeloma and lymphoma are expected.
9. By inhibiting tyrosine kinases, particularly the JAK family. The compound of claim 1, 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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