CN113292561A

CN113292561A - Compound with dipyrrolopyridine structure, preparation method and medical application

Info

Publication number: CN113292561A
Application number: CN202110561592.4A
Authority: CN
Inventors: 尤启冬; 姜正羽; 鲍启超; 孟凡莹; 郭小可; 徐晓莉; 王磊
Original assignee: China Pharmaceutical University
Current assignee: Nanjing Kangyi Biomedical Center LP
Priority date: 2021-05-22
Filing date: 2021-05-22
Publication date: 2021-08-24
Also published as: CN115385911A; WO2022247676A1

Abstract

本发明公开了一种二吡咯并吡啶结构的化合物、制备方法和医药用途。本发明提供的二吡咯并吡啶结构的化合物对JAK家族蛋白具有明显的抑制活性，为有效的JAK抑制剂，因此具备开发成抑制JAK进而治疗疾病的药物的前景。The invention discloses a compound with a dipyrrolopyridine structure, a preparation method and a medical application. The compound of the dipyrrolopyridine structure provided by the present invention has obvious inhibitory activity on JAK family proteins, and is an effective JAK inhibitor, so it has the prospect of being developed into a medicine that inhibits JAK and then treats 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:

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;

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:

wherein:

n＝0、1、2；

m＝4、5、6、7；

X＝O，N；

Y＝C、N；

n₁＝1、2、3；n₂＝1、2、3、4；

Preferably, the above compound 5a is synthesized by the following route:

preferably, the above compound 6a is synthesized by the following route:

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)

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)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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:

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.

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

1. a compound of dipyrrolopyridine structure, is characterized in that, structural formula is as follows:

in:

n=0, 1, 2;

m=4, 5, 6, 7;

X=O,N;

Y=C, N;

A = cyclopropyl, cyclohexyl, cyclopentyl, cyclohexyl, thiophene, furan, benzene ring, pyridine, pyrimidine; pyrrolopyridine, thienopyridine, furanopyridine, benzopyrrole, benzothiophene, benzofuran ;

R ₁ =

n ₁ =1, 2, 3; n ₂ =1, 2, 3, 4;

R ₂ = methyl, ethyl, methoxy, fluoro, chloro, nitro, cyclopropyl, cyano, amino, hydroxy, trifluoromethyl; disubstituted methyl, chloro, fluoro, methoxy; Tri-substituted methyl, methoxy.

2. a method for synthesizing the compound of claim 1, is characterized in that, synthetic route is as follows:

in:

n=0, 1, 2;

m=4, 5, 6, 7;

X=O,N;

Y=C, N;

R ₁ =

n ₁ =1, 2, 3; n ₂ =1, 2, 3, 4;

3. method according to claim 2, is characterized in that, compound 5a is synthesized by following route:

4. method according to claim 2 is characterized in that, compound 6a is synthesized by following route:

5. The medicinal use of the compound of claim 1 for preparing a JAK inhibitor medicine.

6. The compound of claim 1 has JAK kinase inhibitory activity and is therefore useful in its anti-proliferative and/or pro-apoptotic activity and in methods of treating the human or animal body. The present invention also relates to a preparation method of the compound or a pharmaceutically acceptable salt thereof, to a pharmaceutical composition comprising the compound, and to the preparation of a medicament for producing anti-proliferative and/or pro-apoptotic effects and anti-inflammatory effects the use of.

7. By inhibiting tyrosine kinases, especially 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. Treatments include myositis, vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis, multiple sclerosis, major depression, allergies, asthma, Sjögren's syndrome, dry eye, transplant rejection, cancer, inflammation Sexual bowel disease, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritus, allergic reactions in mammals (including atopic dermatitis).

8. By inhibiting tyrosine kinases, especially the JAK family. The compound of claim 1 or a pharmaceutically acceptable salt thereof is 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. Therefore, activity against myeloproliferative diseases is expected, such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelometaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelocytosis disease and chronic myelodysplastic syndromes, myelodysplastic syndromes and neoplastic diseases such as breast, ovarian, lung, colon, prostate or other tissue cancers, as well as leukemia, myeloma and lymphoma.

9. By inhibiting tyrosine kinases, especially the JAK family. The blood-brain barrier permeability of the compound of claim 1 or a pharmaceutically acceptable salt thereof during the test has value in the treatment of central nervous system diseases. Therapeutic approaches target tyrosine kinase activity, particularly the JAK family activity, which is involved in a variety of CNS inflammatory disease-related processes. Thus, activity against central nervous system inflammations such as epilepsy, dementia, Parkinson's disease, depression, etc. is expected.