Cyano-substituted cyclic hydrazine derivatives and uses thereof

Abstract

The present invention provides a cyano-substituted cyclic hydrazine derivative, characterized in that it is a compound represented by the following structural formula, or a stereoisomer, geometric isomer, tautomer, racemate, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, for use in preventing, managing, treating, or alleviating an autoimmune or proliferative disease in a patient, and / or inhibiting or modulating the activity of a protein kinase. [Formula 1] TIFF2022548123000094.tif45169

Description

[Technical field]

[0001] The present invention belongs to the field of pharmaceutical synthesis, specifically, the present invention relates to JAK enzyme inhibitors, and their preparation methods and uses. [Background technology]

[0002] Protein kinases are enzymes that catalyze the phosphorylation of proteins and are important factors regulating cell signaling including cell proliferation and cell differentiation, including cell growth, survival, differentiation, organogenesis, morphogenesis, angiogenesis, tissue repair and regeneration.

[0003] Signal transduction of many cytokines, such as the interferon (IFN) family, glycoprotein 130 (gpl30) family, gamma-C family (common gamma chain, CD132 family), and single chain family, involves the Janus kinase family (JAK) and signal transducers and activators of transcription (STAT) downstream of the JAK kinases. Currently, there are four known mammalian JAK family members: JAK1 (also called Janus kinase-1), JAK2 (also called Janus kinase-2), JAK3 (Janus kinase-3), and TYK2 (also called protein tyrosine kinase 2).

[0004] Blocking signaling at the level of JAK kinases offers the prospect of developing therapeutic approaches for inflammatory, autoimmune, myeloproliferative and cancer diseases. Inhibition of JAK kinases also contributes to the treatment of cutaneous immune disorders such as psoriasis and skin sensitization. Tofacitinib and baricitinib are marketed to treat rheumatoid arthritis, and ruxolitinib to treat myelofibrosis and acute graft-versus-host disease.

[0005] However, some existing JAK enzyme inhibitors also have obvious toxicities and side effects. Immune-related side effects of JAK inhibitors include infections including pneumonia, viral infections (e.g., shingles infections), bacterial infections, actinomycete infections (mycobacterial infections), fungal infections, immunosuppression (e.g., decreased NK cells), and anemia. However, there are also non-immune side effects such as pulmonary embolism (which can be fatal). Research has shown that currently existing JAK inhibitors are not selective for JAK kinase family members, and that the side effect of pulmonary embolism is related to the inhibition of JAK2.

[0006] For these reasons, there is currently an urgent need in this field to develop inhibitors of Janus kinase or its related kinases, in particular inhibitors that are highly selective for JAK1. Summary of the Invention

[0007] The present invention aims to provide a novel inhibitor having high activity against JAK1 kinase and relatively good selectivity against JAK2 kinase, as well as a method for preparing and using the same.

[0008] The present invention provides a cyclic hydrazine derivative substituted with a cyano group, characterized in that it is a compound represented by the following structural formula, or a stereoisomer, a geometric isomer, a tautomer, a racemate, a hydrate, a solvate, a metabolite, or a pharma- ceutically acceptable salt or prodrug thereof: [ka] wherein ring A is a heterocyclyl group, a fused heterocyclyl group, or a spiroheterocyclyl group; The above R 1 are one or more substituents which may be the same or different, The above R 1 is selected from hydrogen, a hydroxy group, a halogen, an amino group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted heterocycloalkyl group; The above R 10 is selected from a cyano group or a group terminated with a cyano group, and the group terminated with a cyano group may be saturated or unsaturated; R 2 is selected from hydrogen, a hydroxy group, a halogen, a nitro group, an amino group, a substituted amino group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted heterocycloalkyl group; R 20 is selected from hydrogen, an amino protecting group.

[0009] The above ring A is most preferably a heterocyclyl group consisting of 4 to 9 atoms, a fused heterobicyclyl group consisting of 6 to 12 atoms, or a spiroheterobicyclyl group consisting of 6 to 12 atoms. wherein the heteroatoms are 1-3 and are selected from nitrogen, oxygen, or sulfur.

[0010] The above ring A may be a structure represented by the following structure or a structure similar thereto. [ka]

[0011] In the present invention, the substituted or unsubstituted alkyl group is The unsubstituted alkyl group is usually a branched alkyl group having 6 or less carbon atoms, or a branched alkyl group, The above-mentioned substituted alkyl group is an alkyl group in which one or more hydrogen atoms in the carbon chain are replaced by other groups, where the other groups are cycloalkyl groups ( [ka] and the like, and any hydrogen atom in the ring of the cycloalkyl group may be further substituted with a halogen, a cyano group, an alkyl group, a hydroxyl group, a carboxyl group, or the like), a heterocycloalkyl group (i.e., based on the above cycloalkyl group, at least one carbon atom in the ring of the alkyl group is substituted with an oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, I), a carboxyl group, a cyano group (-CN), a sulfonyl group (-SOR a , R a is an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR b , R b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (-C(O)OR z , R z is an alkyl group, an aryl group, a heteroaryl group, etc.

[0012] In the present invention, the substituted or unsubstituted cycloalkyl group is The unsubstituted cycloalkyl group is usually a cycloalkyl group having 3 to 8 carbon atoms. The substituted ring alkyl group is one in which one or more hydrogen atoms in the ring of the cyclyl group are replaced by other groups, and the other groups are selected from the group consisting of alkyl groups, substituted alkyl groups (as above), halogens (F, Cl, Br, I), carboxyl groups, cyano groups (-CN), sulfonyl groups (-SOR), and the like. a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR b , R b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (-C(O)OR z , Rz is an alkyl group, an aryl group, a heteroaryl group, etc.

[0013] In the present invention, the substituted or unsubstituted heteroalkyl group is one in which one or more carbon atoms in the carbon chain of the above-mentioned substituted or unsubstituted alkyl group are substituted with oxygen, sulfur or nitrogen.

[0014] In the present invention, the substituted or unsubstituted heterocycloalkyl group is one in which one or more carbon atoms in the ring are substituted with oxygen, sulfur or nitrogen based on the above-mentioned substituted or unsubstituted cycloalkyl group.

[0015] In the present invention, the substituted or unsubstituted alkoxy group is The unsubstituted alkoxy group is usually a branched alkoxy group having 6 or less carbon atoms, or a branched alkoxy group, The above-mentioned substituted alkoxy group is an alkyl group in which one or more hydrogen atoms in the carbon chain are replaced by other groups, and the other groups are cycloalkyl groups ( [ka] and the like, and any hydrogen atom in the ring of the cycloalkyl group may be further substituted with a halogen, a cyano group, an alkyl group, a hydroxyl group, a carboxyl group, or the like), a heterocycloalkyl group (i.e., based on the above cycloalkyl group, at least one carbon atom in the ring of the alkyl group is substituted with an oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, I), a carboxyl group, a cyano group (-CN), a sulfonyl group (-SOR a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR b , R b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR x R y , R x R yis an alkyl group, an aryl group, etc.), an ester group (-C(O)OR z , R z is an alkyl group, an aryl group, a heteroaryl group, etc.

[0016] In the present invention, a substituted amino group is an amino group (-NH2) in which one or more hydrogen atoms have been replaced with another group, and the other group may be an alkyl group, a cycloalkyl group, an amide group, an ester group, or the like.

[0017] Furthermore, the present invention provides a cyclic hydrazine derivative substituted with a cyano group, which is a compound represented by the following structure: [ka] where n is a natural number selected from 1 to 3; The above X is a substituted or unsubstituted alkylene group, a substituted or unsubstituted heteroalkylene group, -(CH2) m N(R3)-, -(CH2) m C(O)N(R3)-, -(CH2) m C(O)-, The bond between X and ring A is a single bond or a double bond. R3 is selected from hydrogen, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted heteroalkyl group; m is selected from natural numbers 1-3.

[0018] In the present invention, the substituted or unsubstituted alkylene group is The above unsubstituted alkylene group is -(CH2) m - is an aspect of The above substituted alkylene group is -(CH2) m -, in which one or more hydrogen atoms in the carbon chain are replaced by other groups, and the other groups are alkyl groups, cycloalkyl groups ( [ka] and the like, and any hydrogen atom in the ring of the cycloalkyl group may be further substituted with a halogen, a cyano group, an alkyl group, a hydroxyl group, a carboxyl group, or the like), a heterocycloalkyl group (i.e., based on the above cycloalkyl group, at least one carbon atom in the ring of the alkyl group is substituted with an oxygen, sulfur, or nitrogen), a halogen (F, Cl, Br, I), a carboxyl group, a cyano group (-CN), a sulfonyl group (-SOR a , R a is hydrogen, an alkyl group, an aryl group, etc.), an alkynyl group (-C≡CH, -C≡CR b , R b is an alkyl group, an aryl group, etc.), an amide group (-C(O)NR x R y , R x R y is an alkyl group, an aryl group, etc.), an ester group (-C(O)OR z , R z is an alkyl group, an aryl group, a heteroaryl group, etc.

[0019] In the present invention, the substituted or unsubstituted heteroalkylene group is the above-mentioned unsubstituted alkylene group in which one or more carbon atoms are substituted with oxygen, sulfur or nitrogen.

[0020] Furthermore, the present invention provides a cyclic hydrazine derivative substituted with a cyano group, which is a compound represented by the following structural formula: [ka] where A, X, R 1 , and R 2 is as defined above, Y is CR 4 , N; R 4 is selected from hydrogen, a hydroxy group, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted alkoxy group.

[0021] Furthermore, the present invention provides a cyclic hydrazine derivative substituted with a cyano group, which is a compound represented by the following structural formula: [ka] Here, a in the above is 0, 1, 2, 3, The above R 10 ' is selected from groups terminated with a cyano group.

[0022] Furthermore, the present invention provides a cyclic hydrazine derivative substituted with a cyano group, which is a compound represented by the following structural formula: [ka] wherein Z is selected from a substituted or unsubstituted alkylene group; R 5 is selected from hydrogen, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted heteroalkyl group.

[0023] The present invention further provides a method for preparing the above cyclic hydrazine derivative substituted with a cyano group, the specific reaction equation of which is as follows: [ka]

[0024] Specifically, it is manufactured in the following steps. Using S1 and II-1 as raw materials, their NH groups are nitrosylated to form the nitroso product II-2. S2, converting the nitroso product II-2 to compound II-3 by reduction; S3, reacting compound II-3 with compound II-4 under basic conditions to obtain compound II-5; S4, hydrogenating the nitro group in compound II-5 and reducing it to an amino group to give compound II-6; S5, compound II-6 is subjected to a ring-closing reaction to obtain compound II-7; S6, compound II-7 is deprotected to give the desired product.

[0025] The specific process of the above reaction may be as follows: The compound represented by formula II-1 may be obtained directly or by known conventional synthetic methods. Formula II-1 is nitrosated with HNO2 (obtained by adding acid to NaNO2) or alkyl nitrite (e.g., butyl nitrite, isopentyl nitrite) to obtain "N" nitrite product II-2. Intermediate product II-2 can be converted to II-3 by iron powder, zinc powder, or catalytic hydrogenation. II-3 and II-4 (Ar is selected from phenyl or benzyl, synthesis see Kulagowski, JJ, et al., Journal of Medicinal Chemistry (2012) 55, 5901) react under basic conditions (dry Na2CO3, anhydrous DMF, heating) to obtain compound II-5. The nitro group in compound II-5 is reduced to amino group by hydrogenation (Pt-C, 1 atm hydrogen gas) to obtain II-6. The ring closure reaction can be achieved by several known conditions. In general, II-6 is converted to an ortho acid triester (R 2 (OMe)3, e.g., triethyl orthoacetate), or dehydration of II-6 and the amide with triethyloxonium tetrafluoroborate or other onium salts. Finally, deprotection with aqueous sodium hydroxide gives compounds of formula I.

[0026] The present invention further provides a pharmaceutical composition comprising the above-mentioned cyclic hydrazine derivative substituted with a cyano group and at least one of a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle. The amount of the cyclic hydrazine derivative substituted with a cyano group used herein is 0.01-99.9% of the total mass of the pharmaceutical composition.

[0027] Furthermore, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent. The additional therapeutic agent is selected from an anti-inflammatory agent, an immunomodulatory or immunosuppressant agent, a neurotrophic factor, an active agent for treating cardiovascular disease, an active agent for treating diabetes, and an active agent for treating an autoimmune disease.

[0028] In addition, the compounds or pharmaceutical compositions according to the present invention may be used to prevent, treat, cure or alleviate an autoimmune or proliferative disease in a patient, and / or to inhibit or modulate the activity of a protein kinase.

[0029] Here, the autoimmune disease may be rheumatoid arthritis, psoriasis, type I diabetes, complications from organ transplantation, xenotransplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, leukemia, lymphoma, lupus, multiple sclerosis, or amyotrophic lateral sclerosis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Example 1 [ka] 1-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-4-carbonitrile The form for carrying out the invention is as follows. [ka]

[0031] Step A: 4-Chloro-7-azaindole (50.0 g, 327.8 mmol) was dissolved in 1 L of dichloromethane, and triethylamine (66.3 g, 655.6 mmol), p-toluenesulfonyl chloride (64.4 g, 37.6 mmol), and 4-dimethylaminopyridine (0.4 g, 3.3 mmol) were added at 0° C., and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was washed with 500 mL of water, and the organic phase was separated, dried, filtered, and the solvent was removed under reduced pressure to obtain the compound 4-chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (99.8 g, 99% yield).

[0032] Step B: Compound 4-chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (50.0 g, 163.0 mmol) was dissolved in 600 mL of dichloromethane. Tetrabutylammonium nitrate (74.4 g, 244.5 mmol) and anhydrous trifluoroacetic acid (53.1 g, 252.6 mmol) were added at 0°C, and the mixture was reacted at room temperature for 20 hours under nitrogen gas protection. After the reaction was completed, 500 mL of saturated aqueous sodium bicarbonate was added to quench the reaction, and the organic phase was separated and the aqueous phase was extracted twice with 1.2 L of dichloromethane. The organic phases were combined and washed with an appropriate amount of water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated on a rotary evaporator. The resulting slurry was ultrasonically triturated with 80 mL of ethyl acetate, filtered, and the filter cake was dried to obtain the compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (30.1 g, yield 52%). 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.26(d,J=4.0Hz,1H),8.05(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),7.09(d,J=4.0Hz,1H),2.37(s,3H).

[0033] Step C: Compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.58 g, 4.5 mmol), N,N-diisopropylethylamine (1.75 g, 13.5 mmol), and 1-amino-4-piperidinol (0.58 g, 5.0 mmol) were added to 50 mL of isopropanol (suspension). The reaction was allowed to proceed for 16 hours under stirring at 95° C. After completion of the reaction, the mixture was cooled to room temperature, charged with 50 mL of water, and extracted with ethyl acetate (3×50 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound 1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-ol (0.91 g, 47% yield). LCMS ESI(+)m / z:432.2(M+1).

[0034] Step D: Compound 1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-ol (0.91 g, 2.1 mmol) was added to a mixture of 15 mL of ethanol and 5 mL of water (suspension), and ammonium chloride solid (0.45 g, 8.4 mmol) and iron powder (0.59 g, 10.5 mmol) were added in this order. The temperature was raised to 80° C. and stirred for 4.5 hours. After the reaction was completed, the reaction solution was filtered and the filter residue was washed with an appropriate amount of ethyl acetate. The filtrate was concentrated under reduced pressure, and the compound 1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-ol (0.75 g, yield 88%) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:402.2(M+1).

[0035] Step E: The compound 1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-ol (750 mg, 1.87 mmol) was dissolved in 10 mL of acetic acid, triethyl orthoformate (2.77 g, 18.7 mmol) was added, the mixture was heated to 116° C., and reacted for 0.5 hours with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain the compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-ol (453 mg, 59% yield). LCMS ESI(+)m / z:412.2(M+1).

[0036] Step F: Compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-ol (150 mg, 0.36 mmol) was dissolved in 10 mL of dichloromethane, methanesulfonyl chloride (82 mg, 0.72 mmol) and triethylamine (109 mg, 1.08 mmol) were added, and the mixture was reacted at room temperature for 1 hour with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure, and the compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl methanesulfonate (144 mg, 82% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:490.2(M+1).

[0037] Step G: The compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl methanesulfonate (95 mg, 0.19 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium cyanide (82 mg, 1.67 mmol) was added, the temperature was raised to 80 ° C, and the reaction was carried out for 16 hours while stirring under nitrogen gas protection. After the reaction was completed, an appropriate amount of aqueous sodium hydroxide was added and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and dried on a rotary evaporator to obtain the compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-4-carbonitrile (42 mg, 50% yield). LCMS ESI(+)m / z:421.2(M+1).

[0038] Step H: The compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-4-carbonitrile (42 mg, 0.1 mmol) was dissolved in 8 mL of methanol, potassium tert-butoxide (56 mg, 0.5 mmol) was added, and the mixture was reacted at room temperature for 6 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by high performance liquid chromatography to obtain the compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidine-4-carbonitrile (12 mg, yield 45%). 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.56(s,1H),8.49(s,1H),7.46(t,1H),6.84(dd,J=3.0,1.8Hz,1 LCMS ESI(+)m / z:267.2(M+1).

[0039] Example 2 [ka] 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0040] Step A: 1-Boc-4-cyanomethylpiperidine (5.0 g, 22.3 mmol) was dissolved in 20 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added slowly at 0° C. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the compound 4-cyanomethylpiperidine trifluoroacetate (5.53 g, 100% yield).

[0041] Step B: Compound 4-cyanomethylpiperidine trifluoroacetate (5.53 g, 20.0 mmol) and sodium nitrite (2.76 g, 40.0 mmol) were dissolved in 30 mL of water, and 5.0 mL of acetic acid was slowly added dropwise at 0°C. The mixture was reacted for 16 hours with stirring at 35°C. After the reaction was completed, the pH of the reaction solution was adjusted to 8 with sodium carbonate, and extracted five times with 250 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator to obtain compound 1-nitroso-4-cyanomethylpiperidine (5.3 g, 70% yield). LCMS ESI(+)m / z:154.1(M+1).

[0042] Step C: Compound 1-nitroso-4-cyanomethylpiperidine (5.2 g, 20.0 mmol) was dissolved in 15 mL of methanol, zinc powder (3.92 g, 60.0 mmol) was added, and 15 mL of acetic acid was slowly added dropwise at 0°C. After the addition was completed, the mixture was reacted for 3 hours while stirring at 30°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated with a rotary evaporator to obtain compound 1-amino-4-cyanomethylpiperidine (5.3 g, 60% yield). LCMS ESI(+)m / z:140.1(M+1).

[0043] Step D: The compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.51 g, 10.0 mmol), N,N-diisopropylethylamine (7.75 g, 60.0 mmol), and 1-amino-4-cyanomethylpiperidine (2.09 g, 15.0 mmol) were added to 200 mL of isopropanol (suspension). The mixture was reacted at 95° C. for 16 hours with stirring. After completion of the reaction, it was cooled to room temperature, added with 200 mL of water, extracted with ethyl acetate (3 x 250 mL), the organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated on a rotary evaporator, and purified by silica gel column chromatography to obtain compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (2.02 g, 44% yield). LCMS ESI(+) m / z: 455.1 (M+1).

[0044] Step E: Compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (1.37 g, 3.0 mmol) was added to a mixture of 60 mL of ethanol and 20 mL of water (suspension), and ammonium chloride solid (0.64 g, 12.0 mmol) and iron powder (0.67 g, 12.0 mmol) were added in this order. The temperature was raised to 80° C. and the mixture was stirred for 2.5 hours. After the reaction was completed, the reaction solution was filtered and the filter residue was washed with 50 mL of ethyl acetate. The filtrate was added with 50 mL of water and extracted with ethyl acetate (3×70 mL). The organic phases were combined, washed with 150 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (1.02 g, 80% yield). LCMS ESI(+)m / z: 425.1 (M+1).

[0045] Step F: The compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (424 mg, 1.0 mmol) was dissolved in 10 mL of acetic acid, triethyl orthoformate (1.48 g, 10 mmol) was added, the mixture was heated to 116° C., and reacted for 0.5 hours with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain the compound 2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (256 mg, 59% yield). LCMS ESI(+)m / z:435.2(M+1).

[0046] Step G: The compound 2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (95 mg, 0.2 mmol) was dissolved in 10 mL of tetrahydrofuran, 60% sodium hydride (40 mg, 1.0 mmol) was added, and the mixture was reacted at room temperature for 6 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (24 mg, yield 42%). 1 H NMR(400MHz,CDCl3)δ10.07(s,1H),8.81(s,1H),8.13(s,1H),7.40(s,1H),6.80(s,1H),3.56-3 .19(m,4H),2.48(d,J=6.4Hz,2H),2.13-2.08(m,2H),2.07-1.94(m,1H),1.91-1.75(m,2H).LCMS ESI(+)m / z:281.2(M+1).

[0047] Example 3 [ka] 2-(1-(methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0048] Step A: Triethyloxonium tetrafluoroborate (190 mg, 1.0 mmol) and acetamide (59 mg, 1.0 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours while stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (212 mg, 0.5 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour while stirring. After the reaction was completed, the mixture was quenched with saturated aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound 2-(1-(2-methyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (180 mg, 80% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 448.1(M+1).

[0049] Step B: The compound 2-(1-(2-methyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (180 mg, 0.4 mmol) was dissolved in 9 mL of methanol, 4 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (70 mg, yield 60%). 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.46(s,1H),7.48(t,J=3.0Hz,1H),6.70(dd,J=3.2Hz,1.6Hz,1H),3.57(t,J=10.2Hz,2 LCMS ESI(+)m / z:295.2(M+1).

[0050] Example 4 [ka] 2-(1-(ethylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0051] Step A: Triethyloxonium tetrafluoroborate (190 mg, 1.0 mmol) and propionamide (73 mg, 1.0 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours while stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (212 mg, 0.5 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour while stirring. After the reaction was completed, the mixture was quenched with saturated aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound 2-(1-(2-ethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (180 mg, 78% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 462.1 (M+1).

[0052] Step B: The compound 2-(1-(2-ethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (180 mg, 0.39 mmol) was dissolved in 9 mL of methanol, 4 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours while stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(2-ethylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (75 mg, yield 62%). 1H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.49(s,1H),7.48(t,J=3.0Hz,1H),6.71(dd,J=3.2Hz,1.6Hz,1H),3.59(t,J=10.2Hz,2H),3.12(d,J=1 0.2Hz,2H),2.92(q,J=7.5Hz,2H),2.65(d,J=6.4Hz,2H),2.16-2.05(m,1H),2.00-1.91(m,2H),1.68-1.56(m,2H),1.31(t,J=7.5Hz,3H).LCMS ESI(+)m / z:309.2(M+1).

[0053] Example 5 [ka] 2-(1-(2-(hydroxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0054] Step A: Triethyloxonium tetrafluoroborate (135 mg, 0.71 mmol) and hydroxyacetamide (53 mg, 0.71 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours with stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (100 mg, 0.24 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour with stirring. After completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound 2-(1-(2-(hydroxymethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (80 mg, 72% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 465.1(M+1).

[0055] Step B: The compound 2-(1-(2-(hydroxymethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (80 mg, 0.17 mmol) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(2-(hydroxymethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (20 mg, yield 38%). 1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.54(s,1H),7.50(t,J=3.0Hz,1H),6 .73(dd,J=3.2,1.8Hz,1H),5.31(t,J=6.0Hz,1H),5.16(q,J=6.6Hz,1H),4.7 0(d,J=6.0Hz,2H),3.57(t,J=10.2Hz,2H),3.15(dd,J=10.2Hz,2H),2.64(d, J=6.4Hz,2H),2.15-2.04(m,1H),1.98-1.89(m,2H),1.72-1.60(m,2H).LCMS ESI(+)m / z:311.2(M+1).

[0056] Example 6 [ka] 2-(1-(2-(2-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0057] Step A: Triethyloxonium tetrafluoroborate (135 mg, 0.71 mmol) and 3-hydroxypropionamide (64 mg, 0.71 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours with stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (100 mg, 0.24 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour with stirring. After completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound 2-(1-(2-(hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (60 mg, 52% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 479.1(M+1).

[0058] Step B: The compound 2-(1-(2-(hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (60 mg, 0.13 mmol) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(2-(hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (20 mg, yield 48%). 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.49(s,1H),7.48(d,J=3.4Hz,1H),6.71(d,J=3.4,1.8Hz,1H),4.80(brs,1H),3.84(t,J=7.0Hz ,2H),3.59(t,J=10.4Hz,2H),3.16-3.06(m,4H),2.65(d,J=6.4Hz,2H),2.15-2.04(m,1H),1.98-1.89(m,2H),1.72-1.60(m,2H).LCMS ESI(+)m / z:325.1(M+1).

[0059] Example 7 [ka] (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0060] Step A: Triethyloxonium tetrafluoroborate (251 mg, 1.32 mmol) and R-lactamide (118 mg, 1.32 mmol) were dissolved in 8 mL of tetrahydrofuran and reacted at room temperature for 2 hours with stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (189 mg, 0.44 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour with stirring. After completion of the reaction, the reaction was quenched with aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound (R)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (110 mg, 52% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:479.1(M+1).

[0061] Step B: The compound (R)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (110 mg, 0.23 mmol) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours while stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and prepared by silica gel column chromatography and high performance liquid chromatography to obtain the compound (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (30 mg, yield 40%). 1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.55(s,1H),7.50(d,J=3.4Hz,1H),6.73( d,J=3.4Hz,1H),5.31(s,1H),5.16(q,J=6.6Hz,1H),3.65-3.53(m,2H),3.15(dd, LCMS ESI(+)m / z:325.0(M+1).

[0062] Example 8 [ka] (S)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0063] Step A: Triethyloxonium tetrafluoroborate (298 mg, 1.56 mmol) and S-lactamide (140 mg, 1.56 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours with stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 5 mL of absolute ethanol containing compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (222 mg, 0.52 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour with stirring. After completion of the reaction, the mixture was quenched with saturated aqueous sodium bicarbonate solution, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound (S)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (160 mg, 64% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:479.1(M+1).

[0064] Step B: The compound (S)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (160 mg) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours while stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and prepared by silica gel column chromatography and high performance liquid chromatography to obtain the compound (S)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (44.6 mg, yield 41%). 1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.55(s,1H),7.50(d,J=3.4Hz,1H),6.73(d,J=3.4Hz,1H),5.31(s,1H),5.16(q,J=6.6Hz,1H),3.65-3.53( LCMS ESI(+)m / z:325.0(M+1).

[0065] Example 9 [ka] 2-(1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0066] Step A: 4-Hydroxymethylpiperidine (3.01 g, 26.1 mmol) and sodium nitrite (2.76 g, 40.0 mmol) were dissolved in 30 mL of water, and 4.0 mL of acetic acid was added dropwise slowly at 0°C. The mixture was reacted for 16 hours with stirring at 30°C. The pH of the reaction solution was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and extracted five times with 250 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated on a rotary evaporator to obtain the compound 1-nitroso-4-hydroxymethylpiperidine (2.87 g, 76% yield). LCMS ESI(+)m / z: 145.1 (M+1).

[0067] Step B: Compound 1-nitroso-4-hydroxymethylpiperidine (2.87 g, 20.0 mmol) was dissolved in 15 mL of methanol, zinc powder (5.23 g, 80.0 mmol) was added, and 15 mL of acetic acid was gradually added dropwise at 0°C. After the addition was completed, the mixture was reacted for 16 hours while stirring at room temperature. The reaction solution was filtered, and the filtrate was evaporated with a rotary evaporator to obtain the crude product compound 1-amino-4-hydroxymethylpiperidine (3.02 g, 65% yield). LCMS ESI(+)m / z:131.1(M+1).

[0068] Step C: The compounds 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.32 g, 6.6 mmol), N,N-diisopropylethylamine (3.41 g, 26.4 mmol), and 1-amino-4-hydroxymethylpiperidine (1.03 g, 7.9 mmol) were added to 60 mL of isopropanol (suspension). The mixture was reacted at 95° C. for 16 hours with stirring. After completion of the reaction, it was cooled to room temperature, charged with 100 mL of water, extracted with ethyl acetate (3 x 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (2.11 g, 71% yield). LCMS ESI(+)m / z: 446.2 (M+1).

[0069] Step D: The compound (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (1.5 g, 3.37 mmol) was dissolved in 30 mL of anhydrous dichloromethane, and triethylamine (1.02 g, 10.1 mmol) was added at 0° C., and methanesulfonyl chloride (465 mg, 4.06 mmol) was added dropwise, and the reaction was carried out at room temperature for 18 hours under nitrogen gas protection. After completion of the reaction, the reaction mixture was quenched with water at 0° C., extracted with dichloromethane (3×80 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (1.6 g, 91% yield). LCMS ESI(+) m / z: 524.1 (M+1).

[0070] Step E: The compound (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (300 mg, 0.57 mmol), iron powder (193 mg, 3.44 mmol), and ammonium chloride (61 mg, 1.15 mmol) were suspended in a mixture of 9 mL of ethanol and 3 mL of water, and stirred at 75° C. for 2 hours under nitrogen gas protection. After the reaction was completed, the mixture was filtered, dried on a rotary evaporator, and purified to obtain the product (1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (85 mg, 30% yield). LCMS ESI(+)m / z: 494.1 (M+1).

[0071] Step F: The compound (1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (80 mg, 0.16 mmol) and cyanogen bromide (0.08 mL) were dissolved in 10 mL of methanol, placed in a sealed tube, and stirred at 30° C. for 20 hours. After the reaction was completed, the mixture was dried using a rotary evaporator and purified by column chromatography to obtain the product (1-(2-amino-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl))methyl methanesulfonate (90 mg, 100% yield). LCMS ESI(+)m / z: 519.1 (M+1).

[0072] Step G: The compound (1-(2-amino-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl))methyl methanesulfonate (80 mg, 0.15 mmol), trimethylcyanosilane (31 mg, 0.31 mmol), and potassium carbonate were dissolved in 10 mL of N,N-dimethylformamide and stirred at room temperature for 20 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness on a rotary evaporator, and purified by column chromatography to obtain compound 2-(1-(2-amino-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (60 mg, 87% yield). LCMS ESI(+) m / z: 450.1 (M+1).

[0073] Step H: Compound 2-(1-(2-amino-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (60 mg, 0.13 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (10 mL), potassium carbonate (301 mg, 2.18 mmol) was added, and the mixture was stirred at room temperature for 18 hours under nitrogen gas protection. After the reaction was completed, the mixture was filtered, 20 mL of water was added, and the mixture was extracted with ethyl acetate (5 x 50 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and purified to obtain compound 2-(1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (20 mg, yield 51%). 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.11(s,1H),7.37(t,J=3.2Hz,1H),6.54(dd,J=3.2,2.0Hz,1H),6.24(s,1H),3.49(t, LCMS ESI(+)m / z:296.1(M+1).

[0074] Example 10 [ka] N-((1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)methanesulfonamide The form for carrying out the invention is as follows. [ka]

[0075] Step A: Under nitrogen gas, Boc-glycinamide (328 mg, 1.88 mmol) and triethyloxonium tetrafluoroborate (358 mg, 1.88 mmol) were added to 15 mL of anhydrous tetrahydrofuran and stirred at 30° C. for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 15 mL of ethanol, and compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (160 mg, 0.38 mmol) was added under nitrogen gas, and the mixture was reacted for 1 hour with stirring at 75° C. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate (15 mL) were added and stirred for 5 minutes. The organic phase was separated, and the aqueous phase was extracted three times with 45 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of water, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound tert-butyl-((1-(4-(cyanomethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate (200 mg, 94% yield). LCMS ESI(+)m / z:564.2(M+1).

[0076] Step B: Compound tert-butyl-((1-(4-(cyanomethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)carbamate (100 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (1 mL) was added dropwise under ice bath. The temperature was raised to room temperature under nitrogen gas protection and stirred for 4 hours. The reaction solution was concentrated under reduced pressure. 5 mL of saturated sodium bicarbonate solution was added and stirred for 5 minutes. Extraction was performed three times with 15 mL of dichloromethane. The organic phases were combined, washed with 5 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give compound 2-(1-(2-(aminomethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (82 mg, 100% yield). LCMS ESI(+)m / z: 464.1(M+1).

[0077] Step C: Compound 2-(1-(2-(aminomethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (82 mg, 0.06 mmol) was dissolved in 3 mL of dichloromethane, and triethylamine (54 mg, 0.53 mmol) and methanesulfonyl chloride (30 mg, 0.27 mmol) were added in an ice bath and nitrogen gas protection. The mixture was stirred for 2 hours in an ice bath. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. Extracted three times with 15 mL of dichloromethane, the organic phases were combined, washed with 3 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound N-((1-(4-(cyanomethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)methanesulfonamide (30 mg, 71% yield). LCMS ESI(+)m / z:542.1(M+1).

[0078] Step D: The compound N-((1-(4-(cyanomethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)methanesulfonamide (16 mg, 0.03 mmol) was dissolved in 3 mL of methanol, and 1N sodium hydroxide solution (1 mL, 1.0 mmol) was added. The mixture was stirred at 35° C. for 6 hours. The reaction solution was diluted with 9 mL of water, and methanol was distilled off under reduced pressure. The residue was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the compound N-((1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl)methanesulfonamide (48 mg, yield 51%). 1 H NMR(400MHz,DMSO-d6)δ11.96(s,1H),8.57(s,1H),7.60(s,1H),7.52(t,J=2.6Hz,1H),6.75(d,J=2.6Hz,1H),4.52(s,2H),3.57(t, LCMS ESI(+)m / z:388.1(M+1).

[0079] Example 11 [ka] 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile The form for carrying out the invention is as follows. [ka] Step A: 4-Piperidineethanol (21.1 g, 100 mmol) was dissolved in 200 mL of water and 90 mL of acetic acid, and sodium nitrite (41.4 g, 600 mmol) was dissolved in 200 mL of water. At 0°C, aqueous sodium nitrite solution was slowly added dropwise to the reaction system, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with 150 mL of ethyl acetate in three portions. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the compound 1-nitroso-4-piperidineethanol (9.5 g, yield 60%) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:159.1(M+1).

[0080] Step B: The compound 1-nitroso-4-piperidineethanol (8.0 g, 50.1 mmol) was dissolved in 40 mL of methanol, zinc powder (3.14 g, 48.0 mmol) was added, and 8 mL of acetic acid was added dropwise at room temperature. After the addition was completed, the mixture was reacted for 15 minutes while stirring at 30°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated with a rotary evaporator to obtain the crude product compound 1-amino-4-piperidineethanol (4.37 g, 60% yield). LCMS ESI(+)m / z:145.1(M+1).

[0081] Step C: Compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.46 g, 7.0 mmol), N,N-diisopropylethylamine (4.5 g, 35.0 mmol), and 1-amino-4-piperidineethanol (2.20 g, 10.0 mmol) were added to 200 mL of isopropanol (suspension). The reaction was allowed to proceed for 16 hours at 95° C. with stirring. After completion of the reaction, it was cooled to room temperature, charged with 300 mL of water, extracted with ethyl acetate (3 x 250 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethanol (1.97 g, 61% yield). LCMS ESI(+) m / z: 460.2 (M+1).

[0082] Step D: Compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethanol (1.17 g, 2.55 mmol) was dissolved in 50 mL of dichloromethane, and methanesulfonyl chloride (876 mg, 7.65 mmol) and triethylamine (1.28 g, 12.75 mmol) were added and reacted at room temperature for 2 hours with stirring. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethyl methanesulfonate (1.37 g, 100% yield). LCMS ESI(+)m / z:518.2(M+1).

[0083] Step E: Compound 2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethyl methanesulfonate (1.37 g, 3.0 mmol) was added to a mixture of 45 mL of ethanol and 15 mL of water (suspension), and ammonium chloride solid (0.64 g, 12.0 mmol) and iron powder (0.67 g, 12.0 mmol) were added in this order. The temperature was raised to 80° C. and the mixture was stirred for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filter residue was washed with an appropriate amount of ethyl acetate. The filtrate was charged with 50 mL of water and extracted with ethyl acetate (3 x 50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to give compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethyl methanesulfonate (1.26 g, 97% yield). LCMS ESI(+) m / z: 430.2 (M+1).

[0084] Step F: The compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)ethyl methanesulfonate (582 mg, 1.35 mmol) was dissolved in 25 mL of acetic acid, triethyl orthoformate (1.00 g, 6.75 mmol) was added, the mixture was heated to 116° C., and reacted for 1 hour with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure, and the compound 2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)ethyl methanesulfonate (253 mg, 42% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:440.2(M+1).

[0085] Step G: The compound 2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)ethyl methanesulfonate (253 mg, 0.45 mmol) was dissolved in 16 mL of N,N-dimethylformamide, and potassium carbonate (187 mg, 1.35 mmol) and trimethylcyanosilane (134 mg, 1.35 mmol) were added. The temperature was raised to 100°C, and the reaction was carried out for 20 hours while stirring under nitrogen gas protection. After completion of the reaction, an appropriate amount of aqueous sodium hydroxide was added, and the mixture was extracted with ethyl acetate (3×100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and purified by column chromatography to obtain compound 3-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile (97 mg, 48% yield). LCMS ESI(+)m / z:449.2(M+1).

[0086] Step H: The compound 3-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile (97 mg, 0.22 mmol) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at room temperature for 16 hours with stirring. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile (30 mg, yield 48%). 1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),8.58(s,1H),8.55(s,1H),7.44(t,J=2.8Hz,1H),6.73(dd,J=3.1,1.9Hz ,1H),3.36-3.33(m,1H),3.31-3.26(m,3H),2.61(t,J=7.0Hz,2H),1.96-1.90(m,2H),1.71-1.46(m,5H).LCMS ESI(+)m / z:295.2(M+1).

[0087] Example 12 [ka] 6-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile The form for carrying out the invention is as follows. [ka]

[0088] Step A: Diethyl(cyanomethyl)phosphonate (3.72 g, 21.0 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and 60% sodium hydride (0.84 g, 21 mmol) was added at 0° C., and the mixture was reacted at this temperature for 0.5 hours. A lithium aluminum hydride solution (10 mL) containing tert-butyl 4-oxopiperidine-1-carboxylate (2.09 g, 10.5 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was quenched with water at 0° C., extracted with ethyl acetate (240 mL) three times, dried, dried on a rotary evaporator, and purified to obtain the product tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (2.2 g, 94% yield). 1 H NMR(400MHz, CDCl3)δ5.19(s,1H),3.54-3.48(m,4H),2.56(t,J=6.0Hz,1H),2.33(t,J=6.0Hz,1H).

[0089] Step B: Potassium tert-butoxide (1.11 g, 9.9 mmol) was dissolved in 20 mL of dimethyl sulfoxide, trimethylsulfoxonium iodide (2.18 g, 9.9 mmol) was gradually added, and the mixture was allowed to react at room temperature for 1.5 hours. A dimethyl sulfoxide solution containing 4-(cyanomethylene)piperidine-1-carboxylate tert-butyl (2.0 g, 9.0 mmol) was added to the reaction solution, and the mixture was heated to 45°C under nitrogen gas protection and stirred for 16 hours. After the reaction was completed, the mixture was quenched with an aqueous ammonium chloride solution, extracted three times with ethyl acetate (240 mL), dried, dried on a rotary evaporator, and purified to obtain the product 1-cyano-6-azaspiro[2,4]octane-6-carboxylate tert-butyl (1.8 g, 85% yield). LCMS ESI(+)m / z:237.1(M+1).

[0090] Step C: The compound 1-cyano-6-azaspiro[2,4]octane-6-carboxylate tert-butyl (1.8 g, 7.6 mmol) was dissolved in 20 mL of dichloromethane, and trifluoroacetic acid (2 mL) was added dropwise in an ice bath, and the mixture was heated to 75° C. and stirred for 18 hours. After the reaction was completed, the mixture was dried on a rotary evaporator to obtain the crude product 6-aza-spiro[2.5]octane-1-carbonitrile trifluoroacetate (1.0 g, 97% yield). LCMS ESI(+)m / z:137.1(M+1).

[0091] Step D: Compound 6-aza-spiro[2.5]octane-1-carbonitrile trifluoroacetate (1.0g, 7.4mmol) was dissolved in 10mL of water and 1mL of glacial acetic acid, and an aqueous solution containing sodium nitrite (1.0g, 14.7mmol) was added dropwise in an ice bath, and the mixture was stirred at room temperature for 20 hours. After the reaction was completed, the mixture was quenched with an aqueous solution of sodium bicarbonate, extracted three times with ethyl acetate (240mL), dried on a rotary evaporator, and purified to obtain compound 6-nitroso-6-aza-spiro[2.5]octane-1-carbonitrile (0.6g, 50% yield). LCMS ESI(+)m / z:166.1.

[0092] Step E: 6-Nitroso-6-aza-spiro[2.5]octane-1-carbonitrile (0.3 g, 1.8 mmol) and zinc powder (1.17 g, 18 mmol) were suspended in methanol (5 mL) and acetic acid (0.5 mL) and stirred for 2 hours at room temperature under nitrogen gas protection. After the reaction was completed, the mixture was filtered and dried on a rotary evaporator to obtain the product 6-amino-6-azaspiro[2.5]octane-1-carbonitrile (274 mg, 100% yield). LCMS ESI(+)m / z:152.1(M+1)

[0093] Step F: The compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (634 mg, 1.8 mmol), N,N-diisopropylethylamine (2.32 g, 18 mmol) and 6-amino-6-azaspiro[2.5]octane-1-carbonitrile (274 mg, 1.8 mmol) were added to 10 mL of isopropanol (suspension). The reaction was carried out at 95° C. for 18 hours with stirring. After completion of the reaction, it was cooled to room temperature, charged with 100 mL of water, extracted with ethyl acetate (3 x 100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound 6-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-6-azaspiro[2.5]octane-1-carbonitrile (430 mg, 51% yield). LCMS ESI(+) m / z: 467.1 (M+1).

[0094] Step G: The compound 6-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-6-azaspiro[2.5]octane-1-carbonitrile (430 mg, 0.92 mmol) was placed in a mixture of 20 mL of ethanol and 4 mL of water (suspension), and ammonium chloride solid (99 mg, 1.84 mmol) and iron powder (300 mg, 5.54 mmol) were added in this order. The temperature was raised to 80° C. and the mixture was stirred for 3 hours. After the reaction was completed, the reaction solution was filtered, and the filter residue was washed with an appropriate amount of ethyl acetate. The filtrate was charged with 20 mL of water and extracted with ethyl acetate (3 x 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to give compound 6-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-6-azaspiro[2.5]octane-1-carbonitrile (347 mg, 62% yield). LCMS ESI(+) m / z: 437.1 (M+1).

[0095] Step H: The compound 6-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-6-azaspiro[2.5]octane-1-carbonitrile (230 mg, 0.53 mmol) was dissolved in 5 mL of acetic acid, triethyl orthoformate (392 mg, 2.65 mmol) was added, the temperature was raised to 116° C., and the reaction was carried out for 2 hours while stirring. After the reaction was completed, the mixture was concentrated under reduced pressure, and the compound 6-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (120 mg, 51% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:446.1(M+1).

[0096] Step I: The compound 6-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (110 mg, 0.25 mmol) was placed in a mixed solvent of 10 mL of methanol and 10 mL of dichloromethane, potassium carbonate (681 mg, 4.9 mmol) was added, and the mixture was stirred at room temperature for 18 hours under nitrogen gas protection. After the reaction was completed, the mixture was filtered, 20 mL of water was added, and the mixture was extracted with ethyl acetate (5 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness on a rotary evaporator. The product was purified by high performance liquid chromatography to obtain compound 6-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (20 mg, yield 28%). 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.59(s,1H),8.57(s,1H),7.47(t,J=3.0Hz,1H),6 .77(dd,J=3.2,2.0Hz,1H),3.41-3.32(m,4H),2.09-1.78(m,5H),1.27-1.19(m,2H).LCMS ESI(+)m / z:293.1(M+1).

[0097] Example 13 [ka] 6-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile The form for carrying out the invention is as follows. [ka]

[0098] Step A: Triethyloxonium tetrafluoroborate (1.31g, 6.9mmol) and R-lactamide (612mg, 6.9mmol) were dissolved in 20mL of tetrahydrofuran and reacted for 2 hours at room temperature while stirring. Concentrated under reduced pressure to obtain a colorless oil, which was dissolved in 10mL of absolute ethanol and added to 10mL of absolute ethanol in which compound 6-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-6-azaspiro[2.5]octane-1-carbonitrile (504mg, 1.11mmol) was dissolved. The temperature was raised to 75°C and the reaction was allowed to proceed for 1 hour while stirring. After the reaction was completed, the mixture was quenched with aqueous sodium bicarbonate, added with 100 mL of water, extracted with ethyl acetate (3 x 100 mL), and the organic phases were combined, washed with 200 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, and the filtrate was concentrated under reduced pressure, and the compound 6-(2-((R)-1-hydroxyethyl)6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (590 mg, 52% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:490.1(M+1).

[0099] Step B: The compound 6-(2-((R)-1-hydroxyethyl)6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (290 mg, 0.59 mmol) was dissolved in 15 mL of methanol, 5 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted for 6 hours with stirring at 30 ° C. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and prepared by silica gel column chromatography and high performance liquid chromatography to obtain the compound 6-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azaspiro[2.5]octane-1-carbonitrile (80 mg, yield 28%). 1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.64(s,1H),7.64(t,J=2.8Hz,1H),7.47(d,J=8.0Hz,1H),6.68(dd,J=3.3,1.8Hz,1H),5.26(q,J=6 .4Hz,1H),3.78-3.62(m,2H),3.33-3.16(m,2H),2.43-2.22(m,2H),1.60(d,J=6.6Hz,3H),1.49(d,J=13.8Hz,1H),1.40-1.21(m,4H).LCMS ESI(+)m / z:337.1(M+1).

[0100] Example 14 [ka] 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile The form for carrying out the invention is as follows. [ka]

[0101] Step A: 1-Boc-4-cyanomethylpiperidine (4.5g, 20.0mmol) was dissolved in 130mL of anhydrous tetrahydrofuran, and sodium bis(trimethylsilyl)amide in tetrahydrofuran (2M, 30mL, 60.0mmol) was added dropwise under nitrogen gas protection and ice bath conditions. After the addition was completed, the mixture was stirred for 10 minutes under ice bath conditions, and iodomethane (6.53g, 46.0mmol) was diluted with 20mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction solution. After the addition was completed, the mixture was reacted for 16 hours at room temperature with stirring under nitrogen gas protection. The reaction solution was quenched with an appropriate amount of saturated ammonium chloride solution, added with 150mL of water, and extracted with 600mL of ethyl acetate in three portions. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product compound tert-butyl 4-(2-cyanoprop-2-yl)piperidine-1-carboxylate (4.02 g, 79% yield).

[0102] Step B: Compound 4-(2-cyanoprop-2-yl)piperidine-1-carboxylate tert-butyl (4.02 g, 15.0 mmol) was dissolved in 30 mL of dichloromethane, and 15 mL of trifluoroacetic acid was gradually added at 0° C. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to obtain compound 2-methyl-2-(piperidin-4-yl)propanenitrile trifluoroacetate (3.79 g, 100% yield).

[0103] Step C: Compound 2-methyl-2-(piperidin-4-yl)propanenitrile trifluoroacetate (3.79 g, crude product, 15.0 mmol) and sodium nitrite (1.55 g, 22.5 mmol) were dissolved in 50 mL of water, and 2.6 mL of acetic acid was slowly added dropwise at 0° C. The mixture was reacted for 16 hours with stirring at 35° C. The pH of the reaction solution was adjusted to 8 with sodium carbonate, and the mixture was extracted five times with 250 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated on a rotary evaporator to obtain compound 2-(1-nitrosopiperidin-4-yl)-2-methylpropanenitrile (2.01 g, 74% yield). LCMS ESI(+)m / z:182.1(M+1).

[0104] Step D: Compound 2-(1-nitrosopiperidin-4-yl)-2-methylpropanenitrile (1.00 g, 5.0 mmol) was dissolved in 30 mL of methanol, and zinc powder (4.71 g, 88.0 mmol) and 6 mL of acetic acid were added, followed by stirring at 30° C. for 25 minutes. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-(1-aminopiperidin-4-yl)-2-methylpropanenitrile (4.73 g, 80% yield). LCMS ESI(+)m / z: 168.2 (M+1).

[0105] Step E: Compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.11 g, 6.0 mmol), N,N-diisopropylethylamine (3.88 g, 30.0 mmol) and 2-(1-aminopiperidin-4-yl)-2-methylpropanenitrile (1.01 g, 6.0 mmol) were added to 150 mL of isopropanol (suspension). The mixture was reacted at 95° C. for 16 hours with stirring. After completion of the reaction, it was cooled to room temperature, added with 250 mL of water, extracted with ethyl acetate (3 x 250 mL), the organic phases were combined, washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated on a rotary evaporator, and purified by silica gel column chromatography to obtain compound 2-methyl-2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)propanenitrile (1.47 g, 50% yield). LCMS ESI(+) m / z: 483.1 (M+1).

[0106] Step F: Compound 2-methyl-2-(1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)propanenitrile (1.47 g, 3.0 mmol) was placed in a mixture of 75 mL of ethanol and 25 mL of water (suspension), and ammonium chloride solid (0.64 g, 12.0 mmol) and iron powder (0.67 g, 12.0 mmol) were added in this order. The temperature was raised to 80° C. and stirred for 2 hours. After the reaction was completed, the reaction solution was filtered and the filter residue was washed with 50 mL of ethyl acetate. The filtrate was added with 50 mL of water and extracted with ethyl acetate (3×150 mL), and the organic phases were combined, washed with 150 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain the crude product compound 2-methyl-2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)propanenitrile (1.74 g). LCMS ESI(+)m / z: 453.1 (M+1).

[0107] Step G: The compound 2-methyl-2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)propanenitrile (540 mg, 1.2 mmol) was dissolved in 30 mL of acetic acid, triethyl orthoformate (890 mg, 6.00 mmol) was added, the mixture was heated to 116° C., and reacted for 45 minutes with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain the compound 2-methyl-2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile (301 mg, 54% yield). LCMS ESI(+)m / z:463.1(M+1).

[0108] Step H: The compound 2-methyl-2-(1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)propanenitrile (301 mg, 0.65 mmol) was dissolved in 12 mL of methanol and 6 mL of tetrahydrofuran, and 4 mL of 1N aqueous sodium hydroxide solution was added and reacted for 6 hours with stirring at 35 ° C. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and prepared by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile (71 mg, yield 35%). 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.56(s,1H),8.53(s,1H),7.46(t,J=2.9Hz,1H),6.74(dd ,J=3.3,1.9Hz,1H),3.40-3.33(m,4H),2.09-1.99(m,2H),1.76-1.60(m,3H),1.38(s,6H).LCMS ESI(+)m / z:309.0(M+1).

[0109] Example 15 [ka] (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile The form for carrying out the invention is as follows. [ka]

[0110] Step A: Triethyloxonium tetrafluoroborate (633 mg, 3.33 mmol) and R-lactamide (297 mg, 3.33 mmol) were dissolved in 10 mL of tetrahydrofuran and reacted at room temperature for 2 hours with stirring. Concentration under reduced pressure gave a colorless oil, which was dissolved in 5 mL of absolute ethanol and added to 10 mL of absolute ethanol containing compound 2-methyl-2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)propanenitrile (504 mg, 1.11 mmol). The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour with stirring. After completion of the reaction, the reaction was quenched with aqueous sodium bicarbonate solution, 50 mL of water was added, and the mixture was extracted with ethyl acetate (3×50 mL), and the organic phases were combined, washed with 100 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The compound (R)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile (289 mg, 57% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:507.2(M+1).

[0111] Step D: The compound (R)-2-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile (289 mg, 0.57 mmol) was dissolved in 15 mL of methanol, 5 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted for 6 hours with stirring at 30 ° C. After the reaction was completed, the pH was adjusted to 7-8 with acetic acid, concentrated under reduced pressure, and prepared by silica gel column chromatography and high performance liquid chromatography to obtain the compound (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)-2-methylpropanenitrile (110 mg, yield 54%). 1 H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.55(s,1H),7.50(t,J=3.0Hz,1H),6 .74(dd,J=3.3,1.8Hz,1H),5.30(d,J=6.3Hz,1H),5.21-5.13(m,1H),3.66- 3.51(m,2H),3.20(dd,J=30.4,10.2Hz,2H),2.02(d,J=10.7Hz,2H),1.88(t ,J=12.0Hz,1H),1.74-1.61(m,2H),1.57(d,J=6.6Hz,3H),1.40(s,6H).LCMS ESI(+)m / z:353.2(M+1).

[0112] Example 16 [ka] 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-ylidene)acetonitrile The form for carrying out the invention is as follows. [ka]

[0113] Step A: Dess-Martin periodinane (2.5 g, 6 mmol) was suspended in 50 mL of dichloromethane, and the compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-ol (1.2 g, 3 mmol) was added, and the mixture was stirred at room temperature for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was dried using a rotary evaporator and purified by column chromatography to obtain the compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-one (550 mg, yield 45%). LCMS ESI(+)m / z:410.1(M+1).

[0114] Step B: The compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-one (110 mg, 0.27 mmol) was dissolved in 12 mL of methanol, and an aqueous solution of sodium hydroxide (2N, 3 mL) was added at 0° C., and the mixture was stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with dichloromethane (5×50 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and purified to obtain the compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-one (50 mg, 73% yield). 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.62(s,1H),8.56(s,1H),7.47(t,J=3.0Hz,1H),6.92 (dd,J=3.6,2.0Hz,1H),3.64-3.26(m,4H),2.72-1.88(m,4H).LCMSESI(+)m / z:256.1(M+1).

[0115] Step C: Diethyl cyanomethylphosphonate (53 mg, 0.3 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran, and 60% sodium hydride (24 mg, 0.6 mmol) was added at 0°C under nitrogen gas protection and stirred for 30 minutes. Compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-one (37 mg, 0.15 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran and added to the reaction solution, and the reaction was carried out at room temperature under nitrogen gas protection with stirring for 3 hours. After the reaction was completed, an appropriate amount of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and purified to obtain compound 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-ylidene)acetonitrile (15 mg, yield 39%). 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.60(s,1H),8.56(s,1H),7.45(d,J=3.2Hz,1H),6.79 (d,J=3.2Hz,1H),5.74(s,1H),3.42-3.33(m,4H),2.86-2.83(m,2H),2.74-2.71(m,2H).LCMS ESI(+)m / z:279.1(M+1).

[0116] Example 17 [ka] 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0117] Step A: Compound ethyl 4-methyl-4-piperidinecarboxylate hydrochloride (2.0 g, 9.6 mmol) was dissolved in 10 mL of water. At 0°C, sodium nitrite (1.66 g, 24.1 mmol) was added, and acetic acid (1.16 g, 19.2 mmol) was added dropwise. The mixture was stirred at 30°C overnight. After the reaction was completed, the reaction solution was cooled to 0°C, and the pH of the solution was adjusted to 7-8 with sodium bicarbonate, extracted with ethyl acetate (2 x 20 mL), the organic phases were combined, washed with brine (40 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and dried on a rotary evaporator to obtain yellow oily compound ethyl 1-nitroso-4-methyl-4-piperidinecarboxylate (1.91 g, 99% yield). LCMS ESI(+) m / z: 201.1 (M+1).

[0118] Step B: The compound 1-nitroso-4-methyl-4-piperidine carboxylate ethyl (1.91 g, 9.5 mmol) was dissolved in 50 mL of tetrahydrofuran. At 0°C, 2.5 M lithium aluminum hydride solution (11.4 mL, 28.6 mmol) was gradually added. The mixture was stirred at room temperature for 3 hours under nitrogen gas. After the reaction was completed, the reaction solution was cooled to 0°C, water (1.1 mL) was gradually added, and then 15% sodium hydroxide (1.1 mL) and water (3.3 mL) were added. The mixture was stirred at room temperature for 15 minutes, filtered, dried on a rotary evaporator, and purified by column chromatography to obtain the compound 1-amino-4-methyl-4-hydroxymethylpiperidine (1.15 g, 80% yield). LCMS ESI (+) m / z: 145.1 (M+1).

[0119] Step C: Compound 1-amino-4-methyl-4-hydroxymethylpiperidine (806 mg, 5.6 mmol), compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (966 mg, 2.8 mmol) and N,N-diisopropylethylamine (2.13 g, 16.5 mmol) were dissolved in 50 mL of isopropanol, and the reaction solution was stirred at 88 ° C overnight. After the reaction was completed, the reaction solution was dried on a rotary evaporator and purified by column chromatography to obtain a yellow solid compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (787 mg, yield 62%). LCMS ESI (+) m / z: 460.1 (M+1).

[0120] Step D: The compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (2.69 g, 5.9 mmol) was dissolved in 30 mL of dichloromethane, and triethylamine (1.19 g, 11.7 mmol) and methanesulfonyl chloride (805 mg, 7.0 mmol) were added and stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was dried on a rotary evaporator and purified by column chromatography to obtain a yellow solid compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (3.06 g, yield 97%). LCMS ESI(+)m / z:538.0(M+1).

[0121] Step E: The compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (2.96 g, 5.5 mmol) was dissolved in 90 mL of ethanol, and iron powder (2.46 g, 44.1 mmol) and a solution of ammonium chloride (2.36 g, 44.1 mmol) dissolved in water (30 mL) were added, and the mixture was stirred at 80 ° C. for 2 hours. After the reaction was completed, the reaction solution was filtered, dried on a rotary evaporator, and purified by column chromatography to obtain the solid compound (4-methyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (2.14 g, yield 77%). LC-MS: m / z 508.1 (M+1).

[0122] Step F: The compound (4-methyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (1.3 g, 2.5 mmol) was dissolved in 40 mL of acetic acid, triethyl orthoformate (1.85 g, 12.5 mmol) was added, and the mixture was heated to 116° C. and stirred for 45 minutes. After the reaction was completed, the reaction solution was dried on a rotary evaporator and purified by column chromatography to obtain the solid compound (4-methyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)methyl methanesulfonate (1.24 g, 94% yield). LCMS ESI(+)m / z:518.0(M+1).

[0123] Step G: The compound (4-methyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)methyl methanesulfonate (100 mg, 0.19 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and sodium cyanide (47 mg, 0.97 mmol) was added and stirred at 120 ° C. for 16 hours. After the reaction was completed, the reaction solution was dried with a rotary evaporator, purified and prepared by column chromatography to obtain the compound 2-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)acetonitrile (28 mg, yield 49%). 1 H NMR(400MHz,CDCl3)δ9.72(s,1H),8.80(s,1H),8.17(s,1H),7.38(t,J=2.8Hz,1H),6.82(dd,J=3.1,2.1Hz,1H ),3.52-3.36(m,2H),3.36-3.24(m,2H),2.49(s,2H),2.04-1.98(m,2H),1.90-1.82(m,2H),1.37(s,3H).LCMS ESI(+)m / z:295.1(M+1).

[0124] Example 18 [ka] (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0125] Step A: R-Lactamide (263 mg, 2.96 mmol) and triethyloxonium tetrafluoroborate (561 mg, 2.96 mmol) were dissolved in 10 mL of tetrahydrofuran and stirred for 2 hours at 28° C. The oily product dried on a rotary evaporator and the compound (4-methyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (500 mg, 0.99 mmol) were dissolved in ethanol (30 mL) and stirred at 75° C. for 2 hours. After the reaction was completed, the reaction solution was dried using a rotary evaporator and purified by column chromatography to obtain the compound (R)-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)methyl methanesulfonate (337 mg, yield 60%). LCMS ESI(+)m / z: 548.0 (M+1).

[0126] Step B: The compound (R)-(1-(2-(1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)methyl methanesulfonate (200 mg, 0.36 mmol), trimethylcyanosilane (106 mg, 1.07 mmol) and potassium carbonate (148 mg, 1.07 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and the reaction solution was stirred at 120° C. for 72 hours. After the reaction was completed, 30 mL of water was added, extracted with dichloromethane (3×30 mL), and the organic phase was combined, washed with brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and dried on a rotary evaporator to prepare the compound (R)-2-(1-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-4-yl)acetonitrile (48 mg, yield 40%). 1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.55(s,1H),7.55(t,J=3.0Hz,1H),6.64(dd,J=3.2,2.0Hz,1H),5.28(d,J=6.0Hz,1H), 5.20-5.14(m,1H),3.65-3.60(m,2H),3.60-3.55(m,2H),2.68(s,2H),1.96-1.94(m,2H),1.88-1.80(m,2H),1.35(s,3H).LCMS ESI(+)m / z:339.1(M+1).

[0127] Example 19 [ka] 2-(4-Hydroxy-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0128] Step A: Lithium diisopropylamide (2M, 50mL, 100.0mmol) was placed in 150mL of tetrahydrofuran, and acetonitrile (4.10g, 100.0mmol) was added at -78℃ under nitrogen gas protection, and stirred for 1 hour under the condition of maintaining -78℃. Then, N-Boc-4-piperidone (10.0g, 50.0mmol) was dissolved in 50mL of tetrahydrofuran and added dropwise to the reaction system. After the addition was completed, the temperature was gradually raised to room temperature and the reaction was maintained for 1 hour. After the reaction was completed, the reaction was quenched with an appropriate amount of saturated aqueous ammonium chloride solution, 150mL of water was added, and the reaction was extracted three times with 600mL of ethyl acetate. The organic phases were combined, washed with 300mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound N-Boc-4-cyanomethyl-4-hydroxypiperidine (6.2 g, 52% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 241.2 (M+1).

[0129] Step B: Compound N-Boc-4-cyanomethyl-4-hydroxypiperidine (6.2 g, 25.8 mmol) was dissolved in 60 mL of dichloromethane, and 15 mL of trifluoroacetic acid was added under the condition of 0°C. After the dropwise addition was completed, the reaction was carried out for 5 hours while stirring at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 4-(cyanomethyl)-4-hydroxypiperidine trifluoroacetate (5.12 g, yield 97%). LCMS ESI(+)m / z: 141.1 (M+1).

[0130] Step C: Compound 4-(cyanomethyl)-4-hydroxypiperidine trifluoroacetate (5.12 g, 25.0 mmol) was dissolved in 30 mL of water and 50 mL of acetic acid, and sodium nitrite (2.59 g, 37.5 mmol) was dissolved in 15 mL of water. At 0°C, sodium nitrite aqueous solution was gradually added dropwise to the reaction system, and the reaction was carried out at room temperature for 16 hours while stirring. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the compound 1-nitroso-4-(cyanomethyl)-4-hydroxypiperidine (2.60 g, yield 61%) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:170.1(M+1).

[0131] Step D: Compound 1-nitroso-4-(cyanomethyl)-4-hydroxypiperidine (2.30 g, 13.5 mmol) was dissolved in 100 mL of methanol, zinc powder (17.8 g, 272.0 mmol) was added, and 20 mL of acetic acid was added dropwise at room temperature. After the addition was completed, the mixture was reacted for 15 minutes while stirring at 30°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated on a rotary evaporator to obtain the crude product compound 1-amino-4-(cyanomethyl)-4-hydroxypiperidine (1.78 g, 85% yield). LCMS ESI(+)m / z:156.1(M+1).

[0132] Step E: Compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (4.02 g, 11.4 mmol), N,N-diisopropylethylamine (5.89 g, 45.6 mmol) and 1-amino-4-(cyanomethyl)-4-hydroxypiperidine (1.78 g, 11.4 mmol) were added to 150 mL of isopropanol (suspension). The reaction was carried out at 95°C (oil bath temperature) for 16 hours while stirring. After the reaction was completed, the mixture was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with 600 mL of ethyl acetate in three portions. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated and purified to give compound 2-(4-hydroxy-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (3.25 g, 61% yield). LCMS ESI(+) m / z: 471.2 (M+1).

[0133] Step F: Compound 2-(4-hydroxy-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (3.25 g, 3.9 mmol) was added to a mixture of 90 mL of ethanol and 30 mL of water (suspension), and ammonium chloride solid (0.88 g, 16.55 mmol) and iron powder (0.92 g, 16.55 mmol) were added in this order. The temperature was raised to 80° C. and stirred for 2.5 hours. After the reaction was completed, the reaction solution was filtered and the filter residue was washed with 50 mL of ethyl acetate. The filtrate was added with 50 mL of water and extracted with 240 mL of ethyl acetate three times. The organic phases were combined, washed with 100 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)4-hydroxypiperidin-4-yl)acetonitrile (1.88 g, 62%) was obtained by silica gel column chromatography. LCMS ESI(+)m / z: 441.2 (M+1).

[0134] Step G: Compound 2-(1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)4-hydroxypiperidin-4-yl)acetonitrile (562 mg, 1.28 mmol) was dissolved in 25 mL of acetic acid, triethyl orthoformate (948 mg, 6.40 mmol) was added, the mixture was heated to 116° C., and stirred for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound 2-(4-hydroxy-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)acetonitrile (360 mg, 62% yield). LCMS ESI(+)m / z:426.2(M+1).

[0135] Step H: 2-(4-hydroxy-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)acetonitrile (360 mg, 0.80 mmol) was dissolved in 15 mL of methanol and 5 mL of tetrahydrofuran, and 5 mL of 2N aqueous sodium hydroxide solution was added and reacted for 16 hours with stirring at room temperature. The pH value of the reaction solution was adjusted to 8-9 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the compound 2-(4-hydroxy-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)acetonitrile (60 mg, yield 26%). 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.76-8.16(m,2H),7.48(s,1H),6.90(s,1H),5.45(s,1H),3. 85-3.54(m,2H),3.08(d,J=9.9Hz,2H),2.81(s,2H),2.03-1.91(m,2H),1.86(d,J=12.2Hz,2H).LCMS ESI(+)m / z:297.1(M+1).

[0136] Example 20 [ka] 2-(8-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile The form for carrying out the invention is as follows. [ka]

[0137] Step A: Nortropine (3.01 g, 26.13 mmol) was dissolved in 80 mL of water, and 80 mL of concentrated hydrochloric acid was added at 0° C., and sodium nitrite (43.5 g, 630.2 mmol) was added in portions at 30° C. The mixture was reacted for 16 hours under continuous stirring at 30° C. After the reaction was completed, the mixture was extracted with 600 mL of ethyl acetate in four portions. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated on a rotary evaporator and purified by silica gel column chromatography to obtain the compound 8-nitroso-8-azabicyclo[3.2.1]octan-3-ol (8.62 g, 70% yield). LCMS ESI(+)m / z:157.1(M+1).

[0138] Step B: The compound 8-nitroso-8-azabicyclo[3.2.1]octan-3-ol (7.0 g, 44.8 mmol) was dissolved in 150 mL of methanol, zinc powder (29.3 g, 448.0 mmol) was added, and 30 mL of acetic acid was added dropwise at 0°C. After the addition was completed, the mixture was reacted for 20 minutes while stirring at 30°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was evaporated on a rotary evaporator to obtain the crude product compound 8-amino-8-azabicyclo[3.2.1]octan-3-ol (3.43 g, 54% yield). LCMS ESI(+)m / z:143.1(M+1).

[0139] Step C: The compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.52 g, 10.0 mmol), N,N-diisopropylethylamine (5.17 g, 40.0 mmol) and 8-amino-8-azabicyclo[3.2.1]octan-3-ol (1.72 g, 12.0 mmol) were added to 150 mL of isopropanol (suspension). The reaction was carried out at 95° C. for 16 hours with stirring. After completion of the reaction, it was cooled to room temperature, charged with 300 mL of water, extracted with ethyl acetate (3 x 250 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary evaporated to dryness, and purified by column chromatography to obtain compound 8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ol (3.17 g, 70% yield). LCMS ESI(+) m / z: 458.2 (M+1).

[0140] Step D: Compound 8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ol (3.17 g, 7.0 mmol) was placed in a mixture of 120 mL of ethanol and 40 mL of water (suspension), and ammonium chloride solid (1.50 g, 28.0 mmol) and iron powder (1.56 g, 28.0 mmol) were added in that order. The temperature was raised to 80° C. and the mixture was stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter residue was washed with an appropriate amount of ethyl acetate, 200 mL of water was added to the filtrate, and it was extracted with ethyl acetate (3 x 250 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator, and purified by column chromatography to obtain compound 8-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ol (3.02 g, 100% yield). LCMS ESI(+) m / z: 428.2 (M+1).

[0141] Step E: The compound 8-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ol (2.95 g, 6.9 mmol) was dissolved in 80 mL of acetic acid, triethyl orthoformate (5.11 g, 34.5 mmol) was added, the mixture was heated to 116° C., and reacted for 1 hour with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure, and the compound 8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ol (2.31 g, 77% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:438.2(M+1).

[0142] Step F: Dess-Martin periodinane (3.01 g, 7.1 mmol) was dissolved in 80 mL of dichloromethane, and compound 8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ol (2.05 g, 4.7 mmol) was dissolved in 20 mL of dichloromethane, added dropwise to the reaction solution, and reacted at room temperature for 2 hours with stirring. After completion of the reaction, the reaction solution was washed with 60mL of saturated aqueous sodium bicarbonate solution and 60mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-one (1.3g, yield 64%). LCMS ESI(+)m / z:436.2(M+1).

[0143] Step G: Diethyl cyanomethylphosphonate (798 mg, 4.5 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, protected with nitrogen gas, and stirred for 30 minutes at 0 ° C. with 60% sodium hydride (180 mg, 4.5 mmol). Compound 8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-one (1.31 g, 3.0 mmol) was dissolved in 15 mL of anhydrous tetrahydrofuran and added to the reaction solution, and the reaction was carried out at room temperature for 2 hours with stirring under nitrogen gas protection. After the reaction was completed, an appropriate amount of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×50 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator, and purified by column chromatography to obtain compound 2-(8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (879 mg, 64% yield). LCMS ESI(+)m / z:459.2(M+1).

[0144] Step H: The compound 2-(8-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (820 mg, 1.8 mmol) was dissolved in 24 mL of methanol and 8 mL of tetrahydrofuran, and 8 mL of 1N aqueous sodium hydroxide solution was added and reacted for 16 hours with stirring at 35 ° C. After the reaction was completed, the pH was adjusted to 8-9 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the compound 2-(8-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (302 mg, yield 55%). 1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),8.55(s,1H),8.26(s,1H),7.43(t,J=2.9Hz,1H),6.90(dd,J=3.2,1.9Hz,1H),5.76(s,J=2.0Hz,1H), 3.98(d,J=20.5Hz,2H),3.00(d,J=14.7Hz,2H),2.79(d,J=15.0Hz,1H),2.57(d,J=15.2Hz,1H),2.36-2.22(m,2H),1.83-1.64(m,2H).LCMS ESI(+)m / z:305.2(M+1).

[0145] Example 21 [ka] 2-(8-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0146] Step A: The compound 2-(8-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (100mg, 0.33mmol) was dissolved in 10mL of methanol, palladium carbon (106mg, 0.10mmol) was added, and the mixture was reacted for 16 hours under hydrogen gas balloon conditions at room temperature with stirring. The reaction solution was filtered, the filter residue was washed with an appropriate amount of methanol, the filtrate was concentrated under reduced pressure, and the compound 2-(8-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile (diastereomeric mixture, 35mg, yield 40%) was obtained. 1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.53(s,1H),8.24(s,0.38H),8.20(s,0.62H),7.45-7 .42(m,1H),6.89(dd,J=3.2,2.0Hz,0.38H),6.81(dd,J=3.2,2.0Hz,0.62H),3.82(s,2H),2. 75(d,J=8.1Hz,1.24H),2.63(d,J=8.1Hz,0.76H),2.59-2.57(m,0.38H),2.41-2.34(m,0.62 LCMS ESI(+)m / z:307.2(M+1).

[0147] Example 22 [ka] 2-(8-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile The form for carrying out the invention is as follows. [ka]

[0148] Step A: Dess-Martin periodinane (7.30g, 17.1mmol) was dissolved in 70mL of dichloromethane, and compound 8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]oct-3-ol (5.20g, 11.4mmol) was dissolved in 50mL of dichloromethane, and added dropwise to the reaction solution, and the mixture was reacted at room temperature for 3 hours with stirring. After the reaction was completed, an appropriate amount of saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane (3×250 mL). The organic phases were combined, washed with 500 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]oct-3-one (5.6 g, 72% yield). LCMS ESI(+)m / z:456.2(M+1).

[0149] Step B: Diethyl cyanomethylphosphonate (3.27g, 18.5mmol) was dissolved in 100mL of anhydrous tetrahydrofuran, protected with nitrogen gas, and 60% sodium hydride (738mg, 60%, 18.5mmol) was added at 0°C and stirred for 30 minutes. Compound 8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]oct-3-one (5.6g, 12.3mmol) was dissolved in 100mL of anhydrous tetrahydrofuran, added to the reaction solution, and reacted at room temperature for 3 hours with stirring under nitrogen gas protection. After the reaction was completed, an appropriate amount of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×250 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated and concentrated on a rotary evaporator. Compound 2-(8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile was obtained by silica gel column chromatography (4.37 g, 74% yield). LCMS ESI(+)m / z:479.2(M+1).

[0150] Step C: The compound 2-(8-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (2.37 g, 5.0 mmol) was placed in a mixture of 120 mL of ethanol and 40 mL of water (suspension), and ammonium chloride solid (1.32 g, 24.8 mmol) and iron powder (1.38 g, 24.8 mmol) were added in that order. The temperature was raised to 80° C. and the mixture was stirred for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filter residue was washed with an appropriate amount of ethyl acetate. 200 mL of water was added to the filtrate, and the mixture was extracted with ethyl acetate (3 x 250 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 2-(8-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (1.58 g, yield 65%) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:449.2(M+1).

[0151] Step D: Triethyloxonium tetrafluoroborate (661 mg, 3.48 mmol) and R-lactamide (310 mg, 3.48 mmol) were dissolved in 20 mL of tetrahydrofuran and reacted for 2 hours at room temperature while stirring. Concentrated under reduced pressure to obtain a colorless oil, which was dissolved in 15 mL of absolute ethanol and added to 15 mL of absolute ethanol in which compound 2-(8-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (520 mg, 1.16 mmol) was dissolved. The temperature was raised to 75° C. and the reaction was allowed to proceed for 1 hour while stirring. After completion of the reaction, the mixture was quenched with aqueous sodium bicarbonate, 50 mL of water was added, and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with 100 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, and the filtrate was concentrated under reduced pressure. Compound 2-(8-(2-((R)-1-hydroxyethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (480 mg, 82% yield) was obtained by silica gel column chromatography. LCMS ESI(+) m / z: 503.2 (M+1).

[0152] Step F: The compound 2-(8-(2-((R)-1-hydroxyethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (360 mg, 0.71 mmol) was dissolved in 9 mL of methanol, 3 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was reacted at 35° C. for 8 hours with stirring. After the reaction was completed, the pH was adjusted to 8-9 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(8-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (32 mg, yield 12%).1 H NMR(400MHz,DMSO-d6)δ11.77(d,J=26.3Hz,1H),8.49(d,J=5.7Hz,1H),7.46-7.30(m,1H),6.95(dd,J=115.2,2.4Hz,1H),5.47(s,1H),4.98 LCMS ESI(+)m / z:326.2(M+1).

[0153] Example 23 [ka] 2-(8-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0154] Step A: Compound 2-(8-(2-((R)-1-hydroxyethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-ylidene)acetonitrile (480 mg, 0.96 mmol) was dissolved in 35 mL of methanol, palladium carbon (202 mg, 0.19 mmol) was added, and the mixture was stirred at room temperature under hydrogen gas balloon conditions. The reaction was continued for 16 hours while stirring. The reaction solution was filtered, the filter residue was washed with an appropriate amount of methanol, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 2-(8-(2-((R)-1-hydroxyethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile (360 mg, 74% yield). LCMS ESI(+)m / z: 505.2 (M+1).

[0155] Step B: The compound 2-(8-(2-((R)-1-hydroxyethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile (360 mg, 0.71 mmol) was dissolved in 9 mL of methanol, and 3 mL of 1N aqueous sodium hydroxide solution was added. The mixture was reacted at 35° C. for 8 hours with stirring. After completion of the reaction, the pH was adjusted to 8-9 with acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 2-(8-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-8-azabicyclo[3.2.1]octan-3-yl)acetonitrile (diastereomer, 32 mg, yield 12%). 1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),11.73(s,1H),8.49(s,1H),8.48(s,1H),7.43(t,J=2.4Hz,1H),7.35(t,J=2.5Hz,1 H),7.09(d,J=2.1Hz,1H),6.80(d,J=2.7Hz,1H),5.55-5.45(m,1H),5.45-5.35(m,1H),4.98-4.88(m,1H),4.88-4.78(m, 1H),4.25(t,J=6.4Hz,1H),4.05-4.00(m,1H),3.84(t,J=6.4Hz,1H),3.80-3.75(m,1H),2.73(d,J=7.0Hz,2H),2.66(d,J LCMS ESI(+)m / z:326.2(M+1).

[0156] Example 24 [ka] 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0157] Step A: 1-Boc-piperazine (1.86 g, 10.0 mmol) was dissolved in 20 mL of water and 9 mL of acetic acid, and sodium nitrite (4.14 g, 60.0 mmol) was dissolved in 20 mL of water. At 0°C, aqueous sodium nitrite solution was slowly added dropwise to the reaction system, and the reaction was allowed to proceed for 16 hours at room temperature with stirring. After the reaction was completed, the mixture was extracted with 150 mL of ethyl acetate in three portions. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the compound 1-Boc-4-nitrosopiperazine (1.46 g, 68% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:159.1(M+1).

[0158] Step B: 1-Boc-4-aminopiperazine At room temperature, 1-Boc-4-nitrosopiperazine (1.46g, 6.8mmol) was dissolved in 10mL of methanol, zinc powder (2.20g, 33.8mmol) was added, the mixture was cooled to 0℃, acetic acid (20mL) was gradually added dropwise, and the mixture was heated to room temperature under nitrogen gas protection and stirred for 2 hours. After the reaction was completed, the mixture was filtered, the pH was adjusted to 9-10 with saturated aqueous sodium bicarbonate solution, 40mL of water was added, and the mixture was extracted three times with 180mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator, and the compound 1-Boc-4-aminopiperazine (1.18g, yield 86%) was obtained.

[0159] Step C: Compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.18 g, 5.87 mmol), N,N-diisopropylethylamine (7.10 g, 55 mmol) and 1-Boc-4-aminopiperazine (1.18 g, 5.87 mmol) were added to 60 mL of isopropanol (suspension), and the mixture was heated to 100° C. under nitrogen gas protection and stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, and ethyl ether was added to precipitate a large amount of yellow solid. The solid was filtered, collected and dried to obtain the product 1-Boc-4-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperazine (2.16 g, 76% yield). LCMS ESI(+)m / z:517.1(M+1).

[0160] Step D: The compound 1-Boc-4-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperazine (1.8 g, 3.49 mmol) was dissolved in 45 mL of ethanol, and iron powder (1.17 g, 20.9 mmol), ammonium chloride (0.37 g, 6.98 mmol) and 15 mL of water were added in this order, and the mixture was heated to 75° C. and stirred for 2 hours. After the reaction was completed, the mixture was filtered, dried on a rotary evaporator, and purified by column chromatography to obtain the product 1-Boc-4-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperazine (930 mg, 54% yield). LCMS ESI(+)m / z:487.1(M+1).

[0161] Step E: The compound 1-Boc-4-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperazine (930 mg, 1.91 mmol) was dissolved in 30 mL of toluene, and triethyl orthoformate (2 mL) and pyridine hydrochloride (23 mg, 0.2 mmol) were added in this order. The mixture was heated to 115° C. under nitrogen gas protection and stirred for 3 hours. After the reaction was completed, the mixture was dried using a rotary evaporator and purified by column chromatography to obtain the product 1-Boc-4-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazine (760 mg, 80% yield). LCMS ESI(+)m / z:497.1.

[0162] Step F: Compound 1-Boc-4-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazine (200 mg, 0.4 mmol) was dissolved in 5 mL of 1,4-dioxane, and a solution of hydrogen chloride in 1,4-dioxane (4N, 2 mL) was added in an ice bath, and the mixture was heated to room temperature under nitrogen gas protection and stirred for 16 hours. After the reaction was completed, the reaction solution was dried on a rotary evaporator to obtain compound 4-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazine hydrochloride (180 mg, 100% yield). LCMS ESI(+)m / z:397.1(M+1).

[0163] Step G: Compound 4-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazine hydrochloride (200 mg, 0.51 mmol) was dissolved in 10 mL of methanol, and aqueous sodium hydroxide solution (2N, 3 mL) was added at 0°C. The mixture was stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with dichloromethane (3 x 80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and purified by column chromatography to obtain compound 1-(piperazin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (120 mg, 97% yield). LCMS ESI(+)m / z:243.1(M+1).

[0164] Step H: Compound 1-(piperazin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (48 mg, 0.2 mmol), bromoacetonitrile (31 mg, 0.26 mmol) and triethylamine (61 mg, 0.6 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 40 mL of water was added, extracted with ethyl acetate (3 x 40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and purified by high performance liquid chromatography to obtain compound 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)acetonitrile (8 mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.93(s,1H),8.74(s,1H),7.57(t,J=3.2Hz,1H), 6.81(dd,J=3.2Hz,2.0Hz,1H),3.91(s,2H),3.41-3.39(m,4H),2.87-2.81(m,4H).LCMS ESI(+)m / z:282.1(M+1).

[0165] Example 25 [ka] 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)propanenitrile The form for carrying out the invention is as follows. [ka]

[0166] Step A: The compound 1-(piperazin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (52 mg, 0.22 mmol) and triethylamine (108 mg, 1.1 mmol) were dissolved in 3 mL of 3-allylnitrile and stirred for 1 hour at 100 ° C under nitrogen gas protection. After the reaction was completed, it was filtered, 20 mL of water was added, and the mixture was extracted with ethyl acetate (5 × 40 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and prepared by high performance liquid chromatography to obtain the compound 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)propanenitrile (32 mg, yield 48%). 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.61(s,1H),8.56(s,1H),7.45(s,1H),6.74(d,J=2.4Hz,1H),3.34(s,4H),2.78-2.71(m,8H).LCMS ESI(+)m / z:296.1(M+1).

[0167] Example 26 [ka] 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)oxopropanenitrile The form for carrying out the invention is as follows. [ka]

[0168] Step A: Compound 1-(piperazin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (70 mg, 0.29 mmol), HATU (165 mg, 0.43 mmol), 2-cyanoacetic acid (30 mg, 0.35 mmol) and N,N-diisopropylethylamine (112 mg, 0.87 mmol) were dissolved in 5 mL of N,N-dimethylformamide and stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 x 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and the product was purified to obtain the compound 3-(4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperazin-1-yl)oxopropanenitrile (30 mg, 33% yield). 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.57(s,1H),8.56(s,1H),7.45(t,J=2.8Hz,1H) ,6.78(dd,J=3.2,2.0Hz,1H),4.19(s,2H),3.85-3.70(m,4H),3.33-3.30(m,4H).LCMS ESI(+)m / z:310.1(M+1).

[0169] Example 27 [ka] 2-(1-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azepan-4-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0170] Step A: Hydroxylamine hydrochloride (6.12 g, 88.1 mmol) was dissolved in 25 mL of water, sodium acetate (9.64 g, 118 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Compound p-cyclohexanone carboxylate ethyl (10.0 g, 58.8 mmol) was added dropwise to the reaction system. The mixture was stirred at 45 ° C for 16 hours. Extracted three times with 50 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of water, washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4-carboxylate ethyl cyclohexanone oxime (10.9 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ8.02(brs,1H),4.19-4.09(m,2H),3.20-3.10(m,1H),2.60-2.51( m,1H),2.49-2.40(m,1H),2.21-2.00(m,4H),1.82-1.66(m,2H),1.26(t,J=7.1Hz,3H).

[0171] Step B: Compound 4-ethyl cyclohexanone oxime carboxylate (3.32 g, 12.9 mmol) was dissolved in pyridine (15 mL) and p-toluenesulfonyl chloride (4.10 g, 21.5 mmol) was added at -15°C under nitrogen gas protection. Stirred at -15°C under nitrogen gas protection for 2 hours. Poured into 60 mL of ice water, stirred for 20 minutes, suction filtered, and washed with 30 mL of water. The filter cake was collected and dried under reduced pressure to obtain compound 4-((p-toluenesulfonyloxy)imino)cyclohexane-1-ethyl carboxylate (4.87 g, 80% yield). 1 H NMR(400MHz,CDCl3)δ7.85(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),4.13(q,J=7.1Hz,2H),3.07-2.97(m,1H),2 .58-2.46(m,2H),2.45(s,4H),2.28-2.12(m,2H),2.11-1.96(m,2H),1.85-1.64(m,2H),1.25(t,J=7.1Hz,3H).

[0172] Step C: Compound 4-((p-toluenesulfonyloxy)imino)cyclohexane-1-carboxylate ethyl (16.6 g, 45.9 mmol) was dissolved in 35 mL of acetic acid and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. 40 mL of saturated aqueous sodium bicarbonate solution was added, stirred for 15 minutes, and the aqueous phase was extracted three times with 150 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound 7-oxoazepane-4-carboxylate ethyl (5.33 g, yield 63%). 1 H NMR(400MHz,CDCl3)δ6.30(s,1H),4.15(q,J=7.1Hz,2H),3.41-3.29(m,1H),3.29-3.17(m,1H), 2.68-2.52(m,2H),2.52-2.39(m,1H),2.15-2.00(m,2H),1.92-1.76(m,2H),1.37-1.18(m,3H).

[0173] Step D: Compound 7-oxoazepane-4-carboxylate ethyl (3.72 g, 20.1 mmol) was dissolved in 50 mL of tetrahydrofuran and added dropwise to a solution of lithium aluminum hydride (3.81 g, 100 mmol) in tetrahydrofuran (300 mL) in an ice bath under nitrogen gas protection. Stirred at room temperature for 2 hours and at 60°C for 4 hours. Cooled to 0°C, water (4 mL), 15% sodium hydroxide solution (4 mL), and water (8 mL) were added dropwise in this order. Stirred at room temperature for 3 hours. Suction filtered through diatomaceous earth and washed with 50 mL of tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain compound 4-hydroxymethylazepane (2.31 g, 89% yield). 1 H NMR(400MHz,CDCl3)δ3.56-3.45(m,2H),3.08-2.72(m,4H),1.94-1.73(m,4H),1.66-1.52(m,1H),1.50-1.35(m,2H).

[0174] Step E: Compound 4-hydroxymethylazepane (2.31 g, 17.9 mmol) was dissolved in 100 mL of dichloromethane, and sodium nitrite (3.70 g, 53.6 mmol) and p-toluenesulfonic acid monohydrate (10.2 g, 53.6 mmol) were added in this order at room temperature. The mixture was stirred at 35°C for 2 hours, and the reaction solution was concentrated under reduced pressure. Compound 1-nitroso-4-hydroxymethylazepane (2.19 g, 77% yield) was obtained by silica gel column chromatography. 1 H NMR(400MHz,CDCl3)δ4.83-4.63(m,1H),4.12-3.96(m,1H),3.92-3.70(m,1H),3.68-3. 43(m,3H),2.30-2.14(m,1H),2.09-1.79(m,3H),1.78-1.40(m,3H),1.27-1.00(m,1H).

[0175] Step F: Compound 1-nitroso-4-hydroxymethylazepane (1.10g, 6.95mmol) was dissolved in 20mL of dichloromethane, and triethylamine (1.19g, 10.4mmol) and methanesulfonyl chloride (1.19g, 10.4mmol) were added dropwise in an ice bath under nitrogen gas protection. The mixture was stirred in an ice bath for 2 hours. Water (10mL) was added and the mixture was stirred at room temperature for 15 minutes. Ethyl acetate (100mL) was added, and the organic phase was separated, washed twice with water (30mL), washed with saturated saline (30mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain the crude product compound (1-nitrosoazepan-4-yl)methyl methanesulfonate (1.64g, yield 100%).

[0176] Step G: The compound (1-nitrosoazepan-4-yl)methyl methanesulfonate (1.64 g, 6.94 mmol) was dissolved in 10 mL of anhydrous N,N-dimethylformamide (10 mL) and sodium cyanide solution (1.02 g, 20.8 mmol) was added under nitrogen gas. The mixture was stirred at 80°C for 5 hours. The mixture was concentrated under reduced pressure. The reaction solution was poured into 20 mL of water and extracted three times with 40 mL of ethyl acetate. The organic phases were combined, washed with water (20 mL), washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The compound 1-nitroso-4-cyanomethylazepane (1.09 g, yield 94%) was obtained by silica gel column chromatography.

[0177] Step H: The compound 1-nitroso-4-cyanomethylazepane (600 mg, 3.59 mmol) was dissolved in 20 mL of methanol, and zinc powder (4.69 g, 71.8 mmol) was added at room temperature, followed by dropwise addition of acetic acid (5 mL). The mixture was stirred at 35°C for 15 minutes. The reaction solution was suction filtered, washed with 20 mL of methanol, and the filtrate was concentrated to obtain an oily product, 1-amino-4-cyanomethylazepane, which was used as is in the next step.

[0178] Step I: The crude product of the previous step, compound 1-amino-4-cyanomethylazepane, was dissolved in 25 mL of isopropanol, and N,N-diisopropylethylamine (2.20 mL, 17.1 mmol) and 4-chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.84 mmol) were added in this order, and the mixture was heated to 85 ° C. under nitrogen gas protection and reacted for 16 hours with stirring. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain compound 2-(1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azepan-4-yl)acetonitrile (450 mg, 34% yield).

[0179] Step J: Compound 2-(1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azepan-4-yl)acetonitrile (527 mg, 1.12 mmol) was added to 25 mL of ethanol, and iron powder (1.26 g, 22.5 mmol) and saturated ammonium chloride (1.5 mL) were added in this order at room temperature, and the mixture was reacted for 5 minutes while stirring at 75 ° C. The mixture was filtered with diatomaceous earth while still hot, washed with 20 mL of methanol, and the filtrate was concentrated. Compound 2-(1-((5-amino-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azepan-4-yl)acetonitrile (200 mg, yield 41%) was obtained by silica gel column chromatography (ethyl acetate).

[0180] Step K: Under nitrogen gas, R-lactamide (107 mg, 1.23 mmol) and triethyloxonium tetrafluoroborate (234 mg, 1.24 mmol) were added to 8 mL of dry tetrahydrofuran and stirred at 30° C. for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 3 mL of dry ethanol, and the compound 2-(1-((5-amino-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)azepan-4-yl)acetonitrile (180 mg, 0.41 mmol) was added under nitrogen gas, and the mixture was reacted for 1 hour with stirring at 75° C. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate solution (10 mL) and ethyl acetate (15 mL) were added and stirred for 5 minutes. The organic phase was separated, and the aqueous phase was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of water, washed with 10 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 2-(1-(2-((R)-1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)azepan-4-yl)acetonitrile (980 mg, yield 49%).

[0181] Step L: The compound 2-(1-(2-((R)-1-hydroxyethyl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)azepan-4-yl)acetonitrile (98 mg, 0.2 mmol) was dissolved in 3 mL of methanol and 1N sodium hydroxide solution (1 mL, 1.0 mmol) was added. The mixture was stirred at 35°C for 7 hours. The reaction solution was diluted with 40 mL of dichloromethane, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The residue was purified by TLC to obtain the compound 2-(1-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-6-azepan-4-yl)acetonitrile (40 mg, yield 59%). 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.59-8.47(m,1H),7.52-7.44(m,1H),6.76-6.64(m,1H),5.36-5.25(m,1H),5.2 5-5.14(m,1H),3.90-3.62(m,2H),3.28-3.01(m,2H),2.69-2.59(m,2H),2.12-1.63(m,7H),1.58(d,J=6.5Hz,3H).LCMS ESI(+)m / z:339.1(M+1).

[0182] Example 28 [ka] 3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile The form for carrying out the invention is as follows. [ka]

[0183] Step A: The compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (4.80 g, 13.7 mmol), tert-butoxycarbonylhydrazine (1.98 g, 15.0 mmol), and N,N-diisopropylethylamine (3.81 mL, 27.3 mmol) were added to 100 mL of isopropanol. The mixture was stirred at 85°C under nitrogen gas protection for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residue was passed through a silica gel column chromatography to obtain the compound 2-(5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]-4-yl)carbazate tert-butyl (4.56 g, 75% yield). 1 H NMR(400MHz,CDCl3)δ9.73(s,1H),9.11(s,1H),8.06(d,J=8.4Hz,2H),7.61(d,J=4.1Hz,1H ),7.31(d,J=8.1Hz,2H),6.96(d,J=4.1Hz,1H),6.68(s,1H),2.40(s,3H),1.46(s,9H).LCMS ESI(+)m / z:448.1(M+1).

[0184] Step B: The compound 2-(5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]-4-yl) tert-butyl carbazate (4.56 g, 10.2 mmol) was dissolved in 250 mL of methanol, and 10% palladium carbon (2.78 g) was added under nitrogen gas. The mixture was stirred at room temperature for 16 hours under a hydrogen gas atmosphere. The reaction solution was filtered and washed twice with methanol (20 mL). The filtrate was decompressed, and the solvent was distilled off to obtain the compound 2-(5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]-4-yl) tert-butyl carbazate (4.25 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ7.99(d,J=8.3Hz,2H),7.87(s,1H),7.49(d,J=4.1Hz,1H),7.23 (d,J=8.2Hz,3H),6.69(d,J=4.1Hz,1H),6.56(s,2H),2.36(s,4H),1.43(s,9H).LCMS ESI(+)m / z:418.1(M+1).

[0185] Step C: Compound 2-(5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]-4-yl) tert-butyl carbazate (4.25 g, 10.2 mmol), triethyl orthoformate (1.81 g, 12.2 mmol) and pyridine hydrochloride (116 mg, 1.0 mmol) were added to 150 mL of toluene. The temperature was raised to 115° C. under nitrogen gas and stirred for 2 hours. After the reaction was completed, the reaction solution was decompressed and the solvent was distilled off. The obtained residue was passed through silica gel column chromatography to obtain compound tert-butyl (6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl) carbamate (4.35 g, yield 100%). 1 H NMR(400MHz,CDCl3)δ8.77(s,1H),8.05(d,J=8.3Hz,2H),7.91(brs,1H),7.91(s,1H),7.58( d,J=2.8Hz,1H),7.25(d,J=8.4Hz,1H),6.58(d,J=2.8Hz,1H),2.35(s,3H),1.49(s,9H).LCMS ESI(+)m / z:428.1(M+1).

[0186] Step D: The compound tert-butyl (6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)carbamate (3.69 g, 8.63 mmol) was dissolved in 400 mL of acetone, and sodium hydroxide (726 mg, 13.0 mmol) powder was added and stirred at room temperature for 10 minutes. Ethyl 2-bromobutyrate (5.05 g, 25.9 mmol) was added to the reaction solution and stirred at room temperature for 1.5 hours. The reaction solution was suction filtered and the filter cake was washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound ethyl 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)butyrate methyl (4.08 g, yield 87%). 1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.38(s,1H),8.14(d,J=8.4Hz,2H),7.78(d,J=4.0Hz,1H),7.29(d,J =8.3Hz,2H),6.69(d,J=3.9Hz,1H),4.98-4.79(m,1H),4.33(q,J=7.1Hz,2H),2.38(s,3H),1 .59-1.48(m,2H),1.36(t,J=9.2,5.1Hz,3H),1.33-1.12(m,9H),0.81(t,J=7.4Hz,3H).LCMS ESI(+)m / z:542.2(M+1).

[0187] Step E: Compound ethyl 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl butyrate (4.08 g, 7.53 mmol) was dissolved in 33 mL of a mixed solvent of dichloromethane and methanol (volume ratio is 10:1), and 4N hydrogen chloride in dioxane solution (15 mL) was added dropwise in an ice bath. The temperature was raised to room temperature under nitrogen gas protection and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. 80 mL of saturated sodium bicarbonate solution was added and stirred for 5 minutes. Extraction was performed with ethyl acetate (3 x 50 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain the compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)butyrate methyl (3.10 g, yield 93%). 1 H NMR(400MHz,CDCl3)δ8.85(s,1H),8.10(d,J=8.4Hz,2H),8.03(s,1H),7.77(d,J=3.9Hz,1H),7.27(s,1H),7.25(s,1H),6.91(d,J=4.0Hz,1H), 5.74(d,J=7.8Hz,1H),4.33-4.16(m,2H),3.85-3.76(m,1H),2.35(s,3H),1.92-1.82(m,2H),1.26(t,J=7.2Hz,3H),1.14(t,J=7.4Hz,3H).LCMS ESI(+)m / z:442.1(M+1).

[0188] Step F: Compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)butyrate methyl (3.10g, 7.02mmol) was dissolved in 200mL of ethanol, and sodium borohydride (797mg, 21.1mmol) was added in an ice bath and nitrogen gas protection, and the mixture was stirred at room temperature for 48 hours. 1N diluted hydrochloric acid solution was added dropwise to the reaction at 0°C to adjust the reaction solution to neutral. 50mL of water was added and the mixture was stirred at room temperature. The mixture was adjusted to neutral with 1N diluted hydrochloric acid, and the solvent was distilled off under reduced pressure. Extraction with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Silica gel column chromatography afforded the compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)butyl-1-ol (1.97 g, 69% yield). 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.30(s,1H),8.02(d,J=8.4Hz,2H),7. 92(d,J=4.0Hz,1H),7.40(d,J=8.1Hz,2H),7.16(d,J=4.0Hz,1H),6.95(d,J= 2.7Hz,1H),4.89(t,J=5.0Hz,1H),3.54-3.44(m,1H),3.37-3-.34(m,1H),3. 23-3.15(m,1H),2.33(s,3H),1.42-1.32(m,2H),0.83(t,J=7.5Hz,3H).LCMS ESI(+)m / z:400.1(M+1).

[0189] Step G: With cooling in an ice bath and nitrogen gas protection, the compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)butyl-1-ol (1.72 g, 4.31 mmol), DBU (3.28 g, 21.5 mmol) and DPPA (3.55 g, 12.9 mmol) were added to 120 mL of toluene. The temperature was raised to 75 ° C. and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound N-(1-azidobut-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.10 g, yield 60%). 1 H NMR(400MHz,CDCl3)δ8.88(s,1H),8.12(d,J=8.4Hz,2H),7.96(s,1H),7.81(d,J=4.0Hz,1H),7.27(d,J=8.4Hz,2H),7.01(d ,J=4.0Hz,1H),5.41(s,1H),3.68(dd,J=12.0,2.8Hz,1H),3.47-3.34(m,2H),1.52-1.41(m,2H),0.91(t,J=7.5Hz,3H).LCMS ESI(+)m / z:425.1(M+1).

[0190] Step H: Compound N-(1-azidobut-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.10 g, 2.59 mmol) was dissolved in 200 mL of methanol, and 10% palladium carbon (220 mg) was added under nitrogen gas protection. The mixture was replaced with hydrogen gas, and stirred at room temperature for 6 hours under hydrogen gas atmosphere. The mixture was filtered by suction, and the filter cake was washed with 20 mL of methanol. The filtrate was concentrated under reduced pressure to obtain compound N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)butane-1,2-diamine (1.03 g, 100% yield) was obtained. 1H NMR(400MHz,CDCl3)δ8.88(s,1H),8.12(d,J=8.4Hz,2H),7.97(s,1H),7.76(d,J=3.9Hz,1H),7.27(d,J=8.0Hz,2H),7.12(d,J=4.0Hz,1H),5.99(d, LCMS ESI(+)m / z:399.1(M+1).

[0191] Step I: Compound N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)butane-1,2-diamine (1.03 g, 2.58 mmol) was dissolved in 50 mL of methanol, and paraformaldehyde (101 mg, 3.36 mmol) was added. The mixture was heated to 70 ° C and stirred for 16 hours. The mixture was cooled to room temperature, suction filtered, and washed with 10 mL of methanol. The filtrate was decompressed, and the solvent was distilled off to obtain the compound 1-(5-ethylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (1.06 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ8.94-8.77(m,1H),8.13-8.07(m,2H),7.79-7.67(m,1H),7.28-7.24(m,1H),7.08(m ,1H),4.53-3.97(m,2H),3.80-3.37(m,3H),2.42-2.30(m,3H),1.83-1.59(m,2H),0.96-0.74(m,3H).LCMS ESI(+)m / z:411.1(M+1).

[0192] Step J: The compound 1-(5-ethylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (60 mg, 0.15 mmol) was dissolved in 3 mL of methanol and 2N sodium hydroxide solution (1.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with 10 mL of water, and methanol was distilled off under reduced pressure. The mixture was extracted with ethyl acetate (3 x 5 mL), the organic phase was combined, the organic phase was washed with 5 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The crude product, compound 1-(5-ethylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (50 mg, crude yield 100%), was obtained. LCMS ESI(+)m / z:257.1(M+1).

[0193] Step K: Compound 1-(5-ethylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (50 mg, 0.2 mmol) was dissolved in 4 mL of dichloromethane, and cyanoacetic acid (20 mg, 0.24 mmol), HOBT (37 mg, 0.27 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol) and EDCI (60 mg, 0.31 mmol) were added in this order under nitrogen gas protection and ice bath. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile (20 mg, yield 32%). 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.75-8.17(m,2H),7.47(s,1H),6.70(s,1H),5.03-4. 68(m,2H),4.24-3.85(m,4H),3.54-3.42(m,1H),1.51-1.28(m,2H),0.82-0.69(m,3H).LCMS ESI(+)m / z:324.1(M+1).

[0194] Example 29 [ka] 3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolidin-1-yl)propanenitrile [ka]

[0195] Step A: Compound 1-(5-ethylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (70 mg, 0.17 mmol) and triethylamine (86 mg, 0.85 mmol) were dissolved in 3 mL of acrylonitrile. The mixture was stirred at 120° C. for 16 hours using a microwave. The solvent was removed under reduced pressure, and the compound 3-(4-ethyl-3-(6-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolidin-1-yl)propanenitrile (50 mg, 63% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:464.1(M+).

[0196] Step O: The compound 3-(4-ethyl-3-(6-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolidin-1-yl)propanenitrile (50 mg, 0.11 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and 60% sodium hydride (22 mg, 0.54 mmol) was added in an ice bath. The temperature was raised to room temperature and stirred for 4 hours. The reaction solution was poured into 15 mL of saturated aqueous ammonium chloride solution. The reaction solution was neutralized, the solvent was distilled off under reduced pressure, and the compound 3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolidin-1-yl)propanenitrile (150 mg, yield 48%) was obtained by silica gel column chromatography. 1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.06-7.99(m,2H),7.85-7.81(m,2H),7.7 5-7.64(m,2H),7.49(d,J=8.4Hz,2H),7.29(dd,J=6.1,2.5Hz,1H),6.16-6.10(m, 2H),5.18(s,2H),2.01(s,1H),0.86-0.76(m,4H).LCMS ESI(+)m / z:310.1(M+1).

[0197] Example 30 [ka] 3-(4-Methyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile The form for carrying out the invention is as follows. [ka]

[0198] Step A: The compound tert-butyl (6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)carbamate (3.60 g, 8.42 mmol) was dissolved in 400 mL of acetone, and sodium hydroxide (709 mg, 12.6 mmol) powder was added and stirred at room temperature for 10 minutes. Ethyl 2-bromopropionate (4.57 g, 25.3 mmol) was added to the reaction solution and stirred at room temperature for 1.5 hours. The reaction solution was suction filtered and the filter cake was washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl propionate (2.85 g, yield 64%). 1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.39(s,1H),8.15(d,J=8.2Hz,2H),7.80(d,J=3.9Hz,1H),7.30(d,J=8.3H z,2H),6.71(d,J=4.0Hz,1H),5.24-5.04(m,1H),4.29(q,J=7.0Hz,2H),2.38(s,3H),1.40-1.14(m,15H).LCMS ESI(+)m / z:528.2(M+1).

[0199] Step B: The compound 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl propionate (2.85 g, 5.4 mmol) was dissolved in 30 mL of a mixed solvent of dichloromethane and methanol (volume ratio is 10:1), and 4N hydrogen chloride in dioxane solution (10 mL) was added dropwise in an ice bath. The temperature was raised to room temperature under nitrogen gas protection and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. 30 mL of saturated sodium bicarbonate solution was added and stirred for 5 minutes. Extraction was performed with ethyl acetate (3 x 50 mL), and the organic phases were combined, washed with 50 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain the compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl propionate (2.12 g, yield 92%). 1 H NMR(400MHz,CDCl3)δ8.86(s,1H),8.11(d, J=8.4Hz,2H),8.05(s,1H),7.78(d,J=3.9Hz,1H),7.26(d,J=8.0Hz,2H),6.90(d,J=3.9Hz,1H),5.80(d,J=6.1 Hz,1H),4.32-4.18(m,2H),4.00-3.91(m,1H),2.35(s,3H),1.43(d,J=7.1Hz,3H),1.27(t,J=7.1Hz,3H).LCMS ESI(+)m / z:428.0(M+1).

[0200] Step C: The compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl propionate (2.12 g, 4.96 mmol) was dissolved in 50 mL of ethanol, and sodium borohydride (563 mg, 14.9 mmol) was added in an ice bath and nitrogen gas protection, and the mixture was stirred at room temperature for 16 hours. 1N diluted hydrochloric acid solution was added dropwise to the reaction at 0°C to adjust the reaction solution to neutral, and the solvent was distilled off under reduced pressure. Extraction with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Silica gel column chromatography afforded the compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)propyl-1-ol (1.48 g, 77% yield). 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.29(s,1H),8.02(d,J=8.4Hz,2H),7.92(d,J=4.0Hz,1H),7.40(d,J=8.2Hz,2H), 7.15(d,J=4.0Hz,1H),7.03(s,1H),4.94(d,J=5.2Hz,1H),3.46-3.33(m,4H),2.32(s,3H),0.90(d,J=5.7Hz,3H).LCMS ESI(+)m / z:386.1(M+1).

[0201] Step D: With cooling in an ice bath and nitrogen gas protection, the compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)propyl-1-ol (1.68 g, 4.36 mmol), DBU (3.32 g, 21.8 mmol) and DPPA (3.60 g, 13.1 mmol) were added to 100 mL of toluene. The temperature was raised to 100 ° C. and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound N-(1-azidoprop-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.26 g, yield 67%). 1H NMR(400MHz,CDCl3)δ8.88(s,1H),8.12(d,J=8.2Hz,2H),7.95(s,1H),7.80(d,J=4.0Hz,1H),7.28(d,2H),6.98(d,J=4. 0Hz,1H),5.49(s,1H),3.68-3.52(m,2H),3.49-3.37(m,1H),2.36(s,3H),1.84-1.53(m,2H),1.04(d,J=6.1Hz,3H).LCMS ESI(+)m / z:411.1(M+1).

[0202] Step E: Compound N-(1-azidoprop-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.20 g, 2.59 mmol) was dissolved in 100 mL of methanol, and 10% palladium carbon (240 mg) was added under nitrogen gas protection. The mixture was replaced with hydrogen gas, and stirred at room temperature for 16 hours under hydrogen gas atmosphere. The mixture was filtered by suction, and the filter cake was washed with 20 mL of methanol. The filtrate was concentrated under reduced pressure to obtain compound N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)propane-1,2-diamine (1.16 g, 98% yield) was obtained. 1 H NMR(400MHz,CDCl3)δ8.88(s,1H),8.11(d,J=8.4Hz,2H),7.96(s,1H),7.76(d,J=3.9Hz,1H),7.26(d,J=8.4Hz,5H),7.10(d,J=4.0Hz,1 LCMS ESI(+)m / z:385.1(M+1).

[0203] Step F: Compound N 2-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)propane-1,2-diamine (1.16 g, 3.02 mmol) was dissolved in 50 mL of methanol, and paraformaldehyde (109 mg, 3.62 mmol) was added. The mixture was heated to 70 ° C and stirred for 16 hours. The mixture was cooled to room temperature, suction filtered, and washed with 10 mL of methanol. The filtrate was decompressed, and the solvent was distilled off to obtain the compound 1-(5-methylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (1.28 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ8.73(s,1H),8.57(s,1H),8.01(d,J=7.7Hz,2H),7.88(dd,J=21.5,3.9Hz,1H),7.39(d,J=7.7Hz,2H),7.24(d,J=8.7Hz,1H) ,4.40-4.24(m,1H),4.15-4.01(m,1H),3.87-3.72(m,1H),3.71-3.49(m ,1H),3.22(dd,J=15.9,8.6Hz,1H),2.32(s,3H),1.55-1.44(m,1H).LCMS ESI(+)m / z:397.1(M+1).

[0204] Step G: The compound 1-(5-methylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (400 mg, 1.01 mmol) was dissolved in 9 mL of methanol and 2N sodium hydroxide solution (3.0 mL, 6.0 mmol) was added. The mixture was stirred at 35°C for 40 hours. The reaction solution was diluted with 15 mL of water, and methanol was distilled off under reduced pressure. The mixture was extracted with ethyl acetate (3 x 6 mL), the organic phase was combined, the organic phase was washed with 5 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The crude product, compound 1-(5-methylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (223 mg, yield 91%), was obtained. LCMS ESI(+)m / z:243.1(M+1).

[0205] Step H: Compound 1-(5-methylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (100 mg, 0.41 mmol) was dissolved in 6 mL of dichloromethane, and cyanoacetic acid (42 mg, 0.50 mmol), HOBT (78 mg, 0.58 mmol), 4-dimethylaminopyridine (81 mg, 0.66 mmol) and EDCI (127 mg, 0.66 mmol) were added in this order under nitrogen gas protection and ice bath. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound 3-(4-methyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile (40 mg, yield 31%). 1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.60(s,1H),8.45(s,1H),7.47(s,1H),6.72(d,J=16.2Hz,1H) ,5.03-4.80(m,2H),4.21-3.92(m,4H),3.44-3.38(m,1H),3.31-3.23(m,1H),1.09-0.88(m,3H).LCMS ESI(+)m / z:310.1(M+1).

[0206] Example 31 [ka] 3-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile The form for carrying out the invention is as follows. [ka]

[0207] Step A: The compound tert-butyl (6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)carbamate (4.00 g, 9.36 mmol) was dissolved in 400 mL of acetone, and sodium hydroxide (787 mg, 14.0 mmol) powder was added and stirred at room temperature for 10 minutes. 2-Bromoethyl acetate (4.69 g, 28.1 mmol) was added to the reaction solution and stirred at room temperature for 1.5 hours. The reaction solution was suction filtered and the filter cake was washed with dichloromethane (400 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl acetate (4.34 g, yield 90%). 1 H NMR(400MHz,CDCl3)δ8.91(s,1H),8.28(s,1H),8.12(d,J=8.2Hz,2H),7.81(d,J=3.9Hz,1H),7.29(d,J=8.4Hz,2H),6.72(d,J LCMS ESI(+)m / z:514.1(M+1).

[0208] Step B: The compound 2-((tert-butoxycarbonyl)(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl acetate (4.34 g, 8.45 mmol) was dissolved in 45 mL of a mixed solvent of dichloromethane and methanol (volume ratio is 10:1), and 4N hydrogen chloride in dioxane solution (15 mL) was added dropwise in an ice bath. The mixture was warmed to room temperature under nitrogen gas protection and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. 30 mL of saturated sodium bicarbonate solution was added and stirred for 5 minutes. Extraction was performed with ethyl acetate (3×30 mL), and the organic phases were combined, washed with 10 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain the compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl acetate (3.49 g, yield 100%). 1 H NMR(400MHz,CDCl3)δ8.85(s,1H),8.10(d,J=8.4Hz,2H),7.78(d,J=4.0Hz,1H),7.24(d,J=8.4Hz,2H),6.92(d,J LCMS ESI(+)m / z:414.0(M+1).

[0209] Step C: The compound ethyl 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)methyl acetate (3.49 g, 4.96 mmol) was dissolved in 100 mL of ethanol, and sodium borohydride (958 mg, 25.3 mmol) was added in an ice bath under nitrogen gas protection. The mixture was stirred at room temperature for 16 hours. 1N diluted hydrochloric acid solution was added dropwise to the reaction at 0°C to adjust the reaction solution to neutral, and the solvent was distilled off under reduced pressure. Extraction with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Silica gel column chromatography gave compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)ethyl-1-ol (2.98 g, 95% yield). LCMS ESI(+)m / z: 372.0 (M+1).

[0210] Step D: With cooling in an ice bath and nitrogen gas protection, the compound 2-((6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)ethyl-1-ol (2.98 g, 8.02 mmol), DBU (6.11 g, 40.1 mmol) and DPPA (6.62 g, 24.1 mmol) were added to 100 mL of toluene. The temperature was raised to 110 ° C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain the compound N-(1-azidoeth-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.16 g, yield 36%). 1 H NMR(400MHz,CDCl3)δ8.86(s,1H),8.11(d,J=8.4Hz,2H),8.00(s,1H),7.80(d,J=4.0Hz,1H),7.26(d,J=8.4H) z,2H),6.94(d,J=4.0Hz,1H),5.40(t,J=5.2Hz,1H),3.61-3.54(m,2H),3.45-3.38(m,2H),2.35(s,3H).LCMS ESI(+)m / z:397.1(M+1).

[0211] Step E: Compound N-(1-azidoeth-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-amine (1.06 g, 2.59 mmol) was dissolved in 60 mL of methanol, and 10% palladium carbon (212 mg) was added under nitrogen gas protection. The mixture was replaced with hydrogen gas, and stirred at room temperature for 16 hours under hydrogen gas atmosphere. The mixture was filtered by suction, and the filter cake was washed with 20 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the crude product compound N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)ethane-1,2-diamine (1.16 g, 100% yield). LCMS ESI(+)m / z: 371.1 (M+1).

[0212] Step F: Compound N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)ethane-1,2-diamine (1.16 g, 3.13 mmol) was dissolved in 50 mL of methanol, and paraformaldehyde (113 mg, 3.76 mmol) was added. The mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to room temperature, suction filtered, and washed with 10 mL of methanol. The filtrate was decompressed, and the solvent was distilled off to obtain the compound 1-(imidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (1.16 g, 97% yield). LCMS ESI(+)m / z:383.1(M+1).

[0213] Step G: The compound 1-(imidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (400 mg, 1.05 mmol) was dissolved in 9 mL of methanol, and 2N sodium hydroxide solution (3.0 mL, 6.0 mmol) was added. The mixture was stirred at room temperature for 7 hours. The reaction solution was diluted with 10 mL of water, and methanol was distilled off under reduced pressure. The residue was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with 5 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The crude product, compound 1-(5-imidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (277 mg, crude yield 100%), was obtained. LCMS ESI(+)m / z:229.1(M+1).

[0214] Step H: Compound 1-(5-imidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (100 mg, 0.44 mmol) was dissolved in 6 mL of dichloromethane, and cyanoacetic acid (45 mg, 0.53 mmol), HOBT (83 mg, 0.61 mmol), 4-dimethylaminopyridine (86 mg, 0.70 mmol) and EDCI (134 mg, 0.70 mmol) were added in this order under nitrogen gas protection and ice bath. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography and high performance liquid chromatography to obtain compound 3-(3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile (40 mg, yield 30%). 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.58(s,1H),8.39-8.32(m,1H),7.50-7.43(m, 1H),6.77-6.70(m,1H),4.95-4.79(m,2H),4.19-3.99(m,2H),3.86-3.74(m,4H).LCMS ESI(+)m / z:296.1(M+1).

[0215] Example 32 [ka] (R)-3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile The form for carrying out the invention is as follows. [ka]

[0216] Step A: Compound D-2-aminobutyric acid (25.0 g, 242 mmol) was dissolved in 200 mL of methanol, and thionyl chloride (35.2 mL, 485 mmol) was added dropwise in an ice bath under nitrogen gas protection. The mixture was stirred in an ice bath for 1 hour, then heated to 70°C and stirred for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain compound D-2-aminobutyric acid methyl hydrochloride (37.2 g, yield 100%). 1 H NMR(400MHz,DMSO-d6)δ8.68(s,3H),3.96(s,1H),3.75(s,3H),1.90-1.80(m,2H),0.92(t,J=7.5Hz,3H).LCMS ESI(+)m / z:117.1(M+1).

[0217] Step B: Compound D-2-aminobutyric acid methyl ester hydrochloride (10.0 g, 65.1 mmol) was dissolved in 200 mL of tetrahydrofuran, and triethylamine (9.05 mL, 65.1 mmol) and benzaldehyde (7.60 g, 71.6 mmol) were added in this order at room temperature. The mixture was stirred at 30°C for 48 hours, filtered, the filter cake was washed with 75 mL of tetrahydrofuran, the filtrate was concentrated under reduced pressure, dissolved in 200 mL of methanol, and sodium borohydride (2.71 g, 71.6 mmol) was added in several portions in an ice bath. The mixture was stirred in an ice bath for 3 hours. The reaction was quenched with 1N dilute hydrochloric acid, and the pH was adjusted to neutral. Extract with ethyl acetate (3×50 mL), combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and subject to silica gel column chromatography to obtain compound D-methyl 2-benzylaminobutyrate (11.4 g, yield 84%). 1 H NMR(400MHz,CDCl3)δ7.38-7.20(m,5H),3.81(d,J=13.0Hz,1H),3.72(s,3H),3.64(d ,J=13.0Hz,1H),3.23(t,J=6.5Hz,1H),1.74-1.62(m,2H),0.94(t,J=7.4Hz,3H).LCMS ESI(+)m / z:208.1(M+1).

[0218] Step C: Compound D-methyl 2-benzylaminobutyrate (11.4 g, 55.0 mmol) was dissolved in 150 mL of dichloromethane, and sodium nitrite (5.69 g, 82.5 mmol) and p-toluenesulfonic acid monohydrate (15.7 g, 82.5 mmol) were added in this order at room temperature. The mixture was stirred at 30° C. for 2 hours, filtered, the filter cake was washed with 50 mL of dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 50 mL of water. The organic phase was separated and extracted with ethyl acetate (3×10 mL), the organic phase was combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound D-methyl 2-((N-benzyl-N-nitroso)amino)butyrate (12.3 g, 95% yield). 1H NMR(400MHz,CDCl3)δ7.41-7.25(m,3.8H),7.11(m,1.2H),5.42-5.25(m,0.9H),5.00(d ,J=14.8Hz,0.6H),4.95(dd,J=9.4,6.0Hz,0.6H),4.73(t,J=7.5Hz,0.4H),4.59(d,J=1 4.8Hz,0.6H),3.61(s,1.8H)),3.46(s,1.2H),2.29-1.90(m,1.6H),1.75-1.57(m,0.5H ),0.87(t,J=7.4Hz,1.9H),0.81(dt,J=28.3,7.4Hz,3H),0.74(t,J=7.5Hz,1.2H).LCMS ESI(+)m / z:237.1(M+1).

[0219] Step D: Lithium aluminum hydride (3.21 g, 84.7 mmol) was suspended in 100 mL of ethyl ether, and a solution of compound D-2-((N-benzyl-N-nitroso)amino)methyl butyrate (5.00 g, 21.2 mmol) in ethyl ether (10 mL) was added dropwise at room temperature under nitrogen gas, and the rate of addition was maintained until the reaction refluxed. The reaction was allowed to proceed with stirring at 40° C. for 0.5 hours. The reaction was quenched in an ice bath with 3.2 mL of water, 3.2 mL of 15% sodium hydroxide solution, and 9.6 mL of water, in that order. The reaction was allowed to proceed with stirring at room temperature for 5 minutes. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain an oily product, (R)-2-(1-benzylhydrazinyl)but-1-ol, which was used as such in the next step. 1 H NMR(400MHz,CDCl3)δ7.39-7.26(m,5H),3.88-3.66(m,4H),2.72-2.62(m,1H),1.74-1.62(m,1H),1.59-1.47(m,1H),0.98(t,J=7.5Hz,3H).LCMS ESI(+)m / z:195.1(M+1).

[0220] Step E: The crude product of the previous step, compound (R)-2-(1-benzylhydrazinyl)but-1-ol, was dissolved in 100 mL of isopropanol, and N,N-diisopropylethylamine (10.2 mL, 56.9 mmol) and compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (5.00 g, 14.2 mmol) were added in this order, and the mixture was heated to 85 ° C. under nitrogen gas protection and reacted for 16 hours with stirring. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain compound (R)-2-(1-benzyl-2-(5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)hydrazinyl)but-1-ol (5.91 g, 82% yield in two steps). 1 H NMR(400MHz,CDCl3)δ10.01(d,J=112.2Hz,1H),9.00(d,J=5.2Hz,1H),8.02(dd,J=8.4,4.3Hz,2H),7.55-7.41(m,2H),7. 33-7.06(m,7H),4.29-3.68(m,4H),3.10-2.90(m,1H),2.40(s,3H),1.87-1.42(m,2H),0.96(dt,J=36.8,7.5Hz,3H).LCMS ESI(+)m / z:510.0(M+1).

[0221] Step F: Compound (R)-2-(1-benzyl-2-(5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)hydrazinyl)but-1-ol (5.90 g, 11.6 mmol) was added to 120 mL of ethanol, and iron powder (12.9 g, 232 mmol) and saturated ammonium chloride (40 mL) were added in this order at room temperature, and the mixture was reacted for 15 minutes while stirring at 80 ° C. The mixture was suction filtered through diatomaceous earth while still hot, washed with 30 mL of methanol, and the filtrate was concentrated. The residue was partitioned between 60 mL of water and 60 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted four times with 60 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of water, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound (R)-2-(1-benzyl-2-(5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)hydrazinyl)but-1-ol (2.45 g, yield 44%). 1 H NMR(400MHz,CDCl3)δ7.99(d,J=8.4Hz,3H),7.71(s,1H),7.45(d,J=4.1Hz,1H),7.26-7.16(m,7H),6.75(d,J=3.9Hz,1H),5.77(s,1H),4. 03-3.90(m,2H),3.89-3.64(m,2H),2.36(s,3H),1.86-1.69(m,2H),1.50-1.39(m,1H),1.26(t,J=7.1Hz,1H),0.95(t,J=7.6Hz,3H).LCMS ESI(+)m / z:480.1(M+1).

[0222] Step G: The compound (R)-2-(1-benzyl-2-(5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)hydrazinyl)but-1-ol (480 mg, 1.0 mmol) was dissolved in 6 mL of acetic acid, and triethyl orthoformate (222 mg, 1.5 mmol) was added under nitrogen gas. The mixture was stirred at 100° C. for 15 minutes under nitrogen gas. The reaction solution was decompressed and the solvent was distilled off. The resulting residue was passed through silica gel column chromatography (pure substance of ethyl acetate) to obtain the compound (R)-2-(benzyl(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)but-1-ol (316 mg, 65% yield). LCMS ESI(+)m / z:490.1(M+1).

[0223] Step H: With cooling in an ice bath and nitrogen gas protection, compound (R)-2-(benzyl(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amino)but-1-ol (316 mg, 0.65 mmol), DBU (491 mg, 3.23 mmol) and DPPA (533 mg, 1.94 mmol) were added to 8 mL of toluene. The temperature was raised to 100 ° C. and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was passed through silica gel column chromatography to obtain compound (R)-N-(1-azidobut-2-yl)-N-benzyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amine (216 mg, yield 65%). LCMS ESI(+)m / z:515.2(M+1).

[0224] Step I: The compound (R)-N-(1-azidobut-2-yl)-N-benzyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amine (167 mg, 0.33 mmol) was dissolved in 8 mL of dichloromethane, and anhydrous aluminum chloride (346 mg, 2.6 mmol) was added under nitrogen gas protection and stirred at room temperature for 1 hour. 10 mL of saturated sodium bicarbonate was added to the reaction solution and stirred for 5 minutes. Extracted three times with 15 mL of dichloromethane, the organic phases were combined, washed with 10 mL of saturated saline, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was passed through silica gel column chromatography to obtain the compound (R)-N-(1-azidobut-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amine (89 mg, yield 62%). 1 H NMR(400MHz,CDCl3)δ8.90(s,1H),8.22(s,1H),8.12(d,J=8.4Hz,2H),7.83(d,J=4.0Hz,1H),7.28(d,2H),7.03(d,J=4.0Hz,1 LCMS ESI(+)m / z:425.0(M+1).

[0225] Step J: The compound (R)-N-(1-azidobut-2-yl)-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)amine (86 mg, 2.59 mmol) was dissolved in 6 mL of methanol, and 10% palladium carbon (43 mg) was added under nitrogen gas protection. The mixture was replaced with hydrogen gas, and stirred at 35°C for 2 hours under hydrogen gas atmosphere. The mixture was filtered by suction and washed with 10 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the compound (R)-N 2-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)butane-1,2-diamine (79 mg, 100% yield). LCMS ESI(+)m / z: 399.1(M+1).

[0226] Step K: Compound (R)-N 2 -(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)butane-1,2-diamine (79 mg, 0.20 mmol) was dissolved in 6 mL of methanol, and paraformaldehyde (7 mg, 0.2 mmol) was added. The mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to room temperature, suction filtered, and washed with 5 mL of methanol. The filtrate was decompressed, and the solvent was distilled off to obtain the compound (R)-1-(5-ethylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (81 mg, 100% yield). 1 H NMR(400MHz,CDCl3)δ8.94-8.77(m,1H),8.13-8.07(m,2H),7.79-7.67(m,1H),7.28-7.24(m,1H),7.08(m ,1H),4.53-3.97(m,2H),3.80-3.37(m,3H),2.42-2.30(m,3H),1.83-1.59(m,2H),0.96-0.74(m,3H).LCMS ESI(+)m / z:411.1(M+1).

[0227] Step L: The compound (R)-1-(5-ethylimidazolidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (50 mg, 0.12 mmol) was dissolved in 6 mL of methanol, and 2N sodium hydroxide solution (1.5 mL, 3.0 mmol) was added. The mixture was stirred at 30°C for 16 hours. The reaction solution was diluted with 10 mL of water, and methanol was distilled off under reduced pressure. The residue was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, washed with 5 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The crude product compound (R)-1-(5-ethylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (31 mg, 100% yield) was obtained. LCMS ESI(+)m / z:257.1(M+1).

[0228] Step M: Compound (R)-1-(5-ethylimidazolidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (31 mg, 0.14 mmol) was dissolved in 6 mL of dichloromethane, and cyanoacetic acid (15 mg, 0.17 mmol), HOBT (27 mg, 0.20 mmol), 4-dimethylaminopyridine (28 mg, 0.23 mmol) and EDCI (44 mg, 0.23 mmol) were added in this order under nitrogen gas protection and ice bath. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography and high performance liquid chromatography to obtain the compound (R)-3-(4-ethyl-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)imidazolin-1-yl)-3-oxopropanenitrile (12 mg, yield 26%). 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.87-8.03(m,2H),7.47(s,1H),6.70(s,1H),5.05-4. 69(m,2H),4.30-3.68(m,4H),3.56-3.41(m,1H),1.54-1.27(m,2H),0.85-0.68(m,3H).LCMS ESI(+)m / z:324.1(M+1).

[0229] Example 33 [ka] 2-Cyano-N-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetamide The form for carrying out the invention is as follows. [ka]

[0230] Step A: tert-Butyl pyrrolidin-3-yl carbamate (4.33 g, 23.3 mmol) was dissolved in 30 mL of acetic acid and 10 mL of water, and an aqueous solution (20 mL) containing sodium nitrite (3.21 g, 46.6 mmol) was slowly added dropwise at 0°C, and the mixture was warmed to room temperature under nitrogen gas protection and stirred for 18 hours. After the reaction was completed, the mixture was quenched with water at 0°C, extracted with ethyl acetate (240 mL) in three portions, filtered, dried on a rotary evaporator, and purified to obtain the product (1-nitrosopyrrolidin-3-yl) tert-butyl carbamate (4.58 g, 93% yield). LCMS ESI(+) m / z: 216.1 (M+1).

[0231] Step B: The compound (1-nitrosopyrrolidin-3-yl) tert-butyl carbamate (4.58 g, 21.3 mmol) and zinc powder (13.8 g, 213 mmol) were suspended in acetic acid (5 mL) and methanol (50 mL) and stirred for 2 hours at room temperature under nitrogen gas protection. After the reaction was completed, the mixture was filtered and dried on a rotary evaporator to obtain the crude product (1-aminopyrrolidin-3-yl) tert-butyl carbamate (4.28 g, 100% yield). LCMS ESI(+)m / z:202.1(M+1).

[0232] Step C: The compound (1-aminopyrrolidin-3-yl) tert-butyl carbamate (7.75 g, 22 mmol) was dissolved in 100 mL of isopropanol, and (1-aminopyrrolidin-3-yl) tert-butyl carbamate (4.28 g, 21.3 mmol) and N,N-diisopropylethylamine (11 g, 85.3 mmol) were added, and the mixture was heated to 100° C. and stirred for 20 hours. After the reaction was completed, the mixture was dried using a rotary evaporator and purified by column chromatography to obtain the compound (1-((5-nitro-1-p-toluenesulfonyl-1-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyridin-3-yl) tert-butyl carbamate (6.6 g, 60% yield). LCMS ESI(+)m / z:517.1(M+1).

[0233] Step D: Compound 1-((5-nitro-1-p-toluenesulfonyl-1-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyridin-3-yl)tert-butylcarbamate (1.5 g, 2.9 mmol), iron powder (977 mg, 17.4 mmol) and ammonium chloride (311 mg, 5.8 mmol) were suspended in 12 mL of ethanol and 4 mL of water, and the mixture was heated to 75° C. under nitrogen gas protection and stirred for 1 hour. After the reaction was completed, the mixture was filtered, dried on a rotary evaporator, and purified by column chromatography to obtain the product 1-((5-amino-1-p-toluenesulfonyl-1-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyridin-3-yl)tert-butylcarbamate (770 mg, 55% yield). LCMS ESI(+)m / z:487.1.

[0234] Step E: The compound 1-((5-amino-1-p-toluenesulfonyl-1-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyridin-3-yl)tert-butylcarbamate (770 mg, 1.58 mmol), triethyl orthoformate (1 mL) and pyridine hydrochloride (18 mg, 0.16 mmol) were dissolved in 20 mL of toluene, and the mixture was heated to 115° C. under nitrogen gas protection and stirred for 2 hours. After the reaction was completed, the mixture was dried using a rotary evaporator and purified by column chromatography to obtain the compound (1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-yl)tert-butylcarbamate (700 mg, 89% yield). LCMS ESI(+)m / z:497.1.

[0235] Step F: The compound (1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-yl) tert-butyl carbamate (700 mg, 1.41 mmol) was dissolved in 10 mL of dichloromethane, trifluoroacetic acid (2 mL) was added at 0° C., and the mixture was stirred at room temperature for 5 hours under nitrogen gas protection. After the reaction was completed, the mixture was dried using a rotary evaporator to obtain the crude product compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-amino trifluoromethanesulfonate (560 mg, crude yield 100%). LCMS ESI(+)m / z:397.1(M+1).

[0236] Step G: Compound 1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-amino trifluoromethanesulfonate (360 mg, 0.91 mmol) was dissolved in 10 mL of methanol, and aqueous sodium hydroxide solution (2N, 3 mL) was added at 0 ° C., and the mixture was stirred at 30 ° C. for 18 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, the pH was adjusted to 8-9, and the mixture was extracted with dichloromethane (6 × 50 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, dried on a rotary evaporator, and purified by column chromatography to obtain compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-amino (140 mg, yield 64%). LCMS ESI(+)m / z:243.1(M+1).

[0237] Step H: Compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-amino (70 mg, 0.29 mmol), 2-cyanoacetic acid (29 mg, 0.35 mmol) and HATU (165 mg, 0.43 mmol) were dissolved in 5 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (112 mg, 0.87 mmol) was added at 0° C., and the mixture was stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness. The product was purified by high performance liquid chromatography to obtain the compound 2-cyano-N-(1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetamide (30 mg, yield 34%). 1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.76(d,J=6.8Hz,1H),8.57(s,1H),8.46(s,1H),7.47(t,J=3.0Hz,1H),6.75(dd,J=3.6,2.0Hz,1H),4.56-4.48 (m,1H),3.70(d,J=1.4Hz,2H),3.68-3.63(m,1H),3.56-3.50(m,1H),3.45- 3.39(m,1H),3.27-3.24(m,1H),2.50-2.44(m,1H),1.99-1.90(m,1H).LCMS ESI(+)m / z:310.1(M+1).

[0238] Example 34 [ka] 2-((1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)amino)acetonitrile [ka]

[0239] Step A: Compound 1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyridin-3-amino (70 mg, 0.29 mmol) and bromoacetonitrile (42 mg, 0.35 mmol) were dissolved in 5 mL of N,N-dimethylformamide, triethylamine (88 mg, 0.87 mmol) was added at 0°C, and the mixture was stirred at room temperature for 16 hours under nitrogen gas protection. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with dichloromethane (5 x 50 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator. Compound 2-((1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)amino)acetonitrile (12 mg, 15% yield) was obtained. 1H NMR(400MHz,CD3OD-d4)δ9.03(s,1H),9.85(s,1H),7.66(d,J=3.4Hz,1H),7.20(d,J=3.4Hz,1H),4.09(s,2H),4.07 LCMS ESI(+)m / z:282.1(M+1).

[0240] Example 35 [ka] (3S,5R)-5-Ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-3-carbonitrile The form for carrying out the invention is as follows. [ka]

[0241] Step A: The compound (2S,4R)-N-Cbz-2-ethyl carboxylate-4-hydroxypyrrolidine (20.0 g, 71.6 mmol) was dissolved in 70 mL of N,N-dimethylformamide, and imidazole (10.7 g, 158 mmol) and TBDPSCl (23.6 g, 85.9 mmol) were added at room temperature and stirred for 16 hours. The reaction solution was poured into water (700 mL), extracted with ethyl acetate (3 x 60 mL), the organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The obtained residue was passed through silica gel column chromatography to obtain the compound (2S,4R)-N-Cbz-2-ethyl carboxylate-4-O-TBDPS pyrrolidine (34.3 g, yield 92%). 1H NMR(400MHz,CDCl3)δ7.65-7.56(m,4H),7.46-7.30(m,11H),5.23-5.04(m,2H),4.60-4.47(m,1H),4.4 1(m,1H),3.70-3.47(s,3H),3.65-3.49(m,2H),2.29-2.21(m,1H),1.93-1.83(m,1H),1.03(s,9H).LCMS ESI(+)m / z:518.2(M+1).

[0242] Step B: The compound (2S,4R)-N-Cbz-2-ethyl carboxylate-4-O-TBDPS pyrrolidine (10.0 g, 19.3 mmol) was dissolved in 80 mL of ethanol (volume ratio is 10:1), and sodium borohydride (2.19 g, 58.0 mmol) was added in several portions in an ice bath. The temperature was raised to room temperature and stirred for 16 hours. The reaction was quenched with 1N hydrochloric acid solution and adjusted to neutral. The reaction solution was concentrated under reduced pressure. It was extracted three times with a mixed solvent of methanol / ethyl acetate (volume ratio is 10:1, 200 mL). The organic phases were combined, washed with 100 mL of saturated saline, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, and the filtrate was concentrated under reduced pressure to obtain the compound (2S,4R)-N-Cbz-2-hydroxymethyl-4-O-TBDPS pyrrolidine (8.92 g, yield 94%). 1 H NMR(400MHz,CDCl3)δ7.67-7.56(m,4H),7.46-7.29(m,11H),5.21-5.09(m,2H),4.38-4.25(m, 2H),3.74-3.50(m,3H),3.31-3.20(m,1H),2.08-1.97(m,1H),1.56-1.45(m,1H),1.03(s,9H).

[0243] Step C: The compound (2S,4R)-N-Cbz-2-hydroxymethyl-4-O-TBDPS pyrrolidine (23.0 g, 4.96 mmol) was dissolved in 700 mL of dichloromethane and Dess-Martin periodinane (29.9 g, 70.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was filtered through diatomaceous earth and washed with 50 mL of dichloromethane. Saturated sodium bicarbonate (200 mL) was added to the filtrate and stirred for 30 minutes. The mixture was filtered through suction, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (100 mL). The organic phases were combined, washed with 30 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Compound (2S,4R)-N-Cbz-2-formaldehyde-4-O-TBDPS pyrrolidine (14.0 g, 61% yield) was obtained by silica gel column chromatography. 1 H NMR(400MHz,CDCl3)δ9.45(dd,J=57.2,2.9Hz,1H),7.68-7.55(m,4H),7.49-7.29(m,11H),5.25-5.09(m ,2H),4.57-4.34(m,2H),3.74-3.34(m,2H),2.10(t,J=10.3Hz,1H),1.88-1.77(m,1H),1.05(s,9H).LCMS ESI(+)m / z:488.2(M+1).

[0244] Step D: Potassium tert-butoxide (6.44 g, 57.4 mmol) was added to a solution of methyltriphenylphosphonium bromide (20.5 g, 57.4 mmol) in tetrahydrofuran (150 mL) under ice bath and nitrogen gas protection. The mixture was heated to 30° C. and stirred for 30 min. The reaction was cooled to 0° C. and a solution of the compound (2S,4R)-N-Cbz-2-formaldehyde-4-O-TBDPS pyrrolidine (14.0 g, 28.7 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred for 1 h while maintaining the temperature. The reaction was charged with water (150 mL) and EA (150 mL), the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (150 mL). The organic phases were combined, washed with water (100 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure. Compound (2S,4R)-N-Cbz-2-vinyl-4-O-TBDPS pyrrolidine (13.0 g, yield 93%) was obtained by silica gel column chromatography. 1 H NMR(400MHz,CDCl3)δ7.73-7.57(m,4H),7.49-7.27(m,11H),5.77-5.58(m,1H),5.22-4.90(m,4H),4.61-4.42(m,1H) ),4.39-4.31(m,1H),3.64-3.45(m,1H),3.46-3.28(m,1H),2.18-2.05(m,1H),1.78-1.62(m,1H),1.04(s,9H).LCMS ESI(+)m / z:487.2(M+1).

[0245] Step E: A 1.0M solution of n-butylammonium fluoride trihydrate in tetrahydrofuran (53.5mL, 53.5mmol) was added dropwise to a solution of the crude product (2S,4R)-N-Cbz-2-vinyl-4-O-TBDPS pyrrolidine in tetrahydrofuran (20mL) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the compound (2S,4R)-N-Cbz-2-vinyl-4-hydroxypyrrolidine (6.15g, 93% yield). 1H NMR(400MHz,CDCl3)δ7.42-7.27(m,5H),5.86-5.67(m,1H),5.25-5.00(m,4H),4 .57-4.40(m,2H),3.70-3.47(m,2H),2.21-2.06(m,1H),1.97-1.86(m,1H).LCMS ESI(+)m / z:248.1(M+1).

[0246] Step F: The compound (2S,4R)-N-Cbz-2-vinyl-4-hydroxypyrrolidine (2.00 g, 8.09 mmol) was dissolved in 50 mL of dichloromethane, and triethylamine (2.25 mL, 16.2 mmol) and methanesulfonyl chloride (1.39 g, 12.1 mmol) were added dropwise in an ice bath under nitrogen gas protection. The mixture was stirred in an ice bath for 3 hours. Water (50 mL) was added and the mixture was stirred for 15 minutes. Ethyl acetate (150 mL) was added, and the organic phase was separated, washed twice with water (30 mL), washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain the crude product compound (2S,4R)-N-Cbz-2-vinyl-4-methanesulfonatopyrrolidine (2.63 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ7.45-7.28(m,5H),5.88-5.66(m,1H),5.28-5.04(m,5H),4.60-4.46(m, 1H),4.06-3.84(m,1H),3.74-3.61(m,1H),3.00(s,3H),2.57-2.41(m,1H),2.13-2.01(m,1H).

[0247] Step G: The compound (2S,4R)-N-Cbz-2-vinyl-4-methanesulfonatopyrrolidine (2.63 g, 8.08 mmol) was dissolved in 50 mL of anhydrous N,N-dimethylformamide (50 mL) and sodium cyanide solution (1.19 g, 24.3 mmol) was added under nitrogen gas. The mixture was stirred at 80°C for 7 hours and then at 100°C for 2 hours. The reaction solution was poured into 300 mL of water, extracted with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with water (50 mL), washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure. The compound (2S,4S)-N-Cbz-2-vinyl-4-cyanopyrrolidine (1.17 g, 56% yield) was obtained by silica gel column chromatography. 1 H NMR(400MHz,CDCl3)δ7.43-7.29(m,6H),5.95-5.81(m,1H),5.34-5.06(m,4H),4.50-4.39(m,1H),4 .08-3.89(m,1H),3.71-3.62(m,1H),3.14-3.03(m,1H),2.58-2.47(m,1H),2.17-2.03(m,1H).LCMS ESI(+)m / z:257.1(M+1).

[0248] Step H: The compound (2S,4S)-N-Cbz-2-vinyl-4-cyanopyrrolidine (1.17 g, 4.56 mmol) was dissolved in 30 mL of methanol, and 10% palladium carbon (234 mg) was added under nitrogen gas protection. The atmosphere was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours. The mixture was filtered by suction and washed twice with 10 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the compound (3S,5R)-5-ethyl-pyrrolidine-3-methylcyanide (567 mg, 100% yield). LCMS ESI(+) m / z: 125.1 (M+1).

[0249] Step I: The compound (3S,5R)-5-ethyl-pyrrolidine-3-methylcyanide (456 mg, 4.57 mmol) was dissolved in 25 mL of dichloromethane, and sodium nitrite (347 mg, 5.03 mmol) and p-toluenesulfonic acid monohydrate (847 mg, 5.03 mmol) were added in this order at room temperature. The mixture was stirred for 3 hours, filtered, the filter cake was washed with 20 mL of dichloromethane, and the filtrate was concentrated under reduced pressure to obtain the compound (3S,5R)-1-nitroso-5-ethyl-pyrrolidine-3-methylcyanide (210 mg, 24% yield) by silica gel column chromatography. 1 H NMR(400MHz,CDCl3)δ4.52-4.40(m,1H),4.31-4.19(m,1H),3.74-3.65(m,1H),3.20-3.09(m,1H),2. 75-2.63(m,1H),2.40-2.28(m,1H),2.26-2.12(m,1H),2.01-1.90(m,1H),1.09(t,J=7.4Hz,3H).LCMS ESI(+)m / z:128.1(M+1).

[0250] Step J: The compound (3S,5R)-1-nitroso-5-ethyl-pyrrolidine-3-methylcyanide (210 mg, 1.37 mmol) was dissolved in 6 mL of methanol, and zinc powder (896 mg, 13.7 mmol) was added at room temperature, followed by dropwise addition of acetic acid (2 mL). The mixture was stirred at 30°C for 2 hours. The reaction solution was suction filtered, washed with 5 mL of methanol, and the filtrate was concentrated. The residue was extracted with 15 mL of dichloromethane, suction filtered, and the filtrate was concentrated to obtain an oily product, (3S,5R)-1-amino-5-ethyl-pyrrolidine-3-methylcyanide, which was used directly in the next step. LCMS ESI(+)m / z:140.1(M+1).

[0251] Step K: The crude product of the previous step, compound (3S,5R)-1-amino-5-ethyl-pyrrolidine-3-methylcyanide, was dissolved in 12 mL of isopropanol, and N,N-diisopropylethylamine (1.86 g, 14.4 mmol) and compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (758 mg, 2.16 mmol) were added in this order, and the mixture was heated to 85 ° C. under nitrogen gas protection and reacted for 16 hours with stirring. The reaction solution was concentrated and subjected to silica gel column chromatography to obtain compound (3S,5R)-5-ethyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide (282 mg, 43% yield for both steps). 1 H NMR(400MHz,CDCl3)δ9.17(s,1H),8.08(d,J=8.4Hz,2H),7.60(d,J=4.0Hz, 1H),7.47(d,J=4.0Hz,1H),7.31(d,J=8.1Hz,2H),3.61(d,J=9.6Hz,1H),3.2 1-3.13(m,1H),2.98-2.90(m,1H),2.80-2.73(m,1H),2.62-2.53(m,1H),2. 40(s,3H),1.52-1.43(m,1H),1.31-1.22(m,2H),0.87(t,J=7.5Hz,3H).LCMS ESI(+)m / z:455.1(M+1).

[0252] Step L: The compound (3S,5R)-5-ethyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide (250 mg, 0.55 mmol) was added to 12 mL of ethanol, and iron powder (922 mg, 16.5 mmol) and saturated ammonium chloride (2 mL) were added in this order at room temperature, and the mixture was reacted for 0.5 hours with stirring at 80 ° C. The mixture was suction filtered through diatomaceous earth while still hot, washed with 10 mL of methanol, and the filtrate was concentrated. The residue was partitioned between 6 mL of water and 20 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated saline, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude product, compound (3S,5R)-5-ethyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide, which was used directly in the next step. LCMS ESI(+)m / z: 425.1(M+1).

[0253] Step M: The crude product, compound (3S,5R)-5-ethyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methyl cyanide, triethyl orthoformate (122 mg, 0.82 mmol) and pyridine hydrochloride (6 mg, 0.05 mmol) were placed in 15 mL of toluene. The temperature was raised to 115° C. under nitrogen gas and stirred for 2 hours. The reaction solution was decompressed and the solvent was distilled off. The obtained residue was passed through silica gel column chromatography to obtain compound (3S,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-3-methyl cyanide (82 mg, yield 34%). 1H NMR(400MHz,CDCl3)δ8.90(s,1H),8.23-8.08(m,3H),7.81(s,1H),7.29(d,J=8.0Hz,2H),7.00(s,1H),3.86-3.72(m,1H) ),3.60-3.27(m,3H),2.74-2.63(m,1H),2.36(s,3H),2.19-2.09(m,1H),1.52-1.40(m,2H),0.80(t,J=7.5Hz,3H).LCMS ESI(+)m / z:435.1(M+1).

[0254] Step N: The compound (3S,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-3-methylcyanide (79 mg, 0.18 mmol) was dissolved in 6 mL of methanol, and 1N sodium hydroxide solution (2.0 mL, 2.0 mmol) was added. The mixture was stirred at 30°C for 7 hours. The reaction solution was diluted with 10 mL of water, and methanol was distilled off under reduced pressure. The residue was extracted four times with 10 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the compound (3S,5R)-5-ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-3-carbonitrile (20 mg, yield 40%). 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),9.10-8.01(m,2H),7.46(s,1H),6.76(s,1H),3.92-3.52(m,4H), 2.67(s,1H),1.98-1.87(m,1H),1.40-1.26(m,2H),0.72(t,J=7.4Hz,3H).LCMSESI(+)m / z:281.2(M+1).

[0255] Example 36 [ka] 2-((5R)-5-Ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile The form for carrying out the invention is as follows. [ka]

[0256] Step A: The compound (2S,4R)-N-Cbz-2-vinyl-4-hydroxypyrrolidine (3.50 g, 14.2 mmol) was dissolved in 200 mL of methanol, and 10% palladium carbon (700 mg) was added under nitrogen gas protection. The atmosphere was replaced with hydrogen gas. The mixture was stirred at room temperature for 16 hours. The mixture was filtered by suction and washed twice with 20 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the compound (2S,4R)-2-ethyl-4-hydroxypyrrolidine (1.63 g, 100% yield). 1 H NMR(400MHz,CDCl3)δ4.42(t,J=5.0Hz,1H),3.37-3.27(m,1H),3.19(dd,J=11.9,4.7Hz,1H),2.9 2(d,J=11.9Hz,1H),1.95(dd,J=13.5,6.4Hz,1H),1.62-1.37(m,3H),0.95(t,J=7.4Hz,3H).LCMS ESI(+)m / z:116.1(M+1).

[0257] Step B: The compound (2S,4R)-2-ethyl-4-hydroxypyrrolidine (1.63 g, 14.2 mmol) was dissolved in 70 mL of dichloromethane, and sodium nitrite (1.46 g, 21.2 mmol) and p-toluenesulfonic acid monohydrate (4.04 g, 21.2 mmol) were added in this order at room temperature. The mixture was stirred for 3 hours, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the compound (2S,4R)-1-nitroso-2-ethyl-4-hydroxypyrrolidine (1.78 g, 87% yield) was obtained by silica gel column chromatography. 1H NMR(400MHz,CDCl3)δ4.63-4.52(m,2H),3.86(d,J=15.8Hz,1H),3.61(ddd,J=15.5 ,4.8,1.7Hz,1H),2.37-2.26(m,2H),1.96-1.74(m,3H),1.04(t,J=7.5Hz,3H).LCMS ESI(+)m / z:145.1(M+1).

[0258] Step C: The compound (2S,4R)-1-nitroso-2-ethyl-4-hydroxypyrrolidine (950 mg, 6.59 mmol) was dissolved in 45 mL of methanol, and zinc powder (8.62 g, 132 mmol) was added at room temperature, followed by dropwise addition of acetic acid (9 mL). The mixture was stirred at 30°C for 20 minutes. The reaction solution was suction filtered, washed with 5 mL of methanol, and the filtrate was concentrated to obtain an oily product, (2S,4R)-1-amino-2-ethyl-4-hydroxypyrrolidine, which was used directly in the next step. LCMS ESI(+)m / z:131.1(M+1).

[0259] Step D: The crude product of the previous step, compound (2S,4R)-1-amino-2-ethyl-4-hydroxypyrrolidine, was dissolved in 50 mL of isopropanol, and N,N-diisopropylethylamine (4.70 mL, 26.3 mmol) and compound 4-chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.01 g, 8.56 mmol) were added in this order, and the mixture was heated to 85 ° C. under nitrogen gas protection and reacted for 16 hours with stirring. The reaction solution was concentrated and the compound (3R,5R)-5-ethyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide (1.61 g, 55% yield) was obtained by silica gel column chromatography. 1H NMR(400MHz,CDCl3)δ9.46(s,1H),9.07(s,1H),8.07(d,J=8.4Hz,2H),7.51(t,J=4 .9Hz,1H),7.35-7.28(m,3H),4.53(d,J=5.5Hz,1H),3.67(dd,J=11.0,5.5Hz,1H), 3.19-3.09(m,1H),2.76(dd,J=11.1,3.4Hz,1H),2.40(s,3H),2.13-2.05(m,1H),1 .84-1.74(m,1H),1.68-1.62(m,2H),1.40-1.27(m,1H),0.84(t,J=7.5Hz,3H).LCMS ESI(+)m / z:446.1(M+1).

[0260] Step E: The compound (3R,5R)-5-ethyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide (1.61 g, 3.61 mmol) was added to 80 mL of ethanol, and iron powder (6.05 g, 108 mmol) and saturated ammonium chloride (20 mL) were added in this order at room temperature, and the mixture was reacted for 20 minutes with stirring at 80 ° C. The mixture was suction filtered through diatomaceous earth while still hot, washed with 10 mL of methanol, and the filtrate was concentrated. The residue was partitioned between 50 mL of water and 50 mL of ethyl acetate. The organic phase was separated, and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated saline, and dried over anhydrous sodium sulfate. Concentration under reduced pressure and silica gel column chromatography gave the compound (3R,5R)-5-ethyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methylcyanide (714 mg, yield 48%). 1H NMR(400MHz,CDCl3)δ8.00(d,J=8.4Hz,2H),7.79(s,1H),7.40(d,J=4.0Hz,1H),7.23(d,J=8 .0Hz,2H),6.89(d,J=4.0Hz,1H),5.61(s,1H),4.45(d,J=5.9Hz,1H),3.60(dd,J=11.0,5.6H z,1H),3.05-2.97(m,1H),2.58(dd,J=10.9,3.7Hz,1H),2.42-2.36(m,1H),2.35(s,3H),2.0 1(dd,J=14.1,6.6Hz,1H),1.81-1.66(m,3H),1.37-1.26(m,2H),0.85(t,J=7.5Hz,3H).LCMS ESI(+)m / z:416.1(M+1).

[0261] Step F: The compound (3R,5R)-5-ethyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-3-methyl cyanide (75 mg, 0.18 mmol) was dissolved in 1 mL of acetic acid, and triethyl orthoformate (40 mg, 0.27 mmol) was added under nitrogen gas. The mixture was stirred at 100° C. for 5 minutes under nitrogen gas. The reaction solution was decompressed and the solvent was distilled off. The resulting residue was passed through silica gel column chromatography (pure substance of ethyl acetate) to obtain the compound (3R,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-ol (55 mg, 72% yield). LCMS ESI(+)m / z:426.1(M+1).

[0262] Step G: The compound (3R,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-ol (55 mg, 0.13 mmol) was dissolved in 10 mL of dichloromethane and Dess-Martin periodinane (112 mg, 0.26 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was filtered with diatomaceous earth and washed with 10 mL of dichloromethane. Saturated sodium bicarbonate (10 mL) was added to the filtrate and stirred for 30 minutes. The mixture was filtered with suction, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (10 mL). The organic phases were combined, washed with 5 mL of brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Silica gel column chromatography afforded the compound (3R,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-one (25 mg, 45% yield). LCMS ESI(+)m / z:424.1(M+1).

[0263] Step H: Diethyl (cyanomethyl)phosphonate (67 mg, 0.38 mmol) was dissolved in 8 mL of tetrahydrofuran, and 60% sodium hydride (15 mg, 0.38 mmol) was added in an ice bath and nitrogen gas protection. The mixture was stirred at room temperature for 0.5 hours. A tetrahydrofuran solution (1 mL) of the compound (3R,5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-one (80 mg, 0.19 mmol) was added in an ice bath and nitrogen gas protection. The mixture was stirred for 2 hours in an ice bath. 5 mL of saturated ammonium chloride solution was added, the mixture was warmed to room temperature, and the mixture was stirred for 5 minutes. Extracted with ethyl acetate (3 x 5 mL), the organic phases were combined, washed with 3 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude product compound (R)-2-(5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-ylidene)acetonitrile was used directly in the next step. LCMS ESI(+) m / z: 447.1 (M+1).

[0264] Step I: The crude product, compound (R)-2-(5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-ylidene)acetonitrile, was dissolved in 10 mL of methanol, and 10% palladium carbon (84 mg) was added under nitrogen gas protection. Hydrogen gas was substituted. The mixture was stirred at room temperature for 16 hours. The mixture was filtered by suction and washed twice with 5 mL of methanol. The filtrate was concentrated under reduced pressure, and the compound 2-((5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile (67 mg, 79% yield) was obtained by silica gel column chromatography. LCMS ESI(+)m / z:449.2(M+1).

[0265] Step J: Compound 2-((5R)-5-ethyl-1-(6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile (30 mg, 0.06 mmol) was dissolved in 3 mL of methanol and 1N sodium hydroxide solution (1.0 mL, 1.0 mmol) was added. The mixture was stirred at 30°C for 6 hours. The residue was extracted four times with 5 mL of ethyl acetate. The organic phases were combined, washed with 1 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and high performance liquid chromatography to obtain compounds 2-((3S,5R)-5-ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile (36-1, 10 mg, yield 58%) and 2-((3R,5R)-5-ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile (36-2, 8 mg, yield 20%).

[0266] Compound 36-1: 2-((3S,5R)-5-ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile: 1 H NMR(400MHz,DMSO-d6)δ11.79(s,1H),9.10-7.84(m,2H),7.42(s,1H),6.84(s,1H),3.94-3.44(m,2H), 3.37-3.25(m,2H),3.05-2.71(m,3H),1.52-1.40(m,1H),1.35-1.19(m,2H),0.69(t,J=7.5Hz,3H).LCMS ESI(+)m / z:295.1(M+1).

[0267] Compound 36-2: 2-((3R,5R)-5-ethyl-1-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-3-yl)acetonitrile: 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.56(s,2H),7.44(s,1H),6.74(s,1H),3.73-3.53(m,2H),3.30-3.22(m, 1H),2.83(d,J=6.6Hz,2H),2.74-2.66(m,1H),2.11-1.90(m,2H),1.38-1.22(m,2H),0.71(t,J=7.4Hz,3H).LCMS ESI(+)m / z:295.1(M+1).

[0268] Example 37 Detecting the activity of small molecule inhibitors of JAK kinases Test plan

[0269] 1. Reagent Preparation (1) Kinase reaction buffer Kinase reaction buffer was prepared. Ingredients: HEPES 50 mM, pH 7.5, EGTA 1 mM, MgCl2 10 mM, DTT 2 mM, 0.01% Tween 20

[0270] (2) 1X Detection Buffer Detection buffer was prepared by diluting 10X detection buffer to 1X measurement buffer with deionized water 9:1.

[0271] (3) 4X kinase solution JAK kinases were diluted in kinase reaction buffer to 4X final concentration (JAK1: 40 nM, JAK2: 0.5 nM).

[0272] (4)4X substrate solution Light in kinase reaction buffer TM -JAK-1 (Tyr1023) substrate was diluted to 200 nM (final concentration: 50 nM).

[0273] (5)4X ATP solution ATP was diluted in kinase reaction buffer to a 4X final concentration (JAK1: 160 μM, JAK2: 40 μM).

[0274] (6) 4X measurement compound solution The test compounds were dissolved in DMSO to a 10 mM stock solution and diluted in a 3-fold gradient to the target concentration. Ten concentration points were set for each compound, and the final concentrations of the test compounds were in the range of 10 μM-0.5 nM.

[0275] (7) 4X Enzyme Reaction Stop Solution: EDTA was dissolved in 1× detection buffer to 40 mM (final EDTA concentration: 10 mM).

[0276] (8) 4X detection antibody solution The Eu-labeled detection antibody (anti-phosphotyrosine (PT66)) was diluted to 8 nM (final antibody concentration: 2 nM) with 1× detection buffer.

[0277] 2. Testing Process (1) 2.5 μL of 4X kinase solution and 2.5 μL of 4X test compound solutions of different diluted concentrations were placed in a 384-well microplate in that order, with two replicate wells for each concentration, and a blank control group and a negative control group (DMSO group) for the enzyme solution were also placed.

[0278] (2) The 384-well plate was shaken to mix the enzyme and compound uniformly, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes.

[0279] (3) 2.5 μL of 4× substrate solution was added to a 384-well plate and centrifuged at 1000 rpm for 1 minute.

[0280] (4) 2.5 μL of 4X ATP solution was added to a 384-well plate and centrifuged at 1000 rpm for 1 minute to initiate the enzyme reaction.

[0281] (5) JAK1 was reacted at room temperature for 2 hours, and JAK2 was reacted at room temperature for 1 hour.

[0282] (6) The final concentrations of each component in the JAK1 reaction were JAK1: 10 nM, substrate: 50 nM, and ATP: 40 uM, and the final concentrations of the test compounds ranged from 10 μM to 0.5 nM. The final concentrations of each component in the JAK2 reaction were JAK2: 0.125 nM, substrate: 50 nM, and ATP: 10 μM, and the final concentrations of the test compounds ranged from 10 μM to 0.5 nM.

[0283] (7) After the enzyme reaction was completed, 5 μL of 4X enzyme reaction stop solution was added to each well of the 384-well plate, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 5 minutes.

[0284] (8) 5 μL of 4× detection antibody solution was added to each well of a 384-well plate (final concentration of detection antibody was 2 nM), centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 1 hour.

[0285] (9) After antibody incubation was completed, the signal value of each well was measured using an Envision plate reader.

[0286] 3. Data Analysis (1) The blank control group of the enzyme solution was set to a 100% inhibition rate, and the negative control group (DMSO group) was set to a 0% inhibition rate, and the percentage inhibition rate corresponding to each concentration of the detected compound was calculated.

[0287] (2) Using the software GraphPad Prism, nonlinear regression analysis was performed on the logarithmic values ​​of the concentrations of the detected compounds and the corresponding percentage inhibition rates to obtain the half inhibitory concentration (IC 50 ) were obtained, and the test results are shown in Table 1.

[0288] [Table 1]

Claims

1. A cyclic hydrazine derivative substituted with a cyano group, selected from compounds represented by the following structural formula, or pharma- ceutically acceptable salts thereof: 【Chemistry 1】 A cyclic hydrazine derivative substituted with a cyano group,

2. A compound represented by the following structural formula, or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】 The cyclic hydrazine derivative substituted with a cyano group according to claim 1 .

3. A compound represented by the following structural formula, or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 The cyclic hydrazine derivative substituted with a cyano group according to claim 1 .

4. A pharmaceutical composition comprising the cyclic hydrazine derivative substituted with a cyano group according to any one of claims 1 to 3 and at least one of a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle, A pharmaceutical composition, wherein the amount of the cyclic hydrazine derivative substituted with a cyano group used is 0.01-99.9% of the total mass of the pharmaceutical composition.

5. further comprising an additional therapeutic agent; 5. The pharmaceutical composition of claim 4, wherein the additional therapeutic agent is selected from anti-inflammatory drugs, immunomodulatory or immunosuppressive agents, neurotrophic factors, active agents for treating cardiovascular disease, active agents for treating diabetes, and active agents for treating autoimmune diseases.

6. Use of a cyclic hydrazine derivative substituted by a cyano group as defined in any one of claims 1 to 3, or a pharmaceutical composition as defined in claim 4 or 5, in the preparation of a medicament, wherein the medicament is for use in preventing, managing, treating or alleviating an autoimmune or proliferative disease in a patient, and / or for inhibiting or modulating the activity of a protein kinase.

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