Prodrugs of JAK kinase inhibitors

Abstract

The present invention relates to prodrugs, compositions and uses thereof containing JAK inhibitors, in particular to compounds of formula (II), pharmaceutical compositions containing the compounds of the invention, and their use as prodrugs of JAK inhibitors in the treatment of inflammatory and tumor-related diseases. TIFF2025528916000090.tif72153

Description

[Technical Field]

[0001] The present invention belongs to the field of medicinal chemistry, and the present invention specifically relates to prodrugs of JAK enzyme inhibitors, as well as methods for preparing and using the same. [Background technology]

[0002] Inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn's disease (CD) IBD (Intestinal Bowel Disease) significantly impacts patients' quality of life. During the active phase of the disease, common IBD symptoms include diarrhea, rectal bleeding, abdominal pain, weight loss, fatigue, nausea, and vomiting. In 2018, there were 12.6 million cases of ulcerative colitis and 6.1 million cases of Crohn's disease worldwide, and these numbers are expected to increase to 13.5 million and 6.5 million, respectively, by 2027.

[0003] Various treatment approaches exist for inducing and maintaining disease remission in IBD patients, but each has limitations. Aminosalicylates are generally effective in mild disease but are less effective in moderate and severe disease. Furthermore, maintaining treatment with long-term steroid use poses safety concerns (e.g., osteoporosis, muscle wasting, and neurological and psychiatric disorders). Systemic immunosuppressants such as azathioprine, mercaptopurine, and methotrexate generally provide therapeutic benefit in moderate to severe disease, but long-term use carries the risk of increased infection and lymphoma. Anti-tumor necrosis factor (TNF) antibodies (e.g., infliximab and adalimumab) require subcutaneous or intravenous injection, and many first-time users fail to respond adequately, with one-third of responding patients eventually losing their response due to the development of drug resistance.

[0004] Current unmet clinical needs require effective oral therapies to induce and maintain remission in IBD and avoid the safety issues associated with chronic systemic immune suppression. Directing pharmaceuticals to the intestinal mucosa is a way to achieve this goal. Compounds or formulations with appropriate physical properties can achieve targeted delivery to the intestinal tract. Another option is to generate the active parent drug by enzymatic cleavage of inactive prodrugs during gastrointestinal transit. Because the enhancement of many inflammatory cytokines in ulcerative colitis (e.g., IL-6, IL-13, IL-15, IL-23, and IFNγ) and Crohn's disease (e.g., IL-13, IL-15, IL-22, IL-24, and IL-27) depends on signaling from the Janus kinase (JAK) tyrosine kinase family, inhibiting JAKs may be beneficial for the treatment of these diseases. Currently, the FDA and EMA have approved tofacitinib for the treatment of moderately to severely active ulcerative colitis, and upadacitinib was approved in March 2022 for the treatment of moderately to severely active ulcerative colitis. These drugs have demonstrated relatively excellent therapeutic efficacy for Crohn's disease in clinical trials. However, the FDA has issued a black box warning for these JAK inhibitors because they increase the risk of cancer, blood clots, adverse cardiac events, and death. Selective inhibition of intestinal JAKs may be sufficient to achieve clinical efficacy, potentially separating the beneficial anti-inflammatory effects of JAK inhibitors from potentially harmful systemic exposure.

[0005] Therefore, it can be used in clinical practice to treat local inflammation or local immune diseases, achieving good therapeutic effects while avoiding the above-mentioned toxicity caused by systemic exposure. There is an urgent need to develop new JAK inhibitors that can effectively treat inflammatory bowel diseases (Crohn's disease, ulcerative colitis). Specifically, it is extremely important to develop orally administrable JAK inhibitors that can treat inflammatory bowel diseases (Crohn's disease, ulcerative colitis) with minimal systemic exposure. Summary of the Invention

[0006] The present invention provides prodrugs of JAK inhibitors that are cleaved by enzymes produced by microorganisms in the gastrointestinal tract, thereby releasing the JAK inhibitor in a targeted or localized manner in the gastrointestinal tract, thereby increasing the level of the JAK inhibitor at the site of gastrointestinal inflammation, enhancing therapeutic efficacy, and minimizing systemic exposure to the JAK inhibitor, thereby reducing side effects.

[0007] On the one hand, the present invention provides a compound of formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, [ka] In Formula I, X is CR a or N, W and Z each independently represent O, N, S, or NR b or CR c W and Z are simultaneously selected from CR c It should not be, R1 is H, halogen, CN, C 1-6 Alkyl group, C 1-6 Alkoxy group or C 1-6 halogenated alkyl groups, 1-6 Alkyl group, C 1-6 Alkoxy groups and C 1-6 the halogenated alkyl group is optionally substituted by one or more Rd; R1' is H, halogen, amino group, hydroxyl group, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups; R2 is -L1-ONO2, -L1-NHC(=O)-L2, -L1-OC(=O)-L2, -L1-C(=O)O-L2, or [ka] is selected from L1 is absent or C 1-14 (Preferably C 1-7 ) in which one, two or three methylene groups are optionally independently selected from -CH(R e )-, -C(R e )2-, C 3-5 Cycloalkylene group, -N(R e )-, -N(R e )C(=O)-, -C(=O)N(R e )-, -N(R e )S(=O)2-, -S(=O)2N(R e )-, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -S-, -S(=O)- or -S(=O)2-, Ring A is absent, C 6-14 an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclyl group, or a 3- to 14-membered carbocyclyl group; 6-14 The aryl group, 5- to 14-membered heteroaryl group, 3- to 14-membered heterocyclyl group, and 3- to 14-membered carbocyclyl group may optionally be one or more R f and optionally substituted by L2 is H, OH, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 alkyl)2, wherein C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 alkyl)2 is optionally hydrogen, halogen, —CN, C 1-6 Alkyl group, C 1-6Halogenated alkyl groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy group, -OR g , -NR g R h , -ONO2, -NO2, -S(=O)2OR g , -N=CR g R h , -COOR g , -CONHR g , -C 0-6 Alkylene-NHC(=O)R g , -C 0-6 Alkylene-C(=O)NHR g and -C(=O)NR g R h and is substituted with one or more selected from the group consisting of R3 independently represents H, OH, a halogen atom, an amino group, or -NR g R h , C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups; R a , R b , R c are independently H, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group or C 1-6 halogenated alkoxy groups; R d are independently H, halogen, CN, -NO2, OH, NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, oxo, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SC 1-6 Alkyl group, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6Alkyl group, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl group, -S(=O)N(C 1-6 alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 2-6 Alkenyl group, -C 0-6 Alkylene-C 6-14 Aryl group, -C 0-6 alkylene-5-14 membered heteroaryl group, -C 0-6 Alkylene-C 3-14 Carbocyclyl group or -C 0-6 alkylene-3- to 14-membered heterocyclyl groups, 1-6 alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -SC 1-6 Alkyl group, -S(=O)-C 1-6 Alkyl group, -S(=O)2-C 1-6 Alkyl group, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl group, -S(=O)N(C 1-6 alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 2-6 Alkenyl group, -C 0-6 Alkylene-C 6-14 Aryl group, -C 0-6 alkylene-5-14 membered heteroaryl group, -C 0-6 Alkylene-C 3-14 Carbocyclyl groups and -C 0-6 The alkylene-3- to 14-membered heterocyclyl group is optionally selected from the group consisting of H, halogen, CN, —NO2, OH, NH2, —COOH, oxo, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 2-6 Alkenyl group, C2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COO(C 1-6 alkyl), -CONH(C 1-6 alkyl), -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl group, -C 0-6 Alkylene-NHC(=O)C 1-6 Halogenated alkyl groups, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl groups, and -CON(C 1-6 substituted with one or more selected from the group consisting of alkyl); R e , R f , R g and R h are independently H, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 2-6 Alkenyl group, -C 0-6 Alkylene-C 6-14 Aryl group, -C 0-6 alkylene-5-14 membered heteroaryl group, -C 0-6 Alkylene-C 3-14 Carbocyclyl group or -C 0-6 alkylene-3- to 14-membered heterocyclyl groups, 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl group, -C(=O)-C 1-6 Alkyl group, -C(=O)-C 2-6Alkenyl group, -C 0-6 Alkylene-C 6-14 Aryl group, -C 0-6 alkylene-5-14 membered heteroaryl group, -C 0-6 Alkylene-C 3-14 Carbocyclyl groups and -C 0-6 The alkylene-3- to 14-membered heterocyclyl group is optionally selected from the group consisting of H, halogen, CN, —NO2, OH, NH2, —COOH, oxo, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -COO(C 1-6 alkyl), -CONH(C 1-6 alkyl), -C 0-6 Alkylene-NHC(=O)C 1-6 Alkyl group, -C 0-6 Alkylene-NHC(=O)C 1-6 Halogenated alkyl groups, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl groups, and -CON(C 1-6 substituted with one or more selected from the group consisting of alkyl); and n is selected from 0, 1, 2, 3, or 4, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof.

[0008] In some embodiments, X is selected from CH or N.

[0009] In some embodiments, W is selected from O, N, S, NH, or CH, preferably W is CH.

[0010] In some embodiments, Z is N, NR b or CR c is selected from.

[0011] In some embodiments, Z is selected from N, NH, or CH, preferably Z is NH.

[0012] In some embodiments, R d is H, OH, halogen, amino group, CN, C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy group, or -NHS(=O)2-C 1-6 alkyl group, 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkoxy groups, and -NHS(=O)2-C 1-6 The alkyl group may optionally be a halogen, CN, OH, NH, -NH(C 1-6 alkyl), and -N(C 1-6 and substituted with one or more selected from the group consisting of alkyl).

[0013] In some embodiments, R1 is H or C 1-4 alkyl group, 1-4 The alkyl group is optionally selected from the group consisting of CN, C 1-6 Alkoxy group, -SC 1-6 Alkyl groups and -NHS(=O)2C 1-6 and alkyl-CN.

[0014] In some embodiments, R1 is H, -CH2-CN, -CH2-S-CH3, or [ka] is selected from.

[0015] In some embodiments, R1' is H or C 1-3 The alkyl group is selected from the group consisting of:

[0016] In some embodiments, R1' is selected from H or CH3.

[0017] In some embodiments, R e is H, amino group, C 1-4 Alkyl group, C 1-4 Halogenated alkyl group or C 1-4 The alkoxy group is selected from the group consisting of alkoxy groups.

[0018] In some embodiments, R e is selected from H, methyl, ethyl, n-propyl or isopropyl.

[0019] In some embodiments, L1 is absent or C 1-14 (Preferably C 1-4 ), wherein one, two or three methylene groups in the hydrocarbon group are optionally independently selected from the group consisting of -CH(R e )-, -C(R e )2-, C 3-5 Cycloalkylene group, -N(R e )-, -N(R e )C(=O)-, -C(=O)N(R e )-, -O-, -C(=O)-, -OC(=O)-, or -C(=O)O-.

[0020] In some embodiments, L is absent, -C 1-6 Alkylene-, -C 1-6 Alkylene-OC 1-6 Alkylene-, -C 1-6 Alkylene-OC(=O)C 1-6 Alkylene-, -C 1-6 Alkylene-OC(=O)OC 1-6 Alkylene-, -C 1-6 Alkylene-OC(=O)C 1-6 Alkylene -O-, -C 1-6 Alkylene-OC(=O)-NR a C 1-6 Alkylene- or -C 1-6Alkylene-OC(=O)-NR a wherein C is selected from 1-6 The alkylene group may optionally contain 1 to 6 R e is replaced by

[0021] In some embodiments, L1 is absent, -CH2-, -CH2CH2-, [ka] is selected from.

[0022] In some embodiments, R g , R h are independently H, C 1-6 It is selected from alkyl groups, amino or -COOH.

[0023] In some embodiments, L2 is hydrogen, OH, C 1-6 Alkyl group, C 2-6 Alkenyl group, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 alkyl)2, wherein C 1-6 Alkyl group, C 2-6 Alkenyl group, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 alkyl)2 is optionally hydrogen, halogen, CN, OH, NH2, -ONO2, -COOH, -S(=O)2OH, -N=C(NH2)2, C 1-6 Alkyl groups and -COO(C 1-6 alkyl).

[0024] In some embodiments, L2 is OH, CH3, [ka] is selected from.

[0025] In some embodiments, L2 is OH.

[0026] In some embodiments, L2 is CH3, [ka] is selected from.

[0027] In some embodiments, L2 is [ka] is selected from.

[0028] In some embodiments, R f is H, C 1-3 The alkyl group is selected from the group consisting of:

[0029] In some embodiments, ring A is absent or C 6-14 aryl groups, wherein C 6-14 The aryl group may optionally contain one or more R f may be substituted by

[0030] In some embodiments, R f is H, C 1-3 The alkyl group is selected from the group consisting of:

[0031] In some embodiments, ring A is absent or C 6-10 aryl groups.

[0032] In some embodiments, ring A is absent or selected from a benzene ring.

[0033] In some embodiments, ring A is absent, [ka] is selected from.

[0034] In some embodiments, R3 is H, hydroxyl, halogen, amino, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Halogenated alkoxy group or C 1-3 The alkoxy group is selected from the group consisting of alkoxy groups.

[0035] In some embodiments, R3 is selected from H or OH.

[0036] In some embodiments, n is selected from 1 or 2.

[0037] In some embodiments, R2 is [ka] is selected from.

[0038] In some embodiments, the compound of formula I is selected from the following compounds of formula II: [ka] The definitions of X, W, Z, R1, R1', L1, L2 and ring A in the compound of formula II are as defined above in formula I.

[0039] In some embodiments, the compound of formula I is selected from the following compounds of formula III: [ka] The definitions of X, W, Z, R1, R1', L1 and L2 in the compound of formula III are as defined in formula I above.

[0040] In some embodiments, the compound of formula I is selected from the following compounds of formula IV: [ka] The definitions of X, W, Z, R1, R1', L1 and ring A in the compound of formula IV are as defined in formula I above.

[0041] In some embodiments, the compound of formula I is selected from the following compounds of formula V: [ka] The definitions of X, W, Z, R1, R1' and L2 in the compound of formula V are as defined in formula I above.

[0042] In some embodiments, the compound of formula I is selected from the following compounds of formula VI: [ka] R4 is C 1-3 Alkylene group or C 1-3 is an alkyleneoxy group, R5 is hydrogen or C 1-3 is an alkyl group, R4 and R5 are each optionally selected from one or more R e is replaced by R e is defined as in formula I above, The definitions of X, W, Z and R1 in the compound of formula VI are as defined above for formula I.

[0043] In some embodiments, the compound of Formula I is selected from the following compounds of Formula VII: [ka] The definitions of X, W, Z, R1, R1' and L1 in the compound of formula VII are as defined above for formula I.

[0044] In some embodiments, the compound of Formula I is selected from the following compounds of Formula VIII: [ka] R5 is hydrogen or C 1-3 is an alkyl group, 1-3 The alkyl group may optionally be a group having 1-6 R e is replaced by R e is defined as in formula I above, The definitions of X, W, Z, R1 and L2 in the compound of formula VIII are as defined in formula I above.

[0045] In some embodiments, the compound of formula I is selected from the following compounds of formula IX: [ka] The definitions of X, R1, R1', L1 and ring A in the compound of formula IX are as defined in formula I above.

[0046] In some embodiments, the compound of formula I is selected from the following compounds of formula X: [ka] The definitions of X, R1, R1' and L2 in the compound represented by formula X are as defined in formula I above.

[0047] In some embodiments, the compound of formula I is selected from the following compounds of formula XI: [ka] R4 is C 1-3 Alkylene group or C 1-3 is an alkyleneoxy group, R5 is hydrogen or C 1-3 is an alkyl group, R4 and R5 are each optionally selected from one or more R e is replaced by R e is defined as in formula I above, The definitions of X and R1 in the compound of formula XI are as defined above for formula I.

[0048] In some embodiments, the compound of formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, wherein the compound of formula I is: (R,E)-5-((2-(3-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-3-oxopropyl)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((4-((((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)oxy)methyl)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((2-((1-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-methyl-1-oxopropan-2-yl)oxy)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((2-((1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)-2-hydroxybenzoic acid, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetic acid ethyl ester, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl-5-(nitrooxy)pentanoate, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycine ester, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl D-valine ester, (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl-L-valine ester, (R)-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl fumarate monomethyl (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl nitrate, 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl nitrate, 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartic acid, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysine, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid, (R)-2-(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)-5-((diaminomethylene)amino)pentanoic acid, 2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)ethane-1-sulfonic acid, (E)-2-hydroxy-5-((1-(piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)benzoic acid, (E)-5-((1-(4-(((cyanomethyl)sulfonamido)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-furan[3,2-b]imidazo[4,5-d]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, 1-(piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine, N-((1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide, 2-((1R,4R)-4-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-ethyl)cyclohexyl)acetonitrile, 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile, or 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile.

[0049] The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I above, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0050] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition further comprises an additional therapeutic agent, preferably 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, an active agent for treating diarrhea, and / or an active agent for treating an autoimmune disease.

[0051] The present invention also relates to the use of the compound of Formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a JAK inhibitor, particularly a prodrug containing the JAK inhibitor, which releases the JAK inhibitor, preferably a JAK1 and / or JAK2 inhibitor, by enzymes in the intestine.

[0052] The present invention also relates to a compound represented by formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound represented by formula I. The composition is for use in the preparation of a medicament relating to the treatment of inflammatory and / or neoplastic diseases.

[0053] The present invention also relates to a method for treating inflammatory diseases and / or neoplastic diseases, which comprises administering to a patient a therapeutically effective amount of the compound represented by formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0054] In some embodiments, the inflammatory and / or neoplastic disease is mediated by JAK.

[0055] In some embodiments, the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease, and the neoplastic disease is selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myeloid leukemia (AML), acute lymphocytic leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSCLC), where the inflammatory bowel disease is a chronic intestinal inflammatory disease, more preferably ulcerative colitis or Crohn's disease.

[0056] Definitions and Explanations The general chemical terms used in the general formula of the structure above have their usual meanings.

[0057] For example, the terms "halogenated" and "halogen" as used herein refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include fluorine, chlorine, and bromine.

[0058] In the present invention, the term "hydrocarbon chain" or "hydrocarbon group" refers to a saturated or unsaturated, straight or branched carbon chain, such as an alkyl group, an alkenyl group, or an alkynyl group. Preferred hydrocarbon chains contain 1-14 carbon atoms, more preferably 1-7 carbon atoms, and most preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, and allyl groups. Divalent "hydrocarbon chain" or "hydrocarbon group" refers to an alkylene group, non-limiting examples of which include methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCHCH-), 1,7-heptylene (-CHCHCHCHCHCHCHCH-), and the like.

[0059] In the present invention, the term "alkyl group" refers to a monovalent saturated hydrocarbon group, including straight or branched chains, and preferably includes "C 1-8 alkyl group," and more preferably "C 1-6 As used herein, alkyl groups can be optionally substituted with one or more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and the like. Similarly, "C 1-6 "C" in "Alkyl group" 1-6" refers to groups containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight, branched or cyclic arrangement.

[0060] The terms "alkenyl group" and "alkynyl group" refer to alkenyl groups and alkynyl groups including straight-chain and branched-chain alkenyl groups, preferably "C 2-8 alkenyl group" or "C 2-8 alkynyl group," and more preferably "C 2-6 alkenyl group" or "C 2-6 a Similarly, "C 2-6 Alkenyl group" and "C 2-6 An "alkynyl group" refers to an alkenyl or alkynyl group having 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain.

[0061] The term "alkoxy group" refers to the oxygen ether form of the straight or branched chain alkyl groups defined above.

[0062] The term "halogenated alkyl group" refers to an "alkyl group" as defined above substituted with one or more halogens.

[0063] As used herein, "a," "one," "the," "at least one," and "one or more" can be used interchangeably. So, for example, a composition comprising "one" pharmaceutically acceptable excipient can be interpreted to mean that the composition comprises "one or more" pharmaceutically acceptable excipients.

[0064] In the present invention, the symbol ○ appearing in a ring in the general formula means that the ring has aromaticity.

[0065] In the present invention, the term "aryl group" refers to a monocyclic, polycyclic, or fused ring aromatic group containing unsubstituted or substituted carbon atoms, unless otherwise specified, and the aryl group is preferably C 6-14 is an aryl group, 6-14 The aryl group is more preferably C 6-10is an aryl group, 6-10 The aryl group is more preferably a phenyl group.

[0066] The term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., fused-ring dicyclo) aromatic heterocycle having at least one heteroatom ring member (e.g., 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms), the heteroatom being selected from N, O, and / or S. The nitrogen or sulfur heteroatom can optionally be oxidized, and the nitrogen heteroatom can optionally be quaternized. The heteroaryl group can be attached to any heteroatom or carbon atom to form a stable structure. The heteroaryl group is preferably a 5- to 10-membered heteroaryl group, and the 5- to 10-membered heteroaryl group is more preferably a 5- to 6-membered heteroaryl group. Specific examples of heteroaryl groups include, but are not limited to, thiophene, furan, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridine, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzthiophene, benzisoxazolyl, benzoxazolyl, benzpyrazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyladeninyl, quinoline, or isoquinoline.

[0067] The term "carbocyclyl group" refers to a cyclic group that is saturated or unsaturated and has no aromatic character. Depending on the specific level of saturation, the terms "cycloalkyl group," "cycloalkenyl group," or "cycloalkynyl group" are used, respectively. Monocyclic carbocyclyl groups include, but are not limited to, similar groups such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene. Polycyclic carbocyclyl groups include spirocyclic, fused, and bridged carbocyclyl groups. The carbocyclyl group is preferably C 3-14 is a carbocyclyl group, 3-14The carbocyclyl group is more preferably C 3-8 is a carbocyclyl group, 3-8 The carbocyclyl group is more preferably C 3-6 is a carbocyclyl group, 3-8 The carbocyclyl group is more preferably C 5-6 It is a carbocyclyl group.

[0068] The term "cycloalkyl group" refers to saturated monocyclic and polycyclic ring systems containing only carbon atoms in the ring, and can be optionally substituted with one or more substituents. Polycyclic "cycloalkyl groups" include bridged, fused, and spirocyclic ring systems. Non-limiting examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, dicyclo[2.2.1]heptane, and the like. The cycloalkyl groups are preferably C 3-14 is a cycloalkyl group, 3-14 The cycloalkyl group is more preferably C 3-8 is a cycloalkyl group, 3-8 The cycloalkyl group is more preferably C 3-6 is a cycloalkyl group, 3-8 The cycloalkyl group is more preferably C 5-6 It is a cycloalkyl group.

[0069] In the present invention, the term "heterocyclyl group," unless otherwise specified, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O, or S, and includes saturated or unsaturated ring systems and polycyclic ring systems with unsaturated and / or aromatic moieties. The nitrogen or sulfur heteroatom can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. Polycyclic heterocycloalkyl groups should be understood to include fused, bridged, and spirocyclic ring systems. The heterocyclyl group is preferably a 3- to 14-membered heterocyclyl group, and the 3- to 14-membered heterocyclyl group is more preferably a 3- to 8-membered heterocyclyl group or a 5- to 10-membered heterocyclyl group, and the 3- to 8-membered heterocyclyl group is even more preferably a 3- to 6-membered heterocyclyl group, and the 3- to 6-membered heterocyclyl group is even more preferably a 5- to 6-membered heterocyclyl group. As used herein, heterocycloalkyl groups can be optionally substituted by one or more substituents. Specific examples of these heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfonyl, and tetrahydrooxadiazolyl.

[0070] However, in any case, heterocyclyl and carbocyclyl groups do not intersect or contain each other, so that, according to the above definition, a heterocyclyl group formed by condensing at least one all-carbon ring with a bi-, poly-, or spiro-ring is still defined as a heterocyclyl group.

[0071] In addition, when one heteroaryl group and one heterocyclyl group are fused to form one bi-, poly-, or spiro-ring, it is defined as a heterocyclyl group, not a heteroaryl group.

[0072] The term "substituted" means that one or more hydrogen atoms in a group are each replaced by the same or different substituents. Typical substituents are halogen (F, Cl, Br, or I), C 1-8 Alkyl group, C 3-12 Cycloalkyl groups, -OR 1 , -SR 1 , =O, =S, -C(O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C(O)NR 1 R 2 , CN, nitro, -S(O)2R 1 , -OS(O2)OR 1 , -OS(O)2R 1 , -OP(O)(OR 1 )(OR 2 ), including but not limited to R 1 and R 2 are independently -H, C 1-6 Alkyl group, C 1-6 In some embodiments, the substituents are independently selected from halogenated alkyl groups, -F, The alkyl group is selected from groups including -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), CN, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl groups.

[0073] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compounds provided by the present invention are acids, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.

[0074] Since the compound of formula I is used as a pharmaceutical, it is preferred to use a certain purity, for example at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% by weight).

[0075] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of other positions in the molecule. As can be easily understood, those skilled in the art can select the substituents and substitution patterns of the compounds of the present invention according to the prior art and the methods described in this invention to obtain chemically stable and easily synthesized compounds.

[0076] The compounds described in this invention may contain one or more asymmetric centers, thereby giving rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0077] The compounds of Formula I above do not clearly define the stereochemistry at certain positions of the compounds. The present invention includes all stereoisomers of the compounds of Formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and resolved specific stereoisomers are also included in the present invention. In the synthetic process for preparing such compounds, or in racemization or epimerization processes known to those skilled in the art, the resulting product may be a mixture of stereoisomers.

[0078] Unless otherwise specified, tautomers exist in the compounds of formula I, and the present invention includes all possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0079] When solvates or polymorphs exist for the compound of Formula I and its pharmaceutically acceptable salts, the present invention encompasses all possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited, as long as it is pharmaceutically acceptable. In the present invention, the term "composition" includes a product containing the specified amounts of each specified component, as well as any product produced directly or indirectly by combining the specified amounts of each specified component. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. Furthermore, some crystals of the compounds may exist as polymorphs, and these polymorphs are also included in the present invention. Furthermore, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.

[0080] The pharmaceutical compositions provided by this invention comprise a compound of Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and other optional therapeutic agents. The pharmaceutical compositions of the present invention may include a therapeutic ingredient or adjuvant. Although the most suitable mode of administration of the active ingredient will in any given case depend on the particular subject receiving the administration, the nature of the subject, and the severity of the condition, the pharmaceutical compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous administration, intramuscular injection, and intravenous administration) administration. The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms well known in the art and may be prepared by any of the methods well known in the art of pharmacy.

[0081] The pharmaceutical composition of the present invention can be prepared by any method known in the art of pharmacy. Usually, this method involves combining the active ingredient with a carrier that constitutes one or more necessary ingredients. Usually, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or a mixture of both. The product can then be conveniently prepared into the desired appearance.

[0082] Thus, pharmaceutical compositions of the invention include a pharmaceutically acceptable carrier and a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof. Also included in pharmaceutical compositions of the invention are combinations of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with one or more other therapeutically active compounds.

[0083] The pharmaceutical carrier used in the present invention may be, for example, a solid carrier, a liquid carrier, or a gas carrier. [Brief explanation of the drawings]

[0084] [Figure 1] FIG. 1 is a comparative graph showing the AUC of the active ingredient A13 in plasma and colon tissue in vivo in rats after administration of compounds A3 and A13, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0085] Prodrug cleavage The azo bond in the compounds of the present invention is cleaved by an azo reductase upon contact with the enzyme in the gastrointestinal tract, releasing the JAK inhibitor. Example 1 [ka] Example 2 [ka]

[0086] Compounds A1 and A2 (see Examples) can be cleaved to release compound A13 using enzymes (eg, azoreductase) in the intestine, similar to the cleavage method of compound A3.

[0087] The compounds of the present invention can be prepared according to many preparative routes known in the literature. Specific examples of synthetic methods for preparing the compounds of the present invention are given in the schemes below. Below is an exemplary general synthesis scheme: [ka]

[0088] Specifically, it is manufactured by the following process steps. In S1, starting from II-1, the carboxy group thereon is protected by a benzyl group to produce compound II-2. In S2, the phenolic hydroxyl group of compound II-2 is protected by Cbz to give compound II-3. In S3, the nitro in compound II-3 is reduced to an amine group to give compound II-4. In S4, the amine group in compound II-4 is nitritated and further reduced to give compound II-5. In S5, compound II-6 is used as another raw material and subjected to an addition reaction (for example, reaction with hydrazine) to obtain compound II-7. In S6, the nitro in compound II-7 is reduced to an amine group to give compound II-8. In S7, compound II-5 and compound II-8 are bonded via a thiocarbonyl group to form compound II-9. In S8, compound II-9 is cyclized and the protecting group of the phenolic hydroxyl group is removed to give compound II-10. In S9, compound II-10 undergoes removal of the carboxy protecting group to give compound II-11, which can be continued as the final product or as an intermediate. In S10, compound II-11 can be condensed with an amine-based compound or a hydroxyl-based compound to give compound V.

[0089] The specific process of the above reaction is as follows: Compound II-1 is directly purchased Compound II-6 can be purchased directly or obtained by conventional synthetic methods. The carboxylic acid group and phenolic hydroxyl group of compound II-1 are protected with protecting groups to obtain compound II-3. The nitro group can be converted to compound II-4 by reducing agents such as iron powder, zinc powder, catalytic hydrogenation, and stannous chloride. Compound II-4 can be nitritated with HNO2 (obtained by adding NaNO2 to an acid) and reduced to compound II-5 by the action of stannous dichloride. Compound II-6 can be purchased directly or obtained by conventional synthetic methods. Compound II-6 can be added with hydrazine to obtain compound II-7, and the nitro group can be reduced to compound II-8 by reducing agents such as iron powder, zinc powder, catalytic hydrogenation, and stannous chloride. Compound II-5 and compound II-8 are bonded by the thiocarbonyl group in the presence of thiocarbonyldiimidazole or sulfur dioxide to give compound II-9. Compound II-9 is then ring-closed with a condensing agent (e.g., EDCI and DCC) and the phenolic hydroxyl protecting group is removed to give compound II-10. Compound II-10 then has its carboxyl protecting group removed to give compound II-11. The carboxylic acid group of compound II-11 can then be condensed with an amine or hydroxyl compound to give a compound of formula V.

[0090] In order to make the above content clearer and more precise, the present invention will further describe the technical solution of the present invention with reference to the following examples. The following examples are used only to describe specific embodiments of the present invention so that those skilled in the art can understand the present invention, but do not limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in this field.

[0091] Unless otherwise specified, all parts and percentages in this invention are calculated by weight and all temperatures are in degrees Celsius.

[0092] All of the materials and reagents used in the examples can be obtained from commercial sources or prepared by conventional methods in the art. [Example]

[0093] Example 1: Synthesis of Compound A1 [ka] (R,E)-5-((2-(3-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-3-oxopropyl)phenyl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0094] Step A: 2-Nitrocinnamic acid (5.0 g) was dissolved in 100 mL of water and 103 mL of 2% NaOH, and then 10% Pd / C (500 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 64 hours. After the reaction was complete, the mixture was filtered and spun to dryness to obtain the crude product compound, sodium o-aminophenylpropionate (6.8 g).

[0095] Step B: Sodium o-aminophenylpropionate (2.0 g) was dissolved in 20 mL of water and 60 mL of dichloromethane, and potassium monopersulfate (9.862 g) was added slowly at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane (2×20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate to obtain the crude product compound o-nitrosophenylpropionic acid (1.8 g).

[0096] Step C: The compound (R)-2-(1-(2-(1-(hydroxyethyl))imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-4-yl)acetonitrile (10.0 g), 4-dimethylaminopyridine (377 mg), and triethylamine (9.352 g) were dissolved in 100 mL of dichloromethane, and di-t-butyl dicarbonate (6.728 g) was slowly added at 0 °C under a nitrogen atmosphere. After the reaction was completed, the mixture was dried over a rotary evaporator and purified by column chromatography to obtain the compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-carboxylate t-butyl ester (11.6 g, 88% yield). LC-MS: m / z 425.0 [M+H] + .

[0097] Step D: The compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-t-butyl carboxylate (1.13 g), the crude compound o-nitrosophenylpropionic acid (1.8 g), dicyclohexylcarbodiimide (1.104 g), and 4-dimethylaminopyridine (33 mg) were dissolved in 50 mL of dichloromethane and stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the compound (R)-1-(4-cyanomethylpiperidin-1-yl)- was filtered, dried by rotary evaporation, and purified by column chromatography. 2-(1-((3-(2-nitrosophenyl)propionyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (568 mg, 37% yield). LC-MS: m / z 586.4 [M+H] + .

[0098] Step E: Compound t-butyl 5-aminosalicylate (568 mg) and compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-((3-(2-nitrosophenyl)propionyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (305 mg) were dissolved in 10 mL of acetic acid. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was dried over a rotary evaporator and purified by column chromatography to give the compound (R,E)-5-((2-(3-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-propionyl)phenyl)diazenyl)-2-hydroxybenzoate t-butyl ester (695 mg). LC-MS: m / z 677.4[M+H] + .

[0099] Step F: The compound (R,E)-5-((2-(3-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-propionyl)phenyl)diazenyl)-2-hydroxybenzoate t-butyl (695 mg) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was rotary evaporated and purified by column chromatography to obtain the compound (R,E)-5-((2-(3-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-3-oxopropyl)phenyl)diazenyl)-2-hydroxybenzoic acid (379 mg, yield 59%). 1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.59(s,1H),8.32(d,J=2.5Hz,1H),8.00(dd,J=8.9,2.5Hz,1H),7.59-7.56(m,1H), 7.52(t,J=3.0Hz,1H),7.47-7.45(m,1H),7.42-7.38(m,1H),7.35-7.31(m,1H),7.07(d,J=8.9Hz,1H),6.73(dd,J=3.6,1.9 Hz,1H),6.30-6.25(m,1H),3.56-3.47(m,3H),3.44-3.32(m,2H),3.14(d,J=10.5Hz,1H),3.01(d,J=10.4Hz,1H),2.76-2.7 1(m,2H),2.55(d,J=6.6Hz,2H),2.13-2.00(m,1H),1.97-1.81(m,2H),1.60(d,J=6.7Hz,3H),1.55-1.32(m,2H).LC-MS:m / z 621.4[M+H] + .

[0100] Example 2: Synthesis of Compound A2 [ka] (R,E)-5-((4-((((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)oxy)methyl)phenyl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0101] Step A: (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))-t-butyl carboxylate (500 mg) was dissolved in 20 mL of dichloromethane, and pyridine (279 mg) and phenyl 4-nitrochloroformate (594 mg) were added. The reaction mixture was stirred at 20 °C for 3 hours. After the reaction was complete, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered, rotary evaporated, and purified by column chromatography to obtain the compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(((4-nitrophenoxy)carbonyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-t-butyl carboxylate (639 mg, 92% yield).

[0102] Step B: The compound t-butyl 5-amino-2-((benzyloxycarbonyl)oxy)benzoate (1.7 g) was dissolved in 40 mL of dichloromethane, and a solution of m-chloroperoxybenzoic acid (1.709 g) in dichloromethane (20 mL) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to obtain the compound t-butyl 5-nitroso-2-((benzyloxycarbonyl)oxy)benzoate (1.238 g, 70% yield).

[0103] Step C: The compound t-butyl 5-amino-2-((benzyloxycarbonyl)oxy)benzoate (1.238 g) and p-aminobenzyl alcohol (950 mg) were dissolved in 10 mL of acetic acid and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was rotary evaporated and purified by column chromatography to obtain the compound (E)-t-butyl 2-((benzyloxycarbonyl)oxy)-5-((4-(hydroxymethyl)phenyl)diazenyl)benzoate (1.167 g, 72.8% yield). LC-MS: m / z 463.1 [M+H] + .

[0104] Step D: The compound (E)-2-((benzyloxycarbonyl)oxy)-5-((4-(hydroxymethyl)phenyl)diazenyl)benzoate t-butyl (500 mg), 4-dimethylaminopyridine (311 mg), triethylamine (257 mg), and the compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(((4-nitrophenoxy)carbonyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl (784 mg) were dissolved in 10 mL of dichloromethane, and the mixture was stirred in a nitrogen atmosphere at 30° C. for 16 hours. After the reaction was completed, the reaction mixture was rotary evaporated and purified by column chromatography to obtain the compound (R,E)-2-(1-((((4-((3-(t-butoxycarbonyl)-4-hydroxyphenyl)diazenyl)benzyl)oxy)carbonyl)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazopyrazolo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (414 mg, 64% yield). LC-MS: m / z 779.4 [M+H] + .

[0105] Step E: The compound (R,E)-2-(1-((((4-((3-(t-butoxycarbonyl)-4-hydroxyphenyl)diazenyl)benzyl)oxy)carbonyl)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazopyrazolo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (410 mg) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 5° C. for 16 hours. After the reaction was completed, the mixture was rotary evaporated and purified by column chromatography to obtain the compound (R,E)-5-((4-((((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)oxy)methyl)phenyl)diazenyl)-2-hydroxybenzoic acid (318 mg, yield 97%). 1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),8.64(s,1H),8.34(d,J=2.6Hz,1H),8.09(dd,J=8.9,2.6Hz,1H),7.88(d,J=8.4Hz ,2H),7.62-7.56(m,2H),7.53(t,J=3.1Hz,1H),7.16(d,J=8.9Hz,1H),6.76(dd,J=3.6,1.9Hz,1H),6.22(q,J=6.6Hz,1H ),5.31(d,J=2.2Hz,2H),3.61-3.50(m,3H),3.25-3.18(m,1H),3.08-3.01(m,1H),2.57(dd,J=6.3,2.8Hz,2H),2.14-2. 03(m,1H),1.98-1.90(m,1H),1.88-1.80(m,1H),1.74(d,J=6.6Hz,3H),1.60-1.49(m,1H),1.45-1.32(m,1H).LC-MS:m / z 623.1[M+H] + .

[0106] Example 3: Synthesis of Compound A3 [ka] (R,E)-5-((2-((1-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-methyl-1-oxopropan-2-yl)oxy)phenyl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0107] Step A: The compound t-butyl 5-nitrosalicylate (5.6 g) was dissolved in 50 mL of N,N-dimethylformamide. Sodium hydride (730 mg) was slowly added at 0 °C, followed by bromomethyl methyl ether (4.095 g). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The resulting mixture was filtered, rotary evaporated, and purified by column chromatography to obtain the compound t-butyl 2-methoxymethyl ether-5-nitrobenzoate (3.5 g, 52.8% yield).

[0108] Step B: The compound t-butyl 2-methoxymethyl ether-5-nitrobenzoate (3.5 g) was dissolved in 50 mL of methanol, and 10% palladium / carbon (350 mg) was added. The mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by column chromatography to obtain the compound t-butyl 2-methoxymethyl ether-5-aminobenzoate (2.753 g, yield 89.2%).

[0109] Step C: The compound 2-methoxymethyl ether-5-aminobenzoate t-butyl ester (900 mg) was dissolved in 30 mL of dichloromethane, and a solution of m-chloroperoxybenzoic acid (1.165 g) in dichloromethane (30 mL) was slowly added at 0° C. The reaction mixture was stirred for 1.5 hours at 0° C. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound 2-methoxymethyl ether-5-nitrosobenzoate t-butyl ester (439 mg, yield 33.6%).

[0110] Step D: Compound 2-hydroxyaniline (2.0 g) was dissolved in 30 mL of N,N-dimethylformamide, and imidazole (1.872 g) and triisopropylchlorosilane (4.593 g) were slowly added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, water (30 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, rotary evaporated, and purified by column chromatography to obtain compound 2-((triisopropylsilyl)oxy)aniline (3.87 g, 79.5% yield).

[0111] Step E: The compound t-butyl 2-methoxymethyl ether-5-nitrosobenzoate (439 mg) and the compound 2-((triisopropylsilyl)oxy)aniline (566 mg) were dissolved in acetic acid (10 mL), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the solution was rotary dried and purified by column chromatography to obtain the compound t-butyl (E)-2-(methoxymethyl ether)-5-((2-((triisopropylsilyl)oxy)phenyl)diazenyl)benzoate (341 mg, yield 40.3%).

[0112] Step F: The compound (E)-2-(methoxymethyl ether)-5-((2-((triisopropylsilyl)oxy)phenyl)diazenyl) t-butyl benzoate (340 mg) and cesium fluoride (301 mg) were added to acetonitrile (6 mL), and the reaction mixture was stirred at 60°C for 1 hour. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound (E)-5-((2-hydroxyphenyl)diazenyl) 2-(methoxymethyl ether)-t-butyl benzoate (211 mg, yield 89.1%).

[0113] Step G: The compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (1.0 g), 1,3-dicyclohexylcarbodiimide (2.634 g), 4-(dimethylamino)pyridine (78 mg), and 2-bromo-2-methylpropionic acid (1.18 g) were added to 50 mL of dichloromethane, and the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the residue was filtered, rotary dried, and purified by column chromatography to obtain the compound (R)-2-(1-((2-bromo-2-methylpyruvic acid)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate tert-butyl ester (1.134 g, yield 83.9%).

[0114] Step H: The compound (E)-5-((2-hydroxyphenyl)diazenyl) 2-(methoxymethyl ether)-benzoate (200 mg), the compound t-butyl (R)-2-(1-((2-bromo-2-methylpyruvate)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (959 mg), and potassium carbonate (231 mg) were added to 10 mL of N, N-dimethylformamide was added, and the reaction mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound (R,E)-2-(1-((2-(2-((3-(t-butoxycarbonyl)-4-(methoxymethylether)phenyl)diazenyl)phenoxy)2-methylpyruvate)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-tert-butyl carboxylate (446 mg, 93.9% yield). LC-MS: m / z 851.6 [M+H] + .

[0115] Step I: The compound (R,E)-2-(1-((2-(2-((3-(t-butoxycarbonyl)-4-(methoxymethyl ether)phenyl)diazenyl)phenoxy)2-methylpyruvic acid)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (200 mg) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at 60° C. for 16 hours. After the reaction was completed, the mixture was rotary evaporated and purified by column chromatography to obtain compound (R,E)-5-((2-((1-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-methyl-1-oxopropan-2-yl)oxy)phenyl)diazenyl)-2-hydroxybenzoic acid (55 mg, yield 36%). 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.61(s,1H),8.32(d,J=2.5Hz,1H),7.98(dd,J=8.9, 2.5Hz,1H),7.57-7.50(m,2H),7.41-7.37(m,1H),7.21-7.06(m,3H),6.75(dd,J=3.6,1.9H z,1H),6.35(q,J=6.6Hz,1H),3.81-3.54(m,2H),3.20-3.12(m,2H),2.61(d,J=6.5Hz,2H), 2.17-2.06(m,1H),1.98-1.89(m,2H),1.69(d,J=6.7Hz,3H),1.61-1.52(m,8H).LC-MS:m / z 651.3[M+H] + .

[0116] Example 4 Synthesis of Compound A4 [ka] (R,E)-5-((2-((1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0117] Step A: The compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-(2-nitrophenoxy)carbonyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (368 mg) and benzenediamine (337 mg) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was stirred at 80°C for 16 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was rotary evaporated and purified by column chromatography to obtain the compound (R)-2-(1-((2-aminobenzamido)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (300 mg, 86% yield).

[0118] Step B: The compound (R)-2-(1-((2-aminobenzamido)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl (150 mg) and the compound t-butyl 5-nitroso-2-((benzyloxycarbonyl)oxy)benzoate (144 mg) were dissolved in 10 mL of acetic acid and stirred at 20° C. for 16 hours. After the reaction was completed, the reaction mixture was rotary evaporated and purified by column chromatography to obtain the compound (R,E)-2-(1-(((2-((4-((benzyloxycarbonyl)oxy)-3-(t-butoxycarbonyl)phenyl)diazenyl)phenyl)carbamoyl)oxy)ethyl)-1-(4-(cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (84 mg, yield 34.8%). LC-MS: m / z 898.4 [M+H] + .

[0119] Step C: The compound (R,E)-2-(1-(((2-((4-((benzyloxycarbonyl)oxy)-3-(t-butoxycarbonyl)phenyl)diazenyl)phenyl)carbamoyl)oxy)ethyl)-1-(4-(cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (75 mg) was dissolved in 10 mL of dichloromethane and trifluoroacetic acid (0.5 mL). ) was added. The mixture was stirred at 45° C. for 16 hours. After the reaction was completed, the mixture was rotary evaporated to dryness to obtain the crude product compound (R,E)-2-(((benzyloxycarbonyl)oxy)-5-((2-(((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)benzoic acid (61 mg, yield 99%).

[0120] Step D: The compound (R,E)-2-(((benzyloxycarbonyl)oxy)-5-((2-(((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)benzoic acid (61 mg) was dissolved in 6 mL of dichloromethane and triethylamine (3.0 mL) was added. The mixture was stirred at 35°C for 72 hours. After the reaction was completed, the mixture was dried by rotation to give the compound (R,E)-5-((2-((1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)-2-hydroxybenzoic acid (18 mg, yield 36%). 1 H NMR(400MHz,DMSO-d6)δ12.06(s,1H),9.76(s,1H),8.65(s,1H),8.36(d,J=2.5Hz,1H),8.17(dd,J=8 .9,2.6Hz,1H),8.07(d,J=8.3Hz,1H),7.65(dd,J=8.1,1.5Hz,1H),7.55-7.47(m,2H),7.21-7.17(m,1 H),7.08(d,J=9.0Hz,1H),6.77(dd,J=3.6,1.9Hz,1H),6.37(q,J=6.6Hz,1H),3.62-3.50(m,2H),3.28 -3.21(m,2H),2.50-2.45(m,1H),2.12-1.91(m,2H),1.79-1.73(m,3H),1.62-1.43(m,2H).LC-MS:m / z 608.3[M+H] + .

[0121] Example 5 Synthesis of Compound A5 [ka] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetic acid ethyl ester Specific embodiments are shown below. [ka]

[0122] Step A: The compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (50 mg), acetic anhydride (120 mg), triethylamine (238 mg), and 4-dimethylaminopyridine (1 mg) were dissolved in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was evaporated to dryness and purified by column chromatography to obtain compound (R)-2-(1-acetyloxyethyl)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))-t-butyl carboxylate (55 mg, yield 100%).

[0123] Step B: The compound (R)-2-(1-acetyloxyethyl)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))-t-butyl carboxylate (55 mg) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (0.3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was washed with saturated sodium bicarbonate solution, dried, and purified to obtain the compound (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl acetate (32 mg, yield 74.1%). 1H NMR(400MHz,CDCl3)δ9.80(s,1H),8.81(s,1H),7.42(dd,J=3.1,2.0Hz,1H),6.66(d,J=2.5Hz,1H),6.41(q,J=6.7Hz ,1H),3.82-3.59(m,2H),3.32-3.29(m,1H),3.19-3.17(m,1H),2.46(d,J=6.6Hz,2H),2.15-1.67(m,11H).LC-MS:m / z 367.2[M+H] + .

[0124] Example 6 Synthesis of Compound A6 [ka] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl-5-(nitrooxy)pentanoate Specific embodiments are shown below. [ka]

[0125] Step A: The compound methyl 5-bromopentanoate (2.00 g) was dissolved in 10 mL of acetonitrile, and silver nitrate (2.61 g) was added under a nitrogen atmosphere. The mixture was stirred at 70°C for 2 hours. The mixture was suction filtered under reduced pressure, the filtrate was collected, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether and ethyl acetate in a ratio of 4:1) to obtain the compound methyl 5-nitratepentanoate (1.8 g, yield 96%). 1 H NMR(400MHz,DMSO-d6)δ4.52(t,J=6.3Hz,2H),3.59(s,3H),2.37(t,J=7.2Hz,2H),1.73-1.54(m,4H).

[0126] Step B: Methyl 5-nitrate pentanoate (1.90 g) was dissolved in 20 mL of acetonitrile, and LiOH (10 mL) was added dropwise in an ice bath under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized to pH 3 with 1N hydrochloric acid and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA ratio 4:1) to obtain 5-nitrate pentanoic acid (1.7 g, 96% yield). 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H),4.52(t,J=6.4Hz,2H),2.35-2.10(m,2H),1.74-1.63(m,2H),1.62-1.51(m,2H).

[0127] Step C: Compound 5-nitrate pentanoic acid (64 mg) was dissolved in 6 mL of dichloromethane, and thionyl chloride (0.2 mL) was added under a nitrogen atmosphere, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain a crude product of compound 5-nitrate pentanoyl chloride (626 mg).

[0128] Step D: Compound 5-nitrate pentanoyl chloride (500 mg) was dissolved in 10 mL of dichloromethane, and in a nitrogen atmosphere, compound t-butyl (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carbonate (50 mg), DMAP (2 mg), and TEA (36 mg) were added, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane ratio 1:10) to obtain the compound t-butyl (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-((5-nitratepentanoyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (70 mg, yield 34%).

[0129] Step E: The compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-((5-nitratepentanoyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (70 mg) was dissolved in 8 mL of dichloromethane, and trifluoroacetic acid (0.2 mL) was added under a nitrogen atmosphere and stirred at room temperature for 3 hours. After the reaction was completed, sodium hydrogen sulfate solution was added. Extraction with dichloromethane was performed, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (methanol and dichloromethane in a ratio of 1:10) to obtain the compound (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl-5-nitrate pentanoate (17 mg, yield 30%). 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.57(d,J=11.0Hz,1H),7.52(t,J=2.9Hz,1 H),6.75(s,1H),6.30(q,J=6.6Hz,1H),4.52(t,J=6.2Hz,2H),3.58(t,J=11.4Hz, 2H),3.18(d,J=9.6Hz,1H),3.10(d,J=9.9Hz,1H),2.62(d,J=6.3Hz,2H),2.41(dd ,J=13.1,7.1Hz,2H),2.11(s,1H),1.95(d,J=11.4Hz,2H),1.74-1.56(m,8H).LCMS ESI(+)m / z:470.3(M+1).

[0130] Example 7: Synthesis of Compound A7 [ka] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycine ester Specific embodiments are shown below. [ka]

[0131] Step A: Dimethylglycine (compound 1.2, 1.093 g), 1,3-dicyclohexylcarbo Diimide (2.187 g) and 4-(dimethylamino)pyridine (43 mg) were added to 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (1.5 g) was added and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, rotary dried, and purified by column chromatography to obtain compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(dimethylglycineethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-t-butyl carboxylate (1.2 g, 66.7% yield). LC-MS: m / z 510.1 [M+H] + .

[0132] Step B: The compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(dimethylglycine ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate t-butyl ester (1.5 g) was added to 10 mL of dichloromethane, trifluoroacetic acid (2.5 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the solution was washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to prepare the compound (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycine ester (911 mg, 75.5% yield). 1H NMR(400MHz,CDCl3)δ14.17(s,1H),8.65(s,1H),7.62(s,1H),6.81(s,1H),6.38(q,J=6.6Hz,1H),3.99(s,2H),3.79-3.64(m,2H) ,3.43(d,J=9.6Hz,1H),3.22(d,J=10.3Hz,1H),2.93(s,6H),2.62-2.43(m,2H),2.27-1.96(m,3H),1.86-1.72(m,5H).LC-MS:m / z 410.2[M+H] + .

[0133] Example 8: Synthesis of Compound A8 [ka] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl D-valine ester Specific embodiments are shown below. [ka]

[0134] Step A: D-Valine (compound 1, 5.0 g) was added to water (30 mL), followed by the addition of sodium hydroxide (1.707 g) and benzyl chloride formate (8.01 g). The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give compound Cbz-D-valine (9.6 g, 89.5% yield). 1 H NMR(400MHz,CDCl3)δ7.42-7.26(m,6H),5.37-5.22(m,1H),5.20-5.02(m,2H),4.47-4.25(m,1H),2.33-2.07(m,1H),1.12-0.79(m,6H).

[0135] Step B: Compound Cbz-D-valine (4.44 g), 1,3-dicyclohexylcarbodiimide (3.645 g), and 4-(dimethylamino)pyridine (86 mg) were added to 60 mL of dichloromethane, and the reaction mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (3.0 g) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound 2-((R)-1-(Cbz-D-valine ethyl ester group)-1-(4-cyanomethylpiperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (1.96 g, yield 42.2%). LC-MS: m / z 658.3 [M+H] + .

[0136] Step C: The compound 2-((R)-1-(Cbz-D-valine ethyl ester group)-1-(4-cyanomethylpiperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (1.96 g) was added to 20 mL of dichloromethane, trifluoroacetic acid (4.0 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solution was washed with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to obtain the compound (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-Cbz-D-valine ethyl ester (1.36 g, 81.8% yield). LC-MS: m / z 558.3 ​​[M+H] + .

[0137] Step D: The compound (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-Cbz-L-valine ethyl ester (1.36 g) and palladium on carbon (200 mg, 10%) were added to 20 mL of methanol, and the reaction mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl D-valine ester (989 mg, 95.7% yield). 1 H NMR(400MHz,CDCl3)δ10.20-9.47(m,1H),8.82(d,J=31.1Hz,1H),7.42(t,J=3.3Hz,1H),6.65-6.64(m,1H),6.51-6.39(m,1H),3.80-3.66(m,2H),3 .43-3.32(m,2H),3.21-3.15(m,1H),2.46(d,J=6.3Hz,2H),2.17-2.04(m ,4H),1.85-1.70(m,4H),1.26-1.22(m,1H),1.03-0.85(m,6H).LC-MS:m / z 424.2[M+H] + .

[0138] Example 9: Synthesis of Compound A9 [ka] (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl L-valine ester Specific embodiments are shown below. [ka]

[0139] Step A: L-valine (3.0 g) was added to water (20 mL), and then sodium hydroxide (1.02 Cbz-L-valine (5.232 g, 81.3% yield) was obtained by adding 4.81 g of benzoyl chloride (Cbz-L-valine) and stirring the reaction mixture at room temperature for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the compound Cbz-L-valine (5.232 g, 81.3% yield). 1 H NMR (400MHz, CDCl3) δ7.40-7.27(m,6H),5.11(s,2H),4.44-4.31(m,1H),2.31-2.13(m,1H),1.06-0.83(m,6H).

[0140] Step B: Compound Cbz-L-valine (3.208 g), 1,3-dicyclohexylcarbodiimide (2.634 g), and 4-(dimethylamino)pyridine (78 mg) were added to 30 mL of dichloromethane, and the reaction mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (2.71 g) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered, rotary dried, and purified by column chromatography to obtain the compound 2-((R)-1-(Cbz-L-valine ethyl ester group)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (2.1 g, 50% yield). LC-MS: m / z 658.3 [M+H] + .

[0141] Step C: The compound 2-((R)-1-(Cbz-L-valine ethyl ester group)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (2.1 g) was added to 10 mL of dichloromethane, trifluoroacetic acid (4.0 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the solution was washed with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to obtain the compound (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2)-Cbz-L-valine ethyl ester (1.622 g, 91.1% yield). LC-MS: m / z 558.3 ​​[M+H] + .

[0142] Step D: The compound (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-Cbz-L-valine ethyl ester (1.62 g) and palladium on carbon (200 mg, 10%) were added to 20 mL of methanol and the reaction mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the mixture was filtered, spun dry, and purified by column chromatography to obtain the compound (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl L-valine ester (960 mg, 78.0% yield). 1 H NMR(400MHz,CDCl3)δ10.55(s,1H),8.82(d,J=15.0Hz,1H),7.44(d,J=3.5Hz,1H),6.65(dd,J=3.5,1.7Hz,1H),6.50-6.42(m,1H),3.81-3 .57(m,2H),3.43-3.32(m,2H),3.19-3.16(m,1H),2.47-2.44(m,2H),2.17-2.01(m,4H),1.82-1.72(m,8H),1.02-0.85(m,6H).LC-MS:m / z 424.2[M+H]+ .

[0143] Example 10: Synthesis of Compound A10 [ka] (R)-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl fumarate monomethyl ester Specific embodiments are shown below. [ka]

[0144] Step A: The compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (300 mg) and sodium hydroxide (85 mg) were added to N,N-dimethylformamide (10 mL), followed by the addition of chloromethyl methyl sulfide (205 mg). The reaction mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere, and the reaction was completed. After the reaction, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to obtain the compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(methylthio)methoxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (262 mg, 76.5% yield). LC-MS: m / z 485.1 [M+H] + .

[0145] Step B: The compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(methylthio)methoxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)) t-butyl carboxylate (200 mg) and thionyl chloride (0.8 mL) were added to 10 mL of dichloromethane, and the reaction mixture was stirred at 55°C for 5 hours in a nitrogen atmosphere. After rotary drying, the rotary dried compound and N,N-diisopropylethylamine (213 mg) were dissolved in dichloromethane (10 mL), and then monomethyl fumarate (107 mg) was added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to give the compound (R)-(1-(6-Boc-1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy. (iii) Methyl monomethyl fumarate (89 mg, yield 38.1%) was obtained. LC-MS: m / z 567.2 [M+H] + .

[0146] Step C: The compound (R)-(1-(6-Boc-1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl monomethyl fumarate (84 mg) was added to 5 mL of dichloromethane, trifluoroacetic acid (0.3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was washed with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by column chromatography to obtain the compound (R)-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl monomethyl fumarate (8 mg, yield 11.6%). 1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.59(d,J=3.7Hz,1H),6.86(q,J=15.8Hz,2H),6.66(d,J=3.7Hz,1H),6.51(s,2H),5.36-5.26(m,2H),3.82 (s,3H),3.77-3.67(m,2H),3.32-3.23(m,2H),2.48(d,J=8.0Hz,2H),2.18-1.97(m,2H),1.73(d,J=6.8Hz,3H),1.35-1.19(m,2H).LC-MS:m / z 467.2[M+H] + .

[0147] Example 11: Synthesis of Compound A11 [ka] (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl nitrate. Specific embodiments are shown below. [ka]

[0148] Step A: Ethyl 4-methylpiperidine-4-carboxylate hydrochloride (5.0 g) and sodium nitrite (4.153 g) were dissolved in 100 mL of water, and acetic acid (2.891 g) was slowly added dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and rotary evaporated to give the crude product compound, ethyl 4-methyl-1-nitrosopiperidine-4-carboxylate (5.944 g, 100% yield).

[0149] Step B: Ethyl 4-methyl-1-nitrosopiperidine-4-carboxylate (5.944 g) was dissolved in 200 mL of tetrahydrofuran and 2.5 N tetrahydrolithium aluminum solution (39 mL) was added dropwise at 0°C. After the addition was complete, the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to 0°C and quenched by the addition of water (3.9 mL). 2 N sodium hydroxide (3.9 mL) and water (11.7 mL) were added in that order. The solution was stirred at room temperature for 0.5 hours, filtered, and rotary evaporated to give the crude product compound ethyl 4-methyl-1-aminopiperidine-4-carboxylate (6.6 g, 100% yield).

[0150] Step C: The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (6.96 g), the crude product compound ethyl 4-methyl-1-nitrosopiperidine-4-carboxylate (6.6 g), and N,N-diisopropylethylamine (15.346 g) were dissolved in 100 mL of isopropanol and stirred at 85° C. for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and rotary dried to obtain the compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (6.496 g, yield 71.5%).

[0151] 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 (6.496 g) was dissolved in 200 mL of dichloromethane, and triethylamine (3.239 g) and methanesulfonyl chloride (1.86 g) were added at 0 ° C. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with saturated brine (3 × 100 mL), dried over anhydrous sodium sulfate, filtered and rotary dried to obtain the crude product compound (4-methyl-1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (7.3 g, yield 99%).

[0152] 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 methyl methanesulfonate (2.7 g) was dissolved in 60 mL of ethanol, and then a solution of iron powder (2.333 g) and ammonium chloride (1.117 g) in water (6 mL) was added and stirred at 80 ° C. for 1 hour. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified to obtain the compound (4-methyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methyl methanesulfonate (2.14 g, yield 84%).

[0153] Step F: Hydroxyacetamide (799 mg) and triethyloxonium tetrafluoroborate (2.021 g) were dissolved in 20 mL of anhydrous tetrahydrofuran, stirred at 35 ° C. for 0.5 hours, and then rotary dried. The compound obtained by rotary drying 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 (600 mg) were dissolved in 30 mL of ethanol and stirred at 75 ° C. for 1 hour. After the reaction was completed, the reaction solution was rotary dried and purified to obtain the crude product compound (4-(2-hydroxymethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1-methylcyclohexyl)methyl methanesulfonate (647 mg, yield 100%).

[0154] Step G: The compound (4-(2-hydroxymethyl-6-p-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1-methylcyclohexyl)methyl methanesulfonate (647 mg) and 20% aqueous sodium methanethiol (2.5 mL) were dissolved in 10 mL of N,N-dimethylformamide and stirred at 100 °C for 1 hour. After the reaction was completed, 60 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (2 × 60 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered, rotary dried, and purified to give the compound (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methanol (126 mg, 30.8% yield).

[0155] Step H: The compound (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methanol (65 mg) and thionyl chloride (0.5 mL) were dissolved in 50 mL of dichloromethane and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with saturated sodium bicarbonate. The resulting mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spun to dryness to give the compound 2-chloromethyl-1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (68 mg, 99% yield).

[0156] Step I: The compound 2-chloromethyl-1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (68 mg) and silver nitrate (327 mg) were added to 10 mL of acetonitrile and stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was filtered and rotary dried to prepare the compound (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)methyl nitrate (18 mg, yield 24.5%). 1 H NMR(400MHz,CDCl3)δ10.09(s,1H),8.79(s,1H),7.48(s,1H),6.84-6.76(m,1H),5.82(s,2H),3.82-3.66(m,2 LC-MS:m / z 391.2[M+H] + .

[0157] Example 12: Synthesis of Compound A12 [ka] 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl nitrate Specific embodiments are shown below. [ka]

[0158] Step A: Ethyl succinamate (2.067 g) and triethyloxonium tetrafluoroborate (2.994 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, stirred at 35° C. for 2 hours, and then rotary dried to obtain the compound (4-methyl-1-((5-amino-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methylmethane. Methyl sulfonate (800 mg) was dissolved in 80 mL of ethanol and stirred at 75°C for 0.5 hours. After the reaction was completed, the reaction solution was rotary evaporated and purified to obtain the crude product compound, 2-(1-(4-methyl-4-(((methanesulfonyl)oxy)methyl)cyclohexyl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl acetate (3.6 g, yield 100%).

[0159] Step B: The compound 2-(1-(4-methyl-4-(((methanesulfonyl)oxy)methyl)cyclohexyl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl acetate (1.0 g) was dissolved in 30 mL of ethanol, and sodium borohydride (1.253 g) was slowly added. The reaction solution was then stirred at 50 ° C for 6 hours. After the reaction was completed, the solution was filtered, rotary dried, and purified by column chromatography to obtain the compound 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1-ethanol (352 mg, yield 37.8%).

[0160] Step C: The compound 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1-ethanol (351 mg) and sodium methanethiol (3 mL) were dissolved in 10 mL of N,N-dimethylformamide. The reaction mixture was then stirred at 80°C for 2 hours. After the reaction was completed, 60 mL of water was added to the reaction mixture, which was then extracted with dichloromethane (2 x 60 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The compound 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-6-p-toluenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1-ethanol was purified by filtration and rotary evaporation. The compound (79 mg, 35.2% yield) was obtained as follows: 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1-ethanol.

[0161] Step D: The compound 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-1-ethanol (79 mg) and thionyl chloride (0.5 mL) were dissolved in 50 mL of dichloromethane and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate, then with saturated brine, and dried over anhydrous sodium sulfate. The resulting mixture was filtered and rotary evaporated to give the compound 2-(2-chloroethyl)-1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (45 mg, 54.2% yield).

[0162] Step E: The compound 2-(2-chloroethyl)-1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (45 mg) and silver nitrate (405 mg) were added to 30 mL of acetonitrile and stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was filtered and rotary dried to prepare the compound 2-(1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl nitrate (10 mg, 10% yield). 1 H NMR(400MHz,CDCl3)δ10.00(s,1H),8.72(s,1H),7.44(s,1H),6.79-6.71(m,1H),5.05-4.93(m,2H),3.82-3.68(m,2H),3.46(t,J=6.8Hz ,2H),3.01(d,J=11.5Hz,2H),2.60(s,1H),2.29(s,1H),2.21(s,2H),1.95-1.66(m,4H),1.38(s,2H),1.22(d,J=28.5Hz,2H).LC-MS:m / z 405.2[M+H] + .

[0163] Example 13: Synthesis of Compound B1 [ka] 1-(Piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine Specific embodiments are shown below. [ka]

[0164] Step A: 4-Chloro-7-azaindole (50.01 g) was dissolved in 1 L of dichloromethane and triethylamine (66.34 g) was added. Then, p-toluenesulfonyl chloride (64.36 g) and 4-dimethylaminopyridine (0.4 g) were added at 0°C, and the mixture was warmed to room temperature and stirred for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product compound, 4-chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (99.8 g, crude yield 99%), was obtained.

[0165] Step B: The compound 4-chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (50.0 g) was dissolved in 600 mL of dichloromethane. Tetrabutylammonium nitrate (74.44 g) and trifluoroacetic anhydride (53.05 g) were added at 0 °C. The reaction was then stirred at room temperature under a nitrogen atmosphere for 20 hours. After the reaction was completed, the mixture was quenched with 500 mL of saturated aqueous sodium bicarbonate solution. The organic phase was separated and extracted twice with 1.2 L of dichloromethane. The combined organic phases were washed with appropriate amounts of water and saturated aqueous sodium chloride, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and rotary evaporated. The slurry obtained by rotary evaporation was ultrasonically beaten with 80 mL of ethyl acetate, filtered, washed with 100 mL of a mixed solvent of ethyl acetate and petroleum ether (volume ratio 3:7), 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%). 1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.26(d,J=4.1Hz,1H),8.05(d,J=8.4Hz,2H),7.47(d,J=8.2Hz,2H),7.09(d,J=4.1Hz,1H),2.37(s,3H).

[0166] Step C: 4-Chloro-5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.78 g), N,N-diisopropylethylamine (5.40 g), and 1-aminopiperidine (2.28 g) were added to 250 mL of isopropanol (suspension). The reaction was stirred at 95 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, 500 mL of water was added, and the mixture was extracted three times with 750 mL of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, rotary evaporated, and purified (40:1 volume ratio of dichloromethane and methanol) to give 5-nitro-N-(piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-amine (5.02 g, 64% yield). LCMS ESI(+)m / z:416.1(M+1).

[0167] Step D: The compound 5-nitro-N-(piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-amine (4.88 g) was added to a mixed solution (suspension) of 30 mL of ethanol and 10 mL of water, followed by the addition of solid ammonium chloride (1.88 g) and iron powder (1.96 g) in that 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 cake was washed with 50 mL of ethyl acetate. 50 mL of water was added to the filtrate, and the mixture was extracted three times with 240 mL of ethyl acetate. The organic phases were combined, washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was suction filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound N 4 -(Piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (4.01 g, crude yield 88%) was obtained. LCMS ESI(+) m / z: 386.1 (M+1).

[0168] Step E: Compound N 4 1-(Piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (150 mg) was dissolved in 3 mL of methanol, and 0.19 mL of 3.0 M cyanogen bromide in dichloromethane was added. The mixture was stirred at room temperature for 16 hours. 10 mL of 1N sodium hydroxide solution was added, and the mixture was stirred for 30 minutes. The mixture was extracted three times with 45 mL of ethyl acetate. The organic phases were combined, washed with 30 mL of saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol volume ratio: 20:1) to give 1-(piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (102 mg, 64% yield). LCMS ESI(+)m / z:411.1(M+1).

[0169] Step F: Compound 1-(piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (102 mg) was dissolved in 3 mL of acetonitrile, sodium hydroxide (25 mg) was added, and the mixture was stirred at 60 °C for 5 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted three times with 45 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol volume ratio 15:1) and high-performance liquid chromatography to obtain compound 1-(piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (17 mg, 26% yield). 1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.61(s,2H),8.35(s,1H),7.68(t,1H),6.71(dd,J=3.3 ,1.7Hz,1H),3.47-3.36(m,2H),3.24-3.13(m,2H),1.91-1.74(m,5H),1.57-1.46(m,1H).LCMS ESI(+)m / z:257.1(M+1).

[0170] Example 14: Synthesis of Compound B2 [ka] N-((1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide Specific embodiments are shown below. [ka]

[0171] Step A: 4-Chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (22 g) was dissolved in 200 mL of isopropanol, and then DIEA (48.5 g) and (1-aminopiperidin-4-yl)methanol (6.35 g) were added. The reaction mixture was stirred at 88°C for 16 hours. After the reaction was completed, the reaction mixture was rotary evaporated and purified by column chromatography. The resulting mixture was purified by HPLC to give the compound (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (27.8 g, 100% yield). LC-MS: m / z 446.30 [M+H] + .

[0172] Step B: (1-((5-nitro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (12 g) was dissolved in 400 mL of ethanol and 80 mL of water, and then iron powder (12.1 g) and ammonium chloride (2890 mg) were added. The reaction mixture was stirred at 75°C for 30 minutes. After the reaction was completed, the mixture was filtered, and the filtrate was rotary evaporated and purified by column chromatography to obtain Compound N. 4 -(Piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (10 g, 89% yield). LC-MS: m / z 415.3 [M+H] + .

[0173] Step C: Compound N 4 3.00 g of 1H-(piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine was dissolved in 10 mL of DMF, and then 1.47 g of imidazole and 1.63 g of t-butyldimethylchlorosilane were added in this order under an ice bath and nitrogen atmosphere. After the dropwise addition was completed, the mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into 100 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate and petroleum ether in a ratio of 1:2) to give compound N. 4 -(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (3.70 g, 97% yield) was obtained. 1H NMR(400MHz,DMSO-d6)δ8.00(d,J=8.4Hz,2H),7.81(s,1H),7.43(d,J=4.0Hz,1H),7.22(d,J=8.1Hz,2H),6.94(d,J=4.1Hz,1H),5.20(s,1H),3 .48(d,J=6.1Hz,2H),3.24-3.16(m,2H),2.35(s,3H),2.33-2.24(m,2H ),1.83-1.75(m,2H),1.47-1.35(m,2H),0.90(s,9H),0.05(s,6H).LCMS ESI(+)m / z:530.0(M+1).

[0174] Step D: Compound N 4 -(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (3.70 g) was suspended in 200 mL of methanol, and cyanogen bromide (814 mg) was added in this order at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and saturated sodium bicarbonate solution (15 mL), saturated sodium thiosulfate (15 mL), and a mixed solvent of methanol and ethyl acetate (volume ratio 1:10, 100 mL) were added, followed by stirring at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted three times with a mixed solvent of methanol and ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product compound 1-(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (3.87 g, 100% yield). LCMS ESI (+) m / z: 555.2 (M+1).

[0175] Step E: The compound 1-(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (3.87 g) was dissolved in 200 mL of methanol, and triethylamine (3.90 mL) and di-t-butyl dicarbonate (1.83 g) were added at room temperature. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:petroleum ether 1:7) to obtain the compound 1-(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (3.03 g, 66% yield). 1 H NMR(400MHz,CDCl3)δ8.53(s,1H),8.04(d,J=8.4Hz,2H),7.78(s,1H),7.62(d,J=4.0Hz,1H),7.26(d,J=8.0Hz,2H),6.96(d,J=4.0Hz,1H),4.08- 3.95(m,2H),3.51(d,J=5.9Hz,2H),3.11-3.02(m,2H),2.36(s,3H),1.89 -1.79(m,2H),1.69(s,9H),1.54-1.37(m,3H),0.91(s,9H),0.06(s,6H).

[0176] Step F: The compound 1-(4-(((t-butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (3.03 g) was dissolved in 120 mL of tetrahydrofuran, and tetra-n-butylammonium fluoride trihydrate (5.84 g) was added at room temperature. The mixture was stirred at room temperature for 2 hours. 250 mL of ethyl acetate was added, and the mixture was washed three times with 100 mL of water. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate and petroleum ether in a ratio of 3:1) to obtain the compound t-butyl (1-(hydroxymethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)carbamate (1.14 g, yield 46%). 1 H NMR(400MHz,CDCl3)δ8.54(s,1H),8.08-8.01(m,2H),7.79(s,1H),7.62(d ,J=4.0Hz,1H),7.29-7.22(m,2H),6.95(d,J=4.0Hz,1H),4.09-3.99(m,2H ),3.63-3.54(m,2H),3.13-3.04(m,2H),2.36(s,3H),1.95-1.86(m,2H),1 .69(s,9H),1.63-1.54(m,1H),1.54-1.41(m,2H),1.41-1.32(m,1H).LCMS ESI(+)m / z:555.2(M+1).

[0177] Step G: Under ice bath cooling and nitrogen atmosphere, 50 mL of toluene was added to t-butyl (1-(hydroxymethyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)carbamate (1.10 g), DPPA (2.24 g), and DBU (2.48 g). The mixture was heated to 100 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to give 1-(4-(methylazido)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (647 mg, 68% yield). 1 H NMR(400MHz,CDCl3)δ8.53(s,1H),8.10(d,J=8.4Hz,2H),7.76(d,J=4.1Hz,1H),7.25(d,J= 8.4Hz,2H),6.64(d,J=4.1Hz,1H),5.17(s,2H),3.52-3.42(m,2H),3.34(d,J=6.4Hz,2H),3 .20-3.12(m,2H),2.35(s,3H),2.04-1.97(m,2H),1.67-1.54(m,3H).LCMS ESI(+)m / z:466.2(M+1).

[0178] Step H: The compound 1-(4-(methylazido)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine (525 mg) was dissolved in 30 mL of dichloroethane, and di-t-butyl dicarbonate (1.23 g), triethylamine (571 mg), and 4,4-dimethylaminopyridine (138 mg) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether and ethyl acetate 4:1) to obtain the compound t-butyl (1-(4-(methylazido)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(t-butoxycarbonyl)carbamate (647 mg, 68% yield). LCMS ESI(+) m / z: 666.2 (M+1).

[0179] Step I: The compound t-butyl (1-(4-(methylazido)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(t-butoxycarbonyl)carbamate (235 mg) was dissolved in 25 mL of methanol, and 10% palladium on carbon (40 mg) was added under a nitrogen atmosphere. The mixture was purged with hydrogen gas. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was suction filtered and washed with 5 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the crude product compound t-butyl (1-(4-aminomethylpiperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(t-butoxycarbonyl)carbamate (145 mg, yield 64%). LCMS ESI(+)m / z:640.3(M+1).

[0180] Step J: The compound t-butyl (1-(4-aminomethylpiperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(t-butoxycarbonyl)carbamate (70 mg) was dissolved in 5 mL of dichloromethane, and triethylamine (33 mg) and cyanomethanesulfonyl chloride (23 mg) were added in this order at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours. The reaction mixture was purified by silica gel column chromatography (petroleum ether and ethyl acetate in a 1:1 ratio) to obtain the compound t-butyl (t-butoxycarbonyl) (1-(4-(((cyanomethyl)sulfonylamino)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)carbamate (70 mg, 89% yield). LCMS ESI(+) m / z: 718.2 (M+1).

[0181] Step K: The compound t-butyl (t-butoxycarbonyl) (1-(4-(((cyanomethyl)sulfonylamino)methyl)piperidin-1-yl)-6-p-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)carbamate (70 mg) was dissolved in 3 mL of dichloromethane, and 4N hydrochloric acid in dioxane (2.5 mL) was added at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product compound N-((1-(2-amino-6-silylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl )-1-cyanomethanesulfonamide was obtained and taken on directly to the next step.

[0182] Step L: The crude product compound N-((1-(2-amino-6-silylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide was suspended in 3 mL of methanol, and 2N sodium hydroxide solution (1 mL) was added. The mixture was stirred at 35° C. for 16 hours. The pH was adjusted to 7 with 1N HCl. Methanol was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane ratio: 1:10) to give compound N-((1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide (2 mg, yield 5%). 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.29-8.01(m,2H),7.46-7.34(m,1H),6.47(dd,J=3.3,1.8Hz,1H),6.24(s,2H) ),4.81(s,2H),3.53-3.42(m,2H),3.11-2.97(m,4H),2.04-1.95(m,1H),1.94-1.87(m,2H),1.60-1.49(m,2H).LCMS ESI(+)m / z:389.0(M+1).

[0183] Example 15: Synthesis of Compound B3 [ka] 2-((1R,4R)-4-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-ethyl)cyclohexyl)acetonitrile Specific embodiments are shown below. [ka]

[0184] Step A: Compound N 41H-(Piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (700 mg) was suspended in methanol (100 mL), and cyanogen bromide (199 mg) was added in this order at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the resulting mixture was diluted with saturated sodium bicarbonate solution (10 mL), saturated sodium thiosulfate solution (10 mL), and a mixture of methanol and ethyl acetate. The combined solvent (volume ratio 1:10, 40 mL) was added and stirred at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted three times with a mixed solvent of methanol and ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the crude product compound 2-((1R,4R)-4-(2-amino-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[4,5-b](6H)-ethyl)cyclohexyl)acetonitrile (740 mg, 100% yield). LCMS ESI(+) m / z: 435.2 (M+1).

[0185] Step B: The compound 2-((1R,4R)-4-(2-amino-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[4,5-b](6H)-ethyl)cyclohexyl)acetonitrile (100 mg) was suspended in 6 mL of methanol, and 2N sodium hydroxide solution (1.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 7 with 1N HCl. The methanol was evaporated under reduced pressure, and the residue was separated by reverse-phase preparative high-performance liquid chromatography to obtain the compound 2-((1R,4R)-4-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-ethyl)cyclohexyl)acetonitrile (35 mg, 52% yield). 1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.13(s,1H),7.44-7.26(m,1H),6.55(dd,J=3.3,1.6Hz,1H),6.21(s,2H),4.49 LCMS ESI(+)m / z:295.2(M+1).

[0186] Example 16: Synthesis of Compound B4 [ka] 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile Specific embodiments are shown below. [ka]

[0187] Step A: CuI (3.6 g), L-proline (4.4 g), potassium carbonate (39.6 g), 3-iodothiophene (20 g), and concentrated aqueous ammonia (8.7 g) were added to a 250 mL three-neck flask in this order. The mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was filtered, the filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous magnesium sulfate, and rotary evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate and petroleum ether = 15%) to give 3-aminothiophene (9 g, 95%).

[0188] Step B: 2,2-Dimethyl-1,3-dioxane-4,6-diketone (14.4 g) was dissolved in 200 mL of isopropanol, followed by the addition of triethyl orthoformate (45 mL, 400 mmol). The mixture was stirred at 100 °C for 1 hour, cooled to room temperature, and a white solid precipitated. This was directly used in the next step. 3-Aminothiophene (10 g) was added, followed by the addition of isopropanol, and the mixture was refluxed for 30 minutes. After cooling to room temperature, a large amount of white solid precipitated. This was filtered to obtain 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-diketone (3 g, 12% yield). 1 H NMR(400MHz,DMSO-d6)δ11.38(d,J=14.7Hz,1H),8.49(d,J=14.7Hz,1H),7.69(dd,J=3.2 ,1.4Hz,1H),7.62(dd,J=5.2,3.2Hz,1H),7.44(dd,J=5.2,1.5Hz,1H),1.66(s,6H).LCMS ESI(+)m / z:196.0(M+1-58)

[0189] Step C: Diphenyl ether was added to a 50 mL round-bottom flask, and the reaction mixture was heated to 250 °C. 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-diketone (3.00 g) was added to the reaction mixture, and the mixture was reacted at 250 °C for 30 minutes. The mixture was then cooled to room temperature and filtered to obtain thieno[3,2-b]pyridin-7-ol (1.2 g, 68% yield) as a white solid. LCMS ESI(+) m / z: 152.0 (M+1).

[0190] Step D: Thieno[3,2-b]pyridin-7-ol (900 mg) was dissolved in propionic acid (20 mL) and heated to 110°C in a nitrogen atmosphere. 4.8 mL of fuming nitric acid was added, and the mixture was reacted at 150°C for 1 hour. The mixture was then cooled to room temperature, ethyl ether was added, and the solid was filtered. The solid was washed with water and dried under reduced pressure to give 6-nitrothieno[3,2-b]pyridin-7-ol (700 mg, 60% yield). LCMS ESI(+)m / z:197.0(M+1).

[0191] Step E: 6-Nitrothieno[3,2-b]pyridin-7-ol (600 mg) was added to phosphorus trichloride (25 mL) and heated to 110°C under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure, and then dichloromethane and saturated sodium bicarbonate solution were added. The organic phases were separated and combined. The organic phases were washed three times with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give 7-chloro-6-nitrothieno[3,2-b]pyridine (483 mg, 75% yield). LCMS ESI(+) m / z: 215.0 (M+1).

[0192] Step F: The compound 7-chloro-6-nitrothieno[3,2-b]pyridine (480 mg) was dissolved in isopropanol (15 mL), and 2-(1-aminopiperidin-4-yl)acetonitrile (471 mg) and diisopropylethylamine (1 mL) were added. The mixture was reacted at 90°C for 2 hours, and then cooled to room temperature. A large amount of solid precipitated. The yellow solid was filtered and dried under reduced pressure to obtain the compound 2-(1-((6-nitrothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (600 mg, yield 85%). 1 H NMR(400MHz,CDCl3)δ9.30(s,1H),9.24(d,J=8.5Hz,1H),7.86(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),4.21(m,J=14. 9,7.3Hz,1H),2.39(d,J=6.2Hz,2H),2.05(d,J=12.9Hz,2H),1.91-1.73(m,1H),1.52(ddd,J=41.0,19.4,8.4Hz,5H).

[0193] Step G: The compound 2-(1-((6-nitrothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (200 mg) was dissolved in ethanol (100 ml), and saturated ammonium chloride solution and Fe (353 mg) were added. The mixture was reacted at 75°C for 30 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered while still hot, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (methanol:dichloromethane ratio 1:10) to obtain the compound 2-(1-((6-aminothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (180 mg, yield 98%). LCMS ESI(+) m / z: 288.2 (M+1)

[0194] Step H: The compound 2-(1-((6-aminothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (72 mg) was dissolved in methanol (5 mL), and cyanogen bromide (53 mg) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure, and saturated sodium bicarbonate solution (5 mL), saturated sodium thiosulfate (5 mL), and a mixed solvent of methanol and ethyl acetate (volume ratio 1:10, 10 mL) were added, followed by stirring at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted three times with a mixed solvent of methanol and ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol and dichloromethane in a ratio of 1:10) to obtain the product 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile (11 mg, yield 15%). 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.78(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),6.70(s ,2H),4.59-4.33(m,1H),2.61(d,J=5.8Hz,2H),2.44-2.32(m,2H),2.00(d,J=11.8Hz,2H) ,1.92(d,J=10.9Hz,2H),1.48-1.32(m,2H).LCMS ESI(+)m / z:313.2(M+1).

[0195] Example 17: Synthesis of Compound B5 [ka] 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile Specific embodiments are shown below. [ka]

[0196] Step A: A clean, dry 500 ml single-neck flask was taken, and 2-bromo-3-hydroxypyridine (25 g), ethynyltrimethylsilane (17 g), cuprous iodide (2.74 g, 14.4 mmol), palladium dichlorobistriphenylphosphine (2.0 g), and 1,4-dioxane (200 ml) were added. The reaction system was purged with nitrogen gas three times, and then stirred at room temperature for 30 minutes. Triethylamine (43.6 g) was added, and the reaction system was reacted at 65°C in a nitrogen atmosphere for 6 hours. The mixture was cooled to room temperature and suction filtered under reduced pressure. The filter cake was washed with 30 ml of methyl t-butyl ether. The filtrate was washed with 400 ml of water. The aqueous phase was extracted twice with 400 ml of methyl t-butyl ether. The combined organic phase was washed with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain a crude product. The crude product was added to 200 ml of petroleum ether and mixed for 30 minutes. The mixture was filtered. The filter cake was washed twice with 30 ml of petroleum ether. The filtrate was rotary evaporated to obtain the compound 2-(trimethylsilyl)furo[3,2-b]pyridine (23.3 g, yield: 85%). 1 H NMR(400MHz,CDCl3)δ8.53(dd,J=4.7,1.1Hz,1H),7.75(dt,J=8.3,1.1Hz,1H),7.19(dd,J =8.3, 4.7Hz,1H),7.15(d,J=1.0Hz,1H),0.38(s,9H).

[0197] Step B: In a clean, dry 1 L single-neck flask, add 2-(trimethylsilyl)furo[3,2-b]pyridine (36.6 g) and dichloromethane (400 mL). Add 70% m-chloroperoxybenzoic acid (76.9 g) at room temperature and react overnight. After the reaction was complete, the mixture was filtered, washed twice with 20 mL of dichloromethane, and the combined filtrate was washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give 2-(trimethylsilyl)furo[3,2-b]pyridine 4-oxide (41.4 g, crude product). 1 H NMR(400MHz,CDCl3)δ8.18(d,J=6.3Hz,1H),7.45(d,J=8.4Hz,1H),7.40(d,J=0.7Hz,1H),7.15(dd,J=8.4,6.3Hz,1H),0.38(s,9H).

[0198] Step C: In a clean, dry 500 mL single-neck flask, add the crude 2-(trimethylsilyl)furo[3,2-b]pyridine 4-oxide (41.4 g) and toluene (150 mL). At 0 °C, add 150 mL of phosphorus trichloride slowly, then heat the reaction mixture to 95 °C and allow it to react for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and rotary evaporated. The resulting residue was diluted with 300 mL of water and adjusted to pH 8 with saturated aqueous sodium bicarbonate. The mixture was extracted three times with 500 mL of methyl t-butyl ether. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by silicon gel column chromatography (eluent: ethyl acetate:petroleum ether = 1:10) to obtain 2-(trimethylsilyl)-7-chlorofuro[3,2-b]pyridine (20.7 g, yield: 46%). 1H NMR(400MHz,CDCl3)δ8.40(d,J=5.2Hz,1H),7.21(d,J=5.2Hz,1H),7.17(s,1H),0.40(s,9H).

[0199] Step D: A clean, dry 500 mL single-neck flask was charged with 2-(trimethylsilyl)-7-chlorofuro[3,2-b]pyridine (20.7 g) and tetrahydrofuran (150 mL). 150 mL of aqueous sodium hydroxide (18 g) was added at room temperature, and the reaction mixture was heated to 50 °C and reacted for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature, the solvent was evaporated, and the resulting aqueous solution was extracted three times with 200 mL of methyl t-butyl ether. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 7-chlorofuro[3,2-b]pyridine (11.8 g, 84% yield). 1 H NMR(400MHz,CDCl3)δ8.46(d,J=5.2Hz,1H),7.92(d,J=2.3Hz,1H),7.28(d,J=5.2Hz,1H),7.05(d,J=2.3Hz,1H).

[0200] Step E: Compound 5 (10.8 g) and methanol (200 ml) were added to a clean, dry 500 ml single-neck flask. 100 ml of aqueous sodium hydroxide (42.6 g) was added at room temperature, and the reaction mixture was heated to 75 °C and allowed to react overnight. After the reaction was complete, the reaction mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The resulting solution was diluted with 100 ml of water and extracted twice with 200 ml of dichloromethane. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give compound 7-methoxyfuro[3,2-b]pyridine (5.6 g, yield: 53.3%). 1 H NMR( 400MHz, CDCl3)δ8.43(s,1H),7.80(d,J=2.2Hz,1H),6.97(d,J=2.2Hz,1H),6.76(d,J=5.5Hz,1H),4.08(s,3H).

[0201] Step F: A clean, dry 25 ml single-neck flask was charged with 7-methoxyfuro[3,2-b]pyridine (5.0 g), a solution of hydrobromic acid in acetic acid (10 ml), and water (4 ml), and the mixture was incubated overnight at 125 °C. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was removed by rotary evaporation. The resulting residue was dissolved in 50 ml of toluene and further evaporated. This process was repeated three times to obtain 7.2 g of crude product. The crude product was purified by C18 reverse-phase column chromatography using a methanol:water (0.1% aqueous ammonia) system as the eluent, followed by 100% water to obtain 7-hydroxyfuro[3,2-b]pyridine (3.1 g, yield: 46.5%). 1 H NMR(400MHz,DMSO-d6)δ8.60(d,J=2.2Hz,1H),8.54(d,J=6.9Hz,1H),7.31(d,J=2.2Hz,1H),7.14(d,J=6.8Hz,1H).

[0202] Step G: A clean, dry 50 mL single-neck flask was charged with 7-hydroxyfuro[3,2-b]pyridine (1.5 g) and dichloromethane (15 mL). Tetrabutylammonium nitrate (10 g) and trifluoroacetic anhydride (11.6 g) were added at 0 °C. The reaction mixture was then incubated overnight at room temperature. After the reaction was complete, the mixture was diluted with 50 mL of water and extracted twice with 50 mL of ethyl acetate. The combined filtrate was washed with saturated aqueous sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain the crude product. The crude product was separated by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain furo[3,2-b]pyridin-7-yl nitrate (540 mg, yield: 27%). 1 H NMR(400MHz,CDCl3)δ8.59(d,J=8.7Hz,1H),7.83(d,J=2.1Hz,1H),7.37(d,J=2.1Hz,1H),6.43(d,J=8.7Hz,1H).

[0203] Step H: A clean, dry 50 ml single-neck flask was charged with furo[3,2-b]pyridin-7-yl nitrate (430 mg) and propionic acid (15 ml), followed by fuming nitric acid (551 mg) at room temperature, followed by reaction at 125° C. for 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 50 ml of methyl t-butyl ether, filtered, and the solid was washed twice with 3 ml of methyl t-butyl ether to obtain 6-nitrofuro[3,2-b]pyridin-7-ol (220 mg, yield: 37.5%). 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.01(s,1H),8.22(d,J=2.1Hz,1H),6.95(d,J=2.1Hz,1H).

[0204] Step I: A clean, dry 25 mL single-neck flask was charged with 6-nitrofuro[3,2-b]pyridin-7-ol (356 mg) and DCE (12 mL). Trichloroisopropylphosphorus trichloride (4.2 mL) was added at room temperature, and the reaction mixture was incubated at 95 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, the solvent was evaporated, and the mixture was diluted with 10 mL of water. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted three times with 50 mL of methyl t-butyl ether. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a yellow solid, 7-chloro-6-nitrofuro[3,2-b]pyridine (287 mg, yield: 73.2%). 1 H NMR(400MHz,CDCl3)δ9.22(s,1H),8.16(d,J=2.2Hz,1H),7.17(d,J=2.2Hz,1H).

[0205] Step J: A clean, dry 10 ml single-neck flask was charged with 70 mg of 7-chloro-6-nitrofuro[3,2-b]pyridine, 74.4 mg of 2-((1r,4r)-4-aminocyclohexyl)acetonitrile, and 5 ml of t-butanol. Then, 100 mg of DIPEA was added at room temperature and the reaction mixture was incubated at 135 °C overnight. After the reaction was completed, the reaction mixture was rotary evaporated to dryness to obtain the crude product. The crude product was separated by normal phase column chromatography (ethyl acetate:petroleum ether = 50%) to obtain a yellow solid, 2-((1r,4r)-4-((6-nitrofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (55 mg, yield: 51.8%). 1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.49-8.39(m,2H),7.14(d,J=2.2Hz,1H),4.33-4.21(m,1H),2.53(d,J=6.4 Hz,2H),2.11(d,J=9.7Hz,2H),1.87(d,J=11.9Hz,2H),1.74-1.64(m,1H),1.61-1.49(m,2H),1.33-1.25(m,2H).

[0206] Step K: A clean, dry 50 mL single-neck flask was taken, and the compound 2-((1R,4R)-4-((6-nitrofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (55 mg) and methanol (10 mL) were added. Palladium on carbon (25 mg, 60% content) was added at room temperature. The reaction system was purged with hydrogen gas three times and reacted for 30 minutes at one hydrogen gas balloon pressure. After the reaction was complete, the reaction solution was filtered using diatomaceous earth as a filter aid. The filter cake was washed with 3 mL of methanol, and the combined filtrate was rotary dried to obtain the compound 2-((1R,4R)-4-((6-aminofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (43 mg, yield: 86.5%). 1H NMR(400MHz,DMSO-d6)δ7.87(d,J=2.3Hz,1H),7.75(s,1H),6.73(d,J=2.3Hz,1H),4.91(d,J=9.1Hz,1H),4.59( s,2H),3.97-3.85(m,1H),2.00(d,J=9.4Hz,2H),1.83(d,J=12.1Hz,2H),1.67-1.59(m,1H),1.37-1.16(m,6H).

[0207] Step L: One clean and dry 25 ml vial was taken, and the compound 2-((1r,4r)-4-((6-aminofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (33 mg) and methanol (5 ml) were added, followed by the addition of cyanogen bromide (14.3 mg) at room temperature, and the reaction system was allowed to react at room temperature overnight. After the reaction was completed, 20 mL of water was added to the reaction mixture, and the aqueous phase was extracted three times with 30 mL of dichloromethane. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain 40 mg of crude product. The crude product was purified by high-pressure liquid chromatography (0.05% aqueous ammonia system) to obtain a white solid compound, 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile (3.8 mg, yield: 10.5%). 1 H NMR(400MHz,CDCl3)δ8.72(s,1H),7.80(d,J=2.2Hz,1H),7.09(d,J=2.2Hz,1H),4.84(s,2H),4.17-4.03(m,1H) ,2.54-2.44(m,2H),2.43(d,J=6.1Hz,2H),2.16-2.02(m,5H),1.47(d,J=12.8Hz,2H).ESI(+)m / z:296.7(M+1).

[0208] Example 18: Synthesis of Compound B6 [ka] 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0209] Step A: 5-Nitrosalicylic acid (5.00 g) was dissolved in 60 mL of DMF, and KHCO3 (3.01 g) and benzyl bromide (5.14 g) were added at room temperature. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. Ethyl acetate (100 mL) was poured into water (50 mL), and the organic phase was separated. The mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate:petroleum ether ratio 1:9) to give compound 2-hydroxy-5-nitrobenzoic acid benzyl (5.84 g, 78% yield). 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.54(d,J=2.9Hz,1H),8.33(dd,J=9.2,3.0Hz,1H),7.51(dd,J=7.7,1.1Hz,2H),7.47-7.34(m,3H),7 .18(d,J=9.2Hz,1H),5.40(s,2H).

[0210] Step B: Benzyl 2-hydroxy-5-nitrobenzoate (5.84 g) was dissolved in dichloromethane (100 mL), and triethylamine (3.24 g) and benzyl chloroformate (4.38 g) were added in this order in an ice bath and under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate:petroleum ether ratio 1:10) to obtain the compound 2-((benzyloxycarbonyl)oxy)-5-nitrobenzoate (6.56 g, 75% yield).1 H NMR(400MHz,CDCl3)δ8.89(d,J=2.8Hz,1H),8.41(dd,J=8.9,2.8Hz,1H),7.46-7.31(m,11H),5.30(s,2H),5.15(s,2H).

[0211] Step C: The compound benzyl 2-((benzyloxycarbonyl)oxy)-5-nitrobenzoate (1.20 g) was dissolved in ethanol (10 mL) and acetonitrile (10 mL), and water (0.5 mL) and stannous chloride dihydrate (3.32 g) were added at room temperature. The mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, adjusted to basicity with saturated aqueous sodium bicarbonate, and stirred for 15 minutes. Ethyl acetate (50 mL) was added, and the mixture was suction filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (50 mL). The organic phase was separated and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate and petroleum ether in a ratio of 1:4) to obtain compound benzyl 2-((benzyloxycarbonyl)oxy)-5-aminobenzoate (662 mg, yield 60%). 1 H NMR(400MHz,DMSO-d6)δ7.43-7.33(m,11H),7.08-7.02(m,2H),6.99(dd,J=8.8, 2.8Hz,1H),5.22(s,2H),5.10(s,2H),4.11(s,2H).LCMS ESI(+)m / z:378.2(M+1).

[0212] Step D: The compound benzyl 2-((benzyloxycarbonyl)oxy)-5-aminobenzoate (2.00 g) was dissolved in acetonitrile (20 mL). The reaction mixture was cooled to -10°C, and then a solution of concentrated hydrochloric acid (3 mL) and sodium nitrite (366 mg) in water (0.6 mL) was added and stirred for 15 minutes. Stannous chloride dihydrate (3.59 g) was then added and stirred for 1 hour. The pH was adjusted to 8 with a 2N aqueous solution of sodium hydroxide. Ethyl acetate (100 mL) was added, and the mixture was suction filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (100 mL). The organic phase was separated and extracted twice with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate and petroleum ether in a 1:1 ratio) to obtain the compound 2-((benzyloxycarbonyl)oxy)-5-hydrazinobenzoic acid benzyl ester (1.3 g, yield 63%). 1 H NMR(400MHz,DMSO-d6)δ7.43-7.33(m,11H),7.08-7.02(m,2H),6.99(dd,J=8.8, 2.8Hz,1H),5.22(s,2H),5.10(s,2H),4.11(s,2H).LCMS ESI(+)m / z:393.2(M+1).

[0213] Step E: 4-Chloro-5-nitro-1-(p-toluenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.15 g) was suspended in t-butanol (80 mL), and 1N aqueous sodium hydroxide solution (38.1 mL) was added, followed by stirring at room temperature for 16 hours. The organic phase was separated and extracted twice with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.01 g, 100% yield). 1H NMR(400MHz,CDCl3)δ9.02(s,1H),7.72(d,J=4.1Hz,1H),7.11-7.02(m,2H),6.77-6 .66(m,2H),6.61(d,J=4.1Hz,1H),6.42-6.34(m,1H),3.71-3.51(m,3H),3.45-3.36( m,1H),3.16-3.09(m,1H),3.00-2.91(m,1H),2.36(d,J=6.7Hz,2H),2.07-1.99(m,1 H),1.98-1.82(m,2H),1.79(d,J=6.7Hz,3H),1.75-1.63(m,11H),1.36-1.23(m,1H).

[0214] Step F: The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.22 g) was suspended in 100 mL of isopropanol, and N,N-diisopropylethylamine (6.32 mL) and 2-((1r,4r)-4-aminocyclohexyl)acetonitrile hydrochloride (3.70 g) were added in this order. The mixture was heated to 90 °C under a nitrogen atmosphere and reacted for 16 hours with stirring. The mixture was cooled to room temperature, suction filtered under reduced pressure, and washed with 20 mL of isopropanol. The filter cake was dried under reduced pressure to obtain the compound 2-((1r,4r)-4-((5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (4.88 g, 100% yield). 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.01(d,J=8.0Hz,1H),8.86(s,1H),7.98(s,1H),7.33(d,J=3.2Hz,1H),6.71(d,J=3.5Hz,1H), 4.13-4.01(m,1H),2.54-2.51(m,2H),2.21-2.12(m,2H),1.91-1.82(m,2H),1.76-1.65(m,1H),1.56-1.45(m,2H),1.42-1.30(m,2H).

[0215] Step G: The compound 2-((1r,4r)-4-((5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (4.98 g) was added to 200 mL of ethanol, and iron powder (18.6 g) and saturated ammonium chloride (19 mL) were added in that order at room temperature. The mixture was stirred at 75 °C for 40 minutes. The mixture was suction filtered through diatomaceous earth while still hot, washed with 40 mL of ethanol, and the filtrate was concentrated. The product was purified by silica gel column chromatography (methanol:dichloromethane ratio 1:9) to obtain the compound 2-((1r,4r)-4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (4.33 mg, 97% yield). 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.10(s,1H),7.54(s,1H),7.26(d,J=3.6Hz,1H),6.70(d,J=8.0Hz,1H),6.60(d,J=3.7Hz,1H),4.06-3.91( m,1H),3.34(s,2H),2.50-2.41(m,2H),2.14-2.02(m,2H),1.86(d,J=11 .6Hz,2H),1.75-1.61(m,1H),1.59-1.46(m,2H),1.40-1.28(m,2H).LCMS ESI(+)m / z:270.2(M+1).

[0216] Step H: Thiocarbonyldiimidazole (744 mg) was dissolved in THF (50 mL), and a solution of compound 5 (1.64 g) in THF (10 mL) was added at room temperature. The mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. Compound 2-((1r,4r)-4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (865 mL) was added. A solution of 2-(2-(benzyloxycarbonyl)oxy)-5-(2-((4-(((1r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)aminomethylthio)hydrazine)benzyl benzoate (1.43 mg, 63% yield) was obtained. LCMS ESI(+) m / z: 704.2 (M+1).

[0217] Step I: In a nitrogen atmosphere, the compound 2-((benzyloxycarbonyl)oxy)-5-(2-((4-(((1r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)aminomethylthio)hydrazine)benzyl benzoate (1.43 g) was dissolved in 50 mL of dry THF, and EDCI (584 mg) and triethylamine (616 mg) were added in this order, followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by C18 reverse-phase silica gel column chromatography (methanol to 0.1% formic acid aqueous solution = 75%) to obtain the compound benzyl 5-((E)-(1-(((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-)diazenyl)-2-hydroxybenzoate (318 mg, 29% yield). LCMS ESI(+) m / z: 534.2 (M+1).

[0218] Step J: The compound benzyl 5-((E)-(1-(((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-)diazenyl)-2-hydroxybenzoate (661 mg) was suspended in 60 mL of isopropanol, and 3.5 N sodium hydroxide solution (12 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5 with HCl. Isopropanol was removed by distillation under reduced pressure, and the residue was suction filtered under reduced pressure, washed with water (30 mL), washed with acetonitrile (30 mL), and lyophilized to obtain the compound (5-((E)-(1-(((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (415 mg, yield 76%). 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.70(s,1H),8.46(d,J=2.4Hz,1H),8.14(dd,J=8.9,2.2Hz,1H),7.58(s,1H),7.10(d,J=9.0Hz,1H),6. 95(s,1H),5.19(s,1H),2.60(d,J=5.9Hz,2H),2.44(d,J=12.3Hz,2H),2.15(d,J=11.1Hz,2H),2.04(d,J=11.5Hz,3H),1.61-1.45(m,2H).LCMS ESI(+)m / z:444.2(M+1).

[0219] Example 19: Synthesis of Compound B7 [ka] (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid Specific embodiments are shown below. [ka]

[0220] Step A: The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.22 g) was suspended in 100 mL of isopropanol, and N,N-diisopropylethylamine (6.32 mL) and 2-((1r,4r)-4-aminocyclohexyl)acetonitrile hydrochloride (3.70 g) were added in this order. The mixture was heated to 90 °C under a nitrogen atmosphere and reacted for 16 hours with stirring. The mixture was cooled to room temperature, suction filtered under reduced pressure, and washed with 20 mL of isopropanol. The filter cake was dried under reduced pressure to obtain the compound 2-(4-((5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (4.88 g, 100% yield). 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.01(d,J=8.0Hz,1H),8.86(s,1H),7.98(s,1H),7.33(d,J=3.2Hz,1H),6.71(d,J=3.5Hz,1H), 4.13-4.01(m,1H),2.54-2.51(m,2H),2.21-2.12(m,2H),1.91-1.82(m,2H),1.76-1.65(m,1H),1.56-1.45(m,2H),1.42-1.30(m,2H).

[0221] Step B: The compound 2-(4-((5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (3.20 g) was added to 100 mL of ethanol, and stannous chloride dihydrate (12.0 g) was added at room temperature. The reaction was allowed to proceed with stirring at 45°C for 2 hours. The mixture was cooled to room temperature, and the pH was adjusted to 8-9 with 2N NaOH solution in an ice bath. The mixture was then stirred at room temperature for 15 minutes. 300 mL of ethyl acetate and diatomaceous earth were added, and the mixture was suction filtered through diatomaceous earth and washed with 30 mL of ethyl acetate. The organic phase was separated and extracted twice with 50 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20) to obtain the compound 2-(4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (1.23 g, yield 43%). 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.54(s,1H),7.00(d,J=1.9Hz,1H),6.70(d,J=2.1Hz,1H),6.31(s,1H),4.40(s,2H),3. 08(d,J=11.0Hz,2H),2.55(d,J=6.5Hz,2H),2.48-2.40(m,2H),1.82-1.74(m,2H),1.72-1.62(m,1H),1.53-1.39(m,2H).LCMS ESI(+)m / z:271.2(M+1).

[0222] Step C: Thiocarbonyldiimidazole (923 mg) was dissolved in THF (100 mL), and a solution of compound 2-(4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (2.03 g) in THF (15 mL) was added at room temperature. The mixture was stirred at room temperature for 15 minutes under a nitrogen atmosphere. A solution of compound 9 (1.00 g) in DMF (30 mL) and triethylamine (524 mg) were added, and the mixture was reacted at 60 °C for 2 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (methanol:dichloromethane = 1:30) to give compound 2-((1-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (2.13 g). LCMS ESI(+) m / z: 705.2 (M+1).

[0223] Step D: In a nitrogen atmosphere, the compound 2-((1-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)acetonitrile (2.13 g) was dissolved in 150 mL of dry THF, and EDCI (1.16 g) and triethylamine (917 mg) were added in this order, followed by stirring at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by C18 reverse-phase silica gel column chromatography (methanol to 0.1% formic acid aqueous solution = 70%) to obtain the compound benzyl (E)-5-((1-(4-(cyanomethyl)pizotiphen-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoate (102 mg, yield 6%). 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.61(s,1H),8.45(m,2H),8.19-8.12(m,2H),7.57-7.49(m,4H),7.50-7.34(m,1H),7.16(d,J=9.0Hz, 1H),6.93-6.88(m,1H),5.42(s,2H),3.64(m,2H),3.41(d,J=10.7Hz,2H),2.63(d,J=5.9Hz,2H),1.95-1.87(m,2H),1.86-1.65(m,3H).LCMS ESI(+)m / z:534.2(M+1).

[0224] Step E: The compound benzyl (E)-5-((1-(4-(cyanomethyl)pizotiphen-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoate (100 mg) was dissolved in 9 mL of isopropanol. The mixture was suspended in ethanol and 3N sodium hydroxide solution (1.5 mL) was added. The mixture was stirred at 25°C for 16 hours. The pH was adjusted to 3 with 1N HCl. The isopropanol was distilled off under reduced pressure, and the residue was suction filtered under reduced pressure, washed with water (30 mL), washed with acetonitrile (30 mL), and lyophilized to obtain compound (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (82 mg, yield 99%). 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.73(s,1H),8.51(d,J=2.6Hz,1H),8.22(dd,J=9.0,2.6Hz,1H),7.61-7.54(m,1H),7.21(d,J=9 .0Hz,1H),7.00-6.96(m,1H),3.73-3.64(m,2H),3.51-3.44(m,2H),2.69(d,J=5.9Hz,2H),2.05-1.85(m,3H),1.82-1.66(m,2H).LCMS ESI(+)m / z:445.2(M+1).

[0225] Example 20: Synthesis of Compound B8 [ka] (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartic acid Specific embodiments are shown below. [ka]

[0226] Step A: The compound 5-((E)-(1-(((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (147 mg) was dissolved in DMF (8 mL), and the compound dibenzyl D-aspartate (260 mg), DCC (171 mg), and pyridine (157 mg) were added in this order at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 48 hours under a nitrogen atmosphere. The mixture was purified by C18 reverse-phase silica gel column chromatography (the ratio of acetonitrile to 0.1% formic acid aqueous solution was 60%) to obtain the compound dibenzyl (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid. ,6-Dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2)-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartic acid ester (73 mg, 30% yield) was obtained. 1H NMR(400MHz,CDCl3)δ12.13(s,1H),8.77-8.62(m,2H),8.10(d,J=8.2Hz,1H) ,7.57(s,1H),7.39-7.25(m,10H),7.17(s,1H),6.93(s,1H),5.17(s,2H),5. 12(s,2H),5.11-5.04(m,1H),3.17-3.02(m,2H),2.59(d,J=6.1Hz,2H),2.48 -2.38(m,2H),2.19-2.08(m,2H),2.08-1.94(m,3H),1.60-1.45(m,2H).LCMS ESI(+)m / z:444.2(M+1).LCMS ESI(+)m / z:739.2(M+1).

[0227] Step B: The compound dibenzyl (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2)-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartate (69 mg) was suspended in 12 mL of isopropanol, and 3 mL of 3.5 N sodium hydroxide solution was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5 with 1 N HCl. The isopropanol was distilled off under reduced pressure, and the mixture was suction filtered under reduced pressure and lyophilized. Water (12 mL) was added, and the mixture was centrifuged. Water (12 mL) was added, and the mixture was centrifuged. Lyophilization gave the compound (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2)-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartic acid (45 mg, 86% yield). 1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),12.57(s,1H),12.17(s,1H),9.46(s,1H),8 .83-8.63(m,2H),8.11(d,J=8.1Hz,1H),7.58(s,1H),7.20(s,1H),6.95(s,1H),5. 20(s,1H),4.86(dd,J=13.4,5.9Hz,1H),2.89(d,J=5.7Hz,2H),2.69-2.56(m,2H) ,2.48-2.37(m,2H),2.20-2.09(m,2H),2.09-1.99(m,3H),1.59-1.46(m,2H).LCMS ESI(+)m / z:559.2(M+1).

[0228] Example 21: Synthesis of Compound B9 [ka] (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysine Specific embodiments are shown below. [ka]

[0229] Step A: The compound 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (285 mg) was dissolved in DMF (15 mL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere to obtain the compound N 6 To the mixture were added 540 mg of benzyl 2-Boc-D-lysine, 332 mg of DCC, and 305 mg of pyridine, in this order. The mixture was stirred at room temperature for 18 hours under a nitrogen atmosphere. The mixture was purified by C18 reverse-phase silica gel column chromatography (50% acetonitrile and 0.1% formic acid solution), yielding Compound N. 6 -Boc-N2 -(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysinebenzyl (120 mg, 25% yield). 1 H NMR(400MHz,CDCl3)δ13.61(s,1H),12.05(s,1H),8.77-8.62(m,2H),8.13(s,1H), 7.95(s,1H),7.54(t,J=2.8Hz,1H),7.38-7.32(m,5H),6.98-6.77(m,3H),5.19-5.1 3(m,3H),4.57-4.55(m,1H),3.17(s,1H),2.59(d,J=6.1Hz,2H),2.48-2.38(m,2H) ,2.19-1.94(m,5H),1.87-1.75(m,2H),1.52-1.48(m,2H),1.45-1.41(m,10H).LCMS ESI(+)m / z:762.2(M+1).

[0230] Step B: Compound Benzyl N 6 -Boc-N 2 -(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysine benzyl (110 mg) was suspended in 10 mL of isopropanol, and 3.5 N sodium hydroxide solution (2.4 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5 with 1 N HCl. The isopropanol was distilled off under reduced pressure, and the mixture was suction filtered under reduced pressure. Water (12 mL) was added, the mixture was centrifuged, and the mixture was lyophilized to give compound (5-((E)-(1-((1r,4R )-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysine (73 mg, yield 89%) was obtained. 1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),9.33(t,J=1.6Hz,1H),8.85(d,J=2.0Hz,1H),8.7 3(s,1H),8.12-8.09(m,1H),7.95-7.89(m,3H),7.60(t,J=3.2Hz,1H),7.23(d,J=8.4Hz, 1H),6.98(s,1H),5.21-5.12(m,1H),4.51-4.47(m,1H),2.78-2.71(m,2H),2.67-2.56( LCMS ESI(+)m / z:572.2(M+1).

[0231] Example 22: Synthesis of Compound B10 [ka] (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid Specific embodiments are shown below. [ka]

[0232] Step A: The compound 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (140 mg) and dibenzyl D-glutamate (246 mg) were dissolved in 5 mL of N,N-dimethylformamide, followed by the addition of dicyclohexylcarbodiimide (163 mg) and pyridine (55 mg). The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was rotary dried and purified by column chromatography to obtain the compound dibenzyl (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid ester (135 mg, yield 56.8%).

[0233] Step B: The compound dibenzyl (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid ester (135 mg) was dissolved in 24 mL of isopropanol, and then 3.5 N sodium hydroxide (6.0 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the solution was adjusted to pH 7 with 1N hydrochloric acid, and the isopropanol was distilled off under reduced pressure. The solution was then adjusted to pH 3 with 1N hydrochloric acid and freeze-dried. Water was added to the resulting solid, which was then centrifuged twice. The supernatant was removed and the solid was freeze-dried to give the compound (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid (95 mg, yield 92.5%). 1H NMR(400MHz,DMSO-d6)δ13.38-12.51(s,2H),12.23-12.09(m,1H),9.32(s,1H),8.82(d,J =2.4Hz,1H),8.70(d,J=6.2Hz,1H),8.12(dd,J=9.1,2.4Hz,1H),7.60-7.55(m,1H),7.18(d ,J=8.9Hz,1H),6.95(s,1H),5.33-5.08(m,1H),4.56-4.49(m,1H),2.59(d,J=6.1Hz,2H), 2.47-2.44(m,1H),2.41(t,J=7.5Hz,2H),2.22-1.98(m,8H),1.58-1.48(m,2H).LC-MS:m / z 573.2[M+H] + .

[0234] Example 23: Synthesis of Compound B11 [ka] (R)-2-(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)-5-((diaminomethylene)amino)pentanoic acid Specific embodiments are shown below. [ka]

[0235] Step A: N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ω-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (1.60 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (0.408 g) and benzyl bromide (0.506 g) were added at room temperature. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered under suction. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound benzyl N. 2 -(((9H- Fluoren-9-yl)methoxy)carbonyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (1.76 g, 96% yield). LCMS ESI(+) m / z: 739.2 (M+1).

[0236] Step B: Compound Benzyl N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ω Compound piperidine (2 mL of piperidine was dissolved in 8 mL of N,N-dimethylformamide) was added to -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (1.66 g). The mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was completed, the solvent was evaporated and purified by column chromatography to obtain compound N. ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (928 mg, 80% yield). LCMS ESI(+) m / z: 517.2 (M+1).

[0237] Step C: The compound 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid (260 mg) was dissolved in DMF (15 mL) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere to give the compound N ω-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (757 mg), HOBT (119 mg), DCC (181 mg), and 4-methylmorpholine (356 mg) were added in this order. The mixture was stirred at 40°C for 18 hours in a nitrogen atmosphere. Purification was performed by C18 reverse-phase silica gel column chromatography to obtain the compound benzyl N- 2 -(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin)-2-yl)diazenyl)-2-hydroxybenzoyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl)sulfonyl)-D-arginine (280 mg, 50% yield) was obtained. 1 H NMR(400MHz,DMSO-d6)δ13.03(s,1H),12.11(s,1H),8.77(s,1H),8.65(s,1H) ,8.14(s,1H),7.56(s,1H),7.37-7.30(m,5H),7.11-6.77(m,3H),6.42(s,1H) ,5.21-5.13(m,3H),4.58-4.56(m,1H),3.11-3.08(m,2H),2.89(s,2H),2.59- 2.51(m,2H),2.46-2.40(m,8H),2.12-1.88(m,10H),1.52-1.23(m,10H).LCMS ESI(+)m / z:943.2(M+1).

[0238] Step D: Compound Benzyl N 2 -(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin)-2-yl)diazenyl)-2-hydroxybenzoyl)-N ω0.27 g of 2,2,4,6,7-pentamethyl-2,3-dihydrobenzfuran-5-yl sulfonyl)-D-arginine was dissolved in 10 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added dropwise in an ice bath. The mixture was then incubated at room temperature for 2 hours. After the reaction was complete, the solvent was removed by rotary evaporation and the resulting mixture was purified by column chromatography to give the compound benzyl(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin)-2-yl)diazenyl)-2-hydroxybenzoyl)-D-arginine (180 mg, 91% yield). LCMS ESI(+) m / z: 590.2 (M+1).

[0239] Step E: The compound benzyl(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin)-2-yl)diazenyl)-2-hydroxybenzoyl)-D-arginine (160 mg) was suspended in 30 mL of isopropanol, and 4N sodium hydroxide solution (5 mL) was added. The mixture was stirred at room temperature for 16 hours. The pH was adjusted to 5 with 1N HCl. The isopropanol was evaporated under reduced pressure, and the resulting mixture was suction filtered under reduced pressure and lyophilized. Water (12 mL) was added, centrifuged, lyophilized, and finally purified by reverse-phase column chromatography to obtain the compound (R)-2-(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin)-2-yl)diazenyl)-2-hydroxybenzoyl)-D-arginine (69.1 mg, 50% yield). 1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),11.34(s,1H),8.56(s,1H),8.45(d,J=2.8Hz,1H),7.82-6.77(m,8H),6.54(d,J=9.2Hz,1H),5.12(q ,J=2.4Hz,1H),4.50(d,J=3.2Hz,1H),3.18-3.17(m,2H),2.61-2.60(m,2H),2.48-2.44(m,1H),2.05-1.73(m,8H),1.58-1.47(m,4H).LCMS ESI(+)m / z:600.2(M+1).

[0240] Example 24: Synthesis of Compound B12 [ka] 2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)ethane-1-sulfonic acid Specific embodiments are shown below. [ka]

[0241] Step A: The compound 5-((E)-(1-(((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) (I)diazenyl)-2-hydroxybenzoic acid (236 mg) was dissolved in DMF (10 mL), and 2,2,2-trifluoroethyl-2-aminoethane-1-sulfonic acid ester (276 mg), DCC (275 mg), and pyridine (253 mg) were added in this order at room temperature under a nitrogen atmosphere. The mixture was stirred at 35° C. for 16 hours under a nitrogen atmosphere. The residue was purified by column chromatography (50% acetonitrile to 0.1% formic acid solution) to obtain the compound 2,2,2-trifluoroethyl-2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diphenylene)-2-hydroxybenzeneaniline amide)ethane-1-sulfonic acid ester (141 mg, 42% yield). 1 H NMR(400MHz,DMSO-d6)δ13.04(s,1H),12.08(s,1H),9.71(s,1H),8.66(s,2H),8.04(d,J=7.2Hz,1H),7.61-7.51(m,1H),7.05(s,1H) ),6.92(s,1H),5.18(s,1H),5.00(q,J=8.6Hz,2H),3.83(m,4H),2.60(d,J=6.1Hz,2H),2.45(m,2H),2.08(m,5H),1.54(m,2H).LCMS ESI(+)m / z:663.4(M+1).

[0242] Step B: The compound 2,2,2-trifluoroethyl-2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diphenylene)-2-hydroxybenzeneanilinamide)ethane-1-sulfonic acid ester (110 mg) was suspended in 12 mL of isopropanol, and 4N sodium hydroxide solution (6 mL) was added. The mixture was stirred at 80°C for 16 hours. The pH was adjusted to 3 with 1N HCl. The isopropanol was distilled off under reduced pressure, and the mixture was suction filtered under reduced pressure and lyophilized. Water (12 mL) was added, and the mixture was centrifuged. The residue was purified by C18 reverse-phase silica gel column chromatography (the ratio of methanol to 0.1% formic acid solution was 20%) to obtain the compound 2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diphenylene)-2-hydroxybenzeneanilineamide)ethane-1-sulfonic acid (25 mg, yield 26%). 1 H NMR(400MHz,DMSO-d6)δ11.93(s,1H),11.00(s,1H),8.58(s,1H),8.48(d,J=2.8Hz ,1H),7.78(dd,J=9.1,2.8Hz,1H),7.49(s,1H),6.85(d,J=3.0Hz,1H),6.53(d,J=9. 1Hz,1H),5.25-4.98(m,1H),3.62(dd,J=12.1,6.2Hz,2H),2.75(t,J=6.4Hz,2H),2 .61(d,J=6.1Hz,2H),2.48-2.42(m,2H),2.07-1.93(m,5H),1.57-1.42(m,2H).LCMS ESI(+)m / z:551.4(M+1).

[0243] The compounds in Table 1 were prepared using methods similar to those in the above examples (eg, Examples 18 and 19) via different reaction starting materials and appropriate reagents.

[0244] [Table 1]

[0245] Example A: Detection of the activity of small molecule inhibitors of JAK kinases Experimental plan 1. Reagent Preparation (1) Kinase reaction buffer A kinase reaction buffer was prepared and consisted of 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween20. (2) 1X detection buffer A detection buffer was prepared by diluting 10X detection buffer to 1X detection buffer 9:1 with deionized water. (3) 4X kinase solution JAK kinases were diluted in kinase reaction buffer to a 4X final concentration (JAK1: 40 nM, JAK2: 0.5 nM). (4)4X substrate solution Ultralight in kinase reaction buffer TM -JAK-1 (Tyr1023) substrate 200 The solution was diluted to 50 nM (final concentration: 50 nM). (5)4X ATP solution ATP was diluted in kinase reaction buffer to a 4X final concentration (JAK1: 160 μM, JAK2: 40 μM). (6) 4X measurement compound solution The test compounds were dissolved in DMSO to a 10 mM stock solution and diluted three-fold to the desired concentration. Ten concentration points were set for each compound, and the final concentration range of the test compounds was 10 μM-0.5 nM. (7) 4X enzyme reaction stop solution EDTA was dissolved in 1X detection buffer to 40 mM (final EDTA concentration: 10 mM). (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.

[0246] 2. Experimental Process (1) 2.5 μL of 4X kinase solution and 2.5 μL of diluted 4X test compound solutions of different concentrations were added to a 384-well microplate in this order, with two replicate wells for each concentration, as well as a blank control group for the enzyme solution and a negative control group (DMSO group). (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. (3) 2.5 μL of 4× substrate solution was added to a 384-well plate, and the plate was centrifuged at 1000 rpm for 1 minute. (4) 2.5 μL of 4X ATP solution was added to the 384-well plate, and the plate was centrifuged at 1000 rpm for 1 minute to initiate the enzyme reaction. (5) JAK1 was reacted at room temperature for 2 hours, and JAK2 was reacted at room temperature for 1 hour. (6) The final concentrations of each component in the JAK1 reaction were JAK1: 10 nM, substrate: 50 nM, and ATP: 40 μM, respectively, 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, respectively, and the final concentrations of the test compounds ranged from 10 μM to 0.5 nM. (7) After the enzyme reaction was completed, 5 μL of 4× enzyme reaction stop solution was added to each well of the 384-well plate, followed by centrifugation at 1000 rpm for 1 minute and incubation at room temperature for 5 minutes. (8) 5 μL of 4× detection antibody solution was added to each well of a 384-well plate (the final concentration of the detection antibody was 2 nM), centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 1 hour. (9) After the antibody incubation was completed, the signal value of each well was measured using an Envision plate reader.

[0247] 3. Data Analysis (1) The enzyme solution blank control group was set to 100% inhibition rate, and the negative control group (DMSO group) was set to 0% inhibition rate, and the percentage inhibition rate corresponding to each concentration of the detected compound was calculated. (2) Using GRaphPad Prism software, nonlinear regression analysis was performed on the logarithmic values ​​of the concentrations of the detected compounds and the corresponding percentage inhibition rates to calculate the half inhibitory concentration (IC 50 The experimental results are shown in Table 2.

[0248] [Table 2] The above results demonstrate that the compounds of the present invention have good kinase inhibitory activity against JAK1 and JAK2.

[0249] Example B: In vivo pharmacokinetic and fecal excretion studies in rats 1. Experimental plan Compounds A1, A2, A3, B3, B6, and B3 were administered orally to SD rats in a single dose, and plasma concentrations of the drugs and their metabolites were collected and measured at different time points. The pharmacokinetic parameters of each compound were calculated to investigate the pharmacokinetic characteristics of the compounds in SD rats. Fecal samples were also collected at 8 and 24 hours to detect the concentrations of prodrugs and degradation products, and the excretion recovery rates were investigated.

[0250] 2. Experimental process Each group consisted of three rats. All SD rats were fasted overnight (more than 12 hours) the day before the experiment. On the day of the experiment, they were weighed and then administered a single oral dose of compounds A1, A2, A3, B3, B6, and B3, respectively, and the test solution. The doses are shown in Table 3. SD rats were allowed to resume eating 4 hours after administration and had free access to water throughout the experiment. Before administration and at 0.5, 1, 2, 4, 8, 12, and 24 hours after administration, 0.20 mL of blood was collected from the jugular vein and placed into EDTA-K2 collection tubes. All whole blood samples were centrifuged at 1500-1600 g for 10 minutes to separate the plasma and store in a refrigerator at -90 to -60°C within 30 minutes of collection for analysis. At 24 hours, all feces on the bottom of the metabolic cage were removed and accurately weighed, and the desired volume of homogenate solution (aqueous solution containing 20% ​​methanol) was added at a weight / volume ratio of 1:10, homogenized, and analyzed.

[0251] 3. Data analysis [Table 3]

[0252] [Table 4] "-": Not applicable. BLOQ: below limit of quantitation. NA: Not applicable. (Note: Metabolite A13 produced from compound A1 was only slightly absorbed within 12 hours. Compound B6 showed only slight absorption at 4 hours, so AUC could not be calculated.

[0253] Table 3 shows that the prodrugs can be degraded in the intestinal tract to release active metabolites.

[0254] From Table 4, it can be seen that the T of the active metabolite maxGenerally, the absorption of metabolites occurs after 4 hours, and often after 12 hours. This indicates that the degradation and absorption of metabolites occurs at the posterior end of the digestive tract, i.e., in the colon. On the other hand, for the active substance B3 administered orally, the T max was 1.2 hours. This indicates that the prodrug can delay the release of the active ingredient and deliver it to the posterior end of the digestive tract. Furthermore, since compounds A1, A2, A3, and B6 are absent or barely present in plasma as prodrugs, they are not absorbed into the blood system, and are cleaved into active metabolites in the intestinal tract, with only a small portion of the corresponding active metabolites being absorbed into the blood system. Compared to direct oral administration of an equimolar amount of the active metabolite B3, oral administration of prodrug B6 significantly reduced the blood absorption (AUC 0-t ) was significantly reduced. This indicates that the design of prodrugs can clearly reduce the exposure of active metabolites in vivo and reduce the side effects of the reaction system.

[0255] Example C: In vivo pharmacokinetic studies in rats 1. Experimental plan Compounds A3 and A13 were administered orally in a single dose to SD rats at equimolar amounts based on rat body weight, and the concentrations of the drugs and their metabolites in plasma and colon tissue were collected and measured at different time points. The pharmacokinetic parameters of each compound were calculated, and the pharmacokinetic characteristics of the prodrugs and active metabolites in SD rats were compared.

[0256] 2. Experimental process Each group consisted of 27 rats. All SD rats were fasted overnight (more than 12 hours) the day before the experiment. On the day of the experiment, they were weighed and then orally administered a single dose of compounds A3 (30 mg / kg) and A13 (15 mg / kg), respectively, followed by oral administration of the test solution. The doses are shown in Table 3. SD rats were allowed to resume eating 4 hours after administration and had free access to water throughout the experiment. Plasma and colon tissue samples were collected at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration, and the concentrations of A13 in the plasma and colon tissue homogenates were determined.

[0257] 3. Data analysis Analysis of the data is shown in Figure 1. 1, when rats were administered with equivalent molar amounts of prodrug A3 or compound A13, it can be seen that administration of prodrug A3 resulted in a lower amount of active metabolite A13 in the blood but a higher amount in the colon tissue, indicating that prodrug A3 can reduce the systemic exposure of compound A13, reduce reactive side effects, and increase its concentration at the target therapeutic site, thereby enhancing the therapeutic effect.

[0258] Although the present invention has been fully described by the embodiments thereof, various changes and modifications will be apparent to those skilled in the art, and such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims

1. A compound of formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, 【Chemical 1】 where: X is CR ａ or N, W and Z each independently represent O, N, S, or NR ｂ or CR ｃ and W and Z are simultaneously selected from CR ｃ It should not be, R １ is H, halogen, CN, C １－６ Alkyl group, C １－６ Alkoxy group or C １－６ halogenated alkyl groups, １－６ Alkyl group, C １－６ Alkoxy groups and C １－６ The halogenated alkyl group may optionally be one or more R ｄ is replaced by R １ ' is H, halogen, amino group, hydroxyl group, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Alkoxy group or C １－６ halogenated alkoxy groups; L １ is absent or C １－１４ (Preferably C １－７ ), wherein one, two, or three methylene groups of the hydrocarbon chain are optionally independently selected from —CH(R ｅ ) -, -C(R ｅ ) ２ -, C ３－５ cycloalkylene group, —N(R ｅ ) -, -N(R ｅ )C(=O)-, -C(=O)N(R ｅ ) -, -N(R ｅ ) S(=O) ２ -, -S(=O) ２ N (R ｅ )-, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-, -S-, -S(=O)- or -S(=O) ２ - may be replaced with, Ring A is absent, C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclyl group, or a 3- to 14-membered carbocyclyl group; ６－１４ The aryl group, the 5- to 14-membered heteroaryl group, the 3- to 14-membered heterocyclyl group, and the 3- to 14-membered carbocyclyl group may optionally be one or more R ｆ and optionally substituted by L ２ is H, OH, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, —C ０－６ Alkylene-NH(C １－６ alkyl) or -C ０－６ Alkylene-N(C １－６ alkyl) ２ and C is selected from １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, —C ０－６ Alkylene-NH(C １－６ alkyl) and —C ０－６ Alkylene-N(C １－６ alkyl) ２ is optionally hydrogen, halogen, —CN, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, —OR ｇ , -NR ｇ R ｈ , -ONO ２ , -NO ２ , -S(=O) ２ OR ｇ , -N=CR ｇ R ｈ , -COOR ｇ , -CONHR ｇ , -C ０－６ Alkylene-NHC(=O)R ｇ , -C ０－６ Archi Ren-C(=O)NHR ｇ and —C(═O)NR ｇ R ｈ and is substituted with one or more selected from the group consisting of: R ａ , R ｂ , R ｃ are each independently H, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Alkoxy group or C １－６ halogenated alkoxy groups; R ｄ is H, halogen, CN, -NO ２ , OH, NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , oxo, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —S—C １－６ Alkyl group, —S(═O)—C １－６ Alkyl group, —S(═O) ２ -C １－６ Alkyl group, —S(═O)NH ２ , -S(=O)NHC １－６ Alkyl group, -S(=O)N(C １－６ alkyl) ２ , -C ０－６ Alkylene-NHS(=O) ２ -C １－６ Alkyl group, —C(═O)—C １－６ Alkyl group, —C(═O)—C ２－６ Alkenyl group, —C ０－６ Alkylene-C ６－１４ aryl group, —C ０－６ alkylene-5-14 membered heteroaryl group, —C ０－６ Alkylene-C ３－１４ Carbocyclyl group or -C ０－６ alkylene-3- to 14-membered heterocyclyl groups, and the —OH, NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —S—C １－６ Alkyl group, —S(═O)—C １－６ Alkyl group, —S(═O) ２ -C １－６ Alkyl group, —S(═O)NH ２ , -S(=O)NHC １－６ Alkyl group, -S(=O)N(C １－６ alkyl) ２ , -C ０－６ Alkylene-NHS(=O) ２ -C １－６ Alkyl group, —C(═O)—C １－６ Alkyl group, —C(═O)—C ２－６ Alkenyl group, —C ０－６ Alkylene-C ６－１４ aryl group, —C ０－６ alkylene-5-14 membered heteroaryl group, —C ０－６ Alkylene-C ３－１４ Carbocyclyl group and —C ０－６ The alkylene-3-14 membered heterocyclyl group is optionally substituted with H, halogen, CN, —NO ２ , OH, NH ２ , -COOH, oxo, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy groups, -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , -COO(C １－６ alkyl), -CONH(C １－６ alkyl), -C ０－６ Alkylene-NHC(=O)C １－６ alkyl group, -C ０－６ Alkylene-NHC(=O)C １－６ Halogenated alkyl group, —C ０－６ Alkylene-NHC(=O)C ２－６ Alkenyl groups, and -CON(C １－６ alkyl) ２ and is substituted with one or more selected from the group consisting of: R ｅ , R ｆ , R ｇ and R ｈ are each independently H, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —C ０－６ Alkylene-NHS(=O) ２ -C １－６ Alkyl group, —C(═O)—C １－６ Alkyl group, —C(═O)—C ２－６ Alkenyl group, —C ０－６ Alkylene-C ６－１４ aryl group, —C ０－６ alkylene-5-14 membered heteroaryl group, —C ０－６ Alkylene-C ３－１４ Carbocyclyl group or -C ０－６ alkylene-3- to 14-membered heterocyclyl groups, １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —C ０－６ Alkylene-NHS(=O) ２ -C １－６ Alkyl group, —C(═O)—C １－６ Alkyl group, —C(═O)—C ２－６ Alkenyl group, —C ０－６ Alkylene-C ６－１４ aryl group, —C ０－６ alkylene-5-14 membered heteroaryl group, —C ０－６ Alkylene-C ３－１４ Carbocyclyl group and —C ０－６ The alkylene-3-14 membered heterocyclyl group is optionally substituted with H, halogen, CN, —NO ２ , OH, NH ２ , -COOH, oxo, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Halogenated alkoxy groups, -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , -COO(C １－６ alkyl), -CONH(C １－６ alkyl), -C ０－６ Alkylene-NHC(=O)C １－６ alkyl group, -C ０－６ Alkylene-NHC(=O)C １－６ Halogenated alkyl group, —C ０－６ Alkylene-NHC(=O)C ２－６ Alkenyl groups, and -CON(C １－６ alkyl) ２ or a compound substituted with one or more selected from the group consisting of stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts thereof.

2. 2. The compound of claim 1, wherein X is selected from CH or N, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 1 or 2, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that W is selected from O, N, S, NH or CH, preferably W is CH.

4. Z is N, NR ｂ or CR ｃ 4. The compound according to any one of claims 1 to 3, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

5. 5. The compound of any one of claims 1 to 4, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that Z is selected from N, NH or CH, preferably Z is NH.

6. R ｄ is H, OH, halogen, amino group, CN, C １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Alkoxy group, or -NHS(=O) ２ -C １－６ alkyl group, １－６ Alkyl group, C １－６ Halogenated alkyl group, C １－６ Alkoxy groups, and -NHS(=O) ２ -C １－６ The alkyl group may optionally be a halogen, CN, OH, NH ２ , —NH(C １－６ alkyl), and —N(C １－６ alkyl) ２ or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that it is substituted with one or more selected from the group consisting of:

7. R １ is H or C １－４ alkyl group, １－４ The alkyl group is optionally selected from the group consisting of CN, C １－６ Alkoxy group, —S—C １－６ Alkyl groups, and -NHS(=O) ２ C １－６ 7. The compound of any one of claims 1 to 6, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the compound is substituted with one or more selected from the group consisting of alkyl-CN.

8. R １ is H, -CH ２ -CN, -CH ２ -S-CH ３ ,or 【Chemistry 2】 8. The compound of any one of claims 1 to 7, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

9. R １ ' is H or C １－３ 9. The compound of any one of claims 1 to 8, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of aryl, arylsulfonyl ...

10. R １ ' is H or CH ３ Any of claims 1 to 9, characterized in that it is selected from 10. A compound according to claim 1, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof.

11. R ｅ is H, amino group, C １－４ Alkyl group, C １－４ Halogenated alkyl group or C １－４ 11. The compound of any one of claims 1 to 10, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the alkoxy group is selected from the group consisting of:

12. R ｅ is selected from H, methyl, ethyl, n-propyl, or isopropyl, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof.

13. L １ is absent, or C １－１４ (Preferably C １－４ ) wherein one, two or three methylene groups in said hydrocarbon group are optionally independently selected from the group consisting of —CH(R ｅ ) -, -C(R ｅ ) ２ -, C ３－５ cycloalkylene group, —N(R ｅ ) -, -N(R ｅ )C(=O)-, -C(=O)N(R ｅ 13. The compound according to any one of claims 1 to 12, wherein the compound is optionally substituted with -C(=O)-, -O-, -C(=O)-, -OC(=O)-, or -C(=O)O-, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof.

14. L １ is absent, -C １－６ Alkylene-, -C １－６ Alkylene -O-C １－６ Alkylene-, -C １－６ Alkylene -OC(=O)C １－６ Alkylene-, -C １－６ Alkylene-OC(=O)OC １－６ Alkylene-, -C １－６ Alkylene -OC(=O)C １－６ Alkylene -O-, -C １－６ Alkylene-OC(═O)-NR ａ C １－６ Alkylene- or -C １－６ Alkylene-OC(═O)-NR ａ -, wherein C １－６ The alkylene may optionally be 1 to 6 R ｅ 14. The compound of any one of claims 1-13, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that it is substituted by

15. L １ is absent, -CH ２ -, -CH ２ CH ２ -, 【Chemistry 3】 15. The compound of any one of claims 1 to 14, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, selected from:

16. R ｇ , R ｈ are each independently H, C １－６ 16. The compound of any one of claims 1-15, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the group is selected from alkyl, amino or -COOH.

17. L ２ is hydrogen, OH, C １－６ Alkyl group, C ２－６ Alkenyl group, —C ０－６ Archi Ren-NH(C １－６ alkyl) or -C ０－６ Alkylene-N(C １－６ alkyl) ２ and C is selected from １－６ Alkyl group, C ２－６ Alkenyl group, —C ０－６ Alkylene-NH(C １－６ alkyl) and —C ０－６ Alkylene-N(C １－６ alkyl) ２ is optionally hydrogen, halogen, CN, OH, NH ２ , -ONO ２ , -COOH, -S(=O) ２ OH, -N=C(NH ２ ) ２ , C １－６ Alkyl groups, and -COO(C １－６ 17. The compound of any one of claims 1-16, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is substituted with one or more selected from the group consisting of: alkyl, aryl, arylsulfonyl ...

18. L ２ OH, CH ３ , 【Chemistry 4】 18. The compound of any one of claims 1 to 17, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

19. L ２ is OH, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof.

20. L ２ is CH ３ , 【Chemistry 5】 19. The compound of any one of claims 1 to 18, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

21. L ２ teeth, 【Chemistry 6】 19. The compound of any one of claims 1 to 18, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

22. R ｆ is H, C １－３ 22. The compound of any one of claims 1-21, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of aryl, arylsulfonyl ...

23. Ring A is absent or C ６－１４ aryl groups, ６－１４ The aryl group may optionally include one or more R ｆ 23. The compound of any one of claims 1-22, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, optionally substituted by:

24. R ｆ is H, C １－３ 24. The compound of any one of claims 1-23, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of aryl, arylsulfonyl ...

25. Ring A is absent or C ６－１０ 25. The compound of any one of claims 1-24, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of:

26. 26. The compound of any one of claims 1-25, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein ring A is absent or selected from a benzene ring.

27. Ring A is absent, 【Chemistry 7】 27. The compound of any one of claims 1 to 26, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, selected from:

28. The compound of formula I is selected from the compounds of formula III: 【Chemistry 8】 X, W, Z, and R in the compound of formula III １ , R １ ', L １ and L ２ 28. A compound according to any one of claims 1 to 27, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the definition of is as defined in any one of claims 1 to 27.

29. The compound of formula I is selected from the compounds of formula IV: 【Chemistry 9】 X, W, Z, and R in the compound of formula IV １ , R １ ', L １ and the definition of ring A is defined as in any one of claims 1-28, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof.

30. The compound of formula I is selected from the compounds of formula V: 【Chemistry 10】 X, W, Z, and R in the compound represented by formula V １ , R １ ' and L ２ 30. A compound according to any one of claims 1 to 29, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the definition of is as defined in any one of claims 1 to 29.

31. The compound of formula I is selected from the compounds of formula VI: 【Chemistry 11】 R ４ is C １－３ Alkylene group or C １－３ is an alkyleneoxy group, R ５ is hydrogen or C １－３ is an alkyl group, R ４ , R ５ optionally one or more R ｅ and R ｅ is defined as in any one of claims 1-30, X, W, Z and R in the compound of formula VI １ 31. A compound according to any one of claims 1 to 30, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the definition of is as defined in any one of claims 1 to 30.

32. The compound of formula I is selected from the compounds of formula IX: 【Chemistry 12】 X and R in the compound of formula IX １ , R １ ', L １ and the definition of ring A is defined as in formula I of any one of claims 1 to 27, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof.

33. The compound of formula I is selected from the compounds of formula X: 【Chemistry 13】 X and R in the compound represented by formula X １ , R １ ' and L ２ or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the definition of is defined as in formula I of any one of claims 1 to 27.

34. The compound of formula I is selected from the compounds of formula XI: 【Chemistry 14】 R ４ is C １－３ Alkylene group or C １－３ is an alkyleneoxy group, R ５ is hydrogen or C １－３ is an alkyl group, R ４ , R ５ optionally one or more R ｅ and R ｅ is defined as in formula I above, X and R in the compound of formula XI １ or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the definition of is defined as in formula I of any one of claims 1 to 27.

35. The compound is (R,E)-5-((2-(3-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-3-oxopropyl)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((4-((((1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)oxy)methyl)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((2-((1-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)-2-methyl-1-oxopropan-2-yl)oxy)phenyl)diazenyl)-2-hydroxybenzoic acid, (R,E)-5-((2-((1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)carbonyl)amino)phenyl)diazenyl)-2-hydroxybenzoic acid, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycine ester, (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl D-valine ester, (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl L-valine ester, 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-aspartic acid, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-lysine, (5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoyl)-D-glutamic acid, (R)-2-(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)-5-((diaminomethylene)amino)pentanoic acid, 2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzamido)ethane-1-sulfonic acid, (E)-2-hydroxy-5-((1-(piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)benzoic acid, (E)-5-((1-(4-(((cyanomethyl)sulfonamido)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid, or 2. The compound of claim 1, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that the compound is selected from 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-furan[3,2-b]imidazo[4,5-d]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid.

36. 36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 35, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

37. 37. Use of a compound according to any one of claims 1 to 35, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36, in the preparation of a prodrug of a JAK inhibitor.

38. 37. Use of a compound according to any one of claims 1 to 35, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36, in the preparation of a JAK inhibitor.

39. A compound according to any one of claims 1 to 35, or a stereoisomer or geometric isomer thereof; 37. Use of a tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 36, in the preparation of a medicament related to the treatment of inflammatory and / or neoplastic diseases.

40. 40. The use according to claim 39, characterized in that the inflammatory and / or neoplastic disease is mediated by JAK.

41. 41. The use according to claim 39 or 40, characterized in that the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease, and the tumor disease is selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma and non-small cell lung cancer.

42. 42. Use according to claim 41, characterized in that the inflammatory bowel disease is a chronic intestinal inflammatory disease, more preferably ulcerative colitis and Crohn's disease.

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