Prodrug of JAK kinase inhibitor

Abstract

The invention relates to a prodrug containing a JAK inhibitor, a composition and application thereof. In particular, the present invention relates to a compound represented by formula (II), a pharmaceutical composition containing the compound of the present invention, and uses of the compound as a JAK inhibitor prodrug in treatment of inflammatory diseases and tumor-related diseases. # imgabs0 #

Description

A prodrug of a JAK kinase inhibitor Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a JAK enzyme inhibitor prodrug and a preparation method and use thereof. Background Art

[0002] Inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), have a significant negative impact on patients' quality of life. During the active stage of the disease, common IBD symptoms include diarrhea, rectal bleeding, painful abdominal bleeding, weight loss, fatigue, nausea, and vomiting. In 2018, there were 12.6 million prevalent cases of ulcerative colitis and 6.1 million prevalent 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] Although a variety of treatment options exist to induce and maintain disease remission in patients with IBD, all have their limitations. Aminosalicylates are generally effective in mild cases but are less effective in moderate and severe cases, and long-term steroid maintenance therapy has safety concerns (such as osteoporosis, muscle atrophy, and neuropsychiatric disorders). Systemic immunosuppressants, such as azathioprine, mercaptopurine, and methotrexate, are generally effective in moderate to severe patients, but long-term use carries an increased risk of infection and lymphoma. Anti-tumor necrosis factor (TNF) antibodies (e.g., infliximab and adalimumab) require subcutaneous or intravenous injections, and up to one-third of first-time users fail to respond adequately, while another one-third of responding patients lose their response due to drug resistance.

[0004] There is currently an unmet clinical need for an effective oral therapy to induce and maintain remission in IBD while avoiding the safety concerns associated with chronic systemic immunosuppression. Direct drug delivery to the intestinal mucosa is one approach to achieve this goal. Compounds or formulations with appropriate physicochemical properties can achieve targeted delivery to the intestine. Another option is enzymatic cleavage of inactive prodrugs to an active parent drug during gastrointestinal transit. Because the elevation of many proinflammatory 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) relies on signaling from the Janus kinase (JAK) family of tyrosine kinases, inhibition of JAKs may be beneficial in the treatment of ulcerative colitis and Crohn's disease. Currently, the FDA and EMA have approved tofacitinib for the treatment of moderately to severely active ulcerative colitis. Upadacitinib was also approved in March 2022 for the treatment of moderately to severely active ulcerative colitis and has shown good therapeutic effects on Crohn's disease in clinical trials. However, because these drugs increase the risk of cancer, blood clots, serious cardiac events, and death, the FDA has issued a black box warning for these JAK inhibitors. If selective intestinal JAK inhibition is sufficient to achieve clinical efficacy, it may be possible to separate the beneficial anti-inflammatory activity of JAK inhibitors from potentially harmful systemic exposure.

[0005] Therefore, there is an urgent need to develop new JAK inhibitors for the treatment of localized inflammatory or immune diseases, which can achieve excellent therapeutic effects while avoiding the aforementioned toxicities caused by systemic exposure. Specifically, it is very necessary to develop JAK inhibitors that can be administered orally and with minimal systemic exposure to treat inflammatory bowel diseases (Crohn's disease, ulcerative colitis).

[0006] Summary of the Invention

[0007] The present invention provides a prodrug of a JAK inhibitor that is cleaved by enzymes produced by microorganisms in the gastrointestinal tract. This cleavage releases the JAK inhibitor locally or locally in the gastrointestinal tract, thereby increasing JAK inhibitor levels at sites of gastrointestinal inflammation to improve efficacy while minimizing systemic exposure to other sites to reduce side effects.

[0008] In one aspect, the present invention provides a compound as shown in Formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof:

[0009] in

[0010] X is selected from CR aor N;

[0011] W and Z are independently selected from O, N, S, NR b or CR c ; W and Z cannot be CR at the same time c ;

[0012] R1 is selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl; the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The haloalkyl group is optionally replaced by one or more R d replace;

[0013] R1' is selected from H, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0014] R2 is selected from -L1-ONO2, -L1-NHC(=O)-L2, -L1-OC(=O)-L2, -L1-C(=O)O-L2 or in,

[0015] L1 is not present or C 1-14 (Preferred C 1-7 ) a divalent saturated or unsaturated straight or branched hydrocarbon group, wherein one, two or three methylene groups in the hydrocarbon group may be optionally and independently replaced by: -CH(R e )-、-C(R e )2-、C 3-5 Cycloalkylene, -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-;

[0016] Ring A is selected from the group consisting of: 6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group or 3-14 membered carbocyclic group; the C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group and 3-14 membered carbocyclic group may be optionally substituted by one or more R f replace.

[0017] L2 is selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 Alkyl) 2; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 Alkyl)2 is optionally replaced by one or more hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -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 or -C(=O)NR g R h replace;

[0018] R3 is independently selected from H, OH, halogen, amino, -NR g R h 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0019] R a 、R b 、R c are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1- 6-haloalkoxy;

[0020] R d independently selected from H, halogen, CN, -NO2, OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl, -S(=O)N(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; said -OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl, -S(=O)N(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclyl and -C 0-6Alkylene-3-14 membered heterocyclic radicals are optionally substituted with one or more H, halogen, CN, -NO2, OH, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -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, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, -CON(C 1-6 alkyl)2 substituted;

[0021] R e 、R f 、R g and R h are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclyl and -C 0-6 Alkylene-3-14 membered heterocyclic radicals are optionally substituted with one or more H, halogen, CN, -NO2, OH, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -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, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, -CON(C 1-6 alkyl)2 substituted;

[0022] n is selected from 0, 1, 2, 3 or 4.

[0023] In certain embodiments, X is selected from CH or N.

[0024] In certain embodiments, W is selected from O, N, S, NH, or CH; preferably, W is selected from CH.

[0025] In certain embodiments, Z is selected from N, NR b or CR c .

[0026] In certain embodiments, Z is selected from N, NH, or CH; preferably, Z is selected from NH.

[0027] In certain embodiments, R d Selected from H, OH, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or -NHS(=O)2-C 1-6 Alkyl; the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NHS(=O)2-C 1-6The alkyl group is optionally substituted with one or more halogen, CN, OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 substituted.

[0028] In certain embodiments, R1 is selected from H or C 1-4 Alkyl; the C 1-4 The alkyl group is optionally replaced by one or more CN, C 1-6 Alkoxy, -SC 1-6 Alkyl or -NHS(=O)2C 1-6 Alkyl-CN substitution.

[0029] In certain embodiments, R1 is selected from H, -CH2-CN, -CH2-S-CH3 or

[0030] In certain embodiments, R1' is selected from H or C 1-3 alkyl.

[0031] In certain embodiments, R1' is selected from H or CH3.

[0032] In certain embodiments, R e Selected from H, amino, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

[0033] In certain embodiments, R e is selected from H, methyl, ethyl, n-propyl or isopropyl.

[0034] In certain embodiments, L1 is selected from absent or C 1-14 (Preferably C 1-4 ) a divalent saturated or unsaturated straight or branched hydrocarbon group; one, two or three methylene groups in the hydrocarbon group may be optionally and independently replaced by: -CH(R e )-、-C(R e )2-、C 3-5 Cycloalkylene, -N(R e )-、-N(R e )C(=O)-、-C(=O)N(R e )-, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-.

[0035] In certain embodiments, L1 is selected from absent, -C 1-6 Alkylene-, -C 1-6 Alkylene-OC 1-6 Alkylene-, -C 1-6 Alkylene-OC(=O)C1-6 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 -; said C 1-6 The alkylene group is optionally substituted with 1 to 6 R e replace.

[0036] In certain embodiments, L1 is selected from absent, -CH2-, -CH2CH2-,

[0037] In certain embodiments, R g 、R h are independently selected from H, C 1-6 Alkyl, amino or -COOH.

[0038] In certain embodiments, L2 is selected from hydrogen, OH, C 1-6 Alkyl, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 Alkyl) 2; said C 1-6 Alkyl, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 The alkyl)2 is optionally substituted with one or more hydrogen, halogen, CN, OH, NH2, -ONO2, -COOH, -S(=O)2OH, -N=C(NH2)2, C 1-6 Alkyl or -COO(C 1-6 alkyl) substituted.

[0039] In certain embodiments, L2 is selected from OH, CH3,

[0040] In certain embodiments, L2 is selected from OH.

[0041] In certain embodiments, L2 is selected from CH3,

[0042] In certain embodiments, L2 is selected from

[0043] In certain embodiments, R f Selected from H, C 1-3 alkyl.

[0044] In certain embodiments, Ring A is selected from absent or C 6-14 Aryl; said C 6-14 The aryl group may be optionally replaced by one or more R f replace.

[0045] In certain embodiments, R f Selected from H, C 1-3 alkyl.

[0046] In certain embodiments, Ring A is selected from absent or C 6-10 Aryl.

[0047] In certain embodiments, Ring A is selected from absent or a benzene ring.

[0048] In certain embodiments, Ring A is selected from absent or

[0049] In certain embodiments, R3 is selected from H, hydroxy, halogen, amino, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy or C 1-3 Alkoxy.

[0050] In certain embodiments, R3 is selected from H or OH.

[0051] In certain embodiments, n is selected from 1 or 2.

[0052] In certain embodiments, R2 is selected from

[0053] In certain embodiments, the compound of formula I is selected from the compounds of formula II shown below:

[0054] The definitions of X, W, Z, R1, R1′, L1, L2 and ring A in the compound of formula II are the same as those of formula I above.

[0055] In certain embodiments, the compound of formula I is selected from the compound of formula III shown below:

[0056] The definitions of X, W, Z, R1, R1′, L1 and L2 in the compound of formula III are as defined above for formula I.

[0057] In certain embodiments, the compound of formula I is selected from the compound of formula IV shown below:

[0058] The definitions of X, W, Z, R1, R1′, L1 and ring A in the compound of formula IV are the same as those of formula I above.

[0059] In certain embodiments, the compound of formula I is selected from the compound of formula V shown below:

[0060] The definitions of X, W, Z, R1, R1' and L2 in the compound of formula V are as defined above for formula I.

[0061] In certain embodiments, the compound of formula I is selected from the compound of formula VI shown below:

[0062] R4 is C 1-3 Alkylene or C 1-3 Alkyleneoxy;

[0063] R5 is hydrogen or C 1-3 alkyl;

[0064] Wherein, R4 and R5 are optionally replaced by one or more R e Replacement, R e As defined in formula I above;

[0065] The definitions of X, W, Z and R1 in the compound of formula VI are as defined above for formula I.

[0066] In certain embodiments, the compound of Formula I is selected from the compound of Formula VII shown below:

[0067] The definitions of X, W, Z, R1, R1′ and L1 in the compound of formula VII are as defined above for formula I.

[0068] In certain embodiments, the compound of Formula I is selected from the compound of Formula VIII shown below:

[0069] R5 is hydrogen or C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with 1 to 6 R e Replacement, R e As defined in formula I above;

[0070] The definitions of X, W, Z, R1 and L2 in the compound of formula VIII are as defined above for formula I.

[0071] In certain embodiments, the compound of Formula I is selected from the compound of Formula IX shown below:

[0072] The definitions of X, R1, R1′, L1 and ring A in the compound of formula IX are as defined above for formula I.

[0073] In certain embodiments, the compound of formula I is selected from the compound of formula X shown below:

[0074] The definitions of X, R1, R1′ and L2 in the compound of formula X are as defined above for formula I.

[0075] In certain embodiments, the compound of formula I is selected from the compound of formula XI shown below:

[0076] R4 is C 1-3 Alkylene or C 1-3 Alkyleneoxy;

[0077] R5 is hydrogen or C 1-3 alkyl;

[0078] Wherein, R4 and R5 are optionally replaced by one or more R e Replacement, R e As defined in formula I above;

[0079] X and R1 in the compound of formula XI are as defined above for formula I.

[0080] In some embodiments, the compound of formula I, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, is selected from:

[0081] (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;

[0082] (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;

[0083] (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;

[0084] (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;

[0085] (R)-ethyl 1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate;

[0086] (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;

[0087] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycinate;

[0088] (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;

[0089] (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl L-valine ester;

[0090] (R)-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl fumaric acid monomethyl ester;

[0091] Methyl (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)nitrate;

[0092] 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;

[0093] 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;

[0094] (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid;

[0095] (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;

[0096] (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;

[0097] (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;

[0098] (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;

[0099] 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;

[0100] (E)-2-Hydroxy-5-((1-(piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)benzoic acid;

[0101] (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;

[0102] 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid;

[0103] 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid;

[0104] 1-(Piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine;

[0105] N-((1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide;

[0106] 2-((1R,4R)-4-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-ethyl)cyclohexyl)acetonitrile;

[0107] 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile; or

[0108] 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile.

[0109] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0110] Furthermore, the present invention also provides a pharmaceutical composition, which also contains an additional therapeutic agent; the additional therapeutic agent is preferably an anti-inflammatory drug, an immunomodulator or an immunosuppressant, 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 autoimmune disease.

[0111] The present invention also relates to the use of the compound of formula I, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites, or pharmaceutically acceptable salts, or the pharmaceutical composition thereof, in the preparation of a JAK inhibitor drug. Specifically, the use comprises a prodrug of a JAK inhibitor, wherein the prodrug releases a JAK inhibitor, preferably a JAK1 and / or JAK2 inhibitor, by intestinal enzymes during the use.

[0112] The present invention also relates to the use of the compound of formula I, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating inflammatory diseases and / or tumor diseases.

[0113] The present invention also relates to a method for treating inflammatory diseases and / or tumor diseases, which comprises administering to a patient a therapeutically effective dose of the compound of formula I, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, or the pharmaceutical composition.

[0114] In certain embodiments, the inflammatory disease and / or neoplastic disease is mediated by JAK.

[0115] In certain embodiments, the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease; the neoplastic disease is selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myelocytic leukemia (AML), acute lymphoblastic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC). The inflammatory bowel disease is a chronic intestinal inflammatory disease, more preferably ulcerative colitis and Crohn's disease.

[0116] Definition and Description

[0117] General chemical terms used in the above structural formulae have their usual meanings.

[0118] For example, the terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine. Preferred halogen groups include fluorine, chlorine and bromine.

[0119] 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, alkenyl, and alkynyl group. Preferred hydrocarbon chains are composed of 1 to 14 carbon atoms, more preferably 1 to 7 carbon atoms, and most preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, allyl, and the like. Wherein the divalent "hydrocarbon chain" or "hydrocarbon group" includes alkylene, non-limiting examples include but are not limited to methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), 1,7-heptylene (-CH2CH2CH2CH2CH2CH2CH2-), and the like.

[0120] In the present invention, the term "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group, preferably "C 1-8 Alkyl", more preferably "C 1-6 Alkyl". The alkyl group used herein may be optionally substituted with one or more substituents. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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" 1-6 ” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight chain, branched or cyclic form.

[0121] The terms "alkenyl" and "alkynyl" refer to straight or branched chain alkenyl and alkynyl groups, preferably "C 2-8 Alkenyl" or "C 2-8 Alkynyl", more preferably "C 2-6 Alkenyl" or "C 2-6 Alkynyl". Similarly, "C 2-6 Alkenyl" and "C 2-6 "Alkynyl" refers to an alkenyl or alkynyl group containing 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or branched form.

[0122] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups.

[0123] The term "haloalkyl" refers to the aforementioned "alkyl" substituted by one or more halogens.

[0124] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

[0125] In the present invention, the o appearing in a ring of the general structure means that the ring has aromaticity.

[0126] The term "aryl" in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic, fused or condensed aromatic group containing carbon atoms, preferably C 6-14 Aryl, the C 6-14 Aryl is more preferably C 6-10 Aryl, the C 6-10 The aryl group is more preferably a phenyl group.

[0127] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom ring member (e.g., 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms), wherein the heteroatoms are selected from N, O, and / or S. The nitrogen or sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom to produce a stable structure. The heteroaryl group is preferably a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is further preferably a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

[0128] The term "carbocyclyl" refers to a saturated or unsaturated cyclic group that is not aromatic. Depending on the specific level of saturation, the terms "cycloalkyl", "cycloalkenyl" or "cycloalkynyl" are used respectively. Monocyclic carbocyclyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane or cyclohexene and the like; polycyclic carbocyclyl groups include spirocyclic, fused ring, bridged ring carbocyclyl groups. The carbocyclyl is preferably C 3-14 Carbocyclic group, the C 3-14 The carbocyclic group is more preferably C 3-8 Carbocyclic group, the C 3-8 The carbocyclic group is more preferably C 3-6 Carbocyclic group, the C 3-8 The carbocyclic group is more preferably C 5-6 Carbocyclic group.

[0129] The term "cycloalkyl" refers to saturated monocyclic and polycyclic ring systems containing only carbon atoms in the ring and may 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, bicyclo[2.2.1]heptane, and the like. The cycloalkyl group is preferably C 3-14 Cycloalkyl, the C 3-14 The cycloalkyl group is more preferably C 3-8 Cycloalkyl, the C 3-8 The cycloalkyl group is more preferably C 3-6 Cycloalkyl, the C 3-8 The cycloalkyl group is more preferably C 5-6 Cycloalkyl.

[0130] The term "heterocyclyl" as used herein, unless otherwise indicated, 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 having unsaturated and / or aromatic moieties. Nitrogen or sulfur heteroatoms may be selectively oxidized, and nitrogen heteroatoms may be selectively quaternized. The heterocyclyl group may be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups include fused rings, bridged rings, and spirocyclic ring systems. The heterocyclyl group is preferably a 3-14 membered heterocyclyl group, the 3-14 membered heterocyclyl group is further preferably a 3-8 membered heterocyclyl group or a 5-10 membered heterocyclyl group, the 3-8 membered heterocyclyl group is further preferably a 3-6 membered heterocyclyl group, the 3-6 membered heterocyclyl group is further preferably a 5-6 membered heterocyclyl group. The heterocycloalkyl group used herein may optionally be substituted with one or more substituents. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, and tetrahydrooxadiazolyl.

[0131] However, in no case will heterocyclyls and carbocyclyls intersect or include each other. Thus, according to the above definition, if at least one all-carbocycle is fused with a heterocyclyl to form a bi-, poly- or spiro-ring, it will still be defined as a heterocyclyl.

[0132] Additionally, if a heteroaryl group is fused with a heterocyclyl group to form a bi-, poly-, or spiro-ring, it will be defined as a heterocyclyl group rather than a heteroaryl group.

[0133] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -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 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), CN, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0134] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases.

[0135] Since the compound represented by Formula I is to be used as a medicine, it is preferably used with a certain purity, for example, at least 60% purity, more preferably at least 75% purity, and particularly preferably at least 98% purity (% is weight ratio).

[0136] Obviously, the definition of any substituent or variable at a particular position in a molecule is independent of the definition of any other position in the molecule. It is readily understood that one skilled in the art can select substituents or substitution patterns for the compounds of the present invention using existing techniques and the methods described herein to obtain chemically stable and readily synthesized compounds.

[0137] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0138] The above-described compounds of Formula I do not have a precise definition of the stereostructure at any particular position of the compound. The present invention encompasses all stereoisomers of the compounds of Formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also encompassed by the present invention. During the synthetic process for preparing such compounds, or using racemization or epimerization processes known to those skilled in the art, the resulting products may be mixtures of stereoisomers.

[0139] When the compound represented by Formula I exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0140] When the compound shown in Formula I and its pharmaceutically acceptable salt exist solvate or polymorph, the present invention includes any possible solvate and polymorph. There is no particular limitation on the type of solvent forming the solvate, as long as the solvent is pharmaceutically acceptable. The term "composition", in the present invention, refers to a product comprising a specified amount of each specified component, as well as any product produced directly or indirectly by a combination of specified amounts of each specified component. Therefore, a pharmaceutical composition containing a compound of the present invention as an active ingredient and a method for preparing the compound of the present invention are also part of the present invention. In addition, some crystalline forms of the compound can exist in polymorph, and this polymorph is included in the present invention. In addition, some compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.

[0141] The pharmaceutical composition provided by the present invention includes the compound shown in formula I as active ingredient (or its pharmaceutically acceptable salt), a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable active ingredient administration mode depends on the specific main body, main body property and the severity of the disease being administered, the pharmaceutical composition of the present invention includes a pharmaceutical composition suitable for oral, rectal, local and parenteral (including subcutaneous administration, intramuscular injection, intravenous administration) administration. The pharmaceutical composition of the present invention can be easily prepared in any preparation method known in the art and in unit dosage form.

[0142] The pharmaceutical compositions of the present invention can be prepared by any pharmaceutical method. Generally, such methods include the step of combining the active ingredient with a carrier comprising one or more essential ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or a mixture thereof. Furthermore, the product can be readily prepared to a desired appearance.

[0143] Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound of Formula I or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites, or pharmaceutically acceptable salts. Combinations of the compound of Formula I or its pharmaceutically acceptable salts with one or more other therapeutically active compounds are also included in the pharmaceutical composition of the present invention.

[0144] The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1: Comparison of the AUC of the active ingredient A13 in plasma and colon tissue of rats after administration of compounds A3 and A13, respectively.

[0146] Cleavage of prodrugs

[0147] When exposed to azoreductase in the gastrointestinal tract, the azo bond in the compound of the present invention will be cleaved by azoreductase and the JAK inhibitor will be released. An example of cleavage is as follows:

[0148] Example 1

[0149] Example 2

[0150] Similar to the cleavage of Compound A3, Compounds A1 and A2 (see Examples) can be released into Compound A13 using intestinal enzymes (eg, azoreductase).

[0151] The compounds of the present invention can be prepared according to a number of preparation routes known in the literature. Examples of synthetic methods for preparing the compounds of the present invention are provided in the following schemes, which are exemplary general synthetic schemes:

[0152] It is manufactured by the following process steps:

[0153] S1, using II-1 as a raw material, the carboxyl group on it is protected by a benzyl group to produce compound II-2;

[0154] S2, the phenolic hydroxyl group of compound II-2 is protected by Cbz to generate compound II-3;

[0155] S3, the nitro group in compound II-3 is reduced to an amine group to obtain compound II-4;

[0156] S4, the amine group in compound II-4 is nitrosated and then reduced to obtain compound II-5;

[0157] S5, compound II-6 is another raw material, and compound II-7 is obtained by addition reaction (such as with hydrazine);

[0158] S6. The nitro group in compound II-7 is reduced to an amino group to obtain compound II-8;

[0159] S7, compound II-5 and compound II-8 are combined via thiocarbonyl to form compound II-9;

[0160] S8, compound II-9 is ring-closed and the protecting group of the phenolic hydroxyl group is removed to obtain compound II-10;

[0161] S9, compound II-10 removes the carboxyl protecting group to obtain compound II-11, which can be used as the final product or as an intermediate for further reaction;

[0162] S10 and compound II-11 can be condensed with an amino or hydroxy compound to obtain compound V.

[0163] The specific process of the above reaction is as follows: the compound of formula II-1 can be purchased directly or obtained by known common synthesis methods. The carboxylic acid and phenolic hydroxyl groups of formula II-1 are protected with protecting groups to obtain II-3. The nitro group of the intermediate product II-3 can be converted into II-4 by reducing agents such as iron powder, zinc powder, catalytic hydrogenation, and stannous chloride. II-4 can be nitrosated with HNO2 (obtained by adding acid to NaNO2) and then reduced to II-5 under the action of stannous chloride. Compound II-6 can be purchased directly or obtained by known common synthesis methods. II-6 can be reacted with hydrazine to obtain compound II-7. The nitro group can be reduced by iron powder, zinc powder, catalytic hydrogenation, stannous chloride, etc. to obtain II-8. Compound II-5 and II-8 are reacted with thiocarbonyldiimidazole or thiophosgene to obtain a thiocarbonyl-linked compound II-9. Compound II-9 undergoes cyclization under the action of a condensing agent (such as EDCI, DCC, etc.) and simultaneously removes the phenolic hydroxyl protecting group to obtain compound II-10. Compound II-10 then removes the carboxyl protecting group to obtain compound II-11. The carboxylic acid group of compound II-11 can be condensed with an amino or hydroxyl compound to produce a compound shown in formula V. DETAILED DESCRIPTION

[0164] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to 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 the art.

[0165] Unless otherwise indicated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius.

[0166] The raw materials and reagents used in the examples can be obtained from commercial sources or prepared by conventional methods in the art.

[0167] Example 1: Synthesis of Compound A1

[0168] (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

[0169] The specific implementation is as follows:

[0170] Step A:

[0171] 2-Nitrocinnamic acid (5.0 g) was dissolved in 100 mL of water and 103 mL of 2% NaOH, followed by the addition of 10% Pd / C (500 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 64 hours. After completion of the reaction, the mixture was filtered and dried to give a crude product, sodium anthranilate (6.8 g).

[0172] Step B:

[0173] Sodium anthranilate (2.0 g) was dissolved in 20 mL of water and 60 mL of dichloromethane. Potassium monopersulfate (9.862 g) was slowly added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was extracted with dichloromethane (2 x 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate to obtain crude o-nitrosophenylpropionic acid (1.8 g).

[0174] Step C:

[0175] 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. Under nitrogen protection, di-tert-butyl dicarbonyl (6.728 g) was slowly added at 0°C. After completion of the reaction, the mixture was spin-dried and purified by column chromatography to obtain compound (R)-tert-butyl 1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-carboxylate (11.6 g, 88% yield). LC-MS: m / z 425.0 [M+H] + .

[0176] Step D:

[0177] Compound (R)-tert-butyl 1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-carboxylate (1.13 g), crude 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 under nitrogen for 16 hours. After completion of the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain compound (R)-tert-butyl 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 (568 mg, 37% yield). LC-MS: m / z 586.4[M+H] + .

[0178] Step E:

[0179] Compound 5-aminosalicylic acid tert-butyl ester (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)-carboxylic acid tert-butyl ester (305 mg) were dissolved in 10 mL of acetic acid. Under nitrogen protection, the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was spin-dried and purified by column chromatography to obtain 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-hydroxybenzoic acid tert-butyl ester (695 mg). LC-MS: m / z 677.4 [M+H] + .

[0180] Step F:

[0181] Dissolve tert-butyl (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 (695 mg) in 20 mL of dichloromethane, and add 3 mL of trifluoroacetic acid. Stir at room temperature under nitrogen for 3 hours. After the reaction, the mixture was dried by spin drying and purified by column chromatography to obtain 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%). 1 H 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] + .

[0182] Example 2: Synthesis of Compound A2

[0183] (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

[0184] The specific implementation is as follows:

[0185] Step A:

[0186] (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))-carboxylic acid tert-butyl ester (500 mg) was dissolved in 20 mL of dichloromethane, and pyridine (279 mg) and 4-nitrophenyl chloroformate (594 mg) were added. The reaction solution was stirred at 20°C for 3 hours. After the reaction was completed, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, dried, 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]pyrrole-2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (639 mg, 92% yield).

[0187] Step B:

[0188] Tert-butyl 5-amino-2-((benzyloxycarbonyl)oxy)benzoate (1.7 g) was dissolved in 40 mL of dichloromethane, and a solution of m-chloroperbenzoic acid (1.709 g) in dichloromethane (20 mL) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation. Tert-butyl 5-nitroso-2-((benzyloxycarbonyl)oxy)benzoate (1.238 g, 70% yield) was obtained by column purification.

[0189] Step C:

[0190] 5-Amino-2-((benzyloxycarbonyl)oxy)benzoic acid tert-butyl ester (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, the reaction solution was dried and purified by column chromatography to obtain tert-butyl (E)-2-((benzyloxycarbonyl)oxy)-5-((4-(hydroxymethyl)phenyl)diazenyl)benzoate (1.167 g, 72.8% yield). LC-MS: m / z 463.1 [M+H] + .

[0191] Step D:

[0192] Compound (E)-tert-butyl 2-((benzyloxycarbonyl)oxy)-5-((4-(hydroxymethyl)phenyl)diazenyl)benzoate (500 mg), 4-dimethylaminopyridine (311 mg), triethylamine (257 mg) and compound (R)-tert-butyl 1-(4-cyanomethylpiperidin-1-yl)-2-(1-(((4-nitrophenoxy)carbonyl)oxy)ethyl)imidazo[4,5-d]pyrrole 2,3-b]pyridine-6(1H)-carboxylate (784 mg) were dissolved in 10 mL of dichloromethane and stirred at 30°C for 16 hours under nitrogen protection. After the reaction, the reaction solution was dried and purified by column chromatography to obtain the compound (R,E)-2-(1-((((4-((3-(tert-butoxycarbonyl)-4-hydroxyphenyl)diazenyl)benzyl)oxy)carbonyl)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazopyrazolo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (414 mg, yield 64%). LC-MS: m / z 779.4 [M+H] + .

[0193] Step E:

[0194] Compound (R,E)-2-(1-((((4-((3-(tert-butoxycarbonyl)-4-hydroxyphenyl)diazenyl)benzyl)oxy)carbonyl)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazopyrazolo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (410 mg) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 35°C for 16 hours. After the reaction, the mixture was dried 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] + .

[0195] Example 3: Synthesis of Compound A3

[0196] (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

[0197] The specific implementation is as follows:

[0198] Step A:

[0199] Dissolve tert-butyl 5-nitrosalicylate (5.6 g) in 50 mL of N,N-dimethylformamide. Slowly add sodium hydride (730 mg) at 0°C, followed by bromomethyl methyl ether (4.095 g). Stir the reaction mixture at room temperature for 2 hours. After the reaction is complete, add 50 mL of water and extract with ethyl acetate (2 x 50 mL). Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, spin dry, and purify by column chromatography to obtain tert-butyl 2-methoxymethylether-5-nitrobenzoate (3.5 g, 52.8% yield).

[0200] Step B:

[0201] tert-Butyl 2-methoxymethylether-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 completion of the reaction, the reaction solution was filtered, dried, and purified by column chromatography to obtain tert-Butyl 2-methoxymethylether-5-aminobenzoate (2.753 g, 89.2% yield).

[0202] Step C:

[0203] tert-Butyl 2-methoxymethylether-5-aminobenzoate (900 mg) was dissolved in 30 mL of dichloromethane. A solution of m-chloroperbenzoic acid (1.165 g) in dichloromethane (30 mL) was slowly added at 0°C. The reaction solution was stirred at 0°C for 1.5 hours. After completion of the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain tert-butyl 2-methoxymethylether-5-nitrosobenzoate (439 mg, 33.6% yield).

[0204] Step D:

[0205] 2-Hydroxyaniline (2.0 g) was dissolved in 30 mL of N,N-dimethylformamide. Imidazole (1.872 g) and triisopropylsilyl chloride (4.593 g) were slowly added at 0°C. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. After the reaction, water (30 mL) was added at 0°C, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, dried, and purified by column chromatography to obtain 2-(triisopropylsilyl)oxy)aniline (3.87 g, 79.5% yield).

[0206] Step E:

[0207] Tert-butyl 2-methoxymethylether-5-nitrosobenzoate (439 mg) and 2-((triisopropylsilyl)oxy)aniline (566 mg) were dissolved in acetic acid (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was spin-dried and purified by column chromatography to obtain tert-butyl (E)-2-(methoxymethylether)-5-((2-((triisopropylsilyl)oxy)phenyl)diazenyl)benzoate (341 mg, 40.3% yield).

[0208] Step F:

[0209] Compound (E)-tert-butyl 2-(methoxymethylether)-5-((2-((triisopropylsilyl)oxy)phenyl)diazenyl)benzoate (340 mg) and cesium fluoride (301 mg) were added to acetonitrile (6 mL), and the reaction solution was stirred at 60°C for 1 hour. After completion of the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain compound (E)-tert-butyl 5-((2-hydroxyphenyl)diazenyl)-2-(methoxymethylether)benzoate (211 mg, 89.1% yield).

[0210] Step G:

[0211] Compound (R)-tert-butyl 1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))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 solution was stirred at room temperature for 16 hours under nitrogen atmosphere. After the reaction, the mixture was filtered, dried by rotary evaporation, and purified by column to obtain compound (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)-carboxylic acid tert-butyl ester (1.134 g, yield 83.9%).

[0212] Step H:

[0213] Compound (E)-5-((2-hydroxyphenyl)diazenyl)2-(methoxymethylether)-benzoate (200 mg), compound tert-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, and the reaction solution was stirred at 80°C for 4 hours under nitrogen environment. After the reaction, the mixture was filtered, dried in a rotary evaporation cycle, and purified by column chromatography to obtain the compound (R,E)-2-(1-((2-(2-((3-(tert-butyloxycarbonyl)-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)-carboxylic acid tert-butyl ester (446 mg, yield 93.9%). LC-MS: m / z 851.6 [M+H] + .

[0214] Step I:

[0215] The compound (R,E)-tert-butyl 2-(1-((2-(2-((3-(tert-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)-carboxylate (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, the mixture was dried by spin drying 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%).

[0216] 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] + .

[0217] Example 4 Synthesis of Compound A4

[0218] (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

[0219] The specific implementation is as follows:

[0220] Step A:

[0221] Compound (R)-tert-butyl 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 (368 mg) and phenylenediamine (337 mg) were dissolved in 5 mL of N,N-dimethylformamide. Under hydrogen protection, the reaction solution was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was spin-dried and purified by column chromatography to obtain compound (R)-tert-butyl 2-(1-((2-aminobenzamido)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (300 mg, 86% yield).

[0222] Step B:

[0223] The compound (R)-tert-butyl 2-(1-((2-aminobenzamide)oxy)ethyl)-1-(4-cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (150 mg) and the compound tert-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, the reaction solution was dried and purified by column chromatography to obtain the compound (R,E)-2-(1-(((2-((4-((benzyloxycarbonyl)oxy)-3-(tert-butyloxycarbonyl)phenyl)diazenyl)phenyl)carbamoyl)oxy)ethyl)-1-(4-(cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (84 mg, yield 34.8%). LC-MS: m / z 898.4 [M+H] + .

[0224] Step C:

[0225] Compound (R,E)-2-(1-(((2-((4-((benzyloxycarbonyl)oxy)-3-(tert-butoxycarbonyl)phenyl)diazenyl)phenyl)carbamoyl)oxy)ethyl)-1-(4-(cyanomethylpiperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (75 mg) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (0. 5 mL). The mixture was stirred at 45°C for 16 hours. After the reaction, the mixture was dried by rotary evaporation to obtain the crude 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, 99% yield).

[0226] Step D:

[0227] 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 spin-dried to obtain 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] + .

[0228] Example 5 Synthesis of Compound A5

[0229] Ethyl (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate

[0230] The specific implementation is as follows:

[0231] Step A:

[0232] Compound (R)-tert-butyl 1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylate (50 mg), acetic anhydride (120 mg), triethylamine (238 mg), and 4-dimethylaminopyridine (1 mg) were dissolved in 5 mL of dichloromethane, and the reaction solution was stirred at room temperature for 0.5 hours. After completion of the reaction, the mixture was spin-dried and purified by column chromatography to obtain compound (R)-tert-butyl 2-(1-acetoxyethyl)-1-(4-(cyanomethyl)piperidin-1-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylate (55 mg, 100% yield).

[0233] Step B:

[0234] Compound (R)-2-(1-acetoxyethyl)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))-carboxylic acid tert-butyl ester (55 mg) was dissolved in 6 mL of dichloromethane, trifluoroacetic acid (0.3 mL) was added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was washed with saturated sodium bicarbonate solution and dried to obtain compound (R)-ethyl 1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)acetate (32 mg, yield 74.1%).

[0235] 1 H 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] + .

[0236] Example 6 Synthesis of Compound A6

[0237] (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

[0238] The specific implementation is as follows:

[0239] Step A:

[0240] Methyl 5-bromovalerate (2.00 g) was dissolved in 10 mL of acetonitrile. Silver nitrate (2.61 g) was added under nitrogen and stirred at 70°C for 2 hours. The filtrate was collected and the solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column (petroleum ether to ethyl acetate 4:1) to obtain methyl 5-nitrate pentanoate (1.8 g, 96% yield). 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).

[0241] Step B:

[0242] Methyl 5-nitropentanoate (1.90 g) was dissolved in 20 mL of acetonitrile. LiOH (10 mL) was added dropwise in an ice bath under nitrogen and stirred at room temperature for 2 hours. The mixture was neutralized with 1N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a silica gel column (PE to EA ratio of 4 to 1) to obtain 5-nitropentanoic 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).

[0243] Step C:

[0244] Dissolve 5-nitropentanoic acid (64 mg) in 6 mL of dichloromethane, add thionyl chloride (0.2 mL) under nitrogen, and stir at room temperature for 3 hours. Evaporate the solvent under reduced pressure to obtain a crude product of 5-nitropentanoyl chloride (626 mg).

[0245] Step D:

[0246] 5-Nitropentanoyl chloride (500 mg) was dissolved in 10 mL of dichloromethane. Under nitrogen, tert-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. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the mixture was purified by silica gel column chromatography (methanol to dichloromethane: 1:10) to obtain tert-butyl (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-((5-nitropentanoyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (70 mg, 34% yield).

[0247] Step E:

[0248] Compound (R)-tert-butyl 1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-((5-nitrate pentanoyl)oxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylate (70 mg) was dissolved in 8 mL of dichloromethane. Trifluoroacetic acid (0.2 mL) was added under nitrogen and stirred at room temperature for 3 hours. After the reaction, sodium bisulfate solution was added. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and chromatographed on a silica gel column (methanol to dichloromethane: 1:10) to obtain 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, 30% yield).

[0249] 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).

[0250] Example 7: Synthesis of Compound A7

[0251] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl dimethylglycinate

[0252] The specific implementation is as follows:

[0253] Step A:

[0254] Dimethylglycine (compound 1.2, 1.093 g), 1,3-dicyclohexylcarbodiimide (2.187 g) and 4-(dimethylamino)pyridine (43 mg) were added to 10 mL of dichloromethane. Under nitrogen, the reaction solution was stirred at room temperature for 1.5 hours. Then, compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (1.5 g) was added and stirred at room temperature for 16 hours. After the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(dimethylglycine ethyl ester)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (1.2 g, yield 66.7%). LC-MS: m / z 510.1 [M+H] + .

[0255] Step B:

[0256] Compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(dimethylglycine ethyl ester)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-carboxylic acid tert-butyl ester (1.5 g) was added to 10 mL of dichloromethane, and trifluoroacetic acid (2.5 mL) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction, the solution was washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to prepare 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, yield 75.5%).

[0257] 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] + .

[0258] Example 8: Synthesis of Compound A8

[0259] (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

[0260] The specific implementation is as follows:

[0261] Step A:

[0262] 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 chloroformate (8.01 g). The reaction solution was stirred at room temperature under nitrogen for 16 hours. After the reaction, the reaction solution was washed with dichloromethane (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound Cbz-D-valine (9.6 g, yield 89.5%). 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).

[0263] Step B:

[0264] 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. Under a nitrogen atmosphere, the reaction solution was stirred for 1.5 hours under stirring. Then, compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (3.0 g) was added and stirred at room temperature for 16 hours. After the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain tert-butyl 2-((R)-1-(Cbz-D-valine ethyl ester)-1-(4-cyanomethylpiperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylate (1.96 g, 42.2% yield). LC-MS: m / z 658.3 [M+H] + .

[0265] Step C:

[0266] Compound 2-((R)-1-(Cbz-D-valine ethyl ester)-1-(4-cyanomethylpiperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (1.96 g) was added to 20 mL of dichloromethane, followed by trifluoroacetic acid (4.0 mL). The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the solution was washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and filtered through a column to obtain 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] + .

[0267] Step D:

[0268] 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 / carbon (200 mg, 10%) were added to 20 mL of methanol. The reaction mixture was stirred for 3 hours under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, dried by spin drying, and purified by column chromatography to obtain 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).

[0269] 1H 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] + .

[0270] Example 9: Synthesis of Compound A9

[0271] (R)-1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl L-valine ester

[0272] The specific implementation is as follows:

[0273] Step A:

[0274] L-valine (3.0 g) was added to water (20 mL), followed by the addition of sodium hydroxide (1.024 g) and benzyl chloroformate (4.81 g). The reaction solution was stirred at room temperature under nitrogen for 16 hours. After the reaction, the reaction solution was washed with dichloromethane (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound Cbz-L-valine (5.232 g, yield 81.3%). 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).

[0275] Step B:

[0276] 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. Under a nitrogen atmosphere, the reaction solution was stirred for 1.5 hours under stirring. Then, compound (R)-1-(4-(cyanomethyl)piperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (2.71 g) was added and stirred at room temperature for 16 hours. After the reaction, the mixture was filtered, dried, and purified by column chromatography to obtain tert-butyl 2-((R)-1-(Cbz-L-valine ethyl ester)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylate (2.1 g, 50% yield). LC-MS: m / z 658.3 [M+H] + .

[0277] Step C:

[0278] Compound 2-((R)-1-(Cbz-L-valine ethyl ester)-1-(4-(cyanomethyl)piperidin-1-yl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (2.1 g) was added to 10 mL of dichloromethane, followed by trifluoroacetic acid (4.0 mL). The reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, the solution was washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and filtered to obtain compound (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)-Cbz-L-valine ethyl ester (1.622 g, 91.1% yield). LC-MS: m / z 558.3[M+H] + .

[0279] Step D:

[0280] 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 / carbon (200 mg, 10%) were added to 20 mL of methanol. The reaction mixture was stirred for 3 hours under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, dried by spin drying, and purified by column chromatography to obtain 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).

[0281] 1H 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] + .

[0282] Example 10: Synthesis of Compound A10

[0283] (R)-(1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl fumaric acid monomethyl ester

[0284] The specific implementation is as follows:

[0285] Step A:

[0286] Compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (300 mg) and sodium hydroxide (85 mg) were added to N,N-dimethylformamide (10 mL), and then chloromethyl methyl sulfide (205 mg) was added. The reaction solution was stirred at room temperature for 3 hours under nitrogen. After the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography to obtain compound (R)-1-(4-cyanomethylpiperidin-1-yl)-2-(1-(methylthio)methoxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylic acid tert-butyl ester (262 mg, yield 76.5%). LC-MS: m / z 485.1[M+H] + .

[0287] Step B:

[0288] Compound (R)-tert-butyl 1-(4-cyanomethylpiperidin-1-yl)-2-(1-(methylthio)methoxy)ethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H))carboxylate (200 mg) and thionyl chloride (0.8 mL) were added to 10 mL of dichloromethane. Under nitrogen, the reaction solution was stirred at 55°C for 5 hours and then dried by rotary evaporation. The dried compound and N,N-diisopropylethylamine (213 mg) were dissolved in dichloromethane (10 mL), and monomethyl fumarate (107 mg) was added, followed by stirring at room temperature for 16 hours. After the reaction, the product was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by rotary evaporation, and purified by column chromatography to obtain compound (R)-(1-(6-Boc-1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methylfumarate (89 mg, 38.1% yield). LC-MS: m / z 567.2 [M+H] + .

[0289] Step C:

[0290] 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 fumaric acid monomethyl ester (84 mg) was added to 5 mL of dichloromethane, followed by trifluoroacetic acid (0.3 mL), and the reaction solution was stirred at room temperature for 3 hours. After the reaction, the solution was washed with saturated sodium bicarbonate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting mixture was purified by column chromatography to obtain compound (R)-(1-(1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethoxy)methyl fumaric acid monomethyl ester (8 mg, 11.6% yield).

[0291] 1 H 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] + .

[0292] Example 11: Synthesis of Compound A11

[0293] Methyl (1-(4-methyl-4-((methylthio)methyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)nitrate

[0294] The specific implementation is as follows:

[0295] Step A:

[0296] Dissolve ethyl 4-methylpiperidine-4-carboxylate hydrochloride (5.0 g) and sodium nitrite (4.153 g) in 100 mL of water. Slowly add acetic acid (2.891 g) dropwise at 0°C. Stir the reaction mixture at room temperature for 16 hours. After the reaction is complete, extract with ethyl acetate (3 x 100 mL). Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and spin dry to obtain the crude compound ethyl 4-methyl-1-nitrosopiperidine-4-carboxylate (5.944 g, 100% yield).

[0297] Step B:

[0298] The compound 4-methyl-1-nitrosopiperidine-4-carboxylic acid ethyl ester (5.944 g) was dissolved in 200 mL of tetrahydrofuran, and 2.5 N lithium aluminum tetrahydride solution (39 mL) was slowly added dropwise at 0° C. After the addition was complete, the mixture was stirred at room temperature for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to 0° C. and slowly quenched by adding water (3.9 mL). Then, 2 N sodium hydroxide (3.9 mL) and water (11.7 mL) were added in sequence. The solution was stirred at room temperature for 0.5 hours, filtered, and dried to obtain the crude compound 4-methyl-1-aminopiperidine-4-carboxylic acid ethyl ester (6.6 g, 100% yield).

[0299] Step C:

[0300] The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (6.96 g), the crude compound 4-methyl-1-nitrosopiperidine-4-carboxylic acid ethyl ester (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 nitrogen protection. After the reaction, the reaction solution was cooled to room temperature, filtered, and dried to obtain the compound (4-methyl-1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (6.496 g, yield 71.5%).

[0301] Step D:

[0302] The compound (4-methyl-1-((5-nitro-1-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 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 dried to give a crude compound (4-methyl-1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (7.3 g, yield 99%).

[0303] Step E:

[0304] The compound (4-methyl-1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (2.7 g) was dissolved in 60 mL of ethanol, and then iron powder (2.333 g) and a solution of ammonium chloride (1.117 g) in water (6 mL) were added, and the mixture was stirred at 80° C. for 1 hour. After the reaction, the reaction solution was filtered and dried to obtain the compound (4-methyl-1-((5-amino-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (2.14 g, yield 84%).

[0305] Step F:

[0306] Hydroxyacetamide (799 mg) and triethyloxonium tetrafluoroborate (2.021 g) were dissolved in 20 mL of anhydrous tetrahydrofuran, stirred at 35 ° C for 0.5 hour, and dried by rotation. The dried compound and the compound (4-methyl-1-((5-amino-1-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, the reaction solution was dried by rotation to give a crude compound (4-(2-hydroxymethyl-6-toluenesulfonylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1-methylcyclohexyl)methyl methanesulfonate (647 mg, yield 100%).

[0307] Step G:

[0308] 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 a 20% aqueous solution of sodium methylthiolate (2.5 mL) were dissolved in 10 mL of N,N-dimethylformamide and stirred at 100°C for 1 hour. After the reaction, 60 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (2×60 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and dried to obtain 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).

[0309] Step H:

[0310] 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, the reaction solution was washed with saturated sodium bicarbonate, then with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and dried to obtain 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).

[0311] Step I:

[0312] 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, the reaction solution was filtered and 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%). 1H 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 H),3.06(d,J=10.7Hz,2H),2.59(s,1H),2.28(s,1H),2.21(s,3H),2.01–1.68(m,4H),1.38(s,3H).LC-MS:m / z 391.2[M+H] + .

[0313] Example 12: Synthesis of Compound A12

[0314] 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

[0315] The specific implementation is as follows:

[0316] Step A:

[0317] 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 dried by rotary evaporation. The dried compound and the compound (4-methyl-1-((5-amino-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methyl methanesulfonate (800 mg) were dissolved in 80 mL of ethanol and stirred at 75 ° C for 0.5 hour. After the reaction, the reaction solution was dried by rotary evaporation to obtain the crude compound 2-(1-(4-methyl-4-(((methylsulfonyl)oxy)methyl)cyclohexyl)-6-toluenesulfonyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl acetate (3.6 g, yield 100%).

[0318] Step B:

[0319] The compound 2-(1-(4-methyl-4-(((methylsulfonyl)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 completion of the reaction, the mixture was filtered, 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, 37.8% yield).

[0320] Step C:

[0321] 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 thiomethoxide (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, 60 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 × 60 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was filtered, dried and purified to give 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, yield 35.2%).

[0322] Step D:

[0323] 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, the reaction solution was washed with saturated sodium bicarbonate, then with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and dried 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).

[0324] Step E:

[0325] 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, the reaction solution was filtered and 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, yield 10%). 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] + .

[0326] Example 13: Synthesis of Compound B1

[0327] 1-(Piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-amine

[0328] The specific implementation is as follows:

[0329] Step A:

[0330] 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 separately at 0°C. The mixture was then warmed to room temperature and stirred for 16 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. This yielded the crude compound 4-chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (99.8 g, crude yield 99%).

[0331] Step B:

[0332] Dissolve the compound 4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (50.0 g) in 600 mL of dichloromethane. Add tetrabutylammonium nitrate (74.44 g) and trifluoroacetic anhydride (53.05 g) at 0°C. Then, react at room temperature under nitrogen and stir for 20 hours. After the reaction is completed, quench with 500 mL of saturated sodium bicarbonate aqueous solution, separate the organic phase, and extract the aqueous phase twice with 1.2 L of dichloromethane. Combine the organic phases and wash with appropriate amounts of water and saturated sodium chloride aqueous solution, respectively. Dry over anhydrous sodium sulfate, filter, and rotary evaporate. The slurry obtained after rotary evaporation was ultrasonically beaten with 80 mL of ethyl acetate, filtered, and washed with 100 mL of a mixed solvent of ethyl acetate and petroleum ether (volume ratio 3:7). The filter cake was dried to obtain the compound 4-chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (30.1 g, yield 52%). 1 H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 8.26 (d, J = 4.1Hz, 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).

[0333] Step C:

[0334] The compound 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 a suspension in 250 mL of isopropanol. The mixture was stirred at 95°C for 16 hours. After completion, the reaction was cooled to room temperature, 500 mL of water was added, and the mixture was extracted with 750 mL of ethyl acetate three times. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and purified by rotary evaporation (dichloromethane:methanol volume ratio 40:1) to obtain the compound 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).

[0335] Step D:

[0336] Compound 5-nitro-N-(piperidin-1-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4-amine (4.88 g) was added to a mixed solution (suspension) of 30 mL of ethanol and 10 mL of water, and then solid ammonium chloride (1.88 g) and iron powder (1.96 g) were added in sequence. The temperature was raised to 80 ° C and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered and the filter residue was washed with 50 mL of ethyl acetate. 50 mL of water was added to the filtrate and 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. Filtered and concentrated the filtrate under reduced pressure to obtain crude compound N 4 -(Piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (4.01 g, crude yield 88%). LCMS ESI (+) m / z: 386.1 (M+1).

[0337] Step E:

[0338] 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 a dichloromethane solution of cyanogen bromide (3.0 M, 0.19 mL) was added. The mixture was stirred at room temperature for 16 hours. 10 mL of 1N sodium hydroxide solution was added and stirred for 30 minutes. The mixture was extracted with 45 mL of ethyl acetate in three portions. The organic phases were combined, washed with 30 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then chromatographed on a silica gel column (dichloromethane:methanol volume ratio 20:1) to afford 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).

[0339] Step F:

[0340] The 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, and sodium hydroxide (25 mg) was added. The reaction mixture was stirred at 60°C for 5 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with 45 mL of ethyl acetate three times. 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 the 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).

[0341] Example 14: Synthesis of Compound B2

[0342] N-((1-(2-Aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide

[0343] The specific implementation is as follows:

[0344] Step A:

[0345] 4-Chloro-5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (22 g) was dissolved in 200 mL of isopropanol, followed by the addition of DIEA (48.5 g) and (1-aminopiperidin-4-yl)methanol (6.35 g). The reaction mixture was stirred at 88°C for 16 hours. After completion of the reaction, the reaction mixture was dried and purified by column chromatography to obtain the compound (1-((5-nitro-1-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] + .

[0346] Step B:

[0347] Dissolve (1-((5-nitro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidin-4-yl)methanol (12 g) in 400 mL of ethanol and 80 mL of water, then add iron powder (12.1 g) and ammonium chloride (2890 mg). Stir the reaction mixture at 75°C for half an hour. After the reaction is complete, filter, spin-dry the filtrate, and purify 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, yield 89%). LC-MS: m / z 415.3 [M+H] + .

[0348] Step C:

[0349] Compound N 4 -(Piperidin-1-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (3.00 g) was dissolved in 10 mL of DMF, and imidazole (1.47 g) and tert-butyldimethylsilyl chloride (1.63 g) were added in sequence under nitrogen protection in an ice bath. After the addition was complete, the mixture was stirred at 0 degrees for 2 hours. The reaction solution was poured into 100 mL of water and extracted 3 times with 50 mL of ethyl acetate. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and chromatographed on a silica gel column (ethyl acetate to petroleum ether was 1 to 2) to obtain compound N 4 -(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-1-p-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4,5-diamine (3.70 g, yield 97%). 1 H 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).

[0350] Step D:

[0351] Compound N 4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)piperidin-1-yl)-1-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 sequentially under nitrogen protection at room temperature. Stir at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and a saturated sodium bicarbonate solution (15 mL), saturated sodium thiosulfate (15 mL) and a mixed solvent of methanol and ethyl acetate (volume ratio 1 to 10, 100 mL) were 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 (50 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product 1-(4-(((tert-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).

[0352] Step E:

[0353] The compound 1-(4-(((tert-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. Triethylamine (3.90 mL) and di-tert-butyl dicarbonate (1.83 g) were added at room temperature. The mixture was stirred at room temperature under nitrogen for 16 hours. The solution was concentrated under reduced pressure and then chromatographed on a silica gel column (ethyl acetate to petroleum ether: 1:7) to afford the compound 1-(4-(((tert-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).

[0354] Step F:

[0355] Dissolve 1-(4-(((tert-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) in 120 mL of tetrahydrofuran, and add tetra-n-butylammonium fluoride trihydrate (5.84 g) at room temperature. Stir at room temperature for 2 hours. Add 250 mL of ethyl acetate, and wash 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 evaporated under reduced pressure. The mixture was purified by silica gel column chromatography (ethyl acetate to petroleum ether: 3 to 1) to give the compound tert-butyl (1-(hydroxymethyl)piperidin-1-yl)-6-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).

[0356] Step G:

[0357] Under ice-cooling and nitrogen protection, tert-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) were added to 50 mL of toluene. The temperature was raised to 100°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 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). 1H 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).

[0358] Step H:

[0359] 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-tert-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 solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether to ethyl acetate in a ratio of 4:1) to obtain the compound tert-butyl(1-(4-(methylazido)piperidin-1-yl)-6-(p-toluenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (647 mg, 68% yield). LCMS ESI (+) m / z: 666.2 (M+1).

[0360] Step I:

[0361] The compound tert-butyl (1-(4-(methylazido)piperidin-1-yl)-6-(p-toluenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (235 mg) was dissolved in 25 mL of methanol, and 10% palladium on carbon (40 mg) was added under nitrogen. The hydrogen atmosphere was replaced. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and washed with 5 mL of methanol. The filtrate was concentrated under reduced pressure to obtain the crude product tert-butyl (1-(4-aminomethylpiperidin-1-yl)-6-(p-toluenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (145 mg, 64% yield). LCMS ESI (+) m / z: 640.3 (M+1).

[0362] Step J:

[0363] The compound tert-butyl (1-(4-aminomethylpiperidin-1-yl)-6-(p-toluenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)(tert-butoxycarbonyl)carbamate (70 mg) was dissolved in 5 mL of dichloromethane. Triethylamine (33 mg) and cyanomethanesulfonyl chloride (23 mg) were added sequentially at 0°C under nitrogen. The mixture was stirred at 0°C for 2 hours. The reaction solution was purified by column chromatography on a silica gel column (petroleum ether to ethyl acetate in a ratio of 1:1) to obtain the compound tert-butyl (tert-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).

[0364] Step K:

[0365] The compound tert-butyl (tert-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. A 4N hydrochloric acid solution in dioxane (2.5 mL) was added at 0°C under nitrogen protection. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound N-((1-(2-amino-6-silylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide, which was used directly in the next step.

[0366] Step L:

[0367] The crude product of 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. Stirring was carried out at 35°C for 16 hours. The pH was adjusted to 7 with 1N HCl. The methanol was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol to dichloromethane: 1:10) to obtain compound N-((1-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-piperidin-4-yl)methyl)-1-cyanomethanesulfonamide (2 mg, 5% yield). 1H 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).

[0368] Example 15: Synthesis of Compound B3

[0369] 2-((1R,4R)-4-(2-aminoimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-ethyl)cyclohexyl)acetonitrile

[0370] The specific implementation is as follows:

[0371] Step A:

[0372] Compound N 4 -(Piperidin-1-yl)-1-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 sequentially at room temperature under nitrogen protection. Stir at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and saturated sodium bicarbonate solution (10 mL), saturated sodium thiosulfate solution (10 mL), and a mixed solvent of methanol and ethyl acetate (volume ratio 1:10, 40 mL) were 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 yield a crude product of 2-((1R,4R)-4-(2-amino-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[4,5-b](6H)-ethyl)cyclohexyl)acetonitrile (740 mg, 100% yield). LCMS ESI (+) m / z: 435.2 (M+1).

[0373] Step B:

[0374] The compound 2-((1R,4R)-4-(2-amino-6-(phenylsulfonyl)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 reverse HPLC was used 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). 1 H 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).

[0375] Example 16: Synthesis of Compound B4

[0376] 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile

[0377] The specific implementation is as follows:

[0378] Step A:

[0379] To a 250 mL three-necked flask, add 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) in sequence. Stir at room temperature under nitrogen for 24 hours. Filter the reaction mixture, extract the filtrate with dichloromethane, combine the organic phases, dry over anhydrous magnesium sulfate, and spin dry. The resulting residue is chromatographed on a silica gel column (ethyl acetate and petroleum ether = 15%) to obtain 3-aminothiophene (9 g, 95%).

[0380] Step B:

[0381] 2,2-Dimethyl-1,3-dioxane-4,6-dione (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. After cooling to room temperature, a white solid precipitated, which was used directly in the next step. 3-Aminothiophene (10 g) was added, followed by isopropanol, and the mixture was refluxed for half an hour. After cooling to room temperature, a large amount of white solid precipitated, which was filtered to yield 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (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)

[0382] Step C:

[0383] Diphenyl ether was added to a 50 mL round-bottom flask, and the reaction solvent was heated to 250°C. The compound 2,2-dimethyl-5-((thiophen-3-ylamino)methylene)-1,3-dioxane-4,6-dione (3.00 g) was added to the system. The reaction was carried out at 250°C for 30 minutes. The mixture was cooled to room temperature and filtered to obtain a white solid compound thieno[3,2-b]pyridin-7-ol (1.2 g, yield 68%). LCMS ESI (+) m / z: 152.0 (M+1)

[0384] Step D:

[0385] Thieno[3,2-b]pyridin-7-ol (900 mg) was dissolved in propionic acid (20 mL) and heated to 110°C under a nitrogen atmosphere. 4.8 mL of fuming nitric acid was then added and the mixture was reacted at 150°C for 1 hour. The mixture was cooled to room temperature, and ether was added. The solid was filtered, washed with water, and dried under reduced pressure to yield 6-nitrothieno[3,2-b]pyridin-7-ol (700 mg, 60% yield). LCMS ESI (+) m / z: 197.0 (M+1).

[0386] Step E:

[0387] 6-Nitrothieno[3,2-b]pyridin-7-ol (600 mg) was added to phosphorus oxychloride (25 mL) and heated to 110°C under a nitrogen atmosphere for 1 hour. The solvent was then evaporated under reduced pressure, followed by the addition of dichloromethane and saturated sodium bicarbonate solution. The organic phases were separated, combined, washed three times with water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 7-chloro-6-nitrothieno[3,2-b]pyridine (483 mg, 75% yield). LCMS ESI (+) m / z: 215.0 (M+1).

[0388] Step F:

[0389] 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 and reacted at 90°C for 2 hours. After cooling to room temperature, a large amount of solid precipitated, which was filtered to obtain a yellow solid, which was 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).

[0390] Step G:

[0391] 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 under nitrogen for 30 minutes. After completion of the reaction, the hot filtrate was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (methanol to dichloromethane ratio of 1:10) to obtain compound 2-(1-((6-aminothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (180 mg, 98% yield). LCMS ESI(+) m / z: 288.2 (M+1)

[0392] Step H:

[0393] Dissolve the compound 2-(1-((6-aminothieno[3,2-b]pyridin-7-yl)amino)piperidin-4-yl)acetonitrile (72 mg) in methanol (5 ml) and add cyanogen bromide (53 mg). Stir at room temperature for 16 hours under a nitrogen atmosphere. Evaporate the solvent under reduced pressure, then add saturated sodium bicarbonate solution (5 mL), saturated sodium thiosulfate (5 mL), and a mixture of methanol and ethyl acetate (volume ratio 1:10, 10 mL). Stir at room temperature for 15 minutes. Separate the organic phase, and extract the aqueous phase three times with a mixture of methanol and ethyl acetate (10 mL). Combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol to dichloromethane: 1:10) to give the product 2-(1-(2-amino-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl)piperidin-4-yl)acetonitrile (11 mg, 15% yield). 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).

[0394] Example 17: Synthesis of Compound B5

[0395] 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile

[0396] The specific implementation is as follows:

[0397] Step A:

[0398] Take a dry and clean 500ml single-necked bottle, add 2-bromo-3-hydroxypyridine (25g), trimethylethynylsilane (17g), cuprous iodide (2.74g, 14.4mmol), bistriphenylphosphine palladium dichloride (2.0g) and 1,4-dioxane (200ml), replace the system with nitrogen three times, stir at room temperature for 30min, add triethylamine (43.6g), and react the system at 65℃ under nitrogen protection for 6 hours. The mixture was cooled to room temperature, filtered under reduced pressure, the filter cake was washed with 30 ml of methyl tert-butyl ether, the filtrate was washed with 400 ml of water, the aqueous phase was extracted twice with 400 ml of methyl tert-butyl ether, the combined organic phases were washed with 1 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. 200 ml of petroleum ether was added to the crude product, the mixture was slurried for 30 min, filtered, the filter cake was washed twice with 30 ml of petroleum ether, and the filtrate was spin-dried to obtain 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).

[0399] Step B:

[0400] To a clean, dry 1L single-necked flask, add 2-(trimethylsilyl)furo[3,2-b]pyridine (36.6 g) and dichloromethane (400 ml). Add (70%) m-chloroperbenzoic acid (76.9 g) at room temperature and allow to react overnight. After the reaction is complete, filter and wash the filter cake twice with 20 ml of dichloromethane. The combined filtrate is washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is dried to yield 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).

[0401] Step C:

[0402] In a clean, dry 500ml single-necked flask, crude 2-(trimethylsilyl)furo[3,2-b]pyridine 4-oxide (41.4g) and toluene (150ml) were added dropwise. 150ml of phosphorus oxychloride was slowly added dropwise at 0°C. After completion of the dropwise addition, the system was heated to 95°C and allowed to react for 3 hours. After the reaction, the system was cooled to room temperature and dried by rotary evaporation. The resulting residue was diluted with 300ml of water and adjusted to pH 8 with saturated sodium bicarbonate aqueous solution. The system was extracted three times with 500ml of methyl tert-butyl ether. The combined filtrates were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporation to obtain the crude product. The crude product was purified on a silica gel column (eluent: ethyl acetate:petroleum ether = 1:10) to obtain 2-(trimethylsilyl)-7-chlorofuro[3,2-b]pyridine (20.7g, yield: 46%). 1 H 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).

[0403] Step D:

[0404] To a clean, dry 500ml single-necked flask, add 2-(trimethylsilyl)-7-chlorofuro[3,2-b]pyridine (20.7g) and tetrahydrofuran (150ml). Add 150ml of sodium hydroxide (18g) aqueous solution at room temperature. After addition, heat the system to 50°C and react for 1 hour. After the reaction is complete, cool the system to room temperature, spin dry the solvent, and extract the resulting aqueous solution three times with 200ml of methyl tert-butyl ether. The combined filtrate is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate spin-dried to obtain 7-chlorofuro[3,2-b]pyridine (11.8g, yield: 84%). 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).

[0405] Step E:

[0406] To a clean, dry 500ml single-necked flask, add compound 5 (10.8g) and methanol (200ml). Add 100ml of sodium hydroxide (42.6g) aqueous solution at room temperature. After addition, heat the system to 75°C and allow to react overnight. After the reaction is complete, cool the system to room temperature, remove the solvent, and dilute the resulting solution with 100ml of water. Extract the resulting solution twice with 200ml of dichloromethane. Wash the combined filtrate with saturated brine, dry over anhydrous sodium sulfate, and filter. The filtrate is then dried to give 7-methoxyfuro[3,2-b]pyridine (5.6g, 53.3% yield). 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).

[0407] Step F:

[0408] To a clean, dry 25ml single-necked flask, add 7-methoxyfuro[3,2-b]pyridine (5.0g), hydrobromic acid in acetic acid (10ml), and water (4ml). The mixture was allowed to react overnight at 125°C. After the reaction, the system was cooled to room temperature, the solvent was evaporated, and the resulting residue was dissolved in 50ml of toluene and evaporated again. This was repeated three times to obtain 7.2g of crude product. The crude product was purified on a C18 reverse-phase column using a methanol:water (0.1% ammonia) system as the eluent, eluting with 100% water to obtain 7-hydroxyfuro[3,2-b]pyridine (3.1g, 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).

[0409] Step G:

[0410] To a clean, dry 50ml single-necked flask, add 7-hydroxyfuro[3,2-b]pyridine (1.5g) and dichloromethane (15ml). Then, add tetrabutylammonium nitrate (10g) and trifluoroacetic anhydride (11.6g) at 0°C. The reaction was allowed to react overnight at room temperature. After completion of the reaction, the system was diluted with 50ml of water and extracted twice with 50ml of ethyl acetate. The combined filtrate was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was separated using a normal phase column (ethyl acetate:petroleum ether = 50%) to obtain furo[3,2-b]pyridin-7-yl nitrate (540mg, yield: 27%). 1H 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).

[0411] Step H:

[0412] To a clean, dry 50ml single-necked flask, add furo[3,2-b]pyridin-7-yl nitrate (430mg) and propionic acid (15ml). Add fuming nitric acid (551mg) at room temperature and react at 125°C for 30 minutes. After the reaction is complete, cool the system to room temperature, dilute with 50ml of methyl tert-butyl ether, filter, and wash the solid twice with 3ml of methyl tert-butyl ether to obtain 6-nitrofuro[3,2-b]pyridin-7-ol (220mg, 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).

[0413] Step I:

[0414] To a clean, dry 25ml single-necked flask, add 6-nitrofuro[3,2-b]pyridin-7-ol (356mg) and DCE (12ml). Phosphorus oxychloride (4.2ml) was added at room temperature and the reaction was carried out at 95°C for 2 hours. After the reaction, the system was cooled to room temperature, the solvent was dried by rotary evaporation, and the mixture was diluted with 10ml of water. The pH was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted three times with 50ml of methyl tert-butyl ether. The combined filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was then rotary evaporation to afford 7-chloro-6-nitrofuro[3,2-b]pyridine (287mg, yield: 73.2%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ9.22 (s, 1H), 8.16 (d, J = 2.2Hz, 1H), 7.17 (d, J = 2.2Hz, 1H).

[0415] Step J:

[0416] To a clean, dry 10ml single-necked flask, add 7-chloro-6-nitrofuro[3,2-b]pyridine (70 mg), 2-((1r,4r)-4-aminocyclohexyl)acetonitrile (74.4 mg), and tert-butyl alcohol (5 ml). DIPEA (100 mg) was added at room temperature, and the system was reacted at 135°C overnight. After the reaction, the reaction solution was spin-dried to obtain a crude product, which was separated using a normal phase column (ethyl acetate:petroleum ether = 50%) to afford 2-((1r,4r)-4-((6-nitrofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (55 mg, yield: 51.8%) as a yellow solid. 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).

[0417] Step K:

[0418] To a clean, dry 50ml single-necked flask, add 2-((1r,4r)-4-((6-nitrofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (55 mg) and methanol (10 ml). Palladium on carbon (25 mg, 60% content) was added at room temperature. The system was purged with hydrogen three times, and the reaction was allowed to proceed under a hydrogen balloon for 30 minutes. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth, the filter cake was washed with 3 ml of methanol, and the combined filtrates were spin-dried to yield 2-((1r,4r)-4-((6-aminofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (43 mg, yield: 86.5%). 1 H 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).

[0419] Step L:

[0420] To a clean, dry 25ml vial, add 2-((1r,4r)-4-((6-aminofuro[3,2-b]pyridin-7-yl)amino)cyclohexyl)acetonitrile (33 mg) and methanol (5 ml). Cyanogen bromide (14.3 mg) was added at room temperature and the system was allowed to react overnight. After the reaction, 20ml of water was added to the reaction solution, and the aqueous phase was extracted three times with 30ml of dichloromethane. The combined filtrates were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness to obtain 40mg of the crude product. This crude product was then purified by high-pressure liquid chromatography (0.05% ammonia system) to obtain 2-((1R,4R)-4-(2-amino-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl)cyclohexyl)acetonitrile as a white solid (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).

[0421] Example 18: Synthesis of Compound B6

[0422] 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

[0423] The specific implementation is as follows:

[0424] Step A:

[0425] 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 concentrated under reduced pressure. The mixture was poured into water (50 mL) and ethyl acetate (100 mL), and the organic phase was separated. The mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate to petroleum ether: 1:9) to obtain the compound 2-hydroxy-5-nitrobenzoic acid benzyl ester (5.84 g, 78% yield). 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.54(d,J=2.9Hz,1H),8.33(dd,J=9.2,3.0Hz,1 H),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).

[0426] Step B:

[0427] Benzyl 2-hydroxy-5-nitrobenzoate (5.84 g) was dissolved in dichloromethane (100 mL). Triethylamine (3.24 g) and benzyl chloroformate (4.38 g) were added sequentially under an ice bath and nitrogen protection. The mixture was stirred at room temperature under nitrogen protection for 16 hours. The solution was concentrated under reduced pressure and then chromatographed on a silica gel column (ethyl acetate to petroleum ether in a ratio of 1:10) to obtain benzyl 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).

[0428] Step C:

[0429] Benzyl 2-((benzyloxycarbonyl)oxy)-5-nitrobenzoate (1.20 g) was dissolved in ethanol (10 mL) and acetonitrile (10 mL). 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 solution was cooled to room temperature, made alkaline with saturated aqueous sodium bicarbonate, and stirred for 15 minutes. Ethyl acetate (50 mL) was added, filtered through celite, and the filter cake was washed with ethyl acetate (50 mL). The organic phase was separated and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate to petroleum ether: 1:4) to obtain benzyl 2-((benzyloxycarbonyl)oxy)-5-aminobenzoate (662 mg, 60% yield). 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).

[0430] Step D:

[0431] Benzyl 2-((benzyloxycarbonyl)oxy)-5-aminobenzoate (2.00 g) was dissolved in acetonitrile (20 mL). The reaction mixture was cooled to -10°C, followed by the addition of concentrated hydrochloric acid (3 mL) and a solution of sodium nitrite (366 mg) in water (0.6 mL). The mixture was 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 sodium hydroxide solution. Ethyl acetate (100 mL) was added, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate (100 mL). The organic phase was separated and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on a silica gel column (ethyl acetate to petroleum ether at a ratio of 1:1) to afford benzyl 2-((benzyloxycarbonyl)oxy)-5-hydrazinobenzoate (1.3 g, 63% yield). 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).

[0432] Step E:

[0433] 4-Chloro-5-nitro-1-(p-toluenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.15 g) was suspended in tert-butanol (80 mL), and 1N aqueous sodium hydroxide solution (38.1 mL) was added. The mixture was stirred at room temperature for 16 hours. Water (200 mL) and ethyl acetate (300 mL) were added, the organic phase was separated, and extracted twice with ethyl acetate (200 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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,1H),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).

[0434] Step F:

[0435] The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.22 g) was suspended in 100 mL of isopropanol. N,N-diisopropylethylamine (6.32 mL) and 2-((1r,4r)-4-aminocyclohexyl)acetonitrile hydrochloride (3.70 g) were added sequentially. The mixture was heated to 90°C under nitrogen and stirred for 16 hours. The mixture was cooled to room temperature, 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).

[0436] Step G:

[0437] 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. Iron powder (18.6 g) and saturated ammonium chloride (19 mL) were added sequentially at room temperature, and the mixture was stirred at 75°C for 40 minutes. The mixture was filtered through hot celite, washed with 40 mL of ethanol, and the filtrate was concentrated. Column chromatography on a silica gel column (methanol to dichloromethane: 1:9) afforded 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).

[0438] Step H:

[0439] 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 nitrogen protection. A solution of compound 2-((1r,4r)-4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (865 mg) in DMF (30 mL) and triethylamine (422 mg) were added, and the mixture was reacted at 60°C under nitrogen protection for 2.5 hours. The residue was concentrated under reduced pressure and then purified by silica gel column chromatography (methanol to dichloromethane: 1:19) to afford 2-((benzyloxycarbonyl)oxy)-5-(2-((4-(((1r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)aminomethylthio)hydrazino)benzoic acid benzyl ester (1.43 mg, 63% yield). LCMS ESI (+) m / z: 704.2 (M+1).

[0440] Step I:

[0441] Under nitrogen, the compound 2-((benzyloxycarbonyl)oxy)-5-(2-((4-(((1r,4r)-4-(cyanomethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-5-yl)aminomethylthio)hydrazino)benzoic acid benzyl ester (1.43 g) was dissolved in 50 mL of dry THF, and EDCI (584 mg) and triethylamine (616 mg) were added sequentially, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then purified by C18 reverse-phase silica gel column chromatography (methanol to 0.1% aqueous formic acid = 75%) to afford 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).

[0442] Step J:

[0443] 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 a 3.5 N sodium hydroxide solution (12 mL) was added. The mixture was stirred at room temperature for 16 hours. Then, a 1 N The pH was adjusted to 5 with HCl. Isopropyl alcohol was evaporated under reduced pressure, the mixture was filtered under reduced pressure, washed with water (30 mL), washed with acetonitrile (30 mL), and freeze-dried 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, 76% yield). 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).

[0444] Example 19: Synthesis of Compound B7

[0445] (E)-5-((1-(4-cyanomethylpiperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid

[0446] The specific implementation is as follows:

[0447] Step A:

[0448] The compound 4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.22 g) was suspended in 100 mL of isopropanol. N,N-diisopropylethylamine (6.32 mL) and 2-((1r,4r)-4-aminocyclohexyl)acetonitrile hydrochloride (3.70 g) were added sequentially. The mixture was heated to 90°C under nitrogen and stirred for 16 hours. The mixture was cooled to room temperature, 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).

[0449] Step B:

[0450] Add the compound 2-(4-((5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (3.20 g) to 100 mL of ethanol and add stannous chloride dihydrate (12.0 g) at room temperature. Stir and react at 45°C for 2 hours. Cool to room temperature, add 2N NaOH solution in an ice bath to adjust the pH to 8-9, and stir at room temperature for 15 minutes. Add 300 mL of ethyl acetate and diatomaceous earth, filter the diatomaceous earth, and wash with 30 mL of ethyl acetate. Separate the organic phase and extract twice with 50 mL of ethyl acetate. Combine the organic phases, wash with 50 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Silica gel column chromatography (methanol to dichloromethane = 1 to 20) gave compound 2-(4-((5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)acetonitrile (1.23 g, 43% yield). 1H 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).

[0451] Step C:

[0452] Thiocarbonyldiimidazole (923 mg) was dissolved in THF (100 mL). A solution of 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, and the mixture was stirred at room temperature for 15 minutes under nitrogen. 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 under nitrogen for 2 hours. The mixture was concentrated under reduced pressure and chromatographed on a silica gel column (methanol to dichloromethane = 1:30) to obtain 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).

[0453] Step D:

[0454] Under nitrogen, the compound 2-((1-((5-amino-1H-pyrrolido[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 sequentially, and the mixture was stirred at room temperature for 48 hours. The reaction solution 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)thiazolyl-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoate (102 mg, 6% yield). 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).

[0455] Step E:

[0456] Benzyl (E)-5-((1-(4-(cyanomethyl)phenylthiazin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)diazenyl)-2-hydroxybenzoate (100 mg) was suspended in 9 mL of isopropanol, 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 evaporated under reduced pressure, and the mixture was filtered under reduced pressure, washed with water (30 mL), then with acetonitrile (30 mL), and lyophilized to obtain (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, 99% yield). 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).

[0457] Example 20: Synthesis of Compound B8

[0458] (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

[0459] The specific implementation is as follows:

[0460] Step A:

[0461] 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 D-aspartic acid dibenzyl ester (260 mg), DCC (171 mg) and pyridine (157 mg) were added in sequence under nitrogen protection at room temperature. The reaction mixture was stirred at room temperature under nitrogen protection for 48 hours. C18 reversed phase silica gel column chromatography (acetonitrile to 0.1% formic acid aqueous solution: 60%) was used 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-aspartate (73 mg, 30% yield). 1 H 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).

[0462] Step B:

[0463] Suspend 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) in 12 mL of isopropanol and add 3.5 N sodium hydroxide solution (3 mL). Stir at room temperature for 16 hours. Adjust the pH to 5 with 1 N HCl. Evaporate the isopropanol under reduced pressure, filter under reduced pressure, and lyophilize. Add water (12 mL) and centrifuge. Add water (12 mL) and centrifuge. 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, yield 86%). 1 H 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).

[0464] Example 21: Synthesis of Compound B9

[0465] (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

[0466] The specific implementation is as follows:

[0467] Step A:

[0468] 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 compound N was added in sequence under nitrogen protection at room temperature. 6 -Boc-D-lysine benzyl ester (540 mg), DCC (332 mg) and pyridine (305 mg). Stir at room temperature for 18 hours under nitrogen protection. C18 reverse silica gel column chromatography (acetonitrile to 0.1% formic acid aqueous solution is 50%) to obtain compound 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 ester (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).

[0469] Step B:

[0470] Compound benzyl N 6 -Boc-N 2Benzo[3-(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 ester (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. Isopropanol was evaporated under reduced pressure, the product was filtered under reduced pressure, water (12 mL) was added, and the product was centrifuged and 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-lysine (73 mg, yield 89%). 1 H 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( m,2H),2.48–2.37(m,1H),2.20–2.09(m,2H),2.09–1.99(m,4H),1.74–1.38(m,7H).LCMS ESI(+)m / z: 572.2(M+1).

[0471] Example 22: Synthesis of Compound B10

[0472] (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

[0473] The specific implementation is as follows:

[0474] Step A:

[0475] 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 D-glutamic acid dibenzyl ester (246 mg) were dissolved in 5 mL of N,N-dimethylformamide, and then dicyclohexylcarbodiimide (163 mg) and pyridine (55 mg) were added. Under nitrogen protection, the reaction solution was stirred at room temperature for 16 hours. After the reaction, the mixture was dried by spin drying 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-glutamate (135 mg, yield 56.8%).

[0476] Step B:

[0477] 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-glutamate (135 mg) was dissolved in 24 mL of isopropanol, and then 3.5N sodium hydroxide (6.0 mL) was added, and the reaction solution was stirred at room temperature for 16 hours. After the reaction, 1N hydrochloric acid was added to adjust the solution to pH = 7. After isopropyl alcohol was evaporated under reduced pressure, the pH was adjusted to pH = 3 with 1N hydrochloric acid solution and freeze-dried. The resulting solid was added with water and centrifuged twice. After removing the supernatant, the solid was freeze-dried 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-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] + .

[0478] Example 23: Synthesis of Compound B11

[0479] (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

[0480] The specific implementation is as follows:

[0481] Step A:

[0482] N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-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. Stirred at room temperature for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered. Concentrated under reduced pressure and purified by column to obtain the compound benzyl N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (1.76 g, 96% yield). LCMS ESI (+) m / z: 739.2 (M+1).

[0483] Step B:

[0484] To compound benzyl N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (1.66 g) was added to piperidine (2 mL dissolved in 8 mL N,N-dimethylformamide). The mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was completed, the solvent was dried and purified by column to obtain compound N ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (928 mg, 80% yield). LCMS ESI (+) m / z: 517.2 (M+1).

[0485] Step C:

[0486] 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 compound N was added in sequence under nitrogen protection at room temperature. ω -((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (757 mg), HOBT (119 mg), DCC (181 mg) and 4-methylmorpholine (356 mg). Stirred at 40°C for 18 hours under nitrogen protection. C18 reverse silica gel column chromatography gave 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-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (280 mg, yield 50%). 1H 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).

[0487] Step D:

[0488] 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-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-D-arginine (0.27 g) was dissolved in 10 mL of dichloromethane. 10 mL of trifluoroacetic acid was added dropwise in an ice bath, and the mixture was allowed to react at room temperature for 2 hours. After the reaction, the solvent was evaporated and the product was purified by column chromatography to yield 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).

[0489] Step E:

[0490] 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. Stir at room temperature for 16 hours. Adjust the pH to 5 with 1N HCl. Evaporate the isopropanol under reduced pressure, filter under reduced pressure, and lyophilize. Water (12 mL) was added, the mixture was centrifuged, lyophilized, and finally purified by reverse column to obtain compound (R)-2-(5-((E)-(1-((1r,4R)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine)-2-yl)diazenyl)-2-hydroxybenzoyl)-D-arginine (69.1 mg, yield 50%).

[0491] 1 H 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).

[0492] Example 24: Synthesis of Compound B12

[0493] 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

[0494] The specific implementation is as follows:

[0495] Step A:

[0496] 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 (236 mg) was dissolved in DMF (10 mL), and compound 2,2,2-trifluoroethyl 2-aminoethane-1-sulfonate (276 mg), DCC (275 mg) and pyridine (2 The mixture was stirred at 35°C for 16 hours under nitrogen protection. Column chromatography (50% acetonitrile to 0.1% aqueous formic acid) afforded 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-hydroxyphenylanilinamide)ethane-1-sulfonate (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) LCMS ESI(+)m / z: 663.4(M+1).

[0497] Step B:

[0498] Suspend 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-hydroxyphenylanilinamide)ethane-1-sulfonate (110 mg) in 12 mL of isopropanol and add 4N sodium hydroxide solution (6 mL). Stir at 80°C for 16 hours. Adjust the pH to 3 with 1N HCl. Evaporate the isopropanol under reduced pressure, filter under reduced pressure, and lyophilize. Add water (12 mL) and centrifuge. C18 reversed phase silica gel column chromatography (methanol to 0.1% formic acid aqueous solution is 20%) gave compound 2-(5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1,6-dihydroimidazole[4,5-d]pyrrol[2,3-b]pyridin-2-yl)diphenyl)-2-hydroxyphenylanilineamide)ethane-1-sulfonic acid (25 mg, 26% yield). 1H 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).

[0499] The compounds in Table 1 were prepared by methods similar to those described in the previous examples (eg, Examples 18 and 19) using different starting materials and appropriate reagents.

[0500] Table 1

[0501] Example A: Activity detection of small molecule inhibitors of JAK kinases

[0502] Experimental plan

[0503] 1. Reagent Preparation

[0504] (1) Kinase reaction buffer

[0505] Prepare kinase reaction buffer with the following components: 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween20

[0506] (2) 1X Assay Buffer

[0507] Prepare the detection buffer by diluting the 10X detection buffer to 1X with deionized water at a ratio of 9:1.

[0508] (3) 4X kinase solution

[0509] Kinase reaction buffer was used to dilute JAK kinase to 4X final concentration (JAK1: 40 nM, JAK2: 0.5 nM)

[0510] (4) 4X substrate solution

[0511] Kinase reaction buffer dilution ULight TM -JAK-1 (Tyr1023) substrate to 200 nM (final concentration: 50 nM)

[0512] (5) 4X ATP solution

[0513] Dilute ATP to 4X final concentration in kinase reaction buffer (JAK1: 160 μM, JAK2: 40 μM)

[0514] (6) 4X test compound solution

[0515] Dissolve the test compound in DMSO to a 10 mM stock solution, and dilute it 3-fold to the desired concentration. Set 10 concentration points for each compound. The final concentration range of the test compound is: 10 μM-0.5 nM

[0516] (7) 4X enzyme reaction termination solution:

[0517] Dissolve EDTA to 40 mM in 1X assay buffer (final EDTA concentration: 10 mM)

[0518] (8) 4X detection antibody solution

[0519] Dilute Eu-labeled detection antibody (anti-phosphotyrosine (PT66)) to 8 nM in 1X detection buffer (final antibody concentration: 2 nM)

[0520] 2. Experimental Procedure

[0521] (1) Add 2.5 μL of 4X kinase solution and 2.5 μL of diluted 4X test compound solution of different concentrations to a 384-well microplate. Set up two replicate wells for each concentration. Set up an enzyme solution blank control group and a negative control group (DMSO group) at the same time.

[0522] (2) Shake the 384-well plate to mix the enzyme and compound, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 60 minutes

[0523] (3) Add 2.5 μL of 4X substrate solution to the 384-well plate and centrifuge at 1000 rpm for 1 minute.

[0524] (4) Add 2.5 μL of 4X ATP solution to the 384-well plate and centrifuge at 1000 rpm for 1 minute to start the enzyme reaction.

[0525] (5) JAK1 reacted at room temperature for 2 hours, and JAK2 reacted at room temperature for 1 hour

[0526] (6) The final concentrations of the components of the JAK1 reaction are: JAK1: 10 nM, substrate: 50 nM, ATP: 40 uM, and the final concentration range of the test compound is: 10 μM-0.5 nM

[0527] The final concentrations of the components of the JAK2 reaction are: JAK2: 0.125 nM, substrate: 50 nM, ATP: 10 μM, and the final concentration range of the test compound is: 10 μM-0.5 nM

[0528] (7) After the enzyme reaction is completed, add 5 μL of 4X enzyme reaction stop solution to each well of the 384-well plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 5 minutes.

[0529] (8) Add 5 μL of 4X detection antibody solution to each well of the 384-well plate (final concentration of detection antibody is 2 nM), centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 1 hour.

[0530] (9) After the antibody incubation is completed, the signal value of each well is measured on the Envision plate reader.

[0531] 3. Data Analysis

[0532] (1) Taking the enzyme solution blank control group as 100% inhibition rate and the negative control group (DMSO group) as 0% inhibition rate, calculate the percentage inhibition rate corresponding to each concentration of the test compound

[0533] (2) Nonlinear regression analysis was performed on the logarithmic values ​​of the concentrations of the test compounds and the corresponding percentage inhibition rates in GraphPad Prism software to obtain the half-maximal inhibitory concentration (IC 50 ), the experimental results are listed in Table 2.

[0534] Table 2 Half maximal inhibitory concentration IC of compounds 50

[0535] The above results indicate that the compounds of the present invention have good kinase inhibitory activity against JAK1 and JAK2.

[0536] Example B Pharmacokinetics and fecal excretion studies in rats

[0537] 1. Experimental plan

[0538] SD rats were administered single oral doses of compounds A1, A2, A3, B3, B6, and B3. Plasma concentrations of the drugs and their metabolites were collected and measured at different time points, and pharmacokinetic parameters were calculated to investigate the pharmacokinetic characteristics of the compounds in SD rats. Fecal samples were collected at 8 and 24 hours to measure the concentrations of the prodrugs and degradation products and to investigate the excretion recovery rate.

[0539] 2. Experimental process

[0540] There were 3 rats in each group. All SD rats were fasted overnight (more than 12 hours) the day before the experiment. On the day of the experiment, after weighing the body weight, compounds A1, A2, A3, B3, B6, and B3 were administered orally by single gavage. The test solution was administered orally, and the dosage was shown in Table 3. SD rats were allowed to resume eating 4 hours after administration and were free to drink water during the experiment. 0.20 mL of blood was collected from the jugular vein before administration and 0.5, 1, 2, 4, 8, 12, and 24 hours after administration, and placed in an EDTA-K2 anticoagulant tube. All whole blood samples were centrifuged at 1500-1600g for 10 minutes within half an hour after collection, and the plasma was separated and stored in a refrigerator at -90 to -60°C for sample analysis. All feces on the bottom plate of the metabolic cage were removed within 24 hours, accurately weighed, and the required volume of homogenate (containing 20% ​​methanol in water) was added at a weight / volume ratio of 1:10, homogenized, and analyzed.

[0541] 3. Data Analysis

[0542] Table 3 Cumulative recovery of prodrugs and metabolites in feces over 24 hours

[0543] Table 4 PK parameters of prodrugs and metabolites in rats “-”: not applicable; BLOQ: below the limit of quantification; NA: not applicable.

[0544] (Note: The metabolite A13 produced by compound A1 was only slightly absorbed at 12 hours, so the AUC could not be calculated. Compound B6 was only slightly absorbed at 4 hours, so the AUC could not be calculated.)

[0545] As can be seen from Table 3, the prodrug can be decomposed in the intestine to release the active metabolite.

[0546] As can be seen from Table 4, the T max Generally, it is after 4 hours, and most of them are 12 hours, which means that the decomposition and absorption of metabolites occur in the back end of the digestive tract, that is, the colon. max The average daily survival time was 1.2 hours, indicating that the prodrug can delay the release of the active ingredient and deliver it to the posterior end of the digestive tract. In addition, compounds A1, A2, A3, and B6, as prodrugs, were not present or were rarely present in the plasma, indicating that they were hardly absorbed through the blood system. They were cleaved into active metabolites in the intestine, and only a small portion of the corresponding active metabolites was absorbed by the blood system. Compared with the direct oral administration of an equal molar amount of the active metabolite B3, oral administration of the prodrug B6 reduced the blood system absorption of the active metabolite B3 (AUC 0-t ) is greatly reduced, indicating that the design of the prodrug can significantly reduce the exposure of active metabolites in the body, thereby reducing systemic side effects.

[0547] Example C Pharmacokinetic Study in Rats

[0548] 1. Experimental plan

[0549] SD rats were given a single oral administration of compounds A3 and A13 in equimolar amounts relative to rat body weight. The concentrations of drugs and their metabolites in plasma and colon tissue at different time points were collected and determined. The pharmacokinetic parameters of each compound were calculated, and the pharmacokinetic characteristics of the prodrug and active metabolite in SD rats were compared.

[0550] 2. Experimental process

[0551] 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, the rats were weighed and given a single oral dose of compound A3 (30 mg / kg) and A13 (15 mg / kg). The test solution was administered orally at the doses shown in Table 3. SD rats were allowed to resume eating 4 hours after administration and were allowed to drink water freely during the experiment. Plasma and colon tissue were collected at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after administration, and the concentration of A13 in plasma and colon tissue homogenates was detected.

[0552] 3. Data analysis, see Figure 1.

[0553] As shown in Figure 1, when rats were given equal molar amounts of prodrug A3 or compound A13, prodrug A3 resulted in lower levels of the active metabolite A13 in the blood and higher levels in the colonic tissue. This suggests that prodrug A3 can reduce the systemic exposure of compound A13, minimizing systemic side effects, while also increasing its concentration at the target therapeutic site, enhancing its therapeutic efficacy.

[0554] Although the present invention has been fully described through its embodiments, it is noteworthy that various changes and modifications are obvious to those skilled in the art. 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: in, X is selected from CR a or N; W and Z are independently selected from O, N, S, NR b or CR c ; W and Z cannot be CR at the same time c ; R1 is selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkyl; the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 The haloalkyl group is optionally replaced by one or more R d replace; R1' is selected from H, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; L1 is not present or C 1-14 (Preferred C 1-7 ) a divalent saturated or unsaturated linear or branched hydrocarbon chain, one, two or three methylene groups of which may be optionally and independently replaced by: -CH(R e )-、-C(R e )2-、C 3-5 Cycloalkylene, -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 selected from the group consisting of: 6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group or 3-14 membered carbocyclic group; the C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group and 3-14 membered carbocyclic group may be optionally substituted by one or more R f replace. L2 is selected from H, OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 Alkyl) 2; said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 Alkyl)2 is optionally replaced by one or more hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -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 or -C(=O)NR g R h replace; R a 、R b 、R c are independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1- 6-haloalkoxy; R d Selected from H, halogen, CN, -NO2, OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl, -S(=O)N(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; said -OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -SC 1-6 Alkyl, -S(=O)-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)NH2, -S(=O)NHC 1-6 Alkyl, -S(=O)N(C 1-6 Alkyl)2, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclyl and -C 0-6 Alkylene-3-14 membered heterocyclic radicals are optionally substituted with one or more H, halogen, CN, -NO2, OH, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy, -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, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, -CON(C 1-6 alkyl)2 substituted; R e 、R f 、R g and R h are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclic or -C 0-6 Alkylene-3-14 membered heterocyclic group; wherein said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-NHS(=O)2-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenyl, -C 0-6 Alkylene-C 6-14 Aryl, -C 0-6 Alkylene-5-14 membered heteroaryl, -C 0-6 Alkylene-C 3-14 Carbocyclyl and -C 0-6 Alkylene-3-14 membered heterocyclic radicals are optionally substituted with one or more H, halogen, CN, -NO2, OH, NH2, -COOH, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -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, -C 0-6 Alkylene-NHC(=O)C 1-6 Haloalkyl, -C 0-6 Alkylene-NHC(=O)C 2-6 Alkenyl, -CON(C 1-6 alkyl)2 substituted.

2. The compound according to claim 1, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, characterized in that: X is selected from CH or N.

3. The compound according to 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 selected from CH.

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, characterized in that: Z is selected from N, NR b or CR c .

5. The compound according to 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 selected from NH.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R d Selected from H, OH, halogen, amino, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6-alkoxy or -NHS(=O)2-C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NHS(=O)2-C 1-6 The alkyl group is optionally substituted with one or more halogen, CN, OH, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 substituted.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from H or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally replaced by one or more CN, C 1-6 Alkoxy, -SC 1-6 Alkyl or -NHS(=O)2C 1-6 Alkyl-CN substitution.

8. The compound according to any one of claims 1 to 7, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from H, -CH2-CN, -CH2-S-CH3 or 9. The compound according to any one of claims 1 to 8, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R1' is selected from H or C 1-3 alkyl.

10. The compound according to any one of claims 1 to 9, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R1' is selected from H or CH3.

11. The compound according to any one of claims 1 to 10, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R e Selected from H, amino, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

12. The compound according to any one of claims 1 to 11, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R e is selected from H, methyl, ethyl, n-propyl or isopropyl.

13. The compound according to any one of claims 1 to 12, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L1 is selected from absent or C 1-14 (Preferably C 1-4 ) a divalent saturated or unsaturated straight or branched hydrocarbon group, wherein one, two or three methylene groups in the hydrocarbon group may be optionally and independently replaced by: -CH(R e )-、-C(R e )2-、C 3-5 Cycloalkylene, -N(R e )-、-N(R e )C(=O)-、-C(=O)N(R e )-, -O-, -C(=O)-, -OC(=O)-, -C(=O)O-.

14. The compound according to any one of claims 1 to 13, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L1 is selected from the group consisting of: 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 1-6 Alkylene-OC(=O)-NR a -; said C 1-6 The alkylene group is optionally substituted with 1 to 6 R e replace.

15. The compound according to any one of claims 1 to 14, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L1 is selected from the group consisting of absent, -CH2-, -CH2CH2-, 16. The compound according to any one of claims 1 to 15, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R g 、R h are independently selected from H, C 1-6 Alkyl, amino or -COOH.

17. The compound according to any one of claims 1 to 16, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from hydrogen, OH, C 1-6 Alkyl, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) or -C 0-6 Alkylene-N(C 1-6 Alkyl) 2; said C 1-6 Alkyl, C 2-6 Alkenyl, -C 0-6 Alkylene-NH(C 1-6 alkyl) and -C 0-6 Alkylene-N(C 1-6 Alkyl)2 is optionally replaced by one or more hydrogen, halogen, CN, OH, NH2, -ONO2, -COOH, -S(=O)2OH, -N=C(NH2)2, C 1-6 Alkyl or -COO(C 1-6 alkyl) substituted.

18. The compound according to any one of claims 1 to 17, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from OH, CH3, 19. The compound according to any one of claims 1 to 18, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from OH.

20. The compound according to any one of claims 1 to 18, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from CH3, 21. The compound according to any one of claims 1 to 18, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: L2 is selected from 22. The compound according to any one of claims 1 to 21, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R f Selected from H, C 1-3 alkyl.

23. The compound according to any one of claims 1 to 22, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from absent or C 6-14 Aryl; said C 6-14 The aryl group may be optionally replaced by one or more R f replace.

24. The compound according to any one of claims 1 to 23, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: R f Selected from H, C 1-3 alkyl.

25. The compound according to any one of claims 1 to 24, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from absent or C 6-10 Aryl.

26. The compound according to any one of claims 1 to 25, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from absent or a benzene ring.

27. The compound according to any one of claims 1 to 26, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from absent or 28. The 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 compound of formula I is selected from the compound of formula III shown below: The definitions of X, W, Z, R1, R1', L1 and L2 in the compound of formula III are as defined in any one of claims 1 to 27.

29. The compound according to any one of claims 1 to 28, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula I is selected from the compound of formula IV shown below: The definitions of X, W, Z, R1, R1', L1 and ring A in the compound of formula IV are as defined in any one of claims 1 to 28.

30. The 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 compound of formula I is selected from the compounds of formula V shown below: The definitions of X, W, Z, R1, R1' and L2 in the compound of formula V are as defined in any one of claims 1 to 29.

31. The 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 compound of formula I is selected from the compounds of formula VI shown below: R4 is C 1-3 Alkylene or C 1-3 Alkyleneoxy; R5 is hydrogen or C 1-3 alkyl; Wherein, R4 and R5 are optionally replaced by one or more R e Replacement; R e As defined in any one of claims 1 to 30; X, W, Z and R1 in the compound of formula VI are as defined in any one of claims 1 to 30.

32. The 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 compound of formula I is selected from the compounds of formula IX shown below: The definitions of X, R1, R1', L1 and ring A in the compound of formula IX are as defined in formula I according to any one of claims 1 to 27.

33. The 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 compound of formula I is selected from the compound of formula X shown below: The definitions of X, R1, R1' and L2 in the compound of formula X are as defined in any one of formula I of claims 1 to 27.

34. The 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 compound of formula I is selected from the compounds of formula XI shown below: R4 is C 1-3 Alkylene or C 1-3 Alkyleneoxy; R5 is hydrogen or C 1-3 alkyl; Wherein, R4 and R5 are optionally replaced by one or more R e Replacement, R e As defined in formula I above; X and R1 in the compound of formula XI are as defined in formula I according to any one of claims 1 to 27.

35. The compound of claim 1, or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof, wherein: The compound is selected from: (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 dimethylglycinate; (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 5-((E)-(1-((1r,4r)-4-(cyanomethyl)cyclohexyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-2-yl)diazenyl)-2-hydroxybenzoic acid.

36. A pharmaceutical composition comprising a therapeutically effective dose of a compound as claimed in 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. Use of the compound according to any one of claims 1 to 35, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 36 in the preparation of a JAK inhibitor prodrug.

38. Use of the compound according to any one of claims 1 to 35, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 36 in the preparation of a JAK inhibitor drug.

39. Use of the compound according to any one of claims 1 to 35, or its stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 36 in the preparation of drugs for treating inflammatory diseases and / or tumor diseases.

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

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

42. The 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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