Pyridocyclic compounds, methods of making, intermediates, compositions, and uses thereof

Abstract

This invention discloses a pyridine-cyclic compound, its preparation method, intermediates, compositions, and applications. The pyridine-cyclic compound has the structure shown in Formula I and exhibits JAK inhibitory activity, making it suitable for treating JAK-related diseases such as autoimmune diseases or cancer.

Description

[0001] This application is a divisional application of Chinese patent application filed on January 6, 2021, with application number 2021100143537, entitled "Pyridine cyclocyclic compounds and their preparation methods, intermediates, compositions and applications". Technical Field

[0002] This invention relates to a pyridine cyclic compound, its preparation method, intermediates, compositions, and applications. Background Technology

[0003] Janus kinase (JAK) belongs to the tyrosine kinase family involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving impaired cartilage regeneration, congenital cartilage malformations, and / or diseases associated with excessive IL6 secretion.

[0004] JAK kinases are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors. Four members of the JAK kinase family have been described in the prior art: JAK1, JAK2, JAK3, and TYK2. When cytokines bind to their receptors, JAK family members autophosphorylate and / or transphosphorylate each other, followed by STAT phosphorylation, which then migrates to the nucleus to regulate transcription. JAK-STAT intracellular signal transduction is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL.

[0005] Combination studies of genetic models and small-molecule JAK inhibitors have revealed the therapeutic potential of several JAKs. JAK3 has been confirmed as an immunosuppressive target through mouse and human genetic studies. JAK3 inhibitors have been successfully developed clinically, initially for organ transplant rejection, but later for other immunoinflammatory indications such as rheumatoid arthritis (RA), psoriasis, and Crohn's disease. TYK2 is a potential target for immunoinflammatory diseases, confirmed through human genetic and mouse knockout studies. JAK2 is an effective target for treating myeloproliferative disorders, with two drugs already marketed for myelofibrosis. JAK1 is a novel target in the field of immunoinflammatory diseases, heterodimerizing JAK1 with other JAKs to transduce cytokine-driven pro-inflammatory signaling. Therefore, inhibition of JAK1 and / or other JAKs is expected to have therapeutic benefits for a range of inflammatory conditions and other diseases driven by JAK-mediated signal transduction.

[0006] Tofacitinib was developed by Pfizer and successfully launched in the United States on November 7, 2012, for the treatment of rheumatoid arthritis, under the brand name Xeljanz.

[0007] Ruxolitinib was jointly developed by Incyte and Novartis and launched in the United States in 2011 for the treatment of myelofibrosis, under the brand name Jakafi.

[0008] Baricitinib was jointly developed by Incyte and Eli Lilly and was launched in the United States in 2018 for the treatment of rheumatoid arthritis, under the brand name Olumiant.

[0009] Upadacitinib is a selective JAK1 inhibitor developed by AbbVie and launched in 2019 for the treatment of rheumatoid arthritis. Its reported activity is a JAK1 inhibitor with an IC50 threshold. 50 =43nM, JAK2 IC 50 =200nM.

[0010] Fedratinib is a selective JAK2 inhibitor developed by Sanofi and launched in 2019 for the treatment of myelofibrosis. Its reported activity is JAK2 IC50. 50 =3nM.

[0011] Summary of the Invention

[0012] The purpose of this invention is to provide a novel pyridine cyclic compound, its preparation method, intermediates, compositions, and applications.

[0013] On one hand, the present invention provides a compound represented by Formula I:

[0014]

[0015] Or a tautomer, stereoisomer, racemate or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound, tautomer, stereoisomer, racemate or isotopic derivative thereof as shown in Formula I), or a crystal form or solvate of any of the foregoing (referring to the compound, tautomer, stereoisomer, racemate, isotopic derivative or pharmaceutically acceptable salt thereof as shown in Formula I).

[0016] Where X is CH or N;

[0017] Y is NH or N; when Y is N, the connection to Y is... It is a double bond; when Y is NH, it is connected to Y. It is a single bond;

[0018] R 1 and R 2The definition is as follows (i), (ii) or (iii):

[0019] (i)R 1 for (For example For example ), R 2 for (For example For example )or (For example );

[0020] Ring B is a benzene ring or a 5–6 membered heteroaromatic ring;

[0021] R 1a C 1–3 Alkyl groups (e.g., methyl groups);

[0022] Each R 3 Independently halogen (e.g., fluorine), cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as –CF3), –O–C 1–4 Alkyl (e.g., –O–CH3) or –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluorinated alkyl groups, such as –OCF3);

[0023] Each R 4 Independently halogen (e.g., fluorine), hydroxyl, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as –CF3), –O–C 1–4 Alkyl groups (e.g., –O–CH3), –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluorinated alkyl groups, such as –OCF3) or C 1–4 Hydroxyalkyl groups (e.g., –CH2OH);

[0024] Alternatively, two R atoms located on the same carbon atom or different carbon atoms 4 Interconnected to form –CH2– or –(CH2)2– (e.g., forming For example );

[0025] R 5 is –S(O)2R 5a –C(O)R 5b –C(O)NR 5c R 5d–C(O)OR 5e –C(O)NHR 5k or –L 1 –R 5f ;

[0026] R 5a C 2–6 Alkyl (e.g., ethyl, n-propyl, or n-butyl), C 2–6 Halogenated alkyl, –L 1 –R 5f Unsubstituted or substituted 6–10-membered aryl (e.g., phenyl or naphthyl) or unsubstituted or substituted 5–10-membered heteroaryl (e.g., 5–6-membered heteroaryl), wherein the substituted 6–10-membered aryl and substituted 5–10-membered heteroaryl refer to 6–10-membered aryl and 5–10-membered heteroaryl where 1, 2, 3, or 4 hydrogen atoms are independently separated by R. 5g replace;

[0027] R 5b R 5c R 5d R 5e and R 5k Each independently is C 1–6 Alkyl, C 1–6 Halogenated alkyl, –L 1 –R 5f Unsubstituted or substituted 6–10-membered aryl (e.g., phenyl or naphthyl) or unsubstituted or substituted 5–10-membered heteroaryl (e.g., 5–6-membered heteroaryl), wherein the substituted 6–10-membered aryl and substituted 5–10-membered heteroaryl refer to 6–10-membered aryl and 5–10-membered heteroaryl where 1, 2, 3, or 4 hydrogen atoms are independently separated by R. 5h replace;

[0028] Each R 5g and R 5h Each is independently a halogen (e.g., fluorine), cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as –CF3), –O–C 1–4 Alkyl groups (e.g., –O–CH3), –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluorinated alkyl groups (–OCF3) or phenyl groups;

[0029] Each L 1 Independently for –[C(R) a R b )] 1-5–(e.g., –CH2–, –(CH2)2–, –(CH2)3–, –(CH2)4–, –(CH2)5– or ), –[C(R) a R b )] 1–2 –C(O)–[C(R a R b )] 1–2 –、–[C(R a R b )] 1–2 –C(O)NH–[C(R a R b )] 1–2 –(e.g. –C(R) a R b )–C(O)NH–C(R a R b )–R 5f ), –[C(R) a R b )] 1–2 –NHC(O)–[C(R a R b )] 1–2 –、–[C(R a R b )] 1–2 –S(O)2–[C(R a R b )] 1–2 –、–[C(R a R b )] 1–2 –NHS(O)2–[C(R a R b )] 1–2 –or–[C(R) a R b )] 1–2 –S(O)2NH–[C(R a R b )] 1–2 –;

[0030] Each R 5f Independently, it can be H, F, CHF2, CH2F, CF3, or CN;

[0031] Each R a Independently H, halogen (e.g., fluorine), or C 1–3 Alkyl groups (e.g., methyl or ethyl);

[0032] Each R b Independently H, halogen (e.g., fluorine), or C 1–3 Alkyl groups (e.g., methyl or ethyl);

[0033] Or, R a and R b Together with the carbon atoms that connect them, they form a cyclopropyl group;

[0034] m can be 0, 1, 2, 3, or 4;

[0035] n can be 0, 1, 2, 3, or 4;

[0036] (ii)R 1 for R 2 for (For example )or (e.g., trans or cis);

[0037] The ring C is a benzene ring or a 5–6 membered heteroaromatic ring (e.g., imidazole, thiazole, furan, thiophene, or pyridine, for example). );

[0038] Each R 6 Independently halogen (e.g., fluorine or chlorine, e.g., fluorine), hydroxyl, amino, cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C 1–4 Alkyl groups (e.g., –O–CH3), –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluoroalkyl groups, such as –O–CF3), –S–C 1–4 Alkyl groups (e.g., –S–CH3), –S(O)2–C 1–4 Alkyl (e.g. –S(O)2–CH3) or C 1–4 Hydroxyalkyl groups (e.g., –CH2–OH);

[0039] Each R 7 Independently for R 4 (i.e. R) 7 R in any of the compounds of Formula I of the present invention 4 (The definitions are the same);

[0040] Alternatively, two R atoms located on the same carbon atom or different carbon atoms 7 They connect to form –CH2– or –(CH2)2–;

[0041] R 8 For R 5 (i.e. R) 8 R in any of the compounds of Formula I of the present invention 5(same definition), –S(O)2R 8a –C(O)R 8b –C(O)NR 8c R 8d –C(O)OR 8e Or –C(O)NHR 8k ;

[0042] R 8a R 8b R 8c R 8d R 8e and R 8k Each is independently a methyl group, -CF3, or C. 2–6 alkenyl (e.g., vinyl) or C 3–6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl);

[0043] Each R 9 Independently for R 4 ;

[0044] Alternatively, two R atoms located on the same carbon atom or different carbon atoms 9 They connect to form –CH2– or –(CH2)2–;

[0045] z can be 0, 1, 2, 3, or 4;

[0046] y is 0, 1, 2, 3 or 4;

[0047] t can be 0, 1, 2, 3, or 4;

[0048] (iii)R 1 For H, CF3 or R 2 for

[0049] Ring D is C 3–6 Cycloalkyl (e.g., cyclopropyl or cyclobutyl), benzene ring, or 5–6 membered heteroaromatic ring (e.g., furan or thiophene, for example) );

[0050] Ring E is a benzene ring or a 5–6 membered heteroaromatic ring (e.g., furan or thiophene, for example). );

[0051] Each R 10 and R 11 Independently halogen (e.g., fluorine or chlorine, e.g., fluorine), hydroxyl, amino, cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C1–4 Alkyl groups (e.g., –O–CH3), –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluoroalkyl groups, such as –O–CF3), –S–C 1–4 Alkyl groups (e.g., –S–CH3), –S(O)2–C 1–4 Alkyl (e.g. –S(O)2–CH3) or C 1–4 Hydroxyalkyl groups (e.g., –CH2–OH);

[0052] R 12 Cyanoyl, -L 3 –R 12f or

[0053] Each R 14a Independently halogen (e.g., fluorine), cyano, C 1–4 Alkyl (e.g., methyl), cyano-substituted C 1–4 Alkyl (e.g., –CH2CN), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C 1–4 Alkyl groups (e.g., –O–CH3), –O–C 1–4 Halogenated alkyl groups (e.g., –O–C) 1–4 Fluorinated alkyl groups, such as –O–CF3) or C 1–4 Hydroxyalkyl groups (e.g., –CH2OH);

[0054] R 14b For R 5 (i.e. R) 14b R in any of the compounds of Formula I of the present invention 5 (Same definition) or –S(O)2–C 1–4 Alkyl groups (e.g., –S(O)2–CH2CH3, –S(O)2–CH2CH2CH3 or –S(O)2–CH2CH2CH2CH3);

[0055] L 3 For –[C(R) e R f )]1-5– (e.g., –CH2–, –(CH2)2–, –(CH2)3–, –(CH2)4– or –(CH2)5–), –C(O)–, –C(O)NH–, –NHC(O)–, –S(O)2–, –NHS(O)2–, –S(O)2NH–, –[C(R e R f )] 1–2 –C(O)–[C(R e R f )]1–2 –、–[C(R e R f )] 1–2 –C(O)NH–[C(R e R f )] 1–2 –、–[C(R e R f )] 1–2 –NHC(O)–[C(R e R f )] 1–2 –、–[C(R e R f )] 1–2 –S(O)2–[C(R e R f )] 1–2 –、–[C(R e R f )] 1–2 –NHS(O)2–[C(R e R f )] 1–2 –or–[C(R) e R f )] 1–2 –S(O)2NH–[C(R e R f )] 1–2 –;

[0056] R 12f It can be H, F, CHF2, CH2F, CF3, or CN;

[0057] Each R e and R f Independently, H, halogens (e.g., fluorine), C 1–3 Alkyl (e.g., methyl or ethyl) or C 3–6 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl);

[0058] Or, R e and R f Together with the carbon atoms that connect them, they form a cyclopropyl group;

[0059] p is 0, 1, 2, 3 or 4;

[0060] q can be 0, 1, 2, 3, or 4;

[0061] v can be 0, 1, 2, or 3;

[0062] u is 0, 1, or 2;

[0063] The heteroatoms in the above heteroaryl groups are independently N, O, or S, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0064] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-1:

[0065]

[0066] Among them, R 1a R 4 R 5 The definitions of X and n are as described in the compound represented by Formula I as defined in any embodiment of the present invention.

[0067] In some embodiments, the compound represented by formula I or I-1 has a structure represented by formulas I-1C, I-1D, I-1E, or I-1F:

[0068]

[0069] Among them, R 1a R 4 R 5 The definitions of X and n are as described in the compound represented by Formula I as defined in any embodiment of the present invention.

[0070] In some embodiments, the compound represented by formula I or I-1 has a structure represented by formulas I-1a, I-1b, I-1c, or I-1d, preferably having the structure represented by I-1d:

[0071]

[0072]

[0073] Among them, R 1a R 4 R 5g X, n, L 1 and R 5f The definition is as described in the compound represented by Formula I as defined in any embodiment of the present invention;

[0074] Each f is independently 0, 1, 2, 3, or 4, for example, 0 or 1.

[0075] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-2, I-2A, or I-2B:

[0076]

[0077] Among them, R 1a R 3The definitions of X and m are as described in the compound represented by Formula I as defined in any embodiment of the present invention.

[0078] In some embodiments, such as compounds of formula I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, I-1d, I-2, I-2A or I-2B, X is CH.

[0079] In some embodiments, such as compounds of formula I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, I-1d, I-2, I-2A or I-2B, X is N.

[0080] In some embodiments, such as compounds of formula I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, I-1d, I-2, I-2A or I-2B, R 1a It is a methyl group.

[0081] In some embodiments, such as the compounds represented by formulas I, I-1, I-1a, I-1b, I-1c, I-1d, or I-2, for Preferred

[0082] In some embodiments, such as the compounds represented by formula I, I-2, I-2A or I-2B, m is 1.

[0083] In some embodiments, such as the compounds represented by formula I, I-1, I-1a, I-1b, I-1c or I-1d, for In some implementation schemes, for In some implementation schemes, for

[0084] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, or I-1d, each R 4 Independently halogen (e.g., fluorine) or C 1–4 Hydroxyalkyl groups (e.g., –CH2OH), or two R atoms located on the same or different carbon atoms. 4 They connect to form –CH2– or –(CH2)2–.

[0085] In some embodiments, such as compounds of formula I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, I-1d, I-2, I-2A or I-2B, n is 0, 1 or 2.

[0086] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, or I-1d, for for (For example ), (For example )or (For example ).

[0087] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, I-1c, or I-1d, for for

[0088] In some embodiments, as shown in Formula I, ring B is a benzene ring.

[0089] In some implementations, m is 1 in compounds such as Formula I.

[0090] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5a C 2–6 Alkyl (e.g., ethyl, n-propyl, or n-butyl), unsubstituted or substituted 6–10 aryl (e.g., phenyl or naphthyl) or unsubstituted or substituted 5–10 heteroaryl (e.g., 5–6 heteroaryl).

[0091] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5a The term "unsubstituted or substituted 6–10 aryl" in the definition can refer to an unsubstituted or substituted phenyl group or an unsubstituted or substituted naphthyl group. The unsubstituted or substituted phenyl group can be, for example, an unsubstituted phenyl group, or a group independently selected by 1, 2, 3, and 4 (e.g., 1) halogens (e.g., fluorine), C... 1–4 Alkyl (e.g., methyl), –O–C 1–4 Halogenated alkyl groups (e.g., –OCF3) and phenyl-substituted phenyl groups, for example Wherein, the unsubstituted or substituted naphthyl group can be, for example, an unsubstituted naphthyl group, such as... In some implementation schemes, R 5a The “unsubstituted or substituted 6–10 aryl” is preferably a –OCF3-substituted phenyl group (e.g. ).

[0092] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5a The "unsubstituted or substituted 5-10 heteroaryl" in the definition can be "unsubstituted or substituted 5 or 6 heteroaryl", such as an unsubstituted or substituted thiophene, preferably.

[0093] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, I-1F, I-1a, I-1b, or I-1c, each R 5g Independent of halogens (e.g., fluorine), C 1–4 Alkyl (e.g., methyl), –O–C 1–4 Halogenated alkyl groups (e.g., –OCF3) or phenyl groups, preferably –OCF3.

[0094] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –S(O)2R in the definition 5a are –S(O)2(CH2)2–CF3, –S(O)2(CH2)2–CH3, –S(O)2CH2–CH3, –S(O)2(CH2)3–CH3, –S(O)2(CH2)2–CF3, Preferably, the following are the possible values: –S(O)2(CH2)2–CF3, –S(O)2(CH2)2–CH3, –S(O)2CH2–CH3, –S(O)2(CH2)3–CH3, –S(O)2(CH2)2–CF3.

[0095]

[0096] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5b For –L 1 –R 5f , or unsubstituted or substituted phenyl.

[0097] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5b –L in the definition1 –R 5f For –C(R) a R b )–R 5f ,For example

[0098] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5b The term "unsubstituted or substituted 6–10 aryl group" in the definition can refer to an unsubstituted or substituted phenyl group, or an unsubstituted or substituted naphthyl group; wherein the unsubstituted or substituted phenyl group can be, for example, an unsubstituted phenyl group, or a phenyl group substituted by 1, 2, 3, and 4 (e.g., 1) substituted groups independently selected from halogens (e.g., fluorine) and cyano groups, for example...

[0099] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –C(O)R in the definition 5b for

[0100] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5e C 1–6 Alkyl groups, such as tert-butyl groups.

[0101] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –C(O)OR in the definition 5e It is –C(O)OC(CH3)2–CH3.

[0102] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5c R 5d and R 5k Each independently as –L 1 –R 5f .

[0103] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5c R 5d and R 5k –L in the definition 1 –R 5f For –C(R) a R b )–R 5fFor example, –CH2–R 5f For example, –CH2–CF3.

[0104] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –C(O)NHR in the definition 5k –C(O)NHC(R) a R b )–R 5f For example, –C(O)NHCH2–R 5f For example, –C(O)NHCH2–CF3.

[0105] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –L in the definition 1 –R 5f For –[C(R) a R b )] 1-5 –R 5f Or – [C(R a R b )] 1–2 –C(O)NH–[C(R a R b )] 1–2 –, Preferred –C(R) a R b )–R 5f 、–[C(R a R b )]2–R 5f 、–[C(R a R b )]3–R 5f 、–[C(R a R b )]4–R 5f Or – [C(R a R b )]5–R 5f Further optimization – [C(R)] a R b )]2–R 5f Or – [C(R a R b )]3–R 5f .

[0106] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –L in the definition 1 –R5f For –C(R) a R b )–R 5f 、–[C(R a R b )]2–R 5f 、–[C(R a R b )]3–R 5f 、–[C(R a R b )]4–R 5f 、–[C(R a R b )]5–R 5f Or –C(R) a R b )–C(O)NH–C(R a R b )–R 5f Preferred – [C(R)] a R b )]2–R 5f Or – [C(R a R b )]3–R 5f .

[0107] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R 5f Independently designated as F, CF3, or CN. In some implementations, each R... 5f Independently for F. In some implementations, each R 5f Independent for CF3. In some implementations, each R 5f It is independent of CN.

[0108] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –L in the definition 1 –R 5f For –C(R) a R b –CN、–[C(R) a R b )]2–CN、–[C(R a R b )]3–CN、–[C(R a R b )]4–CN、–[C(R a R b )]–CF3、–[C(R a R b)]2–CF3、–[C(R a R b )]3–CF3、–C(R a R b )C(O)NH–C(R a R b )CF3 or –[C(R) a R b )]5–F, preferably –C(R a R b –CN、–[C(R) a R b )]2–CN、–[C(R a R b )]3–CN、–[C(R a R b )]4–CN、–[C(R a R b )]–CF3、–[C(R a R b )]2–CF3、–[C(R a R b )]3–CF3, or –[C(R a R b )]5–F.

[0109] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R a Independently H, fluorine, methyl, or ethyl; each R b Independently, it is H, fluorine, methyl, or ethyl; or, R a and R b Together with the carbon atoms that connect them, they form a cyclopropyl group.

[0110] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R a It can be H, fluorine, methyl, or ethyl independently.

[0111] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R a Independently, it is either H or fluorine.

[0112] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R b It can be H, fluorine, methyl, or ethyl independently.

[0113] In some embodiments, such as the compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, each R b It can be H or fluorine, methyl or ethyl independently.

[0114] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 –L in the definition 1 –R 5f The CF3 is –CH2–CN, –(CH2)2–CN, –(CH2)3–CN, –(CH2)4–CN, –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2–CF3, –(CH2)3–CF3, –CH(CH2CH3)C(O)NH–CH2CF3, –CH2C(O)NHCH2–CF3, –CH(CH3)C(O)NHCH2–CF3 or –(CH2)5–F, preferably –(CH2)2–CN, –(CH2)3–CN, –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2–CF3 or –(CH2)3–CF3.

[0115] In some embodiments, such as compounds represented by formulas I, I-1, I-1C, I-1D, I-1E, or I-1F, R 5 are –CH2–CN, –(CH2)2–CN, –(CH2)3–CN, –(CH2)4–CN, –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2 –CF3, –(CH2)3–CF3, –CH(CH2CH3)C(O)NH–CH2CF3, –CH2C(O)NHCH2–CF3, –CH(CH3)C(O)NHCH2–CF3, –(CH2)5–F, –S(O)2(CH2)2–CF3, –C(O)NHCH2–CF3, –S(O)2(CH2)2–CH3, –S(O)2CH2–CH3, –S(O)2(CH2)3–CH3, –S(O)2(CH2)2–CF3, –C(O)OC(CH3)2–CH3、 Preferably, the following are the CF3-C: –CH2–CN, –(CH2)2–CN, –(CH2)3–CN, –(CH2)4–CN, –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2–CF3, –(CH2)3–CF3, –CH(CH2CH3)C(O)NH–CH2CF3, –CH2C(O)NHCH2–CF3, –CH(CH3)C(O)NHCH2–CF3, –(CH2)5–F, –S(O)2(CH2)2–CF3, –S(O)2CH2–CH3, –S(O)2(CH2)3–CH3, –S(O)2(CH2)2–CF3.

[0116] In some embodiments, the compound represented by Formula I has the structure shown in Formula I-3, I-3A, or I-3B:

[0117]

[0118] Among them, X, Y, Ring C, R 6 R 7 R 8 The definitions of z and y are as described in the compound represented by Formula I as defined in any embodiment of the present invention.

[0119] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-4:

[0120]

[0121] Among them, X, Y, Ring C, R 6 R 9 The definitions of z and t are as described in the compound represented by Formula I as defined in any embodiment of this invention.

[0122] In some embodiments, such as the compounds represented by formula I, I-3, I-3A, I-3B or I-4, It is a double bond, and Y is N.

[0123] In some embodiments, such as the compounds represented by formula I, I-3, I-3A, I-3B or I-4, It is a single bond, and Y is NH.

[0124] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, or I-4, the 5–6 membered heteroaromatic ring in the definition of ring C is an imidazole (e.g., ), thiazole (e.g.) ), furans (e.g.) ), thiophene (e.g.) ) or pyridine (e.g. ).

[0125] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-4, I-4A, I-4B, I-4C, or I-4D, R 2 for When the ring C is a benzene ring or an imidazole ring (e.g., ), ), furans (e.g.) ) or pyridine (e.g. ).

[0126] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-4, I-4A, I-4B, I-4C, or I-4D, R 2 for When the ring C is a benzene ring or a thiazole (e.g.) ), furans (e.g.) ) or thiophene (e.g. ).

[0127] In some embodiments, such as the compounds represented by formulas I, I-3, I-3A, I-3B, I-4, I-4A, I-4B, I-4C, or I-4D, for

[0128] In some embodiments, the compound represented by Formula I has a structure as shown in Formulas I-3C, I-3D, I-3E, I-3F, or I-3G:

[0129]

[0130] Among them, X and R 6 R 7 R 8 The definitions of z and y are described in any embodiment of this invention.

[0131] In some embodiments, such as the compounds represented by formulas I, I-3, I-3C, I-3D, I-3E, I-3F, or I-3G, for In some implementation schemes, for In some implementation schemes, for

[0132] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 7 For R 4 R 7 The definition of R is the same as that defined in the compound shown in Formula I of any embodiment of the present invention. 4 same.

[0133] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 8 For R 5 R 8 The definition of R is the same as that defined in the compound shown in Formula I of any embodiment of the present invention. 5 same.

[0134] In some embodiments, such as compounds of formula I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F or I-3G, y is 0.

[0135] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 8 For R 5 –S(O)2R 8a Or –C(O)R 8b , where R 5 The definition of R is the same as that defined in the compound shown in Formula I of any embodiment of the present invention. 5 same.

[0136] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 8 –S(O)2C(R) a R b )–C 1–6 Alkyl, –S(O)2–CF3, –S(O)2C(R) a R b )–R 5f –S(O)2[C(R) a R b )2]–R 5f –S(O)2[C(R) a R b )3]–R 5f –C(R) a R b )–R 5f、–[C(R a R b )2]–R 5f 、–[C(R a R b )3]–R 5f , –C(O)CH=CH2 or –C(O)NHC(R) a R b )–R 5f ;where R 5f The definition of R is the same as that defined in the compound shown in Formula I of any embodiment of the present invention. 5f Same, for example, R 5f It can be either CF3 or CN.

[0137] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 8 –S(O)2C(R) a R b )–CH3, –S(O)2–CF3, –C(O)NHC(R a R b –CF3、–C(O)CH=CH2、 –C(R a R b –CN、–[C(R) a R b )2]–CN or –[C(R a R b )3]–CF3, preferably –S(O)2C(R) a R b –CH3、–S(O)2–CF3、 –[C(R a R b )2]–CN or –[C(R a R b )3]–CF3.

[0138] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, or I-3G, R 8 The possible values ​​are –S(O)2(CH2)2–CH3, –S(O)2–CF3, –C(O)NHCH2–CF3, and –C(O)CH=CH2. –CH2–CN, –(CH2)2–CN, or –(CH2)3–CF3, preferably –S(O)2(CH2)2–CH3 or –S(O)2–CF3. –(CH2)2–CN or –(CH2)3–CF3.

[0139] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-4E, I-4F, I-4J, I-4L, or I-4M:

[0140]

[0141] Among them, X and R 6 R 9 The definitions of z and t are as described in the compound represented by Formula I as defined in any embodiment of this invention.

[0142] In some embodiments, such as compounds represented by formulas I, I-4, I-4E, I-4F, I-4J, I-4L, or I-4M, It can be either cis or trans configuration, such as trans.

[0143] In some embodiments, such as compounds represented by formulas I, I-4, I-4E, I-4F, I-4J, I-4L or I-4M, t is 0.

[0144] In some embodiments, such as compounds represented by formula I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, I-3G, I-4, I-4E, I-4F, I-4J, I-4L or I-4M, X is CH.

[0145] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, I-3G, I-4, I-4E, I-4F, I-4J, I-4L or I-4M, X is N.

[0146] In some embodiments, such as compounds of formula I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, I-3G, I-4, I-4E, I-4F, I-4J, I-4L or I-4M, z is 0, 1 or 2.

[0147] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, I-3G, I-4, I-4E, I-4F, I-4J, I-4L, or I-4M, each R 6 Independently halogen (e.g., fluorine), hydroxyl, amino, cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C1–4 Alkyl groups (e.g., –O–CH3), –S–C 1–4 Alkyl groups (e.g., –S–CH3), –S(O)2–C 1–4 Alkyl (e.g. –S(O)2–CH3) or C 1–4 Hydroxyalkyl groups (e.g., –CH2–OH).

[0148] In some embodiments, such as compounds represented by formulas I, I-3, I-3A, I-3B, I-3C, I-3D, I-3E, I-3F, I-3G, I-4, I-4E, I-4F, I-4J, I-4L, or I-4M, each R 6 It can be fluorine, hydroxyl, amino, cyano, methyl, CF3, –O–CH3, –S–CH3, –S(O)2–CH3 or –CH2–OH independently.

[0149] In some implementations, such as the compounds shown in Formula I-3C, z is 0.

[0150] In some embodiments, such as compounds represented by formula I-3D or I-4F, Independently Where R 6 The definition is as described in the compound represented by Formula I as defined in any embodiment of the present invention, for example C 1–4 Alkyl (e.g., methyl) or C 1–4 Hydroxyalkyl groups (e.g., –CH2–OH). For example, in some embodiments, It can be For example, in some implementation schemes, It can be

[0151] In some embodiments, such as compounds represented by formulas I-3E, I-3G, I-4L, or I-4M, Independently (For example ), (For example ), (For example ), (For example ), (For example ); where each R 6 The definition is independent of compounds of Formula I as defined in any embodiment of the invention, such as halogens (e.g., fluorine), hydroxyl groups, C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C 1–4Alkyl groups (e.g., –O–CH3), –S–C 1–4 Alkyl groups (e.g., –S–CH3) or –S(O)2–C 1–4 Alkyl groups (e.g., –S(O)2–CH3).

[0152] In some embodiments, such as the compounds shown in formula I-3F, for Where R 6 The definition is as described in compounds of Formula I as defined in any embodiment of the present invention, for example, amino.

[0153] In some embodiments, such as the compounds shown in formula I-4E, for Where R 6 The definition is as described in compounds of Formula I as defined in any embodiment of the present invention, such as amino or C 1–4 Alkyl (e.g., methyl). For example, in some embodiments, It can be For example, in some implementation schemes, It can be

[0154] In some embodiments, such as the compounds shown in formula I-4J, for Where R 6 The definition is as described in the compound represented by Formula I as defined in any embodiment of the present invention, for example C 1–4 Alkyl (e.g., methyl). For example, in some embodiments, It can be

[0155] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-5:

[0156]

[0157] Among them, X and R 11 R 12 The definitions of q are as described in the compounds represented by Formula I as defined in any embodiment of this invention.

[0158] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-6:

[0159]

[0160] Among them, X and R 11 R 12 The definitions of q are as described in the compounds represented by Formula I as defined in any embodiment of this invention.

[0161] In some embodiments, such as the compounds shown in formula I-5 or I-6, R 12 Independently for –C(R) e R f –CN、–[C(R) e R f )2]–CN or –[C(R e R f )3]–CN, for example –CH2–CN, –(CH2)2–CN, –(CH2)3–CN or

[0162] In some embodiments, such as the compounds shown in Formula I-5, R 12 Preferably –[C(R) e R f )3]–CN, for example –(CH2)3–CN.

[0163] In some embodiments, such as the compounds shown in Formula I-6, R 12 Preferably –CH2–CN or

[0164] In some embodiments, the compound represented by Formula I has the structure shown in Formulas I-7:

[0165]

[0166] Among them, X, Y, Ring D, Ring E, R 10 R 11 R 12 The definitions of p and q are as described in the compound represented by Formula I as defined in any embodiment of this invention.

[0167] In some embodiments, the compounds represented by formula I or I-7, It is a double bond, and Y is N.

[0168] In some embodiments, the compounds represented by formula I or I-7, It is a single bond, and Y is NH.

[0169] In some embodiments, in the compounds represented by Formula I or I-7, the 5–6 membered heteroaromatic ring in the definition of ring D is a furan (e.g., ) or thiophene (e.g. );

[0170] In some embodiments, in the compounds represented by Formula I or I-7, ring D is cyclopropyl, cyclobutyl, benzene ring, or...

[0171] In some embodiments, the compounds represented by formula I or I-7, Independently

[0172] In some embodiments, the compound represented by Formula I has a structure as shown in Formulas I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F:

[0173]

[0174] Among them, X and R 10 R 11 R 12 The definitions of p and q are as described in any embodiment of the present invention.

[0175] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, R 12 Cyanoyl, –C(R) e R f )–R 12f 、–[C(R e R f )2]–R 12f 、–[C(R e R f )3]–R 12f or

[0176] In some embodiments, such as compounds of formula I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E or I-7F, v is 0.

[0177] In some embodiments, such as the compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, for For example

[0178] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, R 14a C substituted with cyano 1–4 Alkyl groups, such as –CH2CN.

[0179] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, R 12 For –CN, –C(R) e R f –CN、–[C(R) e R f )2]–CN、–[C(R e R f )3]–CN or

[0180] In some embodiments, such as the compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, each R e Independently H or C 1–3 alkyl.

[0181] In some embodiments, such as the compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, each R f Independently H or C 1–3 alkyl.

[0182] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, or I-7F, R 12 is –CN, –CH2–CN, –(CH2)2–CN, –(CH2)3–CN, Preferred are –CH2–CN, –(CH2)2–CN, and –(CH2)3–CN, with –(CH2)2–CN being even more preferred.

[0183] In some embodiments, such as compounds represented by formula I-7A, I-7B or I-7C, R 12 It is a cyano group.

[0184] In some embodiments, such as compounds represented by formula I-7E or I-7F, R 12 For –C(R) e R f )–R 12f 、–[C(R e R f )2]–R 12f 、–[C(R e R f )3]–R 12f or Preferred – C(R) eR f )–R 12f 、–[C(R e R f )2]–R 12f Or – [C(R e R f )3]–R 12f Further optimization – [C(R)] e R f )2]–R 12f .

[0185] In some embodiments, the compounds represented by formula I, I-7E, or I-7F have structures represented by formula I-7G or I-7H:

[0186]

[0187] Among them, X and R 10 R 11 R 14b The definitions of p and q are as described in any embodiment of the present invention.

[0188] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G, or I-7H, R 14b For R 5 R 14b The definition of R is the same as that defined in the compound shown in Formula I of any embodiment of the present invention. 5 same.

[0189] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G, or I-7H, R 14b –S(O)2–C 1–4 Alkyl groups, such as –S(O)2–CH2CH3, –S(O)2–CH2CH2CH3 or –S(O)2–CH2CH2CH2CH3.

[0190] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G or I-7H, X is N.

[0191] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G or I-7H, X is CH.

[0192] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G or I-7H, q is 0.

[0193] In some embodiments, such as compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G or I-7H, p is 0, 1 or 2.

[0194] In some embodiments, such as the compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G, or I-7H, each R 10 Independently halogen (e.g., fluorine or chlorine), hydroxyl, amino, cyano, C 1–4 Alkyl (e.g., methyl), C 1–4 Haloalkyl (e.g., C10) 1–4 Fluorinated alkyl groups, such as CF3), –O–C 1–4 Alkyl groups (e.g., –O–CH3), –S(O)2–C 1–4 Alkyl (e.g. –S(O)2–CH3), or C 1–4 Hydroxyalkyl groups (e.g., –CH2–OH).

[0195] In some embodiments, such as the compounds represented by formulas I, I-5, I-6, I-7, I-7A, I-7B, I-7C, I-7D, I-7E, I-7F, I-7G, or I-7H, each R 10 It can be fluorine, chlorine, hydroxyl, methyl, –S(O)2–CH3 or –CH2–OH independently.

[0196] In some embodiments, such as compounds represented by formula I-7A, I-7F or I-7H, Independently Each R 10 The definition is as described in any embodiment of the present invention, for example, C. 1–4 Alkyl (e.g., methyl) or C 1–4 Hydroxyalkyl groups (e.g., –CH2OH). For example, in some embodiments, It can be For example, in some implementation schemes, It can be

[0197] In some embodiments, such as compounds represented by formula I-7E or I-7G, Independently Each R10 The definition is as described in any embodiment of the present invention, for example, C. 1–4 Alkyl (e.g., methyl).

[0198] In some embodiments, such as the compounds represented by formula I-7B, I-7C or I-7D, for (For example ), (For example )or (For example ), where each R 10 The definition is as described in any embodiment of the invention, for example, hydroxyl, halogen (e.g., fluorine or chlorine) or –S(O)2–C 1–4 Alkyl groups (e.g., –S(O)2–CH3).

[0199] In some embodiments, the compound structure shown in Formula I is as follows:

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] On the other hand, the present invention also provides a method for preparing a compound as shown in Formula I, comprising the following steps: reacting a compound as shown in Formula II with a base (e.g., sodium hydroxide) in an organic solvent (e.g., a mixed solvent of tetrahydrofuran and methanol) to obtain the compound as shown in Formula I;

[0216]

[0217] Among them, X, Y, R 1 and R 2 The definition is as described in any embodiment of this invention.

[0218] On the other hand, the present invention also provides a compound as shown in Formula II:

[0219]

[0220] Among them, X, Y, R 1 and R 2 The definition is as described in any embodiment of this invention.

[0221] On the other hand, the present invention also provides a pharmaceutical composition comprising...

[0222] (i) the compound of formula I, or its tautomers, stereoisomers, racemates or isotopic derivatives, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing; and

[0223] (ii) Pharmaceutically acceptable carriers.

[0224] On the other hand, the present invention also provides the use of the compound represented by Formula I, or its tautomer, stereoisomer, racemate or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition thereof, as a medicine.

[0225] On the other hand, the present invention also provides the use of the compound represented by Formula I, or its tautomer, stereoisomer, racemate or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition thereof as an inhibitor of Janus kinases (e.g., JAK1 and / or JAK2).

[0226] On the other hand, the present invention also provides a method for inhibiting Janus kinases (e.g., JAK1 and / or JAK2) in vivo, in vitro, or ex vivo, comprising contacting the compound of Formula I, or a tautomer, stereoisomer, racemic or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or the pharmaceutical composition thereof, with the Janus kinase.

[0227] On the other hand, the present invention also provides the use of the compound represented by Formula I, or a tautomer, stereoisomer, racemate or isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, or a crystal form or solvate thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating diseases associated with Janus kinases (e.g., JAK1 and / or JAK2).

[0228] On the other hand, the present invention also provides the use of the compound represented by Formula I, or its tautomer, stereoisomer, racemate or isotopic derivative, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition thereof in the preparation of a medicament for treating autoimmune diseases or cancer.

[0229] On the other hand, the present invention also provides a method for treating diseases associated with Janus kinases (e.g., JAK1 and / or JAK2), comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound of Formula I, or a tautomer, stereoisomer, racemate or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition thereof.

[0230] On the other hand, the present invention also provides a method for treating autoimmune diseases or cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound represented by Formula I, or a tautomer, stereoisomer, racemate or isotopic derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a crystal form or solvate of any of the foregoing, or the pharmaceutical composition thereof.

[0231] The diseases associated with Janus kinases (e.g., JAK1 and / or JAK2) described in this invention can be autoimmune diseases or cancer.

[0232] The autoimmune diseases or Janus kinase-related autoimmune diseases described in this invention can be, for example, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, or systemic lupus erythematosus.

[0233] The cancers or cancers related to Janus kinase described in this invention can be, for example, Kaposi's sarcoma, giant lymphadenopathy, lymphoma, leukemia, multiple myeloma, or myeloproliferative disorders. The myeloproliferative disorders can be, for example, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic monocytic leukemia (CMML), eosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

[0234] Unless otherwise stated, the terminology used in this invention has the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art.

[0235] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of a single atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can interconvert through the rapid movement of hydrogen atoms to the oxygen and α-carbon.

[0236] The term "stereoisomer" refers to isomers in a molecule that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements. Examples include cis-trans isomers (e.g., Z-isomers, E-isomers), optical isomers (e.g., enantiomers, diastereomers), and trans-isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. Optical isomers include enantiomers and diastereomers. All of these isomers and mixtures thereof are included within the scope of this invention.

[0237] The term "isotope derivative" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine). 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 18 F, 35 S and 36 Cl). Isotopic compounds can typically be prepared according to the methods described herein by replacing non-isotopic labeled reagents with isotopically labeled reagents. Typical examples of isotopic derivatives include deuterated compounds.

[0238] The term "pharmaceutically acceptable salt" refers to a salt prepared by reacting a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentic acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When a compound contains functional groups with relatively acidic and relatively basic properties, it can be converted into a base addition salt or an acid addition salt. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0239] In some embodiments, a pharmaceutically acceptable salt of a compound of formula (I) described in this invention may be an acid addition salt formed by a compound of formula (I) and a pharmaceutically acceptable acid, including but not limited to: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and ferulic acid. The pharmaceutically acceptable salt of the compound of formula (I) may be prepared by reacting it with an equisical or excess acid (inorganic or organic) in a suitable solvent or solvent mixture. The acid includes, but is not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid. The solvent includes, but is not limited to, methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene, or tetrahydrofuran, or any mixture of several solvents.

[0240] The term "crystal form" refers to the strict periodic arrangement of ions or molecules in three-dimensional space in a defined manner, with a regular repetition pattern at certain intervals. Due to the different periodic arrangements, multiple crystal forms can exist, which is the phenomenon of polymorphism.

[0241] The term "solvate" refers to a substance formed by the combination of molecules with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents mentioned include, but are not limited to, water, methanol, and ethanol.

[0242] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, with fluorine or chlorine being preferred.

[0243] The term "amino" refers to the –NH2 group.

[0244] The term "hydroxyl group" refers to the –OH group.

[0245] The term "cyano" refers to the –CN group.

[0246] The term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group having a certain number of carbon atoms. C 1–4 Alkyl refers to an alkyl group having 1–4 carbon atoms, including C1 alkyl, C2 alkyl, C3 alkyl, and C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.

[0247] The term “halogenated alkyl” refers to an alkyl group substituted with one or more (e.g., 1, 2, 3 or 4) halogens (e.g., fluorine, chlorine, bromine or iodine, preferably fluorine), including but not limited to –CHF2, –CH2F, –CF3, –CHF–CH2Cl.

[0248] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more (e.g., 1, 2, 3, or 4) hydroxyl groups, including but not limited to –CH2OH, –CHOH–CH2OH. 1–4 Hydroxyalkyl groups include, but are not limited to, –CH2OH, –CHOH–CH2OH, and –CH(CH2OH)–CH2OH.

[0249] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having a certain number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group (e.g., C2–C6 alkenyl refers to alkenyl groups having 2–6 carbon atoms, including C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, and hexadienyl.

[0250] The term "alkoxy" refers to –O–R X , where R X It is an alkyl group as defined above. In some embodiments, C 1–4 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0251] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) hydrocarbon group formed from carbon atoms. In some embodiments, the cycloalkyl group is a monocyclic group. In some embodiments, C... 3–6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, C 3–8 Cycloalkyl groups can be C 3–6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0252] The term "heteroaryl" or "heteroary ring" refers to an aromatic cyclic group formed by a carbon atom and at least one heteroatom, wherein the heteroatom can be N, O, or S. Examples of five-membered heteroaryl or heteroary rings include furan, thiophene, pyrrole, pyrazole, oxazole, thiazole, imidazole, or triazole. Examples of six-membered heteroaryl or heteroary rings include pyrazine, pyridazine, pyridine, or pyrimidine.

[0253] In this article, the "x–y" in cyclic groups refers to the number of atoms in the ring being x–y. For example, cyclopropyl is 3-membered, tetrahydropyrrolyl is 5-membered, and piperidinyl is 6-membered.

[0254] The term "substitution" or "substituent" refers to the replacement of one or more hydrogen atoms by a specified group. When the substitution position is not specified, substitution can occur at any position, but it is only permitted if a stable or chemically viable chemical is formed.

[0255] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or variables are only permitted if such combinations produce stable compounds. For example, In this case, w is 0, 1, or 2, and each R is independently methyl or fluorine. include wait.

[0256] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0257] The term "therapeutic effective amount" refers to the amount of a compound sufficient to effectively treat or prevent the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art. Generally, when the compounds of the present invention are used for treatment, the human dosage range is 1-1000 mg / day. Dosages exceeding this range may also be used depending on the dosage form and the severity of the disease.

[0258] Depending on the therapeutic purpose, the pharmaceutical composition can be formulated into various types of dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, and injections (solutions or suspensions), with tablets, capsules, liquids, suspensions, and injections (solutions or suspensions) being preferred.

[0259] The compounds described in this invention can be administered clinically via oral administration, injection, or other methods.

[0260] The term "subject" refers to any animal that is about to receive or has already received a compound or composition, preferably a mammal, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0261] All patents and publications mentioned in this article are incorporated herein by reference in their entirety.

[0262] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0263] The reagents and raw materials used in this invention are all commercially available.

[0264] The positive and progressive effects of this invention are as follows: This invention provides a novel pyridine-cyclic compound with good JAK inhibitory activity. Detailed Implementation

[0265] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention. They should not be construed as limiting the present invention.

[0266] Synthesis of key intermediate 1:

[0267]

[0268] Step 1: 4-Chloro-7-azaindole (25.0 g, 163.8 mmol) was dissolved in 250 mL of dichloromethane. DMAP (2.0 g, 16.5 mmol) and triethylamine (34.0 mL, 245.8 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Benzenesulfonyl chloride (23.3 mL, 180.3 mmol) was dissolved in 50 mL of dichloromethane and slowly added dropwise to the above reaction solution. After stirring at room temperature for approximately 4 hours, the mixture was filtered, and the filtrate was collected and concentrated under vacuum to obtain a brown solid. The solid was then slurried with an appropriate amount of methanol to obtain 4-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine as a grayish-white solid (43.0 g, 90%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 13 H 10 The calculated value of ClN2O2S is 293.0146, and the measured value is 293.0139.

[0269] Step 2: 30.0 g (102.7 mmol) of 4-chloro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 300 mL of dichloromethane. Tetramethylammonium nitrate (28.0 g, 205.5 mmol) was added to the solution at 25 °C with stirring. Trifluoroacetic anhydride (57.3 mL, 410.8 mmol) was slowly added dropwise while maintaining the reaction solution temperature below 30 °C. After the addition was complete, the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow solid. Slurrying with an appropriate amount of methanol yielded 4-chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine as a pale yellow solid (25.9 g, 75%). This product could be used directly for the next step without further purification. 1 HNMR (300MHz, DMSO-d6): δ = 9.09 (s, 1H), 8.29 (d, J = 3.0Hz, 1H), 8.17 (t, J = 4.5Hz, 2H), 7.7 9(t,J=7.5Hz,1H),7.68(t,J=7.5Hz,2H),7.11(d,J=3.0Hz,1H)ppm; HRMS(ESI):m / z[M+Na] + .C 13 The calculated value of H8ClN3NaO4S is 359.9816, and the measured value is 359.9801.

[0270] Step 3: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 29.7 mmol) was dissolved in 100 mL of tetrahydrofuran. DIPEA (7.7 g, 59.3 mmol) and 1-Boc-3-aminopyrrolidine (8.3 g, 44.5 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The solution was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain tert-butyl 3-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid as a yellow solid (10.1 g, 70%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 26 The calculated value of N5O6S is 488.1598, and the measured value is 488.1607.

[0271] Step 4: 10.0 g (20.5 mmol) of 3-(((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 100 mL of methanol. Palladium on carbon (1 g, 10%) was added, and the air in the reaction flask was purged with hydrogen at least three times. The reaction was then carried out under a hydrogen atmosphere with stirring at room temperature for 12 hours. TLC was used to monitor the reaction until complete. After filtration, the filtrate was collected and concentrated under vacuum to obtain 9.2 g (98%) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester as a light pink, foamy solid. This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 28 The calculated value of N5O4S is 458.1857, and the measured value is 458.1862.

[0272] Step 5: Triethyloxonium tetrafluoroboric acid (11.2 g, 59.1 mmol) and (R)-lactamide (5.3 g, 59.1 mmol) were dissolved in 100 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 100 mL of ethanol was added to dissolve the oil, and 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (9.0 g, 19.7 mmol) was added. The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution became weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid as a light green oil (6.0 g, 60%). HRMS(ESI): m / z [M+H] + .C 25 H 30 The calculated value of N5O5S is 512.1962, and the measured value is 512.1983.

[0273] Step 6: 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.0 g, 11.7 mmol) was dissolved in 60 mL of dichloromethane. Trifluoroacetic acid (13.4 g, 117.4 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-1:(1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a light brown oil (4.8 g, 100%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z[M+H] + .C 20 H 22 The calculated value of N5O3S is 412.1438, and the measured value is 412.1448.

[0274] Synthesis of key intermediate 2:

[0275]

[0276] Step 1: At 0°C, a solution of 2-diethoxyphosphorylacetonitrile (5.7 g, 32.1 mmol) in THF (50 mL) was added to a solution of NaH (1.2 g, 30.7 mmol) in THF (50 mL). The mixture was stirred at room temperature for 1 hour, then cooled again to 0°C, and a solution of 3-oxazacyclobutane-1-carboxylic acid tert-butyl ester (5.0 g, 29.2 mmol) in THF (50 mL) was added over 1 hour. The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was complete, an appropriate amount of water was added, and the aqueous phase was extracted twice with EA. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to give 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester as a yellow solid (5.2 g, 78%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 10 H 15 The calculated value of N2O2 is 195.1128, and the measured value is 195.1121.

[0277] Step 2: DBU (11.8 g, 77.4 mmol) was added to a solution of 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (5.0 g, 25.8 mmol) and 4-nitropyrazole (3.2 g, 28.7 mmol) in acetonitrile (30 mL). The mixture was then stirred at room temperature for 16 hours. After the reaction was complete, an appropriate amount of water was added, and the aqueous phase was extracted twice with EA. The organic layers were combined and washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 4:1) to give 3-(cyanomethyl)-3-(4-nitro-1H-pyrazole-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester as a white oil (4.0 g, 50%). HRMS (ESI): m / z [M+H] + .C 13 H 18 The calculated value of N5O4 is 308.1353, and the measured value is 308.1346.

[0278] Step 3: 4.0 g (13.0 mmol) of 3-(cyanomethyl)-3-(4-nitro-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester was dissolved in 50 mL of methanol. Palladium on carbon (0.4 g, 10%) was added, and the air in the reaction flask was purged with hydrogen at least three times. The reaction was then carried out under a hydrogen atmosphere with stirring at room temperature for 12 hours. TLC was used to monitor the reaction until complete. After filtration, the filtrate was collected and concentrated under vacuum to obtain 3-(4-amino-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester as a light brown, foamy solid (3.5 g, 98%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 13 H 20 The calculated value of N5O2 is 278.1612, and the measured value is 278.1610.

[0279] Step 4: Dissolve 3.5 g (10.5 mmol) of 4-chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine in 100 mL of tetrahydrofuran, add DIPEA (4.1 g, 31.5 mmol) and 3-(4-amino-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid tert-butyl ester (3.5 g, 12.6 mmol), and heat to reflux with stirring for 4 hours. The reaction was monitored by TLC until complete. The solution was concentrated under vacuum to obtain a yellow oily liquid. The product was slurryed and solidified with an appropriate amount of methanol to obtain tert-butyl 3-(cyanomethyl)-3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester as a yellow solid (4.3 g, 70%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 27 The calculated value of N8O6S is 579.1769, and the measured value is 579.1782.

[0280] Step 5: Dissolve tert-butyl 3-(cyanomethyl)-3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester (4.3 g, 7.4 mmol) in 50 mL of methanol, add palladium on carbon (0.4 g, 10%), and then purge the air in the reaction flask with hydrogen more than three times. The reaction is then carried out under a hydrogen atmosphere and stirred at room temperature for 12 hours. The reaction is monitored by TLC until it is complete. After filtration, the filtrate was collected and concentrated under vacuum to obtain tert-butyl 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid ester as a light brown, foamy solid (4.0 g, 98%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + Calculated value C 26 H 29 N8O4S 549.2027, measured value 549.2043.

[0281] Step 6: 4.0 g (7.3 mmol) of tert-butyl 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid ester was dissolved in 50 mL of DMF. Na₂S₂O₅ (6.9 g, 36.5 mmol) and 5-hydroxymethylfurfural (1.8 g, 14.6 mmol) were added, and the mixture was heated to 90 °C and stirred for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give 3-(cyanomethyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester as a yellow solid (3.3 g, 69%). HRMS (ESI): m / z [M+H] + .C 32 H 31 The calculated value of N8O6S is 655.2082, and the measured value is 655.2063.

[0282] Step 7: Dissolve 3-(cyanomethyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-bpyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester (3.0 g, 4.6 mmol) in 60 mL of dichloromethane, and slowly add trifluoroacetic acid (5.2 g). After stirring at room temperature for 12 hours (46.0 mmol), the mixture was concentrated under vacuum to give intermediate-2: 2-(3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a pale yellow oil (2.3 g, 91%). This product can be used directly for the next step without further purification. HRMS(ESI): m / z [M+H] + .C 27 H 23 The calculated value of N8O4S is 555.1557, and the measured value is 555.1555.

[0283] Synthesis of key intermediates 3 and 4:

[0284]

[0285] Step 1: 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-carboxylic acid tert-butyl ester (3.0 g, 6.6 mmol) was dissolved in 50 mL of DMF. Na₂S₂O₅ (6.2 g, 32.8 mmol) and 5-hydroxymethylfurfural (1.7 g, 13.2 mmol) were added, and the mixture was heated to 90 °C and stirred for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the ester was separated. Organic phase. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-pyrrolidine-1-carboxylic acid ester as a yellow solid (2.4 g, 65%). HRMS (ESI): m / z [M+H] + .C 28 H 30 The calculated value of N5O6S is 564.1911, and the measured value is 564.1921.

[0286] Step 2: 2.0 g (3.6 mmol) of tert-butyl 3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-ylpyrrolidine-1-carboxylic acid ester was dissolved in 50 mL of dichloromethane. Trifluoroacetic acid (4.1 g, 36.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate -3:(5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol as a pale yellow oil (1.5 g, 91%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 22 The calculated value of N5O4S is 464.1387, and the measured value is 464.1385.

[0287] Step 3: 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-carboxylic acid tert-butyl ester (3.0 g, 6.6 mmol) was dissolved in 50 mL of DMF. Na₂S₂O₅ (6.2 g, 32.8 mmol) and 2-imidazolium carboxaldehyde (1.3 g, 13.2 mmol) were added, and the mixture was heated to 90 °C and stirred for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the mixture was separated. The organic phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester as a yellow solid (2.2 g, 63%). HRMS (ESI): m / z [M+H] + Calculated value C 26 H 28 N7O4S 534.1918, measured value 534.1910.

[0288] Step 4: 2.0 g (3.8 mmol) of tert-butyl 3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester was dissolved in 50 mL of dichloromethane. Trifluoroacetic acid (4.3 g, 38.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-4: 2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine as a pale yellow oil (1.2 g, 74%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z[M+H] + .C 21 H 20 N7O2S 434.1394, measured value 434.1390.

[0289] Synthesis of key intermediates 5, 6, 7 and 8:

[0290]

[0291] Step 1: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.0 g, 14.8 mmol) was dissolved in 50 mL of tetrahydrofuran. DIPEA (3.8 g, 29.7 mmol) and (R)-(+)-1-Boc-3-aminopyrrolidine (4.1 g, 22.3 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid(R)-tert-butyl ester as a yellow solid (4.8 g, 66%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 22 H 26 The calculated value of N5O6S is 488.1598, and the measured value is 488.1605.

[0292] Step 2: 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid(R)-tert-butyl ester (4.8 g, 9.9 mmol) was dissolved in 50 mL of methanol. Palladium on carbon (0.5 g, 10%) was added, and the air in the reaction flask was purged with hydrogen at least three times. The reaction was then carried out under a hydrogen atmosphere with stirring at room temperature for 12 hours. TLC was used to monitor the reaction until complete. After filtration, the filtrate was collected and concentrated under vacuum to obtain (R)-3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid-tert-butyl ester as a light pink, foamy solid (4.2 g, 93%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 28 The calculated value of N5O4S is 458.1857, and the measured value is 458.1850.

[0293] Step 3: Triethyloxonium tetrafluoroboric acid (5.0 g, 26.3 mmol) and (R)-lactamide (2.3 g, 26.3 mmol) were dissolved in 80 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 80 mL of ethanol was added to dissolve the oil, followed by the addition of (R)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (4.0 g, 8.8 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated... The reaction solution was prepared with sodium bicarbonate until it became weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give (R)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester as a light green oil (3.2 g, 72%). HRMS (ESI): m / z [M+H] + .C 25 H 30 The calculated value of N5O5S is 512.1962, and the measured value is 512.1974.

[0294] Step 4: (R)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester (3.0 g, 5.9 mmol) was dissolved in 50 mL of dichloromethane. Trifluoroacetic acid (6.7 g, 58.6 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-5: (R)-1-(6-(benzenesulfonyl)-1-((R-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-yl)ethanol as a light brown oil (2.2 g, 91%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 20 H 22 The calculated value of N5O3S is 412.1438, and the measured value is 412.1433.

[0295] Step 5: 4-Chloro-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.0 g, 23.7 mmol) was dissolved in 80 mL of tetrahydrofuran. DIPEA (6.1 g, 47.5 mmol) and (S)-(-)-1-Boc-3-aminopyrrolidine (6.6 g, 35.6 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid (S)-tert-butyl ester as a yellow solid (8.1 g, 70%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 26 The calculated value of N5O6S is 488.1598, and the measured value is 488.1603.

[0296] Step 6: Dissolve 8.0 g (16.4 mmol) of 3-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid (S)-tert-butyl ester in 80 mL of methanol. Add palladium on carbon (0.8 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain (S)-3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester as a light pink foamy solid (7.4 g, 99%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 28 The calculated value of N5O4S is 458.1857, and the measured value is 458.1850.

[0297] Step 7: Triethyloxonium tetrafluoroboric acid (8.7 g, 46.0 mmol) and (R)-lactamide (4.1 g, 46.0 mmol) were dissolved in 100 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 100 mL of ethanol was added to dissolve the oil, followed by the addition of (S)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 15.3 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution became weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give (S)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester as a light green oil (5.3 g, 68%). HRMS (ESI): m / z [M+H] + .C 25 H 30 The calculated value of N5O5S is 512.1962, and the measured value is 512.1969.

[0298] Step 8: (S)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester (5.0 g, 9.8 mmol) was dissolved in 50 mL of dichloromethane. Trifluoroacetic acid (11.2 g, 97.8 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate -6:(R)-1-(6-(benzenesulfonyl)-1-((S-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-yl)ethanol as a light brown oil (3.8 g, 94%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 20 H 22 The calculated value of N5O3S is 412.1438, and the measured value is 412.1433.

[0299] Step 9: Dissolve (R)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-carboxylic acid tert-butyl ester (3.0 g, 6.6 mmol) in 50 mL of DMF, add Na2S2O5 (6.2 g, 32.8 mmol) and 5-hydroxymethylfurfural (1.7 g, 13.2 mmol), and heat to 90 °C with stirring for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the resulting product was separated. The organic phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give (R)-tert-butyl-3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester as a yellow solid (2.0 g, 54%). HRMS (ESI): m / z [M+H] + .C 28 H 30 The calculated value of N5O6S is 564.1911, and the measured value is 564.1922.

[0300] Step 10: (R)-tert-butyl 3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester (2.0 g, 3.6 mmol) was dissolved in 30 mL of dichloromethane. Trifluoroacetic acid (4.1 g, 36.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-7: (R)-(5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-ylmethanol as a pale yellow oil (1.6 g, 97%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 23 H 22 The calculated value of N5O4S is 464.1387, and the measured value is 464.1380.

[0301] Step 11: Dissolve (R)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 6.6 mmol) in 50 mL of DMF, add Na2S2O5 (6.2 g, 32.8 mmol) and 2-imidazolium carboxaldehyde (1.3 g, 13.2 mmol), and heat to 90 °C with stirring for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the reaction mixture was separated. The organic phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give (R)-tert-butyl 3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester as a yellow solid (2.5 g, 71%). HRMS (ESI): m / z [M+H] + .C 26 H 28 The calculated value of N7O4S is 534.1918, and the measured value is 534.1910.

[0302] Step 12: (R)-tert-butyl 3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester (2.5 g, 4.7 mmol) was dissolved in 30 mL of dichloromethane. Trifluoroacetic acid (5.3 g, 46.9 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-8: (R)-2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine as a pale yellow oil (1.7 g, 84%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 21 H 20 The calculated value of N7O2S is 434.1394, and the measured value is 434.1390.

[0303] Synthesis of key intermediate 9:

[0304]

[0305] Step 1: 10.0 g (41.1 mmol) of 4-(tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid was dissolved in 100 mL of tetrahydrofuran and cooled to -15 °C. Isobutyl chloroformate (11.3 g, 82.2 mmol) was added at low temperature, and the mixture was stirred at this temperature for 1 hour. Then, 100 mL of ammonia was slowly added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was filtered to obtain tert-butyl (4-carbamoylcyclohexyl)carbamate as a white solid (8.0 g, 80%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 12 H 23 The calculated value of N2O3 is 243.1703, and the measured value is 243.1698.

[0306] Step 2: Dissolve tert-butyl (4-carbamoylcyclohexyl)carbamate (8.0 g, 33.1 mmol) in 50 mL of pyridine and cool to -15 °C. Slowly add phosphorus oxychloride (10 g, 66.2 mmol) dropwise at low temperature. After the addition is complete, maintain the temperature and stir for 3 hours. After the reaction is complete, slowly pour the reaction solution into 200 mL of ice-water mixture. Extract the aqueous phase three times using EA. Combine the organic phases and wash with saturated brine. Dry under anhydrous sodium sulfate and concentrate under vacuum to obtain tert-butyl (4-cyanocyclohexyl)carbamate as a milky white solid (5.5 g, 74%). HRMS (ESI): m / z [M+H] + .C 12 H 21 The calculated value of N2O2 is 225.1598, and the measured value is 225.1603.

[0307] Step 3: Step 12: Dissolve tert-butyl (4-cyanocyclohexyl)carbamate (5.5 g, 24.6 mmol) in 50 mL of dichloromethane, slowly add trifluoroacetic acid (28.0 g, 245.5 mmol), stir at room temperature for 12 hours, and concentrate under vacuum to obtain trans-4-aminocyclohexanecarboxynitrile as a light white solid (2.5 g, 82%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C7H 13 The calculated value of N2 is 125.1073, and the measured value is 125.1082.

[0308] Step 4: 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.5 g, 13.4 mmol) was dissolved in 50 mL of tetrahydrofuran. DIPEA (3.5 g, 26.9 mmol) and trans-4-aminocyclohexanecarboxylonitrile (2.5 g, 20.2 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The solution was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain trans-4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile as a yellow solid (4.2 g, 74%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 20 H 20 The calculated value of N5O4S is 426.1231, and the measured value is 426.1237.

[0309] Step 5: Dissolve trans-4-((5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (4.2 g, 9.9 mmol) in 50 mL of methanol. Add palladium on carbon (0.4 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain intermediate-9: trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile as a light brown foamy solid (3.5 g, 90%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 20 H 22 The calculated value of N5O2S is 396.1489, and the measured value is 396.1492.

[0310] Synthesis of key intermediates 10 and 11:

[0311]

[0312] Step 1: Dissolve 4-nitropyrazole (5 g, 44.2 mmol) in 50 mL of DMF, add potassium carbonate (12.2 g, 88.4 mmol) and 3-bromopropionitrile (8.9 g, 66.3 mmol), and stir at room temperature for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase three times with dichloromethane. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, and concentrate under vacuum to obtain 3-(4-nitro-1H-pyrazole-1-yl)propionitrile as a pale yellow solid (4.8 g, 65%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + The calculated value of C6H7N4O2 is 167.0564, and the measured value is 167.0569.

[0313] Step 2: Dissolve 4.8 g (28.9 mmol) of 3-(4-nitro-1H-pyrazol-1-yl)propionitrile in 50 mL of methanol. Add palladium on carbon (0.5 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain 3-(4-amino-1H-pyrazol-1-yl)propionitrile as a light brown, foamy solid (3.5 g, 89%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + The calculated value of C6H9N4 is 137.0822, and the measured value is 137.0833.

[0314] Step 3: 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.8 g, 17.2 mmol) was dissolved in 60 mL of tetrahydrofuran. DIPEA (4.4 g, 34.4 mmol) and 3-(4-amino-1H-pyrazol-1-yl)propionitrile (3.5 g, 25.7 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The solution was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain 3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile as a yellow solid (5.1 g, 68%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 19 H 16 The calculated value of N7O4S is 438.0979, and the measured value is 438.0985.

[0315] Step 4: Dissolve 5.0 g (11.4 mmol) of 3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile in 50 mL of methanol. Add palladium on carbon (0.5 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain intermediate-10: 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile as a pale yellow, foamy solid (4.5 g, 97%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 19 H 18 The calculated value of N7O2S is 408.1237, and the measured value is 408.1241.

[0316] Step 5: Dissolve 4-nitropyrazole (2.5 g, 22.1 mmol) in 50 mL of DMF, add potassium carbonate (6.1 g, 44.2 mmol) and 2-bromoacetonitrile (4.0 g, 33.2 mmol), and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase three times with dichloromethane. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate under vacuum to obtain 3-(4-nitro-1H-pyrazole-1-yl)acetonitrile as a pale yellow solid (2.2 g, 65%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + The calculated value of C5H5N4O2 is 153.0407, and the measured value is 153.0411.

[0317] Step 6: Dissolve 2.2 g (14.5 mmol) of 3-(4-nitro-1H-pyrazol-1-yl)acetonitrile in 30 mL of methanol. Add palladium on carbon (0.3 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain 1.6 g (91%) of 3-(4-amino-1H-pyrazol-1-yl)acetonitrile as a light brown, foamy solid. This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + The calculated value of C5H7N4 is 123.0665, and the measured value is 123.0671.

[0318] Step 7: 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.8 g, 8.2 mmol) was dissolved in 60 mL of tetrahydrofuran. DIPEA (2.1 g, 16.4 mmol) and 3-(4-amino-1H-pyrazole-1-yl)acetonitrile (1.5 g, 12.3 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The solution was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain 3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazole-1-yl)acetonitrile as a yellow solid (2.5 g, 72%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 18 H 14 The calculated value of N7O4S is 424.0822, and the measured value is 424.0833.

[0319] Step 8: Dissolve 2.5 g (5.9 mmol) of 3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)acetonitrile in 30 mL of methanol. Add palladium on carbon (0.3 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain intermediate-11: 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)acetonitrile as a pale yellow, foamy solid (2.0 g, 86%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 18 H 16 The calculated value of N7O2S is 394.1081, and the measured value is 394.1084.

[0320] Synthesis of key intermediate 12:

[0321]

[0322] Step 1: 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.0 g, 5.9 mmol) was dissolved in 50 mL of toluene. Under nitrogen protection, tris(dibenzylacetone)dipalladium (0.2 g, 10%), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (0.2 g, 10%), and p-cyanoaniline (1.4 g, 11.9 mmol) were added. The mixture was heated to reflux and stirred for 5 hours under nitrogen protection. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 2:1) to give 4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile as a yellow solid (1.2 g, 48%). HRMS (ESI): m / z [M+H] + .C 20 H 14 The calculated value of N5O4S is 420.0761, and the measured value is 420.0771.

[0323] Step 2: 4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile (1.2 g, 2.9 mmol) was dissolved in 30 mL of methanol. Palladium on carbon (0.2 g, 10%) was added, and the air in the reaction flask was purged with hydrogen at least three times. The reaction was then carried out under a hydrogen atmosphere with stirring at room temperature for 12 hours. TLC was used to monitor the reaction until complete. After filtration, the filtrate was collected and concentrated under vacuum to obtain intermediate-12: 4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile as a yellow, foamy solid (1.1 g, 99%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 20 H 16 The calculated value of N5O2S is 390.1019, and the measured value is 390.1023.

[0324] Synthesis of key intermediate 13:

[0325]

[0326] Step 1: 4-Chloro-1H-pyrazolo[3,4-b]pyridine (10.0 g, 65.4 mmol) was dissolved in 100 mL of dichloromethane. DMAP (0.8 g, 6.5 mmol) and triethylamine (18.0 mL, 130.7 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Benzenesulfonyl chloride (10.1 mL, 78.5 mmol) was dissolved in 50 mL of dichloromethane and slowly added dropwise to the above reaction solution. After stirring at room temperature for approximately 4 hours, the mixture was filtered, and the filtrate was collected and concentrated under vacuum to obtain a brown solid. The solid was then slurried with an appropriate amount of methanol to obtain 4-chloro-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridine as a grayish-white solid (17.0 g, 89%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 12 The calculated value of H9ClN3O2S is 294.0099, and the measured value is 293.0089.

[0327] Step 2: 15.0 g (51.2 mmol) of 4-chloro-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridine was dissolved in 150 mL of dichloromethane. Tetramethylammonium nitrate (13.9 g, 102.3 mmol) was added to the solution at 25 °C with stirring. Trifluoroacetic anhydride (28.6 mL, 204.8 mmol) was slowly added dropwise while maintaining the reaction temperature below 30 °C. After the addition was complete, the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give a yellow solid. Slurrying with an appropriate amount of methanol yielded 4-chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrazolo[2,3-b]pyridine as a pale yellow solid (12.3 g, 71%). This product could be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 12 The calculated value of H8ClN4O4S is 338.9949, and the measured value is 338.9930.

[0328] Step 3: 4-Chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrazolo[2,3-b]pyridine (5.0 g, 14.8 mmol) was dissolved in 50 mL of tetrahydrofuran. DIPEA (3.8 g, 29.6 mmol) and (S)-(-)-1-Boc-3-aminopyrrolidine (4.2 g, 22.2 mmol) were added, and the mixture was heated to reflux and stirred for 4 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under vacuum to obtain a yellow oily liquid. The liquid was then slurried and solidified with an appropriate amount of methanol to obtain (S)3-(((5-nitro-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (5.1 g, 71%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 21 H 25 The calculated value of N6O6S is 489.1551, and the measured value is 488.1559.

[0329] Step 4: Dissolve (S)3-(((5-nitro-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 10.2 mmol) in 50 mL of methanol. Add palladium on carbon (0.5 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain (S)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester as a pink, foamy solid (4.5 g, 96%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 21 H 27 The calculated value of N6O4S is 459.1809, and the measured value is 459.1813.

[0330] Step 5: Triethyloxonium tetrafluoroboric acid (5.0 g, 26.1 mmol) and (R)-lactamide (2.3 g, 26.1 mmol) were dissolved in 50 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 50 mL of ethanol was added to dissolve the oil, followed by the addition of (S)3-(((5-amino-1-(benzenesulfonyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (4.0 g, 8.7 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution became weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give (S)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrazolo[3,4-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester as a green oil (2.2 g, 49%). HRMS (ESI): m / z [M+H] + .C 24 H 29 The calculated value of N6O5S is 513.1915, and the measured value is 513.1923.

[0331] Step 6: (S)-tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrazolo[3,4-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester (2.0 g, 3.9 mmol) was dissolved in 20 mL of dichloromethane. Trifluoroacetic acid (4.4 g, 39.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain intermediate-13: (R)-1-(6-(benzenesulfonyl)-1-((S)-pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrazolo[3,4-b]pyridine-2-yl)ethanol as a light brown oil (1.5 g, 91%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 19 H 21 The calculated value of N6O3S is 413.1390, and the measured value is 413.1399.

[0332] Example 1

[0333]

[0334] 3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-carboxylic acid tert-butyl ester

[0335]

[0336] Step 1: 0.4 g (0.8 mmol) of tert-butyl 3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid was dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. 5 mL of 1 M sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS01: 3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 69%). 1 HNMR (300MHz, DMSO-d6): δ = 11.95 (s, 1H), 8.59 (s, 1H), 7.51 (s, 1H), 6.35 (s, 1H), 5.75 (t, J = 3.0Hz, 2H), 5.17-5.21 (m, 1H), 3.82-3.93 (m ,2H),3.76(t,J=9.0Hz,1H),3.40-3.47(m,1H),2.58-2.74(m,1H),2.28-2.41(m,1H),1.65(d,J=9.0Hz,3H),1.45(d,J=24.0Hz,9H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.23,148.61,148.53,142.1,129.04,127.15,120.71,115.63, 99.37,79.85,63.60,58.31,53.58,48.13,28.47,27.05,22.81ppm; HRMS(ESI):m / z[M+H] + .C 19 H 26 The calculated value of N5O3 is 372.2030, and the measured value is 372.2018.

[0337] Example 2

[0338]

[0339] 4-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-carbonyl)benzyl nitrile

[0340]

[0341] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add p-cyanobenzoyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 4-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)benzyl nitrile as a brown oil (0.3 g, 76%). This product can be used directly for the next step without further purification. HRMS(ESI): m / z [M+H] + .C 28 H 25 The calculated value of N6O4S is 541.1653, and the measured value is 541.1643.

[0342] Step 2: Dissolve 0.3 g (0.6 mmol) of 4-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)benzyl nitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXSO2: 4-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)benzyl nitrile (0.1 g, 45%). 1HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.87 (s, 1H), 8.21 (d, J = 9.0Hz, 2H), 8.10 (d, J = 9.0Hz, 2H), 7.66 (s, 1H), 6.88 (s, 1H) ),4.28-4.69(m,1H),3.81–3.92(m,2H),3.74-3.79(m,1H),3.30-3.45(m,2H),1.93-2.15(m,2H),1.49(d,J=9.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ172.53,148.69,148.51,142.16,139.53,132.09,129.04,127.91,127.16,120. 75,118.63,115.61,113.69,99.39,63.60,58.45,52.57,47.13,27.11,22.82ppm; HRMS(ESI):m / z[M+H] + .C 22 H 21 The calculated value of N6O2 is 401.1721, and the measured value is 401.1723.

[0343] Example 3

[0344]

[0345] (4-Fluorophenyl)(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl ketone

[0346]

[0347] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add p-fluorobenzoyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (4-fluorophenyl)(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone as a brown oil (0.3 g, 77%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 25 The calculated value of FN5O4S is 534.1606, and the measured value is 534.1619.

[0348] Step 2: Dissolve 0.3 g (0.6 mmol) of (4-fluorophenyl)(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXSO3: (4-fluorophenyl)(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl ketone (0.1 g, 45%). 1HNMR (300MHz, DMSO-d6): δ = 11.97 (s, 1H), 8.60 (d, J = 6.0Hz, 1H), 7.74-7-76 (m, 1H),7.55(d,J=15.0Hz,2H),7.36(t,J=9.0Hz,1H),7.22(t,J=9.0Hz,1H),6.45 (d,J=48.0Hz,1H),5.77(s,2H),5.15-5.23(m,1H),3.97-4.20(m,2H),3.71–3. 93(m,2H),2.66-2.73(m,1H),1.67(d,J=6.0Hz,3H),1.38(t,J=37.5Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ172.58,163.91,148.83,148.29,142.54,130.84,129.03,128.83,127.29,1 20.85,115.61,115.33,99.57,63.67,58.49,52.59,47.83,27.29,22.89ppm; HRMS(ESI):m / z[M+H] + .C 21 H 21 The calculated value of FN5O2 is 394.1674, and the measured value is 394.1682.

[0349] Example 4

[0350]

[0351] (1R)-1-(1-(1-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0352]

[0353] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add ethylsulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-(ethylsulfonyl)pyrrolidinyl-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 82%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 26 The calculated value of N5O5S2 is 504.1370, and the measured value is 504.1389.

[0354] Step 2: Dissolve (1R)-1-(1-(1-(1-(ethylsulfonyl)pyrrolidinyl-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.6 mmol) in a mixed solvent of 5 mL tetrahydrofuran and 5 mL methanol, and add 1 M sodium hydroxide solution. After adding mL, the mixture was stirred at room temperature for 5 hours, and the reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXSO4: (1R)-1-(1-(1-(1-(ethylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 93%). 1HNMR(300 MHz, DMSO-d6): δ=12.03(s,1H),8.97(s,1H),7.69(s,1H),6.78(s,1H),4.18-4.77(m,1H),3.60-3.7 9(m,1H),3.40-3.51(m,2H),3.11–3.32(m,2H),2.74-2.89(m,2H),1.90-2.15(m,2H),1.49(d,J=6.0 Hz,3H),1.22(t,J=9.0 Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ148.77,148.56,142.77,129.19,127.31,120.77,115.68,113.69 ,99.48,63.29,57.53,56.10,51.11,50.09,26.20,22.89,2.69ppm; HRMS(ESI):m / z[M+H] + .C 16 H 22 The calculated value of N5O3S is 364.1438, and the measured value is 364.1472.

[0355] Example 5

[0356]

[0357] (1R)-1-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0358]

[0359] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add propylsulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-(propylsulfonyl)pyrrolidinyl-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 80%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 28 The calculated value of N5O5S2 is 518.1526, and the measured value is 518.1536.

[0360] Step 2: Dissolve 0.3 g (0.6 mmol) of (1R)-1-(1-(1-(1-(propylsulfonyl)pyrrolidin-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS05: (1R)-1-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 91%). 1HNMR (300MHz, DMSO-d6): δ=11.93(s,1H),8.77(s,1H),7.58(s,1H),6.67(s,1H),4.21–4.68(m,1H),3.51–3.73(m,1H),3.21–3.28(m, 2H),3.18(t,J=9.0Hz,2H),2.79-2.99(m,2H),1.83-2.25(m,2H),1.52-1.68(m,2H),1.49(d,J=9.0Hz,3H),0.90(t,J=6.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.66,148.59,142.19,129.02,127.15,120.73,115.61,113.69,99. 31,63.66,60.40,57.59,56.19,50.02,26.28,22.84,13.33,12.44ppm; HRMS(ESI):m / z[M+H] + .C 17 H 24 N5O3S 378.1594, measured value 378.1599.

[0361] Example 6

[0362]

[0363] (1R)-1-(1-(1-(1-(1-(butylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0364]

[0365] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add butylsulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-(butylsulfonyl)pyrrolidinyl-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a pale white oil (0.3 g, 77%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 30 The calculated value of N5O5S2 is 532.1683, and the measured value is 532.1703.

[0366] Step 2: Dissolve 0.3 g (0.6 mmol) of (1R)-1-(1-(1-(1-(butylsulfonyl)pyrrolidin-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS06: (1R)-1-(1-(1-(1-(butylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 91%). 1HNMR (300MHz, DMSO-d6): δ=12.03(s,1H),8.47(s,1H),7.68(s,1H),6.87(s,1H),4.41–4.62(m,1H),3.50-3.79(m,1H),3.11–3.22(m,2H),3.10 (t,J=6.0Hz,2H),2.77-2.80(m,2H),1.93-2.15(m,2H),1.51-1.61(m,2H),1.48(d,J=6.0Hz,3H),1.29-1.31(m,2H),0.93(t,J=9.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.65,148.51,142.18,129.04,127.11,120.79,115.61,99.39,63. 68,57.93,57.58,56.17,50.01,26.28,22.82,21.93,21.05,13.88ppm; HRMS(ESI):m / z[M+H] + .C 18 H 26 The calculated value of N5O3S is 392.1751, and the measured value is 392.1755.

[0367] Example 7

[0368]

[0369] (1R)-1-(1-(1-(1-(((2-fluorophenyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0370]

[0371] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add o-fluorobenzenesulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-(((2-fluorophenyl)sulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a pale yellow oil (0.3 g, 72%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 25 The calculated value of FN5O5S2 is 570.1276, and the measured value is 570.1257.

[0372] Step 2: Dissolve 0.3 g (0.5 mmol) of (1R)-1-(1-(1-((((2-fluorophenyl)sulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS07: (1R)-1-(1-(1-(1-(((2-fluorophenyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.1 g, 44%). 1HNMR (300MHz, DMSO-d6): δ = 12.16 (s, 1H), 8.87 (s, 1H), 7.80-7.84 (m, 1H), 7.63-7.75 (m, 1H), 7.60 (s, 1H), 7.48-7.52 (m, 1H), 7.21-7.43 (m, 1H),6.77(s,1H),4.51–4.70(m,1H),3.63-3.81(m,1H),3.09-3.33(m,2H),2.63-2.83(m,2H),1.89-2.19(m,2H),1.93(d,J=9.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ158.22,148.66,148.57,142.18,133.53,129.03,128.91,127.11,126.33,124. 69,120.74,115.84,115.64,99.38,63.69,57.58,55.70,49.63,26.24,22.89ppm; HRMS(ESI):m / z[M+H] + .C 20 H 21 The calculated value of FN5O3S is 430.1344, and the measured value is 430.1350.

[0373] Example 8

[0374]

[0375] (1R)-1-(1-(1-toluenesulfonylpyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0376]

[0377] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add p-methylbenzenesulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(6-(benzenesulfonyl)-1-(1-toluenesulfonylpyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 73%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 28 The calculated value of N5O5S2 is 566.1526, and the measured value is 566.1523.

[0378] Step 2: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(1-toluenesulfonylpyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.5 mmol) in a mixed solvent of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS08: (1R)-1-(1-(1-toluenesulfonylpyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 89%). 1HNMR (300MHz, DMSO-d6): δ = 11.95 (s, 1H), 8.84 (s, 1H), 7.74 (d, J = 7.5Hz, 2H), 7.68 (s, 1H), 7.40 (d, J = 7.5Hz, 2H), 6.87 (s, 1H), 4.5 3-4.68(m,1H),3.55-3.81(m,1H),3.10-3.25(m,2H),2.79-2.89(m,2H),2.34(s,3H),1.91–2.25(m,2H),1.43(d,J=4.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ148.63,148.59,143.33,142.17,137.66,129.39,129.00,128.33,127.16, 120.71,115.65,99.39,63.64,57.58,55.74,49.63,26.23,22.81,21.39ppm; HRMS(ESI):m / z[M+H] + .C 21 H 24 The calculated value of N5O3S is 426.1594, and the measured value is 426.1596.

[0379] Example 9

[0380]

[0381] (1R)-1-(1-(1-(1-([(1,1'-biphenyl]-4-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0382]

[0383] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add p-phenylbenzenesulfonyl chloride (0.3 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-([[1,1'-biphenyl]-4-ylsulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazolium[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 66%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 32 H 30 The calculated value of N5O5S2 is 628.1683, and the measured value is 628.1686.

[0384] Step 2: Dissolve 0.3 g (0.5 mmol) of (1R)-1-(1-(1-(1-([[1,1'-biphenyl]-4-ylsulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS09: (1R)-1-(1-(1-(1-([(1,1'-biphenyl]-4-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 86%). 1HNMR (300MHz, DMSO-d6): δ = 12.35 (s, 1H), 8.74 (s, 1H), 7.88-7.92 (m, 4H), 7.67 (s, 1H), 7.45-7.52 (m, 4H), 7.28-7.41 (m, 1H), 6.87 (s,1H),4.43-4.71(m,1H),3.52-3.79(m,1H),3.11–3.35(m,2H),2.77-2.88(m,2H),1.90-2.15(m,2H),1.49(d,J=6.0Hz,3H)ppm; 13 CNMR(75MHz,DMSO-d6)δ148.69,148.53,142.19,140.88,138.62,133.06,129.21,129.04,127.93,127.88, 127.11,127.10,120.73,115.63,99.38,63.63,57.58,55.70,49.62,26.25,22.81ppm; HRMS(ESI):m / z[M+H] + .C 26 H 26 The calculated value of N5O3S is 488.1751, and the measured value is 488.1757.

[0385] Example 10

[0386]

[0387] (1R)-1-(1-(1-(1-(naphth-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-ethanol)

[0388]

[0389] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add naphthalenesulfonyl chloride (0.3 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(1-(1-(1-naphth-2-ylsulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a pale yellow oil (0.3 g, 68%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 30 H 28 The calculated value of N5O5S2 is 602.1526, and the measured value is 602.1540.

[0390] Step 2: Dissolve 0.3 g (0.5 mmol) of (1R)-1-(1-(1-(1-naphth-2-ylsulfonyl)pyrrolidine-3-yl)-6-(benzenesulfonyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS10: (1R)-1-(1-(1-(1-(naphth-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-ethanol) (0.2 g, 87%). 1HNMR (300MHz, DMSO-d6): δ = 12.04 (s, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 8.30- 8.41(m,1H),8.03-8.15(m,1H),8.00(d,J=7.5Hz,2H),7.59(d,J=7.5Hz,2H ),7.45(s,1H),6.87(s,1H),4.55-4.69(m,1H),3.45-3.91(m,1H),3.15-3. 35(m,2H),2.69-2.74(m,2H),1.96-2.28(m,2H),1.49(d,J=6.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.62,148.51,142.17,137.03,136.71,134.11,129.44,129.09,128.11,127.11,126. 25,126.04,123.41,120.74,115.60,99.38,63.69,57.57,55.76,49.60,26.22,22.81ppm; HRMS(ESI):m / z[M+H] + .C 24 H 24 The calculated value of N5O3S is 462.1594, and the measured value is 462.1607.

[0391] Example 11

[0392]

[0393] (1R)-1-(1-(1-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0394]

[0395] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add p-trifluoromethoxybenzenesulfonyl chloride (0.3 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(6-(benzenesulfonyl)-1-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)pyrrolidinebut-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 65%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 25 The calculated value of F3N5O6S2 is 636.1193, and the measured value is 636.1195.

[0396] Step 2: Dissolve 0.3 g (0.5 mmol) of (1R)-1-(6-(benzenesulfonyl)-1-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)pyrrolidinebut-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS11: (1R)-1-(1-(1-(1-((4-(trifluoromethoxy)phenyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 86%). 1HNMR (300MHz, DMSO-d6): δ = 12.15 (s, 1H), 8.79 (s, 1H), 7.64 (d, J = 7.5Hz, 2H), 7.59 (s, 1H), 7.12 (d, J = 7.5Hz, 2H), 6.74 (s, 1H) ),4.33-4.58(m,1H),3.65-3.83(m,1H),3.15-3.31(m,2H),2.74-2.86(m,2H),1.95-2.35(m,2H),1.46(d,J=9.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.88,148.61,148.59,142.10,132.00,129.79,129.04,127.17,126.11,1 20.73,115.61,114.67,99.38,63.69,57.58,55.70,49.66,26.25,22.81ppm; HRMS(ESI):m / z[M+H] + .C 21 H 21 The calculated value of F3N5O4S is 496.1261, and the measured value is 496.1262.

[0397] Example 12

[0398]

[0399] (1R)-1-(1-(1-(1-(thiophen-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol

[0400]

[0401] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add thiophene sulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1R)-1-(6-(benzenesulfonyl)-1-(1-(thiophene-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol as a yellow oil (0.3 g, 74%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 24 The calculated value of N5O5S3 is 558.0934, and the measured value is 558.0949.

[0402] Step 2: Dissolve 0.3 g (0.5 mmol) of (1R)-1-(6-(benzenesulfonyl)-1-(1-(thiophene-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS12: (1R)-1-(1-(1-(1-(thiophen-2-ylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.1 g, 45%). 1HNMR (300MHz, DMSO-d6): δ = 12.02 (s, 1H), 8.84 (s, 1H), 7.70 (s, 1H), 7.20 (d, J = 7.5Hz, 1H), 6.96 (d, J = 9.0Hz, 2H), 6.77 (s, 1H) ),4.51–4.69(m,1H),3.57-3.83(m,1H),3.17-3.31(m,2H),2.72-2.85(m,2H),1.93-2.31(m,2H),1.07(d,J=9.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.61,148.57,142.11,129.09,127.21,127.11,126.33,120. 73,115.60,99.31,63.61,57.59,55.74,49.62,26.22,22.81ppm; HRMS(ESI):m / z[M+H] + .C 18 H 20 The calculated value of N5O3S2 is 418.1002, and the measured value is 418.1012.

[0403] Example 13

[0404]

[0405] 2-(1-(ethylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0406]

[0407] Step 1: Dissolve 0.3 g (0.5 mmol) of 2-(3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.3 g, 0.5 mmol), add DIPEA (0.2 g, 1.0 mmol), and then slowly add ethylsulfonyl chloride (0.1 g, 0.8 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1-(ethylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a yellow oil (0.2 g, 57%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + Calculated value C 29 H 27 N8O6S2 647.1489, measured value 647.1482.

[0408] Step 2: Dissolve 0.2 g (0.3 mmol) of 2-(1-(ethylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS13: 2-(1-(ethylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.1 g, 64%). 1HNMR (300MHz, DMSO-d6): δ=11.94(s,1H),8.90(s,1H),8.69(s,1H),8.14(s,1H),7.37(s,1H),6.41(s,2H),5.95(s,1H),5.43(t,J=6.0 Hz,1H),4.62(d,J=9.0Hz,2H),4.47(d,J=6.0Hz,2H),4.34(d,J=9.0Hz,2H),3.78(s,2H),3.25-3.32(m,2H),1.28(t,J=7.5Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ153.88,151.11,148.67,142.16,141.57,130.77,129.79,129.04,127.12,120.74,117. 77,115.65,107.93,104.05,100.53,99.38,59.23,57.39,51.60,50.81,23.20,2.62ppm; HRMS(ESI):m / z[M+H] + Calculated value C 23 H 23 N8O4S 507.1557, measured value 507.1549.

[0409] Example 14

[0410]

[0411] 2-(1-(propylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0412]

[0413] Step 1: Dissolve 0.3 g (0.5 mmol) of 2-(3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.3 g, 0.5 mmol), add DIPEA (0.2 g, 1.0 mmol), and then slowly add propylsulfonyl chloride (0.1 g, 0.8 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1-(propylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a yellow oil (0.3 g, 84%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 30 H 29 The calculated value of N8O6S2 is 661.1646, and the measured value is 661.1649.

[0414] Step 2: Dissolve 0.3 g (0.5 mmol) of 2-(1-(propylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS14: 2-(1-(propylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.1 g, 42%). 1HNMR (300MHz, DMSO-d6): δ = 11.91 (s, 1H), 8.87 (s, 1H), 8.66 (s, 1H), 8.11 (s, 1 H),7.34(s,1H),6.38(s,2H),5.93(s,1H),5.40(t,J=6.0Hz,1H),4.58(d,J=9 .0Hz,2H),4.45(d,J=3.0Hz,2H),4.31(d,J=9.0Hz,2H),3.75(s,2H),3.24(t, J=7.5Hz,2H),1.69-1.77(m,2H),1.18-1.30(m,2H),1.00(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ157.85,145.73,143.25,143.07,139.10,135.78,135.68,134.04,128.63,124.75,119.74, 117.03,113.11,109.22,104.52,96.44,58.75,57.15,56.11,50.29,27.30,16.89,13.16ppm; HRMS(ESI):m / z[M+H] + .C 24 H 25 The calculated value of N8O4S is 521.1714, and the measured value is 521.1695.

[0415] Example 15

[0416]

[0417] 2-(1-(butylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0418]

[0419] Step 1: Dissolve 0.3 g (0.5 mmol) of 2-(3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.3 g, 0.5 mmol), add DIPEA (0.2 g, 1.0 mmol), and then slowly add butylsulfonyl chloride (0.1 g, 0.8 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1-(butylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a yellow oil (0.2 g, 55%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 31 H 31 The calculated value of N8O6S2 is 675.1802, and the measured value is 675.1811.

[0420] Step 2: Dissolve 0.2 g (0.3 mmol) of 2-(1-(butylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS15: 2-(1-(butylsulfonyl)-3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.1 g, 63%). 1HNMR (300MHz, DMSO-d6): δ = 11.95 (s, 1H), 8.90 (s, 1H), 8.69 (s, 1H), 8.14 (s, 1H), 7.37(s,1H),6.41(s,2H),5.96(s,1H),5.44(t,J=6.0Hz,1H),4.62(d,J=9.0Hz,2 H),4.48(d,J=6.0Hz,2H),4.35(d,J=9.0Hz,2H),3.78(s,2H),3.29(t,J=7.5Hz,2 H),2.53(s,2H),1.66-1.76(m,2H),1.38-1.50(m,2H),0.92(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ157.86,145.75,143.27,143.09,139.10,135.80,135.69,134.05,128.65,124.76,119.77,117 .06,113.13,109.23,104.54,96.46,58.78,57.16,56.13,48.45,27.33,25.08,21.36,13.94ppm; HRMS(ESI):m / z[M+H] + .C 25 H 27 The calculated value of N8O4S is 535.1870, and the measured value is also 535.1870.

[0421] Example 16

[0422]

[0423] (5-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)methanol

[0424]

[0425] Step 1: Dissolve 0.3 g (0.6 mmol) of (5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.2 mmol) and then slowly add propylsulfonyl chloride (0.1 g, 0.9 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (5-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylfuran-2-yl)methanol as a yellow oil (0.2 g, 54%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 28 The calculated value of N5O6S2 is 570.1476, and the measured value is 570.1488.

[0426] Step 2: Dissolve 0.2 g (0.4 mmol) of (5-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylfuran-2-yl)methanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS16:(5-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)methanol (0.1 g, 66%). 1HNMR (300MHz, DMSO-d6): δ=12.11(s,1H),8.69(s,1H),7.62(s,1H),7.20(d,J=3.0H z,1H),6.83(s,1H),6.64(d,J=3.0Hz,1H),5.58-5.92(m,1H),5.52(t,J=6.0Hz,1H), 4.59(d,J=6.0Hz,2H),4.04(t,J=10.5Hz,1H),3.79-3.87(m,2H),3.53-3.62(m,1H) ,3.24-3.29(m,2H),2.69-2.83(m,1H),1.76-1.88(m,2H),1.07(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ158.09,144.98,143.27,143.04,136.34,135.19,132.29,125.05,114.29,109 .37,105.02,98.97,56.21,54.67,49.36,48.97,46.90,30.36,16.90,13.35ppm; HRMS(ESI):m / z[M+H] + .C 20 H 24 The calculated value of N5O4S is 430.1544, and the measured value is 430.1550.

[0427] Example 17

[0428]

[0429] Cyclopropyl(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone

[0430]

[0431] Step 1: Dissolve 0.3 g (0.6 mmol) of (5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.2 mmol) and then slowly add cyclopropionyl chloride (0.1 g, 0.9 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give cyclopropyl(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone as a brown oil (0.2 g, 58%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 26 The calculated value of N5O5S is 532.1649, and the measured value is 532.1661.

[0432] Step 2: 0.2 g (0.4 mmol) of cyclopropyl(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone was dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. 5 mL of 1 M sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS17: cyclopropyl(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl) methyl ketone (0.1 g, 68%). 1HNMR (300MHz, DMSO-d6): δ = 12.10 (s, 1H), 8.69 (d, J = 3.0Hz, 1H), 7.60 (t, J = 4.5Hz, 1H), 7.22 (dd, J1=9.0Hz, J2=3.0Hz,1H),6.61(t,J=4.5Hz,1H),6.46(d,J=9.0Hz,1H),5.84-6.03(m,1H),5.50(t ,J=4.5Hz,1H),4.57(d,J=6.0Hz,2H),4.20-4.42(m,1H),4.02-4.12(m,1H),3.81–3.95(m,1H),2. 65-2.86(m,1H),1.72-2.01(m,1H),1.25(s,2H),0.84(t,J=7.5Hz,2H),0.74(d,J=9.0Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ171.92,158.10,158.05,144.98,143.47,142.97,136.41,135.27,132.40,1 25.22,114.32,109.43,105.09,105.01,98.67,56.20,45.58,12.55,7.68ppm; HRMS(ESI):m / z[M+H] + .C 21 H 22 The calculated value of N5O3 is 392.1717, and the measured value is 392.1727.

[0433] Example 18

[0434]

[0435] 2-(1H-imidazol-2-yl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

[0436]

[0437] Step 1: Dissolve 0.3 g (0.7 mmol) of 2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add propylsulfonyl chloride (0.2 g, 1.0 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine as a yellow oil (0.2 g, 54%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 26 The calculated value of N7O4S2 is 540.1482, and the measured value is 540.1485.

[0438] Step 2: Dissolve 0.2 g (0.4 mmol) of 2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS18: 2-(1H-imidazol-2-yl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.1 g, 68%). 1HNMR (300MHz, DMSO-d6): δ=13.34(s,1H),12.09(d,J=9.0Hz,1H),8.72(d,J= 6.0Hz,1H),7.58(t,J=12.0Hz,2H),7.41(s,1H),7.25(d,J=6.0Hz,2H),6.83 (s,1H),4.08(s,2H),3.83-3.97(m,3H),3.20-3.32(m,2H),2.79(t,J=9.0Hz ,1H),2.11(s,2H),1.76-1.86(m,2H),1.25(s,1H),1.08(t,J=6.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ157.04,148.61,142.46,138.11,129.09,127.92,122.74,120.71, 115.15,99.49,60.42,56.83,56.19,50.01,36.27,13.20,12.62ppm; HRMS(ESI):m / z[M+H] + .C 18 H 22 The calculated value of N7O2S is 400.1550, and the measured value is 400.1561.

[0439] Example 19

[0440]

[0441] 2-(1H-imidazol-2-yl)-1-(1-(((trifluoromethyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

[0442]

[0443] Step 1: Dissolve 0.3 g (0.7 mmol) of 2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add trifluoromethanesulfonyl chloride (0.2 g, 1.0 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1H-imidazol-2-yl)-6-(phenylsulfonyl)-1-(1-(((trifluoromethyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrole[2,3-b]pyridine as a yellow oil (0.3 g, 77%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 22 H 19 The calculated value of F3N7O4S2 is 566.0887, and the measured value is 566.0894.

[0444] Step 2: Dissolve 0.3 g (0.5 mmol) of 2-(1H-imidazol-2-yl)-6-(phenylsulfonyl)-1-(1-(((trifluoromethyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated from the aqueous phase. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS19: 2-(1H-imidazol-2-yl)-1-(1-(((trifluoromethyl)sulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.1 g, 44%). 1 HNMR (300MHz, DMSO-d6): δ = 13.36 (s, 1H), 12.16 (s, 1H), 8.72 (s, 1H), 7.66 (s, 1H), 7.41 (s, 1H), 7.26 ( s,2H),6.65(s,1H),4.17(d,J=9.0Hz,2H),3.90(d,J=6.0Hz,1H),2.57-2.72(m,1H),1.25(s,2H)ppm; 13C NMR (75MHz, DMSO-d6) δ144.80,142.52,138.37,136.04,134.54,132.85,125.37,119.82,104.82,98.39,48.52ppm; HRMS (ESI): m / z[M+H] + .C 16 H 15 The calculated value of F3N7O2S is 426.0955, and the measured value is 426.0959.

[0445] Example 20

[0446]

[0447] (R)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

[0448]

[0449] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((R-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add carbonyl diimidazole (0.2 g, 1.4 mmol), followed by slow dropwise addition of trifluoromethylethylamine (0.2 g, 1.4 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the solutions. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a pale yellow oil (0.2 g, 51%). This product can be used directly for the next step without further purification. HRMS(ESI): m / z [M+H] + .C 23 H 24 The calculated value of F3N6O4S is 537.1526, and the measured value is 537.1511.

[0450] Step 2: Dissolve (R)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.2 g, 0.4 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS20: (R)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.1 g, 44%). 1 HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.62 (s, 1H), 7.51 (s, 1H), 7.09 (s, 1H), 6.37 (s, 1H), 5.80 (d, J = 6.0Hz, 2H), 5.22 (t, J = 6.0Hz, 1H), 3.87 -3.96(m,5H),3.49(d,J=6.0Hz,1H),2.64-2.76(m,1H),2.43(s,1H),1. 68(d,J=3.0Hz,3H),1.53(s,1H),1.26(s,3H),0.89(d,J=6.0Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ155.73,148.66,148.57,142.76,129.09,127.12,124.28,120.70, 115.65,99.38,63.64,57.99,54.17,48.74,41.88,26.60,22.82ppm; HRMS(ESI):m / z[M+H] + .C 17 H 20 The calculated value of F3N6O2 is 397.1594, and the measured value is 397.1603.

[0451] Example 21

[0452]

[0453] (R)-1-(1-((R)-1-(propanesulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-2-

[0454] ethanol

[0455]

[0456] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((R-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add propanesulfonyl chloride (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-1-(6-(benzenesulfonyl)-1-((R)-1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) ethanol as a yellow oil (0.3 g, 80%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 28 The calculated value of N5O5S2 is 518.1526, and the measured value is 518.1534.

[0457] Step 2: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((R)-1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.6 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS21: (R)-1-(1-((R)-1-(propanesulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.2 g, 91%). 1HNMR (300MHz, DMSO-d6): δ = 11.97 (s, 1H), 8.62 (s, 1H), 7.56 (s, 1H), 6.72 (s, 1H) ,5.81(d,J=6.0Hz,2H),5.22(t,J=6.0Hz,1H),3.82-3.94(m,2H),3.74(t,J=9.0H z,1H),3.51–3.59(m,1H),3.28(t,J=7.5Hz,2H),2.65-2.75(m,1H),1.78-1.85(m ,2H),1.68(d,J=6.0Hz,3H),1.53(s,1H),1.26(s,1H),1.08(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ155.12,144.83,136.22,134.22,132.43,124.69,104.91,98.76, 62.52,53.69,49.72,49.02,46.86,31.15,22.08,16.98,13.32ppm; HRMS(ESI):m / z[M+H] + .C 17 H 24 The calculated value of N5O3S is 378.1594, and the measured value is 378.1609.

[0458] Example 22

[0459]

[0460] trans-4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0461]

[0462] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-hydroxymethylfurfural (0.2 g, 1.1 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give trans-4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile as a yellow solid (0.2 g, 53%). HRMS (ESI): m / z [M+H] + .C 26 H 24 The calculated value of N5O4S is 502.1544, and the measured value is 502.1556.

[0463] Step 2: Dissolve 0.2 g (0.4 mmol) of trans-4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS22: trans-4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 69%). 1HNMR (300MHz, DMSO-d6): δ=11.99(s,1H),8.60(s,1H),7.51(s,1H),7.03(s,1H),6.87(s,1H),6.57(s,1H),5.47(s,1H),4.88(s,1H),4 .55(s,1H),3.11(s,1H),2.35(d,J=9.0Hz,2H),2.24(d,J=12.0Hz,2H),1.98(s,3H),1.88(d,J=12.0Hz,2H),1.19(t,J=9.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.81,150.11,146.67,144.93,142.06,129.05,127.92,122.75,120.7 1,115.65,105.93,104.75,99.68,64.56,57.69,30.22,26.91,24.60ppm; HRMS(ESI):m / z[M+H] + .C 20 H 20 The calculated value of N5O2 is 362.1612, and the measured value is 362.1625.

[0464] Example 23

[0465]

[0466] (R)-3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

[0467]

[0468] Step 1: Dissolve (R)-(5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-ylmethanol (0.3 g, 0.6 mmol) in 10 mL of tetrahydrofuran. Add carbonyl diimidazole (0.2 g, 1.2 mmol), followed by slow dropwise addition of trifluoromethylethylamine (0.2 g, 1.2 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the... The organic phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a pale yellow oil (0.2 g, 52%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 24 The calculated value of F3N6O5S is 589.1475, and the measured value is 589.1482.

[0469] Step 2: Dissolve (R)-3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.2 g, 0.3 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS23: (R)-3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.1 g, 66%). 1HNMR (300MHz, DMSO-d6): δ = 12.08 (s, 1H), 8.66 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 5.94(d,J=9.0Hz,1H),5.49(s,1H),4.57(d,J=6.0Hz,2H),3.95(d,J=9.0Hz,6H),2.71(t,J=12.0Hz,1H),1.26(s,2H)ppm; 13 C NMR (75MHz, DMSO-d6) δ155.75,153.18,151.71,148.07,144.94,142.96,129.54,127.72,124.74,120. 77,115.35,107.53,104.35,99.68,57.79,54.88,53.59,48.73,41.81,26.20ppm; HRMS(ESI):m / z[M+H] + .C 20 H 20 The calculated value of F3N6O3 is 449.1543, and the measured value is 449.1550.

[0470] Example 24

[0471]

[0472] (R)-3-(2-(1H-imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

[0473]

[0474] Step 1: Dissolve (R)-2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add carbonyl diimidazole (0.2 g, 1.4 mmol), followed by slow dropwise addition of trifluoromethylethylamine (0.2 g, 1.4 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a pale yellow oil (0.2 g, 52%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 The calculated value of F3N8O3S is 559.1482, and the measured value is 559.1479.

[0475] Step 2: Dissolve (R)-3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.2 g, 0.4 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS24: (R)-3-(2-(1H-imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.1 g, 67%). 1 HNMR (300MHz, DMSO-d6): δ=13.34(s,1H),12.10(s,1H),8.72(s,1H),7.58(s,1H),7.41(s,1H),7 .25(s,2H),7.10(s,1H),6.47(s,1H),3.89-4.00(m,6H),2.77(t,J=12.0Hz,1H),2.12(s,2H)ppm;13 C NMR(75MHz,DMSO-d6)δ157.08,155.78,148.66,142.49,138.11,129.00,127.19,124.27,1 22.77,120.75,115.68,99.33,57.26,54.17,48.70,41.80,26.63ppm; HRMS(ESI):m / z[M+H] + .C 18 H 18 The calculated value of F3N8O is 419.1550, and the measured value is 419.1551.

[0476] Example 25

[0477]

[0478] (R)-1-(3-(2-(1H-imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0479]

[0480] Step 1: Dissolve (R)-2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add acryloyl chloride (0.1 g, 1.4 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-1-(3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one as a pale yellow oil (0.2 g, 59%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 22 The calculated value of N7O3S is 488.1499, and the measured value is 488.1511.

[0481] Step 2: Dissolve (R)-1-(3-(2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one (0.2 g, 0.4 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS25: (R)-1-(3-(2-(1H-imidazol-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one (0.1 g, 70%). 1 HNMR (300MHz, DMSO-d6): δ = 13.34 (s, 1H), 12.10 (s, 1H), 8.72 (s, 1H), 7.58 (d, J = 9.0Hz, 1H), 7.41 (s, 1H), 7.25 (s, 1H), 6.46 (s, 1H), 4. 02-4.22(m,2H),3.95(t,J=9.0Hz,1H),3.67(d,J=6.0Hz,2H),3.61(d,J=6.0Hz,1H),3.34(s,2H),3.23(s,1H),2.74-2.88(m,1H)ppm; 13 C NMR(75MHz,DMSO-d6)δ166.30,157.05,148.66,142.96,138.17,131.16,129.05,127.17,12 6.88,122.75,120.74,115.65,99.38,57.73,52.07,46.68,27.17ppm; HRMS(ESI):m / z[M+H] + .C 18 H 18 The calculated value of N7O is 348.1567, and the measured value is 348.1557.

[0482] Example 26

[0483]

[0484] trans-4-(2-(2-methylthiazolyl-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0485]

[0486] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-aldehyde-2-methylthiazole (0.2 g, 1.1 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-methylthiazo-5-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.2 g, 52%). HRMS (ESI): m / z [M+H] + .C 25 H 23 N6O2S2503.1318, measured value 503.1322.

[0487] Step 2: Dissolve 0.2 g (0.4 mmol) of trans-4-(2-(2-methylthiazo-5-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS26: trans-4-(2-(2-methylthiazolyl-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 69%). 1 HNMR (300MHz, DMSO-d6): δ = 12.05 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.56 (s, 1H), 6.89 (s, 1H), 4.76 (s, 1H), 3.20 (t, J = 1 2.0Hz,1H),2.80(s,3H),2.43(t,J=12.0Hz,2H),2.27(d,J=12.0Hz,2H),2.10(d,J=15.0Hz,2H),1.86-1.98(m,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ168.60,144.99,143.26,143.05,136.18,135.29,132.94,127.33,124.63,1 23.32,104.45,100.98,54.58,31.18,29.48,29.16,28.49,26.19,19.36ppm; HRMS(ESI):m / z[M+H] + .C 19 H 19 The calculated value of N6S is 363.1386, and the measured value is 363.1395.

[0488] Example 27

[0489]

[0490] trans-4-(2-(2-aminothiazolyl-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0491]

[0492] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2-aminothiazol-5-carboxaldehyde (0.2 g, 1.1 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-aminothiazo-5-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.2 g, 52%). HRMS (ESI): m / z [M+H] + .C 24 H 22 The calculated value of N7O2S2 is 504.1271, and the measured value is 504.1277.

[0493] Step 2: Dissolve 0.2 g (0.4 mmol) of trans-4-(2-(2-aminothiazo-5-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS27: trans-4-(2-(2-aminothiazo-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 69%). 1 HNMR (300MHz, DMSO-d6): δ = 11.95 (s, 1H), 8.57 (s, 1H), 7.51 (s, 2H), 7.45 (s, 1H), 6.84 (s, 1H), 4.78 (s, 1H), 3.22 (d ,J=12.0Hz,1H),2.44(t,J=13.5Hz,2H),2.28(d,J=12.0Hz,2H),1.01(d,J=12.0Hz,2H),1.91(t,J=13.5Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ168.94,148.64,144.94,142.16,137.74,129.05,127.15,122.7 5,122.29,120.75,115.67,99.39,65.97,30.88,26.95,24.66ppm; HRMS(ESI):m / z[M+H] + .C 18 H 18 The calculated value of N7S is 364.1339, and the measured value is 364.1365.

[0494] Example 28

[0495]

[0496] trans-4-(2-(2-methylthiophene-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0497]

[0498] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-methyl-2-thiophenecarboxaldehyde (0.2 g, 1.1 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(5-methylthiophene-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.2 g, 53%). HRMS (ESI): m / z [M+H] + .C 26 H 24 The calculated value of N5O2S2 is 502.1366, and the measured value is 502.1377.

[0499] Step 2: Dissolve 0.2 g (0.4 mmol) of trans-4-(2-(5-methylthiophene-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS28: trans-4-(2-(2-methylthiophene-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 69%). 1 HNMR (300MHz, DMSO-d6): δ = 12.00 (s, 1H), 8.63 (s, 1H), 7.54 (s, 1H), 7.38 (d, J = 3.0Hz, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 4.84 (d, J = 12.0Hz ,1H),3.21(t,J=12.0Hz,1H),2.58(s,3H),2.45(t,J=12.0Hz,2H),2.29(d,J=12.0Hz,2H),2.03(d,J=6.0Hz,2H),1.81-1.93(m,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ145.90,144.93,143.26,136.04,135.11,132.96,129.68,129.49,127.19,1 24.51,123.28,104.53,100.88,54.70,31.17,29.17,28.65,26.21,15.41ppm; HRMS(ESI):m / z[M+H] + .C 20 H 20 The calculated value of N5S is 362.1434, and the measured value is 362.1432.

[0500] Example 29

[0501]

[0502] trans-4-(2-(2-methylfuran-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0503]

[0504] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-methyl-2-furanaldehyde (0.2 g, 1.1 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(5-methylfuran-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.2 g, 54%). HRMS (ESI): m / z [M+H] + .C 26 H 24 The calculated value of N5O3S is 486.1594, and the measured value is 486.1601.

[0505] Step 2: Dissolve 0.2 g (0.4 mmol) of trans-4-(2-(5-methylfuran-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS29: trans-4-(2-(2-methylfuran-5-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 70%). 1 HNMR (300MHz, DMSO-d6): δ = 12.00 (s, 1H), 8.62 (s, 1H), 7.53 (s, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 6.41 (s, 1H), 4.89 (t, J = 10.5Hz, 1H), 3. 15(t,J=12.0Hz,1H),2.53(s,3H),2.40(d,J=12.0Hz,2H),2.29(d,J=12.0Hz,2H),2.00(d,J=10.0Hz,2H),1.91(d,J=12.0Hz,2H)ppm; 13 C NMR (75MHz, DMSO-d6) δ154.49,145.07,143.04,142.81,136.20,135.14,132.90,124.49,123.34,114. 47,108.68,104.57,100.44,54.96,31.17,29.36,28.78,26.41,22.57,13.91ppm; HRMS(ESI):m / z[M+H] + .C 20 H 20 The calculated value of N5O is 346.1662, and the measured value is 346.1664.

[0506] Example 30

[0507]

[0508] 2-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol

[0509]

[0510] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add o-hydroxybenzaldehyde (0.2 g, 1.4 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(2-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid as a yellow solid (0.2 g, 55%). HRMS (ESI): m / z [M+H] + .C 29 H 30 The calculated value of N5O5S is 560.1962, and the measured value is 560.1965.

[0511] Step 2: 3-(2-(2-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.4 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.5 g, 4.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 2-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol as a pale yellow oil (0.1 g, 61%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 The calculated value of N5O3S is 460.1438, and the measured value is 460.1441.

[0512] Step 3: Dissolve 0.1 g (0.2 mmol) of 2-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.4 mmol), followed by slow dropwise addition of propanesulfonyl chloride (0.1 g, 0.3 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol as a pale yellow oil (0.1 g, 81%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 28 The calculated value of N5O5S2 is 566.1526, and the measured value is 566.1533.

[0513] Step 4: Dissolve 0.1 g (0.2 mmol) of 2-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS30: 2-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol (65.0 mg, 86%). 1HNMR (300MHz, DMSO-d6): δ = 12.06 (s, 1H), 8.67 (s, 1H), 7.59 (t, J = 3.0Hz, 1H), 7.49-7. 52(m,1H),7.41-7.47(m,1H),7.19(d,J=9.0Hz,1H),7.01(t,J=7.5Hz,1H),6.80(d,J= 3.0Hz,1H),5.12-5.24(m,1H),3.98-4.10(m,1H),3.74-3.87(m,2H),3.19-3.25(m,2H ),2.69-2.83(m,1H),2.33-2.42(m,1H),1.77-1.84(m,2H),1.05(t,J=9.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ170.82,156.82,150.94,144.75,136.04,135.50,132.54,131.85,131.74,124.82,119.58,117 .92,116.59,104.91,98.80,60.22,55.10,49.24,46.75,30.10,21.24,16.91,14.55,13.32ppm; HRMS(ESI):m / z[M+H] + .C 21 H 24 The calculated value of N5O3S is 426.1594, and the measured value is 426.1462.

[0514] Example 31

[0515]

[0516] 4-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenyl-1,3-diol

[0517]

[0518] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add 2,4-dihydroxybenzaldehyde (0.2 g, 1.4 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and... The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give 3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-tert-butylcarboxylic acid ester as a yellow solid (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 29 H 30 The calculated value of N5O6S is 576.1911, and the measured value is 576.1919.

[0519] Step 2: 3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-tert-butylcarboxylate (0.3 g, 0.5 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.6 g, 5.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 4-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenyl-1,3-diol as a pale yellow oil (0.2 g, 81%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 N5O4S 476.1387, measured value 476.1391.

[0520] Step 3: Dissolve 0.2 g (0.4 mmol) of 4-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzene-1,3-diol in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.8 mmol), then slowly add propanesulfonyl chloride (0.1 g, 0.6 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 4-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylphenyl-1,3-diol as a pale yellow oil (0.2 g, 82%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 28 The calculated value of N5O6S2 is 582.1476, and the measured value is 582.1501.

[0521] Step 4: Dissolve 0.2 g (0.3 mmol) of 4-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylphenyl-1,3-diol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS31: 4-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzene-1,3-diol (0.1 g, 66%). 1HNMR (300MHz, DMSO-d6): δ = 11.97 (s, 1H), 10.15 (s, 1H), 9.84 (s, 1H), 8.63 (s, 1H), 7.57 (s, 1H), 7.29(d,J=9.0Hz,1H),6.76(d,J=3.0Hz,1H),6.53(d,J=3.0Hz,1H),6.42–6.46(m,1H),5.12-5.3 4(m,1H),3.95(t,J=9.0Hz,1H),3.73-3.81(m,2H),3.17-3.23(m,2H),2.66-2.80(m,1H),2.30- 2.38(m,1H),1.72-1.85(m,2H),1.28-1.31(m,2H),1.08-1.19(m,2H),1.02(t,J=9.0Hz,3H)ppm; 13 CNMR(75MHz,DMSO-d6)δ160.74,157.62,151.30,144.70,135.81,135.33,133.33,131.70,124.76,108.69, 107.72,104.91,102.94,98.78,54.98,53.91,49.43,46.70,18.47,16.95,13.34ppm; HRMS(ESI):m / z[M+H] + .C 21 H 24 The calculated value of N5O4S is 442.1544, and the measured value is 442.1405.

[0522] Example 32

[0523]

[0524]

[0525] 3-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol

[0526]

[0527] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add 0.2 g (1.4 mmol) of 3-hydroxybenzaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and... The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(3-hydroxyphenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid as a yellow solid (0.3 g, 82%). HRMS (ESI): m / z [M+H] + .C 29 H 30 The calculated value of N5O5S is 560.1962, and the measured value is 560.1969.

[0528] Step 2: 3-(2-(3-hydroxyphenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.5 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.6 g, 5.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol as a pale yellow oil (0.2 g, 81%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 The calculated value of N5O3S is 460.1438, and the measured value is 460.1441.

[0529] Step 3: Dissolve 0.2 g (0.4 mmol) of 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.8 mmol), then slowly add propanesulfonyl chloride (0.1 g, 0.6 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylphenol as a pale yellow oil (0.2 g, 81%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 28 The calculated value of N5O5S2 is 566.1526, and the measured value is 566.1529.

[0530] Step 4: Dissolve 0.2 g (0.4 mmol) of 3-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylphenol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was then separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS32: 3-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol (0.1 g, 66%). 1HNMR (300MHz, DMSO-d6): δ=12.06(s,1H),10.04(s,1H),8.68(s,1H),7.60(t,J=3.0Hz,1H ),7.43(t,J=7.5Hz,1H),7.20(t,J=6.0Hz,1H),7.00-7.03(m,1H),6.80(d,J=3.0Hz,1H), 5.41-5.53(m,1H),3.99-4.09(m,1H),3.76-3.89(m,2H),3.46-3.55(m,1H),3.16-3.32(m ,2H),2.71–2.85(m,1H),2.40-2.49(m,1H),1.72-1.84(m,2H),1.05(t,J=9.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ158.03,152.38,144.82,136.27,135.14,132.22,131.63,130.44,120.6 2,117.30,116.85,111.64,105.14,55.07,49.05,30.03,16.88,13.35ppm; HRMS(ESI):m / z[M+H] + .C 21 H 24 The calculated value of N5O3S is 426.1594, and the measured value is 426.1464.

[0531] Example 33

[0532]

[0533] 1-(3-(2-(2,4-dihydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)prop-2-en-1-one

[0534]

[0535] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add 2,4-dihydroxybenzaldehyde (0.2 g, 1.4 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and... The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give 3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-tert-butylcarboxylic acid ester as a yellow solid (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 29 H 30 The calculated value of N5O6S is 576.1911, and the measured value is 576.1918.

[0536] Step 2: 3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-tert-butylcarboxylate (0.3 g, 0.5 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.6 g, 5.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 4-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenyl-1,3-diol as a pale yellow oil (0.2 g, 81%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 The calculated value of N5O4S is 476.1387, and the measured value is 476.1375.

[0537] Step 3: Dissolve 0.2 g (0.4 mmol) of 4-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)benzene-1,3-diol in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.8 mmol) and then slowly add acryloyl chloride (0.1 g, 0.6 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 1-(3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one as a pale yellow oil (0.2 g, 90%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 24 The calculated value of N5O5S is 530.1493, and the measured value is 530.1488.

[0538] Step 4: Dissolve 0.2 g (0.4 mmol) of 1-(3-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS33: 1-(3-(2-(2,4-dihydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)prop-2-en-1-one (0.1 g, 68%). 1HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.62 (s, 1H), 7.52 (d, J = 6.0Hz, 1H), 7.26 (d, J = 6.0Hz, 1H), 6.55 (s, 1H), 6.42 (d, J =9.0Hz,1H),4.03-4.10(m,4H),3.55-3.66(m,3H),2.68-2.79(m,1H),2.32(s,1H),2.02(s,4H),1.21(t,J=6.0Hz,4H)ppm; 13 C NMR(75MHz,DMSO-d6)δ166.39,159.94,156.62,153.78,148.64,142.18,131.16,130.11,129.05,127.14,12 6.89,120.74,115.69,110.95,109.05,105.64,99.38,57.77,52.05,46.69,27.17ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of N5O3 is 390.1561, and the measured value is 390.1692.

[0539] Example 34

[0540]

[0541] 3-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide

[0542]

[0543] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add 0.2 g (1.4 mmol) of 3-hydroxybenzaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and... The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(3-hydroxyphenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid as a yellow solid (0.3 g, 82%). HRMS (ESI): m / z [M+H] + .C 29 H 30 The calculated value of N5O5S is 560.1962, and the measured value is 560.1977.

[0544] Step 2: 3-(2-(3-hydroxyphenyl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.5 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.6 g, 5.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol as a pale yellow oil (0.2 g, 81%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 24 H 22 The calculated value of N5O3S is 460.1438, and the measured value is 460.1441.

[0545] Step 3: Dissolve (R)-2-(1H-imidazol-2-yl)-6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.2 g, 0.4 mmol) in 10 mL of tetrahydrofuran. Add carbonyl diimidazole (0.2 g, 1.0 mmol), followed by slow dropwise addition of trifluoromethylethylamine (0.2 g, 1.0 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as a pale yellow oil (0.2 g, 79%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 27 H 24 The calculated value of F3N6O4S is 585.1526, and the measured value is 585.1531.

[0546] Step 4: Dissolve 0.2 g (0.3 mmol) of 3-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS34: 3-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (0.1 g, 66%). 1HNMR (300MHz, DMSO-d6): δ = 12.04 (s, 1H), 8.69 (s, 1H), 7.56 (t, J = 3.0Hz, 1H), 7.43 (t, J = 7.5Hz, 1H), 7.15 (t, J = 4.5Hz, 2H), 6.99-7 .08(m,2H),6.43(d,J=3.0Hz,1H),5.46(t,J=9.0Hz,1H),3.86-3.98(m,6H),2.71–2.78(m,1H),2.30-2.41(m,1H),1.26(s,1H)ppm; 13 C NMR (75MHz, DMSO-d6) δ158.03,156.37,152.81,152.40,144.80,136.37,135.20,132.31,131.66,130.50,125.03,120. 61,117.57,117.33,116.78,111.67,105.18,98.76,91.18,76.29,73.64,73.34,67.45,30.10ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of F3N6O2 is 445.1594, and the measured value is 445.1459.

[0547] Example 35

[0548]

[0549]

[0550] trans-4-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0551]

[0552] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 3-hydroxybenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 27 H 24 The calculated value of N5O3S is 498.1594, and the measured value is 498.1588.

[0553] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS35: trans-4-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.98 (s, 1H), 9.86 (s, 1H), 8.64 (s, 1H), 7.54 (t, J=3.0Hz,1H),7.41(t,J=7.5Hz,2H),7.10(t,J=4.5Hz,2H),6.98-7.01(m,1H ),6.87(s,1H),4.48-4.56(m,1H),3.21(s,1H),3.19(s,1H),2.41(t,J=12.0 Hz,2H),2.26(d,J=12.0Hz,2H),2.02(t,J=4.5Hz,2H),1.67-1.79(m,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ157.90,152.05,144.92,136.19,135.11,132.69,132.29,130.35,124.39,123.15,1 20.52,117.15,116.76,104.60,100.64,55.37,54.78,49.05,29.34,28.75,26.27ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of N5O is 358.1662, and the measured value is 358.1655.

[0554] Example 36

[0555]

[0556]

[0557] trans-4-(2-(2,4-dihydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0558]

[0559] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2,4-dihydroxybenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 77%). HRMS (ESI): m / z [M+H] + .C 27 H 24 The calculated value of N5O4S is 514.1544, and the measured value is 514.1560.

[0560] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(2,4-dihydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS36: trans-4-(2-(2,4-dihydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.92 (s, 1H), 8.58 (s, 1H), 7.49 (s, 1H), 7.19 (d, J=9.0Hz,1H),6.84(s,1H),6.58(s,1H),6.41–6.44(m,1H),4.23(d,J=9.0Hz, 1H),3.14(t,J=12.0Hz,1H),2.79(d,J=18.0Hz,1H),2.36(d,J=9.0Hz,2H),2 .26(d,J=15.0Hz,2H),2.02(s,1H),1.62-1.74(m,2H),1.18-1.26(m,2H)ppm; 13 C NMR (75MHz, DMSO-d6) δ160.50,157.73,150.96,144.77,135.36,133.04,132.21,124.09,123.21,109. 32,107.49,104.42,85.32,73.67,60.22,54.89,29.20,28.95,26.39,14.55ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of N5O2 is 374.1612, and the measured value is 374.1600.

[0561] Example 37

[0562]

[0563] trans-4-(2-(4-(trifluoromethyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0564]

[0565] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 4-trifluoromethylbenzaldehyde (0.3 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(6-(benzenesulfonyl)-2-(4-(trifluoromethyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 72%). HRMS (ESI): m / z [M+H] + .C 28 H 23 The calculated value of F3N5O2S is 550.1519, and the measured value is 550.1521.

[0566] Step 2: Dissolve 0.3 g (0.5 mmol) of trans-4-(6-(benzenesulfonyl)-2-(4-(trifluoromethyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS37: trans-4-(2-(4-(trifluoromethyl)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 45%). 1HNMR (300MHz, DMSO-d6): δ = 12.04 (s, 1H), 8.68 (s, 1H), 7.97 (d, J = 3.0Hz, 4H), 7.56 (t, J = 3.0Hz, 1H), 6.89 (s, 1H), 4.45-4.53 (m, 1H) ,3.17(t,J=13.5Hz,1H),2.40(t,J=10.5Hz,2H),2.23(d,J=12.0Hz,2H),2.03(t,J=10.5Hz,2H),1.74-1.86(m,2H),1.25(s,1H)ppm; 13 C NMR(75MHz,DMSO-d6)δ150.58,145.02,136.44,135.27,132.89,131.00,130.63,129.90,126.38,12 6.10,124.55,123.21,104.58,100.85,72.19,54.92,29.32,28.50,26.22ppm; HRMS(ESI):m / z[M+H] + .C 22 H 19 The calculated value of F3N5 is 410.1587, and the measured value is 410.1590.

[0567] Example 38

[0568]

[0569] trans-4-(2-(2-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0570]

[0571] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2-hydroxybenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 27 H 24 The calculated value of N5O3S is 498.1594, and the measured value is 498.1600.

[0572] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(2-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS38: trans-4-(2-(2-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.94 (s, 1H), 10.17 (s, 1H), 8.62 (s, 1H), 7.52 (t, J = 3.0Hz, 1H), 7.40-7.46 (m, 2H), 6.98-7.08 (m, 2H), 6.87 (d, J = 3 .0Hz,1H),4.18-4.26(m,1H),3.14(t,J=12.0Hz,1H),2.38(t,J=12.0Hz,2H),2.26(d,J=10.5Hz,2H),1.60-1.72(m,2H),1.18-1.26(m,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ156.49,150.28,144.85,135.95,135.45,132.47,132.24,131.75,124.19,123.1 6,119.68,118.54,116.23,104.41,100.53,72.30,55.03,29.22,28.89,26.37ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of N5O is 358.1662, and the measured value is 358.1658.

[0573] Example 39

[0574]

[0575] trans-4-(2-(2-fluoro-4-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0576]

[0577] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2-fluoro-4-hydroxybenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-fluoro-4-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a pale yellow oil (0.3 g, 77%). HRMS (ESI): m / z [M+H] + .C 27 H 23 The calculated value of FN5O3S is 516.1500, and the measured value is 516.1511.

[0578] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(2-fluoro-4-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS39: trans-4-(2-(2-fluoro-4-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.99 (s, 1H), 8.63 (s, 1H), 7.54 (t, J = 3.0Hz, 1H), 7.43- 7.49(m,1H),6.88(d,J=3.0Hz,1H),6.82–6.85(m,1H),6.80(d,J=3.0Hz,1H),4.24( d,J=12.0Hz,1H),3.13(t,J=13.5Hz,1H),2.34(d,J=12.0Hz,2H),2.23(d,J=12.0Hz ,2H),2.02(s,1H),1.94(d,J=9.0Hz,2H),1.70-1.82(m,2H),1.18-1.26(m,1H)ppm; 13 C NMR(75MHz,DMSO-d6)δ160.11,159.75,153.77,148.62,142.15,130.54,129.04,127.16,122.75,12 0.77,116.16,115.64,112.04,104.54,99.38,65.93,30.88,26.91,23.69ppm; HRMS(ESI):m / z[M+H] + .C 21 H 19 The calculated value of FN5O is 376.1568, and the measured value is 376.1562.

[0579] Example 40

[0580]

[0581] trans-4-(2-(2-fluorophenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0582]

[0583] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2-fluorobenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-fluorophenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a pale yellow oil (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 27 H 23 The calculated value of FN5O2S is 500.1551, and the measured value is 500.1563.

[0584] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(2-fluorophenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS40: trans-4-(2-(2-fluorophenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1HNMR (300MHz, DMSO-d6): δ = 12.06 (s, 1H), 8.70 (s, 1H), 7.70 (t, J = 6.0Hz, 2H), 7.57 (s, 1H), 7.49 (t, J = 9.0Hz, 2H), 6.91 (s, 1H) ),4.27(s,1H),3.13(s,1H),2.35(d,J=12.0Hz,2H),2.24(d,J=9.0Hz,2H),2.01(d,J=6.0Hz,2H),1.75(d,J=12.0Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ162.07,158.80,146.49,145.00,136.27,135.41,133.08,132.92,132.42,125.44,124.54,123.1 1,119.40,119.19,116.62,116.34,104.40,100.51,60.22,55.18,29.42,28.59,26.29,14.51ppm; HRMS(ESI):m / z[M+H] + .C 21 H 19 The calculated value of FN5 is 360.1619, and the measured value is 360.1615.

[0585] Example 41

[0586]

[0587] trans-4-(2-(2-hydroxy-4-methoxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0588]

[0589] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 2-fluoro4-methoxybenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(2-hydroxy-4-methoxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 75%). HRMS (ESI): m / z [M+H] + .C 28 H 26 The calculated value of N5O4S is 528.1700, and the measured value is 528.1711.

[0590] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(2-hydroxy-4-methoxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS41: trans-4-(2-(2-hydroxy-4-methoxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1HNMR (300MHz, DMSO-d6): δ = 11.91 (s, 1H), 10.26 (s, 1H), 8.60 (s, 1H), 7.51 (t, J=3.0Hz,1H),7.34(d,J=9.0Hz,1H),6.86(d,J=3.0Hz,1H),6.58-6.61(m,2H) ,4.24(t,J=13.5Hz,1H),3.83(s,3H),3.15(t,J=12.0Hz,1H),2.39(t,J=12.0 Hz,2H),2.25(d,J=12.0Hz,2H),2.01(d,J=12.0Hz,2H),1.62-1.74(m,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ162.03,157.72,150.38,144.83,135.83,135.37,133.21,132.24,124.14,12 3.19,111.08,105.80,104.42,101.63,55.60,54.94,29.20,28.92,26.38ppm; HRMS(ESI):m / z[M+H] + .C 22 H 22 The calculated value of N5O2 is 388.1768, and the measured value is 366.1782.

[0591] Example 42

[0592]

[0593] trans-4-(2-(4-(methylthio)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0594]

[0595] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 4-methylthiobenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(4-(methylthio)phenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 75%). HRMS (ESI): m / z [M+H] + .C 28 H 26 The calculated value of N5O2S2 is 528.1522, and the measured value is 528.1533.

[0596] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(4-(methylthio)phenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS42: trans-4-(2-(4-(methylthio)phenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.98 (s, 1H), 8.65 (s, 1H), 7.66 (d, J = 9.0Hz, 2H), 7.54 (t, J = 3.0Hz, 1H), 7.48 (d, J = 9.0Hz, 2H), 6.88 (d, J = 3.0Hz, 1H), 4.4 9(t,J=13.5Hz,1H),3.17(t,J=12.0Hz,1H),2.61(s,3H),2.45(t,J=12.0Hz ,2H),2.25(d,J=12.0Hz,2H),2.03(d,J=6.0Hz,2H),1.71-1.83(m,2H)ppm;13 C NMR(75MHz,DMSO-d6)δ153.77,148.43,142.89,139.43,129.04,127.77,127.32,127.17,127.0 1,122.74,120.73,115.64,99.49,65.93,31.96,26.94,24.68,14.88ppm; HRMS(ESI):m / z[M+H] + .C 22 H 22 The calculated value of N5O2 is 388.1590, and the measured value is 388.1599.

[0597] Example 43

[0598]

[0599] trans-4-(2-(4-fluorophenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0600]

[0601] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 4-fluorobenzaldehyde (0.2 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(4-fluorophenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 27 H 23 The calculated value of FN5O2S is 500.1551, and the measured value is 500.1559.

[0602] Step 2: Dissolve 0.3 g (0.6 mmol) of trans-4-(2-(4-fluorophenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS43: trans-4-(2-(4-fluorophenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.99 (s, 1H), 8.65 (s, 1H), 7.74-7.79 (m, 2H), 7.54 (t, J = 3.0Hz, 1H), 7.46 (t, J = 9.0Hz, 2H), 6.88 (d, J = 3.0Hz, 1 H),4.44(t,J=12.0Hz,1H),3.15(t,J=12.0Hz,1H),2.34-2.47(m,2H),2.24(d,J=12.0Hz,2H),2.04(d,J=9.0Hz,2H),1.70-1.81(m,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ162.99,153.74,148.65,142.11,129.19,129.03,127.43,126.22,12 2.74,120.75,116.43,115.64,99.40,65.93,30.82,26.94,21.54ppm; HRMS(ESI):m / z[M+H] + .C 21 H 19 The calculated value of FN5 is 360.1619, and the measured value is 360.1683.

[0603] Example 44

[0604]

[0605] trans-4-(2-(4-(methylsulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylon

[0606]

[0607] Step 1: Dissolve trans-4-((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexanecarboxylonitrile (0.3 g, 0.8 mmol) in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 4-methylsulfonylbenzaldehyde (0.3 g, 1.6 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-4-(2-(4-(methanesulfonyl)phenyl)-6-(phenylsulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxynitrile as a yellow oil (0.3 g, 70%). HRMS (ESI): m / z [M+H] + .C 28 H 28 The calculated value of N5O4S2 is 562.1577, and the measured value is 562.1588.

[0608] Step 2: Dissolve 0.3 g (0.5 mmol) of trans-4-(2-(4-(methanesulfonyl)phenyl)-6-(phenylsulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS44: trans-4-(2-(4-(methylsulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexanecarboxylonitrile (0.2 g, 89%). 1HNMR (300MHz, DMSO-d6): δ = 11.40 (s, 1H), 8.93 (s, 1H), 8.22 (d, J = 9.0Hz, 2H), 8.14(s,1H),8.06(d,J=6.0Hz,2H),7.22(t,J=3.0Hz,1H),6.63(d,J=3.0Hz,1 H),6.07(d,J=9.0Hz,1H),4.02-4.10(m,1H),3.30(s,3H),2.73-2.81(m,1H), 2.12(d,J=9.0Hz,2H),2.03(s,2H),1.76-1.87(m,2H),1.44-1.55(m,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ144.28,139.38,138.74,134.46,131.18,128.94,128.11,127.19,123. 38,122.74,108.17,99.36,83.56,61.28,47.74,28.48,26.94,24.93ppm; HRMS(ESI):m / z[M+H] + .C 22 H 24 The calculated value of N5O2S is 422.1645, and the measured value is 422.1679.

[0609] Example 45

[0610]

[0611] (5-(1-(1-(1-(cyclopropylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-ylmethanol

[0612]

[0613] Step 1: Dissolve 0.3 g (0.6 mmol) of (5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.2 mmol) and then slowly add cyclopropylsulfonyl chloride (0.1 g, 0.9 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (5-(6-(benzenesulfonyl)-1-(1-(cyclopropylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylfuran-2-yl)methanol as a yellow oil (0.3 g, 82%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 26 The calculated value of N5O6S2 is 568.1319, and the measured value is 568.1321.

[0614] Step 2: Dissolve 0.3 g (0.5 mmol) of (5-(6-(benzenesulfonyl)-1-(1-(cyclopropylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylfuran-2-yl)methanol in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS45:(5-(1-(1-(1-(cyclopropylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-ylmethanol (0.1 g, 44%). 1HNMR (300MHz, DMSO-d6): δ = 12.09 (s, 1H), 8.67 (s, 1H), 7.61 (t, J = 3.0Hz, 1H), 7.19 ( d,J=3.0Hz,1H),6.85(s,1H),6.63(d,J=3.0Hz,1H),5.80-5.92(m,1H),5.51(t,J=6 .0Hz,1H),4.58(d,J=6.0Hz,2H),4.04-4.10(m,1H),3.81–3.90(m,2H),3.58-3.67( m,1H),2.89-2.97(m,1H),2.71–2.80(m,2H),1.26(s,1H),1.06(t,J=6.0Hz,4H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.88,151.18,148.60,144.53,142.17,129.04,127.16,120.88,115.63, 107.95,104.05,99.38,57.39,56.43,54.43,49.75,37.55,24.66,4.07ppm; HRMS(ESI):m / z[M+H] + .C 20 H 22 The calculated value of N5O4S is 428.1387, and the measured value is 428.1384.

[0615] Example 46

[0616]

[0617] 3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile

[0618]

[0619] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-hydroxymethylfurfural (0.2 g, 1.4 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile as a yellow oil (0.3 g, 79%). HRMS(ESI): m / z [M+H] + .C 25 H 20 The calculated value of N7O4S is 514.1292, and the measured value is 514.1299.

[0620] Step 2: Dissolve 0.3 g (0.6 mmol) of 3-(4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS46: 3-(4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.59 (s, 1H), 7.02 (d, J = 6. 0Hz,1H),6.78(s,1H),6.59(d,J=6.0Hz,1H),5.04(t,J=7.5Hz,2H),4.39(s,2H),3.28(t,J=7.5Hz,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ153.89,151.18,148.69,142.17,141.89,130.74,129.74,129.04,127.17,12 0.73,117.77,115.63,107.94,104.05,100.05,99.49,57.40,49.27,15.93ppm; HRMS(ESI):m / z[M+H] + .C 19 H 16 The calculated value of N7O2 is 374.1360, and the measured value is 374.1377.

[0621] Example 47

[0622]

[0623] 3-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-amine

[0624]

[0625] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester in 10 mL of DMF, add Na2S2O5 (0.7 g, 3.5 mmol), then add 0.2 g (1.4 mmol) of 2-amino-3-pyridinecarboxaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and... The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(2-(2-aminopyridin-3-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester as a yellow solid (0.3 g, 82%). HRMS (ESI): m / z [M+H] + .C 28 H 30 The calculated value of N7O4S is 560.2074, and the measured value is 560.2077.

[0626] Step 2: 0.3 g (0.5 mmol) of tert-butyl 3-(2-(2-aminopyridin-3-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carboxylic acid ester was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.6 g, 5.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 0.2 g (81%) of 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)pyridine-2-amine as a pale yellow oil. This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 22 The calculated value of N7O2S is 460.1550, and the measured value is 460.1566.

[0627] Step 3: Dissolve 0.2 g (0.4 mmol) of 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)pyridine-2-amine in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.8 mmol), then slowly add propanesulfonyl chloride (0.1 g, 0.6 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylpyridine-2-amine as a pale yellow oil (0.2 g, 81%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 28 The calculated value of N7O4S2 is 566.1639, and the measured value is 566.1645.

[0628] Step 4: Dissolve 0.2 g (0.4 mmol) of 3-(6-(benzenesulfonyl)-1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-ylpyridin-2-amine in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS47: 3-(1-(1-(1-(propylsulfonyl)pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)pyridine-2-amine (0.1 g, 67%). 1 HNMR (300MHz, DMSO-d6): δ=12.06(s,1H),8.83(s,1H),8.03(t,J=7.5Hz,1H ),7.74(s,2H),7.66(d,J=6.0Hz,1H),7.56(s,1H),6.81(s,1H),6.68(t,J= 7.5Hz,1H),3.65-3.79(m,1H),3.12-3.36(m,2H),3.10(t,J=9.0Hz,2H),2. 70-2.81(m,2H),1.85-2.14(m,2H),1.69(m,2H),0.93(t,J=7.5Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ156.68,153.77,148.64,146.69,142.19,134.84,129.04,127.16,120.74,118. 74,115.63,113.59,99.49,60.47,56.83,56.18,50.04,26.25,13.38,12.48ppm; HRMS(ESI):m / z[M+H] + .C 20 H 24 The calculated value of N7O2S is 426.1707, and the measured value is 426.1705.

[0629] Example 48

[0630]

[0631] 2-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)acetonitrile

[0632]

[0633] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 2-bromoacetonitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile as a pale yellow oil (0.2 g, 61%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 22 H 23 The calculated value of N6O3S is 451.1547, and the measured value is 451.1550.

[0634] Step 2: Dissolve 0.2 g (0.4 mmol) of 2-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidone-1-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS48: 2-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile (0.1 g, 73%). 1HNMR (300MHz, DMSO-d6): δ = 11.86 (s, 1H), 8.87 (s, 1H), 7.59 (s, 1H), 6.89 (s, 1H), 4.53-4.68 (m, 1H), 3.68-3 .78(m,1H),3.48(s,2H),2.56-2.81(m,2H),2.20-2.30(m,2H),1.90-2.15(m,2H),1.93(t,J=6.0Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ148.59,142.17,129.04,127.16,120.75,115.63,114.78, 99.28,63.69,58.18,57.39,54.83,50.04,26.97,22.86ppm; HRMS(ESI):m / z[M+H] + .C 16 H 19 The calculated value of N6O is 311.1615, and the measured value is 311.1618.

[0635] Example 49

[0636]

[0637] 3-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile

[0638]

[0639] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 3-bromopropionitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile as a pale yellow oil (0.2 g, 59%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C23 H 25 The calculated value of N6O3S is 465.1703, and the measured value is 465.1709.

[0640] Step 2: Dissolve 0.2 g (0.4 mmol) of 2-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidone-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS49: 2-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile (0.1 g, 72%). 1 HNMR (300MHz, DMSO-d6): δ=12.14(s,1H),8.97(s,1H),7.53(s,1H),6.91(s,1H),4.58-4.72(m,1H),3.69-3.81(m,1H),3.01 (t,J=9.0Hz,2H),2.72-2.85(m,2H),2.70(t,J=9.0Hz,2H),2.22-2.36(m,2H),1.93-2.19(m,2H),1.58(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ148.66,142.98,129.03,127.17,120.77,119.04,115.69, 99.38,63.69,58.94,57.69,55.16,27.64,22.85,17.17ppm; HRMS(ESI):m / z[M+H] + .C 17 H 21 The calculated value of N6O is 325.1771, and the measured value is 325.1777.

[0641] Example 50

[0642]

[0643] 3-(4-(2-(5-methylfuran-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-ylpropionitrile

[0644]

[0645] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 5-methylfurfural (0.2 g, 1.4 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(4-(2-(5-methylfuran-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile as a yellow oil (0.3 g, 82%). HRMS(ESI): m / z [M+H] + .C 25 H 20 The calculated value of N7O3S is 498.1343, and the measured value is 498.1350.

[0646] Step 2: Dissolve 0.3 g (0.6 mmol) of 3-(4-(2-(5-methylfuran-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS50: 3-(4-(2-(5-methylfuran-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-ylpropionitrile (0.1 g, 46%). 1HNMR (300MHz, DMSO-d6): δ = 11.87 (s, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 7.95 (s, 1H), 7.34 (s, 1H), 6.32 (d, J=3.0Hz,1H),6.21(s,1H),5.95(s,1H),4.61(t,J=4.5Hz,2H),3.26(t,J=6.0Hz,2H),2.36(s,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ154.31,145.68,143.29,142.72,138.24,135.85,135.54,134.05,129.75,12 4.57,118.82,118.75,113.43,108.51,104.57,96.45,48.05,19.20,13.73ppm; HRMS(ESI):m / z[M+H] + .C 19 H 16 The calculated value of N7O is 358.1411, and the measured value is 358.1414.

[0647] Example 51

[0648]

[0649] 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile

[0650]

[0651] Step 1: Dissolve 0.3 g (0.6 mmol) of (5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.2 mmol) and then slowly add 3-bromopropionitrile (0.2 g, 0.9 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile as a pale yellow oil (0.2 g, 60%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 25 The calculated value of N6O4S is 517.1653, and the measured value is 517.1659.

[0652] Step 2: Dissolve 0.2 g (0.4 mmol) of 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS51: 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile (0.1 g, 69%). 1HNMR (300MHz, DMSO-d6): δ = 12.03 (s, 1H), 8.88 (s, 1H), 7.59 (s, 1H), 7.02 (d, J = 9.0Hz, 1H), 6.84 (s, 1H), 6.59 (d, J = 9.0Hz, 1H), 4.39 ( s,2H),3.64-3.78(m,1H),3.03(t,J=9.0Hz,2H),2.74-2.86(m,2H),2.73(t,J=9.0Hz,2H),2.20-2.35(m,2H),1.90-2.15(m,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.88,151.18,148.64,144.94,142.17,129.04,127.18,120.79,119.04,1 15.63,107.94,104.06,99.38,57.39,57.01,55.84,55.19,27.05,17.16ppm; HRMS(ESI):m / z[M+H] + .C 20 H 21 The calculated value of N6O2 is 377.1721, and the measured value is 377.1728.

[0653] Example 52

[0654]

[0655] 2-(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-ylacetonitrile

[0656]

[0657] Step 1: Dissolve 0.3 g (0.6 mmol) of (5-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-methanol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.2 mmol) and then slowly add 2-bromoacetonitrile (0.2 g, 0.9 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution shows a weakly positive color. The solution was prepared using an alkaline solution, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile as a pale yellow oil (0.2 g, 61%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 25 H 23 The calculated value of N6O4S is 503.1496, and the measured value is 503.1500.

[0658] Step 2: Dissolve 0.2 g (0.4 mmol) of 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS52: 3-(3-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile (0.1 g, 69%). 1 HNMR (300MHz, DMSO-d6): δ = 11.99 (s, 1H), 8.67 (s, 1H), 7.58 (s, 1H), 7.06 (d, J = 7.5Hz, 1H), 6.88 (s, 1H), 6.54 (d, J = 7 .5Hz,1H),4.33(s,2H),3.69-3.83(m,1H),3.48(s,2H),2.56-2.81(m,2H),2.20-2.30(m,2H),1.93-2.18(m,2H)ppm;13 C NMR(75MHz,DMSO-d6)δ153.97,151.19,148.63,144.95,142.18,129.03,127.17,120.75,115.69,1 14.84,107.94,104.05,99.39,57.36,56.72,55.09,54.81,50.05,26.29ppm; HRMS(ESI):m / z[M+H] + .C 19 H 19 The calculated value of N6O2 is 363.1564, and the measured value is 363.1569.

[0659] Example 53

[0660]

[0661] 2-(3-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)acetonitrile

[0662]

[0663] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)phenol in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol) and then slowly add 2-bromoacetonitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(3-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile as a yellow oil (0.2 g, 61%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 26 H 23 The calculated value of N6O3S is 499.1547, and the measured value is 499.1550.

[0664] Step 2: Dissolve 0.2 g (0.4 mmol) of (3-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS53: 2-(3-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)acetonitrile (0.1 g, 70%). 1 HNMR (300MHz, DMSO-d6): δ = 12.09 (s, 1H), 8.83 (s, 1H), 7.84 (d, J = 6.0Hz, 1H), 7.66 (s, 1H), 7.34 (t, J = 6.0Hz, 1H), 7.04 (s, 1H), 6 .91(d,J=6.0Hz,1H),6.83(s,1H),3.71–3.82(m,1H),3.49(s,2H),2.58-2.83(m,2H),2.17-2.36(m,2H),1.90-2.16(m,2H)ppm; 13 CNMR(75MHz,DMSO-d6)δ157.59,153.75,148.63,142.17,132.05,130.65,129.05,127.16,120.75,1 20.11,115.94,115.65,114.85,112.94,99.38,57.3,54.84,50.04,26.84ppm; HRMS(ESI):m / z[M+H] + .C 20 H 19 The calculated value of N6O is 359.1615, and the measured value is 359.1619.

[0665] Example 54

[0666]

[0667] (R)-4-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile

[0668]

[0669] Step 1: Triethyloxonium tetrafluoroboric acid (0.5 g, 2.4 mmol) and (R)-lactamide (0.2 g, 2.4 mmol) were dissolved in 10 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 10 mL of ethanol was added to dissolve the oil, followed by the addition of 4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile (0.3 g, 0.8 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (R)-4-(2-(1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile as a pale green oil (0.3 g, 88%). HRMS (ESI): m / z [M+H] + .C 23 H 18 The calculated value of N5O3S is 444.1125, and the measured value is 444.1129.

[0670] Step 2: (R)-4-(2-(1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.3 g, 0.7 mmol) was dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. 5 mL of 1 M sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain LXS54: (R)-4-(2-(1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.1 g, 49%). 1 HNMR (300MHz, DMSO-d6): δ = 12.01 (s, 1H), 8.91 (s, 1H), 7.80 (d, J = 9.0Hz, 2H), 7.64 (d, J=9.0Hz,2H),7.56(s,1H),6.88(s,1H),3.98-4.68(m,1H),1.49(d,J=7.5Hz,3H)ppm; 13C NMR(75MHz,DMSO-d6)δ151.75,148.69,142.16,140.48,134.27,129.04,127.18,122 .84,120.73,118.64,115.67,112.17,99.38,62.95,22.84ppm; HRMS(ESI):m / z[M+H] + .C 17 H 14 The calculated value of N5O is 304.1193, and the measured value is 304.1203.

[0671] Example 55

[0672]

[0673] 4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzylnitrile

[0674]

[0675] Step 1: Dissolve 0.3 g (0.8 mmol) of 4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile in 10 mL of DMF, add 0.8 g (4 mmol) of Na2S2O5, then add 0.2 g (1.6 mmol) of 5-hydroxymethylfurfural. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile as a yellow oil (0.3 g, 79%). HRMS (ESI): m / z [M+H] + .C 26 H 18 The calculated value of N5O4S is 496.1074, and the measured value is 496.1080.

[0676] Step 2: Dissolve 0.3 g (0.6 mmol) of 4-(2-(5-(hydroxymethyl)furan-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and then separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS55: 4-(2-(5-(hydroxymethyl)furan-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.1 g, 47%). 1 HNMR (300MHz, DMSO-d6): δ=11.91(s,1H),8.73(s,1H),7.83(d,J=6.0Hz,2H),7.68(d,J=6.0Hz ,2H),7.56(s,1H),7.02(d,J=9.0Hz,1H),6.83(s,1H),6.59(d,J=9.0Hz,1H),4.39(s,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.85,151.17,148.64,142.59,142.31,134.27,129.05,127.17,122 .85,120.73,118.65,115.69,112.15,107.94,104.06,99.38,57.39ppm; HRMS(ESI):m / z[M+H] + .C 20 H 14 N5O2 356.1142, measured value 356.1149.

[0677] Example 56

[0678]

[0679] 4-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile

[0680]

[0681] Step 1: Dissolve 0.3 g (0.8 mmol) of 4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile in 10 mL of DMF, add Na2S2O5 (0.8 g, 4 mmol), then add 0.2 g (1.6 mmol) of 3-hydroxybenzaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. Combine the organic phases and wash with saturated brine. Dry with anhydrous sodium sulfate and concentrate under vacuum to obtain 0.3 g (79%) of 4-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile as a yellow oil. HRMS(ESI):m / z[M+H] + .C 27 H 18 The calculated value of N5O3S is 492.1125, and the measured value is 492.1134.

[0682] Step 2: 4-(2-(3-hydroxyphenyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.3 g, 0.6 mmol) was dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. 5 mL of 1 M sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain LXS56: 4-(2-(3-hydroxyphenyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.1 g, 47%). 1 HNMR (300MHz, DMSO-d6): δ = 12.06 (s, 1H), 8.83 (s, 1H), 7.84-7.93 (m, 1H), 7.81 (d, J = 7.5Hz, 2H), 7.64 (d ,J=7.5Hz,2H),7.58(s,1H),7.34(t,J=9.0Hz,1H),7.08(s,1H),6.91(d,J=9.0Hz,1H),6.88(s,1H)ppm; 13C NMR (75MHz, DMSO-d6) δ157.89,148.99,144.47,142.59,142.16,134.27,132.04,130.64,129.05,127. 49,122.84,120.75,120.16,118.69,115.96,115.61,112.94,112.15,99.54ppm; HRMS(ESI):m / z[M+H] + .C 21 H 14 The calculated value of N5O is 352.1193, and the measured value is 352.1199.

[0683] Example 57

[0684]

[0685] 4-(2-(4-(methylsulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile

[0686]

[0687] Step 1: Dissolve 0.3 g (0.8 mmol) of 4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)benzyl nitrile in 10 mL of DMF, add 0.8 g (4 mmol) of Na2S2O5, then add 0.3 g (1.6 mmol) of 4-methylsulfonylbenzaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 4-(2-(4-(methanesulfonyl)phenyl)-6-(phenylsulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile as a yellow oil (0.3 g, 70%). HRMS (ESI): m / z [M+H] + .C 28 H 22 The calculated value of N5O4S2 is 556.1108, and the measured value is 556.1113.

[0688] Step 2: Dissolve 0.3 g (0.5 mmol) of 4-(2-(4-(methanesulfonyl)phenyl)-6-(phenylsulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS57: 4-(2-(4-(methanesulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)benzyl nitrile (0.1 g, 45%). 1 HNMR (300MHz, DMSO-d6): δ = 11.86 (s, 1H), 7.89 (s, 1H), 7.74 (d, J = 6.0Hz, 2H), 7.63 (s, 1H), 7.54 (d, J =6.0Hz,2H),7.42(d,J=9.0Hz,2H),6.88(s,1H),6.78(d,J=9.0Hz,2H),5.08(s,1H),3.32(s,1H)ppm; 13 C NMR(75MHz,DMSO-d6)δ153.77,149.47,139.04,138.79,134.41,133.05,131.18,128.15,127.93 ,127.16,123.38,118.66,114.28,108.15,101.04,99.37,87.84,47.72ppm; HRMS(ESI):m / z[M+H] + .C 22 H 18 The calculated value of N5O2S is 416.1176, and the measured value is 416.1180.

[0689] Example 58

[0690]

[0691] 3-((R)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile

[0692]

[0693] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((R-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 3-bromopropionitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate to the reaction solution. The solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-((R)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile as a pale yellow oil (0.2 g, 59%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 25 The calculated value of N6O3S is 465.1703, and the measured value is 465.1709.

[0694] Step 2: Dissolve 0.2 g (0.4 mmol) of 3-((R)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS58: 3-((R)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile (0.1 g, 72%). 1HNMR (300MHz, DMSO-d6): δ=11.98(s,1H),8.73(s,1H),7.56(s,1H),6.78(s,1H),4.61–4.75(m,1H),3.65-3.83(m,1H),3.04 (t,J=6.0Hz,2H),2.70-2.83(m,2H),2.73(t,J=6.0Hz,2H),2.20-2.31(m,2H),1.90-2.15(m,2H),1.49(t,J=7.5Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.64,148.59,142.19,129.03,127.16,120.74,119.04,115. 69,99.39,63.62,58.91,57.63,55.16,27.63,22.84,17.19ppm; HRMS(ESI):m / z[M+H] + .C 17 H 21 The calculated value of N6O is 325.1771, and the measured value is 325.1777.

[0695] Example 59

[0696]

[0697] 3-((S)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile

[0698]

[0699] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((S-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 3-bromopropionitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate to the reaction solution. The solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-((S)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile as a pale yellow oil (0.2 g, 59%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 23 H 25 The calculated value of N6O3S is 465.1703, and the measured value is 465.1711.

[0700] Step 2: Dissolve 0.2 g (0.4 mmol) of 3-((S)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS59: 3-((S)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile (0.1 g, 72%). 1HNMR (300MHz, DMSO-d6): δ=11.99(s,1H),8.83(s,1H),7.59(s,1H),6.88(s,1H),4.51–4.69(m,1H),3.65-3.85(m,1H),3.05 (t,J=9.0Hz,2H),2.76-2.89(m,2H),2.73(t,J=9.0Hz,2H),2.20-2.41(m,2H),1.95-2.22(m,2H),1.43(t,J=7.5Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.61,148.57,142.11,128.64,126.11,120.73,118.57,115. 62,99.38,63.62,58.93,57.62,55.17,27.64,22.89,16.14ppm; HRMS(ESI):m / z[M+H] + .C 17 H 21 The calculated value of N6O is 325.1771, and the measured value is 325.1780.

[0701] Example 60

[0702]

[0703] 3-(3-(2-(4-(methylsulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile

[0704]

[0705] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(((5-amino-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)pyrrolidin-1-carboxylic acid tert-butyl ester in 10 In mL of DMF, Na₂S₂O₅ (0.7 g, 3.5 mmol) was added, followed by 4-methylsulfonylbenzaldehyde (0.2 g, 1.4 mmol). After the addition was complete, the mixture was heated to 90 °C and stirred for 12 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give 3-(2-(4-(methylsulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester as a yellow solid (0.2 g, 49%). HRMS (ESI): m / z [M+H] + .C 30 H 34 The calculated value of N5O6S2 is 624.1945, and the measured value is 624.1955.

[0706] Step 2: 3-(2-(4-(methanesulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(6H)-pyrrolidine-1-carboxylic acid ester (0.2 g, 0.3 mmol) was dissolved in 10 mL of dichloromethane. Trifluoroacetic acid (0.4 g, 3.0 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours. The solution was then concentrated under vacuum to obtain 2-(4-(methanesulfonyl)phenyl)-6-(phenylsulfonyl)-1-(pyrrolidine-3-yl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine as a pale yellow oil (0.1 g, 60%). This product can be used directly in the next step without further purification. HRMS(ESI): m / z [M+H] + .C 25 H 26 The calculated value of N5O4S2 is 524.1421, and the measured value is 524.1427.

[0707] Step 3: Dissolve 0.1 g (0.2 mmol) of 2-(4-(methylsulfonyl)phenyl)-6-(phenylsulfonyl)-1-(pyrrolidine-3-yl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.4 mmol), then slowly add 0.1 g (0.3 mmol) dropwise. After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(3-(2-(4-(methanesulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile as a pale yellow oil (0.1 g, 91%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 28 H 29 The calculated value of N6O4S2 is 577.1686, and the measured value is 577.1688.

[0708] Step 4: Dissolve 0.1 g (0.2 mmol) of 3-(3-(2-(4-(methanesulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylpropionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS60: 3-(3-(2-(4-(methanesulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)propionitrile (60.0 mg, 79%). 1HNMR (300MHz, DMSO-d6): δ = 11.46 (s, 1H), 7.89 (s, 1H), 7.74 (d, J = 9.0Hz, 2H), 7.56 (s, 1H), 7.51 (d, J = 9.0Hz, 2H), 6.88 (s, 1H), 5.04 (s, 1H) ,3.32(s,3H),3.03(t,J=9.0Hz,2H),2.75(t,J=9.0Hz,2H),2.66-2.71(m,1H),2.31–2.56(m,2H),2.19-2.33(m,2H),1.66-2.02(m,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ144.28,139.28,138.73,134.49,131.18,128.95,128.15,127.15,123.38,119 .04,108.16,99.38,83.28,62.18,59.28,55.41,55.14,47.72,33.58,17.10ppm; HRMS(ESI):m / z[M+H] + .C 22 H 25 The calculated value of N6O2S is 437.1754, and the measured value is 437.1759.

[0709] Example 61

[0710]

[0711] 1-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-carbonyl)cyclopropanecarboxylonite

[0712]

[0713] Step 1: Dissolve (1R)-1-(6-(benzenesulfonyl)-1-(pyrrolidine-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 3-bromopropanecyanate (0.2 g, 1.1 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 1-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)cyclopropaneformitrile as a yellow oil (0.3 g, 82%). This product can be used directly for the next step without further purification. HRMS(ESI): m / z [M+H] + .C 25 H 25 The calculated value of N6O4S is 505.1653, and the measured value is 505.1660.

[0714] Step 2: Dissolve 0.3 g (0.6 mmol) of 1-(3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)cyclopropanecarboxylonitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS61: 1-(3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-carbonyl)cyclopropaneformonitrile (0.1 g, 46%). 1 HNMR (300MHz, DMSO-d6): δ = 12.06 (s, 1H), 7.55 (s, 1H), 6.87 (s, 1H), 4.33-4.68 (m, 1H), 3.89-4.17 (m, 1H) ),3.77-4.03(m,2H),3.41-3.51(m,2H),2.29-2.54(m,2H),1.48(d,J=9.0Hz,3H),0.67-0.92(m,4H)ppm; 13C NMR(75MHz,DMSO-d6)δ180.77,148.66,148.53,142.17,129.00,127.17,120.73,115.63,114 .47,99.39,63.69,58.42,51.88,46.48,27.15,22.84,13.63,10.06ppm; HRMS(ESI):m / z[M+H] + .C 19 H 21 The calculated value of N6O2 is 365.1721, and the measured value is 365.1711.

[0715] Example 62

[0716]

[0717] 2-(1-(ethylsulfonyl)-3-(4-(2-(5-methylthiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile

[0718]

[0719] Step 1: Dissolve tert-butyl 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid ester (0.3 g, 0.6 mmol) in 10 mL of DMF, add Na2S2O5 (0.6 g, 3.0 mmol), then add 5-methyl-2-thiophenecarboxaldehyde (0.2 g, 0.9 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(cyanomethyl)-3-(4-(2-(5-methylthiophene-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester as a yellow solid (0.2 g, 56%). HRMS (ESI): m / z [M+H] + .C 32 H 31 The calculated value of N8O4S2 is 655.1904, and the measured value is 655.1909.

[0720] Step 2: Dissolve tert-butyl 3-(cyanomethyl)-3-(4-(2-(5-methylthiophen-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester (0.2 g, 0.3 mmol) in 10 mL of dichloromethane, slowly add trifluoroacetic acid (0.4 g, 3.0 mmol), stir at room temperature for 12 hours, and concentrate under vacuum to obtain 2-(3-(4-(2-(5-methylthiophen-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a light yellow oil (0.1 g, 59%). This product requires no further purification and can be used directly in the next step. HRMS(ESI): m / z [M+H] + .C 27 H 23 The calculated value of N8O2S2 is 555.1380, and the measured value is 555.1390.

[0721] Step 3: Dissolve 0.1 g (0.2 mmol) of 2-(3-(4-(2-(5-methylthiophene-2-yl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.1 g, 0.2 mmol), add DIPEA (0.1 g, 0.4 mmol), and then slowly add ethylsulfonyl chloride (0.1 g, 0.3 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(1-(ethylsulfonyl)-3-(4-(2-(5-methylthiophene-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a pale yellow oil (0.1 g, 86%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 29 H 27 The calculated value of N8O4S3 is 647.1312, and the measured value is 647.1318.

[0722] Step 4: Dissolve 0.1 g (0.2 mmol) of 2-(1-(ethylsulfonyl)-3-(4-(2-(5-methylthiophen-2-yl)-6-(phenylsulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (0.2 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS62: 2-(1-(ethylsulfonyl)-3-(4-(2-(5-methylthiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile (65.0 mg, 83%). 1 HNMR (300MHz, DMSO-d6): δ = 12.03 (s, 1H), 8.89 (s, 1H), 8.08 (s, 2H), 7.65 (s, 1H), 7.49 (d, J = 9.0Hz, 1H), 6.89 (s, 1H),6.84(d,J=9.0Hz,1H),3.89-4.06(m,4H),3.45(m,2H),2.81(s,2H),2.36(s,3H),1.22(t,J=7.5Hz,3H)ppm; 13 C NMR(75MHz,DMSO-d6)δ148.69,142.17,141.66,141.61,134.33,130.77,129.73,129.01,127.49,127.11, 120.73,117.74,115.63,100.54,99.31,59.29,51.66,50.83,23.28,15.22,2.69ppm; HRMS(ESI):m / z[M+H] + .C 23 H 23 The calculated value of N8O2S2 is 507.1380, and the measured value is 507.1390.

[0723] Example 63

[0724]

[0725] 2-(1-(ethylsulfonyl)-3-(4-(2-(thiophen-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobut-3-yl)acetonitrile

[0726]

[0727] Step 1: Dissolve tert-butyl 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)-3-(cyanomethyl)azacyclobutane-1-carboxylic acid ester (0.3 g, 0.6 mmol) in 10 mL of DMF, add Na2S2O5 (0.6 g, 3.0 mmol), then add 2-thiophenecarboxaldehyde (0.2 g, 0.9 mmol). After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 3-(cyanomethyl)-3-(4-(6-(benzenesulfonyl)-2-(thiophen-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1-6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester as a yellow solid (0.2 g, 57%). HRMS (ESI): m / z [M+H] + .C 31 H 29 The calculated value of N8O4S2 is 641.1748, and the measured value is 641.1751.

[0728] Step 2: Dissolve tert-butyl 3-(cyanomethyl)-3-(4-(6-(benzenesulfonyl)-2-(thiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid ester (0.2 g, 0.3 mmol) in 10 mL of dichloromethane, slowly add trifluoroacetic acid (0.4 g, 3.0 mmol), stir at room temperature for 12 hours, and concentrate under vacuum to obtain 2-(3-(4-(6-(benzenesulfonyl)-2-(thiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobutane-3-yl)acetonitrile as a light yellow oil (0.1 g, 59%). This product requires no further purification and can be used directly in the next step. HRMS(ESI): m / z [M+H] + .C 26 H 21The calculated value of N8O2S2 is 541.1223, and the measured value is 541.1230.

[0729] Step 3: Dissolve 0.1 g (0.2 mmol) of 2-(3-(4-(6-(benzenesulfonyl)-2-(thiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobut-3-yl)acetonitrile (0.1 g, 0.2 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.1 g, 0.4 mmol) and then slowly add ethylsulfonyl chloride (0.1 g, 0.3 mmol). After the addition is complete, stir at room temperature for 3 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 2-(3-(4-(6-(benzenesulfonyl)-2-(thiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobut-3-yl)acetonitrile as a pale yellow oil (0.1 g, 85%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 28 H 25 The calculated value of N8O4S3 is 633.1155, and the measured value is 633.1160.

[0730] Step 4: Dissolve 0.1 g (0.2 mmol) of 2-(3-(4-(6-(benzenesulfonyl)-2-(thiophene-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobut-3-yl)acetonitrile (0.1 g, 0.2 mmol) in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS63: 2-(1-(ethylsulfonyl)-3-(4-(2-(thiophen-2-yl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)azacyclobut-3-yl)acetonitrile (60.0 mg, 77%). 1HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.74 (s, 1H), 8.10 (s, 2H), 7.85 (d, J = 7.5Hz, 1H), 7.69 (d, J = 7.5Hz, 1H), 7 .67(s,1H),7.13-7.21(m,1H),6.79(s,1H),3.88-4.16(m,4H),3.55(m,2H),2.86(s,2H),1.22(t,J=7.5Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.67,143.88,142.19,141.53,130.77,129.73,129.04,128.63,128.04,127. 17,120.73,117.72,115.69,100.53,99.38,59.28,51.64,50.88,23.37,5.77ppm; HRMS(ESI):m / z[M+H] + .C 22 H 21 The calculated value of N8O2S2 is 493.1223, and the measured value is 493.1230.

[0731] Example 64

[0732]

[0733] 3-(4-(2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile

[0734]

[0735] Step 1: Triethyloxonium tetrafluoroboric acid (0.4 g, 2.1 mmol) and 2,2,2-trifluoroacetamide (0.2 g, 2.1 mmol) were dissolved in 10 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 10 mL of ethanol was added to dissolve the oil, followed by the addition of 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile (0.3 g, 0.7 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3-(4-(6-(benzenesulfonyl)-2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile as a milky white oil (0.3 g, 84%). HRMS (ESI): m / z [M+H] + .C 21 H 15 The calculated value of F3N7O2S is 486.0955, and the measured value is 486.0961.

[0736] Step 2: Dissolve 0.3 g (0.6 mmol) of 3-(4-(6-(benzenesulfonyl)-2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-ylpropionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS64: 3-(4-(2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile (0.1 g, 47%). 1 HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.89 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1 H),7.56(s,1H),6.86(s,1H),5.04(t,J=9.0Hz,2H),3.24(t,J=9.0Hz,2H)ppm; 13C NMR(75MHz,DMSO-d6)δ148.69,144.57,142.18,130.77,129.84,129.04,127.11,120 .73,117.77,116.73,115.69,100.52,99.67,49.28,16.88ppm; HRMS(ESI):m / z[M+H] + .C 15 H 11 The calculated value of F3N7 is 346.1023, and the measured value is 346.1029.

[0737] Example 65

[0738]

[0739] 4-((S)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)butyronitrile

[0740]

[0741] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((S-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 4-bromobutyronitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate to the reaction solution. The solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 4-((S)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylbutadiene nitrile as a pale yellow oil (0.2 g, 57%). This product can be used directly for the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 27 The calculated value of N6O3S is 479.1860, and the measured value is 479.1871.

[0742] Step 2: Dissolve 0.2 g (0.4 mmol) of 4-((S)-3-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-ylbutyronitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline. The organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS65: 4-((S)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidine-1-yl)butyronitrile (0.1 g, 71%). 1 HNMR (300MHz, DMSO-d6): δ=12.16(s,1H),8.89(s,1H),7.69(s,1H),6.88(s,1H),4.53-4.69(m,1H),3.69-3.80(m,1H),2.56-2.81(m, 2H),2,43(t,J=7.5Hz,2H),2.21–2.31(m,2H),1.92-2.16(m,2H),1.87(t,J=7.5Hz,2H),1.66-1.78(m,2H),1.44(d,J=9.0Hz,3H)ppm; 13 C NMR (75MHz, DMSO-d6) δ148.65,148.51,142.17,129.04,127.19,120.77,119.37,115.62,99. 74,63.67,58.92,58.49,55.91,55.53,27.63,22.81,15.92,15.19ppm; HRMS(ESI):m / z[M+H] + .C 18 H 23 The calculated value of N6O is 339.1928, and the measured value is 339.1931.

[0743] Example 66

[0744]

[0745] 3-Cyclopentyl-3-(4-(2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile

[0746]

[0747] Step 1: Dissolve 4-nitropyrazole (0.5 g, 4.4 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (1.2 g, 8.8 mmol), then slowly add 3-bromo-3-cyclopentylpropanenitrile (1.3 g, 6.6 mmol). After addition, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. Combine the organic phases and wash with saturated brine. Dry under anhydrous sodium sulfate and concentrate under vacuum to obtain 3-cyclopentyl-3-(4-nitro-1H-pyrazole-1-yl)propionitrile as a pale yellow oil (0.8 g, 77%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 11 H 15 The calculated value of N4O2 is 235.1190, and the measured value is 235.1194.

[0748] Step 2: Dissolve 0.8 g (3.4 mmol) of 3-cyclopentyl-3-(4-nitro-1H-pyrazole-1-yl)propionitrile in 10 mL of methanol. Add palladium on carbon (0.1 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain 0.7 g (100%) of 3-cyclopentyl-3-(4-amino-1H-pyrazole-1-yl)propionitrile as a pink, foamy solid. This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 11 H 17 The calculated value of N4 is 205.1448, and the measured value is 205.1552.

[0749] Step 3: Dissolve 0.7 g (3.4 mmol) of 3-cyclopentyl-3-(4-amino-1H-pyrazol-1-yl)propionitrile in 10 mL of tetrahydrofuran. Add DIPEA (0.9 g, 6.8 mmol), followed by 0.8 g (2.3 mmol) of 4-chloro-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine. After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. After slurrying with methanol, 3-cyclopentyl-3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile was obtained as a pale yellow oil (0.6 g, 50%). This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 24 The calculated value of N7O4S is 506.1605, and the measured value is 506.1613.

[0750] Step 4: Dissolve 0.6 g (1.2 mmol) of 3-cyclopentyl-3-(4-((5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile in 10 mL of methanol. Add palladium on carbon (0.1 g, 10%), then purge the air in the reaction flask with hydrogen at least three times. Maintain the reaction under a hydrogen atmosphere and stir at room temperature for 12 hours. Monitor the reaction for completeness by TLC. After filtration, collect the filtrate and concentrate under vacuum to obtain 0.5 g (88%) of 3-cyclopentyl-3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile as a pink, foamy solid. This product can be used directly in the next step without further purification. HRMS (ESI): m / z [M+H] + .C 24 H 26 The calculated value of N7O2S is 476.1863, and the measured value is 476.1870.

[0751] Step 5: Triethyloxonium tetrafluoroboric acid (0.6 g, 3.3 mmol) and 2,2,2-trifluoroacetamide (0.1 g, 3.3 mmol) were dissolved in 10 mL of tetrahydrofuran. After stirring at room temperature for 3 hours, the mixture was concentrated under vacuum to obtain an oily substance. Then, 10 mL of ethanol was added to dissolve the oil, followed by the addition of 3-cyclopentyl-3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile (0.5 g, 1.1 mmol). The mixture was heated to reflux and stirred for 3 hours. The reaction was monitored by TLC until complete. Saturated sodium bicarbonate was added until the reaction solution was weakly alkaline, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 2:1) to give 3-cyclopentyl-3-(4-(6-(benzenesulfonyl)-2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile as a pale green oil (0.2 g, 34%). HRMS (ESI): m / z [M+H] + .C 26 H 23 The calculated value of F3N7O2S is 554.1581, and the measured value is 554.1593.

[0752] Step 6: Dissolve 0.2 g (0.4 mmol) of 3-cyclopentyl-3-(4-(6-(benzenesulfonyl)-2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS66: 3-cyclopentyl-3-(4-(2-(trifluoromethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile (0.1 g, 67%). 1 HNMR (300MHz, DMSO-d6): δ = 11.96 (s, 1H), 8.79 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.58 (s,1H),6.77(s,1H),3.53-3.70(m,1H),2.80(d,J=9.0Hz,2H),1.35-1.60(m,9H)ppm;13 C NMR(75MHz,DMSO-d6)δ148.66,144.67,142.19,130.78,129.77,129.03,127.16,120.74,117.7 4,116.74,115.64,100.58,99.39,63.95,34.28,30.95,25.16,18.88ppm; HRMS(ESI):m / z[M+H] + .C 20 H 19 The calculated value of F3N7 is 414.1649, and the measured value is 414.1654.

[0753] Example 67

[0754]

[0755] 3-(4-(2-(4-(methanesulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile

[0756]

[0757] Step 1: Dissolve 0.3 g (0.7 mmol) of 3-(4-((5-amino-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)-1H-pyrazol-1-yl)propionitrile in 10 mL of DMF, add 0.7 g (3.5 mmol) of Na2S2O5, then add 0.2 g (0.9 mmol) of 4-methylsulfonylbenzaldehyde. After the addition is complete, heat to 90 °C and stir for 12 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate to give 3-(4-(2-(4-(methanesulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile as a yellow solid (0.2 g, 47%). HRMS(ESI): m / z [M+H] + .C 27 H 24 The calculated value of N7O4S2 is 574.1326, and the measured value is 574.1331.

[0758] Step 2: Dissolve 0.2 g (0.3 mmol) of 3-(4-(2-(4-(methanesulfonyl)phenyl)-6-(benzenesulfonyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Add 5 mL of 1 M sodium hydroxide and stir at room temperature for 5 hours. Monitor the reaction for completeness by TLC. Add saturated sodium bicarbonate until the reaction solution is weakly alkaline, and separate the organic phase. Extract the aqueous phase twice with dichloromethane. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (petroleum ether: ethyl acetate = 1:1) to give LXS67: 3-(4-(2-(4-(methanesulfonyl)phenyl)-2,3-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-1H-pyrazol-1-yl)propionitrile (0.1 g, 66%). 1 HNMR (300MHz, DMSO-d6): δ = 11.06 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.74 (d, J = 9.0Hz, 2H), 7.58 (s, 1H), 7.5 1(d,J=9.0Hz,2H),7.18(s,1H),6.87(s,1H),5.04(t,J=7.5Hz,3H),3.34(s,3H),3.20(t,J=7.5Hz,2H)ppm; 13 C NMR(75MHz,DMSO-d6)δ149.78,139.07,138.77,134.44,131.17,130.48,130.15,128.19,127.94,12 7.18,123.34,117.79,115.75,108.15,99.43,87.59,49.22,47.78,17.88ppm; HRMS(ESI):m / z[M+H] + .C 21 H 20 The calculated value of N7O2S is 434.1394, and the measured value is 434.1400.

[0759] Example 68

[0760]

[0761] 5-((S)-3-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)pyrrolidin-1-yl)pentonitrile

[0762]

[0763] Step 1: Dissolve (R)-1-(6-(benzenesulfonyl)-1-((S-pyrrolidinyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethanol (0.3 g, 0.7 mmol) in 10 mL of tetrahydrofuran. Add DIPEA (0.2 g, 1.4 mmol), then slowly add 5-bromopentanilonitrile (0.2 g, 1.1 mmol). After the addition is complete, heat to reflux and stir for 3 hours. Monitor the reaction by TLC until complete. Add saturated sodium bicarbonate to the reaction solution. The solution was weakly alkaline, and the organic phase ...

Claims

1. A compound represented by Formula I: ， Or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing; in, X is CH or N; Y is NH or N; when Y is N, the connection to Y is... It is a double bond; when Y is NH, it is connected to Y. It is a single bond; When Y is N, the connection to Y When it is a double bond, R 1 and R 2 The definition is as follows (i) or (ii): (i) R 1 for R 2 for ; R 1a C 1–3 alkyl; Each R 4 Independently halogen or C 1–4 Hydroxyalkyl; Alternatively, two R atoms located on the same carbon atom or different carbon atoms 4 They connect to form –CH2– or –(CH2)2–; R 5 is –S(O)2R 5a –C(O)NHR 5k or –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f or -[C(R a R b )] 1–2 -C(O)NH-[C(R a R b )] 1–2 -R 5f ; R 5a For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; R 5k For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; Each R 5f Independently, it can be F, CHF2, CH2F, or CF3; Each R a Independent of H, halogen or C 1–3 alkyl; Each R b Independent of H, halogen or C 1–3 alkyl; n can be 0, 1, 2, 3, or 4; (ii) R 1 for R 2 for or ; When R 2 for When the ring C is a benzene ring, imidazole, furan, or pyridine; when R 2 for When the ring C is a benzene ring, thiazole, furan, or thiophene; Each R 6 Independently halogen, hydroxyl, amino, cyano, C 1–4 Alkyl, C 1–4 Halogenated alkyl, –O–C 1–4 Alkyl, –O–C 1–4 Halogenated alkyl groups, –S–C 1–4 Alkyl, –S(O)2–C 1–4 Alkyl or C 1–4 Hydroxyalkyl; Each R 7 Independently for R 4 ; Alternatively, two R atoms located on the same carbon atom or different carbon atoms 7 They connect to form –CH2– or –(CH2)2–; R 8 For R 5 –S(O)2R 8a –C(O)R 8b –C(O)NR 8c R 8d –C(O)OR 8e Or –C(O)NHR 8k ; R 8a R 8b R 8c R 8d R 8e and R 8k Each is independently a methyl group, -CF3, or C. 2–6 alkenyl or C 3–6 cycloalkyl; Each R 9 Independently for R 4 ; Each R 4 Independently halogen, hydroxyl, C 1–4 Alkyl, C 1–4 Halogenated alkyl, –O–C 1–4 Alkyl, –O–C 1–4 Halogenated alkyl or C 1–4 Hydroxyalkyl; Alternatively, two R atoms located on the same carbon atom or different carbon atoms 4 They connect to form –CH2– or –(CH2)2–; R 5 is –S(O)2R 5a –C(O)NHR 5k or –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f or -[C(R a R b )] 1–2 -C(O)NH-[C(R a R b )] 1–2 -R 5f ; R 5a For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; R 5k For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; Each R 5f Independently, it can be H, F, CHF2, CH2F, CF3, or CN; Each R a Independent of H, halogen or C 1–3 alkyl; Each R b Independent of H, halogen or C 1–3 alkyl; Alternatively, two R atoms located on the same carbon atom or different carbon atoms 9 They connect to form –CH2– or –(CH2)2–; z can be 0, 1, 2, 3, or 4; y is 0, 1, 2, 3 or 4; t can be 0, 1, 2, 3, or 4; When Y is NH, the connection to Y When it is a single bond, R 1 and R 2 The definition is as follows: R 1 for R 2 for or ; Ring C is a benzene ring; R 6 –S(O)2–C 1–4 alkyl; Each R 7 Independently for R 4 ; R 8 For R 5 –S(O)2R 8a –C(O)R 8b –C(O)NR 8c R 8d –C(O)OR 8e Or –C(O)NHR 8k ; R 8a R 8b R 8c R 8d R 8e and R 8k Each is independently a methyl group, -CF3, or C. 2–6 alkenyl or C 3–6 cycloalkyl; Each R 9 Independently for R 4 ; Each R 4 Independently halogen, hydroxyl, C 1–4 Alkyl, C 1–4 Halogenated alkyl, –O–C 1–4 Alkyl, –O–C 1–4 Halogenated alkyl or C 1–4 Hydroxyalkyl; R 5 is –S(O)2R 5a –C(O)NHR 5k or –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f or -[C(R a R b )] 1–2 -C(O)NH-[C(R a R b )] 1–2 -R 5f ; R 5a For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; R 5k For –L 1 –R 5f , where –L 1 –R 5f For -[C(R) a R b )] 1-5 -R 5f ; Each R 5f Independently, it can be H, F, CHF2, CH2F, CF3, or CN; Each R a Independent of H, halogen or C 1–3 alkyl; Each R b Independent of H, halogen or C 1–3 alkyl; z is 1; y is 0, 1, 2, 3 or 4; t can be 0, 1, 2, 3 or 4.

2. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 1a It is methyl; And / or, R 4 The halogen in the definition is fluorine; And / or, R 4 C in the definition 1–4 The hydroxyalkyl group is –CH2OH; And / or, R a The halogen in the definition is fluorine; And / or, R a C in the definition 1–3 The alkyl group is methyl or ethyl; And / or, R b The halogen in the definition is fluorine; And / or, R b C in the definition 1–3 The alkyl group is methyl or ethyl; And / or, n is 0, 1 or 2; And / or, R 6 The halogen in the definition is fluorine; And / or, R 6 C in the definition 1–4 The alkyl group is methyl; And / or, R 6 C in the definition 1–4 The alkyl halide is C 1–4 Fluorinated alkyl groups; And / or, R 6 –O–C in the definition 1–4 The alkyl group is –O–CH3; And / or, R 6 –O–C in the definition 1–4 The alkyl halide is –O–C 1–4 Fluorinated alkyl groups; And / or, R 6 –S–C in the definition 1–4 The alkyl group is –S–CH3; And / or, R 6 –S(O)2–C in the definition 1–4 The alkyl group is –S(O)2–CH3; And / or, R 6 C in the definition 1–4 The hydroxyalkyl group is –CH2–OH; And / or, R 8a R 8b R 8c R 8d R 8e and R 8k C in the definition 2–6 The alkenyl group is vinyl; And / or, R 8a R 8b R 8c R 8d R 8e and R 8k C in the definition 3–6 The cycloalkyl group is cyclopropyl; And / or, It can be either cis or trans configuration; And / or, t is 0; And / or, y is 0; And / or, when Y is N, connected to Y When it is a double bond, z is 0, 1 or 2.

3. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: Each R a Independently H, fluorine, methyl, or ethyl; each R b Independently, it can be H, fluorine, methyl, or ethyl; And / or, when Y is N, connected to Y It is a double bond, R 2 for When the ring C is a benzene ring, , or ; And / or, when Y is N, connected to Y It is a double bond, R 2 for When the ring C is a benzene ring, , or ; And / or, R 8 For R 5 –S(O)2R 8a Or –C(O)R 8b ; And / or, when Y is N, connected to Y When it is a double bond, each R 6 It can be fluorine, hydroxyl, amino, cyano, methyl, CF3, –O–CH3, –S–CH3, –S(O)2–CH3 or –CH2–OH independently; And / or, when Y is NH, connected to Y When it is a single bond, R 6 is –S(O)2–CH3.

4. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 5 –L in the definition 1 –R 5f For –C(R) a R b )–R 5f 、–[C(R a R b )]2–R 5f 、–[C(R a R b )]3–R 5f 、–[C(R a R b )]4–R 5f Or – [C(R a R b )]5–R 5f ; And / or, R 8 For –S(O)2–CF3, –S(O)2C(R) a R b )–R 5f –S(O)2[C(R) a R b )2]–R 5f –S(O)2[C(R) a R b )3]–R 5f –C(R) a R b )–R 5f 、–[C(R a R b )2]–R 5f 、–[C(R a R b )3]–R 5f , , –C(O)CH=CH2 or –C(O)NHC(R) a R b )–R 5f .

5. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: Each R 5f Independently defined as F or CF3; And / or, R 8 The possible values ​​are –S(O)2(CH2)2–CH3, –S(O)2–CF3, –C(O)NHCH2–CF3, and –C(O)CH=CH2. , –CH2–CN, –(CH2)2–CN, or –(CH2)3–CF3; And / or, for , , or .

6. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 5 –C(O)NHR in the definition 5k It is –C(O)NHCH2–CF3; And / or, R 5 –S(O)2R in the definition 5a It is –S(O)2(CH2)2–CF3; And / or, R 5 –L in the definition 1 –R 5f For –[C(R) a R b )]–CF3、–[C(R a R b )]2–CF3、–[C(R a R b )]3–CF3、–C(R a R b )C(O)NH–C(R a R b )CF3 or –[C(R) a R b )]5–F.

7. The compound of claim 6, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 5 –L in the definition 1 –R 5f For –[C(R) a R b )]–CF3、–[C(R a R b )]2–CF3、–[C(R a R b )]3–CF3 or –[C(R a R b )]5–F.

8. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 5 is –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2–CF3, –(CH2)3–CF3, –CH(CH2CH3)C(O)NH–CH2CF3, –CH2C(O)NHCH2–CF3, –CH(CH3)C(O)NHCH2–CF3, –(CH2)5–F, –S(O)2(CH2)2–CF3 or –C(O)NHCH2–CF3; And / or, for , , or ; And / or, when Y is N, connected to Y It is a double bond, R 2 for hour, for , , , , , , , , , , , , , or ; And / or, when Y is N, connected to Y It is a double bond, R 2 for hour, for , , , , , , , , , , , , , , or ; And / or, R 8 –S(O)2C(R) a R b )–CH3, –S(O)2–CF3, –C(O)NHC(R a R b –CF3、–C(O)CH=CH2、 , –C(R) a R b –CN、–[C(R) a R b )2]–CN or –[C(R a R b )3]–CF3.

9. The compound of claim 1, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: R 5 The values ​​are –(CH2)2–CF3, –CH2(CF2)2–CF3, –(CF2)3–CF3, –(CH2)2CF2–CF3, –(CH2)3–CF3, –CH(CH2CH3)C(O)NH–CH2CF3, –CH2C(O)NHCH2–CF3, –CH(CH3)C(O)NHCH2–CF3, –(CH2)5–F or –S(O)2(CH2)2–CF3; And / or, for or ; And / or, for or .

10. The compound according to any one of claims 1-9, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that: The compound has the structure shown in the following formulas: I-1d, I-3C, I-3D, I-3E, I-3F, I-3G, I-4E, I-4F, I-4J, I-4L or I-4M; 、 、 、 、 、 、 、 、 、 、 。 11. A compound, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt of any of the foregoing, characterized in that, The compound has any of the following structures: 。 12. A method for preparing a compound as shown in Formula I, comprising the following steps: reacting a compound as shown in Formula II with a base in an organic solvent to obtain the compound as shown in Formula I; ； in, X, Y, R 1 and R 2 The definition is as described in any one of claims 1–11.

13. A compound as shown in Formula II: ； in, X, Y, R 1 and R 2 The definition is as described in any one of claims 1–11.

14. A pharmaceutical composition comprising (i) the compound of any one of claims 1–11, or its stereoisomer or racemate, or a pharmaceutically acceptable salt of any of the foregoing; and (ii) Pharmaceutically acceptable carriers.

15. The use of a compound as described in any one of claims 1–11, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 14, in the preparation of a Janus kinase inhibitor.

16. The use of a compound as described in any one of claims 1–11, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 14, in the preparation of a medicament for treating diseases associated with Janus kinase; The diseases associated with Janus kinase are autoimmune diseases or cancer.

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